WO2001047895A1

WO2001047895A1 - Novel compounds having five-membered hetero-aromatic rings

Info

Publication number: WO2001047895A1
Application number: PCT/JP2000/009172
Authority: WO
Inventors: Masashi Nakatsuka; Katsunori Tsuboi; Shoji Watanabe
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 1999-12-28
Filing date: 2000-12-25
Publication date: 2001-07-05

Abstract

Compounds having five-membered hetero-aromatic rings, as represented by general formula [1] (wherein ring A is selected from among thiazole, oxazole, and imidazole; E is optionally fused aryl; G is a connecting group; and L is an amidine). A typical example of the compounds is one represented by formula [2], which is useful in the treatment of immune disorders and chronic inflammation.

Description

Description New 5-membered heteroaromatic compound Technical field

The present invention relates to a thiazole, oxazole or imidazole derivative which has excellent physical properties and is useful as a therapeutic agent for autoimmune diseases, inflammatory diseases and the like. Background 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 due to side effects. In addition, these treatments belong to symptomatic treatment and do not have the effect of improving the underlying causes of the disease. As elucidation of the etiology and pathology of autoimmune diseases such as rheumatoid arthritis with a strong inflammation pattern progresses, it is suggested that abnormalities of the immune system are deeply involved in the development of inflammation and chronic illness. In this regard, drugs that improve the disease state by acting on the immune system, such as gold preparations and D-jesilamine, have attracted attention as causative therapies. However, it is not necessarily in a satisfactory state due to side effects and lack of sustained effects. Disclosure of the invention

Against this background, JP-A-63-152368 reports aralkyl_5-membered heterocyclic compounds containing thiazole and oxazole derivatives as therapeutic agents for autoimmune diseases, inflammation, allergies, asthma and the like. International Patent Publication No. 98/47880 (TO

98/47880), which has excellent ameliorating effects on immunity abnormalities and chronic inflammation, has few side effects, and has been substituted with a guanidino group useful as a therapeutic or preventive agent for autoimmune diseases, inflammatory diseases, etc. Isoxazole derivatives have been reported. On the other hand, a number of 5-membered heterocyclic compounds having a guanidino group useful for inflammatory diseases have been reported. JP-A-9-59258 discloses thiazoles and oxazines having a guanidino group represented by the general formula (1) as compounds having a Maillard reaction inhibitory action and an antioxidant action. Zole and imidazole derivatives have been reported. Japanese Patent Application Laid-Open No. 8-41008 discloses a compound represented by the following formula (2) as a compound having an NOS inhibitory action, and Japanese Patent Application Laid-Open No. 7-149745 discloses a compound having an elastase inhibitory action as a compound having the following formula (3) ) Have been reported.

(3)

Problems to be solved by the invention

An object of the present invention is to provide a compound having better pharmacological activity and physical properties as a therapeutic agent for an autoimmune disease, an inflammatory disease and the like.

Means for solving the problem

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the novel 5-membered aromatic compound has excellent physical properties and shows a strong effect on both the amelioration of immunological abnormalities and the improvement of chronic inflammation. This led to the completion of the present invention. That is, the compound of the present invention is as follows ₍

[ 1 set: '

[Where E is the formula

(Wherein, M is a single bond, one O-, one S-, one SO-, One S0 ₂ -, -CQ- (Q Table 1, 3- Jiokisan ring or 1, 3-Jiokisoran ring with the carbon atoms ), -CH (OR ¹¹ ) one, one C (OR ¹¹ ) ₂ —, one C (= NOR ^u ) one (R ¹¹ represents a hydrogen atom or a lower alkyl group.), One C (= NR ¹² ) 1 (R ¹² represents a hydrogen atom or a lower alkyl group.), 1 C (= NNR ¹³ R ") — (R ¹³ and R ¹⁴ are independently a hydrogen atom, a lower alkyl group or may be substituted. Represents an aryl group), represents —CO— or one CS—), or E represents a formula:

(In the formula, B represents a single bond, one 0_, one S SO— or one SO Co.). E is a halogen atom, a nitro group, a formyl group, an acetyl group, a cyano group, R ¹⁷ (R ¹⁷ represents a lower alkyl group), -OR ¹¹ (R ¹¹ is as defined above), — C〇 ₂ R ²⁹ , -SO ₂ R ²⁹ (R ²⁹ represents a lower alkyl group) and -CONR ³ ° R ³¹ , -SO ₂ NR ³⁰ R ³¹ (R ³ and R ³¹ are independently Represents a hydrogen atom or a lower alkyl group.) It may be substituted with 1 to 4 groups arbitrarily selected from the group consisting of force. G represents the formula: one C (R ⁶ R ⁷ ) one or one C (= CR ⁶ R 7) — and is bonded to the carbon atom of A. R ⁶ and R ⁷ each independently represent a hydrogen atom, a lower alkyl group or a lower alkoxy group. R ⁶ and R ⁷ may combine to form an optionally substituted hydrocarbon ring, 1,3-dioxane ring or 1,3-dioxolane ring together with the carbon atom to which they are attached. .

A represents thiazole, oxazole or imidazole.

R ⁵ represents a substituent bonded to the carbon atom and / or the nitrogen atom of A. r represents an integer of 0 to 2. Thiazole, substituents R ⁵ represents a halogen atom on the carbon atoms of Okisazoru or imidazole, hydroxyl, nitro, Shiano group, a carboxy group, substitution which may be an amino group, an optionally substituted hydroxy § amino group, Optionally substituted sulfamoyl group, optionally substituted sulfamoyl group, one R ⁸ , one OR ⁸ , one CO ₂ R ⁹ , one SR ¹⁰ , one SO—R ¹⁰ , one SO ₂ —R ¹⁰ , one ^{C (O) SR 10, -} C (S) oR 10 or _ CS ₂ R ^W (wherein, R ⁸ is an optionally substituted alkyl group, an alkenyl group which may be substituted, substituted Alkyl group, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, Good heterocyclic group Other represents Ashiru group. R ⁹ is an optionally substituted alkyl group, an optionally substituted Arukeyuru group, an optionally substituted alkynyl, optionally substituted Ariru group, substituted Represents an aralkyl group or an optionally substituted heterocyclic group, and R ^w represents an alkyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted.) Represents The substituent R ⁵ on the nitrogen atom of the imidazole is a nitro group, a cyano group, an optionally substituted sulfamoyl group, an optionally substituted sulfamoyl group, a protecting group for an NH group, one R ⁸ , one OR ⁸ or one C 0 ₂ R ⁹ (wherein, R ⁸ and R ⁹ has the same meaning as defined above.) represents the.

L is a formula attached to the carbon atom of A:

(In the formula, two dashed lines mean a double bond together with a solid line, and the other a single bond together with a solid line. R ¹ is bonded to a nitrogen atom having a bond whose dashed line represents a single bond with the solid line. RR \ R ³ and R ⁴ are each independently a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxamino group, or an optionally substituted Sulfamoyl group which may be substituted, Sulfamoyl group which may be substituted, NH-protecting group, — R ⁸ , -OR ⁸ , _C0 ₂ R ⁹ , -SR ¹⁰ , -SO-R ¹⁰ , —SO ₂ — R ^10, one (CO) SR ¹⁰ _N -. represents a (CS) oR ¹⁰ or a CS ₂ R ¹⁰ (. wherein, R ^8, R ⁹ and R ¹⁰ are as defined above) Further, I ^1, R ² , R ³ and R ⁴ are formed by joining any two of them and placing them together with one nitrogen atom or with two nitrogen atoms or carbon atoms. It may form a nitrogen-containing aliphatic heterocyclic ring which may be substituted.

However, in the formula, when M is a single bond or 1 O—, three or more of RR ² , R ³ and R ⁴ do not simultaneously represent a hydrogen atom.

Also, the formula: one NR ² R ³ is the formula: one N = C (NR ⁴³ R ⁴⁴ ) NH ₂ or one NHC

It may represent a group represented by (NR ⁴³ R ⁴⁴ ) 表 NH. R ⁴³ and R ⁴⁴ are:

(1) or (2).

(1) Independently represents a protecting group for a hydrogen atom, an optionally substituted alkyl group or an NH group.

(2) Together with the nitrogen atom, a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group may be an optionally substituted alkyl group, And may be substituted with one or two substituents arbitrarily selected from the group consisting of a good amino group, a hydroxyl group, an alkoxy group, a protecting group for an NH group, and an oxo group. ) Represents a group represented by ]

Or a pharmaceutically acceptable salt thereof. [2] E is the formula:

[Wherein, M ¹ represents one CQ— (Q represents a 1,3-dioxane ring or a 1,3-dioxolane ring together with a carbon atom)], one CH (OR ¹¹ ) one, one C (OR ¹¹ ) ₂ _ , One C

(= NOR ⁿ ) 1 (R ¹¹ is as defined above.), — C (= NR ¹² ) — (R ¹² represents a hydrogen atom or a lower alkyl group.), — C (= NNR ¹³ R ¹⁴ ) (Wherein R ¹³ and R "independently represent a hydrogen atom, a lower alkyl group or an optionally substituted aryl group.), One CO— or one CS—.

(Wherein, B is a single bond, one O-, one S-, one SO- or a S0 ₂ - represents a.) Represents the. E is a halogen atom, an acetyl group, a nitro group, a formyl group, a cyano group, R ¹⁷ (R ¹⁷ represents a lower alkyl group), OR ¹¹ (R ¹¹ is as defined above),

CO, R ²⁹ , one SO R ²⁹ (R ²⁹ represents a lower alkyl group) and one CONR 30

R ³¹ , -SO ₂ NR ³⁰ R ³¹ (R ³ and R ³¹ independently represent a hydrogen atom or a lower alkyl group.) Substituted with 1 to 4 groups arbitrarily selected from the group consisting of It may be. ] The 5-membered heteroaromatic compound according to [1], or a pharmaceutically acceptable salt thereof.

[3] E is the formula:

[E is a halogen atom, an acetyl group, a nitro group, a formyl group, a cyano group, R ¹⁷ (R ¹⁷ represents a lower alkyl group), OR ¹¹ (R ¹¹ is as defined above); C0 ₂ R ^29, one SO ₂ R ^²⁹ (R ²⁹ represents a lower alkyl group.) and single CON R ³⁰ R ³¹ and one S0 ₂ NR ^3. R ³¹ (R ³ ° and R ³¹ independently represent a hydrogen atom or a lower alkyl group). It may be substituted with 1 to 4 groups arbitrarily selected from the group consisting of: ] The 5-membered heteroaromatic ring compound according to [1], or a pharmaceutically acceptable salt thereof.

[4] E is the formula:

[E is an arbitrary member selected from the group consisting of a halogen atom, an acetyl group, a cyano group, R ¹⁷ (R ¹⁷ represents a lower alkyl group), and OR ¹¹ (R ¹¹ represents a hydrogen atom or a lower alkyl group.) May be substituted with one or two groups selected from ] The 5-membered heteroaromatic ring compound of [1] or a pharmaceutically acceptable salt thereof.

[5] E is the formula:

[The E is a halogen atom, an acetyl group, a cyano group, R ¹⁷ (R ¹⁷ represents a lower alkyl group.), OR ¹¹ (R ¹¹ represents a hydrogen atom or a lower alkyl group.) And may be substituted with one or two groups arbitrarily selected from the group consisting of: ] The 5-membered heteroaromatic ring compound of [1] or a pharmaceutically acceptable salt thereof.

[6] L is the formula:

[Wherein, R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ represent the following (1), (2) or (3). However, when at least one of R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ is a hydrogen atom, a tautomer occurs, and a C CN double bond and a positional isomer of a hydrogen atom exist. Mutants are also included.

(1) R ²⁵ , R ²⁶ , R ²⁷ _s or R ²⁸ are each independently from the following (a)

(c).

(a) Independently protecting group for hydrogen atom, acyl group, NH group, linear or branched alkyl group having 1 to 10 carbon atoms (direct or branched alkyl group having 1 to 10 carbon atoms is nitro Group, cyano group, amino group which may be substituted, hydroxyl group, alkoxy group, acyl group, carboxy group, rubamoinole group which may be substituted, sulfamoyl group which may be substituted, mercapto group, S (O) r - R ³² (.. r are as defined above R ³² is representative of a lower alkyl group), four one CO ₂ R ³² (R ³² has the same meaning as defined above) from 1 selected arbitrarily from the group consisting of May be substituted with a substituent of the formula :). However, when M or M ¹ is a single bond or —0—, three or more of R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ do not simultaneously represent a hydrogen atom.

(b) A 5- to 7-membered nitrogen-containing aliphatic heterocyclic group together with a nitrogen atom in which R ²⁵ and R ²⁶ are linked together (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is a nitro group, a cyano group An optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, _S ( O) r- R ³² (r and R ³² are the same as the above.), single C0 ₂ R ³² (R ³² is as defined above), a group consisting of Okiso group It may be substituted with one or two substituents arbitrarily selected. ). (c) R ²⁷ and R ^28, together with together a connexion bonded to the nitrogen atom, 5-7 membered nitrogen-containing moon effect aliphatic Hajime Tamaki (for 5-7 membered nitrogen-containing aliphatic heterocyclic group, a nitro group, A cyano group, an optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted rubamoyl group, an optionally substituted sulfamoyl group, a mercapto group, one ^{S (0) r- R 32 (} r and R ³² are the same as the above.), single C0 ₂ R ³² (R ³² is as defined above), selected the group Ca et optionally consisting Okiso group May be substituted with one or two substituents.)

(2) R ²⁶ and R ²⁷ are joined together with two nitrogen atoms and one carbon atom to form a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is , Nitro group, cyano group, amino group which may be substituted, alkyl group which may be substituted, hydroxyl group, alkoxy group, acyl group, carboxy group, rubamoyl group which may be substituted, may be substituted a sulfamoyl group, a mercapto group, one ^{S (0) r- R 32 (} r and R ³² are as defined above.), single C0 ₂ R ³² (R ³² is as defined above), a group consisting of Okiso group And may be substituted with one or two substituents arbitrarily selected from.

R ²⁵ and R ^{28 each} independently represent a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) Examples of the group include a nitro group, a cyano group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a menolecapto group, S (〇) r-R ³² (r and R 32 are the same as described above.), And C0 ₂ R ³² (R ³² is as defined above). ) May be substituted.

(3) Or the formula: = C (NR ²⁵ R ²⁶ ) NR ²⁷ R ²⁸ is the formula: = C (NR ¹ R ⁴² ) N = C (NR ³ R ⁴⁴ ) NH ₂ or the formula: = C (NR ⁴¹⁾ R ⁴² ) NHC (NR ³ R ⁴⁴ ) = NH.

R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are as shown in the following (a-1) or (b-1).

(a-1) Independent protection of a hydrogen atom, an optionally substituted alkyl group or an NH group (b-1) together with a nitrogen atom, a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is an alkyl group which may be substituted, And may be substituted with one or two substituents arbitrarily selected from the group consisting of an amino group, a hydroxyl group, an alkoxy group, and an oxo group. ],

The 5-membered heteroaromatic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5].

[7] L is the formula:

^{^{Wherein, R 45, R 46, R}} 47 and R ⁴⁸ are the following (l ^1), is as (2 ¹⁾ or (3 ^1). However, when M or M ¹ is a single bond or one O—, three or more of R ⁴⁶ , R ⁴⁷ and R ⁴⁸ do not simultaneously represent a hydrogen atom.

(I ¹ ) R ⁴⁵ and R ⁴⁸ are as shown in the following (al) or (bl), and R ⁴⁶ and R ⁴⁷ are as described in the above (a) or the following (cl).

(al) R ⁴⁵ represents a lower alkyl group or acetyl. R ⁴⁸ represents a hydrogen atom, a lower alkyl group or acetyl.

(bl) —5-7 membered nitrogen-containing aliphatic heterocyclic group (5-7 membered nitrogen-containing aliphatic heterocyclic group is a nitro group, a cyano group, An optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, 1S ( O) r- R ³² (r and R ³² are as defined above.), one CO ₂ R ³² (R ³² is as defined above), 1 or 2 optionally selected from the group ing from Okiso group May be substituted with a plurality of substituents.).

(cl) together with a nitrogen atom, a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (5- The 7-membered nitrogen-containing aliphatic heterocyclic group includes a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, and an optionally substituted Rubamoiru group, an optionally substituted sulfamoyl group, Melka ^{but-group, - S (O) rR 32} (. r and R ³² are as defined above), one CO _² R ³ ₂ (R ³² is as defined above ), And may be substituted with one or two substituents arbitrarily selected from the group consisting of oxo groups. ).

(2 ¹⁾ R ⁴⁶ and R ⁴⁸ represent said (bl).

R ⁴⁵ and R ⁴⁷ independently represent a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) Examples of the group include a nitro group, a cyano group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, ^{S (0) r- R 32 (} r and R ³² are as defined _{^{above.), _C0 2 R 32 (}} R 32 has the same meaning as defined above) 1 to 4 substituents selected arbitrarily from the group consisting of May be substituted with a group). (3 ¹⁾ R ⁴⁵ and R ⁴⁶ represent said (bl).

R ⁴⁷ and R ⁴⁸ independently represent a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) The group includes a nitro group, a cyano group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted canolebamoyl group, an optionally substituted sulfamoinole group, a mercapto group, 1S (O) rR ³² (r and

^R32 is the same as described above. ), And may be substituted with 1 to 4 substituents arbitrarily selected from the group consisting of C 0 ₂ R ³² (R ³² has the same meaning as described above). ). ] The 5-membered heteroaromatic compound according to any one of [1] to [5] 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.

Examples of the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1_naphthyl, 2-naphthyl, azulenyl, phenanthryl, and anthryl. Examples of the heterocyclic group include a 1 to 3 ring 5- to 14-membered aromatic heterocyclic group or aliphatic heterocyclic group containing 1 to 6 nitrogen atoms, oxygen atoms and Z or sulfur atoms.

Specific examples of the aromatic heterocyclic group include furyl, phenyl, benzoyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzthiazolyl, and benzazolyl. Examples include xazolyl, pyridyl, pyrazur, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolyl, quinazolinyl, quinoxalinyl, and carbazolyl.

Specific examples of the aliphatic heterocyclic group include tetrahydrofuryl, pyrrolidinyl, pyrazoliduryl, imidazolidyl, 4,5-dihydro-1H-imidazolyl, piperidyl, morpholinyl, thiomorpholinyl, and 1-oxothiomorpholinyl. , 1,1-Dioxothiomorpholinyl, piperazur, thiazolidyl, hexahydropyrimidyl, 1,4,5,6-tetrahydropyrimidinyl, 3,6-dihydro- 1H—1,3, 5-oxadiazinyl, 4,5-dihydro-1,1-dioxo

—1, 2, 4-thiadiazolyl, 5, 6-dihydro-1 H — 1, 1-dioxo-1,2,4-thiadiazinyl, 2,3-dihydro-1,1,3_trioxo-1 4H-1, Examples include 2,4,6-thiatriazinyl, azepanyl, chromel, 2,3-dihydro-1,4-benzodioxyl, 4,5,6,7-tetrahydro-1H-dazepinyl and the like.

Examples of the substituent in the substituted aryl group and the substituted heterocyclic group include, for example, any group included in the following groups a) to g), and these groups may be arbitrarily substituted one or more times.

a): a halogen atom, a nitro group, a cyano group, an azide group, a mercapto group, a methylenedioxy group, an amino group which may be substituted by an ethylenedioxy group, a hydroxylamino group which may be substituted, A lower alkoxyamino group, a hydroxyl group, an oxo group, an acyl group, an acyloxy group, a carboxy group, an optionally substituted rubamoyl group, an optionally substituted rubamoyloxy group, and an optionally substituted Sulfamoyl group b): — R ¹⁵ , -OR ¹⁵ , one CO ₂ R ¹⁵ , one S 0 ₃ R ¹⁵ , — SR ¹⁵ , one OCH ₂ R ¹⁵ , — SCH ₂ R ¹⁵ , one C (= NOH) R ¹⁵

[Wherein, R ¹⁵ represents a fuel group or a monocyclic heterocyclic group. The phenyl group or the monocyclic heterocyclic group includes, for example, a halogen atom, a lower alkyl group, a lower haloalkyl group, a cyano group, a nitro group, an azide group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, and an optionally substituted amino group. Optionally selected from the group consisting of an optionally substituted carbamoyl group, a carboxy group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group and a lower alkylsulfonyl group. It may be substituted with one or more groups. c): an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxy (thiocarbonyl) group, an alkylthio group, an (alkylthio) thiocarbol group, an (alkylthio) propyl group, an alkylcarbonyl group, an alkylthioyl group, Alkylsulfinyl, alkylsulfonyl, alkylcarboxy, alkylthioyloxy, alkylsulfonyloxy

[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, which may be force Rubamoiru group, an optionally substituted force Rubamoiruokishi group, an optionally substituted sulfamoyl ^{^{group, - R 15, - OR 15}} , _ SR 15, one OCH ₂ R ^15, one SCH ₂ R ¹⁵ (Wherein, R ¹⁵ has the same meaning as described above.), A lower cycloalkyl group (a lower cycloalkyl group is, for example, a halogen atom, a lower alkyl group, a lower haloalkyl group, an optionally substituted amino group, a hydroxyl group, It may be substituted with one or more groups arbitrarily selected from the group consisting of a lower alkoxy group, a lower haloalkoxy group, etc.), a lower alkoxy group, a lower alkoxy group Coxycarber groups and lower alkylthio groups (lower alkoxy groups, lower alkoxycarbonyl groups and lower alkylthio groups include, for example, a nitrogen atom, a lower cycloalkyl group, a monocyclic heterocyclic group, a phenyl group, a cyano group, and a nitro group. A hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an optionally substituted amino group, an optionally substituted rubamoyl group, a carboxy group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylthio group, and a lower group Alkylsulfiel It may be substituted with one or more groups arbitrarily selected from the group consisting of a group and a lower alkylsulfonyl group. ) May be substituted with one or more groups arbitrarily selected from the group such as ]

d): Alkyl group

[Alkenyl groups include, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower alkoxycarbo group. - group, a lower alkylthio group, Ashiru group, Ashiruokishi group, a carboxy group, an optionally substituted Karubamo I group, one R, - oR ^15, one SR ^{^15,} _ OCH ₂ R ¹⁵ and one SCH ₂ R ¹⁵ (Wherein, R ¹⁵ has the same meaning as described above.) May be substituted with one or more groups arbitrarily selected from the group of ]

e): alkynyl group

[Alkyninole group includes, for example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower alkoxycarbonyl group, A lower alkylthio group, an acyl group, an acyloxy group, a carboxy group, an optionally substituted carbamoyl group, one R ¹⁵ , -OR ¹⁵ , —SR ¹⁵ , one OCH ₂ R ¹⁵ and one SCH ₂ R ¹⁵ (formula In the formula, R ¹⁵ has the same meaning as defined above, and may be substituted with one or more groups arbitrarily selected from the group of ]

f): alkenyloxy group, alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyloxy group, alkynyloxycarbol group

[Each group in this group includes, for example, a halogen atom, an oxo group, an optionally substituted amino group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group, a carboxy group, It may be substituted with one or more groups arbitrarily selected from the group consisting of optionally substituted carbamoyl group, lower alkoxycarbonyl group and phenyl group. ]

g): lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyl Oxycarbonyl, lower cycloalkenyl, lower cycloalkenyloxy, lower cycloalkenylcarbonyl, lower cycloalkenylcarboxy, lower cycloalkenyloxycarbonyl

[Each group in this group includes, for example, a parogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a lower alkyl group, a lower haloalkyl group, a substituted or unsubstituted amino group, a hydroxyl group, and a lower alkoxy group. , A lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group, a carboxy group, an optionally substituted group or a group optionally selected from the group consisting of a rubamoyl group and a lower alkoxycarbonyl group. It may be. ]

Specific examples of the substituents of the substituted aryl group and the substituted heterocyclic group include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, fuegre, triflenorolomethinole, 2 , 2,2-Triphnoleroethyl, 1,1,2,2,2_pentafluoroethyl, 6,6,6-trifluorohexyl, hydroxymethy ^ /, hydroxyethynole, methoxymethinole , Hexinoleoxymethinole, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2- Methoxyethyl, carboxymethyl, methoxycarbonylmethyl, rubamoylmethyl, amidinomethyl , Methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N, N-dimethylaminoethyl, methanesulfonylaminoethyl, sulfamoylethyl, morpholinoethyl, N-methanesulfonylaminoethyl, N-acetylaminoaminomethyl, eturyl, 2-propenyl , Ethininole, 2-propyninole, 2-methoxyphenyle, cinnamon, hydroxy, amino, N, N-dimethylamino, mercapto, sulfo, lipoxy, amidino , Methoxy, cyclopropyl methoxy, 2- (1-pyrrolidyl) ethoxy, methoxycarponyl methoxy, 2-acetoethoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 4,4,5,5 , 5-Pentafluoropent Shi, 2-methane scan Honoré Fini Honoré ethoxy, phenoxy, Benjinoreokishi, 4 main preparative carboxymethyl Penji Honoré oxy, main butoxycarbonyl O alkoxy, 1 one-pyrrolidinyl, 3-hydrate 1-Pyrrolidinyl, acetylamino, N-acetyl-N-methylamino, N-methanes ^ levoni ^ / amino, N-methanes / levoninole N-methinoleamino, methoxycarponinole, 2-methinole 2-propizole Oxycanole Pohenole, 2,2,2-Trifluoroethoxycarbonyl, Caplebamoyl, N, N-Dimethylcarbamoinole, 2-Thiazolidinyl, 2-Oxazolidinole, 5-Tetrazolinole, Methanesolerefinole, Suno Refamoinole, N, N-dimethylsulfomethyl, acetyl, benzoyl, pivaloyl, trifluoroacetyl, forminole, ethylenedioxymethyl, imino, methoxyimino and the like.

Examples of the alkyl group include a straight-chain or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, petinole, 1-methylpropyl, 2-methylpropyl Methyl-1-propyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3-dimethylbutyl Heptinol, 1-ethynolepentyl, 5-methynolehexyl, octynole, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, decyl and the like. Examples of the lower alkyl group include an alkyl group having 1 to 6 carbon atoms.

Examples of the substituent in the substituted alkyl group or the substituted lower alkyl group include, for example, any group contained in each of the following groups a) to d), and these groups may be arbitrarily substituted one or more times.

a): halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, amino group which may be substituted, hydroxylamino group which may be substituted, lower alkoxy which may be substituted Amino group, hydroxyl group, ash group, alkoxy group, carboxy group, optionally substituted canolebamoyl group, optionally substituted, carbamoyloxy group, optionally substituted, sulfamoyl group b) : Lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyloxycarbonyl group, lower cycloalkenyl group, lower cycloalkyloxy group, lower cycloalkenylcarbonyl group , Lower cycloalkenylcarboxyloxy group Lower cycloalkenyl O alkoxycarbonyl group [Each group in this group includes, for example, a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a lower alkyl group, a lower haloalkyl group, a substituted or unsubstituted amino group, a hydroxyl group, and a lower alkoxy group. One or more groups selected arbitrarily from the group of a lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group, a carboxy group, an optionally substituted rubamoyl group and a lower alkoxy group. It may be substituted. ]

c) an alkoxy group, an alkoxycarbonyl group, an alkoxy (thiocarbinole) group, an alkylthio group, an (alkylthio) thiocarbel group, an (alkylthio) carbonyl group, an alkylcarbonyl group, an alkylthioyl group, an alkylsulfiel group, an alkylsulfonyl group, Alkylcarbonyloxy group, alkylthioyloxy group, alkylsulfuroxy group

[Each group in this group includes, for example, a nitrogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an optionally substituted amino group, a hydroxyl group, an acyl group, an acyloxy group, a carboxy group, a substituted Optionally substituted rubamoyl group, optionally substituted sorbamoyloxy group, optionally substituted sulfamoyl group, one R ¹⁵ , one OR, one SR ¹⁵ , one OCH ₂ R, one SCH ₂ R ¹⁵ ( In the formula, R is as defined above.

Lower cycloalkyl group (lower cycloalkyl group is arbitrarily selected from a group such as a halogen atom, a lower alkyl group, a lower haloalkyl group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group and a lower haloalkoxy group; , A lower alkoxy group, a lower alkoxycarbonyl group and a lower alkylthio group (a lower alkoxy group, a lower alkoxycarbonyl group and a lower alkylthio group are, for example, a halogen atom A lower cycloalkyl group, a monocyclic heterocyclic group, a phenyl group, a cyano group, a -toro group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an optionally substituted amino group, Molybmoyl group, carboxy group, lower alkyl carbonyl group, lower alcohol May be substituted with one or more groups arbitrarily selected from the group consisting of a xycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group and a lower alkylsulfonyl group. Substituted with more than one group Is also good. ]

d): one R, - OR ^15, one SR, _ OCH ₂ R, in one SCH ₂ R ¹⁵ (wherein, R ¹⁵ is as defined above).

Specific examples of the substituted alkyl group include trifluoromethyl, 2-troethyl, 2-cyanopropyl, 4-mercaptobutyl, 3-oxobutyl, 2-morpholinoethyl, 2-piperidinoethyl, 2-hydroxyethynole, —Methoxypropynole, ethoxycarbonylmethyl, cyclopropyl propylmethyl, cyclohexylmethyl, 6-cyclohexynolehexynole, 3-cyclohexenedinoleptinole, 2-phenylenolbutyl, benzyl, 2-naphthylmethyl, phenethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl,

3-Chenylpropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethynole,, N-dimethylaminoethyl, carboxymethyl, ethoxycarbonylmethyl, sulfamoylethyl, canolebamoinolemethinole and the like. The lower alkyl group is a lower alkyl group substituted with 1 to 5 halogen atoms. Preferably, it refers to lower alkyl having 1 to 4 carbon atoms and substituted by 1 to 3 fluorine atoms or chlorine atoms. Specific examples include a trifluoromethylinole group, a 2-trifluoroethyl group, a 2-chloroethyl group and the like.

Alkyl carbonyl group, alkylthioyl group, alkylthio group, (alkylthio) thiocarbonyl group, (alkylthio) carbonyl group, alkylsulfinyl group, alkylsulfonyl group, alkylcarbonyloxy group, alkylthiooxy group, or ^ The alkynole in the ^ sulfonyloxy group and represents the same as the above-mentioned alkyl group. The lower alkyl in the lower alkylcarbonyl group, the lower alkylthio group, the lower alkylsulfinyl group, or the lower alkylsulfonyl group represents the same as the above lower alkyl group.

An alkoxy group refers to 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 substituents as those of the substituted alkyl group. Examples of the substituted alkoxy group include, but are not limited to, cyclopropyl methoxy, trifluoromethoxy, 2-pyrrolidino Ethoxy, benzyloxy, 2-pyridylmethoxy and the like.

Examples of the lower alkoxy group include an alkoxy group having 1 to 6 carbon atoms.

In addition, a lower haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms. Preferably, a lower haloalkoxy group having 1 to 4 carbon atoms and substituted by 1 to 3 fluorine atoms or chlorine atoms is used. Specific examples include a trifluoromethyl group, a 2-trifluoroethoxy group, and a 2-chloroethyl group.

An alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbon, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like. Examples of the lower alkoxycarbonyl group include an alkoxycarbonyl group having 1 to 6 carbon atoms. Examples of the substituent in the substituted alkoxycarbonyl group include the same substituents as those in the substituted alkyl group.

The alkoxy in the alkoxy (thiocarbonyl) group or the alkoxyamino group represents the same as the above-mentioned alkoxy group. The lower alkoxy (thiocarbonyl) group or the lower alkoxy in the lower alkoxyamino group is the same as the above lower alkoxy group.

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, ether, 1-propeninole, 2-probel, 1-methylethenyl, 1-pthenyl, 2-ptenol, 3-pteninole, 2-methinolane 2-propeninole, 1-pentenol Nore, 2-penthenore, 4-pentenore, 3-methinole 2-buteninole, 1-hexeninole, 2-hexeninole, 1-heptenyl, 2-heptenyl, 1-octenol, 2-otatul, Examples thereof include 1,3-octactenyl, 2-nonenyl, 1,3-nonagenyl, 2-deceel and the like. Preferred alkenyl groups include, for example, ether, 1-propyl, and 1-propyl groups. Examples of the lower alkyl group include an alkenyl group 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, a substituted amino group, a hydroxyl group, Lower alkoxy groups, lower haloalkoxy groups, lower alkoxycarbonyl group, a lower alkylthio group, Ashiru group, Ashiruokishi group, Karupokishi group, which may be substituted force Rubamoiru group, one R, one OR ^15, One SR ^15, One OCH ₂ R ¹⁵ , one SCH ₂ R ¹⁵ (wherein R ¹⁵ is as defined above), and the like.

Further, an alkoxy group refers to an oxy group to which an alkoxy group is bonded. A lower alkenyl group refers to an oxy group to which a lower alkenyl group is bonded.

Similarly, alkenyl in an alkenyloxycarbonyl group, an alkenylcarbonyl group, an alkenylcarboeroxy group, and an alkenyloxy group represent the same as the above-mentioned alkyl group. The lower alkenyl in the lower alkenyloxycarbyl group, the lower alkenylcarbonyl group, the lower alkenylcarboxy-loxy group and the lower alkenyloxy group is the same as the above-mentioned alkyl group.

Examples of the alkiel group include a linear or branched alkiel group having 2 to 10 carbon atoms and having 1 to 3 triple bonds. Specifically, Ethur, 1-Probul, 2-Probul, 1-Putinyl, 2-Bucher, 3-Putinyl, 1-Penthenole, 2-Pentinole, 4-Pentinole, 1-Octinole, 6- Methylenol 1-heptinole, 2-decyl and the like. Preferred alkynyl groups include, for example, 11-propier and 1-butyl groups. Examples of the lower alkynyl group include an alkynyl group having 2 to 6 carbon atoms.

Examples of the substituent of the substituted alkyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, a substituted amino group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, and an acyl group. group, Ashiruokishi group, a lower § alkylthio group, a carboxy group, which may be substituted force Rubamoiru group, a lower alkoxy Karuponiru group, one R, one OR, one SR ^15, one OCH ₂ R ^15, one SCH ₂ R ¹⁵ (wherein And R ¹⁵ have the same meaning as described above.

Further, an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded. A lower alkyl-oxy group refers to an oxy group to which a lower alkyl group is bonded.

Similarly, alkynyl in the alkynyloxycarbonyl group represents the same as the above alkynyl group.

The alkyl group having a mouth opening is, for example, an alkyl group having 3 to 3 carbon atoms; Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the lower cycloalkyl group include cycloalkyl groups having 3 to 6 carbon atoms. The cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded. Similarly, the cycloalkyl in the cycloalkyl group, the cycloalkylcarbonyl group and the cycloalkylcarbonyl group is the same as the above-mentioned cycloalkyl group. The lower cycloalkyl in the lower cycloalkyloxy group, the lower cycloalkylcarbonyl group, the lower cycloalkyl group, and the lower cycloalkyloxycarboyl group are the same as the lower cycloalkyl groups described above. Represents

Examples of the cycloalkenyl group include those having 3 to 10 carbon atoms, and specific examples include cyclohexenyl. Examples of the lower cycloalkyl group include a cycloalkenyl group having 3 to 6 carbon atoms. Further, the cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded. Similarly, the cycloalkenyl in the cycloalkenylcarbonyl group, cycloalkenylcarbonyloxy group, and cycloalkoxycarbonyl group is the same as the above-mentioned cycloalkenyl group. The lower cycloalkenyl in the lower cycloalkenyloxy group, lower cycloalkenylcarboyl group, lower cycloalkenylcarbonyloxy group and lower cycloalkenyloxycarbonyl group is the same as the above lower cycloalkenyl group. It represents the same thing.

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, a lower alkyl group, a lower haloalkyl group, and an optionally substituted amino group. A hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, an acyloxy group, a lower alkylthio group, a carboxy group, an optionally substituted carbamoyl group, a lower alkoxycarbyl group, and the like.

Examples of the aralkyl group include a lower alkyl group substituted by the aralkyl group. Examples of the lower alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 1-methylethylene, butyl, 1-methylpropyl, and 2-methyl- 1—Propyl, 1, 1 dimethyl Examples include noretyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methinoleptinole, 3-methinolebutinole, hexinole, 2-methinolepentinole, and 3,3-dimethylbutyl. Examples of the substituent in the substituted aralkyl group include the same substituents as those in the substituted aralkyl group.

The acyl group is represented by one C〇R ¹⁶ and one CS—R ¹⁶ . R ¹⁶ is selected from a) to c).

a) hydrogen atom,

b) an alkyl group,

[Where the alkyl group is a halogen atom, a cyano group, an amino group, one R ¹⁵ , -OR ¹⁵ , —SR ¹⁵ , one OCH ₂ R ¹⁵ , -SCH ₂ R ¹⁵ (wherein, R ¹⁵ is as defined above)] A lower cycloalkyl group (the lower cycloalkyl group is, for example, one or more selected from the group of a nitrogen atom, a lower alkyl group, a lower haloalkyl group, an amino group, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, etc. ), A lower alkoxy group, a lower alkoxycarbonyl group, a lower alkylcarboxy group, an amino group substituted with a lower alkyl group, and a lower alkylthio group. Alternatively, it may be substituted with a plurality of groups. ],

c) aryl group, aralkyl group or heterocyclic group

[Each group in this group includes a halogen atom, a cyano group, a carboxy group, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower alkyl carbonyl group, a lower alkylcarbonyloxy group, or a lower alkoxy group. Report

And may be substituted with one or more groups arbitrarily selected from the group such as ]. Alternatively, the acyl group represents a natural or unnatural amino acid residue.

Specific examples of the acetyl group include formyl, acetyl, aminoacetyl, (1-1 morpholino) acetyl, propanol, 2-propanoyl, vivaloyl, valerinole, pivaloyl, trifluoroethyl, benzoyl, naphthoyl, nicotinol and the like. Can be In addition, an acryloxy group means an oxy group to which an acryl group is bonded.

The sulfoyl group is represented by one of S 0 ₂ —R ¹⁶ (where R ¹⁶ is as defined above). Substituents The substituents in the rubamoyl group include, for example, the following _a ) or b): No.

a) an alkyl group which may be substituted with an aryl group or a heterocyclic group,

b) Aryl, aralkyl and heterocyclic groups

[Each group in this group includes a halogen atom, a cyano group, a carboxyl group, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a lower alkyl carbyl group, a lower alkylcarbonyloxy group, or a lower alkoxycarbo group. It may be substituted with one or more groups arbitrarily selected from the group such as nyl. ]

Here, the same or different plural substituents may be independently substituted. Specific examples of the rubamoyl group include ethylcarbamoyl, dimethylcarnomoinole, feninolecanolebamoinole, 2-pyridinolecanolebamoinole, benzinolecanolevamoyl, and (3-pyridylmethyl). Carpamoyl and the like.

A rubamoyloxy group represents an oxy group to which a rubamoyl group is bonded. Substituent power The substituent of the rubamoyloxy group may be the same as the substituent of the rubamoyl group.

Examples of the substituent in the substituted sulfamoyl group include an alkyl group, an arylene group, an aralkyl group, and a heterocyclic group. A plurality of the same or different substituents may be independently substituted. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethinoresnorefamoyl, feninoles / refamoyl, and 2-pyridinole sulfamoyl.

Examples of the substituent in the substituted amino group include, for example, any of the following groups a) and b), which may be arbitrarily substituted one or more times. a) acyl, sulfur, amidino,

b) Alkyl group, alkoxy group

[Each group in this group includes a group such as a halogen atom, a cyano group, a carboxy group, a hydroxyl group, an amino group, an amino group substituted with a lower alkyl group, a lower alkoxy group, a lower alkylcarbonyl group, and a lower alkoxycarbonyl group. And may be substituted with one or more groups arbitrarily selected from ]

The substituent in the substituted hydroxylamino group may be substituted by any of a nitrogen atom and an oxygen atom, and the substituent is the same as the substituent in the substituted amino group. The same thing.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the alkylene group include a linear or branched alkylene group having 1 to L0 carbon atoms. Specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, methinolemethylene, ethinolemethylene, dimethinolemethylene, 1,1-dimethinoleethylene, 1,2-dimethylenolene Ethylene, 1-methynoletrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethylenetrimethylene, 1,3-dimethinoletrimethylene, 2,2-dimethyl / retrimethylene, 1-e Tinoletrimethylene, 2-ethynoletrimethylene, 1,1-ethyltrimethylene, 1,2-getyltrimethylene, 1,3-dimethylthiomethylene, 2,2-dimethylethylmethylene and the like can be mentioned.

Examples of the lower alkylene group include a straight-chain or branched alkylene group having 1 to 6 carbon atoms.

As the protecting group for the NH group, various commonly used protecting groups (T.. Greene and PGM Wuts, "Protective Groups in Organic Synthesis, 2nd Ed.," John Wiley & Sons, Inc. pp. 315-405 (1991) )) Is possible. For example, methoxy canoleboninole, ethoxy canoleponinole, tert-butoxy canoleponinole, canolebamate-type protecting group such as benzyloxy carbyl, amide-type protecting group such as acetyl and benzoyl, benzinole, nitro, p-tonolene benzoylone And benzenesulfonyl, methanesulfonyl and the like.

The optionally substituted nitrogen-containing aliphatic heterocyclic ring formed by bonding any two of RRR ³ and R ⁴ together with a nitrogen atom includes, for example, 1 to 6 nitrogen atoms, oxygen atoms and / or A 5- to 7-membered nitrogen-containing monocyclic or bicyclic saturated or unsaturated heterocyclic ring containing a sulfur atom (including at least one nitrogen atom) is exemplified.

Specifically, pyrrolidine, imidazolidine, thiazolidine, 4,5-dihydro-1H midazole, piperidine, piperidin-4-one, piperazine, mol Holin, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1-1,1-dioxide, 1,4,5,6-tetrahydropyrimidine, hexahydropyrimidine, hexahydropyrimidine-one, 3,6- 1,2-dihydro-1,2,4-dihydro-1,2 dithio-1,2,4-thia diazo mono, 5,6-dihydro-1,4H-1,1,1 dioxo 1,2 , 4-Thiadiazine, 2,3-dihydro-1,1,3-trioxo-1 4H-1,2,4,6-thiatriazine, azepan, 4,5,6,7-tetrahydro-1H-dazepine, etc. Can be

Examples of the substituent in the substituted nitrogen-containing aliphatic heterocyclic ring include the same substituents as those in the substituted heterocyclic group.

Examples of the 5- to 7-membered nitrogen-containing aliphatic heterocycle include pyrrolidine, imidazolidine, villazolidine, piperidine, piperazine, thiazolidine, monorephorin, thiomophorin, thiomorpholine-1-oxide, and thiomorpholine-11. , 1-dioxide, 1,2,4-thiadiazolidine-1,1,1-dioxide and the like.

In the compound of the present invention, preferred L includes a group represented by the formula (4) and the formula (9).

Equation (4): 5 ¹

— N

[X is —CH ₂ —, —O—, one S—, —NR ⁵⁸ — (R ⁵⁸ represents a hydrogen atom, an optionally substituted lower alkyl group, an acyl group, or a sulfonyl group.), Or one S 0 ₂ —. R ⁵ ° and R ⁵¹ each independently represent a hydrogen atom, an optionally substituted alkyl group, or a cyano group. R ⁵ ° and R ⁵¹ may be taken together to form a 5- to 7-membered nitrogen-containing aliphatic heterocyclic ring which may be substituted together with a nitrogen atom. ],

Equation (5):

[Rso and R ⁵¹ are as defined above. However, when M or M ¹ is a single bond or 10—, both R ⁵ ° and R ⁵¹ do not represent a hydrogen atom. ],

Equation (6):

[R ^5C and R ⁵¹ are as defined above. R ⁵³ and R ⁵⁴ each independently represent a hydrogen atom or an optionally substituted alkyl group. However, when M or M ¹ is a single bond or 1 O—, three or more of R ^5G , R ⁵¹ , R ⁵³ , or R ^M do not represent a hydrogen atom. ],

Equation (7):

[R ⁵² represents a hydrogen atom or an optionally substituted alkyl group. R ⁵⁴ represents an alkyl group which may be substituted, an alkoxy group which may be substituted, an amino group which may be substituted, or a hydroxyl group. q represents an integer from 0 to 4. n represents an integer of 2 to 4. R ⁵³ has the same meaning as described above. ],

Equation (8):

[R ⁵ ° R ⁵¹ is as defined above. R ^6. And R ⁶¹ each independently represent a hydrogen atom or an optionally substituted alkynole group. In addition, R ^6. And R ⁶¹ may be taken together to form a 5- to 7-membered nitrogen-containing aliphatic heterocyclic ring which may be substituted together with a nitrogen atom. ]

Examples of the optionally substituted hydrocarbon ring formed by combining R ⁶ and R ⁷ with a carbon atom include, for example, an optionally substituted cycloalkane ring having 3 to 8 carbon atoms or an optionally substituted Examples thereof include a cycloalkene ring having 3 to 8 carbon atoms. Specific examples of the strong cycloalkane ring or cycloalkene ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, and cycloheptene. No. Examples of the substituent in the substituted hydrocarbon ring include the same substituents as those in the substituted cycloalkyl group.

In one (R ⁵ ) r which is a substituent of A, when the r force S 2 is represented, the two substituents of A may be the same or different.

The present invention includes all stereoisomers, optically active isomers, tautomers and the like of the 5-membered heteroaromatic ring compound of the present invention. The present invention also encompasses solvates such as hydrates of the 5-membered heteroaromatic ring compound or the pharmaceutically acceptable salt thereof described in the claims, and crystal forms of all aspects.

Pharmaceutically acceptable salts of the 5-membered heteroaromatic ring compounds of the present invention include acid addition salts and base addition salts. Examples of the acid addition salts include, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, citrate, oxalate, acetate, formate, Organics such as propionate, benzoate, trinoleoacetate, fumarate, maleate, tartrate, aspartate, glutamate, methanesulfonate, benzenesulfonic acid: ^, camphor sulfonate, etc. Acid salts. Base addition salts include sodium salt, potassium salt, calcium Inorganic base salts such as salts, magnesium salts and ammonium salts; and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt.

In the case where the 5-membered heteroaromatic compound of the present invention has one or more asymmetric points, a raw material having the asymmetric point may be used according to a usual method, or 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 and performing optical resolution or the like at an appropriate stage of the production process.

The 5-membered heteroaromatic compound of the present invention or a pharmaceutically acceptable salt thereof may be used orally or parenterally (for example, by intravenous, subcutaneous, or intramuscular injection, topical, It can be administered rectally, transdermally, or nasally. 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, mouthwashes, 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 used in the form of an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dosage and number of administrations of the 5-membered heteroaromatic compound of the present invention or a pharmaceutically acceptable salt thereof vary depending on symptoms, age, body weight, and administration form, but usually the active ingredient of the compound of the present invention is used for adults. As an amount, about 1 to 200 mg, preferably 10 to 500 mg per day can be administered once or in several divided doses.

The compound of the present invention can be produced, for example, by the following method.

[1]

NR ¹¹² R ¹¹³

Ax-NH ₂ + NC-N ¹¹² R ¹¹³ ► Αχ-Ν =

1-1 1-2 1-3 ^ΝΗ 2

[Wherein, R ¹¹² and R ¹¹³ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxylamino Group, optionally substituted force / Rebamoiru group, an optionally substituted Surufamoi group, the protecting group for NH ^{^{group, - R 8, -OR 8,}} - C0 2 R 9, - SR W, -S0- ^{_{^{_{R 10 -S0 2 -R 10 N -}}}} (C0) SR 1 (>, - (CS) 0R 1 () or -. in CS ₂ R ^W (wherein, RR ⁹ and R ^w are as defined above :) . the representative also, R ¹¹² and R ^113, taken together, with the nitrogen atom, may form a good alicyclic aliphatic heterocyclic ring which may be substituted also formula: -. NR ¹¹² R ¹¹³ is the formula: - N = is ^{^{C (NR 43 R 44) NH}} 2 or ^{^{- NHC (NR 4 ¾ 44)}} = NH (. wherein, R ⁴³ and ⁴ has the same meaning as defined above) a group represented by Table may be. bees 5-6- eight ⁵⁾ 1- represents, a, E, G, R 5 and r Ru as defined above der. ]

The compound represented by the formula 1-1 is reacted with a known or a known cyanoamide derivative (1-2) in the presence of a base or an acid in an inert solvent or without solvent. By reacting at a temperature of 15 to 130 ° C., the compound of the present invention represented by Formula 1-3 can be produced. 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 1-1.

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 diisopropinoleamide Magnesium chloride, ptynolemagnesium chloride, sec-ptynolemagnesium chloride, tert-ptynolemagnesium chloride, sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and the like, preferably lithium hydride, sodium hydride, potassium carbonate, lithium amide, sodium amide , Lithium tert- butoxide, potassium tert- butoxide. When an alkoxide is used as a base, it 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, argon The reaction is preferably performed while introducing an inert gas such as a gas into the reaction solution.

Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Lewis acid, etc., preferably, hydrochloric acid, sulfuric acid, phosphoric acid, aluminum chloride, titanium trichloride, titanium tetrachloride, tin dichloride, boron trifluoride ether complex And the like. 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 1-1.

Preferred solvents include, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, acetonitrile, tert-butanol, methylene chloride, chloroform, 1,2-dichloroethane, cyclobenzene and the like. When R ¹¹² or R ¹¹³ in the compound of the formula 1-3 is a protecting group for an NH group, deprotection can be carried out if desired.

This deprotection can be performed by a general method (for example, T. W. Greene and

P. GM Wuts, "Protective uroups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., New York (1991), pp. 315-362).

As the protecting group for the NH group, various types of protecting groups that are generally used are possible, and preferably, for example, methoxycarbonyl, ethoxycarbol, tert-butoxycarbonyl, benzyloxycarbonyl, etc. And amide-type protecting groups such as N-acetyl and N-benzoyl; benzyl, nitro, p-toluenesulfol, and methanesulfol.

If desired, a general amino modification method (for example, RC Larock, “Comprehensive Organic Transformations”, VCH Publishers, Inc., p. 397-398, 401-402 (1989), or TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., P. 315-362 (1991)) Groups or protecting groups can also be introduced.

[2]

2-1 2-3

[Where R ¹² . Represents a lower alkyl group or an aralkyl group; R ^m and R ¹¹⁴ each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group which may be substituted, an hydroxyl group which may be substituted; amino group, an optionally substituted cull Bamoiru group, an optionally substituted sulfamoyl group, a protecting group for NH ^{^{group, - R 8, - 0R 8}} , - C0 2 R 9, -SR 10, - SO- R ^{_{^{w, - S0 2 - R 10}}} , - (C0) SR 10, - (CS) 0R 1 () or - CS ₂ R ^{1 () (in} the formula, R ^8, R ⁹ and R ^1Q is a as defined above ). R ¹¹¹ and R ¹ "may be taken together with a nitrogen atom to form an optionally substituted aliphatic heterocycle. Ax, R ¹¹² , R ¹¹³ and the two dashed lines are as defined above. Synonymous.]

A compound represented by the formula 2-1 and an amine derivative (2-2) which is known or can be produced by a known method are reacted at a reaction temperature of 0 in the presence of a reaction aid if necessary and in an inert solvent if necessary. The compound of the present invention represented by Formula 2-3 can be produced by reacting at a temperature of 140 ° C. and a reaction time of 1 hour to 3 days.

Examples of the reaction adjuvant include silver nitrate, silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium acetate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, 1,8-diazabi-sic [5.4. [0] pendase-7-ene, triethylamine, pyridine, or a mixture thereof. When the reaction auxiliary is a liquid, it can also serve as a solvent. Preferable examples are triethylamine, silver triethylamine mononitrate, ammonium chloride, ammonium acetate, or no reaction aid.

Examples of the solvent include water, acetonitrile; alcohols such as methanol, ethanol, and isopropanol; amides such as N, N-dimethylformamide; ethynoleateno, tert-butizolemethinoleatenole, tetrahydrofuran, dioxane, and the like Ethers; aromatic hydrocarbons such as benzene, toluene, and benzene; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and mixed solvents thereof. And preferably acetonitrile, a Setonitrile tetrahydrofuran mixed system, including alcohols _c

2-12

[Wherein, X is a chlorine atom, a bromine atom, an iodine represent ^{^{atom, Ax, R ul, R 113}} , R 113, R u4, R 12. And the two dashed lines are as defined above. ]

The compound represented by the formula 2-3 can also be produced from the compound represented by the formula 2-11 or 2-12 and the amine derivative (2-2) by the method described above.

Compounds of formulas 2-11 can be converted from compounds of formula 2-1 by known methods. For example, it can be produced by using chlorine, sulfuryl chloride, bromine, and iodine in a solvent of a hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Also, the compounds of formula 2-12 can be prepared by using a suitable oxidizing agent, preferably m-mouth perbenzoic acid.

In the compound of the formula 2-3, when R ^m , R ¹¹² , R ¹¹³ or R ¹¹⁴ is a protecting group for the NH group, deprotection can be carried out in the same manner as described above, if desired.

When an NH group is present in the compound represented by the formula 2-3, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general method for modifying an amino group. Wear.

[Wherein, R ¹²² represents a lower alkyl group or an aryl group; R ¹²¹ represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, or an optionally substituted amino group; Dorokishiruamino group, an optionally substituted force Rubamoiru group, an optionally substituted Surufamoinore group, the protecting group of H ^{^{group, - R 8, -OR 8,}} - C0 2 R 9, - SR 10, -SO - R ^{_{^{10, - S0 2 - R w}}} , - (CO) SR 10, - (CS) 0R 1Q or - CS ₂ R ^{1 () (in} the formula, R ^8, R ⁹ and R ¹⁰ are as defined above.) Represents Ax, R ^U1 , R ¹¹² , R ¹¹³ , R ⁿ R ^12C and the two dashed lines are as defined above. ]

The compound represented by the above formula 2-1 can be produced as follows. That is, a 5-membered heteroaromatic compound having an amino group (2-4) is used as a raw material, and according to a known method (for example, JP-A-63-152368), first, the formula: RC (0) N = C = The acylisothiocyanate compound represented by S is allowed to act to synthesize an acylthioperide compound (2-5), which is hydrolyzed to synthesize a thioureido compound (2-6). Here, if desired, a compound represented by the formula 2-7 may be introduced by introducing a substituent or a protecting group into the compound represented by the formula 2-6 in the same manner as in the above-mentioned general method for modifying an amino group. Compound. Subsequently, the compound represented by the formula 2-6 or 2-7 is subjected to a known S-alkylation 'method (for example, WO 98/47880)! The compound represented by the formula 2-1 can be produced by reacting /, or XR ¹²⁰ (X is a Haguchigen atom).

The compound represented by the formula 2-1 can also be synthesized by the following method according to a known method.

2-10

^{^{Wherein, Ax, R m, R 112}} , R n \ R 114, R 12. And the two dashed lines are as defined above. The compound represented by the formula 2-1 can also be synthesized by the following method according to a known method. Ax- H ₂ compound represented by contrast, presence of an appropriate base, by reacting Chiohosuge down, wherein: Ax- N = synthesizing Isoshianeto compound represented by C = S. After reacting the desired amine, the compound represented by 2-1 is obtained by performing S-alkylation. Can be manufactured.

It can also be synthesized via a compound represented by Formula 2-10.

Compounds of formulas 2-10 can be prepared by reacting carbon disulfide with XR ¹² ° (X is a halogen atom) in the presence of a base. The compound of formula 2 10, wherein: by reacting Amin represented by NHR ¹¹² R, it is possible to produce a compound of formula 2-1.

Examples of bases include sodium hydroxide, potassium hydroxide, triethynoleamine, pyridine, 1,8-diazavicine [5.4.0] pendase-7-ene, sodium hydride, potassium hydride, and hydrogenation Examples of the solvent include water, acetate nitrile; alcohols such as methanol, ethanol, and isopropanol; amides such as N, N-dimethylformamide; getyl ether, tert-butyl methyl ether, and tetrahydrofuran. Ethers such as benzene, dioxane, etc .; aromatic hydrocarbons such as benzene, toluene, and chlorobenzene; chlorinated hydrocarbons such as methylene chloride, chlorophonolem, carbon tetrachloride, 1,2-dichloroethane, or a mixed solvent thereof And so on.

When the compound represented by the formula 2-1 has an NH group, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general method for modifying an amino group. Include.

[3]

[Wherein, R ¹³ °, R ¹³¹ and R ¹³² each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, or an optionally substituted hydroxylamino group, optionally substituted force Rubamoiru group, an optionally substituted sulfa moil group, the protecting group for NH ^{^{group, - R 8, -OR 8,}} - C0 2 R 9, -SR 10, - SO- R ^{^{w, -S0 R 10, - (}} CO) SR 10, - (CS) 0R 1 () or _{^{-. CS 2 R 1 ()}} ( in the formula, R ^8, R ⁹ and R ¹ are as defined above. ). Further, any two of R ¹³ °, R ¹³¹ and R ¹³² may be combined with each other to form an optionally substituted aliphatic heterocyclic ring together with a nitrogen atom. Also, Formula:-NR ¹³¹ R ¹³² has the formula: -N = C (NR ⁴³ R ⁴⁴ ) NH ₂ or -NHC (NR ⁴³ R ⁴⁴ ) = NH (wherein R ⁴³ and R ⁴⁴ are as defined above). ) May be used. Ax, R ¹² ° and R ¹²¹ are as defined above. ]

The compound represented by the formula 2-4 and the compound represented by the formula 3-1 are reacted at a reaction temperature of 0 to 140 ° C in the presence of a reaction aid, if necessary, and in an inert solvent, if necessary. By doing so, the compound of the present invention represented by Formula 3-2 can be produced.

Examples of the reaction aid include glass salt, silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium drunkate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, and 1,8-diazabicyclo [5. 4.0] Pindec-7-ene, triethylamine, pyridine, or a mixture thereof. When the reaction auxiliary is a liquid, it can also serve as a solvent. Preferable examples include triethylamine, silver triethylamine, ammonium chloride, ammonium acetate, pyridine, and no reaction aid.

Solvents include, for example, water; acetonitrile; alcohols such as methanol, ethanol, and isopropanol; amides such as N, N-dimethylformamide; ethenoleatenore, tert-butinolemethyl ether, tetrahydrofuran, Ethers such as 4-dioxane; aromatic hydrocarbons such as benzene, toluene, and benzene; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; or these And a mixed solvent of acetonitrile, acetutrile tetrahydrofuran mixed system, Ν, Ν-dimethylformamide, and alcohols.

When R ^m , R ¹³ °, R ^m or R ¹³² in the compound of the formula 3-2 is a protecting group for an NH group, deprotection can be carried out in the same manner as described above, if desired.

When an NH group is present in the compound represented by the formula 3-2, a substituent or a protecting group may be introduced, if desired, in the same manner as in the general amino group modification method described above. Monkey

[Four] NS0 ₂ R ¹⁴⁰

Ax-NHR ¹²¹ -

R 141

2-4 140 HNR ^{1 2} R ¹¹³ R

= NS0 ₂ R 4-2

p142

R 4-1

[In the formula, R "is an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, R ¹⁴¹ and R ¹⁴² each independently represent a halogen atom or a methylthio group, a cycloalkyl group, an aryl group which may be substituted or an aromatic heterocyclic group which may be substituted Ax, R ^U2 , R ^m and R ¹²¹ are as defined above.

A

It is synonymous. ] X

^

At a reaction temperature of −20 to 80 ° C. in an inert solvent, a compound represented by the formula 2-4

R

Methylene 1 sulfone which can be produced by a known method represented by 1

2 Reaction with an amide derivative (for example, Chem. Ber., 99, 2900 (1966)), followed by addition of an amine represented by the formula 4-2 which can be produced by a known or known method, followed by reaction Thereby, the compound of the present invention represented by Formula 4-3 can be produced.

Examples of the solvent include: acetonitrile; ethers such as getyl ether, tert-butylmethyl ^ / ether, tetrahydrofuran, 1,4-dioxane; aromatic hydrocarbons such as benzene, toluene, and benzene; methylene chloride And chlorophonolem, carbon tetrachloride, 1,2-dichloroethane, and other chlorinated hydrocarbons; and mixed solvents thereof. Preferred examples of the solvent include acetonitrile, getyl ether, tetrahydrofuran, and 1,4-dioxane. , Benzene, toluene, methylene chloride, carbon tetrachloride and the like. Suitable Formula 4-1 compounds include those wherein R " ¹ and are both chlorine atoms.

When R ¹¹² , R ¹¹³ or R ^m is a protecting group for an NH group in the compound of the formula 4-3, if desired, deprotection can be carried out in the same manner as described above. If desired, according to a known method (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, inc., P. 379-385 (1991)) it is also possible to perform the elimination of the groups represented by ₂ R ^140.

If the compound represented by the formula 4-3 has an NH group, Substituents or protecting groups can be introduced in the same manner as in a general method for modifying an amino group.

[Five]

^Ε-

[In the formula, Y represents a halogen atom such as a chlorine atom or a bromine atom, a leaving group such as an anolequinole such as methanesulfonyloxy, monotonoleens / lephoninoleoxy or an arylinolesulfoeroxy group, and X represents It represents an S, 0, NR ^5. ^{E, G, R \ R 2} , R 3, R 4, and R ⁵ are as defined above. ]

The compound of formula 5-1 is reacted with the guanyl derivative of formula 5-2 in an inert solvent at a suitable temperature from room temperature to the boiling point of the solvent used in an inert solvent to give the compound of formula 5-3. Can be produced.

Examples of the solvent include alcohol solvents such as acetone, water, methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, methylene chloride, chlorophorem, 1,2-dichloroethane, and benzene. Examples include a non-hydrogenated hydrocarbon solvent and a mixed solvent thereof. More preferably, acetone, water, and alcohol solvents are used.

In the formula 5-3, the compound of the present invention in which X is O can also be produced by the method shown below.

E-I

[Wherein, E, G, RR \ R ³ , R ⁴ , and R ⁵ are as defined above. ]

A compound represented by the formula 5-4 and a cyanoguanidine derivative represented by the formula 5-5 are reacted with an acid, Alternatively, the compound of the present invention represented by Formula 5-6 can be produced by reacting in an inert solvent at a suitable temperature from room temperature to the boiling point of the solvent used in the presence of a base.

Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, Lewis acid, and the like, and preferably, hydrochloric acid, sulfuric acid, and the like. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. Preferred solvents include, for example, water, alcoholic solvents such as methanol and ethanol, ethereal solvents such as tetrahydrofuran and 1,4-dioxane, dimethylformamide, acetate ditrinole, or methylene chloride, chlorophonolem, Examples of the solvent include a halogenated hydrocarbon solvent such as dichloroethane and benzene, and a mixed solvent thereof.

[6]

EG

6-1 5-2 6-2

[In the formula, Z represents a halogen atom such as a chlorine atom and a bromine atom. ^{E, G, RR 2, R} 3,

R ⁴ and X are as defined above. ]

By reacting the compound of formula 6-1 with the guanyl derivative of formula 5-2 in an inert solvent at a suitable temperature from room temperature to the boiling point of the solvent used, the compound of formula 6-2 Invention compounds can be prepared.

Examples of the solvent include alcohol solvents such as acetone, water, methanol, and ethanol; ether solvents such as tetrahydrofuran and 1,4-dioxane; and methylene chloride, chlorophonolem, 1,2-dichloroethane, and benzene. Examples thereof include halogenated hydrocarbon solvents and mixed solvents thereof. More preferably, acetone, water, and alcohol solvents are used.

[7]

2-10 19-1 19-2

[Wherein, Ax and R ¹² ° are the same as defined above. R ^2fl ° and R ^2C1 each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxylamino group, or an optionally substituted Rbamoyl group, optionally substituted sulfamoyl group, protecting group for NH group, one R ⁸ , one R ⁸ , one C00R ⁹ , -SR ¹⁰ , — SOR ¹⁰ , — S0 ₂ R ¹⁰ ,-(CO) SR ¹⁰ represents one (CS) oR ¹⁰ or a CS ₂ R ^W, (wherein, R ^8, R ⁹ and R ¹⁰ are as defined above.). ]

The compound represented by the formula 2-10 and a diamine derivative (formula 19-1) which can be produced by a method known per se are combined in an inert solvent, if necessary, in the presence of a reaction auxiliary. The compound of the present invention represented by the formula 19-2 can be produced by reacting at a reaction temperature of 0 to 140 ° C. for a reaction time of 1 hour to 3 days.

As reaction aids, for example, glass, silver carbonate, mercury chloride, ammonium chloride, ammonium acetate, sodium acetate, acetic acid, oxalic acid, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, 1, 8- Examples include diazabicyclo [5.4.0] pandec-7-ene, triethylamine, pyridine, and mixtures thereof. When the reaction trapping agent is a liquid, it can also serve as a solvent. Examples of the solvent include water, aceto nitrile; alcohols such as methanol, ethanol, and isopropanol; amides such as N, N-dimethylhonolemamide; and ethyl ether, tert-butylmethyl ether, tetrahydrofuran, dioxane, and the like. Ethers; aromatic hydrocarbons such as benzene, toluene, and chlorobenzene; chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane, and mixed solvents thereof. Preferred examples include acetonitrile, a mixed system of acetonitrile and tetrahydrofuran, and alcohols.

In the compound represented by the formula 19-2, when R ^{2 () ()} or R ^{2 <n} is a protecting group for an NH group, deprotection can be carried out in the same manner as described above, if desired. When an NH group is present in the compound represented by the formula 19-2, a substituent or a protecting group can be introduced, if desired, in the same manner as in the above-mentioned general method for modifying an amino group. Include.

[8]

_R 202 _R 203 _{N +} X _NR 202 _R 203

Ax-NH ₂

Ax-N = <f

(2-4) XX X X

0-1) (20-2)

_NHR 204 _R 205

(20-3) NR ²⁰² R ²⁰³

Ax-N

N _R 204 _R 205

(20-4)

In the ^{^{formula, R 2Q2, R 2Q3, R}} 2. ⁴ and R ^2C5 each independently represent a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxylamino group, an optionally substituted sorbamoyl group , optionally substituted Sulf Amoiru group, the protecting group for NH ^{^{group, - R 8, - 0R 8}} , - C0 2 R 9, -COR 10, -SR 10 N - SO- R w, _S0 2 -R 10 , - represents a CS ₂ R ^1Q (wherein, R ^8, R ⁹ and R ^lfl are as defined ^{above.) - (CO) SR 10} N - (CS) 0R w or. R ^2Q2 and R ^2e3 , R ² ° ⁴ and R ^2W may be taken together with a nitrogen atom to form an ^optionally substituted aliphatic heterocycle. In addition, the ^{_{formula: - NR 2G2 R∞, - NR2}} . 4 _R2fl5 is represented by the formula: _{—N =} c (NR ⁴³ R ⁴⁴ ) NH ₂ or —NHC (NR ⁴³ R ⁴⁴ ) = NH (wherein R ⁴³ and R ⁴ are as defined above). May represent a group. X represents a halogen atom. XX-represents countermeasure of imminium cation. Ax and the broken line are as defined above. ]

A compound represented by the formula 2-4, or a dihalogenomethyleneiminium derivative (20-1) or a dihalogenogenimethyleneimine derivative known per se or can be produced by a known method. (20-5) in the presence of a base in an inert solvent or without solvent at a reaction temperature of −78 to 130 ° C., preferably 0 to 50 ° C .; After conversion to the intermediate compound represented by Formula 6-6, the compound of Formula 20-3 is added and reacted to give the compound of the present invention represented by Formula 20-4 or 20-7, respectively. Can be manufactured.

The amount of the dihalogenomethylene iminium derivative (20-1) or dihalogenomethylene imine derivative (20-5) used is, for example, in the range of 1 to 20 equivalents relative to the compound of the formula 2-4. And preferably 1.0 to 1.2 equivalents. The amount of the compound of 1-4 is, for example, in the range of 1 to 20 equivalents, preferably 1.0 to 1.2 equivalents, relative to the compound of formula 2-4.

Any base can be used as long as it does not adversely affect the reaction. Examples of the base include tertiary amines such as triethylamine. The amount of the base 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 1-1.

Preferred solvents are those that do not adversely affect the reaction, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, acetonitrile, methylene chloride, chloroform, 1,2-dichloroethane, and 1,2-dichloroethane. Benzene and the like can be mentioned. Further, anhydrous conditions are preferred.

In the compounds of the formulas 20-4 and ^20-7 , when R ² , R ^2ra , R ^{2 (M} or R ^{2 (55} is a protecting group for an NH group, deprotection can be carried out if desired. This deprotection can be performed by a general method (for example, TW Greene and PGM Wuts, "Protective Groups in Organic

Synthesis ", 2nd Ed., John Wiley and Sons, inc., New York (1991), p. 315-362).

As the protecting group for the NH group, various types of protecting groups that are commonly used are possible, and preferably, for example, a protected type of protecting group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Groups, amide-type protecting groups such as N-acetyl and N-benzyl, benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like.

If desired, a general amino group modification method (for example, R. C Larock, "Comprehensive Organic Organic Compounds") may be added to the NH group in the compounds represented by the formulas 20-4 and 20-7. Transformations ", VCH Publishers, Inc., p. 397-398, 401-402 (1989), or TW Greene and PGM Wuts," Protective Groups in Organic Synthesis ", 2nd Ed., John Wiley and Sons, inc., P. 315-362 (1991)), substituents or protecting groups may be introduced.

As the dihalogenomethyleneimidium derivative (20-1) or dihamogenomethyleneimine derivative (20-5), known compounds can be used, or

It can also be produced by a known method described in Angew. Chem. Internat. Edit. 12, 1973, 806.

[9]

(20-11)

[ ^Wherein , R, R ^2C7 , R ^2Q8 and R ² ° ⁹ are each independently a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted hydroxylamino group, optionally substituted force Rubamoiru group, an optionally substituted Sulf Amoiru group, the protecting group of H ^{^{group, - R 8, -OR 8,}} - C0 2 R 9, -COR 10, -SR 10 - ^{_{SO- R w, - S0 2 -R}} 10, - (C0) SR 1C, - (CS) 0R 1 () or - CS ₂ R ^lfl (wherein, R ^8, R ⁹ and R ^1G is as defined above ). In addition, R ² ° ⁶ and R ² ° ⁷ , R ² ° ⁶ and R ² ° ⁹ , or R ² ° ⁸ and R ² ° ⁹ are taken together with the nitrogen atom and optionally substituted fat. A heterocyclic ring may be formed. Further, the formula: -NR ^2fl6 R ^2Q7 , -NR ^{2 () 8} R ^{2 <) 9} is represented by the formula: -N = C (NR ⁴³ R ⁴⁴ ) NH ₂ or -NHC (NR ⁴³ R ⁴⁴ ) = H (Formula Wherein R ⁴³ and R ⁴⁴ have the same meanings as defined above. Is also good. Ax, X, XX-, and the broken line are as defined above. ] A halogenoformamidinium derivative (20-8) or a halogenoformamidine derivative which can be produced by a method known per se with a compound represented by the formula 2-4

(20-9) in the presence of a base in an inert solvent or in the absence of a solvent at a reaction temperature of -20 to 130 ° C to obtain a compound represented by the formulas 20-10 and 20-11, respectively. Invention compounds can be produced.

The amount of the halogenoformamidinium derivative (20-8) or halogenoformamidine derivative (20-9) used is, for example, in the range of 1 to 20 equivalents relative to the compound of the formula 2-4, and is preferably 1.0 to 1.2 equivalents.

Any base can be used as long as it does not adversely affect the reaction. Examples of the base include tertiary amines such as triethylamine. The amount of the base 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 20-4.

The preferred solvent is any solvent that does not adversely affect the reaction. And the like. Further, anhydrous conditions are preferred.

In the compounds of the formulas 20-10 and 20-11, when R ² ° ⁶ , R ²⁰⁷ _NR ² ° ⁸ or R∞ is a protecting group for the H group, deprotection can be carried out if desired. This deprotection can be accomplished by common methods (eg, TW Greene and PGM Wuts, "Protective Groups in Organic

Synthesis ", 2nd Ed., John Wiley and Sons, inc., New York (1991), p. 315-362).

As the protecting group for the H group, various types of protecting groups that are commonly used are possible, and preferably, for example, carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like can be used. Protecting groups, amide-type protecting groups such as N-acetyl and N-benzoyl; benzyl, nitro, p-toluenesulfonyl, methanesulfonyl and the like.

If necessary, a general amino group modification method (for example, RC Larock, "Comprehensive Organic Organic Compounds") may be added to the NH group in the compounds represented by the formulas 20-10 and 20-11. Transformations ", VCH Publishers, Inc., p. 397-398, 401-402 (1989), or TW Greene and PGM Wuts," Protective Groups in Organic Synthesis ", 2nd Ed., John Wiley and Sons, inc., P. 315-362 (1991)), it is also possible to introduce substituents or protecting groups.

Known halogenoformamidinium derivatives (20-8) or halogenoformamidine derivatives (20-9) can be used, or Synthesis, 2000, p255, Synth. Commun., 28, pl223, ( 1998), Arch. Pharm. Ber. 'Dtsch. Pharm. Ges., 300, p766, (1967) and the like.

The raw material compounds represented by Formula 1-1, Formula 2-4, Formula 5-1, Formula 5-2, Formula 5-4, Formula 5-5, and Formula 6-1 in the above production method are known compounds per se. Or a compound that can be produced by a known method. For example, it can be produced by the following method.

The compounds represented by Formula 1-1 and Formula 2-4 can be produced, for example, by the following method.

[Wherein, E, G, R ¹²¹ , X, Y and Z are as defined above. ]

According to a known method, the compound of the formula 5-1 or the compound of the formula 7-1 and the compound of the formula 7-1, which is a precursor of the compound of the present invention, It can be produced by reacting at room temperature to 100 ° C in an inert solvent. Preferred solvents include, for example, acetone, water, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, halogenated hydrocarbon solvents such as chloroform, and mixed solvents thereof.

The 2-aminoxazole derivative represented by the formula 7-4 can be prepared by a known method described below (for example, Example, if, _c which can be prepared by JP 63- 152368)

. h _OH NH

5-4 7-4

[Wherein, E, G and R ⁵ are as defined above. ]

Preparation of a compound of formula 7-4 by reacting a hydroxyketone of formula 5-4 with cyanamide in an inert solvent at a suitable temperature from room temperature to the boiling point of the solvent used in the presence of a base. Can be.

Examples of the base include sodium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate and the like. Suitable solvents include water, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, and mixtures thereof.

The conjugates represented by Formula 5-1 and Formula 5-4 can be produced, for example, by the following method.

E-G R.

H

5-4

E-G

E-

O. _Y

8-1 ₂

8-2 5-1 CO, CO ₂ R 150

8-3

[In the formula, R ¹⁵ ° represents a lower alkyl group. E, G, R ⁵ Oyohi Ύ is Ru as defined above der. ]

The compound represented by the formula 5-4 can be obtained by converting a carboxylic acid of the formula 8-1 into an acid chloride according to a known method (for example, A. Wissner, J. Org. Chera., 44, 4617 (1979)). , Tris

(Trimethylsilyloxy) Obtained by reacting with ethylene. The compound of Formula 5-4 can be converted to the compound of Formula 5-1 by a known method ₍ For example, by mixing a compound of formula 5-4 with tripheninolephosphine in carbon tetrachloride, a compound in which the hydroxyl group has been replaced with a chlorine atom can be obtained (for example). B. Lee et al., Tetrahedron , 23, 2789 (1967)).

Further, the compound represented by the formula 8-2 can be synthesized by reacting the carboxylic acid chloride of the formula 8-1 with diazomethane. The compound of the formula 8-2 can be synthesized with hydrogen chloride gas or a salt of a dioxane solution to synthesize the compound of the formula 5-1 in which Y is a chlorine atom. The compound of 5-1 can be prepared by a known method (for example, Y. Oikawa, J. Org. Chem, 43, 2087 (1978)), adding meldrum acid or lower alcohol to the acid chloride of carboxylic acid of formula 8-1. To give a compound of formula 8-3, followed by halogenation and decarboxylation. The carboxylic acid of formula 8-1 is commercially available Kazu, a compound known per se, or can be produced according to a known method (for example, US Pat. No. 3,793,457, Eur. J. Med. Chem., 9, 381 (1974)).

The compound represented by the formula 6-1 can be produced by the following method. 0 ^HG _OH ^ " ^E — ^G _CN ~~ ^ ^CHO

8-1 9-1 9-2 6-1

[Wherein, E, G and Z are as defined above. ]

The compound (9-1) obtained by reducing the compound of the formula 8-1 is halogenated and cyanated to synthesize the compound represented by the formula 9-2. Further, the compound of formula 6-1 can be produced by reducing the nitrinole group of the compound represented by formula 9-2 to an aldehyde using diisobutylaluminum hydride, and then halogenating using bromo or the like.

The compounds represented by the formulas 5-2 and 5-5 can be produced by the following methods. R ³

10-1 5-5

5-2

[Wherein, X, R \ R ² , R \ and R ⁴ are as defined above. ]

Compounds of formula 5-2 and formula 5-5 can be prepared according to the above figures. According to a known method (eg, CG McCarty et al, J. Org. Chem., 35, 2067 (1970)), commercially available dimethyl cyanodithioimide carbonate is used as a starting material, and an inert solvent is used at room temperature. By reacting with an amine represented by the formula: NHR ¹ ^ at an appropriate temperature up to the boiling point of, the compound represented by the formula 9-1 can be obtained.

Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, DMF, and the like. Suitable examples include ethanol. The compound of formula 9-2 is reacted with an amine of the formula: NHR ³ R ⁴ in an inert solvent at 0 ° C to 50 ° C to synthesize a cyanoguanidine derivative of the formula 5-5. it can. If necessary, add a base or metal salt as a reaction aid.

Examples of the solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, DMF, and the like, and preferably, DMF, methanol, and the like.

Preferable bases include triethylamine, Ν, Ν-diisopropylethylamine, 1,8-diazavicine [5.4.0] pandec-7_ene and the like. As a metal salt, nitrate ^! Good is particularly preferred, but also mercury chloride.

The compound of the formula 5-2 can be produced by a known method. For example, a guarthioperiae derivative can be produced by reacting a cyanoguanidine derivative of the formula 5-5 with hydrogen sulfide according to a known method (eg, Org. Synth. Coll. IV, 502). Specific examples of the compounds included in the present invention include the following compounds. However, these compounds are for the purpose of illustration, and the present invention is not limited only to these. In specific examples, the meanings of the abbreviations used are as follows is there.

Me: Mechinore

Et: Echinore

Ph: Phenyl Example 1

No. —NHR No. —NRR '

I \ OH -01-e 3-01 -N N

No. -NHR No. —NRR '

— _N 〜S0 ₂ -NO 4-03 ― rTA〜 ^s

2-04 \ _ f

H ~

f ~~ \

k _l / \ .S0 ₂ N NMe

2-05 4-04 ― NS

~

2-06

222076HCHNCS0- ■ 〇 z〇.

CO

^Z HN ^Z OS ^Z H3 ^Z H03 Goichi οι-ιι ^Z HN ^Z OS ^Z HO ^Z HOHN— (HiH

^{^{^{Z 3WN Z HO Z H09 - 60-}}} ζ 81ΛΙΝ ζ Η0 ε Η0ΗΝ- 60-01.

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O o XI X X 2222oHCHCNH S0H ■: io 2C0H1-22 ZHHCHC0H

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Example 41 Example 43

No. -R No. — R

41-01 — H 43-01 —OH 41-02 One CH ₂ CH ₂ OH 43-02 — H ₂

41-03 — CH ₂ CH ₂ -N ^ ^ 43-03 — HCH ₂ CH ₂ OH

41-04 — CH ₂ CH ₂ NH ₂ 43-04 — C0 ₂ H

41-05 — CH ₂ CH ₂ NHS0 ₂ e 43-05 — HS0 ₂ Me

41-06 — CH ₂ C0 ₂ H 43-06 —OMe

41-07 — CH ₂ CH ₂ S0 ₂ NH ₂ 43-07 = 0

Example 42

No.

42-01

42-02 One CH ₂ CH ₂ OH

42-03 — CH ₂ CH ₂ NO 42-04 — CH ₂ CH ₂ NH ₂ 42-05 CH ₂ CH ₂ NHS0 ₂ Me 42-06 — CH ₂ C0 ₂ H 42-07 — CH ₂ CH ₂ S0 ₂ NH _Two 22: 4750CHHCSO-.

ON ON

Oh

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No. — R No. One R

51-01 —Me 53-01 — Me

51-02 — CO _z H 53-02 — C0 ₂ H

51-03 one C0 _₂ Me 53-03 - C0 ₂ Me

51-04 — CONH ₂ 53-04 — CONH ₂

51-05 — CONMe ₂ 53-05 — CONMe ₂

No. -R No. — R

52-01 ― Me 54-01 —Me

52-02 — C0 ₂ H 54-02 — C0 ₂ H

52-03 — C0 ₂ Me 54-03 — C0 ₂ Me

52-04 — CONH ₂ 54-04 — CONH ₂

52-05 — CO Go e ₂ 54-05 — CONMe ₂ Example

Hereinafter, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto. The abbreviations used in the examples and the like have the following meanings.

and / or: and / or

Boc: tert-butoxycarbo-nore

Bu-t: tert-butyl

t-BuOH: tert-butanol

t-BuOK: Power Realm tert-butoxide

Boc20: di-tert-butino resin carbonate

DMF: N, N-dimethylformamide

DMS0: N, N-dimethyl sulfoxide

EDC: 1,2-dichloroethane

Me: Methyl

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Ts: p—tonoreensenorehoninore Example 1

N '-{4- [2- (2-fluoro [1,1, -bipheninole] _4-inole) -1-methylethyl] _1,3-thiazol-2-yl} -4-morpholinecarboxy Midoamide hydrochloride

To a suspension of 60% sodium hydride (0.51 g) in THF (30 ml) was added a solution of the compound obtained in Reference Example 3 (2.0 g) in THF (30 ml). One hour later, N-cyanomorpholine (0.98 ml) was added, and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified by a silica gel column to obtain 2.3 g of the desired product. This was dissolved in 1,4-dioxane (20 ml) and treated with 4N hydrogen chloride / 1,4-dioxane solution to obtain the desired product (2.3 g). Melting point: 217-220 ° C (decomposition)

_{^ - MR (300MHz, CDC1 3} ) δ ppm: L65 (s, 6H), 3.72- 3.80 (m, 4H), 3.82- 3.91 (m, 4H), 6.62 (s, 1H), 6.94- 7.05 (m, 2H), 7.30— 7.52 (m, 6H)

IR (KBr) [cm " ¹ ]: 3213, 3074, 2971, 1664, 1618, 1552, 1484, 1206, 1115, 774, 701

Elemental analysis (%): Calculated: C, 59.92; H, 5.68; N, 12.15; C1, 7.69, Found: C, 59.64; H, 5.71; N, 12.06; C1, 7.73 Example 2

N '-{4- [1- [2- (2-Fluoro [1, -biphenyl] -4-yl) ethyl] -1,3-thiazol-2-yl} -4-morpholinecarboximimidamide hydrochloride salt

To a suspension of 60% sodium hydride (0.17 g) in THF (7ral) was added a solution of the compound obtained in Reference Example 4 (0.64 g) in THF (14 ml). One hour later, N-cyanomorpholine (0.33 ml) was added, and the mixture was stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified by a silica gel column to obtain the desired product (0.9 g). This was dissolved in 1,4-dioxane (10 ml) and treated with a 4N hydrogen chloride / 1,4-dioxane solution to obtain the desired product (0.4 g).

Melting point: 172-1175 ° C (decomposition)

_{¾- MR (300MHz, CDC1 3)} δ ppm: 1.60 (d, 3H, J = 7.3Hz), 3.74- 3.82 (4H, m), 3.83-3.91 (m, 4H), 4.14 (q, J = 7.3Hz , 1H), 6.57 (s, 1H), 6.92-7.05 (m, 2H), 7.31-7.53 (m, 6H)

IR (KBr) [cm " ¹ ]: 3191, 3096, 2966, 1661, 1619, 1550, 1484, 1451, 1416, 1281, 1204, 1166, 1118, 1062, 991, 914, 872, 774, 728, 697, 663 Example 3

N '-{4-[(2-Fluoro [1, -biphenyl] -4-yl) methyl] -1,3_thiazol-2-yl} -4-morpholinecarboximimidamide hydrochloride

Using the compound obtained in Reference Example 6, the desired product was obtained in the same manner as in Example 1.

Melting point: 200-203 ° C (decomposition)

^{_{X H- MR (300MHz, CDC1 3}} ) δ ppm: 3.76-3.82 (m, 4H), 3.86- 3.94 (m, 4H), 3.96 (s, 2H), 6.51 (s, 1H), 6.94 - 7.04 (m , 2H), 7.33-7.52 (m, 6H)

IR (KBr) [cm " ¹ ]: 3436, 3190, 3101, 2962, 1664, 1621, 1552, 1483, 1120, 699

Elemental analysis (° /.): Calculated: C, 58.26; H, 5.12; N, 12.94; CI, 8.19, Found: C, 58.14; H, 5.17; N, 12.90; CI, 8.40

N, 1- (4- [1- (3-benzoylpheninole) -1-methylethyl] -1,3-thiazol-2-inole) -1-morpholinecarboximimidamide hydrochloride

Using the compound obtained in Reference Example 10, the desired product was obtained in the same manner as in Example 1. Melting point: 95-99 ° C (decomposition)

One _{NMR (300MHz, CDC1 3) δ} ppm: 1.70 (s, 6H), 3.75-3.87 (m, 8H), 6.67 (s, 1H), 7.32-7.62 (ra, 6H), 7.75-7.79 (m, 3H ) IR (KBr) [cm " ¹ ]: 3062, 2972, 1655, 1619, 1549, 1484, 1447, 1281, 1205, 1117, 706

Elemental analysis (%): Calculated: C, 61.20; H, 5.78; N, 11.89; CI, 7.53, Found: C, 60.79; H, 5.85; N, 11.85; CI, 7.63

N,-{4- [1- (3-Benzoylphenyl) ethyl] -1,3-thiazol-2-yl} -4-morpholincarboximidamide hydrochloride

Using the compound obtained in Reference Example 11, the desired product was obtained in the same manner as in Example 1. _{XH-NMR (300MHz, CDC1 3} ) δ ppm: 1.66 (d, 3H, J = 7.2Hz), 3.75- 3.90 (m, 8H), 4.20 (q, 1H, J = 7.2Hz), 6.61 (s, 1H ), 7.35-7.63 (m, 6H), 7.43- 7.79 (m, 3H)

N '-[4- (3-Benzylbenzyl) -1,3-thiazol-2-yl] -4-morpholinecarboximidamide hydrochloride

Using the compound obtained in Reference Example 14, the desired product was obtained in the same manner as in Example 1. Melting point: 167-1168 ° C (decomposition)

_{^ -NMR (300MHz, CDC1 3)} δ ppm: 3.75- 3.82 (m, 4H), 3.85-3.92 (m, 4H), 4.01 (s, 2H), 6.49 (s, 1H), 7.36- 7.49 (m, 4H), 7.56- 7.61 (tn, 2H), 7.68 (m, 1H), 7.75-7.80 (m, 2H)

IR (KBr) [cm ^-1 ]: 3188, 3079, 2866, 1656, 1618, 1554, 1484, 1447, 1318, 1281, 1205, 1118, 718

Elemental analysis (%): Calculated: C, 59.65; H, 5.23; N, 12.65; Cl, 8.00, Found: C, 59.39; H, 5.30; N, 12.56; C1, 7.76 Example 7

tert-butyl (Z) _ ({4_ [1_ (2_fluoro [1,1, -biphenyl] -4-yl) ethyl] -1,3-thiazonole-2-yl} imino) (4-thiomorpholinyl ) Mechinore Carbamate

Acetonitrile (40 ml), THF (40 ml), and thiomorpholine (4.46 g) were added to the compound (8.18 g) obtained in Reference Example 16, and the mixture was stirred at room temperature for 28 days, and concentrated under reduced pressure. (Hexane / ethyl acetate = 50/1 to 25/1) to obtain the desired product (5.25 g).

_{H-NMR (300MHz, CDC1 3} ) δ ppm: 1.45 (s, 9H), 1.67 (d, 3H, J = 7.1Hz), 2.71- 2.74 (m, 4H), 3.81-3.84 (m, 4H), 4 .ll (q, 1H, J = 7.1Hz), 6.41 (d, 1H,

J = 0.7Hz), 7.07-7.15 (m, 2H), 7.32-7.46 (m, 4H), 7.51-7.55 (m, 2H),

11.45 (br-s, 1H) Example 8

N,-{4- [1- (2-Fluoro [1, -biphenyl] -4-yl) ethyl] -1,3-thiazole-2-yl}-4-thiomorpholinecarboximidamide Hydrochloride

Under ice-cooling, add TFA (15 ml) to the Boc form (3.59 g) obtained in Example 7, return to room temperature, stir for 2 hours, concentrate under reduced pressure, add chloroform, and add saturated aqueous sodium bicarbonate. Neutralized and separated. The organic layer was washed with water and concentrated under reduced pressure, and the residue was purified with silica gel gel (hexane / ethyl acetate = 25/1 to 8/1) to obtain the desired product (2.82 g). This is Kuroguchi Holm

(15ml) and treated with 4N hydrogen chloride / 1,4-dioxane solution

(2.91 g) was obtained.

_{^ - MR (270MHz, d 6} - acetone) δ ppm: 1.68 (d, 3H, J = 7.3Hz), 2.81-2.85 (m, 4H), 4.16-4.20 (m, 4H), 4.33 (q, 1H, J = 7.3Hz), 7.01 (d, 1H, J = 1.0Hz), 7.15-7.26 (m, 2H), 7.35- 7.57 (m, 6H)

IR (KBr) [cm " ¹ ]: 3250, 3057, 2688, 1662, 1612, 1546, 1483, 1416, 1266, 1247, 1126

Elemental analysis (° / o): Calculated: C, 52.90; H, 5.04; N, 11.22; S, 12.84; CI, 14.20, Found: C, 52.52; H, 5.01; N, 10.97; S, 13.08; CI, 14.01 Example 9

tert-butyl / (Z)-(l, 1-dioxide-4-thiomorpholinyl) ({4- [1- (2-fluoro [1,1'-bipheninole] -4-1yl) ethyl]- 1,3-thiazole-2-yl} imino) methylca, bamate

The compound (4.28 g) obtained in Example 7 was dissolved in methanol (150 ral), and a solution of oxone (0X0NE, 6.49 g) in water (40 ml) was added dropwise over 30 minutes under ice-cooling. Stirred for hours. After concentration under reduced pressure, the residue was purified by a silica gel column (hexane / ethyl acetate = 5/1 to 1/1) to obtain the desired product (4.35 g).

_{¾-NMR (300MHz, CDC1 3} ) 6 ppm: 1.47 (s, 9H), 1.68 (d, 3H, J = 7.2Hz), 3.18- 3.21 (ra, 4H), 4.00- 4.04 (m, 4H), 4.14 (q, 1H, J = 7.2Hz), 6.51 (s, 1H), 7.07- 7.14 (m, 2H), 7.34-7.46 (m, 4H), 7.51-7.54 (m, 2H), 11.69 (br-s , 1H) Example 10

N,-{4_ [1-(2-Fluoro [1,1, -biphenyl] -4-inole) ethyl] -1,3-thiazonole-2-yl} _4_thiomorpholinecarboximimidamide 1,1 -Dioxide

Under ice cooling, TFA (100 ml) was added to the compound (4.35 g) obtained in Example 9, and the mixture was returned to room temperature and stirred for 1 hour. After concentration under reduced pressure, the residue was neutralized by adding chloroform and saturated aqueous sodium bicarbonate, separated, washed with water and concentrated under reduced pressure. The residue was recrystallized (ethyl acetate / hexane) to obtain the desired product (2.77 g).

_{W - NMR (300MHz, CDC1 3} ) δ ppm: 1.64 (d, 3H, J = 7.2Hz), 3.07 - 3.11 (m, 4H),

3.98-4.01 (m, 4H), 4.12 (q, 1H, J = 7.2Hz), 6.40 (d, 1H, J = 0.9Hz), 7.03- 7.ll (ra, 2H), 7.32-7.46 (m, 4H), 7.52-7.61 (m, 2H)

IR (KBr) [cm " ¹ ]: 3416, 3168, 2972, 1627, 1527, 1461, 1415, 1372, 1294, 1264, 1222, 1123

Elemental analysis (° /.): Calculated: C, 57.62; H, 5.06; N, 12.22, Found: C, 57.20; H,

4.99; N, 12.19 Example 1 1

N, - {5- [1- ( 2 - Furuoro [1, 1, - Bifue two Norre] - 4-I le) Echiru] one 1,3 Chiazoru 2 - I le} - ₄ - morpholine carboxyanhydride Consequences Mi Doami Do hydrochloride

Using the compound obtained in Reference Example 20, the same procedure as in Example 1 was performed to obtain the desired product.

Melting point: 186-1188 ° C

^{X H-NMR (300MHz, CDC1} 3) δ ppm: 1.65 (d, 3H, J = 7.0Hz), 3.72 - 3.88 (m, 8H), 4.20 (br-q, 1H, J = 7.0Hz), 6.94- 7.06 (m, 3H), 7.33-7.52 (ra, 6H)

Elemental analysis (° /.): Calculated: C, 59.12; H, 5.41; N, 12.53; CI, 7.93, Found: C, 58.99; H, 5.46; N, 12.50; CI, 8.09

IR (KBr) [cm " ¹ ]: 3100, 2924, 1657, 1623, 1560, 1484, 1120, 699 Example 12

N- {5_ [1- (3_Benzoylphenyl) ethyl] _1,3-thiazole-2-yl} -4-morpholinecarboxymidamide phosphate

To a solution of the compound (4. Og) obtained in Reference Example 21 and N-cyanomorpholine (1.45 g) in THF (20 ml) was added 55% sodium hydride (506 mg) under ice-cooling, followed by stirring for 1 hour. Later, this reaction solution Neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, concentrated under reduced pressure, and the residue was purified by a silica gel column to obtain the desired product (1.91 g). This morpholino form: N- {5- [1_ ( ³ -benzoylpheninole) ethyl] -1,3-thiazole-2-yl 4-morpholinecarboximimidamide (1.30 g) in ethanol (1.30 g) The solution (10 ml) was added dropwise to a solution of 85% phosphoric acid (33 g) in ethanol (5.0 ml), concentrated under reduced pressure, and recrystallized (ethanol) to obtain the desired phosphate (1.42 g).

¾-NMR (300MHz, d ₆ -DMS0) δ ppm: 1.58 (d, 3H, J = 7.1 Hz), 3.40-3.44 (m, 4H), 3.57-3.60 ( m, 4H), 4.32 (q, 1H, J = 7.1 Hz), 6.98 (s, 1H), 7.47-7.73 (ra, 9H)

Ν'— {4- [1- (2-Fluoro [1,1, —bipheninole] -1-yl) ethyl] _1,3-thiazol-2-inole} -Ν, Ν-dimethyl-4 -Morpholinecarboximidamide hydrochloride

HCI

A known compound of the formula: 1-chloro-3- (2-fluoro [1,1'-biphenyl] -4-yl) -2-butanone (1.0 g) (Japanese Unexamined Patent Publication No. 152368) was dissolved in acetone (20ral), the compound obtained in Reference Example 24 (1.17 g) was added at room temperature, and the mixture was stirred overnight. After concentrating the reaction solution, the residue was neutralized with 1N-aqueous sodium hydroxide solution and neutralized with ethyl acetate. The organic layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to obtain the desired product (1.7 g). This was dissolved in dioxane (20 ml), and a 4N hydrogen chloride-dioxane solution was added dropwise. Getyl ether was added to the reaction solution, and the resulting crystals were collected by filtration and dried to obtain the desired product (1.6 g).

_{- NMR (300MHz, CDC1 3)} δ ppm: 1. 73 (. D, 3H, J = 7 2Hz), 3. 04 (s, 6H), 3. 39- 3. 46 (m, 4H), 3. 64-3.72 (m, 4H), 4.39 (q, 1H, J = 7.2Hz), 6.71 (s, 1H), 7.13-7.26 (ra, 2H), 7. 34—7.55 (m, 2H) Example 1 4 N,-{4- [1- (2-Fluoro [1, -biphenyl] -4-inole) ethyl]-1,3-thiazol-2-yl} -methyl-4-morpholinecarboximidamide Its hydrochloride

Black-mouthed body which is a known compound: 1-black-3- (2-fluoro [1,1, -biphenyl] -4-yl) -2-butanone (l.Og) 152368) was dissolved in ethanol (10 ml), an aqueous solution of the compound obtained in Reference Example 26 was added, and the mixture was heated and stirred at 90 ° C. Two hours later, the mixture was cooled to room temperature, and the reaction solution was neutralized with a 1N aqueous sodium hydroxide solution. Extracted with black-mouthed form, dried and concentrated. The residue was purified by column chromatography to obtain the desired product (1.35 g).

_{XH-NMR (300MHz, CDC1 3} ) δ ppm: 1.65 (d, 3H, J = 7.2Hz), 2.84 (d, 3H,

J = 5.1Hz), 3.28-3.33 (ra, 4H), 3.71-3.76 (m, 4H), 4.ll (brq, 1H, J = 7.2Hz), 6.37 (d, 1H, J = 0.9Hz), 7.05-7.14 (m, 2H), 7.32-7.55 (m, 6H), 9.25 (m, 1H) The obtained target product was dissolved in ethyl ether (30 ml), and a 4N hydrogen chloride dioxane solution was added dropwise at room temperature. The reaction solution was filtered and the crystals were dried under reduced pressure to obtain the desired hydrochloride (1.3 g). Example 15

N, _ {4- [1- (3-Benzoylpheninole) ethyl] -thiazonole-2-yl} -N, N-dimethyl-

4-morpholinecarboximidamide hydrochloride

Example 13 Using the compound obtained in Reference Example 24 and 3- (3-benzoylphenyl) -1-cyclo-2-butanone (JP-A 63-152368) The desired product was obtained by the same operation.

_{¾-NMR (300MHz, CDC1 3} ) δ ppm: 1.69 (d, 3H, J = 7.2Hz), 2.96 (s, 6H), 3.28- 3.40 (m, 4H), 3.65- 3.71 (m, 4H), 4.32 (q, 1H, J = 7.2Hz), 6.54 (s, 1H), 7.40- 7.64 (m, 6H), 7.76-7.82 (m, 2H) Example 16

N '-{4- [1- (3-Benzoylphen-nore) ethyl] -thiazole-2-inole) -N-methyl-4-morpholinecarboximimidamide and its hydrochloride

Example of the use of a compound of the known formula: 3- (3-benzoylphenyl) -1-chloro-2-butanone (JP-A-63-152368) and an aqueous solution of the compound obtained in Reference Example 26 The desired product was obtained in the same manner as in 14.

One _{NMR (300MHz, CDC1 3) 6} ppm: 1.65 (d, 3H, J = 7.2Hz), 2.80 (d, 3H,

J = 5.1Hz), 3.27-3.32 (m, 4H), 3.71-3.76 (m, 4H), 4.15 (brq, 1H, J = 7.2Hz), 6.33 (d, 1H, J = 0.9Hz), 7.36- 7.64 (m, 6H), 7.76-7.81 (m, 2H), 9.22 (m, 1H) The obtained target compound was converted into a hydrochloride salt in the same manner as in Example 14.

Example 17

N- [di (4-morpholinyl) methylene] -N- {4- [1- (2-fluoro [1, -biphenyl] -4-yl) ethyl] -1,3-thiazole-2-y Lumin

The compound (1.30 g) obtained in Reference Example 28, diglyme (12 ml), and morpholine (1.1 ml) were taken, and heated and stirred at 100 ° C. After 4 hours, the reaction solution was distilled off and purified by column chromatography to obtain the desired product (1.05 g).

-删_{R (300MHz, CDC1 3) 0ppm} : 1.65 (d, 3H, J = 7.1Hz), 3.13- 3.28 (m, 8H), 3.56-3.64 (ra, 8H), 4.14 (q, 1H, J = 7.1 Hz), 6.43 (d, 1H, J = 0.9Hz), 7.03-7.16 (m, 2H), 7.30-7.45 (ra, 4H), 7.47-7.55 (m, 2H)

N- {4- [1- (2-Fluoro [1,1, -biphenyl] -4-inole) ethyl] -1,3-thiazol-2-yl} -N-[(E)-(4- Methyl-1-pidazul) (4-morpholinyl) methylidene] amine

Using the compound (1.32 g) obtained in Reference Example 28 and N-methylpiperazine (0.60 g), the desired product (0.63 g) was obtained in the same manner as in Example 17.

-Employment R (300MHz, CDCI3) δ ρηι: 1.65 (d, 3H, J = 7.0Hz), 2.26 (s, 3H), 2.33- 2.38 (m, 4H), 3.13-3.18 (m, 4H), 3.20- 3.27 (m, 4H), 3.57-3.65 (ra, 4H), 4.13 (q, 1H, J = 7.0Hz), 6.39 (d, 1H, J = 0.9Hz), 7.03-7.16 (m, 2H), 7.30 -7.45 (m, 4H), 7.47-7.55 (m, 2H) Example 1 9

N,-{4- [1— (2-Fluoro [1,1 ,,-bipheninole] —4-inole) ethyl] -1,3-thiazole-2-y Nore}-N- [2- (4-morpholinyl) ethyl] -4-morpholinecarboximidamide

Using the compound (1.32 g) obtained in Reference Example 28 and N- (2-aminoethyl) morpholine (1.56 g), the desired product (0.81 g) was obtained in the same manner as in Example 17.

^{L H-NMR (300MHz, CDC1} 3) δ ppm: 1.66 (d, 3H, J = 7.1Hz), 2.23-2.36 (m, 6H), 3.21- 3.35 (m, 6H), 3.53- 3.59 (m, 4H ), 3.70- 3.75 (m, 4H), 4.12 (q, 1H,

J = 7.1Hz), 6.40 (s, 1H), 7.04- 7.13 (m, 2H), 7.31-7.45 (ra, 4H), 7.47-7.55 (m, 2H), 8.98 (br, 1H)

N '— {4- [1- (2_Fluoro [1,1'-bipheninole] -4-yl) ethyl] -1,3-oxazole-2-yl 4-morpholinecarboximimidamide

To a suspension of 60% sodium hydride (0.28 g) in THF (10 ml) was added a solution of the compound (l.Og) obtained in Reference Example 29 in THF (20 ml). One hour later, N-cyanomorpholine (0.53 ml) was added, and the mixture was stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified with silica gel gel (ethyl acetate / hexane = 1/1). (0.3 g) was obtained.

Melting point: 152-153 ° C (decomposition)

_{W-NMR (300MHz, CDC1 3} ) δ ppm: 1.57 (d, 3H, J = 7.2Hz), 3.47-3.54 (ra, 4H), 3.71-3.76 (ra, 4H), 3.95 (br-q, 1H, J = 7.2Hz), 6.98 (d, 1H, J = l.1Hz), 7.04- 7.15 (m, 2H), 7.32-7.57 (m , 6H)

IR (KBr) [cm " ¹ ]: 3382, 1627, .1530, 1451, 1108, 695

Elemental analysis (%): Calculated: C, 66.99; H, 5.88; N, 14.20, Found: C, 66.80; H, 5.86; N, 14.16 Example 21

N,-{4- [1- (3-Benzoylfur) ethyl 3-oxazole-2-yl}-4-morpholinecanolepoximidamide

Using the compound obtained in Reference Example 30, the same procedure as in Example 20 was performed to obtain the desired product. _{XH-NMR (300MHz, CDC1 3} ) δ ppm: 1.57 (d, 3H, J = 7.2Hz), 3.47-3.53 (m, 4H),

3.71-3.76 (m, 4H), 3.99 (br-q, 1H, J = 7.2Hz), 6.93 (d, 1H, J = l.1Hz), 7.36-

7.65 (m, 6H), 7.77-7.82 (m, 3H) Example 22

N '-{4_ [1- (4-Benzoylphenyl) ethyl]-1,3-oxazole-2-yl}-4-morphophosphoric / repoxyimidamide

Using the compound obtained in Reference Example 36, the desired product was obtained in the same manner as in Example 20. XH-NMR (300MHz, CDCL) δ ppm: 1.58 (d, 3H, J = 7.2Hz), 3.47-3.53 (m, 4H), 3.70-3.76 (m, 4H), 4.01 (brq, 1H, J = 7.2Hz), 6.97 (d, 1H, J = l.1Hz), 7.36- 7.41 (m, 2H), 7.44-7.51 (ra, 2H ), 7.58 (m, 1H), 7.73-7.82 (ra, 4H)

Example 23

[3- (1- {2-((5-Hydroxytetrahydro-2 (1H) -pyrimidinylidene) amino]-1,3-oxazosole 4-ethyl} feninole] (feninole) ketone

The target compound was obtained from the compound obtained in Reference Example 37 and 1,3-diamino-2-propanol in the same manner as in Example 60 described later.

_{- MR (400MHz, CDC1 3)} δ ppm: 1.56 (d, 3H, J = 7.2Hz), 3.35-3.53 (m, 4H), 3.96 (brq, 1H, J = 7.2Hz), 4.20 (m, 1H) , 6.84 (d, 1H, J = l.1Hz), 7.37- 7.52 (m, 4H), 7.56-7.65 (m, 2H), 7.76-7.83 (m, 3H) Example 24

(3- {1- [2- (2-imidazolidinylidenamino) -1, 3-oxoxazole-4-inole] ethyl} Fehenole) (Feninole) ketone

From the compound obtained in Reference Example 37 and ethylenediamine, the same procedures as in Example 60 were carried out to obtain the desired product.

_{^ - MR (400MHz, CDC1 3} ) 6 ppm: 1.57 (d, 3H, J = 7.2Hz), 3.50- 3.80 (m, 4H), 3.98 (brq, 1H, J = 7.2Hz), 6.92 (d, 1H, J = l.1Hz), 7.38- 7.53 (m, 4H), 7.56- 7.67 (m, 2H), 7.76- 7.83 (m, 3H ) Example 25

Ν '-{4- [1- [3-Benzylpheninole) ethyl] -1,3-oxazole-2-yl} -Ν-methyl-4-morpholinecarboximimidamide

The compound (2. Og) obtained in Reference Example 38 was dissolved in THF (20ral), a 40% aqueous solution of methylamine (10 ml) was added, and the mixture was heated and stirred at 65 ° C. Two hours later, extraction was performed with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain the desired product (1.8 g).

_{^ -NMR (400MHz, CDC1 3)} δ ppra: 1.59 (d, 3H, J = 7.2Hz), 2.90 (d, 3H,

J = 5.1Hz), 3.28-3.35 (m, 4H), 3.72-3.79 (m, 4H), 4.00 (brq, 1H, J = 7.2Hz), 6.96 (d, 1H, J = l.1Hz), 7.37 -7.54 (m, 4H), 7.56- 7.66 (m, 2H), 7.77-7.83 (ra, 3H) Example 26

N, 2 {4- [1- (3-Benzoylphenole) ethyl] -1,3-oxazole-2-yl} -N- (2-hydroxyxethyl) -4-morpholinecarboximidamide

From the compound obtained in Reference Example 38 and 2-aminoethanol, the same operation as in Example 25: and the desired product was obtained. ^{X H-NMR (400MHz, CDC1} 3) δ ppm: 1.60 (d, 3H, J = 7.2Hz), 3.19-3.30 (ra, 2H), 3.38-3.45 (m, 4H), 3.49-3.63 (m, 2H ), 3.69- 3.76 (m, 4H), 4.00 (brq, IH, J = 7.2Hz), 7.01 (d, IH, J = l.1Hz), 7.14 (t, IH, J = 5.0Hz), 7.38- 7.53 (m, 4H), 7.56-7.63 (m, 2H), 7.76- 7.84 (m, 3H) Example 27

N '_ {4- [1- (3_Benzoylphenyl) ethyl] -1,3-oxazole-2-yl} -N- [2- (Dimethylamino) ethyl] -4-morpholinecarboximidamide Do

The target compound was obtained from the compound obtained in Reference Example 38 and 2-dimethylaminoethylamine by the same operation as in Example 25.

! H-NMR (400MHz, CDC1 3) δ ppm: 1.60 (d, 3H, J = 7.2Hz), 2.16 (s, 6H), 2.35 (t, 2H, J = 6.3Hz), 3.26 (q, 2H, J = 6.3Hz), 3.28-3.35 (m, 4H), 3.70-3.77 (m, 4H), 4.00 (brq, IH, J = 7.2Hz), 6.94 (d, IH, J = l.1Hz), 7.37 -7.65 (m, 6H), 7.75-7.82 (m, 3H), 9.01 (t, IH, J = 6.3Hz) Example 28

N '-[4- [1- (2-Fluoro_1_1,1'-biphenyl-4-yl) ethyl] -1-(phenylsulfo

-Le)-1H-imidazole-2-yl]-4-morpholinecarboximidamide

The desired product was obtained from the compound obtained in Reference Example 42 and aqueous ammonia by the same operation as in Example 25.

-賺_{^{(400MHz, CDC1 3) 5 PP}} m: 1-57 (d, 3H, J = 7.1Hz), 3.37 - 3.44 (m, 4H), 3.63-3.70 (ra, 4H), 3.92 (1H, brq, J = 7.1Hz), 6.93 (d, 1H, J = 1.0Hz), 6.95-7.15 (m, 4H), 7.30-7.63 (ra, 9H), 7.91-7.97 (m, 2H)

N,-{4- [1- (2-Fluoro-1,1, -bipheninole-4-yl) ethyl] -1H-imidazole-2-yl 4-morpholinecarboximidamide

The compound (1.56 g) obtained in Example 28, THF (30ral), methanol (20 ml), and a 2N aqueous sodium hydroxide solution (10 ml) were mixed, and the reaction solution was refluxed. After 8 hours, the solvent was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, and purified by a silica gel column (cloth form / methanol = 20/1 to 1 OZ1) to obtain the desired product (1.07 g).

_{^ -NMR (400MHz, CDC1 3)} δ pptn: 1.59 (d, 3H, J = 7.1Hz), 3.38-3.44 (m, 4H), 3.68 - 3.75 (m, 4H), 4.02 (1H, brq, J = 7.1Hz), 6.47 (brs, 1H), 7.08-7.02 (m, 2H), 7.19 (br, 2H), 7.30-7.55 (m, 6H) Example 30

N '-[4- [1- (3-Benzoylphenyl) ethyl] -1- (phenylsulfonyl) -1H-imidazone-2-enole-N, N-dimethyl-4-morpholinecarboximidamide Do

The compound obtained in Reference Example 44 (2. 0 g) Toryechiruamin of (2 mL) _/ / dichloromethane (20 mL) was added Shioi匕phosgene Lee Mini © beam (l. Og) mixture was stirred for 1 hour. Morpholine (0.8 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. Further, morpholine (0.8 mL) was added, and the mixture was stirred for 30 minutes. A saturated saline solution (100 mL) was added to the reaction mixture, and the mixture was extracted with a porcine (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, the solvent was removed under reduced pressure, and the residue was purified with silica gel column (chloroform / methanol = 99: 1 to 96: 4) to obtain the desired product (2. lg). Obtained.

_{¾-NMR (300MHz, CDC1 3} ) δ ppm:. 1. 58 (. D, 3 H, J = 7 1Hz), 2. 63 (s, 6 H), 2. 98-3 10 (m, 4 H ), 3.54—3.58 (ra, 4H), 3.97 (q, 1H, J = 7.1 Hz), 6.88 (d, 1H, J = l.2 Hz), 7.36-7.52 (m, 6H), 7.55-7.63 (m, 3H), 7.74—7.82 (m, 3H), 7.98-8.03 ( m, 2 H) Example 3 1

N '-{4- [1- (3-benzoylphen-noreth) ethyl] -1H-imidazole-2-inolate N, N-dimethyl-4-morpholinecarboximimidamide hydrochloride

HCI A 4M aqueous solution of sodium hydroxide (15 mL) was added to a solution of the compound (1.49 g) obtained in Example 30 in methanol (20 mL) / THF (20 mL), and the mixture was stirred at room temperature for 30 minutes and at 60 ° C for 2 hours. After cooling, a saturated aqueous solution of ammonium chloride (100 mL) was added, and methanol and THF were removed under reduced pressure. The aqueous residue was extracted three times with Kuguchiguchi form (50 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered and concentrated under reduced pressure. The residue was purified by a silica gel column (cloth form / methanol = 10: 1 to 4: 1) to obtain a crude product (0.96 g). The crude product (0.96 g) obtained in the same manner as above was combined, and the desired free form (1.92 g) was treated with a 10% solution of hydrochloric acid in Z methanol to obtain the desired product (2.2 _g ).

_{Ή-NMR (300MHz, CDC1 3} ) 8 ppm: 1.70 (d, 3 H, J = 7.1 Hz), 3.04 (s, 6 H), 3.44 (br, 4 H), 3.64 (br, 4 H), 4.25 (q, 1 H, J = 7.1 Hz), 6.59 (s, 1 H), 7.42-7.52 (m, 3 H), 7.57-7.65 (m, 3 H), 7.69-7.71 (m, 1 H), 7.77-7.81 (m, 2 H) Example 32

N ''-[4--(3_Benzylphenyl) ethynole]-1- (phenylsulfonyl) -1H-imidazone- 2-yl] _N, N-dimethyl-N,-[2--( 4-morpholininole) ethyl] guazine

The target product (0.53 g) was obtained from the compound (0.5 g) obtained in Reference Example 44 and 2- (4-morpholinyl) ethylamine by the same operation as in Example 30.

E - employment _{R (300MHz, CDC1 3) 6} ppm: 1.58 (d, 3H, J = 7.1Hz), 2.21-

2.32 (m, 2H + 4H), 2.83 (s, 6H), 3.09-3.16 (m, 2H), 3.52-3.57 (m, 4H),

3.97 (q, 1H, J = 7.lHz), 6.89 (d, 1H, J = l.1Hz), 7.35-7.41 (m, 1H), 7.43-7.51 (m, 5H) _: 7.54-7.64 (m, 3H), 7.74-7.81 (m, 3H), 7.98-8.02 (m, 2H), 8.44 (t, 1H, J = 4.6Hz)

N, '-[4- [1- (3-Benzylphenyl) ethyl] -1H-imidazole-2-yl] -N, N-dimethyl-N'-[2- (4-morpholinyl) ethyl ] Guanidine

A solution of the compound obtained in Example 32 (0.53 _g ) in 4 M aqueous sodium hydroxide (lmL) / methanol (20 mL) was stirred at 60 ° C for 3.5 hours. After allowing to cool, methanol was removed under reduced pressure, and a saturated saline solution (50 raL) was added to the aqueous residue, and the mixture was extracted with a porcine (3X20 mL). The organic layers are combined, dried over sodium sulfate, filtered, the solvent is distilled off, and the residue is purified by a silica gel column (form: mouth / methanol / triethylamine = 98: 2: 1 to 95: 5: 1). (0.32 g).

_{W - NMR (300MHz, CDC1 3} ) δ ppm: 1.59 (d, 3H, J = 7.1Hz), 2.35- 2.45 (m, 4H + 2H), 2.84 (s, 6H), 3.22-3.27 (m, 2H) , 3.59—3.63 (m, 4H), 4.06 (q, IH, J = 7.1Hz), 6.36 (s, 1H), 7.32-7.38 (m, IH), 7.42-7.50 (m, 3H), 7.53-7.61 (ra, 2H), 7.72- 7.81 (m, 3H), 9.09 (br, IH) Example 34

N ',-[4- [l- (3-Benzoylphenyl) ethyl]-1- (phenylsulfonyl) -IH-imidazonol-2-yl] -N,-(2-methoxyl) -N , N-dimethyldanidine

The target product (3.42 g) was obtained from the compound (3.0 g) obtained in Reference Example 44 and 2-methoxyethanolanol in the same manner as in Example 30.

_{^ -NR (300MHz, CDC1 3)} δ ppm: 1.58 (d, 3H, J = 7.1Hz), 2.83 (s, 6H), 3.19 (s, 3H), 3.20-3.25 (m, 2H), 3.26-3.32 (ra, 2H), 3.96 (q, 1H, J = 7.1Hz), 6.86 (d, IH, J = l.1Hz), 7.36-7.42 (m, IH), 7.44-7.64 (ra, 8H), 7.74 -7.81 (m, 3H), 7.97- 8.01 (m, 2H), 8.81 (t, IH, J = 4.6Hz) Example 35

N ,,-{4- [1- (3-Benzoylphenyl) ethyl] -IH-imidazole-2-yl}-N'-one (2-meth

I-N, N-dimethyldanidine hydrochloride

From the compound (3.42 g) obtained in HCI Example 34, the desired product (2.34 g) was obtained in the same manner as in Example 31.

_{W-NMR (300MHz, CDC1 3} ) 6 ppm: 1.72 (d, 3H, J = 6.2Hz), 3.18 (s, 6H), 3.46 (s,

3H), 3.56 (br, 4H), 4.30 (br, IH), 6.70 (br, 1H), 7.41-7.65 (ra, 6H), 7.72 (br, 1H), 7.76— 7.81 (ra, 2H), 8.73 (br, IH) Example 36

N, _ [4- [1- (3-Benzoylphenyl) ethyl] -1_ (phenylsulfonyl) -IH-imidazole-2-yl] -N, N-dimethyl-1-pyrrolidinecarboxy Midamide

The target product (3.43 g) was obtained from the compound (3.0 _g ) obtained in Reference Example 44 and pyrrolidine in the same manner as in Example 30.

^{: H-NMR (300MHz, CDC1} 3) δ ppm: 1.55 (d, 3H, J = 7.1Hz), 1.73 - 1.75 (m, 4H), 2.53 (s, 6H), 3.13 - 3.19 (ra, 4H), 3.95 (q, IH, J = 7.1Hz), 6.82 (d, IH, J = 1.3Hz): 7.35-7.41 (m, IH), 7.42-7.51 (ra, 5H), 7.53-7.64 (ra, 3H) , 7.71-7.74 (m, IH), 7.76-7.81 (m, 2H), 7.98- 8.02 (m, 2H) Example 37

N,-{4- [1- (3-Benzoylpheninole) ethyl] -IH-imidazole-2_ylt N, N-dimethyl-1-pyrrolidinecarboximidamide

The target product (2.44 g) was obtained from the compound (3.43 g) obtained in Example 36 by the same operation as in Example 33.

Over Keio _{R (300MHz, CDC1 3) δ} ppm: 1.58 (d, 3H, J = 7.1Hz), 1.78 (br, 4H), 2.61 (s, 6H), 3.29 (br, 4H), 4.08 (q, 1H , J = 7.1Hz), 6.37 (br, IH), 7.34-7.40 (m, IH), 7.43-7.61 (m, 5H), 7.72-7.7 (m, IH), 7.76-7.80 (m, 2H) Example 38

N ,,-[4- [1- (3-Benzylphenyl) ethyl] -1_ (phenylsulfonyl) -1H-imidazole-2-yl] -N'-cyclopropyl N, N-dimethyl Danidine

The target product (3.05 g) was obtained from the compound (3.0 g) obtained in Reference Example 44 and cyclopropylamine in the same manner as in Example 30.

-NMR (300MHz, CDCL) δ ppm: 0.31-0.37 (m, 2 H), 0.55-0.62 (m, 2 H), 1.56 (d, 3 H, J = 7.1Hz), 2.43-2.51 (m, 1H), 2.97 (s, 6H), 3.94 (q, 1H,

J = 7.1Hz), 6.86 (d, 1H, J = l.1Hz), 7.36-7.42 (m, 1H), 7.44- 7.50 (m, 5H), 7.54-7.65 (m, 3H), 7.71-7.73 ( m, 1H), 7.77-7.82 (m, 2H), 7.96-8.00 (m, 2H), 9.18 (br, 1H) Example 39

N ,,-{4- [1- (3-Benzoylphenyl) ethyl] -1H-imidazole-2-yl} -N, -cyclopropyl-N, N-dimethyldananidin hydrochloride

HCI The desired product (2.21 g) was obtained from the compound (3.05 g) obtained in Example 38 by the same operation as in Example 31.

_{- NMR (300MHz, CDC1 3)} δ ppm: 0.61 (br, 2H), 0.86 (br, 2H), 1.71 (d, 3H, J = 7.1 Hz), 2.28 (br, 1H), 3.28 (s, 6H) , 4.31 (q, 1H, J = 7.1Hz), 6.68 (br, 1H), 7.39-7.63 (m, 6H), 7.70 (br, 1H), 7.75-7.79 (m, 2H), 8.98 (br, 1H ) Example 40

N,-[4- [1- (Benzylphenyl) ethyl] -1- (phenylsulfonyl) -1H-imidazoyl-2-yl] -N, N, 4-trimethyl-1-pi Lazine Power Roximide Domide

From the compound (2.60 _g ) obtained in Reference Example 44 and 1-methylbiperazine, the desired product (3.13 g) was obtained in the same manner as in Example 30.

_{¾-NMR (300MHz, CDC1 3} ) 6 ppm: 0.31-0.37 (m, 2 H), 0.55- 0.62 (m, 2 H), 1.56 (. D, 3 H, J = 7 IHz), 2.43-2.51 ( m, 1H), 2.97 (s, 6H), 3.94 (q, 1H, J = 7.IHz), 6.86 (d, 1H, J = l.1Hz), 7.36-7.42 (m, 1H), 7.44-7.50 (m, 5H), 7.54-7.65 (ra, 3H), 7.71-7.73 (m, 1H), 7.77-7.82 (m, 2H), 7.96-8.00 (m, 2H), 9.18 (br, 1H) 41

Ν '-{4- [1- (Benzoylphenyl) ethyl] -1H-imidazole-2-yl N, N, 4-trimethyl-1-piperazinecarboximidamide

From the compound (3.13 g) obtained in Example 40, the desired product (2.30 g) was obtained in the same manner as in Example 33.

-丽_{R (300MHz, CDC1 3) δ} ppm: 1.59 (d, 3H, J = 7.1Hz), 2.26 (s, 3H), 2.36 (br, 4H), 2.67 (s, 6H), 3.19 (br, 4H ), 4.09 (q, 1H, J = 7.1Hz), 6.38 (d, 1H), 7.35-7.40 (m, 1H), 7.43- 7.62 (m, 5H), 7.73 (br, 1H), 7.76-7.81 ( m, 2H) Example 42

Phenyl (3- {1- [1- (phenylsulfonyl) -2- (tetrahydro-2 (1H) -pyrimidiyuridenamino) -1H-imidazole-4-yl] ethyl} ketone

From the compound (3. Og) obtained in Reference Example 45 and 1,3-diaminopropane, the desired product (1.90 g) was obtained in the same manner as in Example 60.

Ichi匪_{R (300MHz, CDC1 3) δ} ppm: 1.54 (d, 3H, J = 7.1Hz), 1.81-1.89 (m, 2H), 3.26-3.31 (m, 4H), 3.91 (q, 1H, J = 7.1Hz), 6.73 (d, 1H, J = l.1Hz), 7.35

7.40 (ra, 1H), 7.43- 7.49 (m, 5H), 7.53-7.63 (m, 3H), 7.75-7.81 (m, 3H), 8.01-

8.05 (m, 2H) Example 43

Phenyl (3- {tri [2- (tetradro-2 (1H) -pyrimidiylideneamino) -1H-imidazole-4-yl] ethyl] phenyl) ketone hydrochloride

From the compound (1.89 g) obtained in HCI Example 42, the desired product (1.lg) was obtained in the same manner as in Example 31.

_{- NMR (300MHz, CDC1 3)} δ ppm: 1.68 (d, 3H, J = 7.1Hz), 2.02 - 2.06 (m, 2H), 3.51 (br, 4H), 4.31 (q, 1H, J = 7.1Hz) , 6.7l (br, 1H), 7.44-7.56 (m, 4H), 7.59-7.67 (m, 2H), 7.72-7.74 (m, 1H), 7.77-7.81 (m, 2H), 9.46 (br, 2H ) Example 44

(3-{1- [2-[(1,3-dimethyltetrahydro-2 (1H) -pyrimidiylidene) amino]-1- ( Heninoresonorehoninore) 1H-i midazonole-4 -inore] echinore

The target product (2.72 g) was obtained from the compound (3.0 g) obtained in Reference Example 45 and N, N ⁵ -dimethyl-1,3-diaminopropane in the same manner as in Example 60 described later.

_{- NMR (300MHz, CDC1 3)} δ ppm: 1.54 (d, 3H, J = 7.1Hz), 1.90-1.97 (m, 2H), 2.61 (s, 6H), 3.12-3.25 (m, 4H), 3.97 ( q, 1H, J = 7.1Hz), 6.76 (br, 1H), 7.35- 7.41 (m, 1H), 7.43-7.51 (m, 5H), 7.54-7.64 (ra, 3H), 7.70- 7.72 (m, 1H), 7.76- 7.82 (ra, 2H), 7.96- 8.00 (m, 2H) Example 45

[3- (1- {2 _ [(1,3-Dimethyltetrahydro-2 (1H) -pyrimidiylidene) amino] -1H-imidazole-4-yl} ethyl) phenyl] (phenyl) ketone hydrochloride

From the compound (2.71 g) obtained in HCI Example 4, the desired product (1.39 g) was obtained in the same manner as in Example 31.

_{- NMR (300MHz, CDC1 3)} δ ppm: 1.72 (d, 3H, J = 6.8Hz), 2.31 (br, 2H),

3.22 (br, 6H), 3.68 (br, 4H), 4.31 (q, 1H, J = 6.8Hz), 6.59 (br, 1H), 7.43- 7.72 (m, 7H), 7.78—7.82 (m, 2H) Example 4 6

(3- {1- [2-[(1,3-Dimethyl-2-imidazolidinylidene) amino] -1- (phenylsulfonyl) -1H-imidazole-4-yl] ethyl} phenyl) ( Feninole) ketone

To a solution of the compound (2.5 g) obtained in Reference Example 44 in triethylamine (5 mL) / dichloromethane (25 mL) was added 1,2-dimethylimidazolium chloride (2.5 g), and the mixture was stirred for 3 hours. Further, to the reaction mixture was added 2-chloride-1,3-dimethylimidazolinium chloride (1.0 g), and the mixture was stirred for 2 hours. Triethylamine (1.5 mL) was further added, and the mixture was stirred for 2 hours. A saturated saline solution (100 mL) and a saturated aqueous solution of ammonium chloride (50 raL) were added to the reaction mixture, and the mixture was extracted with chloroform (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, the solvent was removed under reduced pressure, and the residue was purified with a silica gel column (ethyl acetate-chloroform / methanol: = 98: 2) to obtain the desired product (2.20 g). Was.

_{- NMR (300MHz, CDC1 3)} δ ppra: 1. 55 (. D, 3H, J = 7 OHz), 2. 53 (s, 6H), 3. 28-

3.36 (m, 4H), 3.98 (q, 1H, J = 7.OHz), 6.87 (d, 1H, J = l.1Hz), 7.34-7.40 (m, 1H ), 7.44-7.52 (ra, 5H), 7.54-7.63 (m, 3H), 7.68-7.71 (m, 1H), 7.76-7.81 (m , 2H), 7.97-8.03 (m, 2H) Example 4 7

[3- (1-{2-[(1,3-Dimethyl-2-imidazolidinylidene) amino]]-1H-imidazole-4-inole} ethyl) phenyl] (phenyl) ketone hydrochloride

From the compound (2.20 g) obtained in Example 46, the desired product (1.20 g) was obtained in the same manner as in Example 31.

¾ -删_{R (300MHz, CDC1 3) δ} ppm: 1.73 (d, 3H, J = 7.1Hz), 3.03 (s, 6H),

3.96 (br, 4H), 4.31 (q, 1H, J = 7.1Hz), 6.66 (s, 1H), 7.43—7.54 (m, 3H), 7.56-7.71 (m, 4H), 7.77-7.82 (m, 2H) Example 48

The compound (200 mg) obtained in Reference Example 46 was dissolved in dioxane (2 mL), 1,3-diamino-2-propanol was added, and the mixture was refluxed with heating for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was dried over magnesium sulfate, it was concentrated with an evaporator to obtain a crude product (24 g). High performance liquid chromatography (column: YMC CombiPrep 0DS-A 75χ φ30 mm, solvent: 0.05% trifluoroacetic acid / water: 0.035% trifluoroacetic acid / acetonitrile == 95: 5 to 5:95 ) To give the desired product as an oil (43 _mg ).

HPLC r.t. 15.25 min (column: Waters Puresil C18, eluent: lOmM ammonium acetate aqueous solution (pH 4): acetonitrile = 80: 20 → 20: 80 (30rain))

LC / MS (m / e) 407.3 Example 49 to Example 59

In addition to the above examples, the compounds shown in Tables 1 and 2 described below were synthesized by the same operation as in Examples 25, 29 and Z or Example 48. Each compound was isolated as trifluoroacetate, and the retention time of high performance liquid chromatography (column: Waters Puresil C18, eluent: lOmM ammonium acetate aqueous solution: acetate nitrile = 80: 20 → 20: 80 (30min)) and LC / MS Identified by vector.

Table 2

Example 60

{3- [2-([{((2E) -1_ (2-hydroxyethyl)] tetrahydro-2 (1Η) -pyrimidiylidene] amino} -1,3-oxazole-4-yl) ethyl] phenyl Le} (Hue:

The compound (1.45 g) obtained in Reference Example 37 was dissolved in ethanol (30 ml), 2- (3-aminopropylamino) ethanol (0.56 ml) was added, and the reaction solution was refluxed. After 4 hours, the ethanol was concentrated and extracted with black-mouthed form. The organic layer was dried and concentrated, and the residue was purified using a silica gel column (ethyl acetate / hexane = 1/1 to chloroform / methanol = 20/1) to obtain the desired product (1.02 g). .

_{^ -NMR (400MHz, CDC1 3)} 8 ppm: 1.63 (d, 3H, J = 7.2Hz), 2.57 (brs, 6H), 4.10 (brq, 1H, J = 7.2Hz), 7.ll (d, 1H, J = l.1Hz), 7.39- 7.50 (m, 4H), 7.55- 7.67 (m, 2H), 7.77-7.83 (m , 3H) Reference Example 1

2- (2-Fluoro [1,1, -biphen-nore] -4-yl) -2-methylpropanoic acid

To a suspension of 60% -hydrogenated sodium (11.3 g) in DMF (300ral), a solution of flunorebiprofen (30 g) in DMF (300 ml) was added dropwise at 0 ° C. over 30 minutes. After returning to room temperature and stirring for 1 hour, methyl iodide (18.4 ml) was added, and the mixture was stirred overnight. The reaction solution was poured into ice, extracted with ethyl acetate, the organic layer was washed with water, dried, concentrated under reduced pressure, the residue was dissolved in ethanol (300 ral), and a 6N aqueous solution of potassium potassium hydroxide was added. Was heated at 50 ° C. After 30 minutes, water was added, and ethanol was distilled off under reduced pressure. The obtained aqueous solution was extracted with ethyl acetate / hexane (v / v = l / l). The aqueous layer was made acidic with 1N hydrochloric acid, extracted with ethyl acetate, and separated. The organic layer was washed with water, dried and concentrated under reduced pressure to obtain the desired product (24 g).

W-NMR (300MHz, CDCL) δ ppm: 1.63 (s, 6H), 7.19-7.56 (m, 8H) Reference Example 2

1-Cupro-3- (2_fluoro [1,1, -biphenyl] -4-yl) -3-methyl-2-butanone

EDC (50 ml), thionyl chloride (1.6 ml) and DMF (1 drop) were added to the compound (5. Og) obtained in Reference Example 1, and the mixture was refluxed for 2 hours. After the solvent was distilled off, the obtained acid chloride was dissolved in ethyl ether (50 ml), and diazomethane was blown at room temperature. 4N after raw material disappears A solution of hydrogen chloride / 1,4-dioxane was added dropwise to the reaction at room temperature until gas evolution ceased. After completion of the dropwise addition, the reaction solution was concentrated under reduced pressure to obtain the desired product (6. lg).

_{¾-NMR (300MHz, CDC1 3} ) δ ppra: 1. 57 (s, 6H), 4. 11 (s, 2H), 7. 06- 7. 13 (m,

2H), 7.34-7.57 (m, 6H) Reference example 3

4- [1-(2-Fluoro [1,1'-biphenyl] -4-yl) -1-methylethyl] -1,3-thiazole-1-2-amine

Water (50 ml) and thioperia (1.7 g) were added to the compound (6.lg) obtained in Reference Example 2, and the mixture was stirred at 100 ° C for 3.5 hours. After cooling to room temperature, the reaction solution was made basic with a ⁵ N aqueous sodium hydroxide solution. The mixture was extracted with chloroform, the organic layer was dried, concentrated under reduced pressure, and the residue was recrystallized (ethanol) to obtain the desired product (4.2 g).

_{- NMR (300MHz, CDC1 3)} δ ppm: 1. 66 (s, 6H), 4. 88 (br-s, 2H), 6. 28 (s, 1H), 7. 02- 7. 14 (m, 2H), 7.30-7.55 (ra, 6H) Reference example 4

4-[1- (2-Fluoro [1,1, -biphenyl] 4-yl) ethyl] -1,3-thiazole-2-amine

A known compound, which is a compound of the formula: 1-Couguchi-3- (2-fluoro [1, -biphenyl] -4-yl) -2-butanone (2.Og) (JP-A-63-152368) Add water (15ml) and Choprea (0.66g) This was heated to reflux. After 2 hours, the mixture was cooled to room temperature, the reaction solution was basified with a 1N aqueous solution of sodium hydroxide, and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure to obtain the desired product (2.0 g).

_{^ -NMR (300MHz, CDC1 3)} δ ppm: 1.61 (d, 3H, J = 7.2Hz), 4.06 (q, 1H,

J = 7.2Hz), 4.89 (br-s, 2H), 6.21 (s, 1H), 7.01-7.13 (m, 2H), 7.31-7.56 (m, 6H) Reference example 5

1-Ku-Bro-3-(2-Fluoro [1,1, -bihuenore] -4-yl) aceton

The target compound was obtained in the same manner as in Reference Example 2 using a known compound, 2-fluoro-4--4-biphenylylacetic acid (US Pat. No. 3,793,457).

_{¾- M (300MHz, CDC1 3)} δ ppm: 3.94 (s, 2H), 4.16 (s, 2H), 7.03- 7.17 (m, 2H), 7.33-7.57 (m, 6H) Reference Example 6

4-[(2-Fluoro [1, -biphenyl] -4-yl) methyl] -1,3-thiazole-2-amine

Using the compound obtained in Reference Example 5, the same procedure as in Reference Example 3 was performed to obtain the desired product. _{¾-NMR (300MHz, CDC1 3} ) δ ppm: 3.90 (s, 2H), 4.95 (br-s, 2H), 6.15 (s, 1H), 7.02-7.13 (m, 2H), 7.32- 7.56 (m, 6H) Reference Example 7

2- (3-benzoylphenyl) -2-methylpropanoic acid

The desired product was obtained by the same operation as in Reference Example 1 using the same.

. W - image _{R (300MHz, CDC1 3) δ} ppm: 1. 65 (s, 6H), 7. 42-7 90 (m, 9H) Reference Example 8

2-methyl-2- [3- (2-phenyl-1,3-dioxolan-2-yl) phenic acid

The compound (15 g) obtained in Reference Example 7 was dissolved in benzene (300 tnl), p-toluenesulfonic acid monohydrate (1.5 g) and ethylene glycol (32 ml) were added, and the mixture was refluxed while removing water. After 12 hours, the mixture was cooled to room temperature, an aqueous solution of IN-sodium hydroxide was added, and liquid separation and extraction were performed. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was dissolved in ethanol (200 ml), a 12N aqueous sodium hydroxide solution (20ral) was added, and the mixture was stirred at 50 ° C for 1 hour. Ethanol was distilled off, and the residue was acidified with 1N-hydrochloric acid. After extraction with ethyl acetate, washing with water, drying and concentration under reduced pressure gave the desired product (14.9 g).

_{- NMR (300MHz, CDC1 3)} δ ppra:. 1. 59 (s, 6H), 4. 05 (s, 4H), 7. 24-7 63 (m, 9H) Reference Example 9

1-Chloro-3-methinole-3--[3- (2-Phenyl-1,3-dioxolan-2-yl) pheninole]-2- Butanone

Using the compound obtained in Reference Example 8, _c of the desired product was obtained in the same manner as in Reference Example 2 - Yuzuru _{(300MHz, CDC1 3) δ ppra} : 1. 53 (s, 6H), 3. 96 (s , 2H), 4.04-4.08 (m, 4H), 7.27-7.81 (m, 9H) Reference example 10

{3_ [1- (2-Amino-1,3-thiazol-4-yl) -1-methylethyl] phenyl} (phenyl) methanone

Using the compound obtained in Reference Example 9, the desired product was obtained in the same manner as in Reference Example 3. _{LH-NMR (300MHz, CDC1 3} ) δ ppm: 1. 66 (s, 6H), 5. 02 (br-s, 2H), 6. 22 (s, 1H),

7.35-7.62 (m, 6H), 7.72-7.81 (m, 3H) Reference example 1 1

{3- [1- (2-Amino-1,3-thiazol-4-yl) ethyl] phenyl} (phenyl) methanone

The target compound was obtained in the same manner as in Reference Example 3 using 3- (3-benzoylphenyl) -cyclobut-2-butanone (JP-A-63-152368) as a known compound. Was.

- Yuzuru _{R (300MHz, CDC1 3) δ} ppm: 1. 59 (. D, 3H, J = 7 3Hz), 4. 08 (q, 1H,

J = 7.3 Hz), 5.24 (br-s, 2H), 6.14 (s, 1H), 7.36-7.82 (m, 9H) Reference example 1 2

Tert-butyl 4- (3-benzoylphenyl) -3-oxobutanoate

Carboxylic acids which are known compounds: (3-benzoylphenyl) acetic acid (6.4 g) (Eur. J. Med. Chera., 9, 381 (1974)) in toluene (701111) and thionyl chloride (2.1 ml) ) And a restaurant (1 drop) were added and stirred at 80 ° C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain an acid chloride. Meldrum's acid (7.7 g) was dissolved in EDC (100 ml) and pyridine (8.6 ml), cooled to 0 ° C., and the above solution of acid chloride in EDC (50 ml) was added dropwise over 1 hour. After stirring for 30 minutes, t-Bu0H (7.7ral) was added, and after stirring for another 30 minutes, the reaction solution was refluxed. Two hours later, the mixture was cooled to room temperature, and 1N-hydrochloric acid was added to carry out liquid separation. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain the desired product (8.5 g).

_{-NMR (300MHz, CDC1 3) δ} ppm: 1. 46 (s, 9H), 2. 42 (s, 2H), 3. 92 (s, 2H),

7.41-7.84 (m, 9H) Reference example 1 3

1- (3-Benzoylphenyl) -3-chloroacetone

Dissolved 0D_ ² 873 obtained in Reference Example 12 (8. 5 g) in methylene chloride (lOOral), t - Bu0H the (2. 5 ml) was added, cooled to 0 ° C. To this was added a solution of sulfuryl chloride (2.lml) in methylene chloride (20tnl) over 30 minutes. After further stirring for 30 minutes, water was added and the layers were separated. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was dissolved in toluene (100 ml). After adding a solution of methanesulfonic acid (0.2 g) in methylene chloride (5 ml), the mixture was stirred at 80 ° C. for 1.5 hours. After adding water and saturated aqueous sodium hydrogen carbonate, the organic layer was extracted, dried and concentrated under reduced pressure, and the residue was purified by silica gel column to obtain the desired product (5.0 g).

_{Ή - NMR (300MHz, CDC1 3} ) 6 ppm: 4. 00 (s, 2H), 4. 16 (s, 2H), 7. 41- 7. 84 (m, 9H) Reference Example 1 4 '

{3-[(2-Amino-1,3-thiazol-4-yl) methyl] phenyl} (Feuel) methanone

Using the compound obtained in Reference Example 13, the same procedure as in Reference Example 3 was performed to obtain the desired product. _{W-NMR (300MHz, CDC1 3} ) δ ppm: 3. 94 (s, 2H), 5. 04 (br-s, 2H), 6. 07 (s, 1H), 7. 39- 7. 83 (m , 9H) Reference example 1 5

Methyl Ν '-{4- [1- [2-fluoro [1,1, -biphenyl] -4-inole) ethyl] -1,3-thiazonole-2-inole) imidothiocarbamate

Thioamide compound which is a known compound: N- {4- [1- (2-fluoro [1,1, -biphenyl] -4-yl) ethynole] -1,3_thiazole-2-ynole) thiopere ( Acetone (300 ml) and potassium carbonate (29.2 _g ) were added to 58.0 _g ) (JP-A-63-152368), and methyl iodide (25.3 _g ) was added dropwise to this mixture over 30 minutes under ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, extracted by adding water (200 ml) and ethyl acetate (230 ml), the organic layer was concentrated under reduced pressure, and the residue was purified by a silica gel column (hexane / ethyl acetate = 12/1). The desired product (55.7 g) was obtained.

! H-NMR (300MHz, CDCl ₃ ) Sppra: 1.65 (d, 3H, J = 7.2Hz), 2.48 (s, 3H), 4.15 (q, 1H, J = 7.2Hz), 6.49 (d, 1H, J = 0.9Hz), 7.02—7.11 (m, 2H), 7.33-7.6 (m, 4H), 7.51-7.55 (m, 2H) Reference example 1 6

2-{[(Z)-[(ter-butoxycarbonyl) amino] (methylsulfur-methyl) methylidene] amino} -4- [1- (2-Fluoro [1, -biphenyl] -4-yl) Ethyl] -1,3-thiazole

To a suspension of 60% sodium hydrogen hydride (6.38 g) and THF (500 ml) was added a solution of the compound obtained in Reference Example 15 (53.87 g) in THF (300 ml), and after 10 minutes, Boc20 (34.81 g) Of THF (200 ml) was added and stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with 5% brine, concentrated under reduced pressure, and the residue was purified with a silica gel column (hexane / ethyl acetate = 25/1 to 10/1). The desired product (54.31 g) was obtained.

One _{NMR (300MHz, CDC1 3) 6} pm: 1.53 (s, 9H), 1.69 (d, 3H, J = 7.1Hz), 2.41 (s, 3H), 4.17 (q, 1H, J = 7.1Hz), 6.60 (d, 1H, J = 0.6Hz), 7.10— 7.15 (m, 2H), 7.33—

7.46 (m, 4H), 7.51-7.55 (ra, 2H), 13.00 (br-s, 1H) Reference Example 17

4-methylbenzenesulfonic acid 2- (2-fluoro [1,1'-biphenyl] -4-inole) propynole

Alcohol compound which is a known compound: 2- (2-fluoro [1,1'-biphenyl] -4-inole) -1_propanol (30 g) (US Patent No. 4053639) is dissolved in pyridine (300 ml), After cooling to 0 ° C, P-toluenesulfuryl chloride (25 g) was added, and the mixture was stirred for 30 minutes, then returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added, the mixture was separated, the extracted organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was recrystallized (ethanol) to obtain the desired product (41.4 g).

_{W-NMR (300MHz, CDC1 3} ) δ ppm: 1.30 (d, 3H, J = 7.0Hz), 2.40 (s, 3H), 3.13 (m, 1H), 4.09 (d, 2H, J = 6.8Hz), 6.85 (m, 1H), 6.97 (m, 1H), 7.28—7.55 (m, 8H), 7.65-7.71 (m, 2H) Reference Example 18

3- (2-Fluoro [1,1, -biphenyl] -4-yl) butanenitrile

The compound (36 g) obtained in Reference Example 17 was dissolved in DMF (400 ml), NaCN (5. lg) was added, and the mixture was stirred at 70 ° C for 3 hours. After cooling to room temperature, water and ethyl acetate were added, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate / hexane = 1/10 to 1/4) to obtain the desired product (22.2 g).

One _{NMR (300MHz, CDC1 3) δρρηι} : 1.49 (d, 3H, J = 7.0Hz), 2.59 (dd, 1H, J = 16.5, 7.2Hz), 2.65 (dd, 1H, J = 16.5, 6.6Hz), 3.2l (m, 1H), 7.02- 7.13 (m, 2H), 7.34-7.48 (ra, 4H), 7.51-7.56 (m, 2H) Reference Example 1 9

3- (2-Fluoro mouth [1,1, -biphenyl] -4-yl) ptanal

The compound (I5g) obtained in Reference Example 18 was dissolved in methylene chloride (300 ml) and cooled to 178 ° C. Diisobutylaluminum hydride (70 ml, 0.95 M) was added dropwise over 30 minutes, and then stirred for 30 minutes. After stopping the reaction by adding methanol, the reaction solution was poured into an aqueous solution of sodium potassium tartrate (35 g) (500 ml). After stirring at room temperature for 2 hours, the layers were separated, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain the desired product (14.6 g).

_{W-NMR (300MHz, CDC1 3} ) δ ppm: 1. 35 (. D, 3H, J = 7 0Hz), 2. 70 (. Ddd, 1H, J = 17 0, 7, 5, 1. 8Hz), 2.80 (ddd, 1H, J = 17.0, 7.0, 1.8 Hz), 3.41 (m, 1H), 6.99— 7.10 (m, 2H), 7.32— 7.56 (m, 6H), 9.75 (t, 1H, J = l. 8Hz) Reference example 20

5- [1- (2-Fluoro [1,1, -biphenyl] -4-inole) ethyl] -1,3-thiazole-2-amine

Bromine (2.9 ml) was added dropwise to 1,4-dioxane (10 ml), and the mixture was stirred at room temperature for 10 minutes and dissolved in methylene chloride (50ral). A solution of the compound (14.6 g) obtained in Reference Example 19 in methylene chloride (50 ml) was cooled to 15 ° C., and the above solution of bromine in methylene chloride was added dropwise over 2 hours. After stirring for 1 hour, sodium bicarbonate (4.8 g) and water (50 ml) were added dropwise, and the mixture was extracted with chloroform. The organic layer was dried and concentrated under reduced pressure. Dissolve the residue in ethanol (200ml) (5.0 _g ) was added, and the reaction solution was refluxed. Two hours later, the mixture was cooled to room temperature, added with water, and concentrated. After neutralization with saturated aqueous sodium bicarbonate, the mixture was extracted with chloroform. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel gel to obtain the desired product (5.5 g).

One _{MR (300MHz, CDC1 3) δ} ppm: 1. 65 (. D, 3H, J = 7 2Hz), 4. 18 (. Q, 1H, J = 7 2Hz), 4. 80 (br - s, 2H ), 6.84 (d, 1H, J = 1.3Hz), 7.00-7.12 (m, 2H), 7.32-7.56 (m, 6H) Reference example 2 1

{3- [1- (2-Amino-1,3-thiazole-5-inole) ethyl] phenyl} (phenyl) methanone

To a solution of ketoprofen (50.0 g) in chloroform (100 ml) was added dropwise thionyl chloride (46.8 g) under ice-cooling, and the mixture was heated under reflux for 3 hours, and excess thionyl chloride was distilled off to remove acid. Chloride was obtained. A toluene (lOOral) solution of this acid chloride was added to a suspension of N, 0-dimethoxyammonium chloride (20.9 g) and potassium carbonate (54 g) in toluene (100 ml) -water (200 ml) under ice cooling. It was dropped. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried, and then subjected to Weinreb amide: 2- (3-benzoylfe-nore) -N-methoxy-N -Methinorep mouth panamide (64 g) was obtained. This part (2.0 g) was dissolved in toluene (50 ml), and ethylene glycol (0.83 g) and p-toluenesulfonic acid monohydrate (300 mg) were added. The mixture was refluxed for 6 hours while removing water. . Thereafter, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried and concentrated under reduced pressure. The residue was purified by silica gel column ketoprofen E Ji Ren § Se tar Weinreb amide: N - methoxymethyl - ² - ^[3 - (2-Hue - offset - 1, 3-Jiokisoran - 2-I le) phenyl] Puropanamido (1.71 g) was obtained. To a solution of this amide compound (1.70 g) in THF (20 ml) was added lithium aluminum hydride (47.2 mg) under ice-cooling. After confirming the disappearance of the raw materials, water (0.5 ml) was added, and then a 10% aqueous sodium hydroxide solution was added until a white solid of aluminum appeared. Magnesium sulfate was added, and the precipitate was filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified with a silica gel column to give an aldehyde compound: 2- [ ^3- (2-phenyl-1,3-dioxolan-2-yl) phenyl] propanol (900 mg) Obtained.

_{¾-NMR (300MHz, CDC1 3} ) δ ppm: 1. 42 (. D, 3H, J = 7 0Hz), 3. 62 (. Dq, 1H, J = 7 0, 1. 3Hz), 4. 04- 4.09 (m, 4H), 7.10-7.13 (m, 1H), 7.25-7.53 (m, 8H), 9.66 (d, 1H, J = l. 3Hz)

This aldehyde form: 2- [3- (2-Feninole-1,3-dioxolan-2-yl) pheninole] propanal (360 mg) in THF (2.0 ml) / t-BuOH (2 .0 ml) solution, methoxymethyltriphenylphosphonium chloride (533 rag) was suspended. Under cooling with water, a solution of t-BuOK (214 tng) in THF (2.0 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was neutralized with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried, concentrated under reduced pressure, and the resulting residue was purified on a silica gel column to give a bier ether form: methyl (mixed with 1E and Z) -3- [3- (2-phenyl- 1,3-Dioxolan-2-inole) pheninole] -1-butulether (243 mg) was obtained.

This vinyl ether compound: Methyl (mixed with IE and Z) -3- [3- (2-phenyl-1,3-dioxolan-2-ynole) phenyl] -1-butyrether (3.42 g), methylene chloride ( To a mixture of 20 ml) and water (20 ml) was added dropwise a solution of bromine (0.62 ml) in methylene chloride under ice-cooling. At that time, baking soda was added so that _PH = 7 ~ 8. After the disappearance of the raw materials, the reaction solution was neutralized with 1N-hydrochloric acid, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with brine, dried and concentrated under reduced pressure. Obtained bromo compound: 2-bromo-3- [3- (2-phenyl-1,3-dioxolan-2-yl) phenyl] ptanal was diluted with ethanol (30 ml), and thioperia (837 mg) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, concentrated under reduced pressure, and the residue was purified by silica gel column to purify (1.2 g) was obtained.

_{W-NMR (300MHz, CDC1 3} ) δ ppm: 1. 65 (. D, 3H, J = 7 0Hz), 4. 22 (. Q, 1H, J = 7 0Hz), 4. 77 (br-s, 2H), 6.80 (br-s, 1H), 7.39-7.81 (m, 9H) Reference Example 2 2

Methyl N-cyano-4-morpholinecarbimidothioate

Dimethylcyanodithioiminocarbonate (50 g) was dissolved in ethanol (500 ml), and morpholine (45 ml) was added at room temperature. Two hours later, the generated crystals were filtered and washed with ethanol. The obtained crystals were dried to obtain the desired product (51 _g ).

_{- NR (300MHz, CDC1 3)} δ ppm:.. 2. 80 (s, 3H), 3. 70-3 75 (m, 4H), 3. 83-3 88 (m, 4H) Reference Example 2 3

N'-Cyano_N, N-dimethyl-4-morpholinecarboximimidamide

The compound obtained in Reference Example 22 was dissolved ⁽² 0 g) in Asetonitoriru ⁽² 50ral), Toryechiru Amin (16. 6 ml), was added to Jimechiruamin (36 ml), silver nitrate Aseto nitriles of (20. 6g) (50tnl) The solution was added dropwise at room temperature. After stirring for 3 days, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain the desired product (19.6 g).

^ -NMR (300 MHz, CDCl ₃ ) S ppm: 3.00 (s, 6H), 3.40-3.44 (m, 4H), 3.73-3.78 (m, 4H) Reference example 24

N-[(E)-(dimethylamino) (4-morpholinino -o Hiro Q

.S

NC N- H ₂ N N-

NMe ₂ NMe _{2 The} compound obtained in Reference Example 23 (7.3 g) was dissolved in water (100 ml), and hydrogen sulfide gas was blown at 75 ° C. After 10 hours, the reaction mixture was cooled to room temperature, and the solution was separated and extracted. The chloroform layer was dried and concentrated to obtain the desired product (4.8 g).

_{¾-NMR (300MHz, CDC1 3} ) δ ppra:.. 3. 00 (s, 6H), 3. 43-3 47 (m, 4H), 3. 74-3 79 (ra, 4H), 5. 84 (brs, 2H) Reference example 2 5

N'-cyano-N-methyl_4_morpholinecarboximidamide

The same operation as in Reference Example 23 was performed using the compound (10g) obtained in Reference Example 22. Purification was performed by recrystallization from ethanol to obtain the desired product (4.0 g).

_{'H- MR (300MHz, CDC1 3} ) δ pptn:. 3. 06 (. D, 3H, J = 4 8Hz), 3. 50- 3. 54 (m, 4H), 3. 69-3 74 (m , 4H), 6.36 (br, 1H) Reference example 2 6

N-[(E)-(methylamino) (4-morpholinyl) methylidene] thiopere

Using the compound (4 g) obtained in Reference Example 25 and performing the same operation as in Reference Example 24, Obtained as an aqueous solution.

TLC: Rf 0.20 (Chloronolem: Methanol: 10: 1) Reference Example 27

N_ {4- [1- (2-Fluoro [1,1'-biphenyl] -4-yl) ethyl] -1- 1,3-thiazonole-2-yl} -4-morpholinecarpothioamide

Compound obtained in Reference Example 4 (2.98 g), black form (200 ml), sodium bicarbonate

(4.20 g) and water (50 ml) were taken and stirred under ice cooling. Thiophosgene (1.52 ml) was added dropwise thereto little by little. After the addition, the mixture was stirred under ice cooling for 5 hours, and the reaction solution was separated. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and the solvent was distilled off. Acetonitrile (40 ml) was added to the residue and dissolved, morpholine (1.75 ml) was added, and the mixture was heated under reflux. After 1.5 hours, the reaction solution was distilled off, and the residue was diluted with ethyl acetate, washed with water, washed with saturated saline, dried over sodium sulfate, filtered, and the solvent was distilled off. This was purified by column chromatography to obtain the desired product (2.70 g).

W-NMR (300MHz, CDCl ₃ ) Sppm: 1.62 (d, 3H, J = 7.1Hz), 3.63-3.72 (m, 4H), 3.94-4.07 (m, 5H), 6.26 (d, 1H, J = l .1Hz), 6.93-- 7.05 (m, 4H), 7.35-7.45 (m, 4H), 7.45-7.55 (m, 2H), 10.05 (br, 1H) Reference Example 28

Methyl N- {4- [1- (2-Fluoro [1,1'-biphen-nore] -4-inole) ethyl] -1,3-thiazol-2-yl} -4-morpholinecarbimidothio Eat

The compound (8.55 g) obtained in Reference Example 27 and acetone (80ral) ′ lithium carbonate (4.15 g) were taken and stirred under ice-cooling. Here, methyl iodide (1.5 ml) was added dropwise little by little. After the addition, the mixture was stirred for 3 hours, and water was added to complete the reaction. This was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over sodium sulfate. Filtration and evaporation of the solvent gave the desired product (9.13 g).

_{^ -NMR (300MHz, CDC1 3)} δ ppm: 1. 66 (. D, 3H, J = 7 1Hz), 2. 14 (s, 3H), 3. 68- 3. 73 (m, 4H), 3 74-3. 79 (m, 4H), 4.20 (q, 1H, J = 7.1 Hz), 6.53 (d, 1H,

J = 0.9Hz), 7.06-7.17 (m, 2H), 7.30-7.45 (m, 4H), 7.47—7.55 (m, 2H) Reference example 2 9

4-[1- (2-Fluoro [1, -biphenole] -4-inole) ethyl]-1,3-oxazole-2-ylamine

Alcohol compound which is a known compound: 3- (2-fluoro [1,1, -biphenyl] -4-inole) -1-hydroxy-2-butanone (7.6 g) (JP-A-63-152368) The residue was dissolved in THF (70 ml), and a solution of cyanamide (6.0 g) in water (36 ml) was added dropwise at room temperature. The reaction solution was adjusted to pHIO with a 2N aqueous solution of sodium hydroxide, and stirred overnight. Further, a solution of cyanamide (2.2 g) in water (lOral) was added thereto, followed by stirring for 5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried, concentrated under reduced pressure, and the residue was purified using silica gel gel (ethyl acetate / hexane = 1/2 to 2/1). (3.8 g) was obtained.

Keio _{R (300MHz, CDC1 3) δ} ppm: 1. 55 (. D, 3H, J = 7 2Hz), 3. 90 (br-q, 1H, J = 7.2Hz), 4.58 (br_s, 2H), 6.93 (d, 1H, J = 1.3Hz), 7.02—7.14 (m, 2H), 7.31-7.55 (ra, 6H) Reference example 30

{3- [1- (2-Amino-1,3-oxazo-1- / le-4-inole) ethyl] phenyl} (phenyl) methanone

Alcohol as a known compound: 3- (3-benzoylphenyl) -1-hydroxy-2-butanone (JP-A-63-152368) was used to obtain the desired product by the same operation as in Reference Example 29.

One _{NMR (300MHz, CDC1 3) 6} ppm: 1.54 (d, 3H, J = 7.2Hz), 3.94 (br-q, 1H, J = 7.2Hz), 4.74 (br-s, 2H), 6.89 (d, 1H, J = 1.3Hz), 7.38-- 7.83 (m, 9H) Reference example 31

4 - methyl benzophenone ⁽²⁵ g) was dissolved in carbon tetrachloride ⁽² 50 ml), was added AIBN (0.2g), NBS (22.7g ). After refluxing the reaction solution for 2 hours, the resulting succinimide was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethanol to obtain the desired product (19.6 g).

- dust _{R (300MHz, CDC1 3) S} ppm: 1.58 (s, 3H), 4.54 (s, 2H), 7.46-7.54 (m,

4H), 7.60 (m, 1H), 7.76-7.83 (m, 4H) Reference example 32 Enyl) acetonitrile

The compound (16.) obtained in Reference Example 31 was dissolved in DMF (200 ml), sodium cyanide (3.2 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with water and dried. The solvent was concentrated, and the obtained residue was purified by column chromatography to obtain the desired product (6.1 g).

_{¾-NMR (300MHz, CDC1 3} ) δ ppm: 1.57 (s, 3H), 3.86 (s, 2H), 7.45-7.54 (ra,

4H), 7.61 (m, 1H), 7.77-7.86 (m, 4H) Reference example 33

Methyl acetate (4)

The compound (7.2 g) obtained in Reference Example 32 was dissolved in sulfuric acid (30 ml), acetic acid (30 ml), and water (30 ml) and stirred at 80 ° C. for 5 hours. The reaction solution was poured into ice, stirred for a while, and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain a carboxylic acid. Dissolve the carboxylic acid in toluene (100 ml), and then add thionyl chloride (2.4 ml) and dimethylformamide.

(2 drops) and refluxed for 1 hour. Methanol (15 ml) was added, and the mixture was stirred for 1 hour. After concentration of the reaction solution, the residue was purified by column chromatography to obtain the desired product (8.5 g).

_{¾-NMR (300MHz, CDC1 3} ) δ ppm: 3.72 (s, 2H), 3.73 (s, 3H), 7.38-7.53 (ra, 4H), 7.59 (m, 1H), 7.76- 7.82 (m, 4H) Reference example 34 2- (4-any

A 60% suspension of sodium hydride (0.91 g) in DMF (50 ml) was added. After cooling to C, a solution of the compound obtained in Reference Example 33 (5.8 g) in DMF (50 ml) was added dropwise. 20 minutes later, methyl iodide

(1.42 ml) was added dropwise and stirred for 30 minutes. The reaction solution was poured into ice and extracted with ethyl acetate. The organic layer is washed with water, dried, and the solvent is concentrated.

(60 ml). A 6N-sodium hydroxide aqueous solution (12 ml) was added at room temperature, and the mixture was stirred for 1 hour and heated at 70 ° C for 2 hours. After cooling to room temperature, the ethanol was concentrated, water and ether were added, and the mixture was separated. The aqueous layer was acidified with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain the desired product (5.5 g).

_{HI - NMR (300MHz, CDC1 3} ) δ ppra: 1. 57 (. D, 3H, J = 7 2Hz), 3. 85 (q, 1H,

J = 7.2 Hz), 7.42-7.53 (m, 4H), 7.59 (ra, 1H), 7.76-7.83 (m, 4H) Reference Example 3 5

3_ (4-benzoynolepheninole) -1-hydroxy-2-butanone

The compound (5.5 g) obtained in Reference Example 34 was dissolved in toluene (60 tnl), and thionyl chloride (1.8 ml) and DMF (1 drop) were added, followed by refluxing for 1 hour. The reaction solution was concentrated and dried under reduced pressure. The obtained acid chloride was dissolved in toluene (20 ml) and used as a toluene solution in the next reaction.

Tris (trimethylsilyloxy) ethylene (90%, 10.7g), triethylamine (3.2 ml) was dissolved in toluene, and a toluene solution of acid oxalate was added dropwise to this solution at room temperature. After the dropwise addition, the reaction solution was heated to 85 ° C and stirred. After 3 hours, IN-hydrochloric acid (6 ml) was added, and the mixture was further stirred for 1 hour. After cooling to room temperature, a saturated saline solution was added to the reaction solution, and a toluene layer was extracted. The toluene layer was washed with saturated aqueous sodium hydrogen carbonate and water, dried and concentrated. The residue was purified by column chromatography to obtain the desired product (2.9 g).

_{^ -NMR (300MHz, CDC1 3)} 6 ppm: 1.53 (d, 3H, J = 7.2Hz), 2.99 (t, 1H,

J = 4.8Hz), 3.89 (q, 1H, J = 7.2Hz), 4.27 (d, 2H, J = 4.8Hz), 7.33-7.38 (ra, 2H), 7.46-7.53 (ra, 2H), 7.61 ( m, 1H), 7.77-7.82 (m, 4H) Reference example 36

{4- [1- (2-Amino-1,3-oxazole-4-yl) ethyl] phenyl} (phenyl) methanone

Using the compound obtained in Reference Example 35, the desired product was obtained in the same manner as in Reference Example 29. _{^ - MR (300MHz, CDC1 3} ) δ ppm: 1.56 (d, 3H, J = 7.2Hz), 3.95 (brq, 1H,

J = 7.2Hz), 4.70 (brs, 2H), 6.90 (d, 1H, J = l.3Hz), 7.35-7.40 (m, 2H), 7.44-

7.51 (m, 2H), 7.58 (m, 1H), 7.74- 7.82 (m, 4H) Reference example 37

Dimethyl 4-[[1_ (3 nzoinolefe-nore) ethynole]-1,3-oxazole-2-inole- (dithioimidocarbonate) e

The compound (9. Og) obtained in Reference Example 30 was dissolved in DMF (100 ml), and a 4N aqueous sodium hydroxide solution (8.5ral) was added under ice-cooling. After 30 minutes, carbon disulfide (3.7ral) was added, and after a further 30 minutes, 4N aqueous sodium hydroxide solution (8.5 ml) was added. After 15 minutes, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. After dropwise addition of methyl iodide (4.8 ml), the mixture was left overnight. Water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was purified by a silica gel column (ethyl acetate / hexane = 1Z4) to obtain the desired product (8.4 g).

删_{R (400MHz, CDC1 3) δ} ppm: 1.60 (d, 3H, J = 7.2Hz), 2.16 (s, 6H), 2.35 (t, 2H, J = 6.3Hz), 3.26 (q, 2H, J = (6.3Hz), 3.28-3.35 (m, 4H), 3.70- 3.77 (ra, 4H), 4.00 (brq, 1H, J = 7.2Hz), 6.94 (d, 1H, J = l.1Hz), 7.37-7.65 (ra, 6H), 7.75- 7.82 (m, 3H), 9.01 (t, 1H, J = 6.3Hz) Reference example 38

Methyl N- {4- [1- (3-benzoylphenole) ethyl] -1,3-oxazole-2-inole} -4 -morpholinker boimidothioate

The compound (3.lg) obtained in Reference Example 37 was dissolved in ethanol (50 ml), morpholine (0.68ral) was added, and the reaction solution was refluxed. Two hours later, the ethanol was concentrated, and chloroform and water were added. The mixture was separated and extracted. The organic layer was dried and concentrated, and the residue was purified by a silica gel column (ethyl acetate / hexane = 1/1 to 3/1) to obtain the desired product (2.0 _g ).

-丽 R (400MHz, CDCI3) δ ppm: 1.60 (d, 3H, J = 7.2Hz), 2.04 (s, 3H), 3.66- 3.72 (m, 4H), 3.74-3.80 (m, 4H), 4.05 ( brq, 1H, J = 7.2Hz), 7.08 (d, 1H, J = l.1Hz), 7.37-7.63 (m, 6H), 7.73-7.82 (m, 3H) Reference example 39

N- {4- [2- (2-fluoro-1,1, -biphenyl-4-yl) ethyl]-1H-imidazole-2-yl} acetoamide

An alcohol compound (see Reference Example 29), which is a known compound, (30 g) was dissolved in dichloromethane (500 ml), and trifluorophosphine (32 g) and carbon tetrabromide (44 g) were added at 0 ° C. Two hours later, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, separated, and extracted. The organic layer is dried and concentrated. The residue is purified by a silica gel column (ethyl acetate Z hexane = 1/10 to 1/5), and the bromo form: 1_bromo-3- (2-fluoro [1,1 Enyl] -4-yl) -2-butanone (30 _g ) was obtained.

The bromo compound (30 g) was dissolved in DMF (300 ml), acetyldanidine (23 g) was added, and the mixture was heated at 65 ° C. Four hours later, water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water and dried. Crystallization occurred during the concentration of the solvent, and the mixture was filtered and dried to obtain the desired product (8. lg).

- image _{R (400MHz, CDC1 3) δ} ppm: 1.5l (d, 3H, J = 7.1Hz), 2.01 (s, 3H), 3.99 (q, 1H, J = 7.1Hz), 6.53 (s, 1H) , 7.11-7.20 (m, 2H), 7.34-7.55 (m, 6H), 11.08 (brs, 1H), 11.25 (brs, 1H) Reference example 40

4- [l- (2-fluoro-1,4-biphenyl-4-yl) ethyl] -1- (phenylsulfo;

) -1H-imidazole-2-amine

Compound (8. lg) obtained in Reference Example 39, ethanol (120 ml), concentrated hydrochloric acid

(20ral) and the reaction mixture was refluxed. After 3 hours, the reaction solution was concentrated and dried under reduced pressure. The obtained condensed product was dissolved in THF (150 ml), and triethylamine (17 ml) and benzenesulfonyl chloride (3.5 ml) were added thereto, followed by stirring at room temperature. One hour later, water and ethyl acetate were added to the reaction solution, and the mixture was separated and extracted. The organic layer was washed with water, dried and concentrated, and the residue was recrystallized from ethanol to obtain the desired product (9.0 g).

_{-NMR (400MHz, CDC1 3) δ} ppm: 1.49 (d, 3H, J = 7.1Hz), 3.82 (. Brq, 1H, J = 7 lHz), 5.28 (brs, 2H), 6.63 (d, IE, J = l.1Hz), 6.92 (dd, 1H, J = ll.8, 1.7Hz), 7.02 (dd, 1H, J = 7.9, 1.7Hz), 7.30-7.45 (m, 4H), 7.49-7.59 (m , 4H), 7.64-7.70 (m, 1H), 7.89- 7.95 (m, 2H) Reference example 4 1

Dimethyl 4- [1_ (2-fluoro-1, -biphenyl-4-yl) ethyl] -1- (phenylsulfonyl) -1H-imidazole-2-yl- (dithioimidcarbonate)

After washing sodium hydride (0.21 g) with hexane and applying THF (20 ml), a solution of the compound (2.0 g) obtained in Reference Example 40 (2.0 g) in THF (20 ml) was added dropwise under ice-cooling. . After 30 minutes, carbon disulfide (0.57 ml) was added, and after another 30 minutes, sodium hydride (0.21 g) was added. After stirring for 1 hour, methyl iodide (0.89 ml) was added. After 30 minutes, the reaction was stopped with an aqueous solution of ammonium chloride, and extracted with ethyl acetate. Wash, dry and concentrate the organic layer Thereafter, the residue was purified by a silica gel column (ethyl acetate / hexane = 15 to 1/4) to obtain the desired product (1.9 g).

_{^ -NMR (400MHz, CDC1 3)} δ ppm: 1.62 (d, 3H, J = 7.1Hz), 2.51 (s, 6H), 4.03 (. Brq, 1H, J = 7 IHz), 7.07 (d, 1H, J = 0.9Hz), 7.11-7.18 (m, 2H), 7.32-7.66 (m, 9H), 7.87-7.92 (m, 2H) Reference example 42

Methyl N- [4- [1- (2-fluoro-1,4-biphenyl-4-yl) ethyl] -1- (phenylsulfonyl) -1H-imidazole-2-yl] -4-morpholinebo Imidothioate

The target compound was obtained from the compound obtained in Reference Example 41 and morpholine by the same operation as in Reference Example 38.

^{X H-NMR (400MHz, CDC1} 3) δ ppm: 1.59 (d, 3H, J = 7.1Hz), 1.97 (s, 3H), 3.55- 3.68 (m, 8H), 3.99 (brq, 1H, J = 7.1 Hz), 7.03 (d, 1H, J = 1.0Hz), 7.06 (dd, 1H, J = 12.0, 1.6Hz), 7.13 (dd, 1H, J = 7.9, 1.6Hz), 7.32-7.36 (m, 8H ), 7.64 (m, 1H), 7.92-7.97 (m, 2H) Reference example 43

N-{4— [1— (3-: zonylphenyl) ethyl] -1H-imidazole-2-inole} acetami

The target product (3.36 g) was obtained from the alcohol compound (see Reference Example 30) (10.29 g), which is a known compound, by the same operation as in Reference Example 39.

_{W-NMR (300MHz, CDC1 3} ) δ ppm: 1.62 (d, 3H, J = 7.1Hz), 2.19 (s, 3H), 4.13 (q, 1H, J = 7.1Hz), 6.52 (s, 1H), 7.79 (m, 10H), 10.39 (brs, 1H) Reference example 44

(3- {1- [2-Amino-1- (phenylsulfonyl) -1H-imidazole-4-yl] ethyl} pheninole;) (phenenole) ketone

The compound (3.7 g) obtained in Reference Example 43 was subjected to the same operation as in Reference Example 40 to give the desired product (34.62 g).

! H-NMR (400MHz, CDC1 3) δ ppra: 1.48 (d, 3H, J = 7.1Hz), 3.86 (q, 1H,

J = 7.1Hz), 5.36 (s, 2H), 6.58 (s, 1H), 7.38-7.42 (m, 2H), 7.43-7.48 (m, 2H), 7.51-7.60 (m, 3H), 7.60-7.67 (m, 3H), 7.76-7.80 (m, 2H), 7.86-7.90 (m, 2H) Reference example 45

Dimethyl 4- [1- (3-: benzoylphenyl) ethyl]-1-(phenylsulfoninole) -1H- Midazole-2-yl- (dithioimidocarbonate)

The target compound (9.82 g) was obtained from the compound (lOg) obtained in Reference Example 4 by the same operation as in Reference Example 41.

_{¾-NMR (300MHz, CDC1 3} ) 6 ppra: 1.61 (d, 3H, J = 7.1Hz), 2.46 (s, 6H), 4.08 (q, IH, J = 7.1Hz), 7.04 (d, IH, J = 1.0Hz), 7.37-7.66 (m, 9H), 7.77- 7.82 (m, 3H), 7.85- 7.89 (m, 2H) Reference example 46

Dimethyl 4- [1- (3-benzoylphenyl) ethyl] _1,3-thiazole-2-yl- (dithioimidocarbonate)

From the compound obtained in Reference Example 11, in the same manner as in Reference Example 41 to obtain the desired product, E - employment _{R (400MHz, CDC1 3) δ} ppra: 1.67 (d, 3H, J = 7.2Hz), 2.55 (s, 6H), 4.28 (q,

IH, J = 7.2Hz), 6.65 (s, IH), 7.36-7.49 (in, 3H), 7.55-7.66 (m, 3H), 7.77-

7.85 (m, 3H) Reference example 47

Methyl N '-{4- [1- (3-benzoylphenyl) ethyl] -1,3-thiazole-2-inole} -N- [2- (dimethylamino) ethyl] imidothiocarbamate

The target compound was obtained from the compound obtained in Reference Example 46 and N, N-dimethylethylenediamine by the same operation as in Reference Example 38.

_{¾- MR (400MHz, CDC1 3)} δ ppra: 1.67 (d, 3H, J = 7.2Hz), 2.17 (s, 6H), 2.37- 2.45 (m, 2H), 2.48 (s, 3H), 3.31-3.38 (m, 2H), 4.12 (q, 1H, J = 7.2Hz), 6.33 (s: 1H), 7.41 (t, 1H, J = 7.6Hz), 7.42-7.49 (m, 2H), 7.54- 7.65 ( m, 3H), 7.75-7.81 (m, 3H), 10.45 (brs, 1H) Reference Example 49

Methyl N,-{4- [1_ (3_Benzoylphenyl) ethyl]-1,3-thiazole-2-yl}-N- [2- (dimethylamino) ethyl]-N-methylimidiocarbamate

The target compound was obtained from the compound obtained in Reference Example 46 and N, N, -trimethylethylenediamine in the same manner as in Reference Example 38.

_{^ -NMR (400MHz, CDC1 3)} δ ppm: 1.66 (d, 3H, J = 7.2Hz), 2.05 (s, 3H), 2.26 (s, 6H), 2.49 (t, 2H, J = 7.3Hz), 3.16 (s, 3H), 3.68 (t, 2H, J = 7.3Hz), 4.24 (q, 1H, 1 = 7.1Hz), 6.42 (s, 1H), 7.38 (t, 1H, J = 7.7Hz), 7.43-7.49 (m, 2H), 7.53— 7.62 (m, 3H), 7.73 (m, 1H), 7.76- 7.81 (m, 2H) Test example 1

Suppress adjuvant arthritis

Male SD rats were used as experimental animals. Dead bacteria of Mycobacterium butyricum A solution of the body suspended in liquid paraffin to a concentration of 0.5% was injected subcutaneously into the right hind paw of the rat. After 17 days, animals in which the development of secondary inflammation was clearly observed in the left hind limb were selected, and the compound of the present invention suspended in a 0.5% methylcellulose solution was orally administered for 5 consecutive days. The hind limb volume after 5 hours was compared with the hind limb volume at the start of administration, and the difference was used to evaluate the swelling inhibitory effect. The results are shown in the table below. Table 3

Administered compound Oral dose Increased edema (ml)

kmg / kg) Injectable foot Non-injectable foot

10 0.27 0.07 Compound of Example 21 50 10 -0.42 -0.43 Indomethacin 0.5 10 1 0.54 1 0.45 Effect of the Invention

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

Claims

1 set

Contract

of

[Where E is the formula:

(Wherein, M is a single bond, one O-, one S-, one SO- one S_〇 ₂ -, - CQ- (Q 1 together with the carbon atoms, 3-Jiokisan ring or 1, 3-Jiokisoran ring ), -CH (OR ¹¹ )-, one C (OR ¹¹ ) _2- , one C (= NOR ⁿ ) one (R ¹¹ represents a hydrogen atom or a lower alkyl group.), -C (= NR ^¹²⁾ - (R ¹² represents a hydrogen atom or a lower alkyl group), -. C (= NNR 13 R 14) one (R ¹³ and R "are independently hydrogen, be a lower alkyl group or a substituted Represents a good aryl group), represents —CO— or one CS—) represents, or E represents a formula:

(Wherein, B is a single bond, one O-, one S-, one SO- or a S0 ₂ - represents a.) Represents the. E is a halogen atom, a nitro group, a formyl group, an acetyl group, a cyano group, one R ¹⁷ (R ¹⁷ represents a lower alkyl group), —OR ¹¹ (R ¹¹ is as defined above. - C0 ₂ R ^29, one S0 ₂ R ^²⁹ (. R ²⁹ represents a lower alkyl group) and single C ONR ³ ° R ^31, one _{^{^{S0 2 NR 3 .R 31 (R}}} 3 ° and R ³¹ are independently Represents a hydrogen atom or a lower alkyl group.) It may be substituted with 1 to 4 groups arbitrarily selected from the group consisting of force.

G represents the formula: 1 C (R6R ⁷ ) — or 1 C (= CR ⁶ R ⁷ ), and is bonded to the carbon atom of A. R ⁶ and R ⁷ each independently represent a hydrogen atom, a lower alkyl group or a lower alkoxy group. Also, when R ⁶ and R ⁷ combine to form a hydrocarbon ring, 1,3-dioxane ring or 1,3-dioxolane ring, which may be Good.

A represents thiazole, oxazole or imidazole.

R ⁵ represents a substituent bonded to the carbon atom of A and the Z or nitrogen atom. r represents an integer of 0 to 2. A substituent R ⁵ on a carbon atom of thiazole, oxazole or imidazole is a halogen atom, a hydroxyl group, a nitro group, a cyano group, a carboxy group, an amino group which may be substituted, a hydroxyamino group which may be substituted, Optionally substituted sulfamoyl group, optionally substituted sulfamoyl group, one R ⁸ , one OR ⁸ , one C 0 ₂ R ⁹ , -SR ¹⁰ , one SO—R ¹⁰ , one S 0 ₂ —R ¹⁰ , One C (O) SR ^W , one C (S) OR ¹⁰ or one CS ₂ R ¹⁰ (wherein R ⁸ is an optionally substituted alkyl group, an optionally substituted alkenyl group, Alkynyl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, Good complex It represents a group or Ashiru group. R ⁹ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted Arukyuru group, an optionally substituted Ariru group, substituted R ^1Q represents an alkyl group which may be substituted, an aryl group which may be substituted or an aralkyl group which may be substituted; Represents). The substituent R ⁵ on the nitrogen atom of the imidazole is A nitro group, a cyano group, an optionally substituted sulfamoyl group, an optionally substituted sulfamoyl group, a protecting group for an NH group, one R ⁸ , one OR ⁸ or one C 0 ₂ R ⁹ (wherein, R ⁸ And R ⁹ are as defined above.

L is a formula attached to the carbon atom of A:

(In the formula, two dashed lines mean a double bond together with a solid line, and the other a single bond together with a solid line. R ¹ is bonded to a nitrogen atom having a bond whose dashed line represents a single bond with the solid line. RR ² , R ³ and R ⁴ are each independently a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group which may be substituted, a hydroxyamino group which may be substituted, Optionally substituted rubamoyl groups, optionally substituted

', NH protecting group, one R ⁸ , -OR ^f one C0 ₂ R ⁹ , SR 10 one SO—R ¹⁰ , one SO ₂ —R ¹⁰ , one (CO) SR ¹⁰ , one (CS) OR ¹⁰ Or one CS ₂ R ¹⁰ (wherein, R ⁸ , R ⁹ and R ^w are as defined above). RR ² , R ³ and R ⁴ are a nitrogen-containing aliphatic heterocyclic ring which is bonded to any two of them and may be substituted together with one nitrogen atom or with two nitrogen atoms and carbon atoms. May be formed.

However, in the formula, when M is a single bond or one O—, three or more of RR ² , R ³ and R ⁴ do not simultaneously represent a hydrogen atom.

Also, the formula: one NR ² R ³ is the formula: one N = C (NR43R ⁴ ) NH ₂ or one NHC

(1) or (2).

(2) — 5 to 7-membered nitrogen-containing aliphatic heterocyclic group (5 to 7 members) The nitrogen-containing aliphatic heterocyclic group is arbitrarily selected from the group consisting of an optionally substituted alkyl group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, a protecting group for an NH group, and an oxo group. Or it may be substituted with two substituents. ). ) Represents a group represented by ]

Or a pharmaceutically acceptable salt thereof.

2. E is the formula:

[Wherein, M ¹ represents one CQ— (Q represents a 1,3-dioxane ring or a 1,3-dioxolane ring together with a carbon atom.), One CH (OR ¹¹ ) —, one C (OR ¹¹ ) 2— , One C (= NOR ^u )-(R ¹¹ has the same meaning as described above;;), one C (= NR ¹² ) one (R ¹² represents a hydrogen atom or a lower alkyl group. :), one C (= NNR ¹³ R ¹⁴ )-(R ¹³ and R ¹⁴ independently represent a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aryl group.) ヽ represents one CO— or one CS— . Or the formula:

(Wherein, B is a single bond, one O-, one S-, one SO- or a S0 ₂ - represents a.) Represents the. E is a halogen atom, an acetyl group, a nitro group, a formyl group, a cyano group, one R ¹⁷ (R ¹⁷ represents a lower alkyl group), one OR ¹¹ (R ¹¹ is as defined above), One CO ₂ R ²⁹ , one SO ₂ R ²⁹ (R ²⁹ represents a lower alkyl group) and one CONR ³⁰ R ³ —SO ₂ NR ³ . R ³¹ (R ³ and R ³¹ independently represent a hydrogen atom or a lower alkyl group.). It may be. 5. The 5-membered heteroaromatic compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. E is the formula:

[E is a halogen atom, an acetyl group, a nitro group, a formyl group, a cyano group, -R ¹⁷ (R ¹⁷ represents a lower alkyl group), and one OR ¹¹ (R ¹¹ is as defined above; ), —CO ₂ R ²⁹ , —SO ₂ R ²⁹ (R ²⁹ represents a lower alkyl group) and one C ONR ³ . R ³¹ and one S 0 ₂ NR ³ ° R ³¹ (R ³ and R ³¹ independently represent a hydrogen atom or a lower alkyl group.) 1 to 4 arbitrarily selected from the group consisting of May be substituted with a group of 5. The 5-membered heteroaromatic compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. E is the formula:

[E is a halogen atom, an acetyl group, a cyano group, one R ¹⁷ (R ¹⁷ represents a lower alkyl group)), and -OR ¹¹ (R ¹¹ represents a hydrogen atom or a lower alkyl group;). It may be substituted with one or two groups arbitrarily selected from the group. The 5-membered heteroaromatic ring compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. E is the formula:

[E is a group consisting of a halogen atom, an acetyl group, a cyano group, one R ¹⁷ (R ¹⁷ represents a lower alkyl group), and -OR ¹¹ (R ¹¹ represents a hydrogen atom or a lower alkyl group). And may be substituted with one or two groups arbitrarily selected from 5. The 5-membered heteroaromatic ring compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. L is the formula:

[Wherein, R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ represent the following (1), (2) or (3). However, when at least one of R ²⁵ , R ²⁶ , and R ² R ²⁸ is a hydrogen atom, a tautomer occurs, and a C CN double bond and a positional isomer of a hydrogen atom exist. Sex is also included.

(1) R ²⁵ , R ²⁶ , R ²⁷ , or R ²⁸ are each independently from the following (a)

(c).

(a) Independently a protecting group for a hydrogen atom, an acyl group, an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms is Nitro group, cyano group, amino group which may be substituted, hydroxyl group, anorecoxy group, acyl group, carboxy group, rubamoyl group which may be substituted, sulfamoyl group which may be substituted, mercapto group, 1S (O) r-R ³² (where r has the same meaning as in claim 1; R ³² represents a lower alkyl group); and -C0 ₂ R ³² (where R ³² has the same meaning as described above). And may be substituted with 1 to 4 substituents selected from. However, when M or M ¹ is a single bond or one O—, R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ do not represent more than three hydrogen atoms at the same time.

(b) R ²⁵ and R ^26, together with together a connexion bonded to the nitrogen atom, 5-7 membered nitrogen-containing moon effect aliphatic Hajime Tamaki (for 5-7 membered nitrogen-containing aliphatic heterocyclic group, a nitro group, A cyano group, an optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, one ^{S (0) r- R 32 (} r and R ³² are as defined above.), single C0 ₂ R ³² (R ³² is as defined above), 1 selected arbitrarily from the group consisting of Okiso group Or may be substituted with two substituents.).

(c) R ²⁷ and R ^28, together with together a connexion bonded to the nitrogen atom, 5-7 membered nitrogen-containing aliphatic Hajime Tamaki (for 5-7 membered nitrogen-containing aliphatic heterocyclic group, a nitro group, Shiano group An optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a canolepoxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, 1S (0) r- R ³² (r and R ³² are as defined above.), single C0 ₂ R ³² (R ³² is as defined above), 1 or 2 optionally selected from the group consisting of Okiso group May be substituted with a plurality of substituents.

(2) R ²⁶ and R ²⁷ are joined together with two nitrogen atoms and one carbon atom to form a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is , Aero group, a cyano group, an amino group which may be substituted, an alkyl group which may be substituted, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, a rubamoyl group which may be substituted, and which may be substituted a sulfamoyl group, a mercapto group, one ^{S (0) r- R 32 (} r and R ³² are as defined above.) one C_〇 ₂ R ³² (R ³² is Ru as defined above der), from Okiso group And may be substituted with one or two substituents arbitrarily selected from the group consisting of:

R ²⁵ and R ^{28 each} independently represent a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) The group includes a nitro group, a cyano group, an optionally substituted amino group, a hydroxyl group, an anoreoxy group, an acyl group, a carboxy group, an optionally substituted sorbamoyl group, an optionally substituted sulfamoyl group, a mercapto group, ^{S (O) r- R 32 (} r and R ³² are as defined above.), or a group comprising a single C0 ₂ R ³² (R ³² is as defined above) And may be substituted with 1 to 4 substituents arbitrarily selected. ).

(3) Or the formula: = C (NR ²⁵ R ²⁶ ) NR ²⁷ R ²⁸ is the formula: = C (NR ¹ R ⁴² ) N = C (NR ⁴³ R ⁴⁴ ) NH ₂ or the formula: = C (NR ⁴¹⁾ R ⁴² ) NHC (NR ⁴³ R ⁴⁴ ) = NH.

(a-1) independently represents a protecting group for a hydrogen atom, an optionally substituted alkyl group or an NH group.

(b-1) together with a nitrogen atom, a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is an alkyl group which may be substituted, And may be substituted with one or two substituents arbitrarily selected from the group consisting of an amino group, a hydroxyl group, an alkoxy group, and an oxo group. 5. The 5-membered heteroaromatic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein

7. L is the formula:

^{^{Wherein, R 45, R 46, R}} 47 and R ⁴⁸ are the following (I ^1), is as (2 or (3 ^1). However, M or M ¹ is a single bond or a, O- In the case, R ⁴⁶ , R ^{47 and} R ⁴⁸ do not simultaneously represent a hydrogen atom.

(al) R ⁴⁵ represents a lower alkyl group or acetyl. R ⁴⁸ represents a hydrogen thickener, a lower alkyl group or acetyl.

(bl) taken together with two nitrogen atoms and one carbon atom, together with a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group is a nitro group, a cyano group, a substituted Amino group which may be substituted, alkyl group which may be substituted, hydroxyl group, alkoxy A group, an acyl group, a carboxy group, an optionally substituted sulfamoyl group, an optionally substituted sulfamoyl group, a mercapto group, one S (O) r—R ³² (r and R ³² are the same as described above.) one C0 ₂ R ^³² (R ³² is as defined above), may be substituted with 1 or 2 substituents selected into groups force et optionally consisting Okiso group. ).

(cl) together with a nitrogen atom, a 5- to 7-membered nitrogen-containing aliphatic heterocyclic group (5-

The 7-membered nitrogen-containing aliphatic heterocyclic group includes a nitro group, a cyano group, an optionally substituted amino group, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, and an optionally substituted group. Rubamoyl group, an optionally substituted sulfamoyl group, mercapto group, one S (O) r—R ³² (where r and R ³² are the same as described above), one CO ₂ R ³² (R ³² is as defined above) ) May be substituted with one or two substituents arbitrarily selected from the group consisting of oxo groups. ).

(2 ¹⁾ R ⁴⁶ and R ⁴⁸ represent said (bl).

R ⁴⁵ and R ⁴⁷ are independently a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) Examples of the group include a nitro group, a cyano group, an amino group which may be substituted, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a mercapto group, ^{S (O) r- R 32 (} r and R ³² are as defined above.), the group force comprising a single C_〇 ₂ R ³² (R ³² is as defined above), from 1 chosen et optionally And may be substituted with 4 substituents.).

(3 ¹⁾ R ⁴⁵ and R ⁴⁶ represent said (bl).

R ⁴⁷ and R ⁴⁸ independently represent a hydrogen atom, an acyl group, a protecting group for an NH group, a linear or branched alkyl group having 1 to 10 carbon atoms (a linear or branched alkyl group having 1 to 10 carbon atoms) Examples of the group include a nitro group, a cyano group, an optionally substituted amino group, a hydroxyl group, an alkoxy group, an acyl group, a carboxy group, an optionally substituted rubamoyl group, an optionally substituted sulfamoyl group, a menolecapto group, and — S (O) rR ³² (r and R ³² are as defined above.), one CO ₂ R ³² (R ³² has the same meaning as defined above) substituted four 1 selected in the group or al any consisting And may be substituted with a group. 6. The 5-membered heteroaromatic ring compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. '