HK1150830B - Process for producing thiazole derivative - Google Patents

Description

Process for preparing thiazole derivatives

The patent application of the invention is a divisional application of an invention patent application with the international application number of PCT/JP2004/016874, the international application date of 2004 of 11-12.2004 and the application number of 200480033384.1 in the Chinese national phase and named as a preparation method of thiazole derivatives.

Technical Field

The present invention relates to a process for producing an intermediate of a compound which exhibits an inhibitory action on activated blood coagulation factor X and is useful as a preventive/therapeutic agent for thrombotic diseases.

Background

It is known that a compound having a heterocyclic group and a diamine structure has a good inhibitory effect on activated blood coagulation factor x (fxa) and can be used as a preventive/therapeutic agent for various thrombotic diseases (patent documents 1 to 6, etc.). As an intermediate for introducing a heterocyclic group into the compound, the compound of formula (5)

The 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid (hereinafter referred to as compound (5)) is an important compound.

Conventionally, as a method for producing the compound (5), a method is known in which a piperidone derivative is treated with phosphorus sulfide to form a thiazole ring, and then a methyl group is introduced into the 5-position with lithium aluminum hydride to form a lithium salt of a carboxylic acid at the 2-position (for example, see patent document 7). Further, a method of introducing a protected aminopyridine into a mercapto group for cyclization and then reducing the pyridine ring to form a lithium salt of a carboxylic acid is known (for example, see patent document 1); or a method in which a protected piperidone is converted into 2-amino-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (hereinafter referred to as compound (2)) by using sulfur powder and cyanamide in the presence of a secondary amine, the 2-amino-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine is brominated with copper bromide and an alkyl nitrite, then a methyl group is introduced into the 5-position by using formaldehyde and sodium triacetoxyborohydride, and the obtained 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (hereinafter referred to as compound (3)) is converted into a lithium salt of a carboxylic acid (for example, see patent document 1).

However, any of the above methods involves a reaction which is difficult to handle on an industrial scale, and involves many steps for protection and deprotection, and chromatography for purification requires a long time for the preparation, which is disadvantageous for industrial production. Further, when the compound (5) is isolated as a lithium salt, the hygroscopicity is very high, handling is difficult, and stability is poor, so that there is a problem in storage.

Further, it is known that compound (2) is obtained by reacting 1-methyl-4-piperidone (hereinafter referred to as compound (1)) with bromine (for example, see patent document 8).

However, bromine is difficult to handle, causes a large load on the environment, and is not favorable for industrial production. In addition, the brominated compound must be isolated as an intermediate, which requires 2 steps.

Further, a technique of obtaining the compound (3) by brominating the compound (2) with copper bromide is known (for example, see patent document 9), but it is necessary to use an equal amount or more of copper bromide, and it is difficult to separate the by-produced copper salt after the reaction. In addition, since purification of the compound (3) requires chromatography, it is not favorable for industrial production.

Patent document 1: international publication No. 01/74774 pamphlet

Patent document 2: international publication No. 03/000680 pamphlet

Patent document 3: international publication No. 03/016302 pamphlet

Patent document 4: international publication No. 2004/058715 pamphlet

Patent document 5: international publication No. 2004/058728 pamphlet

Patent document 6: international publication No. 03/000657 pamphlet

Patent document 7: international publication No. 01/62763 pamphlet

Patent document 8: specification of Dutch patent No. 6610324

Patent document 9: international publication No. 92/07849 pamphlet

Disclosure of The Invention

The object of the present invention is to provide a method for efficiently producing an intermediate of a useful compound exhibiting an inhibitory effect on activated blood coagulation factor X in an industrial scale by a small number of steps using an inexpensive raw material.

The present inventors have conducted extensive studies to solve the above problems and have found that (a) compound (5) is efficiently obtained by hydrolyzing 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (compound (4)) obtained by cyanation of compound (3); (b) the compound (5) is obtained by subjecting 4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (compound 6) obtained by reduction of the compound (2) to trihaloacetylation, followed by hydrolysis; (c) compound (2) is conveniently obtained from compound (1) in 1 step by using a catalytic amount of a secondary amine, followed by obtaining compound (3) from compound (2) without using copper bromide, and treating compounds (2) to (6) with an acidic compound to form a salt of the acidic compound, thereby achieving stable isolation; by combining these steps, the compound (5) can be produced in a small number of steps on an industrial scale, thereby completing the present invention.

That is, the present invention provides the formula (5)

A process for producing a compound represented by the formula (3) or a salt thereof

Reacting the compound represented by the formula (4) or a salt thereof with a metal cyanide to obtain a reaction product

The compound represented by (1) or a salt thereof, and hydrolyzing the compound or the salt thereof.

In addition, the invention also provides a compound of formula (4)

A process for producing a compound represented by the formula (3) or a salt thereof

The compound represented by (A) or a salt thereof is reacted with a metal cyanide compound.

In addition, the invention also provides a compound of formula (5)

A process for producing the compound represented by the formula (4) or a salt thereof

The compound represented by (a) or a salt thereof is hydrolyzed.

In addition, the invention also provides a compound of formula (5)

A process for producing a compound represented by the formula (2) or a salt thereof, which comprises reacting an acidic compound in an aqueous solution in the presence of a reducing agent

Reacting the compound represented by the formula (6) or a salt thereof with an alkali metal nitrite

The compound represented by (1) or a salt thereof is reacted with a trihaloacetyl halide in the presence of a base, and then hydrolyzed.

In addition, the invention also provides a compound of formula (6)

A process for producing a compound represented by the formula (2) or a salt thereof, which comprises reacting an acidic compound in an aqueous solution in the presence of a reducing agent

The compound represented by (1) or a salt thereof is reacted with an alkali metal nitrite.

In addition, the invention also provides a compound of formula (5)

A process for producing a compound represented by the formula (6) or a salt thereof, which comprises reacting a compound represented by the formula (6)

The compound represented by (A) or a salt thereof is reacted with a trihaloacetyl halide and then hydrolyzed.

In addition, the invention also provides a compound of formula (5)

A process for producing a compound represented by the formula (1) or a salt thereof, which comprises reacting a compound represented by the formula (1)

Reacting the compound represented by the formula (2) or a salt thereof with sulfur powder and cyanamide

A compound represented by the formula (3) or a salt thereof, and a reaction of the compound or the salt thereof with hydrobromic acid and an alkali metal nitrite

The compound represented by (1) or a salt thereof, and then reacting the compound or the salt thereof with an alkyllithium and carbon dioxide gas.

In addition, the invention also provides a compound of formula (2)

A process for producing a compound represented by the formula (1) or a salt thereof, which comprises reacting a compound represented by the formula (1) with a secondary amine in the presence of the secondary amine

The compound represented by (1) or a salt thereof is reacted with sulfur powder and cyanamide.

In addition, the present invention also provides a method for obtaining the formula (3)

A process for producing a compound represented by the formula (2) or a salt thereof

The compound represented by (1) or a salt thereof is reacted with hydrobromic acid and an alkali metal nitrite.

In addition, the invention also provides a compound of formula (4)

Salts of the compounds shown with acidic compounds.

In addition, the invention also provides a compound of formula (5)

Salts of the compounds shown and acidic compounds.

In addition, the invention also provides a compound of formula (6)

Salts of the compounds shown and acidic compounds.

In addition, the invention also provides a compound of formula (2)

Salts of the compounds shown and acidic compounds.

In addition, the invention also provides a compound of formula (3)

Salts of the compounds shown and acidic compounds.

In addition, the invention also provides a compound of formula (8)

A process for producing the compound represented by the formula (5) or a salt thereof, which comprises reacting the compound represented by the formula (5)

A compound represented by the formula (7)

The diamines or salts thereof represented by (A) are reacted,

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group,

Q¹represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nIn the group, m and n each independently represent an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or SO₂-NH-，

R³And R⁴In the presence of Q¹Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, optionally substituted by 1 to 3 alkyl groupsThe carbamoyl group (carbazoyl), alkylsulfonyl, alkylsulfonylalkyl, 3-to 6-membered heterocyclic carbonyl group which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3-to 6-membered heterocyclic carbonylalkyl group which may have a substituent, 3-to 6-membered heterocyclic carbonyloxyalkyl group which may have a substituent, aryl, aralkyl, 3-to 6-membered heterocyclic group which may have a substituent, 3-to 6-membered heterocyclic alkyl group which may have a substituent, alkylsulfonylamino, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, alkoxycarbonylalkyl, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkyloxy, carboxyalkoxy, alkoxycarbonylalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3 to 6-membered heterocyclic sulfonyl which may have a substituent(s), 3 to 6-membered heterocyclic oxy which may have a substituent(s), N-alkylaminoacyl, N-dialkylaminoacyl, N-dialkylcarbamoylacyl which may have a substituent(s) on the alkyl group, N-dialkylcarbamoylamino, N-alkoxysulfonyl, N-alkoxyalkylsulfonyl, N, N, N-dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, N-arylcarbamoyl, N-3-to 6-membered heterocyclic carbamoyl, N-alkyl-N-arylcarbamoyl, N-alkyl-N-3-to 6-membered heterocyclic carbamoyl, N-arylcarbamoylalkyl, N-3-to 6-membered heterocyclic carbamoylalkyl, N-alkyl-N-arylcarbamoylalkyl, N-alkyl-N-3-to 6-membered heterocyclic carbamoylalkyl, carbonothioyl, N-alkylcarbamothioyl, N-dialkylcarbamothioyl, alkoxyalkyl (thiocarbonyl), alkylthioalkyl or N-acyl-N-alkylaminoalkyl which may have a substituent on the alkyl group, or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or carbonyldioxy group having 1 to 5 carbon atoms,

Q²represents an aryl group which may have a substituent, an arylalkenyl group which may have a substituent, an arylalkynyl group which may have a substituent, a heteroaryl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-ring or 3-ring fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-ring or 3-ring fused heterocyclic group which may have a substituent,

T¹represents a carbonyl group, a sulfonyl group, a group-C (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -a¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -NH-, a group-C (═ S) -NH-, a group-C (═ O) -NH-NH-, a group-C (═ O) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ N-N (R)^e)(R^f))-C(＝O)-N(R^g) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -NH-C (═ O) -, a group-C (═ S) -NH-C (═ O) -, a group-C (═ C) -O) -NH-C (═ S) -, yl-C (═ S) -NHC (═ S) -, yl-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl.

In addition, the invention also provides a compound of formula (8)

A process for producing the compound represented by the formula (5) or a salt thereof, which comprises reacting the compound represented by the formula (5)

A compound represented by the formula (9)

The diamine represented by the formula (10) or a salt thereof

A compound represented by the formula (I) or a salt thereof, R in the compound or the salt thereof^kLeaving, form formula (11)

A compound represented by the formula (I) or a salt thereof, and then reacting the compound or the salt thereof with the compound of the formula (12)

HO-T¹-Q² (12)

The compound represented by (i) or a salt thereof,

in the formula, R¹、R²、R³、R⁴、T¹、Q¹And Q²As previously described, R^kRepresents a protecting group for an amino group.

Further, the present invention provides compounds of formula (8')

A process for producing the compound represented by the formula (5) or a salt thereof, which comprises reacting the compound represented by the formula (5)

A compound represented by the formula (13)

Reaction of diamines or salts thereof to give compounds of the formula (14)

A compound represented by the formula (11')

A compound represented by the formula (12) or a salt thereof, and reacting the compound or the salt with a compound represented by the formula (I)

HO-T¹-Q² (12)

The compound represented by (i) or a salt thereof,

in the formula, R¹、R³、R⁴、T¹、Q¹And Q²As previously described.

By the process of the present invention, the compound (5) can be advantageously produced on an industrial scale. Further, by the method of the present invention, a compound having an excellent FXa inhibitory activity and useful as a prophylactic or therapeutic agent for thrombotic diseases can be advantageously produced on an industrial scale.

Best Mode for Carrying Out The Invention

The process for producing the compound represented by formula (5) of the present invention will be described below for each step.

Step (A): compound (2) or a salt thereof can be obtained by reacting 1-methyl-4-piperidone (1) or a salt thereof with sulfur powder and cyanamide in the presence of a secondary amine. The compound (1) can be produced, for example, by methylation of 4-piperidone according to a conventional method.

The amount of cyanamide used is preferably 1 to 2 equivalents, more preferably 1 equivalent, based on 1 mole of the compound (1). The amount of the sulfur powder to be used is preferably 1 to 2 equivalents, more preferably 1 equivalent based on 1 mol of the compound (1). The secondary amine is not particularly limited, and may, for example, be diethylamine, diisopropylamine, pyrrolidine, piperidine or morpholine, with pyrrolidine being preferred. The secondary amine may be added in a catalytic amount, preferably 0.01 to 1.2 equivalents, more preferably 0.1 to 0.5 equivalents, further preferably 0.1 equivalent, based on 1 mol of the compound (1).

As the reaction solvent, any solvent may be used as long as it is inactive to the reaction, and alcohol solvents such as methanol, ethanol, and 2-propanol, diethyl ether, tetrahydrofuran, and 1, 4-bis (tert-butyl ether) may be usedEther solvents such as alkanes, and alkyl acetate solvents such as acetonitrile, ethyl acetate, and isopropyl acetate. Among these solvents, an alcohol solvent is preferred, and 2-propanol is more preferred.

The reaction temperature varies depending on the solvent used, and is usually in the range of from 0 ℃ to the boiling point of the solvent, preferably from 45 ℃ to the boiling point of the solvent. The reaction is substantially completed in about 1 to 24 hours, preferably substantially completed in about 2 to 5 hours.

The compound (2) can be isolated as crystals by direct filtration from the reaction solution, but can be isolated as a salt by adding an acidic compound to the reaction solution. The acidic compound is a compound which exhibits acidity by itself or in an aqueous solution thereof. Examples of the acidic compound include organic carboxylic acids such as oxalic acid, acetic acid, benzoic acid, p-nitrobenzoic acid, malic acid, tartaric acid, succinic acid, maleic acid, and fumaric acid, organic sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Of these acidic compounds, hydrobromic acid is preferred.

Step (B): compound (3) or a salt thereof can be obtained by reacting compound (2) or a salt thereof with an alkali nitrite in the presence of hydrobromic acid.

As the alkali metal nitrite, sodium nitrite, potassium nitrite, lithium nitrite and the like can be used, and sodium nitrite is preferred. The amount of the alkali metal nitrite to be used is preferably 1 to 3 equivalents, more preferably 1.5 equivalents based on 1 mol of the compound (2).

The reaction is carried out at a temperature of substantially-20 to 100 ℃, preferably-5 to 15 ℃, for about 1 to 36 hours, preferably 3 to 24 hours.

To the compound (2), an alkali metal hydroxide such as sodium, potassium or lithium or an alkaline earth metal hydroxide such as calcium or barium is added, preferably an aqueous sodium hydroxide solution is added to make it basic (about pH12 to 13), and then the mixture is extracted with an appropriate solvent and concentrated under reduced pressure to be separated.

The extraction solvent is not particularly limited, but may, for example, be an ether solvent such as diethyl ether, isopropyl ether or methyl t-butyl ether, an aromatic hydrocarbon solvent such as benzene or toluene, or an alkyl acetate solvent such as ethyl acetate or isopropyl acetate.

Further, the compound (3) can be isolated as a salt by dissolving it in an appropriate solvent and treating it with an acidic compound. The acidic compound may, for example, be the above-mentioned compounds, and among them, p-toluenesulfonic acid is preferred.

The solvent is not particularly limited, and alcohol solvents such as methanol, ethanol, and 2-propanol, diethyl ether, tetrahydrofuran, and 1, 4-bis (tert-butyl ether) can be usedEther solvents such as alkanes, aromatic solvents such as benzene and toluene, and alkyl acetate solvents such as acetonitrile, ethyl acetate and isopropyl acetate. Among these solvents, an alcohol solvent is preferred, and methanol is more preferred.

Step (C): by reacting the compound (3) or a salt thereof with a metal cyanide, 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (hereinafter referred to as compound 4) or a salt thereof can be obtained.

Examples of the metal cyanide include sodium cyanide, potassium cyanide, lithium cyanide, copper cyanide, and zinc cyanide. More than 2 of them may be used in combination, and sodium cyanide and copper cyanide are preferably used in combination. The amount of the metal cyanide compound to be used is preferably 1 to 3 equivalents, more preferably 1.5 equivalents based on 1 mol of the compound (3).

The reaction solvent is not particularly limited as long as it is inactive to the reaction, and amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, aromatic hydrocarbon solvents such as benzene and toluene, and dimethylsulfoxide can be used. Among them, N-dimethylacetamide is preferred.

The reaction temperature is 0 to 200 ℃, preferably 140 to 160 ℃. The reaction is substantially completed in about 8 to 48 hours, preferably 13 to 20 hours.

The compound (4) can be isolated by adding an aqueous solution of sodium hydrogencarbonate and the like, followed by extraction with an appropriate solvent and concentration under reduced pressure.

The extraction solvent is not particularly limited, but may, for example, be an ether solvent such as diethyl ether, isopropyl ether or methyl t-butyl ether, an aromatic hydrocarbon solvent such as benzene or toluene, or an alkyl acetate solvent such as ethyl acetate or isopropyl acetate.

Further, the compound (4) can be isolated as a salt of an acidic compound. The acidic compound may, for example, be the above-mentioned compounds, and among these acidic compounds, hydrochloric acid is preferred.

Step (D): compound (5) or a salt thereof can be obtained by hydrolyzing compound (4) or a salt thereof.

The hydrolysis can be carried out by dissolving the compound (4) in an appropriate solvent and treating with an aqueous solution of an alkali metal hydroxide. The alkali metal hydroxide may, for example, be sodium hydroxide, lithium hydroxide or potassium hydroxide, with lithium hydroxide being preferred. As the solvent, alcohol solvents such as ethanol, methanol and 2-propanol, acetone and acetonitrile can be used, and ethanol is preferred.

The reaction temperature is in the range of 0 ℃ to the boiling point of the solvent, preferably 40 to 70 ℃. The reaction is substantially completed within about 1 to 24 hours, preferably 5 to 10 hours.

By adding an acidic compound to the reaction solution, the compound (5) can be isolated as a salt. The acidic compound may, for example, be the compound described above, and among them, hydrochloric acid is preferred.

A step (E): the compound (5) or a salt thereof can be obtained by reacting the compound (3) or a salt thereof with alkyllithium and carbon dioxide gas.

The reaction is completed in 2 stages, and the 1 st stage is a stage of forming a lithium salt using an alkyllithium. The amount of the alkyllithium to be used is preferably 1 to 2 equivalents, more preferably 1 to 1.2 equivalents, based on 1 mol of the compound (3). As the alkyllithium, n-butyllithium is preferred. The reaction temperature is in the range of-78 ℃ to the boiling point of the solvent, preferably-78 to 0 ℃, and the reaction is substantially completed within minutes to 24 hours, preferably within minutes to 2 hours.

The 2 nd stage is a reaction of the lithium salt obtained in the 1 st stage and carbon dioxide gas. Specifically, carbon dioxide gas is blown into the reaction solution after the formation of the lithium salt, or the inside of the reaction system is put under an atmosphere of carbon dioxide gas. The reaction temperature is in the range of-78 ℃ to the boiling point of the solvent, preferably-78 to 0 ℃. The reaction is substantially completed within several minutes to 24 hours, preferably several minutes to 2 hours. It is preferable that the 2-stage reaction in this step is carried out in an atmosphere of an inert gas such as nitrogen or argon.

The reaction solvent is not particularly limited as long as it is inert to the reaction, and examples thereof may include methyl t-butyl ether, isopropyl ether, tetrahydrofuran and 1, 4-bisEther solvents such as alkanes, chain or cyclic saturated hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane, and aromatic hydrocarbon solvents such as benzene and toluene, among which ether solvents are preferred, and tetrahydrofuran is more preferred.

The compound (5) can be isolated as a lithium salt by filtration directly from the reaction solution, but the lithium salt is unstable, and it is preferable to isolate the lithium salt as a salt of the compound (5) by adding an appropriate second solvent to the free carboxylic acid and treating the mixture with an acidic compound. The acidic compound may, for example, be the above-mentioned compound, but hydrochloric acid is preferred.

The second solvent is not particularly limited, and an alcohol solvent such as methanol, ethanol, or 2-propanol, an alkyl acetate solvent such as acetonitrile, ethyl acetate, or isopropyl acetate, or the like can be used. Among them, preferred is an alcohol solvent, and more preferred is methanol.

Step (F): compound (6) or a salt thereof can be obtained by reacting compound (2) or a salt thereof with an alkali nitrite in an aqueous solution of an acidic compound in the presence of a reducing agent.

The acidic compound may, for example, be the above-mentioned compound, but sulfuric acid is preferred.

The reducing agent may, for example, be hydrogen, sodium borohydride, hypophosphorous acid or formic acid, and hypophosphorous acid is preferred. The alkali metal nitrite may, for example, be sodium nitrite, potassium nitrite or lithium nitrite, but sodium nitrite is preferred.

The amount of the reducing agent to be used is preferably 1 to 3 equivalents, more preferably 2 equivalents, based on 1 mol of the compound (2). The amount of the alkali metal nitrite to be used is preferably 1 to 3 equivalents, more preferably 2 equivalents based on 1 mol of the compound (2). The reaction is carried out at a temperature of-20 to 50 deg.C, preferably-5 to 15 deg.C for about 1 to 36 hours, more preferably 1 to 24 hours.

The compound (6) can be isolated by adding an alkali metal hydroxide such as sodium, potassium or lithium, preferably an aqueous solution of lithium hydroxide to make it alkaline (about pH 12-13), extracting with an appropriate solvent, and concentrating under reduced pressure.

The extraction solvent is not particularly limited, and ether solvents such as diethyl ether, isopropyl ether and methyl t-butyl ether, aromatic hydrocarbon solvents such as benzene and toluene, alkyl acetate solvents such as ethyl acetate and isopropyl acetate, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and the like can be used. Among these solvents, alkyl acetate solvents or halogenated hydrocarbon solvents are preferred, and ethyl acetate is more preferred.

Further, by adding an acidic compound in an appropriate solvent, the compound (6) can be isolated as a salt. The solvent is not particularly limited, and alcohol solvents such as methanol, ethanol, and 2-propanol, diethyl ether, tetrahydrofuran, and 1, 4-bis (tert-butyl ether) can be usedEther solvents such as an alkane, aromatic solvents such as benzene and toluene, and alkyl acetate solvents such as acetonitrile, ethyl acetate and isopropyl acetate may also be used. Of these solvents, preferred is an alcohol-based solvent, and more preferred is 2-propanol.

The acidic compound may, for example, be the above-mentioned compound, preferably p-toluenesulfonic acid.

A step (G): compound (5) or a salt thereof can be obtained by reacting compound (6) or a salt thereof with a trihaloacetyl halide in the presence of a base, followed by hydrolysis.

The amount of the trihaloacetyl halide to be used is preferably 1 to 3 equivalents, more preferably 2 equivalents based on 1 mol of the compound (6). The trihaloacetyl halide may, for example, be tribromoacetyl chloride or trichloroacetyl chloride, and trichloroacetyl chloride is preferred. The base is not particularly limited, and a tertiary amine such as triethylamine, diisopropylethylamine or N-methylmorpholine, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an inorganic base such as a carbonate or a hydrogencarbonate may be used. The amount of the base to be used is 1 mole, preferably 1 to 3 equivalents, more preferably 2 equivalents, based on the compound (6).

The reaction solvent is not particularly limited, and diethyl ether, tetrahydrofuran, and 1, 4-bis (tetrahydrofuran) can be usedEther solvents such as alkanes, aromatic solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and alkyl acetate solvents such as dimethyl sulfoxide, acetonitrile, ethyl acetate and isopropyl acetate. Among these solvents, aromatic hydrocarbon solvents such as toluene and alkyl acetate solvents such as ethyl acetate and isopropyl acetate are preferred, and toluene, ethyl acetate and isopropyl acetate are more preferred.

The reaction temperature varies depending on the solvent used, and is usually in the range of from-78 ℃ to the boiling point of the solvent, preferably in the range of from 0 ℃ to the boiling point of the solvent. The reaction is substantially completed in about 1 to 24 hours, preferably 1 to 5 hours.

The hydrolysis can be continuously carried out by adding an aqueous solution of an alkali metal hydroxide to the above reaction solution. As the alkali metal hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide and the like can be used, and lithium hydroxide is preferred.

The reaction temperature is usually in the range of-5 ℃ to the boiling point of the solvent, preferably in the range of 0 ℃ to the boiling point of the solvent. The reaction is substantially completed in about 1 to 10 hours, preferably 1 to 5 hours.

After completion of the hydrolysis, the organic layer and the aqueous layer are separated by liquid separation, the compound (5) is separated into the aqueous layer, and fat-soluble impurities and the like are separated into the organic layer. Alternatively, the aqueous layer is concentrated after separation, and an appropriate second solvent is added, followed by addition of an acidic compound, whereby the compound (5) can be isolated as a salt.

The second solvent is not particularly limited, and an alcohol solvent such as methanol, ethanol, or 2-propanol, an alkyl acetate solvent such as acetonitrile, ethyl acetate, or isopropyl acetate, or the like can be used. Among these solvents, an alcohol solvent is preferred, and methanol is particularly preferred.

The acidic compound may, for example, be the above-mentioned compound, and hydrochloric acid is preferred.

Hereinafter, a method for producing compound (8) from compound (5) which can be used as a prophylactic and therapeutic agent for thrombotic diseases will be described. The process for producing compound (8) from compound (5) can be carried out according to the process described in the pamphlet of International publication No. 2004/058715 or a similar process. A typical method will be described below.

In the formula, R¹、R²、R³、R⁴、R^k、T¹、Q¹And Q²As previously described.

Step (H): compound (8) or a salt thereof can be obtained by reacting compound (5) or a salt thereof with diamine (7) or a salt thereof.

If necessary, the compound (5) may be derivatized into a mixed acid anhydride, an acid halide or an active ester, and then reacted. The reaction may employ reaction reagents and conditions commonly used for peptide synthesis. The mixed acid anhydride can be produced, for example, by reacting a chloroformate such as ethyl chloroformate or isobutyl chloroformate with the compound (5) in the presence of a base. Compound (5) is treated with an acid halide such as thionyl chloride or oxalyl chloride to obtain an acid halide. There are many active esters, and for example, the active ester can be obtained by reacting a phenol such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, with the compound (5) using a condensing agent such as N, N' -dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Further, the active ester may be obtained by reacting the compound (5) with pentafluorophenyl trifluoroacetate or the like, the compound (5) and 1-benzotriazolyloxytripyrrolidinyl groupHexafluorophosphate, compound (5) and diethyl cyanophosphonate (salt addition method), compound (5) and triphenylphosphine and 2, 2' -dipyridyl disulfide (Moyama method). Compound (8) can be obtained by reacting the mixed acid anhydride, acid halide or active ester of compound (5) obtained above in the presence of diamine (7) and an appropriate base in an inert solvent at-78 ℃ to 150 ℃.

Specific examples of the base used in the above step include carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, alkali metal alkoxides, alkali metal hydroxides and hydrides, organometallic bases typified by lithium dialkylamides such as alkyllithium and lithium diisopropylamide, such as lithium bis (trimethylsilyl) amide, and organometallic bases of disilylamine such as lithium bis (trimethylsilyl) amide, and organic bases such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU).

The inert solvent used in the present reaction may, for example, be a halogenated alkyl solvent such as methylene chloride, chloroform or carbon tetrachloride, tetrahydrofuran, 1, 2-dimethoxyethane or dioxaneEther solvents such as alkanes, aromatic solvents such as benzene and toluene, and amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one. In addition, sulfoxide solvents such as dimethyl sulfoxide and sulfolane, ketone solvents such as acetone and methyl ethyl ketone, and the like may be used as appropriate.

Step (I): the compound (10) or a salt thereof can be obtained by reacting the compound (5) or a salt thereof with the diamine (9) or a salt thereof. Here, as R^kExamples of the protective group for an amino group include an alkanoyl group such as an acetyl group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group, an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxyphenylmethoxycarbonyl group or a p- (or o-) nitrobenzyloxycarbonyl group, an arylmethyl group such as a benzyl group or a triphenylmethyl group, an aroyl group such as a benzoyl group, and an arylsulfonyl group such as a 2, 4-dinitrobenzenesulfonyl group or an o-nitrobenzenesulfonyl group. The reaction of the compound (5) with the diamine (9) is carried out in the same manner as in the step (H).

Step (J): making a protecting group (R)^k) Leaving compound (10) or a salt thereof to obtain compound (11) or a salt thereof. The deprotection reaction may be selected depending on the kind of the protecting groupReagents and conditions generally used. For example, when the protecting group is a tert-butoxycarbonyl group, it may be treated with trifluoroacetic acid or the like at-20 to 70 ℃.

Step (K): compound (8) or a salt thereof is obtained by reacting compound (11) or a salt thereof with compound (12) or a salt thereof. The reaction is carried out in the same manner as in the step (H).

Step (L): compound (14) or a salt thereof is obtained by reacting compound (5) or a salt thereof with compound (13) or a salt thereof. In this reaction, R¹Preferably a hydrogen atom.

The reaction can be carried out in the same manner as in the above-mentioned steps (I) and (H).

A step (M): obtaining a compound (11) or a salt thereof by reducing a compound (14) or a salt thereof, wherein R in the formula (11)²Is a hydrogen atom. The reduction is carried out in the presence of a catalyst such as platinum or palladium, and if necessary, under pressure.

The starting compounds (7), (9), (12) and (13) used in the steps (I) to (M) can be obtained by the method described in the pamphlet of International publication No. 2004/058715.

The substituents in the compound represented by formula (8) are explained below.

(group Q)²)

Group Q²Represents an aryl group which may have a substituent, an arylalkenyl group which may have a substituent, an arylalkynyl group which may have a substituent, a heteroaryl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-ring or 3-ring fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-ring or 3-ring fused heterocyclic group which may have a substituent.

Group Q²In the above formula, the aryl group is an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl, phenanthryl, etc. The arylalkenyl group represents a group composed of an aryl group having 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbon atoms, and may, for example, be a styryl group. Arylalkynyl represents a group consisting of carbon atomsExamples of the group consisting of an aryl group having 6 to 14 carbon atoms and an alkynylene group having 2 to 6 carbon atoms include phenylethynyl and the like.

The heterocyclic group represents an aromatic 1-valent group having at least 1 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and may, for example, be a heteroaryl group having a total of 5 or 6 atoms, such as a pyridyl group, a pyridazinyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group,Oxazolyl, pyrimidinyl, tetrazolyl, and the like. The heteroarylalkenyl group represents a group composed of the above-mentioned heteroaryl group and an alkenylene group having 2 to 6 carbon atoms, and may, for example, be a thienylvinyl group or a pyridylvinyl group.

The saturated or unsaturated 2-or 3-ring fused hydrocarbon group represents a 1-valent group of a saturated or unsaturated 2-or 3-ring fused hydrocarbon, and the saturated or unsaturated 2-or 3-ring fused hydrocarbon represents a 2-or 3-ring fused hydrocarbon obtained by fusing 2 to 3 identical or different saturated or unsaturated 5-to 6-membered cyclic hydrocarbons. Examples of the saturated or unsaturated 5-to 6-membered cyclic hydrocarbon in this case include cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, benzene, and the like. Specific examples of the saturated or unsaturated 2-ring or 3-ring fused hydrocarbon group include indenyl, indanyl, tetrahydronaphthyl and naphthyl. Further, for saturated or unsaturated 2-or 3-ring fused hydrocarbon groups and T¹The bonding position of (3) is not particularly limited.

The saturated or unsaturated 2-or 3-ring fused heterocyclic group represents a 1-valent group of a saturated or unsaturated 2-or 3-ring fused heterocyclic ring represented by the following 1) to 3).

1) 2-ring or 3-ring fused heterocyclic rings obtained by fusing 2 to 3 same or different saturated or unsaturated 5-to 7-membered heterocyclic rings,

2) a 2-or 3-ring fused heterocyclic ring obtained by fusing 1 saturated or unsaturated 5-to 7-membered heterocyclic ring and 1 to 2 saturated or unsaturated 5-to 6-membered cyclic hydrocarbon, and

3) a 3-ring fused heterocyclic ring obtained by fusing 2 saturated or unsaturated 5-to 7-membered heterocyclic rings and 1 saturated or unsaturated 5-to 6-membered cyclic hydrocarbon.

A 2-or 3-ring fused heterocyclic group which is the above-mentioned saturated or unsaturated group and T¹The bonding position of (3) is not particularly limited.

The saturated or unsaturated 5-to 7-membered heterocyclic ring is a heterocyclic ring having at least 1 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and specific examples thereof include furan, pyrrole, thiophene, pyrazole, imidazole, and the like,Azole,Oxazolidine, thiazole, thiadiazole, furazan, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidineOxazine,Diazines, morpholines, thiazines, thiadiazines, thiomorpholines, tetrazoles, triazoles, triazines, thiadiazines,Diazines and azepinesDiaza, diazaTriaza, triazaSulfur and nitrogen hetero(thiazepine), oxazepine(oxazepine) and the like. The saturated or unsaturated 5-to 6-membered cyclic hydrocarbon is the same as the saturated or unsaturated 5-to 6-membered cyclic hydrocarbon exemplified in the description of the saturated or unsaturated 2-or 3-ring fused hydrocarbon group. Specific examples of the saturated or unsaturated 2-or 3-ring fused heterocyclic group include benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, indolinyl, isoindolinyl, indolizinyl, indazolyl, quinolinyl, dihydroquinolinyl, 4-oxodihydroquinolinyl (dihydroquinolin-4-one), tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, chromenyl, chromanyl, isobenzodihydropyranyl, 4H-4-oxobenzopyranyl, 3, 4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, tetrahydroquinoxalinyl, cinnolinyl, tetrahydrocinnolinyl, indolizinyl, tetrahydroindolizinyl, benzothiazolyl, Tetrahydrobenzothiazolyl, benzoAzolyl, benzisothiazolyl, benzisoxazolylOxazolyl, benzimidazolyl, naphthyridinyl, tetrahydronaphthyridinyl, thienopyridinyl, tetrahydrothienopyridinyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl, thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, tetrahydropyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinoxalyl, dihydropyridoquinoxalyl, pyridopyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridinyl, tetrahydrofuropyridinyl, thiazolopyridinyl,Azolopyridinyl, tetrahydroAn azolopyridinyl group,Azolopyridazinyl, tetrahydroAzolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrroloAzolyl, dihydropyrroloAzolyl, thienopyrrolyl, thiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl, 1, 2, 4-benzothiadiazinyl, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 1, 2, 4-benzothiadiazinylDiazinyl, cyclopentopyranyl, thienofuryl, furopyranyl, pyridoAzinyl, pyrazoloAzolyl, imidazothiazolyl, imidazopyridinyl, tetrahydroimidazopyridinyl, pyrazinopyridazinyl, benzisoquinolinyl, furocinnolinyl, pyranothiazolopyridazinyl, tetrahydropyranothiazolopyridazinyl, hexahydrothiazolopyridazinyl, imidazotriazinyl, oxazolotriazolyl, oxazolopyridazinyl, pyrazolopyridazinyl, pyrazinopyridazinyl, benzoxazinyl, pyrazolopyridazinyl, pyrazolopyri,Azolopyridinyl, benzoxazepinylRadical, benzazepineTetrahydro, tetrahydroBenzazepine compoundsRadical, benzodiazepineRadical, benzotriazazepineAryl, thienoazaAryl, tetrahydrothienoazepineAryl, thienodiazepinesAryl, thienotriazaThiazolyl and thiazolyl azaTetrahydro-thiazoloazepineA 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl group, a 5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl group, or the like. The condensed form of the above-mentioned condensed heterocyclic group is not particularly limited.

The above-mentioned aryl group, heteroaryl group, arylalkenyl group, heteroarylalkenyl group, saturated or unsaturated 2-ring or 3-ring fused hydrocarbon group and saturated or unsaturated 2-ring or 3-ring fused heterocyclic group may have 1 to 3 substituents, respectively, and examples of the substituents include a halogen atom such as a hydroxyl group, fluorine atom, chlorine atom, bromine atom and iodine atom, a haloalkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, an amino group, a cyano group, an aminoalkyl group, a nitro group, a hydroxyalkyl group (e.g., hydroxymethyl group and 2-hydroxyethyl group), an alkoxyalkyl group (e.g., methoxymethyl group and 2-methoxyethyl group), a carboxyl group, a carboxyalkyl group (e.g., carboxymethyl group and 2-carboxyethyl group), an alkoxycarbonylalkyl group (e.g., methoxycarbonylmethyl group and ethoxycarbonylmethyl group), an acyl group (e.g., formyl group, acetyl group, Alkanoyl group such as propionyl group), amidino group, hydroxyamidino group (amino (hydroxyimino) methyl group), linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (for example, methyl group, ethyl group and the like), linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (for example, methoxy group, ethoxy group and the like), linear, branched or cyclic alkyl group-substituted amidino group having 1 to 6 carbon atoms (for example, imino (methylamino) methyl group and the like), linear, branched or cyclic alkoxy group-substituted amidino group having 1 to 6 carbon atoms (for example, amino (methoxyimino) methyl group and the like), linear, branched or cyclic alkoxycarbonyl group-substituted amidino group having 2 to 7 carbon atoms (for example, amino (methoxycarbonylimino) methyl group, amino (ethoxycarbonylimino) methyl group and the like), linear, A branched or cyclic alkenyl group having 2 to 6 carbon atoms (e.g., a vinyl group, an allyl group, etc.), a linear or branched alkynyl group having 2 to 6 carbon atoms (e.g., an ethynyl group, a propynyl group, etc.), a linear, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, etc.), a carbamoyl group, a mono-or dialkylcarbamoyl group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms on the nitrogen atom (e.g., a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, an ethylmethylcarbamoyl group, etc.), a linear, branched or cyclic mono-or dialkylamino group substituted with an alkyl group having 1 to 6 carbon atoms (e.g., an ethylamino group, a dimethylamino group, a methylethylamino group) and a 5 to 6-membered nitrogen-containing heterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like).

Group Q²The following 12 groups (a) to (l) among the above groups are preferred. That is to say that the first and second electrodes,

in the radical, R⁵And R⁶Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, or a phenyl group which may be substituted by a cyano group, a hydroxyl group, a halogen atom, an alkyl group or an alkoxy group, R⁷And R⁸Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, R⁹And R¹⁰Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, R¹¹、R¹²And R¹³Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl groupA group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, X¹Represents CH₂CH, NH, NOH, N, O or S, R¹⁴、R¹⁵And R¹⁶Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, X²Represents NH, N, O or S, X³Denotes N, C or CH, X⁴Denotes N, C or CH, R¹⁷And R¹⁸Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group. X³And X⁴Except for the case of a combination of C and CH and the case of both C and CH.

In which N represents R¹⁹1 or 2 carbon atoms of the substituted ring are substituted with nitrogen atoms,R¹⁹、R²⁰and R²¹Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, X⁵Represents CH₂CH, N or NH, Z¹Denotes N, NH or O, Z²Represents CH₂CH, C or N, Z³Represents CH₂、CH、S、SO₂Or C ═ O, X⁵-Z²Represents X⁵And Z²By a single or double bond, R²²And R²³Each independently represents a hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, R²⁴Represents a hydrogen atom or an alkyl group.

In the radical, X⁶Represents O or S, R²⁵And R²⁶Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkane groupAnd (4) a base.

In the radical, R²⁷And R²⁸Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, E¹And E²Each independently represents N or CH, R²⁹And R³⁰Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

In the radical, Y¹Represents CH or N, Y²represents-N (R)³³) - (in the radical, R)³³Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), O or S, R³¹And R³²Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group,Acyl, carbamoyl, N-alkylcarbamoyl, N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl.

In the group, the number of 1 to 8 represents a position, each of N represents 1 to 4 carbon atoms and 1 to 5 to 8 carbon atoms is substituted by 1 nitrogen atom, and R³⁴、R³⁵And R³⁶Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group or an alkoxycarbonylalkyl group.

The above groups are described below.

R in the above-mentioned group⁵～R³⁶Wherein the halogen atom in the description represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, the alkyl group represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, the alkenyl group represents a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms, the alkynyl group represents a linear or branched alkynyl group having 2 to 6 carbon atoms, and the hydroxyalkyl group represents the C-alkyl group₁-C₆A group in which the alkyl group is substituted by 1 hydroxyl group, the alkoxy group represents a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and the alkoxyalkyl group represents the above-mentioned C₁-C₆Alkyl radicals being substituted by 1 of the above-mentioned C₁-C₆A group substituted with an alkoxy group, the carboxyalkyl group being C as defined above₁-C₆A group in which the alkyl group is substituted with 1 carboxyl group, and the acyl group represents an alkanoyl group having 1 to 6 carbon atoms (including formyl group), an aroyl group such as benzoyl group or naphthoyl group, or C₁-C₆Alkanoyl radicals substituted by C₆-C₁₄Aryl-substituted arylalkanoylN-alkylcarbamoyl represents the above-mentioned C₁-C₆Carbamoyl group having alkyl group substituted on nitrogen atom, N, N-dialkylcarbamoyl group represents 2 of the above-mentioned C₁-C₆Carbamoyl group substituted with alkyl group at nitrogen atom, alkoxycarbonyl group represented by the above-mentioned group C₁-C₆Alkoxy and carbonyl, alkoxycarbonylalkyl representing C₁-C₆Alkyl radicals being substituted by 1 of the above-mentioned C₁-C₆A group substituted with alkoxycarbonyl, the haloalkyl representing the above-mentioned C₁-C₆A group in which an alkyl group is substituted with 1 to 3 halogen atoms. In the above description, the substitution position is not particularly limited.

The following groups

(in the group, R⁵、R⁶、R⁷And R⁸As described above, the number of 1 to 6 indicates the position), R is preferably selected from⁵And R⁶Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, R⁵And R⁶More preferably a hydrogen atom or an alkyl group, and in the case of an alkyl group, a methyl group is preferred. Further, R is preferable⁷And R⁸One of them is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group. Among them, the case where the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group is particularly preferable. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the group represented by the above formula include chlorostyryl group, fluorostyryl group, bromostyryl group, ethynylstyryl group and the like, and the substitution position of the halogen atom, alkyl group or alkynyl group in these groups is not particularly limited, but is particularly preferably the 4-position in the above formula. Specific examples thereof include 4-chlorostyryl group,4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl, and the like.

The following groups

(in the group, R⁹And R¹⁰As described above, the number of 1 to 6 indicates the position), R is preferably selected from⁹And R¹⁰Each independently represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. More preferably R⁹Is a hydrogen atom, R¹⁰In the case of a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the above-mentioned groups include chlorophenylethynyl, fluorophenylethynyl, bromophenylethynyl and ethynylphenylethynyl groups, and the substitution position of the halogen atom, alkyl group or alkynyl group in these groups is not particularly limited, but is particularly preferably the 4-position in the above formula. Specific examples thereof include 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl and 4-ethynylphenylethynyl.

The following groups

(in the group, R¹¹、R¹²And R¹³As described above, the number of 1 to 8 represents a position), R is preferably¹¹、R¹²And R¹³Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. R¹¹More preferred are a hydrogen atom, an alkyl group, a halogen atom and a hydroxyl group, and particularly preferred is a hydrogen atom. It is preferable that R is¹²And R¹³One party of (A) is hydrogenThe other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Among the above naphthyl groups, 2-naphthyl group is more preferable than 1-naphthyl group, and in the case of 2-naphthyl group, the position of substitution with a halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 6-position or 7-position, particularly preferably the 6-position in the above formula. Among these naphthyl groups, preferred are those substituted with a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group, etc., particularly preferred are those substituted with a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group, etc., and specific examples thereof include 6-chloro-2-naphthyl group, 6-fluoro-2-naphthyl group, 6-bromo-2-naphthyl group, 6-ethynyl-2-naphthyl group, 7-chloro-2-naphthyl group, 7-fluoro-2-naphthyl group, 7-bromo-2-naphthyl group, 7-ethynyl-2-naphthyl group, etc.

The following groups

(in the group, X¹、R¹⁴、R¹⁵And R¹⁶As described above, 4 to 7 numbers represent positions), X¹Preferably NH, NOH, N, O and S, more preferably NH, O and S, R¹⁴Preferred are a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkyl group, and R is preferred¹⁵And R¹⁶Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. It is preferable that R is¹⁵And R¹⁶One of them is a hydrogen atom or a halogen atom, preferably a fluorine atom or a chlorine atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, particularly preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atomAnd a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 4-, 5-or 6-position in the above formula.

Specific examples of the group represented by the above formula may include 5-chloroindolyl, 5-fluoroindolyl, 5-bromoindolyl, 5-ethynylindolyl, 5-methylindolyl, 5-chloro-4-fluoroindolyl, 5-chloro-3-fluoroindolyl, 5-fluoro-3-chloroindolyl, 5-ethynyl-3-fluoroindolyl, 5-chloro-3- (N, N-dimethylcarbamoyl) indolyl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indolyl, 5-chloro-3-formylindolyl, 5-fluoro-3-formylindolyl, 6-chloroindolyl, 6-fluoroindolyl, etc, 6-bromoindolyl, 6-ethynylindolyl, 6-methylindolyl, 5-chlorobenzothienyl, 5-fluorobenzothienyl, 5-bromobenzothienyl, 5-ethynylbenzothienyl, 5-methylbenzothienyl, 5-chloro-4-fluorobenzothienyl, 6-chlorobenzothienyl, 6-fluorobenzothienyl, 6-bromobenzothienyl, 6-ethynylbenzothienyl, 6-methylbenzothienyl, 5-chlorobenzofuranyl, 5-fluorobenzofuranyl, 5-bromobenzofuranyl, 5-ethynylbenzofuranyl, 5-methylbenzofuranyl, 5-chloro-4-fluorobenzofuranyl, 6-chlorobenzofuranyl, 6-fluorobenzofuranyl, 5-chlorobenzofuranyl, 6-bromobenzofuranyl, 6-ethynylbenzofuranyl, 6-methylbenzofuranyl and the like.

For these substituents and T¹The binding position of (d) is not particularly limited, but it is preferably 2-position or 3-position in the above formula (d), and specifically more preferably 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl-bromo-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl, 5-bromoindol-3-yl, 5-ethynylindol-3-yl, 5-methylindol-3-yl, 5-chloro-4-fluoroindol-3-yl, 5-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 6-chloroindol-3-yl, 6-fluoroindol-3-yl, 6-bromoindol-3-yl, 6-ethynylindol-3-yl, 6-methylindol-3-yl, 5-chlorobenzothien-2-yl, 5-fluorobenzothien-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothien-2-yl, 5-methylbenzothien-2-yl, 5-chloro-4-fluorobenzothien-2-yl, 6-chlorobenzothien-2-yl, 6-fluorobenzothien-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothien-2-yl, 6-bromobenzothien-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzothiophen-3-yl, 5-fluorobenzothiophen-3-yl, 5-bromobenzothiophen-3-yl, 5-ethynylbenzothien-3-yl, 5-methylbenzothiophen-3-yl, 5-chloro-4-fluorobenzothiophen-3-yl, 6-chlorobenzothiophen-3-yl, 6-fluorobenzothiophen-3-yl, 6-bromobenzothiophen-3-yl, 6-ethynylbenzothiophen-3-yl, 6-methylbenzothiophen-3-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-chlorobenzofuran-3-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzofuran-3-yl, 5-fluorobenzofuran-3-yl, 5-bromobenzofuran-3-yl, 5-ethynylbenzofuran-3-yl, 5-methylbenzofuran-3-yl, 5-ethynylbenzofuran-3-yl, 5-chloro-4-fluorobenzofuran-3-yl, 6-chlorobenzofuran-3-yl, 6-fluorobenzofuran-3-yl, 6-bromobenzofuran-3-yl, 6-ethynylbenzofuran-3-yl, 6-methylbenzofuran-3-yl and the like.

Particularly preferred are 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-bromo-3- (N, n-dimethylcarbamoyl) indol-2-yl, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-chlorobenzothien-2-yl, 5-fluorobenzothien-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothien-2-yl, 5-methylbenzothien-2-yl, 5-chloro-4-fluorobenzothien-2-yl, 6-chlorobenzothien-2-yl, 6-fluorobenzothien-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothien-2-yl, m, 6-methylbenzofuran-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl.

The following groups

(in the group, X²、X³、X⁴、R¹⁷And R¹⁸As described above, the number of 4 to 7 indicates the position), X is preferable²Is NH, O or S, X³And X⁴One of them is CH or C, and particularly preferably one is C. It is preferable that R is¹⁷And R¹⁸Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. It is preferable that R is¹⁷And R¹⁸One of them is a hydrogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, particularlyThe other is preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group.

The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 5-position or 6-position in the above formula. Specific examples of the group represented by the above formula include 5-chloroindazolyl, 5-fluoroindazolyl, 5-bromoindazolyl, 5-ethynylindazolyl, 6-chloroindazolyl, 6-fluoroindazolyl, 6-bromoindazolyl, 6-ethynylindazolyl, 5-chlorobenzimidazolyl, 5-fluorobenzimidazolyl, 5-bromobenzimidazolyl, 5-ethynylbenzimidazolyl, 6-chlorobenzimidazolyl, 6-fluorobenzimidazolyl, 6-bromobenzimidazolyl, 6-ethynylbenzimidazolyl, 5-chlorobenzothiazolyl, 5-fluorobenzothiazolyl, 5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl, 6-chlorobenzothiazolyl, 6-fluorobenzothiazolyl, 6-bromobenzothiazolyl, 5-ethynylbenzothiazolyl, 5-chlorobenzothiazolyl, 6-fluorobenzothiazolyl, 6-bromobenzothiazolyl, 6-ethynylbenzothiazolyl, 5-chlorobenzoylAzolyl, 5-fluorobenzoAzolyl, 5-bromobenzoAzolyl, 5-ethynyl benzolsAzolyl, 6-chlorobenzoAzolyl, 6-fluorobenzoAzolyl, 6-bromobenzoAzolyl, 6-ethynyl benzolesAzolyl, 5-chlorobenzoisothiazolyl, 5-fluorobenzoisothiazolyl, 5-bromobenzoisothiazolyl, 5-ethynylbenzisothiazolyl, 6-chlorobenzoisothiazolyl, 6-fluorobenzoisothiazolyl, 6-bromobenzoisothiazolyl, 6-ethynylbenzisothiazolyl, 5-chlorobenzoisothiazolylAzolyl, 5-fluorobenzoisomersAzolyl, 5-bromobenzoiso-iso-phenylAzolyl, 5-ethynylbenzisoxazoAzolyl, 6-chlorobenzoisoinAzolyl, 6-fluorobenzoisomersAzolyl, 6-bromobenzoisoAzolyl, 6-ethynylbenzisothiazoleAzole groups, and the like.

For these substituents and T¹The binding position of (A) is not particularly limited, but preferred are 5-chloroindazol-3-yl, 5-fluoroindazol-3-yl, 5-bromoindazol-3-yl, 5-ethynylindazol-3-yl, 6-chloroindazol-3-yl, 6-fluoroindazol-3-yl, 6-bromoindazol-3-yl, 6-ethynylindazol-3-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl-yl, 6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl, 5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl, 5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl, 5-chlorobenzothiazol-2-ylAzol-2-yl, 5-fluoro-benzoAzol-2-yl, 5-bromobenzoAzol-2-yl, 5-ethynyl benzolsAzol-2-yl, 6-chlorobenzenesAzol-2-yl, 6-fluoro-benzoAzol-2-yl, 6-bromobenzoAzol-2-yl, 6-ethynyl benzolsOxazol-2-yl, 5-chlorobenzoisothiazol-3-yl, 5-fluorobenzoisothiazol-3-yl, 5-bromobenzoisothiazol-3-yl, 5-ethynylbenzisothiazol-3-yl, 6-chlorobenzoisothiazol-3-yl, 6-fluorobenzoisothiazol-3-yl, 6-bromobenzoisothiazol-3-yl, 6-ethynylbenzisothiazol-3-yl, 5-chlorobenzoisothiazol-3-ylAzol-3-yl, 5-fluorobenzoisomersAzol-3-yl, 5-bromobenzoisoAzol-3-yl, 5-ethynylbenzisoxazinesAzol-3-yl, 6-chlorobenzoisoAzol-3-yl, 6-fluorobenzoisomersAzol-3-yl, 6-bromobenzoisoAzol-3-yl, 6-ethynylbenzisoxazinesOxazol-3-yl.

Particularly preferred are 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl, 6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl, 5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl, 5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 2-fluoro-benzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl, 5-chlorobenzothiazolAzol-2-yl, 5-fluoro-benzoAzol-2-yl, 5-bromobenzoAzol-2-yl, 5-ethynyl benzolsAzol-2-yl, 6-chlorobenzenesAzol-2-yl, 6-fluoro-benzoAzol-2-yl, 6-bromobenzoAzol-2-yl, 6-ethynyl benzolsOxazol-2-yl, more preferred among them are 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl and 5-ethynylbenzimidazol-2-yl.

The following groups

(in the group, N represents R¹⁹1 or 2 carbon atoms of the substituted ring being substituted by nitrogen atoms, R¹⁹、R²⁰And R²¹As described above, the number of 5 to 8 represents the position), R is preferable¹⁹、R²⁰And R²¹Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. R¹⁹Particularly preferred is a hydrogen atom, and R is preferred²⁰And R²¹One of them is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 6-position or 7-position in the above formula.

Specific examples of the group represented by the above formula include quinolyl, isoquinolyl and cinnolinyl groups, and preferred are 6-chloroquinolyl, 6-fluoroquinolyl, 6-bromoquinolyl, 6-ethynylquinolyl, 6-chloroisoquinolyl, 6-fluoroisoquinolyl, 6-bromoisoquinolyl, 6-ethynylisoquinolyl, 7-chlorocinnolinyl, 7-fluorocinnolinyl, 7-bromocinnolinyl and 7-ethynylcinnolinyl groups. Particularly preferred are 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 6-chloroquinolin-3-yl, 6-fluoroquinolin-3-yl, 6-bromoquinolin-3-yl, 6-ethynylquinolin-3-yl, 7-chloroquinolin-2-yl, 7-fluoroquinolin-2-yl, 7-bromoquinolin-2-yl, 7-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-bromoquinolin-2-yl, 6-bromoquinolin-3-, 6-chloroisoquinolin-3-yl, 6-fluoroisoquinolin-3-yl, 6-bromoisoquinolin-3-yl, 6-ethynylisoquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl and the like.

Of these, more preferable are 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chlorocinnolin, 7-ethynylcinnolin-3-yl and the like.

The following groups

(in the group, the number of 5 to 8 represents a position, X⁵Represents CH₂CH, N or NH, Z¹Denotes N, NH or O, Z²Represents CH₂CH, C or N, Z³Represents CH₂、CH、S、SO₂Or C ═ O, X⁵-Z²Represents X⁵And Z²By a single or double bond, R²²、R²³And R²⁴As mentioned above), R is preferable²²And R²³Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. It is preferable that R is²²And R²³One of them is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 6-position or 7-position in the above formula. R²⁴Preferably a hydrogen atom or an alkyl group, preferably a methyl group, R²⁴Particularly preferred is a hydrogen atom.

Specific examples of the group represented by the above formula may include 4-oxodihydroquinolinyl, tetrahydroquinolinyl, 4-oxodihydroquinazolin-2-yl, 4-oxotetrahydrocinnolinyl, 4-oxobenzopyranyl, 4-oxobenzothiadiazinyl, 1-dioxido-4-oxobenzothiadiazinyl, benzoDiazinyl groups, and the like.

More specific examples of the group include 6-chloro-4-oxodihydroquinolinyl, 6-fluoro-4-oxodihydroquinolinyl, 6-bromo-4-oxodihydroquinolinyl, 6-ethynyl-4-oxodihydroquinolinyl, 7-chloro-4-oxodihydroquinolinyl, 7-fluoro-4-oxodihydroquinolinyl, 7-bromo-4-oxodihydroquinolinyl, 7-ethynyl-4-oxodihydroquinolinyl, 6-chloro-4-oxo-1, 4-dihydroquinazolinyl, 6-fluoro-4-oxo-1, 4-dihydroquinazolinyl, 6-bromo-4-oxo-1, 4-dihydroquinazolinyl, 6-fluoro-4-dihydroquinolinyl, and optionally substituted quinolinyl, 6-ethynyl-4-oxo-1, 4-dihydroquinazolinyl, 7-chloro-4-oxo-1, 4-dihydroquinazolinyl, 7-fluoro-4-oxo-1, 4-dihydroquinazolinyl, 7-bromo-4-oxo-1, 4-dihydroquinazolinyl, 7-ethynyl-4-oxo-1, 4-dihydroquinazolinylA group, 6-chloro-1, 2, 3, 4-tetrahydroquinolyl, 6-fluoro-1, 2, 3, 4-tetrahydroquinolyl, 6-bromo-1, 2, 3, 4-tetrahydroquinolyl, 6-ethynyl-1, 2, 3, 4-tetrahydroquinolyl, 7-chloro-1, 2, 3, 4-tetrahydroquinolyl, 7-fluoro-1, 2, 3, 4-tetrahydroquinolyl, 7-bromo-1, 2, 3, 4-tetrahydroquinolyl, 7-ethynyl-1, 2, 3, 4-tetrahydroquinolyl, 6-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-chloro-4H-4-oxobenzopyranyl, 6-fluoro-4H-4-oxobenzopyranyl, 6-bromo-4H-4-oxobenzopyranyl, 6-ethynyl-4H-4-oxobenzopyranyl, 7-chloro-4H-4-oxobenzopyranyl, 7-fluoro-4H-4-oxobenzopyranyl, 7-bromo-4H-4-oxobenzopyranyl, 7-ethynyl-4H-4-oxobenzopyranyl, 6-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-ethynyl-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-chloro-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-fluoro-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-bromo-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-ethynyl-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 6-chloro-2H-1, 2, 4-benzothiadiazinylDiazinyl, 6-fluoro-2H-1, 2, 4-benzoDiazinyl, 6-bromo-2H-1, 2, 4-benzoDiazinyl, 6-ethynyl-2H-1, 2, 4-benzoDiazinyl, 7-chloro-2H-1, 2, 4-benzoDiazinyl, 7-fluoro-2H-1, 2, 4-benzoDiazinyl, 7-bromo-2H-1, 2, 4-benzoDiazinyl, 7-ethynyl-2H-1, 2, 4-benzoDiazinyl groups, and the like.

Particularly preferred are 6-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 7-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 7-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 7-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-, 7-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 4-fluoro-1, 4-dihydroquinazolin-2-yl, and pharmaceutically acceptable salts thereof, 7-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-ethynyl-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-chloro-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-fluoro-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-bromo-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-ethynyl-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-chloro-4H-4-oxochromen-2-yl, 6-fluoro-4H-4-oxochromen-2-yl, 6-bromo-4H-4-oxochromen-2-yl, 6-ethynyl-4H-4-oxochromen-2-yl, 7-chloro-4H-4-oxochromen-2-yl, 7-fluoro-4H-4-oxochromen-2-yl, 7-bromo-4H-4-oxochromen-2-yl, 7-ethynyl-2-yl, 7-ethynyl-4H-4-oxobenzopyran-2-yl, 6-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-ethynyl-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-ethynyl-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-chloro-2H-1, 2, 4-benzothiadiazin-3-ylOxazin-3-yl, 6-fluoro-2H-1, 2, 4-benzoDiazin-3-yl, 6-bromo-2H-1, 2, 4-benzoDiazin-3-yl, 6-ethynyl-2H-1, 2, 4-benzoDiazin-3-yl, 7-chloro-2H-1, 2, 4-benzoDiazin-3-yl, 7-fluoro-2H-1, 2, 4-benzoDiazin-3-yl, 7-bromo-2H-1, 2, 4-benzoDiazin-3-yl, 7-ethynyl-2H-1, 2, 4-benzoDiazin-3-yl, and the like.

Of these, more preferable are 6-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, and the like, 6-ethynyl-4-oxo-1, 4-dihydroquinazolin-2-yl.

The following groups

(in the group, X⁶Represents O or S, R²⁵And R²⁶As described above, the numbers of 5 to 8 represent positions), X⁶Preferably O, more preferably R²⁵And R²⁶Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. It is preferable that R is²⁵And R²⁶One of them is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 6-position or 7-position in the above formula.

Specific examples of the group include 6-chloro-2H-chromen-3-yl, 6-fluoro-2H-chromen-3-yl, 6-bromo-2H-chromen-3-yl, 6-ethynyl-2H-chromen-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl. Particularly preferred are 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups.

The following groups

(in the group, R²⁷And R²⁸As described above, the number of 1 to 6 indicates the position), R is preferably selected from²⁷And R²⁸One of them is a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a nitro group, an amino group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group or an N, N-dialkylcarbamoyl group, particularly preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group. Specific examples of the group represented by the above formula include phenyl, chlorophenyl, fluorophenyl, bromophenyl, ethynylphenyl and chlorophenyl. The position of substitution of the halogen atom, alkyl group or alkynyl group in these groups is not particularly limited, and when the number of substituents is 1, the 3-position and 4-position in the above formula are particularly preferred, and when the number of substituents is 2, the combination of the 4-position and 2-position or 3-position in the above formula is particularly preferred.

Specific examples thereof include phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-ethynylphenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 3, 4-dibromophenyl.

The following groups

(in the group, E¹、E²、R²⁹And R³⁰As described above, the number of 1 to 6 indicates the position), R is preferably selected from²⁹And R³⁰One of them is a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group.

Specific examples of the group represented by the above formula include pyridyl, pyrimidyl and pyridazinyl, and the substitution position of the halogen atom, alkyl or alkynyl in these groups is not particularly limited, and the group T¹When the bond (2) in the above formula is a 2-position bond, the bond (4) and the bond (5) in the above formula are particularly preferred.

Specific examples thereof include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, and the like, 5-chloro-4-fluoro-2-pyridyl group, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 5-chloro-2-pyrimidinyl group, 5-fluoro-2-pyrimidinyl group, 5-bromo-2-pyrimidinyl group, 5-ethynyl-2-pyrimidinyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl-3-pyridazinyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyrimidinyl group, 5-fluoro-, 6-ethynyl-3-pyridazinyl and the like.

Particularly preferred are 2-pyridyl, 3-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-2-pyridyl, and the like, 5-chloro-3-pyridyl group, 5-fluoro-3-pyridyl group, 5-bromo-3-pyridyl group, 5-ethynyl-3-pyridyl group, 6-chloro-3-pyridazinyl group, 6-fluoro-3-pyridazinyl group, 6-bromo-3-pyridazinyl group, 6-ethynyl-3-pyridazinyl group, 4-chloro-3-pyridazinyl group, 4-fluoro-3-pyridazinyl group, 4-bromo-3-pyridazinyl group, 4-ethynyl-3-pyridazinyl group.

Of these, more preferable are 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 4-chloro-3-pyridazinyl, 4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl, and 4-ethynyl-3-pyridazinyl.

Further, the following groups

(in the group, Y¹、Y²、R³¹And R³²As described above, the number of 1 to 5 indicates the position), R is preferably³¹And R³²One of them is a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group.

Specific examples of the group represented by the above formula include thienyl, pyrrolyl, furyl, etc,The substituent position of the halogen atom, alkyl group or alkynyl group in the above groups is not particularly limited, but is particularly preferably the 4-position and 5-position in the above formula.

Specifically, it may be mentioned 4-chloro-2-thienyl, 4-fluoro-2-thienyl, 4-bromo-2-thienyl, 4-ethynyl-2-thienyl, 4-chloro-2-pyrrolyl, 4-fluoro-2-pyrrolyl, 4-bromo-2-pyrrolyl, 4-ethynyl-2-pyrrolyl, 4-chloro-2-furyl, 4-fluoro-2-furyl, 4-bromo-2-furyl, 4-ethynyl-2-furyl, 5-chloro-2-thienyl, 5-fluoro-2-thienyl, 5-bromo-2-thienyl, 5-ethynyl-2-thienyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 5-chloro-2-Azolyl, 5-fluoro-2-Azolyl, 5-bromo-2-Azolyl, 5-ethynyl-2-Azole groups, and the like. Particularly preferred are 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, and 5-ethynyl-2-thiazolyl groups.

In addition, the following groups

(in the group, the number of 1-8 represents a position, each of N represents 1 to 4 carbon atoms and 1 of 5-8 carbon atoms is substituted by 1 nitrogen atom, R³⁴～R³⁶As described above), the position of each nitrogen atom may be arbitrary, and R is³⁴Preferably a hydrogen atom or a halogen atom, preferably R³⁵And R³⁶In (1)One is a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group, and particularly, the other is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is preferably a fluorine atom, a chlorine atom or a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is particularly preferably an ethynyl group.

The position of substitution with a halogen atom, an alkyl group or an alkynyl group is not particularly limited, and specific examples of the group represented by the above formula include 6-chloro-1, 5-naphthyridin-2-yl, 6-fluoro-1, 5-naphthyridin-2-yl, 6-bromo-1, 5-naphthyridin-2-yl, 6-ethynyl-1, 5-naphthyridin-2-yl, 7-chloro-1, 5-naphthyridin-2-yl, 7-fluoro-1, 5-naphthyridin-2-yl, 7-bromo-1, 5-naphthyridin-2-yl, 7-ethynyl-1, 5-naphthyridin-2-yl, 6-chloro-1, 5-naphthyridin-3-yl, 6-fluoro-1, 5-naphthyridin-3-yl, 6-bromo-1, 5-naphthyridin-3-yl, 6-ethynyl-1, 5-naphthyridin-3-yl, 7-chloro-1, 5-naphthyridin-3-yl, 7-fluoro-1, 5-naphthyridin-3-yl, 7-bromo-1, 5-naphthyridin-3-yl, 7-ethynyl-1, 5-naphthyridin-3-yl, 6-chloro-1, 7-naphthyridin-2-yl, 6-fluoro-1, 7-naphthyridin-2-yl, 6-bromo-1, 7-naphthyridin-2-yl, 6-ethynyl-1, 7-naphthyridin-2-yl, 6-chloro-1, 7-naphthyridin-3-yl, 6-fluoro-1, 7-naphthyridin-3-yl, 6-bromo-1, 7-naphthyridin-3-yl, 6-ethynyl-1, 7-naphthyridin-3-yl, 6-chloro-1, 8-naphthyridin-2-yl, 6-fluoro-1, 8-naphthyridin-2-yl, 6-bromo-1, 8-naphthyridin-2-yl, 6-ethynyl-1, 8-naphthyridin-2-yl, 7-chloro-1, 8-naphthyridin-2-yl, 7-fluoro-1, 8-naphthyridin-2-yl, 7-naphthyridin-3-yl, 7-bromo-1, 8-naphthyridin-2-yl, 7-ethynyl-1, 8-naphthyridin-2-yl, 6-chloro-1, 8-naphthyridin-3-yl, 6-fluoro-1, 8-naphthyridin-3-yl, 6-bromo-1, 8-naphthyridin-3-yl, 6-ethynyl-1, 8-naphthyridin-3-yl, 7-chloro-1, 8-naphthyridin-3-yl, 7-fluoro-1, 8-naphthyridin-3-yl, 7-bromo-1, 8-naphthyridin-3-yl, 7-ethynyl-1, 8-naphthyridin-3-yl, 6-chloro-2, 5-naphthyridin-3-yl, 6-fluoro-2, 5-naphthyridin-3-yl, 6-bromo-2, 5-naphthyridin-3-yl, 6-ethynyl-2, 5-naphthyridin-3-yl, 7-chloro-2, 5-naphthyridin-3-yl, 7-fluoro-2, 5-naphthyridin-3-yl, 7-bromo-2, 5-naphthyridin-3-yl, 7-ethynyl-2, 5-naphthyridin-3-yl, 7-chloro-2, 6-naphthyridin-3-yl, 7-fluoro-2, 6-naphthyridin-3-yl, 7-bromo-2, 6-naphthyridin-3-yl, 7-ethynyl-2, 6-naphthyridin-3-yl, 6-chloro-2, 8-naphthyridin-3-yl, 6-fluoro-2, 8-naphthyridin-3-yl, 6-bromo-2, 8-naphthyridin-3-yl, 6-ethynyl-2, 8-naphthyridin-3-yl, 7-chloro-2, 8-naphthyridin-3-yl, 7-fluoro-2, 8-naphthyridin-3-yl, 7-bromo-2, 8-naphthyridin-3-yl, 7-ethynyl-2, 8-naphthyridin-3-yl and the like.

Specific examples thereof may include 7-chloro-2, 5-naphthyridin-3-yl group, 7-fluoro-2, 5-naphthyridin-3-yl group, 7-bromo-2, 5-naphthyridin-3-yl group, 7-ethynyl-2, 5-naphthyridin-3-yl group and the like.

In addition to the 12 groups of the above (a) to (l), a thienopyrrolyl group which may have a substituent is preferred. The substituent(s) may have 1 to 3 substituents, and examples of the substituent(s) include a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkoxycarbonyl group, an amidino group and an alkoxycarbonylalkyl group, and among these, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group and a haloalkyl group are preferable.

Specifically, preferable examples thereof include 2-chlorothieno [2, 3-b ] pyrrol-5-yl, 2-fluorothieno [2, 3-b ] pyrrol-5-yl, 2-bromothieno [2, 3-b ] pyrrol-5-yl, 2-ethynylthieno [2, 3-b ] pyrrol-5-yl and the like.

The following groups are described in detail

(in the group, Q)¹、R³And R⁴As mentioned above, 1 and 2 represent positions)

Containing the above-mentioned group Q¹The cyclic structure of (a) is a 3-to 10-membered 2-valent cycloalkyl group which may have 1 double bond or a 5-to 12-membered 2-valent heterocyclic group which may have 1-to 2 hetero atoms, preferably a 3-to 8-membered 2-valent cycloalkyl group or a 5-to 8-membered 2-valent heterocyclic group, more preferably a 5-to 7-membered 2-valent cycloalkyl group or a 5-to 7-membered 2-valent heterocyclic group. It is composed ofIn, Q¹Preferably an alkylene group having 3 to 6 carbon atoms or a group- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n each independently represent 0 or 1, and A is as defined above). Q¹Particularly preferred is an alkylene group having 4 carbon atoms.

In addition, the cycloalkyl group or the heterocyclic group can have a cis structure and a trans structure depending on the position relationship between the 1-position and the 2-position, and in the case of a 5-membered ring, the cis structure is preferably trans, and in the case of a 6-to 7-membered ring, the cis structure or the trans structure may be cis or trans.

For the above substituent R³And R⁴The detailed description is given. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. Examples of the "alkyl" may include straight-chain, branched or cyclic C₁-C₆Examples of the "alkyl" (e.g., methyl, cyclopropyl, isobutyl, etc.) may include a haloalkyl group substituted with 1 to 3 halogen atoms (e.g., chloromethyl, 1-bromoethyl, trifluoromethyl, etc.) on the alkyl group. The cyanoalkyl group may, for example, be C₁-C₆A group substituted with 1 cyano group on the alkyl group (for example, cyanomethyl group, 1-cyanoethyl group, etc.). Examples of the alkenyl group may include linear or branched groups having 2 to 6 carbon atoms and having 1 double bond (e.g., vinyl group, allyl group, etc.). Examples of the "alkynyl" group may include a linear or branched group having 1 triple bond and having 2 to 6 carbon atoms (for example, ethynyl, propynyl and the like). The acyl group may, for example, be C₁-C₆Alkanoyl (e.g., formyl, acetyl, etc.), benzoyl, naphthoyl, etc. C₇-C₁₅Aroyl or in C above₁-C₆Having 1C on alkanoyl₆-C₁₄Aryl-substituted arylalkanoyl (e.g., phenylacetyl, etc.). Examples of the "acylalkyl" may include the above-mentioned C₁-C₆The alkyl group may have 1 or more of the above-mentioned acyl groups substituted (for example, acetylmethyl group, etc.). Examples of the "alkoxy" may include straight, branched or cyclic C₁-C₆Alkoxy (e.g., methoxy, cyclopropoxy, isopropoxy, etc.). The alkoxyalkyl group may, for example, be C as described above₁-C₆Having 1 of the above-mentioned C in the alkyl radical₁-C₆Alkoxy-substituted groups (e.g., methoxymethyl, ethoxymethyl, etc.). Examples of the "hydroxyalkyl" may include the above-mentioned C₁-C₆A group substituted with 1 hydroxyl group on the alkyl group (for example, hydroxymethyl group, 1-hydroxyethyl group, etc.). The carboxyalkyl group may, for example, be C as described above₁-C₆A group substituted with 1 carboxyl group on the alkyl group (for example, carboxymethyl group, 1-carboxyethyl group, etc.). The alkoxycarbonyl group may, for example, be represented by the above-mentioned C₁-C₆Alkoxy group and carbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group and the like). Examples of the "alkoxycarbonylalkyl" may include the above-mentioned C₁-C₆A group substituted with 1 of the above alkoxycarbonyl groups on the alkyl group (for example, methoxycarbonylethyl group, ethoxycarbonylethyl group and the like). Examples of the carbamoylalkyl group may include the above-mentioned C₁-C₆A group substituted with a carbamoyl group on an alkyl group (for example, carbamoylmethyl group, carbamoylethyl group).

The 3-to 6-membered heterocyclic group which may have a substituent(s) represents a saturated or unsaturated 3-to 6-membered heterocyclic group which may contain 1 to 3 hetero atoms (nitrogen atom, oxygen atom, sulfur atom, etc.), and the heterocyclic group may have a hydroxyl group, a halogen atom, an amino group, C₁-C₆Examples of the substituent such as alkyl, oxo or haloalkyl as the 3-to 6-membered heterocyclic group may include pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, and the like,Azolyl group,An azolinyl group,A diazolyl group,Oxazolidinyl, thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyranyl, pyridinyl, pyrimidinylPyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl,An oxazine group,Diazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl, triazinyl, and the like.

More specifically, the thiol group may, for example, be a thiazolyl group, a 4, 5-dihydrothiazolyl group,Azolyl, 4, 5-dihydroAzolyl, 5-methylOxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, tetrahydropyranyl, pyridinyl, 1, 2, 4-Oxadiazolyl, 3-methyl-1, 2, 4-Oxadiazolyl, 5-methyl-1, 2, 4-Oxadiazolyl, 1, 3, 4-Oxadiazolyl, 5-methyl-1, 3, 4-Oxadiazolyl, 5- (trifluoromethyl) -1, 3, 4-Oxadiazolyl, 1, 3-Azolyl, 1, 3, 4-thiadiazolyl, 5-methyl-1, 3, 4-thiadiazolyl, 1, 3-Oxazolidinyl, and the like.

Examples of the 3-to 6-membered heterocycloalkyl group which may have a substituent include groups substituted with 1 of the above 3-to 6-membered heterocyclic groups which may have a substituent (for example, thiazolylmethyl, 4, 5-dihydrothiazolylmethyl, morpholinylmethyl, 1-dioxothiomorpholinylmethyl, and the like). The aryl group may, for example, be an aryl group having 6 to 14 carbon atoms such as phenyl or naphthyl, and the aryl group may be substituted by 1 to 3 groups selected from the above-mentioned C₁-C₆Alkyl group, the above-mentioned C₁-C₆Alkanoyl group, hydroxy group, nitro group, cyano group, halogen atom, the above-mentioned C₂-C₆Alkenyl radical, above C₂-C₆Alkynyl, halo C described above₁-C₆Alkyl group, the above-mentioned C₁-C₆Alkoxy, carboxy, carbamoyl, the above-mentioned C₁-C₆Alkoxycarbonyl, and the like. The aralkyl group may, for example, be C₁-C₆Having 1 of the above-mentioned C in the alkyl radical₆-C₁₄Aryl-substituted groups (e.g., benzyl, phenethyl, and the like). The substitution position in the above description is not particularly limited.

Examples of the "acylamino" which may have a substituent(s) may include those having C as described above on the amino group₁-C₆Acyl substituted group (for example, formylamino, acetylamino, etc.), and further, there may be mentioned 1 to several halogen atoms, hydroxyl group, C on acyl₁-C₆Alkoxy, amino, N-C₁-C₆Alkylamino, N-di-C₁-C₆Alkylamino, carboxyl, C₂-C₆An alkoxycarbonyl group or the like (e.g., a 2-methoxyacetylamino group, a 3-aminopropionylamino group, etc.). As acylaminoalkanesExamples of the "C" group may include the above-mentioned₁-C₆Having the above-mentioned C on the alkyl radical₁-C₆Acylamino-substituted groups (e.g., formylaminomethyl, acetylaminomethyl, etc.). Examples of the "aminoalkyl" may include the above-mentioned C₁-C₆A group having 1 amino group substituted on the alkyl group (for example, aminomethyl group, 1-aminoethyl group, etc.). The N-alkylaminoalkyl group may, for example, be amino-C₁-C₆Having 1C on the nitrogen atom of the alkyl group₁-C₆Alkyl-substituted groups (e.g., N-methylaminomethyl, N-methylaminoethyl, etc.). The N, N-dialkylaminoalkyl group may, for example, be an amino-C group₁-C₆Having 2C atoms on the nitrogen atom of the alkyl group₁-C₆Alkyl-substituted groups (e.g., N, N-dimethylaminomethyl, N-ethyl-N-methylaminoethyl, etc.). The N-alkenylcarbamoyl group may, for example, be a carbamoyl group having a straight or branched C₂-C₆Alkenyl-substituted groups (e.g., allylcarbamoyl, etc.). The N-alkenylcarbamoylalkyl group may, for example, be C₁-C₆Having the above-mentioned N-C on alkyl₂-C₆Alkenylcarbamoyl-substituted group (for example, allylcarbamoylethyl and the like). Examples of the "N-alkenyl-N-alkylcarbamoyl" may include the aforementioned N-C₂-C₆The alkenylcarbamoyl group having a straight or branched C group on the nitrogen atom₁-C₆Alkyl-substituted groups (e.g., N-allyl-N-methylcarbamoyl, etc.). Examples of the "N-alkenyl-N-alkylcarbamoylalkyl" may include the aforementioned N-C₂-C₆The alkenylcarbamoylalkyl group having a straight or branched C atom₁-C₆Alkyl-substituted groups (e.g., N-allyl-N-methylcarbamoylmethyl, etc.). The N-alkoxycarbamoyl group may, for example, be a carbamoyl group having a straight or branched C₁-C₆Alkoxy-substituted groups (e.g., methoxycarbamoyl, etc.). Examples of the "N-alkoxycarbamoylalkyl" may include straight-chain or branched-chain ones₁-C₆Having the above-mentioned N-C on alkyl₁-C₆Alkoxy radicalCarbamoyl-substituted group (for example, methoxycarbamoylmethyl group, etc.). The N-alkyl-N-alkoxycarbamoyl group may, for example, be a carbamoyl group having a straight or branched C₁-C₆Alkoxy and C₁-C₆Alkyl-substituted groups (e.g., N-ethyl-N-methoxycarbamoyl, etc.). Examples of the "N-alkyl-N-alkoxycarbamoylalkyl" may include straight-chain or branched-chain ones having C₁-C₆Having the above-mentioned N-C on alkyl₁-C₆alkyl-N-C₁-C₆Alkoxycarbamoyl-substituted groups (e.g., N-ethyl-N-methoxycarbamoylmethyl, etc.). Examples of the "hydrazinoformyl group" which may be substituted with 1 to 3 alkyl groups include, in addition to the hydrazinoformyl group, a C group which may be straight-chain or branched₁-C₆Alkyl-substituted hydrazinoformyl groups (e.g., 1-methylhydrazinoyl, 1, 2-dimethylhydrazinoformyl, etc.). Examples of the "alkylsulfonyl" may include linear, branched or cyclic C₁-C₆Alkylsulfonyl (e.g., methylsulfonyl, etc.).

Examples of the "alkylsulfonylalkyl" may include straight-chain or branched-chain ones₁-C₆Having the above-mentioned C on the alkyl radical₁-C₆Alkylsulfonyl-substituted groups (e.g., methylsulfonylmethyl and the like). The alkoxyimino group may, for example, be C₁-C₆Alkoxyimino groups (e.g., methoxyimino, ethoxyimino, etc.). The alkoxycarbonylalkylamino group may, for example, be one having 1 or more of the above-mentioned C on the amino group₁-C₆Alkoxycarbonylalkyl substituted groups (for example, methoxycarbonylmethylamino, ethoxycarbonylpropylamino and the like). The carboxyalkylamino group may, for example, be C, which has 1 carboxyl group on the amino group₁-C₆Alkyl-substituted groups (e.g., carboxymethylamino, carboxyethylamino, etc.). The alkoxycarbonylamino group may, for example, be one having 1 of the above-mentioned C on the amino group₁-C₆Alkoxycarbonyl-substituted groups (e.g., methoxycarbonylamino, tert-butoxycarbonylamino, etc.). Examples of the alkoxycarbonylaminoalkyl group may include those having 1 or more of the above-mentioned C in the above-mentioned alkyl group₁-C₆Alkoxycarbonylamino-substituted groups (for example, methoxycarbonylaminomethyl, tert-butoxycarbonylaminoethyl, etc.).

The N-alkylcarbamoyl group which may have a substituent(s) on the alkyl group represents a straight-chain, branched or cyclic C₁-C₆Carbamoyl group substituted with alkyl, the above-mentioned linear, branched or cyclic C₁-C₆The alkyl group being substituted by hydroxy, amino, N-C₁-C₆Alkylamino, amidino, halogen atom, carboxyl, cyano, carbamoyl, C₁-C₆Alkoxy radical, C₁-C₆Alkanoyl radical, C₁-C₆Alkanoylamino, C₁-C₆Alkylsulfonylamino groups and the like, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-cyclopropylcarbamoyl, N- (2-hydroxyethyl) carbamoyl, N- (2-fluoroethyl) carbamoyl, N- (2-cyanoethyl) carbamoyl, N- (2-methoxyethyl) carbamoyl, N-carboxymethylcarbamoyl, N- (2-aminoethyl) carbamoyl, N- (2-amidinoethyl) carbamoyl and the like. The N, N-dialkylcarbamoyl group which may have a substituent(s) on the alkyl group means a C group which is substituted by 2 linear, branched or cyclic C groups₁-C₆Carbamoyl group substituted with alkyl, the above-mentioned linear, branched or cyclic C₁-C₆The alkyl group being substituted by hydroxy, amino, N-C₁-C₆Alkylamino, amidino, halogen atom, carboxyl, cyano, carbamoyl, C₁-C₆Alkoxy radical, C₁-C₆Alkanoyl radical, C₁-C₆Alkanoylamino, C₁-C₆Alkylsulfonylamino groups and the like, for example, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-isopropyl-N-methylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group, N, N-bis (2-hydroxyethyl) carbamoyl group, N, N-bis (2-fluoroethyl) carbamoyl group, N- (2-cyanoethyl) -N-methylcarbamoyl group, N- (2-methoxyethyl) -N-methylcarbamoyl group, N-carboxymethyl-N-methylcarbamoyl group, N,n-bis (2-aminoethyl) carbamoyl, and the like. Examples of the "N-alkylcarbamoylalkyl" which may have a substituent(s) on the alkyl group may include straight-chain or branched-chain C₁-C₆Alkyl radicals being defined by C₁-C₆An N-alkylcarbamoyl group which may have a substituent(s) on the alkyl group (for example, N-methylcarbamoylmethyl group, N- (2-hydroxyethyl) carbamoylmethyl group and the like). Examples of the "N, N-dialkylcarbamoylalkyl" which may have a substituent(s) on the alkyl group may include straight-chain or branched-chain C₁-C₆Alkyl radicals being defined by C₁-C₆An N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group (for example, N, N-dimethylcarbamoylmethyl group, N- (2-hydroxyethyl) -N-methylcarbamoylmethyl group and the like).

Examples of the 3-to 6-membered heterocyclic carbonyl group which may have a substituent include a 3-to 6-membered heterocyclic group which may have a substituent described above and a carbonyl group (for example, aziridinylcarbonyl, azetidinylcarbonyl, 3-hydroxyazetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-dioxothiomorpholinylcarbonyl, tetrahydropyranylcarbonyl, pyridylcarbonyl, furoyl, thiophenecarbonyl and the like). Examples of the 3-to 6-membered heterocyclic carbonylalkyl group which may have a substituent include the above-mentioned C₁-C₆The alkyl group may have 1 to 6-membered heterocyclic carbonyl group (e.g., azetidinylcarbonylmethyl group, pyrrolidinylcarbonylethyl group, etc.) which may have a substituent.

Examples of the optionally substituted 3-to 6-membered heterocyclic carbonyloxyalkyl group may include the above-mentioned C₁-C₆The alkyl group may have 1 to 3-to 6-membered heterocyclic carbonyloxy group substituted by the above 3-to 6-membered heterocyclic carbonyl group which may have a substituent and an oxygen atom (for example, piperidylcarbonyloxyethyl group, morpholinylcarbonyloxymethyl group and the like). Examples of the carbamoyloxyalkyl group may include the above-mentioned C₁-C₆On the alkyl radicalThere are 1 carbamoyloxy group-substituted group consisting of a carbamoyl group and an oxygen atom (for example, carbamoyloxymethyl group, carbamoyloxyethyl group and the like). Examples of the "N-alkylcarbamoyloxyalkyl" may include the aforementioned C₁-C₆1 in the alkyl group being represented by the above-mentioned C₁-C₆An N-alkylcarbamoyloxy group which may be substituted by an N-alkylcarbamoyloxy group which may have a substituent on the alkyl group and an oxygen atom (for example, an N-methylcarbamoyloxymethyl group, an N-methylcarbamoyloxyethyl group or the like). Examples of the N, N-dialkylaminocarboxyloxyalkyl group may include the above-mentioned C₁-C₆1 in the alkyl group being represented by the above-mentioned C₁-C₆An N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, and an N, N-dialkylcarbamoyloxy group which is an oxygen atom (for example, N, N-dimethylcarbamoyloxymethyl group, N-ethyl-N-methylcarbamoyloxyethyl group and the like).

The alkylsulfonylamino group may, for example, be one having 1 of the above-mentioned C groups on the amino group₁-C₆Alkyl sulfonyl of alkyl substituted groups (for example, methylsulfonamido, isopropyl sulfonylamido, etc.). Examples of the arylsulfonylamino group include groups in which 1 of the above-mentioned arylsulfonyl groups having an aryl group is substituted on the amino group (for example, phenylsulfonylamino group, naphthylsulfonylamino group and the like). Examples of the "alkylsulfonylaminoalkyl" group may include the above-mentioned C₁-C₆Having 1 of the above-mentioned C in the alkyl radical₁-C₆Alkylsulfonylamino-substituted groups (for example, methylsulfonylaminomethyl group, methylsulfonylaminoethyl group, etc.). Examples of the arylsulfonylaminoalkyl group may include the above-mentioned C₁-C₆A group substituted with 1 of the above-mentioned arylsulfonylamino groups on the alkyl group (for example, phenylsulfonylaminomethyl group, naphthylsulfonylaminoethyl group, etc.). The alkylsulfonylaminocarbonyl group may, for example, be represented by the above-mentioned C₁-C₆Alkyl sulfonyl amino group and carbonyl group (for example, methyl sulfonyl amino carbonyl, isopropyl sulfonyl amino carbonyl group). Examples of the arylsulfonylaminocarbonyl group may include groups composed of the arylsulfonylamino group and a carbonyl group (for example, phenylsulfonylaminocarbonyl group, naphthylsulfonylaminocarbonyl group and the like)). Examples of the "alkylsulfonylaminocarbonylalkyl" may include the above-mentioned C₁-C₆Having the above-mentioned C on the alkyl radical₁-C₆Alkylsulfonylaminocarbonyl-substituted groups (for example, methylsulfonylaminocarbonylmethyl group, isopropylsulfonylaminocarbonylmethyl group and the like). Examples of the arylsulfonylaminocarbonylalkyl group may include the above-mentioned C₁-C₆The alkyl group may have a group substituted with the above-mentioned arylsulfonylaminocarbonyl group (for example, phenylsulfonylaminocarbonylmethyl group, naphthylsulfonylaminocarbonylmethyl group and the like). Examples of the alkoxycarbonylalkoxy group may include the above-mentioned C₁-C₆The alkoxy group may have a group substituted with the above alkoxycarbonyl group (for example, methoxycarbonylmethoxy group).

The acyloxy group means a group composed of the above-mentioned acyl group and an oxygen atom (for example, formyloxy group, acetyloxy group and the like). Examples of the "acyloxyalkyl" may include the above-mentioned C₁-C₆A group substituted with the above-mentioned acyloxy group (for example, formyloxymethyl group, acetyloxymethyl group and the like) on the alkyl group. The aralkyloxy group may, for example, be C₁-C₆The alkoxy group may have a group substituted with the above-mentioned aryl group (for example, benzyloxy group, naphthylmethoxy group, etc.). Examples of the "carboxyalkoxy group" may include groups substituted with a carboxyl group on the above alkoxy group (for example, carboxymethoxy group, carboxyethoxy group and the like).

The arylsulfonyl group may, for example, be C₆-C₁₄Arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl, and the like). The alkoxycarbonylalkylsulfonyl group may, for example, be represented by the above-mentioned C₁-C₆Alkoxycarbonylalkyl and sulfonyl (for example, methoxycarbonylethylsulfonyl, ethoxycarbonylethylsulfonyl and the like). Examples of the carboxyalkylsulfonyl group may include groups composed of the above carboxyalkyl group and a sulfonyl group (for example, carboxymethylsulfonyl group, carboxyethylsulfonyl group and the like). Examples of the "alkoxycarbonylacyl" group may include groups composed of the aforementioned alkoxycarbonylalkyl group and a carbonyl group (for example, methoxycarbonylmethylcarbonyl group, ethoxycarbonylmethylcarbonyl group and the like). Examples of the "alkoxyalkoxycarbonyl" group may include the alkoxycarbonyl group described above which has 1 of the above C₁-C₆Alkoxy-substituted groups (e.g., methoxymethoxycarbonyl, methoxyethoxycarbonyl, etc.). Examples of the "hydroxyacyl" may include the aforementioned acyl groups (including C)₁-C₆Alkanoyl and aroyl) with 1 hydroxyl group (e.g., glycoloyl, propanooyl, diphenoxyglycoloyl, etc.). Examples of the "alkoxyacyl" group may include those wherein the acyl group has 1 of the above-mentioned C₁-C₆Alkoxy-substituted groups (e.g., methoxyacetyl, ethoxyacetyl, etc.). Examples of the "haloacyl" group may include groups composed of the above-mentioned haloalkyl group and a carbonyl group (for example, chloromethylcarbonyl group, trifluoromethylcarbonyl group and the like). Examples of the "carboxyacyl" group may include those wherein the acyl group is substituted by 1 carboxyl group (for example, carboxyacetyl group, 2-carboxypropionyl group and the like). Examples of the "aminoacyl" may include the aforementioned acyl (including C)₁-C₆Alkanoyl and aroyl) with 1 amino group (e.g., aminomethylcarbonyl, 1-aminoethylcarbonyl, etc.). Examples of the acyloxyacyl group may include groups composed of the acyloxyalkyl group and a carbonyl group (for example, formyloxymethylcarbonyl group, acetyloxymethylcarbonyl group and the like). Examples of the acyloxyalkylsulfonyl group may include groups composed of the acyloxyalkyl group and a sulfonyl group (for example, formyloxymethylsulfonyl group, acetyloxymethylsulfonyl group and the like). The hydroxyalkylsulfonyl group may, for example, be represented by the above-mentioned C₁-C₆Hydroxyalkyl group and sulfonyl group (for example, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group and the like). The alkoxyalkylsulfonyl group may, for example, be represented by the above-mentioned C₁-C₆Alkoxyalkyl groups and sulfonyl groups (for example, methoxymethylsulfonyl group, ethoxyethylsulfonyl group and the like).

Examples of the 3-to 6-membered heterocyclic sulfonyl group which may have a substituent(s) include groups composed of the above 3-to 6-membered heterocyclic ring which may have a substituent(s) and a sulfonyl group (for example, aziridinylsulfonyl group, azetidinylsulfonyl group, pyrrolidinylsulfonyl group, piperidinylsulfonyl group, piperazinylsulfonyl group, morpholinylsulfonyl group, tetrahydropyranyl sulfonyl group and the like). Examples of the 3-to 6-membered heterocyclic oxy group which may have a substituent(s) includeA 3-to 6-membered heterocyclic ring having a substituent and an oxygen atom (e.g., tetrahydrofuryloxy). Examples of the "N-alkylaminoacyl" group may include those having 1 or more of the above-mentioned C on the nitrogen atom of the aminoacyl group₁-C₆Alkyl-substituted groups (e.g., N-methylaminoacetyl, N-ethylaminoacetyl, etc.). Examples of the N, N-dialkylaminoacyl group may include those wherein 2 of the above-mentioned C are present on the nitrogen atom of the aminoacyl group₁-C₆Alkyl-substituted groups (e.g., N, N-dimethylaminoacetyl, N-ethyl-N-methylaminoacetyl, etc.). Examples of the "N, N-dialkylcarbamoylacyl group which may have a substituent(s) on the alkyl group may include the above-mentioned ones having C as the above-mentioned on the acyl group₁-C₆An N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group (for example, N, N-dimethylcarbamoylacetyl group, N, N-diethylcarbamoylacetyl group, N-ethyl-N-methylcarbamoylacetyl group and the like). The N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group may, for example, be represented by the above-mentioned C₁-C₆A group composed of an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group and a sulfonyl group (for example, N, N-dimethylcarbamoyl methylsulfonyl, N- (2-hydroxyethyl) -N-methylcarbamoyl methylsulfonyl, etc.). Examples of the alkylsulfonylacyl group may include acyl groups each having 1 of the above-mentioned C₁-C₆Alkyl sulfonyl of alkyl (for example, methylsulfonylacetyl, isopropylsulfonylacetyl).

Examples of the "N-arylcarbamoyl" group may include those wherein the carbamoyl group is substituted with the above-mentioned aryl group (for example, phenylcarbamoyl group, naphthylcarbamoyl group and the like). Examples of the N-3-to 6-membered heterocyclic carbamoyl group may include those substituted with the above-mentioned 3-to 6-membered heterocyclic group which may have a substituent (for example, pyridylcarbamoyl group, thienylcarbamoyl group and the like) on a carbamoyl group. The N-alkyl-N-arylcarbamoyl group may, for example, be a straight or branched C group which may be attached to the nitrogen atom of the above-mentioned N-arylcarbamoyl group₁-C₆Alkyl-substituted groups (e.g., N-methyl-N-phenylcarbamoyl, etc.).The N-alkyl-N-3-to 6-membered heterocyclic carbamoyl group may, for example, be C which has a straight chain or branched chain at the nitrogen atom of the above-mentioned N-3-to 6-membered heterocyclic carbamoyl group₁-C₆Alkyl-substituted groups (e.g., N-methyl-N-thienylcarbamoyl, etc.). Examples of the "N-arylcarbamoylalkyl" may include straight-chain or branched-chain C₁-C₆The alkyl group may have a group substituted with the above-mentioned N-arylcarbamoyl group (for example, phenylcarbamoylmethyl group). The N-3-to 6-membered heterocyclic carbamoylalkyl group may, for example, be a straight-chain or branched C₁-C₆A group substituted with the above-mentioned N-3 to 6-membered heterocyclic carbamoyl group (for example, pyridylcarbamoylmethyl group and the like) on the alkyl group. Examples of the "N-alkyl-N-arylcarbamoylalkyl" may include the ones wherein the nitrogen atom of the "N-arylcarbamoylalkyl" group is linear or branched C₁-C₆Alkyl-substituted groups (e.g., N-methyl-N-phenylcarbamoylmethyl, etc.). The N-alkyl-N-3-to 6-membered heterocyclic carbamoylalkyl group may, for example, be a straight-chain or branched C group having a nitrogen atom of the above-mentioned N-3-to 6-membered heterocyclic carbamoylalkyl group₁-C₆Alkyl-substituted groups (e.g., N-methyl-N-thienylcarbamoylmethyl, etc.).

The carbothioformyl radical being-C (═ S) -NH₂The group represented by (A), N-alkylaminothioformyl means an aminothiocarbonyl group substituted with 1 of the above-mentioned alkyl groups, for example, (methylamino) thiocarbonyl, (ethylamino) thiocarbonyl and the like. The N, N-dialkylaminothioformyl group means a carbonothioformyl group substituted with 2 of the above-mentioned alkyl groups, for example, a (dimethylamino) thiocarbonyl group, a (diethylamino) thiocarbonyl group, an (ethylmethylamino) thiocarbonyl group and the like. The "alkylthioalkyl" may, for example, be straight, branched or cyclic C₁-C₆Having a straight, branched or cyclic C on the alkyl group₁-C₆Alkylthio-substituted groups (e.g., methylthiomethyl, 1-methylthioethyl, etc.). The N-acyl-N-alkylaminoalkyl group may, for example, be an amino-C group₁-C₆Having C on the nitrogen atom of the alkyl group₁-C₆Alkyl radicalAnd acyl-substituted groups (e.g., N-acetyl-N-methylaminomethyl, etc.). The "alkoxyalkyl group" (thiocarbonyl group) means a group composed of the above-mentioned alkoxyalkyl group and thiocarbonyl group, and may, for example, be a 2-ethoxythioacetyl group.

The alkylene group is a linear or branched alkylene group having 1 to 5 carbon atoms, and examples thereof include a methylene group, an ethylene group, and a propylene group. The alkenylene group is an alkenylene group having 1 double bond and having 2 to 5 carbon atoms, and examples thereof include a vinylene group and a propenylene group. Examples of the alkylenedioxy group include groups having 1 to 5 carbon atoms such as methylenedioxy group, ethylenedioxy group, propylenedioxy group and the like. Carbonyldioxy is a group represented by-O-C (═ O) -O-. In the above description, the substitution position is not particularly limited.

R is as defined above³And R⁴Among the substituents represented, preferred are a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, an amino group, a hydroxyimino group, an alkoxyimino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group, an alkoxycarbonylaminoalkyl group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on an alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on an alkyl group, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, an N-alkyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, hydrazoyl which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3 to 6-membered heterocyclic carbonyl which may have a substituent, 3 to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, 3 to 6-membered heterocyclic group which may have a substituent, carbamoylalkyl, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylaminoalkylA formyloxyalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, an alkylsulfonylamino group, an alkylsulfonylaminoalkyl group, an oxo group, an acyloxy group, an acyloxyalkyl group, an arylsulfonyl group, an alkoxycarbonylalkylsulfonyl group, a carboxyalkylsulfonyl group, an alkoxycarbonylacyl group, a carboxyacyloyl group, an alkoxyalkoxycarbonyl group, a haloacyl group, an N, N-dialkylaminoacyl group, an acyloxyacyl group, a hydroxyacyl group, an alkoxyalkanoyl group, an alkoxyalkylsulfonyl group, an N, N-dialkylcarbamoylacyl group, an N, N-dialkylcarbamoylalkylsulfonyl group, an alkylsulfonylacyl group, a thiocarbamoyl group, an N-alkylaminothioyl group, an N, N-dialkylaminothioformyl group or an alkoxyalkyl group (thiocarbonyl group), etc., or preferably R³And R⁴Together represent an alkylene group, an alkenylene group, an alkylenedioxy group, a carbonyldioxy group or the like.

It is preferable that R is³And R⁴R in (1)³Is a hydrogen atom, R⁴The substituents are exemplified as the above-mentioned preferred groups. R in this case⁴More preferred is a hydrogen atom, a hydroxyl group, an alkyl group, a halogen atom, a hydroxyimino group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylamino group which may have a substituent, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylamino group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, an N-alkenyl-N-alkylcarbamoylalkyl group, an N-alkoxycarbamoyl group, an N-alkyl-N-alkoxycarbamoyl group, an N-alkyl, N-alkyl-N-alkoxycarbamoylalkyl, hydrazinoformyl group which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3 to 6-membered heterocyclic carbonyl group which may have a substituent, 3 to 6-membered heterocyclic carbonyloxyalkyl group which may have a substituent, 3 to 6-membered heterocyclic group which may have a substituent, amino groupFormylalkyl group, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, alkylsulfonylamino group, alkylsulfonylaminoalkyl group, acyloxy group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, carboxyacyl group, alkoxyalkoxycarbonyl group, haloacyl group, N-dialkylaminoacyl group, acyloxyacyl group, hydroxyacyl group, alkoxyacyl group, alkoxyalkylsulfonyl group, N-dialkylcarbamoylacyl group, N-dialkylcarbamoylalkylsulfonyl group, alkylsulfonylacyl group, carbothioyl group, N-alkylaminothioyl group, N, n-dialkylaminothioformyl or alkoxyalkyl (thiocarbonyl) groups, and the like.

Of these groups, as R⁴Specific preferred examples of the group of (b) include a hydrogen atom, a hydroxyl group, an alkyl group, an N, N-dialkylaminoalkyl group, an acylamino group which may have a substituent(s), an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group, a carbamoyl group, an N-alkylcarbamoyl group which may have a substituent(s) on an alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent(s) on an alkyl group, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, an N-alkenyl-N-alkylcarbamoylalkyl group, an N-alkyl-N-alkoxycarbamoyl group, a hydrazoyl group which may be substituted by 1 to 3 alkyl groups, an alkylsulfonyl group, an alkylsulfonylalkyl, A 3-to 6-membered heterocyclic carbonyl group which may have a substituent, a 3-to 6-membered heterocyclic group which may have a substituent, an N, N-dialkylcarbamoyloxyalkyl group, an N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group, an alkylsulfonylamino group, an alkylsulfonylaminoalkyl group, an acyloxy group, an acyl group, an alkoxyalkoxycarbonyl group, a haloacyl group, an N, N-dialkylaminoacyl group, a hydroxyacyl group, an alkoxyacyl group, a thiocarbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylthiocarbamoyl group or an alkoxyalkyl group (thiocarbonylthio group)Basal), and the like.

As R³And R⁴Examples of the preferable specific substituent include a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, an N, N-dimethylaminomethyl group, an N, N-dimethylaminoethyl group, an N, N-diethylaminomethyl group, an acetylamino group, a methoxyacetylamino group, an acetylaminomethyl group, an acetylaminoethyl group, a methoxy group, an ethoxy group, a methoxymethyl group, a methoxyethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methoxycarbonylamino group, an ethoxycarbonylamino group, an N-allylcarbamoyl group, an N-allylcarbamoylmethyl group, an N-allyl-N-methylcarbamoylmethyl group, an N-allyl-N-methylcarbamoyl, N-methoxy-N-methylcarbamoyl, N, N-dimethylhydrazoyl, N, N, N '-trimethylhydrazoyl, methylsulfonyl, methylsulfonylmethyl, ethylsulfonylmethyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclopropylmethylcarbamoyl, N- (1-ethoxycarbonylcyclopropyl) carbamoyl, N- (2-hydroxyethyl) carbamoyl, N- (2-fluoroethyl) carbamoyl, N- (2-methoxyethyl) carbamoyl, N- (carboxymethyl) carbamoyl, N-dimethylcarbamoyl, N, N, N' -trimethylhydrazinoformyl, methylsulfonyl, N-ethylmethyl, N-ethylcarbamoyl, N-cyclopropylcarbamoyl, N- (1-ethoxycarbonylcyclopropyl) carbamoyl, N- (2-hydroxyethyl) carbamoyl, N- (2-fluoroethyl) carbamoyl, N- (carboxymethyl) carbamoyl, n- (2-aminoethyl) carbamoyl, N- (2-amidinoethyl) carbamoyl, N-dimethylcarbamoyl, N-diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl, N-methyl-N-propylcarbamoyl, N- (2-hydroxyethyl) -N-methylcarbamoyl, N- (2-fluoroethyl) -N-methylcarbamoyl, N-bis (2-hydroxyethyl) carbamoyl, N-bis (2-fluoroethyl) carbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, N-carboxymethyl-N-methylcarbamoyl, N-bis (2-aminoethyl) carbamoyl, azetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, 3-hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, 3, 4-dimethoxypyrrolidinylcarbonyl, N-bis (2-aminoethyl) carbamoyl, azetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, 3, 4-dimethoxypyrrolidinylcarbonyl, N-carboxy,Piperidinocarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, (tetrahydropyran-4-yl) carbonyl, benzoyl, pyridylcarbonyl, thiazolyl, 4, 5-dihydrothiazolyl, piperidinocarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, tetrahydropyran-4-yl-carbonyl, benzoylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl,Azolyl, 4, 5-dihydroAzolyl, 5-methylOxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, tetrahydropyranyl, pyridinyl, 1, 2, 4-Oxadiazolyl, 3-methyl-1, 2, 4-Oxadiazolyl, 5-methyl-1, 2, 4-Oxadiazolyl, 1, 3, 4-Oxadiazolyl, 5-methyl-1, 3, 4-Oxadiazolyl, 5- (trifluoromethyl) -1, 3, 4-Oxadiazolyl, 1, 3-Azolyl, 1, 3, 4-thiadiazolyl, 5-methyl-1, 3, 4-thiadiazolyl, 1, 3-Oxazolidinyl, N-methylcarbamoylmethyl, N-methylcarbamoylethyl, N-ethylcarbamoylmethyl, N- (2-fluoroethyl) carbamoylmethyl, N- (2-methoxyethyl) carbamoylmethyl, N-dimethylcarbamoylmethyl, N-dimethylcarbamoylethyl, N- (2-fluoroethyl) -N-methylcarbamoylmethyl, N- (2-methoxyethyl) -N-methylcarbamoylmethyl, N-dimethylcarbamoyloxymethyl, 2- (N-ethyl-N-methylcarbamoyloxy) ethyl, methylsulfonylamino, ethylsulfonylamino, methylsulfonylaminomethyl, ethylsulfonylaminomethyl, isopropylcarbamoyl, Methylsulfonylaminoethyl, acetyl, propionyl, isobutyryl, 2-methoxyethoxycarbonyl, trifluoroacetyl, N-dimethylaminoacetyl, N-ethyl-N-methylaminoacetyl, hydroxyacetyl, 1-dimethyl-2-hydroxyethylcarbonyl, methoxyacetyl, 1-dimethyl-2-methoxyethylcarbonyl, carbonothioyl, (dimethylamino) thiocarbonyl, 2-methoxythioacetyl and the like.

As mentioned above, R is preferred³And R⁴R in (1)³Is a hydrogen atom, R⁴The specific substituents mentioned above are exemplified. Particularly preferred is R⁴In the case of an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, among them, R is more preferable⁴In the case of N, N-dimethylcarbamoyl. However, R³And R⁴And is not limited to these specific substituents.

(group T)¹)

Group T¹Represents a carbonyl group, a sulfonyl group, a group-C (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -a¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -NH-, a group-C (═ S) -NH-, a group-C (═ O) -NH-NH-, a group-C (═ O) -A²-C (═ O) - (a in the group)²Represents a single bondOr an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ N-N (R)^e)(R^f))-C(＝O)-N(R^g) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -NH-C (═ O) -, the group-C (═ S) -NH-C (═ O) -, the group-C (═ O) -NH-C (═ S) -, the group-C (═ S) -NHC (═ S) -, the group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl.

In the above groups, A¹、A²And A³The alkylene group having 1 to 5 carbon atoms in the above-mentioned group represents a linear, branched or cyclic alkylene group having 1 to 5 carbon atoms, for example, a methylene group, an ethylene group, a propylene group, a cyclopropylene group, a 1, 3-cyclopentylene group and the like. R ', R', R^a、R^b、R^c、R^d、R^e、R^fAnd R^gThe alkyl group in the above-mentioned formula is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. The alkoxy group is a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group and an ethoxy group.

R^a、R^c、R^eAnd R^fIn the above formula, the alkanoyl group represents a group consisting of a straight-chain, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group, and examples thereof include an acetyl group and a propionyl group.

R^cThe aryl group in the above formula means a group having 6 to 14 carbon atoms, and examples thereof include phenyl and naphthyl. The aralkyl group is a group in which a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms is substituted with an aryl group having 6 to 14 carbon atoms, and examples thereof include a benzyl group and a phenethyl group.

Group T¹Preference is given to carbonyl, the radicals-C (═ O) -N (R ') -, the radicals-C (═ S) -C (═ O) -N (R') -, the radicals-C (═ O) -C (═ S) -N (R ') -, the radicals-C (═ S) -N (R') -, and the radicals-C (═ O) -CH-, and₂-N (R ' -, particularly preferably carbonyl, the group-C (═ O) -N (R ') -, the group-C (═ S) -C (═ O) -N (R ') -, the group-C (═ O) -C (═ S) -N (R ') -, the group-C (═ S) -N (R ') -.

(group R)¹And a radical R²)

R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom.

R¹And R²The alkyl group in the above-mentioned formula is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. The alkoxy group is a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group and an ethoxy group. It is preferable that R is¹And R²Each independently a hydrogen atom or an alkyl group, and more preferably both hydrogen atoms.

Preferably T¹Is carbonyl or sulfonyl, the radical Q¹When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q²Is (b), (f), (g), (h), (i), (j), (k) and (l) of the 12 groups (in the group (f), N represents R¹⁹2 carbon atoms of the substituted ring are substituted with nitrogen atoms).

Furthermore, T¹Is carbonyl or sulfonyl, the radical Q¹When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, the group Q¹Get atThe substituent is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.

Preferably T¹Is a radical-C (═ O) -N (R ') -, a radical-C (═ S) -C (═ O) -N (R') -, a radical-C (═ O) -C (═ S) -N (R ') -, or a radical-C (═ S) -N (R') -, a radical Q¹When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q²The case of (i), (j) and (k) among the aforementioned 12 groups.

Furthermore, T¹Is a radical-C (═ O) -N (R ') -, a radical-C (═ S) -C (═ O) -N (R') -, a radical-C (═ O) -C (═ S) -N (R ') -, or a radical-C (═ S) -N (R') -, a radical Q¹When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, the group Q¹The substituent(s) is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.

The compound represented by the formula (8) is characterized by the group T¹And a group Q²The combinations of (A) and (B) are roughly classified into the following 2 types ((I) and (II)).

(I)T¹Represents a carbonyl, sulfonyl, group-C (═ O) -NH-C (═ O) -, group-C (═ S) -NH-C (═ O) -, group-C (═ O) -NH-C (═ S) -, group-C (═ S) -NHC (═ S) -, group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl, containing Q¹The group of (A) is as follows

In the group, Q¹With radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nIn the group (A), (B), (C), (₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or SO₂-NH-)。

(II)T¹Represents a group-C (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, where R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -a¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -NH-, a group-C (═ S) -NH-, a group-C (═ O) -NH-NH-, a group-C (═ O) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ N-N (R)^e)(R^f))-C(＝O)-N(R^g) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -NH-C (═ O) -, the group-C (═ S) -NH-C (═ O) -, the group-C (═ O) -NH-C (═ S) -, the group-C (═ S) -NHC (═ S) -, the group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl, containing Q¹The group of (A) is as follows

In the group, Q¹Represents an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atomsOr radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nIn the group (A), (B), (C), (₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or SO₂-NH-)。

Of the above (I) and (II), preferable examples thereof include the following (I) and (II).

(i) Radical R¹And R²Each independently being a hydrogen atom or an alkyl group, the group Q¹Is a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (where m and n are each independently 0 or 1, A is as defined above) and Q is a group²9 groups selected from (a) to (h) and (l) of the 12 groups, group T¹Is carbonyl or sulfonyl.

(ii) Radical R¹And R²Each independently being a hydrogen atom or an alkyl group, the group Q¹Is C3-6 alkylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (where m and n are each independently 0 or 1, A is as defined above) and Q is a group²3 groups selected from (i), (j) and (k) among the aforementioned 12 groups, a group T¹Is the radical-C (═ O) -N (R ') -, the radical-C (═ S) -C (═ O) -N (R') -, the radical-C (═ O) -C (═ S) -N (R ') -, the radical-C (═ S) -N (R') -.

The compound represented by the formula (8) may sometimes have stereoisomers or optical isomers derived from chiral carbon atoms, and any of these stereoisomers, optical isomers and mixtures thereof is also included in the present invention.

The salt of the compound represented by formula (8) is not particularly limited as long as it is a salt acceptable in the field of medicine, and specific examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, organic sulfonic acid salts such as benzoate, methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, and organic carboxylic acid salts such as acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate, citrate and mandelate.

When the compound represented by the formula (8) has an acidic group, a salt of an alkali metal ion or an alkaline earth metal ion can be formed. The compound represented by the formula (8) or a salt thereof may also form a solvate, and the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvate, and specifically, a hydrate, an ethanolate and the like are exemplified. In addition, when a nitrogen atom is present in formula (8), an N-oxide may be formed.

As the compound of the formula (8), the following compounds, salts thereof and the like are particularly preferred.

1)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopropyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

2)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclobutyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

3)N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

4)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) sulfonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

5)N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

6)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

7)N-{(1R^*，2S^*) -2- [ (6-chloro-2-naphthoyl) amino]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

8)N-((1R^*，2R^*) -2- { [ (6-chloro-1-benzothien-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

9)N-((1R^*，2R^*) -2- { [ (5-fluoroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

10)N-((1R^*，2R^*) -2- { [ (5-chloro-6-fluoroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

11)N-((1R^*，2S^*) -2- { [ (5-bromoindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

12)N-((1R^*，2S^*) -2- { [ (5-ethynylindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

13)N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cycloheptyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

14)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclooctyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

15)N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4-methoxycyclopentyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

16) 5-methyl-N- ((1R)^*，2S^*) -2- { [ (5-methylindol-2-yl) carbonyl]Amino } cyclohexyl) -4, 5,6, 7-tetrahydrothiazolo [5, 4-c ]]Pyridine-2-carboxamides

17)(1R^*，3S^*，4R^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester

18) Ethyl (1S, 3R, 4S) -4- { [ (5-chloroindol-2-yl) carbonyl ] amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylate

19)(1R^*，3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid methyl ester

20)(1R^*，3S^*，4R^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester

21)(1R^*，3S^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid methyl ester

22) Methyl (1R, 3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylate

23)N-((1R^*，2S^*，5S^*) -5- (aminocarbonyl) -2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

24)(1R^*，3S^*，4R^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-cyclohexanecarboxylic acids

25)N-{(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

26) (1S, 3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid

27) N- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (cyclopropylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

28) N- [ (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- (pyrrolidin-1-ylcarbonyl) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

29)N-[(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (4-morpholinylcarbonyl) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

30) N- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (ethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

31) N- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

32) N- ((1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- { [ (2-methoxyethyl) (methyl) amino ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

33) N- ((1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- { [ (2-hydroxyethyl) (methyl) amino ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

34) N- ((1R, 2S, 5S) -5- (1-azetidinylcarbonyl) -2- { [ (5-chloroindol-2-yl) carbonyl ] amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

35) N- ((1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- { [ (3S) -3-fluoropyrrolidinyl ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

36)(1R^*，3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-cyclohexanecarboxylic acids

37)N-{(1R^*，2S^*，4S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- [ (dimethylamino) carbonyl group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

38) N- ((1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- { [ (3R) -3-hydroxypyrrolidinyl ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

39)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5, 5-dimethoxycyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4, 4-dimethoxycyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

40)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5-oxocyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4-oxocyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

41)N-[(1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (hydroxyimino) cyclohexyl]-5-methyl-4,5, 6, 7-tetrahydrothiazolo [5, 4-c ]]Pyridine-2-carboxamides, N- [ (1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- (hydroxyimino) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

42)N-((7R^*，8S^*) -8- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 4-dioxaspiro [4.5 ]]Decan-7-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((7R)^*，8S^*) -7- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 4-dioxaspiro [4.5 ]]Decan-8-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

43)N-[(1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (methoxyimino) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- [ (1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- (methoxyimino) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

44)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5-hydroxycyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4-hydroxycyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

45)N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5-hydroxy-5-methylcyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4-hydroxy-4-methylcyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

46)N-[(1R^*，2R^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (hydroxymethyl) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4 ]-c]Pyridine-2-carboxamides

47)N-[(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (methoxymethyl) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

48)N-((1R^*，2R^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- { [ (methylsulfonyl) amino]Methyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

49)N-{(1R^*，2R^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) methyl group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

50)(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester, (3R)^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester

51)N-((1R^*，2S^*) -5-amino-2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -4-amino-2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

52)N-[(1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (methylsulfonyl) amino group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides, N- [ (1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- [ (methylsulfonyl) amino group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides,

53)N-((1R^*，2S^*) -5- (acetylamino) -2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides, N- ((1R)^*，2S^*) -4- (acetylamino) -2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

54) N- ((1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- { [ methoxy (methyl) amino ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

55) N- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (2, 2-dimethylhydrazino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

56) 6-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) -2-quinolinecarboxamide

57) N- { (1R, 2S, 5S) -2- { [ (5-chloro-4-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

58) 7-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) isoquinoline-3-carboxamide

59)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } tetrahydrofuran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

60) N- ((3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } tetrahydrofuran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

61) N- ((3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } tetrahydrofuran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

62) (3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidine-1-carboxylic acid tert-butyl ester

63) N- ((3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } pyrrolidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

64) N- ((3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5-oxotetrahydro-furan-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

65) N- ((3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -2-oxotetrahydro-furan-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

66) (3S, 4R) -ethyl 2- (3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } -2-oxopyrrolidin-1-yl) acetate

67) N- ((3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1-methyl-5-oxopyrrolidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

68) Methyl 2- [ ((3R, 4R) -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) sulfonyl ] acetate

69)2- [ ((3R, 4R) -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) sulfonyl ] acetic acid

70) Methyl 2- ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) acetate

71)2- ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) acetic acid

72) Methyl 3- ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) propanoate

73)3- ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) propanoic acid

74) Ethyl 3- ((3R, 4R) -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) -3-oxopropanoate

75)3- ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) -3-oxopropanoic acid

76)1- [ ((3R, 4R) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) methyl ] cyclopropanecarboxylic acid methyl ester

77)1- [ ((3R, 4R) -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pyrrolidin-1-yl) methyl ] cyclopropanecarboxylic acid

78)(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid tert-butyl ester

79)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

80)(3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid tert-butyl ester

81)N-((3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } piperidin-4-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

82)(3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid tert-butyl ester

83)N-((3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

84)N-((3R^*，4S^*) -1-acetyl-4- { [ (5-chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

85)N-((3R^*，4S^*) -1-acetyl-3- { [ (5-chloroindol-2-yl) carbonyl]Amino } piperidin-4-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

86)N-((3R^*，4S^*) -1-acetyl-4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

87)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (methylsulfonyl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

88)N-[(3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (methylsulfonyl) piperidin-4-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

89)N-[(3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1-(methylsulfonyl) piperazin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

90)(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid methyl ester

91)(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid ethyl ester

92)(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid 2-methoxyethyl ester

93)(3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid ethyl ester

94)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1-propionylpiperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

95)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1-isobutyrylpiperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

96)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2, 2-dimethylpropionyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

97)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3, 3-dimethylbutyryl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

98)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2, 2, 2-trifluoroacetyl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

99)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (cyclopropylcarbonyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

100)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (cyclobutylcarbonyl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

101)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (cyclopentylcarbonyl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

102) Acetic acid 2- ((3R)^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidin-1-yl) -2-oxoethyl ester

103)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1-glycoloylpiperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

104)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

105)N-[(3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

106)N-((3R^*，4S^*) -1- (3- { [ tert-butyl (diphenyl) silyl]Oxy } -2, 2-dimethylpropionyl) -4- { [ (5-chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl group)-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

107)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3-hydroxy-2, 2-dimethylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

108)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3-methoxy-2, 2-dimethylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

109) Acetic acid 2- ((3R)^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidin-1-yl) -1, 1-dimethyl-2-oxoethyl ester

110)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-hydroxy-2-methylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

111)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (3-hydroxycyclobutyl) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

112)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (methoxycyclobutyl) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

113)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (3-methoxy-2- (methoxymethyl) propanoyl group]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

114)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (tetrahydro-2H-pyran-4-ylcarbonyl) piperidin-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazoleAnd [5, 4-c ]]Pyridine-2-carboxamides

115)N-((3R^*，4S^*) -1-benzoyl-4- { [ (5-chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

116)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (dimethylamino) carbonyl group]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

117)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (ethylamino) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

118)N-((3R^*，4S^*) -1- [ (tert-butylamino) carbonyl]-4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

119)2-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidin-3-yl) acetic acid methyl ester

120)2-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-3-yl) acetic acid

121)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyethyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

122)N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-fluoroethyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

123) N- ((3R, 4S) -1-acetyl-4- { [ (5-chloroindol-2-yl) carbonyl ] amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

124) N- ((3R, 4R) -1-acetyl-4- { [ (5-chloroindol-2-yl) carbonyl ] amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

125) N- [ (3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

126) N- [ (3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

127) N- ((3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

128) N- ((3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

129) Ethyl (3R, 4S) -5- { [ tert-butyl (diphenyl) silyl ] oxy } -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pentanoate

130) (3R, 4S) -3- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5-hydroxy-4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } pentanoic acid ethyl ester

131) N- ((3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -6-oxotetrahydro-2H-pyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

132)N-((3R^*，4R^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

133)N-((3R^*，4R^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

134)N-((3R^*，4R^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-4-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

135)N-((3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

136)N-((3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

137)N-((3R^*，4R^*) -3- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-4-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

138) N- ((3S, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1-methyl-6-oxopiperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide, N- ((3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1-methyl-6-oxopiperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

139)N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

140)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

141)N¹- (3-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

142)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-fluorophenyl) oxalamides

143)N¹- (4-bromophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

144)N¹- (4-chloro-2-methylphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

145)N¹- (4-chloro-3-methylphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

146)N¹- (4-chloro-2-fluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

147)N¹- (2, 4-dichlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

148)N¹- (3, 4-dichlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

149)N¹- (2, 4-difluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

150)N¹- (3, 4-difluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

151)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (pyridin-4-yl) oxalamides

152)N¹- (5-bromopyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

153)N¹- (6-chloropyridin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

154)N¹- (6-chloropyridazin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

155)N¹- (5-chlorothiazol-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

156) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) acetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

157) N- { (1R, 2S, 5S) -2- { [2- (4-chloro-2-fluoroanilino) acetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

158) N- { (1R, 2S, 5S) -2- { [ (5-chloro-4-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

159) N- { (1R, 2S, 5S) -2- { [ (5-chloro-3-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

160) N- { (1R, 2S, 5S) -2- { [ (3-bromo-5-chloroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

161) N- { (1R, 2S, 5S) -2- { [ (3-chloro-5-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

162) N- { (1R, 2S, 5S) -2- { [ (5-chloro-3-formylindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

163) 5-chloro-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N³，N³2, 3-Dihydroxydicarboxamides of dimethylindole

164) N- { (1R, 2S, 5S) -2- [ (6-chloro-2-naphthoyl) amino ] -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

165) 7-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) cinnoline-3-carboxamide

166) N- { (1R, 2S, 5S) -2- { [ (5-chlorobenzimidazol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

167) N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) -7-fluoroisoquinoline-3-carboxamide

168) N- { (1R, 2S, 5S) -2- { [ (7-chloro-2H-chromen-3-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

169) N- { (1R, 2S, 5S) -2- { [ (E) -3- (4-chlorophenyl) -2-acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

170) 6-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) -4-oxo-1, 4-dihydroquinoline-2-carboxamide

171) 7-chloro-N- ((1S, 2R, 4S) -4- { [ ethyl (methyl) amino ] carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) isoquinoline-3-carboxamide

172)N-{(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [2- (dimethylamino) -2-oxoethyl]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

173) N- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (methylsulfonyl) methyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

174) N- { (1R, 2S, 5S) -2- { [ (2-chloro-6H-thieno [2, 3-b ] pyrrol-5-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

175) N- { (1R, 2S, 5S) -2- { [3- (4-chlorophenyl) -2-propionyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

176) 6-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) -4-oxo-1, 4-dihydroquinazoline-2-carboxamide

177) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

178) N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

179) N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-thioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

180)N¹- (5-chloro-2-thienyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

181) N- { (1R, 2S, 5S) -2- { [ (4-Chloroanilino) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

182)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-fluoropyridin-2-yl) ethanediamide

183)N¹- [ 4-chloro-2- (trifluoromethyl) phenyl group]-N²-((1S，2R，4S) -4- [ (dimethylamino) carbonyl]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

184)N¹- { 4-chloro-2- [ (dimethylamino) carbonyl group]Phenyl } -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

185)N¹- [ 4-chloro-2- (hydroxymethyl) phenyl group]-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

186)N¹- (4-chloro-2-methoxyphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

187) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -2- (hydroxyimino) acetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

188)N¹- (4-chlorophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

189)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

190)N¹- (5-bromopyridin-2-yl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

191)N¹- (4-chlorophenyl) -N³- ((1S, 2R, 4S) -4- [ (dimethyl)Amino) carbonyl]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) malonamide

192)N¹- (3-chlorophenyl) -N³- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) malonamide

193)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

194)N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

195)N¹- (5-bromopyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

196)N¹- (4-chloro-3-fluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

197) N- { (1R, 2S, 5S) -2- { [3- (4-chlorophenyl) -3-oxopropanoyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

198)N¹- [ (5-Chloropyridin-2-yl) amino]-N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

199)N¹- (4-chlorophenyl) -N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5,6, 7-tetrahydrothiazolo [5, 4-c ]]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

200)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N¹-Methyloxalamide

201)N¹- (5-chloropyrimidin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

202)N¹- (4-chloro-3-methoxyphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

203)N¹- (4-chlorophenyl) -N²-((1R^*，2R^*) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

204)N¹- (5-chloropyridin-2-yl) -N²-((1R^*，2R^*) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

205)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-ethynylphenyl) ethanediamide

206)N¹- (5-chloropyrazin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

207)N¹- (4-chloro-3-nitrophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydro)Thiazolo [5, 4-c ]]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

208)N¹- (4-chloro-2-nitrophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

209)N¹- (3-amino-4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

210)N¹- (2-amino-4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

211)N¹- (6-chloro-4-methylpyridin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

212) N- { (1R, 2S, 5S) -2- ({ [ (E) -2- (4-chlorophenyl) diazenyl ] carbonyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

213) N- { (1R, 2S, 5S) -2- ({ [2- (4-chlorophenyl) hydrazino ] carbonyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

214)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

215)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (1-hydroxycyclopropyl) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

216)N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (1-methoxycyclopropyl) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides

217) 7-chloro-N- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } piperidin-4-yl) -3-isoquinolinecarboxamide

218)N¹- (4-chloro-3-fluorophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

219)N¹- (5-chloro-2-thienyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

220) N- { (1R, 2S, 5S) -2- { [2- (4-chlorophenoxy) acetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

221) N- { (1R, 2S, 5S) -2- { [ (6-chloro-4-oxo-4H-chromen-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

222) 7-chloro-N- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } piperidin-4-yl) -3-cinnolinecarboxamide

223) N- ((1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- { [2- (4-fluoroanilino) -2-oxothioacetyl ] amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

224) N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

225) N- { (1R, 2S, 5S) -2- [ ({ [ (4-chlorophenyl) sulfonyl ] amino } carbonyl) amino ] -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

226)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

227)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

228)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (methylamino) carbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

229) N- { (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-methylpyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

230) N- [ (3R, 4S) -4- { [2- (4-Chloroanilino) -2-oxothioacetyl ] amino } -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

231)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) thiocarbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

232)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-Methoxythioacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidin-4-yl) Oxalamides

233) (1S, 3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid 2, 2, 2-trichloroethyl ester

234) (1S, 3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid

235) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -1-methoxyimino-2-oxoethyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

236)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-ethynylpyridin-2-yl) ethanediamide

237) N- { (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridazin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

238) N- { (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

239)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-methylpyridin-2-yl) ethanediamide

240)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-methylphenyl) ethanediamide

241)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (methylamino) thiocarbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

242) N- { (1R, 2S, 5S) -2- { [ (4-Chloroanilino) sulfonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

243) N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyrimidin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

244) N- { (1R, 2S, 5S) -2- { [2- (4-chloro-3-nitroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

245) N- { (1R, 2S, 5S) -2- { [2- (3-amino-4-chloroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

246) N- { (1R, 2S, 5S) -2- { [ (7-Chlorcinnolin-3-yl) thiocarbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

247) N- { (1R, 2S, 5S) -2- ({ [ (4-chlorobenzoyl) amino ] carbonyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

248) N- { (1R, 2S, 5S) -2- { [ (E) -3- (5-Chloropyridin-2-yl) acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

249) N- { (1R, 2S, 5S) -2- { [ (Z) -3- (4-chlorophenyl) -2-fluoroacryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

250) N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (methylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

251) Tert-butyl (3- { [ ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) amino ] carbonyl } phenyl) (imino) methylcarbamate

252) N- { (1R, 2S, 5S) -2- ({3- [ amino (imino) methyl ] benzoyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

253) N- { (1R, 2S, 5S) -2- [ (3-cyanobenzoyl) amino ] -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

254) N- { (1R, 2S, 5S) -2- ({3- [ amino (hydroxyimino) methyl ] benzoyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

255) Ethyl (3- { [ ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) amino ] carbonyl } phenyl) (imino) methylcarbamate

256) N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({3- [ imino (methylamino) methyl ] benzoyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

257) N- { (1R, 2S, 5S) -2- ({3- [ amino (methoxyimino) methyl ] benzoyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

258) N- { (1R, 2S, 5S) -2- { [ (Z) -3- (5-Chlorothien-2-yl) -2-fluoro-2-acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

259) (1S, 3R, 4S) -tert-butyl 4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylate

260) (1S, 3R, 4S) -4- ({2- [ (5-chloro-2-pyridinyl) amino ] -2-oxothioacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid

261)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4R) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (thiazol-2-yl) cyclohexyl]Oxalamide, N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (thiazol-2-yl) cyclohexyl]Oxalamides

262)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 2, 4-)Oxadiazol-3-yl) cyclohexyl]Oxalamides

263)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) cyclohexyl]Oxalamides

264)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonylBase of]Amino } -4- (1, 3, 4-)Oxadiazol-2-yl) cyclohexyl]Oxalamides

265)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3-)Azol-2-yl) cyclohexyl]Oxalamides

266)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

267)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3, 4-thiadiazol-2-yl) cyclohexyl]Oxalamides

268) N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

269) N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

270)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (5-methyl-1, 3, 4-thiadiazol-2-yl) cyclohexyl]Oxalamides

271)N¹-(5-Chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3-)Azol-5-yl) cyclohexyl]Oxalamides

272)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 2, 4-)Oxadiazol-3-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

273)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (4H-1, 2, 4-triazol-4-yl) cyclohexyl) ethanediamide

274)N¹- (5-chloro-2-thienyl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

275)N¹- (5-bromo-2-pyridinyl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

276)N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothia-neAzolo [5, 4-c ] s]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

277) N- [ (1R, 2S, 5S) -2- { [ (5-chloro-1H-indol-2-yl) carbonyl]Amino } -5- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

278)N¹- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- {5- [2- (trimethylsilyl) ethynyl group]Pyridin-2-yl oxalamides

279)N¹- (5-ethynylpyridin-2-yl) -N²- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

280) 7-chloro-N- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -3-cinnolinecarboxamide

281) N- [ (1R, 2S, 5S) -2- { [ (Z) -3- (4-chlorophenyl) -2-fluoroacryloyl]Amino } -5- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) cyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

282) The reaction product of 7-chloro-N- ((1S,2R, 4S) -4- (5-methyl-1, 3, 4-Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -3-isoquinolinecarboxamides

283) 6-chloro-N- ((1S, 2R, 4S) -4- (5-methyl-1, 3, 4-Oxadiazol-2-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -4-oxo-1, 4-dihydro-2-quinazolinecarboxamide

284)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 2, 4-)Oxadiazol-5-yl) cyclohexyl]Oxalamides

285)N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- [5- (trifluoromethyl) -1, 3, 4-Diazol-2-yl]Cyclohexyl oxalamides

286)N¹- (5-chloro-2-thienyl) -N²- ((1S, 2R, 4S) -4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

287)N¹- (6-chloropyridazin-3-yl) -N²- ((1S, 2R, 4S) -4- (3-methyl-1, 2, 4-)Oxadiazol-5-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

288)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (2-oxo-1, 3-)Oxazolidin-3-yl) cyclohexyl]Oxalamides

289)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (tetrazol-1-yl) cyclohexyl]Oxalamides

290)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1H-pyrrol-1-yl) cyclohexyl]Oxalamides

291)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 2, 4-triazol-5-yl) cyclohexyl]Oxalamides

292)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1-methyl-1H-1, 2, 4-triazol-5-yl) cyclohexyl]Oxalamides

293) 7-chloro-N- ((1S, 2R, 4S) -4- (3-methyl-1, 2, 4-Oxadiazol-5-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -3-cinnolinecarboxamide

294)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -1- (thiazol-2-yl) piperidin-4-yl) ethanediamide

These compounds can be obtained by using the compound of the formula (5) as a starting material and by following the examples described in the pamphlet of International publication No. 2004/058728.

Examples

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Preparation example 1: 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine hydrochloride monohydrate

After N, N-dimethylacetamide (25mL) was added to copper cyanide (2.88g) and sodium cyanide (1.58g), the mixture was heated to 150 ℃ and dissolved to obtain a colorless transparent solution. To the solution was added 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (5.00g), and the mixture was stirred at 150 ℃ for 18 hours. The reaction solution was cooled to room temperature, and then toluene and a saturated aqueous sodium bicarbonate solution were added. After insoluble matter was filtered off, the mixture was separated into a toluene layer and an aqueous layer, and the aqueous layer was extracted with toluene 2 times. The combined toluene layers were dried over anhydrous sodium sulfate, and the insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. After the concentrated residue was dissolved in ethanol (35mL), 1N ethanol hydrochloride solution (25mL) was added dropwise at room temperature to form a hydrochloride salt. After stirring at 0 ℃ for 1 hour, the precipitated crystals were filtered and washed with ethanol (20 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (3.05 g).

¹H-NMR(D₂O)δppm：4.72(br，2H)，3,77(br，2H)，3.36-3.29(t，2H，J＝6.2Hz)，3.13(s，3H).

MS(FAB)m/z：180(M+H)⁺

Elemental analysis: c₁₈H₁₂ClN₃OS

Theoretical value: c, 41.11; h, 5.18; cl, 15.17; n, 17.98; s, 13.72

Measured value: c, 41.22; h, 4.99; cl, 15.26; n, 17.95; s, 13.69

Preparation example 2: 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

After dissolving 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine hydrochloride monohydrate (500.30mg) in water (5mL) containing sodium hydrogencarbonate (272.33mg) at room temperature, the mixture was extracted 3 times with toluene (10 mL. times.3). The combined toluene layers were dried over anhydrous sodium sulfate (2.00g), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure at 40 ℃ to obtain the title compound (384.28 mg).

¹H-NMR(CDCl₃)δppm：3.76-3.73(t，2H，J＝1.5Hz)，3.03-2.98(dt，2H，J＝1.5，5.9Hz)，2.89-2.84(t，2H，J＝5.9Hz)，2.52(s，3H).

MS(FAB)m/z：180(M+H)⁺

Elemental analysis: c₈H₉N₃S

Theoretical value: c, 53.61; h, 5.06; n, 23.44; s, 17.89

Measured value: c, 53.40; h, 5.08; n, 23.41; s, 17.89

Preparation example 3: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid hydrochloride

Ethanol (5mL) and a 4N aqueous solution of lithium hydroxide (1.34mL) were added to 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine hydrochloride monohydrate (500.61mg) at room temperature, and the mixture was stirred at 50 ℃ for 7 hours. After the reaction solution was cooled with ice water, 1N ethanol hydrochloride solution (7.5mL) was added to form a salt with hydrochloric acid, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The precipitated crystals were collected by filtration and washed with ethanol (2 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (466.98 mg).

¹H-NMR(D₂O)δppm：4.82-4.88(d，1H，J＝16.0Hz)，4.51-4.57(d，1H，J＝16.0Hz)，3.88-3.96(m，1H)，3.60-3.70(m，1H)，3.22-3.33(m，2H)，3.15(s，3H).

MS(EI)m/z：198(M)⁺

Elemental analysis: c₈H₁₁ClN₂O₂S

Theoretical value: c, 40.94; h, 4.72; cl, 15.11; n, 11.94; s, 13.66

Measured value: c, 40.50; h, 4.66; cl, 15.31; n, 11.97; s, 13.68

Preparation example 4: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid hydrochloride

Ethanol (2mL) and a 4N aqueous solution of lithium hydroxide (0.42mL) were added to 2-cyano-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (199.30mg) at room temperature, and the mixture was stirred at 50 ℃ for 10 hours. After the reaction solution was cooled with ice water, 1N ethanol hydrochloride solution (2.8mL) was added to form a salt with hydrochloric acid. The precipitated crystals were collected by filtration and washed with ethanol (1 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (215.37 mg).

¹H-NMR(D₂O)δppm：4.82-4.88(d，1H，J＝16.0Hz)，4.51-4.57(d，1H，J＝16.0Hz)，3.88-3.96(m，1H)，3.60-3.70(m，1H)，3.22-3.33(m，2H)，3.15(s，3H).

MS(EI)m/z：198(M)⁺

Preparation example 5: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

2-amino-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (10.00g) is dissolved in a mixture of sulfuric acid (25mL), hypophosphorous acid (50%, 13mL) and water (100mL) at 15-18 ℃ to obtain an orange solution. Then, a solution of sodium nitrite (8.15g) in water (30mL) was added dropwise to the solution at-2 to 3 ℃ over a period of 30 minutes. After stirring at 0 to 10 ℃ for 2 hours and 30 minutes, 8N aqueous potassium hydroxide (130mL) was added dropwise to adjust the pH to 12.6. The precipitated potassium sulfate was filtered off and washed with ethyl acetate (200 mL). After separating the filtrate, the aqueous layer was further extracted 2 times with ethyl acetate (200 mL. times.2). The combined organic layers were dried over anhydrous sodium sulfate (30.00g), and insoluble matter was filtered off and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (6.15 g).

¹H-NMR(CDCl₃)δppm：8.62(s，1H)，3.71-3.67(t，2H，J＝1.7Hz)，3.01-2.95(dt，2H，J＝1.7Hz，5.9Hz)，2.84-2.80(t，2H，J＝5.9Hz)，2.51(s，3H).

Preparation example 6: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridiniump-toluenesulfonate salt

5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (1.00g) was dissolved in 2-propanol (10mL) at room temperature. At room temperature, p-toluenesulfonate monohydrate (1.23g) was added. After stirring at room temperature for 20 minutes, the mixture was cooled to 0 ℃ to crystallize the salt. Subsequently, the mixture was stirred at 0 ℃ for 2 hours, and the precipitated salt was filtered and washed with 2-propanol (2 mmol). The wet body was dried under reduced pressure at room temperature to obtain the title compound (1.91 g).

¹H-NMR(D₂O)δppm：9.00(s，1H)，7.68-7.65(d，2H，J＝8.1Hz)，7.35-7.32(d，2H，J＝8.1Hz)，4.25-4.85(br，2H)，3.40-3.95(br，2H)，3.25-3.18(t，2H，J＝6.0Hz)，3.08(s，3H)，2.38(s，3H).

MS(EI)m/z：154(M)⁺

Elemental analysis: c₁₄H₁₈N₂O₃S₂

Theoretical value: c, 51.51; h, 5.56; n, 8.58; s, 19.65

Measured value: c, 51.24; h, 5.52; n, 8.81; s, 19.37

Preparation example 7: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid hydrochloride

5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (1.00g) was dissolved in toluene (10mL) at room temperature, and triethylamine (1.81mL) and trichloroacetyl chloride (1.45mL) were added in this order at room temperature. After stirring at room temperature for 4 hours, a solution prepared by dissolving lithium hydroxide monohydrate (1.22g) in water (10mL) was added to hydrolyze the mixture. After separating the solution into an organic layer and an aqueous layer, the organic layer was extracted again with water (10 mL). The combined aqueous layers were concentrated under reduced pressure at a bath temperature of 50 ℃ and ethanol (10mL) was added, followed by concentration again under reduced pressure. Ethanol (15mL) was added to the concentrated residue, which was then cooled with ice water. Concentrated hydrochloric acid (2.7mL) was added dropwise to precipitate a hydrochloride, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The precipitated crystals were collected by filtration and washed with ethanol (4 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (1.25 g).

¹H-NMR(D₂O)δppm：4.82-4.88(d，1H，J＝16.0Hz)，4.51-4.57(d，1H，J＝16.0Hz)，3.88-3.96(m，1H)，3.60-3.70(m，1H)，3.22-3.33(m，2H)，3.15(s，3H)

MS(FAB)m/z：199(M+H)⁺

Preparation example 8: 2-amino-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

To a solution of 1-methyl-4-piperidone (180.0g) in 2-propanol (1.44L) heated to 50 ℃ were added a solution of cyanamide (67.0g) in 2-propanol (360mL) and sulfur powder (51.0g) in that order. Then, a catalytic amount of pyrrolidine (13.3mL) was added, and the mixture was stirred at 50 ℃ or higher for 2 hours, then cooled to room temperature, and stirred overnight. After cooling to 10 ℃ or lower with an ice water bath, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were filtered and washed with 2-propanol (540 mL). The wet body was dried under reduced pressure at 40 ℃ to obtain the title compound (209.9 g).

¹H-NMR(CDCl₃)δppm：4.86(br，2H)，3.47-3.46(t，2H，J＝1.9Hz)，2.78-2.71(m，2H)，2.71-2.65(m，2H)，2.47(s，3H).

MS(FAB)m/z：170(M+H)⁺

Elemental analysis: c₇H₁₁N₃S

Theoretical value: c, 49.68; h, 6.55; n, 24.83; s, 18.95

Measured value: c, 49.70; h, 6.39; n, 24.91; s, 19.00

Preparation example 9: 2-amino-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine dihydrobromide salt

1-methyl-4-piperidone (100.0g) was dissolved in 2-propanol (800mL) at room temperature, and then heated in a warm water bath to raise the internal temperature to 50 ℃. A solution of cyanamide (37.16g) in 2-propanol (200mL) and sulfur powder (28.34g) were added at 50 ℃ in this order. Then, a catalytic amount of pyrrolidine (7.4mL) was added, and the mixture was stirred at 50 to 64 ℃ for 1 hour and then cooled to room temperature. After 48% hydrobromic acid (358.0g) was added dropwise at 30 to 40 ℃, the mixture was cooled to 10 ℃ or lower in an ice-water bath, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. The precipitated crystals were filtered and washed with 2-propanol (500 mL). The wet body was dried under reduced pressure at 40 ℃ to obtain the title compound (258.2 g).

¹H-NMR(D₂O)δppm：4.45-4.53(d，1H，J＝15.2Hz)，4.20-4.26(d，1H，J＝15.2Hz)，3.75-3.90(m，1H)，3.50-3.67(m，1H)，3.10(s，3H)，2.91-3.18(m，2H).

Elemental analysis: c₇H₁₃Br₂N₃S

Theoretical value: c, 25.39; h, 3.96; br, 48.27; n, 12.69; s, 9.69

Measured value: c, 25.54; h, 3.93; br, 48.09; n, 12.62; s, 9.72

Preparation example 10: 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

After 2-amino-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (600.0g) was suspended in water (6.0L), 48% hydrobromic acid (4.2L) was added dropwise at 5-15 ℃. Then, a solution of sodium nitrite (367.2g) in water (1.8L) was added dropwise over a period of 1 hour and 30 minutes at 0 to 5 ℃, the temperature was raised to 30 ℃, and the mixture was stirred for 24 hours. After the reaction mixture was neutralized with a 5N aqueous solution (6.0L) of sodium hydroxide to make the reaction mixture strongly basic (pH12.5), the aqueous layer was extracted 2 times with toluene (12.0L, 6.0L). The toluene layers were combined, dried over anhydrous sodium sulfate (1202.0g), insoluble matter was filtered off, and the mother liquor was concentrated under reduced pressure at 40 ℃ to obtain the title compound (557.6 g).

¹H-NMR(CDCl₃)δppm：3.58-3.57(t，3H，J＝1.8Hz)，2.92-2.87(m，2H)，2.81-2.76(m，2H)，2.49(s，3H).

Preparation example 11: 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridinio-p-toluenesulfonate salt

2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (557.6g) was dissolved in methanol (3.9L). To the solution was added dropwise a methanol (1.7L) solution of p-toluenesulfonic acid monohydrate (500.0g) at 30 ℃ and then cooled to 10 ℃ or lower over 1 hour at the same temperature, followed by stirring for 2 hours. The precipitated crystal was filtered, washed with methanol (1.1L), and dried under reduced pressure at 40 ℃ to obtain the title compound (851.9 g).

¹H-NMR(DMSO-d₆)δppm：10.15(br，1H)，7.47-7.43(d，2H，J＝8.2Hz)，7.09-7.07(d，2H，J＝8.2Hz)，4.47(s，2H)，3.58(s，2H)3.04(t，2H，J＝6.1Hz)，2.96(s，3H)，2.29(s，3H).

Elemental analysis: c₁₄H₁₇BrN₂O₃S₂

Theoretical value: c, 41.48; h, 4.23; br, 19.71; n, 6.91; s, 15.82

Measured value: c, 41.52; h, 4.33; br, 19.80; n, 6.99; s, 15.90

Preparation example 12: 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridinio-p-toluenesulfonate salt

2-amino-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine dihydrobromide (50.01g) was added to a mixture of water (250mL) and 48% hydrobromic acid (175mL) at room temperature, and the mixture was suspended. After the internal temperature of the suspension was cooled to 10 ℃ or lower, a solution of sodium nitrite (15.63g) in water (75mL) was added dropwise over a period of 1 hour and 30 minutes while keeping the internal temperature at 10 ℃ or lower. After stirring at 10 ℃ or lower for 20 hours, a 10N aqueous solution of sodium hydroxide (175mL) was added dropwise while keeping the temperature at 20 ℃ or lower to make the solution alkaline, and the pH of the solution was 13.1. The aqueous layer was then extracted 2 times with toluene (375mL, 250mL) and the subsequent operation used 1/4 of the combined toluene layers. The toluene layer was concentrated, and the concentrated residue was dissolved in methanol (43.8 mL). After methanol (18.8mL) of p-toluenesulfonic acid monohydrate (5.03g) was added dropwise thereto at room temperature, the mixture was cooled to 10 ℃ or lower and stirred at the same temperature for 1 hour and 30 minutes. The precipitated crystals were collected by filtration and washed with a methanol (18.8mL) solution. The wet body was dried under reduced pressure at 40 ℃ to obtain the title compound (9.05 g).

¹H-NMR(DMSO-d₆)δppm：10.15(br，1H)，7.47-7.43(d，2H，J＝8.2Hz)，7.09-7.07(d，2H，J＝8.2Hz)，4.47(s，2H)，3.58(s，2H)，3.04(t，2H，J＝6.1Hz)，2.96(s，3H)，2.29(s，3H).

Elemental analysis: c₁₄H₁₇BrN₂O₃S₂

Theoretical value: c, 41.48; h, 4.23; br, 19.71; n, 6.91; s, 15.82

Measured value: c, 41.54; h, 4.18; br, 19.83; n, 7.03; s, 16.02

Preparation example 13: lithium salt of 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid

To 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridinato p-toluenesulfonate (490.0g) was added 2N aqueous sodium hydroxide solution (2.45L), and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted 2 times with toluene (4.9 L.times.2), and the organic layer was dried over anhydrous sodium sulfate (979.8 g). Insoluble matter was filtered, and the mother liquor was concentrated under reduced pressure at 40 ℃ or lower to obtain 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (284.0g) as a brown oil. The obtained 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (284.0g) was dissolved in anhydrous tetrahydrofuran (2.84L), and the inside of the reaction system was adjusted to an argon atmosphere. N-butyllithium (1.59mol/L n-hexane solution, 766mL) was added dropwise at-40 to-30 ℃ and then stirred at the same temperature for 1 hour. Absorbing carbon dioxide at-40 to-25 ℃, and stirring for 1 hour at the same temperature in the atmosphere of carbon dioxide. After warming to room temperature, ethyl acetate (1.42L) was added. The precipitated solid was filtered, washed with ethyl acetate (0.85L), dried under reduced pressure at 40 ℃ and then pulverized to obtain the title compound (235.1 g).

¹H-NMR(DMSO-d₆)δppm：3.54(s，2H)，2.65-2.85(m，4H)，2.36(s，3H).

Preparation example 14: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid hydrochloride

To 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid lithium salt (3.00g) was added 1N ethanol hydrochloride solution (36mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol (9 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (2.76 g).

¹H-NMR(D₂O)δppm：4.82-4.88(d，1H，J＝16.0Hz)，4.51-4.57(d，1H，J＝16.0Hz)，3.88-3.96(m，1H)，3.60-3.70(m，1H)，3.22-3.33(m，2H)，3.15(s，3H).

Elemental analysis: c₈H₁₁ClN₂O₂S

Theoretical value: c, 40.94; h, 4.72; n, 11.94; s, 13.66

Measured value: c, 40.51; h, 4.65; n, 11.79; s, 13.53

Preparation example 15: 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid hydrochloride

2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridinotosylate (40.00g) and a 1N aqueous solution of sodium hydroxide (200mL) were mixed at room temperature, and after stirring for 30 minutes, the aqueous layer was extracted 2 times with toluene (400 mL. times.2). The combined organic layers were washed with 5% brine (200 mL). After the organic layer was concentrated to 80mL under reduced pressure at an external temperature of 50 ℃ or lower, a sample was taken therefrom for moisture measurement (weight of the solution after concentration was 91.03g, weight of the solution after sampling was 87.68 g). The moisture content of the sampled concentrate was measured by a Karl Fischer moisture meter, and found to be 0.0231% (by weight). The concentrated solution after sampling was dissolved in anhydrous tetrahydrofuran (231mL), and the inside of the reaction system was adjusted to an argon atmosphere. After the internal temperature was lowered to-30 ℃ or lower, n-butyllithium (1.59mol/L n-hexane solution, 61.700mL) was added dropwise while keeping the internal temperature at-30 ℃ or lower, and the mixture was stirred at the same temperature for 1 hour. Then, carbon dioxide gas was absorbed while maintaining the internal temperature at-30 ℃ or lower, and the mixture was stirred for 1 hour under an atmosphere of carbon dioxide gas. After the internal temperature was raised to 15 ℃, methanol (193mL) was added to dissolve the precipitated solid. Then, concentrated hydrochloric acid (19.3mL) was added dropwise while maintaining the internal temperature at 20 ℃. After the internal temperature had dropped to 10 ℃ or lower, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and washed with methanol (58 mL). The wet body was dried under reduced pressure at room temperature to obtain the title compound (21.20 g).

¹H-NMR(D₂O)δppm：4.82-4.88(d，1H，J＝16.0Hz)，4.51-4.57(d，1H，J＝16.0Hz)，3.88-3.96(m，1H)，3.60-3.70(m，1H)，3.22-3.33(m，2H)，3.15(s，3H).

MS(EI)m/z：198(M)⁺

Elemental analysis: c₈H₁₁ClN₂O₂S

Theoretical value: c, 40.94; h, 4.72; cl, 15.11; n, 11.94; s, 13.66

Measured value: c, 40.83; h, 4.56; cl, 14.81; n, 11.91; s, 13.87

Preparation example 16: n is a radical of¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

Will N¹- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (5-Chloropyridin-2-yl) ethanediamide (553.4mg) was dissolved in dimethylacetamide (7mL), and 1-hydroxybenzotriazole 1 hydrate (245.1mg), 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] and the mixture were added at room temperature]Pyridine-2-carboxylic acid saltAcid salt (386.0mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (345.0 mg). After stirring for 13 hours, triethylamine and water were added to the solution, and the precipitated crystals were collected by filtration and dried to obtain the title compound (674.1 mg).

¹H-NMR(CDCl₃)δppm：1.60-1.98(3H，m)，2.00-2.16(3H，m)，2.52(3H，s)，2.78-2.90(3H，m)，2.92-2.98(2H，m)，2.95(3H，s)，3.06(3H，s)，3.69(1H，d，J＝15.4Hz)，3.75(1H，d，J＝15.4Hz)，4.07-4.15(1H，m)，4.66-4.72(1H，m)，7.40(1H，d，J＝8.8，0.6Hz)，7.68(1H，dd，J＝8.8，2.4Hz)，8.03(1H，d，J＝7.8Hz)，8.16(1H，dd，J＝8.8，0.6Hz)，8.30(1H，dd，J＝2.4，0.6Hz)，9.72(1H，s).MS(ESI)m/z：548(M+H)⁺.

Claims (9)

1. Formula (5)

A process for producing a compound represented by the formula (6) or a salt thereof, which comprises reacting a compound represented by the formula (6)

The compound represented by (A) or a salt thereof is reacted with a trihaloacetyl halide and then hydrolyzed.

2. Formula (5)

A process for producing the compound represented by the formula (2) or a salt thereof, which comprises dissolving an acidic compound in an aqueous solution in the presence of a reducing agent

Reacting the compound represented by the formula (6) or a salt thereof with an alkali metal nitrite

The compound represented by (1) or a salt thereof is reacted with a trihaloacetyl halide in the presence of a base, and then hydrolyzed.

3. The method according to claim 1 or 2, wherein the base is a tertiary amine.

4. The process according to claim 1 or 2, wherein the trihaloacetyl halide is trichloroacetyl chloride.

5. The process according to claim 1 or 2, wherein the hydrolysis is carried out using an aqueous solution of an alkali metal hydroxide.

6. The method of claim 5, wherein the alkali metal hydroxide is lithium hydroxide.

7. The method of claim 2, wherein the reducing agent is hypophosphorous acid.

8. The method according to claim 2, wherein the alkali metal nitrite is sodium nitrite.

9. The method of claim 2, wherein the acidic compound is sulfuric acid.