WO2011162267A1 - Novel thiophenecarboxamide derivatives and use thereof as medicine - Google Patents

Abstract

Provided are compounds that have glucokinase-activating effect. Disclosed are pharmaceutical compositions which each contain a compound represented by general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. In general formula (I), X is a nitrogen atom or CR2, R2 being a halogen atom, C1-6 alkyl, or the like; Y is a nitrogen atom or CR3, R3 being a hydrogen atom, C1-6 alkyl, or the like, with the proviso that when X is a nitrogen atom, Y is not a nitrogen atom; Z is a nitrogen atom or CR4, R4 being a hydrogen atom, a halogen atom, or (CH2)m-R5 [wherein m is an integer of 1 to 6 and R5 is hydroxyl or the like]; and R1 is amino, mesyl, carbamoyl, CONH-(CH2)n-A-R6 [wherein n is an integer of 1 to 6, A is nil, an oxygen atom, or the like, and R6 is C1-6 alkyl, C1-6 hydroxyalkyl, or the like], or the like.

Description

Novel thiophenecarboxamide derivatives and their pharmaceutical uses

The present invention relates to a novel thiophenecarboxamide derivative and its pharmaceutical use. The compounds have various pharmaceutical uses as glucokinase activators.

Glucokinase (ATP: D-glucose 6-phosphotransferae,
EC2.7.1.1.) Is one of four hexokinases (hexokinase IV) present in mammals. Hexokinase is an enzyme that catalyzes the first step of glucose metabolism and converts glucose to glucose-6 phosphate. Glucokinase is mainly expressed in liver and pancreatic β-cells and acts as a rate-limiting enzyme for glucose metabolism, and plays an important role in systemic glucose homeostasis.

Glucokinase has a low affinity for glucose and a Km value (8-15 mM) close to physiological blood glucose level. Also, glucokinase is not inhibited by physiological concentrations of glucose-6 phosphate. Therefore, glucokinase-mediated glucose metabolism increases when normoglycemia (5 mM) is increased to 10-15 mM by diet. From these results, it was considered that glucokinase works as a glucose sensor in the liver and pancreatic β cells.

The role of glucokinase in animals was confirmed by studies using genetically modified animals. Mice that did not express glucokinase died of severe diabetes soon after birth, whereas mice that overexpressed glucokinase were reported to improve glucose tolerance. These studies confirmed that glucokinase actually has an important role in systemic glucose homeostasis.

Young adult-onset diabetes (MODY-2) is caused by a mutation of loss of function of the glucokinase gene, and a decrease in glucokinase activity causes an increase in blood glucose. In addition, families with mutations that increase glucokinase activity have also been found, and these families show a fasting hypoglycemia due to elevated plasma insulin levels.

Thus, glucokinase works as a glucose sensor and plays an important role in blood glucose regulation, and blood glucose control using a glucose sensor system is considered to be a useful treatment in many type II diabetic patients. A substance that activates glucokinase is expected to have an action of promoting insulin secretion in pancreatic β-cells, promoting glucose uptake in hepatocytes, and suppressing sugar release by enhancing the function of the glucose sensor. It is considered useful as a preventive or therapeutic agent for type 2 diabetes.

So far, many compounds having a glucokinase activating action have been reported (Non-patent Document 1). As a compound in which two 5-membered aromatic heterocycles are amide-bonded, Patent Document 1 reports a compound having a pyrrole ring, and Patent Document 2 reports a compound having an indole ring. The structure is different from the thiophenecarboxamide derivative of the invention. On the other hand, as a thiophenecarboxamide derivative, 2,5-dimethylthiophene-3-carboxylic acid thiazol-2-ylamide is sold as a reagent by Enamine (Ukraine). The structure is different from the compound of the present invention having a benzene ring or a pyridine ring.

International Publication 2008/149382 International Publication No. 2004/031179

The present invention provides a compound having a glucokinase activating action, and is based on the glucokinase activating action, such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or It is an object to provide a preventive or therapeutic agent for chronic complications of diabetes such as arteriosclerosis.

In view of the above points, the present inventors consider that a compound having a new basic structure is effective as a means for solving the above problems, and eagerly researched to create a novel glucokinase activator. Repeated. As a result, the compound represented by the following general formula (I) has a very excellent glucokinase activation action, and also has excellent properties in terms of physical properties as a pharmaceutical such as solubility, Was found to be a safe and useful medicine excellent in the difference between the side effects (effects on hERG and CYP) and drug efficacy, and the present invention was completed.

That is, according to the present invention, the following general formula (I):

[Wherein, X represents a nitrogen atom or CR ² , R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkylthio group; Y represents a nitrogen atom or CR ³ R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkylthio group. However, when X is a nitrogen atom, Y is not a nitrogen atom; Z represents a nitrogen atom or CR ⁴ , R ⁴ represents a hydrogen atom, a halogen atom, or (CH ₂ ) _m -R ⁵ . m represents an integer of 1 to 6, R ⁵ represents a hydroxy group or a C ₁ -C ₆ alkoxy group; R ¹ represents an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, a sulfamoyl group, CONH- (CH ₂ ) _n -AR ⁶ or SO ₂ NH- (CH ₂ ) _n -R ⁷ is meant. n is an integer of 1 to 6, A is absent or an oxygen atom or a sulfur atom, R ⁶ is a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ hydroxy group An alkyl group, R ⁷ represents a hydroxy group or a C ₁ -C ₆ alkoxy group]
Or a pharmacologically acceptable salt thereof, and these compounds are hereinafter referred to as “the compounds of the present invention”.

Listed below are various preferred embodiments of the compound of the present invention. In the above general formula (I), a compound wherein X is a nitrogen atom, CF or C—Cl, and Y is a CH or C— (C ₁ -C ₃ alkyl) group. In the above general formula (I), a compound wherein X is a nitrogen atom and Y is CH or a C— (C ₁ -C ₃ alkyl) group. In the above general formula (I), a compound wherein X is CF or C—Cl and Y is CH. In the above general formula (I), a compound wherein Z is C— (CH ₂ ) ₂ —OH or C— (CH ₂ ) ₃ —OH, and R ¹ is an amino group, a carbamoyl group, or a mesyl group. In the above general formula (I), a compound wherein Z is C— (CH ₂ ) ₂ —OH and R ¹ is a mesyl group. In the general formula (I), Z is CH or CF, R ¹ is CONH- (CH ₂ ) ₂ -OR ⁶ , and R ⁶ is a C ₁ -C ₃ alkyl group or C ₁ -C ₃ hydroxyalkyl. A compound that is a group. In the general formula (I), compounds wherein R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) ₂ —OH. In the general formula (I), X is a nitrogen atom, Y is CH or a C— (C ₁ -C ₃ alkyl) group, Z is C— (CH ₂ ) ₂ —OH, and R ¹ is A compound that is a mesyl group. In the general formula (I), X is a nitrogen atom, Y is CH or a C- (C ₁ -C ₃ alkyl) group, Z is CH or CF, and R ¹ is CONH- (CH ₂ ). _A compound which is ₂ -O- (CH ₂ ) ₂ -OH. In the above general formula (I), a compound in which X is CF or C—Cl, Y is CH, Z is C— (CH ₂ ) ₂ —OH, and R ¹ is a mesyl group. In the general formula (I), X is CF or C—Cl, Y is CH, Z is CH or CF, and R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) _2. A compound that is -OH.

The present invention also provides a compound represented by the following general formula (II), which is an intermediate of the compound of the present invention represented by the above general formula (I).

[Wherein, Z ¹ represents a nitrogen atom or CR ¹⁰ , and R ¹⁰ represents a hydrogen atom, a halogen atom, or (CH ₂ ) _m -R ¹¹ . m represents an integer of 1 to 6, R ¹¹ represents an optionally protected hydroxy group or a C ₁ -C ₆ alkoxy group; R ⁸ represents a nitro group, an amino group, a nitrile group, an acetyl group, It means mesyl group, carbamoyl group, sulfamoyl group, CO ₂ R ¹² , CONH— (CH ₂ ) _n —AR ¹³ , or SO ₂ NH— (CH ₂ ) _n —R ¹⁴ . R ¹² represents a hydrogen atom or a protecting group for a carboxyl group, n represents an integer of 1 to 6, A represents an absent or oxygen atom or a sulfur atom, R ¹³ represents a hydrogen atom, C ₁ -C ₆ alkyl group, hydroxy protecting group, or C ₁ -C ₆ hydroxyalkyl group that may be protected, R ¹⁴ may be protected hydroxy group or C ₁ -C ₆ Means an alkoxy group; R ⁹ means a hydrogen atom or a protecting group for a carboxyl group; ]

The present invention further provides a pharmaceutical composition containing the compound of the present invention as an active ingredient. That is, the pharmaceutical composition of the present invention is used for the prevention or treatment of diabetes.

The compound of the present invention has an excellent glucokinase activation action, and is a chronic complication of diabetes such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or arteriosclerosis It is useful as a preventive or therapeutic agent. The present invention also provides a safe and useful medicament excellent in the difference between various side effects (effects on hERG and CYP) and drug efficacy.

Below, this invention compound is demonstrated.

In the compounds of the present invention represented by the above general formula (I), X is a nitrogen atom or CR ² , R ² is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkylthio group , Y is a nitrogen atom or CR ³ , R ³ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkylthio group. Among these, X is preferably a nitrogen atom, C—Cl, or CF, and Y is preferably CH or a C— (C ₁ -C ₃ ) alkyl group. Among these, when X is a nitrogen atom, Y is preferably CH or a C— (C ₁ -C ₃ ) alkyl group, and when X is C—Cl or CF, Y is preferably CH.

Z is a nitrogen atom or CR ⁴ , R ⁴ is a hydrogen atom, a halogen atom, or (CH ₂ ) _m -R ⁵ , m is an integer of 1 to 6, and R ⁵ is a hydroxy group or C ₁ -C ₆ R ¹ is an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, a sulfamoyl group, CONH- (CH ₂ ) _n -AR ⁶ , or SO ₂ NH- (CH ₂ ) _n- R ⁷ , n is an integer of 1 to 6, A is absent, an oxygen atom, or a sulfur atom, R ⁶ is a hydrogen atom, a C ₁ -C ₆ alkyl group, or C ₁ — A C ₆ hydroxyalkyl group and R ⁷ is a hydroxy group or a C ₁ -C ₆ alkoxy group; Among these, Z is C— (CH ₂ ) ₂ —OH or C— (CH ₂ ) ₃ —OH, R ¹ is an amino group, a carbamoyl group, or a mesyl group, or Z is CH or CF, R ¹ is preferably CONH- (CH ₂ ) ₂ -OR ⁶ , and R ⁶ is preferably a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ hydroxyalkyl group, and among them, Z is C- ( CH ₂ ) ₂ —OH, R ¹ is a mesyl group, or Z is CH or CF, and R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) ₂ —OH. Is more preferable.

Among these, a particularly preferred compound of the present invention is represented by the general formula (I), wherein X is a nitrogen atom, Y is CH or a C- (C ₁ -C ₃ alkyl) group, and Z is C- (CH ₂ ) _2- OH and R ¹ is a mesyl group. Another particularly preferred compound of the present invention is a compound represented by the general formula (I), wherein X is a nitrogen atom, Y is CH or a C- (C ₁ -C ₃ alkyl) group, and Z is CH or CF. , R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) ₂ —OH. Yet another particularly preferred compound of the present invention is that X is CF or C—Cl, Y is CH, Z is C— (CH ₂ ) ₂ —OH, and R ¹ is a mesyl group. Yet another particularly preferred compound of the present invention is that X is CF or C—Cl, Y is CH, Z is CH or CF, and R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) ₂ -OH.

In the compounds of the present invention, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

“C1-C6 alkyl group” means a linear or branched alkyl group composed of 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, i-pentyl group, neo-pentyl group, t-pentyl group, n-hexyl group, i-hexyl group, Examples thereof include 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group and the like.

“C1-C6 alkoxy group” means an —O— (C1-C6 alkyl) group, for example, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group. Group, s-butoxy group, t-butoxy group, n-pentoxy group, i-pentoxy group, neo-pentoxy group, t-pentoxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group Group, n-hexyloxy group and the like.

“C1-C6 alkylthio group” means a —S— (C1-C6 alkyl) group. The “C1-C6 hydroxyalkyl group” means a (C1-C6 alkylene) -OH group, and the “C1-C6 alkylene” means a linear alkylene composed of 1 to 6 carbon atoms. Meaning, for example, methylene, ethylene, n-propylene, n-butylene and the like.

“Pharmaceutically acceptable salt” means a salt that retains the biological effectiveness and properties of the compound represented by the general formula (I) and that is not biologically or otherwise inconvenient. To do. Such pharmacologically acceptable salts are included in the scope of the present invention. Pharmacologically acceptable salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), organic acid addition salts (for example, methanesulfonic acid, p- Toluenesulfonic acid, acetic acid, oxalic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, salt with malic acid), salt with amino acid (for example, salt with lysine, arginine, etc.), alkali metal addition salt (Eg, salts with sodium, potassium, etc.), alkaline earth metal addition salts (eg, salts with calcium, magnesium, etc.), organic amine addition salts (eg, salts with diethylamine, diethanolamine, piperazine, etc.), etc. It is done. The formation reaction of these addition salts can be performed according to a conventional method.

The compounds of the present invention also include prodrugs that mean compounds that are converted to the above general formula (I) by reactions with enzymes, gastric acid, and the like under physiological conditions in vivo, and various prodrugs are known in the art. It is. For example, as a prodrug when the compound represented by the general formula (I) has a hydroxy group, a compound in which the hydroxy group is acylated (for example, acetylation, propionylation, isopropoxycarbonylation, methoxycarbonylation) , Pivaloyloxymethylated compounds) and the like.

The compound represented by the general formula (I) which is the compound of the present invention can be produced by combining the methods shown in the following reaction process formulas I to VII, the methods described in Examples 66 to 74, or known methods. it can.
[Reaction Process Formula I]

[Wherein, Z ² is a nitrogen atom, CH, or C-halogen atom, R ¹⁵ is a protecting group for a carboxyl group, and other symbols are as defined above]

[Step I-1]
The compound represented by the general formula (IIa) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound of the general formula (IV). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (IIa) is converted into an acid chloride using a chlorinating agent (for example, thionyl chloride, oxalyl chloride) in an appropriate solvent (for example, toluene, methylene chloride, etc.) The compound represented by (III) is reacted with a base (eg, triethylamine, N, N-diethylaniline, etc.) in an appropriate solvent (eg, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, etc.). In this way, the compound represented by the general formula (IV) can be obtained. The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. In addition, the compound represented by general formula (III) can be obtained as a commercial item, or can be manufactured using a well-known method.

[Step I-2]
Referring to the method described in "Protecting Groups in Organic Synthesis, 3rd Edition , Wiley (1999) ", by removing the protecting group R ¹⁵ of the compound represented by formula (IV), the general formula (V) The compound represented is obtained.

[Step I-3]
The compound represented by the general formula (V) and the compound represented by the general formula (VI) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound represented by the general formula (Ia). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. In addition, the compound represented by general formula (VI) can be obtained as a commercial item, or can be manufactured combining a well-known method.

[Reaction Process II]

[Wherein R ¹⁶ is a protecting group for carboxyl group, and other symbols are as defined in the above general formula]

[Step II-1]
The compound represented by the general formula (IIc) and the compound represented by the general formula (VI) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound represented by the general formula (IId). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step II-2]
The compound represented by the general formula (IIe) is obtained by removing the protecting group R ¹⁶ of the compound represented by the general formula (IId) with reference to the method described in “Protecting Groups in Organic Synthesis”. .

[Step II-3]
The compound represented by the general formula (IIe) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound represented by the general formula (Ib). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

The compound represented by the general formula (IIa) or (IIc) can be produced by the method of reaction process formula III shown below.
[Reaction Process III]

[Wherein, R ¹⁷ is an alkyl group, a hydroxy group, or an alkoxy group, R ¹⁸ is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonate group, and other symbols are as defined above. ]

[Step III-1]
The compound represented by the general formula (VII) and the compound represented by the general formula (VIII) in an appropriate solvent (eg, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIf) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (VII) or the general formula (VIII) is available as a commercial product, or can be produced by combining the methods described in Reference Examples 1 to 5 or known methods. it can.

[Step III-2]
The compound represented by the general formula (IX) and the compound represented by the general formula (X) are added in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIf) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. In addition, the compound represented by the general formula (IX) or the general formula (X) is available as a commercial product, the method described in Reference Example 7, Reference Example 24, or Reference Example 25, or a known method Can be manufactured in combination.

[Step III-3]
The compound represented by the general formula (IIa) is obtained by removing the protecting group R ¹⁶ of the compound represented by the general formula (IIf) with reference to the method described in “Protecting Groups in Organic Synthesis”. .

[Step III-4]
The compound represented by the general formula (IIc) is obtained by removing the protecting group R ¹⁵ of the compound represented by the general formula (IIf) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. .

The compound represented by the general formula (IIc) can also be produced by the method of the reaction process formula IV shown below.
[Reaction Process IV]

[The symbols in the formula are as defined above.]

[Step IV-1]
Add the compound represented by the general formula (XI) and the compound represented by the general formula (VIII) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (XII) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. In addition, the compound represented by general formula (XI) can be obtained as a commercial item, or can be manufactured combining a well-known method.

[Step IV-2]
Add the compound represented by the general formula (XIII) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (XII) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (XIII) is available as a commercial product or can be produced by combining known methods.

[Step IV-3]
Sodium chlorite and sodium dihydrogen phosphate in a suitable solvent (such as t-butyl alcohol) in the presence of an additive (2-methyl-2-butene, etc.) in a compound represented by general formula (XII) The compound represented by the general formula (IIc) is obtained by oxidation using The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

[Reaction process formula V]

[The symbols in the formula are as defined above.]

[Step V-1]
Using the compound represented by the general formula (XIV) and the compound represented by the general formula (VI) in a suitable solvent (for example, toluene, methylene chloride, tetrahydrofuran, etc.) using a base (for example, triethylamine, dimethylaminopyridine, etc.) To obtain a compound represented by the general formula (XV). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours. In addition, the compound represented by the general formula (XIV) is available as a commercial product, or can be produced by combining known methods.

[Step V-2]
Add the compound represented by the general formula (XV) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIg) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

[Step V-3]
The compound represented by the general formula (IIh) is obtained by removing the protecting group R ¹⁶ of the compound represented by the general formula (IIg) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. .

[Step V-4]
The compound represented by the general formula (IIh) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4- Reaction in the presence or absence of dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Gives a compound represented by the general formula (Ic). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

The compound represented by the general formula (IIg) can also be produced by the method of the reaction process formula VI shown below.
[Reaction process formula VI]

[The symbols in the formula are as defined above.]

[Step VI-1]
Add the compound represented by the general formula (XVI) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIi) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. In addition, the compound represented by the general formula (XVI) is available as a commercial product, or can be produced by combining known methods.

[Step VI-2]
The compound represented by the general formula (IIj) is obtained by reacting the compound represented by the general formula (IIi) with an iron powder in an appropriate solvent (for example, a mixed solvent of acetic acid and water). . The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.

[Step VI-3]
By reacting the compound represented by the general formula (IIj) with nitrous acid or a salt thereof in an appropriate solvent (for example, water, acetic acid, a mixed solvent thereof, etc.) under hydrochloric acid in accordance with a conventional method. After being converted to a diazonium salt, it is represented by the general formula (XVII) by reacting with copper (I) chloride and an aqueous sulfur dioxide solution in an appropriate solvent (for example, water, acetic acid, a mixed solvent thereof, etc.). A compound is obtained. The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 5 minutes to 48 hours.

[Step VI-4]
A compound represented by the general formula (XVII) and a compound represented by the general formula (VI) are used in a suitable solvent (for example, toluene, methylene chloride, tetrahydrofuran, etc.) using a base (for example, triethylamine, dimethylaminopyridine, etc.). To obtain a compound represented by the general formula (IIg). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 10 minutes to 48 hours.

[Reaction process formula VII]

[Wherein, R ¹⁹ represents a nitro group, an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, or a sulfamoyl group, and other symbols are as defined above.]

[Step VII-1]
Add the compound represented by the general formula (XVIII) and the compound represented by the general formula (X) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphinepalladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIk) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (XVIII) can be produced by combining the methods described in Reference Examples 40 to 49, Reference Example 58, Reference Examples 61 to 62, or known methods.

[Step VII-2]
Add the compound represented by the general formula (XIX) and the compound represented by the general formula (VIII) in an appropriate solvent (for example, dimethoxyethane, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, etc.) Palladium catalyst (tetrakistriphenylphosphine palladium (0), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane in the presence of aqueous solution of potassium, cesium carbonate, potassium carbonate, sodium carbonate, etc.) By reacting with a complex, trans-dichlorobis (triphenylphosphine) palladium (II), palladium (II) acetate, etc., a compound represented by the general formula (IIk) is obtained. The reaction temperature is from 0 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (XIX) can be produced by combining the methods described in Reference Examples 65 to 71 or known methods.

[Step VII-3]
The compound represented by the general formula (II l) is obtained by removing the protecting group R ¹⁶ of the compound represented by the general formula (IIk) with reference to the method described in the above “Protecting Groups in Organic Synthesis”. It is done.

[Step VII-4]
The compound represented by the general formula (II l) and the compound represented by the general formula (III) are added in an appropriate solvent (for example, N, N-dimethylformamide, methylene chloride, tetrahydrofuran, etc.) with additives (diisopropylethylamine, 4 In the presence or absence of -dimethylaminopyridine, 1-hydroxy-1H-benzotriazole, etc.) using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, etc.) Thus, a compound represented by the general formula (Id) is obtained. The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours. The compound represented by the general formula (II l) is converted into an acid chloride using a chlorinating agent (eg thionyl chloride, oxalyl chloride) in a suitable solvent (eg toluene, methylene chloride, etc.) Reaction with a compound represented by the formula (III) using a base (eg, triethylamine, N, N-diethylaniline, etc.) in an appropriate solvent (eg, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, etc.) To obtain the compound represented by the general formula (Id). The reaction temperature is from −20 ° C. to the boiling point of the solvent, and the reaction time is from 30 minutes to 48 hours.

Other compounds used as starting materials, intermediates, or reagents necessary for producing the compound of the present invention are available as commercial products, or can be produced by referring to known methods. In addition, substituents (for example, a hydroxyl group, a carboxylic acid group, etc.) contained in the compound of the present invention and the compound used for producing the compound have an appropriate protecting group at the raw material or intermediate stage. Introducing the compound may be effective in producing the compound, and the protecting group described in the above “Protecting Groups in Organic Synthesis” may be appropriately selected and used as necessary.

In order to isolate and purify the compound of the present invention and the compound used for producing the compound from the reaction solution, a commonly used method can be used. For example, solvent extraction, ion exchange resin, column chromatography using silica gel, alumina or the like as a carrier, high performance liquid chromatography (HPLC) fractionation, thin layer chromatography, scavenger resin, recrystallization, etc. can be used. These isolation and purification methods can be performed alone or in combination. Isolation and purification may be performed for each reaction or after completion of several reactions.

Since the compound of the present invention thus produced acts as a glucokinase activator, it can be used as a pharmaceutical composition. The pharmaceutical composition is useful as a prophylactic or therapeutic agent for diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or chronic complications of diabetes such as arteriosclerosis.

As the dosage form when the compound of the present invention is used as a pharmaceutical, various dosage forms described in the “Japanese Pharmacopoeia” preparation general rules can be selected according to the purpose. For example, when it is formed into a tablet form, it is generally sufficient to select an orally ingestible component used in the field. For example, excipients such as lactose, crystalline cellulose, sucrose, potassium phosphate and the like are examples. Furthermore, if desired, various additives commonly used in the field of pharmaceutical preparations such as a binder, a disintegrant, a lubricant, and an aggregation inhibitor may be blended.

The amount of the compound of the present invention contained as an active ingredient in the preparation of the present invention is not particularly limited and is appropriately selected from a wide range. The dose of the active ingredient compound is appropriately determined depending on its usage, patient age, gender and other conditions, and the degree of disease. In the case of oral administration, the amount of the compound of the present invention is about 1 μg / kg body weight per day. The dose can be appropriately administered in a range of ˜100 mg divided into 1 to 4 times a day. However, since the dosage and frequency are determined in view of the relevant conditions including the degree of the condition to be treated, the choice of the compound to be administered and the selected route of administration, the dosage range and frequency are It is not intended to limit the scope of the invention.

The content of the present invention will be described in more detail below with reference to examples, reference examples, and pharmacological test examples, but the technical scope of the present invention is not limited to the description.
The nuclear magnetic resonance ( ¹ H-NMR) spectra in the following examples and reference examples are described with chemical shift values expressed as σ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by “s” for singlets, “d” for doublets, “dd” for double doublets, “t” for triplets, “m” for multiplets, and “brs” for broad singlets. Mass spectrometry was performed by electrospray ionization (ESI). In the table, methyl group is “Me”, ethyl group is “Et”, i-propyl group is “i-Pr”, methanesulfonyl group is “Ms”, acetyl group is “Ac”, 2-tetrahydropyranyl group Is “THP” and the pivaloyl group is “Piv”.

Reference example 1
2- Methylthiophene -3-carboxylic acid diisopropylamine (233 g) was dissolved in tetrahydrofuran (2.30 L), and a hexane solution (1.50 L) of n-butyllithium was added dropwise at 0 ° C., followed by stirring for 40 minutes. The reaction mixture was cooled to −68 to −60 ° C., a solution of thiophene-3-carboxylic acid (223 g) in tetrahydrofuran (500 mL) was added dropwise, and the mixture was stirred for 1 hr. Thereafter, methyl iodide (254 g) was added, the temperature was raised to room temperature, and the mixture was further stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and 6N hydrochloric acid was added to the resulting residue to adjust to pH = 1, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from water / acetic acid to obtain the title compound (209 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.78 (3H, s), 7.01 (1H, d, J = 5.5 Hz), 7.45 (1 H, d, J = 5.5 Hz).
ESI / MS (m / z): 141 (MH) ^- .

Reference example 2
2-methylthiophene-3-carboxylic acid methyl ester 2-methylthiophene-3-carboxylic acid (100 g) was dissolved in methanol (500 mL), thionyl chloride (200 mL) was slowly added dropwise, and the mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with methylene chloride. The organic phase was washed in turn with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (105 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.74 (3H, s), 3.85 (3H, s), 6.98 (1H, d, J = 5.1 Hz), 7.38 (1 H, d, J = 5.5 Hz) .

Reference example 3
5-Bromo-2-methylthiophene-3-carboxylic acid methyl ester 2-methylthiophene-3-carboxylic acid methyl ester (156 g) was dissolved in N, N-dimethylformamide (750 mL) and N-bromosuccinimide (178 g) And stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with hexane. The organic phase was washed in turn with an aqueous sodium hydrogen sulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (226 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.67 (3H, s), 3.84 (3H, s), 7.33 (1H, s).

Reference example 4
5-Bromo-2-methylthiophene-3-carboxylic acid 5-bromo-2-methylthiophene-3-carboxylic acid methyl ester (12.9 g) was dissolved in tetrahydrofuran (130 mL), distilled water (65.0 mL) and hydroxylated. Lithium monohydrate (6.90 g) was added, and the mixture was stirred at 50 ° C. for 17 hours. The reaction mixture was cooled to room temperature and concentrated, distilled water was added, and the mixture was washed with diethyl ether. 6N hydrochloric acid was added little by little to the aqueous layer, adjusted to pH 2, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (11.2 g) as a white solid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.66 (3H, s), 7.38 (1H, s).

Reference Example 5
5-Bromo-2-methylthiophene-3-carboxylic acid benzyl ester Under argon atmosphere, 5-bromo-2-methylthiophene-3-carboxylic acid (5.53 g) was dissolved in N, N-dimethylformamide (100 mL). Sodium hydrogen carbonate (4.62 g) and benzyl bromide (3.27 mL) were added, and the mixture was stirred at 70 ° C. for 2 hr. After cooling to room temperature, distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (7.78 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.67 (3H, s), 5.28 (2H, s), 7.35 (1H, s), 7.32-7.42 (5H, m).

Example 1
5- (2-Ethoxycarbonylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester 5-bromo-2-methylthiophene-3-carboxylic acid benzyl ester (1.96 g) in 1,2-dimethoxy under argon atmosphere Dissolve in ethane (50 mL), ethyl 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (2.26 g), potassium carbonate (3.55 g) and 1 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (257 mg) was added, and the mixture was stirred at 85 ° C. for 6 hours. After cooling to room temperature, the insoluble material was filtered and washed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (2.39 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.17 (3H, t, J = 7.3Hz), 2.76 (3H, s), 4.21 (2H, q, J = 7.3Hz), 5.30 (2H, s) , 7.33 (1H, s), 7.32-7.42 (7H, m), 7.46-7.50 (1H, m), 7.74 (1H, dd, J = 7.7,0.8Hz).
ESI / MS (m / z): 381 (M + H) ⁺ , 379 (MH) ^- .

Example 2
5- (2-Ethoxycarbonylphenyl ) -2-methylthiophene-3-carboxylic acid benzyl ester (2.66 g) in ethanol under argon atmosphere (50.0 mL) and 10% palladium on carbon (500 mg) was added. After substituting the inside of reaction container with hydrogen, it stirred at 50 degreeC for 4 hours. The reaction vessel was purged with argon, filtered through celite, washed with ethyl acetate, and concentrated. Diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to obtain the title compound (1.53 g) as a white powder.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.22 (3H, t, J = 6.9Hz), 2.79 (3H, s), 4.25 (2H, q, J = 6.9Hz), 7.36 (1H, s) 7.40-7.45 (2H, m), 7.48-7.52 (1H, m), 7.77 (1H, dd, J = 7.7,1.1Hz).

Reference Example 6
5- (2-Formylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester 1,2-dimethoxyethane was converted from 5-bromo-2-methylthiophene-3-carboxylic acid benzyl ester (3.95 g) under argon atmosphere. (100 mL), 2-formylphenylboronic acid (2.48 g), potassium carbonate (5.27 g) and tetrakistriphenylphosphine palladium (0) (734 mg) were added, and the mixture was stirred at 85 ° C. for 7 hours. After cooling to room temperature, the insoluble material was filtered and washed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (3.95 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.80 (3H, s), 5.32 (2H, s), 7.38 (1H, s), 7.33-7.43 (5H, m), 7.49 (2H, t, J = 7.8Hz) 7.59-7.63 (1H, m), 7.62 (1H, d, J = 7.8Hz), 10.2 (1H, s).

Example 3
2- (4-Benzyloxycarbonyl-5-methylthiophen-2-yl) benzoic acid 5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester (3.94 g) was added to t-butyl alcohol ( 40.0 mL), and 2-methyl-2-butene was added and stirred. Sodium chlorite (9.19 g) and sodium dihydrogen phosphate (18.3 g) were dissolved in distilled water (80 mL) and added dropwise, followed by stirring for 2.5 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (4.84 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.69 (3H, s), 5.24 (2H, s), 7.38 (1H, s), 7.30-7.40 (7H, m), 7.45-7.52 (1H, m ), 7.81 (1H, d, J = 7.7Hz).
ESI / MS (m / z): 353 (M + H) ⁺ , 351 (MH) ^- .

Example 4
5- (2-methoxycarbonylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester Under argon atmosphere, 2- (4-benzyloxycarbonyl-5-methylthiophen-2-yl) benzoic acid (4.12 g) It melt | dissolved in acetone (100 mL), potassium carbonate (3.23g) and methyl iodide (3.65mL) were added, and it stirred at room temperature for 16 hours. The reaction solution was concentrated, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (4.03 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.76 (3H, s), 3.76 (3H, s), 5.30 (2H, s), 7.34 (1H, s), 7.33-7.43 (7H, m), 7.47-7.52 (1H, m), 7.74 (1H, dd, J = 7.5,1.3Hz).
ESI / MS (m / z): 367 (M + H) ⁺ , 365 (MH) ^- .

Example 5
5- (2-Methoxycarbonylphenyl) -2-methylthiophene- 3-carboxylic acid benzyl ester (4.03 g) in ethanol under argon atmosphere (80.0 mL) and 10% palladium on carbon (800 mg) was added. After substituting the inside of reaction container with hydrogen, it stirred at 50 degreeC for 4 hours. After replacing the inside of the reaction vessel with argon, the reaction solution was filtered through celite, washed with ethyl acetate, and concentrated. Diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to give the title compound (3.01 g) as a white powder.
¹ H-NMR ((DMSO-d ₆ ) δ (ppm): 2.69 (3H, s), 3.72 (3H, s), 7.23 (1H, s), 7.47-7.50 (1H, m), 7.51 (1H, d, J = 7.7Hz), 7.57-7.61 (1H, m), 7.66 (1H, d, J = 7.7Hz).
ESI / MS (m / z): 277 (M + H) ⁺ , 275 (MH) ^- .

Reference Example 7
3- Bromopicolinic acid methyl ester 3-Bromopicolinic acid (505 mg) was dissolved in methanol (25.0 mL), a few drops of concentrated sulfuric acid was added, and the mixture was stirred at 70 ° C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated and the solvent was distilled off. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (521 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 4.02 (3H, s), 7.31 (1H, dd, J = 8.1, 4.7 Hz), 8.01 (1H, dd, J = 8.0, 1.5 Hz), 8.62 ( (1H, dd, J = 4.7,1.5Hz).

Example 6
3- (4-Benzyloxycarbonyl-5-methylthiophen-2-yl) picolinic acid methyl ester Under argon atmosphere, 5-bromo-2-methylthiophene-3-carboxylic acid benzyl ester (1.56 g) was added to tetrahydrofuran (16.0 mL). ) And cooled to -40 ° C. A 0.78 M tetrahydrofuran solution (6.50 mL) of isopropylmagnesium bromide was added dropwise, followed by stirring for 1 hour. Triisopropyl borate (350 μL) was added dropwise at −40 ° C., followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to adjust to pH = 3, and the mixture was stirred at room temperature for 2 hr. After concentration and evaporation of the solvent, hexane was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with hexane to obtain a crude product (1.35 g) as a white powder. Under an argon atmosphere, 3-bromopicolinic acid methyl ester (414 mg) was dissolved in tetrahydrofuran (8.00 mL), and the resulting crude product (624 mg) and tetrakistriphenylphosphine palladium (0) (66.2 mg) were added. For 10 minutes. A 2.0 M aqueous sodium carbonate solution (4.79 mL) was added, and the mixture was stirred at 70 ° C. for 17 hours. After cooling to room temperature, the insoluble material was filtered and washed with ethyl acetate. The organic layer was washed with distilled water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 3/2) to obtain the title compound (645 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (3H, s), 3.87 (3H, s), 5.31 (2H, s), 7.36-7.45 (6H, m), 7.44 (1H, s), 7.79 (1H, dd, J = 7.9,1.8Hz), 8.62 (1H, dd, J = 4.5,1.8Hz).
ESI / MS (m / z): 368 (M + H) ⁺ , 366 (MH) ^-

Example 7
5- (2-Methoxycarbonylpyridin-3-yl) -2-methylthiophene-3-carboxylate under argon atmosphere, 3- (4-benzyloxycarbonyl-5-methylthiophen-2-yl) picolinic acid methyl ester ( 645 mg) was dissolved in ethanol (9.00 mL), and 10% palladium carbon (130 mg) and acetic acid (3.00 mL) were added. After substituting the inside of reaction container with hydrogen, it stirred at 70 degreeC for 14 hours. After replacing the inside of the reaction vessel with argon, the reaction solution was filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure. Toluene was added and azeotroped and dried to obtain the title compound (474 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71 (3H, s), 3.81 (3H, s), 7.38 (1H, s), 7.62 (1H, dd, J = 8.0, 4.7 Hz), 8.04 (1H, dd, J = 8.0,1.4Hz), 8.59 (1H, dd, J = 4.7,1.4Hz).
ESI / MS (m / z): 278 (M + H) ⁺ , 276 (MH) ^-

Reference Example 8
2- [4- (5-Chlorothiazol-2-ylcarbamoyl) -5-methylthiophen-2-yl] benzoic acid ethyl ester 5- (2-ethoxycarbonylphenyl) -2-methylthiophene-3-carboxylic acid ( 1.53 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.93 g) and 1-hydroxy-1H-benzotriazole (1.42 g) are dissolved in N, N-dimethylformamide (15.0 mL). And stirred at room temperature for 30 minutes. Diisopropylethylamine (2.75 mL) and 5-chlorothiazol-2-amine hydrochloride (1.80 g) were added to the reaction mixture, and the mixture was stirred at 50 ° C. for 18 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to obtain the title compound (1.07 g) as a white powder.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.22 (3H, t, J = 7.1Hz), 2.82 (3H, s), 4.26 (2H, q, J = 7.1Hz), 7.19 (1H, s) , 7.21 (1H, s), 7.41 (1H, dd, J = 7.5,1.3Hz), 7.43-7.47 (1H, m), 7.51-7.55 (1H, m), 7.84 (1H, dd, J = 7.9, 1.3Hz), 10.0 (1H, br, s).
ESI / MS (m / z): 407 (M + H) ⁺ , 405 (MH) ^- .

With reference to the method of Reference Example 8, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 1, and the data are shown in Table 2.

Reference Example 16
2- [4- (5-chlorothiazol-2-ylcarbamoyl) -5-methylthiophen-2-yl] benzoic acid 2- [4- (5-chlorothiazol-2-ylcarbamoyl) -5-methylthiophene- 2-yl] benzoic acid ethyl ester (1.08 g) was dissolved in tetrahydrofuran (10.0 mL), distilled water (5.00 mL) and lithium hydroxide monohydrate (334 mg) were added, and the mixture was stirred at 50 ° C. for 17 hours. The reaction mixture was cooled to 0 ° C., distilled water was added, pH was adjusted to 2 with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to give the title compound (905 mg) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.73 (3H, s), 7.46-7.50 (1H, m), 7.52-7.54 (1H, m), 7.56-7.61 (1H, m), 7.57 (1H, s), 7.69 (1H, d, J = 7.7Hz), 7.76 (1H, s).
ESI / MS (m / z): 379 (M + H) ⁺ , 377 (MH) ^- .

With reference to the method of Reference Example 16, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 3, and the data are shown in Table 4.

Example 8
N- (5-chlorothiazol-2-yl) -5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxamide 2- (4- (5-chlorothiazol -2-yl) Rucarbamoyl) -5-methylthiophen-2-yl) benzoic acid (37.9 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (38.3 mg) and 1-hydroxy-1H-benzotriazole (27.0 mg) ) Was dissolved in N, N-dimethylformamide (500 μL) and stirred at room temperature for 30 minutes. Diisopropylethylamine (52.2 μL) and 2-methoxyethanamine (17.3 μL) were added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. After cooling to room temperature, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with diethyl ether to obtain the title compound (35.4 mg) as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71 (3H, s), 3.18 (3H, s), 3.30-3.60 (4H, m), 7.35-7.40 (1H, m), 7.42 (1H , d, J = 6.5Hz), 7.48-7.52 (1H, m), 7.56 (1H, d, J = 5.1Hz), 7.57 (1H, s), 7.77 (1H, s), 8.36 (1H, t, J = 5.5Hz), 12.5 (1H, brs).
ESI / MS (m / z): 436 (M + H) ⁺ , 434 (MH) ^- .

With reference to the method of Example 8, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 5, and the data are shown in Table 6.

Reference Example 23
5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid methyl ester 5-bromo-2-methylthiophene-3-carboxylic acid Instead of benzyl ester, 5-bromo-2-methylthiophene-3- Reaction was carried out in the same manner as in Reference Example 6 using carboxylic acid methyl ester to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.80 (3H, s), 3.87 (3H, s), 7.35 (1H, s), 7.37-7.60 (2H, m), 7.60-7.64 (1H, m ), 8.01 (1H, dd, J = 8.4,1.8Hz), 10.2 (1H, s)
ESI / MS (m / z): 261 (M + H) ⁺ , 259 (MH) ⁻ .

Example 21
5- (2-carboxyphenyl) -2-methylthiophene-3-carboxylic acid methyl ester 5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid instead of benzyl ester, 5- (2-formyl (Phenyl) -2-methylthiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 3 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.76 (3H, s), 3.83 (3H, s), 7.35 (1H, s), 7.43 (2H, m), 7.54 (1H, m), 7.93 ( 1H, m).
ESI / MS (m / z): 277 (M + H) ⁺ , 275 (MH) ⁻ .

Reference Example 24
(4-methoxycarbonyl-5-methylthiophen-2-yl) boronic acid under argon atmosphere, 5-bromo-2-methylthiophene-3-carboxylic acid methyl ester (18.3 g) was dissolved in tetrahydrofuran (180 mL), Cooled to 40 ° C. A 0.78 M tetrahydrofuran solution (100 mL) of isopropylmagnesium bromide was added dropwise, followed by stirring for 1 hour. Triisopropyl borate (27.0 mL) was added dropwise at −40 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to adjust to pH = 3, and the mixture was stirred at room temperature for 2 hr. After concentration and evaporation of the solvent, hexane was added to the resulting residue, and the precipitated crystals were collected by filtration and washed with hexane to obtain the title compound (12.1 g) as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.70 (3H, s), 3.78 (3H, s), 7.76 (1H, s).

Reference Example 25
3-Bromopicolinic acid Benzyl ester Under argon atmosphere, 3-bromopicolinic acid (3.00 g) was dissolved in N, N-dimethylformamide (60.0 mL), and sodium bicarbonate (2.73 g) and benzyl bromide (2.10 mL) were added. In addition, the mixture was stirred at 70 ° C. for 7 hours. After cooling to room temperature, distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1 → 2/1) to give the title compound (4.12 g).
¹ HNMR (CDCl ₃ ) δ (ppm): 5.46 (2H, s), 7.28 (1H, dd, J = 8.2, 4.6Hz), 7.35-7.40 (3H, m), 7.48-7.50 (2H, m), 7.98 (1H, dd, J = 8.1,1.5Hz), 8.60 (1H, dd, J = 4.6,1.3Hz)
ESI-MS (m / e): 293 [M + H] ⁺ .

Example 22
3- (4-Methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid benzyl ester Under an argon atmosphere, 3-bromopicolinic acid benzyl ester (4.12 g) was dissolved in tetrahydrofuran (35.0 mL), and (4- ( Methoxycarbonyl) -5-methylthiophen-2-yl) boronic acid (4.22 g), 2.0 M aqueous sodium carbonate solution (17.6 mL) and tetrakis (triphenylphosphine) palladium (0) (489 mg) were added at 70 ° C. Stir for 15 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, distilled water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 3/1 → 2/1) to give the title compound (5.11 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.70 (3H, s), 3.84 (3H, s), 5.31 (2H, s), 7.26-7.31 (5H, m), 7.34 (1H, s), 7.43 (1H, dd, J = 7.7,4.8Hz), 7.77 (1H, dd, J = 8.1,1.5Hz), 8.63-8.64 (1H, m).

Example 23
3- (4-Methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid in an argon atmosphere was mixed with 3- (4-methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid benzyl ester (1.00 g) in ethanol. (15.0 mL), 10% palladium carbon (200 mg) was added, and the mixture was stirred at room temperature for 10 minutes. After substituting the inside of reaction container with hydrogen, it stirred at 70 degreeC for 4 hours. The reaction mixture was filtered through celite, washed with ethyl acetate, concentrated under reduced pressure, and dried to obtain the title compound (730 mg).
¹ H-NMR (CD ₃ OD) δ (ppm): 2.75 (3H, s), 3.84 (3H, s), 7.51 (1H, s), 7.58 (1H, dd, J = 8.1, 4.8Hz), 7.99 (1H, dd, J = 7.7,1.5Hz), 8.54 (1H, dd, J = 4.9,1.3Hz).
ESI / MS (m / z): 278 (M + H) ⁺ , 276 (MH) ⁻ .

Reference Example 26
5- (3-Fluoro-2-formylphenyl) -2-methylthiophene-3-carboxylic acid methyl ester 2-chloro-6-fluorobenzaldehyde (5.00 g) is dissolved in dimethoxyethane (75.0 mL), and (4- Methoxycarbonyl-5-methylthiophen-2-yl) boronic acid (9.46 g), tetrakistriphenylphosphine palladium (0) (3.64 g) and tripotassium phosphate (6.69 g) were added and refluxed for 17 hours. The reaction solution was filtered and washed with ethyl acetate. Water was added to the filtrate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 10-1 / 4) to give the title compound (4.67 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (3H, s), 3.87 (3H, s), 7.17 (1H, t, J = 9.3 Hz), 7.24-7.31 (1H, m), 7.34 ( 1H, s), 7.50-7.58 (1H, m), 10.14 (1H, s).
ESI / MS (m / z): 279 (M + H) ⁺ , 277 (MH) ⁻ .

Example 24
Instead of 2-fluoro-6- (4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid 5- (2-formylphenyl) -2-methylthiophene-3-carboxylic acid benzyl ester, 5- ( 3-Fluoro-2-formylphenyl) -2-methylthiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 3 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71 (3H, s), 3.79 (3H, s), 7.29-7.38 (2H, m), 7.24-7.31 (1H, m), 7.45 (1H , s), 7.48-7.59 (1H, m).
ESI / MS (m / z): 295 (M + H) ⁺ , 293 (MH) ⁻ .

Reference Example 27
5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxylic acid methyl ester under argon atmosphere, 2- (4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid ( 7.50 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (10.4 g) and 1-hydroxy-1H-benzotriazole (8.30 g) were dissolved in N, N-dimethylformamide (163 mL). Stir at room temperature for 1 hour. Diisopropylethylamine (9.20 mL) and 2-methoxyethanamine (4.70 mL) were added to the reaction solution, and the mixture was further stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, distilled water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 1/1 → 1/2) to give the title compound (3.86 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.76 (3H, s), 3.23 (3H, s), 3.38 (2H, t, J = 5.1 Hz), 3.50-3.54 (2H, m), 3.84 ( 3H, s), 5.99 (1H, br, s), 7.36-7.43 (4H, m), 7.56-7.58 (1H, m).
ESI / MS (m / z): 334 (M + H) ⁺ , 332 (MH) ⁻ .

With reference to the method of Reference Example 27, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 7 and the data are shown in Table 8.

Reference Example 30
5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxylic acid 5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (3.86 g) was dissolved in tetrahydrofuran (19.0 mL), distilled water (9.60 mL) and lithium hydroxide monohydrate (1.69 g) were added, and the mixture was stirred at 50 ° C. for 15 hr. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and distilled water was added to the resulting residue. Subsequently, 1N hydrochloric acid was added little by little to adjust to pH = 2, and the precipitated crystals were collected by filtration and washed with hexane to obtain the title compound (3.12 g) as a white powder.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (3H, s), 3.26 (3H, s), 3.42 (2H, t, J = 4.9Hz), 3.52-3.56 (2H, m), 6.10 ( 1H, br, s), 7.37-7.47 (4H, m), 7.56-7.58 (1H, m).
ESI / MS (m / z): 320 (M + H) ⁺ , 318 (MH) ⁻ .

With reference to the method of Reference Example 30, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 9 and the data are shown in Table 10.

Example 25
N- (3-ethyl-1,2,4-thiadiazol-5-yl) -5- [2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxamide under an argon atmosphere, 5- [ 2- (2-methoxyethylcarbamoyl) phenyl] -2-methylthiophene-3-carboxylic acid (50 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (60 mg) and 1-hydroxy-1H— Benzotriazole (48 mg) was dissolved in N, N-dimethylformamide (0.50 mL) and stirred at room temperature for 1 hour. Diisopropylethylamine (53 μL) and 5-amino-3-ethyl-1,2,4-thiadiazole (40 mg) were added to the reaction mixture, and the mixture was stirred at 60 ° C. for 10 hr. The reaction solution was diluted with ethyl acetate, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, distilled water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (dichloromethane / methanol = 20/1) to give the title compound (60 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.35 (3H, t, J = 7.5Hz), 2.83 (3H, s), 2.84-2.88 (2H, m, J = 7.5Hz), 3.41 (3H, s), 3.50 (2H, t, J = 5.2Hz), 3.56-3.59 (2H, m), 6.06 (1H, brs), 7.37-7.46 (4H, m), 7.45 (1H, s), 7.54 (1H , d, J = 6.6Hz).
ESI / MS (m / z): 431 (M + H) ⁺ , 429 (MH) ^- .

With reference to the method of Example 25, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 11 and the data are shown in Table 12.

Example 31
5- [3-Fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester under argon atmosphere 2 -Fluoro-6- (4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid (369 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (480 mg) and 1-hydroxy-1H -Benzotriazole (384 mg) was dissolved in N, N-dimethylformamide (4.00 mL) and stirred at room temperature for 1 hour. To the reaction mixture were added diisopropylethylamine (437 μL) and 2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethanamine (364 mg), and the mixture was further stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 4/1 → 1/1) to obtain the title compound (460 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.34-1.73 (5H, m), 2.74 (3H, s), 3.37-3.42 (1H, m), 3.48-3.66 (8H, m), 3.71-3.80 (2H, m) 3.84 (3H, s), 4.54 (1H, brs), 6.55 (1H, brs), 7.07 (1H, t, J = 8.1Hz), 7.23-7.28 (1H, m), 7.32-7.39 (1H, m), 7.52 (1H, s).
ESI / MS (m / z): 466 (M + H) ⁺ , 464 (MH) ^- .

Example 32
2-Methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylcarbamoyl] phenyl] thiophene-3-carboxylic acid methyl ester 2- [2- (tetrahydro-2H-pyran-2- The title compound was obtained in the same manner as in Example 31 except that 2- (tetrahydro-2H-pyran-2-yloxy) ethanamine was used instead of (yloxy) ethoxy] ethanamine.
¹ HNMR (CDCl ₃ ) δ (ppm): 1.41-1.73 (6H, m), 2.75 (3H, s), 3.41-3.52 (3H, m), 3.59-3.65 (1H, m), 3.71-3.75 (2H , m), 3.84 (3H, s), 4.38-4.39 (1H, m), 6.20 (1H, brs), 7.36-7.44 (4H, m), 7.55-7.57 (1H, m).

Example 33
2-Methyl-5- [2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] pyridin-3-yl] thiophene-3-carboxylic acid methyl ester 2-fluoro-6 Similar to Example 31 except that 3- (4-methoxycarbonyl-5-methylthiophen-2-yl) picolinic acid was used instead of-(4-methoxycarbonyl-5-methylthiophen-2-yl) benzoic acid. Reaction was carried out by the method to obtain the title compound.
¹ HNMR (CDCl ₃ ) δ (ppm): 1.47-1.83 (6H, m), 2.76 (3H, s), 3.46-3.50 (2H, m), 3.59-3.69 (8H, m), 3.83 (3H, s ), 3.85-3.90 (1H, m), 4.63-4.65 (1H, m), 7.39-7.43 (2H, m), 7.76 (1H, dd, J = 7.9, 1.6Hz), 8.03 (1H, brs), 8.54 (1H, dd, J = 4.8,1.5Hz).
ESI / MS (m / z): 447 (MH) ^- .

Example 34
5- [3-Fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid 5- [3-fluoro- 2- [2- [2- (Tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (1.46 g) dissolved in tetrahydrofuran (15.0 mL) Distilled water (15.0 mL) and lithium hydroxide monohydrate (395 mg) were added, and the mixture was stirred at 50 ° C. for 15 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and distilled water was added to the resulting residue. Subsequently, 1N hydrochloric acid was added little by little to adjust to pH = 2, and the precipitated crystals were collected by filtration and washed with hexane to obtain the title compound (1.36 g) as a white powder.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.35-1.73 (5H, m), 2.76 (3H, s), 3.38-3.44 (1H, m), 3.52-3.68 (8H, m), 3.75-3.84 (2H, m)
4.56 (1H, brs), 6.59 (1H, brs), 7.08 (1H, t, J = 8.1Hz), 7.23-7.28 (1H, m), 7.33-7.40 (1H, m), 7.56 (1H, s) .
ESI / MS (m / z): 452 (M + H) ⁺ , 450 (MH) ^- .

With reference to the method of Example 34, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 13, and the data are shown in Table 14.

Reference Example 33
N- (5-chlorothiazol-2-yl) -5- [3-fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methyl Thiophene-3-carboxamide Under an argon atmosphere, 5- [3-fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3- Carboxylic acid (150 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (127 mg) and 1-hydroxy-1H-benzotriazole (102 mg) were dissolved in N, N-dimethylformamide (2.00 mL). And stirred at room temperature for 1 hour. Diisopropylethylamine (116 μL) and 5-chlorothiazol-2-amine hydrochloride (114 mg) were added to the reaction mixture, and the mixture was stirred at 60 ° C. for 17 hours. The reaction mixture was diluted with ethyl acetate, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography (hexane / ethyl acetate = 1/2) to obtain the title compound (100 mg).
ESI / MS (m / z): 568 (M + H) ⁺ , 566 (MH) ^- .

With reference to the method of Reference Example 33, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 15 and the data are shown in Table 16.

Example 37
N- (5-chlorothiazol-2-yl) -5- [3-fluoro-2- [2- (2-hydroxyethoxy) ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxamide N- (5- Chlorothiazol-2-yl) -5- [3-fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxamide ( 100 mg) was dissolved in tetrahydrofuran (1.50 mL), 6N aqueous hydrochloric acid solution (150 μL) was added, and the mixture was stirred at 50 ° C. for 2 hr. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (methanol / chloroform = 1/9) to obtain the title compound (30.0 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71 (3H, s), 3.20-3.51 (8H, m), 4.46 (1H, brs), 7.27 (1H, t, J = 8.2Hz), 7.40-7.55 (2H, m), 7.57 (1H, s), 7.84 (1H, s), 8.70 (1H, t, J = 5.5Hz), 12.55 (1H, brs).
ESI / MS (m / z): 484 (M + H) ⁺ , 482 (MH) ^- .

With reference to the method of Example 37, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 17, and the data are shown in Table 18.

Reference Example 38
2-Bromo-N- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] benzenesulfonamide 2- (tetrahydro-2H-pyran-2-yloxy) ethanamine (194 mg) dissolved in tetrahydrofuran (4.80 mL) Triethylamine (280 μL) and dimethylaminopyridine (16.0 mg) were added and cooled to 0 ° C. Next, a solution of 2-bromobenzene-1-sulfonyl chloride (310 mg) in tetrahydrofuran (1.55 mL) was added dropwise at 0 ° C., stirred at 0 ° C. for 1 hour, and then stirred at room temperature for 17 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate) to give the title compound (409 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46-1.61 (4H, m), 1.63-1.86 (2H, m), 3.07-3.17 (2H, m), 3.42-3.51 (2H, m), 3.70 -3.82 (2H, m), 4.47 (1H, t, J = 3.7Hz), 5.79 (1H, brs), 7.39-7.49 (2H, m), 7.74 (1H, dd, J = 7.7,1.1Hz), 8.14 (1H, dd, J = 7.7,1.1Hz).

Example 42
Instead of 2-methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxylic acid methyl ester 2-chloro-6-fluorobenzaldehyde, The title compound was obtained in the same manner as in Reference Example 26 using 2-bromo-N- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] benzenesulfonamide.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.34-1.78 (6H, m), 2.77 (3H, s), 2.92-3.04 (2H, m), 3.37-3.50 (2H, m), 3.63-3.76 (2H, m), 3.84 (3H, s), 4.42 (1H, t, J = 3.7Hz), 4.74 (1H, brs), 7.40-7.59 (3H, m), 7.64 (1H, s), 8.16 ( (1H, dd, J = 8.1,1.5Hz).
ESI / MS (m / z): 440 (M + H) ⁺ , 438 (MH) ^- .

Reference Example 39
N- (5-chlorothiazol-2-yl) -2-methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxamide 2- Methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxylic acid methyl ester (152 mg) was added to tetrahydrofuran (2.00 mL) and water (2.00 mL). ) And mixed with lithium hydroxide monohydrate (44.0 mg) and stirred at 60 ° C. for 17 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (150 mg).
The obtained crude product (150 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (135 mg), 1-hydroxy-1H-benzotriazole monohydrate (108 mg) and diisopropylamine (123 μL) And 2-amino-5-chlorothiazole hydrochloride (120 mg) was dissolved in N, N-dimethylformamide (2.00 mL), stirred at room temperature for 2 hours, and further stirred at 60 ° C. for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (80.0 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.34-1.73 (7H, m), 2.63 (3H, s), 2.95-3.01 (2H, m), 3.31-3.49 (2H, m), 3.61-3.77 (2H, m), 4.42 (1H, t, J = 3.7Hz), 7.18 (1H, s), 7.35-7.60 (3H, m), 7.76 (1H, s), 8.13 (1H, dd, J = 8.1 , 1.5Hz).
ESI / MS (m / z): 542 (M + H) ⁺ , 540 (MH) ^- .

Example 43
N- (5-chlorothiazol-2-yl) -5- [2- (2-hydroxyethylsulfamoyl) phenyl] -2-methylthiophene-3-carboxamide N- (5-chlorothiazol-2-yl) Instead of -5- [3-fluoro-2- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] ethylcarbamoyl] phenyl] -2-methylthiophene-3-carboxamide, N- (5 Example 37 using -chlorothiazol-2-yl) -2-methyl-5- [2- [2- (tetrahydro-2H-pyran-2-yloxy) ethylsulfamoyl] phenyl] thiophene-3-carboxamide The reaction was carried out in the same manner as in to give the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (3H, s), 3.11 (2H, t, J = 4.8Hz), 3.85 (2H, t, J = 4.8Hz), 7.18 (1H, s) , 7.41-7.45 (2H, m), 7.53-7.63 (2H, m), 8.13 (1H, dd, J = 7.9,1.6Hz).
ESI / MS (m / z): 458 (M + H) ⁺ , 456 (MH) ^- .

Example 44
2-methyl-5- (2-nitrophenyl) thiophene-3-carboxylic acid methyl ester The same reaction as in Reference Example 26 was carried out using 1-bromo-2-nitrobenzene instead of 2-chloro-6-fluorobenzaldehyde. And the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.77 (3H, s), 3.84 (3H, s), 7.37 (1H, s), 7.46-7.52 (2H, m), 7.55-7.61 (1H, m ), 7.79 (1H, dd, J = 7.6Hz, 1.3Hz).

Example 45
5- (2-aminophenyl) -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- (2-nitrophenyl) thiophene-3-carboxylic acid methyl ester (621 mg) with acetic acid (6.75 mL) It melt | dissolved in the mixed solvent of water (750 microliters), iron powder (625 mg) was added, and it stirred at 60 degreeC for 2 hours. Water and ethyl acetate were added to the reaction solution, filtered, and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to give the title compound (546 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.76 (3H, s), 3.86 (3H, s), 2.11 (1H, brs), 6.75-6.80 (2H, m), 7.12-7.17 (1H, m ), 7.21 (1H, dd, J = 7.6Hz, 1.3Hz), 7.46 (1H, s).

Example 46
5- [2- (2-Methoxyethylsulfamoyl) phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- (2-aminophenyl) -2-methylthiophene-3-carboxylic acid methyl ester (156 mg ) In acetic acid (1.60 mL), hydrochloric acid (700 μL) was added at 0 ° C., and a solution of sodium nitrite (74.0 mg) in water (200 μL) was added dropwise, followed by stirring at 0 ° C. for 15 minutes (reaction solution A). ). Copper (I) chloride (31.0 mg) was suspended in acetic acid (1.00 mL), an aqueous sulfur dioxide solution (2.50 mL) was added, and the mixture was stirred at 0 ° C. for 30 min (reaction solution B). Reaction solution A was added dropwise to reaction solution B at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (127 mg). The obtained crude product (125 mg) was dissolved in thionyl chloride (3.00 mL), N, N-dimethylformamide (2.00 μL) was added, and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in tetrahydrofuran (3.00 mL), and a solution of 2-methoxyethanamine (69.0 μL), triethylamine (168 μL) and dimethylaminopyridine (10.0 mg) in tetrahydrofuran (500 μL) was added dropwise at 0 ° C. And stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (104 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.79 (3H, s), 2.91-2.98 (1H, m), 3.19 (3H, s), 3.30 (1H, t, J = 5.4Hz), 3.85 ( 3H, s), 7.44 (1H, dd, J = 7.7Hz, 1.5Hz), 7.48-7.59 (2H, m), 7.61 (1H, s), 8.14 (1H, dd, J = 7.7Hz, 1.5Hz) .
ESI / MS (m / z): 370 (M + H) ⁺ , 368 (MH) ^- .

Example 47
N- (5-chlorothiazol-2-yl) -5- [2- (2-methoxyethylsulfamoyl) phenyl] -2-methylthiophene-3-carboxamide 5- [2- (2-methoxyethylsulfa) Moyl) phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (101 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.00 mL) and water (1.00 mL), and lithium hydroxide monohydrate (34.0 mg) was dissolved. In addition, the mixture was stirred at 60 ° C. for 17 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (101 mg). The obtained crude product (101 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (109 mg), 1-hydroxy-1H-benzotriazole monohydrate (87.0 mg) and diisopropylamine (99.0) μL) and 2-amino-5-chlorothiazole hydrochloride (97.0 mg) were dissolved in N, N-dimethylformamide (1.50 mL), stirred at room temperature for 2 hours, and further stirred at 60 ° C. for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (79.0 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.74 (3H, s), 2.92-2.98 (2H, m), 3.12 (3H, s), 3.22-3.40 (5H, m), 7.43 (1H , t, J = 5.7Hz), 7.51-7.59 (2H, m), 7.60-7.73 (2H, m), 7.75 (1H, s), 8.00 (1H, dd, J = 7.7Hz, 1.1Hz), 12.45 (1H, bs).
ESI / MS (m / z): 472 (M + H) ⁺ , 470 (MH) ^- .

Reference Example 40
3- (3-Bromo-2-nitrophenyl) -2-oxopropanoic acid ethyl ester potassium ethoxide (3.9 g) is suspended in a mixed solvent of ethanol (3.0 mL) and N, N-dimethylformamide (50 mL). Diethyl oxalate (9.4 mL) was added dropwise at 0 ° C. N, N-dimethylformamide (20 mL) of 3-bromo-2-nitrotoluene (5.0 g) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A 1N aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 3, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 10-1 / 4) to give the title compound (6.8 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.38 (3H, t, J = 7.1Hz), 4.33-4.40 (2H, m), 6.24 (1H, s), 6.88 (1H, s), 7.37 ( 1H, t, J = 7.9Hz), 7.55 (1H, dd, J = 7.9Hz, 1.5Hz), 8.29 (1H, dd, J = 7.9Hz, 1.5Hz).

Reference Example 41
2- (3-Bromo-2-nitrophenyl) acetic acid 3- (3-Bromo-2-nitrophenyl) -2-oxopropanoic acid ethyl ester (6.8 g) was dissolved in ethanol (70.0 mL) and dissolved in 5N at room temperature. Aqueous sodium hydroxide (17.2 mL) was added, and the mixture was stirred at 60 ° C. for 1 hr. A 6N aqueous hydrochloric acid solution was added to the reaction solution to adjust to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was suspended in water and dissolved by adding 5N aqueous sodium hydroxide solution (17.2 mL). A 30% aqueous hydrogen peroxide solution (5.2 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 6N aqueous hydrochloric acid solution was added to the reaction solution to adjust to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the title compound (5.2 g) was obtained by concentrating the filtrate under reduced pressure.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 3.68 (2H, s), 7.50-7.59 (2H, m), 7.81 (1H, dd, J = 7.7Hz, 1.1Hz), 12.65 (1H, brs).

Reference Example 42
2- (3-Bromo-2-nitrophenyl) ethanol 2- (3-Bromo-2-nitrophenyl) acetic acid (5.2 g) was dissolved in tetrahydrofuran (60 mL), and 1M borane-tetrahydrofuran complex-tetrahydrofuran solution (11 mL) Was added dropwise at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 9-1 / 1) to give the title compound (4.1 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.85 (2H, t, J = 6.4Hz), 3.87 (2H, t, J = 6.4Hz), 7.31 (1H, t, J = 7.9Hz), 7.38 (1H, dd, J = 7.9Hz, 1.3Hz), 7.56 (1H, dd, J = 7.9Hz, 1.3Hz).

Reference Example 43
2- (3-Bromo-2-nitrophenoxy) tetrahydro-2H-pyran 2- (3-bromo-2-nitrophenyl) ethanol (2.00 g) was dissolved in methylene chloride (18.0 mL) and dihydropyranyl ( 882 μL) and p-toluenesulfonic acid (155 mg) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Triethylamine (341 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 9-1 / 4) to give the title compound (2.26 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.45-1.84 (6H, m), 2.89 (2H, t, J = 6.6Hz), 3.43-3.49 (1H, m), 3.53-3.62 (1H, m ), 3.66-3.73 (1H, m), 3.90-3.97 (1H, m), 4.55 (1H, t, J = 3.5Hz), 7.28 (1H, t, J = 8.1Hz), 7.39 (1H, dd, J = 8.1Hz, 1.1Hz), 7.53 (1H, dd, J = 8.1Hz, 1.1Hz).

Reference Example 44
1-Bromo-3-bromomethyl-2-nitrobenzene 3-Bromo-2-nitrotoluene (6.00 g) is dissolved in carbon tetrachloride (60.0 mL), and N-bromosuccinimide (5.34 g) and 2,2 ′ are dissolved at 0 ° C. -Azobis (isobutyronitrile) (900 mg) was added, and the mixture was stirred for 5 minutes and refluxed for an additional 14 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 10-1 / 4) to give the title compound (1.72 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 4.42 (2H, s), 7.36 (1H, t, J = 9.6Hz), 7.50 (1H, d, J = 9.6Hz), 7.65 (1H, d, J = 9.6Hz).

Reference Example 45
2- (3-Bromo-2-nitrobenzyl) malonic acid Diethyl ester diethyl malonate (1.50 mL) was dissolved in tetrahydrofuran (30.0 mL), 50% sodium hydride (525 mg) was added, and the mixture was stirred at room temperature for 30 min. did. A solution of 1-bromo-3-bromomethyl-2-nitrobenzene (2.98 g) in N, N-dimethylformamide (15 mL) was added dropwise, followed by stirring at room temperature for 17 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with a 1N hydrochloric acid aqueous solution, a saturated aqueous hydrogen carbonate solution and a saturated brine in that order, and dried over anhydrous sodium sulfate. After filtration, the filter station was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 20-1 / 3) to give the title compound (3.06 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 3.21 (2H, d, J = 7.7Hz) 3.73 (6H, s), 7.29-7.33 (2H, m), 7.57 (1H, dd, J = 7.7Hz , 1.5Hz).

Reference Example 46
3- (3-Bromo-2-nitrophenyl) propanoic acid methyl ester 2- (3-bromo-2-nitrobenzyl) malonic acid dimethyl ester was dissolved in a mixed solvent of dimethyl sulfoxide (300 mL) and water (1.50 mL). , And stirred at 180 ° C. for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 15-1 / 7) to give the title compound (1.46 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.65 (2H, t, J = 7.7Hz), 2.93 (2H, t, J = 7.7Hz), 3.68 (3H, s), 7.26-7.35 (2H, m), 7.55 (1H, dd, J = 7.7Hz, 1.5Hz).

Reference Example 47
3- (3-Bromo-2-nitrophenyl) propanoic acid 3- (3-bromo-2-nitrophenyl) propanoic acid methyl ester is dissolved in a mixed solvent of tetrahydrofuran (8.50 mL) and water (4.30 mL), and water is added. Lithium oxide monohydrate (646 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1N aqueous hydrochloric acid solution was added to the resulting residue to adjust to pH = 1, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.35 g).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.55 (2H, t, J = 7.5Hz), 2.78 (2H, t, J = 7.5Hz), 3.68 (3H, s), 7.46-7.58 ( 2H, m), 7.73 (1H, dd, J = 7.9Hz, 1.3Hz), 12.30 (1H, brs).

Reference Example 48
Instead of 3- (3-bromo-2-nitrophenyl) propan-1-ol 2- (3-bromo-2-nitrophenyl) acetic acid, 3- (3-bromo-2-nitrophenyl) propanoic acid was used. In the same manner as in Reference Example 42, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.40 (1H, brs), 1.83-1.93 (2H, m), 2.68-2.78 (2H, m), 3.65 (2H, t, J = 6.8Hz), 7.27-7.38 (2H, m), 7.52 (1H, dd, J = 7.1Hz, 2.0Hz).

Reference Example 49
Instead of 2- [3- (3-bromo-2-nitrophenyl) propoxy] tetrahydro-2H-pyran 2- (3-bromo-2-nitrophenyl) ethanol, 3- (3-bromo-2-nitrophenyl) ) The reaction was carried out in the same manner as in Reference Example 43 using propan-1-ol to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.49-1.96 (8H, m), 2.68-2.76 (2H, m), 3.35-3.43 (1H, m), 3.48-3.53 (1H, m), 3.71 -3.88 (2H, m), 4.56 (1H, t, J = 3.7Hz), 7.24-7.34 (2H, m), 7.51 (1H, dd, J = 7.7Hz, 1.5Hz).

Example 48
2-methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde , 2- (3-Bromo-2-nitrophenoxy) tetrahydro-2H-pyran was reacted in the same manner as in Reference Example 26 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.44-1.61 (4H, m), 1.63-1.73 (1H, m), 1.74-1.86 (1H, m), 2.75 (3H, s), 2.91 (2H , t, J = 6.6Hz), 3.44-3.51 (1H, m), 3.60-3.67 (1H, m), 3.70-3.77 (1H, m), 3.84 (3H, s), 3.94-4.00 (1H, m ), 4.58 (1H, t, J = 3.3Hz), 7.32-7.44 (4H, m).
ESI / MS (m / z): 406 (M + H) ⁺ , 404 (MH) ^- .

Example 49
2-Methyl-5- [2-nitro-3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 2- (3-bromo-2-nitrophene Tox) Instead of tetrahydro-2H-pyran, 2- [3- (3-bromo-2-nitrophenyl) propoxy] tetrahydro-2H-pyran was reacted in the same manner as in Example 48, and the title compound Got.
ESI / MS (m / z): 420 (M + H) ⁺ , 418 (MH) ^- .

Example 50
2-methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylate 2-methyl-5-[-nitro-3- [ 2- (Tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester (463 mg) was dissolved in a mixed solvent of tetrahydrofuran (4.50 mL) and water (4.50 mL) to obtain lithium hydroxide. Monohydrate (144 mg) was added and stirred at 60 ° C. for 20 hours. To the reaction solution was added 1N aqueous hydrochloric acid solution to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (446 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.44-1.62 (4H, m), 1.63-1.73 (1H, m), 1.74-1.86 (1H, m), 2.77 (3H, s), 2.91 (2H , t, J = 6.8Hz), 3.44-3.51 (1H, m), 3.60-3.67 (1H, m), 3.70-3.77 (1H, m), 3.94-4.00 (1H, m), 4.59 (1H, t , J = 3.5Hz), 7.34-7.39 (1H, m), 7.40-7.48 (3H, m).
ESI / MS (m / z): 392 (M + H) ⁺ , 390 (MH) ^- .

Example 51
2-methyl-5- [2-nitro-3- [3- (tetrahydro-2H-pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylate 2-methyl-5- [2-nitro-3- Instead of [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, 2-methyl-5- [2-nitro-3- [3- (tetrahydro-2H -Pyran-2-yloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester was used in the same manner as in Example 50 to obtain the title compound.
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.38-1.51 (4H, m), 1.54-1.62 (1H, m), 1.63-1.73 (1H, m), 1.77-1.85 (2H, m) , 2.58-2.66 (2H, m), 2.69 (3H, s), 3.32-3.43 (2H, m), 3.59-3.75 (2H, m), 4.52 (1H, t, J = 3.5Hz), 7.26 (1H , s), 7.44-7.62 (3H, m).
ESI / MS (m / z): 392 (M + H) ⁺ , 390 (MH) ^- .

Reference Example 50
N- (5-chlorothiazol-2-yl) -2-methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxamide 2 -Methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxylic acid (467 mg) and 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide (457 mg), 1-hydroxy-1H-benzotriazole monohydrate (365 mg), diisopropylamine (415 μL) and 2-amino-5-chlorothiazole hydrochloride (408 mg) were mixed with N, N-dimethyl Dissolved in formamide (5.00 mL), stirred at room temperature for 2 hours, and further stirred at 60 ° C. for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (321 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.44-1.86 (6H, m), 2.80 (3H, s), 2.92 (2H, t, J = 6.6Hz), 3.44-3.51 (1H, m), 3.60-3.68 (1H, m), 3.70-3.78 (1H, m), 3.94-4.01 (1H, m), 4.58 (1H, t, J = 3.5Hz), 7.10 (1H, s), 7.21 (1H, s), 7.36 (1H, t, J = 4.4Hz), 7.46 (1H, d, J = 4.4Hz), 10.38 (1H, bs).
ESI / MS (m / z): 508 (M + H) ⁺ , 506 (MH) ^- .

With reference to the method of Reference Example 50, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 19, and the data are shown in Table 20.

Example 52
5- [2-Amino-3- (2-hydroxyethyl) phenyl] -N- (5-chlorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5-chlorothiazol -2-yl) ) -2-Methyl-5- [2-nitro-3- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] phenyl] thiophene-3-carboxamide (320 mg) with acetic acid (3.40 mL) and water ( 370 μL) was dissolved in a mixed solvent, iron powder (176 mg) was added, and the mixture was stirred at 60 ° C. for 2 hours. Water and ethyl acetate were added to the reaction solution, filtered, and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (152 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.69-2.74 (5H, m), 3.62-3.69 (2H, m), 4.70 (1H, t, J = 3.6Hz), 5.00 (2H, brs ), 6.60 (1H, t, J = 7.1Hz), 6.98-7.05 (2H, m), 7.56 (1H, s), 7.64 (1H, s), 12.53 (1H, brs).
ESI / MS (m / z): 394 (M + H) ⁺ , 392 (MH) ^- .

With reference to the method of Example 27, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 21, and the data are shown in Table 22.

Reference Example 58
1-Bromo-3- (2-methoxyethyl) -2-nitrobenzene 2- (3-bromo-2-nitrophenyl) ethanol (1.23 g) was dissolved in tetrahydrofuran (15.0 ml), and t-butoxypotassium (690 mg) Was added at 0 ° C. After stirring for 30 minutes, iodomethane (0.35 mL) was added at 0 ° C. After stirring for 5 hours, water was added and the organic layer was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1) to obtain the title compound (470 mg) as a yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.86 (2H, t, J = 6.4Hz), 3.33 (3H, s), 3.59 (2H, t, J = 6.4Hz), 7.30 (1H, d, J = 7.9Hz), 7.37 (1H, d, J = 8.1Hz), 7.55 (1H, t, J = 7.9Hz)

Example 60
5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 1-bromo-3- (2- Reaction was carried out in the same manner as in Reference Example 26 using methoxyethyl) -2-nitrobenzene to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.72 (3H, s), 2.84 (2H, t, J = 6.6Hz), 3.31 (3H, s), 3.62 (2H, t, J = 6.6Hz) , 7.31 (1H, s), 7.40-7.53 (3H, m)

Example 61
5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid 2-methyl-5-[-nitro-3- [2- (tetrahydro-2H-pyran-2) Instead of -yloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, 5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxylic acid methyl ester was used. In the same manner as in Example 50, the title compound was obtained.
¹ H-NMR (CD ₃ OD) δ (ppm): 2.72 (3H, s), 2.84 (2H, t, J = 6.6Hz), 3.31 (3H, s), 3.60 (2H, t, J = 6.6Hz) ), 7.31 (1H, s), 7.43-7.51 (3H, m)

Reference Example 59
N- (5-Fluorothiazol-2-yl) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide 5- [3- (2-methoxyethyl) -2-Nitrophenyl] -2-methylthiophene-3-carboxylic acid (140 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (167 mg), 1-hydroxy-1H-benzotriazole monohydrate The product (133 mg) and diisopropylethylamine (225 μL) were dissolved in N, N-dimethylformamide (2.00 mL), stirred at room temperature for 20 minutes, 2-amino-5-fluorothiazole hydrochloride (135 mg) was added, Stir at 15 ° C. for 15 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 5/1) to obtain the title compound (18.0 mg) as a yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.81 (3H, s), 2.88 (2H, t, J = 6.6 Hz), 3.34 (3H, s), 3.62 (2H, t, J = 6.6 Hz) , 7.00 (1H, d, J = 2.6Hz), 7.39-7.46 (3H, m), 7.52 (1H, s)
ESI-MS (m / e): 422 [M + H] ⁺ , 420 [MH] ^-

Reference Example 60
N- (5-Chlorothiazol-2-yl) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide 2-amino-5-fluorothiazole hydrochloride Instead, the title compound was obtained in the same manner as in Reference Example 59 using 5-chlorothiazol-2-amine hydrochloride.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.74 (3H, s), 2.88 (2H, t, J = 6.2Hz), 3.34 (3H, s), 3.62 (2H, t, J = 6.2Hz) , 7.23 (1H, s), 7.37-7.47 (4H, m)
ESI-MS (m / e): 438 [M + H] ⁺ , 436 [MH] ^-

Example 62
5- [2-Amino-3- (2-methoxyethyl) phenyl] -N- (5-fluorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5 -fluorothiazol - 2-yl) ) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide (18 mg) was dissolved in acetic acid (260 μL) and water (30 μL), and iron powder (14 mg) And stirred at 65 ° C. for 3 hours. After filtration and washing with ethyl acetate and water, the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine solution and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1) to obtain the title compound (13 mg) as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.82-2.88 (5H, m), 3.34 (3H, s), 3.67 (2H, d, J = 6.2Hz), 6.75 (1H, t, J = 7.5 Hz), 7.06 (1H, dd, J = 7.7,1.4Hz), 7.12 (1H, dd, J = 7.7,1.5Hz), 7.43 (1H, d, J = 5.5Hz), 7.55 (1H, s).
ESI-MS (m / e): 392 [M + H] ⁺ , 390 [MH] ^-

Example 63
5- [2-Amino-3- (2-methoxyethyl) phenyl] -N- (5-chlorothiazol-2-yl) -2-methylthiophene-3-carboxamide N- (5 -fluorothiazol - 2-yl) ) -5- [3- (2-methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide instead of N- (5-chlorothiazol-2-yl) -5- [3- (2-Methoxyethyl) -2-nitrophenyl] -2-methylthiophene-3-carboxamide was used in the same manner as in Example 62 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.64-2.71 (5H, m), 3.19 (3H, s), 3.51 (2H, d, J = 6.2Hz), 6.60 (1H, t, J = 7.5 Hz), 6.89-6.94 (3H, m), 7.11 (1H, s), 10.58 (1H, brs).
ESI-MS (m / e): 408 [M + H] ⁺ , 406 [MH] ^-

Reference Example 61
3-Bromo-2-nitrophenethylpivalate 2- (3-bromo-2-nitrophenyl) ethanol (3.97 g) is dissolved in methylene chloride (40.0 mL), pyridine (1.95 mL) and dimethylaminopyridine (200 mg) And pivaloyl chloride (2.95 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1 / 9-1 / 3) to give the title compound (5.08 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.16 (9H, s), 2.93 (2H, t, J = 6.8Hz), 4.27 (2H, t, J = 6.8Hz), 7.26-7.36 (2H, m), 7.57 (1H, dd, J = 7.7Hz, 1.5Hz).

Reference Example 62
3- (3-Bromo-2-nitrophenyl) propylpivalate Instead of 2- (3-bromo-2-nitrophenyl) ethanol, 3- (3-bromo-2-nitrophenyl) propan-1-ol And the reaction was conducted in the same manner as in Reference Example 61 to give the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (9H, s), 1.92-1.99 (2H, m), 2.68 (2H, dd, J = 8.6, 6.8Hz), 4.07 (2H, t, J = 6.2Hz), 7.28-7.32 (2H, m), 7.53 (1H, dd, J = 7.0,
2.2 Hz)

Example 64
2-methyl-5- [2-nitro-3- [2- (pivaloyloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 3-bromo-2-nitro Reaction was carried out in the same manner as in Reference Example 26 using phenethyl pivalate to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.17 (9H, s), 2.75 (3H, s), 2.94 (2H, t, J = 6.8Hz), 3.84 (3H, s), 4.30 (2H, t, J = 6.8Hz), 7.31-7.48 (4H, m).
ESI / MS (m / z): 406 (M + H) ⁺ , 404 (MH) ^- .

Example 65
Instead of 2-methyl-5- [2-nitro-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 3-bromo-2-nitrophenethylpivalate, 3- (3- Reaction was carried out in the same manner as in Example 64 using bromo-2-nitrophenyl) propyl pivalate to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (9H, s), 1.95-2.02 (2H, m), 2.66-2.70 (2H, m), 2.75 (3H, s), 3.84 (3H, s ), 4.06-4.15
(2H, m), 7.28-7.37 (3H, m), 7.44 (1H, t, J = 7.7Hz)

Example 66
5- [2-Amino-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- [2-nitro-3- [2- (pivaloyloxy)] Ethyl] phenyl] thiophene-3-carboxylic acid methyl ester (3.38 g) is dissolved in a mixed solvent of ethanol (25.0 mL) and tetrahydrofuran (25.0 mL), 10% palladium on carbon (340 mg) is added, and hydrogen atmosphere is added at room temperature. For 17 hours. The reaction solution was filtered and washed with ethyl acetate. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to give the title compound (2.73 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.20 (9H, s), 2.77 (3H, s), 2.87 (2H, t, J = 7.7Hz), 3.86 (3H, s), 4.27 (2H, t, J = 7.7Hz), 4.42 (2H, brs), 6.71 (1H, t, J = 7.5Hz), 7.04 (1H, d, J = 7.5Hz), 7.12 (1H, d, J = 7.5Hz) , 7.45 (1H, s).
ESI / MS (m / z): 376 (M + H) ⁺ , 374 (MH) ^- .

Example 67
5- [2-Amino-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 2-methyl-5- [2-nitro-3- [2- (pivaloyloxy) Instead of ethyl] phenyl] thiophene-3-carboxylic acid methyl ester, using 2-methyl-5- [2-nitro-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 66 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.23 (9H, s), 1.26 (2H, t, J = 7.3 Hz), 1.94-2.04 (2H, m), 2.62 (2H, t, J = 7.7 Hz), 2.76 (3H, s), 3.85 (3H, s), 4.02 (2H, brs), 6.74 (1H, t, J = 7.7Hz), 7.04 (1H, d, J = 7.3Hz), 7.10 ( 1H, d, J = 6.2Hz), 7.44 (1H, s)

Example 68
5- [2-Cyano-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl] -2-Methylthiophene-3-carboxylic acid methyl ester (1.06 g) was dissolved in a mixed solvent of 1,4-dioxane (4.00 mL) and water (1.50 mL), hydrochloric acid (2.00 mL) was added at 0 ° C., and Further, a solution of sodium nitrite (330 mg) in water (1.00 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust pH = 7 (reaction solution A). Potassium cyanide (881 mg) and copper (I) cyanide (959 mg) are suspended in a mixed solvent of 1,4-dioxane (5.00 mL) and water (5.00 mL), and the reaction solution A is added dropwise at 0 ° C. Stir for hours. Water and ethyl acetate were added to the reaction solution, filtered, and washed with ethyl acetate. The filtrate was separated, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to give the title compound (799 mg).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.15 (9H, s), 2.78 (3H, s), 3.26 (2H, t, J = 6.4Hz), 3.86 (3H, s), 4.38 (2H, t, J = 6.4Hz), 7.32 (1H, d, J = 7.7Hz), 7.43 (1H, d, J = 7.7Hz), 7.52 (1H, t, J = 7.7Hz), 7.79 (1H, s) .
ESI / MS (m / z): 386 (M + H) ⁺ , 384 (MH) ^- .

Example 69
5- [2-Cyano-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl] Instead of 2-methylthiophene-3-carboxylic acid methyl ester, using 5- [2-amino-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 68 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.23 (9H, s), 2.04-2.11 (2H, m), 2.80 (3H, s), 3.00 (2H, t, J = 7.7Hz), 3.87 ( 3H, s), 4.15 (2H, t, J = 6.2Hz), 7.29-7.41 (2H, m), 7.51 (1H, t, J = 7.7Hz), 7.80 (1H, s)

Example 70
5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-cyano-3- [2- (pivaloyloxy) ethyl] phenyl] -2-Methylthiophene-3-carboxylic acid methyl ester (3.89 g) is dissolved in a mixed solvent of ethanol (38.5 mL) and water (19.3 mL), and is designated as IIa in Tetrahedron Letters, 1995, 36, 8657-8660. The described platinum catalyst (127 mg) was added and stirred at 90 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (3.83 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.16 (9H, s), 2.75 (3H, s), 3.08 (2H, t, J = 6.8Hz), 3.84 (3H, s), 4.36 (2H, t, J = 6.8Hz), 5.69 (2H, d, J = 12.8Hz), 7.24-7.27 (1H, m), 7.28-7.35 (2H, m), 7.49 (1H, s).
ESI / MS (m / z): 386 (M + H) ⁺ , 384 (MH) ^- .

Example 71
5- [2-carbamoyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-cyano-3- [2- (pivaloyloxy) ethyl] phenyl] Instead of 2-methylthiophene-3-carboxylic acid methyl ester, using 5- [2-cyano-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester Reaction was carried out in the same manner as in Example 70 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (9H, s), 1.98-2.06 (2H, m), 2.75 (3H, s), 2.81 (2H, t, J = 7.9 Hz), 3.84 ( 3H, s), 4.12 (2H, t, J = 6.2Hz), 5.54 (1H, brs), 5.63 (1H, brs), 7.22-7.29 (2H, m), 7.35 (1H, t, J = 7.7Hz ), 7.49 (1H, s).

Reference Example 63
5- [2-Chlorosulfonyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl ] 2-Methylthiophene-3-carboxylic acid methyl ester (4.56 g) was dissolved in acetic acid (28.0 mL), hydrochloric acid (10.0 mL) was added at 0 ° C., and sodium nitrite (1.43 g) in water (2.20). mL) The solution was added dropwise and stirred at 0 ° C. for 15 minutes (reaction solution A). Copper (I) chloride (603 mg) was suspended in acetic acid (15 mL), an aqueous sulfur dioxide solution (29.0 mL) was added, and the mixture was stirred at 0 ° C. for 30 min. The reaction liquid A was dripped at 0 degreeC, and it stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to give the title compound (2.67 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.19 (9H, s), 2.78 (3H, s), 3.55 (2H, t, J = 6.6Hz), 3.85 (3H, s), 4.44 (2H, t, J = 6.6Hz), 7.37-7.43 (2H, m), 7.51-7.61 (2H, m).
ESI / MS (m / z): 459 (M + H) ⁺ , 457 (MH) ^- .

Reference Example 64
5- [2-Chlorosulfonyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester 5- [2-amino-3- [2- (pivaloyloxy) ethyl] phenyl ] Instead of 2-methylthiophene-3-carboxylic acid methyl ester, 5- [2-amino-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester was used. In the same manner as in Reference Example 63, the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.23 (9H, s), 2.07-2.14 (2H, m), 2.76 (3H, s), 3.22-3.30 (2H, m), 3.84 (3H, s ), 4.20 (2H, t, J = 6.2Hz), 7.33-7.39 (2H, m), 7.46 (1H, dd, J = 7.9Hz, 1.3Hz), 7.58 (1H, t, J = 7.9Hz).

Example 72
2-methyl-5- [2-methylsulfonyl-3- [2- (pivaloyloxy) ethyl] phenyl] thiophene-3-carboxylic acid methyl ester sodium sulfite (2.27 g) and sodium hydrogen carbonate (1.51 g) were added to water (38.0 5- [2-chlorosulfonyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (3.88 g) 1,4-dioxane (76.0 mL) The solution was added dropwise and stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in N, N-dimethylformamide (40.0 mL), iodomethane (2.62 mL) was added, and the mixture was stirred at 40 ° C. for 17 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to obtain the title compound (2.10 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.17 (9H, s), 2.78 (3H, s), 2.99 (3H, s), 3.53 (2H, t, J = 6.6Hz), 3.84 (3H, s), 4.43 (2H, t, J = 6.6Hz), 7.33 (1H, dd, J = 7.3Hz, 1.5Hz), 7.39-7.50 (3H, m).

Example 73
2-Methyl-5- [2-methylsulfonyl-3- [3- (pivaloyloxy) propyl] phenyl] thiophene-3-carboxylic acid methyl ester 5- [2-chlorosulfonyl-3- [2- (pivaloyloxy) ethyl] Instead of phenyl] -2-methylthiophene-3-carboxylic acid methyl ester, 5- [2-chlorosulfonyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester Was used in the same manner as in Example 72 to obtain the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.23 (9H, s), 2.03-2.14 (2H, m), 2.77 (3H, s), 2.96 (3H, s), 3.19-3.28 (2H, m ), 3.84 (3H, s), 4.16 (2H, t, J = 5.9Hz), 7.23-7.31 (1H, m), 7.32-7.41 (2H, m), 7.47 (1H, t, J = 7.7Hz) .

Example 74
2-Methyl-5- [3- [2- (pivaloyloxy) ethyl] -2-sulfamoylphenyl] thiophene-3-carboxylic acid methyl ester 5- [2-chlorosulfonyl-3- [2- (pivaloyloxy) ethyl ] Phenyl] -2-methylthiophene-3-carboxylic acid methyl ester (4.92 g) was dissolved in tetrahydrofuran (90.0 mL), triethylamine (2.49 mL), dimethylaminopyridine (131 mg), 28% aqueous ammonia (2.49 mL) And stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) to give the title compound (2.98 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.14 (9H, s), 2.78 (3H, s), 3.51 (2H, t, J = 6.6Hz), 3.85 (3H, s), 4.46 (2H, t, J = 6.6Hz), 4.83 (2H, bs), 7.29 (1H, dd, J = 7.3Hz, 1.8Hz), 7.35-7.43 (2H, m), 7.47 (1H, s).
ESI / MS (m / z): 440 (M + H) ⁺ , 438 (MH) ^- .

Reference Example 65
1- [2-Hydroxy-6- (methoxymethoxy) phenyl] ethanone Argon-substituted sodium hydride (16.0 g) was dissolved in N, N-dimethylformamide (24.0 mL) and 2,6-dihydroxyacetophenone (61.0 g) was dissolved. ) Was added at 0 ° C. After stirring at 0 ° C. for 30 minutes, methoxymethyl chloride (3.10 mL) in N, N-dimethylformamide (24.0 mL) was added at 0 ° C. Stir at room temperature for 5 hours and add water in an ice bath. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 9/1) to obtain the title compound (44.6 g) as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.70 (3H, s), 3.51 (3H, s), 5.27 (2H, s), 6.59 (2H, td, J = 8.4, 1.1 Hz), 7.31 ( 1H, t, J = 8.1Hz), 13.08 (1H, s)

Reference Example 66
2-Acetyl-3- (methoxymethoxy) phenyl trifluoromethanesulfonate 1- [2-hydroxy-6- (methoxymethoxy) phenyl] ethanone (16.1 g), dissolved in pyridine (150 mL), trifluoromethanesulfonic anhydride (14.3 mL) was added at 0 ° C. After stirring at room temperature for 3 hours, 1N aqueous hydrochloric acid solution was added, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 6/1) to obtain the title compound (26.3 g) as a light brown liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.58 (3H, s), 3.48 (3H, s), 5.23 (2H, s), 6.98 (1H, d, J = 8.4Hz), 7.21 (1H, t, J = 4.4Hz), 7.39 (1H, t, J = 8.4Hz)
ESI-MS (m / e): 329 [M + H] ⁺ , 327 [MH] ^-

Reference Example 67
1- [2- (3-Hydroxy-1-propyn-1-yl) -6- (methoxymethoxy) phenyl] ethanone 2-acetyl-3- (methoxymethoxy) phenyl trifluoromethanesulfonate (8.3 g), bistriphenyl Phosphine palladium (II) dichloride (1.4 g), copper iodide (0.60 g), diethylamine (54 mL), tetrabutylammonium iodide (27.9 g) were substituted with argon, and then dissolved in N, N-dimethoxymethane (58 mL). Then, propargyl alcohol (3.0 mL) was added at room temperature. After stirring at 70 ° C. for 6 hours, the mixture was allowed to cool to room temperature and a saturated aqueous ammonium chloride solution was added. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate = 3/1) to obtain the title compound (2.9 g) as a brown liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.89 (1H, brs), 2.59 (3H, s), 3.50 (3H, s), 4.49 (2H, brd, J = 5.5Hz), 5.22 (2H, s), 7.15-7.18 (2H, m), 7.29 (1H, d, J = 6.6Hz)

Reference Example 68
1- [2- (3-hydroxypropyl) -6- (methoxymethoxy) phenyl] ethanone 1- [2- (3-hydroxy-1-propyn-1-yl) -6- (methoxymethoxy) phenyl] ethanone ( 250 mg), 10% palladium carbon (30.0 mg) was suspended in ethanol (1.50 mL), and purged with argon and hydrogen. After stirring for 14 hours at room temperature under a hydrogen atmosphere, the mixture was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure to obtain the title compound (230 mg) as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.81-1.88 (2H, m), 2.53 (3H, s), 2.57-2.61 (2H, m), 3.46 (3H, s), 3.55-3.59 (2H , m), 5.17 (2H, s), 6.88 (1H, d, J = 8.2Hz), 6.98 (1H, d, J = 8.2Hz), 7.22-7.26 (1H, m)

Reference Example 69
3- [2-acetyl-3- (methoxymethoxy) phenyl] propyl pivalate 1- [2- (3-hydroxypropyl) -6- (methoxymethoxy) phenyl] ethanone (2.33 g), pyridine (1.58 mL), 4-Dimethylaminopyridine (244 mg) was dissolved in methylene chloride (20.0 mL), and pivaloyl chloride (1.79 mg) was added at 0 ° C. After stirring at room temperature for 11 hours, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (3.74 g) as a colorless liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.19 (9H, s), 1.85-1.92 (2H, m), 2.51 (3H, s), 2.57 (2H, dd, J = 9.0, 6.8Hz), 3.45 (3H, s), 4.05 (2H, t, J = 6.4Hz), 5.16 (2H, s), 6.85 (1H, d, J = 7.7Hz), 6.98 (1H, d, J = 8.1Hz), 7.22 (1H, t, J = 8.1Hz)

Reference Example 70
3- (2-acetyl-3-hydroxyphenyl) propyl pivalate 3- [2-acetyl-3- (methoxymethoxy) phenyl] propyl pivalate (3.4 g) was charged with trifluoroacetic acid (13.6 mL) in an ice bath. In addition, water (3.4 mL) was added at 0 ° C. Stir at 0 ° C. for 2 hours. Water (30 mL) was added at 0 ° C., and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (3.1 g) as a colorless liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (9H, s), 1.92-1.99 (2H, m), 2.69 (3H, s), 2.94-2.98 (2H, m), 4.10 (2H, t , J = 6.2Hz), 6.76 (1H, d, J = 7.0Hz), 6.84 (1H, d, J = 8.4Hz), 7.30 (1H, t, J = 7.9Hz), 11.13 (1H, brs)

Reference Example 71
3- [2-acetyl-3- (trifluoromethylsulfonyloxy) phenyl] propyl pivalate 3- (2-acetyl-3-hydroxyphenyl) propyl pivalate (0.78 g), diluted in pyridine (8.00 mL), Trifluoromethanesulfonic anhydride (0.56 mL) was added at 0 ° C. After stirring at room temperature for 3 hours, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The filtered filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate = 20/1) to obtain the title compound (0.94 g) as a pale yellow liquid.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.21 (9H, s), 1.89-1.96 (2H, m), 2.57 (3H, s), 2.64-2.68 (2H, m), 4.08 (2H, t , J = 6.2Hz), 7.23-7.28 (2H, m), 7.41 (1H, t, J = 8.1Hz)

Example 75
5- [2-acetyl-3- [3- (pivaloyloxy) propyl] phenyl] -2-methylthiophene-3-carboxylic acid methyl ester instead of 2-chloro-6-fluorobenzaldehyde 3- [2-acetyl- The title compound was obtained in the same manner as in Reference Example 26 using 3- (trifluoromethylsulfonyloxy) phenyl] propyl pivalate.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.20 (9H, s), 1.92-1.97 (2H, m), 2.18 (3H, s), 2.61-2.65 (2H, m), 2.76 (3H, s ), 3.84 (3H, s), 4.10 (2H, t, J = 6.2Hz), 7.21-7.27 (3H, m), 7.32-7.38 (1H, m)

Example 76
5- [2-carbamoyl-3- (2-hydroxyethyl) phenyl] -2-methylthiophene-3-carboxylic acid 5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methyl Thiophene-3-carboxylic acid methyl ester (3.83 g) is dissolved in a mixed solvent of tetrahydrofuran (38.0 mL) and water (38.0 mL), lithium hydroxide monohydrate (1.19 g) is added, and the mixture is heated at 60 ° C. for 17 hours. Stir. To the reaction solution was added 1N aqueous hydrochloric acid solution to pH = 1, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (2.89 g).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.68 (3H, s), 2.78 (2H, t, J = 7.1Hz), 3.58-3.66 (2H, m), 4.63 (1H, bs), 7.34-7.41 (3H, m), 7.43-7.55 (2H, m), 7.76 (1H, s), 12.49 (1H, brs).

The compound was synthesized according to the following reaction formula with reference to the method of Example 76. The synthesized compounds are shown in Table 23 and the data are shown in Table 24.

Example 81
5- [2-carbamoyl-3- (2-hydroxyethyl) phenyl] -N- (5-fluorothiazol-2-yl) -2-methylthiophene-3-carboxamide 5- [2-carbamoyl-3- (2 -Hydroxyethyl) phenyl] -2-methylthiophene-3-carboxylic acid (150 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (188 mg) and 1-hydroxy-1H-benzotriazole monohydrate (150 mg), diisopropylamine (257 μL) and 2-amino-5-fluorothiazole hydrochloride (228 mg) were dissolved in N, N-dimethylformamide (3.00 mL), stirred at room temperature for 2 hours, and further at 60 ° C. Stir for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (methanol / chloroform = 1 / 50-1 / 10) to give the title compound (17.0 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.69 (3H, s), 2.80 (2H, t, J = 7.1 Hz), 3.59-3.70 (2H, m), 4.64 (1H, t, J = 5.1Hz), 7.28-7.53 (5H, m), 7.74 (2H, s), 12.30 (1H, brs).
ESI / MS (m / z): 406 (M + H) ⁺ , 404 (MH) ^- .

With reference to the method of Example 81, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 25 and the data are shown in Table 26.

Example 98
5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid 5- [2-carbamoyl-3- [2- (pivaloyloxy) ethyl] phenyl] -2 -Methylthiophene-3-carboxylic acid methyl ester (1.67 g) was dissolved in pyridine (25.0 mL), lithium iodide (2.77 g) was added, and the mixture was refluxed for 18 hours. Water was added to the reaction solution, pH was adjusted to 1 with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (1.58 g).
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.17 (9H, s), 2.75 (3H, s), 3.10 (2H, t, J = 6.8Hz), 4.38 (2H, t, J = 6.8Hz) , 5.83 (1H, brs), 7.26-7.40 (4H, m), 7.67 (1H, s), 8.04 (1H, brs).
ESI / MS (m / z): 386 (M + H) ⁺ , 384 (MH) ^- .

With reference to the method of Example 98, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 27 and the data are shown in Table 28.

Reference Example 72
2-carbamoyl-3- [5-methyl-4- (5-methylthio-1,3,4-thiadiazol-2-ylcarbamoyl) thiophen-2-yl] phenethylpivalate 5- [2-carbamoyl-3- [ 2- (Pivaloyloxy) ethyl] phenyl] -2-methylthiophene-3-carboxylic acid (300 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (295 mg) and 1-hydroxy-1H-benzotriazole Monohydrate (236 mg), diisopropylamine (268 μL) and 2-amino-5-methylthio-1,3,4-thiadiazole (227 mg) were dissolved in N, N-dimethylformamide (3.00 mL) and dissolved at room temperature. The mixture was stirred for an hour and further stirred at 60 ° C for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) to give the title compound (321 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.15 (9H, s), 2.72 (3H, s), 2.73 (3H, s), 2.95 (2H, t, J = 7.0 Hz), 4.24 ( 1H, t, J = 7.0Hz), 7.31-7.35 (1H, m), 7.38-7.44 (2H, m), 7.53 (1H, brs), 7.82 (2H, s), 12.74 (1H, brs).
ESI / MS (m / z): 519 (M + H) ⁺ , 517 (MH) ^- .

With reference to the method of Reference Example 72, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 29 and the data are shown in Table 30.

Example 103
5- [2-carbamoyl-3- (2-hydroxyethyl) phenyl] -2-methyl-N- (5-methylthio-1,3,4-thiadiazol-2-yl) thiophene-3-carboxamide 2-carbamoyl- 3- [5-Methyl-4- (5-methylthio-1,3,4-thiadiazol-2-ylcarbamoyl) thiophen-2-yl] phenethyl pivalate mixed with methanol (2.25 mL) and dichloroethane (750 μL) Into the solution, potassium carbonate (192 mg) was added and stirred at 60 ° C. for 17 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (methanol / chloroform = 1/9) to obtain the title compound (65.0 mg).
¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.71 (3H, s), 2.72 (3H, s), 2.80 (2H, t, J = 7.3Hz), 3.61-3.70 (2H, m), 4.65 (1H, t, J = 4.9Hz), 7.29-7.40 (3H, m), 7.48 (1H, brs), 7.74 (1H, brs), 7.79 (1H, brs).
ESI / MS (m / z): 435 (M + H) ⁺ , 433 (MH) ^- .

With reference to the method of Example 103, the compound was synthesized according to the following reaction formula. The synthesized compounds are shown in Table 31 and the data are shown in Table 32.

Pharmacological test example 1
(1) Expression and purification of human glucokinase DNA fragment with the same restriction enzyme site added to the N-terminal deletion (1-15 amino acid deletion) coding region of human GK at EcoRI and HindIII sites of pQE-80 expression vector did. E. coli was transformed with this plasmid to express human glucokinase and purified as follows. The cells recovered from the 200 ml E. coli culture solution are collected and suspended in 20 ml of Extraction buffer A (20 mM HEPES, pH 8.0, 1 mM MgCl2, 150 mM NaCl, 2 mM mercaptoethanol, 0.25 mg / ml lysozyme, 50 mg / ml sodium azide). It was allowed to stand at room temperature for 5 minutes. 20 ml of Extraction buffer B (1.5 M NaCl, 100 mM CaCl 2, 100 mM MgCl 2, 0.02 mg / ml DNA-degrading enzyme 1, protease inhibitor tablet (Complete (registered trademark) 1697498): one tablet per 20 ml of buffer) was added and allowed to stand at room temperature for 5 minutes. The extract was centrifuged at 15,000 g for 30 minutes at 4 ° C., and the supernatant was used as an E. coli extract. The E. coli extract was filtered through a 0.45 μm filter and applied to Ni-NTAagarose 2 mLbed equilibrated with a buffer containing 20 mM imidazole (20 mM HEPES pH 8.0, 0.5 M NaCl). It was washed with about 10 ml of washing buffer and eluted stepwise with a buffer containing 20 to 500 mM imidazole (20 mM HEPES pH 8.0, 0.5 M NaCl). Each column fraction was analyzed using SDS gel electrophoresis, and the fraction containing hGK (MW: 52 KDa) was concentrated. Next, the concentrated sample was passed through a Sephacryl S-200HR (11/60) gel filtration column and eluted with buffer B (20 mM HEPES, pH 8.0, 1 mM MgCl 2, 150 mM NaCl, 1 mM DTT). The eluted fraction was analyzed by SDS gel electrophoresis, and the fraction containing hGK was concentrated. Finally, 50% glycerol was added and stored at -20 ° C.

(2) Measurement of glucokinase activation 178 μl of GKassaymix (25 mM Hepes buffer (pH 7.1), 25 mM KCl, 2 mM MgCl 2, 1 mM NADP, 1 mM Dithiotheitol, 2 unit / mL G6PDH, 5 mM D-glucose, GK) was added to a UV-permeable 96-well plate. After adding 2 μl of a test compound dissolved in DMSO, the mixture was allowed to stand at room temperature for 10 minutes, and then 20 μl of 20 mM ATP was added to start the reaction. Absorbance at 340 nm was measured with SpectraMaxPlus for 5 minutes at 30-second intervals at room temperature, and the compound was evaluated by the first 3 minutes of reaction. The activity of the test compound at a final concentration of 10 μM was calculated by comparison with wells not containing it and is shown in Table 33. As a result, it was found that the compounds of the present invention tested this time have a human GK activation action of 600% or more at 10 μM compared to wells not containing the test compound.

Since the compound of the present invention has a glucokinase activating action, it is a chronic complication of diabetes such as diabetes or diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ischemic heart disease, or arteriosclerosis. It is useful as a preventive or therapeutic agent.

Claims (15)

1. Formula (I):
   

   

   [Wherein, X represents a nitrogen atom or CR ² , R ² represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkylthio group; Y represents a nitrogen atom or CR ³ R ³ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkylthio group. However, when X is a nitrogen atom, Y is not a nitrogen atom; Z represents a nitrogen atom or CR ⁴ , R ⁴ represents a hydrogen atom, a halogen atom, or (CH ₂ ) _m -R ⁵ . m represents an integer of 1 to 6, R ⁵ represents a hydroxy group or a C ₁ -C ₆ alkoxy group; R ¹ represents an amino group, a nitrile group, an acetyl group, a mesyl group, a carbamoyl group, a sulfamoyl group, CONH- (CH ₂ ) _n -AR ⁶ or SO ₂ NH- (CH ₂ ) _n -R ⁷ is meant. n is an integer of 1 to 6, A is absent or an oxygen atom or a sulfur atom, R ⁶ is a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ hydroxy group An alkyl group, R ⁷ represents a hydroxy group or a C ₁ -C ₆ alkoxy group]
   Or a pharmacologically acceptable salt thereof.
2. The compound according to claim 1, wherein in the general formula (I), X is a nitrogen atom, CF, or C-Cl, and Y is a CH or C- (C ₁ -C ₃ alkyl) group.
3. The compound according to claim 2, wherein X is a nitrogen atom and Y is CH or a C- (C ₁ -C ₃ alkyl) group.
4. The compound according to claim 2, wherein X is C-F or C-Cl, and Y is C-H.
5. 2. In the general formula (I), Z is C— (CH ₂ ) ₂ —OH or C— (CH ₂ ) ₃ —OH, and R ¹ is an amino group, a carbamoyl group, or a mesyl group. Compound described in 1.
6. Z is _{C- (CH 2) 2 -OH,} R 1 is a mesyl group, a compound of claim 5.
7. In the general formula (I), Z is CH or CF, R ¹ is CONH- (CH ₂ ) ₂ -OR ⁶ , and R ⁶ is a C ₁ -C ₃ alkyl group or C ₁ -C ₃ hydroxyalkyl. The compound according to claim 1, which is a group.
8. R ¹ is _{CONH- (CH 2) 2 -O- (} CH 2) 2 -OH, A compound according to claim 7.
9. In the general formula (I), X is a nitrogen atom, Y is CH or a C— (C ₁ -C ₃ alkyl) group, Z is C— (CH ₂ ) ₂ —OH, and R ¹ is The compound according to claim 1, which is a mesyl group.
10. In the general formula (I), X is a nitrogen atom, Y is CH or a C- (C ₁ -C ₃ alkyl) group, Z is CH or CF, and R ¹ is CONH- (CH ₂ ). The compound according to claim 1, which is _2- O- (CH ₂ ) ₂ -OH.
11. In the general formula (I), X is CF or C—Cl, Y is CH, Z is C— (CH ₂ ) ₂ —OH, and R ¹ is a mesyl group. The described compound.
12. In the general formula (I), X is CF or C—Cl, Y is CH, Z is CH or CF, and R ¹ is CONH— (CH ₂ ) ₂ —O— (CH ₂ ) _2. The compound of claim 1, which is —OH.
13. General formula (II):
    

    

    [Wherein, Z ¹ represents a nitrogen atom or CR ¹⁰ , and R ¹⁰ represents a hydrogen atom, a halogen atom, or (CH ₂ ) _m -R ¹¹ . m represents an integer of 1 to 6, R ¹¹ represents an optionally protected hydroxy group or a C ₁ -C ₆ alkoxy group; R ⁸ represents a nitro group, an amino group, a nitrile group, an acetyl group, It means mesyl group, carbamoyl group, sulfamoyl group, CO ₂ R ¹² , CONH— (CH ₂ ) _n —AR ¹³ , or SO ₂ NH— (CH ₂ ) _n —R ¹⁴ . R ¹² represents a hydrogen atom or a protecting group for a carboxyl group, n represents an integer of 1 to 6, A represents an absent or oxygen atom or a sulfur atom, R ¹³ represents a hydrogen atom, C ₁ -C ₆ alkyl group, hydroxy protecting group, or C ₁ -C ₆ hydroxyalkyl group that may be protected, R ¹⁴ may be protected hydroxy group or C ₁ -C ₆ Means an alkoxy group; R ⁹ means a hydrogen atom or a protecting group for a carboxyl group; ]
    A compound represented by
14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 as an active ingredient.
15. The pharmaceutical composition according to claim 14, for the prevention or treatment of diabetes.