Method for promoting plant growth

Abstract

The present invention provides a method for promoting plant growth, which comprises treating a plant with a compound represented by the following Formula (1): ##STR00001## provided that a method for promoting plant growth which comprises treating plants with a compound corresponding to any one of the following (1) to (8) is excluded: (1) Methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (2) Methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (3) Methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (4) Methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (5) Ethyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (6) Ethyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (7) Ethyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, and (8) Ethyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate.

Claims

1. A method for promoting plant growth, which comprises treating a plant with a compound represented by the following Formula (1): ##STR00183## wherein, W represents OR.sup.6, ONCR.sup.7R.sup.8, or SR.sup.9, R.sup.1 represents a hydrogen atom, a halogen atom, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from a group X, a phenyl group optionally having one or more groups selected from a group Y, a 6-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a carboxy group, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5, R.sup.2 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from the group X, a phenyl group optionally having one or more groups selected from the group Y, a 6-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a carboxy group, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.12R.sup.13, S(O).sub.2NR.sup.7R.sup.11, OR.sup.13, S(O).sub.mR.sup.13, or SF.sub.5, R.sup.3 and R.sup.4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from the group X, a phenyl group optionally having one or more groups selected from the group Y, a 6-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a carboxy group, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5, R.sup.5 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from the group X, a carboxy group, a C2-C6 alkoxycarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.14, a phenyl group optionally having one or more groups selected from the group Y, a 6-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, or a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, R.sup.6 represents a C3-C6 alkyl group optionally having one or more groups selected from a group Z, a C3-C6 alkenyl group optionally having one or more groups selected from the group X, a C3-C6 alkynyl group optionally having one or more groups selected from the group X, a C4-C7 cycloalkylalkyl group optionally having one or more halogen atoms, a C3-C6 cycloalkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, or a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, R.sup.7 and R.sup.8 are the same or different and each represents a C1-C6 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, or a hydrogen atom, R.sup.9 represents a hydrogen atom, a C1-C6 alkyl group optionally having one or more groups selected from the group Z, a C3-C6 alkenyl group optionally having one or more groups selected from the group X, a C3-C6 alkynyl group optionally having one or more groups selected from the group X, a phenyl group optionally having one or more groups selected from the group Y, or a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, R.sup.11 represents a C1-C6 alkyl group optionally having one or more groups selected from the group X, a C3-C6 alkenyl group optionally having one or more groups selected from the group X, a C3-C6 alkynyl group optionally having one or more groups selected from the group X, a C4-C7 cycloalkylalkyl group optionally having one or more halogen atoms, a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, a 6-membered aromatic heterocyclic-C1-C3 alkyl group wherein a 6-membered aromatic heterocyclic portion may have optionally one or more groups selected from the group Y, a phenyl group optionally having one or more groups selected from the group Y, a C3-C6 cycloalkyl group optionally having one or more halogen atoms, or a hydrogen atom (provided that when m in S(O).sub.mR.sup.11 is 1 or 2, R.sup.11 is not a hydrogen atom), R.sup.12 represents a hydrogen atom, a C1-C4 alkyl group optionally having one or more halogen atoms, a C1-C4 alkylsulfonyl group optionally having one or more halogen atoms, a phenylsulfonyl group optionally having one or more groups selected from the group Y, a C7-C9 phenylalkylsulfonyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, C(O)R.sup.15, or C(O)NR.sup.7R.sup.8, R.sup.13 represents a C1-C6 alkyl group optionally having one or more groups selected from the group X, a C3-C6 alkenyl group optionally having one or more groups selected from the group X, a C3-C6 alkynyl group optionally having one or more groups selected from the group X, a C4-C7 cycloalkylalkyl group optionally having one or more halogen atoms, a C3-C6 cycloalkyl group optionally having one or more halogen atoms, a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, or a hydrogen atom (provided that when m in S(O).sub.mR.sup.13 is 1 or 2, R.sup.13 is not a hydrogen atom), R.sup.14 represents a C1-C6 alkyl group optionally having one or more groups selected from the group X, a C3-C6 alkenyl group optionally having one or more groups selected from the group X, a C3-C6 alkynyl group optionally having one or more groups selected from the group X, a C4-C7 cycloalkylalkyl group optionally having one or more halogen atoms, a C3-C6 cycloalkyl group optionally having one or more halogen atoms, a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, a phenyl group optionally having one or more groups selected from the group Y, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C1-C6 alkylsulfonyl group optionally having one or more halogen atoms, a phenylsulfonyl group optionally having one or more groups selected from the group Y, or a hydrogen atom, R.sup.15 represents a hydrogen atom, a C1-C6 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, or a 6-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, and m represents 0, 1, or 2, the group X represents a group consisting of a halogen atom, a cyano group, and a C1-C6 alkoxy group optionally having one or more halogen atoms, the group Y represents a group consisting of a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group optionally having one or more halogen atoms, and a C1-C6 alkoxy group optionally having one or more halogen atoms, and the group Z represents a group consisting of a halogen atom, a hydroxy group, a C1-C6 alkoxy group optionally having one or more halogen atoms, and a C2-C6 alkoxycarbonyl group, provided that a method for promoting plant growth which comprises treating plants with a compound corresponding to any one of the following (1) to (8) is excluded, (1) Methyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (2) Methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (3) Methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (4) Methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (5) Ethyl 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (6) Ethyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, (7) Ethyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, and (8) Ethyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate; and wherein the plant is a plant that has been or will be exposed to an abiotic stress, and the abiotic stress is a high-temperature stress, a low-temperature stress or a drought stress.

2. The method according to claim 1, in which the compound represented by Formula (1) is a compound wherein R.sup.1 represents a hydrogen atom, a halogen atom, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from the group X, a phenyl group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a carboxy group, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5, and R.sup.4 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group optionally having one or more groups selected from the group X, a phenyl group optionally having one or more groups selected from the group Y, a 5-membered aromatic heterocyclic group optionally having one or more groups selected from the group Y, a carboxy group, a C2-C6 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C6 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5.

3. The method according to claim 1, in which the compound represented by Formula (1) is a compound wherein R.sup.1 represents a hydrogen atom, a halogen atom, a nitro group, a C1-C4 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, a pyridyl group optionally having one or more groups selected from the group Y, a pyrimidinyl group optionally having one or more groups selected from the group Y, a thienyl group optionally having one or more groups selected from the group Y, a pyrrolyl group optionally having one or more groups selected from the group Y, a C2-C5 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C4 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5, R.sup.2 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, a pyridyl group optionally having one or more groups selected from the group Y, a pyrimidinyl group optionally having one or more groups selected from the group Y, a thienyl group optionally having one or more groups selected from the group Y, a pyrrolyl group optionally having one or more groups selected from the group Y, a C2-C5 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C4 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.12R.sup.13, OR.sup.13, S(O).sub.mR.sup.13, or SF.sub.5, R.sup.3 and R.sup.4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, a pyridyl group optionally having one or more groups selected from the group Y, a pyrimidinyl group optionally having one or more groups selected from the group Y, a thienyl group optionally having one or more groups selected from the group Y, a pyrrolyl group optionally having one or more groups selected from the group Y, a C2-C5 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a C2-C4 alkoxycarbonyl group, an aminocarbonyl group, NR.sup.11R.sup.12, OR.sup.11, S(O).sub.mR.sup.11, or SF.sub.5, R.sup.5 represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C1-C4 alkyl group optionally having one or more halogen atoms, a C2-C5 alkoxycarbonyl group, NR.sup.11R.sup.12, S(O).sub.2NR.sup.7R.sup.11, OR.sup.14, or a phenyl group optionally having one or more groups selected from the group Y, R.sup.6 represents a C3-C6 alkyl group optionally having one or more groups selected from the group Z, a C3-C6 alkenyl group optionally having one or more halogen atoms, a C3-C6 alkynyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, or a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, R.sup.7 and R.sup.8 are the same or different and each represents a C1-C4 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, or a hydrogen atom, R.sup.9 represents a hydrogen atom, a C1-C6 alkyl group optionally having one or more groups selected from the group Z, a C3-C6 alkenyl group optionally having one or more halogen atoms, a C3-C6 alkynyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, or a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, R.sup.11 represents a C1-C3 alkyl group optionally having one or more halogen atoms, a C3-C4 alkynyl group optionally having one or more groups selected from the group X, a C7-C9 phenylalkyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, a pyridyl-C1-C3 alkyl group wherein a pyridine ring portion may have optionally one or more groups selected from the group Y, a phenyl group optionally having one or more groups selected from the group Y, or a hydrogen atom (provided that when m in S(O).sub.mR.sup.11 is 1 or 2, R.sup.11 is not a hydrogen atom), R.sup.12 represents a hydrogen atom, a C1-C4 alkyl group optionally having one or more halogen atoms, a C1-C4 alkylsulfonyl group optionally having one or more halogen atoms, a phenylsulfonyl optionally having one or more groups selected from the group Y, a benzylsulfonyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, C(O)R.sup.15, or C(O)NR.sup.7R.sup.8, R.sup.13 represents a C1-C3 alkyl group optionally having one or more halogen atoms or a hydrogen atom (provided that when m in S(O).sub.mR.sup.13 is 1 or 2, R.sup.13 is not a hydrogen atom), R.sup.14 represents a C1-C4 alkyl group optionally having one or more groups selected from the group X, a C3-C6 alkenyl group optionally having one or more halogen atoms, a benzyl group wherein a benzene ring portion may have optionally one or more groups selected from the group Y, a phenyl group optionally having one or more groups selected from the group Y, a C2-C5 alkylcarbonyl group optionally having one or more halogen atoms, a benzoyl group optionally having one or more groups selected from the group Y, a phenylsulfonyl group optionally having one or more groups selected from the group Y, or a hydrogen atom, and R.sup.15 represents a hydrogen atom, a C1-C4 alkyl group optionally having one or more halogen atoms, a phenyl group optionally having one or more groups selected from the group Y, a thienyl group optionally having one or more groups selected from the group Y, a pyrazolyl group optionally having one or more groups selected from the group Y, or an isoxazolyl group optionally having one or more groups selected from the group Y.

4. The method according to claim 1, in which the treatment of the plant is a spraying treatment, a soil treatment, a seed treatment, or a hydroponic treatment.

5. The method according to claim 4, in which the treatment of the plant is the seed treatment.

6. The method according to claim 1, in which the plant is rice, corn, or wheat.

7. The method according to claim 1, in which the plant is a transgenic plant.

8. The method according to claim 1, in which the abiotic stress is the high-temperature stress.

9. The method according to claim 1, in which the abiotic stress is the low-temperature stress.

10. The method according to claim 1, in which the abiotic stress is the drought stress.

11. The method according to claim 1, in which the plant is soybean.

12. The method according to claim 1, in which the plant is cotton.

Description

EXAMPLES

(1) Hereinafter, the production examples, formulation examples, and test examples of the present invention are described in more detail, but the present invention is not limited to the following examples. Moreover, in the following examples, part(s) indicates part(s) by weight unless otherwise specified.

Production Example 1

(2) A mixture of 1.10 g of 5-chloro-2-fluorobenzaldehyde, 803 mg of methyl thioglycolate, 956 mg of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 2 hours at 60 C. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 1.42 g of methyl 5-chlorobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 7 of the present invention).

(3) Compound 7 of the Present Invention

(4) ##STR00030##

(5) .sup.1H-NMR (CDCl.sub.3) : 7.99 (s, 1H), 7.86 (d, 1H, J=2.2 Hz), 7.79 (d, 1H, J=8.7 Hz), 7.42 (dd, 1H, J=8.7, 2.2 Hz), 3.95 (s, 3H).

Production Example 2

(6) A mixture of 500 mg of methyl 4-bromobenzo[b]thiophene-2-carboxylate, 161 mg of methylboronic acid, 1.17 g of potassium phosphate, 151 mg of a [1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct, 6 ml of 1,4-dioxane, and 0.1 ml of water was stirred for 3 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The filtrate was extracted using chloroform, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 340 mg of methyl 4-methylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 22 of the present invention).

(7) Compound 22 of the Present Invention

(8) ##STR00031##

(9) .sup.1H-NMR (CDCl.sub.3) : 8.17-8.16 (m, 1H), 7.71-7.69 (m, 1H), 7.37-7.35 (m, 1H), 7.20-7.18 (m, 1H), 3.95 (s, 3H), 2.64 (s, 3H).

Production Example 3

(10) Step 1

(11) A mixture of 5.2 g of bromoacetaldehyde diethylacetal and 10 ml of tetrahydrofuran was added to a mixture of 4.00 g of 4-methylbenzenethiol, 1.4 g of 60% sodium hydride, and 35 ml of tetrahydrofuran. The reaction mixture was stirred for 15 hours at room temperature. Ten (10) ml of aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were added to a mixture of 5 g of diphosphorus pentoxide and 10 g of phosphoric acid that had been stirred for 45 minutes at 175 C., and the residue was stirred for 5 minutes. The reaction mixture was poured into ice water, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 2.77 g of 5-methylbenzo[b]thiophene.

(12) ##STR00032##

(13) Step 2

(14) A mixture of 2.77 g of 5-methylbenzo[b]thiophene and 40 ml of diethylether was stirred at 0 C., and 18 ml of n-butyllithium (2.6 M hexane solution) was added thereto. The reaction mixture was stirred for 2 hours, and then 1 g of dry ice was added thereto. After the temperature of the reaction mixture was set to room temperature, water was added thereto, and the residue was washed three times with tert-butyl methyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and then and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. Eight hundreds (800) mg of oxalyl chloride was added to a mixture of the residues and 20 ml of methanol under ice cooling. This mixture was stirred for 2 hours at 80 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 387 mg of methyl 5-methylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 23 of the present invention).

(15) ##STR00033##

(16) Compound 23 of the Present Invention

(17) .sup.1H-NMR (CDCl.sub.3) : 7.99 (s, 1H), 7.75 (d, 1H, J=8.6 Hz), 7.67 (s, 1H), 7.29 (d, 1H, J=8.6 Hz), 3.94 (s, 3H), 2.48 (s, 3H).

Production Example 4

(18) A mixture of 600 mg of methyl 7-bromobenzo[b]thiophene-2-carboxylate, 199 mg of methylboronic acid, 1.41 g of potassium phosphate, 181 mg of a [1,1-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct, 7 ml of 1,4-dioxane, and 0.12 ml of water was stirred for 2.5 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The filtrate was extracted using chloroform, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 402 mg of methyl 7-methylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 25 of the present invention).

(19) Compound 25 of the Present Invention

(20) ##STR00034##

(21) .sup.1H-NMR (CDCl.sub.3) : 8.09 (s, 1H), 7.74-7.72 (m, 1H), 7.35-7.33 (m, 1H), 7.27-7.25 (m, 1H), 3.95 (s, 3H), 2.57 (s, 3H).

Production Example 5

(22) A mixture of 7.80 g of bromoacetaldehyde diethylacetal and 20 ml of tetrahydrofuran was added to a mixture of 8.00 g of 4-tert-butylbenzenthiol, 2.10 g of sodium hydride, and 70 ml of tetrahydrofuran. The reaction mixture was stirred for 15 hours at room temperature. Twenty (20) ml of an aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were added to a mixture of 10 g of diphosphorus pentoxide which had been stirred for 45 minutes at 175 C. and 20 g of phosphoric acid, and the residue was stirred for 5 minutes. The reaction mixture was poured into ice water, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 6.7 g of 5-tert-butylbenzo[b]thiophene.

(23) ##STR00035##

(24) A mixture of 3.00 g of 5-tert-butylbenzo[b]thiophene and 40 ml of diethylether was stirred at 0 C., and 15 ml of n-butyllithium (2.6 M hexane solution) was added thereto. The reaction mixture was stirred for 2 hours, and then 1 g of dry ice was added thereto. After the temperature of the reaction mixture was set to room temperature, water was added thereto, and the residue was washed three times with using tert-butyl methyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. Four hundreds and two (402) mg of oxalyl chloride was added to a mixture of the residues and 30 ml of methanol under ice cooling. This mixture was stirred for 2 hours at 80 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 416 mg of methyl 5-tert-butylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 27 of the present invention).

(25) Compound 27 of the Present Invention

(26) ##STR00036##

(27) .sup.1H-NMR (CDCl.sub.3) : 8.04 (s, 1H), 7.85-7.84 (m, 1H), 7.80-7.78 (m, 1H), 7.56-7.54 (m, 1H), 3.94 (s, 3H), 1.39 (s, 9H).

Production Example 6

(28) A mixture of 1.00 g of 2-fluorophenyl(trifluoromethyl)ketone, 633 mg of methyl thioglycolate, 737 g of triethylamine, and 15 ml of acetonitrile was stirred for 18 hours at 90 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with a 1 M aqueous hydrochloric acid solution, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 415 mg of methyl 3-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 28 of the present invention).

(29) Compound 28 of the Present Invention

(30) ##STR00037##

(31) .sup.1H-NMR (CDCl.sub.3) : 8.15-8.14 (m, 1H), 7.90-7.87 (m, 1H), 7.53-7.51 (m, 2H), 3.99 (s, 3H).

Production Example 7

(32) A mixture of 325 mg of methyl 4-iodobenzo[b]thiophene-2-carboxylate, 1.90 g of sodium pentafluoropropionate, 486 mg of copper (1) iodide, 5 ml of N-methyl-2-pyrrolidone, and 5 ml of xylene was stirred for 5 hours at 160 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, chloroform and water were added thereto, and insoluble matter was separated by filtration. Extraction was performed on the filtrate by using chloroform, and then the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 80 mg of methyl 4-pentafluoroethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 29 of the present invention).

(33) Compound 29 of the Present Invention

(34) ##STR00038##

(35) .sup.1H-NMR (CDCl.sub.3) : 8.26 (s, 1H), 8.09-8.07 (m, 1H), 7.70-7.68 (m, 1H), 7.58-7.56 (m, 1H), 3.98 (s, 3H).

Production Example 8

(36) A mixture of 1.00 g of methyl 5-iodobenzo[b]thiophene-2-carboxylate, 2.92 g of sodium pentafluoropropionate, 1.50 g of copper (I) iodide, 15 ml of N,N-methyl-2-pyrrolidone, and 15 ml of N-dimethylformamide was stirred for 5 hours at 160 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated ammonia solution were added thereto, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 556 mg of methyl 5-pentafluoroethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 30 of the present invention).

(37) Compound 30 of the Present Invention

(38) ##STR00039##

(39) .sup.1H-NMR (CDCl.sub.3) : 8.15-8.12 (m, 2H), 8.00 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=8.8 Hz), 3.99 (s, 3H).

Production Example 9

(40) A mixture of 1,000 mg of methyl 5-iodobenzo[b]thiophene-2-carboxylate, 2.79 g of 1-iodoheptafluoropropane, 600 mg of copper (0), and 20 ml of N,N-dimethylformamide was stirred for 8 hours at 150 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, tert-butyl methyl ether and an aqueous saturated ammonia solution were added thereto, and filtration was performed using Celite. The filtrate was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 351 mg of methyl 5-pentafluoropropylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 31 of the present invention).

(41) Compound 31 of the Present Invention

(42) ##STR00040##

(43) .sup.1H-NMR (CDCl.sub.3) : 8.14 (s, 1H), 8.12 (s, 1H), 8.00 (d, 1H, J=8.5 Hz), 7.63 (d, 1H, J=8.5 Hz), 3.97 (s, 3H).

Production Example 10

(44) A mixture of 500 mg of methyl 6-bromobenzo[b]thiophene-2-carboxylate, 877 mg of tributyl vinyl tin, 213 mg of tetrakis(triphenylphosphine)palladium (0), and 4 ml of toluene was stirred for 5 hours at 110 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, an aqueous saturated ammonium chloride solution and ethyl acetate were added thereto, and insoluble matter was separated by filtration. Extraction was performed on the filtrate by using ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 229 mg of methyl 6-vinylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 32 of the present invention).

(45) Compound 32 of the Present Invention

(46) ##STR00041##

(47) .sup.1H-NMR (CDCl.sub.3) : 8.03 (s, 1H), 7.84-7.81 (m, 2H), 7.52-7.50 (m, 1H), 6.82 (dd, 1H, J=17.6, 11.0 Hz), 5.87 (d, 1H, J=17.6 Hz), 5.36 (d, 1H, J=11.0 Hz), 3.95 (s, 3H).

Production Example 11

(48) A mixture of 900 mg of methyl 6-bromobenzo[b]thiophene-2-carboxylate, 2.28 ml of diisopropylamine, 116 mg of dichlorobis(triphenylphosphine)palladium (II), 32 mg of copper iodide (1), 0.92 ml of trimethylsilyl acetylene, and 15 ml of toluene was stirred for 20 hours at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, hexane was added to the residues, and insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the residues were subjected to silica gel column chromatography, thereby obtaining 590 mg of methyl 6-(trimethylsilylethynyl)benzo[b]thiophene-2-carboxylate.

(49) ##STR00042##

(50) Step 2

(51) A mixture of 590 mg of methyl 6-(trimethylsilylethynyl)benzo[b]thiophene-2-carboxylate, 215 mg of lithium hydroxide monohydrate, 4 ml of water, and 12 ml of methanol was stirred for 1 hour at 80 C. After the reaction mixture was cooled to room temperature, water and concentrated hydrochloric acid were added thereto, and the precipitated solids were collected by filtration and dried under reduced pressure, thereby obtaining 402 mg of 6-ethynylbenzo[b]thiophene-2-carboxylic acid.

(52) ##STR00043##

(53) Step 3

(54) Four point three (4.3) ml of trimethylsilyldiazomethane (2 M diethylether solution) was added dropwise at 0 C. to a mixture of 217 mg of 6-ethynylbenzo[b]thiophene-2-carboxylic acid and 10 ml of methanol. After being stirred for 15 hours at 0 C., the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, methanol was added to the residues, and insoluble matter was collected by filtration, thereby obtaining 182 mg of methyl 6-ethynylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 33 of the present invention).

(55) Compound 33 of the Present Invention

(56) ##STR00044##

(57) .sup.1H-NMR (CDCl.sub.3) : 6.04 (s, 1H), 8.01 (s, 1H), 7.83-7.81 (m, 1H), 7.51-7.48 (m, 1H), 3.95 (s, 3H), 3.19 (s, 1H).

Production Example 12

(58) A mixture of 750 ng of methyl 4-bromobenzo[b]thiophene-2-carboxylate, 438 mg of phenyl boronic acid, 610 mg of lithium chloride, 528 mg of sodium carbonate, 160 mg of tetrakis(triphenylphosphine)palladium (0), 30 ml of 1,4-dioxane, and 15 ml of water was stirred for 4 hours at 100 C. under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 477 mg of methyl 4-phenylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 34 of the present invention).

(59) Compound 34 of the Present Invention

(60) ##STR00045##

(61) .sup.1H-NMR (CDCl.sub.3) : 8.17-8.16 (m, 1H), 7.87-7.85 (m, 1H), 7.57-7.48 (m, 5H), 7.47-7.42 (m, 1H), 7.41-7.39 (m, 1H), 3.93 (s, 3H).

Production Example 13

(62) A mixture of 500 mg of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 292 mg of phenyl boronic acid, 406 mg of lithium chloride, 351 mg of sodium carbonate, 106 mg of tetrakis(triphenylphosphine)palladium (0), 20 ml of 1,4-dioxane, and 10 ml of water was stirred for 3 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added to the residues, and extraction was performed three times by using chloroform. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 295 mg of methyl 5-phenylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 35 of the present invention).

(63) Compound 35 of the Present Invention

(64) ##STR00046##

(65) .sup.1H-NMR (CDCl.sub.3) : 8.11 (s, 1H), 8.07 (s, 1H), 7.93 (d, 1H, J=8.5 Hz), 7.71 (d, 1H, J=8.5 Hz), 7.66-7.64 (m, 2H), 7.49-7.47 (m, 2H), 7.40-7.38 (m, 1H), 3.97 (s, 3H).

Production Example 14

(66) A mixture of 750 mg of methyl 6-bromobenzo[b]thiophene-2-carboxylate, 438 mg of phenyl boronic acid, 610 mg of lithium chloride, 528 mg of sodium carbonate, 160 mg of tetrakis(triphenylphosphine)palladium (0), 30 ml of 1,4-dioxane, and 15 ml of water was stirred for 4 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 475 mg of methyl 6-phenylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 36 of the present invention).

(67) Compound 36 of the present invention

(68) ##STR00047##

(69) .sup.1H-NMR (CDCl.sub.3) : 8.08 (s, 1H), 8.07-8.06 (m, 1H), 7.95-7.93 (m, 1H), 7.67-7.65 (m, 3H), 7.49-7.47 (m, 2H), 7.40-7.38 (m, 1H), 3.96 (s, 3H).

Production Example 15

(70) A mixture of 750 mg of methyl 7-bromobenzo[b]thiophene-2-carboxylate, 438 mg of phenyl boronic acid, 610 mg of lithium chloride, 528 mg of sodium carbonate, 160 mg of tetrakis(triphenylphosphine)palladium (0), 30 ml of 1,4-dioxane, and 15 ml of water was stirred for 4 hours at 100 C. in a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 118 mg of methyl 7-phenylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 37 of the present invention).

(71) Compound 37 of the Present Invention

(72) ##STR00048##

(73) .sup.1H-NMR (CDCl.sub.3) : 8.14 (s, 1H), 7.88-7.86 (m, 1H), 7.72-7.71 (m, 2H), 7.54-7.41 (m, 5H), 3.94 (s, 3H).

Production Example 16

(74) A mixture of 274 mg of methyl 3-chlorobenzo[b]thiophene-2-carboxylate, 221 mg of phenyl boronic acid, 541 mg of potassium, 31.7 mg of triphenyl phosphine, bis(triphenylphosphine)nickel (II) dichloride, 7 ml of toluene was stirred for 6 hours at 120 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed using ethyl acetate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 260 mg of methyl 3-phenylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 38 of the present invention.

(75) Compound 38 of the Present Invention

(76) ##STR00049##

(77) .sup.1H-NMR (CDCl.sub.3) : 7.90-7.88 (m, 1H), 7.56-7.35 (m, 8H), 3.78 (s, 3H).

Production Example 17

(78) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 750 mg of 2-chlorophenyl boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 871 mg of methyl 5-(2-chlorophenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 39 of the present invention).

(79) Compound 39 of the Present Invention

(80) ##STR00050##

(81) .sup.1H-NMR (CDCl.sub.3) : 8.10 (s, 1H), 7.94-7.91 (m, 2H), 7.57-7.55 (m, 1H), 7.52-7.50 (m, 1H), 7.41-7.38 (m, 1H), 7.37-7.30 (m, 2H), 3.96 (s, 3H).

Production Example 18

(82) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 750 mg of 3-chlorophenyl boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. in a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 870 mg of methyl 5-(3-chlorophenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 40 of the present invention).

(83) Compound 40 of the Present Invention

(84) ##STR00051##

(85) .sup.1H-NMR (CDCl.sub.3) : 8.11 (s, 1H), 8.04 (d, 1H, J=1.9 Hz), 7.94 (d, 1H, J=8.5 Hz), 7.67 (dd, 1H, J=8.5, 1.9 Hz), 7.64-7.63 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 7.37-7.35 (m, 1H), 3.97 (s, 3H).

Production Example 19

(86) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 750 mg of 4-chlorophenyl boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. in a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 721 mg of methyl 5-(4-chlorophenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 41 of the present invention).

(87) Compound 41 of the Present Invention

(88) ##STR00052##

(89) .sup.1H-NMR (CDCl.sub.3) : 8.11 (s, 1H), 8.03 (d, 1H, J=1.8 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.66 (dd, 1H, J=8.3, 1.8 Hz), 7.57 (d, 2H, J=8.8 Hz), 7.44 (d, 2H, J=8.8 Hz), 3.97 (s, 3H).

Production Example 20

(90) A mixture of 750 mg of methyl 7-bromobenzo[b]thiophene-2-carboxylate, 489 mg of 3-methylphenyl boronic acid, 610 mg of lithium chloride, 528 mg of sodium carbonate, 160 ng of tetrakis(triphenylphosphine)palladium (0), 30 ml of 1,4-dioxane, and 15 ml of water was stirred for 3 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. After water was added to the filtrate, extraction was performed by using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 385 mg of methyl 7-(3-methylphenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 42 of the present invention).

(91) Compound 42 of the Present Invention

(92) ##STR00053##

(93) .sup.1H-NMR (CDCl.sub.3) : 8.13 (s, 1H), 7.86-7.84 (m, 1H), 7.52-7.46 (m, 4H), 7.41-7.39 (m, 1H), 7.26-7.23 (m, 1H), 3.94 (s, 3H), 2.45 (s, 3H).

Production Example 21

(94) A mixture of 1.0 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 911 mg of 4-trifluoromethylphenylboronic acid, 913 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 2.5 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. After water was added to the filtrate, extraction was performed using chloroform. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and insoluble matter was collected by filtration and dried under reduced pressure, thereby obtaining 845 mg of methyl 5-(4-trifluoromethylphenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 43 of the present invention).

(95) Compound 43 of the Present Invention

(96) ##STR00054##

(97) .sup.1H-NMR (CDCl.sub.3) : 8.13 (s, 1H), 8.09-8.08 (m, 1H), 7.98-7.95 (m, 1H), 7.76-7.75 (m, 4H), 7.71-7.69 (m, 1H), 3.97 (s, 3H).

Production Example 22

(98) A mixture of 750 mg of methyl 7-bromobenzo[b]thiophene-2-carboxylate, 575 mg of 2-methoxyphenyl boronic acid, 610 mg of lithium chloride, 528 mg of sodium carbonate, 160 mg of tetrakis(triphenylphosphine)palladium (0), 30 ml of 1,4-dioxane, and 15 ml of water was stirred for 3 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. After water was added to the filtrate, extraction was performed using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 543 mg of methyl 7-(2-methoxyphenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 44 of the present invention).

(99) Compound 44 of the Present Invention

(100) ##STR00055##

(101) .sup.1H-NMR (CDCl.sub.3) : 8.11 (s, 1H), 7.87-7.85 (m, 1H), 7.50-7.41 (m, 4H), 7.08-7.05 (m, 2H), 3.91 (s, 3H), 3.79 (s, 3H).

Production Example 23

(102) A mixture of 500 mg of methyl 6-bromobenzo[b]thiophene-2-carboxylate, 494 mg of 4-(trifluoromethoxy)phenylboronic acid, 407 mg of lithium chloride, 352 mg of sodium carbonate, 107 mg of tetrakis(triphenylphosphine)palladium (0), 20 ml of 1,4-dioxane, and 10 ml of water was stirred for 3.5 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. After water was added to the filtrate, extraction was performed using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 509 mg of methyl 6-(4-trifluoromethoxyphenyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 45 of the present invention)

(103) Compound 45 of the Present Invention

(104) ##STR00056##

(105) .sup.1H-NMR (CDCl.sub.3) : 8.09 (s, 1H), 8.03 (s, 1H), 7.96-7.94 (n, 1H), 7.68-7.66 (m, 2H), 7.62-7.60 (m, 1H), 7.34-7.32 (m, 2H), 3.97 (s, 3H).

Production Example 24

(106) A mixture of 500 mg of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 679 mg of 2-(tributyl-stannyl)pyridine, 107 mg of tetrakis(triphenylphosphine)palladium (O), and 4 ml of toluene was stirred for 4.5 hours at 120 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto. The aqueous layer was extracted twice by using ethyl acetate, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 368 mg of methyl 5-(2-pyridyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 46 of the present invention).

(107) Compound 46 of the Present Invention

(108) ##STR00057##

(109) .sup.1H-NMR (CDCl.sub.3) : 8.74-8.72 (m, 1H), 8.52-8.51 (m, 1), 8.14-8.11 (m, 2H), 7.97-7.95 (m, 1H), 7.83-7.77 (m, 2H), 7.29-7.27 (m, 1H), 3.97 (s, 3H).

Production Example 25

(110) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 623 mg of 3-pyridyl boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 754 mg of methyl 5-(3-pyridyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 47 of the present invention).

(111) Compound 47 of the Present Invention

(112) ##STR00058##

(113) .sup.1H-NMR (CDCl.sub.3) : 8.93-8.90 (m, 1H), 8.64-8.63 (m, 1H), 8.13 (s, H), 8.07 (s, 1H), 7.99-7.97 (m, 1H), 7.95-7.93 (m, 1H), 7.70-7.67 (m, 1H), 7.42-7.40 (m, 1H), 3.97 (s, 3H).

Production Example 26

(114) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 623 mg of 4-pyridyl boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 467 mg of methyl 5-(4-pyridyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 48 of the present invention).

(115) Compound 48 of the Present Invention

(116) ##STR00059##

(117) .sup.1H-NMR (CDCl.sub.3) : 8.70 (dd, 2H, J=4.5, 1.5 Hz), 8.15-8.13 (m, 2H), 8.00-7.97 (m, 1H), 7.74-7.72 (m, 1H), 7.57 (dd, 2H, J=4.5, 1.5 Hz), 3.98 (s, 3H).

Production Example 27

(118) A mixture of 500 mg of methyl 6-bromobenzo[b]thiophene-2-carboxylate, 458 mg of 2-trifluoromethyl-5-pyridyl boronic acid, 407 mg of lithium chloride, 352 mg of sodium carbonate, 107 mg of tetrakis(triphenylphosphine)palladium (0), 20 ml of 1,4-dioxane, and 10 ml of water was stirred for 2 hours at 100 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and insoluble matter was separated by filtration. After water was added to the filtrate, extraction was performed using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 366 mg of methyl 6-(6-trifluoromethyl-3-pyridyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 49 of the present invention).

(119) ##STR00060##

(120) Compound 49 of the Present Invention

(121) .sup.1H-NMR (CDCl.sub.3) : 9.02 (s, 1H), 8.12-8.10 (m, 3H), 8.03-8.01 (m, 1H), 7.81-7.79 (m, 1H), 7.66-7.63 (m, 1H), 3.98 (s, 3H).

Production Example 28

(122) A mixture of 1.00 g of 2-methoxycarbonylbenzo[b]thiophen-5-yl-boronic acid, 518 mg of 2-bromopyrimidine, 718 mg of lithium chloride, 622 mg of sodium carbonate, 188 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 3.5 hours at 100 C. in a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residue. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from chloroform and ethyl acetate, thereby obtaining 329 mg of methyl 5-(2-pyrimidinyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 50 of the present invention).

(123) Compound 50 of the Present Invention

(124) ##STR00061##

(125) .sup.1H-NMR (CDCl.sub.3) : 8.99 (d, 1H, J=1.8 Hz), 8.85 (d, 2H, J=4.8 Hz), 8.57 (dd, 1H, J=8.8, 1.8 Hz), 8.16 (s, 1H), 7.98 (d, 1H, J=8.8 Hz), 7.23 (t, 1H, C=4.8 Hz), 3.97 (s, 3H).

Production Example 29

(126) A mixture of 353 mg of methyl 4-bromobenzo[b]thiophene-2-carboxylate, 217 mg of 2-thiophene boronic acid, 287 mg of lithium chloride, 248 mg of sodium carbonate, 75 mg of tetrakis(triphenylphosphine)palladium (0), 10 ml of 1,4-dioxane, and 5 ml of water was stirred for 3 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 350 mg of methyl 4-(2-thienyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 52 of the present invention).

(127) Compound 52 of the Present Invention

(128) ##STR00062##

(129) .sup.1H-NMR (CDCl.sub.3) : 8.42 (s, 1H), 7.84-7.82 (m, 1H), 7.51-7.48 (m, 2H), 7.44-7.42 (m, 1H), 7.36-7.35 (m, 1H), 7.20-7.18 (m, 1H), 3.95 (s, 3H).

Production Example 30

(130) A mixture of 1.00 g of methyl 5-bromobenzo[b]thiophene-2-carboxylate, 613 mg of 2-thiophene boronic acid, 813 mg of lithium chloride, 704 mg of sodium carbonate, 213 mg of tetrakis(triphenylphosphine)palladium (0), 40 ml of 1,4-dioxane, and 20 ml of water was stirred for 4 hours at 100 C. under a nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. The aqueous layer was extracted twice by using chloroform, and the collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 607 mg of methyl 5-(2-thienyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 53 of the present invention).

(131) Compound 53 of the Present Invention

(132) ##STR00063##

(133) .sup.1H-NMR (CDCl.sub.3) : 8.09-8.08 (m, 1H), 8.07 (s, 1H), 7.87-7.85 (m, 1H), 7.74-7.71 (m, 1H), 7.38-7.37 (m, 1H), 7.32-7.31 (m, 1H), 7.12-7.11 (m, 1H), 3.96 (s, 3H).

Production Example 31

(134) A mixture of 340 mg of 2-fluoro-5-acetylbenzaldehyde, 283 mg of methyl thioglycolate, 567 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 2 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and the precipitated solids were collected by filtration. The obtained solids were washed with water and dried under reduced pressure, thereby obtaining 277 mg of methyl 5-acetylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 54 of the present invention).

(135) Compound 54 of the present invention

(136) ##STR00064##

(137) .sup.1H-NMR (CDCl.sub.3) : 8.48 (d, 1H, J=1.8 Hz), 8.15 (s, 1H), 8.06 (dd, 1H, J=8.6, 1.8 Hz), 7.94 (d, 1H, J=8.6 Hz), 3.97 (s, 3H), 2.70 (s, 3H).

Production Example 32

(138) Step 1

(139) A mixture of 7.0 g of 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane and 10 ml of tetrahydrofuran was added dropwise to a mixture of 895 mg of magnesium and 20 ml of tetrahydrofuran at 50 C., followed by stirring for 30 minutes. Thereafter, 3.82 g of N-methoxy-N-methyltrifluoroacetamide was added to the reaction mixture at 0 C., followed by stirring for 1.5 hours at room temperature. Forty (40) ml of 1 M hydrochloric acid was added to the reaction mixture, and the residue was stirred for 3 hours under reflux. After the reaction mixture was cooled to room temperature, extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 2.69 g of 2-fluoro-5-trifluoroacetylbenzaldehyde.

(140) ##STR00065##

(141) Step 2

(142) A mixture of 1.00 g of 2-fluoro-5-(trifluoroacetyl)benzaldehyde, 391 mg of methyl thioglycolate, 763 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 1 hour at 80 C. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 462 mg of methyl 5-trifluoroacetylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 55 of the present invention).

(143) Compound 55 of the Present Invention

(144) ##STR00066##

(145) .sup.1H-NMR (CDCl.sub.3) : 8.60 (s, 1H), 8.19-8.20 (m, 1H), 8.14-8.11 (m, 1H), 8.04-8.01 (m, 1H), 3.99 (s, 3H).

Production Example 33

(146) Step 1

(147) Five point one (5.1) ml of n-butyllithium (1.6 M hexane solution) was added dropwise to a mixture of 2.00 g of 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane and 10 ml of tetrahydrofuran at 70 C., followed by stirring for 30 minutes. A mixture of 919 mg of benzonitrile and 5 ml of tetrahydrofuran was added dropwise to the reaction mixture at 70 C., followed by stirring for 1 hour. Thereafter, the reaction mixture was stirred for 1.5 hours at room temperature, and then 30 ml of 1 M hydrochloric acid was added thereto, followed by stirring for 3 hours at 65 C. After the reaction mixture was cooled to room temperature, extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 414 mg of 5-benzoyl-2-fluorobenzaldehyde.

(148) ##STR00067##

(149) Step 2

(150) A mixture of 414 mg of 5-benzoyl-2-fluorobenzaldehyde, 250 mg of methyl thioglycolate, 501 mg of potassium carbonate, and 3 ml of N,N-dimethylformamide was stirred for 1 hour at 80 C. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 271 mg of methyl 5-benzoylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 56 of the present invention).

(151) Compound 56 of the Present Invention

(152) ##STR00068##

(153) .sup.1H-NMR (CDCl.sub.3, : 8.30 (s, 1H), 8.13 (s, 1H), 7.98-7.94 (m, 2H), 7.84-7.82 (m, 2H), 7.64-7.62 (m, 1H), 7.54-7.50 (m, 2H), 3.97 (s, 3H:

Production Example 34

(154) Step 1

(155) A mixture of 250 mg of methyl 4-cyanobenzo[b]thiophene-2-carboxylate, 608 mg of sodium hydroxide, 2 ml of water, and 3 ml of methanol was stirred for 14 hours under reflux. After the reaction mixture was cooled to room temperature, 5 ml of water and 2 ml of concentrated hydrochloric acid were added thereto, and the precipitated solids were collected by filtration and dried under reduced pressure, thereby obtaining 331 mg of benzo[b]thiophene-2,4-dicarboxylic acid.

(156) ##STR00069##

(157) Step 2

(158) A mixture of 200 mg of benzo[b]thiophene-2,4-dicarboxylic acid, 100 mg of sulfuric acid, and 5 ml of methanol was stirred for 23 hours under reflux. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 220 mg of dimethyl benzo[b]thiophene-2,4-dicarboxylate(hereinafter, described as a compound 57 of the present invention).

(159) Compound 57 of the Present Invention

(160) ##STR00070##

(161) .sup.1H-NMR (CDCl.sub.3) : 8.89 (s, 1H), 8.18-8.16 (m, 1H), 8.07-8.05 (m, 1H), 7.53-7.51 (m, 1H), 4.02 (s, 3H), 3.97 (s, 3H).

Production Example 35

(162) A mixture of 1.00 g of methyl 3-formyl-4-nitrobenzoate, 609 mg of methyl thioglycolate, 761 mg of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 3 hours at 60 C. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 323 mg of dimethyl benzo[b]thiophene-2,5-dicarboxylate (hereinafter, described as a compound 58 of the present invention).

(163) Compound 58 of the Present Invention

(164) ##STR00071##

(165) .sup.1H-NMR (CDCl.sub.3) : 8.60-8.56 (m, 1H), 8.13-8.10 (m, 2H), 7.93-7.91 (m, 1H), 3.97 (s, 3H), 3.97 (s, 3H).

Production Example 36

(166) Step 1

(167) A mixture of 1.87 g of 2,3-dihydro-1-benzothiophene-2,3-dione, 1.5 g of sodium carbonate, and 13.5 ml of water was stirred for 1 hour at room temperature. An aqueous solution composed of 1.16 g of chloroacetic acid, 0.6 g of sodium carbonate, and 5.4 ml of water was added dropwise to the mixture, followed by stirring for 1 hour at 80 C. After the reaction mixture was cooled to room temperature, insoluble matter was separated by filtration. Fifteen (15) g of sodium hydroxide was added to the filtrate under ice cooling, followed by stirring for 2 hours at room temperature. Concentrated hydrochloric acid was added to the aqueous solution under ice cooling, and the precipitated solids were collected by filtration and dried under reduced pressure, thereby obtaining 440 mg of benzo[b]thiophene-2,3-dicarboxylic acid.

(168) ##STR00072##

(169) Step 2

(170) A mixture of 280 mg of benzo[b]thiophene-2,3-dicarboxylic acid, 200 mg of concentrated sulfuric acid, and 6 ml of methanol was stirred for 4 hours at 80 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residues, and the residue was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 220 mg of dimethyl benzo[b]thiophene-2,3-dicarboxylate (hereinafter, described as a compound 60 of the present invention).

(171) Compound 60 of the Present Invention

(172) ##STR00073##

(173) .sup.1H-NMR (CDCl.sub.3) : 7.95-7.93 (m, 1H), 7.87-7.85 (m, 1H), 7.50-7.47 (m, 2H), 4.03 (s, 3H), 3.95 (s, 3H).

Production Example 37

(174) Step 1

(175) Two point zero zero (2.00) g of molecular sieves (4 ), 341 mg of copper (II) chloride dehydrate, and 200 ml of water were stirred for 7 hours at room temperature, and the residue was collected by filtration. The substance collected by filtration was washed with 20 ml of water and 20 ml of acetone and then vacuum-dried for 1 hour at 150 C., thereby obtaining 2.00 g of light green solids.

(176) Step 2

(177) A mixture of 500 mg of light green solids obtained in Step 1, 1.00 g of methyl 5-cyanobenzo[b]thiophene-2-carboxylate, 2.8 ml of acetaldoxime, and 20 ml of methanol was stirred for 24 hours at 65 C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Acetone was added to the residues, and insoluble matter was collected by filtration and dried under reduced pressure, thereby obtaining 696 mg of methyl 5-aminocarbonylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 61 of the present invention).

(178) Compound 61 of the Present Invention

(179) ##STR00074##

(180) .sup.1H-NMR (CDCl.sub.3) : 8.37-8.36 (m, 1H), 8.12 (s, 1H), 7.95-7.92 (m, 1H), 7.89-7.89 (m, 1H), 6.10 (br s, 1H), 5.64 (br s, 1H), 3.97 (s, 3H).

Production Example 38

(181) A mixture of 1.20 g of methyl 4-aminobenzo[b]thiophene-2-carboxylate, 2.7 g of methyl iodide, 1.76 g of potassium carbonate, and 4 ml of acetonitrile was stirred for 7 hours at 60 C. After the reaction mixture was cooled to room temperature, 60 ml of water and 60 ml of ethyl acetate were added thereto, insoluble matter was separated by filtration, and extraction was performed on the filtrate by using ethyl acetate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 255 mg of 4-(dimethylamino)benzo[b]thiophene-2-carboxylic acid (hereinafter, described as a compound 66 of the present invention).

(182) Compound 66 of the Present Invention

(183) ##STR00075##

(184) .sup.1H-NMR (CDCl.sub.3) : 8.25 (s, 1H), 7.42-7.41 (m, 1H), 7.35-7.33 (m, 1H), 6.82-6.80 (m, 1H), 3.94 (s, 3H), 2.97 (s, 6H).

Production Example 39

(185) A mixture of 500 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 323 mg of acetic anhydride, 623 mg of diisopropylethylamine, and 10 ml of dichloromethane was stirred for 4 hours at room temperature. The reaction mixture was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 449 mg of methyl 5-(acetylamino)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 67 of the present invention).

(186) Compound 67 of the Present Invention

(187) ##STR00076##

(188) .sup.1H-NMR (CDCl.sub.3) : 8.22-8.21 (m, 1H), 7.99 (s, 1H), 7.78-7.76 (m, 1H), 7.44-7.40 (m, 2H), 3.94 (s, 3H), 2.22 (s, 3H).

Production Example 40

(189) A mixture of 300 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 310 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 294 mg of benzoic acid, 18.4 mg of N,N-dimethyl-4-aminopyridine, and 20 ml of tetrahydrofuran was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and tert-butyl methyl ether was added to the residues. The organic layer was washed with a 1 M aqueous hydrochloric acid solution, a 1 M aqueous sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure, thereby obtaining 318 mg of methyl 5-benzoylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 68 of the present invention).

(190) Compound 68 of the Present Invention

(191) ##STR00077##

(192) .sup.1H-NMR (CDCl.sub.3) : 8.40 (br s, 1H), 8.05 (s, 1H), 7.91-7.90 (m, 3H), 7.86-7.84 (m, 1H), 7.58-7.53 (m, 4H), 3.96 (s, 3H).

Production Example 41

(193) A mixture of 5.60 g of acetic anhydride and 3.11 g of formic acid was stirred for 2 hours at 60 C. After the reaction mixture was cooled to room temperature, 10 ml of tetrahydrofuran was added thereto. A mixture of 4.37 g of methyl 3-amino-benzo[b]thiophene-2-carboxylate and 50 ml of tetrahydrofuran was added dropwise to the above mixture under ice cooling. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residues was recrystallized from tetrahydrofuran, thereby obtaining 4.06 g of methyl 3-formylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 69 the present invention).

(194) Compound 69 of the Present Invention

(195) ##STR00078##

(196) .sup.1H-NMR (DMSO-D.sub.6) : 10.45 (br s, 1H), 8.45-8.43 (m, 1H), 8.05-8.03 (m, 1H), 7.90 (br s, 1H), 7.60-7.58 (m, 1H), 7.51-7.49 (m, 1H), 3.84 (s, 3H).

Production Example 42

(197) A mixture of 10 of methyl 3-amino-benzo[b]thiophene-2-carboxylate and 2 ml of tetrahydrofuran was stirred under ice cooling, and then 24 mg of 60% sodium hydride was added thereto. Forty and five (45) mg of acetyl chloride was added dropwise to the reaction mixture under ice cooling, followed by stirring for 46 hours at room temperature. Water was added to the mixture, and the precipitated solids were collected by filtration, washed with hexane, and then dried under reduced pressure, thereby obtaining 82 mg of methyl 3-acetylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 70 of the present invention).

(198) Compound 70 of the Present Invention

(199) ##STR00079##

(200) .sup.1H-NMR (CDCl.sub.3) : 9.47 (br s, 1H), 8.10-8.08 (m, 1H), 7.77-7.75 (m, 1H), 7.50-7.46 (m, 1H), 7.42-7.38 (m, 1H), 3.94 (s, 3H), 2.33 (s, 3H).

Production Example 43

(201) A mixture of 200 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 456 mg of trifluoroacetic anhydride, 205 mg of triethylamine, and 10 ml of tetrahydrofuran was stirred for 24 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, 1 M hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 260 mg of methyl 5-trifluoroacetylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 71 of the present invention).

(202) Compound 71 of the Present Invention

(203) ##STR00080##

(204) .sup.1H-NMR (DMSO-D.sub.6) : 11.48 (br s, 1H), 8.40 (d, 1H, J=2.0 Hz), 8.27 (s, 1H), 8.11 (d, 1H, J=8.8 Hz), 7.75 (dd, 1H, J=8.8, 2.0 Hz), 3.92 (s, 3H).

Production Example 44

(205) A mixture of 150 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 170 mg of chloroacetyl chloride, 304 mg of triethylamine, and 10 ml of tetrahydrofuran was stirred for 24 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, 1 M hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 160 mg of methyl 5-chloroacetylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 72 of the present invention).

(206) Compound 72 of the Present Invention

(207) ##STR00081##

(208) .sup.1H-NMR (CDCl.sub.3) : 8.36 (br s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.85-7.83 (m, 1H), 7.52-7.50 (m, 1H), 4.24 (s, 2H), 3.95 (s, 3H).

Production Example 45

(209) Step 1

(210) A mixture of 500 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 552 mg of methanesulfonyl chloride, 623 mg of diisopropylethylamine, and 10 ml of dichloromethane was stirred for 4 hours at room temperature. After the reaction mixture was concentrated under reduced pressure, water was added to the residues, and the precipitated solids were collected by filtration. The obtained solids were washed with water and hexane and dried under reduced pressure, thereby obtaining 449 mg of methyl 5-[bis(methylsulfonyl)amino]benzo[b]thiophene-2-carboxylate.

(211) ##STR00082##

(212) Step 2

(213) A mixture of 760 mg of methyl 5-[bis(methylsulfonyl)amino]benzo[b]thiophene-2-carboxylate, 228 mg of lithium hydroxide monohydrate, 3 ml of water, and 6 ml of methanol was stirred for 2 hours at 80 C. The reaction mixture was concentrated under reduced pressure, water was added to the residues, and the residue was washed with tert-butyl methyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and extraction was performed by using tert-butyl methyl ether. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 568 mg of 5-methylsulfonylaminobenzo[b]thiophene-2-carboxylic acid.

(214) ##STR00083##

(215) Step 3

(216) A mixture of 406 mg of 5-(methylsulfonyl)aminobenzo[b]thiophene-2-carboxylic acid, 200 mg of sulfuric acid, and 6 ml of methanol was stirred for 6 hours at 90 C. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 315 mg of methyl 5-methylsulfonylaminobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 81 of the present invention).

(217) Compound 81 of the Present Invention

(218) ##STR00084##

(219) .sup.1H-NMR (CDCl.sub.3) : 8.02 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.79 (d, 1H, J=2.3 Hz), 7.33 (dd, 1H, J=8.8, 2.3 Hz), 6.70 (s, 1H), 3.96 (s, 3H), 3.04 (s, 3H).

Production Example 46

(220) Step 1

(221) A mixture of 500 mg of methyl 5-aminobenzo[b]thiophene-2-carboxylate, 1.37 g of trifluoromethanesulfonic anhydride, 623 mg of diisopropylethylamine, and 10 ml of dichloromethane was stirred for 4 hours at room temperature. An aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and extraction was performed using chloroform. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 500 mg of methyl 5-[bis(trifluoromethylsulfonyl)amino]benzo[b]thiophene-carboxylate.

(222) ##STR00085##

(223) Step 2

(224) A mixture of 493 mg of methyl 5-[bis(trifluoromethylsulfonyl)amino]benzo[b]thiophene-2-carboxylate, 152 mg of lithium hydroxide monohydrate, 3 ml of water, and 6 ml of methanol was stirred for 2 hours at 80 C. The reaction mixture was concentrated under reduced pressure, water was added to the residues, and the residue was washed with tert-butyl methyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and extraction was performed using tert-butyl methyl ether. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 308 mg of 5-(trifluoromethylsulfonylamino)benzo[b]thiophene-2-carboxylic acid.

(225) ##STR00086##

(226) Step 3

(227) A mixture of 182 mg of 5-(trifluoromethylsulfonylamino)benzo[b]thiophene-2-carboxylic acid, 100 mg of sulfuric acid, and 6 ml of methanol was stirred for 6 hours at 80 C. Water was added to the reaction mixture, and extraction was performed using ethyl acetate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 169 mg of methyl 5-(trifluoromethylsulfonylamino)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 83 of the present invention).

(228) Compound 83 of the Present Invention

(229) ##STR00087##

(230) .sup.1H-NMR (CDCl.sub.3) : 8.04 (s, 1H), 7.88 (d, 1H, J=8.7 Hz), 7.83 (d, 1H, J=2.1 Hz), 7.38 (dd, 1H, J=8.7, 2.1 Hz), 3.97 (s, 3H).

Production Example 47

(231) A mixture of 600 mg of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate, 819 mg of methyl iodide, 797 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 4 hours at 70 C. After the reaction mixture was cooled to room temperature, tert-butyl methyl ether was added thereto. The residue was washed with water, an aqueous 1 M sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and then dried under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 195 mg of methyl 3-methoxybenzo[b]thiophene-2-carboxylate. Hereinafter, the compound is described as a compound 94 of the present invention.

(232) Compound 94 of the Present Invention

(233) ##STR00088##

(234) .sup.1H-NMR (CDCl.sub.3) : 7.90-7.88 (m, 1H), 7.76-774 (m, 1H), 7.52-7.46 (m, 1H), 7.42-7.38 (m, 1H), 4.17 (s, 3H), 3.93 (s, 3H).

Production Example 48

(235) A mixture of 600 mg of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate, 800 mg of ethyl iodide, 797 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added thereto, and the residue was washed with water, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 540 mg of methyl 3-ethoxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 95 of the present invention).

(236) Compound 95 of the Present Invention

(237) ##STR00089##

(238) .sup.1H-NMR (CDCl.sub.3) : 7.89-7.87 (m, 1H), 7.76-7.74 (m, 1H), 7.50-7.46 (m, 1H), 7.42-7.38 (m, 1H), 4.40 (q, 2H, J=7.0 Hz), 3.92 (s, 3H), 1.48 (t, 3H, J=7.0 Hz).

Production Example 49

(239) A mixture of 300 mg of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate, 450 mg of isopropyl iodide, 400 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 12 hours at 70 C. After the reaction mixture was cooled to room temperature, tert-butyl methyl ether was added thereto. The residue was washed with water, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 321 mg of methyl 3-isopropoxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 96 of the present invention).

(240) Compound 96 of the Present Invention

(241) ##STR00090##

(242) .sup.1H-NMR (CDCl.sub.3) : 7.87 (d, 1H, J=8.0 Hz), 7.74 (d, 1H, J=8.0 Hz), 7.49-7.45 (m, 1H), 7.41-7.37 (m, 1H), 4.87-4.81 (m, 1H), 3.92 (s, 3H), 1.41-1.40 (m, 6H).

Production Example 50

(243) A mixture of 600 mg of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate, 933 mg of benzyl bromide, 797 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 560 mg of methyl 3-benzyloxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 97 of the present invention).

(244) Compound 97 of the Present Invention

(245) ##STR00091##

(246) .sup.1H-NMR (CDCl.sub.3) : 7.81-7.79 (m, 1H), 7.76-7.74 (m, 1H), 7.54-7.45 (m, 3H), 7.42-7.34 (m, 4H), 5.36 (s, 2H), 3.93 (s, 3H).

Production Example 51

(247) A mixture of 3.00 g of 2-fluoro-3-trifluoromethoxybenzaldehyde, 1.33 g of methyl thioglycolate, 2.66 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 2 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 1.38 g of methyl 5-trifluoromethoxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 98 of the present invention).

(248) Compound 98 of the Present Invention

(249) ##STR00092##

(250) .sup.1H-NMR (CDCl.sub.3) : 8.05 (s, 1H), 7.87 (d, 1H, J=8.8 Hz), 7.73 (d, 1H, J=1.0 Hz), 7.34 (dq, 1H, J=8.8, 1.0 Hz), 3.96 (s, 3H).

Production Example 52

(251) A mixture of 300 mg of methyl 6-hydroxybenzo[b]thiophene-2-carboxylate, 206 mg of propargyl bromide, 260 mg of potassium carbonate, and 5 ml of acetonitrile was stirred for 4 hours at 60 C. Ethyl acetate was added to the reaction mixture, and the residue was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 327 mg of methyl 6-prepargyloxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 99 of the present invention).

(252) Compound 99 of the Present Invention

(253) ##STR00093##

(254) .sup.1H-NMR (CDCl.sub.3) : 7.98 (s, 1H), 7.77 (d, 1H, J=8.8 Hz), 7.40 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 4.78 (s, 2H), 3.93 (s, 3H), 2.57 (s, 1H).

Production Example 53

(255) A mixture of 300 mg of methyl 6-hydroxybenzo[b]thiophene-2-carboxylate, 414 mg of 4-(trifluoromethyl)benzyl bromide, 260 mg of potassium carbonate, and 5 ml of acetonitrile was stirred for 4 hours at 60 C. Chloroform was added to the reaction mixture, and the residue was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were washed with a mixture of 6 ml of hexane and 18 ml of ethyl acetate and then dried under reduced pressure, thereby obtaining 486 mg of methyl 6-(4-trifluoromethylbenzyloxy)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 100 of the present invention).

(256) Compound 100 of the Present Invention

(257) ##STR00094##

(258) .sup.1H-NMR (CDCl.sub.3) : 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.67 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 7.35 (s, 1H), 7.12-7.10 (m, 1H), 5.21 (s, 2H), 3.93 (s, 3H).

Production Example 54

(259) A mixture of 300 mg of methyl 6-hydroxybenzo[b]thiophene-2-carboxylate, 348 mg of 3-methoxybenzyl bromide, 260 mg of potassium carbonate, and 5 ml of acetonitrile was stirred for 4 hours at 60 C. Ethyl acetate was added to the reaction mixture, and the residue was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 442 mg of methyl 6-(3-methoxybenzyloxy)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 101 of the present invention).

(260) Compound 101 of the Present Invention

(261) ##STR00095##

(262) .sup.1H-NMR (CDCl.sub.3) : 7.97 (s, 1H), 7.75 (d, 1H, J=8.8 Hz), 7.35 (d, 1H, J=2.3 Hz), 7.33-7.31 (m, 1H), 7.10 (dd, 1H, J=8.8, 2.3 Hz), 7.04-7.01 (m, 2H), 6.90-6.87 (m, 1H), 5.12 (s, 2H), 3.92 (s, 3H), 3.83 (s, 3H).

Production Example 55

(263) A mixture of 450 mg of methyl 7-hydroxybenzo[b]thiophene-2-carboxylate, 565 mg of 2-iodo toluene, 41.1 mg of copper iodide, 1.41 g of cesium carbonate, 90.4 mg of N,N-dimethylglycine hydrochloride, and 5 ml of 1,4-dioxane was stirred for 23 hours under reflux. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed by using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 91 mg of methyl 7-(2-methylphenoxy)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 102 of the present invention).

(264) Compound 102 of the Present Invention

(265) ##STR00096##

(266) .sup.1H-NMR (CDCl.sub.3) : 8.10 (s, 1H), 7.59-7.57 (m, 1H), 7.31-7.28 (m, 2H), 7.22-7.18 (m, 1H), 7.14-7.12 (m, 1H), 7.01-6.99 (m, 1H), 6.71-6.69 (m, 1H), 3.95 (s, 3H), 2.26 (s, 3H).

Production Example 56

(267) A mixture of 450 mg of methyl 7-hydroxybenzo[b]thiophene-2-carboxylate, 705 mg of 4-iodobenzotrifluoride, 41.1 mg of copper iodide, 1.41 g of cesium carbonate, 90.4 mg of N,N-dimethylglycine hydrochloride, and 5 ml of 1,4-dioxane was stirred for 23 hours under reflux. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed by using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 333 mg of methyl 7-(4-trifluoromethylphenoxy)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 103 of the present invention).

(268) Compound 103 of the Present Invention

(269) ##STR00097##

(270) .sup.1H-NMR (CDCl.sub.3) : 8.11 (s, 1H), 7.74-7.72 (m, 1H), 7.61 (d, 2H, J=8.6 Hz), 7.42-0.40 (m, 1H), 7.12 (d, 2H, J=8.6 Hz), 7.07-7.05 (m, 1H), 3.94 (s, 3H).

Production Example 57

(271) A mixture of 450 mg of methyl 7-hydroxybenzo[b]thiophene-2-carboxylate, 746 mg of 1-iodo-4-(trifluoromethoxy)benzene, 41.1 mg of copper iodide, 1.41 g of cesium carbonate, 90.4 mg of N,N-dimethylglycine hydrochloride, and 5 ml of 1,4-dioxane was stirred for 23 hours under reflux. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed by using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 241 mg of methyl 7-[4-(trifluoromethoxy)phenoxy)]benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 104 of the present invention).

(272) Compound 104 of the Present Invention

(273) ##STR00098##

(274) .sup.1H-NMR (CDCl.sub.3) : 8.10 (s, 1H), 7.68-7.66 (m, 1H), 7.38-7.36 (m, 1H), 7.22 (d, 2H, J=9.1 Hz), 7.09 (d, 2H, J=9.1 Hz), 6.97-6.95 (m, 1H), 3.94 (s, 3H).

Production Example 58

(275) A mixture of 300 mg of methyl 3-hydroxybenzo[b]thiophene-2-carboxylate, 294 mg of acetyl chloride, 291 mg of triethylamine, and 10 ml of tetrahydrofuran was stirred for 12 hours at room temperature. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and the residue was washed with water and 1 M hydrochloric acid, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure, thereby obtaining 343 mg of methyl 3-acetyloxybenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 105 of the present invention).

(276) Compound 105 of the Present Invention

(277) ##STR00099##

(278) .sup.1H-NMR (CDCl.sub.3) : 7.82-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.53-7.49 (m, 1H), 7.45-7.41 (m, 1H), 3.91 (s, 3H), 2.48 (s, 3H).

Production Example 59

(279) Step 1

(280) Six point zero (6.0) ml of n-butyllithium (1.6 M hexane solution) was added dropwise to a mixture of 2.27 g of 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane and 10 ml of tetrahydrofuran at 70 C., followed by stirring for 30 minutes. A mixture of 1.04 g of dimethyl disulfide and 10 ml of tetrahydrofuran was added dropwise to the reaction mixture at 70 C., followed by stirring for 1 hour. Thereafter, the reaction mixture was stirred for 1.5 hours at room temperature, and 30 ml of 1 M hydrochloric acid was added thereto, followed by stirring for 3 hours at 65 C. After the reaction mixture was cooled to room temperature, extraction was performed by using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 1.00 g of 2-fluoro-5-methylthiobenzaldehyde.

(281) ##STR00100##

(282) Step 2

(283) A mixture of 1.00 g of 2-fluoro-5-methylthiobenzaldehyde, 811 mg of methyl thioglycolate, 1.62 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 1 hour at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 385 mg of methyl 5-methylthiobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 108 of the present invention).

(284) Compound 108 of the Present Invention

(285) ##STR00101##

(286) .sup.1H-NMR (CDCl.sub.3) : 7.98 (s, 1H), 7.76 (d, 1H, J=8.6 Hz), 7.72 (d, 1H, J=2.0 Hz), 7.39 (dd, 1H, J=8.6, 2.0 Hz), 3.95 (s, 3H), 2.55 (s, 3H).

Production Example 60

(287) Step 1

(288) A mixture of 7.0 g of 2-(5-bromo-2-fluorophenyl)-1,3-dioxolane and 10 ml of tetrahydrofuran was added dropwise to a mixture of 895 mg of magnesium and 20 ml of tetrahydrofuran at 50 C., followed by stirring for 30 minutes. Thereafter, 1.36 g of sulfur was added to the reaction mixture at 0 C., followed by stirring for 1.5 hours at room temperature. Fifty (50) ml of an aqueous saturated ammonium chloride solution and 50 ml of ethyl acetate was added to the reaction mixture, and insoluble matter was separated by filtration. Extraction was performed on the filtrate by using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 3.78 g of bis[3-(1,3-dioxolan-2-yl)-4-fluorophenyl]disulfide.

(289) ##STR00102##

(290) Step 2

(291) A mixture of 804 mg of [3-(1,3-dioxolan-2-yl)-4-fluorophenyl]disulfide, 267 mg of sodium borohydride, and 10 ml of tetrahydrofuran was stirred for 10 hours at room temperature. Fifty (50) ml of an aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. A mixture of 734 mg of 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxole and 5 ml of dichloromethane was added to a mixture of the obtained residues and 10 ml of dichloromethane at 78 C., followed by stirring for 3 hours. Thereafter, the reaction mixture was stirred for 20 hours at room temperature, and then the residue was subjected to silica gel column chromatography, thereby obtaining 785 mg of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-(trifluoromethylthio)benzene.

(292) ##STR00103##

(293) Step 3

(294) Six (6) ml of 1 M hydrochloric acid was added to a mixture of 785 mg of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-(trifluoromethylthio)benzene and 10 ml of tetrahydrofuran, followed by stirring for 10 hours under reflux. After the reaction mixture was cooled to room temperature, 40 ml of water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 604 mg of 2-fluoro-5-trifluoromethylthiobenzaldehyde.

(295) ##STR00104##

(296) Step 4

(297) A mixture of 600 mg of 2-fluoro-5-(trifluoromethylthio)benzaldehyde, 369 mg of methyl thioglycolate, 556 mg of potassium carbonate, and 6 ml of N,N-dimethylformamide was stirred for 1 hour at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 489 mg of methyl 5-trifluoromethylthiobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 109 of the present invention).

(298) Compound 109 of the Present Invention

(299) ##STR00105##

(300) .sup.1H-NMR (CDCl.sub.3) : 8.20 (s, 1H), 8.08 (s, 1H), 7.92 (d, 1H, J=8.6 Hz), 7.69 (d, 1H, J=8.6 Hz), 3.97 (3H, s).

Production Example 61

(301) Step 1

(302) M-chloroperbenzoic acid (ca. 70%) 588 mg was added to a mixture of 609 mg of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-(trifluoromethylthio)benzene and 10 ml of chloroform at 0 C. The temperature of the reaction mixture was returned to room temperature, followed by stirring for 19 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the mixture, and extraction was performed using chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 506 mg of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-trifluoromethylsulfinylbenzene.

(303) ##STR00106##

(304) Step 2

(305) Five (5) ml of 1 M hydrochloric acid was added to a mixture of 504 ml of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-trifluoromethylsulfinylbenzene and 5 ml of tetrahydrofuran, followed by stirring for 15 hours under reflux. After the reaction mixture was cooled to room temperature, 20 ml of water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. A mixture of 432 g of the obtained residues, 210 mg of methyl thioglycolate, 323 mg of potassium carbonate, and 5 ml of N,N-dimethylformamide was stirred for 2 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 409 mg of methyl 5-(trifluoromethylsulfinyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 110 of the present invention).

(306) Compound 110 of the Present Invention

(307) ##STR00107##

(308) .sup.1H-NMR (CDCl.sub.3) : 6.36 (s, 1H), 8.16 (d, 1H, J=0.8 Hz), 8.10 (d, 1H, J=8.6 Hz), 7.80 (dd, 1H, J=8.6, 0.8 Hz), 3.99 (s, 3H).

Production Example 62

(309) One point zero three (1.03) g (ca. 70%) of m-chloroperbenzoic acid was added to a mixture of 450 mg of 3-(1,3-dioxolan-2-yl)-4-fluoro-1-(trifluoromethylthio)benzene and 10 ml of chloroform at 0 C. The temperature of the reaction mixture was returned to room temperature, followed by stirring for 28 hours. An aqueous saturated sodium hydrogen carbonate solution was added to the mixture, and extraction was performed using chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Five (5) ml of 1 M hydrochloric acid was added to the mixture of the obtained residues and 5 ml of tetrahydrofuran, followed by stirring for 15 hours under reflux. After the reaction mixture was cooled to room temperature, 20 ml of water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. A mixture of 432 mg of the obtained residues, 196 mg of methyl thioglycolate, 302 mg of potassium carbonate, and 5 ml of N,N-dimethylformamide was stirred for 2 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 178 mg of methyl 5-trifluoromethylsulfonylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 111 of the present invention).

(310) Compound 111

(311) ##STR00108##

(312) .sup.1H-NMR (CDCl.sub.3) : 8.60 (s, 1H), 8.22-8.21 (m, 1H), 8.16-8.14 (m, 1H), 8.03-8.01 (m, 1H), 4.00 (s, 3H).

Production Example 63

(313) A mixture of 1.20 g of 2-fluoro-5-pentafluorosulfuranylbenzaldehyde, 520 mg of methyl thioglycolate, 607 mg of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 2 hours at 60 C., and the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 1.40 g of methyl 5-pentafluorosulfuranylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 117 of the present invention).

(314) Compound 117 of the Present Invention

(315) ##STR00109##

(316) .sup.1H-NMR (CDCl.sub.3) : 8.29 (d, 1H, J=2.2 Hz), 8.13 (s, 1H), 7.94 (d, 1H, J=90 Hz), 7.83 (dd, 1H, J=9.0, 2.2 Hz), 3.99 (s, 3H).

Production Example 64

(317) A mixture of 2.0 g of 2,3-dichloro-6-fluorobenzaldehyde, 1.16 g of methyl thioglycolate, 1.87 g of potassium carbonate, and 20 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from methanol, thereby obtaining 2.03 g of methyl 4,5-dichlorobenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 118 of the present invention).

(318) Compound 118 of the Present Invention

(319) ##STR00110##

(320) .sup.1H-NMR (CDCl.sub.3) : 8.18 (s, 1H), 7.68 (d, 1H, J=8.7 Hz), 7.51 (d, 1H, J=8.7 Hz), 3.98 (s, 3H).

Production Example 65

(321) A mixture of 2.0 g of 3-chloro-5-trifluoromethyl-2-fluorobenzaldehyde, 985 mg of methyl thioglycolate, 1.16 g of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 4 hours at 60 C. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from methanol, thereby obtaining 2.07 g of methyl 7-chloro-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 122 of the present invention).

(322) Compound 122 of the Present Invention

(323) ##STR00111##

(324) .sup.1H-NMR (CDCl.sub.3) : 8.15 (s, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 4.00 (s, 3H).

Production Example 66

(325) A mixture of 5.42 g of 3-trifluoromethyl cinnamic acid, 1.25 ml of N,N-dimethylformamide, and 0.5 ml of pyridine was stirred under ice cooling, and then 8.92 g of thionyl chloride was added dropwise thereto. After being stirred for 1 hour at 140 C., the mixture was cooled to room temperature. Twenty (20) ml of methanol was added to the mixture, followed by stirring for 1 hour at 140 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed using ethyl acetate. The collected organic layer was washed with aqueous saturate sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography and concentrated under reduced pressure. The residues were washed with hexane and dried under reduced pressure, thereby obtaining 234 mg of methyl 3-chloro-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 123 of the present invention).

(326) Compound 123 of the Present Invention

(327) ##STR00112##

(328) .sup.1H-NMR (CDCl.sub.3) : 8.26 (s, 1H), 7.96 (d, 1H, J=8.6 Hz), 7.76 (d, 1H, J=8.6 Hz), 4.00 (s, 3H).

Production Example 67

(329) A mixture of 1.00 g of 2-fluoro-5-trifluoromethylacetophenone, 2.01 g of potassium carbonate, 669 mg of methyl thioglycolate, and 5 ml of N,N-dimethylformamide was stirred for 7 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed using ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. Hexane was added to the residues, and the precipitated solids were collected by filtration and dried under reduced pressure, thereby obtaining 474 mg of methyl 5-trifluoromethyl-3-methylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 124 of the present invention).

(330) Compound 124 of the Present Invention

(331) ##STR00113##

(332) .sup.1H-NMR (CDCl.sub.3), : 8.10 (s, 1H), 7.94 (d, 1H, J=8.6 Hz), 7.68 (d, 1H, J=8.6 Hz), 3.95 (s, 3H), 2.82 (s, 3H).

Production Example 68

(333) Step 1

(334) Three point eight (3.8) ml of n-butyllithium (2.6 M hexane solution) was added dropwise to a mixture of 3.00 g of 1-chloro-2-iodo-4-(trifluoromethyl)benzene and 15 ml of tetrahydrofuran at 70 C., followed by stirring for 30 minutes. Thereafter, a mixture of 1.69 g of N-methoxy-N-methyltrifluoroacetamide and 5 ml of tetrahydrofuran was added dropwise thereto at 70 C. Subsequently, after the reaction mixture was stirred for 1 hour at room temperature, water was added thereto, and extraction was performed using ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 1.66 g of 2,2,2-trifluoro-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone.

(335) ##STR00114##

(336) Step 2

(337) A mixture of 1.66 g of 2,2,2-trifluoro-1-[2-chloro-5-(trifluoromethyl)phenyl]ethanone, 422 mg of methyl thioglycolate, 650 mg of potassium carbonate, and 5 ml of N,N-dimethylformamide was stirred for 2 hours at 80 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using ethyl acetate. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 685 mg of methyl 3,5-bis(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 125 of the present invention).

(338) Compound 125 of the Present Invention

(339) ##STR00115##

(340) .sup.1H-NMR (CDCl.sub.3) : 8.41 (s, 1H), 8.01 (d, 1H, J=8.6 Hz), 7.75 (d, 1H, J=8.6 Hz), 4.01 (s, 3H).

Production Example 69

(341) A mixture of 15.0 g of 2-fluoro-5-trifluoromethylbenzoic acid, 0.1 ml of concentrated sulfuric acid, and 50 ml of methanol was stirred for 12 hours at 70 C. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and the residue was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Methyl thioglycolate 7.24 g, potassium carbonate 8.6 g, and 100 ml of N,N-dimethylformamide were added to the residues, and this mixture was stirred for 4 hours at 60 C. After the reaction mixture was cooled to room temperature, water was added thereto, and the residue was washed three times with tert-butyl methyl ether. Concentrated hydrochloric acid was added to the aqueous layer, and extraction was performed three times using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from ethyl acetate, thereby obtaining 14.2 g of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 126 of the present invention).

(342) Compound 126 of the Present Invention

(343) ##STR00116##

(344) .sup.1H-NMR (CDCl.sub.3) : 10.10 (br s, 1H), 8.23 (s, 1H), 7.86 (d, 1H, J=8.6 Hz), 7.71 (d, 1H, J=8.6 Hz), 3.98 (s, 3H).

Production Example 70

(345) A mixture of 1.20 g of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 1.2 g of methyl iodide, 1.2 g of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, a 1 M aqueous sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography to obtain a roughly-purified product. The roughly-purified product was recrystallized from methanol, thereby obtaining 574 mg of methyl 3-methoxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 127 of the present invention).

(346) Compound 127 of the Present Invention

(347) ##STR00117##

(348) .sup.1H-NMR (CDCl.sub.3) : 8.15 (s, 1H), 7.86 (d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz), 4.21 (s, 3H), 3.95 (s, 3H).

Production Example 71

(349) A mixture of 800 mg of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 631 mg of ethyl iodide, 801 mg of potassium carbonate, and 20 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. After the reaction mixture was cooled to room temperature, tert-butyl methyl ether was added thereto. The residue was washed with a 1 M aqueous sodium hydroxide solution, water, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure, thereby obtaining 480 mg of methyl 3-ethoxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 128 of the present invention).

(350) Compound 128 of the Present Invention

(351) ##STR00118##

(352) .sup.1H-NMR (CDCl.sub.3) : 8.13 (s, 1H), 7.87-7.85 (m, 1H), 7.69-7.67 (m, 1H), 4.45 (q, 2H, J=7.0 Hz), 3.93 (s, 3H), 1.50 (d, 3H, J=7.0 Hz).

Production Example 72

(353) A mixture of 812 mg of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 985 mg of isopropyl iodide, 802 mg of potassium carbonate, and 20 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure, thereby obtaining 766 mg of methyl 3-isopropoxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 129 of the present invention).

(354) Compound 129 of the Present Invention

(355) ##STR00119##

(356) .sup.1H-NMR (CDCl.sub.3) : 8.12 (s, 1H), 7.87-7.84 (m, 1H), 7.69-7.66 (m, 1H), 4.92-4.88 (m, 1H), 3.94 (s, 3H), 1.42-1.40 (m, 6H).

Production Example 73

(357) A mixture of 900 mg of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 790 mg of allyl bromide, 900 mg of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography to obtain a roughly purified product. The roughly-purified product was recrystallized from methanol, thereby obtaining 673 mg of methyl 3-allyloxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 130 of the present invention).

(358) Compound 130 of the Present Invention

(359) ##STR00120##

(360) .sup.1H-NMR (CDCl.sub.3) : 8.15-8.14 (m, 1H), 7.86 (d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz), 6.19-6.09 (m, 1H), 5.46-5.41 (m, 1H), 5.33-5.29 (m, 1H), 4.91-4.89 (m, 2H), 3.94 (s, 3H).

Production Example 74

(361) A mixture of 500 mg of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 378 mg of acetyl chloride, 377 mg of triethylamine, and 20 ml of tetrahydrofuran was stirred for 12 hours at room temperature. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and the residue was washed with water, 1 M hydrochloric acid, a 1 N aqueous saturated sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure, thereby obtaining 550 mg of methyl 3-acetyloxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 131 of the present invention)

(362) Compound 131 of the Present Invention

(363) ##STR00121##

(364) .sup.1H-NMR (CDCl.sub.3) : 7.99 (s, 1H), 7.93 (d, 1H, J=8.5 Hz), 7.72 (d, 1H, J=8.5 Hz), 3.93 (s, 3H), 2.50 (s, 3H).

Production Example 75

(365) A mixture of 1.51 g of methyl 3-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 1.86 g of benzyl bromide, 1.50 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred for 12 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, a 1 M aqueous sodium hydroxide solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 1.18 g of methyl 3-benzyloxy-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 132 of the present invention).

(366) Compound 132 of the Present Invention

(367) ##STR00122##

(368) .sup.1H-NMR (CDCl.sub.3) : 7.96 (s, 1H), 7.86-7.84 (m, 1H), 7.66-7.64 (m, 1H), 7.49-7.47 (m, 2H), 7.40-7.35 (m, 3H), 5.39 (s, 2H), 3.95 (s, 3H).

Production Example 76

(369) A mixture of 15.0 g of 2-chloro-5-trifluoromethylbenzonitrile, 7.10 g of methyl thioglycolate, 9.70 g of potassium carbonate, and 100 ml of N,N-dimethylformamide was stirred for 8 hours at 60 C. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 9.57 g of methyl 3-amino-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 133 of the present invention).

(370) Compound 133 of the Present Invention

(371) ##STR00123##

(372) .sup.1H-NMR (CDCl.sub.3) : 7.91 (s, H), 7.86-7.84 (m, 1H), 7.69-7.67 (m, 1H), 5.96 (br s, 2H), 3.91 (s, 3H).

Production Example 77

(373) A mixture of 1.50 g of methyl 3-amino-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 6.00 g of methyl iodide, 6.0 g of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 12 hours at 40 C. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water and saturated saline and dried over magnesium sulfate, followed by concentration under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 250 mg of methyl 3-(N-methylamino)-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 134 of the present invention).

(374) Compound 134 of the Present Invention

(375) ##STR00124##

(376) .sup.1H-NMR (CDCl.sub.3) : 9.44 (s, 1H), 7.83-7.81 (m, 1H), 7.64-7.62 (m, 1H), 3.68 (s, 3H), 3.49 (d, 1H, J=5.6 Hz), 3.46 (d, 3H, J=5.6 Hz).

Production Example 78

(377) A mixture of 1.50 g of methyl 3-amino-5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 6.00 g of methyl iodide, 6.0 g of potassium carbonate, and 15 ml of N,N-dimethylformamide was stirred for 12 hours at 40 C. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 141 mg of methyl 3-(N,N-dimethylamino)-5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 135 of the present invention).

(378) Compound 135 of the Present Invention

(379) ##STR00125##

(380) .sup.1H-NMR (CDCl.sub.3) : 8.19 (s, 1H), 7.84-7.82 (m, 1H), 7.64-7.63 (m, 1H), 3.91 (s, 3H), 3.14 (s, 6H).

Production Example 79

(381) A mixture of 961 mg of acetyl anhydride and 533 mg of formic acid was stirred for 2 hours at 60 C. The reaction mixture was cooled to room temperature, and then 10 ml of tetrahydrofuran was added thereto. A mixture of 1.00 g of methyl 3-amino-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate and 10 ml of tetrahydrofuran was added dropwise to the reaction mixture under ice cooling. The reaction mixture was stirred for 6 hours under reflux. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residues were recrystallized from ethyl acetate, thereby obtaining 940 mg of methyl 3-formylamino-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 136 of the present invention).

(382) Compound 136 of the Present Invention

(383) ##STR00126##

(384) .sup.1H-NMR (DMSO-D.sub.6) : 10.60 (br s, 1H), 8.45 (s, 1H), 8.32-8.30 (m, 2H), 7.90-7.88 (m, 1H), 3.87 (s, 3H).

Production Example 80

(385) A mixture of 435 mg of methyl 3-amino-5-(trifluoromethyl)-benzo[b]thiophene-2-carboxylate, 371 mg of acetyl chloride, 460 mg of triethylamine, and 30 ml of tetrahydrofuran was stirred for 12 hours under reflux. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the residues, and the residue was washed with 1 M hydrochloric acid, a 1 N aqueous saturated sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 105 mg of methyl 3-(acetylamino)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 137 of the present invention)

(386) Compound 137 of the Present Invention

(387) ##STR00127##

(388) .sup.1H-NMR (CDCl.sub.3) : 9.56 (br s, 1H), 8.44 (s, 1H), 7.87 (d, 1H, J=8.3 Hz), 7.68 (d, 1H, J=8.3 Hz), 3.97 (s, 3H), 2.36 (s, 3H).

Production Example 81

(389) A mixture of 500 mg of methyl 3-amino-5-(trifluoromethyl)-benzo[b]thiophene-2-carboxylate, 763 mg of trifluoroacetic anhydride, 377 mg of potassium carbonate, and 20 ml of N,N-dimethylformamide was stirred for 24 hours at room temperature. Tert-butyl methyl ether was added to the reaction mixture, and the residue was washed with water, 1 M hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 201 mg of methyl 3-(trifluoroacetylamino)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 138 of the present invention).

(390) Compound 138 of the Present Invention

(391) ##STR00128##

(392) .sup.1H-NMR (CDCl.sub.3) : 10.72 (br s, 1H), 8.50-8.48 (m, 1H), 7.95-7.93 (m, 1H), 7.76-7.74 (m, 1H), 4.02 (s, 3H).

Production Example 82

(393) A mixture of 200 mg of methyl 5-iodobenzo[b]thiophene-2-carboxylate, 2.79 g of 1-iodoheptafluoropropane, 600 mg of copper (0), and 20 ml of N,N-dimethylformamide was stirred for 8 hours at 150 C. under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, tert-butyl methyl ether and an aqueous saturated ammonia solution were added thereto, and filtration was performed using Celite. The filtrate was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 140 mg of methyl 3,5-(bisheptafluoropropyl)benzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 139 of the present invention).

(394) Compound 139 of the Present Invention

(395) ##STR00129##

(396) .sup.1H-NMR (CDCl.sub.3) : 8.25 (s, 1H), 8.03 (d, 1H, J=8.5 Hz), 7.71 (d, 1H, J=8.5 Hz), 3.99 (s, 3H).

Production Example 84

(397) Step 1

(398) One point one five (1.15) ml of oxalyl chloride and 47.2 l of N,N-dimethylformamide were added to a mixture of 3.00 g of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid and 15 ml of dichloromethane at room temperature, followed by stirring for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, thereby obtaining 3.18 g of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride.

(399) ##STR00130##

(400) Step 2

(401) 5-Trifluoromethylbenzo[b]thiophene-2-carbonyl chloride 325 mg was added to 2 ml of 1-propanol at room temperature, followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography, thereby obtaining 336 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid-1-propyl ester (hereinafter, described as a compound 144 of the present invention).

(402) Compound 144 of the Present Invention

(403) ##STR00131##

(404) .sup.1H-NMR (CDCl.sub.3) : 8.16 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H, J=8.3 Hz), 7.67 (d, 1H, J=8.3 Hz), 4.34-4.33 (m, 2H), 1.83-1.82 (m, 2H), 1.06-1.04 (m, 3H).

Production Example 85

(405) Oxalyl chloride 254 mg was added to a mixture of 400 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid and 20 ml of 2-propanol under ice cooling. The mixture was stirred for 24 hours under reflux. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residues, and the organic layer was washed with a 1 M aqueous sodium hydroxide solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 217 mg of isopropyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 145 of the present invention).

(406) Compound 145 of the Present Invention

(407) ##STR00132##

(408) .sup.1H-NMR (CDCl.sub.3) : 8.14 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 5.28 (m, 1H), 1.41 (m, 6H).

Production Example 86

(409) 5-Trifluoromethylbenzo[b]thiophene-2-carbonyl chloride 325 mg was added to 2 ml of 1-butanol at room temperature, followed by stirring for 1.5 hours. The mixture was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography, thereby obtaining 349 mg of butyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 146 of the present invention).

(410) Compound 146 of the Present Invention

(411) ##STR00133##

(412) .sup.1H-NMR (CDCl.sub.3, : 8.16 (s, 1H), 8.11 (s, 1H), 7.97 (d, 1H, J=8.6 Hz), 7.66 (d, 1H, J=8.6 Hz), 4.39-4.37 (m, 2H), 1.79-1.75 (m, 2H), 1.52-1.48 (m, 2H), 1.01-0.99 (m, 3H).

Production Example 87

(413) 5-Trifluoromethylbenzo[b]thiophene-2-carbonyl chloride 325 mg was added to 2 ml of n-amyl alcohol at room temperature, followed by stirring for 67 hours. The mixture was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography, thereby obtaining 380 mg of pentyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 147 of the present invention).

(414) Compound 147 of the Present Invention

(415) ##STR00134##

(416) .sup.1H-NMR (CDCl.sub.3) : 8.16 (s, 1H), 8.11 (s, 1H), 7.98 (d, 1H, J=8.6 Hz), 7.67 (d, 1H, J=8.6 Hz), 4.37-4.36 (m, 2H), 1.81-1.77 (m, 2H), 1.45-1.41 (m, 4H), 0.96-0.93 (m, 3H).

Production Example 88

(417) 5-Trifluoromethylbenzo[b]thiophene-2-carbonyl chloride 325 mg was added to 2 ml of propargyl alcohol at room temperature, followed by stirring for 67 hours. The mixture was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography, thereby obtaining 173 mg of propargyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 148 of the present invention).

(418) Compound 148 of the Present Invention

(419) ##STR00135##

(420) .sup.1H-NMR (CDCl.sub.3) : 8.18-8.17 (m, 2H), 7.99 (d, 1H, J=8.6 Hz), 7.69 (d, 1H, J=8.6 Hz), 4.97 (d, 2H, J=2.5 Hz), 2.57 (t, 1H, J=2.5 Hz).

Production Example 89

(421) A mixture of 325 mg of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride and 0.5 ml of dichloromethane was added dropwise to a mixture of 0.5 ml of ethylene glycol, 369 l of triethylamine, and 0.5 ml of dichloromethane at 0 C. The reaction mixture was stirred for 6.5 hours at room temperature. Ethyl acetate was added to the mixture, and insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography, thereby obtaining 279 mg of (2-hydroxyethyl) 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 149 of the present invention).

(422) Compound 149 of the Present Invention

(423) ##STR00136##

(424) .sup.1H-NMR (CDCl.sub.3) : 8.18-8.15 (m, 2H), 7.99 (d, 1H, J=8.6 Hz), 7.69 (d, 1H, J=8.6 Hz), 4.53-4.51 (m, 2H), 4.02-3.98 (m, 2H), 1.94-1.92 (m, 1H).

Production Example 90

(425) A mixture of 5.02 g of 2-fluoro-5-(trifluoromethyl)benzaldehyde, 5.00 g of benzyl mercaptoacetate, 4.69 g of potassium carbonate, and 20 ml of N,N-dimethylformamide was stirred for 2 hours at 60 C. The reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 6.54 g of benzyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 150 of the present invention).

(426) Compound 150 of the Present Invention

(427) ##STR00137##

(428) .sup.1H-NMR (CDCl.sub.3) : 8.16-8.15 (m, 2H), 7.99-7.96 (m, 1H), 7.68-7.66 (m, 1H), 7.48-7.46 (m, 2H), 7.44-7.35 (m, 3H), 5.41 (s, 2H).

Production Example 91

(429) A mixture of 300 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 257 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride, 14.9 mg of N,N-dimethyl-4-aminopyridine, 156 mg of 4-chlorobenzyl alcohol, and 20 ml of tetrahydrofuran was stirred for 12 hours under reflux. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residues. The collected organic layer was washed with 1 M hydrochloric acid and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 291 mg of (4-chlorobenzyl) 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 151 of the present invention).

(430) Compound 151 of the Present Invention

(431) ##STR00138##

(432) .sup.1H-NMR (DMSO-D.sub.6) : 8.49 (s, 1H), 8.41 (s, 1H), 8.35 (d, 1H, J=8.5 Hz), 7.84 (d, 1H, J=8.5 Hz), 7.51 (m, 4H), 5.41 (s, 2H).

Production Example 92

(433) A mixture of 325 mg of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride, 131 mg of methyl glycolate, 369 l of triethylamine, and 2 ml of tetrahydrofuran was stirred for 6.5 hours at room temperature. The mixture was concentrated under reduced pressure, hexane was added to the obtained residues, and insoluble matter was collected by filtration and then washed with water and hexane. The collected substance was dried under reduced pressure, thereby obtaining 229 mg of methoxycarbonylmethyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate (hereinafter, described as a compound 152 of the present invention).

(434) Compound 152 of the Present Invention

(435) ##STR00139##

(436) .sup.1H-NMR (CDCl.sub.3) : 8.22 (s, 1H), 8.18 (s, 1H), 8.00 (d, 1H, J=8.6 Hz), 7.69 (d, 1H, J=8.6 Hz), 4.90 (s, 2H), 3.82 (s, 3H).

Production Example 93

(437) A mixture of 325 mg of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride and 1.5 ml of dichloromethane was added dropwise to a mixture of 106 mg of acetoxime, 369 l of triethylamine, and 2 ml of dichloromethane at 0 C. The reaction mixture was stirred for 6.5 hours at room temperature. The mixture was concentrated under reduced pressure, ethyl acetate was added to the residues, and insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, hexane was added to the obtained residues, and insoluble matter was collected by filtration. The collected substance was washed with water and hexane and then dried under reduced pressure, thereby obtaining 325 mg of O-[(5-trifluoromethylbenzo[b]thiophen-2-yl)carbonyl]acetoxime (hereinafter, described as a compound 153 of the present invention).

(438) Compound 153 of the Present Invention

(439) ##STR00140##

(440) .sup.1H-NMR (CDCl.sub.3) : 8.22 (s, 1H), 8.18 (s, 1H), 7.99 (d, 1H, J=6.6 Hz), 7.69 (d, 1H, J=8.6 Hz), 2.17 (s, 3H), 2.15 (s, 3H).

Production Example 94

(441) Oxalyl chloride 515 mg was added to a mixture of 500 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid and 10 ml of tetrahydrofuran under ice cooling. The mixture was stirred for 3 hours under reflux. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Ten (10) ml of tetrahydrofuran was added to the residues, and then 1 ml of saturated aqueous ammonia was added thereto, followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residues, and extraction was performed using ethyl acetate. The collected organic layer was washed with a 1 M aqueous sodium hydroxide solution and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure, thereby obtaining 235 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 154 of the present invention).

(442) ##STR00141##

(443) Compound 154 of the Present Invention

(444) .sup.1H-NMR (DMSO-D.sub.6) : 8.64-8.61 (m, 1H), 8.25-8.23 (m, 1H), 8.17-8.13 (m, 1H), 8.03-7.99 (m, 1H).

Production Example 95

(445) A mixture of 150 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 117 mg of i-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2.8 ml of methylamine (2 M tetrahydrofuran solution), 7.5 mg of N,N-dimethyl-4-aminopyridine, and 10 ml of tetrahydrofuran was stirred for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and chloroform and water were added to the residues. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, 1 M hydrochloric acid, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 100 mg of N-methyl-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 155 of the present invention).

(446) Compound 155 of the Present Invention

(447) ##STR00142##

(448) .sup.1H-NMR (CDCl.sub.3) : 8.10 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 3.06 (m, 3H).

Production Example 96

(449) A mixture of 325 mg of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride and 1 ml of dichloromethane was added dropwise to a mixture of 61 mg of cyanamide, 369 l of triethylamine, and 1 ml of dichloromethane at 0 C. The reaction mixture was stirred for 6 hours at room temperature. The mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residues, and insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the obtained residues were subjected to silica gel column chromatography to obtain a roughly-purified product. Ethyl acetate was added to the obtained roughly-purified product, and the residue was washed with an aqueous saturated ammonium chloride solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residues were washed with chloroform and hexane and then dried under reduced pressure, thereby obtaining 172 mg of N-cyano-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 156 of the present invention).

(450) Compound 156 of the Present Invention

(451) ##STR00143##

(452) .sup.1H-NMR (Methanol-D.sub.4) : 8.19 (s, 1H), 6.04 (d, 1H, J=8.6 Hz), 7.99 (s, 1H), 7.62 (d, 1H, J=8.6 Hz).

Production Example 97

(453) A mixture of 300 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 257 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 14.9 mg of N,N-dimethyl-4-aminopyridine, 170 mg of aniline, and 20 ml of tetrahydrofuran was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residues. The organic layer was washed with a M aqueous sodium hydroxide solution, 1 M hydrochloric acid, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from tert-butyl methyl ether, thereby obtaining 317 mg of N-phenyl-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 157 of the present invention).

(454) ##STR00144##

(455) Compound 157 of the Present Invention

(456) .sup.1H-NMR (DMSO-D.sub.6) : 10.70 (br s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.33 (m, 1H), 7.79 (m, 2H), 7.77 (m, 1H), 7.40 (m, 2H), 7.15 (m, 1H).

Production Example 98

(457) A mixture of 300 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 257 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 14.9 mg of N,N-dimethyl-4-aminopyridine, 259 me of 4-amino-2-chlorotoluene, and 20 ml of tetrahydrofuran was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residues. The organic layer was washed with a 1 M aqueous sodium hydroxide solution, 1 M hydrochloric acid, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from tert-butyl methyl ether, thereby obtaining 270 mg of N-(3-chloro-4-methylphenyl)-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 158 of the present invention).

(458) ##STR00145##

(459) Compound 158 of the Present Invention

(460) .sup.1H-NMR (DMSO-D.sub.6) : 10.77 (br s, 1H), 8.47 (s, 1H), 8.46 (s, 1H), 8.34 (d, 1H, J=8.5 Hz), 7.93 (m, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.61 (m, 1H), 7.36 (m, 1H), 2.32 (s, 3H).

Production Example 99

(461) A mixture of 300 mg of 5-trifluoromethylbenzo[b]thiophene-2-carboxylic acid, 257 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 14.9 mg of N,N-dimethyl-4-aminopyridine, 280 mg of 2,4-dimethoxyaniline, and 20 ml of tetrahydrofuran was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residues. The organic layer was washed with a 1 M aqueous sodium hydroxide solution, 1 M hydrochloric acid, and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 125 mg of N-(2,4-dimethoxyphenyl)-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 159 of the present invention).

(462) Compound 159 of the Present Invention

(463) ##STR00146##

(464) .sup.1H-NMR (DMSO-D.sub.6) : 9.92 (br, 1H), 8.42 (m, 2H), 8.31 (d, 1H, J=8.7 Hz), 7.78 (d, 1H, J=8.7 Hz), 7.44 (m, 1H), 6.68 (s, 1H), 6.56 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H).

Production Example 100

(465) A mixture of 1.00 g of methyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 803 mg of hydroxylamine hydrochloride, 276 mg of triethylamine, and 15 ml of methanol was stirred for 12 hours under reflux. The reaction mixture was concentrated under reduced pressure, and tert-butyl methyl ether was added to the residues. The organic layer was washed with 1 M hydrochloric acid and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 217 mg of N-hydroxy-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 160 of the present invention).

(466) Compound 160 of the Present Invention

(467) ##STR00147##

(468) .sup.1H-NMR (DMSO-D.sub.6) : 11.66 (br s, 1H), 9.37 (br s, 1H), 8.39 (s, 1H), 8.29 (d, 1H, J=8.5 Hz), 8.06 (s, 1H), 7.75 (d, 1H, J=8.5 Hz).

Production Example 101

(469) A mixture of 1.00 g of methyl 5-trifluoromethylbenzo[b]thiophene-2-carboxylate, 772 mg of hydrazine monohydrate, and 15 ml of ethanol was stirred for 12 hours under reflux. The reaction mixture was concentrated under reduced pressure, and tert-butyl methyl ether was added to the residues. The organic layer was washed with 1 M hydrochloric acid and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were recrystallized from tert-butyl methyl ether and ethanol, thereby obtaining 595 mg of N-amino-5-trifluoromethylbenzo[b]thiophene-2-carboxamide (hereinafter, described as a compound 161 of the present invention).

(470) Compound 161 of the Present Invention

(471) ##STR00148##

(472) .sup.1H-NMR (DMSO-D.sub.6) : 10.21 (br s, 1H), 8.37 (s, 1H), 8.33-8.28 (m, 1H), 9.14 (s, 1H), 7.76-7.73 (m, 1H), 4.62 (br s, 2H).

Production Example 102

(473) A mixture of 325 mg of 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride and 2 ml of dichloromethane was added dropwise to a mixture of 106 mg of sodium methyl mercaptan and 1 ml of dichloromethane at 0 C. The reaction mixture was stirred for 3.5 hours at 0 C. The mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residues, and insoluble matter was separated by filtration. The filtrate was concentrated, and the residues were subjected to silica gel column chromatography, thereby obtaining 242 mg of S-methyl 5-trifluoromethylbenzo[b]thiophene-2-carbothioate (hereinafter, described as a compound 162 of the present invention).

(474) Compound 162 of the Present Invention

(475) ##STR00149##

(476) .sup.1H-NMR (CDCl.sub.3), : 8.17 (s, 1H), 8.11 (s, 1H), 7.99 (d, 1H, J=8.6 Hz), 7.68 (d, 1H, J=8.6 Hz), 2.55 (s, 3H).

Production Example 103

(477) A mixture of 325 mg 5-trifluoromethylbenzo[b]thiophene-2-carbonyl chloride, 154 mg of methyl thioglycolate, 369 l of triethylamine, and 2 ml of tetrahydrofuran was stirred for 4.5 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residues were washed with hexane, thereby obtaining 389 mg of S-methoxycarbonylmethyl 5-trifluoromethylbenzo[b]thiophene-2-carbothioate (hereinafter, described as a compound 163 of the present invention).

(478) Compound 163 of the Present Invention

(479) ##STR00150##

(480) .sup.1H-NMR (CDCl.sub.3) : 8.19 (s, 1H), 8.16 (s, 1H), 8.00 (d, 1H, J=8.3 Hz), 7.70 (d, 1H, J=8.3 Hz), 3.95 (s, 2H), 3.80 (s, 3H).

(481) ##STR00151##

(482) Specific examples of the compounds of the present invention include the compounds (compounds 1 to 163 of the present invention) represented by Formula (1) wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 form a combination of groups shown in Tables 1 to 7.

(483) In the following tables, Me represents a methyl group, Et represents a ethyl group, nPr represents a propyl group, iPr represents an isopropyl group, nBu represents a butyl group, tBu represents a tert-butyl group, Ph represents a phenyl group, and Bn represents a benzyl group.

(484) TABLE-US-00001 TABLE 1 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 1 H H H H H MeO 68.1 C. 2 F H H H H MeO 95.6 C. 3 H F H H H MeO * 4 H H F H H MeO 91.5 C. 5 H H H B H MeO 84.0 C. 6 Cl H H H B MeO 89.4 C. 7 H Cl H H H MeO 8 H H Cl H H MeO 100.8 C. 9 H H H Cl H MeO 82.1 C. 10 H H H H Cl MeO * 11 Br H H H H MeO * 12 H Br H H H MeO * 13 H H Br H H MeO * 14 H H H Br H MeO * 15 I H H H H MeO * 16 H I H H H MeO * 17 H CN H H H MeO * 18 NO.sub.2 H H H H MeO * 19 H NO.sub.2 H H H MeO * 20 H H NO.sub.2 H H MeO * 21 H H H H NO.sub.2 MeO 104.8 C. 22 Me H H H H MeO 23 H Me H H H MeO 24 H H Me H H MeO * 25 H H H Me H MeO

(485) TABLE-US-00002 TABLE 2 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 26 H H H H Me MeO 103.1 C. 27 H t Bu H H H MeO 28 H H H H CF.sub.3 MeO 29 C.sub.2F.sub.5 H H H H MeO 30 H C.sub.2F.sub.5 H H H MeO 31 H C.sub.3F.sub.7 H H H MeO 32 H H H.sub.2CCH H H MeO 33 H H HCC H H MeO 34 Ph H H H H MeO 35 H Ph H H H MeO 36 H H Ph H H MeO 37 H H H Ph H MeO 38 H H H H Ph MeO 39 H (2-Cl)Ph H H H MeO 40 H (3-Cl)Ph H H H MeO 41 H (4-Cl)Ph H H H MeO 42 H H H (3-Me)Ph H MeO 43 H (4-CF.sub.3)Ph H H H MeO 44 H H H (2-MeO)Ph H MeO 45 H H (4-CF.sub.3O)Ph H H MeO 46 H 2-pyridyl H H H MeO 47 H 3-pyridyl H H H MeO 48 H 4-pyridyl H H H MeO 49 H H 6-(trifluoromethyl)-3-pyridyl- H H MeO 50 H 2-pyrimidinyl- H H H MeO

(486) TABLE-US-00003 TABLE 3 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 51 H H H H 1-pyrrolyl- MeO 114.4 C. 52 2-thienyl- H H H H MeO 53 H 2-thienyl- H H H MeO 54 H MeC(O) H H H MeO 55 H CF.sub.3C(O) H H H MeO 56 H PhC(O) H H H MeO 57 MeOC(O) H H H H MeO 58 H MeOC(O) H H H MeO 59 H H MeOC(O) H H MeO * 60 H H H H MeOC(O) MeO 61 H NH.sub.2C(O) H H H MeO 62 NH.sub.2 H H H H MeO * 63 H NH.sub.2 H H H MeO * 64 H H NH.sub.2 H H MeO * 65 H H H H NH.sub.2 MeO * 66 Me.sub.2N H H H H MeO 67 H MeC(O)NH H H H MeO 66 H PhC(O)NH H H H MeO 69 H H H H HC(O)NH MeO 70 H H H H MeC(O)NH MeO 71 H CF.sub.3C(O)NH H H H MeO 72 H ClCH.sub.2C(O)NH.sub.2 H H H MeO 73 H H H H PhC(O)NH MeO 146.1 C. 74 H H H H [(3-methyl-5- MeO 208.0 C. isoxazolyl) (decomp.) carbonyl]amino- 75 H H H H [(1-methyl-1H- MeO 191.6 C. pyrazol-3yl) carbonyl]amino-

(487) TABLE-US-00004 TABLE 4 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 76 H H H H [(1,4-dimethyl-1H-pyrazol- MeO 201.9 C. 5-yl)carbonyl]amino- (decomp.) 77 H H H H [(1,5-dimethyl-1H-pyrazol- MeO 157.7 C. 3-yl)carbonyl]amino- 78 H (2-thienyl) H H H MeO 217.6 C. C(O)NH 79 H H H H [3-(2.5-dichlorothienyl)] MeO 169.9 C. C(O)NH 80 H H H H [2-(5-Bromothienyl)]C(O)NH MeO 136.3 C. 81 H MeSO.sub.2NH H H H MeO 82 H BnSO.sub.2NH H H H MeO 156.1 C. 83 H CF.sub.3SO.sub.2NH H H H MeO 84 H (4-ClPh)SO.sub.2NH H H H MeO * 85 H (4-MePh)SO.sub.2NH H H H MeO * 86 H OH H H H MeO * 87 H H OH H H MeO * 88 H H H OH H MeO * 89 H H H H OH MeO * 90 MeO H H H H MeO * 91 H MeO H H H MeO * 92 H H MeO H H MeO * 93 H H H MeO H MeO * 94 H H H H MeO MeO 95 H H H H EtO MeO 96 H H H H iPrO MeO 97 H H H H BnO MeO 98 H CF.sub.3O H H H MeO 99 H H HCCCH.sub.2O H H MeO 100 H H (4-CF.sub.3Bn)O H H MeO

(488) TABLE-US-00005 TABLE 5 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 101 H H (3-MeOBn)O H H MeO 102 H H H (2-Me)PhO H MeO 103 H H H (4-CF.sub.3)PhO H MeO 104 H H H (4-CF.sub.3O)PhO H MeO 105 H H H H MeC(O)O MeO 106 H H H H (2-ClPh)C(O)O MeO 150.6 C. 107 H H H H (4-MePh)S(O).sub.2O MeO 154.9 C. 108 H MeS H H H MeO 109 H CF.sub.3S H H H MeO 110 H CF.sub.3S(O) H H H MeO 111 H CF.sub.3S(O).sub.2 H H H MeO 112 H H H H MeNHS(O).sub.2 MeO 186.5 C. (decomp.) 113 H H H H (4-MePh)CH.sub.2NHS(O).sub.2 MeO 109.5 C. (decomp.) 114 H H H H (3-ClPH)CH.sub.2NHS(O).sub.2 MeO * 115 H H H H [(2-pyridinylmethyl) MeO 146.2 C. amino]sulfonyl- (decomp.) 116 H H H H (4-MePh)NHS(O).sub.2 MeO 161.2 C. (decomp.) 117 H SF.sub.5 H H H MeO 118 Cl Cl H H H MeO 119 Cl H H H NH.sub.2 MeO * 120 H H [{1-(difluoromethyl)- H Cl MeO 227.4 C. 1H-pyrazol-3-yl-} (decomp.) carbonyl]amino- 121 H NO.sub.2 H H OH MeO * 122 H CF.sub.3 H Cl H MeO 123 H CF.sub.3 H H Cl MeO

(489) TABLE-US-00006 TABLE 6 Compound of the present Melting invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W point 124 H CF.sub.3 H H Me MeO 125 H CF.sub.3 H H CF.sub.3 MeO 126 H CF.sub.3 H H OH MeO 127 H CF.sub.3 H H MeO MeO 128 H CF.sub.3 H H EtO MeO 129 H CF.sub.3 H H iPrO MeO 130 H CF.sub.3 H H H.sub.2CCHCH.sub.2O MeO 131 H CF.sub.3 H H MeC(O)O MeO 132 H CF.sub.3 H H BnO MeO 133 H CF.sub.3 H H NH.sub.2 MeO 134 H CF.sub.3 H H MeNH MeO 135 H CF.sub.3 H H Me.sub.2N MeO 136 H CF.sub.3 H H HC(O)NH MeO 137 H CF.sub.3 H H MeC(O)NH MeO 138 H CF.sub.3 H H CF.sub.3C(O)NH MeO 139 H C.sub.3F.sub.7 H H C.sub.3F.sub.7 MeO 140 H H CF.sub.3 H NH.sub.2 MeO 125.3 C. 141 H (2-ClPh) H H MeO MeO 235.3 C. NHC(O)NH (decomp.) 142 CF.sub.3 H H H H EtO 50.8 C. 144 H CF.sub.3 H H H nPrO 145 H CF.sub.3 H H H iPrO 146 H CF.sub.3 H H H nBuO 147 H CF.sub.3 H H H nC.sub.5H.sub.11O 148 H CF.sub.3 H H H HCCCH.sub.2O 149 H CF.sub.3 H H H HOCH.sub.2CH.sub.2O 150 H CF.sub.3 H H H BnO

(490) TABLE-US-00007 TABLE 7 Compound of the present invention R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W 151 H CF.sub.3 H H H (4-ClBn)O 152 H CF.sub.3 H H H MeOC(O)CH.sub.2O 153 H CF.sub.3 H H H Me.sub.2C=NO 154 H CF.sub.3 H H H NH.sub.2 155 H CF.sub.3 H H H MeNH 156 H CF.sub.3 H H H (NC)NH 157 H CF.sub.3 H H H PhNH 158 H CF.sub.3 H H H (3-Cl-4-MePh)NH 159 H CF.sub.3 H H H (2,4-diMeOPh)NH 160 H CF.sub.3 H H H HCNH 161 H CF.sub.3 H H H NH.sub.2NH 162 H CF.sub.3 H H H MeS 163 H CF.sub.3 H H H MeOC(O)CH.sub.2S

(491) Regarding compounds marked with * in the column of a melting point in Tables 1 to 7, .sup.1H-NMR data thereof are shown below.

(492) Compound 3 of the Present Invention

(493) ##STR00152##

(494) .sup.1H-NMR (CDCl.sub.3) : 8.01 (s, 1H), 7.81-7.79 (m, 1H), 7.54-7.52 (m, 1H), 7.24-7.22 (m, 1H), 3.95 (s, 3H)

(495) Compound 10 of the Present Invention

(496) ##STR00153##

(497) .sup.1H-NMR (CDCl.sub.3) : 8.00-7.97 (m, 1H), 7.84-7.82 (m, 1H), 7.56-7.48 (m, 2H), 3.97 (s, 3H)

(498) Compound 11 of the Present Invention

(499) ##STR00154##

(500) .sup.1H-NMR (CDCl.sub.3) : 8.19 (s, 1H), 7.80-7.78 (m, 1H), 7.59-7.57 (m, 1H), 7.31-7.29 (m, 1H), 3.97 (s, 3H)

(501) Compound 12 of the Present Invention

(502) ##STR00155##

(503) .sup.1H-NMR (CDCl.sub.3) : 8.03 (s, 1H), 7.98 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.55 (d, 1H, J=8.7 Hz), 3.96 (s, 3H)

(504) Compound 13 of the Present Invention

(505) ##STR00156##

(506) .sup.1H-NMR (CDCl.sub.3) : 8.02-8.01 (m, 2H), 7.74-7.72 (m, 1H), 7.52-7.50 (m, 1H), 3.95 (s, 3H)

(507) Compound 14 of the Present Invention

(508) ##STR00157##

(509) .sup.1H-NMR (CDCl.sub.3) : 8.15 (s, 1H), 7.85-7.83 (m, 1H), 7.62-7.60 (m, 1H), 7.31-7.29 (m, 1H), 3.96 (s, 3H)

(510) Compound 15 of the Present Invention

(511) ##STR00158##

(512) .sup.1H-NMR (CDCl.sub.3) : 8.12-8.11 (m, 1H), 7.83-7.81 (m, 2H), 7.16-7.14 (m, 1H), 3.96 (s, 3H)

(513) Compound 16 of the Present Invention

(514) ##STR00159##

(515) .sup.1H-NMR (CDCl.sub.3) : 8.23 (d, 1H, J=_0.5 Hz), 7.96 (s, 1H), 7.71 (dd, 1H, J=8.6, 1.5 Hz), 7.61 (d, 1H, J=8.6 Hz), 3.95 (s, 3H)

(516) Compound 17 of the Present Invention

(517) ##STR00160##

(518) .sup.1H-NMR (CDCl.sub.3) : 8.22 (s, 1H), 8.10 (s, 1H), 7.98 (d, 1H, J=8.3 Hz), 7.66 (d, 1H, J=8.3 Hz), 3.98 (s, 3H)

(519) Compound 18 of the Present Invention

(520) ##STR00161##

(521) .sup.1H-NMR (CDCl.sub.3) : 8.88 (s, 1H), 8.39 (d, 1H, J=8.1 Hz), 8.19 (d, 1H, J=8.1 Hz), 7.61 (t, 1H, J=8.1 Hz), 4.01 (s, 3H)

(522) Compound 19 of the Present Invention

(523) ##STR00162##

(524) .sup.1H-NMR (DMSO-D.sub.6) : 9.01-9.00 (m, 1H), 8.46 (s, 1H), 8.37-8.32 (m, 2H), 3.93 (s, 3H)

(525) Compound 20 of the Present Invention

(526) ##STR00163##

(527) .sup.1H-NMR (CDCl.sub.3) : 8.82-8.80 (m, 1H), 8.28-8.25 (m, 1H), 8.14 (s, 1H), 8.02-7.99 (m, 1H), 3.99 (s, 3H)

(528) Compound 24 of the Present Invention

(529) ##STR00164##

(530) .sup.1H-NMR (CDCl.sub.3) : 8.01 (s, 1H), 7.76 (d, 1H, J=8.3 Hz), 7.66 (s, 1H), 7.23 (d, 1H, J=8.3 Hz), 3.94 (s, 3H), 2.49 (s, 3H)

(531) Compound 59 of the Present Invention

(532) ##STR00165##

(533) .sup.1H-NMR (CDCl.sub.3) : 8.60-8.58 (m, 1H), 8.10-8.08 (m, 1H), 8.07-8.05 (m, 1H), 7.93-7.91 (m, 1H), 3.98 (s, 3H), 3.97 (s, 3H)

(534) Compound 62 of the Present Invention

(535) ##STR00166##

(536) .sup.1H-NMR (CDCl.sub.3) : 8.05 (s, 1H), 7.26-7.25 (m, 2H), 6.63-6.62 (m, 1H), 4.17 (br s, 2H), 3.94 (s, 3H)

(537) Compound 63 of the Present Invention

(538) ##STR00167##

(539) .sup.1H-NMR (DMSO-D.sub.6) : 7.92 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.05 (d, 1H, J=2.2 Hz), 6.89 (dd, 1H, J=8.8, 2.2 Hz), 5.28 (br s, 2H), 3.85 (s, 3H)

(540) Compound 64 of the Present Invention

(541) ##STR00168##

(542) .sup.1H-NMR (CDCl.sub.3) : 7.91 (s, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.06 (d, 1H, J=2.3 Hz), 6.77 (dd, 1H, J=8.6, 2.3 Hz), 3.94 (hr s, 2H), 3.90 (s, 3H)

(543) Compound 65 of the Present Invention

(544) ##STR00169##

(545) .sup.1H-NMR (CDCl.sub.3), : 7.74-7.72 (m, 1H), 7.65-7.63 (m, 1H), 7.49-7.46 (m, 1H), 7.38-7.36 (m, 1H), 5.91 (s, 2H), 3.89 (s, 3H)

(546) Compound 84 of the Present Invention

(547) ##STR00170##

(548) .sup.1H-NMR (DMSO-D.sub.6) : 10.54 (br s, 1H), 8.17 (s, 1H), 7.96-7.93 (m, 1H), 7.77-7.74 (m, 3H), 7.62-7.60 (m, 2H), 7.25-7.23 (m, 1H), 3.87 (s, 3H)

(549) Compound 85 of the Present Invention

(550) ##STR00171##

(551) .sup.1H-NMR (DMSO-D.sub.6) : 10.40 (br s, 1H), 8.15 (s, 1H), 7.91 (d, 1H, J=8.8 Hz), 7.74 (d, 1H, J=2.3 Hz), 7.66 (d, 2H, J=8.3 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.25 (dd, 1H, J=8.8, 2.3 Hz), 3.87 (s, 3H), 2.30 (s, 3H)

(552) Compound 86 of the Present Invention

(553) ##STR00172##

(554) .sup.1H-NMR (CDCl.sub.3) : 7.94 (s, 1H), 7.71 (d, 1H, J=8.8 Hz), 7.28 (d, 1H, J=2.5 Hz), 7.05 (dd, 1H, J=8.8, 2.5 Hz), 5.02 (br s, 1H), 3.94 (s, 3H)

(555) Compound 87 of the Present Invention

(556) ##STR00173##

(557) .sup.1H-NMR (CDCl.sub.3) : 7.97 (s, 1H), 7.75-7.73 (m, 1H), 7.28-7.27 (m, 1H), 6.97-6.95 (m, 1H), 5.33 (s, 1H), 3.93 (s, 3H)

(558) Compound 88 of the Present Invention

(559) ##STR00174##

(560) .sup.1H-NMR (CDCl.sub.3) : 8.06 (s, 1H), 7.50 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=7.8 Hz), 6.85 (d, 1H, J=7.8 Hz), 5.54 (s, 1H), 3.96 (s, 3H)

(561) Compound 89 of the Present Invention

(562) ##STR00175##

(563) .sup.1H-NMR (CDCl.sub.3) : 10.13 (br s, 1H), 7.96-7.94 (m, 1H), 7.75-7.74 (m, 1H), 7.53-7.49 (m, 1H), 7.42-7.40 (m, 1H), 3.96 (s, 3H)

(564) Compound 90 of the Present Invention

(565) ##STR00176##

(566) .sup.1H-NMR (CDCl.sub.3) : 8.24-8.23 (m, 1H), 7.41-7.38 (m, 2H), 6.76-6.74 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H)

(567) Compound 91 of the Present Invention

(568) ##STR00177##

(569) .sup.1H-NMR (CDCl.sub.3) : 7.99 (s, 1H), 7.73-7.71 (m, 1H), 7.29-7.28 (m, 1H), 7.13-7.11 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H)

(570) Compound 92 of the Present Invention

(571) ##STR00178##

(572) .sup.1H-NMR (CDCl.sub.3) : 7.97 (s, 1H), 7.74 (d, 1H, J=6.8 Hz), 7.29 (d, 1H, J=2.3 Hz), 7.02 (dd, 1H, J=8.8, 2.3 Hz), 3.93 (s, 3H), 3.89 (s, 3H)

(573) Compound 93 of the Present Invention

(574) ##STR00179##

(575) .sup.1H-NMR (CDCl.sub.3) : 8.05 (s, 1H), 7.48 (d, 1H, J=7.8 Hz), 7.35 (t, 1H, J=7.8 Hz), 6.86 (d, 1H, J=7.8 Hz), 4.01 (s, 3H), 3.94 (s, 3H)

(576) Compound 114 of the Present Invention

(577) ##STR00180##

(578) .sup.1H-NMR (CDCl.sub.3) : 8.77-8.76 (m, 1H), 7.84-7.82 (m, 1H), 7.55-7.53 (m, 2H), 7.06-6.94 (m, 4H), 4.27-4.24 (m, 2H), 3.98 (s, 3H)

(579) Compound 119 of the Present Invention

(580) ##STR00181##

(581) .sup.1H-NMR (CDCl.sub.3) : 7.61-7.59 (m, 1H), 7.32-7.28 (m, 2H), 6.84 (br s, 2H), 3.88 (s, 3H)

(582) Compound 121 of the Present Invention

(583) ##STR00182##

(584) .sup.1H-NMR (CDCl.sub.3) : 10.10 (s, 1H), 8.84 (s, 1H), 8.34 (d, 1H, J=8.8 Hz), 7.87 (d, 1H, J=8.8 Hz), 4.00 (s, 3H)

Formulation Example 1

(585) One of the compounds 1 to 163 of the present invention is dissolved in an amount of 10 parts in a mixture of 35 parts of xylene and 35 parts of N,N-dimethylformamide, and 14 parts of polyoxyethylene styryl phenyl ether and 6 parts of calcium dodecylbenzene sulfonate were added thereto. The residue is mixed well by stirring, thereby obtaining 10% emulsion of each compound.

Formulation Example 2

(586) One of the compounds 1 to 163 of the present invention is added in an amount of 20 parts to a mixture of 4 parts of sodium laurylsulfate, 2 parts of calcium lignin sulfonate, 20 parts of fine powder of synthetic hydrous silicon oxide, and 54 parts of diatomaceous earth. The residue is mixed well by stirring, thereby obtaining a 20% wettable powder of each compound.

Formulation Example 3

(587) 1 part of fine powder of synthetic hydrous silicon oxide, 2 parts of calcium lignin sulfonate, 30 parts of bentonite, and 65 parts of kaolin clay are added to 2 parts of one of the compounds 1 to 163 of the present invention, and the residue is sufficiently mixed by stirring. Subsequently, water is added in an appropriate amount to the mixture, and the residue is stirred, granulated by a granulator, and dried with air, thereby obtaining 2% granules of each compound.

Formulation Example 4

(588) One of the compounds 1 to 163 of the present invention is dissolved in an amount of 1 part in acetone in an appropriate amount, and 5 parts of fine powder of synthetic hydrous silicon oxide, 0.3 parts of PAP, and 93.7 parts of Fubasami clay are added thereto. The residue is sufficiently mixed by stirring, and acetone is removed by evaporation, thereby obtaining 1% powder of the each compound.

Formulation Example 5

(589) Ten (10) parts of one of the compounds 1 to 163 of the present invention, 17.5 parts of a polyoxyethylene alkyl ether sulfate ammonium salt, 17.5 parts of white carbon, and 55 parts of water are mixed with each other, and the mixture is finely pulverized by a wet pulverization method, thereby obtaining a 10% flowable agent of the each compound.

Formulation Example 6

(590) One of the compounds 1 to 163 of the present invention is dissolved in an amount of 0.1 parts in 5 parts of xylene and 5 parts of trichloroethane, and the residue is mixed with 89.9 parts of deodorized kerosene, thereby obtaining 0.1% oil of each compound.

(591) Next, application examples of the composition of the present invention to plant seeds are described.

Application Example 1

(592) One hundred (100) kg of dried corn seeds are smeared with 200 ml of the respective flowable agents prepared in Formulation example 5 by using a rotary seed treatment machine (seed dresser, manufactured by Hans-Ulrich Hege GmbH), thereby obtaining the respective seeds treated.

Application Example 2

(593) Ten (10) kg of dried wheat seeds are smeared with 40 ml the respective flowable agents prepared in Formulation example 5 by using a rotary seed treatment machine (seed dresser, manufactured by Hans-Ulrich Hege GmbH), thereby obtaining the respective seeds treated.

Application Example 3

(594) One hundred (100) kg of dried rice seeds are smeared with 200 ml the respective flowable agents prepared in Formulation example 5 by using a rotary seed treatment machine (seed dresser, manufactured by Hans-Ulrich Hege GmbH), thereby obtaining the respective seeds treated.

Test Example 1. Test for Evaluating Promotion of Root Growth by Hydroponics of Rice

(595) (Test Plant)

(596) Rice (variety: Nipponbare)

(597) (Cultivation and Compound Treatment)

(598) A DMSO solution, which contained one of the compounds 3, 9, 11, 14, 15, 20, 22, 23, 26, 27, 29 to 31, 34, 35, 37, 38, 40 to 43, 45, 47, 49, 50, 52, 54 to 56, 58, 60, 61, 63 to 69, 71, 74, 77, 79, 80, 82, 87, 88, 95 to 97, 100, 102 to 104, 106, 108, 109, 114, 120 to 124, 126 to 129, 131, 133, 136, 139 to 142, 144, 145, 147, 148, 150, 153, 157, 159, and 162 of the present invention at a concentration of 100,000 ppm, was added to Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1950 Circular 347 pp. 34) of -fold concentration at a volume ratio of 1/10,000. In this manner, hydroponic solutions containing one of the compounds 3, 9, 11, 14, 15, 20, 22, 23, 26, 27, 29 to 31, 34, 35, 37, 38, 40 to 43, 45, 47, 49, 50, 52, 54 to 56, 58, 60, 61, 63 to 69, 71, 74, 77, 79, 80, 82, 87, 88, 95 to 97, 100, 102 to 104, 106, 108, 109, 114, 120 to 124, 126 to 129, 131, 133, 136, 139 to 142, 144, 145, 147, 148, 150, 153, 157, 159, and 162 of the present invention at 10 ppm were prepared respectively. As an untreated control plot, a hydroponic solution obtained by adding DMSO to Hoagland hydroponic solution of -fold concentration at a volume ratio of 1/10,000 was used.

(599) Rice seeds were soaked in a 1% aqueous sodium hypochlorite solution for 10 minutes, then soaked in a 70% ethanol solution for surface sterilization, and then washed with distilled water. The sterilized seeds were soaked in a hydroponic solution containing the test compound described above at 10 ppm and incubated in a dark place for 3 days at 28 C. to perform treatment for hastening germination.

(600) Thereafter, 30 ml of hydroponic solution containing the test compound at 10 ppm was dispensed in a plastic tube (diameter of 20 mmheight of 113 mm) of which the side was covered with cardboard to block light. A float prepared using a styrene board and vinyl mesh was floated, and the rice seeds that had undergone the treatment for hastening germination were placed on the float on the surface of the hydroponic solution. The seeds were cultured for 3 days at 26 C., under the conditions of an illuminance of 4,000 lux of the top surface of the tube, a humidity of 50%, and a day length of 16 hours.

(601) (Evaluation Method)

(602) The nursery plants of rice obtained after culturing were measured in terms of the length of seminal root by using WinRHIZO system (manufactured by Regent Instruments Inc.). For each test plot, an average of the measured values of the seminal root of 4 or 5 individuals were determined. As a result, as shown in Table 8, the seminal root was obviously longer in the test plot treated with one of the compounds 3, 9, 11, 14, 15, 20, 22, 23, 26, 27, 29 to 31, 34, 35, 37, 38, 40 to 43, 45, 47, 49, 50, 52, 54 to 56, 58, 60, 61, 63 to 69, 71, 74, 77, 79, 80, 82, 87, 88, 95 to 97, 100, 102 to 104, 106, 108, 109, 114, 120 to 124, 126 to 129, 131, 133, 136, 139 to 142, 144, 145, 147, 148, 150, 153, 157, 159, and 162 of the present invention than in the untreated control plot.

(603) TABLE-US-00008 TABLE 8 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 3 >5 Present Compound 9 >5 Present Compound 11 >5 Present Compound 14 >5 Present Compound 15 >5 Present Compound 20 >5 Present Compound 22 >5 Present Compound 23 >5 Present Compound 26 >5 Present Compound 27 >5 Present Compound 29 >5 Present Compound 30 >5 Present Compound 31 >5 Present Compound 34 >5 Present Compound 35 >5 Present Compound 37 >5 Present Compound 38 >5 Present Compound 40 >5 Present Compound 41 >5 Present Compound 42 >5 Present Compound 43 >5 Present Compound 45 >5 Present Compound 47 >5 Present Compound 49 >5 Present Compound 50 >5 Present Compound 52 >5 Present Comoound 54 >5 Present Compound 55 >5 Present Compound 56 >5 Present Compound 58 >5 Present Compound 60 >5 Present Compound 61 >5 Present Compound 63 >5 Present Compound 64 >5 Present Compound 65 >5

(604) TABLE-US-00009 TABLE 9 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 66 >5 Present Compound 67 >5 Present Compound 68 >5 Present Compound 69 >5 Present Compound 71 >5 Present Compound 74 >5 Present Compound 77 >5 Present Compound 79 >5 Present Compound 80 >5 Present Compound 82 >5 Present Compound 87 >5 Present Compound 88 >5 Present Compound 95 >5 Present Compound 96 >5 Present Compound 97 >5 Present Compound 100 >5 Present Compound 102 >5 Present Compound 103 >5 Present Compound 104 >5 Present Compound 106 >5 Present Compound 108 >5 Present Compound 109 >5

(605) TABLE-US-00010 TABLE 10 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 114 >5 Present Compound 120 >5 Present Compound 121 >5 Present Compound 122 >5 Present Compound 123 >5 Present Compound 124 >5 Present Compound 126 >5 Present Compound 127 >5 Present Compound 128 >5 Present Compound 129 >5 Present Compound 131 >5 Present Compound 133 >5 Present Compound 136 >5 Present Compound 139 >5 Present Compound 140 >5 Present Compound 141 >5 Present Compound 142 >5 Present Compound 144 >5 Present Compound 145 >5 Present Compound 147 >5 Present Compound 148 >5 Present Compound 150 >5 Present Compound 153 >5 Present Compound 157 >5 Present Compound 159 >5 Present Compound 162 >5

Test Example 2. Test for Evaluating Promotion of Root Growth by Hydroponics of Rice

(606) (Test Plant)

(607) Rice (Variety: Nipponbare)

(608) (Cultivation and Compound Treatment)

(609) A DMSO solution, which contained one of the compounds 1, 4, 5, 7, 8, 10, 13, 16 to 18, 24, 25, 28, 32, 33, 36, 44, 46, 48, 53, 75, 76, 78, 90, 91, 94, 98, 99, 101, 105, 111, 112, 130, 132, 134, 135, 138, 146, 151, 152, 154, 155, 160, 161, and 163 of the present invention at a concentration of 100,000 ppm, was added to Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1950 Circular 347 pp. 34) of -fold concentration at a volume ratio of 1/10,000. In this manner, hydroponic solutions containing one of the compounds 1, 4, 5, 7, 8, 13, 16 to 18, 24, 25, 28, 32, 33, 36, 44, 46, 48, 53, 75, 76, 78, 90, 91, 94, 98, 99, 101, 105, 111, 112, 130, 132, 134, 135, 138, 146, 151, 152, 154, 155, 160, 161, and 163 of the present invention at 1 ppm were prepared respectively. As an untreated control plot, a hydroponic solution obtained by adding DMSO to Hoagland hydroponic solution of -fold concentration at a volume ratio of 1/10,000 was used. Rice seeds were soaked in a 1% aqueous sodium hypochlorite solution for 10 minutes, then soaked in a 70% ethanol solution for surface sterilization, and then washed with distilled water. The sterilized seeds were soaked in a hydroponic solution containing the zest compound described above at 1 ppm and incubated in a dark place for 3 days at 28 C. to perform treatment for hastening germination.

(610) Thereafter, 30 ml of hydroponic solution containing the test compound at 1 ppm was dispensed in a plastic tube (diameter of 20 mmheight of 113 mm) of which the side was covered with cardboard to block light. A float prepared using a styrene board and vinyl mesh was floated, and the rice seeds that had undergone the treatment for hastening germination were placed on the float on the surface of the hydroponic solution. The seeds were cultured for 3 days at 26 C., under the conditions of an illuminance of 4,000 lux of the top surface of the tube, a humidity of 50%, and a day length of 16 hours.

(611) (Evaluation Method)

(612) The nursery plants of rice obtained after cultivation were measured in terms of the length of seminal root by using WinRHIZO system (manufactured by Regent Instruments Inc.). For each test plot, an average of the measured values of the seminal root of 4 or 5 individuals were determined. As a result, as shown in Tables 11 and 12, the seminal root was obviously longer in the test plot treated with one of the compounds 1, 4, 5, 7, 8, 10, 13, 16 to 18, 24, 25, 28, 32, 33, 36, 44, 46, 48, 53, 75, 76, 78, 90, 91, 94, 98, 99, 101, 105, 111, 112, 130, 132, 134, 135, 138, 143, 146, 151, 152, 154, 155, 160, 161, and 163 of the present invention than in the untreated control plot.

(613) TABLE-US-00011 TABLE 11 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 1 >5 Present Compound 4 >5 Present Compound 5 >5 Present Compound 7 >5 Present Compound 8 >5 Present Compound 10 >5 Present Compound 13 >5 Present Compound 16 >5 Present Compound 17 >5 Present Compound 18 >5 Present Compound 24 >5 Present Compound 25 >5 Present Compound 28 >5 Present Compound 32 >5 Present Compound 33 >5

(614) TABLE-US-00012 TABLE 12 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 36 >5 Present Compound 44 >5 Present Compound 46 >5 Present Compound 48 >5 Present Compound 53 >5 Present Compound 75 >5 Present Compound 76 >5 Present Compound 78 >5 Present Compound 90 >5 Present Compound 91 >5 Present Compound 94 >5 Present Compound 98 >5 Present Compound 99 >5 Present Compound 101 >5 Present Compound 105 >5 Present Compound 111 >5 Present Compound 112 >5 Present Compound 130 >5 Present Compound 132 >5 Present Compound 134 >5 Present Compound 135 >5 Present Compound 138 >5 Present Compound 143 >5 Present Compound 146 >5 Present Compound 151 >5 Present Compound 152 >5 Present Compound 154 >5 Present Compound 155 >5 Present Compound 160 >5 Present Compound 161 >5 Present Compound 163 >5

Test Example 3. Test for Evaluating Promotion of Root Growth by Hydroponics of Rice

(615) (Test Plant)

(616) Rice (Variety: Nipponbare)

(617) (Cultivation and Compound Treatment)

(618) A DMSO solution, which contained one of the compounds 6, 12, 39, 51, 57, 59, 62, 73, 86, 89, 92, 107, 110, 113, 123, 137, 149, and 156 of the present invention at a concentration of 1,000 ppm, was added to Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1953 Circular 347 pp. 34) of -fold concentration at a volume ratio of 1/10,000. In this manner, hydroponic solutions containing one of the compounds 6, 12, 39, 51, 57, 59, 62, 73, 86, 89, 92, 107, 110, 113, 125, 137, 149, and 156 of the present invention at 0.1 ppm were prepared respectively. As an untreated control plot, a hydroponic solution obtained by adding DMSO to Hoagland hydroponic solution of -fold concentration at a volume ratio of 1/10,000 was used. Rice seeds were soaked in a 1% aqueous sodium hypochlorite solution for 10 minutes, then soaked in a 70% ethanol solution for surface sterilization, and then washed with distilled water. The sterilized seeds were soaked in a hydroponic solution containing the test compound described above at 0.1 ppm and incubated in a dark place for 3 days at 28 C. to perform treatment for hastening germination.

(619) Thereafter, 30 ml of hydroponic solution containing the test compound at 0.1 ppm was dispensed in a plastic tube (diameter of 20 mmheight of 113 mm) of which the side was covered with cardboard to block light. A float prepared using a styrene board and vinyl mesh was floated, and the rice seeds that had undergone the treatment for hastening germination were placed on the float on the surface of the hydroponic solution. The seeds were cultured for 3 days at 26 C., under the conditions of an illuminance of 4,000 lux of the top surface of the tube, a humidity of 50%, and a day length of 16 hours.

(620) (Evaluation Method)

(621) The nursery plants of rice obtained after culturing were measured in terms of the length of seminal root by using WinRHIZO system (manufactured by Regent Instruments Inc.). For each test plot, an average of the measured values of the seminal root of 4 or 5 individuals were determined. As a result, as shown in Table 10, the seminal root was obviously longer in the test plot treated with one of the compounds 6, 12, 39, 51, 57, 59, 62, 73, 86, 89, 92, 107, 110, 113, 125, 137, 149, and 156 of the present invention than in the untreated control plot.

(622) TABLE-US-00013 TABLE 13 Relative value of length of seminal Test compound root (%-untreated control plot) Present Compound 6 >5 Present Compound 12 >5 Present Compound 39 >5 Present Compound 51 >5 Present Compound 57 >5 Present Compound 59 >5 Present Compound 62 >5 Present Compound 73 >5 Present Compound 86 >5 Present Compound 89 >5 Present Compound 92 >5 Present Compound 107 >5 Present Compound 110 >5 Present Compound 113 >5 Present Compound 125 >5 Present Compound 137 >5 Present Compound 149 >5 Present Compound 156 >5

Test Example 4. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Hydroponics of Nicotiana benthamiana

(623) (Test Plant)

(624) Nicotiana benthamiana

(625) (Cultivation and Compound Treatment)

(626) A DMSO solution, which contained one of the compounds 3, 4, 10, 12, 14, 22, 26, 28, 31, 39, 40, 42, 45, 54, 57, 58, 60, 65, 66, 68, 69, 71, 73, 76, 82, 89, 90, 97, 98, 101, 102, 104, 106, 108 to 111, 116, 118, 123, 133, 139, 141, 142, 150, 155, and 161 of the present invention a: a concentration of 10,000 ppm, was prepared. The DMSO solution of the compound of the present invention was added at a volume ratio of 1/1,000 to the MurashigeScoog medium of a -fold concentration (a medium containing 2.3 g of mixed salts (manufactured by Wako Pure Chemical Industries, Ltd.), 200 mg of Myo-inositol (manufactured by Sigme-Aldrich Co. LLC.), 2 mg of niconitic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 2 mg of pyridoxine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.), 20 mg of thiamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.), 20 g of sucrose (manufactured by Wako Pure Chemical Industries, Ltd.), and 1 g of MES (manufactured by DOJINDO LABORATORIES) respectively per 1 L of water and having pH adjusted to 5.8), thereby preparing a medium containing the compound of the present invention at a concentration of 10 ppm.

(627) Seeds of Nicotiana benthamiana were seeded in the 5 L of the medium and cultured overnight at 22 C. Thereafter, 45 L of the medium containing the compound of the present invention at a concentration of 10 ppm was added thereto, and the seeds are cultured for 7 days at 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours, and the nursery plants raised from the Nicotiana benthamiana were treated with the compound. Moreover, instead of the above medium a test plot, which was obtained by performing the same treatment by using a medium prepared by adding DMSO to the MurashigeScoog medium of -fold concentration at a volume ratio of 1/1,000, was used as a control plot not treated with the compound.

(628) (Low-Temperature Stress Treatment)

(629) The nursery plants of the Nicotiana benthamiana treated with the compound were subjected to low-temperature treatment by being cultured for 7 days at 1.51.0 C., under the conditions of an illuminance of 2,000 lux, and a day length of 16 hours.

(630) (Evaluation)

(631) The nursery plants of the Nicotiana benthamiana having undergone the low-temperature stress treatment were cultured for 3 days at 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours. Thereafter, the area of green leaf was quantified by Scanalyzer HTS (manufactured by LemnaTec GmbH). Moreover, the value of the control plot not treated with the compound that had not yet been subjected to the low-temperature stress treatment was measured in the same manner. A value of a relative leaf area was calculated based on the following equation (1), and if the relative value of leafed area was 5 or greater, the compound was evaluated to have a growth promotion effect. As a result of the evaluation, it was confirmed that when the plant was treated with one of the compounds 3, 4, 10, 12, 14, 22, 26, 28, 31, 39, 40, 42, 45, 54, 57, 58, 60, 65, 66, 68, 69, 71, 73, 76, 82, 89, 90, 97, 98, 101, 102, 104, 106, 108 to 111, 116, 118, 123, 133, 139, 141, 142, 150, 155, and 161 of the present invention at 10 ppm, the value of a relative leaf area was 5 or greater, compared to the area of green leaf of the control plot not treated with compound. Accordingly, it was confirmed that the treatment using the compound of the present invention improve a growth promotion effect.
Relative leaf area=100*(a green area of a plot treated with the compound of the present invention minus () a green area of a plot not treated with the compound of the present invention)/(a green area of a control plot not treated with the compound of the present invention that had not yet been subjected to low-temperature stress treatment minus () a green area of a control plot not treated with the compound of the present invention)Equation (1):

Test Example 5. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Hydroponics of Nicotiana benthamiana

(632) (Test Plant)

(633) Nicotiana benthamiana

(634) (Cultivation and Compound Treatment)

(635) A DMSO solution, which contained one of the compounds 5, 6, 8, 9, 11, 13, 18, 21, 24, 30, 33 to 38, 43, 44, 46, 48, 49, 56, 61, 72, 74, 77, 79, 80, 86, 93, 96, 100, 103, 107, 115, 117, 122, 125, 126, 128, 130, 132, 134 to 137, 140, 151, and 157 to 160 of the present invention at a concentration of 1,000 ppm, was prepared. The DMSO solution of the compound of the present invention was added at a volume ratio of 1/1,000 to the MurashigeScoog medium of a -fold concentration (a medium containing 2.3 g of mixed salts (manufactured by Wako Pure Chemical Industries, Ltd.), 200 mg of Myo-inositol (manufactured by Sigme-Aldrich Co. LLC.), 2 mg of niconitic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 2 mg of pyridoxine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.), 20 mg of thiamine hydrochloride (manufactured by Wacko Pure Chemical Industries, Ltd.), 20 g of sucrose (manufactured by Wako Pure Chemical Industries, Ltd.), and 1 g of MES (manufactured by DOJINDO LABORATORIES) respectively per 1 L of water and having pH adjusted to 5.8), thereby preparing a medium containing the compound of the present invention at a concentration of 1 ppm.

(636) Seeds of Nicotiana benthamiana were seeded in the 5 L of the medium and cultured overnight at 22 C. Thereafter, 45 L of the medium containing the compound of the present invention at a concentration of 1 ppm was added thereto, and the seeds are cultured for 7 days at 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours, and the nursery plants raised from the Nicotiana benthamiana were treated with the compound. Moreover, instead of the above medium a test plot, which was obtained by performing the same treatment by using a medium prepared by adding DMSO to the MurashigeScoog medium of -fold concentration at a volume ratio of 1/1,000, was used as a control plot not treated with the compound.

(637) (Low-Temperature Stress Treatment)

(638) The nursery plants of the Nicotiana benthamiana treated with the compound were subjected to low-temperature treatment by being cultured for 7 days at 1.51.0 C., under the conditions of an illuminance of 2,000 lux, and a day length of 16 hours.

(639) (Evaluation)

(640) The nursery plants of the Nicotiana benthamiana having undergone the low-temperature stress treatment were cultured for 3 days at 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours. Thereafter, the area of green leaf was quantified by Scanalyzer HTS (manufactured by LemnaTec GmbH). Moreover, the value of the control plot not treated with the compound that had not yet been subjected to the low-temperature stress treatment was measured in the same manner. A value of a relative leaf area was calculated based on the following equation (1), and if the relative value of leaf area was 5 or greater, the compound was evaluated to have a growth promotion effect. As a result of the evaluation, it was confirmed that when the plan: was treated with one of the compounds 5, 6, 8, 9, 11, 13, 18, 21, 24, 30, 33 to 38, 43, 44, 46, 48, 49, 56, 61, 72, 74, 77, 79, 80, 86, 93, 96, 100, 103, 107, 115, 117, 122, 125, 126, 128, 130, 132, 134 to 137, 140, 151, and 157 to 160 of the present invention at 1 ppm, the value of a relative leaf area was 5 or greater, compared to the area of green leaf of the control plot not treated with compound. Accordingly, it was confirmed that the treatment using the compound of the present invention improve a growth promotion effect.
Relative leaf area=100*(a green area of a plot treated with the compound of the present invention minus () a green area of a plot not treated with the compound of the present invention)/(a green area of a control plot not treated with the compound of the present invention that had not yet been subjected to low-temperature stress treatment minus () a green area of a control plot not treated with the compound of the present invention)Equation (1):

Test Example 6. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Hydroponics of Nicotiana benthamiana

(641) (Test Plant)

(642) Nicotiana benthamiana

(643) (Cultivation and Compound Treatment)

(644) A DMSO solution, which contained one of the compounds 1, 2, 7, 16, 17, 25, 29, 41, 47, 50 to 52, 55, 59, 64, 75, 78, 85, 87, 88, 95, 99, 112 to 114, and 127, 154 of the present invention at a concentration of 100 ppm, was prepared. The DMSO solution of the compound of the present invention was added at a volume ratio of 1/1,000 to the MurashigeScoog medium of a -fold concentration (a medium containing 2.3 g of mixed salts (manufactured by Wako Pure Chemical Industries, Ltd.), 200 mg of Myo-inositol (manufactured by Sigme-Aldrich Co. LLC.), 2 mg of niconitic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 2 mg of pyridoxine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.), 20 mg of thiamine hydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.), 20 g of sucrose (manufactured by Wako Pure Chemical Industries, Ltd.), and 1 g of MES (manufactured by DOJINDO LABORATORIES) respectively per 1 L of water and having pH adjusted to 5.8), thereby preparing a medium containing the compound of the present invention at a concentration of 0.1 ppm.

(645) Seeds of Nicotiana benthamiana were seeded in the 5 L of the medium and cultured overnight at 22 C. Thereafter, 45 L of the medium containing the compound of the present invention at a concentration of 0.1 ppm was added thereto, and the seeds are cultured for 7 days at 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours, and the nursery plants raised from the Nicotiana benthamiana were treated with the compound. Moreover, instead of the above medium a test plot, which was obtained by performing the same treatment by using a medium prepared by adding DMSO to the MurashigeScoog medium of -fold concentration at a volume ratio of 1/1,000, was used as a control plot not treated with the compound.

(646) (Low-Temperature Stress Treatment)

(647) The nursery plants of the Nicotiana benthamiana treated with the compound were subjected to low-temperature treatment by being cultured for 7 days at 1.51.0 C., under the conditions of an illuminance of 2,000 lux, and a day length of 16 hours.

(648) (Evaluation)

(649) The nursery plants of the Nicotiana benthamiana having undergone the low-temperature stress treatment were cultured for 3 days a: 22 C., under the conditions of an illuminance of 4,000 lux, and a day length of 16 hours. Thereafter, the area of green leaf was quantified by Scanalyzer HTS (manufactured by LemnaTec GmbH). Moreover, the value of the control plot not treated with the compound that had not yet been subjected to the low-temperature stress treatment was measured in the same manner. A value of a relative leaf area was calculated based on the following equation (1), and if the relative value of leaf area was 5 or greater, the compound was evaluated to have a growth promotion effect. As a result of the evaluation, it was confirmed that when the plant was treated with one of the compounds 1, 2, 7, 16, 17, 25, 29, 41, 47, 50 to 52, 55, 59, 64, 75, 78, 85, 87, 88, 95, 99, 112 to 114, 127, and 154 of the present invention at 0.1 ppm, the value of a relative leaf area was 5 or greater, compared to the area of green leaf of the control plot not treated with compound. Accordingly, it was confirmed that the treatment using the compound of the present invention improves a growth promotion effect.
Relative leaf area=100*(a green area of a plot treated with the compound of the present invention minus () a green area of a plot not treated with the compound of the present invention)/(a green area of a control plot not treated with the compound of the present invention that had not yet been subjected to low-temperature stress treatment minus () green area of a control plot not treated with the compound of the present invention)Equation (1):

Test Example 7. Test for Evaluating Growth Promotion by Corn Seed Treatment

(650) (Test Plant)

(651) Corn (Variety: Pioneer 31P41 (Manufactured by Pioneer Hi-Bred Japan))

(652) (Seed Treatment)

(653) A blank slurry solution containing 10% (V/V) color coat red (Becker Underwood, Inc.), 10% (V/V) CF-Clear (Becker Underwood, Inc.), and 1.66% Maxim4FS (Syngenta) is prepared. One of the compounds 1 to 163 of the present invention is dissolved in the blank slurry such that a predetermined amount of the compound is used for treatment per 100 kg corn seeds, thereby preparing a slurry solution. 0.35 ml of the slurry solution per 14.4 g of the seeds is put into a 50 ml centrifugal settling tube (manufactured by Becton, Dickinson and Company, Japan), and the slurry solution is stirred until it dries, thereby coating the seeds. Moreover, the seeds coated with the blank slurry are used as seeds for an untreated control plot.

(654) (Cultivation)

(655) Each of the seeds having undergone the seed treatment is seeded one by one in a culture soil (Aisai) in a pot (55 mmheight of 58 mm), and cultured for 18 days at 27 C., under the conditions of an illuminance of 5,000 lux, and a day length of 16 hours.

(656) (Evaluation Method)

(657) After cultivation, a fresh weight of the aerial part of each individual of the grown plant is measured, and an average weight of each individual is determined.

(658) As a result, the fresh weight of the aerial part is expected to be larger in the plot having undergone seed treatment by using one of the compounds 1 to 163 of the present invention than in the untreated control plot.

Test Example 8. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Corn Seed Treatment

(659) (Test Plant)

(660) Corn (Variety: Pioneer 31P41 (Manufactured by Pioneer Hi-Bred Japan)

(661) (Seed Treatment)

(662) A blank slurry solution containing 10% (V/V) color coat red (Becker Underwood, Inc.), 10% (V/V) CF-Clear (Becker Underwood, Inc.), and 1.66% Maxim4FS (Syngenta) was prepared. One of the compounds 1 and 30 of the present invention was dissolved in the blank slurry such that 0.5 g, 5 g or 50 g of the compound was used for treatment per 100 kg corn seeds, thereby preparing a slurry solution. Zero point three five (0.35) ml of the slurry solution per 14.4 g of the seeds was put into a 50 ml centrifugal settling tube (manufactured by Becton, Dickinson and Company, Japan), and the slurry solution was stirred until it dries, thereby coating the seeds. Moreover, the seeds coated with the blank slurry were used as seeds for an untreated control plot.

(663) (Cultivation)

(664) Each of the seeds having undergone the seed treatment was seeded one by one in a culture soil (Aisai) in a pot (55 mmheight of 58 mm), and cultured for 19 days at 27 C., under the conditions of an illuminance of 5,000 lux, and a day length of 16 hours. The grown nursery plants were used for a test.

(665) (Low-Temperature Stress Treatment Method)

(666) A pot in which the seeds were seeded 10 days ago was put in a phytotron set to the following temperature condition, followed by cultivation for 4 days under the following conditions.

(667) Conditions; a temperature of 2.51 C., a day length of 16 hours, and an illuminance of 5,000 lux

(668) (Evaluation)

(669) After low-temperature stress treatment was performed, the seeds were cultured for 4 days at 27 C., under the conditions of an illuminance of 5,000 lux, and a day length of 16 hours. Thereafter, a fresh weight of the overground portion of each individual of the plant having grown was weighed, and an average weight of each individual was determined.

(670) As a result, the fresh weight of the aerial part was expected to be larger in the plot having undergone seed treatment by using one of the compounds 1 and 30 of the present invention at an amount of 0.5 g, 5 g or 50 g per 100 kg of the corn seeds than in the untreated control plot.

Test Example 9. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Soaking Treatment of Rice

(671) (Test Plant)

(672) Rice (Variety: Nipponbare)

(673) (Cultivation)

(674) Rice seeds in a required amount are soaked in an aqueous benlate solution at 1,000 ppm, and cultured overnight at 30 C. in a dark place. The aqueous benlate solution is then replaced with distilled water, and the seeds are cultured overnight again at 30 C. in a dark place to perform treatment for hastening germination.

(675) Filter paper is placed in holes of a 406-hole plug tray, and rice seeds having undergone the germination hastening treatment are seeded on the filter paper. The Kimura B hydroponic solution (refer to Plant Science 119:39-47 (1996)) of -fold concentration is added thereto, and the seeds are cultured for 5 days in a phytotron under the following conditions.

(676) Conditions; a temperature 28 C. for day/23 C. for night, a humidity of 70%, an illuminance of 8,500 lux, a day length of 12 hours

(677) (Compound Treatment)

(678) A DMSO solution containing one of the compounds 1 to 163 of the present invention at a predetermined concentration is prepared and diluted with the Kimura B hydroponic solution of -fold concentration. The hydroponic solution containing the compound is dispensed by 2 ml to each well of a 24-well plate, and each of nursery plants having grown is transferred to each well and cultured for 2 days on an illuminated culture shelf under the following conditions.

(679) Conditions; a temperature of 25 C., an illuminance of 5,000 lux, a day length of 12 hours

(680) Moreover, the nursery plants of rice cultured in the same manner by using a hydroponic solution containing 0.1% DMSO are used as an untreated control plot.

(681) (Low-Temperature Stress Treatment)

(682) The nursery plants of rice in a state of being in the 24-well plate are transferred to a cooling box and cultured for 5 days under the following conditions by using cold-cathode fluorescent lamps.

(683) Conditions; a temperature of 4 C., an illuminance of 3,500 lux, a day length of 12 hours

(684) (Evaluation)

(685) After the low-temperature stress treatment, the nursery plants of rice having undergone the low-temperature stress treatment are transferred to an illuminated culture shelf and cultured for 4 more days under the following conditions.

(686) Conditions; a temperature of 25 C., an illuminance of 5,000 lux, a day length of 12 hours

(687) After 4 days, an image of the aerial part of the individual nursery plant of rice in each treated plot is taken, and an area of a green portion of the obtained image data is quantified by image analysis software Win Roof (manufactured by MITANI CORPORATION) to determine a green area of each individual of the aerial part of the plant. For each of the treated plots, an average of the green areas of the aerial part of individual nursery plant of rice is determined. As a result, the green area is expected to be larger in the plot treated with one of the compounds 1 to 163 of the present invention than in an untreated control plot.

Test Example 10. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Rice Seed Treatment

(688) (Test Plant)

(689) Rice (Variety: Nipponbare)

(690) (Seed Treatment)

(691) A blank slurry solution containing 5% (V/V) color coat red (Becker Underwood, Inc.), 5% (V/V) CF-Clear (Becker Underwood, Inc.), and 1% Maxim XL (Syngenta) is prepared. One of the compounds 1 to 163 of the present invention is dissolved in the blank slurry such that a predetermined amount of the compound is used for treatment per 100 kg rice seeds, thereby preparing a slurry solution. Zero point one (0.1) ml of the slurry solution per 3 g of the rice seeds is put into a 15 ml centrifugal settling tube (manufactured by AGC Techno Glass, Co., Ltd.), and the slurry solution is stirred until it dries, thereby coating the seeds. Moreover, the seeds coated with the blank slurry are used as seeds for an untreated control plot.

(692) (Cultivation Method)

(693) Filter paper is placed in holes of a 406-hole plug tray, and rice seeds having undergone the seed treatment are seeded. The Kimura B hydroponic solution (refer to Plant Science 119:39-47 (1996)) of -fold concentration is added thereto, and the seeds are cultured for 10 days in a phytotron under the following conditions.

(694) Conditions; a temperature 28 C. for day/23 C. for night, a humidity of 70%, an illuminance of 8,500 lux, a day length of 12 hours

(695) (Low-Temperature Stress Treatment)

(696) Nursery plants of rice having grown after 10 days of cultivation that are in state of being in the plug tray are transferred to a cooling box, and cultivated for 5 days under cold-cathode fluorescent lamps under the following conditions.

(697) Conditions: a temperature of 4 C., an illuminance of 3,500 lux, a day length of 2 hours

(698) (Evaluation)

(699) Four individuals of the nursery plant of rice in the same treated plot having undergone low-temperature stress treatment are transferred to a cup (C-AP square cup 88, manufactured by SHINGI CORPORATION) containing 60 ml of Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1950 Circular 347 pp. 34) and cultured for 12 days on an illuminated culture shelf under the following conditions.

(700) Conditions: a temperature of 25 C., an illuminance of 5,000 lux, a day length of 12 hours

(701) After 12 days, a fresh weight of the aerial part of each individual of the plant is measured for each treated plot, and an average of the fresh weight of the aerial part of each individual of the plant is determined.

(702) As a result, the fresh weight of the aerial part is expected to be larger in the plot having undergone treatment by using one of the compounds 1 to 163 of the present invention than in the untreated control plot.

Test Example 11. Test for Evaluating Growth Promotion Under Drought Stress by Soaking Treatment of Rice

(703) (Test Plant)

(704) Rice (variety: Nipponbare)

(705) (Cultivation)

(706) Rice seeds are soaked in an aqueous benlate solution at 1,000 ppm and cultured overnight at 30 C. in a dark place. The aqueous Benlate solution is discarded and replaced with distilled water, and the seeds are further cultured overnight at 30 C. in a dark place.

(707) Filter paper is placed in holes of a 406-hole plug tray, and rice seeds having undergone the germination hastening treatment are seeded on the filter paper. A DMSO solution containing one of the compounds 1 to 163 of the present invention at a predetermined concentration is added to the Kimura B hydroponic solution (refer to Plant Science 119:39-47 (1996)) of -fold concentration at a volume ratio of 1/10,000, and the seeds are cultivated for 14 days under the conditions of a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 days.

(708) (Drought Stress Treatment)

(709) The grown nursery plants of rice are put into an empty flat-bottomed test tube (Assist/Sarstedt) by five individuals and left to standstill for 2 days without putting a lid under the conditions of a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 hours.

(710) (Evaluation)

(711) The plants having undergone drought stress treatment are put in a centrifugal settling tube (manufactured by AGC Techno Glass, Co., Ltd.) containing 100 ml of Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1950 Circular 347 pp. 34) and cultivated for 14 days under the conditions of a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 hours.

(712) After 14 days, a fresh weight of the overground portion of the test plant in each test plot is weighed, and an average is determined. As a result, the fresh weight of the aerial part of the rice treated with one of the compounds 1 to 163 of the present invention is expected to be larger than that of the rice in the untreated control plot.

Test Example 12. Test for Evaluating Growth Promotion Under High-Temperature Stress by Drench Treatment of Wheat

(713) (Test Plant)

(714) Wheat (Variety: Apogee)

(715) (Spraying Treatment)

(716) Wheat seeds are seeded by five seeds in a culture soil (Aisai) in a plastic pot and cultivated for 10 days in a phytotron under the conditions of a temperature of 18 C. for day/15 C. for night, an illuminance of 7,000 lux, and a day length of 16 hours. Before the stress test, thinning is performed to leave three individuals per pot.

(717) One of the compounds 1 to 163 of the present invention in a predetermined amount is dissolved in DMSO to conduct 1,000-fold dilution. Fifteen (15) ml of an aqueous solution containing the compound of the present invention at a predetermined concentration is used to perform soil drench treatment on the pot in which nursery plants of wheat have grown. Moreover, a 0.1% DMSO solution not containing the compound of the present invention is used as an untreated control plot.

(718) (High-Temperature Stress Treatment)

(719) The test plants obtained on the 13.sup.th days after seeding are left to standstill for 2.5 hours in a phytotron under the conditions of a temperature of 49 C., a humidity of 50%, and an illuminance of 7,000 lux.

(720) (Evaluation)

(721) After the high-temperature stress treatment, the plants are cultivated for 14 days in a phytotron under the conditions of a temperature of 18 C. for day/15 C. for night and an illuminance of 7,000 lux. The wheat obtained on the 14.sup.th days after the high-temperature stress treatment is imaged using Scanalyzer 3D-VIS (manufactured by LemnaTec GmbH), and an area of the green portion of the leaves is calculated. As a result, the wheat treated with one of the compounds 1 to 163 of the present invention is expected to have an effect of increasing the green leaf area, compared to the wheat (untreated control plot) not treated with the compound of the present invention.

Test Example 13. Test for Evaluating Growth Promotion Under Drought Stress by Rice Seed Treatment

(722) (Test Plant)

(723) Rice (variety: Nipponbare)

(724) (Seed Treatment)

(725) A blank slurry solution containing 5% (V/V) color coat red (Becker Underwood, Inc.), 5% (V/V) CF-Clear (Becker Underwood, Inc.), and 1% Maxim XL (Syngenta) is prepared.

(726) One of the compounds 1 to 163 of the present invention is dissolved in the blank slurry such that a predetermined amount of the compound is used per 100 kg rice seeds, thereby preparing a slurry solution. Zero point three zero (0.30) ml of the slurry solution per 13 g of the rice seeds is put into a 50 ml centrifugal settling tube (manufactured by AGC Techno Glass, Co., Ltd.), and the slurry solution is stirred until it dries, thereby coating the seeds. Moreover, the seeds coated with the blank slurry solution are used as seeds for an untreated control plot.

(727) (Cultivation)

(728) Filter paper is placed in holes of a 406-hole plug tray, and rice seeds having undergone the seed treatment as above are seeded on the filter paper. The Kimura B hydroponic solution (refer to Plant Science 119:39-47 (1996)) of -fold concentration is added thereto, and the seeds are cultured for 17 days under the conditions of t a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 hours.

(729) (Drying Stress Treatment)

(730) The grown nursery plants of rice are put into a 35 ml empty flat-bottomed test tube (Assist/Sarstedt) by five individuals and left to standstill for 2 days without putting a lid under the conditions of a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 hours.

(731) (Evaluation)

(732) The plants having undergone drought stress treatment a put in a centrifugal settling tube (manufactured by AGC Techno Glass, Co., Ltd.) containing 100 ml of Hoagland hydroponic solution (Hoagland and Arnon, California Agricultural Experiment Station 1950 Circular 347 pp. 34) and cultivated for 14 days under the conditions of a temperature of 28 C. for day/23 C. for night, a humidity of 60%, an illuminance of 8,500 lux, and a day length of 12 hours.

(733) After 14 days, a fresh weight of the aerial part of the five individuals of the test plant in each test plot is weighed, and an average of each test plot is determined. As a result, the plot treated with one of the compounds 1 to 163 of the present invention is expected to have an effect of increasing the fresh weight of the aerial part, compared to the untreated control plot.

Test Example 14. Test for Evaluating Growth Promotion Under Low-Temperature Stress by Corn Soil Drench Treatment

(734) Corn seeds (variety: Pioneer 31P41) was seeded in a culture soil (Aisai) in a plastic pot (55 mmheight of 58 mm), and cultured for 7 days under the conditions of a temperature of 20-25 C., an illuminance of about 5,000 lux, and a day length of 16 hours.

(735) A DMSO solution which contained one of the compounds 1, 3, 7, 10, 12, 13, 19, 26, 27, 30, 32, 38 to 43, 48, 49, 52, 55 to 58, 60, 62, 63, 65, 67, 69, 70, 73, 83, 85, 88, 93, 97, 100, 110, 111, 119, 125, 129 to 133, 135, 141, 145, 147, 152, 153, 156, 157, 159, 160 and 161 of the present invention was prepared at a 1,000-fold concentration as opposed to each test concentration, and was diluted with distilled water to prepare a test solution.

(736) The 20 ml of obtained test solutions were soil drenched into plant foot and the plants were cultured for 2 days under the conditions of a temperature of 27 C., a humidity of 40-80%, an illuminance of about 5,000 lux, and a day length of 16 hours, to make it a treated plot with the present compound. A plot was treated by the soil drench treatment with a 20 ml of 0.1% DMSO solution in place of the DMSO solution of the compound to make it an untreated control plot.

(737) The soil drenched plant was cultivated for 5 days in a phytotron under the conditions of a temperature of 2.5 C., a humidity of 40-80%, an illuminance of about 5,000 lux, and a day length of 16 hours, whereby the plants were exposed to low-temperature stress. After being exposed to the low-temperature stress, the plants were cultivated for 4 days in a phytotron under the conditions of a temperature of 27 C., a humidity of 40-80%, an illuminance of about 5,000 lux, and a day length of 16 hours.

(738) After the cultivation, a degree of healthy of each plant individuals was scored according to the following performance index.

(739) 5: the number of the leave, of which or greater of the area is healthy, is four or more;

(740) 4: the number of the leave, of which or greater of the area is healthy, is three;

(741) 3: the number of the leave, of which or greater of the area is healthy, is two;

(742) 2: the number of the leave, of which or greater of the area is healthy, is one;

(743) 1: the number of the leave, of which or greater of the area is healthy, is zero (0);

(744) 0: the number of the withered and died leaves.

(745) The average values of the above healthy scores of four plant individuals were calculated. As a result of the evaluation, as shown in Tables 14, 15 and 16, it was evident that the treated plot of the plants, wherein the plants were treated with one of the compounds 1, 3, 7, 10, 12, 13, 19, 26, 27, 30, 32, 38 to 43, 48, 49, 52, 55 to 58, 60, 62, 63, 65, 67, 69, 70, 73, 83, 85, 88, 93, 97, 100, 110, 111, 119, 125, 129 to 133, 135, 141, 145, 147, 152, 153, 156, 157, 159, 160 and 161 of the present invention, had much higher scores than those of the non-treated plot.

(746) TABLE-US-00014 TABLE 14 Test Relative value of concentration scores (%-untreated Test compound (ppm) control plot) Present compound 1 10 >5 Present compound 3 0.3 >5 Present compound 7 10 >5 Present compound 10 10 >5 Present compound 12 10 >5 Present compound 13 10 >5 Present compound 19 0.3 >5 Present compound 26 1 >5 Present compound 27 10 >5 Present compound 30 10 >5 Present compound 32 3 >5 Present compound 38 3 >5 Present compound 39 1 >5 Present compound 40 10 >5 Present compound 41 0.3 >5 Present compound 42 0.3 >5 Present compound 43 3 >5 Present compound 48 10 >5 Present compound 49 10 >5 Present compound 52 1 >5

(747) TABLE-US-00015 TABLE 15 Test Relative value of concentration scores (%-untreated Test compound (ppm) control plot) Present compound 55 10 >5 Present compound 56 10 >5 Present compound 57 10 >5 Present compound 58 10 >5 Present compound 60 10 >5 Present compound 62 0.3 >5 Present compound 63 3 >5 Present compound 65 0.3 >5 Present compound 67 3 >5 Present compound 69 1 >5 Present compound 70 10 >5 Present compound 73 1 >5 Present compound 83 0.3 >5 Present compound 85 10 >5 Present compound 88 3 >5 Present compound 93 10 >5 Present compound 97 0.3 >5 Present compound 100 3 >5 Present compound 110 1 >5 Present compound 111 10 >5

(748) TABLE-US-00016 TABLE 16 Test Relative value of concentration scores (%-untreated Test compound (ppm) control plot) Present compound 119 1 >5 Present compound 125 0.3 >5 Present compound 129 10 >5 Present compound 130 1 >5 Present compound 131 3 >5 Present compound 132 0.3 >5 Present compound 133 3 >5 Present compound 135 3 >5 Present compound 141 0.3 >5 Present compound 145 0.3 >5 Present compound 147 0.3 >5 Present compound 152 1 >5 Present compound 153 1 >5 Present compound 156 1 >5 Present compound 157 0.3 >5 Present compound 159 0.3 >5 Present compound 160 10 >5 Present compound 161 3 >5

INDUSTRIAL APPLICABILITY

(749) The use of the method of the present invention makes it possible to effectively promote the plant growth.