HK1241355B - Urat1 inhibitor - Google Patents

Description

URAT1 inhibitors

Technical Field

The present invention relates to a compound which inhibits uric acid reabsorption mediated by the uric acid transporter URAT1 and promotes uric acid excretion.

Background Art

Hyperuricemia is the cause of urate deposition disease represented by gouty arthritis and renal injury (non-patent literature 1). It has been reported that the incidence rate of hyperuricemia in Japan is 21.5% in adult males, and is the highest in 30 to 40 years old by age, which is about 30% (non-patent literature 2). On the other hand, it is known that women's serum uric acid levels rise after menopause. It has been reported that the incidence rate of hyperuricemia in women under 50 years old is 1.3%, and in women over 50 years old, it is 3.7%, which means that the number of male patients is larger. The number of gout patients has a tendency to increase year by year (non-patent literature 3), and it is speculated that the number of asymptomatic hyperuricemia patients as its reserve army has reached 8 million people in our country alone.

As previously mentioned, in the past, hyperuricemia has attracted much attention as the reason of urate deposition diseases such as gouty arthritis, gouty nodules and urinary calculi.But, report in recent years that above-mentioned concept has been had subversive clinical research result, that is, report following result, this result means that uric acid is irrelevant with deposition, and uric acid itself may be closely related as causal factor in the morbidity/development of chronic kidney disease, cardiovascular disease and metabolic syndrome (non-patent literature 4).In addition, show allopurinol (allopurinol) as one of hyperuricemia therapeutic drug, uric acid level can not only be made to decline, also may curb the cardiovascular diseases (non-patent literature 5) such as hypertension, ischemic heart disease, heart failure.

The reabsorption and secretion of uric acid in the proximal renal tubules of the kidney can participate in the control of serum uric acid value (non-patent literature 6). In uric acid reabsorption, the transporter Urate Transporter1 (URAT1) present in the proximal renal tubules plays an important role (non-patent literature 7). URAT1 is a member of the organic anion transporter-shaped molecule identified by expression function analysis and gene database analysis using oocytes (non-patent literature 7). URAT1, a 12-transmembrane protein, is found in the brush border membrane side of the proximal renal tubular epithelial cells, and it is found that uric acid is exchanged with chloride ions or organic anions to transport uric acid. Because lactic acid and pyrazine carboxylic acid (pyrazine carboxylic acid) as uricosuric agents can promote the activity of URAT1, the uric acid reabsorption in the kidney can be promoted (non-patent literature 9). On the other hand, URAT1 is inhibited by benzbromarone (benzbromarone), probenecid (probenecid) and losartan (losartan). Reported some renal hypouricemia patients, due to the variation of URAT1, the uric acid reabsorption function of the kidneys significantly decreased, showing a low serum uric acid value (non-patent literature 9). Therefore, inhibition of URAT1 has the effect of reducing serum uric acid value, so the aforementioned probenecid, benzbromarone etc. are used as hyperuricemia therapeutic drugs.

Hyperuricemia is roughly divided into three types: uric acid excessive generation type, uric acid underexcretion type and mixed type, wherein the number of patients with uric acid underexcretion type is the largest, for these patients, select probenecid, benzbromarone etc. to promote the medicine of uric acid excretion as therapeutic drug (non-patent literature 1). Further, the hyperuricemia of concurrent lifestyle-related disease is mainly uric acid underexcretion type hyperuricemia, and it is believed that the enhancement of uric acid reabsorption positioned at the proximal renal tubule of kidney causes the morbidity of hyperuricemia (non-patent literature 8). Therefore, in the treatment of hyperuricemia patients with concurrent lifestyle-related disease, it is reasonable to use the medicament that suppresses the uric acid underexcretion of kidney and promotes uric acid excretion. However, the drug interaction of known probenecid is many, and it is necessary to pay attention to when used in conjunction, and, for concurrent hyperuricemia patients with renal injury, the effect of probenecid significantly weakens (non-patent literature 1). On the other hand, while benzbromarone is reportedly effective for patients with hyperuricemia who have reduced renal function to a certain extent, it can cause serious side effects such as fulminant hepatitis (Non-Patent Document 1), and some countries overseas have discontinued its use. Therefore, there is a growing expectation that URAT1 inhibitors, with their high safety profile, will be widely used as first-in-class drugs for treating hyperuricemia with decreased uric acid excretion, the most common disease.

Recently, Patent Documents 1 and 2 reported that naphthalene-substituted triazolethioacetic acid derivatives (triazole thioacetic acid inducers) or pyridylthioacetic acid derivatives represented by the following formula (A) and the following formula (B) exhibit excellent hURAT1 inhibitory activity in a uric acid uptake assay utilizing the hURAT1 transporter and are useful as therapeutic agents for hyperuricemia.

[Chemical Formula 1]

[Chemical Formula 2]

Furthermore, Patent Document 3 reports that benzbromarone derivatives represented by the following formula (C) exhibit hURAT1 inhibitory activity, have no drug-drug interaction with cytochrome P450 (CYP450), exhibit selectivity among organic anion transporters, and have higher solubility and metabolic stability.

[Chemical Formula 3]

The difference between the compound represented by the general formula (I) described below and the compounds represented by the above formulas (A) and (B) is that the ring to which the thioalkanoic acid is bonded in the former is a bicyclic compound, while the latter is a monocyclic compound.

The compound represented by the general formula (I) described below is clearly different in structure from the benzbromarone derivative represented by the above formula (C).

On the other hand, Patent Document 4 and Non-Patent Documents 10 and 11 report compounds represented by Formulas (D), (E), and (F) in which the quinoline or naphthalene ring is substituted with a phenyl group and a thioalkanoic acid or an oxoalkanoic acid. On the other hand, Non-Patent Documents 12 and 13 report compounds represented by Formulas (G) and (H) in which the 1,1'-binaphthyl structure is formed, wherein one naphthalene has an oxyacetic acid group at the 2-position and the other naphthalene has a hydroxyl group or a methoxy group at the 2'-position. However, these documents do not describe that all compounds represented by Formulas (D) to (H) have hURAT1 inhibitory activity.

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula 8]

Prior art literature

Patent Literature

Patent Document 1: WO2009/070740;

Patent Document 2: WO2011/159839;

Patent Document 3: Japanese Patent No. 5314123;

Patent Document 4: US2005/0080105;

Non-patent literature

Non-Patent Literature 1: Japan Gout/Nucleic Acid Metabolism Society Guidelines Revision Committee, Hyperuricemia/Gout Treatment Guidelines, 2nd Edition (Japan Gout/Nucleic Acid Metabolism Society Guidelines Revision Committee, Hyperuricemia/Gout Treatment Guidelines, 2nd Edition). Medical Review Co., Ltd. (2010);

Non-patent literature 2: Tomita Masako, Mizuno Shoichi, Is hyperuricemia increasing? Focusing on gender differences (高尿酸症は増加しているか？；性差を中心に). Gout and nucleic acid metabolism (苦风と納碼謝). 30, 1-4, 2006;

Non-Patent Document 3: Ministry of Health, Labour and Welfare, Basic Survey of National Life (Total Injury and Illness Numbers from Health Vote), and National Institute of Population and Social Security Research. Projected Population of Japan (Ministry of Health, Labour and Welfare, Basic Survey of National Life (Total Injury and Illness Numbers from Health Vote), National Institute of Population and Social Security Research, Japan's Future Projected Population) (December 2006 estimate).

Non-patent literature 4: Fini MA1, Elias A, Johnson RJ, Wright RM., Contribution ofuric acid to cancer risk, recurrence, and mortality. Clin Transl Med., 2012, 1, 1-15;

Non-patent literature 5: Zangcheng Masafumi, Hyperuricemia and Gout (Hyperuricemia and Gout). 2014, 22, 29-33;

Non-Patent Literature 6: Lipkowitz MS., Regulation of Uric Acid Excretion by the Kidney. Curr. Rheumatol. Rep. 2012, 14, 179-188;

Non-patent literature 7: Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, ChaSH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H., Molecular identification of arena urate anion exchanger that regulates blood urate levels.Nature.2002,417,447-452;

Non-patent literature 8: Kurumi Ichiro, Hyperuricemia and Gout (Hyperuricemia and Gout). 2014, 22, 16-22;

Non-patent literature 9: So A, Thorens B., Uric acid transport and disease. J. Clin. Invest. 2010, 120, 1791-1799;

Non-patent literature 10: European Journal of Organic Chemistry. 2011, 1, 53-57, S53/1-S53/65;

Non-patent document 11: Journal fuer Praktische Chemie (Leipzig). 1980, 322, 42-8;

Non-patent document 12: American Laboratory (Shelton, Connecticut). 1999, 31, 43-44, 46-47;

Non-patent literature 13: Bioorganic & Medicinal Chemistry. 2010, 18, 4793-4800.

Summary of the Invention

Problems to be solved by the invention

The object of the present invention is to provide a highly safe therapeutic or preventive agent for gout or hyperuricemia, which has an excellent effect of promoting uric acid excretion and does not cause serious side effects such as liver damage and cardiotoxicity.

In addition, the present invention also aims to provide a therapeutic or preventive agent for gout or hyperuricemia, which has an excellent effect of promoting uric acid excretion and has better solubility and metabolic stability.

Technical solutions to the problem

Specifically, the present invention relates to a compound represented by the following general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[Chemical Formula 9]

(Wherein, dotted lines represent single bonds or double bonds,

Q represents CR ⁸ , NR ⁹ or N,

When Q is CR ⁸ , R ³ and R ⁸ are combined with the ring formed by the dotted line to form a naphthalene ring or a quinoline ring.

Alternatively, they are bonded in any combination selected from the group consisting of ^R1 and ^R2 , ^R2 and ^R8 , and ^R3 and ^R8 , and are integrated with the two carbon atoms to which the combination is bonded to form a five-membered heteroaromatic ring, wherein the heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituents, and further, the heteroaromatic ring forms a condensed ring with the ring formed by the dotted line.

Here, the ring formed by the dotted line is the ring with the largest number of double bonds within the ring;

When Q is N, R ¹ and R ² are combined and become one with the ring formed by the dotted line to form a quinoline ring;

When Q is NR ⁹ , R ³ and R ⁹ or R ² and R ⁹ are combined and become one with the ring formed by the dotted line to form an imidazo[1,2-a]pyridine ring;

When R ¹ , R ² , R ³ and R ⁸ do not form a ring, they may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 12 carbon atoms, an alkyloxycarbonyl group having 1 to 8 carbon atoms, a hydroxyl group, an amino group, a carboxyl group, a nitro group, a cyano group, CONR'R", SR', or SO ₂ NR'R".

Here, R' and R" may be the same or different and are a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;

When R ¹ , R ² , R ³ and R ⁸ form a ring, the ring may have 1 to 4 identical or different substituents, which are the same as those for R ¹ in the case where they do not form a ring;

A represents phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl, and the phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl or isoquinolyl group may have 1 to 5 identical or different substituents, which are the same as ^R1 in the case of not forming a ring.

Here, A is bonded to the ring formed by the dotted line through the carbon atoms that constitute the ring;

X represents NR ¹¹ , an oxygen atom or a sulfur atom,

Here, R ¹¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms;

Y represents an alkylene chain having 1 to 8 carbon atoms,

Here, the alkylene chain may be substituted by 1 to 4 of the following groups, which are the same or different: an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a 3- to 7-membered cycloalkyl group, or a 4- to 7-membered saturated heterocyclic ring, wherein the 4- to 7-membered saturated heterocyclic ring contains 1 to 2 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms as ring constituents. In addition, the alkylene chain may be a linear alkylene chain or a branched alkylene chain. The side chains of the branched alkylene chain bonded to the same or different carbon atoms may be integrated with the carbon atom to which the side chains are bonded to form a 3- to 7-membered ring. Furthermore, when the alkylene chain is an alkylene chain having 2 to 8 carbon atoms, the chain may have a double bond.

Z represents CO ₂ H, CON(R ¹² )(R ¹³ ), CO ₂ (R ¹⁴ ), SO ₂ N(R ¹⁵ )(R ¹⁶ ) or tetrazolyl,

Here, R ¹² , R ¹⁴ and R ¹⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms;

^R13 and ^R16 represent: a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a phenyl group which may have a substituent, a pyridyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group which may have a substituent, or a five-membered heteroaromatic ring which may have a substituent and contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as ring constituents.

However, when ^R3 and ^R8 are bonded to form a naphthalene ring, X is an oxygen atom, A is naphthalene, and is bonded to the ring formed by the dotted line via the 1-position of A, the 2-position of A is not an alkoxy group having 1 to 8 carbon atoms or a hydroxy group, and is not ethyl 3-[[1-(2-fluorophenyl)naphthalen-2-yl]thio]propionate.)

The present invention also relates to a compound represented by the following general formula (III), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[Chemical Formula 10]

(wherein, R ^1a , R ^2a , R ^6a and R ^7a may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group or a cyano group;

R ^3a and R ^8a , together with the two carbon atoms to which R ^3a and R ^8a are bonded, form a benzene ring or a five-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituents.

Here, the benzene ring and the heteroaromatic ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

R ^4a and R ^5a are integrated with the two carbon atoms to which R ^4a and R ^5a are bonded to form a benzene ring, or R ^4a and R ^5a represent the same group as R ^1a above,

Here, the benzene ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

W ^a represents CR ^10a or N,

Here, R ^10a represents the same group as R ^1a above;

^Xa represents ^NR11a , an oxygen atom or a sulfur atom,

Here, R ^11a represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms;

Y ^a represents an alkylene chain having 1 to 8 carbon atoms,

Here, the alkylene chain may be substituted with 1 to 4 groups, which are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. In addition, the alkylene chain may be a linear alkylene chain or a branched alkylene chain. The side chains of the branched alkylene chain, which are bonded to the same or different carbon atoms, may be integrated with the carbon atoms to which the side chains are bonded to form a 3- to 7-membered ring. Furthermore, when the alkylene chain is an alkylene chain having 2 to 8 carbon atoms, the chain may have a double bond.

^Za represents _CO2H , ^tetrazolyl or _SO2NR15aR16a ^,

Here, R ^15a and R ^16a may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

However, when ^R3a and ^R8a are combined with the two carbon atoms to which ^R3a and ^R8a are bonded to form a benzene ring, ^Xa is an oxygen atom, and ^R4a and ^R5a are combined with the two carbon atoms to which ^R4a and ^R5a are bonded to form a benzene ring, ^R7a is not an alkoxy group having 1 to 8 carbon atoms or a hydroxy group.)

Furthermore, the present invention relates to a compound represented by the following general formula (IV), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[Chemical Formula 11]

(wherein, R ^1b , R ^2b , R ^4b , R ^5b , R ^6b , R ^7b and R ^10b may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group or a cyano group;

R ^3b and R ^8b , and the two carbon atoms to which R ^3b and ^8b are bound, are integrated to represent a five-membered heteroaromatic ring containing a total of two heteroatoms as ring constituents, one of which is a nitrogen atom and the other is an oxygen atom or a sulfur atom;

Here, the heteroaromatic ring may have a substituent selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

^Xb represents an oxygen atom or a sulfur atom;

^Yb represents an alkylene chain having 1 to 8 carbon atoms,

Here, the alkylene chain may be substituted with 1 to 4 groups, which are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. In addition, the alkylene chain may be a linear alkylene chain or a branched alkylene chain. The side chains of the branched alkylene chain, which are bonded to the same or different carbon atoms, may be integrated with the carbon atoms to which the side chains are bonded to form a 3- to 7-membered ring. Furthermore, when the alkylene chain is an alkylene chain having 2 to 8 carbon atoms, the chain may have a double bond.

The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, a compound represented by the above-mentioned general formula (I), (III) or (IV), a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention also relates to a URAT1 inhibitor comprising, as an active ingredient, a compound represented by the above-mentioned general formula (I), (III) or (IV), a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a solvate thereof.

In addition, the present invention relates to a therapeutic agent for gout or hyperuricemia, which contains, as an active ingredient, a compound represented by the above-mentioned general formula (I), (III) or (IV), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate thereof.

In addition, the present invention relates to the use of the compound represented by the above-mentioned general formula (I), (III) or (IV), the tautomers, stereoisomers of the compound, or their pharmaceutically acceptable salts, or the above-mentioned solvates in the treatment of gout or hyperuricemia.

In addition, the present invention relates to a method for treating gout or hyperuricemia in humans, which comprises the following steps: administering to humans an effective amount of a compound represented by the above-mentioned general formula (I), (III) or (IV), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or the above-mentioned solvate.

Furthermore, the present invention also relates to a method for screening a substance having a URAT1 inhibitory effect, the method comprising: culturing HEK293 cells stably expressing the URAT1 gene or HEK293 cells combined with an empty vector at a temperature of 37±1°C, then adding an uptake solution at a temperature of 37±1°C and a pH of 7.4±0.1, wherein the uptake solution is added with [ ¹⁴ C]uric acid and contains or does not contain a test compound, and further, after culturing at a temperature of 37±1°C for 2 to 10 minutes, stopping the reaction, washing, lysing the cells, and measuring the radiation dose.

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail.

In the present specification, examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

Examples of the C _1-3 alkyl group include a methyl group and an ethyl group.

Examples of the 3- to 7-membered cycloalkyl group include cyclopentyl and cyclohexyl.

Examples of the alkenyl group having 2 to 8 carbon atoms include allyl group.

Examples of the alkynyl group having 2 to 8 carbon atoms include propargyl and the like.

Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.

Examples of the C1-8 alkyl group substituted with 1 to 3 halogen atoms include methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups substituted with 1 to 3 halogen atoms such as fluorine, chlorine or bromine atoms, and preferably trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl groups are mentioned.

Examples of the alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy groups substituted by 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms and bromine atoms, and preferably trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy and 2-fluoroethoxy groups.

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

Examples of the alkylamino group having 1 to 8 carbon atoms include methylamino and ethylamino.

Examples of the dialkylamino group having 2 to 12 carbon atoms include dimethylamino and diethylamino.

Examples of the alkoxycarbonyl group having an alkyl group with 1 to 8 carbon atoms include a methoxycarbonyl group and an ethoxycarbonyl group.

In the general formula (I), when Q is CR ⁸ , it is bonded in any combination selected from R ¹ and R ² , R ² and R ⁸ , and R ³ and R ⁸ , and together with the two carbon atoms to which the any combination is bonded, forms a five-membered heteroaromatic ring. The five-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as ring constituent elements. Examples of the five-membered heteroaromatic ring include thiazole, isothiazole, oxazole, isoxazole, and 2,1,3-thiadiazole.

In the general formula (I), Y is an alkylene chain having 1 to 8 carbon atoms, and the substituent that Y may have is a 4- to 7-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms as ring constituent elements. Examples of the 4- to 7-membered saturated heterocyclic ring include a pyrrolidine ring, a piperidine ring, a tetrahydrofuran ring, and a morpholine ring.

In Z of the general formula (I), when R ¹³ or R ¹⁶ is a phenyl group which may have a substituent, a pyridyl group, a pyridazinyl group, a pyrimidinyl group or a pyrazinyl group which may have a substituent, or a five-membered heteroaromatic ring which may have a substituent, examples of the substituent include 1 to 4 identical or different substituents of the following: a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group or a cyano group, and the five-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as ring constituents.

In Z of the general formula (I), when R ¹³ or R ¹⁶ is a five-membered heteroaromatic ring which may have a substituent, examples of the heteroaromatic ring include thiazole and isothiazole, and the five-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as ring constituent elements.

In the general formula (III), when R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bonded to form a five-membered heteroaromatic ring, examples of the heteroaromatic ring include thiazole, isothiazole, oxazole, isoxazole, and 2,1,3-thiadiazole. The five-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms as ring constituents.

In the general formula (IV), examples of the five-membered heteroaromatic ring formed by integrating R ^3b and R ^8b with the two carbon atoms to which R ^3b and R ^8b are bonded include thiazole, isothiazole, oxazole, and isoxazole. The five-membered heteroaromatic ring contains a total of two heteroatoms as ring constituent elements, one of which is a nitrogen atom and the other is an oxygen atom or a sulfur atom.

When Y, ^Ya , and ^Yb in the general formulae (I), (III), and (IV), i.e., the alkylene chain, is a branched alkylene chain, the side chains bonded to the same or different carbon atoms may be integrated with the carbon atom to which the side chains are bonded to form a 3- to 7-membered ring. Examples of the 3- to 7-membered ring include cyclopropane, cyclobutane, and cyclopentane.

As the compound of the present invention represented by the above-mentioned general formula (I), the following compounds are preferred.

(1)

The compound represented by the above general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the above solvates, wherein A is a phenyl group, a naphthyl group or a pyridyl group which may have a substituent, and the substituent is selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a cyano group.

(2)

The compound represented by the above general formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein A is the following general formula (II),

[Chemical Formula 12]

(Here,

^R4 and ^R5 are integrated with the two carbon atoms to which ^R4 and ^R5 are bonded to form a benzene ring, or ^R4 and ^R5 may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

Here, the benzene ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

^R6 and ^R7 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group, or a cyano group;

W means CR ¹⁰ or N;

Here, R ¹⁰ represents the same group as R ⁶ above,

— indicates a bond.)

(3)

The compound as described in (2) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the solvate thereof, wherein:

^R4 and ^R5 are integrated with ^the two carbon atoms to ^which they are bonded to form a benzene ring, or ^R4 and ^R5 may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group;

Here, the benzene ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3-7 membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group;

^R6 and ^R7 are the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group.

(4)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein Q is CR ⁸ , the ring formed by the dotted line represents a benzene ring, R ³ and R ⁸ are bonded to form a naphthalene ring via the two carbon atoms to which R ³ and R ⁸ are bonded.

(5)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein Q is CR ⁸ , the ring formed by the dotted line represents a benzene ring, R ³ and R ⁸ are bonded to form a five-membered heteroaromatic ring together with the two carbon atoms to which R ³ and R ⁸ are bonded, and the five-membered heteroaromatic ring contains 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as ring constituents.

(6)

The compound of the above general formula (I) or any one of the above (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein Q is CR ⁸ , the ring formed by the dotted line represents a benzene ring, R ³ and R ⁸ are bonded to form a thiazole or isothiazole with the two carbon atoms to which R ³ and R ⁸ are bonded.

(7)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a solvate thereof, wherein, when R ¹ , R ² , R ³ and R ⁸ do not form a ring, R ¹ , R ² , R ³ and R ⁸ may be the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group or a cyano group.

(8)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein, when R ¹ , R ² , R ³ and R ⁸ do not form a ring, R ¹ , R ² , R ³ and R ⁸ may be the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group.

(9)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein, when R ¹ , R ² , R ³ and R ⁸ do not form a ring, R ¹ , R ² , R ³ and R ⁸ may be the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

(10)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein, when R ¹ , R ² , R ³ and R ⁸ form a ring, the substituent is a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, an alkylthio group having 1 to 8 carbon atoms, a nitro group or a cyano group.

(11)

The compound of the above-mentioned general formula (I) or any one of the above-mentioned (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein, when R ¹ , R ² , R ³ and R ⁸ form a ring, the substituent is a halogen atom, an alkyl group having 1 to 8 carbon atoms, a 3- to 7-membered cycloalkyl group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group.

(12)

The compound of the above general formula (I) or any one of the above (1) to (3), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or its solvate, wherein, when R ¹ , R ² , R ³ and R ⁸ form a ring, the substituents may be 1 to 4 identical or different groups, and the substituents are halogen atoms, alkyl groups having 1 to 8 carbon atoms, or alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

(13)

The compound as described in any one of (2) to (12) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the solvate thereof, wherein ^R4 and ^R5 may be the same or different and are a hydrogen atom, a halogen atom or an alkyl group having 1 to 8 carbon atoms.

(14)

The compound as described in any one of (2) to (13) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the solvate thereof, wherein ^R6 and ^R7 may be the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms or a cyano group.

(15)

The compound according to any one of (2) to (13) above, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or its solvate, wherein R ⁶ is cyano.

(16)

The compound according to any one of (2) to (15) above, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or its solvate, wherein W is CR ¹⁰ .

(17)

The compound as described in (16) above, its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or the solvate thereof, wherein R ¹⁰ is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 8 carbon atoms.

(18)

The compound of the above general formula (I) or any one of the above (1) to (17), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein X is an oxygen atom or a sulfur atom.

(19)

The compound of the above general formula (I) or any one of the above (1) to (17), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein X is a sulfur atom.

(20)

The compound of the above general formula (I) or any one of the above (1) to (19), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y represents an alkylene chain having 1 to 8 carbon atoms,

Here, the alkylene chain may be substituted by 1 to 4 identical or different groups, and the groups are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, and alkoxy groups having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms.

(twenty one)

The compound of the above general formula (I) or any one of the above (1) to (19), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y is C(C _1-3 alkyl) ₂ .

(twenty two)

The compound of the above general formula (I) or any one of the above (1) to (19), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y is CH=CH.

(twenty three)

The compound of the above general formula (I) or any one of the above (1) to (19), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y is C(C _1-3 alkyl)=CH.

(twenty four)

The compound of the above general formula (I) or any one of the above (1) to (19), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y is the following general formula (V),

[Chemical Formula 13]

(In the formula, R ⁰¹ and R ⁰² may be the same or different and represent an alkyl group having 1 to 8 carbon atoms, or R ⁰¹ and R ⁰² are bonded to form a 3- to 7-membered ring together with the carbon atom to which R ⁰¹ and R ⁰² are bonded, and — represents a bond.)

(25)

The compound of the above general formula (I) or any one of the above (1) to (24), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein:

Z represents CO ₂ H, CON(R ¹² )(R ¹³ ), CO ₂ (R ¹⁴ ), SO ₂ N(R ¹⁵ )(R ¹⁶ ) or tetrazolyl,

Here, R ¹² , R ¹⁴ and R ¹⁵ represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

R ¹³ and R ¹⁶ are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a phenyl group which may have a substituent, or a pyridyl group which may have a substituent.

(26)

The compound of the above general formula (I) or any one of the above (1) to (24), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Z is CO ₂ H.

As the compound of the present invention represented by the above-mentioned general formula (III), the following compounds are preferred.

(27)

The compound represented by the above-mentioned general formula (III), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned solvates, wherein R ^1a , R ^2a , R ^6a and R ^7a may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group;

R ^3a and R ^8a , together with the two carbon atoms to which R ^3a and R ^8a are bonded, form a benzene ring or a five-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituents;

Here, the benzene ring and the heteroaromatic ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group;

R ^4a and R ^5a are integrated with the two carbon atoms to which R ^4a and R ^5a are bonded to form a benzene ring, or R ^4a and R ^5a represent the same group as R ^1a described above;

Here, the benzene ring may have 1 to 4 identical or different substituents selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group.

(28)

The compound represented by the above-mentioned general formula (III) or the compound as described in the above-mentioned (27), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein R ^1a , R ^2a , R ^6a and R ^7a may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a cyano group.

(29)

The compound represented by the above general formula (III) or the compound described in (27) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein R ^6a is cyano.

(30)

The compound represented by the above general formula (III) or the compound as described in any one of (27) to (29) above, the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bonded to form a benzene ring.

(31)

The compound represented by the above-mentioned general formula (III) or the compound as described in any one of the above-mentioned (27) to (29), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bound to form a benzene ring, and the benzene ring may be substituted by 1 to 4 identical or different groups, which are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms or cyano groups.

(32)

The compound of the above-mentioned general formula (III) or any one of the above-mentioned (27) to (29), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bound to form a five-membered heteroaromatic ring, and the five-membered heteroaromatic ring contains two heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms as ring constituent elements.

(33)

The compound of the above-mentioned general formula (III) or any one of the above-mentioned (27) to (29), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bound to form thiazole or isothiazole.

(34)

The compound as described in (33) above, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the solvates thereof, wherein R ^3a and R ^8a are integrated with the two carbon atoms to which R ^3a and R ^8a are bound to form a thiazole or isothiazole, and the thiazole or isothiazole may be substituted by an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a cyano group.

(35)

The compound of the above general formula (III) or any one of the above (27) to (34), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein R ^4a and R ^5a may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a cyano group.

(36)

The compound of the above general formula (III) or any one of the above (27) to (35), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein ^Wa is ^CR10a .

(37)

The compound of the above general formula (III) or any one of the above (27) to (36), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein ^Xa is an oxygen atom or a sulfur atom.

(38)

The compound of the above general formula (III) or any one of the above (27) to (36), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein X ^a is a sulfur atom.

(39)

The compound of the above general formula (III) or any one of the above (27) to (38), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein ^Ya is represented by C( _C1-3alkyl ) ₂ .

(40)

The compound of the above general formula (III) or any one of the above (27) to (38), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein:

^Ya is represented by the following general formula (VI),

[Chemical Formula 14]

(In the formula, ^Ra01 and ^Ra02 may be the same or different and represent an alkyl group having 1 to 8 carbon atoms, or ^Ra01 and ^Ra02 are combined to form a 3- to 7-membered ring with the carbon atoms to which ^Ra01 and ^Ra02 are combined, and — represents a bonding bond.)

(41)

The compound of the above general formula (III) or any one of the above (27) to (40), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein ^Za is _CO2H .

As the compound of the present invention represented by the above-mentioned general formula (IV), the following compounds are preferred.

(42)

The compound represented by the above general formula (IV), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein:

R ^1b , R ^2b , R ^4b , R ^5b , R ^6b , R ^7b and R ^10b may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group or a cyano group;

R ^3b and R ^8b, together with the two carbon atoms to which R ^3b and ^8b are bonded, form a five-membered heteroaromatic ring, wherein the five-membered heteroaromatic ring contains a total of two heteroatoms as ring constituents, one heteroatom being a nitrogen atom, and the other heteroatom being an oxygen atom or a sulfur atom;

Here, the heteroaromatic ring may have a substituent selected from a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, a mercapto group, a nitro group, or a cyano group.

(43)

The compound represented by the above-mentioned general formula (IV) or the compound described in the above-mentioned (42), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned solvate, wherein R ^1b , ^{R 2b} , R 4b , R ^5b , R ^6b , R ^7b and R ^10b may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms or a cyano group.

(44)

The compound represented by the above general formula (IV) or the compound described in (42) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein R ^6b is cyano.

(45)

The compound represented by the above general formula (III) or the compound as described in any one of (42) to (44) above, the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the solvate thereof, wherein R ^3b and R ^8b are integrated with the two carbon atoms to which R ^3b and ^8b are bound to form thiazole or isothiazole.

(46)

The compound as described in (45) above, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the solvates thereof, wherein R ^3b and R ^8b are integrated with the two carbon atoms to which R ^3b and ^8b are bound to form a thiazole or isothiazole, and the thiazole or isothiazole may be substituted by a substituent selected from an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and a cyano group.

(47)

The compound represented by the above general formula (IV) or the compound as described in any one of (42) to (46) above, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein X ^b is a sulfur atom.

(48)

The compound of the above general formula (IV) or any one of the above (42) to (47), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y ^b is represented by C(C _1-3 alkyl) ₂ .

(49)

The compound of the above general formula (IV) or any one of the above (42) to (47), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the above solvate, wherein Y ^b is represented by the following general formula (VII),

[Chemical Formula 15]

(In the formula, R ^b01 and R ^b02 may be the same or different and represent an alkyl group having 1 to 8 carbon atoms, or R ^b01 and R ^b02 may be bonded to form a 3- to 7-membered ring together with the carbon atom to which R ^b01 and R ^b02 are bonded.)

Furthermore, the compounds of the present invention represented by the above-mentioned general formulae (I), (III) and (IV) are preferably the compounds shown below.

(50)

A compound, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from:

2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropanoic acid,

2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropanoic acid,

tert-Butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylic acid,

(Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylic acid,

2-methyl-2-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]propionic acid,

(E)-methyl 3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate,

(E)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylic acid,

(Z)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylic acid,

2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropanoic acid,

2-[[5-(4-cyanophenyl)quinolin-6-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[5-(4-cyanophenyl)quinolin-6-yl]thio]-2-methylpropanoic acid,

ethyl 2-[[7-(4-cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoic acid,

ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoic acid,

tert-Butyl (E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylate

(E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylic acid,

ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate,

tert-Butyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid,

ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoic acid,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropanoic acid,

2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropanoic acid,

2-[[4-(4-cyanophenyl)-1H-indol-5-yl]oxy]-2-methylpropanoic acid,

2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoic acid,

ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoate,

2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoic acid,

2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropanoic acid,

2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropanoic acid,

2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropanoic acid,

2-[[3-(4-cyanophenyl)quinolin-4-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[3-(4-cyanophenyl)quinolin-4-yl]thio]-2-methylpropanoic acid,

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-butenoic acid ethyl ester,

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-butenoic acid,

tert-Butyl 2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoate,

2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoic acid,

tert-Butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]acrylate

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]acrylic acid,

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropionamide,

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-N-(5-fluoropyridin-2-yl)-2-methylpropionamide,

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methyl-N-(1,3,4-thiadiazol-2-yl)propionamide,

tert-Butyl 2-[[4-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate,

and 2-[[4-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-22-methylpropanoic acid.

(51)

A compound, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from:

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-pentenoic acid ethyl ester,

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-pentenoic acid,

tert-Butyl 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid,

2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoic acid,

1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid ethyl ester,

1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid,

1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentane-1-carboxylic acid methyl ester,

1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentane-1-carboxylic acid,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3-methylbutanoate,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3-methylbutanoic acid,

ethyl 2-methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propionate,

2-Methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propanoic acid,

tert-Butyl 2-methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoic acid,

tert-Butyl 2-[[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoic acid,

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoic acid,

tert-Butyl 2-methyl-2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(4-cyanonaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyanonaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoic acid,

ethyl 2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoic acid,

ethyl 2-methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoate,

2-methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoic acid,

tert-Butyl 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate,

2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropionic acid ethyl ester,

2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropanoic acid,

2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropionic acid ethyl ester,

2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid,

tert-Butyl 5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]thio]-3-methylbenzo[d]isothiazol-7-yl]picolinate, and

2-[[7-[6-(Ethoxycarbonyl)pyridin-3-yl]-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid.

(52)

A compound, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is selected from:

5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]thio]-3-methylbenzo[d]isothiazol-7-yl]picolinic acid ethyl ester,

Ethyl 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylate

1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-ethylbutanoic acid,

2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3,3-dimethylbutanoic acid,

(E)-tert-Butyl 3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-butenoate,

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-butenoic acid, and

1-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclohexane-1-carboxylic acid.

Pharmaceutically acceptable salts of the compounds represented by the above-mentioned general formula (I), (III) or (IV) include: acid addition salts of the compounds with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, citric acid, tartaric acid and methanesulfonic acid; salts with inorganic salts such as sodium salts, potassium salts, lithium salts and calcium salts; and base addition salts with organic bases such as arginine and piperazine.

Furthermore, the compounds of the present invention may exist in stereoisomers such as cis/trans isomers, optically active forms, and racemic forms, all of which are encompassed by the present invention.

Furthermore, the compounds of the present invention may be tautomers, hydrates, solvates with organic solvents such as alcohols, derivatives substituted with stable isotopes such as deuterium, and prodrugs.

Next, a synthesis scheme of the compound of the present invention represented by the above-mentioned general formula (I), (III) or (IV) is shown below.

( 1) When X is an oxygen atom, Y is C(CH ₃ ) ₂ , and Z is CO ₂ H or CO ₂ (R ¹⁴ )

[Chemical Formula 16]

Method A

(First process)

[Chemical Formula 17]

(Second process)

[Chemical Formula 18]

(Third Process)

[Chemical Formula 19]

(Fourth Process)

[Chemical Formula 20]

(In the formula, Halo represents a halogen such as chlorine, bromine, or iodine; L is a halogen atom, a leaving group such as a methanesulfonyloxy group, and R ¹ , R ² , R ³ , R ¹⁴ , Q, A, and the dotted line are the same as those described above.)

1) Starting material (a) can be synthesized by known methods (WO2012/145728, WO2007/121484, etc.) and methods based on these methods. In addition, starting material (b) can be synthesized by known methods (Glen J. Pernia et al., J. Am. Chem. Soc., 1996, 118, 10220.; WO2001/021606, etc.) and methods based on these methods.

2) First process

The compound of general formula (c) can be obtained by coupling the starting materials (a) and (b) in a non-reactive solvent such as toluene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ethanol, or water in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide, and with or without an additive such as triphenylphosphine or cesium fluoride, using a catalyst such as tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex, or tris(dibenzylideneacetone)dipalladium. In this case, the reaction temperature is 60°C to 110°C.

3) Second process

The compound of general formula (d) can be obtained by the following methods: a method using boron tribromide or the like in a solvent that does not participate in the reaction, such as dichloromethane; or a method of carrying out a demethylation reaction of general formula (c) in a solvent that does not participate in the reaction, such as N,N-dimethylformamide, in the presence of an additive such as p-toluenesulfonic acid monohydrate, using lithium bromide or the like, at a temperature of 130°C to 200°C; or a method of carrying out a demethylation reaction of general formula (c) in the absence of a solvent, using pyridine hydrochloride or the like, at a temperature of 200°C to 230°C.

4) The third process

The compound (f) of the present invention can be derived by carrying out an alkylation reaction of the general formula (d) with the general formula (e) in a non-reactive solvent such as acetonitrile or N,N-dimethylformamide in the presence of a base such as potassium carbonate, sodium carbonate, or cesium carbonate. In this case, the reaction temperature is room temperature to 80°C.

5) The fourth process

The compound (g) of the present invention can be derived from the compound of the general formula (f) which is both a compound of the present invention and a production intermediate by using lithium hydroxide, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, etc. in a solvent such as methanol, ethanol, or water, or by using trifluoroacetic acid, etc. in a solvent that does not participate in the reaction such as dichloromethane, or under solvent-free conditions.

Alternatively, the compound of general formula (c) can also be produced by the following method B.

Method B

[Chemical Formula 21]

(In the formula, Halo represents a halogen such as chlorine, bromine, or iodine, and R ¹ , R ² , R ³ , Q, A, and the dotted line are the same as those described above.)

Starting material (h) can be synthesized by known methods (Pingping Tang et al., J. Am. Chem. Soc., 2010, 132, 12150; WO2001/055146, etc.) or methods based thereon. The coupling reaction of starting material (a) and starting material (h) can be carried out in the same manner as described in Method A above.

Alternatively, the compound of the general formula (c) can also be produced by the following method C.

Method C

[Chemical Formula 22]

(In the formula, Halo represents a halogen such as chlorine, bromine, or iodine, and R ¹ , R ² , R ³ , Q, and A are the same as those described above.)

Starting material (i) can be synthesized by known methods (WO2002/0019527, etc.) and methods based on these methods. In addition, starting material (j) can be synthesized by known methods (Lei Yu et al., Org. Lett., 2014, 16, 1346, etc.) and methods based on these methods. The coupling reaction of starting material (i) and starting material (j) can be carried out in the same manner as the method described in method A above.

(2) When X is a sulfur atom, Y is C(CH ₃ ) ₂ , and Z is CO ₂ H or CO ₂ (R ¹⁴ )

[Chemical Formula 23]

<D method>

(First process)

[Chemical Formula 24]

(Second process)

[Chemical Formula 25]

(Third Process)

[Chemical Formula 26]

(Fourth Process)

[Chemical Formula 27]

(Fifth Process)

[Chemical Formula 28]

(In the formula, L is a leaving group such as a halogen atom or a methanesulfonyloxy group, and R ¹ , R ² , R ³ , R ¹⁴ , Q, A, and the dotted line are the same as those described above.)

1) First process

The thiocarbamylation reaction of the general formula (d) is carried out using dimethylaminothiocarbonyl chloride in a solvent inert to the reaction, such as tetrahydrofuran, dioxane, or 1,2-dimethoxyethane, in the presence of a base such as triethylamine, pyridine, or 1,4-diazabicyclo[2.2.2]octane, and in the presence of an additive such as dimethylaminopyridine, thereby obtaining a compound of the general formula (j).

In this case, the reaction temperature is 60°C to 80°C.

2) Second process

The rearrangement reaction of the general formula (j) can be carried out in a solvent such as diphenyl ether or tetradecane that does not participate in the reaction, or in the absence of a solvent, thereby obtaining a compound of the general formula (k). In this case, the reaction temperature is 200°C to 250°C.

3) The third process

The compound of general formula (I) can be obtained by solvolysis of general formula (k) using sodium methoxide, sodium ethoxide, sodium hydroxide, etc. in a solvent such as methanol, ethanol, or water. In this case, the reaction temperature is 20°C to 70°C.

4) The fourth process

The alkylation reaction of the general formula (I) and the general formula (e) can be carried out in the same manner as in the third step of the aforementioned method A.

5) The fifth process

By carrying out the reaction in the same manner as described in the fourth step of the aforementioned method A, the compound (n) of the present invention can be derived from the compound of the general formula (m) which is both the compound of the present invention and a production intermediate.

Alternatively, the compound of general formula (I) can also be produced by the following method E.

<E Method>

(First process)

[Chemical Formula 29]

(Second process)

[Chemical formula 30]

(Third Process)

[Chemical Formula 31]

(In the formula, R ¹ , R ² , R ³ , Q, A and the dotted line are the same as those described above.)

1) First process

In a solvent that does not participate in the reaction, such as dichloromethane or N,N-dimethylformamide, in the presence of a base such as triethylamine or potassium carbonate, and in the presence of an additive such as dimethylaminopyridine, a trifluoromethanesulfonic acid anhydride, N-phenylbis(trifluoromethanesulfonimide), etc., a trifluoromethanesulfonic acid esterification reaction of the general formula (d) is carried out, thereby obtaining a compound of the general formula (o).

2) Second process

The compound of general formula (p) can be obtained by carrying out a coupling reaction of general formula (o) in a non-reactive solvent such as toluene, dioxane, or 1,2-dimethoxyethane in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, or lithium bis(trimethylsilyl)amide, and in the presence or absence of an additive such as triphenylphosphine or (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene, using a catalyst such as palladium acetate. Alternatively, a coupling reaction of general formula (o) can be carried out in a non-reactive solvent such as tert-butanol or water in the presence of a base such as potassium carbonate, cesium carbonate, or sodium carbonate, and in the presence of an additive such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, using a catalyst such as palladium acetate. In this case, the reaction temperature is 70°C to 110°C.

3) The third process

The compound of general formula (I) can be obtained by desilylation of general formula (p) using tetrabutylammonium fluoride or the like in a solvent inert to the reaction, such as tetrahydrofuran, or using an acidic aqueous solution such as hydrochloric acid or sulfuric acid.

(3) When X is an oxygen atom or a sulfur atom, Y is CH=CH, and Z is CO ₂ H or CO ₂ (R ¹⁴ )

[Chemical Formula 32]

<F method>

(First process)

[Chemical Formula 33]

(Second process)

[Chemical Formula 34]

(Wherein, R ¹ , R ² , R ³ , R ¹⁴ , X, Q, A and the dotted line are the same as those described above.)

(First process)

In a solvent that does not participate in the reaction, such as dichloromethane, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, in the presence of a base such as potassium carbonate, sodium carbonate, 1,4-diazabicyclo[2.2.2]octane, an olefination reaction of the general formula (d) with the general formula (q), or an olefination reaction of the general formula (I) with the general formula (q) is carried out to derive the compound (r) or the compound (s) of the present invention.

(Second process)

By carrying out the reaction in the same manner as described in the fourth step of the aforementioned method A, the compound (t) or (u) of the present invention can be derived from the compound of the general formula (r) or (s) which is both the compound of the present invention and a production intermediate.

(4) When X is an oxygen atom or a sulfur atom, Y is C(CH ₃ ) ₂ or CH═CH, and Z is CON(R ¹² )(R ¹³ )

[Chemical Formula 35]

G Method

(First process)

[Chemical Formula 36]

(Second process)

[Chemical Formula 37]

(Wherein, R ¹ , R ² , R ³ , R ¹² , R ¹³ , X, Y, Q, A and the dotted line are the same as those described above.)

(First process)

By conducting an acid chlorination reaction of the general formula (v) in a non-reactive solvent such as toluene or dichloromethane in the presence of thionyl chloride, oxalyl chloride, or the like, the general formula (w) can be derived as an intermediate.

(Second process)

The compound (y) of the present invention can be derived by subjecting the compound (w) to amidation reaction with the compound (x) in a solvent unrelated to the reaction, such as tetrahydrofuran or 1,2-dimethoxyethane, or by reacting the compound (w) with aqueous ammonia solution when R ¹² ═R ¹³ ═hydrogen.

Alternatively, the compound (y) of the present invention can also be produced by the following method H.

H Method

[Chemical Formula 38]

In a solvent that does not participate in the reaction, such as dichloromethane, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as triethylamine or diisopropylethylamine, a dehydration condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate is used to cause an amidation reaction between the general formula (v) and the general formula (x), thereby deriving the compound (y) of the present invention.

Other compounds of the present invention represented by the above-mentioned general formula (I), (III) or (IV) can be produced by referring to the above-mentioned synthesis scheme, the synthesis examples described below, and the above-mentioned patent documents.

Next, the pharmacological effects of the compounds of the present invention are described.

The present inventors conducted a study on the effect on URAT1, a uric acid transporter involved in uric acid uptake in the kidney.

More specifically, the assay involved culturing HET293 cells stably expressing the URAT1 gene (HEK-URAT1) or HET293 cells harboring an empty vector (HEK-mock) in a DMEM incubator. 1×10 ⁵ cells were seeded into a 24-well dish coated with poly-D-lysine and incubated before initiating the uptake assay.

After washing the cells with an experimental solution heated to 37°C, the cells were kept in equilibrium. After removing the buffer from the cells, 0.5 mL of an uptake solution containing or not containing a detection compound and 5 μM [14C] uric acid was added and cultured. Hanks buffer was added to stop cell uptake and washed. The cells were dissolved with 0.1N sodium hydroxide and the radiation dose was measured using LSC6100 (Aloka, Tokyo). The uptake of HEK-mock cells was subtracted from the value of HEK-URAT1 and converted to the amount of protein per mg of the cell. The uptake in the absence of a detection compound was taken as 100% to obtain the uptake rate of HEK-URAT1.

As described in Tables 1 to 3 of Examples 118 and 119 described later, it was found that the compounds of the present invention have excellent URAT1 inhibitory activity.

Therefore, the compounds of the present invention represented by the above-mentioned general formula (I), (III) or (IV) have excellent effects on promoting uric acid excretion and do not cause serious side effects such as liver damage and cardiotoxicity (hERG), and can be expected to be highly safe therapeutic or preventive agents for hyperuricemia.

In addition, the present invention has an excellent effect of promoting uric acid excretion, excellent solubility, and excellent metabolic stability in liver microsomes (MS), and can be expected to be a therapeutic or preventive agent for gout or hyperuricemia.

In addition, Patent Document 1 states: "Uric acid is a product of xanthine oxidation. However, uric acid metabolism disorders are not limited to these disorders and also include polycythemia vera, myelofibrosis, gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, heart disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, renal insufficiency, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, or sarcoidosis." Therefore, the compounds of the present invention having excellent URAT1 inhibitory activity may also be used for the same diseases.

The compound of the present invention can also be used as a therapeutic or preventive agent for gout or hyperuricemia by combining it with XOD inhibitors such as febuxostat, allopurinol, and topirox, or urine alkalinizing agents such as Uralyt (registered trademark) and baking soda.

The compound of the present invention can be administered to humans by an appropriate administration method such as oral administration or parenteral administration, preferably oral administration.

For preparation, the preparation can be made into dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories, etc. by methods commonly used in the field of pharmaceutical preparation technology.

In the preparation of these dosage forms, for example, when preparing tablets, commonly used excipients, disintegrants, binders, lubricants, dyes, etc. can be used. Here, as excipients, lactose, D-mannitol, crystalline cellulose, glucose, etc. can be mentioned; as disintegrants, starch, carboxymethylcellulose calcium (CMC-Ca), etc. can be mentioned; as lubricants, magnesium stearate, talc, etc. can be mentioned; as binders, hydroxypropyl cellulose (HPC), gelatin, polyvinyl pyrrolidone (PVP), etc. can be mentioned. When preparing injections, solvents, stabilizers, dissolution aids, suspending agents, emulsifiers, pain-relieving agents, buffers, preservatives, etc. can be used.

The dosage for an average adult is about 0.01 mg to 100 mg per day of the compound of the present invention as an active ingredient in the form of an injection, and 1 mg to 2000 mg per day in the form of an oral administration. However, the dosage can be increased or decreased depending on age, symptoms, etc.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

(Example 1)

Ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropanoate

[Chemical Formula 39]

(1) 2'-Methoxy-(1,1'-binaphthyl)-4-carbonitrile

4-Bromo-1-naphthonitrile (200 mg, 0.86 mmol), (2-methoxynaphthalen-1-yl)boronic acid (260 mg, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (70 mg, 0.09 mmol), potassium tert-butoxide (145 mg, 1.92 mmol), and cesium fluoride (196 mg, 1.29 mmol) were dissolved in dioxane (9 mL) and stirred at 80°C under a nitrogen atmosphere. After 16 hours, the reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2) to obtain the title compound (200 mg, 76% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.77 (s, 3H), 7.03 (d, 1H, J=9Hz), 7.2-7.3 (m, 1H), 7.3-7.5 (m, 3H), 7.44 (d, 1H, J=9H z), 7.48 (d, 1H, J=7Hz), 7.6-7.7 (m, 1H), 7.88 (d, 1H, J=8Hz), 8.0-8.1 (m, 2H), 8.34 (d, 1H, J=9Hz).

(2) 2'-Hydroxy-(1,1'-binaphthyl)-4-carbonitrile

The 2'-methoxy-(1,1'-binaphthyl)-4-carbonitrile (200 mg, 0.65 mmol) obtained above was dissolved in dichloromethane (7 mL). A 1.0 M solution of boron tribromide in dichloromethane (3.25 ml, 3.25 mmol) was added under an ice bath, and the mixture was stirred at room temperature under a nitrogen atmosphere. After 3 hours, 7 mL of 25% aqueous ammonia solution was added to the reaction mixture under an ice bath, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain the title compound (158 mg, yield 82%).

¹ H NMR (CDCl ₃ , 400MHz): δ=6.99 (d, 1H, J=8Hz), 7.2-7.4 (m, 3H), 7.4-7.6 (m, 2H), 7.61 (d, 1H, J=7Hz), 7.7- 7.8 (m, 1H) 7.87 (d, 1H, J=8Hz), 7.93 (d, 1H, J=9Hz), 8.10 (d, 1H, J=8Hz), 8.38 (d, 1H, J=8Hz).

(3) Ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropionate

The above-obtained 2'-hydroxy-(1,1'-binaphthyl)-4-carbonitrile (78 mg, 0.26 mmol) and potassium carbonate (108 mg, 0.78 mmol) were dissolved in dimethylformamide (3 mL), and ethyl 2-bromoisobutyrate (58 μL, 0.39 mmol) was added and stirred at 60 ° C. After 16 hours, the reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and then washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4) to obtain the title compound (108 mg, yield 100%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.2-1.3 (m, 9H), 4.20 (q, 2H, J=7Hz), 7.08 (d, 1H, J=9Hz), 7.23 (d, 1H, J=9Hz), 7 .3-7.6 (m, 5H), 7.68 (t, 1H, J=9Hz), 7.8-8.0 (m, 2H), 8.05 (d, 1H, J=7Hz), 8.34 (d, 1H, J=8Hz).

(Example 2)

2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 40]

Ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]oxy]-2-methylpropanoate (108 mg, 0.26 mmol) obtained in Example 1 was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and a 2M aqueous sodium hydroxide solution (0.5 mL) was added, followed by stirring at room temperature. After 1 hour, 1M hydrochloric acid (1 mL) was added to the reaction mixture to adjust the pH to 7, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol:chloroform = 1:10) to obtain the title compound (pale yellow crystals, 65 mg, 63% yield).

¹ H NMR (CDCl ₃ , 400MHz): 1.24 (s, 6H), 7.08 (d, 1H, J = 8Hz), 7.2-7.5 (m, 5H), 7.51 (d, 1H, J = 7Hz), 7.68 (t, 1H, J=6Hz), 7.87 (t, 2H, J=6Hz), 8.03 (d, 1H, J=7Hz), 8.34 (d, 1H, J=8Hz).

(Example 3)

Ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropanoate

[Chemical Formula 41]

(1) O-[4'-cyano-(1,1'-binaphthyl)-2-yl]dimethylthiocarbamate

2'-Hydroxy-(1,1'-binaphthyl)-4-carbonitrile (158 mg, 0.53 mmol) and 1,4-diazabicyclo[2.2.2]octane (119 mg, 1.06 mmol) obtained in Example 1 (2) were dissolved in dimethylformamide (5 mL), and dimethylaminothiocarbonyl chloride (98 mg, 0.80 mmol) was added and stirred at 80°C under a nitrogen atmosphere. After 16 hours, the reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain the title compound (63 mg, yield 31%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.55 (s, 3H), 3.17 (s, 3H), 7.17 (d, 1H, J = 8Hz), 7.3-7.4 (m, 1H), 7.4-7.6 (m, 4H) 7 .66 (d, 1H, J=7Hz), 7.6-7.8 (m, 1H), 7.97 (d, 1H, J=8Hz), 8.0-8.1 (m, 2H), 8.25 (d, 1H, J=8Hz).

(2) S-[4'-cyano-(1,1'-binaphthyl)-2-yl]dimethylthiocarbamate

The above-obtained dimethylthiocarbamic acid O-[4'-cyano-(1,1'-binaphthyl)-2-yl] (63 mg, 0.17 mmol) was stirred at 200°C. After 24 hours, the mixture was allowed to cool to room temperature. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2) to obtain the title compound (25 mg, 40% yield).

¹ H NMR (CDCl ₃ , 400MHz): 2.77 (br s, 3H), 2.90 (br s, 3H), 7.05 (d, 1H, J=8Hz), 7.2-7.8 (m, 6H), 7.76 (d, 1H, J=9Hz), 7.95 (d, 1H, J=8Hz), 8.0-8.1 (m, 2H), 8.36 (d, 1H, J=8Hz).

(3) 2'-Mercapto-(1,1'-binaphthyl)-4-carbonitrile

The above-obtained S-[4'-cyano-(1,1'-binaphthyl)-2-yl]dimethylthiocarbamate (25 mg, 0.065 mmol) was added to a 2M aqueous sodium hydroxide solution (0.5 mL) and stirred at room temperature. After 16 hours, 1M hydrochloric acid (1 mL) was added to the reaction mixture to adjust the pH to 7, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain the title compound (11 mg, 54% yield).

¹ H NMR (CDCl ₃ , 400MHz): 3.19 (s, 1H), 6.95 (d, 1H, J=8Hz), 7.2-7.3 (m, 1H), 7.35 (d, 1H, J=8Hz), 7.4-7.5 (m, 2 H), 7.5-7.6 (m, 2H), 7.7-7.8 (m, 1H), 7.8-8.0 (m, 2H), 8.10 (d, 1H, J=7Hz), 8.39 (d, 1H, J=8Hz).

(4) Ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropionate

Using the above-obtained 2'-mercapto-(1,1'-binaphthyl)-4-carbonitrile (11 mg, 0.035 mmol), the title compound (12 mg, yield 80%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.2-1.3 (m, 9H), 4.11 (q, 2H, J = 7Hz), 7.2-7.3 (m, 3H), 7.3-7.5 (m, 3H), 7.63 (d, 1H, J=9Hz), 7.6-7.7 (m, 1H), 7.8-8.0 (m, 2H), 8.04 (d, 1H, J=7Hz), 8.35 (d, 1H, J=9Hz).

(Example 4)

2-[[4'-Cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropanoic acid

[Chemical Formula 42]

Using ethyl 2-[[4'-cyano-(1,1'-binaphthyl)-2-yl]thio]-2-methylpropanoate (12 mg, 0.03 mmol) obtained in Example 3, the title compound (white crystals, 9 mg, yield 81%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.34 (s, 3H), 1.35 (s, 3H), 7.03 (d, 1H, J = 8Hz), 7.2-7.3 (m, 2H), 7.40-7.45 (m, 2H), 7.49 (t, 1H, J =7Hz), 7.68 (t, 1H, J=8Hz), 7.72 (d, 1H, J=9Hz), 7.91 (t, 2H, J=8Hz), 8.02 (d, 1H, J=7Hz), 8.35 (d, 1H, J=9Hz).

(Example 5)

tert-Butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate

[Chemical Formula 43]

tert-Butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate

[Chemical Formula 44]

4-(2-Hydroxynaphthalen-1-yl)benzonitrile (83 mg, 0.34 mmol) was dissolved in dimethylformamide (4 mL), and potassium carbonate (94 mg, 0.68 mmol) and tert-butyl propiolate (70 μL, 0.51 mmol) were added and stirred at 120°C. After 5 hours, the reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain tert-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (colorless oil, 32 mg, yield 25%) and tert-butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (colorless oil, 28 mg, yield 22%).

¹ H NMR (tert-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate, CDCl ₃ , 400 MHz): δ=1.45 (s, 9H), 5.20 (d, 1H, J=12 Hz), 7.34 (d, 1H, J=9 Hz), 7.4-7.5 (m, 5H), 7.57 (d, 1H, J=12 Hz), 7.80 (d, 2H, J=8 Hz), 7.92 (d, 1H, J=8 Hz), 7.97 (d, 1H, J=9 Hz).

¹ H NMR (tert-butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate, CDCl ₃ , 400 MHz): δ=1.40 (s, 9H), 4.90 (d, 1H, J=7 Hz), 6.60 (d, 1H, J=7 Hz), 7.38 (d, 1H, J=9 Hz), 7.4-7.6 (m, 5H), 7.79 (d, 2H, J=8 Hz), 7.91 (d, 1H, J=8 Hz), 7.95 (d, 1H, J=9 Hz).

(Example 6)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]oxy]acrylic acid

[Chemical Formula 45]

Tert-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (32 mg, 0.086 mmol) obtained in Example 5 was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added, followed by stirring at room temperature. After 4 hours, the pH was adjusted to 6 with a 2M aqueous sodium hydroxide solution in an ice bath, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 5:1) to obtain the title compound (brown powder, 8 mg, 67%).

¹ H NMR (CD ₃ OD, 400MHz): δ=5.17 (d, 1H, J=12Hz), 7.43 (d, 1H, J=9Hz), 7.5-7.6 (m, 5H), 7. 69 (d, 1H, J=12Hz), 7.8-7.9 (m, 2H), 7.98 (d, 1H, J=8Hz), 8.06 (d, 1H, J=9Hz).

(Example 7)

(Z)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]oxy]acrylic acid

[Chemical Formula 46]

Using tert-butyl (Z)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]acrylate (28 mg, 0.075 mmol) obtained in Example 5, the title compound (light brown powder, 10 mg, yield 42%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ = 4.95 (d, 1H, J = 7Hz), 6.95 (d, 1H, J = 7Hz), 7.4-7.5 (m, 4H), 7.5 -7.6 (m, 2H), 7.8-7.9 (m, 2H), 7.94 (dd, 1H, J=2Hz, 7Hz), 8.03 (d, 1H, J=9Hz).

(Example 8)

2-Methyl-2-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]propanoic acid

[Chemical Formula 47]

(1) 1-(Pyridin-3-yl)naphthalen-2-ol

Using 3-(2-methoxynaphthalen-1-yl)pyridine (450 mg, 1.91 mmol) as a starting material, the title compound (423 mg, yield 100%) was obtained by the same method as in Example 1(2).

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 7.3-7.4 (m, 4H), 7.90 (d, 1H, J = 9Hz), 7.92 (d, 1H, J = 9Hz), 7.99 (dd, 1H, J=5Hz, 8Hz), 8.36 (d, 1H, J=8Hz), 8.84 (d, 1H, J=5Hz), 8.87 (s, 1H), 10.06 (br s, 1H).

(2) 2-Methyl-2-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]propanoic acid

Using the above-obtained 1-(pyridin-3-yl)naphthalen-2-ol (50 mg, 0.23 mmol), the title compound (white powder, 8 mg, yield 41%) was obtained by the same method as in Example 1(3) and Example 2.

¹ H NMR (CD ₃ OD, 400 MHz): δ = 1.37 (s, 3H), 1.38 (s, 3H), 7.3-7.4 (m, 4H), 7.60 (dd, 1H, J = 5Hz, 8Hz), 7.8-7.9 (m, 3H), 8.5-8.6 (m, 2H).

(Example 9)

Methyl (E)-3-[[1-(Pyridin-3-yl)naphthalen-2-yl]oxyacrylate

[Chemical Formula 48]

1-(Pyridin-3-yl)naphthalen-2-ol (80 mg, 0.26 mmol) obtained in Example 8 (1) was dissolved in dimethylformamide (2 mL), and sodium hydroxide (16 mg, 0.4 mmol) was added under ice-cooling, and the mixture was stirred at room temperature. After 10 minutes, methyl propiolate (91 μL, 1.1 mmol) was added to the reaction solution, and the mixture was further stirred at 110°C. After 16 hours, water was added to the reaction solution under ice-cooling, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain (E)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate (25 mg, yield 22%) and (Z)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate crude product.

¹ H NMR ((E)-methyl 3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate, CDCl ₃ , 400 MHz): δ=3.65 (s, 3H), 5.25 (d, 1H, J=12 Hz), 7.32 (d, 1H, J=9 Hz), 7.4-7.5 (m, 4H), 7.6-7.7 (m, 2H), 7.90 (d, 1H, J=7 Hz), 7.95 (d, 1H, J=9 Hz), 8.60 (dd, 1H, J=1 Hz, 2 Hz), 8.68 (dd, 1H, J=2 Hz, 5 Hz).

(Example 10)

(E)-3-[[1-(Pyridin-3-yl)naphthalen-2-yl]oxy]acrylic acid

[Chemical Formula 49]

Using methyl (E)-3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate (16 mg, 0.05 mmol) obtained in Example 9, the title compound (white powder, 11 mg, yield 73%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ = 5.22 (d, 1H, J = 12Hz), 7.33 (d, 1H, J = 9Hz), 7.4-7.5 (m, 4H), 7.7-7.8 ( m, 2H), 7.91 (d, 1H, J=9Hz), 7.96 (d, 1H, J=9Hz), 8.61 (s, 1H), 8.69 (d, 1H, J=5Hz).

(Example 11)

(Z)-3-[[1-(Pyridin-3-yl)naphthalen-2-yl]oxy]acrylic acid

[Chemical Formula 50]

The crude product of (Z)-methyl 3-[[1-(pyridin-3-yl)naphthalen-2-yl]oxy]acrylate obtained in Example 9 was used in the same manner as in Example 2 to give the title compound (white powder, 2.6 mg, yield 84%).

¹ H NMR (CDCl ₃ , 400MHz): δ=5.04 (d, 1H, J=7Hz), 6.81 (d, 1H, J=7Hz), 7.39 (d, 1H, J=9Hz), 7.4-7.5 (m, 3H), 7.59 (d, 1H, J=9Hz), 7.81 (d, 1H, J=8Hz), 7.91 (d, 1H, J=9Hz), 7.97 (d, 1H, J=9Hz), 8.73 (d, 1H, J=4Hz), 8.78 (s, 1H).

(Example 12)

Ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropanoate

[Chemical Formula 51]

(1) 4-(6-methoxyquinolin-5-yl)benzonitrile

The title compound (slightly brown crystals, 160 mg, yield 48%) was obtained by the same method as in Example 1(1) using 5-bromo-6-methoxyquinoline (300 mg, 1.26 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ=3.89 (s, 3H), 7.29 (dd, 1H, J=4Hz, 9Hz), 7.49 (d, 2H, J=9Hz), 7.60 (d, 1H, J=9 Hz), 7.7-7.8 (m, 1H), 7.80 (d, 2H, J=8Hz), 8.21 (d, 1H, J=9Hz), 8.81 (dd, 1H, J=1Hz, 4Hz).

(2) Ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropanoate

The 4-(6-methoxyquinolin-5-yl)benzonitrile obtained above (160 mg, 0.61 mmol) was dissolved in dimethylformamide (6 mL), and lithium bromide (1.06 g, 12.2 mmol) and p-toluenesulfonic acid monohydrate (116 mg, 0.61 mmol) were added. The mixture was stirred at 180°C under a nitrogen atmosphere. After 2 hours, the reaction solution was allowed to cool to room temperature, adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Toluene (10 mL) was added to the resulting residue, and dimethylformamide was removed by azeotropic distillation to obtain crude 4-(6-hydroxyquinolin-5-yl)benzonitrile.

Using a portion of the crude 4-(6-hydroxyquinolin-5-yl)benzonitrile obtained above (82 mg, 0.33 mmol), the title compound (23 mg, yield 75%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.27 (t, 3H, J=7Hz), 1.41 (s, 6H), 4.26 (q, 2H, J=7H), 7.31 (dd, 1H, J=4Hz, 9Hz), 7.41 ( d, 1H, J=9Hz), 7.52 (d, 2H, J=9Hz), 7.7-7.9 (m, 3H), 8.80 (d, 1H, J=9Hz), 8.83 (dd, 1H, J=4Hz, 1Hz).

(Example 13)

2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 52]

Using ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]oxy]-2-methylpropanoate (30 mg, 0.08 mmol) obtained in Example 12, the title compound (pale yellow crystals, 6 mg, yield 22%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.38 (s, 6H), 7.3-7.4 (m, 1H), 7.51 (d, 2H, J=8Hz), 7.60 (d, 1H, J=9Hz), 7.7-7.9 (m, 3H), 8.00 (d, 1H, J=9Hz), 8.74 (dd, 1H, J=1Hz, 4Hz).

(Example 14)

Ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]thio]-2-methylpropanoate

[Chemical Formula 53]

(1) O-[5-(4-cyanophenyl)quinolin-6-yl]dimethylthiocarbamate

The crude 4-(6-hydroxyquinolin-5-yl)benzonitrile (82 mg) obtained in Example 12(2) was used as a starting material and the title compound (yellow crystals, 23 mg, yield 21%) was obtained by the same method as in Example 3(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.04 (s, 3H), 3.34 (s, 3H), 7.36 (dd, 1H, J=5Hz, 9Hz), 7.5-7.6 (m, 3H), 7.7-7.8 (m, 3H), 8.20 (d, 1H, J=9Hz), 8.93 (dd, 1H, J=2Hz, 4Hz).

(2) S-[5-(4-cyanophenyl)quinolin-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[5-(4-cyanophenyl)quinolin-6-yl] (23 mg, 0.07 mmol), the title compound (yellow amorphous, 4.5 mg, yield 20%) was obtained by the same method as in Example 3(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.96 (s, 6H), 7.34 (dd, 1H, J=4Hz, 9Hz), 7.44 (d, 2H, J=8Hz), 7.6-7.7 (m, 1H) , 7.79 (d, 2H, J=8Hz), 7.90 (d, 1H, J=9Hz), 8.18 (d, 1H, J=9Hz), 8.95 (dd, 1H, J=2Hz, 4Hz).

(3) Ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[5-(4-cyanophenyl)quinolin-6-yl] (4.5 mg, 0.01 mmol), the title compound (light yellow amorphous, 4.5 mg, yield 85%) was obtained by the same method as Example 3(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.2-1.4 (m, 3H), 1.38 (s, 6H), 4.0-4.2 (m, 2H), 7.34 (dd, 1H, J = 4Hz, 9Hz), 7.39 (d, 2H, J = 8Hz), 7.65 (d, 1H, J=9Hz), 7.80 (d, 2H, J=8Hz), 7.84 (d, 1H, J=9Hz), 8.10 (d, 1H, J=8Hz), 8.93 (dd, 1H, J=2Hz, 4Hz).

(Example 15)

2-[[5-(4-Cyanophenyl)quinolin-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 54]

Using ethyl 2-[[5-(4-cyanophenyl)quinolin-6-yl]thio]-2-methylpropanoate (4.5 mg, 0.012 mmol) obtained in Example 14, the title compound (pale yellow powder, 2.8 mg, yield 67%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.25 (s, 6H), 7.3-7.5 (m, 3H), 7.75 (d, 1H, J=8Hz), 7.82 (d, 2H, J=8Hz), 7.98 (d, 1H, J=9Hz), 8.00 (d, 1H, J=9Hz), 8.9-9.0 (m, 1H).

(Example 16)

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoate

[Chemical Formula 55]

(1) 2-iodo-3-methoxy-6-nitrophenol

2-Iodobenzene-1,3-diol (1 g, 4.24 mmol) was dissolved in acetic acid (10 mL), and fuming nitric acid (210 μL, 5.08 mmol) was added dropwise in a water bath. After 5 minutes, ice was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.

The obtained residue was dissolved in dimethylformamide (15 mL), and potassium carbonate (1.89 g, 13.7 mmol) and iodomethane (1.69 mL, 27.4 mmol) were added and stirred at room temperature. After 18 hours, 1 M hydrochloric acid (1 mL) was added to the reaction solution, the pH was adjusted to 5, and diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (180 mg, yield 22%).

¹ H NMR (CDCl ₃ , 400MHz): δ=4.03 (s, 3H), 6.56 (d, 1H, J=9Hz), 8.21 (d, 1H, J=9Hz), 11.73 (s, 1H).

(2) 2'-Hydroxy-6'-methoxy-3'-nitro-(1,1'-biphenyl)-4-carbonitrile

The above-obtained 2-iodo-3-methoxy-6-nitrophenol (180 mg, 0.61 mmol), 4-cyanophenylboronic acid (108 mg, 0.73 mmol), tetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 6 μmol), triphenylphosphine (21 mg, 0.08 mmol), and potassium carbonate (169 mg, 1.22 mmol) were dissolved in toluene (6 mL), ethanol (3 mL), and water (1.5 mL). The mixture was stirred at 80°C under a nitrogen atmosphere. After 16 hours, the reaction mixture was allowed to cool to room temperature, adjusted to pH 5 by adding 1M hydrochloric acid, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain the title compound (110 mg, 76% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.89 (s, 3H), 6.71 (d, 1H, J=9Hz), 7.49 (d, 2H, J=8Hz), 7.74 (d, 2H, J=8Hz), 8.25 (d, 1H, J=9Hz), 11.19 (s, 1H).

(3) 4-(6-methoxybenzo[d]oxazol-7-yl)benzonitrile

The 2'-hydroxy-6'-methoxy-3'-nitro-(1,1'-biphenyl)-4-carbonitrile (50 mg, 0.19 mmol) obtained above was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 10% palladium on carbon (10 mg) was added under a nitrogen atmosphere, and a catalytic hydrogenation reaction was carried out at room temperature for 2 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure.

The resulting residue was dissolved in triethyl orthoformate (2 mL) and stirred at 150°C under a nitrogen atmosphere for 16 hours. The reaction solution was allowed to cool to room temperature, toluene (10 mL) was added, and the solvent was removed by azeotropic distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2) to obtain the title compound (20 mg, 42% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.91 (s, 3H), 7.13 (d, 1H, J=9Hz), 7.7-8.0 (m, 5H), 8.03 (s, 1H).

(4) Ethyl 2-[[7-(4-cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(6-methoxybenzo[d]oxazol-7-yl)benzonitrile (20 mg, 0.08 mmol), a crude product of 4-(6-hydroxybenzo[d]oxazol-7-yl)benzonitrile was obtained by the same method as in Example 12(2). The crude product was then used in the same manner as in Example 1(3) to obtain the title compound (colorless, transparent oil, 11 mg, 0.03 mmol, 39% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.27 (t, 3H, J = 7Hz), 1.45 (s, 6H), 4.25 (q, 2H, J = 7Hz), 7.03 (d, 1H, J =9Hz), 7.68 (d, 1H, J=9Hz), 7.78 (d, 2H, J=9Hz), 7.86 (d, 2H, J=9Hz), 8.06 (s, 1H).

(Example 17)

2-[[7-(4-Cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 56]

Using ethyl 2-[[7-(4-cyanophenyl)benzo[d]oxazol-6-yl]oxy]-2-methylpropanoate (11 mg, 0.03 mmol) obtained in Example 16, the title compound (white crystals, 2.9 mg, yield 29%) was obtained by the same method as in Example 2.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.44 (s, 6H), 7.17 (d, 1H, J=9Hz), 7.67 (d, 1H, J=9Hz), 7.84 (d, 2H, J=9Hz), 7.90 (d, 2H, J=9Hz), 8.42 (s, 1H)

(Example 18)

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoate

[Chemical Formula 57]

(1) 4-(6-methoxybenzo[d]thiazol-7-yl)benzonitrile

The title compound (off-white crystals, 761 mg, yield 70%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]thiazole (1.0 g, 4.1 mmol) and 4-cyanophenylboronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ=3.87 (s, 3H), 7.24-7.28 (m, 1H), 7.68 (d, 2H, J=8Hz), 7.77 (d, 2H, J=9Hz), 8.11 (d, 1H, J=9Hz), 8.82 (s, 1H).

(2) 4-(6-Hydroxybenzo[d]thiazol-7-yl)benzonitrile

The above-obtained 4-(6-methoxybenzo[d]thiazol-7-yl)benzonitrile (870 mg, 3.27 mmol) was mixed with pyridine hydrochloride (9 g) and stirred at 200°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate. The precipitated crystals were separated by filtration and dried under reduced pressure to obtain the title compound (830 mg, 100%).

¹ H NMR (CD ₃ OD, 400MHz): δ=7.20 (d, 1H, J=9Hz), 7.79 (d, 2H, J=8Hz), 7.85 (d, 2H, J=8Hz), 7.90 (d, 1H, J=9Hz), 8.98 (s, 1H).

(3) Ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(6-hydroxybenzo[d]thiazol-7-yl)benzonitrile (38 mg, 0.15 mmol), the title compound (colorless oil, 36 mg, yield 67%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.27 (t, 3H, J=7Hz), 1.43 (s, 6H), 4.25 (q, 2H, J=7Hz), 7.17 (d, 1H, J =9Hz), 7.74 (d, 2H, J=8Hz), 7.78 (d, 2H, J=8Hz), 8.02 (d, 1H, J=9Hz), 8.88 (s, 1H).

(Example 19)

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 58]

Using ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropanoate (36 mg, 0.1 mmol) obtained in Example 18, the title compound (white crystals, 22 mg, yield 65%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.46 (s, 6H), 7.29 (d, 1H, J=9Hz), 7.72 (d, 2H, J=8Hz), 7.80 (d, 2H, J=8Hz), 8.05 (d, 1H, J=9Hz), 8.93 (s, 1H).

(Example 20)

tert-Butyl (E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylate

[Chemical Formula 59]

4-(6-Hydroxybenzo[d]thiazol-7-yl)benzonitrile (50 mg, 0.98 mmol) obtained in Example 18 (2) was dissolved in dichloromethane (2 mL), 1,4-diazabicyclo[2.2.2]octane (2.2 mg, 0.02 mmol) and tert-butyl propiolate (33 μL, 0.24 mmol) were added, and the mixture was stirred at room temperature. After 2 hours, water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1) to obtain the title compound (69 mg, yield 92%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.46 (s, 9H), 5.31 (d, 1H, J=12Hz), 7.39 (d, 1H, J=9Hz), 7.58 (d, 1H, J=12Hz ), 7.66 (dd, 2H, J=2Hz, 8Hz), 7.80 (dd, 2H, J=2Hz, 8Hz), 8.18 (d, 1H, J=9Hz), 9.00 (s, 1H).

(Example 21)

(E)-3-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylic acid

[Chemical Formula 60]

Using tert-butyl (E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylate (67 mg, 0.18 mmol) obtained in Example 20, the title compound (33 mg, yield 58%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ = 5.36 (d, 1H, J = 12Hz), 7.52 (d, 1H, J = 9Hz), 7.55 (d, 1H, J = 12Hz), 7.7 6 (dt, 2H, J=2Hz, 9Hz), 7.89 (dt, 2H, J=2Hz, 9Hz), 8.16 (d, 1H, J=9Hz), 9.22 (s, 1H).

(Example 22)

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 61]

(1) O-[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]dimethylthiocarbamate

4-(6-Hydroxybenzo[d]thiazol-7-yl)benzonitrile (800 mg, 3.17 mmol), triethylamine (1.1 mL, 7.93 mmol), and dimethylaminopyridine (97 mg, 0.79 mmol) obtained in Example 18 (2) were dissolved in 1,2-dimethoxyethane (20 mL), and dimethylaminothiocarbonyl chloride (802 mg, 6.34 mmol) was added, and the mixture was stirred at 80°C under a nitrogen atmosphere. After 15 hours, the reaction solution was allowed to cool to room temperature, water was added, and extraction was carried out with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain the title compound (641 mg, yield 60%).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.12 (s, 3H), 3.33 (s, 3H), 7.36 (d, 1H, J=9Hz), 7.69 (d, 2H, J=9Hz), 7.76 (d, 2H, J=9Hz), 8.16 (s, 1H), 8.98 (s, 1H).

(2) S-[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)benzo[d]thiazol-6-yl] (640 mg, 1.89 mmol), the title compound (yellow crystals, 420 mg, yield 66%) was obtained by the same method as in Example 3(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.94 (s, 6H), 7.55 (d, 2H, J=8Hz), 7.7-7.8 (m, 3H), 8.15 (d, 1H, J=9Hz), 9.02 (s, 1H).

(3) 4-(6-Mercaptobenzo[d]thiazol-7-yl)benzonitrile

The above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)benzo[d]thiazol-6-yl] (100 mg, 0.30 mmol) was dissolved in ethanol (3 mL), and 20% sodium ethoxide-ethanol solution (167 μ, 0.38 mmol) was added and stirred at 40° C. for 21 hours under a nitrogen environment. 3 M hydrochloric acid was added to the reaction solution to adjust the pH to 6. After extraction with ethyl acetate, the organic layer was washed with saturated brine. Dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 1:20) to obtain the title compound (71 mg, yield 90%).

¹ H NMR (CDCl ₃ , 400MHz): δ=7.54 (d, 1H, J=8Hz), 7.60 (d, 2H, J=8Hz), 7.84 (d, 2H, J=9Hz), 8.00 (d, 1H, J=9Hz), 8.88 (s, 1H).

(4) Ethyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained 4-(6-mercaptobenzo[d]thiazol-7-yl)benzonitrile (36 mg, 0.13 mmol), the title compound (colorless oil, 43 mg, yield 85%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.19 (t, 3H, J=7Hz), 1.31 (s, 6H), 4.02 (q, 2H, J=7Hz), 7.57 (d, 2H, J =9Hz), 7.76 (d, 1H, J=9Hz), 7.80 (d, 2H, J=9H), 8.10 (d, 1H, J=9Hz), 9.04 (s, 1H).

(Example 23)

tert-Butyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 62]

Using 4-(6-mercaptobenzo[d]thiazol-7-yl)benzonitrile (110 mg, 0.41 mmol) and tert-butyl 2-bromoisobutyrate (152 μL, 0.82 mmol) obtained in Example 22(3), the title compound (pale yellow oil, 94 mg, yield 60%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.25 (s, 6H), 1.45 (s, 9H), 7.55 (d, 2H, J=8Hz), 7.80-7.82 (m, 3H), 8.09 (d, 1H, J=8Hz), 9.01 (s, 1H).

(Example 24)

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 63]

Using tert-butyl 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate (94 mg, 0.23 mmol) obtained in Example 23, the title compound (pale yellow crystals, 52 mg, yield 64%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.36 (s, 6H), 7.59 (d, 2H, J=8Hz), 7.78 (d, 2H, J=8Hz), 7.84 (d, 1H, J=8Hz), 8.08 (d, 1H, J=8Hz), 9.08 (s, 1H).

(Example 25)

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate

[Chemical Formula 64]

(1) 7-Bromobenzo[d]isothiazol-6-ol

Benzo[d]isothiazol-6-ol (410 g, 2.7 mmol) was dissolved in acetic acid (8 mL), bromine (0.14 mL, 2.7 mmol) was added, and the mixture was stirred at room temperature. After 2 hours, ice water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, 10% sodium thiosulfate aqueous solution, and saturated brine, and then dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane to obtain the title compound (540 mg, 87% yield).

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 5.94 (s, 1H), 7.15 (d, 1H, J = 9Hz), 7.90 (d, 1H, J = 9Hz), 8.87 (s, 1H).

(2) 4-(6-Hydroxybenzo[d]isothiazol-7-yl)benzonitrile

Using the above-obtained 7-bromobenzo[d]isothiazol-6-ol (750 mg, 3.26 mmol) and (4-cyanophenyl)boronic acid, the title compound (brown crystals, 280 mg, yield 34%) was obtained by the same method as in Example 1(1).

¹ H NMR (DMSO-d ₆ , 400MHz): δ=5.64 (s, 1H), 7.14 (d, 1H, J=9Hz), 7.79 (d, 2H, J=8Hz), 7.86 (d, 2H, J=8Hz), 7.96 (d, 1H, J=9Hz), 8.84 (s, 1H).

(3) Ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(6-hydroxybenzo[d]isothiazol-7-yl)benzonitrile (20 mg, 0.08 mmol), the title compound (colorless oil, 20 mg, yield 28%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.25 (t, 3H, J=7Hz), 1.51 (s, 6H), 4.25 (q, 2H, J=7Hz), 7.06 (d, 1H, J=9Hz), 7.7-7.8 (m, 4H), 7.94 (d, 1H, J=9Hz), 8.85 (s, 1H).

(Example 26)

2-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 65]

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate (8 mg, 0.022 mmol) obtained in Example 25 was dissolved in tetrahydrofuran (0.1 mL) and methanol (0.1 mL). Water (0.1 mL) and lithium hydroxide monohydrate (1.9 mg, 0.045 mmol) were added and stirred at room temperature. After 18 hours, the reaction mixture was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol = 20:1) to obtain the title compound (brown crystals, 7 mg, 95% yield).

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.50 (s, 6H), 7.16 (d, 1H, J=9Hz), 7.84 (d, 2H, J=8Hz), 8.01 (d, 2H, J=8Hz), 8.20 (d, 1H, J=9Hz), 9.09 (s, 1H).

(Example 27)

Ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 66]

(1) O-[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using 4-(6-hydroxybenzo[d]isothiazol-7-yl)benzonitrile (0.25 mg, 1.0 mmol) obtained in Example 25(2), the title compound (pale yellow crystals, 190 mg, yield 56%) was obtained by the same method as in Example 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.17 (s, 3H), 3.37 (s, 3H), 7.33 (d, 1H, J=9Hz), 7.75 (d, 2H, J=8Hz), 7.79 (d, 2H, J=8Hz), 8.09 (d, 1H, J=9Hz), 8.95 (s, 1H).

(2) S-[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl] (190 mg, 0.56 mmol), the title compound (slightly yellow crystals, 150 mg, yield 79%) was obtained at 250°C by the same method as in Example 3(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.60 (d, 2H, J=8Hz), 7.72 (d, 1H, J=8Hz), 7.79 (d, 2H, J=8Hz), 8.08 (d, 1H, J=8Hz), 8.97 (s, 1H).

(3) 4-(6-Mercaptobenzo[d]isothiazol-7-yl)benzonitrile

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl] (146 mg, 0.43 mmol), the title compound (slightly yellow oil, 35 mg, yield 30%) was obtained by the same method as Example 22(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.52 (s, 1H), 7.45 (d, 1H, J=8Hz), 7.66 (d, 2H, J=8Hz), 7.86 (d, 2H, J=8Hz), 7.91 (d, 1H, J=8Hz), 8.87 (s, 1H).

(4) Ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (35 mg, 0.13 mmol), the title compound (colorless oil, 33 mg, yield 66%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.20 (t, 3H, J=7Hz), 1.35 (s, 6H), 4.05 (q, 2H, J=7Hz), 7.61 (d, 2H, J =8Hz), 7.66 (d, 1H, J=8Hz), 7.81 (d, 2H, J=8Hz), 8.01 (d, 1H, J=8Hz), 8.95 (s, 1H).

(Example 28)

2-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 67]

Using ethyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (33 mg, 0.09 mmol) obtained in Example 27, the title compound (white crystals, 20 mg, yield 65%) was obtained by the same method as in Example 26.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.29 (s, 6H), 7.67 (d, 2H, J=8Hz), 7.74 (d, 1H, J=8Hz), 8.01 (d, 2H, J=8Hz), 8.26 (d, 1H, J=8Hz), 9.23 (s, 1H).

(Example 29)

Ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropanoate

[Chemical Formula 68]

(1) 4-(5-Hydroxybenzo[c][1,2,5]thiadiazol-4-yl)benzonitrile

The title compound (yellow crystals, 110 mg, yield 18%) was obtained by the same method as in Example 1(1) using benzo-4-bromobenzo[c][1,2,5]thiadiazol-5-ol (560 mg, 2.42 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ=5.73 (s, 1H), 7.45 (d, 1H, J=10Hz), 7.81 (d, 2H, J=8Hz), 7.88 (d, 2H, J=8Hz), 7.96 (d, 1H, J=10Hz).

(2) Ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(5-hydroxybenzo[c][1,2,5]thiadiazol-4-yl)benzonitrile (28 mg, 0.11 mol), the title compound (colorless oil, 24 mg, yield 59%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.29 (t, 3H, J=7Hz), 1.47 (s, 6H), 4.27 (q, 2H, J=7Hz), 7.43 (d, 1H, J=9Hz), 7.79 (d, 2H, J=9Hz), 7.86 (d, 2H, J=9Hz), 7.94 (d, 1H, J=9Hz).

(Example 30)

2-[[4-(4-Cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 69]

Using ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropanoate (24 mg, 0.07 mmol) obtained in Example 29, the title compound (slightly brown crystals, 17 mg, yield 77%) was obtained by the same method as Example 26.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.49 (s, 6H), 7.53 (d, 1H, J=9Hz), 7.80 (d, 2H, J=8Hz), 7.84 (d, 2H, J=8Hz), 7.98 (d, 1H, J=9Hz).

(Example 31)

Ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropanoate

[Chemical Formula 70]

(1) O-[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]dimethylthiocarbamate

Using 4-(5-hydroxybenzo[c][1,2,5]thiadiazol-4-yl)benzonitrile (110 mg, 0.43 mmol) obtained in Example 29(1), the title compound (pale yellow crystals, 140 mg, yield 95%) was obtained by the same method as Example 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.19 (s, 3H), 3.40 (s, 3H), 7.54 (d, 1H, J = 9Hz), 7.79 (s, 4H), 8.02 (d, 1H, J = 9Hz).

(2) S-[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazole-5-yl] (116 mg, 0.34 mmol), the title compound (brown crystals, 80 mg, yield 69%) was obtained by the same method as in Example 3(2) at a temperature of 250°C.

¹ H NMR (CDCl ₃ , 400MHz): δ=3.01 (s, 6H), 7.61 (d, 2H, J=8Hz), 7.80 (d, 2H, J=8Hz), 7.82 (d, 1H, J=9Hz), 8.03 (d, 1H, J=9Hz).

(3) 4-(5-Mercaptobenzo[c][1,2,5]thiadiazol-4-yl)benzonitrile

Using the above-obtained dimethylthiocarbamic acid S-[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl] (79 mg, 0.23 mmol), the title compound (yellow-brown crystals, 55 mg, yield 87%) was obtained by the same method as Example 22(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.61 (s, 1H), 7.58 (d, 1H, J=9Hz), 7.67 (d, 2H, J=8Hz), 7.87 (d, 2H, J=8Hz), 7.92 (d, 1H, J=9Hz).

(4) Ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropanoate

Using the above-obtained 4-(5-mercaptobenzo[c][1,2,5]thiadiazol-4-yl)benzonitrile (54 mg, 0.2 mmol), the title compound (slightly yellow crystals, 49 mg, yield 65%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.22 (t, 3H, J=7Hz), 1.39 (s, 6H), 4.07 (q, 2H, J=7Hz), 7.60 (d, 2H, J=9Hz), 7.79 (d, 1H, J=9Hz), 7.81 (d, 2H, J=9Hz), 7.97 (d, 1H, J=9Hz).

(Example 32)

2-[[4-(4-Cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropanoic acid

[Chemical Formula 71]

Using ethyl 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropanoate (49 mg, 0.13 mmol) obtained in Example 31, the title compound (pale yellow crystals, 30 mg, yield 65%) was obtained by the same method as in Example 26.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.43 (s, 6H), 7.60 (d, 2H, J=8Hz), 7.79 (d, 2H, J=8Hz), 7.87 (d, 1H, J=9Hz), 7.99 (d, 1H, J=9Hz).

(Example 33)

2-[[4-(4-Cyanophenyl)-1H-indol-5-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 72]

(1) 4-[5-Hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]benzonitrile

The title compound (330 mg, yield 57%) was obtained by the same method as in Example 1(1) using 4-bromo-1-(phenylsulfonyl)-1H-indol-5-ol (530 mg, 1.5 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ=4.94 (s, 1H), 6.41 (d, 1H, J=4Hz), 6.97 (d, 1H, J=9Hz), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 4H), 7.78 (d, 2H, J=8Hz,), 7.8-8.0 (m, 3H).

(2) 2-[[4-(4-Cyanophenyl)-1H-indol-5-yl]oxy]-2-methylpropanoic acid

Using the above-obtained 4-[5-hydroxy-1-(phenylsulfonyl)-1H-indol-4-yl]benzonitrile (78 mg, 0.2 mmol), the title compound (white crystals, 3 mg, yield 5%) was obtained by the same method as in Example 1(3) and Example 26.

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 1.21 (s, 6H), 6.20 (s, 1H), 6.88 (d, 1H, J = 9Hz), 7.37 (d, 1H, J = 9Hz), 7.38 (s, 1H), 7.72 (d, 2H, J=8Hz), 7.91 (d, 2H, J=8Hz,), 11.22 (s, 1H).

(Example 34)

Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate

[Chemical Formula 73]

(1) 4-(5-methoxybenzo[d]thiazol-6-yl)benzonitrile

The title compound (brown crystals, 99 mg, yield 29%) was obtained by the same method as in Example 1(1) using 6-bromo-5-methoxybenzo[d]thiazole (332 mg, 1.36 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.91 (s, 3H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 3H), 7.82 (s, 1H), 9.01 (s, 1H).

(2) 4-(5-Hydroxybenzo[d]thiazol-6-yl)benzonitrile

Using the above-obtained 4-(5-methoxybenzo[d]thiazol-6-yl)benzonitrile (98 mg, 0.37 mmol), the title compound (brown crystals, 98 mg, yield 100%) was obtained by the same method as in Example 18(2).

¹ H NMR (CD ₃ OD, 400MHz): δ = 7.7-7.8 (m, 5H), 7.84 (s, 1H), 9.03 (s, 1H).

(3) Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(5-hydroxybenzo[d]thiazol-6-yl)benzonitrile (140 mg, 0.56 mmol), the title compound (yellow amorphous, 53 mg, yield 26%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.27 (t, 3H, J = 7Hz), 1.53 (s, 6H), 4.27 (q, 2H, J = 7Hz), 7.61 (s, 1H), 7.72 (s, 4H), 7.86 (s, 1H), 9.01 (s, 1H).

(Example 35)

2-[[6-(4-Cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 74]

Using ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate (52 mg, 0.142 mmol) obtained in Example 34, the title compound (white crystals, 23 mg, yield 48%) was obtained by the same method as in Example 2.

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 1.53 (s, 6H), 7.65 (s, 1H), 7.80 (s, 4H), 8.04 (s, 1H), 9.25 (s, 1H).

(Example 36)

Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoate

[Chemical Formula 75]

(1) 4-(7-methoxybenzo[d]thiazol-6-yl)benzonitrile

Using 6-bromo-7-methoxybenzo[d]thiazole (396 mg, 1.62 mmol) and (4-cyanophenyl)boronic acid (357 mg, 2.43 mmol), the title compound (white crystals, 267 mg, yield 62%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.70 (s, 3H), 7.48 (d, 1H, J=8Hz), 7.7-7.8 (m, 4H), 7.95 (d, 1H, J=8Hz), 9.02 (s, 1H).

(2) 4-(7-Hydroxybenzo[d]thiazol-6-yl)benzonitrile

Using the above-obtained 4-(7-methoxybenzo[d]thiazol-6-yl)benzonitrile (267 mg, 1.0 mmol), the title compound (brown oil, 221 mg, yield 87%) was obtained by the same method as in Example 12(2).

¹ H NMR (CDCl ₃ , 400MHz): δ = 5.80 (br s, 1H), 7.41 (d, 1H, J = 8Hz), 7.6-7.7 (m, 2H), 7.8-7.9 (m, 3H), 9.04 (s, 1H).

(3) Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(7-hydroxybenzo[d]thiazol-6-yl)benzonitrile (78 mg, 0.31 mmol), the title compound (37 mg, yield 33%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.18 (s, 6H), 1.30 (t, 3H, J=7Hz), 4.17 (q, 2H, J=7Hz), 7.47 (d, 1H, J=8Hz), 7.7-7.8 (m, 4H), 8.01 (d, 1H, J=9Hz), 9.02 (s, 1H).

(Example 37)

2-[[6-(4-Cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 76]

Using ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]oxy]-2-methylpropanoate (37 mg, 0.10 mmol) obtained in Example 36, the title compound (slightly brown amorphous, 8.5 mg, yield 25%) was obtained by the same method as in Example 2.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.12 (s, 6H), 7.58 (d, 1H, J=8Hz), 7.8-7.9 (m, 4H), 7.96 (d, 1H, J=8Hz), 9.26 (s, 1H).

(Example 38)

Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropanoate

[Chemical Formula 77]

(1) O-[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]dimethylthiocarbamate

Using 4-(7-hydroxybenzo[d]thiazol-6-yl)benzonitrile (221 mg, 0.88 mmol) obtained in Example 36(2), the title compound (yellow oil, 216 mg, yield 73%) was obtained by the same method as in Example 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.21 (s, 3H), 3.34 (s, 3H), 7.50 (d, 1H, J=8Hz), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 8.10 (d, 1H, J=8Hz), 9.02 (s, 1H).

(2) Ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid O-[6-(4-cyanophenyl)benzo[d]thiazol-7-yl] (216 mg, 0.64 mmol), the title compound (colorless oil, 8 mg, yield 3%) was obtained by the same method as Example 3(2), Example 3(3) and Example 1(3).

¹ H NMR (CD ₃ OD, 400MHz): δ = 1.17 (s, 6H), 1.31 (t, 3H, J = 7Hz), 3.21 (q, 2H, J = 7Hz), 7.65 (d, 1H, J=8Hz), 7.73 (d, 2H, J=9Hz), 7.80 (d, 2H, J=8Hz), 8.17 (d, 1H, J=8Hz), 9.30 (s, 1H).

(Example 39)

2-[[6-(4-Cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropanoic acid

[Chemical Formula 78]

Using ethyl 2-[[6-(4-cyanophenyl)benzo[d]thiazol-7-yl]thio]-2-methylpropanoate (8 mg, 0.02 mmol) obtained in Example 38, the title compound (pale pink amorphous, 5.5 mg, yield 74%) was obtained by the same method as in Example 2.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.17 (s, 6H), 7.64 (d, 1H, J=8Hz), 7.7-7.8 (m, 4H), 8.16 (d, 1H, J=8Hz), 9.29 (s, 1H).

(Example 40)

Ethyl 2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropanoate

[Chemical Formula 79]

(1) 4-(7-methoxyimidazo[1,2-a]pyridin-8-yl)benzonitrile

The title compound (pale yellow crystals, 200 mg, yield 71%) was obtained by the same method as in Example 1(1) using 8-iodo-7-methoxyimidazo[1,2-a]pyridine (350 mg, 1.13 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ=3.89 (s, 3H), 6.83 (d, 1H, J=7Hz), 7.56 (d, 2H, J=8Hz), 7.75 (d, 2H, J=8Hz), 7.87 (d, 2H, J=8Hz), 8.15 (d, 1H, J=7Hz).

(2) S-[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]dimethylthiocarbamate

Using the above-obtained 4-(7-methoxyimidazo[1,2-a]pyridin-8-yl)benzonitrile (200 mg, 0.80 mmol), the title compound (brown crystals, 36 mg, yield 14%) was obtained by the same method as in Example 12(2), Example 3(1) and Example 3(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.04 (d, 1H, J=7Hz), 7.62 (d, 2H, J=8Hz), 7.65-7.70 (m, 2H), 7.76 (d, 2H, J=8Hz), 8.15 (d, 1H, J=7Hz).

(3) Ethyl 2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl] (36 mg, 0.11 mmol), the title compound (brown oil, 26 mg, yield 65%) was obtained by the same method as in Example 3(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.22 (t, 3H, J = 7Hz), 1.36 (s, 6H), 4.07 (q, 2H, J = 7Hz), 6.99 (d, 1H, J=7Hz), 7.6-7.7 (m, 3H), 7.77 (d, 2H, J=8Hz), 8.02 (s, 1H), 8.09 (d, 1H, J=7Hz).

(Example 41)

2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropanoic acid

[Chemical formula 80]

Using ethyl 2-[[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]thio]-2-methylpropanoate (26 mg, 0.07 mmol) obtained in Example 40, the title compound (off-white crystals, 7 mg, yield 29%) was obtained by the same method as in Example 2.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.38 (s, 6H), 7.24 (d, 1H, J=7Hz), 7.5-7.6 (m, 3H), 7.8-7.9 (m, 2H), 7.94 (d, 1H, J=1Hz), 8.43 (d, 1H, J=7Hz).

(Example 42)

Ethyl 2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropanoate

[Chemical Formula 81]

(1) 4-(7-methoxyimidazo[1,2-a]pyridin-6-yl)benzonitrile

The title compound (white crystals, 52 mg, yield 21%) was obtained by the same method as in Example 1(1) using 6-bromo-7-methoxyimidazo[1,2-a]pyridine (227 mg, 1.0 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.89 (s, 3H), 7.01 (s, 1H), 7.48 (s, 1H), 7.54 (s, 1H), 7.6-7.65 (m, 2H), 7.7-7.8 (m, 2H), 8.00 (s, 1H).

(2) 4-(7-Hydroxyimidazo[1,2-a]pyridin-6-yl)benzonitrile

Using the above-obtained 4-(7-methoxyimidazo[1,2-a]pyridin-6-yl)benzonitrile (31 mg, 0.13 mmol), the title compound (slightly yellow oil, 22 mg, yield 62%) was obtained by the same method as in Example 18(2).

¹ H NMR (DMSO-d ₆ , 400MHz): δ=7.81 (d, 1H, J=8Hz), 7.9-8.2 (m, 7H), 8.93 (s, 1H).

(3) Ethyl 2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(7-hydroxyimidazo[1,2-a]pyridin-6-yl)benzonitrile (22 mg, 0.06 mmol), the title compound (slightly brown crystals, 9 mg, yield 48%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.27 (t, 3H, J=7Hz), 1.61 (s, 6H), 4.26 (q, 2H, J=7Hz), 6.84 (s, 1H), 7.48 (d , 1H, J=1Hz), 7.54 (d, 1H, J=1Hz), 7.65 (d, 2H, J=9Hz), 7.73 (d, 2H, J=9Hz), 8.02 (s, 1H).

(Example 43)

2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 82]

The title compound was obtained by the same method as in Example 26 using ethyl 2-[[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]oxy]-2-methylpropanoate obtained in Example 42 (yield 48%).

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 1.54 (s, 6H), 6.74 (s, 1H), 7.45 (s, 1H), 7.78 (s, 1H), 7.79 (d, 2H, J = 8Hz), 7.93 (d, 2H, J = 8Hz), 8.62 (s, 1H).

(Example 44)

Ethyl 2-[[3-(4-cyanophenyl)quinolin-4-yl]thio]-2-methylpropanoate

[Chemical Formula 83]

(1) 4-(4-Hydroxyquinolin-3-yl)benzonitrile

The title compound (brown crystals, 50 mg, yield 9%) was obtained by the same method as in Example 16(2) using 3-iodoquinolin-4-ol (580 mg, 2.14 mmol) and (4-cyanophenyl)boronic acid.

¹ H NMR (CD ₃ OD, 400MHz): δ=7.4-7.9 (m, 5H), 7.90 (d, 2H, J=8Hz), 8.23 (s, 1H), 8.35 (dd, 1H, J=1Hz, 8Hz).

(2) Ethyl 2-[[3-(4-cyanophenyl)quinolin-4-yl]thio]-2-methylpropanoate

The above-obtained 4-(4-hydroxyquinolin-3-yl)benzonitrile (90 mg, 0.37 mmol) was dissolved in tetrahydrofuran (4 mL), and Lawesson's reagent (449 mg, 1.11 mol) was added, and stirred at 70°C under a nitrogen atmosphere. After 16 hours, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Using the obtained residue, the title compound (yellow oil, 44 mg, yield 32%) was obtained by the same method as in Example 1 (3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.19 (s, 6H), 1.26 (t, 3H, J=7Hz), 3.55 (q, 2H, J=7Hz), 7.6-7.9 (m, 6H), 8.18 (d, 1H, J=9Hz), 8.69 (d, 1H, J=9Hz), 8.94 (s, 1H).

(Example 45)

2-[[3-(4-Cyanophenyl)quinolin-4-yl]thio]-2-methylpropanoic acid

[Chemical formula 84]

Using ethyl 2-[[3-(4-cyanophenyl)quinolin-4-yl]thio]-2-methylpropanoate (44 mg, 0.12 mmol) obtained in Example 44, the title compound (pale yellow crystals, 15 mg, yield 31%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.28 (s, 6H), 7.6-7.8 (m, 6H), 8.11 (d, 1H, J=8Hz), 8.8-8.9 (m, 1H), 8.88 (s, 1H).

(Example 46)

(E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-butenoic acid ethyl ester

[Chemical Formula 85]

The title compound (white crystals, 111 mg, yield 76%) was obtained by the same method as in Example 3(1) using 4-(2-hydroxynaphthalen-1-yl)benzonitrile (100 mg, 0.41 mmol) and ethyl 2-butynoate (71 μL, 0.61 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.19 (t, 3H, J=7Hz), 2.24 (s, 3H), 4.06 (q, 2H, J=7Hz), 4.82 (s, 1H), 7.26 (d , 1H, J=9Hz), 7.4-7.6 (m, 5H), 7.7-7.8 (m, 2H), 7.93 (d, 1H, J=8Hz), 7.96 (d, 1H, J=9Hz).

(Example 47)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]oxy]-2-butenoic acid

[Chemical Formula 86]

Using ethyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-butenoate (111 mg, 0.31 mmol) obtained in Example 46, the title compound (white crystals, 16 mg, yield 16%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=2.21 (s, 3H), 4.80 (s, 1H), 7.25 (d, 1H, J=9Hz), 7.4-7.6 (m, 5H), 7.7-7.8 (m, 2H), 7.93 (d, 1H, J=8Hz), 7.96 (d, 1H, J=9Hz).

(Example 48)

tert-Butyl 2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoate

[Chemical Formula 87]

(1) O-[1-(4-cyanophenyl)naphthalen-2-yl]dimethylthiocarbamate

The title compound (pale yellow crystals, 258 mg, yield 76%) was obtained by the same method as in Example 22(1) using 4-(2-hydroxynaphthalen-1-yl)benzonitrile (250 mg, 1.02 mmol).

¹ H NMR (CD ₃ OD, 400MHz): δ=2.99 (s, 3H), 3.31 (s, 3H), 7.34 (d, 1H, J=9Hz), 7.4-7.5 (m, 3H), 7.57 (d, 2H, J=8Hz), 7.76 (d, 2H, J=8Hz), 7.9-8.0 (m, 2H).

(2) S-[1-(4-cyanophenyl)naphthalen-2-yl]dimethylthiocarbamate

Using the dimethylthiocarbamic acid O-[1-(4-cyanophenyl)naphthalen-2-yl] (256 mg, 0.77 mmol) obtained above, the title compound (slightly brown crystals, 231 mg, yield 90%) was obtained at 230°C by the same method as Example 3(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.93 (s, 6H), 7.29 (d, 1H, J=9Hz), 7.38 (dt, 1H, J=1Hz, 8Hz), 7.43 (d, 2H, J=8 Hz), 7.52 (dt, 1H, J=1Hz, 8Hz), 7.65 (d, 1H, J=9Hz), 7.75 (d, 2H, J=9Hz), 7.8-7.9 (m, 2H).

(3) 4-(2-Mercaptonaphthalen-1-yl)benzonitrile

Using S-[1-(4-cyanophenyl)naphthalen-2-yl]dimethylthiocarbamate (230 mg, 0.69 mmol) obtained above, the title compound (pale yellow crystals, 80 mg, yield 44%) was obtained by the same method as in Example 22(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.32 (s, 1H), 7.20 (d, 1H, J=8Hz), 7.3-7.5 (m, 5H), 7.77 (d, 1H, J=9Hz), 7.8-7.9 (m, 3H).

(4) tert-Butyl 2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoate

Using the above-obtained 4-(2-mercaptonaphthalen-1-yl)benzonitrile (30 mg, 0.12 mmol) and tert-butyl 2-bromoisobutyrate (43 μL, 0.23 mmol), the title compound (pale yellow crystals, 37 mg, yield 80%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.31 (s, 6H), 1.47 (s, 9H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 3H), 7.49 (t, 1H, J＝ 8Hz), 7.67 (d, 1H, J=9Hz), 7.79 (d, 2H, J=8Hz), 7.83 (d, 1H, J=9Hz), 7.87 (d, 1H, J=8Hz).

(Example 49)

2-[[1-(4-Cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoic acid

[Chemical Formula 88]

Using tert-butyl 2-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-methylpropanoate (36 mg, 0.09 mmol) obtained in Example 48, the title compound (white crystals, 28 mg, yield 90%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ = 1.36 (s, 6H), 7.27 (d, 1H, J = 9Hz), 7.3-7.5 (m, 3H), 7.53 (dt, 1H, J = 1Hz, 7Hz), 7.73 (d, 1H, J=9Hz), 7.85 (d, 2H, J=9Hz), 7.90 (d, 1H, J=9Hz), 7.93 (d, 1H, J=8Hz).

(Example 50)

tert-Butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]acrylate

[Chemical Formula 89]

Using 4-(2-mercaptonaphthalen-1-yl)benzonitrile (40 mg, 0.15 mol) obtained in Example 48(3) and tert-butyl propiolate (63 μL, 0.46 mmol), the title compound (white crystals, 24 mg, yield 41%) was obtained by the same method as in Example 9.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.43 (s, 9H), 5.46 (d, 1H, J = 15Hz), 7.32 (d, 1H, J = 8Hz), 7.4-7.5 (m , 3H), 7.5-7.6 (m, 2H), 7.63 (d, 1H, J=8Hz), 7.78 (d, 2H, J=8Hz), 7.9-8.0 (m, 2H).

(Example 51)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]thio]acrylic acid

[Chemical formula 90]

Using tert-butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]acrylate (24 mg, 0.06 mmol) obtained in Example 50, the title compound (white amorphous, 11 mg, yield 55%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=5.46 (d, 1H, J=15Hz), 7.34 (d, 1H, J=8Hz), 7.41 (d, 2H, J=8Hz), 7.46 (t, 1H, J=7Hz), 7 .59 (t, 1H, J=8Hz), 7.63 (d, 1H, J=9Hz), 7.7-7.8 (m, 3H), 7.94 (d, 1H, J=8Hz), 7.97 (d, 1H, J=9Hz).

(Example 52)

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropionamide

[Chemical Formula 91]

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid (30 mg, 0.09 mmol) obtained in Example 24 was dissolved in toluene (1 mL), and thionyl chloride (62 μL, 0.85 mmol) was added. The mixture was stirred at 80°C under a nitrogen atmosphere. After 6 hours, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (2 mL). 25% aqueous _NH₃ solution (2 mL) was added, and the mixture was stirred at room temperature. After 14 hours, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2) to obtain the title compound (white crystals, 7 mg, yield 23%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.40 (s, 6H), 5.22 (br s, 1H), 6.36 (br s, 1H), 7.55 (d, 2H, J=8Hz), 7.78 (d, 1H, J=9Hz), 7.81 (d, 2H, J=8Hz), 8.11 (d, 1H, J=9Hz). 9.01 (s, 1H).

(Example 53)

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]thio]-N-(5-fluoropyridin-2-yl)-2-methylpropanamide

[Chemical Formula 92]

2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid (30 mg, 0.09 mmol), 5-fluoropyridin-2-amine (11 mg, 0.10 mmol), diisopropylethylamine (29 μL, 0.19 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.10 mmol) obtained in Example 24 were dissolved in tetrahydrofuran (1 mL) and stirred at room temperature. After 3 hours, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain the title compound (white crystals, 10 mg, yield 26%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.46 (s, 6H), 7.4-7.6 (m, 3H), 7.62 (d, 2H, J=8Hz), 7.71 (d, 1H, J=8Hz), 8.0 5 (d, 1H, J=8Hz), 8.10 (dd, 1H, J=4Hz, 9Hz), 8.17 (d, 1H, J=3Hz), 8.65 (s, 1H), 9.0 (s, 1H).

(Example 54)

2-[[7-(4-Cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methyl-N-(1,3,4-thiadiazol-2-yl)propionamide

[Chemical Formula 93]

Using 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid (30 mg, 0.09 mmol) and 1,3,4-thiazol-2-amine (10 mg, 0.1 mmol) obtained in Example 24, the title compound (white crystals, 21 mg, yield 57%) was obtained by the same method as in Example 53.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.48 (s, 6H), 7.54 (d, 2H, J=9Hz), 7.62 (d, 2H, J=8Hz), 7.80 (d, 1H, J=9Hz), 8.04 (d, 1H, J=9Hz), 9.06 (s, 1H), 9.29 (s, 1H).

(Example 55)

tert-Butyl 2-[[4-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate

[Chemical Formula 94]

(1) 4-Bromo-5-methoxybenzo[d]thiazol-2-amine

Sodium thiocyanate (1.6 g, 19.8 mmol) was dissolved in acetic acid (20 mL), and 2-bromo-3-methoxyaniline (1 g, 4.95 mmol) dissolved in acetic acid (20 mL) was added dropwise. After the addition was complete, bromine (281 μL, 5.45 mmol) dissolved in acetic acid (10 mL) was added dropwise, and the mixture was stirred at room temperature. After 16 hours, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The precipitated material was separated by filtration, and the resulting crystals were washed with chloroform (20 mL) and methanol (20 mL) to obtain the title compound (brown crystals, 756 mg, yield 59%).

¹ H NMR (DMSO-d ₆ , 400MHz): δ=3.87 (s, 3H), 6.84 (d, 1H, J=8Hz), 7.61 (d, 1H, J=8Hz), 7.87 (br s, 2H).

(2) 4-Bromo-5-methoxybenzo[d]thiazole

The above-obtained 4-bromo-5-methoxybenzo[d]thiazole-2-amine (756 mg, 2.92 mmol) was dissolved in tetrahydrofuran (30 mL), tert-butyl nitrite (831 μL, 7.00 mmol) was added, and the mixture was stirred at 60°C under a nitrogen environment. After 1 hour, the mixture was allowed to cool to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (yellow crystals, 300 mg, 42% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ=4.02 (s, 3H), 7.15 (d, 1H, J=9Hz), 7.85 (d, 1H, J=9Hz), 9.09 (s, 1H).

(3) 4-(5-methoxybenzo[d]thiazol-4-yl)benzonitrile

Using the above-obtained 4-bromo-5-methoxybenzo[d]thiazole (240 mg, 0.98 mmol) and (4-cyanophenyl)boronic acid (216 mg, 1.47 mmol), the title compound (pale yellow crystals, 74 mg, yield 28%) was obtained by the same method as in Example 1(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.88 (s, 3H), 7.26 (d, 1H, J=9Hz), 7.72 (d, 2H, J=8Hz), 7.76 (d, 2H, J=8Hz), 7.95 (d, 1H, J=9Hz), 8.98 (s, 1H).

(4) tert-Butyl 2-[[4-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(5-methoxybenzo[d]thiazol-4-yl)benzonitrile (74 mg, 0.28 mmol), the crude title compound was obtained by the same method as in Example 18(2).

The obtained crude product (15 mg) and tert-butyl 2-bromoisobutyrate (33 μL, 0.18 mmol) were used in the same manner as in Example 1(3) to obtain the title compound (pale yellow oil, 5 mg, yield 20%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.40 (s, 6H), 1.46 (s, 9H), 7.20 (d, 1H, J=9Hz), 7.7-7.8 (m, 4H), 7.85 (d, 1H, J=9Hz), 8.97 (s, 1H).

(Example 56)

2-[[4-(4-Cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 95]

Using tert-butyl 2-[[4-(4-cyanophenyl)benzo[d]thiazol-5-yl]oxy]-2-methylpropanoate (5 mg, 0.01 mmol) obtained in Example 55, the title compound (white crystals, 1.2 mg, yield 30%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.27 (s, 6H), 7.67 (d, 2H, J=8Hz), 7.83 (d, 1H, J=8Hz), 8.02 (d, 2H, J=8Hz), 8.18 (d, 1H, J=8Hz), 9.50 (s, 1H).

(Example 57)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]oxy]-2-pentenoic acid ethyl ester

[Chemical Formula 96]

The title compound (colorless oil, 45 mg, yield 30%) was obtained by the same method as in Example 9 using 4-(2-hydroxynaphthalen-1-yl)benzonitrile (100 mg, 0.41 mmol) and ethyl 2-pentynoate (81 μL, 0.61 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=0.86 (t, 3H, J=8Hz), 1.17 (t, 3H, J=7Hz), 2.71 (q, 2H, J=8Hz), 4.03 (q, 2H, J=7Hz), 4.71 (s, 1H), 7.23 (d, 1H, J=9Hz), 7.4-7.6 (m, 5H), 7.75 (d, 2H, J=8Hz), 7.91 (d, 1H, J=8Hz), 7.94 (d, 1H, J=9Hz).

(Example 58)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]oxy]-2-pentenoic acid

[Chemical Formula 97]

Using ethyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]oxy]-2-pentenoate (45 mg, 0.12 mmol) obtained in Example 57, the title compound (white crystals, 3.2 mg, yield 38%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=0.84 (t, 3H, J=7Hz), 2.68 (q, 2H, J=7Hz), 4.70 (s, 1H), 7.21 (d, 1H, J=9 Hz), 7.4-7.6 (m, 5H), 7.75 (d, 2H, J=8Hz), 7.91 (d, 1H, J=8Hz), 7.95 (d, 1H, J=9Hz).

(Example 59)

tert-Butyl 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 98]

(1) 7-Bromo-6-methoxy-2-(trifluoromethyl)benzo[d]thiazole

Using 6-methoxy-2-(trifluoromethyl)benzo[d]thiazole (1.14 g, 4.89 mmol), the title compound (white crystals, 1.1 g, yield 74%) was obtained by the same method as in Example 25(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=4.03 (s, 3H), 7.24 (d, 1H, J=9Hz), 8.13 (d, 1H, J=9Hz).

(2) 4-[6-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl]benzonitrile

Using the above-obtained 7-bromo-6-methoxy-2-(trifluoromethyl)benzo[d]thiazole (450 mg, 1.44 mmol) and (4-cyanophenyl)boronic acid (254 mg, 1.73 mmol), the title compound (white crystals, 462 mg, yield 95%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.91 (s, 3H), 7.36 (d, 1H, J=9Hz), 7.67 (d, 2H, J=8Hz), 7.80 (d, 2H, J=8Hz), 8.19 (d, 1H, J=9Hz).

(3) O-[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-[6-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl]benzonitrile (456 mg, 1.36 mmol), the title compound (white crystals, 441 mg, yield 92%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.13 (s, 3H), 3.33 (s, 3H), 7.45 (d, 1H, J = 9Hz), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 8.21 (d, 1H, J = 9Hz).

(4) S-[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl] (535 mg, 1.31 mmol), the title compound (white crystals, 521 mg, yield 95%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.95 (s, 6H), 7.5-7.6 (m, 2H), 7.7-7.8 (m, 2H), 7.86 (d, 1H, J=9Hz), 8.21 (d, 1H, J=8Hz).

(5) tert-Butyl 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl] (521 mg, 1.27 mmol), the title compound (white crystals, 254 mg, yield 42%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.28 (s, 6H), 1.43 (s, 9H), 7.52-7.55 (m, 2H), 7.7-7.9 (m, 2H), 7.86 (d, 1H, J=9Hz), 8.13 (d, 1H, J=9Hz).

(Example 60)

2-[[7-(4-Cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 99]

Using tert-butyl 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazol-6-yl]thio]-2-methylpropanoate (252 mg, 0.53 mol) obtained in Example 59, the title compound (white crystals, 193 mg, yield 87%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.35 (s, 6H), 7.65 (d, 2H, J=9Hz), 7.89 (d, 2H, J=9Hz), 8.00 (d, 1H, J=9Hz), 8.19 (d, 1H, J=9Hz).

(Example 61)

Ethyl 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 100]

(1) 7-Bromo-6-methoxy-2-methylbenzo[d]thiazole

Using 6-methoxy-2-methylbenzo[d]thiazole (540 mg, 3.0 mmol), the title compound (yellow crystals, 774 mg, yield 100%) was obtained by the same method as in Example 25(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.30 (s, 3H), 4.06 (s, 3H), 7.34 (d, 1H, J=9Hz), 8.39 (d, 1H, J=9Hz).

(2) 4-(6-methoxy-2-methylbenzo[d]thiazol-7-yl)benzonitrile

Using the above-obtained 7-bromo-6-methoxy-2-methylbenzo[d]thiazole (774 mg, 3.0 mmol) and (4-cyanophenyl)boronic acid (440 mg, 3.0 mmol), the title compound (white crystals, 110 mg, yield 13%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.77 (s, 3H), 3.85 (s, 3H), 7.19 (d, 1H, J=9Hz), 7.67 (d, 2H, J=9Hz), 7.76 (d, 2H, J=9Hz), 7.92 (d, 1H, J=9Hz).

(3) O-[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(6-methoxy-2-methylbenzo[d]thiazol-7-yl)benzonitrile (640 mg, 2.28 mmol), the title compound (yellow oil, 730 mg, yield 87%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.81 (s, 3H), 3.12 (s, 3H), 3.34 (s, 3H), 7.29 (d, 1H, J=9Hz), 7.68 (d, 2H, J=9Hz), 7.75 (d, 2H, J=9Hz), 7.97 (d, 1H, J=9Hz).

(4) S-[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl] (730 mg, 1.98 mmol), the title compound (yellow crystals, 190 mg, yield 26%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.80 (s, 3H), 2.95 (s, 6H), 7.54 (d, 2H, J=9Hz), 7.71 (d, 1H, J=9Hz), 7.74 (d, 2H, J=9Hz), 7.96 (d, 1H, J=9Hz).

(5) Ethyl 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl] (190 mg, 0.51 mmol), the title compound (white crystals, 68 mg, yield 33%) was obtained by the same method as Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.18 (t, 3H, J = 7Hz), 1.28 (s, 6H), 2.80 (s, 3H), 4.00 (q, 2H, J = 7Hz), 7.55 (d, 2H, J=9Hz), 7.68 (d, 1H, J=9Hz), 7.77 (d, 2H, J=9Hz), 7.90 (d, 1H, J=9Hz).

(Example 62)

2-[[7-(4-Cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 101]

Using ethyl 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazol-6-yl]thio]-2-methylpropanoate (68 mg, 0.17 mol) obtained in Example 61, the title compound (white crystals, 40 mg, yield 65%) was obtained by the same method as in Example 26.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.31 (s, 6H), 2.85 (s, 3H), 7.58 (d, 2H, J = 8Hz), 7.7-7.8 (m, 3H), 7.84 (d, 1H, J = 8Hz).

(Example 63)

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoate

[Chemical Formula 102]

(1) 6-Methoxy-7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazole

Using 7-bromo-6-methoxybenzo[d]thiazole (500 mg, 2.05 mmol) and [4-(trifluoromethoxy)phenyl]boronic acid (464 mg, 2.25 mmol), the title compound (yellow crystals, 631 mg, yield 95%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.88 (s, 3H), 7.2-7.3 (m, 1H, CDCl ₃ ), 7.33 (d, 2H, J=8Hz), 7.5-7.7 (m, 2H), 8.09 (d, 1H, J=9Hz), 8.83 (s, 1H).

(2) O-[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazole (629 mg, 1.98 mmol), the title compound (colorless oil, 539 mg, yield 72%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.11 (s, 3H), 3.35 (s, 3H), 7.33 (d, 2H, J=8Hz), 7.39 (d, 1H, J=9Hz), 7.6-7.7 (m, 2H), 8.15 (d, 1H, J=9Hz), 8.99 (s, 1H).

(3) S-[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl] (537 mg, 1.97 mmol), the title compound (yellow oil, 406 mg, yield 76%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.97 (s, 6H), 7.32 (d, 2H, J=8Hz), 7.4-7.5 (m, 2H), 7.79 (d, 1H, J=8Hz), 8.15 (d, 1H, J=8Hz), 9.03 (s, 1H).

(4) tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl] (403 mg, 1.01 mmol), the title compound (white crystals, 84 mg, yield 18%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.24 (s, 6H), 1.44 (s, 9H), 7.33 (d, 2H, J=8Hz), 7.4-7.5 (m, 2H), 7.80 (d, 1H, J=8Hz), 8.05 (d, 1H, J=8Hz), 9.01 (s, 1H).

(Example 64)

2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoic acid

[Chemical Formula 103]

Using tert-butyl 2-methyl-2-[[7-(4-trifluoromethoxy)phenyl]benzo[d]thiazol-6-yl]thio]propanoate (82 mg, 0.18 mmol) obtained in Example 63, the title compound (white crystals, 54 mg, yield 75%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.17 (s, 6H), 7.4-7.6 (m, 4H), 7.75 (d, 1H, J=8Hz), 8.05 (d, 1H, J=8Hz), 9.39 (s, 1H).

(Example 65)

Ethyl 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylate

[Chemical Formula 104]

Using 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (50 mg, 0.19 mmol) and 1-bromocyclobutane-1-carboxylic acid ethyl ester (45 μL, 0.28 mmol) obtained in Example 27(3), the title compound (pale yellow oil, 43 mg, yield 59%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.16 (t, 3H, J = 7Hz), 1.8-2.3 (m, 4H), 2.7-2.9 (m, 2H), 4.0-4.2 (m, 2H), 7.43 (d, 1H, J=9Hz), 7.64 (d, 2H, J=9Hz), 7.83 (d, 2H, J=9Hz), 7.96 (d, 1H, J=9Hz), 8.89 (s, 1H).

(Example 66)

1-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid

[Chemical Formula 105]

Using ethyl 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylate (43 mg, 0.11 mmol) obtained in Example 65, the title compound (white crystals, 5.2 mg, yield 13%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.9-2.3 (m, 4H), 2.7-2.9 (m, 2H), 7.46 (d, 1H, J=9Hz), 7.63 (d, 2H, J=9Hz), 7.81 (d, 2H, J=9Hz), 7.97 (d, 1H, J=9Hz), 8.90 (s, 1H).

(Example 67)

1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentane-1-carboxylic acid methyl ester

[Chemical Formula 106]

Using 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (30 mg, 0.11 mmol) and 1-bromocyclopentane-1-carboxylic acid methyl ester (46 mg, 0.22 mmol) obtained in Example 27(3), the title compound (yellow oil, 42 mg, yield 100%) was obtained by the same method as Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.5-1.7(m, 4H), 1.7-1.8(m, 2H), 2.1-2.3(m, 2H), 3.65(s, 3 H), 7.5-7.7 (m, 3H), 7.81 (d, 2H, J=9Hz), 7.99 (d, 1H, J=9Hz), 8.93 (s, 1H).

(Example 68)

1-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentane-1-carboxylic acid

[Chemical Formula 107]

Using 1-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclopentane-1-carboxylic acid methyl ester (42 mg, 0.11 mmol) obtained in Example 67, the title compound (white crystals, 14 mg, yield 33%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.5-1.7(m, 4H), 1.7-1.8(m, 2H), 2.1-2.3(m, 2H), 7.61(d, 2H, J=8 Hz), 7.69 (d, 1H, J=8Hz), 7.79 (d, 2H, J=8Hz), 7.99 (d, 1H, J=8Hz), 8.93 (s, 1H).

(Example 69)

Methyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3-methylbutanoate

[Chemical Formula 108]

Using 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (50 mg, 0.19 mmol) and methyl 2-bromo-3-methylbutyrate (49 mg, 0.25 mmol) obtained in Example 27(3), the title compound (pale yellow oil, 42 mg, yield 100%) was obtained by the same method as in Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=0.92 (d, 3H, J=7Hz), 0.95 (d, 3H, J=7Hz), 1.9-2.1 (m, 1H), 3.37 (d, 1H, J=9H z), 3.60 (s, 3H), 7.6-7.7 (m, 3H), 7.82 (d, 2H, J=8Hz), 8.00 (d, 1H, J=8Hz), 8.91 (s, 1H).

(Example 70)

2-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3-methylbutanoic acid

[Chemical Formula 109]

Using methyl 2-[[7-(4-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3-methylbutanoate (42 mg, 0.11 mmol) obtained in Example 69, the title compound (pale yellow crystals, 10 mg, yield 25%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=0.97 (d, 3H, J=7Hz), 0.98 (d, 3H, J=7Hz), 1.9-2.1 (m, 1H), 3.36 (d, 1H, J=8Hz), 7 .61 (d, 2H, J=8Hz), 7.69 (d, 1H, J=8Hz), 7.79 (d, 2H, J=8Hz), 7.99 (d, 1H, J=8Hz), 8.91 (s, 1H).

(Example 71)

Ethyl 2-methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propionate

[Chemical Formula 110]

(1) 6-Methoxy-7-(4-nitrobenzene)benzo[d]isothiazole

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-nitrobenzene)boronic acid (163 mg, 0.98 mmol), the title compound (yellow crystals, 205 mg, yield 82%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.95 (s, 3H), 7.26 (d, 1H, J=9Hz), 7.81 (d, 2H, J=9Hz), 8.07 (d, 1H, J=9Hz), 8.36 (d, 2H, J=9Hz), 8.86 (s, 1H).

(2) O-[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-(4-nitrobenzene)benzo[d]isothiazole (205 mg, 0.72 mmol), the title compound (yellow crystals, 170 mg, yield 72%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.18 (s, 3H), 3.36 (s, 3H), 7.34 (d, 1H, J=9Hz), 7.83 (d, 2H, J=9Hz), 8.10 (d, 1H, J=9Hz), 8.35 (d, 2H, J=9Hz), 8.96 (s, 1H).

(3) S-[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl] (170 mg, 0.42 mmol), the title compound (yellow oil, 165 mg, yield 97%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.68 (d, 2H, J=9Hz), 7.73 (d, 1H, J=9Hz), 8.09 (d, 1H, J=9Hz), 8.35 (d, 2H, J=9Hz), 8.98 (s, 1H).

(4) Ethyl 2-methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propionate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl] (165 mg, 0.46 mmol), the title compound (light yellow oil, 100 mg, yield 54%) was obtained by the same method as in Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.19 (t, 3H, J=7Hz), 1.36 (s, 6H), 4.06 (q, 2H, J=7Hz), 7.6-7.7 (m, 3H), 8.02 (d, 1H, J=9Hz), 8.37 (d, 2H, J=9Hz), 8.96 (s, 1H).

(Example 72)

2-Methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 111]

Using ethyl 2-methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazol-6-yl]thio]propanoate (100 mg, 0.25 mmol) obtained in Example 71, the title compound (yellow crystals, 63.5 mg, yield 68%) was obtained by the same method as in Example 2.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.29 (s, 6H), 7.7-7.9 (m, 3H), 8.26 (d, 1H, J=9Hz), 8.37 (d, 2H, J=9Hz), 9.23 (s, 1H).

(Example 73)

tert-Butyl 2-methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical Formula 112]

(1) 6-Methoxy-7-(p-toluene)benzo[d]isothiazole

The title compound (yellow oil, 232 mg, yield 111%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and p-tolueneboronic acid (134 mg, 0.98 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.43 (s, 3H), 3.90 (s, 3H), 7.22 (d, 1H, J=9Hz), 7.30 (d, 2H, J=8Hz), 7.51 (d, 2H, J=8Hz), 7.97 (d, 1H, J=9Hz), 8.82 (s, 1H).

(2) O-[7-(p-toluene)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-(p-toluene)benzo[d]isothiazole (230 mg, 0.91 mmol), the title compound (brown amorphous, 175 mg, yield 59%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.43 (s, 3H), 3.14 (s, 3H), 3.36 (s, 3H), 7.28 (d, 2H, J=8Hz), 7.32 (d, 1H, J=9Hz), 7.49 (d, 2H, J=8Hz), 8.00 (d, 1H, J=9Hz), 8.91 (s, 1H).

(3) S-[7-(p-toluene)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(p-toluene)benzo[d]isothiazol-6-yl] (178 mg, 0.54 mmol), the title compound (orange amorphous, 142 mg, yield 80%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.44 (s, 3H), 2.98 (s, 6H), 7.28 (d, 2H, J=8Hz), 7.36 (d, 2H, J=8Hz), 7.68 (d, 1H, J=9Hz), 7.98 (d, 1H, J=8Hz), 8.92 (s, 1H).

(4) tert-Butyl 2-methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(p-toluene)benzo[d]isothiazol-6-yl] (140 mg, 0.43 mmol), the title compound (white crystals, 41 mg, yield 26%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.31 (s, 6H), 1.45 (s, 9H), 2.45 (s, 3H), 7.30 (d, 2H, J=8Hz), 7.35 (d, 2H, J=8Hz), 7.66 (d, 1H, J=8Hz), 7.91 (d, 1H, J=8Hz), 8.90 (s, 1H).

(Example 74)

2-Methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 113]

Using tert-butyl 2-methyl-2-[[7-(p-toluene)benzo[d]isothiazol-6-yl]thio]propanoate (40 mg, 0.10 mmol) obtained in Example 73, the title compound (white crystals, 33 mg, yield 96%) was obtained by the same method as Example 6.

¹ H NMR (CD ₃ OD, 400 MHz): δ = 1.32 (s, 6H), 2.45 (s, 3H), 7.32 (s, 4H), 7.75 (d, 1H, J = 9Hz), 8.05 (d, 1H, J = 9Hz), 8.98 (s, 1H).

(Example 75)

tert-Butyl 2-[[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical formula 114]

(1) 7-(4-Isopropylphenyl)-6-methoxybenzo[d]isothiazole

The title compound (232 mg, yield 100%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-isopropylphenyl)boronic acid (134 mg, 0.98 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.32 (d, 6H, J=7Hz), 2.9-3.1 (m, 1H), 3.91 (s, 3H), 7.22 (d, 1H, J=9 Hz), 7.35 (d, 2H, J=8Hz), 7.56 (d, 2H, J=8Hz), 7.97 (d, 1H, J=8Hz), 8.82 (s, 1H).

(2) O-[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 7-(4-isopropylphenyl)-6-methoxybenzo[d]isothiazole (230 mg, 0.81 mmol), the title compound (175 mg, yield 51%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.31 (d, 6H, J = 7Hz), 2.9-3.1 (m, 1H), 3.11 (s, 3H), 3.35 (s, 3 H), 7.3-7.4 (m, 3H), 7.52 (d, 2H, J=8Hz), 8.00 (d, 1H, J=8Hz), 8.91 (s, 1H).

(3) S-[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl] (114 mg, 0.32 mmol), the title compound (55 mg, yield 48%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.32 (d, 6H, J=7Hz), 2.9-3.1 (m, 1H), 2.98 (s, 6H), 7.32 (d, 2H, J=8 Hz), 7.39 (d, 2H, J=8Hz), 7.69 (d, 1H, J=8Hz), 7.99 (d, 1H, J=8Hz), 8.92 (s, 1H).

(4) tert-Butyl 2-[[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl] (54 mg, 0.15 mmol), the title compound (pale yellow oil, 35 mg, yield 54%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.31 (s, 6H), 1.33 (d, 6H, J = 7Hz), 1.44 (s, 9H), 2.9-3.1 (m, 1H), 7.34 (d, 2H, J=8Hz), 7.39 (d, 2H, J=8Hz), 7.66 (d, 1H, J=8Hz), 7.91 (d, 1H, J=8Hz), 8.90 (s, 1H).

(Example 76)

2-[[7-(4-Isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 115]

Using tert-butyl 2-[[7-(4-isopropylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (35 mg, 0.082 mmol) obtained in Example 75, the title compound (pale yellow amorphous, 21 mg, yield 69%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.32 (s, 6H), 1.33 (d, 6H, J=7Hz), 2.9-3.1 (m, 1H), 7.33 (d, 2H, J=8 Hz), 7.38 (d, 2H, J=8Hz), 7.70 (d, 1H, J=8Hz), 7.91 (d, 1H, J=8Hz), 8.89 (s, 1H).

(Example 77)

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical Formula 116]

(1) 6-Methoxy-7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazole

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (187 mg, 0.98 mmol), the title compound (yellow crystals, 241 mg, yield 95%) was obtained by the same method as in Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.93 (s, 3H), 7.2-7.3 (m, 1H), 7.75 (s, 4H), 8.04 (d, 1H, J=9Hz), 8.85 (s, 1H).

(2) O-[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazole (240 mg, 0.78 mmol), the title compound (brown crystals, 223 mg, yield 76%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.14 (s, 3H), 3.36 (s, 3H), 7.34 (d, 1H, J = 9Hz), 7.75 (s, 4H), 8.07 (d, 1H, J = 8Hz), 8.95 (s, 1H).

(3) S-[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl] (221 mg, 0.58 mmol), the title compound (yellow crystals, 190 mg, yield 86%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.60 (d, 2H, J=8Hz), 7.72 (d, 1H, J=8Hz), 7.75 (d, 2H, J=8Hz), 8.06 (d, 1H, J=8Hz), 8.97 (s, 1H).

(4) tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl] (188 mg, 0.49 mmol), the title compound (colorless oil, 67 mg, yield 36%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.33 (s, 6H), 1.45 (s, 9H), 7.60 (d, 2H, J=8Hz), 7.71 (d, 1H, J=8Hz), 7.77 (d, 2H, J=8Hz), 7.98 (d, 1H, J=9Hz), 8.94 (s, 1H).

(Example 78)

2-Methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 117]

Using tert-butyl 2-methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate (65 mg, 0.14 mmol) obtained in Example 77, the title compound (white crystals, 41 mg, yield 72%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.36 (s, 6H), 7.65 (d, 2H, J=8Hz), 7.81-7.83 (m, 3H), 8.13 (d, 1H, J=9Hz), 9.02 (s, 1H).

(Example 79)

tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical Formula 118]

(1) 6-Methoxy-7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazole

The title compound (yellow oil, 233 mg, yield 87%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and [4-(trifluoromethoxy)phenyl]boronic acid (203 mg, 0.98 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.93 (s, 3H), 7.24 (d, 1H, J=9Hz), 7.34 (d, 2H, J=8Hz), 7.6-7.7 (m, 2H), 8.02 (d, 1H, J=9Hz), 8.84 (s, 1H).

(2) O-[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazole (230 mg, 0.71 mmol), the title compound (white crystals, 231 mg, yield 85%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.12 (s, 3H), 3.34 (s, 3H), 7.3-7.4 (m, 3H), 7.63 (d, 2H, J=9Hz), 8.03 (d, 1H, J=9Hz), 8.93 (s, 1H).

(3) S-[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl] (229 mg, 0.58 mmol), the title compound (white crystals, 201 mg, yield 88%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.60 (d, 2H, J=8Hz), 7.7-7.8 (m, 3H), 8.06 (d, 1H, J=8Hz), 8.97 (s, 1H).

(4) tert-Butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl] (198 mg, 0.50 mmol), the title compound (colorless oil, 36 mg, yield 17%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.30 (s, 6H), 1.43 (s, 9H), 7.33 (d, 2H, J=8Hz), 7.49 (d, 2H, J=9Hz), 7.70 (d, 1H, J=8Hz), 7.94 (d, 1H, J=8Hz), 8.91 (s, 1H).

(Example 80)

2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 119]

Using tert-butyl 2-methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazol-6-yl]thio]propanoate (34 mg, 0.072 mmol) obtained in Example 79, the title compound (white crystals, 8 mg, yield 27%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.37 (s, 6H), 7.40 (d, 2H, J=8Hz), 7.55 (d, 2H, J=9Hz), 7.88 (d, 1H, J=9Hz), 8.04 (d, 1H, J=9Hz), 8.94 (s, 1H).

(Example 81)

tert-Butyl 2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 120]

(1) 7-(4-chlorophenyl)-6-methoxybenzo[d]isothiazole

The title compound (white crystals, 233 mg, yield 85%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-chlorophenyl)boronic acid (141 mg, 0.98 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.09 (s, 3H), 7.21 (d, 1H, J=9Hz), 7.45 (d, 2H, J=9Hz), 7.55 (d, 2H, J=9Hz), 7.99 (d, 1H, J=8Hz), 8.82 (s, 1H).

(2) O-[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 7-(4-chlorophenyl)-6-methoxybenzo[d]isothiazole (220 mg, 0.68 mmol), the title compound (white amorphous, 200 mg, yield 83%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.15 (s, 3H), 3.36 (s, 3H), 7.31 (d, 1H, J=9Hz), 7.46 (d, 2H, J=9Hz), 7.55 (d, 2H, J=9Hz), 8.03 (d, 1H, J=8Hz), 8.93 (s, 1H).

(3) S-[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl] (200 mg, 0.57 mmol), the title compound (yellow oil, 138 mg, yield 70%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.97 (s, 6H), 7.40 (d, 2H, J=9Hz), 7.46 (d, 2H, J=9Hz), 7.69 (d, 1H, J=9Hz), 8.02 (d, 1H, J=8Hz), 8.94 (s, 1H).

(4) tert-Butyl 2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl] (138 mg, 0.40 mmol), the title compound (pale yellow oil, 30 mg, yield 18%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.31 (s, 6H), 1.44 (s, 9H), 7.40 (d, 2H, J=9Hz), 7.48 (d, 2H, J=9Hz), 7.67 (d, 1H, J=9Hz), 7.94 (d, 1H, J=8Hz), 8.91 (s, 1H).

(Example 82)

2-[[7-(4-Chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 121]

Using tert-butyl 2-[[7-(4-chlorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (30 mg, 0.071 mmol) obtained in Example 81, the title compound (pale yellow crystals, 23 mg, yield 89%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.28 (s, 6H), 7.46 (d, 2H, J=8Hz), 7.58 (d, 2H, J=8Hz), 7.70 (d, 1H, J=9Hz), 8.20 (d, 1H, J=8Hz), 9.19 (s, 1H).

(Example 83)

tert-Butyl 2-[[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical formula 122]

(1) 3-(6-methoxybenzo[d]isothiazol-7-yl)benzonitrile

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (3-cyanophenyl)boronic acid (145 mg, 0.98 mmol), the title compound (white crystals, 182 mg, yield 83%) was obtained by the same method as in Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.94 (s, 3H), 7.2-7.3 (m, 1H), 7.61 (t, 1H, J=8Hz), 7.70 (dt, 1H, J=1Hz, 8 Hz), 7.87 (dt, 1H, J=1Hz, 8Hz), 7.92 (t, 1H, J=1Hz), 8.05 (d, 1H, J=9Hz), 8.85 (s, 1H).

(2) O-[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 3-(6-methoxybenzo[d]isothiazol-7-yl)benzonitrile (180 mg, 0.68 mmol), the title compound (brown crystals, 179 mg, yield 82%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.18 (s, 3H), 3.35 (s, 3H), 7.33 (d, 1H, J = 9Hz), 7.62 (t, 1H, J =8Hz), 7.7-7.8(m, 1H), 7.8-8.0(m, 2H), 8.08(d, 1H, J=9Hz), 8.95(s, 1H).

(3) S-[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl] (178 mg, 0.52 mmol), the title compound (orange amorphous, 162 mg, yield 91%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.62 (t, 1H, J=8Hz), 7.7-7.8 (m, 4H), 8.08 (d, 1H, J=8Hz), 8.97 (s, 1H).

(4) tert-Butyl 2-[[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl] (160 mg, 0.47 mmol), the title compound (colorless oil, 37 mg, yield 22%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.32 (s, 6H), 1.44 (s, 9H), 7.63 (t, 1H, J=8Hz), 7.6-7.8 (m, 4H), 7.99 (d, 1H, J=9Hz), 8.93 (s, 1H).

(Example 84)

2-[[7-(3-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical formula 123]

Using tert-butyl 2-[[7-(3-cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (36 mg, 0.088 mmol) obtained in Example 83, the title compound (white crystals, 8 mg, yield 26%) was obtained by the same method as in Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.38 (s, 6H), 7.7-7.8 (m, 4H), 7.90 (d, 1H, J=9Hz), 8.09 (d, 1H, J=8Hz), 8.97 (s, 1H).

(Example 85)

Ethyl 2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 124]

(1) 4-(6-methoxybenzo[d]isothiazol-7-yl)-3-methylbenzonitrile

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-cyano-2-methylphenyl)boronic acid (158 mg, 0.98 mmol), the title compound (white crystals, 129 mg, yield 56%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.12 (s, 3H), 3.88 (s, 3H), 7.22 (d, 1H, J=9Hz), 7.39 (d, 1H, J=8Hz), 7.57 (d, 1H, J=8Hz), 7.63 (s, 1H), 8.06 (d, 1H, J=9Hz), 8.84 (s, 1H).

(2) S-[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(6-methoxybenzo[d]isothiazol-7-yl)-3-methylbenzonitrile (129 mg, 0.46 mmol), the crude product of dimethylthiocarbamic acid O-[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl] (yellow oil, 219 mg) was obtained by the same method as in Examples 18(2) and 22(1).

Using the crude product of dimethylthiocarbamic acid O-[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl] (219 mg) obtained above, the title compound (colorless oil, 132 mg, yield 81%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.04 (s, 3H), 2.92 (s, 6H), 7.33 (d, 1H, J=9Hz), 7.56 (d, 1H, J=8Hz), 7.62 (s, 1H), 7.69 (d, 1H, J=9Hz), 8.06 (d, 1H, J=8Hz), 8.95 (s, 1H).

(3) Ethyl 2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl] (132 mg, 0.37 mmol), the title compound (colorless oil, 25 mg, yield 17%) was obtained by the same method as Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.26 (t, 3H, J=7Hz), 2.05 (s, 3H), 4.0-4.3 (m, 2H), 7.31 (d, 1H, J=8Hz), 7.5-7.7 (m, 3H), 7.99 (d, 1H, J=8Hz), 8.92 (s, 1H).

(Example 86)

2-[[7-(4-Cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 125]

Using ethyl 2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (25 mg, 0.063 mmol) obtained in Example 85, the title compound (white crystals, 9.7 mg, yield 42%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.40 (s, 3H), 1.48 (s, 3H), 2.05 (s, 3H), 7.31 (d, 1H, J = 8Hz), 7.56 (d , 1H, J=8Hz), 7.63 (s, 1H), 7.67 (d, 1H, J=8Hz), 7.99 (d, 1H, J=8Hz), 8.92 (s, 1H).

(Example 87)

tert-Butyl 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 126]

(1) 4-(6-methoxybenzo[d]isothiazol-7-yl)-2-methylbenzonitrile

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-cyano-3-methylphenyl)boronic acid (198 mg, 1.23 mmol), the title compound (white crystals, 190 mg, yield 56%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.64 (s, 3H), 3.94 (s, 3H), 7.25 (d, 1H, J=9Hz), 7.54 (d, 1H, J=9Hz), 7.59 (s, 1H), 7.73 (d, 1H, J=9Hz), 8.05 (d, 1H, J=9Hz), 8.85 (s, 1H).

(2) O-[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(6-methoxybenzo[d]isothiazol-7-yl)-2-methylbenzonitrile (190 mg, 0.68 mmol), the title compound (white amorphous, 160 mg, yield 67%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.62 (s, 3H), 3.17 (s, 3H), 3.36 (s, 3H), 7.32 (d, 1H, J = 9Hz), 7.54 (d , 1H, J=9Hz), 7.61 (s, 1H), 7.72 (d, 1H, J=9Hz), 8.07 (d, 1H, J=9Hz), 8.94 (s, 1H).

(3) S-[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl] (160 mg, 0.45 mmol), the title compound (pale yellow oil, 159 mg, yield 99%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.62 (s, 3H), 2.99 (s, 6H), 7.39 (d, 1H, J=8Hz), 7.45 (s, 1H), 7.6-7.8 (m, 2H), 8.06 (d, 1H, J=8Hz), 8.96 (s, 1H).

(4) tert-Butyl 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl] (159 mg, 0.45 mmol), the title compound (pale yellow oil, 110 mg, yield 58%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.33 (s, 6H), 1.44 (s, 9H), 2.64 (s, 3H), 7.39 (d, 1H, J = 8Hz), 7.43 (s , 1H), 7.69 (d, 1H, J=8Hz), 7.74 (d, 1H, J=8Hz), 7.98 (d, 1H, J=8Hz), 8.93 (s, 1H).

(Example 88)

2-[[7-(4-Cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 127]

Using tert-butyl 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (110 mg, 0.26 mmol) obtained in Example 87, the title compound (white crystals, 40 mg, yield 42%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.31 (s, 6H), 2.64 (s, 3H), 7.47 (d, 1H, J=8Hz), 7.57 (s, 1H), 7.73 (d, 1H, J=8Hz), 7.93 (d, 1H, J=8Hz), 8.25 (d, 1H, J=8Hz), 9.22 (s, 1H).

(Example 89)

tert-Butyl 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 128]

(1) 2-Fluoro-4-(6-methoxybenzo[d]isothiazol-7-yl)benzonitrile

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-cyano-3-fluorophenyl)boronic acid (162 mg, 0.98 mmol), the title compound (pale yellow crystals, 194 mg, yield 78%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.95 (s, 3H), 7.25 (d, 1H, J=9Hz), 7.5-7.6 (m, 2H), 7.75 (dd, 1H, J=7Hz, 8Hz), 8.08 (d, 1H, J=9Hz), 8.86 (s, 1H).

(2) O-[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 2-fluoro-4-(6-methoxybenzo[d]isothiazol-7-yl)benzonitrile (194 mg, 0.64 mmol), the title compound (yellow crystals, 191 mg, yield 86%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.22 (s, 3H), 3.38 (s, 3H), 7.32 (d, 1H, J=8Hz), 7.5-7.6 (m, 2H), 7.78 (t, 1H, J=7Hz), 8.11 (d, 1H, J=8Hz), 8.96 (s, 1H).

(3) S-[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl] (191 mg, 0.53 mmol), the title compound (orange amorphous, 150 mg, yield 79%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.3-7.5 (m, 2H), 7.71 (d, 1H, J=8Hz), 7.76 (t, 1H, J=7Hz), 8.08 (d, 1H, J=8Hz), 8.97 (s, 1H).

(4) tert-Butyl 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl] (150 mg, 0.45 mmol), the title compound (pale yellow oil, 100 mg, yield 56%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.33 (s, 6H), 1.44 (s, 9H), 7.3-7.5 (m, 2H), 7.70 (d, 1H, J=8Hz), 7.7-7.8 (m, 1H), 8.02 (d, 1H, J=8Hz), 8.94 (s, 1H).

(Example 90)

2-[[7-(4-Cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 129]

Using tert-butyl 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (100 mg, 0.23 mmol) obtained in Example 89, the title compound (white crystals, 6.5 mg, yield 8%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.31 (s, 6H), 7.55 (dd, 1H, J=2Hz, 8Hz), 7.7-7.8 (m, 2H), 8.11 (t, 1H, J=8Hz), 8.29 (d, 1H, J=8Hz), 9.25 (s, 1H).

(Example 91)

tert-Butyl 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 130]

(1) 7-(4-Fluoronaphthyl-1-yl)-6-methoxybenzo[d]isothiazole

Using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and (4-fluoronaphthyl-1-yl)boronic acid (187 mg, 0.98 mmol), the title compound (orange oil, 219 mg, yield 86%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.81 (s, 3H), 7.2-7.3 (m, 2H), 7.41 (d, 2H, J=4Hz), 7.4-7.6 (m, 2H), 8.10 (d, 1H, J=9Hz), 8.20 (d, 1H, J=8Hz), 8.87 (s, 1H).

(2) O-[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 7-(4-fluoronaphthyl-1-yl)-6-methoxybenzo[d]isothiazole (219 mg, 0.71 mmol), the title compound (slightly brown amorphous, 220 mg, yield 81%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.60 (s, 3H), 3.13 (s, 3H), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 3H), 8.14 (d, 1H, J=9Hz), 8.20 (d, 1H, J=8Hz), 8.97 (s, 1H).

(3) S-[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl] (220 mg, 0.58 mmol), the title compound (slightly brown amorphous, 135 mg, yield 61%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.77 (s, 3H), 2.90 (s, 3H), 7.2-7.3 (m, 1H), 7.31 (d, 1H, J = 8Hz), 7.3-7.5 (m, 2H), 7.57 (d, 1H, J=8Hz), 7.80 (d, 1H, J=9Hz), 8.14 (d, 1H, J=9Hz), 8.21 (d, 1H, J=8Hz), 8.98 (s, 1H).

(4) tert-Butyl 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl] (135 mg, 0.35 mmol), the title compound (pale yellow oil, 61 mg, yield 38%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.32 (s, 6H), 1.47 (s, 9H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 2H), 7.57 (t, 1H) , J=8Hz), 7.71 (d, 1H, J=9Hz), 8.04 (d, 1H, J=9Hz), 8.22 (d, 1H, J=8Hz), 8.93 (s, 1H).

(Example 92)

2-[[7-(4-Fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 131]

Using tert-butyl 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (61 mg, 0.13 mmol) obtained in Example 91, the title compound (white crystals, 20 mg, yield 39%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ = 1.26 (s, 3H), 1.29 (s, 3H), 7.15 (d, 1H, J = 9Hz), 7.4-7.6 (m, 3H), 7.68 (t, 1H, J=7Hz), 7.85 (d, 1H, J=8Hz), 8.18 (d, 1H, J=8Hz), 8.29 (d, 1H, J=8Hz), 8.20 (s, 1H).

(Example 93)

tert-Butyl 2-[[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 132]

(1) Methyl 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthoate

Using 7-bromo-6-methoxybenzo[d]isothiazole (400 mg, 1.6 mmol) and [4-(methoxycarbonyl)naphthalen-1-yl]boronic acid (452 mg, 2.0 mmol), the title compound (white amorphous, 373 mg, yield 65%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.81 (s, 3H), 4.05 (s, 3H), 7.30 (d, 1H, J=9Hz), 7.41 (t, 1H, J=1Hz, 7Hz), 7.49 (d, 1H, J=8Hz), 7.59 (d , 1H, J=7Hz), 7.63 (t, 1H, J=1Hz, 7Hz), 8.14 (d, 1H, J=9Hz), 8.27 (d, 1H, J=8Hz), 8.88 (s, 1H), 8.99 (d, 1H, J=9Hz).

(2) 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthonitrile

Using the above-obtained methyl 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthoate (372 mg, 1.07 mmol), the crude product of 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthoic acid was obtained by the same method as in Example 2.

The crude product was dissolved in toluene (5 mL), and thionyl chloride (117 μL, 1.6 mmol) was added, followed by stirring at room temperature. After 1 hour, the reaction solution was concentrated, and the crude product was dissolved in chloroform (5 mL). NH₃ _{- CHCl₃} solution (the filtrate obtained by extracting _a 2M _NH₃ aqueous solution (10 mL) with CHCl₃ (10 mL), drying over sodium sulfate, and filtering) was added. The precipitated crystals were separated by filtration and washed with hexane (5 mL) to obtain crude 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthamide.

The obtained crude product was dissolved in acetonitrile (8 mL), dimethylformamide (160 μL) was added, and then oxalyl chloride (205 μL, 2.39 mmol) was added at -15 ° C under nitrogen flow conditions. After 30 minutes, pyridine (400 μL) was added. After 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution and extracted with ethyl acetate/hexane = 1/1 (20 mL). The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (white crystals, 211 mg, yield 62%).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.83 (s, 3H), 7.31 (d, 1H, J=9Hz), 7.4-7.6 (m, 2H), 7.62 (d, 1H, J=7Hz), 7.73 (dt , 1H, J=2Hz, 7Hz), 8.04 (d, 1H, J=7Hz), 8.16 (d, 1H, J=9Hz), 8.36 (d, 1H, J=9Hz), 8.89 (s, 1H).

(3) O-[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(6-methoxybenzo[d]isothiazol-7-yl)-1-naphthocarbonitrile (210 mg, 0.70 mmol), the title compound (yellow oil, 271 mg, yield 100%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.63 (s, 3H), 3.14 (s, 3H), 7.43 (d, 1H, J = 8Hz), 7.53 (dt, 1H, J = 1Hz, 7Hz), 7.66 (d, 1H, J=9Hz), 7.7-7.8 (m, 2H), 8.01 (d, 1H, J=8Hz), 8.18 (d, 1H, J=9Hz), 8.35 (d, 1H, J=8Hz), 8.98 (s, 1H).

(4) S-[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl] (271 mg, 0.70 mmol), the title compound (white amorphous, 135 mg, yield 50%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.7-2.9 (m, 6H), 7.41 (d, 1H, J=8Hz), 7.47 (dt, 1H, J=1Hz, 7Hz), 7.57 (d, 1H, J=7Hz), 7.71 (dt, 1H , J=1Hz, 7Hz), 7.80 (d, 1H, J=8Hz), 8.01 (d, 1H, J=7Hz), 8.17 (d, 1H, J=8Hz), 8.35 (d, 1H, J=9Hz), 8.99 (s, 1H).

(5) tert-Butyl 2-[[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl] (133 mg, 0.34 mmol), the title compound (white amorphous, 86 mg, yield 54%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.28 (s, 3H), 1.31 (s, 3H), 1.47 (s, 9H), 7.36 (d, 1H, J=8Hz), 7.49 (d, 1H, J=8Hz), 7.54 (d, 1H, J=7Hz), 7.7-7.6 (m, 2H), 8.05 (d, 1H, J=7Hz), 8.09 (d, 1H, J=9Hz), 8.38 (d, 1H, J=9Hz), 8.95 (s, 1H).

(Example 94)

2-[[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 133]

Using tert-butyl 2-[[7-(4-cyanonaphthalen-1-yl)benzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (82 mg, 0.18 mmol) obtained in Example 93, the title compound (white crystals, 49 mg, yield 68%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.36 (s, 3H), 1.40 (s, 3H), 7.35 (d, 1H, J=8Hz), 7.51 (d, 1H, J=7Hz), 7.56 (d, 1H, J=7 Hz), 7.7-7.8 (m, 2H), 8.04 (d, 1H, J=7Hz), 8.12 (d, 1H, J=9Hz), 8.38 (d, 1H, J=9Hz), 8.98 (s, 1H).

(Example 95)

tert-Butyl 2-methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical formula 134]

(1) 6-Methoxy-7-(pyridin-3-yl)benzo[d]isothiazole

The title compound (yellow crystals, 250 mg, yield 63%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (400 mg, 1.6 mmol) and pyridin-3-ylboronic acid (242 mg, 1.96 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.89 (s, 3H), 7.21 (d, 1H, J = 9Hz), 7.27 (dd, 1H, J = 5Hz, 8Hz), 7.90 (d , 1H, J=8Hz), 8.00 (d, 1H, J=9Hz), 8.61 (d, 1H, J=5Hz), 8.81 (s, 1H), 8.83 (s, 1H).

(2) O-[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-(pyridin-3-yl)benzo[d]isothiazole (250 mg, 1.03 mmol), the title compound (yellow oil, 141 mg, yield 44%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.17 (s, 3H), 3.34 (s, 3H), 7.34 (d, 1H, J=9Hz), 7.44 (dd, 1H, J=5Hz, 8Hz), 7.99 ( dt, 1H, J=2Hz, 8Hz), 8.08 (d, 1H, J=9Hz), 8.69 (dd, 1H, J=2Hz, 5Hz), 8.84 (s, 1H), 8.95 (s, 1H).

(3) S-[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl] (141 mg, 0.45 mmol), the title compound (colorless oil, 18 mg, yield 13%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.97 (s, 6H), 7.44 (dd, 1H, J=5Hz, 8Hz), 7.73 (d, 1H, J=8Hz), 7.8-7.9 (m, 1H), 8.07 (d, 1H, J=8Hz), 8.6-8.8 (m, 2H), 8.97 (s, 1H).

(4) tert-Butyl 2-methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl] (18 mg, 0.06 mmol), the title compound (pale yellow oil, 5 mg, yield 23%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.31 (s, 6H), 1.44 (s, 9H), 7.46 (dd, 1H, J=5Hz, 8Hz), 7.71 (d, 1H, J=8 Hz), 7.82 (dt, 1H, J=1Hz, 8Hz), 7.99 (d, 1H, J=8Hz), 8.6-8.8 (m, 2H), 8.94 (s, 1H).

(Example 96)

2-Methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 135]

Using tert-butyl 2-methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazol-6-yl]thio]propanoate (5 mg, 0.01 mmol) obtained in Example 95, the title compound (white crystals, 6 mg, yield 100%) was obtained by the same method as Example 6.

¹ H NMR (CD ₃ OD, 400MHz): δ=1.36 (s, 6H), 7.61 (dd, 1H, J=6Hz, 7Hz), 7.84 (d, 1H, J=8Hz), 7.98 (dt, 1H, J=2Hz, 8Hz), 8.17 (d, 1H, J=8Hz), 8.6-8.7 (m, 2H), 9.05 (s, 1H).

(Example 97)

Ethyl 2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical Formula 136]

(1) 6-Methoxy-7-(pyridin-4-yl)benzo[d]isothiazole

The title compound (white crystals, 122 mg, yield 63%) was obtained by the same method as in Example 16(2) using 7-bromo-6-methoxybenzo[d]isothiazole (200 mg, 0.82 mmol) and pyridin-4-ylboronic acid (121 mg, 0.98 mmol).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.93 (s, 3H), 7.23 (d, 1H, J=9Hz), 7.55 (dd, 2H, J=2Hz, 5Hz), 8.04 (d, 1H, J=9Hz), 8.72 (dd, 2H, J=2Hz, 5Hz), 8.83 (s, 1H).

(2) O-[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-(pyridin-4-yl)benzo[d]isothiazole (122 mg, 0.50 mmol), the title compound (pale yellow crystals, 156 mg, yield 99%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.16 (s, 3H), 3.35 (s, 3H), 7.31 (d, 1H, J=9Hz), 7.5-7.6 (m, 2H), 8.06 (d, 1H, J=9Hz), 8.74 (d, 2H, J=6Hz), 8.93 (s, 1H).

(3) S-[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl] (156 mg, 0.47 mmol), the title compound (colorless oil, 89 mg, yield 57%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.95 (s, 6H), 7.3-7.5 (m, 2H), 7.70 (d, 1H, J=8Hz), 8.05 (d, 1H, J=8Hz), 8.73 (d, 2H, J=5Hz), 8.94 (s, 1H).

(4) Ethyl 2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl] (89 mg, 0.27 mmol), the title compound (colorless oil, 33 mg, yield 34%) was obtained by the same method as Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.21 (t, 3H, J=7Hz), 1.42 (s, 6H), 3.02 (q, 2H, J=7Hz), 7.54 (dd, 2H, J=2Hz , 5Hz), 7.83 (d, 1H, J=8Hz), 7.94 (d, 1H, J=8Hz), 8.68 (dd, 2H, J=2Hz, 5Hz), 8.89 (s, 1H).

(Example 98)

2-Methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 137]

Using ethyl 2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazol-6-yl]thio]propanoate (33 mg, 0.09 mmol) obtained in Example 97, the title compound (white crystals, 8.5 mg, yield 28%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.43 (s, 6H), 7.73 (d, 2H, J=5Hz), 7.83 (d, 1H, J=8Hz), 8.02 (d, 1H, J=8Hz), 8.59 (d, 2H, J=5Hz), 8.95 (s, 1H).

(Example 99)

Ethyl 2-methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoate

[Chemical Formula 138]

(1) 6-methoxy-7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazole

Using 7-bromo-6-methoxybenzo[d]isothiazole (300 mg, 1.23 mmol) and [6-(methylthio)pyridin-3-yl]boronic acid (249 mg, 1.47 mmol), the title compound (white crystals, 254 mg, yield 72%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.61 (s, 3H), 3.89 (s, 3H), 7.20 (d, 1H, J = 9Hz), 7.28 (d, 1H, J = 8Hz), 7.73 (dd, 1H, J=2Hz, 8Hz), 7.99 (d, 1H, J=9Hz), 8.68 (d, 1H, J=2Hz), 8.83 (s, 1H).

(2) O-[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 6-methoxy-7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazole (254 mg, 0.88 mmol), the title compound (purple oil, 64 mg, yield 20%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.62 (s, 3H), 3.19 (s, 3H), 3.35 (s, 3H), 7.2-7.4 (m, 2H), 7.75 (dd, 1H, J=2Hz, 8Hz), 8.03 (d, 1H, J=9Hz), 8.6-8.7 (m, 1H), 8.92 (s, 1H).

(3) S-[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl] (64 mg, 0.18 mmol), the title compound (purple oil, 38 mg, yield 59%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.63 (s, 3H), 2.97 (s, 6H), 7.28 (d, 1H, J=8Hz), 7.61 (dd, 1H, J=2Hz, 8H z), 7.69 (d, 1H, J=8Hz), 8.03 (d, 1H, J=8Hz), 8.53 (dd, 1H, J=1Hz, 2Hz), 8.94 (s, 1H).

(4) Ethyl 2-methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl] (38 mg, 0.11 mmol), the title compound (colorless oil, 16 mg, yield 37%) was obtained by the same method as Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.18 (t, 3H, J=7Hz), 1.35 (s, 6H), 2.64 (s, 3H), 4.02 (q, 2H, J=7Hz), 7.30 (d, 1H, J=8Hz), 7.60 (dd, 1H, J=2Hz, 8Hz), 7.63 (d, 1H, J=8Hz), 7.95 (d, 1H, J=8Hz), 8.54 (d, 1H, J=2Hz), 8.92 (s, 1H).

(Example 100)

2-Methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoic acid

[Chemical Formula 139]

Using ethyl 2-methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazol-6-yl]thio]propanoate (16 mg, 0.09 mmol) obtained in Example 99, the title compound (brown amorphous, 5.5 mg, yield 37%) was obtained by the same method as in Example 2.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.42 (s, 6H), 2.63 (s, 3H), 7.31 (d, 1H, J=8Hz), 7.64 (dd, 1H, J=2Hz, 8Hz), 7.75 (d, 1H, J=8Hz), 7.97 (d, 1H, J=8Hz), 8.57 (d, 1H, J=2Hz), 8.94 (s, 1H).

(Example 101)

tert-Butyl 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 140]

(1) 7-Bromo-4-fluoro-6-methoxybenzo[d]isothiazole

Using 4-fluoro-6-methoxybenzo[d]isothiazole (260 mg, 1.42 mmol), the title compound (pale yellow crystals, 367 mg, yield 100%) was obtained by the same method as in Example 25(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 4.02 (s, 3H), 7.42 (d, 1H, J = 12Hz), 9.25 (s, 1H).

(2) 4-(4-Fluoro-6-methoxybenzo[d]isothiazol-7-yl)benzonitrile

Using the above-obtained 7-bromo-4-fluoro-6-methoxybenzo[d]isothiazole (367 mg, 1.4 mmol) and (4-cyanophenyl)boronic acid (313 mg, 2.13 mmol), the title compound (white crystals, 160 mg, yield 40%) was obtained by the same method as in Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.91 (s, 3H), 6.94 (d, 1H, J=11Hz), 7.70 (d, 2H, J=8Hz), 7.79 (d, 2H, J=8Hz), 8.92 (s, 1H).

(3) O-[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(4-fluoro-6-methoxybenzo[d]isothiazol-7-yl)benzonitrile (160 mg, 0.56 mmol), the title compound (yellow amorphous, 140 mg, yield 89%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.15 (s, 3H), 3.35 (s, 3H), 7.04 (d, 1H, J=10Hz), 7.71 (d, 2H, J=8Hz), 7.79 (d, 2H, J=8Hz), 9.03 (s, 1H).

(4) S-[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl] (120 mg, 0.34 mmol), the title compound (yellow oil, 120 mg, yield 100%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.98 (s, 6H), 7.42 (d, 1H, J=9Hz), 7.58 (d, 2H, J=9Hz), 7.79 (d, 2H, J=9Hz), 9.05 (s, 1H).

(5) tert-Butyl 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl] (130 mg, 0.36 mmol), the title compound (pale yellow oil, 90 mg, yield 58%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.35 (s, 6H), 1.47 (s, 9H), 7.40 (d, 1H, J=9Hz), 7.56 (d, 2H, J=9Hz), 7.81 (d, 2H, J=9Hz), 9.00 (s, 1H).

(Example 102)

2-[[7-(4-Cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 141]

Using tert-butyl 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (90 mg, 0.21 mmol) obtained in Example 101, the title compound (white crystals, 12 mg, yield 15%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.31 (s, 6H), 7.40 (d, 1H, J=10Hz), 7.66 (d, 2H, J=8Hz), 8.01 (d, 2H, J=9Hz), 9.31 (s, 1H).

(Example 103)

tert-Butyl 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 142]

(1) 7-Bromo-5-fluoro-6-methoxybenzo[d]isothiazole

5-Fluoro-6-methoxybenzo[d]isothiazole (225 mg, 1.23 mmol) was dissolved in acetic acid (5 mL), bromine (70 μL, 1.35 mmol) was added and stirred at 60 ° C. After 11 hours, the reaction solution was concentrated, saturated sodium bicarbonate aqueous solution was added to the obtained residue, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (yellow crystals, 203 mg, yield 63%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 4.08 (d, 3H, J = 2Hz), 7.72 (d, 1H, J = 10Hz), 8.90 (s, 1H).

(2) 4-(5-Fluoro-6-methoxybenzo[d]isothiazol-7-yl)benzonitrile

Using the above-obtained 7-bromo-5-fluoro-6-methoxybenzo[d]isothiazole (201 mg, 0.77 mmol) and (4-cyanophenyl)boronic acid (135 mg, 0.92 mmol), the title compound (white amorphous, 190 mg, yield 86%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.86 (d, 3H, J=2Hz), 7.7-7.9 (m, 5H), 8.86 (s, 1H).

(3) O-[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 4-(5-fluoro-6-methoxybenzo[d]isothiazol-7-yl)benzonitrile (189 mg, 0.66 mmol), the title compound (white amorphous, 193 mg, yield 82%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 3.23 (s, 3H), 3.40 (s, 3H), 7.81 (s, 4H), 7.85 (d, 1H, J = 9Hz), 8.93 (s, 1H).

(4) S-[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl] (191 mg, 0.53 mmol), the title compound (white amorphous, 165 mg, yield 86%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=3.00 (s, 3H), 3.03 (s, 3H), 7.59 (d, 2H, J=8Hz), 7.81 (d, 2H, J=9Hz), 7.84 (d, 1H, J=8Hz) 8.94 (s, 1H).

(5) tert-Butyl 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl] (133 mg, 0.34 mmol), the title compound (white amorphous, 21 mg, yield 17%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.25 (s, 6H), 1.39 (s, 9H), 7.60 (d, 2H, J = 8Hz), 7.7-7.9 (m, 3H), 8.92 (s, 1H).

(Example 104)

2-[[7-(4-Cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 143]

Using tert-butyl 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (20 mg, 0.05 mmol) obtained in Example 103, the title compound (white crystals, 7.4 mg, yield 43%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.36 (s, 6H), 7.61 (d, 2H, J=8Hz), 7.80-7.82 (m, 3H), 8.94 (s, 1H).

(Example 105)

Ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate

[Chemical formula 144]

(1) 1-[2-(Benzylthio)-4-methoxyphenyl]-1-ethanone

Under nitrogen flow conditions, benzyl mercaptan (0.64 mL, 5.5 mmol) was dissolved in tetrahydrofuran (30 mL), and potassium tert-butoxide (620 mg, 5.5 mmol) was added little by little. After 1 hour, a solution of 1-(2-fluoro-4-methoxyphenyl)-1-ethanone (840 mg, 5 mmol) in tetrahydrofuran (10 mL) was added and stirred under heating reflux. After 3 hours, the reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (slightly brown crystals, 1.09 g, yield 80%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.56 (s, 3H), 3.79 (s, 3H), 4.12 (s, 2H), 6.67 (dd, 1H, J = 3Hz, 9Hz) , 6.86 (d, 1H, J=3Hz), 7.2-7.4 (m, 3H), 7.44 (d, 2H, J=7Hz), 7.83 (d, 1H, J=9Hz).

(2) 6-Methoxy-3-methylbenzo[d]isothiazole

The 1-[2-(benzylthio)-4-methoxyphenyl]-1-ethanone (1.09 g, 4 mmol) obtained above was dissolved in dichloromethane (11 mL), and sulfonyl chloride (320 μL, 4 mmol) was added under a nitrogen flow/ice bath. After 1 hour, the reaction solution was concentrated, and the resulting residue was dissolved in tetrahydrofuran (10 mL). 2M NH3 _- EtOH (10 mL) was added, and the mixture was stirred at room temperature. After 20 hours, the reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:2) to obtain the title compound (yellow crystals, 0.54 g, yield 75%).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.69 (s, 3H), 3.91 (s, 3H), 7.03 (dd, 1H, J=3Hz, 9Hz), 7.29 (d, 1H, J=3Hz), 7.78 (d, 1H, J=9Hz).

(3) 7-Bromo-6-methoxy-3-methylbenzo[d]isothiazole

The above-obtained 6-methoxy-3-methylbenzo[d]isothiazole (0.54 g, 3.0 mmol) was dissolved in chloroform (11 mL), and bromine (370 μL, 3.0 mmol) was added and stirred. After 2 hours, the suspended reaction solution was filtered, and the resulting crystals were washed with chloroform to obtain the title compound (yellow crystals, 0.75 g, 97% yield).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.70 (s, 3H), 4.03 (s, 3H), 7.08 (d, 1H, J=9Hz), 7.83 (d, 1H, J=9Hz).

(4) 4-(6-Methoxy-3-methylbenzo[d]isothiazol-7-yl)benzonitrile

Using the above-obtained 7-bromo-6-methoxy-3-methylbenzo[d]isothiazole (0.75 g, 2.9 mmol) and (4-cyanophenyl)boronic acid (0.59 g, 4.0 mmol), the title compound (white amorphous, 0.51 g, yield 62%) was obtained by the same method as Example 16(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.73 (s, 3H), 3.93 (s, 3H), 7.22 (d, 1H, J=9Hz), 7.74 (d, 2H, J=9Hz), 7.78 (d, 2H, J=9Hz), 7.93 (d, 1H, J=9Hz).

(5) Ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate

Using the above-obtained 4-(6-methoxy-3-methylbenzo[d]isothiazol-7-yl)benzonitrile (0.51 g, 1.8 mmol), a crude product of 4-(6-hydroxy-3-methylbenzo[d]isothiazol-7-yl)benzonitrile (0.34 g) was obtained by the same method as in Example 18(2).

The obtained crude product (27 mg) was used in the same manner as in Example 1(3) to obtain the title compound (colorless oil, 7 mg, yield 18%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.25 (t, 3H, J=7Hz), 1.48 (s, 6H), 2.71 (s, 3H), 4.24 (q, 2H, J=7Hz), 7.04 (d, 1H, J=9Hz), 7.77 (s, 4H), 7.80 (d, 1H, J=9Hz).

(Example 106)

2-[[7-(4-Cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropanoic acid

[Chemical Formula 145]

Using ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]oxy]-2-methylpropanoate (7 mg, 0.02 mmol) obtained in Example 105, the title compound (white crystals, 5 mg, yield 78%) was obtained by the same method as in Example 6.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.49 (s, 6H), 2.72 (s, 3H), 7.16 (d, 1H, J=9Hz), 7.74 (d, 2H, J=9Hz), 7.78 (d, 2H, J=9Hz), 7.84 (d, 1H, J=9Hz).

(Example 107)

Ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

[Chemical Formula 146]

(1) O-[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the crude 4-(6-hydroxy-3-methylbenzo[d]isothiazol-7-yl)benzonitrile (0.31 g) obtained in Example 105(5), the title compound (slightly brown crystals, 0.27 g, yield 63%) was obtained by the same method as 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.77 (s, 3H), 3.19 (s, 3H), 3.36 (s, 3H), 7.31 (d, 1H, J = 9Hz), 7.75 (d, 2H, J = 9Hz), 7.78 (d, 2H, J = 9Hz), 7.95 (d, 1H, J = 9Hz).

(2) S-[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl] (0.27 g, 0.73 mmol), the title compound (brown crystals, 0.27 g, yield 100%) was obtained by the same method as in Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.76 (s, 3H), 2.96 (s, 6H), 7.56 (d, 1H, J=9Hz), 7.69 (d, 2H, J=9Hz), 7.76 (d, 2H, J=9Hz), 7.92 (d, 1H, J=9Hz).

(3) Ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate

Using the above-obtained dimethylthiocarbamic acid S-[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl] (0.27 g, 0.73 mmol), the title compound (colorless oil, 150 mg, yield 52%) was obtained by the same method as Example 22(3) and Example 1(3).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.22 (t, 3H, J = 7Hz), 1.34 (s, 6H), 2.76 (s, 3H), 4.05 (d, 2H, J = 7Hz), 7.59 (d, 1H, J=9Hz), 7.63 (d, 2H, J=9Hz), 7.79 (d, 2H, J=9Hz), 7.87 (d, 1H, J=9Hz).

(Example 108)

2-[[7-(4-Cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 147]

Using ethyl 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoate (150 mg, 0.38 mmol) obtained in Example 107, the title compound (white crystals, 85 mg, yield 61%) was obtained by the same method as in Example 26.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.38 (s, 6H), 2.77 (s, 3H), 7.59 (d, 2H, J=8Hz), 7.74 (d, 1H, J=8Hz), 7.77 (d, 2H, J=8Hz), 7.89 (d, 1H, J=8Hz).

(Example 109)

Ethyl 5-[6-[[1-(tert-Butoxy)-2-methyl-1-oxopropan-2-yl]thio]-3-methylbenzo[d]isothiazol-7-yl]picolinate

[Chemical Formula 148]

(1) 5-(6-methoxy-3-methylbenzo[d]isothiazol-7-yl)pyridine cyanide

Using 7-bromo-6-methoxy-3-methylbenzo[d]isothiazole (100 mg, 0.39 mmol) obtained in Example 105(3) and (6-cyanopyridin-3-yl)boronic acid (69 mg, 0.47 mmol), the title compound (white crystals, 67 mg, yield 62%) was obtained by the same method as in Example 1(1).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.74 (s, 3H), 3.95 (s, 3H), 7.23 (d, 1H, J=9Hz), 7.82 (dd, 1H, J=1Hz, 8Hz), 7.96 (d, 1H, J=9Hz), 8.10 (dd, 1H, J=2Hz, 8Hz), 8.98 (d, 1H, J=1Hz).

(2) O-[7-(6-cyanopyridin-3-yl)-3-methylbenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained 5-(6-methoxy-3-methylbenzo[d]isothiazol-7-yl)pyridine cyanide (0.21 g, 0.75 mmol), the title compound (185 mg, yield 69%) was obtained by the same method as in Examples 18(2) and 22(1).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.79 (s, 3H), 3.22 (s, 3H), 3.36 (s, 3H), 7.32 (d, 1H, J = 8Hz), 7.83 ( d, 1H, J=8Hz), 8.00 (d, 1H, J=9Hz), 8.15 (dd, 1H, J=2Hz, 7Hz), 8.93-8.94 (m, 1H).

(3) S-[7-(6-cyanopyridin-3-yl)-3-methylbenzo[d]isothiazol-6-yl]dimethylthiocarbamate

Using the above-obtained dimethylthiocarbamic acid O-[7-(6-cyanopyridin-3-yl)-3-methylbenzo[d]isothiazol-6-yl] (184 mg, 0.52 mmol), the title compound (yellow amorphous, 140 mg, yield 76%) was obtained by the same method as Example 27(2).

¹ H NMR (CDCl ₃ , 400MHz): δ=2.79 (s, 3H), 2.9-3.0 (m, 6H), 7.73 (d, 1H, J=8Hz), 7.83 (d, 1H, J=8Hz), 7.9-8.1 (m, 2H), 8.80-8.81 (m, 1H).

(4) Ethyl 5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]thio]-3-methylbenzo[d]isothiazol-7-yl]picolinate

Using the above-obtained dimethylthiocarbamic acid S-[7-(6-cyanopyridin-3-yl)-3-methylbenzo[d]isothiazol-6-yl] (138 mg, 0.39 mmol), the title compound (yellow oil, 76 mg, yield 46%) was obtained by the same method as in Example 22(3) and Example 23.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.30 (s, 6H), 1.46 (s, 9H), 1.51 (t, 3H, J=7Hz), 2.77 (s, 3H), 4.55 (q, 2H, J=7Hz), 7.72 (d , 1H, J=8Hz), 7.90 (d, 1H, J=8Hz), 7.97 (dd, 1H, J=2Hz, 9Hz), 8.29 (d, 1H, J=8Hz), 8.86 (d, 1H, J=2Hz).

(Example 110)

2-[[7-[6-(Ethoxycarbonyl)pyridin-3-yl]-3-methylbenzo[d]isothiazol-6-yl]thio]-2-methylpropanoic acid

[Chemical Formula 149]

Using ethyl 5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl]thio]-3-methylbenzo[d]isothiazol-7-yl]picolinate (74 mg, 0.17 mmol) obtained in Example 109, the title compound (slightly brown crystals, 30 mg, yield 47%) was obtained by the same method as in Example 6.

¹ H NMR (DMSO-d ₆ , 400MHz): δ=1.28 (s, 6H), 1.38 (t, 3H, J=7Hz), 2.76 (s, 3H), 4.40 (q, 2H, J=7Hz), 7.7 9 (d, 1H, J=8Hz), 8.11 (dd, 1H, J=2Hz, 8Hz), 8.20 (d, 2H, J=8Hz), 8.77 (d, 1H, J=2Hz).

(Example 111)

Ethyl 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylate

[Chemical Formula 150]

4-(6-mercapto-3-methylbenzo[d]isothiazol-7-yl)benzonitrile (43 mg, 0.15 mmol) and sodium carbonate (48 mg, 0.46 mmol) were dissolved in dimethylformamide (1.5 mL), and 1-bromocyclobutane-1-carboxylic acid ethyl ester (49 μL, 0.30 mmol) was added and stirred at 60°C for 17 hours. The reaction solution was allowed to cool to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (NH silica, ethyl acetate: hexane = 1:9) to obtain the title compound (pale yellow crystals, 20 mg, yield 33%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.14 (t, 3H, J = 8Hz), 1.8-2.0 (m, 2H), 2.0-2.1 (m, 2H), 2.6-2.7 (m, 2H), 2.78 (s, 3H), 4. 04 (q, 2H, J=8Hz), 7.52 (d, 1H, J=9Hz), 7.58 (d, 2H, J=9Hz), 7.79 (d, 2H, J=9Hz), 7.86 (d, 1H, J=9Hz).

(Example 112)

1-[[7-(4-Cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid

[Chemical Formula 151]

The 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazol-6-yl]thio]cyclobutane-1-carboxylic acid ethyl ester (20 mg, 0.049 mmol) obtained in Example 111 was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and a 2M aqueous sodium hydroxide solution (1 mL) was added and stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, 3M hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over sodium sulfate and filtering, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol: chloroform = 5:95) to obtain the title compound (white crystals, 16 mg, yield 86%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.9-2.1 (m, 4H), 2.6-2.7 (m, 2H), 2.80 (s, 3H), 7.56 (d, 1H, J=9Hz), 7.59 (d, 2H, J=8Hz), 7.78 (d, 2H, J=8Hz), 7.85 (d, 1H, J=9Hz).

(Example 113)

2-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]-2-ethylbutanoic acid

[Chemical formula 152]

4-(6-Mercaptobenzo[d]isothiazol-7-yl)benzonitrile (101 mg, 0.376 mmol) and sodium carbonate (80 mg, 0.75 mmol) obtained in Example 27 (3) were dissolved in dimethylformamide (0.5 mL), 2-bromo-2-ethylbutyric acid (113 mg, 0.579 mmol) was added, and the mixture was stirred at 60°C for 4 hours and at 75°C for 2 hours. The reaction solution was allowed to cool to room temperature, 1M hydrochloric acid was added, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:chloroform = 1:29) to obtain the title compound (white crystals, 31 mg, yield 21%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 0.72 (t, 6H, J = 8Hz), 1.5-1.6 (m, 2H), 1.7-1.8 (m, 2H), 7.63 (d, 2H, J =8Hz), 7.73 (d, 1H, J=8Hz), 7.81 (d, 2H, J=8Hz), 7.98 (d, 1H, J=8Hz), 8.94 (s, 1H).

(Example 114)

2-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]-3,3-dimethylbutanoic acid

[Chemical Formula 153]

Using 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (83 mg, 0.31 mmol) and 2-bromo-3,3-dimethylbutanoic acid (72 mg, 0.37 mmol) obtained in Example 27(3), the title compound (white crystals, 37 mg, yield 31%) was obtained by the same method as in Example 113.

¹ H NMR (CDCl ₃ , 400MHz): δ=1.02 (s, 9H), 3.42 (S, 1H), 7.64 (d, 2H, J=8Hz), 7.70 (d, 1H, J=8Hz), 7.81 (d, 2H, J=8Hz), 8.01 (d, 1H, J=8Hz), 8.91 (s, 1H).

(Example 115)

tert-Butyl (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-butenoate

[Chemical formula 154]

4-(2-Mercaptonaphthalen-1-yl)benzonitrile (100 mg, 0.383 mmol) obtained in Example 48 (3) was dissolved in dimethylformamide (2 mL), sodium hydride (18 mg, 0.44 mmol) was added, and the mixture was stirred at room temperature. After 15 minutes, tert-butyl 2-butynoate (86 mg, 0.61 mmol) was added to the reaction solution, and the mixture was further stirred for 45 minutes. 1 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:9) to obtain the title compound (colorless oil, 58 mg, yield 36%).

¹ H NMR (CDCl ₃ , 400MHz): δ=1.41 (s, 9H), 2.23 (s, 3H), 5.19 (s, 1H), 7.35 (d, 1H, J=8Hz), 7.40 (d, 2H, J=8Hz), 7.44 (t, 1H, J= 8Hz), 7.57 (t, 1H, J=8Hz), 7.62 (d, 1H, J=8Hz), 7.76 (d, 2H, J=8Hz), 7.92 (d, 1H, J=8Hz), 7.93 (d, 1H, J=8Hz).

(Example 116)

(E)-3-[[1-(4-Cyanophenyl)naphthalen-2-yl]thio]-2-butenoic acid

[Chemical formula 155]

The (E)-3-[[1-(4-cyanophenyl)naphthalen-2-yl]thio]-2-butenoic acid tert-butyl ester (58 mg, 0.14 mmol) obtained in Example 115 was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added under ice bath. After warming to room temperature, the mixture was stirred for 10 minutes. Trifluoroacetic acid (0.2 mL) was added again under ice bath, and the mixture was warmed to room temperature. After 20 minutes, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (white crystals, 35 mg, 69%).

¹ H NMR (CDCl ₃ , 400MHz): δ = 2.28 (s, 3H), 5.12 (s, 1H), 7.35 (d, 1H, J = 8Hz), 7.39 (d, 2H, J = 9Hz), 7.45 (t, 1H, J = 8Hz), 7.59 (t, 1H, J=8Hz), 7.61 (d, 1H, J=8Hz), 7.77 (d, 2H, J=9Hz), 7.94 (d, 1H, J=9Hz), 7.96 (d, 1H, J=9Hz).

(Example 117)

1-[[7-(4-Cyanophenyl)benzo[d]isothiazol-6-yl]thio]cyclohexane-1-carboxylic acid

[Chemical formula 156]

Using 4-(6-mercaptobenzo[d]isothiazol-7-yl)benzonitrile (68 mg, 0.25 mmol) and 1-bromocyclohexane-1-carboxylic acid (67 mg, 0.32 mmol) obtained in Example 27(3), the title compound (white crystals, 31 mg, yield 31%) was obtained by the same method as in Example 113.

¹ H NMR (CDCl ₃ , 400MHz): δ = 1.25-1.26 (m, 3H), 1.5-1.6 (m, 5H), 2.00-2.02 (m, 2H), 7.62 (d, 2H, J =9Hz), 7.74 (d, 1H, J=9Hz), 7.80 (d, 2H, J=9Hz), 7.99 (d, 1H, J=9Hz), 8.94 (s, 1H).

(Example 118)

[ ¹⁴ C]uric acid uptake by HEK-URAT1

(1) Experimental methods

HEK293 cells stably expressing the URAT1 gene (HEK-URAT1) or HEK293 cells harboring an empty vector (HEK-mock) were cultured in DMEM supplemented with 10% fetal bovine serum at 37°C in an incubator under 5% carbon dioxide conditions. 1×10 ⁵ cells were seeded into 24-well culture dishes coated with poly-D-lysine and cultured for 3 days before initiating the uptake experiment.

Uric acid uptake experiments were performed at 37°C. Cells were washed three times with a pH 7.4 uptake assay solution (Hanks buffer, chloride-free; 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.2 mM KH ₂ PO ⁴ , 1.2 mM MgSO ₄ , 1.3 mM calcium gluconate, 25 mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid), 5.6 mM glucose, and 12.4 mM tris(hydroxymethylaminomethane) (Tris)) heated to 37°C and equilibrated at 37°C for 10 minutes. After removing the buffer from the cells, 0.5 mL of the uptake solution supplemented with 5 μM [ ¹⁴ C]uric acid was added, with or without the test compound, and incubated for 2 minutes. Cell uptake was stopped by adding ice-cold chloride-free Hanks buffer, and the cells were washed three times. Cells were lysed with 0.1N sodium hydroxide, and radiation doses were measured using an LSC6100 (Aloka, Tokyo). The amount of uptake into HEK-URAT1 was calculated by subtracting the amount into HEK-mock cells from the value for HEK-URAT1 and converting the result to mg protein per cell. The uptake in the absence of the test compound was set as 100%, and the uptake rate was calculated. Uptake was performed three times under each condition, and each value is expressed as the mean ± standard deviation.

(2) Test results

The test results are shown in Table 1.

[Table 1]

Test compound % control (10 μM) Example 2 45.4 2.06 Example 4 15.1 0.79 Example 6 5.4 Example 7 29.5 Example 8 61.3 Example 10 27.1 Example 15 50.1 3.44 Example 17 59.3 Example 19 15.6 Example 21 48.7 Example 24 7.4 0.17 Example 26 11.6 Example 28 0.1 Example 37 78.6 Example 45 36.5 1.58

As shown in Table 1, the compounds of the present invention have excellent URAT1 inhibitory effects.

(Example 119)

[ ¹⁴ C]uric acid uptake by HEK-URAT1

(1) Experimental methods

Using the same method as in Example 118, the inhibitory effect of URAT1 was measured.

(2) Test results

The test results are shown in Tables 2 and 3.

[Table 2]

Example No. % control (10 μM) 58 12.0 N.T 60 69.2 N.T 62 49.0 N.T 64 30.1 N.T 66 1.8 0.0215 68 <0.1 0.0262 70 6.4 N.T 72 <0.1 0.012 74 6.8 N.T 76 12.7 N.T 78 3.2 0.104 80 29.2 N.T 82 <0.1 0.106 84 2.3 0.205 86 12.1 N.T 88 3.8 N.T 90 3.6 0.161

[Table 3]

Example No. % control (10 μM) 112 13.8 2.433 113 <0.1 0.021 114 5.8 0.474 116 1.3 0.025 117 2.7 0.296

As shown in Tables 2 and 3, the compounds of the present invention have excellent URAT1 inhibitory effects.

Claims (25)

1. A compound represented by the following general formula (III), a tautomer, a stereoisomer of the compound, or a pharmaceutically permissible salt thereof, In general formula (III), ^R1a , ^R2a , ^R6a and ^R7a may be the same or different, representing hydrogen atom, halogen atom, alkyl group of carbon 1 to 8, alkoxy group of carbon 1 to 8, alkyl group of carbon 1 to 8 substituted with 1 to 3 halogen atoms, alkoxy group of carbon 1 to 8 substituted with 1 to 3 halogen atoms, hydroxyl group, amino group, carboxyl group, mercapto group, alkylthio group of carbon 1 to 8, nitro group or cyano group; ^R3a and ^R8a combine with the two carbon atoms bonded to ^R3a and ^R8a to form thiazoles or isothiazoles. The thiazole or isothiazole may be without substituents or have 1 to 4 identical or different substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, alkylthio groups having 1 to 8 carbon atoms, nitro groups, or cyano groups. ^R4a and ^R5a combine with the two carbon atoms bonded to ^R4a and ^R5a to form a benzene ring, or ^R4a and ^R5a represent the same groups as ^R1a mentioned above. The benzene ring may be without substituents or have 1 to 4 identical or different substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, alkylthio groups having 1 to 8 carbon atoms, nitro groups, or cyano groups. ^Wa indicates CR ^10a or N. R ^10a represents the same group as the aforementioned R ^1a ; X ^_a represents a sulfur atom. ^Ya represents an alkylene chain with 1 to 8 carbon atoms. The alkylene chain is either unsubstituted or substituted with 1 to 4 groups, which are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or alkoxy groups having 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms. The aforementioned alkylene chain is either a straight-chain alkylene chain or a branched alkylene chain. The branched alkylene chain is bonded to the same or different carbon atoms as a side chain, and forms a 3 to 7-membered ring with the carbon atom to which the side chain is bonded, or does not form a 3 to 7-membered ring with the carbon atom to which the side chain is bonded. In the case where the aforementioned alkylene chain is an alkylene chain having 2 to 8 carbon atoms, the alkylene chain may or may not have a double bond. ^Za represents _CO₂H , tetrazolium, or _SO₂NR ^15a R ^16a . R ^15a and R ^16a may be the same or different, representing a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. 2. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R1a , ^R2a , ^R6a and ^R7a may be the same or different, representing hydrogen atom, halogen atom, alkyl group with 1 to 8 carbon atoms, alkoxy group with 1 to 8 carbon atoms, alkyl group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl group, amino group, carboxyl group, mercapto group, nitro group or cyano group; ^R3a and ^R8a combine with the two carbon atoms bonded to ^R3a and ^R8a to form thiazoles or isothiazoles. The thiazole or isothiazole may be without substituents or have 1 to 4 identical or different substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl, amino, carboxyl, mercapto, nitro, or cyano groups. ^R4a and ^R5a can be combined with the two carbon atoms bonded to ^R4a and ^R5a to form a benzene ring, or ^R4a and ^R5a can represent the same groups as ^R1a mentioned above. The aforementioned benzene ring may or may not have 1 to 4 identical or different substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, nitro groups, or cyano groups. 3. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R1a , ^R2a , ^R6a , and ^R7a may be the same or different, and are hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, or cyano groups. 4. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, R ^6a is a cyano group. 5. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R3a and ^R8a combine with the two carbon atoms bonded to ^R3a and ^R8a to form a thiazole or isothiazole, which is either unsubstituted or substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a cyano group. 6. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R4a and ^R5a may be the same or different, and are hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, or cyano groups. 7. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^Wa is CR ^10a . 8. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, Ya ^is represented by C(C _1-3 alkyl) ₂ . 9. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^Ya is represented by the following general formula (VI), In general formula (VI), ^RaO1 and ^RaO2 may be the same or different, representing alkyl groups with 1 to 8 carbon atoms, or ^RaO1 and ^RaO2 may combine and become integrated with the carbon atoms bonded to ^RaO1 and ^RaO2 to form a 3 to 7-membered ring, and — represents a bonding bond. 10. The compound of claim 1, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^Za is _CO2H . 11. A compound represented by the following general formula (IV), a tautomer, a stereoisomer of the compound, or a pharmaceutically permissible salt thereof, In general formula (IV), ^R1b , ^R2b , ^R4b , ^R5b , ^R6b , ^R7b and ^R10b are the same or different, representing hydrogen atom, halogen atom, alkyl group of carbon 1 to 8, alkoxy group of carbon 1 to 8, alkyl group of carbon 1 to 8 substituted with 1 to 3 halogen atoms, alkoxy group of carbon 1 to 8 substituted with 1 to 3 halogen atoms, hydroxyl group, amino group, carboxyl group, mercapto group, alkylthio group of carbon 1 to 8, nitro group or cyano group; ^R3b and ^R8b combine with the two carbon atoms bonded to ^R3b and ^R8b to form a thiazole or isothiazole. The thiazole or isothiazole may or may not have substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, alkylthio groups having 1 to 8 carbon atoms, nitro groups, or cyano groups. ^Xb represents a sulfur atom; ^Yb represents an alkylene chain with 1 to 8 carbon atoms. The alkylene chain is either unsubstituted or substituted with 1 to 4 groups, which are alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or alkoxy groups having 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms. The aforementioned alkylene chain is either a straight-chain alkylene chain or a branched alkylene chain. The branched alkylene chain is bonded to a side chain of the same or different carbon atoms, and forms a 3 to 7-membered ring with the carbon atom to which the side chain is bonded, or does not form a 3 to 7-membered ring with the carbon atom to which the side chain is bonded. In the case where the aforementioned alkylene chain is an alkylene chain having 2 to 8 carbon atoms, the alkylene chain may or may not have a double bond. 12. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R1b , ^R2b , ^R4b , ^R5b , ^R6b , ^R7b , and ^R10b may be the same or different, representing hydrogen atoms, halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, nitro groups, or cyano groups; ^R3b and ^R8b combine with the two carbon atoms bonded to ^R3b and ^R8b to form a thiazole or isothiazole; The thiazole or isothiazole may or may not have substituents selected from halogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, hydroxyl groups, amino groups, carboxyl groups, mercapto groups, nitro groups, or cyano groups. 13. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R1b , ^R2b , ^R4b , ^R5b , ^R6b , ^R7b , and ^R10b may be the same or different, and may be a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an alkoxy group with 1 to 8 carbon atoms, or a cyano group. 14. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, R ^6b is a cyano group. 15. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^R3b and ^R8b are integrated with the two carbon atoms bonded to ^R3b and ^R8b to form a thiazole or isothiazole, which is either unsubstituted or substituted with a substituent selected from alkyl, alkoxy, or cyano groups having 1 to 8 carbon atoms. 16. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^Yb is represented by C(C _1-3 alkyl) ₂ . 17. The compound of claim 11, its tautomers, stereoisomers, or pharmaceutically permissible salts thereof, wherein, ^Yb is represented by the following general formula (VII), In general formula (VII), ^Rb01 and ^Rb02 may be the same or different, representing alkyl groups having 1 to 8 carbon atoms, or ^Rb01 and ^Rb02 may be combined and integrated with the carbon atoms of ^Rb01 and ^Rb02 to form a 3 to 7-membered ring. 18. A compound, a tautomer, a stereoisomer, or a pharmaceutically permissible salt thereof, wherein the compound is selected from: 2-[[7-(4-cyanophenyl)benzo[d]thiazo-6-yl]oxy]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]-2-methylpropionic acid, (E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]tert-butyl acrylate, (E)-3-[[7-(4-cyanophenyl)benzo[d]thiazol-6-yl]oxy]acrylic acid, 2-[[7-(4-cyanophenyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyanophenyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]oxy]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]oxy]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropionate ethyl ester, 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]oxy]-2-methylpropionic acid, 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropionate ethyl ester, 2-[[4-(4-cyanophenyl)benzo[c][1,2,5]thiadiazol-5-yl]thio]-2-methylpropionic acid, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-5-yl]oxy]-2-methylpropionate ethyl ester, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-5-yl]oxy]-2-methylpropionic acid, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-7-yl]oxy]-2-methylpropionate ethyl ester, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-7-yl]oxy]-2-methylpropionic acid, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-7-yl]thio]-2-methylpropionate ethyl ester, 2-[[6-(4-cyanophenyl)benzo[d]thiazo-7-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionamide, 2-[[7-(4-cyanophenyl)benzo[d]thiazolyl-6-yl]thio]-N-(5-fluoropyridin-2-yl)-2-methylpropionamide, 2-[[7-(4-cyanophenyl)benzo[d]thiazolyl-6-yl]thio]-2-methyl-N-(1,3,4-thiadiazol-2-yl)propionamide, 2-[[4-(4-cyanophenyl)benzo[d]thiazolyl-5-yl]oxy]-2-methylpropionate tert-butyl ester, and, 2-[[4-(4-cyanophenyl)benzo[d]thiazo-5-yl]oxy]-2-methylpropionic acid. 19. A compound, a tautomer, a stereoisomer, or a pharmaceutically permissible salt thereof, wherein the compound is selected from: 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyanophenyl)-2-(trifluoromethyl)benzo[d]thiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazo-6-yl]thio]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)-2-methylbenzo[d]thiazo-6-yl]thio]-2-methylpropionic acid, 2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazo-6-yl]thio]tert-butyl propionate, 2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]thiazo-6-yl]thio]propionic acid, 1-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]cyclobutane-1-carboxylic acid ethyl ester 1-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]cyclobutane-1-carboxylic acid, 1-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]cyclopentane-1-carboxylic acid methyl ester, 1-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]cyclopentane-1-carboxylic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-3-methylbutyrate methyl ester, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-3-methylbutyric acid, ethyl 2-methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazo-6-yl]thio]propionate, 2-Methyl-2-[[7-(4-nitrobenzene)benzo[d]isothiazo-6-yl]thio]propionic acid, 2-Methyl-2-[[7-(p-toluene)benzo[d]isothiazo-6-yl]thio]tert-butyl propionate, 2-Methyl-2-[[7-(p-toluene)benzo[d]isothiazo-6-yl]thio]propionic acid, 2-[[7-(4-isopropylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-isopropylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-Methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazo-6-yl]thio]tert-butyl propionate, 2-Methyl-2-[[7-[4-(trifluoromethyl)phenyl]benzo[d]isothiazo-6-yl]thio]propionic acid, 2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazo-6-yl]thio]tert-butyl propionate, 2-Methyl-2-[[7-[4-(trifluoromethoxy)phenyl]benzo[d]isothiazo-6-yl]thio]propionic acid, 2-[[7-(4-chlorophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-chlorophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(3-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(3-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate ethyl ester, 2-[[7-(4-cyano-2-methylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyano-3-methylphenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyano-3-fluorophenyl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-fluoronaphthyl-1-yl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanonaphthal-1-yl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyanonena-1-yl)benzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-Methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazo-6-yl]thio]tert-butyl propionate, 2-Methyl-2-[[7-(pyridin-3-yl)benzo[d]isothiazo-6-yl]thio]propionic acid, ethyl 2-methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazo-6-yl]thio]propionate, 2-Methyl-2-[[7-(pyridin-4-yl)benzo[d]isothiazo-6-yl]thio]propionic acid, 2-Methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazo-6-yl]thio]propionate ethyl ester, 2-Methyl-2-[[7-[6-(methylthio)pyridin-3-yl]benzo[d]isothiazo-6-yl]thio]propionic acid, 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyanophenyl)-4-fluorobenzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazo-6-yl]thio]-2-methylpropionate tert-butyl ester, 2-[[7-(4-cyanophenyl)-5-fluorobenzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]oxy]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]oxy]-2-methylpropionic acid, 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]thio]-2-methylpropionate ethyl ester, 2-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid, 5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropane-2-yl]thio]-3-methylbenzo[d]isothiazolyl]tert-butyl pyridinecarboxylate, and 2-[[7-[6-(ethoxycarbonyl)pyridin-3-yl]-3-methylbenzo[d]isothiazo-6-yl]thio]-2-methylpropionic acid. 20. A compound, a tautomer, a stereoisomer, or a pharmaceutically permissible salt thereof, wherein the compound is selected from: 5-[6-[[1-(tert-butoxy)-2-methyl-1-oxopropane-2-yl]thio]-3-methylbenzo[d]isothiazolyl]ethyl pyridinecarboxylate, 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]thio]cyclobutane-1-carboxylic acid ethyl ester 1-[[7-(4-cyanophenyl)-3-methylbenzo[d]isothiazo-6-yl]thio]cyclobutane-1-carboxylic acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-2-ethylbutyric acid, 2-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]-3,3-dimethylbutyric acid, and 1-[[7-(4-cyanophenyl)benzo[d]isothiazo-6-yl]thio]cyclohexane-1-carboxylic acid. 21. A pharmaceutical composition wherein, as an active ingredient, it comprises any one of claims 1 to 20, a tautomer, a stereoisomer of the compound, or a pharmaceutically permissible salt thereof. 22. A URAT1 inhibitor, wherein, as an active ingredient, it comprises any one of claims 1 to 20, a tautomer, a stereoisomer of the compound, or a pharmaceutically permissible salt thereof. 23. A treatment for gout or hyperuricemia, wherein, as an active ingredient, it comprises any one of claims 1 to 20, a tautomer, a stereoisomer of the compound, or a pharmaceutically permissible salt thereof. 24. The use of any compound of claims 1 to 20, tautomers, stereoisomers of the compound, or pharmaceutically permissible salts thereof in the manufacture of a medicament for the treatment of gout or hyperuricemia. 25. A method for screening substances with URAT1 inhibitory activity, comprising: culturing HEK293 cells stably expressing the URAT1 gene or HEK293 cells combined with an empty vector at a temperature of 37±1℃, then adding an uptake solution containing [ ^14C ]uric acid at a temperature of 37±1℃ and a pH of 7.4±0.1, the uptake solution containing the compound of any one of claims 1 to 20, the tautomer, stereoisomer or pharmaceutically permissible salt thereof, culturing at 37±1℃ for 2 to 10 minutes, stopping the reaction, washing, lysing the cells, and measuring the radiation dose.