JP2002322162A - Thiazolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel thiazolidine derivative having telomerase inhibitory activity or anitumor activity, and a pharmacologically acceptable salt thereof. SOLUTION: The thiazolidine derivative is represented by general formula (I), [wherein Q represents oxygen atom or sulfur atom, R<1> represents a substituted or unsubstituted aralkyl group, X represents a benzene ring, pyridine ring or thiophene ring, and when X is the benzene ring, then Y represents a hydrogen atom, or a substituted or unsubstituted lower alkenyl group and others, and when X is the pyridine ring or thiophene ring, then Y is represented by formula (III) (wherein R<2> represents a hydrogen atom)], or a pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a thiazolidine derivative used for treating diseases associated with telomerase activity such as malignant tumors.

[0002]

2. Description of the Related Art It is known that a telomere present at the end of a chromosome of a eukaryote is an important region for stabilizing the chromosome. In the case of human, its sequence is composed of a TTAGGG repeat sequence from the 5 'end. With few exceptions, telomere shortening usually occurs in normal cells depending on the number of divisions, and when shortened to a certain length, the cells become senescent cells and stop dividing (M1 phase). However, when the mitotic arrest mechanism does not function normally due to mutation of a tumor suppressor gene such as the p53 gene, the cell further divides. As a result, telomeres are shortened to the utmost extent, chromosomal instability occurs, and cells die (M2 phase) [Proceeding of the National Academy of Science of the USA. (Proc. Natl. Acad. Sci. USA), 89 , 1
0114-10118 (1992), Trends in Cell Biology, 5 , 293-297 (1995)].
On the other hand, telomerase, an enzyme that extends telomeres, is expressed in more than 80% of cancer cells [Journal of the
National Cancer Institute (Journa
l of the NCI), 87 , 884-894 (1995)]. This enzyme, R
A reverse transcriptase that extends telomeres using NA as a template,
It is composed of template RNA (hTR) and catalytic subunit protein (hTERT). Therefore, it is considered that telomerase suppresses telomere shortening in cancer cells and stably maintains telomeres, enabling infinite growth as immortalized cells. This concept, the “telomere hypothesis”, is based on the proceedings of
The National Academy of Science of the USA (Proc. Natl. Acad. Sci. US
A), 89 , 10114-10118 (1992). Experimental results to prove this telomere hypothesis include antisense to hTR [Science, 269 , 1236-1240
(1995)] and a dominant-negative mutant hTERT that inhibits wild-type telomerase [Jeans & Development, Genes & Development, 13 , 2388-2399
(1999), Nature Medicine, 5 ,
1164-1170 (1999)] has been reported to induce cell death with telomere shortening in cancer cells.
Therefore, it is expected that a substance that specifically inhibits telomerase may be a new type of antitumor agent that induces telomere shortening and gives life to cancer cells. Furthermore, since telomerase is expressed only in cancer tissues with some exceptions such as germ cells, it is expected to be a low-toxic antitumor agent that hardly affects normal tissues.

[0003] Low molecular substances that inhibit telomerase in vitro include AZTTP, ddGTP [Molecular and Cellular Biology (Mol. Cell. Biol.), 16 ,
53-65 (1996)], nucleic acid analogs such as 7-deaza-dGTP [Biochemistry, 35 , 15611-15617 (1996)], and hetero 5-membered condensed pyridine derivatives (US Pat. No. 5760062), benzothiophene derivatives (US Pat. No. 5,703,116), phenylisothiazole derivatives (WO99 / 08679) and the like are known. There are also reports on thiazolidine derivatives (WO01 / 02377, WO
01/02394, WO01 / 07020), but their activity is not sufficient.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel thiazolidine derivative having excellent telomerase inhibitory activity or antitumor activity.

[0005]

The present invention provides the following (1).
To (7). (1) Formula (I)

[0006]

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Wherein Q represents an oxygen atom or a sulfur atom; R ¹ represents a substituted or unsubstituted aralkyl;
Represents a benzene ring, a pyridine ring or a thiophene ring; 1) when X is a benzene ring, Y is a hydrogen atom, a substituted or unsubstituted lower alkenyl, carboxy, a substituted or unsubstituted lower alkoxycarbonyl, a carbamoyl, a substituted or unsubstituted Unsubstituted lower alkylcarbamoyl,
CH = N-OH, hydroxysulfonyl (sulfo, SO
₃ H), sulfamoyl, lower alkylsulfamoyl, lower alkanoylsulfamoyl, nitro, amino, sulfamoylamino, halogen or formula (II)

[0008]

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(Wherein Q ^A represents an oxygen atom or a sulfur atom, R ² represents a hydrogen atom or a substituted or unsubstituted lower alkyl, and when Q ^A is a sulfur atom, Z represents NH
Or a sulfur atom, and when Q ^A is an oxygen atom, Z
Represents -NH (C = O)-or NH);
The substitution position of Y on the (benzene ring) may be any position. 2) When X is a pyridine ring or a thiophene ring, Y
Is of the formula (III)

[0010]

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Wherein R ² has the same meaning as described above, and the substitution position of Y on X (pyridine ring or thiophene ring may be any position). An acceptable salt, (2) the thiazolidine derivative or the pharmaceutically acceptable salt thereof according to the above (1), wherein Q is an oxygen atom, or (3) the (1) or (1) wherein X is a pyridine ring or a thiophene ring. (2) the thiazolidine derivative or the pharmaceutically acceptable salt thereof according to the above,
(4) The thiazolidine derivative or the pharmaceutically acceptable salt thereof according to the above (1) or (2), wherein X is a pyridine ring, and (5) the thiazolidine derivative according to any one of the above (1) to (4). A medicament containing a thiazolidine derivative or a pharmacologically acceptable salt thereof; and (6) a thiazolidine derivative according to any one of (1) to (4) or a pharmacologically acceptable salt thereof as an active ingredient. Telomerase inhibitors, including (7)
The present invention relates to an antitumor agent comprising the thiazolidine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (4) as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a compound represented by the formula (I) is referred to as a compound (I). The same applies to compounds of other formula numbers. In the definition of each group in the formula (I), the lower alkyl is a linear or branched C1-C6 group.
Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The lower alkenyl is a straight-chain or branched alkenyl having 2 to 6 carbon atoms, for example, vinyl, allyl, 1-propenyl, methacryl, crotyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4-pentenyl , 2-hexenyl, 5-hexenyl and the like.
Examples of aralkyl include aralkyl having 7 to 15 carbon atoms, such as benzyl, phenethyl, diphenylmethyl and the like.

The lower alkyl moiety in lower alkoxycarbonyl, lower alkylcarbamoyl, lower alkylsulfamoyl and lower alkanoylsulfamoyl has the same meaning as the above definition of lower alkyl. Examples of the halogen include iodine, bromine, chlorine and fluorine atoms.

Substituted lower alkyl, substituted lower alkenyl,
As the substituent in the substituted aralkyl, substituted lower alkoxycarbonyl and substituted lower alkylcarbamoyl, 1 to 1 substitutable number, preferably 1 to 3 substituted
Lower alkyl, lower alkenyl, hydroxy, hydroxy-substituted lower alkyl, lower alkylsulfonyl, cyano, CO ₂ R ³ (where R ³ represents hydrogen or lower alkyl), CONR ⁴ R ⁵ (where R ⁴ and R ⁵ is the same or different and represents a hydrogen atom, lower alkyl, hydroxy-substituted lower alkyl or 2-carboxy-4,5-dimethoxyphenyl) and the like. Examples of the substituent of the substituted aralkyl include, in addition to the above substituents, 1 to 1 substitutable number, preferably 1 to 3 halogen atoms, trifluoromethyl and the like.

Substituted lower alkyl, substituted lower alkenyl,
In the definition of the substituent in substituted aralkyl, substituted lower alkoxycarbonyl and substituted lower alkylcarbamoyl, lower alkyl, lower alkenyl and halogen are as defined above, respectively, and the lower alkyl part in hydroxy-substituted lower alkyl is a hydrogen atom from the lower alkyl. This is a group excluding one, and the lower alkyl part of the lower alkylsulfonyl has the same meaning as the lower alkyl.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate, and the like.
Organic acid salts such as methanesulfonate, oxalate, malonate, succinate, and tartrate are listed, and pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt. , Magnesium salts, alkaline earth metal salts such as calcium salts, aluminum salts, zinc salts and the like, and pharmacologically acceptable ammonium salts include
Ammonium, salts such as tetramethylammonium, etc., as pharmacologically acceptable organic amine addition salts, morpholine, addition salts such as piperidine, etc., as pharmacologically acceptable amino acid addition salts, Addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like can be mentioned.

Among the compounds (I), various stereoisomers,
Some may have regioisomers, tautomers, and the like. The present invention includes all of these possible isomers and mixtures thereof, and the mixing ratio may be any ratio.
The production method of compound (I) is described below.

In the production methods described below, when the defined group changes under the conditions of the practice method or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, Protection and deprotection of functional groups [eg Protective Groups in Organic Synthesis, by TW Greene, John Wiley & Sons, Inc.
s, Inc.) (1981)] can be easily carried out.

The order of the reaction steps such as introduction of a substituent can be changed as required. Production Method 1 Compound (I) can be produced by the following reaction steps. Step (1)

[0021]

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(Wherein Q, R ¹ , X and Y have the same meanings as described above). Compound (I) can be obtained by condensing compound (IV) with compound (V). Compound (IV)
Can be produced according to a known production method [Liebigs Annare der Chemie (Liebigs Ann. Chem.), 409 (1984) and the like], a method described in Reference Examples described later, and the like. Some are available as commercial products.

The condensation reaction is carried out, if necessary, in the presence of a base catalyst and, if necessary, in a solvent. Examples of the base catalyst include piperidine, piperidinium acetate, diethylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate, butyllithium, lithium hydroxide, lithium diisopropylamide and the like. The base catalyst is used in an amount of 0.1 to 20 equivalents based on compound (IV). As the solvent, methanol, ethanol, propanol, ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, dioxane, hexane, benzene, toluene, xylene, N, N-dimethylformamide (DMF), N, N-dimethylacetamide ( DMA), dimethyl sulfoxide (DMSO) or the like is used alone or in combination.

Compound (V) is reacted with compound (IV)
The reaction is carried out between room temperature and 200 ° C., preferably between 50 and 100 ° C., and is completed in 0.1 to 50 hours.

Production Method 2 In the compound (I), X is a benzene ring, and Y is a compound of the formula
(VIa)

[0026]

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Wherein R ⁶ is a hydrogen atom, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, CO
₂ R ³ (wherein R ³ is as defined above) or CONR ⁴
R ⁵ (wherein, R ⁴ and R ⁵ have the same meanings as described above, respectively, and n is 0 or 1). it can. Step (2)

[0028]

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Wherein Q, R ¹ , R ⁶ and n are as defined above, and when n is 0, R ⁷ is substituted or unsubstituted lower alkyl (the lower alkyl is as defined above;
The substituent of the substituted lower alkyl represents the same as defined above, and when n is 1, R ⁷ represents a lower alkyl (the lower alkyl has the same meaning as described above.) The compound (Ia) is a compound (Ib) ) Can be obtained by hydrolysis.

The hydrolysis reaction is carried out in a solvent if necessary at 0.1
The reaction is performed in the presence of 2020 equivalents of a base catalyst or an acid catalyst. As the solvent, alcohols such as methanol, ethanol and propanol, ethers, ethers such as THF, 1,2-dimethoxyethane and dioxane, water and the like are used alone or in combination.

Examples of the base catalyst include potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like. , Hydrochloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like. The reaction is carried out between room temperature and 200 ° C, preferably between room temperature and 100 ° C, and is completed in 0.1 to 50 hours.

Production method 3 In the compound (I), X is a benzene ring, and Y is a compound of the formula
(VIb)

[0033]

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[Wherein R⁶, N are as defined above.
Yes, when n is 0, R⁸Represents hydrogen and R ⁹Is hydrogen or
Substituted or unsubstituted lower alkyl (the lower alkyl is
Has the same meaning as described above, and the substituent of the substituted lower alkyl is as defined above.
Synonymous), and when n is 1, R⁸And R⁹Is it
Each of the above R^FourAnd R^FiveAs defined above]
(Ic) can also be produced by the following reaction step.
Wear. Process (3)

[0035]

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(Wherein Q, R ¹ , R ⁶ , R ⁸ , R ⁹ and n are as defined above). Compound (Ic) is obtained by activating compound (Ia) by a suitable method. It can be obtained by condensation with compound (VII). For example, compound (Ia) is converted to a suitable solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and tetrachloroethane, esters such as methyl acetate, ethyl acetate and butyl acetate, ethers such as ether, THF and dioxane. Aprotic polar solvents such as acetonitrile, DMF and DMSO, aromatic hydrocarbons such as benzene, toluene, xylene and the like, or a mixed solvent thereof, at 0 ° C to the boiling point of the solvent,
Reaction with 1 equivalent to an excess of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc. for 0.1 to 48 hours, conversion to acid chlorides, acid bromides, etc., and then 1 to 20 equivalents as necessary 1 to 20 equivalents of a compound in the presence of a base
(VII). As the base, triethylamine, diisopropylethylamine,
N-methylmorpholine, piperidine, pyrrolidine, 1,2,2,
Alkylamines such as 6,6-pentamethylpiperidine, pyridines such as pyridine, lutidine, collidine, 4-dimethylaminopyridine, alkali metal carbonates such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, and hydroxides And alkali metal hydroxides such as potassium, sodium hydroxide and lithium hydroxide. The reaction between the acid chloride or the acid bromide and the compound (VII) is from −20 to 10
Carried out between 0 ° C., preferably between 0 ° C. and room temperature, from 0.1 to 2
Ends in 0 hours.

Compound (Ia) and compound (VII) are
Compound (Ic) can also be obtained by reacting in the presence of an equivalent to excess condensing agent, for example, dicyclohexylcarbodiimide, carbonyldiimidazole, and the like. The reaction is carried out between -20 and 100 ° C, preferably between 0 and 60 ° C, and is completed in 0.1 to 200 hours.

Production Method 4 Compound (Id) in which X is a benzene ring and Y is substituted or unsubstituted vinyl in compound (I) can also be produced by the following reaction step. Process (4)

[0039]

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(Where Q, R¹Is the same as above
R^TenIs hydrogen atom, lower alkyl, hydroxy-substituted
Represents lower alkyl, lower alkoxycarbonyl, cyano, etc.
Then R ¹¹Represents lower alkyl or phenyl) R^TenLower alkyl, hydroxy-substituted lower in the definition of
Alkyl and lower alkoxycarbonyl are as defined above.
Synonymous with R¹¹Lower alkyl in the definition of
It is synonymous.

Compound (Id) comprises compound (A) and compound
It can be obtained by condensation of (VIII). The condensation reaction is carried out in the presence of one equivalent to an excess amount of a base, if necessary, and in a solvent, if necessary. As the solvent, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and tetrachloroethane, esters such as methyl acetate, ethyl acetate and butyl acetate, alcohols such as methanol, ethanol and propanol, ethers such as ether, THF and dioxane , Acetonitrile, DMF, DMS
Aprotic polar solvents such as O, aromatic hydrocarbons such as benzene, toluene and xylene, water and the like, or a mixed solvent thereof are used, preferably alcohols such as methanol, ethanol and propanol, ether, and TH.
Ethers such as F, 1,2-dimethoxyethane and dioxane, and water are used alone or in combination. Compound (V
III) is used in an amount of 1 to 20 equivalents based on compound (A).
The reaction is carried out between room temperature and 200 ° C, preferably between room temperature and 100 ° C, and is completed in 0.1 to 50 hours.

Production method 5 In compound (I), X is a benzene ring, and Y is C
Compound (If) in which H = N—OH can also be produced by the following reaction step. Process (5)

[0043]

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(Wherein Q and R ¹ have the same meanings as described above). Compound (If) can be obtained by condensation of compound (A) with hydroxylamine or a salt thereof. Examples of hydroxylamine salts include hydrochloride.

The condensation reaction is carried out in the presence of 0.1 to 100 equivalents of a base, if necessary, in a solvent, if necessary. As the solvent, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as tetrachloroethane, esters such as methyl acetate, ethyl acetate, and butyl acetate; alcohols such as methanol, ethanol, and propanol; ethers such as ether, THF, 1,2-dimethoxyethane, and dioxane; Aprotic polar solvents such as acetonitrile, DMF and DMSO, aromatic hydrocarbons such as benzene, toluene and xylene, water and the like are used alone or in combination. Preferably, alcohols such as methanol, ethanol and propanol, ethers are used. , THF, 1,2-dimethoxyethane, dioxane and the like, and water, alone or as a mixture. As the base, triethylamine, diisopropylethylamine, N-methylmorpholine, piperidine, pyrrolidine, alkylamines such as 1,2,2,6,6-pentamethylpiperidine, pyridine, lutidine, collidine, 4-dimethylaminopyridine and the like Alkali metal carbonates such as pyridines, potassium carbonate, cesium carbonate, sodium carbonate, and sodium hydrogen carbonate; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and lithium hydroxide; sodium acetate, potassium acetate, and sodium oxalate And sodium formate. Hydroxylamine or a salt thereof is compound (A) with 1
It is used in an equivalent amount to an excess amount. The reaction is carried out between -20 and 100 ° C, preferably between room temperature and 50 ° C, and is completed in 0.1 to 50 hours.

Production Method 6 In the compound (I), X is a benzene ring and Y is a compound of the formula (VIc)

[0047]

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[In the formula, R ¹² and R ¹³ are the same or different and are lower alkoxycarbonyl (the lower alkoxycarbonyl is as defined above), cyano or lower alkylsulfonyl (the lower alkylsulfonyl is as defined above) )] Can also be produced by the following reaction step. Process (6)

[0049]

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(Wherein Q, R ¹ , R ¹² and R ¹³ have the same meanings as described above). The compound (Ig) can be obtained by condensing the compound (A) with the compound (IX). .

The condensation reaction is carried out in the presence of a base catalyst or an acid catalyst, if necessary, and in a solvent, if necessary. Examples of the solvent include hydrocarbons such as toluene, benzene, xylene, hexane, and pentane; ethers such as ether, THF, and dioxane; aprotic polar solvents such as acetonitrile, DMF, and DMSO; methanol, ethanol, and propanol. Alcohols are used alone or in combination. As the base catalyst, piperidine, pyrrolidine,
Pyridine, triethylamine, β-alanine and the like, and as the acid catalyst, acetic acid, trifluoroacetic acid, sulfuric acid,
Formic acid or diethyl zinc, zinc (II) chloride, tin chloride (I
Lewis acids such as I), tin (IV) chloride, aluminum chloride, titanium tetrachloride and the like are used. These catalysts are used alone or as a mixture in an amount of 0.1 to 100 equivalents based on compound (A). The reaction is carried out between 0 and 200 ° C, preferably between room temperature and 100 ° C.
Between 0.05 and 50 hours.

Production Method 7 In the compound (I), the compound (Ih) in which X is a benzene ring and Y is the above formula (II) can also be produced by the following reaction steps. Process (7)

[0053]

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(Wherein Q, Q ^A , R ¹ , R ² , and Z have the same meanings as described above). Compound (Ih) can be obtained by condensing compound (A) with compound (X). it can.

The condensation reaction is carried out in a solvent, if necessary, in the presence of a base catalyst or an acid catalyst, if necessary. Examples of the base catalyst include piperidine, pyrrolidine, pyridine, triethylamine, β-alanine, and the like.Examples of the acid catalyst include acetic acid, trifluoroacetic acid, sulfuric acid, formic acid, and diethyl zinc, zinc chloride (II), and tin chloride ( II), tin chloride (I
V), Lewis acids such as aluminum chloride and titanium tetrachloride, and the like, alone or as a mixture with respect to compound (A).
0.1-100 equivalents are used. As the solvent, methanol,
Alcohols such as ethanol and propanol; ethers such as ether, THF, 1,2-dimethoxyethane and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and tetrachloroethane; methyl acetate, ethyl acetate, butyl acetate and the like And aprotic polar solvents such as acetonitrile, DMF, and DMSO; aromatic hydrocarbons such as benzene, toluene, and xylene; and a mixed solvent thereof. The reaction is carried out between 0 and 200 ° C, preferably between room temperature and 100 ° C, and is completed in 0.1 to 50 hours.

Production Method 8 Compound (Ii) in which X is a benzene ring and Y is sulfamoyl or lower alkylsulfamoyl in compound (I) can also be produced by the following reaction step. Process (8)

[0057]

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(In the formula, R ¹⁶ represents hydrogen or lower alkyl, and Q and R ¹ have the same meanings as described above.) Lower alkyl in the definition of R ¹⁶ has the same meaning as described above.
Compound (Ii) can be obtained by activating compound (Ij) by an appropriate method and then condensing the compound with an amine represented by R ¹⁶ NH ₂ .

As an activation method, for example, the compound (I)
j) in a suitable solvent, for example, dichloromethane, chloroform, ethyl acetate, ether, THF, acetonitrile, DMF, DMSO, benzene, toluene, xylene or the like, or a mixed solvent thereof, if necessary, in the presence of 1 to 20 equivalents of a base. , 1 to 20 equivalents of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc. for 0.1 to 48 hours at -10 to 100 ° C, and the corresponding sulfonic acid chloride or sulfonic acid bromide And the like. Then compound be brought into amine condensed represented by 20 equivalents of R ¹⁶ NH ₂ (Ii) is obtained. Examples of the base include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide and the like. Sulfonic acid chloride or sulfonic acid bromide and R ¹⁶ N
Reaction with an amine represented with H ₂ during the -20 to 100 ° C., preferably performed between 0 ° C. ~ room temperature, terminated with 0.1 to 20 hours.

Production Method 9 In compound (I), compound (Ik) wherein X is a benzene ring and Y is lower alkanoylsulfamoyl is
It can also be produced by the following reaction step. Process (9)

[0061]

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[0062] (wherein, Q, R ¹ represents the same meanings as defined above, respectively, R ¹⁴ represents lower alkyl, Hal represents a chlorine atom or a bromine atom) lower alkyl in the definition of R ¹⁴ is a as defined above .
Compound (Ik) can be obtained by reacting compound (Iia) with 1 equivalent to an excess amount of compound (XI) in an inert solvent, if necessary, in the presence of 0.1 to 20 equivalents of a base.

As the inert solvent, DMF, DMSO,
THF, 1,2-dimethoxyethane, ether, dichloromethane, toluene, hexane and the like are used alone or in combination. As a base, sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, Butyl lithium or the like is used. The reaction is carried out between -78 and 50 ° C, preferably between -20 and 30 ° C and is completed in 0.1 to 20 hours.

Production Method 10 Compound (IL) in which X is a benzene ring and Y is amino in compound (I) can also be produced by the following reaction step. Process (10)

[0065]

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(Wherein Q and R ¹ have the same meanings as described above). Compound (IL) is prepared by converting compound (Im) in a solvent, if necessary.
It can be obtained by treating with 1 to 50 equivalents of a suitable reducing agent in the presence of 0.1 to 20 equivalents of an acid. As the solvent,
DMF, DMSO, THF, 1,2-dimethoxyethane, ether, dichloromethane, toluene, hexane, etc. are used alone or in combination, hydrochloric acid, sulfuric acid, etc. are used as acids, and tin (II) chloride is used as a reducing agent. , Iron (II) chloride,
Sodium borohydride or the like is used. Reaction is 0-120
C., preferably between room temperature and 100.degree. C., ending in 1-50 hours.

Production Method 11 Compound (Im) in which X is a benzene ring and Y is sulfamoylamino in compound (I) can also be produced by the following reaction step. Step (11)

[0068]

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(In the formula, Hal ^A represents a chlorine atom or a bromine atom, and Q and R ¹ have the same meanings as described above.) Compound (Im) is prepared by converting compound (IL) into an inert solvent in an inert solvent, if necessary. 1-50 equivalents of compound in the presence of 20 equivalents of base
It can be obtained by reacting with (XII).

As the inert solvent, DMF, DMA, D
MSO, THF, 1,2-dimethoxyethane, ether, dichloromethane, toluene, hexane and the like are used alone or in combination. As bases, sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxy And butyllithium are used. The reaction is between -78 and 100 ° C, preferably between -78 and 3
Performed between 0 ° C. and ends in 0.1-20 hours.

Production method 12 In compound (I), Y is a group represented by formula (XIII)

[0072]

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A compound (Io) represented by the formula (wherein Q ^B represents an oxygen atom or a sulfur atom) and Q = Q ^B can also be produced by the following reaction step. Step (12)

[0074]

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(Wherein Q, Q ^B , R ¹ , and X have the same meanings as described above, but Q = Q ^B in Production Method 12.) Compound (Io) is composed of compound (XIV) and compound (V ) Is condensed. Compound (XIV) can be prepared by a known production method [Liebigs Ann. Der Chem., 409 (198)
4) etc.] and the method described below, etc., but there are also products available as commercial products.

The condensation reaction is carried out, if necessary, in the presence of a base catalyst and, if necessary, in a solvent. Examples of the base catalyst include piperidine, piperidinium acetate, diethylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate, butyllithium, lithium hydroxide, lithium diisopropylamide, and the like.
V) is used in an amount of 0.1 to 50 equivalents, and alcohols such as methanol, ethanol, and propanol are used as solvents.
Ethers such as ether, THF, 1,2-dimethoxyethane and dioxane, and hydrocarbons such as hexane, benzene, toluene and xylene are used alone or in combination. Compound (V) is 2 to 20 to compound (XIV)
Use equivalent. The reaction is between room temperature and 200 ° C., preferably 50-1
It is performed between 00 ° C and ends in 0.1-50 hours.

Compound (XIVa) contained in Compound (XIV) below

[0078]

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(Wherein, R ¹ is as defined above, and W ¹ is C
= Represents N or a sulfur atom).

Production Method 13 Step (13-1)

[0081]

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[Wherein W ¹ is as defined above, and Hal ^B
Represents a chlorine atom or a bromine atom, R ^{1 5} represents a hydrogen atom or a substituted or unsubstituted aralkyl, P is a protecting group which can be deprotected hydroxyl groups by acidic conditions (e.g., t
ert-butyldimethylsilyl, triethylsilyl, triphenylmethyl, etc. are exemplified.] The substituted or unsubstituted aralkyl in the definition of R ^{15 is} as defined above.

Compound (XV) can be obtained by condensing compound (XVI) with compound (XVII). The condensation reaction is carried out in the presence of a suitable base, if necessary, and in the presence of a suitable metal catalyst and a suitable ligand, if necessary, in a solvent, if necessary. Examples of the base include sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate and the like, and the compound (XV
It is used in an amount of 0.1 to 50 equivalents based on II). Tris (dibenzylideneacetone) dipalladium as metal catalyst
(0), tetrakis (triphenylphosphino) palladium (0) and the like.
Used up to 10 equivalents. Examples of the ligand include di-tert-butyl-2-biphenylphosphine, tri-tert-butylphosphine, and the like.
Used 20 equivalents. As the solvent, ether, THF,
DMF, DMA, dioxane, hexane, benzene, toluene and the like are used alone or as a mixture. Compound (XVI) is used in 0.1 to 10 equivalents based on compound (XVII). The reaction is between room temperature and 200 ° C, preferably 50-100 ° C
And between 0.1 and 50 hours.

Compound (XVa) wherein R ¹⁵ is a substituted or unsubstituted aralkyl in compound (XV) can also be produced by the following method: Step (13-2)

[0085]

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(In the formula, Hal ^C represents a chlorine atom or a bromine atom, and W ¹ , R ¹ and P have the same meanings as described above.) In the compound (XVa), R ¹⁵ is a hydrogen atom in the compound (XV). inert solvent a compound (XVb), 0.1 to 20 presence of one equivalent of base necessary, 1-50 equivalents R ¹ Hal ^C
(Wherein R ¹ and Hal ^C have the same meanings as described above).

As the inert solvent, DMF, DMA, D
MSO, THF, 1,2-dimethoxyethane, ether, dichloromethane, toluene, hexane and the like are used alone or in combination. As a base, sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxy is used. And butyllithium are used. The reaction is between -78 and 100 ° C, preferably between 0 and 30
C. and ends in 0.1-20 hours.

Compound (XVa) can be converted to compound (XVIII) by the following steps. Step (13-3)

[0089]

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(Wherein W ¹ , R ¹ and P have the same meanings as described above). Compound (XVIII) can be obtained by treating compound (XVa) with 0.1 equivalent to an excess amount of an acid in a solvent, if necessary. Obtainable. As the acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc. are used, and as the solvent, DMF, DMA, DMSO, THF, 1,2-dimethoxyethane, acetonitrile, etc. Are used alone or as a mixture. The reaction is carried out between -78 and 100 ° C, preferably between 0 and 30 ° C and is completed in 0.1 to 50 hours.

Compound (XIVa) is the compound (XVIa)
II) can be obtained by subjecting it to the following step (13-4). Step (13-4)

[0092]

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(Wherein W ¹ and R ¹ are the same as defined above). Compound (XIVa) is obtained by treating compound (XVIII) with 1 equivalent to an excess amount of an oxidizing agent in a solvent, if necessary. Obtainable. Manganese dioxide, pyridinium chlorochromate, pyridinium dichromate and the like are used as the oxidizing agent, and DMF, DMA,
DMSO, dichloromethane, chloroform, acetonitrile and the like are used alone or in combination. Reaction is -78
~ 100 ° C, preferably between 0 ~ 40 ° C, 1 ~ 200 ° C
End in time.

The intermediates and the target compounds in the above-mentioned production methods are isolated and purified by a purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like. can do. When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is. Compound (I) may be dissolved or suspended in a solvent, a desired acid may be added to form a salt, and the compound may be isolated and purified.

The compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of adducts with water or various solvents, and these adducts are also included in the scope of the present invention. Hereinafter, specific examples of the compound (I) obtained by the present invention are shown in Tables 1 and 2, but the compound of the present invention is not limited thereto. The compounds described in Reference Examples are shown in Tables 3 and 4.

In Tables 1, 2, 3, and 4, Me, Et, ⁿ Pr, and ^t Bu represent methyl, ethyl, n-propyl, and tert-butyl, respectively. In the tables, for example, the notation “CH ₂ (3,4-Cl ₂ C ₆ H ₃ )” indicates 3,4-dichlorobenzyl (the same applies to other notations).

[0097]

[Table 1]

[0098]

[Table 2]

[0099]

[Table 3]

[0100]

[Table 4]

[0101]

[Table 5]

[0102]

[Table 6]

Next, the pharmacological activity of the representative compound (I) will be described with reference to Test Examples. Test Example 1 In vitro telomerase inhibitory activity The telomerase inhibitory activity of compound (I) was measured according to a known method (US Patent No. 5760062). That is, a DMSO solution of a test compound was mixed with telomerase obtained by partially purifying a nuclear extract derived from HEK293 cells in the presence of oligodeoxynucleotide and deoxynucleotide triphosphate as substrates, and incubated. The obtained reaction product (DNA having a telomere sequence) was adsorbed on a membrane, and hybridization was performed using a labeled oligonucleotide probe having a sequence complementary to the telomere sequence. The inhibition rate was calculated from the ratio of the signal intensity in the presence of the test compound to the signal intensity of the label on the membrane in the absence of the test compound (control). Further, the compound concentration that inhibits enzyme activity by 50% relative to the control as IC _50.

According to the above-mentioned method, typical compounds 2, 11, 27, 31, 38 and 41 of the present invention exhibited IC ₅₀ values of ₅₀ μmol / L or less. From the above, it was shown that Compound (I) has excellent telomerase inhibitory activity and is useful as a therapeutic agent for diseases related to telomerase activity such as malignant tumors.

Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms depending on its pharmacological action and its purpose of administration. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or parenteral administration, such as injection.

Examples of the administration form include tablets, capsules, granules, injections and the like. In preparing tablets, excipients such as lactose, glucose, sucrose, mannitol, methylcellulose, etc., disintegrants such as starch, sodium alginate, calcium carboxymethylcellulose, crystalline cellulose, and lubricants such as magnesium stearate, talc , Gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose,
Binders such as methylcellulose, sucrose fatty acid esters,
A surfactant such as sorbitol fatty acid ester may be used according to a conventional method. Tablets containing 1 to 300 mg of active ingredient per tablet are preferred.

In preparing granules, for example, lactose,
Excipients such as sucrose, disintegrating agents such as starch, binders such as gelatin, and the like may be used in a conventional manner. In preparing a capsule, for example, gelatin, water, sucrose, acacia, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, and the like may be used in a conventional manner. Capsules containing 1 to 300 mg of active ingredient per capsule are preferred.

In preparing injections, water, physiological saline, vegetable oils (eg, olive oil, peanut oil, etc.), solvents such as ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate, urethane, etc. Isotonic agents such as salt and glucose, preservatives such as phenol, cresol, p-hydroxybenzoate, and chlorobutanol, and antioxidants such as ascorbic acid and sodium pyrosulfite may be used in a conventional manner.

The compound (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally such as injection. The effective dose and the number of doses vary depending on the form of administration, the age, weight, and condition of the patient, but it is usually preferable to administer 0.01 to 20 mg / kg once to four times a day.

[0110]

The present invention will be described below in detail with reference to examples. In the nuclear magnetic resonance spectrum ( ¹ H-NMR) used in Examples or Reference Examples, exchangeable hydrogen may not be clearly observed depending on the compound and measurement conditions. The signal multiplicity is usually represented by br, but br indicates that the signal is apparently wide.

The nuclear magnetic resonance spectrum ( ¹ H NMR) of each compound in the following Examples and Reference Examples was measured by the following instruments. JEOL Lambda 300 (300 MHz) / JEOL J
NM-EX270 (270 MHz) / JEOL JNM-GX270 (270 MHz)

Example 1 (Compound 1) Compound a (109 mg, 0.378 mmol), 2,4-thiazolidinedione (59.9 mg, 0.511 mmol) and piperidine (0.045 mL,
(0.46 mmol) was heated to reflux in ethanol (5.0 mL) for 6 hours. After the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid was added and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (20: 1 chloroform / methanol) to obtain Compound 1 (123 mg, 84%).
I got ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.08 (s, 2H), 6.8
8 (d, J = 8.6 Hz, 2H), 7.15-7.45 (m, 12H), 7.61 (s,
1H), 12.38 (br s, 1H)

Example 2 (Compound 2) Compound b (249 mg, 0.700 mmo) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (177 mg, 1.51 mmol)
Thus, Compound 2 (59.7 mg, 19%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.08 (s, 2H), 6.8
9 (d, J = 9.1 Hz, 2H), 7.15-7.47 (m, 8H), 7.54 (d,
J = 2.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.64 (s,
1H), 12.40 (br s, 1H)

Example 3 (Compound 3) Compound d (37.0 mg, 0.102 mmo) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (48 mg, 0.41 mmo
From l), compound 3 (34.0 mg, 73%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.60 (s, 1H), 6.6
4 (d, J = 8.9 Hz, 2H), 7.08-7.59 (m, 18H), 12.40 (b
rs, 1H)

Example 4 (Compound 4) Compound h (176 mg, 0.424 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (99.2 mg, 0.848 mm
ol) to give Compound 4 (130 mg, 58%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.38 (t, J = 6.9 H
z, 3H), 4.36 (q, J = 6.9 Hz, 2H), 5.05 (s, 2H), 7.
13-7.20 (m, 5H), 7.30-7.42 (m, 4H), 7.77 (s, 1H),
8.00 (d, J = 8.3 Hz, 2H), 8.22 (br s, 1H)

Example 5 (Compound 5) Compound 4 (130 mg, 0.245 mmol) and potassium hydroxide (41.2 mg, 0.735 mmol) were added to water (2 mL) and ethanol (4 mL).
(mL) in a mixed solvent for 3 hours. The reaction solution was cooled to room temperature, water and 1 mol / L hydrochloric acid were added, and the resulting crystals were collected by filtration, dried, and purified by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol / water) to give the compound. 5 (96.
1 mg, 78%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.07 (s, 2H), 6.9
4-7.21 (m, 4H), 7.38 (br s, 1H), 7.39 (d, J = 8.9
Hz, 2H), 7.44 (d, J = 8.9 Hz, 2H), 7.80 (s, 1H), 8.
02 (d, J = 8.9 Hz, 2H), 9.87 (br s, 1H), 12.38 (br
s, 1H)

Example 6 (Compound 6) Compound 5 (29.7 mg, 0.0590 mmol) was dissolved in chloroform and stirred at 0 ° C., followed by oxalyl chloride (2.0 mL, 23 mL).
mmol) and the temperature was raised to room temperature. After stirring at the same temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was dissolved by adding THF (1 mL), cooled to 0 ° C, and cooled to 7 mol / L ammonia-
A methanol solution (3.0 mL, 21 mmol) was added. After stirring at the same temperature for 3 hours, the solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol /
Water) to obtain Compound 6 (21.8 mg, 75%). ^{1 H NMR (270MHz, DMSO-} d 6) δ (ppm) 5.00 (s, 2H), 7.1
3 (br d, J = 8.3 Hz, 2H), 7.19 (br d, J = 8.6 Hz,
1H), 7.21-7.30 (m, 6H), 7.34-7.39 (m, 2H), 7.71
(s, 1H), 9.75 (br s, 2H), 12.40 (br s, 1H)

Example 7 (Compound 7) Compound 5 (12.0 mg, 0.0240 mm) was prepared in the same manner as in Example 6.
ol), oxalyl chloride (1.0 mL, 13 mmol) and propylamine (1.0 mL, 12 mmol) from compound 7 (0.4 mg,
3%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.99 (t, J = 7.3 H
z, 3H), 1.63 (m, 2H), 3.40 (m, 2H), 5.02 (s, 2H),
6.06 (br s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.17
(d, J = 8.9 Hz, 1H), 7.22-7.30 (m, 2H), 7.35-7.38
(m, 4H), 7.74 (d, J = 8.6 Hz, 2H), 7.75 (s, 1H)

Example 8 (Compound 8) Compound 5 (30.5 mg, 0.0611 mm) was prepared in the same manner as in Example 6.
ol), oxalyl chloride (0.040 mL, 0.46 mmol) and ethanolamine (37.3 mg, 0.611 mmol) to give compound 8 (24.8 mg, 75%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.32 (br s, 2H),
3.48 (m, 2H), 4.10 (m, 1H), 4.75 (br s, 1H), 5.16
(br s, 2H), 7.13 (d, J = 8.6 Hz, 2H), 7.27 (m, 2
H), 7.48 (d, J = 8.6 Hz, 2H), 7.56 (m, 3H), 7.66
(s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 8.33 (br s, 1H)

Example 9 (Compound 9) Compound 5 (44.0 mg, 0.0880 mm) was prepared in the same manner as in Example 6.
ol), oxalyl chloride (0.045 mL, 0.52 mmol), triethylamine (30 mg, 0.30 mmol) and glycine tert
Compound 9 (31.6 mg, 59%) was obtained from -butyl ester hydrochloride (20 mg, 0.12 mmol). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.51 (s, 9H), 4.14
(m, 2H), 5.03 (s, 2H), 6.64 (br s, 1H), 7.05 (d, J
= 8.9 Hz, 2H), 7.12 (br d, J = 6.7 Hz, 1H), 7.21
(d, J = 8.9 Hz, 2H), 7.78 (m, 4H), 7.81 (m, 4H)

Example 10 (Compound 10) Compound L (115 mg, 0.299 mmol) was dissolved in THF (3 mL), and methyltriphenylphosphoranylidene acetate was added at room temperature. After stirring at the same temperature for 20 hours, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (20: 1 chloroform / methanol) to obtain Compound 10 (123 m 2).
g, 76%). ¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 3.81 (s, 3H), 5.02
(s, 2H), 6.37 (d, J = 16.2 Hz, 1H), 7.02 (d, J = 8.
9 Hz, 2H), 7.15 (d, J = 16.2 Hz, 1H), 7.20 (br d, J
= 8.2 Hz, 1H), 7.37-7.72 (m, 9H), 8.80 (br s, 1H)

Example 11 (Compound 11) Compound 10 (123 mg, 0.228 mm) was prepared in the same manner as in Example 5.
ol) and potassium hydroxide (30.7 mg, 0.547 mmol) to give compound 11 (105 mg, 88%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.16 (s, 2H), 6.4
2 (d, J = 15.8 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H),
7.23-7.30 (m, 2H), 7.47-7.69 (m, 10H), 12.48 (br s,
1H)

Example 12 (Compound 12) Compound 11 (21.2 mg, 0.0401) was prepared in the same manner as in Example 6.
mmol), oxalyl chloride (0.014 mL, 0.16 mmol) and 7 mol / L ammonia-methanol solution (3.0 mL, 21 mm
ol) to give Compound 12 (16.6 mg, 79%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.15 (s, 2H), 6.5
2 (d, J = 15.8 Hz, 1H), 7.04-7.68 (m, 12H), 8.31
(s, 1H), 12.50 (br s, 1H)

Example 13 (Compound 13) In the same manner as in Example 6, compound 11 (29.8 mg, 0.057 m
mol), oxalyl chloride (0.040 mL, 0.46 mmol) and n-propylamine (37.3 mg, 0.611 mmol) to give compound 13 (22.5 mg, 70%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.97 (t, J = 7.5 H
z, 3H), 1.60 (tq, J = 7.5 Hz, 2H), 3.37 (m, 2H),
5.00 (s, 2H), 5.62 (br s, 1H), 6.32 (d, J = 15.5 H
z, 1H), 6.98 (d, J = 8.6 Hz, 2H), 7.13 (br d, J =
8.3 Hz, 1H), 7.19 (br d, J = 8.3 Hz, 1H), 7.21-7.30
(m, 5H), 7.39 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 1
5.5 Hz, 1H), 7.74 (s, 1H), 8.06 (br s, 2H)

Example 14 (Compound 14) Compound 11 (24.0 mg, 0.0457) was prepared in the same manner as in Example 6.
mmol), oxalyl chloride (0.040 mL, 0.46 mmol) and diethylamine (100 mg, 1.37 mmol).
4 (13.0 mg, 49%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.20 (br t, J = 6.7
Hz, 3H), 1.26 (br t, J = 7.6 Hz, 3H), 3.49 (m, 4
H), 5.01 (s, 2H), 6.77 (d, J = 15.5 Hz, 1H), 6.97
(d, J = 8.6 Hz, 2H), 7.14 (br d, J = 8.3 Hz, 1H),
7.22 (d, J = 8.6Hz, 2H), 7.33-7.45 (m, 3H), 7.49
(br d, J = 8.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H),
7.69 (d, J = 15.5 Hz, 1H), 7.75 (s, 1H), 8.29 (br
s, 1H)

Example 15 (Compound 15) Compound 11 (24.3 mg, 0.0632) was prepared in the same manner as in Example 6.
mmol), oxalyl chloride (0.030 mL, 0.35 mmol) and ethanolamine (127 mg, 2.08 mmol) to give compound 15 (16.3 mg, 45%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.00-3.60 (m, 4
H), 4.73 (br s, 1H), 5.14 (br s, 2H), 6.58 (d, J =
14.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 7.25-7.34
(m, 3H), 7.43 (d, J = 14.0 Hz, 1H), 7.50 (d, J =
8.9 Hz, 2H), 7.57 (m, 5H), 8.08 (br s, 1H), 8.30 (b
rs, 1H)

Example 16 (Compound 16) In the same manner as in Example 6, compound 11 (16.4 mg, 0.0311
mmol), oxalyl chloride (0.014 mL, 0.14 mmol), triethylamine (10.1 mg, 0.100 mmol) and 2-amino-4,5-dimethoxybenzoic acid (9.9 mg, 0.050 mmol) from compound 16 (13.6 mg, 62%) I got ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.00 (br s, 1H),
3.17 (s, 6H), 5.15 (s, 2H), 6.40 (d, J = 15.7 Hz, 1
H), 7.14-7.26 (m, 6H), 7.29 (m, 2H), 7.47-7.65 (m,
7H), 12.20 (br s, 2H)

Example 17 (Compound 17) Compound L (27.8 mg, 0.0723 mmol) was added to ethanol (0.5 m
L) and sodium acetate (28.7 mg, 0.350 mm) at room temperature
ol), hydroxylamine hydrochloride (20.0 mg, 0.289 mmo
l) was added sequentially. After stirring at the same temperature for 3 hours, the solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (90: 10: 1).
(Chloroform / methanol / water) to give Compound 1.
7 (24 mg, 67%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.11 (s, 2H), 7.08
(d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.2
8 (m, 3H), 7.43-7.59 (m, 5H), 8.08 (s, 7H), 12.05
(br s, 1H)

Example 18 (Compound 18) Compound L (34.6 mg, 0.885 mmol) was dissolved in THF (0.5 mL), and cyanomethylene tri-n-butylphosphorane was added. Was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol / water) to give Compound 18 (27.9 mg,
62%). ¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 5.03 (s, 2H), 5.76
(d, J = 15.8 Hz, 1H), 7.09-7.42 (m, 13H), 7.74 (s,
1H)

Example 19 (Compound 19) Compound L (106 mg, 0.276 mmol) was dissolved in toluene (4 mL), and acetic acid (100 mg, 16.6 mmol) and piperidine (94 m
g, 1.10 mmol) and methyl cyanoacetate (137 mg, 2.76
mmol) and heated under reflux for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. After dissolving the residue in ethanol, water and 1 mol / L hydrochloric acid were added, and the resulting crystals were collected by filtration, dried, and purified by preparative thin-layer chromatography (20: 1 chloroform / methanol) to give compound 19 ( 147 mg, 9
4%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 3.39 (s, 3H), 5.05
(s, 2H), 7.05 (d, J = 8.9 Hz, 2H) 7.12 (br d, J =
8.6 Hz, 1H), 7.27 (d, J = 8.9 Hz, 2H), 7.36 (br s,
1H), 7.40 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.9 H
z, 2H), 7.79 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 8.1
1 (s, 1H)

Example 20 (Compound 20) Compound 19 (47.1 mg, 0.0834) was prepared in the same manner as in Example 5.
mmol) and sodium hydroxide (12.9 mg, 0.330 mmo)
Compound 20 (36.4 mg, 79%) was obtained from l). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.12 (s, 2H), 6.8
4-7.87 (m, 13H), 9.76 (br s, 2H)

Example 21 (Compound 21) Compound L (153 mg, 0.398 mmol) was prepared in the same manner as in Example 19.
l), acetic acid (144 mg, 2.39 mmol), piperidine (135 m
g, 1.59 mmol) and diethyl malonate (400 mg, 2.13
mmol) to give compound 21 (144 mg, 58%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.31 (t, J = 7.3 H
z, 6H), 3.46 (br s, 1H), 4.28 (q, J = 7.3 Hz, 2H),
4.34 (q, J = 7.3 Hz, 2H), 4.97 (s, 2H), 6.85 (d, J
= 8.9 Hz, 2H), 6.96 (br s, 1H), 7.14 (br d, J =
8.3 Hz, 1H), 7.20 (br d, J = 8.6 Hz, 2H), 7.21 (s,
1H), 7.26-7.32 (m, 3H), 7.38 (d, J = 8.6 Hz, 2H),
7.60 (s, 1H)

Example 22 (Compound 22) Compound 21 (12.3 mg, 0.0197 mg) was prepared in the same manner as in Example 5.
mmol) and sodium hydroxide (2.0 mg, 0.050 mmol)
Thus, compound 22 (10.3 mg, 87%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 4.99 (br s, 2H),
6.80-7.05 (m, 3H), 7.14-7.21 (m, 4H), 7.21-7.40
(m, 5H), 7.60 (s, 1H), 8.54 (br s, 2H), 12.10 (br
s, 1H)

Example 23 (Compound 23) In the same manner as in Example 19, compound L (20.1 mg, 0.0520 m
mol), acetic acid (38 mg, 0.63 mmol), piperidine (36 mg,
0.42 mmol) and methylsulfonylacetonitrile (400 mg, 3.77 mmol) to give compound 23 (26.4 mg, 87
%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 3.18 (s, 3H), 5.08
(s, 2H), 7.02 (d, J = 8.6 Hz, 2H), 7.11 (br d, J =
8.3 Hz, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.37 (br s,
1H), 7.42 (br d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.6
Hz, 2H), 7.82 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H),
7.96 (s, 1H), 8.60 (br s, 1H)

Example 24 (Compound 24) In the same manner as in Example 19, compound L (15.5 mg, 0.0400 m
mol), acetic acid (24 mg, 0.4 mmol), piperidine (26 mg,
0.30 mmol) and malononitrile (27 mg, 0.40 mmo
Compound 24 (16.6 mg, 78%) was obtained from l). ¹ H NMR (270MHz, DMSO-d ₆ ) δ (ppm) 5.08 (s, 2H), 7.0
2 (d, J = 8.6 Hz, 2H), 7.11-7.21 (m, 3H), 7.37 (m,
2H), 7.54 (d, J = 8.6 Hz, 2H), 7.82 (m, 3H), 7.96
(s, 1H), 12.30 (br s, 1H)

Example 25 (Compound 25) Compound L (60.0 mg, 0.124 mmo) was prepared in the same manner as in Example 1.
l) and rhodanin (33 mg, 0.25 mmol) to give compound 25
(59.0 mg, 80%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 4.35 (br s, 1H),
5.21 (s, 2H), 7.23 (s, 1H), 7.24-7.34 (m, 4H), 7.51
-7.60 (m, 7H), 12.45 (br s, 1H)

Example 26 (Compound 26) In the same manner as in Example 1, compound L (28.5 mg, 0.742 mmo
Compound 26 (12.7 mg, 26%) was obtained from l) and rhodanin-3-acetic acid (56.7 mg, 0.297 mmol). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.16 (s, 2H), 3.5
0 (br s, 1H), 5.09 (brs, 2H), 6.97 (d, J = 8.5 Hz,
2H), 7.20 (d, J = 8.5 Hz, 2H), 7.32 (br s, 1H), 7.
34 (d, J = 8.6 Hz, 1H), 7.38 (br d, J = 8.6 Hz, 1
H), 7.57 (br s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 8.14
(d, J = 8.5 Hz, 2H), 8.31 (br s, 1H)

Example 27 (Compound 27) Compound L (60.7 mg, 0.126 mmo) was prepared in the same manner as in Example 1.
Compound 27 (30.6 mg, 42%) was obtained from l) and thiohydantoin (29.3 mg, 0.252 mmol). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.18 (s, 2H), 6.4
5 (s, 1H), 7.30 (m, 5H), 7.49-7.70 (m, 7H), 12.10
(br s, 1H), 12.45 (br s, 2H)

Example 28 (Compound 28) In the same manner as in Example 19, compound L (23.0 mg, 0.0570 m
mol), triethylamine (13.8 mg, 0.137 mmol) and barbituric acid (17.5 mg, 0.137 mmol) to give compound 2.
8 (20.8 mg, 94%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.25 (s, 2H), 7.2
9 (d, J = 8.6 Hz, 2H), 7.38 (br d, J = 8.3 Hz, 1H),
7.46 (d, J = 8.6 Hz, 2H), 7.59 (m, 4H), 7.76 (s,
1H), 8.17 (s, 1H), 8.32 (d, J = 8.6 Hz, 2H), 11.11
(br s, 1H), 11.23 (br s, 1H), 12.58 (br s, 1H)

Example 29 (Compound 29) Compound L (55.9 mg, 0.116 mmol) was prepared in the same manner as in Example 19.
l), β-alanine (13.5 mg, 0.151 mmol) and hydantoin (25.5 mg, 0.255 mmol) to give compound 29 (23.
9 mg, 36%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.16 (s, 2H), 6.3
9 (s, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.26 (d, J =
8.6 Hz, 2H), 7.29 (br d, J = 8.3 Hz, 1H), 7.47 (d,
J = 8.6 Hz, 2H), 7.55 (s, 1H), 7.58 (br d, J = 8.
3 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.68 (s, 1H),
10.48 (s, 1H), 11.21 (s, 1H), 12.45 (s, 1H)

Example 30 (Compound 30) Compound g (265 mg, 0.610 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (189 mg, 1.62 mmo
Compound 30 (248 mg, 75%) was obtained from l). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 4.95 (s, 2H), 6.84
(d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 7.1
3 (br s, 1H), 7.32-7.42 (m, 4H), 7.51 (d, J = 8.6 H
z, 2H), 7.75 (s, 1H), 8.41 (br s, 1H)

Example 31 (Compound 31) Compound m (248 mg, 0.542 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (130 mg, 1.11 mmo
From l), compound 31 (145 mg, 48%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.09 (s, 2H), 6.9
4 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.
28 (dd, J = 2.0, 8.2 Hz, 1H), 7.41 (d, J = 8.7 Hz,
2H), 7.54 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.2 H
z, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H), 1
2.38 (br s, 1H)

Example 32 (Compound 32) Compound 31 (62.5 mg, 0.112 mmol) was suspended in dichloromethane (5 mL) and DMF (2.5 mL), and thionyl chloride (0.049 mL, 0.65 mmol) was added. Stirred for hours. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the obtained brown oil was dissolved in dichloromethane (5 mL), and a 30% aqueous ammonia solution (2.0 mL, 29 mmol) was added.
Stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol / water) to give Compound 32 (26.5 mg, 43%).
I got ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.17 (s, 2H), 7.1
8-7.34 (m, 6H), 7.47-7.55 (m, 3H), 7.58 (d, J = 8.
6 Hz, 1H), 7.69 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H),
12.50 (br s, 1H)

Example 33 (Compound 33) In the same manner as in Example 32, compound 31 (62.5 mg, 0.112
mmol) with thionyl chloride (0.049 mL, 0.65 mmol) followed by a 40% methylamine-methanol solution (2.0 m
Reaction with L) gave compound 33 (25.3 mg, 40%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 2.38 (s, 3H), 5.1
8 (s, 2H), 7.22-7.32 (m, 6H), 7.50-7.60 (m, 4H),
7.63 (s, 1H), 7.68 (d, J = 8.9 Hz, 2H), 12.50 (br
s, 1H)

Example 34 (Compound 34) Compound 32 (35.5 mg, 0.0638 mmol) was added to DMA (2 mL).
In 60% sodium hydride mineral oil dispersion (16.6 mg,
0.415 mmol), and the mixture was stirred at room temperature for 30 minutes, acetyl chloride (0.025 mL, 0.35 mmol) was added, and the mixture was further stirred at the same temperature for 2 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol / water) to obtain Compound 34 (22.2 mg, 58%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 1.90 (s, 3H), 5.1
7 (s, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.27 (dd, J =
2.0, 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.54
(d, J = 2.0 Hz, 1H), 7.54-7.62 (m, 3H), 7.71 (s, 1
H), 7.74 (d, J = 8.7 Hz, 2H), 12.19 (br s, 2H)

Example 35 (Compound 35) Compound n (116 mg, 0.288 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (76.4 mg, 0.652 mm
ol) to give Compound 35 (93.0 mg, 65%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.22 (s, 2H), 7.0
6 (d, J = 9.2 Hz, 2H), 7.27 (dd, J = 2.0, 8.4 Hz, 1
H), 7.49 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 2.0 Hz,
1H), 7.58 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.7 H
z, 2H), 7.76 (s, 1H), 8.08 (d, J = 9.2 Hz, 2H), 1
2.59 (br s, 1H)

Example 36 (Compound 36) Compound 35 (78.4 mg, 0.157 mmol) was added to DMF (5 mL).
And dissolved in tin (II) chloride dihydrate (338 mg, 1.50 mmol)
Was added, and the mixture was heated to 80 ° C. and stirred for 9 hours. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin layer chromatography (90:10:
Purification with 1 chloroform / methanol / water) gave Compound 36 (42.8 mg, 58%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 4.91 (s, 2H), 6.6
0 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 9.2 Hz, 2H), 6.
94 (d, J = 8.6 Hz, 2H), 7.28 (dd, J = 2.0,8.4 Hz,
1H), 7.34 (d, J = 9.2 Hz, 2H), 7.52 (d, J = 2.0 H
z, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H)

Example 37 (Compound 37) Compound 36 (10.1 mg, 0.0215 mmol) was added to DMA (2 mL).
And dissolved in sulfamoyl chloride (20.4 mg, 0.177 mmol)
Was added and stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol / water) to give Compound 37 (10.1 m 2).
g, 86%). ^{1 H NMR (270MHz, DMSO-} d 6) δ (ppm) 5.01 (s, 2H), 6.7
8 (d, J = 9.0 Hz, 2H), 7.11 (br s, 2H), 7.20 (d, J
= 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.29 (dd,
J = 2.0, 8.2 Hz, 1H), 7.38 (d, J = 9.0 Hz, 2H),
7.54 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H),
7.62 (s, 1H), 9.58 (br s, 1H), 12.35 (br s, 1H)

Example 38 (Compound 38) Compound r (44.0 mg, 0.110 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (77.0 mg, 0.657 mm
ol) to give Compound 38 (24.7 mg, 38%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.35 (s, 2H), 6.8
9 (d, J = 9.2 Hz, 1H), 7.24 (dd, J = 2.0, 8.4 Hz, 1
H), 7.48-7.55 (m, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.
53 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H),
7.70 (dd, J = 2.3, 9.2 Hz, 1H), 7.72 (s, 1H), 7.76
(s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 12.54 (br s, 2H)

Example 39 (Compound 39) Compound u (49.4 mg, 0.125 mmol) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (100 mg, 1.88 mmo
From l), compound 39 (19.8 mg, 24%) was obtained. ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.54 (s, 2H), 6.9
2 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.
64 (d, J = 8.6 Hz, 2H), 7.73 (s, 1H), 7.73 (dd, J =
2.6, 9.0 Hz, 1H), 7.76 (s, 1H), 7.92 (s, 2H), 7.9
6 (s, 1H), 8.52 (d, J = 2.6 Hz, 1H), 12.54 (br s,
2H)

Example 40 (Compound 40) Compound y (42.7 mg, 0.109 mmo) was prepared in the same manner as in Example 1.
l) and 2,4-thiazolidinedione (92.0 mg, 0.785 mm
ol) to give Compound 40 (13.1 mg, 20%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.05 (s, 2H), 6.9
6 (d, J = 8.9 Hz, 2H), 7.20-7.30 (m, 2H), 7.30 (br
d, J = 9.2 Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.53
(br s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.63 (s, 1
H), 7.66 (s, 1H), 12.41 (br s, 2H)

Example 41 (Compound 41) In the same manner as in Example 1, compound k (78.5 mg, 0.204 mmo
Compound 41 (89.9 mg, 71%) was obtained from l) and rhodanin (109 mg, 0.816 mmol). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.21 (s, 2H), 7.2
0-7.35 (m, 5H), 7.46-7.60 (m, 8H)

Example 42 (Compound 42) Compound z (96.1 mg, 0.213 mmol) was prepared in the same manner as in Example 1.
Compound 42 (110 mg, 76%) was obtained from l) and rhodanin (96.4 mg, 0.852 mmol). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.42 (s, 2H), 7.3
2 (d, J = 8.9 Hz, 4H), 7.56 (d, J = 8.9 Hz, 4H), 7.
58 (s, 2H), 7.92 (s, 2H), 8.00 (s, 1H)

The following is a reference example. Reference Example 1 (Compound a) N-benzyldiphenylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL), hexamethylenetetramine (1.12 g, 7.96 mmol) was added, and the mixture was stirred at 90 ° C for 12 hours. The reaction solution was cooled to room temperature, a 6 mol / L aqueous sodium hydroxide solution and water were added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (20: 1 to 10: 1 hexane / ethyl acetate).
The compound a (742 mg, 72%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.04 (s, 2H), 6.80
(d, J = 8.6 Hz, 2H), 7.20-7.46 (m, 10H), 7.63 (d,
J = 8.6 Hz, 2H), 9.72 (s, 1H)

Reference Example 2 (Compound b) Step 1 Diphenylamine (7.04 g, 41.6 mmol) was added to THF (100
dissolved in 60% sodium hydride mineral oil dispersion (2.0 mL).
4 g, 51.0 mmol) and stirred at room temperature for 1 hour. Then, 3,4-dichlorobenzyl chloride (11.5 g, 58.8 mmol) was added, and the mixture was further stirred at room temperature for 56 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (20: 1).
Purification with hexane / ethyl acetate) gave N- (3,4-dichlorobenzyl) diphenylamine (13.4 g, 98%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 4.92 (s, 2H), 6.90-
7.05 (m, 6H), 7.15-7.30 (m, 5H), 7.35 (d, J = 8.2
Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H)

Step 2 The compound obtained in Step 1 (7.34 g, 22.4 mmol) was suspended in acetic acid (50 mL), and hexamethylenetetramine (8.64
g, 61.6 mmol) and stirred at 90 ° C. for 72 hours. The reaction solution was cooled to room temperature, a 6 mol / L aqueous sodium hydroxide solution and water were added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (10: 1 to 4: 1 hexane / ethyl acetate).
Compound b (1.67 g, 21%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 4.98 (s, 2H), 6.77
(d, J = 8.9 Hz, 2H), 7.15 (dd, J = 2.0, 8.2 Hz, 1
H), 7.23-7.32 (m, 3H), 7.35-7.47 (m, 4H), 7.68 (d,
J = 8.9 Hz, 2H), 9.76 (s, 1H)

Reference Example 3 (Compound c) In the same manner as in Step 1 of Reference Example 2, 4,4'-dibromodiphenylamine (0.987 g, 3.57 mmol), diphenylmethane bromide (1.76 g, 7.14 mmol) and 60% hydrogen Compound c from sodium chloride mineral oil dispersion (143 mg, 3.57 mmol)
(1.58 g, 99%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.28 (s, 1H), 6.70
(d, J = 6.9 Hz, 4H), 7.18-7.23 (m, 14H)

Reference Example 4 (Compound d) Compound c (174 mg, 0.353 mmol) was dissolved in THF (10 mL) and cooled to -78 ° C. Then, n-butyllithium (hexane solution; 0.51 mL, 0.78 mmol) was added, and the mixture was added at the same temperature for 30 minutes.
After stirring for minutes, DMF (1.5 mL, 19 mmol) was added, and the mixture was heated to room temperature and stirred at the same temperature for 50 minutes. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) and water (5 mL) were added to the reaction solution,
Extracted with ethyl acetate. Wash the organic layer with saturated saline,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform) to obtain compound d (42.1 mg, 33%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.46 (s, 1H), 6.64
(d, J = 8.9 Hz, 2H), 7.03 (d, J = 6.9 Hz, 2H), 7.0
5-7.57 (m, 13H), 7.59 (d, J = 7.3 Hz, 2H), 9.72
(s, 1H)

Reference Example 5 (Compound e) 4,4'-dibromodiphenylamine (2.13 g, 6.51 mmol)
Was dissolved in THF (100 mL), and di-tert-butyl dicarbonate (3.00
mL, 13.1 mmol), and the mixture was stirred at room temperature for 8 hours, and then heated and refluxed for 4 hours. Then 4-dimethylaminopyridine (1.7
0 g, 13.9 mmol), and the mixture was further heated under reflux for 4 hours. The reaction solution was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform) to obtain compound e (2.50 g, 99
%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.44 (s, 9H), 7.06
(d, J = 8.9 Hz, 4H), 7.42 (d, J = 8.9 Hz, 4H)

Reference Example 6 (Compound f) Compound e (4.00 g, 9.36 mmo) was prepared in the same manner as in Reference Example 4.
l), n-butyllithium (hexane solution; 6.2 mL, 9.4 m
mol) and DMF (3.0 mL, 39 mmol) from compound f (1.9
7 g, 65%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.46 (s, 9H), 7.07
(d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.4
9 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 9.
95 (s, 1H)

Reference Example 7 (Compound g) Compound f (1.97 g, 6.04 mmol) was added to dichloromethane (10 m
L) and cooled to 0 ° C. Then, trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform to obtain a white powder. This powder was dissolved in THF, and a 60% sodium hydride mineral oil dispersion (143 mg, 3.57 mmol) was added at room temperature.
After stirring at the same temperature for 5 minutes, 3,4-dichlorobenzyl bromide was added, and the mixture was further stirred at the same temperature for 2 hours. 1 mol in the reaction solution
/ L Hydrochloric acid was added, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to obtain Compound g (1.58 g, 58%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 4.96 (s, 2H), 6.82
(d, J = 8.6 Hz, 2H), 7.14 (m, 3H), 7.38 (m, 2H),
7.53 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2
H), 9.78 (s, 1H)

Reference Example 8 (Compound h) Compound g (249 mg, 0.572 mmol), diphenylphosphinoferrocene (63.2 mg, 0.114 mmol), and 1,2 were added to a mixed solvent of methanol (3.0 mL) and xylene (3.2 mL). 2,2,6,
6, -pentamethylpiperidine (114 mg, 0.731 mmol) and palladium trifluoroacetate (19 mg, 0.057 mmo)
l) were sequentially added, and the mixture was stirred at room temperature in a carbon monoxide atmosphere, then heated to 90 ° C., and further stirred at the same temperature for 12 hours.
The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20: 1 chloroform / methanol) to obtain Compound h (175 mg, 74%).
I got ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.91 (s, 3H), 5.0
6 (s, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.12 (br d, J
= 8.6 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 7.38 (br
s, 1H), 7.39 (br d, J = 8.6 Hz, 1H), 7.76 (d, J =
8.9 Hz, 2H), 8.02 (d, J = 8.9 Hz, 2H), 9.85 (s, 1
H)

Reference Example 9 (Compound i) Compound e (1.47 g, 3.46 mmo) was prepared in the same manner as in Reference Example 4.
l), n-butyl lithium (1.50 mol / L hexane solution; 6.0
Compound i (739 mg, 79%) was obtained from DMF (1.10 mL, 14.3 mmol). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.47 (s, 9H), 7.35
(d, J = 8.4 Hz, 4H), 7.86 (d, J = 8.4 Hz, 4H), 9.9
8 (s, 2H)

Reference Example 10 (Compound j) Compound i (2.33 g, 7.16 mmol) was added to dichloromethane (20
trifluoroacetic acid (10 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. A 6 mol / L aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform.
The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with methanol to obtain a compound j (1.18 g, 73%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.51 (br s, 1H), 7.
25 (d, J = 8.6 Hz, 4H), 7.86 (d, J = 8.6 Hz, 4H),
9.89 (s, 2H)

Reference Example 11 (Compound k) In the same manner as in Step 1 of Reference Example 2, compound j (432 mg, 1.
92 mmol), 60% sodium hydride mineral oil dispersion (92.0 m
g, 2.30 mmol) and 3,4-dichlorobenzyl bromide to give compound k (680 mg, 92%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.10 (s, 2H), 7.12
(d, J = 8.6 Hz, 4H), 7.22 (br d, J = 8.3 Hz, 1H),
7.39 (br s, 1H), 7.41 (br d, J = 8.3 Hz, 1H), 7.84
(d, J = 8.6 Hz, 4H), 9.90 (s, 2H)

Reference Example 12 (Compound L) Compound k (296 mg, 0.770 mmol) was prepared in the same manner as in Example 1.
l), 2,4-thiazolidinedione (90.0 mg, 0.770 mmol)
And lithium hydroxide (18.5 mg, 0.770 mmol)
Compound L (245 mg, 81%) was obtained. ¹ H NMR (270MHz, CDCl ₃ ) δ (ppm) 5.08 (s, 2H), 7.14
(m, 3H), 7.28 (m, 2H) 7.47 (m, 2H), 7.47 (d, J = 8.
6 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.80 (s, 1H),
7.81 (br s, 1H), 9.87 (s, 1H)

Reference Example 13 (Compound m) Compound b (249 mg, 0.700 mmol) was added to ethyl acetate (5 mL).
And chlorosulfuric acid (0.060 mL, 0.90 mmol) was added thereto, followed by stirring at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by resin adsorption column chromatography (HP-20, acetonitrile) to obtain Compound m (265 mg, 98%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 5.10 (s, 2H), 6.8
8 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.
28 (dd, J = 2.0, 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz,
1H), 7.57 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.7 H
z, 2H), 7.70 (d, J = 8.7 Hz, 2H), 9.70 (s, 1H)

Reference Example 14 (Compound n) Compound b (200 mg, 0.561 mmol) was added to chloroform (10
dissolved in water (0.10 mL), concentrated nitric acid (0.60 mL, 9.6 m
mol) were sequentially added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by preparative thin-layer chromatography (2: 1 hexane / ethyl acetate) and (chloroform) to obtain Compound n (116 m
g, 51%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.09 (s, 2H), 7.07
(d, J = 9.4 Hz, 2H), 7.10 (dd, J = 2.0, 8.2 Hz, 1
H), 7.31 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 2.0 Hz,
1H), 7.41 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.6 H
z, 2H), 8.14 (d, J = 9.4 Hz, 2H), 9.94 (s, 1H)

Reference Example 15 (Compound o) Step 1 2-chloro-5- (hydroxymethyl) pyridine (849 mg, 5.9
1 mmol) in DMF (10 mL) and imidazole (82
1 mg, 12.1 mmol) and tert-butyldimethylsilyl chloride (1.30 g, 8.64 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20: 1 hexane / ethyl acetate) to give 2-chloro-5-[(tert-butyldimethylsilyloxy)
Methyl] pyridine (1.48 g, 92%) was obtained. ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.11 (s, 6H), 0.93
(s, 9H), 4.73 (s, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.
62 (dd, J = 2.0, 8.2 Hz, 1H), 8.33 (d, J = 2.0 Hz,
1H)

Step 2 The compound obtained in Step 1 (312 mg, 1.14 mmol) and 4
-[(tert-Butyldimethylsilyloxy) methyl] aniline (269 mg, 1.13 mmol) was dissolved in toluene (5 mL),
Di-tert-butyl-2-biphenylphosphine (77.0 mg, 0.
258 mmol), tris (dibenzylideneacetone) dipalladium (0) (124 mg, 0.125 mmol) and sodium ter
t-Butoxide (277 mg, 2.88 mmol) was added, the temperature was raised to 80 ° C, and the mixture was stirred at the same temperature for 3 hours. After cooling to room temperature, water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (4: 1
Purification with hexane / ethyl acetate) gave Compound o (157 m
g, 29%). ¹ H NMR (300MHz, CDCl ₃ ) δ (ppm) 0.10 (s, 6H), 0.10
(s, 6H), 0.93 (s, 9H), 0.93 (s, 9H), 4.64 (s, 2H),
4.71 (s, 2H), 6.48 (br s, 1H), 6.85 (d, J = 8.4 Hz,
1H), 7.25-7.30 (m, 4H), 7.48 (dd, J = 2.2, 8.4 H
z, 1H), 8.13 (br s, 1H)

Reference Example 16 (Compound p) In the same manner as in Step 1 of Reference Example 2, compound o (82.5 mg,
0.174 mmol), 60% sodium hydride mineral oil dispersion (36.5 m
g, 0.913 mmol) and 3,4-dichlorobenzyl bromide (0.10
mL) to give compound p (75.5 mg, 69%). ¹ H NMR (300MHz, CDCl ₃ ) δ (ppm) 0.09 (s, 6H), 0.11
(s, 6H), 0.92 (s, 9H), 0.95 (s, 9H), 4.61 (s, 2H),
4.72 (s, 2H), 5.17 (s, 2H), 6.49 (d, J = 8.6 Hz, 1
H), 7.09-7.16 (m, 3H), 7.24-7.42 (m, 5H), 8.13 (br
s, 1H)

Reference Example 17 (Compound q) Compound p (115 mg, 0.182 mmol) was added to acetonitrile (10 m
L), 1 mol / L hydrochloric acid (4.0 mL, 4.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (90: 10: 1 chloroform / methanol /
Water) to give compound q (66.0 mg, 90%). ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.52 (br t, J = 4.6
Hz, 1H), 1.68 (br t, J = 4.6 Hz, 1H), 4.57 (d, J =
4.6 Hz, 2H), 4.70 (d, J = 4.6 Hz, 2H), 5.19 (s, 2
H), 6.52 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 2.0,
8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.31 (d, J
= 8.4 Hz, 1H), 7.34-7.44 (m, 2H), 7.37 (d, J = 8.4
Hz, 2H), 8.18 (d, J = 2.0 Hz, 1H)

Reference Example 18 (Compound r) Compound q (63.0 mg, 0.156 mmol) was added to dichloromethane (10
manganese dioxide (370 mg, 4.26 mmol)
Was added and stirred at room temperature for 6 hours. Filtering the reaction mixture,
The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (2: 1 hexane / ethyl acetate) to give compound r.
(60.7 mg, 97%). ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 5.33 (s, 2H), 6.67
(d, J = 9.0 Hz, 1H), 7.09 (dd, J = 2.2, 8.4 Hz, 1
H), 7.35 (d, J = 8.4 Hz, 1H), 7.357.41 (m, 1H), 7.
38 (d, J = 8.4 Hz, 2H), 7.88 (dd, J = 2.2, 9.0 Hz,
1H), 7.94 (d, J = 8.4 Hz, 2H), 8.69 (d, J = 2.2 H
z, 1H), 9.88 (s, 1H), 10.01 (s, 1H)

Reference Example 19 (Compound s) In the same manner as in Step 1 of Reference Example 2, compound o (96.9 mg, 0.1%) was obtained.
205 mmol), 60% sodium hydride mineral oil dispersion (45.6 mg,
1.14 mmol) and 3,5-bis (trifluoromethyl) benzyl bromide (0.10 mL, 0.54 mmol) to give compound s
(109 mg, 76%). ¹ H NMR (300MHz, CDCl ₃ ) δ (ppm) 0.08 (s, 6H), 0.10
(s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 4.62 (s, 2H),
4.73 (s, 2H), 5.32 (s, 2H), 6.50 (d, J = 8.6 Hz, 1
H), 7.13 (d, J = 8.2 Hz, 2H), 7.30-7.38 (m, 3H),
7.71 (s, 1H), 7.75 (s, 2H), 8.12 (d, J = 2.4 Hz, 1
H)

Reference Example 20 (Compound t) In the same manner as in Reference Example 17, compound s (108 mg, 0.154 mm
ol) and 1 mol / L hydrochloric acid (4.0 mL, 4.0 mmol) to give compound t (66.5 mg, 92%). ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.52 (br t, J = 5.0
Hz, 1H), 1.68 (br t, J = 5.0 Hz, 1H), 4.58 (d, J =
5.0 Hz, 2H), 4.71 (d, J = 5.0 Hz, 2H), 5.33 (s, 2
H), 6.53 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.4 Hz,
2H), 7.40 (d, J = 8.4 Hz, 2H), 7.42 (dd, J = 2.0,
8.6 Hz, 1H), 7.72 (s, 1H), 7.76 (s, 2H), 8.17 (d, J
= 2.0 Hz, 1H)

Reference Example 21 (Compound u) Compound t (65.8 mg, 0.140 m) was prepared in the same manner as in Reference Example 18.
mol) and manganese dioxide (365 mg, 4.20 mmol)
Compound u (60.4 mg, 92%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 5.48 (s, 2H), 6.69
(d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.7
4 (s, 2H), 7.77 (s, 1H), 7.90 (dd, J = 2.2,8.8 Hz,
1H), 7.97 (d, J = 8.4 Hz, 2H), 8.69 (d, J = 2.2 H
z, 1H), 9.90 (s, 1H), 10.02 (s, 1H)

Reference Example 22 (Compound v) 4-[(tert-butyldimethylsilyloxy) methyl] aniline (2.00 g, 8.42 mmol) was added to 1,2-dichloroethane (50 mL).
And cooled to 0 ° C. Then, 3,4-dichlorobenzaldehyde (2.46 g, 14.1 mmol), acetic acid (0.482 mL, 8.
42 mmol) and sodium triacetoxyborohydride
(3.90 g, 18.4 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate and water were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (Fuji Silysia).
Purification was performed using chromatorex NH, 7: 1 hexane / ethyl acetate) to obtain a compound v (2.76 g, 83%). ¹ H NMR (300MHz, CDCl ₃ ) δ (ppm) 0.07 (s, 6H), 0.92
(s, 9H), 4.08 (br s, 1H), 4.30 (s, 2H), 4.61 (s, 2
H), 6.56 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz,
2H), 7.19 (dd, J = 2.0, 8.2 Hz, 1H), 7.39 (d, J =
8.2 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H)

Reference Example 23 (Compound w) In the same manner as in Step 2 of Reference Example 15, compound v (370 mg, 0.9
32 mmol), 4-bromo-2-[(tert-butyldimethylsilyloxy) methyl] thiophene (503 mg, 1.64 mmol), di-
tert-butyl-2-biphenylphosphine (97.1 mg, 0.325
mmol), tris (dibenzylideneacetone) dipalladium (0) (119 mg, 0.130 mmol) and sodium tert-
Compound w (487 m) was obtained from butoxide (200 mg, 2.09 mmol).
g, 84%). ¹ H NMR (300MHz, CDCl ₃ ) δ (ppm) 0.08 (s, 6H), 0.09
(s, 6H), 0.91 (s, 9H), 0.93 (s, 9H), 4.66 (s, 2H),
4.77 (s, 2H), 4.82 (s, 2H), 6.42 (d, J = 2.0 Hz, 1
H), 6.70-6.72 (m, 1H), 6.95 (d, J = 8.6 Hz, 2H),
7.10-7.20 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.35
(d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.0Hz, 1H)

Reference Example 24 (Compound x) Compound w (265 mg, 0.425 mmol) was prepared in the same manner as in Example 17.
l) and 1 mol / L hydrochloric acid (1.0 mL, 1.0 mmol) to give compound x (129 mg, 77%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.83 (br s, 1H), 3.
49 (br s, 1H), 4.60 (br s, 2H), 4.73 (br s, 2H),
4.84 (s, 2H), 6.51 (d, J = 1.6 Hz, 1H), 6.82 (dt, J
= 1.6, 0.8 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 7.1
4 (dd, J = 2.0, 8.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2
H), 7.36 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 2.0 Hz,
1H),

Reference Example 25 (Compound y) Compound x (126 mg, 0.318 mm) was prepared in the same manner as in Example 18.
ol) and manganese dioxide (670 mg, 7.71 mmol)
Compound y (48.0 mg, 39%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.97 (s, 2H), 6.92
(d, J = 8.8 Hz, 2H), 7.12 (dd, J = 2.0, 8.3 Hz, 1
H), 7.37 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 1.5,
1.5 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.70 (d, J
= 1.5 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 9.83 (s,
1H), 9.88 (d, J = 1.5 Hz, 1H)

Reference Example 26 (Compound z) In the same manner as in Step 1 of Reference Example 2, compound j (1.00 g, 4.
45 mmol), 60% sodium hydride mineral oil dispersion (257 mg,
6.42 mmol) and 3,5-bis (trifluoromethyl) benzyl bromide (1.39 mL, 7.57 mmol) to give compound z
(1.94 g, 97%). ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.26 (s, 2H), 7.21
(d, J = 8.6 Hz, 4H), 7.73 (s, 2H), 7.80 (s, 1H),
7.84 (d, J = 8.6 Hz, 4H), 9.90 (s, 2H)

[0182]

According to the present invention, a thiazolidine derivative having telomerase inhibitory activity or antitumor activity is provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 35/00 A61P 35/00 43/00 111 43/00 111 C07D 277/36 C07D 277/36 417/12 417/12 417/14 417/14 (72) Inventor Junnori Yamashita 1188 Shimotsukari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Hakko Kogyo Co., Ltd. Fermentation Industry Co., Ltd. Pharmaceutical Research Laboratory F term (reference) 4C033 AD01 AD02 AD06 AD17 AD20 4C063 AA01 AA03 BB09 CC62 CC92 DD12 DD23 DD29 DD62 EE01 4C086 AA02 AA03 BC82 GA04 GA07 GA08 GA10 MA01 MA04 NA14 ZB26 ZC20

Claims (7)

[Claims] 1. A compound of the formula (I) [Wherein, Q represents an oxygen atom or a sulfur atom, R ¹ represents a substituted or unsubstituted aralkyl, X represents a benzene ring,
Represents a pyridine ring or a thiophene ring, 1) when X is a benzene ring, Y is a hydrogen atom, substituted or unsubstituted lower alkenyl, carboxy, substituted or unsubstituted lower alkoxycarbonyl, carbamoyl, substituted or unsubstituted lower Alkylcarbamoyl, CH = N-OH,
Hydroxysulfonyl (sulfo, SO ₃ H), sulfamoyl, lower alkylsulfamoyl, lower alkanoylsulfamoyl, nitro, amino, sulfamoylamino, halogen or formula (II) (Wherein, Q ^A represents an oxygen atom or a sulfur atom, R ² represents a hydrogen atom or a substituted or unsubstituted lower alkyl, and when Q ^A is a sulfur atom, Z represents NH or a sulfur atom; when ^a is an oxygen atom, Z is -NH (C
ＯO)-or NH), and X (benzene ring)
The substitution position of the above Y may be any position. 2) When X is a pyridine ring or a thiophene ring, Y is a compound of the formula (III) Wherein R ² has the same meaning as described above, and the substitution position of Y on X (pyridine ring or thiophene ring may be any position); or a pharmacologically acceptable derivative thereof. salt. 2. The thiazolidine derivative according to claim 1, wherein Q is an oxygen atom, or a pharmaceutically acceptable salt thereof. 3. The thiazolidine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X is a pyridine ring or a thiophene ring. 4. The method according to claim 1, wherein X is a pyridine ring.
Or a pharmacologically acceptable salt thereof. 5. A medicament comprising the thiazolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof. 6. A telomerase inhibitor comprising, as an active ingredient, the thiazolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof. 7. An antitumor agent comprising the thiazolidine derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.