WO2001030771A1 - Thiazolidinedione derivatives - Google Patents

Abstract

Thiazolidinedione derivatives of the general formula (I) or pharmacologically acceptable salts thereof, exhibiting a telomerase-inhibiting effect, wherein R?1a and R1b¿ are each hydrogen, lower alkyl, or the like; r?1 and r2¿ are each a single or double bond; and X is a group of the general formula (II) [wherein Y is NR2 (wherein R2 is hydrogen, lower alkyl, or the like) or the like] or the like..

Description

 Specification

 Thiazolidinedione derivatives

 The present invention relates to a thiazolidinedione derivative used for treating a disease associated with telomerase activity such as a malignant tumor.

Background art

It is known that the telomere present at the chromosome end of eukaryotes is an important region for chromosome stabilization. In humans, the sequence is composed of a TTAGGG repeat 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 (Ml phase). However, when the mitotic arrest mechanism does not work properly due to mutations in tumor suppressor genes such as the p53 gene, cells repeatedly divide. As a result, telomeres are shortened to the utmost extent, chromosome instability occurs, and cells die (M2 phase). [Proceding 'of the National Academy of Sciences of the Sciences of the University of Tokyo] Natl. Acad. Sci. USA, 89, 10114-10118 (1992); Trends in Cell Biology, 5, 293-297 (1995)] . On the other hand, more than 80% of cancer cells express the telomere-prolonging enzyme telomerase [Journal of the NCI, 87, 884-894 (1995)] _c this enzyme is reverse transcriptase which extends the Teromea RNA as錡型, consists protein (hTERT) is the catalytic Sabuyuni' preparative RNA (hTR) ing and錶型I have. Therefore, it is considered that telomerase suppresses telomere shortening in cancer cells and stably maintains telomeres, thereby enabling infinite proliferation as immortalized cells. This concept, or "telomere hypothesis," is based on the Proc. Natl. Acad. Sci. USA ), 89, 10114-10118 (1992). Have been. Experimental results supporting this telomere hypothesis include antisense to hTR [Science, ^, 1236-1240 (1995)] and a dominant-negative mutant hTERT [jeans' and 'Development (Genes & Development), 13, 2388-2399 (1999), Nature Medicine, 5, 1164-1170 (1999)] shows cell death with telomere shortening for cancer cells Has been reported to induce Therefore, a substance that specifically inhibits telomerase is expected to be a new type of antitumor agent that induces telomere shortening and gives life to cancer cells. Furthermore, telomerase is expressed only in cancer tissues with some exceptions such as germ cells, so it is expected to be a low-toxic antitumor agent that hardly affects normal tissues Have been.

 AZTTP and ddGTP [Molecula 'and' Cellular 'biology (Mol. Cell. Biol.), 16, 53-65 (1996)], 7- Nucleic acid analogs such as Daza-dGTP [Biochemistry, 35, 15611-15617 (1996)], hetero 5-membered condensed pyridine derivatives (US Patent No. 5656638; US Patent No. 5760062), benzothiophene derivatives (US Patent No. 5703116) and phenylisothiazol derivatives (W099 / 08679) are known.

 On the other hand, as a compound having a plurality of thiazolidinedione structures in one molecule, US Patent Nos. 5,063,240, W092 / 00967 and W093 / 03021 disclose a bisheterocyclic compound having a hypoglycemic effect.

が記載されている。 The RTECS [Registry of Toxic Effects of Chemical Substances] database contains the compounds represented by the formula below.

Is described.

 However, the telomerase inhibitory action of thiazolidinedione derivatives has not been known.

Disclosure of the invention

 An object of the present invention is to provide a novel thiazolidinedione derivative having excellent telomerase inhibitory activity or antitumor activity. The present invention relates to the following (1) to (8).

(1) Equation (I)

{Wherein, R ^{1 a} and R ^lb represents the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru or substituted or is unsubstituted lower Arukanoiru, gamma ¹ and gamma ² represent identical or different and their respective single or double bond, X is formula (II)

[Wherein, Y is NR ² (wherein R ² is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted aryl) Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted Substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted lower alkylsulfonyl, substituted Or unsubstituted aryl sulfoni Or a substituted or unsubstituted arylo or substituted or unsubstituted heterocarbonyl), or CR ³ R ⁴ (where R ³ is a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl) Substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower Alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkoxy,

(i) When R ³ is a hydrogen atom or unsubstituted lower alkyl, R ⁴ is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted Or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy,

(ii) R ³ is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxy carbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, Or when substituted or unsubstituted lower alkoxy, R ⁴ is hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted Or unsubstituted aryl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted carbamoyl, cyano Represents a substituted or unsubstituted aralkyl, a substituted or unsubstituted aralkyloxy, a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted cycloalkyloxy,

R ³ and R ⁴ together represent = 0 or a substituted or unsubstituted lower alkylidene, or

Or R ³ and R ⁴ are taken together with adjacent carbon atoms to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted alicyclic heterocyclic group)] or the formula (III)

,

(In the formula, n represents an integer of 0 to 2, W represents a hydrogen atom, substituted or unsubstituted arylthio, or substituted or unsubstituted arylsulfinyl.) Thiazolidinedione derivative represented by Or a pharmacologically acceptable salt thereof. (2) X is the formula (IIA)

Wherein, Y ^a is NR ^{2 f} (wherein, R ^{2 f} is a hydrogen atom, a substituted or unsubstituted lower § alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Ari Le, substituted or unsubstituted Aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted rubamoyl, Represents a substituted or unsubstituted thiocarbamoyl, a substituted or unsubstituted lower alkylsulfonyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroarylcarbonyl), or C R ^{3 f} R ^{4 f} (wherein, R ^3f represents a hydrogen atom, human Dorokishi, a substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxycarbonyl,

(I) if R ^3f is a hydrogen atom or an unsubstituted lower alkyl, R ^{4 f} is human de port alkoxy, substituted lower alkyl, carboxy, substituted or unsubstituted lower an alkoxy carbonyl, substituted or unsubstituted force Lubamoyl, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy,

(ii) When R ^3f is a substituted lower alkyl or a substituted or unsubstituted lower alkoxycarbonyl, R ^4f is a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxycarbonyl or a substituted or unsubstituted lower alkoxycarbonyl. Represents a substituted lower alkoxy,

R ^3f and R ^4f together represent two

Or R ^3f and R ^4f are taken together with adjacent carbon atoms to form a substituted or unsubstituted cycloalkyl or an alicyclic heterocyclic group). The thiazolidinedione derivative according to the above (1), which represents a group represented by the formula, or a pharmacologically acceptable salt thereof. -

(3) 1 and 1 ¹¹⁵ represent a hydrogen atom, and X is a group represented by the formula (IIB)

Wherein Y ^b is NR ^2g (where R ^2g represents a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted lower alkoxycarbonyl), or CR ^3g R ^4g Wherein R ^3g represents a hydrogen atom or a substituted or unsubstituted lower alkyl, and R ^4g represents a substituted or unsubstituted aralkyloxy or a substituted or unsubstituted cycloalkyloxy. The thiazolidinedione derivative according to the above (1) or a pharmacologically acceptable salt thereof.

(4) A medicament comprising the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3). (5) A telomerase inhibitor comprising, as an active ingredient, the thiazolidinedione derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (3).

 (6) An antitumor agent comprising, as an active ingredient, the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).

 (7) A method for treating a disease associated with telomerase activity, which comprises administering an effective amount of the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).

 (8) The thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3) for producing a pharmacological composition useful for treating a disease associated with telomerase activity. Use of.

 Hereinafter, the compound represented by the formula (I) may be referred to as a compound (I). The same applies to the compounds of other formula numbers.

 In the definition of each group in the formula, lower alkyl includes straight-chain or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Butyl, pentyl, hexyl and the like.

 Lower alkenyl includes straight-chain or branched alkenyl having 2 to 6 carbon atoms, for example, vinyl, aryl, 1-propenyl, methacrylic, crotyl, 1-butenyl, 3-butenyl, 2-pentenyl, 4 —Pentenyl, 2-hexenyl, 5-hexenyl and the like.

 The cycloalkyl of cycloalkyl and cycloalkyloxy includes cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Examples of lower alkynyl include straight-chain or branched alkynyl having 2 to 6 carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Examples of the lower alkylidene include a straight or branched C1-6 alkylene such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, and isopropylidene.

 Examples of aryl include aryl having 6 to 14 carbon atoms, such as phenyl, naphthyl, and anthryl.

 The heteroaryl includes, for example, a 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered fused ring. A condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in a ring or tricyclic ring, and more specifically, pyridyl, virazinyl, pyrimidinyl , Pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, pivalyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, isothiazolyl, zothiazolyl, zothiazolyl Indolyl, indazolyl, benzimidazolyl, benzoto Azolyl, benzothiazolyl, O hexa benzisoxazolyl, Benzochi Eniru, benzofuryl, Benzobirazoriru, purinyl and the like.

 The alicyclic heterocyclic group formed together with adjacent carbon atoms includes, for example, a 5- or 6-membered monocyclic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. An alicyclic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring and a condensable alicyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom Heterocyclic groups and the like, and more specifically, pyrrolidinyl, piberidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydrofuranyl Drobenzofuranyl, dioxolanyl and the like.

Aralkyl, aralkyloxycarbonyl, aralkyloxy, aryloxy, arylsulfonyl, arylsulfinyl and aryl in aryloyl The rule part is synonymous with the above reel.

 The heteroaryl moiety in the heteroarylalkyl, the heteroarylalkyloxycarbonyl and the heteroarylcarbonyl has the same meaning as the above-mentioned heteroaryl.

 The lower alkyl moiety in lower alkanoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower alkylsulfonyl and lower alkoxy has the same meaning as the above lower alkyl.

 The alkylene moiety in aralkyl, aralkyloxycarbonyl, aralkyloxy, heteroarylalkyl, or heteroarylalkyloxycarbonyl represents a group obtained by removing one hydrogen atom from the above lower alkyl.

Substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl, substituted aryl, substituted arylthio, substituted arylsulfinyl, substituted heteroaryl, substituted aralkyl, substituted heteroarylalkyl, substituted lower alkanol, substituted lower alkoxycarbonyl, substituted α Ralquiloxycarbonyl, substituted heteroaryloxycarbonyl, substituted aryl, substituted heteroarylcarbonyl, substituted lower alkanoyloxy, substituted lower alkoxy, substituted alkylsulfonyl, substituted arylsulfonyl, substituted aralkyloxy The substituent in the substituted cycloalkyloxy, the substituted cycloalkyl, the substituted alicyclic heterocyclic group and the substituted lower alkylidene includes a halogen atom having 1 to 3 substitutable numbers, preferably 1 to 3 substitutable numbers. , Lower alkyl, lower alkenyl, hydroxy, hydroxy-substituted lower alkyl, halogen-substituted lower alkyl, cycloalkyl, lower alkoxy, halogen-substituted lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, mercapto, Lower alkylthio, halogen-substituted lower alkylthio, NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ are the same or different, and represent a hydrogen atom, lower alkyl, hydroxy-substituted lower alkyl, lower alkanol, lower alkoxycarbonyl, aryl) Represents a heteroaryl, aralkyl or heteroarylalkyl, or a nitrogen atom in which R ⁵ and R ⁶ are adjacent Nitro, cyano, C0 ₂ R ⁷ (where R ⁷ represents a water atom, lower alkyl, aryl, heteroaryl, .aralkyl or heteroarylalkyl) , CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meanings as R ⁵ and R ⁶ , respectively), aryl, heteroaryl, alicyclic heterocyclic group, substituted aryl, substituted Heteroaryl, substituted alicyclic heterocyclic group [Substituents of the above-mentioned substituted aryl, substituted heteroaryl or substituted alicyclic heterocyclic group have 1 to 1 substitutable number, preferably 1 to 3 substituents. Lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio, NR ^ R ¹¹ (wherein R ^{1 D} and R ¹¹ are the same or different and each of R ⁵ and R ⁶ Synonymous), nitro, Shiano in C 0 ₂ R ¹² (wherein, R ¹² has the same meaning as the R ^7), CONR ¹³ R ¹⁴ (wherein, R ¹³ and R ¹⁴ are the same or different and each Which is the same as R ⁵ and R ⁶ ), aryl, heteroaryl or a halogen atom 1, formula (IV)

[Wherein P ¹ and P ² are the same or different and represent an oxygen atom, a sulfur atom or NR ¹⁵ (wherein R ¹⁵ represents a hydrogen atom or lower alkyl), and Q ¹ and Q ² are the same or different Differently represents an oxygen atom or a sulfur atom]. The lower alkyl moiety in lower alkyl and lower alkoxy, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, and lower alkylthio includes the same as the above lower alkyl. As the lower alkenyl, those similar to the aforementioned lower alkenyl can be mentioned. Examples of the aryl moiety of aryl and aralkyl include the same as those described above, and the alkylene moiety of aralkyl represents a group obtained by removing one hydrogen atom from the lower alkyl. Examples of the heteroaryl portion of the heteroaryl and the heteroarylalkyl include the same as the above-mentioned heteroaryl. The alkylene portion of the alkoxyalkyl represents a group in which one hydrogen atom has been removed from the lower alkyl. Examples of the alicyclic heterocyclic group include those similar to the alicyclic heterocyclic group. Examples of the cycloalkyl include the same as the above-described cycloalkyl. The number of halogen substitution in the halogen-substituted lower alkyl, the halogen-substituted lower alkoxy and the halogen-substituted lower alkylthio is from 1 to a substitutable number, preferably from 1 to 3.

 Examples of the halogen moiety of a halogen atom, a halogen-substituted lower alkyl, a halogen-substituted lower alkoxy and a halogen-substituted lower alkylthio include iodine, bromine, chlorine and fluorine atoms.

 The number of substituted hydroxy in the hydroxy-substituted lower alkyl is 1 to a substitutable number, preferably 1 to 3.

 Examples of the heterocyclic group formed together with the adjacent nitrogen atom include, for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic compound). The ring group may contain another nitrogen atom, oxygen atom or sulfur atom), a bicyclic or tricyclic fused 3- to 8-membered ring containing at least one nitrogen atom Ring group (the condensed heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom), and more specifically, pyrrolidinyl, piberidin.no, piperazinyl, morpholino, thio Examples include morpholino, homopiperidino, homobiradizinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, benzimidazolyl and the like.

 Examples of the substituent of the substituent are the same as the substituents in the above-mentioned substituted alkyl and the like, and in addition, the nitrogen atom in the substituent is combined with an adjacent substituent to form a heterocyclic group. It may be formed. Examples of the heterocyclic group formed by combining a nitrogen atom with an adjacent substituent include those similar to the heterocyclic group formed by forming a nitrogen atom together with an adjacent nitrogen atom.

Examples of the substituent of the substituted thiocarbamoyl include the above-described substituents of the substituent of rubamoyl. And similar ones.

 Pharmaceutically acceptable salts of compound (I) include pharmacologically 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 salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, quaterate, and the like. Organic salts such as methanesulfonate, oxalate, malonate, succinate, and tartrate are listed. As pharmacologically acceptable metal salts, alkali metal salts such as sodium salt and potassium salt , Magnesium salts, calcium salts and other alkaline earth metal salts, aluminum salts, zinc salts, and the like. Pharmacologically acceptable ammonium salts include salts such as ammonium and tetramethylammonium. Examples of pharmacologically acceptable organic amine addition salts include addition salts of morpholine, piperidine and the like, and pharmacologically acceptable amino acid addition salts of glycine Phenylene Ruaranin, lysine, Asuparagin acid addition salts of the glutamic acid and the like.

 Some of the compounds (I) in the present invention may have various stereoisomers, positional isomers, 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 shown below, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, a functional group Protection and deprotection [eg, Protective Groups in Organic Synthesis, written by TW Greene, John 'Willy' and 'Sands' Inc. 1981), etc.] can be easily carried out.

In addition, the order of the reaction steps such as introduction of a substituent can be changed as necessary. The following Production Methods 1 to 7 illustrate typical production methods of the compound of the present invention. Manufacturing method 1

The compound (Ia) in which R ^la and R ^lb are both hydrogen atoms in the formula (I) can be produced by the following reaction steps.

Process (1-1)

(Wherein, X, r \ r ² are as defined above)

 Compound (Ia) can be obtained by condensing compound (V) with compound (VI).

 The compound (VI) as a raw material can be produced by a known production method, for example, a method described in Liebigs Ann. Chem., 409 (1984), or a reference example described later. Although it can be manufactured according to the methods described, etc., there are some that are available as commercial products.

In the condensation reaction, a base catalyst, a solvent, and the like may be used as necessary. Examples of the base catalyst include piperidine, piperidinium acetate, getylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate, butyllithium, lithium diisopropylamide, potassium tert-butoxide, and lithium hydroxide. These are used in an amount of 0.1 to 10 equivalents to the compound (VI). Examples of the solvent include alcohols such as methanol, ethanol, and propanol, ether, tetrahydrofuran (THF), 1,2-dimethyloxetane, and dioxane. Ethers such as hexane, benzene, toluene, xylene and the like, N, N-dimethylformamide (DMF), N, N-dimethylacetamide and the like are used alone or in combination. Compound (V) is used in an amount of 2 to 10 equivalents based on compound (VI). The reaction is carried out at room temperature to 200 ° C, preferably at 50 to 100 ° C, and is completed in 0.1 to 50 hours.

(In the formula, X and rr ² have the same meanings as described above, and R ^le and R ^ld are the same or different and each represents a substituted or unsubstituted aralkyl or a substituted or unsubstituted alkanol.)

Examples of the substituted or unsubstituted aralkyl and substituted or unsubstituted alkanol in the definition of R ^le and R ^ld are the same as those described above.

 Compound (lb) can be obtained in the same manner as in the above step (1-1).

 Compound (la) can also be obtained by treating compound (lb) with 0.5 equivalent to an excess amount of an acid in a solvent.

 Examples of the acid include trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, P-toluenesulfonic acid, hydrochloric acid, and sulfuric acid. Examples of the solvent include DMF, dimethylsulfoxide (DMS0), dichloromethane, chloroform, and methylform. Evening ethanol, ethanol, toluene, etc. are used alone or in combination. The reaction is carried out at −78 to 50 ° C., preferably 0 to 30 ° C., and is completed in 0.5 to 48 hours.

Manufacturing method 2

Wherein R ^{1 a} in (I) is a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru or substituted or unsubstituted compounds that are Arukanoiru of

(I c) can be produced by the following reaction steps.

Process (2)

 R 1θ-

(In the formula, 1 ¹⁶ represents a group other than a hydrogen atom in the definition of 11 ^{1! 1} , R ^lb , X and r \ r ² have the same meanings as above, and Z represents a halogen atom.)

Examples of the halogen atom in the definition of Z include the same as those described above. Compound (I c), the compound (la), in an inert solvent, 0.5 presence of equivalents to an excess amount of a salt group, can be obtained by reacting 1 to 10 equivalents of R ^le Z. As the inert solvent, DMF, DMS0, THF, 1,2-dimethoxetane, ether, dichloromethane, acetone, toluene, hexane and the like are used alone or as a mixture, and as the base, triethylamine, diisopropyl ester or the like is used. Alkylamines such as tilamine and N-methylmorpholine, pyridines such as pyridine, lutidine, collidine and 4-dimethylaminoviridine, sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium Dimethoxide, lithium carbonate, sodium carbonate, butyllithium, etc. are used. The reaction is carried out at a temperature of from 78 to 50 ° C, preferably from 0 to 30 ° C, and is completed in 0.1 to 24 hours.

Manufacturing method 3

In the formula (I), X is the formula (Ila)

(In the formula, 11 ^{2! 1} represents a group other than a hydrogen atom in the definition of 1 ^ ² ), or a compound (Id) where X is a formula (lib)

(Wherein, R ¹⁶ represents a hydrogen atom, a substituent of the above-mentioned substituted rubamoyl or a substituent of the above-described substituted rubamoyl, and Q ³ represents an oxygen atom or a sulfur atom). It can be produced by a reaction step. Process (3)

R ^2a Z

 or

(Wherein, R ^la , R ^lb , R ^2a , R ¹⁶ , Z, Q ³ , and r \ r ² are as defined above)

Compound (Id) or (Ie) is a compound (the If), in an inert solvent, 0.5; 10 presence of one equivalent of base is reacted with one equivalent to an excess amount of R ^2a Z or R ¹⁶ NCQ ^3, This can be obtained.

As the inert solvent, DMF, DMS0, THF, 1,2-dimethoxetane, ether, dichloromethane, toluene, hexane, etc. are used alone or in combination. As the group, sodium hydride, potassium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, butyllithium and the like are used. The reaction is carried out at −78 to 50 ° C., preferably at about 78 to 30 ° C., and is completed in 0.1 to 20 hours.

Manufacturing method 4

In equation (I), X is the equation (lie)

(Wherein, 1 ²¹⁾ in the definition of 11 ^2, represents a group containing carboxyl group) at a reduction compound (I g),

Or X is the formula (II d)

(Wherein, R ^{3 a} and R ^{4 a} are the same as R ³ and R ^4, respectively. However, at least one or more carboxyl groups are present in the R ^3a or R ^4a) der Ru compound ( Ih) can be produced by the following step 4.

Process (4)

[Where R ² . During the the R ² definition, C_〇 ₂ R ⁷ (wherein R ⁷ has the same meaning as defined above) represents a group containing, R ^3b and R ^4b is the same meaning as R ³ and R ^4, respectively , provided that 1 ³¹⁾ or 1 at least one CO ₂ R ⁷ in ⁴ is ^{present, R la, R lb, R} 2b, R 3a, R 4a, rr 2 each have the same meanings as defined above] The compound (Ig) or (Ih) is obtained by hydrolyzing the compound (Ii) or (Ij) obtained according to the method described in Example 85 described below, etc. by an appropriate method. Can be obtained by For example, compound (Ii) or (Ij) can be prepared by adding sodium hydroxide, potassium hydroxide, or hydroxide in dioxane, ethers such as THF, alcohols such as methanol and ethanol, water, or a mixed solvent thereof. The compound (Ig) or (Ih) can be obtained by treating with an alkali metal hydroxide such as lithium at room temperature to the boiling point of the solvent for 0.5 to 48 hours. Alternatively, an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as trifluoroacetic acid may be used in place of the alkali metal hydroxide. The metal hydroxide or inorganic acid or organic acid is preferably used in an amount of 0 :! to 20 equivalents to the compound (Ii) or (Ij).

Further, when R ⁷ is aralkyl, it is possible to lead to the compound (Ig) or (Ih) by catalytic reduction in addition to the method described above. Catalytic reduction is usually carried out at normal pressure in the presence of a catalytic amount of a catalyst such as palladium on carbon in a suitable solvent, such as 0.5 to 24 at a temperature between room temperature and the boiling point of the solvent in alcohols such as ethanol and ethanol, esters such as methyl acetate, ethyl acetate and butyl acetate, ethers such as THF and dioxane, or a mixed solvent thereof. End in time.

Manufacturing method 5

 In equation (I), X is the equation (l i e)

Wherein R ^2d represents a group containing CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are as defined above) in the definition of R ² (I k ),

Or X is the formula (I If)

Where R ³ . And R ^4. Is synonymous with R ³ and R ⁴ , respectively. However, R ^3. Or at least one of CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ have the same meanings as described above) in R ^4c , respectively, is produced by the following reaction step. can do.

Process (5)

 (VII)

(式中、 R ^{l a}、 R ^{l b}、 R^{2 b}、 R ^{2 d}、 R

^{(Wherein, R la, R lb, R} 2 b, R 2 d, R

rr ² is as defined above.

Compound (Ik) or (II) can be obtained by activating compound (Ig) or (Ih) by an appropriate method and then condensing with compound (VII). For example, the compound (Im) or (In) is converted to a suitable solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, tetrachloroethane, methyl acetate, ethyl acetate, butyl acetate, etc. Esters, ethers such as ether, THF, and dioxane; non-protonic polar solvents such as acetonitrile, DMF, and DMS0; aromatic hydrocarbons such as benzene, toluene, and xylene, or mixtures thereof 1-20 equivalents of thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc. in a solvent, etc., in the presence of 1-20 equivalents of base, if necessary, at 0 ° C and the boiling point of the solvent For 10 minutes to 48 hours to convert to acid chloride, acid bromide and the like, and then to condense with compound (VII). Examples of the base include alkylamines such as triethylamine, diisopropylethylamine, and N-methylmorpholine; pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyridine; and alkali metals such as potassium carbonate and sodium hydrogencarbonate. Alkali such as carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide Metal hydroxide and the like. In addition, 1 to 10 equivalents of a condensing agent such as dicyclohexyl carpoimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carpo imide, hydrochloride (WSC HC1), Use a condensing agent such as rudimidazole (CDI), or convert the carboxyl group to a highly reactive group such as an ester such as p-ditophenoxy, benzene fluorophenoxy, or penfluorophenylthio according to a standard method. After conversion, it can be obtained according to the above method.

Manufacturing method 6

 In the formula (I), X is the formula (I I g)

 (iig)

(Wherein R ³ is as defined above), can be produced by the following reaction step.

(Wherein, R ^la , R ^lb. R r and r ² are as defined above)

Process (6)

Compound (Io) can be obtained by dehydrating compound (Ip) by an appropriate method. The reaction is carried out by halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and tetrachloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, THF and dioxane; In a mixed solvent or the like, or in the absence of a solvent, in the presence of 1 to an excess amount of a suitable dehydrating agent, for example, thionyl chloride, oxalyl chloride, acetic anhydride, etc., at room temperature to 200 ° C, preferably 50 to At 100 ° C, 0 :! ~ 24 hours to end. Manufacturing method 7

Compounds (Iq) and (Ir) in which rr ² is a single bond in formula (I) can also be produced by the following reaction steps.

 (IX)

 Man

H ₂ N ", NH ₂

(VIII)

17-17

 (XI)

 (lq) Cr)

(Wherein, R ¹⁵ has the same meaning as R ⁷ , and R ^lb , R ^le , X and Z have the same meanings as above.)

 Compound (Iq) is described in Chemical and Pharmaceutical Bretane (Chem. Pharm. Bull.), Vol. 30, No. 3, pages 3563-3573 (1982), pages 3580-3600 (1982), etc. Can be produced according to the process described in (1).

Process (7-1)

Compound (VI II) is obtained as a commercial product, or can be obtained by synthesizing according to or according to a known method. For example, in the compound (VI II), X is a compound of the formula (II h)

 The compound (Villa), which is (llh), is described in the journal "American" Chemical "Social" (J. Am. Chem. So), Vol. 114, No. 25, pp. 9959-9969 (1992). It can be obtained according to the method or the like.

 Compound (X) is obtained by converting compound (VIII) into a ketone such as acetone or methyl ethyl ketone, an ether such as THF or dioxane, or water, or a mixed solvent thereof in an amount of 2 equivalents to an excess amount of an acid, For example, in the presence of hydrochloric acid, hydrobromic acid, or the like, 2 to equivalents of excess sodium nitrite are treated at 0 to 50 ° C for 0.1 to 2 hours to convert to diazonium salt, and then 2 equivalents to excess It can be obtained by treating the compound (IX) with a catalytic amount of copper oxide at 0 to 50 ° C for 0.1 to 2 hours.

Process (7-2)

 Compound (XI) is prepared by converting compound (X) in a suitable solvent in an amount of from 2 equivalents to an excess amount of a suitable base, for example, an alkali metal salt such as sodium formate, potassium formate, sodium acetate, potassium acetate, etc. React with 2 equivalent to excess amount of thiourea in the presence of alkylamines such as lyethylamine, diisopropylethylamine, N-methylmorpholine, and pyridines such as pyridine, lutidine, collidine, and 4-dimethylaminopyridine. Can be obtained. As the solvent, alcohols such as methanol, ethanol, propanol, and 2-methoxyethanol, and nonprotonic polar solvents such as acetate nitrile, DMF, and DMS0 are used alone or as a mixture. The reaction is carried out at room temperature to 150 ° C, preferably 50 to 100 ° C, and is completed in 0.1 to 24 hours.

Process (7-3)

Compound (Iq) is prepared by converting compound (XI) from 2 to 10 equivalents of an acid, for example, hydrochloric acid, sulfuric acid. It can be obtained by reacting in an appropriate solvent in the presence of an inorganic acid such as an acid or an organic acid such as trifluoroacetic acid. As the solvent, alcohols such as methanol, ethanol, propanol and 2-methoxyethanol, or water and the like can be used alone or as a mixture. The reaction is carried out at a temperature between room temperature and 150 ° C., preferably at 50-150 ° C., and is completed in 0.1-24 hours.

Process (7-4)

 Compound (Ir) can be obtained by treating compound (Iq) according to the method described in Production Method 2.

 The compounds (la) to (Iq) may be appropriately modified with a functional group (esterification of carboxyl group, hydrolysis of ester, acylation of amino group or alkylation) by a method commonly used in organic synthetic chemistry. , Amidation of carboxyl group, cyanation by dehydration of carbamoyl group, etc.) to obtain the desired compound.

 The target compound in the above production method can be 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.

 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, and if compound (I) is obtained in a free form, it may be purified by a usual method, What is necessary is just to dissolve or suspend in a solvent, add a desired acid to form a salt, and isolate and purify.

 Compound (I) or a pharmacologically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

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. You. 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.

 In preparing tablets, for example, excipients such as lactose, glucose, sucrose, mannite, methylcellulose, starch, sodium alginate, carboxymethylcellulose calcium, disintegrants such as crystal cell mouth, magnesium stearate, talc Lubricants such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropylcellulose, methylcellulose, etc., and surfactants such as sucrose fatty acid ester, sorbite fatty acid ester, etc. in accordance with the usual methods. Tablets containing 1 to 300 mg of active ingredient per tablet are preferred.

 In preparing the granules, for example, excipients such as lactose and sucrose, disintegrants such as starch, binders such as gelatin, and the like may be used in a conventional manner. In preparing the powder, for example, excipients such as lactose and mannite may be used in a conventional manner. In preparing capsules, for example, gelatin, water, sucrose, arabia gum, 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, for example, water, physiological saline, vegetable oils (eg, olive oil, peanut oil, etc.), solvents such as ethyl oleate, propylene glycol, etc., solubilization of sodium benzoate, sodium salicylate, urethane, etc. Agents, tonicity agents such as sodium chloride, glucose, etc., preservatives such as phenol, cresol, p-hydroxybenzoate, chlorobutanol, and antioxidants such as ascorbic acid, sodium pyrosulfite, etc. It may be used by a conventional method.

Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally such as ointment or injection. The effective dose and frequency of administration vary depending on the dosage form, patient age, body weight, symptoms, etc. Preferably, 20 mg / k is administered one to four times. "

 Hereinafter, specific examples of the compound (I) are shown in Tables 1 to 4, but the compound of the present invention is not limited thereto. Table 1

 Example Compound number

17 18 Structure

 Construction

18 19

2 tables

Examples Compound

Replacement position R ^la R No. ²

 4, 4 'H

2表 （続き）

Table 2 (continued)

Examples Compound

R ² number

13 14 4, 4 'H

16 17 4, 4 'H

Table 2 (continued)

 Compound

Example R ^lb R ² number

2表 （続き）

Table 2 (continued)

38 42 4, 4 'HH Table 2 (continued)

実施例 化合物 置換

Example Compound Substitution

R ^lb R ² IS.

1 o ony 4, 4 X XJI τχ

1

 41 β 41, A 4 'Shirishi 3 3 Shiri 3 3 TJ

 XT

 4 ί 41, 4 'then (ί 5 3 then 6X 5 ^ 3 jn

Λ QAA ^} J

 4ο 4, 4 shi (i δ T

 3 τ XτX then-

43 49 4, 4, C1CGH ₄ ) C1C ₆ H ₄ ) H

、し 6X15 2

Then 6X15 2

 44 ου A A 'XT

K ο 丄 4, 4 XJ ρτ

 4, 4 '1 2 1 t> 4 no

49 55 4, 4 'Η Η CH ₂ (3-C1C ₆ H ₄ )

50 56 4, 4 'Η Η CH ₂ (4-C1C ₆ H ₄ )

CH ₂ (3,4-

51 57 4, 4 'Η Η

 C 2 then 6 13

52 58 4,4 'Η Η COCHa

54 60 4,4 'Η Η C0 (3,4-C1 ₂ C ₆ H3)

55 61 4, 4, Η Η

Table 2 (continued)

 Compound

Ohno JtBl Guri l ί5¾: lil ¾ Τ? La R ib τ> ν2

number

59 65 4 4 Η Η CONHC ₂ H ₅

60 66 4, 4 'Η Η CSNHCHa

62 68 3 3 'Η Η C0 ₂ C (CH ₃ ) ₃

63 69 3 3 'Η Η H

67 73 4, 4 'Η ₂ CH ₂ (2,6-F ₂ C _G H ₃ )

CH ₂ (2,6-

68 74 4, 4 'Η Η

 CbCeHa)

69 75 4, 4 'Η Η CH ₂ (4-FCeH ₄ )

70 76 4, 4 Η Η CH ₂ (3-FC ₆ H4)

71 77 4, 4 'Η Η CH ₂ (2-FC ₆ H ₄ )

72 78 4 '4' Η Η CH ₂ (4-CH ₃ C ₆ H ₄ )

73 79 4 4 Η Η CH2 (3-Cxi3 6H4)

75 81 4, 4 'Η Η CH ₂ (4-CF ₃ C ₆ H ₄ )

76 82 4, 4 'Η Η CH ₂ (3-CF ₃ C ₆ H ₄ )

77 83 4, 4 'Η Η CH ₂ (2-CF ₃ C ₆ H ₄ )

CH ₂ (3,5-

78 84 4, 4 'Η Η

CI2C6XI3 Table 2 (continued)

 Compound

Example Rib R ²

―No. 1

 79 85 4, 4 'H H

84 90 4, 4, HH

Table 3

4表

Table 4

Example Chemical compound replacement

R ^la RR ³

 Number Number Position

HH CH ₃ OH

88 94 Q, HH CH. 34-Cl ₂ C _G H ₃ CH ₂₀

 y4 ππ 4 '4' X nJ t 13r.Π3 N XI 2

Q K Π 1 4, 4 X inJ XJ

 l 13 n 3

4, 4 XT tr

 JX3 _ JTL3 ノ 2

Q7

 y / 4, 4 XX 1 TT TT 2

 0 / ~ \

98 104 4, 4 'HH CH ₃ N 0

_ _ /

 100 1U6 4, 4 'H H then _b 3

 101 107 4, 4 'J! Rl

102 lUo 4, 4 xl ± 1 3 3 2 n

I HQ 4, 4 X nT XJ

 n _ XI 2 I 2 _

 1 10 4, 4 (Η

105 111 4, 4 'H H H OH

106 112 4, 4 'H H = 0

 107 113 3, 3 'H H H OH

108 114 3, 3 'H H = 0

109 115 4, 4 'HH CH ₃ CF ₃

 111 117 3, 4 'H H = 0

112 118 2, 4 'HH = 0 9S

Ο¾Ο ^ε Η ⁹ 0 ² ΟΝ

 H H H, 'f Lfl Ifl

Ο ^ε ΗΟ ^ε Η ⁹ 0 ³ ΟΝ-ε-ΐΟ- ^ HHH, '9tl

 H H H <f 'f fl

Ο¾Ο ^ε Η ⁹ 3¾-9'2 HHH <f 'ffl

Ο ² ΗΟ ^ε Η ⁹ 0¾-3'2 HHH ₍ f 'f £ l

 H H H ^ 'f Zfl 9ετ

Ο¾Ο ^ε Η ⁹ 0 ² ΐΟ-9 ^ HHH 'f I l

 H H H, 'f o ετ

O ^z H3 ^e H ⁹ O ^s 10-8'2 HHH _t 'βετεετ

^{Ο ε ΗΟ · Ή 9 ί HHH} , S £ l ^ ετ

Ο ^ζ Η0 ^ε Η ⁹ 0 ^ε (Ο ^ε Η0) · ε HHH, f 'f L £ l τετ

0¾0¾ ⁹ 00¾0-8 HHH 'f 921 οετ

Ο¾0 "Η ⁹ 0Ο¾0-3 HHH <'£ l 6ΖΙ

 H H H <'f £ l ΖΙ

0¾0¾ ⁹ 0 ^ -5-¾0-8 HHH 'f εετ LZI

0¾0¾ ⁹ 3 ^ ¾0) -9'2 HHH 'f 9ΖΙ

 U H H 6 H xl iV V θ6 I COL

O¾0 ⁸ H ⁹ 0¾-S '£ HHH ZZl

O¾D "H ⁹ 0I0-2 HHH _t 'OZl ο¾ο ^ε Η ⁹ ο¾-ε'2 HHH' f ZI 6Π ο¾θΉ ⁹ οτο-ε HHH ₍ 'fZl 8TT

O ^s HO "H ⁹ OIO- ^ HHH _t f 'f £ Zl Lll

O ² HO ^E H ⁹ O ^s IO-f '£ HHH ZZl 9TT

² ( ^G HO) HOO HHH 'f IZl STT

t SLO / OOdt / Ud ILLO iO OAV Table 4 (continued)

 Medium / Kll le eight / Μπ

 Replace

R ^lb R ³ R ⁴ No. """position

 142 148, A 'H H H 3-NO2C6H4CH2O

143 149 A, A * x ^f HHH 2,4-Cl ₂ C ₆ H ₃ CH ₂ O

144 150 A 4 'H H H 3-CF3C6H4CH2O

145 151 A 4 'H H H 3-CH3C6H4CH2O

146 152 4 4 'H H H 4-CF3C6H4CH2O

147 153 4 4 'H H H 3-CNC6H4CH2O

148 154 A, A ^y HHH 4-CH3SC6H4CH2O

149 155 'AA ^f HHH 3,5 CI2C6H3CH2O

151 157, 4. 'HHH 2,5-Cl ₂ C ₆ H ₃ CH2O

152 158, H H H 4-CH3C6H4CH2O

153 159 * ±, * ± HHH _3, 5- (CF ₃ ) ₂ C ₆ H ₃ CH2O

154 160 4 4 'H H H 4-CH3O2CC6H4CH2O

155 161 4 4, HHH 3,4- (CH3) 2C _G H ₃ CH2O

156 162 4 'H H H 4-CF3OC6H4CH2O

157 163 * ±, * ± H H H cyclohexylmethyloxy

158 164 4 4 'H H H cyclopentylmethyloxy

159 165 HHH 3,4-Cl2C (iH3CH ₂ CH ₂ O

160 166 4, 4 'H H H 4-F-2-CF3C6H3CH2O

161 167 4: 4, H H H 2-F-4-CF3C6H.3CH2O

162 168 4, 4 'H H H 2-F-3-CF3C6H3CH2O

163 169 4, 4 'H H H 4-F-3-CF3C6H3CH2O

164 170 4, 4 'H H H 2-F-5-CF3C6H3CH20

165 171 4, 4 'H H H cyclohexyloxy

166 172 4, 4 'H H H 3-F-4-CF3C6H3CH2O

167 173 4, 4, H H H 2-CHF2OC6H4CH2O

168 174 4, 4 'H H H 4-CHF2OC6H4CH2O

169 175 4, 4 'H H H 4-CF3SC6H4CH2O

170 176 4, 4 'H H H 2-F-6-CF3C6H3CH2O

171 177 4, 4, HHH ₂ , 4- (CF ₃ ) ₂ C ₆ H ₃ CH ₂₀ Table 4 (continued)

 Lily

RR ⁴

R ^{1 b} — N f NR ^{1 a}

 0 Z 2 4 0

⁴ '3' 3

 Example Compound Substitution

R ^la R ^lb R ³ R ⁴

 Number

172 178 4, 4 'HH CF ₃ OH

173 179 3, 3 'HH CF ₃ OH

174 180 4, 4, HH CF ₃ OCH ₃

175 181 3, 3, H H H OCHs

Next, the pharmacological activity of the representative compound (I) will be described in 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 Pat. No. 5760062). That is, a DMS0 solution of a test compound is mixed with telomerase obtained by partially purifying a nuclear extract derived from HEK293 cells in the presence of oligodoxynucleotide and deoxynucleotide triphosphate as substrates. I had a base. The obtained reaction product (DNA having a telomere sequence) was adsorbed on a membrane, and hybridization was performed using a lapelated 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 (control) of the test compound. The concentration of the compound that inhibits the enzyme activity by 50% relative to the control was defined as _IC5fl . By the above-mentioned method, compounds 3, 4, 16, 18, 43, 52, 56, 57, 92, 97, 100, 106, 110, 114, 122, 141 and 182 are represented as typical compounds of the present invention. It showed an IC _5fl value of 50 mol / L or less. Test Example 2 In vivo telomerase inhibitory activity

After contacting the test compound with the human kidney cancer cell line ACHN for 3 days, a cell extract was prepared by a known method (US Pat. No. 5,629,154), and the enzyme activity was measured. Sand A cell extract was prepared using a buffer containing 0.5% CHAPS (3-[(3-colamidopropyl) dimethylammonio] -1 propanesulfonic acid). By using the extract, TRAP in in vitro (Telomeric Repeat Amplification Protocol) Atsusi was (Intergen ^{_{Co., TRAP EZE TM EL ISA Telomerase Detection}} Kit) for enzyme activity of the extract from _c test compound untreated cells The ratio (%) of the enzyme activity value of the extract from the test compound-treated cells was calculated. By the above method, Compound 5 of the present invention inhibited telomerase activity by 50% or more at 30 / mol / L.

 As described above, compound (I) has excellent telomerase inhibitory activity, and is useful as a therapeutic agent for diseases associated with telomerase activity such as malignant tumors.

BEST MODE FOR CARRYING OUT THE INVENTION

 Examples will be described below. The physicochemical data of each compound in the following Examples and Reference Examples were measured by the following instruments.

 Thigh: JEOL Lambda 300 (300 MHz) / JE0L JNM-EX270 (270 MHz) / JE0L JNM-GX270 (270 MHz)

 FABMS: JEOL JMS-HX110

 ESIMS: Micro thigh ss Quattro Example 1 (Compound 1)

 2,2 ': 5,, 2 "-fuichiofen-5,5, -dicarboxyaldehyde (152 mg, 0.500 mmol), 2,4-thiazolidinedione (176 mg, 1.50 mmol), and Lysine (0.099 mL, 1.0 mL) was heated and refluxed for 4 hours in ethanol (8 mL) The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration to give Compound l (263 mg, quantitative). ) Got.

^! H NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.48 (s, 2H), 7.5-7.6 (m, 4H), 7.81 (br s, 2H)

FABMS m / z 501 (M—H)-C ₂₀ H ₁₀ N ₂ 0 ₄ S ₅ = 502

Example 2 (Compound 2)

4,4, -Diformyl rifenylamine obtained in Reference Example 1 (371 mg, 1.23 mmol), 2,4-thiazolidinedione (433 mg, 3.70 mmol), and piperidine (0.245 mL, 2.46 mmol) was heated under reflux in ethanol (12 mL) for 2.5 hours. The reaction solution was cooled to room temperature, added with 1 mol / L hydrochloric acid (2 mL), and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate / isopropyl ether to obtain Compound 2 (379 mg, 62%).

^! H NMR (300 MHz, DMSO- d ₆ ) δ (ppm) 7.12 (d, J = 8.8 Hz, 4H), 7.17 (d, J = 7.3 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H ), 7.44 (t, J = 7.5 Hz, 2H), 7.54 (d, J = 8.8 Hz, 4H), 7.92 (s, 2H), 12.5 (br s, 2H)

^{FABMS m / z 499 (M +} ) C 26 H 17 N 3 0 4 S 2 = 499

Example 3 (Compound 3)

Tris (4-formylphenyl) amine (66 mg, 0.20 thigh 01), 2,4-thiazolidinedione (117 mg, 1.00 mmol) and piperidine (0.099 mL, 1.0 thigh ol) obtained in Reference Example 1 were added to ethanol. (8 mL) and refluxed for 7 hours. The reaction solution was cooled to room temperature, added with lmol / L hydrochloric acid (I mL), and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / hexane to obtain Compound 3 (83 mg, 66%). 'Η NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.21 (d, J = 8.8 Hz, 6H), 7.60 (d, J = 8.8 Hz, 6H), 7.75 (s, 3H), 12.6 (br s, 3H)

FABMS m / z 627 (M + H) + C 3. _{H 18 N 4 0 6 S 3} = 626

Example 4 (Compound 4)

 4-Promo-4 ', 4 "-diformyltriphenylamine (231 mg, 0.608 mmol), 2,4-thiazolidinedione (214 mg, 1.80 mmol) obtained in Reference Example 2, and piberidine (0.122 mL, 1.22 mmol) was heated under reflux in ethanol (8 mL) for 7 hours, the reaction solution was cooled to room temperature, lmol / L hydrochloric acid (I mL) was added, and the mixture was extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with hexane / isopropyl ether to obtain Compound 4 (347 mg, 99%).

1 NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.11 (d, J = 8.8 Hz, 2H), 7.14 (d, J two 8.8 Hz, 4H), 7.56 (d, J = 8.6 Hz, 4H) , 7.58 (d, J = 8.8 Hz, 2H), 7.73 (s, 2H), 12.5 (br s, 2H)

FABMS m / z 579, 577 ( M +) C 26 H 16 79 BrN 3 0 4 S 2 = 577

Example 5 (Compound 5)

 4- [bis (4-formylphenyl) amino] biphenyl (27 mg, 0.072 mmol), 2,4-thiazolidinedione (25 mg, 0.21 mmol) and piperidine (0,014 mL, 0.14 t) obtained in Reference Example 3 ol) was heated to reflux in ethanol (3 mL) for 3 hours. The reaction solution was cooled to room temperature, lmol / L hydrochloric acid (1mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, purified by preparative thin-layer chromatography (10: 1 chloroform / methanol), and triturated with hexane / isopropyl ether to give compound 5 (32 mg, 17%).

^! H NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.18 (d, J = 8.6 Hz, 4H), 7.24 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H ), 7.47 (dd, J = 7.9, 7.2 Hz, 2H), 7.57 (d, J = 8.8 Hz, 4H), 7.6-7.8 (m, 4H), 7.74 (s, 2H), 12.5 (br s., 2H) FABMS m / z 574 ( M- H) - C 32 H 21 N 3 0 4 S 2 = 575

Example 6 (Compound 6)

 2- {4- [bis (4-formylphenyl) amino] phenyl} furan (20 mg, 0.054 mmol), 2,4-thiazolidinedione (19 mg, 0.16 mmol) obtained in Reference Example 4, and pyridine Compound 6 (15 mg, 49%) was obtained from lysine (0.011 mL, 0.11 mmol) in the same manner as in Example 5.

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 6.60 (dd, J = 3.3, 1.8 Hz, 1H), 6.93 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.8 Hz, 4H), 7.19 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 4H), 7.72 (s, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 1.8 Hz, 1H), 12.5 (br s, 2H)

FABMS m / z 564 (MH) "C ₃₀ H ₁₉ N ₃ 0 ₅ S ₂ = 565

Example 7 (Compound 7)

2- {4- [bis (4-formylphenyl) amino] phenyl} thiophene (26 mg, 0.068 mmol), 2,4-thiazolidinedione (24 mg, 0.21 mmol) obtained in Reference Example 5, and From lysine (0.014 mL, 0.14 mmol), compound was obtained in the same manner as in Example 5. Compound 7 (24 mg, 60%) was obtained.

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.1-7.2 (m, 1H), 7.17 (d, J-8.6 Hz, 4H), 7.18 (d, J = 8.4 Hz, 2H), 7.50 ( d, J = 3.1 Hz, 1H), 7.5-7.6 (m, 1H), 7.57 (d, J = 8.6 Hz, 4H), 7.69 (d, J = 8.4 Hz, 2H), 7.73 (s, 2H), 12.5 (br s, 2H)

FABMS m / z 580 (M-H)-C ₃₀ H ₁₉ N ₃ 0 ₄ S ₃ = 581

Example 8 (Compound 8) ''

 4,4'-Diformyl-4 "-(hydroxymethyl) triphenylamine (44 mg, 0.13 mmol) obtained in Reference Example 6, 2,4-thiazolidinedione (46 mg, 0.39 mmol), and piperidine (0.026 mL, 0.26 mmol) was heated under reflux in ethanol (4 mL) for 3 hours, the reaction solution was cooled to room temperature, lmol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the compound 8 (40 mg, 58%) was obtained by recrystallizing from izopropyl ether. .

^J H NMR (300 MHz, DMSO- d ₆ ) δ (ppm) 4.51 (br s, 2H), 5.23 (br s, 1H), 7.11 (d, J = 8.8 Hz, 4H), 7.14 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 4H), 7.72 (s, 2H), 12.5 (br s, 2H)

FABMS m / z 528 (M_H)-C ₂₇ H ₁₉ N ₃ 0 ₅ S ₂ = 529

Example 9 (Compound 9)

 N- (4-bromobenzyl) -4,4'-diformyldiphenylamine (110 mg, 0.279 mmol), 2,4-thiazolidinedione (98 mg, 0.84 mmol) obtained in Reference Example 7, and Piperidine (0.055 mL, 0.56 mmol) was heated to reflux in ethanol (5 m for 3 hours). The reaction solution was cooled to room temperature, lmol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, followed by trituration with isopropyl ether to obtain Compound 9 (145 mg, 88%).

NM NM (300 MHz, DMSO-d ₆ ) δ (ppm) 5.16 (s, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.8 Hz, 4H), 7.52 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.8 Hz, 4H), 7.71 (s, 2H), 12.5 (br s, 2H) FABMS m / z 592, 590 ( M - H) - C 27 H 18 79 BrN 3 0 4 S 2 = 591

Example 10 (Compounds 10 and 11)

 Compound 3 (63 mg, 0.10 mmol) was dissolved in DMF (2 mL) under an argon atmosphere, and methyl iodide (0.010 mL, 0.16 mmol) and potassium tert-butoxide (22 mg, 0.20 mmol) were dissolved under ice-cooling. Was added and stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (5: 1 column-form / acetonitrile) to obtain Compound 10 (23 mg, 36%) and Compound 11 (18 mg, 28% ).

Compound 10

'Η NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 3.11 (s, 3H), 7.21 (d, J = 8.3 Hz, 6H),

7.60 (d, J = 8.3 Hz, 4H), 7.63 (d, J = 8.4 Hz, 2H), 7.75 (s, 2H), 7.88 (s,

1H), 12.6 (br s, 2H)

FABMS m / z 639 (M-H) — C ₃₁ H ₂₀ N ₄ 0 ₆ S ₃ = 640

Compound 1 1

lU NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 3.11 (s, 6H), 7.22 (d, J = 8.4 Hz, 6H),

7.60 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.6 Hz, 4H), 7.75 (s, 1H), 7.88 (s,

2H), 12.6 (br s, 1H)

FABMS m / z 653 (M-H)-C ₃₂ H ₂₂ N ₄ 0 ₆ S ₃ 654

Example 11 (Compound 12)

 4,4, -Diformyl-4 "-vinyltriphenylamine (20 mg, 0.061 mmol), 2,4-thiazolidinedione (21 mg, 0.18 mmol) and piberidine (0.012 mL, 0.12 The resulting solution was cooled to room temperature, added with lmol / L hydrochloric acid (I mL), and extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was triturated with isopropyl ether to obtain Compound 12 (16 mg, 50%).

NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 5.27 (d, J = 11.0 Hz, 1H), 5.80 (d, J = 17.4 Hz, 1H), 6.74 (dd, J = 17.4, 11.0 Hz, 1H ), 7.12 (d, J = 8.4 Hz, 2H), 7.14 (d, J 2 8.6 H, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 9.0 Hz, 4H), 7.73 (s, 2H), 12.5 (br s, 2H)

FAB S m / z 524 (M- H) one _{C 28 H 19 N 3 0 4} S 2 = 525 Example 1 2 (Compound 1 3)

 4,4'-Diformyl-4 "-hydroxytriphenylamine (52 mg, 0.16 mmoDs) obtained in Reference Example 9, 2,4-thiazolidinedione (58 mg, 0.49 mmol), and piperidine (0.032 mL, 0.32 mmol) The mixture was refluxed for 4.5 hours in ethanol (4 mL), cooled to room temperature, added with 1 mol / L hydrochloric acid (1 mL), extracted with ethyl acetate, and the organic layer was extracted with water and saturated saline. The solvent was washed, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Trituration with isopropyl ether gave Compound 13 (49 mg, 59%).

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 6.84 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 4H) , 7.51 (d, J = 9.0 Hz, 4H), 7.70 (s, 2H), 9.66 (s, 1H), 12.5 (br s, 1H)

FABMS m / z 514 (M-H) _ C ₂₆ H ₁₇ N ₃ 0 ₅ S ₂ = 515 Example 13 (Compound 14)

 4,4'-Diformyl-4 "-methoxytriphenylamine (68 mg, 0.21 mmol), 2,4-thiazolidinedione (74 mg, 0.63 mmol) obtained in Reference Example 10, and piperidine (0.042 mL) , 0.42 mmol) was heated under reflux in ethanol (4 mL) for 3 hours, the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was triturated with isopropyl ether to obtain Compound 14 (82 mg, 74%).

^! H NMR (300 MHz, DMS0-d ₆ ) ό "(ppm) 3.79 (s, 3H), 7.02 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 8.8 Hz, 4H), 7.15 ( d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 4H), 7.71 (s, 2H), 12.5 (br s, 2H)

FABMS m / z 528 (M—H) _ C ₂₇ H ₁₉ N ₃ 0 ₅ S ₂ = 529 Example 14 (Compound 15)

4-cyano-4 ', 4 "-diformyltriphenylamine (115 mg, 0.353 mmol), 2,4-thiazolidinedione (124 mg, 1.06 mmol) and piperidine (0.070) obtained in Reference Example 11 mL, 0.71 mmol) was cooled to room temperature _c reaction solution was heated to reflux for 4 hours in ethanol (6 mL), 1 mol / L hydrochloric acid (1 mL) was added and extracted with acetic acid Echiru. the organic layer was washed with water The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain Compound 15 (125 mg, 68%).

ΐ NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.16 (d, J = 8.6 Hz, 4H), 7.23 (d, J two 8.8 Hz, 4H), 7.61 (d, J = 8.8 Hz, 4H) , 7.75 (d, J = 8.6 Hz, 2H), 7.76 (s, 2H), 12.6 (br s, 2H)

FAB S m / z 523 (M—H) —C ₂₇ H ₁₆ N ₄ 0 ₄ S ₂ = 524 Example 15 (Compound 16).

 4,4'-Diformyl-4 "-methyltrifuridylamine (60 mg, 0.19 mmol), 2,4-thiazolidinedione (67 mg, 0.57 mmol) and biperidine (0.038 mL, 0.38 mmol) obtained in Reference Example 12 ) Was heated to reflux in ethanol (6 mL) for 3 hours, the reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography (6: 1 chloroform / acetonitrile), and triturated with isopropyl ether to give compound 1. 6 (63 mg, 65%) was obtained.

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 2.33 (s, 3H), 7.07 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.6 Hz, 4H), 7.25 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.8 Hz, 4H), 7.71 (s, 2H), 12.5 (br s, 2H)

FABMS m / z 512 (M- H ) _ C 27 H 19 N 3 0 4 S 2 = 513 Example 16 (Compound 17) N-aryl-4,4'-diformyldiphenylamine obtained in Reference Example 13 (1.25 g, 4.72 thigh ol), 2,4-thiazolidinedione (1.66 g, 14.2 麵 ol), and biberidine (0.93 t mL, 9.4) were refluxed for 4 hours in ethanol (40 mL). The reaction solution was cooled to room temperature, lmol / L hydrochloric acid (20 mL) was added, and the organic layer _c extracted with ethyl acetate was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate to obtain compound 17 (1.72 g, 79%).

'Η NMR (300 MHz, DMSO- d ₆ ) δ (ppm) 4.53 (br s, 2H), 5.1-5.3 (m, 2H), 5.95 (m, 1H), 7.24 (d, J = 8.8 Hz, 4H ), 7.54 (d, J = 8.8 Hz, 4H), 7.73 (s, 2H), 12.5 (br s, 2H)

^{FABMS m / z 463 (M +} ) C 23 H 17 N 3 0 4 S 2 = 463 Example 1 7 (Compound 1 8)

 2- (4-chlorophenylthio) -3,5-diformylthiophene obtained in Reference Example 14 (85 mg, 0.30 mmol), 2,4-thiazolidinedione (85 mg, 0.72 mmol) and Piperidine (0.060 mL, 0.60 mmol) was heated to reflux in ethanol (7 mL) for 5 hours. The reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (0.6 mL) was added, and the precipitated crystals were collected by filtration to obtain Compound 18 (85 mg, 59%).

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.31 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.72 (s, 1H), 7.91 (s, 1H), 8.19 (s, 1H ), 12.7 (br s, 2H) FABMS m / z 479 (M-H) - C 18 H 9 35 C1N 2 0 4 S 4 two 480 example 1 8 (compound 1 9)

 Compound 18 (18 mg, 0.037 mmol) was suspended in dichloromethane (3 mU and methanol (1 mL), and m-chloroperbenzoic acid (purity 50%; 19 mg, 0.056 mmol) was added. The insolubles were collected by filtration and washed with dichloromethane-methanol (4: 1) to give compound 19 (10 mg, 54%).

Ή NMR (300 MHz, DMS0-d ₆ ) δ (ppm) 7.72 (d, J = 8.4 Hz, 2H), 7.79 (d, J 8.4 Hz, 2H), 7.86 (s, 1H), 7.93 (s, 1H), 8.18 (s, 1H), 12.8 (br s, 2H) FABMS m / z 495 (M_H) - C 18 H 9 35 C1N 2 0 5 S 4 = 496 Example 1 9 (Compound 2 0)

 4-carboxy-4 ', 4 "-diformyltriphenylamine (458 mg, 1.33 bandol), 2,4-thiazolidinedione (464 mg, 3.97 mmol) and piperidine obtained in Reference Example 15 (0.289 mL, 2.93 mmol) was heated to reflux in ethanol (20 mL) for 6 hours, then added with piperidine (0.132 mL, 1.33 bandol) and heated to reflux for an additional 9 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (1000: 10: 1 to 500: 10: 1 to 90: 10: 1, form / solvent / water) to give Compound 2. 0 (286 mg, 39%) was obtained.

• H NMR (270MHz, DMS0- d 6) δ (ppm) 7.14 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 4H), 7.57 (d, J = 8.6 Hz, 4H) , 7.72 (s, 2H), 7.89 (d, J = 8.6 Hz, 2H), 12.67 (br s, 2H) Example 20 (Compound 21)

 Compound 20 (16.3 mg, 0.0299 ol) was suspended in dichloromethane (10 m), oxalyl chloride (O.lO mL, 1.2 mmol) was added, and the mixture was stirred at room temperature for 8 hours, and then methanol (15 mL, 370 mL) was added. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol. Then, 0.1 mol / L hydrochloric acid was added, and the resulting crystals were collected by filtration to give Compound 21. (12.0 mg, 72 mg) was obtained.

lE NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 3.82 (s, 3H), 7.15 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.9 Hz, 4H), 7.59 (d, J = 8.9 Hz, 4H), 7.73 (s, 2H), 7.91 (d, J = 8.6 Hz, 2H), 12.53 (br s, 2H) Example 21 (Compound 22)

Compound 20 (31.3 mg, 0.0574 ol) was dissolved in methanol (10 mL), and trimethylsilyldiazomethane (2.0 mol / L hexane solution; 2.0 mL, 4.0 mmol) was added. Stirred for minutes. Acetic acid (0.1 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes, and then hexane was added. I got

_{Ή NMR (270MHz, CDC1 3)} <5 (ppm) 3.25 (s, 6H), 3.91 (s, 3H), 7.16 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 4H) , 7.45 (d, J: 8.6 Hz, 4H), 7.85 (s, 2H), 7.98 (d, J = 8.6 Hz, 2H) Example 22 (Compound 23)

 In the same manner as in Example 20, compound 23 (18.6 mg, 78%) was obtained from compound 20 (23.8 mg, 0.0438 acetyl) and ethanol (1.0 mL, 17 faces).

Ή NMR (270MHz, DMS0-d ₆ ) (5 (ppm) 1.30 (t, J = 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H) , 7.19 (d, J = 8.7 Hz, 4H), 7.58 (d, J = 8.7 Hz, 4H), 7.73 (s, 2H), 7.91 (d, J = 8.7 Hz, 2H), 12.55 (br s, 2H Example 23 (Compound 24)

 Compound 24 (62.8 mg, 72%) was obtained from compound 20 (80.5 mg, 0.148 mmol) and 2-propanol (5.0 mL, 65 mmol) in the same manner as in Example 20. .

NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.30 (d, J = 6.3 Hz, 6H), 5.12 (septet, J = 6.3 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 4H), 7.57 (d, J = 8.7 Hz, 4H), 7.71 (s, 2H), 7.89 (d, J = 8.7 Hz, 2H), 12.56 (br s, 2H) Example 24 (Compound 25)

 Compound 25 (55.3 mg, 54%) was obtained from compound 20 (92.9 mg, 0.171 mmol) and 2-methyl-2-propanol (5.0 mL, 53 mmol) in the same manner as in Example 20. .

Ή Anonymous (270 MHz, Keio _{0- d 6) 5 (ppm)} 1.52 (s, 9H), 7.14 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 4H), 7.57 (d, J = 8.4 Hz, 4H), 7.72 (s, 2H), 7.85 (d, J = 8.4 Hz, 2H), 12.57 (br s, 2H) Example 25 (Compound 26) Compound 26 (80.0 mg, 79%) was obtained in the same manner as in Example 20 from compound 20 (102 mg, 0.186 cited ol) and a 7 mol / L ammonia-methanol solution (4 mL, 28 mmol).

Ή NMR (270MHz, DMS0-d _fi ) 5 (ppm) 3.31 (br s, 2H), 7.10-7.20 (m, 6H), 7.56 (d, J = 8.9 Hz, 4H), 7.73 (s, 2H), 7.87 (d, J = 8.7 Hz, 2H), 12.53 (br s, 2H) Example 26 (Compound 27)

Compound 27 (69.5 mg, 67%) was obtained from Compound 20 (102 mg, 0.186 mmol) and a 40% methylamine-methanol solution (4 mL) in the same manner as in Example 20. ^l E NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.27 (d, J = 4.3 Hz, 3H), 7.14 (d, J =

8.7 Hz, 4H), 7.15 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.7 Hz, 4H)., 7.72 (s, .2H), 7.83 (d, J = 8.7 Hz, 2H) , 8.39 (br q, J = 4.3 Hz, 1H), 12.54 (br s, 2H) Example 27 (Compound 28)

 In the same manner as in Example 20, Compound 28 (65.9 mg, 62%) was obtained from Compound 20 (102 mg, 0.186 ol) and a 40% aqueous solution of dimethylamine (4 mL).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.97 (s, 6H), 7.08-7.20 (m, 6H), 7.42 (d, J-8.4 Hz, 2H), 7.55 (d, J = 8.9 Hz , 4H), 7.72 (s, 2H), 12.54 (br s, 2H) Example 28 (Compound 29)

 In the same manner as in Example 20, compound 29 (81.4 mg, 71%) was obtained from compound 20 (102 mg, 0.186 mmol) and aniline (0.068 mL, 0.75 tmol).

^ Thigh _{(270MHz, DMS0-d 6)} d (ppm) 7.00-7.26 (m, 7H), 7.33 (dd, J = 7.8,

7.8 Hz, 2H), 7.58 (d, J 2 8.9 Hz, 4H), 7.70-7.80 (m, 4H), 7.96 (d, J = 8.7 Hz, 2H), 10.20 (br s, 1H), 12.53 (br s, 2H) Example 29 (Compound 30)

Compound 30 (80.6 mg, 74%) was obtained from compound 20 (102 mg, 0.186 tmol) and 2-aminoenoethanol (0.045 mL, 0.75 mmol) in the same manner as in Example 20 < Ή NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 3.32 (dt, J = 5.6, 5.8 Hz, 2H), 3.49 (t, J2 5.8 Hz, 2H), 4.70 (br s, 1H), 7.15 ( d, J = 8.6 Hz, 4H), 7.16 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 4H), 7.73 (s, 2H), 7.86 (d, J = 8.6 Hz, 2H), 8.39 (br t, J = 5.6 Hz, 1H), 12.54 (br s, 2H) Example 30 (Compound 31)

 In the same manner as in Example 20, compound 31 (35.6 mg, 32%) was obtained from compound 20 (102 mg, 0.186 r ol) and butylamine (0.019 mL, 0.75 t ol).

■ H NMR (270MHz, D S0-d ₆ ) d (ppm) 0.89 (t, J = 7.2 Hz, 3H), 1.23-1.55 (m, 4H), 3.24 (dt, J = 5.4, 6.6 Hz, 2H) , 7.10-7.22 (m, 6H), 7.56 (d, J = 8.6 Hz, 4H), 7.73 (s, 2H), 7.84 (d, J = 8.6 Hz, 2H), 8.40 (brt, J = 5.4 Hz , 1H), 12.55 (br s, 2H) Example 31 (Compound 32)

Compound 32 (22.6 mg, 20%) was obtained from compound 20 (101 mg, 0.185 mmol) and ethylamine (0.076 mL, 0.73 ol) in the same manner as in Example 20. ^{: H NMR (270MHz, DMS0-} d B) 6 (ppm) 1.11 (t, J = 6.9 Hz, 6H), 3.10-3.50 (m, 4H), 7.16 (d, J = 8.6 Hz, 4H), 7.16 ( d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 4H), 7.72 (s, 2H), 12.53 (br s, 2H) 3 2 (Compound 3 3)

 Compound 33 (15.2 mg, 14%) was obtained from compound 20 (101 mg, 0.185 mmol) and pyrrolidine (0.061 mL, 0.73 mmol) in the same manner as in Example 20.

ΐ NMR (270MHz, DMSO- d ₆ ) d (ppm) 1.70-1.90 (m, 4H), 3.40-3.50 (m, 4H), 7.14 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz, 4H), 7.54 (d, J 2 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 4H), 7.72 (s, 2H), 12.54 (br s, 2H) Example 33 (Compound 34)

 Compound 34 (23.3 mg, 21%) was obtained from compound 20 (101 mg, 0.185 mmol) and piberidine (0.073 mL, 0.73 mmol) in the same manner as in Example 20.

Ή NMR (270MHz, D S0-d ₆ ) δ (ppm) 1.20-1.44 (m, 6H), 3.00-3.50 (m, 4H), 6.97 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.6 Hz, 4H), 7.20 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.6 Hz, 4H), 7.54 (s, 2H), 12.35 (br s, 2H) Example 34 (compound 35)

 In the same manner as in Example 20, compound 35 (5.5 mg, 5%) was obtained from compound 20 (101 mg, 0.185 tmol) and piperazine (0.139 mL, 1.62 mmol).

Ή NMR (270MHz, DMS0-d 6) (5 (ppm) 3.60-3.90 (m, 4H) ,. 4.20-4.50 (m, 4H), 7.80-7.90 (m, 6H), 8.15 (d, J = 8.6 Hz, 2H), 8.23 (s, 2H), 8.24 (d, J = 8.2 Hz, 4H), 10.72 (br s, 1H) Example 35 (compounds 36, 37)

 4-carboxy-4 ', 4 "-diformyltriphenylamine obtained in Reference Example 15

(6.19 g, 17.9 mmol), 2,4-thiazolidinedione (8.39 g, 71.6 ol) and piperidine (14.2 mL, 137 mmol) in ethanol (100 mL) under nitrogen atmosphere for 22 hours After the reflux, the reaction solution was cooled to room temperature, 6 mol / L hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

(400: 10: 1 to 200: 10: 1 to 100: 10: 1 pore form / methanol / water) to give an orange solid (2.32 g). A part (1.01 g) of the obtained orange solid was suspended in dichloromethane (100 mL), oxalyl chloride (0.807 mL, 9.25 ol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was evaporated under reduced pressure, redissolved in tetrahydrofuran (10 mL), added with morpholine (1.39 mL, 14.8 t ol)), stirred at the same temperature for 10 hours, and added water and 6 mol / l to the reaction solution. L Hydrochloric acid was added, and the precipitated crystals were collected by filtration, dried, and separated by preparative thin-layer chromatography (90: 10: 1 chloroform-form-formanol / water) and Purification by preparative HPLC (0DS, 20:80 acetonitrile / 0.3% aqueous ammonia), 6 mol / L hydrochloric acid was added, and the resulting crystals were collected by filtration to give Compound 36 (67.2 mg, 1%) and Compound 37 (197 mg, 4%) was obtained.

Compound 3 6

lU NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 3.40-3.70 (m, 8H), 7.12-7.22 (m, 6H), 7.42 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.9 Hz, 4H), 7.72 (s, 2H), 12.54 (br s, 2H)

Compound 3 7

Ή NMR (270MHz, DMS0-d _B ) δ (ppm) 3.11 (dd, J = 9.6, 14.2 Hz, 1H), 3.30 -3.62 (m, 9H), 4.90 (dd, J = 4.5, 9.6 Hz, 1H) , 6.99 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7,68 (s, 1H), 12.06 (br s, 1H), 12.48 (br s, 1H) 6 (compounds 38, 39, 40)

Step 1: Triphenylamine (5.24 g, 21.4 mmol) was dissolved in chloroform (50 mL) and cooled to 0 ° C. Next, concentrated nitric acid (2.33 mL, 32.1 tmol) was added, and the mixture was stirred at the same temperature for 30 minutes, heated to room temperature, and stirred at the same temperature for 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate (100 mL) was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from isopropyl ether (250 mL) to obtain 4-nitrotriphenylamine (3.02 g, 49%).

_{^{! H NMR (270MHz, CDC1 3}} ) ά (ppm) 6.92 (d, J = 9.6 Hz, 2H), 7.15-7.24 (m,

6H), 7.30-7.40 (m, 4H), 8.03 (d, J = 9.6 Hz, 2H)

Step 2: In the same manner as in Step 2 of Reference Example 15 from the above compound (2.83 g, 9.76 mmol) and hexamethylenetetramine (6.85 g, 48.9 mmol), 4,4'-diformyl-4 "-nitro Triphenylenylamine (967 mg, 21%) was obtained.

Ή Yuzuru _{(270MHz, CDC1 3) 5 (} ppm) 7.20 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.6

Hz, 4H), 7.87 (d, J = 8.6 Hz, 4H), 8.18 (d, J = 8.9 Hz, 2H), 9.97 (s, 2H) Step 3: The above compound (1.59 g, 4.58 mmol), 2,4-thiazolidinedione (2.15 g, 18.4 mmol), and piperidine (3.6 mL, 36 mmol) were mixed with argon (30 mL) under an argon atmosphere. The mixture was heated under reflux for 22 hours. The reaction solution is cooled to room temperature, water and 6 mol / L hydrochloric acid are added, and the crystals are collected by filtration, dried, and purified by silica gel column chromatography (100: 1 to 50: 1 chloroform / methanol) and preparative HPLC ( Purification with 0DS, 20:80 acetonitrile / 0.3% aqueous ammonia) gave compound 38 (30.1 mg, 1%), compound 39 (116 mg, 5%) and compound 40 (133 mg, 5%). Was.

Compound 3 8

^{! H NMR (270MHz, DMS0 -} d 6) δ (ppm) 7.14 (d, J two 9.2 Hz, 2H), 7.29 ( d, J = 8.9 Hz, 4H), 7.64 (d, J = 8.9 Hz, 4H) , 7.76 (s, 2H), 8.15 (d, J = 9.2 Hz, 2H), 12.60 (br s, 2H)

Compound 39

Ή NMR (270 MHz, DMS0-d ₆ ) (5 (ppm) 3.12 (dd, J: 9.6, 14.2 Hz, 2H), 3.41 (dd, J = 4.3, 14.2 Hz, 2H), 4.91 (dd, J-4.3 , 9.6 Hz, 2H), 6.73 (d, J = 9.2 Hz, 2H), 7.18 (d, J = 8.6 Hz, 4H), 7.32 (d, J = 8.6 Hz, 4H), 8.05 (d, J2 9.2) Hz, 2H), 12.07 (br s, 2H)

Compound 40

Ή NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 3.14 (dd, J = 9.4, 14.2 Hz, 1H), 3.43 (dd, J-4.3, 14.2 Hz, 1H), 4.92 (dd, J = 4.3, 9.4 Hz, 1H), 6.97 (d, J = 9.2 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz , 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.74 (s, 1H), 8.10 (d, J = 9.2 Hz, 2H), 12.00-12.70 (m, 2H) Example 37 (compound 41 )

Compound 38 (155 mg, 0.347 ol) and tin (11) chloride dihydrate (417 mg, 1.85 benzyl) were stirred in DMF (10 mL) at 70 ° C for 6 hours. The reaction solution was cooled to room temperature, water and 6 mol / L hydrochloric acid were added, and the mixture was extracted with chloroform / methanol. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (100: 1 to 50: 1 gel form / methanol). The compound 41 (107 mg, 74%) was obtained.

^! H賺_{(270MHz, DMS0-d 6)} d (ppm) 6.61 (d, J = 8.7 Hz, 2H), 6.86 (d, J: 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 4H) , 7.48 (d, J = 8.7 Hz, 4H), 7.67 (s, 2H), 12.50 (br s, 1H) Example 38 (Compound 42)

 Compound 41 (53.8 mg, 0.104 mmol) was suspended in dichloromethane (10), acetyl chloride (0.074 mL, 1.04 recited ol) and triethylamine (0.072 mL, 0.52 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water and 6 mol / L hydrochloric acid were added to the reaction solution, and the mixture was extracted with black hole form. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, a 3.5 mol / L ammonia solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform (form Z). The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound 42 (59.5 mg, 100%).

! H NMR (270 MHz, DMS0-d ₆ ) d (ppm) 2.04 (s, 3H), 7.09 (d, J = 8.6 Hz, 4H), 7.11 (d, J = 8.6 Hz, 2H), 7.52 (d, J 2 8.6 Hz, 4H), 7.63 (d, J = 8.6 Hz, 2H), 7.69 (s, 2H), 10.04 (br s, 1H), 12.51 (br s, 2H) Example 39 (compound 43, 44)

 In the same manner as in Step 3 of Example 36, N- (tert-butoxycarbonyl) -4,4'-diformyldiphenylamine (8.08 g, 24.8 mmol) and 2,4 obtained in Reference Example 16 were obtained. Compound 43 (160 mg, 14%) and compound 44 (75.4 mg, 7%) were obtained from -thiazolidinedione (7.30 g, 62.3 mmol).

Compound 43

^{! H NMR (270MHz, DMS0-} d 6) d (ppm) 1.40 (s, 9H), 7.33 (d, J = 8.6 Hz, 4H), 7.59 (d, J = 8.6 Hz, 4H), 7.76 (s, 2H), 12.60 (br s, 2H)

Compound 44

Ή NMR (270MHz, DMS0-d 6) d (ppm) 1.37 (s, 9H), 3.13 (dd, J = 9.2, 14.1 Hz, 1H), 3.22-3.41 (m, 1H), 4.91 (dd, J two 4.4, 9.2 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 7.55 (d, J two 8.6 Hz, 2H), 7.73 (s, 1H), 12.03 ( br s, 1H), 12.54 (br s, 1H) Example 40 (Compound 45)

 Compound 45 (252 mg, 40%) was obtained from compound 43 (705 mg, 1.50 recited ol) in the same manner as in Reference Example 17.

^{! HNR (270MHz, DMS0-d} 6) δ (ppm) 7.28 (d, J = 8.6 Hz, 4H), 7.52 (d, J = 8.6 Hz, 4H), 7.70 (s, 2H), 9.33 (br s, 1H), 12.45 (br s, 2H) Example 4 1 (Compound 46)

 Compound 45 (51.6 mg, 0.140 mmol) was suspended in dichloromethane (5 mL), and bivaloyl chloride (0.060 mL, 0.48 mmol) and 4-dimethylaminopyridine (71 mg, 0.58 fold) were added. Stir for 12 hours. Hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (closure form) to obtain Compound 46 (47.5 mg, 57%).

^J H NMR (270 MHz, D S0-d ₆ ) δ (ppm) 1.27 (s, 18H), 7.32 (d, J = 8.9 Hz, 4H), 7.59 (d, J = 8.9 Hz, 4H), 7.88 (s , 2H), 9.51 (s, 1H) Example 42 (compounds 47, 48)

 Compound 45 (50.9 mg, 0.138 t) was suspended in dichloromethane (10 m), trityl chloride (189 mg, 0.677 face) and triethylamine (0.077 mL, 0.56 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure, and purified by silica gel column chromatography (Cloform form) and preparative thin-layer chromatography (20: 20: 1 hexane / Cloform form / methanol) to obtain compound 47 (78.5 mg, 678.5 mg, 67%). %) And compound 48 (11.9 mg, 14%).

Compound 4 7

^{! H NMR (270MHz, DMS0-} d 6) δ (ppm) 7.12-7.30 (m, 22H), 7.40-7.52 (m 5 16H), 7.69 (s, 2H), 9.36 (s, 1H) Compound 48

^{! H NMR (270MHz, DMS0-} d 6) 6 (ppm) 7.12-7.32 (m, 13H), 7.40-7.55 (m, 10H), 7.69 (s, 2H), 9.33 (s, 1H), 12.46 (br s, 1H) Example 43 (Compound 49)

 In the same manner as in Example 42, Compound 49 (471 mg, 88%) was obtained from Compound 45 (231 mg, 0.546 ol) and 2-chloromethylphenyldiphenylmethyl chloride (521 mg, 1.66 mmol). Obtained.

Ή thigh _{(270MHz, CDC1 3) (5} (ppm) 7.10-7.50 (m, 36H), 7.71 (s, 2H) Example 44 (Compound 5 0)

 Compound 47 (178 mg, 0.196 mmol) was dissolved in tetrahydrofuran (5 mL), potassium tert-butoxide (55.4 mg, 0.494 mol) was added, and the mixture was stirred at room temperature for 10 minutes. Then, methyl iodide (0.050 mL, 0.803 mol) was added, and the mixture was stirred at the same temperature for 0.1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline 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: 20: 1 hexane / chloroform / methanol) to obtain an orange solid (105 mg). The obtained solid was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform to give Compound 50 (34.0 mg, 40%).

1 accessories (270 MHz, DMS0-d ₆ ) δ (ppm) 3.40 (s, 3H), 7.23 (d, J = 8.7 Hz, 4H), 7.54 (d, J = 8.7 Hz, 4H), 7.73 (s, 2H ), 12.49 (br s, 2H) Example 45 (Compound 51)

In the same manner as in Example 44, compound 51 (28.9 mg, 38%) was obtained from compound 47 (154 mg, 0.170 ol) and thiol iodide (0.200 mL, 2.49 mmol). H NMR (270MHz, DMS0-d 6) ((ppm) 1.16 (t, J = 7.0 Hz, 3H), 3.91 (q, J = 7.0 Hz, 2H), 7.20 (d, J = 8.7 Hz, 4H), 7.54 (d, J = 8.7 Hz, 4H), 7.72 (s, 2H), 12.49 (br s, 2H) Example 4 6 (Compound 52)

Step 1: Diphenylamine (2.04 g, 12.1 ol) was dissolved in DMF (10 m), 60% sodium hydride mineral oil dispersion (1.03 g, 25.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Isopropyl iodide (1.81 mL, 18.1 mol) was added, and the mixture was stirred at room temperature for 26 hours, 6 mol / L hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, dissolved in hexane (200 mL), washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. And purified by silica gel column chromatography (50: 1 to 20: 1 hexane / ethyl acetate) and preparative thin-layer chromatography (9: 1 hexane / ethyl acetate). Diphenylamine (288 mg, 7%) was obtained.

_{NMR (270MHz, CDC1 3) 5} (ppm) 1.15 (d, J = 6.3 Hz, 6H), 4.32 (septet, J = 6.3 Hz, 1H), 6.80- 6,88 (m, 4H), 6.92-7.02 ( m, 2H), 7.22-7.32 (m, 4H) Step 2: The above compound (252 rag, 0.770 mmol) was dissolved in chloroform (5 mL) and tetra-n-butylammonium tribromide (833 mg, 1.73 ol) and stirred at room temperature for 1.5 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100: 1 to 20: 1 hexane / ethyl acetate) to give N-isoprovir-4,4'-dibumododiphenylamine. (319 mg, 85%).

_{Έ NMR (270MHz, CDC1 3)} d (ppm) 1.13 (d, J = 6.6 Hz, 6H), 4.23 (septet, J = 6.6 Hz, 1H), 6.70 (d, J = 8.9 Hz, 4H), 7.36 ( d, J = 8.9 Hz, 4H) Step 3: In the same manner as in Step 2 of Reference Example 6, N-isopropyl-4 was obtained from the above compound (375 mg, 0.774 tmol) and DMF (0.20 mL, 2.6 mmol). , 4'-Diformyldiphenylamine (209 mg, 100%) was obtained.

_{1 NMR (270MHz, CDC1 3)} δ (ppm) 1.23 (d, J = 6.6 Hz, 6H), 4.48 (septet, J = 6.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 4H), 7.83 ( d, J = 8.6 Hz, 4H), 9.91 (s, 2H)

Step 4: The above compound (203 mg, 0.757 ol), 2,4-thiazolidinedione (424 mg, 3.62 mmol), and potassium tert-butoxide (653 mg, 5.82 mmol) were added to N, N-dimethylacetamide ( (5 mL) at room temperature for 21 hours. Methanol (5 mL), water (30 mL) and 6 mol / L hydrochloric acid (4 mL) were sequentially added to the reaction solution, and the resulting crystals were collected by filtration and silica gel column chromatography (100: 1 to 20: 1 gel form). / Methanol) to obtain Compound 52 (61.2 mg, 17%).

l NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.12 (d, J = 6.3 Hz, 6H), 4.46 (septet, J = 6.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 4H), 7.83 (d, J = 8.6 Hz, 4H), 9.91 (s, 2H) Example 47 (Compound 53)

Step 1: N, N-diphenylbenzylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL), hexamethylenetetramine (1.12 g, 7.96 fractions) was added, and the mixture was stirred at 90 ° C for 12 hours. Stirred. The reaction solution was cooled to room temperature, a 6 mol / L sodium hydroxide aqueous 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 (20: 1 to 10: 1 hexane / ethyl acetate). N-Penzyl-4,4, -diformyldiphenylamine (100 mg, 9%).

_{^ NMR (270MHz, CDC1 3)} (5 (ppm) 5.16 (s, 2H), 7.20-7.36 (m, 9H), 7.79 (d, J = 8.9 Hz, 4H), 9.86 (s, 2H)

Step 2: In the same manner as in Example 19, compound 53 (46.8 mg, 51%) was obtained from the above compound (61.8 mg, 0.196 mmol) and 2,4-thiazolidinedione.

'Η NMR (270 MHz, DMS0-d ₆ ) d (ppm) 5.18 (s, 2H), 7.16-7.36 (m, 9H), 7.51 (d, J = 8.6 Hz, 4H), 7.69 (S, 2H), 12.47 (br s, 2H) Example 48 (Compound 54)

Compound 49 (148 mg, 0.151 mmol) was dissolved in THF (10 mL) and cooled to -78 ° C. Then n-butyllithium (1.60 mol / L hexane solution; 0.25 mL, 0.40 mmol) and stirred at the same temperature for 1.5 hours. Then, 2-chlorobenzyl bromide (0.150 mL, 1.16 ol) was added, and the mixture was stirred at the same temperature for 10 minutes, then heated to room temperature, and stirred at the same temperature for 5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline 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: 20: 1 hexane / chloroform / methanol) to obtain a yellow solid (23.4 mg). The obtained solid was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 3 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 obtain Compound 54 (3.2 mg, 4%). ^{! H NMR (270MHz, DMSO- d} 6) 5 (ppm) 5.18 (s, 2H), 7.26 (d, J = 8.7 Hz, 4H), 7.20-7.36 (m, 3H), 7.53 (d, J = 8.7 Hz, 4H), 7.45-7.55 (m, 1H), 7.70 (s, 2H), 12,48 (br s, 2H) Example 49 (Compound 55)

 In the same manner as in Example 48, compound 55 (3.6 mg, 6%) was obtained from compound 49 (116 mg, 0.118 awake ol) and 3-chlorobenzyl bromide (0.150 mL, 1.14 awake ol). .

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 5.19 (s, 2H), 7.27 (d, J = 8.7 Hz, 4H), 7.20-7.36 (m, 4H), 7.53 (d, J = 8.7 Hz , 4H), 7.70 (s, 2H), 12.49 (br s, 2H) Example 50 (Compound 56)

 In the same manner as in Example 48, compound 56 (11.5 mg, 15%) was obtained from compound 49 (134 mg, 0.137 marl ol) and 4-chloromethylbenzene (161 mg, 0.781 mmol). .

Ή NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 5.16 (s, 2H), 7.24 (d, J = 8.9 Hz, 4H), 7.30 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.9 Hz, 4H), 7.65 (s, 2H), 12.52 (br s, 2H) Example 5 1 (Compound 57)

In the same manner as in Example 4 8, Compound 4 7 (93.3 mg, 0.103 negation ol) and bromide 3, 4-dichloro base Njiru (0.10 mL, 0.42 thigh ol) than compound 5 7 (17.0mg ₃ 28%) I got

^! H NMR (270MHz, DMSO-dJ δ (ppm) 5.19 (s, 2H), 7.20-7.32 (m, 5H), 7.45 — 7.60 (m, 6H), 7.70 (s, 2H) ₃ 12.50 (br s, 2H) Example 52 (Compound 58)

 Compound 47 (165 mg, 0.181 ol) was dissolved in THF (5 mL), and a 0.60% sodium hydride mineral oil dispersion (107 mg, 2.67 mmol) was added, followed by stirring at room temperature for 3 hours. Then, acetyl chloride (1.0 mL, 14 tmol) was added, and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained solid was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (90: 10: 1 form / methanol / water) to obtain Compound 58 (11. mg, 14%).

Ή thigh _{(270MHz, DMS0-d 6)} δ (ppm) 1.99 (s, 3H), 7.47 (d, J = 8.4 Hz, 4H), 7.63 (d, J = 8.4 Hz, 4H), 7.76 (s, 2H ), 12.62 (br s, 2H) Example 53 (Compound 59)

In the same manner as in Example 48, compound 59 (9.8 mg, 14%) was obtained from compound 49 (132 mg, 0.135 ol) and benzoyl chloride (0.150 mL, 1.30 mmol). 'Η NMR (270MHz, DMS0-d ₆ ) δ (ppm) 7.25-7.35 (m, 1H), 7.40-7.70 (m, 8H), 7.90-7.98 (m, 6H), 12.90 (br s, 2H) Example 54 (Compound 60)

As in Example 48, Compound 60 (13.2 mg, 12%) was obtained from Compound 49 (115 mg, 0.117 ol) and 3,4-dichlorobenzoyl chloride (106 mg, 0.506 ol). I got

Ή NMR (270MHz, recommendation 0-d ₆ ) d (ppm) 7.35-7.45 (m, 5H), 7.53-7.64 (m, 5H), 7.70-7.77 (m, 3H), 12.63 (br s, 2H) Example 55 (Compound 61)

 In the same manner as in Example 48, compound 61 (3.5 mg, 5%) was obtained from compound 49 (142 mg, 0.146 mmol) and 2-furancarboxylic acid chloride (0.150 mL, 1.52 mmol).

Ή NMR (270MHz, DMS0-d ₆ ) d (ppm) 6.38 (d, J = 3.3 Hz, 1H), 6.50 (dd, J = 1.5, 3.3 Hz, 1H), 7.40 (d, J = 8.6 Hz, 4H ), 7.63 (d, J = 8.6 Hz, 4H), 7.72 (d, J = 1.5 Hz, 1H), 7.77 (s, 2H), 12.90 (br s, 2H) Example 56 (Compound 62)

Compound 62 (14.4 mg, 15%) was obtained from compound 47 (179 mg, 0.1.97 mol) and methyl chloroformate (0.100 mL, 1.29 mmol) in the same manner as in Example 52. . ■ H Anonymous _{(270MHz, DMS0-d 6)} d (ppm) 3.68 (s, 3H), 7.40 (d, J = 8.6 Hz, 4H), 7.61 (d, J = 8.6 Hz, 4H), 7.77 (s, 2H), 12.62 (brs, 2H) Example 57 (Compound 63)

In the same manner as in Example 48, compound 63 (14.5 mg, 23%) was obtained from compound 47 (113 mg, 0.125 mmol) and ethyl ethyl chloroformate (0.10 mL, 1.1 tmol). ^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.16 (t, J = 7.0 Hz, 3H), 4.16 (q, J-7.0 Hz, 2H), 7.39 (d, J = 8.6 Hz, 4H) , 7.60 (d, J = 8.6 Hz, 4H), 7.76 (s, 2H), 12.60 (br s, 2H) Example 58 (Compound 64)

In the same manner as in Example 48, compound 64 (5.4 mg, 7%) was obtained from compound 49 (144 mg, 0.147 mL) and benzyloxycarbonyl chloride (0.150 mL, 1.06 mol). Ή NMR (270 MHz, DMS0-d ₆ ) (5 (ppm) 5.19 (s, 2H), 7.26-7.38 (m, 5H), 7.42 (d, J-8.6 Hz, 4H), 7.61 (d, J = 8.6 Hz, 4H), 7.76 (s, 2H), 12.60 (br s, 2H) Example 59 (Compound 65)

 In the same manner as in Example 48, compound 65 (5.0 mg, 10%) was obtained from compound 47 (89.1 mg, 0.0981 ol) and ethyl ethyl isocyanate (0.200 mL, 2.56 mmol).

Ή NMR (270MHz, D S0-d _G ) δ (ppm) 0.80-1.20 (m, 3H), 2.90-3.20 (m, 2H), 6.22 (br t, J = 5.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 4H), 7.58 (d, J = 8.0 Hz, 4H), 7.76 (s, 2H), 12.55 (br s, 2H) Example 60 (compound 66)

 In the same manner as in Example 48, compound 66 (2.1 mg, 3%) was obtained from compound 49 (121 mg,, 0.124 mmol) and methyl isothiocyanate (0.150 mL, 2.19 mmol).

n NMR (270 MHz, brain 0-d ₆ ) d (ppm) 2.85 (d, J = 4.3 Hz, 3H), 7.38 (d, J two 8.4 Hz, 4H), 7.64 (d, J = 8.4 Hz, 4H) , 7.77 (s, 2H), 12.53 (br s, 2H) Example 61 (Compound 67)

 In the same manner as in Example 48, compound 67 (2.0 mg, 3%) was obtained from compound 49 (120 mg, 0.123 mmol) and methyl sulfonyl chloride (0.150 mL, 1.94 mmol).

Ή NMR (270 MHz, DMS0-d ₆ ) c (ppm) 3.37 (s, 3H), 7.51 (d, J = 8.6 Hz, 4H), 7.65 (d, J = 8.6 Hz, 4H), 7.77 (s, 2H ), 12.62 (br s, 2H) Example 62 (Compound 68)

Step 1: In the same manner as in Step 1 of Reference Example 6, 3,3-dimethyldiphenylamine (1.00 mL, 5.27 mmol) and di-tert-butyl dicarbonate (1.82 mL, 7.92 bandol) As a result, N- (tert-butoxycarbonyl) -3,3′-dimethyldiphenylamine (1.20 g, 77%) was obtained.

_{'Η NMR (270MHz, CDC1 3} ) d (ppm) 1.44 (s, 9H), 2.31 (s, 6H), 6.92-7.04 (m, 6H), 7.18 (dd, J = 7.6, 7.6 Hz, 2H)

Step 2: The above compound (1.05 g, 3.53 cited ol) was dissolved in carbon tetrachloride (50 mL), and N-bromosuccinic acid imide (4.02 g, 22.6 mmol) and azobisisobutyronitrile (1992) were dissolved. mg, 1.21 mmol) and heated under reflux for 6 hours. The reaction solution was cooled to room temperature, a saturated aqueous solution of sodium thiosulfate was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution 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). N- (tert-butoxycarbonyl) -3,3'-bis (dibromomethyl) diphenylamine

(793 mg, 35) was obtained.

_{} H NMR (270MHz, CDC1 3} ) δ (ppm) 1.48 (s, 9H), 6.60 (s, 2H), 7.11 (ddd, J = 1.3, 2.0, 7.9 Hz, 2H), 7.32 (dd, J two 7.9 , 7.9 Hz, 2H), 7.41 (ddd, J = 1.3, 2.0, 7.9 Hz, 2H), 7.46 (dd, J = 2.0, 2.0 Hz, 2H)

Step 3: The above compound (790 mg, 1.25 cited ol) was dissolved in 1,4-dioxane (15 mL), 1.0 mol / L aqueous sodium carbonate solution (10 mL) was added, and the mixture was heated under reflux for 48 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with black hole form. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by preparative thin-layer chromatography (4: 1 hexane / ethyl acetate) to give N- (tert-butoxycarbonyl) -3,3, -diformyldiphenylamine. (123 mg, 30%). _{Ή NMR (270MHz, CDC1 3)} δ (ppm) 1.46 (s, 9H), 7.46-7.58 (m, 4H), 7.70- 7.78 (m, 4H), 9.97 (s, 2H)

Step 4: The above compound (120 mg, 0.369 mmol), 2,4-thiazolidinedione (182 mg, 1.55 mmol), and lithium hydroxide (52.9 mg, 2.21 mmol) were heated to reflux in ethanol (10 mL) for 1 hour. . The reaction solution was cooled to room temperature, water and lmol / L hydrochloric acid were added, the resulting crystals were collected by filtration, dried, and purified by preparative thin-layer chromatography (90: 10: 1 pore-form / methanol / water). As a result, Compound 68 (137 mg, 71%) was obtained. ^} H NMR (270 MHz, DMS0-d _G ) δ (ppm) 1.40 (s, 9H), 7.37 (ddd, J = 1.6, 1.6, 7.9 Hz, 2H), 7.40-7.48 (m, 4H), 7.52 (dd 7.9, 8.2 Hz, 2H), 7.76 (s, 2H), 12.62 (br s, 2H) Example 63 (Compound 69)

 Compound 68 (94.7 mg, 0.181 mmol) was suspended in dichloromethane (4 m), trifluoroacetic acid (2.0 mL, 26 ol) was added, and the mixture was stirred at room temperature for 3 hours. Trituration was carried out with a mouth form to obtain compound 69 (52.2 mg, 68%).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 7.10 (br d, J = 7.9 Hz, 2H), 7.20 (br d, J = 7.9 Hz, 2H), 7.30 (br s, 2H), 7.41 ( dd, J = 7.9, 7.9 Hz, 2H), 7.73 (s, 2H), 8.68 (br s, IE), 12.58 (br s, 2H) Example 6.4 (Compound 70)

Step 1: Compound 69 (53.5 mg, 0.126 mmol) and 2-chloromouth phenyldiphenylmethyl chloride (202 mg, 0.646 mmol) were applied to the thiazolidine ring of compound 69 in the same manner as in Example 42. A compound (111 mg, 90%) in which the nitrogen atom was 2-methylphenylphenylphenyl methylated was obtained.

_{'Ε NMR (270MHz, CDC1 3} ) δ (ppm) 5.87 (br s, 1H), 7.00-7.50 (m, 36H), 7.70 (s, 2H)

Step 2: In the same manner as in Example 48, Compound 70 (6.6 mg, 6.6 mg, 0.099 mml) and 3,4-dichlorobenzyl bromide (0.20 mL, 0.83 mol) were used. 11%).

'Η NMR (270MHz, DMS0-d _fi ) d (ppm) 5.10 (s, 2H), 7.14-7.24 (m, 4H), 7.25 -7.29 (m, 2H), 7.32 (dd, J = 2.0, 8.2 Hz , 1H), 7.43 (dd, J = 7.9, 7.9 Hz, 2H), 7.53-7.60 (m, 2H), 7.70 (s, 2H), 12.57 (br s, 2H) Example 65 (Compound 71)

Step 1: Iminostilbene (4.08 g, 25.1 g) was prepared in the same manner as in Step 1 of Example 46. mmol) and di-tert-butyl dicarbonate (11.0 mL, 47.9 mmol) to give N- (tert-butoxycarbonyl) iminostilbene (5.01 g, 68%).

_{Ή NMR (270MHz, CDC1 3)} δ (ppm) 1.33 (s, 9H), 6.90 (s, 2H), 7.20-7.50 (m, 8H)

Step 2: The above compound (2.51 g, 8.52 mol) was dissolved in 1,4-dioxane (50 m or water (10 mL)), and osmium tetroxide (2.5% by weight 2-methyl: 2-propanol solution; 1.0 mL, 0.080 t ol) and sodium periodate (10.8 g, 50.3 t ol) were added, and the mixture was stirred at room temperature for 48 hours, and a saturated aqueous solution of sodium thiosulfate was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, silica gel column chromatography (5: 1 hexane / ethyl acetate), and preparative thin-layer chromatography ( Purification was performed sequentially with 2: 1 hexane / ethyl acetate) to obtain N- (tert-butoxycarbonyl) -2,2'-diformyldiphenylamine (175 mg, 6%).

_{Ή NMR (270MHz, CDC1 3)} (5 (ppm) 1.40 (s, 9H), 7.06 (dd, J = 1.2, 7.6 Hz, 2H), 7.35-7.45 (m, 2H), 7.53 (ddd, J = 1.6 , 7.6, 7.6 Hz, 2H), 7.94 (dd, J 1.6, 7.6 Hz, 2H), 10.25 (s, 2H)

Step 3: In the same manner as in Step 4 of Example 62, Compound 71 (6.3 mg, 4%) was obtained from the above compound (129 mg, 0.395 mmol) and 2,4-thiazolidinedione (192 mg, 1.64 t ol). ).

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 6.76 (br dd, J = 7.6, 7.6 Hz, 2H), 6.93 (dd, J = 1.6, 7.6 Hz, 2H), 7.13 (ddd, J = 1.6, 7.6, 7.6 Hz, 2H), 7.26 -7.38 (m, 2H), 7.89 (dd, J = 1.6, 7.6 Hz, 2H), 9.28 (br s, 1H), 12.41 (br s, 2H) 6 6 (Compound 7 2)

Step 1: In the same manner as in Step 1 of Example 46, N- (3,4) was obtained from iminostilbene (2.01 g, 10.4 thigh ol) and 3,4-dichlorobenzyl chloride (2.0 mL, 14 ol). -Dichloromouth benzyl) iminostilbene (3.31 g, 90%) was obtained.

_{'HNMR (270MHz, CDC1 3)} d (ppm) 4.89 (s, 2H), 6.81 (s, 2H), 6.92- 7.02 (m, 4H), 7.07 (dd, J = 1.7, 7.3 Hz, 2H), 7.15-7.32 (m, 4H), 7.48-7.54 (m, 1H) Step 2: In the same manner as in Step 2 of Example 65, the above compound (2.49 _g , 7.07 mmol), osmium tetroxide (2.5% by weight 2-methyl-2-propanol solution; 1.0 mL, 0.080 ol) and sodium periodate (7.29 g, 34.1 mmol) from N- (3,4- Benzyl dichloro) -2,2'-diformyldiphenylamine (81.5 mg, 11%) was obtained.

Ή Anonymous _{(270MHz, CDC1 3) (5} (ppm) 4.93 (s, 2H), 6.99 (d, J = 8.2 Hz, 2H), 7.20 (dd, J = 7.4, 7.4 Hz, 2H), 7.23-7.30 ( m, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.40-7.49 (m, 3H), 7.81 (dd, J two 1.6, 7.4 Hz, 2H), 10.17 (br s, 2H) Step 3: Compound 72 (47.5 mg, 42%) was obtained from the above compound (75.3. Mg, 0.196 ol) and 2,4-thiazolidinedione (114 mg, 0.976 ol) in the same manner as in Step 4 of Example 62. Obtained.

Ή NMR (270 MHz, DMS0-d ₆ ) d (ppm) 4.75 (s, 2H), 7,12 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 6.9 Hz, 2H) ₃ 7.30-7.35 (m, 4H), 7.40 (dd, J = 1.6, 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 1.6 Hz, .1H), 7.80 (s, 2H ), 12.45 (br s, 2H) Example 6 7 (Compound 73)

Step 1: In the same manner as in Step 1 of Example 46, 4,4'-diformyldiphenylamine (76.0 mg, 0.337 mmol) obtained in Reference Example 17 and 2,6-difluorobenzyl bromide (76.0 mg, 0.337 mmol) N- (2,6-difluorobenzyl) -4,4'-diformyldiphenylamine (94.5 mg, 80%) was obtained from 424 mg, 2.05 mmol).

^! H Anonymous _{(270MHz, CDC1 3) δ (} ppm) 5.13 (s, 2H), 6.78-6.88 (m, 2H), 7.14 -7.28 (m, 1H) S 7.20 (d, J = 8.6 Hz, 4H), 7.79 (d, J: 8.6 Hz, 4H), 9.88 (s, 2H)

Step 2: Compound 73 (46.6 mg, 33%) was obtained from the above compound (90.0 mg, 0.256 mmol) and 2,4-thiazolidinedione (120 mg, 1.03 mmol) in the same manner as in Step 4 of Example 6 2. Obtained.

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 5.16 (s, 2H), 7.05-7.10 (m, 2H), 7.17 (d, J = 8.7 Hz, 4H), 7.24-7.42 (m, 1H) , 7.50 (d, J = 8.7 Hz, 4H), 7.68 (s, 2H), 12.47 (br s, 2H) Example 6 8 (Compound 74)

Step 1: 4,4, -Diformyldiphenylamine (75.1 mg, 0.333 mmol) obtained in Reference Example 17 and 2,6-dichlorobenzyl bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 From (473 mg, 1.97 mmol), N- (2,6-dichlorobenzyl) -4,4'-diformyldiphenylamine (106 mg, 83%) was obtained.

_{Ή NMR (270MHz, CDC1 3)} (5 (ppm) 5.20 (s, 2H), 7.04-7.22 (m, 7H), 7.75 (d, J = 8.9 Hz, 4H), 9.87 (s, 2H)

Step 2: Compound 74 (54.3 mg ₅ 36%) from the above compound (98.5 mg, 0.256 mmol) and 2,4-thiazolidinedione (126 mg, 1.08 mmol) in the same manner as in Step 4 of Example 6 2. I got .

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 5.19 (s, 2H), 7.05-7.10 (m, 1H), 7.07 (d, .J 8.7 Hz, 4H), 7.20-7.40 (m, 2H), 7.47 (d, J = 8.7 Hz, 4H), 7,68 (s, 2H), 12.46 (br s, 2H) Example 6 9 (Compound 75)

Step 1: 4,4'-Diformyldiphenylamine (80.3 mg, 0.356 mmol) and 4-fluorobenzyl bromide (0.174 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. , 1.40 mmol) to give N- (4-fluorobenzyl) -4,4'-diformyldiphenylamine (79.4 mg, 67%).

_{'Η NMR (270MHz, CDC1 3} ) δ (ppm) 5.12 (s, 2H), 6.90-7.10 (m, 2H), 7.20 -7.28 (m, 6H), 7.80 (d, J = 8.6 Hz, 4H), 9.88 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 6, 2, the compound 75 (39.2 mg, 34%) was prepared from the above compound (73.4 mg, 0.220 mol) and 2,4-thiazolidinedione (196 mg, 1.67 mmol). ).

^{! H NMR (270MHz, DMS0-} d 6) 6 (ppm) 5.16 (s, 2H), 7.08-7.38 (m, 4H), 7.26 (d, J = 8.7 Hz, 4H), 7.52 (d, J = 8.7 Hz, 4H), 7.70 (s, 2H), 12.48 (br s, 2H) Example 70 (Compound 76)

Step 1: In the same manner as in Step 1 of Example 46, 4,4'-diformyldiphenylamine (75.3 mg, 0.334 mmol) obtained in Reference Example 17 and 3-fluorobenzyl bromide (0.171 mL) , 1.39 mmol) to give N- (3-fluorobenzyl) -4,4'-diformyldiphenylamine (67.2 mg, 60%).

_{Ή NMR (270MHz, CDC1 3)} δ (ppm) 5.14 (s, 2H), 6.90-7.10 (m, 3H), 7.20 -7.35 (m 5 5H), .7.81 (d, J = 8.9 Hz, 4H), 9.88 (s, 2H)

Step 2: In the same manner as in Step 6 of Example 62, Compound 7 6 (56.6 mg, 0.16 ol) and 2,4-thiazolidinedione (189 mg, 1.61 wake ol) were used. 54%).

Ή NMR (270MHz, DMSO-dJ δ (ppm) 5.20 (s, 2H), 7.00-7.42 (m, 4H), 7.28 (d, J = 8.7 Hz, 4H) ₃ 7.53 (d, J = 8.7 Hz, 4H ), 7.70 (s, 2H), 12.49 (br s, 2H) Example 71 (Compound 77)

Step 1: 4,4′-Diformyldiphenylamine (78.2 mg, 0.347 mmol) obtained in Reference Example 17 and 2-fluorobenzyl bromide (0.168 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. , 1.39 mmol) to give N- (2-fluorobenzyl) -4,4'-diformyldiphenylamine (75.2 mg, 65%).

_{^{! H NMR (270MHz, CDC1 3}} ) δ (ppm) 5.19 (s, 2H), 7.00-7.15 (m, 2H), 7.18 -7.32 (m, 2H), 7.25 (d, J = 8.7 Hz, 4H), 7.81 (d, J = 8.7 Hz, 4H), 9.88 (s, 2H)

Step 2: Compound 77 (34.3 mg, 31%) from the above compound (68.2 mg, 0.205 mmol) and 2,4-thiazolidinedione (225 mg, 1.92 referred to as ol) in the same manner as in Step 4 of Example 6 2 I got

^{! H NMR (270MHz, DMS0- d} 6) (5 (ppm) 5.20 (s, 2H), 7.05-7.30 (m, 4H), 7.27 (d, J = 8.7 Hz, 4H), 7.53 (d, J = 8.7 Hz, 4H), 7.70 (s, 2H), 12.48 (br s, 2H) Example 7 2 (Compound 7 8)

Step 1: 4,4′-Diformyldiphenylamine (80.4 mg, 0.357 mmol) and 4-methylbenzyl bromide (230 mg) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 , 1.24 mmol) to give 4,4'-diformyl-N- (4-methylbenzyl) diphenylamine (68.1 mg, 58%).

Ή賺_{(270MHz, CDC1 3) 6 (} ppm) 2.32 (s, 3H), 5.11 (s, 2H), 7.10-7.32 (m, 8H), 7.79 (d, J two 8.7 Hz, 4H), 9.87 ( s , 2H)

Step 2: In a similar manner to Step 4 of Example 6 2, the compound (61.1mg, 0,185誦_ol); and 2, 4-thiazolidinedione (202 mg, 1.72 mmol) from compound 7 8 (22.7 mg, 23¾ ).

Ή NMR (270MHz, DMS0-d 6) 5 (ppm) 2.24 (s, 3H), 5.13 (s, 2H), 7.05-7.35 (m, 4H), 7.26 (d, J = 7.9 Hz, 4H), 7.51 (d, J = 7.9 Hz, 4H), 7.69 (s, 2H), 12.48 (br s, 2H) Example 7 3 (Compound 79)

Step 1: 4,4′-Diformyldiphenylamine (75.3 mg, 0.334 mmol) obtained in Reference Example 17 and 3-methylbenzyl bromide (0.189 mL) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 , 1.40 mmol) to give 4,4'-diformyl-N- (3-methylbenzyl) diphenylamine (74.1 mg, 67%).

_{Ή NMR (270MHz, CDC1 3)} d (ppm) 2.32 (s, 3H), 5.11 (s, 2H), 7.02-7.12 (m, 3H), 7.16-7.30 (m, 1H), 7.35 (d, J = 8.7 Hz, 4H), 7.93 (d, J = 8.7 Hz, 4H), 9.87 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 62, Compound 79 (41.0 mg, 37 mg) was obtained from the above compound (68.7 mg, 0.209 bandol) and 2,4-thiazolidinedione (214 mg, 1.82 mol). %).

^{! H NMR (270MHz, DMS0-} d 6) ό (ppm) 2.25 (s, 3H), 5.14 (s, 2H), 7.00-7.30 (m, 4H), 7.27 (d, J: 8.6 Hz, 4H), 7.52 (d, J = 8.6 Hz, 4H), 7.69 (s, 2H), 12.48 (br s, 2H) Example 74 (Compound 80)

 Step 1: 4,4′-Diformyldipheniramine (74.1 mg, 0.329 mmol) and 2-methylpentyl bromide (0.188 mL, 1.40 mmol) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. ), 4,4'-Diformyl-N- (2-methylbenzyl) diphenylamine (95.2 mg, 88%) was obtained.

_{^{! H NMR (270MHz, CDC1 3}} ) (5 (ppm) 2.35 (s, 3H), 5.07 (s, 2H), 7.10-7.29 (m, 4H), 7.23 (d, J = 8.7 Hz, 4H), 7.79 (d, J = 8.7 Hz, 4H), 9.87 (s, 2H) Step 2: In the same manner as in Step 4 of Example 62, the above compound (90.3 mg, 0.274 reference ol) and 2,4-thiazolidinedione Compound (80 mg, 40%) was obtained from (228 mg, 1.94 mol).

^! H NMR (270MHz, DMS0-d ₆ ) δ (ppm) 2.33 (s, 3H), 5.11 (s, 2H), 7.05-7.30 (m, 4H), 7.27 (d, J: 8.7 Hz, 4H), 7.52 (d, J = 8.7 Hz, 4H), 7.69 (s, 2H), 12.48 (br s, 2H) Example 75 (Compound 81)

 Step 1: In the same manner as in Step 1 of Example 46, 4,4, -diformyldiphenylamine (78.9 mg, 0.350 mol) obtained in Reference Example 17 and 4-trifluoromethylbenzyl bromide (326 mg, 1.36 mmol) to give 4,4′-diformyl-N- (4-trifluoromethylbenzyl) diphenylamine (111 mg, 83%).

^ Thigh _{(270MHz, CDC1 3) d (} ppm) 5.20 (s, 2H), 7.23 (d, J = 8.7 Hz, 4H), 7.40 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.7 Hz, 4H), 9.89 (s, 2H)

Step 2: In the same manner as in Example 4, step 4 of Example 2, Compound 81 (58.8 mg, 36%) was obtained from the above compound (107 mg, 0.279 bandol) and 2,4-thiazolidinedione (209 mg, 1.78 bandol). ).

ΊΗ NMR (270MHz, D S0-d ₆ ) δ (ppm) 5.29 (s, 2H), 7.28 (d, J = 8.7 Hz, 4H), 7.45-7.57 (m, 6H), 7.65-7.72 (m, 4H ), 12.49 (br s, 2H) Example 7 6 (Compound 82)

Step 1: In the same manner as in Step 1 of Example 46, 4,4′-diformyldipheniramine (74.9 mg, 0.333 t) obtained in Reference Example 17 and 3-trifluoromethylbenzyl bromide (0.214 mL, From 1,40 fractions, 4,4′-diformyl-N- (3-trifluoromethylbenzyl) diphenylamine (103 mg, 80%) was obtained.

_{l NMR (270MHz, CDC1 3)} δ (ppm) 5.20 (s, 2H), 7.23 (d, J = 8.7 Hz, 4H),

7.40-7.56 (m, 4H), 7.82 (d, J = 8.7 Hz, 4H), 9.89 (s, 2H)

Step 2: Compound 62 (42.9 mg, 29%) from the above compound (97.1 mg, 0.253 mmol) and 2,4-thiazolidinedione (184 mg, 1.57 mmol) in the same manner as in Step 4 of Example 6 2. I got

Ή thigh _{(270MHz, DMS0-d 6)} δ (ppm) 5.29 (s, 2H), 7.28 (d, J = 8.6 Hz, 4H), 7.45-7.65 (m, 4H), 7.53 (d, J = 8.6 Hz , 4H), 7.70 (s, 2H), 12.49 (br s, 2H) Example 7 7 (Compound 83)

Step 1: 4,4′-Diformyldiphenylamine (80.5 mg, 0.357 mmol) obtained in Reference Example 17 and 2-trifluoromethylpentyl bromide (332 mg, 1.39) obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. mmol) to give 4,4'-diformyl-N- (2-trifluoromethylbenzyl) diphenylamine (46.3 mg, 34%).

_{Ή MR (270MHz, CDC1 3)} δ (ppm) 5.34 (s, 2H), 7.24 (d, J two 7.9 Hz, 4H), 7.32-7.50 ( m, 3H), 7.73 (d, J = 7.6 Hz, 1H ), 7.81 (d, J = 8.7 Hz, 4H), 9.88 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 62, Compound 83 (8.1 mg, 12 mg) was obtained from the above compound (44.2 mg, 0.115 mol) and 2,4-thiazolidinedione (97.5 mg, 0.83 mol). %).

Ή NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 5.29 (s, 2H), 7.26 (d, J = 8.9 Hz, 4H), 7.35-7.65 (m, 4H), 7.54 (d, J = 8.9 Hz , 4H), 7.70 (s, 2H), 12.48 (br s, 2H) Example 7 8 (Compound 84)

Step 1: 4,4′-Diformyldiphenylamine (75.0 mg, 0.333 mmol) obtained in Reference Example 17 and 3,5-dichloropentane bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46 N- (3,5-dichlorobenzyl) -4,4'-diformyldiphenylamine (73.7 mg, 58%) was obtained from toluene (319 mg, 1.33 mmol).

_{Ή NMR (270MHz, CDC1 3)} δ (ppm) 5.09 (s, 2H), 7.13-7.30 (m, 3H), 7.21 (d, J = 8.7 Hz, 4H), 7.83 (d, J = 8.7 Hz, 4H ), 9.90 (s, 2H)

Step 2-: In the same manner as in Step 4 of Example 62, Compound 84 (12.7 mg, 137.9 mg) was obtained from the above compound (65.7 mg, 0.171 mol) and 2,4-thiazolidinedione (210 mg, 1.79 mol). %).

1 NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 5.20 (s, 2H), 7.20-7.35 (m, 2H), 7.27 (d, J = 8.9 Hz, 4H), 7.45-7,50 (m, 1H), 7.54 (d, J = 8.9. Hz, 4H), 7.70 (s, 2H), 12.50 (br s, 2H) Example 7 9 (Compound 85)

Step 1: Dissolve 4,4'-diformyldiphenylamine (100 mg, 0.444 tmol) obtained in Reference Example 17 in DMF (2 mL), and add 60% sodium hydride mineral oil After stirring at the same temperature for 5 minutes, 2-picolyl chloride hydrochloride (87.4 mg, 0.553 hall) and sodium iodide (110 mg, 0.734 mmol) were added. The mixture was further stirred for 12 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. 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 / acetonitrile and 1: 1 hexane Z ethyl acetate) to give 4,4′-diformyl-N- (pyridine- 2- (methyl) diphenylamine (84.8 mg, 60%) was obtained. _{Ή NMR (270MHz, CDC1 3)} 5 (ppm) 5.23 (s, 2H), 7.20 (dd, J = 4.9, 7.6 Hz, 1H), 7.29 (d, J = 8.9 Hz, 4H), 7.63 (dt, J = 1.6, 7.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 4H), 8.60 (d, J = 4.9 Hz, 1H), 9.88 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 6, 2, the compound 85 (43.2 mg) was obtained from the above compound (84.8 mg, 0.268 alcohol) and 2,4-thiazolidinedione (125 mg, 1.07 marl). mg, 31%).

Ή NMR (270MHz, DMS0-d ₆ ) δ (ppm) 5.23 (s, 2H), 7.24-7.35 (m, 6H), 7.53 (d, J = 8.9 Hz, 4H), 7.71 (s, 2H), 7.74 (dt, J = 2.0, 7.6 Hz, 1H), 8.54 (d, J = 3.0 Hz, 1H), 12.50 (br s, 2H) Example 80 (Compound 86)

Step 1: Example 4 In the same manner as in Step 1 of Example 9, 4,4'-diformyldiphenylamine (100 mg, 0.444 mmol) obtained in Reference Example 17 and 3-picolyl chloride hydrochloride (87.4 mg) , 0.553 mmol) to give 4,4, -diformyl-N- (pyridine-3-ylmethyl) diphenylamine (67.1 mg, 48%).

_{Ή NMR (270MHz, CDC1 3)} (5 (ppm) 5.17 (s, 2H), 7.21-7.29 (m, 5H), 7.60 (m, 1H), 7.82 (d, J = 8.7 Hz, 4H), 8.53 ( dd, J = 1.6, 4.6 Hz, 1H), 8.59 (d, J 2 1.6 Hz, 1H), 9.89 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 6, 2, the compound 86 (28.2 mg, 28.2 mg, 0.848 mol) was prepared from the above compound (67.1 mg, 0.212 rec. 26%).

l NMR (270MHz, DMS0-d ₆ ) δ (ppm) 5.23 (s, 2H), 7.28-7.36 (m, 5H), 7.53 (d, J = 8.6 Hz, 4H), 7.64-7.71 (m, 3H) , 8.43 (d, J = 4.8 Hz, 1H), 8.52 (s, 1H), 12.49 (br s, 2H) Example 8 1 (Compound 87)

Step 1: 4,4′-Diformyldiphenylamine (50.0 mg, 0.222 mmol) obtained in Reference Example 17 and 5,6-dichloro-3-bromide obtained in Reference Example 17 in the same manner as in Step 1 of Example 46. -N- (5,6-Dichloropyridine-3-ylmethyl) -4,4'-diformyldiphenylamine (84.8 mg, 60%) was obtained from -picolyl (58.8 mg, 0.244 mmol).

_{'Η NMR (270MHz, CDC1 3} ) d (ppm) 5.14 (s, 2H), 7.21 (d, J = 8.6 Hz, 4H), 7.69 (d, J = 2.3 Hz, 1H), 7.83 (d, J two 8.9 Hz, 4H), 8.26 (d, J = 2.3 Hz, 1H), 9.90 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 6 2, the above compound (69.1 mg, 0.179 marl ol) Compound 87 (17.5 mg, 17%) was obtained from 2,4-thiazolidinedione (83.9 mg, 0.716 thigh ol). .

'Eta testimony _{(270MHz, .D S0-d 6} ) d (ppm) 5.25 (s, 2H), 7.31 (d, J = 8.9 Hz, 4H), 7.55 (d, J two 8.6 Hz, 4H), 7.73 ( s, 2H), 8.02 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 12.52 (br s, 2H) Example 82 (compound 88)

Step 1: Example 7 In the same manner as in Step 1 of Example 9, 4,4'-diformyldiphenylamine (100 mg, 0.444 mmol) obtained in Reference Example 17 and 4-chloromethyl-2-methylthiazo 4,4, -Diformyl-N- (2-methylthiazol-4-ylmethyl) diphenylamine (73.2 mg, 49%) was obtained from monohydrochloride (98.1 mg, 0.553 t).

Thigh _{(270MHz, CDC1 3). Δ} (ppm) 2.71 (s, 3H), 5.18 (d, J = 1.0 Hz, 2H), 6.82 (t, J = 1.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 4H), 7.81 (d, J = 8.6 Hz, 4H), 9.88 (s, 2H)

Step 2: In the same manner as in Step 4 of Example 62, Compound 88 (47.2 mg, 43%) was obtained from the above compound (69.5 mg, 0.207 mmol) and 2,4-thiazolidinedione (100 mg, 0.856 mol). I got

'Η NMR (270 MHz, DMS0-d ₆ ) 5 (ppm) 2.62 (s, 3H), 5.14 (s, 2H), 7.28 (s, 1H), 7.34 (d, J = 8.9 Hz, 4H), 7.53 ( d, J = 8.6 Hz, 4H), 7.72 (s, 2H), 12.50 (br s, 2H) Example 83 (Compound 89)

Step 1: Example 7, 4,4′-diformyldiphenylamine (100 mg, 0.444 mmol) and 3-chloromethyl-5-methyl obtained in Reference Example 17 in the same manner as in Step 1 of 9 4,4′-Diformyl-N- (5-methylisoxazol-3-ylmethyl) diphenylamine (49.7 mg, 35%) was obtained from isoxazole (87.6 mg, 0.666 mmol).

_{'Η NMR (270MHz, CDC1 3} ) δ (ppm) 2.37 (s, 3H), 5.09 (s, 2H), 5.80 (s, 1H), 7.26 (d, J = 8.6 Hz, 4H), 7.83 (d, J = 8.6 Hz, 4H), 9.90 (s, 2H) Step 2: In the same manner as in Example 4, step 4 of Example 2, compound 89 (19.7 mg, 25%) was obtained from the above compound (49.7 mg, 0.155 mmol) and 2,4-thiazolidinedione (72.6 mg, 0.620 ol). ).

Ή NMR (270MHz, DMS0-d 6) d (ppm) 2.34 (s, 3H), 5.14 (s, 2H), 6.12 (d, J = 0.7 Hz, 1H), 7.27 (d, J = 8.9 Hz, 4H ), 7.55 (d, J = 8.9 Hz, 4H), 7.73 (s, 2H), 12.52 (s, 2H) Example 84 (Compound 90)

Step 1: In the same manner as in Step 1 of Example 46, 4,4-dibromodiphenylamine (9.11 g, 27.9 mmol) and acrylyl bromide (10.2 g, 84 mol) were converted to N-aryl- 4,4'-Dibromodiphenylamine (9.51 g, 93%) was obtained.

Ή Anonymous _{(270MHz, CDC1 3) 5 (} ppm) 4.29 (d, J two 5.0 Hz, 2H), 5.19 ( br d, J = 4.6 Hz, 1H), 5.22 (br d, J: 12.5 Hz, 1H), 5.81-5.94 (m, 1H), 6.88 (d, J = 8.9 Hz, 4H), 7.34 (d, J = 8.9 Hz, 4H)

Step 2: The above compound (2.61 g, 7.11 bandol) was dissolved in a mixed solvent of acetonitrile (34 mL) and water (17 mL), and then 4-methylmorpholine-4-oxide (682 mg, 5.82 mmol) And osmium tetroxide (2.5% by weight 2-methyl-2-propanol solution; 1.7 mL, 0.26 recited ol) were added. After heating under reflux for 5 hours, a saturated aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes 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 to obtain an N- (2,3-dihydroxypropyl) compound (2.76 g, 97%) of the above compound.

Ή 270 (270MHz, CDCI3) (^ (ppm) 1.81 (br s, 2H), 3.56 (dd, J = 5.6, 11.5 Hz, 1H), 3.68-3.85 (m, 3H), 3.99 (m, 1H), 6.92 (d, J = 8.9 Hz, 4H), 7.36 (d, J = 8.9 Hz, 4H)

Step 3: The above compound (2.49 g, 6.21 ol) was dissolved in DMF (60 mL) and stirred at room temperature. Next, 2-methoxypropene (0.89 ml, 9.3 mmol) and (1R)-(-)-camphorsulfonic acid (13.9 mg, 0.06 ol) were added, and the mixture was stirred at the same temperature for 36 hours. An aqueous solution (20 mL) and water (100 mL) were added, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Purification was performed by silica gel column chromatography (cloth form) to obtain an acetate (1.21 g, 44%) of the above compound.

Ή testimony _{(270MHz, CDC1 3) d (} ppm) 1.33 (s, 3H), 1.41 (s, 3H), 3.61 (dd, J =

5.9, 8.6 Hz, 1H), 3.79 (dd, J = 5.8, 15.1 Hz, 1H), 3.84 (dd, J = 5.6, 15.1

Hz 1H), 3.98 (dd, J-6.3, 8.6 Hz, 1H), 4.34 (dddd, J = 5.6, 5.8, 5.9, 6.3

Hz), 6.89 (d, J = 8.9 Hz, 4H), 7.36 (d, J = 8.9 Hz, 4H)

Step 4: In a similar manner to Step 2 of Reference Example 1 6, the compound (1.21 g, 2.73 mmol) from and DMF (2 mL), 4,4' diformyl of the compound (177 mg ₃ 19%) Obtained.

_{Ή NMR (270MHz, CDC1 3)} d (ppm) 1.33 (s, 3H), 1.42 (s, 3H), 3.63 (dd, J = 5.9, 8.6 Hz, 1H), 3.94-4.10 (m, 3H), 4.39 -4.45 (m, 1H), 7.23 (d, J = 8.9 Hz, 4H), 7.83 (d, J = 8.9 Hz, 4H), 9.90 (s, 2H)

Step 5: In the same manner as in Step 4 of Example 62, Compound 90 (37 * mg, 234 mg, 2.00 black ol) was obtained from the above compound (170 mg, 0.50 cited 01) and 2,4-thiazolidinedione. 14%).

Ή NMR (270MHz, DMS0-d ₆ ) δ (ppm) 1.22 (s, 3H), 1.30 (s, 3H), 3.57 (dd, J = 6.3, 7.9 Hz, 1H), 3.89 (dd, J = 7.6, 15.8 Hz, 1H), 4.02 (dd, J = 6.2, 7.9 Hz, 1H), 4.13 (dd, J = 4.2, 15.8, Hz, 1H), 4.17-4.36 (m, 1H), 7.26 (d, J = 7.4 Hz, 4H), 7.55 (d, J = 7.4 Hz, 4H), 7.73 (s, 2H), 12.51 (br s, 2H) Example 85 (Compound 91)

Reference Example 21 1,1-bis (4-formylphenyl) ethanol (150 mg, 0.59 mmol), 2,4-thiazolidinedione (230 mg, 1.8 t ol) and piperidine (0.14 mL, 1.4 Ol) was heated to reflux in ethanol (10 mL) for 8 hours. The reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and triturated with diisopropyl ether to obtain a crude product. Then, silica gel column chromatography (from 2: 1 to 1: 1) The residue was purified with hexane / ethyl acetate) and triturated again with diisopropyl ether to obtain Compound 91 (121 mg, 45%).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.87 (s, 3H), 7.53 (d, J = 8.6 Hz, 4H),

7.60 (d, J = 8.6 Hz, 4H), 7.74 (s, 2H), 12.58 (brs, 2H)

ESI -MS m / z 451 (MH ) _ C 22 H 16 N 2 0 5 S 2 = 452

Example 8 6 (Compound 92)

 Reference Example 22 1,1, bis (4-formylphenyl) -1-methoxetane (160 mg, 0.6 mmol), 2,4-thiazolidinedione (210 mg, 1.8 mmol), and piperidine (0.24 mL, 2.4 mmol) was refluxed under heating for 5 hours and 50 minutes in ethanol (15 mL). The reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to obtain Compound 92 (54 mg, 19%).

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 1.88 (s, 3H), 3.12 (s, 3H), 7.49 (d, J-8.4 Hz, 4H), 7.55 (d, J = 8.4 Hz, 4H), 7.72 (s, 2H ), 12.57 (brs, 2H) ESI-MS m / z 465 (MH) "C 23 H 18 N 2 0 5 S 2 = 466 example 8 7 (compound 9 3)

 Compound 93 was obtained according to Example 85, except that 1, tribis (4-formylphenyl) -1-ethoxyxetane obtained in Reference Example 23 was used.

Ή NMR (270 MHz, D S0-d ₆ ) δ (ppm) 1.24 (t, J = 6.9 Hz, 3H), 1.90 (s, 3H), 3.32 (q, J = 6.9 Hz, 2H), 7.44 (d , J = 8.7 Hz, 4H), 7.49 (d, J = 8.7 Hz, 4H), 7.83 (s, 2H), 9.72 (brs, 2H)

ESI-MS m / z 479 ( MH) - C 23 H 18 N 2 0 5 S 2 = 480 Example 8 8 (Compound 94)

Compound 94 was prepared according to Example 85, except that 1- (3,4-dichlorobenzyloxy) -1,1- [bis (3-formylphenyl)] ethane obtained in Reference Example 24 was used. Was obtained. ^J H NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 2.03 (s, 3H), 4.39 (s, 2H), 7.42 (dd, J = 8.1, 2.0 Hz, 1H), 7.50 (s, 6H) , 7.60 (d, J: 8.1 Hz, 1H), 7.68 (s, 2H) ₃ 7.70 (d, J = 2.0 Hz, 1H), 7.78 (s, 2H), 12.58 (brs, 2H) Example 89 (compound 9 5)

 Ethyl 2,2-bis (4-formylphenyl) propionate (1.0 g, 3.2 mmol), 2,4-thiazolidinedione (1.1 g, 9.7 mmol) and piperidine (1.3 mL) obtained in Reference Example 18 , 13 mmol) was refluxed for 6 hours in ethanol (50 mL). The reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (7 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (40: 1 chloroform Z methanol) and recrystallized from ethanol to obtain Compound 95 (770 mg, 47%).

Ή NMR (270 MHz, DMS0-d ₆ ) ό "(ppm) 1.16 (t, J = 7.1 Hz, 3H), 1.91 (s, 3H), 4.18 (q, J = 7.1. Hz, 2H), 7.33 ( d, J = 8.4 Hz, 4H), 7.57 (d, J = 8.4 Hz, 4H), 7.77 (s, 2H), 12.61 (brs, 2H)

ESI- MS m / z 507 (MH ) "C 25 H 20 N 2 0 6 S 2 = 508 Example 90 (Compound 9 6)

 Compound 96 was obtained in the same manner as in Example 89, except that getyl ketomalonate was used in Example 18 instead of ethyl bilate.

ΐ NMR (270 MHz, DMSO-) 6 (ppm) 1.19 (t, J = 6.9 Hz, 6H), 4.28 (q, J = 6.9 Hz, 4H), 7.37 (d, J = 8.9 Hz, 4H), 7.59 (d, J = 8.9 Hz, 4H), 7.75 (s, 2H), 12.64 (brs, 2H)

ESI- MS m / z 565 (M- H) - C 27 H 22 N 2 0 8 S 2 = 566 Example 9 1 (Compound 9 7)

Reference example 19 2,2-bis (4-formylphenyl) propanol (300 mg, 1.1 t ol), 2,4-thiazolidinedione (390 mg, 3.4 t ol), and piperidine (0.44 mL, 4.5 ol) was refluxed for 4 hours and 25 minutes in ethanol (15 mL). The reaction solution was cooled to room temperature, added with mol / L hydrochloric acid (2 mL), and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (10: 1 chloroform / methanol). The compound 97 (410 mg, 78¾) was obtained by trituration with diisopropyl ether.

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.66 (s, 3H), 3.93 (s, 2H), 7.36 (d, J = 8.6 Hz, 4H), 7.75 (s, 2H), 7.51 ( d, J two 8.6 Hz, 4H), 12.58 ( brs, 2H) FABMS m / z 467 (M + H) + C 23 H 18 N 2 0 5 S 2 = 466 example 9 2 (compound 9 8)

 Reference Example 20 2,2-bis (4-formylphenyl) -trimethoxypropane (160 mg, 0.56 ol), 2,4-thiazolidinedione (200 mg, 1.7 mmol) and piperidine ( (0.16 mL, 2.2 mmol) was refluxed for 4 hours in ethanol (8 mL). The reaction solution was cooled to room temperature, 1 mol / L hydrochloric acid (2.0 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2: 1 hexane / ethyl acetate) and recrystallized from ethanol to obtain Compound 98 (59 mg, 22%).

'Η NMR (270 MHz / DMS0-d ₆ ) δ (ppm) 1.69 (s, 3H), 3.28 (s, 3H), 3.83 (s, 2H), 7.34 (d, J = 8.4 Hz, 4H), 7.52 (d, J = 8.4 Hz, 4H), 7.75 (s, 2H), 12.57 (brs, 2H)

ESI-MS m / z 479 ( MH) "C 24 H 2 .N 2 0 5 S 2 = 480 Example 9 3 (Compound 9.9)

Compound 95 (370 mg, 0.73 mmol) obtained in Example 89 was dissolved in methanol (7.3 mL), a 2 mol / L aqueous sodium hydroxide solution (1.5 mL, 2.9 mmol) was added, and the mixture was heated under reflux for 6.5 hours. To this was added 211101/1 ^ sodium hydroxide aqueous solution (0.73 mL, 1.5 t ol), and the mixture was further heated under reflux for 2 hours and 20 minutes. Cool the reaction to room temperature, 1 mol / L hydrochloric acid and then water were added, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (1: 2 hexane / ethyl acetate) and recrystallized from ethyl acetate to obtain Compound 99 (96 mg, 27%).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.88 (s, 3H), 7.36 (d, J = 8.6 Hz, 4H),

7.57 (d, J = 8.6 Hz, 4H), 7.77 (s, 2H), 12.61 (brs, 2H)

ESI-MS m / z 479 (MH) "C ₂₃ H ₁₆ N ₂ 0 _C S ₂ = 480 Example 94 (Compound 100)

 Compound 93 (1.5 g, 3.1 mmol) obtained in Example 93 was dissolved in THF (31 mL), and thionyl chloride (0.46 mL, 6.2 ol) and DMF (catalytic amount) were added, and the mixture was added for 2 hours. The mixture was heated under reflux for 20 minutes. Thionyl chloride (0.46 mL, 6.2 mmol) was added thereto, and the mixture was further heated under reflux for 1 hour and 45 minutes. The reaction solution was concentrated under reduced pressure, and dichloromethane (15 mL) was added to the residue. To this dichloromethane solution (10 mL) was added saturated ammonia / ethanol (5 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added 0.2 mol / L hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was triturated with diisopropyl ether to obtain a crude product (750 mg). The compound was recrystallized from ethanol to give Compound 100 (159 mg, 16%).

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.90 (s, 3H), 7.10 (brs, 2H), 7.35 (d, J = 8.4 Hz, 4H), 7.55 (d, J = 8.4 Hz , 4H), 7.77 (s, 2H), 12.59 (brs, 2H) ESI- MS m / z 478 (MH) " according to _{C 23 H 17 N 3 0 5} S 2 = 479 example 9 below 5-98 Compounds 101 to 104 were synthesized in the same manner as in Example 94, except that instead of saturated ammonium / ethanol, methylamine, dimethylamine, getylamine, and morpholine were used, respectively.

Example 9 5 (Compound 101)

NR (270 MHz, D S0-d ₆ ) δ (ppm) 1.89 (s, 3H), 2.62 (d, J = 4.5 Hz, 3H), 7.30 (d, J = 8.4 Hz, 4H), 7.47 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 4H), 7.76 (s, 2H), 12.59 (brs, 2H) ESI-MS m / z 492 ( -H) 'C 24 H 19 N 3 0 5 S 2 = 493 Example 9 6 (Compound 1 0 2)

lH NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.86 (s, 3H), 2.38 (s, 3H), 2.89 (s, 3H), 7.37 (d, J = 8.2 Hz, 4H), 7.60 ( d, J = 8.2 Hz, 4H), 7.77 (s, 2H), 12.62 (brs, 2H)

ESI-MS m / z 506 (MH) 'C ₂₅ H ₂₁ N ₃ 0 ₅ S ₂ = 507 Example: 9 7 (Compound 10 3)

»H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 0.10-0.40 (m, 3H), 1.00-1.30 (m, 3H), 1.81 (s, 3H), 2.70-2.95 (m, 2H), 3.15-3.40 (m, 2H), 7.40 (d, J = 8.2 Hz, 4H), 7.62 (d, J two 8.2 Hz, 4H), 7.78 (s, 2H), 12.60 (brs, 2H)

ESI-MS m / z 534 ( MH) "C 27 H 25 N 3 0 5 S 2 = 535 Example 98 (Compound 104)

Ή NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 1.88 (s, 3H), 3.31 (brs, 8H), 7.42 (d,

J = 8.6 Hz, 4H), 7.61 (d, J = 8.6 Hz, 4H), 7.78 (s, 2H), 12.61 (brs, 2H) ESI-MS m / z 548 (MH) "C ₂₇ H ₂₃ N ₃ 0 ₆ S ₂ = 549 Example 99 (Compound 105)

 The compound 100 (300 mg, 0.62 mol) obtained in Example 94 was dissolved in thionyl chloride (20 mL), and the mixture was heated under reflux for 9 hours and 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was azeotropically distilled. The compound was purified by silica gel column chromatography (2: 1 to 1: 1 hexane Z ethyl acetate) and recrystallized from ethanol to obtain compound 105 (50 mg, 18%).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.15 (s, 3H), 7.57 (d, J = 8.6 Hz, 4H), 7.66 (d, J-8.6 Hz, 4H), 7.78 (s, 2H), 12.65 (brs, 2H)

ESI-MS m / z 460 ( MH) "C 23 H 15 N 3 0 4 S 2 = 461 Example 100 (Compound 106)

 4,4 '-(Hexafluoroisopropylidene) bis (benzaldehyde) obtained in Reference Example 25 (1.9 g, 5.2 mmol), 2,4-thiazolidinedione (2.0 g, 16 ol), And piperidine (1.2 mL, 12 mmol) were heated and refluxed in ethanol (52 mL) for 10 hours. The reaction solution was concentrated under reduced pressure, 2 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (3: 1 hexane / ethyl acetate), and triturated with disopropyl ether to give compound 106 (960%). mg, 33%).

^] H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 7.50 (d, J = 8.6 Hz, 4H), 7.74 (d, J = 8.6 Hz, 4H), 7.81 (s, 2H), 12.71 (brs , 2H)

ESI -MS m / z 557 (MH ) - C 23 H 12 F 6 N 2 0 4 S 2 = 558 The following Example 1 0 1, 1 0 the compound described in 2 1 0 7 1 0 8, reference Example 18 Synthesized according to the method of obtaining compounds 95 and 97 described in Example 89 and Example 91 except that in step 1 instead of pyruvic acid ethyl ester, trifluorovirbic acid ethyl ester was used. .

Example 101 (Compound 107)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.19 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.36 (d, J = 8.6 Hz, 4H) , 7.67 (d, J = 8.6 Hz, 4H), 7.78 (s, 2H), 12.65 (brs, 2H)

ESI-MS m / z 561 ( MH) "C 25 H 17 F 3 N 2 0 6 S z = 562 Example 1 0 2 (Compound 1 0 8)

^J H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.30 (s, 2H), 5.51 (brs, 1H), 7.40 (d, J = 8.6 Hz, 4H), 7.60 (d, J = 8.6 Hz , 4H), 7.77 (s, 2H), 12.62 (brs, 2H) ESI-MS m / z 519 (MH) "C 23 H 15 F 3 N 2 0 5 S 2 = 520 example 1 0 3 (compound 1 0 9) Reference Example 26 2,2-Bis (4-formylphenyl) -1,3-dioxolane (500 mg, 1.8 mmoDs 2,4-thiazolidinedione (690 mg, 5.3 recitation ol) and piperidine (0.42 The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and then washed with water and saturated saline. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (1: 1 hexane / ethyl acetate), and recrystallized from ethyl acetate to give Compound 109 (150 mg, _C Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.01 (s, 4H), 7.59 (s, 8H), 7,74 (s, 2H), 12.61 (brs, 2H) )

ESI- MS m / z 479 (MH ) "C 23 H 16 N 2 0 6 S 2 = 480 Example 104 (Compound 1 10)

 Reference Example 27 1,1-bis (4-formylphenyl) cyclohexane (580 mg, 2.0 mmol), 2,4-thiazolidinedione (775 mg, 6.0 mmol) and piperidine (0.47 mL, .7) obtained in Reference Example 27. (4.8 mmol) was refluxed for 4 hours and 40 minutes in ethanol (20 mL). The reaction solution was cooled to room temperature, 2 mol / L hydrochloric acid (1 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized with a mixed solvent of ethyl acetate and acetonitrile to obtain Compound 110 (338 mg, 35%).

Ή NMR (270 MHz, DMS0- d ₆ ) δ (ppm) 1.45 (brs, 6H), 2.31 (brs, 4H), 7.50 (s, 8H), 7.71 (s, 2H), 12.57 (brs, 2H)

ESI-MS m / z 489 ( MH) "C 26 H 22 N 2 0 4 S 2 490 Example 105 (Compound 1 1 1)

4,4'-Diformylbenzhydrol (180 mg, 0.75 mmol), 2,4-thiazolidinedione (210 mg, 1.8 mmol) and piperidine (0.15 mL, 1.5 mmol) obtained in Reference Example 28 were dissolved in ethanol. (10 mL) and heated under reflux for 23 hours. The reaction solution was cooled to room temperature, 2 mol / L hydrochloric acid (1 mL) was added, and the precipitated crystals were collected by filtration to obtain Compound 111 (230 mg, 70%). Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 5.82 (d, J 2 4.0 Hz, 1H), 6.18 (d, J = 4.0 Hz, 1H), 7.54 (s, 8H), 7.74 (s, 2H), 12.57 (br, 2H)

ESI-MS m / z 437 ( MH) 'C 21 H 14 N 2 0 5 S 2 = 438 Example 1 0 6 (Compound 1 1 2)

 Reference Example 29 4,4, -Diformylbenzophenone (100 mg, 0.42 mmol), 2,4-thiazolidinedione (120 mg, 1.0 mmol), and bidiridine (0.08 mL, 0.84 ) Was refluxed under heating for 5 hours and 50 minutes in ethanol (10 mL). The reaction solution was cooled to room temperature, 2 mol / L hydrochloric acid (1 mL) was added, and the precipitated crystals were collected by filtration to obtain Compound 112 (84 mg, 46%).

Awake (270 MHz, DMS0-d ₆ ) δ (ppm) 7.78 (d, J = 8.4 Hz, 4H) ₃ 7.87 (s, 2H),

7.89 (d, J = 8.4 Hz, 4H),

ESI-MS m / z 435 ( MH) "C 21 H i2 N 2 0 5 S 2 two 436 Example 1 0 7 (Compound 1 1 3),

 In Reference Example 28, the compound 113 was prepared in place of 4,4'-dibromobenzhydrol in place of the collection 'Czechoslovakia' Chemical Communication (Collect. Czech. Chem. , 3496-3505 (1973), etc., except that 3,3′-dibromobenzhydrol, which can be synthesized by the method described in Example 105, is used. And synthesized.

] H NMR (270 MHz, DMS0 -d 6) δ (ppm) 5.85 (d, J = 3.6 Hz, 1H), 6.23 (d, J = 4.0 Hz, 1H), 7.4-7.5 (m 5 6H), 7.62 (s, 2H), 7.76 (s, 2H)

ESI-MS m / z 437 ( MH) "C 21 H 14 N 2 0 5 S 2 two 438 Example 1 0 8 (Compound 1 1 4)

 Compound 114 was prepared in the same manner as in Example 106 except that 3,3'-diformylbenzhydrol was used instead of 4,4'-diformylbenzhydrol in Reference Example 29. And synthesized.

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 7.72-7.77 (m, 2H), 7.85-7.96 (m, 8H) ESI-MS m / z 435 (Μ-ΗΓ C ₂₁ H ₁₂ N ₂ 0 ₅ S ₂ = 436) The compounds 1 15 and 1 16 described in the following Examples 1 0 9 and 1 10 are reference examples 1 In place of 2,2-bis (4-tolyl) propionic acid ester, Bulletin de la Societe Chimique de France (Bull. Soc. Chim. Fr.), Vol. 6, pp. 933-936 (1986) 1,1,:!-Trifluoro-2,2-bis (4-tolyl) propane or 1,1,1,1-trifluoro-2,2-bis (4-tolyl) butane synthesized by the method described Synthesis was performed in the same manner as in Example 89 except that was used.

Example 10 9 (Compound 1 15)

lH NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.97 (s, 3H), 7.43 (d, J = 8.6 Hz, 4H), 7.62 (d, J = 8.6 Hz, 4H), 7.77 (s, 2H)

FAB-MS m / z 505 ( M + H) + C 23 H 15 F 3 N 2 0 4 S 2 = 504 Example 1 1 0 (Compound 1 1 6)

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 0.77 (t, J = 7.3 Hz, 3H), 2.55 (q, J = 8.6 Hz, 2H), 7.41 (d, J = 8.3 Hz, 4H ), 7.64 (d, J = 8.6 Hz, 4H), 7.79 (s, 2H), 12.65 (brs, 2H)

ESI-MS m / z 517 (MH) "C ₂₄ H ₁₇ F ₃ N ₂ 0 ₄ S ₂ = 518 The following Examples 11 1 to 17 5 Compounds 11 17 to 18 1 are Reference Examples 3 The synthesis was carried out according to Production Method 1 using aldehydes synthesized by the methods described in 0 to 40 and the like.

Example 1 1 1 (Compound 1 17)

'Η NMR (270 MHz, DMS0 -d 6) δ (ppm) 7.70-7.94 (m, 10H), 12.72 (s, 2H) ESI-MS m / z 435 (MH) "C 21 H 12 N 2 0 5 S ₂ = 436Example 1 1 2 (Compound 1 1 8)

^{! H NMR (270 MHz, DMS0} -d 6) 6 (ppm) 7.60-7.86 (m, 10H), 12.65 (s, 2H) ESI-MS m / z 435 (MH) "C 21 H 12 N 2 0 5 S ₂ = 436 Example 1 13 (Compound 1 19)

Ή NMR (270 MHz, D S0-d ₆ ) δ (ppm) 3.30 (s, 3H), 5.48 (s, 1H), 7.53 (d,

J 2 8.6 Hz, 4H), 7.58 (d, J = 8.6 Hz, 4H), 7.75 (s, 2H), 12.59 (s, 2H)

ESI-MS m / z 451 ( MH) "C 22 H 16 N 2 0 5 S 2 = 452 Example 1 14 (Compound 120)

H NMR (270 MHz, D SO-d ₆ ) δ (ppm) 1.20 (t, J = 6.9 Hz, 3H), 3.46 (q, J = 6.9 Hz, 2H), 5.58 (s, 1H), 7.53 (d , J = 8.7 Hz, 4H), 7.57 (d, J = 8.7 Hz, 4H), 7.74 (s, 2H), 12.59 (s, 2H)

ESI-MS m / z 465 ( MH) "C 23 H 18 N 2 0 5 S 2 = 466 Example 1 15 (Compound 12 1)

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.48 (d, J = 6.1 Hz, 6H), 3.92 (septet, J = 6.1 Hz, 1H), 6.04 (s, 1H), 7.85 (d , J = 8.9 Hz, 4H), 7.89 (d, J = 8.9 Hz, 4H), 8.06 (s, 2H), 12.91 (s, 2H) Example 1 16 (Compound 122)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.52 (s, 2H), 5.72 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.59-7.64 (m, 10H) , 7.75 (s, 2H), 12.64 (s, 2H) Example 117 (Compound 123)

Ή NMR (270 MHz, D S0-d ₆ ) δ (ppm) 4.49 (s, 2H), 5.68 (s, 1H), 7.39 (s, 4H), 7.57 (s, 8H), 7.74 (s, 2H) , 12.58 (brs, 2H)

ESI-MS m / z 561 ( MH) "C 28 H 19 35 C1N 2 0 5 S 2 = 562 Example 1 18 (Compound 124)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.45 (s, 2H), 5.70 (s, 1H), 7.30-7.45 (m, 4H), 7.57 (s, 8H), 7.74 (s, 2H ), 12.58 (brs, 2H) ESI-MS m / z 561 ( MH) "C 28 H 19 35 C1N 2 0 5 S 2 = 562 Example 1 1 9 (Compound 1 2 5)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.61 (s, 2H), 5.75 (s, IH), 7.15-7.45 (m, 3H), 7.58 (s, 8H), 7.75 (s, 2H ), 12.60 (brs, 2H)

ESI-MS m / z 563 ( MH) "C 28 H 18 F 2 N 2 0 5 S 2 two 564 Example 1 2 0 (Compound 1 2 6)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.59 (s, 2H), 5.78 (s, 1H), 7.30-7.50 (m, 3H), 7.60 (s, 9H), 7.76 (s, 2H ), 12.60 (brs, 2H)

ESI-MS m / z 561 ( M- H) _ C 28 H 19 35 C1N 2 0 5 S 2 = 562 Example 1 2 1 (Compound 1 2 7)

NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.53 (s, 2H), 5,72 (s, IH), 7.05-7.30 (m, 2H), 7.57 (s, 9H), 7.76. , 2H), 12.60 (brs, 2H)

ESI-MS m / z 563 ( MH) "C 28 H 18 F 2 N 2 0 5 S 2 = 564 Example 1 2 2 (Compound 1 2 8)

^{! H NMR (270 MHz, DMS0} -d 6) 6 (ppm) 4.55 (s, 2H), 5.74 (s, IH), 7.05-7.20 (m, 3H), 7.60 (s, 8H), 7.76 (s, 2H), 12.60 (brs, 2H)

ESI-MS m / z 563 ( MH) "C 28 H 18 F 2 N 2 0 5 S 2 = 564 Example 1 2 3 (Compound 1 2 9)

1 NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.68 (s, 2H), 5.80 (s, 1H), 7.50-7.85 (m, 4H), 7.60 (s, 8H), 7.76 (s, 2H ), 12.60 (brs, 2H)

ESI-MS m / z 595 ( MH) 'C 29 H 19 F 3 N 2 0 5 S 2 = 596 Example 1 24 (Compound 1 3 0)

Ή NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 4.69 (s, 2H), 5.75 (s, 1H), 7.20-7.95 (9 ε τ ^ ο ε τ m

Ζΐ9 = ' ⁹ 0 ¥ J ⁶¹ H ^6Z 0 ₊ (H + W) CT9 V ^ra SHHVi (HZ ^£ sjq) ^C (H2 ^c s) H'L ^C (H8 ^c s) S'Z' (Ht '

QL-L-0 £ 'L' (HI ^c s) S '(HZ ^c s) 9' ^ () 9 ( ⁹ P- OS 'OLZ) Hire H,

 (g £ i ^) 6 z \ mm

089 = ² S ^s 0¾jI0 _Si ; ^8, H ^8Z 3 ( ₊ H) 089 z / ^ra S 丽 J (HZ ^ Jq) 09 I ^C (HT 's) 9' ^{ (H8 'Q' L ^C (HT ' s) 99Ά ^C (H2 ^C ZH = f 'ρ) 9 £''(ΗΪ ^c s) U'S ^C (H2 (s) TS ^ (mdd) ρ ( ⁹ p-0SWd' ZHW OLZ) 丽 H, ε T ^ 8 ZT ¾ traction

^{H9 = Z S 9 0 8 '} H 6 ¾ + (H + W) 9T9 z / ra SW9VJ {c s)''(H8 (s) 09 · C (HC c m) 0Z'Z-9S'i' ( HI ^c s) 9Z * S ^C (H2 's) 9 () 9 ( ⁹ P-0SWa' ZHW OLZ) ¾HN H,

 (ε ε τ m ^) L Z ι um

^{^ 99 = 'S s O¾ 9} j 8, H 0i:. 0 (HW) 899 z / ra SW-I 3 (HZ' sjq) 19 I '(HS c m) 0 8 ~ 38 * C (HZ c s ) U'L '(H8 (s) 8S''(Ηΐ ^c s) C8 * S' (HZ 's) 9' (uidd) g ( ⁹ p-0SW0 'lia OLZ) 丽 H _t

(z £ i 9 z T mm) 9 = 'S ⁹ 0¾¾ ^K 0-(HW) ε09 z / ra SW-IS3 (HZ ^c sjq) 69'2T' (HZ ^c s) 9 "'(HI ^£ Ο'-θε'Α'(HT ^c s) ci-g ^C (H2 ^c s) 99 (mdd) g ( ⁹ p-0SWa' ring QLZ) 丽 H,

 (ΐ S ΐ 9 Ζ I

8AS = ^z S ^s O ¥ ^ε 3-(HW) AL9 ζ / πι SW-IS3 (HZ ^c sjq) 09 I ^C (HZ ^c s) 92 ^£ (Η9Ϊ 'πι) t78SZ.0 / 00dT / X3d ILLO O OAV 'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.58 (s, 2H), 5.73 (s, 1H), 7.25-7.65 (m, 4H), 7.59 (s, 8H), 7.76 (s, 2H), 12.60 (brs, 2H)

FABMS m / z 613 (M + H) + C 29 H 19 F 3 N 2 0 6 S 2 = 612 Example 131 (Compound 137)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 3.73 (s, 3H), 3.75 (s, 3H), 4.44 (s, 2H), 5.65 (s, 1H), 6.85-6.95 (m, 3H ), 7.58 (s, 8H), 7.76 (s, 2H), 12.60 (brs, 2H)

ESI-MS m / z 587 ( MH) "C 3 .H 24 N 2 0 7 S 2 = 588 Example 1 3 2 (Compound 1 3 8)

ΐ NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.50 (s, 2H) ₅ 5.69 (s, 1H), 7.15-7.45 (m, 4H), 7.58 (s, 8H), 7.76 (s, 2H ), 12.60 (brs, 2H)

ESI-MS m / z 545 ( MH) "C 28 H 19 FN 2 0 5 S 2 = 546 Example 133 (Compound 139)

'Η NMR (270 MHz, D S0-d ₆ ) 6 (ppm) 4.62 (s, 2H), 5.81 (s, 1H), 7.42 (t, J = 7.3 Hz, 1H), 7.50-7.70 (m, 10H ), 7.76 (s, 2H) , 12.60 (brs, 2H) ESI-MS m / z 595 (MH) "C 28 H 18 35 C1 2 N 2 0 5 S 2 = 596 example 1 34 (compound 1 4 0 )

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.56 (s, 2H), 5.74 (s, 1H), 7.15-7.25 (m, 2H), 7.30-7.45 (m, 1H), 7.50-7.65 (m, 9H), 7.75 (s, 2H), 12.61 (brs, 2H)

ESI-MS m / z 545 ( MH) "C 28 H 19 FN 2 0 5 S 2 = 546 Example 1 3 5 (Compound 1 4 1)

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 4.70 (s, 2H), 5.75 (s, 1H), 7.35-7.65 (m, 11H), 7.55 (s, 2H), 12.60 (brs, 2H ) ESI-MS m / z 595 ( MH) "C 28 H 18 35 C1 2 N 2 0 5 S 2 = 596 Example 1 3 6 (Compound 1 4 2)

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.52 (s, 2H), 5.71 (s, 1H), 7.05-7.25 (m, 3H), 7.30-7.45 (m, 1H), 7.59 ( s, 8H), 7.75 (s , 2H), 12.60 (brs, 2H) ESI-MS m / z 545 (MH) "C 28 H 19 FN 2 0 5 S 2 = 546 example 1 3 7 (compound 1 4 3)

NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.54 (s, 2H), 5.75 (s, 1H), 7.15-7.45 (m, 3H), 7.50-7.70 (m, 8H), 7.58 (s, 2H), 12.59 (brs, 2H)

ESI-MS m / z 563 ( MH) "C 28 H 18 F 2 N 2 0 5 S 2 = 564 Example 1 3 8 (Compound 1 44)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.56 (s, 2H), 5.71 (s, 1H), 7.11 (t, J = 7.7 Hz, 2H), 7.40-7.65 (m, 9H), 7.73 (s, 2H): 12.59 (brs, 2H) ESI-MS m / z 563 (MH) "C 28 H 18 F 2 N 2 0 5 S 2 = 564 example 1 3 9 (compound 1 4 5)

^! H NMR (270 MHz, DMSO-dJ δ (ppm) 4.49 (s, 2H), 5.71 (s, 1H), 7.15-7.30 (m, 1H), 7.35-7.65 (m, 10H), 7.74 (s, 2H), 12.59 (brs, 2H)

ESI-MS m / z 563 ( MH) "C 28 H] 8 F 2 N 2 0 5 S 2 = 564 Example 1 40 (Compound 1 4 6)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.61 (s, 2H), 5.77 (s, 1H), 7.60 (s,

8H), 7.65-7.80 (m, 4H), 8.07 (d, J = 1.7 Hz, 1H), 12.61 (brs, 2H) ESI-MS m / z 606 (MH) "C ₂₈ H ₁₈ ³⁵ C1N ₃ 0 ₇ S ₂ = 607 Example 14 1 (Compound 1 4 7)

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.50 (s, 3H), 4.58 (s, 2H), 5.74 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.59 (s, 8H), 7.63 (dd, J = 1.3, 7.9 Hz, 1H), 7.75 (s, 2H), 7.96 (d, J = 1.3 Hz, 1H), 12.60 (brs, 2H)

ESI-MS m / z 586 ( MH) "C 29 H 21 N 3 0 7 S 2 = 587 Example 142 (Compound 148)

^] H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.67 (s, 2H), 5.78 (s, 1H), 7.61 (s, 8H), 7.67 (t, J2 7.9 Hz, 1H), 7.76 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 8.21 (s, 1H), 12.62 (brs, 2H)

ESI-MS m / z 572 ( MH) "C 28 H 19 N 3 0 7 S 2 two 573 Example 143 (Compound 149)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.55 (s, 2H), 5.76 (s, 1H), 7.45 (d,

J = 8.2 Hz, 1H), 7.50-7.70 (m, 10H), 7.74 (s, 2H), 12.59 (brs, 2H) ESI-MS m / z 595 (-H) "C 28 H 18 3 C1 2 N ₂ 0 ₅ S ₂ = 596 Example 144 (Compound 150)

Ή NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 4.62 (s, 2H), 5.75 (s, 1H), 7.50-7.70 (m, 12H), 7.75 (s, 2H), 12.58 (brs, 2H )

ESI-MS m / z 595 ( MH) "C 29 H 19 F 3 N 2 0 5 S 2 = 596 Example 145 (Compound 151)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.29 (s, 3H), 4.45 (s, 2H), 5.67 (s, 1H), 7.00-7.30 (m, 4H), 7.57 (s, 8H ), 7.73 (s, 2H) , 12.56 (brs, 2H) ESI-MS m / z 541 (MH) "C 29 H 22 N 2 0 5 S 2 - 542 example 146 (compound 152)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.62 (s, 2H), 5.75 (s, 1H), 7.60 (s, 8H), 7.61 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.75 (s, 2H), 12.59 (brs, 2H) ESI-MS m / z 595 ( MH) "C 29 H 19 F 3 N 2 0 5 S 2 = 596 Example 1 4 7 (Compound 1 5 3)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.58 (s, 2H), 5.74 (s, 1H), 7.45-7.80 (m, 13H), 7.83 (s, 1H), 12.60 (brs, 2H )

ESI-MS m / z 552 (MH) "C ₂₉ H ₁₉ N ₃ 0 ₅ S ₂ = 553 Example 1 4 8 (Compound 15 4)

'Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.45 (s, 3H), 4.45 (s, 2H), 5.65 (s, 1H), 7.27 (q, J = 8.2 Hz, 4H), 7.56 (s, 8H), 7.74 (s, 2H), 12.57 (brs, 2H) ESI-MS m / z 573 (MH) -C ₂₉ H ₂₂ N ₂ 0 ₅ S ₃ = 574 Example 1 4 9 (Compound 1 5 5)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.54 (s, 2H), 5.73 (s, 1H), 7.42 (d, J = 2.0 Hz, 2H), 7.52 (t, J = 2.0 Hz, 1H), 7.59 (s, 8H), 7.75 (s, 2H), 12.60 (brs, 2H)

ESI-MS m / z 595 ( MH) "C 28 H 18 35 C1 2 N 2 0 5 S 2 = 596 Example 1 5 0 (Compound 1 5 6)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.51 (s, 2H), 5.70 (s, 1H), 7.28-7.38 (m, 5H), 7.59 (s, 8H), 7.75 (s, 2H), 12.59 (brs, 2H)

FABMS m / z 529 (M + H) + C 28 H 2. N ₂ 0 ₅ S ₂ = 528 Example 15 1 (Compound 15 7)

H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.57 (s, 2H), 5.81 (s, 1H), 7.42 (dd, J. = 9.9, 2.3 Hz, 2H), 7.47 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 9.9 Hz, 1H), 12.60 (brs, 2H)

ESI-MS m / z 595 ( MH) + C 28 H 18 35 C1 2 N 2 0 5 S 2 = 596 Example 15 2 (Compound 15 8)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.30 (s, 3H), 4.46 (s, 2H), 5.66 (s, IH), 7.17 (d, J = 7.9 Hz, 2H), 7.25 ( d, J = 7.9 Hz, 2H), 7.58 (s, 8H), 7.75 (s, 2H), 12.59 (brs, 2H) Example 15 3 (Compound 15 9)

^{ Η NMR (270 MHz, DMS0-d ₆ ) 6 (ppm) 4.74 (s, 2H), 5.80 (s, IH), 7.60 (s, 8H), 7.75 (s, 2H), 8.02 (s, 1H) , 8.05 (s, IH), 12.60 (brs, 2H) Example 1 54 (Compound 16 0)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 3.85 (s, 3H), 4.60 (s, 2H), 5.73 (s,

1H), 7.53 (d, J = 8.3 Hz, 2H), 7.60 (s, 8H), 7.76 (s, 2H), 7.95 (d, J2 8.3 Hz, 2H), 12.61 (brs, 2H) 5 5 (Compound 1 6 1)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.21 (s, 6H), 4.42 (s, 2H), 5.66 (s,

1H), 7.05-7.13 (m, 2H), 7.53 (d, J2 8.2 Hz, IH), 7.58 (s, 8H), 7.75 (s, 2H), 12.61 (brs, 2H) Compound 16 2)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.54 (s, 2H), 5.73 (s, IH), 7.35 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz , 2H), 7.59 (s, 8H), 7.75 (s, 2H), 12.61 (brs, 2H) Example 15 7 (Compound 16 3)

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 0.88-1.00 (m, 2H), 1.09-1.35 (m, 3H), 1.64-1.76 (m, 6H), 3.22 (d, J = 5.7 Hz , 2H), 5.53 (s, 1H), 7.52 (d, J = 8.6 Hz, 4H), 7.57 (d, J = 8.6 Hz, 4H), 7.74 (s, 2H), 12.59 (brs, 2H) Example 1 58 (Compound 164)

Ή NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 1.21-1.27 (m, 2H), 1.50-1.51 (m, 4H), 1.68-1.73 (m, 2H), 2,18 (septet, J = 7.1 Hz, IH), 3.23 (d, J = 7.1 Hz, 2H), 5.55 (s, IH), 7.52 (d, J = 8.3 Hz, 4H), 7.57 (d, J = 8.3 Hz, 4H), 7.74 (s, 2H), 12.59 (brs, 2H)

FABMS m / z 521 (M + H) + C 27 H 24 N 2 0 5 S 2 = 520 Example 1 59 (Compound 1 6 5)

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 2.90 (t, J = 6.2 Hz, 2H), 3.63 (t, J 6.2 Hz, 2H), 5.59 (s, IH), 7.26 (dd, J = 8.2, 2.0 Hz, IH), 7.43 (d, J = 8.4 Hz, 4H), 7.527 (d, J = 8.4 Hz, 4H), 7.534 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 2.0 Hz), 7.71 (s, 2H), 12.62 (brs, 2H)

FABMS m / z 611 (M + H) + C 29 H 2n 35 Cl 2 N 2 0 5 S 2 = 610 Example 1 60 (Compound 1 6 6)

 Ή NMR (270 MHz, DMSO −) δ (ppm) 4.64 (s, 2H), 5.79 (s, 1H), 7.53-7.70 (m, 10H), 7.75 (s, 2H), 7.82-7.88 (m, IH ), 12.60 (brs, 2H)

FABMS m / z 615 (M + H) + C 29 H 18 F 4 N 2 0 5 S 2 = 614 Example 1 6 1 (Compound 1 6 7)

Ή NMR (270 MHz, DMSO- d _fi ) δ (ppm) 4.64 (s, 2H), 5.78 (s, IH), 7.58 (s, 8H), 7.64-7.71 (m, 2H), 7.75 (s, 2H ), 7.79-7.87 (m, 1H) , 12.61 (brs, 2H) FABMS m / z 615 (M + H) + C 29 H 18 F 4 N 2 0 5 S 2 = 614 example 1 62 (compound 1 68 )

^! H NMR (270 MHz, also DMSO-) δ (ppm) 4.65 (s, 2H), 5.78 (s, 1H), 7.43 (t, J = 7.7 Hz, IH), 7.58 (s, 8H), 7.71- _{7.74 (m 3 1H), 7.75} (s, 2H), 7.88 (t, J = 7.1 Hz, IH), 12.61 (brs, 2H) Example 163 (Compound 169)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.59 (s, 2H), 5.74 (s, 1H), 7.43-7.67

(m, 2H), 7.59 ( s, 8H), 7.72-7.75 (m, 1H), 7.75 (s, 2H), 12.57 (brs, 2H) FABMS m / z 615 (M + H) + C 29 H 18 F ₄ N ₂ 0 ₅ S ₂ = 614 Example 164 (Compound 170)

Ή NMR (270 MHz, DMS0-d ₆ ) 6 (ppm) 4.65 (s, 2H), 5.78 (s, 1H), 7.42-7.48 (m, 1H), 7.58 (s, 8H), 7.74 (s, 2H ), 7.77-7.87 (m ₅ 2H), 12.61 (brs, 2H) Example 165 (Compound 171)

^! H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 1.18-1.43 (m, 7H), 1.58-1.72 (m, 2H), 1.80-1.92 (m, 2H), 5.76 (s, 1H), 7.54 (s, 8H), 7.74 (s, 2H), 12.58 (brs, 2H) Example 166 (Compound 172)

^! H NMR (270 MHz, DMSO-) δ (ppm) 4.63 (s, 2H), 5.77 (s, 1H), 7.42-7.54 (m, 2H), 7.60 (s, 8H), 7.76 (s, 2H) , 7.76-7.80 (m, 1H), 12.61 (brs, 2H) Example 167 (Compound 173)

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 4.54 (s, 2H), 5.75 (s, 1H), 7.17 (t, J = 75.0 Hz, 1H), 7.22 (t, J = 74.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.59 (s, 8H), 7.75 (s, 2H), 12.61 (brs, 2H) Example 168 (Compound 174)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.50 (s, 2H), 5.70 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.1 Hz , 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.59 (s, 9H), 7.75 (s, 2H), 12.59 (brs, 2H) 169 (Compound 175) Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.59 (s, 2H), 5.75 (s, 1H), 7.55 (d,

J = 8.1 Hz, 2H), 7.60 (s, 8H), 7.71 (d, J2 8.1 Hz, 2H), 7.75 (s, 2H), 12.60 (brs, 2H) Example 170 (Compound 176)

»Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.62 (s, 2H), 5.78 (s, 1H), 7.52 (d, J 8.3 Hz, 2H), 7.58 (d, J = 8.4 Hz , 2H), 7.62-7.64 (m, 3H), 7.75 (s, 2H), 12.61 (brs, 2H) Example 171 (Compound 177)

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 4.76 (s, 2H), 5.85 (s, 1H), 7.60 (s, 8H), 7.76 (s, 2H), 8.01 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 12.59 (brs, 2H) Example 172 (Compound 178)

^! H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 7.57 (d, J 8.6 Hz, 4H), 7.64 (d, J 8.6 Hz, 4H), 7.77 (s, 2H), 12.65 (s , 2H)

ESI-MS m / z 505 ( MH) - C 22 H 13 F 3 N 2 0 5 S 2 = 506 Example 173 (Compound 179)

^[ Η NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 7.57-7.63 (m, 8H), 7.80 (s, 2H), 12.62 (s, 2H)

ESI-MS m / z 505 ( MH) "C 22 H 13 F 3 N 2 0 5 S 2 = 506 Example 1 7 4 (Compound 1 8 0)

H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 3.28 (s, 3H), 7.48 (d, J = 8.6 Hz, 4H),

7.68 (d, J = 8.6 Hz, 4H), 7.78 (s, 2H), 12.67 (s, 2H) Example 175 (Compound 18 1) Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 3.33 (s, 3H), 5.51 (s, 1H), 7.50 (s, 6H), 7.58 (s, 2H), 7.77 (s, 2H), 12.59 (s, 2H) Example 176 (Compound 182)

Step 1: Dissolve 2,2-bis (4-aminophenyl) hexafluoropropane (2.0 g, 6.0 mL) in acetone (40 mL) and concentrate with concentrated hydrochloric acid (5.2 mL) under ice-cooling. Sodium nitrite (1.2 g, 18 ol) dissolved in water (5 mL) was added and stirred at room temperature for 3 minutes. The reaction solution was heated to 35 ° C, methyl acrylate (3.2 mL, 36 ol) and copper (I) oxide (catalyst amount) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to 1/3, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate) to give 2,2-bis {4-[(2-chloro-2-methoxycarbonyl) ethyl] phenyl. Nil} -1,1,1,1,3,3,3-hexafluopropane (2.0 g, 61 mg) was obtained.

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.20 (dd, J = 14, 6.9 Hz, 2H), 3.40 (dd, J = 14, 6.9 Hz, 2H), 3.76 (s, 6H), 4.47 ( t, J = 6.9 Hz, 2H), 7.23 (d, J = 8.6 Hz, 4H), 7.32 (d, J = 8.6 Hz, 4H)

Step 2: The above compound (200 mg, 0.37 mmol) is dissolved in 2-methoxyethanol (5 mL), and thiopurea (84 mg, 1.1 ol) and sodium acetate (60 mg, 0.73 mmol) are added. The mixture was stirred at C for 3 hours. The reaction solution was cooled to room temperature, water and hexane were added, and the precipitated crystals were collected by filtration. The crystals were dissolved again in 2-methoxyethanol (5 mL), and thioperia (84 mg, 1.1 mmol) and sodium acetate (60 mg, 0.73 mmol) were added, followed by stirring at 100 ° C for 6 hours and 45 minutes. The reaction solution is cooled to room temperature, water and hexane are added, and the precipitated crystals are collected by filtration. 2,2-Bis {4-[(2-imino-4- 4-year-old oxothiazolidine-5-yl) methyl] [Fenyl] -1,1,1,1,3,3,3-hexafluorop mouth bread (118 mg, 57%) was obtained.

lE NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 2.85-3.00 (m, 2H), 3.30-3.50 (m, 2H), 4.59 (d, J 2 9.9 Hz, 1H), 4.61 (d, J = 9.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 4H), 7.35 (d, J = 8.1 Hz, 4H), 8.71 (brs, 2H), 8.96 (brs, 2H) Step 3: The above compound (820 mg, 1.5 mmol) was dissolved in 2-methoxyethanol (40 mL), added with mol / L hydrochloric acid (5.9 mL), and heated under reflux for 5 hours. Water was added to the residue, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The compound was purified with 1 hexane / ethyl acetate) and triturated with water to give compound 182 (264 mg ₅ 32%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.10-3.35 (m, 2H), 3.50-3.60 (m, 2H), 4.55 (d, J = 9.6 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 7.25 (d, J = 8.1 Hz, 4H), 7.32 (d, J = 8.1 Hz, 4H), 8.70 (brs, 1H), 8.73 (brs, 1H) Reference examples are shown below.

Reference Example 1: 4,4'-Diformyltrifenylamine and tris (4-formylphenyl) amine

 Under an argon atmosphere, tris (4-bromophenyl) amine (7.23 g, 15.0 mmol) was dissolved in THF (100 mL) and cooled to 178 ° C. N-Butyllithium (1.6 mol / L hexane solution; 34 mL, 54 mmol) and DMF (4.6 mL, 60 mmol) were added dropwise at an internal temperature of -60 ° C or lower, and the mixture was stirred at the same temperature for 10 minutes. . Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate, then 30: 1 chloroform / acetonitrile) to give 4,4, -diformyltriphenylamine (447 mg). , 10%) and tris (4-formylphenyl) amine (2.97 g, 60%).

4,4, -Diformylt rifenylamine:

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 7.18 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 8.6 Hz, 4H), 7.26 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.78 (d, J = 8.8 Hz, 4H), 9.90 (s, 2H)

FABMS m / z 302 (M + H) + C 20 H 15 N0 2 = 301

Tris (4-formylphenyl) amine: _{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 7.25 (d, J = 8.8 Hz, 6H), 7.85 (d, J =

8.8 Hz, 6H), 9.95 (s, 3H)

FABMS m / z 330 (M + H) + C 21 H 15 N0 3 = 329

Reference Example 2: 4,4'-dibromo-4 "-formyltriphenylamine and 4-bromo-4 ', 4" -diforminoletriphenylamine

 Under an argon atmosphere, tris (4-bromophenyl) amine (7.71 g, 16.0 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to 178 ° C. To this, n-butyllithium (1.6 mol / L hexane solution; 15 mL, 24 mL) and DMF (2.5 mL, 32 mmol) were added dropwise at an internal temperature of less than 60 ° C, and the temperature was raised to 0 ° C. While stirring for .20 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (8: 1 to 4: 1 hexane / ethyl acetate) and triturated with hexane to give 4,4, -dibromo-4 "-formyl. Triphenylamine (2.71 g, 39%) and 4-bromo-4,, 4 "-diformyltriphenylamine (2.46 g, 40%) were obtained.

 4,4'-dibromo-4 "-formyl rifenylamine

_{• HNR (300 MHz, CDC1 3} ) δ (ppm) 7.02 (d, J = 8.8 Hz, 4H), 7.04 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.8 Hz, 4H), 7.71 (d, J: 8.8 Hz, 2H), 9.84 (s, 1H)

FABMS m / z 433, 431, 429 (M ⁺ ) C ₁₉ H ₁₃ ⁷⁹ Br ₂ N0 = 429

4-promo-4 ', 4 "-diformyltriphenylamine

'Η NMR (300 MHz, CDC1 3) δ (ppm) 7.05 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.6 Hz, 4H), 7.50 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 4H), 9.91 (s, 2H)

FABMS m / z 382, 380 ( M + H) + C 20 H 14 79 BrN0 2 = 379 Reference Example 3: 4- [bis (4-Horumirufuweniru) amino] Biff: Y nil

Under an argon atmosphere, 4-bromo-4 ', 4 "-diformyltriphenylamine (37 mg, 0.097 mmol) obtained in Reference Example 2 was dissolved in 1,2-dimethoxetane (5 m Phenylboric acid (24 mg, 0.19 mmol), tetrakistriphenylphosphine palladium (5.6 mg, 5 mol%), and a 0.5 mol / L aqueous sodium carbonate solution (0.38 mL, 0.19 mmol) were added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4: 1 hexane / ethyl acetate) to obtain the title compound (29 mg, 79%).

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 7.24 (d, J = 8.4 Hz, 2H), 7.25 (d, J =

8.6 Hz, 4H), 7.37 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.5-.

7.7 (m, 4H), 7.80 (d, J 8.6 Hz, 4H), 9.91 (s, 2H)

FABMS m / z 378 (M + H) + C 26 H 19 N0 2 = 377

Reference Example 4: 2- {4- [bis (4-formylphenyl) amino] phenyl} furan

 Under an argon atmosphere, tris (dibenzylideneacetone) dipalladium: (9.2 mg, 0.010 mmol) and triphenylphosphine (10 mg, 0.040 mmol) were dissolved in THF (3 mL) and stirred at room temperature for 20 minutes. To this, 4-bromo-4,4,4 "-diformyltriphenylamine (38 mg, 0.10 mmol) obtained in Reference Example 2 and 2-tributylsylfuran (0.063 mL, 0.20 mmol) were added. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by thin-layer chromatography (5: 2 hexane / ethyl acetate) gave the title compound (23 mg, 63%).

^{! H NMR (300 MHz, CDC1} 3) δ (ppm) 6.49 (dd, J = 3.3, 1.8 Hz, 1H), 6.66 (dd, J = 3.3, 0.6 Hz, 1H), 7.18 (d, J = 8.8 Hz , 2H), 7.22 (d, J = 8.6 Hz, 4H), 7.48 (dd, J = 1.8, 0.6 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz , 4H), 9.90 (s, 2H)

^{FABMS m / z 367 (M +} ) C 24 H 17 N0 3 = 367

Reference Example 5: 2- {4- [bis (4_formylphenyl) amino] phenyl} thiophene 4-bromo-4 ', 4 "-diformyltriphenylamine obtained in Reference Example 2 (38 mg, 0.10 mmol) In the same manner as in Reference Example 4, the title compound (34 mg, 89%) was obtained from, and 2-triptylsylthiophene (0.063 mL, 0.20 mmol). _{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 7.09 (dd, J = 5.1, 3.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.4 Hz, 4H) , 7.3-7.4 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 4H), 9.90 (s, 2H)

^{FABMS m / z 383 (M +} ) C 24 H 17 N0 2 S two 383

Reference Example 6: 4,4, -Diformyl-4 "-(hydroxymethyl) triphenylamine

 Tris (4-formylphenyl) amine (165 mg, 0.502 mmol) obtained in Reference Example 1 was dissolved in methanol (8 mL) and chloroform (5 mL), and sodium borohydride (9.5 mg) was added under ice-cooling. , 0.25 mmol) and stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline 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 to 10: 1 chloroform / acetonitrile) to obtain the title compound (107 mg, 64%).

_{ln NMR (300 MHz, CDC1 3} ) δ (ppm) 2.11 (br s, 1H), 4.74 (s, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.8 Hz, 4H ), 7.41 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 4H), 9.89 (s, 2H)

FABMS m / z 332 (M + H) + C 21 H 17 N0 3 = 331

Reference Example 7: N- (4-bromopentyl) -4,4'-diformyldiphenylamine

 Under an argon atmosphere, diphenylamine (338 mg, 2.00 mmol) and 4-bromobenzyl bromide (500 mg, 2.00 mmol) were dissolved in DMF (8 mL), and sodium hydride (88 mg, 2.2 mmol) was dissolved in ice. ) Was added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (14: 1 hexane / acetone) to obtain N- (4-bromobenzyl) diphenylamine (478 mg, 71%).

Ή testimony _{(300 MHz, CDC1 3) δ} (ppm) 4.93 (s, 2H), 6.94 (tt, J = 7.3, 1.1 Hz, 2H), 7.03 (dd, J = 8.8, 1.1 Hz, 4H), 7.2- 7.3 (m, 6H), 7.42 (d, J = 8.6 Hz, 2H)

FABMS m / z 339, 337 (M ⁺ ) C ₁₉ H ₁₆ ⁷⁹ BrN = 337

N- (4-bromobenzyl) diphenylamine (34 mg, 0.10 mmol) and Xamethylenetetramine (280 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (4 mL) and heated under reflux for 20 minutes. The solvent was distilled off under reduced pressure to about half, water was added, the pH was adjusted to 8 with an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (3: 1 hexane / ethyl acetate) to obtain the title compound (17 mg, 43%).

_{^ NMR (300 MHz, CDC1 3} ) δ (ppm) 5.10 (s, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 4H), 7.45 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.8 Hz, 4H), 9.88 (s, 2H)

FABMS m / z 396, 394 (M + H) ⁺ C ₂₁ H ₁₆ ⁷⁹ BrN0 ₂ = 393

Reference Example 8: 4,4'-Diformyl-4 "-vinyltriphenylamine

In an argon atmosphere, 4,4'-dibromo-4 "-formyltriphenylamine (173 mg, 0.401 mmol) obtained in Reference Example 2 was dissolved in DMF (5 mL), and trimethylphosphonium bromide (179 mg, 0.50 mmol) was dissolved. ), Potassium carbonate (69 mg, 0.50 mmol), and 18-crown-6 (22 mg, 0.083 tmol) were added, and the mixture was stirred at room temperature for 5 hours, again trimethylphosphonium bromide (179 mg, 0.50 mmol). , Potassium carbonate (69 mg, 0.50 mmol), and 18-crown-6 (22 mg, 0.083 mmol), and the mixture was stirred at room temperature for 17 hours and at 50 ° C. for 5 hours. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (19: 1 hexane / ethyl acetate). '-Dipromo-4 "-vinyltriphenylamine (86 mg, 50%) was obtained. _{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 5.18 (d, J = 10.8 Hz, 1H), 5.64 (d, J two 17.6 Hz, 1H), 6.65 ( dd, J = 17.6, 10.8 Hz, 1H) , 6.93 (d, J = 8.8 Hz, 4H), 6.99 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.8 Hz, 4H)

FABMS m / z 427 (M + H) + C 2. H ₁₅ ⁷⁹ Br ₂ N = 427

Under an argon atmosphere, the above compound (85 mg, 0.20 mol) was dissolved in THF (2 mL) and cooled to 178 ° C. To this, n-butyllithium (1.6 mol / L hexane solution; 0.38 mL, 0.61 mmol) and DMF (0.077 mL, 0.80 mmol) were added dropwise, and the mixture was added for 10 minutes. Stirred. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (2: 1 hexane / ethyl acetate) to obtain the title compound (22 mg, 34%).

Ή thigh _{(300 MHz, CDC1 3) δ} (ppm) 5.29 (d, J = 11.4 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 6.72 (dd, J = 17.6, 11.0 Hz, 1H) , 7.12 (d, J = 8.4 Hz, 2H) ₅ 7.20 (d, J = 8.6 Hz, 4H), 7.43 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.8 Hz, 4H), 9.90 (s, 2H)

FABMS m / z 328 (M + H) + C 22 H 17 N0 2 = 327 Reference Example 9: 4, 4, - diformyl - 4 "- hydroxycarboxylic triphenyl amine

 4; 4'-Dibromo-4 "-formyltriphenylamine (862 mg, 2.00 mmol) obtained in Reference Example 2 was dissolved in dichloromethane (40 mL), and m-chloroperbenzoic acid (purity 50%, 2.08 g, 6.00 t) and stirred at room temperature for 20 minutes, further added m-chloroperbenzoic acid (purity 50%, 1.38 g, 4.00 mmol), and stirred at room temperature for 3 hours. An aqueous sodium solution was added, and the mixture was extracted with chloroform.The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The mixture was stirred at room temperature for 10 minutes, added with lmol / L hydrochloric acid (5 mL), and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by ram chromatography (6: 1 ethyl hexanenoacetate) gave 4,4'-dibromo-4 "-hydroxytrifurenylamine (436 mg, 52%).

^{! H NMR (300 MHz, CDC1} 3) δ (ppm) 5.14 (br s, 1H), 6.78 (d, J = 8.6 Hz, 2H), 6.88 (d, J: 8.8 Hz, 4H), 6.98 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.8 Hz, 4H)

FABMS m / z 421, 419, 417 (M + H) ⁺ C ₁₈ H ₁₃ ⁷⁹ Br ₂ N0 = 416

Under an argon atmosphere, the above compound (466 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), and tert-butyldimethylsilyl chloride (252 mg, 1.67 bandol) and Imidazole (151 mg, 2.22 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, 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 4,4'-dibromo-4 "-(tert-butyldimethylsilyloxy) triphenylamine ( 436 mg, 745 were obtained.

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 0.21 (s, 6H), 0.99 (s, 9H), 6.77 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 4H) , 6.95 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 4H)

FABMS m / z 535, 533, 531 (M ⁺ ) C ₂₄ H ₂₇ ⁷⁹ Br ₂ N0Si = 531

 The above compound (409 mg, 0.767 mol) was dissolved in THF (5 mL) and cooled to -78 ° C. To this, n-butyllithium (1.6 mol / L hexane solution; 1.5 mL, 2.4 mmol) and DMF (0.24 mL, 3.1 mmol) were added dropwise and stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5: 1 hexane / ethyl acetate) to give 4- (tert-butyldimethylsilyloxy) -4 ', 4 "-diformyltriphenylamine. (178 mg, 54%).

Ή thigh _{(300 MHz, CDC1 3) δ} (ppm) 0.16 (s, 6H), 0.91 (s, 9H), 6.78 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H) , 7.07 (d, J = 8.8 Hz, 4H), 7.66 (d, J = 8.8 Hz, 4H), 9.76 (s, 2H)

FABMS m / z 432 (M + H) + C 26 H 29 N0 3 Si = 431

 The above compound (176 mg, 0.408 mmol) was dissolved in THF (4 mL), and a 1 mol / L THF solution (0.4 mL) of tetrabutylammonium fluoride was added under ice-cooling, followed by stirring for 10 minutes. . A 0.1 mol / L aqueous solution of citrate was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (3: 2 hexane / ethyl acetate) to obtain the title compound (127 mg, 98%).

_{lH NMR (300 MHz, CDC1 3} ) δ (ppm) 6.94 (d, J = 8.8 Hz, 2H), 7.05 (d, J two 8.8 Hz, 2H), 7.17 ( d, J = 8.8 Hz, 4H), 7.31 (br s, 1H), 7.76 (d, J = 8.6 Hz, 4H), 9.85 (s, 2H)

FABMS m / z 318 (M + H) + C 20 H 15 N0 3 = 317 Reference Example 1 0: 4,4'-diformyl - 4 "- Main butoxy DOO Rifueniruami down

 In an argon atmosphere, 4,4'-diformyl-4 "-hydroxytriphenylamine (75 mg, 0.24 tmol) obtained in Reference Example 9 was dissolved in DMF (3 mL), and potassium carbonate (66 mg, 0.48 mmoD and iodide Methyl (0.154 mL, 2.4 mmol) was added, and the mixture was stirred for 3.5 hours at 50 ° C. Water was added to the reaction mixture, which was extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (70 mg, 88%).

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 3.85 (s, 3H), 6.94 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 8.6 Hz, 4H), 7.76 (d, J = 8.6 Hz, 4H), 9.87 (s, 2H)

FABMS m / z 332 (M + H) + C 21 H 17 N0 3 = 331 Reference Example 1 1: 4 Shiano - 4 ', 4 "- Jihorumiruto Rifueniruamin

Under an argon atmosphere, 4-diphenylaminobenzaldehyde (273 mg, 1.00 bandol) was dissolved in acetonitrile (10 mL), and hydroxylamine hydrochloride (104 mg, 1.50 mmol) ヽ and triethylamine (0.209 mL, 1.50 mL) were dissolved. mmol) and stirred for 30 minutes. To the mixture was added anhydrous anhydride (222 mg, 1.50 mmol), and the mixture was stirred for 11 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To this was added trifluoroacetic acid (20 mL) and hexamethylenetetramine (1.40 g, 10.0 t ol), and the mixture was heated under reflux for 15 minutes. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2: 1 hexane / ethyl acetate) to obtain the title compound (119 mg, 37 °). _{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 7.20 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 4H), 7.61 (d, J = 9.0 Hz, 2H), 7.85 (d, J = 8.8 Hz, 4H), 9.95 (s, 2H)

FABMS m / z 327 (M + H) ⁺ C ₂₁ H ₁₄ N ₂ 0 ₂ = 326 Reference Example 12: 4,4'-Diformyl-4 "-methyltriphenylamine

 4-Diphenylaminobenzaldehyde (500 mg, 1.83 mmol) was dissolved in chloroform / methanol (9: 1, 15 mL), and sodium borohydride (70 mg, 1.8 ol) was added under ice cooling. Stir for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Pyridine (10 mL) and acetic anhydride (0.29 mL, 3.0 ol) were added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ether. The organic layer was washed with a 0.1 mol / L aqueous solution of citric acid, water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), 10% palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (9: 1 hexane / ethyl acetate). 4-methyltriphenylamine (373 mg, 79% in three steps) ).

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 2.31 (s, 3H), 6.9-7.1 (m, 10H), 7.2-7.3 (m, 4H)

FABMS m / z 259 (M ⁺ ) C ₁₉ H ₁₇ N = 259

 Under an argon atmosphere, the above compound (130 mg, 0.502 mmol) was dissolved in DMF (3 mL), phosphorus oxychloride (0.92 mL, 10.0 mmol) was added, and the mixture was stirred at 100 ° C for 7 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (9: 1 to 5: 1 hexane Z ethyl acetate) to obtain the title compound (69 mg, 44%).

^{! H NMR (300 MHz, CDC1} 3) δ (ppm) 2.39 (s, 3H), 7.07 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.8 Hz, 4H), 7.21 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.8 Hz, 4H), 9.89 (s, 2H)

FABMS m / z 316 (M + H) ⁺ C ₂₁ H ₁₇ N0 ₂ = 315 Reference Example 13: N-aryl-4,4, -diformyldiphenylamine

Under an argon atmosphere, diphenylamine (3,38 g, 20.0 mmol) was dissolved in DMF (30 m), and under ice-cooling, arylpromide (2.1 mL, 24 t ol) and sodium hydride (960 mg, 24 recitation) ol), and the mixture was stirred at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. Then, N-aryldiphenylamine (4.49 g, quantitative) was obtained.

^{! H NMR (300 MHz, CDC1} 3) δ (ppm) 4.36 (dt, J = 4.8, 1.8 Hz, 2H), 5.16 (dq, J = 10.3, 1.7Hz, 1H), 5.26 (dq, J = 17.2, 1.7 Hz, 1H), 5.93 (m, 1H), 6.9-7.1 (m, 6H), 7.2-7.3 (m, 4H)

Under an argon atmosphere, the above compound (4.13 g, 19.8 mmol) was dissolved in DMF (120 mL), phosphorus oxychloride (36 mL, 0.40 mmol) was added under ice cooling, and the mixture was stirred at 100 ° C for 3 hours. . The reaction solution was ice-cooled, poured into a 1.2 mol / L aqueous sodium carbonate solution (1.0 L), and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4: 1 to 3: 1 hexane / ethyl acetate) to obtain the title compound (1.25 g, 24%) c-NMR (300 MHz, CDC1 ₃ ) δ (ppm) 4.52 (dt, J = 4.6, 2.2 Hz, 2H), 5.2-5.3 (m, 2H), 5.93 (m, 1H), 7.21 (d, J = 8.6 Hz, 4H), 7.82 ( d, J2 8.8 Hz, 4H), 9.89 (s, 2H)

FABMS m / z 266 (M + H) + C 17 H 15 N0 2 = 265 Reference Example 1 4: 2- (4-click every mouth phenylene thio) -3, 5-formyl-thiophene

5-Bromo-2- (4-chlorophenylthio) thiophene-3-carboxyaldehyde (1.00 g, 2.99 mmol) was dissolved in methanol (75 mL), and p-toluenesulfonic acid (52 mg, 0.30 rnol) was added. The mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure to about 30 mL, water and a saturated aqueous solution of sodium hydrogen carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2- (4-chlorophenylthio) -3- (dimethoxymethyl) thiol. (1.12 g, 100%).

'Η NMR (300 MHz, CDC1 3) δ' (ppm) 3.36 (s, 6H), 5.55 (s, 1H), 7.07 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.24 ( d, J = 8.8 Hz, 2H)

= 378 FABMS m / z 380, 378 (M ⁺ )

= 378

 The above compound (175 mg, 0.46 mmol) was dissolved in THF (6 mL) and cooled to 178 ° C. N-Butyllithium (1.6fflol / L hexane solution; 0.45 inL, 0.72 mmol) and DMF (0.072 mL, 0.93 mmol) were added dropwise thereto, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (15: 1 hexane / ethyl acetate) to give 2- (4-chlorophenylthio) -3- (dimethoxymethyl) thiophen-5-carboxy. The aldehyde (109 mg, 72%) was obtained.

_{Ή NMR (300 MHz, CDC1 3} ) δ (ppm) 3.34 (s, 6H), 5.50 (d, J = 0.7 Hz 5 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 1.1 Hz, 1H), 10.1 (s, 1H)

FABMS m / z 329 (M + H) ⁺ C ₁₄ H ₁₃ ³⁵ C10 ₃ S ₂ = 328

 The above compound (108 mg, 0.329 mmol) was dissolved in THF (4 mL), 1 mol / L hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (89 mg, 96%).

^{! H NMR (300 MHz, CDC1} 3) δ (ppm) 7.49 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 8.00 (s, 1H), 9.72 (s, 1H ), 10.0 (s, 1H)

FABMS m / z 283 (M + H) ⁺ C ₁₂ H ₇ ³⁵ C10 ₂ S ₂ = 282 Reference Example 15: 4-carboxy-4 ', 4 "-diformyltriphenylamine

Step 1: 4- (diphenylamino) benzaldehyde (10.2 g, 37.3 mmol) was suspended in 2-methyl-2-propanol (100 mL), and 2-methyl-2-butene (40 mL, 380 mmol) chlorite was added. Sodium (13.5 g, 150 mmol) and sodium dihydrogen phosphate (13.6 g, 113 mmmoD water (50 mL) were added, and the mixture was stirred at room temperature for 26 hours. After adding until pH 1, it was extracted with black-mouthed form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from hexane (500 mL) to obtain 4- (diphenylamino) benzoic acid (9.34 g, 87%).

_{Ή NR (270MHz, CDC1 3)} δ (ppm) 6.98 (d, J = 8.6 Hz, 2H), 7.08-7.20 (m, 6H), 7.25-7.35 (m, 4H), 7.90 (d, J = 8.6 Hz , 2H)

Step 2: The above compound (9.09 g, 31.4 mol) was dissolved in trifluoroacetic acid (200 mL), hexamethylenetetramine (22.6 g, 161 mmol) was added, and the mixture was heated under reflux for 24 hours. The reaction solution was cooled to room temperature, concentrated hydrochloric acid and water were added, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100: 10: 1 column / methanol / water) to obtain the title compound (6,47 g, 60%).

Ή NMR (270 negation _{z, CDC 1 3 (ppm)} 7.22 (d, J two 8.9 Hz, 2H), 7.25 ( d, J. = 8.7 Hz, 4H), 7.85 (d, J = 8.7 Hz, 4H), 8.08 (d, J = 8.9 Hz, 2H), 9,77 (br s, 1H), 9.93 (s, 2H) Reference Example 16: N- (tert-butoxycarbonyl) -4,4, -diformyldiphenylamine Step 1: 4,4'-Dibromodiphenylamine (2.13 g, 6.51 mmol) was dissolved in THF (100 mL), di-butyl dicarbonate (3.00 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 8 hours. Then, the mixture was heated under reflux for 4 hours, then 4-dimethylaminopyridine (1.70 g, 13.9 mmol) was added and the mixture was heated under reflux for further 4 hours, the reaction solution was cooled to room temperature, and an aqueous solution of sodium hydrogencarbonate was added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform form). tert - Bed Tokishikarubo sulfonyl) -. 4,4-dibromo-diphenyl obtain a enyl § Min (2.50 g, 99%) » H Anonymous _{(270MHz, CDC1 3) 5 (} ppm) 1.44 (s, 9H), 7.06 ( d, J = 8.9 Hz, 4H), 7.42 (d, J two 8.9 Hz, 4H)

Step 2: The above compound (1.47 g, 3.46 mmol) was dissolved in THF (20 mL) and cooled to -78 ° C. Then n-butyl lithium (1.50 mol / L hexane solution; 6.0 mL, After adding 9.0 mmol) and stirring at the same temperature for 40 minutes, DMF (1.10 mL, 14.3 mol) was added, and the mixture was further stirred at the same temperature for 30 minutes. Then, the mixture was heated to room temperature and stirred at the same temperature for 8 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with black hole form. The organic layer was washed with saturated saline 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: 1-6: 1-3: 1-2: 1 hexane Z ethyl acetate) to obtain the title compound (739 mg, 79%). Was. _{Ή NMR (270MHz, CDC1 3)} δ (ppm) 1.47 (s, 9H), 7.35 (d, J = 8.4 Hz, 4H), 7.86 (d, J = 8.4 Hz, 4H), 9.98 (s, 2H) Reference Example 17: 4,4, -Diformyldiphenylamine

Reference Example 16 6-Butoxycarbonyl) -4,4'-diformyldiphenylamine (2.33 g, 7.16 mmol) obtained in 16 was dissolved in dichloromethane (20 mU), and drifluoroacetic acid (10 mL) was added at room temperature. A 6 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform.The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Trituration with methanol gave the title compound (1.18 g, 73%).

_{JH NMR (270MHz, CDC1 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 18: 2,2-bis (4-formylphenyl) propionic acid ethyl ester Step 1: 2,2-bis (4-tolyl) propionic acid ethyl ester

 Under ice-cooling, pyruvate ethyl ester (3.2 mL, 29 ol) was dissolved in concentrated sulfuric acid (24 mL), toluene (6.9 mL, 65 mmol) was added thereto, and the mixture was stirred at 5 ° C for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (7.8 g, 61%).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.12 (t, J = 6.9 Hz, 3H), 1.80 (s, 3H), 2.27 (s, 6H), 4.12 (q, J = 6.9 Hz, 2H), 7.03 (d, J = 8.3 Hz, 4H), 7.11 (d, J = 8.3 Hz, 4H) Step 2: Ethyl 2,2-bis (4-bromomethylphenyl) propionate

Ethyl 2,2-bis (4-tolyl) propionate (10 g, 35 ol) was dissolved in carbon tetrachloride (200 mL), and N-promosquenimide (14 g, 78 t ol) was added. And azobisisobutyronitrile (catalytic amount) were added, and the mixture was heated under reflux for 2 hours and 15 minutes. The reaction solution was cooled to room temperature, and the precipitate was removed by filtration under reduced pressure. The filtrate was distilled off under reduced pressure to obtain the title compound (18 g, quantitative).

Ή NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.13 (t, J = 7.1 Hz, 3H), 1.84 (s, 3H), 4.14 (q, J = 7.1 Hz, 2H), 4.68 (s, 4H), 7.14 (d, J = 8.1 Hz, 4H), 7.39 (d, J two 8.1 Hz, 4H)

Step 3: Ethyl 2,2-bis (4-acetoxymethylphenyl) propionate Ethyl 2,2-bis (4-bromomethylphenyl) propionate (16 g, 35 t) was added to DMF (98 mL). ), Sodium acetate (12 g, 140 ol) was added thereto, and the mixture was stirred at 120 ° C for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (6: 1 to 4: 1 hexane / ethyl acetate) to obtain the title compound (7.0 g, 34%). H NMR (270 MHz, DMS0-d ₆ ) δ (ppm) 1.14 (t, J 2 7.3 Hz, 3H), 1.85 (s, 3H), 2.06 (s, 6H), 4.14 (q, J = 7.3 Hz , 2H), 5.05 (s, 4H), 7.16 (d, J = 8.3 Hz, 4H), 7.32 (d, J = 8.3 Hz, 4H)

Step 4: Ethyl 2,2-bis (4-hydroxymethylphenyl) propionate Ethyl 2,2-bis (4-acetoxymethylphenyl) propionate (6.8 g, 18 ol) was added to methanol (180 Then, a 2 mol / L aqueous sodium hydroxide solution (53 mL, 110 mol / l) was added thereto, and the mixture was stirred at room temperature for 2 hours and 15 minutes. After 2 mol / L hydrochloric acid was added to the reaction solution to neutralize it, methanol was distilled off under reduced pressure. Water and then 2 mol / L hydrochloric acid were added to the residue to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2: 1 to 1: 1 hexane / ethyl acetate) to obtain the title compound (4.2 g, 79%).

_{lH NMR (270 MHz, CDC1 3} ) δ (ppm) 1.21 (t, J = 7.1 Hz, 3H), 1.91 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H), 4.67 (s, 4H), 7.21 (d, J = 8.4 Hz, 4H), 7.30 (d, J = 8.4 Hz, 4H)

Process 5 Ethyl 2,2-bis (4-formylphenyl) propionate

 Dissolve 2,2-bis (4-hydroxymethylphenyl) propionic acid ethyl ester (3.73, 12 thighs1) in chloroform (120 mL), and add manganese dioxide (20 g, 240 mol) to it. The mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, and the precipitate was removed by filtration under reduced pressure. The residue was concentrated under reduced pressure, purified by silica gel column chromatography (4: 1 to 2: 1 hexane / ethyl acetate), and 2,2-bis (4-formylphenyl) propionic acid ethyl ester (2.9 g, 80% ).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 1.22 (t, J = 7.3 Hz, 3H), 1.99 (s, 3H), 4.24 (q, J = 7.3 Hz, 2H), 7.40 (d, J = 8.6 Hz, 4H), 7.85 (d, J = 8.6 Hz, 4H), 10.02 (s, 2H) Reference example 19: 2,2-bis (4-formylphenyl) propanol

Step 1: 2,2-bis (4-hydroxymethylphenyl) propanol

 Reference Example 18 A THF solution (50 mL) of 2,2-bis (4-acetoxymethylphenyl) propionic acid ethyl ester (1.3 g, 3.2 mmol) obtained according to Step 3 of Example 8 was added under argon atmosphere. And lithium aluminum hydride (370 mg, 9.6 mmol) suspended in THF (90 mL) were added dropwise under ice-cooling, and the mixture was stirred at 0 ° C for 25 minutes and then at room temperature for 1 hour and 20 minutes. . Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and 20 minutes. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (600 mg, 69%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 1.68 (s, 3H), 4.02 (s, 2H), 4.58 (s, 4H), 7.18 (d, J = 8.2 Hz, 4H), 7.26 (d, (J = 8.2 Hz, 4H)

Step 2: 2,2-bis (4-formylphenyl) propanol

The above 2,2-bis (4-hydroxymethylphenyl) propanol (0.6 g, 2.2 mmol) was dissolved in DMF (100 mL), and manganese dioxide (3.8, 44 t1) was added thereto. The mixture was stirred for 16 hours and 35 minutes, and then at 60 ° C for 4 hours and 20 minutes. The reaction solution was cooled to room temperature, and the precipitate was removed by filtration under reduced pressure. Add water to the residue and add ethyl acetate Extracted. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (410 mg, 70%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 1.77 (s, 3H), 4.16 (s, 2H), 7.40 (d, J

= 8.4 Hz, 4H), 7.83 (d, J = 8.6 Hz, 4H), 9.99 (s, 2H) Reference Example 20: 2,2-bis (4-formylphenyl) -1-methoxypropane

 Reference Example 19 2,2-Bis (4-formylphenyl) propanol (650 mg, 2.4 ol) obtained in Step 2 of Step 9 is dissolved in methyl iodide (26 mU) under shading, and the silver oxide ( 1.7 g, 7.3 mmol) and stirred for 5 hours and 40 minutes at 50 ° C. Silver oxide (1.1 g, 4.8 mmol) was added to the reaction solution, and the mixture was further stirred at 50 ° C. for 40 minutes. After filtration through celite, water was added to the filtrate, extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5: 1 to 4: 1 hexane Z ethyl ethyl acetate). The title compound (140 mg, 20%) was obtained.

l NMR (270 negation _{z, CDC1 3) δ (ppm} ) 1.78 (s, 3H), 3.36 (s, 3H), 3.84 (s, 2H), 7.38 (d, J = 8.2 Hz, 4H), 7.81 (d , J = 8.6 Hz, 4H), 9.97 (s, 2H) Reference Example 21: 1,1, bis (4-formylphenyl) ethanol

Step 1: 1, tribis (4-bromophenyl) ethanol

 4,4, -Dibromopenzophenone (500 mg, 1.5 mmol) was dissolved in THF (10 mL) and cooled to-† 8 ° C under an argon atmosphere. To this, methyllithium (1.14 mol / L gethyruether solution; 3.9 mL, 4.4 mmol) and then DMF (2 mL) were added dropwise so that the internal temperature would be -60 ° C or lower. After completion of the dropwise addition, the mixture was stirred for 15 minutes while raising the temperature to 0 ° C. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (560 mg, quantitative).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 1.90 (s, 3H), 7.26 (d, J = 8.6 Hz, 4H), 7.43 (d, J = 8.6 Hz, 4H)

Step 2: 1,1-bis (4-formylph: r: nil) ethanol

The above 1,1-bis (4-bromophenyl) ethanol (562 mg, 1.6 t ol) was added to THF (28 mL) and cooled to −78 ° C. under an argon atmosphere. To this, n-butyllithium (1.6 mol / L hexane solution; 9.9 mL, 16 mmol) and then DMF (2 mL) were added dropwise at an internal temperature of -60 ° C or lower, and the temperature was raised to 0 ° C. While stirring for 15 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, silica gel column chromatography:;: was purified by (4 1-1 hexane / acetic Echiru to 1) to give the title compound (150 mg ₃ 38%).

Ή thigh _{(270 MHz, CDC1 3) δ} (ppm) 2.03 (s, 3H), 7.60 (d, J = 8.2 Hz, 4H), 7.85 (d, J = 8.2 Hz, 4H), 9.99 (s, 2H) Reference Example 2 2: 1, tribis (4-formylphenyl) -tolmetoxetane

Step 1: 1,1-bis (4-bromophenyl) -1-methoxetane

 Reference Example 2 1, Tobis (4-butamophenyl) ethanol (530 mg, 1.4 ol), which was obtained according to Step 1 of 1, was dissolved in DMF (5 mL), and cooled to 60% hydrogen under ice-cooling. Sodium chloride (56 mg, 1.4 tmol) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added methyl iodide (0.087 mL, 1.4 tmol), and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (560 mg, quantitative).

'Η NMR (270 MHz, CDC1 3) δ (ppm) 1.80 (s, 3H), 3.12 (s, 3H), 7.19 (d, J = 8.6 Hz, 4H), 7.41 (d, J = 8.6 Hz, 4H )

Process 2: 1,1-bis (4-formylphenyl) -trimethoxetane

The above 1,1-bis (4-promophenyl) -1-methoxetane (560 mg, 1.5 ol) was dissolved in THF (30 mL) and cooled to −78 ° C. under an argon atmosphere. Here, n-butyllithium (1.6 mol / L hexane solution; 9.5 mL, 15 mmol) and then DMF (2.3 mL) were added dropwise so that the internal temperature would be below -60 ° C. The mixture was stirred for 15 minutes while raising the temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (6: 1 to 4: 1 hexane / ethyl acetate) to obtain the title compound (160 mg, 40%). _{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 1.93 (s, 3H), 3.19 (s, 3H), 7.54 (d, J = 8.6 Hz, 4H), 7.84 (d, J = 8.6 Hz, 4H) , 9.99 (s, 2H) Reference Example 23: 1, Tobis (4-formylphenol)-Toletokishetan

 The title compound was obtained in the same manner as in Reference Example 22 except for using methyl iodide instead of methyl iodide.

* H NMR (270 MHz, CDC1 3) δ (ppm) 1.24 (t, J = 6.9 Hz, 3H), 1.93 (s, 3H), 3.32 (q, J = 6.9 Hz, 2H), 7.55 (d, J = 8.2 Hz, 4H), 7.83 (d, J = 8.2 Hz, 4H), 9.98 (s, 2H) Reference Example 24: Tri (3,4-dichlorobenzyloxy)-1, Tri [bis (3-Hミ ル フ ミ ル ミ ル

Step 1: 1,1-bis (3-bromophenyl) ethanol

 Instead of 4,4′-dibromobenzophenone, it can be synthesized by a method described in Chemische Berchte (Chen L. Ber.), Vol. 124, pp. 897-902 (1991). The title compound was obtained in the same manner as in Step 1 of Reference Example 21 except that dibromobenzophenone was used. ,

Step 2: 1- (3,4-dichlorobenzyloxy) -1,2- [bis (3-promophenyl)] ethane

 Except that the above 1,1-bis (3-bromophenyl) ethanol was used instead of 1, tribis (4-bromophenyl) ethanol and 3,4-dichlorobenzylamide was used instead of methyl iodide. The title compound was obtained in the same manner as in Step 1 of Reference Example 22.

Step 3: 1- (3,4-dichlorobenzyloxy) -1, tri [bis (3-formylphenyl)]

 Other than using the above 1- (3,4-dichloropentyl benzoyloxy) -1, 1,2- [bis (3-bromophenyl)] ene instead of 1,2-bis (4-bromophenyl) -tomethoxetane In the same manner as in Step 2 of Reference Example 22, the title compound was obtained.

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 2.04 (s, 3H), 4.29 (s, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.40-7.44 (m, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H ), 7.92 (s, 2H), 10.00 (s, 2H) Reference Example 25: 4,4 '-(hexafluoroisopropylidene) bis (benzaldehyde Step 1: 4,4'-(hexafluoro Loisopropylidene) bis (benzyl alcohol) Lithium aluminum hydride (730 mg, 19 mmol) was suspended in THF (150 mL) under an argon atmosphere, and 4,4 '-(hexafluoroisopropyl) was suspended in ice. A THF solution (150 mL) of (redene) bis (benzoic acid) (2.5 g, 6.4 t ol) was added dropwise, and the mixture was stirred for 1 hour and 55 minutes at 60 ° C. The sodium sulfate decahydrate was added to the reaction solution. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.3 g, 97%).

'Η NMR (270 MHz, DMS0-d ₆ ) ό "(ppm) 4.54 (d, J = 5.6 Hz, 4H), 5,30 (t, J = 5.6 Hz, 2H), 7.29 (d, J = 8.3 Hz, 4H), 7.43 (d, J = 8.3 Hz, 4H), step 2: 4,4,-(hexafluoroisopropylidene) bis (benzaldehyde) 4,4 '-(hexafluoro) Loisopropylidene) bis (benzyl alcohol) (2.3 g, 6.9 t) was dissolved in chloroform (110 mL), and manganese dioxide (18 g, 210 t) was added thereto. The reaction solution was filtered using celite, and the filtrate was evaporated under reduced pressure to obtain the title compound (1.9 g, 84).

Ή NMR (270 MHz, D S0-d ₆ ) δ (ppm) 7.58 (d, J = 8.6 Hz, 4H), 8.03 (d, J = 8.6 Hz, 4H), 10.07 (s, 2H) Reference Example 26 : 2,2-bis (4-formylphenyl) -1,3-dioxolan

Step 1: Benzophenone-4,4'-dicarboxylic acid dimethyl ester

Benzophenone-4,4'-dicarboxylic acid (23 g, 85 t) was dissolved in thionyl chloride (100 mL), DMF (catalytic amount) was added, and the mixture was heated under reflux for 45 minutes. Excess thionyl chloride was distilled off under reduced pressure, and dichloromethane (100 mL) was added to the residue. This solution was slowly added dropwise to methanol (1000 mL), and the precipitated crystals were collected by filtration. The title compound (23 g, 89%) was obtained.

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.97 (s, 6H), 7.85 (d, J = 8.1 Hz, 4H), 8.16 (d, J = 8.1 Hz, 4H)

Step 2: 2,2-bis (4-methoxycarbonylphenyl) -1,3-dioxolane

 The above benzophenone-4,4'-dicarboxylic acid dimethyl ester (3 g, lOmmol) was dissolved in toluene (33 mL), and diethylene glycol (1.7 mL, 30 mmol) and 4-toluenesulfonic acid monohydrate ( The amount of the catalyst was added, and the mixture was heated and refluxed for 4.5 hours while dehydrating using a generous reaction tube. The reaction solution was cooled to room temperature, and the precipitated crystals were removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (2.2 g, 6450).

_{Ή NR (270 MHz, CDC1 3} ) δ (ppm) 3.97 (s, 6H), 4.08 (s, 4H), 7.85 (d, J = 8,1 Hz, 4H), 8.16 (d 3 J = 8.1 Hz, 4H)

Step 3: 2,2-bis (4-hydroxymethylphenyl) -1,3-dioxolan

 Lithium aluminum hydride (480 mg, 13 mmol.) Was suspended in THF (33 mL) under an argon atmosphere, and the above 2,2-bis (4-methoxycarbonylphenyl) -1.3 was suspended on ice. A solution of -dioxolane (2.2 g, 6.3 mmol) in THF (30 mL) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.5 g, 85%).

_{Ή NMR (270 MHz, CDC1 3} ) ό "(ppm) 4.05 (s, 4H), 4.65 (s, 4H), 7.31 (d, J

= 8.6 Hz, 4H), 7.49 (d, J = 8.6 Hz, 4H)

Process 4: 2,2-bis (4-formylphenyl) -1,3-dioxolan

The above 2,2-bis (4-hydroxymethylphenyl) -1,3-dioxolane (1.5 g, 5.2 mmol) was dissolved in a mixed solvent of chloroform (52 mL) and DMF (10 mL). Manganese dioxide (9.1 g, 110 ol) was added thereto, and the mixture was stirred at room temperature for 25 hours and 15 minutes. Manganese dioxide (2.1 g, 23 t ol) was added to the reaction solution, and the mixture was heated under reflux for 3 hours. The reaction solution was filtered using celite, and the filtrate was distilled off under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.1, 73%). ^{! H NMR (270 MHz, CDC1} 3) δ (ppm) 4.10 (s, 4H), 7.70 (d, J = 8.4 Hz, 4H), 7.86 (d, J = 8.4 Hz, 4H), 10.00 (s, 2H Reference Example 27: 1,1, bis (4-formylphenyl) cyclohexane

Step 1: 1,1-bis (4-hydroxymethylphenyl) cyclohexane

 Lithium aluminum hydride (350 mg, 9.2 mmol) was suspended in THF (20 mL) under an argon atmosphere, and the mixture was cooled with ice under a method described in EP414062 published in Europe. A THF solution (11 mL) of 4-carboxylphenyl) cyclohexane (1 g, 3.1 ol) was added dropwise, and the mixture was stirred at 70 ° C for 2 hours. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (830 mg, 91%).

'Η NMR (270 MHz, CDC1 3) δ (ppm) 1.45-1.65 (m, 6H), 2.25-2.35 (m, 4H), 4.63 (s, 4H), 7.27 (s, 8H)

Step 2: 1,1-bis (4-formylphenyl) cyclohexane

 The above 1,2- (4-hydroxymethylphenyl) cyclohexane (830 mg, 2.8 mmol) was dissolved in chloroform (20 mL), and manganese dioxide (7.3 g, 84 t ol) was added. Was added and stirred at room temperature for 1.5 hours. After heating under reflux for 2 hours, the reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (7: 1 hexane / ethyl acetate) to obtain the title compound (580 mg, 71%).

^{! H NMR (270 MHz, CDC1} 3) δ (ppm) 2.25-2.40 (m, 4H), 2.45-2.65 (m 3 6H), 7.46 (d, J = 8.3 Hz, 4H), 7.80 (d, J = 8.3 Hz, 4H), 9.96 (s, 2H) Reference Example 28: 4,4, -Diformylpenzhydrol ''

4,4'-Dibromobenzhydryl (500 mg, 1.5 mmol) was dissolved in THF (20 mL) and cooled to 178 ° C under an argon atmosphere. To this, n-butyllithium (1.5 mol / L hexane solution; 5.9 mL, 8.8 mmol) and then DMF (0.7 mL) were added dropwise at an internal temperature of -60 ° C or lower, and the temperature was raised to 0 ° C. Stir for 15 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer is washed with water and a saturated saline solution, and dried over anhydrous magnesium sulfate. Dried. The solvent was distilled off under reduced pressure, was purified by silica gel column chromatography (3: 1-2 hexane / acetic Echiru to 1), the title compound _{(110 mg, 31%) c} NMR (270 MHz , which was obtained, CDC1 ₃ ) δ (ppm) 2.47 (d, J = 3.3 Hz, 1H), 5.99 (s, 1H), 7.57 (d, J = 7.9 Hz, 4H), 7.88 (d, J = 8.3 Hz, 4H), 10.00 ( s, 2H) Reference Example 29: 4,4, -Diformylbenzophenone

 4,4, -Diformylpenzhydrol (100 mg, 0.42 mmol) obtained in Reference Example 28 was dissolved in chloroform (10 mL), and manganese dioxide (720 mg, 8.3 mmol) was added thereto. Stirred for 24 hours. The precipitate was removed by vacuum filtration. The solvent was distilled off under reduced pressure to obtain the title compound (100 mg, 100%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 2.47 (d, J = 3.3 Hz, 1H), 5.99 (s, 1H), 7.57 (d, J = 7.9 Hz, 4H), 7.88 (d, J = 8.3 Hz, 4H), 10.00 (s, 2H) Reference example 30: 3,4, -Diformylbenzophenone

Step 1: 3-bromobenzaldehyde dimethyl acetal

3-Bromobenzaldehyde (3 g, 16.2 mmol) was dissolved in methanol (150 mL), and triethyl orthoformate (5 mL, 30 mmol) and p-toluenesulfonic acid (catalytic amount) were added. The mixture was stirred for 2 hours and 15 minutes. After adding sodium methoxide (catalytic amount) to the reaction solution, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the reaction crude product, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.72 g, 100%). ^{l E MR (270 MHz, CDC1} 3) δ (ppm) 3.32 (s, 6H), 5.36 (s, 1H), 7.23 (t, J- = 7.9 Hz, 1H), 7.37 (d, J 7.9 Hz, 1H ), 7.45 (d, J = 7.9 Hz, 1H), 7.62 (brs, 1H)

Step 2: 4-formyl-N-methoxy-N-methylbenzamide

After dissolving 4-formylbenzoic acid (3 g, 20 t ol) in DMF (100 mL), N, 0-dimethylhydroxylamine hydrochloride (5.6 g, 57.4 mmol),; -hydroxybenzotriazole (5.4 g, 40 mmol), WSC HC1 (7.8 g, 40 mmol) and triethylamine (16 mL, 120 mmol) were added, and the mixture was stirred overnight. After adding ethyl acetate to the reaction solution, After washing with saturated saline and 1 mol / L hydrochloric acid, the mixture was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The reaction crude product was purified by silica gel column chromatography (10: 1 to 1: 1 hexane / ethyl acetate) to obtain the title compound (1.8 g, 47%). _{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.38 (s, 3H), 3.54 (s, 3H), 7.80 (d, J two 8.2 Hz, 2H), 7.92 ( d, J 8.2 Hz, 2H), 10.07 (s, 1H)

Step 3: 4-Dimethoxymethyl-N-methoxy-N-methylbenzamide

 The above compound (1.8 g, 9.3 mentioned in 01) was dissolved in methanol (150 mL), and trimethyl orthoformate (3 mL, 27.4 bandages 01) and p-toluenesulfonic acid (catalyst amount) were added. Stirred for hours. After adding sodium methoxide (catalytic amount) to the reaction solution, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the reaction crude product, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.1 g, 95%).

'Η NMR (270 MHz, CDC1 3) δ (ppm) 3.34 (s, 6H), 3.36 (s, 3H), 3.54 (s, 3H), 5.42 (s, 1H), 7.49 (d, J two 8.4 Hz , 2H), 7.68 (d, J = 8.4 Hz ₅ 2H) Step 4: 3,4'-Diformylbenzophenone

In an argon atmosphere, a THF solution of the compound obtained in Step 1 (322 mg, 1.4 tmol) in THF was cooled to −78 ° C, and then n-butyllithium (1.6 mol / L hexane solution; 1.1 mL, 1.7 The ol) was dropped. To this reaction solution, a THF solution (4 mL) of the compound (427 mg, 1.79 mmol) obtained in Step 3 was added dropwise. Thereafter, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of ammonium chloride, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the crude product was dissolved in THF (5 mL), after adding ₂ mol / LH 2 S0 ₄ a (5 mL), was carried out for 7 hours pressurized heat reflux. Water was added to the reaction solution, and after extraction with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The reaction crude product was purified by silica gel column chromatography (10: 1: 2.5 to 1: 4: 2.5 hexane / ethyl acetate / chloroform) to obtain the title compound (179 mg, 51%).

! H NMR (270 MHz, CDC1 3) δ (ppm) 7.72 (t, J = 8.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 8,04 (d, J = 8.2 Hz, 2H ), 8.10 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.28 (s, 1H), 10.10 (s, 1H), 10.15 (s, 1H) Reference Example 31: 2,4'-diformylbenzophenone

 The title compound was synthesized in the same manner as in Reference Example 30 using 2-bromobenzaldehyde instead of 3-bromobenzaldehyde.

Ή thigh _{(270 MHz, CDC1 3) δ} (ppm) 7.49-7.54 (m, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.75 (d, J two 5.3 Hz, 1H), 7.90-8.05 ( m, 5H), 10.01 (s, 1H), 10.11 (s, 1H) Reference Example 32: 1,1-bis (4, formylphenyl) -1-methoxymethane

Step 1: 1,1-bis (4-hydroxymethylphenyl) methanol

 Lithium aluminum hydride (1.78 g, 46.9 mmol) was suspended in THF (70 mL) under an argon atmosphere, and THF (90 mL) of 4,4'-dimethoxycarbonylbenzoylphenzophenone (3.5 g, 12 bandol) was suspended in ice (70 mL). ) The solution was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. Sodium sulfate decahydrate was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. The reaction solution was subjected to celite filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.6 g, 91%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 4.67 (s, 4H), 5.85 (s, 1H), 7.33 (d, J = 8.4 Hz, 4H), 7.38 (d, J = 8.4 Hz, 4H)

Step 2: 1, tribis (4-benzoyloxymethylphenyl) methanol

 The above compound (2.6 g, 11 mmol) was dissolved in a solution of triethylamine (4.5 mL, 32 mmol) in dichloromethane (30 mL), and benzoyl chloride (2.5 mL, 21 tmol) was added, followed by stirring overnight. did. The reaction solution was washed with a 1 mol / L hydrochloric acid aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (5.6 g, apparent yield 107%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 5.34 (s, 4H), 5.87 (s, 1H), 7.39-7.45 (m, 12H), 7.52-7.55 (m, 2H), 8.04-8.07 (m , 4H)

Step 3: 1, tribis (4-benzoyloxymethylphenyl) methoxymethane The above compound (1.58 g, 3.69 mmol) was dissolved in methanol, and methanesulfonic acid (4607.1 mmol) was added. The mixture was heated under reflux for an hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue to separate the layers. Organic layer is saturated saline , And dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound.

(1.66 g, 96%).

Step 4: 1,1-bis (4-hydroxymethylphenyl) methoxymethane

 After the above compound (1.66 g, 3.6 mmol) was dissolved in THF (15 mL), a 1 mol / L aqueous sodium hydroxide solution (9.2 mL) was added, and the mixture was heated with stirring at 60 ° C for 5.5 hours. After adding ethyl acetate to the reaction solution, the mixture was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.94 g, 100%).

'Η NMR (270 MHz, CDC1 3) δ (ppm) 3.38 (s, 3H), 4.66 (s, 4H), 5.25 (s, 1H), 7.33 (brs, 8H)

Step 5: 1, tribis (4-formylphenyl) -trimethoxymethane

 The above compound (0.94 g, 3.6 mmol) was dissolved in chloroform (50 mL), manganese dioxide (6.36 g, 73.1 tmol) was added, and the mixture was stirred at room temperature for 13 hours and heated under reflux for 2.5 hours. Was. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The reaction crude product was purified by silica gel column chromatography (10: 1 to 4: 1 hexane / ethyl acetate) to obtain the title compound (648 mg, 7.1%).

! H NMR (270 negation _{z, CDC1 3) δ (ppm} ) 3.42 (s, 3H), 5.37 (s, 1H), 7.53 (d, J = 8.4 Hz, 4H), 7.86 (d, J = 8.4 Hz, 4H), 9.99 (s, 2H) Reference example 3 3: 1,1-bis (4-formylphenyl) -ethoxyethoxymethane

 The title compound was synthesized according to the method described in Reference Example 32, except that ethanol was used instead of methanol in Step 3 of Reference Example 32.

Awakening: _{(270 MHz, CDC1 3) δ} (ppm) 1.30 (t, J two 7.1 Hz, 3H), 3.55 ( q, J = 7.1 Hz, 2H), 5.48 (s, 1H), 7.54 (d, J = 8.3 Hz, 4H), 7.85 (d, J = 8.3 Hz, 4H), 9.99 (s, 2H) Reference Example 34: 1,3-bis (4-formylphenyl) -1-isopropyloxymethane Reference Example 32 The title compound was synthesized according to the method described in Reference Example 32 except that isopropanol was used instead of methanol in step 3 of.

'Η NMR (270 MHz, CDC1 3) δ (ppm) 1.24 (d, J = 6.3 Hz, 6H), 3.67 (septet, J = 6.3 Hz, 1H), 5.60 (s, 1H), 7.54 (d, J = 8.1 Hz, 4H), 7.85 (d, J2 8.1 Hz, 4H), 9.99 (s, 2H) Reference example 35: 3,4-dichlorobenzyloxy [bis (4-formylphenyl)] methane

Reference Example 32 1,2-bis (4-benzoyloxymethylphenyl) methanol (1.2 g, 2.8 mmol) obtained in Step 2 of 2, and 3,4-dichlorobenzyl alcohol (2.5 g, 14 g) Ol) was dissolved in THF (70 mL), and then maleic sulfonic acid (365 nL, 5.6 mmol) was added, followed by heating under reflux for 6 hours and 45 minutes. After the reaction solution was concentrated under reduced pressure, dichloromethane (40 mL) was added to the residue. Further, after heating under reflux for 2 hours, water was added to the reaction solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (10: 1 hexane / ethyl acetate) to give bis (4-benzoyloxymethyl). Phenyl) -3,4-dichlorobenzyloxymethane (1.4 g _s 82 ° /). The title compound was synthesized according to the method described in Steps 4 to 5 in Byeon, Reference Example 32. the.. 'Eta thigh _{(270 MHz, CDC1 3) δ} (ppm) 4.50 (s, 2H), 5.55 (s, 1H), 7.17 (d, J two 8.1 Hz, 1H), 7.42-7.44 ( m, 2H ), 7.69 (d, J: 8.2 Hz, 4H), 7.88 (d, J = 8.2 Hz, 4H), 10.00 (s, 2H) Reference Example 36: 3,4-Dimethoxybenzyloxy [bis (4 -Formylphen)) methane

Step 1: 4-Dimethoxymethyl-4'-ethoxymethylpenzhydrol

4-Bromobenzaldehyde dimethyl acetate (5.03 g, 21.9 mmol) was dissolved in THF (80 mL) and then cooled to -78 ° C. To this was added n-butyllithium (1.59 mol / L hexane solution; 14.4 mL, 22.9 mmol), and then terephthalaldehyde ethylethyl acetate (4.8 mL, 24.1 mmol), and the temperature was raised to room temperature. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound (apparent yield: 8.67 g, 110%). Step 2: 3,4-Dimethoxybenzyloxy [bis (4-formylphenyl)] methane The above compound (0.60 g, 1.66) was dissolved in THF (6 ml), and the mixture was dissolved in 60% sodium hydride. (0.13 g, 3.33 dragonol) was added and the mixture was stirred at room temperature for 30 minutes. 3,4-Dimethyloxybenzyl bromide (1.15 g, 4.99 mmol) was added to the reaction solution, and the mixture was stirred under heating and reflux for 3 hours and 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was dissolved in dioxane (12 mL), and 2 mol / L HC1 (6 mL) was added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. The product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (4: 1 to 2.5: 1 hexane / ethyl acetate) to obtain the title compound (0.41 g, 63%). .

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.85 (s, 3H), 3.90 (s, 3H), 4,51 (s, 2H), 5.54 (s, 1H), 6.85-6.86 (m ,. 3H), 7.55 (d, J = 8.23 Hz, 4H), 7.87 (d, J = 8.23 Hz, 4H), 10.00 (s, 2H) Reference example 37: 1, tribis (4-formylphenyl) -2, 2,2-Trifluoroethanol 4-bromobenzaldehyde dimethyl acetal (7.35 g, 32.0 mmol) was added to THF

(150 mL) and then cooled to −78 ° C. To this was added dropwise a THF solution of n-butyllithium (1.6 mol / L hexane solution; 20 mL, 32 ol) and then trifluoroacetic anhydride (2.3π2.3), followed by stirring at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in dioxane.

(73 mL) and stirred overnight at room temperature. After evaporating the solvent under reduced pressure and adding ethyl acetate, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (10: 1 to 4: 1 hexane / ethyl acetate), and recrystallized from diisopropyl ether to give the title compound (2.96 g, 60%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.31 (s, 1H), 7.68 (d, J = 8.1 Hz, 4H), 7.90 (d, J = 8.1 Hz, 4H), 10.03 (s, 2H) Reference example 38: 1, tribis (3-formylphenyl) -2,2,2-trifluoroethanol

The title compound was synthesized according to the method described in Reference Example 37, except that 3-bromobenzaldehyde dimethyl acetal was used instead of 4-bromobenzaldehyde dimethyl acetal.

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.39 (s, 1H), 7.57 (t, J = 7.9 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 7.91 (d, J = 7.9 Hz, 2H), 8.03 (s, 2H), 10.00 (s, 2H) Reference Example 3 9 Bis (4-formylphenyl) -tritrifluoromethyl methane

Step 1: 1, Tobis (4-dimethoxymethylphenyl) -2,2,2-trifluoroethanol.

 After adding methanol (10 mL) to 1, tribis (4-formylphenyl) -2,2,2-trifluoroethanol (487 mg, 1.6 mmol) obtained in Reference Example 37, trimethyl orthoformate (520%) was added. L, 4.8 t) and P-toluenesulfonic acid (catalytic amount) were added, and the mixture was heated under reflux for 2 hours and 10 minutes. After adding sodium methoxide (catalytic amount) to the reaction mixture, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the reaction crude product, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (633 mg, 99%).

Ή NMR (270 MHz, DMSO- d ₆ ) δ (ppm) 3.24 (s, 12H), 5.38 (s, 2H), 7.39 (d, J = 8.9 Hz, 4H), 7.44 (d, J = 8.9 Hz, 4H)

Step 2: Dissolve the above compound (436 mg, 1.1 bandol) in THF (10 mL) and add 60% hydrogen under ice-cooling. Sodium chloride (87 mg, 2.2 mol) was added, and the mixture was stirred at room temperature for 5 minutes. Methyl iodide (204 L, 3.3 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5.5 hours. After adding an aqueous solution of ammonium chloride to the reaction solution, extraction was performed with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Dioxa in residue (6 mL) and a 1 mol / L aqueous hydrochloric acid solution (3 mL) were added, and the mixture was stirred at room temperature for 3 hours and 10 minutes. After evaporating the solvent under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (10: 1 to 6: 1 hexane / ethyl acetate) to obtain the title compound (348 mg, 99%).

_{Ή NMR (270 MHz, CDC1 3} ) δ (ppm) 3.37 (q, J = 1.6 Hz, 3H), 7.58 (d, J = 8.7 Hz, 4H), 7.89 (d, J = 8.7 Hz, 4H), 10.05 (s, 2H) Reference Example 40: 1,1-bis (3-formylphenyl) -1-methoxymethane

Step 1: 1, tribis (3-bromophenyl) -trimethoxymethane

 It can be synthesized by the method described in Collection, Czechoslovakia, Chemical 'Communication (Collect. Czech. Chem. Co., un.), Vol. 38, No. 11, 3496-3505 (1973) 1 , Tribis (3-bromophenyl) methanol (1.49 g, 4.4 Awake 01) was dissolved in THF, 60% sodium hydride (350 mg, 8.7 mmol) was added under ice-cooling, and then iodide. Methyl (850 L, 13.8 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After adding an aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.67 g, apparent yield: 108%). Step 2: 1, tribis (3-formylphenyl) -1-methoxymethane

 The above compound (1.67 g, 4.69 mmol) was dissolved in THF (15 mL) and cooled to -78 ° C. To this, n-butyllithium (1.6 mol / L hexane solution; 16 mL, 25.6 mmol). Then, DMF (3.4 mL) was added dropwise, followed by stirring at room temperature for 15 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (8: 1 to 5: 1 hexane / ethyl acetate) to obtain the title compound (860 mg, 78%).

Ή thigh _{(270 MHz, CDC1 3) δ} (ppm) 3.41 (s, 3H), 5.39 (s, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H) , 7.80 (d, J = 7.6 Hz, 2H), 7.89 (s, 2H), 10.01 (s, 2H) Industrial applicability

 The present invention provides a thiazolidinedione derivative having telomerase inhibitory activity or antitumor activity.

Claims

The scope of the claims

{Wherein, R ^{1 a} and R ^lb represents the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Ararukiru or substituted or is unsubstituted lower Arukanoiru, gamma ¹ and gamma ² represent identical or different and their respective single or double bond, X is formula (II)

[Wherein, Y is NR ² (wherein R ² is a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, a substituted or unsubstituted aryl) Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted Substituted or unsubstituted heteroarylalkyloxycarbonyl, substituted or unsubstituted rubamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted lower alkylsulfonyl, substituted Or unsubstituted arylsulfonyl, substituted or unsubstituted Aroiru or substituted or unsubstituted to represent Teroari one ylcarbonyl). Or CR ³ R ⁴ (wherein, R ³ represents a hydrogen atom, hydroxy sheet, a substituted or unsubstituted lower alkyl, lower substituted or unsubstituted Alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substitution Or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted Bamoyl, cyano, substituted or unsubstituted aralkyl, substituted or unsubstituted aralkyloxy or substituted or unsubstituted lower alkoxy, (i) When R ³ is a hydrogen atom or unsubstituted lower alkyl, R ⁴ is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted Or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy, (ii) R ³ is hydroxy, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl; Unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted rubamoyl, cyano, substituted or unsubstituted aralkyloxy, or When substituted or unsubstituted lower alkoxy, R ⁴ represents a hydrogen atom, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkynyl. Unsubstituted aryl, substituted or unsubstituted Loaryl, substituted or unsubstituted lower alkanoyloxy, carboxy, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted Represents aralkyl, substituted or unsubstituted aralkyloxy, substituted or unsubstituted lower alkoxy or substituted or unsubstituted cycloalkyloxy, R ³ and R ⁴ together = 0 or substituted or unsubstituted lower alkylidene Or Or R ³ and R ⁴ together with adjacent carbon atoms form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted alicyclic heterocyclic group)] or formula (III)

(In the formula, n represents an integer of 0 to 2, W represents a hydrogen atom, substituted or unsubstituted arylthio, or substituted or unsubstituted arylsulfinyl.) Thiazolidinedione derivative represented by Or a pharmacologically acceptable salt thereof 2. X is the formula (IIA)

Wherein in Y ^a is NR ^{2 f} (wherein, R ²¹ "represents a hydrogen atom, a substituted or unsubstituted lower § alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted § Li one Le, substituted or Unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted lower alkanol, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, substituted or unsubstituted force Rubamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroarylcarbonyl), or CR ^3f R ^{4f 3 f} is hydrogen, hydroxy, substituted or unsubstituted lower alkyl or substituted or unsubstituted Represents an unsubstituted lower alkoxycarbonyl, (i) When R ^3f is a hydrogen atom or an unsubstituted lower alkyl, R ^4f is a hydroxy, a substituted lower alkyl, a carboxy, a substituted or unsubstituted lower alkoxycarbonyl, a substituted or unsubstituted rubamoyl. Represents a substituted or unsubstituted aralkyloxy, a substituted or unsubstituted aralkyl, a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted cycloalkyloxy, (ii) When R ^3f is a substituted lower alkyl or a substituted or unsubstituted lower alkoxycarbonyl, R ^4f is a hydroxy, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxycarbonyl or a substituted or unsubstituted lower alkoxycarbonyl. Represents a substituted lower alkoxy, R ^3f and R ^4f together represent = 0, or Or R ^3f and R ^4f are taken together with adjacent carbon atoms to form a substituted or unsubstituted cycloalkyl or an alicyclic heterocyclic group). The thiazolidinedione derivative according to claim 1, which represents a group represented by the formula, or a pharmacologically acceptable salt thereof. 3. R ^{1 a} and R ^{1 b} represent a hydrogen atom, and X is a group represented by the formula (IIB)

Wherein Y ^b is NR ^2g (wherein R ^2g represents substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or substituted or unsubstituted lower alkoxycarbonyl), or CR ^3g R ^4g (wherein, R ^{3 g} is a hydrogen atom or a substituent if Ku represents lower alkyl unsubstituted, R ^{4 g} is a substituted or unsubstituted Ararukiru Okishi or a substituted or unsubstituted cycloalkyl O carboxymethyl) the 2. The thiazolidinedione derivative according to claim 1 or a pharmacologically acceptable salt thereof.  4. A medicament comprising the thiazolidinedione derivative according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof.  5. A telomerase inhibitor comprising the thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.  6. An antitumor agent comprising the thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A method for treating a disease associated with telomerase activity, which comprises administering an effective amount of the thiazolidinedione derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3. 8. The thiazolidinedione derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3 for producing a pharmacological composition useful for treating a disease associated with telomerase activity. use.