JP2003507473A - Telomerase inhibitors and methods of use thereof - Google Patents

Abstract

  (57) [Summary] Provided are thiazolidinedione compounds, compositions, and methods of inhibiting telomerase activity in vitro and methods of ex vivo and in vivo treatment of telomerase-mediated conditions or diseases. The methods, compounds and compositions of the present invention can be used alone or in combination with other pharmaceutically active agents to treat conditions or diseases mediated by telomerase activity (eg, cancer). . Novel methods for assaying or screening for telomerase activity are also provided.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to thiazolidinone compounds that inhibit telomerase activity, pharmaceutical compositions containing the compounds, and compounds and compositions in the treatment of telomerase-mediated conditions or diseases (eg, cancer). Relates to the use of the products alone or in combination with other pharmaceutically active agents.

BACKGROUND OF THE INVENTION Telomerase catalyzes the synthesis of telomeres. Telomeres are characteristic tandem repeats found in the ends of most eukaryotic chromosomes (T in mammals).
TAGGG). Telomeres can be 15-25 kilobases long in human germline cells. At each cell division, approximately 60-100 bases are lost from the ends of the chromosome, and telomeres shorten, and the cell eventually becomes a crisis (
Crisis) and induces apoptosis. Harley et al., (
1991) Mutation Res. 256: 271-282.
Telomerase acts to maintain telomere length just above the critical level and is therefore responsible for chromosomal stability and is involved in cell cycle regulation.

Telomerase is a ribonucleoprotein reverse transcriptase that contains its own RNA template for the synthesis of telomeric DNA. Blackburn, 1992, A
nnu. Rev. Biochem. 61: 113-129. Telomerase is present in normal tissue stem cells and germline cells, and is present at significantly higher levels in> 85% of tumors (Kim et al., 1994, Science).
Ce, 266: 2011-2014). Thus, drugs that target telomerase may have a high degree of selectivity for tumors as compared to normal tissue.
In conclusion, inhibition of telomerase has been proposed as a new approach for cancer treatment.

Inhibition of telomerase activity by antisense strategies directed towards the telomerase RNA component (eg, peptide nucleic acid (Norton et al., (1996) Nat).
ure Biotech. 14: 615-619) and phosphorothioate oligonucleotides) have been reported. Since telomerase is a reverse transcriptase, the use of inhibitors of reverse transcriptase (eg AZT and other nucleosides) has also been reported. Inhibition of telomerase by cisplatin is also known, probably due to bridging of telomeric repeats (Burger et al., (1997) E.
ur. J. Cancer 33: 638-644).

The thiazolidinediones comprise a group of structurally related antidiabetic compounds that increase the insulin sensitivity of target cells (skeletal muscle, liver, fat) in insulin resistant animals. In addition to these effects on hyperglycemia, thiazolidinediones also reduce lipid and insulin levels in animal models of NIDDM. In recent years, thiazolidinedione troglitazone has been linked to metabolic states that precede the onset of NIDDM, such as in patients with impaired glucose tolerance (NIDDM) (Nolan et al., (1994) N. Eng. J. Med. 33).
1, 1188-1193)), and it was shown to have similar beneficial effects in human patients. Although their mechanism of action remains unclear, it is known that thiazolidinediones do not cause an increase in insulin secretion nor an increase in the number or affinity of insulin receptor binding sites. This suggests that the thiazolidinedione amplifies post-receptor events in insulin signaling (Colca, JR and Morton, DR (1990).
), New Antibiotic Drugs, edited by C. J. Bailey and PR Flatt, Smith-Gordon, New York, 2.
55-261; Chang et al., (1983) Diabetes 32, 839-.
845).

The thiazolidinedione has been found to be an effective inducer of differentiation in cultured preadipocyte cell lines (Hiragun et al. (1988) JC.
ell Physiol. 134, 124-130; Sparks et al. (1991).
) J. Cell. Physiol. 146, 101-109; Kleitzie
n et al., (1992) Mol. Pharmacol. 41, 393-398). Furthermore, thiazolidinediones are implicated in appetite regulation disorders (see WO94 / 25026A1) and increased bone marrow fat content. Further, thiazolidinedione compounds have been suggested for use in the treatment of psoriasis (US Pat. No. 5,824,694) and menopausal disorders and mesenchymal tumors (US Pat. No. 5,814,647).

Some of the compounds useful in practicing the methods of the present invention, and methods of producing some of these compounds, are known. For example, some of these compounds are described in WO91 / 07107; WO92 / 02520; WO94 / 01433; W
O89 / 08651; JP-A-4-69383; EP0155845; EP015
5848; EP 0193256; EP 0295828; and U.S. Pat.
No. 287,200; No. 4,340,605; No. 4,376,777; No. 4,438,141; No. 4,444,779; No. 4,461,902.
No. 4,486,594; No. 4,572,912; No. 4,582.
No. 839; No. 4,687,777; No. 4,703,052; No. 4,7.
No. 25,610; No. 4,738,972; No. 4,775,687; No. 4,791,125; No. 4,812,570; No. 4,873,255; No. 4,897,393; No. 4,897,405; No. 4,918,0.
No. 91; No. 4,948,900; No. 5,002,953; No. 5,02.
No. 3,085; No. 5,053,420; No. 5,061,717; No. 5
, 120,754; 5,132,317; 5,143,928;
No. 5,194,443; No. 5,223,522; No. 5,232,92.
No. 5; No. 5,252,735; No. 5,260,445; No. 5,814.
, 647; 5,824, 694; and 5,874, 454.

The identification of compounds that inhibit telomerase activity provides important advantages to efforts to treat human disease. Cancer cells express telomerase activity, and normal human somatic cells display telomerase activity at biologically relevant levels (ie, levels sufficient to maintain telomere length over many cell divisions). As they do not, compounds that inhibit telomerase activity can be used to treat telomerase-mediated disorders such as cancer. Unfortunately, few such compounds, especially those with high potency or activity, and orally bioavailable compounds have been identified and characterized. Thus, compounds that act as telomerase inhibitors, have relatively high potency or activity, and are orally bioavailable, as well as compositions for treating cancer and other diseases in which telomerase activity is abnormally present, and There remains a need for methods. The present invention meets these needs and others.

SUMMARY OF THE INVENTION The present invention provides methods and compounds specific and effective for treating telomerase-mediated disorders, such as malignant conditions, by targeting cells having telomerase activity. A composition is provided. The methods, compounds, and compositions of the invention include
It can be applied to a wide variety of malignant cell types and avoids the problems inherent in current cancer treatment modalities that are non-specific and overly toxic.

In a first aspect, the present invention provides that certain known thiazolidinone compounds and the novel thiazolidinone derivatives disclosed herein are effective in inhibiting telomerase enzymatic activity in vitro, ex vivo and in vivo. Based on the discovery that. Thus, in one aspect, the invention provides a method of inhibiting telomerase by contacting the compounds described herein with telomerase. In a particular embodiment, the telomerase to be inhibited is a mammalian telomerase, eg a human telomerase. A related aspect of the invention is the discovery that thiazolidinone compounds inhibit the growth of cells having telomerase activity (eg, many cancer cells). That is, this aspect of the invention
Preferably, there is provided a method of inhibiting telomerase activity in a mammal suffering from a telomerase-mediated condition or disease, which method comprises providing a patient with a thiazolidinone compound or a thiazolidinone compound that inhibits a therapeutically effective amount of telomerase. The step of administering a pharmaceutically acceptable salt is included.

In another aspect, the invention provides methods, compounds and compositions for inhibiting telomerase enzymes. The method comprises contacting a telomerase enzyme with a compound of formula (I) or a pharmaceutically acceptable salt or composition thereof:

[0012]

[Chemical 12]

[0013] Where X is oxygen or sulfur,

[0014]

[Chemical 13]

Is a single or double bond; A is aryl or heteroaryl; R ₁ is hydrogen or lower alkyl; R ₂ , R ₃ and R ₄ are independently hydrogen. , Halo, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, cyano, nitro, alkylcarbamide, arylcarbamide, dialkylcarbamide, diarylcarbamide, alkylarylcarbamide, alkylthiocarbamide, arylthiocarbamide, dialkylthiocarbamide, diarylthiocarbamide , Alkylarylthiocarbamide, amino, alkylamino, arylamino, dialkylamino, diarylamino,
Arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamide , Arylsulfonamide, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl and heteroaryl; L is a direct bond or is independently of an unsubstituted or substituted carbon, N, O or S. Selected by 1
Is a linking group having 3 atoms; and n is 1 or 2.

In another aspect, the invention provides methods, compounds and compositions for inhibiting telomerase enzymes. This involves contacting the telomerase enzyme with a compound having formula (IV), or a pharmaceutically acceptable salt thereof:

[0017]

[Chemical 14]

[0018] Where X is O or S;

[0019]

[Chemical 15]

Is a single bond or a double bond; R ₅ is H or lower alkyl;
Ar is then substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl or heteroarylalkynyl.

In another aspect, the invention provides methods, compounds and compositions for inhibiting telomerase enzymes. This involves contacting the compound of formula (V) or a pharmaceutically acceptable salt or composition thereof with a telomerase enzyme:

[0022]

[Chemical 16]

Where X is O or S; R ₆ is H or lower alkyl; W is CH═CH, S, or —N═C—; R ₇ is OH, Halogen, mercapto, nitro, cyano, lower alkylthio, lower alkyl, lower alkoxy, lower alkanoyloxy, NR ₁₁ R ₁₂ (wherein R ₁₁ and R ₁₂ are independently hydrogen, lower alkyl, lower alkanoyl, aryl, Heteroaryl, selected from the group consisting of heteroarylalkyl, or R ₁₁ and R ₁₂ form a substituted or unsubstituted heterocyclic ring), CO ₂ R ₁₃ (wherein R ₁₃ is hydrogen, Lower alkyl, aralkyl, and heteroarylalkyl), CONR ₁₁ R ₁₂ , substituted or unsubstituted aryl, substituted or unsubstituted hetero. Aryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, lower alkanoyl, aroyl, lower alkenyl,
Arylthio, or lower alkynyl; and when W represents S, R ⁷ can also be H; L is O, S, SO, SO ₂ , OCH ₂ , SCH ₂ , SOCH ₂ ,
SO ₂ CH ₂ or N (R ₁₀ ) (CH ₂ ) _m, where R ₁₀ is substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroarylalkyl, and m is 0 or 1. , (CH ₂ ) N (R ₁₀ ) (CH ₂ ) _m , or CR ₁₃ R ₁₄ (wherein R ₁₃ and R ₁₄ are independently hydrogen, hydroxy, aryl, and heteroaryl. A ₁ is the formula (
A1) is a cycloalkyl:

[0024]

[Chemical 17]

Here, Z _{1 to} Z ₅ are independently hydrogen, lower alkyl, lower alkenyl, lower alkanoyloxy, mercapto, alkylthio, NR ₁₁ R ₁₂ , nitro, cyano,
CO ₂ R ₁₃ , CONR ₁₁ R ₁₂ , aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, halogen, and lower alkanoyl. However, W is CH
= CH, A may also be pyridyl (may also by p
yridyl).

The novel compounds of the present invention have many valuable uses as inhibitors of harmful telomerase activity. For example, by way of example, mammals (eg, humans)
Treatment of cancer in. The pharmaceutical composition of the present invention may be used in a therapeutic regimen in which cancer cells are killed in vivo. Alternatively, it can be used to kill cancer cells ex vivo. Accordingly, the present invention provides therapeutic compounds and compositions for treating cancer as well as humans and other mammals (eg, cows, horses, sheep, bulls, pigs and animals for veterinary purposes such as cats and dogs). )
For treating cancer and other telomerase-mediated conditions or diseases in.

DETAILED DESCRIPTION 1. Definitions Unless otherwise defined below, terms used herein have their commonly accepted scientific meanings. Definitions of standard chemical terms can be found in the references. For example, Carey and Sundberg (1992) “Adv
advanced Organic Chemistry 3rd edition, Volumes A and B,
Plenum Press, New York.

As used herein, the term “thiazolidinone” or “thiazolidinone derivative” has the general formula:

[0029]

[Chemical 18]

The compound of Here, X is O or S. When X is O, this derivative is a thiazolidinedione derivative. When X is S, this derivative is a thiazolidinonethione derivative, also known as rhodanins (see Examples 25-28 below).

As used herein, the term “alkyl” is a straight chain, branched chain containing between about 1 and about 20 carbon atoms, more preferably between about 1 and about 10 carbon atoms. Or a cyclic hydrocarbon chain fragment or group (for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, iso-butyl, tert-butyl, cyclobutyl, adamantyl, noradamantyl, etc.). Straight chain, branched or cyclic hydrocarbon chains having up to 8 carbon atoms are also referred to herein as "lower alkyl". The hydrocarbon chain further has one or more degrees of unsaturation, ie one or more double or triple bonds (eg vinyl, propargyl, allyl, 2-buten-1-yl, 2-cyclopenten-1-yl, 1 , 3-Cyclohexadiene-1-yl, 3-cyclohexen-1-yl, etc.). An alkyl group having a double bond as described herein is also referred to herein as "alkene." Similarly, an alkyl group having a triple bond is also referred to herein as "alkyne." However, when used in the context of cyclic alkyl groups, the combination of double and / or triple bonds does not include those combinations whose arrangement makes the cyclic hydrocarbon chains aromatic.

In addition, the term “alkyl” as used herein may further have one or more substitutions on one or more carbon atoms of the hydrocarbon fragment or group. Such substitutions include the following, but are not limited to: aryl; heteroaryl ring; halogen (e.g., trifluoromethyl, - forming a CF _3); nitro (-
NO ₂ ); cyano (--CN); hydroxyl (also referred to herein as "hydroxy"), alkoxyl (also referred to herein as alkoxy) or aryloxyl (also referred to herein as "aryloxy"). ) (-OR); thio or mercapto, alkyl- or arylthio (-SR); amino, alkylamino, arylamino, dialkyl- or diarylamino, or arylalkylamino (-NRR '); aminocarbonyl, Alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl or arylalkylaminocarbonyl (--C (O) NR
R '); carboxyl, or alkyl- or aryloxycarbonyl (
--C (O) OR); carboxaldehyde (carboxaldehyde)
, Or aryl- or alkylcarbonyl (-C (O) R); iminyl, aryl- or alkyliminyl (-C (= NR) R '); sulfo (-
-SO ₂ OR); alkyl - or arylsulfonyl (--SO ₂ R); ureido (--HNC (= O) NRR '); or thioureido (--HNC (= S
) NRR '); where R and R'are independently hydrogen, aryl or alkyl as defined herein. Substituents including heterocyclic groups (ie, heterocycle, heteroaryl, and heteroaralkyl) are defined similarly to the terms above. For example, the term “heterocycleoxy” refers to the group —OR, where R
Is a heterocycle as defined below.

“Lower alkanoyl”, “lower alkoxy”, “lower alkanoyloxy”,
The alkyl part of “lower alkylthio” has the same meaning as “alkyl” defined above.

The term “methylene” refers to the group ——CH ₂ ——.

The term “methine” refers to a methylene group in which one hydrogen atom has been replaced by a substituent as defined above. The term "methine" refers to substituted sp ² 1 one hydrogen atom is the binding - may also mean a methylene group that forms a hybridized carbon center (i.e.,
> C = O).

The term “halo” or “halogen” as used herein refers to the substituents fluoro, bromo, chloro, and iodo.

The term “carbonyl” as used herein refers to the functional group —C (O) —. However, this group is a well-known group having similar electronic and / or steric characteristics (for example, thiocarbonyl (-C (S) ---); sulfinyl (-
-S (O) -); sulfonyl (--SO ₂ -), phosphonyl (--PO ₂ -
), And methylidene (--C (═CH ₂ )-)). Other carbonyl equivalents are well known to those skilled in the fields of medicine and organic chemistry.

The term “aryl” as used herein refers to a cyclic aromatic hydrocarbon chain having up to 20 carbon atoms. For example, phenyl, naphthyl, biphenyl, anthracenyl and the like. One or more carbon atoms of the aryl group can also be substituted with: For example: alkyl; aryl; heterocycle; formyl; halogen;
Nitro; cyano; hydroxyl, alkoxyl or aryloxyl; thio or mercapto, alkyl-, or arylthio; amino, alkylamino, arylamino, dialkyl-, diaryl-, or arylalkylamino; aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl , Dialkylaminocarbonyl, diarylaminocarbonyl or arylalkylaminocarbonyl; carboxyl, or alkyl- or aryloxycarbonyl; carboxaldehyde,
Or aryl- or alkylcarbonyl; iminyl, or aryl- or alkyliminyl; sulfo; alkyl- or arylsulfonyl; hydroxyiminyl, or aryl- or alkoxyiminyl; ureido;
Or thioureido. In addition, two or more alkyl or heteroalkyl substituents on an aryl group can be joined to form a fused aryl-alkyl or aryl-heteroalkyl ring system (eg, tetrahydronaphthyl). Substituents including heterocyclic groups (eg, heterocycleoxy, heteroaryloxy,
And heteroaralkylthio) are defined similarly to the above terms.

The term “aralkyl”, as used herein, refers to an aryl group attached to the parent structure by an alkyl group, as defined above. For example, benzyl, α-methylbenzyl, phenethyl and the like. "Aralkylsulfonyl" The aralkyl moiety of aralkyloxy is synonymous with "aralkyl" as defined above.

The aryl portion of “aroyl”, “arylalkenyl”, “arylalkenyl”, “arylsulfonyl”, “arylthio”, “aryloxy”, “arylalkenylsulfonyl”, “arylalkynylsulfonyl” is defined above. Is synonymous with the term "aryl."

As used herein, the term “heterocycle” is 1
Refers to a cyclic alkyl or aryl group as defined above in which one or more carbon atoms has been replaced by a non-carbon atom, especially nitrogen, oxygen or sulfur. Non-aromatic heterocycles are also referred to herein as “cyclic heteroalkyl”. Aromatic heterocycles are also referred to herein as "heteroaryl." For example, examples of such groups include: furyl, tetrahydrofuryl, pyrrolyl,
Pyrrolidinyl, thienyl, tetrahydrothienyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolinyl, pyridyl, pyridinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, pyrazolyl , benzothienyl, indolyl, indolinyl, indolizinyl, indazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pteridinyl, quinuclidinyl, carbazolyl, acridinyl (acridiniyl), phenothiazinyl, Fenokisajini , Purinyl, benzimidazolyl, benzthiazolyl, and benzoxazolyl.

“Heteroarylalkyl”, “heteroarylalkenyl”, “heteroarylalkynyl”, “heteroarylsulfonyl”, “heteroarylalkylsulfonyl”, “heteroarylalkenylsulfonyl”, “heteroarylalkynylsulfonyl”, “hetero” The arylaryl of "aryloxy" and "heteroarylalkyloxy" has the same meaning as "heteroaryl" defined above.

The above-mentioned heterocyclic group further has one or more substituents, which are the same as those of the heteroaryl group.
It may have at the above carbon and / or non-carbon atoms. The substituents are, for example: alkyl; aryl; heterocycle; halogen; nitro; cyano; hydroxyl, alkoxyl or aryloxyl; thio or mercapto, alkyl-
Or arylthio; amino, alkyl-, aryl-, dialkyl-diaryl-, or arylalkylamino; aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl or arylalkylaminocarbonyl; carboxyl,
Or alkyl- or aryloxycarbonyl; carboxaldehyde (
carboxaldehyde), or aryl- or alkylcarbonyl; iminyl, or aryl- or alkyliminyl; sulfo; alkyl- or arylsulfonyl; hydroxyiminyl, or aryl- or alkoxyiminyl; ureido; or thioureido. In addition, two or more alkyl substituents may be joined to form a fused heterocycle-alkyl or heterocycle-aryl ring system. Substituents including heterocyclic groups (eg, heterocycleoxy, heteroaryloxy, and heteroaralkylthio) are defined similarly to the above terms.

The term “heterocyclealkyl” refers to a heterocycle group attached to the parent structure by one or more alkyl groups described above (eg, 2-piperidylmethyl, etc.). The term "heteroaralkyl", as used herein, refers to a heteroaryl group attached to the parent structure by one or more alkyl groups above. For example, 2-thienylmethyl and the like.

The compounds of the present invention can be used to inhibit or reduce telomerase enzymatic activity and / or proliferation of cells having telomerase activity. In these contexts inhibition or reduction of enzyme or cell proliferation refers to lower levels of measured activity as compared to a control experiment in which the enzyme or cells are not treated with the test compound. In certain embodiments, the inhibition or reduction in activity measured is at least 10% reduction or inhibition. Those skilled in the art will appreciate at least 20
It is understood that a%, 50%, 75%, 90% or 100% reduction or inhibition of the measured activity may be preferred for a particular application.

II. Telomerase Inhibitors As mentioned above, immortalization of cells includes, inter alia, activation of telomerase.
More specifically, telomerase activity and many tumor cell lines (eg, skin, connective tissue, fat, breast, lung, stomach, pancreas, ovary, cervix, uterus, kidney, bladder, colon,
A relationship between the prostate, central nervous system (CNS), retina and hematological tumor cell lines) and their ability to remain immortalized has been demonstrated by analysis of telomerase activity (K
im et al.). This analysis, complemented by data showing that shortening telomere length may provide a signal for senescence of normal cell replication (see WO93 / 23575), indicates that inhibition of telomerase activity is effective. Demonstrate that it could be an anti-cancer treatment. An "inhibitor" is simply a reagent that can reduce the activity of a telomerase enzyme in vitro or in vivo,
Means a drug or chemical. Such inhibitors (inhibitors)
) Places a cell extract or other preparation having telomerase activity in contact with a potential inhibitor and in the presence or absence of that inhibitor, or in the presence of varying amounts of the inhibitor. Can be readily identified using standard screening protocols that measure the level of telomerase activity in. In this way not only useful inhibitors can be identified,
Optimal levels of such inhibitors can be determined in vivo for further testing in vivo.

In a related aspect, the present invention demonstrates a method for inhibiting the ability of cells to grow or replicate. In this way, one or more thiazolidinedione compounds of the invention capable of inhibiting telomerase enzyme activity are provided during cell replication.
As explained above, telomeres have a linear chromosomal DNA at the end of which 5
It plays an important role in perfect replication without loss of terminal bases at the'end. Immortal cells and readily proliferating cells have telomere D at the end of the chromosome.
Use telomerase to add NA repeats. Inhibition of telomerase results in proliferating cells that cannot add telomeres, which eventually stop dividing. As will be apparent to one of skill in the art, this method for inhibiting the ability of cells to proliferate may be used to increase cells such as cancer (telomerase activity in malignant cells) and hematopoiesis (telomerase activity in hematopoietic stem cells). Useful for treating conditions associated with proliferation rate.

Accordingly, in one aspect, the invention provides compositions and compounds for the prevention or treatment of many types of malignancy. In particular, having telomerase activity,
As demonstrated by the highly versatile human tumor cell lines and tumors, the compounds of the invention may provide highly general methods of treatment of many, if not most, malignant diseases. More importantly, the thiazolidinone compounds of the present invention are highly deleterious to most of the current chemotherapeutic therapies that rely on drugs that highly discriminate between malignant and normal cells and kill the dividing cells indiscriminately. Can be effective in providing a treatment that avoids many of these side effects. Typical known thiazolidinedione compounds include glitazone (eg, troglitazone (
CS-045 (Sankyo) and CI-991 (Park-Davis)), pioglitazone (AD-48).
33 and U-72107E), rosiglitazone (rosig
litzone (also known as BRL 49653), englitazone (
englitazone (also known as CP-68,722), and ciglitazone).

In another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods relating to the novel compounds or pharmaceutically acceptable salts thereof for inhibiting a telomerase enzyme, comprising: Is a telomerase enzyme, a compound having formula (I),
Or contacting with a pharmaceutically acceptable salt thereof:

[0050]

[Chemical 19]

[0051] Where X is oxygen or sulfur,

[0052]

[Chemical 20]

Is a single or double bond; A is aryl or heteroaryl; R ₁ is hydrogen or lower alkyl; R ₂ , R ₃ and R ₄ are independently hydrogen. , Halo, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, cyano, nitro, alkylcarbamide, arylcarbamide, dialkylcarbamide, diarylcarbamide, alkylarylcarbamide, alkylthiocarbamide, arylthiocarbamide, dialkylthiocarbamide, diarylthiocarbamide , Alkylarylthiocarbamide, amino, alkylamino, arylamino, dialkylamino, diarylamino,
Arylalkylamino, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamide , Arylsulfonamide, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl and heteroaryl; L is a direct bond or is independently of an unsubstituted or substituted carbon, N, O or S. Selected by 1
Is a linking group having 3 atoms; and n is 1 or 2.

In certain embodiments, the novel compounds of the invention have the general structure shown in Formula II below and pharmaceutically acceptable salts thereof:

[0055]

[Chemical 21]

Where X is O or S, and R ₂ , R ₃ , R ₄ , L and n are as defined above.

In compounds of formula I, A can be, for example, aryl to form a phenyl moiety. Alternatively, A can be heteroaryl. For example, pyridine, quinoline, isoquinoline, thiophene, furan, imidazole, benzimidazole, pyrazole and the like. In a preferred embodiment of the invention A is phenyl as in formula (II). In another preferred embodiment of the invention when n is 1, R ₁ cannot be hydrogen. In yet another preferred embodiment of the invention at least one of R ₂ and R ₃ is other than hydrogen. In a particularly preferred embodiment of the invention at least one of R ₂ and R ₃ is halo, and most preferably both R ₂ and R ₃ are halo to form a dihalo-substituted phenyl moiety.

As mentioned above, L may be a direct bond or a linking group of 1 to 3 atoms. Here, the atoms of the linking group are independently selected from unsubstituted or substituted carbon, N, O or S. Representative linking groups useful in the compounds of the invention include
For example, -O -, - S -, - NH -, - CH 2 -, - OCH 2 -, - OC (O)
_{-, - CO 2 -, -} NHC (O) -, - C (O) NH -, - OC (O) CH 2 -,
-OC (O) NH- and -NHC (O) NH- are included.

For illustration purposes, representative compounds include, but are not limited to: 5- (2- (3,4-dichlorophenyl) benzylidene) thiazolidine-
2,4-dione, 5- (3- (3,4-dichlorophenyl) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4- Dione, 5- (2- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3
, 4-dichlorobenzamido) benzylidene) thiazolidine-2,4-dione,
5- (4- (N-3,4-dichlorophenyl (pheny) ureido) benzylidene) thiazolidine-2,4-dione, 5- (2- (N-3,4-dichlorophenyl (pheny) ureido) benzylidene) thiazolidine- 2,4-dione,
5- (2- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione, 5- (3- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione, 5- (4- (N-3,4-
Dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione,
5- (4- (N-3,4-dichlorophenylcarbamoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione, 5- (2- (3,4
-Dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione, 5- (2- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione, 5- (3- (3,4-dichlorophenylacetoxy) )
Benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione, 5- (2
-(3,4-Dichlorobenzoyloxy) benzylidene) thiazolidine-2,4
-Dione, 5- (3- (3,4-dichlorobenzoyloxy) -benzylidene)
Thiazolidine-2,4-dione, 5- (4- (3,4-dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (3,4-bis- (3
, 4-Dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione, 5- (2- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2
, 4-dione, 5- (4- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2,4-dione, 5- (2,5-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine- 2,4-dione, 5- (2,4-bis-
(3,4-Dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione, 5- (2- (3,4-dichlorobenzylthio) -3H-pyrimidine-4-
On-6-ylmethylidene) rodanine, 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rodanine, 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) Rhodanine, 5- (3-cyano-2- (3,4-dichlorobenzylthio) pyridin-6-ylmethylidene)
Thiazolidine-2,4-dione and 5- (3- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione.

In certain embodiments, the novel compounds of the invention have the general structure shown below in Formula III and pharmaceutically acceptable salts thereof:

[0061]

[Chemical formula 22]

Where X is O or S, and R ₁ , R ₂ , R ₃ , R ₄ , and L are as defined above.

In another embodiment, the present invention provides a method for inhibiting a telomerase enzyme,
Compounds and compositions are provided. This method comprises the step of contacting a telomerase enzyme with a compound having formula (IV) or a pharmaceutically acceptable salt thereof:

[0064]

[Chemical formula 23]

[0065] Where X is O or S;

[0066]

[Chemical formula 24]

Is a single bond or a double bond; R ₅ is H or lower alkyl;
And Ar is a substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroarylalkyl (alky), arylalkenyl, heteroarylalkenyl, arylalkynyl or heteroarylalkynyl.

The compound of formula (IV) having a double bond can be obtained by reacting a thiazolidine derivative with an aromatic carbonyl compound. The reaction may optionally be carried out in the presence of a base catalyst and optionally in a solvent. The base catalyst (usually present in about 0.1 to about 1 equivalent) is piperidine, piperidinium acetate,
It can be diethylamine, pyridine, sodium acetate, potassium carbonate, sodium carbonate and the like. The solvent may be an alcohol (eg, methanol, ethanol, propanol, etc.), an ether (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), or a hydrocarbon (eg, benzene, toluene (roll)).
uene), xylene, etc.), and mixtures thereof. The reaction is carried out at a temperature of about room temperature to about 200 ° C, preferably about 50-100 ° C, and about 1
It takes about 50 hours to complete.

[0069]

[Chemical 25]

Compounds of formula (IV) where is a single bond can be synthesized by reducing the double bond of the compound made above. Typically the hydrogenation is carried out using a noble metal catalyst (eg palladium, platinum, rhodium etc.) as is well known in the art.

In another aspect, the invention provides methods, compounds and compositions for inhibiting telomerase enzymes. The method comprises contacting a compound having formula (V) or a pharmaceutically acceptable salt thereof with a telomerase enzyme:

[0072]

[Chemical formula 26]

Where X is O or S; R ₆ is H or lower alkyl; W is CH═CH, S, or —N═C—; R ₇ is H, OH, halogen, mercapto, nitro, cyano, lower alkylthio, lower alkyl, lower alkoxy, lower alkanoyloxy, NR ₁₁ R ₁₂ (wherein R ₁₁ and R ₁₂ are independently hydrogen, lower alkyl, lower alkanoyl, Selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, or R ₁₁ and R ₁₂ form a substituted or unsubstituted heterocyclic ring), CO ₂ R ₁₃ (wherein R ₁₃ is Hydrogen, lower alkyl, aralkyl, and heteroarylalkyl), CONR ₁₁ R ₁₂ , substituted or unsubstituted aryl, substituted or unsubstituted aryl, Teloaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, lower alkanoyl, aroyl, lower alkenyl, arylthio, or lower alkynyl; L is O, S, SO, SO ₂
, OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂ CH ₂ , or N (R ₁₀ ) (CH ₂ ) _m (
Here, R ₁₀ is substituted or unsubstituted aryl, heteroaryl, aralkyl,
Or heteroarylalkyl, and m is 0 or 1), (C
H ₂ ) N (R ₁₀ ) (CH ₂ ) _m , or CR ₁₃ R ₁₄ (wherein R ₁₃ and R ₁₄ are
Independently, selected from the group consisting of hydrogen, hydroxy, aryl, and heteroaryl); and A ₁ is cycloalkyl (arky) of formula (A1)
l) is:

[0074]

[Chemical 27]

Here, Z _{1 to} Z ₅ are independently hydrogen, lower alkyl, lower alkenyl, lower alkanoyloxy, mercapto, alkylthio, NR ₁₁ R ₁₂ , nitro, cyano,
CO ₂ R ₁₃ , CONR ₁₁ R ₁₂ , aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, halogen and lower alkanoyl, where W is CH═CH
When A ₁ can also be pyridyl.

Examples of compounds of the present invention of Formulas IV are shown in Tables 1-6 below. However, the compounds of the present invention are not limited to these.

[0077]

[Table 1]

[0078]

[Table 2]

[0079] * P-Tol = 4-methylphenyl

[0080]

[Table 3]

[0081]

[Table 4]

[0082]

[Table 5]

[0083]

[Chemical 28]

[0084]

[Table 6]

III. Synthesis of Telomerase Inhibitors The compounds of the present invention can be synthesized, for example, using the techniques and materials known to those skilled in the art, as described below. For example, March, ADVANCED ORG
ANIC CHEMISTRY 4th Edition, (Wiley 1992); Care
y and Sundberg, ADVANCED ORGANIC CHEM
ISTRY 3rd Edition, Volumes A and B (Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN.
ORGANIC SYNTHESIS Second Edition (Wiley 1991). Starting materials for the compounds of the present invention can be obtained using standard techniques and commercially available precursor materials. For example, Aldrich Chemical Co. (M
ilwaukee, Wis. ), Sigma Chemical Co. (St
． Louis, Mo. ), Lancaster Synthesis (Wind
ham, N.N. H. ), Pin Chemicals, Ltd. (New Br
unswick, N.W. J. ), Ryan Scientific (Columb
ia, S.I. C. ), Maybridge (Cornwall, England)
, Arcos (Pittsburgh, Pa.), And Trans World.
d Chemicals (Rockville, Md.).

The procedures described herein for synthesizing the compounds of the invention can include one or more steps of protection and deprotection (eg, formation and removal of acetal groups). In addition, the synthetic procedures disclosed below are used for various purifications (eg, column chromatography, flash chromatography, thin layer chromatography (TL).
C), recrystallization, distillation, high pressure liquid chromatography (HPLC), etc.). Also, various techniques well known in the chemical arts for the identification and quantification of chemical reaction products can be used as well. For example, proton and carbon-13 nuclear magnetic resonance ( ¹ H and ¹³ C NMR), infrared and ultraviolet spectroscopy (IR and UV).
, X-ray crystallography, elemental analysis (EA), HPLC and mass spectroscopy (MS) can be used as well. Methods of protection and deprotection, purification, identification and quantitation are well known in the field of chemistry.

Compounds of the class of formulas I, II and III can be synthesized using General Procedure 1 and General Procedure 2 detailed in the examples below. Detailed protocols by which the individual compounds described above can be synthesized are also provided in the examples. Compounds of formula IV, where L is SO or SO ₂ , can be synthesized by oxidizing the corresponding S compound in an inert solvent. This inert solvent is dichloromethane, methanol, tetrahydrofuran, ether, hexane,
It can be toluene, cyclohexane, etc., and mixtures thereof. The oxidant is
It can be m-chloroperbenzoic acid, hydrogen peroxide and the like. The reaction is carried out at a temperature in the range of about -78 ° C to the boiling point of the solvent, preferably about 0 ° C to about 30 ° C, for about 0.5 to about 12 hours.

IV. Antitumor Activity of Telomerase Inhibitors of the Invention As demonstrated and can be demonstrated as described below, the compounds of the invention demonstrate inhibitory activity against telomerase activity in vivo. . The in vitro activity of the compounds of this invention can also be demonstrated using the methods described herein.
As described herein, the term "ex vivo" refers to a test performed with living cells in tissue culture.

One method used to identify compounds of the present invention that inhibit telomerase activity is to contact with some known concentration of a test compound in a buffer compatible with telomerase activity, Disposing cells, tissues, or preferably cell extracts, or other preparations containing telomerase. The level of telomerase activity for each concentration of test compound was measured and the I for this compound was determined.
The C ₅₀ (concentration of the test compound at which the observed activity for the sample preparation is observed to drop to half its original activity or control value) is determined using standard techniques. Other methods of determining the inhibitory concentration of a compound of the invention against telomerase may be utilized based on the disclosure herein, as will be apparent to those of skill in the art.

According to the method described above, IC ₅₀ values were determined for some of the compounds of the invention and were found to be less than 100 μM.

With respect to the treatment of malignant diseases using the compounds described herein, the compounds of the invention are expected to induce crisis in telomerase positive cell lines. Treatment of telomerase positive cell lines (eg HEK-293 cells and HeLa cells) with compounds of the invention is also expected to induce a decrease in telomerase length in the treated cells.

The compounds of the present invention can be administered to human tumor cell lines (eg, ovarian tumor cell line OVCAR-5
And SK-OV-3) is also expected to induce telomerase reduction during cell division. However, importantly, in normal human cells used as controls (eg, BJ cells of fibroblast origin), the observed decrease in telomerase length is due to the control substance (eg, dimethylsulfoxide (DMSO). )) Treated cells are not expected to be any different. The compounds of the invention are also expected to show no significant cytotoxic effect at concentrations below about 5 μM in normal cells.

[0093]   Furthermore, the specificity of the compounds of the invention for telomerase is related to telomerase.
Their activity (IC₅₀) And a nucleic acid binding activity similar to telomerase in vitro.
It can be determined by comparison with other enzymes having sex or modifying activity. That
Such enzymes include DNA polymerase I, HeLa RNA polymerase I
I, T3 RNA polymerase, MMLV reverse transcriptase, topoisomerase I,
Poisomerase II, terminal transferase and single-stranded DNA binding target
Quality (SSB). ICs for other enzymes screened ₅₀ Lower IC for telomerase compared to₅₀Compounds with value are terror
It is said to have specificity for merase.

In vivo studies have also been performed in mouse xenograft models (eg OVCAR here).
-5 tumor cells are transplanted into nude mice). Mice treated with a compound of the invention herein may, on average, have a tumor mass that may increase during a period of time after the first dose, but that the tumor mass begins to shrink as treatment continues. is expected. In contrast, control treated mice (eg DM
SO) is expected to have a growing tumor mass.

From the foregoing, those skilled in the art will appreciate that the present invention also provides methods for selecting a therapeutic regimen involving administration of a compound of the present invention. For such purposes, it may be beneficial to perform terminal restriction fragment (TRF) analysis. Here, the tumor cell-derived DNA is analyzed by digestion with a restriction enzyme specific for sequences other than the telomere (T ₂ AG ₃ ) _N sequence. After digestion of DNA, gel electrophoresis is performed to separate the restriction fragments according to size. The separated fragments are then probed with a nucleic acid probe specific for telomeric sequences to determine the length of the terminal fragment containing the telomeric DNA of the cells in the sample. Telomere DN
By measuring the length of A, one can predict how long the telomerase inhibitor should be administered, and whether other treatment modalities (eg, surgery, chemotherapy and radiation) should also be utilized. Furthermore, during treatment, cells may be tested to determine if there is a reduction in telomere length as cell division progresses, demonstrating the efficacy of treatment.

V. Telomerase Inhibiting Compositions and Methods for Treating Diseases The present invention also inhibits telomerase-positive cell outgrowth, and cancer and other conditions where inhibition of telomerase is effective. The present invention provides a pharmaceutical composition for the treatment of These compositions contain a therapeutically effective amount of a telomerase inhibitor compound of the present invention in a pharmaceutically acceptable carrier or salt.

In one embodiment, the present invention provides methods, compounds and compositions for inhibiting telomerase enzymes, for inhibiting the proliferation of telomerase positive cells and for treating cancer in mammals. The compositions of the present invention comprise a therapeutically effective amount of a compound of formula IV (or a pharmaceutically acceptable salt thereof) in a pharmaceutically acceptable carrier. The compounds and compositions of the present invention may also include other telomerase-mediated conditions or diseases (eg, psoriasis, rheumatoid arthritis, immune system disorders requiring immune system suppression, poison ivy, or poisonous beetle (p).
It can be used for the treatment of other hyperproliferative or autoimmune disorders, such as the immune system response to oison oak).

Further, the therapeutic benefit to the treatment of cancer is that telomerase inhibitors of the present invention can be used with other anti-cancer agents (eg, US Pat. Nos. 5,656,638, 5,760,
062, 5,767,278, 5,770,613 and 5
, 863,936, including other telomerase inhibitors)
It is understood that it can be realized by combining and. The choice of such a combination depends on various factors, including but not limited to: type of disease, age and general health of the patient, aggressiveness of disease progression, TRF length and morbidity to be treated. Cellular telomerase activity, as well as the patient's ability to tolerate drugs, including combinations. For example, when tumor progression reaches an advanced state, compounds of the invention that inhibit telomerase and other agents and other therapeutic regimens effective in reducing tumor size (eg, radiation, surgery, chemotherapy). And / or hormonal treatment) may be recommended. Further, in some cases, an agent that inhibits telomerase of the invention and one or more agents that treat the side effects of the disease (eg, an analgesic, or an agent effective to stimulate the patient's own immune response (eg, , Colony stimulating factor)) may be recommended.

In one such method, the pharmaceutical formulation comprises an anti-angiogenic agent (eg,
It includes the telomerase inhibitor of the present invention together with fumagillin, a fumagillin derivative, or AGM-1470). The latter compound was taken by Takeda Chemi
cal Industries, Ltd. While the former compound is commercially available from Ingber et al., December 6, 1990, "Synthetic a.
analogues of fumagillin that at inhibit angiogenesis and supress tumor gro
Wth ", Nature 348: 555-557. Other combinations include, but are not limited to, the telomerase inhibitors of the invention in addition to one or more antitumor agents or adjuvants (eg, folinic acid or mesna).

Suitable anti-tumor agents for combination with the compounds of the present invention include, but are not limited to, alkylating agents such as alkyl sulfonates (eg, busulfan, improsulfan, piposulfan); Aziridine (eg, benzodizepa, carbocon, metudedepa and uredepa); ethyleneimine and methylmelamine.
e) (eg altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine (tr
Nitrogen mustard (eg, chlorambucil, chlornafazine, cyclophosphamide, estramustine,
Phosphamide, mechlorethamine, mechlorethamine oxide hydroch
loride), melphalan, nombicine,
Phenesterine, predonimustine, trofosfamide, and uracil mustard); nitrosoureas (eg, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine). Additional agents include dacarbazine, mannomustine, mitbronitol, mitractol and pipobroman. Yet another class of related agents includes antibiotics, hormonal antitumor agents and antimetabolites. Still other combinations will be apparent to those of skill in the art.

Additional agents suitable for combination with the compounds of the present invention include protein synthesis inhibitors (eg, abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edein (ede).
ine) A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl imido diphosphate, kanamycin, kasugamycin, kyromycin and O-methyl threonine). Can be mentioned. Further protein synthesis inhibitors include modesin, neomycin, norvaline, pactamycin, paromomycin, puromycin, lysine, _-sarcin, Shiga toxin, shodomycin,
Examples include sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton and trimethoprim. Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, mitomycin C, nitrogen mustard and mustard gas (
sulfur must), MNNG and NMS); an insert (eg,
Acridine dye, actinomycin, adriamycin, anthracene, benzopyrene, ethidium bromide, propidium diiodo-interwoven.
ing) and distamycin and netropsin
A), which may also be combined with the compounds of this invention in a pharmaceutical composition. Base analogues of DNA (eg, acyclovir, adenine β-1-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, azaserine, 6-azauracil, 2′-azido-2 ′. -Deoxynucleosides, 5-bromodeoxycytidine, cytosine β-1-D-arabinoside, diazooxynorleucine, dideoxynucleosides, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea and 6-mercaptopurine. ) May also be used in combination therapy with the compounds of the invention. Topoisomerase inhibitors (eg coumermycin, nalidixic acid, novobiocin and oxophosphate), inhibitors of cell division (including colcemid, colchicine, vinblastine and vincristine); and RNA synthesis inhibitors (eg actinomycin D, α-amanitin and other fungi) Amatoxin, cordycepin (3'-deoxyadenosine), dichlororibofuranosylbenzimidazole, rifampicin, streptovaricin (stre)
ptovaricin) and streptolydin
igin)) may also be combined with a compound of the invention to provide a pharmaceutical composition.

In another embodiment, the invention provides that the telomerase inhibitor is combined with a cytotoxic agent (eg, a monoclonal antibody (eg, mouse monoclonal antibody or humanized monoclonal antibody)) that binds to a targeting agent, Or compounds that are either covalently attached to them and compositions. It is understood that the latter combination may allow cytotoxic agents to be introduced into cancer cells with greater specificity. Therefore, the active form (ie, the free form) of the cytotoxic agent is only present in the cells targeted by the antibody. Of course, the telomerase inhibitors of the present invention can also be combined with monoclonal antibodies that have therapeutic activity against cancer.

In addition to applying the telomerase inhibitors of the present invention to the treatment of mammalian diseases characterized by telomerase activity, telomerase inhibitors as disclosed herein are agriculturally characterized by telomerase activity. Can be applied to specific plant pathogens. These organisms include Cenororhabdi
nematodes such as tis elegans, in which telomerase activity was found, and in fungi, the fungus Ustilago may.
It is predicted to have telomerase activity based on the determination that dis indicates telomeres with tandem TTAGGG repeats maintained by telomerase.
Also, protozoa have TTAGGG telomeres and cause human disease. The telomerase-inhibiting compounds of the present invention can be applied to plants and soil infected with plant pathogens having telomerase activity, alone or in combination with other telomerase inhibitors and / or other agents used to control plant diseases. , Administered. The determination of compositions used to control such plant pathogens, and suitable embodiments for delivering such compositions, are known to those of ordinary skill in the agricultural arts.

The determination that nematodes, protozoa and possibly fungi have telomerase activity can also be determined using the telomerase inhibitors provided by the invention in nematodes in humans and veterinary animals of interest (eg dogs and cats). Indicates that infection can be treated. Nematode infections in humans and animals are often a form of hookworm or roundworm infections and lead to deadly secondary diseases to the host, such as meningitis, myocarditis and various neurological diseases. Thus, administration of a telomerase inhibitor compound (eg, a compound of the invention) (alone or in combination with other telomerase inhibitors and / or other therapeutic agents) may be used to control nematodes, protozoa and protozoa in humans and animals. It is understood that fungal infections can be controlled.

In general, a suitable effective dose of a compound of the invention will be in the range of 0.001 to 1000 mg / kg body weight of the recipient per day, preferably 0.001 to 100 mg / kg body weight per day. Range, more preferably per day,
It may range between 0.1 and 100 mg / kg body weight, and even more preferably from 0.1 to 10 mg / kg body weight per day. The desired medication is
Preferably, once, twice, three times, four times, administered at appropriate intervals throughout the day,
Or more subdose or by continuous pump actuation. These sub-doses may be divided into unit dosage forms (eg, unit dosage forms (fro
m) 5 to 10,000 mg of active ingredient per m), preferably 10 to 1000 m
g of the active ingredient). Preferably, this dosage is given once daily with a dosage at least equal to the TID, or administered using a continuous pump delivery system.

The compositions used in these treatments can be in various forms. These include, for example, solid, semi-solid, and liquid dosage forms (eg,
Tablets, pills, powders, liquids or suspensions, liposomes, and injectable and infusible solutions). The preferred form depends on the intended mode of administration and therapeutic application. The composition preferably comprises a conventional pharmaceutically acceptable carrier and adjuvant, as is well known to those skilled in the art. For example, REMINGTON '
S PHARMACEUTICAL SCIENCE, Mack Publics
ing Co. : Easton, Pa. , 17th Edition (1985). Preferably administration is by the oral or parenteral route, including subcutaneous, intramuscular, intravenous, and transdermal. More preferably, the route of administration is oral. The therapeutic methods and agents of the present invention can, of course, be used simultaneously with or in combination with other methods and agents for treating a particular disease or condition.

While it is possible for the active ingredient of the present invention to be administered alone, it is preferable to present the therapeutic agent as part of a pharmaceutical formulation or composition. A formulation of the invention comprises at least one of the invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically or therapeutically acceptable carriers and optionally other therapeutic ingredients. Telomerase activity inhibitory compounds. Various considerations for preparing such formulations are described, for example, by Gilman et al. (Eds.) GOODMAN AND GI.
LMAN'S: THE PHARMA COLOGICAL BASES OF
THERAPEUTICS, 8th Edition, Pergamon Press (1990)
); And REMINGTON'S (supra). Modes of administration are discussed therein, for example, oral, intravenous, intraperitoneal, intramuscular, and other modes of administration. Typically, the method of administering the pharmaceutical composition is either topical, parenteral, or oral for prophylactic and / or therapeutic treatments. Oral administration is preferred. The pharmaceutical composition may be administered in various unit dosage forms depending on the method of administration. As mentioned above, suitable unit dosage forms for oral administration include powders, tablets and capsules.

Topical administration may be used to deliver the compounds of the invention by transdermal passage of the drug into the systemic circulation of the patient. Skin sites for transdermal administration of drugs include, for example, forearms, abdomen, chest, back, buttocks, and mastoids.
An anatomical region such as a region of. The compound is administered to the skin by placing either a topical formulation containing the compound or a transdermal drug delivery device to administer the compound on the skin. In either embodiment, the delivery vehicle is designed, shaped, sized and adapted for easy placement and sufficient retention on the skin.

A variety of transdermal drug delivery devices may be utilized with the compounds of this invention. For example, a simple adhesive patch including a backing material and an acrylate adhesive can be prepared. The drug and optional permeability enhancer can be formulated into the adhesive casting solution. The adhesive casting solution can be cast directly onto the backing material or can be applied to the skin to form an adhesive coating. For example, U.S. Pat. Nos. 4,310,509; 4,560,555; and 4,54.
See 2,012.

In another embodiment, the compounds of the invention are delivered using a liquid reservoir system drug delivery device. These systems typically include a backing material, a membrane, an acrylate-based adhesive, and a release liner. The membrane is attached to the backing to form a reservoir. The drug or compound and any vehicle, enhancer, stabilizer, gelling agent, etc. are then incorporated into the reservoir. For example, U.S. Pat. Nos. 4,597,961; 4,485,097; 4,608,249; 4,505,891; 3,843,4.
No. 80; No. 3,948,254; No. 3,948,262; No. 3,05.
3,255; and 3,993,073.

Matrix patches containing a backing, drug / permeation enhancing matrix, membranes, and adhesives may also be utilized to deliver the compounds of the invention transdermally. The matrix material typically comprises polyurethane foam. Drug, optional enhancer,
Vehicles, stabilizers, etc. are combined with the foam precursor. The foam is allowed to cure to produce a tacky elastomeric matrix that can be directly attached to the backing material. For example, U.S. Pat. Nos. 4,542,013; 4,460,5.
No. 62; No. 4,466,953; No. 4,482,534; and No. 4.
, 533, 540.

Preparations for topical application to the skin containing the compounds of the invention (typically about 0.
Also included in the invention are non-toxic pharmaceutically acceptable topical carriers, at concentrations ranging from 001% to 10%. These topical preparations may be prepared by combining the active ingredient according to the present invention with conventional pharmaceutical diluents and carriers commonly used in dry, liquid and cream formulations for topical use. Ointments and creams may, for example, be formulated with a suitable thickening and / or gelling agent added to the aqueous or oily base. Such bases include water and / or oils such as liquid paraffin or vegetable oils such as peanut oil or castor oil. Thickeners that can be used according to the properties of this base include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, wool fat, hydrogenated lanolin, beeswax and the like.

Lotions may be formulated with an aqueous or oil base and will also generally contain one or more of the following: stabilizers, emulsifying agents, dispersing agents, suspending agents, thickening agents, coloring agents, perfumes. Such. The powder may be formed with the aid of any suitable powder base such as talc, lactose, starch and the like. Drops may be formulated with an aqueous or non-aqueous base that also includes one or more dispersing agents, suspending agents, solubilizing agents, and the like. Topical administration of the compounds of this invention may also be preferred in treating diseases such as skin cancer and fungal infections of the skin (pathogenic fungi typically express telomerase activity).

The topical pharmaceutical compositions of the present invention may also include one or more preservatives or bacteriostats such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride and the like. Topical pharmaceutical compositions may also include other active ingredients such as antimicrobial agents, especially antibiotics, anesthetics, analgesics,
And an antipruritic agent).

The compounds of this invention may also be delivered transmucosally. Transmucosal (eg sublingual,
Buccal and vaginal) drug delivery provides effective entry of the active substance into the systemic circulation,
And it reduces the immediate metabolism by the liver and intestinal wall flora. Transmucosal drug dosage forms (eg, tablets, suppositories, ointments, pessaries, membranes, and powders) typically maintain contact with the mucous membrane and rapidly disintegrate and / or dissolve,
Allows immediate systemic absorption. It is noted that certain such routes may be used even if the patient is unable to take the therapeutic composition orally. If delivery of the telomerase inhibitors of the present invention is enhanced, one may choose a composition for mucosal delivery (eg, in the case of colon cancer, one of skill in the art would use suppositories to deliver the telomerase inhibitor. Is also noted.

For delivery to the buccal or sublingual membranes, oral formulations (eg lozenges, tablets or capsules) are typically used. Methods of making these formulations are known in the art and include the addition of pharmacological agents to the tablets prior to manufacture; either inert fillers, binders, and pharmacological agents or substances containing the agents. Cold compression (as described in US Pat. No. 4,806,356); as well as, but not limited to, encapsulation. Another oral formulation is one that is applied with an adhesive to the oral mucosa (eg, the cellulose derivative hydroxypropylcellulose), as described, for example, in US Pat. No. 4,940,587. When applied to the buccal membrane, the buccal adhesive formulation allows for controlled, sustained release of the pharmacological agent through the buccal membrane into the mouth.

Parenteral administration is generally characterized by infusion (subcutaneous, intramuscular or intravenous). The invention thus provides a composition for intravenous administration comprising a solution of a compound of the invention dissolved or suspended in an acceptable carrier. Injectables can be prepared in conventional forms, either liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. Suitable excipients are, for example, water, buffer, saline, dextrose, glycerol, ethanol and the like. These compositions are sterilized by conventional, well-known sterilization techniques (eg, sterile filtration). The resulting solution can be packaged for ready use or lyophilized. The lyophilized preparation is combined with a sterile solution before administration. Furthermore, if desired, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents such as sodium acetate, sorbitan monolaurate.
monolaurate), triethanolamine oleate, etc.) and the like). Such formulations are useful in treating ovarian cancer.

Another method of parenteral administration utilizes implantation of a slow-release or sustained-release system, so that a constant level of dosage is maintained. For example, US Pat. No. 3,710,795.
See issue.

Liquid pharmaceutically administrable compositions may be prepared, for example, by using an active compound as defined above and a pharmaceutical adjuvant, optionally in an excipient (eg water, saline, aqueous dextrose, glycerol, It may be prepared by dissolving, dispersing, etc. ethanol, olive oil, and other lipophilic solvents) to form a liquid or suspension. If desired, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents such as sodium acetate,
Sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, etc.) and the like) may also be included. The actual methods for preparing such dosage forms are known and will be apparent to those skilled in the art; eg, REMINGTON '.
See S PHARMACEUTICAL SCIENCES (supra).
The composition or formulation administered will contain an effective amount of the active compound of the invention.

For solid compositions, conventional non-toxic solid carriers may be used. Examples of this solid carrier are, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum.
cum), cellulose, glucose, sucrose, magnesium carbonate and the like. For oral administration, a pharmaceutically acceptable non-toxic composition may be formulated with any of the commonly employed excipients, such as the carriers listed above, and generally 0.1-95% of the active ingredient. , Preferably 20%).

The compositions containing the compounds of the invention can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the composition is administered to a patient already afflicted with a disease in an amount sufficient to cure the symptoms of the disease and its complications, or at least partially slow the progression, as described above. . An amount adequate to accomplish this is defined as "therapeutically effective amount or dose." The effective amount for this use depends on the severity of the disease, as well as the weight and general condition of the patient.

In addition to internal (in vivo) administration, the compounds and compositions of the invention may be applied ex vivo to achieve a therapeutic effect, eg, in the case of patients with leukemia. In such applications, the cells to be treated (eg blood cells or bone marrow cells) are removed from the patient and treated with a pharmaceutically effective amount of a compound of the invention. The cells are returned to the patient after treatment. Such a procedure provides a longer concentration of the therapeutic agent at a higher concentration than the other methods available.
exposure) to the cells.

Once an improvement in the patient's condition has occurred, such as due to the onset of remission in the case of cancer patients, maintenance doses are optionally administered. The dosage and / or frequency of administration, or both, may then be reduced to a level where improved conditions are maintained as a function of the system. Treatment may be discontinued once the symptoms are alleviated to the desired level. However, the patient may require additional treatment upon any recurrence of disease symptoms.

In prophylactic applications (eg chemoprevention), compositions containing a compound of the invention are
It is administered to patients who are predisposed to certain diseases or have other risks. Such an amount is defined to be a "prophylactically effective amount or dose." For this use, the exact amount will again depend on the health and weight of the patient.

In reading this disclosure, as will be apparent to those of skill in the art, the present invention provides valuable reagents for human and mammalian telomerase. The need for the above description provides only limited descriptive examples of particular compounds. The above description should not be construed as limiting the scope of the invention. Other features and advantages of the invention will be apparent from the following examples and the appended claims.

Examples The following examples describe specific aspects of the invention, illustrate the invention, and can also be used to identify and test compounds that inhibit the activity of telomerase. A description of the method is provided to assist one of ordinary skill in understanding and carrying out the invention. These examples should not be construed as limiting the invention in any manner.

In the following Examples 1-24, the following general procedure was adopted: General Procedure 1: Coupling of 2,4-thiazolidinedione (TZD) to an aldehyde An appropriately substituted aldehyde (1 Equivalent), 2,4-thiazolidinedione (1.
5 eq) and piperidine (1.5 eq) in EtOH at 90 ° C. for 2
Heated for 16 hours. The resulting solution was acidified with 1N aqueous HCl solution. The solid obtained was filtered and washed with water and / or ether to give a pure product. Alternatively, the acidified solution was extracted with chloroform or ethyl acetate, the organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product as a solid. . It was purified either by column chromatography or by recrystallisation from a suitable solvent system.

[0128]   Reactions were generally performed on a 0.5 mmol scale.

Example 1 5- (2- (3,4-dichlorophenyl) benzylidene) thiazolidine-2,
Preparation of 4-dione

[0130]

[Chemical 29]

Step A: Preparation of Aldehyde To a solution of 2-bromobenzaldehyde (1 eq) and 3,4-dichlorophenylboronic acid (1.2 eq) in acetonitrile was added K ₂ CO ₃ (1.5 eq). Then, Pd (PPh ₃ ) ₄ (catalyst) was added subsequently. While stirring the reaction system 7
Heat to 5 ° C. for 16 hours, at which time the reaction was diluted with EtOAc, washed with water,
It was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude aldehyde, which was purified by column chromatography.

Step B. General procedure 1. Then, according to General Procedure 1, 5- (2- (3,4-dichlorophenyl)-
Benzylidene) thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 7.70 (d, 1H), 7.76 (d, 1H)
), 7.59-7.42 (m, 5H), 7.28 (dd, 1H). MS (ESI) calcd 349. Found 348 (M-H) ^-.

Example 2 5- (3- (3,4-dichlorophenyl) benzylidene) thiazolidine-2,
Preparation of 4-dione

[0135]

[Chemical 30]

Step A: Preparation of Aldehyde Using the procedure of Example 1, Step A, the required aldehyde was prepared from 3-bromobenzaldehyde.

Step B. General procedure 1. Then, according to General Procedure 1, 5- (3- (3,4-dichlorophenyl)-
Benzylidene) -thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 7.98 (s, 1H), 7.94 (s, 1H)
), 7.84 (s, 1H), 7.79 (d, 1H), 7.74-7.66 (m,
2H), 7.63-7.53 (m, 2H). MS (ESI) calcd 349, found 348 (M−H) ⁻ .

Example 3 Preparation of 5- (4- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione

[0140]

[Chemical 31]

Step A: Preparation of Aldehyde To a solution of 4-hydroxybenzaldehyde in acetonitrile was added K ₂ CO ₃ (1
． 5 eq) was added, followed by 3,4-dichlorobenzyl chloride (3 eq). The resulting reaction mixture was heated to 90 ° C. for 2-16 hours, at which point the precipitate was filtered off. The filtrate was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ ,
And it concentrated under pressure reduction and the crude product was obtained. The product was purified by recrystallization from CH ₂ Cl ₂ / hexane solvent system to give pure aldehyde.

Step B. General procedure 1. Then following general procedure 1 5- (4- (3,4-dichlorobenzyloxy) -benzylidene) thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 7.69 (d, 2H), 7.62 (d, 1H)
), 7.52 (d, 2H), 7.41 (d, 1H), 7.12 (d, 2H), 5
． 20 (s, 2H). MS (ESI) calcd 379. Found 378 (M-H) ^-.

Example 4 Preparation of 5- (2- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione

[0145]

[Chemical 32]

Step A: Preparation of Aldehyde The procedure of Example 3, Step A was used to prepare the required aldehyde from 2-hydroxybenzaldehyde.

Step B. General procedure 1. Then following general procedure 1 5- (2- (3,4-dichlorobenzyloxy) -benzylidene) thiazolidine-2,4-dione was obtained.

Example 5 5- (4- (3,4-dichlorobenzamido) benzylidene) thiazolidine-
Preparation of 2,4-dione

[0149]

[Chemical 33]

Step A: Preparation of Aldehyde To a solution of 4-nitrobenzaldehyde (1 equivalent) in trimethylorthoformate was added PTSA (catalyst) and the resulting mixture was heated to reflux for 3-5 hours. At this time the reaction mixture was concentrated under reduced pressure. The residue is dissolved in ether and N
Washed with aHCO ₃ , followed by water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give dimethyl acetal.

This crude dimethyl acetal was dissolved in EtOH, followed by Raney Ni (catalyst).
Was added. This mixture was added to hydrazine hydrate (5
(Equivalent) was added dropwise to control boiling. Warm the reaction system to room temperature, then
Stir for hours, then filter the catalyst. The filtrate was concentrated under reduced pressure. The residue is EtO
Redissolved in Ac, washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude 4-aminobenzaldehyde dimethyl acetal.

A solution of 4-aminobenzaldehyde dimethyl acetal in CH ₂ Cl ₂ was added at 0 ° C.
At, TEA (2 eq) was added, followed by 3,4-dichlorobenzoyl chloride (1.5 eq). The resulting mixture was stirred for 2-16 hours at room temperature, at which time it was diluted with water and EtOAc. The organic layer was separated, washed with water and subsequently concentrated under reduced pressure. The residue was dissolved in CHCl ₃ , followed by addition of 2N aqueous HCl solution. The mixture was stirred for 1 hour, at which time the organic layer was separated, washed with saturated NaHCO ₃ , water, dried over Na ₂ SO ₄ and subsequently concentrated under reduced pressure to give the crude aldehyde. This was purified either by column chromatography or by recrystallisation from a suitable solvent system to give pure 4- (3,4-dichlorobenzamido) benzaldehyde.

Step B. General procedure 1. Then following general procedure 1 5- (2- (3,4-dichlorobenzyloxy) -benzylidene) thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 12.50 (br s, 1H), 10.60
(S, 1H), 8.18 (d, 1H), 7.90-7.86 (m, 3H), 7.
78 (d, 1H), 7.70 (s, 1H), 7.56 (d, 1H). MS (ESI) calcd 392. Found 391 (MH) ^- .

Example 6 Preparation of 5- (4- (N-3,4-dichlorophenyl (pheny) ureido) benzylidene) thiazolidine-2,4-dione

[0156]

[Chemical 34]

Step A: Preparation of Aldehyde To a solution of 4-nitrobenzaldehyde (1 equivalent) in trimethyl orthoformate was added PTSA (catalyst) and the resulting mixture was heated to reflux for 3-5 hours. At that time, the reaction mixture was concentrated under reduced pressure. Dissolve the residue in ether,
It was washed with NaHCO ₃ followed by water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give dimethyl acetal.

This crude dimethyl acetal was dissolved in EtOH, followed by the addition of Raney Ni (catalyst). Hydrazine hydrate (5 equivalents) was added to the mixture at 0 ° C.
It was added dropwise over 15 minutes to control boiling. Warm the reaction system to room temperature,
Stirred for a further 3 hours, then filtered the catalyst. The filtrate was concentrated under reduced pressure. The residue was redissolved in EtOAc, washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude aminobenzaldehyde dimethyl acetal.

To a solution of aminobenzaldehyde dimethyl acetal (1 eq) in acetonitrile was added solid 3,4-dichlorophenylisocyanate (2 eq). The resulting mixture was stirred for 6-16 hours, at which time the reaction was treated with EtOA.
Diluted with c, washed with water, dried over Na ₂ SO ₄ and then concentrated under reduced pressure to give crude urea. The urea was dissolved in CH ₂ Cl ₂ followed by the addition of 50% aqueous TFA solution. The resulting mixture was stirred for 2 hours, at which time the organic layer was separated, washed with saturated aqueous NaHCO ₃ solution and water and dried over Na ₂ SO ₄ , followed by concentration under reduced pressure to give a crude mixture. The product was obtained.

Step B. General Procedure Then, following general procedure 1, 5- (4- (N-3,4-dichlorophenyl (phenyl) ureido) -benzylidene) thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 9.40 (d, 2H), 8.58 (s, 1H
), 7.84 (d, 1H), 7.76 (d, 2H), 7.54 (d, 2H), 7
． 48 (d, 1H), 7.30 (dd, 1H). MS (ESI) calcd 407. Found 406 (MH) ^- .

Example 7 Preparation of 5- (2- (N-3,4-dichlorophenyl (pheny) ureido) benzylidene) thiazolidine-2,4-dione

[0163]

[Chemical 35]

Step A: Preparation of Aldehyde The procedure of Example 6, Step A was used to prepare the required aldehyde from 2-nitrobenzaldehyde.

Step B. General procedure 1. Then following general procedure 1 5- (2- (N-3,4-dichlorophenyl (pheny) ureido) -benzylidene) thiazolidine-2,4-dione was obtained.

NMR (DMSO-d ₆ , δ): 10.10 (Br s, 1H), 7.70 (
d, 1H), 7.62 (d, 1H), 7.42 (dd, 1H), 7.26-7.
22 (m, 2H), 6.94 (t, 1H), 6.90 (d, 1H), 6.70 (
d, 1H), 5.86 (d, 1H).

Example 8 Preparation of 5- (2- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione

[0168]

[Chemical 36]

Step A: Preparation of 5- (2-Carboxybenzylidene) thiazolidine-2,4-dione 5- (2-Carboxybenzylidene) thiazolidine-2,4-dione was prepared by the procedure of General Procedure 1 Prepared from carboxybenzaldehyde.

Step B. Generation of carboxy group. 5- (2-carboxybenzylidene) thiazolidine-2,4-dione was added to SO ₂
Dissolved in Cl ₂ followed by 1-2 drops of DMF. The resulting mixture was heated to about 80 ° C. for 15-30 minutes, at which time the reaction was concentrated under reduced pressure. The residue was dissolved in THF and added dropwise to a solution of 3,4-dichloroaniline (1.5 eq) and TEA (2 eq). The mixture was stirred for an additional 1-2 hours, at which time solids in the reaction mixture were filtered. The filtrate was concentrated under reduced pressure to give a solid, which was washed with water and ether to give the pure product.

NMR (DMSO-d ₆ , δ): 10.80 (Br s, 1H), 8.06 (
d, 1H), 7.93 (s, 1H), 7.73-7.54 (m, 6H). MS (ESI) calcd 392. Found 391 (MH) ^- .

Example 9 Preparation of 5- (3- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione

[0173]

[Chemical 37]

5- (3- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione was prepared from 3-carboxybenzaldehyde in two steps by the method of Example 8.

NMR (DMSO-d ₆ , δ): 8.12 (d, 1H), 8.08 (s, 1H
), 7.97 (d, 1H), 7.82 (s, 1H), 7.77 (d, 1H), 7
． 72-7.64 (m, 2H), 7.60 (d, 2H). MS (ESI) calcd 392. Found 391 (MH) ^- .

Example 10 Preparation of 5- (4- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione

[0177]

[Chemical 38]

5- (4- (N-3,4-dichlorophenylcarbamido) benzylidene) -thiazolidine-2,4-dione was prepared from 4-carboxybenzaldehyde by the method of Example 8.

NMR (DMSO-d ₆ , δ): 10.60 (Br s, 1H), 8.12 (
s, 1H), 8.02 (d, 2H), 7.82 (s, 1H), 7.71 (d, 3)
H), 7.58 (d, 1H). MS (ESI) calcd 392. Found 391 (MH) ^- .

Example 11 Preparation of 5- (4- (N-3,4-dichlorophenylcarbamoyloxy) benzylidene) thiazolidine-2,4-dione

[0181]

[Chemical Formula 39]

Step A: Preparation of 5- (4-Hydroxybenzylidene) thiazolidine-2,4-dione 5- (4-Hydroxybenzylidene) thiazolidine-2,4-dione was prepared by the procedure of General Procedure 1 from 4- Prepared from hydroxybenzaldehyde.

Step B. Generation of Hydroxy Group K ₂ CO ₃ (xs) was added to a solution of 5- (4-hydroxybenzylidene) thiazolidine-2,4-dione (1 equivalent) in acetonitrile, followed by solid 3,3.
4-Chlorphenylisocyanate (2 eq) was added. The resulting mixture was stirred for 6-16 hours, at which point the solid was filtered and washed with water to give the pure product.

NMR (DMSO-d ₆ , δ): 12.60 (Brs, 1H), 10.60
(Br s, 1H), 7.76 (d, 2H), 7.62 (d, 2H), 7.56
(Dd, 1H), 7.41 (dd, 1H), 7.37 (dd, 1H). MS (ESI) calcd 408. Found 407 (MH) ^- .

Example 12 Preparation of 5- (4- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione

[0186]

[Chemical 40]

5- (4-Carboxybenzylidene) thiazolidine-2,4-dione (from Example 8, Step A) was dissolved in SO ₂ Cl ₂ followed by the addition of 1-2 drops of DMF. . The resulting mixture was heated to about 80 ° C. for 15-30 minutes, at which time the reaction was concentrated under reduced pressure. The residue was dissolved in THF and added dropwise to a solution of 3,4-dichlorophenol (1.5 eq) and TEA (2 eq). The resulting mixture was stirred for an additional 1-2 hours, at which time solids in the reaction mixture were filtered off.
The filtrate was concentrated under reduced pressure to give a solid which was washed with water and ether to give the pure ester. Alternatively, DCC (1 eq) was added to a solution of 5- (4-carboxybenzylidene) thiazolidine-2,4-dione (1 eq) and 3,4-dichlorophenol (1 eq) in CH ₂ Cl ₂ . The resulting reaction mixture was added to 16
Stir for an hour, at which time the reaction was filtered, the filtrate washed with water, and concentrated under reduced pressure to give the crude product, which was purified by recrystallization.

NMR (DMSO-d ₆ , δ): 8.18 (d, 2H), 7.80 (d, 2H)
), 7.77-7.68 (m, 3H), 7.38-7.33 (m, 1H). MS (ESI) calcd 393. Found 392 (M-H) ^-.

Example 13 Preparation of 5- (2- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione

[0190]

[Chemical 41]

By the method of Example 12, 5- (2- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione was prepared.

NMR (DMSO-d ₆ , δ): 8.28 (s, 1H), 8.22 (d, 1H)
), 7.80 (t, 1H), 7.76 (d, 1H), 7.73 (d, 1H), 7
． 64 (d, 1H), 7.38 (dd, 1H). MS (ESI) calcd 393. Found 392 (M-H) ^-.

Example 14 Preparation of 5- (2- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione

[0194]

[Chemical 42]

Step A: Preparation of 5- (2-Hydroxybenzylidene) thiazolidine-2,4-dione 5- (2-Hydroxybenzylidene) thiazolidine-2,4-dione was prepared according to general procedure 1 to 2-hydroxybenzaldehyde. Prepared from.

Step B. Generation of Hydroxy Group 3,4-Dichlorophenylacetic acid was dissolved in SO ₂ Cl ₂ followed by a few drops of D
MF was added. The resulting mixture was heated to 80 ° C. for 15-30 minutes, then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in THF and 5- (
Hydroxybenzylidene) thiazolidine-2,4-dione (1.5 eq) and TEA (1.5 eq) were slowly added to a solution in THF. The resulting reaction was stirred for 1-2 hours, at which point the solid was filtered off and the filtrate concentrated under reduced pressure to give a light yellow solid. The solid was dissolved in EtOAc, followed by washing with saturated aqueous K ₂ CO ₃ . The organic layer was separated and dried over Na ₂ SO ₄ , followed by concentration under reduced pressure to give pure compound.

NMR (DMSO-d ₆ , δ): 12.65 (Br s, 1H), 7.65 (
d, 1H), 7.57 (d, 1H), 7.55 (s, 1H), 7.54 to 7.6.
(M, 2H), 7.41 (d, 1H), 7.37 (dd, 1H), 7.30 (d
, 1H), 4.00 (s, 2H). MS (ESI) calcd 407. Found 406 (MH) ^- .

Example 15 Preparation of 5- (3- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione

[0199]

[Chemical 43]

5- (3- (3,4-Dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione was prepared from 3-hydroxybenzaldehyde by the method of Example 14.

NMR (DMSO-d ₆ , δ): 12.60 (Br s, 1H), 7.74 (
s, 1H), 7.66 (d, 1H), 7.59 (d, 1H), 7.53 (t, 1)
H), 7.45 (d, 1H), 7.38-7.33 (m, 2H), 7.24 (d
, 1H), 4.00 (s, 2H). MS (ESI) calcd 407. Found 406 (MH) ^- .

Example 16 Preparation of 5- (4- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione

[0203]

[Chemical 44]

5- (4- (3,4-Dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione was prepared from 4-hydroxybenzaldehyde by the method of Example 14.

NMR (DMSO-d ₆ , δ): 7.76 (s, 1H), 7.66 (d, 1H)
), 7.60 (m, 3H), 7.36 (dd, 1H), 7.28 (d, 2H),
4.00 (s, 2H). MS (ESI): calculated 407. Found 406 (MH) ^- .

Example 17 Preparation of 5- (2- (3,4-dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione

[0207]

[Chemical formula 45]

Step A: Preparation of 5- (2-Hydroxybenzylidene) thiazolidine-2,4-dione 5- (2-Hydroxybenzylidene) thiazolidine-2,4-dione was prepared according to general procedure 1 to 2-hydroxybenzaldehyde. Prepared from.

Step B. Hydroxy group acylation A solution of 3,4-dichlorobenzoyl chloride in THF was slowly added to 5-
(Hydroxybenzylidene) thiazolidine-2,4-dione (1.5 eq) and TEA (1.5 eq) were added to a solution in THF. The obtained reaction system is
Stirred for 2 hours, at which time the solid was filtered and the filtrate concentrated under reduced pressure to give a light yellow solid. The solid was dissolved in EtOAc, followed by washing with saturated aqueous K ₂ CO ₃ . The organic phase was separated and dried over Na ₂ SO ₄ , followed by concentration under reduced pressure to give the pure compound.

NMR (DMSO-d ₆ , δ): 8.30 (s, 1H), 8.09 (dd, 1)
H), 7.90 (d, 1H), 7.68-7.62 (m, 1H), 7.42-7
． 28 (m, 3H), 7.18 (s, 1H). MS (ESI): calcd 393. Found 392 (M-H) ^-.

Example 18 Preparation of 5- (3- (3,4-dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione

[0212]

[Chemical formula 46]

5- (3- (3,4-Dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione was prepared from 3-hydroxybenzaldehyde by the method of Example 17.

NMR (DMSO-d ₆ , δ): 8.27 (s, 1H), 8.06 (d, 1H)
), 7.86 (d, 1H), 7.52-7.38 (m, 3H), 7.24 (s,
1H), 7.20 (d, 1H). MS (ESI): calcd 393. Found 392 (M-H) ^-.

Example 19 Preparation of 5- (4- (3,4-dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione

[0216]

[Chemical 47]

5- (4- (3,4-Dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione was prepared from 4-hydroxybenzaldehyde by the method of Example 17.

NMR (DMSO-D ₆ , δ): 8.26 (d, 1H), 8.04 (dd, 1)
H), 7.85 (d, 1H), 7.58 (d, 2H), 7.36 (d, 2H),
7.39-7.34 (m, 3H). MS (ESI): calcd 393. Found 392 (M-H) ^-.

Example 20 Preparation of 5- (3,4-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione

[0220]

[Chemical 48]

Step A: Preparation of Aldehyde 3,4-Dichlorobenzyl chloride (415 μl, 3 mmol) was added to 138
mg (1 mmol) 3,4-dihydroxybenzaldehyde and 690 mg
Was added to a mixture of potassium carbonate in DMF. The resulting mixture was warmed to 70 ° C. and stirred overnight. The reaction was then diluted with 20 mL water and the mixture filtered. The resulting white precipitate was collected by filtration and air dried, 426
Obtained mg (93%) of the desired product.

¹ H NMR (part) (400 MHz, DMSO-d ₆ ) δ 9.9 (s, 1 H)
5.24 (s, 2H), 5.19 (s, 2H).

Step B. General procedure 1. NMR (400 MHz, DMSO-d ₆ , δ): 7.68-7.66 (m, 2
H), 7.65 (s, 1H), 7.63-7.59 (m, 2H), 7.41-7
． 37 (m, 2H), 7.21 to 7.20 (m, 1H), 7.18 to 7.15 (
m, 2H). MS (ESI): Calculated 553 Found 552 (M-H) ^-.

Example 21 5- (2- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2
Preparation of 4-dione

[0225]

[Chemical 49]

Step A: Preparation of Aldehyde 2-Fluorobenzaldehyde (248.23 mg 210 μL, 2 mmol
) And 3,4-dichlorophenol with potassium carbonate, 5 mL
In dimethyl acetamide of 90 ° C. for 12 hours. The reaction was diluted with 20 mL water and extracted with 25 mL ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated in vacuo to give a brown oil that was removed without further purification. It was

Step B. General procedure 1. NMR (DMSO-d ₆ , δ): 7.73 (s, 1H), 7.59 (m, 2H)
), 7.46 (t, 1H), 7.34 (m, 2H), 7.02 (m, 2H). MS (ESI): calculated 365. Found 364 (M-H) ^-.

Example 22 5- (4- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2
Preparation of 4-dione

[0229]

[Chemical 50]

5- (4- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2
, 4-dione was prepared by the method of 5- (2- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2,4-dione (Example 21). MS (ESI): calculated 365. Found 364 (M-H) ^-.

Example 23 Preparation of 5- (2,5-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione

[0232]

[Chemical 51]

5- (2,5-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione was converted into 5- (3,4-bis- (3,4-dichlorobenzyloxy) Method for benzilidine) thiazolidine-2,4-diones (Example 20)
).

NMR (DMSO-d ₆ , δ): 7.88 (s, 1H), 7.70-7.66
(M, 2H), 7.64-7.60 (m, 2H), 7.42-7.34 (m, 2)
H), 7.12-7.10 (m, 2H), 6.90 (br s, 1H). MS (ESI): Calculated 553. Found 552 (M-H) ^-.

Example 24 Preparation of 5- (2,4-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione

[0236]

[Chemical 52]

5- (2,4-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione was converted to 5- (3,4-bis- (3,4-dichlorobenzyloxy) Method for benzilidine) thiazolidine-2,4-diones (Example 20)
). MS (ESI): Calculated 553. Found 552 (M-H) ^-.

In Examples 25-28 below, the following general procedure 2 was used: General procedure 2: Coupling of Rhodanine to Aldehyde Appropriately substituted aldehyde (1 eq), Rhodanine (1 eq). ) And ethylenediamine diacetate (1 equivalent) in methanol were heated to reflux for 1-3 hours. The resulting precipitate was isolated and washed with methanol, water, 10% aqueous sodium bisulfate solution, saturated aqueous sodium bicarbonate solution and water, then air dried.

[0239]   Reactions were generally performed on a 0.1 mmol scale.

Example 25 Preparation of 5- (2- (3,4-dichlorobenzylthio) -3H-pyrimidin-4-one-6-ylmethylidene) rhodanine

[0241]

[Chemical 53]

Step A: Preparation of Aldehyde 0.75 g (3.7 mmol) 6-dimethoxymethyl-2-mercapto-3
To a suspension of H-pyrimidin-4-one in DMF (having 0.66 g potassium carbonate) was added 0.512 mL (3.7 mmol) 3,4-dichlorobenzyl chloride. The suspension was left for 2 days. The mixture was diluted with 40 mL ethyl acetate and 40 mL 10% aqueous sodium bisulfate solution. The precipitate was isolated by filtration and washed with water to give 1.0 g of pure acetal.

0.8 g of 6-dimethoxymethyl-2- (in 70% trifluoroacetic acid in water
A solution of 3,4-dichlorobenzylthio) -3H-pyrimidin-4-one was added to 12
Stir for hours. The solution was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. 1: 1
Trituration of the residue with ether: hexane gave 600 mg of pure product.

Step B. General procedure 2. Following general procedure 2 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-one-6-ylmethylidene) rhodanine was obtained.

Example 26 Preparation of 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanine

[0246]

[Chemical 54]

[0247] Step A: Preparation of aldehyde.   1.66 g (7.98 mmol) 4-dimethoxymethylpyrimidin-2-thiol
On sodium salt, 2.7 g potassium carbonate and α, 3,4-trichlorotolu
The suspension of ene was stirred for 2 days. Pour the mixture into water and extract with ethyl acetate
did. The organic layer was washed with saturated aqueous sodium chloride solution and then dried (MgSO 4. _Four ) And concentrated to give 1.65 g of product, mercaptoacetal.

A suspension of 0.8 g of this acetal in 5 mL of concentrated hydrochloric acid was refluxed for approximately 5 minutes until the solution became clear. The solution was allowed to cool then diluted with water, neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried (anhydrous sodium sulfate) and concentrated to give 100 mg of the desired aldehyde.

Step B. General procedure 2. Followed General Procedure 2 to give 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanine.

Example 27 Preparation of 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanine

[0251]

[Chemical 55]

To a stirred suspension of 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanine (Example 25, 0.3 mmol) in toluene (5 mL) was added diethyl 2,6. -Dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (109 mg, 0.39 mmol) and 0.3 g of activated silica gel were added. The mixture was heated to 80 ° C. for 20 hours and then warm filtered. The filter cake was rinsed with ethyl acetate and the combined filtrates were evaporated to dryness. The residue was redissolved in ethyl acetate and extracted with 1N aqueous hydrochloric acid solution. The organic layer was dried (sodium sulfate) and concentrated to give 11 mg of pure product.

Example 28 Preparation of 5- (3-Cyano-2- (3,4-dichlorobenzylthio) pyridin-6-ylmethylidene) thiazolidine-2,4-dione

[0254]

[Chemical 56]

Step A: Preparation of Aldehyde 0.2 g (1 mmol) of 3-cyano-6-dimethoxymethyl-pyridine-2
-Thiols, excess potassium carbonate and α, 3,4-trichlorotoluene (3 m
mol) in acetonitrile was heated at 75 ° C. for 10 minutes. Tlc showed the reaction was complete. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give the product mercaptoacetal as a solid, which was washed with hexane.

The acetal was dissolved in chloroform (2 ml) and 2 mL of 50
% Aqueous trifluoroacetic acid solution was added. After 16 hours, TLC showed the reaction was almost complete. The mixture was evaporated to dryness and used immediately in step B (NMR spectrum consistent with the proposed structure).

Step B. General procedure 1. Following general procedure 1 gave 5- (3-cyano-2- (3,4-dichlorobenzylthio) -pyridin-6-ylmethylidene) thiazolidine-2,4-dione.

NMR (DMSO-d ₆ , δ): 8.12 (d, 1H), 7.68 (d, 1H)
), 7.53 (d, 1H) 7.48 (d, 1H) 7.38-7.34 (m, 1H
) 7.31 (s, 1H) 4.80 (s, 1H).

Example 29 Preparation of 5- (3- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione

[0260]

[Chemical 57]

Step A: Preparation of Aldehyde A solution of 3-hydroxybenzaldehyde in acetonitrile was treated with K ₂ CO ₃ (1
． 5 eq), followed by 3,4-dichlorobenzyl chloride (3 eq)
Was added. The resulting reaction mixture was heated to 90 ° C. for 2-16 hours, at which time the precipitate was filtered off. The filtrate was diluted with EtOAc, washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude product. The product was purified by recrystallisation from a CH ₂ Cl ₂ / hexane solvent system to give pure aldehyde.

Step B. General procedure 1. Following general procedure 1 gave 5- (3- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione.

NMR (DMSO-d ₆ , δ): 7.69 (d, 2H), 7.61 (d, 1H)
), 7.43-7.31 (m, 3H), 7.12-7.08 (m, 2H), 6.
96 (d, 1H), 5.11 (s, 2H). MS (ESI): calcd 378.98. Found 378 (M-H) ^-.

Example 30 Preparation of Compound 1 2- (4-Methylphenylthio) -5-nitrobenzaldehyde (1.00 g
, 3.66 mmol), 2,4-thiazolidinedione (1.72 g, 14.7 m)
mol) and piperidine (0.14 mL, 1.5 mmol) with ethanol (
It was heated to reflux in 40 mL) for 26 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration to give compound 1 (577 mg, 42%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.38 (s, 3
H), 7.07 (d, J = 8.8 Hz, 1 H), 7.37 (d, J = 8.1 Hz)
, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.89 (s, 1H), 8
． 14 (dd, J = 8.8, 2.2 Hz, 1 H), 8.22 (d, J = 2.2 H
z, 1H), 12.8 (br s, 1H) FABMS m / z 373 (M + H) ⁺ C ₁₇ H ₁₂ N ₂ O ₄ S ₂ = 372.

Example 31 Preparation of Compound 2 Compound 1 (200 mg, 0.538 mmol) was dissolved in acetone (30 mL) and the solution was mixed with titanium trichloride (20% aqueous solution, 4 mL) and allowed to stand at room temperature for 30
Stir for minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate / hexane to give compound 2 (69 mg, 38%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.21 (s, 3H)
, 5.86 (br s, 2H), 6.70 (dd, J = 8.4, 2.6 Hz, 1
H), 6.82 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.3 Hz)
, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.4).
Hz, 1H), 8.06 (s, 1H), 12.5 (br s, 1H) FABMS m / z 342 (M ⁺ ) C ₁₇ H ₁₄ N ₂ O ₂ S ₂ = 342.

Example 32 Preparation of Compound 3 Compound 2 (20 mg, 0.058 mmol) was added to dimethylformamide (1 mL).
) And acetic anhydride (1 mL) and triethylamine (0.0
16 mL, 0.12 mmol) was added, and then the mixture was stirred at room temperature for 50 minutes. 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 then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
And the residue is subjected to preparative thin layer chromatography (chloroform / methanol = 9/1).
Compound 3 (7.0 mg, 31%) was obtained by purification with (1).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.08 (s, 3
H), 2.25 (s, 3H), 7.07 (d, J = 8.3 Hz, 2H), 7.1
4 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7
． 58 (dd, J = 8.4, 2.2 Hz, 1H), 8.08 (s, 1H), 8.
09 (d, J = 2.4 Hz, 1H), 10.3 (s, 1H), 12.6 (br
s, 1H) FABMS m / z 385 (M + H) ⁺ C ₁₉ H ₁₆ N ₂ O ₃ S ₂ = 384.

Example 33 Preparation of Compound 4 Compound 1 (100 mg, 0.269 mmol) was added to dichloromethane (2
It was dissolved in a mixed solvent of 0 mL) and methanol (4 mL), and m-chloroperbenzoic acid (purity 50%, 100 mg, 0.289 mmol) was mixed with the solution, and then stirred at room temperature for 3 hours. The reaction was mixed with 10% aqueous sodium hydrogen sulfite solution and extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate to give compound 4
(86 mg, 82%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3
H), 7.32 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.3 Hz)
, 2H), J7.88 (s, 1H), 8.20 (d, J = 2.2Hz, 1H),
8.32 (d, J = 8.6 Hz, 1H), 8.50 (dd, J = 8.6, 2.2)
Hz, 1H), 12.6 (br s, 1H) FABMS m / z 387 (M-H) - C 17 H 12 N 2 O 5 S 2 = 388.

Example 34 Preparation of Compound 5 Compound 1 (20 mg, 0.054 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and methanol (1 mL), and the solution was treated with m-chloroperbenzoic acid (purity 50%, 187 mg, 0.540 mmol) and then stirred at room temperature for 1.5 hours. The reaction was mixed with 10% aqueous sodium hydrogen sulfite solution and extracted 4 times with chloroform-methanol (9: 1). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / acetonitrile = 6/1) to give compound 5 (10 mg
, 46%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.36 (s, 3
H), 7.43 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.4 Hz)
, 2H), 8.06 (s, 1H), 8.28 (br s, 1H), 8.49 (s
, 2H), 12.9 (br s , 1H) FABMS m / z 403 (M-H) - C 17 H 12 N 2 O 6 S 2 = 404.

Example 35 Preparation of Compound 6 2- (4-chlorophenylthio) benzaldehyde (249 mg, 1.00 m
mol), 2,4-thiazolidinedione (176 mg, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) in ethanol (8 mL).
Heated to reflux for hours. The reaction was cooled to room temperature and water and 1N HCl (1
mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with ethyl acetate to give compound 6 (274 mg, 7
0%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.24 (d, J
= 8.4 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.5-7.
6 (M, 4H), 8.03 (s, 1H), 12.7 (br s, 1H) FABMS m / z 348 (M + H) ⁺ C ₁₆ H ₁₀ ³⁵ ClNO ₂ S ₂ = 347.

Example 36 Preparation of Compound 7 Compound 6 (20 mg, 0.057 mmol) was added to dichloromethane (5 m) under ice cooling.
L), and the suspension is m-chloroperbenzoic acid (purity 50%, 22 m
g, 0.063 mmol) and then stirred for 20 minutes. 10 in the reaction solution
% Aqueous sodium bisulfite solution was added and the mixture was extracted with chloroform-methanol (9: 1). The organic layer was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
Then, the residue was triturated with diisopropyl ether to obtain compound 7 (15 mg, 72%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.55 (d, J
= 9.0 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 7.6-7.
8 (M, 2H), 7.9-8.0 (M, 2H), 8.02 (s, 1H), 12.
7 (br s, 1H) FABMS m / z 364 (M + H) ⁺ C ₁₆ H ₁₀ ³⁵ ClNO ₃ S ₂ = 363.

Example 37 Preparation of Compound 8 Compound 6 (20 mg, 0.057 mmol) was added to dichloromethane (5 m) under ice cooling.
L) and suspend the suspension in m-chloroperbenzoic acid (purity 50%, 200
mg, 0.57 mmol) and then stirred for 3 hours. To the reaction solution was added 10% aqueous sodium hydrogen sulfite solution, and chloroform-methanol (9: 1).
It was extracted with. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with diisopropyl ether to give compound 8 (16m
g, 74%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.60 (d, J
= 7.5 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.7-7.
8 (M, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.87 (td, J
= 7.7, 1.3 Hz, 1H), 8.11 (s, 1H), 8.27 (dd, J =
7.9, 1.3 Hz, 1H), 12.8 (br s, 1H) FABMS m / z 380 (M + H) ⁺ C ₁₆ H ₁₀ ³⁵ ClNO ₄ S ₂ = 379.

Example 38 Preparation of Compound 9 4- (4-methylphenylthio) -3-nitrobenzaldehyde (273 mg
, 1.00 mmol), 2,4-thiazolidinedione (176 mg, 1.50 m
mol) and piperidine (0.40 mL, 0.40 mmol) were heated under reflux in ethanol (8 mL) for 19 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration to give compound 9 (175 mg, 47%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.41 (s, 3
H), 6.92 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 7.9 Hz)
, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.72 (dd, J = 8.
6, 2.2 Hz, 1H), 7.73 (s, 1H), 8.46 (d, J = 1.8H
z, 1H), 12.7 (br s, 1H) FABMS m / z 373 (M + H) ⁺ C ₁₇ H ₁₂ N ₂ O ₄ S ₂ = 372.

Example 39 Preparation of Compound 10 2-phenoxybenzaldehyde (Synthesis, 28 (1995))
(198 mg, 1.00 mmol), 2,4-thiazolidinedione (176 mg
, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated under reflux in ethanol (5 mL) for 4 hours. The reaction was cooled to room temperature, water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give compound 10 (199 mg, 67%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.95 (d, J
= 8.1 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 7.20 (t
, J = 7.3 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 7.4-
7.5 (M, 3H), 7.58 (dd, J = 7.7, 1.3 Hz, 1H), 7.
95 (s, 1H), 12.6 (br s, 1H) FABMS m / z 298 (M + H) + C 16 H 11 NO 3 S = 297.

Example 40 Preparation of Compound 11 3-phenoxybenzaldehyde (0.172 mL, 1.00 mmol), 2
, 4-thiazolidinedione (176 mg, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated to reflux in ethanol (5 mL) for 10 hours. The reaction was cooled to room temperature, water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with diisopropyl ether to give compound 11 (141
mg, 47%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.0-7.3 (
m, 5H), 7.35 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 8)
． 4,7.5 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.82
(S, 1H), 12.6 ( br s, 1H) FABMS m / z 298 (M + H) + C 16 H 11 NO 3 S = 297.

Example 41 Preparation of Compound 12 3- (4-Methylphenoxy) benzaldehyde (0.193 mL, 1.00)
mmol), 2,4-thiazolidinedione (176 mg, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated to reflux in ethanol (5 mL) for 7 hours. The reaction was cooled to room temperature, and water and 1N HCl (
1 mL) was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from ethanol / ethyl acetate to give compound 12 (
98 mg, 32%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3)
H), 6.9-7.0 (m, 3H), 7.12 (t, J = 2.0Hz, 1H),
7.23 (d, J = 8.4 Hz, 2H), 7.29 (br d, J = 7.9 Hz)
, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.49 (s, 1H) FABMS m / z 312 (M + H) ⁺ C ₁₇ H ₁₃ NO ₃ S = 311.

Example 42 Preparation of Compound 13 3- (3,4-dichlorophenoxy) benzaldehyde (0.198 mL, 1
． 00 mmol), 2,4-thiazolidinedione (176 mg, 1.50 mmo
l) and piperidine (0.10 mL, 1.0 mmol) in ethanol (5 mL
) Under reflux for 7 hours. The reaction solution was cooled to room temperature, water and 1 mol / L
HCl (1 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate to give compound 13 (252 mg, 69%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.0-7.2 (
m, 2H), 7.25 (t, J = 2.0 Hz, 1H), 7.38 (d, J = 7.
7 Hz, 1 H), 7.38 (d, J = 2.8 Hz, 1 H), 7.52 (t, J =
8.0 Hz, 1 H), 7.53 (s, 1 H), 7.66 (d, J = 8.8 Hz,
1H) FABMS m / z 366 (M + H) ⁺ C ₁₆ H ₉ ³⁵ Cl ₂ NO ₃ S = 365.

Example 43 Preparation of Compound 14 4-phenoxybenzaldehyde (0.175 mL, 1.00 mmol), 2
, 4-thiazolidinedione (176 mg, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated to reflux in ethanol (5 mL) for 6 hours. The reaction was cooled to room temperature and water and 1 mol / L HCl (1 mL
) Was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with hexane / diisopropyl ether to give compound 14 (252 mg, 85%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.0-7.2 (
m, 4H), 7.23 (t, J = 7.3Hz, 1H), 7.4-7.5 (m, 2)
H), 7.62 (d, J = 8.8 Hz, 2H), 7.78 (s, 1H), 12.
6 (br s, 1H) FABMS m / z 298 (M + H) + C 16 H 11 NO 3 S = 297.

Example 44 Preparation of Compound 15 4-Fluorobenzaldehyde (0.53 mL, 5.0 m) under argon atmosphere.
mol) and p-cresol (648 mg, 6.0 mmol) were dissolved in dimethylacetamide (8 mL), and to this solution was added potassium carbonate (828 mg, 6 mmol).
． 0 mmol) and cupric oxide (95 mg, 0.50 mmol) were added and the mixture was heated to reflux for 1.5 hours. Cool the reaction to room temperature and add water,
The mixture was then extracted with ethyl acetate. The organic layer was washed with 0.5N aqueous sodium hydroxide solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 4- (4-methylphenoxy) benzaldehyde (697 mg, 66%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.37 (s, 3H)
, 6.98 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2
H), 7.21 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 9.0 Hz)
, 2H), 9.91 (s, 1H) FABMS m / z 213 (M ⁺ ) C ₁₄ H ₁₂ O ₂ = 212.

The 4- (4-methylphenoxy) benzaldehyde (2
12 mg, 1.00 mmol), 2,4-thiazolidinedione (176 mg, 1
． 50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated under reflux in ethanol (5 mL) for 4 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give compound 15 (252 mg, 81%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3
H), 7.01 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.8 Hz
, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.8)
Hz, 2H), 7.76 (s, 1H), 12.6 (br s, 1H) FABMS m / z 312 (M ⁺ ) C ₁₇ H ₁₃ NO ₃ S = 311.

Example 45 Preparation of Compound 16 (1) 5-Nitrosalicylaldehyde (334 mg, 2.
00 mmol) in dimethylformamide (5 mL), and this solution was mixed with benzyl bromide (0.238 mL, 2.00 mmol) and sodium hydride (88 mg, 2.4 mmol), then stirred at 70 ° C. for 13 hours. did. The reaction solution was ice-cooled, water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether to give 2-benzyloxy-5-nitrobenzaldehyde (337 mg, 6
6%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 5.33 (s, 2H)
, 7.18 (d, J = 9.2 Hz, 1H), 7.4-7.5 (m, 5H), 8.
42 (dd, J = 9.2, 2.9 Hz, 1H), 8.73 (d, J = 2.9 Hz
, 1H), 10.5 (s, 1H) FABMS m / z 258 (M + H) ⁺ C ₁₄ H ₁₁ NO ₄ = 257.

(2) The obtained 2-benzyloxy-5-nitrobenzaldehyde (257 m
g, 1.00 mmol), 2,4-thiazolidinedione (176 mg, 1.50)
mmol) and piperidine (0.10 mL, 1.0 mmol) were heated under reflux in ethanol (5 mL) for 11 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether to give compound 16 (211 mg, 59%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.42 (s, 2
H), 7.3-7.6 (m, 6H), 7.91 (s, 1H), 8.25 (d, J).
= 2.6 Hz, 1H), 8.35 (dd, J = 9.2, 2.8 Hz, 1H), 1
2.7 (br s, 1H) FABMS m / z 357 (M + H) ⁺ C ₁₇ H ₁₂ N ₂ O ₅ S = 356.

Example 46 Preparation of Compound 17 (1) From 5-nitrosalicylaldehyde (334 mg, 2.00 mmol) and 3,4-dichlorobenzyl chloride (0.305 mL, 2.20 mmol), Example 45 (1). 2- (3,4-Dichlorobenzyloxy) -5-nitrobenzaldehyde (482 mg, 74%) was obtained in the same manner as described in.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 5.27 (s, 2H)
, 7.14 (d, J = 9.2 Hz, 1H), 7.30 (dd, J = 8.3, 2.
2 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 7.56 (d, J =
2.2 Hz, 1 H), 8.43 (dd, J = 9.2, 2.9 Hz, 1 H), 8.
74 (d, J = 2.9 Hz, 1H), 10.5 (s, 1H).

(2) 2- (3,4-dichlorobenzyloxy) -5 thus obtained
-Nitrobenzaldehyde (326 mg, 1.00 mmol) to Example 45
Compound 17 (142 mg, 33%) was obtained in the same manner as described in (2).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.42 (s, 2
H), 7.44 (d, J = 9.4 Hz, 1H), 7.49 (dd, J = 8.3,
2.0 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.80 (d,
J = 1.8Hz, 1H), 7.90 (s, 1H), 8.26 (d, J = 2.6H
z, 1H), 8.36 (dd, J = 9.4, 2.8 Hz, 1H), 12.8 (b
r s, 1H) FABMS m / z 425 (M + H) ⁺ C ₁₇ H ₁₀ ³⁵ Cl ₂ N ₂ O ₅ S = 424.

Example 47 Preparation of Compound 18 (1) Described in Example 45 (1) from 5-nitrosalicylaldehyde (334 mg, 2.00 mmol) and 4-methylbenzyl bromide (370 mg, 2.00 mmol). 2- (4-methylbenzyloxy)-in the same manner as
5-Nitrobenzaldehyde (413 mg, 76%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.18 (s, 3H)
, 5.28 (s, 2H), 7.18 (d, J = 9.4 Hz, 1H), 7.24 (
d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 8.4
0 (dd, J = 9.2, 2.9 Hz, 1H), 8.72 (d, J = 2.9 Hz,
1H), 10.5 (s, 1H ) FABMS m / z 272 (M + H) + C 15 H 13 NO 4 = 271.

(2) From 2- (4-methylbenzyloxy) -5-nitrobenzaldehyde (271 mg, 1.00 mmol) thus obtained, Example 45 (2)
Compound 18 (200 mg, 54%) was obtained in the same manner as described in.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.32 (s, 3)
H), 5.35 (s, 2H), 7.24 (d, J = 7.9Hz, 2H), 7.3.
8 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 9.3 Hz, 1H), 7
． 88 (s, 1H), 8.24 (d, J = 2.8Hz, 1H), 8.34 (dd
, J = 9.2, 2.8 Hz, 1H), 12.7 (br s, 1H) FABMS m / z 371 (M + H) ⁺ C ₁₈ H ₁₄ N ₂ O ₅ S = 370.

Example 48 Preparation of Compound 19 (1) 3-Hydroxy-4-nitrobenzaldehyde (334 mg, 2.00
mmol) and 4-methylbenzyl bromide (370 mg, 2.00 mmol)
), 3- (4-methylbenzyloxy) -4-nitrobenzaldehyde (315 mg, 58%) was obtained in the same manner as described in Example 45 (1).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.36 (s, 3H)
, 5.27 (s, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.34 (
d, J = 8.1 Hz, 2H), 7.53 (dd, J = 8.1, 1.5 Hz, 1H
), 7.64 (d, J = 1.5 Hz, 1 H), 7.92 (d, J = 8.1 Hz,
1H), 10.0 (s, 1H ) FABMS m / z 272 (M + H) + C 15 H 13 NO 4 = 271.

(2) Treating the resulting 3- (4-methylbenzyloxy) -4-nitrobenzaldehyde (271 mg, 1.00 mmol) in the same manner as described in Example 45 (2), Then, Compound 19 (95 mg, 26%) was obtained by recrystallization from ethyl acetate / hexane.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3
H), 5.32 (s, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.2
9 (dd, J = 8.4, 1.5 Hz, 1H), 7.36 (d, J = 8.1 Hz,
2H), 7.64 (d, J = 1.7Hz, 1H), 7.81 (s, 1H), 8.
02 (d, J = 8.4 Hz, 1H), 12.8 (br s, 1H) FABMS m / z 371 (M + H) ⁺ C ₁₈ H ₁₄ N ₂ O ₅ S = 370.

Example 49 Preparation of Compound 20 (1) 4-Hydroxy-3-nitrobenzaldehyde (334 mg, 2.00
mmol) and 4-methylbenzyl bromide (370 mg, 2.00 mmol)
From 4-), 4- (4-methylbenzyloxy) -3-nitrobenzaldehyde (365 mg, 67%) was obtained in the same manner as described in Example 45 (1).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.36 (s, 3H)
, 5.31 (s, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.26 (
d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 8.0
2 (dd, J = 8.6, 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz,
1H), 9.92 (s, 1H ) FABMS m / z 272 (M + H) + C 15 H 13 NO 4 = 271.

(2) 4- (4-Methylbenzyloxy) -3-nitrobenzaldehyde (271 mg, 1.00 mmol) thus obtained was treated in the same manner as described in Example 45 (2). Compound 20 (123 mg, 33%) was obtained by treatment with and recrystallization from ethyl acetate / hexane.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3)
H), 5.34 (s, 2H), 7.22 (d, J = 7.9Hz, 2H), 7.3
5 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 9.0 Hz, 1H), 7
． 81 (s, 1H), 7.84 (dd, J = 9.0, 2.2Hz, 1H), 8.
15 (d, J = 2.2 Hz, 1H), 12.7 (br s, 1H) FABMS m / z 371 (M + H) ⁺ C ₁₈ H ₁₄ N ₂ O ₅ S = 370.

Example 50 Preparation of Compound 21 (1) 5-Hydroxy-2-nitrobenzaldehyde (334 mg, 2.00
mmol) and 4-methylbenzyl bromide (370 mg, 2.00 mmol)
), 5- (4-methylbenzyloxy) -2-nitrobenzaldehyde (413 mg, 76%) was obtained in the same manner as described in Example 45 (1).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.37 (s, 3H)
, 5.16 (s, 2H), 7.19 (dd, J = 9.0, 2.9 Hz, 1H),
7.21 (d, J = 7.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H)
), 7.41 (d, J = 2.9 Hz, 1H), 8.15 (d, J = 9.2 Hz,
1H), 10.5 (s, 1H ) FABMS m / z 272 (M + H) + C 15 H 13 NO 4 = 271.

(2) 5- (4-Methylbenzyloxy) -2-nitrobenzaldehyde (271 mg, 1.00 mmol) thus obtained, 2,4-thiazolidinedione (176 mg, 1.50 mmol), and Piperidine (0.10 mL,
1.0 mmol) was heated to reflux in ethanol (8 mL) for 1.5 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / acetonitrile = 19/1) and preparative thin layer chromatography (chloroform / methanol = 10/1) to give compound 21 (30 mg, 8 .1%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.38 (s, 3H)
, 5.16 (s, 2H), 7.04 (d, J = 2.4 Hz, 1H), 7.09 (
dd, J = 9.2, 2.6 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H)
), 7.30 (d, J = 7.8 Hz, 2H), 8.22 (d, J = 9.2 Hz,
1H), 8.24 (s, 1H), 9.00 (br s, 1H) FABMS m / z 371 (M + H) ⁺ C ₁₈ H ₁₄ N ₂ O ₅ S = 370.

Example 51 Preparation of Compound 22 Salicylaldehyde (0.213 mL, 2.00 mmol) under an argon atmosphere.
) In dimethylformamide (5 mL) and to this solution 4-methylbenzyl bromide (370 mg, 2.00 mmol) and sodium hydride (8
8 mg, 2.4 mmol) was added, and then the mixture was stirred at 70 ° C. for 1.5 hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 2,4-thiazolidinedione (176mg, 1.50m)
mol), piperidine (0.10 mL, 1.0 mmol) and ethanol (5
(mL) and then heated to reflux for 1.5 hours. The reaction was cooled to room temperature, water and 1N HCl (1 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with hexane / diisopropyl ether to give compound 22 (542 mg, 83% for 2 steps).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3)
H), 5.19 (s, 2H), 7.10 (t, J = 7.5 Hz, 1H), 7.2
2 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 7.5 Hz, 1H), 7
． 35 (d, J = 8.1 Hz, 2H), 7.4-7.5 (m, 2H), 8.01
(S, 1H), 12.6 ( br s, 1H) FABMS m / z 326 (M + H) + C 18 H 15 NO 3 S = 325.

Example 52 Preparation of Compound 23 5-Methoxysalicylaldehyde (0.249 mL, 2.
00 mmol) in dimethylformamide (5 mL) and to this solution 4-methylbenzyl bromide (370 mg, 2.00 mmol) and sodium hydride (88 mg, 2.4 mmol) are added, followed by 1.5 at 70 ° C. Stir for hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 2,4-thiazolidinedione (176mg
, 1.50 mmol), piperidine (0.10 mL, 1.0 mmol) and ethanol (5 mL) were added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature, and the precipitated crystal was collected by filtration to give compound 23 (419 mg,
A two-step yield of 59%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3)
H), 3.75 (s, 3H), 5.12 (s, 2H), 6.90 (d, J = 2.
9 Hz, 1 H), 7.05 (dd, J = 9.0, 2.9 Hz, 1 H), 7.18
(D, J = 9.0 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.
32 (d, J = 8.1 Hz, 2H), 7.95 (s, 1H), 12.6 (br
s, 1H) FABMS m / z 356 (M + H) + C 19 H 17 NO 4 S = 355.

Example 53 Preparation of Compound 24 5-Chlorosalicylaldehyde (313 mg, 2.00 m) under argon atmosphere.
mol) was dissolved in dimethylformamide (5 mL) and the solution was treated with 4-methylbenzyl bromide (370 mg, 2.00 mmol) and sodium hydride (
88 mg, 2.4 mmol) was added, and then the mixture was stirred at 70 ° C. for 0.5 hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 2,4-thiazolidinedione (176 mg, 1.50)
mmol), piperidine (0.10 mL, 1.0 mmol) and ethanol (
15 mL) was added, and the mixture was heated under reflux for 4 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with hexane / diisopropyl ether to give compound 24 (428 mg, 60% for 2 steps).
Got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3
H), 5.19 (s, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.2
7 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7
． 36 (d, J = 2.9 Hz, 1H), 7.51 (dd, J = 9.0, 2.8H
z, 1H), 7.87 (s, 1H), 12.6 (br s, 1H) FABMS m / z 360 (M + H) ⁺ C ₁₈ H ₁₄ ³⁵ ClNO ₃ S = 359.

Example 54 Preparation of Compound 25 5-Bromosalicylaldehyde (1.00 g, 5.00 m) under argon atmosphere.
mol) in dimethylformamide (10 mL) and to the solution 4-methylbenzyl bromide (925 mg, 5.00 mmol) and sodium hydride (220 mg, 5.50 mmol) are added, followed by 0.5 at 70 ° C. Stir for hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 2,4-thiazolidinedione (702 mg, 6.
00 mmol), piperidine (0.50 mL, 5.0 mmol) and ethanol (40 mL) were added, and then heated under reflux for 4 hours. The reaction was cooled to room temperature and water and 1N HCl (5 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with hexane / diisopropyl ether to give compound 25 (1.27 mg, 2 steps 6).
3%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3
H), 5.19 (s, 2H), 7.21 (d, J = 8.8Hz, 3H), 7.3
4 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 2.4 Hz, 1H), 7
． 62 (dd, J = 8.8, 2.4 Hz, 1H), 7.86 (s, 1H), 12
． 6 (br s, 1H) FABMS m / z 406,404 (M + H) ⁺ C ₁₈ H ₁₄ ⁷⁹ BrNO ₃ S = 4
03.

Example 55 Preparation of Compound 26 4-Diphenylaminobenzaldehyde (273 mg, 1.00 mmol),
2,4-thiazolidinedione (176 mg, 1.50 mmol) and piperidine (0.10 mL, 1.0 mmol) were heated under reflux in ethanol (8 mL) for 4 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate to give compound 26 (293 mg,
79%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.93 (d, J
= 7.2 Hz, 2H), 7.1-7.2 (m, 6H), 7.3-7.5 (m, 6)
H), 7.67 (s, 1H), 12.5 (br s, 1H) FABMS m / z 373 (M + H) ⁺ C ₂₂ H ₁₆ N ₂ O ₂ S = 372.

Example 56 Preparation of Compound 27 2-Phenylbenzaldehyde [tetrahedron letters (Tetrahhe
dron Lett. ), 38 (32), 5575 (1997)] (2
73 mg, 1.50 mmol), 2,4-thiazolidinedione (263 mg, 2
． 25 mmol) and piperidine (0.15 mL, 1.5 mmol) were heated to reflux in ethanol (8 mL) for 3 hours. The reaction was cooled to room temperature and water and 1N HCl (2 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give compound 27 (344 mg, 82%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.3-7.4 (
m, 2H), 7.4-7.7 (m, 8H), 12.6 (br s, 1H) FABMS m / z 282 (M + H) ⁺ C ₁₆ H ₁₁ NO ₂ S = 281.

Example 57 Preparation of Compound 28 3-phenylbenzaldehyde [tetrahedron letters (Tetrahhe
dron Lett. ), 38 (32), 5575 (1997)] (2
69 mg, 1.48 mmol), 2,4-thiazolidinedione (259 mg, 2
． 22 mmol) and piperidine (0.15 mL, 1.5 mmol) were heated under reflux in ethanol (8 mL) for 3 hours. The reaction was cooled to room temperature and water and 1N HCl (2 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give Compound 28 (355 mg, 85%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.3-7.8 (
m, 8H), 7.89 (s, 2H), 12.6 (br s, 1H) FABMS m / z 282 (M + H) ⁺ C ₁₆ H ₁₁ NO ₂ S = 281.

Example 58 Preparation of Compound 29 4-Phenylbenzaldehyde (182 mg, 1.00 mmol), 2,4-
Thiazolidinedione (176 mg, 1.5 mmol), and piperidine (0.
10 mL, 1.0 mmol) was heated under reflux in ethanol (6 mL) for 3 hours.
The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
Then, it was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with diisopropyl ether to give compound 29 (187 mg).
, 67%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.4-7.6 (
m, 3H), 7.70 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 7.
2Hz, 2H), 7.85 (s, 1H), 7.86 (d, J = 8.1Hz, 2H
), 12.6 (br s, 1H) FABMS m / z 282 (M + H) ⁺ C ₁₆ H ₁₁ NO ₂ S = 281.

Example 59 Preparation of Compound 30 4- (α-Hydroxybenzyl) benzaldehyde [Journal of Organic Chemistry (J. Org. Chem.), 62, 4643 (1997)] (1.35 g) , 6.37 mmol), 2,4-thiazolidinedione (894 mg, 7.64 mmol), and piperidine (0.64 mL, 6).
． 4 mmol) was heated under reflux in ethanol (6 mL) for 10 hours. The reaction was cooled to room temperature and water and 1N HCl (7 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with diisopropyl ether to give compound 30 (1.73 g, 87%).
Got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.75 (d, J
= 2.7 Hz, 1 H), 6.03 (d, J = 2.7 Hz, 1 H), 7.21 (t
t, J = 7.2, 1.5 Hz, 1H), 7.31 (t, J = 7.2 Hz, 2H
), 7.38 (d, J = 7.3 Hz, 2H), 7.53 (s, 4H), 7.75
(S, 1H), 12.6 (br s, 1H) FABMS m / z 312 (M + H) ⁺ C ₁₇ H ₁₃ NO ₃ S = 311.

Example 60 Preparation of Compound 31 Compound 30 (622 mg, 2.00 mmol) was added to acetonitrile (80 mL).
, Manganese dioxide (2.61 g) was added to the solution, and the mixture was added to 4
． The mixture was heated under reflux for 5 hours. The reaction was cooled to room temperature and filtered through Celite, then the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (
Compound 31 (73 mg, 12%) by purification with chloroform / acetonitrile = 9/1) and trituration with diisopropyl ether.
Got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.58 (t, J
= 7.5 Hz, 2H), 7.6-7.8 (m, 5H), 7.86 (d, J = 7.
9 Hz, 2H), 7.87 (s, 1H), 12.7 (br s, 1H) FABMS m / z 310 (M + H) ⁺ C ₁₇ H ₁₁ NO ₃ S = 309.

Example 61 Preparation of Compound 32 Compound 30 (115 mg, 0.39 mmol) was added to dichloromethane (15 mL).
And trifluoroacetic acid (0.30 mL, 3.9 mmol) and triethylsilane (0.81 mL, 5.1 mmol) were added to the solution and the mixture was heated to reflux for 12 hours. The solvent was evaporated under reduced pressure and the residue was recrystallized from acetone / hexane to give compound 32 (70 mg, 61%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.00 (s, 2
H), 7.1-7.3 (m, 5H), 7.39 (d, J = 8.1Hz, 2H),
7.52 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 12.6 (b
r s, 1H) FABMS m / z 296 (M + H) ⁺ C ₁₇ H ₁₃ NO ₂ S = 295.

Example 62 Preparation of Compound 33 4-Formyltrityl Alcohol [Journal of Organic Chemistry (J. Org. Chem.), 63, 9924 (1998)]
(576 mg, 2.00 mmol), 2,4-thiazolidinedione (281 mg
, 2.40 mmol) and piperidine (0.20 mL, 2.0 mmol) were heated under reflux in ethanol (15 mL) for 9 hours. The reaction was cooled to room temperature and water and 1N HCl (2 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate / diisopropyl ether to give compound 33 (684 mg, 78%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.61 (s, 1
H), 7.2-7.4 (m, 10H), 7.37 (d, J = 8.4Hz, 2H).
, 7.55 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 12.6 (
br s, 1H) FABMS m / z 388 (M + H) ⁺ C ₂₃ H ₁₇ NO ₃ S = 387.

Example 63 Preparation of Compound 34 Compound 33 (219 mg, 0.566 mmol) was added to dichloromethane (15 mL).
) And trifluoroacetic acid (0.385 mL, 0.50 mmo)
1) and triethylsilane (0.80 mL, 0.50 mmol) were added, and then the mixture was stirred at room temperature for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was triturated with hexane to give compound 34 (198 mg, 94%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.70 (s, 1
H), 7.1-7.4 (m, 12H), 7.55 (d, J = 8.3Hz, 2H)
, 7.75 (s, 1H), 12.6 (br s, 1H) FABMS m / z 372 (M + H) ⁺ C ₂₃ H ₁₇ NO ₂ S = 371.

Example 64 Preparation of Compound 35 Dissolve diphenylamine (338 mg, 2.00 mmol) and 4-bromobenzyl bromide (500 mg, 2.00 mmol) in dimethylformamide (8 mL) under an argon atmosphere, and under ice cooling, Sodium hydride (88
(mg, 2.2 mmol) was added, 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 then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane / acetone = 14/1).
N- (4-bromobenzyl) diphenylamine (47
8 mg, 71%) was obtained.

¹ H NMR (300 MHz, CDCl 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, 2 H) FABMS m / z 339, 337 (M ⁺ ) C ₁₉ H ₁₆ ⁷⁹ BrN = 337.

Under an argon atmosphere, N- (4-bromobenzyl) diphenylamine (440 mg, 1.30 mmol) thus obtained was dissolved in tetrahydrofuran (6 mL).
) And cooled to -78 ° C. 1.6 mol / n-butyllithium
L hexane solution (1.3 mL, 2.0 mmol) was added and after 5 minutes dimethylformamide (0.20 mL, 2.6 mmol) was added, followed by stirring for an additional 5 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 4- (N, N-diphenylaminomethyl) benzaldehyde (213 mg, 57%). Obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 5.06 (s, 2H)
, 6.96 (t, J = 7.3 Hz, 2H), 7.03 (d, J = 8.6 Hz, 4
H), 7.25 (dd, J = 8.6, 7.3 Hz, 4H), 7.52 (d, J =
8.4 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 9.97 (s,
1H) FABMS m / z 287 ( M +) C 20 H 17 NO = 287.

The obtained 4- (N, N-diphenylaminomethyl) benzaldehyde (198
mg, 0.690 mmol), 2,4-thiazolidinedione (117 mg, 1.
10 mmol) and piperidine (0.068 mL, 0.69 mmol) were heated under reflux in ethanol (6 mL) for 5 hours. The reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration to give compound 35 (240 mg, 90%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.06 (s, 2
H), 6.92 (t, J = 7.2 Hz, 2H), 7.05 (d, J = 8.4 Hz)
, 4H), 7.25 (t, J = 7.7 Hz, 4H), 7.48 (d, J = 8.3).
Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.75 (s, 1H)
, 12.6 (br s, 1H) FABMS m / z 386 (M ⁺ ) C ₂₃ H ₁₈ N ₂ O ₂ S = 386.

Example 65 Preparation of Compound 36 4-Bromoaniline (344 mg, 2.00 mmol) was dissolved in dimethylformamide (5 mL) under an argon atmosphere, and sodium hydride (200 mg, 5. 00 mmol) and benzyl bromide (0.52 mL)
, 4.4 mmol) and then stirred at room temperature for 11 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,
It was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then recrystallized from ethyl acetate / hexane to give 4-bromo-N, N-dibenzyl-4-bromoaniline (442 mg, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.63 (s, 4H)
, 6.59 (d, J = 9.0Hz , 2H), 7.2-7.4 (m, 12H) FABMS m / z 353,351 (M +) C 20 H 18 79 BrN = 351.

Under an argon atmosphere, the obtained 4-bromo-N, N-dibenzylaniline (42
5 mg, 1.21 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78 ° C. 1.6 M hexane solution of n-butyllithium (1.1 m
L, 1.8 mmol) and after 5 minutes dimethylformamide (0.1
86 mL, 2.4 mmol) was added and then stirred for another 5 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 4- (dibenzylamino) benzaldehyde (192 mg, 53%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.75 (s, 4H)
, 6.79 (d, J = 9.0 Hz, 2H), 7.2-7.4 (m, 10H), 7
． 69 (d, J = 9.0 Hz, 2H), 9.73 (s, 1H) FABMS m / z 302 (M + H) ⁺ C ₂₁ H ₁₉ NO = 301.

The obtained 4- (dibenzylamino) benzaldehyde (181 mg, 0.60
1 mmol), 2,4-thiazolidinedione (105 mg, 0.900 mmol
), And piperidine (0.059 mL, 0.60 mmol) in ethanol (7
(mL) and heated to reflux for 5 hours. The reaction was cooled to room temperature and water and 1N
HCl (0.6 mL) was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether to give compound 36 (207 mg, 86%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.81 (s, 4
H), 6.81 (d, J = 8.8 Hz, 2H), 7.2-7.4 (m, 12H)
, 7.61 (s, 1H), 12.3 (br s, 1H) FABMS m / z 400 (M ⁺ ) C ₂₄ H ₂₀ N ₂ O ₂ S = 400.

Example 66 Preparation of Compound 39 5-Nitro-2-[(4-trifluoromethyl) phenoxy] benzaldehyde (311 mg, 1.00 mmol), 2,4-thiazolidinedione (234 m)
g, 2.00 mmol), and piperidine (0.10 mL, 1.0 mmol)
Was heated to reflux in ethanol (8 mL) for 13 hours. Cool the reaction to room temperature,
Then water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / acetonitrile = 15/1), and then triturated with diisopropyl ether to give compound 39 (146 mg,
36%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.16 (d, J
= 9.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.89 (d
, J = 8.4 Hz, 2H), 7.93 (s, 1H), 8.30 (dd, J = 9.
2, 2.8 Hz, 1 H), 8.39 (d, J = 2.2 Hz, 1 H), 12.8 (
br s, 1H) FABMS m / z 411 (M + H) ⁺ C ₁₇ H ₉ F ₃ N ₂ O ₅ S = 410.

Example 67 Preparation of Compound 40 2-Bromo-5-hydroxybenzaldehyde (201 m
g, 1.00 mmol) was dissolved in dimethylformamide (3 mL), and 4-methylbenzyl bromide (185 mg, 1.00 mmol) and sodium hydride (48 mg, 1.2 mmol) were added to the solution, then at 70 ° C. Stir for 3 hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. 2,4-thiazolidinedione (176mg
, 1.5 mmol), piperidine (0.10 mL, 1.0 mmol) and ethanol (6 mL) were added, and the mixture was heated under reflux for 13 hours. The reaction was cooled to room temperature and water and 1N HCl (5 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / acetonitrile = 20/1), and triturated with diisopropyl ether to give compound 40 (142).
mg, 35% in 2 steps).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3
H), 5.13 (s, 2H), 7.0-7.1 (m, 2H), 7.21 (d, J).
= 7.7 Hz, 2 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.69 (d
, J = 8.6 Hz, 1H), 7.79 (s, 1H), 12.7 (br s, 1H)
) FABMS m / z 406,404 (M + H) ⁺ C ₁₈ H ₁₄ ⁷⁹ BrNO ₃ S = 4
03.

Example 68 Preparation of Compound 41 2,5-Dihydroxybenzaldehyde (138 mg, 1 under argon atmosphere)
． 00 mmol) in dimethylformamide (5 mL) and add 4 to the solution.
-Methylbenzyl bromide (370 mg, 2.00 mmol) and sodium hydride (88 mg, 2.2 mmol) were added, followed by stirring at 70 ° C for 2 hours.
The reaction was ice-cooled and water was added, then 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. 2,4-thiazolidinedione (176 mg, 1.5 mmo)
l), piperidine (0.10 mL, 1.0 mmol) and ethanol (8 mL
) Was added, and the mixture was heated under reflux for 2 hours. The reaction was cooled to room temperature and water and 1N HCl (5 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with hexane / diisopropyl ether to give compound 41 (340 mg, 76% for 2 steps).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 6
H), 5.05 (s, 2H), 5.11 (s, 2H), 6.93 (br s, 1
H), 7.1-7.2 (m, 2H), 7.20 (d, J = 7.7 Hz, 4H),
7.32 (d, J = 7.9 Hz, 4H), 7.93 (s, 1H), 12.6 (s
, 1H) FABMS m / z 446 (M + H) + C 26 H 23 NO 4 S = 445.

Example 69 Preparation of Compound 42 5′-Bromo-2′-hydroxyacetophenone (215
mg, 1.00 mmol) was dissolved in dimethylformamide (5 mL) and the solution was mixed with 4-methylbenzyl bromide (185 mg, 1.00 mmol) and potassium carbonate (152 mg, 1.1 mmol), then at 5O <0> C. Stir for hours. The reaction was ice-cooled and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N aqueous sodium hydroxide solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Two here
4-Thiazolidinedione (176 mg, 1.5 mmol) and sodium acetate (123 mg, 1.5 mmol) were added, and then reacted at 190 ° C. for 3 to 5 hours. The reaction was cooled to room temperature and water and 1N HCl (1 mL) were added, then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / acetonitrile = 30 /
Compound 42 (102 mg, 24% in 2 steps) was obtained by purification in 1).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.35 (s, 3
H), 2.61 (s, 3H), 6.88 (d, J = 9.0Hz, 1H), 7.1
-7.3 (m, 5H), 7.41 (dd, J = 8.8, 2.6Hz, 1H), 8
． 14 (br s, 1H) FABMS m / z 420,418 (M + H) ⁺ C ₁₉ H ₁₆ ⁷⁹ BrNO ₃ S = 4
17.

Example 70 Preparation of Compound 43 5-Bromo-2- (4-chlorophenylthio) thiophene-3-carboxaldehyde (167 mg, 0.500 mmol), 2,4-thiazolidinedione (
88 mg, 0.75 mmol), and piperidine (0.049 mL, 0.5 m
(mol) was heated to reflux in ethanol (5 mL) for 6 hours. The reaction solution was cooled to room temperature, water and 1 mol / L HCl (0.5 mL) were added, and then the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with diisopropyl ether / ethyl acetate to give compound 43 (138 m
g, 64%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.32 (d, J
= 8.6 Hz, 2 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.82 (s
, 1H), 7.98 (s, 1H), 12.7 (br s, 1H) FABMS m / z 433, 431 (M ⁺ ) C ₁₄ H ₇ ⁷⁹ Br ³⁵ ClNO ₂ S ₃ =
431.

Example 71 Preparation of Compound 44 Compound 43 (22 mg, 0.051 mmol) was dissolved in dimethoxyethane (2 mL) under argon atmosphere and tetrakis (triphenylphosphine) palladium (6 mg, 10 mol%) was added to the solution. Aqueous sodium carbonate solution (0.5mo
(1 / L, 0.6 mL) and phenylboric acid (31 mg, 0.25 mmol) were added, and the mixture was heated under reflux for 12 hours. The reaction was cooled to room temperature and water was added, then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / acetone = 10/1) to give compound 44 (8.3 mg, 38%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.17 (d, J
= 8.4 Hz, 2H), 7.2-7.5 (m, 8H), 7.91 (s, 1H),
8.16 (br s, 1H) FABMS m / z 429 (M +) C 20 H 12 35 ClNO 2 S 3 = 429.

Example 72 Preparation of Compound 45 Compound 43 (32 mg, 0.075 mmol) was dissolved in tetrahydrofuran (5 mL) under an argon atmosphere and cooled to -78 ° C. N-Butyllithium (1.6 mol / L hexane solution, 0.3 mL) was added thereto, and then 15
Stir for minutes. The reaction was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue is then subjected to preparative thin layer chromatography (chloroform / acetone = 10/1
Compound 45 (3.8 mg, 14%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.24 (d, J
= 4.2 Hz, 1H), 7.27 (d, J = 9.0 Hz, 2H), 7.30 (d
, J = 3.9 Hz, 1H), 7.31 (d, J = 9.2 Hz, 2H), 7.91
(S, 1H), 8.42 ( br s, 1H) FABMS m / z 353 (M +) C 14 H 8 35 ClNO 2 S 3 = 353.

Example 73 Preparation of Compound 46 Tris (4-bromophenyl) amine (964 mg, 2.
00 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to -78 ° C. N-Butyllithium (1.6 mol / L hexane solution; 1.
5 mL, 2.4 mmol), and dimethylformamide (0.19 mL, 2.
4 mmol) was added dropwise at an internal temperature of −60 ° C. or lower, and then stirred for 10 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 8/1), 4- [bis (4-bromophenyl) amino] benzaldehyde (377 mg, 44%). ) Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.02 (d, J = 8)
． 8 Hz, 4 H), 7.04 (d, J = 8.6 Hz, 2 H), 7.45 (d, J
= 8.8 Hz, 4 H), 7.71 (d, J = 8.8 Hz, 2 H), 9.84 (s
, 1H) FABMS m / z 433, 431, 429 (M ⁺ ) C ₁₉ H ₁₃ ⁷⁹ Br ₂ NO =
429.

This 4- [bis (4-bromophenyl) amino] benzaldehyde (356 m
g, 0.826 mmol), 2,4-thiazolidinedione (145 mg, 1.2
4 mmol) and piperidine (0.083 mL, 0.83 mmol) were heated under reflux in ethanol (8 mL) for 4 hours. The reaction was cooled to room temperature, mixed with water and 1 mol / L HCl (1 mL), and extracted with chloroform. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform / acetonitrile = 15/1), and triturated with hexane to give compound 46 (388 mg, 89%). It was

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.03 (d, J
= 8.8 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 4 H), 7.51 (d
, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 4H), 7.70
(S, 1H), 12.5 (br s, 1H) FABMS m / z 532, 530, 528 (M ⁺ ) C ₂₂ H ₁₄ ⁷⁹ Br ₂ N ₂ O ₂ S = 528.

Example 74 Preparation of Compound 47 Under an argon atmosphere, Compound 25 (40 mg, 0.10 mmol) was dissolved in 1,2-dimethoxyethane (4 mL), and phenylboric acid (24 mg, 0.20 mm) was added.
ol), 2 mol / L aqueous sodium carbonate solution (0.15 mL), water (0.5 m
L), and tetrakis (triphenylphosphine) palladium (6 mg, 5 m
ol%) was added and the product was heated to reflux for 8 hours. The reaction was cooled to room temperature, mixed with water and 1 mol / L HCl and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by preparative thin layer chromatography (developing solvent: chloroform / acetonitrile = 12/1), and triturated with isopropyl ether to give compound 47 (27 mg, 67%). ) Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.32 (s, 3
H), 5.25 (s, 2H), 7.23 (d, J = 8.1Hz, 2H), 7.3
-7.4 (m, 4H), 7.49 (t, J = 7.6Hz, 2H), 7.63 (d
, J = 8.6 Hz, 2H), 7.64 (d, J = 1.7 Hz, 1H), 7.76
(Dd, J = 8.6, 2.2 Hz, 1H), 8.03 (s, 1H), 12.6 (
br s, 1H) FABMS m / z 401 (M ⁺ ) C ₂₄ H ₁₉ NO ₃ S = 401.

Example 75 Preparation of Compound 48 2-Thienyl boric acid (26 mg, 0.20 mmol) instead of phenyl boric acid.
Compound 48 (7.5 mg, 18%) was obtained from Compound 25 (40 mg, 0.10 mmol) by the same method as in Example 74.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.32 (s, 3
H), 5.23 (s, 2H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H
), 7.22 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 8.8 Hz,
1H), 7.36 (d, J = 8.1Hz, 2H), 7.44 (d, J = 3.5H)
z, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.62 (d, J = 2.
0Hz, 1H), 7.75 (dd, J = 8.8, 2.0Hz, 1H), 7.98
(S, 1H), 12.6 ( br s, 1H) FABMS m / z 407 (M +) C 22 H 17 NO 3 S 2 = 407.

Example 76 Preparation of Compound 49 Tris (4-bromophenyl) amine (7.23 g, 15) under argon atmosphere.
． 0 mmol) in tetrahydrofuran (100 mL) and -78 ° C.
Cooled to. N-butyllithium (1.6 mol / L hexane solution; 3
4 mL, 54 mmol), and dimethylformamide (4.6 mL, 60 mm
ol) was added dropwise at an internal temperature of −60 ° C. or lower, and then stirred at the same temperature for 10 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1 then chloroform / acetonitrile = 30/1), and tris (4-formylphenyl) amine (2 .97 g, 60%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.25 (d, J = 8)
． 8 Hz, 6 H), 7.85 (d, J = 8.8 Hz, 6 H), 9.95 (s, 3
H) FABMS m / z 330 (M + H) ⁺ C ₂₁ H ₁₅ NO ₃ = 329.

The above tris (4-formylphenyl) amine (165 mg, 0.502 mm
was dissolved in methyl alcohol (8 mL) and chloroform (5 mL). Sodium borohydride (9.5 mg, 0.25 mmol) was added to the solution under ice cooling, and then the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the product was extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform / acetonitrile = 20/1 to 10/1), 4-[[bis (4-hydroxymethyl) phenyl] amino]. Benzaldehyde (107 mg, 64%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.46 (br s,
2H), 4.66 (s, 4H), 6.99 (d, J = 8.8Hz, 2H), 7.
13 (d, J = 8.4 Hz, 4H), 7.32 (d, J = 8.4 Hz, 4H),
7.64 (d, J = 8.8Hz, 2H), 9.75 (s, 1H) FABMS m / z 333 (M +) C 21 H 19 NO 3 = 333.

The above 4-[[bis (4-hydroxymethyl) phenyl] amino] benzaldehyde (100 mg, 0.300 mmol), 2,4-thiazolidinedione (5
3 mg, 0.45 mmol), and piperidine (0.030 mL, 0.30 m
(mol) was heated to reflux in ethanol (5 mL) for 3 hours. The reaction was cooled to room temperature, water and 1 mol / L HCl (1 mL) were added, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and trituration with hexane gave compound 49 (113 mg, 87%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.48 (d, J
= 4.4 Hz, 4H), 5.16 (brt, J = 5.1 Hz, 2H), 6.8
9 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.3 Hz, 4H), 7
． 32 (d, J = 8.5 Hz, 4H), 7.44 (d, J = 9.0 Hz, 2H)
, 7.66 (s, 1H), 12.4 (br s, 1H) FABMS m / z 432 (M ⁺ ) C ₂₄ H ₂₀ N ₂ O ₄ S = 432.

Example 77 Preparation of Compound 50 N- (4-bromobenzyl) diphenylamine (169 mg, 0.500 mmol) obtained in Example 64 was added to dimethylformamide (1.
5 mL) and phosphorus oxychloride (0.116 mL, 1.25 mmol)
) Was added and then stirred at 100 ° C. for 30 minutes. The reaction was cooled to room temperature, poured into saturated aqueous sodium acetate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1), 4- [N- (4-bromobenzyl) -N-phenylamino] benzaldehyde. (159 mg, 87%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.98 (s, 2H)
, 6.78 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2
H), 7.26 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.4
2 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.65 (d, J =
8.8 Hz, 2 H), 9.75 (s, 1 H) FABMS m / z 368,366 (M + H) ⁺ C ₂₀ H ₁₆ ⁷⁹ BrNO = 36
5.

4- [N- (4-Bromobenzyl) -N-phenylamino] benzaldehyde (153 mg, 0.418 mmol), 2,4-thiazolidinedione (7
3 mg, 0.63 mmol), and piperidine (0.042 mL, 0.42 m
(mol) was heated to reflux in ethanol (5 mL) for 3 hours. The reaction solution was cooled to room temperature, water and 1 mol / L HCl (1 mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and trituration with hexane / isopropyl ether gave compound 50 (150 mg, 87%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 5.06 (s, 2
H), 6.88 (d, J = 8.8 Hz, 2H), 7.21 (t, J = 7.3 Hz)
, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 7.5)
Hz, 2H), 7.40 (d, J = 8.8Hz, 2H), 7.42 (t, J = 7)
． 3Hz, 2H), 7.51 (d, J = 8.3Hz, 2H), 7.64 (s, 1
H), 12.4 (br s, 1H) FABMS m / z 466, 464 (M ⁺ ) C ₂₃ H ₁₇ ⁷⁹ BrN ₂ O ₂ S = 46.
4.

Example 78 Preparation of Compound 51 Compound 43 (50 mg, 0.12 mmol) was added to dichloromethane (8 m) under ice cooling.
It was dissolved in a mixed solvent of L) and methanol (2 mL). m-Chloroperbenzoic acid (purity 50%, 65 mg, 0.19 mmol) was added, and then stirred at room temperature for 18 hours. A 5% aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the product was extracted with chloroform. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was triturated with methanol to give compound 51 (30 mg, 56
%) Was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.73 (d, J
= 8.4 Hz, 2 H), 7.75 (s, 1 H), 7.84 (d, J = 8.6 Hz
, 2H), 7.98 (s, 1H), 12.8 (br s, 1H) FABMS m / z 450,448 (M-H) - C 14 H 7 79 Br 35 ClNO 3
S ₃ = 449.

Example 79 Preparation of Compound 52 Compound 43 (50 mg, 0.12 mmol) was added to dichloromethane (8 m) under ice cooling.
It was dissolved in a mixed solvent of L) and methanol (2 mL). m-Chloroperbenzoic acid (purity 50%, 398 mg, 1.2 mmol) was added, and then the mixture was stirred at room temperature for 17 hours. A 5% aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the product was extracted with chloroform. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and trituration with methanol gave compound 52 (23 mg, 41%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.71 (d, J
= 8.6 Hz, 2H), 7.78 (s, 1H), 8.00 (s, 1H), 8.0
5 (d, J = 8.6Hz, 2H), 12.9 (br s, 1H) FABMS m / z 466,464 (M-H) - C 14 H 7 79 Br 35 ClNO 4
S ₃ = 465.

Example 80 Preparation of Compound 53 Commercially available (MAYBRIDGE, Catalog No. KM05476) 5-bromo-2- (4-chlorophenylthio) thiophene-3-carboxaldehyde (1
． 00 g, 2.99 mmol) was dissolved in methanol (75 mL). p-Toluenesulfonic acid (52 mg, 0.30 mol) was added and the mixture was heated at reflux for 1.5 hours. The solvent was distilled off under reduced pressure to about 30 mL. Water and saturated aqueous sodium hydrogen carbonate solution were added and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and 5-bromo-2- (4-chlorophenylthio) -3- (dimethoxymethyl)
Thiophene (1.12 g, 100%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.36 (s, 6H)
, 5.55 (s, 1H), 7.07 (s, 1H), 7.15 (d, J = 8.6H
z, 2H), 7.24 (d , J = 8.8Hz, 2H) FABMS m / z 380,378 (M +) C 13 H 12 79 Br 35 ClO 2 S 2 = 3
78.

Under an argon atmosphere, 5-bromo-2- (4-chlorophenylthio) -3- (dimethoxymethyl) thiophene (1.04 g, 2.75 mmol) was dissolved in tetrahydrofuran (15 mL), and the mixture was- Cooled to 78 ° C. N-butyllithium (1.6 mol / L hexane solution; 2.5 mL, 4.1 mm)
ol) was added, followed by stirring for 5 minutes. Dry ice (about 1 g) was added thereto, and then stirred for 10 minutes. Water and 1 mol / L aqueous sodium hydroxide solution were added to the reaction solution to adjust the pH to 10, and the mixture was washed with ether. 1m in the water layer
The pH was adjusted to 3 with ol / L hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). 1mo
l / L hydrochloric acid (2 mL) was added, and then the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with isopropyl ether to give 2- (4-chlorophenylthio) -3-formyl-5-thiophenecarboxylic acid (439 mg, 54%).
) Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.50 (d, J = 8)
． 6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 8.06 (s, 1
H), 9.68 (s, 1H) FABMS m / z 299 (M + H) ⁺ C ₁₂ H ₇ ³⁵ ClO ₃ S ₂ = 298.

2- (4-chlorophenylthio) -3-formyl-5-thiophenecarboxylic acid (400 mg, 1.34 mmol), 2,4-thiazolidinedione (188 mg)
, 1.01 mmol), and piperidine (0.133 mL, 1.34 mmol)
Was heated to reflux with ethanol (12 mL) for 3.5 hours. The reaction mixture was cooled to room temperature, 1 mol / L hydrochloric acid (1.5 mL) was added, and the precipitated crystals were collected by filtration to give compound 53 (411 mg, 77%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J
= 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.83 (s
, 1H), 7.90 (s, 1H), 12.6 (br s, 1H), 13.4 (b
r s, 1H) FABMS m / z 396 (M-H) - C 15 H 8 35 ClNO 4 S 3 = 397.

Example 81 Preparation of Compound 54 Compound 53 (80 mg, 0.20 mmol) was added to dimethylformamide (3 mL).
) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (77 mg, 0.40 mmol) and diethylamine (0.04).
1 mL, 0.40 mmol) was added and then stirred at room temperature for 3 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin layer chromatography (9: 1 chloroform / methanol) and triturated with hexane to give compound 54 (22 mg).
, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.06 (br
s, 6H), 3.13 (br s, 2H), 3.41 (br s, 2H), 7.
41 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H),
7.69 (s, 1H), 8.00 (s, 1H), 12.7 (br s, 1H) FABMS m / z 451 (M ⁺ ) C ₁₉ H ₁₇ ³⁵ ClN ₂ O ₃ S ₃ = 452.

Example 82 Preparation of Compound 55 Compound 55 (37 mg, 39%) was obtained in the same manner as in Example 81, except that aniline (0.037 mL, 0.40 mmol) was used instead of diethylamine.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.13 (t, J
= 7.3 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.60 (d
, J = 8.4 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 7.71
(D, J = 7.7 Hz, 2H), 7.84 (s, 1H), 8.04 (s, 1H)
, 10.3 (s, 1H), 12.6 (br s, 1H) FABMS m / z 471 (M-H) - C 21 H 13 ClN 2 O 3 S 3 = 472.

Example 83 Preparation of Compound 56 1-Methylpiperazine (0.044 mL, 0.40 in place of diethylamine
mmol) and using the same method as in Example 81 for compound 56 (11 mg, 12
%) Was obtained.

[0405]   Compound 56 was obtained as the hydrochloride salt.

¹ H NMR (300 MHz, DMSO-d ₆ , hydrochloride) δ (ppm) 2.80
(S, 3H), 3.25 (m, 8H), 7.46 (d, J = 8.8Hz, 2H)
, 7.49 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.98 (
s, 1H) FABMS m / z 478 (M-H) - C 20 H 18 ClN 3 O 3 S 3 = 479.

Example 84 Preparation of Compound 57 Morpholine instead of diethylamine (0.035 mL, 0.40 mmol)
Was used in the same manner as in Example 81 to give compound 57 (22 mg, 24%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.32 (m, 4
H), 3.55 (m, 4H), 7.43 (d, J = 8.6Hz, 2H), 7.4
7 (d, J = 8.6 Hz, 2H), 7.69 (s, 1H), 7.98 (s, 1H)
), 12.7 (br s, 1H ) FABMS m / z 465 (M-H) - C 19 H 15 ClN 2 O 4 S 3 = 466.

Example 85 Preparation of Compound 58 Compound 53 (36 mg, 0.090 mmol) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (2 mL). Thionyl chloride (0.032 mL
, 0.36 mmol) and the mixture was heated at reflux for 2 hours. The reaction solution was ice-cooled. Methanol (1 mL) and triethylamine (0.038 mL, 0.
27 mmol) and then stirred for 10 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin layer chromatography (9: 1 chloroform / methanol) and triturated with isopropyl ether to give compound 58 (15 mg, 4
0%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.85 (s, 3
H), 7.67 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.4 Hz)
, 2H), 7.88 (s, 1H), 7.92 (s, 1H), 12.6 (br s)
, 1H) FABMS m / z 410 (M-H) - C 16 H 10 35 ClNO 4 S 3 = 411.

Example 86 Preparation of Compound 59 Commercially available (MAYBRIDGE, Catalog No. KM05428) 3-phenoxythiophene-2-carboxaldehyde (204 mg, 1.00 mmol).
, 2,4-thiazolidinedione (176 mg, 1.5 mmol) and piperidine (0.099 mL, 1.0 mmol) were used to give compound 59 (260 mg, 86%) using the same method as in Example 70.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.93 (d, J
= 5.5 Hz, 1H), 7.02 (dd, J = 8.6, 1.1 Hz, 2H), 7
． 15 (t, J = 7.5 Hz, 1H), 7.39 (dd, J = 8.6, 7.5H)
z, 2H), 7.61 (s , 1H), 7.91 (d, J = 5.5Hz, 1H) FABMS m / z 302 (M-H) - C 14 H 9 NO 3 S 2 = 303.

Example 87 Preparation of Compound 60 4-Bromothiophene-2-carboxaldehyde (2.00 g, 10.5 m
(mol) was dissolved in methanol (80 mL). p-toluenesulfonic acid (18
1 mg, 1.05 mmol) was added and then stirred for 3 hours. The solvent was distilled off under reduced pressure to about 20 mL. Aqueous sodium hydrogen carbonate solution was added and the product was extracted with ether. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4-bromo-2-dimethoxymethylthiophene (2.36 g, 100%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.36 (s, 6H)
, 5.58 (s, 1H), 7.00 (t, J = 1.0 Hz, 1H), 7.20 (
d, J = 1.3 Hz, 1H).

Under an argon atmosphere, 4-bromo-2-dimethoxymethylthiophene (236 m
g, 1.00 mmol) in tetrahydrofuran (4 mL) and -7
Cooled to 8 ° C. n-Butyllithium (1.6 mol / L hexane solution; 0.8
1 mL, 1.3 mmol), 4,4'-dichlorodiphenyl disulfide (28
A solution of 7 mg, 1.0 mmol) in tetrahydrofuran (1.5 mL) was added, and then the mixture was stirred for 15 minutes. Water was added to the reaction solution and the product was extracted with ether. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in tetrahydrofuran (6 mL),
Then, 1 mol / L hydrochloric acid (1 mL) was added, and then the mixture was stirred at room temperature for 1 hour. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin layer chromatography (9: 1 hexane / ethyl acetate) to give 4- (4-chlorophenylthio) thiophene-2.
-Carboxaldehyde (71 mg, 28%), 2,3-bis (4-chlorophenylthio) thiophene-5-carboxaldehyde (29 mg, 7.3%), and 5- (4-chlorophenylthio) thiophene-2-carboxy. aldehyde(
53 mg, 21%) was obtained.

4- (4-chlorophenylthio) thiophene-2-carboxaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.21 (d, J = 8)
． 8 Hz, 2 H), 7.28 (d, J = 9.0 Hz, 2 H), 7.65 (d, J
= 1.5 Hz, 1H), 7.69 (t, J = 1.4 Hz, 1H), 9.87 (d
, J = 1.3 Hz, 1 H) FABMS m / z 254 (M ⁺ ) C ₁₁ H ₇ ³⁵ ClOS ₂ = 254.

2,3-Bis (4-chlorophenylthio) thiophene-5-carboxaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.19 (d, J = 8)
． 4Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 7.37 (d, J
= 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.53 (s
, 1H), 9.67 (s, 1H) FABMS m / z 397 (M +) C 17 H 10 35 Cl 2 OS 3 = 396.

5- (4-chlorophenylthio) thiophene-2-carboxaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.13 (d, J = 3)
． 9 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.37 (d, J
= 9.0 Hz, 2H), 7.63 (d, J = 3.9 Hz, 1H), 9.78 (s
, 1H) FABMS m / z 255 (M +) C 11 H 7 35 ClOS 2 = 254.

4- (4-chlorophenylthio) thiophene-2-carboxaldehyde (7
0 mg, 0.28 mmol), 2,4-thiazolidinedione (39 mg, 0.3
3 mmol) and piperidine (0.028 mL, 0.28 mmol) were heated under reflux in ethanol (4 mL) for 4 hours. The reaction was cooled to room temperature, mixed with water and 1 mol / L hydrochloric acid (1 mL), and the product was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give compound 60 (57 mg, 58%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.25 (d, J
= 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.65 (m
, 1H), 8.02 (s, 1H), 8.12 (m, 1H), 12.6 (br s)
, 1H) FABMS m / z 352 (M-H) - C 13 H 8 35 ClNO 2 S 2 = 353.

Example 88 Preparation of Compound 61 2,3-bis (4-chlorophenylthio) thiophene-obtained in Example 87
5-Carboxaldehyde (28 mg, 0.071 mmol), 2,4-thiazolidinedione (10 mg, 0.085 mmol), and piperidine (0.00
7 mL, 0.07 mmol) from compound 61 (using the same method as in Example 87).
19 mg, 54%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.30 (d, J
= 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.42 (d
, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.56
(S, 1H), 7.96 ( s, 1H), 12.7 (br s, 1H) FABMS m / z 494 (M-H) - C 19 H 11 35 Cl 2 NO 2 S 4 = 495.

Example 89 Preparation of Compound 62 5- (4-chlorophenylthio) thiophene-2-carboxaldehyde (132 mg, 0.520 mmol) obtained in Example 87, 2,4-thiazolidinedione (73 mg, 0.62 mmol) ), And piperidine (0.052 mL,
0.52 mmol) and using the same method as in Example 87 for compound 62 (113 m
g, 62%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.33 (d, J
= 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.54 (d
, J = 3.9 Hz, 1H), 7.68 (d, J = 3.9 Hz, 1H), 8.01
(S, 1H), 12.6 ( br s, 1H) FABMS m / z 352 (M-H) - C 13 H 8 35 ClNO 2 S 2 = 353.

Example 90 Preparation of Compound 63 Under an argon atmosphere, a solution of diisopropylamine (0.21 mL, 1.5 mol) in tetrahydrofuran (3 mL) was ice-cooled, and n-butyllithium (1.6 mo)
1 / L hexane solution; 0.81 mL, 1.3 mmol) was added and the mixture was cooled to -78 ° C. 4-Bromo-2-dimethoxymethylthiophene (236 mg, 1.00 mmol) obtained in Example 87 in tetrahydrofuran (1 mL)
The solution was added and then stirred for 30 minutes. Then 4,4'-dichlorodiphenyl disulfide (287 mg, 1.0 mmol) in tetrahydrofuran (1 mL)
The solution was added and then stirred for 10 minutes. Water was added to the reaction solution and the product was extracted with ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-bromo-2- (4-chlorophenylthio) -5-dimethoxymethylthiophene (355 mg, 94%). ) Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.36 (s, 6H)
, 5.55 (d, J = 0.7 Hz, 1H), 7.07 (d, J = 0.9 Hz, 1
H), 7.16 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz)
, 2H) FABMS m / z 380, 378 (M ⁺ ) C ₁₃ H ₁₂ ⁷⁹ Br ³⁵ ClO ₂ S ₂ =
378.

3-Bromo-2- (4-chlorophenylthio) -5-dimethoxymethylthiophene (170 mg, 0.449 mmol) was dissolved in tetrahydrofuran (4 mL), and 1 mol / L hydrochloric acid (0.5 mL) was added, Then, it stirred at room temperature for 4.5 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (9: 1 hexane / ethyl acetate), 3-bromo-2- (4-
Chlorophenylthio) thiophene-5-carboxaldehyde (126 mg, 8
5%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.38 (d, J = 8)
． 4 Hz, 2 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.63 (s, 1
H), 9.71 (s, 1H) FABMS m / z 335, 333 (M + H) ⁺ C ₁₁ H ₆ ⁷⁹ Br ³⁵ ClOS ₂
= 332.

3-Bromo-2- (4-chlorophenylthio) thiophene-5-carboxaldehyde (114 mg, 0.342 mmol), 2,4-thiazolidinedione (
48 mg, 0.41 mmol), and piperidine (0.034 mL, 0.34
mmol) using the same method as in Example 87 for compound 63 (73 mg, 49%
) Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.31 (d, J
= 8.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.81 (s
, 1H), 7.96 (s, 1H), 12.7 (br s, 1H) FABMS m / z 432,430 (M-H) - C 14 H 7 79 Br 35 ClNO 2
S ₃ = 431.

Example 91 Preparation of Compound 64 From compound 63 (19 mg, 0.044 mmol), m-chloroperbenzoic acid (purity 50%; 23 mg, 0.066 mol), using the same method as in Example 78,
Compound 64 (14 mg, 714) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.73 (d, J
= 9.0 Hz, 2H), 7.75 (s, 1H), 7.84 (d, J = 8.6 Hz)
, 2H), 7.98 (s, 1H), 12.8 (br s, 1H) FABMS m / z 448,446 (M-H) - C 14 H 7 79 Br 35 ClNO 3
S ₃ = 447.

Example 92 Preparation of Compound 65 3-Bromo-2- (4-chlorophenylthio) -5-dimethoxymethylthiophene (500 mg, 1.32 mmol) obtained in Example 90 under an argon atmosphere.
) Was dissolved in tetrahydrofuran (6 mL) and cooled to -78 ° C. n-
Butyl lithium (1.6 mol / L hexane solution; 0.81 mL, 1.3 mmo
1), and 4-chloro-N-methoxy-N-methylbenzamide (528 mg
, 2.64 mmol) in tetrahydrofuran (1 mL), and then 1
Stir for 0 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (15: 1).
Purified with hexane / ethyl acetate), 3- (4-chlorobenzoyl) -2- (4
-Chlorophenylthio) -5-dimethoxymethylthiophene (345 mg, 60
%) Was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.31 (s, 6H)
, 5.45 (s, 1H), 7.15 (d, J = 1.1 Hz, 1H), 7.39 (
d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.5
3 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H) FABMS m / z 439 (M + H) ⁺ C ₂₀ H ₁₆ ³⁵ Cl ₂ O ₃ S ₂ = 438.

3- (4-Chlorobenzoyl) -2- (4-chlorophenylthio) -5-dimethoxymethylthiophene (335 mg, 0.763 mmol) was dissolved in tetrahydrofuran (6 mL). 1 mol / L hydrochloric acid (1 mL) was added, and then the mixture was stirred at room temperature for 1.5 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (5: 1 hexane / ethyl acetate) and recrystallized from ethyl acetate / hexane to give 3- (4-chlorobenzoyl) -2-.
(4-Chlorophenylthio) thiophene-5-carboxaldehyde (203m
g, 68%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.50 (d, J = 8)
． 4Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.62 (d, J
= 8.8 Hz, 2 H), 7.74 (d, J = 8.8 Hz, 2 H), 7.83 (s
, 1H), 9.65 (s, 1H) FABMS m / z 393 (M + H) ⁺ C ₁₈ H ₁₀ ³⁵ Cl ₂ O ₂ S ₂ = 392.

3- (4-chlorobenzoyl) -2- (4-chlorophenylthio) thiophene-5-carboxaldehyde (193 mg, 0.490 mmol), 2,4-thiazolidinedione (69 mg, 0.59 mmol), and piperidine (0.0
49 mL, 0.49 mmol) from compound 65 using the same method as in Example 70.
(211 mg, 88%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.64 (d, J
= 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.73 (d
, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.87
(S, 1H), 7.94 ( s, 1H), 12.6 (br s, 1H) FABMS m / z 490 (M-H) - C 21 H 11 35 Cl 2 NO 3 S 3 = 491.

Example 93 Preparation of Compound 66 Compound 66 (50 mg, 0.10 mmol) and m-chloroperbenzoic acid (purity 50%; 53 mg, 0.15 mol) were used in the same manner as in Example 78 to prepare Compound 66. (14 mg, 28%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.60 (d, J
= 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.72 (d
, J = 8.8 Hz, 2H), 7.82 (s, 1H), 7.89 (d, J = 8.8.
Hz, 2H), 8.04 (s , 1H), 12.8 (br s, 1H) FABMS m / z 506 (M-H) - C 21 H 11 35 Cl 2 NO 4 S 3 = 507.

Example 94 Preparation of Compound 67 Commercially available (MAYBRIDGE, Catalog No. XAX00154) 2-[(
4-chlorophenyl) thio] -5-nitrobenzaldehyde (0.3 g, 1.0
dissolved in ethanol (8 mL) and thiazolidinedione (0.
36 g, 3.0 mmol) and piperidine (0.1 mL, 1.0 mmol) were added and the mixture was heated to reflux in a flask equipped with a reflux condenser and drying tube (CaCl ₂ ) for 5 hours and a half to bring the temperature to room temperature. Drop and add 1M aqueous HCl. After the usual treatment, the residue was purified by silica gel karaku chromatography (chloroform to chloroform: methanol = 99: 1) and recrystallized from ethyl acetate and hexane to give compound 67 (0.109 g, 27.9%). ) Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.24 (d, J
= 8.8 Hz, 1H), 7.59 (s, 4H), 7.88 (s, 1H), 8.
17 (dd, J = 2.6, 8.8 Hz, 1H), 8.24 (d, J = 2.6 Hz
, 1H), 12.84 (br s, 1H) FABMS m / z 393 (M + H) ⁺ C ₁₆ H ₉ ³⁵ ClN ₂ O ₄ S ₂ = 392.

Example 95 Preparation of Compound 68 Using compound 67 (0.02 g, 0.051 mmol) and the same method as in Example 78, compound 68 (0.0137 g, 65.7%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.61 (d, J
= 2.6 Hz, 4 H), 7.67 (s, 1 H), 8.25 (d, J = 8.8 Hz
, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.40 (dd, J = 2.
3, 8.8 Hz, 1 H), NH not found EIMS m / z 409 (M + H) ⁺ C ₁₆ H ₉ ³⁵ ClN ₂ O ₅ S ₂ = 408.

Example 96 Preparation of Compound 69 Compound 67 (0.03 g, 0.077 mmol) was added to dichloromethane (5 mL).
And dissolved in methanol (1 mL) and m-chloroperbenzoic acid (0.03
g, 0.0092 mmol) was added, and then the mixture was stirred at room temperature for 1 hour. After addition of 10% aqueous sodium hydrogen sulfite solution and usual treatment, the residue was purified by thin layer chromatography (chloroform: methanol = 12: 1) and then again thin layer chromatography (chloroform: acetonitrile = 6: 1). Compound 69 (0.014 g, 15.9%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.71 (dt,
J = 2.0, 8.8 Hz, 2H), 7.87 (dt, J = 2.0, 8.8 Hz,
2H), 7.98 (s, 1H), 8.31 (s, 1H), 8.49 (d, J = 2)
． 0 Hz, 2H), NH is not found. EIMS m / z 423 (M- H) - C 16 H 9 35 ClN 2 O 6 S 2 = 424.

Example 97 Preparation of Compound 70 2.5 chloro in 3-chlorobenzenethiol (0.11 g, 0.73 mmol).
A 1 / L aqueous sodium hydroxide solution (1.2 mL, 3.1 mmol) and tetrabutylammonium bromide (0.012 g, 0.031 mmol) were added, and then the mixture was stirred at 25 ° C. for 10 minutes. A toluene (1.2 mL) solution of 2-fluoro-5-nitrobenzaldehyde (0.12 g, 0.73 mmol) was added to the reaction solution, and then the mixture was stirred at 110 ° C. for 1.5 hours. After the usual post-treatment, the residue was purified by silica gel chromatography (eluted with chloroform) to give 2-[(3-chlorophenyl) thio] -5-nitrobenzaldehyde (72 mg, 34%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.01 (d, J = 8)
． 8 Hz, 1 H), 7.44-7.54 (m, 3 H), 7.58 (br s, 1
H), 8.17 (dd, J = 2.4, 8.8 Hz, 1H), 8.69 (d, J =
2.6 Hz, 1 H), 10.29 (s, 1 H) FABMS m / z 294 (M + H) ⁺ C ₁₃ H ₈ ³⁵ ClNO ₃ S = 293.

2-[(3-chlorophenyl) thiol-5-nitrobenzaldehyde (70
mg, 0.24 mmol) was dissolved in toluene (3.5 mL). 2,4-thiazolidinedione (0.11 g, 0.95 mmol), piperidine (0.0094
mL, 0.095 mmol), acetic acid (0.0054 mL, 0.095 mmol)
And Molecular Sieve 4A (0.35 g) were added, and then the mixture was stirred at 110 ° C. for 3 hours. After the usual work-up, the residue is subjected to thin layer chromatography (chloroform /
Compound 70 (41 mg, 440) after purification with acetonitrile = 10/1)
Got

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.34 (d, J
= 8.8 Hz, 1H), 7.60-7.47 (m, 3H), 7.63 (br s)
, 1H), 7.88 (s, 1H), 8.20 (dd, J = 8.8, 2.6 Hz,
1H), 8.26 (d, J = 2.6Hz, 1H), 12.83 (m, 1H) FABMS m / z 391 (M-H) - C 16 H 9 35 ClN 2 O 4 S 2 = 392 .

Example 98 Preparation of Compound 71 2.5 mol in 2-chlorobenzenethiol (0.17 g, 1.0 mmol)
/ L aqueous sodium hydroxide solution (1.7 mL, 4.4 mmol) and tetrabutylammonium bromide (0.017 g, 0.051 mmol) were added, and then the mixture was stirred at 25 ° C for 10 minutes. A toluene (1.7 mL) solution of 2-fluoro-5-nitrobenzaldehyde (0.18 g, 1.0 mmol) was added to the reaction solution,
Then, it stirred at 110 degreeC for 2 hours. After the usual post-treatment, the residue was purified by silica gel chromatography (eluted with chloroform) to give 2-[(2-chlorophenyl).
Thio] -5-nitrobenzaldehyde (0.25 g, 83%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.88 (d, J = 8)
． 8Hz, 1H), 7.42 (ddd, J = 7.5, 7.5, 1.4Hz, 1H
), 7.51 (7.3, 7.3, 1.6 Hz, 1H), 7.62 (dd, J = 8)
． 1,1.5Hz, 1H), 7.69 (dd, J = 7.5, 1.7Hz, 1H)
, 8.16 (dd, J = 8.8, 2.6 Hz, 1H), 8.70 (d, J = 2.
5 Hz, 1 H), 10.32 (s, 1 H) FABMS m / z 293 (M ⁺ ) C ₁₃ H ₈ ³⁵ ClNO ₃ S = 293.

2-[(2-chlorophenyl) thio] -5-nitrobenzaldehyde (0.1
4 g, 0.49 mmol) was dissolved in ethanol (5.8 mL). 2,4-thiazolidinedione (0.23 g, 2.0 mmol) and piperidine (0.03
9 mL, 0.39 mmol) was added, and then the mixture was stirred at 80 ° C. for 3 hours. After the usual post-treatment, the residue was subjected to thin layer chromatography (chloroform / acetonitrile = 1
Purification by 0/1) to give compound 71 (24 mg, 13%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.20 (d, J
= 8.8 Hz, 1H), 7.43-7.62 (m, 3H), 7.71 (m, 1H)
), 7.89 (s, 1H), 8.20 (dd, J = 8.8, 2.6 Hz, 1H)
, 8.28 (m, 1H), 12.82 (m, 1H) FABMS m / z 391 (M-H) - C 16 H 9 35 ClN 2 O 4 S 2 = 392.

Example 99 Preparation of Compound 72 Using the same method as Example 97, 3,4-dichlorobenzenethiol (0.1
2 g, 0.68 mmol), 2.5 mol / L sodium hydroxide aqueous solution (1.
2 mL, 2.9 mmol), tetrabutylammonium bromide (0.011 g)
, 0.034 mmol) and 2-fluoro-5-nitrobenzaldehyde (0
． 12 [g, 0.68 mmol] in toluene (1.2 mL) from 2-[(3,
4-dichlorophenyl) thio] -5-nitrobenzaldehyde (0.16 g, 7
9%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.02 (d, J = 8)
． 8 Hz, 1 H), 7.41 (dd, J = 8.2, 2.0 Hz, 1 H), 7.6
0 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 8
． 18 (dd, J = 8.8, 2.5 Hz, 1H), 8.69 (d, J = 2.6H
z, 1H), 10.28 (s, 1H) FABMS m / z 328 (M + H) ⁺ C ₁₃ H ₇ ³⁵ Cl ₂ NO ₃ S = 327.

2-[(3,4-Dichlorophenyl) thio] was prepared using the same method as in Example 97.
-5-nitrobenzaldehyde (0.12 g, 0.35 mmol), toluene (
5.8 mL), 2,4-thiazolidinedione (0.16 g, 1.4 mmol),
Piperidine (0.014 mL, 0.14 mmol), acetic acid (0.0080 mL,
0.14 mmol) and molecular sieve 4A (0.58 g) to compound 7
2 (74 mg, 49%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.39 (d, J
= 8.8 Hz, 1H), 7.50 (dd, J = 8.4, 1.8 Hz, 1H), 7
． 75 (d, J = 8.5 Hz, 1H), 7.88-7.83 (m, 2H), 8.
18 (d, J = 8.6, 2.2 Hz, 1H), 8.25 (m, 1H), 12.8
2 (m, 1H) FABMS m / z 425 (M-H) - C 16 H 8 35 Cl 2 N 2 O 4 S 2 = 426.

Example 100 Preparation of Compound 73 Using the same method as Example 97, 4-bromobenzenethiol (0.19 g,
1.0 mmol), 2.5 mol / L aqueous sodium hydroxide solution (1.7 mL,
4.3 mmol), tetrabutylammonium bromide (0.016 g, 0.0
51 mmol) and 2-fluoro-5-nitrobenzaldehyde (0.17 g
, 1.0 mmol) in toluene (1.7 mL) to give 2-[(4-bromophenyl) thio] -5-nitrobenzaldehyde (0.28 g, 82%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.98 (d, J = 8)
． 9 Hz, 1H), 7.41-7.46 (m, 2H), 7.63-7.69 (m
, 2H), 8.13 (dd, J = 8.8, 2.4 Hz, 1H), 8.68 (d,
J = 2.6 Hz, 1 H), 10.29 (s, 1 H) FABMS m / z 338 (M + H) ⁺ C ₁₃ H ₈ ⁷⁹ BrNO ₃ S = 337.

Using the same method as Example 97, 2-[(4-bromophenyl) thio] -5-
Nitrobenzaldehyde (0.031 g, 0.091 mmol), toluene (1
． 5 mL), 2,4-thiazolidinedione (0.043 g, 0.36 mmol)
, Piperidine (0.0036 mL, 0.036 mmol), acetic acid (0.0025
Compound 73 (26 mg, 66%) was obtained from Molecular Sieve 4A (0.092 g).

Compound 73: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7
． 25 (d, J = 8.8 Hz, 1H), 7.48-7.52 (m, 2H), 7.
20-7.25 (m, 2H), 7.88 (s, 1H), 8.18 (dd, J = 8)
． 8, 2.6 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 12.8
5 (br s, 1H) FABMS m / z 435 (M-H) - C 16 H 9 79 BrN 2 O 4 S 2 = 436.

Example 101 Preparation of Compound 74 Using the same method as Example 98, 4-methoxybenzenethiol (0.14 g
, 0.99 mmol), 2.5 mol / L aqueous sodium hydroxide solution (1.8 m
L, 4.4 mmol), tetrabutylammonium bromide (0.016 g, 0
． 050 mmol) and 2-fluoro-5-nitrobenzaldehyde (0.1
2-[(4-methoxyphenyl) thio] -5-nitrobenzaldehyde (0.22 g, 76%) was obtained from a toluene (1.8 mL) solution of 7 g, 0.99 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.89 (s, 3H)
, 6.92 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2
H), 7.49 (d, J = 8.6 Hz, 2H), 8.08 (dd, J = 9.0,
2.4 Hz, 1 H), 8.63 (d, J = 2.2 Hz, 1 H), 10.29 (s
, 1H) FABMS m / z 289 (M +) C 14 H 11 N 2 O 4 = 289.

Using the same method as in Example 98, 2-[(4-methoxyphenyl) thio] -5
-Nitrobenzaldehyde (0.11 g, 0.39 mmol), ethanol (4
． 4 mL), 2,4-thiazolidinedione (0.18 g, 1.5 mmol), and piperidine (0.015 mL, 0.15 mmol) to compound 74 (26 m).
g, 18%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.34 (s, 3
H), 6.98 (d, J = 8.8 Hz, 1 H), 7.13 (d, J = 9.0 Hz)
, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.89 (s, 1H), 8
． 14 (dd, J = 8.6, 2.4 Hz, 1H), 8.21 (d, J = 2.4H
z, 1H) FABMS m / z 387 (M-H) - C 17 H 12 N 2 O 5 S 2 = 388.

Example 102 Preparation of Compound 75 Using the same method as Example 97, 4-ethylbenzenethiol (0.13 g,
0.95 mmol), 2.5 mol / L sodium hydroxide aqueous solution (1.6 mL
, 4.0 mmol) and tetrabutylammonium bromide (0.015 g, 0.
047 mmol) and 2-fluoro-5-nitrobenzaldehyde (0.16
2-[(4-ethylphenyl) thio] -5-nitrobenzaldehyde (0.22 g, 82%) was obtained from a toluene (1.6 mL) solution of g, 0.95 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.30 (t, J = 7)
． 6 Hz, 3 H), 2.74 (q, J = 7.5 Hz, 2 H), 6.96 (d, J
= 9.0 Hz, 1H), 7.36 (d, J = 7.5 Hz, 2H), 7.48 (d
, J = 8.1 Hz, 2H), 8.10 (dd, J = 9.0, 2.2 Hz, 1H)
, 8.66 (d, J = 2.6 Hz, 1H), 10.31 (s, 1H) FABMS m / z 288 (M + H) ⁺ C ₁₅ H ₁₃ NO ₃ S = 287.

Using the same method as Example 97, 2-[(4-ethylphenyl) thio] -5-
Nitrobenzaldehyde (0.20 g, 0.69 mmol), toluene (9.9
mL), 2,4-thiazolidinedione (0.32 g, 2.7 mmol), piperidine (0.027 mL, 0.27 mmol), acetic acid (0.016 mL, 0.27).
Compound) (0..mmol) and molecular sieve 4A (0.99g) from compound 75 (0.
14 g, 51%) was obtained.

Compound 75: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1
． 21 (t, J = 7.7 Hz, 3H), 2.68 (q, J = 7.7 Hz, 2H)
, 7.09 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2
H), 7.51 (d, J = 8.1 Hz, 2H), 7.39 (s, 1H), 8.1
6 (dd, J = 8.8, 2.3 Hz, 1H), 8.22 (d, J = 2.0 Hz,
1H), 12.82 (m, 1H ) FABMS m / z 385 (M-H) - C 18 H 14 N 2 O 4 S 2 = 386.

Example 103 Preparation of Compound 76 Using commercially available (MAYBRIDGE, Catalog No. XAX00131) 2-benzylthio-5-nitrobenzaldehyde (0.27 g, 1.0 mmol) and using the same method as in Example 94. , Compound 76 (0.134 g, 35.9%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.51 (s, 2
H), 7.31 (m, 3H), 7.46 (dt, J = 1.7, 6.6 Hz, 2H
), 7.78 (s, 1H), 7.81 (d, J = 8.9Hz, 1H), 8.17
(D, J = 2.6 Hz, 1 H), 8.22 (dd, J = 2.6, 8.9 Hz, 1
H), 12.82 (br s, 1H) EIMS m / z 371 (M-H) - C 17 H 12 N 2 O 4 S 2 = 372.

Example 104 Preparation of Compound 77 Using the same method as in Example 96, using Compound 76 (0.03 g, 0.081 mmol), Compound 77 (0.0055 g, 17.6%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.24 (d, J
= 6.8 Hz, 2H), 6.94 (dd, J = 2.2, 5.0 Hz, 2H), 7
． 20 (dd, J = 2.2, 5.0 Hz, 3H), 7.4 (s, 1H), 7.8
9 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8
． 38 (dd, J = 2.2, 8.7 Hz, 1 H), NH not found EIMS m / z 389 (M + H) ⁺ C ₁₇ H ₁₂ N ₂ O ₅ S ₂ = 388.

Example 105 Preparation of Compound 78 Using compound 76 (0.03 g, 0.081 mmol) and the same method as in Example 96, compound 78 (0.0192 g, 59.0%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.78 (s, 2)
H), 7.10 (dd, J = 1.8, 4.5 Hz, 2H), 7.27 (dd, J
= 1.8, 4.5 Hz, 3H), 8.06 (d, J = 8.8 Hz, 1H), 8.
08 (s, 1H), 8.36 (dd, J = 2.5, 8.8Hz, 1H), 8.3
9 (d, J = 2.5 Hz, 1H), NH is not found. EIMS m / z 403 (M- H) - C 17 H 12 N 2 O 6 S 2 = 404.

Example 106 Preparation of Compound 79 Using the same method as Example 97, 4-chlorobenzylthiol (0.11 g,
0.83 mmol), 2.5 mol / L sodium hydroxide aqueous solution (1.4 mL
, 3.5 mmol) and tetrabutylammonium bromide (0.013 g, 0.
041 mmol) and 2-fluoro-5-nitrobenzaldehyde (0.14
g, 0.83 mmol) in toluene (1.4 mL) to give 2-[(4-chlorobenzyl) thio] -5-nitrobenzaldehyde (0.17 g, 67%),
Using the same method as in Example 97, 2-[(4-chlorobenzyl) thio] -5-nitrobenzaldehyde (0.12g, 0.39mmol), toluene (6.1m).
L), 2,4-thiazolidinedione (0.18 g, 1.6 mmol), piperidine (0.016 mL, 0.16 mmol), acetic acid (0.0090 mL, 0.16).
Compound 79 (0. mmol) and molecular sieve 4A (0.61 g).
11 g, 70%) was obtained.

2-[(4-chlorobenzyl) thio] -5-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 4.26 (s, 2H)
, 7.34 (s, 4H), 7.49 (d, J = 8.8Hz, 1H), 8.29 (
dd, J = 8.8, 2.6 Hz, 1H), 8.65 (d, J = 2.5 Hz, 1H)
), 10.23 (s, 1H) FABMS m / z 307 (M +) C 14 H 10 35 ClNO 3 S = 307.

Compound 79: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 4.
50 (s, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.46 (d, J
= 8.4 Hz, 2 H), 7.77 (s, 1 H), 7.80 (d, J = 8.8 Hz)
, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 9.
0,2.6Hz, 1H), 12.81 (m , 1H) FABMS m / z 406 (M-H) - C 17 H 11 35 ClN 2 O 4 S 2 = 405.

Example 107 Preparation of Compound 80 Commercially available (MAYBRIDGE, Catalog No. XAX00146) 4-[(
4-Bromophenyl) thio] -3-nitrobenzaldehyde (0.12 g, 0.
35 mmol) was dissolved in toluene (5.9 mL). 2,4-thiazolidinedione (0.16 g, 1.4 mmol), piperidine (0.014 mL, 0.14)
mmol), acetic acid (0.0080 mL, 0.14 mmol) and molecular sieve 4A (0.59 g) were added, and then the mixture was stirred at 110 ° C. for 3 hours. After the usual post-treatment, the residue was tritylated with ethanol to give compound 80 (21
mg, 14%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.01 (d, J
= 8.6 Hz, 1H), 7.58-7.62 (m, 2H), 7.73-7.82
(M, 4H), 8.50 (d, J = 2.0Hz, 1H), 12.71 (m, 1H)
) FABMS m / z 435 (M -H) - C 16 H 9 79 BrN 2 O 4 S 2 = 436.

Example 108 Preparation of Compound 81 Commercially available (MAYBRIDGE, Catalog No .: NRB00117) 4-[(
4-chlorophenyl) thio] -3-nitrobenzaldehyde (0.31 g, 1.
0 mmol) was dissolved in ethanol (12 mL). 2,4-thiazolidinedione (0.16 g, 1.4 mmol) and piperidine (0.014 mL, 0.1
4 mmol) and then stirred at 80 ° C. for 3 hours. The reaction solution was cooled to 25 ° C., and the precipitated crystals were collected by filtration to give compound 81 (0.15 g, 36%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.98 (d, J
= 8.5 Hz, 1H), 7.08 (brs, 1H), 7.70-7.59 (m
, 5H), 7.73 (dd, J = 8.6, 2.0 Hz, 1H), 8.45 (d,
J = 2.0Hz, 1H) FABMS m / z 391 (M-H) - C 16 H 9 35 ClN 2 O 4 S 2 = 392.

Example 109 Preparation of Compound 82 Using compound 9 (0.03 g, 0.081 mmol) and the same method as in Example 96, compound 82 (0.0195 g, 62.0%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3)
H), 7.31 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz)
, 2H), 7.84 (s, 1H), 8.28 (dd, J = 1.8, 8.4 Hz)
, 1H), 8.46 (s, 1H), 8.49 (t, J = 1.8Hz, 1H), N
H is not found. EIMS m / z 389 (M + H) + C 17 H 12 N 2 O 5 S 2 = 388.

Example 110 Preparation of Compound 83 Compound 9 (0.07 g, 0.19 mmol) was added to dichloromethane (12 mL),
Dissolve in methanol (2.3 mL) and m-chloroperbenzoic acid (0.13 g
, 0.38 mmol) and then stirred at room temperature for 1 hour. A 10% aqueous sodium hydrogen sulfite solution was added. After the usual treatment, the residue was purified by thin layer chromatography (chloroform: methanol = 12: 1) and then tritylated with chloroform to give compound 83 by tritylation with chloroform.
(0.019 g, 25.4%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.41 (s, 3)
H), 7.50 (d, J = 8.3 Hz, 2H), 7.84 (s, 1H), 7.8
6 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.3 Hz, 1H), 8
． 23 (d, J = 1.7 Hz, 1H), 8.44 (d, J = 8.3 Hz, 1H)
, NH not found EIMS m / z 405 (M + H) ⁺ C ₁₇ H ₁₂ N ₂ O ₆ S ₂ = 404.

Example 111 Preparation of Compound 84 Commercially available (MAYBRIDGE, Catalog No. XAX00135) 2- (cyclohexylthio) -5-nitrobenzaldehyde (0.26 g, 1.0 mmo).
1) and using the same method as in Example 94, compound 84 (0.152 g, 41.
8%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.30 (m, 1)
H), 1.46 (m, 4H), 1.61 (m, 1H), 1.73 (m, 2H),
2.00 (m, 2H), 3.67 (m, 1H), 7.79 (d, J = 8.5Hz
, 1H), 7.83 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H),
8.22 (dd, J = 2.4, 8.5 Hz, 1H), 12.82 (br s, 1
H) EIMS m / z 363 ( M + H) + C 16 H 16 N 2 O 4 S 2 = 364.

Example 112 Preparation of Compound 85 Using Compound 84 (0.02 g, 0.055 mmol) and in the same manner as in Example 96, Compound 85 (0.0149 g, 71.3%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.30 (m, 8)
H), 1.77 (m, 2H), 2.73 (m, 1H), 7.60 (s, 1H),
8.24 (s, 1H), 8.05 (d, J = 8.6Hz, 1H), 8.36 (d
, J = 2.2 Hz, 1H), 8.43 (dd, J = 2.2, 8.6 Hz, 1H)
, NH is not found. FBMS m / z 381 (M + H) - C 16 H 16 N 2 O 5 S 2 = 380.

Example 113 Preparation of Compound 86 Using compound 84 (0.03 g, 0.082 mmol) and in the same manner as in Example 96, compound 86 (0.0034 g, 10.9%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.27 (m, 6
H), 1.59 (m, 1H), 1.69 (m, 4H), 8.23 (d, J = 8.
4 Hz, 1H), 8.24 (s, 1H), 8.44 (s, 1H), 8.46 (d
, J = 8.4Hz, 1H), EIMS m / z 395 that NH is not found _{^{(M-H) - C 16}} H 16 N 2 O 6 S 2 = 396.

Example 114 Preparation of Compound 87 p-Toluenethiol (0.12 g, 1.0 mmol) was dissolved in 10% aqueous sodium hydroxide solution (1.7 mL) and tetrabutylammonium bromide (0
． 016 g, 0.05 mmol) was added, and then the mixture was stirred at room temperature for 5 minutes. Subsequently, 5-bromo-2-fluorobenzaldehyde (0.2 g, 1.0 mmol) dissolved in toluene (1.7 mL) was added dropwise, and then the mixture was stirred at room temperature for 4 hours. After normal treatment, recrystallize and refine with ethanol and hexane,
Bromo-2-[(4-methylphenyl) thio] benzaldehyde (0.23 g,
74.1%) was obtained.

¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm) 2.39 (s, 3H),
6.90 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H
), 7.35 (dd, J = 1.7, 8.1 Hz, 2H), 7.46 (dd, J =
2.4, 8.4 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 10.
32 (s, 1H). FABMS m / z 308 (M + H) + C 14 H 11 79 BrOS = 307.

5-Bromo-2-[(4-methylphenyl) thio] benzaldehyde (0.0
3g, 0.1 mmol) and compound 87 (0
． 021g, 52%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.31 (s, 3)
H), 7.14 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.3 Hz)
, 2H), 8.28 (d, J = 8.3 Hz, 2H), 7.60 (s, 1H), 7
． 62 (dd, J = 2.2, 8.8 Hz, 1H), 7.90 (s, 1H), 12
． 82 (br s, 1H) EIMS m / z 407 (M + H) ⁺ C ₁₇ H ₁₂ ⁷⁹ BrNO ₂ S ₂ = 406.

Example 115 Preparation of Compound 88 3-Bromo-4-fluorobenzaldehyde (0.2 g, 0.99 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 3-bromo-4-[(4-methylphenyl) thio] benzaldehyde (0 .19 g, 63.6%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.44 (s, 3H)
, 6.73 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2
H), 7.47 (d, J = 8.1 Hz, 2H), 7.54 (dd, J = 1.7,
8.4 Hz, 1 H), 8.00 (d, J = 1.7 Hz, 1 H), 9.84 (s,
1H) FABMS m / z 307 ( M +) C 14 H 11 BrOS = 307.

3-Bromo-4-[(4-methylphenyl) thio] benzaldehyde (0.1
5 g, 0.49 mmol) and using the same method as in Example 94 for compound 88 (
0.087 g, 43.9%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3
H), 6.74 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.1 Hz)
, 2H), 7.44 (dd, J = 2.0, 8.5 Hz, 1H), 7.48 (d,
J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.89 (d, J = 2.0H)
z, 1H), 12.64 (br s, 1H) EIMS m / z 407 (M + H) ⁺ C ₁₇ H ₁₂ ⁷⁹ BrNO ₂ S ₂ = 406.

Example 116 Preparation of Compound 89 5-Bromo-2-[(4-methylphenyl) thio] benzaldehyde (0.0
6 g, 0.2 mmol) and 2-pyridyl trifluoromethanesulfonate (0.
03g, 0.2mmol), using the literature (Tetrahedron Lette
rs Vol. 36, No. 50, pp. 9085-9088, 1995) to carry out the reaction and treat the product. The residue was purified by thin layer chromatography (hexane: ethyl acetate = 8: 1), 2-[(4-methylphenyl) thio].
-5- (2-Pyridyl) benzaldehyde (0.024g, 38.5%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.41 (s, 3H)
, 7.09 (d, J = 8.4 Hz, 1H), 7.24 (m, 3H), 7.42 (
d, J = 8.4 Hz, 2H), 7.76 (dd, J = 1.7, 6.6 Hz, 2H)
), 8.01 (dd, J = 2.2, 8.5 Hz, 1H), 8.50 (d, J = 2)
． 2 Hz, 1 H), 8.69 (d, J = 4.6 Hz, 1 H), 10.43 (s,
1H). EIMS m / z 306 (M + H) + C 19 H 15 NOS = 305.

Compound 89 (0.026 g) was prepared using 2-[(4-methylphenyl) thio] -5- (2-pyridyl) benzaldehyde (0.024 g, 0.08 mmol) using the same method as in Example 94. , 84.4%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.32 (s, 3)
H), 7.26 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz)
, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.41 (m, 1H), 7
． 92 (m, 1H), 7.97 (d, J = 7.7 Hz, 1H), 8.08 (s,
1H), 8.07 (dd, J = 2.0, 7.7 Hz, 1H), 8.32 (d, J
= 1.7 Hz, 1H), 8.71 (d, J = 4.8 Hz, 1H), 12.70 (
brs, 1H). EIMS m / z 405 (M- H) - C 22 H 16 N 2 O 2 S 2 = 406.

Example 117 Preparation of Compound 90 Tri (dibenzylideneacetone) -dipalladium (0.18 g, 0.2 mmo)
1) and triphenylphosphine (0.21 g, 0.8 mmol) were dissolved in tetrahydrofuran (60 mL), and then stirred at room temperature for 30 minutes. Then, 5-bromo-2-fluorobenzaldehyde (0.4 g, 2.0 mmol),
And 2- (tributylstannyl) furan (1.25 mL, 4.0 mmol)
Was added, and the mixture was heated under reflux for 10 hours. The mixture was cooled to room temperature and subjected to usual treatment, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give 2-fluoro-5- (2-furyl) benzaldehyde (
0.38 g, 100%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.49 (dd, J =
1.8, 3.5 Hz, 1H), 6.69 (d, J = 3.3 Hz, 1H), 7.2
1 (t, J = 9.9 Hz, 1H), 6.49 (d, J = 1.8 Hz, 1H), 7
． 90 (m, 1H), 8.14 (dd, J = 2.4, 6.6 Hz, 1H), 10
． 39 (s, 1H) FABMS m / z 190 (M +) C 11 H 7 19 FO 2 = 190.

2-Fluoro-5- (2-furyl) benzaldehyde (0.1 g, 0.53 m
2-((4-methylphenyl) thio] -5- (2) using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde). -Furyl) benzaldehyde (0.14 g, 87.8%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.39 (s, 3H)
, 6.59 (d, J = 1.8 Hz, 1 H), 6.69 (d, J = 3.3 Hz, 1
H), 7.07 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.3 Hz)
, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.48 (s, 1H), 7
． 66 (dd, J = 2.0, 8.3 Hz, 1H), 8.14 (d, J = 2.0H
z, 1H), 10.41 (s , 1H) FABMS m / z 294 (M +) C 18 H 14 O 2 S = 294.

Compound 90 (0.17 g) was prepared using 2-[(4-methylphenyl) thio] -5- (2-furyl) benzaldehyde (0.14 g, 0.47 mmol) in the same manner as in Example 94. , 92.8%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.50 (s, 3
H), 6.65 (m, 1H), 7.04 (d, J = 3.5 Hz, 1H), 7.2
2 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7
． 32 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H)
, 7.81 (d, J = 7.7 Hz, 1H), 8.03 (s, 1H), 12.71
(Br s, 1H) EIMS m / z 392 (M-H) - C 21 H 15 NO 3 S 2 = 393.

Example 118 Preparation of Compound 91 Using compound 74 (0.1 g, 0.25 mmol) and in the same manner as in Example 96, compound 91 (0.069 g, 66.5%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3)
H), 6.67 (dd, J = 1.8, 3.5 Hz, 1H), 7.17 (d, J =
8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.45 (d,
J = 8.3 Hz, 2H), 7.76 (s, 1H), 7.87 (d, J = 1.8H
z, 1H), 8.01 (d, J = 5.9 Hz, 2H), 8.02 (s, 1H),
12.77 (br s, 1H). EIMS m / z 410 (M + H) +, C 21 H 15 NO 4 S 2 = 409.

Example 119 Preparation of Compound 92 2- (tributylstannyl) thiophene (0.63 mL, 2.
0 mmol) and 2-fluoro-5- (2-thienyl) benzaldehyde (0.2 g, 100%) using the same method as in Example 117 (Synthesis of 2-fluoro-5- (2-furyl) benzaldehyde). Got

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.10 (t, J = 4)
． 4 Hz, 1 H), 7.21 (dd, J = 8.8, 9.9 Hz, 1 H), 7.3
3 (d, J = 4.4 Hz, 2H), 7.83 (m, 1H), 8.08 (dd, J
= 2.6, 6.5 Hz, 1H), 10.40 (s, 1H) FABMS m / z 206 (M ⁺ ) C ₁₁ H ₇ ¹⁹ FOS = 206.

2-Fluoro-5- (2-thienyl) benzaldehyde (0.1 g, 0.49
mmol) in Example 114 (5-bromo-2-[(4-methylphenyl)
2-[(4-methylphenyl) thio] -5- (2-thienyl) benzaldehyde (0.12 g, 77.4%)
) Got.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.39 (s, 3H)
, 7.06 (d, J = 8.3 Hz, 1H), 7.10 (m, 1H), 7.24 (
d, J = 8.3 Hz, 2H), 7.33 (m, 4H), 7.37 (d, J = 8.
1Hz, 2H), 7.60 (dd, J = 2.4, 8.3Hz, 1H), 8.07
(D, J = 2.4Hz, 1H ), 10.42 (s, 1H) FABMS m / z 310 (M +) C 18 H 14 OS 2 = 310.

2-[(4-Methylphenyl) thio] -5- (2-thienyl) benzaldehyde (0.12 g, 0.38 mmol) was used in the same manner as in Example 94 to give compound 92 (0.14 g). , 91.3%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3)
H), 7.18 (t, J = 3.8 Hz, 1H), 7.24 (d, J = 4.8 Hz)
, 4H), 7.56 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 5.1)
Hz, 1H), 7.72 (s, 1H), 7.73 (d, J = 7.5Hz, 1H)
, 8.03 (s, 1H), 12.71 (br s, 1H). EIMS m / z 408 (M- H) - C 21 H 15 NO 2 S 3 = 409.

Example 120 Preparation of Compound 93 Using compound 92 (0.1 g, 0.24 mmol) and in the same manner as in Example 96, compound 93 (0.051 g, 49.4%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3)
H), 7.20 (dd, J = 3.7, 5.0 Hz, 1H), 7.32 (d, J =
8.1 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.66 (d,
J = 3.7 Hz, 1H), 7.69 (d, J = 3.7 Hz, 2H), 8.01 (
m, 3H), 12.78 (br s, 1H) EIMS m / z 426 (M + H) ⁺ C ₂₁ H ₁₅ NO ₃ S ₃ = 425.

Example 121 Preparation of Compound 94 Diisopropylamine (0.35 mL, 2.5 mmol) was dissolved in tetrahydrofuran (3.5 mL) and the temperature was brought to 0 ° C. Then, n-butyllithium (hexane solution) (1.24 mL, 2.0 mmol) was added dropwise, and then 10
Stir for minutes. Then, the reaction temperature was lowered to −78 ° C., 4-fluorobenznitrile (0.2 g, 1.65 mmol) was added, and the mixture was stirred for 1 hour. Then, dimethylformamide (0.19 mL, 2.5 mmol) was added dropwise, followed by stirring for 20 minutes,
After that, usual treatment was performed. The residue was purified by thin layer chromatography (hexane: ethyl acetate = 8: 1), and 2-fluoro-5-cyanobenzaldehyde (
0.11 g, 43.4%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.46 (t, J = 8)
． 8 Hz, 1H), 7.90 (m, 1H), 7.71 (dd, J = 2.2, 6.
2Hz, 1H), 10.36 (s, 1H). ^{EIMS m / z 148 (M -} ) C 8 H 4 19 FNO = 149.

2-Fluoro-5-cyanobenzaldehyde (0.1 g, 0.67 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 5-cyano-2-[(4-methylphenyl) thio] benzaldehyde (0 0.15 g, 86.9%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.44 (s, 3H)
, 6.92 (d, J = 8.6 Hz, 1 H), 7.31 (d, J = 7.9 Hz, 2
H), 7.44 (d, J = 8.3 Hz, 2H), 7.49 (dd, J = 1.8,
8.4 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 10.27 (s
, 1H). ^{EIMS m / z 253 (M +} ) C 15 H 11 NOS = 253.

5-Cyano-2-[(4-methylphenyl) thio] benzaldehyde (0.1
g, 0.4 mmol) and using the same method as in Example 94.
09g, 64.5%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.37 (s, 3
H), 7.00 (d, J = 8.3 Hz, 1 H), 7.34 (d, J = 8.3 Hz)
, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.76 (dd, J = 1.
7, 8.4 Hz, 1H), 7.80 (s, 1H), 7.84 (s, 1H), 12
． 01 (br s, 1H) EIMS m / z 353 (M + H) ⁺ C ₁₈ H ₁₂ N ₂ O ₂ S ₂ = 352.

Example 122 Preparation of Compound 95 2-Fluoro-5-formylbenzonitrile (0.2g, 1.34mmol)
Using a method similar to Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 3-cyano-4-[(4-methylphenyl) thio] benzaldehyde ( 0.3 g, 89.9%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.44 (s, 3H)
, 6.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2
H), 7.47 (dd, J = 1.8, 8.1 Hz, 2H), 7.78 (dd, J
= 1.8, 8.4 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 9.
90 (s, 1H) FABMS m / z 254 (M + H) + C 15 H 11 NOS = 253.

Compound 95 (0.126 g, 0.126 g, using the same method as in Example 94, using 3-cyano-4-[(4-methylphenyl (phenyl)) thio] benzaldehyde (0.2 g, 0.79 mmol). 45.3%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.50 (s, 3
H), 7.06 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.4 Hz)
, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.66 (s, 1H), 7
． 71 (dd, J = 2.0, 8.5 Hz, 1H), 8.08 (d, J = 2.0H
z, 1H), NH are not found. ^{EIMS m / z 352 (M +} ) C 18 H 12 N 2 O 2 S 2 = 352.

Example 123 Preparation of Compound 96 3-Bromo-4-fluorobenzaldehyde (0.12 g, 1.0 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 3-bromo-4-[(4-methylphenyl) thio] benzaldehyde (0 .18 g, 59.0%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.44 (s, 3H)
, 6.73 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 2
H), 7.47 (d, J = 8.1 Hz, 2H), 7.54 (dd, J = 1.7,
8.3 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), 9.84 (s,
1H). ^{EIMS m / z 307 (M +} ) C 14 H 11 79 BrOS = 307.

3-Bromo-4-[(4-methylphenyl) thio] benzaldehyde (0.2
g, 0.65 mmol) in methanol (6.0 mL) and dichloromethane (6
． 0 mL). Sodium borohydride (0.025g, 0.65mm
ol) was added, followed by stirring for 15 minutes and normal processing. The solvent was removed with a vacuum dryer. The residue was dissolved in dichloromethane (7.0 mL) and tert.
-Butyldimethylsilyl chloride (0.12 g, 0.78 mmol) and imidazole (0.053 g, 0.65 mmol) were added, followed by stirring for 2 hours and then normal treatment. The product was purified by silica gel chromatography (hexane: ethyl acetate = 16: 1) to give 3-bromo-4-[(4-methylphenyl) thio] benzyl (tert-butyldimethylsilyl) ether (0.27).
g, 96.4%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 0.62 (s, 6H), 0.8
4 (s, 9H), 2.29 (s, 3H), 4.56 (s, 2H), 6.76 (d
, J = 8.3 Hz, 1H), 7.00 (dd, J = 1.8, 8.3 Hz, 1H)
, 7.11 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 1.8 Hz, 2
H), 7.43 (d, J = 1.7 Hz, 1H). EIMS m / z 424 (M + H) + C 20 H 27 79 BrOSSi = 423.

Hexane (1.4 mL) and diethyl ether (10.
4 mL) was cooled to -78 ° C. n-Butyl lithium (hexane solution) (2.1
7 mL, 3.47 mmol) and tetramethylethylenediamine (0.52 m
L, 3.47 mmol) and then stirred for 15 minutes. 3-bromo-4-
[4-Methylphenyl) thio] benzyl tert-butyldimethylsilyl ether (0.37 mL, 0.87 mmol) was added, and the mixture was further stirred for 30 minutes. Then, what melt | dissolved dimethylformamide (0.3 mL, 3.47 mmol) in diethyl ether (4.3 mL) was added dropwise, and it stirred for 45 minutes after that. The mixture was allowed to warm to room temperature and then processed normally. The product was purified by thin layer chromatography (hexane: ethyl acetate = 16: 1) to give 5-hydroxymethyl-2-[(4-methylphenyl) thio] benzaldehyde (0.58 g, 6
6.7%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.62 (s, 6H)
, 0.84 (s, 9H), 2.28 (s, 3H), 4.64 (s, 2H), 6.
95 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 7.9 Hz, 2H),
7.23 (d, J = 8.3 Hz, 2H), 7.28 (dd, J = 2.2, 8.2)
Hz, 1H), 7.70 (d, J = 1.8Hz, 1H), 10.29 (9, 1H)
) EIMS m / z 373 (M + H) ⁺ C ₂₁ H ₂₈ O ₂ SSi = 372.

Compound 96 (0.067g, 70.70) was prepared using 5-hydroxymethyl-2-[(4-methylphenyl) thio] benzaldehyde (0.1g, 0.27mmol) in the same manner as in Example 94. 4%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.27 (s, 3)
H), 4.53 (d, J = 5.5 Hz, 2H), 5.37 (t, J = 5.5 Hz)
, 1H), 7.16 (d, J = 3.5 Hz, 4H), 7.31 (s, 1H), 7
． 58 (s, 1H), 7.98 (s, 1H), 12.00 (br s, 1H). EIMS m / z 356 (M- H) - C 18 H 15 NO 3 S 2 = 357.

Example 124 Preparation of Compound 97 5-Bromo-2-fluorobenzaldehyde (0.2 g,
1.0 mmol) was dissolved in toluene (2 mL). Tributyl (1-ethoxyvinyltin) (0.37 mL, 1.1 mmol) and bis (triphenylphosphine) palladium chloride (0.007 g, 0.01 mmol) were added, and then heated at 100 ° C for 10 hours. Then, when the temperature had dropped to room temperature, usual treatment was performed. Thin-layer chromatography of the product (hexane: ethyl acetate = 8
1), 5-acetyl-2-fluorobenzaldehyde (0.19 g,
58.3%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.65 (s, 3H)
, 7.31 (d, J = 9.3 Hz, 1H), 8.27 (m, 1H), 8.45 (
dd, J = 2.4, 6.6 Hz, 1H), 10.40 (s, 1H) CIMS m / z 167 (M + H) ⁺ C ₉ H ₇ ¹⁹ FO ₂ = 166.

5-Acetyl-2-fluorobenzaldehyde (0.1 g, 0.6 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 5-acetyl-2-[(4-methylphenyl) thio] benzaldehyde (0. 0.043 g, 26.5%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.43 (s, 3H)
, 2.60 (s, 3H), 6.93 (d, J = 8.6 Hz, 1H), 7.29 (
d, J = 7.9 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.8
6 (dd, J = 8.5, 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz,
1H), 10.34 (s, 1H) FABMS m / z 271 (M + H) ⁺ C ₁₆ H ₁₄ O ₂ S = 270.

5-Acetyl-2-[(4-methylphenyl) thio] benzaldehyde (0.
043g, 0.16mmol) and using the same method as in Example 94
7 (0.059 g, 99.8%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3
H), 2.51 (s, 3H), 7.09 (d, J = 8.3 Hz, 1H), 7.3
1 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 6.8 Hz, 2H), 7
． 89 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 8.01 (s,
1H), 12.00 (br s, 1H). EIMS m / z 370 (M + H) + C 19 H 15 NO 3 S 2 = 369.

Example 125 Preparation of compound 98 Using compound 97 (0.083 g, 0.21 mmol) and the same method as in example 96, compound 98 (0.040 g, 49.8%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.29 (s, 3
H), 2.50 (s, 3H), 7.30 (d, J = 8.3 Hz, 2H), 7.4
7 (d, J = 7.9 Hz, 2H), 7.78 (s, 1H), 7.88 (s, 1H)
), 8.04 (s, 1H), 8.16 (s, 1H), 8.17 (d, J = 3.3).
Hz, 1H), NH not found EIMS m / z 386 (M + H) ⁺ C ₁₉ H ₁₅ NO ₄ S ₂ = 385.

Example 126 Preparation of Compound 98 2-Fluoro-6- (trifluoromethyl) benzaldehyde (0.19 g,
1.5 mmol) and 2-[(4-methylphenyl) thio] -6- using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde). (Trifluoromethyl) benzaldehyde (0.44g
, 100%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.42 (s, 3H)
, 7.08 (d, J = 8.3 Hz, 1 H), 7.27 (d, J = 7.3 Hz, 2
H), 7.33 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 8.1 Hz)
, 2H), 7.50 (d, J = 7.7 Hz, 1H), 10.53 (q, J = 2.
2 Hz, 1 H) EIMS m / z 296 (M ⁺ ) C ₁₅ H ₁₁ ¹⁹ F ₃ OS = 296.

2-[(4-Methylphenyl) thio] -6- (trifluoromethyl) benzaldehyde (0.1 g, 0.3 mmol) was used using the same method as in Example 94 (Synthesis of Compound 67). Compound 99 (0.11 g, 81.2%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.34 (s, 3
H), 7.23 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.9 Hz)
, 2H), 7.37 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.7).
Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.70 (s, 1H)
, 12.00 (br s, 1H). EIMS m / z 394 (M- H) - C 18 H 12 19 F 3 NO 2 S 2 = 395.

Example 127 Preparation of Compound 100 2-Fluoro-5- (trifluoromethyl) benzaldehyde (0.1 g, 0
． 5 mmol) and using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde), 2-[(4-methylphenyl) thio] -5- ( Trifluoromethyl) benzaldehyde (0.45g
, 86.4%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.43 (s, 3H)
, 6.99 (d, J = 8.6 Hz, 1 H), 7.28 (d, J = 11.0 Hz,
2H), 7.43 (d, J = 8.1Hz, 2H), 7.52 (d, J = 8.4H)
z, 1H), 8.07 (s, 1H), 10.34 (s, 1H) FABMS m / z 296 (M ⁺ ) C ₁₅ H ₁₁ ¹⁹ F ₃ OS = 296.

Compound 100 (0.068 g) was prepared using 2-[(4-methylphenyl) thio] -5- (trifluoromethyl) benzaldehyde (0.1 g, 0.34 mmol) using the same method as in Example 94. , 50.9%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.35 (s, 3
H), 7.15 (d, J = 8.8 Hz, 1 H), 7.32 (d, J = 7.7 Hz)
, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.70 (s, 1H), 7
． 71 (d, J = 7.0 Hz, 1H), 7.92 (s, 1H), 12.80 (b
r s, 1H) EIMS m / z 394 (M-H) - C 18 H 12 19 F 3 NO 2 S 2 = 395.

Example 128 Preparation of Compound 101 2-Fluoro-4- (trifluoromethyl) benzaldehyde (0.1 g, 0
． 5 mmol) and 2-[(4-methylphenyl) thio] -4- (tri) using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde). Fluoromethyl) benzaldehyde (0.47 g,
89.5%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.41 (s, 3H)
, 7.23 (d, J = 4.6 Hz, 2H), 7.24 (m, 1H), 7.38 (
d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.9
5 (d, J = 7.9 Hz, 1H), 10.41 (s, 1H) FABMS m / z 296 (M ⁺ ) C ₁₅ H ₁₁ ¹⁹ F ₃ OS = 296.

2-[(4-Methylphenyl) thio] -4- (trifluoromethyl) benzaldehyde (0.1 g, 0.34 mmol) was used in the same manner as in Example 94 to give compound 101 (0.082 g). , 60.9%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.33 (s, 3
H), 7.28 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.3 Hz)
, 2H), 7.38 (s, 1H), 7.71 (d, J = 8.1Hz, 1H), 7
． 77 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 12.78 (b
r s, 1H) EIMS m / z 394 (M-H) - C 18 H 12 19 F 3 NO 2 S 2 = 395.

Example 129 Preparation of Compound 102 2-Fluoro-3- (trifluoromethyl) benzaldehyde (0.19 g,
1.5 mmol) and using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) 2-[(4-methylphenyl) thio] -3- (Trifluoromethyl) benzaldehyde (0.44g
, 100%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.26 (s, 3H)
, 6.97 (d, J = 2.2 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2
H), 7.64 (t, J = 7.9 Hz, 1H), 8.02 (d, J = 7.9 Hz)
, 1H), 8.09 (d, J = 7.7 Hz, 1H), 10.60 (d, J = 0.
7Hz, 1H). ^{EIMS m / z 296 (M +} ) C 15 H 11 19 F 3 OS = 296.

2-[(4-Methylphenyl) thio] -3- (trifluoromethyl) benzaldehyde (0.1 g, 0.3 mmol) was used using the same method as in Example 94 to give compound 102 (0.13 g). , 97.5%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.19 (s, 3
H), 6.89 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 7.9 Hz)
, 2H), 7.80 (s, 1H), 7.81 (d, J = 4.0Hz, 1H), 7
． 87 (s, 1H), 8.00 (dd, J = 2.8, 6.6 Hz, 1H), 12
． 01 (br s, 1H). EIMS m / z 394 (M- H) - C 18 H 12 19 F 3 NO 2 S 2 = 395.

Example 130 Preparation of Compound 103 Using Compound 102 (0.1 g, 0.25 mmol) and in the same manner as in Example 96, Compound 103 (0.043 g, 41.7%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.27 (s, 3
H), 7.23 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.8 Hz
, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.93 (t, J = 7.7).
Hz, 1H), 8.07 (d, J = 7.7Hz, 1H), 8.18 (s, 1H)
, 12.62 (br s, 1H) EIMS m / z 412 (M + H) ⁺ C ₁₈ H ₁₂ ¹⁹ F ₃ NO ₃ S ₂ = 411.

Example 131 Preparation of Compound 104 2-Fluoro-5-methoxybenzaldehyde (0.25 g, 2.0 mmol)
), The reaction described in Example 114 (synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde), purification by thin layer chromatography (hexane: ethyl acetate = 8: 1), Then further thin layer chromatography (
Purification with hexane: ethyl acetate = 24: 1) yielded 2-[(4-methylphenyl) thio] -5-methoxybenzaldehyde (0.05 g, 10.1%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.32 (s, 3H)
, 3.86 (s, 3H), 7.07 (dd, J = 3.1, 8.6 Hz, 2H),
7.13 (m, 4H), 7.32 (d, J = 8.6Hz, 1H), 7.44 (d
, J = 3.1 Hz, 1H), 10.51 (s, 1H). ^{EIMS m / z 258 (M +} ) C 15 H 14 O 2 S = 258.

2-[(4-methylphenyl) thio] -5-methoxybenzaldehyde (0.
05g, 0.2 mmol) and using the same method as in Example 94
(0.07 g, 97.1%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.24 (s, 3
H), 3.84 (s, 3H), 7.02 (d, J = 8.3 Hz, 2H), 7.0
9 (m, 2H), 7.12 (d, J = 8.1Hz, 2H), 7.52 (d, J =
8.6Hz, 1H), 8.04 (s , 1H), 12.01 (br s, 1H) EIMS m / z 356 (M-H) - C 18 H 15 NO 3 S 2 = 357.

Example 132 Preparation of Compound 105 2-Fluoro-4-methoxybenzaldehyde (0.1 g, 0.65 mmol)
) Was used in the same manner as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) to prepare 2-[(4-methylphenyl) thio] -4-methoxybenzaldehyde ( 0.078 g, 46.2%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.39 (s, 3H)
, 3.70 (s, 3H), 6.45 (d, J = 2.4 Hz, 1H), 6.76 (
dd, J = 2.4, 8.6 Hz, 1H), 7.22 (d, J = 7.7 Hz, 2H
), 7.39 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.6 Hz,
1H), 10.20 (s, 1H) FABMS m / z 259 (M + H) ⁺ C ₁₅ H ₁₄ O ₂ S = 258.

2-[(4-methylphenyl) thio] -4-methoxybenzaldehyde (0.
Compound 78 (0.091 g, 85.2%) was obtained in the same manner as in Example 94 (Synthesis of Compound 67) using 078 g (0.3 mmol).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3)
H), 3.74 (s, 3H), 6.75 (d, J = 2.7Hz, 1H), 7.0
7 (dd, J = 2.7, 8.6 Hz, 1 H), 7.23 (d, J = 8.3 Hz,
2H), 7.49 (d, J = 8.8Hz, 1H), 8.04 (s, 1H), 12
． 59 (br s, 1H) EIMS m / z 358 (M + H) ⁺ C ₁₈ H ₁₅ NO ₃ S ₂ = 357.

Example 133 Preparation of Compound 106 4-Chlorofluorobenzene (0.48 mL, 4.5 mmol) was used and 5-using the same method as Example 121 (Synthesis of 2-fluoro-5-cyanobenzaldehyde). Chloro-2-fluorobenzaldehyde (0.55 g, 77.6%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.16 (t, J = 9)
． 4 Hz, 1H), 7.56 (m, 1H), 7.84 (dd, J = 2.8, 5.
9 Hz, 1 H), 10.32 (s, 1 H) EIMS m / z 157 (M ⁻ ) C ₇ H ₄ ³⁵ Cl ¹⁹ FNO = 158.

5-Chloro-2-fluorobenzaldehyde (0.15 g, 0.95 mmol
) Was used in the same manner as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) to give 5-chloro-2-[(4-methylphenyl) thio] benzaldehyde. (0.21 g, 85.1%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.38 (s, 3H)
, 6.99 (d, J = 8.6 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 2
H), 7.33 (m, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.8
2 (d, J = 2.4Hz, 1H), 10.34 (s, 1H) FABMS m / z 262 (M +) C 14 H 11 35 ClOS = 262.

5-chloro-2-[(4-methylphenyl) thio] benzaldehyde (0.1
g, 0.38 mmol) and using the same method as in Example 94.
0.096 g, 70.1%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3)
H), 7.23 (d, J = 8.6 Hz, 2H), 7.25 (m, 1H), 7.2
7 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.49 (d, J =
7.0 Hz, 1H), 7.91 (s, 1H), 12.01 (br s, 1H) EIMS m / z 362 (M + H) ⁺ C ₁₇ H ₁₂ ³⁵ ClNO ₂ S ₂ = 361.

Example 134 Preparation of Compound 107 Using compound 106 (0.1 g, 0.28 mmol) and in the same manner as in Example 96, compound 107 (0.094 g, 90.0%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3)
H), 7.31 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.1 Hz)
, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 2.
0, 8.5 Hz, 1H), 7.88 (s, 1H), 8.02 (d, J = 8.4H
z, 1H), NH are not found. EIMS m / z 378 (M + H) + C 17 H 12 35 ClNO 3 S 2 = 377.

Example 135 Preparation of Compound 108 4-Chloro-2-fluorobenzaldehyde (0.32 g, 2.0 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 4-chloro-2-[(4-methylphenyl) thio] benzaldehyde (0. .32 g, 60.4%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.41 (s, 3H)
, 6.90 (d, J = 1.8 Hz, 1H), 7.24 (m, 3H), 7.40 (
d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.3 Hz, 1H), 10.
29 (s, 1H) EIMS m / z 262 (M +) C 14 H 11 35 ClOS = 262.

4-chloro-2-[(4-methylphenyl) thio] benzaldehyde (0.0
Compound 108 (5 g, 0.2 mmol) using the same method as in Example 94
0.052 g, 75.1%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.33 (s, 3
H), 7.11 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 8.3 Hz)
, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 2.2)
Hz, 1H), 7.51 (s, 1H), 7.95 (s, 1H), 12.72 (b
r s, 1H) EIMS m / z 326 (M ⁺ ) C ₁₇ H ₁₂ NO ₂ S ₂ = 326.

Example 136 Preparation of Compound 109 3-Chloro-4-fluorobenzaldehyde (0.2 g, 1.26 mmol)
Using the same method as in Example 114 (Synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde) using 3-chloro-4-[(4-methylphenyl) thio] benzaldehyde (0 .29 g, 87.9%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.44 (s, 3H)
, 6.77 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2
H), 7.46 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 1.8,
8.4 Hz, 1 H), 7.82 (d, J = 1.7 Hz, 1 H), 9.85 (s,
1H) FABMS m / z 262 ( M +) C 14 H 11 35 ClOS = 262.

3-Chloro-4-[(4-methylphenyl) thio] benzaldehyde (0.1
5 g, 0.57 mmol) and using the same method as in Example 94
(0.13 g, 65.1%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.38 (s, 3
H), 6.79 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.9 Hz)
, 2H), 7.41 (dd, J = 2.2, 8.7 Hz, 1H), 7.48 (d,
J = 8.1 Hz, 2H), 7.71 (s, 1H), 7.75 (d, J = 1.8H
z, 1H), NH not found EIMS m / z 361 (M ⁺ ) C ₁₇ H ₁₂ ³⁵ ClNO ₂ S ₂ = 361.

Example 137 Preparation of Compound 110 2-Fluoro-5-nitrobenzaldehyde (0.055 g, 0.33 mmo
1) was dissolved in N, N-dimethylformamide (2.8 mL) and phenol (0.077 g, 0.82 mmol) and potassium carbonate (0.11 g, 0.
82 mmol) and then stirred at 25 ° C. for 1 hour. After usual treatment, the residue was purified by silica gel chromatography (eluted with chloroform) to give 5-nitro-2-phenoxybenzaldehyde (77 mg, 98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.91 (d, J = 9)
． 4 Hz, 1H), 7.20-7.14 (m, 2H), 7.35 (dd, J = 7)
． 2 Hz, 1 H), 7.47-7.55 (m, 2 H), 8.31 (dd, J = 9)
． 2, 2.8 Hz, 1 H), 8.79 (d, J = 3.0 Hz, 1 H), 10.6
0 (s, 1H) FABMS m / z 244 (M + H) + C 13 H 9 NO 4 = 243.

5-Nitro-2-phenoxybenzaldehyde (77 mg, 0.32 mmol
) In toluene (3.9 mL) and 2,4-thiazolidinedione (0
． 15 g, 1.3 mmol), piperidine (0.013 mL, 0.13 mmol)
), Acetic acid (0.0073 mL, 0.13 mmol) and molecular sieve 4
A (0.39 g) was added, and then the mixture was stirred at 110 ° C. for 3 hours. After normal post-treatment,
The residue was purified by thin layer chromatography (developed with chloroform / acetonitrile = 10/1) to give compound 110 (67 mg, 61%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.94 (d, J
= 9.2 Hz, 1H), 7.27 (d, J = 7.7 Hz, 2H), 7.36 (d
d, J = 7.1, 7.1 Hz, 1H), 7.50-7.58 (m, 2H), 7.
99 (s, 1H), 8.28 (dd, J = 2.7, 9.2 Hz, 1H), 8.3
8 (d, J = 2.8Hz, 1H), 12.81 (m, 1H) FABMS m / z 341 (M-H) - C 16 H 10 N 2 O 5 = 342.

Example 138 Preparation of Compound 111 2-Fluoro-5-nitrobenzaldehyde (0.13 g, 0.79 mmol)
Was dissolved in N, N-dimethylformamide (6.7 mL) and p-cresol (0.22 g, 2.0 mmol) and potassium carbonate (0.27 g, 2.0).
mmol), and then stirred at 25 ° C. for 1.5 hours. After usual treatment, the residue was purified by silica gel chromatography (eluted with chloroform) to give 5-nitro-2- (4-methylphenoxy) benzaldehyde (0.20 g, 98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.41 (s, 3H)
, 6.89 (d, J = 9.4 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 2
H), 7.25-7.32 (m, 2H), 8.39 (dd, J = 9.2, 3.0).
Hz, 1H), 8.79 (d, J = 2.9Hz, 1H), 10.60 (s, 1H)
) FABMS m / z 257 (M +) C 14 H 11 NO 4 = 257.

5-Nitro-2- (4-methylphenoxy) benzaldehyde (0.11 g,
0.41 mmol) was dissolved in toluene (5.3 mL) and 2,4-thiazolidinedione (0.19 g, 1.6 mmol), piperidine (0.016 mL,
0.16 mmol), acetic acid (0.0094 mL, 0.16 mmol) and molecular sieve 4A (0.53 g) were added, and then the mixture was stirred at 110 ° C. for 2 hours. After the usual post-treatment, the residue was tritylated with ethanol to give compound 111 (
60 mg, 41%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.36 (s, 3
H), 6.90 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 8.2 Hz)
, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.99 (s, 1H), 8
． 25 (dd, J = 9.2, 2.8 Hz, 1H), 8.36 (d, J = 2.6H
z, 1H), 12.80 (m , 1H) FABMS m / z 355 (M-H) - C 17 H 12 N 2 O 5 S = 356.

Example 139 Preparation of Compound 112 Commercially available (MAYBRIDGE, Catalog No. XAX00137) 2- [4
-(2,2-Dimethylethyl) phenoxy] -5-nitrobenzaldehyde (0
． 12 g, 0.41 mmol) was dissolved in ethanol (4.9 mL) and 2
, 4-thiazolidinedione (0.19 g, 1.6 mmol) and piperidine (
0.016 mL, 0.16 mmol) was added, and then the mixture was stirred at 80 ° C. for 2 hours. After the usual post-treatment, the residue was purified by thin layer chromatography (developed with chloroform / acetonitrile = 10/1) to obtain Compound 112 (49 mg, 30%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.31 (s, 9
H), 6.92 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 8.6 Hz)
, 2H), 7.53 (d, J = 8.6 Hz, 2H), 7.98 (s, 1H), 8
． 27 (dd, J = 9.2, 2.4 Hz, 1H), 8.35 (d, J = 2.2H)
z, 1H), 12.78 (br s, 1H) FABMS m / z 397 (M-H) - C 20 H 18 N 2 O 5 S = 398.

Example 140 Preparation of Compound 113 Using compound 100 (0.11 g, 0.27 mmol) and in the same manner as in Example 96, compound 113 (0.079 g, 71.1%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.29 (s, 3
H), 7.31 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.1 Hz)
, 2H), 7.74 (s, 1H), 7.77 (s, 1H), 8.03 (d, J =
7.9 Hz, 1 H), 8.24 (d, J = 7.9 Hz, 1 H), NH is not found EIMS m / z 412 (M + H) ⁺ C ₁₈ H ₁₂ ¹⁹ F ₃ NO ₃ S ₂ = 411.

Example 141 Preparation of Compound 114 Using the same method as in Example 96, using Compound 94 (0.1 g, 0.28 mmol), Compound 114 (0.046 g, 43.5%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.29 (s, 3
H), 7.29 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.3 Hz)
, 2H), 7.83 (s, 1H), 7.86 (d, J = 7.9Hz, 1H), 8
． 01 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H)
, NH is not found. EIMS m / z 369 (M + H) + C 18 H 12 N 2 O 3 S 2 = 368.

Example 142 Preparation of Compound 115 Using the same method as Example 97, 4-trifluoromethylbenzenethiol (
74 mg, 0.42 mmol), 2.5 mol / L sodium hydroxide aqueous solution (
0.71 mL, 1.8 mmol), tetrabutylammonium bromide (6.7
mg, 0.021 mmol) and 2-fluoro-5-nitrobenzaldehyde (70 mg, 0.41 mmol) in toluene (0.71 mL) from 2-[(
4-trifluoromethylphenyl) thio] -5-nitrobenzaldehyde (0.
13 g, 93%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.04 (d, J = 8)
． 8 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 2 H), 7.77 (d, J
= 8.6 Hz, 2H), 8.18 (dd, J = 8.8, 2.5 Hz, 1H), 8
． 71 (d, J = 2.5Hz, 1H), 10.31 (s, 1H) FABMS m / z 327 (M -) C 14 H 8 19 F 3 NO 3 S = 327.

Using the same method as in Example 97, 2-[(4-trifluoromethylphenyl)
Thio] -5-nitrobenzaldehyde (0.12 g, 0.35 mmol), toluene (5.8 mL), 2,4-thiazolidinedione (0.17 g, 1.4 mmo)
l), piperidine (0.014 mL, 0.14 mmol), acetic acid (0.0080
Compound 115 (44 mg, 51%) was obtained from mL, 0.14 mmol) and the molecular sieve 4A (0.58 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.52 (d, J
= 8.7 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.81 (d
, J = 8, 2 Hz, 2H), 7.88 (s, 1H), 8.24 (dd, J = 8.
6,2.5 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 12.82
(M, 1H) FABMS m / z 425 (M-H) - C 17 H 9 19 F 3 N 2 O 4 S 2 = 426.

Example 143 Preparation of Compound 116 Compound 74 (57 mg, 0.15 mmol) obtained in Example 101 is dissolved in dichloromethane (11 mL) and methanol (2.3 mL), and m-chloroperbenzoic acid (55 mg). , 0.16 mmol), and then 1.
Stir for 5 hours. After the usual post-treatment, the residue was purified by thin layer chromatography (developed with chloroform / methanol = 15/1) to give compound 116 (34 mg, 57%
) Got.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.76 (s, 3)
H), 7.02-7.08 (m, 2H), 7.49-7.55 (m, 2H), 7
． 81 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.33 (d,
J = 8.6 Hz, 1 H), 8.52 (dd, J = 8.6, 2.2 Hz, 1 H),
12.86 (m, 1H) FABMS m / z 403 (M-H) - C 17 H 12 N 2 O 6 S 2 = 404.

Example 144 Preparation of Compound 117 Using the same method as Example 143, compound 71 (52 mg) obtained in Example 98
, 0.13 mmol), dichloromethane (10 mL), methanol (2.1 mL
), And m-chloroperbenzoic acid (50 mg, 0.15 mmol) to compound 1
17 (37 mg, 68%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.55-7.6
6 (m, 3H), 7.80-7.85 (m, 1H), 8.08 (s, 1H), 8
． 15 (d, J = 8.6 Hz, 1H), 8.27 (m, 1H), 8.45 (dd
, J = 8.6,2.2Hz, 1H), 12.88 (m, 1H) FABMS m / z 407 (M-H) - C 16 H 9 35 ClN 2 O 5 S 2 = 408.

Example 145 Preparation of Compound 118 3-Bromo-4-[(4-methylphenyl) thio] benzaldehyde (0.2
g, 0.65 mmol) was dissolved in acetone (3 mL), cooled to 0 ° C., and Jones reagent (0.082 mL) was added, followed by stirring for 3 hours and a half. Then isopropyl alcohol (0.1 mL) was added. After the usual treatment, the residue was recrystallized and purified with hexane and ethyl acetate to obtain 3-bromo-4-[(4-methylphenyl) thio] benzoic acid (0.18 g, 84.7%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.39 (s, 3
H), 6.70 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.3 Hz)
, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.76 (dd, J = 1.
1,8.7Hz, 1H), 8.07 (d , J = 1.1Hz, 1H), CO 2 H is not found FABMS m / z 322 (M- H) - C 14 H 11 79 BrO 2 S = 323.

3-Bromo-4-[(4-methylphenyl) thio] benzoic acid (0.1 g, 0.
31 mmol) and using the same method as in Example 115 (Synthesis of 3-bromo-4-[(4-methylphenyl) thio] benzaldehyde), 5-carboxy-2.
-[(4-Methylphenyl) thio] benzaldehyde (0.031g, 36.7)
%) Was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.50 (s, 3)
H), 6.84 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.1 Hz)
, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.93 (dd, J = 2.
0, 8.4Hz, 1H), 8.46 (d, J = 2.0Hz, 1H), 10.22
_{(S, 1H), CO 2} H is not found FABMS m / z 271 (M- H) -, C 15 H 12 O 3 S = 272.

5-Carboxy-2-[(4-methylphenyl) thio] benzaldehyde (0
． Compound 94 (0.032 g, 25.3%) was obtained using the same method described in Example 94, using 094 g, 0.34 mmol).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.34 (s, 3)
H), 6.96 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.1 Hz)
, 2H), 7.33 (s, 1H), 7.37 (d, J = 7.2Hz, 2H), 7
． 64 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 8.20 (s,
IH), NH is not found FABMS m / z 370 (M- H) -, C 18 H 13 NO 4 S 2 = 371.

Example 146 Preparation of Compound 119 Commercially available (MAYBRIDGE, Catalog No. XAX00153) 5-nitro-2- (pyrid-2-ylthio) benzaldehyde (0.26 g, 1.0 mmo)
l) and using the same method as in Example 94, compound 119 (0.120 g, 3
3.5%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.28 (dd,
J = 4.8, 7.7 Hz, 1H), 7.40 (dd, J = 0.9, 7.7 Hz,
1H), 7.78 (dd, J = 1.3, 7.7 Hz, 1H), 7.86 (s 2,
1H), 7.87 (d, J = 8.4 Hz, 1H), 8.28 (dd, J = 2.4)
, 8.4 Hz, 1 H), 8.32 (d, J = 2.4 Hz, 1 H), 8.42 (d
d, J = 0.9, 4.8 Hz, 1H), 12.78 (br s, 1H) EIMS m / z = 360 (M + H) ⁺ C ₁₅ H ₉ N ₃ O ₄ S ₂ = 359.

Example 147 Preparation of Compound 120 Using the compound 119 obtained in Example 146 (0.02 g, 0.056 mmol) and the same method as in Example 96, compound 120 (0.0044 g, 21.
2%) was obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.49 (m, 1
H), 7.87 (s, 1H), 7.98 (d, J = 7.9Hz, 1H), 8.0
7 (m, 1H), 8.08 (d, J = 8.5Hz, 1H), 8.26 (dd, J
= 2.2, 8.5 Hz, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.
54 (d, J = 4.8 Hz, 1H), NH is not found. EIMS m / z = 376 (M + H) + C 15 H 9 N 3 O 5 S 2 = 375.

Example 148 Preparation of Compound 121 N, N-Diphenylbenzylamine (935 mg, 3.60 mmol) was suspended in acetic acid (20 mL) and hexamethylenetriamine (1.12 g, 7.9).
6 mmol) was added, and then the mixture was stirred at 90 ° C. for 12 hours. The reaction solution was cooled to room temperature, 6 mol / L sodium hydroxide aqueous solution and water were added, and then the product was extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 20/1 → 10/1),
4- (N-phenylbenzylamino) benzaldehyde (742 mg, 72%)
Got

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.04 (s, 2H)
, 6.80 (d, J = 8.6 Hz, 2H), 7.20-7.45 (m, 10H)
, 7.63 (d, J = 8.6 Hz, 2H), 9.73 (s, 1H).

4- (N-phenylbenzylamino) benzaldehyde (109 mg, 0.3
78 mmol), 2,4-thiazolidinedione (59.9 mg, 0.511 mm)
ol) and piperidine (0.045 mL, 0.46 mmol) in ethanol (
Heated to reflux in 5 mL) for 6 hours. The reaction solution was cooled to room temperature and 1 mol / L H
Cl was added, then the product was extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform / methanol = 20/1) to give compound 121 (123 mg, 84%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 5.08 (s, 2H)
, 6.88 (d, J = 8.6 Hz, 2H), 7.15-7.45 (m, 12H)
, 7.61 (s, 2H), 12.38 (br s, 1H).

Example 149 Preparation of Compound 129 2-Fluoro-5-nitrobenzaldehyde (31 mg, 0.18 mmol)
Was dissolved in N, N-dimethylformamide (3.1 mL) and 4-mercaptobenzoic acid (85 mg, 0.55 mmol) and triethylamine (0.13).
(mL, 0.92 mmol) was added and then stirred at 25 ° C. for 20 minutes. After the usual work-up, the product was subjected to thin layer chromatography (chloroform / methanol = 10
/ Developed with / 1) to give 5-nitro-2-[(4-carboxylphenyl) thio] benzaldehyde (60 mg, 100%).

5-nitro-2-[(4-carboxylphenyl) thio] benzaldehyde (
60 mg, 0.20 mmol) was dissolved in ethanol (2.4 mL) and 2
, 4-thiazolidinedione (92 mg, 0.79 mmol), piperidine (0.
027mL, 0.28mmol), acetic acid (0.0045mL, 0.079mmo
1) and Molecular Sieves 4A (0.30 g) were added, and then the mixture was stirred at 80 ° C. for 2.5 hours. After the usual post-treatment, compound 129 (12 mg, 15%) was obtained by thin layer chromatography (developed with chloroform / methanol = 5/1).

5-Nitro-2-[(4-carboxylphenyl) thio] benzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.04 (d, J = 8)
． 8 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 2 H), 8.09 (d, J
= 8.2 Hz, 2H), 8.28 (dd, J = 8.8, 2.5 Hz, 1H), 8
． 87 (d, J = 2.5 Hz, 1H), 10.28 (s, 1H), 13.10 (
m, 1H).

Compound 129: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.46 (d, J
= 8.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.87 (s
, 1H), 7.98 (d, J = 8.7 Hz, 2H), 8.21 (dd, J = 8.
7, 2.4 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 12.57
-13.31 (m, 2H) FABMS m / z 401 (M-H) - C 17 H 10 N 2 O 6 S 2 = 402.

Example 150 Preparation of Compound 130 5-Nitro-2-[(4-carboxylphenyl) thio] benzaldehyde (71 mg, 0.23 mmol) obtained in Example 106 was added to N, N-dimethylformamide (7.1 mL). ), And a 2.0 mol / L dimethylamine methanol solution (0.23 mL, 0.47 mmol), hydrochloric acid 1-ethyl-3- (
3-Dimethylaminopropyl) carbodiimide (90 mg, 0.47 mmol)
And 1-hydroxybenzotriazole hydrate (0.11 g, 0.94 mmo
1) was added and then stirred at 25 ° C. for 30 minutes. After usual work-up, the product was purified by silica gel chromatography (eluted with chloroform) to give N, N-dimethyl-4-[(2-formyl-4-nitrophenyl) thio] benzamide (59m).
g, 75%).

N, N-Dimethyl-4-[(2-formyl-4-nitrophenyl) thio] benzamide (0.12 g, 0.36 mmol) was dissolved in toluene (6.0 mL) and 2,4- Thiazolidinedione (0.17 g, 1.5 mmol), piperidine (0.014 mL, 0.15 mmol), acetic acid (0.0083 mL, 0.1
5 mmol) and molecular sieves 4A (0.60 g), and then
The mixture was stirred at 110 ° C for 4.5 hours. After the usual post-treatment, thin layer chromatography (developed with chloroform / acetonitrile = 3/1) gave compound 130 (48 mg, 31).
%) Was obtained.

N, N-Dimethyl-4-[(2-formyl-4-nitrophenyl) thio] benzamide: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.02 (br s,
3H), 3.16 (br s, 3H), 7.02 (d, J = 9.0Hz, 1H)
, 7.53-7.64 (m, 4H), 8.13 (dd, J = 8.8, 2.6 Hz
, 1H), 8.69 (d, J = 2.6 Hz, 1H), 10.31 (s, 1H) FABMS m / z 331 (M + H) ⁺ C ₁₆ H ₁₄ N ₃ O ₄ S = 330.

Compound 130: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.92 (br
s, 3H), 2.99 (br s, 3H), 7.36 (d, J = 8.8Hz, 1
H), 7.50 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.0 Hz
, 2H), 7.89 (s, 1H), 8.21 (dd, J = 8.8, 2.2Hz,
1H), 5.27 (d, J = 2.2Hz, 1H), 12.83 (m, 1H) FABMS m / z 428 (M-H) - C 19 H 15 N 3 O 5 S 2 = 429.

Example 151 Preparation of Compound 131 Using the same method as Example 150, 5-nitro-2-obtained in Example 149.
[(4-Carboxyphenyl) thio] benzaldehyde (0.13 g, 0.4
2 mmol), N, N-dimethylformamide (7.1 mL), morpholine (
0.073 mL, 0.83 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.16 g, 0.83 mmol) and 1-
Hydroxybenzotriazole monohydrate (0.11 g, 1.7 mmol) to 4
-{4-[(2-Formyl-4-nitrophenyl) thio] benzoyl} morpholine (0.13 g, 78%) was obtained.

4- {4-[(2-formyl-4-nitrophenyl) thio] benzoyl} morpholine (0.13 g, 0.34 mmol), toluene (6.3 mL), 2,4-
Thiazolidinedione (0.16 g, 1.3 mmol), piperidine (0.013
mL, 0.13 mmol), acetic acid (0.0077 mL, 0.13 mmol) and molecular sieves 4A (0.63 g) to compound 131 (48 mg, 31).
%) Was obtained.

4- {4-[(2-formyl-4-nitrophenyl) thio] benzoyl} -morpholine: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 3.39-3.93 (
m, 8H), 7.04 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 8.
2Hz, 2H), 7.62 (d, J = 8.3Hz, 2H), 8.13 (dd, J
= 8.8, 2.5 Hz, 1H), 8.69 (d, J = 2.6 Hz, 1H), 10
． 30 (s, 1H) FABMS m / z 373 (M + H) + C 18 H 16 N 2 O 5 S = 372.

Compound 131: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.27-3.4
5 (m, 4H), 3.61 (br s, 4H), 7.39 (d, J = 8.9Hz
, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4)
Hz, 2H), 7.89 (s, 1H), 8.21 (dd, J = 8.8, 2.6H)
z, 1H), 8.27 (d , J = 2.2Hz, 1H), 12.83 (m, 1H) FABMS m / z 470 (M-H) - C 21 H 17 N 3 O 6 S 3 = 471.

Example 152 Preparation of Compound 132 4- (methylthio) benzenethiol (0.15 mL, 0.93 mmol) in 2.5 mol / L aqueous sodium hydroxide solution (1.6 mL, 4.0 mmol) and tetrabutylammonium bromide. (15 mg, 0.047 mmol) was added, and then the mixture was stirred at 25 ° C. for 10 minutes. A toluene solution of 2-fluoro-5-nitrobenzaldehyde (0.16 g, 0.93 mmol) (1.6 mL) was added to the reaction solution.
) Was added, followed by stirring at 110 ° C. for 1.5 hours. After the usual work-up, the product was purified by silica gel chromatography (eluted with chloroform) to give 5-nitro-
2-[(4-methylthio) phenyl] thiobenzaldehyde (0.25 g, 89
%) Was obtained.

5-nitro-2- [4- (methylthio) phenyl] thiobenzaldehyde (0
． 23 g, 0.76 mmol) was dissolved in toluene (12 mL) and 2,4
-Thiazolidinedione (0.35 mg, 3.0 mmol), piperidine (0.0
30 mL, 0.30 mmol), acetic acid (0.017 mL, 0.30 mmol) and Molecular Sieves 4A (1.2 g) were added and stirred at 110 ° C. for 4 hours. After the usual post-treatment, tritylate the product with ethanol,
Compound 132 (12 mg, 15%) was obtained.

5-Nitro-2- [4- (methylthio) phenyl] thiobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.55 (s, 3H)
, 6.98 (d, J = 9.0 Hz, 1H), 7.32-7.38 (m, 2H),
7.44-7.50 (m, 2H), 8.11 (dd, J = 9.0, 2.5Hz,
1H), 8.66 (d, J = 2.4 Hz, 1H), 10.30 (s, 1H) FABMS m / z 306 (M + H) ⁺ C ₁₄ H ₁₁ NO ₃ S ₂ = 305.

Compound 132: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.52 (s, 3
H), 7.09 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.6 Hz
, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.38 (s, 1H), 8
． 16 (dd, J = 8.8, 2.6 Hz, 1H), 8.23 (d, J = 2.4H
z, 1H), 12.83 (m , 1H) FABMS m / z 403 (M-H) - C 17 H 12 N 2 O 4 S 3 = 464.

Example 153 Preparation of Compound 133 Using the same method as Example 134, compound 75 obtained in Example 102 (0.
11 g, 0.27 mmol), dichloromethane (21 mL), methanol (4.
Compound 133 (0.12 g, 100%) was obtained from 2 mL) and m-chloroperbenzoic acid (0.10 g, 0.30 mmol).

Compound 133: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.46-2.5
5 (m, 3H), 3.93-4.04 (m, 2H), 8.73 (br d, J =
7.7 Hz, 2 H), 8.88 (br d, J = 7.5 Hz, 2 H), 9.27
(S, 1H), 9.58 (s, 1H), 9.72 (d, J = 8.6Hz, 1H)
, 9.91 (br d, J = 8.3Hz, 1H), 14.21 (m, 1H) FABMS m / z 401 (M-H) - C 18 H 14 N 2 O 5 S 2 = 402.

Example 154 Preparation of Compound 134 Using the same method as Example 134, compound 70 (0.1
1 g, 0.29 mmol), dichloromethane (23 mL), methanol (4.5
(mL) and m-chloroperbenzoic acid (0.11 g, 0.32 mmol) to give compound 134 (90 mg, 76%).

Compound 134: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.49-7.6
2 (m, 3H), 7.66 (s, 1H), 7.99 (s, 1H), 8.21 (d
, J = 1.7 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.49
(Dd, J = 8.4,2.0Hz, 1H ), 12.89 (m, 1H) FABMS m / z 407 (M-H) - C 16 H 9 35 ClN 2 O 5 S 2 = 408.

Example 155 Preparation of Compound 135 Using the same method as Example 134, compound 72 obtained in Example 99 (83m
g, 0.19 mmol), dichloromethane (17 mL), methanol (3.3 m
L) and m-chloroperbenzoic acid (74 mg, 0.21 mmol) to give compound 1
35 (32 mg, 37%) was obtained.

Compound 135: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.52 (dd,
J = 8.4, 1.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7
． 86 (d, J = 2.1 Hz, 1H), 7.99 (s, 1H), 8.22 (d,
J = 2.0Hz, 1H), 8.30 (d, J = 8.6Hz, 1H), 8.48 (
dd, J = 8.6,2.0Hz, 1H) , 12.88 (m, 1H) FABMS m / z 441 (M-H) - C 16 H 8 35 Cl 2 N 2 O 5 S 2 = 442.

Example 156 Preparation of Compound 136 Compound 80 (60 mg, 0.14 mmol) obtained in Example 107 was treated with N, N
-Dissolved in dimethylformamide (3.0 mL) and added m-chloroperbenzoic acid (0.11 g, 0.33 mmol), then stirred at 25 <0> C for 1 hour.
After usual post-treatment, thin layer chromatography (chloroform / methanol = 20 /
Compound 1 (20 mg, 33%) was obtained.

Compound 136: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J
= 8.6 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.99 (s
, 1H), 8.27-8.32 (m, 1H), 8.48 (d, J = 8.2Hz,
1H), 8.54 (d, J = 1.8Hz, 1H), 12.83 (m, 1H) FABMS m / z 451 (M-H) - C 16 H 9 79 BrN 2 O 5 S 2 = 452 .

Example 157 Preparation of Compound 137 4-Fluoro-3-phenoxybenzaldehyde (0.20 g, 0.93 mm
was used to carry out a reaction similar to the synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde in Example 114, and then a usual treatment was carried out.

The solvent was removed from the obtained mixture of the raw material and the product by a vacuum dryer, and the whole amount of the mixture was used to synthesize the compound 137 (0.11 g, 45%) in the same manner as in the synthesis of the compound 67.
) Got.

Compound 137: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ2.50 (s, 3H), 6.
90 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H),
7.07 (m, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.30 (m
, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1)
Hz, 4H), 7.63 (s , 1H), 12.55 (br s, 1H) EI-MS m / z 419 (M +), C 23 H 17 NO 3 S 2 = 419.

Example 158 Preparation of Compound 138 4-Fluoro-3-methoxybenzaldehyde (0.20 g, 1.3 mmol
) Was used to carry out the same reaction as in the synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde in Example 114, and then the usual treatment was carried out.

The solvent was removed from the obtained mixture of the raw material and the product by a vacuum dryer, and the whole amount thereof was used to synthesize the compound 138 (0.13 g, 44%) in the same manner as in the synthesis of the compound 67.
) Got.

Compound 138: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ2.36 (s, 3H), 3.
90 (s, 3H), 6.71 (d, J = 8.1Hz, 1H), 7.06 (d, J
= 8.1 Hz, 1H), 7.24 (d, J = 1.3 Hz, 1H), 7.31 (d
, J = 8.3 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.74
(S, 1H), 12.57 (br s, 1H). EI-MS m / z 357 ( M +), C 18 H 15 NO 3 S 2 = 357.

Example 159 Preparation of Compound 139 Compound 118 (0.33 g, 0.89 mmol) obtained in Example 145 was dissolved in dimethylformamide (15 mL), and potassium carbonate (0.12 g, 0.89 g) was added.
9 mmol) and benzyl bromide (0.13 mL, 1.1 mmol) were added and then stirred at room temperature for 10 hours. Then the usual work-up was carried out and the product was purified by thin layer chromatography (hexane / ethyl acetate = 8/1) to give compound 13
9 (0.077 g, 50%) was obtained.

Compound 139: ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.33 (s, 3H), 5.
37 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.31 (d, J
= 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.39 (m
, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 7.3)
Hz, 2H), 7.91 (dd, J = 1.8, 8.4 Hz, 1H), 7.96 (
s, 1H), 8.08 (d, J = 1.5 Hz, 1H), 12.76 (br s,
1H) EI-MS m / z 461 (M +), C 25 H 19 NO 4 S 2 = 461.

Example 160 Preparation of Compound 140 Using Compound 95 (0.1 g, 0.28 mmol), Example 96 (Compound 69)
Compound 140 (0.067 g, 64.0%) was obtained by using the same method as in (1).

Compound 140: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.34 (s, 3
H), 7.40 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.1 Hz)
, 2H), 7.80 (s, 1H), 8.09 (dd, J = 1.7, 8.4 Hz,
1H), 8.19 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 8.3H)
z, 1H), 12.80 (br s, 1H) FABMS m / z 369 (M + H) ⁺ C ₁₈ H ₁₂ N ₂ O ₃ S ₂ = 368.

Example 161 Preparation of Compound 141 Using Compound 109 (0.1 g, 0.28 mmol), Example 96 (Compound 6)
Compound 141 (0.094 g, 89.9%) was obtained by the same method as in (Synthesis of 9).

Compound 141: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3
H), 7.36 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.1 Hz)
, 2H), 7.76 (s, 1H), 7.79 (s, 1H), 7.82 (d, J =
8.3 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 12.77 (b
r s, 1H) FABMS m / z 377 (M-H) - C 17 H 12 35 ClNO 3 S 2 = 378.

Example 162 Preparation of Compound 142 3-Bromo-4-[(4-methylphenyl) thio] benzaldehyde (0.1 g, 0.33 mmol) obtained in Example 123 was dissolved in methanol (5 mL), p-Toluenesulfonic acid monohydrate (0.0006 g, 0.003 mmol)
And methyl orthoformate (0.035 mL, 0.33 mmol) were added and the product was heated to reflux for 3 hours. After the usual treatment, remove the solvent with a vacuum dryer,
And 3-bromo-4-[(4-methylphenyl) thio] benzaldehyde dimethyl acetal was obtained as a crude product.

5-Bromo-4-[(4-methylphenyl) thio] benzaldehyde 5- [Hydroxymethyl-2-[(4-methylphenyl) thio] in Example 123 was prepared using the entire crude product of dimethyl acetal. 3-Formyl-4-[(4-methylphenyl) thio] benzaldehyde dimethyl acetal (0.09 g, yield 90.3%) was obtained in the same manner as the synthesis of benzaldehyde.

3-formyl-4-[(4-methylphenyl) thio] benzaldehyde dimethyl acetal (0.2 g, 0.67 mmol) was used in Example 94 (Compound 67).
Compound 142 (0.21 g, 76.3%) was obtained in the same manner as described above.

3-Formyl-4-[(4-methylphenyl) thio] benzaldehyde dimethyl acetal: ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.39 (s, 3H)
, 3.32 (s, 6H), 5.39 (s, 1H), 6.99 (d, J = 8.3H)
z, 1H), 7.22 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 8.
3Hz, 2H), 7.43 (dd, J = 2.0, 8.3Hz, 1H), 7.94
(D, J = 2.0Hz, 1H ), 10.35 (s, 1H) FABMS m / z = 302 (M +), C 17 H 18 O 3 S = 302.

Compound 142: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3)
H), 3.27 (s, 6H), 5.44 (s, 1H), 7.26 (d, J = 2.
6 Hz, 4 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.54 (s, 1 H
), 8.04 (s, 1H) , 12.68 (br s, 1H) FABMS m / z 401 (M-H) - C 20 H 19 NO 4 S 2 = 402.

Example 163 Preparation of Compound 143 Using Compound 88 (0.07 g, 0.17 mmol), Example 96 (Compound 6)
Compound 143 (0.049 g, 69.4%) was obtained by using the same method as in (Synthesis of 9).

Compound 143: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.33 (s, 3)
H), 7.35 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.3 Hz)
, 2H), 7.79 (s, 1H), 7.86 (d, J = 8.4Hz, 1H), 7
． 91 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 12.76 (b
r s, 1H) FABMS m / z 422 (M ⁺ ) C ₁₇ H ₁₂ ⁷⁹ BrNO ₃ S ₂ = 422.

Example 164 Preparation of Compound 144 Compound 142 (0.17 g, 0.43 mmol) was added to dichloromethane (14 m
L) and methanol (2.6 mL), and a 1 mol / L hydrogen chloride aqueous solution (0.5 mL) was added. After heating at reflux for 2 hours, the product was cooled to room temperature and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane to give compound 144 (0.15 g, 98.2%).

Compound 144: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3
H), 7.12 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.3 Hz)
, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.3)
Hz, 1H), 7.95 (s, 1H), 7.97 (s, 1H), 9.97 (s,
1H), 12.78 (br s, 1H) FABMS m / z 356 (M + H) ⁺ C ₁₈ H ₁₃ NO ₃ S ₂ = 355.

Example 165 Preparation of Compound 145 Compound 144 (0.05 g, 0.14 mmol) was dissolved in chloroform (4 mL) and [(tert-butoxycarbonyl) methylene] triphenylphosphine (0.13 g, 0. 35 mmol) was added. After heating under reflux for 2 hours,
The product was cooled to room temperature and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: chloroform / acetonitrile = 18/1). Then, the product was recrystallized from ethyl acetate and hexane to obtain compound 145 (0.038 g, 59.8%).

Compound 145: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.48 (s, 9)
H), 2.33 (s, 3H), 6.49 (d, J = 16.1 Hz, 1H), 7.
08 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H),
7.35 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 16.1 Hz, 1
H), 7.69 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.9
5 (s, 1H), 12.70 (br s, 1H) FABMS m / z 453 (M-H) - C 24 H 23 NO 4 S 2 = 454.

Example 166 Preparation of Compound 146 Compound 145 (0.02 g, 0.04 mmol) was added to dichloromethane (4 mL).
, And trifluoroacetic acid (1 mL) was added, followed by stirring at room temperature for 1 hour. Then, the usual treatment was carried out, the solvent was evaporated under reduced pressure, and the residue was triturated with ethyl acetate to obtain a compound 146 (0.015 g, 87.5%).

Compound 146: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.50 (s, 3)
H), 6.51 (d, J = 16.0 Hz, 1H), 7.11 (d, J = 8.1H)
z, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.
1 Hz, 2 H), 7.60 (d, J = 16.0 Hz, 1 H), 7.70 (s, 1
H), 7.72 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 12.
50 (br s, 1H), 12.71 (br s, 1H) FABMS m / z 396 (M-H) - C 20 H 15 NO 4 S 2 = 397.

Example 167 Preparation of Compound 147 4-Fluoro-5- (trifluoromethyl) benzaldehyde (0.20 g,
1.0 mmol) was used and 4-[(4-methylphenyl) thio] -3- was prepared in the same manner as in the synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde.
(Trifluoromethyl) benzaldehyde (0.30 g, 100%) was obtained.

Using 4-[(4-methylphenyl) thio] -3- (trifluoromethyl) benzaldehyde (0.2 g, 0.7 mmol) and using the same method as in Example 94 (Synthesis of Compound 67). Compound 147 (0.13 g, 50.2%) was obtained.

4-[(4-Methylphenyl) thio] -3- (trifluoromethyl) benzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.43 (s, 3H)
, 7.01 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2
H), 7.46 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.4 Hz)
, 1H), 8.11 (s, 1H), 9.93 (s, 1H) FABMS m / z 296 (M +) C 15 H 11 F 3 OS = 296.

Compound 147: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3)
H), 7.08 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.1 Hz)
, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.4)
Hz, 1H), 7.82 (s, 1H), 8.02 (s, 1H), 12.68 (b
r s, 1H) FABMS m / z 395 (M ⁺ ) C ₁₈ H ₁₂ ¹⁹ F ₃ NO ₂ S ₂ = 395.

Example 168 Preparation of Compound 148 Compound 148 (0.047 g, 64.3%) was prepared using compound 147 (0.07 g, 0.18 mmol) in the same manner as in Example 96 (synthesis of compound 69). ) Got.

Compound 148: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.49 (s, 3)
H), 7.37 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.3 Hz)
, 2H), 7.93 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 8
． 11 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 12.80 (b
r s, 1H) FABMS m / z 412 (M + H) ⁺ C ₁₈ H ₁₂ ¹⁹ F ₃ NO ₃ S ₂ = 411.

Example 169 Preparation of Compound 149 5-Carboxy-2-[(4-methylphenyl) thio] benzaldehyde (0
． 10 g, 0.37 mmol) was used to carry out the same reaction as in Example 81 to give 5- (
N, N-diethylaminocarbonyl) -2-[(4-methylphenyl) thio] benzaldehyde (0.046 g, 36.7%) was obtained.

5- (N, N-diethylaminocarbonyl) -2-[(4-methylphenyl)
Example 9 using thio] benzaldehyde (0.046g, 0.13mmol)
Compound 149 (0.043 g, 76) using the same method as in 4 (Synthesis of Compound 67).
． 1%) was obtained.

5- (N, N-diethylaminocarbonyl) -2-[(4-methylphenyl)
Thio] benzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.19 (m, 3H)
, 1.53 (m, 4H), 2.41 (s, 3H), 6.98 (d, J = 8.3H)
z, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 2)
． 0, 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.86
(D, J = 2.0 Hz, 1 H), 10.35 (s, 1 H) FABMS m / z 328 (M + H) ⁺ C ₁₉ H ₂₁ NO ₂ S = 327.

Compound 149: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.1 (m, 6H
), 2.50 (s, 3H), 3.38 (m, 4H), 7.16 (d, J = 8.3).
Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8)
． 4 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.39 (s, 1
H), 7.97 (s, 1H ), 12.03 (br s, 1H) FABMS m / z 427 (M) + C 22 H 22 N 2 O 3 S 2 = 427.

Example 170 Preparation of Compound 150 Compound 150 (0.024 g, 26.2%) was prepared using compound 149 (0.09 g, 0.21 mmol) and the same method as in Example 96 (synthesis of compound 69). ) Got.

Compound 150: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.1 (m, 6H
), 2.29 (s, 3H), 2.49 (m, 4H), 7.31 (d, J = 8.4).
Hz, 2H), 7.40 (s, 1H), 7.46 (d, J = 8.1Hz, 2H)
, 7.63 (d, J = 7.9 Hz, 1H), 7.84 (s, 1H), 8.05 (
d, J = 8.1 Hz, 1 H), NH not found FABMS m / z 443 (M) ⁺ C ₂₂ H ₂₂ N ₂ O ₄ S ₂ = 443.

Example 171 Preparation of Compound 151 5-Carboxy-2-[(4-methylphenyl) thio] benzaldehyde (0
． 3 g, 1.1 mmol) and morpholine (0.19 mL, 2.2 mmol) in place of diethylamine, using the same method as in Example 81, 4
-{3-Formyl-4-[(4-methylphenyl) thio] benzoyl} -morpholine (0.092g, 24.4%) was obtained.

Example 94 (compound 67) was prepared using 4- {3-formyl-4-[(4-methylphenyl) thio] benzoyl} -morpholine (0.092 g, 0.27 mmol).
Compound 151 (0.066 g, 55.8%) was obtained by using the same method as in (1).

4- {3-formyl-4-[(4-methylphenyl) thio] benzoyl} -morpholine: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.41 (s, 3H)
, 2.89 (s, 4H), 2.97 (s, 4H), 6.97 (d, J = 8.3H)
z, 1H), 7.22 (m, 1H), 7.26 (d, J = 7.9Hz, 2H),
7.41 (d, J = 8.1Hz, 2H), 7.89 (d, J = 1.8Hz, 1H
), 10.34 (s, 1H) FABMS m / z 342 (M + H) ⁺ C ₁₉ H ₁₉ NO ₃ S = 341.

Compound 151: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.30 (s, 3
H), 3.40 (s, 4H), 3.60 (s, 4H), 7.13 (d, J = 8.
3 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.35 (d, J =
7.7 Hz, 2 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.92 (s,
1H), 8.29 (d, J = 3.9 Hz, 1H), 12.02 (br s, 1H)
) FABMS m / z 441 (M) ⁺ C ₂₂ H ₂₀ N ₂ O ₄ S ₂ = 441.

Example 172 Preparation of Compound 152 5-Bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol) was used in the same manner as in the synthesis of 5-acetyl-2-fluorobenzaldehyde in Example 124. Acetyl-4-fluorobenzaldehyde (0.38 g, 4
7.0%) was obtained.

3-Acetyl-4-fluorobenzaldehyde (0.38 g, 2.3 mmol)
) And 3,4-dichlorothiophenol instead of 4-methylthiophenol, similar to the synthesis of 5-bromo-2-[(4-methylphenyl) thio] benzaldehyde in Example 114. Acetyl-4-[(3,4-
Dichlorophenyl) thio] benzaldehyde (0.10 g, 13.7%) was obtained.

Using the same method as in Example 94 (Synthesis of Compound 67) using 3-acetyl-4-[(3,4-dichlorophenyl) thio] benzaldehyde (0.1 g, 0.32 mmol), Compound 152 ( 0.044 g, 32.5%) was obtained.

3-Acetyl-4-fluorobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.64 (s, 3H)
, 7.25 (dd, J = 8.4, 10.4 Hz, 1H), 8.01 (m, 1H)
, 8.35 (dd, J = 2.4, 7.1 Hz, 1H), 9.95 (s, 1H) CIMS m / z 167 (M + H) ⁺ C ₉ H ₇ FO ₂ = 166.

3-Acetyl-4-[(3,4-dichlorophenyl) thio] benzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.72 (s, 3H)
, 6.95 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 2.0, 8.
1 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.62 (d, J =
2.0 Hz, 1 H), 7.72 (dd, J = 1.8, 8.3 Hz, 1 H), 8.
35 (d, J = 1.8Hz, 1H), 9.95 (s, 1H) FABMS m / z 325 (M +) C 15 H 10 Cl 2 O 2 S = 325.

Compound 152: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.69 (s, 3
H), 6.96 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 2.0,
8.3 Hz, 1 H), 7.66 (dd, J = 1.8, 8.5 Hz, 1 H), 7.
74 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.86 (d, J
= 2.0Hz, 1H), 8.32 ( d, J = 1.8Hz, 1H), FABMS m / z 424 that are not found _{^{NH (M +) C 18 H}} 11 Cl 2 NO 3 S 2 = 424.

Example 173 Preparation of Compound 153 Compound 153 (0.094 g, 89.9%) was prepared using compound 152 (0.03 g, 0.071 mmol) in the same manner as in Example 96 (synthesis of compound 69). )
Got

Compound 153: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.50 (s, 3)
H), 7.65 (dd, J = 2.0, 8.3 Hz, 1H), 7.74 (d, J =
8.6 Hz, 1 H), 7.93 (d, J = 1.7 Hz, 1 H), 7.96 (s,
1H), 8.11 (dd, J = 1.8, 8.3 Hz, 1H), 8.43 (s, 1
H), 8.46 (d, J = 8.8 Hz, 1H), 12.77 (br s, 1H) FABMS m / z 440 (M ⁺ ) C ₁₈ H ₁₁ Cl ₂ NO ₄ S ₂ = 440.

Example 174 Preparation of Compound 154 5-Nitro-2-fluorobenzaldehyde (0.30 g, 1.77 mmol)
), And 2,3-dichlorothiophenol in place of p-toluenethiol, 5-bromo-2-[(4-methylphenyl) in Example 114.
Similar to the synthesis of thio] benzaldehyde, 2-[(2,3-dichlorophenyl)
Thio] -5-nitrobenzaldehyde (0.57 g, 97.9%) was obtained.

2-[(2,3-dichlorophenyl) thio] -5-nitrobenzaldehyde (
Compound 154 (0.088 g, 22.5%) was obtained by the same method as in Example 96 (synthesis of compound 69) using 0.3 g, 0.91 mmol).

2-[(2,3-Dichlorophenyl) thio] -5-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.91 (d, J = 8)
． 8 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.58 (dd,
J = 1.5, 7.7 Hz, 1H), 7.66 (dd, J = 1.7, 8.1 Hz,
1H), 8.19 (dd, J = 2.6, 8.9 Hz, 1H), 8.72 (d, J
= 2.6 Hz, 1H), 10.31 (s, 1H) FABMS m / z 328 (M ⁺ ) C ₁₃ H ₇ Cl ₂ NO ₃ S = 328.

Compound 153: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.25 (d, J
= 8.6 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.57 (s
, 1H), 7.81 (s, 1H), 7.92 (d, J = 2.0 Hz, 1H), 8
． 16 (dd, J = 2.4, 8.7 Hz, 1H), 8.30 (d, J = 2.4H
z, 1H), FABMS m / z 425 that are not found ^{NH (M-H) - C} 16 H 8 35 Cl 2 N 2 O 4 S 2 = 426.

Example 175 Preparation of Compound 155 5-Nitro-2-fluorobenzaldehyde (0.30 g, 1.77 mmol)
) And 2,4-dichlorothiophenol in place of p-toluenethiol, 5-bromo-2-[(4-methylphenyl) in Example 114.
Similar to the synthesis of thio] benzaldehyde, 2-[(2,4-dichlorophenyl)
Thio] -5-nitrobenzaldehyde (0.53 g, 91.7%) was obtained.

2-[(2,4-dichlorophenyl) thio] -5-nitrobenzaldehyde (
Compound 155 (0.13 g, 32.4%) was obtained by the same method as in Example 96 (synthesis of compound 69) using 0.3 g, 0.91 mmol).

2-[(2,4-Dichlorophenyl) thio] -5-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.86 (d, J = 8)
． 8 Hz, 1 H), 7.40 (dd, J = 2.2, 8.3 Hz, 1 H), 7.6
1 (s, 1H), 7.64 (t, J = 2.6 Hz, 1H), 8.17 (dd, J
= 2.6,8.8 Hz, 1H), 8.71 (d, J = 2.6 Hz, 1H), 10
． 30 (s, 1H) FABMS m / z 328 (M + H) ⁺ C ₁₃ H ₇ ³⁵ Cl ₂ NO ₃ S = 327.

Compound 155: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.38 (d, J
= 8.8 Hz, 1H), 7.41 (s, 1H), 7.43 (d, J = 1.3 Hz
, 1H), 7.75 (dd, J = 3.9, 5.7 Hz, 1H), 7.80 (s,
1H), 8.20 (dd, J = 2.4, 8.8 Hz, 1H), 8.32 (d, J
= 2.4Hz, 1H), FABMS m / z 425 that are not found ^{NH (M-H) - C} 16 H 8 35 Cl 2 N 2 O 4 S 2 = 426.

Example 176 Preparation of Compound 156 Compound 156 (0.016 g, 43.1%) was prepared using compound 154 (0.037 g, 0.085 mmol) in the same manner as in Example 96 (synthesis of compound 69).
) Got.

Compound 156: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.74 (dd,
J = 2.0, 8.4 Hz, 1H), 7.77 (s, 1H), 7.79 (s, 1H)
), 7.82 (t, J = 2.2 Hz, 1H), 8.00 (d, J = 8.6 Hz,
1H), 8.30 (dd, J = 2.2, 8.7 Hz, 1H), 8.42 (d, J
= 2.2Hz, 1H), FABMS m / z 441 that are not found ^{NH (M-H) - C} 16 H 8 35 Cl 2 N 2 O 5 S 2 = 442.

Example 177 Preparation of Compound 157 Compound 157 (0.030 g, 44.1%) was prepared using compound 155 (0.066 g, 0.15 mmol) in the same manner as in Example 96 (synthesis of compound 69). )
Got

Compound 157: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.67 (t, J
= 7.7 Hz, 1 H), 7.85 (d, J = 0.9 Hz, 1 H), 7.88 (s
, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 8
． 28 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H)
, FABMS m / z 441 that are not found ^{NH (M-H) - C} 16 H 8 35 Cl 2 N 2 O 5 S 2 = 442.

Example 178 Preparation of Compound 158 Compound 158 (0.0085 g, 26.4%) was prepared using compound 154 (0.03 g, 0.070 mmol) in the same manner as in Example 96 (synthesis of compound 69).
) Got.

Compound 158: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.19 (d, J
= 8.8 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.55 (s
, 1H), 7.70 (s, 1H), 7.92 (s, 1H), 8.11 (dd, J
= 2.6,8.8 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), NH
Not found.

Example 179 Preparation of Compound 159 Compound 159 (0.013 g, 38.9%) was prepared using compound 155 (0.03 g, 0.070 mmol) in the same manner as in Example 96 (synthesis of compound 69). )
Got

Compound 159: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.35 (d, J
= 8.8 Hz, 1H), 7.40 (s, 1H), 7.42 (d, J = 4.4 Hz)
, 1H), 7.75 (dd, J = 2.4, 6.7 Hz, 1H), 7.76 (s,
1H), 8.18 (dd, J = 2.6, 8.8 Hz, 1H), 8.35 (d, J
= 2.6 Hz, 1H), NH not found.

Example 180 Preparation of Compound 160 2-Fluoro-5-nitrobenzaldehyde (0.16 g, 0.95 mmol)
) Was dissolved in N, N-dimethylformamide (8.1 mL) and 4-mercaptophenol (0.11 g, 0.86 mmol) and triethylamine (0.
． 27 mL, 1.9 mmol) was added, and then the mixture was stirred at 25 ° C. for 1 hour. After the usual work-up, the product was purified by silica gel column chromatography (eluted with n-hexane / acetone = 4/1 to 1/1) to give 5-nitro-2-[(4-hydroxyphenyl) thio] benzaldehyde. (0.18 g, 70%) was obtained.

5-Nitro-2-[(4-hydroxyphenyl) thio] benzaldehyde (0
． 17 g, 0.61 mmol) in toluene (8.4 mL) and 2,
4-thiazolidinedione (0.29 mg, 2.4 mol), piperidine (0.0
24 mL, 0.24 mmol), acetic acid (0.014 mL, 0.24 mmol) and molecular sieves 4A (0.84 g) were added, and then the mixture was stirred at 110 ° C. for 2 hours. After the usual post-treatment, compound 160 (34 mg, 15%) was obtained by thin layer chromatography (developed with chloroform / methanol = 10/1).

5-Nitro-2-[(4-hydroxyphenyl) thio] benzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.97 (d, J = 9)
． 0 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 2 H), 7.40 (d, J
= 8.8 Hz, 2H), 8.06 (m, 1H), 8.61 (br s, 1H),
8.63 (d, J = 2.3 Hz, 1H), 10.29 (s, 1H).

Compound 160: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.94 (d, J
= 8.8 Hz, 3 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.87 (s
, 1H), 8.13 (dd, J = 2.4, 8.8 Hz, 1H), 8.20 (d,
J = 2.2 Hz, 1H), 10.20 (s, 1H), 12.86 (br s, 1)
H) FABMS m / z 373 ( M-H) - C 16 H 10 N 2 O 5 S 2 = 374.

Example 181 Preparation of Compound 161 Using the same method as Example 97, 3,4-dimethylbenzenethiol (0.1
6 mL, 1.2 mmol), 2.5 mol / L sodium hydroxide aqueous solution (2.
1 mL, 5.2 mmol), tetrabutylammonium bromide (0.020 g)
, 0.61 mmol) and 2-fluoro-5-nitrobenzaldehyde (0.
21 g, 1.2 mmol) of toluene solution (2.1 mL) to 2-[(3,4-
Dimethylphenyl) thio] -5-nitrobenzaldehyde (0.16 g, 45%
) Got.

2-[(3,4-dimethylphenyl) thio] -5-nitrobenzaldehyde (
0.16 g, 0.54 mmol), toluene (7.8 mL), 2,4-thiazolidinedione (0.26 g, 2.2 mmol), piperidine (0.022 mL, 0)
． Compound 161 (0.13 g, 64%) was obtained from 22 mmol), acetic acid (0.012 mL, 0.22 mmol) and Molecular Sieves 4A (0.78 g).

2-[(3,4-Dimethylphenyl) thio] -5-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 2.31 (s, 3H)
, 2.36 (s, 3H), 6.97 (d, J = 9.0Hz, 1H), 7.24-
7.36 (m, 3H), 8.09 (dd, J = 9.0, 2.5Hz, 1H), 8
． 67 (d, J = 2.6Hz, 1H), 10.31 (s, 1H) FABMS m / z 287 (M) + C 15 H 13 NO 3 S = 287.

Compound 169: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 2.25 (s, 3)
H), 2.28 (s, 3H), 7.06 (d, J = 9.0Hz, 1H), 7.3
3 (s, 2H), 7.40 (s, 1H), 7.88 (s, 1H), 8.15 (m
, 1H), 8.21 (m, 1H), 12.86 (br s, 1H) FABMS m / z 385 (M-H) - C 18 H 14 N 2 O 4 S 2 = 386.

Example 182 Preparation of Compound 162 Using the same method as Example 134, compound 72 (0.0) obtained in Example 56.
61 g, 0.14 mmol), dichloromethane (6.1 mL), methanol (1
． Compound 162 (0.60 mg, 0.9%) was obtained from 2 mL) and m-chloroperbenzoic acid (0.75 g, 2.1 mmol).

Compound 162: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.96 (d, J
= 8.4 Hz, 1H), 8.02 (dd, J = 8.7, 2.2 Hz, 1H), 8
． 17 (s, 1H), 8.28 (s, 1H), 8.32 (d, J = 2.2 Hz,
1H), 8.44 (d, J = 1.3 Hz, 2H).

Example 183 Preparation of Compound 163 Using the same method as Example 156, compound 81 (0.
Compound 163 from 10 g, 0.26 mmol), N, N-dimethylformamide (5.1 mL) and m-chloroperbenzoic acid (0.14 g, 0.82 mmol).
(0.034 g, 32%) was obtained.

Compound 163: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.58 (d, J
= 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 8.00 (s
, 1H), 8.30 (dd, J = 8.2, 1.4 Hz, 1H), 8.48 (d,
J = 8.2 Hz, 1H), 8.53 (d, J = 1.4 Hz, 1H), 12.83
(Br s, 1H) FABMS m / z 407 (M-H) - C 16 H 9 35 ClN 2 O 5 S 2 = 408.

Example 184 Preparation of Compound 164 2.5 mol in 4-ethylbenzenethiol (0.20 g, 1.2 mmol)
/ L Sodium hydroxide aqueous solution (2.0 mL, 4.9 mmol) and tetrabutylammonium bromide (0.019 g, 0.58 mmol) were added, and then the mixture was stirred at 25 ° C for 5 minutes. Toluene solution (2.0 mL) of 4-fluoro-3-nitrobenzaldehyde (0.20 g, 1.2 mmol) was added to the reaction solution, and then the mixture was stirred at 25 ° C. for 12 hours. After the usual post-treatment, the product was purified by silica gel column chromatography (eluted with chloroform) to obtain 4-[(4-ethylphenyl) thio] -3-nitrobenzaldehyde (0.25 g, 75%). .

4-[(4-ethylphenyl) thio] -3-nitrobenzaldehyde (0.2
5 g, 0.86 mmol) was dissolved in ethanol (9.9 mL) and 2,4
-Thiazolidinedione (0.40 g, 3.4 mmol) and piperidine (0.
(034 mL, 0.34 mmol) was added, and then the mixture was stirred at 80 ° C. for 7 hours. The precipitated crystals were collected by filtration to give compound 164 (0.061 g, 19%).

4-[(4-Ethylphenyl) thio] -3-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.31 (t, J = 7)
． 7 Hz, 3 H), 2.76 (q, J = 7.5 Hz, 2 H), 7.01 (d, J
= 8.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.50 (d
, J = 8.2 Hz, 2H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H)
, 8.69 (d, J = 1.6 Hz, 1H), 9.97 (s, 1H) FABMS m / z 287 (M) ⁺ C ₁₅ H ₁₃ NO ₃ S = 287.

Compound 164: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.24 (t, J
= 7.5 Hz, 3H), 2.70 (q, J = 7.3 Hz, 2H), 6.92 (d
, J = 8.6 Hz, 1 H), 7.08 (br s, 1 H), 7.43 (d, J =
8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.58 (s,
1H), 7.72 (dd, J = 8.6, 2.0 Hz, 1H), 8.44 (d, J
= 1.8Hz, 1H) FABMS m / z 385 (M-H) - C 18 H 14 N 2 O 4 S 2 = 386.

Example 185 Preparation of Compound 165 and Compound 166 Using the same method as Example 156, compound 164 (0) obtained in Example 184
． 052 g, 0.14 mmol), N, N-dimethylformamide (2.6 mL)
) And m-chloroperbenzoic acid (0.44 g, 1.3 mmol) from compound 16
5 (0.014 g, 26%) and compound 166 (0.016 g, 26%) were obtained.

Compound 165: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.13 (t, J
= 7.5 Hz, 3 H), 2.61 (q, J = 7.5 Hz, 2 H), 7.34 (d
, J = 8.3 Hz, 2H), 7.51-7.56 (m, 2H), 7.95 (s,
1H), 8.30 (dd, J = 8.4, 1.6 Hz, 1H), 8.48-8.5
2 (m, 2H), 12.87 (m, 1H) FABMS m / z 401 (M-H) - C 18 H 14 N 2 O 5 S 2 = 402.

Compound 166: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.19 (t, J
= 7.7 Hz, 3 H), 2.71 (q, J = 8.4 Hz, 2 H), 7.51-7
． 60 (m, 2H), 7.80 (s, 1H), 7.86-7.95 (m, 2H)
, 8.03 (dd, J = 8.8, 1.5 Hz, 1H), 8.21 (d, J = 1.
1 Hz, 1 H), 8.45 (d, J = 8.2 Hz, 1 H), 12.90 (m, 1
H) FABMS m / z 417 ( M-H) - C 18 H 14 N 2 O 6 S 2 = 418.

Example 186 Preparation of Compound 167 Using the same method as Example 184, 3,4-dichlorobenzenethiol (0.
13 mL, 1.0 mmol), 2.5 mol / L sodium hydroxide aqueous solution (1
． 8 mL, 4.4 mmol), tetrabutylammonium bromide (0.017)
g, 0.52 mmol) and 4-fluoro-3-nitrobenzaldehyde (0
． 18 g, 1.0 mmol) in toluene solution (1.8 mL) to 4-[(3,4
-Dichlorophenyl) thio] -3-nitrobenzaldehyde (0.29 g, 84
%) Was obtained.

4-[(3,4-dichlorophenyl) thio] -3-nitrobenzaldehyde (
0.40 g, 1.2 mmol), ethanol (16 mL), 2,4-thiazolidinedione (0.57 g, 4.9 mmol) and piperidine (0.048 mL,
Compound 167 (0.077 g, 15%) was obtained from 0.49 mmol).

4-[(3,4-Dichlorophenyl) thio] -3-nitrobenzaldehyde: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.03 (d, J = 8)
． 4 Hz, 1 H), 7.44 (dd, J = 8.3, 2.0 Hz, 1 H), 7.6
3 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7
． 88 (dd, J = 8.4, 1.8 Hz, 1H), 8.73 (d, J = 1.8H
z, 1H), 10.00 (s, 1H) FABMS m / z 328 (M + H) ⁺ C ₁₃ H ₇ ³⁵ Cl ₂ NO ₃ S = 327.

Compound 167: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.11 (d, J
= 8.6 Hz, 1H), 7.65 (dd, J = 8.3, 2.2 Hz, 1H), 7
． 77 (dd, J = 2.0, 8.6 Hz, 1H), 7.85 (d, J = 8.2H
z, 1H), 7.87 (s, 1H), 8.02 (d, J = 2.0Hz, 1H),
8.52 (d, J = 2.0Hz, 1H), 12.74 (br s, 1H) FABMS m / z 425 (M-H) - C 16 H 8 35 Cl 2 N 2 O 4 S 2 = 426 .

Example 187 Preparation of Compound 168 Using the same method as Example 156, compound 167 (0) obtained in Example 186
． 031 g, 0.073 mmol), N, N-dimethylformamide (1.6 m
L) and m-chloroperbenzoic acid (0.035 g, 0.10 mmol) gave compound 168 (0.017 g, 54%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.69 (m, 1
H), 7.78 (d, J = 8.5 Hz, 1H), 8.00 (s, 2H), 8.2
8 (d, J = 8.1 Hz, 1H), 8.48 (d, J = 8.9 Hz, 1H), 8
． 53 (s, 1H), 12.84 (br s, 1H) FABMS m / z 441 (M-H) - C 16 H 8 35 Cl 2 N 2 O 5 S 2 = 442.

Example 188 Preparation of Compound 169 and Compound 170 Using the same method as Example 156, compound 161 (0) obtained in Example 181.
． 10 g, 0.27 mmol), N, N-dimethylformamide (5.2 mL)
And m-chloroperbenzoic acid (0.46 g, 4.0 mmol) to give compound 169
(0.080 g, 75%) and compound 170 (2.5 mg, 2.3%) were obtained.

[0741] Compound 169: FABMS m / z 401 ( M-H) - C 18 H 14 N 2 O 5 S 2 = 402.

[0742] Compound 170: FABMS m / z 417 ( M-H) - C 18 H 14 N 2 O 6 S 2 = 418.

Example 189 N- (4-chlorophenyl) -4- (2,4-dioxo-thiazolidine-5-
Preparation of (ylidenemethyl) benzenesulfonamide

[0744]

[Chemical 58]

Step A: General Procedure 1. 5-Benzylidene-thiazolidine-2,4-dione was obtained following the general procedure 1 using benzaldehyde.

NMR (DMSO-d ₆ ): 7.75 (s, 1H), 7.6-7.4 (m, 5)
H) MS (ESI) 205. Found 204 (MH).

Step B. Preparation of 4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -benzenesulfonyl chloride To a flask charged with chlorosulfonic acid (10 eq) cooled in an ice bath was added.
5-Benzylidene-thiazolidine-2,4-dione was added. This solution at 0 ℃
Stir at 1 h, warm to room temperature, and stir overnight. The reaction was then carefully poured onto ice and the resulting precipitate filtered and air dried to give the pure product.

NMR (DMSO-d ₆ ): 7.72 (s, 1H), 7.66 (d, 2H),
7.51 (d, 2H) MS (ESI) 303. Found 302 (MH).

Step C. Sulfonylation reaction The sulfonyl chloride and 4-chloro-phenylamine are combined together at 60 ° C.
Stir in pyridine heated to room temperature for 12 hours. The solution was diluted with EtOAc,
Then, it was washed with a 10% NaHSO ₄ aqueous solution and then with a saturated NaCl aqueous solution. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give pure compound. MS (ESI) 394. Found 393 (MH).

Example 190 Preparation of 4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -Np-tolyl-benzenesulfonamide

[0751]

[Chemical 59]

4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -Np-tolyl-benzenesulfonamide was prepared from p-toluidine by the method of Example 189. MS (ESI) 374. Found 373 (MH).

Example 191 4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -N- (4-
Preparation of methoxy-phenyl) -benzenesulfonamide

[0754]

[Chemical 60]

4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -N- (4-
Methoxy-phenyl) -benzenesulfonamide was prepared from p-anisidine by the method of Example 189. MS (ESI) 390. Found 389 (MH).

Example 192 4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -N- (4-
Preparation of trifluoromethyl-phenyl) -benzenesulfonamide

[0757]

[Chemical formula 61]

4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -N- (4-
Trifluoromethyl-phenyl) -benzenesulfonamide was prepared from 4- (trifluoromethyl) aniline by the method of Example 189. MS (ESI) 428. Found 427 (MH).

Example 193 Preparation of 4,5-dichloro-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -phthalamic acid

[0760]

[Chemical formula 62]

Step A: Coupling of 2,4-thiazolidinedione (TZD) to aldehyde under acidic conditions 3-Nitrobenzaldehyde, TZD (1.25 eq), NaOAc (2 eq).
, And acetic anhydride (1 equivalent) were dissolved in acetic acid and heated to reflux for 12 hours.
The reaction was allowed to cool and the precipitate was collected, washed and air dried to give pure product. The filtrate was poured into water and the resulting precipitate was filtered to give an additional yield of product. MS (ESI) 250. Found 249 (MH).

Step B: Reduction of Nitro Group 5- (3-Nitro-benzylidene) -thiazolidine-2,4-dione was dissolved in a large amount of acetic acid. A small amount of methanol was added as needed to completely dissolve the starting material. The solution was warmed gently and iron powder (5 eq) was added. Four
After time, the mixture was filtered to remove iron, then diluted with an equal volume of water and extracted with EtOAc. The organic phase was concentrated under vacuum to give a brown solid. The residue was dissolved in methanol and impurities were removed by filtration. The filtrate was concentrated, and the resulting residue was triturated with hexane and collected by filtration to give the product. MS (ESI) 220. Found 219 (MH).

Step C: Condensation with Anhydride 5- (3-Amino-benzylidene) -thiazolidine-2,4-dione was reacted with TH
Dissolved in F and 4,5-dichlorophthalic anhydride and catalytic amount of DMAP
Was treated with the above solution. The solution was stirred for 8 hours then filtered and concentrated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was concentrated to an oil and triturated with hexane to give the product as a solid, which was collected by filtration. MS (ESI) 436. Found 435 (MH).

Example 194 Preparation of 3,6-dichloro-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -phthalamic acid

[0765]

[Chemical formula 63]

3,6-Dichloro-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -phthalamic acid was treated with 3% by the method of Example 193.
, 6-dichlorophthalic anhydride. MS (ESI) 436. Found 435 (MH).

Example 195 4-tert-butyl-N- [3- (2,4-dioxo-thiazolidine-5-
Preparation of ylidenemethyl) -phenyl] -phthalamic acid

[0768]

[Chemical 64]

4-tert-Butyl-N- [3- (2,4-dioxo-thiazolidine-5-
Ylidenemethyl) -phenyl] -phthalamic acid was prepared from 4-tert-butylphthalic anhydride by the method of Example 193 and the regioisomer (re
isolated as a 64:36 mixture of (Gioisomer). MS (ESI) 425. Found 423 (M-2H).

Example 196 Preparation of N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -3-hydroxy-phthalamic acid

[0771]

[Chemical 65]

N- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -3-hydroxy-phthalamic acid was treated with 3-N- by the method of Example 193.
Prepared from hydroxyphthalic anhydride to give an 80:20 mixture of regioisomers. MS (ESI) 384. Found 383 (MH).

Example 197 Preparation of 3- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -pyrazine-2-carboxylic acid

[0774]

[Chemical formula 66]

3- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -pyrazine-2-carboxylic acid was prepared according to the method of Example 193 to give 2,3-pyrazinedicarboxylic anhydride. Prepared from. MS (ESI) 370. Found 369 (MH).

Example 198 Preparation of 3- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -isonicotinic acid

[0777]

[Chemical formula 67]

3- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -isonicotinic acid was treated with pyridine- by the method of Example 193.
Prepared from 3,4-dicarboxylic anhydride as a 70:30 mixture of isomers. MS (ESI) 369. Found 368 (MH).

Example 199 Preparation of 3- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -pyridine-2-carboxylic acid

[0780]

[Chemical 68]

3- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenylcarbamoyl] -pyridine-2-carboxylic acid was prepared according to the method of Example 193 to give 2,3-pyridinedicarboxylic anhydride. And isolated as a mixture of isomers. MS (ESI) 369. Found 368 (MH).

Example 200 Preparation of 4- (4-chloro-benzenesulfonylamino) -N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -benzamide

[0783]

[Chemical 69]

Step A: Condensation with Acid Chloride The prepared 5- (3-amino-benzylidene) -thiazolidine-2,4-dione is dissolved in pyridine and 4-nitrobenzoyl chloride and a catalytic amount of DMAP. Processed. The reaction was stirred for 20 minutes, then the precipitate was collected by filtration. The solid was washed repeatedly with water, saturated aqueous NaHCO ₃ and 10% aqueous HCl. The resulting solid was air dried. MS (ESI) 369. Found 368 (MH).

Step B: Reduction of Nitro Group 4-Nitro-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -benzamide was suspended in isopropanol. A small amount of ammonium chloride dissolved in water was added and the mixture was heated to 70 ° C for several hours. Iron powder was added and stirring was continued for 4 hours. Solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic layer was concentrated to an oil and hexane was added to precipitate the product. MS (ESI) 339. Found 338 (MH).

Step C: Condensation with Sulfonyl Chloride 4-Amino-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -benzamide was dissolved in pyridine and 4 in pyridine. Treated with -chloro-benzenesulfonyl chloride at 60 ° C for 12 hours. The solution was cooled and diluted with EtOAc, then washed with 10% aqueous NaHSO ₄ solution followed by saturated aqueous NaCl solution. The organic phase was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give an oil. Trituration with hexane gave pure product. MS (ESI) 513. Found 512 (MH).

Example 201 Preparation of N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (toluene-4-sulfonylamino) -benzamide

[0788]

[Chemical 70]

N- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (toluene-4-sulfonylamino) -benzamide was prepared according to Example 20.
Prepared from p-toluenesulfonyl chloride by method 0. MS (ESI) 493. Found 492 (M-H).

Example 202 Preparation of N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (4-methoxy-benzenesulfonylamino) -benzamide

[0791]

[Chemical 71]

N- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (4-methoxy-benzenesulfonylamino) -benzamide was treated with 4-methoxy by the method of Example 200. Prepared from benzenesulfonyl chloride. MS (ESI) 509. Found 508 (MH).

Example 203 Preparation of N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (4-trifluoromethoxy-benzenesulfonylamino) -benzamide

[0794]

[Chemical 72]

N- [3- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -4- (4-trifluoromethoxy-benzenesulfonylamino) -benzamide was treated with 4 by the method of Example 200. Prepared from-(trifluoromethoxy) benzenesulfonyl chloride. MS (ESI) 563. Found 562 (MH).

Example 204 Preparation of 4-benzenesulfonylamino-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -benzamide

[0797]

[Chemical formula 73]

4-Benzenesulfonylamino-N- [3- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenyl] -benzamide was prepared from benzenesulfonyl chloride by the method of Example 200. MS (ESI) 479. Found 478 (MH).

Example 205 Preparation of N- (4-chloro-phenyl) -4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonamide

[0800]

[Chemical 74]

Step A: Preparation of 4-phenoxy-benzaldehyde A suspension of potassium carbonate (1 eq), 4-flurobenzaldehyde and phenol (1.2 eq) is heated to 150 ° C and stirred for 2 days. did. The reaction was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate solution and ice. The solution was extracted with ether. The combined organic layers were washed with water and dried over Na ₂ SO ₄ . Concentration under reduced pressure gave the pure product as an orange oil.

Step B: Condensation with TZD to give 5- (4-phenoxy-benzylidene) -thiazolidine-2,4-dione 4-phenoxy-benzaldehyde, TZD (1.5 eq) and piperidine (2 eq). Solution of EtOH in EtOH was heated to 70 ° C. and stirred overnight. The reaction was cooled to room temperature and poured into 10% aqueous HCl solution. The resulting precipitate was filtered, washed with water and air dried. MS (ESI) 297. Found 296 (MH).

Step C: Chlorosulfonylation to give 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonyl chloride 5- (4-phenoxy-benzylidene) -thiazolidine- 2,4-dione,
It was dissolved in chlorosulfonic acid and stirred at 0 ° C. for 30 minutes. The solution was then poured onto ice and the precipitate collected by filtration and air dried to give the crude product. MS (ESI) 395. Found 394 (MH).

Step D: Condensation with 4-chloroaniline to give sulfonamide 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonyl chloride and 4-chloroaniline ( 1.1 eq.) Solution was stirred in pyridine with gentle warming. The pyridine was then removed under vacuum and the residue was dissolved in EtOAc. Organic phase is 10% HC
1 aqueous solution, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution and then concentrated in vacuo. The resulting residue was triturated with hexane to give a pure product. MS (ESI) 486. Found 485 (MH).

Example 206 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -Np-tolyl-benzenesulfonamide

[0806]

[Chemical 75]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -Np-tolyl-benzenesulfonamide was prepared from p-toluidine by the method of Example 205. MS (ESI) 466. Found 465 (MH).

Example 207 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-trifluoromethoxy-phenyl) -benzenesulfonamide

[0809]

[Chemical 76]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-trifluoromethoxy-phenyl) -benzenesulfonamide was converted to 4 by the method of Example 205. Prepared from-(trifluoromethoxy) aniline. MS (ESI) 536. Found 535 (MH).

Example 208 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-methoxy-phenyl) -benzenesulfonamide

[0812]

[Chemical 77]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-methoxy-phenyl) -benzenesulfonamide was treated with p-anisidine by the method of Example 205. Prepared from. MS (ESI) 482. Found 481 (MH).

Example 209 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N-phenyl-benzenesulfonamide

[0815]

[Chemical 78]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N-phenyl-benzenesulfonamide was prepared from aniline by the method of Example 205. MS (ESI) 452. Found 451 (MH).

Example 210 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (3,4,5-trimethoxy-phenyl) -benzenesulfonamide

[0818]

[Chemical 79]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (3,4,5-trimethoxy-phenyl) -benzenesulfonamide was prepared by the method of Example 205. , 3,4,5-trimethoxyaniline. MS (ESI) 542. Found 541 (MH).

Example 211 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-morpholin-4-yl-phenyl) -benzenesulfonamide

[0821]

[Chemical 80]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-morpholin-4-yl-phenyl) -benzenesulfonamide was prepared by the method of Example 205. , 4-morpholinoaniline. MS (ESI) 537. Found 536 (MH).

Example 212 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-isopropyl-phenyl) -benzenesulfonamide

[0824]

[Chemical 81]

4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-isopropyl-phenyl) -benzenesulfonamide
Prepared from 4-isopropylaniline by the method of Example 205. MS (ESI) 494. Found 493 (MH).

Example 213 Preparation of N- (2-chloro-phenyl) -4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonamide

[0827]

[Chemical formula 82]

N- (2-Chloro-phenyl) -4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] benzenesulfonamide was prepared as in Example 2.
Prepared from 2-chloroaniline by method 05. MS (ESI) 486. Found 485 (MH).

Example 214 Preparation of N- (3-chloro-phenyl) -4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] benzenesulfonamide

[0830]

[Chemical 83]

N- (3-Chloro-phenyl) -4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonamide was treated with 3-chloro by the method of Example 205. Prepared from aniline. MS (ESI) 486. Found 485 (MH).

Example 215 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-hydroxy-phenyl) -benzenesulfonamide

[0833]

[Chemical 84]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (4-hydroxy-phenyl) -benzenesulfonamide was treated with 4-amino by the method of Example 205. Prepared from phenol. MS (ESI) 468. Found 467 (MH).

Example 216 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (2-hydroxy-phenyl) benzenesulfonamide

[0836]

[Chemical 85]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (2-hydroxy-phenyl) benzenesulfonamide was treated with 2-aminophenol by the method of Example 205. Prepared from. MS (ESI) 468. Found 467 (MH).

Example 217 N- (2-tert-butyl-phenyl) -4- [4- (2,4-dioxo-
Preparation of thiazolidine-5-ylidenemethyl) -phenoxy] benzenesulfonamide

[0839]

[Chemical 86]

N- (2-tert-butyl-phenyl) -4- [4- (2,4-dioxo-
Thiazolidine-5-ylidenemethyl) -phenoxy] -benzenesulfonamide was prepared from 2-tert-butylaniline by the method of Example 205.
MS (ESI) 508. Found 507 (MH).

Example 218 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N-isopropyl-N-phenyl-benzenesulfonamide

[0842]

[Chemical 87]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N-isopropyl-N-phenyl-benzenesulfonamide was prepared from N-isopropylaniline by the method of Example 205. Prepared. MS (ESI) 494. Found 493 (MH).

Example 219 Preparation of 4- [4- (2,4-dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (3-hydroxy-phenyl) -benzenesulfonamide

[0845]

[Chemical 88]

4- [4- (2,4-Dioxo-thiazolidine-5-ylidenemethyl) -phenoxy] -N- (3-hydroxy-phenyl) -benzenesulfonamide was treated with 3-amino by the method of Example 205. Prepared from phenol. MS (ESI) 468. Found 467 (MH).

Example 220 5- [2- (3,4-dichloro-benzylsulfanyl) -pyrimidine-4-
Preparation of Ilmethyl] -2-thioxo-thiazolidin-4-one

[0848]

[Chemical 89]

Step A: Alkylation of Pyrimidine Thiol with Benzyl Halide To a suspension of sodium salt of 4-dimethoxymethyl-pyrimidine-2-thiol in potassium carbonate (2 eq) in DMF was added α, 3,4-. Trichlorotoluene (1 eq) was added. The suspension was stirred for 2 days. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, aqueous sodium chloride solution, dried over MgSO _4, and concentrated in vacuo.

Step B: Deprotection of Acetal 2- (3,4-Dichloro-benzylsulfanyl) -4-dimethoxymethyl-
A suspension of pyrimidine in concentrated HCl was refluxed for 5 minutes. The reaction was cooled and poured into water.

Saturated aqueous sodium bicarbonate solution was added and the neutralized solution was extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum to give the product.

Step C: Condensation with Rhodanine Rhodanine (1 eq), ethylenediamine diacetate (1 eq) and 2- (
A solution of 3,4-dichloro-benzylsulfanyl) -pyrimidine-4-carbaldehyde in methanol was stirred and refluxed for 1 hour. The resulting precipitate was collected by filtration and washed with methanol, water, aqueous sodium bisulfate solution and aqueous sodium bicarbonate solution. The solid was air dried.

Step D: Reduction of Double Bond 5- [2- (3,4-Dichloro-benzylsulfanyl) -pyrimidine-4-
A suspension of ylmethylene] -2-thioxo-thiazolidin-4-one in toluene was added to 2,6-dimethyl-1,4-dihydro-3,5-pyridinecarboxylate (
1.1 eq) and activated silica gel in the presence of 80 ° C. The suspension was filtered and rinsed with EtOAc. The filtrate is evaporated under vacuum,
The resulting residue was then redissolved in EtOAc and washed with 1N aq HCl. The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give crude product. Flash chromatography gave pure product. MS (ESI) 415. Found 414 (MH).

Example 221 5- [3-amino-2- (2,4-dichloro-benzoyl) -thieno [2,3]
-B] Pyridin-6-ylmethylene] -thiazolidine-2,4-dione

[0855]

[Chemical 90]

Step A: Alkylation and cyclization of 6-dimethoxymethyl-2-mercapto-nicotinonitrile A mixture of 6-dimethoxymethyl-2-mercapto-nicotinonitrile and potassium carbonate (1.52 equivalents) is added to 2 , 4-dibromoacetophenone (aceto)
phenone) (3.1 eq) and stirred overnight. The alkylated and cyclized product was isolated as a solid precipitate.

Step B: Deprotection of Acetal (3-Amino-6-dimethoxymethyl-thieno [2,3-b] pyridine-2-
Yl) - (2,4-dichloro - phenyl) methanone of TFA and H ₂ O solution in a mixture of the reaction to be completed up indicated TLC, was stirred at room temperature. The reaction was neutralized with chilled aqueous NaHCO ₃ solution and extracted with EtOAc. The organic layer was washed with aqueous sodium chloride solution, then partially concentrated under vacuum and stored at 0 ° C. overnight. The resulting precipitate was collected and the product was obtained as a pure yellow powder.

Step C: Condensation with TZD The aldehyde was heated with TZD and piperidine in ethanol for 3 days at 90 ° C. The reaction was allowed to cool then poured into 10% aqueous HCl. The pure product was isolated by filtration as a yellow solid. MS (ESI) 449. Found 448 (MH).

Example 222 2-Chloro-3- (2,4-dioxothiazolidine-5-ylidene-methyl)
Preparation of quinoline

[0860]

[Chemical Formula 91]

Step A: Coupling of 2,4-thiazolidinedione (TZD) to an aldehyde under basic conditions 2-Chloro-3-quinolinecarboxaldehyde (carboxaldehy)
de), TZD (1.5 eq), piperidine (1.5 eq) were dissolved in ethanol and heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and poured into ethanol, 1N HCl was added, and a yellow precipitate was collected, washed with ether several times and air dried at room temperature for 24 hours to give pure product. (Yield-45%).

¹ H NMR (DMSO-d ₆ ) δ: 12.8 (br.s, 1H, NH), 8.
5 (s, 1H), 8.2 (d, 1H), 8.0-7.8 (m, 3H), 7.7 (
t, 1H). MS (ESI) 290. Found 289 (M-H). HPLC: 92% purity.

Example 223 Preparation of 2-phenylthio-3- (2,4-dioxothiazolidine-5-ylidene-methyl) quinoline

[0864]

[Chemical Formula 92]

Step A: 2-Chloro-3- (2,4-dioxothiazolidine-5-ylidene-]
Methyl) quinoline and thiophenol (1.2 eq) were mixed with ethoxyethanol and heated to reflux under N ₂ for 2 hours. The reaction mixture was allowed to cool to room temperature, ether was added and the light yellow precipitate was filtered off, washed several times with ether,
Air dried at room temperature for 24 hours to give pure product (36% yield).

¹ H NMR (DMSO-d ₆ ) δ (br.s, 1H, NH), 8.3 (s, 1)
H); 8.1 (d, 1H), 7.7 (t, 1H), 7.6-7.5 (m, 4H).
, 7.5-7.4 (m, 3H) MS (ESI) 364. Found 363 (MH). HPLC: 88% purity.

Example 224 2- (4-chlorophenylthio) -3- (2,4-dioxothiazolidine-5
Preparation of -ylidene-methyl) quinoline

[0868]

[Chemical formula 93]

[0869]   The title compound was prepared by the method of Example 223. Yield-69%.

¹ H NMR (DMSO-d ₆ ) δ12.8 (br, s, 1H, NH), 8.3
(S, 1H), 8.00 (d, 2H), 7.9 (s, 1H), 7.7 (t, 1H)
), 7.6-7.4 (m, 6H). MS (ESI) 398. Found 397 (M-H); 399 (M + H). HPL
C: 92% purity.

Example 225 Preparation of 2- (3,4-dichlorophenylthio) -3- (2,4-dioxothiazolidine-5-ylidene-methyl) quinoline

[0872]

[Chemical 94]

The title compound was prepared by the method of Example 223 using ethanol as the solvent. Yield-72%. ¹ H NMR (DMSO-d ₆ ) δ12.8 (br.s, 1H, NH), 8.3
4 (s, 1H), 8.05 (d, 1H, J = 8), 7.87 (d, 1H, J = 1)
． 6), 7.83 (s, 1H), 7.71-7.53 (m, 6H). MS (ESI) 433. Found 431; 432; 433 (M-H). 433;
435; 436 (M + H), HPLC: 96% purity.

Example 226 2- (4-fluorophenylthio) -3- (2,4-dioxothiazolidine-
Preparation of 5-ylidene-methyl) quinoline

[0875]

[Chemical 95]

The title compound was prepared by the method of Example 223. Yield-23%. ¹ H NMR (DMSO-d ₆ ) δ12.6 (br.s, 1H, NH), 8.3
(S, 1H), 8.00 (d, 1H), 7.9 (s, 1H), 7.7-7.4 (
m, 5H), 7.3 (t, 2H). MS (ESI) 382. Found 381 (MH). HPLC: 100% purity.

Example 227 2- (4-methylphenylthio) -3- (2,4-dioxothiazolidine-5
Preparation of -ylidene-methyl) quinoline The title compound was prepared by the method of Example 223. Yield -24%.

¹ H NMR (DMSO-d ₆ ) δ12.8 (br.s, 1H, NH), 8.3
(S, 1H), 8.00 (d, 1H), 7.9 (s, 1H), 7.7 (t, 1H)
), 7.6-7.5 (m, 2H), 7.4 (d, 2H), 7.3 (d, 2H),
2.1 (s, 3H). MS (ESI) 378. Found 377 (MH). HPLC: 86% purity.

Example 228 2- (4-methoxyphenylthio) -3- (2,4-dioxothiazolidine-
Preparation of 5-ylidene-methyl) quinoline

[0880]

[Chemical 96]

[0881]   The title compound was prepared by the method of Example 223. Yield-35%.

¹ H NMR (DMSO-d ₆ ) δ 12.8 (br.s, 1H, NH), 8.2
(S, 1H), 8.0 (d, 1H), 7.9 (s, 1H), 7.8-7.4 (m
, 5H), 7.0 (d, 2H), 3.8 (s, 3H). MS (ESI) 394. Found 393 (MH). HPLC: 98% purity.

Example 229 Preparation of 2- [4-trifluoromethylphenylthio] -3- (2,4-dioxothiazolidine-5-ylidene-methyl) quinoline

[0884]

[Chemical 97]

The title compound was prepared by the method of Example 223. Yield-55% ¹ H NMR (DMSO-d ₆ ) δ 12.8 (br.s.1H, NH), 8.3.
(S, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 7.8-7.6 (m
, 5H), 7.5 (t, 2H) MS (ESI) 432. Found 431 (MH). HPLC: 100% purity.

Example 230 Preparation of 2- (4-chlorophenylsulfinyl) -3- (2,4-dioxothiazolidine-5-ylidene-methyl) quinoline

[0887]

[Chemical 98]

Step A. The compound prepared in Example 224 was dissolved in CH ₂ Cl ₂ / CH ₃ OH (5: 1) and to this solution was added 3-chloroperoxybenzoic acid (2 equivalents of 77% pure). Was added. The mixture was stirred at room temperature for 4 hours before TLC analysis showed the disappearance of the starting compound. The reaction mixture was stirred for another 2 hours. At the end of the reaction, a white crystalline product precipitated. The product was collected by filtration, washed several times with ether and air dried for 48 hours to give the final product in 30% yield.

¹ H NMR (DMSO-d ₆ ) δ 12.8 (br.s, 1H, NH), 8.5
(S, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H)
, 7.9 (t, 1H), 7.7 (t, 1H), 7.6-7.4 (m, 4H). MS (ESI) 414. Found 413 (M-H); 415 (M + H). HPL
C: 100% purity.

Reference Example 1 Preparation of Compound 122 Compound 5 (23 mg, 0.056 mmol) obtained in Example 5 was treated with dimethyl sulfoxide (2.0 mL) and 0.04 mol / L disodium hydrogen phosphate-.
It is dissolved in potassium dihydrogen phosphate buffer (pH 7.2) (4.1 mL), 2-mercaptoethanol (0.012 mL, 0.17 mmol) is added, and the solution is added at 25 ° C. to 40
Stir for minutes. After the usual post-treatment, the product was purified by thin layer chromatography (developed with chloroform / methanol = 10/1) to obtain a crude product. This is further collected by HPL
C [ODS column, eluted with acetonitrile / disodium hydrogen phosphate-potassium dihydrogen phosphate buffer (0.04 mol / L, pH 7.2) = 30/70], and compound 122 (5.7 mg, 31) %) Was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.26-3.3
9 (m, 2H), 3.65-3.73 (m, 2H), 5.12 (m, 1H), 7
． 73 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 8.16-8.
24 (m, 2H), 12.80 (m, 1H) FABMS m / z 325 (M-H) - C 12 H 10 N 2 O 5 S 2 = 326.

Reference Example 2 Preparation of Compound 123 2-Fluoro-5-nitrobenzaldehyde (48 mg, 0.28 mmol)
Dissolved in N, N-dimethylformamide (2.4 mL), di-n-propylamine (0.15 mL, 1.1 mmol) and potassium carbonate (0.16 g, 1.1).
mmol) was added and the mixture was stirred at 25 ° C. for 1 hour. After the usual post-treatment, the residue was purified by silica gel chromatography (eluted with chloroform) to obtain 2- (N, N-di-n-propylamino) -5-nitroaldehyde (49 mg, 69%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 0.89 (t, J = 7)
． 6 Hz, 6 H), 1.66 (tq, J = 7.6, 7.6 Hz, 4 H), 3.3
8 (m, 4H), 7.03 (d, J = 9.1 Hz, 1H), 8.21 (dd, J
= 9.1, 2.7 Hz, 1H), 8.60 (d, J = 3.0 Hz, 1H), 10
． 01 (s, 1H) FABMS m / z 251 (M + H) + C 13 H 18 O 3 N 2 = 250.

2- (N, N-di-n-propylamino) -5-nitrobenzaldehyde (4
6 mg, 0.18 mmol) was dissolved in ethanol (1.8 mL) and 2,4-thiazolidinedione (86 mg, 0.74 mmol) and piperidine (0.00
(73 mL, 0.073 mmol) was added, and the mixture was stirred at 80 ° C for 1 hr. After ordinary post-treatment, thin-layer column chromatography (chloroform / acetonitrile = 10 /
The compound 123 (53 mg, 82%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 0.81 (t, J
= 7.3 Hz, 6H), 1.48-1.61 (m, 4H), 3.21 (t, J =
7.2 Hz, 4 H), 7.24 (d, J = 9.4 Hz, 1 H), 7.62 (s,
1H), 8.13 (m, 1H), 8.20 (m, 1H), 12.63 (br s)
, 1H) FABMS m / z 348 (M-H) - C 16 H 19 O 4 N 3 S = 349.

Reference Example 3 Preparation of Compound 124 2-Fluoro-5-nitrobenzaldehyde (0.11 g, 0.63 mmol)
) Was dissolved in ethanol (4.2 mL), and 2,4-thiazolidinedione (0.2
9 g, 2.5 mmol) and piperidine (0.025 mL, 0.25 mmol)
) Was added and the mixture was stirred at 80 ° C. for 6.5 hours. After the usual post-treatment, the residue was purified by thin layer column chromatography (eluted with chloroform / acetonitrile = 10/1) to obtain Compound 124 (24 mg, 12%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.57-1.7
2 (m, 6H), 3.08-3.14 (m, 4H), 7.26 (d, J = 8.6
Hz, 1H), 7.65 (s, 1H), 8.20 (m, 1H), 8.21 (s,
1H), 12.66 (m, 1H ) m / z 332 (M-H) - C 15 H 15 N 3 O 4
S = 333.

Reference Example 4 Preparation of Compound 125 Commercially available (MAYBRIDGE, catalog number: RH01290) 2-morpholino-5-nitrobenzaldehyde (0.11 g, 0.44 mmol) was dissolved in ethanol (4.2 mL), and 2 , 4-thiazolidinedione (0.21 g, 1.
8 mmol) and piperidine (0.018 mL, 0.18 mmol),
The mixture was stirred at 80 ° C for 6 hours. The reaction solution was cooled to 25 ° C., and the precipitated crystals were collected by filtration to give compound 125 (0.12 g, 82%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.10-3.1
6 (m, 4H), 3.73-3.80 (m, 4H), 7.30 (m, 1H), 7
． 67 (brs, 1H), 8.221-8.28 (m, 2H), 12.65 (
m, 1H) FABMS m / z 334 (M-H) - C 14 H 13 N 3 O 5 S = 335.

Reference Example 5 Preparation of Compound 126 In the same manner as in Reference Example 4, 4-hydroxy-2-methoxybenzaldehyde (71 m
g, 0.47 mmol), ethanol (2.8 mL), 2,4-thiazolidinedione (0.22 g, 1.9 mmol) and piperidine (0.019 mL, 0.
Compound 126 (85 mg, 73%) was obtained from 19 mmol).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 3.82 (s, 3)
H), 6.51 (s, 1H), 6.53 (dd, J = 11.7, 2.2 Hz, 1
H), 7.25 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 10.
39 (s, 1H), 12.38 (br s, 1H) FABMS m / z 250 (M-H) - C 11 H 9 NO 4 S = 251.

Reference Example 6 Preparation of Compound 127 In the same manner as in Reference Example 3, 2-trifluoromethoxybenzaldehyde (73 mg,
0.38 mmol), ethanol (2.9 mL), 2,4-thiazolidinedione (0.18 g, 1.5 mmol) and piperidine (0.015 mL, 0.15).
Compound 127 (53 mg, 47%) was obtained from (mmol).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.53 to 7.6
8 (m, 4H), 7.80 (s, 1H) FABMS m / z 288 (M-H) - C 11 H 6 19 F 3 NO 3 S = 289.

Reference Example 7 Preparation of Compound 128 10-[(4-chlorophenyl) thio] anthracene-9 was prepared in the same manner as in Reference Example 4.
-Carboxaldehyde (0.13 g, 0.38 mmol), ethanol (5.4 m
L), 2,4-thiazolidinedione (0.18 g, 1.5 mmol) and piperidine (0.015 mL, 0.15 mmol) to compound 126 (34 mg, 2).
0%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 6.92 (d, J
= 8.6 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.64-7
． 77 (m, 4H), 8.18 (d, J = 7.9 Hz, 2H), 8.65 (s,
1H), 8.78 (d, J = 8.1Hz, 2H), 12.68 (m, 1H) FABMS m / z 446 (M-H) - C 24 H 14 35 ClNO 2 S 2 = 447.

Reference Example 8 Preparation of Compound 171 2-naphthalenethiol (0.20 g, 1.2 mmol) was added to 2.5 mol / L aqueous sodium hydroxide solution (2.1 mL, 5.2 mmol) and tetrabutylammonium bromide (0. 020 g, 0.061 mmol) was added, and the mixture was stirred at 25 ° C. for 15 minutes. 2-Fluoro-5-nitrobenzaldehyde (0.
21 g, 1.2 mmol) in toluene (2.1 mL) was added, and the mixture was added at 110 ° C.
． Stir for 5 hours. After usual treatment, 2-[(2-formyl-4-nitrophenyl) thio] naphthalene was obtained. 2-[(2-formyl-4-nitrophenyl) thio] naphthalene (0.30 g, 0.98 mmol) was dissolved in toluene (15 mL) to prepare 2,4-thiazolidinedione (0.46 g, 3.9 mmol), Piperidine (0.039mL, 0.39mmol), acetic acid (0.022mL, 0.39m
mol) and molecular sieves 4A (1.5 g) were added, and the mixture was heated at 110 ° C. for 2.
Stir for 5 hours. After the usual post-treatment, tritylation was performed using ethanol to obtain Compound 171 (0.13 g, yield 33%).

2-[(2-formyl-4-nitrophenyl) thio] naphthalene: ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 6.99 (d, J = 8)
． 8 Hz, 1 H), 7.52 (dd, J = 8.4, 1.7 Hz, 1 H), 7.5
6-7.68 (m, 2H), 7.85-7.98 (m, 3H), 8.05 (dd
, J = 2.4, 8.8 Hz, 1H), 8.15 (s, 1H), 8.68 (d, J
= 2.4 Hz, 1H), 10.33 (s, 1H) FABMS m / z 310 (M + H) ⁺ C ₁₇ H ₁₁ NO ₃ S = 309.

Compound 171: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.19 (d, J
= 8.8 Hz, 1H), 7.57 (br d, J = 8.5 Hz, 1H), 7.5
9-7.68 (m, 2H), 7.95 (s, 1H), 7.97-8.04 (m,
2H), 8.08 (d, J = 8.8 Hz, 1H), 8.13 (dd, J = 8.4)
, 1.8 Hz, 1 H), 8.28 (br s, 2 H), 12.82 (m, 1 H) FABMS m / z 407 (MH) ⁺ C ₂₀ H ₁₂ N ₂ O ₄ S ₂ = 464.

Example 231 (Preparation of Affinity Purified Extract) The extract used for the screening of telomerase inhibitors was routinely prepared from 293 cells overexpressing the protein catalytic subunit of telomerase (hTERT). These cells were found to have 2-5 fold greater telomerase activity than the parental 293 cell line. 200 ml packed (p
acked) cells (recovered from about 100 liters of culture) were treated with an equal volume of hypotonic buffer (10 mM Hepes pH 7.9, 1 mM MgCl ₂ , 1 mM).
Resuspended in DTT, 20 mM KCl, 1 mM PMSF) and lysed using a Dounce homogenizer. The glycerol concentration was adjusted to 10% and NaCl was added slowly to a final concentration of 0.3M. 3 lysed cells
Stir for 0 minutes and then pellet at 100,000 xg for 1 hour. Solid ammonium sulfate was added to the S100 supernatant and brought to 42% saturation. The material is centrifuged; the pellet is resuspended in the original 1/5 volume and 50 mM
It was dialyzed against buffer "A" containing NaCl. After dialysis, add this extract to 25,
Centrifuged at 000 × g for 30 minutes. Triton X-100 (0.5%), KCl (0.3M) and tRNA prior to affinity chromatography.
(50 μg / ml) was added. Affinity oligo (5 'biotin TEG-
Biotin TEG-Biotin TEG-GTA GAC CTG TTA CCA
Guu agg gu ag 3 '; lowercase letters represent 2'O-methylribonucleotides, uppercase letters represent deoxyribonucleotides) and this extract (10m
1 nmol / l extract). After incubation for 10 minutes at 30 ° C., Neutravidin beads (Pierce; 250 μl of 5
0% suspension) was added and the mixture was spun at 4 ° C. overnight. Pellet these beads and buffer with buffer "B" containing 0.3 M KCl three times.
It was washed twice with buffer "B" containing 6M KCl and twice more with buffer B containing 0.3M KCl. Telomerase was added to 0.3M KCl, 0.15% T
Ritton X-100 and a 2.5 molar excess of substituted oligo (125
0.5 ml of 5'-C per μl of packed Neutravidin beads
TA ACC CTA ACT GGT AAC AGG TCT AC-3 '
) For 30 minutes at room temperature. A second elution was performed and pooled with the first. Purified extracts typically had uptake of 10 fmol nucleotides / min / μl extract, or a specific activity of 200 nucleotides / min / mg total protein.

[0910]

[Chemical 99]

Example 232 (Determination of Telomerase Specific Activity) Three separate 100 μl telomerase assays are set up with the following buffer solutions: 50 mM Tris Acetate, pH 8.2, 1 mM DTT, 1 mM.
EGTA, 1 mM MgCl ₂ , 100 mM K acetate, 500 μM d
ATP, 500 μM TTP, 10 μM ³² P-dGTP (25 Ci / mmol
), And a00 nM d (TTAGGG) ₃ . To each reaction, 2.5, 5 or 10 μl of affinity purified telomerase (see Example 231) is added and the reaction is incubated at 37 ° C. At 45 and 90 minutes, 40 μl aliquots were removed from each reaction and 160 μl of stop buffer (100 mM NaCl, 10 mM, Na pyrophosphate, 0.2% S).
DS, 2 mM EDTA, 100 μg / ml tRNA). 10 μl trichloroacetic acid (TCA) (100%) is added and the sample is incubated on ice for 30 minutes. This sample was microcentrifuged for 15 minutes (120 min.
Pellet with 00xg). The pellet is washed with 1 ml of 95% ethanol and repelleted by microcentrifugation (12000 xg) for 5 minutes. The pellet was resuspended in 50 μl dH ₂ O and 5% TCA and 10
Transfer to a 12 x 75 glass tube containing 2.5 ml ice cold solution of mM Na pyrophosphate. The sample is incubated on ice for 30 minutes. This sample was placed on a vacuum filtration manifold with a 2.5 cm wet (dH ₂ O) GFC membrane (S & S).
). The filter is washed 3 times under reduced pressure with 5 ml ice-cold 1% TCA and once with 5 ml 95% ethanol. The filters are dried and counted in a scintillation counter using scintillation solution. The fmol of incorporated nucleotide is determined from the specific activity of the radiotracer. The activity of the extract was calculated based on the incorporated dNTP and is expressed as fmol dNTP / min / μl extract.

Example 233 Telomerase Activity Assay Biotin-telomerase FlashPlate Assay Telomerase by measuring the addition of the telomeric repeats of TTAGGG to a biotinylated telomerase substrate primer (a reaction catalyzed by telomerase). An assay for the detection and / or measurement of activity is provided. The biotinylated product was captured on streptavidin coated microtiter plates.
An oligonucleotide probe complementary to the 3.5 telomere repeat labeled with [ ³³ P] is used to measure telomerase product, as described below.
Unbound probe is removed by washing, and the amount of probe annealing to the captured telomerase product is determined by scintillation counting.

Method: 1. Compounds are stored as concentrated stocks and dissolved in 100% dimethyl sulfoxide (DMSO).

[0914] 2. For testing, these compounds are diluted in 15x study stock in 50% DMSO and 2 μl are distributed into two wells of 96-well microtiter dishes (assay in duplicate).

[0915] 3. The telomerase extract was added 0.04 to 0.09 in telomerase dilution buffer.
Dilute to a specific activity of fmol of incorporated dNTP / min / μl and
1 is added to each sample well and pre-incubated with compound for 30 minutes at room temperature.

[0916] The telomerase reaction is initiated by adding 10 μl of master mix to wells containing telomerase extract and compound. The plates are sealed and incubated at 37 ° C for 90 minutes.

[0917]   5. The reaction is stopped by the addition of 10 μl HCS.

Transfer 6.25 μl of reaction mixture to streptavidin-coated 96-well flash plate (NEN) and incubate for 2 hours at room temperature with gentle agitation.

7. The wells are washed 3 times with 180 μl 2 × SSC without any incubation.

8. Counts of probes annealed to the biotinylated telomerase product are detected with a scintillation counter.

Buffers: Telomerase Dilution Buffer 50 mM Tris-acetate, pH 8.2 1 mM DTT 1 mM EGTA 1 mM MgCl ₂ 830 nM BSA Master Mix (MM) 50 mM Tris-acetate, pH 8.2 1 mM DTT 1 mM EGTA 1 mM MgCl ₂ 1 mM MgCl ₂ K acetate 10 μM dATP 20 μM dGTP 120 μM dTTP 100 nM biotinylated primer (5′-biotin-AATCCGTCGAGCAGAGTT-3 ′) 5.4 nM labeled probe [5′-CCCTAACCCCTAACCCTAACC
_{^{C- (33 P) A 1-50 -3}} ']; approximately 10 ⁹ cpm / μg or higher specific activity hybridization capture solution (HCS) 12X SSC (1X = 150mM NaCl / 30mM Citrate Na ₃₎ 40mM EDTA 40mM Tris -HCl, using the pH 7.0 the assays described above, the compound of example 1-29 was shown to have telomerase an IC ₅₀ value of less than 100 [mu] M.

Example 234 (Anti-tumor activity) (Ex vivo study) (a. Reduction of telomerase length in tumor cells) Tumor cell lines (eg ovarian tumor cell lines OVCAR-5 and SK-OV-3).
And colonies of normal human cells (eg, human BJ cells) used as controls are prepared using standard methods and materials. 1 in 1 test
These colonies are prepared by seeding approximately 10 ⁶ cells in each dish in a 5 cm dish. Incubate these dishes and allow the cell colonies to grow to approximately 80% confluence. Each colony is split into two groups when 80% confluent. One group is exposed to a subacute dose of a compound of the invention at a given concentration (eg, between about 5 μM and about 20 μM) for a period of about 4-8 hours after plating following splitting; Groups are exposed to controls (eg DMSO).

Then, continue dividing each group, and divide these groups again uniformly (
Almost confluent). Equal numbers of cells are seeded for continuous growth. Compounds or controls are added to this sample every 4 days at the same concentrations initially added. The remaining cells are analyzed for telomerase length. These samples are subdivided exactly as just described, while untested cells are grown to near confluence. Cell doubling
gs) and division iterations continue until about 20-25 fold increase. In this way, a determination of telomerase length as a function of cell doubling is obtained.

[0924] Telomere length is determined by digesting the DNA of these cells using a restriction enzyme specific for sequences other than the repetitive T ₂ AG ₃ sequence of human telomeres (TRF.
analysis). The digested DNA is separated by size to determine the length of telomere repeats using standard techniques of gel electrophoresis. It appears on the gel as a smear of high molecular weight DNA (approximately 2 Kb to 15 Kb) after probing with a telomere DNA probe.

The results of telomere length analysis are expected to indicate that the compounds of the invention have no effect on the rate of decrease in telomere length in control cells as a function of progressive cell doubling. However, for tumor cell lines, it is expected that for tumor cells exposed to the compounds of the invention, a measurable reduction in telomerase length will be determined for tumor cell lines. Tumor cells exposed to the control are expected to maintain a constant telomerase length. Therefore, the compounds of the present invention are expected to cause the restoration of the normal loss of telomerase length as a function of tumor cell division.

In another experiment, HEK-293 cells are incubated with a compound of the invention and a control at a concentration of between about 1 μM and about 20 μM, using the protocol just described above. The cells are expected to be in crisis (ie, dysfunction of cells) within a few weeks after administration of the test compound of the invention. Furthermore, TRF analysis of cells using standard methodologies is expected to show that the test compounds of the invention are effective in reducing telomerase length. In addition to the HEK-296 cells described above, this assay was performed using any telomerase positive cell line (eg HeL
a cells).

B. Specificity The compounds of the present invention are tested for activity against telomerase and several enzymes with telomerase-related nucleic acid binding or modifying activity using standard techniques (
IC ₅₀₎ is screened for. Enzymes to be screened include telomerase, DNA polymerase I, HeLa RNA polymerase II, T3.
RNA polymerase, MMLV reverse transcriptase, topoisomerase I, topoisomerase II, terminal transferase (Terminal Transferases
e) and single-stranded DNA binding protein (SSB). The specificity of the compounds of the invention against telomerase, and an IC ₅₀ value of the compound for each of the enzymes being screened are determined by comparing the IC ₅₀ of compounds against telomerase. IC ₅₀ for telomerase compound is lower than an IC ₅₀ value of each of the enzymes being screened, the compound is determined to have a high specificity for telomerase.

Alternatively, the telomerase inhibitory activity of these compounds was measured according to a known method (US Pat. No. 5,760,062). That is, a dimethylsulfoxide (DMSO) solution of each drug was mixed with telomerase partially purified from nuclear extracts of HEK293 cells and incubated in the presence of substrate and oligodeoxynucleotides used as deoxynucleotide triphosphates. did. The resulting reaction product (DNA with telomere sequence) was adsorbed to a membrane and hybridization was performed using a labeled oligonucleotide probe with a sequence complementary to the telomere sequence. The percentage of inhibition was calculated based on the ratio of the labeled signal on the membrane in the presence of drug to the labeled signal in the absence of drug (control). In addition, 50% of the enzyme activity based on the control
The concentration of each agent that inhibits was used as the IC ₅₀ . Table 7 shows the measurement results of the inhibitory activity of the selected compounds.

[0929]

[Table 7]

[0930]

[0931]

In parenthesis, the residual activity of telomerase activity in vitro in the presence of the compound at a concentration of 10 μm is shown.

C. Cytotoxicity The XTT assay for cytotoxicity is performed using HeLa cells.
The cell line used in this assay is exposed to the compounds of the invention for 72 hours at concentrations ranging from about 1 μM to about 1,000 μM. During this period, the optical density of the sample (
OD) is determined with 540 nanometer (nm) light. It is expected that no significant cytotoxic effect will be observed at concentrations below about 5 μM. Other tumor cell lines such as ovarian tumor cell lines OVCAR-5 and SK-OV-3 can be used in addition to control cell lines such as normal BJ cells to determine cytotoxicity. Be understood. Other assays for cytotoxicity (eg, MTT assay (Berridge et al., 1996, Biochemica 4: 14-1.
9) and the alamarBlue ^™ assay (US Pat. Nos. 5,5,5).
01,959)) can be used as well.

Some compounds have concentrations higher than about 5 μM (ie 10 μM to 20 μM).
G2 arrest can be induced at concentrations above M). Preferably, these compounds should be administered at concentrations below the level of cytotoxicity in order to observe any telomerase inhibitory effect. Nevertheless, since the efficacy of many cancer chemotherapeutic agents derives from their cytotoxic effects, the compounds of the invention may be administered at any dose at which the chemotherapeutic effect is observed. Are within the scope of the invention.

In Vivo Studies A human tumor xenograft model in which OVCAR-5 tumor cells are transplanted into nude mice can be constructed using standard techniques and materials. The mice are divided into two groups. One group is treated intraperitoneally with the compounds of the invention. DM the other group
Treat with a control containing either SO or ethanol and a mixture of emulphor (oily) and phosphate buffered saline (PBS). The average tumor mass of mice in each group is determined over time after xenotransplantation using standard methods and materials.

In the group treated with the compounds of the present invention, the average tumor mass is expected to increase after the first treatment for a period of time, after which the average tumor mass is expected to stabilize and then begin to decline. It Tumor mass in the control group is expected to increase throughout the study. Thus, the compounds of the invention are expected to dramatically reduce the rate of tumor growth and ultimately induce a reduction in tumor size and elimination of this tumor.

In another experiment, each drug was contacted with the human kidney cancer cell line ACHN for 3 days,
Cell extracts were then prepared by known methods (US Pat. No. 5,629,154) and enzyme activity was measured. That is, a cell extract was prepared using a buffer solution containing 0.5% CHAPS. A TRAP (Telomere Repeat Amplification Protocol) assay was performed in vitro using this extract (TRAP _EZE ^™ E
LISA Telomerase Detection Kit, (manufactured by Intergen)). The ratio (%) of the enzyme activity in the extract from the drug-treated cells to the enzyme activity in the extract from the drug-untreated cells was calculated. The results are shown in Table 8.

[0938]

[Table 8]

Accordingly, the present invention provides novel compounds, compositions and methods for inhibiting telomerase activity and treating disease states, particularly cancer, where telomerase activity has deleterious effects. The compounds of the invention provide a highly selective and effective treatment for malignant cells that require telomerase activity to remain immortal without affecting non-malignant cells.

While the preferred embodiment of the invention has been illustrated and described, it will be apparent that various changes can be made herein without departing from the spirit and scope of the invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/454 A61K 31/454 31/4709 31/4709 31/497 31/497 31/5377 31/5377 A61P 35/00 A61P 35/00 43/00 105 43/00 105 111 111 111 C07D 277/36 C07D 277/36 417/06 417/06 417/12 417/12 495/04 105 495/04 105A (31) Priority Claim number Japanese Patent Application No. 11-307576 (32) Priority date October 28, 1999 (October 28, 1999) (33) Country claiming priority Japan (JP) (81) Designated country EP (AT, BE, CH) , CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN , GW, ML, MR, NE, SN, TD, G), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB , GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG , US, UZ, VN, YU, ZA, ZW (72) Inventor Holcombe, Ryan United States of America California 94070, San Carlos, Graceland A. Venue 2410 (72) inventor peer Sevilla Zek, Mikujisurou et Lee. United States California 95037, Morgan Hill, Vendor Circle 165 (72) Inventor Singh, Appinder United States California 94555, Fremont, Topello Street 34229 (72) Inventor Torman, Richard El. United States California 94024, Los Altos, Foothill Boulevard 2456 (72) Inventor Tsutomu Akama United States California 94061, Redwood City, Howes Court 1540 (72) Inventor Hiroshi Kanda 1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Kyowa Fermentation Co., Ltd. Inside the Pharmaceutical Research Institute (72) Inventor Akira Asai 1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation Industry Co., Ltd.In-house Pharmaceutical Research Institute (72) Junnori Yamashita 1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Kyowa Fermentation Industry Co., Ltd. Inside the Research Institute (72) Kaori Endo 3-6-6 Asahimachi, Machida, Tokyo Kyowa Hakko Kogyo Co., Ltd. Inside the Tokyo Research Institute (72) Hiroyuki Yamaguchi 3-6-6 Asahimachi, Machida-shi, Tokyo Kyowa Fermentation Industry Co., Ltd. Tokyo Laboratory F-term (reference) 4C033 AD01 AD02 AD17 AD20 4C063 AA01 BB03 CC62 DD12 DD14 DD29 EE01 4C071 AA01 BB01 CC01 CC21 DD12 EE13 F F06 GG03 HH17 JJ07 LL01 4C086 AA01 AA03 BC82 CB26 GA04 GA07 GA08 GA10 GA12 MA01 MA02 MA04 MA05 NA14 ZB21 ZB26 ZC20 ZC41

Claims (49)

[Claims] 1. A telomerase inhibitory composition comprising a compound having a 2,4-dioxothiazolidine skeleton or a 4-oxo-2-thioxothiazolidine skeleton and having telomerase inhibitory activity. 2. The composition of claim 1, wherein the compound is
A composition having a 2,4-dioxothiazolidine skeleton. 3. The composition of claim 1, wherein the compound is
A composition having a 4-oxo-2-thioxothiazolidine skeleton. 4. A 2,4-dioxothiazolidine skeleton or 4-oxo-2-
An antitumor composition comprising a compound having a thioxothiazolidine skeleton and having telomerase inhibitory activity. 5. The composition of claim 4, wherein the compound is 2
A composition having a 4,4-dioxothiazolidine skeleton. 6. The composition of claim 4, wherein the compound is
A composition having a 4-oxo-2-thioxothiazolidine skeleton. 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Telomerase inhibitor composition: Where X is O or S; Is a single bond or a double bond; A is aryl or heteroaryl; R ₁ is hydrogen or lower alkyl; R ₂ , R ₃ and R ₄ are independently the group consisting of Selected from: hydrogen, halo, alkyl, aryl, hydroxyl, alkoxyl, aryloxyl, aralkoxyl, cyano, nitro, alkylcarbamide, arylcarbamide, dialkylcarbamide, diarylcarbamide, alkylarylcarbamide, alkylthiocarbamide, arylthiocarbamide, dialkylthio. Carbamide, diarylthiocarbamide, alkylarylthiocarbamide, amino, alkylamino, arylamino, dialkylamino, diarylamino, arylalkylamino, aminocarbonyl, alkylaminocarbamide Rubonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, sulfo, alkylsulfonylamide, arylsulfonylamide, alkylsulfonyl, aryl Sulfonyl, alkylsulfinyl, arylsulfinyl and heteroaryl; L is a direct bond or is an unsubstituted or substituted carbon, N, O or S
Is a linking group having 1 to 3 atoms independently selected from; and n is 1 or 2. 8. The composition according to claim 7, wherein X is O.
Composition. 9. A composition according to claim 9, wherein: Is a single bond. 10. The composition according to claim 7, wherein: Is a double bond. 11. The composition according to claim 7, wherein R ₁ is H. 12. The composition of claim 7, wherein A is aryl. 13. The composition of claim 12, wherein the aryl is selected from the group consisting of phenyl, biphenyl, naphthyl and anthryl. 14. The composition of claim 13, wherein the compound has Formula (II) or is a pharmaceutically acceptable salt thereof: Where X, R ₂ , R ₃ , R ₄ , L, and n are as defined above. 15. The composition of claim 13, wherein X is O, R ₁ is H, A is anthryl, and L is S. The composition wherein R ₃ is 4-halogen, R ₄ is hydrogen, and n is 1. 16. The compound according to claim 7, wherein A is heteroaryl. 17. The composition of claim 16, wherein the heteroaryl is selected from the group consisting of pyridine, quinoline, isoquinoline, thiophene, furan, imidazole, benzimidazole, and pyrazole. Composition. 18. The composition of claim 17, wherein said compound has formula (III) or is a pharmaceutically acceptable salt thereof: embedded image ] Where X, R ₁ , R ₂ , R ₃ , R ₄ , and L are as defined above. 19. The composition according to claim 7, wherein R ₃ and R ₄ are halo. 20. The composition of claim 7, wherein n is 1 and R ₂ is not hydrogen. 21. The composition of claim 7, wherein the compound is selected from the group consisting of: 5- (2- (3,4-dichlorophenyl) benzylidene). Thiazolidine-2,4
-Dione, 5- (3- (3,4-dichlorophenyl) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione, 5 -(2- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-
Dichlorobenzamido) benzylidene) thiazolidine-2,4-dione, 5- (
4- (N-3,4-dichlorophenyl (phenyl) ureido) benzylidene)
Thiazolidine-2,4-dione, 5- (2- (N-3,4-dichlorophenyl (
phenyl) ureido) benzylidene) thiazolidine-2,4-dione, 5- (
2- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione, 5- (3- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione, 5- ( 4- (N-3,4-dichlorophenylcarbamido) benzylidene) thiazolidine-2,4-dione, 5- (
4- (N-3,4-dichlorophenylcarbamoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione, 5- ( 2- (3,4-dichlorophenoxycarbonyl) benzylidene) thiazolidine-2,4-dione, 5
-(2- (3,4-Dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione, 5- (3- (3,4-dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4-Dichlorophenylacetoxy) benzylidene) thiazolidine-2,4-dione, 5- (2- (3
, 4-Dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (3- (3,4-dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (4- (3,4) -Dichlorobenzoyloxy) benzylidene) thiazolidine-2,4-dione, 5- (3,4-bis- (3,4-dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione, 5- (
2- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2,4-dione, 5- (4- (3,4-dichlorophenoxy) benzilidine) thiazolidine-2,4-dione, 5- (2,5- Bis- (3,4-dichlorobenzyloxy)
Benzyridine) thiazolidine-2,4-dione, 5- (2,4-bis- (3,4
-Dichlorobenzyloxy) benzilidine) thiazolidine-2,4-dione, 5
-(2- (3,4-dichlorobenzylthio) -3H-pyrimidin-4-one-6
-Ilmethylidene) rodanine, 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanin, 5- (2- (3,4-dichlorobenzylthio) pyrimidin-4-ylmethylidene) rhodanine, 5 -(3-cyano-2
-(3,4-Dichlorobenzylthio) pyridin-6-ylmethylidene) thiazolidine-2,4-dione and 5- (3- (3,4-dichlorobenzyloxy) benzylidene) thiazolidine-2,4-dione and their A pharmaceutically acceptable salt. 22. A telomerase inhibitory composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt thereof: embedded image Where X is O or S; Is a single bond or a double bond; R ₅ is H or lower alkyl; and Ar is a substituted or unsubstituted aryl, heteroaryl, aralkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl. Or heteroarylalkynyl. 23. The composition of claim 22, wherein: The composition is a double bond. 24. A telomerase inhibitory composition comprising a compound of formula (V) or a pharmaceutically acceptable salt thereof: Here, X is S or O; W is CH = CH, S, or -N = a C-,; R ₆ is H or lower alkyl; R ₇ is, OH, halogen, mercapto , Nitro, cyano, lower alkylthio, lower alkyl, lower alkoxy, lower alkanoyloxy, NR ₁₁ R ₁₂ (where
R ₁₁ and R ₁₂ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkanoyl, aryl, heteroaryl, heteroarylalkyl, or R ₁₁ and R ₁₂ are substituted or unsubstituted heterocyclic Form a ring), CO ₂
R ₁₃ (wherein R ₁₃ is selected from the group consisting of hydrogen, lower alkyl, aralkyl, and heteroarylalkyl), CONR ₁₁ R ₁₂ , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aryloxy. , Heteroaryloxy, aralkyloxy, heteroarylalkyloxy, lower alkanoyl, aroyl, lower alkenyl, arylthio, or lower alkynyl;
And when W represents S, R ₇ can also be H; L is O, S, SO, SO ₂ , OCH ₂ , SCH ₂ , SOCH ₂ , SO ₂ CH ₂ , or N (R ₁₀ ). (CH ₂ ) _m (wherein R ₁₀ is substituted or unsubstituted aryl, heteroaryl, aralkyl, or heteroarylalkyl, and m is
0 or 1), (CH ₂ ) N (R ₁₀ ) (CH ₂ ) _m , or CR ₁₃ R ₁₄ (wherein R ₁₃ and R ₁₄ are independently hydrogen, hydroxy, aryl, and heteroaryl). Is selected from the group consisting of); and A ₁ is cycloalkyl or formula (A1): Here, Z _{1 to} Z ₅ are independently hydrogen, lower alkyl, lower alkenyl, lower alkanoyloxy, mercapto, alkylthio, NR ₁₁ R ₁₂ , nitro, cyano,
CO ₂ R ₁₃ , CONR ₁₁ R ₁₂ , aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, halogen, and lower alkanoyl, provided that W is CH═C.
When H, A ₁ may also be pyridyl. 25. The composition of claim 24, wherein W is S. 26. The composition of claim 24, wherein W is CH
= CH, the composition. 27. The composition of claim 24, wherein L is OC.
A composition that is H ₂ . 28. The composition of claim 24, wherein L is N (
R ₁₀ ) (CH ₂ ). 29. The composition of claim 24, wherein L is S. 30. The composition of claim 24, wherein L is SO
A composition. 31. The composition of claim 24, wherein L is SO ₂ A composition. 32. The composition of claim 26, wherein L is SO
A composition. 33. The composition of claim 26, wherein L is SO ₂ A composition. 34. The composition of claim 24, wherein R ₇ is nitro. 35. The composition according to claim 24, wherein A ₁ is 4
-A composition which is methylphenyl. 36. The composition of claim 26, wherein A ₁ is 4
-A composition which is methylphenyl. 37. A method of inhibiting a telomerase enzyme, comprising the step of contacting telomerase with the composition of any of claims 1-35. 38. A method of inhibiting the growth of telomerase positive cells, comprising the step of contacting said cells with the composition of any one of claims 1-35. 39. The method of claim 38, wherein the cells are
The method, which is a mammalian cell. 40. The method of claim 39, wherein the cells are
The method is a human cell. 41. The method of claim 40, wherein the cells are
A method that is a cancer cell. 42. A method of treating a tumor, comprising contacting the tumor with the composition of any of claims 1-35. 43. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claims 1-35 and a pharmaceutically acceptable carrier. 44. Use of a composition according to any of claims 1-35 for inhibiting telomerase activity. 45. A method for inhibiting the growth of telomerase positive cells.
36. Use of a composition according to any one of to 35. 46. In the manufacture of a medicament for inhibiting telomerase activity,
Use of the composition according to any of claims 1 to 35. 47. Use of a composition according to any of claims 1-35 in the manufacture of a medicament for the inhibition of telomerase activity in cells. 48. The medicament according to claim 47, wherein the disease is cancer. 49. Use of a composition according to any one of claims 1 to 35 in the manufacture of a medicament for the inhibition of telomerase activity in cells.