JPWO1999024415A1 - Retinoid receptor agonists - Google Patents

Abstract

(57) [Abstract] The present invention provides a retinoid receptor-active substance having a retinoic action or a modulating action such as enhancing or suppressing the action of retinoids. Such substances include compounds represented by the following general formula (I) and general formula (II).

Description

[Detailed Description of the Invention] TECHNICAL FIELD The present invention relates to a retinoid receptor agonist having physiological activity similar to that of retinoids such as retinoic acid or an action of regulating the action of retinoids, and to a medicine containing said compound as an active ingredient.

BACKGROUND ART Retinoic acid (vitamin A acid) is an active metabolite of vitamin A, and has extremely important physiological effects such as the differentiation of immature cells in the process of development into mature cells with specific functions, the promotion of cell proliferation, and the life-sustaining effect.Various vitamin A derivatives have been synthesized so far, for example, benzoic acid derivatives described in Japanese Patent Application Laid-Open Nos. 61-22047 and 61-76440, and derivatives of vitamin A described in the Journal of Medicinal Chemistry.
Chemistry, 1988, Vol. 31, No. 11, p. 2182)
It has been revealed that the compounds described in the above also have similar physiological effects. Retinoic acid and the above compounds having retinoic acid-like biological activity are called "retinoids."
They are collectively referred to as:

For example, all-trans retinoic acid binds to the nuclear receptor superfamily present in the cell nucleus (Evans, R.M., S
It has been revealed that α-glucan binds as a ligand to retinoic acid receptors (RARs) belonging to the retinoic acid receptor family (Petkovich, M., et. al., Science, 240, p. 889, 1988) and controls the proliferation, differentiation and cell death of animal cells (Petkovich, M., et.
al, Nature, 330, pp. 444-450, 1987). The above compounds (e.g., 4-[(5,6,7,8-te
trahydro-5,5,8,8-tetramethyl-2-napht
It has been suggested that retinoic acid, such as benzoic acid (e.g., benzoyl)benzoic acid (e.g., benzoyl)benzoic acid (e.g., Am80), also binds to RAR and exerts physiological activity in the same way as retinoic acid (Hashimoto, Y., Cell Struct. Funct.
．． , 16, pp. 113-123, 1991; Hashimoto, Y. ,et
al. , Biochem. Biophys. Res. Commun. ,166
, pp. 1300-1307, 1990).

These compounds have been found to be clinically useful in the treatment and prevention of vitamin A deficiency, epithelial hyperkeratosis, rheumatism, delayed-type allergies, bone diseases, leukemia, and certain cancers. However, because these retinoids have diverse biological activities, they are not necessarily satisfactory medicines in terms of side effects. Therefore, there has been a strong demand for the development of retinoids with distinctive actions and their regulatory molecules.

Retinoid action regulators include 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4]diazepine-
Benzodiazepine derivatives such as 4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepin-5-yl]benzoic acid and 4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepin-5-yl]benzoic acid are known (PCT/JP96
/2709, International Publication WO97/11061. Although these compounds themselves have no retinoid activity or only a weak retinoid activity, they have the effect of significantly enhancing the activity of retinoids such as retinoic acid, and it has been suggested that they are useful in the treatment and prevention of vitamin A deficiency, epithelial keratosis, rheumatism, delayed-onset allergies, bone diseases, leukemia, and certain types of cancer.

The physiological activity of retinoic acid is expressed through the retinoid X receptor (RXR)
The existence of retinoid X receptors (which use 9-cis-retinoic acid as a ligand) has been demonstrated. Retinoid X receptors form dimers with retinoic acid receptors (RARs),
It has been revealed that it regulates the expression of the physiological activity of retinoic acid by inducing or suppressing gene transcription (Mangelsdorf, D.J. et al.,
Nature, 345, pp. 224-229). Retinoid X receptor (R
XR) has been shown to bind to the retinoic acid receptor (RAR), as well as the nuclear receptor for active vitamin _D3 , PPARs that are said to be involved in fat metabolism, and other receptors, and to control the expression of the effects of physiologically active substances such as vitamin _D3 and thyroxine that bind to these receptors (Man et al.
gelsdorf, D. J. et al. , The Retinoids, 2n
d Ed. , Ravan Press, pp. 319-350, 1994).

In addition, as a retinoid action regulator, it acts antagonistically against retinoids,
It is also known that there exist compounds that weaken the typical effects of the above retinoids (Eyr
olles, L. , et al. , Journal of Medicine
Chemistry, 37(10), pp, 1508-1517, 1994)
This publication describes, for example, 4-(5H-7,8,9,10-tetrahydro-5
, 7,7,10,10-pentamethylbenzo[e]naphtho[2,3-b][1,
It has been disclosed that compounds such as 4-(13-diazepine-13-yl)benzoic acid act as retinoid antagonists.
H-10,11,12,13-tetrahydro-10,10,13,13,15-
Pentamethyldinaphtho[2,3-b][1,2-e][1,4]diazepine-7
Compounds such as (-yl)benzoic acid have been found to act as retinoid antagonists (Japanese Patent Application No. 7-255912).

On the other hand, the carboxyl groups of retinoids such as retinoic acid and Am80, and the carboxyl groups of the retinoid action-enhancing compounds and retinoid antagonists mentioned above, have conventionally been considered to be functional groups essential for the desired biological activity, respectively.
For example, it is known that substitution with functional groups such as sulfonamide or tetrazole results in the loss of desired biological activity. Compounds such as diglitazone and troglitazone, which have a thiazolidine skeleton, bind to PPs belonging to the nuclear receptor superfamily.
AR (peroxisome proliferator-activated
Although it has been suggested that these compounds act on the γ subtype of retinoid receptors, it has not been known that compounds in which the carboxyl group of the above-mentioned physiologically active compounds is replaced with a thiazolidine ring interact with retinoid receptors and exert their physiological activity.

Thiazolidinedione derivatives include N-benzyl-2-benzothiazolinone, which has hypoglycemic effect.
,4-thiazolidinedione derivatives are known (see Japanese Patent Laid-Open No. 9-48771 and Abstracts of the 17th Medicinal Chemistry Symposium and the 6th Annual Meeting of the Pharmaceutical Chemistry Division, pp. 114-115, 1-P-30, October 27, 1997,
(Published by the Pharmaceutical Society of Japan) However, the above publication does not suggest or teach at all that these thiazolidinedione derivatives have a retinoid-like action or function as a retinoid action regulator.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a retinoid receptor agonist having a retinoin-like action or a modulating action on the action of retinoids (e.g., an action of enhancing or suppressing the action of retinoids). Another object of the present invention is to provide a pharmaceutical comprising the above compound as an active ingredient.

As a result of intensive efforts to solve the above problems, the present inventors have found that thiazolidine compounds represented by the following general formula have biological actions similar to those of retinoic acid, or have the effect of enhancing or suppressing the action of retinoids. The present invention was completed based on the above findings.

That is, the present invention relates to a compound represented by the following general formula (I):[In the formula, R¹, R², R³, R⁴, and R⁵are each independently a hydrogen atom or a lower alkyl group.
The alkyl groups are bonded together when two adjacent groups are joined together.
having one or more alkyl groups attached to the carbon atoms on the phenyl ring
X may form a 5- or 6-membered ring;⁶)=CH-, -CH
= C(R⁷) -, -N(R⁸)-CO-, -CO-N(R⁹) -, -C(=CH
R¹⁰), —CO—, or —NR¹¹- (wherein R⁶, R⁷, R⁸
, R⁹, R¹⁰, and R¹¹each independently represents a hydrogen atom or a lower alkyl group.
or a compound represented by the following general formula (II):[In the formula, R²¹, R²², R²³, and R²⁴are each independently a hydrogen atom or a low
The two adjacent groups together represent the alkyl groups.
It has one or more alkyl groups attached to the carbon atom on the phenyl ring.
may form a 5-membered or 6-membered ring; R²⁵is a hydrogen atom or a lower alkyl
The present invention provides a compound represented by the formula [representing a methyl group], or a salt thereof.

From another perspective, there is provided a medicament comprising, as an active ingredient, a compound represented by the above general formula, a physiologically acceptable salt thereof, or a hydrate or solvate thereof, which is useful as a retinoid-like agent or a retinoid activity regulator (preferably a retinoid activity enhancer or retinoid activity suppressor).

From another perspective, the use of the above substance for the manufacture of the above medicine; and the use of the above substance for the manufacture of the above medicine;
, p. 889, 1988), preferably retinoid receptors (RAR and/or RXR), are involved, the method comprising the step of administering an effective amount of the above-mentioned substance to a mammal, including a human.

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 each independently represent a hydrogen atom or a lower alkyl group. As the lower alkyl group, a linear or branched alkyl group having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be used. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, or a tert-butyl group can be used.

In addition, two adjacent groups selected from the group consisting of R ¹ , R ² , R ³ , R ⁴ , and R ⁵
The groups may be combined together with the carbon atoms on the phenyl ring to which they are attached to form one or two, preferably one, five- or six-membered rings which may have one or more alkyl groups.
A linear or branched alkyl group having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be used. For example, a methyl group, an ethyl group, etc. can be used.
Preferably, the phenyl ring substituted with R2 and R3 may be substituted with 2 to 4 methyl groups, more preferably 4 methyl groups. For example, it is preferred that the phenyl ring substituted with ^R2 and ^R3 , together with ^R2 and ^R3 , form a 5,6,7,8-tetrahydronaphthalene ring or a 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring.

X is -C( ^R6 )=CH-, -CH=C( ^R7 )-, -N( ^R8 )-CO-,
In these groups, R ⁶ , R ⁷ , R 8 , R 9 , R ¹⁰ , R 11 , R ¹² , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R ⁴⁰ , R 41 , R 42 , R 43 , R 44 , R 45 , R ⁴⁶ , R 47 , R ^4
R10 and ^R11 each independently represent a hydrogen atom or a lower alkyl group, and the lower alkyl group may be, for example, a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. More specifically, it is preferable to use a methyl group, an ethyl group, or the like. X on the phenyl group of the benzylidene thiazolidinedione moiety
The substitution position of is not particularly limited, but is preferably meta- or para-substituted.

In the above general formula (II), ^R21 , ^R22 , ^R23 , and ^R24 each independently represent a hydrogen atom or a lower alkyl group. As the lower alkyl group, a linear or branched alkyl group having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be used. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, or a tert-butyl group can be used. ^R25 represents a hydrogen atom or a lower alkyl group, and as the lower alkyl group, for example, a linear or branched alkyl group having 1 to 4 carbon atoms can be used. More specifically, it is preferable to use a methyl group, an ethyl group, or the like.

In addition, two adjacent groups selected from the group consisting of R ²¹ , R ²² , R ²³ , and R ²⁴ may be taken together to form a phenyl ring with the carbon atoms to which they are attached.
or one or two 5- or 6-membered rings which may have two or more alkyl groups;
Preferably, one alkyl group may be formed. As the alkyl group that can be substituted on the ring, a linear or branched alkyl group having about 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, can be used. For example, a methyl group, an ethyl group, etc. can be used, and preferably 2 to 4 methyl groups, more preferably 4 methyl groups, may be substituted. For example, the phenyl ring substituted with R ²² and R 23 and the phenyl ring substituted with R 22 and R ²³ may be substituted with R ²² and R ^23.
3 , it is preferred to form a 5,6,7,8-tetrahydronaphthalene ring or a 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring.

The above compounds may form base addition salts, and may exist as, for example, metal salts such as sodium salts, potassium salts, magnesium salts, or calcium salts, ammonium salts, or organic amine salts such as triethylamine salts or ethanolamine salts. Of these salts, physiologically acceptable salts can be used as the active ingredient of the medicament of the present invention. In addition, the above compounds may have one or more asymmetric carbon atoms depending on the type of substituent, and may be any optical isomer based on these asymmetric carbon atoms, any mixture of optical isomers, a racemate,
The scope of the present invention includes diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, etc. Furthermore, the scope of the present invention also includes geometric isomers based on cis or trans bonds of double bonds, any mixture of geometric isomers, and any hydrates or solvates of compounds in the form of free compounds or salts.

Among the compounds of the present invention, the following compounds can be mentioned as preferred compounds, but the compounds of the present invention or compounds that can be used as the active ingredient of the medicament of the present invention are not limited to the following compounds (in the following explanation, para and m
"eta" and "eta" respectively indicate that the substitution positions of X on the phenyl group of the benzylidene thiazolidinedione moiety are para and meta positions, and "Me" indicates a methyl group).
Regarding the production methods of the compounds of the above formula (I) and formula (II), synthesis examples for the above representative compounds are specifically and in detail shown in the Examples of this specification. Therefore, by referring to these Examples and, if necessary, by making appropriate changes or modifications to these methods, a person skilled in the art can easily produce any compound included in the compounds of the present invention represented by the above general formula (I) or (II).

The compounds of formula (I) and formula (II) above can interact with retinoid receptors (the term "retinoid receptor" used in this specification includes retinoic acid receptors RAR and RXR, and means one or more receptors with which retinoids such as retinoic acid can interact), and either exert retinoid-like physiological activity as agonists themselves, or have the effect of enhancing or suppressing the physiological activity of retinoids.

Therefore, a medicine containing the above compound as an active ingredient is useful as a retinoid-like agent or a retinoid action regulator. Which of the above actions the compounds of formula (I) and formula (II) have can be easily confirmed by the method described in detail in the examples of this specification. In addition, a method for evaluating a compound with retinoid action enhancing properties is described in International Publication WO97/11061 (PCT/JP96/2002).
709), and the method for evaluating compounds that inhibit the action of retinoids is described in Eyerolles, L., et al., Journal of Medicinal Chemistry, Vol.
nal Chemistry, 37(10), pp. 1508-1517,19
94 and the specification of Japanese Patent Application No. 7-255912.

Among the above compounds, compounds having retinoid-like activity have, for example, a cell differentiation activity, a cell proliferation-promoting activity, and a life-sustaining activity, and can be used as an active ingredient in medicines for the prevention and treatment of vitamin A deficiency, epithelial keratosis, psoriasis, allergic diseases, immune diseases such as rheumatism, bone diseases, leukemia, or cancer.

Furthermore, among the above-mentioned compounds, compounds that enhance retinoid activity either have substantially no retinoid-like activity or have weak or moderate retinoid-like activity themselves, but when these compounds are allowed to coexist with a retinoid such as retinoic acid, the physiological activities of the retinoid (typical examples include cell differentiation activity, cell proliferation-promoting activity, and life-sustaining activity) are significantly enhanced.

Without being bound by any particular theory, when such a compound capable of enhancing retinoid activity itself has a retinoid activity, the activity is synergistic. Therefore, the compound capable of enhancing retinoid activity is a compound such as retinoic acid or the above-mentioned compound having a retinoic acid-like biological activity (e.g., 4-[(5,6,7,8-tetrahydro-2,4-dihydroxybenzoyl)-4-(4-(5,6,7,8-tetrahydro ...
ahydro-5,5,8,8-tetramethyl-2-naphtha
(phenyl)carbamoyl)benzoic acid: Am80, etc.)
When a retinoid such as the above is administered as a medicine for the prevention or treatment of vitamin A deficiency, epithelial tissue keratosis, psoriasis, allergic diseases, immune diseases such as rheumatism, bone diseases, leukemia, or cancer, the compound can be used as an agent for enhancing the action of the retinoid.

Furthermore, even when retinoids are not administered for the treatment or prevention of the above-mentioned diseases, the above-mentioned retinoid action-enhancing compounds enhance the action of retinoic acid already present in the body, so that the above-mentioned compounds can be administered as medicines for the purpose of treating or preventing the above-mentioned diseases. Furthermore, these compounds not only have the effect of enhancing the action of retinoids, but also have the effect of activating the nuclear receptor superfamily present in the nucleus of cells (Evans, R.M., Science, 240, p.889, 1988).
The compound can also be used as an enhancer of physiologically active substances such as steroid compounds that exert their physiological effects by binding to receptors belonging to the steroid family, vitamin D compounds such as vitamin _D3 , or thyroxine. For example, it is useful as a pharmaceutical for preventing and/or treating diseases such as diabetes, arteriosclerosis, hyperlipidemia, hypercholesterolemia, bone diseases, rheumatism, and immune diseases.

Known examples of such nuclear receptors include the nuclear receptor for active vitamin _D3 , PPARs involved in fat metabolism, thyroxine receptors, and COUP (see Mangelsdorf, D.J.
．． et al. , The Retinoids, 2nd Ed. , Ravan
Press, pp. 319-350, 1994), it has been revealed that all of these receptors bind to retinoid X receptors (RXR) to cause the above physiologically active substances to exert their actions.

Among the above compounds, compounds that inhibit retinoid action have the effect of significantly inhibiting the physiological activities of retinoids (typically cell differentiation activity, cell proliferation promoting activity, and life-sustaining activity). Without being bound by any particular theory, compounds that have such an effect are thought to inhibit the retinoic acid receptor (RAR)
) and forms a dimer with the retinoid X receptor (RXR), and is thought to regulate the expression of the physiological activity of retinoids such as retinoic acid. This compound is a compound that binds to retinoic acid or a compound having retinoic acid-like biological activity (e.g., 4-[(5,6
,7,8-tetrahydro-5,5,8,8-tetramethyl-
2-naphthalenyl)carbamoyl]benzoic ac
Treatment of exogenous hypervitaminosis A caused by vitamin A (e.g., Am80) and/or
Or it is useful for prevention.

The retinoid action inhibitory compounds can be administered alone or in combination with other retinoids or anticancer drugs to treat cancers such as leukemia. Furthermore, the compounds inhibit the activity of the nuclear receptor superfamily present in the cell nucleus (Evans, R.M., Science, 240, p. 88).
9, 1988), for example, steroid compounds, vitamin D compounds such as vitamin _D3 , or thyroxine, or orphan receptors with unknown ligands, can be inhibited.
The compounds can also be used to regulate the expression of the physiological activity of these substances. Therefore, compounds that inhibit the action of retinoids by binding to retinoid X receptors (RXR) include, for example:
The compound can be used for the prevention and/or treatment of diseases accompanied by abnormalities in biological functions involving one or more nuclear receptors belonging to the nuclear receptor superfamily.

The pharmaceutical of the present invention comprises a substance selected from the group consisting of the compound represented by the above formula (I) and a salt thereof, and a hydrate and solvate thereof, or a compound represented by the above formula (II)
The pharmaceutical composition of the present invention contains, as an active ingredient, one or more substances selected from the group consisting of compounds represented by the formula (I) and salts thereof, and hydrates and solvates thereof. The pharmaceutical composition of the present invention may be administered as the above substance itself, but is preferably administered as an oral or parenteral pharmaceutical composition that can be produced by a method well known to those skilled in the art. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups, while pharmaceutical compositions suitable for parenteral administration include, for example, injections, suppositories, inhalants, eye drops,
Examples include nasal drops, ointments, creams, and patches.

The above pharmaceutical composition can be prepared by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, pigments,
Examples of the additives include diluents, bases, solubilizers or solubilizing agents, isotonicity adjusting agents, pH adjusting agents, stabilizers, propellants, and adhesives.

The dosage of the medicament of the present invention is not particularly limited and can be appropriately selected depending on the type and strength of its action, and further depending on the weight and age of the patient, the type and symptoms of the disease,
The dosage can be increased or decreased as appropriate depending on various factors that should normally be taken into consideration, such as the route of administration.
In general, for pharmaceuticals containing a compound with retinoid-like action as an active ingredient, the dosage can be selected appropriately according to or with reference to the dosage when retinoic acid, etc. is used as a pharmaceutical. For example, in the case of oral administration, the dosage can be in the range of about 0.01 to 1,000 mg per day for an adult.
Similarly, the dosage can be selected for pharmaceuticals containing a retinoid action-enhancing or retinoid action-suppressing compound as an active ingredient. For example, in the case of oral administration, the dosage can be in the range of approximately 0.01 to 1,000 mg per day for an adult.

EXAMPLES The present invention will now be described in more detail with reference to examples, but the scope of the present invention is not limited to the scope of the following examples. The compound numbers in the examples correspond to the compounds specifically shown above as preferred examples and the numbers in the following synthesis schemes.

Example 1: Synthesis of TZ91 24 mg (0.072 mmol) of 4-[2-(5,6,7,8-tetramethyl-5,5,8,8-tetrahydro-2-naphthyl)propenyl]benzaldehyde
10 mg (0.085 mmol) of 2,4-thiazolidinedione and 5 mg (0.058 mmol) of piperidine were dissolved in 2.5 ml of ethanol and refluxed overnight. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and
After dehydration _{with a2SO4} and distillation of the solvent, the residue was recrystallized from methanol to obtain TZ91 (quantitative).

TZ91: Yellow needles (methanol); mp227-229
°C;¹H-NMR (400MHz, CDCl₃)8.24(br s, 1H),
7.87 (s, 1H), 7.51 (d, 2H, J=8.8Hz), 7.48 (d
, 2H, J = 8.8Hz), 7.45 (d, 1H, J = 1.5Hz), 7.33
(d, 1H, J=8.4Hz), 7.30 (dd, 1H, J=8.4, 1.8H
z), 6.78 (br s, 1H), 2.32 (d, 3H, J=1.5Hz),
1.71 (s, 4H), 1.34 (s, 6H), 1.31 (s, 6H); Ana
l. Calcd. for C₂₇H₂₉NO₂S, C: 75.15%, H: 6.
77%, N, 3.25%; Found C: 75.08%, H: 6.97%, N
, 3.11%. Example 2: Synthesis of TZ151 3,5-di-tert-butylbenzoic acid (I-1) 1.00 g (4.27 mm
2.50 g (21.0 mmol) of thionyl chloride and 1.0 g of anhydrous benzene
The mixture was suspended in 2 ml of HCl and refluxed for 14 hours.
645 mg (4.27 mmol) of methyl benzoate was added, and 30 ml of anhydrous benzene was added.
The reaction mixture was suspended in 1 ml of anhydrous pyridine and stirred at room temperature for 1.5 hours.
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and₄Take off
The mixture was washed with water, concentrated, and purified by silica gel column chromatography (methylene chloride).
As a result, 1.03 g (66%) of compound I-2 was obtained.¹ H-NMR (400MHz, CDCl₃)8.06(d,2H,J=8.8H
z), 7.90 (br s, 1H), 7.75 (d, 2H, J=8.8Hz),
7.66 (d, 2H, J = 1.5Hz), 7.64 (t, 1H, J = 1.8Hz
), 3.92 (s, 3H), 1.37 (s, 18H). Dissolve 1.02 g (2.78 mmol) of compound I-2 in 30 ml of THF.
DIBAL 8.34 ml (1 M toluene solution, 8.34 mmol) at −20° C.
After 30 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine and₄The residue was dehydrated with silica gel and the solvent was concentrated.
Gel column chromatography (ethyl acetate:n⁻Hexane = 1:1)
As a result, 786 mg (83%) of compound I-3 was obtained.¹ H-NMR (400MHz, CDCl₃) 7.78 (br s, 1H), 7.
67 (d, 2H, J = 1.8Hz), 7.65 (d, 2H, J = 8.8Hz),
7.62 (t, 1H, J = 1.8Hz), 7.38 (d, 2H, J = 8.8Hz
), 4.69 (d, 2H, J = 5.9 Hz), 1.37 (s, 18H). Compound I-3 (780 mg, 2.30 mmol) was dissolved in methanol-free methylene chloride.
Dissolve in 22 ml of toluene, add 992 mg (4.60 mmol) of PCC, and let stand at room temperature.
The reaction mixture was stirred for 2.5 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (
ethyl acetate:n-hexane=1:4) to give 704 mg (
91%) was obtained.¹ H-NMR (400MHz, CDCl₃) 9.96 (s, 1H), 7.97 (
br s, 1H), 7.92 (d, 2H, J=8.4Hz), 7.85 (d, 2
H, J = 8.4Hz), 7.67 (d, 2H, J = 1.8Hz), 7.66 (t
, 1H, J = 1.8 Hz), 1.38 (s, 18H). Compound I-4 150 mg (0.45 mmol), 2,4-thiazolidinedione
52 mg (0.45 mmol) of ethanol was suspended in 10 ml of anhydrous toluene, and piperidine
11 mg (0.13 mmol) of acetic acid and 8 mg (0.13 mmol) of acetic acid were dissolved in anhydrous toluene.
A solution of the reaction mixture in 1.4 ml of ethanol was added and the mixture was refluxed at 120°C for 3.5 hours.
The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and₄
The mixture was dehydrated with HCl and the solvent was concentrated to give 194 mg (99%) of TZ151.

TZ151: Yellow powder (ethyl acetate/n-hexane);
>300°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 10.4
3 (s, 1H), 7.93 (d, 2H, J = 8.4Hz), 7.75 (s, 1H
), 7.74 (d, 2H, J=1.8Hz), 7.63 (m, 3H), 1.35
(s, 18H); Anal. Calcd, for C ₂₅ H ₂₈ N ₂ O ₃ S,C
: 68.78%, H: 6.46%, N: 6.42%; Found C: 68.7
0%, H: 6.59%, N: 6.15%. Example 3: Synthesis of TZ153 TZ153 was synthesized according to the method of Example 2 using 3,5-di-tert-butylbenzoic acid (I-1) and methyl m-aminobenzoate as starting materials.

TZ153: Pale yellow powder (ethyl acetate/n-hexane); mp 252°C; ^1H -NMR (400 MHz, DMSO- _d6 , 30°C)
10.36 (s, 1H), 8.16 (br s, 1H), 7.76 (m, 4H)
, 7.63 (t, 1H, J = 1.8Hz), 7.52 (t, 1H, J = 8.1H
z), 7.37 (d, 1H, J=8.0Hz), 1.35 (s, 18H); An
al. Calcd. for C ₂₅ H ₂₈ N ₂ O ₃ S, C: 68.78%, H:
6.46%, N: 6.42%; Found C: 68.81%, H: 6.60%
, N: 6.59%. Example 4: Synthesis of TZ155 p-Formylbenzoic acid (II-1) 1.00 g (6.67 mmol), 2,4
- 858 mg (7.33 mmol) of thiazolidinedione in 40 ml of anhydrous toluene
The mixture was suspended in 170 mg (2.00 mmol) of piperidine and 120 mg (2
A solution of 1.00 mmol) in 20 ml of anhydrous toluene was added, and the mixture was heated at 120°C for 6 hours.
The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, washed with toluene, benzene, and a 20% aqueous acetone solution, and dried to obtain Compound II-2 in an amount of 1.57 hours.
g (94%) was obtained. ^1H -NMR (400MHz, DMSO- _d6 , 30°C) 8.04 (d, 2H,
J=8.4Hz), 7.79(s, 1H), 7.70(d, 2H, J=8.4H
250 mg (1.00 mmol) of compound II-2 was suspended in 12 ml of anhydrous benzene, and 627 mg (5.27 mmol) of SOCl ₂ was added and refluxed for 14 hours. After distilling off SOCl ₂ , the compound II-2 was suspended in 10 ml of anhydrous benzene and 3,5-di-t
210 mg (1.00 mmol) of tert-butylaniline, 4 ml of anhydrous pyridine
The mixture was added and stirred at room temperature for 2 hours. 2N hydrochloric acid with floating ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane=3:2) to obtain 390 mg (89%) of TZ155.

TZ155: Pale yellow powder (ethyl acetate/n-hexane); mp 266-267°C; ^1H -NMR (400MHz, DMSO- _d6 ,
30℃) 10.20 (s, 1H), 8.08 (d, 2H, J=8.4Hz), 7
．． 87 (s, 1H), 7.74 (d, 2H, J=8.4Hz), 7.69 (d,
1H, J = 1.5Hz), 7.16 (t, 1H, J = 1.5Hz), 1.30 (
s, 18H); Anal. Calcd. for _{C25H28N2O3S , C :}
68.78%, H: 6.46%, N: 6.42%, Found C: 68.52
%, H: 6.52%, N: 6.37%. Example 5: Synthesis of TZ157 m-Formylbenzoic acid (III-1) 800 mg (5.33 mmol), 2,
686 mg (5.87 mmol) of 4-thiazolidinedione was dissolved in 40 ml of anhydrous toluene.
The mixture was suspended in 1 L of acetic acid.
A solution of 16 ml of anhydrous toluene was added, and the mixture was heated at 120°C for 4 hours.
The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, washed with toluene, benzene, and a 20% aqueous acetone solution, and dried to obtain Compound III-2.
Obtained 0.017 g (77%). ¹ H-NMR (400 MHz, DMSO-d ₆ , 30° C.) 8.14 (s, 1H)
, 8.01 (d, 1H, J=7.7Hz), 7.86 (s, 1H), 7.85 (
d, 1H, J = 7.7 Hz), 7.66 (t, 1H, J = 7.7 Hz). Compound III-2 (250 mg, 1.00 mmol) was dissolved in 14 ml of anhydrous benzene.
After adding 627 mg (5.27 mmol) of SOCl ₂ , the mixture was refluxed for 14 hours. After removing SOCl ₂ by distillation, the mixture was suspended in 10 ml of anhydrous benzene and 3,5-di-
210 mg (1.00 mmol) of tert-butylaniline, 4 m of anhydrous pyridine
1 was added and stirred at room temperature for 2 hours. 2N hydrochloric acid with floating ice was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane = 3:4) to obtain 292 mg (67%) of TZ157.

TZ157: Colorless needles (ethyl acetate/n-hexane)
) ; mp 263 ° C;¹H-NMR (400MHz, DMSO-d₆, 30 ° C) 1
0.20 (s, 1H), 8.15 (s, 1H), 8.04 (d, 1H, J=7.
7Hz), 7.87 (s, 1H), 7.78 (d, 1H, J=7.7Hz), 7
．． 69 (t, 1H, J = 7.7Hz), 7.67 (d, 2H, J = 1.5Hz)
, 7.17 (t, 1H, J=1.5Hz), 1.30 (s, 18H); Anal
．． Calcd. for C₂₅H₂₈N₂O₃S, C: 68.78%, H: 6.
46%, N: 6.42%, Found C: 68.82%, H: 6.65%, N
: 6.56%. Example 6: Synthesis of TZ161 97.6 mg (60%, 2.45 mmol) of NaH was washed with n-hexane and
Aldehyde I-4 (see Example 2) 550 mg (1.63
(mmol) dissolved in 10 ml of DMF was added and stirred at room temperature for 20 minutes.
0.19 ml (3.05 mmol) of ethyl acetate was added and stirred for 45 minutes. DMF was evaporated.
Water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine and₄in
The residue was purified by silica gel column chromatography (ethyl acetate).
The resulting mixture was purified with a 1:3 mixture of ethanol and n-hexane to give 389 mg (68%) of compound IV-1.
) obtained.¹ H-NMR (400MHz, CDCl₃) 9.90 (s, 1H), 7.73 (
d, 2H, J=8.4Hz), 7.31 (t, 1H, J=1.8Hz), 7.
31 (t, 1H, J = 1.8Hz), 7.15 (d, 2H, J = 8.4Hz),
7.13 (d, 2H, J = 1.8Hz), 3.56 (s, 3H), 1.14 (s
, 18H). Compound IV-1 385 mg (1.10 mmol), 2,4-thiazolidinedione
128 mg (1.10 mmol) of ethanol was suspended in 8 ml of anhydrous toluene, and piperidine was added.
26 mg (0.33 mmol) of ethanol and 20 mg (0.33 mmol) of acetic acid were dissolved in anhydrous toluene.
A solution of the reaction mixture in 3 ml of toluene was added and the mixture was refluxed at 120°C for 1.5 hours.
The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and₄
The residue was purified by silica gel column chromatography (ethyl acetate).
The resulting mixture was purified with a 1:1 mixture of ethyl acetate and n-hexane to give 417 mg (84.5%) of TZ161.
%) obtained.

TZ161: Yellow plate (ethyl acetate/n-hexane); mp2
65°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 7.70 (s
, 1H), 7.46 (d, 2H, J = 8.4Hz), 7.29 (t, 1H, J =
1.5Hz), 7.26 (d, 2H, J=8.4Hz), 7.09 (d, 2H,
J=1.5Hz), 3.41 (s, 3H), 1.12 (s, 18H); Anal
．． Calcd. for C ₂₆ H ₃₀ N ₂ O ₃ S, C: 69.31%, H: 6.
71%, N: 6.22%, Found C: 69.01%, H: 6.68%, N
: 5.93%. Example 7: Synthesis of TZ163 TZ163 was synthesized according to the method of Example 6 using 3-(3,5-di-tert-butylphenylcarbamoyl)benzaldehyde (synthesized from methyl m-aminobenzoate in the same manner as in Compound I-4) as a starting material.

TZ163: Yellow plates (ethyl acetate/n-hexane); mp
195°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 7.61 (
s, 1H), 7.46 (t, 1H, J=7.7Hz), 7.38 (m, 2H),
7.27 (t, 1H, J=1.8Hz), 7.14 (br s, 1H), 7.0
8 (d, 2H, J = 1.8Hz), 3.42 (s, 3H), 1.11 (s, 18
H); Anal. Calcd. _{for C26H30N2O3S ,} C: _69.3
1%, H: 6.71%, N: 6.22%, Found C: 69.41%, H:
6.92%, N: 5.99%. Example 8: Synthesis of TZ165 Thiazolidine II-2 (see Example 4) and 3,5-di-tert-butyl-N
TZ165 was synthesized (79%) according to the method of Example 4 using -methylaniline as the starting material.

TZ165: Pale yellow prisms (ethyl acetate/n-hexane); mp 253-254°C; ^1H -NMR (400MHz, DMSO- _d6 ,
30°C) 7.67 (s, 1H), 7.38 (d, 2H, J=8.4Hz), 7.
29 (d, 2H, J = 8.4Hz), 7.11 (s, 1H), 6.93 (s, 2
H), 3.42 (s, 3H), 1.12 (s, 18H); Anal, Calcd
．． for C ₂₆ H ₃₀ N ₂ O ₃ S, C: 69.31%, H: 6.71%, N:
6.22%, Found C: 69.05%, H: 6.53%, N: 6.48%
Example 9: Synthesis of TZ167 Thiazolidine III-2 (see Example 5) and 3,5-di-tert-butyl-
Starting from N-methylaniline, TZ167 was synthesized according to the method of Example 5 (76%).

TZ167: Colorless prisms (ethyl acetate/n-hexane)
;mp 238°C;¹H-NMR (400MHz, DMSO-d₆, 30℃)7.
58 (s, 1H), 7.48 (m, 2H,) 7.23 (br s, 1H), 7.
10 (s, 1H), 6.93 (d, 2H, J=1.5Hz), 3.44 (s, 3
H), 1.11 (s, 18H); Anal. Calcd. for C₂₆H₃₀
N₂O₃S, C: 69.31%, H: 6.71%, N: 6.22%, Found
C: 69.13%, H: 6.78%, N: 6.34%. Example 10: Synthesis of TZ175 Starting from 2,4-xylidine and thiazolidine II-2 (see Example 4),
TZ175 was synthesized according to the method of Example 4 (88%).

TZ175: Pale pink powder (methylene chloride/methanol;
mp269°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C) 9.8
9 (s, 1H), 8.08 (d, 2H, J = 8.4Hz), 7.86 (s, 1H
), 7.73 (d, 2H, J = 8.4Hz), 7.21 (d, 1H, J = 8.1
Hz), 7.08 (s, 1H), 7.02 (d, 1H, J=8.1Hz), 2.
29 (s, 3H), 2.20 (s, 3H); Anal. Calcd. for C
₁₉ H ₁₆ N ₂ O ₃ S, C: 64.76%, H: 4.58%, N: 7.95%;
Found C: 64.51%, H: 4.67%, N: 8.07%. Example 11: Synthesis of TZ177 Starting from 2,4-xylidine and thiazolidine III-2 (see Example 5), TZ177 was synthesized (31%) according to the method of Example 5.

TZ177: Colorless needles (methylene chloride/methanol); mp 245°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C)
．． 90 (s, 1H), 8.15 (s, 1H), 8.04 (d, 1H, J=7.7
Hz), 7.87 (s, 1H), 7.79 (d, 1H, J=8.1Hz), 7.
68 (t, 1H, J = 7.7Hz), 7.23 (d, 1H, J = 8.1Hz),
7.09 (s, 1H), 7.03 (d, 1H, J=8.1Hz), 2.29 (s
, 3H), 2.21 (s, 3H); Anal. Calcd. for C ₁₉ H _1
6 N ₂ O ₃ S, C: 64.76%, H: 4.58%, N: 7.95%; Foun
d C: 64.57%, H: 4.41%, N: 7.89%. Example 12: Synthesis of TZ181 700 mg (3.01 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoic acid (V-1) was suspended in 8 ml of thionyl chloride, and one drop of DMF was added and stirred at room temperature for 2 hours. The thionyl chloride was distilled off, and 450 mg (2.98 mmol) of methyl p-aminobenzoate and 5 mg of 4-dimethylaminopyridine were added, dissolved in 20 ml of anhydrous pyridine, and stirred at room temperature overnight. The reaction solution was poured into 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 2 N hydrochloric acid, water, and brine, dehydrated _{over Na2SO4} , and concentrated to obtain compound V-2 (
97%).

183 mg (0.50 mmol) of compound V-2 was dissolved in 10 ml of THF.
1.5 ml of DIBAL (1 M toluene solution, 1.5 mmol) was slowly added at −45° C. After 30 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine, dehydrated _{over Na2SO4} , and the solvent was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methylene chloride=1:3) to obtain 142 mg (84%) of compound V-3. ^1H -NMR (400 MHz, _CDCl3 ) 7.86 (d, 1H, J=2.2H
z), 7.78 (br s, 1H), 7.63 (d, 2H, J=8.4Hz),
7,55 (dd, 1H, J=2.0, 8.2Hz), 7.40 (d, 1H, J=
8.8Hz), 7.37 (d, 2H, J=8.4Hz), 4.68 (s, 2H)
, 1.72 (s, 4H), 1.33 (s, 6H), 1.31 (s, 6H). 140 mg (0.42 mmol) of compound V-3 was dissolved in 10 ml of methanol-free methylene chloride, 100 mg (0.46 mmol) of PCC was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (methylene chloride) to obtain 99 mg (71%) of compound V-4. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.95 (s, 1H), 7.92 (
br s, 1H), 7.91 (d, 2H, J=8.8Hz), 7.87 (d, 1
H, J = 1.8Hz), 7.84 (d, 2H, J = 8.8Hz), 7.56 (d
d, 1H, J = 2.0, 8.3Hz), 7.43 (d, 1H, J = 8.4Hz)
, 1.73 (s, 4H), 1.34 (s, 6H), 1.32 (s, 6H). 73 mg (0.22 mmol) of compound V-4 and 30 mg (0.26 mmol) of 2,4-thiazolidinedione were suspended in 4 ml of anhydrous toluene. Piperidine 1
73 μl of the reaction mixture and 100 μl of acetic acid were dissolved in 25 ml of anhydrous toluene, and 3 ml of this solution was added and refluxed at 120° C. for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and water, dehydrated with Na ₂ SO ₄ , and the solvent was concentrated to obtain T
100 mg (quantitative) of Z181 was obtained.

TZ181: Yellow needles (ethyl acetate/n-hexane);
p288-290°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C)
12.52 (s, 1H), 10.36 (s, 1H), 7.94 (d, 2H, J=
8.8Hz), 7.88 (d, 1H, J=2.2Hz), 7.76 (s, 1H)
, 7.71 (dd, 2H, J = 2.2, 8.4Hz), 7.60 (d, 2H, J
= 8.8Hz), 7.48 (d, 1H, J = 98.3Hz), 1.68 (s, 4
H), 1.31 (s, 6H), 1.28 (s, 6H); Anal. Calcd.
for C ₂₅ H ₂₆ N ₂ O ₃ S, C: 69.10%, H: 6.03%, N: 6
．． 45%; Found C: 69.05%, H: 6.23%, N: 6.55%.
Example 13: Synthesis of TZ183 TZ183 was synthesized according to the method of Example 12 using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoic acid (V-1) and methyl m-aminobenzoate as starting materials.

TZ183: Colorless powder (ethyl acetate/n-hexane)
; mp183°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C) 10
．． 29 (s, 1H), 8.15 (s, 1H), 7.88 (d, 1H, J=1.8
Hz), 7.76 (d, 1H, J=1.8Hz), 7.26 (s, 1H), 7.
26 (s, 1H), 6, 71 (dd, 1H, J=8.4Hz, 1.8Hz), 6
．． 50 (t, 1H, J = 7.7Hz), 6.49 (d, 1H, J = 8.1Hz)
, 6.35 (d, 1H, J=2.1Hz), 1.69 (s, 4H), 1.31 (
s, 6H), 1.28 (s, 6H); Anal. Calcd. for _C25H
26 N ₂ O ₃ S, C: 69.10%, H: 6.03%, N: 6.45%; Fou
nd C: 68.81%, H: 5.92%, N: 6.51%. Example 14: Synthesis of TZ185 TZ185 was synthesized according to the method of Example 4 using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine and thiazolidine II-2 (see Example 4) as starting materials.

TZ185: Pale orange plates (ethyl acetate/n-hexane); mp 234°C; ^1H -NMR (400 MHz, DMSO- _d6 , 30°C)
10.18 (s, 1H), 8.07 (d, 2H, J=8.4Hz), 7.86 (
s, 1H), 7.73 (d, 2H, J = 8.4Hz), 7.68 (d, 1H, J
= 2.2Hz), 7.57 (dd, 1H, J = 8.4Hz, 2.2Hz), 7.
28 (d, 1H, J = 8.4Hz), 1.65 (s, 4H), 1.25 (s, 6
H), 1.24 (s, 6H); Anal. Calcd. for C ₂₅ H ₂₆ N
₂ O ₃ S, C: 69.10%, H: 6.03%, N: 6.45%; Found
C: 69.40%, H: 6.10%, N: 6.55%. Example 15: Synthesis of TZ187 TZ187 was synthesized according to the method of Example 5 using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine and thiazolidine III-2 (see Example 5) as starting materials.

TZ187: Colorless plates (ethyl acetate/n-hexane)
; mp187°C; ¹ H-NMR (40MHz, DMSO-d ₆ , 30°C) 10.
18 (s, 1H), 8.14 (s, 1H), 8.03 (d, 2H, J=7.7H
z), 7.87 (s, 1H), 7.78 (d, 1H, J=7.7Hz), 7.6
8 (t, 1H, J = 7.7Hz), 7.68 (d, 1H, J = 2.2Hz), 7
．． 56 (dd, 1H, J = 8.8Hz, 2.2Hz), 7.29 (d, 1H, J
=8.4Hz), 1.65(s, 4H), 1.26(s, 6H), 1.24(s
, 6H); Anal. Calcd. _{for C25H26N2O3S ,} C: ₆₉
．． 10%, H: 6.03%, N: 6.45%; Found C: 68.81%,
H: 6.21%, N: 6.37%. Example 16: Synthesis of TZ191 18 mg of NaH (60%, 0.45 mmol) was washed with n-hexane and
Aldehyde V-4 (see Example 12) 100 mg (0.30 mm
ol) was dissolved in 4 ml of DMF and added, and the mixture was stirred at room temperature for 15 minutes.
0.07 ml (1.12 mmol) of DMF was added and stirred for 30 minutes. DMF was distilled off, water was added and extracted with methylene chloride. The organic layer was washed with brine, dehydrated over _MgSO4 , and the solvent was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:
The compound VI-1 was obtained by purifying with n-hexane (1:2) to give 388.9 mg (63%) of the compound VI-1.
) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.92 (s, 1H), 7.75 (
d, 2H, J = 8.4Hz), 7.24 (dd, 1H, J = 8.1, 1.8Hz
), 7.19 (d, 1H, J = 8.4Hz), 7.18 (d, 1H, J = 8.4
Hz), 7.04 (d, 1H, J=1.8Hz), 3.55 (s, 3H), 1.
60 (m, 4H), 1.20 (s, 6H), 0.93 (s, 6H). 60 mg (0.17 mmol) of compound VI-1 and 20 mg (0.17 mmol) of 2,4-thiazolidinedione were suspended in 4 ml of anhydrous toluene, and piperidine 4
A solution of 4 mg (0.052 mmol) of acetic acid and 3.1 mg (0.052 mmol) of acetic acid dissolved in 0.5 ml of anhydrous toluene was added and refluxed at 120°C for 40 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and MgS
The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = ₁ :3) to obtain 417 mg (93%) of TZ191.
%) was obtained.

TZ191: Yellow powder (ethyl acetate/n-hexane);
235°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 7.71 (
s, 1H), 7.48 (d, 2H, J = 8.8Hz), 7.28 (d, 2H, J
= 8.4Hz), 7.27 (d, 1H, J = 8.4Hz), 7.22 (dd, 1
H, J=8.4, 1.5Hz), 6.98 (d, 1H, J=1.8Hz), 3.
40 (s, 3H), 1.53 (m, 4H), 1.17 (s, 6H), 0.89 (
s, 6H); Anal, Calcd. _{for C26H28N2O3S ,} C: ₆
9.62%, H: 6.29%, N: 6.24%, Found C: 69.33%
, H: 6.38%, N: 6.31%. Example 17: Synthesis of TZ193 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
TZ193 was synthesized according to the method of Example 16 using (naphthylcarbamoyl)benzaldehyde (synthesized from methyl m-aminobenzoate in the same manner as in Compound V-4) as a starting material.

TZ193: Colorless plates (ethyl acetate/n-hexane)
; mp188°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C)7.
64 (s, 1H), 7.47 (t, 1H, J=7.7Hz), 7.38 (m, 2
H), 7.24 (d, 1H, J = 8.1Hz), 7.16 (dd, 1H, J = 8
．． 4, 1.8Hz), 7.03 (d, 1H, J=1.8Hz), 3.41 (s,
3H), 1.52 (s, 4H), 1.14 (s, 6H), 0.91 (s, 6H)
;Anal. Calcd. for _{C26H28N2O3S ,} C: _{69.62 %}
, H: 6.29%, N: 6.24%, Found C: 69.65%, H: 6.
16%, N: 6.08%. Example 18: Synthesis of TZ195 Thiazolidine II-2 (see Example 4) and 5,6,7,8-tetrahydro-N
, 5,5,8,8-pentamethyl-2-naphthylamine according to the method of Example 4 (80%).

TZ195: Pale yellow plates (ethyl acetate/n-hexane); mp 233°C; ^1H -NMR (400 MHz, DMSO- _d6 , 30°C)
7.69 (s, 1H), 7.39 (d, 2H, J=8.1Hz), 7.31 (d
, 2H, J=8.1Hz), 7.26 (d, 2H, J=8.8Hz), 7.06
(dd, 1H, J=8.4, 2.6Hz), 6.83 (br s, 1H), 3.
37 (s, 3H), 1.50 (m, 4H), 1.16 (s, 6H), 0.91 (
s, 6H); Anal. Calcd. _{for C26H28N2O3S ,} C: ₆
9.62%, H: 6.29%, N: 6.24%, Found C: 69.38%
, H: 6.42%, N: 6.02%. Example 19: Synthesis of TZ197 Thiazolidine III-2 (see Example 5) and 5,6,7,8-tetrahydro-
Synthesized from N,5,5,8,8-pentamethyl-2-naphthylamine according to the method of Example 5 (70%).

TZ197: Pale yellow prisms (ethyl acetate/n-hexyl
mp 237°C;¹H-NMR (400MHz, DMSO-d₆, 30 ° C)
7.59 (s, 1H), 7.48 (d, 1H, J=7.0Hz), 7.42 (m
, 2H), 7.24 (d, 1H, J=8.4Hz), 7.19 (s, 1H), 7
．． 04 (d, 1H, J=8.4, 2.2Hz), 6.85 (d, 1H, J=2.
2Hz), 3.41 (s, 3H), 1.51 (s, 4H), 1.14 (s, 6H
), 0.91 (s, 6H); Anal. Calcd. for C₂₆H₂₈N₂
O₃S, C: 69.62%, H: 6.29%, N: 6.24%, Found C
: 69.51%, H: 6.37%, N: 6.27%. Example 20: Synthesis of TZ201 Ester VII-1 (110 mg, 0.24 mmol) was dissolved in 10 ml of THF.
Dissolve and add 1.5 ml of DIBAL (1 M toluene solution, 1.5 mmol) at -20°C.
After 3 hours, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with brine and₂SO₄The residue was dehydrated and the solvent was concentrated.
Silica gel column chromatography (ethyl acetate:methylene chloride=1:4)
Purification gave 100 mg (97%) of compound VII-2.¹ H-NMR (400MHz, CDCl₃)7.81(d,2H,J=8.4H
z), 7.40 (d, 2H, J=8.4Hz), 7.31 (d, 1H, J=7.
3Hz), 7.13 (dt, 1H, J=1.8, 7.3Hz), 7.08 (dt
, 1H, J=1.5, 7.3Hz), 6.97 (dd, 1H, J=1.5, 7.
7Hz), 6.94 (s, 1H), 6.92 (s, 1H), 4.77 (d, 2H
, J=4.4Hz), 3.25 (s, 3H), 1.64 (m, 4H), 1.32
(s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.05 (s,
3H). Compound VII-2 100 mg (0.24 mmol) was dissolved in methanol-free chloride.
Dissolve in 10 ml of methylene, add 60 mg (0.28 mmol) of PCC, and let the mixture stand at room temperature.
The reaction mixture was concentrated and purified by silica gel column chromatography (acetic acid).
The resulting mixture was purified with ethyl acetate:methylene chloride (1:50) to give 72 mg of compound VII-3.
(72%) was obtained.¹ H-NMR (400MHz, CDCl₃) 10.10 (s, 1H), 7.98
(d, 2H, J=8.0Hz), 7.92 (d, 2H, J=8.8Hz), 7.
32 (d, 1H, J=7.7Hz), 7.17 (dt, 1H, J=1.5, 8.
0Hz), 7.10 (dt, 1H, J=1.5, 7.7Hz), 6.98 (dd
, 1H, J=1.5, 8.1Hz), 6.93 (s, 1H), 6.86 (s, 1
H), 3.26 (s, 3H), 1.65 (m, 4H), 1.32 (s, 3H),
1.27 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H). Compound VII-3 70 mg (0.17 mmol), 2,4-thiazolidinedione
20 mg (0.17 mmol) of piperidine was suspended in 4 ml of anhydrous toluene.
Dissolve 173 μl of ethanol and 100 μl of acetic acid in 25 ml of anhydrous toluene, and mix the resulting solution.
The reaction mixture was poured into ice water and ethyl acetate was added.
The organic layer was washed with 2N hydrochloric acid and water, and₂SO₄Dehydrate and concentrate the solvent
The resulting mixture was concentrated to give 73 mg (84%) of TZ201.

TZ201: Red needles (ethyl acetate/methanol); mp>30
0°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C) 12.62 (s
, 1H), 7.83 (s, 1H), 7.82 (d, 2H, J=8.7Hz), 7
．． 69 (d, 2H, J=8.3Hz), 7.16-7.22 (m, 2H), 7.
09 (m, 2H), 7.06 (s, 1H), 6.90 (s, 1H), 3.21 (
s, 3H), 1.62 (m, 4H), 1.30 (s, 3H), 1.26 (s, 3H)
H), 1.13 (s, 3H), 1.03 (s, 3H); Anal. Calcd.
for C ₃₂ H ₃₁ N ₃ O ₂ S・H ₂ O, C: 71.23%, H: 6.16%
, N: 7.79%; Found C: 71.12%, H: 6.02%, N: 7.
71%. Example 21: Synthesis of TZ221 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (
1.00 g (5.32 mmol) of compound VIII-1 and 1.06 g (5.32 mmol) of terephthalic acid monomethyl ester chloride were dissolved in 20 ml of methanol-free methylene chloride, and 1.42 g (10.64 mmol) of aluminum chloride was added under ice-cooling, followed by refluxing for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:hexane = 1:20, then 1:10) to obtain 1.30 g (70%) of compound VIII-2. ¹ H-NMR (400
MHz, _CDCl3 ) 8.14 (d, 2H, J=8.4Hz), 7.83 (d,
2H, J = 8.4Hz), 7.78 (d, 1H, J = 1.8Hz), 7.53 (
dd, 1H, J=8.4, 1.8Hz), 7.40(d, 1H, J=8.0Hz
), 3.97 (s, 3H), 1.72 (s, 4H), 1.32 (s, 6H), 1
29 (s, 6H). Compound VIII-2 1.20 g (3.43 mmol) was added to T
Dissolve in 15 ml of HF and add 13.7 ml of DIBAL at -78°C with stirring.
(1M toluene solution, 13.7 mmol) was slowly added dropwise. After 1 hour, the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and MgS
After dehydration with _O4 and concentration, the product was purified by silica gel column chromatography (ethyl acetate:hexane = 1:3), and the compound in which only the ketone was reduced (937.5
This was again reduced with DIBAL at 0° C. for 30 minutes, and the same post-treatment was carried out to obtain 896 mg (81%) of compound VIII-3. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.40 (d, 2H, J=8.1H
z), 7.34 (m, 3H), 7.25 (d, 1H, J=8.0Hz), 7.0
5 (dd, 1H, J=8.0, 1.8Hz), 5.80 (s, 1H), 4.68
(s, 2H), 2.15 (br s, 1H), 1.67 (s, 4H), 1.26
(s, 6H), 1.25(s, 6H). 4.70 g of alumina and 2.65 g (12.3 mmol) of PCC were suspended in 10 ml of methanol-free methylene chloride under argon atmosphere to obtain compound VIII-3.
10 mg (2.50 mmol) of the compound was dissolved in 10 ml of methanol-free methylene chloride and slowly added. After 1 hour, the reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:7) to obtain Compound VIII.
798 mg (99.7%) of 1H-4 was obtained. ^1H -NMR (400 MHz, _CDCl3 ) 10.14 (s, 1H), 8.00
(d, 2H, J=8.4Hz), 7.91 (d, 2H, J=8.1Hz), 7.
80 (d, 1H, J=1.8Hz), 7.53 (dd, 1H, J=8.4, 2.
2Hz), 7.41 (d, 1H, J=8.1Hz), 1.73 (s, 4H), 1
.32 (s, 6H), 1.30 (s, 6H). Compound VIII-4 (790 mg, 2.47 mmol) and 2,4-thiazolidinedione (319 mg, 2.72 mmol) were suspended in 20 ml of anhydrous toluene, and a solution of piperidine (63 mg, 0.74 mmol) and acetic acid (45 mg, 0.741 mol) in 8 ml of anhydrous toluene was added and refluxed at 120°C for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and filtered.
After dehydration and concentration using ₄ , the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 328 mg (32%) of TZ221.

TZ221: Colorless powder (ethyl acetate/n-hexane)
; mp204°C; ¹ H-NMR (400 MHz, CDCl ₃ ) 8.46 (s, 1
H), 7.90 (d, 2H, J=8.4Hz), 7.80 (d, 1H, J=1.
8Hz), 7.60 (d, 2H, J = 8.1Hz), 7.53 (dd, 1H, J
= 8.0, 1.8Hz), 7.41 (d, 1H, J = 8.1Hz), 1.73 (
s, 4H), 1.33 (s, 6H), 1.31 (s, 6H); Anal. Cal
cd. for C ₂₅ H ₂₅ NO ₃ S, C, 71.57; H, 6.01%; N,
3.34%; Found, C, 71.28%; H, 5.92%; N, 3.09%
Example 22: Synthesis of TZ223 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (
VIII-1) and isophthalic acid monomethyl ester chloride as starting materials,
TZ223 was synthesized according to the method of Example 21.

TZ223: Yellow prisms (ethyl acetate/n-hexane); mp
189°C; ¹ H-NMR (400 MHz, CDCl ₃ ) 8.46 (br s, 1
H), 7.91 (s, 1H), 7.90 (s, 1H), 7.86 (d, 1H, J
= 7.7Hz), 7.81 (d, 1H, J = 1.8Hz), 7.70 (d, 1H
, J = 7.7Hz), 7.61 (t, 1H, J = 7.7Hz), 7.52 (dd
, 1H, J=8.1, 1.8Hz), 7.42(d, 1H, J=8.1Hz),
1.73 (s, 4H), 1.33 (s, 6H), 1.31 (s, 6H); Ana
l. Calcd. for C ₂₅ H ₂₅ NO ₃ S, C: 71.57%, H: 6.
01%, N: 3.34%; Found, C: 71.64%, H: 6.16%, N
: 3.19%. Example 23: Synthesis of TZ225 TZ225 was synthesized according to the method of Example 21 using 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene and terephthalic acid monomethyl ester chloride as starting materials.

TZ225: Yellow prisms (ethyl acetate/n-hexane); mp
245°C; ^1H -NMR (400MHz, _CDCl3 ) 8.67 (s, 1H),
7.91 (d, 1H, J=8.4Hz), 7.90 (s, 1H), 7.58 (d
, 1H, J=8.8Hz), 7.26 (s, 1H), 7.21 (s, 1H), 2
．． 33 (s, 3H), 1.70 (s, 4H), 1.32 (s, 6H), 1.22
(s, 6H); Anal. Calcd. for _{C26H27NO3S ,} C: ₇
2.03%, H: 6.28%, N: 3.23%; Found, C: 71.87%
, H: 6.35%, N: 3.14%. Example 24: Synthesis of TZ227 TZ227 was synthesized according to the method of Example 21 using 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene and isophthalic acid monomethyl ester chloride as starting materials.

TZ227: Pale yellow prisms (ethyl acetate/n-hexane); mp 191°C; ^1H -NMR (400MHz, _CDCl3 ) 8.40 (s
, 1H), 7.87-7.92 (m, 2H), 7.86 (s, 1H), 7.69
(d, 1H, J=7.7Hz), 7.59 (t, 1H, J=7.7Hz), 7.
25 (s, 1H), 7.23 (s, 1H), 2.32 (s, 3H), 1.71 (
s, 4H), 1.33 (s, 6H), 1.22 (s, 6H); Anal. Cal
cd. for C ₂₆ H ₂₇ NO ₃ S, C: 72.03%, H: 6.28%, N
: 3.23%; Found, C: 72.21%, H: 6.37%, N: 2.96
%. Example 25: Synthesis of TZ241 4.04 g (10.1 mmol) _{of Ph3PCH3I} was suspended in 5 ml of THF, and 8.36 ml (13.4 mmol) of n-butyllithium was added at -78°C.
The mixture was stirred for 5 minutes. Compound VIII-2 (2.35 g, 6.71 mmol) was added to 12 ml of the mixture.
The resulting solution was dissolved in THF and added to the reaction mixture, followed by stirring for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dehydrated over _MgSO4 , concentrated, and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:12.5) to obtain Compound IX-1.
680 mg (30%) of the compound was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 8.00 (d, 2H, J=8.6H
z), 7.43 (d, 2H, J=8.4Hz), 7.26 (d, 1H, J=8.
1Hz), 7.22 (d, 1H, J = 1.8Hz), 7.07 (dd, 1H, J
= 8.3, 2.2Hz), 5.53 (d, 1H, J = 1.1Hz), 5.47 (
d, 1H, J=1.1Hz), 3.93 (s, 3H), 1.69 (s, 4H),
1.30 (s, 6H), 1.23 (s, 6H). 675 mg (2.01 mmol) of compound IX-1 was dissolved in 5 ml of THF.
At -78°C, 6.0 ml of DIBAL (1 M toluene solution, 6.0 mmol) was gradually added, followed by stirring at 0°C for 30 minutes. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain 619 mg (quantitative) of compound IX-2. ^1H -NMR (400 MHz)
z, CDCl ₃ ) 7.35 (m, 4H), 7.27 (d, 1H, J = 1.8Hz
), 7.25 (d, 1H, J=8.4Hz), 7.08 (dd, 1H, J=8.
4, 2.2Hz), 5.44 (d, 1H, J = 1.5Hz), 5.40 (d, 1
H, J=1.1Hz), 4.72 (s, 2H), 1.69 (s, 4H), 1.2
9 (s, 6H), 1.24 (s, 6H). Compound IX-2 620 mg (2.01 mmol) was dissolved in 10 ml of methanol-free methylene chloride, and PCC 866 mg (4.02 mmol) was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain compound IX-3 at 428.
5 mg (70%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 10.03 (s, 1H), 7.85
(d, 2H, J=8.4Hz), 7.53 (d, 2H, J=8.4Hz), 7.
27 (d, 1H, J = 8.1Hz), 7.23 (d, 1H, J = 1.8Hz),
7.06 (dd, 1H, J=8.1, 1.8Hz), 5.57 (d, 1H, J=
1.1Hz), 5.51 (d, 1H, J=0.7Hz), 1.70 (s, 4H)
, 1.30 (s, 6H), 1.24 (s, 6H). 420 mg (1.37 mmol) of compound XII-4 and 162 mg (1.38 mmol) of 2,4-thiazolidinedione were taken and suspended in 8 ml of anhydrous toluene.
Piperidine 32 mg (0.38 mmol) and acetic acid 23 mg (0.38 mmol)
A solution of the compound in 4 ml of anhydrous toluene was added and the mixture was refluxed at 120°C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and MgS
After dehydration with _O4 and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:
The crude product was purified with n-hexane (1:4) to give 449.2 mg (81%) of TZ241.

TZ241: Pale yellow needles (ethyl acetate/n-hexane); mp 198°C; ^1H -NMR (400 MHz, _CDCl3 ) 8.42 (
s, 1H), 7.88 (s, 1H), 7.48 (m, 4H), 7.27 (d, 1
H, J = 8.4Hz), 7.24 (d, 1H, J = 1.8Hz), 7.06 (d
d, 1H, J=8.4, 1.8Hz), 5.52 (s, 1H), 5.51 (s,
1H), 1.70 (s, 4H), 1.30 (s, 6H), 1.25 (s, 6H)
;Anal. Calcd. for _{C26H27NO2S , C} :74.79%,
H: 6.52%, N: 3.35%; Found C: 74.59%, H: 6.5
1%, N: 3.32%. Example 26: Synthesis of TZ243 m-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
TZ243 was obtained according to the method of Example 25 using methyl naphthoylbenzoate as the starting material.
was synthesized.

TZ243: Colorless powder (ethyl acetate/n-hexane)
;mp168°C; ^1H -NMR (400MHz, _CDCl3 )8.30(br
s, 1H), 7.85 (s, 1H), 7.46 (m, 4H), 7.28 (d, 1
H, J = 8.1Hz), 7.25 (d, 1H, J = 2.2Hz), 7.05 (d
d, 1H, J = 8.1Hz, 2.2Hz), 5.51 (d, 1H, J = 0.7H
z), 5.46 (d, 1H, J=1.1Hz), 1.70 (s, 4H), 1.3
3 (s, 6H), 1.25 (s, 6H); Anal. Calcd. for _C2
6 H ₂₇ NO ₂ S・1/4H ₂ O, C: 74.00%, H: 6.57%, N: 3
．． 32%; Found C: 74.00%, H: 6.60%, N: 3.36%.
Example 27: Synthesis of TZ245 _1.09 g (2.70 mmol) of _Ph3PCH3I was suspended in 5 ml of THF, and 2.22 ml (3.56 mmol) of n-butyllithium was added at -78°C.
The mixture was stirred for 5 minutes. 800 mg (1.78 mmol) of TZ225 (see Example 23) was added to 6
The resulting solution was dissolved in 1 ml of THF, added to the reaction mixture, and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over _MgSO4 , concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain 5 ml of TZ245.
2 mg (6.5%) was obtained.

TZ245: Pale yellow powder (ethyl acetate/n-hexane); mp 281°C; ^1H -NMR (400MHz, _CDCl3 ) 8.29 (s
, 1H), 7.84 (s, 1H), 7.42 (m, 4H), 7.12 (s, 1H
), 7.09 (s, 1H), 5.83 (d, 1H, J=1.1Hz), 5.32
(d, 1H, J=1, 1Hz), 1.96 (s, 3H), 1.70 (s, 4H)
, 1.31 (s, 6H), 1.28 (s, 6H); Anal. Calcd. fo
r C ₂₇ H ₂₉ NO ₂ S, C: 75.14%, H: 6.77%, N: 3.25
%; Found C: 74.86%, H: 6.81%, N: 3.33%. Example 28: Synthesis of TZ247 m-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-
TZ2 was prepared according to the method of Example 25 using methyl 2-naphthoylbenzoate as the starting material.
47 was synthesized.

TZ247: Pale yellow powder (ethyl acetate/n-hexane); mp 185°C; ^1H -NMR (400 MHz, _CDCl3 ) 8.19 (b
r s, 1H), 7.79 (s, 1H), 7.49 (d, 1H, J=7.7Hz
), 7.43 (t, 1H, J = 7.7Hz), 7.37 (d, 1H, J = 7.7
Hz), 7.25 (s, 1H), 7.13 (s, 1H), 7.12 (s, 1H)
, 5.80 (d, 1H, J = 1.1Hz), 5.31 (d, 1H, J = 1.1H
z), 1.96 (s, 3H), 1.72 (s, 4H), 1.32 (s, 6H),
1.29 (s, 6H); Anal. Calcd. for C ₂₇ H ₂₉ NO ₂ S
, C: 75.14%, H: 6.77%, N: 3.25%; Found C: 74
85%, H: 6.72%, N: 2.98%. Example 29: Synthesis of TZ315 3,5-di-tert-butylaniline (X-1) 1.00 g (4.88 mm
ol), ethyl 4-iodobenzoate 1.37 g (4.95 mmol), tert
549 mg (5.68 mmol) of -BuONa was dissolved in 15 ml of anhydrous toluene, and the solution was heated under argon atmosphere with tris(dibenzylideneacetone)dipalladium(O)91
The mixture was stirred at 100°C for 1 hour. After cooling to room temperature, it was extracted with ether. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:6) to obtain 0.94 g (55%) of compound X-2.
%) obtained. ^1H -NMR (400MHz, _CDCl3 ) 7.92 (d, 2H, J=8.8H
z), 7.14 (t, 1H, J=1.8Hz), 7.02 (d, 2H, J=1.
8Hz), 6.96 (d, 2H, J = 8.8Hz), 4.33 (q, 2H, J =
7.3Hz), 1.37 (t, 3H, J=7.3Hz), 1.32 (s, 18H
935 mg (2.65 mmol) of compound X-2 was dissolved in 10 ml of anhydrous benzene, and the solution was added with 249 mg (3.18 mmol) of acetyl chloride and 0.05 mg of anhydrous pyridine.
The resulting mixture was stirred at room temperature for 5 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4) to obtain 956 mg (92%) of compound X-3. ^1H -NMR (400 MHz, _CDCl3 ) 7.99 (d, 2H, J = 8.4H
z), 7.39 (s, 1H), 7.34 (d, 2H, J=8.8Hz), 7.0
5 (d, 2H, J = 1.8Hz), 4.35 (q, 2H, J = 7.3Hz), 2
．． 04 (s, 3H), 1.37 (t, 1H, J=7.0Hz), 1.30 (s,
18H). Compound X-3 (950 mg, 2.40 mmol) was dissolved in 8 mL of THF under argon atmosphere.
The reaction mixture was dissolved in 1 ml of toluene, and 7.2 ml of DIBAL (1 M toluene solution, 7.20 mmol) was slowly added dropwise to the solution while stirring at -78°C. After 15 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane =
The compound X-4 was purified by a 1:2 HCl/HCl (HCl 3 HCl 3 HCl ₃ HCl) ¹ :2 (1:2) to obtain 412 mg (55%) of compound X-4.
m, 3H), 6.96 (d, 2H, J=1.5Hz), 4.61 (s, 2H),
1.31 (s, 18H). 400 mg (1.29 mmol) of compound X-4 was dissolved in 8 ml of methanol-free methylene chloride, and 1.32 _g (85%, 12.9 mmol) of activated MnO2 was added thereto and stirred at room temperature for 12 hours. After filtering the reaction solution, the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:8, then 1:4).
) to obtain 184 mg (46%) of compound X-5. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.78 (s, 1H), 7.74 (
d, 2H, J = 8.8Hz), 7.20 (t, 1H, J = 1.8Hz), 7.0
5 (d, 1H, J = 1.8Hz), 6.99 (d, 2H, J = 8.4Hz), 6
17 (s, 1H), 1.33 (s, 18H). 34 mg of NaH (60%, 0.87 mmol) was washed with n-hexane and dissolved in DMF.
180 mg (0.58 mmol) of compound X-5 was suspended in 1 ml of DMF.
The mixture was stirred at room temperature for ₁₅ minutes.
4 ml (2.25 mmol) of the mixture was added and the mixture was stirred for another hour. DMF was distilled off, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:6) to obtain 173 mg (92%) of compound X-6. ¹ H-NMR (400 MHz, _CDCl3 ) 9.75 (s, 1H), 7.68 (
d, 2H, J = 8.8Hz), 7.33 (t, 1H, J = 1.8Hz), 7.0
5 (d, 2H, J = 1.8Hz), 6.74 (d, 2H, J = 8.8Hz), 3
40 (s, 3H), 1.33 (s, 18H). 170 mg (0.53 mmol) of compound X-6 and 62 mg (0.53 mmol) of 2,4-thiazolidinedione were suspended in 4 ml of anhydrous toluene, and a solution of 13.4 mg (0.16 mmol) of piperidine and 9.5 mg (0.16 mmol) of acetic acid in 1.6 ml of anhydrous toluene was added, followed by refluxing at 120°C for 1.5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine,
After dehydration over _MgSO4 and concentration, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain 197 mg (89%) of TZ315. TZ315: Yellow needles (ethyl acetate/n-hexane);
mp254°C; ^1H -NMR (400MHz, _CDCl3 ) 8.11 (br s
, 1H), 7.77 (s, 1H), 7.34 (m, 3H), 7.04 (d, 1H
, J = 1.8Hz), 6.77 (d, 2H, J = 8.8Hz), 3.39 (s,
3H), 1.33 (s, 18H); Anal. Calcd. for C ₂₅ H _3
0 N ₂ O ₂ S, C: 71.06%, H: 7.16%, N: 6.63%; Foun
d C: 70.96%, H: 7.17%, N: 6.81%. Example 30: Synthesis of TZ317 Methyl 3-iodobenzoate 1.37 g (5.23 mmol), 3,5-di-t
tert-butylaniline (X-1) 1.00 g (4.88 mmol), tert
549 mg (5.68 mmol) of -BuONa was dissolved in 15 ml of anhydrous toluene, and the solution was heated under argon atmosphere with tris(dibenzylideneacetone)dipalladium(O)91
mg, and 139 mg (0.22 mmol) of (R)-BINAP were added, and the mixture was heated at 80°C for 1
The mixture was stirred for 2 hours. After cooling to room temperature, it was extracted with ether. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain compound XI-1 (crude product) in an amount of 51
4 mg (31%) was obtained. ^1H -NMR (400MHz, _CDCl3 ) 7.87 (d, 1H, J=7.7H
z), 7.75 (m, 1H), 7.53 (m, 1H), 7.29 (t, 1H, J
= 7.7Hz), 7.07 (t, 1H, J = 1.5Hz), 6.98 (d, 2H
, J = 1.5 Hz), 3.88 (s, 3H), 1.32 (s, 18H). 88 mg of NaH (60%, 2.21 mmol) was washed with n-hexane and
Compound XI-1 (crude product) 500 mg (1.47 mmol) was suspended in 1 ml of HCl.
) was dissolved in 8 ml of DMF and added, and the mixture was stirred at room temperature for 15 minutes.
5 ml (5.62 mmol) of DMF was added and the mixture was stirred for 3 hours. DMF was distilled off, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with brine. After dehydration with _MgSO4 and distillation of the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:
The compound XI-2 was purified with n-hexane (1:10) to give 180 mg (34.5%) of the compound XI-2.
%. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.60 (m, 1H), 7.47 (
d, 1H, J = 7.7Hz), 7.23 (t, 1H, J = 8.0Hz), 7.1
7 (t, 1H, J = 1.8Hz), 7.04 (m, 1H), 6.99 (d, 2H
, J=1.8Hz), 3.92 (s, 3H), 3.88 (s, 3H), 1.30
(s, 18H). Compound XI-2 (170 mg, 0.48 mmol) was dissolved in THF under argon atmosphere.
The mixture was dissolved in 4 ml of HCl, and 1.44 ml of DIBAL (1 M toluene solution, 1.44 mmol) was slowly added dropwise to the mixture at -78°C while stirring. After 30 minutes, the mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , and the solvent was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain 130 mg (83%) of compound XI-3. ^1H -NMR (400 MHz, _CDCl3 ) 7.20 (t, 1H, J = 1.8H)
z), 7.14 (t, 1H, J=1.8Hz), 6.98 (d, 2H, J=1.
8Hz), 6.92 (s, 1H), 6.81 (d, 2H, J=8.1Hz), 4
．． 62 (d, 2H, J=5.9Hz), 3.34 (s, 3H), 1.30 (s,
18H). 125 mg (0.38 mmol) of compound XI-3 was dissolved in 4 ml of methanol-free methylene chloride, and 394 _mg (85%, 3.85 mmol) of activated MnO2 was added.
The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:6) to give 43.5 mg (35%) of compound XI-4 (51 mg of XI-3 was recovered). ¹ H-NMR (400 MHz, CDCl ₃ ) 9.92 (s, 1H), 7.35 (
m, 1H), 7.32 (t, 1H, J=7.7Hz), 7.27 (m, 1H),
7.23 (t, 1H, J = 1.8Hz), 7.07 (m, 1H), 7.02 (d
, 1H, J = 1.8 Hz), 3.37 (s, 3H), 1.31 (s, 18H). Compound XI-4 (65 mg, 0.20 mmol) and 2,4-thiazolidinedione (23 mg, 0.20 mmol) were suspended in 3 ml of anhydrous toluene. Piperidine 5
A solution of 1 mg (0.060 mmol) of acetic acid and 3.6 mg (0.060 mol) of acetic acid in 0.6 ml of anhydrous toluene was added and refluxed at 120°C for 3.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and then filtered.
The residue was purified by _silica gel column chromatography (ethyl acetate:n-hexane=1:2) to obtain 88 mg (quantitative) of TZ317.
Got it.

TZ317: Yellow needles (ethyl acetate/n-hexane);
p234°C; ^1H -NMR (400MHz, _CDCl3 ) 8.41 (br s,
1H), 7.77 (s, 1H), 7.22-7.57 (d, 2H), 7.01 (
d, 2H, J = 1.5Hz), 6.89 (dd, 2H, J = 8.1, 2.2Hz
), 6.83 (t, 1H, J=1.6Hz), 3.35 (s, 3H), 1.32
(s, 18H); Anal. Calcd. for C ₂₅ H ₃₀ N ₂ O ₂ S,C
:71.06%, H:7.16%, N:6.63%; Found C:70.8
8%, H: 7.09%, N: 6.36%. Example 31: Synthesis of TZ321 2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (XII-1) 1.50 g (7.39 mmol), ethyl 4-iodobenzoate 1.70 g (6.16 mmol), tert-BuONa 0.83 g (
8.62 mmol) in 30 ml of anhydrous toluene, and 138 mg (0.15 mmol) of tris(dibenzylideneacetone)dipalladium(O) was added under argon atmosphere.
) and 210 mg (0.33 mmol) of (R)-BINAP were added to the mixture and stirred at 80° C. After 1 hour, the reaction mixture was cooled to room temperature and extracted with ether.
The organic layer was washed with brine, dried over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain 1.38 g (64%) of compound XII-2. ^1H -NMR (400 MHz, _CDCl3 ) 7.90 (d, 2H, J = 8.8H
z), 7.26 (d, 2H, J=8.4Hz), 7.10 (d, 1H, J=2.
5Hz), 6.96 (dd, 1H, J=8.4, 2.6Hz), 6.93 (d,
2H, J = 8.8Hz), 4.33 (q, 2H, J = 7.0Hz), 1.69 (
s, 4H), 1.37 (t, 3H, J=7.0Hz), 1.28 (s, 6H),
1.27 (s, 6H). Compound XII-2 (1.95 g, 5.56 mmol) was dissolved in 10 ml of anhydrous pyridine.
The mixture was dissolved in 100 ml of ethyl acetate, 523 mg (6.67 mmol) of acetyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Ice water was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with dilute hydrochloric acid and brine. After dehydration and concentration with _MgSO4 , the mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain compound XII-3 in an amount of 1.3 ml.
4g (61.5%) was obtained. ^1H -NMR (400MHz, _CDCl3 ) 8.00 (d, 2H, J=8.4H
z), 7.32 (d, 2H, J=8.8Hz), 7.31 (d, 1H, J=8.
8Hz), 7.14 (d, 1H, J = 2.2Hz), 6.95 (dd, 1H, J
= 8.4, 2.2Hz), 4.35 (q, 2H, J = 6.9Hz), 2.05 (
s, 3H), 1.69 (s, 4H), 1.37 (t, 3H, J=6.9Hz),
1.28 (s, 6H), 1.24 (s, 6H). Compound XII-3 (1.34 g, 3.41 mmol) was dissolved in 6 ml of THF.
10.2 ml of DIBAL (1.0 M toluene solution, 10.2 mmol) at −78°C
After 1 hour, the mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate.
The organic layer was dehydrated with MgSO ₄ and concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2) to obtain 621 mg of compound XII-4.
(59%) obtained. ^1H -NMR (400MHz, _CDCl3 ) 7.24 (d, 2H, J=8.4H
z), 7.03 (d, 1H, J=2.2Hz), 7.00 (d, 2H, J=8.
4Hz), 6.89 (dd, JH, J=8.4, 2.2Hz), 4.60 (s,
2H), 1.68 (s, 4H), 1.27 (s, 6H), 1.26 (s, 6H)
615 mg (2.0 mmol) of compound XIII-4 was dissolved in 8 ml of methanol-free methylene chloride, and 2.05 g (85%, 20.0 mmol) of activated MnO ₂ was added.
) was added and stirred at room temperature for 16 hours. After filtering the reaction solution, the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4) to obtain 271 mg (44%) of compound XII-5. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.78 (s, 1H), 7.73 (
d, 2H, J = 8.8Hz), 7.29 (d, 1H, J = 8.4Hz), 7.1
1 (d, 1H, J = 2.2Hz), 6.99 (m, 3H), 1.70 (s, 4H
), 1.29 (s, 6H), 1.28 (s, 6H). Compound XII-5 (150 mg, 0.49 mmol) and 2,4-thiazolidinedione (63 mg, 0.54 mmol) were suspended in anhydrous toluene (6 ml), and the suspension was treated with piperidine (12.7 mg, 0.15 mmol) and acetic acid (8.9 mg, 0.15 mmol).
A solution of 1.5 ml of anhydrous toluene was added to the reaction mixture and refluxed at 120°C for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine,
Drying over _MgSO4 and concentration gave 178 mg (90%) of TZ321.

TZ321: Orange needles (ethyl acetate/n-hexane);
p297°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 8.69
(s, 1H), 7.65 (s, 1H), 7.42 (d, 2H, J=8.8Hz)
, 7.26 (d, 1H, J = 8.8Hz), 7.07 (d, 1H, J = 2.6H
z), 7.06 (d, 2H, J = 8.4Hz), 6.98 (dd, 1H, J = 8
．． 4, 2.6Hz), 1.64 (s, 4H), 1.24 (s, 6H), 1.24
(s, 6H), Anal. Calcd. for _{C24H26N2O2S , C :}
70.91%, H: 6.45%, N: 6.89%; Found, C: 71.06
%, H: 6.42%, N: 6.88%. Example 32: Synthesis of TZ325 20 mg of NaH (60%, 0.49 mmol) was washed with a small amount of n-hexane.
The suspension was suspended in 1 ml of DMF. To this suspension, 100 mg (0.3
0.3 mmol) was dissolved in 4 ml of DMF and added, followed by stirring at room temperature for 20 minutes. To this mixture was added 0.08 ml (1.28 mmol) of CH _{3 I} , followed by stirring for 30 minutes.
The MF was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dehydrated over MgSO ₄ , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:5) to obtain 80 mg (
76.59%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.75 (s, 1H), 7.68 (
d, 2H, J = 9.2Hz), 7.34 (d, 1H, J = 8.4Hz), 7.1
4 (d, 1H, J = 2.2Hz), 6.96 (dd, 1H, J = 8.4, 2.2
Hz), 6.76 (d, 2H, J=9.2Hz), 3.37 (s, 3H), 1.
71 (s, 4H), 1.31 (s, 6H), 1.26 (s, 6H). 75 mg (0.23 mmol) of Compound XII-6 and 30 mg (0.26 mmol) of 2,4-thiazolidinedione were suspended in 4 ml of anhydrous toluene, and a solution of 6.0 mg (0.07 mmol) of piperidine and 12 mg (0.07 mmol) of acetic acid in 0.75 ml of anhydrous toluene was added, followed by refluxing at 120° C. After 30 minutes,
The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and
After dehydration with SO ₄ and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:n
The resulting mixture was purified with hexane (hexane = 1:2) to give 105 mg (quantitative) of TZ325.

TZ325: Yellow powder (ethyl acetate/n-hexane);
238°C;¹H-NMR (400MHz, CDCl₃)8.29(s, 1H),
7.77 (s, 1H), 7.33 (d, 2H, J=8.2Hz), 7,33 (d
, 1H, J=8.4Hz), 7.13 (d, 1H, J=2.6Hz), 6.95
(dd, 1H, J=8.4, 2.6Hz), 6.79(d, 2H, J=8.8H
z), 3.36 (s, 3H), 1.71 (s, 4H), 1.31 (s, 6H),
1.26 (s, 6H), Anal. Calcd. for C₂₅H₂₈N₂O₂
S, C: 71.40%, H: 6.71%, N: 6.66%; Found, C: 7
1.51%, H: 6.70%, N: 6.60%. Example 33: Synthesis of TZ327 Methyl 3-iodobenzoate 1.24 g (4.73 mmol), 5,6,7,8
- tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine 1.03
g (5.07 mmol), tert-BuONa571 mg (5.92 mmol)
) was dissolved in 30 ml of anhydrous toluene, and tris(dibenzylidene
(acetone)dipalladium(O) 117 mg (0.13 mmol), (R)-BI
177 mg (0.28 mmol) of NAP was added and stirred at 80° C. for 1 hour.
The solution was cooled to room temperature and extracted with ether. The organic layer was washed with brine and₄
After dehydration and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:n-hexane
The resulting mixture was purified by HPLC (pH 7.0, pH 7.0, 1:8) to give 877 mg (55%) of compound XIII-1.
¹H-NMR (400MHz, CDCl₃)7.70 (t, 1H, 2.0Hz)
, 7.50 (d, 1H, J = 7.7Hz), 7.28 (t, 1H, J = 7.9H
z), 7.23 (d, 1H, J = 8.4Hz), 7.17 (dd, 1H, J = 8
．． 1, 1.5Hz), 7.06 (d, 1H, J=2.2Hz), 6.90 (dd
, 1H, J=8.4, 2.2Hz), 3.89 (s, 3H), 1.69 (s, 4
72 mg of NaH (60%, 1.78 mmol) was washed with n-hexane and dried.
400 mg (1.19 mmol) of compound XIII-1 was suspended in 1 ml of MF.
The mixture was dissolved in 10 ml of DMF and added to the flask, followed by stirring at room temperature. After 20 minutes, 0.0 ml of methyl iodide was added.
28 ml (4.50 mmol) of DMF was added and stirred for 40 minutes.
The organic layer was washed with brine, the solvent was distilled off, and then the mixture was washed with silica gel.
The product was purified by column chromatography (ethyl acetate: n-hexane = 1:8).
Compound XIII-2 was obtained in an amount of 371.5 mg (94.5%).¹ H-NMR (400MHz, CDCl₃)7.60 (t, 1H, 2.0Hz)
, 7.47 (d, 1H, 7.7Hz), 7.25 (d, 1H, 8.4Hz), 7
．． 22 (d, 1H, 7.7Hz), 7.08 (d, 1H, 2.6Hz), 7.0
5 (dd, 1H, 8.4, 2.7Hz), 6.88 (dd, 1H, 8.4Hz,
2.6Hz), 3.88 (s, 3H), 3.33 (s, 3H), 1.68 (s,
4H), 1.29 (s, 6H), 1.24 (s, 6H). Compound XIII-2 (570 mg, 1.62 mmol) was heated under argon atmosphere.
HF 7 ml, and the solution was stirred at -78°C.
ml (1M toluene solution, 4.87 mmol) was slowly added dropwise.
The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate.
Wash with sodium bicarbonate solution and brine, and then add MgSO₄After dehydration and concentration,
Column chromatography (ethyl acetate:n-hexane = 1:4, then 1
:3) to give 500 mg (91%) of compound XIII-3.¹ H-NMR (400MHz, CDCl₃) 7.23 (d, 1H, 8.3Hz)
, 7.19 (d, 1H, 8.1Hz), 7.06 (d, 1H, 2.6Hz), 6
．． 94 (br, 1H), 6.88 (dd, 1H, 8.4, 2.2Hz), 6.8
4 (m, 2H), 4.62 (s, 2H), 3.31 (s, 3H), 1.68 (s
, 4H), 1.29 (s, 6H), 1.24 (s, 6H). Compound XIII-3 100 mg (0.30 mmol) was dissolved in methanol-free salt.
Dissolve in 4 ml of methylene chloride and activate MnO₂303 mg (85%, 2.97 mmo
The reaction mixture was filtered, and the filtrate was concentrated.
The mixture was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:9).
As a result, 71.6 mg (72%) of compound XIII-4 was obtained.¹ H-NMR (400MHz, CDCl₃)9.92(s,1H),7.27-
7.38 (m, 4H), 7.10 (d, 1H, 2.6Hz), 7.06-7.0
9 (m, 1H), 6.92 (dd, 1H, 8.4, 2.2Hz), 3.34 (s
, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.24 (s, 6H
) Compound XIII-4 220 mg (0.66 mmol), 2,4-thiazolidinol
84 mg (0.72 mmol) of piperidone was suspended in 6 ml of anhydrous toluene, and
17 mg (0.20 mmol) of ginseng and 12 mg (0.20 mmol) of acetic acid were added to anhydrous
A solution of the reaction mixture in 2 ml of toluene was added and the mixture was refluxed at 120° C. for 1 hour.
The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and₄in
After dehydration and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:n-hexadecyl ether).
The mixture was purified using a solvent (ethanol = 1:3) to obtain 312 mg (quantitative) of TZ327.

TZ327: Orange prisms (ethyl acetate/n-hexane); mp
196°C; ¹ H-NMR (400 MHz, CDCl ₃ ) 8.39 (s, 3H) 7
．． 76 (s, 3H) 7.31 (d, 1H, 8.4Hz) 7.27 (d, 1H, 8
．． 4Hz) 7.10 (d, 1H, 2.2Hz) 6.92 (dd, 1H, 8.4H
z, 2.2Hz) 6.89 (d, 2H, 7.0Hz) 6.83 (t, 1H, 2.
0Hz) 3.32 (s, 3H) 1.71 (s, 4H) 1.31 (s, 6H) 1.
26 (s, 6H); Anal. Calcd. for C ₂₅ H ₂₈ N ₂ O ₂ S,
C: 71.40%, H: 6.71%, N: 6.66%; Found, C: 71.
15%, H: 6.61%, N: 6.44%. Example 34: Synthesis of TZ331 2.69 g (13.3 mmol) of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalene was dissolved in 20 ml of acetic anhydride and cooled to 0° C. 0.74 ml (16.0 mmol) of 61% nitric acid was slowly added to this solution.
After 2 hours, the reaction mixture was poured into ice water, neutralized with sodium hydroxide, and extracted with ether. The organic layer was shaken with brine, dehydrated over _MgSO4 , and concentrated to give Compound XIV.
3.03 g (92%) of 1H-2 was obtained. ^1H -NMR (400 MHz, _CDCl3 ) 7.96 (s, 1H), 7.21 (
s, 1H), 2.56 (s, 3H), 1.70 (s, 4H), 1.30 (s, 6
3.02 g (12.2 mmol) of compound XIV-2 was dissolved in 20 ml of ethyl acetate and 30 ml of ethanol, and 400 mg of Pd/C was added thereto, followed by catalytic hydrogenation at room temperature.
After 6.5 hours, the catalyst was removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4) to obtain 1.48 g (56%) of compound XIV-3. ¹ H-NMR (400 MHz, CDCl ₃ ) 6.97 (s, 1H), 6.61 (
s, 1H), 3.45 (br s, 2H), 2.14 (s, 3H), 1.64 (
s,4H), 1.24(s,6H), 1.24(s,6H). Methyl 4-iodobenzoate 3.82 g (13.8 mmol), Compound XIV-
33.00 g (13.8 mmol) and 1.55 g (1
6.1 mmol) was dissolved in 30 ml of anhydrous toluene, and the mixture was heated under argon atmosphere with tris(
Dibenzylideneacetone)dipalladium(O) 320 mg (0.35 mmol)
480 mg (0.77 mmol) of (R)-BINAP was added and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and extracted with ether. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (
The compound XIV-4 was purified with ethyl acetate:n-hexane=1:10 to give 2.0% yield.
4g (40%) obtained. ^1H -NMR (400MHz, _CDCl3 ) 7.89 (d, J=8.8Hz, 2
H), 7.21 (s, 1H), 7.18 (s, 1H), 6.76 (d, J=8.
8Hz, 2H), 4.32 (q, J = 7.0Hz, 2H), 2.19 (s, 3H
), 1.68 (s, 4H), 1.37 (t, J=7.0Hz, 3H), 1.29
(s, 6H) 1.24 (s, 6H). Compound XIV-4 2.03 g (5.56 mmol) was dissolved in 30 ml of anhydrous benzene.
The reaction mixture was dissolved in 1 ml of acetyl chloride, 524 mg (6.67 mmol) of acetyl chloride, and 1 ml of anhydrous pyridine were added, and the mixture was stirred at room temperature for 2 hours.
1 was added, and the mixture was stirred at 50°C for 4 hours and then at 60°C for 23 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and brine, and then extracted with MgSO
The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:4) to give 1.66 g (62%) of compound XIV-5 _.
) got. ^1H -NMR (400MHz, _CDCl3 ) 7.97 (d, J=8.8Hz, 2
H), 7.33 (d, J=8.8Hz, 2H), 7.17 (s, 1H), 7.1
3 (s, 1H), 4.34 (q, J = 7.0Hz, 2H), 2.06 (s, 3H
), 1.97 (s, 3H), 1.69 (s, 4H), 1.36 (t, J=7.0
Hz, 3H), 1.29 (s, 6H), 1.26 (s, 6H). Compound XIV-5 (1.62 g, 3.98 mmol) was dissolved in THF under argon.
The solution was stirred at -78°C and 11.9 ml of DIBAL was added.
After 30 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and
After drying with _SO4 and concentrating, the extract was purified by silica gel column chromatography (ethyl acetate:
n-hexane = 1:2) to give 0.99 g (77%) of compound XIV-6.
¹ H-NMR (400 MHz, CDCl ₃ ) 7.23 (d, J = 8.4 Hz, 2
H), 7.19 (s, 1H), 7.12 (s, 1H), 6.87 (d, J=8.
4Hz, 2H), 5.33 (s, 1H), 4.60 (d, J=5.5Hz, 2H
), 2.20 (s, 3H), 1.67 (s, 4H), 1.51 (t, J=5.6
Hz, 1H), 1.28 (s, 6H), 1.22 (s, 6H). 985 mg (3.05 mmol) of compound XIV-6 was dissolved in 14 ml of methanol-free methylene chloride, and 3.11 g (85%, 30.5 mmol) of activated MnO ₂ was added.
The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4) to obtain 297 mg (30%, 282 mg of raw material recovered) of compound XIV-6.
^1H -NMR (400MHz, _CDCl3 ) 9.76 (s, 1H), 7.71 (
d, J=8.8Hz, 2H), 7.20 (s, 1H), 7.18 (s, 1H),
6.78 (d, J=8.4Hz, 2H), 5.80 (s, 1H), 2.05 (s
, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.25 (s, 6H
70 mg (0.22 mmol) of compound XIV-6 and 25.5 mg (0.22 mmol) of 2,4-thiazolidinedione were suspended in 4 ml of anhydrous toluene, and the suspension was mixed with 5.6 mg (0.065 mmol) of piperidine and 3.9 mg (0.065 mmol) of acetic acid.
A solution of TZ331 in 0.67 ml of anhydrous toluene was added and the mixture was refluxed at 120°C for 7 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain 72.5 mg (79%) of TZ331.
) obtained.

TZ331: Yellow needles (methylene chloride/n-hexane);
mp284°C; ^1H -NMR (400MHz, _CDCl3 ) 8.31 (brs
, 1H), 7.77 (s, 1H), 7.36 (d, J=8.8Hz, 2H), 7
．． 19 (s, 1H), 7.17 (s, 1H), 6.81 (d, J=8.8Hz,
2H), 5.74 (s, 1H), 2.19 (s, 3H), 1.69 (s, 4H)
, 1.29 (s, 6H), 1.25 (s, 6H); Anal. Calcd. fo
r C ₂₅ H ₂₈ N ₂ O ₂ S, C: 71.40%, H: 6.71%, N: 6.6
6%. Example 35: Synthesis of TZ333 Methyl 3-iodobenzoate 1.77 g (6.77 mmol), Compound XIV-
3 1.47 g (6.77 mmol) and tert-BuONa 763 mg (
7.91 mmol) in 15 ml of anhydrous toluene, and 122 mg (0.14 mmol) of tris(dibenzylideneacetone)dipalladium(O) was added under argon atmosphere.
), (R)-BINAP 187 mg (0.30 mmol), and the mixture was heated at 100°C for 2
The mixture was stirred for 5 hours. The reaction mixture was cooled to room temperature and extracted with ether. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain compound XV-1 in an amount of 1.45.
g (61%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.59 (t, J = 2.0 Hz, 1
H), 7.48 (td, J=7.7, 1.2Hz, 1H), 7.27 (t, J=
7.8Hz, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 7.04
(m, 1H), 5.42 (br s, 1H), 3.88 (s, 3H), 2.19
(s, 3H), 1.68 (s, 4H), 1.29 (s, 6H), 1.24 (s,
6H). 1.44 g (4.10 mmol) of compound XV-1 was dissolved in 16 ml of anhydrous benzene, and 386 mg (4.92 mmol) of acetyl chloride and 1 ml of anhydrous pyridine were added.
The reaction mixture was stirred at room temperature for 2 hours.
The mixture was stirred at 50°C for 4 hours and then at 70°C for 6 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and brine, dehydrated over _MgSO4 , and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:n
The resulting mixture was purified with hexane (hexane = 1:2) to obtain 1.37 g (85%) of compound XV-2. ¹ H-NMR (400 MHz, CDCl ₃ ) 8.00 (s, 1H), 7.82 (
br d, 1H), 7.45 (td, J=8.0, 2.2Hz, 1H), 7.3
7 (bt, J=8.3Hz, 1H), 7.19 (br s, 1H), 7.15 (
s, 1H), 3.88 (s, 3H), 2.10 (s, 3H), 1.96 (s, 3H)
1.37 g (3.49 mmol) of compound XV-2 was dissolved in THF under argon.
The mixture was dissolved in 8 ml of toluene and stirred at -78°C, to which 10.5 ml of DIBAL (1 M toluene solution, 10.5 mmol) was slowly added dropwise. After 30 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and brine.
After dehydration with MgSO ₄ and concentration, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:3) to obtain 0.91 g (81%) of compound XV-3.
Got it. ^1H -NMR (400MHz, _CDCl3 ) 7.21 (t, J=7.7Hz, 1
H), 7.20 (s, 1H), 7.12 (s, 1H), 6.92 (s, 1H),
6.82 (m, 2H), 5.35 (br s, 1H), 4.62 (d, J=5.
8Hz, 2H), 2.19 (s, 3H), 1.68 (s, 4H), 1.59 (t
, J = 5.8 Hz, 1H), 1.28 (s, 6H), 1.23 (s, 6H). 900 mg (2.79 mmol) of compound XV-3 was dissolved in 12 ml of methanol-free methylene chloride, and 2.86 g (85%, 27.9 mmol) of activated MnO ₂ was added.
) was added and stirred at room temperature for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:8) to obtain 119 mg (13%) of compound XV-4. ¹ H-NMR (400 MHz, CDCl ₃ ) 9.92 (s, 1H), 7.37 (
t, J=7.7Hz, 1H), 7.31 (m, 2H), 7.18 (s, 1H),
7.15 (s, 1H), 7.09 (m, 1H), 5.48 (br s, 1H),
2.19 (s, 3H), 1.68 (s, 4H), 1.29 (s, 6H), 1.2
4 (s, 6H). Compound XV-4 (115 mg, 0.36 mmol) and 2,4-thiazolidinedione (84 mg, 0.72 mmol) were suspended in 8 mL of anhydrous toluene, and a solution of piperidine (9.2 mg, 0.11 mmol) and acetic acid (6.4 mg, 0.11 mmol) in 1.1 mL of anhydrous toluene was added and refluxed at 120° C. for 7 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine and filtered.
After dehydration and concentration using ₄ , the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to obtain 138 mg (92%) of TZ333.

TZ333: Yellow needles (ethyl acetate/n-hexane);
p223°C;¹H-NMR (400MHz, CDCl₃)8.29(br s,
1H), 7.75 (s, 1H), 7.30 (t, J=8.1Hz, 1H), 7.
17 (s, 1H), 7.15 (s, 1H), 6.93 (m, 2H), 6.81 (
m, 1H), 5.43 (s, 1H), 2.19 (s, 3H), 1.69 (s, 4
H), 1.30 (s, 6H). 1.24 (s, 6H); Anal. Calcd.
for C₂₅H₂₈N₂O₂S, C: 71.40%, H: 6.71%, N: 6
．． 66%; Found, C: 71.20%, H: 6.76%, N: 6.65%.
Example 36: Synthesis of TZ335 Wash 40 mg of NaH (60%, 1.01 mmol) with a small amount of n-hexane.
The suspension was suspended in 1 ml of DMF. 216 mg (0.67 mm
ol) dissolved in 6 ml of DMF was added, and the mixture was stirred at room temperature for 20 minutes.
₃0.08 ml (1.35 mmol) of 100 ml of HCl was added and stirred for 30 minutes.
The mixture was evaporated, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and
₄After dehydration and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:n-hexane
Purification with hexane (1:4) gave 140 mg (62%) of XIV-8.¹ H-NMR (400MHz, CDCl₃) 9.73 (s, 1H), 7.67 (
d, J=8.1Hz, 2H), 7.20 (s, 1H), 7.03 (s, 1H),
6.54 (br s, 2H), 3.30 (s, 3H), 2.04 (s, 3H),
1.69 (s, 4H), 1.31 (s, 6H), 1.23 (s, 6H). XIV-8 130 mg (0.39 mmol). 2,4-Thiazolidinedione
45 mg (0.39 mmol) of piperidine was suspended in 6 ml of anhydrous toluene.
9 mg (0.12 mmol) and 7 mg (0.12 mmol) of acetic acid were dissolved in anhydrous toluene.
A solution of 1.2 ml of the solution was added and refluxed at 120° C. After 6 hours, the reaction solution
The mixture was poured into ice water and extracted with methylene chloride. The organic layer was washed with brine and₄
After dehydration and concentration, the extract was purified by silica gel column chromatography (ethyl acetate:n-hexane
Purification by HPLC (MS/MS ratio 1:3) gave 145 mg (86%) of TZ335.

TZ335: Yellow powder (methylene chloride/methanol;
300°C; ¹ H-NMR (400MHz, DMSO-d ₆ , 30°C) 12.30
(br s, 1H), 7.63 (s, 1H), 7.39 (d, J=8.4Hz,
2H), 7.29 (s, 1H), 7.09 (s, 1H), 6.53 (d, J=8
．． 3Hz, 2H), 3.29 (s, 3H), 1.99 (s, 3H), 1.65 (
s, 4H), 1.27 (s, 6H), 1.21 (s, 6H), Anal. Cal
cd. for C ₂₆ H ₃₀ N ₂ O ₂ S, C: 71.86%, H: 6.96%,
N: 6.45%; Found, C: 71.60%, H: 6.99%, N: 6.6
7%. Example 37: Synthesis of TZ337 146 mg of NaH (60%, 3.65 mmol) was washed with a small amount of n-hexane and suspended in 1 ml of DMF.
ol) was dissolved in 12 ml of DMF and added, and the mixture was stirred at room temperature for 20 minutes.
0.30 ml (4.87 mmol) of _H3I was added and stirred for 1 hour. DMF was distilled off under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and MgS
After dehydration with _O4 and concentration, the extract was purified by silica gel column chromatography (ethyl acetate: n-
The resulting mixture was purified with hexane (hexane = 1:10) to give 788.5 mg (89%) of XVI-1. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.34 (d, J = 7.7 Hz, 1
H), 7.30 (m, 1H), 7.17 (s, 1H), 7.16 (t, J=7.
7Hz, 1H), 7.04 (s, 1H), 6.59 (dd, J=7.4, 1.8
Hz, 1H), 3.88 (s, 3H), 3.25 (s, 3H), 2.04 (s,
3H), 1.68 (s, 4H), 1.30 (s, 3H), 1.22 (s, 3H)
750 mg (2.05 mmol) of XVI-1 was dissolved in 7 ml of THF under argon atmosphere.
The mixture was dissolved in 100 ml of toluene, and 6.16 ml of DTBAL (1 M toluene solution, 6.16 mmol) was slowly added dropwise to the solution while stirring at -78°C. After 30 minutes, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:
2) to obtain 616 mg (89%) of XVI-2. ¹ H-NMR (400 MHz, CDCl ₃ ) 7.16 (s, 1H), 7.14 (
t, J=7.7Hz, 1H), 7.04 (s, 1H), 6.68 (d, J=7.
3Hz, 1H), 6.58 (s, 1H), 6.41 (dd, J=8.1, 2.2
Hz, 1H), 4.60 (d, J=5.8Hz, 2H), 3.22 (s, 3H)
, 2.06 (s, 3H), 1.68 (s, 4H), 1.52 (t, J=5.9H
610 mg (1.81 mmol) of XVI-2 was dissolved in 8 ml of methanol-free methylene chloride, and 1.85 g (85%, 18.1 mmol) of activated _MnO2 was added and stirred at room temperature for 30 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:10) to obtain 423 mg (70%) of XV-3. ¹ H-NMR (400 MHz, _CDCl3 ) 9.91 (s, 1H), 7.28 (
t, J=7.3Hz, 1H), 7.18 (m, 2H), 7.07 (m, 1H),
7.04 (s, 1H), 6.69 (dd, J=8.4, 2.6Hz, 1H), 3
．． 26 (s, 3H), 2.05 (s, 3H), 1.69 (s, 4H), 1.31
(s,6H), 1.22(s,6H). XV-3 415 mg (1.24 mmol), 2,4-thiazolidinedione 1
45 mg (1.42 mmol) of piperidine 3 was suspended in 10 ml of anhydrous toluene.
A solution of 2 mg (0.37 mmol) of TZ337 and 22 mg (0.37 mmol) of acetic acid in 4 mL of anhydrous toluene was added and refluxed at 120°C. After 6 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:3) to obtain 504 mg (94%) of TZ337.

TZ337: Orange crystals (ethyl acetate/n-hexane);
mp 219°C;¹H-NMR (400MHz, CDCl₃) 8.22 (br s
, 1H), 7.74 (s, 1H), 7.27 (t, J=7.7Hz, 1H), 7
．． 04 (s, 1H), 6.80 (d, J=8.4Hz, 1H), 6.64 (dd
, J=8.0, 2.2Hz, 1H), 6.48 (s, 1H), 3.26 (s, 3
H), 2.05 (s, 3H), 1.70 (s, 4H), 1.32 (s, 6H),
1.24 (s, 6H); Anal. Calcd. for C₂₆H₃₀N₂O₂
S, C: 71.86%, H: 6.96%, N: 6.45%; Found, C: 7
1.65%, H: 7.16%, N: 6.75%. Example 38: Test Example Each compound of the present invention was used to test the cell differentiation-inducing effect alone and the effect of coexisting retinoblasts.
The effect of retinoides on the cell differentiation induction activity of the retinoides was investigated.
Am80 [4-1(5,6,7,8-tetrahydro-5,5,8,8
[2-(tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid was used.
Using the leukemia cell line HL-60, differentiation into granulocytic lineage was investigated by morphological changes and
The results were determined by measuring the reduction ability of nitroblue tetrazolium (NBT).
The percentage of differentiated cells shown was calculated from NBT reducing activity.

(A) The concentration-dependent differentiation-inducing ability of each compound alone and the concentration-dependent effect on the differentiation-inducing ability of 1 × 10 ⁻⁹ M Am80 were measured. TZ91 and TZ181 exhibited cell differentiation-inducing activity alone, and furthermore, enhanced the activity of coexisting Am80 at concentrations that did not exhibit cell differentiation-inducing activity. Furthermore, TZ201 had no activity by itself, but suppressed the activity of coexisting Am80.

(B) Concentration-dependent differentiation-inducing ability of each compound alone and 1×10 ⁻¹⁰ M Am80
The concentration-dependent effect of TZ151 on the differentiation-inducing ability of TZ151 was measured. TZ151 alone exhibited cell differentiation-inducing activity, and even at a concentration that did not exhibit cell differentiation-inducing activity, the coexistence of TZ151 and A
Furthermore, TZ161 and TZ191 do not have activity by themselves, but they enhance the activity of coexisting Am80, and at high concentrations (1 × 1
^0-6 M), it had an inhibitory effect.

(C) The concentration-dependent differentiation-inducing ability of each compound alone and the concentration-dependent effect on the differentiation-inducing ability of 3×10 ⁻⁹ M Am80 were measured.
All the compounds other than the above exhibited cell differentiation-inducing activity even when used alone, and furthermore, all five compounds were found to enhance the activity of Am80 in the presence of Am80 at concentrations that did not exhibit cell differentiation-inducing activity.

(D) The effect of each compound on the concentration-dependent differentiation-inducing ability of retinoid (Am80) was measured at a fixed concentration of 1 × 10 ⁻⁶ M. The above four compounds alone did not exhibit cell differentiation-inducing activity, but suppressed the activity of coexisting Am80.

(E) Japanese Patent Laid-Open Publication No. 9-48771 discloses that N-benzyldioxothiazolidylbenzamide derivatives represented by the following general formula have an insulin resistance improving effect. For comparison, TZ105 was synthesized as an N-benzyl derivative and examined for its retinoid activity.

150 mg (0.60 mmol) of II-2 (see Example 4) was dissolved in 12 ml of anhydrous benzene.
The residue was suspended in 10 ml of anhydrous benzene, and 358 mg (3.01 mmol) of SOCl ₂ was added thereto and refluxed for 14 hours. After distilling off the SOCl ₂ , the residue was suspended in 10 ml of anhydrous benzene, and 106 mg (0.60 mmol) of 4-trifluorobenzylamine and 1 ml of anhydrous pyridine were added thereto.
The reaction mixture was added with 2N hydrochloric acid with ice floating therein, and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated over _MgSO4 , concentrated, and then purified by silica gel column chromatography (ethyl acetate:n-hexane=3:2) to obtain 128 mg (52%) of TZ105.

TZ105: Colorless needles (ethyl acetate/n-hexane); mp 204°C; ^1H -NMR (400MHz, DMSO- _d6 , 30°C)
．． 23 (t, 1H, J=5.9Hz), 8.10 (s, 1H), 7.97 (d,
1H, J = 8.7Hz), 7.83 (s, 1H), 7.76 (d, 1H, J = 8
．． 7Hz), 7.70 (d, 2H, J = 8.1Hz), 7.65 (t, 1H, J
= 7.7Hz), 7.55 (d, 2H, J = 8.0Hz), 4.59 (d, 2H
, J=5.9Hz); Anal. Calcd. for C ₁₉ H ₁₃ N ₂ O ₃ F
₃ , C: 56.16%, H: 3.22%, N: 6.89%, Found C: 5
6.36%, H: 3.04%, N: 6.98%. In the test system using the HL-60 cells described above, TZ105 showed no differentiation-inducing activity, nor did it affect the action of the coexisting retinoid Am80. Therefore, the N-benzyl derivative does not exert retinoid or retinoid-regulating activity, and it is thought that the presence of an aromatic ring on the nitrogen atom, as in TZ185, is essential for this skeleton.

INDUSTRIAL APPLICABILITY The compounds of the present invention act on retinoid receptors to exhibit retinoid-like effects and their regulatory effects (enhancing or suppressing the effects of retinoids), and are therefore useful as active ingredients of pharmaceuticals for the prevention and/or treatment of diseases such as cancer, diabetes, arteriosclerosis, bone diseases, rheumatism, and immune diseases.

─────────────────────────────────────────────────────────── Continued from the front page (51) Int.Cl. ⁷ identification FI A61P 19/08 A61P 19/08 29/00 101 29/00 101 35/00 35/00 37/00 37/00 C07D 417/10 C07D 417/10 (81) Designated States 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, TG), AP (GH, GM, K E, LS, MW, SD, SZ, UG, ZW), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, D K, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, L V, MD, MG, MK, MN, MW, MX, NO, NZ , PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, U S, UZ, VN, YU, ZW [Summary continued] (Note) This publication is based on the gazette published internationally by the International Bureau of Patents (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act), and is unrelated to this publication.

Claims (5)

[Claims] Claim 1: A compound of the following general formula (I): [wherein R ¹ , R ² , R ³ , R ¹ , and R ⁵ each independently represent a hydrogen atom or a lower alkyl group, and adjacent two of them may combine to form a 5- or 6-membered ring which may have one or more alkyl groups together with the carbon atoms on the phenyl ring to which they are attached; X represents -C(R ⁶ )=CH-, -CH=
C( ^R7 )-, -N( ^R8 )-CO-, -CO-N( ^R9 )-, -C(=CHR
¹⁰ ), —CO—, or —NR ¹¹ — (wherein R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , and R ¹¹ each independently represent a hydrogen atom or a lower alkyl group); or a compound represented by the following general formula (II): [wherein R ²¹ , R ²² , R ²³ , and R ²⁴ each independently represent a hydrogen atom or a lower alkyl group, and adjacent two of these groups may be joined to form a 5- or 6-membered ring which may have one or more alkyl groups together with the carbon atoms on the phenyl ring to which they are attached; and R ²⁵ represents a hydrogen atom or a lower alkyl group], or a salt thereof. [Claim 2] A medicine containing as an active ingredient a substance selected from the group consisting of the compound of formula (I) or formula (II) according to claim 1, physiologically acceptable salts thereof, and hydrates and solvates thereof. 3. The pharmaceutical agent according to claim 2, which is a retinoid receptor agonist. 4. The pharmaceutical agent according to claim 2 or 3, which has the effect of enhancing the effect of retinoid. 5. The regulator according to claim 2 or 3, which has the effect of suppressing the action of retinoids.