Substituted thiazolidinedione derivative compounds and pharmaceutical compositions containing the same for preventing or treating cancer

Abstract

The present invention relates to a substituted thiazolidinedione derivative compound having a novel structure, which acts as an SREBP1 (sterol regulatory element-binding protein-1) inhibitor, a hydrate thereof or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer, comprising the compound as an active ingredient.

Description

[Technical field]

[0001] The present invention relates to a substituted thiazolidinedione derivative compound having a novel structure, which acts as an SREBP1 (sterol regulatory element-binding protein-1) inhibitor, a hydrate thereof or a pharma- ceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer, comprising the same as an active ingredient. [Background technology]

[0002] Sterol regulatory element-binding protein-1 (SREBP1) is a key transcriptional regulator in fat synthesis and metabolism, precisely regulating the expression of enzymes required for the synthesis of endogenous cholesterol, fatty acids (FAs), triacylglycerol, and / or phospholipids.

[0003] Recently, SREBP1 has been reported in various publications as a very important link in cancer metabolism and tumor signal transduction. Recent research has shown that SREBP1 is required for the survival of brain tumor cells with an EGF (epidermal growth factor) signal-dependent anticancer drug resistance mechanism, and in this study, SREBP1 was confirmed to be dependent on LDLR (low density lipoprotein receptor) and increased fatty acid synthesis. As a result, it is known that brain tumor cells promote survival and proliferation through the EGFR / PI3K / Akt / SREBP1 signal transduction pathway.

[0004] Brain tumors are the common names for primary brain cancers that occur in brain tissue and the meninges that surround the brain, and secondary brain cancers that metastasize from cancers that occur in the skull or other parts of the body, and are distinguished from cancers that occur in other organs in many ways. Cancers that occur in the lungs, stomach, breast, etc. are limited to one or two types per organ and are the same or similar in nature, whereas in the brain, a wide variety of cancers occur, such as glioblastoma multiforme, malignant glioma, lymphadenoma, germ cell tumor, metastatic tumor, etc.

[0005] Brain tumors found in adults include glioma, glioblastoma, meningioma, pituitary adenoma, and schwannoma, among which glioblastoma is a tumor that originates from glial cells in brain tissue, accounts for 12-15% of all brain tumors, and is known to be the most frequent primary brain tumor in adults. Such brain tumors are representative intractable solid cancers in which the improvement in survival rate through treatment is minimal, and existing cancer treatment methods cannot derive fundamental therapeutic effects.

[0006] Therefore, there is a need to develop an inhibitor that can selectively inhibit SREBP1, which plays a vital role in cancer metabolism and tumor signal transduction. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, the inventors have synthesized compounds with novel structures that can act as inhibitors of SREBP1, and have found that these show anticancer effects in vitro and in vivo in cancer, particularly in brain tumor models, and therefore can be used as new anticancer agents, thus completing the present invention.

[0008] An object of the present invention is to provide a substituted thiazolidinedione derivative compound having a novel structure, a hydrate thereof or a pharma- ceutically acceptable salt thereof, which can act as an SREBP1 inhibitor.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which comprises the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0010] Another object of the present invention is to provide a health functional food composition for preventing or improving cancer, which contains the substituted thiazolidinedione derivative compound, its hydrate or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0011] Another object of the present invention is to provide a method for treating cancer, comprising the step of administering said substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0012] Another object of the present invention is to provide said substituted thiazolidinedione derivative compound, its hydrate or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer.

[0013] Another object of the present invention is to provide the use of said substituted thiazolidinedione derivative compound, its hydrate or its pharma- ceutically acceptable salt for use in the manufacture of a medicament for the treatment of cancer. [Means for solving the problem]

[0014] In order to achieve the above objective, One aspect of the present invention provides a substituted thiazolidinedione derivative compound represented by the following chemical formula 1, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. [Chemical formula 1] [ka] In the above Chemical Formula 1, [ka] is a single or double bond, Ar 1 teeth, [ka] or [ka] and R 1 is C1-C10 alkyl, R 2 is haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R 3 is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X 1 is CH or N, R A is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L 1 -Het 1 and L 1 is C1-C10 alkylene, Het 1 is a C3-C10 heterocycloalkyl; a1 is an integer of 0 to 3, b1 and c1 each independently represent an integer of 0 to 5.

[0015] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a substituted thiazolidinedione derivative compound represented by the following chemical formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient. [Chemical formula 2] [ka] In the above Chemical Formula 2, [ka] is a single or double bond, Ar 2 teeth, [ka] or [ka] and R 11 is C1-C10 alkyl, R 12 is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R 13 is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X 2 is CH or N, R B is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L 2 -Het 2 and L 2 is C1-C10 alkylene, Het 2 is a C3-C10 heterocycloalkyl; a2 is an integer of 0 to 3, b2 and c2 each independently represent an integer of 0 to 5.

[0016] Another aspect of the present invention provides a health functional food composition comprising the substituted thiazolidinedione derivative compound represented by the above chemical formula 2, a hydrate thereof, or a food-based acceptable salt thereof as an active ingredient.

[0017] Another aspect of the present invention provides a method for treating cancer, comprising administering a substituted thiazolidinedione derivative compound represented by Chemical Formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof to an individual or subject in need thereof.

[0018] Another aspect of the present invention provides a substituted thiazolidinedione derivative compound represented by the above Chemical Formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer.

[0019] Another aspect of the present invention provides the use of the substituted thiazolidinedione derivative compound represented by the above formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the manufacture of a medicament for treating cancer. Effect of the Invention

[0020] The present disclosure relates to a novel substituted thiazolidinedione derivative compound and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. The compound according to one embodiment is highly biocompatible, highly selective, and can act as an effective orally bioavailable SREBP1 inhibitor, and therefore can be effectively used as a pharmaceutical composition for preventing or treating cancer.

[0021] According to one embodiment, the compound is not toxic to normal cells and acts as an SREBP1 inhibitor, and therefore can specifically induce the death of cancer cell lines, particularly brain tumors, and can be effectively used without side effects as an efficient agent for improving, preventing and treating brain tumors having an EGF (epidermal growth factor) signal-dependent anticancer drug resistance mechanism. [Brief description of the drawings]

[0022] [Figure 1]FIG. 1 shows activity measurement of derivatives using a cell-based assay system [(a) cell-based assay system using 6xSRE reporter vector, (b) (c) expression levels of activated forms of SREBP1a and SREBP1c in isolated GFP-low cells and changes in GFP expression, (d) changes in GFP expression when treated with the control group DMSO, and fatostatin and FGH10019, which are known to inhibit SREBP activity]. [Diagram 2] FIG. 1 shows a comparative experiment of cell viability by compound treatment in brain tumor stem cells HOG-GSC. [Diagram 3] FIG. 1 shows the results of a Western blot assay of compound 11 (Example 11). [Figure 4] 1 is a graph showing cell viability of brain tumor stem cells HOG-GSC depending on the concentration of compound 11 (Example 11). [Diagram 5] 1 is a graph showing the drug concentration in plasma after oral administration (25 mg / kg). [Figure 6] 1 is a graph showing drug concentration in brain tissue after oral administration (25 mg / kg). [Figure 7] FIG. 1 is a schematic diagram for evaluating efficacy in vivo. [Figure 8] Graph showing survival rate over time. [Figure 9] This is a photograph of the brain tissue of the last surviving mouse on day 66 after tumor implantation. [Figure 10] This is a photograph of mouse brain tissue 16 days after tumor implantation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention will be described in detail below. In this case, unless otherwise defined, the technical and scientific terms used have the meanings that are commonly understood by those having ordinary knowledge in the technical field to which the present invention belongs, and the description of known functions and configurations that may make the gist of the present invention unclear in the following description will be omitted.

[0024] The embodiments described in this specification can be modified into various other forms, and the technology according to one embodiment is not limited to the embodiment described below. In addition, the embodiment of one embodiment is provided to more completely explain the present invention to those having average knowledge in the art. Furthermore, throughout the specification, "including" a certain component does not mean excluding other components, but may further include other components, unless otherwise specified to the contrary.

[0025] Numerical ranges used herein include lower and upper limits and all values ​​within the range, increments logically derived by the form and width of the range defined, all values ​​that are doubly limited, and all possible combinations of upper and lower limits of numerical ranges that are limited in different forms. For example, if the content of a composition is limited to 10% to 80% or 20% to 50%, the total numerical range of 10% to 50% or 50% to 80% should also be interpreted as being described in this specification. In this specification, unless otherwise specified, values ​​outside the numerical range that may occur due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0026] Hereinafter, unless otherwise defined, "about" is understood to mean a value within 30%, 25%, 20%, 15%, 10% or 5% of the specified value.

[0027] The following terms used herein are defined as follows, but are for illustrative purposes only and are not intended to limit the invention, application or use.

[0028] As used herein, the singular forms "a," "an," and "the" can be intended to include the plural forms as well, unless the context indicates otherwise.

[0029] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" may be used interchangeably.

[0030] As used herein, the term “C A -C B " means "the number of carbon atoms is A or more and B or less", and the term "A to B" means "A or more and B or less".

[0031] As used herein, the term "hydrocarbyl" means a radical having one bonding point derived from a hydrocarbon, and "aromatic hydrocarbyl" means a radical having one bonding point derived from an aromatic hydrocarbon compound.

[0032] In the context of the term "substituted or unsubstituted" used herein, "substituted" refers to a group or moiety having one or more substituents attached to the structural backbone of the group or moiety, meaning that the recited group or structural backbone is substituted with a group other than hydrogen, without any limitation.

[0033] As used herein, the term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon radical composed solely of carbon and hydrogen atoms. The alkyl can have 1 to 10 carbon atoms, or 1 to 7 carbon atoms, or 1 to 4 carbon atoms. By way of example, the alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.

[0034] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic radical composed of a single ring. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0035] As used herein, the term "alkoxy" refers to an -O-alkyl radical, where "alkyl" is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

[0036] As used herein, the terms "halo" or "halogen" refer to elements of the halogen family and include, for example, fluoro, chloro, bromo and iodo.

[0037] As used herein, the term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms, respectively, where alkyl, alkoxy, and halogen are as defined above. For example, haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl, etc., and haloalkoxy includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, perfluoroethoxy, etc.

[0038] As used herein, the term "aryl" refers to an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, and includes single or fused ring systems, suitably containing 4 to 7, preferably 5 or 6, ring atoms in each ring, including multiple aryls linked by single bonds. Examples include, but are not limited to, phenyl, naphthyl, biphenyl, terphenyl, anthryl, fluorenyl, and the like.

[0039] As used herein, the term "heterocycloalkyl" refers to a monovalent radical of a saturated heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, which may be monocyclic, polycyclic, or spirocyclic, or may be fused to an aromatic hydrocarbon ring such as benzene, and may be bonded via a heteroatom or a carbon atom. Additionally, the carbon atom in the saturated heterocycle may be substituted with iodine. Examples of such heterocycloalkyl radicals include monovalent radicals of saturated heterocycles such as aziridine, oxetane, pyrrolidine, tetrahydrofuran, dioxolane, dithiolane, imidazolidine, tetrahydropyran, pyrazolidine, pyrrolidinone, azetidine, piperidine, piperazine, morpholine, thiomorpholine, dioxane, hexahydroazepine, thiolane, dihydroisoindole, benzodioxole, dihydrobenzodioxine, isoindolinone, indolinone, dihydroisoquinolinone, tetrahydrobenzoazepinone, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazaspiro[4.4]nonane, 2-azaspiro[4.4]nonane, and the like.

[0040] As used herein, the term "pharmaceutical acceptable" means a composition that exhibits the property of being non-toxic to cells or individuals, such as humans, exposed to the composition and is suitable for use as a pharmaceutical formulation, and generally means a composition that is considered safe for such use and is officially approved for such use by a national regulatory agency or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0041] As used herein, the term "pharmaceutical acceptable salt" refers to any and all organic or inorganic addition salts of the compounds of the present invention that are relatively non-toxic to patients and have innocuous effective concentrations such that the side effects attributable to the salt do not diminish the beneficial effects of the compounds of the present invention themselves.

[0042] As used herein, the terms "pharmacologically acceptable excipient" and "pharmacologically acceptable carrier" refer to a substance that aids in the administration and absorption by a subject of an active agent.

[0043] As used herein, the term "prevention" refers to any action that inhibits or delays the onset, spread and recurrence of cancer.

[0044] As used herein, the term "amelioration" refers to any action that at least reduces a parameter associated with the condition being treated, e.g., the severity of a symptom.

[0045] As used herein, the term "treatment" refers to any action that reverses or favorably alters the symptoms of cancer.

[0046] As used herein, the term "individual" refers to any animal, including a human, that is afflicted with or may be afflicted with cancer, and may be, but is not limited to, a mammal, such as a cow, horse, sheep, pig, goat, camel, antelope, dog, or cat, that requires treatment for a condition similar to that of a human.

[0047] As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention into an individual in a suitable manner, and the administration route of the composition of the present invention can be one that can reach the target tissue, such as oral or parenteral, via various routes.

[0048] As used herein, the term "pharmacologically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and that does not cause side effects, and the level of an effective dose can be readily determined by one of ordinary skill in the art depending on factors including the patient's sex, age, weight, health condition, type and severity of disease, drug activity, sensitivity to the drug, administration method, administration time, administration route, and excretion rate, treatment period, co-administered or concomitant drugs, and other factors well known in the medical field.

[0049] In this specification, the term "food" includes meat, sausages, bread, chocolate, candy, snacks, sweets, pizza, ramen and other noodles, gums, dairy products including ice cream, various soups, beverages, tea, energy drinks, alcoholic beverages, vitamin complexes, functional health foods and health foods, and the like, and includes all foods in the ordinary sense of the word.

[0050] In this specification, the term "health functional food" refers to food manufactured and processed using raw materials and ingredients that have functional properties effective for the human body as stipulated in Law No. 6727 on Health Functional Foods, and "functional" means that the food is ingested for the purpose of regulating nutrients for the structure and function of the human body or obtaining effective health effects such as physiological actions.

[0051] As used herein, the term "phytomedically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

[0052] One embodiment provides a substituted thiazolidinedione derivative compound represented by the following chemical formula 1, a hydrate thereof, or a pharma- ceutically acceptable salt thereof:

[0053] [Chemical formula 1] [ka] In the above Chemical Formula 1, [ka] is a single or double bond, Ar 1 teeth, [ka] or [ka] and R 1 is C1-C10 alkyl, R 2 is haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R 3 is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X 1 is CH or N, R A is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L 1 -Het 1 and L 1 is C1-C10 alkylene; Het 1 is a C3-C10 heterocycloalkyl; a1 is an integer of 0 to 3, b1 and c1 each independently represent an integer of 0 to 5.

[0054] The substituted thiazolidinedione derivative compound of Chemical Formula 1 according to the present invention is a compound with a novel structure, and can be used as an active ingredient for preventing or treating cancer by inhibiting SREBP1, which is essential for the survival of cancer stem cells. Cancer stem cells, which cause the growth and metastasis of cancer cells and resistance to anticancer drugs, are highly dependent on lipid metabolism regulation by SREBP1, a transcription factor protein that promotes lipid synthesis. Therefore, the compound according to the present invention acts as an SREBP1 inhibitor and selectively suppresses SREBP1 to eliminate cancer stem cells and cancer cells, and therefore can be effective as a targeted anticancer agent.

[0055] In addition, the compound of the present invention is highly biocompatible, highly selective, orally bioavailable, non-toxic to normal cells, and acts as an SREBP1 inhibitor to specifically induce death only in cancer cell lines, so it can be effectively used as an efficient preventive and therapeutic agent for cancer without side effects. Cancer diseases that can be prevented, treated, or improved by treatment with the compound of the present invention are refractory solid cancers, and specifically, brain tumors such as glioma, glioblastoma, meningioma, pituitary adenoma, and neurilemmoma.

[0056] In one embodiment, a1 may be an integer of 0 to 2, and b1 may be an integer of 0 to 2.

[0057] In one embodiment, c1 may be an integer of 0 to 2.

[0058] In one embodiment, [ka] is a double bond, and Ar 1 teeth, [ka] and R 2 is haloC1-C4 alkyloxy or C6-C12 arylC1-C4 alkyloxy, a1 is an integer of 0 to 2, b1 is an integer of 0 to 2, R A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L 1 -Het 1 And L 1 is C1-C4 alkylene, Het 1 can be a C3-C8 heterocycloalkyl.

[0059] In one embodiment, [ka] is a double bond, and Ar 1 teeth, [ka] , [ka] or [ka] and R a and R b are each independently C1-C4 alkyl; R 2 is haloC1-C4 alkyloxy or C6-C12 arylC1-C4 alkyloxy, b1 is an integer of 0 to 2, R A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or [ka] where Z is O or S, and d can be an integer from 1 to 4.

[0060] In one embodiment, [ka] is a single or double bond, and Ar 1 teeth, [ka] and X 1 is CH or N, and R 3 is C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkoxy or C6-C12 arylC1-C4 alkyloxy, c1 is an integer of 0 to 2, R A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L 1 -Het 1 And L 1 is C1-C4 alkylene, Het 1can be a C3-C8 heterocycloalkyl.

[0061] In one embodiment, [ka] is a single or double bond, and Ar 1 teeth, [ka] , [ka] , [ka] , [ka] or [ka] and R 3 is C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkoxy or C6-C12 arylC1-C4 alkyloxy, c1 is an integer of 0 to 2, R A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or [ka] where Z is O or S, and d can be an integer from 1 to 4.

[0062] In one embodiment, the Ar 1 can be selected from the following structures:

[0063] [ka]

[0064] In one embodiment, R A is hydrogen, methyl, ethyl or [ka] It can be.

[0065] In one embodiment, the substituted thiazolidinedione derivative compound may be any one selected from the following compound group, but is not limited thereto:

[0066] (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, 5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione, (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(4-(t-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(t-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, and (Z)-5-((6-(4-(t-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.

[0067] The above-mentioned compounds can be prepared based on the following examples. In the following examples, representative examples are described, but if necessary, substituents can be added or removed, and the positions of the substituents can be changed. In addition, starting materials, reactants, reaction conditions, etc. can be changed based on techniques known in the art. If necessary, the type or position of the substituents at the remaining positions can be changed by those skilled in the art using techniques known in the art. More details will be described in the following examples.

[0068] The substituted thiazolidinedione derivative compounds according to one embodiment include all pharma- ceutically acceptable salts thereof as well as possible hydrates and solvates which may be prepared thereby.

[0069] The substituted thiazolidinedione derivative compound may be prepared and used in the form of a prodrug, hydrate, solvate, or pharma- ceutically acceptable salt in order to enhance in vivo absorption or increase solubility. The scope of the present invention includes not only the compound of Chemical Formula 1, but also its prodrug, hydrate, solvate, or pharma- ceutically acceptable salt.

[0070] The substituted thiazolidinedione derivative compound according to one embodiment can be used in the form of a pharma- ceutically acceptable salt, which is a salt prepared according to a method commonly used in the art, and the preparation method thereof is known to those skilled in the art. Specifically, the pharma- ceutically acceptable salt includes, but is not limited to, salts derived from pharmacologically or physiologically acceptable free acids and bases.

[0071] Acid addition salts formed with pharma- ceutically acceptable free acids are derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, and from organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid. Such pharma- ceutically non-toxic salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butane-1,4-dioate, hexaphosphate ... including san-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0072] The acid addition salt may be prepared by a conventional method. For example, the acid addition salt may be prepared by dissolving the substituted thiazolidinedione derivative compound according to an embodiment in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, or acetonitrile, adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess amount of acid under reduced pressure, drying, and crystallizing the resulting salt in an organic solvent.

[0073] Also, a pharma- ceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the substituted thiazolidinedione derivative compound according to one embodiment in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Here, as the metal salt, it is pharma-ceutical suitable to prepare sodium, potassium, or calcium salt, but it is not limited thereto. Also, the corresponding silver salt can be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0074] Hydrates of substituted thiazolidinedione derivative compounds according to one embodiment refer to compounds or pharma- ceutically acceptable salts thereof that contain stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0075] A solvate of a substituted thiazolidinedione derivative compound according to one embodiment refers to a compound or a pharma- ceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Solvents that can be used include those that are volatile and non-toxic.

[0076] That is, a substituted thiazolidinedione derivative compound according to an embodiment may be dissolved in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then a free acid or free base may be added thereto, followed by crystallization or recrystallization to form a solvate, including a hydrate.

[0077] Another embodiment provides a pharmaceutical composition for preventing or treating cancer, comprising a substituted thiazolidinedione derivative compound represented by the following chemical formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0078] [Chemical formula 2] [ka] In the above Chemical Formula 2, [ka] is a single or double bond, Ar 2 teeth, [ka] or [ka] and R 11 is C1-C10 alkyl, R 12 is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R 13 is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X 2 is CH or N, R Bis hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L 2 -Het 2 and L 2 is C1-C10 alkylene, Het 2 is a C3-C10 heterocycloalkyl; a2 is an integer of 0 to 3, b2 and c2 each independently represent an integer of 0 to 5.

[0079] In one embodiment, the pharmaceutical composition can be used for the purpose of treating, preventing and alleviating cancer diseases caused by abnormal cell growth. The cancer disease that can be prevented, treated or alleviated by the treatment of the pharmaceutical composition can be brain tumor.

[0080] Specifically, the pharmaceutical composition can selectively inhibit SREBP1 (sterol regulatory element-binding protein 1), and by selectively inhibiting SREBP1, it can exert a preventive or therapeutic effect against cancer. As a result, the pharmaceutical composition acts as an SREBP1 inhibitor and can specifically induce the death of cancer cell lines, particularly brain tumors, and can be effectively used without side effects as an efficient ameliorative, preventive and therapeutic agent for brain tumors having an EGF (epidermal growth factor) signal-dependent anticancer drug resistance mechanism.

[0081] According to one embodiment, the treatment with the substituted thiazolidinedione derivative compound inhibited SREBP1 and inhibited the proliferation of brain tumor cells. Thus, the substituted thiazolidinedione derivative compound according to the present invention may be effective in treating or preventing cancer diseases by selectively inhibiting SREBP1 in cancer tissues such as brain tumors, thereby inhibiting the proliferation of cancer cells.

[0082] In one embodiment, in Formula 2, a2 ​​may be an integer of 0 to 2, and b2 may be an integer of 0 to 2.

[0083] In one embodiment, in Formula 2, c2 may be an integer of 0 to 2.

[0084] In one embodiment, in Formula 2, [ka] is a double bond, and Ar 2 teeth [ka] and R 12 is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy, a2 is an integer of 0 to 2, b2 is an integer of 0 to 2, R B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L 2 -Het 2 And L 2 is C1-C4 alkylene, Het 2 can be a C3-C8 heterocycloalkyl.

[0085] In one embodiment, in Formula 2, [ka] is a double bond, and Ar 2 teeth, [ka] , [ka] or [ka] and R c and Rd are each independently C1-C4 alkyl; R 12 is C1-C4 alkyl, hydroxy, haloC1-C4 alkyloxy or C6-C12 arylC1-C4 alkyloxy; b2 is an integer of 0 to 2; R B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or [ka] where Z is O or S, and e can be an integer from 1 to 4.

[0086] In one embodiment, in Formula 2, [ka] is a single or double bond, and Ar 2 teeth, [ka] and X 2 is CH or N, and R 13 is C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkoxy or C6-C12 arylC1-C4 alkyloxy, c2 is an integer from 0 to 2, R B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L 2 -Het 2 And L 2 is C1-C4 alkylene, Het 2 can be a C3-C8 heterocycloalkyl.

[0087] In one embodiment, in Formula 2, [ka] is a single or double bond, and Ar 2 teeth, [ka] , [ka] , [ka] , [ka] or [ka] and R 13 is C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkoxy or C6-C12 arylC1-C4 alkyloxy, c2 is an integer from 0 to 2, R B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or [ka] where Z is O or S, and e can be an integer from 1 to 4.

[0088] In one embodiment, in Formula 2, Ar 2 can be selected from the following structures:

[0089] [ka]

[0090] In one embodiment, in Formula 2, R B is hydrogen, methyl, ethyl or [ka] It can be.

[0091] The substituted thiazolidinedione derivative compound of Formula 2 according to one embodiment may be any one selected from the following compound group, but is not limited thereto.

[0092] (Z)-5-((1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(p-tolyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(t-butyl)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((3,4-dimethyl-1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-phenyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, 5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione, (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(4-(t-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(t-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, and (Z)-5-((6-(4-(t-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.

[0093] The pharmaceutical composition according to one embodiment may further contain a conventional non-toxic pharma- ceutically acceptable carrier and / or excipient in addition to the active ingredient, and may be formulated into a conventional formulation in the pharmaceutical field, i.e., an oral or parenteral formulation, and may further contain a diluent such as a filler, extender, binder, wetting agent, disintegrant, or surfactant.

[0094] The pharma- ceutically acceptable carriers, excipients or diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, dextrin, cyclodextrin, such as α-, β-, and γ-cyclodextrin, hydroxyalkylcyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrin), talc, magnesium stearate, or mineral oil.

[0095] The pharmaceutical composition can be formulated into various forms, such as oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and injections of sterile injection solutions, by a conventional method depending on the purpose of use, and can be administered orally or via various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.

[0096] The oral formulation may optionally be enteric coated and exhibit delayed or sustained release due to the enteric coating, i.e., the oral formulation may be in a dosage form with immediate or modified release pattern.

[0097] The formulation for parenteral administration may be in a form having an immediate or modified release pattern, which may be a delayed or sustained release pattern.

[0098] The pharmaceutical composition according to one embodiment may further include fillers, anti-agglomerating agents, lubricants, wetting agents, flavorings, emulsifiers, preservatives, and the like.

[0099] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc., and these dosage forms may contain at least one commonly used diluent or excipient, such as a filler, extender, wetting agent, disintegrant, lubricant, binder, surfactant, etc., in addition to the active ingredient. As disintegrants, agar, starch, alginic acid or its sodium salt, anhydrous calcium hydrogen phosphate, etc. may be used, as lubricants, silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol, etc. may be used, and as binders, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropylcellulose, etc. may be used. Other diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc. can be used, and in some cases, commonly known boiling mixtures, absorbents, colorants, flavorings, sweeteners, etc. can be used together.

[0100] Examples of preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used. As bases for suppositories, witepsol, macrogol, twin 61, cacao butter, laurin butter, glycerol, gelatin, etc. can be used. Meanwhile, injections can include conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives. To prepare injections, the active ingredient is mixed with a stabilizer or buffer in water to prepare a solution or suspension, which can be prepared into a unit dosage form such as an ampoule or vial.

[0101] The pharmaceutical compositions according to one embodiment may be sterilized or may further comprise auxiliary substances such as preservatives, stabilizers, thickeners, wetting or emulsifying agents, salts for adjusting the osmotic pressure and / or buffers, and may further comprise other therapeutically effective substances, and may be formulated by conventional methods such as dissolving, dispersing, mixing, granulating, gelling or coating.

[0102] The pharma- ceutical effective amount of the substituted thiazolidinedione derivative compound, which is an active ingredient in the pharmaceutical composition according to one embodiment, can be determined by factors including the patient's health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route and excretion rate, treatment period, mixed or co-used drugs, and other factors well known in the medical field. Specifically, the effective amount of the substituted thiazolidinedione derivative compound in the pharmaceutical composition can vary depending on the patient's age, sex, and weight, and is generally about 0.001 to 500 mg / kg / day, preferably 0.01 to 100 mg / kg / day, and can be administered daily or every other day, or once or several times a day. However, it can be increased or decreased depending on the administration route, disease severity, sex, weight, age, etc., and the dosage does not limit the scope of the present invention in any way.

[0103] The pharmaceutical composition according to one embodiment can be administered orally or parenterally, and as an anti-cancer drug for oral administration to treat cancer, the substituted thiazolidinedione derivative compound can enter the gastrointestinal tract by oral administration or can be absorbed directly into the bloodstream from the mouth, e.g., by buccal or sublingual administration.

[0104] The pharmaceutical composition according to one embodiment can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered in sequence or simultaneously with conventional therapeutic agents, and can be administered as single or multiple doses. Taking into account all of the above factors, it is important to administer an amount that can obtain the maximum effect at the minimum amount without side effects, which can be easily determined by one skilled in the art.

[0105] Another embodiment provides a health functional food composition for preventing or improving cancer, comprising the substituted thiazolidinedione derivative compound, a hydrate thereof, or a food-logically acceptable salt thereof.

[0106] The food-based acceptable salts can be obtained by reacting the compound of the present invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. Also, the compound of the present invention can be obtained by reacting with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and amino acid salts such as arginine and lysine, but are not limited thereto.

[0107] The health functional food composition can be provided in the form of powder, granule, tablet, capsule, syrup or drink, and the health functional food can be used with other foods or food additives other than the compound of the present invention as an active ingredient, and can be used appropriately according to a conventional method.The amount of the active ingredient mixed can be appropriately determined according to its purpose of use, such as prevention, health or therapeutic treatment.

[0108] The health functional food composition may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc. In addition, it may contain natural fruit juice and fruit pulp for the production of fruit juice drinks and vegetable drinks. Such ingredients may be used independently or in combination.

[0109] In addition, the health functional food may further contain food additives, and the suitability of a substance as a "food additive" shall be determined in accordance with the specifications and standards for the relevant item, such as the general provisions and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified.

[0110] Examples of items listed in the "Food Additives Code" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon coloring, licorice extract, crystalline cellulose, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0111] The substituted thiazolidinedione derivative compound of the present invention contained in the health functional food composition can be used in an amount equivalent to the effective amount of the pharmaceutical composition. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health regulation, the amount can be less than the above range. Needless to say, the active ingredient can be used in an amount greater than the above range since there is no problem in terms of safety.

[0112] The health functional food composition can be formulated into various dosage forms such as meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, energy drinks, alcoholic beverages, vitamin complexes, etc.

[0113] Another embodiment provides a selective inhibitor of SREBP1 comprising the above-mentioned substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0114] Another embodiment provides a method for preventing or treating cancer, comprising the step of administering said substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, or said pharmaceutical composition to an individual suffering from or at risk of developing cancer.

[0115] The present invention also provides the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer.

[0116] The present invention also provides the use of the substituted thiazolidinedione derivative compound, its hydrate or its pharma- ceutically acceptable salt for the manufacture of a medicament for treating cancer.

[0117] Examples and experimental examples are specifically illustrated below. However, the examples and experimental examples described below are only a partial example, and the technology described in this specification is not limited thereto.

[0118] Example I: Synthesis of Phenyl-pyrrole e Skeleton Compound [Example 1] Preparation of (Z)-5-((1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 1) [ka]

[0119] Step 1: Preparation of 1-phenyl-1H-pyrrole-2-carbaldehyde (compound a-1) 1H-Pyrrole-2-carbaldehyde (200 mg, 2.1 mmol), copper(II) acetate hydrate (840 mg, 4.2 mmol), and triethylamine (851 mg, 8.4 mmol) were added to dichloromethane (15 ml), and then phenylboronic acid (769 mg, 6.31 mmol) was added dropwise and stirred at room temperature for 48 hours. After the reaction was completed, the mixture was extracted with EtOAc and water, and the organic layer was washed with salt water, dried over magnesium sulfate, and filtered. The filtered solution was distilled under reduced pressure, and the residue obtained was separated and purified by medium pressure liquid chromatography to obtain 1-phenyl-1H-pyrrole-2-carbaldehyde (compound a-1) (158 mg, 44% yield).

[0120] 1 H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.50-7.37 (m, 3H), 7.37-7.31 (m, 2H), 7.16 (dd, J = 4.0, 1.7 Hz, 1H), 7.06 (t, J = 1.9 Hz, 1H), 6.39 (dd, J = 4.0, 2.6 Hz, 1H).

[0121] Step 2: Preparation of (Z)-5-((1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 1) Compound a-1 (50 mg, 0.292 mmol) obtained in step 1, thiazolidine-2,4-dione (37 mg, 0.321 mmol), piperidine (0.029 ml, 0.292 mmol), and acetic acid (0.017 ml, 0.292 mmol) were dissolved in toluene (5 ml) and then stirred at 100 ° C for 2 hours to react. After the reaction was completed, the mixture was extracted with EtOAc and water, and the obtained organic layer was washed with salt water, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure was separated and purified using medium pressure liquid chromatography (silica gel, 0-30% EtOAc / hexane) to obtain the compound. The obtained compound was recrystallized using EtOAc to obtain the final target compound, (Z)-5-((1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 1) (28 mg, 35% yield).

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (br s, 1H), 7.65-7.52 (m, 3H), 7.46-7.41 (m, 3H), 7.30 (s, 1H), 6.72 (d, J = 3.8 Hz, 1H), 6.57-6.53 (m, 1H); LCMS (ESI), m / z = 270.95 [M+H] + .

[0123] [Example 2] Preparation of (Z)-5-((1-(p-tolyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 2) [ka]

[0124] Step 1: Preparation of 1-(p-tolyl)-1H-pyrrole-2-carbaldehyde (compound a-2) 1-(p-tolyl)-1H-pyrrole-2-carbaldehyde (compound a-2) was obtained (180 mg, 30% yield) in the same manner as in Step 1 of Example 1, except that 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane was used instead of phenylboronic acid.

[0125] 1 H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.27-7.20 (m, 4H), 7.15 (dd, J = 4.0, 1.6 Hz, 1H), 7.05-7.02 (m, 1H), 6.38 (dd, J = 3.9, 2.6 Hz, 1H), 2.41 (s, 3H).

[0126] Step 2: Preparation of (Z)-5-((1-(p-tolyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 2) The target compound, (Z)-5-((1-(p-tolyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 2) was obtained (25 mg, 53% yield) in the same manner as in Step 2 of Example 1, except that compound a-2 (0.162 mmol) was used instead of compound a-1.

[0127] 1 H NMR (400 MHz, (CD3)2CO) δ 10.88 (br s, 1H), 7.44 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.34-7.29 (m, 2H), 7.27 (dd, J = 2.7, 1.4 Hz, 1H), 6.74 (dd, J = 4.1, 0.9 Hz, 1H), 6.56-6.49 (m, 1H), 2.44 (s, 3H); LCMS (ESI), m / z = 284.93 [M+H] + .

[0128] [Example 3] Preparation of (Z)-5-((1-(4-(tert-butyl)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 3) [ka]

[0129] Step 1: Preparation of 1-(4-(tert-butyl)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-3) 1H-Pyrrole-2-carbaldehyde (300mg, 3.15mmol), copper(II) acetate hydrate (1.26g, 6.3mmol), and triethylamine (1.59g, 15.7mmol) were added to dichloroethane (15ml), and then (4-(tert-butyl)phenyl)boronic acid (1.12g, 3.15mmol) was added dropwise and stirred at 80°C for 48 hours. After the reaction was completed, the mixture was extracted with EtOAc and water, and the organic layer was washed with salt water, dried over magnesium sulfate, and filtered. The filtered solution was distilled under reduced pressure, and the residue obtained was separated and purified by medium pressure liquid chromatography to obtain 1-(4-(tert-butyl)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-3) (130mg, 18% yield).

[0130] 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 4.0, 1.6 Hz, 1H), 7.07 (t, J = 1.9 Hz, 1H), 6.40 (dd, J = 3.9, 2.7 Hz, 1H), 1.37 (s, 9H).

[0131] Step 2: Preparation of (Z)-5-((1-(4-(tert-butyl)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 3) The reaction was carried out at 100°C for 3 hours with stirring in the same manner as in step 2 of Example 1, except that compound a-3 (30 mg, 0.132 mmol) was used instead of compound a-1. After the reaction was completed, the mixture was extracted with EtOAc and water, and the organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure was separated by medium pressure liquid chromatography (silica gel, 0-30% EtOAc / hexane), and then further purified by preparative liquid chromatography (30-50% water / MeCN with 0.1% TFA) to obtain the target compound, (Z)-5-((1-(4-(tert-butyl)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 3) (20 mg, 46% yield, TFA salt).

[0132] 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.5 Hz, 2H), 7.47 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.21 (dd, J = 2.3, 1.5 Hz, 1H), 6.75 (d, J = 3.4 Hz, 1H), 6.53-6.47 (m, 1H), 1.40 (s, 9H); LCMS (ESI), m / z = 326.97 [M+H] + .

[0133] [Example 4] Preparation of (Z)-5-((1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 4) [ka]

[0134] Step 1: Preparation of 1-(4-hydroxyphenyl)-1H-pyrrole-2-carbaldehyde (compound a-4) 1-(4-hydroxyphenyl)-1H-pyrrole-2-carbaldehyde (compound a-4) was obtained (110 mg, 18% yield) in the same manner as in step 1 of example 1, except that (4-hydroxyphenyl)boronic acid was used instead of phenylboronic acid.

[0135] Step 2: Preparation of (Z)-5-((1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 4) The target compound, (Z)-5-((1-(4-hydroxyphenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 4) was obtained (7 mg, 15% yield) in the same manner as in Step 2 of Example 1, except that compound a-4 (30 mg, 0.160 mmol) was used instead of compound a-1.

[0136] 1 LCMS (ESI), m / z = 286.91 [M+H] + .

[0137] [Example 5] Preparation of (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 5) [ka]

[0138] Step 1: Preparation of 1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-5) Except for using (4-(trifluoromethoxy)phenyl)boronic acid instead of phenylboronic acid, 1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-5) was obtained (130 mg, 16% yield) in the same manner as in step 1 of example 1.

[0139] Step 2: Preparation of (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 5) The target compound, (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 5) was obtained (15 mg, 27% yield) in the same manner as in Step 2 of Example 1, except that compound a-5 (40 mg, 0.157 mmol) was used instead of compound a-1.

[0140] 1 LCMS (ESI), m / z = 354.87 [M+H] + .

[0141] [Example 6] Preparation of (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 6) [ka]

[0142] Step 1: Preparation of 1-(4-(benzyloxy)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-6) 1-(4-(benzyloxy)phenyl)-1H-pyrrole-2-carbaldehyde (compound a-6) was obtained (160 mg, 18% yield) in the same manner as in step 1 of example 1, except that (4-(benzyloxy)phenyl)boronic acid was used instead of phenylboronic acid.

[0143] 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 7.49-7.38 (m, 4H), 7.36 (d, J = 7.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.14 (dd, J = 4.0, 1.6 Hz, 1H), 7.04 (dd, J = 9.4, 2.6 Hz, 3H), 6.38 (dd, J = 3.9, 2.6 Hz, 1H), 5.11 (s, 2H).

[0144] Step 2: Preparation of (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 6)

[0145] The target compound, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 6) was obtained (28 mg, 41% yield) in the same manner as in Step 2 of Example 1, except that Compound a-6 (50 mg, 0.180 mmol) was used instead of Compound a-1.

[0146] 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.50-7.32 (m, 5H), 7.22 (d, J = 8.8 Hz, 2H), 7.13-7.03 (m, 3H), 6.74 (d, J = 3.8 Hz, 1H), 6.54-6.46 (m, 1H), 5.13 (s, 2H); LCMS (ESI), m / z = 377.02 [M+H] + .

[0147] [Example 7] Preparation of (Z)-5-((3,4-dimethyl-1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 7) [ka]

[0148] Step 1: Preparation of 3,4-dimethyl-1-phenyl-1H-pyrrole-2-carbaldehyde (compound a-7) 3,4-Dimethyl-1-phenyl-1H-pyrrole-2-carbaldehyde was obtained in the same manner as in step 1 of example 1, except that 3,4-dimethyl-1H-pyrrole-2-carbaldehyde was used instead of 1H-pyrrole-2-carbaldehyde (compound a-7) (210 mg, 65% yield).

[0149] 1 H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.48-7.34 (m, 3H), 7.34-7.27 (m, 2H), 6.80 (s, 1H), 2.38 (s, 3H), 2.06 (s, 3H).

[0150] Step 2: Preparation of (Z)-5-((3,4-dimethyl-1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 7) The target compound, (Z)-5-((3,4-dimethyl-1-phenyl-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione (compound 7) was obtained (10 mg, 17% yield) in the same manner as in Step 2 of Example 1, except that compound a-7 (40 mg, 0.201 mmol) was used instead of compound a-1.

[0151] 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.73 (s, 1H), 7.45-7.38 (m, 2H), 7.37-7.31 (m, 1H), 7.22 (d, J = 7.7 Hz, 2H), 6.88 (s, 1H), 2.17 (s, 3H), 2.06 (s, 3H); LCMS (ESI), m / z = 299.03 [M+H] + .

[0152] [Example 8] Preparation of (Z)-5-((1-phenyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 8) [ka]

[0153] Step 1: Preparation of 1-phenyl-1H-pyrrole e-3-carbaldehyde (compound a-8) 1-Phenyl-1H-pyrrole e-3-carbaldehyde (compound a-8) was obtained (158 mg, 44% yield) in the same manner as in step 1 of example 1, except that 1H-pyrrole e-3-carbaldehyde was used instead of 1H-pyrrole-2-carbaldehyde.

[0154] 1 H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.52-7.45 (m, 2H), 7.42 (dd, J = 8.6, 1.3 Hz, 2H), 7.36 (ddd, J = 8.3, 2.4, 1.2 Hz, 1H), 7.09 (dd, J = 3.7, 1.5 Hz, 1H), 6.81 (dd, J = 2.9, 1.6 Hz, 1H).

[0155] Step 2: Preparation of (Z)-5-((1-phenyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (compound 8) The target compound, (Z)-5-((1-phenyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (compound 8) was obtained (25 mg, 52% yield) in the same manner as in Step 2 of Example 1, except that compound a-8 (30 mg, 0.175 mmol) was used instead of compound a-1.

[0156] 1 H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.61-7.59 (m, 1H), 7.52 (t, J LCMS (ESI), m / z = 271.00 [M+H] + .

[0157] [Example 9] Preparation of (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 9) [ka]

[0158] Step 1: Preparation of 1-(4-(benzyloxy)phenyl)-1H-pyrrole-3-carbaldehyde (compound a-9) 1-(4-(benzyloxy)phenyl)-1H-pyrrole e-3-carbaldehyde (compound a-9) was obtained (20 mg, 3% yield) in the same manner as in step 1 of example 1, except that 1H-pyrrole e-3-carbaldehyde and (4-(benzyloxy)phenyl)boronic acid were used instead of 1H-pyrrole-2-carbaldehyde and phenylboronic acid.

[0159] 1 H NMR (400 MHz, CDCl3) δ 9.83 (s, 1H), 7.57 (t, J = 1.9 Hz, 1H), 7.47-7.29 (m, 7H), 7.07-7.03 (m, 2H), 6.99 (t, J = 2.3 Hz, 1H), 6.77 (dt, J = 5.4, 2.2 Hz, 1H), 5.11 (s, 2H).

[0160] Step 2: Preparation of (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (compound 9) The target compound, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (compound 9) was obtained (33 mg, 77% yield) in the same manner as in Step 2 of Example 1, except that compound a-9 (30 mg, 0.108 mmol) was used instead of compound a-1.

[0161] 1H NMR (400 MHz, DMSO-d6) δ 12.29 (br s, 1H), 7.82 (s, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.55 (dd, J = 8.9, 4.2 Hz, 2H), 7.51-7.44 (m, 2H), 7.44-7.37 (m, 2H), 7.37-7.31 (m, 1H), 7.14 (dd, J = 8.9, 4.2 Hz, 2H), 6.51 (s, 1H), 5.16 (d, J = 3.6 Hz, 2H); LCMS (ESI), m / z = 376.95 [M+H] + .

[0162] Example II: Synthesis of Phenyl-Pyridine or Phenyl-Pyrimidine Backbone Compounds [Example 10] Preparation of (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 10) [ka]

[0163] Step 1: Preparation of 2-(p-tolyl)isonicotinaldehyde (compound b-1) 2-Bromoisonicotinaldehyde (0.390g, 2.1mmol), 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (0.916g, 4.2mmol), Pd(PPh3)4 (0.242g, 0.210mmol) were added to toluene (5ml) under nitrogen, 2M Na2CO3 (5.3ml) was added dropwise, and the mixture was stirred at 100°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with EtOAc and water, and the organic layer was washed with salt water, dried over magnesium sulfate, and filtered. The filtered solution was distilled under reduced pressure, and the residue obtained was separated and purified by medium pressure liquid chromatography to obtain 2-(p-tolyl)isonicotinaldehyde (compound b-1) (151mg, 36% yield).

[0164] 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 8.01-7.93 (m, 2H), 7.61 (dd, J = 5.0, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 2.43 (s, 3H).

[0165] Step 2: Preparation of (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 10) Compound b-1 (100 mg, 0.507 mmol), thiazolidine-2,4-dione (71.3 mg, 0.608 mmol), and piperidine (60.2 μL, 0.608 mmol) were dissolved in ethanol (3 ml), and then the mixture was reacted at 100 ° C for 1.5 hours using a microwave reactor with stirring. After the reaction was completed, the mixture was extracted with EtOAc and water, and the organic layer obtained was washed with salt water, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure was separated and purified using medium pressure liquid chromatography (silica gel, 0-50% EtOAc / hexane) to obtain the compound. The obtained compound was recrystallized using EtOAc to obtain the final target compound, (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 10), which was solidified (6 mg, 4% yield).

[0166] 1 H NMR (400 MHz, MeOD) δ 8.71 (d, J = 5.2 Hz, 1H), 7.95-7.87 (m, 3H), 7.81 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H); LCMS (ESI), m / z = 297.01 [M+H] + .

[0167] [Example 11] Preparation of (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 11) [ka]

[0168] Step 1: Preparation of 2-(4-(tert-butyl)phenyl)isonicotinaldehyde (compound b-2) 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane was replaced with 4-(tert-butyl)phenyl)boronic acid in the same manner as in step 1 of example 10, except that 2-(4-(tert-butyl)phenyl)isonicotinaldehyde was obtained (compound b-2) (2.1 g, 82% yield).

[0169] 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.61 (dd, J = 4.9, 1.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 1.38 (s, 9H).

[0170] Step 2: Preparation of (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 11) The target compound, (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 11) was obtained (159 mg, 27% yield) in the same manner as in Step 2 of Example 10, except that compound b-2 (418 mg, 1.747 mmol) was used instead of compound b-1.

[0171] 1 H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 5.1 Hz, 1H), 8.43 (br s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.75 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.26-7.23 (m, 1H), 1.38 (s, 9H); LCMS (ESI), m / z = 339.09 [M+H] + .

[0172] [Example 12] Preparation of (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 12) [ka]

[0173] Step 1: Preparation of 2-(4-(trifluoromethyl)phenyl)isonicotinaldehyde (compound b-3) 2-(4-(trifluoromethyl)phenyl)isonicotinaldehyde (compound b-3) was obtained (219 mg, 41% yield) in the same manner as in step 1 of example 10, except that (4-(trifluoromethyl)phenyl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0174] 1 H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 9.00 (d, J = 4.8 Hz, 1H), 8.21 (s, 1H), 8.20-8.15 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 4.8, 1.1 Hz, 1H).

[0175] Step 2: Preparation of (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 12) The target compound, (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 12) was obtained (9 mg, 13% yield) in the same manner as in Step 2 of Example 10, except that compound b-3 (50 mg, 0.199 mmol) was used instead of compound b-1.

[0176] 1 H NMR (400 MHz, MeOD) δ 8.83 (d, J = 5.3 Hz, 1H), 8.23 ​​(d, J = 8.2 Hz, 2H), 8.11 (s, 1H), 7.92-7.82 (m, 3H), 7.61 (dd, J = 5.3, 1.3 Hz, 1H); LCMS (ESI), m / z = 350.95 [M+H]+ .

[0177] [Example 13] Preparation of (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 13) [ka]

[0178] Step 1: Preparation of 2-(4-methoxyphenyl)isonicotinaldehyde (compound b-4) 2-(4-Methoxyphenyl)isonicotinaldehyde (compound b-4) was obtained (364 mg, 79% yield) in the same manner as in step 1 of example 10, except that (4-methoxyphenyl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0179] 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.08 (s, 1H), 8.06-7.98 (m, 2H), 7.58 (dd, J = 4.9, 1.3 Hz, 1H), 7.08-6.97 (m, 2H), 3.89 (s, 3H).

[0180] Step 2: Preparation of (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 13) The target compound, (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 13) was obtained (5 mg, 2% yield) in the same manner as in Step 2 of Example 10, except that compound b-4 (140 mg, 0.657 mmol) was used instead of compound b-1.

[0181] 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 5.1 Hz, 1H), 8.00-7.92 (m, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.22 (dd, J = 5.2, 1.4 Hz, 1H), 7.06-7.00 (m, 2H), 3.89 (s, 3H); LCMS (ESI), m / z = 312.96 [M+H] + .

[0182] [Example 14] Preparation of (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 14) [ka]

[0183] Step 1: Preparation of 2-(4-(trifluoromethoxy)phenyl)isonicotinaldehyde (compound b-5) 2-(4-(trifluoromethoxy)phenyl)isonicotinaldehyde (compound b-5) was obtained (345 mg, 60% yield) in the same manner as in step 1 of example 10, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0184] 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.96 (d, J = 4.9 Hz, 1H), 8.14-8.09 (m, 3H), 7.67 (dd, J = 4.9, 1.3 Hz, 1H), 7.40-7.32 (m, 2H).

[0185] Step 2: Preparation of (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 14) The target compound, (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 14) was obtained (11 mg, 11% yield) in the same manner as in Step 2 of Example 10, except that compound b-5 (75 mg, 0.281 mmol) was used instead of compound b-1.

[0186] 1 H NMR (400 MHz, CDCl3) δ 8.91 (br s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.09-7.99 (m, 2H), 7.83 (s, 1H), 7.74 (s, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 5.1, 1.4 Hz, 1H); LCMS (ESI), m / z = 366.98 [M+H] + .

[0187] [Example 15] Preparation of (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 15) [ka]

[0188] Step 1: Preparation of 2-(4-(benzyloxy)phenyl)isonicotinaldehyde (compound b-6) 2-(4-(benzyloxy)phenyl)isonicotinaldehyde (compound b-6) was obtained (532 mg, 86% yield) in the same manner as in step 1 of example 10, except that (4-(benzyloxy)phenyl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0189] 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.86 (d, J = 4.9 Hz, 1H), 8.04-8.02 (m, 1H), 8.02-7.98 (m, 2H), 7.56-7.49 (m, 1H), 7.47-7.42 (m, 2H), 7.42-7.36 (m, 2H), 7.36-7.32 (m, 1H), 7.11-7.03 (m, 2H), 5.11 (s, 2H).

[0190] Step 2: Preparation of (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 15) The target compound, (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 15) was obtained (3 mg, 4.5% yield) in the same manner as in Step 2 of Example 10, except that compound b-6 (50 mg, 0.173 mmol) was used instead of compound b-1.

[0191] 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 5.1 Hz, 1H), 8.33 (br s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.51-7.31 (m, 7.22 (dd, J = 5.1, 1.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H); LCMS (ESI), m / z = 388.98 [M+H] + .

[0192] [Example 16] Preparation of (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 16) [ka]

[0193] Step 1: Preparation of 2-(o-tolyl)isonicotinaldehyde (compound b-7) 2-(o-tolyl)isonicotinaldehyde (compound b-7) was obtained (82.5 mg, 78% yield) in the same manner as in step 1 of example 10, except that o-tolylboronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0194] 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.96 (d, J = 4.9 Hz, 1H), 7.82 (s, 1H), 8.01 (dd, J = 4.9, 1.4 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.37-7.29 (m, 3H), 2.39 (s, 3H).

[0195] Step 2: Preparation of (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 16) The target compound, (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 16) was obtained (5.0 mg, 17% yield) in the same manner as in Step 2 of Example 10, except that compound b-7 (20 mg, 0.101 mmol) was used instead of compound b-1.

[0196] 1 H NMR (400 MHz, MeOD) δ 8.72 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.38-7.31 (m, 4H), 2.33 (s, 3H); LCMS (ESI), m / z = 297.00 [M+H] + .

[0197] [Example 17] Preparation of (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 17) [ka]

[0198] Step 1: Preparation of 2-(m-tolyl)isonicotinaldehyde (compound b-8) 2-(m-tolyl)isonicotinaldehyde (compound b-8) was obtained (97.8 mg, 92% yield) in the same manner as in step 1 of example 10, except that m-tolylboronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0199] 1 H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 4.9, 1.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H).

[0200] Step 2: Preparation of (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 17) The target compound, (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 17) was obtained (8.1 mg, 18% yield) in the same manner as in Step 2 of Example 10, except that compound b-8 (30 mg, 0.152 mmol) was used instead of compound b-1.

[0201] 1 H NMR (400 MHz, MeOD) δ 8.70 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 5.2, 1.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H); LCMS (ESI), m / z = 297.00 [M+H] + .

[0202] [Example 18] Preparation of (Z)-5-((2-(3-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 18) [ka]

[0203] Step 1: Preparation of 2-(3-(tert-butyl)phenyl)isonicotinaldehyde (compound b-9) 2-(3-(tert-butyl)phenyl)isonicotinaldehyde (compound b-9) was obtained (135 mg, 99% yield) in the same manner as in step 1 of example 10, except that (3-(tert-butyl)phenyl)boronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0204] 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.95 (d, J = 4.8 Hz, 1H), 8.12 (s, 1H), 8.10 (t, J = 1.8 Hz, 1H), 7.84 (dt, J = 7.5, 1.4 Hz, 1H), 7.63 (dd, J = 4.9, 1.4 Hz, 1H), 7.53-7.51 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 1.41 (s, 9H).

[0205] Step 2: Preparation of (Z)-5-((2-(3-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 18) The target compound, (Z)-5-((2-(3-(tert-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 18) was obtained (7.0 mg, 17% yield) in the same manner as in Step 2 of Example 10, except that compound b-9 (30 mg, 0.125 mmol) was used instead of compound b-1.

[0206] 1H NMR (400 MHz, MeOD) δ 8.72 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.43 (m, 2H), 1.40 (s, 9H); LCMS (ESI), m / z = 339.02 [M+H] + .

[0207] [Example 19] Preparation of (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 19) [ka]

[0208] Step 1: Preparation of 2-(3,5-dimethylphenyl)isonicotinaldehyde (compound b-10) 2-(3,5-Dimethylphenyl)isonicotinaldehyde (compound b-10) was obtained (247.5 mg, 44% yield) in the same manner as in step 1 of example 10, except that 3,5-dimethylphenylboronic acid was used instead of 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0209] 1 H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 7.68 (s, 2H), 7.62 (dd, J = 4.9, 1.3 Hz, 1H), 7.12 (s, 1H), 2.42 (s, 6H).

[0210] Step 2: Preparation of (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (compound 19) The target compound, (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 19) was obtained (16.5 mg, 22% yield) in the same manner as in Step 2 of Example 10, except that compound b-10 (50 mg, 0.237 mmol) was used instead of compound b-1.

[0211] 1 H NMR (400 MHz, MeOD) δ 8.61 (d, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.55 (s, 2H), 7.50 (s, 1H), 7.46 (dd, J = 5.3, 1.4 Hz, 1H), 7.12 (s, 1H), 2.40 (s, 6H); LCMS (ESI), m / z = 311.02 [M+H] + .

[0212] [Example 20] Preparation of 5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione (Compound 20) [ka]

[0213] Compound 11 (50 mg, 0.148 mmol) was dissolved in ethanol (3 ml), and Pd / C (31.4 mg, 0.030 mmol) and 37% HCl (0.121 ml, 1.477 mmol) were then added dropwise. The reaction mixture was stirred for 12 hours under hydrogen gas at 75 °C. After the reaction was completed, the mixture was filtered using a filter syringe, and the filtrate was distilled under reduced pressure to obtain a residue. The residue was separated and purified using medium pressure liquid chromatography (silica gel, 0-50% EtOAc / hexane) to obtain the target compound, 5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione (compound 20) (8 mg, 16% yield).

[0214] 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.12 (dd, J = 5.1, 1.4 Hz, LCMS (ESI), m / z = 341.05 [M+H] + .

[0215] [Example 21] Preparation of (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione (Compound 21) [ka]

[0216] Compound 11 (10 mg, 0.030 mmol) and K2CO3 (4.9 mg, 0.035 mmol) were dissolved in DMF (0.3 ml), and then iodomethane (2.2 μL, 0.035 mmol) was added and stirred for 4 hours. When the reaction was completed, it was extracted with EtOAc and water, and the obtained organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate and filtered. The filtered solution was distilled under reduced pressure, and the residue obtained was separated and purified by medium pressure liquid chromatography (silica gel, 0-50% EtOAc / hexane) to obtain the target compound, (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione (compound 21) (6 mg, 58% yield).

[0217] 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.26-7.24 (m, 1H), 3.28 (s, 3H), 1.38 (s, 9H); LCMS (ESI), m / z = 353.08 [M+H] + .

[0218] [Example 22] Preparation of (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione (Compound 22) [ka]

[0219] The same procedure as in Example 21 was followed, except that 4-(2-chloroethyl)morpholine·HCl salt was used instead of iodomethane, to obtain the target compound, (Z)-5-((2-(4-(tert-butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione (Compound 22) (10 mg, 38% yield).

[0220] 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.30-7.24 (m, 1H), 3.91 (t, J = 6.3 Hz, 2H), 3.72-3.58 (m, 4H), 2.64 (t, J = 6.3 Hz, 2H), 2.56-2.45 (m, 4H), 1.38 (s, 9H); LCMS (ESI), m / z = 452.22 [M+H] + .

[0221] [Example 23] Preparation of (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 23) [ka]

[0222] Step 1: Preparation of 6-phenylnicotinaldehyde (compound b-11) 6-Phenylnicotinaldehyde (compound b-11) was obtained (425 mg, 86% yield) in the same manner as in step 1 of example 10, except that 6-bromonicotinaldehyde and phenylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0223] 1 H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.13 (d, J = 1.9 Hz, 1H), 8.23 ​​(dd, J = 8.3, 2.2 Hz, 1H), 8.09 (dd, J = 7.8, 1.8 Hz, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.57-7.44 (m, 3H).

[0224] Step 2: Preparation of (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 23) The target compound, (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 23) was obtained (10 mg, 16% yield) in the same manner as in Step 2 of Example 10, except that compound b-11 (40 mg, 0.218 mmol) was used instead of compound b-1.

[0225] 1 H NMR (400 MHz, (CD3)2CO) δ 11.35 (br s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.24-8.14 (m, 2H), 8.10 (s, 1H), 7.85 (s, 1H), 7.58-7.43 (m, 4H); LCMS (ESI), m / z = 283.01 [M+H] + .

[0226] [Example 24] Preparation of (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 24) [ka]

[0227] Step 1: Preparation of 6-(4-methoxyphenyl)nicotinaldehyde (compound b-12) 6-(4-Methoxyphenyl)nicotinaldehyde (compound b-12) was obtained (382 mg, 83% yield) in the same manner as in step 1 of example 10, except that 6-bromonicotinaldehyde and (4-methoxyphenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0228] 1 H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.08 (d, J = 1.9 Hz, 1H), 8.19 (dd, J = 8.3, 2.1 Hz, 1H), 8.13-7.93 (m, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.09-6.90 (m, 2H), 3.89 (s, 3H).

[0229] Step 2: Preparation of (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 24) The target compound, (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 24) was obtained (15.4 mg, 21% yield) in the same manner as in Step 2 of Example 10, except that compound b-12 (50 mg, 0.234 mmol) was used instead of compound b-1.

[0230] 1H NMR (400 MHz, DMSO-d6) δ 12.72 (br s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.5 Hz, 1H), 7.98 (dd, J = 8.5, LCMS (ESI), m / z = 313.09 [M+H] + .

[0231] [Example 25] Preparation of (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 25) [ka]

[0232] Step 1: Preparation of 6-(4-(trifluoromethoxy)phenyl)nicotinaldehyde (compound b-13) 6-(4-(trifluoromethoxy)phenyl)nicotinaldehyde (compound b-13) was obtained (332 mg, 58% yield) in the same manner as in step 1 of example 10, except that 6-bromonicotinaldehyde and (4-(trifluoromethoxy)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0233] 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 9.14 (d, J = 1.6 Hz, 1H), 8.26 (dd, J = 8.2, 2.1 Hz, 1H), 8.19-8.07 (m, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.41-7.30 (m, 2H).

[0234] Step 2: Preparation of (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 25) The target compound, (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 25) was obtained (15 mg, 21% yield) in the same manner as in Step 2 of Example 10, except that compound b-13 (50 mg, 0.187 mmol) was used instead of compound b-1.

[0235] 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 8.9 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.04 (dd, J = 8.5, 2.2 Hz, 1H), 7.72 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H); LCMS (ESI), m / z = 366.99 [M+H] + .

[0236] [Example 26] Preparation of (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 26) [ka]

[0237] Step 1: Preparation of 5-phenylnicotinaldehyde (compound b-14) 5-Phenylnicotinaldehyde (compound b-14) was obtained (430 mg, 87% yield) in the same manner as in step 1 of example 10, except that 5-bromonicotinaldehyde and phenylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0238] 1 H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 9.08 (dd, J = 12.8, 1.9 Hz, 2H), 8.36 (t, J = 2.1 Hz, 1H), 7.66-7.59 (m, 2H), 7.55-7.38 (m, 3H).

[0239] Step 2: Preparation of (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 26)

[0240] The target compound, (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 26) was obtained (16 mg, 21% yield) in the same manner as in Step 2 of Example 10, except that Compound b-14 (50 mg, 0.273 mmol) was used instead of Compound b-1.

[0241] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.20 (t, J = 2.1 Hz, 1H), 7.91 (s, 1H), 7.81-7.75 (m, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.52-7.43 (m, 1H); LCMS (ESI), m / z = 282.95 [M+H] + .

[0242] [Example 27] Preparation of (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 27) [ka]

[0243] Step 1: Preparation of 5-(p-tolyl)nicotinaldehyde (compound b-15) 5-(p-Tolyl)nicotinaldehyde (compound b-15) was obtained (468 mg, 88% yield) in the same manner as in step 1 of example 10, except that 5-bromonicotinaldehyde and p-tolylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0244] 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 9.05 (d, J = 2.3 Hz, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.31 (t, J = 2.1 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H).

[0245] Step 2: Preparation of (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 27) The target compound, (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 27) was obtained (33 mg, 45% yield) in the same manner as in Step 2 of Example 10, except that compound b-15 (50 mg, 0.254 mmol) was used instead of compound b-1.

[0246] 1 H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.16 (t, J = 2.1 Hz, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H); LCMS (ESI), m / z = 296.99 [M+H] + .

[0247] [Example 28] Preparation of (Z)-5-((5-(4-(tert-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 28) [ka]

[0248] Step 1: Preparation of 5-(4-(tert-butyl)phenyl)nicotinaldehyde (compound b-16) 5-(4-(tert-butyl)phenyl)nicotinaldehyde (compound b-16) was obtained in the same manner as in step 1 of example 10, except that 5-bromonicotinaldehyde and 4-(tert-butyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (689 mg, 99% yield).

[0249] 1 H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 9.03 (d, J = 1.8 Hz, 1H), 8.34 (t, J = 2.1 Hz, 1H), 7.60-7.53 (m, 4H), 1.38 (s, 9H).

[0250] Step 2: Preparation of (Z)-5-((5-(4-(tert-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (compound 28) The target compound, (Z)-5-((5-(4-(tert-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 28) was obtained (1.9 mg, 3% yield) in the same manner as in Step 2 of Example 10, except that Compound b-16 (50 mg, 0.209 mmol) was used instead of Compound b-1.

[0251] 1 H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.18 (t, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 1.38 (s, 9H); LCMS (ESI), m / z = 338.93 [M+H] + .

[0252] [Example 29] Preparation of (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 29) [ka]

[0253] Step 1: Preparation of 4-phenylpicolinaldehyde (compound b-17) 4-Phenylpicolinaldehyde (compound b-17) was obtained (361 mg, 73% yield) in the same manner as in step 1 of example 10, except that 4-bromopicolinaldehyde and phenylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0254] Step 2: Preparation of (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 29) The target compound, (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 29) was obtained (30 mg, 38% yield) in the same manner as in Step 2 of Example 10, except that compound b-17 (50 mg, 0.273 mmol) was used instead of compound b-1.

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 5.1 Hz, 1H), 7.62-7.45 (m, 3H); LCMS (ESI), m / z = 282.90 [M+H] + .

[0256] [Example 30] Preparation of (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 30) [ka]

[0257] Step 1: Preparation of 4-(p-tolyl)picolinaldehyde (compound b-18) 4-(p-Tolyl)picolinaldehyde (compound b-18) was obtained (200 mg, 47% yield) in the same manner as in step 1 of example 10, except that 4-bromopicolinaldehyde and p-tolylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0258] 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 5.1, 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).

[0259] Step 2: Preparation of (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 30) The target compound, (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 30) was obtained (25 mg, 33% yield) in the same manner as in Step 2 of Example 10, except that compound b-18 (50 mg, 0.254 mmol) was used instead of compound b-1.

[0260] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.76 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.89 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.73 (dd, J = 5.2, 1.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); LCMS (ESI), m / z = 296.96 [M+H] + .

[0261] [Example 31] Preparation of (Z)-5-((4-(4-(tert-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 31) [ka]

[0262] Step 1: Preparation of 4-(4-(tert-butyl)phenyl)picolinaldehyde (compound b-19)

[0263] (4-(tert-butyl)phenyl)boronic acid (compound b-19) was obtained in the same manner as in step 1 of example 10, except that 4-bromopicolinaldehyde and 4-(tert-butyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (496 mg, 77% yield).

[0264] 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.73 (dd, J = 5.1, 1.9 Hz, 1H), 7.66-7.61 (m, 2H), 7.56-7.51 (m, 2H), 1.37 (s, 9H).

[0265] Step 2: Preparation of (Z)-5-((4-(4-(tert-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 31) The target compound, (Z)-5-((4-(4-(tert-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 31) was obtained (16 mg, 23% yield) in the same manner as in Step 2 of Example 10, except that compound b-19 (50 mg, 0.209 mmol) was used instead of compound b-1.

[0266] 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.78 (d, J = 5.2 Hz, 1H), 8.23 ​​(d, J = 1.1 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.73 (dd, J = 5.2, 1.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 1.33 (s, 9H); LCMS (ESI), m / z = 339.07 [M+H] + .

[0267] [Example 32] Preparation of (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 32) [ka]

[0268] Step 1: Preparation of 4-(4-(trifluoromethyl)phenyl)picolinaldehyde (compound b-20) 4-(4-(trifluoromethyl)phenyl)picolinaldehyde (compound b-20) was obtained (150 mg, 37% yield) in the same manner as in step 1 of example 10, except that 4-bromopicolinaldehyde and (4-(trifluoromethyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0269] 1 H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.89 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 2.2 Hz, 3H), 7.77 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H).

[0270] Step 2: Preparation of (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 32) The target compound, (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 32) was obtained (24 mg, 43% yield) in the same manner as in step 2 of example 10, except that compound b-20 (40 mg, 0.159 mmol) was used instead of compound b-1.

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.86 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.08 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), 7.82 (dd, J = 5.2, 1.7 Hz, 1H); LCMS (ESI), m / z = 351.00 [M+H] + .

[0272] [Example 33] Preparation of (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 33) [ka]

[0273] Step 1: Preparation of 4-(4-(trifluoromethoxy)phenyl)picolinaldehyde (compound b-21) 4-(4-(trifluoromethoxy)phenyl)picolinaldehyde (compound b-21) was obtained (337 mg, 47% yield) in the same manner as in step 1 of example 10, except that 4-bromopicolinaldehyde and (4-(trifluoromethoxy)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0274] 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.21-8.14 (m, 1H), 7.77-7.70 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H).

[0275] Step 2: Preparation of (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 33) The target compound, (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (compound 33) was obtained (16 mg, 29% yield) in the same manner as in step 2 of example 10, except that compound b-21 (40 mg, 0.150 mmol) was used instead of compound b-1.

[0276] 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.71-7.63 (m, 3H), 7.47 (dd, J = 5.1, 1.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H); LCMS (ESI), m / z = 367.02 [M+H] + .

[0277] [Example 34] Preparation of (Z)-5-((6-(4-(tert-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Compound 34) [ka]

[0278] Step 1: Preparation of 4-(4-(trifluoromethyl)phenyl)picolinaldehyde (compound b-20) 6-(4-(tert-butyl)phenyl)pyrimidine-4-carbaldehyde (compound b-22) was obtained (26 mg, 41% yield) in the same manner as in step 1 of example 10, except that 6-bromopyrimidine-4-carbaldehyde and 4-(tert-butyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane.

[0279] 1 H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 9.50-9.41 (m, 1H), 8.26-8.19 (m, 1H), 8.17-8.07 (m, 2H), 7.61-7.53 (m, 2H), 1.38 (s, 9H).

[0280] Step 2: Preparation of (Z)-5-((6-(4-(tert-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (compound 34) The target compound, (Z)-5-((6-(4-(tert-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (compound 34) was obtained (3 mg, 8% yield) in the same manner as in Step 2 of Example 10, except that compound b-22 (26 mg, 0.108 mmol) was used instead of compound b-1.

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 9.34 (s, 1H), 8.50 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 1.34 (s, 9H); LCMS (ESI), m / z = 340.10 [M+H] + .

[0282] <Experimental Example 1> Measurement of derivative activity using a cell-based assay system After confirming that the cell-based analysis system using the 6xSRE reporter vector (FIG. 1a) showed a specific copGFP change in response to the change in SREBP protein activity, the activity of the compound of the present invention was measured as follows.

[0283] First, as shown in (a) of FIG. 1, 6 copies of SRE (5'-ATCACCCCAC-3'), a DNA sequence to which the active form of the transcription factor SREBP binds, were inserted into the front end of the minimal CMV promoter 5' of the pGreenfire-Lenti-reporter vector to prepare a 6xSRE reporter vector. The 6xSRE reporter vector is a vector system in which the minimal CMV promoter is activated and copGFP is expressed only when the active form of SREBP binds to 6xSRE. The vector was introduced into HOG-GSC, a brain tumor stem cell, and then GFP high cells and GFP low cells were separated by FACS sorting. The active forms of SREBP1a and SREBP1c were overexpressed in the separated GFP-low cells (b of FIG. 1), and the increase in GFP expression was measured. As a result, it was confirmed that overexpression of active forms of SREBP1a and SREBP1c in isolated GFP-low cells increased GFP expression to 43.30% and 93.49% (Fig. 1c). The isolated GFP-high cells were treated with the control group DMSO, and fatostatin and FGH10019, which are known to inhibit SREBP activity, respectively, and changes in the amount of GFP expression were measured. As a result, it was confirmed that GFP expression was suppressed by approximately 50% when treated with the known substances fatostatin and FGH10019, respectively (Fig. 1d).

[0284] From the above results, it was confirmed that the cell-based analysis system using the 6xSRE reporter vector showed a specific change in copGFP in response to changes in SREBP protein activity, and this was used to screen the following derivatives.

[0285] HOG-GSC-6xSRE-copGFP_HIGH cells were dispensed into a 96-well plate (Corning) at 5000 cells / well, and after 24 hours, the compounds of the present invention were treated three times in each well at a concentration of 1 μM, and then all wells were photographed every 3 hours for 72 hours in an incubator (ThermoFisher) at 37°C and 5% CO2 using a real-time cell imaging device (Incucyte), and the changes in copGFP intensity were photographed. Then, the copGFP intensity of the HOG-GSC-6xSRE-copGFP_HIGH cells treated with DMSO as a control group was taken as 1 as the reference point, and the activity for each compound was normalized, and the activities of 11 compounds showing excellent efficacy were normalized and listed in Table A below.

[0286] [Table A] [Table 1]

[0287] <Experimental Example 2> Comparison of cell viability in brain tumor stem cells (MTS assay) HOG-GSC cells, which are brain tumor stem cells, were treated with 10 μM of 11 compounds or DMSO as a control, and the number of surviving cells after 72 hours was evaluated using the MTS assay.

[0288] Brain tumor stem cells, HOG-GSC, were seeded in a 96-well plate at 5000 cells per well, and cultured in an incubator (ThermoFisher) at 37°C and 5% CO2 for 24 hours to stabilize the cells. Then, 11 compounds of the present invention were treated at a concentration of 5μM, and the control group was treated with DMSO at the same volume as that of each compound. After treatment with the compound of the present invention and the control group, the cells were cultured in an incubator at 37°C and 5% CO2 for 72 hours. Then, cell viability was quantified using a Cell viability assay kit (LPS solution), which becomes darker due to the large amount of living cells in each well. The cell viability assay solution was treated, and the reaction was allowed to develop color for 3 hours in an incubator at 37°C and 5% CO2, and the absorbance at 450 nm was measured using a microplate reader (BioTek). The absorbance intensity of the control group was set to 1, and the absorbance of the cells treated with each compound was normalized and illustrated in Figure 2.

[0289] As a result, compounds with normalized MTS values ​​of less than 0.5 showed a 50% or greater decrease in cell viability compared to the control group, confirming that compounds 3, 10, 11, 12, 14, 15, 18, 19, 25, 28, and 31 of the present invention have a significant cell survival inhibitory effect on brain tumor stem cells (Figure 2).

[0290] <Experimental Example 3> Western blot assay HOG-GSC-6xSRE-copGFP_HIGH cells were treated with Compound 11 (Example 11) at 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.312 μM, 0.156 μM, or 0.078 μM, or with DMSO as a control, and cell samples were collected 24, 48, and 72 hours later.

[0291] The same amount of protein extracted from each cell sample was subjected to 8% SDS-PAGE gel electrophoresis. The proteins separated on the SDS-PAGE gel were transferred to a PVDF (Millipore, Billerica, MA, USA) membrane, and the protein-free parts of the membrane were blocked by reacting with 5% skim milk-Tris-Buffered Saline 0.1% Tween-20 (TBS-T) solution at room temperature for 1 hour.

[0292] The primary antibodies, anti-SREBP1 (BD Bioscience) and anti-SREBP2 (R&d systems), were diluted 1:1500 in 1% BSA (bovine serum albumin)-TBST solution, and anti-ACTIN (Sigma) was diluted 1:20000 in 1% BSA-TBS-T solution and incubated at 4°C for 16 hours.

[0293] The PVDF membrane was washed three times in TBS-T solution at room temperature with rocking at 30 rpm for 10 minutes, and then goat anti-rabbit IgG HRP (horseradish peroxidase) antibody and goat anti-mouse IgG HRP secondary antibody were diluted 1:10000 in 5% skim milk-TBS-T solution and rocked slowly at room temperature for 1 hour. The membrane was washed three times in TBS-T with rocking at 30 rpm for 10 minutes at room temperature, and then exposed to light using HRP substrate and visualized on film. The results are shown in Figure 3.

[0294] <Experimental Example 4> Cell viability analysis HOG-GSC, which is a brain tumor stem cell, was seeded in a 96-well plate at 5000 cells per well, and after 24 hours, compound 11 (Example 11) was treated three times at concentrations of 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.312 μM, 0.156 μM, and 0.078 μM, and the control group was treated three times at the same volume. After treatment, the cells were cultured in an incubator (ThermoFisher) at 37 ° C and 5% CO2 for 72 hours. Then, cell viability according to the concentration of compound 11 (Example 11) was compared using a Cell viability assay kit (LPS solution) in which the color becomes darker due to the large amount of living cells in each well. Then, the absorbance at 450 nm was measured using a microplate reader (BioTek), and the absorbance at each concentration was normalized based on the absorbance intensity of the control group set at 1, and the normalized values ​​are shown in FIG.

[0295] Brain tumor stem cells HOG-GSC were treated with various doses of compound 11 (Example 11) and cell viability was measured. The cell viability of HOG-GSC was significantly decreased compared to the control group DMSO, and the cell viability of HOG-GSC was decreased in proportion to the concentration of compound 11 (Example 11) (Figure 4).

[0296] This demonstrates that the compounds of the present invention have excellent cell-killing effects on brain tumor stem cells and can be used as brain tumor therapeutic agents that target brain tumor stem cells.

[0297] <Experimental Example 5> In vivo PK study and in vivo brain tissue distribution study I. In vivo PK studies 1.1. Experimental drugs and excipients Test drug: Compound 11 Vehicle: 10% DMSO, 75% PEG400, 15% Saline

[0298] 1.2.Experimental system Mice, CRljOri:CD1(ICR), SPF, 6 weeks old (7 weeks old at time of administration)

[0299] 1.3. Route of Administration Oral (PO), Intravenous (IV)

[0300] 1.4. Method and frequency of administration After obtaining the mice, they were used in the experiment after a 5-day acclimatization period. The dosage was 25 mg / kg for oral administration and 5 mg / kg for intravenous administration. The dosage for each individual was calculated based on the body weight after fasting (on the day of administration). The oral administration group (PO) was administered orally once using a disposable syringe (1 ml) with an oral administration probe attached, and the intravenous administration group (IV) was administered intravenously into the tail vein using a disposable syringe (1 ml).

[0301] 1.5. Blood collection and plasma separation Approximately 0.3 mL of blood was collected from the jugular vein using a 1 mL syringe (25G) that had been treated with 3.8% sodium citrate (approximately 30-40 μL), placed in a microtube (QSP, 1.5 mL), and centrifuged at 12,000 RPM / 3 min to collect plasma. Plasma was stored frozen at -80°C until analysis, and all animals in the pharmacokinetics experimental group were euthanized after blood collection.

[0302] Blood was collected at the following times:

[0303] [Table 2]

[0304] [Table 3]

[0305] 1.6. Concentration Analysis and Evaluation Experimental materials Mouse blank plasma (Biochemed, 029-APSC-MP-ICR, Sodium citrate)

[0306] Internal standard compound: Chlorpropamide (TRC, C424800)

[0307] Sample preparation 580 μl of acetonitrile (containing an internal standard) was added to 20 μl of plasma / tissue, followed by vortexing and centrifugation at 15,000 rpm for 5 minutes at 4° C. After centrifugation, the resulting supernatant was analyzed by LC-MS / MS.

[0308] 1.7.Result analysis PK parameters were calculated using the Phoenix WinNonlin 6.4 version (Pharsight, USA) program with a non-compartmental analysis model.

[0309] 1.8.Experimental Results Table 1 below and FIG. 5 show the plasma drug concentrations after oral administration (25 mg / kg).

[0310] [Table 1] [Table 4]

[0311] Table 2 below shows the plasma drug concentrations after intravenous administration (5 mg / kg).

[0312] [Table 2] [Table 5]

[0313] When administered orally at 25 mg / kg, the half-life was 3.9 hours, the Tmax was 1.6 hours, the Cmax was 5042.5 ng / ml, and the AUClast was 39412.0 hr. * ng / ml. In addition, when 25 mg / kg was administered orally, the bioavailability (BA) was 62.4% compared to when 5 mg / kg was administered intravenously. Therefore, it was confirmed that the compound according to the present invention exhibits a degree of exposure in the body suitable for oral administration.

[0314] II.In vivo brain tissue distribution test 2.1. Experimental drugs and excipients Test drug: Compound 11 Vehicle: 20% hydroxypropyl-β-cyclodextrin in water with 1% DMSO

[0315] 2.2.Experimental system Mice, Hsd:ICR (CD-1R, SPF, 4 weeks old (7 weeks old at time of administration)

[0316] 2.3. Route of Administration Oral Administration (PO)

[0317] 2.4. Method and frequency of administration After obtaining the mice, they were quarantined and acclimatized for two weeks before being used in the experiment. The dosage was 25 mg / kg. The dosage for each individual was calculated based on the body weight after 15 hours of fasting (on the day of administration), and was orally administered once using a disposable syringe (1 ml) with an oral administration probe attached.

[0318] 2.5. Blood collection and brain tissue collection After inhalation anesthesia, blood was collected by cardiac sampling using a 1 mL syringe, placed in a K2-EDTA-treated tube, and centrifuged at 8,000 RPM and 4°C for 20 minutes, and plasma was collected from the supernatant. After blood collection, animals were perfused with the heart, and brain tissue was extracted. The olfactory bulb, cerebellum, pons, and medulla oblongata were removed from the extracted brain tissue. The collected plasma and brain tissue were frozen and stored at -80°C until analysis.

[0319] Blood and brain tissue collection times are as follows:

[0320] [Table 6]

[0321] To ensure sufficient samples for analysis, brain tissue and blood samples obtained from two individuals were mixed (pulled) and used (three repeated samples were obtained from six animals per collection). Plasma and brain tissue were collected in the same way from mice of the same age that had not been administered the compound, and used as blank plasma and blank tissue, respectively, when analyzing the substance concentration.

[0322] 2.6. Concentration Analysis and Evaluation Experimental materials Internal standard compound: Verapamil hydrochloride (TCI, V0118)

[0323] Sample preparation 10μL of plasma sample was mixed with 190μL of acetonitrile containing 200ng / mL of internal standard, and vortexed at 2,500RPM for 60 seconds. Then, centrifuged at 12,000RPM for 5 minutes, and 50μL of the supernatant was taken and mixed with 50μL of acetonitrile. 2μL of this was injected into the LC-MS / MS.

[0324] The brain tissue was weighed, and then triple distilled water equivalent to 4 times the weight (w / v=1 / 4) was added and homogenized using a homogenizer. 10μL of the homogenized tissue mixture was taken, and 190μL of acetonitrile containing 50ng / mL of an internal standard was added, followed by vortexing at 2,500RPM for 60 seconds. Then, it was centrifuged at 12,000RPM for 10 minutes, and 2μL of the supernatant was taken and injected into the LC-MS / MS.

[0325] 2.7.Result analysis PK parameters were calculated using a non-compartmental analysis model using PKSolver 2.0 software.

[0326] 2.8.Experimental Results FIG. 6 shows the concentrations of Compound 11 in the blood and brain tissue after oral administration (25 mg / kg), and the PK parameters calculated therefrom are shown in Table 3 below.

[0327] [Table 3] [Table 7]

[0328] After oral administration, the concentration of the drug in the brain tissue was analyzed, and the ratio of the concentration in the brain tissue to that in the blood was found to be 0.470 on average and 0.777 at maximum. The ratio of the drug exposure in the brain tissue to that in the blood (area under the curve, AUC) was found to be 0.543.

[0329] <Experimental Example 6> In vivo efficacy evaluation In order to confirm the tumor growth inhibitory efficacy of the example compounds according to the present invention in an animal model, the following anticancer efficacy evaluation was carried out (FIG. 7).

[0330] First, a brain tumor stem cell line, HOG-GSC, was transplanted into the caudate putamen in the brain of a BALB / C nude mouse to establish an orthotopic xenograft model. After transplantation of the brain tumor stem cells, the compound of the present invention was orally administered for three weeks, starting from the seventh day, with a schedule of five days on and two days off, and the control group was administered only the vehicle in the same manner. Thereafter, the survival time of the mice was investigated based on the clinical findings that appeared as the brain tumor grew in the animals, and it was confirmed whether the administration of the compound of the present invention delayed the death of the animals due to the tumor. In addition, on the 16th day after tumor transplantation, the control group mice and the mice administered with the compound of the present invention were simultaneously euthanized, and brain tissue was excised to compare the size of the brain tumor on the same day.

[0331] The results of this anticancer efficacy evaluation are shown in FIGS.

[0332] FIG. 8 is a graph showing the survival rate of mice over time, which shows that animals administered with an embodiment compound of the present invention survived for a longer period of time than control animals.

[0333] FIG. 9 is a photograph of the brain tissue of the last surviving mouse on day 66 after tumor implantation, in which no tumor was observed.

[0334] Figure 10 is a photograph of mouse brain tissue 16 days after tumor implantation, and Table 4 is a quantification of the experimental results of Figure 10 as the ratio of tumor cross-sectional area to the cross-sectional area of ​​the entire brain tissue. It was confirmed that the tumor size was reduced or no tumor was found in the case of administration of the compound of the present invention compared to the control group. This shows that the compound of the present invention has excellent tumor growth inhibitory effect and can be used as a new brain tumor therapeutic agent that targets brain tumor stem cells.

[0335] [Table 4] [Table 8]

Claims

1. A substituted thiazolidinedione derivative compound represented by the following chemical formula 1, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. [Chemical formula 1] 【Chemistry 1】 In the above Chemical Formula 1, 【Chemistry 2】 is a single or double bond, Ar １ teeth, 【Chemistry 3】 or 【Chemistry 4】 and R １ is C1-C10 alkyl, R ２ is halo C1-C10 alkyloxy or C6-C12 aryl C1-C10 alkyloxy; R ３ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X １ is CH or N, R Ａ is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L １ -Het １ and L １ is C1-C10 alkylene; Het １ is a C3-C10 heterocycloalkyl; a1 is an integer from 0 to 3, b1 and c1 each independently represent an integer of 0 to 5.

2. The above 【Chemistry 5】 is a double bond, and Ar １ teeth, 【Chemistry 6】 and R ２ is haloC1-C4 alkyloxy or C6-C12 arylC1-C4 alkyloxy; a1 is an integer from 0 to 2, b1 is an integer from 0 to 2, R Ａ is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L １ -Het １ and L １ is C1-C4 alkylene; Het １ The substituted thiazolidinedione derivative compound, its hydrate, or a pharma- ceutically acceptable salt thereof according to claim 1, wherein: is C3-C8 heterocycloalkyl.

3. The Ar １ teeth 【Chemistry 7】 and X １ is CH or N, R ３ is C1-C4 alkyl, haloC1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkoxy or C6-C12 arylC1-C4 alkyloxy; c1 is an integer from 0 to 2, R Ａ is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or -L １ -Het １ and L １ is C1-C4 alkylene; Het １ The substituted thiazolidinedione derivative compound, its hydrate, or a pharma- ceutically acceptable salt thereof according to claim 1, wherein: is C3-C8 heterocycloalkyl.

4. Ar １ The substituted thiazolidinedione derivative compound according to claim 1, its hydrate or a pharma- ceutically acceptable salt thereof, wherein: 【Chemistry 8】

5. The R Ａ is hydrogen, methyl, ethyl or 【Chemistry 9】 The substituted thiazolidinedione derivative compound according to claim 1, wherein:

6. The compound represented by Chemical Formula 1 is any one selected from the following compound group, a stereoisomer thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof according to claim 1: (Z)-5-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((1-(4-(benzyloxy)phenyl)-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(p-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(o-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(m-tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3-(t-butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione, 5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione, (Z)-5-((2-(4-(t-butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione, (Z)-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(p-tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((5-(4-(t-butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(p-tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(t-butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, (Z)-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione, and (Z)-5-((6-(4-(t-butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.

7. A pharmaceutical composition for preventing or treating cancer, comprising a substituted thiazolidinedione derivative compound represented by the following chemical formula 2, a hydrate thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient: [Chemical formula 2] 【Chemistry 10】 In the above Chemical Formula 2, 【Chemistry 11】 is a single or double bond, Ar ２ teeth, 【Chemistry 12】 or 【Chemistry 13】 and R １１ is C1-C10 alkyl, R １２ is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R １３ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X ２ is CH or N, R Ｂ is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ２ -Het ２ and L ２ is C1-C10 alkylene; Het ２ is a C3-C10 heterocycloalkyl; a2 is an integer from 0 to 3, b2 and c2 each independently represent an integer of 0 to 5.

8. The pharmaceutical composition of claim 7, wherein the cancer is a brain tumor.

9. The pharmaceutical composition according to claim 7, which selectively inhibits SREBP1 (sterol regulatory element-binding protein-1).

10. A health functional food composition for preventing or improving cancer, comprising as an active ingredient a substituted thiazolidinedione derivative compound represented by the following chemical formula 2, a hydrate thereof or a food-logically acceptable salt thereof. [Chemical formula 2] 【Chemistry 14】 In the above Chemical Formula 2, 【Chemistry 15】 is a single or double bond, Ar ２ teeth, 【Chemistry 16】 or 【Chemistry 17】 and R １１ is C1-C10 alkyl, R １２ is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; R １３ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy; X ２ is CH or N, R Ｂ is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ２ -Het ２ and L ２ is C1-C10 alkylene; Het ２ is a C3-C10 heterocycloalkyl; a2 is an integer from 0 to 3, b2 and c2 each independently represent an integer of 0 to 5.

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