KR102304478B1 - Heterocyclic compound decomposing Ras and use thereof - Google Patents

Abstract

The present invention relates to a compound by simultaneously degrading β-catenin and a Ras protein containing a K-Ras mutation, and the compound according to the present invention inhibits cancer proliferation by regulating the signal transduction in key major signaling pathways related to cancer And by inducing apoptosis of cancer cells, it has an effect on cancer treatment of cancer patients who show resistance to conventional anticancer drugs due to Wnt signaling system abnormality and Ras gene mutation.

Description

Heterocyclic compound decomposing Ras and use thereof

The present invention relates to a compound that simultaneously decomposes β-catenin and Ras protein, a method for preparing the same, and uses thereof.

After President Nixon declared war on cancer in the 1970s, the development of anticancer drugs that target the rapid cell growth of cancer cells has been promoted to develop anticancer drugs that specifically act on signal transmitters. However, cancer is caused by simultaneous mutations of various oncogenes (increased amount of beta-catenin due to phosphorylation deficiency mutation, abnormal activation by Ras protein mutation, abnormal activation of PI3K and mTOR signaling systems, etc.) In recent years, the need for multi-target anticancer drugs that can control complex problems at once has begun to emerge. Therefore, there is a current need to develop a multi-target anticancer drug having a certain degree of specificity without being toxic.

Ras is a protein that regulates signal transduction in key key signaling pathways related to cancer, such as PI3K and mTOR, and can be a good target for the development of multi-target anticancer drugs. Ras is found to have an average of 30% mutations in cancer (72 to 90% for pancreatic cancer, 32 to 57% for colorectal cancer, and 15 to 50% for lung cancer in the case of K-Ras). A lot of effort has been made to do this.

Numerous pharmaceutical companies have made efforts to develop farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase inhibitors (GGTIs) that inhibit the movement to the cell membrane, one of the most important processes for Ras activation. Or, most of the studies in the clinical stage have ended in failure due to reasons such as limited patient application. Currently, there is no anticancer drug that can control Ras that can be applied clinically, and some researchers have tried to control Ras expression using siRNA or shRNA in vitro as a temporary measure, but in actual patient application and industrialization, extremely limited [(a) World J Gastroenterol 11, (2005), 2026; (b) Cancer Sci 98, (2007), 1128; (c) Cancer Res. 70, (2010), 7253].

The present inventors have continuously investigated the mechanism by which the Ras protein itself is degraded into a polyubiquitination-dependent form by inhibition of the Wnt/β-catenin signaling pathway. The present inventors have identified that Ras protein can be degraded through inhibition of this signaling system through APC, Axin, and glycogen synthase kinase 3β (GSK3β), which are negative regulators of the wint/beta-catenin signaling system. When the wint/betacatenin signaling pathway was negatively regulated, betacatenin and Ras proteins were degraded together. Ras protein was phosphorylated by GSK3β and β-TrCP E3 linker was involved, and proteolysis proceeded [(a) Journal of Cell Science. 118, (2005), 313-322; (b) Journal of Cell Science. 119, (2006); Science Signaling. 5, (2012), ra30]. As described above, both Wnt/β-catenin and Ras pathways are abnormally activated and interact to promote the development and progression of most cancers, so inhibition of the signal transduction may be an ideal strategy for cancer treatment have. Accordingly, the development of a novel substance capable of simultaneously inhibiting the Wnt/β-catenin and Ras signaling pathways is required.

[Prior art literature]

[Non-patent literature]

World J Gastroenterol 11, (2005), 2026

Cancer Sci 98, (2007), 1128

Cancer Res. 70, (2010), 7253

Journal of Cell Science. 118, (2005), 313-322

Journal of Cell Science. 119, (2006) 819-827

Science Signaling. 5, (2012), ra30

The problem to be solved by the present invention is to provide a compound that simultaneously decomposes β-catenin and Ras protein as a novel anticancer agent that can solve the problem of existing anticancer drugs that do not exhibit anticancer effects due to Ras gene mutation.

Another object to be solved by the present invention is to provide a pharmaceutical composition for the treatment of cancer of a cancer patient having a K-Ras mutant type comprising a compound that simultaneously decomposes β-catenin and Ras protein as an active ingredient.

The present invention provides a compound that simultaneously decomposes β-catenin and Ras protein represented by the following [Formula 1].

[Formula 1]

In the above [Formula 1],

은 E-form 또는 Z-form 이고;

is E-form or Z-form;

Y is S or O;

Z is S or NR _x ;

R _x is H, C _1-6 alkyl or C _{1-3 alkylC 6-12} aryl;

X is a 5-6 membered heteroaryl containing 1 to 2 heteroatoms nitrogen, 8 to 9 membered condensed heteroaryl containing 1 to 2 heteroatom nitrogens, and 10 membered fused heteroaryl containing 2 heteroatoms nitrogen is selected from; The heteroaryl and condensed heteroaryl are unsubstituted, N-substituted with a substituent selected from phenyl, benzyl and pyridyl, or 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy C-substituted with dog; wherein said N-substituted phenyl, benzyl or pyridyl is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;

R ₁ is hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH ₂ ) _n C(O)R ₂ , (CH ₂ ) _m R ₄ , (CH ₂ ) _n CONHR ₅ , CHR ₃ R ₄ , (CH ₂ ) _m COONHR ₃ , CH ₂ CR ₃ R ₆ R ₇ , -L ₁ -C(O)NHR ₃ , naphthyl, (CH ₂ ) _m NHC(O)R ₃ , (CH ₂ ) _m COR ₇ or (CH ₂ ) _m NHSO ₂ R ₃ , the heteroatom of the 4-6 membered heterocycloalkyl is nitrogen, and the 4-6 membered heterocycloalkyl is unsubstituted, C _1-6 alkyl, C _1-6 alkyl C _6-12 Aryl, C _6-12 ArylC _1-6 Alkyl, TrifluoroC _2-6 Alkyl, C _2-6 Alkenyl, -C(O)R ₅ , -SO ₂ R ₃ , -COOR ₃ , -SO ₂ NHCOOR ₃ , -SO ₂ NH ₂ and C(O)NR ₂ N-substituted with a substituent selected from R ₃ or C _{-substituted with -COOC 1-6 alkylC 6-12} aryl group, the C _{1-6 alkylC 6-12} aryl and C _6-12 arylC _1-6 alkyl is unsubstituted or _{selected from among C 1-6} alkoxy, nitrile, halogen, C _1-6 alkyl, CF ₃ , hydroxy and OCF ₃ . substituted with one or more selected substituents,

R ₂ is selected from C _1-6 alkyl, C _1-6 alkoxy, dibenzylaminyl and C _1-3 alkylpiperazinyl,

R ₃ is C _1-6 alkyl,

R ₄ is OH, COOH, indolyl, benzooxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C _1-3 alkylpiperazinyl, mono- or di-C _1-3 alkylamino, selected from C _1-3 alkyloxadiazolyl, imidazolyl, triazolyl and C _6-12 aryl, wherein the C _6-12 aryl is unsubstituted or C _1-6 alkoxy, nitrile, halogen, C _{1 - 6} alkyl, CF ₃ , C(O)C _1-6 alkyl, -SC _1-6 alkyl, hydroxy, OCF ₃ , may be substituted with 1 to 3 substituents selected from dimethylaminyl and diisopropylaminyl; , when the substituents are plural, the substituents are the same as or different from each other, and the indolyl and benzoxazolyl may be unsubstituted or substituted with 1 to 2 substituents selected from _{hydroxy, halogen and C 1-6 alkyl.} and when the substituents are plural, the substituents are the same as or different from each other;

R ₅ is C _1-6 alkyl, C _6-12 aryl, C _6-12 arylC _1-6 alkyl, oxazole, pyridinylC _1-3 alkyl or morpholinoC _1-3 alkyl;

R ₆ is C _1-6 alkyl;

R ₇ is (CH ₂ ) _m CONH(CH ₂ )mCH ₃ , (CH ₂ ) _m COOH or C(O)NHR ₃ ;

L ₁ is phenylene;

n is an integer from 0 to 5,

m is an integer from 1 to 5,

Adjacent R ₃ and R ₆ each independently exist or combine with each other to form a ring.

In addition, the present invention provides a pharmaceutical composition for cancer treatment of a cancer patient having a K-Ras mutant type comprising the compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient.

According to the present invention, the cancer patient may be a cancer patient having a Wnt signaling system abnormality.

According to the present invention, the cancer is selected from the group consisting of colon cancer, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, kidney cancer, thyroid cancer, rectal cancer, hematopoietic tumor, malignant melanoma, neuroblastoma, malignant melanoma and rhabdomyosarcoma. can

According to the present invention, the cancer may be metastatic cancer.

The compound according to the present invention binds to axin, a negative regulator of the Wnt/β-catenin signaling system, and promotes the binding of axin and β-catenin destruction complex to β-catenin By simultaneously degrading Ras protein and K-Ras mutation, it can inhibit the proliferation of cancer and induce apoptosis of cancer cells by regulating the signal transduction in key key signaling pathways related to cancer. In particular, since the Wnt signaling system abnormality and Ras gene mutation (K-ras) can exhibit anticancer effects with excellent efficiency against cancers that are resistant to conventional anticancer drugs, treatment of cancer patients with resistance to conventional anticancer drugs It can also be usefully applied as a pharmaceutical composition for

1 to 3 are results of comparing the degradation of β-catenin and Ras protein by treating the SW480 colorectal cancer cell line having APC and K-Ras mutations with the comparative drug KYA1797K and derivatives according to an embodiment of the present invention.
4 is a result of comparing the inhibition of cell formation by treating the SW480 colorectal cancer cell line having APC and K-Ras mutations with the comparative drug KYA1797K and derivatives according to an embodiment of the present invention.

Abnormal activation of the Wnt/β-catenin signaling pathway due to mutations in genes involved in the Wnt/β-catenin signaling pathway is often the cause of cancer. . However, even if a substance that inhibits the Wnt/β-catenin signaling system is primarily selected, cancer development is not due to overexpression of a ligand that activates the Wnt/β-catenin signaling system, but rather a key molecule such as APC or β-catenin. ), it is important to discover small-molecular compounds that target the signaling substances that act in the cytoplasm or nucleus of this signaling system because most of them are caused by mutations in the genes.

On the other hand, there are many reports that the occurrence of such cancer is not caused by the Wnt/β-catenin signaling system alone, but is induced by the genetic mutation of the Ras/MAPK signaling system-related gene, which is closely related to cancer, is also induced. In fact, many anticancer drugs have been selected as substances that inhibit major proteins constituting the Ras/MAPK signaling system. Many developed anticancer drugs were developed as substances that inhibit EGFR, the most upstream of the Ras-MAPK signaling system, or inhibit MEK, an intermediate phosphorylation protein. However, recently, it has been reported that these anticancer drugs have little effect on cancers with Ras mutations.

Accordingly, the present inventors tried to discover a substance that simultaneously inhibits the Wnt/β-catenin signaling system and the Ras/MAPK signaling system, and through this, β-catenin and Ras and Ras mutations, specifically K-Ras, are simultaneously degraded. The present invention was completed by discovering compounds that can do this, and confirming that these compounds are effective in the treatment of cancer in cancer patients who are resistant to conventional anticancer drugs.

The present invention provides a compound that simultaneously decomposes β-catenin and Ras protein represented by the following [Formula 1].

[Formula 1]

In the above [Formula 1],

은 E-form 또는 Z-form 이고;

is E-form or Z-form;

Y is S or O;

Z is S or NR _x ;

R _x is H, C _1-6 alkyl or C _{1-3 alkylC 6-12} aryl;

X is a 5-6 membered heteroaryl containing 1 to 2 heteroatoms nitrogen, 8 to 9 membered condensed heteroaryl containing 1 to 2 heteroatom nitrogens, and 10 membered fused heteroaryl containing 2 heteroatoms nitrogen is selected from; The heteroaryl and condensed heteroaryl are unsubstituted, N-substituted with a substituent selected from phenyl, benzyl and pyridyl, or 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy C-substituted with dog; wherein said N-substituted phenyl, benzyl or pyridyl is unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;

R ₁ is hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH ₂ ) _n C(O)R ₂ , (CH ₂ ) _m R ₄ , (CH ₂ ) _n CONHR ₅ , CHR ₃ R ₄ , (CH ₂ ) _m COONHR ₃ , CH ₂ CR ₃ R ₆ R ₇ , -L ₁ -C(O)NHR ₃ , naphthyl, (CH ₂ ) _m NHC(O)R ₃ , (CH ₂ ) _m COR ₇ or (CH ₂ ) _m NHSO ₂ R ₃ , the heteroatom of the 4-6 membered heterocycloalkyl is nitrogen, and the 4-6 membered heterocycloalkyl is unsubstituted, C _1-6 alkyl, C _1-6 alkyl C _6-12 Aryl, C _6-12 ArylC _1-6 Alkyl, TrifluoroC _2-6 Alkyl, C _2-6 Alkenyl, -C(O)R ₅ , -SO ₂ R ₃ , -COOR ₃ , -SO ₂ NHCOOR ₃ , -SO ₂ NH ₂ and C(O)NR ₂ N-substituted with a substituent selected from R ₃ or C _{-substituted with -COOC 1-6 alkylC 6-12} aryl group, the C _{1-6 alkylC 6-12} aryl and C _6-12 arylC _1-6 alkyl is unsubstituted or _{selected from among C 1-6} alkoxy, nitrile, halogen, C _1-6 alkyl, CF ₃ , hydroxy and OCF ₃ . substituted with one or more selected substituents,

R ₂ is selected from C _1-6 alkyl, C _1-6 alkoxy, dibenzylaminyl and C _1-3 alkylpiperazinyl,

R ₃ is C _1-6 alkyl,

R ₄ is OH, COOH, indolyl, benzooxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C _1-3 alkylpiperazinyl, mono- or di-C _1-3 alkylamino, selected from C _1-3 alkyloxadiazolyl, imidazolyl, triazolyl and C _6-12 aryl, wherein the C _6-12 aryl is unsubstituted or C _1-6 alkoxy, nitrile, halogen, C _{1 - 6} alkyl, CF ₃ , C(O)C _1-6 alkyl, -SC _1-6 alkyl, hydroxy, OCF ₃ , may be substituted with 1 to 3 substituents selected from dimethylaminyl and diisopropylaminyl; , when the substituents are plural, the substituents are the same as or different from each other, and the indolyl and benzoxazolyl may be unsubstituted or substituted with 1 to 2 substituents selected from _{hydroxy, halogen and C 1-6 alkyl.} and when the substituents are plural, the substituents are the same as or different from each other;

R ₅ is C _1-6 alkyl, C _6-12 aryl, C _6-12 arylC _1-6 alkyl, oxazole, pyridinylC _1-3 alkyl or morpholinoC _1-3 alkyl;

R ₆ is C _1-6 alkyl;

R ₇ is (CH ₂ ) _m CONH(CH ₂ ) _m CH ₃ , (CH ₂ ) _m COOH or C(O)NHR ₃ ;

L ₁ is phenylene;

n is an integer from 0 to 5,

m is an integer from 1 to 5,

Adjacent R ₃ and R ₆ each independently exist or combine with each other to form a ring.

According to the present invention, the ring formed by combining _{R 3} and R _{6 may be cyclohexyl.}

"Alkyl" generally means a straight chain (linear) or branched saturated hydrocarbon group having the specified number of carbon atoms. Examples of the alkyl group are not limited and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and heptyl and the like.

"Heterocycloalkyl" means a saturated or polycyclic hydrocarbon ring containing from one to several heteroatoms independently selected from nitrogen, oxygen and sulfur. In the present invention, the heteroatom of heterocycloalkyl may be nitrogen. The heterocycloalkyl is unsubstituted, C _1-6 alkyl, C _{1-6 alkylC 6-12} aryl, C _6-12 arylC _1-6 alkyl, trifluoroC _2-6 alkyl, C _2-6 N-substituted with a substituent selected from alkenyl, -C(O)R ₅ , -SO ₂ R ₃ , -COOR ₃ , -SO ₂ NHCOOR ₃ , -SO ₂ NH ₂ and C(O)NR ₂ R _{3 , or} or -COOC _{1-6 alkylC 6-12} aryl group may be C-substituted. The _{definitions of R 2} , R ₃ and R ₅ are the same as previously presented.

"Halogen" means fluoro, chloro, bromo and iodo.

In the present invention, the 5-6 membered heteroaryl may be selected from pyrrolyl, pyrazolyl and pyridyl.

In the present invention, the 8 to 9-membered condensed heteroaryl may be selected from benzoimidazolyl, indolyl, indazolyl and imidazopyridyl.

In the present invention, the 10-membered condensed heteroaryl may be quinoxalyl.

는 하기 구조로부터 선택될 수 있다.In the present invention, the

may be selected from the following structures.

In the above structure, R ₉ is hydrogen, phenyl, benzyl or pyridyl, and _{phenyl, benzyl and pyridyl of R 9} are unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;

R ₁₁ is halogen, nitrophenyl, pyridyl, trifluoromethyl or phenoxy;

a is an integer from 0 to 2.

In the present invention, the compound represented by the [Formula 1] may be selected from compounds represented by the following [Formula 2] to [Formula 5].

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In Formulas 2 to 5,

는 하기 구조로부터 선택되고;

is selected from the following structures;

R ₉ is hydrogen, phenyl, benzyl or pyridyl, wherein _{phenyl, benzyl and pyridyl of R 9} are unsubstituted or substituted with one or more substituents selected from nitro, halogen and trifluoromethyl;

R ₁₁ is halogen, nitrophenyl, pyridyl, trifluoromethyl or phenoxy;

a is an integer from 0 to 2;

R _x is H or C _1-6 alkyl;

R ₁ is hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH ₂ ) _n C(O)R ₂ , (CH ₂ ) _m R ₄ or (CH ₂ ) _n CONHR ₅ , wherein 4-6 The heteroatom of the membered heterocycloalkyl is nitrogen, and the 4-6 membered heterocycloalkyl is unsubstituted or with a substituent selected from _{C 6-12} arylC _1-6 alkyl, —C(O)R ₅ and —COOR _{3 .} N-substituted, wherein the C _6-12 arylC _1-6 alkyl is unsubstituted or at least one selected from _{C 1-6} alkoxy, nitrile, halogen, C _1-6 alkyl, CF ₃ , hydroxy and OCF _{3 .} substituted with a substituent;

R ₂ is C _1-6 alkyl, C _1-6 alkoxy or C _1-3 alkylpiperazinyl;

R ₃ is C _1-6 alkyl;

R ₄ is OH, COOH, indolyl, benzooxazolyl, oxazolyl, morpholino, C _1-3 alkylpiperazinyl, mono- or di-C _1-3 alkylamino, C _1-3 alkyloxadiazolyl , imidazolyl, triazolyl or C _6-12 aryl, wherein the C _6-12 aryl is unsubstituted or C _1-6 alkoxy, nitrile, halogen, C _1-6 alkyl, CF ₃ , C(O) C _1-6 alkyl, -SC _1-6 alkyl, hydroxy, OCF ₃ , may be substituted with 1 to 3 substituents selected from dimethylaminyl and diisopropylaminyl, and when the substituents are plural, the substituents are The same or different from each other, the indolyl and benzoxazolyl may be unsubstituted or _{substituted with 1 to 2 substituents selected from hydroxy, halogen and C 1-6} alkyl, and if the substituents are plural, the substituents are the same as or different from each other;

R ₅ is C _1-6 alkyl, C _6-12 aryl, C _6-12 arylC _1-6 alkyl, oxazole, pyridinylC _1-3 alkyl or morpholinoC _1-3 alkyl;

n is an integer from 1 to 4, and m is an integer from 1 to 5.

When a is 2, R ₁₁ may be two, and the two R ₁₁ may be the same as or different from each other.

In the present invention, the compound of [Formula 1] may be selected from the following [Formula 6] to [Formula 13].

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

In Formulas 6 to 13,

Y is S or O,

R ₉ is hydrogen, phenyl or pyridyl, wherein _{phenyl and pyridyl of R 9} are unsubstituted or one or more substituted with nitro;

R ₁₁ is nitrophenyl or trifluoromethyl;

a is an integer from 1 to 2;

R ₁ is hydrogen, 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH ₂ ) _n C(O)R ₂ , (CH ₂ ) _m R ₄ or (CH ₂ ) _n CONHR ₅ , wherein 4-6 The heteroatom of a membered heterocycloalkyl is nitrogen, said 4-6 membered heterocycloalkyl is unsubstituted or N-substituted with _{-COOR 3 ;}

R ₂ is C _1-6 alkyl, C _1-6 alkoxy or C _1-3 alkylpiperazinyl;

R ₃ is C _1-6 alkyl;

R ₄ is OH, COOH, morpholino, C _1-3 alkylpiperazinyl, mono- or di-C _1-3 alkylamino or C _6-12 aryl, said C _6-12 aryl being unsubstituted;

R ₅ is C _1-6 alkyl, pyridinylC _1-3 alkyl or morpholinoC _1-3 alkyl;

n is an integer from 2 to 4, and m is an integer from 2 to 5.

According to the present invention, the compound represented by the [Formula 1] may be preferably selected from the following [Formula 14] to [Formula 17].

[Formula 14]

[Formula 15]

[Formula 16]

[Formula 17]

In Formulas 14 to 17,

Y is S or O,

R ₂₁ is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH ₂ ) _a R ^a or (CH ₂ ) _a C(O)R ^b ;

R ₂₂ is hydrogen or nitro;

R ₂₃ is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH ₂ ) _a R ^a , (CH ₂ ) _b C(O)R ^c , (CH ₂ ) _c COOR ^d , ( CH ₂ ) _d CONHR ^e or (CH ₂ ) _e OH;

R ₂₄ is 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH ₂ ) _b C(O)R ^d or (CH ₂ ) _d CONHR ^e ;

R ^a is OH, morpholino, C _1-3 alkylpiperazinyl or mono- or di-C _1-3 alkylamino;

R ^b is C _1-3 alkylpiperazinyl;

R ^c is C _1-6 alkyl, C _1-3 alkylpiperazinyl or hydroxy;

R ^d is C _1-6 alkyl;

R ^e is C _1-6 alkyl or morpholinoC _1-3 alkyl;

a is an integer of 2 or 3, b is an integer of 2 to 5, c, d and e are each independently an integer of 2 to 4, and f is an integer of 1 to 2.

According to the present invention, the compound represented by the [Formula 1] may be more preferably selected from the following [Formula 18] and [Formula 19].

[Formula 18]

[Formula 19]

In Formulas 18 and 19,

R ₂₁ is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH ₂ ) _a R ^a or (CH ₂ ) _a C(O)R ^b ;

R ₂₂ is hydrogen or nitro;

R ₂₃ is hydrogen, 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH ₂ ) _a R ^a , (CH ₂ ) _b C(O)R ^c , (CH ₂ ) _c COOR ^d , ( CH ₂ ) _d CONHR ^e or (CH ₂ ) _e OH;

R ^a is OH, morpholino, C _1-3 alkylpiperazinyl or mono- or di-C _1-3 alkylamino;

R ^b is C _1-3 alkylpiperazinyl;

R ^c is C _1-6 alkyl, C _1-3 alkylpiperazinyl or hydroxy;

R ^d is C _1-6 alkyl;

R ^e is C _1-6 alkyl or morpholinoC _1-3 alkyl;

a is an integer of 2 or 3, and b is an integer of 2-5.

According to the present invention, the compound represented by [Formula 1] may be specifically selected from the following compounds or pharmaceutically acceptable salts thereof.

(Z)-4-[4-oxo-5-{(5-phenoxypyridin-2-yl)-methylene}-2-thioxo-thiazolidin-3-yl]-butanoic acid;

(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-4-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;

(Z)-2-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetic acid;

(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoic acid;

(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;

(Z)-5-{(2,3′-bipyridin)-6-ylmethylene}-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;

(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;

(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]cyclohexane carboxylic acid;

(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;

(Z)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)pentanamide;

(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;

(Z)-N-(2-morpholinoethyl)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]butanamide;

(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;

(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;

(Z)-N-(2-morpholinoethyl)-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]propanamide;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)butanamide;

(Z)-3-benzyl-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(3-hydroxypropyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-phenethylthiazolidine-2,4-dione;

(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]cyclohexane carboxylic acid;

(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;

(Z)-3-{2-(5-hydroxy-1H-indol-3-yl)ethyl}-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene] -2-thioxothiazolidin-4-one;

(Z)-4-[5-[{1-(4-fluorophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid ;

(Z)-4-[5-[{1-(3-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;

(Z)-methyl 4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoate ;

(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;

(Z)-ethyl 4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoate ;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;

(Z)-ethyl 2-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetate;

(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ;

(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-phenethylthiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)-2-thioxothiazolidine-4 -on hydrochloride;

(Z)-methyl 2-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetate;

(Z)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoic acid;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]-N -(pyridin-3-ylmethyl)butanamide;

(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-3-(piperidin-4-yl)-2-thioxothiazolidine-4 -on hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-2-thioxoimidazolidin-4-one;

(Z)-3-benzyl-5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-2-thioxoimidazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{1-(4-nitrobenzyl)-1H-pyrrol-2-yl}methylene]-2-thioxoimidazolidin-4-one;

(Z)-methyl 4-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]butano eight;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]imidazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(4-oxopentyl)-2-thioxothiazolidin-4-one;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]-N- (pyridin-3-ylmethyl)butanamide;

(Z)-N-benzyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl ]butanamide;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]-N- propylbutanamide;

(Z)-tert-Butyl 4-[4-oxo-5-[{1-(pyridin-2-yl)-1H-pyrrol-2-yl}methylene]-2-thioxothiazolidin-3-yl ]piperidine-1-carboxylate;

(Z)-1-methyl-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]imidazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-3-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]-N- (pyridin-2-ylmethyl)propanamide;

(Z)-3-[5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]-N- propylpropanamide;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(pyrrolidin-3-yl)-2-thioxothiazolidine-4- on hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-3-yl}methylene]-2-thioxoimidazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-3-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrrol-3-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]butanoic acid ;

(Z)-tert-butyl 4-[5-{(5-fluoro-1H-indazol-3-yl)methylene}-4-oxo-2-thioxothiazolidin-3-yl]piperidine -1-carboxylate;

(Z)-5-{(5-chloro-1H-indol-2-yl)methylene}-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-2-thioxo thiazolidin-4-one;

(Z)-5-{(5,6-difluoro-1H-indol-2-yl)methylene}-3-(piperidin-4-yl)-2-thioxothiazolidin-4-one hydrochloride;

(Z)-3-[5-{(1H-indol-2-yl)methylene}-4-oxo-2-thioxothiazolidin-3-yl]propanoic acid;

(Z)-3-[5-{(1H-indol-6-yl)methylene}-4-oxo-2-thioxothiazolidin-3-yl]propanoic acid;

(Z)-3-(piperidin-4-yl)-5-(quinoxalin-2-ylmethylene)-2-thioxothiazolidin-4-one hydrochloride; and

(Z)-3-{5-(imidazo[1,2-a]pyridin-2-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(oxazole- 2-yl)propanamide.

According to the present invention, the compound represented by [Formula 1] may be preferably selected from the following compounds or pharmaceutically acceptable salts thereof.

(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;

(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-4-oxo-2-thioxothiazolidin-3-yl]cyclohexane carboxylic acid;

(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;

(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;

(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;

(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)butanamide;

(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;

(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;

(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ;

(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)-2-thioxothiazolidine-4 -on hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;

(Z)-tert-Butyl 4-[4-oxo-5-[{1-(pyridin-2-yl)-1H-pyrrol-2-yl}methylene]-2-thioxothiazolidin-3-yl ]piperidine-1-carboxylate;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(pyrrolidin-3-yl)-2-thioxothiazolidine-4- on hydrochloride; and

(Z)-3-[5-{(1H-indol-6-yl)methylene}-4-oxo-2-thioxothiazolidin-3-yl]propanoic acid.

According to the present invention, the compound represented by the [Formula 1] may be more preferably selected from the following compounds or pharmaceutically acceptable salts thereof.

(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;

(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;

(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;

(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;

(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;

(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;

(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;

(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;

(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;

(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ;

(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2-thioxothiazolidin-4-one;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-3-(pyrrolidin-3-yl)-2-thioxothiazolidine-4- on hydrochloride; and

(Z)-3-[5-{(1H-indol-6-yl)methylene}-4-oxo-2-thioxothiazolidin-3-yl]propanoic acid.

The pharmaceutically acceptable salt is not particularly limited as long as it is commonly used in the art, and specific examples include non-toxic inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid and nitric acid, acetic acid, and propionic acid. Non-toxic organic acids such as , succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, ethanesulfonic acid and methanesulfonic acid can be used to form salts.

According to the present invention, the Ras protein may be a wild-type Ras protein or a Ras mutant protein, and the Ras mutant protein is preferably a K-Ras mutant protein.

The compound represented by [Formula 1] according to the present invention may bind to axin and decompose β-catenin or Ras protein, and preferably decompose β-catenin and Ras protein at the same time. .

The compound represented by [Formula 1] according to the present invention can inhibit the Wnt/β-catenin signal transduction system, and inhibit the growth of cancer cells in vitro and in vivo by simultaneously degrading β-catenin and Ras protein, It can be used as a pharmaceutical composition for cancer treatment of cancer patients, preferably cancer patients having a Ras mutation, more preferably a cancer patient having a K-Ras mutation and not showing therapeutic efficacy to conventional anticancer drugs.

More specifically, it binds to Axin, a negative regulator of the Wnt/β-catenin signal transduction system, and promotes the binding of axin and the β-catenin destruction complex to degrade β-catenin and Ras proteins. Thereby, the Wnt/β-catenin signaling system and the Ras/ERK signaling system are inhibited. Ras consists of K, N, and H-Ras, among which K-Ras has many mutations found in colon cancer, lung cancer, and metastatic cancer, and acts as an important tumor regulator in these cancers.

As a conventional anticancer agent, compounds that modulate the activity of the Ras protein or inhibit the Ras signaling system have been developed, but there is a problem in showing resistance in patients with mutant Ras. The compound represented by [Formula 1] according to the present invention is characterized in that the amount of the compound is reduced by decomposing the Ras protein, not the activity of the Ras protein. The Ras protein has the characteristic of decomposing not only the wild-type Ras but also the K-Ras mutant protein, so it shows an anticancer effect in a cancer having a K-Ras mutation, particularly a cancer that is resistant to an antibody/anticancer agent targeting EGFR. Specifically, it was clinically confirmed that the anticancer effect was significantly excellent in colorectal cancer, lung cancer, gastric cancer, and metastatic cancer that were resistant to conventional anticancer drugs.

The compound represented by [Formula 1] according to the present invention can inhibit the Ras/ERK signaling system as well as the Ras/PI3K/Akt signaling system below it by inhibiting the Ras protein.

The cancer according to the present invention may be a cancer caused by an abnormality in the Wnt/β-catenin signaling system or a Ras protein, and specifically, colorectal cancer, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, kidney cancer, thyroid cancer, rectal cancer, hematopoietic phase These include tumors, malignant melanoma, neuroblastoma, melanoma malignant and rhabdomyosarcoma.

In addition, the cancer according to the present invention may be a metastatic cancer.

The pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier in addition to the compound represented by the above [Formula 1], and may be appropriately selected according to techniques known in the art.

In the present invention, a pharmaceutically acceptable carrier means a known pharmaceutical excipient useful when formulating a pharmaceutically active compound for administration and which is virtually nontoxic and insensitive under the conditions of use. The exact proportions of these excipients are determined by the solubility and chemical properties of the active compound, the route of administration chosen, as well as standard pharmaceutical practice.

The pharmaceutical composition of the present invention may be formulated in a form suitable for the desired administration method using suitable and physiologically acceptable adjuvants such as excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, flavoring agents, and the like. can

The pharmaceutical composition according to the present invention may be formulated in the form of tablets, capsules, pills, granules, powders, injections or liquids.

Formulations suitable for oral administration include solid preparations such as tablets, particulates, capsules containing liquid or powder, pills, granules, powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solutions, liposomes, films (including muco-adhesive), ovules, sprays and solutions. Liquid preparations include, for example, suspensions, solutions, syrups and elixirs.

In addition to the drug, tablets generally contain a disintegrant. As a disintegrant, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxyl Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, crosslinked celluloses such as sodium croscarmellose, gums such as guar gum and xanthan gum, and crosslinked crospovidone A polymer and an effervescent agent such as sodium bicarbonate or citric acid may be mixed and used. Generally, the disintegrant will comprise, but is not limited to, from about 1% to about 25% by weight of the dosage form, preferably from about 2% to about 10% by weight of the dosage form.

Binders are generally used to impart tack to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, starch, copovidone, highly dispersible silica, mannitol, lactose. , hydroxypropyl cellulose and hydroxypropyl methylcellulose. Generally, the binder will comprise, but is not limited to, from about 1% to about 40% by weight of the dosage form, preferably from about 2% to about 25% by weight of the dosage form. In addition, the tablet may be used as a diluent, for example, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate. Generally, the diluent will comprise, but is not limited to, from about 1% to about 70% by weight of the dosage form, preferably from about 2% to about 50% by weight of the dosage form.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise from about 0.2% to about 5% by weight of the tablet and the glidant may comprise from about 0.2% to about 1% by weight of the tablet.

Also as lubricants, such as talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate Late, polyethylene glycol 4000, etc. can be used. Lubricants generally comprise from about 0.25% to about 5%, preferably from about 0.5% to about 3%, by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste-masking agents.

The tablet formulation may be compressed directly or compressed with a roller to form tablets. Alternatively, the tablet formulation or portion thereof may be wet, dry, melt-granulated, melt congealed or extruded prior to tableting. The final formulation may include one or more layers, may be coated or uncoated, and may be encapsulated.

Solid preparations for oral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

In one embodiment, the pharmaceutical composition of the present invention may be a tablet. The tablets may optionally be film coated. The total amount of drug per dosage unit can be such that it provides a dosage form of a convenient size for the patient.

In one embodiment, the pharmaceutical composition of the present invention may be formulated in the form of a sustained-release tablet. For the production of sustained-release tablets, a component selected from an enteric polymer, a hydrophobic material, a hydrophilic polymer, and the like may be used as the matrix base.

The enteric polymer is a mixture of at least one selected from polyvinyl acetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, Eudragit L and Eudragit S. can be used

The hydrophobic material is pharmaceutically acceptable, as polyvinyl acetate, polymethacrylate copolymer, poly(ethyl acrylate, methyl methacrylate) copolymer, poly(ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) acrylate) copolymers, ethyl cellulose and cellulose acetate, fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic materials, etc. can be selectively used, specifically, glyceryl palmitostearate as fatty acids and fatty acid esters, Fatty acid alcohols such as glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid, such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol, as waxes such as carnauba wax, beeswax and microcrystalline wax As an inorganic material such as talc, precipitated calcium carbonate, calcium monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and veegum, one or two selected from the group can be used.

The hydrophilic polymer may be selected from saccharides, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. Specifically, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin, etc. can be selectively used, and hydroxypropylmethylcellulose as a cellulose derivative , hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose, etc. can be selected and used, and guar gum as a gum , locust bean gum, tragacantha, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, etc. can be selectively used, and gelatin, casein or zein can be selectively used as proteins, and polyvinyl as a polyvinyl derivative Alcohol, polyvinyl pyrrolidone and polyvinyl acetal diethyl amino acetate can be selectively used, and poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate as a polymethacrylate copolymer) rate) copolymer, poly(methacrylic acid, methyl methacrylate) copolymer, poly(methacrylic acid, ethyl acrylate) copolymer, etc. can be selected and used, and polyethylene glycol, polyethylene oxide, etc. are selected as polyethylene derivatives It can be used, and a carbomer can be used as a carboxyvinyl polymer.

According to the present invention, the pharmaceutical composition is the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of formulation and the age, weight, general health status, sex and diet, administration of the patient. The effective amount may be adjusted according to various factors including time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs. For example, in the case of an adult, the compound of [Formula 1] or a pharmaceutically acceptable salt thereof may be administered in divided doses of 4000 mg/day to several times a day at regular time intervals according to the judgment of a doctor or pharmacist. can

The pharmaceutical composition comprising the compound represented by [Formula 1] or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient may be used in combination with a second anticancer agent.

The second anticancer agent according to the present invention may be any known anticancer agent. For example, known chemotherapeutic agents such as alkylating agents, metabolic antagonists, natural agents, hormones and antagonists, and biological agents such as immunotherapeutic agents and gene therapy agents may be included.

Examples of the second anticancer agent according to the present invention include nitrogen mustard, imatinib, oxaliplatin, erlotinib, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, cisplatin, viscumalbum, asparagi Naze, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamicin, ibritumomab tucetan, heptaplatin, methylaminolevulinic acid, amsacrine, procarbazine, alprostadil , holmium nitrate chitosan, gemcitabine, doxyfluridine, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine , enocitabine, decitabine, mercaptopurine, thioguanine, cladribine, carmopher, raltitrexed, docetaxel, paclitaxel, irinotecan, belotecan, topotecan, vinorelbine, etoposide, vincristine, vinbla Steen, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temozolo one selected from the group consisting of amide, busulfan, ifosfamide, cyclophosphamide, melparan, altretmine, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, lomustine and carmustine or two or more drugs.

The present invention provides a combination preparation comprising a second anticancer agent and a pharmaceutical composition comprising the compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof as an active ingredient. The type of the second anticancer agent is as exemplified above.

Hereinafter, the present invention will be described in more detail with reference to preferred embodiments to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the content of the present invention is not limited thereto.

Example

Compounds were synthesized using the same methods as those prepared in Examples unless otherwise specified.

Preparation Example 1. Rhodanine intermediate 1 (4-oxo-2-thioxothiazolidine) synthesis

Triethylamine (1 eq.) and an amine compound (1 eq.) were added to 1,2-diethoxyethane in which bis (carboxymethyl) trithiocarbonate (1 eq.) was dissolved, 100 ° C. for 15 minutes The reaction proceeded through a microwave reactor under conditions. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting concentrate was purified by column chromatography (eluent: 3% methanol/dichloromethane) to obtain the desired compound (yield: 34 to 85%)

Preparation Example 2. Rhodanine intermediate 2 (4-oxo-2-thioxothiazolidine-3-alkyl acid ester) synthesis

After dissolving 4-oxo-2-thioxothiazolidine-3-alkyl acid (1 eq.) and (±)-camphor-10-sulfonic acid (3 eq.) in low alcohol alcohol, reacted for a minute. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the pH was adjusted to neutrality by adding an aqueous solution of saturated sodium carbonate, followed by extraction with dichloromethane, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting concentrate was purified by column chromatography (eluent: ethyl acetate: hexane = 1:3-1:1) to obtain the desired compound (yield: 41- 92%).

Preparation Example 3. Preparation of thiazolidine-2,4-dione potassium salt

Thiazolidine-2,3-dione (1 eq.) was dissolved in ethanol, and ethanol in which potassium hydroxide (1.1 eq.) was dissolved was added thereto, followed by stirring for 2 hours to obtain a white precipitate. The resulting precipitate was collected by filtration and washed several times with ethanol to obtain the desired compound (yield 98%).

Preparation Example 4. Preparation of thiazolidine-2,4-dione intermediate

Thiazolidine-2,4-dione potassium salt (1 eq.), potassium iodide (1 eq.) and a halogen compound (X-R) were dissolved in N.N'-dimethylformamide and refluxed for 12 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with dimethylmethane. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting concentrate was purified by column chromatography (eluent: 1% methanol/dichloromethane) to obtain the desired compound (yield: 15 to 53%).

Preparation 5. Preparation of thiazolidine-2,4-dione-3-alkyl acid

Thiazolidine-2,4-dione 3-alkyl acid ester (1 eq.) was dispersed in 35% aqueous hydrogen chloride solution and refluxed for 8 hours. After completion of the reaction, the reaction mixture was concentrated, and the concentrate was purified by column chromatography (eluent: 3% methanol/dichloromethane) to obtain the desired compound (yield: 74 to 96%).

Preparation Example 6. Synthesis of thiohydantoin intermediate

Ethyl isothiocyanate (1 eq.), ethyl aminoalkylate (1.1 eq.) and triethylamine (3 eq.) were dissolved in acetonitrile, followed by stirring at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated, and the concentrate was purified by column chromatography (eluent: ethyl acetate: hexane = 3:1-2:1) to obtain the desired compound (yield: 84-89%). .

Preparation Example 7. Synthesis of 1-(4-nitrophenyl)-1H-pyrrole-2-carbaldehyde

Furan-2-carbaldehyde (1 eq.) and 4-nitroaniline (2 eq.) were dissolved in ethanol, and then 2N aqueous hydrogen chloride solution (2 eq.) was slowly added dropwise. The reaction mixture was refluxed for 2 hours, cooled to room temperature, and water was added. The resulting precipitate was filtered, washed with ethanol, and the washed precipitate was obtained and purified by column chromatography (eluent: ethyl acetate: hexane = 1:10-1:3) to obtain the desired compound.

Preparation 8. Synthesis of indazole 3-carboxylic acid

An aqueous solution of sodium hydroxide (1.05 eq.) in which indoline-2,3-dione (1 eq.) is dissolved in an aqueous solution of sulfuric acid (1.9 eq.) was slowly added while maintaining the temperature not to exceed 50 °C. The reaction mixture was cooled to 0 °C, and an aqueous solution in which sodium nitrite (1.1 eq.) was dissolved was added while maintaining the temperature not to exceed 4 °C. Next, the mixture was stirred at 0° C. for 15 minutes, and 35% aqueous hydrogen chloride solution in which stannous chloride (2.4 eq.) was dissolved was added while maintaining 0° C., followed by stirring for 1 hour. After completion of the reaction, the resulting precipitate was filtered, washed with acetic acid, and the washed precipitate was collected to obtain the desired compound.

Preparation 9. Synthesis of indazole 3-carbaldehyde

Indazole 3-carboxylic acid (1 eq.) was dissolved in tetrahydrofuran, stirred at 0 °C, and 1M lithium aluminum hydride (1.05 eq.) tetrahydrofuran solution was slowly added thereto at 0 °C. stirred for hours. When the reaction was completed, water was added to remove the remaining lithium aluminum hydride, followed by extraction with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture containing indazole-3-methyl alcohol. This was dissolved in dimethylmethane, pyridinedichromic acid (2 eq.) was added, stirred at room temperature for 2 hours, filtered, and the filtrate was concentrated under reduced pressure by column chromatography (eluent: ethyl acetate: n-hexane = 1: 5-1:2) to obtain the desired compound (yield: 23-33%).

Preparation 10. Synthesis of 3-[2-(benzo [d] oxazol-2-yl) ethyl] -2-thioxothiazolidin-4-one

3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (1 eq.) and 2-aminophenol (1.1 eq.) were added to excess polyphosphoric acid, and then at 160° C. Stirred for 14 hours. When the reaction was completed, it was cooled to room temperature, an excess of water was added, and the pH was adjusted to neutral (pH 7-8) by adding a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ether. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the concentrate was purified by column chromatography (eluent: ethyl acetate: n-hexane = 1:3-1:1) to obtain the desired compound ( yield 26%).

Preparation 11. Synthesis of 2-substituted pyridine-6-carbaldehyde

6-bromopyridine-2-carbaldehyde (1 eq.), aryl boronic acid (1.05 eq.), tetrakis (triphenylphosphine) palladium (0.05 eq.), 2M aqueous potassium carbonate solution (1.5 eq.) After dispersing in toluene/ethanol (1:1 mixed solvent), it was refluxed for 8 hours. After completion of the reaction, water and ethyl acetate were added to terminate the reaction, and the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated. The desired compound was obtained by purification by column chromatography (eluent: ethyl acetate: n-hexane = 1:10 to 1:3). (Yield: 64%)

Preparation 12. Synthesis of ethyl 1- (4-nitrophenyl) pyrazole-3-carboxylate

1-iodine-4-nitrobenzene (1 eq.), ethyl pyrazole-3-carboxylate (1 eq.), divalent copper acetate (0.1 eq.) and cesium carbonate (1 eq.) were mixed with N.N' -Dissolved in dimethylformamide and refluxed for 4 hours. After completion of the reaction, it was cooled to room temperature, and an excess of water was added to form a precipitate. The resulting precipitate was filtered, dried and used in the next reaction.

Preparation 13. Preparation of 1- (4-nitrophenyl) pyrazole-3-methyl alcohol

Anhydrous tetrahydrofuran was added to ethyl 1- (4-nitrophenyl) pyrazole-3-carboxylate (1 eq.) under an argon stream, followed by stirring at 0 ° C. for 20 minutes, and then 1M lithium aluminum hydride (1.1 eq.) .) The tetrahydrofuran solution was slowly added and stirred at 0 °C for 2 hours. After completion of the reaction, water and ethyl acetate were added to terminate the reaction, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to use in the next experiment.

Preparation 14. 1- (4-nitrophenyl) pyrazole-3-carbaldehyde

1-(4-nitrophenyl)pyrazole-3-methyl alcohol (1 eq.) and pyridine chromic acid (2 eq.) were dissolved in dimethylmethane, and the reaction was confirmed by TLC while stirring at room temperature for 3 hours. . After completion of the reaction, the reaction was filtered, the filtrate was concentrated, and purified by column chromatography (eluent: ethyl acetate: n-hexa=1:5) to obtain the desired compound (yield: 12%).

Example 1. Compound KY1220

(Z)-5-[{1-(4-nitrophenyl)-1H-pyrrol-2-yl}methylene]-2-thioxoimidazolidin-4-one;

1-(4-nitrophenyl)-1H-pyrrole-2-carbaldehyde (1 eq.) and thiohytodyne (1 eq.) were dispersed in ethanol, and then sodium acetate (1 eq.) was added thereto. Stirred at 60 °C for 6 hours. After completion of the reaction, the formed precipitate was filtered, washed with ethanol, and the washed precipitate was obtained to obtain the desired compound (yield: 38%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.3 (br, 1H), 12.0 (br, 1H), 8.42 (d, 2H, J=8.8 Hz), 7.71 (d, 2H, J=8.8 Hz), 7.47 - 7.44 (m, 2H), 6.54 (m, 1H), 6.13 (s, 1H)

Example 2. Compound A2927

(Z)-N-ethyl-5-[5-[[1-(4-nitrophenyl)-1H-pyrazol-3-yl]methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;

(Z)-5-(5-((1-(4-nitrophenyl)-1H-pyrazol-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)pentanoic acid ( 1 eq.) was dissolved in anhydrous tetrahydrofuran under an argon stream, stirred at 0 ° C. for 20 minutes, and then N-methylmorpholine (3 eq.) and isobutylchloro formic acid ester (1.5eq.) were sequentially added. The mixture was further stirred at 0° C. for 15 minutes. Next, 2M ethylamine tetrahydrofuran solution (1.1 eq.) was added, and the temperature was gradually raised to room temperature, followed by further stirring for 5 hours. After completion of the reaction, the formed precipitate was filtered and washed with ether, and the washed precipitate was separated by column chromatography (eluent 2% methanol/dimethylmethane) to obtain the desired compound (yield 68%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.86 (s, 1H), 8.42 (d, 2H, J=8.0 Hz), 8.18 (d, 2H, J=6.0 Hz), 7.84 (s, 1H), 7.74(s, 1H), 7.06 (s, 1H), 3.64 (t, 2H, J=10.0 Hz), 3.05 - 2.98 (m, 2H), 2.05 (t, 2H, J = 10.0 Hz), 1.60 - 1.51 (m, 2H), 1.51 - 1.42 (m, 2H), 0.97 (t, 3H, J = 8.0 Hz); ESI (m/z) 444 (MH+).

Example 3. Compound A4278

(Z)-4-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;

2-(4-nitrophenyl)pyridine-2-carbaldehyde (1 eq.) and thiazolidine-2,4-dione-3-butanoic acid (1 eq.) were dispersed in ethanol, followed by After adding peridine (1 eq.), the mixture was stirred at 60° C. for 10 hours. After completion of the reaction, the formed precipitate was filtered, washed with ethanol and diethyl ether, and the washed precipitate was obtained to obtain the desired compound (yield: 73%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40(m, 4H), 8.14-8.08(m, 2H), 7.98(s, 1H), 7.94-7.92(m, 1H), 3.66(m, 2H) , 2.19(m, 2H), 1.77(m, 2H); ESI (m/z) 412 (MH-)

Example 4. Compound A4283

(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;

Conducted using 2-(4-nitrophenyl)pyridine-2-carbaldehyde (1 eq.) and 3-(2-hydroxyethyl)thiazolidine-2,4-dione (1 eq.) The desired compound was obtained in the same manner as in Example 3 (yield: 65%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40(m, 4H), 8.14-8.06(m, 2H), 7.99(s, 1H), 7.94-7.92(m, 1H), 4.88(t, J= 5.8 Hz, 1H), 3.70-3.69 (m, 2H), 3.56-3.55 (m, 2H); ESI (m/z) 370 (MH-)

Example 5. Compound A3004

(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione ;

Using 1-(4-nitrophenyl)pyrazole-3-carbaldehyde (1 eq.) and 3-(2-hydroxyethyl)thiazolidine-2,4-dione (1 eq.), The desired compound was obtained in the same manner as in Example 3 (yield: 40%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.86 (d, 1H, J = 4.0 Hz), 8.42 (d, 2H, J = 8.0 Hz), 8.16 (d, 2H, J = 8.0 Hz), 7.82 ( s, 1H), 7.06 (d, 1H, J = 4.0 Hz), 4.90 (t, 1H, J = 4.0 Hz), 3.70 (t, 2H, J = 4.0 Hz), 3.56 (t, 2H, J = 6.0) Hz); ESI (m/z) 359 (MH-)

Example 6. Compound A2725

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic Mountain;

Example using 1-(4-nitrophenyl)pyrazole-3-carbaldehyde (1 eq.) and thiazolidine-2,4-dione-3-butanoic acid one (1 eq.) The desired compound was obtained in the same manner as in 3 (yield: 90%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.07 (s, 1H), 8.83 (s, 1H), 8.39 (d, 2H, J = 9.2 Hz), 8.14 (d, 2H, J = 9.2 Hz), 7.79 (s, 1H), 7.03 (s, 1H), 3.66 (t, 2H, J = 6.4 Hz), 2.25 (t, 2H, J = 6.8 Hz), 1.81 - 1.78 (m, 2H); ESI (m/z) 401 (MH-)

Example 7. Compound A2725K

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid potassium ;

(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid Prepared with 0.1M methanol solution, while stirring at 60°C, 1M potassium hydroxide methanol solution (1 eq.) was added dropwise and stirred at 60°C for 1 hour. Then, the temperature was lowered to room temperature, the formed precipitate was stirred, and washed 2-3 times with methanol to obtain the desired compound (yield: 76%).

Example 8. Compound A4278K

(Z)-4-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid potassium;

(Z)-4-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid in 0.2M methanol solution and while stirring at 60°C, 1M potassium hydroxide methanol solution (1 eq.) was added dropwise and stirred at 60°C for 1 hour. Then, the temperature was lowered to room temperature, the formed precipitate was stirred, and washed 2-3 times with methanol to obtain the desired compound (yield: 60%).

The compounds of Table 1 were prepared using the method of Examples 1 to 6, and identification data of the prepared compounds are shown in Table 2 below.

[Table 1]

[Table 2]

test example

Cell Culture, Transformation and Drug Treatment

SW480 cells were obtained from the American Type Culture Collection (ATCC, Manassas, Va.). HEK293 reporter cells (HEK293 cells with the TOPflash gene in their chromosomes) were provided by Sangtaek Oh (Kuk Min University, Seoul, Korea).

HEK293 reporter cells were cultured in DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS; Gibco). SW480 cells were cultured in RPMI 1640 medium containing 10% FBS.

Measurement of inhibition of TOPflash reporter activity

In order to identify compounds that degrade β-catenin and Ras proteins from the compounds of [Table 1] prepared in Examples 1 to 82, a TOPflash reporter gene that can detect the activation level of the Wnt/β-catenin signaling system was inserted In HEK293 reporter cells, the comparative substance KYA1797K and each compound were treated with Wnt3a-CM or L-CM at a concentration of 1 μM to check their effect on Wnt/β-catenin signaling system activity. Each activity was normalized using 100% of the activity of the TOPflash reporter activated by the Wnt3a-CM control group. Compared to the comparative compound KYA1797K, the compounds that showed 40% or less of the inhibition of the TOPflash reporter activity compared to the control (100%) activity are shown in [Table 3].

[Table 3]

As shown in Table 3 above, compounds A2927, A4283, A3004, A4267, A4284, A2698, A2925, A2926, A2966, A2968, A2969, A2971, A3250, A2630, A2730, The TOPflash reporter activity of A2731, A3249, A4280, A4297, A3249, A2483, A3461 and A3011 was similar to or lower than that of the comparative compound KYA1797K. It is experimentally confirmed that the compounds of the present invention have superior inhibitory ability on the Wnt/β-catenin signaling system than the comparative compound KYA1797K.

Control compound KYA1797K and 21 types of compounds (A3004, A2698, A2725, A2973, A3249, A3250, A4267, A4278, A4267) in SW480 cells, colon cancer cells, in which Wnt/β-catenin signaling and Ras/EKR signaling are activated , A4283, A4284, A2725K, A4278K, A4352, A4352H, A4353, A4354, A4363, A4364, A4365, A4365H) at a concentration of 5 or 25 μM for 24 hours and then immunoblotting was performed. Changes in the amount of each protein were observed using anti-pan-Ras, anti-β-catenin, and anti-α-tubulin antibodies, and the intensity of each pan-Ras and β-catenin band was quantified to quantify α-tubulin. After standardization, the intensity of the control (DMSO) was set to 1 and normalized to a relative value, and is shown as a graph in FIGS. 1 to 3 . Compounds A3249, A4365, and A4365H showed cytotoxicity, and compounds A3004, A2698, A2725, A3250, A4267, A4278, A4267, A4283, A4284, A4352, A4353, A4354, A4363, and A4364 compounds were pan-Ras compared to the control compound KYA1797K. Or it was confirmed that the amount of β-catenin was further reduced. These compounds were experimentally confirmed that they can simultaneously inhibit the Wnt/β-catenin signaling system and Ras.

Measurement of inhibition of cell formation

Colorectal cancer cells, SW480 cells in which the Wnt/β-catenin signaling system and the Ras/EKR signaling system are activated, were seeded in a 12-well plate (500 cells/well for SW480 cells). Each cell was treated with DMSO (control), a compound of the present invention (A3004, A2698, A2725, A4267, A4283 and A4284) and a comparative compound (KYA1797K), and every 3 days, until cells were visible, a new medium containing the drug was used. replaced. Finally, cells were fixed by treatment with 4% paraformaldehyde (PFA) for 30 minutes, and stained by treatment with 0.5% crystal violet solution dissolved in 20% ethanol for 30 minutes. The number of stained cells was measured and shown as a numerical graph in FIG. 4 .

This result is a result of confirming the cell proliferation inhibitory ability of the compounds of the present invention against the human colon cancer cell line SW480, and all compounds effectively inhibited cell formation in a concentration-dependent manner. In particular, A3004 and A4283 showed superior cell proliferation inhibition ability than the comparative compound KYA1797K. However, A2698, A2725, A4268 and A4284 showed a weaker cell proliferation inhibitory ability than the comparative compound KYA1797K, but showed effective results. It was experimentally confirmed that the compound of the present invention has the ability to inhibit cell proliferation against colorectal cancer cell lines.

Claims (17)

delete delete delete delete delete Cancer having a K-Ras mutant type and having abnormalities in the Wnt signaling system, comprising a compound or a pharmaceutically acceptable salt thereof as an active ingredient, characterized in that it is selected from the compounds represented by the following Chemical Formulas 7 to 9 A pharmaceutical composition for the treatment of cancer in a patient:
[Formula 7]

[Formula 8]

[Formula 9]

In Formulas 7 to 9,
Y is O,
R9 is hydrogen, phenyl or pyridyl, wherein the phenyl and pyridyl of R9 are unsubstituted or substituted with one or more nitro;
R11 is nitrophenyl or trifluoromethyl;
a is an integer from 1 to 2;
R1 is 4-6 membered heterocycloalkyl, carboxycyclohexyl, (CH2)nC(O)R2, (CH2)mR4 or (CH2)nCONHR5, the heteroatom of the 4-6 membered heterocycloalkyl is nitrogen, -6-membered heterocycloalkyl is unsubstituted or N-substituted with -COOR3;
R2 is C1-6alkyl, C1-6alkoxy or C1-3alkylpiperazinyl;
R3 is C1-6 alkyl;
R 4 is OH, COOH, morpholino, C 1-3 alkylpiperazinyl, mono- or di-C 1-3 alkylamino or C 6-12 aryl, said C 6-12 aryl being unsubstituted;
R5 is C1-6alkyl, pyridinylC1-3alkyl or morpholinoC1-3alkyl;
n is an integer from 2 to 4, and m is an integer from 2 to 5; 7. The method of claim 6,
The compound is a pharmaceutical composition, characterized in that selected from the compounds represented by the following formulas 14 to 15:
[Formula 14]

[Formula 15]

In the above formulas 14 to 15,
Y is O,
R21 is 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH2)aRa or (CH2)aC(O)Rb;
R22 is hydrogen or nitro;
R23 is 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH2)aRa, (CH2)bC(O)Rc, (CH2)cCOORd, (CH2)dCONHRe or (CH2)eOH;
R a is OH, morpholino, C 1-3 alkylpiperazinyl or mono- or di-C 1-3 alkylamino;
Rb is C1-3alkylpiperazinyl;
R c is C 1-6 alkyl, C 1-3 alkylpiperazinyl or hydroxy;
Rd is C 1-6 alkyl;
Re is C 1-6 alkyl or morpholino C 1-3 alkyl;
a is an integer of 2 or 3, b is an integer of 2 to 5, and c, d and e are each independently an integer of 2 to 4. 8. The method of claim 7,
The compound is a pharmaceutical composition, characterized in that selected from compounds represented by the following formula 18 or formula 19:
[Formula 18]

[Formula 19]

In Formulas 18 and 19,
R21 is 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH2)aRa or (CH2)aC(O)Rb;
R22 is hydrogen or nitro;
R23 is 4-6 membered heterocycloalkyl containing one nitrogen as a heteroatom, (CH2)aRa, (CH2)bC(O)Rc, (CH2)cCOORd, (CH2)dCONHRe or (CH2)eOH;
R a is OH, morpholino, C 1-3 alkylpiperazinyl or mono- or di-C 1-3 alkylamino;
Rb is C1-3alkylpiperazinyl;
R c is C 1-6 alkyl, C 1-3 alkylpiperazinyl or hydroxy;
Rd is C 1-6 alkyl;
Re is C 1-6 alkyl or morpholino C 1-3 alkyl;
a is an integer of 2 or 3, b is an integer of 2 to 5, and c, d and e are each independently an integer of 2 to 4. 7. The method of claim 6,
The compound is
(Z)-4-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;
(Z)-2-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetic acid;
(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-[5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoic acid;
(Z)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;
(Z)-5-{(2,3′-bipyridin)-6-ylmethylene}-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride;
(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;
(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;
(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;
(Z)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)pentanamide;
(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;
(Z)-N-(2-morpholinoethyl)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]butanamide;
(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;
(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;
(Z)-N-(2-morpholinoethyl)-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]propanamide;
(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)butanamide;
(Z)-3-benzyl-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(3-hydroxypropyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-phenethylthiazolidine-2,4-dione;
(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;
(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;
(Z)-4-[5-[{1-(4-fluorophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid ;
(Z)-4-[5-[{1-(3-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;
(Z)-methyl 4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoate ;
(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;
(Z)-ethyl 4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoate ;
(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]butanoic acid;
(Z)-ethyl 2-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetate;
(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ;
(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-phenethylthiazolidine-2,4-dione;
(Z)-methyl 2-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]acetate;
(Z)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoic acid;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride; and
(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-4-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide; A pharmaceutical composition, characterized in that it is a compound, characterized in that selected from. 10. The method of claim 9,
The compound is
(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;
(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;
(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;
(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;
(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;
(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;
(Z)-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]-N-( pyridin-3-ylmethyl)butanamide;
(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;
(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;
(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;
(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ;
(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ; and
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(piperidin-4-yl)thiazolidine-2,4-dione hydrochloride; A pharmaceutical composition, characterized in that it is a compound, characterized in that selected from. 11. The method of claim 10,
The compound is
(Z)-3-(2-hydroxyethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(3-hydroxypropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-(2-morpholinoethyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-3-{2-(dimethylamino)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione;
(Z)-3-{3-(4-methylpiperazin-1-yl)-3-oxopropyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{4-(4-methylpiperazin-1-yl)-4-oxobutyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine -2,4-dione;
(Z)-3-{2-(4-methylpiperazin-1-yl)ethyl}-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4 -Dion;
(Z)-3-(3-morpholinopropyl)-5-[{6-(4-nitrophenyl)pyridin-2-yl}methylene]thiazolidine-2,4-dione hydrochloride;
(Z)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-3-(4-oxopentyl)thiazolidine-2,4-dione;
(Z)-N-ethyl-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] pentanamide;
(Z)-N-ethyl-4-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] butanamide;
(Z)-N-(2-morpholinoethyl)-5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxotia jolidin-3-yl]pentanamide;
(Z)-N-ethyl-3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl] propanamide;
(Z)-3-(2-hydroxyethyl)-5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]thiazolidine-2,4-dione;
(Z)-4-[2,4-dioxo-5-{(1-phenyl-1H-pyrazol-3-yl)methylene}thiazolidin-3-yl]butanoic acid;
(Z)-6-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]hexanoic acid;
(Z)-ethyl 3-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]propanoate ; and
(Z)-ethyl 5-[5-[{1-(4-nitrophenyl)-1H-pyrazol-3-yl}methylene]-2,4-dioxothiazolidin-3-yl]pentanoate ; Pharmaceutical composition, characterized in that selected from. 12. The method according to any one of claims 6 to 11,
The pharmaceutically acceptable salts include hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, amidosulfonic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para-toluenesulfonic acid, ethanesulfonic acid A pharmaceutical composition, characterized in that any one selected from phonic acid and methanesulfonic acid. delete delete 12. The method according to any one of claims 6 to 11,
The cancer is a pharmaceutical composition, characterized in that the metastatic cancer (metastatic cancer). 12. The method according to any one of claims 6 to 11,
The cancer is selected from the group consisting of colon cancer, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, kidney cancer, thyroid cancer, rectal cancer, hematopoietic tumor, malignant melanoma, neuroblastoma, malignant melanoma and rhabdomyosarcoma. . 12. The method according to any one of claims 6 to 11,
The pharmaceutical composition is a pharmaceutical composition, characterized in that formulated in the form of tablets, capsules, pills, granules, powders, injections or liquids.

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