WO2017176040A1 - Heterocyclic compound decomposing ras and uses thereof - Google Patents

Abstract

The present invention relates to a compound which simultaneously degrades β-catenin and a Ras protein comprising a K-Ras mutation. The compound according to the present invention induces the inhibition of cancer proliferation and the death of cancer cells by regulating a signal input into a key signal transduction system involved with cancer, thereby exhibiting an effect on the treatment of cancer in cancer patients showing resistance to conventional anticancer agents due to Wnt signal transduction abnormality and Ras gene mutation.

Description

Heterocyclic compounds decomposing Ras and uses thereof

The present invention relates to a compound which simultaneously degrades? -Catenin and Ras protein, a process for producing the same, and uses thereof.

In the 1970s, after President Nixon declared war on cancer, the development of anticancer drugs that specifically work on signaling substances has been pursued in the development of anticancer drugs targeting rapid cell growth of cancer cells. However, cancer is caused by multiple mutations of the various cancer genes (increased β-catenin by phosphorylation deficiency mutations, abnormal activation by mutation of Ras protein, abnormal activation of PI3K, mTOR signaling system, etc.) In recent years, the need for multi-target anticancer drugs that can control multiple problems all at once has begun to arise. Therefore, it is required to develop an anticancer drug having a specificity to a certain extent even without toxicity.

Ras is a protein that regulates signal entry into key signaling systems related to cancer, such as PI3K and mTOR, and can be a good target for developing multi-target cancer drugs. Ras has an average of 30% mutation in cancer (72-90% in the case of K-Ras, 72-90% in the case of pancreatic cancer, 32-57% in colorectal cancer and 15-50% in lung cancer) There have been numerous efforts to do so.

Numerous pharmaceutical companies have been working on the development of farnesyltransferase inhibitors (FTIs) and geranylgeranyltransferase inhibitors (GGTIs) that inhibit migration to the cell membrane, one of the most important processes for activation of Ras, Or because of limited patient applications, most of the clinical trials have failed. At present, there is no anticancer agent that can control Ras that can be applied in clinical practice. Some researchers have attempted to control Ras expression using siRNA or shRNA in vitro as a temporary measure, but in actual patient application and industrialization [(A) World J Gastroenterol 11, (2005), 2026; (b) Cancer Sci 98, (2007), 1128; (c) Cancer Res. 70, (2010), 7253].

The present inventors have continued to disclose the mechanism by which the Ras protein itself is degraded into a form dependent on polyubiquitination by inhibition of the Wnt / β-catenin signaling system. We have shown that Ras protein can be degraded by the inhibition of this signal transduction system through APC, Axin, and glycogen synthase kinase 3β (GSK3β), which are the voice regulators of the wint / beta-catenin signaling system. When the wint / beta-catenin signaling system was negatively regulated, beta-catenin and las protein were degraded together. Ras protein was phosphorylated by GSK3β and β-TrCP E3 linker was involved and protein degradation 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, since both the Wnt /? - catenin and Ras pathways are abnormally activated and interact to promote the development and progression of most cancers, inhibition of the signal transduction may be an ideal strategy for the treatment of cancer have. Therefore, it is required to develop a novel substance capable of inhibiting the signal transduction system of Wnt /? - catenin and Ras at the same time.

[Prior Art Literature]

[Non-Patent Document]

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

A problem to be solved by the present invention is to provide a novel anticancer agent capable of solving the problems of existing anticancer drugs which do not exhibit anticancer effects due to Ras gene mutation, and which simultaneously decompose? -Catenin and Ras protein.

Another object to be solved by the present invention is to provide a pharmaceutical composition for treating cancer in a cancer patient having K-Ras mutant type comprising as an active ingredient a compound capable of simultaneously decomposing the? -Catenin and the Ras protein.

The present invention provides a compound capable of simultaneously decomposing β-catenin and Ras protein represented by the following formula (1).

[Chemical Formula 1]

In the above formula (1)

Is an E-form or a 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} alkyl, C _{6 - 12} aryl;

X is a five to six membered heteroaryl containing from one to two nitrogen atoms, an eight to nine membered fused heteroaryl containing from one to two nitrogen atoms and a ten atom fused heteroaryl containing two nitrogen atoms, ; Said heteroaryl and fused heteroaryl being unsubstituted or N-substituted by a substituent selected from phenyl, benzyl and pyridyl or substituted with 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy, Gt; C-substituted < / RTI > 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 selected from the group consisting of 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 , and wherein the 4-6 heteroatom won the nitrogen of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C _{1- 6} alkyl, C _{1- 6} alkyl C _{6 -12} aryl, C _{6- 12} aryl C _{1 - 6} alkyl, trifluoro C _{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 R 3} N- substituted with a substituent selected from or -COOC _{1 - 6} alkyl, C _{6 - 12} aryl, and substituted with a C-, wherein C from ₆ alkyl is unsubstituted or C _{1- 6} alkoxy, nitrile, halogen, C _{1- 6} alkyl, CF _3, hydroxy, OCF _{3 - 1- 6} alkyl, C _{6 - 12} aryl and C _{6- 12} aryl C ₁ Lt; / RTI > is substituted with one or more substituents selected <

R ₂ is selected from C _{1- 6} alkyl, C _{1- 6} alkoxy, dibenzyl amino carbonyl and C _{1- 3} alkyl-piperazinyl,

R ₃ is C _{1- 6} alkyl,

R ₄ is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkylamino, C _1-3 alkyl-oxadiazolyl, pyridazinyl imidazole, triazolyl and C _{6- 12} is selected from aryl, wherein 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, dimethyl amino carbonyl and diisopropyl amino carbonyl substituent may be one to three substitutions selected from , if the substituents are plural, said substituents may be the same or different from each other, and the indolyl and benzo-oxazolyl may be unsubstituted or substituted by hydroxy, halogen or C _{1- 6} may be substituted with one to two substituents selected from among alkyl And when the substituent is 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} aryl C _{1 - 6} alkyl, oxazole, pyridinyl C _{1 - 3} alkyl or morpholino C _{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 of 0 to 5,

m is an integer of 1 to 5,

Adjacent R < ₃ > and R < ₆ > are each independently present or bonded to each other to form a ring.

The present invention also provides a pharmaceutical composition for treating cancer in a cancer patient having a K-Ras mutation 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 signal transduction system abnormality together.

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 .

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

The compounds according to the present invention bind to axin, a negative regulator of the Wnt / beta -catenin signaling system, to promote the binding of axin to the beta-catenin destruction complex, And Ras proteins, including K-Ras mutations, to regulate signal entry into key signaling pathways involved in cancer, thereby inhibiting cancer growth and killing cancer cells. In particular, since the Wnt signal transduction system abnormality and the Ras gene mutation (K-ras) can exhibit the anticancer effect with respect to the cancer showing resistance to the conventional anticancer agent, The present invention is also useful as a pharmaceutical composition for treating cancer.

FIGS. 1 to 3 show the results of comparing the degradation of β-catenin with that of Ras by treating the SW480 colon cancer cell line with APC and K- Ras mutations according to the embodiment of the present invention, with the comparative drug KYA1797K and its derivatives.

FIG. 4 shows the results of comparing the ability of the SW480 colon cancer cell lines with APC and K- Ras mutants to treat the comparative drug KYA1797K and derivatives according to the embodiment of the present invention.

The abnormal activation of the Wnt / β-catenin signaling system by the mutation of the genes involved in the Wnt / β-catenin signaling system is often the cause of cancer, so the discovery of inhibitors for this signal transduction system is key to cancer therapy . However, even if a substance that primarily inhibits the Wnt / β-catenin signaling pathway is selected, it is not the overexpression of the ligand that activates the Wnt / β-catenin signal transduction system, but the key molecule such as APC or β-catenin ), It is important to identify low-molecular-weight compounds that target signal transduction agents that act in the cytoplasm or nucleus of the signal transduction system.

On the other hand, there are many reports that such cancer is induced not by the Wnt / β-catenin signal transduction system alone but by the genetic mutation of the Ras / MAPK signal transduction system gene closely related to the carcinogenesis. Indeed, many anticancer agents have been screened for inhibiting key proteins that constitute the Ras / MAPK signaling system. Many anti-cancer drugs have been developed as inhibitors of EGFR, the most upstream of the Ras-MAPK signaling system, or inhibitors of MEK, an intermediate-stage phosphorylated protein. Recently, however, these anticancer agents have been reported to have little effect in cancer with Ras mutation.

Accordingly, the present inventors have sought to find a substance that simultaneously inhibits the Wnt /? -Catenin signaling pathway system and the Ras / MAPK signal transduction system, thereby simultaneously degrading? -Catenin and Ras and Ras mutations, specifically K-Ras And found that these compounds are effective in the treatment of cancer in cancer patients who are resistant to conventional anticancer drugs, thereby completing the present invention.

The present invention provides a compound capable of simultaneously decomposing β-catenin and Ras protein represented by the following formula (1).

[Chemical Formula 1]

In the above formula (1)

Is an E-form or a 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} alkyl, C _{6 - 12} aryl;

X is a five to six membered heteroaryl containing from one to two nitrogen atoms, an eight to nine membered fused heteroaryl containing from one to two nitrogen atoms and a ten atom fused heteroaryl containing two nitrogen atoms, ; Said heteroaryl and fused heteroaryl being unsubstituted or N-substituted by a substituent selected from phenyl, benzyl and pyridyl or substituted with 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy, Gt; C-substituted < / RTI > 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 selected from the group consisting of 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 , and wherein the 4-6 heteroatom won the nitrogen of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C _{1- 6} alkyl, C _{1- 6} alkyl C _{6 -12} aryl, C _{6- 12} aryl C _{1 - 6} alkyl, trifluoro C _{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 R 3} N- substituted with a substituent selected from or -COOC _{1 - 6} alkyl, C _{6 - 12} aryl, and substituted with a C-, wherein C from ₆ alkyl is unsubstituted or C _{1- 6} alkoxy, nitrile, halogen, C _{1- 6} alkyl, CF _3, hydroxy, OCF _{3 - 1- 6} alkyl, C _{6 - 12} aryl and C _{6- 12} aryl C ₁ Lt; / RTI > is substituted with one or more substituents selected <

R ₂ is selected from C _{1- 6} alkyl, C _{1- 6} alkoxy, dibenzyl amino carbonyl and C _{1- 3} alkyl-piperazinyl,

R ₃ is C _{1- 6} alkyl,

R ₄ is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkylamino, C _1-3 alkyl-oxadiazolyl, pyridazinyl imidazole, triazolyl and C _{6- 12} is selected from aryl, wherein 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, dimethyl amino carbonyl and diisopropyl amino carbonyl substituent may be one to three substitutions selected from , if the substituents are plural, said substituents may be the same or different from each other, and the indolyl and benzo-oxazolyl may be unsubstituted or substituted by hydroxy, halogen or C _{1- 6} may be substituted with one to two substituents selected from among alkyl And when the substituent is 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} aryl C _{1 - 6} alkyl, oxazole, pyridinyl C _{1 - 3} alkyl or morpholino C _{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 of 0 to 5,

m is an integer of 1 to 5,

Adjacent R < ₃ > and R < ₆ > are each independently present or bonded to each other to form a ring.

According to the present invention, the ring formed by combining R ₃ and R ₆ with each other may be cyclohexyl.

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

&Quot; Heterocycloalkyl " means a saturated or polycyclic hydrocarbon ring containing one to several heteroatoms independently selected from nitrogen, oxygen and sulfur. In the present invention, the heteroatom of the heterocycloalkyl may be nitrogen. Said heterocycloalkyl is unsubstituted, C _{1- 6} alkyl, C _{1- 6} alkyl, C _{6 - 12} aryl, C _{6- 12} aryl C _{1 -} to ₆ alkyl, trifluoro C _{2 - 6} alkyl, C _{2- 6} Substituted with a substituent selected from -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 -COOC _{1 - 6} alkyl, C _{6 - 12} aryl may be substituted with a C-. The definitions of R ₂ , R ₃ and R ₅ are the same as those given above.

&Quot; Halogen " means < / RTI > fluoro, chloro, bromo and iodo.

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

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

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

In the present invention,

Can be selected from the following structures.

In this structure, R ₉ is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R ₉ is 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 of 0 to 2;

In the present invention, the compound represented by the formula (1) may be selected from compounds represented by the following formulas (2) to (5).

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In the above formulas 2 to 5,

Is selected from the following structures;

R ₉ is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R ₉ is 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, _{carboxy-cyclohexyl, (CH 2) n C (} O) R 2, (CH 2) m R 4 or (CH _{2) n} CONHR _5, and said 4-6 the nitrogen source is a heteroatom of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C _{6- 12} aryl C _{1 -} to ₆ alkyl, -C (O) R _5, and the substituent is selected from -COOR ₃ N- substituted, wherein C _{6- 12} aryl C _{1 - 6} alkyl which is unsubstituted or substituted one or more C _{1- 6} alkoxycarbonyl, nitrile, halogen, C _{1- 6} alkyl, CF _3, hydroxy, selected from OCF ₃ Lt; / RTI >

R ₂ is C _{1- 6} alkyl, C _{1- 6} alkoxy, or C _{1- 3} alkyl-piperazinyl and;

R ₃ is C _{1- 6} alkyl;

R ₄ is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkylamino, C _1-3 alkyl-oxadiazolyl , an imidazolyl, triazolyl or C _{6- 12} aryl, wherein 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, dimethyl amino carbonyl and diisopropyl amino, and carbonyl substituents can be one to three substitutions selected from the group consisting of, when the plurality of the substituent, the substituent be the same or different from each other, and the indolyl and benzo-oxazolyl is is unsubstituted or substituted by hydroxy, halogen or C _{1- 6} can be optionally substituted with 1 to 2 substituents selected from the open-circuit-alkyl, wherein the substituents plurality, wherein the substituent Are the same or different from each other;

R ₅ is C _{1- 6} alkyl, C _{6- 12} aryl, C _{6- 12} aryl C _{1 - 6} alkyl, oxazole, pyridinyl C _{1 - 3} alkyl or morpholino C _{1 -3} alkyl;

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

When a is 2, the number of R ₁₁ is two, and the two R ₁₁ may be the same or different.

In the present invention, the compound of formula (1) may be selected from the following formulas (6) to (13).

[Chemical Formula 6]

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

(11)

[Chemical Formula 12]

[Chemical Formula 13]

In the above formulas (6) to (13)

Y is S or O,

R ₉ is hydrogen, phenyl or pyridyl, and the phenyl and pyridyl of R ₉ are unsubstituted or substituted with one or more Nitro;

R < ₁₁ > is nitrophenyl or trifluoromethyl;

a is an integer of 1 to 2;

R ₁ is hydrogen, 4-6 membered heterocycloalkyl, _{carboxy-cyclohexyl, (CH 2) n C (} O) R 2, (CH 2) m R 4 or (CH _{2) n} CONHR _5, and said 4-6 The heteroatom of the one heterocycloalkyl is nitrogen and the 4-6 membered heterocycloalkyl is unsubstituted or N-substituted by -COOR ₃ ;

R ₂ is C _{1- 6} alkyl, C _{1- 6} alkoxy, or C _{1- 3} alkyl-piperazinyl and;

R ₃ is C _{1- 6} alkyl;

R ₄ is OH, COOH, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkyl amino or C _{6- 12} aryl, wherein C _{6- 12} aryl is unsubstituted;

R ₅ is C _{1- 6} alkyl, pyridinyl C _{1 - 3} alkyl or morpholino C _{1 - 3} alkyl;

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

According to the present invention, the compound represented by the formula (1) may be preferably selected from the following formulas (14) to (17).

[Chemical Formula 14]

[Chemical Formula 15]

[Chemical Formula 16]

[Chemical Formula 17]

In the above 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 heteroatom which ^{_{characters, (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 heteroaryl, 4-6 membered heterocycloalkyl containing one nitrogen, (CH ₂ ) _b C (O) R ^d or (CH ₂ ) _d CONHR ^e ;

R ^a is OH, morpholino, C _{1- 3} alkyl-piperazinyl or a mono- or di -C _1-3 alkyl amino;

R ^b is C _{1- 3} alkyl-piperazinyl and;

R ^c is C _{1- 6} alkyl, C _{1- 3} alkyl-piperazinyl or hydroxy;

R ^d is C _{1- 6} alkyl;

R ^e 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, 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 formulas (18) and (19).

[Chemical Formula 18]

[Chemical Formula 19]

In the above 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 heteroatom which ^{_{characters, (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} alkyl-piperazinyl or a mono- or di -C _1-3 alkyl amino;

R ^b is C _{1- 3} alkyl-piperazinyl and;

R ^c is C _{1- 6} alkyl, C _{1- 3} alkyl-piperazinyl or hydroxy;

R ^d is C _{1- 6} alkyl;

R ^e is C _{1- 6} alkyl or morpholino C _{1 - 3} alkyl;

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

According to the present invention, the compound represented by the formula (1) can be specifically selected from the following compounds or pharmaceutically acceptable salts thereof.

(Z) -4- [4-oxo-5 - {(5-phenoxypyridin-2-yl) -methylene} -2-thioxothiazolidin-3-yl] -butanooic acid;

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

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

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

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

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

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

(Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " Carboxylic acid;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

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

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

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

(Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

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

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

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

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

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

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " 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} Thioxothiazolidin-4-one;

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

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

Yl) methylene] -2,4-dioxothiazolidin-3-yl] butanoate (Z) ;

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

Yl) methylene] -2,4-dioxothiazolidin-3-yl] butanoate (Z) ;

(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-phenethylthiazolidin-2,4-dione;

(Z) -5 - [{1- (4-nitrophenyl) -1H-pyrazol-3-yl} methylene] -3- (piperidin- -One 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] pentanobic 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) thiazolidin- Hydrochloride;

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

(Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-4-yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

(Z) -5 - [{1- (4-nitrophenyl) -lH-pyrazol-4-yl} methylene] -3- (piperidin- 4- yl) -2-thioxothiazolidin- -One 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;

Yl) methylene] -4-oxo-2-thioxothiazolidin-3-yl] butanoic acid (Z) Eight;

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

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

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

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2-methoxyphenyl) (Pyridin-3-ylmethyl) butanamide;

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl (methyl) ] Butanamide;

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2-methoxyphenyl) Propylbutanamide;

Yl} methylene] -2-thioxothiazolidin-3-yl (Z) -tert-butyl 4- [4-oxo- ] Piperidine-1-carboxylate;

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

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

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2- (Pyridin-2-ylmethyl) propanamide;

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2- Propyl propanamide;

Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >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;

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] butanoic acid (hereinafter referred to as ";

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

(4-methylpiperazin-1-yl) -3-oxopropyl} -2-thioxo Thiazolidin-4-one;

(Z) -5 - {(5,6-difluoro-1H-indol-2-yl) methylene} -3- (piperidin- 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- 2-yl) propanamide.

According to the present invention, the compound represented by the formula (1) can be preferably selected from the following compounds or pharmaceutically acceptable salts thereof.

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

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

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

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

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

(Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " Carboxylic acid;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

(Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

(Z) -3- (2-hydroxyethyl) -5 - [{1- (4-nitrophenyl) -1H-pyrazol-3-yl} methylene] thiazolidin-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- -One 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) thiazolidin- Hydrochloride;

Yl} methylene] -2-thioxothiazolidin-3-yl (Z) -tert-butyl 4- [4-oxo- ] Piperidine-1-carboxylate;

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

Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >hydrochloride; And

(Z) -3- [5 - {(lH-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] thiazolidin-2,4-dione;

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

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

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

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

(Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

(Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >hydrochloride; And

(Z) -3- [5 - {(lH-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 ordinarily used in the art, and specific examples thereof include non-toxic inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid and nitric acid, , Salicylic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, para toluenesulfonic acid, ethanesulfonic acid and methanesulfonic acid.

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 type protein.

The compound represented by Formula 1 according to the present invention may be one which binds to Axin to degrade β-catenin or Ras protein, and preferably decomposes β-catenin and Ras protein simultaneously .

The compound represented by Formula 1 according to the present invention can inhibit the Wnt / beta -catenin signal transduction system and inhibits the growth of cancer cells on invitro and invivo by simultaneously degrading beta -catenin and Ras protein, The present invention can be used as a pharmaceutical composition for cancer treatment of cancer patients having a cancer patient, preferably a cancer patient having a Ras mutation type, more preferably a K-Ras mutant type and showing no therapeutic effect on conventional anticancer drugs.

More specifically, it binds to Axin, a negative regulator of the Wnt / β-catenin signaling system, which catalyzes the binding of exciton and β-catechin destructive complex to decompose β-catenin and Ras protein. This inhibits the Wnt / beta -catenin signal transduction system and the Ras / ERK signal transduction system. Ras is composed of K, N, and H-Ras. Among them, K-Ras has many mutations in colorectal cancer, lung cancer, metastatic cancer, etc. and acts as an important tumor regulator in such cancer.

Compounds that regulate the activity of Ras protein or inhibit the Ras signal transduction system beyond that have been developed as conventional anticancer drugs, however, there is a problem of resistance in patients with mutant Ras. The compound represented by the above formula (1) according to the present invention is characterized by decomposing the Ras protein which is not the activity of the Ras protein and decreasing the amount thereof. The Ras protein is characterized not only by the wild-type Ras but also by the K-Ras mutation, and thus exhibits an anticancer effect against cancer having a K-Ras mutation, particularly cancer that is resistant to antibody / anticancer drugs targeting EGFR And clinically confirmed that the anticancer effect was remarkably excellent in colorectal cancer, lung cancer, stomach cancer, metastatic cancer and the like which are resistant to conventional anticancer drugs.

The compound represented by Formula 1 according to the present invention can inhibit Ras / PI3K / Akt signal transduction system as well as the lower Ras / ERK signal transduction system by inhibiting Ras protein.

The cancer according to the present invention may be an abnormality of the Wnt /? - catenin signal transduction system or a cancer caused by Ras protein. Specifically, the cancer may be cancer of the colon, stomach cancer, pancreatic cancer, brain tumor, lung cancer, bladder cancer, renal cancer, Tumor, malignant melanoma, neuroblastoma, malignant melanoma, and rhabdomyosarcoma.

The cancer according to the present invention may also be a metastatic cancer.

The pharmaceutical composition according to the present invention may contain a pharmaceutically acceptable carrier in addition to the compound represented by the 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 that is useful when formulating the pharmaceutically active compound for administration and is substantially non-toxic and non-sensitive under the conditions of use. The exact ratio of such excipients is determined by standard pharmaceutical practice, as well as the solubility and chemical properties of the active compound, the route of administration chosen.

The pharmaceutical composition of the present invention may be formulated into a form suitable for a desired administration method using suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, .

The pharmaceutical composition according to the present invention may be formulated into tablets, capsules, pills, granules, powders, injections or solutions.

Formulations suitable for oral administration include solid preparations such as tablets, microparticles, capsules containing liquid or powder, pills, granules, powders, lozenges (including liquid-filled ones), chews, Gels, solid solutions, liposomes, films (including mucosal-tackiness), ovules, sprays and liquids. Liquid preparations include, for example, suspensions, solutions, syrups and elixirs.

The tablets generally contain a disintegrant in addition to the drug. Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrant, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropylcellulose or carboxy Cellulose such as methyl cellulose, alginate such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum and xanthan gum, cross-linking such as crospovidone, A polymer, a boiling agent such as sodium bicarbonate, citric acid or the like may be mixed and used. In general, the disintegrant will include, 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 the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, starch, copovidone, highly disperse silica, mannitol, lactose , Hydroxypropylcellulose, and hydroxypropylmethylcellulose. Generally, the binder will comprise 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, but is not limited thereto. The tablets may be, for example, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate as diluents. Generally, the diluent will comprise 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, but is not limited thereto.

Tablets may also optionally contain a surfactant, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If 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.

As lubricants there may also be mentioned 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 Polyethylene glycol 4000, and the like can be used. The lubricant generally comprises 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, flavors, preservatives and taste-masking agents.

Tablet formulations can be pressed directly or squeezed with a roller to form tablets. Alternatively, the tablet formulation or a portion of the formulation may be wet, dry, melt-granulated, melt congealed or extruded prior to tableting. The final formulation may comprise one or more layers, may be coated or uncoated, and may be encapsulated.

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

In one embodiment, the pharmaceutical composition of the present invention may be a tablet. Tablets may optionally be film coated. The total amount of the drug per unit dose may be an amount that provides a convenient size dosage form to the patient.

In one embodiment, the pharmaceutical compositions of the invention may be formulated in the form of sustained release tablets. For the preparation of sustained-release tablets, a matrix polymer selected from an enteric polymer, a hydrophobic substance, and a hydrophilic polymer may be used as the matrix base.

Examples of the enteric polymer include a mixture of at least one selected from the group consisting of 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 substance may be a polyvinyl acetate, a polymethacrylate copolymer, a poly (ethyl acrylate, methyl methacrylate) copolymer, a poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate, Ethylcellulose and cellulose acetate, fatty acid and fatty acid esters, fatty acid alcohols, waxes and inorganic substances can be selected. Specific examples of the fatty acid and fatty acid esters include glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid; waxes such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; carnauba wax, beeswax and microcrystalline wax As an inorganic substance, talc, precipitated carbon Can be used to select one or more selected from calcium, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and bigeom.

The hydrophilic polymer may be selected from saccharides, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. Specific examples of the hydrophilic polymer include dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinozaylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin, and the like can be selected. As the cellulose derivative, hydroxypropylmethylcellulose , Hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxyethylmethylcellulose and the like can be used. , To Gelatin, casein or zein may be selected as the protein, and polyvinyl alcohol such as polyvinyl alcohol may be used as the polyvinyl derivative , Polyvinylpyrrolidone and polyvinyl acetal diethylaminoacetate. As the polymethacrylate copolymer, poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate ), Poly (methacrylic acid, methyl methacrylate) copolymer, poly (methacrylic acid, ethyl acrylate) copolymer and the like can be selected and polyethylene glycol, polyethylene oxide and the like can be selectively used as a polyethylene derivative And carbomers can be used as the carboxyvinyl polymer.

According to the present invention, the pharmaceutical composition can be administered orally or parenterally in any desired dosage form, depending on the kind of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, The effective amount can be adjusted depending on various factors including time, route of administration and minute of composition, duration of treatment, concurrent medication, and the like. For example, in the case of an adult, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered at a dose of 4000 mg / day at intervals of one to several times, .

The pharmaceutical composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient can be used in combination with the second anticancer drug.

The second anticancer agent according to the present invention can 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 immunotherapies and gene therapy agents may be included.

Examples of the second anticancer agent according to the present invention include nitrogene mustard, imatinib, oxaliplatin, erlotinib, gefitinib, bortezomib, sunitinib, carboplatin, sorafenib, cisplatin, viscum alum, But are not limited to, nadir, tretinoin, hydroxycarbamide, dasatinib, estramermin, gemtuzumab ozogamicin, ibritumomat cetane, heptaplatin, methylaminelebulinic acid, amsacrine, proccarbazine, , Holmium nitrate chitosan, gemcitabine, doxifluridine, femetrexed, tegafur, capecitabine, gimeracin, atheracil, azacytidine, methotrexate, uracil, cytarabine, fluorouracil, , Antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, antibiotics, But are not limited to, tin, vinblastine, tenifocide, doxorubicin, dirubicin, epirubicin, mitoxantrone, mitomycin, blormomycin, daunorubicin, dactinomycin, pyrarbicin, aclarubicin, A group consisting of mucin, temozolomide, epidermis, iphosphamide, cyclophosphamide, melphalan, altretin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, ≪ RTI ID = 0.0 > and / or < / RTI >

The present invention provides a pharmaceutical composition comprising a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and a combined preparation comprising a second anticancer drug. The kind of the second anticancer agent is as exemplified above.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to preferred embodiments for better understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Example

The compounds were synthesized using the same method as the one prepared in the examples, unless otherwise indicated.

Manufacturing example  One. Rhodanin  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. The reaction was carried out through a microwave reactor under the 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: 34-85%

Manufacturing example  2. Rhodanin  Intermediate 2 (4-oxo-2- Thioxothiazolidine -3- Alkyl  Acid ester) Synthesis

(1 eq.) And (±) -camphor-10-sulfonic acid (3 eq.) Were dissolved in low-alcohol, Min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the pH was adjusted to neutral by adding an aqueous solution of saturated sodium carbonate, extracted with dichloromethane, and then the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: ethyl acetate: hexane = 1: 3-1: 1) to obtain the desired compound (yield: 92%).

Manufacturing example  3. Thiazolidine -2,4- Dion  Manufacture of potassium salts

Thiazolidin-2,3-dione (1 eq.) Was dissolved in ethanol, followed by addition of ethanol in which potassium hydroxide (1.1 eq.) Was dissolved and stirred for 2 hours to obtain a white precipitate. The obtained precipitate was collected by filtration and then washed several times with ethanol to obtain the desired compound (yield: 98%).

Manufacturing example  4. Thiazolidine -2,4- Dion  Preparation of intermediate

Thiazolidine-2,4-dione potassium salt (1 eq.), Potassium iodide (1 eq.) And 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, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (eluent: 1% methanol / dichloromethane) to give the desired compound (yield: 15-53%).

Manufacturing example  5. Thiazolidine -2,4- Dion -3- Alkyl  Manufacture of acid

Thiazolidin-2,4-dione 3-alkyl acid ester (1 eq.) Was dispersed in a 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: 74-96%).

Manufacturing example  6. Thiohydantoin  Synthesis of intermediates

Ethyl isothiocyanate (1 eq.), Ethyl amino alkylate (1.1 eq.) And triethylamine (3 eq.) Were dissolved in acetonitrile and stirred 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 to 2: 1) to obtain the desired compound (yield: 84 to 89% .

Manufacturing example  7. 1- (4- Nitrophenyl ) -1H-pyrrole-2- Carbaldehyde  synthesis

Furan-2-carbaldehyde (1 eq.) And 4-nitroaniline (2 eq.) Were dissolved in ethanol and 2N aqueous hydrogen chloride solution (2 eq.) Was slowly added dropwise. The reaction mixture was refluxed for 2 hours, then cooled to room temperature and water was added. The resulting precipitate was filtered and 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.

Manufacturing example  8. Indazole  3- Carboxylic Acid's  synthesis

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

Manufacturing example  9. Indazole  3- Carbaldehyde  synthesis

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

Manufacturing example  10. 3- [2- ( Benzo [d] oxazole Yl) ethyl] -2- Thioxothiazolidine -One

(1 eq.) And 2-aminophenol (1.1 eq.) Were added to an excess amount of polyphosphoric acid, and the mixture was stirred at 160 占 폚 Stir for 14 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, excess water was added, and a saturated aqueous solution of sodium hydrogencarbonate was added to adjust the pH to neutral (pH 7 to 8), followed by extraction with ether. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: ethyl acetate: n-hexane = 1: 3-1: 1) to obtain the desired compound Yield 26%).

Manufacturing example  11. 2-Substituted pyridine-6- Carbaldehyde  synthesis

(1.0 eq.), Tetrakis (triphenylphosphine) palladium (0.05 eq.) And a 2M aqueous potassium carbonate solution (1.5 eq.) Were added to a solution of Dispersed in toluene / ethanol (1: 1 mixed solvent), and refluxed for 8 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. The desired compound was obtained by purifying the residue by column chromatography (eluent: ethyl acetate: n-hexane = 1:10 to 1: 3). (Yield: 64%

Manufacturing example  12. Ethyl 1- (4- Nitrophenyl ) Pyrazole -3- Carboxylate  synthesis

(1 eq.), Ethyl pyrazole-3-carboxylate (1 eq.), Divalent copper acetate (0.1 eq.) And cesium carbonate (1 eq.) Were added to N, N ' -Dimethylformamide and refluxed for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and excess water was added to form a precipitate. The resulting precipitate was filtered and dried to the next reaction.

Manufacturing example  13. 1- (4- Nitrophenyl ) Pyrazole -3- Of methyl alcohol  Produce

Anhydrous tetrahydrofuran was added to ethyl 1- (4-nitrophenyl) pyrazole-3-carboxylate (1 eq.) Under an argon atmosphere and stirred at 0 ° C for 20 minutes. Then, 1M lithium aluminum hydride (1.1 eq .) The tetrahydrofuran solution was added slowly and stirred at 0 < 0 > C for 2 h. 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.

Manufacturing example  14. 1- (4- Nitrophenyl ) Pyrazole -3- Carbaldehyde

The reaction was confirmed by TLC while stirring at room temperature for 3 hours after dissolving 1- (4-nitrophenyl) pyrazole-3-methyl alcohol (1 eq.) And pyridine chromic acid chloride (2 eq.) In dimethyl methane . After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated. The desired compound was obtained (yield: 12%) by column chromatography (eluent: ethyl acetate: n-hexane = 1: 5).

Example  1. Compound KY1220

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

After 1 - (4-nitrophenyl) -1H-pyrrole-2-carbaldehyde (1 eq.) And thiohydantoin (1 eq.) Were dispersed in ethanol, sodium acetate (1 eq.) Was added, The mixture was stirred at 60 占 폚 for 6 hours. After completion of the reaction, the formed precipitate was filtered, washed with ethanol, and washed precipitate was obtained to obtain the desired compound (yield: 38%).

^{1 H NMR (400MHz, 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 = 8.8Hz), 7.47-7.44 (m, 2H), 6.54 (m, 1H), 6.13 (s, 1H)

Example  2. Compound A2927

Yl] methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

(Z) -5- (5 - ((1- (4-nitrophenyl) -1H-pyrazol-3-yl) methylene) -2,4- dioxothiazolidin-3-yl) pentanone acid 1 eq.) Was dissolved in anhydrous tetrahydrofuran under an argon stream and stirred at 0 ° C for 20 min. N-methylmorpholine (3 eq.) And isobutyl chloroformic acid ester (1.5 eq.) And further stirred at 0 ° C for 15 minutes. Then, 2M ethylamine tetrahydrofuran solution (1.1 eq.) Was added, the temperature was slowly raised to room temperature and further stirred for 5 hours. After completion of the reaction, the formed precipitate was filtered off and washed with ether. The washed precipitate was separated by column chromatography (eluent 2% methanol / dimethylmethane) to obtain the desired compound (yield 68%).

^{1 H NMR (400MHz, 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), 2H), 2.05 (t, 2H, J = 10.0Hz), 1.60-1.51 (m, 2H) (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-carbaldehyde (1 eq.) And thiazolidin-2,4-dione-3-butanoic acid (1 eq.) Were dispersed in ethanol, (1 eq.) Was added thereto, followed by stirring at 60 ° C for 10 hours. After completion of the reaction, the formed precipitate was filtered, washed with ethanol and diethyl ether, and washed precipitate was obtained to obtain the desired compound (yield: 73%).

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

Example  4. Compound A4283

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

(1 eq.) And 3- (2-hydroxyethyl) thiazolidin-2,4-dione (1 eq.) Were used as the starting materials. The target compound was obtained in the same manner as in Example 3 (yield: 65%).

^{1 H NMR (400MHz, 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, 1 H), 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] thiazolidin- ;

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

^{1 H NMR (400MHz, 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 ( 2H), 7.06 (d, 1H, J = 4.0 Hz), 4.90 (t, 1H, J = 4.0 Hz), 3.70 Hz); ESI (m / z) 359 (MH <">)

Example  6. Compound A2725

Yl} methylene] -2,4-dioxothiazolidin-3-yl] butyrate (hereinafter referred to as "mountain;

Using 1 - (4-nitrophenyl) pyrazole-3-carbaldehyde (1 eq.) And thiazolidin-2,4-dione-3-butanoic acid on (1 eq. 3, the desired compound was obtained (yield: 90%).

^{1 H NMR (400MHz, 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), 2H, J = 6.8 Hz), 7.79 (s, 1H), 7.03 (s, 1H), 3.66 (t, 2H, J = 6.4 Hz). 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} methylene] -2,4-dioxothiazolidin-3-yl] butanoic acid was prepared from (Z) -4- [5- 0.1 M methanol solution was prepared, and 1 M potassium hydroxide methanol solution (1 eq.) Was added dropwise while stirring at 60 캜, followed by stirring at 60 캜 for 1 hour. Then, the temperature was lowered to room temperature, and the formed precipitate was stirred and washed with methanol 2-3 times 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] butyrate potassium;

Yl} methylene] -2,4-dioxothiazolidin-3-yl] butanoic acid was dissolved in a 0.2M methanol solution (5 ml) , 1M potassium hydroxide methanol solution (1 eq.) Was added dropwise at 60 占 폚 while stirring, and the mixture was stirred at 60 占 폚 for 1 hour. Then, the temperature was lowered to room temperature, and the formed precipitate was stirred and washed with methanol 2-3 times to obtain the desired compound (yield: 60%).

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

[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 TOPflash gene chromosome) were obtained from Oh Sang Taek (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.

TOPflash  reporter activity Degree of inhibition  Measure

In order to identify the compounds decomposing β-catenin and Ras proteins from the compounds of Table 1 prepared in Examples 1 to 82, a TOPflash reporter gene capable of detecting the activation level of the Wnt / β-catenin signaling system was inserted The effect of the compound KYA1797K and each compound on the activity of the Wnt / β-catenin signaling system was confirmed by treatment with Wnt3a-CM or L-CM at a concentration of 1 μM in the HEK293 reporter cells. Each activity was normalized using the activity of the TOPflash reporter activated by the Wnt3a-CM control as 100%. Compounds having a degree of inhibition of the activity of TOPflash reporter of less than 40% as compared with the control (100%) activity as compared with the comparative compound KYA1797K are shown in [Table 3].

[Table 3]

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

A comparison of the control compound KYA1797K and 21 kinds of compounds (A3004, A2698, A2725, A2973, A3249, A3250, A4267, A4278, A4267 , A4283, A4284, A2725K, A4278K, A4352, A4352H, A4353, A4354, A4363, A4364, A4365, A4365H) at a concentration of 5 or 25 μM for 24 hours, followed by immunoblotting. The changes in the amount of each protein were observed using anti-pan-Ras, anti-β-catenin and anti-α-tubulin antibodies and quantification of each pan-Ras and β- , And normalized to a relative value with the gain of the control group (DMSO) set to 1, and the graphs are shown in Figs. 1 to 3. The compounds A3249, A4365 and A4365H showed cytotoxicity and the compounds A3004, A2698, A2725, A3250, A4267, A4278, A4267, A4283, A4284, A4352, A4353, A4354, A4363, Or [beta] -catenin, respectively. These compounds have been experimentally confirmed to be capable of simultaneously inhibiting the Wnt / β-catenin signal transduction system and Ras.

Measurement of inhibition of cell formation

Cells (500 cells / well for SW480 cells) were plated on a 12-well plate of SW480 cells, Wnt / β-catenin signal transduction system and Ras / EKR signaling system activated colonic cancer cells. Each cell was treated with DMSO (control), the compounds of the present invention (A3004, A2698, A2725, A4267, A4283 and A4284) and the comparative compound (KYA1797K) Respectively. Finally, the cells were fixed with 4% paraformaldehyde (PFA) for 30 minutes and stained with 0.5% crystal violet solution in 20% ethanol for 30 minutes. The number of stained cells was measured and shown in a numerical value graph in Fig.

These results confirmed that the compounds of the present invention inhibited cell proliferation in human colorectal cancer cell line SW480. As a result, all compounds effectively inhibited cell formation in a concentration-dependent manner. In particular, A3004 and A4283 showed better cell proliferation inhibitory ability than comparative compound KYA1797K. However, A2698, A2725, A4268 and A4284 showed 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 a colon cancer cell line.

Claims (17)

1. 1. A compound represented by the following formula (1): < EMI ID =

   [Chemical Formula 1]

   

   In the above formula (1)

   

   Is an E-form or a 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} alkyl, C _{6 - 12} aryl;

   X is a five to six membered heteroaryl containing from one to two nitrogen atoms, an eight to nine membered fused heteroaryl containing from one to two nitrogen atoms and a ten atom fused heteroaryl containing two nitrogen atoms, ; Said heteroaryl and fused heteroaryl being unsubstituted or N-substituted by a substituent selected from phenyl, benzyl and pyridyl or substituted with 1 to 2 substituents selected from halogen, nitrophenyl, pyridyl, trifluoromethyl and phenoxy, Gt; C-substituted < / RTI > 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 selected from the group consisting of 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 , and wherein the 4-6 heteroatom won the nitrogen of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C _{1- 6} alkyl, C _{1- 6} alkyl C _{6 -12} aryl, C _{6- 12} aryl C _{1 - 6} alkyl, trifluoro C _{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 R 3} N- substituted with a substituent selected from or -COOC _{1 - 6} alkyl, C _{6 - 12} aryl, and substituted with a C-, wherein C from ₆ alkyl is unsubstituted or C _{1- 6} alkoxy, nitrile, halogen, C _{1- 6} alkyl, CF _3, hydroxy, OCF _{3 - 1- 6} alkyl, C _{6 - 12} aryl and C _{6- 12} aryl C ₁ Lt; / RTI > is substituted with one or more substituents selected <

   R ₂ is selected from C _{1- 6} alkyl, C _{1- 6} alkoxy, dibenzyl amino carbonyl and C _{1- 3} alkyl-piperazinyl,

   R ₃ is C _{1- 6} alkyl,

   R ₄ is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, tetrahydrofuranyl, furanyl, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkylamino, C _1-3 alkyl-oxadiazolyl, pyridazinyl imidazole, triazolyl and C _{6- 12} is selected from aryl, wherein 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, dimethyl amino carbonyl and diisopropyl amino carbonyl substituent may be one to three substitutions selected from , if the substituents are plural, said substituents may be the same or different from each other, and the indolyl and benzo-oxazolyl may be unsubstituted or substituted by hydroxy, halogen or C _{1- 6} may be substituted with one to two substituents selected from among alkyl And when the substituent is 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} aryl C _{1 - 6} alkyl, oxazole, pyridinyl C _{1 - 3} alkyl or morpholino C _{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 of 0 to 5,

   m is an integer of 1 to 5,

   Adjacent R < ₃ > and R < ₆ > are each independently present or bonded to each other to form a ring.
2. The method according to claim 1,

   Wherein said 5- to 6-membered heteroaryl is selected from pyrrolyl, pyrazolyl and pyridyl; or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1,

   Wherein said 8 to 9-atom condensed heteroaryl is selected from benzoimidazolyl, indolyl, indazolyl and imidazopyridyl, said 10 atomic condensed heteroaryl being quinoxalyl.
4. The method according to claim 1,

   remind

   

   Lt; / RTI > is selected from the following structures.

   

   In this structure, R ₉ is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R ₉ is 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 of 0 to 2;
5. 5. The method of claim 4,

   Wherein said compound is selected from compounds represented by the following formulas (2) to (5): < EMI ID = 25.1 >

   (2)

   (3)

   

   [Chemical Formula 4]

   

   [Chemical Formula 5]

   

   In the above formulas 2 to 5,

   

   Is selected from the following structures;

   

   R ₉ is hydrogen, phenyl, benzyl or pyridyl, and the phenyl, benzyl and pyridyl of R ₉ is 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, _{carboxy-cyclohexyl, (CH 2) n C (} O) R 2, (CH 2) m R 4 or (CH _{2) n} CONHR _5, and said 4-6 the nitrogen source is a heteroatom of the heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl are unsubstituted, C _{6- 12} aryl C _{1 -} to ₆ alkyl, -C (O) R _5, and the substituent is selected from -COOR ₃ N- substituted, wherein C _{6- 12} aryl C _{1 - 6} alkyl which is unsubstituted or substituted one or more C _{1- 6} alkoxycarbonyl, nitrile, halogen, C _{1- 6} alkyl, CF _3, hydroxy, selected from OCF ₃ Lt; / RTI >

   R ₂ is C _{1- 6} alkyl, C _{1- 6} alkoxy, or C _{1- 3} alkyl-piperazinyl and;

   R ₃ is C _{1- 6} alkyl;

   R ₄ is OH, COOH, indolyl, benzo-oxazolyl, oxazolyl, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkylamino, C _1-3 alkyl-oxadiazolyl , an imidazolyl, triazolyl or C _{6- 12} aryl, wherein 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, dimethyl amino carbonyl and diisopropyl amino, and carbonyl substituents can be one to three substitutions selected from the group consisting of, when the plurality of the substituent, the substituent be the same or different from each other, and the indolyl and benzo-oxazolyl is is unsubstituted or substituted by hydroxy, halogen or C _{1- 6} can be optionally substituted with 1 to 2 substituents selected from the open-circuit-alkyl, wherein the substituents plurality, wherein the substituent Are the same or different from each other;

   R ₅ is C _{1- 6} alkyl, C _{6- 12} aryl, C _{6- 12} aryl C _{1 - 6} alkyl, oxazole, pyridinyl C _{1 - 3} alkyl or morpholino C _{1 -3} alkyl;

   n is an integer of 1 to 4, and m is an integer of 1 to 5.
6. 6. The method of claim 5,

   Wherein said compound is selected from compounds represented by the following formulas (6) to (13): < EMI ID = 17.1 >

   [Chemical Formula 6]

   

   [Claim 7]

   

   [Claim 8]

   

   [Claim 9]

   

   [Claim 10]

   

   [Claim 11]

   

   [Claim 12]

   

   [Claim 13]

   

   In the above formulas (6) to (13)

   Y is S or O,

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

   R < ₁₁ > is nitrophenyl or trifluoromethyl;

   a is an integer of 1 to 2;

   R ₁ is hydrogen, 4-6 membered heterocycloalkyl, _{carboxy-cyclohexyl, (CH 2) n C (} O) R 2, (CH 2) m R 4 or (CH _{2) n} CONHR _5, and said 4-6 The heteroatom of the one heterocycloalkyl is nitrogen and the 4-6 membered heterocycloalkyl is unsubstituted or N-substituted by -COOR ₃ ;

   R ₂ is C _{1- 6} alkyl, C _{1- 6} alkoxy, or C _{1- 3} alkyl-piperazinyl and;

   R ₃ is C _{1- 6} alkyl;

   R ₄ is OH, COOH, morpholino, C _{1- 3} alkyl-piperazinyl, mono- or di -C _1-3 alkyl amino or C _{6- 12} aryl, wherein C _{6- 12} aryl is unsubstituted;

   R ₅ is C _{1- 6} alkyl, pyridinyl C _{1 - 3} alkyl or morpholino C _{1 - 3} alkyl;

   n is an integer of 2 to 4, and m is an integer of 2 to 5.
7. The method according to claim 6,

   Wherein said compound is selected from compounds represented by the following general formulas (14) to (17).

   [Chemical Formula 14]

   

   [Chemical Formula 15]

   

   [Chemical Formula 16]

   

   [Chemical Formula 17]

   

   In the above 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 heteroatom which ^{_{characters, (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 heteroaryl, 4-6 membered heterocycloalkyl containing one nitrogen, (CH ₂ ) _b C (O) R ^d or (CH ₂ ) _d CONHR ^e ;

   R ^a is OH, morpholino, C _{1- 3} alkyl-piperazinyl or a mono- or di -C _1-3 alkyl amino;

   R ^b is C _{1- 3} alkyl-piperazinyl and;

   R ^c is C _{1- 6} alkyl, C _{1- 3} alkyl-piperazinyl or hydroxy;

   R ^d is C _{1- 6} alkyl;

   R ^e 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, c, d and e are each independently an integer of 2 to 4, and f is an integer of 1 to 2.
8. 8. The method of claim 7,

   Wherein said compound is selected from compounds represented by the following general formula (18) or (19): < EMI ID = 25.1 >

   [Chemical Formula 18]

   

   [Chemical Formula 19]

   

   In the above 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 heteroatom which ^{_{characters, (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} alkyl-piperazinyl or a mono- or di -C _1-3 alkyl amino;

   R ^b is C _{1- 3} alkyl-piperazinyl and;

   R ^c is C _{1- 6} alkyl, C _{1- 3} alkyl-piperazinyl or hydroxy;

   R ^d is C _{1- 6} alkyl;

   R ^e is C _{1- 6} alkyl or morpholino C _{1 - 3} alkyl;

   a is an integer of 2 or 3, and b is an integer of 2 to 5.
9. The method according to claim 1,

   The compound

   (Z) -4- [4-oxo-5 - {(5-phenoxypyridin-2-yl) -methylene} -2-thioxothiazolidin-3-yl] -butanooic acid;

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

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

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

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

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

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

   (Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " Carboxylic acid;

   Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

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

   Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

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

   (Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

   Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

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

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

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

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

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

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " 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} Thioxothiazolidin-4-one;

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

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

   Yl) methylene] -2,4-dioxothiazolidin-3-yl] butanoate (Z) ;

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

   Yl) methylene] -2,4-dioxothiazolidin-3-yl] butanoate (Z) ;

   (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-phenethylthiazolidin-2,4-dione;

   (Z) -5 - [{1- (4-nitrophenyl) -1H-pyrazol-3-yl} methylene] -3- (piperidin- -One 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] pentanobic 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) thiazolidin- Hydrochloride;

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

   (Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-4-yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

   (Z) -5 - [{1- (4-nitrophenyl) -lH-pyrazol-4-yl} methylene] -3- (piperidin- 4- yl) -2-thioxothiazolidin- -One 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;

   Yl) methylene] -4-oxo-2-thioxothiazolidin-3-yl] butanoic acid (Z) Eight;

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

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

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

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2-methoxyphenyl) (Pyridin-3-ylmethyl) butanamide;

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl (methyl) ] Butanamide;

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2-methoxyphenyl) Propylbutanamide;

   Yl} methylene] -2-thioxothiazolidin-3-yl (Z) -tert-butyl 4- [4-oxo- ] Piperidine-1-carboxylate;

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

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

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2- (Pyridin-2-ylmethyl) propanamide;

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] -N- (2- Propyl propanamide;

   Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >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;

   Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] butanoic acid (hereinafter referred to as ";

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

   (4-methylpiperazin-1-yl) -3-oxopropyl} -2-thioxo Thiazolidin-4-one;

   (Z) -5 - {(5,6-difluoro-1H-indol-2-yl) methylene} -3- (piperidin- 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- 2-yl) propanamide, or a pharmaceutically acceptable salt thereof.
10. 10. The method of claim 9,

    The compound

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

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

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

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

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

    (Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

    Yl} methylene] -4-oxo-2-thioxothiazolidin-3-yl] cyclohexane (hereinafter referred to as " Carboxylic acid;

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

    (Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

    (Z) -3- (2-hydroxyethyl) -5 - [{1- (4-nitrophenyl) -1H-pyrazol-3-yl} methylene] thiazolidin-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- -One 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) thiazolidin- Hydrochloride;

    Yl} methylene] -2-thioxothiazolidin-3-yl (Z) -tert-butyl 4- [4-oxo- ] Piperidine-1-carboxylate;

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

    Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >hydrochloride; And

    (Z) -3- [5 - {(1 H-indol-6-yl) methylene} -4-oxo-2-thioxothiazolidin-3-yl] propanoic acid. Or a pharmaceutically acceptable salt thereof.
11. 11. The method of claim 10,

    The compound

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

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

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

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

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

    (Z) -3- {3- (4-methylpiperazin-1-yl) -3-oxopropyl} -5- [ -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] thiazolidin- - Dion;

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

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

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

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Pentanamide;

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Lt; / RTI >

    (Z) -N- (2- morpholinoethyl) -5- [5 - [{1- (4-nitrophenyl) -lH-pyrazol-3- yl} methylene] -2,4-dioxothiazole 3-yl] < / RTI >pentanamide;

    Yl} methylene] -2,4-dioxothiazolidin-3-yl] -1H-pyrazol- Propanamide;

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

    Yl) methylene] -3- (pyrrolidin-3-yl) -2-thioxothiazolidin-4- Lt; / RTI >hydrochloride; And

    (Z) -3- [5 - {(1 H-indol-6-yl) methylene} -4-oxo-2-thioxothiazolidin-3-yl] propanoic acid. Or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1,

    The pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, tartaric acid, citric acid, paratoluenesulfonic acid, Lt; RTI ID = 0.0 > methanesulfonic < / RTI > acid, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition for treating cancer in a cancer patient having a K-Ras mutant type comprising as an active ingredient a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.
14. 14. The method of claim 13,

    Lt; RTI ID = 0.0 > Wnt < / RTI > signal transduction system.
15. 14. The method of claim 13,

    Wherein said cancer is a metastatic cancer.
16. 14. The method of claim 13,

    Wherein 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 .
17. 14. The method of claim 13,

    Wherein the pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions.

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