KR20190139637A - Composition for preventing or treating cancer comprising novel mTOR inhibitor - Google Patents

Abstract

The present invention relates to a composition for preventing or treating cancer comprising a novel mTOR inhibitor. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating cancer comprising a novel compound represented by chemical formula 1 exhibiting mTORC1 inhibitory activity as an active component. A compound represented by the chemical formula 1 according to the present invention has excellent effects of inhibiting mTORC1 and inhibiting growth of cancer cells, thereby being able to be very usefully used for preventing or treating cancer.

Description

Composition for preventing or treating cancer comprising novel mTOR inhibitor}

The present invention relates to a composition for preventing or treating cancer comprising a novel mTOR inhibitor, and more particularly to a pharmaceutical composition for preventing or treating cancer comprising a novel compound represented by the formula (1) showing mTORC1 inhibitory activity as an active ingredient. It is about.

Amino acids not only serve as raw materials for protein synthesis, but also act as nutrients that regulate protein metabolism. The activity of amino acids available intracellularly is mediated by the mechanistic target of rapamycin complex 1 (mTORC1), which regulates various cellular responses such as protein synthesis, autophagy, and cell growth, as well as cancer, obesity, It is also closely associated with various human diseases, including diabetes and neurodegeneration (Guertin and Sabatini, 2005; Zoncu et al., 2011; Laplante and Sabatini, 2012; Oddo, 2012).

The mTOR (mammalian target of rapamycin), also known as FRAP (FKBP12 and rapamycin related proteins), does not phosphorylate phospholipids, but the 289-kDa serine / threonine kinase of the PIKK family (phosphoinositide 3-kinase-like kinase) to be.

This protein is also present in the C-terminal kinase domain, FKBP12-rapamycin binding domain, 20 N-terminal HEAT repeats involved in protein-protein interactions, FAT (FRAP-ATM-TRRAP) domain, and C-terminal FAT domain also present in other PIKKs. Several domains including (Wullschleger et al. (2006) Cell, 124, 471-484).

mTOR kinases are central regulators of cell growth and proliferation and play important roles in cell metabolism and angiogenesis. mTOR is activated by the PI3K / Akt axis, which in turn is the downstream effector of the PI3K / Akt signaling pathway, particularly the ribosomal protein S6 kinase (S6K1) and the eukaryotic initiation factor 4E binding protein (4E-BP1), two major regulators of the cellular protein translation machinery. (MTOR signal pathway is described in Zoncu et al. (2011) Nature Rev. Mol. Cell Biol. 12, 21-35).

On the other hand, mTORC1 regulates various upstream signals such as cell growth, protein synthesis, and growth factor regulation. Tuberous Sclerosis Complex (TSC), which transmits growth factors and energy signals to mTORC1, is a GTPase-activating protein (GAP) for Ras-like small GTPase, Rheb, and GTP hydrolysis of Rheb. MTORC1 is negatively regulated by promoting.

Rheb can migrate to late endosomes / lysosomes and is required for mTORC1 activation induced by amino acids. In lysosomal membranes, Rag GTPases and Ragulator complexes (MAPKSP1, ROBLD3 and c11orf59) act as amino acid inducible docking sites for mTORC1.

Mammals express four Rag GTPases (RagA, RagB, RagC, RagD). Rag GTPases essentially form a heterodimer of RagA / C or RagB / D to mediate amino acid induced mTORC1 activation. The amino acid induces the transfer of mTORC1 to the lysosome, in which Rag hetero dimers containing RagB with GTP are interacted with mTORC1.

Leucine and glutamine can activate mTORC1 by Rag GTPase-dependent and independent mechanisms, respectively. In RagA / B deficient cells, glutamine can still activate mTORC1 via ADP ribosylation factor 1 (ARF1) GTPase. Therefore, mTORC1 can be regulated differently by glutamine and leucine. However, the functional significance of Rag GTPase-dependent leucine signaling is not well known.

On the other hand, mTOR (also called FRAP, RAPT1 or RAFT1) is expressed in almost all organs and tissues and is involved in the PI3K-Akt signal transduction system. mTOR forms mTORC1 complex and mTORC2 complex with adapter proteins such as raptor and rictor, respectively, and transmits signals from the extracellular matrix. mTORC1 activates the translation of cancer-related proteins (cyclin D1, myc, HIF-1α, etc.) by phosphorylating S6K, 4EBP-1, etc., and mTORC2 phosphorylates Ser473 of Akt, thereby activating survival signals of cancer cells. It is thought to let you do it.

In clinical practice, the improvement of the mTOR signal transduction system is recognized in many carcinomas, including kidney cancer, osteosarcoma, lung cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer and liver cancer. One of the mTOR inhibitors, rapamycin, binds to FKBP12 (FK-506 binding protein) within the cell to form a complex, and the rapamycin / FKBP12 complex binds to mTOR, which inhibits kinase activity of mTOR and protein synthesis also increases cell proliferation. Inhibits. The antitumor effect of rapamycin in actual tumor patients has been reported, and various mTOR inhibitors are in clinical trials as anticancer agents.

As such, mTOR may be an effective therapeutic target in the treatment of cancer, and compounds having an effect of inhibiting the kinase activity of mTOR may exhibit excellent therapeutic effects against cancer treatment, particularly cancers with mTOR signal enhanced. .

On the other hand, aminoacyl-tRNA-synthetases (ARSs) are not only required for protein synthesis but are also involved in the physiological response of various cells. ARS promotes the binding of amino acids to the corresponding tRNAs. To maintain protein homeostasis, ARS must sensitize amino acid utility. Leucine-tRNA-synthase (LRS) functions as a leucine sensor for mTORC1 activation by interacting with RagD GTPase and acting as a GAP for RagD GTPase.

Thus, if LRS detects a substance that inhibits its function as a leucine sensor, it inhibits the binding of LRS and RagD to inhibit the activation of mTORC1 and consequently has an effect on potential therapeutic indications for mTOR inhibitors such as cancer. Will indicate.

Accordingly, the present inventors have made diligent efforts to find a novel compound that can inhibit the activity of mTOR to exhibit a therapeutic effect against cancer, and as a result, the compound represented by the formula (1) inhibits mTOR activity and cancer The present invention has been completed and found that the effect of inhibiting the growth of cells is very good and can have a cancer prevention or treatment effect.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

In Chemical Formula 1,

R ₁ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₂ -C ₅ alkenyl; C ₃ -C ₁₀ heteroarylalkyl; Or C ₁ -C ₅ hydroxyalkyl,

R ₂ is hydrogen; Substituted or unsubstituted C ₁ to C ₅ straight or branched alkyl,

R ₃ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₆ -C ₁₅ aryl; Or C ₃ -C ₁₅ heteroaryl,

X is oxygen; sulfur; Or nitrogen,

Y ₁ and Y ₂ are each independently oxygen or sulfur,

n is 0, 1 or 2.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

In Chemical Formula 1,

R ₁ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₂ -C ₅ alkenyl; C ₃ -C ₁₀ heteroarylalkyl; Or C ₁ -C ₅ hydroxyalkyl,

R ₂ is hydrogen; Substituted or unsubstituted C ₁ to C ₅ straight or branched alkyl,

R ₃ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₆ -C ₁₅ aryl; Or C ₃ -C ₁₅ heteroaryl,

X is oxygen; sulfur; Or nitrogen,

Y ₁ and Y ₂ are each independently oxygen or sulfur,

n is 0, 1 or 2.

Hereinafter, the present invention will be described in more detail.

The term "alkyl" in the present invention means an aliphatic hydrocarbon group which may be straight or branched, containing 1 to 5 carbon atoms in the chain. Preferred alkyl groups contain 1 to 3 carbon atoms in the chain. More preferred alkyl groups contain about 1, 2 or 3 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkyl chain. "Loweralkyl" means a group having from 1 to 5 carbon atoms in the chain, which may be straight or branched. "Alkyl" may be unsubstituted or may be optionally substituted by one or more substituents which may be the same or different.

In the present invention, "alkenyl" refers to a monovalent straight or branched hydrocarbon radical having 2 to 5 carbon atoms and at least one double bond in the chain, examples of which are ethenyl, propenyl, 1-but-3 -Enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein the alkenyl radicals can be independently substituted by one or more groups independently of the substituents described herein, It includes radicals having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. "Alkenyl" may be unsubstituted or may be optionally substituted by one or more substituents which may be the same or different.

In the present invention, the "aryl" refers to a single ring (eg, phenyl), multiple rings (eg, biphenyl) or multiple condensed rings (at least one of which is aromatic; for example 1,2, Monovalent aromatic carbocyclic radical with 3,4-tetrahydronaphthyl, naphthyl), which may be mono-, di- or tri-substituted with any substituent.

In the present invention, the "heteroaryl" includes a fused ring system containing one to four heteroatoms selected from nitrogen, oxygen or sulfur and having 5 to 15 atoms, at least one of which is aromatic. Monovalent aromatic radicals having 6-, 7- or 7-membered rings. Examples of heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl , Quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl, puteri Dinyl, purinyl, oxdiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl And furopyridinyl. Spiro residues are also within the scope of this definition. Heteroaryl groups may be mono-, di- or tri-substituted with any substituent.

In the present invention, the term "heteroarylalkyl" means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (as defined above). More preferred heteroarylalkyl radicals may be 5- or 6-membered heteroaryl-C _1-3 -alkyl. Heteroarylalkyl may be mono-, di- or tri-substituted with any substituent.

In the present invention, the "hydroxyalkyl" refers to a straight or branched monovalent hydrocarbon radical substituted with one or two hydroxy groups and containing 1 to 5 carbon atoms, for example, but not limited to, hydroxy Methyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl , 2,3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, 2- (hydroxymethyl)- 3-hydroxypropyl and the like.

In the present invention, the "halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

When the groups disclosed herein are expressed as "substituted," these groups may be substituted with any suitable substituent or substituents. Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, and halogens (chloro, urethral, bromo or fluoro groups), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkyl Amino, carboxy, nitro, ano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonato, phosphine, thiocarbonyl, sulfonyl, sulfone, Sulfonamides, ketones, aldehydes, esters, urea, urethanes, oximes, hydroxyl amines, alkoxyamines, aralkyloxyamines, N-oxides, hydrazines, hydrazides, hydrazones, azides, isocyanates, isothiocyanates, Cyanate, thiocyanate, etc. are mentioned.

In Formula 1 of the present invention, R ₁ is preferably hydrogen; Substituted or unsubstituted C ₁ -C ₃ straight or branched alkyl; C ₂ -C ₃ alkenyl; C ₃ -C ₆ heteroarylalkyl; Or C ₁ -C ₃ straight or branched hydroxyalkyl, more preferably hydrogen; Substituted or unsubstituted C ₁ -C ₂ straight alkyl; C ₂ -C ₃ alkenyl; C ₃ -C ₅ heteroarylalkyl; Or C ₁ -C ₂ straight hydroxyalkyl, most preferably hydrogen, methyl, ethyl, ethenyl, propenyl, furylmethyl and hydroxyethyl.

In Formula 1 of the present invention, R ₂ is preferably hydrogen; Or substituted or unsubstituted C ₁ -C ₃ straight or branched alkyl, more preferably substituted or unsubstituted C ₁ -C ₂ alkyl, most preferably in the group consisting of hydrogen, methyl and ethyl Can be selected.

In Formula 1 of the present invention, R ₃ is preferably substituted or unsubstituted C ₁ ~ C ₃ straight or branched alkyl; C ₆ -C ₁₀ aryl; Or C ₃ -C ₁₀ heteroaryl, more preferably substituted or unsubstituted C ₁ -C ₂ alkyl; C ₆ -C ₁₀ aryl; Or C ₃ to C ₅ heteroaryl, most preferably selected from the group consisting of substituted or unsubstituted methyl, phenyl, naphthyl and pyridyl.

When R ₃ is substituted in Formula 1 of the present invention, the substituent is preferably halogen; C ₁ -C ₅ straight or branched alkyl; And it may be selected from the group consisting of C ₁ ~ C ₅ alkoxy, more preferably halogen; C ₁ -C ₄ straight or branched alkyl; And it may be selected from the group consisting of C ₁ ~ C ₃ alkoxy, most preferably from the group consisting of chlorine, fluorine, methyl, butyl, isopropyl and methoxy.

In Formula 1 of the present invention, preferably Y ₁ is sulfur, Y ₂ may be oxygen.

In the present invention, the compound of Formula 1 may be selected from the following compounds:

(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3- (2-furylmethyl) -5-[(1-methylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-methyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-ethyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-allyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

(5Z) -3-allyl-5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

(5Z) -3-allyl-5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-methyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-ethyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-allyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-ethyl-5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3-ethyl-5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3- (2-hydroxyethyl) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -3- (2-hydroxyethyl) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[(5-methyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[(3-methyl-1-phenyl-pyrazol-4-yl) methylene] thiazolidine-2,4-dione

(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl] methylene] thiazolidine-2,4-dione

 (5Z) -5-[[1- (4-chlorophenyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

(5Z) -5-[[1-phenylpyrazol-3-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione and

(5Z) -5-[[1- (4-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

The structural formulas of the compounds listed above are summarized in Table 1 below:

One

(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 2

(5Z) -3- (2-furylmethyl) -5-[(1-methylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 3

(5Z) -3-methyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 4

(5Z) -3-ethyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 5

(5Z) -3-allyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 6

(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 7

(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 8

(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 9

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 10

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one 11

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one 12

(5Z) -3-allyl-5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 13

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 14

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one 15

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one 16

(5Z) -3-allyl-5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 17

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 18

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one 19

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one 20

(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 21

(5Z) -3-methyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 22

(5Z) -3-ethyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 23

(5Z) -3-allyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 24

(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 25

(5Z) -3-ethyl-5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 26

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 27

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one 28

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 29

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one 30

(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 31

(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 32

(5Z) -3-ethyl-5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 33

(5Z) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 34

(5Z) -3- (2-hydroxyethyl) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 35

(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 36

(5Z) -3- (2-hydroxyethyl) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one 37

(5Z) -5-[(5-methyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 38

(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one 39

(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] thiazolidine-2,4-dione 40

(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 41

(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 42

(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 43

(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 44

(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 45

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 46

(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 47

(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 48

(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 49

(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 50

(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 51

(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 52

(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione 53

(5Z) -5-[(3-methyl-1-phenyl-pyrazol-4-yl) methylene] thiazolidine-2,4-dione 54

(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl] methylene] thiazolidine-2,4-dione 55

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one 56

(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one 57

(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one 58

(5Z) -5-[[1-phenylpyrazol-3-yl] methylene] thiazolidine-2,4-dione 59

(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione 60

(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione 61

(5Z) -5-[[1- (4-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

The compound of formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid. , Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, and the like can be used. Can be used.

Compounds of formula (I) of the present invention may include all salts, hydrates and solvates, racemates, or stereoisomers that may be prepared by conventional methods, as well as pharmaceutically acceptable salts.

The compound of Formula 1 of the present invention may be prepared according to the following method, but is not limited thereto.

Scheme 1

In Scheme 1,

R ₁ , R ₂ , R ₃ , X, Y ₁ , Y ₂ and n are as defined in claim 1.

In the above production method, the reaction may be carried out by mixing and heating compound 2 and compound 3 in the presence or absence of a solvent in the presence of Lewis or photocatalyst. Examples of useful catalysts include HCl, HBr, H ₂ SO ₄ , acetic acid, trifluoro acid, p-toluenesulfonic acid, trimethylsilylchloride, trimethylsilyl iodide, boron trifluoride etherate, copper chloride (I), Ferric chloride, indium (III) chloride, ytterbium triflate, cerium (III) chloride, zirconium (IV) chloride, zirconium oxychloride (IV), lithium bromide, phenylpyruvic acid, calcium chloride, polyphosphate ester, or solid clay acid Catalysts such as montmorillonite KSF clay or combinations of these catalysts.

Useful solvents may preferably include polar solvents such as acetonitrile, acetic acid, methanol, ethanol, or other alcohols, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dioxane.

Heating can be done under conventional heating conditions or microwave conditions.

Preferably, the preparation method may prepare the compound of Formula 1 by applying the compound 2 and compound 3 in a conventional condensation reaction. For example, the compound of Chemical Formula 1 may be prepared by knoevenagel condensation of Compound 2 and Compound 3 in an organic solvent, followed by stirring at 50 to 80 ° C. for 10 to 20 hours. have.

The product prepared according to Scheme 1 may be purified through additional steps such as washing, concentration, ethyl acetate extraction, drying, column chromatography, and the like through IR, NMR, melting point (mp) measurement, and physicochemical properties. You can analyze the characteristics.

Meanwhile, Compound 2 and Compound 3 in Scheme 1 may each use a commercially available compound, or for example, Compound 2 may be used according to Scheme 2 below, and Compound 3 may be synthesized according to Scheme 3 below. have:

Scheme 2

Scheme 3

In Schemes 2 and 3,

R ₁ , R ₂ , R ₃ , X, Y ₁ , Y ₂ and n are as defined in claim 1.

Meanwhile, according to one embodiment of the present invention, the compound of Formula 1 or a pharmaceutically acceptable salt thereof inhibits the binding of LRS and RagD, thereby inhibiting the activity of mTORC1, which is known to be highly active in cancer cells. It was confirmed to be very excellent. In addition, it was confirmed that the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be cytotoxic to cancer cells and thus directly inhibit the growth of cancer cells.

The pharmaceutical composition according to the present invention may contain the compound of Formula 1 or a pharmaceutically acceptable salt thereof alone or may further contain one or more pharmaceutically acceptable carriers, excipients or diluents.

Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like, and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Other pharmaceutically acceptable carriers may be referred to those described in the following documents (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).

The pharmaceutical composition of the present invention can be administered to any mammal, including humans. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be. For example, the pharmaceutical composition of the present invention can be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin needle or by applying it directly to the skin.

The pharmaceutical composition of the present invention may be formulated into a preparation for oral or parenteral administration according to the route of administration as described above.

In the case of preparations for oral administration, the compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like. Can be. For example, oral formulations can be obtained by tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granule mixtures. Examples of suitable excipients include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, including starch, corn starch, wheat starch, rice starch and potato starch, and the like. Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant. Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.

Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time. . The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. Preferably, the total dose of the pharmaceutical composition of the present invention may be about 0.01 ug to 1,000 mg, most preferably 0.1 ug to 100 mg per kg of patient body weight per day. However, the dosage of the pharmaceutical composition of the present invention is effective for the patient in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment. In this regard, one of ordinary skill in the art will be able to determine an appropriate effective dosage according to the specific use of the pharmaceutical composition of the present invention as a therapeutic agent for neurodegenerative diseases. The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is shown.

In the present invention, the cancer is not limited thereto, but may be a cancer showing rapamycin resistance, preferably leukemia, brain tumor, kidney cancer, gastric cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, melanoma, thyroid cancer, head and neck cancer, Lymphoma, gallbladder cancer, esophageal cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, colon cancer, peritoneal cancer, peritoneal metastasis cancer and pancreatic cancer.

In the present invention, the term 'treatment' refers generically to ameliorating the symptoms of cancer, which may preferably include treating, substantially preventing, or ameliorating the condition, wherein It includes, but is not limited to, alleviating, healing or preventing the symptoms or most of the symptoms.

Compound represented by the formula (1) according to the present invention is very excellent in inhibiting the effect of inhibiting the growth of mTORC1 and cancer cells can be very useful in the prevention or treatment of cancer.

1 is a result of confirming whether phosphorylation of S6K by immunoblotting after treatment of a compound of Example 1-1 or a salt thereof with NIH3T3 cells carrying an mTOR C1483Y mutation (A) and a graph showing quantification thereof (B) Leu: Leucine.
Figure 2 shows the results of immunoblotting of RagD GTP hydrolysis after treatment of the compound of Example 1-1 or a salt thereof in SW620 cells (Leu: Leucine)
Figure 3 shows the result of confirming whether the interaction of LRS and RagD is inhibited by immunoprecipitation method after treatment of the compound of Example 1-1 or a salt thereof to SW620 cells.
4 shows neocortex and hippocampus of brain after intraperitoneal administration of salt (100 mg / kg) or rapamycin (Rapa, 2 mg / kg) of the compound of Example 1-1 to 7-week-old C57BL / 6 male mice. This is the result of confirming whether phosphorylation of S6K and expression of protein through immunoblotting.
FIG. 5 shows the immunoblotting of S6K phosphorylation and protein expression in neocortex and hippocampus of brain after intraperitoneal administration of salts of the compound of Example 1-1 to 7-week-old C57BL / 6 male mice at various concentrations. This is the result of the test.

Hereinafter, the present invention will be described in detail.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

<Example 1>

Preparation of the compound

In the present invention, the compound of Chemical Formula 1 was prepared according to the method described in Korean Patent Application No. 10-2018-0048774, and the compounds used in the following experiments are as follows, and the structure of each compound is shown in Table 1 above:

Example 1-1 (5Z) -5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-1 Potassium Salt Potassium salt of (5Z) -5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-2 (5Z) -3- (2-furylmethyl) -5-[(1-methylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-3 (5Z) -3-methyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-4 (5Z) -3-ethyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-5 (5Z) -3-allyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-6 (5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-7 (5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-8 (5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-9 (5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-10 (5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

Example 1-11 (5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

Example 1-12 (5Z) -3-allyl-5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-13 (5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-14 (5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

Example 1-15 (5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

Example 1-16 (5Z) -3-allyl-5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-17 (5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-18 (5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one

Example 1-19 (5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

Example 1-20 (5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-21 (5Z) -3-methyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-22 (5Z) -3-ethyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-23 (5Z) -3-allyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-24 (5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-25 (5Z) -3-ethyl-5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-26 (5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-27 (5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one

Example 1-28 (5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-29 (5Z) -5-[[1- (3,4-Dimethylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidine-4- On

Example 1-30 (5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-31 (5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-32 (5Z) -3-ethyl-5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-33 (5Z) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-34 (5Z) -3- (2-hydroxyethyl) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazoli Din-4-one

Example 1-35 (5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-36 (5Z) -3- (2-hydroxyethyl) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazoli Din-4-one

Example 1-37 (5Z) -5-[(5-methyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-38 (5Z) -5-[(3,5-Dimethyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one

Example 1-39 (5Z) -5-[(1-phenylpyrazol-4-yl) methylene] thiazolidine-2,4-dione

Example 1-40 (5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-41 (5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-42 (5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-43 (5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-44 (5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-45 (5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-46 (5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-47 (5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-48 (5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-49 (5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-50 (5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-51 (5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-52 (5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-53 (5Z) -5-[(3-methyl-1-phenyl-pyrazol-4-yl) methylene] thiazolidine-2,4-dione

Example 1-54 (5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl] methylene] thiazolidine-2,4-dione

Example 1-55 (5Z) -5-[[1- (4-Chlorophenyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-56 (5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-57 (5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one

Example 1-58 (5Z) -5-[[1-phenylpyrazol-3-yl] methylene] thiazolidine-2,4-dione

Example 1-59 (5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

Example 1-60 (5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

Example 1-61 (5Z) -5-[[1- (4-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione

<Example 2>

mTORC1 inhibitory activity assessment

<2-1> Evaluation of inhibitory effect of mTORC1 activity (1)

In order to evaluate the inhibitory effect of mTORC1 on the compounds of the present invention, the experiment was carried out as follows.

Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). Cell lines were divided into 24 well plates and cultured for 24 hours, and then treated for 1 hour and 30 minutes in a medium containing no leucine amino acid, followed by further culture for 15 minutes in a medium containing leucine. The compounds of Examples 1-1 to 1-62 were added upon incubation in a medium containing leucine at a final concentration of 20 uM. 20 ug of cell lysate was isolated by electrophoresis and analyzed by Western blotting using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to see the mTORC1 activity. Inhibition of mTORC1 activity was evaluated by comparing the negative control group treated with DMSO only and the compound treated group of each well.

mTORC1 inhibitory effect (1) (%, 20uM) Example Inhibitory effect (%) Example Inhibitory effect (%) Example Inhibitory effect (%) 1-1 98.54 ± 0.33 1-22 77.21 ± 0.84 1-43 52.34 ± 3.97 1-2 74.4 ± 0.2 1-23 15.74 ± 10.22 1-44 50.76 ± 5.28 1-3 53.97 ± 1.49 1-24 93.18 ± 2.50 1-45 64.18 ± 3.13 1-4 68.36 ± 1.69 1-25 36.86 ± 3.47 1-46 74.39 ± 0.62 1-5 45.82 ± 3.59 1-26 59.73 ± 3.55 1-47 74.36 ± 1.23 1-6 86.58 ± 2.50 1-27 51.70 ± 7.12 1-48 69.53 ± 2.04 1-7 88.23 ± 0.55 1-28 47.13 ± 3.15 1-49 68.36 ± 2.99 1-8 97.1 ± 1.8 1-29 4.02 ± 6.64 1-50 38.93 ± 16.04 1-9 92.76 ± 1.09 1-30 88.27 ± 1.18 1-51 53.08 ± 1.81 1-10 50.52 ± 3.69 1-31 40.20 ± 1.02 1-52 93.50 ± 1.38 1-11 67.22 ± 1.41 1-32 75.04 ± 5.32 1-53 71.70 ± 1.70 1-12 70.93 ± 2.39 1-33 93.50 ± 1.59 1-54 71.17 ± 4.46 1-13 94.90 ± 0.77 1-34 82.94 ± 1.10 1-55 74.6 ± 6.5 1-14 46.72 ± 14.22 1-35 96.45 ± 0.55 1-56 97.04 ± 0.65 1-15 72.46 ± 1.79 1-36 80.88 ± 1.10 1-57 90.20 ± 1.29 1-16 3.74 ± 10.43 1-37 96.82 ± 0.71 1-58 59.51 ± 4.35 1-17 86.7 ± 3.1 1-38 75.78 ± 2.60 1-59 91.00 ± 1.78 1-18 50.17 ± 12.77 1-39 93.53 ± 1.84 1-60 81.52 ± 3.79 1-19 54.17 ± 8.55 1-40 41.03 ± 10.21 1-61 91.50 ± 1.30 1-20 83.30 ± 1.76 1-41 49.37 ± 7.34 1-1K 98.26 ± 0.16 1-21 71.18 ± 5.04 1-42 73.81 ± 2.77

As shown in Table 2, the compounds according to the invention it can be seen that significantly inhibit the activity of mTORC1 at 20uM. In particular, Example 1-1, Example 1-1K (Potassium salt of Example 1-1) Example 1-6, Example 1-7, Example 1-8, Example 1-9, and Example 1 -13, Example 1-17, Example 1-24, Example 1-30, Example 1-33, Example 1-35, Example 1-37, Example 1-39, Example 1-52 , Examples 1-56, Examples 1-57, Examples 1-59 and Examples 1-61 were found to exhibit an excellent inhibitory effect of more than 85% at a concentration of 20uM.

Therefore, the compound of Formula 1 according to the present invention was excellent in inhibiting mTOR which is closely related to the occurrence of cancer, it could be determined that it may exhibit a cancer prevention or treatment effect.

<2-2> Evaluation of mTORC1 activity inhibitory effect (IC50) (2)

In order to evaluate the inhibitory effect (IC50) on mTORC1 of the compounds selected in Example <2-1>, the experiment was performed as follows.

Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). Cell lines were aliquoted into 24 well plates and incubated for 24 hours, and then each selected compound (final concentration 0.1, 0.5, 1, 2, 5, 10, 20 uM) was added upon incubation for 6 hours in medium containing 10% FBS. . 20 ug of cell lysate was isolated by electrophoresis and analyzed by Western blotting using phospho-p70 S6 Kinase (Thr380) antibody (# 9206, Cell Signaling Technology) to see the mTORC1 activity. Inhibition of mTORC1 activity was evaluated by comparing the negative control group treated with DMSO only and the compound treated group of each well.

The results are shown in Table 3 below.

Evaluation of mTORC1 Inhibitory Effect (IC50) Example Inhibitory effect IC50 (uM) Example Inhibitory effect IC50 (uM) 1-1 0.045 ± 0.002 1-35 0.0872 ± 0.0146 1-6 0.1237 ± 0.0235 1-37 0.0799 ± 0.0113 1-7 0.0917 ± 0.0012 1-39 0.1076 ± 0.0133 1-8 0.086 ± 0.002 1-52 0.0934 ± 0.0197 1-9 0.1623 ± 0.0279 1-56 0.083 ± 0.010 1-13 0.1298 ± 0.0073 1-57 0.103 ± 0.015 1-17 0.069 ± 0.004 1-59 0.216 ± 0.038 1-24 0.0890 ± 0.0094 1-61 0.094 ± 0.019 1-30 0.0942 ± 0.0019 1-1K 0.024 ± 0.004 1-33 0.0896 ± 0.0289

Among the compounds of Examples 1-1 to 1-61, the compounds showing excellent inhibitory activity (more than 85% inhibitory activity at 20uM) were selected to further evaluate the inhibitory activity of mTORC1.

As a result, as shown in Table 3, each compound was confirmed that the IC50 is 1uM or less, and further it was confirmed that some compounds exhibit a very excellent effect of IC50 100nM or less.

<Example 3>

Evaluation of LRS and RagD's Binding Inhibition Activity

The present inventors, after confirming that the compounds of the formula (1) in Example 2 has a very good effect of inhibiting the activity of mTOR, and to determine the mechanism by which these compounds inhibit the activity of mTOR.

As mentioned above, leucyl tRNA synthetase (LRS) functions as a key mediator of amino acid signaling to mTORC1. LRS binds directly to Rag GTPase, a signaling mediator to mTORC1, and acts as a GTPase-activating protein (GAP) for Rag GTPase, thereby activating mTORC1.

Therefore, when the binding of LRS and RagD is blocked, GTP degradation of RagD is lowered, and as a result, the activity of mTOR is suppressed.

<3-1> RagD GTP Hydrolysis Inhibitory Activity (GTP-agarose Bead Pulldown Assay)

GTP-agarose bead pulldown assay was performed to analyze RagD bound to GTP.

SW620 cells were treated with 10 uM of Example 1-1 compound or salt thereof for 1 hour, deficient in leucine for 90 minutes, and then restimulated with leucine for 15 minutes. After washing the cells with cold PBS, GTP-binding buffer (20 mM Tris-HCl, pH 7.5, 5 mM MgCl ₂ , 2 mM PMSF, 20 μg / ml leupeptin, 10 μg / ml aprotinin, 150 mM NaCl, 1%) Cells were obtained from Triton X-100, 1xphosphatase inhibitor cocktail. Cells were lysed by sonication for 15 seconds, and the supernatant was obtained after cell lysates were centrifuged at 13000 xg for 10 minutes at 4 ° C. The obtained protein solution (containing 500 ul of GTP-binding buffer) was treated with 100 ul of GPT-agarose bead (Sigma Aldrich, Cat no. G9768) and left at 4 ° C for 30 minutes. The beads were then washed with GTP-binding buffer and the supernatant was recovered. The washed beads were treated once again for 30 minutes. The beads were washed again and the recovered supernatant was left overnight at 4 ° C. After washing five times with GTP-binding buffer to isolate any contaminants that may have been included, GTP-binding proteins were analyzed by performing immunoblot analysis with anti-RagD or ARF1 antibodies. ARF1 was used as a negative control. As a positive control, Example 1-214 compound (indicated by "0186" in the figure) described in Korean Patent Laid-Open Publication No. 10-2017-0107404 was used.

The results are shown in FIG. 2.

As shown in FIG. 2, RagD was not detected when leucine was treated in the control group (Con), which was not treated with the compound. That is, it was confirmed that GTP was hydrolyzed in RagD by LRS and was not detected. In contrast, in the test group treated with the compound of Example 1-1 or a salt thereof, RagD was detected to a degree similar to that of the leucine-treated control group, which means that the compound of Example 1-1 or the salt thereof was treated with LRS. Inhibition of activity means that GTP hydrolysis of RagD by leucine treatment was inhibited.

<3-2> Direct Inhibitory Activity on the Interaction of LRS with RagD

In Example 3-1, it was confirmed that the compound according to the present invention or a salt thereof has an activity of inhibiting GTP hydrolysis of RagD by LRS.

Thus, the inventors next tried to determine whether the compounds according to the invention directly inhibit the interaction of LRS and RagD.

SW620 cells were treated with 10 uM of Example 1-1 compound or salt thereof for 1 hour, deficient in leucine for 90 minutes, and then restimulated with leucine for 15 minutes. Cells were lysed using a lysis buffer containing protease inhibitors and primary antibodies were added to the cell lysates for immunoprecipitation and left to stir at 4 ° C. for 2 hours. 50% protein agarose G-sepharose slurry was added and left for another 4 hours. After washing three times with cold lysis buffer, the precipitate was dissolved in SDS sample buffer, separated by SDS-PAGE and immunoblotted with anti-LRS or anti-RagD antibody. As a positive control, Example 1-214 compound described in Korean Patent Laid-Open No. 10-2017-0107404 (indicated by "0186" in the figure) was used.

The results for this are shown in FIG. 3.

As shown in FIG. 3, both RagD and LRS were detected in the control (Con) cells not treated with the compound, indicating that RagD and LRS interacted directly. In contrast, RagD was hardly detected in the precipitate using the anti-LRS antibody in cells treated with the compound of Example 1-1 or a salt thereof according to the present invention, and LRS was almost detected in the precipitate using the anti-RagD antibody. It was found that these interactions were directly inhibited by the compound of Example 1-1 or a salt thereof.

<Example 4>

in vivo  mTOR inhibitory activity

After 7 days of intraperitoneal administration of rapamycin as a salt or positive control of the compound of Example 1-1, 7-week-old C57BL / 6 male mice were analyzed for the degree of phosphorylation of S6K in the neocortex and hippocampus of the brain. Thereby assessing the effect of the compound on the activation of mTOR.

Example 1-1 The salt of the compound is 100 mg / kg (in 10% DMAC, 15% Tween 80, 75% 0.1M Na2HPO4, pH9.4), and rapamycin is 2 mg / kg (in 10% DMAC, 15% Tween). 80, 75% saline).

The results for this are shown in FIG. 4.

As shown in FIG. 4, it was confirmed that phosphorylated S6K was not detected in the animal administered with the salt of the compound of Example 1-1, and that the activity of mTORC1 was inhibited by the treatment of the compound.

On the other hand, since the degree of phosphorylation of AKT was not changed by the salt treatment of the compound of Example 1-1, it was found that the activity of mTORC2 was not inhibited, and autophagy confirmed by the degradation of LC3 II or p62 was observed. It was found that the action was increased by treatment of the compound.

On the other hand, the inventors tried to evaluate the mTOR inhibitory activity of each salt concentration of the compound of Example 1-1 based on the results. In other words, in the same manner as in the above experimental method, after administering salts 0, 1, 2.5, 5, 10, 20 and 50 mg / kg of compound 1 to animals, the degree of phosphorylation of S6K in the neocortex and hippocampus of the brain The expression level of the protein was analyzed.

The results for this are shown in FIG. 5.

As shown in Figure 5, it was confirmed that the salt of the compound of Example 1-1 inhibits the phosphorylation of S6K in the brain of the animal in a concentration-dependent manner, which means that the salt of the compound of Example 1-1 is concentration-dependent in the animal It was determined that the mTOR inhibitory activity was observed through the blood-brain barrier.

As described above, the compound of Chemical Formula 1 according to the present invention showed excellent mTOR inhibitory activity and blood-brain barrier permeability, it could be seen that it can be very useful as a therapeutic agent for mTOR pathway-related brain disease.

Example 5

Evaluation of Growth Inhibitory Effects on Colorectal Cancer Cells (SW620)

<5-1> Preparation of RFP expressing cell line

In order to evaluate the effect of inhibiting the growth of colorectal cancer cell SW620 of the compounds according to the present invention was prepared RFP fluorescently labeled cell line. Colon cancer cell line SW620 was purchased from the American Type Culture Collection (ATCC). NucLight Red Lentivirus Reagent (EF1a, Puro) (# 4476, Essen Bioscience) was purchased for the preparation of RFP fluorescent labeled SW620 cell lines. The cells were transfected into the cells by adding NucLight Red Lentivirus Reagent to the SW620 cell line for 24 hours and incubated under 37 ° C. and 5% CO 2 in RPMI 1640 medium containing 10% FBS and 1% penicillin / streptomycin. Thereafter, puromycin was added to the medium at a concentration of 0.5 ug / ml, and then cultured under 37 ° C. and 5% CO 2 conditions for 4 days.

<5-2> Colorectal Cancer Cell (SW620) Growth Inhibitory Effect

RFP fluorescently labeled SW620 cell line was dispensed into 96 well plates for 24 hours, and then the compounds having excellent mTORC1 inhibitory activity among the compounds of Examples 1-1 to 1-61 in the medium containing 10% FBS for 24 hours Treatment (final concentrations 0.000282, 0.000847, 0.00254, 0.0076, 0.0229. 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM). Cell phase difference and red fluorescence images were obtained using the Incucyte Zoom (Essen Bioscience) long-term cell observation analysis system at two-hour intervals after compound treatment and quantitative analysis of RFP fluorescence was performed using the Incucyte Zoom basic analyzer (Essen Bioscience) program. Was carried out. RFP fluorescence values for each concentration of the compound were calculated using the GraphPad Prism tool program to calculate the GI50 (50% growth inhibition). The SW620 cell growth inhibition effect was evaluated by comparing the RFP fluorescence of each well with the DMSO-only negative control group and the compound-treated group.

The results are shown in Table 4 below.

Colon Cancer Cell (SW620) Growth Inhibitory Effect GI50 (nM) Example GI50 (nM) Example GI50 (nM) 1-2 3.51 ± 0.40 1-33 10.29 ± 1.76 1-6 74.65 ± 6.04 1-35 10.11 ± 0.53 1-7 38.15 ± 2.72 1-37 9.52 ± 0.26 1-8 9.45 ± 0.39 1-39 33.61 ± 7.01 1-9 37.20 ± 2.83 1-52 32.65 ± 2.84 1-13 48.31 ± 5.81 1-56 9.07 ± 0.37 1-17 4.34 ± 0.23 1-57 46.14 ± 3.89 1-24 13.92 ± 0.94 1-59 21.24 ± 1.09 1-30 71.66 ± 9.04 1-61 23.36 ± 3.40

As shown in Table 4, the compounds according to the present invention was found to inhibit the growth of SW620 cells, in particular, exhibited an excellent growth inhibitory effect of GI50 or less 100nM.

Therefore, the compounds of the formula (1) according to the present invention, because of the excellent effect of inhibiting the growth of cancer cells, can be usefully used for the treatment of cancer.

<5-3> Cytotoxicity Evaluation on Colorectal Cancer Cells (SW620)

In order to evaluate the cytotoxic effect of the compounds according to the present invention on colorectal cancer cells, experiments were performed as follows.

RFP fluorescently labeled SW620 cell line was dispensed into 96 well plates for 24 hours, and then the compounds having excellent mTORC1 inhibitory activity among the compounds of Examples 1-1 to 1-61 in the medium containing 10% FBS for 24 hours Treatment (final concentrations 0.000282, 0.000847, 0.00254, 0.0076, 0.0229. 0.0686, 0.206, 0.617, 1.85, 5.56, 16.67, 50 uM). CellTox Green (# G8741, Promega Co., Ltd.), which shows green fluorescence upon cell death, was added to observe the cytotoxicity during compound treatment. Green fluorescence images were obtained using Incucyte Zoom (Essen Bioscience) long-term cell observation analysis system at 2 hour intervals after compound treatment, and quantitative analysis of green fluorescence was performed using Incucyte Zoom basic analyzer (Essen Bioscience) program. Green fluorescence values for each concentration of the compound were calculated using the GraphPad Prism tool program to calculate EC50 (50% cell death). Cytotoxicity against SW620 cells was evaluated by comparing the green fluorescence of each well with the DMSO-only negative control group and the compound-treated group.

The results are shown in Table 5 below.

Cytotoxic EC50 (nM) against colorectal cancer cells (SW620) Example EC50 (nM) Example EC50 (nM) 1-2 8.61 ± 1.12 1-33 50.41 ± 6.85 1-6 97.45 ± 2.73 1-35 79.50 ± 3.92 1-7 58.76 ± 4.61 1-37 28.74 ± 2.82 1-8 19.69 ± 0.80 1-39 56.58 ± 5.22 1-9 84.12 ± 7.18 1-52 70.32 ± 4.98 1-13 53.53 ± 6.47 1-56 33.08 ± 2.14 1-17 20.78 ± 1.11 1-57 93.09 ± 6.53 1-24 21.39 ± 2.08 1-59 41.02 ± 4.15 1-30 80.55 ± 8.19 1-61 82.14 ± 8.44

As shown in Table 5, the compounds of Formula 1 according to the present invention was found to induce the death of SW620 cells. In addition, these compounds were found to exhibit excellent cytotoxicity of less than EC50 100nM.

Therefore, the compound of Formula 1 according to the present invention has excellent effects of inducing cancer cell death, and thus may be usefully used as a therapeutic agent for cancer.

Compound represented by the formula (1) according to the present invention is very excellent in inhibiting the effect of mTORC1 and inhibiting the growth of cancer cells can be very useful in the development of cancer prevention or treatment, it has excellent industrial applicability Do.

Claims (8)

A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

In Chemical Formula 1,
R ₁ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₂ -C ₅ alkenyl; C ₃ -C ₁₀ heteroarylalkyl; Or C ₁ -C ₅ hydroxyalkyl,
R ₂ is hydrogen; Substituted or unsubstituted C ₁ to C ₅ straight or branched alkyl,
R ₃ is hydrogen; Substituted or unsubstituted C ₁ -C ₅ straight or branched alkyl; C ₆ -C ₁₅ aryl; Or C ₃ -C ₁₅ heteroaryl,
X is oxygen; sulfur; Or nitrogen,
Y ₁ and Y ₂ are each independently oxygen or sulfur,
n is 0, 1 or 2.
The method of claim 1, wherein R ₁ is hydrogen; Substituted or unsubstituted C ₁ -C ₃ straight or branched alkyl; C ₂ -C ₃ alkenyl; C ₃ -C ₆ heteroarylalkyl; Or C ₁ -C ₃ straight or branched hydroxyalkyl.
The method of claim 1, wherein R ₂ is hydrogen; Or substituted or unsubstituted C ₁ -C ₃ straight or branched alkyl.
The compound of claim 1, wherein R ₃ is substituted or unsubstituted C ₁ -C ₃ straight or branched alkyl; C ₆ -C ₁₀ aryl; Or C ₃ to C ₁₀ heteroaryl, where they are substituted, halogen; C ₁ -C ₅ straight or branched alkyl; And C ₁ -C ₅ alkoxy.
The pharmaceutical composition of claim 1, wherein Y ₁ is sulfur and Y ₂ is oxygen.
The compound of claim 1, wherein the compound is
(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3- (2-furylmethyl) -5-[(1-methylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-methyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-ethyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-allyl-5-[(1-phenylpyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one
(5Z) -3-allyl-5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one
(5Z) -3-allyl-5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-methyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-methyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-ethyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-allyl-5-[[1- (p-tolyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-ethyl-5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] -3-ethyl-2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3-ethyl-5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3- (2-hydroxyethyl) -5-[[1- (2-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -3- (2-hydroxyethyl) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[(5-methyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl) methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[(1-phenylpyrazol-4-yl) methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (2-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (3-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (4-fluorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (2-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (3-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (4-chlorophenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (p-tolyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (4-isopropylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (4-butylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (3,4-dimethylphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (2-methoxyphenyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (2-naphthyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (3-pyridyl) pyrazol-4-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[(3-methyl-1-phenyl-pyrazol-4-yl) methylene] thiazolidine-2,4-dione
(5Z) -5-[(3,5-dimethyl-1-phenyl-pyrazol-4-yl] methylene] thiazolidine-2,4-dione

(5Z) -5-[[1- (4-chlorophenyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] -2-thioxo-thiazolidin-4-one
(5Z) -5-[[1-phenylpyrazol-3-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (2-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione
(5Z) -5-[[1- (3-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione and
(5Z) -5-[[1- (4-pyridyl) pyrazol-3-yl] methylene] thiazolidine-2,4-dione.
The pharmaceutical composition of claim 1, wherein the cancer is a rapamycin resistant cancer.
According to claim 1, wherein the cancer is leukemia, brain tumor, kidney cancer, stomach cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, melanoma, thyroid cancer, head and neck cancer, lymphoma, gallbladder cancer, esophageal cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, A pharmaceutical composition, characterized in that selected from the group consisting of liver cancer, colorectal cancer, peritoneal cancer, peritoneal metastasis cancer and pancreatic cancer.

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