KR102295963B1 - Novel hydroxamic acids bearing 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole and its use - Google Patents

Abstract

The present invention relates to a novel hydroxamic acid compound containing 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole as a histone deacetylase (HDAC) inhibitor, and an anticancer composition comprising the same as an active component. More specifically, the compound according to the present invention has strong HDAC inhibitory activity, and thus can be used as a proliferation inhibitor for various cancer cells. Therefore, the compound according to the present invention is expected to be developed as an active component of a powerful anticancer agent.

Description

Novel hydroxamic acids bearing 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole and its use

The present invention relates to novel hydroxamic acid compounds comprising 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole and uses thereof. More specifically, the present invention relates to a novel hydroxamic acid compound comprising 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole as a histone deacetylase (HDAC) inhibitor and its use as an anticancer agent. .

Histone deacetylases (HDACs) have become interesting molecular targets for the design and development of anticancer drugs over the past few decades [1]. It results in chromosome condensation and inhibition of the transcription process [2, 3]. So far, 18 different isoforms of HDACs have been identified in eukaryotes [2-4]. They are classified into four classes based on their relative sequence similarity. Among them, classes I and II have been studied the most [3-5]. For example, HDACs 1, 2, 3 and 8 (class I) are known to promote cell proliferation and block apoptosis [3-5]. On the other hand, HDACs 3, 8 (class I) and HDACs 4, 5 (class II) are known to prevent cell differentiation [4-5]. Other isoforms of class II, including HDAC 4, 6, 7 and 10, have been reported to promote migration and angiogenesis, two important processes associated with cancer metastasis [4,5]. Inhibition of different HDAC isoforms in different types of tumor cells results in a number of cascading events related to cell differentiation, apoptosis, and cell cycle arrest [6-8]. The inhibitory effect of HDAC inhibition on tumor cell growth has been clearly demonstrated not only in vitro, but also in numerous in vivo preclinical models and clinical stages. Therefore, HDAC inhibition has recently become an interesting approach in the field of cancer treatment. As a result, until recently, hundreds of HDAC inhibitors have been reported by medical chemists. Such inhibitors include short chain fatty acids (eg, phenylbutyrate or valproic acid), hydroxamic acids (eg, SAHA or suberoylanilide hydroxamic acid), cyclic peptides (eg, defci peptides) and benzamides [9-15]

To date, at least 5 HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, Zoinza®), romidepsin (Istodax®), verinostat (PXD101), panobenostat (LBH-589, Farydak®) ), and chidamide (Epidaza®) have been approved for use as anticancer agents. In addition, a number of HDAC inhibitors, such as entinostat (MS-27-527), mostinostat (MGCD0103), and givinostat (ITF2357), are in different clinical trial stages [14-17].

prior literature

(Non-Patent Document 1) Nam, N.H.; Parang, K. Current targets for anticancer drugs discovery. Curr. Drugs Targets, 2003, 4, 159-179.

(Non-Patent Document 2) Witt, O.; Deubzer, H. E.; Milde, T.; Oehme, I. HDAC family: What are the cancer relevant targets Cancer Lett., 2009, 277, 8-21.

(Non-Patent Document 3) De Ruijter, A.J.M.; Gennip, A. H. V.; Caron, H. N.; Kemp, S.; Kuilenburg, A.B.P.V. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J., 2003, 370, 737-739.

(Non-Patent Document 4) Zwergel C1, Valente S, Jacob C, Mai A. Emerging approaches for histone deacetylase inhibitor drug discovery. Expert Opin. Drug Discov., 2015, 10, 599-613.

(Non-Patent Document 5) West, A.C.; Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest., 2014, 124, 30-39.

(Non-Patent Document 6) Hamm, C.A., Costa, F.F. Epinomes as therapeutic targets. Pharmacol Ther., 2015, 151, 72-86.

(Non-Patent Document 7) Glaser, K.B. HDAC inhibitors: clinical update and mechanism-based potential. Biochem. Pharmacol., 2007, 74, 659-671.

(Non-Patent Document 8) Bolden, J.E.; Peart, M. J.; Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 2006, 5, 769-784.

(Non-Patent Document 9) Dallavalle, S.; Cincinelli, R.; Nannei, R.; Merlini, L.; Morini, G.; Penco, S.; Pisano, C.; Vesci, L.; Barbarino, M.; Zuco, V.; De Cesare, M.; Zunino, F. Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Eur J. Med. Chem., 2009, 44, 1900-1912.

(Non-Patent Document 10) Bracker, TU, Sommer, A., Fichtner, I., Faus, H., Haendler, B., Hess-Stumpp, H. Efficacy of MS-275, a selective inhibitor of class I histone deacetylases , in human colon cancer models. Int. J. Oncol., 2009, 35, 909-920.

(Non-Patent Document 11) Barbarotta L., Hurley K. Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. J. Adv. Pract. Oncol., 2015, 6, 22-36.

(Non-Patent Document 12) Valente, S.; Mai, A. Small-molecule inhibitors of histone deacetylase for the treatment of cancer and non-cancer diseases: a patent review (2011-2013). Expert. Opin. Ther. Pat., 2014, 24, 401-415.

(Non-Patent Document 13) Li, J.; Li, G.; Xu, X. Histone deacetylase inhibitors: an attractive strategy for cancer therapy. Curr. Med. Chem., 2013, 20, 1858-1886.

(Non-Patent Document 14) Ververis, K.; Hiong, A.; Karagiannis, T.C.; Licciardi, P.V. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents. Biologics, 2013, 7, 47-60.

(Non-Patent Document 15) Qiu T, Zhou L, Zhu W, Wang T, Wang J, Shu Y, Liu P. Effects of treatment with histone deacetylase inhibitors in solid tumors: a review based on 30 clinical trials. Future Oncol., 2013, 9, 255-269.

(Non-Patent Document 16) Guha, M. HDAC inhibitors still need a home run, despite recent approval. Nat. Rev. Drug Discov., 2015, 14, 365-365.

(Non-Patent Document 17) Malini G. HDAC inhibitors still need a home run, despite recent approval. Nature Reviews Drug Dis. 2015, 14, 225-226.

(Non-Patent Document 18) Skehan, P.; Storeng, R.; Scudiero, D.; Monk, A.; MacMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd. M.R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.

(Non-Patent Document 9) Ye, G., Nam, NH, Kumar, A., Saleh, A., Shenoy, DB, Amiji, MM, Lin, X., Sun, G., Parang, K. Synthesis and Evaluation of Tripodal Peptide Analogues for Cellular Delivery of Phosphopeptides. J. Med. Chem. 2007, 50, 3604-3617.

(Non-Patent Document 20) You, Y.J., Kim, Y., Nam, N.H., Ahn, B.Z. Antitumor activity of unsaturated fatty acid esters of 4'-demethyldeoxypodophyllotoxin. Bioorg. Med. Chem. Lett. 2003, 13, 2629-2632.

(Non-Patent Document 21) Nam, N.H., Lee, C.W., Hong, D.H., Kim, H.M., Bae, K.H., Ahn, B.Z. Antiinvasive, antiangiogenic and antitumour activity of Ephedra sinica extract. Phytother. Res. 2003, 17, 70-76.

(Non-Patent Document 22) Wu, L.; Smythe, A. M.; Stinson, S. F.; Mullendore, L.A.; Monks, A.; Scudiero, D. A.; Paul, K. D.; Koutsoukos, A.D.; Rubinstein, L.V.; Boyd, M. R.; Shoemaker, R.H. Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res., 1992, 52, 3029-3034.

(Non-Patent Document 23) Trott, O.; Olson, A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455-461.

(Non-Patent Document 24) Lauffer, B.E.; Mintzer, R.; Fong, R.; Mukund, S.; Tam, C.; Zilberleyb, I.; Flicke, B.; Ritscher, A.; Fedorowicz, G.; Vallero, R.; Ortwine, D. F.; Gunzner, J.; Modrusan, Z.; Neumann, L.; Koth, C. M.; Lupardus, P. J.; Kaminker, J. S.; Heise, C. E.; Steiner, P. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability, J. Biol. Chem., 2013, 288, 26926-26943.

(Non-Patent Document 25) Schuttelkopf, A.W.; van Aalten, D.M. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta crystallographica. Section D, Biological crystallography, 2004, 60, 1355-1363.

(Non-Patent Document 26) Spulak, M.; Novak, Z.; Palat, K.; Kune, J.; Pourova, J.; Pour, M. The unambiguous synthesis and NMR assignment of 4-alkoxy and 3-alkylquinazolines. Tetrahedron, 2013, 69, 1705-1711.

(Non-Patent Document 27) Blackburn, C.; Barrett, C.; Chin, J.; Garcia, K.; Gigstad, K.; Gould, A.; Gutierrez, J.; Harrison, S.; Hoar, K.; Lynch, C.; Rowland, R. S.; Tsu, C.; Ringeling, J.; Xu, H. Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform. J Med Chem. 2013, 56, 7201-11.

(Non-Patent Document 28) Pelzel, H.R.; Schlamp, C. L.; Nickells, R. W. Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neuroscience, 2010, 11, 62.

The present inventors have made diligent efforts to develop novel compounds having histone deacetylase (HDAC) inhibitory activity, and as a result, hydroxamic acid compounds including 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole They were newly synthesized, and the present invention was completed by experimentally confirming their histone deacetylase inhibitory activity and proliferation inhibitory activity against cancer cells.

As used herein, “HDAC” and “histone deacetylase” refer to any one of a family of enzymes that remove an ^{N ε} -acetyl group from the ε-amino group of a lysine residue of a protein (eg, histone, or tubulin). The term "histone" is intended to refer to any histone protein from any species, including H1, H2A, H2B, H3, H4, and H5. In some embodiments, the histone deacetylase is HDAC4 , HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10.

As used herein, the terms “HDAC inhibitor” and “inhibitor of histone deacetylase” refer to a compound described herein, or a pharmaceutical thereof, capable of interacting with a histone deacetylase and inhibiting its enzymatic activity. means an acceptable salt.

An object of the present invention is to provide a novel hydroxamic acid compound comprising 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide an anticancer composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

According to the first embodiment,

The present invention is to provide a novel hydroxamic acid compound compound comprising 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole or a pharmaceutically acceptable salt thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to a conventional acid addition salt or base addition salt that retains the biological efficacy and properties of the compound and is formed from an appropriate non-toxic organic or inorganic acid, or a non-toxic organic or inorganic base. means Examples of acid addition salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, Acid addition salts derived from organic acids such as fumaric acid and the like are included. Examples of base addition salts include base addition salts derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds (i.e. drugs) into salts in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds is a technique well known to pharmaceutical chemists, as described in H . Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457, which are incorporated herein by reference.

As used herein, the term "pharmaceutically acceptable" means that, for example, a pharmaceutically acceptable carrier, excipient, etc., is pharmacologically acceptable to a patient to which a particular compound is administered and is substantially non-toxic. do.

In the compound according to the present invention or a pharmaceutically acceptable salt thereof, the compound is characterized in that it is represented by the following formula (1) or (2):

[Formula 1]

[Formula 2]

(In Formula 1 or 2,

wherein X is O or S;

wherein R represents hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy)

In the compound according to the present invention or a pharmaceutically acceptable salt thereof, the halogen is fluorine (F) or chlorine (Cl).

In the compound according to the present invention or a pharmaceutically acceptable salt thereof, the compound is characterized in that it is any one of the following compounds:

2-benzamido-N-hydroxyoxazole-4-carboxamido (5a)

2- (2-chlorobenzamido) -N-hydroxyoxazole-4-carboxamido (5b)

2- (3-chlorobenzamido) -N-hydroxyoxazole-4-carboxamido (5c)

2-(4-chlorobenzamido)-N-hydroxyoxazole-4-carboxamido (5d)

2-(4-fluorobenzamido)-N-hydroxyoxazole-4-carboxamido (5e)

N-hydroxy-2-(4-methylbenzamido)oxazole-4-carboxamido (5f)

N-hydroxy-2-(4-methoxybenzamido)oxazole-4-carboxamido (5g)

2-benzamido-N-hydroxythiazole-4-carboxamido (6a)

2- (2-chlorobenzamido) -N-hydroxythiazole-4-carboxamido (6b)

2- (3-chlorobenzamido) -N-hydroxythiazole-4-carboxamido (6c)

2- (4-chlorobenzamido) -N-hydroxythiazole-4-carboxamido (6d)

2-(4-fluorobenzamido)-N-hydroxythiazole-4-carboxamido (6e)

N-hydroxy-2-(4-methylbenzamido)thiazole-4-carboxamido (6f)

N-hydroxy-2-(4-methoxybenzamido)thiazole-4-carboxamido (6g)

N-hydroxy-2-(phenylsulfonamido)thiazole-4-carboxamido (8a)

2-((4-chlorophenyl)sulfonamido)-N-hydroxythiazole-4-carboxamido (8b)

N-hydroxy-2-((4-methylphenyl)sulfonamido)thiazole-4-carboxamido (8c)

According to the second embodiment,

An object of the present invention is to provide an anticancer composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term “cancer” refers to an aggressive property in which cells divide and grow ignoring normal growth limits, an invasive property of penetrating into surrounding tissues, and a disease in which cells spread to other parts of the body. It is a generic term for diseases caused by cells with metastatic properties.

In the anticancer composition according to the present invention, the cancer is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colon It is characterized in that it is cancer, fallopian tube cancer, endometrial cancer, cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer.

In the anticancer composition according to the present invention, the compound or a pharmaceutically acceptable salt thereof is characterized in that it has an activity of promoting histone acetylation through inhibition of histone deacetylase (HDAC).

In the anticancer composition according to the present invention, the anticancer composition comprises (i) a pharmaceutically effective amount of a compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof; And (ii) it is characterized in that it is provided in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

Carriers that may be included in the anticancer composition according to the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.

The anticancer agent composition according to the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent or a preservative. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

A suitable dosage of the anticancer composition according to the present invention may vary according to factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity of the patient. can be prescribed.

The dosage of the anticancer composition according to the present invention may be preferably 0.001-1000 mg/kg (body weight) per day.

The anticancer composition according to the present invention may be administered orally or parenterally, and when administered parenterally, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.

The concentration of the active ingredient contained in the anticancer composition according to the present invention is determined in consideration of the purpose of treatment, the condition of the patient, the required period, the severity of the disease, and the like, and is not limited to a concentration within a specific range.

The anticancer composition according to the present invention is formulated in a unit dosage form by using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. It may be prepared or prepared by placing it in a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion in oil or an aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.

The novel hydroxamic acid compound containing 2-benzamidooxazole/thiazole or 2-phenylsulfonamidothiazole according to the present invention has potent HDAC inhibitory activity and exhibits antiproliferative activity against various cancer cells. Therefore, it is expected that the compound according to the present invention can be developed as an active ingredient of a powerful anticancer agent.

1 shows the synthesis route of the compounds of Formulas 1 and 2 according to the present invention. Reagents and conditions: a) benzoyl chloride or derivatives thereof, DCM, DMAP, 50° C.; b) ArSO ₂ Cl, DCM, DMAP, 50° C.; c) H ₂ N.OH.HCl, NaOH, MeOH.

Hereinafter, various examples are presented to help the understanding of the invention. The following examples are provided for easier understanding of the invention, and the protection scope of the invention is not limited to the following examples.

<Experimental materials and methods>

chemical substance

All products were obtained homogeneously and confirmed by thin layer chromatography on Whatman® 250 μm Silica Gel GF Uniplates and visualization with UV light at 254 nm and 365 nm. Boiling points were measured using a Gallenkamp Melting Point Apparatus (LabMerchant, London, United Kingdom) and were not calibrated. Purification using chromatography was performed through open flash silica gel column chromatography using Merck silica gel 60 (240 - 400 mesh). Nuclear magnetic resonance spectrum ( ¹ H NMR) was measured on a Bruker 500 MHz spectrometer using tetramethylsilane as an internal standard and dimethylsulfoxide- d ₆ (DMSO- d _{6 ) as a solvent unless otherwise specified.} Chemical shifts were recorded in parts per million (ppm) downfield from tetramethylsilane, an internal standard. Electron ionization (EI), electrospray ionization (ESI) and high-resolution mass spectra were obtained from PE Biosystems API 200 (Perkin Elmer, Palo Alto, CA, USA) and Mariner® (Azco Biotech, Inc. Oceanside, respectively). CA, USA) was measured using a mass spectrometer. Reagents and solvents are sold by Aldrich or Fluka Chemical Corp. unless otherwise specified. (Milwaukee, WI, USA) or Merck (Merck) was purchased and used. The solvent was distilled and dried before use.

<Example>

Steps shown in FIG. 1 of a hydroxamic acid compound comprising 2-benzamidooxazole/thiazole ( 5a-g , 6a-g ) or 2-phenylsulfonamidothiazole ( 8a-c) according to the present invention was synthesized according to

Example 1. Compounds 5a-g synthesis of

First, DMAP (244 mg, 2 mmol) was added to DMF (10 mL) containing ethyl 2-aminooxazole-4-carboxylate (2 mmol), and the resulting mixture was stirred for 10 minutes, after which each benzoyl Chloride (2.2. mmol) was added. The reaction mixture was stirred at 50° C. for 12 hours, and after the reaction was completed, the solvent was removed under reduced pressure. A white solid was formed by gradually adding a 5% solution of _{NaHCO 3 to adjust the pH to 7.} The solid was filtered, washed with cold water, and dried at 60°C. The crude product was further purified by chromatography (DCM/methanol = 95:5) to give the corresponding compound 3 (yield 67-82%).

Each intermediate ester compound 3 was dissolved in methanol (10 mL) and hydroxylamine.HCl (685 mg, 10 mmol) was added followed by dropwise addition of a solution of NaOH (400 mg in 1 mL of water). The mixture was stirred at -5°C until the reaction was completed (1-2 h), and upon completion of the reaction, the resulting reaction mixture was poured into cold water, neutralized to pH~7, and acidified by dropwise addition of HCl 5%. Precipitation was induced. The precipitate was filtered, dried and recrystallized in methanol to give the corresponding target compound 5.

2-Benzamido-N-hydroxyoxazole-4-carboxamide (5a)

white solid; Yield: 65%. mp: 175-176oC. Rf = 0.47 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3362 (NH), 3181, 3119 (OH); 3030, 3009 (CH, aren); 1686, 1655 (C=O); 1624, 1599, 1553 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.67 (1H, s, NHOH), 11.04 (1H, s, CO-NH), 9.11 (1H, s, NHOH), 8.44 (1H, s, H-5), 7.97 (2H, dd, J = 8.00 Hz, J' = 1.00 Hz, H-3', H-7'), 7.66 (1H, t, J = 7.50 Hz, H-5'), 7.56 (2H, t, J = 7.75 Hz, H-4', H-6'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 165.92, 158.23, 153.43, 139.09, 134.58, 133.23, 132.93, 129.12, 128.57. HR-MS (ESI) m/z: 248.0670 [M+H]+.

2-(2-Chlorobenzamido)-N-hydroxyoxazole-4-carboxamide (5b)

white solid; Yield: 72%. mp: 191-192oC. Rf = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3460 (NH); 3254, 3123 (OH); 2982 (CH, aren); 1651 (C=O); 1595, 1557, 1530 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.12 (1H, s, NHOH), 11.00 (1H, s, CO-NH), 9.30 (1H, s, NHOH), 8.67 (1H, s, H-5), 7.79 (4H, m, H-4', H-5', H-6', H-7'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 163.60, 161.04, 153.44, 142.38, 135.26, 133.06, 132.44, 132.02, 131.08, 129.60, 127.71. HR-MS (ESI) m/z: 282.0279 [M+H]+.

2-(3-Chlorobenzamido)-N-hydroxyoxazole-4-carboxamide (5c)

white solid; Yield: 76%. mp: 193-194oC. Rf = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3356 (NH); 3156 (OH); 2988, 2872, 2805 (CH, aren); (1686, 1659 (C=O); 1616, 1564 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.00 (1H, s, CO-NH), 9.11 (1H, s) , NHOH), 8.44 (1H, s, H-5), 8.02 (1H, s, H-3'), 7.93 (1H, d, J = 7.50 Hz, H-5'), 7.73 (1H, d, J = 7.50 Hz, H-7'), 7.59 (1H, t, J = 7.75 Hz, H-6') 13C NMR (125 MHz, DMSO-d6, ppm): δ 164.58, 158.20, 153.48, 138.96, 135.16, 134.54, 133.86, 132.91, 131.09, 128.38, 127.36 HR-MS (ESI) m/z: 282.0281 [M+H]+.

2-(4-Chlorobenzamido)-N-hydroxyoxazole-4-carboxamide (5d)

white solid; Yield: 75%. mp: 198-199oC. Rf = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3354 (NH); 3156 (OH); 3134, 2988, 2843 (CH, aren); 1690, 1661 (C=O); 1614, 1568 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.74 (1H, s, NHOH), 11.02 (1H, s, CO-NH), 9.11 (1H, s, NHOH), 8.44 (1H, s, H-5), 7.99 (2H, d, J = 8.50 Hz, H-3'. H-7'), 7.63 (2H, d, J = 8.50 Hz, H-4', H-6'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 164.96, 158.21, 153.45, 139.03, 138.06, 134.55, 131.84, 130.56, 129.21. HR-MS (ESI) m/z: 282.0281 [M+H]+.

2-(4-Fluorobenzamido)-N-hydroxyoxazole-4-carboxamide (5e)

white solid; Yield: 77%. mp: 179-180oC. Rf = 0.45 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3358 (NH); 3154 (OH); 2988, 2884 (CH, aren); 1686, 1661 (C=O); 1603, 1570, 1504 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.61 (1H, s, NHOH), 10.92 (1H, s, CO-NH), 9.01 (1H, s, NHOH), 8.35 (1H, s, H-5), 7.97 (2H, dd, J = 8.50 Hz, J' = 5.50 Hz, H-3', H-7'), 7.31 (2H, t, J = 8.75 Hz, H-4', H -6'). 13 C NMR (125 MHz, DMSO-d6, ppm): δ 166.19, 164.81, 164.20, 158.23, 153.37, 139.11, 134.58, 131.54, 131.46, 129.44, 116.24, 116.07. HR-MS (ESI) m/z: 264.0433 [M+H]+.

N-Hydroxy-2-(4-methylbenzamido)oxazole-4-carboxamide (5f)

white solid; Yield: 74%. mp: 185-186oC. Rf = 0.44 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3374 (NH); 3161, 3125 (OH); 3042, 2988, 2864 (CH, aren); 1680, 1647 (C=O); 1624, 1551, 1506 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.46 (1H, s, NHOH), 10.92 (1H, s, CO-NH), 9.01 (1H, s, NHOH), 8.635 (1H, s, H-5), 7.80 (2H, d, J = 7.50 Hz, H-3', H-7'), 7.27 (2H, d, J = 7.50 Hz, H-4', H-6'), 2.31 (3H, s, CH3). 13C NMR (125 MHz, DMSO-d6, ppm): δ 165.78, 158.26, 153.54, 143.51, 139.11, 134.58, 130.10, 129.64, 128.64, 21.55. HR-MS (ESI) m/z: 260.0680 [M+H]+.

N-Hydroxy-2-(4-methoxybenzamido)oxazole-4-carboxamide (5g)

white solid; Yield: 65%. mp: 181-182oC. Rf = 0.43 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3460, 3368 (NH); 3163, 3121 (OH); 3009, 2847 (CH, aren); 1676, 1651 (C=O); 1597, 1551, 1506 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 11.47 (1H, s, NHOH), 11.01 (1H, s, CO-NH), 9.10 (1H, s, NHOH), 8.43 (1H, s, H-5), 7.98 (2H, d, J = 8.50 Hz, H-3', H-7'), 7.08 (2H, d, J = 9.00 Hz, H-4', H-6'), 3.85 (3H, s, OCH3). 13 C NMR (125 MHz, DMSO-d6, ppm): δ 165.25, 163.27, 158.28, 153.67, 139.07, 134.55, 130.71, 124.93, 114.38, 56.02. HR-MS (ESI) m/z: 278.0776 [M+H]+.

Example 2. Compounds 6a-g synthesis of

Compounds 6a-g were synthesized through the two-step route described in Scheme 1. This synthesis method was prepared using the same method as the synthesis method of Compound 5 , except that ethyl 2-aminothiazole-4-carboxylate was used instead of ethyl 2-aminoester.

2-Benzamido-N-hydroxythiazole-4-carboxamide (6a)

white solid; Yield: 68%. mp: 189-188oC. Rf = 0.52 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3339 (NH); 3262, 3111 (OH); 3057, 2994 (CH, aren); 1655 (C=O); 1601, 1545 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.64 (1H, s, NHOH), 10.73 (1H, s, CO-NH), 9.05 (1H, s, NHOH), 8.01 (2H, d, J = 8.00 Hz, H-3', H-7'), 7.71 (1H, d, J = 2.50 Hz, H-5), 7.57 (1H, t, J = 7.50 Hz, H-5'), 7.47 (2H, t, J = 7.75 Hz, H-4', H-6'). 13C NMR (125 MHz, DMSO-d6, ppm): δ165.98, 159.80, 158.99, 143.72, 133.24, 132.29, 129.12, 128.64, 117.50. HR-MS (ESI) m/z: 262.0302 [M+H]+.

2-(2-Chlorobenzamido)-N-hydroxythiazole-4-carboxamide (6b)

white solid; Yield: 72%. mp: 198-199oC. Rf = 0.54 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3337 (NH); 3175, 3117 (OH); 3057, 2967, 2872 (CH, aren); 1680, 1655 (C=O); 1589, 1545 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.80 (1H, s, NHOH), 10.75 (1H, s, CO-NH), 9.02 (1H, s, NHOH), 7.75 (1H, s, H-5), 7.58-7.37 (4H, m, H-4', H-5', H-6', H-7'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 165.80, 159.56, 158.02, 143.84, 134.65, 132.48, 130.70, 130.24, 129.90, 127.72, 117.88. HR-MS (ESI) m/z: 295.9898 [M+H]+.

2-(3-Chlorobenzamido)-N-hydroxythiazole-4-carboxamide (6c)

white solid; Yield: 74%. mp: 201-202oC. Rf = 0.54 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3393 (NH); 3125 (OH); 3065, 2967 (CH, aren); 1651 (C=O); 1599, 1549 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 8.07 (1H, d, J = 1.50 Hz, H-3'), 7.96 (1H, d, J = 8.00 Hz, H-7'), 7.77 (1H, s, H-5), 7.61 (1H, dd, J = 8.00 Hz, J' = 1.50 Hz, H-5'), 7.49 (1H, t, J = 7.75 Hz, H-6'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 164.76, 159.71, 157.59, 143.62, 134.43, 133.90, 132.91, 131.05, 128.48, 127.40, 117.62. HR-MS (ESI) m/z: 295.9903 [M+H]+.

2-(4-Chlorobenzamido)-N-hydroxythiazole-4-carboxamide (6d)

white solid; Yield: 74%. mp: 207-208oC. Rf = 0.54 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3395, 3332 (NH); 3142 (OH); 3061, 2968, 2803 (CH, aren); 1651 (C=O); 1593, 1547 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.75 (1H, s, NHOH), 10.75 (1H, s, CO-NH), 9.07 (1H, s, NHOH), 8.02 (2H, d, J = 9.00 Hz, H-3', H-7'), 7.72 (1H, s, H-5), 7.54 (2H, d, J = 8.50 Hz, H-4', H-6'). 13 C NMR (125 MHz, DMSO-d6, ppm): δ 165.06, 159.74, 158.94, 143.73, 138.11, 131.18, 130.60, 129.22, 117.59. HR-MS (ESI) m/z: 295.9905 [M+H]+.

2-(4-Fluorobenzamido)-N-hydroxythiazole-4-carboxamide (6e)

white solid; Yield: 75%. mp: 188-189oC. Rf = 0.45 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3399, 3321 (NH); 3142 (OH); 3075, 2984, 2820 (CH, aren); 1657 (C=O); 1601, 1547, 1510 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.46 (1H, s, NHOH), 10.73 (1H, s, CO-NH), 9.07 (1H, s, NHOH), 8.10 (2H, dd, J = 8.50 Hz, J' = 5.50 Hz, H-3', H-7'), 7.73 (1H, s, H-5), 7.31 (2H, t, J = 8.75 Hz, H-4', H -6'). 13C NMR (125 MHz, DMSO-d6, ppm): δ 166.22, 164.92, 164.22, 159.82, 158.95, 143.69, 131.64, 131.57, 128.82, 128.80, 117.47, 116.25, 116.08. HR-MS (ESI) m/z: 280.0204 [M+H]+.

N-Hydroxy-2-(4-methylbenzamido)thiazole-4-carboxamide (6f)

white solid; Yield: 72%. mp: 179-180oC. Rf = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3447 (NH); 3221 (OH); 3107, 2974, 2903 (CH, aren); 1649 (C=O); 1609, 1541 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.64 (1H, s, NHOH), 10.70 (1H, s, CO-NH), 9.05 (1H, s, NHOH), 7.92 (2H, d, J = 8.50 Hz, H-3', H-7'), 7.70 (1H, s, H-5), 7.27 (2H, d, J = 8.00 Hz, H-4', H-6'), 2.30 (3H, s, CH3). 13 C NMR (125 MHz, DMSO-d6, ppm): δ 165.80, 159.88, 159.20, 143.70, 143.55, 129.67, 129.43, 128.69, 117.41, 21.57. HR-MS (ESI) m/z: 276.0454 [M+H]+.

N-Hydroxy-2-(4-methoxybenzamido)thiazole-4-carboxamide (6g)

white solid; Yield: 76%. mp: 197-198oC. Rf = 0.48 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3337 (NH); 3215, 3179, 3117 (OH); 2992, 2837 (CH, aren); 1661 (C=O); 1605, 1547, 1501 (C=C). 1H-NMR (500 MHz, DMSO-d6, ppm): δ 12.50 (1H, s, NHOH), 10.67 (1H, s, CO-NH), 9.04 (1H, s, NHOH), 8.02 (2H, d, J = 8.50 Hz, H-3', H-7'), 7.69 (1H, s, H-5), 7.00 (2H, d, J = 8.50 Hz, H-4', H-6'), 3.77 (3H, s, OCH3). 13C NMR (125 MHz, DMSO-d6, ppm): δ 165.25, 163.31, 159.92, 159.14, 143.66, 130.78, 124.25, 117.26, 114.42, 56.02. HR-MS (ESI) m/z: 294.0539 [M+H]+.

Example 3. Compounds 8a-c synthesis of

Compounds 8a-c were synthesized via the two-step route described in Scheme 1. This synthesis method was prepared using the same method as the synthesis method of Compound 6 , except that benzenesulfonyl chloride was used instead of benzoyl chloride.

N-Hydroxy-2-(phenylsulfonamido)thiazole-4-carboxamide ( 8a )

white solid; Yield: 65%. mp: 193-194 ^o C. R _f = 0.38 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm ⁻¹ ): 3248, 3117 (OH); 3061, 2982, 2905 (CH, aren); 1645 (C=O); 1549 (C=C). ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.07 (1H, s, N H OH), 11.22 (1H, s, SO 2 -N H), 10.86 (1H, s, NHO H), 9.24(1H,s,H-5),8.01(2H,d, J = 8.00 Hz, H-2', H-6'), 7.57 (1H, t, J = 7.50 Hz, H-4'), 7.47 (2H, d, J = 7.75 Hz, H-3', H-5'). ¹³ CNMR (125MHz, DMSO-d ₆ ,ppm) : δ 159.13, 156.10, 141.50, 137.44, 129.63, 128.21, 126.36, 111.50. HR-MS (ESI) m/z : 297.9965 [M+H] ⁺ .

2-((4-Chlorophenyl)sulfonamido)-N-hydroxythiazole-4-carboxamide ( 8b )

white solid; Yield: 68%. mp: 221-222 ^o C. R _f = 0.39 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm ⁻¹ ): 3179 (OH); 3098, 2990, 2903 (CH, aren); 1663 (C=O); 1580, 1520 (C=C). ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 13.07 (1H, s, N H OH), 11.22 (1H, s, SO 2 -N H), 10.86 (1H, s, NHO H), 9.24(1H,s,H-5),7.72(2H,d, J = 8.50 Hz, H-2', H-6'), 7.53 (2H, d, J = 8.50 Hz, H-3', H -5'). ¹³ CNMR (125MHz, DMSO-d ₆ ,ppm) : δ 159.13, 156.09, 141.50, 137.44, 129.63, 128.21, 126.35, 111.50. HR-MS (ESI) m/z : 331.9579 [M+H] ⁺ .

N-Hydroxy-2-((4-methylphenyl)sulfonamido)thiazole-4-carboxamide ( 8c )

white solid; Yield: 66%. mp: 214-215 ^o C. R _f = 0.42 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm ⁻¹ ): 3181, 3127 (OH); 3075, 2974, 2920 (CH, aren); 1649 (C=O); 1595, 1539, 1516 (C=C). ^{1 H-NMR (500MHz, DMSO} -d 6, ppm): δ 11.18 (1H, s, SO 2 -N H), 10.86 (1H, s, NHO H), 9.24 (1H, s, H-5), 7.60(2H,s, J = 8.00 Hz, H-2', H-6'), 7.26 (2H, d, J = 8.50 Hz, H-3', H-5'), 2.27 (3H, s, CH ₃ ). ¹³ CNMR (125MHz, DMSO-d ₆ ,ppm) : δ 159.12, 156.19, 142.99, 139.61, 129.93, 129.91, 126.36, 117.65, 21.42. HR-MS (ESI) m/z : 312.0122 [M+H] ⁺ .

<Experimental example>

1. Experimental method

(1) Cytotoxicity assay

SW620 (colon cancer cells), PC3 (prostate cancer cells), and NCI-H23 (lung cancer cells) were used for evaluation. The cell line was purchased from the cancer cell bank in Korea Research Institute of Bioscience and Biotechnology (KRIBB). The medium, serum and other reagents used for cell culture were obtained from GIBCO Co. Ltd. (Grand Island, New York, USA). The cells were cultured in DMEM. Then, the cells were suspended at a concentration of ^{3 × 10 4 cells/mL after trypsinization.} On day 0, each well of a 96-well plate was seeded with 180 μL of cell suspension. Then, the plate containing _{5% CO 2} Incubated at 37° C. for 24 hours in an incubator. The compound was first dissolved in dimethyl sulfoxide (DMSO) and diluted before use. 20 μL of each compound sample prepared in the above example was added to each well of a 96-well plate seeded with cell suspension, and incubated for 24 hours at different concentrations. The plates were further incubated for 24 hours. The cytotoxicity of the compound was measured by a method [19-21] with slight modifications to the content described in the known literature [18]. IC ₅₀ values were calculated according to the Probits method [22]. The value measured for each compound was expressed as an average value of three independent measurement results (SD≤10%).

(2) HDAC enzyme analysis

HDAC enzyme (Hela cell nuclear extract) was purchased from BPS Bioscience (SanDiego, CA, USA). The HDAC enzyme assay was performed using a fluorescent HDAC assay kit (BPS Bioscience) according to the manufacturer's instructions. Briefly, HDAC enzymes were incubated with vehicle or various concentrations of assay samples or SAHA at 37° C. for 30 minutes in the presence of HDAC fluorescent substrate. An HDAC assay developer generating a fluorophore in the reaction mixture was added, and fluorescence was measured with an excitation wavelength of 360 nm and an emission wavelength of 460 nm using a ^{VICTOR 3 (PerkinElmer, Waltham, MA, USA).} The vehicle-treated control enzyme activity was subtracted from the measured activity, and IC ₅₀ values were determined using GraphPad Prism (GraphPad Software, San Diego, CA, USA).

2. Results

The HDAC inhibitory ability of all the synthesized compounds was evaluated using Hela cell nuclear extraction assay and cytotoxicity assay for human cancer cell lines including SW620, PC3, and NCI-H23. SAHA was used as a positive control. The results are shown in Table 1 below.

Cpd. code X Ar LogP ¹ HDAC
(Hela extract)
Inhibition
(IC ₅₀ , ² μM) Cytotoxicity (IC ₅₀ , ² mM)/Cell lines ³ SW620 PC3 NCI-H23 5a O H 0.16 0.068±0.012 1.98±0.13 4.35±0.58 3.29±0.20 5b O 2-Cl 0.80 0.056±0.010 2.31±0.14 2.33±0.05 4.92±0.30 5c O 3-Cl 0.80 0.029±0.003 3.22±0.39 3.35±0.10 3.79±0.43 5d O 4-Cl 0.80 0.069±0.011 2.40±0.05 3.48±0.01 2.70±0.23 5e O 4-F 0.36 0.038±0.001 5.36±0.39 5.44±0.86 5.80±0.77 5f O 4-CH ₃ 0.71 0.010±0.001 6.68±0.91 5.11±0.10 3.87±0.46 5g O 4-OCH ₃ 0.24 0.069±0.003 3.43±0.38 7.50±0.91 5.65±0.53 6a S H 1.07 0.037±0.002 4.22±0.17 8.48±1.11 6.14±0.27 6b S 2-Cl 1.72 0.051±0.001 5.99±0.48 3.78±0.53 7.69±0.83 6c S 3-Cl 1.72 0.038±0.007 3.02±0.20 5.02±0.82 5.02±0.37 6d S 4-Cl 1.72 0.033±0.001 4.42±0.56 6.57±0.50 6.78±0.23 6e S 4-F 1.27 0.035±0.002 3.47±0.21 4.64±0.43 6.24±0.02 6f S 4-CH ₃ 1.62 0.131±0.052 2.21±0.01 4.34±0.64 3.29±0.51 6g S 4-OCH ₃ 1.15 0.073±0.009 6.54±0.01 6.05±0.08 6.41±0.08 8a S H 0.25 0.059±0.006 2.28±0.07 2.11±0.09 1.57±0.05 8b S 4-Cl 0.90 0.036±0.004 2.17±0.15 1.96±0.01 1.45±0.10 8c S 4-OCH ₃ 0.33 0.044±0.000 1.91±0.18 2.24±0.34 1.73±0.08 SAHA ⁴ 264.32 1.44 0.025±0.002 1.12±0.10 1.82±0.09 1.44±0.17

(Superscript 1 in Table 1 was calculated with ChemDraw 9.0 software; Superscript 2 is the concentration (μM) of compounds that reduce enzyme activity or cell growth by 50%, and numbers are those with an error of less than 10%. These are the average results of three replicates; superscript 3 indicates SW620, colorectal cancer; PC3, prostate cancer; NCI-H23, and lung cancer cell lines, respectively; superscript 4 indicates SAHA as a positive control.)

As can be seen from Table 1, most of the compounds according to the present invention synthesized in the above Examples exhibited the same or superior anticancer activity compared to SAHA in HDAC enzyme inhibitory ability as well as cytotoxicity to cancer cell lines.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (7)

A compound selected from the group of compounds, or a pharmaceutically acceptable salt thereof:
2-benzamido-N-hydroxyoxazole-4-carboxamido
2-(2-chlorobenzamido)-N-hydroxyoxazole-4-carboxamido
2-(3-chlorobenzamido)-N-hydroxyoxazole-4-carboxamido
2-(4-chlorobenzamido)-N-hydroxyoxazole-4-carboxamido
2-(4-fluorobenzamido)-N-hydroxyoxazole-4-carboxamido
N-hydroxy-2-(4-methylbenzamido)oxazole-4-carboxamido
N-hydroxy-2-(4-methoxybenzamido)oxazole-4-carboxamido
2-benzamido-N-hydroxythiazole-4-carboxamido
2-(2-chlorobenzamido)-N-hydroxythiazole-4-carboxamido
2-(3-chlorobenzamido)-N-hydroxythiazole-4-carboxamido
2-(4-chlorobenzamido)-N-hydroxythiazole-4-carboxamido
2-(4-fluorobenzamido)-N-hydroxythiazole-4-carboxamido
N-hydroxy-2-(4-methylbenzamido)thiazole-4-carboxamido
N-hydroxy-2-(4-methoxybenzamido)thiazole-4-carboxamido
N-hydroxy-2-(phenylsulfonamido)thiazole-4-carboxamido
2-((4-chlorophenyl)sulfonamido)-N-hydroxythiazole-4-carboxamido; and
N-hydroxy-2-((4-methylphenyl)sulfonamido)thiazole-4-carboxamido.
delete delete The anticancer composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
5. The method of claim 4,
The cancer is breast cancer, lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or eye melanoma, uterine sarcoma, ovarian cancer, rectal cancer, anal cancer, colorectal cancer, fallopian tube cancer, endometrial cancer, Cervical cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, kidney cancer, soft tissue tumor, urethral cancer, prostate cancer, bronchial cancer, or bone marrow cancer, characterized in that, anticancer composition.
5. The method of claim 4,
The compound or a pharmaceutically acceptable salt thereof is characterized in that it has an activity to promote histone acetylation through inhibition of HDAC (histone deacetylase), anticancer composition.
5. The method of claim 4,
The anticancer composition comprises (i) a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof; And (ii) characterized in that provided in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, anticancer composition.

Images