KR101209702B1 - Novel hydroxamic acid derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the prevention or treatment of proliferative diseases containing the same as an active ingredient - Google Patents

Abstract

(상기 화학식 1에서, R¹, R² 및 R³는 본 명세서에서 정의된 바와 같다.)The present invention relates to a novel hydroxamic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating abnormal cell growth disease containing the same as an active ingredient. According to the present invention, since it shows an excellent inhibitory effect on various protein kinases useful for the treatment of abnormal cell growth diseases, for example, b-raf, Fak, Fms, etc., it can be usefully used for the prevention or treatment of abnormal cell growth diseases.
[Formula 1]

(In Chemical Formula 1, R ¹ , R ² And R ³ is as defined herein.)

Description

Novel hydroxamic acid derivatives or pharmaceutically acceptable salts, preparation method of the novel hydroxyxamic acid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for the prevention or treatment of abnormal cell growth disease containing the same as an active ingredient and pharmaceutical composition for the prevention or treatment of proliferative diseases containing the same as an active ingredient}

The present invention relates to a novel hydroxamic acid derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating aberrant cell growth disease containing the same as an active ingredient.

Protein kinases are enzymes that catalyze the phosphorylation of hydroxy groups located in tyrosine, serine and threonine residues of proteins and play an important role in the growth factor signal transduction that causes cell growth, differentiation and proliferation.

In order to maintain the homeostasis of the living body, the signaling system in vivo should be smoothly turned on and off. However, mutation or overexpression of certain protein kinases disrupts normal cellular signaling systems (mainly in vivo), leading to a variety of diseases, including cancer, inflammation, metabolic diseases, and brain diseases.

It is estimated that there are 518 human protein kinases, which account for about 1.7% of all human genes (Manning et al, Science, 2002, 298, 1912), largely tyrosine protein kinases (more than 90 species) and serine / threonine protein kinases. Divide into Tyrosine protein kinases can be divided into 58 receptor tyrosine kinases divided into 20 subfamily and 32 cytoplasmic / non-receptors separated into 10 subfamily. Receptor tyrosine kinases have a domain that can accommodate growth factors on the cell surface and an active site that can phosphorylate tyrosine residues on the cytoplasm. When the growth factor is bound to the growth factor receptor site on the receptor tyrosine kinase cell surface, the receptor tyrosine kinase forms a polymer and the tyrosine residues of the cytoplasm are autophosphorylated. Signal transduction proceeds into the nucleus through sequential phosphorylation of the lower family proteins, eventually overexpressing transcription factors that cause cancer.

Raf is a serine / threonine (Ser / Thr) protein kinase and is responsible for delivering the biological signals from the growth factor receptors activated in the cell membrane into the nucleus. Mitogen-activated protein kinase (MAPK) signaling is essential for cell proliferation, division, survival, and cell death. Is formed by a sequential phosphorylation process. Raf is MAPK kinase kinase (MAPKK), MEK is MAPK kinase (MAPKK) and extracellular signal-regulated kinase (ERK) is MAPK. When the receptor is activated, Ras, a small GTP-binding protein, is activated and MAPK signal transduction into the nucleus through sequential phosphorylation of Raf-MEK-ERK.

Ras oncogenes (especially k-Ras), which are always active, are characterized by pancreatic cancer (about 90%), rectal cancer (about 45%), liver cancer (about 30%), non-small cell lung cancer (35%) and kidney cancer (about 10%) is closely related to the induction of solid cancer.

Raf-1 is activated when Raf-1 binds to activated Ras and phosphorylation of Raf-1 338 serine (Avruch, J. Recent Progress in Hormone Research, 2001, 56, 127). On the other hand, Raf-1 is inactivated when 14-3-3 protein binds to Raf-1, which is phosphorylated serine 259.

Raf kinase is also involved in nuclear factor-kB (NF-kB) signaling, which plays an important role in immune response and inflammation (Caraglia, M. et al, Annals of Oncology, 2006, 17, 124). Raf phosphorylates the inactivated IkB protein and induces a positional change of the NFkB protein into the nucleus, thereby promoting a transcription factor that ultimately inhibits apoptosis.

Other mechanisms of inhibition of apoptosis by Raf are as follows. Raf forms a dimer with Bcl-2, changes its position to the mitochondria, and phosphorylates and substitutes Bad there to inhibit Bcl-2 apoptosis. Raf thus immunoprecipitates with Bcl-2 (Yuryev, A. et al, Mol. Cell. Biol., 2000, 20, 4870).

Three subtypes of Raf proteins (A-Raf, B-Raf, C-Raf / Raf-1) have three (CR1, CR2, CR3) conserved regions in the N-terminal regulatory domain and the C-terminal kinase domain. Have CR1 contains Ras-binding domain (RBD) such as Cystein-rich domain (CRD), and CR2 is the site where 14-3-3 protein binds (No. 259 of Raf-1). Serine, etc.), and CR3 contains a catalytic domain (Tran et al., J Biol Chem, 2005, 280, 16244), which has two active-fragmented phosphorylation sites (threonine 491 of Raf-1). And Serine 494) (Wellbrock, C. Nature Reviews Molecular Cell Biology, 2004, 5, 875).

The tissues in which the three subtypes of Raf proteins are expressed are different. C-Raf is expressed in almost all tissues, while A-Raf is mainly expressed in urogenital tissues (kidney, uterus, prostate) and B-Raf is mainly expressed in nerve, spleen, and hematopoietic tissues (Jaiswal, RK et al, J. Biol. Chem., 1966, 271, 23626).

Mutations in B-Raf are associated with about 7% of all human cancers. In particular, mutations of B-Raf are observed at high (about 70%) frequency in melanoma, a type of skin cancer. Among the mutations in B-Raf, the B-raf-V600E mutant, in which valine 600, located at exon 15, was mutated to glutamic acid, mainly caused melanoma (about 90%) (Davies, H. et al, Nature 2002, 417). , 949). Compared with wild-type B-Raf, the in vitro kinase activity of B-raf-V600E is about 500 times higher. Thus, compared to wild-type B-Raf, B-raf-V600E induces cancer by inducing overactivation of MAPK kinase signaling system. The reason why the kinase activity of B-raf-V600E is high is as follows. Glutamic acid 600, substituted with a point mutation, acts as a phosphate model between the phosphorylation sites (threonine 598 and serine 601) located in the activation segment, resulting in a conformal conformation of the always active B-Raf kinase domain. ) (Tuveson, DA, Cancer Cell, 2003, 4, 95). On the other hand, there have been about 40 B-raf mutants identified (mostly occurring in the active fragment site located in the kinase active domain and G-loops rich in glycine), and the incidence of mutants other than V600E is markedly low. About 10% of B-Raf mutants in colorectal cancer occur in the G-loop of the kinase domain (Rajagopalan et al., Nature 2002 418, 934).

There is an auto-inhibition domain at the N-terminus of B-Raf, but when activated H-Ras binds, B-Raf is always activated. It is formed through the phosphorylation of serine 445. The phosphorylation of C-Raf serine 338 corresponds to the phosphorylation of B-Raf serine 445. The B-Raf V600E mutant interferes with the self-suppressive mechanism of B-Raf and remains active at all times.

The B-Raf-V600E mutant is also found at a high (about 50%) frequency in papillary thyroid cancer (Salvatore, G. J. Clin. Endocrinol. Metab. 2004, 89, 5175). At the same time, the B-Raf-V600E mutant is closely associated with the induction of colon cancer (about 20%) and uterine cancer (about 30%).

On the other hand, without expression of oncogenetic mutants, over-activation of C-Raf is observed in about 50% in renal cancer (renal cell carcinoma) and 100% in liver cancer (HCC).

Sorafenib (BAY 43-9006, trade name Nexavar), jointly developed by Bayer and Onyx, strongly inhibits both C-Raf and wild-type or mutant B-Raf. Sorafenib is also a platelet-derived growth factor receptor, vascular endothelial growth factor receptor 1/2/3, fibroblast growth factor receptor, a receptor tyrosine kinase. Inhibit kinase activity such as, Flt-3, c-Kit, RET. Sorafenib inhibits kinases through a mechanism by which the DGF motif of the kinase domain is stabilized to have inactive conformation (Wan, P. T. et. Al. Cell, 2004, 116, 855). Sorafenib was approved in 2005 for the treatment of advanced renal cell carcinoma. Sorafenib's renal cancer treatment is due to the complex inhibition of several kinases including vascular endothelial growth factor receptor 1/2/3 rather than Raf inhibition. The maximum allowable dose of Sorafenib in phase II trials was 400 mg (twice daily). Sorafenib at 600 mg (twice a day) causes grade 3 skin toxic side effects. A common side effect of Sorafenib is peeling of the hands and feet and hand-foot syndrome with erythema and edema. Sorafenib was approved in 2008 for the treatment of hepatocellular carcinoma (HCC). In addition, sorafenib has been shown to be effective in treating thyroid cancer, hormonal refractory prostate cancer and breast cancer. However, sorafenib is not effective in treating melanoma, a skin cancer.

PLX4720, a 7-azaindole derivative from Plexxikon, induces apoptosis of melanoma cell lines such as 1205Lu (Raf-V660E overexpressing cell line) (Tsai, J. et. Al. PNAS, 2008, 105, 3041). ). PLX4720 strongly inhibits the kinase activity of Raf-V660E (IC50 = 13 nM) and also inhibits the proliferation of A375 melanoma cell lines (IC50 = 0.5 uM).

CHIR265 from Novartis / Chiron is also B-Raf-V600E (IC50 = 19 nM), KDR (IC50 = 70 nM), PDGFR-b (IC50 = 30 nM), c-Kit (IC50 = 20 nM) Strongly inhibits kinase activity. CHIR265 is currently in Phase I clinical trials for patients with melanoma.

On the other hand, the emergence of resistance to Raf inhibitors is emerging. Montagut et al. Demonstrated the resistance mechanism of Raf inhibitors by obtaining clones resistant to Raf inhibitors (AZ628) by culturing M14 cell lines (human melanoma cell lines) with Raf inhibitors (AZ628) and B-Raf-V600E mutant species. . When B-Raf is inhibited, the protein expression level of C-Raf is increased and drug inhibition against B-Raf-V600E is reduced. However, the sensitivity of geldanamycin, an HSP90 inhibitor, is increased in melanoma cell lines resistant to Raf inhibitors (AZ628). Thus, HSP90 inhibition may be a way to overcome the resistance of Raf inhibitors (Montagut, C. Cancer Research, 2008, 68, 4853).

Vascular Endothelial Growth Factors Receptors (VEGFRs) are receptor tyrosine kinases (RTKs) and are important regulators for angiogenesis. It is involved in the development and maintenance of blood vessels and lymphatic vessels, and has an important effect on nerve cells. VEGF is produced mainly in vascular endothelial cells, hematopoietic cells, and stromal cells by hypoxia and stimulation of cell growth factors such as TGF, interleukin, PDGF. VEGF binds to VEGF receptors (VEGFR) -1, -2, and -3, and each VEGF isoform binds to a specific receptor, inducing the formation of a homozygous or heterozygous receptor, and then activates each signaling system. Signal specificity of VEGFR is more finely regulated by coreceptors such as neurophilin, heparan sulfate, integrin, cadherin, and so on.

The biological function of VEGF is mediated through type III RTK, VEGFR-1 (Flt-1), VEGFR-2 (KDR / Flk-1), VEGFR-3 (Flt-4). EGFR is closely related to Fms, Kit and PDGFR, and VEGF binds to specific receptors, respectively, while VEGF-A binds to VEGFR-1, -2 and receptor heteropolymers, while VEGF-C binds to VEGF-2, Bind to -3. Also, PIGF and VEGF-B are exclusive to VEGFR-1, and VEGF-E only interacts with VEGFR-2. The VEGF-F variant interacts with VEGFR-1 or -2. VEGF-A, -B, and PIGF are primarily required for blood vessel formation, while VEGF-C, -D are essential for lymphatic vessel formation. New blood vessels supply nutrients and oxygen to tumors and provide a pathway for cancer cell metastasis, essential for their proliferation and metastasis. Angiogenesis is normally balanced by the mutual regulation of angiogenic stimulators and angiogenic suppressors in vivo, but the greatest impact on vascular endothelial cells when such balances are broken, such as in cancer cells. The receptor, VEGFR, is activated by a vascular endothelial growth factor (VEGF). Among various mechanisms of action, various inhibitors that inhibit the receptor tyrosine kinase of VEGF using low molecular weight synthetic materials have been researched and developed. Most of them have the potential to be commonly used in solid tumors and activated neovascularization only in cancer cells. Because of the relatively low side effects have the advantage that you can expect effective drug.

Tie2 is a type of receptor tyrosine kinase that is highly associated with angiogenesis and vasculature. The domain structure of Tie2 is very highly conserved in all vertebrates (Lyons et al., 1998). Ligands of Tie2 are angiopoietins (Ang). Ang2 does not induce autophosphorylation of Tie2, but interferes with the activation of Tie2 induced by Ang1. Activation of Tie2 by Ang2 in endothelial cells leads to the activation of PI3K-Akt (Jones et al., 1999). In the mitogen-activated protein kinase (MAPK) signaling pathway, Tie2's main signaling system, the adapter protein GRB2 and the protein tyrosine phosphatase SHP2 are involved in the dimerization process via autophosphorylation of Tie2 receptor tyrosine kinase. Plays an important role. Ang / Tie2 and vascular endothelial growth factor (VEGF) signaling pathways play an important role in the neovascularization of cancer cells. Tie2 is expressed in vascular endothelial cells, especially in the place where cancer cells invade. Overexpression of Tie2 has been identified in breast cancer (Peters et al., 1998), and at the same time in uterine cancer, liver cancer and brain cancer.

It is an object of the present invention to provide novel hydroxamic acid derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing a novel hydroxyxamic acid derivative or a pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating abnormal cell growth disease, which contains a novel hydroxyxamic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a novel hydroxyxamic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

R ¹ , R ² and R ³ are as defined herein.)

The present invention also provides a method for preparing a novel hydroxyxamic acid derivative or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating abnormal cell growth disease, which contains a novel hydroxyxamic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel hydroxyxamic acid derivatives or pharmaceutically acceptable salts thereof according to the present invention exhibit excellent inhibitory activity against protein kinases and are therefore useful for treating various protein kinases such as B-raf, Fak, Since it shows an excellent inhibitory effect on Fms and the like, it can be usefully used for the prevention or treatment of abnormal cellular sexual disease.

1 is a result of Western blotting of the compounds of the present invention.

Hereinafter, the present invention will be described in detail.

The present invention provides a hydroxyxamic acid derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula 1,

R ¹ is hydrogen; C ₁ -C ₁₀ straight or branched chain alkyl unsubstituted or substituted with one or more halogens; Halogen or -OR ⁴ , wherein R ⁴ is a 5-12 membered heteroaryl containing an N atom in the ring;

R ² is hydrogen, halogen, —OR ⁵ , —NHR ⁵ , wherein R ⁵ is unsubstituted or substituted with C; C ₅ to C ₈ cycloalkyl C ₅ to C ₁₂ aryl, or unsubstituted or substituted with = O 5-8 membered heterocycloalkyl C ₅ -C ₁₂ aryl containing N atoms in the ring;

로 이루어지는 군으로부터 선택되는 1 이상의 치환기로 치환된 C₆~C₁₅ 아릴이다.)
R ³ is C ₁ to C ₁₀ straight or branched chain alkyl substituted with halogen, unsubstituted or one or more halogen; C ₁ -C ₁₀ straight or branched alkoxy unsubstituted or substituted with one or more halogens; Unsubstituted or halogen, C ₁ ~ C ₄ linear or branched alkyl, substituted C ₁ ~ C ₄ linear or branched alkyl with one or more halogen, and C ₁ ~ C ₄ linear or branched alkoxy of 1 or more substituents selected from the group consisting of C ₆ ~ C ₁₅ aryl substituted with; Unsubstituted or halogen, C ₁ ~ C ₄ linear or branched alkyl, substituted C ₁ ~ C ₄ linear or branched alkyl with one or more halogen, and C ₁ ~ C ₄ linear or branched alkoxy of 1 or more substituents selected from the group consisting of C ₆ to C ₁₅ aryl C ₁ to C ₁₀ alkyl substituted with NHR _6, wherein R ₆ is unsubstituted or halogen, C ₁ to C ₄ straight or branched alkyl, C ₁ to substituted with one or more halogens C ₄ straight or branched alkyl, C ₁ to C ₄ straight or branched alkoxy, and

C ₆ ~ C ₁₅ aryl substituted with one or more substituents selected from the group consisting of:

Preferably,

, 또는

이고;R ¹ is hydrogen, F, Cl, Br, Me, Et, CF ₃ ,

, or

ego;

,

,

또는

이고;R ² is hydrogen, F, Cl, Br,

,

,

or

ego;

R ³ is F, Cl, Br, Me, Et, OMe, OEt, CF ₃ , phenyl, benzyl, unsubstituted or substituted with one or more F, Cl, Br, Me, Et, OMe, OEt, CF ₃ At least one substituent selected from the group consisting of NH-R ⁶ ; At this time, R ⁶ is unsubstituted or substituted with F, Cl, OMe, CF ₃ phenyl.

More preferably,

, 또는

이고;R ¹ is hydrogen, Br, CF ₃ ,

, or

ego;

,

,

또는

이고;R ² is hydrogen, Cl,

,

,

or

ego;

R ³ is one or more substituents selected from the group consisting of Me, unsubstituted or substituted with one or more F, Cl, OMe, CF ₃ , benzyl, or —NH—R ⁶ ; In this case, R ⁶ is unsubstituted or substituted with Cl, OMe, CF ₃ .

Specific compounds of the novel hydroxamic acid derivatives represented by Formula 1 of the present invention are as follows.

1) preparation of 4- (tripuloormethyl) -N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;

2) N-hydroxy-4-methoxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;

3) 4-pulluor-N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;

4) 2,4-dichloro-N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;

5) 3- (4-chloro-3- (tripuloormethyl) phenyl) -1-hydroxy-1- (3- (pyridine-3 -yloxy) phenyl) urea;

6) 1-hydroxy-3- (4-methoxyphenyl) -1- (3- (pyridin-3-yloxy) phenyl) urea;

7) 1-hydroxy-3-phenyl-1- (3- (pyridin-3-yloxy) phenyl) urea;

8) 3- (4-chloro-3- (tripuloorphenyl) phenyl) -1-hydroxy-1- (3- (pyridin-3-yloxy) phenyl) urea;

9) 1-hydroxy-3-phenyl-1- (3- (pyridin-4-yloxy) phenyl) urea;

10) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) benzamide;

11) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) acetamide;

12) 3- (4-chloro-3- (tripuloormethyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino ) Phenyl) urea;

13) 1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) -3-phenylurea;

14) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) cinnamamide;

15) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) cinnamicamide;

16) N-hydroxy-N- (4- (3-oxo-2,3-dihydroxy-1H-indene-5-yloxy) phenyl) benzamide;

17) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl)

Acetamide;

18) 1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -3-

Phenylurea;

19) 3- (4-chloro-3- (trifullumethyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy ) Phenyl) urea;

20) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -1-

Naphthaamide;

21) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -2-

Naphthaamide;

22) N-hydroxy-2- (naphthalen-1-yl) -N- (4- (3-oxo-2,3-dihydro-1H-inden-5-yloxy) phenyl) acetamide;

23) 4- (2-bromo-4-((4-chloro-3- (tripuloorphenyl) phenyl) (hydroxy) vcarbamoyl) phenoxy) -N-methylpicolinamide;

24) 4- (4- (3- (4-chloro-3- (tripoolormethyl) phenyl) -3-hydroxyurido) phenoxy) -N-methoxypicolinamide;

25) N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy) phenyl) benzamide; And

26) N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy) phenyl) acetamide.

The hydroxyxamic acid derivative represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term pharmaceutically acceptable salt means a concentration that is relatively non-toxic to a patient and has a beneficial effect that is harmless to the patient, such that the side effects caused by the salt are any organic or inorganic salt of the base compound of Formula 1 that does not impair the beneficial effects of the base compound of Formula An inorganic addition salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, succinic acid, tartaric acid, galacturonic acid, embic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, acid addition salts include acetates, aspartates, benzates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, camsylates, citrates, edisylates, ecylates, formates, fumarates, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrochloride / Chloride, Hydrobromide / Bromide, Hydroiodide / Iodide, Isetionate, Lactate, Maleate, Mali Eate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccha Laterate, stearate, succinate, tartrate, tosylate, trifluoroacete , Aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Heavy hydrochloride or trifluoroacetate are preferred.

In addition, the hydroxyxamic acid derivative represented by Chemical Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates, and solvates that can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. The solvent or excess acid may then be evaporated and dried in this mixture to obtain an addition salt or the precipitated salt may be prepared by suction filtration.

Isomers herein means compounds of the present invention or salts thereof having the same chemical formula or molecular formula, but which are optically or sterically different, and such isomers and mixtures thereof are also included within the scope of the present invention.

The present invention also provides a method for preparing a hydroxamic acid derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

The compound of Formula 1 according to the present invention may be prepared by a method as shown in Schemes 1 to 6 below.

Hereinafter, the above production method will be described using the reaction scheme.

Manufacturing Method 1

As represented by Scheme 1, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

Preparing a compound of Chemical Formula 3 by hydrolyzing a starting compound of Chemical Formula 2 using lithium hydroxide (step 1);

Preparing a compound of formula 5 by condensing the compound of formula 3 prepared in step 1 with the compound of formula 4 (step 2); And

The compound of Chemical Formula 5 prepared in Step 2 may be added to a compound of Chemical Formula 6 to prepare a compound of Chemical Formula 1a (Step 3).

[Reaction Scheme 1]

(In Scheme 1,

Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Manufacturing Method 2

As represented by Scheme 2 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

Reacting a compound of formula 7 with a compound of formula 8 to prepare a compound of formula 9 in the presence of a DME solvent (step 1);

Preparing a compound of formula 10 by hydrolyzing the compound of formula 9 prepared in step 1 using lithium hydroxide (step 2);

Preparing a compound of formula 12 by condensing the compound of formula 10 prepared in step 2 with a compound of formula 11 (step 3); And

The compound of Formula 12 prepared in Step 3 may be prepared by a condensation reaction with a compound of Formula 13 to prepare a compound of Formula 1b (Step 4).

Scheme 2

(In Scheme 2, Formula 1b is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Manufacturing Method 3

As represented by Scheme 3 below, the derivative of Formula 1 of the present invention or a pharmaceutically acceptable salt thereof

Condensing the compound of Formula 14 to produce a compound of Formula 15 (step 1);

Preparing a compound of formula 16 by benzylating the compound of formula 15 prepared in step 1 (step 2);

Preparing a compound of formula 17 by reducing a compound of formula 16 prepared in step 2 (step 3); And

The compound of Chemical Formula 17 prepared in Step 3 may be prepared by a condensation reaction of the compound of Chemical Formula 18 with DPPA and a base to prepare a compound of Chemical Formula 1c (Step 4).

Scheme 3

(In Scheme 3, Formula 1c is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Manufacturing Method 4

As shown in Scheme 4, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

Coupling a compound of Formula 19 with a compound of Formula 20 in the presence of a catalyst and a centforce to prepare a compound of Formula 21 (step 1);

Preparing a compound of Chemical Formula 22 by reducing the compound of Chemical Formula 21 prepared in Step 1 in the presence of zinc (Step 2); And

The compound of formula 22 prepared in step 2 may be prepared by an addition reaction with a compound of formula 23 to prepare a compound of formula 1d (step 3).

[Reaction Scheme 4]

(In Scheme 4, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Manufacturing Method 5

As shown in Scheme 5, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

Preparing a compound of formula 26 by performing a substitution reaction of the compound of formula 24 with a compound of formula 25 in the presence of a base (step 1);

Preparing a compound of formula 27 by reducing the compound of formula 26 prepared in step 1 in the presence of zinc (step 2); And

The compound of Formula 27 prepared in Step 2 may be added to the compound of Formula 28 to prepare a compound of Formula 1e (Step 3).

Scheme 5

(In Scheme 5, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Manufacturing Method 6

As shown in Scheme 6, the derivative of Formula 1 or a pharmaceutically acceptable salt thereof

Preparing a compound of Chemical Formula 30 by reducing a compound of Chemical Formula 29 (step 1);

Preparing a compound of Chemical Formula 31 by performing a substitution reaction of the compound of Chemical Formula 30 prepared in Step 1 (step 2);

Preparing a compound of Chemical Formula 33 by coupling a compound of Chemical Formula 31 and a compound of Chemical Formula 32 prepared in Step 2 (Step 3);

Preparing a compound of formula 34 by reducing the compound of formula 33 prepared in step 3 (step 4); And

The compound of Formula 34 prepared in Step 4 and the compound of Formula 35 may be added to prepare a compound of Formula 1f (Step 5).

[Reaction Scheme 6]

(In Scheme 6, Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)

Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of abnormal cell growth diseases containing a hydroxyxamic acid derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The hydroxyxamic acid derivatives represented by Formula 1 or pharmaceutically acceptable salts, solvates and hydrates thereof have excellent inhibitory effects against various protein kinases that cause abnormal cell growth diseases, such as b-raf, Fak, Fms, etc. Therefore, it can be usefully used for the prevention or treatment of abnormal cell growth diseases.

Examples of the abnormal cell growth disease include stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney Cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, leukemia, multiple myeloma, blood cancers such as myelodysplastic syndrome, lymphomas such as Hochkin's disease, non-Hodgkin's lymphoma, psoriasis and fibroadenoma are preferred.

The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001 to 100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient with a weight of 70 kg, it is generally 0.07 ~ 7000 mg / day, preferably 0.7 ~ 2500 mg / day, once a day at regular intervals depending on the judgment of the doctor or pharmacist Multiple doses may be administered.

Hereinafter, the present invention will be described in detail with reference to examples.

However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

< Example  1> 4- ( Trifluoromethyl ) -N-hydroxy-N- (3- (pyridine-3- Iloxy ) Phenyl ) Preparation of Benzamide

Step 1: N- (3- (pyridine-3- Iloxy ) Phenyl ) Hydroxyamine  Produce

3- (3-nitrophenoxy) pyridine (1.5 g, 6.94 mmol) was dissolved in acetone (90 mL) and treated with an ultrasonic apparatus at 0 ° C to 10 ° C with saturated aqueous ammonium chloride solution (4.5 mL) and water (4.5 mL). ) Was added and zinc (907 mg, 13.9 mmol) was added slowly. At this time, the reaction temperature is 15 ℃, the reaction time should not exceed about 30 minutes. After completion of the reaction, the volatiles were removed at 0 ° C to 10 ° C, dichloromethane (20 mL) was added, the insoluble material was filtered off with celite, the filtrate was dried over sodium sulfate, filtered and concentrated to N- (3 -(Pyridin-3-yloxy) phenyl) hydroxyl amine (970 mg, yellow oil, 69%) was obtained as the target compound.

LC Mass (M ⁺ , 203.16).

Step 2: N-hydroxy-N- (3- (pyridine-3- Iloxy ) Phenyl )-4-( Trifluoromethyl ) Benzamide  Produce

N- (3- (pyridin-3-yloxy) phenyl) hydroxyl amine (100 mg, 0.49 mmol) obtained in step 1 was dissolved in dichloromethane (1 mL), and 4- (trifluoromethyl) benzoyl chloride ( 126 μl, 0.49 mmol) was added. Triethylamine (69 μl, 0.49 mmol) was added dropwise at 0 ° C., and when the reaction was completed, volatiles were removed, water (20 mL) was added, and extracted with dichloromethane (20 mL) 2-3 times. Dry with sodium carbonate and purify by column chromatography to give the title compound N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) -4- (trifluoromethyl) benzamide (42 mg, 23) as a brown oil. %) Was obtained as the product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.43-8.38 (m, 2H), 8.2 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H) , 7.34-7.29 (m, 2H), 6.9 (d, J = 6.0 Hz, 1H), 6.82 (s, 1H), 6.74 (d, J = 9.0 Hz, 1H).

LC Mass (M ⁺ , 375.22).

< Example  2> N-hydroxy-4- Methoxy -N- (3- (pyridine-3- Iloxy ) Phenyl ) Benzamide  Produce

N- (3- (pyridin-3-yloxy) phenyl) hydroxyamine (200 mg, 0.98 mmol) prepared in step 1 of Example 1 was dissolved in dichloromethane (1 mL), and p-methoxybenzoyl Chloride (169 mg, 0.98 mmol) was added. Triethylamine (137 μl, 0.98 mmol) was added dropwise at 0 ° C. At the end of the reaction, the volatiles were removed and water (2 mL) was added, extracted with ethyl acetate (3 mL), dried over sodium sulfate and purified by column chromatography to give the title compound N-hydroxy-4- as yellow oil. Methoxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide (108 mg, 32%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 8.4 (dd, J = 13, 2.7 Hz, 2H), 8.05 (d, J = 9.0 Hz, 2H), 7.33-7.24 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.68 (dd, J = 8.4, 2.4 Hz, 1H), 3.88 ( s, 3H).

LC Mass (M ⁺ , 321.26).

< Example  3> 4-ple Luor -N-hydroxy-N- (3- (pyridine-3- Iloxy ) Phenyl ) Benzamide Manufacturing

4-fluorobenzoyl chloride was used instead of p-methoxybenzoyl chloride in Example 2, and dichloromethane was used in the same manner as in Example 2, except that ethyl chloride was used as a target compound of brown oil (4-fluor-N- Hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide) was obtained (78 mg, 49%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.03 (s, 1H), 8.43 to 8.38 (m, 2H), 8.14 to 8.09 (m, 2H), 7.34 to 7.15 (m, 6H), 6.89 (dd, J = 8.4, 1.5 Hz, 1 H), 6.8 (s, 1 H), 6.7 (dd, J = 8.5, 2.4 Hz, 1 H).

LC Mass (M ⁺ , 325.24).

< Example  4> 2,4- Dichloro -N-hydroxy-N- (3- (pyridine-3- Iloxy ) Phenyl ) Benzami Manufacture of de

Except for using 2,4-dichlorobenzoyl chloride instead of p-methoxybenzoyl chloride used in Example 2, dichloromethane instead of ethyl acetate was carried out in the same manner as in Example 2 to give the target compound of the brown oil (2,4- Dichloro-N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide) was obtained (127 mg, 69%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.43-8.39 (m, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 1.98 Hz, 1H) , 7.38-7.28 (m, 4H), 6.89 (dd, J = 8.7, 2.5 Hz, 1H), 6.82-6.81 (m, 1H), 6.73 (dd, J = 8.5, 2.5 Hz, 1H).

LC Mass (M ⁺ , 375.12).

< Example  5 > 3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -1-hydroxy-1- (3- (pyridine-3- Iloxy ) Phenyl ) Urea  Produce

Step 1: N- (3- (pyridine-3- Iloxy ) Phenyl ) Of hydroxylamine  Produce

3- (3-nitrophenoxy) pyridine (300 mg, 1.39 mmol) was dissolved in acetone (18 mL) and saturated aqueous ammonium chloride solution (0.9 mL) was added at 0 ° C to 10 ° C, followed by water (1 mL) and zinc. (192 mg, 2.9 mmol) was added slowly. At the end of the reaction, the volatiles were removed at 0 ° C ~ 10 ° C, dichloromethane (3 mL) was added, the insoluble material was filtered off with celite, the filtrate was dried over sodium sulfate and distilled under reduced pressure. The obtained product was recrystallized to obtain the target compound (N- (3- (pyridin-3-yloxy) phenyl) hydroxylamine) in a mixture (300 mg, 99%).

Step 2: 3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -1-hydroxy-1- (3- (pyridin-3-yl rock city) Phenyl ) Urea  Produce

N- (3- (pyridin-3-yloxy) phenyl) hydroxylamine (mix 300 mg, about 1.49 mmol) was dissolved in tetrahydrofuran (10 mL) and 4-chloro-3 (tripuloor) at 0 ° C. Methyl) phenylisocyanate (329 mg, 0.49 mmol) was added. After stirring for 13 hours at room temperature, the reaction was terminated, purified by column chromatography to give the target compound of the white solid (3- (4-chloro-3- (tripulormethyl) phenyl) -1-hydroxy-1- (3- (pyridin-3-yloxy) phenyl) urea) was obtained (25 mg, 8.3%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.24 (d, J = 4.5 Hz, 1H), 7.83 (s, 2H), 7.68 (d, J = 9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.44-7.37 (m, 2H), 7.32-7.26 (m, 1H), 6.72 (d, J = 8.1 Hz, 1H).

LC Mass (M ⁺ , 424.23).

< Example  6> 1-hydroxy-3- (4- Methoxyphenyl ) -1- (3- (pyridine-3- Iloxy ) Phenyl ) Thunder A) manufacture

Except for using 4-methoxy phenylisocyanate in place of 4-chloro-3 (trifluoromethyl) phenylisocyanate used in Step 2 of Example 5, the procedure was carried out in the same manner as in Step 2 of Example 5, to obtain a white solid target compound. (1-hydroxy-3- (4-methoxyphenyl) -1- (3- (pyridin-3-yloxy) phenyl) urea)) was obtained (16 mg, 6.5%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.25 (d, J = 3.4 Hz, 1H), 8.24-8.00 (m, 1H), 7.53-7.43 (m, 2H), 7.35 (m, 6H), 6.85 ( dd, J = 6.8, 2.1 Hz, 1H), 6.72 (dd, J = 8.1 2.3 Hz, 1H), 3.78 (s, 3H).

LC Mass (M ⁺ , 352.2).

< Example  7> 1-hydroxy-3- Phenyl -1- (3- (pyridine-3- Iloxy ) Phenyl ) Urea  Produce

Except for using phenylisocyanate instead of 4-chloro-3 (trifluoromethyl) phenylisocyanate used in Step 2 of Example 5, the procedure was carried out in the same manner as Step 2 of Example 5 to give the target compound of the yellow oil (1-hydr Oxy-3-phenyl-1- (3- (pyridin-3-yloxy) phenyl) urea) was obtained (20 mg, 18%).

LC Mass (M ⁺ , 322.2).

< Example  8> 3- (4- Chloro -3- ( Tripuloorphenyl ) Phenyl ) -1-hydroxy-1- (3- (pyridine-3- Iloxy ) Phenyl ) Urea  Produce

Performed in the same manner as Step 2 of Example 5, except that 4-chloro-3 (trifluoromethyl) phenyl isocyanate was used instead of 4-chloro-3 (trifluoromethyl) phenyl isocyanate used in Step 2 of Example 5 To give the title compound (3- (4-chloro-3- (tripulophenyl) phenyl) -1-hydroxy-1- (3- (pyridin-3-yloxy) phenyl) urea) as a white solid ( 25 mg, 4%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.24 (d, J = 4.5 Hz, 1H), 7.83 (s, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.44-7.37 (m, 2H), 7.32-7.26 (m, 1H), 6.72 (d, J = 8.1 Hz, 1H).

LC Mass (M ⁺ , 424.23).

< Example  9> 1-hydroxy-3- Phenyl -1- (3- (pyridine-4- Iloxy ) Phenyl ) Urea  Produce

Performed in the same manner as Step 2 of Example 5, except that 4-chloride-3 (trifluoromethyl) phenyl isocyanate was used instead of 4-chloro-3 (trifluoromethyl) phenyl isocyanate used in Step 2 of Example 5 To give the title compound (1-hydroxy-3-phenyl-1- (3- (pyridin-4-yloxy) phenyl) urea) as a white solid (35 mg, 17%).

LC Mass (M ⁺ , 424.23).

< Example  10> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Phenyl ) Benzamide

Step 1: 6- (4- Nitrophenylamino ) -2,3- Dehydroindene Preparation of -1-one

6-Bromo-2,3-dihydroinden-1-one (250 mg, 1.18 mmol) was dissolved in toluene (3 mL), palladium acetate (5 mg, 2 mol%), centforce (Xantphos, 10 mg). , 4 mol%), cesium carbonate (579 mg, 1.78 mmol) was added in this order, and 4-nitrobenzeneamine (196 mg, 1.42 mmol) was added at 0 ° C., and the mixture was reacted at 110 ° C. for 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered with dichloromethane (5 mL) to remove insoluble materials, and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain a solid target compound (6- ( 4-nitrophenylamino) -2,3-dihydroinden-1-one) was obtained (210 mg, 84%).

TLC (ethyl acetate / hexane = 1/4) Rf 0.15

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, 2H, J = 13.8 Hz), 7.61 (d, 1H, J = 11.7 Hz), 7.53 (d, 2H, J = 10.5 Hz), 7.02 (d , 2H, J = 3.3 Hz), 3.20 (t, 2H, J = 7.8 Hz), 2.80 (t, 2H, J = 3.3 Hz).

Step 2: 6- (4- ( Hydroxyamino ) Phenylamino ) -2,3- Dehydroindene Preparation of -1-one

6- (4-nitrophenylamino) -2,3-dihydroinden-1-one (78 mg, 0.29 mmol) obtained in step 1 was dissolved in acetone (5 ml) and saturated aqueous ammonium chloride solution (0.25 mL) And water (0.25 mL) and then zinc (40 mg, 0.61 mmol) was slowly added, and reacted for 10 minutes with an ultrasonic generator at 15 ℃. Upon completion of the reaction, zinc was removed by filtration through celite and the solvent was removed under reduced pressure in a 15 ° C. water bath. Dichloromethane was added to the remaining residue, followed by filtration and removal of the solvent under reduced pressure to give the desired compound as a desired brown solid (6- (4- (hydroxyamino) phenylamino) -2,3-dihydroinden-1-one ) (75 mg, 96%).

TLC (ethyl acetate / hexane = 1/2), Rf 0.50

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29 (d, 1H, J = 2.1 Hz), 7.15 (d, 2H, J = 6.0 Hz), 7.00 (d, 2H, J = 8.4 Hz), 6.68 (d , 2H, J = 3.0 Hz), 3.03 (t, 2H, J = 5.4 Hz), 2.69 (t, 2H, J = 3.9 Hz), 2.17 (s, 1H, OH).

MS (LC, 70 eV) m / z 254 (M &lt; + &gt;), 238, 195, 180, 148, 107.

Step 3: N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Phenyl ) Ben Preparation of Zamide

6- (4- (hydroxyamino) phenylamino) -2,3-dihydroinden-1-one (35 mg, 0.14 mmol) obtained in step 2 was dissolved in dichloromethane (2 mL), and then 0. Triethylamine (0.021 mL, 0.15 mmol) was added at 占 폚, benzoyl chloride (0.017 mL, 0.15 mmol) was added, followed by stirring for 30 minutes. After raising to room temperature and stirring for further 1 hour, an aqueous solution of ice was added to terminate the reaction. Extraction with dichloromethane, drying, filtration, concentration under reduced pressure and purification by silica gel column chromatography gave the desired compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5). -Ylamino) phenyl) benzamide) (35 mg, 89%).

TLC (ethyl acetate / hexane = 1/2), Rf 0.25

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 12.9, 5.7 Hz), 7.57 (d, 2H, J = 6.9 Hz), 7.50 (m, 4H), 7.34 (d, 1H, J = 3.9 Hz), 7.27 (d, 2H, J = 3.9 Hz), 7.18 (d, 2H, J = 2.1 Hz), 3.04 (t, 2H, J = 5.7 Hz), 2.69 (t, 2H, J = 4.2 Hz).

MS (LC, 70 eV) m / z 358 (M &lt; + &gt;), 342, 237, 168, 104.

< Example  11> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Phenyl ) Acetamide  Produce

Except for using acetyl chloride instead of benzoyl chloride, it was carried out in the same manner as in step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro-) as a solid. 1H-inden-5-ylamino) phenyl) acetamide) was obtained (35 mg, 16%).

TLC (ethylacetate / hexane = 1/2), Rf 0.20

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.69 (dd, 1H, J = 8.4, 2.0 Hz), 7.41 (d, 1H, J = 8.4 Hz), 7.28 (d, 2H, J = 2.1 Hz), 6.85 (dd, 1H, J = 9.9, 1.8 Hz), 6.52 (dd, 2H, J = 9.9, 2.1 Hz), 3.12 (t, 2H, J = 6.0 Hz), 2.74 (t, 2H, J = 6.0 Hz) , 2.21 (s, 3 H).

MS (LC, 70 eV) m / z 297 (M + l), 280, 238, 163, 145, 120, 90.

< Example  12> 3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -1-hydroxy-1- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Phenyl ) Urea  Produce

The same procedure as in Step 3 of Example 10 was carried out except that 3-tripuloormethyl-4-chlorophenyl was used instead of benzoyl chloride to give the solid as a target compound (3- (4-chloro-3- (tripuloor Methyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) urea) was obtained (28 mg, 40%).

TLC (ethyl acetate / hexane = 1/2), Rf 0.45

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (t, 1H, J = 6.9 Hz), 7.55 (dd, 2H, J = 5.4, 2.7 Hz), 7.32 (m, 3H), 7.26 (m, 3H) , 7.15 (d, 1H, J = 6.9 Hz), 3.07 (t, 2H, J = 5.4 Hz), 2.71 (t, 2H, J = 5.7 Hz).

MS (LC, 70 eV) m / z 476 (M + 1), 416, 238, 221, 195.

< Example  13> 1-hydroxy-1- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Pe Nil) -3- Phenylurea  Produce

Except for using phenyl isocyanate instead of benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to give the target compound (1-hydroxy-1- (4- (3-oxo-2,3-dihydro-) as a solid. 1H-inden-5-ylamino) phenyl) -3-phenylurea) was obtained (18 mg, 38%).

TLC (ethyl acetate / hexane = 1/2), Rf 0.30

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, 2H, J = 7.8 Hz), 7.27 (m, 7H), 7.11 (m, 3H), 3.12 (t, 2H, J = 5.7 Hz), 2.76 (t, 2H, J = 5.7 Hz).

MS (LC, 70 eV) m / z 374 (M + l), 357, 308, 264, 238, 195, 118.

< Example  14> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Amino ) Phenyl ) Cinnamic  Produce

Except for using cinnamoyl chloride instead of benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro) as a solid. -1H-inden-5-ylamino) phenyl) cinnamamide) (25 mg, 75%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.10

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.80 (d, 2H, J = 8.4 Hz), 7.52 (m, 4H), 7.28 (m, 4H), 6.96 (d, 2H, J = 7.2 Hz), 6.63 (d, 1H, J = 7.2 Hz), 6.44 (d, 1H, J = 14.4 Hz), 3.07 (t, 2H, J = 4.8 Hz), 2.70 (t, 2H, J = 5.7 Hz).

MS (LC, 70 eV) m / z 384 (M &lt; + &gt;), 368, 238, 130, 102, 77.

< Example  15> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Phenyl ) Preparation of cinnamic amide

Step 1: 6- (4- Nitrophenoxy ) -2,3- Dehydroindene Preparation of -1-one

6-hydroxy-2,3-dihydroinden-1-one (500 mg, 3.37 mmol) was dissolved in dimethylformamide (5 mL) and potassium carbonate (933 mg, 6.75 mmol), 1-fluoro-4- Nitrobenzene (0.36 ml, 3.37 mmol) was added sequentially and then heated / refluxed for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (10 mL), filtered, the solvent was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography to obtain a brown solid target compound (6- (4). -Nitrophenoxy) -2,3-dihydroinden-1-one) was obtained (173 mg, 58%).

TLC (ethyl acetate / hexane = 1/2), Rf 0.60.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (d, 2H, J = 5.1 Hz), 7.60 (d, 1H, J = 10.8 Hz), 7.29 (dd, 2H, J = 8.1, 2.4 Hz), 7.01 (d, 2H, J = 3.3 Hz), 3.20 (t, 2H, J = 11.4 Hz), 2.79 (t, 2H, J = 5.7 Hz).

Step 2: 6- (4- ( Hydroxyamino ) Phenoxy ) -2,3- Dehydroindene Preparation of -1-one

Except for using 6- (4-nitrophenoxy) -2,3-dihydroinden-1-one, it was carried out according to the method of step 2 of Example 10 to obtain the target compound (6- (4- (hydr Oxyamino) phenoxy) -2,3-dihydroinden-1-one) was obtained (38 mg. 96%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.25

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.28 (d, 2H, J = 8.1 Hz), 7.50 (t, 1H, J = 7.8 Hz), 7.43 (d, 2H, J = 8.4 Hz), 7.05 (d , 2H, J = 9.3 Hz), 3.15 (t, 2H, J = 3.3 Hz), 2.77 (t, 2H, J = 3.3 Hz), 2.12 (s, 1H, OH).

Step 3: N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Phenyl ) Excitement Preparation of amide

Except for using cinnamoyl chloride instead of benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro) as a solid. -1H-indene-5-yloxy) phenyl) cinnamamide) (48 mg, 67%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.20

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.80 (d, 2H, J = 4.8 Hz), 7.37 (d, 2H, J = 5.7 Hz), 7.26 (m, 5H), 7.10 (d, 2H, J = 8.4 Hz), 6.99 (t, 1H, J = 15.3 Hz), 6.66 (d, 1H, J = 2.4 Hz), 6.49 (d, 1H, J = 16.2 Hz), 3.08 (t, 2H, J = 5.7 Hz ), 2.73 (t, 2H, J = 6.0 Hz). MS (LC, 70 eV) m / z 385 (M &lt; + &gt;), 255, 239, 131, 102, 77.

< Example  16> N-hydroxy-N- (4- (3-oxo-2,3- Dihidlock -1H- Inden -5- Iloxy ) Phenyl Preparation of Benzamide

Except for using benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain a solid target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydroxy-1H-). Inden-5-yloxy) phenyl) benzamide) was obtained (38 mg, 84%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.24

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.25 (dd, 2H, J = 8.1, 7.2 Hz), 7.89 (d, 1H, J = 6.9 Hz), 7.62 (d, 1H, J = 4.2 Hz), 7.46 (m, 5H), 7.05 (m, 3H), 3.13 (t, 2H, J = 3.9 Hz), 2.77 (t, 2H, J = 2.7 Hz).

MS (LC, 70 eV) m / z 359 (M &lt; + &gt;), 343, 239, 223, 122, 104, 88, 77.

< Example  17> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Phenyl Preparation of Acetamide

Except for using acetyl chloride instead of benzoyl chloride, it was carried out in the same manner as in step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro-) as a solid. 1H-indene-5-yloxy) phenyl) cinnamamide) (24 mg, 30%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.15

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J = 4.8 Hz), 7.00 (m, 3H), 3.11 (t, 2H, J = 5.4 Hz), 2.75 (t, 2H, J = 6.0 Hz), 2.21 (s, 3H).

MS (LC, 70 eV) m / z 297 (M &lt; + &gt;), 281, 255, 239, 123, 108, 77.

< Example  18> 1-hydroxy-1- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Phenyl ) -3- Phenylurea  Produce

Except for using phenyl isocyanate instead of benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxo-2,3-dihydro-) as a solid. 1H-indene-5-yloxy) phenyl) cinnamamide) was obtained (7 mg, 74%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.10

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.24 (d, 1H, J = 13.5 Hz), 7.50 (d, 1H, J = 6.9 Hz), 7.39 (d, 1H, J = 6.9 Hz), 7.26 (m , 7H), 7.07 (d, 1H, J = 3.3 Hz), 7.01 (d, 1H, J = 8.4 Hz), 3.10 (t, 2H, J = 6.6 Hz), 2.72 (t, 2H, J = 6.0 Hz ).

MS (LC, 70 eV) m / z 374 (M &lt; + &gt;), 358, 265, 239, 119, 93, 77.

< Example  19> 3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -1-hydroxy-1- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Phenyl ) Urea  Produce

Except for using 3-trifluoro-4-chlorophenylisocyanate in place of benzoyl chloride, it was carried out in the same manner as in step 3 of Example 10 to obtain the target compound as a solid (3- (4-chloro-3- (tripuloor Methyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) urea) was obtained (28 mg, 41%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.20

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (d, 2H, J = 9.3 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.37 (m, 5H), 6.99 (d, 2H, J = 8.7 Hz), 3.14 (t, 2H, J = 5.7 Hz), 2.76 (t, 2H, J = 6.0 Hz).

MS (LC, 70 eV) m / z 476 (M &lt; + &gt;), 460, 265, 239, 221, 195, 108.

< Example  20> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Pe Nil) -1- Naphthaamide  Produce

Except for using 1-naphthoylchloride instead of benzoyl chloride, it was carried out in the same manner as in step 3 of Example 10 to obtain a solid target compound (N-hydroxy-N- (4- (3-oxo-2,3- Dihydro-1H-indene-5-yloxy) phenyl) -1-naphthaamide) was obtained (10 mg, 16%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.20

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, 2H, J = 7.8 Hz), 7.91 (d, 2H, J = 9.6 Hz), 7.55 (m, 4H), 7.35 (m, 4H), 6.90 (d, 2H, J = 8.7 Hz), 3.13 (t, 2H, J = 9.6 Hz), 2.70 (t, 2H, J = 6.0 Hz).

MS (LC, 70 eV) m / z 409 (M &lt; + &gt;), 393, 155, 127.

< Example  21> N-hydroxy-N- (4- (3-oxo-2,3- Dihydro -1H- Inden -5- Iloxy ) Pe Yl) -2- Naphthaamide  Produce

Except for using 2-naphthoyl chloride instead of benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain a solid target compound (N-hydroxy-N- (4- (3-oxo-2,3- Dihydro-1H-indene-5-yloxy) phenyl) -2-naphthaamide) was obtained (7 mg, 15%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.30

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.85 (m, 4H), 7.54 (m, 5H), 7.28 (d, 2H, J = 5.4 Hz), 7.08 (d, 2H, J = 4.8 Hz), 3.11 (t, 2H, J = 5.1 Hz), 2.73 (t, 2H, J = 6.0 Hz).

MS (LC, 70 eV) m / z 409 (M &lt; + &gt;), 393, 155, 127.

< Example  22> N-hydroxy-2- (naphthalen-1-yl) -N- (4- (3-oxo-2,3- Dihydro -1H-indene-5- Iloxy ) Phenyl ) Acetamide  Produce

Except for using 2- (naphthalen-5-yl) acetylchloride instead of benzoyl chloride, the procedure was carried out in the same manner as in Step 3 of Example 10, except that the target compound (N-hydroxy-2- (naphthalen-1-yl) was obtained. ) -N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) acetamide) was obtained (5.6 mg, 18%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.40.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 (d, 1H, J = 6.9 Hz), 7.81 (m, 4H), 7.53 (m, 5H), 7.26 (d, 2H, J = 5.4 Hz), 7.07 (d, 2H, J = 5.4 Hz), 3.78 (s, 2H), 3.11 (t, 2H, J = 5.7 Hz), 2.74 (t, 2H, J = 6.3 Hz).

MS (LC, 70 eV) m / z 423 (M &lt; + &gt;), 407, 239, 141, 115.

< Example  23> 4- (2- Bromo -4-((4- Chloro -3- ( Tripuloorphenyl ) Phenyl ) (Hydroxy) Cabamo ) Phenoxy ) -N- Methylpicolinamide  Produce

Step 1: ethyl 4- (2- ( Methylcarbamoyl Pyridine-4- Iloxy ) Benzoate  Produce

Ethyl-4-hydroxybenzoate (1 g, 6.01 mmol) and diethylene glycol methyl ether (2 mL) were added to a pressure tube reactor and stirred at 160 ° C. After completion of the reaction, the reaction mixture was cooled to room temperature, volatiles were removed by distillation under reduced pressure, extracted with ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL), dried over magnesium sulfate, purified by column chromatography, and purified. The desired compound as a yellow solid (ethyl 4- (2- (methylcarbamoyl) pyridin-4-yloxy) benzoate) was obtained (530 mg, 29%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (d, J = 5,4 Hz, 1H), 8.12 (dd, J = 9.0, 0.6 Hz, 2H), 8 (brs. 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.02-6.99 (m, 1H), 4.4 (q, J = 6.3 Hz, 2H), 3.02 (dd, J = 5.1, 0.6 Hz, 3H), 1.41 (t, J = 9.0 Hz, 3H).

LC Mass (M &lt; + &gt;, 301.24).

Step 2: 4- (2- ( Methylcarbamoyl Pyridine-4- Iloxy Production of benzoic acid

Dissolve ethyl 4- (2- (methylcarbamoyl) pyridin-4-yloxy) benzoate (530 mg, 1.76 mmol) in trifluoroacetic acid: methyl alcohol: water (2 mL: 2 mL: 2 mL), and Lithium (423 mg, 17.6 mmol) was added and stirred at room temperature. After the reaction was completed, the volatiles were removed, water (5 mL) was added, and the precipitated solid was filtered with a buffer solution (pH = 6) to obtain a target compound as a white solid (4- (2- (methylcarbamoyl) pyridine). -4-yloxy) benzoic acid) was obtained (370 mg, 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.47 (d, J = 5,4 Hz, 1H), 8.12 (d, J = 8.7 Hz, 3H), 8.32 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.1 (dd, J = 5.7, 2.4 Hz, 1H), 4.65 (brs, 1H), 3.04 (d, J = 5.1 Hz, 3H).

Step 3: 2,5- Dioxopyrrolidine -1-yl 4- (2- ( Methylcarbamoyl Pyridine-4- Iloxy ) Benzoate  Manufacturing

Dissolve 4- (2- (methylcarbamoyl) pyridine-4-hydroxy) benzoic acid (100 mg, 0.37 mmol), n-hydroxy succinimide (42 mg, 0.37 mmol) in tetrahydrofuran (2 mL) And diisopropyl carmoimide (56 µl, 0.37 mmol) was slowly added dropwise at 0 ° C, and the mixture was stirred for 4 hours. Upon completion of the reaction, the crystals were recrystallized and the precipitated solid was filtered and the desired compound (5-dioxopyrrolidin-1-yl 4- (2- (methylcarbamoyl) pyridin-4-yloxy) benzoate) as a white solid was obtained. Was obtained (150 mg, 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (d, J = 5,4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 2.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 5.7, 2.7 Hz, 1H), 3.49 (d, J = 4.5 Hz, 2H), 2.73 (s, 3H), 1.15 (d, J = 5.7 Hz, 2H).

Step 4: 4- (2- Bromo -4-((4- Chloro -3- ( Tripulormethyl ) Phenyl ) (Hydroxy) Cabamo ) Phenoxy ) -N- Methylpicolinamide  Produce

2,5-dioxopyridin-1-yl 4- (2- (methoxycamamoyl) pyridin-4-yloxy) benzoate (150 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL) and 0 ° C. Triethylamine (56 μl, 0.41 mmol) was added below, followed by the dropwise addition of N- (4-chloro-3- (tripulormethyl) phenyl) hydroxyamine (68 mg, 0.33 mmol), followed by stirring at room temperature. I was. Upon completion of the reaction, the volatiles were removed and purified by column chromatography to give the title compound as a light brown solid (4- (2-bromo-4-((4-chloro-3- (tripulormethyl) phenyl) (hydroxy) ) Carbamoyl) phenoxy) -N-methylpicolinamide) (81 mg, 41%).

¹ H NMR (300 MHz, CDCl 3) δ 9.09 (s, 1H), 8.48 (d, J = 5,4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8 (brs, 1H), 7.78 (d, J = 2.7 Hz, 1H), 7.48-7.44 (m, 2H), 7.26-7.2 (m, 2H), 7.07 (dd, J = 5.4, 2.1 Hz, 1H), 3.03 (d, J = 5.1 Hz, 3H).

< Example  24> 4- (4- (3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -3- Hydroxyurido ) Phenoxy ) -N- Of methoxypicolinamide  Produce

Step 1: N- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) Of hydroxylamine  Produce

Dissolve 1-chloro-4-nitro-2- (tripulorurmethyl) benzene (1 g, 4.43 mmol) in acetone (60 mL), add saturated aqueous ammonium chloride solution (3 mL) at 0 ° C to 10 ° C, and After the solid precipitated, water (3 mL) was added and zinc (600 mg, 9.3 mmol) was added slowly. After the reaction was completed, the mixture was distilled under reduced pressure at 0 ° C. to 10 ° C. to remove volatiles, ice water and dichloromethane were added, and the material which was not dissolved in the resulting solution was filtered through celite. The filtrate was dried over sodium sulfate, and the resulting solution was crystallized to give a white solid target compound (N- (4-chloro-3- (tripulormethyl) phenyl) hydroxylamine) (700 mg, 75% ).

Step 2: N- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -N- Of hydroxybenzamide  Produce

N- (4-chloro-3- (trifulluormethyl) phenyl) hydroxylamine (1.4 g, 6.62 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine (738 μL, 5.3 mmol at 0 ° C.). ) Was added dropwise, and benzoyl chloride (615 μl, 5.30 mmol) was added and stirred. When the reaction was completed, the volatiles were removed and then recrystallized to obtain the target compound (N- (4-chloro-3- (tripulormethyl) phenyl) -N-hydroxybenzamide) as a white solid (1.4 g, 67%).

¹ H NMR (300 MHz, CDCl3) δ 9.1 (brs, 1H), 8.11 (dd, J = 8.4, 1.2 Hz, 2H), 7.69-7.74 (m, 1H), 7.55-7.5 (m, 4H), 7.46 ˜7.44 (m, 1 H), 7,22 (dd, J = 8.4, 2.7 Hz, 1 H).

Step 3: N- ( Benzoyloxy ) -N- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) Benzamide  Produce

N- (4-chloro-3- (tripuloormethyl) phenyl) -N-hydroxybenzamide (700 mg, 2.22 mmol) was dissolved in dimethylformamide (2 mL) and potassium carbonate (618 mg, 4.44 mmol) ), Potassium iodide (2 mg) was added, and benzyl bromide (394 µl, 3.33 mmol) was added and stirred at 0 ° C. After completion of the reaction, the reaction mixture was cooled to room temperature, distilled under reduced pressure to remove volatiles, extracted with ethyl acetate (10 mL) and water (5 mL), dried over magnesium sulfate, purified by column chromatography, and purified of yellow oil. The desired compound (N- (benzoyloxy) -N- (4-chloro-3- (tripulormethyl) phenyl) benzamide) was obtained (324 mg, 36%).

¹ H NMR (300 MHz, CDCl3) δ 8.08 (d, J = 6.9 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.6-7.57 (m, 1H), 7.48-7.2 (m, 10H ), 4. 7 (s, 1 H).

Step 4: O -Benzyl-N- (4- Chloro -3- ( Trifluoromethyl ) Phenyl ) Of hydroxylamine  Produce

N- (benzyloxy) -N- (4-chloro-3- (trifluoromethyl) phenyl) benzamide (250 mg, 0.62 mmol) was dissolved in dimethylformamide (2 mL), and hydrazine hydrate (250 μl) was added. After dropwise addition, the mixture was stirred at room temperature. At the end of the reaction, the mixture was extracted with ethyl acetate (10 mL) and water (5 mL), dried over magnesium sulfate, purified by column chromatography to give the title compound ( O -benzyl-N- (4-chloro-) as a yellow solid. 3- (trifluoromethyl) phenyl) hydroxylamine) was obtained (73 mg, 39%).

¹ H NMR (300 MHz, CDCl 3) δ 9.4 (s, 1H), 7.54 to 7.48 (m, 2H), 7.4 to 7.26 (m, 2H), 4.6 (s, 2H).

LC Mass (M &lt; + &gt;, 302.2).

Step 5: 4- (4- (3- (4- Chloro -3- ( Tripulormethyl ) Phenyl ) -3- Hydroxyureido ) Phenoxy) -N- Methylpicolinamide   Produce

Dissolve 4- (2- (methylcarbamoyl) pyridin-4-yloxy) benzoic acid (30 mg, 0.11 mmol) in benzene (1 mL) and diphenylphosphoryl azide (24 μl, 0.11 mmol), triethylamine (15 μl, 0.11 mmol) was added thereto, and the resulting mixture was heated and stirred at 60 ° C. for 1 hour. To this was added O -benzyl-N- (4-chloro-3- (tripuloormethyl) phenyl) hydroxylamine (33 mg, 0.11 mmol) obtained in step 4 in benzene (1 mL) and added dropwise thereto. , Heated and stirred at 60 ° C. At the end of the reaction, the volatiles were removed by distillation under reduced pressure, and purified by column chromatography to give the title compound as a white solid (4- (4- (3- (4-chloro-3- (trifullumethyl) phenyl)- 3-hydroxyureido) phenoxy) -N-methylpicolinamide) was obtained (1.7 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.3 7 (d, J = 5.4 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.7, 2.7 Hz, 1H), 7.6-7.53 (m, 3H), 7.43 (d, J = 8.7 Hz, 1H), 7-6.98 (m, 3H), 3.02 (s, 3H).

< Example  25> 6- (4- ( Hydroxyamino ) Phenoxy ) Isoindoline Preparation of -1-one

Step 1: N-hydroxy-N- (4- (3- Oxoindolin -5- Iloxy ) Phenyl ) Benzamide 6 - Bromo Preparation of Indolin-1-one

Zinc powder (1.82 g, 27.85 mmol) was dissolved in water (10 ml) and mercury chloride (II) (319 mg, 2.67 mmol) was added thereto, followed by addition of aqueous hydrochloric acid solution (240 μl), followed by stirring for 10 minutes. After removing the water layer, the zinc amalgam was washed with water and ethanol and ethanol (50 ml) was added and stirred. 5-Bromoindolein-1,3-dione (100 mg, 0.44 mmol) was added, concentrated aqueous hydrochloric acid solution (60 μl) was added, and the mixture was heated to reflux for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and ethyl acetate (100 mL) was added thereto, followed by washing with saturated sodium bicarbonate solution (20 mL) and brine (10 mL). The residue obtained by drying, filtration and removal of the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (N-hydroxy-N- (4- (3-oxoindolin-5-yloxy) phenyl as a white solid). ) Benzamide6-bromoindolin-1-one) was obtained (96 mg, 96%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.35

¹ H NMR (300 MHz, CDCl ₃ ) d 7.95 (s, 1H), 7.84 (d, 1H, J = 10.2 Hz), 7.73 (d, 1H, J = 3.0 Hz), 3.47 (m, 2H).

MS (LC, 70 eV) m / z 212 (M &lt; + &gt;), 211, 130, 102, 74.

Step 2: 6- Hydroxyisoindolin Preparation of -1-one

Dissolve 6-6-hydroxyisoindolin-1-one (100 mg, 0.47 mmol) in water / dioxane (2 mL), potassium hydroxide (40 mg, 0.71 mmol), dibenzylacetylacetone palladium (2 mg, 2 mol%), and xantphos (8 mg, 8 mol%) were added in order, and then reacted at 100 ° C. for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography to obtain the title compound (6-hydroxyisoindolin-1-one) as a white solid (38 mg, 40%). ).

TLC (ethyl acetate / hexane = 1/2) Rf 0.35.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (m, 2H), 7.18 (d, 1H, J = 14. 1 Hz), 3.83 (m, 2H).

MS (LC, 70 eV) m / z 149 (M &lt; + &gt;), 105, 87, 71.

Step 3: 6- (4- Nitrophenoxy ) Isoindoline Preparation of -1-one

6-hydroxyisoindolin-1-one (37 mg, 0.25 mmol) was dissolved in dimethylformamide (1 mL), potassium carbonate (69 mg, 0.50 mmol), 1-fluoro-4-nitrobenzene (0.027 ml, 0.25 mmol) was added sequentially, followed by heating to reflux for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (10 mL), dried, filtered, and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography to obtain the title compound as a brown solid (6- (4- Nitrophenoxy) isoindolin-1-one) was obtained (28 mg, 77%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.80.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (d, 3H, J = 3.3 Hz), 7.26 (m, 4H), 3.12 (s, 2H).

Step 4: 6- (4- ( Hydroxyamino ) Phenoxy ) Isoindoline Preparation of -1-one

Except for using 6- (4-nitrophenoxy) isoindolin-1-one, it was carried out in the same manner as in Step 1 of Example 24 to obtain the target compound (6- (4- (hydroxyamino) phenoxy) Isoindolin-1-one) (35 mg, 100%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.20.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.28 (d, 2H, J = 3.3 Hz), 7.22 (m, 5H), 3.10 (s, 2H), 2.11 (s, 1H, OH).

MS (LC, 70 eV) m / z 256 (M &lt; + &gt;).

Step 5: N-hydroxy-N- (4- (3- Oxoisoindolin -5- Iloxy ) Phenyl ) Benzamide  Produce

Except for using benzoyl chloride, it was carried out in the same manner as in Step 3 of Example 10 to obtain the target compound (N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy) phenyl) benz as a solid. Amide) (18 mg, 39%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.10.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (dd, 2H, J = 7.2, 7.2 Hz), 7.94 (d, 2H, J = 8.7 Hz), 7.55 (m, 4H), 7.20 (m, 4H) , 4.05 (t, 2H, J = 6.9 Hz).

MS (LC, 70 eV) m / z 360 (M &lt; + &gt;).

< Example  26> N-hydroxy-N- (4- (3- Oxoisoindolin -5- Iloxy ) Phenyl ) Acetamide  Produce

Except for using acetyl chloride instead of benzoyl chloride, the process was carried out in the same manner as in Step 3 of Example 10 to obtain a solid target compound (N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy). ) Phenyl) acetamide) was obtained (8 mg, 30%).

TLC (ethyl acetate / hexane = 1/2) Rf 0.05.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.56 (d, 2H, J = 8.7 Hz), 7.07 (m, 4H), 3.39 (m, 2H), 2.24 (s, 3H) .

MS (LC, 70 eV) m / z 298 (M &lt; + &gt;).

< Experimental Example > MTT  Determination of A375P Cell Line (Melanoma) Proliferation Inhibition Activity by Activity Screening Method

A375P cell lines purchased from ATCC were incubated at 37 ° C. in DMEM culture [including 10% FBS, 1% penicillin / streptomycin] in the presence of 5% CO ₂ . Cultured A375P cell lines were taken with 0.05% trypsin-0.02% EDTA and 5 × 10 3 cells per well were placed in 96-well plates. MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] activity screening method (CellTiter 96 Assay, Promega) was used to measure cell viability as follows. 15 μl of dye per well was added and incubated for 2 hours, and then 100 μl of stop solution was treated and absorbance was measured 24 hours later. Compounds were treated one day after plating. When the compound is treated, a 10 mM stock is prepared, and serial dilution is performed in 1/3 of dimethyl sulfoxide (DMSO) to prepare a test material plate at 12 points. Add (final concentration DMSO 0.5%). Reading at 590 nm wavelength using EnVision2103, IC ₅₀ values were calculated using GraphPad Prism 4.0 software.

The example compound inhibits proliferation of A375P, a human melanoma cell line overexpressed with B-raf-V600E mutant, with a GI ₅₀ range of 0.001-10 μM.

Example A375P Cell Line Proliferation
Inhibitory activity (GI ₅₀ , μM) Example A375P Cell Line Proliferation
Inhibitory activity (GI ₅₀ , μM) One > 100 15 6.95 2 2.26 16 > 50 3 5.73 17 38.4 4 2.58 18 14.5 5 > 100 19 4.7 6 5.28 20 25.3 7 1.52 21 9.57 8 25.4 22 1.72 9 1.37 23 > 100 10 > 10 24 4.77 11 > 10 25 > 20 12 3.58 26 > 20 13 <2.57 14 28.4

As shown in Table 1 above, the GI 50 of the compounds according to the invention was measured at low values in μM, in particular Examples 2, 3, 4, 6, 7, 9, 12, 13, 19, 21, 22, The GI ₅₀ of the compound of 24 showed a low value of 10 μM or less, of which the GI ₅₀ of the compound of Example 9 showed a very low value of 2 μM or less. From this, it can be seen that the hydroxyxamic acid derivative or the pharmaceutically acceptable salt thereof according to the present invention has an excellent proliferation inhibitory effect on the A375P cell line.

< Experimental Example  2> Western  Blat ( Western Blotting )

RIPA buffer solution (50 mM Tris, pH 7.4, 150 mM NaCl), including phosphatase inhibitors (Phosphatase Inhibitor Cocktail I & II) and protease inhibitors (Complete, Mini, EDTA-free; Roche Applied Science) , 1 mM EDTA, 1% NP-40, 0.25% sodium deoxycholate) were used to lyse the A375P cell line and centrifuged at 13000 rpm for 30 minutes at 4 ° C. Total protein was stained with Bio-Rad reagent (Bio-Rad # 500-0006) and quantified in comparison to positive control BSA. A 12% gel was made using acrylamide 30%, 1.5 M Tris (pH 8.8), 10% SDS solution, 10% APS solution, TEMED. 100 ug of protein per lane of gel was loaded and then sodium dodecyl sulphate pullyacrylamide gel electrophoresis (SDS-PAGE, 250 mM Tris base, 2.5 M Glycine, 0.1% SDS, 140 V, 2 hours electrophoresis) Proteins were separated and subjected to nitrocellulose filter (2 hours run at 200 mA). It was reacted with antibody [Rabbit anti-Map Kinase (Zymed # 61-7400) and phosphor-p44 / 42 MAP kinase (Thr202 / Tyr204) (Cell Signaling # 9101)] at 4 ° C. for 1 day. And it was washed four times for 5 minutes with TBST buffer solution containing 0.05% tween20. The secondary antibody [anti-rabbit IgG (Amersham # NA934V)] was reacted at room temperature for 1 hour and then washed in the same manner. Protein band identification was performed using imaging equipment (Gelliance), as shown in FIG.

Examples of formulations for the composition of the present invention are illustrated below.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Sanje  Produce

2 g of a novel hydroxamic acid derivative of formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of tablets

100 mg of a novel hydroxamic acid derivative of formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-3 > Preparation of capsules

100 mg of a novel hydroxamic acid derivative of formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Preparation of Injection Solution

10 μg / ml of a novel hydroxyxamic acid derivative of formula (1)

Until dilute hydrochloric acid BP pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the hydroxyxamic acid derivative according to the invention in an appropriate volume of sodium chloride BP for injection, adjust the pH of the resulting solution to pH 3.5 with dilute hydrochloric acid BP, and adjust the volume with sodium chloride BP for injection and sufficiently Mixed. The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

Claims (16)

Hydroxamic acid derivatives represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In Formula 1,
R ¹ is hydrogen; Halogen or -OR ⁴ , wherein R ⁴ is a 5-12 membered heteroaryl containing an N atom in the ring;
R ² is hydrogen, —OR ⁵ , or —NHR ⁵ , wherein R ⁵ is unsubstituted or substituted with C; C ₅ to C ₈ cycloalkyl C ₅ to C ₁₂ aryl, or unsubstituted or substituted with = O 5-8 membered heterocycloalkyl C ₅ -C ₁₂ aryl including N atoms in the ring;
R ³ is unsubstituted C ₁ -C ₁₀ straight or branched alkyl; C ₆ -C ₁₅ aryl substituted with one or more substituents selected from the group consisting of unsubstituted or halogen, C ₁ -C ₄ straight or branched alkyl substituted with one or more halogens, and C ₁ -C ₄ straight or branched alkoxy; C ₆ -C ₁₅ aryl C ₁ -C ₁₀ alkyl substituted with one or more substituents selected from the group consisting of C ₁ -C ₄ straight or branched alkoxy, or NHR _6, wherein R ₆ is unsubstituted or halogen, C ₁ to C ₄ straight or branched alkyl, C ₁ to C ₄ straight or branched alkyl substituted with one or more halogens, C ₁ to C ₄ straight or branched alkoxy, and

C ₆ ~ C ₁₅ aryl substituted with one or more substituents selected from the group consisting of
Wherein R ¹ and R ² are not simultaneously hydrogen, R ² is not hydrogen if R ¹ is halogen.
The method of claim 1,
R ¹ is hydrogen, F, Cl, Br,

, or

ego;
R ² is hydrogen,

,

,

or

ego;
R ³ is Me,

,

,

,

,

,

,

,

,

,

And

Novel hydroxamic acid derivative or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of.
delete The novel hydroxamic acid derivative represented by Formula 1 is
1) preparation of 4- (tripuloormethyl) -N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;
2) N-hydroxy-4-methoxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;
3) 4-pulluor-N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;
4) 2,4-dichloro-N-hydroxy-N- (3- (pyridin-3-yloxy) phenyl) benzamide;
5) 3- (4-chloro-3- (tripuloormethyl) phenyl) -1-hydroxy-1- (3- (pyridine-3 -yloxy) phenyl) urea;
6) 1-hydroxy-3- (4-methoxyphenyl) -1- (3- (pyridin-3-yloxy) phenyl) urea;
7) 1-hydroxy-3-phenyl-1- (3- (pyridin-3-yloxy) phenyl) urea;
8) 3- (4-chloro-3- (tripuloorphenyl) phenyl) -1-hydroxy-1- (3- (pyridin-3-yloxy) phenyl) urea;
9) 1-hydroxy-3-phenyl-1- (3- (pyridin-4-yloxy) phenyl) urea;
10) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) benzamide;
11) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) acetamide;
12) 3- (4-chloro-3- (tripuloormethyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino ) Phenyl) urea;
13) 1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) -3-phenylurea;
14) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-inden-5-ylamino) phenyl) cinnamamide;
15) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) cinnamicamide;
16) N-hydroxy-N- (4- (3-oxo-2,3-dihydroxy-1H-indene-5-yloxy) phenyl) benzamide;
17) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl)
Acetamide;
18) 1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -3-
Phenylurea;
19) 3- (4-chloro-3- (trifullumethyl) phenyl) -1-hydroxy-1- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy ) Phenyl) urea;
20) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -1-
Naphthaamide;
21) N-hydroxy-N- (4- (3-oxo-2,3-dihydro-1H-indene-5-yloxy) phenyl) -2-
Naphthaamide;
22) N-hydroxy-2- (naphthalen-1-yl) -N- (4- (3-oxo-2,3-dihydro-1H-inden-5-yloxy) phenyl) acetamide;
23) 4- (2-bromo-4-((4-chloro-3- (tripuloorphenyl) phenyl) (hydroxy) carbamoyl) phenoxy) -N-methylpicolinamide;
24) 4- (4- (3- (4-chloro-3- (tripoolormethyl) phenyl) -3-hydroxyurido) phenoxy) -N-methoxypicolinamide;
25) N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy) phenyl) benzamide; And
26) Novel hydroxyxamic acid derivatives or pharmaceutically acceptable thereof, which are selected from the group consisting of N-hydroxy-N- (4- (3-oxoisoindolin-5-yloxy) phenyl) acetamide. salt.
As shown in Scheme 1 below,
Preparing a compound of Chemical Formula 3 by hydrolyzing a compound of Chemical Formula 2 as a starting material (Step 1);
Preparing a compound of formula 5 by condensing the compound of formula 3 prepared in step 1 with the compound of formula 4 (step 2); And
A method for preparing the hydroxyxamic acid derivative of claim 1 comprising the step (step 3) of preparing a compound of Formula 1a by addition reaction of the compound of Formula 5 prepared in Step 2 with a compound of Formula 6:

[Reaction Scheme 1]

(In Scheme 1,
Formula 1a is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
As shown in Reaction Scheme 2 below,
Reacting a compound of formula 7 with a compound of formula 8 to prepare a compound of formula 9 (step 1);
Preparing a compound of formula 10 by hydrolyzing the compound of formula 9 prepared in step 1 (step 2);
Preparing a compound of formula 12 by condensing the compound of formula 10 prepared in step 2 with a compound of formula 11 (step 3); And
A method for preparing the hydroxamic acid derivative of claim 1 comprising the step (step 4) of preparing a compound of Formula 1b by condensing a compound of Formula 12 prepared in Step 3 with a compound of Formula 13:

[Reaction Scheme 2]

(In Scheme 2, Formula 1b is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
As shown in Scheme 3 below,
Condensing the compound of Formula 14 to produce a compound of Formula 15 (step 1);
Preparing a compound of formula 16 by benzylating the compound of formula 15 prepared in step 1 (step 2);
Preparing a compound of formula 17 by reducing a compound of formula 16 prepared in step 2 (step 3); And
A method for preparing the hydroxamic acid derivative of claim 1 comprising the step of condensing a compound of Formula 17 prepared in Step 3 with a compound of Formula 18 to prepare a compound of Formula 1c:

[Reaction Scheme 3]

(In Scheme 3, Formula 1c is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
As shown in Scheme 4,
Coupling a compound of Formula 19 with a compound of Formula 20 to prepare a compound of Formula 21 (step 1);
Preparing a compound of Chemical Formula 22 by reducing a compound of Chemical Formula 21 prepared in Step 1 (Step 2); And
A method for preparing the hydroxyxamic acid derivative of claim 1 comprising the step (step 3) of preparing a compound of Formula 1d by addition reaction of a compound of Formula 22 prepared in Step 2 with a compound of Formula 23:

[Reaction Scheme 4]

(In Scheme 4, Formula 1d is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
As shown in Scheme 5,
Preparing a compound of formula 26 by reacting the compound of formula 24 with the compound of formula 25 (step 1);
Preparing a compound of formula 27 by reducing the compound of formula 26 prepared in step 1 (step 2); And
A method for preparing the hydroxyxamic acid derivative of claim 1 comprising the step (step 3) of preparing a compound of Formula 1e by adding a compound of Formula 27 prepared in Step 2 with a compound of Formula 28:

Scheme 5

(In Scheme 5, Formula 1e is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
As shown in Scheme 6,
Preparing a compound of Chemical Formula 30 by reducing a compound of Chemical Formula 29 (step 1);
Preparing a compound of Chemical Formula 31 by performing a substitution reaction of the compound of Chemical Formula 30 prepared in Step 1 (step 2);
Preparing a compound of Chemical Formula 33 by coupling a compound of Chemical Formula 31 and a compound of Chemical Formula 32 prepared in Step 2 (Step 3);
Preparing a compound of formula 34 by reducing the compound of formula 33 prepared in step 3 (step 4); And
A method for preparing the hydroxyxamic acid derivative of claim 1, comprising the step (step 5) of preparing a compound of Formula 1f by adding a compound of Formula 34 and a compound of Formula 35 prepared in Step 4;

[Reaction Scheme 6]

(In Scheme 6, Formula 1f is a derivative of Formula 1 or a pharmaceutically acceptable salt thereof.)
A pharmaceutical composition for preventing or treating abnormal cell growth diseases, comprising the novel hydroxamic acid derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition for preventing or treating abnormal cell growth disease according to claim 11, wherein the novel hydroxyxamic acid derivative or pharmaceutically acceptable salt thereof inhibits protein kinase to inhibit cell proliferation.
The pharmaceutical composition of claim 12, wherein the protein kinase is selected from the group consisting of b-raf, Fak, and Fms.
The method of claim 11, wherein the abnormal cell growth disease is gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, A pharmaceutical composition for preventing or treating abnormal cell growth diseases, characterized in that it is selected from the group consisting of parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematologic cancer, lymphoma, psoriasis and fibroadenomas.
15. The pharmaceutical composition of claim 14, wherein the hematologic cancer is selected from the group consisting of leukemia, multiple myeloma and myelodysplastic syndrome.
The pharmaceutical composition for preventing or treating abnormal cell growth disease according to claim 14, wherein the lymphoma is Hodgkin's disease or non-Hodgkin's lymphoma.

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