KR20010101732A - Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase(mmp) inhibitors/tnf-alpha converting enzyme(tace) inhibitors - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

Formula I

Wherein R ₁ is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms alkyl, or -C ₄ -C ₈ - cycloalkyl and heteroalkyl; R ₂ and R ₃ are hydrogen, alkyl of 1-6 carbon atoms, -CN or -CCH; R ₈ , R ₉ , R ₁₀ and R ₁₁ are independently selected from hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, alkyl of 1-18 carbon atoms, An alkenyl having 1 to 18 carbon atoms and an alkynyl having 2 to 18 carbon atoms, provided that one of R ₈ and R ₉ , R ₉ and R ₁₀ or a pair of R ₁₀ and R ₁₁ is a carbon atom or Together with the carbon atoms form a cycloalkyl ring of 3-6 carbon atoms, or a -C ₄ -C ₈ -cycloheteroalkyl ring); R ₁₂ is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, or alkyl of 1-6 carbon atoms; A, X is O, S, SO, SO ₂ , NR ₇ or CH ₂ ; Y is aryl or heteroaryl, provided that A and X do not bond to adjacent Y atoms; n is 0-2. This is useful for the treatment of arthritis, tumor metastasis, tissue ulcers, abnormal wound healing, dental disease, skeletal disease, diabetes (insulin resistance) and HIV infection.

Description

ALKYNYL CONTAINING HYDROXAMIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE (WO / 2006/035514) USE THEREOF AS ALKYNYL CONTAINING HYDROXAMIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MATRIX METALLOPROTEINASE (MMP) INHIBITORS / TNF-ALPHA CONVERTING ENZYME (TACE) INHIBITORS}

Matrix metalloproteinases (MMPs) are enzymes involved in the pathological breakdown of connective tissue and basement membrane. These zinc-containing endopeptidases are composed of several downstream enzymes including collagenase, stromelysin and gelatinase. Of these classes, gelatinase was the most closely related to the proliferation and spread of tumors. The level of expression of gelatinase is elevated in malignant tumors, and gelatinase is known to destroy the basal membrane and cause tumor metastasis. Angiogenesis, which is required for the proliferation of solid tumors, has also recently been shown to have gelatinase components in its pathology. There is also evidence that gelatinase is involved in plaque destruction associated with atherosclerosis. Other manifestations mediated by MMPs include but are not limited to restenosis, MMP-mediated osteopenia, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, osteoarthritis, corneal ulceration, abnormal wound healing, Aortic disease, degenerative cartilage damage following traumatic joint wounds, dehydration of the nervous system, cirrhosis, gangrene disease, premature destruction of fetal membranes, inflammatory bowel disease, dermatomyositis, age related macular degeneration, diabetic retinopathy, proliferative vitreous retina Diabetic retinopathy, ocular inflammation, keratoconus, sgrenic syndrome, myopia, ocular tumor, ocular angiogenesis / neovascularization, and corneal transplant rejection. Recent reports include (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4 (1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5 (2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5 (12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8 (3): 281-259.

TNF-α converting enzyme (TACE) catalyzes the formation of TNF-α from membrane-bound TNF-α precursor proteins. TNF-α is a well-documented anti-tumor positive [Old, L. Science, 1985, 230, 630.], as well as rheumatoid arthritis [Shire, M. G .; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8 (5), 531; Grossman, J. M .; Brahn, E. J. Women's Health 1997, 6 (6), 627; Isomaki, P .; Punnonen, J. Ann. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55 (5), 613], septic shock [Mathison, et al. J. Clin. Invest. 1988, 81, 1925; Miethke, et al., J. Exp. Med. 1992, 175, 91], transplant rejection [Piguet, P. F .; Grau, G. E .; et al. J. Exp. Med. 1987, 166, 1280], scleroderma [Beutler, B .; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505], anorexia, inflammation [Ksontini, R; Mackay, S. L. D .; Moldawer, L.L.Arch. 1998, 133, 558], hemorrhagic heart failure [Packer, M. Circulation, 1995, 92 (6), 1379; Ferrari, R .; Bachetti, T .; et. al. Circulation, 1995, 92 (6), 1479], reperfusion injury after ischemia, inflammatory diseases of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G.S .; Shargill, N.S .; Spiegelman, B. M .; et al. Science, 1993, 259, 87] and HIV infection [Peterson, P. K .; Gekker, G .; et al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujilo, J .; Lopez-Soriano, F.J. Argiles, J.M.M. Res. Reviews, 1995, 15 (6), 533]. For example, irradiation with anti-TNF- [alpha] antibodies and transgene animals has been shown to inhibit the progression of arthritis by blocking TNF- [alpha] formation [Rankin, E.C .; Choy, E. H .; Kassimos, D .; Kingsley, G. H .; Sopwith, A. M .; Isenberg, D. A .; Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au197-M2Z]. This observation has recently been extended to humans and is described in the literature "TNF-α in Human Diseases", Current Pharmaceutical Design, 1996, 2, 662.

Small molecule inhibitors of TACE are expected to have potential in treating various diseases. While various TACE inhibitors are known, many of these molecules are peptides and quasi-peptides that are experiencing biofeedback and drug bio-response problems. In addition, many of these molecules, which are potent inhibitors of matrix metalloproteinases, particularly MMP-1, are non-selective. Inhibition of MMP-1 (collagenase 1) has been suggested to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20]. TACE nonpeptide inhibitors of long-acting, selective, oral bioavailability are highly desirable for the treatment of the diseases described above.

Sulfonated hydroxamic acid inhibitors of MMPs of formula I are known [Burgess, L. E .; Rizzi, J. P .; Rawson, D.J.Eur Patent Appl. 818442. Groneberg, R. D .; Neuenschwander, K. W .; Djuric, S. W .; McGeehan, G. M .; Burns, C. J .; Condon, S. M .; Morrissette, M. M.; Salvino, J. M .; Scotese, A. C .; Ullrich, J. W. PCT Int. Appl. WO 97/24117. Bender, S. L .; Broka, C.A .; Campbell, J.A .; Castelhano, A. L .; Fisher, L. E .; Hendricks, R.T .; Sarma, K. Eur. Patent Appl. 780386. Venkatesan, A. M .; Grosu, G.T .; Davis, J. M .; Hu, B .; O.Dell, M. J. PCT Int. WO 98/38163]. A typical example of this class of MMP inhibitors is RS-130830, shown below.

Within the sulfone-hydroxanic acid class of MMP inhibitors, the linker between the sulfone and the hydroxamic acid moiety is extended to three carbons (I, n = 2) with little loss in efficacy [Barta, T. E .; Becker, D.P .; Villamil, C.I .; Freskos, J. N .; Mischke, B. V .; Mullins, P. B .; Heintz, R. M .; Getman, D.P .; McDonald, J. J. PCT Int. Appl. WO 98/39316. McDonald, J. J.; Barta, T. E .; Becker, D.P .; Bedell, L. J .; Rao, S. N .; Freskos, J. N .; Mischke, B.V. PCT Int. Appl. WO 98/38859].

Piperidine sulfone hydrox- y acid II (n = 1) has been reported [Becker, D. P .; Villamil, C.I .; Boehm, T. L .; Getman, D.P .; McDonad, J. J.; DeCrescenzo, G.A.PCT Int. Appl. WO 98/39315]. A similar piperidine derivative (II, n = 0) in which methylene is deleted connecting the piperidine ring to the sulfone has been reported [Venkatesan, A. M .; Grosu, G.T .; Davis, J. M .; Baker, J. L. PCT Int. Appl. WO 98/37877].

Sulfone-hydroxamic acid III is known in which the hydroxyl group is located in the alpha position of the hydroxamic acid [Freskos, J. N .; Boehm, T. L .; Mischke, B. V .; Heintz, R. M .; McDonald, J. J.; DeCrescenzo, G.A .; Howard, S.C. PCT Int. Appl. WO 98/39326. Robinson, R. P. PCT Int. Appl. WO 98/34915].

Sulfone-based MMP inhibitors of formula IV using thiols as zinc chelators have been reported [Freskos, J. N .; Abbas, Z.S .; DeCrescenzo, G.A .; Getman, D.P .; Heintz, R. M .; Mischke, B. V .; McDonald, J.J. PCT Int. Appl. WO 98/03164].

Stromelysin inhibitors with the formula V are known [Shuker, S.B .; Hajduk, P.J .; Meadows, R.P .; Fesik, S.W. Science, 1996, 274, 1531-1534. Hajduk, P.J .; Sheppard, G .; Nettesheim, D. G .; Olejniczak, E.T .; Shuker, S. B .; Meadows, R.P .; Steinman, D. H .; Carrera, Jr., G. M .; Marcotte, P. A .; Severin, J .; Walter, K .; Smith, H .; Gubbins, E .; Simmer, R .; Holzman, T. F .; Morgan, D. W .; Davidsen, S. K .; Summers, J.B .; Fesik, S.W.J.am. Chem. Soc. 1997, 119, 5818-5827. Olejniczak, E.T .; Hajduk, P.J .; Marcotte, P. A .; Nettesheim, D. G .; Meadows, R.P .; Edalji, R .; Holzman, T. F .; Fesik, S.W. J. Am. Chem. Soc. 1997, 119, 5828-5832. Fesik, S. W .; Summers, J.B .; Davidsen, S. K .; Sheppard, G.S .; Steinman, D. H .; Carrera, G. M .; Florjancic, A .; Holms, J. H. PCT Int. Appl. WO 97/18188].

Salah et al., Liebigs Ann. Chem. 195, (1973) describes some aryl substituted thio and aryl substituted sulfonylacetohydroxamic acid derivatives of formula (I). This compound was prepared to study the Mannich reaction. Thereafter, its bactericidal activity was tested.

Some sulfonic carboxylic acids are described in U.S. Patent 4,933,367. This compound has been reported to exhibit hypoglycemic activity.

The present invention relates to acetylenic hydroxamic acid which acts as a TNF-alpha converting enzyme (TACE) inhibitor. The compounds of the present invention are useful for diseases mediated by TNF-a, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage damage.

The present invention relates to a method for the treatment of matrix metalloproteinase (MMP) and TNF-a converting enzyme in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, papillary disease, skeletal disease, diabetes (insulin resistance) To a novel low molecular weight nonpeptide inhibitor.

According to the present invention there is provided a group of compounds of formula I, or a pharmaceutically acceptable salt thereof:

Wherein:

R ₁ is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C ₄ -C ₈ -cycloheteroalkyl;

R ₂ and R ₃ are independently of each other hydrogen, alkyl of 1-6 carbon atoms, -CN or -CCH;

R ₇ is hydrogen, aryl, aralkyl, heteroaryl, hetero aralkyl, 1-6 carbon atoms alkyl, 2-6 alkenyl carbon atoms, alkynyl of 1-6 carbon atoms, 3-6 cycloalkyl, -C carbon atoms _{(O) -R 1, -SO 2} -R 1, -C (O) -NHR 1, -C (O) NR 5 R 6, -C (O) R 1 NR 5 R ₆ , -C (O) -OR ₁ , -C (NH) -NH ₂ ;

R ₅ and R ₆ independently of one another are hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C ₄ -C ₈ -cyclo Heteroalkyl;

R ₈ , R ₉ , R ₁₀ and R ₁₁ independently of one another are hydrogen, aryl or heteroaryl, cycloalkyl of 3 to 6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, Alkyl, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms, provided that one of R ₈ and R ₉ , R ₉ and R ₁₀ or a pair of R ₁₀ and R ₁₁ is attached thereto Together with the carbon atom or the carbon atoms, form a cycloalkyl ring of 3-6 carbon atoms, or a -C ₄ -C ₈ -cycloheteroalkyl ring;

R ₁₂ is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, or alkyl of 1-6 carbon atoms;

A is O, S, SO, SO ₂ , NR ₇ or CH ₂ ;

X is O, S, SO, SO ₂ , NR ₇ or CH ₂ ;

Y is aryl or heteroaryl, provided that A and X do not bond to adjacent Y atoms;

n is 0-2.

In some preferred aspects of the invention, Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl, or thiadiazolyl, provided that A and X do not bond to adjacent Y atoms.

In another preferred embodiment of the invention, Y is phenyl, thienyl or furanyl.

According to certain preferred embodiments of the present invention, R ₈ and R ₉ together with the carbon atoms to which they are attached form a C ₄ -C ₈ cycloheteroalkyl ring and K is NR ₇ .

The most preferred matrix metalloproteinases and TACE inhibiting compounds of the present invention are:

L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide;

L-Benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide;

L- (4-Bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

L- (4-Bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-fluoro-benzyl) -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methyl-benzyl) -piperidine-4-carboxylic acid hydroxamide;

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid hydroxamide;

L- (4-Bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

Synthesis of 1- (4-bromo-benzyl) -4- [4- (4-piperidin-4-yl-but- 2-ynyloxy) -benzenesulfonyl] -piperidine-4- carboxylic acid hydroxyamide ;

1- (4-Bromo-benzyl) -4- [4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-phenylsulfanyl) -4-hydroxycarbamoyl-piperidine-1-carboxylic acid tert-butyl ester;

4- (4-But-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide;

L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

4- (4-But-2-ynyloxy-benzenesulfinylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide;

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pyran-4-carboxamide;

1-benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide;

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1-isopropyl-4-piperidinecarboxamide;

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxamide;

3 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy-3-piperidinecarboxamide;

3 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide;

- [4- (2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4- carboxylic acid hydrobromide Lt; / RTI >

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4-carboxylic acid hydroxyamide;

L- (4-Methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

L- (4-Chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide;

tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

4 - ({[4- (but-2-ynyloxy) phenyl] thio} methyl) -N-hydroxypiperidine-4-carboxamide;

tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfinyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

4 - [[[4- (2-butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide;

methyl-4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate;

tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

1-acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide;

1- (2-Butynyl) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride;

Methyl-N-4-hydroxy-1,4- [4- (2-butynyl) Methyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-1,4-l] sulfonyl} -methyl) -N-4-hydroxy-1,4-piperidine dicarboxamide;

Methyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

Benzyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

Methyl} -N-hydroxy-4-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy- 4-piperidinecarboxamide;

Methyl] -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) Carbonyl] -4-piperidinecarboxamide;

Methyl] -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4-piperidinecarboxamide;

-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-oxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide;

Phenyl] sulfonyl} methyl) -N- (4-hydroxy-2-butynyl) -Hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide,

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -1-ethyl-N-hydroxypiperidine-4-carboxamide trifluoroacetate;

Phenyl) -sulfonyl} methyl) -1 - [(5-chlorothien-2-yl) Methyl] -N-hydroxypiperidine-4-carboxamide trifluoroacetic acid salt;

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-4-ylmethyl) piperidine-4-carboxamide trifluoro Acetic acid salt;

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide trifluoro Rosacetate;

1-Benzoyl-4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-piperidine-4-carboxamide;

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidine-4-carboxamide;

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-1-ethyl-N-4-hydroxy-piperidine-1,4-dicarboxamide;

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-N-1-phenylpiperidine-1,4-dicarboxamide;

Phenyl) sulfonyl} methyl) -N-1-, N-1-diethyl-N-4-hydroxypiperidine- Copy Mid;

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidine-4-carboxamide;

Methyl-N-1-phenylpiperidine-1, 4-dicarboxylic acid methyl ester was used in place of 4 - ({[4- Copy Mid;

Octyl-4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate;

4-methoxyphenyl) -4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate;

4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (phenylsulfonyl) piperidine-4-carboxamide;

Methyl-1H-imidazol-4-yl) sulfonyl] piperidine (hereinafter referred to as "4-carboxamide;

1- [2- (benzylamino) acetyl] -4 - ({[4- (but-2-ynyloxy) phenyl] -sulfonyl} methyl) -N-hydroxypiperidine-4-carboxamide;

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (2-morpholin-4-ylacetyl) piperidine-4-carboxamide ;

Hydroxy-1- [2- (4-methyl-piperazin-1-yl) acetyl] piperidine < / RTI >-4-carboxamide;

1-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide;

1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide;

1- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide;

4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidine-1-carbonyl) -4-piperidinecarboxamide;

Ethyl 4- (4-but-2-ynyloxybenzenesulfonyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide;

4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide;

4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide;

4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxamide;

Hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4- Piperidinecarboxamide;

tert-butyl-4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate;

4 - {[4- (2-butynyloxy) -phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride;

Methyl {4- {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoate hydrochloride;

4 - ({4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoic acid hydrochloride;

1- [4- (aminocarbonyl) benzyl] -4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride;

tert-butyl-4 - {[4- (but-2-ynyloxy) phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate;

4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride; and

L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride;

And pharmaceutical salts thereof.

The heteroaryl used throughout is a mono- or bicyclic aromatic ring of 5-10 members having 1-3 heteroatoms selected from N, NR 7, S and O. Heteroaryl is preferably:

Wherein K is defined as O, S or -NR ₇ and R ₇ is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms , Alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C (O) -R ₁ , -SO ₂ -R ₁ , -C (O) -NHR ₁ , -C ) NR ₅ R ₆ , -C (O) R ₁ , NR ₅ R ₆ , -C (O) -OR ₁ , -C (NH) -NH ₂ . Preferred heteroaryl rings are pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzo But are not limited to, furan, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole and benzoxazole. The heteroaryl group of the present invention may be mono- or disubstituted.

-C ₄ -C ₈ -cycloheteroalkyl is defined by the formula:

Where K is O, S or NR < 7 > and R < 7 > is as defined above. Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. The heterocycloalkyl groups of the present invention may be optionally mono- or disubstituted.

Aryl as used herein refers to a phenyl or naphthyl aromatic ring which may optionally be mono- or disubstituted.

Alkyl, alkenyl, alkynyl and perfluoroalkyl include both straight and branched chain moieties. The alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted or substituted (hydrogen bonded carbon, or other carbon in the chain or ring).

Aralkyl as used herein refers to a substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl, preferably alkyl of 1-3 carbon atoms, and aryl is as previously defined.

Heteroaralkyl as used herein refers to a substituted alkyl group, alkyl-heteroaryl, wherein aryl is lower alkyl, preferably alkyl of 1-3 carbon atoms, and heteroaryl is as previously defined.

Halogen means bromine, chlorine, fluorine, and iodine.

Suitable substituents for aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include halogen, alkyl of 1-6 carbon atoms; Alkenyl of 2 to 6 carbon atoms; 2-6 carbon alkenyl, 3-6 carbon atoms in the cycloalkyl _{atoms, -OR 5, = O, -CN} , -COR 5, perfluoroalkyl of 1-4 carbon atoms, 1-4 alkyl in -O- perfluoroalkyl carbon _{atoms, -CONR 5 R 6, -S (} O) nR 5, -OPO (OR 5) OR 6, -PO (OR 5) R 6, -OC (O) OR 5 _{, -OR 5 NR 5 R 6,} -OC (O) NR 5 R 6, -C (O) NR 5 OR 6, -COOR 5, -SO 3 H, -NR 5 R 6, -N [(CH 2 ) ₂ ] ₂ NR ₅ , -NR ₅ COR ₆ , -NR ₅ COOR ₆ , -SO ₂ NR ₅ R ₆ , -NO ₂ , -N (R ₅ ) SO ₂ R ₆ , -NR ₅ CONR ₅ R ₆ , _{-NR 5 C (= NR 6)} NR 5 R 6, -NR 5 C (= NR 6) N (SO 2 R 5) R 6, -NR 5 C (= NR 6) N (C = OR 5) R _{6, -tetrazol-5-yl, -SO 2 NHCN, -SO 2 NHCONR} 5 R 6, phenyl, heteroaryl, or -C ₄ -C ₈ - cycloalkyl including heteroalkyl, however, not limited to this; Wherein -NR ₅ R ₆ may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine or azetidine ring;

R ₅ and R ₆ are independently of each other hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or C ₄ -C ₈ -cyclohetero Alkyl;

R ₇ is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, -C (O) -R ₁ , -SO ₂ -R ₁ , -C (O) -NHR ₁ , -C (O) -OR ₁ , -C (NH) -NH ₂ ;

n is 0-2.

Where a moiety contains one or more substituents of the same name, each of these substituents may be the same or different.

Pharmaceutically acceptable salts include those derived from organic acids with inorganic acids such as acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, Such as hydrochloric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, and similarly known acceptable acids when the compound of the present invention contains a basic moiety. When the compound of the present invention contains an acidic site, the salt may also be formed from organic and inorganic bases, and preferably it may be an alkali metal salt such as a sodium salt, a lithium salt or a potassium salt.

The compounds of the present invention may contain asymmetric carbon atoms and some of the compounds of the present invention may contain one or more asymmetric centers, resulting in optical isomers and diastereomers. When stereochemistry is not considered, the present invention relates to such optical isomers and diastereomers; And purely R and S stereoisomers as racemic and fractionated, enantiomers; And other mixtures of R and S stereoisomers and pharmaceutically acceptable salts thereof. It is understood that one optical isomer, including a diastereomer and an enantiomer, or a stereoisomer, may have a property of preference over the others. Thus, when describing and claiming the present invention, it is made clear that when describing a 1-racemic mixture, it describes and claims an optical isomer, or a stereoisomer, including a diastereomer and an enantiomer substantially free of the remainder.

The compounds of the present invention have been shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and TNF-α converting enzyme (TACE) and are thus useful in the treatment of arthritis, tumor metastasis, tissue ulcers, abnormal wound healing, Rejection, insulin resistance, skeletal disease and HIV infection. In particular, the compounds of the present invention provide enhanced inhibition of the level of TACE activity and / or increased selectivity for MMP-1 in vitro and in cell assays and are therefore particularly useful for the treatment of diseases mediated by TNF.

According to the present invention there is provided a process for the production of a compound of the invention which comprises one of the following processes:

a) reacting a reactive derivative of the formula or a reactive derivative thereof with an R ₁₂ NHOH compound, wherein R ₁₂ is as defined above, to obtain a compound of formula (I);

Wherein n, X, Y, A, R ₁ , R ₂ , R ₃ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined above; or

b) deprotecting the following compounds to give the corresponding compounds of formula (I);

(Wherein, n, X, Y, A, R _1, R _2, R _3, R _8, R _9, R _10, R ₁₁ and R ₁₂ are as defined above, R ₃₀ is t- butyl, benzyl , And trialkylsilyl); or

c) trimming the resin-supported hydroxamate derivative containing the following group to obtain the compound of formula (I);

(Wherein n, X, Y, A, R ₁ , R ₂ , R ₃ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined above; or

d) separating a mixture of optically active isomers of a compound of formula (I) (for example, racemates) to separate substantially enantiomeric or diastereoisomeric enantiomers or diastereomers; or

e) acidifying the basic compound of formula I with a pharmaceutically acceptable acid to obtain a pharmaceutically acceptable salt; or

f) converting a compound of formula (I) having a single reactive substituent group or moiety into a compound of formula (I) having another substituent group or moiety.

The reaction in step a) can be carried out by methods known in the art, for example by reacting an acid chloride or mixed anhydrous reactive derivative with a compound of formula R < ₁₂ > NHOH.

Removal of the protecting group described in step b) can be carried out by processes known in the art for obtaining hydroxamic acid (see Scheme 16 below).

Step c) can be carried out using a strong acid such as TFA to cleave the hydroxamate from the resin.

In step d), standard separation techniques can be used, in particular for separating the enantiomeric or diastereomeric forms. For example, the racemic mixture can be converted to a mixture of optically active diastereomers (e. G., By diastereomeric salt formation or covalent bond formation) by reaction with a single enantiomer of a " resolving agent ". The resulting mixture of optically active diastereoisomers can be separated by standard techniques (e. G., Crystallization or chromatography) and the individual optically active diastereoisomers are treated to remove the " resolving agent " . Chiral chromatography (using a chiral support, eluent or ion pairing agent) may also be used to directly isolate the enantiomeric mixture.

Compounds of formula I can be separated into the pharmaceutically acceptable acids, for example, salts of organic acids or inorganic acids, by treatment of the acids described above.

In the case of step e), the compounds of formula I having a reactive substituent group such as hydroxy or amino or a moiety such as -S- can be converted to other compounds of formula I in a known manner, Or an ether. Reactive sites, such as sulfur atoms, can be oxidized to SO or SO ₂ (see, for example, Scheme 4 below). If desired, reactive substituent groups can be protected during synthesis of compounds of formula I and removed at the last step (see Schemes 4 and 17 below).

The process of the present invention

The compounds of the present invention can conveniently be prepared according to one of the general processes outlined below.

A compound of the present invention wherein n = 0, X = O, S or NR ⁷ , and R ⁸ and R ⁹ are six membered heterocycles containing NR ⁷ , S or O, Form a click ring and A = S, SO or SO ₂ ) can be prepared according to one of the general processes outlined below.

As shown in Scheme 1, a suitably substituted mercaptan derivative was alkylated with an alpha -bromoacetic acid ester derivative in refluxed chloroform using N, N-diisopropylethylamine as the base. The sulfide derivative thus obtained was reacted with a suitably substituted propargyl bromide derivative in refluxing acetone using K ₂ CO ₃ as the base. If X = -NR ⁷ , N-alkylation can be performed in DMF / NaH at room temperature. The sulfide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH ₂ Cl ₂ or oxone in methanol / water. The sulfones thus obtained can be converted to the corresponding piperidine derivatives by reacting them with bis (2-chloroethyl) N-substituted amine derivatives.

Bis-2-chloroethyl N-substituted amines may be prepared from substituted diethanolamine and thionyl chloride. (Scheme 2). The cyclic product obtained by the above-mentioned operation can be hydrolyzed to the carboxylic acid and subsequently converted to the hydroxamic acid outlined in Scheme 1.

Corresponding sulfides and sulfoxides can be prepared starting from the corresponding saturated heterocyclic carboxylic acid derivatives (Scheme 3). N-Boc protected isonipecotic acid can be lithiated using tert-butyl lithium and the resulting anion reacted with an appropriately substituted disulfide. The sulfide derivative can be converted to the hydroxamic acid by the process shown above.

This sulfide can subsequently be converted to the sulfoxide with 30% hydrogen peroxide at room temperature. The required disulfide can be prepared from appropriately substituted thiols and DMSO / HCl oxidation. This process can be applied to any saturated, fused or unfused heterocyclic carboxylic acid derivative (Scheme 4).

Alternatively, the sulfone derivative can be lithiated or carbonylated using dry ice or CO ₂ gas (Scheme 5). Sulfone derivatives may be mono-heterocyclic, bicyclic, benzo-fused or heteroaryl, such as pyridyl, thienyl, furanyl, pyrazinyl, pyrimidyl, thiazolyl fused ring systems.

Oxygen analogs can be prepared from appropriately substituted alkynyloxy-benzenesulfonyl acetic acid ethyl ester and 2-chloroethyl ether (Scheme 6). The corresponding pyran derivatives can be hydrolyzed to carboxylic acids (which can be converted to hydroxamic acid derivatives).

Thiols used as intermediate products for the synthesis of compounds of the present invention can be prepared according to Scheme 7. According to this, the sulfonic acid salt 1 (wherein XR ₅₀ is a hydroxy, thiol or substituted amino moiety) is acetylene (2) wherein J is a suitable leaving group such as a halide mesylate, tosylate, Can be alkylated to form (3). Acetylene (2) can be synthesized by commercially available or known compounds, or by methods known to those skilled in the art. The sulfonic acid salt (3) can be converted into the corresponding sulfonyl chloride or other sulfonylating agent (for example, by oxalyl chloride, phosphorous oxychloride or the substituents R ₁ , R ₂ and R ₃ and acetylene- 4). ≪ / RTI > The sulfonyl chloride (4) can be reduced to the corresponding thiol (5) using triphenylphosphine in a suitable solvent mixture such as dichloromethane / DMF at a temperature between -20 ° C and 30 ° C.

Alternatively, disulfide (6) can be reacted with compound (2) and converted to diacetylene (7), followed by reduction of the disulfide bond to give the desired thiol (5). Bisacetylen (7) can also be converted to thiol (5) by sulfonyl chloride (4). (9) is obtained by alkylation of a phenol, thiophenol, aniline or protected aniline (8) using the compound (2) and then reacting with chlorosulfonic acid to give the sulfonic acid (10) (4) and subsequently reduced to thiol (5). Thiophenol (11) is a precursor to (5) by protection of the thiol with triphenylmethyl or other suitable protecting groups, alkylation of XH (X is O, N or S), and deprotection of the sulfur.

Compounds of the present invention wherein X is N, O, S, SO or SO ₂ can be synthesized according to Scheme 8 and Scheme 9. Alkylation of para-substituted aryl (14) or protected equivalents with acetylene (2) in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetone or DMF at a temperature between 20 < 0 & To produce pargyl ether (15). Those skilled in the art know that protecting groups may be required to avoid undesired side reactions and increase reaction yield. The need and choice of a protection group for a particular reaction is known to those skilled in the art. Reaction of this compound with a propiolactone or a substituted propiolactone derivative wherein the substituents are as defined above in the presence of a base such as potassium t-butoxide in a polar solvent or solvent mixture such as THF or DMF gives the carboxylic acid ( 16) is obtained. Conversion of the carboxylic acid (16) to the corresponding hydroxamic acid (17) is accomplished by reaction with hydroxylamine followed by formation of the active ester derivative such as acid chloride or acid anhydride. It will be appreciated by those skilled in the art that when A is sulfur, in Scheme 8 and in all subsequent reaction schemes, a suitable oxidizing agent, such as oxone, air, m-chloroperbenzoic acid or hydrogen peroxide, Lt; RTI ID = 0.0 > sulfone < / RTI > or sulfone.

Compound (18) is also available from the Michael addition of cyclic acrylate ester, or substituted acrylate ester, of compound (15), wherein the substituents are as defined above, wherein R ₃₀ is hydrogen or a suitable carboxylic acid protecting group to be. The deprotection of the ester moiety provides a carboxylic acid (which can be converted to a similar hydroxamic acid). Likewise, the Michael addition of the mono-protected 1,4-disubstituted aryl (19) wherein XR ₂₅ is hydroxy or protected hydroxy, thiol or amine gives compound (20). Removal of the protecting group gives the thiol, aniline or phenol (21) which can be alkylated with the propargyl derivative (2) to give (18). The mono protected compound (19) can also be reacted with? -Propionolactone to give (22). Alternatively, (22) can be deprotected and then alkylated (16 and 17).

The linker between the heteroatom and the hydroxamic acid near the base and the synthesis of the compound of the present invention wherein X is N, O, S, SO, or SO ₂ is a chain of 1 to 3 carbon atoms which can be synthesized according to Scheme 9. Compounds (19) wherein XR ₂₅ is hydroxy or protected hydroxy, thiol or amine can be prepared from a compound of formula (I) wherein R ₃₀ is hydrogen or a suitable carboxylic acid protecting group such as a halogen, tosylate, mesylate or triflate (25) can be obtained by reacting with ester (24) or lactone (24a). Exposure of the heteroatom X of compound (25) produces (26), which can be alkylated using the propargyl derivative (2) to give the acetylene-ester (27). The ester (27) can be converted to the carboxylic acid by acid or base hydrolysis followed by conversion to the hydroxam described in scheme 1 to the corresponding hydroxamic acid (28). Alternatively, compound 15, prepared as shown in Scheme 8, can be directly alkylated (27 and 28) using ester (24) or lactone (24a). Substituents on alpha carbon for hydroxamic acid are described above.

Compounds of the invention in which A is methylene or a substituted methylene group and X is oxygen can be obtained according to Scheme 10. The ester or carboxylic acid (29), which is commercially available or known in the literature, can be converted to the corresponding phenol (30). Alkylation of the phenol with acetylene (2) gives the propargyl ether (31), which can be converted to the corresponding hydroxamic acid (33) following the corresponding carboxylic acid as described in Scheme 1. Substituents on alpha carbon for hydroxamic acid are defined above.

A is -SO ₂ -, and the compounds of the invention R ₈ and R ₉ are other than hydrogen can be obtained by starting with 4-fluoro shown in Scheme 11 from benzenethiol (34). Reaction of the thiol with a propiolactone, or an acrylate ester, or an ester derivative (24) followed by oxidation of the resulting thioether results in a sulfonic acid (35). (16) is obtained by replacing the 4-fluoro substituent of formula (35), or a corresponding ester thereof, with a propargyl derivative (36) (wherein X is N, O or S). Compound (16) can be converted to the compound of the present invention according to Scheme 1. The fluoroaryl (35) is reacted with a hydroxyl, thiol or amino group (HXR ₄₀ , wherein R ₄₀ is a suitable protecting group) in the presence of a base such as sodium hydride in a polar aprotic solvent such as DMF (36) can be obtained. (16) is obtained by deprotection of the acetylene derivative (36) followed by alkylation with the acetylene derivative (2).

Compounds of the present invention wherein X is NH are available starting from the appropriate commercially available nitroaryl compound (38) (Scheme 12). Thus, the anion of the compound (38) was used to alkylate the? -Propiolactone, or the substituted derivative or the cyclic acrylate ester, to obtain (40 and 39), respectively. Alkylation of the resulting aniline followed by reduction of the nitro group gives (16). Compound 38 can be alkylated using ester derivative 24 to give the nitro-ester 40 followed by reduction to give the corresponding aniline analogous to compound 26 in Scheme 9.

The compounds of the present invention wherein R < ₁₁ > in the alpha position to the hydroxamic acid is a hydroxy group can be obtained by epoxide (41) as shown in Scheme 13. These epoxides are available either through oxidation of the corresponding acrylate esters or by Darzens reaction of alpha-halo esters and ketones. Reaction of the epoxide with a thiol, phenol or aniline (19) in the presence of a base or Lewis acid catalyzed epoxide ring gap gives the alpha-hydroxy ester (42). (44) is obtained by deprotection of the compound (42) followed by alkylation with the propargyl derivative (2). (45) is obtained by converting the ester of (44) to a similar hydroxamic acid as described in Scheme 1. Compound (45) wherein A is sulfur may be converted to a similar sulfoxide or sulfone at this point via oxidation with hydrogen peroxide, air, oxone or other suitable reagent. Likewise, thiol, phenol or aniline (15) can be reacted with (41) to give (44). The hydroxyl group of compound (43) can also be manipulated through conversion to a suitable leaving group, such as a halide or sulfonate ester, and then substituted with various nucleophiles, including amines (44).

Another route to the alpha-hydroxyhydroxamic acid of the present invention is shown in Scheme 14. Compound (15) can be alkylated using alcohol (46) to give (47). Oxidation of the alcohol (A = S) in the presence or absence of simultaneous oxidation of the thioether gives the aldehyde (48). Reaction of the aldehyde 48 with trimethylsilyl cyanide or other suitable reagent yields cyanohydrin 49. Hydrolysis of the nitrile 49 to the corresponding carboxylic acid followed by conversion to the hydroxamic acid described in Scheme 1 yields (50).

The compounds described in the present invention (Examples 30-63) were prepared according to Scheme 15 and Scheme 16. In Scheme 15, t-Boc-protected ethyl isonipecotate (51) was carefully alkylated using diiodomethane to give the monoiodo compound (52). Which was subsequently converted to several hydroxamic acid derivatives as shown in Scheme 15. In Scheme 16, the N-Boc group was selectively removed using TMSOTf / 2,6-lutidine. After derivatization of the nitrogen, O-tBu was removed using TFA in methylene chloride.

Alternatively, the compounds described in Examples 64-74 and 80 wherein A = SO ₂ and n = 0 were prepared as shown in Scheme 17.

Example 1

4- (4-But-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Step 1:

To a stirred solution of 4-mercaptophenol (12.6 g, 100 mmol) and N, N-diisopropylethylamine (13.0 g, 100 mmol) in chloroform (200 mL) was added ethyl bromoacetate 17.0 g, 100 mmol) was slowly added at room temperature. After the addition was complete, the reaction mixture was refluxed for 1 hour and then cooled to room temperature. The reaction mixture was sufficiently washed with water, dried over anhydrous MgSO ₄ and; Filtered and concentrated. The resulting oily product was taken for the next step without purification.

Step 2:

A mixture of K ₂ CO ₃ (15 gm, excess), (4-hydroxy-phenylsulfanyl) -acetic acid ethyl ester (5 g, 23.6 mmol) and 1-bromo-2-butyne (9.34 g, 35.4 mmol) Was refluxed with stirring for 8 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting product was taken and used in the next step without purification. Yield 6.0 g (96%); Yellow oil; MS: 264.0 EI (M ⁺ H).

Step 3:

Acetic acid ethyl ester (101 g, 380 mmol) in MeOH: THF (3: 1) (1000 mL) was added oxone ( 670.0 g, excess) was added at room temperature. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with chloroform (600 mL) and then filtered. The organic layer was separated and washed once with saturated NaHSO ₃ (400 ㎖) solution. The chloroform layer was washed thoroughly with water, dried and concentrated. The oily product was dissolved in MeOH (100 mL) and hexane (600 mL) was added. The separated colorless solid was filtered and washed with hexane. Yield 108 g (96%); mp. 91-93 占 폚; MS: 297 (M ⁺ H) < ^{+ &} gt ^; .

Step 4:

A mixture of diethanolamine (22.5 g, 150 mmol), 4-bromobenzyl bromide (25 g, 100 mmol) and N, N-diisopropylethylamine (19.0 g, 150 mmol) At reflux for 24 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. It was washed thoroughly with water, dried over anhydrous MgSO ₄ , filtered and concentrated. The obtained crude product was taken in the next step without purification. Yield 33.6 g (99%); Yellow oil, MS: 273.8 (M + H) <^+> .

Step 5:

2 - [(4-bromobenzyl) - (2-hydroxy-ethyl) -amino] -ethanol (33.28 g, 122 mmol) was dissolved in methanolic hydrogen chloride (100 mL) at 0 ° C. The methanol was removed in vacuo and the hydrochloride salt was suspended in CH ₂ Cl ₂ (300 mL). Thionyl chloride (30 g, excess) was slowly added to the above-mentioned stirred suspension at room temperature. The reaction mixture was gently refluxed for 3 hours. The reaction mixture was concentrated and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine was used in the next step without purification. Yield: 47 g (99%); Brown solids; mp 125 [deg.] C; MS: 309.8 (M + H) &lt; ⁺ & gt ^; .

Step 6:

(1.0 g), (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (2.8 g) in anhydrous K ₂ CO ₃ (10 g, excess), 18-crown- g, 9.46 mmol) and (4-bromo-benzyl) -bis (2-chloro-ethyl) -amine (4.9 g, 14.2 mmol) in anhydrous acetone (200 mL) was refluxed for 24 h. The reaction mixture was cooled, filtered and the filtrate was concentrated. The crude product was extracted with chloroform, washed thoroughly with water, dried and concentrated. The brown material was purified by column chromatography on silica gel, eluting with 50% ethyl acetate: hexane. Yield 1.36 g (27%); Brown oil; MS: 534 (M + H) &lt; ⁺ & gt ^; .

Step 7:

To a solution of l- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine in THF: methanol (100: 50 mL) and 10 N NaOH (15 mL) (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (1.36 g, 2.54 mmol) -Carboxylic acid. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was cooled and neutralized with concentrated HCl. The separated solid was extracted with chloroform: methanol (3: 1) (300 mL) and washed with water. The chloroform layer was dried and concentrated. The product was crystallized from methanol. Yield 800 mg (62%); Off-white solid; mp 197 [deg.] C; MS: 507.9 (M + H) &lt; ⁺ & gt ^; .

Step 8:

(750 mg, 1.5 mmol) and CH ₂ Cl ₂ (100 mg, 1.5 mmol) were added to a solution of 1- (4-bromo-benzyl) -4- To a stirred solution of DMF (1 mL) in methylene chloride (2 mL) was added oxalyl chloride (508 mg, 4.0 mmol) at 0 ° C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The acid chloride thus formed was concentrated to remove excess oxalyl chloride and redissolved in CH ₂ Cl ₂ (30 mL). In a separate flask, hydroxylamine hydrochloride (690 mg, 10 mmol) was dissolved in DMF (10 mL) and triethylamine (10 g, 10 mmol) was added. The reaction mixture was further diluted with acetonitrile (25 mL) and stirred at 0 &lt; 0 &gt; C. The acid chloride was slowly added to the hydroxylamine and after the addition was complete, the reaction mixture was warmed to room temperature and then stirred for 24 hours. And the reaction mixture was concentrated and the residue was extracted with chloroform, it was thoroughly washed with water and dried over anhydrous Na ₂ SO _4. The product was purified by silica gel column chromatography eluting with 10% methanol: ethyl acetate. 270 mg of 1- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide was isolated as a white powder in the form of the hydrochloride salt did. Yield 52%; mp 153 [deg.] C; MS: 522.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 2.38 (m, 2H), 3.36 (m, 2H), 4.28 (s, 2H), 4.89 (m, (d, J = 2.2 Hz, 2H), 7.18 (d, J = 9 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.68 (m, 4H), 9.37 (s, 1 H).

Example 2

Benzyl) -piperidine-4-carboxylic acid hydroxyamide &lt; RTI ID = 0.0 &gt;

2 - [(2-Hydroxy-ethyl) - (4-methoxy-benzyl) -amino] -ethanol was prepared according to the general method as outlined in example 1 (step 4). Starting from diethanolamine (10.5 g, 100 mmol) and 4-methoxybenzyl chloride (15.6 g, 100 mmol). Yield 21 g (98%); Yellow oil; MS: 226 (M + H) &lt; ⁺ & gt ^; .

Bis- (2-chloro-ethyl) - (4-methoxy-benzyl) -amine was prepared according to the general procedure outlined in Example 1 (step 5). Starting from 2 - [(2-hydroxy-ethyl) - (4-methoxy-benzyl) -amino] -ethanol (11.2 g, 50 mmol). Yield 14 g (99%); Dark brown, low melting solids; MS: 263 (M + H) &lt; ⁺ & gt ^; .

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methoxy-benzyl) -piperidine-4- carboxylic acid ethyl ester was prepared according to the general method outlined in example 1 . (2-chloro-ethyl) - (4-methoxy-benzyl) -amine (2.61 g, 8.75 mmol, ) And 2.5 g of product were isolated according to the procedure outlined in Example 1 (step 6). Yield 2.5 g (77%); Yellow oil; MS: 486 (M + H) &lt; ⁺ & gt ^; .

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-methoxy-benzyl) - 4-carboxylic acid ethyl ester (2.5 g, 5.15 mmol) to give 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (4- methoxy-benzyl) -piperidine -4-carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 1.26 g (54%); Off-white solid; mp 223 [deg.] C; MS: 458 (M + H) &lt; ⁺ & gt ^; .

Starting from 4 - (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-methoxy- benzyl) -piperidine- 4- carboxylic acid (1 g, 2.19 mmol) ), 350 mg of 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (4-methoxy-benzyl) -piperidine-4- carboxylic acid hydroxyamide It was separated into the hydrochloride salt form of the solid. Yield 31%; mp 162 [deg.] C; MS: 473 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6): δ1.86 (t, J = 2.13 Hz, 3H), 2.23 (m, 2H), 2.49 (m, 2H), 2.73 (m, 2H), 3.39 ( (m, 2H), 3.77 (s, 3H), 4.21 (d, J = 4.26 Hz, 2H), 4.89 (d, J = 2.28 Hz, 2H) 1H, d, J = 9 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 9.37 1H).

Example 3

- (4-Chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide

2 - [(4-chlorobenzyl) - (2-hydroxy-ethyl) -amino] -ethanol was prepared according to the general procedure outlined in Example 1 (step 4). Starting from diethanolamine (14.3 g, 95 mmol) and 4-chlorobenzyl chloride (10.2 g, 63 mmol). Yield 12.1 g (84%); Yellow oil; MS: 230 (M + H) &lt; ⁺ & gt ^; .

(4-chloro-benzyl) -bis (2-chloro-ethyl) -amine was prepared according to the general procedure outlined in Example 1 (step 5). Starting from 2 - [(4-chlorobenzyl) - (2-hydroxy-ethyl) -amino] -ethanol (12 g, 52.4 mmol). Yield 41.27 g, (90%); Yellow powder; mp 115 [deg.] C; MS: 303 (M + H) &lt; ⁺ & gt ^; .

The title compound was prepared from 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine- 4- carboxylic acid ethyl ester in accordance with the general method outlined in example 1 Respectively. (4 g, 13.5 mmol) and (4-chloro-benzyl) -bis- (2-chloro-ethyl) -amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); White crystals; MP 91.8 DEG C; MS: 490 (M + H) &lt; ⁺ & gt ^; .

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine in THF: methanol 3: 1 (100 mL) and 10 N NaOH (10 mL) (4-chloro-benzyl) -piperidine-4-carboxylic acid ethyl ester (3.14 g, 6.42 mmol) Carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 2.37 g (80%); White solid; mp 205 [deg.] C; MS: 461.9 (M + H) &lt; ⁺ & gt ^; .

Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine- 4- carboxylic acid (2.31 g, 5.01 mmol) 790 mg of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine-4- carboxylic acid hydroxyamide was obtained as a yellow solid Lt; / RTI &gt; hydrochloride salt. Yield 31%; mp 130 [deg.] C; MS: 476.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 4.89 (d, 2H), 7.18 (d, 2H), 4.28 (m, 2H) J = 8.94 Hz, 2H), 7.54 (s, 4H), (d, J = 8.88 Hz, 2H), 9.40 (s, 1H), 10.3 (s, 1H).

Example 4

Benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide

Bis- (2-chloro-ethyl) -benzylamine was prepared according to the general procedure outlined in Example 1 (step 5). Starting from N-benzyl diethanolamine (164.6 g, 844 mmol). Yield 178.5 g (79%); Brown solids; MS: 231.9 (M + H) &lt; ⁺ & gt ^; .

1-Benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 1 (step 6). (2 g, 6.73 mmol) and bis- (2-chloro-ethyl) -benzylamine (2.3 g, 8.8 mmol). Yield 3.33 g (99%); Yellow oil; MS: 455.9 (M + H) &lt; ⁺ & gt ^; .

To a solution of 1-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester dissolved in THF: methanol (3: 1, 150 ml) and 10 N NaOH (15 ml) Benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared starting from the ester (3 g, 6.6 mmol). The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 1.65 g (59%); Off-white powder; mp 191 [deg.] C; MS: 428 (M + H) &lt; ⁺ & gt ^; .

Starting from 1-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (1.55 g, 3.63 mmol) and following the procedure outlined in Example 1 Thus, 1.08 g of l-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide was isolated in the form of the hydrochloride salt of off- white powder. Yield 62%; mp 175 [deg.] C; MS: 443 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); (m, 2H), 4.28 (d, J = 4.3 Hz, 2H), 4.89 (d, J = 2.16 Hz, 3H), 2.25 1H, J = 2.28, 2H), 7.18 (m, 2H), 7.46 (m, 5H), 7.73 (m, 2H), 9.36 (s,

Example 5

4-Bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide

(4-pent-2-ynyloxy-phenylsulfanyl) -acetic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 2). (7.1 g, starting from 4-hydroxy-phenylsulfanyl) -acetic acid ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol). Yield 7.15 g (86%); Brown oil; MS: 278 EI (M + H) &lt; ⁺ & gt ^; .

(4-pent-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 3). (4-pent-2-ynyloxy-benzenesulfonyl) -acetic acid was prepared starting from 4- (4-pent-2-ynyloxy-phenylsulfanyl) -acetic acid ethyl ester (7.04 g, 25.3 mmol) Ethyl ester was separated. Yield 8 g (99%); Yellow oil; MS: 310.9 (M + H) &lt; ⁺ & gt ^; .

4-carboxylic acid ethyl ester was reacted with the general method as outlined in example 1 (step 6) from 4- (4-bromo-benzyl) -4- . (4-bromo-benzyl) -bis (2-chloro-ethyl) -amine (5.83 g, 16.8 mmol), 2.85 g of the product was isolated. Yield 2.85 g (31%); Low melting white solid; MS: 549.9 (M + H) &lt; ⁺ & gt ^; .

To a solution of 1- (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine in THF: methanol (100: 50 mL) and 10 N NaOH (10 mL) (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (2.64 g, 4.8 mmol) -Carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 1.6 g (65%); Off-white solid; mp 217 [deg.] C; MS: 521.9 (M + H) &lt; ⁺ & gt ^; .

Starting from l- (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid (1.55 g, 2.98 mmol) Benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide was reacted with 200 mg The yellow solid was separated into its HCl salt form. Yield 12%; mp 62 [deg.] C; MS: 536.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 3.40 (d, 2H), 4.26 (m, 2H), 2.73 (m, (m, 2H), 4.9 (m, 2H), 7.18 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.66 (m, 4H), 10.39 1H).

Example 6

4-Bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide

(4-oct-2-ynyloxy-phenylsulfanyl) -acetic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 2). (6.9 g, 36.6 mmol) and (4-hydroxy-phenyl-sulfanyl) -acetic acid ethyl ester (5 g, 30 mmol) Oxy-phenylsulfanyl) -acetic acid ethyl ester (8.9 g). Yield 8.9 g (92%); Yellow oil; MS: 320 EI (M + H) &lt; ⁺ & gt ^; .

(4-oct-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester was prepared according to the general method as described in example 1 (step 3). (4-oct-2-ynyloxy-phenylsulfonyl) -acetic acid ethyl ester (8.8 g, 27.5 mmol) was isolated starting from 4- (4-oct-2-ynyloxy-phenylsulfanyl) did. Yield 8.45 g (87%); Yellow oil; MS: 352 EI (M + H) &lt; ⁺ & gt ^; .

4-Carboxylic acid ethyl ester was reacted with the general method outlined in example 1 (step 6) from 4- (4-bromo-benzyl) -4- . (5.1 g, 11.4 mmol) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine 1.47 g of 1- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid ethyl ester was isolated starting from 4- Yield 1.47 g (22%); Yellow solid; MS: 591.9 (M + H) &lt; ⁺ & gt ^; .

To a solution of 1- (4-bromobenzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine dissolved in THF: methanol (50:50 mL) and 10 N NaOH (10 mL) 4- carboxylic acid ethyl ester (1.36 g, 2.3 mmol) to give l- (4-bromobenzyl) -4- (4-oct-2-ynyloxy- benzenesulfonyl) -piperidine- . The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 660 mg (51%); Off-white solid; mp 199 [deg.] C; MS: 562 (M + H) &lt; ⁺ & gt ^; .

4-carboxylic acid (570 mg, 1.01 mmol) and starting from Example 1 (step (c), starting from l- (4-bromo-benzyl) -4- 100 mg of l- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide was reacted according to the procedure outlined in 8) It was isolated in the form of the hydrochloride salt of the white powder. Yield 17%; mp 140 [deg.] C; MS: 579 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 2.27 (m, 2H), 2.49 (m, 4H), 2.73 (m, 2H), 4.03 (m, 2H) (m, 2H), 4.91 (s, 2H), 7.18 (d, J = 9 Hz, 2H), 7.47 10.25 (s, 1 H), 11.19 (s, 1 H).

Example 7

- (4-fluoro-benzyl) -piperidine-4-carboxylic acid hydroxyamide

2 - [(4-Fluoro-benzyl) - (2-hydroxy-ethyl) -amino] -ethanol was prepared according to the general method outlined in Example 1 (step 4). Starting from diethanolamine (15.7 g, 150 mmol) and 4-fluoro-benzyl chloride (14.4 g, 100 mmol), 20 g of product was isolated. Yield 20 g, (93%); Yellow oil; MS: 215 (M + H) &lt; ⁺ & gt ^; .

(4-Fluoro-benzyl) -bis- (2-chloro-ethyl) -amine was prepared according to the general method as outlined in example 1 (step 5). Starting with 2 - [(4-fluoro-benzyl) - (2-hydroxy-ethyl) -amino] -ethanol (23.6 g, 110 mmol), 28 mg of the product was isolated. Yield 28 g, (96%); Brown solids; mp 98-99 [deg.] C; MS: 251 (M + H) &lt; ⁺ & gt ^; .

4-Carboxylic acid ethyl ester was reacted with 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-fluoro-benzyl) -piperidine- . (5 g, 16.9 mmol) and (4-fluoro-benzyl) -bis- (2-chloro-ethyl) -amine (5.8 g, &Lt; / RTI &gt; 20.1 mmol). Yield 5.3 g (67%); Brown oil; MS: 474 (M + H) &lt; ⁺ & gt ^; .

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-fluoro-benzyl) -piperidin-l-ylmethanol dissolved in THF: methanol 3: 1 (100 mL) and 10 N NaOH (20 mL) (4-fluoro-benzyl) -piperidine-l-carboxylic acid ethyl ester (9.5 g, 20 mmol) Carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 5.7 g (63%); White solid; mp 106-106 [deg.] C; MS: 447 (M + H) &lt; ⁺ & gt ^; .

Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-fluoro-benzyl) -piperidine- 4- carboxylic acid (5.7 g, 13 mmol) 4.1 g of 4- (4-butyn-2-ynyloxy-benzenesulfonyl) -1- (4-fluoro-benzyl) -piperidine-4- carboxylic acid hydroxyamide was reacted with The solid was separated into its HCl salt form. Yield 64%; mp 162-4 C; MS: 461 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, CDCl} 3); (m, 2H), 3.41 (d, 2H), 4.84 (d, 2H), 7.01 (d, J = 8.94 Hz, 2H) , 7.15 (d, J = 8.88 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 9.4-9.7 (bs, 1H).

Example 8

Benzyl) -piperidine-4-carboxylic acid hydroxyamide &lt; RTI ID = 0.0 &gt;

Methyl} benzonitrile was reacted with diethanolamine (10.2 g, 97 mmol) and &lt; RTI ID = 0.0 &gt; a-bromo- &lt; / RTI & Starting from mo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); White solid; mp 163 [deg.] C MS: 221.2 (M + H) &lt; ⁺ & gt ^; .

(2-chloroethyl) -amino] -methyl} benzonitrile was prepared from 4 - {[bis- (2-hydroxyethyl) -amino ] -Methyl} benzonitrile (33.38 g, 122 mmol). Yield g, (%); Brown solids; mp DEG C; MS: (M + H) &lt; ⁺ & gt ^; .

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-cyano-benzyl) -piperidine-4- carboxylic acid ethyl ester was reacted with the general method outlined in example 1 . (5.46 g, 19.8 mmol) and 4- cyano-benzyl-bis- (2-chloro-ethyl) -amine (5.4 g, 18 mmol) to isolate 4.7 g of the product. Yield (52%); Amber oil; MS: 481 (M + H) &lt; ⁺ & gt ^; .

THF: To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-cyano-benzyl) -piperidine in methanol (60:30 ml) and 10 N NaOH (4-cyano-benzyl) -piperidine-4-carboxylic acid ethyl ester (4 g, 8.3 mmol) -Carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 1.8 g (48%); Off-white solid; MS: 441.9 (M + H) &lt; ⁺ & gt ^; .

Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-cyano-benzyl) -piperidine-4-carboxylic acid (1.8 g, 4 mmol) 0.20 g of 4- (4-butyn-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4- carboxylic acid hydroxamide was obtained as white And separated into the hydrochloride salt form of the solid. Yield 20%; mp 109.6 [deg.] C; MS: 468.0 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 4.88 (s, 2H), 4.85 (s, 2H), 7.15-7.19 (d, 2H) 2H), 7.67-7.70 (d, J = 13.5, 2H), 7.78 (m, 2H), 7.96-7.99 (d, J = 9.6, 2H), 9.42 , &Lt; / RTI &gt; 1H), 11.20 (s, 1H).

Example 9

- (4-methyl-benzyl) -piperidine-4-carboxylic acid hydroxamide

2 - [(2-Hydroxy-ethyl) - (4-methyl-benzyl) -amino] -ethanol was prepared according to the general method outlined in Example 1 (step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 4-methylbenzylbromide (8.5 g, 46 mmol), 8.2 g of the product was isolated. Yield, (85%); White solid; MS: 210.1 (M + H) &lt; ⁺ & gt ^; .

4-Methyl-benzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method as outlined in example 1 (step 5). Starting with 2 - [(2-hydroxy-ethyl) - (4-methyl-benzyl) -amino] -ethanol (6.0 g, 20 mmol) 5.2 g of the product were isolated. Yield: (84%); Yellow solid; mp 145-147 [deg.] C; MS: 245.9 (M + H) &lt; ⁺ & gt ^; .

4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methyl-benzyl) -piperidine-4- carboxylic acid ethyl ester was prepared in analogy to the general procedure outlined in example 1 Respectively. (5.75 g, 19.0 mmol) and 4-methyl-benzyl-bis- (2-chloro-ethyl) -amine (6.04 g, 208 mmol, ) To isolate 6.47 g of the product. Yield: (72%); Amber oil; MS: 470 (M + H) &lt; ⁺ & gt ^; .

To a stirred solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (4-methyl-benzyl) -piperidine 4-carboxylic acid ethyl ester (6.4 g, 13.6 mmol) to give 4- (4-but-2-ynyloxy- benzenesulfonyl) . The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 2.3 g (48%); Off-white solid; mp 213 [deg.] C; MS: 441.9 (M + H) &lt; ⁺ & gt ^; .

Starting from 2.0 g (5.0 mmol) of 4- (4-but-2-ynyloxy- benzenesulfonyl) - l- (4- methyl- benzyl) -piperidine- -Benzyl) -piperidine-4-carboxylic acid hydroxamide (3.6 g) as an off-white solid HCl salt form. Yield 1.2 g (28%); mp 188 [deg.] C; MS: 457.0 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); (d, J = 4.5, 2H), 4.89 (d, J = 1.8, m, 2H) (D, J = 8.1 Hz, 2H), 7.16-7.19 (d, J = 9 2H), 7.24-7.26 (d, J = 7.5 Hz, 2H), 7.37-7.40 10.11 (s, 1 H), 11.20 (s, 1 H).

Example 10

- (3,4-Dichloro-benzyl) -piperidine-4-carboxylic acid hydroxamide

2 - [(2-Hydroxy-ethyl) - (3,4-dichloro-benzyl) -amino] -ethanol was prepared according to the general method outlined in Example 1 (step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (8.97 g, 46 mmol), 9.4 g of product was isolated. Yield, (78%); White solid; MS: 264.3 (M + H) &lt; ⁺ & gt ^; .

3,4-Dichloro-benzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method as outlined in example 1 (step 5). Starting with 2. [(2-hydroxy-ethyl) - (3,4-dichloro-benzyl) -amino] -ethanol (10.7 g, 41 mmol), 10.7 g of the product was isolated. Yield: (84%); Yellow solid; mp 218-220 [deg.] C; MS: 301.8 (M + H) &lt; ⁺ & gt ^; .

The title compound was prepared in accordance with the general method outlined in example 1 (step 6) from 4- (4-but-2-ynyloxy- benzenesulfonyl) - l- (3,4- dichloro-benzyl) -piperidine- &Lt; / RTI &gt; (2-chloro-ethyl) -amine (8.6 g, 25 mmol) was added to a stirred solution of (4-but-2-ynyloxy-benzenesulfonyl) 0.0 &gt; mmol) &lt; / RTI &gt; Yield (41%); Amber oil; MS: 523.8 (M + H) &lt; ⁺ & gt ^; .

To a stirred solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) - l- (3,4-dichloro-benzyl) -piperidin-4- 4-carboxylic acid ethyl ester (8.6 g, 16.4 mmol) to give 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (3,4- dichloro- benzyl) -piperidine -4-carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 2.1 g (38%); Off-white solid; mp 232 ° C; MS: 495.9 (M + H) &lt; ⁺ & gt ^; .

Starting from 2.06 g (4.0 mmol) of 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (3,4- dichloro-benzyl) -piperidine- According to the procedure outlined in step 8), 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (3,4- dichloro-benzyl) -piperidine-4- carboxylic acid hydroxamide 1.2 g &lt; / RTI &gt; was separated into the HCl salt form of an off-white solid. Yield 1.2 g (56%); mp 213 [deg.] C; MS: 510.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 4.90 (s, 2H), 7.16-7.19 (d, 2H), 1.80 (m, 2H) J = 9.2H), 7.51-7.54 (d, J = 8.4,2H), 7.66-7.69 (d, J = 9.0, 2H), 7.75-7.86 ), 9.38 (s, 1 H), 10.44 (s, 1 H), 11.19 (s, 1 H).

Example 11

4- (4-Prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

Step 1:

(4-prop-2-ynyloxy-phenylsulfanyl) -acetic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 2). 2.4 g of the product was isolated starting from (4-hydroxy-phenylsulfanyl) -acetic acid ethyl ester (example 1, first paragraph) (2.12 g, 10 mmol) and propargylbromide (1.8 g, 15 mol) did. Yield: (96%); Amber oil; MS: 251 (M + H) &lt; ⁺ & gt ^; .

Step 2:

(4-prop-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester was prepared according to the general method as outlined in example 1 (step 3). 2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (2.8 g, 10 mmol) was obtained starting from 4- (4-prop-2-ynyloxy-phenylsulfanyl) . Yield (99%); Brown oil; MS: 283 (M + H) &lt; ⁺ & gt ^; .

Step 3:

4- (4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid ethyl ester was prepared in accordance with the general method outlined in example 1 &Lt; / RTI &gt; (31.6 g, 76.7 mmol) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine , 92 mmol), 23 g of the ester derivative was isolated. Yield: (58%); Yellow oil; MS: 521.9 (M + H) &lt; ⁺ & gt ^; .

Step 4:

(4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) - (4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid ethyl ester (5 g, 9.59 mmol) 4-carboxylic acid. &Lt; / RTI &gt; The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 3.4 g (72%); Brown low melting point solids; MS: 491.9 (MH) ^- .

Step 5:

Starting from l- (4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine- 4- carboxylic acid (3 g, 6.1 mmol) 4- (4-prop-2-ynyloxy-benzene-sulfonyl) -piperidine-4-carboxylic acid hydroxyamide 580 (prepared according to the procedure outlined in 8) mg &lt; / RTI &gt; was separated into the HCl salt form of off-white powder. Yield 18%; mp 155 [deg.] C; MS: 508.8 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6): δ2.22 (m, 2H), 2.50 (m, 2H), 2.79 (m, 2H), 3.45 (m, 2H), 4.27 (m, 2H), 2H), 7.48 (m, 2H), 7.68 (m, 4H), 9.37 (s, 1H), 10.36 , &Lt; / RTI &gt; 11.19 (s, 1H).

Example 12

Synthesis of 1- (4-bromo-benzyl) -4- [4- (4-piperidin-4-yl-but- 2-ynyloxy) -benzenesulfonyl] -piperidine-4- carboxylic acid hydroxyamide

Acetic acid (5 mL) was added to a stirred solution of piperidine (1.63 g, 19.2 mmol) diluted in dioxane (100 mL). The reaction was fumed and stirred for 5 min. 4-carboxylic acid ethyl ester (5.0 g, 9.6 mmol), paraformaldehyde (prepared as described for the preparation of 0.29 g, 9.6 mmol) and copper (I) chloride (0.35 g) were added to the piperidine solution. The reaction turned green and it turned brown when heated in reflux for 1 hour. It was concentrated, diluted in ice water, adjusted to pH 8 with NH ₄ OH, and extracted with CHCl ₃ . Washed with water four times and then the organic layer was dried over Na ₂ SO ₄ and concentrated. The product was purified by silica gel column chromatography, eluting with a 5% methanol: chloroform solution. Yield 5.15 g (87%); Brown oil; MS: 309.9 (M + 2H) ²⁺ , 618.8 (M + H) ^& lt ^;

To a stirred solution of l- (4-bromo-benzyl) -4- [4- (4-piperidin-l-yl-but-2 (4-bromo-benzyl) -4- [4- (4-piperidin-4-ylmethyl) -piperidine-4- carboxylic acid ethyl ester (4.64 g, 7.5 mmol) Di-l-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 3.35 (76%); Off-white solid; mp 180 [deg.] C; MS: 295.9 (M + 2H) ²⁺ 590.9 (M + H) &lt; ⁺ & gt ^; .

Synthesis of l- (4-bromo-benzyl) -4- [4- (4-piperidin- l-yl-but- 2-ynyloxy) -benzene- sulfonyl] -piperidine- g, 3.2 mmol) and following the procedure outlined in Example 1 (step 8), l- (4-bromo-benzyl) -4- [4- (4-piperidin- -2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide (810 mg) was isolated as a pale yellow solid in the form of the hydrochloride salt. Yield 40%; mp 209 [deg.] C; MS: 303.4 (M + 2H) ²⁺ 605.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 7.24 (d, J = 9 Hz, 2H), 7.24 (m, 2H) 2H), 7.51 (d, J = 8.4Hz, 2H), 7.67 (m, 4H), 9.39 (s, 1H), 10.45 (s, 1H).

Example 13

4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4- carboxylic acid hydroxyamide

Acetic acid (5 mL) was added to a stirred solution of morpholine (1.68 g, 19.2 mmol) diluted in dioxane (100 mL). The reaction was fumed and stirred for 5 min. 4-carboxylic acid ethyl ester (5.0 g, 9.6 mmol), paraformaldehyde (prepared as described in Example 1, step 2) and 4- (4-bromo-benzyl) 0.29 g, 9.6 mmol) and copper (I) chloride (0.35 g) were added to the piperidine solution. The reaction turned green and upon heating at reflux for 1 hour it turned brown. It was concentrated, diluted in ice water, adjusted to pH 8 with NH ₄ OH and extracted with CHCl ₃ . It was washed with water four times and the organic layer dried over Na ₂ SO ₄ then was concentrated. 4-carboxylic acid ethyl ester was reacted with l- (4-bromo-benzyl) -4- [4- (4-morpholin- And purified by silica gel column chromatography eluting with a 5% methanol: chloroform solution. Yield 3.0 g (50%); Colorless solid; mp 110 [deg.] C; MS: 311 (M + 2H) ²⁺ , 621 (M + H) &lt; ⁺ & gt ^; .

4- (4- (4-morpholin-4-yl-but-thiazol-2-yl) -thiazol- (4-bromo-benzyl) -4- [4- (4-morpholino) benzylsulfonyl] -piperidine-4- carboxylic acid ethyl ester (2.87 g, 4.6 mmol) 4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 2.26 g (83%); White powder; mp 198 [deg.] C; MS: 593.1 (M + H) &lt; ⁺ & gt ^; .

- benzenesulfonyl] -piperidine-4-carboxylic acid (2.1 g, &lt; RTI ID = 0.0 &gt; 4- (4-morpholin-4-yl-but-2-ynyloxy) - Benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide was isolated in the form of the hydrochloride salt of a white solid. Yield 80%; mp 94 [deg.] C; MS: 304.4 (M + 2H) ²⁺ 607.9 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 2.46 (m, 2H), 2.75 (m, 2H), 3.35 (m, 2H), 3.87 2H), 7.67 (m, 4H), 9.42 (s, 1H), 10.69 (s, 1H, ), 11.13 (s, 1 H).

Examples of compounds wherein A = S or S = O.

Example 14

4- (4-But-2-ynyloxy-phenylsulfanyl) -4- hydroxycarbamoyl-piperidine-l-carboxylic acid tert-butyl ester

To a solution of triphenylphosphine (24.7 g, 94.2 mmol) and dimethylformamide (0.6 mL) in dichloromethane (25 mL) was added 4-but-2-ynyloxy- phenylsulfonyl chloride (7.69 g, 31.4 mmol) was sparged over 30 minutes. After an additional 2 hours, 1 N aqueous hydrochloric acid (20 mL) and water were added. The organic layer was separated and concentrated in vacuo. Aqueous sodium hydroxide (1N, 50 mL) was added and filtered to remove solids. The aqueous phase was washed with diethyl ether (3 times), treated with 1 N aqueous hydrochloric acid (50 mL) and extracted with ether (3 times). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated to give an oil-like thiol (3.77 g). This material was dissolved in dimethylsulfoxide (40 mL) and concentrated hydrochloric acid was added (2 mL). After 18 hours diethyl ether was added and the organic phase was washed with water (5 times) and dried over anhydrous magnesium sulfate. Concentration in vacuo yielded a yellow solid which was filtered through silica gel with hexane: ethyl acetate to afford bis (4-but-2-ynyloxyphenyl) disulfide as a yellow solid (3.0 g, 80%). _{^{1 H NMR (CDCl 3: 300}} MHz): 1.86 (s, -CH3, 3H), 4.63 (s, -CH2, 2H), 6.90 (d, ArH, 2H, J = 9Hz), 7.40 (d, ArH, 2H, J = 9 Hz).

To a solution of N-BOC-isonipecotic acid (0.62 g, 2.7 mmol) in tetrahydrofuran (20 mL) at -78 <0> C was added tert-butyllithium (3.4 mL, 1.7 M in hexanes, 5.7 mmol). After 10 min at -78 [deg.] C, the yellow solution was warmed to 0 [deg.] C in an ice bath. After 30 min, the colorless solution was cooled to -78 캜 while bis (4-but-2-ynyloxyphenyl) disulfide (1.0 g, 2.8 mmol) was added in tetrahydrofuran (6 mL) in solution. The reaction mixture was warmed to 25 &lt; 0 &gt; C. After 1.5 hours, ethyl acetate was added followed by 6 mL of 1N aqueous hydrochloric acid in 20 mL of water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (methanol / methylene chloride) gave the product (0.55 g). _{^{1 H NMR (DMSO-d 6}} ): 1.38 (s, OtBu, 9H), 1.5-1.6 (m, CH H, 2H), 1.84 (s, CH3, 3H), 1.89-1.99 (m, CH H, 2H ), 2.95-3.05 (m, CH H , 2H), 3.6-3.7 (m, CH H, 2H), 4.8 (s, CH2, 2H), 6.95 (d, ArH, 2H, J = 9Hz), 7.38 ( d, ArH, 2H, J = 9 Hz).

Dimethylformamide (0.163 mL) was added to a solution of oxalyl chloride (1.06 mL of 2.0 M solution in dichloromethane) in dichloromethane (2 mL) at 0 ° C. After 15 minutes, an acid solution (5 mL) in dimethylformamide was added and the reaction mixture was warmed to room temperature. After 1 hour the reaction mixture was added to a mixture of hydroxylamine hydrochloride (0.737 g), triethylamine (2.22 mL), water (5.7 mL) and tetrahydrofuran (22.8 mL) stirred at 0 ° C for 15 minutes. The reaction was maintained at 0 &lt; 0 &gt; C for 18 h, then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate (3x), dried over potassium carbonate and concentrated in vacuo to give 4- (4- -Phenylsulfanyl) -4-hydroxycarbamoyl-piperidine-l-carboxylic acid tert-butyl ester as a colorless oil. ^{1 H NMR (DMSO-d6)} : 1.37 (s, OtBu, 9H), 1.5-1.6 (m, CH H, 2H), 1.84 (s, CH 3, 3H), 1.9-2.0 (m, CH H, 2H ), 3.05-3.15 (m, CH H , 2H), 3.5-3.6 (m, CH H, 2H), 4.8 (s, CH 2, 2H), 6.9 (d, ArH, 2H), 7.4 (d, ArH , 2H), 8.8 (s, NHOH, 1H), 10.7 (d, NHOH, 1H).

Example 15

4- (4-But-2-ynyloxy-phenylsulfanyl) -piperidine-4- carboxylic acid hydroxyamide

4- (4-But-2-ynyloxy-phenylsulfanyl) -4-hydroxycarbamoyl-piperidine-l-carboxylic acid tert-butyl ester prepared by the process outlined in Example 14 (step 3) Was treated with 4N hydrochloric acid in dioxane (5 mL) at 25 &lt; 0 &gt; C for 1 hour and 15 minutes. The reaction mixture was concentrated in vacuo, diethyl ether was added and the resulting precipitate was separated by filtration to give 4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine 4-carboxylic &lt; / RTI &gt; acid hydroxyamide. Electrospray mass analysis: ((M + H) &lt; ⁺ & gt ^; = 321).

Example 16

Synthesis of l- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4- carboxylic acid hydroxyamide

To a solution of 4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide (prepared as outlined in example 15) in methanol (5 mL) and dimethylformamide (0.15 g, 0.5 mmol) was treated with triethylamine (0.15 mL, 1.1 mmol) followed by 4-bromobenzyl bromide (0.13 g, 0.53 mmol). After 6 h, the solution was diluted with ethyl acetate, acidified to pH 6 using 1N aqueous hydrochloric acid, and then washed with water, aqueous sodium bicarbonate and brine in this order and dried over anhydrous sodium sulfate. Concentration in vacuo gave l- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4- carboxylic acid hydroxyamide. ^{1 H NMR (DMSO-d6)} : 1.5-1.6 (m, CH H, 2H), 1.8 (s, CH3, 3H), 1.9-2.2 (m, CH H, 4H), 2.5-2.6 (m, CH H 2H), 7.3 (d, ArH, 2H), 7.5 (d, ArH, 2H) (d, ArH, 2H), 8.8 (s, NHOH, 1H), 10.6 (d, NHOH, 1H). Electrospray mass spectrometry: ((M + H) ⁺ = 489/491).

Examples of compounds wherein n = 1 and A = S, S = O or SO ₂ .

Example 17

4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide

4-But-2-ynyloxy-benzenesulfonic acid sodium salt

59.96 (0.45 mol) of 1-bromo-2-butyne was added to a solution of 52.35 g (0.225 mol) of 4-hydroxybenzenesulfonate sodium salt in 1 liter of isopropanol and 225 ml of a 1.0N sodium hydroxide solution. The resulting mixture was heated to 70 &lt; 0 &gt; C for 15 hours and the isopropanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether, and then dried in vacuo to give 56.0 g (100%) of a white solid butinyl ether.

4-But-2-ynyloxy-benzenesulfonyl chloride

To a 0 ° C solution of 43.8 mL (0.087 mol) of oxalyl chloride in 29 mL of dichloro-methane was added 6.77 mL (0.087 mol) of DMF followed by 7.24 g (0.029 mol) of 4-but- 2-ynyloxy-benzenesulfonic acid sodium salt, . The reaction mixture was stirred at 0 占 폚 for 10 minutes, warmed to room temperature and then stirred for 2 days. The reaction was poured into ice and extracted with 150 mL of hexane. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 6.23 g (88%) of the sulfonyl chloride in the yellow solid: mp. 63-65 ° C. EI mass spectrometry: 243.9 (M <^+> ).

But-2-ynyloxy-benzene

1.75 mL (23.40 mmol) of 2-butyn-1-ol was added to a solution of 6.14 g (23.40 mmol) of triphenylphosphine dissolved in 100 mL of benzene and 50 mL of THF. After 5 minutes, 2.00 g (21.28 mmol) of phenol dissolved in 10 mL of THF was added to the reaction followed by 3.69 mL (23.40 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane (1:10) to give 2.18 g (70%) of the desired propargyl ether of the clear liquid. EI mass spectrometry: 146.0 M ⁺

4-But-2-ynyloxy-benzenesulfonyl chloride

To a solution of 0.146 g (1.0 mmol) of but-2-ynyloxy-benzene in 0.3 mL of dichloromethane in an acetone / ice bath under N ₂ was added dropwise a 0.073 mL (1.1 mmol) solution of chlorosulfonic acid in 0.3 mL of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. 0.113 mL (1.3 mmol) of oxalyl chloride was added to the reaction, and 0.015 mL of DMF was added. The reaction was heated to reflux for 2 hours, diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 0.130 g (53%) of the desired product as a light brown solid.

4-But-2-ynyloxy-benzenethiol

To a solution of 11.8 g (0.045 mol) of triphenylphosphine dissolved in 10 mL of dichloromethane and 0.3 mL of DMF was added 3.67 g (0.015 mol) of 4-but-2-ynyloxy-benzenesulfonyl chloride, And the resulting mixture was stirred at room temperature for 2 hours. After 5 mL of 1N HCl was added, the reaction was stirred for 0.5 hour, followed by the addition of 15 mL of brine. The organic layer was separated and concentrated in vacuo and the residue was diluted with ether and 2.5 N sodium hydroxide solution. The resulting precipitate was filtered, the aqueous layer was acidified to pH 2 and extracted with ether. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , then filtered through Magnesol ^R and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane / ether (4: 1) to give 1.13 g (42%) of the thiol of the yellow oil. CI Mass Spec: 179 (M + H).

4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid

0.500 g (2.81 mmol) of 4-but-2-ynyloxybenzenethiol was added to a solution of 0.112 g (2.81 mmol) of 60% sodium hydride in 2 mL of THF cooled at 0 ° C and dissolved in 3 mL of THF. The resulting mixture was stirred at room temperature for 0.5 hour and then cooled to 5 ° C followed by the addition of 0.518 g (3.65 mmol) of knit 2,7-dioxaspiro [3.5] nonan-1-one ) Was added. The reaction was warmed to room temperature and stirred for an additional 0.5 h, then cooled with 3 mL of 3N HCl solution and 3 mL of water. The resultant mixture is washed and the formed organic layer extracted with dichloromethane with water and brine, and was dried over Na ₂ SO _4, and then, filtered through a silica gel plug and concentrated in vacuo. The residue was triturated with hexane and acetonitrile and filtered to yield 0.72 g of the semi-solid carboxylic acid. Electrospray mass analysis: 319 (MH) ^- .

4- (4-But-2-ynyloxy-phenylsulfanylmethyl-tetrahydro-pyran-4-carboxylic acid hydroxyamide

To a 0 ° C solution of 4-74 (4-but-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid (0.74 g, 2.31 mmol) dissolved in 7 mL of dichloromethane and 0.175 mL of DMF was added oxalyl chloride 2 M solution (1.27 mL, 2.54 mmol). The reaction was warmed to room temperature, stirred for 2 hours and then re-cooled to 0 &lt; 0 &gt; C. A mixture of 0.875 mL (14.2 mmol) of a 50% hydroxylamine solution, 5.0 mL of THF and 2.0 mL of t-butanol was added to the reaction. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was extracted with dichloromethane and the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane / methanol (92: 8) to give 0.212 g of a white solid, sulfide-hydroxamic acid; mp 135-137 [deg.] C. Electrospray mass analysis: 336 (M + H) &lt; ⁺ & gt ^;

Example 18

4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -tetrahydro-pyran-4- carboxylic acid hydroxyamide

To a 0 ° C solution of 0.186 g (0.56 mmol) 4- (4-but-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide dissolved in 1.2 mL of THF and 4.8 mL of methanol was added water A solution of 0.619 g (1.008 mmol) of Oxone ^R in 3 mL was added dropwise maintaining the temperature below 20 &lt; 0 &gt; C. After the addition was complete, the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into a cold solution of 2.5 mL of toluene and 5 mL of ethyl acetate and the precipitate was filtered off. The filtrate was extracted with ethyl acetate / toluene and the organic layer was washed with water, combined, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with ethyl acetate / toluene (5: 2), filtered and then dried in vacuo to yield 0.12 g (55%) of a white solid, sulfone-hydroxamic acid; mp 184-185 [deg.] C. Electrospray mass analysis: 368 (M + H) &lt; ⁺ & gt ^; .

Example 19

4- (4-But-2-ynyloxy-benzenesulfinylmethyl) -tetrahydro-pyran-4- carboxylic acid hydroxyamide

To a 0 C solution of 0.288 g (0.80 mmol) 4- (4-but-2-ynyloxy-benzenesulfanylmethyl) -tetrahydro-pyran-4- carboxylic acid hydroxyamide dissolved in 20 mL methanol was added 30% 7.0 mL of an oxide solution was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction mixture was re-cooled to 0 ℃, cooled with saturated Na ₂ SO ₃ and then concentrated in vacuo. The residue was diluted with water and dichloromethane. The organic layer was washed with water and brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane / methanol (95: 5) to give 0.050 g of the sulfoxide of the white solid. Electrospray mass spectrometry: 351.9 (M + H) &lt; ⁺ & gt ^;

Example 20

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pyran-

Step 1:

Ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-

Acetic acid ethyl ester (10 g, 33.8 mmol) was added to a solution of potassium carbonate (12 g), 18-crown-6 (0.5 g), 2- chloroethyl ether (4.75 ML, 40.5 mmol) and tetrabutylammonium bromide (0.5 g) in methyl ethyl ketone (200 mL). The mixture was heated at reflux overnight, then the salt was filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The compound was eluted with 20% ethyl acetate: hexane solution and separated using silica-gel column chromatography. The ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carboxylate of the yellow oil was isolated (10.06 g). Yield 80%; MS: 367.2 (M + H) &lt; ⁺ & gt ^; .

Starting from ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carboxylate (10 g, 27.3 mmol) 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carbox7lic acid was prepared according to the method; 2.7 g white solid. mp: 197 [deg.] C; Yield 30%; MS: 337.2 (MH) ^- .

Starting from a crude mixture of 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carboxylic acid (2.59 g, 7.66 mmol) According to the procedure outlined, 1.51 g of 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pyran-4-carboxamide was isolated in off- . Mp: 210 占 폚; Yield: 58%; MS: 354.2 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); (d, J = 13.1 Hz, 2H), 3.15 (t, J = 11.52, 2H), 3.86 (d, (D, J = 8.9 Hz, 2H), 4.88 (d, J = 2.34 Hz, 2H), 7.16 1H).

Example 21

Benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide

(3-hydroxyphenyl) -piperidine was prepared according to the general procedure outlined in Example 1 (step 1) starting from ethyl bromoacetate (7.95 g, 47.6 mmol) and 3-hydroxythiophenol (7.95 g, ) &Lt; / RTI &gt; sulfanyl] acetate; 4.21 g yellow oil. Yield 41%; MS: 211.2 (MH) ^- .

(Step 2), starting from ethyl [(3-hydroxy-phenyl) sulfanyl] acetate (3.87 g, 18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol) Ethyl {[3- (2-butynyloxy) phenyl] sulfanyl} acetate was prepared according to a general method; 5.16 g yellow oil. Yield 100%; MS (EI): 264.1 (M + H) &lt; ⁺ & gt ^; .

The general procedure outlined in Example 1 (step 3) starting from ethyl {[3- (2-butynyl-phenyl) sulfanyl} acetate (5 g, 18.9 mmol) and oxone (23.3 g, 37.9 mmol) Thereby preparing ethyl {[3- (2-butynyloxy) phenyl] sulfonyl} acetate; 6.19 g yellow oil. Yield 100%; MS (EI): 296.1 (M + H) &lt; ⁺ & gt ^; .

Starting from ethyl {[3- (2-butynyloxy) phenyl] sulfonyl} acetate (3 g, 10.1 mmol) and benzyl-bis- (2- chloro-ethyl) amine hydrochloride (2.88 g, 10.7 mmol) Benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylate was prepared according to the general method as outlined in example 1 (step 6) from 2.91 g Yellow oil. Yield 63%; MS: 456.3 (M + H) &lt; ⁺ & gt ^; .

Starting from ethyl 1-benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylate (2.9 g, 6.37 mmol) Benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid; 1.10 g off-white powder. mp: 171 [deg.] C; Yield 40%; MS: 428.4 (M + H) &lt; ⁺ & gt ^; .

Starting from 1-benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid (1 g, 2.34 mmol) and following the procedure outlined in Example 1 460 mg of 1-benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide was isolated in the form of off-white solid. mp: 91.4 DEG C; Yield: 41%; MS: 443.4 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -D 6): δ1.83 (t, 3H), 2.23-2.27 (m, 2H), 2.73-2.89 (m, 2H), 3.29 (m, 2H), 3.68 (q 2H), 4.31 (m, 1H), 4.39 (d, J = 5 Hz, 1H), 4.85 (d, J = 2.25, 2H), 7.25-7.61 11.2 (s, 1 H).

Example 22

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1-isopropyl-4-piperidinecarboxamide

(4.88 g, 22.3 mmol) and isopropyl [bis (2-chloroethyl)] amine hydrochloride (4.88 g, 22.3 mmol) in DMF Prepared ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-isopropyl-4-piperidinecarboxylate according to the general procedure outlined in Example 1 (step 6); 5.28 g brown oil. Yield 64%; MS: 408.2 (M + H) &lt; ⁺ & gt ^; .

Starting from ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-isopropyl-4-piperidinecarboxylate (5.25 g, 13 mmol) 4 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1-isopropyl-4-piperidinecarboxylic acid was prepared according to the general method outlined above; 2.06 g yellow solid. mp: 233 [deg.] C; Yield 42%; MS: 380.1 (M + H) &lt; ⁺ & gt ^; .

Starting from 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-isopropyl-4-piperidinecarboxylic acid (1.9 g, 5 mmol) 107 mg of 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1-isopropyl-4-piperidinecarboxamide was isolated as a brown solid did. mp: 105 [deg.] C; Yield: 5%; MS: 395.2 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 3.52 (m, 2H), 3.57 (m, 2H), 3.57 (m, 2H) , 4.89 (m, 2H), 7.19 (m, 2H), 7.71 (m, 2H), 9.3 (s,

Example 23

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxamide

(4.18 g, 18.6 mmol) and 3-pyridylmethyl [bis (2-chloroethyl)] amine hydrochloride were obtained as a colorless oil from 4- (4-but-2-ynyloxy-benzenesulfonyl) Starting from ethyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-pyridinylmethyl) -4-piperidylcarbamate according to the general procedure as outlined in example 1 Lt; / RTI &gt;carboxylate; 370 mg brown oil. Yield 5%; MS: 457.4 (M + H) &lt; ⁺ & gt ^; .

4-piperidinecarboxylate (320 mg, 0.7 mmol), starting from 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3- pyridinylmethyl) (2-butynyloxy) phenyl] sulfonyl} -1- (3-pyridinylmethyl) -4-piperidinecarboxylic acid was prepared according to the general method as outlined in step 6 (step 6); 150 mg yellow solid. Yield 50%; MS: 429.2 (M + H) &lt; ⁺ & gt ^; .

Starting from 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-pyridinylmethyl) -4-piperidinecarboxylic acid (860 mg, (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxylic acid tert-butyl ester according to the procedure outlined in step 8). 800 mg of the radiide was isolated in the form of a white solid. mp: 115 [deg.] C; Yield: 84%; MS: 444.1 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 2.84 (m, 2H), 3.46 (d, J = 12 Hz, 2H), 4.45 (s, 2H) J = 8.9 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H) 8.0 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.87 (d, J = 4.6 Hz, 1H), 8.99 (s, 1H), 11.4 (s, 1H).

Example 24

3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy-

Step 1: Piperidine-l, 3-dicarboxylic acid l-tert-butyl 3-ethyl ester

Di-t-butyl dicarbonate (7.1 g, 33 mmol) was sliced into a stirred solution of ethylnipecotate (5.1 g, 33 mmol) and triethylamine (3.7 g, 36 mmol) in CH ₂ Cl ₂ Was added. The reaction mixture was stirred at room temperature for 18 hours, cooled with ice water and then extracted with chloroform. The organic layer was dried over sodium sulfate, concentrated and then chromatographed on a silica-gel column of 20: 80 ethyl acetate: hexane. Piperidine 1,3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester was isolated in the form of a wax solids. Yield 6.86 g (82%). MS (ES): m / z 258.2 (M + H) &lt; ⁺ & gt ^; .

Step 2: 1- (tert-Butyl) -3-ethyl-3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1,3-piperidinecarboxylate

To a stirred solution of diisopropylamine (7.2 g, 28 mmol) in THF (25 mL) at -78 <0> C was added n-butyllithium (1.6 m solution in hexanes, 19.0 mL, 30.8 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes. The mixture was cooled to -78 C and piperidine-l, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (5.3 g, 28 mmol) in THF (20 mL) was slowly added. The reaction mixture was stirred for 30 min and then 4-but-2-ynyloxy-benzenesulfonyl fluoride (6.4 g, 28 mmol) in THF (15 mL) was slowly added. The reaction was warmed to room temperature, and after 4 hours, it was cooled with ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed on a silica-gel column using 20% ethyl acetate: hexanes to give 1- (tert-butyl) 3-ethyl- - (2-butynyloxy) phenyl] -sulfonyl} -1,3-piperidine dicarboxylate. Yield 9.8 g (76%); mp 103.4 [deg.] C; MS (ES): m / z 466.4 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 4.91 (m, 4H), 4.00 (m, 2H), 4.83 (d, 2H) , &Lt; / RTI &gt; 7.22 (d, 2H), 7.71 (d, 2H).

Step 3: To a solution of l- (tert-butyl) 3-ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1,3-piperidinedicarboxylic acid (5.45 g, 11.7 mmol) in methylene chloride (25 mL) was added a saturated solution of hydrogen chloride in methylene chloride (25 mL). After 5 h the solution is concentrated to give ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -3-piperidinecarboxylate hydrogen chloride which is stored under nitrogen. White hygroscopic solids; Yield 3.47 g (74%); MS (ES): m / z 366.2 (M + H) &lt; ⁺ & gt ^; .

Step 4: (Ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -l-ethyl-3-piperidinecarboxylate)

(2.97 g, 8.0 mmol), ethyl iodide (1.28 g, 8 mmol) and dry acetone &lt; RTI ID = 0.0 &gt; (3.8 g) in dry powdered potassium carbonate (60 ml) was heated at reflux for 18 hours. The mixture was cooled and the potassium salt was filtered off and concentrated. The residue was extracted with chloroform, washed with H ₂ O, dried over sodium sulfate and then concentrated to give ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidine Carboxylate was obtained. This product was used without further purification. Amber gum, yield 3.47 g (99%); MS (ES): m / z 394 (M + H) &lt; ⁺ & gt ^; .

Step 5: Ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidine dissolved in THF: methanol (15:25 mL) and NaOH (15 mL) Phenyl] sulfonyl} -1-ethyl-3-piperidinecarboxylic acid 3 - {[4- (2- (4- Butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidinecarboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7). Yield 2.11 g (71%), white solid; mp 159.2 C; MS (ES): m / z 366.3 (M + H) &lt; ⁺ & gt ^; .

Step 6: Synthesis of 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy-3-piperidinecarboxamide

Starting from 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1-ethyl-3-piperidinecarboxylic acid (2.0 g, 5.5 mmol) and following the procedure outlined in Example 1 Phenyl] sulfonyl} -1-ethyl-N-hydroxy-3-piperidinecarboxamide hydrogen chloride in the form of a white solid did. Yield 10%; mp 190.3 [deg.] C; MS (ES): m / z: 405.3 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); 3H), 3.82 (d, IH), 4.91 (m, 2H), 3.51 (m, 2H) , 7.19 (d, 2H), 7.51 (s, 5H), 8.67 (s, 1H), 9.48 (s, 1H).

Example 25

3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide

Step 1: Ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -3-piperidinecarboxylate

Carboxylate Hydrochloride (1.1 g, 2.7 mmol) and 4-chlorobenzyl chloride in dry acetone (50 mL) were added to a solution of 2- (4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-methoxyphenyl) propanoic acid ethyl ester was obtained as a brown oil, starting from (0.485, 3.0 mmol) and following the procedure outlined in example 24 -Chlorobenzyl) -3-piperidinecarboxylate was isolated. This product was taken and used in the next step without further purification. Yield 1.66 g (99%); MS (ES): m / z 491.3 (M + H) &lt; ⁺ & gt ^; .

Step 2: Preparation of 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4- chlorobenzyl) -3-piperidinecarboxylic acid

To a stirred solution of ethyl 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chloro-benzyl) -3- (2-butynyloxy) phenyl] sulfonyl} - l- (4-chlorobenzyl) -1-3-piperidinecarboxylic acid tert- Carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 1 (step 7); Yield 1.11 g (75%), white solid: mp 115.2 [deg.] C; MS (ES): m / z 462.1 (M + H) &lt; ⁺ & gt ^; .

Step 3: Preparation of 3 - {[4- (2-butynyloxy) phenyl] sulfonyl] -1- (4- chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide

Starting from 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4- chlorobenzyl) -3-piperidinecarboxylic acid (1.1 g, 2.4 mmol) ), Was prepared as white solids from 3 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -3-N-hydroxy- 0.48 g of dicycarboxamide hydrogen chloride was isolated. Yield 43%; mp 124.4 [deg.] C; MS (ES); m / z: 477.1 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 7.15 (m, 4H), 7.61 (d, 2H), 7.19 (m, 2H) , 8.95 (s, 1 H), 9.46 (s, 1 H).

Example 26

- [4- (2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4- carboxylic acid hydrobromide Roxyamide

A mixture of diethanolamine (2.1 g, 20 mmol), 4- (2-piperidin-l-yl-ethoxy) -benzyl chloride (5.9 g, 20 mmol) and K ₂ CO ₃ (10 g, Was refluxed in acetone (100 mL) for 24 hours. Finally, the reaction mixture was cooled to room temperature and filtered. It was concentrated to dryness and redissolved in toluene (200 mL) and thionyl chloride (6.75 g, 50 mmol). This was heated to 80 &lt; 0 &gt; C for 1 h and bis- (2-chloro-ethyl) - [4- (2- piperidin- 1- yl- ethoxy) -benzyl] -amine, which was a brown solid, did. The crude product was taken and used in the next step without purification. Yield: 7.0 g, (89%).

(2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethyl) 4- (2-butynyloxy) phenyl] -4-methylpiperidine-1-carboxylic acid ethyl ester was prepared according to the general procedure as outlined in example 1 (step 6) starting from 4- Sulfonyl} -1- [4- (2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid ethyl ester. 2.8 g of the product (brown oil) was isolated. Yield 48%; MS: 583 (M + H) &lt; ⁺ & gt ^; .

4 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1- [4- (2-piperidin- 1- yl-ethoxy) -benzyl] -piperidine- (4- (2-butynyloxy) phenyl] sulfonyl} -1- [4- ((4-fluorophenyl) 2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid; White powder 2.2 g. mp: 172 [deg.] C; Yield 77%; MS: 555 (M + H) &lt; ⁺ & gt ^; .

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- [4- (2-piperidin- 1- yl-ethoxy) -benzyl] -piperidine- 5.0 g, 9.0 mmol) and following the procedure outlined in Example 1 (step 8), 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} - [4- (2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4- carboxylic acid hydroxyamide. The free amine was dissolved by using methanolic hydrochloric acid to prepare a dihydrochloride salt. mp: 124 DEG C; Yield: 1.8 g (32%); MS: 570 (M + H) &lt; ⁺ & gt ^; .

Example 27

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4- carboxylic acid hydroxyamide

Phenyl) sulfonyl} acetate (8.8 g, 30.0 mmol) and bis- (2-chloro-ethyl) - (3-fentanyl) -amine dihydrochloride (7.4 g, (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine hydrochloride was prepared according to the general procedure as outlined in example 1 (step 6) starting from 4- -4-carboxylic acid ethyl ester. 3.5 g of the product (brown oil) was isolated. Yield 26%; MS: 436 (M + H) &lt; ⁺ & gt ^; .

Starting from 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4- carboxylic acid ethyl ester (3.0 g, 6.8 mmol) (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4-carboxylic acid was prepared according to the general method as outlined in step 7); Spongy yellow solid 2.5 g. mp: 98 [deg.] C; Yield 90%; MS: 408 (M + H) &lt; ⁺ & gt ^; .

Starting from 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4-carboxylic acid (2.5 g, 6.1 mmol) 4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4-carboxylic acid hydrobromide of yellow spongy solids according to the procedure outlined in Scheme 8 1.8 g of &lt; RTI ID = 0.0 &gt; The free amine was dissolved in methanol hydrochloric acid to prepare a hydrochloride salt. mp: 101-103 [deg.] C; Yield: 1.1 g (42%); MS: 460 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); (m, 2H), 3.4 (s, 3H), 3.6 (m, 2H) (d, 2H), 4.9 (s, 2H), 7.21 (d, 2H), 7.8 (d, 2H), 9.3

Example 28

4- (4-Prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

(10.0 g, 35.0 mmol) and 4-methoxy-benzenesulfonyl) -acetic acid ethyl ester (prepared as in steps 1 and 2 of Example 11) and 4-methoxy- (4-methoxy-benzyl) -4- (4-methoxy-benzyl) -amine according to the general procedure outlined in Example 1 (step 6) starting from 2- Propyn-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester. 6.0 g of the product (brown oil) was isolated. Yield 36%; MS: 472 (M + H) &lt; ⁺ & gt ^; .

Carboxylic acid ethyl ester (6.0 g, 12.73 mmol) in an analogous manner to that described in example (b), starting from l- (4-methoxy-benzyl) -4- (4-methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid was prepared according to the general method as outlined in example 1 did; Yellowish solid of sea surface type 5.0 g. mp; 208 DEG C; Yield 92%; MS: 444 (M + H) &lt; ⁺ & gt ^; .

Starting from 6.0 g (13.5 mmol) of 1- (4-methoxy-benzyl) -4- (4-prop-2-ynyloxy- benzenesulfonyl) -piperidine- (4-methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine- l-carboxylic acid ethyl ester as a yellowish sponge- 0.0 &gt; 4-carboxylic &lt; / RTI &gt; acid hydroxyamide was isolated. The free amine was dissolved in methanol hydrochloric acid to prepare a hydrochloride salt. mp: 150 [deg.] C; Yield: 2.0 g (29%); MS: 459 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 7.3 (d, 2H), 7.5 (d, 2H), 4.2 (s, 2H) 2H), 7.6 (d, 2H), 7.7 (d, 2H), 10.9 (s, 1H), 11.2 (s, 1H).

Conduct 29

4- (4-Chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid hydroxyamide

(10.0 g, 35.0 mmol) and 4-chloro-benzyl) -bis (tert-butoxycarbonyl) -acetic acid ethyl ester (prepared as described in steps 11 and 2 of Example 11) (4-chloro-benzyl) -4- (4 (trifluoromethyl) phenyl) -acetic acid was prepared in accordance with the general method as outlined in example 1 (step 6) starting from 5- -Prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester, 8.0 g of product (brown oil) was isolated. Yield 48%; MS: 475 (M + H) &lt; ⁺ & gt ^; .

Carboxylic acid ethyl ester (6.0 g, 12.63 mmol), starting from 1- (4-chloro-benzyl) -4- (4-prop-2-ynyloxy- benzenesulfonyl) -piperidine- (4-chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared according to the general method outlined in step 7 (step 7); Yellowish solid of sea surface type 5.0 g. mp: 205 [deg.] C; Yield 92%; MS: 448 (M + H) &lt; ⁺ & gt ^; .

Starting from l- (4-chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine- 4- carboxylic acid (6.0 g, 13. 4 mmol) (4-chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-one as a yellowish solid of spongy form according to the procedure outlined in step 1 -Carboxylic acid hydroxyamide were separated. The free amine was dissolved using methanolic hydrochloric acid to prepare a hydrochloride salt. mp: 146 [deg.] C; Yield: 4.0 g (59%); MS: 499 (M + H) &lt; ⁺ & gt ^; . ^{1 H NMR (300 MHz, DMSO} -d 6); 2H), 7.71 (d, 2H), 7.71 (d, 2H), 7.71 (d, 2H) 2H), 7.85 (d, 2H), 11.0 (s, 1H), 11.2 (s, 1H).

Example 30

phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Step 1: Piperidine-l, 4-dicarboxylic acid tert-butyl ester ethyl ester

To a solution of ethyl isonipecotate (4.72 g, 0.03 mmol) in 30 mL of THF at room temperature was slowly added di-tert-butyl dicarbonate (7.2 g, 0.03 mmol). The resulting mixture was stirred for 2 h and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ was filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate: hexane (1: 9) to give 7.52 g (97%) of the desired product of a colorless oil. Electrospray mass spectrometry: 258.3 (M + H) &lt; ⁺ & gt ^; .

Step 2: 1- (tert-Butyl) -4-ethyl-4- (iodomethyl) piperidine-1,4-dicarboxylate

To a solution of piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (12.8 g, 49.74 mmol) in dry THF (73 mL) under N ₂ atmosphere at -42 ° C was added heptane / THF / ethyl 24.87 mL (49.74 mmol) of 2M lithium diisopropylamine in benzene was added dropwise. After 1 hour, 4.0 mL (49.74 mmol) of diiodomethane was added and the solution was warmed to ambient temperature overnight. The resulting solution was diluted with H ₂ O and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ which then, when filtered and concentrated in vacuo to give a 18.84 g (95%) desired product of a brown oil was obtained. Electrospray mass spectrometry: 398.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: 4-But-2-ynyloxy-benzenesulfonic acid sodium salt

59.96 g (0.45 mol) of 1 bromo-2-butyne was added to a solution of 4-hydroxybenzenesulfonate sodium salt (52.35 g, 0.225) in 1 liter of isopropanol and 225 mL of a 1.0 N sodium hydroxide solution. The resulting mixture was heated to 70 &lt; 0 &gt; C for 15 hours and evaporated in vacuo to remove isopropanol. The resulting white precipitate was collected by filtration, washed with isopropanol and ether and dried in vacuo to give 45.08 g (81%) of the desired product as a white solid.

Step 4: 4-But-2-ynyloxy-benzenesulfonyl chloride

To a stirred solution of oxalyl chloride (47.8 mL, 0.545 mol) in 240 mL of CH ₂ Cl ₂ at 0 ° C was added dropwise a solution of 4-but-2-ynyloxy-benzenesulfonic acid sodium salt DMF (43.0 mL). The reaction mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes, then warmed to room temperature and stirred for 18 hours. The reaction was poured into ice and extracted with hexane. The organic layer was washed with water and brine, dried over MgSO _4, filtered and concentrated in vacuo when the 42.0 g (95%) desired product as a yellow solid was obtained.

Step 5: 4-But-2-ynyloxy-benzenethiol

To a solution of 11.8 g (0.045 mol) of triphenylphosphine in 10 mL of CH ₂ Cl ₂ and 0.3 mL of DMF was added dropwise a solution of 4-but-2-ynyloxy-benzene-sulfonyl chloride in 15 mL of CH ₂ Cl ₂ . Stir at room temperature for 2 hours, add 5 mL of 1N HCl, stir for 30 minutes, and add 15 mL of brine. The organic layer was separated and concentrated in vacuo. The residue was diluted with ether and the insoluble material was filtered off. The filtrate was washed with 2.5 N NaOH, the aqueous solution was separated, acidified and extracted with ether. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 1.54 g (58%) of the desired product of pale yellow oil.

Step 6: Preparation of l- (tert-butyl) 4-ethyl-4 - ({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -1,4-piperidinecarboxylate

0.294 g (0.74 mmol) of 4-ethyl-4- (iodomethyl) piperidine-1,4-dicarboxylate and 0.145 ) And 0.204 g (1.48 mmol) of K ₂ CO ₃ in 2.0 mL of DMF was stirred at room temperature for 18 hours. The resulting mixture was diluted with EtOAc, washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: hexane (1:19) to give 0.328 g (99%) of the desired product of a colorless oil. Electrospray mass spectrometry: 448.3 (M + H) &lt; ⁺ & gt ^; .

Step 7: 4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -piperidine-l, 4-dicarboxylic acid mono-tert-butyl ester

Phenyl) sulfanyl} methyl) -1,4-piperidinecarboxylate (0.288 g, 0.0643 mmol), 1N (4-ethylpiperazin- A mixture of 3.25 mL of NaOH, 3.25 mL of THF and 3.25 mL of MeOH was heated to reflux for 3 hours. The organic layer was removed and the residue was diluted with H ₂ O, acidified and extracted with EtOAC. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 0.241 g (89%) of the desired product as an off-white gum. Electrospray mass analysis: 464.3 (M + FA-H) ^-

Step 8: WAY 173665 Preparation of tert-butyl 4 - ({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbonyl]

0.204 g (0.49 mmol) of 4- (4-but-2-ynyloxy-phenylsulfanylmethyl) -piperidine- 1,4-dicarboxylic acid mono-tert-butyl ester, 1-hydroxy (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.112 g, 0.84 mmol) was added to a solution of 0.079 g (0.058 mmol) of benzotriazole at room temperature. 0.3 mL of 50% aqueous hydroxylamine was added and stirred for 18 hours. The resulting mixture was diluted with EtOAc, washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH / CH ₂ Cl ₂ to give 0.077 g (36%) of the desired product as a white solid. Electrospray mass analysis: 435.2 (M + H) &lt; ⁺ & gt ^; .

Example 31

4 - ({[4- (but-2-ynyloxy) phenyl] thio} methyl) -N-hydroxypiperidine-

CH ₂ Cl ₂ 5 mL MeOH and 1 mL of tert- butyl 4 - ({[4- (2-butynyl) phenyl] sulfanyl} methyl) -4 - [(hydroxy amino) carbonyl] -1 -Piperidinecarboxylate (0.143 g, 0.033 mmol) in 5 mL of dioxane was added 5 mL of 4M HCl in dioxane and the mixture was stirred for 1 hour. The reaction was concentrated in vacuo, the residue was triturated with ether and then filtered to give 0.093 g (76%) of the desired product as a pale orange solid. Electrospray mass analysis: 335.3 (M + H) &lt; ⁺ & gt ^; .

Example 32

methyl] -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

To a solution of tert-butyl 4 - ({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidine Carboxylate (0.24 g, 0.55 mmol) was slurried in 3.5 mL of 30% hydrogen peroxide. The reaction was warmed to room temperature and stirred for 18 hours. The reaction was cooled to 0 ℃ and saturated Na ₂ SO ₃ solution was cooled to 3.5 mL. The organic layer was removed and the aqueous solution was extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether to give 0.166 g (67%) of the desired product as an off-white solid. Electrospray mass spectrometry: 451.3 (M + H) &lt; ⁺ & gt ^; .

Implementation 33

4 - [[[4- (2-butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide

phenyl] sulfinyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate (0.082 g, 0.18 ({[4- (2-butynyloxy) phenyl] sulfinyl} methyl) -N-hydroxy-4-piperidinecarboxamide was prepared according to the general method as described in Example 31 starting from 0.066 g (95%) of the desired product of the white solid was isolated. Electrospray mass analysis: 351.2 (M + H) &lt; ⁺ & gt ^; .

Example 34

phenyl) sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate

({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbamoylmethoxy) carbonyl chloride in 8 mL of MeOH, 4 mL of CH ₂ Cl ₂ and 2 mL of THF, Yl] -1-piperidinecarboxylate (0.422 g, 0.97 mmol) in 100 mL of H ₂ O was added 1.79 g (2.91 mmol) of OXONE in 8 mL of H ₂ O and the mixture was stirred at room temperature for 18 hours. The solid was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated to give 0.351 g (77%) of the desired product as a white solid. Electrospray mass analysis: 467.3 (M + H) &lt; ⁺ & gt ^; .

Example 35

phenyl) sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

methyl] -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate was synthesized in the same manner as in Example 31 to give tert-butyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} Were prepared according to the general methods outlined. phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate (0.10 g, 0.214 mmol), 0.074 g (86%) of the desired product of a white solid was isolated. Electrospray mass spectrometry: 367.3 (M + H) &lt; ⁺ & gt ^; .

Example 36

Acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide

Step 1: 4 - [[[4- (2-Butynyloxy) phenyl] sulfonyl] methyl] -1,4-piperidinedicarboxylic acid, 1-tert-

1- (tert- butyl) 4-ethyl-4 in _{CH 2 Cl 2 20 mL - (} {[4- (2- butynyl) phenyl] sulfanyl} methyl) -1,4-piperidine dicarboxylate ( 1.66 g, 3.7 mmol) (prepared in Step 6 of Example 30) in tetrahydrofuran (20 mL) was added tetrabutylammonium oxone (17.38 g, 14.7 mmol) and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was diluted with EtOAc and washed with H ₂ O, 5% KHSO ₄ , brine, dried over MgSO ₄ and then concentrated to give 1.69 g (95%) of the desired product as a pale yellow gum, . Electrospray mass spectrometry: 480.3 (M + H) &lt; ⁺ & gt ^; .

Step 2 4 - [[[4- (2-Butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, ethyl ester

4 - [[[[4- (2-Butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester was prepared according to the general method outlined in Example 31. [ Starting from 1-tert-butyl 4-ethyl ester (1.62 g, 3.4 mmol), starting from 4 - [[[[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] 1.335 g (95%) of the desired product of the tan solid were isolated. Electrospray mass analysis: 380.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: 1-Acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, ethyl ester

Methyl] -4-piperidinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol), triethylamine (0.32 mL) and CH ₂ Cl _{2 To a} solution of the catalytic amount of 4-dimethylaminopyridine in 6.0 mL was added a solution of acetyl chloride (0.068 mL, 0.864 mmol) in 1.0 mL of CH ₂ Cl ₂ . The reaction was stirred at room temperature for 4 hours, washed with H ₂ O and brine, dried over MgSO ₄ , filtered through a pad of silica gel and then concentrated to give 0.242 g (100%) of the desired product as a colorless gum. Electrospray mass spectrometry: 422.2 (M + H) &lt; ⁺ & gt ^; .

Step 4: l-Acetyl-4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine-4-

4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-4-carboxylic acid was prepared according to the general method as outlined in example 30 (step 7). Starting from l-acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, ethyl ester (0.22 g, 0.524 mmol) 0.141 g of the product was isolated. Electrospray mass spectrometry: 438.2 (M + FA-H ) -.

Step 5: Preparation of 1-acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide

Phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide was prepared in a manner similar to that described in Example 30 (step 8) &Lt; / RTI &gt; 0.048 g (38%) of the desired product of light yellow solid, starting from l-acetyl-4- (4-but-2- . Electrospray mass analysis: 409.2 (M + H) &lt; ⁺ & gt ^; .

Example 37

-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride

Step 1: 1- (2-Butynyl) -4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, ethyl ester

Methyl] -4-piperidinecarboxylic acid ethyl ester (0.208 g, 0.5 mmol), 1-bromo-2-butyne (0.044 ml, , 0.53 mmol) and K ₂ CO ₃ (0.138 g, 1.0 mmol) in 5.0 mL of DMF was stirred at room temperature for 6 hours. The reaction was diluted with EtOAc, washed with H ₂ O and brine, then dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: hexane (1: 1) to give 0.183 g (85%) of the desired product of pale yellow gum. Electrospray mass spectrometry: 432.2 (M + H) &lt; ⁺ & gt ^; .

Step 2: 1- (2-Butynyl) -4- [4- (2-butynyloxy) benzenesulfonylmethyl] -piperidine-4- carboxylic acid

Preparation of 1- (2-Butynyl) -4- [4- (2-butynyloxy) benzenesulfonylmethyl] -piperidine-4- carboxylic acid was prepared according to the general method outlined in example 30 (step 7) did. Phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, ethyl ester (0.153 g, 0.354 mmol) to give the title compound 0.12 g (84%) of the desired product of a white solid were isolated. Electrospray mass analysis: 404.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: Preparation of 1- (2-butynyl) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl] methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride

Phenyl) sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride was prepared in the same manner as in Example 30 ((2-butynyl) Was prepared according to the general method outlined in step 8). Starting from 0.1 g (0.34 mmol) of 1- (2-butynyl) -4- [4- (2-butynyloxy) benzenesulfonylmethyl] -piperidine- gain, was dissolved in CH ₂ Cl ₂ 1.0 mL and treated with 1M HCl 0.225 mL of CH ₂ Cl _2. The solution was stirred for 1 hour and concentrated in vacuo. The residue was triturated with ether to give 0.044 g (28%) of the hydrochloride, the desired product of the beige solid. Electrospray mass analysis: 419.2 (M + H) &lt; ⁺ & gt ^; .

Example 38

N-4-hydroxy-1,4- [4- (2-butynyloxy) phenyl] sulfonyl} methyl- Oxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-1,4-l] sulfonyl} methyl) -N-4-hydroxy-1,4-piperidinecarboxamide

Step 1: 1-tert-Butylcarbamoyl-4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine-

To a solution of tert-butyl isocyanate (0.097 mL, 0.85 mmol) in 8.0 mL of CH ₂ Cl ₂ was added 4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester (Prepared in Step 2 of Example 36) (0.337 g, 0.81 mmol) and triethylamine (0.135 mL, 0.97 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was diluted with CH ₂ Cl ₂ , washed with H ₂ O and brine, then dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether: hexane (1: 1) to afford 0.284 g (73%) of the desired product as a white solid. Electrospray mass spectrometry: 479.2 (M + H) &lt; ⁺ & gt ^; .

Step 2: 1 - [(tert-Butylamino) carbonyl] -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxylic acid

4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) Butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxylic acid was prepared according to the general method outlined in Example 30 (step 7). Starting from 0.259 g (0.54 mmol) of 1-tert-butylcarbamoyl-4- (4-but- 0.169 g (69%) of the desired product was isolated. Electrospray mass analysis: 451.4 (M + H) &lt; ⁺ & gt ^; .

Step 3: Preparation of N-1- (tert-butyl) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) 2-butynyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-l, 4- lsulfonyl} methyl) -N-4-hydroxy-1,4-piperidinecarboxamide

Methyl-N-4-hydroxy-1,4- [4- (2-butynyl) Sulfonyl} methyl) -N-4-hydroxy-1,4-piperidinecarboxamide was obtained in the same manner as in Example 30 (Step 8). 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) Phenyl) sulfonyl} methyl) -4-piperidinecarboxylic acid (0.149 g, 0.33 mmol), 0.077 g of the desired product of a pale yellow solid was isolated. Electrospray mass analysis: 466.3 (M + H) &lt; ⁺ & gt ^; .

Example 39

Methyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Step 1: 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid ethyl ester methyl ester

Under N ₂ atmosphere CH ₂ Cl ₂ 1,0 mL of 4 - [[[4- (2-butynyl) phenyl] sulfonyl] methyl] -4-piperidine-carboxylic acid ethyl ester (0.354 g, 0.85 mmol ) Was added dropwise a solution of N, O-bis (trimethylsilyl) acetamide (0.462 mL, 1.87 mmol) in 0.5 mL of CH ₂ Cl ₂ and stirred for 1 hour. The reaction was cooled to 0 &lt; 0 &gt; C and 0.079 mL (1.02 mmol) solution of methyl chloroformate in 0.5 mL of CH ₂ Cl ₂ was added dropwise. The reaction was stirred at room temperature for 1 hour, cooled to 0 &lt; 0 &gt; C, then cooled to pH 7 buffer and extracted with EtOAc. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: hexane (1: 2) to give 0.315 g (85%) of the desired product of a colorless oil. Electrospray mass spectrometry: 438.3 (M + H) &lt; ⁺ & gt ^; .

Step 2: 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid monomethyl ester

4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid monomethyl ester was prepared according to the general method as outlined in example 30 (step 7). Starting from 0.277 g (0.633 mmol) of methyl ester (0.177 g, 0.633 mmol) in the form of a white solid. MS (m / e) (67%). Electrospray mass analysis: 410.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: Methyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Methyl] -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate was prepared in a manner analogous to Example 30 (step 8) from methyl 4- ({[4- (2-butynyloxy) phenyl] sulfonyl} &Lt; / RTI &gt; Starting from 0.15 g (0.366 mmol) of 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid monomethyl ester 0.053 g 34%). Electrospray mass spectrometry: 425.3 (M + H) &lt; ⁺ & gt ^; .

Example 40

Benzyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Step 1: 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid benzyl ester ethyl ester

4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid benzyl ester ethyl ester was prepared according to the general method as outlined in example 39 (step 1). Starting from 0.312 g (0.75), 0.337 g (87%) of the desired product of the colorless oil was obtained as a colorless oil starting from 4 - [[[[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4- piperidinecarboxylic acid ethyl ester . Electrospray mass ^{spectrometry: 514.2 (M + H) -} .

Step 2: 4- (But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid monobenzyl ester

4- (But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-l, 4-dicarboxylic acid monobenzyl ester was prepared according to the general method as outlined in example 30 (step 7). Starting with benzyl 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) piperidine-l, 4-dicarboxylic acid ethyl ester (0.32 g, 0.623 mmol) 0.2 g of the desired product of the white solid Separated. Electrospray mass analysis: 484.2 (MH) ^- .

Step 3: Benzyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Benzyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl ]- 1- piperidinecarboxylate. &Lt; / RTI &gt; Starting with 0.18 g (0.37 mmol) of the desired product of off-white solid, 0.106 g (0.37 mmol) of 4- 57%). Electrospray mass analysis: 501.3 (M + H) &lt; ⁺ & gt ^; .

Example 41

Methyl} -N-hydroxy-4-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy- 4-piperidinecarboxamide

Step 1: Ethyl-1-benzyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-4- (2-butynyloxy) phenyl] sulfonyl} methyl) 4-piperidinecarboxylate

Phenyl) sulfonyl} methyl) -4-piperidinecarboxylate (hereinafter, referred to as &quot;Lt; / RTI &gt; carboxylate was prepared according to the general method outlined in Example 37 (step 1). Starting from the ethyl ester (example 36, step 2) (0.312 g, 0.75 mmol), starting from 4 - [[[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester 0.265 g of the desired product of the solid was isolated. Electrospray mass spectrometry: 470.2 (M + H) &lt; ⁺ & gt ^; .

Step 2: Preparation of 1-benzyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxyl- Oxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxylic acid

Benzyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxyl- ] Sulfonyl} methyl) -4-piperidinecarboxylic acid was prepared according to the general method as outlined in example 30 (step 7). Phenyl) sulfonyl} methyl) -4-piperidinecarboxylate (hereinafter, referred to as &quot; Starting from the feridine carboxylate (0.25 g, 0.53 mmol), 0.227 g (90%) of the desired product of the white solid was isolated. Electrospray mass analysis: 442.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: Preparation of 1-benzyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-butynyloxy) phenyl] sulfonyl} Hydroxy-4-piperidinecarboxamide

Methyl} -N-hydroxy-4-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy- 4-piperidinecarboxamide was prepared according to the general method outlined in example 30 (step 8). Benzyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxyl- ] Sulfonyl} methyl) -4-piperidinecarboxylic acid (0.211 g, 0.44 mmol), 0.108 g of the desired product of a white solid was isolated. Electrospray mass spectrometry: 457.2 (M + H) &lt; ⁺ & gt ^; .

Example 42

Methyl] -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) Carbonyl] -4-piperidinecarboxamide

Step 1: Preparation of ethyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -1 - [(2,2,5-trimethyl-1,3-dioxan- Yl] -4-piperidinecarboxylate

Methyl] -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] - 4-piperidinecarboxylate was prepared according to the general method outlined in Example 30 (Scheme 8). Methyl] -4-piperidinecarboxylic acid ethyl ester (0.333 g, 0.8 mmol) to give 0.339 g (79 mmol) of the desired product in the form of a white solid %). Electrospray mass spectrometry: 536.1 (M + H) &lt; ⁺ & gt ^; .

Step 2: Preparation of 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -1 - [(2,2,5-trimethyl-1,3-dioxan- ] -4-piperidinecarboxylic acid

Methyl] -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4 -Piperidinecarboxylic acid was prepared according to the general method as outlined in example 30 (step 7). Methyl] -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] - Starting with 4-piperidinecarboxylate (0.299 g, 0.558 mmol), 0.235 g (83%) of the desired product of the white solid was isolated. Electrospray mass analysis: 506.2 (MH) ^- .

Step 3: Synthesis of 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1 - [(2,2,5-trimethyl- Yl) carbonyl] -4-piperidinecarboxamide

Methyl] -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) Carbonyl] -4-piperidinecarboxamide was prepared according to the general method outlined in Example 30 (step 8). Methyl] -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4 -Piperidinecarboxylic acid (0.22 g, 0.433 mmol), 0.16 g of the desired product of the white solid was isolated. Electrospray mass spectrometry: 523.2 (M + H) &lt; ⁺ & gt ^; .

Example 43

Methyl] -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4-piperidinecarboxamide

Methyl] -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) Carbonyl] -4-piperidinecarboxamide (0.106 g, 0.2 mmol) and 2 mL of 1N HCl in 2 mL of THF was stirred at room temperature for 4 hours. The reaction was diluted with EtOAc and washed with H ₂ O, saturated NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether to give 0.67 g (17%) of the desired product as an off-white solid. Electrospray mass analysis: 483.2 (M + H) &lt; ⁺ & gt ^; .

Example 44

-4 - {[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-oxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide

Step 1: N, N'-t- Boc- protected thiourea: 60% of the minerals in oil to a stirred solution of thiourea (0.57 g, 7.5 mmol) in 150 mL THF under N ₂ eseo 0 ℃ NaH (1.35 g, 33.8 mmol). After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 C and 3.6 g (16.5 mmol) of di-tert-butyl dicarbonate was added. After 30 minutes, the ice bath was removed and the reaction was stirred for 2 hours. Cool the reaction with saturated NaHCO ₃ solution, and extracted three times with EtOAc, and then poured into water. The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with hexane to give 1.72 g (83%) of the desired product as a white solid.

Step 2: tert-Butyl 4 - [(tert-butoxyamino) carbonyl] -4 - ({[4- (2-yloxy) phenyl] sulfonyl} methyl) -1-piperidinecarboxylate

phenyl) sulfonyl} methyl) -1-piperidinecarboxylate was reacted with (l- (4-fluorophenyl) Was prepared according to the general method outlined in step 8). Butyl ester (2.53 g, 5.6 mmol) and O-tert-butyl-hydroxysuccinimide were added to a solution of 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine- Starting with 1.4 g (11.2 mmol) of amine hydrochloride, 2.31 g (79%) of the desired product of the white solid was isolated. Electrospray mass spectrometry: 523.2 (M + H) &lt; ⁺ & gt ^; .

Step 3: Preparation of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} } Methyl) -4-piperidinecarboxamide

CH ₂ Cl ₂ 6 mL of tert- butyl 4 - [(tert- butoxycarbonyl-amino) carbonyl] -4 - ({[4- (2-yloxy) phenyl] sulfonyl} methyl) -1-piperidine To a solution of the carboxylate (3.0 g, 5.5 mmol) was added trimethylsilyltrifluoromethylsulfonate (1.1 mL, 6.05 mmol) followed by 0.7 mL of 2,6-lutidine. The reaction was stirred for 1 h and diluted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O, saturated NaHCO ₃ , brine, dried over MgSO ₄ , then filtered and concentrated in vacuo to give 2.01 g (86%) of the desired product as an off-white solid. Electrospray mass spectrometry: 423.2 (M + H) &lt; ⁺ & gt ^; .

Step 4: Preparation of [[4 - [(tert-butoxyamino) carbonyl] -4 - [[[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxamide Carbonyl) amino] methylene] carbamic acid, tert-butyl ester

Methyl] -4- [4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4- (4- (0.127 g, 0.3 mmol), di-t-boc-protected thiourea (obtained in step 1) (0.091 g, 0.33 mmol) and triethylamine (0.092 ML) was added mercury (II) chloride (0.09 g, 0.33 mmol), and the mixture was stirred at 0 ° C for 1 hour. The reaction was diluted with EtOAc and filtered through a pad of celite. The organic layer was washed with H ₂ O, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was triturated with hexane to give the desired product as a white solid. Electrospray mass analysis: 665.5 (M + H) &lt; ⁺ & gt ^; .

Step 5: Preparation of 1- [amino (imino) methyl] -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N- Methyl] -N- hydroxy-4-oxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide

Phenyl] sulfonyl} methyl) -4-piperidinecarboxamide &lt; / RTI &gt; Butoxycarbonyl) amino] methylene] carbamic acid, tert-butyl ester (0.135 g, 0.2 mmol) and 3 mL of trifluoroacetic acid in 2 mL of CH ₂ Cl ₂ was heated at 60 ° C for 24 hours. The reaction was concentrated in vacuo and preparative HPLC gave 0.032 g (31%) of the desired product of the beige solid. Electrospray mass analysis: 409.3 (M + H) &lt; ⁺ & gt ^; .

Example 45

Phenyl] sulfonyl} methyl) -N- (4-hydroxy-2-butynyl) -Hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide

Step 1: Preparation of ethyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -1- (4 - {[(3- chloroanilino) carbonyl] oxy} Yl) -4-piperidinecarboxylate

Phenyl) sulfonyl} methyl) -1- (4 - {[(3-chloroanilino) carbonyl] oxy} -2-butynyl) - 4-piperidinecarboxylate was prepared according to the general method outlined in example 37 (step 1). Methyl-4-piperidinecarboxylic acid ethyl ester (0.291 g, 0.7 mmol) and 4-chloro-2-butynyl- (3- Chlorobenzyl) carbamate (0.19 g, 0.735), 0.27 g (64%) of the desired product of pale yellow oil was isolated. Electrospray mass spectrometry: 601.3 (M + H) &lt; ⁺ & gt ^; .

Step 2: Synthesis of ethyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -1- (4-hydroxy-2-butynyl) } Methyl) -1- (4-hydroxy-2-butynyl) -4-piperidinecarboxylate

Phenyl) sulfonyl} methyl) -1- (4 - {[(3-chloroanilino) carbonyl] oxy} -2-butynyl) - A solution of 4-piperidinecarboxylate (from step 1) (0.22 g, 0.366 mmol) and lithium hydroxide hydrate (0.019 g, 0.44 mmol) in 4 mL of MeOH was heated to reflux for 3 hours. The reaction was concentrated, diluted with H ₂ O, acidified to pH 3 and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3% MeOH / CH ₂ Cl ₂ to give 0.12 g (73%) of the desired product of the yellow oil. Electrospray mass spectrometry: 448.3 (M + H) &lt; ⁺ & gt ^; .

Step 3: 4 - ({[4- (2-Butynyloxy) phenyl] sulfonyl} methyl) -1- (4-hydroxy- - (4-hydroxy-2-butynyl) -4-piperidinecarboxylic acid

Methyl) -1- (4-hydroxy-2-butynyl) -4-methylsulfanyl} -Hydroxy-2-butynyl) -4-piperidinecarboxylic acid was prepared according to the general method as outlined in example 30 (step 7). Phenyl) sulfonyl} methyl) -1- (4-hydroxy-2-butynyl) -4-piperidinecarboxylate (0.115 g, 0.257 mmol), 0.08 g (74%) of the desired product of the white solid was isolated. Electrospray mass analysis: 420.4 (M + H) &lt; ⁺ & gt ^; .

Step 4: Preparation of 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (4-hydroxy- ) -N-hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide

Phenyl] sulfonyl} methyl) -N- (4-hydroxy-2-butynyl) -Hydroxy-l- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide was prepared according to the general method outlined in example 30 (step 8). Methyl) -1- (4-hydroxy-2-butynyl) -4-methylsulfanyl} Starting from 0.073 g (0.174 mmol), 0.026 g (34%) of the desired product of the white solid was isolated. Electrospray mass analysis: 435.3 (M + H) &lt; ⁺ & gt ^; .

The solution phase synthesis method of the compound of the present invention is shown by the following formula.

Example 46

Phenyl) sulfonyl} methyl) -1-ethyl-N-hydroxypiperidine-4-carboxamide trifluoroacetic acid salt

Step A: Preparation of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (0.096 g, 0.23 mmol), ethyl iodide (0.019 mL, 0.24 mmol) and a solution of triethylamine (0.096 mL, 0.69 mmol) in 2 mL of CH ₂ Cl ₂ at room temperature For 18 hours and then concentrated in vacuo.

Step B: CH ₂ Cl ₂ solution of the residue was heated with 1mL Step A in 1 mL of trifluoroacetic acid in 50 ℃ for two hours and then obtain a desired product was concentrated in vacuo.

Phenyl) sulfonyl} methyl) -1-ethyl-N-hydroxypiperidine-4-carboxamide trifluoroacetic acid salt of the 4 - ({[4- The following hydroxamic acid was synthesized according to the procedure.

Example 47: Synthesis of 2-chloro-5- (chloromethyl) thiophene-4 - ({[4- (butyl- 2-ynyloxy) phenyl] sulfonyl} methyl) -2-yl) methyl] -N-hydroxypiperidine-4-carboxamide trifluoroacetic acid salt 0.029 mL (0.24 mmol).

Example 48: Tet-4-picolyl chloride hydrochloride To a solution of 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (pyridin- ) Piperidine-4-carboxamide trifluoroacetic acid salt 0.0496 g (0.24 mmol).

Example 49

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide trifluoro Rosacetate

Step A: Preparation of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} } methyl-4-piperidine-carboxylic amide (0.097 g, 0.23 mmol) solution, triethylamine (0.064 mL, 0.64 mmol), nicotinoyl chloride hydrochloride (0.061 g, 0.34 mmol), and CH ₂ Cl _{2 2} 4-dimethylaminopyridine (0.002 g) in dichloromethane was shaken at room temperature for 18 hours and then concentrated in vacuo.

Step B: Same as Step B of Example 46

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidin-4- The following hydroxamic acid was synthesized according to the procedure of carboxamide trifluoroacetate.

Example 50

Tert-benzoyl chloride 0.04 mL (0.276 mmol)

Phenyl) sulfonyl} methyl) -N-hydroxypiperidine-4-carboxamide &lt; / RTI &gt;

Example 51

0.037 mL (0.276 mmol) of 2-thiophenecarbonyl chloride &lt; RTI ID = 0.0 &gt;

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidine-4-carboxamide

Example 52

Phenyl) sulfonyl} methyl) -N-1-ethyl-N-4-hydroxypiperidine-1,4-dicarboxamide

Step A: Preparation of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} } methyl-4-piperidine-carboxylic amide (0.097 g, 0.23 mmol) solution, triethylamine (0.064 mL, 0.64 mmol) and CH ₂ Cl _{2 2} isocyanate (0.02 mL, 0.253 mmol) at room temperature in a 18 mL Shaken for hours and then concentrated in vacuo.

Step B: Same as Step B of Example 46

The following hydroxamic acid was synthesized according to the procedure of Example 52 using an appropriate tester.

Example 53

Tris-phenylisocyanate 0.275 mL (0.253 mmol)

Phenyl) piperidine-1, &lt; / RTI &gt; 4-dicarboxamide &lt; RTI ID = 0.0 &

Example 54

Tissue-diethylcarbamoyl chloride 0.32 mL (0.253 mmol)

Phenyl) sulfonyl} methyl) -N-1-, N-1-diethyl-N-4-hydroxypiperidine- Copy Mid

Example 55

0.0 &gt; mmol &lt; / RTI &gt; (0.253 mmol)

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidine-4-carboxamide

Example 56

0.043 g (0.253 mmol) of the thione-methylphenylcarbamoyl chloride,

Methyl-N-1-phenylpiperidine-1, 4-dicarboxylic acid methyl ester was used in place of 4 - ({[4- Copy Mid

Implementation 57

Phenyl) sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate

Step A: Synthesis of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} A solution of diisopropylethylamine (0.08 mL, 0.46 mmol) in methylene-4-piperidine-carboxamide (0.097 g, 0.23 mmol), octyl chloroformate (0.0495 mL, 0.253 mmol) and 2 mL of CH ₂ Cl ₂ Shaken at room temperature for 18 hours and then concentrated in vacuo.

Step B: Same as Step B of Example 46

The following hydroxamic acid was synthesized according to the procedure of Example 57 using an appropriate tester.

Example 58

Trifluoro-4-methoxyphenyl chloroformate 0.038 mL (0.253 mmol)

Phenyl) sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate

Example 59

Tense-benzenesulfonyl chloride 0.323 mL (0.253 mmol)

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (phenylsulfonyl) piperidine-4-carboxamide

Example 60

Trifluoro-1-methylimidazole-4-sulfonyl chloride 0.0457 g (0.253 mmol)

Methyl-1H-imidazol-4-yl) sulfonyl] piperidine (hereinafter referred to as &quot; 4-carboxamide

Example 61

Phenyl] sulfonyl} methyl) -N-hydroxypiperidine-4-carboxamide (Compound

Step A: Preparation of N- (tert-butoxy) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} (0.064 g, 0.23 mmol) in CH ₂ Cl ₂ and a solution of 4- (4-fluorophenyl) -4-piperidinecarboxamide (0.097 g, 0.23 mmol), triethylamine Dimethylaminopyridine (0.002 g) was shaken at room temperature for 18 hours. The solution was treated with benzylamine (0.075 mL, 0.69 mmol), shaken for 18 h and then concentrated in vacuo.

Step B: Same as Step B of Example 46

The following hydroxamic acid was synthesized according to the procedure of Example 61 using an appropriate reagent.

Example 62

0.060 mL (0.69 mmol) &lt; RTI ID = 0.0 &gt;

Phenyl) sulfonyl} methyl) -N-hydroxy-1- (2-morpholin-4-ylacetyl) piperidine-4-carboxamide

Example 63

0.076 mL (0.69 mmol) of N-methylpiperazine &lt; RTI ID = 0.0 &gt;

(4-methylpiperazin-1-yl) acetyl] piperidin-4-ylmethyl) 4-carboxamide

Example # HPLC Retention Time (min) ¹ MS ² (M + H) &lt; ⁺ & gt ^; 46 1.85 395 47 2.20 498 48 1.71 458 49 2.11 472 52 2.30 438 53 2.85 486 57 3.80 523 58 2.98 517 54 2.87 466 55 2.33 480 56 2.84 500 59 2.92 507 60 2.40 511 50 2.67 471 51 2.64 477 61 2.14 514 62 1.86 494 63 1.84 507 ¹ LC Condition: Hewlett Packard 1100; YMC ODS-A 4.6 mm x 50 mm 5 column 23 ° C; 10 [mu] l injection; Solvent A: 0.05% TFA / water; Solvent B: 0.05% TFA / acetonitrile; Tilt: Time 0: 98% A: 1 min: 98% A; 7 min: 10% A, 8 min: 98% A; After 1 minute. Flow rate 2.5 mL / min; Detection: 220 and 254 nm DAD ² Mass spectrometry conditions: API-electric field

Example 64

Synthesis of 1-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide

Step 1: 4-But-2-ynyloxybenzenesulfonyl fluoride:

KF-CaF ₂ (2.85 g, 16.3 mmol) was added to a solution of 4-but- ₂ -ynyloxybenzenesulfonyl chloride (prepared in example 30, step 4) in acetonitrile (10 mL) Lt; / RTI &gt; for 4 hours. The resulting mixture was filtered and the filtrate was concentrated. The crude product was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent removed to give the product 1.5 g (80%) of solid.

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -piperidine-l, 4-dicarboxylic acid tert-butyl ester methyl ester

2.5 M n-BuLi (4.68 mL, 11.7 mmol) was added to a solution of diisopropylamine (1.58 mL, 11.3 mmol) in THF (25 mL) at 0 ° C and the resulting mixture was stirred at this temperature for 15 minutes. The reaction mixture was cooled to -78 ° C and a solution of 1- (tert-butyl) -4-methyl 1,4-piperidinecarboxylate (prepared in Example 30 Step 1) (2.67 g, 11.0 mmol) in THF ) Solution. The resulting mixture was stirred for 1 hour and a solution of 4-but-2-ynyloxybenzenesulfonyl fluoride (2.5 g, 11.0 mmol) in THF (25 mL) was added. After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH ₄ Cl solution, extracted with EtOAc and dried over anhydrous Na ₂ SO ₄ . Purification by purification of the crude product by silica gel chromatography gave 2.6 g (53%) of the product as a solid; ^{1 H NMR (300 MHz, CDCl} 3) δ1.44 (s, 9H), 1.87 (m, 3H), 1.98 (m, 2H), 2.32 (m, 2H), 2.62 (m, 2H), 3.74 (s 2H), 7.09 (d, 2H, J = 7.2 Hz), 7.71 (d, 2H, J = 7.2 Hz).

Step 3: 4- (4-But-2-ynyloxy-benzenesulfonyl) -piperidine-4- carboxylic acid methyl ester:

To a solution of the product of step 2 (500 mg, 1.11 mmol) in methylene chloride (10 mL) was added 4M HCl (2 mL) and the resulting mixture was stirred at room temperature for 2 hours. The solid was filtered and washed with ether to give 410 mg (95%) of the product as a solid. ^{1 H NMR (300 MHz, CDCl} 3): δ1.86 (m, 3H), 2.52 (m, 4H), 2.89 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 4.74 ( m, 2H), 7.10 (d, 2H, J = 8.7Hz), 7.69 (d, 2H, J = 8.7Hz).

Step 4: 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid methyl ester

To the solution of the product of Step 3 (105 mg, 0.23 mmol) in methylene chloride (1 mL) was added triethylamine (93 mg, 0.92 mmol) and acetyl chloride (18 mg, 0.23 mmol) followed by a catalytic amount of dimethylaminopyridine . The resulting mixture was stirred at room temperature for 8 hours, cooled with water and then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid.

Step 5: l-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-

Lithium hydroxide (18 mg, 0.75 mmol) in a mixture of ester (240 mg, 0.61 mmol) from step 4 and tetrahydrofuran / methanol / water (3: 3: 2) was stirred at room temperature for 15 hours . The mixture was concentrated, acidified to pH 3-5 using 1N aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removing the solvent under vacuum leaves the acid. Yield: 200 mg (87%). ¹ H NMR (300 MHz, acetone _{-d 6): δ1.84 (t,} 3H, J = 2.8 Hz), 1.90-2.05 (m, 2H), 2.06 (s, 3H), 2.25-2.51 (m, 3H ), 3.06 (m, IH), 4.04 (m, IH), 4.63 (m, IH), 4.86 (q, IH, J = 2.0).

Step 6: l-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid hydroxamide:

To a solution of 1-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid (180 mg, 0.48 mmol) in dimethylformamide was added hydroxybenzotriazole (77 mg, 0.57 mmol) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (127 mg, 0.66) and N-methylmorpholine (0.078 ml, 0.71 mmol). When a 50% aqueous hydroxylamine solution (0.145 mL, 2.37 mmol) was added, the resulting mixture was stirred at room temperature for 1 hour and the mixture was stirred at this temperature for 15 hours. The solvent was removed in vacuo and ethyl acetate / water was added to the crude product. The organic layer was separated and washed successively with 1N aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give 100 mg (53%) of the product as a solid. ^{1 H NMR (300 MHz, CDCl} 3): δ1.64 (m, 1H), 1.85 (m, 3H), 1.99 (s, 3H), 2.31 (m, 4H), 2.83 (m, 1H), 3.88 ( 2H, J = 9.0 Hz), 7.66 (d, 2H, J = 9.0 Hz), 9.20 (m, 11.00 (m, 1 H); MS-ES: m / z 395.2 (M + H) &lt; ⁺ & gt ^; .

Example 65

4- benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid hydroxamide

Step 1: 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid methyl ester

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 mL) was added 416 mg ), Benzoyl chloride (144 [mu] L, 1.24 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. MS-ES: m / z 456.1 (M + H) &lt; ⁺ & gt ^; .

Step 2: 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-

Was prepared starting from l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-4- carboxylic acid methyl ester (300 mg, 0.66 mmol) and lithium hydroxide (18 mg, 0.75 mmol) To give 1-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid. The resulting reaction mixture was carried out as outlined in Example 64 (step 5). Yield: 250 mg (86%) of the acid. HR-MS: m / z Calcd for C ₂₃ H ₂₃ NO ₆ S 442.1319; Found 442.1317.

Step 3: 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4- carboxylic acid hydroxamide

To a solution of 1-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid (100 mg, 0.23 mmol), 1-hydroxybenzotriazole ( 36 mg, 0.27 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (62 mg, 0.32 mmol), N-methylmorpholine (0.038 mL, 0.35 mmol) Following the general procedure of step 6 (Example 64), 40 mg (38%) of the product as a solid were obtained using thexylamine (0.083 mL, 1.15 mmol). MS-ES: m / z 457.2 (M + H) &lt; ⁺ & gt ^; .

Example 66

Synthesis of 1- (4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide

Step 1: 1- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine- 4- carboxylic acid methyl ester

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (260 mg, 0.77 mmol) in chloroform (7 mL) was added triethylamine (311 mg, 3.08 mmol ) And 4-methoxybenzoyl chloride (158 mg, 0.92 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) of the product as a solid. HR-MS: m / z Calcd for C ₂₅ H ₂₇ NO ₇ S 486.1581; Found 486.1576.

Step 2: l- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-

(4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid was prepared following the procedure of Example 64 (step 5). A solution of l- (4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -4-methoxybenzenesulfonyl chloride (1.0 g, 1.03 mmol) in 4 mL of tetrahydrofuran: methanol (1: 1) and 1 N sodium hydroxide ) Piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol), 150 mg (62%) of the acid was isolated. HR-MS: m / z Calcd for C ₂₄ H ₂₅ NO ₇ S 472.1425; Found 472.1426.

Step 3: l- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine- 4- carboxylic acid hydroxamide:

(4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide was prepared according to Example 64 (step 6). To a solution of 1- (4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-4-carboxylic acid (90 mg, 0.19 mmol), 1 (31 mg, 0.23 mmol), 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride (51 mg, 0.27 mmol) and N-methylmorpholine Starting with 70 mg (76%) of the product as a solid, starting from the hydroxylamine (0.068 mL, 0.95 mmol). HR-MS: m / z Calcd for C ₂₄ H ₂₆ N ₂ O ₇ S 487.1534; Found 487. 1531.

Example 67

(4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidine-1-carbonyl) -4-piperidinecarboxamide

Step 1: 4- (4-But-2-ynyloxybenzenesulfonyl) -l- (pyrrolidine-l-carbonyl) -4-carboxylic acid methyl ester

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 mL) was added 208 mg ), Pyrrolidine carbonyl chloride (206 mg, 1.54 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of the product as a solid; MS-ES: m / z 449.3 (M + H) &lt; ⁺ & gt ^; .

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -l- (pyrrolidine- 1 -carbonyl) -piperidine-

4- (4-But-2-ynyloxybenzenesulfonyl) - l- (pyrrolidine-l-carbonyl) -piperidine-4- carboxylic acid was prepared according to the procedure for example 64 (step 5) . To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (pyrrolidin-l-yl) -pyridine in 4 ml of tetrahydrofuran: methanol (1: 1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol) Carboxylic acid methyl ester (250 mg, 0.52 mmol), 150 mg (62%) of the acid was isolated. HR-MS: m / z Calcd for C ₂₄ H ₂₅ NO ₇ S 472.1425; Found 472.1426.

Step 3: A mixture of 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy- 1- (pyrrolidine- 1 -carbonyl) -4-piperidinecarboxamide, 6). To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidine-1-carbonyl) -4-piperidinecarboxylic acid ( Hydroxybenzotriazole (96 mg, 0.71 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol) Starting from N-methylmorpholine (0.099 mL, 0.84 mmol) and hydroxylamine (0.181 mL, 2.9 mmol) 150 mg (60%) of the product as a solid were isolated. HR-MS: m / z C 21 H 27 N 3 O 6 S calculated for 450.1693; Found 450.1692.

Example 68

4- (4-But-2-ynyloxybenzenesulfonyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Step 1: 1-Ethyl-4-methyl-4- (4-but-2-ynyloxybenzenesulfonyl) -1,4- piperidine-dicarboxylate

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 mL) was added sodium bicarbonate (865 mg, 10.3 mmol ) And ethyl chloroformate (0.147 mL, 1.54 mmol). The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of the product as a solid. MS-ES: m / z 424.4 (M + H) &lt; ⁺ & gt ^; .

Step 2: l- (Ethylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) - l-piperidine-

1- (ethylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -1-piperidine-carboxylic acid was prepared according to the procedure for example 64 (step 5). To a solution of 1-ethyl 4-methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1,4-piperidine-dicarboxylate (1 g) in 8 mL tetrahydrofuran: methanol: water Starting with 400 mg (0.95 mmol) of the compound obtained in the previous step and lithium hydroxide (50 mg, 2.04 mmol), 340 mg (88%) of the acid was isolated. HR-MS: m / z Calcd for C ₁₉ H ₂₃ NO ₇ S 408.1122; Found 408.1126.

Step 3: Ethyl 4- (4-but-2-ynyloxybenzenesulfonyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Ethyl 4- (4-but-2-ynyloxybenzenesulfonyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate was prepared according to the procedure for example 64 (step 6) . To a solution of 1- (ethylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -1-piperidinecarboxylic acid (225 mg, 0.55 mmol) (89 mg, 0.66 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), N-methylmorpholine 0.64 mmol) and hydroxylamine (0.168 mL, 2.75 mmol), 150 mg (64%) of the product as a solid were isolated. NR-MS: m / z C 19 H 24 N 2 O 7 S Calcd 425.1377; Found 425.1375.

Example 69

N-hydroxy-1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide

Step 1: Methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylate

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (350 mg, 0.90 mmol) in chloroform (10 mL) was added triethylamine (182 mg, 1.81 mmol ) And trifluoromethanesulfonyl chloride (0.125 mL, 1.17 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 245 mg (56%) of the product as a solid. HR-MS: m / z Calcd for C ₁₈ H ₂₀ F ₃ NO ₇ S ₂ 484.0706; Found 484.0700.

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -1- [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylic acid

4- (4-But-2-ynyloxybenzenesulfonyl) - l - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylic acid was prepared according to the procedure for example 64 (step 5). To a solution of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(trifluoromethyl) sulfonyl] -4- (4-methylpiperazin-1- 175 mg (80%) of the acid was isolated starting from the compound (225 mg, 0.47 mmol) and lithium hydroxide (24 mg, 0.98 mmol). MS-ES: m / z 468.1 (MH) ^- .

Step 3: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide.

Hydroxy-1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide was reacted with 4- (4-but- &Lt; / RTI &gt; (Trifluoromethyl) sulfonyl] -4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 mL) , 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol) Starting from 0.051 mL, 0.47 mmol) and hydroxylamine (0.095 mL, 1.55 mmol), 90 mg (60%) of the product as a solid were isolated. HR-MS: Calcd for _{m / z C 17 H 19 F} 3 N 2 O 7 S 2 485.0659; Found 485.0666.

Example 70

Hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide

Step 1: Methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylate

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 mL) was added triethylamine (443 mg, 4.39 mmol), nicotinyl chloride (276 mL, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 460 mg (78%) of the product as a solid. HR-MS: m / z C 23 H 24 N 2 O 6 S calculated for 457.1428; Found 457.1428.

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -l- (3-pyridinylcarbonyl) -4-piperidine-

4- (4-But-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylic acid was prepared according to the procedure for example 64 (step 5). To a solution of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinyl) thiophene in 8 mL of tetrahydrofuran: methanol (1: 1) and 1N sodium hydroxide (1.89 mL, 1.89 mmol) Carbonyl) -4-piperidinecarboxylate (430 mg, 0.94 mmol), 235 mg (57%) of the acid was obtained. HR-MS: m / z C 22 H 22 N 2 O 6 S calculated for 443.1271; Found 443.1270.

Step 3: A mixture of 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4- piperidinecarboxamide, &Lt; / RTI &gt; To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylic acid (195 mg, 0.44 mmol), 1 (72 mg, 0.53 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol) and N-methylmorpholine , 0.66 mmol) and hydroxylamine (0.135 mL, 2.2 mmol), 65 mg (32%) of the product as a solid were isolated. HR-MS: m / z C 22 H 23 N 3 O 6 S calculated for 458.1380; Found 458.1373.

Example 71

N-Hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide

Step 1: Methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-thienylcarbonyl) -4-piperidinecarboxylate

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 mL) mmol) and thiophenylcarbonyl chloride (227 mg, 1.55 mmol) were added followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) of the product as a solid. HR-MS: Calcd for _{m / z C 22 H 23 NO} 6 S 2 462.1040; Found 462.1039.

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -l- (2-thienylcarbonyl) -4-piperidine-

4- (4-But-2-ynyloxybenzenesulfonyl) -1- (2-thienylcarbonyl) -4-piperidine-carboxylic acid was prepared according to the procedure for example 64 (step 5). To a solution of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-thienylcarbonyl) -4-piperidinecarboxylate (435 mg) in 8 mL of methanol (1: mg, 0.94 mmol) and 1N sodium hydroxamide (1.89 mL, 1.89 mmol) to give 360 mg (86%) of the acid. HR-MS: Calcd for _{m / z C 21 H 21 NO} 6 S 2 448.0883; Found 448.0882.

Step 3: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide

Hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide was subjected to the procedure of Example 64 (step 6) to give the title compound Respectively. To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (2-thienylcarbonyl) -4-piperidinecarboxylic acid (335 mg, 0.75 mmol), 1 -Carbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 g, 0.90 mmol), 1- Starting with 216 mg (3.75 mmol) of the hydroxylamine, 216 mg (62%) of the product as a solid were isolated. HR-MS: Calcd for _{m / z C 21 H 22 N} 2 O 6 S 2 463.0992; Found 463.0988.

Example 72

Synthesis of 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(4- methoxyphenyl) sulfonyl] -4-piperidinecarboxamide

Step 1: Synthesis of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxylate

To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 mL) mmol) and 4-methoxyphenylsulfonyl chloride (320 mg, 1.55 mmol) were added followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred at room temperature for 15 hours, cooled with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. HR-MS: m / z calcd for C ₂₄ H ₇₂ NO ₈ S ₂ 522.1251; Found 522.1252.

Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -l - [(4-methoxyphenyl) sulfonyl] -4-piperidine-

4- (4-But-2-ynyloxybenzenesulfonyl) -1- [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxylic acid was prepared according to the procedure of Example 64 did. To a solution of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(4-methoxyphenyl) -sulfonyl] -4-piperidinecarboxamide in 8 ml of methanol (1: Starting with 545 mg (1.04 mmol) of the carboxylate and 1N sodium hydroxide (2.09 mL, 2.09 mmol), 446 mg (85%) of the acid were obtained. HR-MS: m / z calcd for C ₂₃ H ₂₅ NO ₈ S ₂ 508.1094; Found 508.1073.

Step 3: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(4- methoxyphenyl) -sulfonyl] -4- piperidinecarboxamide

Hydroxy-1 - [(4-methoxyphenyl) -sulfonyl] -4-piperidinecarboxamide was reacted with 4- (4-but- ). &Lt; / RTI &gt; To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- [(4-methoxyphenyl) -sulfonyl] -4-piperidinecarboxylic acid (402 mg, 0.79 mmol) in dimethylformamide (8 mL) (128 mg, 0.95 mmol), 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride (212 mg, 1.11 mmol) Starting with morpholine (0.130 mL, 1.19 mmol) and hydroxylamine (0.242 mL, 3.95 mmol), 396 mg (96%) of the product as a solid were isolated. HR-MS: m / z Calcd for C ₂₃ H ₂₆ N ₂ O ₈ S ₂ 523.1203; Found 523.1198.

Example 73

Hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4- Piperidinecarboxamide

Step 1: Preparation of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4- Pyridine carboxylate

1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylate The rate was prepared according to the procedure of Example 64 (step 6). To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol), (2,2,5-trimethyl (209 mg, 1.56 mmol), 1- [3- (dimethylamino) propyl] -3, 7- dihydroxybenzoic acid Starting from 346 mg (1.81 mmol) of ethylcarbodiimide hydrochloride and N-methylmorpholine (0.212 mL, 1.94 mmol), 385 mg (59%) of the product as a solid were obtained. HR-MS: m / z Calcd for C ₂₅ H ₃₃ NO ₈ S 508.2000; Found 508.1998.

Step 2: Preparation of 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(2,2,5-trimethyl-1,3- dioxan-5-yl) carbonyl] Deoxycarboxylic acid

1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid was used instead of 4- (4- Prepared according to the procedure of Example 40 (step 5). To a solution of methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(2,2,5-trimethyl-1,3-dioxane-5-yl) 315 mg (97%) of the acid was obtained starting from 335 mg (0.66 mmol) of the carbonyl] -4-piperidinecarboxylate and 1N sodium hydroxide (1.3 ml, 1.3 mmol). HR-MS: m / z Calcd for C ₂₄ H ₃₁ NO ₈ S 494.1843; Found 494.1835.

Step 3: Preparation of 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(2,2,5-trimethyl-1,3- dioxan- -4-piperidinecarboxamide

Hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4- Piperidinecarboxamide was prepared according to the procedure of Example 64 (step 6). To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -1- [(2,2,5-trimethyl-1,3-dioxan-5- yl) carbonyl] -4-piperidinecarboxylic acid (280 mg, 0.57 mmol), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1- [3- (dimethylamino) Starting from the chloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol) and hydroxylamine (0.174 ml, 2.85 mmol) 180 mg (62%) of the product as a solid were isolated. HR-MS: m / z Calcd for C ₂₄ H ₃₂ N ₂ O ₈ S 531.1771; Found 531.1768.

Example 74

Hydroxy-1- (3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4-piperidinecarboxylic acid Copy Mid

To a solution of the product of Example 73 (150 mg, 0.29 mmol) in tetrahydrofuran (2 mL) was added 1 N aqueous hydrochloric acid (2 mL) and the reaction mixture was stirred for 4 hours. The organic layer was washed with sodium bicarbonate and brine and dried over anhydrous sodium sulfate. The solvent was removed to yield 40 mg (29%) of the product. HR-MS: m / z C 21 H 28 N 2 O 8 S Calcd 469.1639; Found 469.1637.

Example 75

butyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Step 1: 1- (tert-Butoxycarbonyl) -4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid

To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-l, 4-dicarboxylic acid tert-butyl ester (100 mg) in water (100 mL), methanol (50 mL) and tetrahydrofuran A solution of the methyl ester (Example 64, step 2) (15 g, 33.2 mmol) was treated with lithium hydroxide hydrate (2.73 g, 66.4 mmol) and heated at reflux for 8 h. The reaction mixture was concentrated in vacuo and filtered through celite. To the filtrate was added aqueous 1N hydrochloric acid. A thick gum was obtained which was dissolved in dichloromethane and washed with water. Concentration of the organic phase gave foam (14.9 g). The mixture was triturated with diethyl ether to give 1- (tert-butoxycarbonyl) -4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid as a white powder . Electrospray MS m / z 482 (MH) ^- .

Step 2: tert-Butyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate

Dimethylformamide (3.53 mL, 46 mmol) was added to a solution of oxalyl chloride (22.9 mL of a 2.0 M solution in dichloromethane) in dichloromethane (25 mL) at 0 ° C. After 15 minutes, a solution of l- (tert-butoxycarbonyl) -4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid (10 g, 22.9 mmol ) Solution was added and the reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was treated with hydroxylamine hydrochloride (16 g, 229 mmol), triethylamine (48 mL, 344 mmol), water (123 mL) and tetrahydrofuran (500 mL) Lt; / RTI &gt; The reaction was warmed to room temperature. After 18 h, it was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (3 times), dried over potassium carbonate and concentrated in vacuo. Diethyl ether gave the title compound as a white powder which was obtained as a white powder from tert-butyl 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate The mortality rate was obtained (6.3 g). _{^{1 H NMR (DMSO d 6,}} 300 MHz) δ1.38 (s, 9H, t- butyl), 1.6-1.7 (m, 2H, CHH), 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.2 2H, OCH2, J = 2.2Hz), 7.1-7.7 (m, 2H, CHCH) m, 4H, ArH). Electrospray MS m / z 453 (M + H) &lt; ⁺ & gt ^; .

Example 76

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride

phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate (prepared in Example 75) (6.3 g, g, 13.9 mmol) was added 4N hydrochloric acid in dioxane. After 6 h, the reaction mixture was concentrated in vacuo. Methanol was added and the resulting mixture was concentrated in vacuo. Dichloromethane was added and removed in vacuo (2x). Phenyl) sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride (5.14 g) as a white powder was obtained as a white powder. . _{^{1 H NMR (DMSO d 6,}} 300 MHz) δ1.86 (t, 3H, CH3, J = 2.2 Hz), 2.0-2.7 (m, 8H, CH2), 4.89 (q, 2H, OCH2, J = 2.2 Hz ), 7.1-7.8 (m, 4H, ArH), 8.8-11.0 (m, 4H, NH2, NHOH). Electrospray MS m / z 353 (M + H) &lt; ⁺ & gt ^; .

Example 77

Methyl {4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoate hydrochloride

(2.5 g, 6.43 mmol) prepared in Example 76 and 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride (2.62 mL, 16.1 mmol) was added to methyl 4- (bromomethyl) benzoate (1.62 g, 7.07 mmol) in dichloromethane (100 mL) at 50 ° C. After 30 minutes additional methanol (50 mL) was added. After 18 h, the reaction mixture was concentrated in vacuo and 1N aqueous hydrochloric acid (10 mL) and water were added. The resulting solid was isolated and methanol (20 mL) and 1 N hydrochloric acid in diethyl ether (15 mL) were added. Diethyl ether was added to the resulting solution. The precipitate was triturated to give methyl ({4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) Benzoate hydrochloride (2.4 g). _{^{1 H NMR (DMSO d 6,}} 300 MHz) δ1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1-3.5 (m, 8H, CH2), 3.87 (s, 3H, OCH3), 4.40 (bd 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.1-8.1 (m, 8H, ArH), 9.3-11.2 (m, 3H, NH, NHOH). Electrospray MS m / z 501.5 (M + H) &lt; ⁺ & gt ^; .

Example 78

Phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoic acid hydrochloride

({4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoate Hydrochloride (prepared in example 77) (0.072 g, 0.134 mmol) was added 1N aqueous sodium hydroxide (0.5 mL). After 18 hours 1 N aqueous hydrochloric acid (0.5 mL) was added and the reaction mixture was concentrated in vacuo. Water was added and the precipitate was triturated to give an off-white solid of 4 - ({4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] Methyl} benzoic acid hydrochloride (0.040 g) was obtained. _{^{1 H NMR (DMSO d 6,}} 300 MHz) δ1.85 (t, 3H, J = 2.2 Hz), 2.1-3.5 (m, 8H, CH2), 4.37 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.0-8.1 (m, 8H, ArH), 9.3-11.2 (m, 3H, NH, NHOH), 13.1 (bd s, 1H, COOH). Electrospray MS m / z 487.1 (M + H) &lt; ⁺ & gt ^; .

Example 79

4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride

({4- {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoate To the hydrochloride (Example 77) (0.20 g) was added concentrated aqueous ammonium hydroxide (4 mL). After several weeks, the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol / dichloromethane) to give a white powder which was dissolved in dichloromethane and methanol. Additional 1 N hydrochloric acid in diethyl ether was added followed by additional diethyl ether. Phenyl) sulfonyl} -N-hydroxy-4-piperidinecarboxamide as a white powder and a white powder of 1- [4- (aminocarbonyl) benzyl] -4 - {[4- (2-butynyloxy) Hydrochloride (0.106 g) was obtained. ^{1 H NMR (DMSO d6, 300} MHz) δ1.85 (t, 3H, CH3, J = 2.2 Hz), 2.2-3.5 (m, 8H, CH2), 4.33 (bd s, 2H, NCH2Ar), 4.89 (q 2H, OCH2, J = 2.2 Hz), 7.1-8.0 (m, 8H, ArH), 7.47 (s, 1H, CONH), 8.04 (s, 1H, CONH), 9.35 10.44 (bd s, 1H, NHOH), 11.1 (s, 1H, NH). Electrospray MS m / z 486.3 (M + H) &lt; ⁺ & gt ^; .

Example 80

phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate

Phenyl] sulfanyl} -4 - [(hydroxyamino) carbonyl] -piperidine-1-carboxylate (0.30 g) (obtained in example 14) was added 30% aqueous hydrogen peroxide (3 mL). After 3 days water was added and dichloromethane and the organic phase was washed with aqueous Na ₂ SO _3. Concentration of the organic phase gave material which was dissolved in methanol (8 mL) and treated with 30% aqueous hydrogen peroxide. After several days, the procedure described above gave the title compound as a colorless foam which was the same as that of tert-butyl 4 - {[4- (but-2-ynyloxy) phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine -1-carboxalate (0.26 g) was obtained. ^{1 H NMR (DMSO d6, 300} MHz) δ1.38 (s, 9H, t- butyl), 1.5-1.7 (m, 2H, CHH), 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1- (M, 2H, CHCH), 2.5-2.7 (m, 2H, NCHH), 3.8-4.0 (m, 2H, NCHH), 4.81 (q, 2H, OCH2, J = 2.2 Hz), 7.1-7.4 , 4H, ArH), 9.1 (s, 1H, NHOH), 10.8 (s, 1H, NHOH). Electrospray MS m / z 437.2 (M + H) &lt; ⁺ & gt ^; .

Example 81

4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride

(prepared in Example 80) from tert-butyl 4 - {[4- (but-2-ynyloxy) phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine- (0.26 g) was added 4N hydrochloric acid in dioxane (4 mL). After 1 h, the reaction mixture was concentrated in vacuo. Methanol was added and removed in vacuo. Dichloromethane was added and removed in vacuo three times to give 4- (4- (but-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride (0.19 g) as a yellow solid ^{. 1 H NMR (DMSO d6,} 300 MHz) δ1.86 (t, 3H, CH3, J = 2.2 Hz), 1.7-2.8 (m, 8H, CH2), 4.82 (q, 2H, OCH2, J = 2.2 Hz ), 7.1-7.5 (m, 4H, ArH), 8.4-11.0 (m, 4H, NH2, NHOH). Electrospray MS m / z 337.2 (M + H) <^+> .

Example 82

4- (4-But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride

4-carboxylic acid hydroxamide hydrochloride (0.162 g, 0.434 mmol) (prepared as described in Example 81) in methanol was added a solution of 4- (4- (butyl- 2-ynyloxy-benzenesulfinyl) -piperidine- To the 4-bromobenzyl bromide (0.120 g, 0.478 mmol) was added triethylamine (0.13 mL, 0.91 mmol) After 4 hours the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol / dichloromethane) (1 mL) in ether was added to the solution, which was concentrated in vacuo to give a yellowish brown solid 1- (4-bromo-benzyl) -4- ( ¹ H NMR (DMSO d6, 300 MHz) [delta] 1.85 (t, 3H), 1.20 (s, 3H, CH3, J = 2.2 Hz), 1.9-3.5 (m, 8H, CH2), 3.87 (s, 3H, OCH3), 4.3 (bd s, 2H, NCH2Ar) 2.2 Hz), 7.0-7.8 (m, 8H, ArH), 9.2-11.1 (m, 3H, NH, NHOH) Electrospray MS m / z 505.1 / 507.2 (M + H) &lt; ⁺ & gt ^; .

Pharmacology

Representative compounds of the invention were evaluated as inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-a converting enzyme (TACE). The standard pharmacological test procedure used to define its biological profile and the results obtained therefrom are shown below.

Test procedure to measure MMP-1, MMP-9 and MMP-13 inhibition rates

This standard pharmacological test procedure involves the use of a thiopeptide substrate such as Mat-metalloproteinase MMP-1, MMP-13 (collagenase) or MMP-9 (gelatinase), such as Ac-Pro-Leu-Gly (2-mercapto-4-methyl-pentanoyl) -Leu-Gly-OEt, and this incision causes a colorimetric reaction with DTNB (5,5'-dithiobis The thiopeptide substrate is freshly prepared in a 20 mM stock form in 100% DMSO and the DTNB is dissolved in 100% DMSO in 100 mM stock form and stored in a dark room at room temperature Both substrate and DTNB are diluted with 1 mM substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl ₂ ) before use. The enzyme stock is diluted with buffer (50 mM HEPES, pH 7.5, 5 mM CaCl ₂ , 0.02% Brij) The buffer, enzyme, vehicle or inhibitor, and DTNB / substrate are placed in a 96-well plate It was added to 200 ㎕) and monitored for 5 minutes at 405 nm on a plate reader increased color with a spectrophotometer, and shows an increase in color over time in a linear gradient.

Alternatively, a fluorescent peptide substrate is used. In this test procedure, the peptide substrate contains a fluorescent group and a light extinction group. When the MMP cleaves the substrate, the resulting fluorescence is quantified on a fluorescence plate reader. Analysis is performed in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca ⁺² , 0.02% Brij, 0.5% cysteine) with human recombinant MMP-1, MMP-9 or MMP-13. The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. For analysis, the substrate and enzyme are diluted to the desired concentration in HCBC buffer. The compound is added to a 96 well plate containing the enzyme and the reaction is initiated by adding the substrate. Read the reaction value for 10 minutes (excitation state 340 nm, emission state 444 nm), and the fluorescence increase with time is expressed as a linear slope.

For the thiopeptide or fluorescent peptide test procedure, a linear slope is calculated, which indicates the rate of the reaction. Confirm the linearity of the reaction rate (r ² > 0.85). Calculate the mean of the control rate (x ± sem) and compare the statistical significance (p <0.05) with the drug-treated rate using the Dunnett multiple comparison test. Dose-response correlations can be found using multiple doses of the drug and IC ₅₀ values using 95% CI are calculated using linear regression.

Test procedure to measure TACE inhibition rate

Using a 96-well black microtiter plate, each well was treated with 10 ㎕ TACE (final concentration 1 / / mL), 70 T Tris buffer (final concentration 10 mM), pH 7.4, containing 10% glycerol, Add 10 μl of the test compound solution (final concentration 1 μM, DMSO concentration <1%), and incubate at room temperature for 10 minutes. A fluorescent peptidyl substrate (final concentration 100 μM) is added to each well, followed by shaking in a stirrer for 5 seconds to initiate the reaction.

The reaction value (excitation state 340 nm, emission state 420 nm) for 10 minutes is read and the fluorescence increase with time is shown linearly. Calculates the slope of the line, which represents the reaction rate.

Confirm the linearity of the reaction rate (r ² > 0.85). Calculate the mean control rate (x ± sm) and compare the statistical significance (p <0.05) with the drug-treatment rate using the Dunnett multiple comparison test. Multiple doses of the drug can be used to confirm the dose-response relationship and linear regression is used to calculate the IC ₅₀ value for 95% CI.

Human mononuclear THP-1 cell differentiation assay for soluble protein (THP-1 soluble protein assay)

(TNF-α) and TNF receptor (TNF-R p75 / 80 and TNF-R p55 / 60) and interleukin-8 (IL-8) Resulting in differentiation into giant cells at the same time. Additionally, non-promoted THP-1 cells release both the p75 / 80 and p55 / 60 receptors over time. The release of TNF-α and possibly TNF-R p75 / 80 and TNF-R p55 / 60 (but not IL-8) attached to the membrane is mediated by TNF-α converting enzyme or TACE. These assays can be used to demonstrate the effect of inhibitory or irritant compounds on these TACE enzymes and the cytotoxic results of these compounds.

THP-1 cells (ATCC) are human mononuclear cell lines obtained from peripheral blood of a 1 year old male suffering from acute mononuclear leukemia. It can be proliferated in culture medium and stimulated with mitotic material to differentiate into giant cells.

For analysis, THP-1 cells are obtained from pre-proliferated ATCC stock frozen at 5 x 106 / ml / vial. 1 vials were incubated with Glutamax (Gibco) medium containing 10% fetal bovine serum, 100 units / ml penicillin, 100 占 퐂 / ml streptomycin, and 5 x ^10-5 M 2-mercaptoethanol and RPMI-1640 16 ml flask (THP-1 medium). Each cell vial is incubated for approximately 2 weeks and used for analysis and used for compound screening for only 4 to 6 weeks. Cells are cultured on Monday and Thursday at a concentration of 1 x 10 &lt; 5 &gt; / ml.

To perform the analysis, THP-1 cells were incubated with lipopolysaccharide (LPS) (Calbiochem Lot # 1) at 37 ° C, 5% CO ₂ at a concentration of 1.091 × 10 ⁶ cells / ml (1.1 ml / B13189) Stock 24 mg / ml with 50 ml / well together in a 24 well plate. At the same time, 50 ml / well of drug, vehicle or THP-1 medium is added to appropriate wells to make a final volume of 1.2 ml / well. The standard and test compounds were dissolved in DMSO at a concentration of 36 mM and diluted to the appropriate concentration in THP-1 medium and then added to the wells at the beginning of the incubation to a final concentration of 100 mM, 30 mM, 10 mM, 3 mM, 1 mM, 300 nM and 100 nM, respectively. Cell exposure to DMSO is limited to 0.1% final concentration. Positive control wells were included in a drug-free experiment with mitotic material. Includes the same vehicle control wells as the positive control wells except that DMSO is added to a final concentration of 0.083%. Negative control wells with vehicle but no mitotic material or agent added to cells were included in the experiment. LPS can be replaced with 50 ml / well THP-1 medium to assess the effect of compounds on the basal (non-stimulatory) release of the receptor. The plates are placed in an incubator set at 5% CO ₂ and 37 ° C. After 4 hours of incubation, 300 ml / well tissue culture supernatant (TCS) is transferred for use in TNF-alpha ELISA. After 24 hours of incubation, TCS 700 ml / well are transferred and used for TNF-R p75 / 80, TNF-R p55 / 60 and IL-8 ELISA assays.

Additionally, for 24 hours, the cells for each treatment group were resuspended in 500 μl / well of THP-1 medium and transferred to a FACS tube. Add 2 ml / tube of 0.5 mg / ml propidium iodide (PI) stock (Boerhinger Mannheim cat. # 1348639). Samples are flowed into a Becton Dickinson FaxCaliber FLOW cytometry machine and the amount of dye taken from each cell is measured at high red wavelength (FL3). Only cells with damaged membranes (dead or dying) can take PI. Calculate the percentage of viable cells by dividing the number of unstained cells in PI by the total number of cells in the sample. The calculated survival values in the case of the treated group were compared to the survival values calculated for the vehicle-treated mitosis-promoting group (" vehicle positive control ") and the " percent change from control " This "% change from control" value is an indicator of drug toxicity.

The amounts of soluble TNF- [alpha], TNF-R p75 / 80 and TNF-R p55 / 60 and IL-8 in TCS of THP-1 cell culture were inferred from standard curves prepared using standard kits, . The number of cells taken or excluded from the PI is measured using a FLOW cytometry machine and visualized with a histogram using commercially available Cytologic software for each treatment group containing all controls.

In terms of the response magnitude of the THP-1 cell culture, the biological parameters require a comparison between experiments based on the% change from the " vehicle positive control " for each drug concentration. The% change in each soluble protein evaluated in the " vehicle positive control " for each compound concentration was calculated using the following formula:

For study of soluble proteins (TNF-a, p75 / 80, p55 / 60, IL8) under stimulation conditions, the average pg / ml of double wells was measured and the results are expressed as% change from "vehicle positive control". For studies of soluble proteins (p75 / 80 and p55 / 60 receptors) under non-stimulating conditions, the mean pg / ml of the double wells was measured and the results are expressed as% change from the " vehicle positive control &

IC ₅₀ values for each compound are calculated by non-linear regression analysis using custom software using the JUMP statistical package.

For cell survival studies, the viability (PI exclusion) of the collected double wells was measured and the results expressed as a% change from the " vehicle positive control ". The calculated survival value in the case of the compound treated group is compared to the survival value calculated in the case of " vehicle positive control " and the "% change from control " is determined as follows. This value "% change from control " is an indicator of drug toxicity.

The in vitro matrix metalloproteinase inhibition, TACE inhibition and THP standard pharmacological test results are given in Table 1 below.

Based on the results obtained in the standard pharmacological test procedure described above, the compounds of the present invention were shown to be inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-a converting enzyme (TACE) , Tumor metastasis, tissue ulceration, abnormal wound healing, rhizome disease, graft rejection, insulin resistance, skeletal disease and HIV infection.

The compounds of the present invention may also be used in the treatment of atherosclerotic arteriosclerosis, atherosclerotic plaque formation, coronary arterial thrombosis due to atherosclerotic plaque destruction, restenosis, MMP-mediated osteopenia, inflammatory diseases of the central nervous system, Osteoarthritis, rheumatoid arthritis, corneal ulcer, proteinuria, aortic disease, degenerative cartilage loss following traumatic joint injury, dehydration of the nervous system, cirrhosis, Inflammatory bowel disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, prematurity retinopathy, ocular inflammation, keratoconus, sgrenic syndrome, myopia, ocular neoplasm, ocular neurogenesis / neuropathy Treatment or inhibition of pathological changes mediated by matrix metalloproteinases such as angiogenesis and corneal transplant rejection It is useful for keying.

The compounds of the present invention may be administered to a patient in need thereof, either purely or together with a pharmaceutical carrier. The pharmaceutical carrier may be a solid or a liquid.

Applicable solid carriers may include flavoring agents, lubricants, solubilizers, suspending agents, excipients, lubricants, compression aids, binders or one or more substances or encapsulating materials which may act as a tablet-disintegrating agent. In the case of powders, the carrier is a finely divided solid, which is a mixture with finely divided active ingredients. In the case of tablets, the active ingredient is mixed with the carrier having the necessary compressibility in suitable proportions and compressed to the desired shape and size. The powders and tablets preferably contain 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting wax, .

Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the present invention may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carriers may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspensions, thickeners, pigments, viscosity modifiers, stabilizers or osmo-regulators. Suitable liquid carriers for oral and parenteral administration include water (especially those containing such additives, such as cellulose derivatives, the preferred sodium carboxymethyl cellulose solution), alcohols (monohydric alcohols and polyhydric alcohols such as glycols, , And derivatives thereof, and oils (e.g., finely divided coconut oil and arachis oil). For parenteral administration, the carrier may also be a fatty acid such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in the form of sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. The sterile solution may also be administered intravenously. Oral administration can be in the form of a liquid or solid composition.

The compounds of the present invention may be administered rectally in conventional suppository form. For intranasal or bronchial administration by inhalation or insufflation, the compounds of the present invention may be formulated as an aqueous solution or a partial aqueous solution and used in the form of an aerosol. The compounds of the present invention may also be transdermally administered using a transdermal patch containing the active compound and a carrier that is inert to the active compound, harmless to the skin, and capable of delivering the agent for systemic absorption into the blood vessel through the skin. The carrier may take many forms such as creams, ointments, pastes, gels, and occlusive devices. The cream and ointment may be a viscous liquid or semi-solid emulsion in the form of oil-in-water or water-in-oil. Pastes comprising mineral oil containing the active ingredient or absorbing powder dispersed in a hydrophilic mineral oil may also be suitable. Various occlusion devices can be used to release the active ingredient into the bloodstream, such as a reservoir containing the active ingredient in the presence or absence of a carrier, or a semi-permeable membrane covering a matrix containing the active ingredient. Other occlusive devices are known in the literature.

The dosage used to treat a particular patient suffering from MMP or TACE dependent disease is subjectively determined by the primary care physician. Related variables include the severity of the dysfunction, and the patient's height, age, and response pattern. Treatment will generally be initiated at a lower dose than the optimal dose of the compound. The dose is then increased until the optimum effect is achieved. The precise dosage for oral, parenteral, nasal, or intratracheal administration will be determined by the physician administering it based on the subject being treated and on the basis of standard drug principles.

Preferably, the pharmaceutical composition is in unit dosage form, for example in tablet or capsule form. In this form, the composition is further subdivided into unit doses containing the appropriate amount of active ingredient; The unit dosage form can be a package composition, for example, a package powder, a vial, an ampoule, a syringe containing a pre-filled liquid, or a sachet. The unit dosage form may be, for example, a capsule or tablet itself, or a suitable number of such compositions in packaged form.

Claims (7)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I Wherein: R ₁ is selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C ₄ -C ₈ -cycloheteroalkyl; R ₂ and R ₃ are independently of each other hydrogen, alkyl of 1-6 carbon atoms, -CN or -CCH; R ₇ is hydrogen, aryl, aralkyl, heteroaryl, hetero aralkyl, 1-6 carbon atoms alkyl, 2-6 alkenyl carbon atoms, alkynyl of 1-6 carbon atoms, 3-6 cycloalkyl, -C carbon atoms _{(O) -R 1, -SO 2} -R 1, -C (O) -NHR 1, -C (O) NR 5 R 6, -C (O) R 1 NR 5 R ₆ , -C (O) -OR ₁ , -C (NH) -NH ₂ ; R ₅ and R ₆ independently of one another are hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or -C ₄ -C ₈ -cyclo Heteroalkyl; R ₈ , R ₉ , R ₁₀ and R ₁₁ independently of one another are hydrogen, aryl or heteroaryl, cycloalkyl of 3 to 6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, Alkyl, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms, provided that one of R ₈ and R ₉ , R ₉ and R ₁₀ or a pair of R ₁₀ and R ₁₁ is attached thereto Together with the carbon atom or atoms form a cycloalkyl ring of 3-6 carbon atoms, or a -C ₄ -C ₈ -cycloheteroalkyl ring; R ₁₂ is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C ₄ -C ₈ -cycloheteroalkyl, or alkyl of 1-6 carbon atoms; A is O, S, SO, SO ₂ , NR ₇ or CH ₂ ; X is O, S, SO, SO ₂ , NR ₇ or CH ₂ ; Y is aryl or heteroaryl, provided that A and X do not bond to adjacent Y atoms; n is 0-2. 2. The compound according to claim 1, wherein Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl or triazolyl or thiadiazolyl. The method according to claim 1, L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; L-Benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide; L- (4-Bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; L- (4-Bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-fluoro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (4-methyl-benzyl) -piperidine-4-carboxylic acid hydroxamide; 4- (4-But-2-ynyloxy-benzenesulfonyl) - l- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid hydroxamide; L- (4-Bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Synthesis of 1- (4-bromo-benzyl) -4- [4- (4-piperidin-4-yl-but- 2-ynyloxy) -benzenesulfonyl] -piperidine-4- carboxylic acid hydroxyamide ; 1- (4-Bromo-benzyl) -4- [4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-phenylsulfanyl) -4-hydroxycarbamoyl-piperidine-1-carboxylic acid tert-butyl ester; 4- (4-But-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide; L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxy-benzenesulfinylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pyran-4-carboxamide; 1-benzyl-4 - {[3- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide; 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1-isopropyl-4-piperidinecarboxamide; 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxamide; 3 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy-3-piperidinecarboxamide; 3 - {[4- (2-Butynyloxy) phenyl] sulfonyl} -1- (4-chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide; - [4- (2-piperidin-l-yl-ethoxy) -benzyl] -piperidine-4- carboxylic acid hydrobromide Lt; / RTI &gt; 4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-fentanyl) -piperidine-4-carboxylic acid hydroxyamide; L- (4-Methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; L- (4-Chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfanyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; 4 - ({[4- (but-2-ynyloxy) phenyl] thio} methyl) -N-hydroxypiperidine-4-carboxamide; tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfinyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; 4 - [[[4- (2-butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide; methyl-4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate; tert-butyl-4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; 1-acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide; 1- (2-Butynyl) -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride; Methyl-N-4-hydroxy-1,4- [4- (2-butynyl) Methyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-1,4-l] sulfonyl} -methyl) -N-4-hydroxy-1,4-piperidine dicarboxamide; Methyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; Benzyl 4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; Methyl} -N-hydroxy-4-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy- 4-piperidinecarboxamide; Methyl] -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) Carbonyl] -4-piperidinecarboxamide; Methyl] -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4-piperidinecarboxamide; -4 - ({[4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-oxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide; Phenyl] sulfonyl} methyl) -N- (4-hydroxy-2-butynyl) -Hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide, 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -1-ethyl-N-hydroxypiperidine-4-carboxamide trifluoroacetate; Phenyl) -sulfonyl} methyl) -1 - [(5-chlorothien-2-yl) Methyl] -N-hydroxypiperidine-4-carboxamide trifluoroacetic acid salt; Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-4-ylmethyl) piperidine-4-carboxamide trifluoro Acetic acid salt; Phenyl) sulfonyl} methyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide trifluoro Rosacetate; 1-Benzoyl-4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-piperidine-4-carboxamide; 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidine-4-carboxamide; 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-1-ethyl-N-4-hydroxy-piperidine-1,4-dicarboxamide; 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-N-1-phenylpiperidine-1,4-dicarboxamide; Phenyl) sulfonyl} methyl) -N-1-, N-1-diethyl-N-4-hydroxypiperidine- Copy Mid; 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidine-4-carboxamide; Methyl-N-1-phenylpiperidine-1, 4-dicarboxylic acid methyl ester was used in place of 4 - ({[4- Copy Mid; Octyl-4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate; 4-methoxyphenyl) -4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate; 4 - ({[4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (phenylsulfonyl) piperidine-4-carboxamide; Methyl-1H-imidazol-4-yl) sulfonyl] piperidine (hereinafter referred to as &quot;4-carboxamide; 1- [2- (benzylamino) acetyl] -4 - ({[4- (but-2-ynyloxy) phenyl] -sulfonyl} methyl) -N-hydroxypiperidine-4-carboxamide; Phenyl) sulfonyl} methyl) -N-hydroxy-1- (2-morpholin-4-ylacetyl) piperidine-4-carboxamide ; Hydroxy-1- [2- (4-methyl-piperazin-1-yl) acetyl] piperidine &lt; / RTI &gt;-4-carboxamide; 1-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide; 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide; 1- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidine-1-carbonyl) -4-piperidinecarboxamide; Ethyl 4- (4-but-2-ynyloxybenzenesulfonyl) -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxamide; Hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4- Piperidinecarboxamide; tert-butyl-4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxylate; 4 - {[4- (2-butynyloxy) -phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride; Methyl {4- {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoate hydrochloride; 4 - ({4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinyl} methyl) benzoic acid hydrochloride; 1- [4- (aminocarbonyl) benzyl] -4 - {[4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide hydrochloride; tert-butyl-4 - {[4- (but-2-ynyloxy) phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate; 4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride; and L- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride; And a pharmaceutical salt thereof. A therapeutically effective amount of a compound of formula I as defined in claim 1; Or a pharmaceutically acceptable salt thereof, to a mammal in need thereof, comprising administering to a mammal in need thereof a therapeutically effective amount of a TNF-alpha converting enzyme (TACE). The method according to claim 4, wherein the symptom to be treated is rheumatoid arthritis, graft rejection, malaise, inflammation, fever, insulin resistance, septic shock, hemorrhagic heart failure, central nervous system inflammatory disease, inflammatory bowel disease or HIV infection. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof; And a pharmaceutically acceptable carrier. a) reacting a reactive derivative of the formula or a reactive derivative thereof with an R ₁₂ NHOH compound, wherein R ₁₂ is as defined in claim 1, to obtain a compound of formula I; (Wherein n, X, Y, A, R ₁ , R ₂ , R ₃ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in claim 1; or R _{12 is} NHOH b) deprotecting the following compounds to give the corresponding compounds of formula (I); Wherein R ₁ , R ₂ , R ₃ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are as defined in claim 1, and R ₃₀ is t- Butyl, benzyl, and trialkylsilyl); or c) cleaving a resin-supported hydroxamate derivative containing the following group to obtain a compound of formula (I) wherein R _{12 is} hydrogen; Wherein R ₁ , R ₂ , R ₃ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in claim 1; or d) separating a mixture of optically active isomers of a compound of formula (I) (for example, racemates) to separate substantially enantiomeric or diastereoisomeric enantiomers or diastereomers; or e) acidifying the basic compound of formula I with a pharmaceutically acceptable acid to obtain a pharmaceutically acceptable salt; or f) converting a compound of formula I having a single reactive substituent group or moiety into a compound of formula I having another substituent group or moiety.