CN1213021C - N-Hydroxy-2-(alkyl, aryl or heteroarylsulfanyl, sulfinyl or sulfonyl)-3-substituted alkanes as matrix metalloproteinase inhibitors - Google Patents

Abstract

Matrix Metalloproteinases (MMPs) are a group of enzymes involved in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subtypes of enzymes, including collagenases, stromelysins and gelatinases. TNF- α converting enzyme (TACE) catalyzes the formation of TNF- α, a proinflammatory cytokine, from membrane-bound TNF- α precursor protein. Therefore, small molecule inhibitors of MMPs and TACE are expected to have potential in the treatment of various disease states. The present invention provides low molecular weight, non-peptide inhibitors of Matrix Metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) useful for the treatment of arthritis, tumor metastasis, tissue ulcers, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection, these inhibitors having the structure of formula (I), wherein R is²And R³Form a heterocycle, A is S, S or S ₂，R¹And R⁴Defined in the specification.

Description

N-Hydroxy-2-(alkyl, aryl or heteroarylsulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroaryl amides as matrix metalloproteinase inhibitors

Background of the Invention

Matrix metalloproteinases (MMPs) are a group of enzymes involved in the pathological destruction of connective tissue and basement membrane. These zinc-containing endopeptidases consist of several subtypes of enzymes, including collagenases, stromelysins, and gelatinases. Among these enzymes, gelatinase has been shown to be the MMP enzyme most closely related to the growth and spread of tumors. Gelatinase is known to be expressed at elevated levels in malignant tumors, and gelatinase can degrade basement membranes, leading to tumor metastasis. Angiogenesis required for the growth of solid tumors has also recently been demonstrated to have a gelatinase component in their pathology. Additionally, there is evidence that gelatinase is involved in plaque rupture associated with atherosclerosis. Other diseases mediated by MMPs include restenosis, MMP-mediated osteopenia, central nervous system inflammatory diseases, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcers , abnormal wound healing, bone disease, proteinuria, aortic aneurysm disease, degenerative cartilage loss from traumatic joint injury, demyelinating disease of the nervous system, liver cirrhosis, glomerular disease, early rupture of fetal membranes, inflammatory Bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular Angiogenesis/neovascularization and corneal graft rejection. For a recent review, see: (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.

TNF-α converting enzyme (TACE) can catalyze the formation of TNF-α from membrane-bound TNF-α precursor protein. TNF-α is a proinflammatory cytokine that, in addition to its well-defined antineoplastic properties, is thought to have a role in the following diseases: rheumatoid arthritis, septic shock, transplant rejection, cachexia, anorexia, inflammation, Congestive heart failure, central nervous system inflammatory disease, inflammatory bowel disease, insulin resistance, and HIV infection. For example, studies with anti-TNF-alpha antibodies and transgenic animals have demonstrated that blocking TNF-alpha formation can inhibit the development of arthritis. This observation has recently been extended to humans as well,

Therefore, it is expected that small molecule MMP and TACE inhibitors can be used in the treatment of various diseases. Although various MMP and TACE inhibitors have been identified and disclosed in the literature, many of these molecules are peptides and peptide analogs that have bioavailability and pharmacokinetic issues that limit their clinical effectiveness. There is therefore a great need for low molecular weight, potent, long-acting, orally bioavailable MMP and/or TACE inhibitors for effective long-term treatment of the various diseases mentioned above.

More recently, two documents (U.S. 5,455,258 and European Patent Application 606,046) have disclosed arylsulfonylamino substituted hydroxyacylamino acids. These documents include compounds exemplified by CGS 27023A. These are the only non-peptide matrix metalloproteinase inhibitors disclosed so far.

Salah et al. in Liebigs Ann. Chem. 195, (1973) disclose certain aryl-substituted thio- and aryl-substituted sulfonylacetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, its fungicidal activity was studied.

Certain sulfone carboxylic acids are disclosed in US Patent 4,933,367. These compounds have been shown to have hypoglycemic activity.

Invention Summary

The present invention relates to novel, low molecular weight, non-peptidic matrix metalloproteinases (MMPs) useful in the treatment of arthritis, tumor metastasis, tissue ulcers, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection ) and TNF-α converting enzyme (TACE) inhibitors.

According to the present invention, a group of compounds of general formula I and pharmaceutically acceptable salts thereof are provided:

in

R ¹ is an alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An aryl group of 6-10 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A cycloalkyl group of 3-8 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ;

or heteroaryl-(CH ₂ ) _0-6- , wherein the heteroaryl is a 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from O, S and N, and can be composed of 1 Or 2 groups independently selected from R ⁵ are optionally substituted;

A is -S-, -SO- or SO ₂ -;

R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached;

^R4 is hydrogen,

An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ;

R ⁵ is H, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, F, Cl , Br, I, CN, CHO, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₆ alkoxyaryl, C ₁ -C ₆ alkoxyheteroaryl, C ₁ -C ₆ alkylamino-C ₁ -C ₆ alkoxy, C ₁ -C ₂ alkylenedioxy, Aryloxy-C ₁ -C ₆ alkylamine, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n -aryl, wherein n is 0 , 1 or 2; OCOOC ₁ -C ₆ alkyl, OCOO aryl, OCONR ⁶ , COOH, COOC ₁ -C ₆ alkyl, COO aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ₂ NR ⁶ R ⁶ , NR ⁶ SO ₂ aryl, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ aryl group, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ aryl, NH ₂ , OH, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl; or containing one selected from O, S or NR ⁷ heteroatom saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle, wherein C ₁ -C ₆ alkyl is straight or branched, and heteroaryl is containing 1-3 independently selected A 5-10 membered mono- or bicyclic heteroaryl group consisting of heteroatoms from O, S or ^NR , and the aryl group is composed of 1 or 2 selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy or hydroxyl group optionally substituted phenyl or naphthyl;

R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n aryl, wherein n is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl contains 1-3 independently selected from O, S or A 5-10 membered mono- or bicyclic heteroaryl group with a heteroatom of NR ⁷ , and the aryl group is composed of 1 or 2 members selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy groups optionally substituted phenyl or naphthyl;

R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n - Aryl, where n is 0, 1 or 2; COO-C ₁ -C ₆ alkyl, COO aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO-C ₁ -C ₆ alkyl, CONHSO ₂ aryl, aryl or heteroaryl, wherein aryl is independently selected from halogen, cyano, Amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy optionally substituted phenyl or naphthyl; heteroaryl is a group containing 1-3 independently selected from O, 5-10 membered mono- or bicyclic heteroaryl of S or NC ₁ -C ₆ alkyl heteroatoms;

An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Arylalkyl groups of 7-16 carbon atoms, wherein the aryl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced;

A biphenylalkyl group of 13-18 carbon atoms, wherein the biphenyl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

8-16 carbon atom aryl alkenyl, wherein aryl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted with a heteroatom selected from O, S or N _{-C 1} -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

or R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between The nitrogens between the two together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl group is phenyl or naphthyl.

A more preferred aspect of the present invention is a group of compounds of the following general formula (Ia) and pharmaceutically acceptable salts thereof:

in

R ¹ is an alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An aryl group of 6-10 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A cycloalkyl group of 3-8 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ;

or heteroaryl-(CH ₂ ) _0-6- , wherein the heteroaryl is a 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from O, S and N, and can be composed of 1 Or 2 groups independently selected from R ⁵ are optionally substituted;

A is -S-, -SO- or SO ₂ -;

R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached;

^R4 is hydrogen,

An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

R ⁵ is H, F, Cl, Br, I, CN, CHO, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl , C ₂ -C ₁₂ alkynyl, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₆ alkoxyaryl, C ₁ -C ₆ alkoxyheteroaryl, C ₁ -C ₆ alkylamino-C ₁ -C ₆ alkoxy, C ₁ -C ₂ alkylenedioxy , aryloxy-C ₁ -C ₆ alkylamine, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n aryl, wherein n is 0 , 1 or 2; OCOO-C ₁ -C ₆ alkyl, OCOO aryl, OCONR ⁶ , COOH, COO-C ₁ -C ₆ alkyl, COO aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ₂ NR ⁶ R ⁶ , NR ⁶ SO ₂ aryl, NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ aryl, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ aryl, NH ₂ , OH, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl; or containing A saturated or unsaturated 5-10 membered mono-or biheterocyclic ring selected from O, S or NR ⁷ heteroatoms, wherein the heteroaryl group contains 1-3 heteroatoms independently selected from O, S or NR ⁷ 5-10 membered mono- or bicyclic heteroaryl, and aryl is composed of 1 or 2 independently selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or A hydroxy group optionally substituted phenyl or naphthyl;

R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _nAlkyl or aryl, wherein n is 0, 1 or 2; or CO heteroaryl; wherein heteroaryl is a 5-10 membered unit containing 1-3 heteroatoms independently selected from O, S or ^NR or bicyclic heteroaryl, and aryl is optionally selected from 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxyl Substituted phenyl or naphthyl;

R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -alkyl, S(O) _n -aryl, wherein n is 0, 1 or 2; COO-alkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl , CONHSO ₂ alkyl, CONHSO ₂ aryl, aryl, heteroaryl; where the C ₁ -C ₆ alkyl is straight or branched, and the heteroaryl contains 1-3 independently selected from O, S or NR A 5-10 membered mono- or bicyclic heteroaryl group with ⁷ heteroatoms, the aryl group is composed of 1 or 2 members selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkane phenyl or naphthyl optionally substituted by an oxy or hydroxy group;

An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Arylalkyl groups of 7-16 carbon atoms, wherein the aryl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced;

A biphenylalkyl group of 13-18 carbon atoms, wherein the biphenyl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

8-16 carbon atom aryl alkenyl, wherein aryl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted with a heteroatom selected from O, S or N _{-C 1} -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between two The nitrogens between them together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl is phenyl or naphthyl.

The most preferred group of compounds are those compounds having the following formula (Ib) and pharmaceutically acceptable salts thereof:

in:

R ¹ is phenyl, naphthyl, alkyl or heteroaryl with 1-18 carbon atoms such as pyridyl, thienyl, imidazolyl or furyl, optionally composed of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, halogen substituted; or S(O) _n -C ₁ -C ₆ alkylC ₁ -C ₆ alkoxyaryl or C ₁ -C ₆ alkoxyheteroaryl;

A is -S-, -SO- or SO ₂ -;

R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached;

^R4 is hydrogen,

An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

R ⁵ is H, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, F, Cl , Br, I, CN, CHO, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₆ alkylamino-C ₁ -C ₆ alkoxy, C ₁ -C ₂ alkylenedioxy, aryloxy-C ₁ -C ₆ alkylamine, C ₁ -C ₁₂ perfluoroalkyl , S(O) _n -C ₁ -C ₆ alkyl, S(O) _n -aryl, wherein n is 0, 1 or 2; OCOOC ₁ -C ₆ alkyl, OCOO aryl, OCONR ⁶ , COOH, COO-C ₁ -C ₆ alkyl, COO aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ₂ NR ⁶ R ⁶ , NR ⁶ SO ₂ aryl, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ aryl, SO ₂ NHCO aryl, CONHSO ₂ -C ₁ -C ₆ alkyl, CONHSO ₂ Aryl, NH ₂ , OH, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl; saturated or ^unsaturated 5-10 membered mono or di Heterocycle, wherein C ₁ -C ₆ alkyl is straight chain or branched, and heteroaryl is 5-10 membered mono- or bicyclic heteroaryl containing 1-3 heteroatoms independently selected from O, S or NR ⁷ , and aryl is phenyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy, or naphthyl;

R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _nAlkyl or aryl, wherein n is 0, 1 or 2; or CO heteroaryl; wherein heteroaryl is a 5-10 membered unit containing 1-3 heteroatoms independently selected from O, S or ^NR or bicyclic heteroaryl, and aryl is optionally selected from 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxyl Substituted phenyl or naphthyl;

R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -alkyl, S(O) _n -aryl, wherein n is 0, 1 or 2; COO alkyl, COO aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO ₂ alkyl, CONHSO ₂ aryl, aryl or heteroaryl; wherein aryl is independently selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy or hydroxy group optionally substituted phenyl or naphthyl; heteroaryl is 5-10 heteroatoms containing 1-3 independently selected from O, S or N C ₁ -C ₆ alkyl Mono- or bicyclic heteroaryl;

An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An arylalkyl group of 7-16 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced;

A biphenylalkyl group of 13-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

An arylalkenyl group of 8-16 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted by a heteroatom selected from O, S or NR-C ₁ -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ;

R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between two The nitrogens between them together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl is phenyl or naphthyl.

The most preferred matrix metalloproteinase and TACE inhibitory compounds of the present invention are following compounds and pharmaceutically acceptable salts thereof:

1-Benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Methoxy-benzenesulfonyl)-1-naphthalen-2-yl-methylpiperidine-4-carboxylic acid hydroxyamide,

1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxyamide,

1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide,

1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,

1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,

1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylic acid hydroxyamide,

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylic acid hydroxyamide,

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide,

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxyamide and

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxyamide.

Of course, when R ¹ , R ² , R ³ and R ⁴ contain asymmetric carbons, the definition of compounds of formulas I, Ia and Ib includes all possible stereoisomers and mixtures thereof having the activities discussed below. Specifically included are the racemic variants and any optical isomers having the indicated activity. Optical isomers can be obtained in pure form by standard separation techniques. Unless otherwise specified, the term "alkyl" refers to straight or branched C ₁ -C ₆ alkyl, and aryl refers to phenyl or naphthyl. Pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic acid, citric acid, acetic acid, tartaric acid, succinic acid, maleic acid, malonic acid, Hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid and similar other acids known to be acceptable.

The present invention thus provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. In particular, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.

The compositions are preferably suitable for oral administration. However, they may also be administered by other routes, such as parenterally to a patient.

In order to obtain uniformity of administration, the compositions of the present invention are preferably presented in unit dosage form. Suitable unit dosage forms include tablets, capsules and powders in sachets or vials. Such unit dosage forms may contain 0.1-100 mg of a compound of the invention. The compounds of the present invention can be orally administered at a dose of about 0.01-100 mg per kilogram. Such compositions may be administered 1-6 times daily, more typically 1-4 times daily.

The composition of the present invention can be formulated with conventional excipients such as fillers, disintegrants, binders, lubricants, flavoring agents and the like. Formulation can be carried out in conventional manner.

According to the present invention, there are also provided processes for preparing the compounds of the present invention.

Invention method

The compounds of the invention can be prepared according to one of the following general methods.

Alkylation of appropriately substituted thiol derivatives can be achieved from substituted (Scheme 1) or unsubstituted (Scheme 2) α-bromoacetate derivatives using potassium carbonate as the base in refluxing acetone. The sulfide derivatives thus obtained are oxidized with m-chloroperbenzoic acid in dichloromethane or with potassium persulfate preparations in methanol/water. The sulfones obtained in the above procedure can be further alkylated with various alkyl halides to give disubstituted derivatives or hydrolyzed with sodium hydroxide/methanol at room temperature. But if the tert-butyl ester was present instead of the ethyl ester, the hydrolysis was carried out with trifluoroacetic acid/dichloromethane at room temperature. Subsequently, the obtained carboxylic acid derivatives were converted into hydroxamic acid derivatives by reaction with oxalyl chloride/DMX (catalyzed) and hydroxylamine/triethylamine.

Process 1

Synthesis :

a. potassium carbonate/acetone/reflux; b. m-chloroperbenzoic acid;

c. Potassium carbonate/18-crown-6/R ₃ Br/acetone/reflux/

d.NaOH/MeOH/THF/RT

e. (COCl) ₂ /CH ₂ Cl ₂ /Et ₃ N/NH ₂ OH·HCl.

Process 2

Synthesis :

a. potassium carbonate/acetone/reflux; b. m-chloroperbenzoic acid;

c. Potassium carbonate/18-crown-6/R ₃ Br/acetone/reflux/

dR ₃ Br/10N NaOH/Bz(Et) ₃ /CH ₂ Cl ₂ /RT

e.NaOH/MeOH/THF/RT

f. (COCl) ₂ /CH ₂ Cl ₂ /Et ₃ N/NH ₂ OH·HCl.

As shown in Scheme 3, the above sulfide derivatives can be further alkylated with lithium bis(trimethylsilyl)amide in THF at 0°C. Alkylated or monosubstituted compounds are hydrolyzed and converted to hydroxamic acid derivatives. Sulfinyl derivatives can be prepared by oxidation of sulfide hydroxamic acid derivatives with hydrogen peroxide in MeOH solution.

Process 3

Synthesis :

a. Potassium carbonate/acetone/reflux; bR ₃ Br/HMDS/THF;

c.NaOH/MeOH/THF/RT

d.(COCl) ₂ /CH ₂ Cl ₂ /Et ₃ N/NH ₂ OH·HCl.

e.MeOH/H ₂ O ₂ /RT

Starting from diethanolamine and appropriately substituted alkyl or aryl halides, the corresponding 1-substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamides can be prepared (Scheme 4 ). The N-substituted diethanolamine derivatives were converted to the dichloro compounds with thionyl chloride. The corresponding dichloride was reacted with the substituted ethyl sulfoacetate in the presence of potassium carbonate/18-crown-6 in boiling acetone. As shown in Scheme 4, the 1-substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl esters thus obtained were converted into the hydroxyamides.

Alternatively, such compounds and other heterocyclic compounds can be prepared as shown in Schemes 5 and 6.

Process 4

a. potassium carbonate/RBr/acetone/reflux;

b. SOCl ₂ /CH ₂ Cl ₂

cR ¹ SO ₂ CH ₂ COOEt/potassium carbonate/18-crown-6/acetone/reflux

d.NaOH/THF/RT

e.(COCl) ₂ /NH ₂ OH·HCl/Et ₃ N

Process 5

Y＝N or CH

a. RBr/R ¹ SH/chloroform/reflux; b. Potassium persulfate/MeOH;

e.(COCl) ₂ /NH ₂ OH·HCl/Et ₃ N

Process 6

a. LiN(TMS) ₂ /THF/0℃/carbon dioxide; b. (COCl) ₂ /NH ₂ OH·HCl/Et ₃ N

In addition, schemes 7-11 show methods for preparing hydroxamic acid compounds using solid phase supports (P).

Process 7

Reagents and conditions: a) 2-haloacid (3.0eq); 1-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0eq. ); DMF, 25° C.; 2-16 hours. b) Thiol (5.0eq.); Sodium iodide (5.0eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0eq.); THF; 25°C ; 12-16 hours. c) 70% tert-butyl hydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25°C; 12-24 hours. e) TFA:DCM (1:1); 25°C; 1 hour.

Coupling of 4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin (hydroxylamine resin) with a 2-haloacid yields a hydroxamate resin. The coupling reaction can be performed in an inert solvent such as DMF at room temperature in the presence of a carbodiimide such as DIC. Halogen groups can be replaced by thiol groups in the presence of a base such as DBU in an inert solvent such as THF at room temperature. Sulfides can be oxidized to sulfoxides by reaction with an oxidizing agent such as tert-butyl hydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid in an inert solvent such as DCM at room temperature. Alternatively the sulfide is oxidized to the sulfone by reaction with an oxidizing agent such as m-chloroperbenzoic acid in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide or sulfone can be treated with an acid such as trifluoroacetic acid in an inert solvent such as DCM to release the free hydroxamic acid.

Scheme 8 shows a method for the preparation of hydroxamic acids having an alkoxy group attached to the aromatic ring.

Process 8

Reagents and conditions: a) 2-haloacid (3.0eq); 1-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0eq. ); DMF, 25° C.; 2-16 hours. b) 4-fluorobenzenethiol (5.0eq.); Sodium iodide (5.0eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0eq.); THF; 25°C; 12-16 hours. c) Ethanol (15.0 eq.); Sodium hydride (15.0 eq.); DMF; 80° C.; 15 hours. d) 70% tert-butyl hydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25°C; 12-24 hours. f) TFA:DCM (1:1); 25°C; 1 hour.

The hydroxylamine resin was coupled with a 2-haloacid and the halo group was replaced with a fluorobenzenethiol according to the aforementioned method. The fluoro group can then be replaced with an alcohol in the presence of a base such as sodium hydride in an inert solvent such as DMF at about 80°C. The alkoxyphenylsulfanyl hydroxamate is then oxidized to the corresponding sulfinyl or sulfonyl hydroxamate according to the method described above. The free hydroxamic acid was released as described previously.

Scheme 9 shows a method for the preparation of 2-bisarylsulfanyl-, sulfinyl- and sulfonylhydroxamic acids.

Process 9

Reagents and conditions: a) 2-haloacid (3.0eq); 1-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0eq. ); DMF, 25° C.; 2-16 hours. b) 4-bromobenzenethiol (5.0eq.); Sodium iodide (5.0eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0eq.); THF; 25°C; 12-16 hours. c) 70% tert-butyl hydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25°C; 12-24 hours. e) Arylboronic acid (2.0 eq.); Tetrakis(triphenylphosphine)palladium(0) (0.1 eq.); 10% aqueous sodium carbonate solution (10.0 eq.); DME; 80° C.; 8 hours. f) TFA:DCM (1:1); 25°C; 1 hour.

The hydroxylamine resin was coupled with a 2-haloacid and the halo group was replaced with bromobenzenethiol according to the previous method. The bromophenylsulfanyl hydroxamate is then oxidized to the corresponding sulfinyl or sulfonyl hydroxamate according to the methods described previously. The bromo group is then replaced by reaction with arylboronic acid in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as sodium carbonate in an inert solvent such as DME at about 80°C. The free hydroxamic acid is then released according to the method described previously.

Scheme 10 shows a method for the preparation of hydroxamic acids with amine groups attached to the aromatic rings.

Process 10

Reagents and conditions: a) 2-haloacid (3.0eq); 1-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0eq. ); DMF, 25° C.; 2-16 hours. b) 4-bromobenzenethiol (5.0eq.); Sodium iodide (5.0eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0eq.); THF; 25°C; 12-16 hours. c) Amine (20.0eq.); Tris(dibenzylideneacetone)-dipalladium(0) (0.2eq.); (S)-(-)-2,2'-bis(diphenylphosphino) -1,1'-binaphthyl ((S)-BINAP, 0.8eq.); Sodium tert-butoxide (18.0eq.); Dioxane; 80°C, 8 hours; d) TFA:DCM (1:1 ); 25°C; 1 hour.

The hydroxylamine resin was coupled with a 2-haloacid and the halo group was replaced with bromobenzenethiol according to the previous method. Then in the presence of a catalyst such as tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide in an inert solvent such as dioxane at about Replacement of bromo groups with amines at 80°C. The free hydroxamic acid is then released according to the method described previously.

Scheme 11 shows a method for preparing hydroxamic acids with a sulfonate group attached to the aromatic ring.

Process 11

Reagents and conditions: a) 2-haloacid (3.0eq); 1-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0eq. ); DMF, 25° C.; 2-16 hours. b) 4-hydroxybenzenethiol (5.0eq.); sodium iodide (5.0eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0eq.); THF; 25°C; 12-16 hours. c) Sulfonyl chloride (5.0 eq.); Triethylamine (2.0 eq.); DCM; 25°C; 8 hours. d) 70% tert-butyl hydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25° C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25°C; 12-24 hours. f) TFA:DCM (1:1); 25°C; 1 hour.

The hydroxylamine resin was coupled with a 2-haloacid and the halo group was replaced with hydroxybenzenethiol according to the previous method. The hydroxyphenylsulfanyl hydroxamate is then oxidized to the corresponding sulfinyl or sulfonyl hydroxamate according to the methods previously described. The hydroxy group is then sulfonylated by reaction with sulfonyl chloride in the presence of a base such as triethylamine in an inert solvent such as DME at about room temperature. The free hydroxamic acid is then released according to the method described previously.

The following examples are provided to illustrate the scope of the invention and not to limit it. The HPLC purities of compounds prepared according to the combined methods are expressed as area percentages (% at nm) at the indicated wavelengths.

Example 1

  N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide

To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 mL) in a round bottom flask was added 2-bromo-propionic acid ethyl Ester (3.6 g, 20 mmol) and the reaction mixture was heated at reflux for 8 hours with good stirring. Finally, the reaction was cooled and the potassium salt was filtered off, and the above reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5N sodium hydroxide solution. The organic layer was further washed extensively with water, dried over magnesium sulfate, filtered and concentrated to give ethyl 2-(4-methoxy-phenylsulfanyl)-propionate as a light yellow oil. Yield 4.5 g (94%); MS; 241 (M+H) ⁺ .

To a stirred solution of ethyl 2-(4-methoxy-phenylsulfanyl)-propionate (2.44 g, 10 mmol) in THF (100 ml) at -4°C, bis(trimethylsilyl)ammonia was added slowly Lithium chloride (1M solution, 15ml, 15mmol). The orange reaction mixture was stirred at room temperature for 15 minutes, then it was cooled to 0° C. while stirring for an additional 1 hour. The reaction temperature was lowered to -40°C again, and benzyl bromide (1.72 g, 10 mmol) was added dropwise in THF. The reaction was warmed to room temperature and stirred overnight, then quenched with ice water, extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated, and column chromatographed on silica gel eluting with 10% ethyl acetate:hexanes to give 2-(4-methoxy-phenylsulfanyl)-2- Methyl-3-phenyl-propionic acid ethyl ester. Yield: 860 mg, (26%); MS: 331 (M+H) ⁺ .

2-(4-Methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12g, 12mmol) was dissolved in methanol (50ml) and 10N sodium hydroxide ( 20ml). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:ether and extracted with water. The aqueous layer was ice-cooled and acidified to pH3. The above acid was then extracted with chloroform, the organic layer was dried over magnesium sulfate, filtered and concentrated to give 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid . Yield: 580 mg, 16%; MS: 303.2 (M+H) ⁺ .

2-(4-Methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g, 1.65 mmol) and DMF (2 drops) in dichloromethane ( 100ml) to the stirred solution was added dropwise oxalyl chloride (1.0g, 8mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Meanwhile, in a separate flask, a mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. After 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 mL of dichloromethane and added slowly to the above hydroxylamine at 0°C. The above reaction mixture was stirred at room temperature for 24 hours and concentrated. The resulting residue was extracted with chloroform and washed well with water. The resulting product was purified by silica gel column chromatography and eluted with ethyl acetate. N-Hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-phenyl-propionamide was isolated as a colorless solid. mp 88°C; Yield: 300mg, 57%; MS: 318(M+H) ⁺ ; 1H NMR (300MHz, CDCl ₃ ): δ1.32(s, 3H), 3.07(d, J=11Hz, 1H), 3.23 (d, J = 11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).

Example 2

   N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide

Ethyl 2-(4-methoxyphenylsulfanyl)-phenylacetate was prepared according to the general procedure described in Example 1. Starting from ethyl [alpha]-bromophenylacetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4.4 g, 31.4 mmol), 8.5 g of product were isolated as a pale yellow oil. Yield 90%; MS: 303.1 (M+H) ⁺ .

2-(4-Methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g, 10 mmol) was first dissolved in methanol (50 ml) and 10 N sodium hydroxide (20 ml) to prepare 2-( 4-methoxy-phenylsulfanyl)-2-phenylacetic acid. The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273 (M+H) ⁺ .

Using 2-(4-methoxy-phenylsulfanyl)-2-phenylacetic acid (1.05 g, 3.83 mmol) as raw material, according to the method described in the examples, 154 mg of N-hydroxyl was isolated as a colorless solid -2-(4-Methoxy-phenylsulfanyl)-2-phenyl-acetamide. mp 155°C; yield 14%; MS: 290(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ3.72(s, 3H), 4.68(s, 1H), 6.86-7.44 (m, 9H).

Example 3

  2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide

According to the method in the second paragraph of Example 1, 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester was prepared. Starting from ethyl (4-methoxy-phenylsulfanyl)-propionate (3.5 g, 14.3 mmol) and isoprene bromide (2.25 g, 15 mmol), 2.2 g of product were isolated as an oil . Yield 50%; MS: 310 (M+H) ⁺ .

First, ethyl 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoate (2.0 g, 6.4 mmol) was dissolved in methanol (50 ml) and 10N hydrogen 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was prepared in sodium oxide (20ml). The resulting reaction mixture was worked up as described in Example 1. Yield of low melting solid 1.9 g, 99%. MS: 28 (M+H) ⁺ .

Using 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid (1.67g, 5.8mmol) as raw material, according to the method described in the examples, it was separated to obtain 1.5 g of 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide as a colorless solid. mp 89°C; Yield 94%; MS: 296(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.34(s, 3H), 1.61(s, 3H), 1.74(s, 3H ), 2.41-2.58(m, 2H), 3.80(s, 3H), 5.17(t, J=7.5Hz, 1H), 6.86(d, J=12.4Hz, 2H), 7.35(d, J=12.4Hz , 2H).

Example 4

   N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butanamide

2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general procedure described in Example 1. Starting from ethyl 2-bromo-3-methylbutyrate (20.9 g, 100 mmol) and 4-methoxythiophenol (14.0 g, 100 mmol), 30 g of product were isolated. Yield 99%; pale yellow oil; MS: 271 (M+H) ⁺ .

2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester (5.8 g, 21.6 mmol) was first dissolved in methanol (50 ml) and 10N sodium hydroxide (30 ml), Preparation of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butanoic acid. The resulting reaction mixture was worked up as described in Example 1. Yield 5.0 g, 99%. Low melting solid. MS: 242 (M+H) ⁺ .

Using 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (4.39g, 18.3mmol) as raw material, according to the method described in Example 1, 1.5g was isolated as a colorless solid N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butanamide. mp 119°C; yield 33%; MS: 256(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.90-1.07(m, 6H), 1.84-1.96(m, 1H) , 3.07(d, J=8.8Hz, 1H), 3.75(s, 3H), 6.88(d, J=15Hz, 2H), 7.35(d, J=15Hz, 2H).

Example 5

  N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100ml), add 30% hydrogen peroxide (10ml). The reaction mixture was stirred at room temperature for 48 hours while it was cooled to 0°C and quenched with saturated sodium sulfite (20ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours, then concentrated in a room temperature water bath, diluted with water, extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The title compound was isolated by column chromatography on silica gel, eluting with 75% ethyl acetate:hexanes. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).

Example 6

  2-(4-Methoxy-phenylsulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide

Starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide (900 mg, 3.0 mmol) (prepared in Example 3), According to the method described in Example 5, 2-(4-methoxy-phenylsulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. Yield: 104 mg (10%); mp 108°C; MS: 312 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ0.88 (s, 3H), 1.59 (s, 3H), 1.68(s, 3H), 2.27-2.80(m, 2H), 5.02(t, J=7.5Hz, 1H), 7.09(d, J=9Hz, 2H), 7.39(d, J=9Hz, 2H).

Example 7

   N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide

N-hydroxyl-2-(4-methoxyl-phenylsulfanyl)-3-methyl-butyramide (1g, 3.9mmol) prepared in Example 4 was used as raw material, according to the method described in Example 5 , N-Hydroxy-2-(4-methoxy-phenylsulfinyl)-3-methyl-butanamide was isolated as a colorless solid. Yield: 420 mg (40%); mp 163°C; MS: 272 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ0.89-1.12 (m, 6H), 1.63-1.74 (m , 1H), 3.13 (d, J=7Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H).

Example 8

   N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide

Using N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide (240 mg, 0.83 mmol) prepared in Example 2 as raw material, according to the method described in Example 5 , N-Hydroxy-2-(4-methoxy-phenylsulfinyl)-2-phenyl-acetamide was isolated as a colorless solid. Yield: 100 mg (40%); mp 135°C; MS: 304 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H).

Example 9

    N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide

To a stirred solution of 4-methoxythiophenol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 mL) in a round bottom flask was added ethyl α-bromoacetate (3.3 g, 20 mmol), and with thorough stirring, the reaction mixture was heated at reflux for 8 hours. Then, the reaction was cooled and the potassium salt was filtered off, and the above reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5N sodium hydroxide solution. The organic layer was further washed well with water, dried over magnesium sulfate, filtered and concentrated. (4-Methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as a light yellow oil. Yield 4.4 g (100%); MS; 227 (M+H) ⁺ .

To a stirred solution of 60% 3-chloroperbenzoic acid (14.0 g, 40 mmol) in dichloromethane (100 ml) was slowly added (4-methoxy-phenylsulfanyl)-ethyl acetate ( 4.4g, 20mmol) in dichloromethane (15ml). The reaction mixture became cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexane (300ml) and stirred for 15 minutes. The solid was filtered off and the sodium sulfite solution was added to the organic layer, and after stirring for at least 3 hours, the above mixture was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to isolate ethyl (4-methoxy-benzenesulfonyl)-acetate as a colorless oil. Yield: 100%; MS: 259.1 (M+H) ⁺ .

To a stirred solution of (4-methoxy-benzenesulfonyl)-ethyl acetate (2.5g, 10mmol), benzyl bromide (1.8g, 10mmol) and 18-crown-6 (500mg) in acetone (250ml) was added Potassium carbonate (10 g, excess), and the mixture was refluxed for 24 hours. Then, the above reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. 2-(4-Methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 g, 86%; low melting point solid; MS: 349 (M+H) ⁺ .

To a stirred solution of ethyl 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionate (348mg, 1mmol) in methanol (25ml) was added 10N sodium hydroxide (10ml). The above reaction mixture was stirred at room temperature for 48 hours. Then, the reaction mixture was concentrated and carefully neutralized with dilute hydrochloric acid. The resulting residue was extracted with chloroform, washed well with water, dried and concentrated. The resulting product was purified by silica gel column chromatography eluting with ethyl acetate:methanol (95:5) to give 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid as a colorless oil . Yield: 250 mg, 89%; MS: 321 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200 mg, 0.625 mmol) as raw material, according to the method described in Example 1, 150 mg of N-hydroxyl was isolated as a brown solid -2-(4-Methoxy-benzenesulfonyl)-3-phenyl-propionamide. Yield: 71%; mp 180°C; MS: 336(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ3.2(m, 1H), 3.8(s, 3H), 4.0-4.2( m, 2H), 7.0-8.0 (m, 9H).

Example 10

    2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the general procedure described in Example 1. Starting from ethyl 2-bromohexanoate (7 g, 32 mmol) and 4-methoxythiophenol (4.2 g, 30 mmol), 8.3 g of product were isolated. Yield 98%; pale yellow oil; MS: 283 (M+H) ⁺ .

Taking 2-(4-methoxy-phenylsulfanyl)-ethyl hexanoate (2.8 g, 10 mmol) as raw material, according to the method of Example 9, 3 g of 2-(4- Methoxy-benzenesulfonyl)-ethyl hexanoate. Yield 95%; mp 62°C; MS: 314 (M+H) ⁺ .

Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (2 g, 6.3 mmol), according to the method of Example 9, 1.5 g (83%) of 2- (4-Methoxy-benzenesulfonyl)-hexanoic acid. Mp 116°C; MS: 287 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1 mmol) as raw material, according to the method of Example 1, 700 mg of 2-(4-methoxyl) was isolated as a colorless solid -benzenesulfonyl)-hexanoic acid hydroxyamide. Yield: 60%; mp 130°C; MS: 302(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.786(t, J=7.2Hz, 3H), 1.1-1.3(m, 4H), 1.6-1.8(m, 2H), 3.7(m, 1H), 3.9(s, 3H), 7.2(d, J=11Hz, 2H), 7.8(d, J=11Hz, 2H), 9.3( s, 1H), 10.9 (s, 1H).

Example 11

    2-(4-Methoxy-benzenesulfonyl)-tetradecanoic acid hydroxyamide

2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general procedure described in Example 1. Starting from the corresponding ethyl 2-bromotetradecanoate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of product were isolated. Yield 98%; pale yellow oil; MS: 393 (M+H) ⁺ .

Using 2-(4-methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester (3.9g, 10mmol) as raw material, according to the method of Example 9, 3.2g of 2- (4-Methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester. Yield 76%; oil; MS: 425 (M+H) ⁺ .

Starting from 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester (2.5 g, 5.9 mmol), according to the method of Example 9, 2.0 g (85%) was isolated as a colorless solid 2-(4-Methoxy-benzenesulfonyl)-tetradecanoic acid. mp 82°C; MS: 397 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-tetradecanoic acid (1.14 g, 2.9 mmol) as raw material, according to the method of Example 1, 670 mg of 2-(4-methoxy yl-benzenesulfonyl)-tetradecanoic acid hydroxyamide. Yield: 57%; mp 114°C; MS: 414(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.85(t, J=7Hz, 3H), 1.16-1.27(m , 20H), 1.66 (m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J=15Hz, 2H), 7.73 (d, J=15Hz, 2H).

Example 12

  N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide

To ethyl 2-(4-methoxy-phenylsulfonyl)-3-phenyl-propionate (1.0 g, 3 mmol) (Example 9), methyl iodide (1 ml, excess) and 18-crown-6 Potassium carbonate (10 g, excess) was added to a stirred solution of (500 mg) in acetone (250 ml) and the reaction mixture was refluxed for 24 hours. After completion, the above reaction mixture was filtered, and the acetone layer was concentrated. The resulting residue was extracted with chloroform and washed well with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography eluting with 30% ethyl acetate: hexanes to give 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl as a colorless oil - ethyl propionate. Yield 1.0 g, 98%; MS: 349 (M+H) ⁺ .

Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (900mg, 2.7mmol), according to the method described in Example 9, 850mg was isolated (Quantitative) 2-(4-Methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid. Colorless oil, MS: 335 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid (900mg, 2.7mmol) as raw material, according to the method described in Example 1, it was isolated as a brown solid N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide. Yield: 48%; mp 58°C; MS: 350(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.4(s, 3H), 3.1(d, J=9Hz, 1H), 3.6 (d, J=9Hz, 1H), 3.9 (s, 3H), 6.8-7.8 (m, 9H).

Example 13

  2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide

Using 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (Example 1, 12g, 50mmol) as raw material, according to the method of Example 9, 12g was isolated as semi-solid 2-(4 -methoxy-benzenesulfonyl)-ethyl propionate. Yield 100%; MS: 256.1 (M+H) ⁺ .

According to the method described in Example 12, using ethyl 2-(4-methoxy-benzenesulfonyl)-propionate (1 g, 3.6 mmol) and isoprene bromide (1.0 g, 6 mmol) as starting materials, prepared 2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester. Yield: 1.0 g, 81%; colorless oil; MS: 341 (M+H) ⁺ .

Taking 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (900mg, 2.6mmol) as raw material, according to the method described in Example 9, separate 800 mg (96%) of 2-(4-methoxybenzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid were obtained as a semisolid. MS: 313 (M+H) ⁺ .

Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid (1.0 g, 3.2 mmol), according to the method described in Example 1, 700 mg was isolated 2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide as a low melting solid. Yield 67%; MS: 328(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.3(s, 3H), 1.5(d, J=6.2Hz, 6H), 2.5-3.0( m, 2H), 3.9 (s, 3H), 7.0 (d, J=11 Hz, 2H), 7.8 (d, J=11 Hz, 2H).

Example 14

3-(biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

According to the method of Example 12, with (2.7g, 10mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4-(chloromethyl)biphenyl (2.5g, 12mmol) as Starting material, preparation of 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester. Yield 4.0 g, 91%; colorless oil; MS: 438 (M+H) ⁺ .

Taking 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methylpropanoic acid ethyl ester (3g, 6.8mmol) as raw material, according to the method described in Example 9 method, 2.5 g (89%) of 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methylpropanoic acid were isolated as a colorless solid. mp 161°C; MS: 411 (M+H) ⁺ .

Using 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0g, 4.8mmol) as raw material, according to the method described in Example 1 method, 1.2 g of 3-(biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide were isolated as a colorless solid. Yield: 58%; mp 177°C; MS: 426(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.4(s, 3H), 3.2(d, J=9Hz, 1H), 3.7 (d, J=9Hz, 1H), 3.9 (s, 3H), 7.0-7.8 (m, 13H), 9.7 (bs, 1H).

Example 15

2-(4-Methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid hydroxyamide

According to the method described in Example 12, starting from (2.7 g, 10 mmol) of ethyl 2-(4-methoxy-benzenesulfonyl)-propionate and geranyl bromide (3.0 g, 13 mmol), prepared 2-(4-Methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid ethyl ester. Yield 4.0 g, 98%; colorless oil; MS: 409 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid ethyl ester (3g, 7.4mmol) as raw material, according to Example 9 method, 2.8 g (96%) of 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid were isolated as a colorless oil. MS: 379 (MH) ^- .

Using 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid (2.0 g, 5.2 mmol) as raw material, according to the method of Example 1 , 1.8 g of 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-dec-4,8-dienoic acid hydroxyamide were isolated as a colorless oil. Yield: 88%; MS: 396(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.4(s, 3H), 1.6(s, 3H), 1.65(s, 3H), 1.7 (s, 3H), 2.0-3.1(m, 6H), 3.9(s, 3H), 5.5(m, 2H), 6.98(d, J=9.0Hz, 2H), 7.7(d, J=9.0Hz, 2H).

Example 16

  3-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide

According to the method of Example 12, using (2.7g, 10mmol) ethyl 2-(4-methoxy-benzenesulfonyl)-propionate and bromo-methylcyclohexane (1.8g, 10mmol) as raw materials, Preparation of 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester. Yield 3.5 g, 95%; yellow oil; MS: 369 (M+H) ⁺ .

Using 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester (3g, 8.1mmol) as raw material, according to the method described in Example 9, 2.5 g (90%) 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid as a colorless solid. mp 116°C; MS: 341 (M+H) ⁺ .

Using 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0g, 5.8mmol) as raw material, according to the method described in Example 1, 1.1g was isolated 3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide as a colorless solid. Yield: 55%; mp 58°C; MS: 356(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.4(s, 3H), 2.3-1.0(m, 13H), 3.9( s, 3H), 7.0 (d, 8.8Hz, 2H), 7.69 (d, 9.0Hz, 2H).

Example 17

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-

                                                                           

According to the method of Example 12, with (2.7g, 10mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4-(2-piperidin-1-yl-ethoxy)- Benzyl chloride (2.9 g, 10 mmol) was used as starting material for the preparation of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy) -Phenyl]-Ethyl propionate. Yield 4.8 g, 98%; brown oil; MS: 490 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 g, 7.9 mmol) as raw materials, according to the method of Example 9, isolated 3.5 g (yield: 94%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl- 3-[4-(2-Piperidin-1-yl-ethoxy)-phenyl]-propionic acid. Mp 106°C; MS: 462.5 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid (2.0g, 4.2mmol) as a raw material, according to the method described in Example 1, separate and obtain 1g of N-hydroxyl-2-(4-methoxyl-benzenesulfonyl)-2-methyl-3-[4 -(2-Piperidin-1-yl-ethoxy)-phenyl]-propionamide. Yield: 1 g, 48%; mp 98°C; MS: 477 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.2 (s, 3H), 3.5-1.5 (m, 16H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 18

2-[4-(2-Azepine((azepan)-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl

...

According to the method of Example 12, with (2.7g, 10mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 1-[2-(4-chloromethyl-phenoxy) Starting from ethyl]-azepane (azepane) (3.03 g, 10 mmol), 2-[4-(2-azepane-1-yl-ethoxy)-benzyl]-2-(4- Methoxy-benzenesulfonyl)-propionic acid ethyl ester. Yield 4.5 g, 90%; brown oil; MS: 504 (M+H) ⁺ .

With 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester (4.0g, 7.9mmol ) as a raw material, according to the method of Example 9, isolated 3.5g (yield: 94%) as semisolid 2-[4-(2-azepine-1-yl-ethoxy)-benzyl] -2-(4-Methoxy-benzenesulfonyl)-propionic acid. MS: 476 (M+H) ⁺ .

Take 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid (2.0g, 4.2mmol) as Starting material, according to the method described in Example 1, 1 g of 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methanol) was isolated as a colorless solid Oxy-phenylsulfonyl)-propionic acid hydroxyamide. Yield: 1.8g, 87%; mp 68°C; MS: 491 (M+H) ⁺ ; ¹ HNMR (300MHz, CDCl ₃ ): δ1.23 (s, 3H), 3.5-1.7 (m, 18H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H), 10.9 (bs, 1H).

Example 19

2-[4-(2-Azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid hydroxy

                       

According to the general procedure of Example 12, ethyl 2-(4-methoxy-benzenesulfonyl)-pentanoate (3.5 g, 11.7 mmol) and 1-[2-(4-chloromethyl-phenoxy Base)-ethyl]-azepine (3.9g, 12.8mmol) as raw material, prepare 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4 -methoxy-benzenesulfonyl)-ethyl valerate. Yield 2.58 g (42%); brown oil; MS: 532.4 (M+H) ⁺ .

First 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (2g, 3.76mmol ) was dissolved in methanol (300ml) and 10N sodium hydroxide (15ml) to prepare 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy -phenylsulfonyl)-pentanoic acid. The resulting mixture was worked up in the manner of Example 1. Yield 830 mg (44%); brown solid; mp 55°C; MS: 504.4 (M+H) ⁺ .

Starting from 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid (690mg, 1.37mmol) , according to the method described in Example 1, 240 mg of 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxyl) was isolated as a yellow solid -phenylsulfonyl)-pentanoic acid hydroxyamide. Yield 34%; mp 85°C; MS: 519.2(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): d 0.71(t, J=7.3Hz, 3H), 0.78-1.77(m, 16H), 3.04-3.46(m, 4H), 3.87(s, 3H), 4.26(m, 2H), 6.87(d, J=8.7Hz, 2H), 7.14(m, 4H), 7.71(d, J =9Hz, 2H), 9.07(s, 1H), 10(s, 1H).

Example 20

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-

Ethoxy)-phenyl]-propionamide

According to the method of Example 12, with ethyl 2-(4-methoxy-benzenesulfonyl)propionate (5.4g, 20mmol) and 4-(2-N,N-diisopropylamino-ethoxy) -Benzyl chloride (6.1g, 20mmol) as starting material for the preparation of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino- Ethoxy)-phenyl]-propionic acid ethyl ester. Yield 8.9 g, 88%; yellow oil; MS: 506.5 (M+H) ⁺ .

2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0g, 7.9mmol) as a raw material, according to the method of Example 9, isolated 3.5g (yield: 92%) of 2-(4-methoxy-benzenesulfonyl)-2-methanol as colorless crystals -3-[4-(2-N,N-Diisopropylamino-ethoxy)-phenyl)]-propionic acid. Mp 68°C; MS: 478.6 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropylamino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.1mmol) as a raw material, according to the method described in Example 1, separate and obtain 1g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-( 2-N,N-Diisopropylamino-ethoxy)-phenyl]-propionamide. Yield: 1g, 49%; mp 98°C (hydrochloride); MS: 493(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.2(s, 3H), 1.3(d, 6H ), 1.4 (d, 6H), 3.5-1.5 (m, 6H), 3.9 (s, 3H), 4.4 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 21

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethyl

Oxy)-phenyl]-propionamide

According to the method of Example 12, with 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester (5.4g, 20mmol) and 4-(2-N, N-diethylamino-ethoxy) -Benzyl chloride (5.5g, 20mmol) as starting material for the preparation of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethyl Oxy)-phenyl]-propionic acid ethyl ester. Yield 8.5 g, 89%; brown oil; MS: 478.6 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester ( 3.5g, 7.7mmol) as raw materials, according to the method of Example 9, isolated 3.0g (yield: 85%) as colorless crystals of 2-(4-methoxy-benzenesulfonyl)-2-methyl -3-[4-(2-N,N-Diethylamino-ethoxy)-phenyl]-propionic acid. Mp 96-98°C; MS: 450.5 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (2.0g , 4.4mmol) as a raw material, according to the method described in Example 1, separate and obtain 1g of 2-(4-methoxyl-benzenesulfonyl)-2-methyl-3-[4-(2 -N,N-Diethylamino-ethoxy)-phenyl]-propionamide. Yield: 1g, 48%; mp 56-59°C (hydrochloride); MS: 465.5(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.1(t, 6H), 1.3(s , 3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 22

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-

                                                                           

According to the method of Example 12, with 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester (5.2g, 20mmol) and 3-(2-piperidin-1-yl-ethoxy)- Starting from benzyl chloride (6.0 g, 20 mmol), preparation of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy )-phenyl]-ethyl propionate. Yield 8.2, 83%; brown oil; MS: 490 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (6.0 g, 12.2mmol) as raw materials, according to the method of Example 9, isolated 4.9g (yield: 79%) as colorless crystals of 2-(4-methoxy-benzenesulfonyl)-2-methyl- 3-[3-(2-Piperidin-1-yl-ethoxy)-phenyl]-propionic acid. Mp 112°C; MS: 462.5 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid (3.0g, 6.5mmol) as a raw material, according to the method described in Example 1, separate and obtain 1.8g of 2-(4-methoxyl-benzenesulfonyl)-2-methyl-3-[3-(2 -piperidin-1-yl-ethoxy)-phenyl]-propionamide. Yield: 1.8g, 58%; mp 74°C; MS: 477(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.25(s, 3H), 1.6-1.8(m, 6H), 2.5-3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (bs, 1H).

Example 23

3-(4-{3-[4-(3-Chloro-phenyl)-piperazin-1-yl]propoxy}-phenyl)-N-hydroxy-2-(4-methyl

                                                                                           

According to the method of Example 12, with 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester (2.72g, 10mmol) and 1-[2-(4-chloromethyl-phenoxy) -Ethyl]-4-(3-chloro-phenyl)-piperazine (4.2 g, 11 mmol) was used as starting material to prepare 3-(4-{3-[4-(3-chloro-phenyl)- piperazin-1-yl]propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester. Yield 5.5, 89%; brown oil; MS: 616 (M+H) ⁺ .

With 3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl )-2-methyl-propionic acid ethyl ester (4.0g, 6.5mmol) was used as a raw material, and according to the method of Example 9, 3.0g (yield: 78%) of 3-(4-{ 3-[4-(3-Chloro-phenyl)-piperazin-1-yl]-propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl - Propionic acid. Mp 196°C; MS: 588.1 (M+H) ⁺ .

With 3-(4-{3-[4-(3-chloro-phenyl)-piperazin-1-yl]propoxy}-phenyl)-2-(4-methoxy-benzenesulfonyl )-2-methyl-propionic acid (3.0g, 5.1mmol) is raw material, according to the method described in Example 1, separates and obtains 3-(4-{3-[4-(3 -Chloro-phenyl)-piperazin-1-yl]propoxy}-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide. Yield: 1.8g, 55%; mp 122°C (hydrochloride); MS: 640 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.2(s, 3H), 3.4-1.5( m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3 (bs, 1H).

Example 24

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-

           Hex-4-enoic acid hydroxyamide

To a stirred solution of (4-methoxy-benzenesulfonyl)-ethyl acetate (5.16g, 20mmol), isoprene bromide (30g, 20mmol) and 18-crown-6 (500mg) in acetone (250ml) Potassium carbonate (10 g, excess) was added and the reaction mixture was refluxed for 24 hours. After completion, the above reaction mixture was filtered, and the acetone layer was concentrated. The resulting residue was extracted with chloroform and washed well with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. The product ethyl 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoate was isolated as a colorless oil. Yield 3.0 g, 93%.

According to the method of Example 12, with 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester (3.26g, 10mmol) and 4-(2-morpholine- Starting from 1-yl-ethoxy)-benzyl chloride (3.0 g, 11 mmol), the preparation of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morphol (olin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid ethyl ester. Yield 4.5, 82%; brown oil; MS: 546 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid Ethyl ester (3.0g, 5.5mmol) was used as raw material. According to the method of Example 9, 2.1g (yield: 75%) of 2-(4-methoxy-benzenesulfonyl)-5- Methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid. MS: 518.6 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid (1.0g, 1.9mmol) was a raw material, and according to the method described in Example 1, 450 mg of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-[4 -(2-Morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid hydroxyamide. Yield: 450 mg, 45%; mp92°C (hydrochloride); MS: 570 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.3 (d, 3H), 1.65 (d, 2H) , 3.5-1.8 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m, 1H), 6.7-7.9 (m, 8H), 11.5 (bs, 1H).

Example 25

N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethyl

Oxy)-phenyl]-propionamide

To a stirred solution of 4-hydroxythiophenol (12.6g, 100mmol) and triethylamine (15.0g, 150mmol) in chloroform (400ml) was added dropwise ethyl 2-bromopropionate (18.2g, 100mmol). The reaction mixture was refluxed for 1 hour, cooled to room temperature, the above reaction mixture was washed with water, dried and concentrated. 2-(4-Hydroxy-phenylsulfanyl)-propionic acid ethyl ester was isolated as a colorless oil. Yield: 22.0 g, 99%, MS: 227 (M+H).

To a stirred solution of ethyl 2-(4-hydroxy-phenylsulfanyl)-propionate (11.3 g, 50 mmol) and potassium carbonate (50 g, excess) in acetone (300 ml) was added ethyl iodide (20 ml, excess) , reflux for 8 hours. After completion, the above reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform and washed well with water. Dried and concentrated. The product ethyl 2-(4-ethoxy-phenylsulfanyl)-propionate was isolated as a colorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H).

Conversion of 2-(4-ethoxy-phenylsulfanyl)-propionic acid ethyl ester to 2-(4-ethoxy-phenylsulfonyl)-propionate according to the procedure described in the second paragraph of Example 9 ethyl acetate

According to the method of Example 12, with 2-(4-ethoxy-benzenesulfonyl)-propionic acid ethyl ester (3.5g, 12.2mmol) and 4-(2-N, N-diethylamino-ethoxy )-benzyl chloride (3.5g, 12.2mmol) as starting material to prepare 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino -ethoxy)-phenyl]-propionic acid ethyl ester. Yield 4.8 g, 80%; brown oil; MS: 492.6 (M+H) ⁺ .

With 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid ethyl ester ( 4.0g, 8.1mmol) as raw materials, according to the method of Example 9, isolated 3.2g (yield: 80%) as a colorless semi-solid 2-(4-ethoxy-benzenesulfonyl)-2-methyl yl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid. MS: 464.5 (M+H) ⁺ .

With 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (2.0g , 4.3mmol) as a raw material, according to the method described in Example 1, separate and obtain 1.2g of 2-(4-ethoxyl-benzenesulfonyl)-2-methyl-3-[4 -(2-N,N-Diethylamino-ethoxy)-phenyl]-propionamide. Yield: 1.2g, 57%; (hydrochloride); MS: 478.5(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.9(t, 3H), 1.1(t, 6H), 1.3 (s, 3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).

Example 26

(4E)-2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy

yl)-benzyl]-dec-4,8-dienoic acid hydroxyamide

To a stirred solution of (4-methoxy-phenylsulfonyl)-ethyl acetate (5.16g, 20mmol), geranium bromide (4.2g, 20mmol) and 18-crown-6 (500mg) in acetone (250ml) Potassium carbonate (10 g, excess) was added and the reaction was refluxed for 24 hours. After completion, the above reaction mixture was filtered, and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed well with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexane. The product ethyl 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-dec-4,8-dienoate was isolated as a colorless oil. Yield: 7.0 g, 89%.

According to the method described in Example 12, with (1.0 g, 2.5 mmol) of 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-decane-4,8-dienoic acid ethyl Starting from the ester and 4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (800 mg, 2.5 mmol), the preparation of 2-(4-methoxy-benzenesulfonyl)-5,9- ethyl dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-dec-4,8-dienoate. Yield 1.2 g, 76%; brown oil; MS: 614 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-decane-4 , 8-dienoic acid ethyl ester (2.0g, 3.2mmol) is raw material, according to the method for embodiment 9, separates and obtains 1.5g (yield: 80%) as semisolid 2-(4-methoxyl-benzene Sulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-dec-4,8-dienoic acid. MS: 586.6 (M+H) ⁺ .

With 2-(4-methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-decane-4 , 8-dienoic acid (1.0g, 1.7mmol) was used as a raw material, and according to the method of Example 1, 550 mg of (4E)-2-(4-methoxy-benzenesulfonyl)-5 was isolated as a light yellow solid , 9-Dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-dec-4,8-dienoic acid hydroxyamide. Yield: 550 mg, 53%; mp 61°C (hydrochloride); MS: 638 (M+H) ⁺ .

Example 27

2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxy

amide

According to the general procedure of Example 12, ethyl 2-(4-methoxy-benzenesulfonyl)-hexanoate (4 g, 12.7 mmol) and [2-(4-chloromethyl-phenoxy)- Starting from ethyl]-diethylamine (3.38 g, 14 mmol), the preparation of 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl )-ethyl hexanoate. Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H) ⁺ .

First, ethyl 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoate (8 g, 15.4 mmol) was dissolved in methanol (200ml) and 10N sodium hydroxide (30ml) to prepare 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid . The resulting mixture was worked up as described in Example 1. Yield: 3.88 g crude (51%); brown oil; MS: 492 (M+H) ⁺ .

Starting from 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid (3.88g, 7.89mmol), according to the implementation 1,800 mg of 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) was isolated as a pale yellow powder by the method described in Example 1 - Caproic acid hydroxyamide. Yield 20%; mp 67°C; MS: 507.4(M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ0.75(t, J=7.1Hz, 3H), 1.05(m, 2H) , 1.23(t, J=7.2Hz, 6H), 1.37-1.91(m, 2H), 3.13(m, 4H), 3.38-3.51(m, 4H), 3.87(s, 3H), 4.3(t, J =4.8Hz, 2H), 6.88(d, J=8.7Hz, 2H), 7.15(m, 4H), 7.7(d, J=9Hz, 2H), 9.07(s, 1H), 10.1(s, 1H) .

Example 28

N-Hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-benzene

]-propionamide

According to the method of Example 12, prepare 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl ]-propionic acid ethyl ester, using (3.1g, 10mmol) 2-(4-n-butoxy-benzenesulfonyl)-propionic acid ethyl ester (from 2-(4-hydroxyl-benzenesulfonyl) according to the method described in Example 27 sulfanyl)-ethyl propionate and n-butyl bromide) and 4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (3.0 g, 10.1 mmol) as starting materials. Yield 4.5 g, 84%; brown oil; MS: 532.7 (M+H) ⁺ .

According to the method described in Example 9, with 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-benzene Starting from ethyl]-propionate (5.0 g, 9.4 mmol), 4.2 g (88% yield) of 2-(4-n-butoxy-benzenesulfonyl)-2-methanol were isolated as a colorless solid yl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid. MS: 504.6 (M+H) ⁺ .

Using 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid (3.0g , 5.9 mmol) and according to the method described in Example 1, 1.3 g of 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2- Piperidin-1-yl-ethoxy)-phenyl]-propionamide. MP 65°C; Yield: 1.3g, 42%; (HCl salt); MS: 478.5(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.9(t, 3H), 1.2(s, 3H), 1.3-1.9 (m, 10H), 2.8-4.5 (m, 12H), 6.8-7.8 (m, 8H), 10.8 (bs, 1H).

Example 29

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-

                                                                           

According to the method of Example 12, prepare 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N, N-diethylamino-ethoxy)-phenyl ]-Ethyl propionate using (5.0 g, 18 mmol) ethyl 2-(4-methoxy-benzenesulfonyl)-propionate and 3-(2-N,N-diethylamino-ethoxy) - Benzyl chloride (4.9 g, 18 mmol) as starting material. Yield 8.1 g, 93%; brown oil; MS: 478.1 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N, N-diethylamino-ethoxy)-benzene 2-(4-methoxy-phenylsulfonyl)-2-methyl-propionate (8.1 g, 16.9 mmol), isolated 6.7 g (88% yield) of 2-(4-methoxy-benzenesulfonyl)-2-methyl- 3-[3-(2-N,N-Diethylamino-ethoxy)-phenyl]-propionic acid. MP: 78-81; MS: 450.1 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid (6.7g , 15mmol) and according to the method described in Example 1, 1.5g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2- N,N-Diethylamino-ethoxy)-phenyl]-propionamide. Yield: 1.5 g, 21%; (HCl salt); MS: 450.5 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.21 (t, 6H), 1.26 (S, 3H) , 3.18-3.24(m, 2H), 3.38(m, 4H), 3.43-3.46(m, 2H), 3.80(s, 3H), 4.30(s, 2H), 6.76-6.78(d, 2H), 6.84 -7.2 (m, 6H), 10.3 (bs, 1H).

Example 30

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-benzene

]-propionamide

According to the method of Example 12, prepare 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl] - Ethyl propionate using (5.2 g, 20 mmol) ethyl 2-(4-methoxy-benzenesulfonyl)-propionate and 3-(2-morpholin-1-yl-ethoxy)-benzyl Dichloromethane (6.0 g, 20 mmol) was used as starting material. Yield 9.1 g, 93%; brown oil; MS: 492 (M+H) ⁺ .

According to the method described in Example 9, with 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl ]-ethyl propionate (10.0 g, 20.3 mmol), isolated 8.0 g (86% yield) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3- [3-(2-Morpholin-1-yl-ethoxy)-phenyl]-propionic acid. MS: 464.5 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionic acid (4.55g, 9.8 mmol) and according to the method described in Example 1, 440 mg of 2-(4-methoxyl-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine- 1-yl-ethoxy)-phenyl]-propionamide. Yield: 440 mg, 9%; mp 63°C; MS: 479.5 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.26 (s, 3H), 3.18-3.8 (m, 12H) , 3.9 (s, 3H), 4.4 (m, 2H), 6.7-8.8 (m, 8H), 10.8 (bs, 1H).

Example 31

6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexyl

Acid hydroxyamide

According to the method of Example 9, prepare 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2 -Methyl-hexanoic acid ethyl ester, using (5.0g, 20mmol) 2-(4-methoxy-benzenesulfonyl)-ethyl acetate and 4-phthalimido (phathalimido) bromobutane (5.66 g, 20mmol) as raw material. Yield 8.4g, 97%; colorless oil; MS: 474 (M+H).

According to the method described in Example 9, with 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)- 2-Methyl-hexanoic acid ethyl ester (8.4 g, 17.7 mmol), isolated 6.95 g (88% yield) of 6-(1,3-dioxo-1,3-dihydro as a colorless oil -isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid. MS: 446 (MH) ^- .

Using 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ( 4.9 g, 11 mmol) and according to the method described in Example 1, 3.1 g of 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)- 2-(4-Methoxy-benzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide. Yield: 46%; mp 146-148°C; MS: 461.2(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.55(s, 3H), 1.61-3.77(m, 8H ), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (bs, 1H), 11.20 (bs, 1H).

Example 32

3-[4-(2-Diethylamino-ethoxy)-phenyl]-2-(4-furan-2-yl-benzenesulfonyl)-N-hydroxy-2-methyl

yl-propionamide

To a stirred solution of 4-bromothiophenol (19.0 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in chloroform (400 ml) was added dropwise 2-bromoethyl propionate (18.2 g, 100 mmol) . The reaction mixture was refluxed for 1 hour, then cooled to room temperature. The reaction mixture was washed with water, dried and concentrated to isolate ethyl 2-(4-bromo-phenylsulfanyl)-propionate as a colorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H).

Conversion of ethyl 2-(4-bromo-phenylsulfanyl)-propionate to ethyl 2-(4-bromo-phenylsulfonyl)-propionate according to the procedure described in paragraph 2 of Example 9 ester.

2-(4-Bromo-phenylsulfonyl)-propionic acid ethyl ester (6.4 g, 20 mmol), 2-(tributylstannyl)furan (7.5 g, 21 mmol) and (Ph ₃ P) ₄ Pd (500 mg) mixture was refluxed for 8 hours. Finally filtered through celite and concentrated. The product was purified by silica gel column chromatography eluting with 50% ethyl acetate: hexane. Colorless oil. Yield: 5.9 g, 95%, MS: 309 (M+H).

According to the method described in Example 12, 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy) was prepared -Phenyl]-propionic acid ethyl ester, using (3.08g, 10.0mmol) 2-(4-(2-furyl-benzenesulfonyl)-propionic acid ethyl ester and 4-(2-N,N-diethyl Amino-ethoxy)-benzyl chloride (3.5 g, 12.2 mmol) as starting material. Yield 5.0 g, 97%; brown oil; MS: 514.6 (M+H) ⁺ .

According to the method described in Example 9, with 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethylamino-ethoxy) -Phenyl]-propionic acid ethyl ester (5.1 g, 10.0 mmol), isolated 3.8 g (78% yield) of 2-(4-(2-furyl-benzenesulfonyl)-2- Methyl-3-[4-(2-N,N-diethylamino-ethoxy)-phenyl]-propionic acid. MP: 58°C, MS: 486.5 (M+H) ⁺ .

Using 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylamino-ethoxy)-phenyl]-propionic acid ( 5.0 g, 10.3 mmol) and according to the method described in Example 1, 1.2 g of 2-(4-ethoxyl-benzenesulfonyl)-2-methyl-3-[4- (2-N, N-diethylamino-ethoxy)-phenyl]-propionamide. Yield: 3.2 g, 62%; (HCl salt); MS: 502 (M+H) ⁺ ; ¹ H NMR ( 300MHz, CDCl ₃ ): δ1.23(t, 6H), 1.4(s, 2H), 2.8(q, 4H), 3.0(t, 2H), 4.1(t, 2H), 6.5-8.0(m, 7H ).

Example 33

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyryl

Amine

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-phenylsulfanyl)-butyrate was prepared. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H ) ⁺ .

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-benzenesulfonyl)-butyrate was prepared. 2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester (5 g, 20 mmol) was used as starting material. Yield 5.74 g (100%); clear oil; MS: 287.1 (M+H) ⁺ .

According to the method of Example 12, prepare 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyric acid ethyl ester , using (3.5 g, 12.2 mmol) ethyl 2-(4-methoxy-benzenesulfonyl)-butanoate and 4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine ( 2.34 g, 6.7 mmol) as starting material. Yield 5.7 g, 100%; brown oil; MS: 506.4 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyric acid ethyl Ester (5.54 g, 11 mmol), isolated 2.9 g (55% yield) of 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholine-4) as a colorless semi-solid -yl-ethoxy)-benzyl]-butanoic acid. MS: 478,3 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butanoic acid (2.6 g, 5.4 mmol) was used according to According to the method described in Example 1, 510 mg of N-hydroxyl-2-(4-methoxyl-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxyl) was isolated as a brown solid )-benzyl]-butanamide. Yield 2%; mp 51°C; MS: 493.3(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.90(t, J=7.2Hz, 3H), 1.69-1.96(m , 4H), 2.67(t, 2H), 3.34(m, 8H), 3.87(s, 3H), 4.04(m, 2H), 6.8(d, J=8.7Hz, 2H), 7.14(m, 4H) , 7.73 (d, J=4.7Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).

Example 34

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)

-Benzyl]-butyramide

According to the method of Example 12, 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyric acid ethyl ester was prepared , with (1.0 g, 3.33 mmol) 2-(4-methoxy-benzenesulfonyl)-acid ethyl ester and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (0.85 g, 3.36 mmol) as starting material. Yield 1.07g, 62%; brown oil; MS: 504.4 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyric acid ethyl Esters (3.7 g, 7.3 mmol), isolated 2.2 g (63% yield) of 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidine- 1-yl-ethoxy)-benzyl]-butanoic acid. MS: 476 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-butanoic acid (2.2 g, 4.63 mmol) was used and according to According to the method described in Example 1, 360 mg of N-hydroxyl-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxyl) was isolated as a brown solid )-benzyl]-butanamide. Yield 16%; mp 75°C; MS: 491.3(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.90(t, J=7.1Hz, 3H), 1.36-1.96(m , 4H), 2.4-2.63(m, 14H), 3.87(s, 3H), 4.01(t, J=5.9Hz, 2H), 6.8(d, J=8.5Hz, 2H), 7.11(m, 4H) , 7.71 (d, J=8.8Hz, 2H), 9.09 (s, 1H), 10.8 (s, 1H).

Example 35

2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid hydroxyamide

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-phenylsulfanyl)-pentanoate was prepared. Starting from ethyl 2-bromovalerate (8.23g, 39.3mmol) and 4-methoxythiophenol (5g, 35.7mmol), 10.46g (100%); clear oil; MS: 269 (M+ H) ⁺ .

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-benzenesulfonyl)-pentanoate was prepared. 2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4 mmol) was used as starting material. Yield 7.07 g (86%); clear oil; MS: 300.9 (M+H) ⁺ .

According to the method of Example 12, 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid ethyl ester was prepared , using ethyl 2-(4-methoxy-benzenesulfonyl)-pentanoate (3.0 g, 10.8 mmol) and 4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine ( 3.45 g, 11.9 mmol) as starting material. Yield 3.08g, 62%; brown oil; MS: 520.4 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid ethyl Esters (2.73 g, 5.27 mmol), isolated 1.45 g (56% yield) of 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholine- 4-yl-ethoxy)-benzyl]-pentanoic acid. MS: 492.3 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid (1.01 g, 2.05 mmol) was used according to According to the method described in Example 1, 190 mg of 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl was isolated as a brown solid ]-valeric acid hydroxyamide. Yield 18%; mp 101°C; MS: 507.4(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.71(t, J=7Hz, 3H), 1.58-1.82(m, 4H), 3.12-3.98(m, 12H), 3.87(s, 3H), 4.35(t, 2H), 6.89(d, J=8.7Hz, 2H), 7.15(m, 4H), 7.74(d, J =8.9Hz, 2H), 9.08(s, 1H).

Example 36

  2-[4-(2-Azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy

-Phenylsulfonyl)-octanoic acid hydroxyamide

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-phenylsulfanyl)-octanoate was prepared. Starting materials were ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield 7.24 g (57%); clear oil; MS: 311.2 (M+H) ⁺ .

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-benzenesulfonyl)-octanoate was prepared. 2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester (4.0 g, 13.6 mmol) was used as starting material. Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H) ⁺ .

According to the method of Example 12, prepare 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-octanoic acid ethyl ester , using ethyl 2-(4-methoxy-benzenesulfonyl)-octanoate (1.69 g, 5.18 mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepine  (1.73 g, 6.0 mmol) as starting material. Yield 4.86g, 99%; brown oil; MS: 574.5 (M+H) ⁺ .

According to the method described in Example 9, 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-octanoic acid ethyl Ester (4.8 g, 8.37 mmol), isolated 1.55 g (34% yield) of 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]- 2-(4-Methoxy-benzenesulfonyl)-octanoic acid. MS: 551 (M+H) ⁺ .

Using 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-octanoic acid (1.09 g, 2.0 mmol) and according to According to the method described in Example 1, 300 mg of 2-[4-(2-azepine-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonate) was isolated as a yellow solid acyl)-octanoic acid hydroxyamide. Yield 27%; mp 65°C; MS: 561.6(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.81(t, J=6.6Hz, 3H), 1.08-1.82(m , 14H), 3.13-3.51(m, 12H), 3.87(s, 3H), 4.33(t, 2H), 6.88(d, J=8.7Hz, 2H), 7.14(m, 4H), 7.7(d, J=9Hz, 2H), 9.06(s, 1H), 10.28(s, 1H).

Example 37

    2-(4-Methoxy-phenylsulfanyl)-octanoic acid hydroxyamide

According to the general procedure described in Example 9, ethyl 2-(4-methoxy-phenylsulfanyl)-octanoate was prepared. Starting materials were ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield 7.24 g (57%); clear oil; MS: 311.2 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-methoxy-phenylsulfanyl)-octanoic acid ethyl ester (3.1 g, 10 mmol) as starting material, 2.55 g (yield 90%) was isolated as colorless semi 2-(4-Methoxy-phenylsulfanyl)-octanoic acid as a solid. MS: 283 (M+H) ⁺ .

Using 2-(4-methoxy-phenylsulfanyl)-octanoic acid (4.25 g, 16 mmol) as starting material and according to the method of Example 1, 3.64 g of 2-(4-methoxyl) was isolated as a colorless solid -phenylsulfanyl)-octanoic acid hydroxyamide. Yield 76%; MP: 90°C; MS: 298.2 (M+H).

Example 38

    2-(4-Fluoro-phenylsulfanyl)-octanoic acid hydroxyamide

According to the general procedure described in Example 9, ethyl 2-(4-fluoro-phenylsulfanyl)-octanoate was prepared. Starting materials were ethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-fluoro-phenylsulfanyl)-octanoic acid ethyl ester (3.1 g, 10 mmol) as starting material, 2.89 g (yield 100%) was isolated as a colorless semi-solid 2-(4-Fluoro-phenylsulfanyl)-octanoic acid. MS: 268.9 (M+H) ⁺ .

Using 2-(4-fluoro-phenylsulfanyl)-octanoic acid (2.49 g, 9.2 mmol) as starting material and according to the method of Example 1, 2.72 g of 2-(4-fluoro-phenylsulfanyl) was isolated as a colorless solid Alkyl)-octanoic acid hydroxyamide. Yield 99%; MP: 58°C; MS: 284 (M-H).

Example 39

  2-(1-Methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide

According to the general procedure described in Example 9, 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester was prepared. Starting with ethyl 2-bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercaptoimidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clear oil; MS: 285 (M+H) ⁺ .

According to the method described in Example 9, using 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester (12 g, 42.2 mmol) as starting material, 10.2 g (yield 95% ) 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid as a colorless solid. MP: 95°C, MS: 257.1 (M+H) ⁺ .

Using 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid (7.84 g, 30.6 mmol) as starting material and according to the method of Example 1, 2.77 g of 2- (1-Methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide. Yield 33%; MP: 125°C; MS: 272.2 (M+H).

Example 40

  N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide

According to the method described in Example 9, prepare 2-(4-methoxy-benzenesulfonyl)-3-naphthalene-2-yl-propionic acid ethyl ester, use (5.0g, 20mmol) 2-(4-methoxy (4.4 g, 20 mmol) as starting materials. Yield 7.2g, 91%; colorless oil; MS: 399 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-3-naphthalene-2-yl-propionic acid ethyl ester (3.7g, 9mmol) was used as raw material, and 3.3g (product Yield 96%) 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionic acid as a colorless oil. MS: 369.1 (MH) ^- .

Using 2-(4-methoxy-benzenesulfonyl)-3-naphthalene-2-yl-propionic acid (2.2g, 5.9mmol) as starting material and according to the method of Example 1, 820mg of a light brown solid was isolated N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide. Yield 36%; mp 161-163°C; MS: 385.9 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ3.32 (d, J=7.0Hz, 1H), 3.69 (d, J =7.0Hz, 1H), 3.82(s, 3H), 5.02(s, 1H), 6.92-7.89(m, 11H).

Example 41

N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenylpropionic acid hydroxyamide

Under reflux, 150ml of 4-methoxybenzylthiol (7.0g, 45mmol), ethyl 2-bromopropionate (8.2g, 46mmol) and powdered oven-dried potassium carbonate (10g, 72mmol) were mixed The acetone mixture was heated for 18 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was dissolved in 150ml dichloromethane, washed with water (150ml), dried over anhydrous sodium sulfate and evaporated to give 12g (99%) of product; colorless liquid; MS 255.1 (M+H). The product was used without further purification.

To an ice-cooled (5°C) solution of ethyl 2-(4-methoxy-phenylmethylsulfanyl)-propionate (5.7 g, 21 mmol) in 100 ml of dichloromethane was added m-chloroperphenyl in portions Formic acid (7.2 g, 42 mmol), and the mixture was stirred for 1 hour. The reaction was diluted with hexane (500ml) and stirred at 25°C for 30 minutes. The mixture was filtered and the organic layer was treated with saturated aqueous sodium bisulfite (200 mL). The hexane solution containing the product was washed with water, dried (sodium sulfate) and concentrated. Yield 5.5 g (91%); colorless oil; MS 287.1 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester was prepared by using 2-(4-methoxy- Phenylmethylsulfonyl)-propionic acid ethyl ester (2 g, 7 mmol) and benzyl bromide (1.3 g, 7.7 mmol) were used as starting materials. Yield 3.0 g, 100%; low melting point solid; MS: 377 (M+H) ⁺ .

2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (3.5 g, 9.0 mmol) as starting material for the preparation of 2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 930mg, 31%; colorless solid, mp: 106-108°C; MS: 347 (MH) ⁺ .

Using 2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid (2.7, 7.0 mmol) as starting material and according to the method of Example 1, 266 mg was isolated as N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid hydroxyamide as a colored solid. Yield: 10%; mp 58-59°C; MS: 364.2(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.28(s, 3H), 2.84-2.88(d, 1H ), 3.75(s, 3H), 3.81-3.86(d, 1H), 4.59-4.63(d, 1H), 4.69-4.74(d, 1H), 6.94-6.98(d, 2H), 7.19(m, 2H ), 7.29-7.33 (d, 4H), 9.24 (s, 1H), 10.88 (s, 1H).

Example 42

5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid hydroxyamide

5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid ethyl ester was prepared according to the general procedure of Example 9. Ethyl α-(p-toluenesulfonyl)acetate (2.9 g, 10.9 mmol) and 4-bromo-2-methylbutene (3.42 g, 23 mmol) were used as starting materials. Yield: 4.6 g; brown oil; MS 379.2 (M+H) ⁺ .

5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid was prepared according to the general procedure of Example 9. Using ethyl 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoate (4.5 g, 11 mmol), ethanol ( 15ml) and 10N sodium hydroxide as starting materials.

Using 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid (4.1 g, 11 mmol) as starting material and according to the implementation According to the method described in Example 1, 1.07 g of 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hexyl-4 was isolated as a colorless solid -enoic acid hydroxyamide; Yield: 30%; mp 108-110°C; MS: 366.2(M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ1.49(s, 6H), 1.62( s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 ( s, 1H), 10.80 (s, 1H).

Example 43

2-Methyl-2-(2-methyl-furan-3-iodoyl)-3-phenyl-propionic acid hydroxyamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid ethyl ester (from 3-mercapto-2-methyl furan preparation). Using ethyl 2-(2-methyl-furan-3-ylsulfanyl)-propionate (2.9g, 11.9mmol), benzyl bromide (2.22g, 13mmol) and potassium carbonate (10g) in acetone (75ml ); Yield (99%); Amber oil; MS 337.1 (M+H) ⁺ .

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid was prepared according to the general procedure described in Example 9. 2-(2-Methyl-furan-3-ylsulfanyl)-propionic acid ethyl ester (4.8 g, 14.3 mmol) dissolved in ethanol (25 ml) and 10 N sodium hydroxide (10 ml) was used as starting material. Yield 3.7 g (84%), white solid, MS 307.4 (M-H).

Using 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid (3.58 g, 12 mmol) as starting material and according to the method described in Example 1, 1.078 g was isolated 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid hydroxyamide as an orange solid; Yield: 29%; mp68-70°C; MS: 324( M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.27(s, 3H), 2.81-2.86(d, 1H), 3.33(s, 3H), 3.61-3.66(d, 1H ), 6.66 (s, 1H), 7.19-7.25 (m, 5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H).

Example 44

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propane

Acid hydroxyamide

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy) was prepared according to the general procedure described in Example 9 -Phenyl]-Ethyl propionate. 2-(2-Methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4 g, 9.8 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piper Pyridine (2.96 g, 10.7 mmol) as starting material; yield 2.4 g (92%); amber oil; MS 464.2 (M+H) ⁺ .

2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy) was prepared according to the general procedure described in Example 1 -phenyl]-propionic acid. Using 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidine-1) dissolved in ethanol (20ml) and 10N sodium hydroxide (10ml) -Ethyl-ethoxy)-phenyl]-propionic acid ethyl ester (2.01 g, 4.5 mmol) was used as starting material. The resulting mixed liquor was processed according to the method described in Example 9. Yield 2.03g; amber crystals mp 66-68°C, MS 434(M-H).

Using 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid (2.03 g, 6.0 mmol) as starting material and according to the method described in Example 1, 1.36 g of 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4 -(2-Piperidin-1-yl-ethoxy)-phenyl]-propionic acid hydroxyamide; Yield: 32%; mp 115-117°C; MS: 451.1 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.15-1.22(m, 2H), 1.75(s, 3H), 1.78(s, 3H), 2.98-3.03(m, 2H), 3.42-3.47(m, 2H ), 3.5(s, 3H), 6.65(s, 1H), 6.87-6.90(d, 2H), 7.12-7.17(d, 2H), 10.35(s, 1H), 10.60(s, 1H), 11.70( s, 1H).

Example 45

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxyacyl

Amine

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propane was prepared according to the general procedure described in Example 9 ethyl acetate. Using ethyl 2-(thiophene-2-sulfonyl)-propionate (prepared from 2-mercaptothiophene and ethyl 2-bromopropionate) (4.4 g, 17.7 mmol) and 1-[2-(4-chloromethyl phenoxy)-ethyl]-piperidine (5.3 g, 19.5 mmol) as starting material; yield (96%); semi-solid; MS 466.

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propane was prepared according to the general procedure described in Example 9 acid. Using 2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-sulfonyl] dissolved in ethanol (20ml) and 10N sodium hydroxide (20ml) - Ethyl propionate (9.8 g, 20 mmol) as starting material. The resulting mixture was processed as described in Example 1. Yield 4.5 g (49%); white solid mp 170-172°C, MS 436.3 (M-H).

2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid (3.6 g, 8.0 mmol) was used as Starting material and according to the method described in Example 1, 345 mg of 2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene) was isolated as a colorless solid. -2-sulfonyl)-propionic acid hydroxyamide; Yield: 10%; mp 115-118°C; MS: 451.2 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.29( s, 3H), 1.66-1.78(m, 6H), 2.81-2.86(d, 1H), 2.96-3.99(m, 4H), 3.39-3.47(m, 2H), 3.51-3.59(d, 1H), 4.32(m, 2H), 6.72-6.74(d, 1H), 6.87-6.96(d, 2H), 7.01-7.20(m, 3H), 7.31-7.33(m, 1H), 7.69-7.72(m, 1H ), 7.83-7.84 (m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H), 10.0 (s, 1H), 10.78 (s, 1H).

Example 46

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid hydroxyamide

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general procedure described in Example 9. Using 2-(octane-1-sulfonyl)-propionic acid ethyl ester (50g, 18mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (56g, 19.7mmol ) as starting material; yield 8.9 g (96%); amber oil; MS 495.

2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general procedure described in Example 9. Using 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester (8.9g, 18mmol), ethanol (25ml) and 10N sodium hydroxide (25ml) as starting material. Yield 6.0 g (72%).

Using 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid (3.6 g, 7.7 mmol) as starting material and according to Example 1, isolated 3.3 g of 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid hydroxyl Amide; Yield: 89%; mp 69-70°C; MS: 483.2(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ.687(t, 3H), 1.27-1.69(m , 15H), 2.71-2.75(d, 1H), 3.51(s, 3H), 3.65-3.69(d, 1H), 6.86-6.89(d, 2H), 7.08-7.11(d, 2H), 9.16(s , 1H), 10.70 (s, 1H).

Example 47

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid hydroxyamide

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general procedure described in Example 9. 2-Methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester (prepared from 1-methyl-2-mercaptoimidazole and 2-bromoethylpropionate) (3.0 g, 12.2 mmol) and 4-chloromethylbiphenyl (2.97 g, 15 mmol) as starting materials. Yield 5.0 g (99%); low melting solid; MS 413 (M+H) ⁺ .

3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid was prepared according to the general procedure described in Example 9. Using 3-biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid ethyl ester (5.0g, 11.9mmol), ethanol (15ml) and 10N sodium hydroxide (10 ml) was used as starting material. Yield 2.8 g (61%); brown solid mp 119-122°C; MS 385.2 (M+H).

Using 3-biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid (2.8g, 7.0mmol) as raw material and according to Example 1 According to the method described, 112 mg of 3-biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid hydroxyamide was isolated and obtained as a brown solid; Productive rate: 4%; mp 112°C; MS: 399.0(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.911(t, 3H), 3.3(s, 3H), 3.5(d, 1H ), 4.2 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m, 5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).

Example 48

  2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxyamide

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general procedure described in Example 9. 2-(thiophene-2-sulfonyl)-propionic acid ethyl ester (3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol) were used as starting materials; yield 5.2 g (%); brown oil; MS 339.1 (M +H).

2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared according to the general procedure described in Example 9. 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 ml) and 10 N sodium hydroxide (10 ml) were used as starting materials. Yield 5.6 g. MS 310.0 (M+H).

Using 2-methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid (5.0 g, 16 mmol) as starting material and according to the method described in Example 1, 1.8 g of a colorless solid was isolated 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxyamide; Yield: 40%; mp 116-117°C; MS: 325.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.29(s, 3H), 3.33(d, 1H), 3.69(d, 1H), 7.18-7.30(m, 5H), 7.74(m, 1H), 8.22 (m, 1H), 9.13(s, 1H), 10.80(s, 1H).

Example 49

  2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid hydroxyamide

2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid ethyl ester was prepared according to the general procedure described in Example 9. 2-[8-(1-Ethoxycarbonyl-ethylsulfanyl)-octylsulfanyl]-propionic acid ethyl ester (10.2g, 26mmol) and sodium peroxymonopersulfate (64g, 104mmol) as raw material. Yield 9.87 g (86%); colorless liquid; MS 422.9 (M+H).

2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid was prepared according to the general procedure described in Example 1. Using ethyl 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionate (3.0 g, 6.8 mmol), ethanol (15 ml) and 10 N sodium hydroxide (15 ml) as raw material. Yield 2.7 g (98%); white solid mp 99-102°C; MS 387 (M+NH3) ⁺ .

Using 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid (2.5 g, 6.5 mmol) as starting material and according to the method described in Example 1, 641 mg was isolated as succinate 2-[8-(1-carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid hydroxyamide of colored oil; yield: 23%; MS: 434.0 (M+NH4) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.27-3.23 (m, 22H), 3.33 (m, 2H), 8.9 (s, 1H), 9.28 (s, 1H).

Example 50

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]

- Hydroxyamide propionate

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl] was prepared according to the general procedure described in Example 9 - ethyl propionate. Using ethyl α-(4-bromophenyl-sulfonyl)acetate (5.0g, 16mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97g, 16mmol ) as a raw material. Yield 6.1 g (71%); brown oil; MS 5411 (M+H) ⁺ .

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl] was prepared according to the general procedure described in Example 9 - Propionic acid. Using 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (6.5g, 20mmol), ethanol (30ml) and 10N sodium hydroxide (15ml) as starting materials. Yield 6.3 g (100%); yellow solid mp 125-127°C; MS 512.5 (M+H) ⁺ .

2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid (6.1 g, 612 mmol) As starting material and according to the method described in Example 1, 1.07 g of 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1- 1-ethoxy)-phenyl]-propionic acid hydroxyamide; Yield: 17%; MS: 525.4 (M+H) ⁺ .

Example 51

3-(4-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methylpropionamide

According to the method described in Example 9, 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared using 2-(4- Methoxy-phenylsulfonyl)-propionic acid ethyl ester (3.0 g, 11 mmol) and 4-bromo-benzyl bromide (3.0 g, 12 mmol) were used as starting materials. Yield 4.67g, 96%; colorless oil; MS: 441 (M+H) ⁺ .

Using ethyl 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionate dissolved in methanol (50ml) and 10N sodium hydroxide (30ml) The ester (4.0 g, 9.0 mmol) was used as starting material for the preparation of 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H) ⁺ .

Using 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.7 g, 6.5 mmol) as starting material and following the procedure described in Example 1 , isolated 2.26 g of 3-(4-bromophenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide as a colorless solid; yield: 81 %; mp 86-88°C; MS: 429.8 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.42 (s, 3H), 1.77 (bs, 1H), 3.26 (d, J= 7.0Hz, 1H), 3.68(d, J=7.0Hz, 1H), 3.85(s, 3H), 7.01-7.76(m, 8H), 9.71-9.88(bs, 1H).

Example 52

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-methyl-3-naphthalen-2-yl-propionamide

According to the method described in Example 9, prepare 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalene-2-yl-propionic acid ethyl ester, using 2-(4-methoxy -Benzenesulfonyl)-propionic acid ethyl ester (5.4 g, 20 mmol) and 2-bromo-methylnaphthalene (4.4 g, 20 mmol) as starting materials. Yield 8.0 g, 97%; colorless crystals, mp 182-184°C; MS: 443 (M+H) ⁺ .

According to the method described in Example 9, 4.2 g (98%) is colorless crystals of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid. mp 144-146°C; MS: 384.9 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid (2.4g, 6.2mmol) as raw material and according to the method described in Example 1, isolated 1.6 g of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide as a colorless solid; yield: 64%; mp 185- 187°C; MS: 400.2(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.56(s, 3H), 3.28(d, J=8.0Hz, 1H), 3.81(d, J= 8Hz, 1H), 3.93(s, 3H), 4.88(bs, 1H), 7.02-7.92(m, 11H).

Example 53

  N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butanamide

According to the general procedure described in Example 1, ethyl 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyrate was prepared. Using ethyl 2-bromo-3-methyl-butyrate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol) as starting materials, 30 g of 2-(4-methoxy- (Phenylsulfanyl)-3-methyl-butyric acid ethyl ester. Yield 99%; pale yellow oil; MS: 269 (M+H) ⁺ .

Using ethyl 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyrate (2.68 g, 10 mmol) as starting material and oxidizing according to the method described in Example 9, 3 g was isolated as colorless 2-(4-Methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester as a solid. Yield 99%; mp 53°C; MS: 273 (M+H) ⁺ .

According to the method described in Example 9, using ethyl 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyrate (3 g, 10 mmol) as starting material, 2.7 g (96%) of 2-(4-Methoxy-benzenesulfonyl)-3-methyl-butanoic acid as a colored solid. Mp 96°C; MS: 273 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-3-methyl-butanoic acid (2.0 g, 7.34 mmol) as starting material and according to the method described in Example 9, 590 mg of N- hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butanamide. Mp 220°C; Yield 28%; MS: 288(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.88(d, J=6.7Hz, 3H), 1.07(d, J =6.7Hz, 3H), 2.09-2.20(bs, 1H), 3.53(d, J=9, 1H), 7.12-7.17(m, 2H), 7.74-7.79(m, 2H).

Example 54

    1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid hydroxyamide

According to the method described in Example 9, 1-(4-methoxy-benzenesulfonyl)-ethyl cyclopentanecarboxylate was prepared by using 2-(4-methoxy-benzenesulfonyl)-ethyl acetate (3.0 g, 11.6 mmol) and 1,4-dibromobutane (2.4 g, 7.6 mmol) as starting materials. Yield 2.4g, 78%; colorless solid, mp 86-88°C; MS: 313 (M+H) ⁺ .

1-( 4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 1.66g, 83%. Colorless solid; mp 112-115°C; MS: 285 (M+H) ⁺ .

Using 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid (442 mg, 1.5 mmol) as starting material and according to the method described in Example 1, 410 mg of 1-(4-methanol) was isolated as a colorless solid Oxy-benzenesulfonyl)cyclopentanecarboxylic acid hydroxyamide. mp 89-91°C; Yield: 88%; MS: 300(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.65-1.82(m, 4H), 2.17-2.42(m, 4H ), 3.87 (s, 3H), 7.0 (d, J=8Hz, 2H), 7.7 (bs, 1H), 7.72 (d, J=8Hz, 2H), 9.73 (bs, 1H).

Example 55

3-(2-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methylpropionamide

According to the method described in Example 9, 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared using 2-(4- Methoxy-phenylsulfonyl)-propionic acid ethyl ester (2.0 g, 7.3 mmol) and 2-bromobenzyl bromide (2.0 g, 8 mmol) were used as starting materials. Yield 3.1 g, 87%; colorless oil; MS: 441 (M+H) ⁺ .

Using ethyl 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionate dissolved in methanol (50ml) and 10N sodium hydroxide (30ml) The ester (3.0 g, 68 mmol) was used as starting material for the preparation of 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 1.7 g, 63%; waxy solid; MS: 414 (M+H) ⁺ .

Using 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (470 mg, 1.1 mmol) as starting material and according to the method described in Example 9, 380 mg of 3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide were isolated as a colorless solid. mp 93-96°C; Yield 77%; MS: 429(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.3(s, 3H), 3.32(d, J=7.0Hz, 1H ), 3.69 (d, J.=7.0Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).

Example 56

2-(4-Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid ethyl ester was prepared using 2-(4-methoxy phenylsulfonyl)-propionic acid ethyl ester (3.0 g, 11 mmol) and cinnamoyl bromide (2.1 g, 11 mmol) as starting materials. Yield 3.51 g, 82%; colorless oil; MS: 389 (M+H) ⁺ .

Using ethyl 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoate dissolved in methanol (50ml) and 10N sodium hydroxide (30ml) ( 3.0 g, 11 mmol) was used as starting material for the preparation of 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 1.9g, 68%; yellowish oil; MS: 361 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid (440mg, 1.2mmol) as raw material and according to the method described in Example 1, isolate 420 mg of 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide as a colorless solid. mp162-164°C; Yield: 92%; MS: 376 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.41 (s, 3H), 3.0-3.16 (m, 1H), 3.30 (d, J=11Hz, 2H), 3.92(s, 3H), 5.9-6.1(m, 1H), 6.53(d, J=11Hz, 1H), 7.1-7.72(m, 9H), 9.12(bs, 1H).

Example 57

2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid hydroxyamide

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-ethyl pentanoate was prepared by using 2-(4 -Methoxy-benzenesulfonyl)-ethyl acetate (4.0 g, 15.8 mmol) and 3-bromopropylbenzene (6.4 g, 32 mmol) as starting materials. Yield 3.7g, 47%; colorless oil; MS: 495 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid dissolved in methanol (50ml) and 10N sodium hydroxide (30ml) Ethyl ester (2.0 g, 4 mmol) was used as starting material to prepare 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 1.18g, 63%. Waxy solid; MS: 449.2 (M+HH ₂ O) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid (600 mg, 1.2 mmol) as starting material and according to the method described in Example 1 , 420 mg of 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid hydroxyamide were isolated as a colorless solid. Mp 118-120°C; Yield: 68%; MS: 482(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.52-1.68(m, 2H), 1.74-1.92(m, 2H ), 1.98-2.20(m, 4H), 2.58-2.72(m, 4H), 3.86(s, 3H), 6.93(d, J=11Hz, 2H), 7.02-7.63(m, 10H), 7.81(d , J=11Hz, 2H).

Example 58

  2-Allyl-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide

According to the method described in Example 9, 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester was prepared by using 2-(4-methoxy-benzenesulfonyl Acyl)-ethyl acetate (3.0 g, 11.6 mmol) and allyl bromide (4 ml, excess) were used as starting materials. Yield 3.6 g, 92%; yellow oil; MS: 338 (M+H) ⁺ .

2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester (2.2 g, 6.5 mmol) as starting material for the preparation of 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 1.76g, 87%; yellowish oil; MS: 311 (M+H) ⁺ .

Using 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid (1.5g, 4.8mmol) as starting material and according to the method described in Example 1, 1.5g was isolated as 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide as a colorless solid. Mp 114-116°C; Yield: 99%; MS: 326(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.62(s, 1H), 2.70-2.80(m, 4H), 3.9 (s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d, J=8Hz, 2H).

Example 59

  2-(4-Methoxy-benzenesulfonyl)-2-propyl-pentanoic acid hydroxyamide

Dissolve 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide (326mg, 1.0mmol) (Example 26) in methanol (50ml) at room temperature , 49 psi pressure over 10% Pd/C (100 mg) catalytic hydrogenation for 4 hours. Then, the reaction mixture was filtered to remove methanol. The resulting solid was crystallized from methanol. Yield 250 mg, 75%; MS: 330 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78 -2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d, J=9Hz, 2H).

Example 60

2-Benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide

According to the method described in Example 9, 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was prepared using 2-(4-methoxy-benzenesulfonyl Acyl)-ethyl acetate (1.0 g, 3.8 mmol) and benzyl bromide (4 ml, excess) were used as starting materials. Yield 1.2 g, 72%; yellow oil; MS: 439 (M+H) ⁺ .

2-Benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 g, 2.2 mmol) as starting material for the preparation of 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 580 mg, 62%; waxy solid; MS: 409 (MH) ^- .

Using 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (410 mg, 1 mmol) as starting material and according to the method described in Example 1, 225 mg was isolated as a waxy solid 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide. Yield: 52%; MS: 426 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ3.25 (d, J=14Hz, 2H), 3.52 (d, J=14Hz, 2H), 3.9(s, 3H), 6.93(d, J=8Hz, 2H), 7.02-7.26(m, 9H), 7.61(d, J=8Hz, 2H), 7.87(d, J=4Hz, 1H), 9.58 (bs, 1H).

Example 61

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide

To stirred ethyl 2-(4-methoxy-benzenesulfonyl)propanoate (2.7g, 10mmol), 3-picoline chloride hydrochloride (3.2g, 20mmol) and triethylbenzyl chloride To a solution of ammonium chloride (1g) in dichloromethane (400ml) was added 10N sodium hydroxide (30ml). The reaction was continued at room temperature for 48 hours. Then, the organic layer was separated and washed well with water. The organic layer was dried, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography. The column was eluted with 50% ethyl acetate: hexanes. 2-(4-Methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid ethyl ester was isolated as a brown oil. Yield 3.0 g, 82%; brown oil; MS: 364 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid ethyl ester (2.5g, 6.8mmol) was used as raw material, 1.8 g (79%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid were isolated as a colorless solid. mp 58°C; MS: 336 (M+H) ⁺ .

225 mg of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide as colorless solid. Yield: 52%; mp 98°C; MS: 351 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.4 (s, 3H), 3.1 (d, J=9.0, 1H), 3.65 (d, J=9.1, 1H), 3.9 (s, 3H), 7-8.5 (m, 8H).

Example 62

  2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid hydroxyamide

According to the method described in Example 9, using 2-(4-methoxy-benzenesulfonyl)-ethyl acetate (7.5g, 29mmol) and 1-bromooctane (6.7g, 35mmol) as raw materials, isolated 8g Monooctylated compound 2-(4-Methoxy-benzenesulfonyl)-decanoic acid ethyl ester. Yield 8.0 g, 74%; MS: 370 (M+H) ⁺ .

According to the method described in Example 29, 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-capric acid ethyl ester was prepared using 2-(4-methoxy-benzenesulfonyl Acyl)-capric acid ethyl ester (8.0 g, 21.6 mmol) and 3-picoline chloride hydrochloride (4.1 g, 25 mmol) were used as starting materials. Yield 6.5 g, 68%; brown oil; MS: 462 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethyl ester (5.0 g, 11 mmol) as raw material, isolated 4.5 g (91%) 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid as a colorless solid. Mp 159°C; MS: 434 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid (2.5 g, 5.7 mmol) as starting material and according to the method described in Example 1, 1.4 g was isolated as 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid hydroxyamide as a colorless solid. Yield: 50%; mp 62°C; MS: 448(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.86(t, 6.9Hz, 3H), 1.25-2.17(m, 14H) , 3.3(d, J=14Hz, 1H), 3.5(d, J=14Hz, 1H), 3.9(s, 3H), 6.8-8.6(m, 8H).

Example 63

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-ethyl acetate (6.0 g, 23 mmol) and isoprene bromide (3.0 g, 20 mmol) were used as raw materials to prepare 2- (4-Methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester. Yield 6.52g, 86%; colorless oil; MS: 327 (M+H) ⁺ .

According to the method described in Example 29, 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester was prepared using 2- (4-Methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester (4.0 g, 12.2 mmol) and 3-picoline chloride hydrochloride (2.1 g, 13 mmol) as raw material. Yield 4.14g, 81%; brown oil; MS: 418 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid dissolved in methanol (50ml) and 10N NaOH (30ml) Ethyl ester (4.0 g, 9.5 mmol) was used as starting material to prepare 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid. The resulting reaction mixture was worked up as described in Example 9. Yield 3.2g, 87%; ivory solid, mp 117-119°C; MS: 390 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid (2.1 g, 5.4 mmol) as starting material and according to Example 1 Said method, isolated 1.82 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid hydroxyamide as a colorless solid . Yield: 82%; mp 89-92°C; MS: 405(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ1.63(s, 3H), 1.76(s, 3H), 2.62- 2.78(m, 2H), 3.3(d, J=4.0Hz, 1H), 3.63(d, J=4.0Hz, 1H), 3.82(s, 3H), 5.26(m, 1H), 7.12-7.88(m , 6H), 8.27-8.33 (m, 2H).

Example 64

2-Benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butanamide

According to the method described in Example 29, 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester was prepared using 2-(4-methoxy -Benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (Example 9) (3.0 g, 8.5 mmol) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 mmol) were used as starting materials. Yield 3.2g, 79%; ivory solid, mp 89-91°C; MS: 476.4 (M+H) ⁺ .

According to the method described in Example 9, 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester (3.53g, 7.5mmol) was used as raw material, 2.8 g (86%) of 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid were isolated as colorless crystals. Mp 136-138°C; MS: 448.5 (M+H) ⁺ .

Using 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid (1.85g, 4.1mmol) as raw material and according to the method described in Example 1, isolated 1.3 g of 2-benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butanamide as a low melting waxy solid. Yield: 68%; MS: 463.3 (M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.98 (d, J=11Hz, 6H), 1.16 (d, J=11Hz, 6H), 1.92(m, 2H), 2.46(m, 2H), 2.71(m, 2H), 3.18(m, 1H), 3.48(m, 1H), 3.86(s, 3H), 6.98(d, J=8Hz, 2H), 7.18-7.22 (m, 5H), 7.92 (d, J=8Hz, 2H), 8.12 (s, 1H).

Example 65

3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionamide

According to the method described in Example 9, using (4.0 g, 15 mmol) 2-(4-methoxy-benzenesulfonyl)-ethyl acetate and 1-bromomethylcyclohexane (2.7 g, 15 mmol) as raw materials, Preparation of 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester. Yield 5.0 g, 94%; colorless oil; MS: 355 (M+H) ⁺ .

According to the method described in Example 29, prepare 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid ethyl ester, using 3-cyclohexyl-2 -(4-Methoxy-benzenesulfonyl)-propionic acid ethyl ester (1.5 g, 4.2 mmol) and 3-picoline chloride (1.0 g, 6 mmol) as starting materials. Yield 1.0 g, 38%; colorless oil; MS: 446 (M+H) ⁺ .

According to the method described in Example 9, 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid ethyl ester (1.3g, 2.9mmol) was used as Starting material, isolated 1.0 g (83%) of 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid as colorless crystals. Mp 92°C; MS: 417.5 (M+H) ⁺ .

Using 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid (1.0 g, 2.4 mmol) as starting material and according to the method described in Example 1, 80 mg of 3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionamide were isolated as the colorless hydrochloride salt. Yield: 71%; mp 57-60°C; MS: 433(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.8-2.08(m, 13H), 3.3(d, J=14Hz , 1H), 3.7 (d, J=14Hz, 1H), 3.9 (s, 3H), 7.0-8.5 (m, 8H).

Example 66

2-(4-Methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide

According to the method described in Example 9, (5.0 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)-ethyl acetate and 1-bromo-2-methylpropane (2.6 g, 20 mmol) were used as starting materials , Preparation of ethyl 2-(4-methoxy-benzenesulfonyl)-4-methyl-pentanoate. Yield 6.0 g, 95%; colorless oil; MS: 315 (M+H) ⁺ .

According to the method described in Example 29, 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid ethyl ester was prepared by using 2-(4-methyl Oxy-phenylsulfonyl)-4-methylpentanoic acid ethyl ester (3.1 g, 10 mmol) and 3-picoline chloride hydrochloride (1.8 g, 11 mmol) were used as starting materials. Yield 3.0 g, 75%; colorless oil; MS: 406 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid ethyl ester (1.2g, 2.9mmol) was used as Starting material, 1.0 g (91%) of 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid was isolated as colorless crystals. Mp 188-186°C; MS: 378 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid (800 mg, 2.1 mmol) as starting material and according to the method described in Example 1, separate This gave 180 mg of 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide as a colorless solid. Yield: 21%; mp 78°C; MS: 393.4(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): δ0.65(d, 6.3Hz, 3H), 0.89(d, J=6.2Hz , 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5 (m, 10H).

Example 67

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide

According to the method described in Example 29, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid ethyl ester was prepared using 2-(4-methoxy (4.4 g, 20 mmol) and 7-bromomethylquinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; pale yellow solid; mp 86°C; MS: 414 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid ethyl ester (3.0 g, 7.2 mmol) was used as raw material , 2.5 g (90%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid were isolated as colorless crystals. mp 106-108°C; MS: 386.4 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid (2.0 g, 5.2 mmol) as starting material and according to the method described in Example 1, separate 1.2 g of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide are obtained as a colorless solid. Yield: 57%; mp 206 °C; MS: 401.4 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.4 (s, 3H), 3.19 (m, 1H), 3.8-4.0 ( m, 4H), 7.1-8.95 (m, 12H).

Example 68

2-(4-Methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-ethyl hexanoate was prepared by using 2-(4-methoxy-benzenesulfonyl)-acetic acid Ethyl ester (2.5 g, 10 mmol) and 1-bromo-4-phenoxybutane (2.2 g, 10 mmol) were used as starting materials. Yield 3.8g, 93%; colorless oil; MS: 407 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester (3.1g, 10mmol) and 3-picoline chloride (1.8g, 11 mmol) as starting material for the preparation of ethyl 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoate. Yield 3.5 g, 71%; colorless oil; MS: 498 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester (3.0g, 6.0mmol) was used As starting material, 2.8 g (quantitative yield) of 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid were isolated as colorless crystals . Mp 148-151°C; MS: 470.5 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid (2.0 g, 4.3 mmol) as starting material and according to the method described in Example 1 , isolated 1.5 g of 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide as a colorless solid. Yield: 72%; mp 68 °C; MS: 485.5 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ1.5-2.5 (m, 8H), 3.4 (bs, 2H), 3.8 ( s, 3H), 6.8-8.7 (m, 13H).

Example 69

2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

According to the method described in Example 9, to prepare ethyl 2-(4-methoxy-benzenesulfonyl)-5-hexanoate, 2-(4-methoxy-benzenesulfonyl)-ethyl acetate (10.0 g, 39 mmol) and 1-bromo-3-methylbutane (6.0 g, 40 mmol) as starting materials. Yield 8.5 g, 62%; colorless oil; MS: 329 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-hexanoic acid ethyl ester (6.0 g, 18 mmol) and picolyl chloride hydrochloride (4.1 g, 25 mmol) as starting material for the preparation of ethyl 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoate. Yield 4.5 g, 60%; brown oil; MS: 420 (M+H) ⁺ .

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester (3.0g, 7.1mmol) was used as Starting material, isolated 2.6 g (92%) of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid as a colorless solid. Mp 173°C; MS: 392 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid (1.0 g, 2.5 mmol) as starting material and according to the method described in Example 1, 800 mg of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide were isolated as a colorless solid. Yield: 72%; mp 62 °C (HCl salt); MS: 408 (M+H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ): δ0.76 (m, 6H), 1.2-2.0 (m, 5H ), 3.5 (bq, 2H), 7.1-8.8 (m, 8H), 11.1 (bs, 1H).

Example 70

  2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide

According to the general procedure described in Example 1, (4-methoxy-phenylsulfanyl)-tert-butyl acetate was prepared. Starting from the corresponding 1-bromo-tert-butyl acetate (5.3 g, 27 mmol) and 4-methoxybenzenethiol (3.7 g, 27 mmol), 6.4 g of product were isolated. Yield 98%; pale yellow oil; MS: 255 (M+H) ⁺ .

According to the general procedure described in Example 9, tert-butyl 2-(4-methoxy-benzenesulfonyl)-acetate was prepared. Starting from 2-(4-methoxy-phenylsulfanyl)-tert-butyl acetate (5.0 g, 20 mmol) and 3-chloroperbenzoic acid (57% (12.0 g, 40 mmol), 5.3 g of product were isolated .Yield 92%; waxy solid; MS: 287.1 (M+H) ⁺ .

According to the method described in Example 9, tert-butyl 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionate was prepared. Using 2-(4-methoxy-benzenesulfonyl)-tert-butyl acetate (20.0g, 70.0mmol) and 3-picoline chloride (7.28g, 44.4mmol) as starting materials, silica gel chromatography (50% Ethyl acetate:hexanes) isolated 10.5 g of product. Yield 63%; white solid; mp 93-94°C; MS: 378.0 (M+H) ⁺ .

According to the method described in Example 9, tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoate was prepared. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionate (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol), isolated 1.20 g product. Yield 52%; yellowish gum; MS: 434.3 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-tert-butyl hexanoate (1.1 g, 2.5 mmol) was dissolved in dichloromethane/trifluoroacetic acid ( 1:1) mixture was stirred for about 2 hours. The solvent was then evaporated and 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid was purified by silica gel chromatography (30% methanol/dichloromethane). Yield 0.90 g, 94%; white solid; mp 70° C.; MS: 376.1 (MH) ⁻ .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), isolated 0.13 g product. Yield: 37%; Pale yellow solid; mp 65°C; MS: 392.9 (M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ0.80 (t, J=7.2Hz, 3H), 1.10 -1.25(m, 2H), 1.25-1.50(m, 2H), 1.70-2.00(m, 2H), 3.53(d, J=14.4Hz, 1H), 3.62(d, J=14.4Hz, 1H), 3.88(s, 3H), 7.15(d, J=8.9Hz, 2H), 7.71(d, J=8.9Hz, 2H), 7.90-8.00(m, 1H), 8.40-8.45(m, 1H), 8.70 -8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm ^-1 ): 3064m, 2958s, 2871m, 1671m.

Example 71

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide

According to the method described in Example 9, the title compound was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-tert-butyl acetate (2.86 g, 10 mmol) and 1-bromo-2-octyne (3.80 g, 20 mmol), 4.4 g of product were isolated. Yield 100%; yellowish gum; MS: 446.9 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid was prepared according to the method described in Example 70. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoate (4.40 g, 10.0 mmol), 2.0 g of product were isolated. Yield 49%; white solid; mp 61°C; MS: 345.1 (MH) ^- .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), separation 0.25 g of product were obtained. Yield: 62%; white solid; mp 83-84°C; MS: 462.0 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.82-0.90 (m, 6H), 1.15- 1.45(m, 12H), 1.90-2.05(m, 4H), 2.86(brd, J=17.0Hz, 2H), 3.00(brd, J=17.0Hz, 2H), 3.87(s, 3H), 7.15(d , J=10.0Hz, 1H), 7.71(d, J=10.0Hz, 1H), 9.20(brs, 1H), 10.90(brs, 1H); IR(KBr, cm ^-1 ): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s;

Anal. Calcd. for _C25H35NO5S : C, 65.05; _H , 7.64; _N , 3.03;

Found: C, 65.26; H, 7.68; N, 2.90.

Example 72

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide

According to the method described in Example 9, tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoate was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-tert-butyl acetate (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of product were isolated. Yield 90%; white solid; mp 85-87°C; MS: 391.0 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was prepared according to the method described in Example 70. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoate (3.0 g, 7.7 mmol), 2.5 g of product were isolated. Yield 97%; white solid; mp 141-143°C; MS: 333.1 (MH) ^- .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), separation 0.23 g of product were obtained. Yield: 89%; white solid; mp 135-137°C; MS: 349.9 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.67(s, 6H), 2.70-3.10( m, 4H), 3.88 (s, 3H), 7.15 (d, J = 10.0Hz, 2H), 7.71 (d, J = 10.0Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm ^-1 ): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

Example 73

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide

According to the method described in Example 9, tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoate was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 g of product were isolated. Yield 75%; white solid; mp 113-115°C; MS: 362.1 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid was prepared according to the method described in Example 70. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoate (1.70 g, 4.7 mmol), 1.30 g of product were isolated. Yield 90%; white solid; mp 156°C; MS: 305.1 (MH) ^- .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared. Starting from (4-methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), isolated 0.22 g product. Yield: 85%; white solid; mp 156 °C; MS: 321.9 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ2.00-2.13 (m, 2H), 3.00-3.30 ( m, 4H), 3.90(s, 3H), 7.01(d, J=9.0Hz, 2H), 7.82(d, J=9.0Hz, 2H), 8.76(brs, 1H), 10.65(brs, 1H); IR (KBr, cm ^-1 ): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s.

Anal. Calcd. for _C15H15NO5S : C, 56.07; _{H ,} 4.70; N, 4.36;

Found: C, 55.65; H, 4.67; N, 4.10.

Example 74

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide

According to the method described in Example 38, the title compound was prepared. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionate (2.20 g, 5.8 mmol) and 1-bromo-2-octyne (1.14 g, 6 mmol), 2.60 g of product were isolated. Yield 92%; pale yellow gum; MS: 486.0 (M+H) ⁺ .

At room temperature, dichloromethane/ The trifluoroacetic acid (1:1) mixture was stirred for about 2 hours (see Example 70). The solvent was then evaporated and 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid was purified by silica gel chromatography (approximately 30% methanol/dichloromethane). Yield: 2.0 g, 87%; white solid; mp 146°C; MS: 428.1 (MH) ^- .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of product was isolated. Yield: 67%; off-white solid; mp 65°C; MS: 445.0 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.84 (t, J = 6.8Hz, 3H), 1.10 -1.40(m, 6H), 1.85-2.00(m, 2H), 2.79(d, J=17.9Hz, 1H), 2.90(d, J=17.9Hz, 1H), 3.50(d, J=13.7Hz, 1H), 3.74(d, J=13.7Hz, 1H), 3.89(s, 3H), 7.19(d, J=9.0Hz, 2H), 7.76(d, J=9.0Hz, 2H), 7.85-7.89( m, 1H), 8.37-8.40(m, 1H), 8.70-8.80(m, 2H), 11.0(brs, 1H); IR(KBr, cm ^-1 ): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m , 1593s.

_{Anal. Calcd} . _{for C23H28N2O5S.HCl.0.9H2O} : C, _55.56 ; H, 6.24; N, 5.63; Found: C, 55.84; H, 6.19; N, 5.59.

Example 75

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide

According to the method described in Example 38, tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoate was prepared. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionate (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of product were isolated . Yield 60%; yellowish solid; mp 132-133°C; MS: 416.0 (M+H) ⁺ .

2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid was prepared according to the method described in Example 70. Starting from tert-butyl 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoate (2.0 g, 4.8 mmol), 1.2 g of product were isolated. Yield 69%; white solid; mp 119-121°C; MS: 358.1 (MH) ^- .

According to the method described in Example 1, 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.065 g of product was isolated. Yield: 25%; off-white solid; mp 70°C; MS: 375.0 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55(d, J=13.8Hz, 1H), 3.67(d, J=13.8Hz, 1H), 3.89(s, 3H), 7.18(d, J=9.0Hz, 2H), 7.75(d, J=9.0Hz, 2H), 7.80-7.89(m, 1H), 8.35-8.40(m, 1H), 8.70-8.80(m, 2H), 11.1(brs, 1H); IR(KBr, cm ^-1 ) : 3168m, 3095s, 1670m, 1593s.

Example 76

  2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid hydroxyamide

According to the method described in Example 1, 2-(4-fluoro-phenylsulfanyl)-tert-butyl acetate was prepared. Starting from 4-fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67 g, 230 mmol), 53.4 g of product were isolated. Yield 100%; pale yellow oil; MS: 243.1 (M+H) ⁺ .

According to the general procedure described in Example 9, tert-butyl 2-(4-fluoro-benzenesulfonyl)-acetate was prepared. Starting from 2-(4-fluoro-phenylsulfanyl)-tert-butyl acetate (48.4 g, 200 mmol) and 3-chloroperbenzoic acid (121.3 g (57%), 400 mmol), 48.0 g of product were isolated. Yield 88%; pale yellow oil; MS: 275.1 (M+H) ⁺ .

According to the method described in Example 70, the title compound was prepared. Using tert-butyl 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionate (1.83g, 5.0mmol) and 1-bromo-2-butyne (0.67g, 5.0mmol) as Starting material, 2.18 g of product were isolated. Yield 100%; yellowish gum; MS: 419.2 (M+H) ⁺ .

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid was prepared according to the method described in Example 38. Starting from tert-butyl 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoate (2.1 g, 5.0 mmol), 1.20 g of product were isolated. Yield 67%; off-white solid; mp 150°C; MS: 360.2 (MH) ^- .

According to the method described in Example 1, 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), isolated 0.15 g of product. Yield: 45%; white solid; mp 190°C; MS: 377.2(M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ1.60(s, 3H), 2.70-3.00(m, 2H ), 3.53(d, J=13.8Hz, 1H), 3.74(d, J=13.8Hz, 1H), 7.50-7.58(m, 2H), 7.80-7.95(m, 3H), 8.35-8.40(m, 1H), 8.74-8.79(m, 2H), 11.1(brs, 1H); IR(KBr, cm ^-1 ): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s;

_Anal. Calcd. for _{C18H17FN2O4S.HCl.0.5H2O} : _C , 51.24; H, _4.54 ; N, 6.64; Found: C _, 51.21; H, 4.35; N, 6.46.

Example 77

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide

According to the method described in Example 9, the title compound was prepared. Using tert-butyl 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionate (1.83g, 5.0mmol) and 1-bromo-2-octyne (0.95g, 5.0mmol) as Starting material, 1.80 g of product was isolated. Yield 56%; yellowish gum; MS: 474.3 (M+H) ⁺ .

2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid was prepared according to the method described in Example 70. Starting from tert-butyl 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoate (1.80 g, 3.8 mmol), 1.40 g of product were isolated. Yield 88%; off-white solid; mp 123-124°C; MS: 416.3 (MH) ^- .

According to the method described in Example 1, 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), isolated 0.22 g of product. Yield: 29%; white solid; mp 180-182°C; MS: 433.2 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.84 (t, J=6.8Hz, 3H) , 1.20-1.40(m, 6H), 1.90-2.05(m, 2H), 2.75(d, J=19.9Hz, 1H), 2.94(d, J=19.9Hz, 1H), 3.54(d, J=13.7 Hz, 1H), 3.75(d, J=13.7Hz, 1H), 7.40-7.60(m, 2H), 7.70-8.00(m, 3H), 8.30-8.40(m, 1H), 8.70-8.80(m, 2H), 11.1 (brs, 1H); IR (KBr, cm ^-1 ): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m;

_{Anal. Calcd} . _{for C22H25FN2O4S.HCl} : C, 56.34; H, 5.59; N, 5.97;

Found: C, 56.18; H, 5.54; N, 5.76.

Example 78

  2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide

According to the method described in Example 9, tert-butyl 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoate was prepared. Starting from 2-(4-fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of product were isolated. Yield 77%; white solid; mp 85°C; MS: 379.1 (M+H) ⁺ .

According to the method described in Example 70, 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was prepared using 2-(4-fluoro-benzenesulfonyl)- 2-But-2-ynyl-hex-4-ynoic acid tert-butyl ester (3.50 g, 8.47 mmol) was used as starting material and 2.35 g of product were isolated. Yield 79%; white solid; mp 129-131°C; MS: 642.8 (MH) ^- .

According to the method described in Example 1, 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared. Starting from 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), isolated 0.21 g product. Yield: 77%; white solid; mp 161-163°C; MS: 338.1 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.67(s, 6H), 2.80-3.10( m, 4H), 7.51 (dd, J=9.0, 9.0Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm ^-1 ): 3336s , 3245m, 1681s, 1589m, 1493m;

Anal. Calcd. for _C16H16FNO4S : C, 56.96; _H , 4.78; _N , 4.15;

Found: C, 56.59; H, 4.75; N, 4.04.

Example 79 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid hydroxyacyl

Amine

According to the method described in Example 9, 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid was prepared Ethyl ester, starting from 2-(4-methoxy-benzenesulfonyl)-ethyl acetate (5.0 g, 20 mmol) and prenyl bromide (6.0 g, 40 mmol). Yield 7.0 g, 88%; colorless oil; MS: 395 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid Ethyl ester (3.5 g, 9 mmol) was used as starting material and 3.3 g (97%) of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methanol) was isolated as a colorless oil yl-but-2-enyl)-hex-4-enoic acid. MS: 365(MH) ^- .

Using 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid (2.6 g, 7.0 mmol) as Raw materials and according to the method described in Example 1, 1.36 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-butan-2- alkenyl)-hex-4-enoic acid hydroxyamide. Yield: 67%; mp 93-96°C; MS: 383(M+H) ⁺ ; ¹ HNMR (300MHz, CDCl ₃ ): δ1.68(s, 6H), 1.73(s, 6H), 2.72(m , 4H), 3.82(s, 3H), 5.12(m, 2H), 6.92(d, J=8Hz, 2H), 7.33(bs, 1H), 7.72(d, J=8Hz, 2H), 9.71(bs , 1H).

Example 80

    2-(4-Methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide

According to the general method described in Example 1, ethyl 2-(4-methoxy-phenylsulfanyl)-heptanoate (13.8 g, 98%) was prepared using ethyl 2-bromo-heptanoate (11 g , 47 mmol) and 4-methoxythiophenol (6 g, 42.8 mmol) as starting materials, as yellow oil; MS: 297.2 (M+H) ⁺ .

2-(4-(4- Methoxy-phenylsulfanyl)-heptanoic acid. The resulting reaction mixture was worked up as described in Example 1. Yield 3 g (83%). Yellow oil. MS: 267.1 (MH) ^- .

Using 2-(4-methoxy-phenylsulfanyl)-heptanoic acid (2.49 g, 9.32 mmol) as starting material and according to the method described in Example 1, 1.83 g of 2-(4- Methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide. Mp 90-95°C; Yield 70%; MS: 284.0 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.826 (t, J=6.9Hz, 3H), 1.135-1.76 (m, 8H), 3.35 (m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).

Example 81

(49A) 2R ^* -(4-methoxy-phenyl-S ^* -sulfinyl)-heptanoic acid hydroxyamide and

(49B) 2S ^* -(4-methoxy-phenyl-R ^* -sulfinyl)-heptanoic acid hydroxyamide

Starting with 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide (1.69 g, 6 mmol) and following the procedure described in Example 5, eluting with 75% ethyl acetate:hexane, The two diastereomers of 2-(4-methoxy-phenylsulfinyl)-heptanoic acid hydroxyamide were separated by silica gel column chromatography. The less polar isomer 2R ^* -(4-methoxy-phenyl-S ^* -sulfinyl)-heptanoic acid hydroxyamide was isolated as a white powder. Yield: 390 mg (22%); mp 115° C.; MS: 300.0 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): 0.828 (t, J=6.2 Hz, 3H), 1.18-1.23 ( m, 6H), 1.73-1.99 (m, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61 (m, 4H). The more polar isomer 2S ^* -(4-methoxy-phenyl-R ^* -sulfinyl)-heptanoic acid hydroxyamide was isolated as a gray solid. Yield: 200 mg (11%); mp 112 °C; MS: 300.0 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ0.754 (t, J=6.9 Hz, 3H), 1.014- 1.121 (m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H), 7.13-7.65 (m, 4H).

Example 82-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-propionic acid hydroxy

amide hydrochloride

According to the method described in Example 12, 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl ]-propionic acid ethyl ester using 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester (4.0 g, 15 mmol) and 4-(morpholin-1-yl-ethoxy)-benzyl Chlorohydrochloride (2.9 g, 10 mmol) was used as starting material. Yield 4.8g, 98%; brown oil; MS: 492 (M+H) ⁺ .

According to the method described in Example 9, using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl ]-Ethyl propionate (4.0 g, 8.1 mmol) as starting material, 3.2 g (84% yield) of 2-(4-methoxy-benzenesulfonyl)-2-methyl- 3-[4-(2-Morpholin-1-yl-ethoxy)-phenyl]-propionic acid. Mp 171°C; MS: 464 (M+H) ⁺ .

Using 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl-ethoxy)-phenyl]-propionic acid (4.0g, 8.6 mmol) as raw material and according to the method described in Example 1, 2.5 g of 2-(4-methoxyl-benzenesulfonyl)-2-methyl-3-[4-(2- Morpholin-1-yl-ethoxy)-phenyl]-propionic acid hydroxyamide. The hydrochloride salt was prepared by reacting the free base with methanolic hydrogen chloride at 0°C. Yield 2.5g, 60%; mp 98°C; MS: 479(M+H) ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ): 1.36(s, 3H), 3.8-12.6(m, 16H), 3.9(s , 3H), 4.1-4.3(m, 1H), 6.6(d, J=8Hz, 2H), 6.96(d, J=9Hz, 2H), 7.1(d, 8Hz, 2H), 7.84(d, 9Hz, 2H), 10.8 (bs, 1H).

Example 83

1-Benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 ml) in a round bottom flask was added α-bromoethylacetic acid Ester (3.3 g, 20 mmol) and the reaction mixture was heated at reflux with good stirring for 8 hours. Then, the reaction mixture was cooled, the potassium salt was filtered off, and the reaction mixture was concentrated. The residue was extracted with chloroform, washed with water and 0.5N NaOH solution. The organic layer was washed well with water, dried over magnesium sulfate, filtered and concentrated. (4-Methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as a pale yellow oil. Yield 4.4 g (100%); MS 277 (M+H) ⁺ .

To a stirred solution of 60% 3-chloroperbenzoic acid (14.0 g, 40 mmol) in dichloromethane (100 ml) was slowly added (4-methoxy-phenylsulfanyl)-ethyl acetate ( 4.4g, 20mmol) in dichloromethane (15ml). The reaction mixture became cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexane (300ml) and stirred for 15 minutes. The solid was filtered off and the sodium sulfite solution was added to the organic layer, stirred for at least 3 hours, then extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to isolate colorless ethyl (4-methoxy-benzenesulfonyl)-acetate as an oil. Yield: 100%; MS 259.1 (M+H) ⁺ .

To a stirred solution of diethanolamine (10.5 g, 100 mmol) and anhydrous potassium carbonate (30 g, excess) in anhydrous acetone (250 ml) in a round bottom flask was added benzyl bromide (17.2 g, 100 mmol) and stirred thoroughly The reaction mixture was heated at reflux for 8 hours. The reaction mixture was then cooled, the potassium salt was filtered off, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water. The organic layer was washed well with water, dried over magnesium sulfate, filtered and concentrated. Colorless oil. Yield 19.0 g, 97%; MS: 196 (M+H) ⁺ .

N-Benzyldiethanolamine (9.75 g, 50 mmol) was dissolved in saturated methanolic hydrochloric acid and concentrated to dryness. The hydrochloride thus formed was dissolved in dichloromethane (300ml), thionyl chloride (20g, excess) was added dropwise, and stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness and the product bis-(2-chloro-ethyl)-benzylamine hydrochloride was used for further transformation without any purification. Yield 13.0 g, 97%; MS: 232 (M+H) ⁺ .

To stirred bis-(2-chloro-ethyl)-benzylamine hydrochloride (6.6 g, 24.7 mmol), 18-crown-6 (500 mg) and anhydrous potassium carbonate (30 g, excess ) in anhydrous acetone (250ml) was added (4-methoxy-benzenesulfonyl)-ethyl acetate (6.12g, 24mmol), and the reaction mixture was heated under reflux for 16 hours with thorough stirring. The reaction mixture was then cooled, the potassium salt was filtered off, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water. The organic layer was washed well with water, dried over magnesium sulfate, filtered and concentrated. The dark brown reaction mixture was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes, to isolate the product 4-(4-methoxy-benzenesulfonyl)-1-benzyl- Ethyl piperidine-4-carboxylate. Yield 6.0 g, 60%; MS: 418 (M+H).

Dissolve ethyl 4-(4-methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylate (5.0g, 11.9mmol) in methanol/tetrahydrofuran (1:1, 200ml) in Stir at room temperature for 72 hours. After this time the reaction mixture was concentrated and the product was dissolved in water (200ml) and neutralized with concentrated HCl. After neutralization the reaction mixture was concentrated to dryness. Ice-cold water (100ml) was added to the solid and filtered. The product 4-(4-methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid was dried at 50°C and used in the next step without further purification. Colorless solid. Yield 3.2 g, 69%; MS: 390 (M+H).

Add 4-(4-methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (2.0 g, 5.1 mmol) and dimethylformamide (2 drops) to stirring at 0° C. Oxalyl chloride (1.0 g, 8 mmol) was added dropwise to a solution of dichloromethane (100 ml). After the addition, the reaction mixture was stirred at room temperature for 1 hour. Meanwhile in a separate flask, a mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) and triethylamine (5 ml, excess) was stirred in tetrahydrofuran:water (5:1, 30 ml) at 0° C. for 1 hour. After 1 hour, the oxalyl chloride reaction mixture was concentrated, and the pale yellow residue was dissolved in 10 mL of dichloromethane and added slowly to hydroxylamine at 0°C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The obtained residue was extracted with chloroform and washed well with water. The product obtained was purified by column chromatography on silica gel, eluting with chloroform, to isolate the product 4-(4-methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide as a colorless solid . mp 90-95°C; Yield 1.2g, 48%; MS: 405(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.29(m, 3H), 2.76-2.79(m, 2H), 3.43(m, 4H), 4.30(s, 2H), 7.14-7.17(d, 2H), 7.50-7.73(m, 5H), 9.37(s, 1H), 10.53(s, 1H), 11.18 (s, 1H).

Example 84

4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was prepared. Diethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g, 31.9 mmol) were used as starting materials. Yield 9.28g, 99%; yellow oil; MS: 226 (M+H) ⁺ .

According to the general procedure described in Example 83, 3-methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared. 3-Methoxy-benzyldiethanolamine (4.4 g, 20 mmol) was used as starting material. Yield 4.5g, 93%; yellow solid; mp 86-88°C; MS: 263 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylate was prepared. 4-(Methoxy-benzenesulfonyl)-ethyl acetate (5.0 g, 22 mmol) and bis-(2-chloro-ethyl)-(3-methoxy-benzyl)-amine (8.0 g, 23.5 mmol) as starting material. Yield 2.4 g, 24%; low melting point solid; MS: 447.9 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperate dissolved in methanol (30ml), 10N sodium hydroxide (10ml), tetrahydrofuran (20ml) Ethyl pyridine-4-carboxylate (2.4 g, 5.36 mmol) was used as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4- formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 710 mg, 32%; white solid; mp 199°C, MS: 419.9 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid (830 mg, 198 mmol) and following the procedure described in Example 83, 190 mg of 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide were isolated as a white solid. mp 130°C; yield 20.4%; MS: 435.0 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.24-2.32 (m, 2H), 2.51 (d, 2H), 2.73 -2.83(m, 2H), 3.37(d, 2H), 3.76(s, 3H), 3.88(s, 3H), 4.32(s, 2H), 7.01-7.77(m, 8H), 9.38(s, 1H ), 10.1(s, 1H).

Example 85

1-(3,4-Dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(3,4-dichlorobenzyl)-amino]-ethanol was prepared. Diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 mmol) were used as starting materials. Yield 13.8g, 99%; colorless oil; MS: 264.3 (M+H) ⁺ .

According to the general procedure described in Example 83, 3,4-dichlorobenzyl-bis-(2-chloro-ethyl)-amine was prepared. 3,4-Dichlorobenzyldiethanolamine (10.7 g, 41 mmol) was used as starting material. Yield 99%; yellow solid; mp 218-220°C; MS: 301.8 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 1-(3,4-dichlorobenzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. 4-(Methoxy-benzenesulfonyl)-ethyl acetate (2.9 g, 11 mmol) and 3,4-dichlorobenzyl-bis-(2-chloro-ethyl)-amine (3.4 g, 11 mmol) as raw material. Yield 5.9 g, 60%; brown oil; MS: 494.5 (M+H) ⁺ .

Using 1-(3,4-dichlorobenzyl)-4-(methoxy-benzenesulfonyl)-piperidine- Ethyl 4-carboxylate (5.0 g, 10 mmol) was used as starting material to prepare 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.94g, 62%; MS: 458.3 (M+H) ⁺ .

Starting from 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.67 g, 5.8 mmol) and as described in Example 83 method, isolated .2 g of 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide as a white solid. mp 192-195°C; Yield 10%; MS: 472.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.20-2.28(m, 2H), 2.76-2.79(m, 2H), 3.43-3.44(m, 4H), 4.30(s, 2H), 7.14-7.17(d, J=.030, 2H), 7.50-7.73(d, J=.027, 1H), 7.65-7.68 (d, J=.029, 2H), 7.72-7.75 (d, J=.027, 2H), 7.87(s, 1H), 9.37(s, 1H), 10.53(s, 1H), 11.18(s, 1H).

Example 86

4-(4-Methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was prepared. Diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol) were used as starting materials. Yield 9.8 g, 99%; MS: 209.9 (M+H) ⁺ .

According to the general procedure described in Example 83, 4-methylbenzyl-bis-(2-chloro-ethyl)-amine was prepared. 4-Methyl-benzyldiethanolamine (6 g, 20 mmol) was used as starting material. Yield 5.2g, 84%; yellow solid; mp 145-147°C; MS: 245.9 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-carboxylate was prepared. Starting from 4-(4-methoxy-benzenesulfonyl)-ethyl acetate (7.0 g, 27 mmol) and 4-methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol) . Yield 4.64g, 63%; low melting point solid; MS: 431.9 (M+H) ⁺ .

Using ethyl 4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (4.3g, 9.9mmol) dissolved in methanol (30ml), 10N sodium hydroxide (10ml), tetrahydrofuran (20ml) ) as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.6g, 40%; white solid; mp 207-208°C, MS: 404.3 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid (1.59 g, 3.9 mmol) and following the procedure described in Example 83, 505 g of 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a white solid. mp 176-177°C; Yield 32%; MS: 419.0(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.24-2.32(m, 2H), 2.51(t, 3H) , 2.73-2.80 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24 (s, 2H), 7.13-7.17 (d, J = .039, 2H), 7.23-7.60 (d, J=.036, 2H), 7.38-7.41 (d, J=.025, 2H), 7.65-7.68 (d, J=.039, 2H).

Example 87

4-(4-Methoxy-benzenesulfonyl)-1-naphthalen-2-yl-methylpiperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(2-naphthalen-2-ylmethyl)-amino]-ethanol was prepared. Diethanolamine (6.18 g, 59 mmol) and 2-(bromomethyl)naphthalene (10 g, 45 mmol) were used as starting materials. Yield 12.7g, 96%; yellow solid; mp 162-164°C; MS: 246.0 (M+H) ⁺ .

According to the general procedure described in Example 83, 2-naphthalen-2-ylmethyl-bis-(2-chloro-ethyl)-amine was prepared. 2-Naphthalene-ylmethyl-diethanolamine (10 g, 36 mmol) was used as starting material. Yield 9.1 g, 9%; brown solid; mp 124-126°C; MS: 281.9 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-naphthalene-ylmethyl-piperidine-4-carboxylate was prepared. 4-(Methoxy-benzenesulfonyl)-ethyl acetate (8.4 g, 32 mmol) and 1-naphthalene-ylmethyl-bis-(2-chloro-ethyl)-amine (8.6 g, 27 mmol) were used as raw material. Yield 6.5 g, 52%; low melting point solid; MS: 440.0 (M+H) ⁺ .

Using ethyl 4-(4-methoxy-benzenesulfonyl)-naphthalene-ylmethyl-piperidine-4-carboxylate dissolved in methanol (30ml), 10N sodium hydroxide (30ml) and tetrahydrofuran (30ml) (6.3 g, 13 mmol) as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-naphthalene-ylmethyl-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.3g, 36%; yellow solid; mp 226-228°C, MS: 440.0 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-naphthalen-2-yl-methylpiperidine-4-carboxylic acid (2.18 g, 5.0 mmol) as starting material and according to the method described in Example 83, isolated This gave 753 g of 4-(4-methoxy-benzenesulfonyl)-1-naphthalen-2-ylmethylpiperidine-4-carboxylic acid hydroxyamide as an off-white solid. mp 168-170°C; Yield 31%; MS: 455.0(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.29-2.33(m, 2H), 2.86-2.89(m, 2H), 3.42-3.46(m, 4H), 3.85(s, 3H), 4.46(s, 2H), 7.13-7.16(d, J=.030, 2H), 7.56-7.64(m, 3H), 7.65 -7.68 (d, J=.030, 2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s, 1H).

Example 88

1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(1-biphenyl-4-ylmethyl)-amino]-ethanol was prepared. Diethanolamine (5.2 g, 49 mmol) and 4-(chloromethyl)biphenyl (10 g, 49 mmol) were used as starting materials. Yield 9.98g, 66%; white solid; mp 160-162°C; MS: 271.9 (M+H) ⁺ . This was converted to the dihydrochloride salt as described in Example 83.

Following the general procedure described in Example 83, ethyl 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Using 4-(4-methoxy-benzenesulfonyl)-ethyl acetate (2.85 g, 11 mmol) and 1-biphenyl-4-ylmethyl-bis-(2-chloro-ethyl)-amine (3.4 g, 11 mmol) as starting material. Yield 2.1 g, 39%; beige solid; mp 176-178°C; MS: 494.1 (M+H) ⁺ .

Using 1-biphenyl-4-ylmethyl-(4-methoxy-benzenesulfonyl)-piperidine-4- Ethyl formate (5.7 g, 12 mmol) was used as starting material to prepare 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.1 g, 39%, MS: 465.8 (M+H) ⁺ .

Starting from 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.0 g, 2.2 mmol) and following the procedure described in Example 83, 132 g of 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide was isolated as a brown solid. mp 168°C; Yield 20%; MS: 440.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.30-2.35(m, 2H), 2.83-2.87(m, 2H) , 3.35-3.5(m, 4H), 3.87(s, 3H), 7.15-7.721(d, J=.059Hz, 2H), 7.49-7.65(m, 5H), 7.68-7.74(d,=.06Hz, 2H), 9.3(s, 1H), 10.3(s, 1H), 11.15(s, 1H).

Example 89

4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol was prepared. Diethanolamine (4.1 g, 39 mmol) and 4-bromo-2-methyl-butene (6.0 g, 40 mmol) were used as starting materials. Yield 98%; brown oil; MS: 173.8 (M+H) ⁺ .

1-(3-Methyl-but-2-enyl)-bis-(2-chloro-ethyl)-amine was prepared according to the general procedure described in Example 83. 2-[(2-Hydroxy-ethyl)-1-(3-methyl-but-2-enyl)-amino]-ethanol (10.4 g, 50 mmol) was used as starting material. Yield 10.5 g, 99%; brown solid; MS: 210.3 (M+H) ⁺ .

According to the general procedure described in Example 1, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylate was prepared. Using 4-(methoxy-benzenesulfonyl)-ethyl acetate (11.32g, 44mmol) and 3-methyl-but-2-enyl-bis-(2-chloroethyl)-amine (10.4g , 50mmol) as raw material. Yield 6.2 g, 36%; brown oil; MS: 395.6 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl) dissolved in ethanol (15ml), 10N sodium hydroxide (10ml) and tetrahydrofuran (75ml) )-piperidine-4-carboxylic acid ethyl ester (6.2 g, 16 mmol) as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)- Piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.2g, 21%; brown solid; mp 196-197°C, MS: 367.9 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid (1.0 g, 3.0 mmol) as starting material and according to Example 83, isolated. 110 mg of 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid hydroxy as a yellow solid amides. mp 142-145°C; Yield 12%; MS: 382.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.67(s, 3H), 1.79(s, 3H), 2.18 -2.23(m, 2H), 2.66-2.73(m, 2H), 3.37-3.46(m, 2H), 3.67-3.69(m, 2H), 5.19-5.24(m, 1H), 7.15-7.18(d, J = .03, 2H), 7.67-7.70 (d, J = .030, 2H), 9.34 (s, 1H), 9.88 (s, 1H), 11.15 (s, 1H).

Example 90

1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(4-bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared. Diethanolamine (22.5 g, 150 mmol) and 4-bromobenzyl bromide (25 g, 100 mmol) were used as starting materials. Yield 33.66 g, 99%; yellow oil; MS: 273.8 (M+H) ⁺ .

According to the general procedure described in Example 83, (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine was prepared. 2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol (33.28 g, 122 mmol) was used as starting material. Yield 47g, 99%; brown solid; mp 125°C; MS: 309.8 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (8.6g, 33.5mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (13.3g, 38.6mmol ) as a raw material. Yield 17 g (44%); brown oil; MS: 497.8 (M+H) ⁺ .

Using 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid dissolved in THF:methanol 3:1 and 10N sodium hydroxide (20ml) Ethyl ester (16.5 g, 33.3 mmol) was used as starting material to prepare 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 6.18 g (40%); brown solid; mp 215°C, MS: 469.7 (M+H) ⁺ .

Starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.95 g, 4.2 mmol) and following the procedure described in Example 83, 1.29 g of 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white solid. Yield 60%; mp 180°C; MS: 484.7 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.18-2.29 (m, 2H), 2.46 (d, 2H), 2.74 -2.89(m, 2H), 3.39(d, 2H), 3.87(s, 3H), 4.28(s, 2H), 7.18(d, J=17Hz, 2H), 7.49(d, J=8.1Hz, 2H ), 7.65-7.68 (m, 4H), 9.37 (s, 1H), 10.5 (s, 1H).

Example 91

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was prepared. Diethanolamine (15.8 g, 151 mmol) and 1-bromo-3-phenylpropane (20 g, 101 mmol) were used as starting materials. Yield 21.31 g, 95%; yellow oil; MS: 223.9 (M+H) ⁺ .

Following the general procedure described in Example 83, bis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine was prepared. 2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol (20.32 g, 90.7 mmol) was used as starting material. Yield 24.9 g, 92%; brown oil; MS: 259.8 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (12g, 46.5mmol) and bis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine (24.8g, 93.8mmol ) as a raw material. Yield 11.24g, 54%; brown oil; MS: 446 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine- Ethyl 4-carboxylate (10.74 g, 24.13 mmol) was used as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.67g, 47%; off-white powder; mp 203°C, MS: 418.2(M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid (4.37 g, 10.4 mmol) and following the procedure described in Example 83 , 1.64 g of 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white solid. Yield 37%; mp 143°C; MS: 432.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.92-1.97(m, 2H), 2.18-2.29(m, 2H) , 2.47(d, 2H), 2.58(t, J=7.7Hz, 2H), 2.6-2.73(m, 2H), 3.0-3.06(m, 2H), 3.60(d, J=12.3Hz, 2H), 3.87 (s, 2H), 7.15-7.30 (m, 7H), 7.68 (d, J=9Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

Example 92

1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, tert-butyl-bis-(2-chloro-ethyl)-amine was prepared. 1-tert-butyl-diethanolamine (6 g, 37.2 mmol) was used as starting material. Yield 11.15 g, 99%; white solid; MS: 197.8 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (10 g, 38.76 mmol) and tert-butyl-bis-(2-chloro-ethyl)-amine (5.25 g, 22.53 mmol) were used as starting materials. Yield 5.37g, 62%; brown oil; MS: 384 (M+H) ⁺ .

Using ethyl 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (5.37g, 14mmol) dissolved in methanol (300ml) and 10N sodium hydroxide (23ml) ) as starting material to prepare 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.52g, 30.6%; white powder; mp 204°C, MS: 356 (M+H) ⁺ .

Using 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (320 mg, 0.9 mmol) as starting material and following the procedure described in Example 83, 190 mg was isolated as a green solid 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 52%; mp 40°C; MS: 371.1(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.29(s, 9H), 1.54(m, 2H), 1.66(m , 2H), 2.39 (m, 2H), 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.67 (d, 2H).

Example 93

  1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, butyl-bis-(2-chloro-ethyl)-amine was prepared. N-butyldiethanolamine (6 g, 37.2 mmol) was used as starting material. Yield 11.3 g, 99%; white powder; mp 165°C; MS: 197.9 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (5 g, 19.38 mmol) and butyl-bis-(2-chloro-ethyl)-amine (4.52 g, 19.38 mmol) were used as starting materials. Yield 6.86g, 93%; brown oil; MS: 384 (M+H) ⁺ .

Using ethyl 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (6.42g, 16.8mmol) dissolved in methanol (200ml) and 10N sodium hydroxide (20ml) ) as starting material to prepare 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.6g, 27%; white powder; mp 206°C, MS: 356.4 (M+H) ⁺ .

Starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.51 g, 4.3 mmol) and following the procedure described in Example 83, 200 mg was isolated as an off-white solid 1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 9.3%; mp75°C; MS: 371.1 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.87 (t, J=7.2Hz, 3H), 1.27 (m, 2H) , 1.59(m, 2H), 2.27(m, 2H), 2.45(m, 2H), 2.50(m, 2H), 2.65(m, 2H), 2.97(m, 2H), 3.88(s, 3H), 7.18 (d, 2H), 7.69 (d, 2H).

Example 94

1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, cyclooctyl-bis-(2-chloro-ethyl)-amine was prepared. N-Cyclooctyldiethanolamine (6 g, 28 mmol) was used as starting material. Yield 10 g, 99%; off-white solid; mp 158°C; MS: 251.9 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (5 g, 19.4 mmol) and cyclooctyl-bis-(2-chloro-ethyl)-amine (5.57 g, 19.4 mmol) were used as starting materials. Yield 8.2 g, 96%; brown oil; MS: 438 (M+H) ⁺ .

Using ethyl 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (8g, 18.3mmol) dissolved in methanol (200ml) and 10N sodium hydroxide (25ml) ) as starting material to prepare 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.36g, 32%; white powder; mp 180°C, MS: 410 (M+H) ⁺ .

Using 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.26 g, 5.53 mmol) as starting material and following the procedure described in Example 83, 570 mg was isolated as white Powdered 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 22%; mp>200°C; MS: 425(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.42-1.66(m, 14H), 1.83(m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H), 3.88 (s, 3H), 7.17 (d, 2H), 7.66 (d, 2H).

Example 95

  1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (3 g, 11.6 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.39 g, 11.6 mmol) were used as starting materials. Yield 3.09g, 75%; brown solid with low melting point; MS: 356 (M+H) ⁺ .

Using ethyl 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (2.42g, 6.8mmol) dissolved in methanol (100ml) and 10N sodium hydroxide (15ml) ) as starting material to prepare 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.29g, 58%; white solid; mp 209°C, MS: 328 (M+H) ⁺ .

Using 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.23 g, 3.76 mmol) as starting material and following the procedure described in Example 83, 1.02 g was isolated as off-white Powdered 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 80%; mp 85°C; MS: 343(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.926(t, J=7.1Hz, 3H), 1.68-1.89(m , 4H), 2.05-2.24 (m, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H).

Example 96

1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, ethyl 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (5.7 g, 22.2 mmol) and isopropyl-bis-(2-chloro-ethyl)-amine (4.9 g, 22.2 mmol) were used as starting materials. Yield 5.64g, 68%; brown solid with low melting point; MS: 370 (M+H) ⁺ .

Using ethyl 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (5.6 g, 15.2 mmol) as starting material for the preparation of 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.18g, 42%; white powder; mp 204°C, MS: 341.9 (M+H) ⁺ .

Using 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.13 g, 6.25 mmol) as starting material and following the procedure described in Example 83, 590 mg was isolated as white Powdered 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 2.4%; mp 75°C; MS: 357(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.21(d, J=6.6Hz, 6H), 233-3.53(m , 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d, 2H).

Example 97

  1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(methoxy-benzenesulfonyl)acetate (3 g, 11.6 mmol) and methyl-bis-(2-chloro-ethyl)-amine (2.2 g, 11.6 mmol) were used as starting materials. Yield 3.09g, 75%; brown solid with low melting point; MS: 342 (M+H) ⁺ .

Using ethyl 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (8.7g, 25.6mmol) dissolved in methanol (300ml) and 10N sodium hydroxide (35ml) ) as starting material to prepare 1-methyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3.23g, 41%; white solid; mp 204°C, MS: 313.9 (M+H) ⁺ .

Using 1-methyl-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.0 g, 6.38 mmol) as starting material and according to the method described in Example 83, 1.10 g of a yellow powder was isolated 1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 53%; mp 89°C; MS: 329 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H) , 2.05(s, 3H), 2.17(d, J=11.4Hz, 2H), 2.57(d, J=10.4Hz, 2H), 3.83(s, 3H), 7.02(d, 2H), 7.62(d, 2H).

Example 98

  1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Ethyl 4-(butoxy-benzenesulfonyl)acetate (6 g, 20 mmol) and bis-(2-chloro-ethyl)-benzylamine (10 g, 30 mmol) were used as starting materials. Yield 5.15 g, 56%; yellow oil; MS: 460 (M+H) ⁺ .

Using ethyl 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate (5.1 g, dissolved in THF:methanol 3:1 and 10 N sodium hydroxide (10 ml), 11.1 mmol) as starting material for the preparation of 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.66g, 56%; off-white solid; mp 210°C, MS: 432 (M+H) ⁺ .

Using 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.61 g, 6.06 mmol) as starting material and following the procedure described in Example 83, 860 mg was isolated as an off-white powder 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 32%; mp 144°C; MS: 446.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.94(t, J=7.3Hz, 3H), 1.44(q, J= 7.5Hz, 2H), 1.70(q, 2H), 2.28-2.32(m, 2H), 2.50(d, 2H), 2.74-2.83(m, 2H), 3.35(d, 2H), 4.08(t, J =6.3Hz, 2H), 4.34(s, 2H), 7.13(d, J=8.7, 2H), 7.45(s, 3H), 7.54(s, 2H), 7.74(d, J=8.7, 2H), 9.35(s, 1H), 10.7(s, 1H).

Example 99

1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, ethyl 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (18.8g, 72.8mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (20.8g, 73mmol) as raw material. Yield 25g, 79%; brown oil; MS: 436.9 (M+H) ⁺ .

Using 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid dissolved in THF:methanol 3:1 and 10N sodium hydroxide (40ml) Ethyl ester (17.4 g, 40 mmol) was used as starting material to prepare 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 10.8 g, 66%; colorless solid; mp 154°C, MS: 408 (M+H) ⁺ .

Using 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (8.14 g, 20 mmol) as starting material and according to the method described in Example 83, isolated 4.3 g of 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide were obtained as an off-white solid. Yield 51%; mp 176-178°C; MS: 484.7(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.12-2.20(m, 2H), 2.64-2.79(m, 2H), 3.32-3.45(m, 4H), 3.87(s, 3H), 4.31(s, 2H), 7.14-7.19(d, J=17Hz, 2H), 7.27-7.33(d, J=8.1Hz, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).

Example 100

1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, ethyl 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate was prepared. Starting from ethyl 4-(butoxy-benzenesulfonyl)acetate (6 g, 20 mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (4.73 g, 20 mmol) . Yield 8.2g, 86%; yellow oil; MS: 478 (M+H) ⁺ .

Using 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid dissolved in THF:methanol 3:1 and 10N sodium hydroxide (10ml) Ethyl ester (4.77 g, 10 mmol) was used as starting material to prepare 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3.5 g, 79%; off-white solid; mp 114°C, MS: 450 (M+H) ⁺ .

Starting from 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.24 g, 5.0 mmol) and following the procedure described in Example 83, 200 mg of 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white powder. Yield 9%; mp 112°C; MS: 465.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.94(t, J=7.3Hz, 3H), 1.35-1.50(m , 2H), 1.68-1.77(m, 2H), 2.20-2.28(m, 2H), 2.66-2.77(m, 2H), 3.77-3.78(m, 4H), 4.06-4.10(m, 2H), 4.19 (s, 2H), 7.14-7.19 (d, J=8.7, 2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.34 (s, 1H), 10.55 (s, 1H).

Example 101

4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared. Diethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g, 100 mmol) were used as starting materials. Yield 17.5 g (77%); yellow oil; 226 (M+H).

According to the general procedure described in Example 83, 4-methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared. 4-Methoxy-benzyldiethanolamine (10 g, 44 mmol) was used as starting material. Yield 10 g (75%); yellow solid; mp 55°C; 263.1 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylate was prepared. Using 4-(methoxy-benzenesulfonyl)-ethyl acetate (5.0 g, 20 mmol) and bis-(2-chloroethyl)-(4-methoxy-benzyl)-amine (7.0 g, 22mmol) as raw material. Yield 5.0 g, 56%; low melting point solid; MS: 448.5 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperene dissolved in methanol (30ml), 10N sodium hydroxide (10ml) and tetrahydrofuran (20ml) Ethyl pyridine-4-carboxylate (4.2 g, 10 mmol) was used as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid . The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g, 71%; white solid; mp 190°C, MS: 420.4 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid (2.0 g, 4.7 mmol) and as described in Example 83 method, isolated 1.2 g of 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide as a white solid. mp 175°C (HCl); Yield: 1.2g, 59%; MS: 433.0(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.8(m, 4H), 2.3(m, 2H), 2.73(m, 2H), 3.37(d, 2H), 3.76(s, 3H), 3.88(s, 3H), 6.87(d, 2H), 7.11(d, 2H), 7.21(d, 2H ), 7.65 (d, 2H), 9.2 (bs, 1H), 10.9 (bs, 1H).

Example 102

4-(4-Methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine

-4-Formic acid hydroxyamide

According to the general procedure described in Example 83, 2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol was prepared. Diethanolamine (10.0 g, excess) and 1-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol) were used as starting materials. Yield 11 g (92%); yellow oil; 240 (M+H) ⁺ .

Following the general procedure described in Example 83, the corresponding dichloride bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine was prepared. 2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol (10 g, 41.8 mmol) was used as starting material. Yield 11 g (95%); brown oil; 277.2 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylate was prepared ester. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-amine (6.4 g, 20 mmol) as starting material. Yield 6.0 g, 65%; brown oil; MS: 462.5 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)- Ethyl]-piperidine-4-carboxylate (5.0 g, 10.8 mmol) was used as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl )-ethyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.0 g, 85%; off-white powder; mp 205°C, MS: 434.5 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid (1.5 g, 3.46 mmol) and According to the method described in Example 83, 900 mg of 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine was isolated as an off-white solid -4-Formic acid hydroxyamide. Yield 58%; mp 206 °C (HCl); MS: 449.5 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ2.3 (m, 2H), 2.5 (m, 3H), 2.8(m, 2H), 2.95(m, 2H), 3.25(m, 2H), 3.4(m, 4H), 3.60(d, J=12.3Hz, 2H), 3.77(s, 3H), 3.99(s , 3H), 6.9 (d, 2H), 7.1-7.25 (q, 4H), 7.7 (d, 2H), 9.3 (s, 1H), 10.6 (s, 1H).

Example 103

4-(4-Methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol was prepared. Diethanolamine (6.0 g, 57) and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol) were used as starting materials. Yield 9 g (90%); yellow oil; 210 (M+H) ⁺ .

According to the general procedure described in Example 83, bis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine was prepared. 2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol (8.5 g, 40.6 mmol) was used as starting material. Yield 11 g (95%); brown oil; 247.1 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (5.0g, 20mmol) and bis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine (5.6g, 20mmol ) as a raw material. Yield 5.5 g, 63%; brown oil; MS: 432.5 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine- Ethyl 4-carboxylate (3.0 g, 6.9 mmol) was used as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.0 g, 72%; off-white powder; mp 208°C, MS: 404.5 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid (1.5 g, 3.7 mmol) and following the procedure described in Example 83 , isolated 900 mg of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide as an off-white solid. Yield 58%; mp 205 °C (HCl); MS: 419.4 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ2.3 (m, 2H), 2.5 (m, 3H), 2.8(m, 2H), 2.95(m, 2H), 3.25(m, 2H), 3.4(m, 4H), 3.9(s, 3H), 7.22-7.8(m, 9H), 10.6(s, 1H) , 11.2 (bs, 1H).

Example 104

4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylate was prepared. Using 4-(n-butoxy-benzenesulfonyl)-ethyl acetate (2.5 g, 10 mmol) and bis-(2-chloroethyl)-(4-methoxy-benzyl)-amine (3.0 g , 10mmol) as raw material. Yield 3.5 g, 71%; low melting point solid; MS: 490.5 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperene dissolved in methanol (30ml), 10N sodium hydroxide (10ml) and tetrahydrofuran (20ml) Ethyl pyridine-4-carboxylate (3.0 g, 6.1 mmol) was used as starting material to prepare 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4 - formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.5 g, 53%; white solid; mp 207°C, MS: 462.5 (M+H) ⁺ .

Using 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid (1.0 g, 2.1 mmol) as starting material and according to Example 83 According to the method described, 1.2 g of 4-(4-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a white solid. mp 173°C (HCl); Yield: 800 mg, 77%; MS: 477.5 (M+H) ⁺ ; ¹ HNMR (300 MHz, DMSO-d ₆ ): δ0.9 (t, 3H), 1.4 (m, 2H) , 1.7(m, 2H), 2.3(m, 2H), 2.5(m, 2H), 2.7(m, 2H), 3.3(m, 2H), 3.5(m, 2H), 4.1(t, 2H), 4.3 (m, 2H), 6.97 (d, 2H), 7.14 (d, 2H), 7.48 (d, 2H), 7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).

Example 105

4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was prepared. Diethanolamine (15.8 g, 151 mmol) and 3-phenoxypropyl bromide (21.5 g, 100 mmol) were used as starting materials. Yield 21.31 g (95%); yellow oil; 238.1 (M+H) ⁺ .

Following the general procedure described in Example 83, bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine was prepared. 2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol (20.0 g, 84 mmol) was used as starting material. Yield 24.0 g (91%); brown oil; 277.8 (M+H) ⁺ .

Following the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (5.2 g, 20 mmol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22mmol) as raw material. Yield 6.5 g, 70%; brown oil; MS: 462.5 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine dissolved in THF:methanol (3:1) and 10N sodium hydroxide (40ml) - Ethyl 4-carboxylate (4.2 g, 9.1 mmol) as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid . The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g, 75%; off-white powder; mp 195°C, MS: 434.5 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid (2.5 g, 5.77 mmol) and as described in Example 83 method, isolated 1.2 g of 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide as an off-white solid. Yield 46%; mp 101°C; MS: 448.5(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.18(m, 2H), 2.3(m, 2H), 2.58(m , 2H), 2.6-2.73(m, 2H), 3.0-3.06(m, 2H), 3.60(m, 2H), 3.87(s, 3H), 4.01(t, 2H), 6.9-7.7(m, 9H ), 9.33 (bs, 1H), 10.29 (bs, 1H).

Example 106

4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(butoxy-benzenesulfonyl)acetate (3.0 g, 10 mmol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (3.0 g, 11 mmol) as starting material. Yield 4.5 g, 89%; brown oil; MS: 504.6 (M+H) ⁺ .

Using 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperide dissolved in THF:methanol (3:1) and 10N sodium hydroxide (40ml) Ethyl pyridine-4-carboxylate (4.0 g, 7.9 mmol) was used as starting material to prepare 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine- 4-Formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g, 79%; off-white powder; mp 191° C., MS: 476.5 (M+H) ⁺ .

Starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid (700 mg, 1.4 mmol) and as described in Example 83 method, 300 mg of 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white solid. Yield 43%; mp 84°C; MS: 491.5(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9(t, 3H), 1.5(m, 2H), 1.8(m , 2H), 2.18(m, 2H), 2.3(m, 2H), 2.58(m, 2H), 2.6-2.73(m, 2H), 3.2(m, 2H), 3.40(m, 6H), 3.97( t, 2H), 4.1 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).

Example 107

4-(4-Methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, 2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol was prepared. Diethanolamine (15.0 g, 150) and 2-chloro-phenetol (15.6 g, 100 mmol) were used as starting materials. Yield 18 g (80%); colorless oil; 226 (M+H) ⁺ .

According to the general procedure described in Example 83, bis-(2-chloro-ethyl)-(2-phenoxy-propyl)-amine was prepared. 2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino)-ethanol (20.0 g, 88.8 mmol) was used as starting material. Yield 25 g (94%); brown oil; 263.1 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (6.0 g, 20mmol) as raw material. Yield 5.8 g, 64%; brown oil; MS: 448.5 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine dissolved in tetrahydrofuran:methanol (3:1) and 10N sodium hydroxide (40ml) - Ethyl 4-carboxylate (5.0 g, 11.1 mmol) as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid . The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g, 63%; off-white powder; mp 235°C, MS: 420.5 (M+H) ⁺ .

Starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid (2.5 g, 5.9 mmol) and as described in Example 83 method, 1.3 g of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white solid. Yield 50%; mp 168-172°C (HCl); MS: 435.5(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.3(m, 2H), 2.5(m, 2H ), 2.9(m, 2H), 3.4(m, 4H), 3.5(m, 2H), 3.7(m, 2H), 3.9(s, 3H), 4.4(m, 2H), 6.9-7.8(m, 9H), 9.3(s, 1H), 10.2(bs, 1H), 11.3(s, 1H).

Example 108

4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, ethyl 4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylate was prepared. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (2.5 g, 10 mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (2.98 g, 10mmol) as raw material. Yield 3.0 g, 69%; brown oil; MS: 490.6 (M+H) ⁺ .

Using 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperene dissolved in THF:methanol (3:1) and 10N sodium hydroxide (40ml) Ethyl pyridine-4-carboxylate (2.5 g, 5.76 mmol) was used as starting material to prepare 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4 - formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.5g, 56%; off-white powder; mp 204°C, MS: 462.5 (M+H) ⁺ .

Using 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid (1.0 g, 2.16 mmol) as starting material and according to Example 83 According to the method described, 600 mg of 4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off-white solid. Yield 58%; mp 112°C (HCl); MS: 477.4 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.942 (t, 3H), 1.4 (m, 2H), 1.7(m, 2H), 2.3(m, 2H), 2.5(m, 4H), 2.8(m, 2H), 2.9-3.4(m, 4H), 3.3(m, 4H), 4.2(t, 2H) , 4.4 (m, 2H), 6.9-7.7 (m, 9H), 9.4 (s, 1H), 10.5 (bs, 1H), 11.3 (s, 1H).

Example 109

4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy

                       

Following the general procedure described in Example 83, bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared. Diethanolamine (15.0 g, 150) and 4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol) were used as starting materials. Yield 5.5 g (85%); brown semi-solid; 323 (M+H) ⁺ .

Following the general procedure described in Example 83, bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared. 2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (3.22 g, 10 mmol) was used as starting material. Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H) ⁺ .

4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine was prepared according to the general procedure described in Example 83 - Ethyl 4-carboxylate. Using ethyl 4-(methoxy-benzenesulfonyl)acetate (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy )-benzyl]-amine (8.6 g, 20 mmol) as starting material. Yield 6.0 g, 55%; brown oil; MS: 545.7 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl) dissolved in tetrahydrofuran:methanol (3:1) and 10N sodium hydroxide (40ml) Ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) was used as starting material to prepare 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piper Pyridin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.0 g, 77%; off-white powder; mp 174°C, MS: 517.6 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid (3.5g, 6.78 mmol) as starting material and according to the method described in Example 83, 1.8 g of 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidine-1- yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide. Yield 49%; mp 114°C (HCl); MS: 532 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.4-1.6 (m, 4H), 1.9 (m, 2H ), 2.3(m, 2H), 2.8(m, 2H), 3.4(m, 4H), 3.9(s, 3H), 4.2(m, 1H), 6.9-7.8(m, 8H), 9.1(s, 1H), 10.8 (bs, 1H).

Example 110

   N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide

Step A: Coupling of 2-Bromopropionic Acid and Hydroxylamine Resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and suspended in dimethylformamide (20ml). Add 2-bromopropionic acid (0.6ml, 3.0eq.), 1-hydroxybenzotriazole hydrate (HOBt, 1.8g, 6.0eq.) and 1,3-diisopropylcarbodiimide (DIC , 1.4ml, 4.0eq.). The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test shows the presence of free amine (resin turns blue), then repeat the above coupling reaction, otherwise wash the resin with DCM (3 x 20 ml), MeOH (2 x 20 ml) and DCM (2 x 20 ml) (one wash includes addition of solvent, by blowing nitrogen or shaking on an orbital shaker for 1-5 minutes, followed by vacuum filtration). The resin was dried under vacuum at room temperature.

Cleavage of resin samples (5-20 mg) was performed with DCM (0.5 ml) and TFA (0.5 ml) at room temperature. The reaction was filtered and the resin was washed with DCM (1 x 1 ml). The filtrate and washings were combined and concentrated in vacuo on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. Then the product was identified by H ¹ NMR (DMSO-d6): δ 4.54 (q, 1H), 1.83 (d, 3H).

Step B: Displacement of bromine with 4-methoxybenzenethiol

N-Hydroxy-2-bromo-propionamide (0.35 g, 1.1 meq/g) from step A was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 4-methoxybenzenethiol (0.23ml, 5.0eq.), sodium iodide (288mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU , 0.17ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The N-hydroxy-2-(4-methyl-phenylsulfanyl)-propionamide resin (175mg, 1.1meq/g) prepared in step B was suspended in DCM (3.0ml), and 70% t-hydroperoxide was added Butyl (1.0ml) and benzenesulfonic acid (50mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-propionamide resin (175 mg, 1.1 meq/g) prepared in step B was suspended in DCM (30 ml), and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide from the resin

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide resin (73 mg, 1.2 meq/g) prepared in step D was suspended in DCM (1.0 ml), and TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated.

At 215nm, 84%; ¹ H NMR (DMSO d-6): δ10.75(brs, 1H), 7.95(brs, 1H), 7.71(dd, 2H), 7.16(dd, 2H), 3.87(s , 3H), 3.83(q, 1H), 1.26(d, 3H).

Using appropriate starting materials and following the procedure of Example 110, the hydroxamic acid compounds of Examples 111-113 were synthesized.

Example 111

N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-propionamide at 215 nm, 72%.

N-Hydroxy-2-(4-methoxy-phenylsulfinylalkyl)-propionamide. At 215nm, 76%; ¹ HNMR (DMSO d-6): δ10.90 & 10.60 (brs, 1H), 7.95 (brs, 1H), 7.61 & 7.52 (dd, 2H), 7.15 & 7.10 (dd, 2H ), 3.83 & 3.82 (s, 3H), 3.42 & 3.28 (q, 1H), 1.23 & 0.97 (d, 3H).

Example 112

N-Hydroxy-2-(3-methyl-butane-1-sulfanyl)-propionamide at 215 nm, 74%.

N-Hydroxy-2-(3-methyl-butane-1-sulfinyl)-propionamide. ¹ H NMR (DMSO d-6): δ10.8 (brs, 1H), 7.95 (brs, 1H), 3.45 & 3.31 (q, 1H), 2.71-2.50 (m, 2H), 1.71-1.46 (m, 3H), 1.33 & 1.25(d, 3H), 0.94-0.82(m, 6H).

Example 113

N-Hydroxy-2-(3-methyl-butane-1-sulfonyl)-propionamide at 215 nm, 84%.

Example 114

  N-Hydroxy-3-methyl-2-(naphthalene-2-ylsulfanyl)-butanamide

Step A: Coupling of 2-bromo-3-methyl-butyric acid with hydroxylamine resin

4-O-Methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in dimethylformaldehyde in methyl formamide (40ml). 2-Bromo-3-methyl-butyric acid (9.96g, 10.0eq.) and DIC (9.04ml, 10.5eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Bromine Displacement with 2-Naphthylthiol

The 2-bromohydroxamate resin prepared in step A (0.15 g, 1.1 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 2-naphthylthiol (138mg, 5.0eq.), sodium iodide (129mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.078ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(2-naphthylsulfanyl)-N-hydroxypropionamide resin (175mg, 1.1meq/g) prepared in step B was suspended in DCM (30ml), and 70% tert-butyl hydroperoxide (1.0ml ) and benzenesulfonic acid (50 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2-(2-naphthylsulfanyl)-N-hydroxypropionamide resin (175 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (30 ml), and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide from the resin

2-(2-Naphthylsulfanyl)-N-hydroxypropionamide resin (73mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml) and TFA (1.0ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated.

At 215nm, 83%; LCMS (API-electrospray) m/z 276 (M+H) ⁺ ; ¹ HNMR (DMSO d-6): δ10.7 (brs, 1H), 7.91 (brs, 1H), 7.91-7.81 (m, 4H), 7.55-7.45 (m, 3H), 3.41 (d, 1H), 2.09-1.97 (m, 1H), 1.05 (d, 3H), 0.97 (d, 3H).

Using appropriate starting materials and following the procedure of Example 114, the hydroxamic acid compounds of Examples 115-118 were synthesized.

Example 115

N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfinyl)-butanamide. At 215nm, 67%.

Example 116

N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfonyl)-butanamide. 97% at 215 nm; LCMS (API-electrospray) m/z 308 (M+H) ⁺ .

Example 117

N-Hydroxy-3-methyl-2-phenethylsulfinyl-butanamide. 93% at 215 nm; LCMS (API-electrospray) m/z 254 (M+H) ⁺ .

Example 118

N-Hydroxy-3-methyl-2-phenethylsulfonyl-butanamide. 97% at 215 nm; LCMS (API-electrospray) m/z 286 (M+H) ⁺ .

Example 119

 (1-Hydroxycarbamoyl-propane-1-sulfanyl)-methyl acetate

Step A: Coupling of 2-bromobutyric acid with hydroxylamine resin

4-O-Methylhydroxylamine-phenoxymethyl-co(styrene-1% divinylbenzene)-resin ¹ (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in dimethyl formamide (40ml). 2-Bromobutanoic acid (3.0 g, 3.0 eq.), HOBt (4.86 g, 6.0 eq.) and DIC (3.75 ml, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Bromine Displacement with Methyl Thioglycolate

The 2-bromohydroxamate resin prepared in step A (0.45 g, 1.1 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add methyl thioglycolate (286mg, 5.0eq.), sodium iodide (404mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24ml , 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-methyl acetate resin (150 mg, 1.1 meq/g) prepared in step B was suspended in DCM (30 ml), and 70% tert-butyl hydroperoxide was added base (1.0ml) and benzenesulfonic acid (50mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-methyl acetate resin (150 mg, 1.1 meq/g) prepared in step B was suspended in DCM (30 ml) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of (1-hydroxycarbamoyl-propane-1-sulfanyl)-acetate methyl ester from the resin

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-methyl acetate resin (150mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml) and TFA (1.0ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. LCMS (API-electrospray) m/z 228 (M+Na) ⁺ .

Using appropriate starting materials and following the procedure of Example 119, the hydroxamic acid compounds of Examples 120-124 were synthesized.

Example 120

(1-Hydroxycarbamoyl-propane-1-sulfonyl)-acetic acid hydroxyamide. LCMS (API-electrospray) m/z 224 (M+H) ⁺ .

Example 121

(1-Hydroxycarbamoyl-propane-1-sulfinyl)-acetic acid hydroxyamide. At 220 nm, 100%; LCMS (API-electrospray) m/z 240 (M+H) ⁺ .

Example 122

(1-Hydroxycarbamoyl-propane-1-sulfanyl)-propionic acid hydroxyamide.

¹ H NMR (DMSO d-6) δ10.7 (brs, 1H), 4.03 (t, 2H), 2.95 (q, 1H), 2.75-2.70 (m, 1H), 2.60-2.54 (m, 1H), 1.74-1.66 (m, 2H), 1.58-1.50 (m, 4H), 1.32 (sextet, 2H), 0.88 (t, 3H), 0.85 (t, 3H); LCMS (API-electrospray) m/ z 264(M+H) ⁺ .

Example 123

(1-Hydroxycarbamoyl-propane-1-sulfinyl)-propionic acid hydroxyamide. 83% at 220 nm; LCMS (API-electrospray) m/z 280 (M+H) ⁺ .

Example 124

(1-Hydroxycarbamoyl-propane-1-sulfonyl)-propionic acid hydroxyamide. At 220nm, 100%.

Example 125

  2-(4-Hydroxyphenylsulfanyl)-N-hydroxy-3-phenyl-propionamide

Step A: Coupling of 2-bromo-3-phenyl-propionic acid with hydroxylamine resin

4-O-Methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in dimethylformaldehyde in methyl formamide (40ml). 2-Bromo-3-phenyl-propionic acid (3.5 g, 3.0 eq.), HOBt (4.4 g, 6.0 eq.) and DIC (3.4 ml, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of Bromine with 4-Hydroxythiophenol

The 2-bromohydroxamate resin prepared in step A (0.33 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 4-hydroxythiophenol (250mg, 5.0eq.), sodium iodide (297mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.18ml , 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

2-(4-Hydroxyphenylsulfanyl)-N-hydroxy-3-phenyl-propionamide resin (110 mg, 1.1 meq/g) prepared in step B was suspended in DCM (3.0 ml) and 70% hydrogen was added tert-butyl peroxide (0.73ml) and benzenesulfonic acid (36mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2-(4-hydroxyphenylsulfanyl)-N-hydroxy-3-phenyl-propionamide resin (110mg, 1.1meq/g) prepared in step B was suspended in DCM (3.0ml), and mCPBA (132mg ). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(4-hydroxyphenylsulfanyl)-N-hydroxy-3-phenyl-propionamide from the resin

2-(4-Hydroxyphenylsulfanyl)-N-hydroxy-3-phenyl-propionamide resin (110mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml), TFA (1.0ml ). The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215 nm, 84%; ¹ H NMR (DMSO d-6) δ 10.41 (brs, 1H), 7.95 (brs, 1H), 7.30-7.15 (m, 5H), 7.10 (dd, 2H), 6.75 ( dd, 2H), 3.53 (q, 1H), 3.05 (dd, 1H), 2.79 (dd, 1H).

Using appropriate starting materials and following the procedure of Example 125, the hydroxamic acid compounds of Examples 126-130 were synthesized.

Example 126

2-(4-Hydroxyphenylsulfinyl)-N-hydroxy-3-phenyl-propionamide. At 215nm, 73%.

Example 127

2-(4-Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. At 215nm, 77%. ¹ H NMR (DMSO d-6) δ10.50 (brs, 1H), 7.95 (brs, 1H), 7.68-7.57 (m, 2H), 7.28-7.17 (m, 3H), 7.08-7.98 (m, 2H) , 6.95-6.87 (m, 2H), 3.96 (t, 1H), 3.02 (d, 2H).

Example 128

2-(4-Acetamido-phenylsulfanyl)-N-hydroxy-3-phenyl-propionamide. At 215nm, 86%; ¹ HNMR (DMSO d-6) δ10.50(brs, 1H), 10.03(brs, 1H), 8.13(brs, 1H), 7.56-7.12(m, 9H), 3.67(q , 1H), 3.08(dd, 1H), 2.84(dd, 1H), 2.04(s, 3H).

Example 129

2-(4-Acetamido-phenylsulfinyl)-N-hydroxy-3-phenyl-propionamide. At 215nm, 73%.

Example 130

2-(4-Acetamido-benzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. At 215nm, 95%.

Example 131

4-Hydroxycarbamoyl-4-(4-methylsulfanyl-phenylsulfanyl)-butyric acid methyl ester

Step A: Coupling of 2-bromo-5-methylglutaric acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (40ml). S-2-Bromo-5-methylglutarate (3.87g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of Bromine with 4-Hydroxythiophenol

The 2-bromohydroxamate resin prepared in step A (0.22 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 4-methylthiothiophenol (206mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

4-Hydroxycarbamoyl-4-(4-methylsulfanyl-phenylsulfanyl)-butyric acid methyl ester resin (73 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (1.5 ml) , 70% tert-butyl hydroperoxide (0.49ml) and benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

4-Hydroxycarbamoyl-4-(4-methylsulfanyl-phenylsulfanyl)-butyric acid methyl ester resin (73 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (1.5 ml) , mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 4-hydroxycarbamoyl-4-(4-methylsulfanyl-phenylsulfanyl)-butyric acid methyl ester from the resin

4-Hydroxycarbamoyl-4-(4-methylsulfanyl-phenylsulfanyl)-butyric acid methyl ester resin (73mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml) , TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 77% at 215 nm; LCMS (API-electrospray) m/z 316 (M+H) ⁺ .

Using appropriate starting materials and following the procedure of Example 131, the hydroxamic acid compounds of Examples 132-139 were synthesized.

Example 132

4-Hydroxycarbamoyl-4-(4-methanesulfinyl-phenylsulfinyl)-butyric acid hydroxyamide. At 215 nm, 79%; LCMS (API-electrospray) m/z 348 (M+H) ⁺ .

Example 133

4-Hydroxycarbamoyl-4-(4-methylsulfonyl-phenylsulfonyl)-butyric acid hydroxyamide. 78% at 215 nm; LCMS (API-electrospray) m/z 380 (M+H) ⁺ .

Example 134

4-Hydroxycarbamoyl-4-(4-bromo-phenylsulfanyl)-butyric acid hydroxyamide. At 215nm, 93%.

Example 135

4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfinyl)-butyric acid hydroxyamide. At 215nm, 80%.

Example 136

4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfonyl)-butyric acid hydroxyamide. At 215nm, 77%.

Example 137

4-Hydroxycarbamoyl-4-(2-trifluoromethyl-phenylsulfanyl)-butyric acid hydroxyamide. At 215nm, 93%.

Example 138

4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfinyl)-butyric acid hydroxyamide. At 215nm, 72%.

Example 139

4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfonyl)-butyric acid hydroxyamide. At 215nm, 90%.

Example 140

    2-(3-Methoxy-phenylsulfanyl) decanoic acid hydroxyamide

Step A: Coupling of 2-bromo-decanoic acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (40ml). 2-Bromo-decanoic acid (4.07g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of bromine with 3-methoxy-benzenethiol

The 2-bromohydroxamate resin prepared in step A (0.22 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 3-methoxy-benzenethiol (185mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU , 0.12ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(3-methoxy-phenylsulfanyl)decanoic acid hydroxyamide resin (73 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (1.5 ml), and 70% tert-butyl hydroperoxide was added (0.49ml) and benzenesulfonic acid (24mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

2-(3-Methoxy-phenylsulfanyl)decanoic acid hydroxyamide resin (73 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (1.5 ml) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(3-methoxy-phenylsulfanyl)decanoic acid hydroxyamide from the resin

2-(3-Methoxy-phenylsulfanyl)-decanoic acid hydroxyamide resin (73mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml) and TFA (1.0ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215nm, 89%.

Using appropriate starting materials and following the procedure of Example 140, the hydroxamic acid compounds of Examples 141-145 were synthesized.

Example 141

2-(3-Methoxy-phenylsulfinyl)decanoic acid hydroxyamide. At 215nm, 96%.

Example 142

2-(3-Methoxy-benzenesulfonyl)-decanoic acid hydroxyamide. At 215nm, 96%.

Example 143

2-(4-Methylsulfanyl-phenylsulfanyl)decanoic acid hydroxyamide. 85% at 215 nm; LCMS (API-electrospray) m/z 342 (M+H) ⁺ .

Example 144

2-(4-Methanesulfinyl-phenylsulfinyl)decanoic acid hydroxyamide. 86% at 215 nm; LCMS (API-electrospray) m/z 374 (M+H) ⁺ .

Example 145

2-(4-Methanesulfonyl-benzenesulfonyl)decanoic acid hydroxyamide. At 215nm, 92%.

Example 146

  3-Benzyloxy-N-hydroxy-2-(4-methylsulfanyl-phenylsulfanyl)-propionamide

Step A: Coupling of 2-bromo-3-benzyloxy-propionic acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin 1 (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (40ml). S-2-Bromo-3-benzyloxy-propionic acid (4.2g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of bromine with 4-methylthiothiophenol

The 2-bromohydroxamate resin prepared in step A (0.22 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 4-methylthiothiophenol (206mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

3-Benzyloxy-N-hydroxy-2-(4-methylsulfanyl-phenylsulfanyl)-propionamide resin (73 mg, 1.1 meq/g) prepared in step B was suspended in DCM (1.5 ml) , 70% tert-butyl hydroperoxide (0.49ml) and benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

3-Benzyloxy-N-hydroxy-2-(4-methylsulfanyl-phenylsulfanyl)-propionamide resin (73 mg, 1.1 meq/g) prepared in step B was suspended in DCM (1.5 ml) , mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 3-benzyloxy-N-hydroxy-2-(4-methylsulfanyl-phenylsulfanyl)-propionamide from the resin

3-Benzyloxy-N-hydroxy-2-(4-methylsulfanyl-phenylsulfanyl)-propionamide resin (73mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml) , TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215 nm, 76%; LCMS (API-electrospray) m/z 350 (M+H) ⁺ .

Using appropriate starting materials and following the procedure of Example 146, the hydroxamic acid compounds of Examples 147-152 were synthesized.

Example 147

3-Benzyloxy-N-hydroxy-2-(4-methanesulfinyl-benzenesulfinyl)-propionamide. At 215 nm, 70%; LCMS (API-electrospray) m/z 382 (M+H) ⁺ .

Example 148

3-benzyloxy-N-hydroxy-2-(4-methylsulfonyl-benzenesulfonyl)propanamide. 63% at 215 nm; LCMS (API-electrospray) m/z 414 (M+H) ⁺ .

Example 149

3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfanyl)-propionamide. At 215nm, 90%.

Example 150

3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfinyl)-propionamide. At 215nm, 70%.

Example 151

3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfonyl)-propionamide. At 215nm, 72%.

Example 152

  2-(2-Bromo-phenylsulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide

Step A: Coupling of 2-bromo-3-(3H-imidazol-4-yl)-propionic acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (40ml). Add S-2-bromo-3-(3H-imidazol-4-yl)-propionic acid (3.55g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.) . The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of bromine with 2-bromothiophenol

The 2-bromohydroxamate resin prepared in step A (0.22 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 2-bromothiophenol (249mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 ml, 3.0 eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(2-bromo-phenylsulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin (73 mg, 1.1 meq/g) prepared in step B was suspended in DCM ( 1.5ml), 70% tert-butyl hydroperoxide (0.49ml) and benzenesulfonic acid (24mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2-(2-bromo-phenylsulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin (73 mg, 1.1 meq/g) prepared in step B was suspended in DCM ( 1.5ml), mCPBA (87mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(2-bromo-phenylsulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide from the resin

The 2-(2-bromo-phenylsulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin (73mg, 1.2meq/g) prepared in step B was suspended in DCM ( 1.0ml), TFA (1.0ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215nm, 86%.

Using appropriate starting materials and following the procedure of Example 152, the hydroxamic acid compounds of Examples 153-154 were synthesized.

Example 153 2-(4-Bromo-benzenesulfinyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide. At 215nm, 69%.

Example 154 2-(4-Chloro-benzenesulfonyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide.

Example 155

  2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide

Step A: Coupling of 2-bromo-5-guanidino-pentanoic acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (40ml). S-2-Bromo-5-guanidino-pentanoic acid (3.85g, 3.0eq.), HOBt (4.4g, 6.0eq) and DIC (3.4ml, 4.0eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of bromine with 3-fluorothiophenol

The 2-bromohydroxamate resin prepared in step A (0.22 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Add 3-fluorothiophenol (169mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 ml, 3.0 eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin (73mg, 1.1meq/g) prepared in step B was suspended in DCM (1.5ml), and 70% hydrogen peroxide was added tert-Butyl oxide (0.49ml) and benzenesulfonic acid (24mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin (73 mg, 1.1 meq/g) prepared in step B was suspended in DCM (1.5 ml), and mCPBA (87 mg) was added . The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide from the resin

Suspend 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin (73mg, 1.2meq/g) prepared in step B in DCM (1.0ml), add TFA (1.0ml ). The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215nm, 93%.

Using appropriate starting materials and following the procedure of Example 155, the hydroxamic acid compounds of Examples 156-159 were synthesized.

Example 156

2-(3-Fluorophenylsulfinyl)-5-guanidino-pentanoic acid hydroxyamide. At 220 nm, 80%; LCMS (API-electrospray) m/z 317 (M+H) ⁺ .

Example 157 2-(2-Bromosulfanyl)-5-guanidino-pentanoic acid hydroxyamide. At 220nm, 92%; ¹ H NMR (DMSO d-6) δ 10.90 (brs, 2H), 10.41 (brs, 1H), 7.95 (brs, 1H), 7.66-7.14 (m, 5H), 3.72 ( q, 1H), 3.13 (q, 2H), 1.90-1.66 (m, 2H), 1.58-1.43 (2H).

Example 158

2-(2-Bromosulfinyl)-5-guanidino-pentanoic acid hydroxyamide. At 220 nm, 79%; LCMS (API-electrospray) m/z 379 (M+H) ⁺ .

Example 159

2-(2-Bromosulfonyl)-5-guanidino-pentanoic acid hydroxyamide. ¹ H NMR (DMSO d-6) δ 8.03-7.45 (m, 5H), 4.52 (q, 1H), 3.16 (q, 2H), 2.07-1.90 (m, 2H), 1.66-1.59 (2H).

Example 160

  2-(2,5-Dichlorophenylsulfanyl)-octanoic acid hydroxyamide

Step A: Coupling of 2-bromo-octanoic acid with hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-co(styrene-1%-divinylbenzene)-resin ¹ (10.0 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in two in methylformamide (80ml). 2-Bromo-octanoic acid (8.4g, 3.0eq.), HOBt (8.8g, 6.0eq.) and DIC (7.2ml, 4.0eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with dimethylformamide (3 x 20ml). Resin samples were taken and subjected to a Kaiser test. If the test showed the presence of free amine (resin turned blue) then the above coupling reaction was repeated, otherwise the resin was washed with DCM (3x20ml), MeOH (2x20ml) and DCM (2x20ml). The resin was dried under vacuum at room temperature.

Step B: Displacement of bromine with 2,5-dichlorothiophenol

The 2-bromohydroxamate resin prepared in step A (0.45 g, 1.2 meq/g) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (6 ml). Add 2,5-dichlorothiophenol (483mg, 5.0eq.), sodium iodide (404mg, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU , 0.24ml, 3.0eq.). The reaction was shaken for 12-16 hours at room temperature. The reaction mixture was poured into a polypropylene syringe with a polypropylene filter plate, filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x2ml), DMF (2ml), MeOH (2x2ml) and DCM (2 x 2ml) wash. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(2,5-dichlorophenylsulfanyl)-octanoic acid hydroxyamide resin (150 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (3.0 ml), and 70% tert-butyl hydroperoxide was added (1.0ml) and benzenesulfonic acid (50mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

2-(2,5-Dichlorophenylsulfanyl)-octanoic acid hydroxyamide resin (150 mg, 1.1 meq/g) prepared in Step B was suspended in DCM (3.0 ml), and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(2,5-dichlorophenylsulfanyl)-octanoic acid hydroxyamide from the resin

2-(2,5-Dichlorophenylsulfanyl)-octanoic acid hydroxyamide resin (73 mg, 1.2 meq/g) prepared in step B was suspended in DCM (1.0 ml), and TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. At 215nm, 92%; ¹ H NMR (DMSO d-6) δ10.96 (brs, 1H), 9.26 (brs, 1H), 7.93-7.76 (m, 3H), 4.07 (q, 1H), 2.04- 1.95 (m, 1H), 1.78-1.64 (m, 1H), 1.32-1.09 (m, 8H), 0.81 (t, 3H).

Using appropriate starting materials and following the procedure of Example 160, the hydroxamic acid compounds of Examples 161-167 were synthesized.

Example 161

2-(2,5-Dichlorobenzenesulfonyl)-octanoic acid hydroxyamide. At 215nm, 96%.

Example 162

2-(3-Methoxyphenylsulfanyl)-octanoic acid hydroxyamide. 86% at 220 nm; LCMS (API-electrospray) m/z 298 (M+H) ⁺ .

Example 163

2-(3-Methoxybenzenesulfinyl)-octanoic acid hydroxyamide. At 220nm, 96%.

Example 164

2-(3-Methoxybenzenesulfonyl)-octanoic acid hydroxyamide. At 220nm, 83%.

Example 165

2-(3,4-Dimethoxyphenylsulfanyl)-octanoic acid hydroxyamide. 87% at 215 nm; LCMS (API-electrospray) m/z 328 (M+H) ⁺ .

Example 166

2-(3,4-Dimethoxybenzenesulfinyl)-octanoic acid hydroxyamide. At 215nm, 90%.

Example 167

2-(3,4-Dimethoxybenzenesulfonyl)-octanoic acid hydroxyamide. At 215nm, 87%.

Using appropriate starting materials and following the procedure of Example 160, the hydroxamic acid compounds of Examples 168-198 were synthesized. The crude product was dissolved in DMSO:methanol (1:1, 2ml) and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20mm×50mm, 5μm particle size (YMC, Inc.Wilmington, North Carolina)

Solvent Gradient Time Water Acetonitrile

0.0 95 5

                                                                                                                                            

Flow rate: 15ml/min.

Example 168

2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 81 %; LCMS (API-electrospray) m/z 308 (M+H) ⁺ .

Example 169

2-(2-Benzoxazol-2-ylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 72%; LCMS (API-electrospray) m/z 309 (M+H) ⁺ .

Example 170

2-(2-Benzothiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 72%; LCMS (API-electrospray) m/z 325 (M+H) ⁺ .

Example 171

2-(2-Pyridine-2-sulfanyl)-octanoic acid hydroxyamide. 76% at 215 nm; LCMS (API-electrospray) m/z 269 (M+H) ⁺ .

Example 172

2-(4-Phenyl-thiazole-2-sulfanyl)-octanoic acid hydroxyamide. 97% at 215 nm; LCMS (API-electrospray) m/z 336 (M+H) ⁺ .

Example 173

2-(2-Pyridin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide. 84% at 215 nm; LCMS (API-electrospray) m/z 297 (M+H) ⁺ .

Example 174

2-(2-Phenyl-5H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide. 67% at 215 nm; LCMS (API-electrospray) m/z 338 (M+H) ⁺ .

Example 175

2-(2-Pyrazin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide. 98% at 215 nm; LCMS (API-electrospray) m/z 298 (M+H) ⁺ .

Example 176

2-(1-Methyl-1H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide. 66% at 215 nm; LCMS (API-electrospray) m/z 274 (M+H) ⁺ .

Example 177

2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide. At 215nm, 81%.

Example 178

2-(2-Pyridine-2-sulfinyl)-octanoic acid hydroxyamide. At 215nm, 76%.

Example 179

2-(4-Phenyl-thiazole-2-sulfinyl)-octanoic acid hydroxyamide. At 215nm, 78%.

Example 180

2-(2-Pyrazin-2-yl-ethylsulfinyl)-octanoic acid hydroxyamide. 96% at 215 nm; LCMS (API-electrospray) m/z 314 (M+H) ⁺ .

Example 181

2-(3-Oxy-1H-benzothiazole-2-sulfonyl)-octanoic acid hydroxyamide. 63% at 215 nm; LCMS (API-electrospray) m/z 356 (M+H) ⁺ .

Example 182

2-(4-Phenyl-thiazole-2-sulfonyl)-octanoic acid hydroxyamide. At 215 nm, 70%; LCMS (API-electrospray) m/z 383 (M+H) ⁺ .

Example 183

2-[2-(1-Oxy-pyridin-2-yl)-ethanesulfonyl]-octanoic acid hydroxyamide. 77% at 215 nm; LCMS (API-electrospray) m/z 345 (M+H) ⁺ .

Example 184

3-(1-Hydroxycarbamoyl-heptanyl)-benzoic acid hydroxyamide. At 220 nm, 100%; LCMS (API-electrospray) m/z 312 (M+H) ⁺ .

Example 185

3-[4-(1-Hydroxyoxyformyl-heptylsulfanyl)-phenyl]-propionic acid hydroxyamide. 90% at 220 nm; LCMS (API-electrospray) m/z 340 (M+H) ⁺ .

Example 186

2-(Thiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. 75% at 215 nm; LCMS (API-electrospray) m/z 275 (M+H) ⁺ .

Example 187

2-(2,5-Dioxo-imidazolidin-4-ylmethylsulfanyl)-octanoic acid hydroxyamide. 98% at 215 nm; LCMS (API-electrospray) m/z 304 (M+H) ⁺ .

Example 188

3-(1-Hydroxycarbamoyl-heptylsulfinyl)-benzoic acid hydroxyamide. 84% at 220 nm; LCMS (API-electrospray) m/z 328 (M+H) ⁺ .

Example 189

3-[4-(1-Hydroxycarbamoyl-heptylsulfinyl)-phenyl]-propionic acid hydroxyamide. At 220 nm, 78%; LCMS (API-electrospray) m/z 356 (M+H) ⁺ .

Example 190

2-(Quinoline-8-sulfinyl)-octanoic acid hydroxyamide. 87% at 220 nm; LCMS (API-electrospray) m/z 335 (M+H) ⁺ .

Example 191

2-(Naphthalene-2-ylcarbamoylmethanesulfinyl)-octanoic acid hydroxyamide. 83% at 220 nm; LCMS (API-electrospray) m/z 391 (M+H) ⁺ .

Example 192

3-(1-Hydroxycarbamoyl-heptylsulfonyl)-benzoic acid hydroxyamide. At 215nm, 72%.

Example 193

3-[4-(1-Hydroxycarbamoyl-heptylsulfonyl)-phenyl]-propionic acid hydroxyamide. At 215nm, 67%.

Example 194

2-(1H-Imidazole-2-sulfonyl)-octanoic acid hydroxyamide. 95% at 215 nm; LCMS (API-electrospray) m/z 290 (M+H) ⁺ .

Example 195

2-(Thiazol-2-ylsulfonyl)-octanoic acid hydroxyamide. At 215 nm, 91 %; LCMS (API-electrospray) m/z 307 (M+H) ⁺ .

Example 196

2-(Quinoline-8-sulfonyl)-octanoic acid hydroxyamide. 94% at 220 nm; LCMS (API-electrospray) m/z 351 (M+H) ⁺ .

Example 197

2-(Naphthalen-2-ylcarbamoylmethylsulfonyl)-octanoic acid hydroxyamide. At 220 nm, 79%; LCMS (API-electrospray) m/z 407 (M+H) ⁺ .

Example 198

2-(2,5-Dioxo-imidazolidin-4-ylmethylsulfonyl)-octanoic acid hydroxyamide. At 215nm, 97%.

Example 199

Step A: Displacement of bromine with 4-fluorothiophenol

The 2-bromohydroxamate resin prepared in step A of Example 160 (9.4 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (50 ml). Add 4-fluorothiophenol (6.6g, 5.0eq.), sodium iodide (7.7g, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU , 4.6ml, 3.0eq.). The reaction was shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2x30ml), DMF:water 9:1 (2x30ml), DMF (30ml), MeOH (2x20ml) and DCM (2 x 20ml) wash. The resin was dried under vacuum at room temperature.

Step B: Coupling of 2-(4-fluorophenylsulfanyl)-octanoic acid hydroxyamide resin with benzyl alcohol

The 2-(4-fluorophenylsulfanyl)-octanoic acid hydroxyamide resin (330mg, 1.1meq/g) prepared in step A was suspended in dimethylformamide (2.0ml), and benzyl alcohol (731mg, 15eq. ) and sodium hydride (237mg, 15eq.). The reaction was heated to 80°C for 15 hours while shaking on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x3ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 2-(4-benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin (110 mg, 1.1 meq/g) prepared in step B was suspended in DCM (2.2 ml), and 70% tert-butyl hydroperoxide was added base (0.73ml) and benzenesulfonic acid (36mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin prepared in step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 ml) and mCPBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x2ml), DMF (2x2ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(4-benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide from the resin

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin prepared in step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 ml) and TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in dimethylsulfoxide:methanol (1:1, 2ml) and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20mm×50mm, 5μm particle size (YMC, Inc.Wilmington, North Carolina)

Solvent Gradient Time Water Acetonitrile

0.0 95 5

                                                                                                                                                  

Flow rate: 15ml/min.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 100%; LCMS (API-electrospray) m/z 374 (M+H) ⁺ .

Using appropriate starting materials and following the procedure described in Example 199, the hydroxamic acid compounds of Examples 200-220 were synthesized.

Example 200

2-(4-Butoxy-phenylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 100%; LCMS (API-electrospray) m/z 374 (M+H) ⁺ .

Example 201

2-[4-(2-Piperazin-1-yl-ethoxy)-phenylsulfanyl]-octanoic acid hydroxyamide. 98% at 215 nm; LCMS (API-electrospray) m/z 370 (M+H) ⁺ .

Example 202

2-[4-(5-Hydroxy-pentyloxy)-phenylsulfanyl]-octanoic acid hydroxyamide. 65% at 215 nm; LCMS (API-electrospray) m/z 370 (M+H) ⁺ .

Example 203

2-[4-(3-Pyridin-2-yl-propoxy)-phenylsulfanyl]-octanoic acid hydroxyamide. 95% at 215 nm; LCMS (API-electrospray) m/z 403 (M+H) ⁺ .

Example 204

2-(4-Benzyloxy-phenylsulfinyl)-octanoic acid hydroxyamide. At 215nm, 100%.

Example 205

2-(4-Butoxy-phenylsulfinyl)-octanoic acid hydroxyamide. At 215nm, 98%.

Example 206

2-[4-(2-Piperazin-1-yl-ethoxy)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215nm, 98%.

Example 207

2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215nm, 99%.

Example 208

2-(4-Benzyloxy-benzenesulfonyl)-octanoic acid hydroxyamide. At 215nm, 100%.

Example 209

2-(4-Butoxy-benzenesulfonyl)-octanoic acid hydroxyamide. At 215nm, 100%.

Example 210

2-[4-(2-Piperazin-1-yl-ethoxy)-benzenesulfonyl]-octanoic acid hydroxyamide. At 215nm, 97%.

Example 211

2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide. At 215nm, 100%.

Example 212

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-phenylsulfanyl]-octanoic acid hydroxyamide. 91% at 215 nm; LCMS (API-electrospray) m/z 367 (M+H) ⁺ .

Example 213

2-[4-(1-Ethyl-propoxy)-phenylsulfanyl]-octanoic acid hydroxyamide. At 215 nm, 100%; LCMS (API-electrospray) m/z 354 (M+H) ⁺ .

Example 214

2-[4-(Tetrahydro-pyran-4-yloxy)-sulfanyl]-octanoic acid hydroxyamide. 97% at 215 nm; LCMS (API-electrospray) m/z 368 (M+H) ⁺ .

Example 215

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215nm, 96%.

Example 216

2-[4-(1-Ethyl-propoxy)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215nm, 97%.

Example 217

2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215nm, 97%.

Example 218

2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]-octanoic acid hydroxyamide. At 215nm, 96%.

Example 219

2-[4-(1-Ethyl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide. At 215nm, 100%.

Example 220

2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfonyl]-octanoic acid hydroxyamide. At 215nm, 100%.

Example 221

Step A: Displacement of bromine with 4-bromothiophenol

The 2-bromo-octanoic acid hydroxamate resin prepared in step A of Example 160 (5.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (60 ml). Add 4-bromothiophenol (5.2g, 5.0eq.), sodium iodide (4.1g, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU , 2.5ml, 3.0eq.). The reaction was shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2x30ml), DMF:water 9:1 (2x30ml), DMF (30ml), MeOH (2x20ml) and DCM (2 x 20ml) wash. The resin was dried under vacuum at room temperature.

Step B: Oxidation of sulfide to sulfoxide

The 2-(4-bromophenylsulfanyl)-octanoic acid hydroxyamide resin (4.4g, 1.1meq/g) prepared in step A was suspended in DCM (60ml), and 70% tert-butyl hydroperoxide (30ml ) and benzenesulfonic acid (1.5 g). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x30ml), DMF (2x30ml), MeOH (2x30ml) and DCM (2x30ml). The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfone

2-(4-Bromophenylsulfanyl)-octanoic acid hydroxyamide resin (4.4 g, 1.1 meq/g) prepared in step B was suspended in DCM (60 ml), and mCPBA (5.2 g) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x30ml), DMF (2x30ml), MeOH (2x30ml) and DCM (2x30ml). The resin was dried under vacuum at room temperature.

Step D: Coupling of 2-(4-bromophenylsulfinyl)-octanoic acid hydroxyamide resin with 4-chlorophenylboronic acid

The 2-(4-bromobenzenesulfinyl)-octanoic acid hydroxyamide resin (150mg, 1.1meq/g) prepared in step B was suspended in dimethylformamide (2.0ml), and blown into the suspension Nitrogen for 1-2 minutes. 4-Chlorophenylboronic acid (51.6mg, 2eq.), tetrakis(triphenylphosphine)palladium(0) (19.07mg, 0.1eq.) and sodium carbonate (2M solution, 0.825ml, 10eq.) were added. The reaction was heated to 80°C for 8 hours while shaking on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x3ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of 2-(4'-chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide from the resin

The 2-(4'-chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide resin (150mg, 1.1meq/g) prepared in step D was suspended in DCM (1.0ml), and TFA (1.0 ml). The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in dimethylsulfoxide:methanol (1:1, 2ml) and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20mm×50mm, 5μm particle size (YMC, Inc.Wilmington, North Carolina)

Solvent Gradient Time Water Acetonitrile

0.0 95 5

                                                                                                                                                                              , 

Flow rate: 15ml/min.

2-(4'-Chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide. 96% at 215 nm; LCMS (API-electrospray) m/z 394 (M+H) ⁺ .

Using appropriate starting materials and following the procedure described in Example 221, the hydroxamic acid compounds of Examples 222-224 were synthesized.

Example 222

2-[4-(5-Chloro-phenylthio-2-yl)-benzenesulfinyl]-octanoic acid hydroxyamide. At 215 nm, 100%; LCMS (API-electrospray) m/z 400 (M+H) ⁺ .

Example 223

2-(4'-Chloro-biphenyl-4-sulfonyl)-octanoic acid hydroxyamide. 94% at 215 nm; LCMS (API-electrospray) m/z 410 (M+H) ⁺ .

Example 224

2-[4-(5-Chloro-phenylthio-2-yl)-benzenesulfonyl]-octanoic acid hydroxyamide. 85% at 215 nm; LCMS (API-electrospray) m/z 416 (M+H) ⁺ .

Example 225

Step A: Coupling of 2-(4-bromophenylsulfanyl)-octanoic acid hydroxyamide resin with N-(3-aminopropyl)-morpholine

The 2-(4-bromophenylsulfanyl)-octanoic acid hydroxyamide resin (100mg, 1.1meq/g) prepared in step A of Example 199 was suspended in dioxane (2.0ml), and added to the suspension Nitrogen was blown in for 1-2 minutes. Add N-(3-aminopropyl)-morpholine (346mg, 20eq.), tris(dibenzylideneacetone)-dipalladium(0) (22mg, 0.2eq.), (S)-(-)- 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((S)-BINAP, 60 mg, 0.8 eq.) and sodium tert-butoxide (207 mg, 18 eq.). The reaction was heated to 80°C for 8 hours while shaking on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with DMF (2x2ml), DMF:water 9:1 (2x3ml), MeOH (2x2ml) and DCM (2x2ml). The resin was dried under vacuum at room temperature.

Step B: Cleavage of 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide from the resin

2-[4-(3-Morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide resin (100 mg, 1.1 meq/g) prepared in step A was suspended in DCM (1.0 ml) , TFA (1.0 ml) was added. The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in dimethylsulfoxide:methanol (1:1, 2ml) and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20mm×50mm, 5μm particle size (YMC, Inc.Wilmington, North Carolina)

Solvent Gradient Time Water Acetonitrile

0.0 95 5

                                                                                                                 

Flow rate: 15ml/min.

2-[4-(3-Morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide. 88% at 215 nm; LCMS (API-electrospray) m/z 410 (M+H) ⁺ .

Using appropriate starting materials and following the procedure of this example, the hydroxamic acid compounds of Examples 226-231 were synthesized.

Example 226

2-[4-(Biphenyl-4-ylamino)-phenylsulfanyl]-octanoic acid hydroxyamide. 95% at 215 nm; LCMS (API-electrospray) m/z 435 (M+H) ⁺ .

Example 227

2-[4-(Pyridin-4-ylamino)-phenylsulfanyl]-octanoic acid hydroxyamide. 97% at 215 nm; LCMS (API-electrospray) m/z 360 (M+H) ⁺ .

Example 228

2-(4-Cyclopentylamino-phenylsulfanyl)-octanoic acid hydroxyamide. 77% at 215 nm; LCMS (API-electrospray) m/z 351 (M+H) ⁺ .

Example 229

2-(4-Methylamino-phenylsulfanyl)-octanoic acid hydroxyamide. 99% at 215 nm; LCMS (API-electrospray) m/z 297 (M+H) ⁺ .

Example 230

2-(4-Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide. At 215 nm, 72%; LCMS (API-electrospray) m/z 351 (M+H) ⁺ .

Example 231

2-(4-Piperazin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide. 74% at 215 nm; LCMS (API-electrospray) m/z 352 (M+H) ⁺ .

Example 232

Step A: Bromine Displacement with 4-Hydroxythiophenol

The 2-bromo-octanoic acid hydroxamate resin (15.0 g, 1.1 meq/g) prepared in step A of Example 160 was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (120 ml). Add 4-hydroxythiophenol (11.3g, 5.0eq.), sodium iodide (13.5g, 5.0eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 8.1ml, 3.0eq.). The reaction was shaken at room temperature for 12-16 hours, then filtered and washed with DMF (2x60ml), DMF:water 9:1 (2x60ml), DMF (60ml), MeOH (2x60ml) and DCM (2 x 60ml) wash. The resin was dried under vacuum at room temperature.

Step B: Coupling of 2-(4-hydroxyphenylsulfanyl)-octanoic acid hydroxyamide resin with benzenesulfonyl chloride

2-(4-Hydroxyphenylsulfanyl)-octanoic acid hydroxyamide resin prepared in step A (240 mg, 1.2 meq/g) was suspended in DCM (3.0 ml). Benzenesulfonyl chloride (225mg, 5eq.) and triethylamine (0.06ml, 2eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 8 h, then filtered and washed with DME (2 x 2 ml), DMF:water 9:1 (2 x 3 ml), MeOH (2 x 2 ml) and DCM (2 x 2 ml). ×2ml) for washing. The resin was dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin (80mg, 1.2meq/g) prepared in Step B was suspended in DCM (3ml), and 70% hydrogen peroxide was added tert-Butyl oxide (1ml) and benzenesulfonic acid (23mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x3ml), DMF (2x3ml), MeOH (2x3ml) and DCM (2x3ml). The resin was dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin (80mg, 1.2meq/g) prepared in step B was suspended in DCM (3ml), mCPBA (84mg) was added . The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2x3ml), DMF (2x3ml), MeOH (2x3ml) and DCM (2x3ml). The resin was dried under vacuum at room temperature.

Step E: Cleavage of benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin

Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin (80mg, 1.2meq/g) prepared in Step B was suspended in DCM (1.0ml), TFA (1.0 ml). The reaction was shaken at room temperature for 1 hour. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washings were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in dimethylsulfoxide:methanol (1:1, 2ml) and purified by reverse phase HPLC under the following conditions:

Column: ODS-A, 20mm×50mm, 5μm particle size (YMC, Inc.Wilmington, North Carolina)

Solvent Gradient Time Water Acetonitrile

0.0 95 5

                                                                                                                                           

Flow rate: 15ml/min.

4-(1-Hydroxycarbamoyl-heptylsulfanyl)-phenyl benzenesulfonate. 91% at 215 nm; LCMS (API-electrospray) m/z 424 (M+H) ⁺ .

Using appropriate starting materials and following the procedure described in Example 232, the hydroxamic acid compounds of Examples 233-240 were synthesized.

Example 233

2,5-Dichloro-thiophene-3-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide. 98% at 215 nm; LCMS (API-electrospray) m/z 498 (M+H) ⁺ .

Example 234

4-(1-Hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide of ethanesulfonic acid. At 215 nm, 72%; LCMS (API-electrospray) m/z 376 (M+H) ⁺ .

Example 235

5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide. 99% at 215 nm; LCMS (API-electrospray) m/z 492 (M+H) ⁺ .

Example 236

2,5-Dichloro-thiophene-3-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide. 96% at 215 nm; LCMS (API-electrospray) m/z 514 (M+H) ⁺ .

Example 237

5-Pyridin-2-yl-thiophene-2-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide. 96% at 215 nm; LCMS (API-electrospray) m/z 523 (M+H) ⁺ .

Example 238

2-Nitro-benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide. 97% at 215 nm; LCMS (API-electrospray) m/z 501 (M+H) ⁺ .

Example 239

3-Bromo-2-chloro-thiophene-2-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide. 97% at 215 nm; LCMS (API-electrospray) m/z 576 (M+H) ⁺ .

Example 240

Benzo[1,2,5]thiadiazole-4-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide. 83% at 215 nm; LCMS (API-electrospray) m/z 514 (M+H) ⁺ .

Example 241

1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

To a stirred solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 ml) in a round bottom flask was added α-bromoethyl ethyl acid ester (3.3 g, 20 mmol), the reaction mixture was heated under reflux for 8 hours with thorough stirring. The reaction mixture was then cooled, the potassium salt was filtered off, and the reaction mixture was concentrated. The residue was extracted with chloroform, washed with water and 0.5N NaOH solution. The organic layer was washed well with water, dried over magnesium sulfate, filtered and concentrated. (4-Methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as a light yellow oil. Yield 4.4g, 100%; MS: 227 (M+H).

To a stirred solution of (4-methoxy-phenylsulfanyl)-ethyl acetate (4.4 g, 20 mmol), anhydrous potassium carbonate (10 g, excess) in anhydrous acetone (100 mL) was added benzyl bromide ( 3.5g, 20mmol), reflux for 4 hours. The reaction mixture was then filtered, concentrated, and the residue was extracted with chloroform. Wash well with water, dry and concentrate. The crude product obtained was converted to ethyl (4-benzyloxy-benzenesulfonyl)-acetate by oxidation with m-chloroperbenzoic acid according to the method described in Example 83. Low melting solid. Yield 6.6 g, 97%; MS: 335 (M+1).

To stirred bis-(2-chloro-ethyl)-benzylamine hydrochloride (6.6 g, 24.7 mmol), 18-crown-6 (500 mg) and anhydrous potassium carbonate (30 g, excess ) in anhydrous acetone (250ml) was added (4-benzyloxy-benzenesulfonyl)-ethyl acetate (8.01g, 24mmol), and the reaction mixture was heated under reflux for 16 hours with thorough stirring. The reaction mixture was then cooled, the potassium salt was filtered off, and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water. The organic layer was washed well with water, dried over magnesium sulfate, filtered and concentrated. The dark brown reaction mixture was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes, to isolate the product 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl- Ethyl piperidine-4-carboxylate. Yield 6.5 g, 55%; MS: 494 (M+H).

Dissolve ethyl 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylate (5.0g, 10.1mmol) in methanol/tetrahydrofuran (1:1, 200ml) in Stir at room temperature for 72 hours. After this time the reaction mixture was concentrated and the product was dissolved in water (200ml) and neutralized with concentrated HCl. After neutralization the reaction mixture was concentrated to dryness. Ice-cold water (100ml) was added to the solid and filtered. The product 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid was dried at 50°C and used in the next step without further purification. Colorless solid. MP: 66-68°C; Yield 4.3g, 91%; MS: 466 (M+H). Using 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (4.65 g, 10.0 mmol) as starting material and following the procedure described in Example 83, 1.1 g was isolated as free 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide as a colored solid. Yield 21%; mp 89°C; MS: 481.1 ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.27(m, 3H), 2.76-2.79(m, 2H), 3.43(m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).

Example 242

4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy

                       

2 -[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine. Yield 5.5 g, 85%; brown semi-solid; MS: 323 (M+H) ⁺ .

According to the general procedure described in Example 83, 2-[(2-hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (3.22 g, 10 mmol ) as starting material to prepare bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine. Yield 4.0 g, 92%; brown semi-solid; MS: 361.1 (M+H) ⁺ .

According to the general procedure described in Example 83, ethyl 4-(butoxy-benzenesulfonyl)acetate (6.0 g, 20 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidine -1-yl-ethoxy)-benzyl]-amine (8.6g, 20mmol) as starting material for the preparation of 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidine- 1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester. Yield 8.0 g, 68%; brown oil; MS: 587.7 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy) dissolved in THF:methanol 3:1 and 10N sodium hydroxide (40ml) Base)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8g, 10mmol) as starting material for the preparation of 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidine- 1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.8 g, 86%; spongy brown solid; mp 98°C, MS: 559.6 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid (5.5g, 10mmol ) as starting material and according to the method described in Example 83, 2.4 g of 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl- Ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide. Yield 41%; mp 155°C (HCl); MS: 574 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9(t, 3H), 1.1-1.8(m, 6H ), 1.9.(m, 4H), 2.3(m, 4H), 2.8(m, 6H), 3.2-3.6(m, 8H), 4.2(m, 2H), 6.9-7.8(m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

Example 243

4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy

                       

According to the general procedure described in Example 83, using diethanolamine (15.0 g, 150 g) and 3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol) as starting materials, bis(R) -(2-Hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine. Yield 6.2 g, 95%; brown semi-solid; MS: 325 (M+H) ⁺ .

Following the general procedure described in Example 83 using bis-(2-hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine (3.24 g, 10 mmol) As starting material, bis-(2-chloro-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine was prepared. Yield 4.0 g, 92%; brown semi-solid; MS: 363.1 (M+H) ⁺ .

According to the general procedure described in Example 83, 4-(butoxy-benzenesulfonyl)-ethyl acetate (6.0 g, 20 mmol) and bis-(2-chloro-ethyl)-[3-(2-mol) Starting from olin-1-yl-ethoxy)-benzyl]-amine (8.6 g, 20 mmol), preparation of 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine -1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester. Yield 8.5 g, 72%; brown oil; MS: 589.7 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy) dissolved in THF:methanol 3:1 and 10N sodium hydroxide (40ml) Base)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8g, 10mmol) as starting material for the preparation of 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine- 1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.8 g, 85%; spongy brown solid; mp 98°C, MS: 561.6 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid (5.6g, 10mmol ) as starting material and according to the method described in Example 83, 4.02 g of 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholin-1-yl- Ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide. Yield 62%; mp 123°C; MS: 576(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9(t, 3H), 1.4(m, 2H), 1.8(t , 2H), 2.3-4.7 (m, 24H), 7.0-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).

Example 244

  1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(butoxy-benzenesulfonyl)acetate (3 g, 10 mmol) and methyl-bis-(2-chloro-ethyl)-amine (2.2 g, 11.6 mmol) as starting material to prepare ethyl 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate. Yield 4.0 g, 98%; brown solid with low melting point; MS: 384 (M+H) ⁺ .

Using ethyl 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate (7.6 g, 20 mmol) dissolved in methanol (300 ml) and 10 N sodium hydroxide (35 ml) As starting material, 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared. The resulting reaction mixture was worked up as described in Example 83. Yield 6.0 g, 84%; white solid; mp 195°C, MS: 356.4 (M+H) ⁺ .

Using 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (4.0 g, 11.2 mmol) as starting material and following the procedure described in Example 83, isolated 3.9 g as yellow Powdered 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 85%; mp 118°C; MS: 371(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9(t, 3H), 1.45(q, 2H), 1.8(q , 2H), 2.1(s, 3H), 2.3(d, J=11.4Hz, 2H), 2.5-3.7(m, 8H), 4.1(t, 2H), 7.16(d, 2H), 7.67(d, 2H).

Example 245

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(butoxy-benzenesulfonyl)acetate (3 g, 10 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.2 g, 10.6 mmol) as starting material to prepare ethyl 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate. Yield 3.5g, 88%; brown solid with low melting point; MS: 398 (M+H) ⁺ .

1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.94g, 20mmol) dissolved in methanol (300ml) and 10N sodium hydroxide (35ml) As starting material, 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared. The resulting reaction mixture was worked up as described in Example 83. Yield 6.5 g, 88%; white solid; mp 162°C, MS: 370 (M+H) ⁺ .

Using 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.7 g, 10 mmol) as starting material and following the procedure described in Example 83, 3.2 g were isolated as a yellow powder 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 76%; mp 98°C; MS: 385(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9(t, 3H), 1.2(t, 3H), 1.46(q , 2H), 1.9(q, 2H), 2.3(d, J=11.4Hz, 2H), 2.5-3.6(m, 10H), 4.1(t, 2H), 7.16(d, 2H), 7.67(d, 2H).

Example 246

1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(butoxy-benzenesulfonyl)acetate (3 g, 10 mmol) and n-butyl-bis-(2-chloro-ethyl)-amine (2.0 g, 10.1 mmol) as starting material to prepare ethyl 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate. Yield 3.8g, 89%; brown solid with low melting point; MS: 426 (M+H) ⁺ .

Using ethyl 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylate (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 N sodium hydroxide (35 ml) ) as starting material to prepare 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 7.5 g, 88%; white solid; mp 182°C, MS: 398 (M+H) ⁺ .

Using 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.9 g, 10 mmol) as starting material and following the procedure described in Example 83, 1.8 g was isolated as yellow Powdered 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide. Yield 40%; mp 121°C; MS: 413(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.9-1.0(m, 6H), 1.2-1.8(m, 8H), 2.2-2.8(m, 8H), 3.0-3.6(m, 4H), 4.2(t, 2H), 7.16(d, 2H), 7.67(d, 2H), 9.3(bs, 1H), 10.3(bs, 1H), 11.1 (bs, 1H).

Example 247

     [4-(4-Chloro-phenoxy)-phenylsulfanyl]-ethyl acetate

4-Bromochlorobenzene (1.92g, 10mmol), (4-hydroxy-phenylsulfanyl)-ethyl acetate (2.12g, 10mmol), sodium hydride (460mg, 10mmol) and copper(II) chloride ) (500mg) in anhydrous pyridine (50ml) was refluxed for 12 hours. The above reaction mixture was carefully quenched with ice-cold water and acidified with concentrated hydrochloric acid. The product was extracted with chloroform, washed well with water, dried and concentrated. The product was purified by silica gel column chromatography, eluting with 30% ethyl acetate: hexanes. Yield 2.5 g (77%); colorless low melting solid; MS: 323 (M+H) ⁺ . The title compound was also prepared as described in Example 83 using 4-(4-chloro-phenoxy)-benzenethiol and ethyl bromoacetate.

Example 248

     [4-(4-Chloro-phenoxy)-benzenesulfonyl]-ethyl acetate

According to the general procedure described in Example 83, using [4-(4-chloro-phenoxy)-phenylsulfanyl]-ethyl acetate (3.23 g, 10 mmol) and potassium persulfate (10 g) was Starting material, Preparation of [4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester. Yield 3.5 g, 99%; oil; MS: 356EI(M+H) ⁺ .

Example 249

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid hydroxyamide

According to the general method described in Example 83, using [4-(4-chloro-phenoxy)-benzenesulfonyl]-ethyl acetate (2.0 g, 5.6 mmol) and nitrogen mustard hydrochloride (Aldrich) (1.9 g, 10 mmol) ) as starting material to prepare ethyl [4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylate. Yield 2g, 81%; brown oil; MS: 438 (M+H) ⁺ .

[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4- Ethyl formate (4.3 g, 10 mmol) was used as starting material to prepare 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3.5g, 86%; white solid; mp 185°C, MS: 410 (M+H) ⁺ .

Starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid (1.0 g, 2.4 mmol) and following the procedure described in Example 83, 460 mg of 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt, white powder. Yield 41%; mp 52°C; MS: 426(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.3(s, 3H), 2.2-2.9(m, 6H), 3.5 (bd, 2H), 7.2-7.9 (m, 8H), 8.1 (s, 1H), 11.0 (bs, 1H).

Example 250

4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-ethyl-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(4-chloro-phenoxy)-benzenesulfonyl]-ethyl acetate (4 g, 11.3 mmol) and ethyl-bis-(2-chloro-ethyl )-amine (2.32 g, 16.9 mmol) was used as starting material to prepare ethyl 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylate. Yield 3.36g, 66%; brown oil; MS: 452.0 (M+H) ⁺ .

Using 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine- Ethyl 4-carboxylate (3.02 g, 6.7 mmol) was used as starting material to prepare 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 185g, 65%; white solid; mp 184°C, MS: 423.9 (M+H) ⁺ .

Starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid (1.75 g, 4.14 mmol) and following the procedure described in Example 83, 650 mg of 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt, white powder. Yield 33%; mp 158°C; MS: 438.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.78(t, J=7.23Hz, 3H), 2.23-2.27(m , 2H), 2.51-2.73(m, 4H), 3.04(m, 2H), 3.81(d, J=24Hz, 2H), 7.16-7.27(m, 4H), 7.50-7.57(m, 2H), 7.76 (d, J=7Hz, 2H), 9.34(s, 1H), 9.85(s, 1H).

Example 251

1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(4-chloro-phenoxy)-benzenesulfonyl]-ethyl acetate (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl )-amine (5.2 g, 22 mmol) was used as starting material to prepare ethyl 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylate. Yield 3.3g, 38%; yellow oil; MS: 480 (M+H) ⁺ .

Using 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine dissolved in THF: methanol (3:1 150ml) and 10N sodium hydroxide (25ml) Ethyl 4-carboxylate (3.3 g, 6.9 mmol) was used as starting material to prepare 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 2.08g, 67%; white solid; mp 201°C, MS: 451.9 (M+H) ⁺ .

Starting from 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (2 g, 4.43 mmol) and according to the method described in Example 83, isolated This gave 630 mg of 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide as the hydrochloride salt, a white solid. Yield 31%; mp 212°C; MS: 466.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.87(t, J=7.3Hz, 3H), 1.32(m, 2H ), 1.60(m, 2H), 2.21(m, 2H), 2.50(m, 2H), 2.70(q, 2H), 3.00(m, 2H), 3.57(d, 2H), 7.16-7.26(m, 4H), 7.49-7.56 (m, 2H), 7.77 (d, J=9Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).

Example 252

1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 16.9 mmol) and bis-(2-chloro-ethyl)-benzyl 1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared from phenylamine (6.44 g, 24 mmol). Yield 2.21 g, 25%; yellow oil; MS: 513.9 (M+H) ⁺ .

Using 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine- Ethyl 4-carboxylate (2.11 g, 4.1 mmol) was used as starting material to prepare 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.11 g, 56%; white solid; mp 201 °C, MS: 485.9 (M+H) ⁺ .

Using 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (1 g, 2.06 mmol) as starting material and according to the method described in Example 83, isolated This gave 430 mg of 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide as the hydrochloride salt as an off-white solid. Yield 39%; mp 90.4°C; MS: 500.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.18-2.30(m, 2H), 2.73-2.81(m, 4H) , 3.36(d, 2H), 4.28(d, J=4.5Hz, 2H), 7.15-7.25(m, 4H), 7.43-7.48(m, 3H), 7.51-7.56(m, 4H), 7.74(d , J=9Hz, 2H), 9.53(s, 1H), 10.47(s, 1H).

Example 253

    [4-(3-Methyl-butoxy)-phenylsulfanyl]-ethyl acetate

To a stirred solution of (4-hydroxy-phenylsulfanyl)-ethyl acetate (2.12 g, 10 mmol), potassium carbonate (anhydrous, 10 g) and 1-bromo-3-methylbutane (3 g, excess) Add boiling acetone. The above reaction mixture was refluxed for 24 hours and cooled to room temperature. The reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform; washed well with water and concentrated. The obtained crude product was used in the next reaction without purification. Yield 2.7 g (94%); MS: (M+H) ⁺²⁸³ .

Example 254

     [4-(3-Methyl-butoxy)-benzenesulfonyl]-ethyl acetate

According to the general procedure described in Example 83, using [4-(3-methyl-butoxy)-phenylsulfanyl]-ethyl acetate (2.8 g, 10 mmol) and potassium persulfate formulation (10 g) Starting material, [4-(3-Methyl-butoxy)-benzenesulfonyl]-acetic acid ethyl ester was prepared. Yield 3.0 g, 99%; oil; MS: 314EI(M+H) ⁺ .

Example 255

1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(3-methyl-butoxy)-benzenesulfonyl]-ethyl acetate (6.2 g, 20 mmol) and bis-(2-chloro-ethyl)- Benzylamine (6.44 g, 24 mmol) was used as starting material to prepare ethyl 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylate. Yield 8g, 84%; yellow oil; MS: 474 (M+H) ⁺ .

Using 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (20ml) -Ethyl 4-carboxylate (4.7 g, 10 mmol) was used as starting material for the preparation of 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3g, 67%; white solid; mp 182°C, MS: 446 (M+H) ⁺ .

Starting from 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (2.2 g, 5 mmol) and following the procedure described in Example 83, 1.82 g of 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt as an off-white solid. Yield 73%; mp 106 °C; MS: 498 (M+H) ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ0.8 (d, 6H), 1.5 (m, 1H), 1.6-2.0 (m; 6H), 2.73-2.81(m, 4H), 3.5(d, 2H), 4.28(d, J=4.5Hz, 2H), 7.15-7.25(m, 4H), 7.43-7.48(m, 3H ), 7.51-7.56 (m, 4H), 7.74 (d, J=9Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).

Example 256

1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(3-methyl-butoxy)-benzenesulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared using (5.2 g, 22 mmol) as starting material. Yield 7g, 79%; yellow oil; MS: 440 (M+H) ⁺ .

Using 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (20ml) - Ethyl 4-carboxylate (4.4 g, 10 mmol) was used as starting material to prepare 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 3.2g, 77%; white solid; mp 188°C, MS: 412 (M+H) ⁺ .

Starting from 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (2.0 g, 5 mmol) and following the procedure described in Example 83, 1.6 g of 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt as an off-white solid. Yield 69%; mp 201°C; MS: 464 (M+H) ⁺ .

Example 257

     [4-(2-Ethyl-butoxy)-phenylsulfanyl]-ethyl acetate

To a stirred solution of (4-hydroxy-phenylsulfanyl)-ethyl acetate (2.12 g, 10 mmol), potassium carbonate (anhydrous, 10 g) and 1-bromo-2-ethylbutane (3 g, excess) Add boiling acetone. The above reaction mixture was refluxed for 24 hours and cooled to room temperature. The reaction mixture was filtered and concentrated. The resulting residue was extracted with chloroform; washed well with water and concentrated. The obtained crude product was used in the next reaction without purification. Yield 2.8 g (94%); MS: (M+H) ⁺²⁹⁷ .

Example 258

    [4-(2-Ethyl-butoxy)-benzenesulfonyl]-ethyl acetate

According to the general procedure described in Example 83, using [4-(2-ethyl-butoxy)-phenylsulfanyl]-ethyl acetate (2.96 g, 10 mmol) and potassium persulfate formulation (10 g) Starting material, [4-(2-Ethyl-butoxy)-benzenesulfonyl]-acetic acid ethyl ester was prepared. Yield 3.1 g, 99%; oil; MS: 329EI(M+H) ⁺ .

Example 259

1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [4-(2-ethyl-butoxy)-benzenesulfonyl]-ethyl acetate (6.4 g, 20 mmol) and bis-(2-chloro-ethyl)- Benzylamine (6.44 g, 24 mmol) was used as starting material to prepare ethyl 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylate. Yield 8g, 82%; yellow oil; MS: 488 (M+H) ⁺ .

Using 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (20ml) -Ethyl 4-carboxylate (4.8 g, 10 mmol) was used as starting material to prepare 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4g, 87%; semi-solid; MS: 460 (M+H) ⁺ .

Starting from 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (2.2 g, 5 mmol) and following the procedure described in Example 83, 1.02 g of 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt as an off-white solid. Yield 40%; mp 114°C; MS: 512 (M+H) ⁺ .

Example 260

4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using ethyl 4-(4-butoxy-benzenesulfonyl)-acetate (20 g, 77.5 mmol) and bis-(2-chloro-ethyl)-(3-methoxy 4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester. Yield 9.53g, 25%; brown oil; MS: 490.2 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperide dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (15ml) Ethyl pyridine-4-carboxylate (2.61 g, 5.34 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4- formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1 g, 41%; brown solid; mp 175°C; MS: 462.0 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid (900 mg, 1.95 mmol) as starting material and following the procedure described in Example 83 , 200 mg of 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide were isolated as hydrochloride salt, brown powder. Yield 20%; mp 137°C; MS: 477.0 (M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ0.96 (t, J=7.11Hz, 3H), 1.48 (m, 2H) , 1.73(m, 2H), 2.27(m, 2H), 2.47(m, 2H), 2.78(m, 2H), 3.35(m, 2H), 3.77(s, 2H), 4.08(t, J=6.3 Hz, 3H), 4.32(s, 2H), 7.03(t, 2H), 7.15(m, 3H), 7.36(t, J=7.8Hz, 1H), 7.64(d, J=9Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).

Example 261

4-(4-Methoxy-benzenesulfonyl)-1-(4-phenylthio-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide

In the presence of tetrapalladium(0), ethyl 1-(4-bromo-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylate (3 g, 6.05mmol) and 2-(tributylstannyl)-thiophene (6.8g, 18.14mmol) as starting materials; preparation of 4-(4-methoxy-benzenesulfonyl)-1-(4-phenylthio-2- Base-benzyl)-piperidine-4-carboxylic acid ethyl ester. Yield 1.58g, 52%; brown solid; mp 130°C; MS: 500 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(4-phenylthio-2-yl-benzyl) dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (20ml) )-piperidine-4-carboxylic acid ethyl ester (1.3g, 2.61mmol) as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(4-phenylthio-2-yl-benzyl) -piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 950 mg, 77%; brown solid; mp 235°C, MS: 471.8 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(4-phenylthio-2-yl-benzyl)-piperidine-4-carboxylic acid (920 mg, 1.95 mmol) as starting material and according to Example 83 The method described, isolated 510 mg of 4-(4-methoxy-benzenesulfonyl)-1-(4-phenylthio-2-yl-benzyl)-piperidine-4- Formic acid hydroxyamide. Yield 50%; mp 166°C; MS: 486.9 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.12-2.21 (m, 2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39(m, 2H), 3.87(s, 3H), 4.29(d, 2H), 7.17(m, 3H), 7.54-7.75(m, 8H), 9.36(s, 1H), 10.07(s, 1H).

Example 262

4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 261, ethyl 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylate (4.65 g, 9.38 mmol ) and 2-(tributylstannyl)-pyridine (12.08g, 32.8mmol) as starting materials for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl base)-piperidine-4-carboxylic acid ethyl ester. Yield 2.79g, 60%; brown oil; MS: 495.1 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl) dissolved in THF:methanol (3:1 150ml) and 10N sodium hydroxide (10ml) -Ethyl piperidine-4-carboxylate (1.83g, 3.7mmol) as starting material for the preparation of 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine pyridine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.38g, 80%; off-white solid; mp 217°C, MS: 466.9 (M+H) ⁺ .

Using 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) as starting material and according to Example 83 According to the method, 480 mg of 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid was isolated as hydrochloride salt and white powder Hydroxyamide. Yield 33%; mp 214°C; MS: 482.0(M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): δ2.30(m, 2H), 2.80(m, 2H), 3.42(d, J=12.5Hz, 2H), 3.75(m, 2H); 3.88(s, 3H), 4.36(s, 2H), 7.15(d, J=8.9Hz, 2H), 7.59-7.74(m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J=8.1Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H).

Example 263

1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide

Following the general procedure described in Example 83, ethyl 4-(4-butoxy-benzenesulfonyl)-1-(3,4-dichlorobenzyl)-piperidine-4-carboxylate was prepared. Using ethyl (4-butoxy-benzenesulfonyl)acetate (13.2g, 44mmol) and (3,4-dichlorobenzyl)-bis-(2-chloro-ethyl)-amine (14.3g, mmol ) as a raw material. Yield 14.1 g, 60%; white solid, MP 86°C; MS: 527.9 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperide dissolved in THF:methanol (100:50ml) and 10N sodium hydroxide (20ml) Pyridine-4-carboxylic acid ethyl ester (14.0 g, 26.5 mmol) was used as starting material to prepare 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4- formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 7.87g, 60%; off-white solid; mp 239°C, MS: 501.9 (M+H) ⁺ .

Starting from 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (7.7 g, 15.5 mmol) and as described in Example 83 method, isolated 4.05 g of 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide as hydrochloride salt, white solid. Yield 48%; mp 256.8°C; MS: 514.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.94(t, 3H), 1.38-1.48(q, 2H), 1.68 -1.75(q, 2H), 2.27(m, 4H), 2.72(m, 2H), 4.10(t, 2h), 4.24(s, 2H), 7.12-7.15(d, J=8.9, 2H), 7.51 -7.53(d, J=8.1, 1H), 7.63-7.65(d, J=8.8, 2H), 7.72-7.75(d, J=9.9, 2H), 7.87(s, 1H), 9.36(s, 1H ), 10.5(s, 1H), 11.2(s, 1H).

Example 264

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, ethyl [4-(4-chloro-benzyloxy)-benzenesulfonyl]acetate (13.97 g, 37 mmol) and 4-(4-chloro-benzyloxy)-bis -(2-Chloro-ethyl)-amine (8.7 g, 45 mmol) as starting material for the preparation of [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester. Yield 10.9 g, 65%; brown oil; MS; 451.9 (M+H) ⁺ .

Ethyl [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylate dissolved in THF:methanol (75:75ml) and 10N sodium hydroxide (20ml) The ester (10.7 g, 24 mmol) was used as starting material to prepare [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.9 g, 50%; off-white solid; MS: 426.2 (M+H) ⁺ .

Starting from [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid (4.9 g, 12 mmol) and following the procedure described in Example 83, 1.2 g were isolated [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxyamide as hydrochloride salt, off-white solid. Yield 24%; mp 117.8°C; MS: 438.9(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ2.2(m, 2H), 2.49(m, 4H), 2.5(s , 3H), 2.6(m, 2H), 5.2(s, 2H), 7.25-7.23(d, t=8.7, 2H), 7.5(d, t=2.7, 4H), 7.68-7.71(d, t= 9.6, 2H), 9.33 (s, 1H), 10.11 (s, 1H).

Example 265

4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (10.1 g, 34 mmol) and 1-(3-phenoxy-benzyl)-bis-( 2-Chloro-ethyl)-amine (18 g, 50 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4- ethyl formate. Yield 8.9, 49%; brown oil; MS: 552.1 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine dissolved in THF:methanol (75:50ml) and 10N sodium hydroxide (20ml) - Ethyl 4-carboxylate (10.7 g, 24 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 5.0 g, 76%; off-white solid; MS: 524.3 (M+H) ⁺ .

Starting from 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid (5.9 g, 11 mmol) and following the procedure described in Example 83 , 0.39 g of 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as the hydrochloride salt as a brown solid. Yield 11%; mp 92.5°C; MS: 539.1 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.93-0.97 (t, J=3.6, 3H), 1.49 (m, 2H), 1.73(m, 2H), 2.51(m, 4H), 4.09(t, 2H), 4.29(bs, 2H), 7.06-7.10(d, J=12, 2H), 7.13-7.15(m, 3H), 7.39-7.42(d, 2H), 7.63-7.66(d, 2H), 9.50(s, 1H), 9.98(s, 1H).

Example 266

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using [1-(4-chloro-benzyloxy)-benzenesulfonyl]-ethyl acetate (5.47 g, 15 mmol) and 1-(4-methyl-benzyl)- Bis-(2-chloro-ethyl)-amine (5.23g, 18mmol) as starting material for the preparation of [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl) -Ethyl piperidine-4-carboxylate. Yield 8.0 g, 96%; brown oil; MS: 542.0 (M+H) ⁺ .

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)- Ethyl piperidine-4-carboxylate (7.9 g, 124 mmol) was used as starting material to prepare [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine- 4-Formic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 4.6 g, 61%; off-white solid, mp 204°C; MS: 514.2 (M+H) ⁺ .

[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid (4.2 g, 8 mol) was used as starting material and prepared according to Example 83 According to the method described, 1.3 g of [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was isolated as hydrochloride and yellow solid Hydroxyamide. Yield 24%; mp 172°C; MS: 528.9 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ

Example 267

4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (5.47 g, 15 mmol) and 1-(4-methyl-benzyl)-bis-(2 -Chloro-ethyl)-amine (15.3 g, 51 mmol) as starting material for the preparation of ethyl 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylate ester. Yield 10.1 g, 57%; white solid, MP 93°C; MS: 474.1 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4 dissolved in THF:methanol (50:50ml) and 10N sodium hydroxide (20ml) - Ethyl formate (10.0 g, 22 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 7.2 g, 72%; off-white solid, mp 244°C; MS: 446.3 (M+H) ⁺ .

Starting from 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid (6.6 g, 1.5 mmol) and following the procedure described in Example 83, 2.06 g of 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide were isolated as the hydrochloride salt, yellow solid. Yield 28%; mp 137°C; MS: 461.3 (M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ0.91-0.964 (t, J=7.3, 3H), 1.41 (m, 2H), 1.70(m, 4H), 1.79(t, s, 3H), 2.52(m, 2H), 2.76(m, 2H), 3.33(bd, 2H), 4.10(t, 2H), 4.22(d , 2H), 7.12-7.14 (d, J=8.7, 2H), 7.25-7.28 (d, J=8.1, 2H), 7.42-7.45 (d, J=7.8, 2H), 7.63-7.65 (d, J =8.7, 2H), 10.31 (s, 1H), 10.75 (bs, 1H).

Example 268

4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-hydroxyamide formic acid hydroxyamide

According to the general procedure described in Example 83, ethyl 4-(4-butoxy-benzenesulfonyl)acetate (5.29 g, 17.6 mmol) and 1-(4-cyano-benzyl)-bis-(2 -Chloro-ethyl)-amine (6.19 g, 21 mmol) as starting material for the preparation of 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester. Yield 6.8g, 80%; brown oil; MS: 485.0 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine- Ethyl 4-carboxylate (10.0 g, 124 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield. 7g, 11%; off-white solid; MS: 456.0 (M+H) ⁺ .

Starting from 4-(4-butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylic acid (.600 g, 1.2 mmol) and following the procedure described in Example 83, Isolated .21 g of 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxyamide as the hydrochloride salt as an off-white solid. Yield 34%; mp 241.6°C; MS: 472.0(M+H) ⁺ ; ¹ H NMR (300MHz, DMSO-d ₆ ): δ.915-.964(t, J=7.2, 3H), 1.51(q , 2H), 1.75(q, 2H), 2.27(m, 2H), 2.49(m, 4H), 4.11-4.19(t, 2H), 4.37(s, 1H), 7.12-7.15(d, J=8.7 , 2H), 7.63-7.66(d, J=9, 2H), 7.72-7.74(d, J=7.8, 2H), 9.36(s, 1H), 10.23(s, 1H), 11.16(s, 1H) .

Example 269

4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxyamide

According to the general procedure described in Example 83, using 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (6.0 g, 20.0 mmol) and pyridin-4-ylmethyl-bis-(2-chloro- Ethyl)-amine (4.89 g, 21 mmol) was used as starting material to prepare ethyl 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylate. Yield 4.5 g, 48%; brown oil; MS: 461.0 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4- Ethyl formate (3.0 g, 6.5 mmol) was used as starting material to prepare 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid. The resulting reaction mixture was worked up as described in Example 83. Yield 1.2 g, 42%; off-white solid; MS: 433.0 (M+H) ⁺ .

Using 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid (0.864 mg, 2.0 mmol) as starting material and according to the method described in Example 83, isolated This gave 600 mg of 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxyamide as the hydrochloride salt as an off-white solid. Yield 67%; mp 118°C; MS: 447.9(M+H) ⁺ ; ¹ HNMR (300MHz, DMSO-d ₆ ): d 0.94(t, 3H), 1.11(t, 1H), 1.23(t, 1H ), 1.44(m, 1H), 1.73(m, 1H), 2.34(m, 2H), 2.78(m, 2H), 3.10(m, 2H), 3.38(m, 2H), 4.08(t, 2H) , 4.42(br s, 2H), 7.13(d, 2H), 7.64(d, 2H), 7.94(d, 2H), 8.82(d, 2H), 11.2(nr s, 2H), 11.4(br s, 1H).

references:

1. Rickter, L.S.; Desai, M.C. Tetrahedron Letters, 1997, 38, 321-322.

The biological activity of the compounds of the present invention was tested according to the following methods.

In vitro gelatinase assay

The assay is based on the cleavage of a thiopeptide substrate ((Ac-Pro-Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt) from Bachem Bioscience) by gelatinase, whereby A substrate product that can react color with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)) is released. The enzyme activity is determined by the rate of color increase.

The thiopeptide substrate was freshly prepared as a 20 mM stock solution in 100% DMSO and DTNB was dissolved in 100% DMSO as a 100 mM stock solution and stored at room temperature in the dark. The substrate and DTNB were diluted to 1 mM with substrate buffer (50 mM HEPES, pH 7.5, 5 mM calcium chloride) before use. Human neutrophil gelatinase B was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM calcium chloride, 0.02% Brij) to a final concentration of 0.15 nM.

Assay buffer, enzyme, DTNB/substrate (500 μM final concentration) and vehicle or inhibitor were added to a 96-well plate (200 μl total reaction volume) and the color increase was monitored spectrophotometrically at 405 nm for 5 minutes on a plate reader.

The increase in _OD405 was plotted and the slope of the resulting line was calculated, the slope representing the reaction rate.

The reaction rate was confirmed to be linear (r ² >0.85). The mean (x±sem) of control rates was calculated and compared to drug-treated group rates for statistical significance (p<0.05) according to Dunnett's multiple comparison test. Dose-response relationships were obtained with multiple drug doses, and _IC50 values with 95% CI were estimated based on linear regression (IPRED, HTB).

References: Weingarten, H and Feder, J., "Spectrophotometric Assay for Vertebrate Collegenase", Anal. Biochem ., 147:437-440, (1985).

In vitro collagenase assay

The assay is based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH ₂ ) from Peptide International, Inc.) by collagenase, whereby Fluorescent NMa groups are generated which are quantified using a fluorometer. Dnp quenches the fluorescence of NMa in the intact substrate. The assay was performed in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM calcium ion, 0.02% Brij, 0.5% cysteine) containing recombinant human fibroblast collagenase (truncated, mw=18,828, WAR Radnor) in progress. The substrates were dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in 25 μm aliquots in buffer. For the assay, the substrate was dissolved in HCBC buffer to a final concentration of 10 μM and the final concentration of collagenase was 5 nM. Test compounds were dissolved in methanol, DMSO or HCBC. Methanol and DMSO were diluted to <1.0% with HCBC. The compounds are added to the 96-well plate containing the enzyme and the reaction is initiated by adding the substrate.

The reaction was read for 10 minutes (excitation at 340 nm, emission at 444 nm) and the increase in fluorescence over time was plotted as a line. Calculate the slope of this line representing the reaction rate.

The reaction rate was confirmed to be linear (r ² >0.85). The mean (x±sem) of control rates was calculated and compared to drug-treated group rates for statistical significance (p<0.05) according to Dunnett's multiple comparison test. Dose-response relationships were obtained with multiple drug doses, and _IC50 values with 95% CI were estimated based on linear regression (IPRED, HTB).

References: Bickett, DM et al. in "A High Throughput Fluorogenic Substrate for Interstitial Collagenase (MMP-1) and Gelatinase (MMP-9)", Anal. Biochem. 212:58-64, (1993).

Methods for Determining TACE Inhibition

A solution containing the following was added to each well of a 96-well black microtiter plate: 10 μl TACE (obtained from Immunex) (final concentration 1 μg/mL), 70 μl Tris buffer (pH 7.4 and containing 10 % glycerol) and 10 μl of the test compound in DMSO (final concentration 1 μM, DMSO concentration < 1%), and the plate was incubated at room temperature for 10 minutes. Fluorescent peptide substrate was added to each well (final concentration 100 [mu]M) while shaking on a shaker for 5 seconds to initiate the reaction.

The reaction was read for 10 minutes (excitation at 340nm, emission at 420nm) and the increase in fluorescence versus time was plotted as a line. Calculate the slope of this line representing the reaction rate.

The reaction rate was confirmed to be linear (r ² >0.85). The mean (x±sem) of control rates was calculated and compared to drug-treated group rates for statistical significance (p<0.05) according to Dunnett's multiple comparison test. Dose-response relationships were obtained with multiple drug doses, and _IC50 values with 95% CI were estimated based on linear regression.

The results obtained by these standard laboratory test methods are given in the table below.

IC50 (nM or % inhibition at 1 μM or 10 μM ( ^* ))

Example MMP1 MMP9 MMP13 TACE

1 NT 559.6 193.3 31.62%

2 NT 10.50% 0% 403

3 NT 308.9 169.4 27.43%

4 371 22.20% 17.10% 21%

5 NT 7.7 4.7 25%

6 267 21.4 15.6 40.43%

7 844 72.9 42.1 33%

8 NT 346 307.9 47%

9 313 107 NT 20.30%

10 8% 128 64 54.75%

11 18.80% 2925 319 942

12 100 10.8 11 15.50%

13 239 11 14 626

14 158 23 8 17.18%

15 285 17 4 137

16 325 9 24 180

17 238.6 8.9 1.4 41.00%

18 540 18.9 11.5 29.2%

19 446 95.8 4.8 33.1%

20 423 14.6 18.7 31%

21 318 13.2 15.3 39%

22 219 3.2 2.5 30%

23 593 7.9 4.0 40.6%

24 413 20.9 31.3 47.5

25 262 26.7 8.0 NT

26 304.6 6.3 3.2 34.6

27 629 106 30.1 NT

28 761 3.1 2.0 30.6%

29 297 4.3 3.6 41%

30 397 8.1 5.7 25.2%

31 162 15.2 5.7 688

32 13.7 3.7 1.0 NT

33 318 53.9 18.4 23.9%

34 519.8 34.7 26.1 28.1%

35 455.8 233.6 48.2 44.9

36 622 83.8 20.7 826

37 9% 31.6% 14.3% 87

38 48.3% 1.7% 5.8% 55.1%

39 29.4% 35.2% 26.6% 69.4

40 583 197 14 160

41 100 10.8 11 15.50%

42 262 50.9 6.2 36.5

43 66.1% 34.7% 55.5% 46.6%

44 47.1% 36.9% 39.5% 14.9%

Example MMP1 MMP9 MMP13 TACE

45 49% 48.6% 36.7% 20.4%

46 78.9% 79.12% 84.7% 1.4%

47 17.1% 12.9% 7.12% 3.3%

48 99.1% 79.1% 85.4% 51.1%

49 10.1% 23.7% 54.6% NT

50 51.1 58.4 10.6 NT

51 178.1 10.4 13.1 48.14%

52 139.3 7.9 9.1 NT

53 647.9 27.80% 188 52.57%

54 110 66 21 55.10%

55 303 10 7 21.70%

56 299 16 12 65%

57 258 332 191 16.57%

58 211 35 39 7.70%

59 30.20% 447 141 24.86%

60 NT 184 NT 23.60%

61 258 38 22 17.21%

62 522 174 43 669

63 156 9 3 203

64 40.90% 25.60% 36.70% 29.70%

65 1000 63 13 42.21%

66 1600 131 226 42.33%

67 364 2.3 43.7 690

68 297 29 27 522

69 574.5 120.2 90 41.32%

70 1139 88.80% 127 764

71 1000 63 13 42.21%

72 117 11 1 51.64%

73 300 141 12 20.17%

74 138.1 9.2 4.3 47.86%

75 672.3 83.4 32.7 23.77%

76 805 NT 500 NT

77 205.5 NT 170 NT

78 262 560 34 24.58%

79 25 0.54 0.4 805

80 22.1% 26% 63.6% 191

81a 2036 230.9 43.9 27.1

81b 3765 154 15.7 228

82 237.6 19.4 5.1 34.5%

83 492 10.2 2.0 229

84 519 8.8 2.0 213

85 450 5.8 1.5 115

86 494 16.8 1.5 222

87 368 5.0 1.6 170.7

88 1329 12.8 3.1 610

Example MMP1 MMP9 MMP13 TACE

89 1389 38.6 7.0 49%

90 598 10.3 2.2 71.9

91 1929 13.3 10.8 503

92 59.6% 649 148 9.7

93 56.3% 452 38 15.8%

94 2640 138 28.6 22.9

95 3681 364 33.1 25.4%

96 4437 374 33.8 18.1

97 5109 484 43.7 20.20%

98 2383 3.8 1.2 154

99 656 16.2 2.4 250

100 4729 19.1 5.3 39.5%

101 642 12.3 2.1 197

102 662 33.7 1.9 53%

103 1306 45.1 8.8 470

104 2610 3.1 1.4 208

105 1214 44.2 4.1 50.2%

106 3788 5.1 0.9 631

107 629 26.8 2.5 293

108 2896 5.4 1.7 270

109 393 2.7 2.5 386

241 48.2% ^* 2.7 15.8 277

242 1950 2 1.3 581

243 2181 1.9 1.5 506

244 3417 9.8 1.5 594

245 7062 43.4 2.2 51.95% ^*

246 50.30% ^* 28.3 2.4 880

249 1412 2 1.6 270

250 1717 1.6 0.8 413

251 1067 0.8 0.9 301

252 801 1.1 0.9 278

255 2558 3.6 1.5 565

256 10000 7.2 2.9 43.01% ^*

259 3160 14.3 5.3 39% ^*

260 1495 2.9 1.3 272

261 513 10.9 2.7 273

262 422 6.1 2.3 298

263 3669 20.3 5.2 57.70% ^*

264 4293 2.9 3.1 182

265 1944 9.3 7.8 1037

266 4746 6 5.7 421

267 3620 5.4 2.3 508

268 2292 2.8 1.1 278

269 2071 2.2 1.4 296

Compound Data Prepared by Solid Phase Synthesis: Examples 110-240

Example number MMP1 MMP9 MMP13 MMP13 TACE

At 0.2μM At 0.2μM At 1mM

% of Inhibition % of Inhibition % of Inhibition

(HTS) (manual)

110 75 17.6

111 10 40.4

112 50 33.7

113 0 13.1

114 0 0 0

115 0 0 0

116 0 9.1

117 7 8.1

118 24 16.7

119 0 7.8

120 31 19.9

121 0 6.1

122 0 3.1

123 0 2.5

124 0 0 0

125 5 2.3

126 25 10.4

127 47 29.2

128 1.9mM 213nM 91 255nM 19.31

129 90 32.77

130 28 27.9

131 71 20.73

132 71 20.76

133 53 22.04

134 25 25 -9.31

135 79 42.67

136 89 42.69

137 83 13.35

138 20 5.284

139 8 28.05

140 29 29 -4.22

141 32 11.76

142 69 54.27

143 53 43.9

144 38 19.7

145 45 2.5

146 68 7.317

147 73 11.95

148 15 43.46

149 13 4.408

150 54 1.818

151 6 5.927

152 9 10.03

153 12 11.8

154 89 13.14

155 31 18.62

156 23 23 -2.09

Example number MMP1 MMP9 MMP13 MMP13 TACE

At 0.2μM At 0.2μM At 1mM

% of Inhibition % of Inhibition % of Inhibition

(HTS) (manual)

157 19 13.7

158 33 33 -7.48

159 49 5.852

160 14 -3.57

161 0 12.7

162 13 0

163 84 9.515

164 74 62.69

165 71 73.7

166 9 4.16

167 27 8.961

168 21 3.688

Example serial number MMP13 MMP13 MMP13 TACE TACE

at 36nM at 0.36mM at 3.6mM IC ₅₀ nM at 1mM

Inhibition % Inhibition % Inhibition % Inhibition % Inhibition

(HTS) (HTS) (HTS)

169 28 40 72 41.7

170 32 49 90 25.5

171 31 38 48 16.6

172 34 32 42 29.4

173 18 46 56 25.5

174 10 19 40 27.7

175 16 20 37 32.9

176 6 5 16 26.6

177 5 1 9 9 38.5

178 -10 74 39 26

179 12 32 60 42.7

180 14 19 45 34.4

181 6 35 62 15.7

182 -9 -8 -8 7 28.6

183 -6 12 70 34.6

184 16 24 44 24.8

185 9 0 23 7.21

186 -14 -4 -4 35 19.5

187 -14 -12 20 85.5

188 -27 -24 4 16.2

189 -30 -18 -9 -9 14.

190 -35 -28 -13 38.3

191 -45 -3 22 2.9

192 -32 5 61 33.2

193 -32 -15 56 14.9

194 -17 -8 -8 5 5.4

195 -9 -2 -2 10 27.0

196 -18 1 11 35.7

197 -33 -26 -3 -3 17.8

198 -39 -7 15 17.1

199 -10 -7 -30 -1.0

Example serial number MMP13 MMP13 MMP13 TACE TACE

at 36nM at 0.36mM at 3.6mM IC ₅₀ nM at 1mM

Inhibition % Inhibition % Inhibition % Inhibition % Inhibition % Inhibition

(HTS) (HTS) (HTS)

200 37.9

201 50.9

202 10.6

203 32.8

204 7.75

205 84.0

206 89.8

207 -6.3

208 67.7

209 31.2

210 52.2

211 20.7

212 56.0

213 -17.5

214 11.03

215 895 60.12

216 2.49

217 55.1

218 380 68.7

219 7.3

220 256 53.1

221 146 98.9

222 212 89.3

223 226 107.3

224 -404 75.0

225 96.6 114.3

226 28 22 28 2.2

227 15 -16 22 7.3

228 37 28 65 6.8

229 29 17 33 34.4

230 29 31 26 700 72.1

231 23 13 5 41.6

232 30 17 42 20.8

233 33 29 46 19.8

234 26 28 40 18.4

235 59 70 70 48.3

236 44 44 64 35

237 55 65 72 38.2

238 22 11 24 930 54.4

239 54 74 83 45.9

240 48 51 46 40.3

                                              

The compounds of the present invention may be administered to a patient in need thereof neat or with a pharmaceutically acceptable carrier. The pharmaceutical carrier can be solid or liquid.

Suitable solid carriers include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents or encapsulated material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active material. In the form of tablets, the active substance can be mixed with a carrier having the necessary tableting properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can also contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmotic agents. pressure regulator. Suitable examples of liquid carriers for oral and parenteral administration include water (especially may contain the above-mentioned additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols such as dihydric alcohols) and their derivatives, as well as oils such as fractionated coconut oil and peanut oil. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers can be used in sterile liquid form compositions for parenteral administration.

Sterile solutions or suspensions. Liquid pharmaceutical compositions may be administered, eg, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be in the form of liquid or solid compositions.

The compounds of this invention may be administered rectally in the form of conventional suppositories. For intranasal or intratracheal inhalation or insufflation, the compound of the present invention can be prepared as an aqueous solution or a partial aqueous solution, and then applied in the form of an aerosol. The compounds of the present invention may also be administered transdermally by using a transdermal patch containing the active compound and a carrier which is inert to the active compound, nontoxic to the skin, and capable of imparting The drug is absorbed systemically through the skin into the bloodstream. The carrier can be in various forms, such as creams and ointments, pastes, gels and occlusive devices. Creams and ointments may be viscous liquids or semisolid oil-in-water or water-in-oil emulsions. Pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient are also suitable. The active ingredient may be released into the bloodstream using various occlusive devices, such as semipermeable membranes covering a reservoir containing the active ingredient (with or without a carrier) or a matrix containing the active ingredient. Other closing devices are known from the literature.

Dosages for treating a particular patient with a disease or condition involving MMPs and TACE must be determined by the attending physician. Variables included included the severity of the disease and the patient's size, age, and response pattern. Treatment will generally be initiated with small dosages which are less than the optimum dose of the compound. Thereafter the dosage is gradually increased until the optimum effect is obtained under these factors. The exact dosage for oral, parenteral, intranasal or intratracheal administration will be at the discretion of the attending physician on the basis of the particular patient being treated and standard medical principles.

The pharmaceutical compositions are preferably presented in unit dosage form, such as tablets or capsules. When in such form, the composition can be subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, such as packaged powders, vials containing liquids, ampoules, Prefilled syringe or sachet. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of such compositions in package form.

Claims (42)

1. A compound of formula 1 or a pharmaceutically acceptable salt thereof:

in R ¹ is an alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An aryl group of 6-10 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A cycloalkyl group of 3-8 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ; or heteroaryl-(CH ₂ ) _0-6- , wherein the heteroaryl is a 5-6 membered heteroaryl having 1 or 2 heteroatoms independently selected from O, S and N, and can be composed of 1 Or 2 groups independently selected from R5 are optionally substituted; A is -S-, -SO- or SO ₂ -; R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached; ^R4 is hydrogen, An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ; R ⁵ is H, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, F, Cl , Br, I, CN, CHO, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₆ alkoxyaryl, C ₁ -C ₆ alkoxyheteroaryl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n -Aryl, where n is 0, 1 or 2; COOH, COOC ₁ -C ₆ alkyl, COO aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , NH ₂ , OH, aryl, heteroaryl , C ₃ -C ₈ cycloalkyl; or a saturated or unsaturated 5-10 membered mono- or bicyclic heterocycle containing a heteroatom selected from O, S or NR ⁷ , wherein the C ₁ -C ₆ alkyl is a straight chain Or branched, heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl containing 1-3 heteroatoms independently selected from O, S or NR ⁷ , and the aryl is composed of 1 or 2 selected from halogen, A cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy group optionally substituted phenyl or naphthyl; R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n aryl, wherein n is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl contains 1-3 independently selected from O, S or A 5-10 membered mono- or bicyclic heteroaryl group with a heteroatom of NR ⁷ , and the aryl group is composed of 1 or 2 members selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy groups optionally substituted phenyl or naphthyl; R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n - Aryl, where n is 0, 1 or 2; COO-C ₁ -C ₆ alkyl, COO aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO-C ₁ -C ₆ alkyl, CONHSO ₂ aryl, aryl or heteroaryl, wherein aryl is independently selected from halogen, cyano, Amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy optionally substituted phenyl or naphthyl; heteroaryl is a group containing 1-3 independently selected from O, 5-10 membered mono- or bicyclic heteroaryl of S or NC ₁ -C ₆ alkyl heteroatoms; An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Arylalkyl groups of 7-16 carbon atoms, wherein the aryl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced; A biphenylalkyl group of 13-18 carbon atoms, wherein the biphenyl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; 8-16 carbon atom aryl alkenyl, wherein aryl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted with a heteroatom selected from O, S or N _{-C 1} -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ; or R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between The nitrogens between the two together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl group is phenyl or naphthyl. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is an alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An aryl group of 6-10 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A cycloalkyl group of 3-8 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated 5-10 membered mono- or biheterocyclic ring optionally substituted by 1 or 2 groups independently selected from R ⁵ and containing a heteroatom selected from O, S or NR ⁷ ; or heteroaryl-(CH ₂ ) _0-6- , wherein the heteroaryl is a 5-6 membered group having 1 or 2 heteroatoms independently selected from O, S and N, and may consist of 1 or 2 groups independently selected from R ⁵ are optionally substituted; A is -S-, -SO- or SO ₂ -; R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached; ^R4 is hydrogen, An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; R ⁵ is H, F, Cl, Br, I, CN, CHO, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl , C ₂ -C ₁₂ alkynyl, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₆ alkoxyaryl, C ₁ -C ₆ alkoxyheteroaryl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n Aryl, where n is 0, 1 or 2; COOH, COO-C ₁ -C ₆ alkyl, COO aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , NH ₂ , OH, aryl, heteroaryl group, C ₃ -C ₈ cycloalkyl; or a saturated or unsaturated 5-10 membered mono- or biheterocyclic ring containing a heteroatom selected from O, S or NR ⁷ , wherein the heteroaryl group contains 1-3 A 5-10 membered mono- or bicyclic heteroaryl group independently selected from O, S or NR ⁷ heteroatoms, and the aryl group is independently selected from 1 or 2 halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy optionally substituted phenyl or naphthyl; R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _n alkyl or aryl, wherein n is 0, 1 or 2; or CO heteroaryl; wherein Heteroaryl is a 5-10 membered mono- or ^bicyclic heteroaryl containing 1-3 heteroatoms independently selected from O, S or NR, and aryl is composed of 1 or 2 heteroatoms selected from halogen, cyano, amino , nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy optionally substituted phenyl or naphthyl; R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -alkyl, S(O) _n -aryl, wherein n is 0, 1 or 2; COO alkyl, COO aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl, SO ₂ NHCO aryl, CONHSO ₂ alkyl, CONHSO ₂ aryl, aryl, heteroaryl radical, wherein C ₁ -C ₆ alkyl is straight or branched, and heteroaryl is a 5-10 membered mono- or bicyclic heteroaryl containing 1-3 heteroatoms independently selected from O, S or NR ⁷ , Aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy ; An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Arylalkyl groups of 7-16 carbon atoms, wherein the aryl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced; A biphenylalkyl group of 13-18 carbon atoms, wherein the biphenyl group is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; 8-16 carbon atom aryl alkenyl, wherein aryl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted with a heteroatom selected from O, S or N _{-C 1} -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ; R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between two The nitrogens between them together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl is phenyl or naphthyl. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is phenyl, naphthyl, alkyl or heteroaryl with 1-18 carbon atoms such as pyridyl, thienyl, imidazolyl or furyl, optionally composed of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, halogen substituted; or S(O) _n -C ₁ -C ₆ alkylC ₁ -C ₆ alkoxyaryl or C ₁ -C ₆ alkoxyheteroaryl; A is -S-, -SO- or -SO ₂ -; R ² and R ³ together form a 5-7 membered heterocyclic ring containing O, S or NR ⁷ and optionally having 1 or 2 double bonds with the carbon atom to which they are attached; ^R4 is hydrogen, An alkyl group of 1-6 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Phenyl or naphthyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; C ₃ -C ₈ cycloalkyl or bicycloalkyl optionally substituted by 1 or 2 groups independently selected from R ⁵ ; R ⁵ is H, C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, F, Cl , Br, I, CN, CHO, C ₁ -C ₆ alkoxy, aryloxy, heteroaryloxy, C ₃ -C ₆ alkenyloxy, C ₃ -C ₆ alkynyloxy, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -C ₁ -C ₆ alkyl, S(O) _n aryl, wherein n is 0, 1 or 2; COOH, COOC ₁ -C ₆ alkyl, COO Aryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , NH ₂ , OH, aryl, heteroaryl, C ₃ -C ₈ cycloalkyl; containing a heteroatom selected from O, S or NR ⁷ Saturated or unsaturated 5-10 membered mono or biheterocyclic ring, wherein C ₁ -C ₆ alkyl is straight chain or branched, heteroaryl is containing 1-3 heteroatoms independently selected from O, S or NR ⁷ 5-10 membered mono- or bicyclic heteroaryl, and the aryl is composed of 1 or 2 selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or A hydroxy group optionally substituted phenyl or naphthyl; R ⁶ is H, C ₁ -C ₁₈ alkyl optionally substituted by OH; C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, C ₁ -C ₆ perfluoroalkyl, S(O) _nAlkyl or aryl, wherein n is 0, 1 or 2; or CO heteroaryl; wherein heteroaryl is a 5-10 membered unit containing 1-3 heteroatoms independently selected from O, S or ^NR or bicyclic heteroaryl, and aryl is optionally selected from 1 or 2 groups selected from halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxyl Substituted phenyl or naphthyl; R ⁷ is C ₇ -C ₁₁ aroyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₁₂ perfluoroalkyl, S(O) _n -alkyl, S(O ) _n -aryl, wherein n is 0, 1 or 2; COO alkyl, COO aryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NH heteroaryl Base, SO ₂ NHCO aryl, CONHSO ₂ alkyl, CONHSO ₂ aryl, aryl or heteroaryl; wherein aryl is independently selected from halogen, cyano, amino, nitro, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxyl group optionally substituted phenyl or naphthyl; heteroaryl is a group containing 1-3 independently selected from O, S or N C ₁ -C ₆ alkane A 5-10 membered mono- or bicyclic heteroaryl group of heteroatoms in the group; An alkyl group of 1-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkenyl group of 3-18 carbon atoms with 1-3 double bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An alkynyl group of 3-18 carbon atoms with 1-3 triple bonds optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An arylalkyl group of 7-16 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Heteroarylalkyl, wherein the alkyl group contains 1-6 carbon atoms, the heteroaryl group contains 1 or 2 heteroatoms selected ^from O, S or N and optionally consists of 1 or 2 groups independently selected from R group replaced; A biphenylalkyl group of 13-18 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; An arylalkenyl group of 8-16 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; Cycloalkylalkyl or bicycloalkylalkyl with 4-12 carbon atoms optionally substituted by 1 or 2 groups independently selected from R ⁵ ; A saturated or unsaturated mono- or bicyclic heterocycle optionally substituted by a heteroatom selected from O, S or NR-C ₁ -C ₆ alkyl and optionally substituted by 1 or 2 groups independently selected from R ⁵ ; R ⁸ R ⁹ NC ₁ -C ₆ alkoxyaryl-C ₁ -C ₆ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ₁ -C ₆ alkyl, or R ⁸ and R ⁹ are between two The nitrogens between them together form a 5-7 membered saturated heterocyclic ring optionally containing oxygen atoms, wherein the aryl is phenyl or naphthyl. 4. The compound of claim 1, which is 1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, which is 4-(4-methoxyl-benzenesulfonyl)-1-(3-methoxyl-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Accepted salt. 6. The compound of claim 1, which is 1-(3,4-dichlorobenzyl)-4-(4-methoxyl-benzenesulfonyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Accepted salt. 7. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Salt. 8. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-naphthalene-2-yl-methylpiperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable salt thereof . 9. The compound of claim 1, which is 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl) piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Salt. 10. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl) piperidine-4-formic acid hydroxyamide or its pharmaceutical acceptable salt. 11. The compound of claim 1, which is 1-(4-bromo-benzyl)-4-(4-methoxyl-benzenesulfonyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Salt. 12. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine -4-Formic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, which is 1-benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine -4-Formic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1, which is 4-(4-butoxyl-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxyl)-benzyl]-piper Pyridine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 16. The compound of claim 1, which is 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 17. The compound of claim 1, which is 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 18. The compound of claim 1, which is 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 19. The compound of claim 1, which is 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-methyl-piperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable salt thereof . 20. The compound of claim 1, which is 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-ethyl-piperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable salt thereof . 21. The compound of claim 1, which is 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Salt. 22. The compound of claim 1, which is 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable Salt. 23. The compound of claim 1, which is 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable of salt. 24. The compound of claim 1, which is 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable of salt. 25. The compound of claim 1, which is 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable of salt. 26. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Accepted salt. 27. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutical acceptable salt. 28. The compound of claim 1, which is 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutical acceptable salt. 29. The compound of claim 1, which is 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Accepted salt. 30. The compound of claim 1, which is [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 31. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable Accepted salt. 32. The compound of claim 1, which is [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide or Pharmaceutically acceptable salts. 33. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable Salt. 34. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-formic acid hydroxyamide or its pharmaceutically acceptable of salt. 35. The compound of claim 1, which is 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-formic acid hydroxyamide or a pharmaceutically acceptable salt thereof . 36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide and 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide. 37. Use of the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting matrix metalloproteinase-mediated pathological changes in mammals. 38. The use according to claim 37, wherein said pathological change is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis caused by atherosclerotic plaque rupture, restenosis, MMP-mediated Osteopenia, CNS inflammatory disease, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulcer, abnormal wound healing, bone disease, proteinuria , aortic aneurysm disease, degenerative cartilage loss from traumatic joint injury, demyelinating disease of the nervous system, liver cirrhosis, glomerular disease, early rupture of fetal membranes, inflammatory bowel disease, or periodontal disease. 39. The use of claim 37, wherein said pathological change is age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia , ocular tumors, ocular angiogenesis/neovascularization and corneal transplant rejection. 40. Use of the compound according to any one of claims 1-36 or a pharmaceutically acceptable salt thereof for inhibiting pathological changes mediated by TNF-α converting enzyme in mammals. 41. The purposes of claim 40, wherein said pathological changes are rheumatoid arthritis, transplant rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, central nervous system inflammatory disease, inflammatory bowel disease, or HIV infection. 42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a matrix metalloproteinase or TNF-α converting enzyme inhibitory compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-36.