BG104782A - N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors - Google Patents

Abstract

Matrix metalloproteinase (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. The zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-alpha converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-alpha from membrane bound TNF-alpha procursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulcerations, abnormal wound healing, periodontal disease, bone disease, diabetes insulin resistance) and HIV infection having formula wherein R2 and R3 form a heterocyclic ring and A is S, S(O), or S(O)2 and R1 and R4 are defined herein. 42 claims

Description

M-HYDROXY-2- (alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl) -3-substituted-alkyl, aryl or heteroarylamides such as matrices

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a group of enzymes that are associated with the pathological degradation of connective tissues and major membranes. These zinc-containing endopeptidases consist of several subgroups of enzymes including collagenases, stromelysins and gelatinases. Of these classes, gelatinases have been shown to be the MMPs that are most closely associated with tumor growth and spread. It is known that the level of gelatinase expression is increased in malignancies and that gelatinase can degrade the main membrane, leading to tumor metastasis. The angiogenesis required for the growth of solid tumors has recently also been shown to have a gelatinase component in its pathology. Moreover, there is evidence to suggest that gelatinase is involved in atherosclerosis-related plaque rupture. Other MMPs mediated conditions include restenosis, MMP mediated osteopenia, central nervous system inflammatory diseases, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal healing, anesthesia, anesthesia aortic disease, degenerative cartilage loss after traumatic injury to the joint, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular kidney disease, premature rupture of the fetuses membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, premature retinopathy, ocular inflammation, keratoconus, Sjogren's syndrome, myopia For more information, see (1) Recent Advances in Matrix Metalloprateunase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley, and M. Whittaker, Research Ficus, Vol. I, 16 - 26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4 (1): Ί - 16, (3) Curr. Medicinal Chem. (1995) 2: 743–762, (4) Enp. Opin. Ther. Patents (1995) 5 (2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5 (12): 1287 - 1196.

The TNF-α conversion enzyme (TACE) catalyzes the formation of TNF-αο membrane-bound TNF-α precursor protein. TNF-a is a pro-inflammatory cytokine now thought to play a role in rheumatoid arthritis, septic shock, implant rejection, cachexia, anorexia _and inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease and HC infections in addition to its well-documented anti-tumor properties. For example, studies with anti-TNF-α antibodies and transgenic animals have shown that blocking the formation of TNF-α inhibits the progression of arthritis. This observation has also recently been conducted in humans.

Therefore, small-molecule inhibitors of MMPs and TACE are expected to have the ability to treat a variety of disease states.

Various MMPs and TACE inhibitors have been identified and described in the literature, the vast majority of these molecules being peptide and peptide-like compounds; which would be expected to have bioavailability and create pharmacokinetic problems common with such compounds that would limit their clinical efficacy. Therefore, small-molecule, highly active, long-acting, orally bioavailable MMPs and / or TACE inhibitors for effective chronic treatment of the above-mentioned disease conditions are highly desirable.

Recently, two publications (U.S. Pat. No. 5,455,258 and European Patent 606,046) have appeared that describe arylsulfonamido-substituted hydroxyamino acids. These documents cover the compounds exemplified by CGS 27-23A. To date, these are the only non-peptide matrix metalloproteinase inhibitors described.

Me '

CGS 27023A

Salah et al., Liebigs Ann. Chem. 195, (1973) describes some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of the general formula 1. These compounds were prepared to investigate the Manich reaction. They were subsequently tested for their fungicidal activity.

Some sulfonecarboxylic acids are described in U.S. Patent 4,933,377. These compounds have been shown to exhibit hypoglycemic activity.

SUMMARY OF THE INVENTION

The invention relates to novel, low molecular weight, non-peptide matrix metalloproteinase inhibitors (MMPs) and TNF-α conversion enzyme (TACE) for the treatment of arthritis, tumor metastases, tissue ulceration, diabetes (insulin resistant) and HIV.

According to the invention, a group of compounds of general formula I have been developed

wherein:

R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ;

a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ;

or heteroaryl- (CH 2) _O- 6, wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and may be optionally substituted by one or two groups selected independently from R ⁵ ;

A represents -S-, -SO- or SO ₂ -;

R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds;

R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ;

_C3 ^ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5;

saturated or unsaturated 5 to 10 membered Monde or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ^7, optionally substituted with one or two groups selected independently from R ^5;

R ⁵ denotes H, SA11 aroyl, C2-6 alkanoyl, Ci-allyl, C 2-12 alkenyl, C 2-12 alkynyl, F, Cl, Br, I , CN, CHO, C ^ alkoxy, aryloxy, heteroaryloxy, C3 ^ alkenyloxy, C alkynyloxy, C1-6 alkoxyaryl, C1-6 alkoxyheteroaryl, C1-6alkylamino-C1-6alkoxy, C1-6alkylenedioxy, aryloxy-C1-6alkylamine, C1-6 perfluoroalkyl, C1-6-alkyl, S (O) aryl, where denotes 0, 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC, C 1-6 alkyl, COOaryl, CONR ^e R ^e , CONHOH, NR ^e R ^e , SO ² N R ⁶ R ⁶ , NR ^ Ojapwn, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, COINbO-C 1 -C 6 alkyl, CONH 5 C 3 -alkyl, SO ₂ NHCOapnn, CONHSOg-C ^ nKnn, CONHSO ^ pnn, NH ₂ , OH, aryl, heteroaryl, cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein C 1-6 alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 up to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy;

R ⁶ denotes H, _M8 alkyl optionally substituted by OH; C ₃ _b alkenyl, C ^ alkynyl, C ₁ ^ perfluoroalkyl, in ^ n-C ^ alkyl, 3 (O) _n -aryl where η is 0, 1 or 2; or SOheteroaril wherein heteroaryl means 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups selected from halogen, cyano, , amino, nitro, Οι-θβηκπη, C 1-4 alkoxy or hydroxy;

and R ⁷ is C 1-10 aroyl, C 2 -C 6 alkanoyl, CH 2 perfluoroalkyl, C 1 -C 4 alkyl, S (O) n-apnn, where η is 0,1 or 2; COOC ^ alkyl, COOaryl, CONHR®, CONR ⁶ R®, CONHOH, SO2NR ⁸ R ^e , SO ₂ CF ₃ . bOH ₁ H ₂ heteroaryl, SO ₂ NHCO 3, COCH 3 -C 1-6 alkyl ₎ CON H 2C 1 aryl, aryl or heteroaryl, in which aryl represents phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, alkyl, C1-6 alkoxy or hydroxy; and heteroaryl means a 5- to 10-membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from O, S or N-C 1-6 alkyl;

alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ;

biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

MM cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ;

a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ;

or

R ^ NC ^ anKOKcnapMn- C ^ alkyl wherein R ⁸ and R ⁹ are independently selected from C ^ alkyl, or R ⁸ and R ⁹ together with the nitrogen form a mezhdinnopostaveniya 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;

and pharmaceutically acceptable salts thereof.

A more preferred aspect of the invention is a group of compounds of general formula (Ia):

la

wherein:

R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ;

a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ;

or heteroaryl- (CH 2) 0-6-wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and may be optionally substituted by one or two groups selected independently from R ⁵ ;

A represents -S-, -SO- or SO ₂ -;

R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds;

R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ;

C ₃ _8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5;

R ⁵ is H, F, Cl, Br, I, CN, CHO, C ₇ . _n aroyl, _C2 ^ alkanoyl, C _b12 alkyl, C _{2. 12} alkenyl, C ₂ . ₁₂ alkynyl, C ^ alkoxy, aryloxy, heteroaryloxy, _C3 ^ alkenyloxy, _{C3-alkynyloxy,} C ^ alkoxyaryl, C alkoxyheteroaryl, C ^ alkylamino-C ^ alkoxy, alkylenedioxy, aryloxy-C ^ alkylamino, C _M2 perfluoroalkyl , 3 (O) _n -C 1-4 alkyl, S (O) _n aryl, where η is 0, 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC, C 1-6 alkyl, COOaryl, CONR ^e R ^e , CONHOH, NR ^e R®, SO2NR ⁶ R ⁶ , NR ^e SO2apwi, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , S0 ₂ NHxerepoapMn, SO ₂ NHCOapnn, COINvO-C ^ alkyl, CONHSO ^ pnn, SO ₂ NHCOapnn, COINvO-C ^ alkyl, CONHSO ^ pnn, NH _2i OH, aryl, heteroaryl, N ^ cyclo; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, ® S or NR ⁷ , wherein the heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups independently selected from halogen, cyano, amino, nitro, C ₁ _ _is alk14l, C ^ alkoxy or hydroxy;

R ⁶ denotes H, _H8 alkyl optionally substituted by OH;

alkenyl, C ^ alkynyl, C ^ perfluoroalkyl, c (O) _n -C ₁ _ ₆ alkyl or aryl, where η is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from 0, S or NR ⁷ , and aryl being phenyl or naphthyl optionally substituted by 1 to 2 groups selected from halogen, cyano , amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or hydroxy;

and R ⁷ represents C 1-6 aroyl, C 2-4 alkanoyl, C 2-4 perfluoroalkyl, 3 (O) n'C 1 -alkyl, S (O) n-apnn, where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR ⁸ , CONR ^e R ⁸ , CONHOH, SO ₂ N R ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, COINvOalkyl, CONHSO ^ pnn, aryl or heteroaryl, where C 1 is straight alkyl. branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having up to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C1-6 alkyl, alkoxy or hydroxy;

alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ;

biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ;

a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or

R ⁸ R ⁹ NC ₁ C 1 -C 3 alkyl-C 1-6 alkyl wherein R ⁸ and R ⁹ are independently selected from C 1-6 alkyl or R ⁸ and R ⁹ together with the intermediate nitrogen form a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, where the aryl group is phenyl or naphthyl;

and pharmaceutically acceptable salts thereof.

The most preferred group of compounds are those of the general formula

R ^:

R '

R '

lb in which:

R ¹ means phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, C ₆ . ₁₀ aryloxy, heteroaryloxy, alkenyloxy, _{C3-alkynyloxy,} halogen; or C 1-6 -C 1-4 alkyl alkoxyaryl or C 1-6 alkoxyheteroaryl;

A represents -S-, -SO- or -SO ₂ -;

R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds;

R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently

phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ;

C 3-6 cycloalkyl or bicycloalkyl optionally substituted by one or two groups selected independently from R ⁵ ;

R ⁵ represents H, C 1-6 aroyl, C 2-4 alkanoyl, CH 2 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, F, Cl, Br, I, CN, CHO, C 1-4 alkoxy, aryloxy, heteroaryloxy, C 3-4 alkenyloxy, C 3 C 1-6 alkynyloxy, C 1-6 alkylamino-C 1-6 alkoxy, C 1-2 alkylenedioxy, aryloxy-C 1-6 alkylamine, C 12-12 perfluoroalkyl, C 1-6 -C 1-6 alkyl, in (O) n-aryl, where η is 0, 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC ^ alkyl, • COOaryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO ² NR ⁶ R ⁶ , NR ^ O ^ pHn, NR ⁶ CONR ⁶ R ^e , NHSO2CF3, SO2NHxerepoapm, SO2NHC0apnn, CONHSO2C4alkyl, CONHSO2apnn, SO2NHCOapnn, CONHSO2-C1-6anKnn, CONHSO2apnn, NH2, OH, aryl, heteroaryl, C3-8cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ where alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 to 2 groups independently selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy;

R ⁶ represents H, C _1-18 alkyl, optionally substituted with OH; _C3 ^ alkenyl, C ^ alkynyl, C ^ perfluoroalkyl, c (O) _n alkyl or aryl where η is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from 0, S or NR ⁷ , and aryl being phenyl or naphthyl optionally substituted by 1 to 2 groups selected from halogen, cyano , amino, nitro, _b6 alkyl, _b6 alkoxy or hydroxy;

and R ⁷ represents C 1-6 aroyl, C 2-6 alkanoyl, C 1-6 perfluoroalkyl, in (O) n-alkyl, in (O) n-aryl, where η is 0, 1 or 2; COOalkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO2NR ⁶ R ⁶ , SO ₂ CF ₃ , C 0 H 3 Heteroaryl, SO ₂ NHCOapnn, CONHSO ₂ anKnn, CON H SO 4 pnn, aryl or heteroaryl; wherein aryl means phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, amino, nitro, C ^ alkyl, _C1 ^ alkoxy or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from O, S or C 1-6 alkyl;

alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ;

alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ;

biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ;

arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ;

cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ;

optionally phenyl or TACE

N, N-C 1-4 alkoxyaryl-C 1-6 alkyl wherein R ⁸ and R ⁹ are independently selected from C 1-6 alkyl or R ⁸ and R ⁹ together with the intermediate nitrogen form a 5-7 membered saturated heterocyclic ring containing an oxygen atom, wherein the aryl the group is naphthyl;

and pharmaceutically acceptable salts thereof.

The most preferred matrix metalloproteinase inhibitory compounds of the invention are:

1-Benzyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide, 4- (4-methoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid hydroxyamide, hydroxyamide 1- (3,4-Dichlorobenzyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid hydroxyamide, 4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-2-ylmethylpiperidine-4-carboxylic acid hydroxyamide, 1-biphenyl-4-ylmethyl-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxy hydroxyamide 4- (4-Methoxy-benzenesulfonyl) -1- (3-methyl-but-2enyl) -piperidine-4-carboxylic hydroxyamide of benzenesulfonyl) -piperidine-4-carboxylic hydroxyamide of propyl-piperidine-4 -piperidine-4-carboxylic hydroxyamide hydroxyamide piperidine-4-carboxylic acid,

1- (4-bromo-benzyl) -4- (4-methoxyacid,

4- (4-methoxy-benzenesulfonyl) -1- (3-phenylacid,

1-tert-butyl-4- (4-methoxy-benzenesulfonyl) acid, 1-butyl-4- (4-methoxy-benzenesulfonyl) acid,

1-tert-butyl-4- (4-methoxy-benzenesulfonyl) acid, 1-butyl-4- (4-methoxy-benzenesulfonyl) acid,

-cyclooctyl-4- (4-methoxy-benzenesulfonyl) acid, 1-ethyl-4- (4-methoxy-benzenesulfonyl) acid,

1-Isopropyl-4- (4-methoxy-benzenesulfonyl) acid, 1-methyl-4- (4-methoxy-benzenesulfonyl) acid, 1-benzyl-4- (4-butoxy-benzenesulfonyl) acid, 1- (4-Fluoro-benzyl) -4- (4-methoxy- ⁴ benzenesulfonyl) -piperidine-4-carboxylic acid 1- (4-fluoro-benzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4- hydroxamide carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxyhydroxyamide) piperidine-4-carboxylic hydroxyamide piperidine-4-carboxylic hydroxyamide piperidine-4-carboxylic hydroxyamide piperidine-4-carboxylic acid hydroxamide piperidine-4-carboxylic hydroxamide piperidine-4-carboxylic hydroxamide benzyl) -piperidine-4-carboxylic acid 4- (4-methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -1-carboxylic acid ] -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) piperidine-4-carboxylic acid hydroxamide, 4- (4-n-butoxy-benzenesulfonyl) -1- (4-Methoxybenzyl) -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid hydroxamide, hydroxamide 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxypropyl) piperidine-4-carboxylic acid,

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxamide, 4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine hydroxamide -4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid hydroxamide, 1-benzyl- 4- (4-Benzyloxy-benzenesulfonyl) piperidine-4-carboxylic acid 4- (4-butoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4- hydroxamide carboxylic acid 4- (4-butoxy-benzenesulfonyl) -1- (3- (2morph) hydroxamide folinyl-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid, 1-methyl-4- (4-boxy-benzenesulfonyl) piperidine-4-carboxylic acid, 1-ethyl-4- ( 4-Butoxy-benzenesulfonyl) -piperidine-

4-carboxylic acid, 1-n-butyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxamide, 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -1-methylpiperidine -4-carboxylic acid, 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -1-ethylpiperidine-4-carboxylic acid hydroxamide, 1-butyl-4- [4- (4-chloro-phenoxy) hydroxamide ) -benzenesulfonyl] piperidine-4-carboxylic acid, 1-butyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] piperidine-4-carboxylic acid, 1-benzyl-4- [4- (3-methyl-butoxy) benzenesulfonyl] - piperidine-4-ca 1-butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] piperidine-4-carboxylic acid hydroxamide, 1-benzyl-4- [4- (2-ethyl-butoxy) -hydroxamide - benzenesulfonyl] piperidine-4-carboxylic acid, 4- (4-butoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid hydroxamide, 4- (4-methoxy-benzenesulfonyl) -1- (4-Thiophen-2-ylbenzyl) -piperidine-4-carboxylic acid 4- (4-methoxy-benzenesulfonyl) -1- (4-pyridin-2-yl-benzyl) -piperidine-4-carboxylic acid hydroxamide 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzene) lfonyl) -piperidine-4-carboxylic acid, [4- (4-chloro-benzyloxy) -benzenesulfonyl] -1methylpiperidine-4-carboxylic acid hydroxamide, 4- (4-butoxy-benzenesulfonyl) -1- (3- phenoxybenzyl) -piperidine-4-carboxylic acid, [4- (4-chloro-benzyloxy) -benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid hydroxamide, 4- (4-butoxy-benzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid, 4- (4-butoxy-benzenesulfonyl) -1- (4-cyanobenzyl) -piperidine-4-carboxylic acid hydroxamide and 4- (4-butoxy hydroxamide) -but zensulfonil) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid and pharmaceutically acceptable salts thereof.

It is to be understood that the definitions of the compounds of formulas I, Ia and Ib, when R ¹ , R ² , R ³ and R ⁴ contain asymmetric carbons, cover all possible stereoisomers and mixtures thereof having the activity described below. In particular, racemic modifications and all optical isomers having the activity shown are included. Optical isomers can be obtained in pure form by standard separation methods. Unless otherwise stated, the term "alkyl" refers to a straight or branched alkyl group and aryl is phenyl or naphthyl. pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and the like known acceptable acids.

The present invention also includes a pharmaceutical composition comprising a compound of the invention in combination or in association with a pharmaceutically acceptable carrier. More particularly, the invention provides a pharmaceutical composition which comprises an effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

The compounds are preferably suitable for oral administration. However, they can be administered to patients in other ways, such as parenteral.

For ease of administration, it is preferred that the composition of the invention be in unit dosage form. Suitable single dose forms are tablets, capsules and powders in cachets or vials. Such unit dosage forms may contain from 0.1 to 100 mg of a compound of the invention. The compounds of the invention can be administered orally at a dosage in the range of about 0.01 to 100 mg per kg. Such compositions may be administered 1 to 6 times daily, most commonly 1 to 4 times daily.

The compositions of the invention may be formulated with conventional additives such as fillers, disintegrants, binders, lubricants, and the like, formulated in the usual way.

Methods for preparing the compounds of the invention have also been devised.

Preparation methods according to the invention

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

A suitably substituted mercaptan derivative is alkylated using either a substituted (Scheme 1) or unsubstituted (Scheme 2) α-bromoacetic acid ester in boiling acetone using K ₂ CO ₃ as the base. The sulfide derivative thus obtained is oxidized using m-chloroperbenzoic acid in methylene chloride and using oxone in methanol / water. The oxone obtained from the above process can either be further alkylated using various alkyl halides to obtain the disubstituted derivative or can be hydrolyzed using sodium hydroxide / methanol at room temperature. Instead of using ethyl ester, if tert-butyl ester is present, the hydrolysis can be carried out with TEA / methylene chloride at room temperature. The resulting carboxylic acid is then converted to a hydroxamic acid derivative by reaction with oxalyl chloride / DMX (catalytic) and hydroxylamine / triethylamine.

Scheme 1

Synthesis

R2 R2 I R < _c 1 / ° ^E ' ^Br t ^S 1 R ¹ -SH ₊ 0 a --- ► 0

a. K ₂ COd / acetone / boiling;

b. m-chloroperbenzoic acid;

c. K ₂ CO3 / 18-Crown-6 / R ³ Br / aijeTOH / boiling

d. NaOH / MeOH / THF / room temperature

e. (COCl) ₂ / methylene chloride / Et ₃ N / N Η ₂ OH. H Cl.

Scheme 2

Synthesis

b and

R2

d 1 <· - Ri R ² * No HH * ¹ * Wow O 0 ^β '\ ά b 0

a. K ₂ CO 3 / acetone / boiling;

b. m-chloroperbenzoic acid;

c. K ₂ CO 3/18-Crown-6 / R ² Br / acetone / boiling

d. R ³ Br / 10 N NaOH / BzN (Et) 3 / methylene chloride / room temperature. e. NaOH / MeOH / THF / room temperature

f. (COCl) ₂ / methylene chloride / Et ₃ N / NH ₂ OH.HCI.

As shown in Scheme 3, the sulfide derivative can be further alkylated using lithium bis (trimethylsilyl) amide in tetrahydrofuran at 0 ° C. The alkylated or monosubstituted compound is hydrolyzed and converted to a hydroxamic acid derivative. The sulfinyl derivative is obtained by oxidation of a hydroxamic sulfide derivative

acid with H ₂ O ₂ in methanol solution. Scheme 3 Synthesis R2 I R ² | Rll ^ OEt ^cd 11 ^s if R1-SH ₊ O ^a > 0

s

a. K ₂ CO 3 / acetone / boiling;

b. Fr'Br / HMDS / THF;

c. NaOH / MeOH / THF / room temperature

d. (COCl) ₂ / methylene chloride / Et ₃ N / NH ₂ OH.HCI.

e. methanol / HjXV room temperature

The corresponding hydroxyamides of 1-substituted-4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid were prepared starting from diethanolamine and suitably substituted alkyl or aryl halides (Scheme 4). The N-substituted diethanolamine derivatives were converted to dichloro compounds using thionyl chloride. The corresponding dichlorides are reacted with ethyl ester derivatives of the substituted sulfonylacetic acid in the presence of K ₂ CO 3 / 18Crown-6 in boiling acetone. The 1-substituted-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl esters thus obtained are converted to hydroxamides as shown in the scheme

4.

Alternatively, this class of compounds and other heterocycles can be prepared as shown in Schemes 5 and 6.

Scheme 4

a. K ₂ CO 3 / acetone / boiling;

b. SOCI ₂ / methylene chloride

c. R ¹ SO ₂ CH ₂ COOEt / K ₂ CO 3/18-Soupup-6 / acetone / boiling;

d. NaOH / MeOH / THF / room temperature

e. (COCI) ₂ / NH ₂ OH.HCI / Et ₃ N /

Figure 5

“Go

a. RBr / R'SH / chloroform / boiling;

b. Oxone / MeOH;

e. (COCIW NH ₂ OH.HCI / Et ₃ N Scheme 6

R-N, s, 0

a. LiN (TMS) ₂ / tetrahydrofuran / 0 ° C;

b. (COCI) ₂ / NH ₂ OH.HCI / Et ₃ N

Alternatively, Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support (P).

Scheme 7 ''

'/ \

Reagents and conditions: a) 2-halogenated acid (3.0 eq); 1hydroxybenzotriazole hydrate (HOBt, 6.0 eq); 1,3 diisopropylcarbodiimide (DIC, 4.0 eq); dimethylformamide, 25 ° C; 2 -16 hours.

b) thiol (5.0 eq); sodium iodide (5.0 eq); 1,8diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq); tetrahydrofuran, 25 ° C; 12 -16 hours.

c) 70% tert-butyl hydroxyperoxide (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.

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinyl-benzene)-resin (hydroxylamine resin) can be coupled with 2-halogenated acid to give a hydroxamate ester resin. The coupling reaction can be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as dimethylformamide at room temperature. The halogen group may be substituted by a thiol in the presence of a base, such as DBU, in an inert solvent such as tetrahydrofuran at room temperature. The sulfide may be oxidized to the sulfoxide 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 may be oxidized to the sulfone by reacting with an oxidizing agent such as meta-chloroperoxybenzoic acid in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide or sulfone can be reacted with an acid, such as trifluoroacetic acid, in an inert solvent such as DCM to release free hydroxamic acid.

Scheme 8 shows a process for the preparation of hydroxamic acids with alkoxy groups attached to the aromatic ring.

Scheme 8

Reagents and conditions: a) 2-halogenated acid (3.0 eq); 1hydroxybenzotriazole hydrate (HOBt, 6.0 eq); 1,3 diisopropylcarbodiimide (DIC, 4.0 eq); dimethylformamide, 25 ° C; 2 -16 hours.

b) 4-fluorobenzenethiol (5.0 eq); sodium iodide (5.0 eq); 1,8diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq); tetrahydrofuran, 25 ° C; 12 -16 hours.

c) alcohol (15.0 eq.); sodium hydride (15.0 eq); dimethylformamide; 80 ° C; 15 hours.

d) 70% tert-butyl hydroperoxide (40 eq); benzenesulfonic acid (2.0 eq); DCM; 25 ° C; 12 - 24 hours.

e) mCRP (5.0 eq); DCM; 25 ° C; 12-24 hours.

f) TFA: DCM (1: 1); 25 ° C; 1 hour.

The hydroxylamine resin may be coupled to 2-halogenated acid and the halogen group substituted with fluorobenzentiol as previously described. The fluoro group may then be substituted with alcohol in the presence of a base such as sodium hydride in an inert solvent such as dimethylformamide at about 80 ° C. described. Free hydroxamic acids can be prepared as previously described.

Scheme 9 shows a process for the preparation of 2-bisarylsulfanyl-,

Reagents and conditions: a) 2-halogenated acid (3.0 eq); 1hydroxybenzotriazole hydrate (HOBt, 6.0 eq); 1,3 diisopropylcarbodiimide (DIC, 4.0 eq); dimethylformamide, 25 ° C; 2 -16 hours.

b) 4-bromobenzentiol (5.0 eq); sodium iodide (5.0 eq); 1,8diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq); tetrahydrofuran, 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 (O) (0.1 eq.); 10% aqueous sodium carbonate (10.0 eq.); DME; 80 ° C; 8:00.

f) TFA: DCM (1: 1); 25 ° C; 1 hour.

The hydroxylamine resin may be coupled to 2-halogenated acid and the halogen group substituted with bromobenzentiol as previously described. The bromobenzenesulfanyl hydroxamate ester can then be oxidized to the corresponding sulfinyl or sulfanyl hydroxamate ester as previously described.

The bromo group can then be substituted with an aryl group by reaction with an 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 DM E at about 80 ° C. Free hydroxamic acids can are obtained as previously described.

Scheme 10 shows a method for the preparation of hydroxam

acids with amino groups attached to the aromatic ring.

Reagents and conditions: a) 2-halogenated acid (3.0 eq); 1hydroxybenzotriazole hydrate (HOBt, 6.0 eq); 1,3 diisopropylcarbodiimide (DIC, 4.0 eq); dimethylformamide, 25 ° C; 2 -16 hours.

B) 4-bromobenzentiol (5.0 eq); sodium iodide (5.0 eq); 1,8diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq); tetrahydrofuran, 25 ° C; 12 - 16 hours.

c) an amine (20.0 eq.); tris (dibenzylideneacetone) -dipaladium (0) (0.2 eq.); (8) - (-) - 2,2'-bis (diphenylphosphino) -1, Gbinaftyl ((S) -BINAP, 0.8 eq.); dioxane; 80 ° C; 8:00.

♦ d) TFA: DCM (1: 1); 25 ° C; 1 hour.

The hydroxylamine resin may be coupled to 2-halogenated acid and the halogen group substituted with bromobenzentiol as previously described. The bromo group can then be replaced by

an amino group in the presence of a catalyst such as tris (dibenzylideneacetone) -dipaladium (0) and a ligand such as (S) -BINAP as well as a base such as sodium tert-butoxide in an inert solvent such as dioxane at about 80 ° C. The free hydroxamic acids can be received as previously described.

Scheme 11 shows a process for the preparation of hydroxamic acids with sulfonate groups attached to the aromatic ring.

Scheme 11

Reagents and conditions: a) 2-halogenated acid (3.0 eq); 1hydroxybenzotriazole hydrate (HOBt, 6.0 eq); 1,3 diisopropylcarbodiimide (DIC, 4.0 eq); dimethylformamide, 25 ° C; 2 -16 hours.

b) 4-hydroxybenzenethiol (5.0 eq); sodium iodide (5.0 eq); 1,8diazabicyclo [5.4.0] undec-7-ene (DBU, 3.0 eq); tetrahydrofuran, 25 ° C; 12 - 16 hours.

c) sulfonyl chloride (5.0 eq); triethylamine (2.0 eq); DCM; 25 ° C;

o'clock.

d) 70% tert-butyl hydroperoxide (40 eq); benzenesulfonic acid (2.0 eq); DCM; 25 ° C; 12-24 hours.

e) PLC cut (5.0 eq); DCM; 25 ° C; 12 - 24 hours

f) TFA: DCM (1: 1); 25 ° C; 1 hour.

The hydroxylamine resin may be coupled to 2-halogenated acid and the halogen group substituted with hydroxybenzenethiol as previously described. The hydroxybenzenesulfanyl hydroxamate ester can then be oxidized to either the corresponding sylphinyl or sulfonyl hydroxamate ester as previously described. The hydroxyl group can then be sulfonylated by reacting with sulfonyl chloride in the presence of a base such as triethylamine in an inert solvent such as DCM at about room temperature. Free hydroxamic acids can be prepared as previously described.

The following examples are intended to illustrate, but not limit, the scope of the invention. HPLC purity of the compounds obtained by combining the methodologies is given as a percentage area at the indicated wavelength (% @ nm).

Example 1

N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenylpropionamide

To a solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in dry acetone (100 ml) in a round-bottom flask was added ethyl 2-bromopropionate (3.6 g, 20 mmol) and the reaction the mixture is heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off. The reaction mixture was concentrated. The residue was extracted with chloroform and washed with water and 0.5 N NaOH solution. The organic layer was then washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated to give 2- (4-methoxy-phenylsulfanyl) -propionic ethyl ester as a pale yellow oil. Yield 4.5 g (94%); MS: 241 (M + H) ⁺ .

To a solution of 2- (4-methoxy-phenylsulfanyl) propionic acid ethyl ester (2.44 g, 10 mmol) in tetrahydrofuran (100 ml) at -4 ° C was slowly added with stirring, lithium bis (trimethylsilyl) amide (1M solution). (15 ml, 15 mmol). The orange-colored reaction mixture was stirred at room temperature for 15 min and then cooled to 0 ° C, during which time it was further stirred for an additional 1 h. The temperature of the mixture was again brought to -40 ° C and benzyl bromide (1.72 g added). , 10 mmol) in tetrahydrofuran. The reaction mixture was warmed to room temperature and stirred overnight before ice water was added, extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated and chromatographed on silica gel with 10% ethyl acetate: hexane to give 2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil . Yield 860 mg, (26%); MS: 331 (M + H) ⁺ .

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

To a solution of 2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenylpropionic acid (0.5 g, 1.65 mmol) and dimethylformamide (2 drops) in methylene chloride (100 ml) at 0 ° C was added oxalyl chloride (1.0 g , 8 mmol) by dropwise addition. After the addition was complete, the mixture was stirred at room temperature for 1 h. Simultaneously 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 h. At the end of the hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of methylene chloride and slowly added to hydroxylamine at 0 ° C. The 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 eluting with ethyl acetate. N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenyl-propionamide was isolated as a colorless solid, m.p. 88 ° C; Yield 300 mg, 57%; MS: 318 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl 3): δ 1.32 (s, 3H), 3.07 (d, J = 11 Hz, 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 2- (4-methoxyphenylsulfanyl) -phenylacetic acid ethyl ester was prepared according to the general method described in example 1. Starting from ethyl α -bromophenyl acetate (7.18 g, 31.4 mmol) and 4methoxythiophenol (4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a pale yellow oil. Yield 90%; MS: 303.1 (M + H) ⁺ .

2- (4-Methoxyphenylsulfanyl) -phenylacetic acid was obtained starting from 2- (4-methoxy-phenylsulfanyl) -phenylacetic acid ethyl ester (3.0 g, 10 mmol) dissolved in methanol (50 ml) and 10 N NaOH. (20 ml). The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low-melting solid. MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxyphenylsulfanyl) -phenylacetic acid (1.05 g, 3.83 mmol) and following the procedure described in Example 1, 1.154 mg of N-hydroxy-2- (4-methoxyphenylsulfanyl) -2-phenyl-acetamide was obtained as a colorless solid, m.p. 155 ° C. Yield 14%; MS: 290 (Μ + H) ⁺ . 1 H NMR (300 MHz, DMSO-d6): δ 3.72 (3, 3H), 4.68 (S, 1H), 6.86 - 7.44 (m, 9H).

Example 3

2- (4-Methoxy-phenylsulfanyl) -2,5-dimethyl-hex4-enicarboxylic acid hydroxyamide

2- (4-Methoxy-phenylsulfanyl) -2,5-dimethyl-hex-4enecarboxylic acid ethyl ester was prepared following the method of Example 1, second paragraph. Starting from (4-methoxyphenylsulfanyl) -propionic acid ethyl ester (3.5 g, 14.3 mmol) and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of the product was isolated as an oil. Yield 50%; MS: 310 (M + H) ⁺ .

2- (4-Methoxy-phenylsulfanyl) -2,5-dimethyl-hex-4-enicarboxylic acid is obtained by starting from 2- (4-methoxyphenylsulfanyl) -2,5-dimethyl-hex-4-enicarboxylic ethyl ester acid (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 1. Yield 1.9 g, 99% low melting solid. MS: 280 (M + H) ⁺ .

Starting from 2- (4-methoxy-phenylsulfanyl) -2,5-dimethyl-hex4-enicarboxylic acid (1.67 g, 5.8 mmol) and following the procedure given in Example 1, 1.5 g of 2- (4-hydroxyamide) is obtained. -methoxyphenylsulfanyl) -2,5-dimethyl-hex-4-encarboxylic acid, which is isolated as a colorless solid, m.p. 89 ° C. Yield 94%; MS: 296 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.34 (s, 3H), 1.61 (s, 3H), 1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 ( t, J = 7.5 Hz, 1H), 6.86 (d, J = 12.4 Hz, 2H), 7.35 (d, J = 12.4 Hz, 2H).

Example 4

N-hydroxy-2- (4-methoxy-phenylsulfanyl) -3-methyl-butyramide

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

2- (4-Methoxy-phenylsulfanyl) -3-methyl-butyric acid was obtained by starting from 2- (4-methoxyphenylsulfanyl) -3-methyl-butyric acid ethyl ester (5.8 g, 21.6 mmol) dissolved in methanol ( 50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 1. Yield 5.0 g, 99%, low melting solid. MS: 242 (M + H) ⁺ .

Starting from 2- (4-methoxy-phenylsulfanyl) -3-methyl-butyric acid (4.39 g, 18.3 mmol) and following the procedure of Example 1 se, 1.5 g of N-hydroxy-2- (4-methoxy) are obtained. -phenylsulfanyl) -3-methylbutyramide as a colorless solid, m.p. 119 ° C and yield 33%; MS: 256 (Μ + H) ⁺ . ^Ί Η NMR (300 MHz, DMSO-de): δ 0.90 -1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d, J = 8.8 Hz, 1H), 3.75 (S, 3H). 6.88 (d, J = 15 Hz, 2H), 7.35 (d, J = 15 Hz, 2H).

Example 5

N-hydroxy-2- (4-methoxy-phenylsulfinyl) -2-methyl-3-phenylpropionamide

N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-methyl-3-phenylpropionamide (400 mg, 1.26 mmol) (obtained in Example 1) was dissolved in methanol (100 ml) and 30% H ₂ was added. O ₂ (10 ml). The reaction mixture was stirred for 48 h at room temperature and then cooled to 0 ° C and saturated sodium sulfite solution (20 ml) was added. The reaction mixture becomes cloudy. It was stirred for 4 h before being concentrated in a water bath at room temperature, 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 silica gel column chromatography eluting with 75% ethyl acetate: hexane. A low-melting solid was obtained. Yield 220 mg (52%); MS: 334.1 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3: δ 1.11 (S, 2H), 1.22 (S, 3H), 3.84 (S, 3H), 7.00 - 7.61 (m, 9H).

Example 6

2- (4-Methoxy-benzenesulfinyl) -2,5-dimethylhex-4-enicarboxylic acid hydroxyamide

Starting from 2- (4-methoxy-benzenesulfanyl) -2,5-dimethyl-hex-4-enicarboxylic acid hydroxamide (900 mg, 3.0 mmol) (obtained in Example 3) and following the procedure of Example 5 to isolates 2- (4-methoxy-benzenesulfinyl) -2,5-dimethyl-hex-4encarboxylic acid hydroxyamide as a colorless solid. Yield: 104 mg (10%) m.p. 108 ° C; MS: 312 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 2.27-2.8 (m, 2H), 5.02 (t, J = 7.5) Hz, 1H), 7.09 (d, J = 9 Hz, 2H), 7.39 (d, J = 9 Hz, 2H).

Example 7

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

Starting from N-hydroxy-2- (4-methoxy-benzenesulfanyl) -3-methyl-butyramide (1 g, 3.9 mmol) as obtained in Example 4, and following the method of Example 5, M-hydroxy-2 was isolated - (4-Methoxybenzenesulfinyl) -3-methyl-butyramide as a colorless solid. Yield 420 mg (40%), m.p. 163 ° C. MS: 272 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.89 -1.12 (m, 6H), 1.63 - 1.74 (m, 1 Η), 3.13 (d, J = 7 Hz, 1H), 3.83 (S, 3H ), 6.94 - 7.65 (m, 4H).

Example 8

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

Starting from N-hydroxy-2- (4-methoxy-phenylsulfanyl) -2-phenyl-acetamide (240 mg, 0.83 mmol) as obtained in Example 2, and following the method of Example 5, M-hydroxy-2- (4-methoxy42 benzenesulfinyl) -2-phenyl-acetamide as a colorless solid in 100 mg (40%) yield, m.p. 135 ° C; MS: 304 (M + H) ⁺ . 1 H NMR (300 MHz,

DMSO-de): δ 3.75 (s, 3H), 4.38 (s, 1 Η), 6.92 - 7.69 (m, 9H).

Example 9 Hydroxy-2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionamide

To a solution of 4-methoxybenzentiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in dry acetone (100 ml) was added α-bromo ethyl acetate (3.3 g, 20 mmol) in a round-bottom flask with stirring and the reaction the mixture is heated at reflux for 8 hours with good stirring. The reaction mixture was then allowed to cool and the potassium salt filtered off and the reaction mixture concentrated. The residue was extracted with chloroform and washed with water and 0.05 N NaOH solution. The organic layer was further washed well with water, dried over magnesium sulfate, filtered and concentrated. (4methoxy-phenylsulfanyl) -acetic acid ethyl ester was isolated as a pale yellow oil in a yield of 4.4 t (100%); MS: 227 (M + H) ⁺ .

To a solution of 60% 3-chloroperoxybenzoic acid (14.0 g, 40 mmol) in methylene chloride (100 ml) at 0 ° C was added slowly (4-methoxy-phenylsulfanyl) -acetic acid ethyl ester (4.4 g, 20 mmol). ) in methylene chloride (15 ml). The reaction mixture became cloudy and stirred at room temperature for 6 hours. The mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solids were filtered off and a solution of sodium sulfite was added to the organic layer and stirred for at least 3 hours before the mixture was extracted with chloroform and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated and the colorless 4-methoxy-phenylsulfonyl) -acetic acid ethyl ester was isolated as an oil. Yield: 100%, MS: 259.1 (M + H) ⁺

By stirring to a solution of 4-methoxyphenylsulfonyl) -acetic acid ethyl ester, benzyl bromide (1.8 g, 10 mmol) and

18-Crown-6 (500 mg) in acetone (250 ml) was added potassium carbonate (10 g, excess) and the mixture was refluxed for 24 hours. The mixture was then filtered and the acetone layer concentrated. The resulting residue was extracted with chloroform, washed well with b water, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting product was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexane. 2- (4-Methoxybenzenesulfonyl) -3-phenyl-propionic acid ethyl ester is obtained as a low melting point solid. Yield 3.0 g, 86% yield; MS: 349 (M + H) ⁺

To a solution of 2- (4-methoxy-benzenesulfonyl) ethyl ester -

3-Phenyl-propionic acid (348 mg, 1 mmol) in methanol (25 ml) was added 10 N NaOH (10 ml) with stirring. The reaction mixture was stirred at room temperature for 48 hours. Finally, the reaction mixture was concentrated and carefully neutralized with dilute HCl. 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-phenylpropionic acid as a colorless oil. Yield 250 mg, 89%; MS: 321 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -3-phenylpropionic acid (200 mg, 0.625 mmol) and following the method of Example 1, 150 mg of N-hydroxy-2- (4-methoxy-benzenesulfonyl) was isolated.

3-Phenyl-propionamide as a brown solid. Yield 71% m.p. MS: 336 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 3.2 (m, 1 Η), 3.8 (s, 3H), 4.0 - 4.2 (m, 2H). 7.0 - 8.0 (m, 9H).

Example 10

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

2- (4-Methoxy-phenylsulfanyl) -hexanecarboxylic acid ethyl ester was prepared according to the general method described in Example 1. Starting from ethyl 2-bromo hexanate (7 g, 32 mmol) and 4-methoxybenzentiol (4.2 g, 30 mmol) was isolated 8.3 g of product. Yield 98%. Light yellow oil; MS: 283 (M + H) ⁺ .

Starting from 2- (4-methoxy-phenylsulfanyl) hexanecarboxylic acid ethyl ester (2.8 g, 10 mmol) and following the method of Example 9, 3 g of 2- (4-methoxybenzenesulfonyl) -hexanecarboxylic acid ethyl ester was isolated as colorless solid. 95% yield, m.p. 62 ° C. MS: 314 (M + H) ⁺ .

® Starting with 2- (4-methoxy-benzenesulfonyl) hexanecarboxylic acid ethyl ester (2 g, 6.3 mmol), 1.5 g (83%) of 2 (4-methoxy-benzenesulfonyl) -hexanecarboxylic acid were isolated as a colorless solid following the method of Example 9. M.P. 116 ° C. MS: 287 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) hexanecarboxylic acid (1.g, 3.1 mmol) and following the method of Example 1, 700 mg of 2- (4-methoxybenzenesulfonyl) -hexanecarboxylic acid hydroxyamide was obtained as a colorless solid <substance. Yield 60%. Mp 130 ° C; MS: 302 (M + H) ⁺ . ¹ H NMR (300 MHz,

CDCl3): δ 0.786 (t, J = 7.2 Hz, 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 = 11 Hz, 2H), 9.3 (s, 1H), 10.9 (s, 1H).

Example 11

2- (4-Methoxy-benzenesulfonyl) -tetradecanecarbonyl hydroxyamide

2- (4-Methoxy-phenylsulfanyl) tetradecanecarboxylic acid ethyl ester was prepared by the general method of Example 1. Starting from the corresponding ethyl-2-bromo myristate (5.0 g,

14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol) were isolated 5.0 g of the product. Yield 98%. Light yellow oil; MS: 393 (M + H) ⁺ .

Starting from 2- (4-methoxy-phenylsulfanyl) tetradecanecarboxylic acid ethyl ester (3.9 g, 10 mmol) and following the method of Example 9, 3.2 g of 2- (4-methoxybenzenesulfonyl) -tetradecanecarboxylic acid is obtained as example colorless solid in 76% yield. Butter; MS: 425 (M + H) ⁺ .

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

Starting from 2- (4-methoxy-benzenesulfonyl) tetradecanecarboxylic acid (1.14 g, 2.9 mmol) and following the method of Example 1, 2- (4-methoxy-benzenesulfonyl) - Λ tetradecanecarboxylic hydroxyamide was obtained as an off-white solid. Yield 57%, m.p. 114 ° C; MS: 414 (M + H) ⁺ 1 H NMR (300 MHz, DMSO-de): δ 0.85 ¢, J = 7Hz, 3H), 1.16 -1.27 (m, 10H), 1.66 (m, 2H), 3.62 - 3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J = 15 Hz, 2H), 7.73 (d, J = 15 Hz, 2H).

Example 12

L1-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenylpropionamide

To a solution of 2- (4-methoxy-benzenesulfonyl) -3-phenyl-propionic acid ethyl ester (1.0 g, 3 mmol) (Example 9), methyl iodide (1 ml excess) and 18-Crown-6 (500 mg) in acetone (250 ml) was added potassium carbonate (10 g, excess) and the reaction mixture was heated at reflux for 24 hours. Finally, the reaction mixture was filtered and the acetone layer was concentrated. The resulting residue was extracted with chloroform, washed 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 to give 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1.0 g, 98%. MS: 349 (M + H) ⁺ . ¹

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

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-phenyl-propionic acid (900 mg, 2.7 mmol) and following the procedure of Example 1, 450 mg of N-hydroxy-2- (4-methoxy) is obtained -benzenesulfonyl) 2-methyl-3-phenyl-propionamide as a brown solid. Yield 48%, m.p. 58 ° C; MS: 350 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.4 (8, 3H), 3.1 (d, J = 9 Hz, 1H), 3.6 (d, J = 9 Hz, 1H), 3.9 (s, 3H), 6.8 7.9 (m, 9H).

Example 13

2- (4-Methoxy-benzenesulfonyl) -2,5-dimethylhex-2-enicarboxylic acid hydroxyamide

Starting from 2- (4-methoxy-phenylsulfanyl) propionic acid ethyl ester (Example 1) (12 g, 50 mmol) and following the method of Example 9, 12 g of 2- (4-methoxybenzenesulfonyl) propionic acid are obtained. acid as a semi-solid in 100% yield. MS: 256.1 (M + H) ⁺ .

Following the procedure of Example 12, 2- (4-methoxy-benzenesulfonyl) -2,5-dimethyl-hex-4-enicarboxylic acid ethyl ester was obtained starting from (1 g, 3.6 mmol) ethyl ester of 2 - (4methoxy-benzenesulfonyl) propionic acid and isoprenyl bromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; colorless oil; MS: 341 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 2,5-dimethyl-hex-4-enicarboxylic acid ethyl ester (900 mg, 2.6 mmol) to give 800 mg (96%) of 2- (4-methoxybenzenesulfonyl) -2,5-dimethyl-hex-4 enicarboxylic acid as semi-solid according to the method of Example 9. MS: 313 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2,5-dimethylhex-4-enicarboxylic acid (1.0 g, 3.2 mmol) and following the procedure of Example 1, 700 mg of 2- (4-methoxybenzenesulfonyl) was obtained. -2,5-Dimethyl-hex-2-enicarboxylic acid as low melting point substance. Yield 67%. MS: 328 (M + H) ^+, H NMR (300 MHz, CDCl 3): δ 1.3 (s, 3H), 1.5 (d, J = 6.2 Hz, 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

Following the method of Example 12, 3- (biphenyl-4yl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid ethyl ester was prepared starting from (2.7 g, 10 mmol) ethyl ester of 2 - (4methoxy-benzenesulfonyl) -propionic acid and 4- (chloromethyl) biphenyl (2.5 g, 12 mmol). Yield 4.0 g 91%. Colorless oil; MS: 438 (M + H) ⁺ .

Starting from 3- (biphenyl-4-yl) -2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89 were isolated) %) 3- (Biphenyl-4-yl) -2 (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid as a colorless solid. Mp 161 ° C; MS: 411 (M + H) ⁺ .

Starting from 3- (biphenyl-4-yl) -2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid (2.0 g, 4.8 mmol), 1.2 g of 3- (biphenyl- 4-yl) -Nhydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid. Yield 58%. Mp 177 ° C. MS: 426 (M + H) ⁺

1 H NMR (300 MHz, CDCl 3): δ 1.4 (s, 3H), 3.2 (d, J = 9 Hz, 1H), 3.7 (d, J = 9 Hz, 1H), 3.9 (S, 3H) , 7.0 - 7.8 (m, 13H), 9.7 (bs. 1H).

Example 15

Hydroxyamide 2- (4-methoxy-benzenesulfonyl) _-2-1 5,9 trimetildeka-4,8-dienkarbonova acid

Following the method of Example 12, 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienecarboxylic acid ethyl ester was prepared starting from (2.7 g, 10 mmol) ethyl ester of 2 - (4methoxy-benzenesulfonyl) -propionic acid and geranyl bromide (3.0 g, 13 mmol). Yield 4.0 g, 98%). Colorless oil; MS: 409 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 2,5,9-trimethyl-deca-4,8-dienecarboxylic acid ethyl ester (3 g, 7.4 mmol) by the method of Example 9, 2.8 g (96 was obtained) %) 2- (4-methoxybenzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienecarboxylic acid as a colorless oil. MS: 379 (M-H) -.

Starting from 2- (4-methoxy-benzenesulfonyl) -2,5,9-trimethyldeca-4,8-dienecarboxylic acid (2.0 g, 5.2 mmol) and following the procedure of Example 1, 1.8 g of 2- (hydroxyamide) is obtained. 4-Methoxybenzenesulfonyl) -2,5,9-trimethyl-deca-4,8-dienecarboxylic acid as a colorless oil. Yield 88%. MS: 396 (M + H) ⁺ . 1 H NMR (300 MHz,

CDCI3): δ L4 (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 = 9.0 Hz, 2H), 7.7 (d, J = 9.0 Hz, 2H).

Example 16

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

The method of Example 12 afforded 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-methyl-propionic methoxy-benzenesulfonyl) -propionic acid ethyl ester and bromoacid starting from (2.7 g, 10 mmol) ethyl 2- (449 methylcyclohexanone (1.8 g, 10 mmol). Yield 3.5 g, 95%; yellow oil; MS: 369 (M + H) ⁺ .

Leaving 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid ethyl ester (3 g, 8.1 mmol) afforded 2.5 g (90%) of 3-cyclohexyl-2- (4 -methoxy-benzenesulfonyl) -2-methyl-propionic acid as a colorless solid according to the method of Example 9, m.p. 116 ° C. MS: 341 (M + H) ⁺ .

Starting from 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid (2.0 g, 5.8 mmol) to give the colorless solid of 1.1 g of 3-cyclohexyl-N-hydroxy-2 by the method of Example 1 - (4-Methoxy-benzenesulfonyl) -2-methyl-propionamide. Yield 55% m.p. 58 ° C.%. MS: 356 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3: δ 1.4 (s, 3H), 2.3 -1.0 (m, 13H), 3.9 (s, 3H), 7.0 (d, 8.8 Hz, 2H), 7.69 (d, 9.0 Hz. 2H).

Example 17

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide

Following the method of Example 12, 2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] -propionic acid ethyl ester was prepared using ( 2.7 g, 10 mmol) 2- (4-Methoxy-benzenesulfonyl) -propionic acid ethyl ester and 4- (2-piperidin-1-yl-ethoxy) -benzyl chloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; brown oil; MS: 490 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester (4.0 g, 7.9 mmol) yields 3.5 g (94% yield) of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid as colorless crystals by the method of Example 9 with mp 106 ° C; MS: 462.5 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (2.0 g, 4.2 mmol) and by the method described in Example 1 gave N-hydroxy-2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionamide as a colorless solid. Yield 1 g, 48%. Mp 98 ° C; MS: 477 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.2 (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-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid hydroxyamide

In the method of Example 12, 2- [4- (2-Azepan-1-ylethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester was obtained starting from (2.7 g, 10 mmol) 2- (4-Methoxy-benzenesulfonyl) -propionic acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl] -azepane (3.03 g, 10 mmol). Yield 4.5 g, 90%; brown oil; MS: 504 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester (4.0 g, 7.9 mmol), 3.5 g ( 94% yield) of 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid as a semi-solid according to the method of Example 9. MS: 476 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid (2.0 g, 4.2 mmol) and following the procedure of Example 1, 1 2- (4- (2azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -propionic acid hydroxyamide as a colorless solid. Yield 1.8 g, 87% mp 68 ° C; MS: 491 (M + H) ⁺ . NMR (300 MHz, CDCl 3): δ 1.23 (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-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanecarboxylic acid hydroxyamide

2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -pentanecarboxylic acid ethyl ester was prepared according to the general method of Example 12. Starting from 2- (4-methoxybenzenesulfonyl) -pentanecarboxylic acid (3.5 g, 11.7 mmol) and 1- (2- (4-chloromethyl-phenoxy) -ethyl] -azepane (3.9 g, 12.8 mmol). Yield 2.58 g (42%); brown oil; MS: 532.4 (M + H) ⁺

2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -pentanecarboxylic acid is obtained from 2- [4- (2-azepan-1-yl- ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -pentanecarboxylic acid (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10 N NaOH (15 ml). The resulting mixture was developed by the method of Example 1. Yield 830 mg (44%); brown solid, m.p. 55 ° C; MS: 504.4 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -pentanecarboxylic acid (690 mg, 1.37 mmol) and following the procedure described in Example 1, was obtained 240 mg of 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -pentanecarboxylic acid hydroxyamide, which was isolated as a yellow solid. Yield 34%; mp. 85 ° C. MS: 519.2 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 0.71 (t, J = 7.3 Hz, 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 = 8.7 Hz, 2H), 7.14 (m, 4H), 7.71 (d, J = 9 Hz, 2H), 9.07 (s, 1H), 10 (s, 1H) ).

Example 20

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, methylisopropyl amino-ethoxy) -phenyl] -propionamide

Following the procedure described in Example 12, 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N -isisopropyl amino-ethoxy) -phenyl] -propionic acid ethyl ester is obtained starting from (5.4 g, 20 mmol) 2- (4-methoxybenzenesulfonyl) -propionic acid ethyl ester and 4- (2-N, N-diisopropyl amino ethoxy) -benzyl chloride (6.1 g, 20 mmol). Yield 8.9 g, 88%; yellow oil; MS: 506.5 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) 2-methyl-3- [4- (2-N, N-diisopropyl amino-ethoxy) -phenyl] -propionic acid ethyl ester (4.0 g, 7.9 mmol) 3.5 g (92% yield) of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, N-diisopropyl amino-ethoxy) phenyl] -propionic acid are obtained as colorless crystals by the method of Example 9. Mp 68 ° C. MS: 478.6 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2N, N-diisopropyl amino-ethoxy) -phenyl] -propionic acid (2.0 g, 4.1 mmol) and follow the procedure Example 1 gave 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2- N -diisopropyl amino-ethoxy) phenyl] -propionamide as a colorless solid. Yield 1 g, 49% m.p. 98 ° C (hydrogen chloride salt); MS: 493 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.2 (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-H, N-diethylamino-ethoxy) phenyl] -propionamide

Following the method of Example 12, -2 (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-H, N-diethylaminoethoxy) phenyl] -propionic acid ethyl ester was obtained starting from ethyl ester of (5.4 d, 20 mmol) 3- (4-methoxy-benzenesulfonyl) -propionic acid and

4- (2-H, N-diethylamino-ethoxy) -benzyl chloride (5.5 g, 20 mmol). Yield 8.5 g, 89%; brown oil; MS: 478.6 (M + H) ⁺ .

Starting from -2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-H, N-diethylamino-ethoxy) phenyl] propionic acid ethyl ester (3.5 g, 7.7 mmol) is obtained - 2- (4-Methoxybenzenesulfonyl) -2-methyl-3- [4- (2-N-diethylamino-ethoxy) phenyl] propionic acid as colorless crystals according to the method of Example 9. M.p. 96-98 ° C; MS: 450.5 (M + H) ⁺ .

Starting from -2- (4-methoxy-benzenesulfanyl) -2-methyl-3- [4- (2M, N-diethylamino-ethoxy) phenyl] -propionic acid (2.0 g, 4.4 mmol) and following the procedure of Example 1 gave 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) phenyl] propionamide as a colorless solid. Yield 1 g, 48% m.p. 56 59 ° C (HCl salt);); MS: 465.5 (M + H) ⁺ . ¹ H NMR (300 MHz, COOD: δ 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 22

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide

Following the method of Example 12, 2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) phenyl] -propionic acid ethyl ester was prepared starting from 2- (4-Methoxy-benzenesulfonyl) -propionic acid ethyl ester and 3- (2-piperidin-1-yl-ethoxy) -benzyl chloride (5.2 g, 20 mmol) (6.0 g, 20 mmol). Yield 8.2 g, 93%; brown oil; MS: 490 (M-H) ⁺ .

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

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (3.0 g, 6.5 mmol) and by the method of Example 1 gives 2- (4-methoxy-benzenesulfonyl) -2methyl-3- [3- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide as a colorless solid. Yield 1.8 g 58% m.p. 74 ° C. MS: 477 (M +

H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.25 (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) -Nhydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide by the method of Example 12, 3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] -propoxy} -phenyl) N-hydroxy-2- ethyl ester is obtained (4-Methoxy-benzenesulfonyl) -2-methyl-propionic acid starting from (2.72 g, 10 mmol) 2- (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester and 1- [2- (4-chloromethylphenoxy) ethyl ] -4- (3-chloro-phenyl) -piperazine (4.2 g, 11 mmol). Yield 5.5 g, 89%; brown oil; MS: 616 (M + H) ⁺ .

Starting from 3- (4- {3- [4- (3-chloro-phenyl) piperazin-1-yl] -propoxy} -phenyl) -N-hydroxy-2- (4-methoxybenzenesulfonyl) ethyl ester - 2-methyl-propionic acid (4.0 g, 6.5 mmol) gave 3.0 g (78% yield) of 3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] propoxy} - phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methylpropionic acid as colorless crystals according to the method of Example 9. Mp 196 ° C. MS: 588.1 (M + H) ⁺ .

Starting from 3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] propoxy} -phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2 -methylpropionic acid (3.0 g, 5.1 mmol) and by the method of Example 1, 1.8 g of 3- (4- {3- [4- (3-chloro-phenyl) -piperazin-1-yl] propoxy} - phenyl) -N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methylpropionamide as a pale yellow solid, 55%; mp 122 ° C (HCl salt); MS: 640 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.2 (s, 3H), 3.4 -1.5 (m, 14 Η), 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-enicarboxylic acid hydroxyamide

Potassium carbonate was added to a solution of (4-methoxy-benzenesulfonyl) acetic acid ethyl ester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml). (10 g, excess) and the mixture was refluxed for 24 hours. The reaction mixture was then filtered and the acetone layer concentrated. The 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 resulting 2- (4-methoxybenzenesulfonyl) -5-methyl-hex-4-enicarboxylic acid ethyl ester was isolated as a colorless oil. Yield 3.0 g, 93%.

In the method of Example 12, 2- (4-Methoxybenzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4enecarboxylic acid ethyl ester was prepared starting from ( 3.26 g, 10 mmol) 2- (4-Methoxy-benzenesulfonyl) -5-methyl-hex-4-carboxylic acid ethyl ester and 4- (2-morpholin-1-yl-ethoxy) -benzyl chloride (3.0 g, 11 mmol) ). Yield 4.5 g, 82%; brown oil; MS: 546 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

5-Methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4-enicarboxylic acid (3.0 g, 5.5 mmol) according to the method of Example 9 gave 2.1 g (yield 75%) 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4-enicarboxylic acid as a semi-solid. MS: 518.6 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4-enicarboxylic acid (1.0 g, 1.9 mmol) and Following the method of Example 1, 450 mg of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -hex-4-enicarboxylic acid hydroxyamide is obtained as a pale yellow solid. Yield: 45%, m.p. 92 ° C (HCl salt); MS: 570; (Μ + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.3 (d, 3H), 1.65 (d, 2H), 3.5 -1.8 (m,

14H), 3.9 (S, 3H), 4.5 (m, 2H), 5.4 (m, 1H), 6.5-7.9 (m, 8H), 11.5 (bs, 1H).

Example 25

N-hydroxy-2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, methyl-amino-ethoxy) -phenyl] -propionamide

To a solution of 4-hydroxy thiophenol (12.6 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in chloroform (400 ml) was added dropwise 2-bromo ethyl propionate (18.2 g, 100 mmol). The reaction mixture was refluxed for 1 h and cooled to room temperature, then 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 solution of 2- (4-hydroxy-phenylsulfanyl) propionic acid ethyl ester (11.3 g, 50 mmol) and potassium carbonate (50 g, excess) in acetone (300 ml) was added with stirring ethyl iodide (20 ml, excess). and boil for 8 hours. The reaction mixture was then filtered and concentrated. The resulting residue was extracted with chloroform and washed well with water. It is dried and concentrated. 2 (4-Ethoxy-phenylsulfanyl) -propionic acid ethyl ester was isolated as a colorless oil. Yield: 12.0 g, 98%; MS: 255 (M + H) ⁺ .

2- (4-Ethoxy-phenylsulfanyl) -propionic acid ethyl ester is converted to 2- (4-ethoxy-phenylsulfonyl) propionic acid by the method described in Example 9 (2).

Working by the method of Example 12, 2- (4-Ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethyl amino-ethoxy) phenyl] -propionic acid ethyl ester is obtained from ( 2- (4-Ethoxy-benzenesulfonyl) -propionic acid ester and 4- (2-N, N-flune (amino-ethoxy) -benzyl chloride (3.5 g, 12.2 mmol) 3.5 g, 12.2 mmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M + H) ⁺ .

Starting from 2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, 1-diethyl amino-ethoxy) -phenyl] propionic acid ethyl ester (4.0 g, 8.1 mmol) 3.2 g (80% yield) of 2 (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethyl amino-ethoxy) phenyl] -propionic acid are obtained as a colorless semi-solid by the method from Example 9. MS: 464.5 (M + H) ⁺ .

Starting from 2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2Ν, N-diethyl amino-ethoxy) -phenyl] -propionic acid (2.0 g, 4.3 mmol) and follow the procedure from Example 1 gave 1-hydroxy-2- (4-ethoxy-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethyl amino-ethoxy) phenyl] -propionamide as a colorless low-melting solid . Yield 1.2 g, 57%; (HCl salt); MS: 478.5 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δθ.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-dimethyl2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -deca-4,8-dienecarboxylic acid hydroxyamide

To a solution of (4-methoxy-benzenesulfonyl) acetic acid ethyl ester (5.16 g, 20 mmol), geranyl bromide (4.2 g, 20 mmol) and 18Crown-6 (500 mg) in acetone (250 ml) was added with potassium stirring. carbonate (10 g, excess) and the mixture was refluxed for 24 hours. The reaction mixture was then filtered and the acetone layer 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) 5,9-dimethyl-deca-4,8-dienecarboxylic acid ethyl ester was isolated as a colorless oil. Yield: 7.0 g, 89%.

HtMl

Using the method of Example 12, 2- (4-Methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) benzyl] -decan -4,8- dienecarboxylic acid was prepared by starting from (1.0 g, 2.5 mmol) 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-deca-4,8-dienecarboxylic acid ethyl ester and 4- (2-morpholine-1- elethoxy) -benzyl chloride (800 mg, 2.5 mmol). Yield 1.2 g, 76%; brown oil; MS: 614 (M + H) ⁺ .

Starting from 2- (4-methoxybenzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] deca-4,8-dienecarboxylic acid ethyl ester (2.0 d, 3.2 mmol), 1.5 g (80% yield) of 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -decane are obtained. 4,8-dienecarboxylic acid as a semi-solid by the method of Example 9. MS: 586.6 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4 (2-morpholin-4-yl-ethoxy) -benzyl] -deca -4,8-dienecarboxylic acid (1.0 g , 1.7 mmol) and by the method of Example 1, 550 mg of (4E) -2- (4-methoxy-benzenesulfonyl) -5,9-dimethyl-2- [4- (2morpholin-4-yl-ethoxy) was obtained ) benzyl] -deca-4,8-dienecarboxylic acid as a pale yellow solid. Yield 550 mg, 53% m.p. 61 ° C (HCl salt); MS: 638 (M + H) ⁺ .

Example 27

2- [4- (2-Diethylamino-egoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) hexanecarboxylic acid hydroxyamide

2- [4- (2-Diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) hexanecarboxylic acid ethyl ester was prepared according to the general method of Example 12. Starting from 2- (4-methoxy-benzenesulfonyl) -hexanecarboxylic acid (4 g, 12.7 mmol) and [2 (4-chloromethyl-phenoxy) -ethyl] -diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude product (100%); brown oil; MS: 520.4 (M + H) ⁺ .

2- [4- (2-Diethylamino-ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -hexanecarboxylic acid is obtained from 2- [4- (2-diethylamino-ethoxy) -benzyl] ethyl ester -2- (4-Methoxybenzenesulfonyl) hexanecarboxylic acid (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10 N NaOH (30 ml). The resulting mixture was worked up as in Example 1. Yield 3.88 g crude product (51%); brown oil; MS: 492 (M + H) ⁺ .

Starting from 2- [4- (2-diethylamino-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -hexanecarboxylic acid (3.88 g, 7.89 mmol) and following the procedure of Example 1, 800 mg of hydroxyamide was obtained. 2- [4- (2-Diethylamino-ethoxy) -benzyl] -2- (4-methoxybenzenesulfonyl) -hexanecarboxylic acid as a yellow powder. 20% yield, m.p. 67 ° C; MS: 507.4 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d6): δ 0.75 (t, J = 7.1 Hz, 3H), 1.05 (m, 2H), 1.23 ¢, J = 7.2 Hz, 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 = 4.8 Hz, 2H), 6.88 (d, j = 8.7 Hz, 2H), 7.15 (m, 4H), 7.7 (d, J = 9 Hz, 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) -phenyl] -propionamide

Following the method of Example 12, 2- (4-n-butoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ylethoxy) -phenyl] -propionic acid ethyl ester was obtained from (3.1 g, 10 mmol) 2- (4-n-butoxy-benzenesulfonyl) -propionic acid ethyl ester (obtained from 2- (4-hydroxy-phenylsulfanyl) propionic acid ethyl ester and n-butyl bromide as follows the method of Example 27) and 4- (2-piperidin-1-yl-ethoxy)) -benzyl chloride (3.0 g, 10.1 mmol). Yield 4.5 g, 84%); brown oil; MS: 532.7 (M + H) ⁺ .

Starting from 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid ethyl ester (5.0 g, 9.4 mmol) yields 4.2 g (88% yield) of 260 (4-n-butoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] -propionic acid as a colorless solid by the method from Example 9. MS: 504.6 (M + H) ⁺ .

Starting from 2- (4-n-butoxy-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (3.0 g, 5.9 mmol) and follow the method of Example 1 gave 1.3 g of 2- (4-n-butoxybenzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionamide as a colorless solid, m.p. . 65 ° C and yield 1.3 g / (42%) (HCl salt); MS: 478.5 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 0.9 (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, methyl-amino-ethoxy) -phenyl] -propionamide

The method of Example 12 gave 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethyl amino-ethoxy) phenyl-propionic acid ethyl ester starting from (5.0 g, 18 mmol) 2- (4-Methoxy-benzenesulfonyl) -propionic acid ethyl ester and 3-1,2-N-diethyl amino-ethoxy) -benzyl chloride (4.9 g, 18 mmol). Yield 8.1 g, 93 Q%; brown oil; MS: 478.1 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 2-methyl-3- [3- (2-N, N-diethyl amino-ethoxy) -phenyl] -propionic acid ethyl ester (8.1 g, 16.9 mmol) 6.7 g (88% yield) of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethyl amino-ethoxy) -phenyl] propionic acid are obtained as a colorless semi-solid by the method of Example 9, m.p. 78 -81 ° C. MS: 450.1 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2Ν, N-diethyl amino-ethoxy) -phenyl] -propionic acid (6.7 g, 15 mmol) and follow the procedure Example 1 afforded 1.5 g of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-N, N-diethyl amino-ethoxy) -phenyl] 61 propionamide as a colorless, low melting point solid . Yield 1.5 g (21%) (HCl salt); MS: 478.5 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 1.21 (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- (2morpholin-1-yl-ethoxy) phenyl] -propionamide

Working according to the method of Example 12, 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-ylethoxy) phenyl] -propionic acid ethyl ester was obtained starting from ( 5.2 g, 20 mmol) 2- (4-Methoxy-benzenesulfonyl) -propionic acid ethyl ester and 3- (2-morpholin-1-yl-ethoxy) -benzyl chloride (6.0 g, 20 mmol). Yield 9.1 g, 93%; brown oil; MS: 492 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester (10.0 g, 20.3 mmol) yields 8.0 g (86% yield) of 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) -phenyl] propionic acid as colorless crystals by the method of Example 9. MS: 464.5 (M + H) &lt; + & gt ^; .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [3- (2morpholin-1-yl-ethoxy) -phenyl] -propionic acid (4.55 g, 9.8 mmol) and follow the procedure according to Example 1, 440 mg 2- (4-methoxybenzenesulfonyl) -2-methyl-3- [3- (2-morpholin-1-yl-ethoxy) phenyl] propionamide was isolated as a colorless solid. Yield: 440 mg, 9% m.p. 63 ° C; MS: 479.5 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.26 (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- (462 methoxy-benzenesulfonyl) -2-methyl-hexanecarboxylic acid hydroxyamide

Working according to the method of Example 9, ethyl ester is obtained

6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methyl-hexanecarboxylic acid using (5.0 g, 20 mmol) 2- ( 4-methoxybenzenesulfonyl) -acetic acid and 4-phthalimido bromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%. Colorless oil; MS: 474 (M + H) ⁺ .

Starting from 6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -2- (4-methoxy-benzenesulfononyl) -2-methylhexanecarboxylic acid ethyl ester (8.4 g, 17.7 mmol) working according to Example 9 yields 6.95 g (88%) of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfononyl) -2-methyl-hexanecarboxylic acid as a colorless butter. MS: 446 (M + H) ⁺ .

Starting from 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxy-benzenesulfononyl) -2-methyl-hexanecarboxylic acid (4.9 g, 11 mmol) and follow The process according to Example 1 gave 3.1 g of 6- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -2- (4-methoxybenzenesulfonyl) -2-methyl-hexanecarboxylic acid hydroxyamide as a light brown solid. Yield: 46% m.p. MS: 461.2 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.55 (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-ylbenzenesulfonyl) -N-hydroxy-2-methyl-propionamide

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

2- (4-Bromo-phenylsulfanyl) -propionic acid ethyl ester was converted to 2- (4-bromo-phenylsulfonyl) -propionic ethyl ester by the method described in Example 9, paragraph 2.

A mixture of 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) was added. boil in degassed toluene (250 ml) for 8 hours. The reaction mixture was then filtered through celite and concentrated. The product was purified by column chromatography over silica gel eluting with 50% ethyl acetate: hexane. Colorless oil; yield: 5.9 g, 95%, MS: 309 (M + H) +

In the method of Example 12, 2- (4- (2-furanylbenzenesulfonyl) -2-methyl-3- [4- (2-N, 1-diethylamino-ethoxy) -phenyl] propionic acid ethyl ester was prepared by starting 2- (4- (2-Furanyl-benzenesulfonyl) -propionic acid and 4- (2-N, N-diethylamino-ethoxy) -benzyl chloride (3.5 g, 12.2 mmol) from (3.08 g, 10.0 mmol). Yield 5.0 g, 97%; brown oil; MS: 514.6 (M + H) ⁺ .

Starting from 2- (4- (2-furanylbenzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] propionic acid ethyl ester (5.1 g, 10.0 mmol) 3.8 g (78% yield) of 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylaminoethoxy) -phenyl] -propionic acid are obtained as a colorless solid by the method of Example 9. Melting point 58 ° C, MS: 486.5 (M + H) ⁺ .

Starting from 2- (4- (2-furanyl-benzenesulfonyl) -2-methyl-3- [4 (2-N, N-diethylamino-ethoxy) -phenyl] -propionic acid (5.0 g, 10.3 mmol) and Following the method of Example 1, 1.2 g of 2- (4-ethoxybenzenesulfonyl) -2-methyl-3- [4- (2-N, N-diethylamino-ethoxy) -phenyl] propionamide are obtained as a low-melting solid. g, 62%; (HCl inllitiiO salt); MS: 502 (Μ + H) ⁺ . 1 H NMR (300 MHz, CDCl 3: δ 1.23 (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-ylethoxy) -benzyl] -butyramide

2- (4-Methoxy-phenylsulfanyl) -butyric acid ethyl ester was prepared according to the general method of Example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol) 5.19 g (40%) of a clear oil are obtained; MS: 255.2 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -butyric acid ethyl ester was prepared according to the general method of Example 9. Starting from 2- (4-methoxy-phenylsulfanyl) -butyric acid ethyl ester (5 g, 20 mmol). yield 5.74 g (100%); colorless oil; MS: 287.1 (M + H) ⁺ .

Following the method of Example 12, 2- (4-Methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid ethyl ester was obtained from (3.5 g, 12.2 mmol) ethyl 2- (4-Methoxy-benzenesulfonyl) -butyric acid ester and 4- [2- (chloromethylphenoxy) -ethyl] -morpholine (2.34 g, 6.7 mmol). Yield 5.7 g. 100%; brown oil; MS: 506.4 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid ethyl ester (5.54 g, 11 mmol) gave 2.9 g (yield 55%) 2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid as a semi-solid colorless substance according to the method of Example 9. MS: 478.3 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyric acid (2.6 g, 5.4 mmol) to give the method of Example 1 510 mg of N-hydroxy-2- (4-methoxybenzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -butyramide, which is isolated as a brown solid. Yield 2%, m.p. 51 ° C. MS: 493.3 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.90 (t, J-7.2 Hz, 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 = 8.7 Hz, 2H), 7.14 (m, 4H), 7.73 (d, J = 4.7 Hz, 2H), 9.08 (s, 1H).

Example 34

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyramide

Following the method of Example 12, 2- (4-Methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -6enzyl] -butyric acid ethyl ester was obtained from (1.0 g, 3.33 mmol) ethyl 2- (4-Methoxy-benzenesulfonyl) -butyric acid ester and 1- [2- (4-chloromethylphenoxy) -ethyl] -piperidine (0.85 g, 3.36 mmol). Yield 1.07 g, 62%; brown oil; MS: 504.4 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid ethyl ester (3.7 g, 7.3 mmol) gave 2.2 g (yield 63%) 2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid as a semi-solid colorless substance according to the method of Example 9. MS: 476 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyric acid (2.2 g, 4.63 mmol) to give 360 according to the method of Example 1 mg of N-hydroxy-2- (4-methoxybenzenesulfonyl) -2- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -butyramide, which is isolated as a brown solid. Yield 16%, m.p. 75 ° C. MS: 491.3 (M + H) ^{+ 1} H NMR (300 MHz, DMSO-d ₆ ): δ 0.90 (t, J = 7.2 Hz, 3H), 1.36 - 1.96 (m, 4H), 2.4 - 2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, J = 5.9 Hz, 2H),

6.8 (d, J = 8.5 Hz, 2H), 7.11 (m, 4H), 7.71 (d, J = 8.8 Hz, 2H), 9.09 (s, 1H) q

10.8 (s, 1H).

Example 35

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

2- (4-Methoxy-phenylsulfanyl) - pentanecarboxylic acid ethyl ester was prepared according to the general method of Example 9. Starting from ethyl 2-bromohalerate (8.23 g, 39.3 mmol) and 4methoxythiophenol (5 g, 35.7 mmol) were obtained. 10.46 g (100%) of a clear oil; MS: 269 (M + H) ⁺ .

2- (4-Methoxy-phenylsulfonyl) - pentanecarboxylic acid ethyl ester was prepared according to the general method of Example 9. It was derived from 2- (4-methoxy-phenylsulfanyl) -pentanecarboxylic acid ethyl ester (6.95 g, 27.4 mmol). yield 7.07 g (86%); clear oil; MS: 300.9 (M + H) ⁺ .

/ Following the method of Example 12, 2- (4-Methoxyfenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] pentanecarboxylic acid ethyl ester was obtained from (3.0 g, 10.8 mmol) 2- (4-Methoxy-benzenesulfonyl) -pentanecarboxylic acid ethyl ester and 4 [2- (chloromethyl-phenoxy) -ethyl] -morpholine (3.45 g, 11.9 mmol). Yield 3.08 g, 62%; brown oil; MS: 520.4 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanecarboxylic acid ethyl ester (2.73 g, 5.27 mmol) afforded 1.45 g (yield 56%) 2- (4-Methoxy-benzenesulfonyl) -2 [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanecarboxylic acid as a semi-solid colorless substance according to the method of Example 9. MS: 492.3 (M + НH) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] -pentanecarboxylic acid (1.01 g, 2.05 mmol) to give 190 mg of 2 (4-methoxy-benzenesulfonyl) -2- [4- (2-morpholin-4-yl-ethoxy) -benzyl] pentanecarboxylic acid hydroxyamide, which is isolated as a brown solid. Yield 18%, m.p. 101 ° C. MS: 507.4 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 0.71 (t, J = 7 Hz, 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 = 8.7 Hz, 2H), 7.15 (m, 4H), 7.74 (d, J = 8.9 Hz, 2H), 9.08 (S, 1H).

Example 36

2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid hydroxyamide

2- (4-Methoxy-phenylsulfanyl) -octanecarboxylic acid ethyl ester was prepared according to the general method of Example 9. It was obtained from ethyl 2-bromoctanate (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) ⁺ .

2- (4-Methoxy-phenylsulfonyl) -octanecarboxylic acid ethyl ester was prepared according to the general method of Example 9 starting from 2- (4-methoxy-phenylsulfanyl) -octanecarboxylic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M + H) +

According to the method of Example 12, 2- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid ethyl ester was obtained starting from (1.69 ethyl ester) g, 5.18 mmol) 2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid and 1- [2 (4-chloromethyl-phenoxy) -ethyl] -azepane (1.73 g, 6.0 mmol). Yield 4.86 g, 99%; brown oil; MS: 574.5 (M + H) ⁺ .

Starting from 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid ethyl ester (4.8 g, 8.37 mmol) afforded 1.55 g ( yield 34%) 2- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid as a colorless semi-solid by the method of Example 9. MS: 551 (M + H) ⁺ .

Starting from 2- (4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) -octanecarboxylic acid (1.09 g, 2.0 mmol) and using the method of Example 1, yields 300 mg of 2- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-methoxy-benzenesulfonyl) octanecarboxylic acid hydroxyamide as a yellow solid. Yield 27%, mp 65 ° C MS: 561.6 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.81 (t, J = 6.6 Hz, 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 = 8.7 Hz, 2H), 7.14 (m, 4H), 7.7 (d, J = 9Hz, 2H), 9.06 (s, 1H), 10.28 (S, 1H).

Example 37

2- (4-Methoxy-benzenesulfanyl) -octanecarboxylic acid hydroxyamide

2- (4-Methoxy-phenylsulfanyl) -octanecarboxylic acid ethyl ester was prepared according to the general method of Example 9. It was obtained from ethyl 2-bromoctanate (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) ⁺ .

u Starting from 2- (4-methoxy-benzenesulfanyl) octanecarboxylic acid ethyl ester (3.1 g, 10 mmol) to give 2- (4-methoxybenzenesulfanyl) -octanecarboxylic acid, a colorless semi-solid was isolated by the method of Example 9. MS: 283 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfanyl) -octanecarboxylic acid (4.25 g, 16 mmol) to give 3.64 g of 2- (4-methoxy-benzenesulfanyl) -octanecarboxylic acid hydroxyamide as a colorless solid body. Yield 76% m.p. 90 ° C. MS: 298.2 (M + H) ⁺ .

Example 38 u 2- (4-Fluoro-phenylsulfanyl) -octanecarboxylic acid hydroxyamide

2- (4-Fluoro-phenylsulfanyl) -octanecarboxylic acid ethyl ester was prepared according to the method of Example 9. It was obtained from 2bromo-octanate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); colorless oil; MS: 299 (M + H) ⁺ .

Starting from 2- (4-fluoro-phenylsulfanyl) octanecarboxylic acid ethyl ester (3.1 g, 10 mmol) was prepared according to the method of Example 9 2.89 g (100% yield) of 2- (4-fluoro-phenylsulfanyl) octanecarboxylic acid . MS: 268.9 (M + H) ⁺ .

-> ΙπίίΗ ·

Starting from 2- (4-fluoro-phenylsulfanyl) -octanecarboxylic acid (2.49 g, 9.2 mmol) and following the method of Example 1, 2.72 g of 2- (4-fluoro-phenylsulfanyl) -octanecarboxylic acid hydroxyamide was obtained as colorless solid. Yield 99%; Mp 58 ° C; MS: 284 (M + H) ⁺ .

Example 39

2- (1-Methyl-1H-imidazol-2-ylsulfanyl) oxanecarboxylic acid hydroxyamide / 2- (1-methyl-1H-imidazol-2-ylsulfanyl) octanecarboxylic acid ethyl ester was prepared according to the general method of Example 9. It was obtained from ethyl 2-bromoctanate (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) ⁺

2- (1-Methyl-1H-imidazol-2-ylsulfanyl) octanecarboxylic acid ethyl ester (12 g, 42.2 mmol) was prepared according to the method of Example 9, 10.2 g (95% yield) of 2- (1-methyl-1H- imidazol-2-ylsulfanyl) octanecarboxylic acid, which is isolated as a colorless solid, m.p. 95 ° C; MS: 257.1 (M + H) ⁺ .

Starting from 2- (1-methyl-1H-imidazol-2-ylsulfanyl) 0-octanecarboxylic acid (7.84 g, 30.6 mmol) and following the method of Example 1, 2.77 g of 2- (1-methyl-1H) hydroxyamide is obtained. -imidazol-2ylsulfanyl) -octanecarboxylic acid as a colorless solid, m.p. 125 ° C; yield 33%; MS: 272.2 (M + H) ⁺ .

Example 40

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

Following the method of Example 9, 2- (4-Methoxybenzenesulfonyl) -3-naphthalen-2-yl propionic acid ethyl ester was prepared starting from (5.0 g, 20 mmol) 2- (4-methoxy benzenesulfonyl) ethyl ester - acetic acid and 2-bromomethyl naphthalene (4.4 g, 20 mmol). Yield 7.2 g, 91%; colorless oil; MS: 399 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 3-naphthalen-2-yl propionic acid ethyl ester (3.7 g, 9 mmol) according to the method of Example 9, 3.3 g (96%) of 2- (4- methoxy-benzenesulfonyl) -3-naphthalen-2-yl propionic acid as a colorless oil. MS: 369.1 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -3-naphthalen-2-yl propionic acid (2.2 g, 5.9 mmol) to give 820 mg of N-hydroxy-2- (4-methoxy) by the method of Example 1 -benzenesulfonyl) -3-naphthalen2-yl propionamide as a pale brown solid. Yield 36%; mp 161-163 ° C. MS: 385.9 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 3.32 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92 7.89 (m, 11H).

Example 41

1,1-Hydroxy-2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid hydroxyamide

A mixture of 4-methoxybenzyl mercaptan (7.0 g, 45 mmol), ethyl 2 bromopropionate (8.2 g, 46 mmol) and powdered potassium carbonate (10 g, 72 mmol) in 150 ml of acetone was refluxed for 18 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was taken up in 150 ml of methylene chloride, washed with water (150 ml), dried over anhydrous sodium sulfate and evaporated to give 12 g (99%) of a colorless liquid; MS: 255.1 (M + H) ⁺ . This compound was used without further purification.

To a solution of 2- (4-methoxyphenylmethanesulfanyl) -propionic acid (5.7 g, 21 mmol) in 100 ml of methylene chloride cooled with ice (5 ° C) was added portions (7.2 g, 40 mmol) of chloroperbenzoic acid and the mixture The reaction mixture was diluted with hexanes (500 ml) and stirred at 25 ° C for 30 minutes. The mixture

The mixture was filtered and the organic layer was treated with saturated aqueous sodium bisulfite solution (200 ml). The hexane solution containing the product was washed with water, dried over sodium sulfate and concentrated. Gives 5.5 g (91%) of a colorless oil; MS: 287.1 (M + H) +

The method of Example 9 gave 2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid ethyl ester starting from 2- (4-methoxy-phenylmethanesulfonyl) propionic acid ethyl ester (2 g, 7 mmol) and benzyl bromide (1.3 g, 7.7 mmol). Yield 3.0 g, 100%, low melting solid; MS: 377 (M + H) ⁺ .

2- (4-Methoxy-phenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid was obtained from 2- (4-methoxyphenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid ethyl ester (3.5 g, 9.0 mmol). dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 930 mg, 31%; colorless solid, m.p. 106 - 108 ° C; MS: 347 (MH) ⁺ .

2- (4-Methoxy-phenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid (2.7 g, 7.0 mmol) and the procedure described in Example 1 afforded 266 mg of N-hydroxy-2- (4- methoxyphenylmethanesulfonyl) -2-methyl-3-phenyl propionic acid as a colorless solid. Yield 10%, m.p. 58-59 ° C. MS: 364.2 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-dg): δ 1.28 (S, 3H), 2.84-2.88 (d, 1 Η), 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-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enicarboxylic acid hydroxyamide

5-Methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enicarboxylic acid ethyl ester was prepared according to the general method described in Example 9. Starting from ethyl a - (p-tolylsulfonyl) acetate (2.9 g, 10.9 mmol) and 4-bromo-2-methyl butene (3.42 g, 23 mmol). Yield 4.6 g, light brown oil; MS: 379.2 (M + H) ⁺ .

5-Methyl-2- (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4enecarboxylic acid was prepared according to the general method described in Example 9. Starting from 5- methyl-2- (3-methyl-but-2-enyl) 2- (toluene-4-sulfonyl) -hex-4-enicarboxylic acid (4.5 g, 11 mmol), ethanol (15 ml) and 10 N sodium hydroxide.

Starting from 5-methyl-2- (3-methyl-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enicarboxylic acid (4.1 g, 11 mmol) was prepared according to the method described in example 1, 1.07 g of 5-methyl-2 (3-methyl-but-2-enyl) -2- (toluene-4-sulfonyl) -hex-4-enicarboxylic acid hydroxyamide as a colorless solid; yield of 30%; MS: 366.2 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 1.49 (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), 6.59 - 7.62 (d, 2H), 9.04 (S, 1H), 10.80 (S, 1H).

Example 43

2-Methyl-2- (2-methyl-furan-3-sulfonyl) -3-phenylpropionic acid hydroxyamide

2-Methyl-2- (2-methyl-furan-3-sulfonyl) -3-phenylpropionic acid ethyl ester (prepared from 3-mercapto-2-methylfuran) was prepared according to the general method described in Example 9. It was derived from ethyl 2- (2-Methyl-furan-3-ylsulfanyl) -propionic acid ester (2.9 g, 11.9 mmol), benzyl bromide (2.22 g, 13 mmol) and potassium carbonate (10 g) in acetone (75 ml). 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 method described in Example 9. It was derived from 2-methyl-2- (2-methyl ethyl ester) -Furan-3-ylsulfanyl) -3-phenylpropionic acid (4.8 g, 14.3 mmol) dissolved in ethanol (25 ml) and 10 N sodium hydroxide (10 ml). Yield 3.7 g (84%), white solid. MS: 307.4 (MH).

<

Starting from 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3-phenylpropionic acid (3.58 g, 12 mmol) and following the method described in Example 1, 1.078 g of 2-methyl hydroxyamide was isolated. -2- (2-Methyl-furan-3-sulfonyl) -3-phenyl-propionic acid as an orange colored solid. Yield 29%; mp 68-70 ° C; MS: 324 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 1.27 (s, 3H), 2.81-2.86 (d, 1 Η), 3.33 (s, 3H), 3.61 3.66 (d, 1 Η), 6.66 (S. 1 Η), 7.19 - 7.25 (m, 5H), 7.76 (s, 1 Η), 9.09 (S, 1 Η), 10.81 (s, 1H).

Example 44

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

2-Methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester was prepared according to the general method described in Example 9 It is derived from 2- (2-methyl-furan-3-ylsulfonyl) -propionic acid ethyl ester (2.4 g, 9.8 mmol) and 1- [2- (4-chloromethylphenoxy) -ethyl] piperidine (2.96 g, 10.7 mmol). 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-ylethoxy) -phenyl] -propionic acid was prepared according to the general method described in Example 1. Exit of 2-methyl-2- (2-methylfuran-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 ml) and 10 N sodium hydroxide (10 ml). The resulting mixture was worked up as in Example 9. Yield 2.03 g, amber crystals m.p. 66-68 ° C. MS: 434 (MH).

Starting from 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (2.03 g, 6.0 mmol) and Following the method of Example 1, 1.36 g of 2-methyl-2- (2-methyl-furan-3-sulfonyl) -3- [4- (2-piperidin-1-yl-ethoxy) phenyl] -propionic acid is obtained as 1.36 g. amber colored solid. Yield: 32% m.p. 115-117 ° C; ; MS: 451.1 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d6): δ 1.15-1.22 (m, 2H), 1.75 (s, 3H), 1.78 (s, 2H), 2.98 3.03 (m, 2H), 3.42 - 3.47 (m. 2H), 3.5 (s, 2H), 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, ΪΗ).

Example 45

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

2-Methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] 2- (thiophene-3-sulfonyl) -propionic acid ethyl ester was prepared according to the general method described in Example 9. Exit 2 (Thiophene-2-sulfonyl) -propionic acid ethyl ester (obtained from 2-mercaptothiophene and 2-bromopropionic acid (4.4 g, 17.7 mmol) and 1 [2- (4-chloromethylphenoxy) -ethyl] -piperidine (5.3 g, 19.5 mmol); yield (96%); semi-solid; MS 466.

2-Methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -2- (thiophene-3-sulfonyl) -propionic acid was prepared according to the general method of Example 9. Starting from ethyl ester of 2 - methyl-3- [4- (2-piperidin-1-ylethoxy) -phenyl] -2- (thiophene-3-sulfonyl) -propionic acid (9.8 g, 20 mmol) dissolved in ethanol (20 ml) and 10 N sodium hydroxide (20 ml). The resulting mixture was worked up as described in Example 1. Yield 4.5 g (49%); white solid, m.p. 170-172 ° C. MS: 436.3 (MH).

Starting from 2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] 2- (thiophene-3-sulfonyl) -propionic acid (3.6 g, 8.0 mmol) and follow the procedure Example 1 afforded 345 mg of 2-methyl-3- (4- (2-piperidin-1-yl-ethoxy) -phenyl] -2- (thiophene-3-sulfonyl) propionic acid hydroxyamide as a colorless solid. mp 115-118 ° C. MS: 451.2 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 1.29 (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, 1 Η), 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, 1 Η), 8.07 - 8.08 (dd, 1 Η), 8.17 (dd, 1 Η), 9.0 (s, 1H), 10.0 (s, 1 Η), 10.78 (s, 1H).

Example 46

2- (Oxane-1-sulfonyl) -3- [4- (2-piperidin-ylethoxy) -phenyl] -propionic acid hydroxyamide

2- (octane-1-sulfonyl) -3- [4- (2-piperidin-ylethoxy) -phenyl] -propionic acid ethyl ester was prepared according to the general method of Example 9. Exit 2- (octane ethyl ester) -1-sulfonyl) propionic acid (5.0 g, 18 mmol) and 1- [2- (4-chloro-methylphenoxy) ethyl] -piperidine (5.6 g, 19.7 mmol). 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 method of Example 9. Starting from 2- (octane-1 ethyl ester) -sulfonyl) -3- [4- (2-piperidin-ylethoxy) -phenyl] -propionic acid (8.9 g, 18 mmol), ethanol (25 ml) and 10 N sodium hydroxide (25 ml). Yield 6.0 g (72%).

Starting from 2- (octane-1-sulfonyl) -3- [4- (2-piperidin-ylethoxy) -phenyl] -propionic acid (3.6 g, 7.7 mmol) and following the procedure of Example 1, hydroxyamide was obtained. 2- (octane-1-sulfonyl) 3- [4- (2-piperidin-yl-ethoxy) -phenyl] -propionic acid as a light brown solid; Yield: 89%; mp 69-70 ° C; MS: 483.2 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 0.687 (t, 3H), 1.27 - 1.69 (m, 15 Η), 2.71 - 2.75 (d, 1H), 3.51 (s, 3H), 3.65 - 3.69 ( d, 1 Η), 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 method of Example 9. Starting from 2-methyl- (1-methyl-1H76 imidazolesulfonyl) -propionic acid, obtained from 1-methyl-2 mercapto imidazole and 2-bromo ethyl propionate (3.0 g, 12.2 mmol) and 4chloromethylbiphenyl (2.97 g, 15 mmol). Yield 5.0 g, (99%); low-solids; 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 method of Example 9. Starting from 3-biphenyl-4 ethyl ester -yl-2-methyl-2- (1-methyl-1H-imidazole-2sulfonyl) -propionic acid (5.0 g, 11.9 mmol), ethanol (15 ml) and 10 N sodium hydroxide (10 ml). Yield 2.8 g (61%); brown solid, m.p. 119 -122 ° C; MS: 385.2 (M + H) ⁺ .

Starting from 3-biphenyl-4-yl-2-methyl-2- (1-methyl-1 Nimidazole-2-sulfonyl) -propionic acid (2.8 g, 7.0 mmol) and follow the procedure of Example 1 to give 112 mg of 3biphenyl-4-yl-2-methyl-2- (1-methyl-1H-imidazole-2-sulfonyl) -propionic acid hydroxyamide as a light brown solid; Yield 4%; mp 112 ° C; MS: 399.0 (M + H) ⁺ . ^f H NMR (300 MHz, DMSO-de): δ 0.911 (s, 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 method of Example 9. It was derived from 2- (thiophene-2-sulfonyl) -propionic ethyl ester ( 3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g of a light brown oil; MS: 339.1 (M + H) ⁺ .

2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) -propionic acid was prepared according to the method of Example 9. Starting from 2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) ethyl ester - propionic acid (5.0 g, 15 mmol), ethanol (30 ml) and 10 N sodium hydroxide (10 ml). Yield 5.6 g. MS: 310.0 (M + H) ⁺

Starting from 2-methyl-3-phenyl-2- (thiophene-2-sulfonyl) propionic acid (5.0 g, 16 mmol) and following the method of Example 1, 1.8 g of 2-methyl-3-phenyl hydroxyamide is obtained. -2- (Thiophene-2-sulfonyl) -propionic acid as a colorless solid; yield 40%; mp 116 - 117 ° C. MS: 325.9 (M + H) ⁺ NMR (300 MHz, DMSO-de): δ 1.29 (s, 3H), 3.33 (d, 1 Η), 3.69 (d, 1 Η), 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-Carboxyl-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid ethyl ester was prepared according to the general method of Example 9. It was derived from 2- (8- (1-ethoxycarbonylethylsulfanyl) -octylsulfanyl ethyl ester ] -propionic acid (10.2 g, 26 mmol) and sodium peroxymonopersulfate (64 g, 104 mmol)) Yield 9.87 g (86%); colorless liquid; MS: 442.9 (M + H) ⁺ .

2- (8- (1-Carboxy-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid was prepared according to the method of Example 1. It was derived from 2- (8- (1-carboxyl-ethanesulfonyl) -octane ethyl ester -1-sulfonyl] propionic acid (3.0 g, 6.8 mmol), ethanol (15 ml) and 10 N sodium hydroxide (15 ml) Yield 2.7 g (98%); white solid, mp 99 102 ° C. MS: 387 (M + MH +) ⁺ .

Starting from 2- (8- (1-carboxyl-ethanesulfonyl) -octane-1-sulfonyl] -propionic acid (2.5 g, 6.5 mmol) and following the method of Example 1, 641 mg of hydroxyamide 2- (8- (1 -carboxyethanesulfonyl) -octane-1-sulfonyl] -propionic acid as amber oil Yield 23%; MS: 434.0 (M + NH ₄ ) ^{+ 1} H NMR (300 MHz, DMSO-de): 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] -propionic acid hydroxyamide

2- (4-Bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid ethyl ester was prepared according to the general method of Example 9. Exit from ethyl α- (4-bromophenylsulfonyl) acetate (5.0 g, 16 mmol) and 1- [2- (4-chloromethylphenoxy) -ethyl] piperidine (4.97 g, 16 mmol). Yield 6.1 g (71%); light brown oil; MS: 541.1 (M + H) ⁺ .

2- (4-Bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-ylethoxy) -phenyl] -propionic acid was prepared according to the general method of Example 9. Starting from ethyl ester of 2 - (4-bromo-benzenesulfonyl) -

2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (6.5 g, 20 mmol), ethanol (30 ml) and 10 N sodium hydroxide (15 ml). Yield 6.3 g (100%); yellow solid, m.p. 125 - 127 ° C. MS: 512.5 (M + H) ⁺ .

Starting from 2- (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionic acid (6.1 g, 612 mmol) and follow the procedure of Example 1 gave 1.07 g of 2 (4-bromo-benzenesulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] -propionic acid hydroxyamide as a light yellow solid. Yield 17%. MS: 525.4 (M + H) ⁺ .

Example 51

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

Following the method of Example 9, ethyl ester was obtained

3- (4-Bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid from (3.0 g, 11 mmol) 2- (4-methoxybenzenesulfonyl) -propionic acid ethyl ester and 4- benzyl bromide bromo (3.0 g, 12 mmol). Yield 4.67 g, 96%; colorless oil; MS: 441 (M + H) ⁺

3- (4-Bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methylpropionic acid is obtained by starting from 3 (4-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) ethyl ester ) -2-methyl-propionic acid (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 3.0 g, 78%. Low-solids. MS: 413 (M + H) ⁺ .

Starting from 3- (4-bromo-phenyl) -2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid (2.7 g, 6.5 mmol) and following the method of Example 1, 2.26 g of 3- (4 -bromo-phenyl) -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 (300 MHz, CDCl 3): δ 1.42 (s, 3H), 1.77 (bs, 1H), 3.26 (d, J = 7.0 Hz, 1H), 3.68 (d, J = 7.0 Hz, 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) -2-methyl-3-naphthalen-2yl-propionamide

Following the method of Example 9, 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester was obtained starting from (5.4 g, 20 mmol) ethyl ester. 2- (4-methoxy-benzenesulfonyl) -propionic acid and 2-bromo-methyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; colorless crystals of m.p. Mp 182 - 184 ° C; MS: 413 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) 2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester (4.6 g, 11 mmol), 4.2 g (98%) of 2- (4- methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid as colorless crystals according to the method of Example 9. Mp 144-146 ° C. MS: 384.9 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionic acid (2.4 g, 6.2 mmol) and following the procedure described in Example 1, 1.6 g of M-hydroxy-2 is obtained - (4-Methoxybenzenesulfonyl) -2-methyl-3-naphthalen-2-yl-propionamide as a colorless solid. Yield 64%. Mp 185 - 187 ° C. MS: 400.2 (M + H) ⁺ . NMR (300 MHz, CDCl3): δ 1.56 (s, 3H), 3.28 (d, J = 8.0 Hz, 1H), 3.81 (d, J = 8 Hz, 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-butyramide

2- (4-Methoxy-phenylsulfanyl) -3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting with ethyl 2-bromo-3-methyl-butanate (20.9 g, 100 mmol) and 4 -methoxybenzentiol (14.0 g, 100 mmol) to give 30 g of 2- (4-methoxyphenylsulfanyl) -3-methyl-butyric acid ethyl ester. Yield 99%. Light yellow oil; MS: 269 (M + H) ⁺ .

Starting from 2- (4-methoxy-phenylsulfanyl) 3-methyl-butyric acid ethyl ester (2.68 g, 10 mmol) and following the oxidation method of Example 9, 3 g of 2- (4- methoxybenzenesulfonyl) -3-methyl-butyric acid as a colorless solid. Yield 99%. Mp 53 ° C; MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) 3-methyl-butyric acid ethyl ester (3 g, 10 mmol) afforded 2.7 g (96%) of 2- (4-methoxy-benzenesulfonyl) -3-methyl-butyric acid according to the method of Example 9, m.p. 96 ° C; MS: 273 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -3-methyl-butyric acid (2.0 g, 7.34 mmol) and following the method of Example 9, 590 mg of N-hydroxy-2- (4-methoxy-benzenesulfonyl) is obtained ) -3-methyl-butyramide as a colorless solid, m.p. 220 ° C. Yield 28%; MS: 288 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.88 (d, J = 6.7 Hz, 3H), 1.07 (d,

J = 6.7 Hz, 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) cyclopentylcarboxylic acid hydroxyamide

Following the method of Example 9, ethyl ester was obtained

1- (4-Methoxy-benzenesulfonyl) -cyclopentanecarboxylic acid using (3.0 g, 11.6 mmol) 2- (4-methoxybenzenesulfonyl) -acetic acid ethyl ester and 1,4-dibromobutane (2.4 g, 7.6 mmol). Yield 2.4 g, 78%; colorless solid, mp 86-88 ° C; MS: 313 (M + H) ⁺ .

1- (4-Methoxy-benzenesulfonyl) -cyclopentanecarboxylic acid was obtained starting from 1- (4-methoxybenzenesulfonyl) -cyclopentanecarboxylic acid ethyl ester (2.2 g, 7.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as indicated in Example 9. Yield 1.66 g, 83%. Colorless solid, m.p. 112-115 ° C; MS: 285 (M + H) ⁺ .

Starting from 1- (4-methoxy-benzenesulfonyl) cyclopentanecarboxylic acid (442 mg, 1.5 mmol) and following the method of Example 1, 410 mg of 1- (4-methoxybenzenesulfonyl) -cyclopentylcarboxylic acid hydroxyamide was obtained as a colorless solid with mp 89 - 91 ° C. Yield 88%; MS: 300 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.65 - 1.82 (m, 4H), 2.17 - 2.42 (m, 4H), 3.87 (s, 3H), 7.0 (d, J = 8 Hz, 2H), 7.7 ( bs, 1H), 7.72 (d, J = 8 Hz, 2H), 9.73 (bs, 1H).

Example 55

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

In the method of Example 9, 3- (2-bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methyl-propionic acid ethyl ester was obtained starting from (2.0 g, 7.3 mmol) of 2- (4-Methoxybenzenesulfonyl) -propionic acid and 2- (bromo) -benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g 87%; colorless oil; MS: 44 D (M + H) ⁺ .

3- (2-Bromo-phenyl) -2- (4-methoxy-benzenesulfonyl) -2-methylpropionic acid is obtained from 3- (2-bromophenyl) -2- (4-methoxy-benzenesulfonyl) -2- methylpropionic acid (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.7 g, 63%. Waxy substance; MS: 414 (M + H) ⁺ .

Starting from 3- (2-bromo-phenyl) -2- (4-methoxybenzenesulfonyl) -2-methyl-propionic acid (470 mg, 1.1 mmol) and following the method of Example 9, 380 mg of 3- (2 -bromo-phenyl) hydroxy-2- (4-methoxy-benzenesulfonyl) -2-methyl-propionamide as a colorless solid, m.p. 93 - 96 ° C. Yield 77%; MS: 429 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.3 (s, 3H), 3.32 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H), 6.92 7.89 (m, 8H).

Example 56

2- (4-Methoxy-benzenesulfonyl) -2-methyl-5-phenylpent-4-enicarboxylic acid hydroxyamide

In the method of Example 9, 2- (4-methoxybenzenesulfonyl) -2-methyl-5-phenyl-pent-4-enicarboxylic acid ethyl ester was prepared starting from (3.0 g, 11 mmol) of 2- ( 4methoxy-benzenesulfonyl) propionic acid and cinnamyl bromide (2.1 g, 11 mmol), Yield 3.51 g, 82%; colorless oil; MS: 389 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pentenecarboxylic acid is obtained from 2- (4-methoxybenzenesulfonyl) -2-methyl-5-phenyl-pent-4-enicarboxylic acid ethyl ester (3.0 g, 11 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.9 g, 68%. yellowish oil; MS: 361 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-5-phenyl-pent-4-enicarboxylic acid (440 mg, 1.2 mmol) and following the method of Example 1, 420 mg of 2- (4-hydroxyamide) is obtained. -methoxybenzenesulfonyl) -2-methyl-5-pheyl-pent-4-enicarboxylic acid as a colorless solid, m.p. 162-164 ° C. Yield 92%; MS: 376 (M + H) ^{+ 1} H NMR (300 MHz, CDCl 3): δ 1.41 (s, 3H), 3.0 - 3.16 (m, 1H), 3.30 (d, J = 11 Hz, 2H), 3.92 ( s, 3H), 5.9-1.1 (m, 1H), 6.53 (d, J = 11 Hz, 1H), 7.1 7.72 (m, 9H), 9.12 (bs, 1H).

Example 57

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

Following the procedure of Example 9, 2- (4-Methoxybenzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanecarboxylic acid ethyl ester was prepared starting from (4.0 g, 15.8 mmol) of 2- (4-Methoxy-benzenesulfonyl) -acetic acid and 3-bromo-propylbenzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; colorless oil; MS: 495 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) pentanecarboxylic acid is obtained from 2- (4-methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl- propyl) -pentanecarboxylic acid (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.18 g, 63%. yellowish oil; MS: 449.2 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanecarboxylic acid (600 mg, 1.2 mmol) and following the method of Example 1, 420 mg of hydroxyamide of 2- (4methoxy-benzenesulfonyl) -5-phenyl-2- (3-phenyl-propyl) -pentanecarboxylic acid as a colorless solid, m.p. 118-120 ° C. Yield 68%; MS: 482 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.52 - 1.68 (m, 2H), 1.74 84

1.92 (m, 2H), 1.98-2.20 (m, 4H). 2.58-2.72 (m, 4H), 3.86 (S, 3H), 6.93 (d.

J = 11 Hz, 2H), 7.02 - 7.63 (m, 10H), 7.81 (d, J = 11 Hz, 2H).

Example 58

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

Following the method of Example 9, 2-allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enicarboxylic acid ethyl ester was prepared starting from (3.0 g, 11.6 mmol) 2- (4-methoxybenzenesulfonyl) ethyl ester -acetic acid and allyl bromide (4 ml, excess). Yield 3.6 g, 92%; yellow oil; MS: 338 (M + H) ⁺

2-Allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-enicarboxylic acid was obtained from 2-allyl-2- (4-methoxybenzenesulfonyl) -pent-4-enicarboxylic acid ethyl ester (2.2 g, 6.5 mmol) ) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 1.76 g, 87%. yellowish oil; MS: 311 (M + H) ⁺

Starting from 2-allyl-2- (4-methoxy-benzenesulfonyl) -pent-4encarboxylic acid (1.5 g, 4.8 mmol) and following the method of Example 1, 1.5 g of 2-allyl-2- (4-hydroxyamide) is obtained. -methoxybenzenesulfonyl) -pent-4-encarboxylic acid as a colorless solid, m.p. 114-116 ° C. Yield 99%; MS: 326 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.62 (s, 1H), 2.70-2.88 (m, 4H), 3.9 (s, 3H), 5.16-2.27 (m, 4H), 5.81 - 5.94 (m, 2H) ), 7.12 (d, J = 8 Hz, 2H).

Example 59

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

2-Allyl-2- (4-methoxy-benzenesulfonyl) -pent-4-carboxylic acid hydroxyamide (326 mg, 1.0 mmol) (Example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% palladium on carbon (100 mg) at room temperature under pressure of 49 lb / in ² for 4 hours. The reaction mixture was then filtered and the methanol removed. The resulting solid was crystallized from methanol. Yield: 250 mg; 75%; MS: 330 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 0.92 (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 = 9 Hz, 2H), 7.76 (d, J = 9 Hz, 2H).

Example 60

2-benzyl-1-1-hydroxy-2- (4-methoxy-benzenesulfonyl) -3-phenylpropionamide

Following the method of Example 9, 2-Benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-acid ethyl ester was prepared starting from (1.0 g, 3.8 mmol) 2- (4-methoxy-benzenesulfonyl) ethyl ester acetic acid and benzyl bromide (4 ml, excess). Yield 1.2 g, 72%; yellow oil; MS: 439 (M + H) ⁺ .

2-Benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-acid was obtained from 2-benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-acid ethyl ester (1.0 g, 2.2 mmol). dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as described in Example 9. Yield 580 mg, 62%. waxy substance; MS: 409 (M + H) ⁺ .

Starting from 2-benzyl-2- (4-methoxy-benzenesulfonyl) -3-phenyl-acid (410 mg, 1 mmol) and following the method of Example 1, 225 mg of 2-benzyl-N-hydroxy-2- ( 4-Methoxy-benzenesulfonyl) -3-phenyl-propionamide as a waxy substance. Yield 52%; MS: 426 (M + H) ⁺ 'H NMR (300 MHz, CDCI3): δ 3.25 ( d, J = 14 Hz, 2H), 3.52 (d , J = 14 Hz, 2H), 3.9 (s , 3H) , 6.93 (d, J = 8 Hz, 2H), 7.02 - 7.26 (m, 9H), 7.61 (d, J = 8 Hz, 2H), 7.87 (d, J = 4 Hz, 1H), 9.58 (bs. 1H).

Example 61

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

To a solution of 2- (4-methoxybenzenesulfonyl) propionic acid ethyl ester (2.7 mg, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 mmol) and triethylbenzylammonium chloride (1 g) in methylene chloride (400 mL) was added to 10 mL of brine. N NaOH (30 ml). The reaction was continued at room temperature for 48 hours. The organic layer was then separated and washed well with water. The organic layer was dried, filtered and concentrated. The crude product obtained was eluted with 50% ethyl acetate: hexane. 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) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

2-methyl-3-pyridin-3-yl-propionic acid (2.5 g, 6.8 mmol) yielded 1.8 g (79%) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridine-

3-yl-propionic acid as a colorless solid according to the method of Example 9. Mp 58 ° C; MS: 336 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid (410 mg, 1 mmol) and following the method of Example 1, 225 mg of N-hydroxy-2- (4-Methoxybenzenesulfonyl) -2-methyl-3-pyridin-3-yl-propionamide as a colorless solid. Yield 52% to 98%. MS: 351 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.4 (s, 3H), 3.1 (d, J = 9.0 Hz, 1H), 3.65 (d, J = 9.1 Hz, 1H), 3.9 (S, 3H), 7 - 8.5 (m, 8H).

Example 62

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

Starting from 2- (4-methoxy-benzenesulfonyl) acetic acid ethyl ester (7.5 g, 29 mmol) and 1-bromo-octane (6.7 g, 35 mmol), 8 g of the 2- (487 methoxy) ethyl-octylated compound are obtained. -benzenesulfonyl) -decanecarboxylic acid according to the method of Example 9. Yield 8.0 g, 74%; MS: 370 (M + H) ⁺ .

Following the method described in Example 29, 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decanecarboxylic acid ethyl ester was obtained from (8.0 g, 21.6 mmol) 2- (4- methoxy-benzenesulfonyl) - decanecarboxylic acid and 3-picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; brown oil; MS: 462 (M + H) ⁺ .

Leaving 2- (4-methoxy-benzenesulfonyl) 2-pyridin-3-ylmethyl-decanecarboxylic acid ethyl ester (5.0 g, 11 mmol) yielded 4.6 g (91%) of 2- (4-methoxy-benzenesulfonyl) -2-Pyridin-3-ylmethyl-decanecarboxylic acid as a colorless solid according to the method of Example 9. Mp 159 ° C; MS: 434 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-decanecarboxylic acid (2.5 g, 5.7 mmol) and following the method of Example 1, 1.4 g of 2- (4-methoxybenzenesulfonyl) hydroxyamide is obtained - 2-Pyridin-3-ylmethyl-decanecarboxylic acid as a colorless solid. Yield 50% m.p. 62 ° C; MS: 448 (M + H) ⁺ . NMR (300 MHz, CDCI3): δ 0.86 (t, 6.9 Hz, 3H), 1.25 - 2.17 (m, 14 Η), 3.3 (d, J = 14 Hz, 1H), 3.5 (d, J = 14 Hz. 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-enicarboxylic acid hydroxyamide

According to the method of Example 9, 2- (4-methoxybenzenesulfonyl) -5-methyl-hex-4-encarboxylic acid ethyl ester was prepared starting from (6.0 g, 23 mmol) 2- (4-methoxybenzenesulfonyl) ethyl ester -acetic acid and isoprenyl bromide (3.0 g, 20 mmol). Yield 6.52 g, 86%; colorless oil; MS: 327 (M + H) ⁺

Following the method described in Example 29, 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl88 hex-4-enicarboxylic acid ethyl ester was obtained to give (4.0 g, 12.2 mmol) 2- (4-Methoxy-benzenesulfonyl) -5-methyl-hex-4-enicarboxylic acid ethyl ester (2.1 g, 13 mmol). Yield 4.1'4'g, 81%; brown oil; MS: 418 (M + H) ⁺ . ¹

Starting from 2- (4-methoxy-benzenesulfonyl) 5-methyl-2-pyridin-3-ylmethyl-hex-4-enicarboxylic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml) gave 2 (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4-carboxylic acid. The reaction mixture was worked up as described in Example 9. Yield 3.2 g, 87%, cream solid, m.p.

• 117 - 119 ° C; MS: 390 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4-enicarboxylic acid (2.1 g, 5.4 mmol) and following the method of Example 1, 1.82 g of hydroxyamide was obtained. 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hex-4encarboxylic acid as a colorless solid. Yield 82% m.p. Mp 89 92 ° C; MS: 405 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.88 (m, 2H), 3.3 (d, J = 4.0 Hz, 1H), 3.63 (d. J = 4.0 Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m, 2H).

Example 64 ^w 2-Benzyl-4-diisopropylamino-N-hydroxy-2- (4-methoxybenzenesulfonyl) -butyramide

Following the method described in Example 29, 2-benzyl-4-diisopropylamino-2- (4-methoxy-benzenesulfonyl) butyric acid ethyl ester was obtained starting from (3.0 g, 8.5 mmol) of 2 (4- methoxy-benzenesulfonyl) -3-phenyl-propionic acid (Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 mmol). Yield 3.2 g, 79%; an off-white solid, mp 89-91 ° C; MS: 476.4 (M + H) ⁺ .

Starting from 2-benzyl-4-diisopropylamino 2- (4-methoxy-benzenesulfonyl) -butyric acid ethyl ester (3.53 g, 7.5 mmol), 2.8 g (86%) of 2-benzyl-4-diisopropylamino-2- is obtained. (4-Methoxybenzenesulfonyl) -butyric acid as colorless crystals according to the method of Example 9. Mp 136-138 ° C; MS: 448.5 (M + H) ⁺ .

Starting from 2-benzyl-4-diisopropylamino-2- (4-methoxybenzenesulfonyl) -butyric acid (1.85 g, 4.1 mmol) and following the procedure described in Example 1, 1.3 g of 2-benzyl-4 diisopropylamino-N-hydroxy is obtained -2- (4-methoxy-benzenesulfonyl) butyramide as a low-foaming waxy substance; Yield 68%. MS: 463.3 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 0.98 (d, J = 11 Hz, 6H), 1.16 (d, J = 11 Hz, 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 = 8 Hz, 2H), 7.18 - 7.22 (m, 5H), 7.92 ( d, J = 8 Hz, 2H), 8.12 (s, 1H).

Example 65

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

Following the method of Example 9, 3-cyclohexyl-2 (4-methoxy-benzenesulfonyl) -propionic acid ethyl ester was prepared starting from (4.0 g, 15 mmol) 2- (4-methoxybenzenesulfonyl) -acetic acid ethyl ester and 1-bromomethyl cyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; colorless oil; MS: 355 (M + H) ⁺ .

Following the method of Example 29, 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethylpropionic acid ethyl ester was prepared by starting from 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl ethyl ester) ) -propionic acid (1.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g, 38%. Colorless oil; MS: 446 (M + H) ⁺ .

Starting from 3-cyclohexyl-2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-propionic acid ethyl ester (1.3 g, 2.9 mmol), 1.0 g (83%) of 3-cyclohexyl-2- is obtained. (4-Methoxybenzenesulfonyl) -2-pyridin-3-ylmethyl-propionic acid as colorless crystals following the method of Example 9. M.p. 92 ° C; MS: 417.5 (M + H) ⁺ ?

Starting from 3-cyclohexyl-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-propionic acid (1.0 g, 2.4 mmol) and following the method of Example 1, 80 mg of 3-cyclohexyl-N- hydroxy-2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-propionamide as a colorless hydrochloride salt; yield 71%; mp 57 - 60 ° C; MS: 433 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 0.8 - 2.08 (m, 13H), 3.3 (d, J = 14 Hz, 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-pentanecarboxylic acid hydroxyamide

Following the method of Example 9, 2- (4-methoxybenzenesulfonyl) -4-methyl-pentanecarboxylic acid ethyl ester was prepared starting from (5.0 g, 20 mmol) 2- (4-methoxybenzenesulfonyl) -acetic acid ethyl ester and 1-bromo-2-methyl propane (2.6 g, 20 mmol). Yield 6.0 g, 95%; colorless oil; MS: 315 (M + H) ⁺ .

In the method of Example 29, 2- (4-methoxybenzenesulfonyl) -4-methyl-2-pyridin-3-ylmethyl-pentanecarboxylic acid ethyl ester was prepared starting from (3.1 g, 10 mmol) of 2- ( 4-Methoxy-benzenesulfonyl) -4-methyl-pentanecarboxylic acid and

3- picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, 75%; colorless oil; MS: 406 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

4- methyl-2-pyridin-3-ylmethyl-pentanecarboxylic acid (1.2 g, 2.9 mmol) afforded 1.0 g (91%) of 2- (4-methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethyl-pentanecarboxylic acid acid in the form of colorless crystals following the method of Example 9. Mp 188-186 ° C; MS.378 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethyl-pentanecarbic acid (800 mg, 2.1 mmol) and following the procedure of Example 1, 180 mg of 2- (4-methoxy hydroxyamide) is obtained. -benzenesulfonyl) -4-methyl-2-pyridin-3-ylmethylpentanecarboxylic acid as a colorless solid; yield 21%; mp 78 ° C; MS: 393.4 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 0.65 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.2 Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 2H), 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 of Example 29, 2- (4-Methoxybenzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid ethyl ester was prepared starting from 2- (4-methoxybenzenesulfonyl) -propionic ethyl ester (5.2 g, 20 mmol) and 7bromomethyl quinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%. A pale yellow solid, mp 86 ° C; MS: 414 (M + H) ⁺

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

2-methyl-3-quinolin-6-yl-propionic acid (3.0 g, 7.2 mmol) afforded 2.5 g (90%) of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-yl-propionic acid acid as colorless crystals following the method of Example 9. Mp 106 - 108 ° C; MS: 386.4 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-methyl-3-quinolin-6-ylpropionic acid (2.0 g, 5.2 mmol) and following the procedure of Example 1, 1.2 mg of 1 '-hydroxy-2- is obtained (4-Methoxy-benzenesulfonyl) 2-methyl-3-quinolin-6-yl-propionamide as a colorless solid; yield 57%; mp 206 ° C; MS: 401.4 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3): δ 1.4 (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-hexanecarboxylic acid hydroxyamide

Following the method of Example 9, 2- (4-methoxybenzenesulfonyl) -6-phenoxy-hexanecarboxylic acid ethyl ester was prepared starting from (2.5 g, 10 mmol) 2- (4-methoxybenzenesulfonyl) -acetic acid ethyl ester and 1-bromo-4-phenoxy butane (2.2 g, 10 mmol). Yield 3.8 g, 93%; colorless oil; MS: 407 (M + H) ⁺ .

Following the method of Example 9, 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethylhexanecarboxylic acid ethyl ester was prepared starting from (3.1 g, 10 mmol) of 2- ( 4-methoxy-benzenesulfonyl) -6-phenoxyhexanecarboxylic acid and 3-picolyl chloride (1.8 g, 11 mmol). Yield 3.5 g, 71%; colorless oil; MS: 498 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

6-Phenoxy-2-pyridin-3-ylmethyl-hexanecarboxylic acid (3.0 g, 6.0 mmol) yielded 2.8 g (quantitative yield) of 2- (4-methoxybenzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl- hexanecarboxylic acid as colorless crystals following the method of Example 9. Mp 148-151 ° C; MS: 470.5 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethyl-hexanecarboxylic acid (2.0 g, 4.3 mmol) and following the method of Example 1, 1.5 g of 2- (4-methoxy hydroxyamide) is obtained. -benzenesulfonyl) -6-phenoxy-2-pyridin-3-ylmethylhexanecarboxylic acid as a colorless solid; yield 72%; mp 68 ° C; MS: 485.5 (M + H) ⁺ . 1 H NMR (300 MHz, CDCl 3: δ 1.5 - 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-methyl2-pyridin-3-ylmethyl hexanecarboxylic acid hydroxyamide

Following the method of Example 9, 2- (4-methoxybenzenesulfonyl) -5-hexanecarboxylic acid ethyl ester was prepared starting from (10.0 g, 39 mmol) 2- (4-methoxybenzenesulfonyl) -acetic acid ethyl ester and 1- bromo-3-methyl butane (6.0 g, 40 mmol). Yield 8.5 g, 62%; colorless oil; MS: 329 (M + H) ⁺ .

Following the method of Example 9, 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethylhexanecarboxylic acid ethyl ester was prepared starting from (6.0 g, 18 mmol) of 2- ( 4-methoxy-benzenesulfonyl) -5-methylhexanecarboxylic acid and picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; brown oil; MS: 420 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) ethyl ester -

5-Methyl-2-pyridin-3-ylmethyl-hexanecarboxylic acid (3.0 g, 7.1 mmol) afforded 2.6 g (92%) of 2- (4-methoxy-benzenesulfonyl) -5methyl-2-pyridin-3-ylmethyl- hexanecarboxylic acid as colorless crystals following the method of Example 9. Mp 173 ° C; MS: 392 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -5-methyl-2-pyridin-3-ylmethyl-hexanecarboxylic acid (1.0 g, 2.5 mmol) and following the procedure of Example 1, 800 mg of 2- (4-methoxy hydroxyamide) is obtained. -benzenesulfonyl) -5-methyl-hexanecarboxylic acid as a colorless solid. Hydrochloride is obtained by passing hydrogen chloride gas through a methanol solution of hydroxamide; yield 72%; mp 62 ° C (HCl salt); MS: 408 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 0.76 (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-hexanecarboxylic acid hydroxyamide

(4-Methoxy-phenylsulfanyl) -acetic acid tert-butyl ester was prepared according to the general method described in Example 1. Ex.

1 N was obtained from the corresponding 1-bromo-tert-butyl acetate (5.3 g, 27 mmol) and 4methoxybenzentiol (3.7 g, 27 mmol) to give 6.4 g of the product. Light yellow oil; MS: 225 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -acetic acid tert-butyl ester was prepared according to the general method described in Example 9. It was derived from 2- (4-methoxy-benzenesulfanyl) -acetic acid tert-butyl ester ( 5.0 g, 20 mmol) and 3-chloroperoxybenzoic acid 57% (12.0 g, 40 mmol) to give 5.3 g of product. Yield 92%; waxy substance; MS: 287.1 (M + H) ⁺

2- (4-Methoxy-benzenesulfonyl) -pyridin-3-propionic acid tert-butyl ester was prepared according to the general method described in Example 9. It was derived from 2- (4-methoxybenzenesulfonyl) -acetic acid tert-butyl ( 20.0 g, 70.0 mmol) and 3 picolyl chloride (7.28 g, 44.4 mmol) to isolate 10.5 g of the product by silica gel chromatography (50% ethyl acetate: hexane). Yield 63%; white solid, m.p. 93-94 ° C; MS: 378.0 (M + H) ⁺

2- (4-Methoxy-benzenesulfonyl) -2-pyridine tert-butyl ester-

3-ylmethyl-hexanecarboxylic acid was prepared according to the general method described in Example 9. It was obtained from 2- (4-methoxy-benzenesulfonyl) -pyridin-3-yl-propionic acid tert-butyl ester (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol) to isolate 1.20 g of the product. Yield 52%; yellowish resin; MS: 434.3 (M + H) ⁺ .

A mixture of 2- (4-methoxybenzenesulfonylsulfonyl) -2-pyridin-3-ylmethyl-hexanecarboxylic acid tert-butyl ester (1.1 g, 2.5 mmol) in methylene chloride / TFA (1: 1) was stirred at room temperature for about 2 o'clock. The solvents were then evaporated to give 2- (4-methoxy-benzenesulfonylsulfonyl) -2-pyridin-3-ylmethyl-hexanecarboxylic acid, which was purified by silica gel chromatography (30% methanol / methylene chloride). Yield 0.90 g, 94%; white solid, mp 70 ° C; MS: 376.1 (MH) '.

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-hexanecarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-methoxy-benzenesulfonylsulfonyl) -2-pyridin-3-ylmethyl-hexanecarboxylic acid g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to give 0.13 g of product. Yield 37%; a pale yellowish solid; mp 65 ° C; MS: 288 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 0.80 (t, J = 7.2 Hz, 3H), 1.10 -

I. 25 (m, 2H), 1.25 - 1.50 (m, 2H), 1.70 - 2.00 (m, 2H), 3.53 (d, J = 14.4 Hz, 1H), 3.62 (d, J = 14.4 Hz, 1H) , 3.88 (s, 3H), 7.15 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.90 - 8.00 (m, 1H), 8.40 - 8.45 (m, 1H). 8.70 - 8.85 (m, 2H),

II. O (brs, 1H); IR (KBr, cm ' ¹ ): 3064m, 2958s, 2871m, 1671m.

Example 71

2- (4-Methoxy-benzenesulfonyl) -2-oxg-2-ynyl-dec- hydroxyamide

4-incarboxylic acid

The title compound was prepared according to the method described in Example 9. It was derived from 2- (4-methoxybenzenesulfonyl) -acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octin (3.80 g, 20 mmol) to isolate 4.4 g of product. Yield 100%;

yellowish resin; MS: 446.9 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-oct-2-ynyl-dec-4-incarboxylic acid was prepared according to the method of Example 70. Starting from 2- (4-methoxy-benzenesulfonyl) - 2-oct-2-ynyl-dec-4incarboxylic acid (4.40 g, 10.0 mmol) to isolate 2.0 g of product. Yield 49%; white solid, m.p. 61 ° C; MS: 345.1 (MH) '.

2- (4-Methoxy-benzenesulfonyl) -2-oct-2-ynyl-dec4-incarboxylic acid hydroxyamide was prepared according to the method described in Example 1. Starting from 2- (4-methoxy-benzenesulfonyl) -2-oct- 2-ynyl-dec-4incarboxylic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to isolate 0.25 g of product. Yield 62%; white solid, mp 83 - 84 ° C; MS: 462.0 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 0.82-0.90 (m, 6H), 1.15 -1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J = 17.0 Hz, 2H) ), 3.00 (br, J = 17.0 Hz, 2H), 3.87 (s, 3H),

7.15 (d, J = 10.0 Hz, 1H), 7.71 (d, J = 10.0 Hz, 1H), 9.20 '(brs, 1H), 10.90 (brs,

1H); IR (KBr, cm ^'1): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s;

Analysis calculated for C ₂₅ H ₃₅ NO ₅ S: 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-Bug-2-ynylhex-4-incarboxylic acid hydroxyamide

2- (4-Methoxy-benzenesulfonyl) -2-but-2-nickelhex-4-incarboxylic acid tert-butyl ester was prepared according to the method of Example 9. Starting from 2- (4- methoxy-benzenesulfonyl) acetic acid (2.86 g, 10 mmol) and 1-bromo-2-butin (2.68 g, 20 mmol) to isolate 3.50 g of the product. Yield 90%; white solid mp 85-87 ° C; MS: 391.0 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-Bug-2-nyl-hex-4-incarboxylic acid was prepared according to the method of Example 70. Starting from 2- (4-methoxy-benzenesulfonyl) - 2-but-2-nyl-hex-4incarboxylic acid (3.0 g, 7.7 mmol) to isolate 2.5 g of the product. Yield 97%; white solid, mp 141-143 ° C. MS: 333.1 (MH) '.

2- (4-Methoxy-benzenesulfonyl) -2-but-2-nyl-hex4-incarboxylic acid hydroxyamide was prepared according to the method described in Example 1. Starting from 2- (4-methoxy-benzenesulfonyl) -2-boron- 2-Nyl-hex-4incarboxylic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to isolate 0.23 g of product. Yield 89%; white solid mp 135-137 ° C. MS: 349.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.67 (s, 6H), 2.70-3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d, J = 10.0 Hz, 2H), 7.71 (d, J-10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm '): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

Example 73

2- (4-Methoxy-benzenesulfonyl) -2-prop-2-ynylpent-4-incarboxylic acid hydroxyamide

2- (4-Methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-incarboxylic acid tert-butyl ester was prepared according to the method of Example 9. Starting from 2- (4- methoxybenzenesulfonyl) -acetic acid (2.0 g, 7 mmol) and propargyl bromide (1.77 g, 15 mmol) to isolate 1.90 g of the product. Yield 75%; white solid mp 113 -115 ° C; MS: 362.1 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-prop-2-ynyl-pent-4-incarboxylic acid was prepared according to the method of Example 70. It was obtained from 2- (4-methoxy-benzenesulfonyl) - 2-prop-2-ynyl-pent-4-carboxylic acid (1.70 g, 4.7 mmol) to isolate 1.30 g of the product. Yield 90%; white solid mp 156 ° C. MS: 305.1 (ΜΗ);

2- (4-Methoxy-benzenesulfonyl) -2-prop-2-ynylpent-4-incarboxylic acid hydroxyamide was prepared according to the method described in Example 1. Starting from 2- (4-methoxy-benzenesulfonyl) -2-prop- 2-Inylpent-4-incarboxylic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to isolate 0.22 g of product. Yield 85%; white solid mp 156 ° C. MS: 321.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 2.00 - 2.13 (m, 2H), 3.00 - 3.30 (m, 4H), 3.90 (s, 3H), 7.01 (d, 4 = 9.0 Hz, 2H). 7.82 (d, J = 9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm ' ¹ ): 339201s, 3293s, 3271m, 2955s, 1650s, 1594s;

Analysis calculated for C ₁₅ H ₁₅ NO ₅ S: 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-incarboxylic acid hydroxyamide

The title compound was prepared according to the method of Example 38. It was derived from 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylpropionic acid tert-butyl ester (2.20 g, 5.8 mmol) and 1-bromo-2- octin (1.14 g, 6 mmol) to isolate 2.60 g of product. Yield 92%; yellowish resin; MS: 486.0 (M + H) ⁺

A mixture of 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-incarboxylic acid tert-butyl ester (2.60 g, 5.35 mmol) in methylene chloride was stirred at room temperature for 1 hour. about 2 hours (see Example 70). The solvents were then evaporated to give 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4incarboxylic acid, which was purified by silica gel chromatography (~ 30% methanol / methylene chloride). Yield 2.00 g, 87%; white solid, mp 146 ° C; MS: 428.1 (MH) '.

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-incarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl -dex-4-incarboxylic acid (0.71 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) to give 0.48 g of product. Yield 67%; an off-white solid; mp 65 ° C; MS: 445.0 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.84 (t, J = 6.8 Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J = 17.9 Hz, 1H), 2.90 (d, J = 17.9 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 3.74 (d, J = 13.7 Hz, 1H), 3.89 (S, 3H), 7.19 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 9.0 Hz, 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;

Analysis calculated for C ₂ 3H _{2 8} N ₂ O ₅ S.HCI.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-399-ylmethyl-pent-4-incarboxylic acid hydroxyamide

The title compound was obtained according to the method of Example 38. It was obtained from 2- (4-methoxybenzenesulfonyl) -2-pyridin-3-ylpropionic acid tert-butyl ester (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol) to isolate 2.50 g of the product. Yield 60%; yellowish solid; MS: 416.0 (M + H) ⁺ .

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-carboxylic acid was prepared according to Example 70. It was derived from 2- (4-methoxy-benzenesulfonyl) -2-pyridine tert-butyl ester -3ylmethyl-pent-4-incarboxylic acid (2.0 g, 4.8 mmol) to isolate 1.2 g of the product. Yield 69%; white solid, mp 119 121 ° C; MS: 358.1 (MH) '.

2- (4-Methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl-pent-4-incarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-methoxy-benzenesulfonyl) -2-pyridin-3-ylmethyl -pent-4-incarboxylic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to give 0.065 g of product. Yield 25%; an off-white solid; mp 70 ° C; MS: 375.0 (M + H) ⁺ . * H NMR (300 MHz, DMSO-de): δ 1.19 (brs, 1 Η), 2.90-3.00 (m, 2H), 3.55 (d, J = 13.8 Hz, 1H), 3.67 (d, J = 13.8 Hz) , 1H), 3.89 (s, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 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-incarboxylic acid hydroxyamide

2- (4-Fluoro-benzenesulfanyl) -acetic acid tert-butyl ester was obtained according to the method of Example 1. It was obtained from 4fluorothiophenol (30.0 g, 230 mmol) and tert-bromoacetate (45.67 g, 230

100 mmol) to isolate 53.4 g of the product. Yield 100%. pale yellowish oil; MS: 243.1 (M + H) ⁺ .

2- (4-Fluoro-benzenesulfonyl) -acetic acid tert-butyl ester was prepared according to the method of Example 9. It was derived from 2- (4-fluoro-benzenesulfanyl) -acetic acid tert-butyl ester (48.4 g, 200 mmol) and 3-chloroperoxybenzoic acid (121.3 g, (57%), 400 mmol) to isolate 48.0 g of the product. Yield 88%; pale yellowish oil; MS: 275.1 (M + H) ⁺ .

The title compound was prepared according to the method described in Example 70. It was obtained from 2- (4-fluorobenzenesulfonyl) -3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2 -butin (0.67 g, 5.0 mmol) to isolate 2.18 g of the product. Yield 100%, yellowish resin; MS: 419.2 (M + H) ⁺ .

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-carboxylic acid was prepared according to the method of Example 38. It was obtained from tert-butyl ester of 2- (4-fluoro-benzenesulfonyl) -2-pyridine -3-ylmethyl-hex-4-incarboxylic acid (2.1 g, 5.0 mmol) to isolate 1.20 g of the product. Yield 67%; an off-white solid, mp 150 ° C. MS: 360.2 (MH) '.

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-hex-4-incarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl -hex-4-incarboxylic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to isolate 0.15 g of product. Yield 45%; white solid, mp 190 ° C. MS: 377.2 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J = 13.8 Hz, 1H), 3.74 (d, J = 13.8 Hz. 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;

Analysis calculated for C ₁₈ H ₁₇ FN ₂ O ₄ S. HCl.0.5H ₂ O:

101

C, 51.24; Η 4.54; N6.64;

Found: C, 51.21; H, 4.35; N6.46.

Example 77

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

The title compound was prepared according to the method of Example 9. It was derived from 2- (4-methoxybenzenesulfonyl) -3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2- octin (0.95 g, 5.0 mmol) to isolate 1.80 g of product. Yield 56%; yellowish resin; MS: 474.3 (M + H) ⁺

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-carboxylic acid was prepared according to the method described in Example 70. It was obtained from 2- (4-fluoro-benzenesulfonyl) - 2-pyridin-3-ylmethyl-dec-4-incarboxylic acid (1.80 g, 3.8 mmol) to isolate 1.40 g of the product. Yield 88%, off-white solid; mp 123 - 124 ° C; MS: 416.3 (MH).

2- (4-Fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl-dec-4-incarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-fluoro-benzenesulfonyl) -2-pyridin-3-ylmethyl -dex-4-incarboxylic acid (0.67 g, 1.62 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) to isolate 0.22 g of product. Yield 29%; white solid, mp 180 - 182 ° C. MS: 433.2 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 0.84 (t, J = 6.8 Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J = 19.9 Hz, 1H), 2.94 (d, J = 19.9 Hz, 1H), 3.54 (d, J = 13.7 Hz, 1H), 3.75 (d, J = 13.7 Hz, 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 '): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m.

Analysis: Calculated for C24H12F4Cl3S. HCI:

C 56.34; H5.59; N5.97;

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

102

Example 78

2- (4-Fluoro-benzenesulfonyl) -2-but-2-ynyl-hex4-incarboxylic acid hydroxyamide

2- (4-Fluoro-benzenesulfonyl) -2-but-2-ynylhex-4-incarboxylic acid tert-butyl ester was prepared according to the method of Example 9. It was obtained from 2- (4- fluoro-benzenesulfonyl) acetic acid (4.87 g, 20 mmol) and 1-bromo-2-butin (5.36 g, 40 mmol) to isolate 6.0 g of the product. Yield 77%; white solid; mp 85 ° C; MS: 379.1 (M + H) ⁺ .

2- (4-Fluoro-benzenesulfonyl) -2-but-2-ynyl-hex-4-incarboxylic acid was prepared according to the method described in Example 70. It was obtained from 2- (4-fluoro-benzenesulfonyl) tert-butyl ester ) -2-but-2-ynylhex-4-incarboxylic acid (3.50 g, 8.47 mmol) to isolate 2.35 g of the product. Yield 79%, white solid; mp 129-131 ° C; MS: 642.8 (MH) *.

2- (4-Fluoro-benzenesulfonyl) -2-but-2-ynyl-hex4-incarboxylic acid hydroxyamide was prepared according to the method of Example 1. Starting from 2- (4-fluoro-benzenesulfonyl) -2-but-2 -inyl-hex-4incarboxylic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol) to isolate 0.21 g of product. Yield 77%; white solid m.p. 161-163 C. MS: 338.1 (M + H) ⁺ . NMR (300 MHz, DMSO-de): δ 1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J = 9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 ( brs, 1H), 10.95 (brs, 1H); IR (KBr, cm ^'1): 3336s, 3245m, 1681s, 1589m, 1493m;

Analysis calculated for C ₁₆ H ₁₆ FNO ₄ S: C 56.96; H, 4.78; N, 4.15;

Found: C, 56.59; H, 4.75; N4.04.

Example 79

2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-2-enyl) -hex-4-enicarboxylic acid hydroxyamide

103

2- (4-Methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enicarboxylic acid ethyl ester was prepared according to the method of Example 9. Starting from ethyl ester of 2 - (4-Methoxybenzenesulfonyl) -acetic acid (5.0 g, 20 mmol) and isoprenyl bromide (6.0 g, 40 mmol). Yield 7.0 g 88%; colorless oil; MS: 395 (M + H) ⁺ .

Isolated from 2- (4-methoxy-benzenesulfonyl) 5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enicarboxylic acid ethyl ester (3.5 g, 9 mmol). g (97%) 2- (4-Methoxy-benzenesulfonyl) -5-methyl-2 (3-methyl-but-2-enyl) -hex-4-enicarboxylic acid as a colorless oil by the method of Example 9. MS : 365 (M + H) ⁺ .

Starting from 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-enicarboxylic acid (2.6 g, 7.0 mmol) and follow the procedure of Example 1 1.36 g of 2- (4-methoxy-benzenesulfonyl) -5-methyl-2- (3-methyl-but-2-enyl) -hex-4-carboxylic acid hydroxyamide is obtained as a colorless solid. Yield 67% m.p. 93-96 ° C; MS: 383 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3): δ 1.68 (s, 6H), 1.73 (s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d. J = 8 Hz, 2H), 7.33 (bs, 1H), 7.72 (d, J = 8 Hz, 2H), 9.71 (bs, 1H).

Example 80

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

2- (4-Methoxy-phenylsulfanyl) -heptanecarboxylic acid ethyl ester (13.8 g, 98%) was obtained according to the general method of Example 1, starting from ethyl 2-bromoheptanate (11 g, 47 mmol) and 4methoxythiophenol (6 g , 42.8 mmol) as a yellow oil; MS: 297.2 (M + H) ⁺ .

2- (4-Methoxy-phenylsulfanyl) -heptanecarboxylic acid was obtained from 2- (4-methoxyphenylsulfanyl) -heptanecarboxylic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH. (25 ml). The reaction mixture obtained was

104 developed as described in Example 1. Yield 3 g (83%) of a yellow oil. MS: 267.1 (M-H) '.

Starting from 2- (4-methoxy-phenylsulfanyl) -heptanecarboxylic acid (2.49 g, 9.32 mmol) and following the method of Example 1, 1.83 g of 2- (4-methoxy-phenylsulfanyl) heptanecarboxylic acid hydroxyamide is obtained as an off-white solid substance. Yield 70% m.p. 90 - 95 ° C; MS: 284.0 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 0.826 (t, J = 6.9 Hz, 3H), 1.135-1.76 (m, 8H), 3.35 (m, 1H), 3.82 (s, 3H), 6.91

7.49 (m, 4H).

Example 81

(49A) 2N * - (4-Methoxy-phenyl-8 * -sulfinyl) heptanecarboxylic acid hydroxyamide and (49B) 28 * - (4-methoxy-phenyl-B * -sulfinyl) heptanecarboxylic acid hydroxyamide

Starting from 2- (4-methoxy-phenylsulfanyl) heptanecarboxylic acid hydroxamide (1.69 g, 6 mmol) and following the method of Example 5, isolate the two diastereoisomers of 2- (4-methoxyphenylsulfinyl) -heptanecarboxylic acid on silica gel using 75% ethyl acetate: hexanes. The less polar hydroxyamide of 2N * - (4-methoxy-phenyl-5 * -sulfinyl) -heptanecarboxylic acid is isolated as a white powder. Yield 390 mg (22%) m.p. 115 ° C; MS: 300.0 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 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 of 25 * - (4-methoxyphenyl-β * -sulfinyl) -heptanecarboxylic 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-dg): δ 0.754 (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

105

2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-ylethoxy) -phenyl] -propionic hydroxyamide hydrochloride

Following the method of Example 12, 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-yl-ethoxy) phenyl] -propionic acid ethyl ester was obtained by leaving of 4 (morpholin-1-yl-ethoxy) -benzyl chloride hydrochloride ethyl ester (2.9 g, 10 mmol). Yield 4.8 g, 98%; brown oil; MS: 492 (M + H) ⁺ .

Stepping from 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -propionic acid ethyl ester (4.0 g, 8.1 mmol) afforded 3.2 g (84% yield) 2- (4-Methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-yl-ethoxy) -phenyl] -propionic acid as colorless crystals by the method of Example 9. mp 171 ° C; MS: 464 (M + H) ⁴ ·.

From 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4- (2-morpholin-4-ylethoxy) -phenyl] -propionic acid (4.0 g, 8.6 mmol) and by the method of Example 1, afforded 2.5 g of 2- (4-methoxy-benzenesulfonyl) -2-methyl-3- [4 (2-morpholin-4-yl-ethoxy) -phenyl] -propionic hydroxyamide as a colorless solid. The hydrochloride salt was obtained as the free base was reacted with methanol hydrogen chloride at 0 ° C. Yield 2.5 g, 60%; mp 98 ° C; MS: 479 (M + H) ⁺ . ¹ H NMR (300 MHz, CDCl 3):

• δ 1.36 (S, 3H), 3.8 -12.6 (m, 16 Η), 3.9 (S, 3H), 4.1 - 4.3 (m, 1 Η), 6.6 (d, J = 8 Hz, 2H), 6.96 ( d, J = 9 Hz, 2H), 7.1 (d, 8 Hz, 2H), 7.84 (d, 9 Hz, 2H), 10.8 (bs, 1H).

Example 83

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

In a round-bottom flask, a solution of 4-methoxybenzentiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in dry acetone (100 ml) was added while stirring α-bromoethyl acetate (3.3 g, 20 mmol) and the reaction mixture. heated at reflux for 8 hours at

106 vigorously stirring. The reaction mixture is then allowed to cool, the potassium salts are filtered off and the reaction mixture is concentrated. The residue was extracted with chloroform and washed with water and 0.5 N NaOH solution. The organic layer was washed again 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: 227 (M + H) ⁺ .

To a solution of 60% 3-chloroperoxybenzoic acid (14.0 g, 40 mmol) in methylene chloride (100 ml) at 0 ° C was added slowly with stirring (4-methoxy-phenylsulfanyl) -acetic acid ethyl ester (4.4 g, 20 mmol). ) in methylene chloride (15 ml). The reaction mixture became cloudy and stirred at room temperature for 6 hours. The mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solid was separated by filtration and a solution of Na ₂ SO ₃ was added to the organic layer, stirring for at least 3 hours before extracting with chloroform and stirring. wash with water. The organic layer was dried over magnesium sulfate, filtered and concentrated to isolate (4methoxy-phenylsulfonyl) -acetic acid ethyl ester as an oil. Yield 100%; MS: 259.1 (M + H) ⁺ .

Benzyl bromide (17.2 g, 100 mmol) was added to a stirred flask while stirring to a solution of diethanolamine (10.5 g, 100 mmol) and anhydrous potassium carbonate (30 g, excess) in dry acetone (250 ml) and the reaction mixture was heated at reflux. 8 hours with good stirring. Finally, the reaction mixture is allowed to cool, the potassium salts are filtered off and the reaction mixture is concentrated. The residue was extracted with chloroform and washed with water. The organic layer was washed again 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. That's right

107 the hydrochloride formed was dissolved in methylene chloride (300 ml), thionyl chloride (20 g, excess) was added dropwise and stirred at room temperature for 1 h. The reaction mixture was then concentrated to dryness and the product bis (2-chloro-ethyl) ) -benzyl amine hydrochloride is further used without purification. Yield 13.0 g, 97%; MS: 232 (M + H) ⁺ .

To a solution of bis- (2-chloro-ethyl) -benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg) and anhydrous potassium carbonate (30 mg, excess) in dry acetone in a round-bottom flask (4-Methoxy-phenylsulfonyl) -acetic acid ethyl ester (6.12 g, 24 mmol) was added with stirring and the reaction mixture was heated at reflux for 16 hours with vigorous stirring. At the end, the reaction mixture was allowed to cool, the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with water. The organic layer was further thoroughly washed with water, dried over magnesium sulfate, filtered and concentrated. The dark brown reaction mixture was purified by silica gel column chromatography eluting with 30% ethyl acetate: hexane to isolate the product 4- (4methoxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid ethyl ester as a brown oil. Yield 6.0 g, 60%; MS: 418 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1-benzylpiperidine-4-carboxylic acid ethyl ester (5.0 g, 11.9 mmol) was dissolved in methanol / tetrahydrofuran (1: 1, 200 ml) and stirred at room temperature for 72 hours . Finally, the reaction mixture was concentrated and the product was neutralized with concentrated hydrochloric acid when dissolved in water. After neutralization, the reaction mixture was concentrated to dryness. Ice-cooled water (100 ml) was added to the solid and filtered. The product, 4- (4-methoxybenzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid, was dried at 50 ° C and used in the next step without purification. Colorless solid. Yield 3.2 g, 69%; MS: 390 (M + H) ⁺ .

108

To a solution of 4- (4-methoxy-benzenesulfonyl) -1-benzylpiperidine-4-carboxylic acid (2.0 g, 5.1 mmol) in dimethylformamide (2 drops) and methylene chloride (100 ml) at 0 ° C was added dropwise oxalyl chloride ( 1.0 g, 8 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. Simultaneously 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 h. After this hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of methylene chloride and slowly added to the hydroxylamine at 0 ° C. The reaction mixture was stirred at room temperature for 24 h 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 chloroform to isolate 1-benzyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as a colorless solid, mp 90-95 ° C. Yield 1.2 g, 48%. MS: 405 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.29 (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, 1 Η), 11.18 (s, 1H).

Example 84

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

2 - [(2-hydroxy-ethyl) - (3-methoxy-benzyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g, 31.9 mmol). Yield 9.28 g, (99%); yellow oil; MS: 226 (M + H) ⁺ .

3-Methoxy-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from 3-methoxy-benzyl diethanolamine (4.4 g, 20 mmol). Yield 4.5 g (93%); yellow solid mp 86-88 ° C; MS: 263 (M + H) ⁺ .

109

4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy-benzenesulfonyl) ethyl ester - acetic acid (5.0 g, 22 mol) and bis- (2-chloro ethyl) -3-methoxy-benzyl) -amine (8.0 g, 23.5 mmol). Yield 2.4 g (24%); low-solids; MS: 447.9 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid is prepared by starting from 4 (4-methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) ethyl ester ) -piperidine-4-carboxylic acid (2.4 g, 5.36 mmol) dissolved in methanol (30 ml), 10 N NaOH (10 ml) and tetrahydrofuran (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 710 mg (32%), white solid, mp 199 ⁹ C; MS: 419.9 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid (830 mg, 1.98 mmol) and following the procedure of Example 83, 190 mg of hydroxyamide was obtained. 4- (4-Methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid, mp 130 ° C; Yield: 20.4%. MS: 435.0 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.24-2.32 (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, 10H), 10.1 (s, 1H).

Example 85

1- (3,4-Dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) - (3,4-dichloro-benzyl) -amino] - ethanol was prepared according to the general method described in Example 83. It was obtained from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 mmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M + H) ⁺ .

3,4-Dichloro-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. It was obtained from 3,4-dichlorobenzyl diethanolamine (10.7

HWftintIMIlIHlIl .......... ·

110 g, 41 mmol). Yield 99%; yellow solid mp 218-220 ° C; MS: 301.8 (M + H) ⁺ .

1- (3,4-Dichloro-benzyl) -4- (methoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy-benzenesulfonyl) -acetic ethyl ester acid (2.9 g, 11 mmol) and 3,4 dichlorobenzyl-bis- (2-chloroethyl) -amine (3.4 g, 11 mmol). Yield 5.9 g (60%); brown oil; MS: 494.5 (M + H) ⁺ .

1- (3,4-Dichlorobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is prepared by starting from 1- (3,4-dichloro-benzyl) -4- (methoxy- benzenesulfonyl) -piperidine-4carboxylic acid (5.0 g, 10 mmol) dissolved in methanol (50 ml), 10 N sodium hydroxide (15 ml) and tetrahydrofuran (75 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.94 g (62%); MS: 458.3 (M + H) ⁺ .

Starting from 1- (3,4-dichlorobenzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid (2.67 g, 5.8 mmol) and following the procedure of Example 83, 0.2 g of hydroxyamide per 1 ( 3,4-dichlorobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white solid, mp 192-195 ° C. Yield 10%; MS: 472.9 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 2.20 - 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 = 0.30, 2H), 7.50 - 7.73 (d, J = 0.027, 1H), 7.65 - 7.68 (d, J = 0.029, 2H), 7.72 7.75 (d, J = 0.027, 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

2 - [(2-hydroxy-ethyl) - (4-methyl-benzyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine

Ill (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99%); MS: 209.9 (M + H) ⁺ .

4-Methylbenzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from 4-methyl-benzyl diethanolamine (6 g, 20 mmol). Yield 5.2 g (84%); yellow solid mp 145 147 ° C; MS: 245.9 (M + H) ⁺ .

4- (Methoxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester ( 7.0 g, 27 mmol) and 4-methyl-bis- (2-chloroethyl) -amine (5.0 g, 17 mmol). Yield 4.64 g (63%); low-solids; MS: 413.9 (M + H) ⁺ .

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

Starting from 4- (methoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid (1.59 g, 3.9 mmol) and following the method of Example 83, 0.505 g of hydroxyamide of 4 (methoxy- benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid as a white solid, mp 176 - 177 ° C. Yield 32%; MS: 419.0 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-dJ: δ 2.24-2.32 (m, 2H), 2.51 (t, 3H), 2.73-2.88 (m, 2H), 3.35-3.55 (m, 4H), 3.87 (s. 3H), 4.24 (s, 2H), 7.13 7.17 (d, J = 0.39, 2H), 7.23 - 7.60 (d, J = 0.036, 2H), 7.38 - 7.41 (d, J = 0.025, 2H), 7.65 - 7.68 (d, J = 0.039, 2H).

Example 87

4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-2-yl112 methylpiperidine-4-carboxylic acid hydroxyamide

2 - [(2-hydroxy-ethyl) - (2-naphthyl-2-ylmethyl) -amino] -ethanol was prepared according to the general method described in Example 83. It was obtained from diethanolamine (6.18 g, 59 mmol) and 2- ( bromomethyl) naphthalene (10 g, 45 mmol). Yield 12.7 g (96%); yellow solid, m.p. Mp 162-164 ° C; MS: 246.0 (M + H) ⁺ .

2-Naphthyl-2-ylmethyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from 2-naphthyl-ylmethyldiethanolamine (10 g, 36 mmol). Yield 9.1 g (79%); brown solid mp 124-126 ° C; MS: 281.9 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-ylmethylpiperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (8.4 g, 32 mmol) and 1-naphthalenylmethyl-bis- (2-chloro-ethyl) -amine (8.6 g, 27 mmol). Yield 6.5 g (52%); low-solids; MS: 440.0 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1-naphthalen-yl-methylpiperidine-4-carboxylic acid is prepared by starting from 4 (4-methoxy-benzenesulfonyl) -1-naphthalen-yl-methyl-piperidine-4-carboxylic acid ethyl ester (6.3 g, 13 mmol) dissolved in methanol (30 ml), 10 N sodium hydroxide (30 ml) and tetrahydrofuran (30 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.3 g (36%); yellow solid, mp 226 - 228 ° C; MS: 440.0 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1-naphthalen-ylmethylpiperidine-4-carboxylic acid (2.18 g, 5.0 mmol) and following the method of Example 83, 0.753 g of 4- (4-methoxybenzenesulfonyl) hydroxyamide is obtained. ) -1-naphthalen-yl-methylpiperidine-4-carboxylic acid as an off-white solid, mp 168-170 ° C. Yield 31%; MS: 455.0 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 2.29-2.33 (m, 2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s , 2H), 7.13 113

7.16 (d, J = 0.30, 2H), 7.56 - 7.64 (m, 3H), 7.65 - 7.68 (d, J = 0.030, 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-methoxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) - (1-biphenyl-4-ylmethyl) -amino] -ethanol according to the general method described in Example 83. Starting from diethanolamine (5.2 g, 49 mmol) and 4- (chloromethyl) biphenyl (10 g, 49 mmol). Yield 9.98 g (66%); white solid, m.p. 160-162 ° C; MS: 271.9 (M + H) ⁺ . It was converted to dichloride as described in Example 83.

1-Biphenyl-4-ylmethyl -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy-benzenesulfonyl) -acetic acid ethyl ester ( 2.85 g, 11 mmol) and 1biphenyl-4-ylmethyl-bis- (2-chloro-ethyl) -amine (3.4 g, 11 mmol). Yield 2.1 g (39%); beige solid mp 176 - 178 ° C; MS: 494.1 (M + H) ⁺ .

1-Biphenyl-4-ylmethyl -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is prepared from ethyl ester of 1-biphenyl-4-yl methyl -4- (4-methoxy-benzenesulfonyl) - piperidine-4carboxylic acid (5.7 g, 12 mmol) dissolved in methanol (20 ml), 10 N sodium hydroxide (10 ml) and tetrahydrofuran (20 ml). 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-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid (1.0 g, 2.2 mmol) and following the procedure of Example 83, 0.132 g of 1-biphenyl-4- hydroxyamide is obtained. ylmethyl -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a light brown solid, mp 168 ° C. Yield 20%; MS: 440.9 (M + Hf. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.30-2.35 (m, 2H), 2.83-2.87 (m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15 - 7.21 (d, tMti

114

J = 0.059, 2H), 7.49- 7.65 (m, 5H), 7.68-7.74 (d, J = 0.06 Hz, 2H), 9.3 (s, 1H), 10.3 (s, 1H), 11.15 (s, 1H) .

Example 89

4- (4-Methoxy-benzenesulfonyl) -1- (3-methyl-2-yl) piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) -1- (3-methyl-but-2 -enyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine (4.1 g, 39 mmol) and 4-bromo-2-methyl-butene (6.0 g, 40 mmol). 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 method of Example 83. Starting from 2 - [(2-hydroxy-ethyl) 1- ( 3-methyl-but-2-enyl) -amino] -ethanol (10.4 g, 50 mmol). Yield 10.5 g (99%); brown solid; MS: 210.3 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 1 Exit 4- (methoxybenzenesulfonyl) ethyl ester - acetic acid (11.32 g, 44 mmol) and 3-methyl-but-2enyl) -bis- (2-chloroethyl) -amine (10.4 g, 50 mmol). Yield 6.2 g (36%); brown oil; MS: 395.6 (M + H) ⁺ .

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

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (3-methyl-but-2enyl) piperidine-4-carboxylic acid (1.0 g, 3.0 mmol) and following the method of Example 83, 0.110 g of hydroxyamide is obtained of 4- (4-methoxybenzenesulfonyl) -1- (3-methyl-but-2-enyl) piperidine-4-carboxyl

115 acid as a yellow solid, mp 142-145 ° C. Yield 12%; MS: 382.9 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 1.67 (s, 3H), 1.79 (s, 3H), 2.18-2.33 (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 = 0.03, 2H), 7.67 - 7.70 (d, J = 0.030, 2H), 9.34 ( s, 1H), 9.88 (s, 1H), 11.15 (s, 1H).

Example 90

1- (4-Bromo-benzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide 2 - [(4-bromobenzyl) - (2-hydroxyethyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine (22.5 g, 150 mmol) and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66 g, (99%); yellow oil; MS: 273.8 (M + H) ⁺ .

1- (4-Bromo-benzyl) -bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. It was derived from 2 - [(4-bromobenzyl) - (2-hydroxyethyl) -amino] -ethanol (33.28 g, 122 mmol). Yield 47 g (99%); brown solid mp 125 ° C; MS: 309.8 (M + H) ⁺ .

1- (4-Bromo-benzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy-benzenesulfonyl) -acetic ethyl ester acid (8.6 g, 33.5 mmol) and (4bromo-benzyl) -bis- (2-chloroethyl) -amine (13.3 g, 38.6 mmol). Yield 17 g (44%); brown oil; MS: 497.8 (M + H) ⁺ .

1- (4-Bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is prepared by starting from 1 (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) ethyl ester ) -piperidine-4carboxylic acid (16.5 g, 33.3 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 6.18 g (40%); light brown solid, mp 215 ° C; MS: 469.7 (M + H) ⁺ .

116

Starting from 1- (4-bromo-benzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid (1.95 g, 4.2 mmol) and following the method of Example 83, 1.29 g of hydroxyamide was obtained. 1 (4-bromo-6enzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as an off-white solid, mp 180 ° C. Yield 60%; MS: 484.7 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 2.18-2.99 (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 = 17 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.65 - 7.68 (m, 4H), 9.37 (S, 1H), 10.5 (s, 1H).

Example 91

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

2 - [(2-hydroxy-ethyl) - (3-phenyl-propyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine (15.8 g, 151 mmol) and 1-bromo-3 -phenylpropane (20 g, 101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - (3-phenyl-propyl) -amine was prepared according to the general method of Example 83. It was derived from 2 - [(2-hydroxy-ethyl) - (3-phenylpropyl) -amino] ethanol (20.32 g, 90.7 mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-phenylpropyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (12 g, 46.5 mmol) and bis- (2-chloroethyl) - (3-phenyl-propyl) -amine (24.8 g, 93.8 mmol). Yield 11.24 g (54%); brown oil; MS: 446 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid is obtained by starting from 4 (4-methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) ethyl ester ) -piperidine-4carboxylic acid (10.74 g, 24.13 mmol) dissolved in

117 tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.67 g (47%); an off-white solid, mp 203 ° C; MS: 418.2 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (3-phenylpropyl) -piperidine-4-carboxylic acid (4.37 g, 10.4 mmol) and following the procedure of Example 83, 1.64 g of hydroxyamide of 4- was obtained. (4methoxy-benzenesulfonyl) -1- (3-phenyl-propyl) -piperidine-4-carboxylic acid as an off-white solid, mp 143 ° C. Yield 37%; MS: 432.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.92 - 1.97 (m, 2H), 2.18 - 2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, J = 7.7 Hz, 2H) , 2.6 - 2.73 (m, 2H), 3.0 - 3.06 (m, 2H), 3.60 (d, J-12.3 Hz, 2H), 3.87 (s, 2H), 7.15 - 7.30 (m, 7H), 7.68 (d , J = 9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

Example 92

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

1-tert-butyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from 1-tert-butyl-diethanolamine (6 g, 37.2 mmol). Yield 11.15 g (99%); white solid; MS: 197.8 _is (M + H) ⁺

1-tert-Butyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (10 g, 38.76 mmol) and tert-butyl bis (2-chloro-ethyl) -amine (5.25 g, 22.53 mmol). Yield 5.37 g (62%); brown oil; MS: 384 (M + H) ⁺ .

1-tert-Butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is prepared by starting from 1-tert-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester acid (5.37 g, 14 mmol) dissolved in methanol (300 ml) and 10 N sodium

118 hydroxide (23 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.52 g (30.6%); white powder, mp 204 ° C; MS: 356 (M + H) +

Starting from 1-tert-butyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid (320 mg, 0.9 mmol) and following the method of Example 83, 190 mg of 1-tert hydroxyamide was obtained. -butyl 4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a green solid, mp 40 ° C. Yield 52%; MS: 371.1 (M + H) ⁺ . NMR (300 MHz, DMSO-dg): δ 1.29 (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

Butyl bis (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from N-butyldiethanolamine (6 g, 37.2 mmol). Yield 11.3 g (99%); white powder, mp 165 ° C; MS: 197.9 (M + H) ⁺ .

1-Butyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5 g, 19.38 mmol) and butyl-bis- (2-chloro-ethyl) -amine (4.52 g, 19.38 mmol). Yield 6.86 g (93%); brown oil; MS: 384 (M + H) ⁺ .

1-Butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was obtained by starting from 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (6.42 g , 16.8 mol) dissolved in methanol (200 ml) and 10 N sodium hydroxide (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.6 g (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 follow

119 of Example 83 yields 200 mg of 1-butyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white solid, m.p. 75 ° C. Yield 9.3%; MS: 371.1 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 0.87 (t, J = 7.2 Hz, 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 1-cyclooctyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from N- cyclooctyldiethanolamine (6 g, 28 mmol). Yield 10 g (99%); off-white solid, mp 158 ° C; MS: 251.9 (M + H) ⁺ .

1-Cyclooctyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5 g, 19.4 mmol) and cyclooctyl-bis- (2-chloro-ethyl) -amine (5.57 g, 19.4 mmol '; yield 8.2 g (96%); brown oil; MS: 438 (M + H) ⁺ .

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

Starting from 1-cyclooctyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid (2.26 g, 5.53 mmol) and following the method of Example 83, 570 mg of hydroxyamide of 1-cyclooctyl4- (4- methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid such as

120 white powder. Yield 22%, m.p. MS: 425 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-de): δ 1.42-1.66 (m, 14H), 1.83 (m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.88 (m, 3H). 7.17 (d, 2H), 7.66 (d, 2H).

Example 95

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

1-Ethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxy-benzenesulfonyl) -acetic acid ethyl ester (3 g, 11.6 mmol) and ethyl bis- (2-chloro-ethyl) -amine (2.39 g, 11.6 mmol). Yield 3.09 g (75%); low-fat brown solid; MS: 356 (M + H) ⁺

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

Starting from 1-ethyl -4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid (1.23 g, 3.76 mmol) and following the method of Example 83, 1.02 g of hydroxyamide of 1-ethyl -4- ( 4methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as an off-white powder C. Yield 80%; mp 85 °; MS: 343 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.926 (t, J = 7.12 Hz, 3H), 1.68-1.99 (m, 4H), 2.05-2.44 (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

121

1- Isopropyl -4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5.7 g, 22.2 mmol) and isopropyl-bis (2-chloro-ethyl) -amine (4.9 g, 22.2 mmol). Yield 5.64 g (68%); low-fat brown solid; MS: 370 (M + H) ⁺ .

1-Isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared by starting from 1-isopropyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mol) dissolved in methanol (75 ml) and 10 N sodium hydroxide (25 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.18 g (42%); white powder, mp 204 ° C; MS: 341.9 (M + H) ⁺ .

Starting from 1-isopropyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid (2.13 g, 6.25 mmol) and following the procedure of Example 83, 590 mg of 1- isopropyl 4- (4-hydroxyamide) is obtained. -methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a white powder C. Yield 2.4%; mp 75 °; MS: 357 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.21 (d, J = 6.6 Hz, 6H), 2.33-2.53 (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

1-Methyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (3 g, 11.6 mmol) and methyl-bis- (2-chloro-ethyl) -amine (2.2 g, 11.6 mmol). Yield 3.09 g (75%); low-fat brown solid; MS: 342 (M + H) ⁺ .

122

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

Starting from 1-methyl -4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid (2.0 g, 6.38 mmol) and following the method of Example 83, 1.10 g of hydroxyamide of 1- methyl -4- ( 4methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a yellow powder C. Yield 53%; mp 89 °; MS: 329 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSOde): δ 1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2.17 (d, J = 11.4 Hz, 2H), 2.57 ( d, J = 10.4 Hz, 2H), 3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).

Example 98

1-Benzyl-4- (4- boxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

1-Benzyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. It was obtained from 4- ((butoxy-benzenesulfonyl) acetic acid ethyl ester (6 g, 20 mmol) and bis- (2-chloro-ethyl) -benzylamine (10 g, 30 mmol). Yield 5.15 g (56%); yellow oil; MS: 460 (M + H) ⁺ .

1-Benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was obtained by starting from 1- benzyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (5.1 g , 11.1 mol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.66 g (56%); an off-white solid, mp 210 ° C; MS: 432 (M + H) ⁺ .

Starting from 1-benzyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid (2.61 g, 6.06 mmol) and follow

123 of the method of Example 83 gave 860 mg of 1- benzyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide as an off-white powder. Yield 32%; mp 144 °; MS: 446.9 (M + H) ⁺ . NMR (300 MHz, DMSO-dg): δ 0.94 (t, J = 7.3 Hz, 3H), 1.44 (q, J = 7.5 Hz, 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 = 6.3 Hz, 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-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide

1- (4-Fluoro-benzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy-benzenesulfonyl) -acetic ethyl ester acid (18.8 g, 72.8 mmol) and (4fluoro-benzyl) -bis- (2-chloro-ethyl) -amine (20.8 g, 73 mmol). Yield 25 g (79%); brown oil; MS: 436.9 (M + H) ⁺ .

1- (4-Fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is obtained from ethyl ester of 1 (4-fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) ) -piperidine-4carboxylic acid (17.4 g, 40 mol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). 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) ⁺ .

Starting from 1- (4-fluoro-benzyl) -4- (4-methoxybenzenesulfonyl) -piperidine-4-carboxylic acid (8.14 g, 20 mmol) and following the procedure of Example 83, 4.3 g of hydroxyamide per 1 ( 4-Fluoro-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as an off-white solid. Yield 51%; mp 176-178 °; MS: 484.7 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 2.12 2.20 (m, 2H), 2.64 - 2.79 (m, 2H), 3.32 - 3.45 (m, 4H), 3.87 (s, 3H), 4.31 (S ,

124

2H), 7.14 - 7.19 (d, J = 8.1 Hz, 2H), 7.27 - 7.33 (d, J = 8.1 Hz, 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-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide 1- (4-fluoro-benzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4 ethyl ester -carboxylic acid was prepared according to the general method of Example 83. Starting from 4 (butoxy-benzenesulfonyl) -acetic acid ethyl ester (6 g, 20 mmol) and (4-fluorobenzyl) -bis- (2-chloro-ethyl) -amine (5.73 g, 20 mmol). Yield 8.2 g (86%); yellow oil; MS: 478 (M + H) ⁺ .

1- (4-Fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is obtained from ethyl ester of 1 (4-fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) ) -piperidine-4carboxylic acid (4.77 g, 10 mol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.5 g (79%); an off-white solid, mp 114 ° C; MS: 450 (M + H) ⁺ .

Starting from 1- (4-fluoro-benzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid (2.24 g, 5.0 mmol) and following the procedure of Example 83, 200 mg of hydroxyamide per 1 ( 4-Fluoro-benzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as an off-white solid. Yield 9%; mp 112 °; MS: 465.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.94 (t, J = 7.3 Hz, 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 Hz, 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-125-benzyl) -piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) - (4-methoxy-benzyl) -amino] -ethanol was prepared according to the general method described in Example 83. Starting from diethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g, 100 mmol). Yield 17.5 g, (77%); yellow oil; MS: 226 (M + H) ⁺ .

4-Methoxybenzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method of Example 83. Starting from 4-methoxy-benzyl diethanolamine (10 g, 44 mmol). Yield 10 g (75%); yellow solid, m.p. 55 ° C; MS: 263.1 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5.0 g, 20 mmol) and bis- (2-chloro-ethyl) (4-methoxy-benzyl) -amine (7.0 g, 22 mmol). Yield 5.0 g (56%); low-solids; MS: 448.5 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid is prepared by starting from 4 (4-methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) ethyl ester ) -piperidine-4carboxylic acid (4.2 g, 10 mmol) dissolved in methanol (30 ml) and 10 N sodium hydroxide (10 ml) and tetrahydrofuran (20 ml). 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-methoxybenzyl) -piperidine-4-carboxylic acid (2.0 g, 4.7 mmol) and following the procedure of Example 83, 1.2 g of hydroxyamide of 4- (4methoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid. Yield 1.2 g; 59%, m.p. 175 ° C. MS: 433.0 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 1.8 (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).

126

Example 102

4- (4-Methoxy-benzenesulfonyl) -1- (2- (4-methoxyphenyl) -ethyl] -piperidine-4-carboxylic acid hydroxyamide 2 - {(2-hydroxy-ethyl) - (2- (4-methoxyphenyl) - ethyl] -amino} -ethanol was prepared according to the general method described in Example 83. It was obtained from diethanolamine (10.0 g, excess) and 1- (2-chloroethyl) -4-methoxybenzene (8.5 g, 50 mmol). , (92%); yellow oil; MS: 240 (M + H) ⁺ .

The corresponding dichloride, bis- (2-chloro-ethyl) - (4-methoxyphenyl-2-ethyl) -amine, was prepared according to the general method of Example 83. Starting from 2 - {(2-hydroxy-ethyl) - [2- (4 -methoxyphenyl) -ethyl] -amino} -ethanol (10 g, 41.8 mmol). Yield 11 g (95%); brown oil; MS: 277.2 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (2- (4-methoxyphenyl) -ethyl] -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4 (methoxy- benzenesulfonyl) -acetic acid (5.0 g, 20 mmol) and bis- (2-chloro-ethyl) - (4-methoxyphenyl-2-ethynyl) -amine (6.4 g, 20 mmol) Yield 6.0 g (65%); brown oil MS: 462.5 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- [2- (4-methoxyphenyl) -ethyl] piperidine-4-carboxylic acid was prepared by starting from 4- (4-methoxy-benzenesulfonyl) -1- (2- (4-methoxyphenyl) ethyl] -piperidine-4-carboxylic acid (5.0 g, 10.8 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml) The resulting reaction mixture was worked up as is given in Example 83. Yield 4.0 g (85%); 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 following the procedure of Example 83, 900 mg was obtained 4- (4-Methoxy-benzenesulfonyl) -1- (2- (4-methoxyphenyl) ethyl] -piperidine-4-carboxylic acid hydroxyamide as an off-white solid, 58% yield, mp 206 ° C (HCl) MS: 449.5 (M + H) ⁺ . 1H NMR (300 MHz, DMSO-dJ: δ 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H). , 3.25

127 (m, 2H), 3.4 (m, 4H), 3.60 (d, J = 12.3 Hz, 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

2 - [(2-hydroxy-ethyl) - (2-phenyl-ethyl) -amino] -ethanol was prepared according to the general method described in example 1. Starting from diethanolamine (6.0 g, 57) and 2-bromo-ethylbenzene ( 9.0 g, 48.3 mmol). Yield 9 g, (90%); yellow oil; MS: 210 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - (2-phenyl-ethyl) -amine was prepared according to the general method of Example 83. It was derived from 2 - [(2-hydroxy-ethyl) - (2-phenylethyl) -amino] ethanol (8.5 g, 40.6 mmol). Yield 11 g (95%); brown oil; MS: 247.1 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic ethyl ester acid (5.0 g, 20 mmol) and bis- (2-chloro-ethyl) (2-phenyl-ethyl) -amine (5.6 g, 20 mmol). Yield 5.5 g (63%); brown oil; MS: 432.5 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid is prepared by starting from 4 (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) ethyl ester ) -piperidine-4-carboxylic acid (3.0 g, 6.9 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.0 g (72%); whitish powder, mp 208 ° C; MS: 404.5 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (2-phenylethyl) -piperidine-4-carboxylic acid (1.5 g, 3.7 mmol) and following the method of Example 83, 900 mg of hydroxyamide of 4- was obtained. (4-Methoxybenzenesulfonyl) -1- (2-phenyl-ethyl) -piperidine-4-carboxylic acid as an off-white solid. Yield 58% m.p. 205 ° C (HCl). MS:

128

419.4 (Μ + Η) ⁺ . 1 H NMR (300 MHz, DMSO-dj): δ 2.3 (m, 2,), 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-methoxybenzyl) -piperidine-4-carboxylic acid hydroxyamide

4- (4-n-Butoxy-benzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (4-n-ethyl) -butoxybenzenesulfonyl) -acetic acid (2.5 g, 10 mmol) and bis- (2-chloro-ethyl) (4-methoxy-benzyl) -amine (3.0 g, 10 mmol). Yield 3.5 g (71%); low-solids; MS: 490.5 (M + H) ⁺ .

4- (4-n-Butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid was prepared by starting from 4- (4-n-butoxy-benzenesulfonyl) -1- (ethyl) 4-methoxy-benzyl) -piperidine-4carboxylic acid (3.0 g, 6.1 mmol) dissolved in methanol (30 ml), 10 N sodium hydroxide (10 ml) and tetrahydrofuran (20 ml). 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) ⁺ .

Starting from 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid (1.0 g, 2.1 mmol) and following the procedure of Example 83, 1.2 g of hydroxyamide was obtained. 4- (4-Butoxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid as a white solid, m.p. 173 ° (HCl); Yield: 800 mg, 77%; MS: 477.5 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.9 (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-phenoxy129 propyl) -piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) - (3-phenoxy-propyl) -amino] -ethanol was obtained according to the general method described in Example 83. It was obtained from diethanolamine (15.8 g, 151 mmol) and 3-phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - (3-phenoxy-propyl) -amine was prepared according to the general method of Example 83. It was derived from 2 - [(2-hydroxy-ethyl) (3-phenoxy-propyl) -amino ] ethanol (20.0 g, 84 mmol). Yield 24.0 g (91%); brown oil; MS: 277.8 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5.2 g, 20 mmol) and bis- (2-chloro-ethyl) (3-phenoxy-propyl) -amine (7.0 g, 22 mmol). Yield 6.5 g (70%); brown oil; MS: 462.5 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid is obtained by starting from 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxy) ethyl ester. propyl) -piperidine-4carboxylic acid (4.2 g, 9.1 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (75%); whitish powder, mp 195 ° C; MS: 434.5 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid (2.5 g, 5.77 mmol) and following the procedure of Example 83, 1.2 g of hydroxyamide of 4- was obtained. (4methoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid as an off-white solid. Yield 46% m.p. 101 ° C MS: 448.5 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 3H), 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), 10.28 (bs, 1H).

130

Example 106

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

4- (4-n-Butoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (4-n-ethyl ester) -butoxybenzenesulfonyl) -acetic acid (3.0 g, 10 mmol) and bis- (2-chloro-ethyl) (3-phenoxy-propyl) -amine (3.0 g, 11 mmol). Yield 4.5 g (89%); brown oil; MS: 504.6 (M + H) ⁺

4- (4-n-Butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid was prepared by starting from 4- (4-n-butoxy-benzenesulfonyl) -1- (ethyl) 3-Phenoxy-propyl) -piperidine-4carboxylic acid (4.0 g, 7.9 mmol) dissolved in THF: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (79%); whitish powder, mp 191 ° C; MS: 476.5 (M + H) ⁺ .

Starting from 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid (700 mg, 1.4 mmol) and following the method of Example 83, 300 mg of hydroxyamide was obtained. 4- (4-Butoxy-benzenesulfonyl) -1- (3-phenoxy-propyl) -piperidine-4-carboxylic acid as an off-white solid, Yield: 43%; MS: 491.5 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.9 (t, 3H). 1.5 (m, 2H) "

I. 8 (m, 2H), 2.18 (m, 3H), 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),

II. 28 (bs, 1H).

Example 107

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxyamide 2 - [(2-hydroxy-ethyl) - (2-phenoxy-ethyl) -amino] -ethanol prepared according to the general method described in Example 83. Starts from diethanolamine

131 (15.0 g, 150 mmol) and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); colorless oil; MS: 226 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - (2-phenoxy-ethyl) -amine was prepared according to the general method of Example 83. It was derived from 2 - [(2-hydroxy-ethyl) - (2-phenoxy-ethyl) -amino] ethanol (20.0 g, 88.8 mmol). Yield 25 g (94%); brown oil; MS: 263.1 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (methoxybenzenesulfonyl) -acetic acid ethyl ester (5.0, 20 mmol) and bis- (2-chloro-ethyl) (2-phenoxy-ethyl) -amine amine (6.0 g, 20 mmol). Yield 5.8 g (64%); brown oil; MS: 448.5 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid is obtained by starting from 4 (4-methoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) ethyl ester ) -piperidine-4carboxylic acid (5.0 g, 11.1 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.0 g (63%); whitish powder, mp 235 ° C; MS: 420.5 (M + H) ⁺ .

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid (2.5 g, 5.9 mmol) and following the method of Example 83, 1.3 g of hydroxyamide of 4- (4-Methoxybenzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid as an off-white solid. Yield 50% m.p. 168-172 ° C (HCl). MS: 435.4 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.3 (m, 2H), 2.5 (ΓΠ, 2Η), 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 (bs, 1H).

Example 108

4- (4-n-Bugoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid hydroxyamide

132

4- (4-n-Butoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from 4- (4-n-ethyl ester) -butoxybenzenesulfonyl) -acetic acid (2.5 g, 10 mmol) and bis- (2-chloro-ethyl) (2-phenoxy-ethyl) -amine (2.98 g, 10 mmol). Yield 3.0 g (69%); brown oil; MS: 490.6 (M + H) ⁺ .

4- (4-n-Butoxy-benzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid is obtained by starting from 4 (4-n-butoxy-benzenesulfonyl) -1- (2 -phenyl-ethoxy) -piperidine-4-carboxylic acid (2.5 g, 5.76 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N sodium hydroxide (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.5 g (56%); whitish powder, mp 204 ° C; MS: 462.5 (M + H) ⁺ .

Starting from 4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid (1.0 g, 2.16 mmol) and following the method of Example 83, 600 mg of hydroxamide was obtained. 4- (4-n-butoxybenzenesulfonyl) -1- (2-phenoxy-ethyl) -piperidine-4-carboxylic acid as an off-white solid, Yield: 58%; mp 112 ° C (HCl); MS: 477.4 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 0.942 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 2H), 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 hydroxyamide

Bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine was prepared according to the general method of Example 83. Starting from diethanolamine (15.0 g, 150 mmol) and 4- (2-Piperidin-1-yl-ethoxy) -benzyl

133 chloride (5.9 g, 20 mmol). Yield 5.5 g, (85%); brown semi-solid; MS: 323 (M + H) +

Bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine was prepared according to the general method of Example 83. Starting from 2 - ((2-hydroxy-ethyl) - [4- (2-piperidinyl-1-yl-ethoxy) benzyl] -amine (3.22 g, 10 mmol); 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-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83. Starting from ethyl 4- (4 • Methoxy-benzenesulfonyl) -acetic acid ester (5.0 g, 20 mmol) and bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine ( 8.6 g, 20 mmol). Yield 6.0 g (55%); brown oil; MS: 545.7 (M + H) ⁺ .

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

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid (3.5 g, 6.78 mmol) and follow the procedure of Example 83 gave 1.8 g of 4- (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) -benzyl] -piperidine-4-carboxylic acid hydroxamide as a pale yellow solid, Yield: 49 %; mp 114 ° C (HCl); MS: 532 (M + H) ⁺ . * H NMR (300 MHz, DMSO-d ₆ ): δ 1.4 -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).

134

Example 110

N-hydroxy-2- (4-methoxy-benzenesulfonyl) -propionamide Step A: Coupling of 2-bromo-propionic acid to a hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene ^ resin ¹ (2 g, 1.1 meq / r) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and suspended in dimethylformamide (20 ml) 2-bromopropionic acid (0.6 ml, 3.0 eq) and 1-hydroxybenzotriazole hydrate (HOBt, 1.8 g, 6.0 eq) and 1,3-diisopropyl carbodiimide (DIC, 1.4 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). A resin sample was collected and subjected to the Kaiser test. and indicate the presence of an amine (the resin is colored blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). Each wash consists of adding the solvent by bubbling nitrogen or shaking the orbital shaker for 1 - 5 minutes and then filtering in vacuo.) The resin is dried in vacuo at room temperature.

A resin sample (5 - 20 mg) was cleaved with DCM (0.5 ml) and trifluoroacetic acid (0.5 ml) for 1 hour at room temperature. The reaction mixture was filtered and the resin was washed with DCM (1 x 1 ml). The filtrate and washes were combined and concentrated in vacuo with Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The product was then characterized by ¹ H NMR (DMSO-de): δ 4.54 (q, 1H), 1.83 (d, 3H).

Step B: Substitution of bromide with 4-methoxybenzenethiol

The N-hydroxy-2-bromo-propionamide resin obtained in step A (0.35 g, 1.1 meq / r) was placed in a 20 ml scintillation vial and

135 was suspended in tetrahydrofuran (2 ml). 4-Methoxybenzenethiol (0.23 ml, 5.0 eq), sodium iodide (288 mg, 5.0 eq) and 1,8diazabicyclo [5.4.0] -undec-7-ene (DBU, 0.17 ml, 3.0 eq) were added. The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2 x 2 ml), dimethylformamide: water 9: 1 (2 x 2 ml), with dimethylformamide (2 ml). with methanol (2 x 2 ml) and DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide resin obtained in step B (175 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and 70% tert-butyl hydroperoxide (1.0 was added) ml) and benzenesulfonic acid (50 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide resin obtained in step B (175 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and mPCBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then 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 obtained in step D (73 mg, 1.2 meq / r) was suspended in DCM (1.0; 136 ml) and trifluoroacetic acid (1.0 ml) was added. . The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2x2 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 84% @ 215 nm; 1H NMR (DMSO-dg): δ 10.75 (brs, 1H), 7.95 (brs, 1Η), 7.71 (dd, 2Η), 7.16 (dd, 2H), 3.87 (s, 3H), 3.83 (q, 1H), 1.26 (d, 3H).

The hydroxamic acids of Examples 111 - 113 were synthesized using the appropriate starting materials and following the steps of Example 110.

Example 111 N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide, 72% @ 215 nm

N-hydroxy-2- (4-methoxy-benzenesulfinyl) -propionamide, 76% @ 215 nm 1 H NMR (DMSO-d ₆ ): δ 10.90 & 10.60 (brs, 1Η), 7.95 (brs, 1 Η), 7.61 & 7.52 (dd, 2Η), 7.15 & 7.10 (dd, 2H), 3.83 & 3.82 (s, 3H), 3.42 & 3.28 (q, 1Η). 1.23 & 0.97 (d, 3H).

Example 112 N-hydroxy-2- (3-methyl-butane-1-sulfanyl) -propionamide. 74% @

215 nm

N-hydroxy-2- (3-methyl-butane-1-sulfinyl) -propionamide. 1 H NMR (DMSO-d ₆ ): δ 10.8 (brs, 1 Η), 7.95 (brs, 1 Η), 3.45 & 3.31 (q, 1 Η), 2.71 - 2.50 (m, 2Η), 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-boron-1-sulfonyl) -propionamide. 84% @

215 nm.

Example 114 N-Hydroxy-3-methyl-2- (naphthalen-2-ylsulfanyl) -butyramide Step A: Coupling of 2-bromo-3-methyl-butyric acid to a hydroxylamine resin

NM

137

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene-resin ¹ (5 g, 1.1 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). 3-methyl-butyric acid (9.96 g, 10.0 eq.) And DIC (9.04 mL, 10.5 eq.) The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide ( 3 x 20 ml) Remove the resin sample and pass the Kaiser test If the test shows the presence of an amine / (the resin turns blue) the above coupling is repeated in In the opposite case, the resin was washed with DCM (3 x 20 mL), methanol (2 x 20 mL) and DCM (2 x 20 mL), and the resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 2-naphthalenethiol

The 2-bromo-hydroximate resin obtained in step A (0.15 g, 1.1 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 2-Naphthalenethiol (138 mg, 5.0 eq), sodium iodide (129 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU, 0.078 ml, 3.0 eq) were added. ). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2x2 ml), dimethylformamide: water 9: 1 (2 x 2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide N-hydroxy-2- (4-methoxy-benzenesulfanyl) -propionamide resin obtained in step B (175 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and added 70% tert-butyl hydroperoxide (1.0 ml) and benzenesulfonic acid (50 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml) with dimethylformamide (2x2

138 ml), with methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2- (2-naphthalenesulfanyl) -N-hydroxypropionamide resin obtained in step B (175 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and mPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

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

The 2- (2-naphthalenesulfanyl) -N-hydroxypropionamide resin obtained in step B (73 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant Speed Vac Plus. Methanol (1 ml) was added and the mixture was concentrated.

f 83% @ 215 nm; LCMS (API electrospray) m / z 276 (M + H) ⁺ ; ^1H

NMR (DMSO-d ₆ ): δ 10.7 (brs, 1 Η), 7.91 (brs, 1 Η), 7.91 - 7.81 (m, 4Η), 7.55 7.45 (m, 3H), 3.41 (d, 1H), 2.09 - 1.97 (m, 1H), 1.05 (d, 3H), 0.97 (d, 3H).

The hydroxamic acids of Examples 115 - 118 were synthesized using the appropriate starting materials and following the steps of Example 114.

Example 115 N-Hydroxy-3-methyl-2- (naphthalen-2-ylsulfinyl) -butyramide, 67% @ 215 nm.

Example 116

139

N-hydroxy-3-methyl-2- (naphthalen-2-ylsulfonyl) -butyramide, 97% @ 215 nm; LCMS (API electrospray) m / z 308 (M + H) ⁺ .

Example 117

N-hydroxy-3-methyl-1-phenethylsulfinyl-butyramide, 93% @ 215 nm; LCMS (API electrospray) m / z 254 (M + H) ⁺ .

Example 118

N-hydroxy-3-methyl-2-phenethylsulfonyl-butyramide, 97% @ 215 nm; LCMS (API electrospray) m / z 286 (M + H) ⁺ .

Example 119

(1-Hydroxycarbamoyl-propane-1-sulfanyl) acetic acid methyl ester

Step A: Coupling of 2-bromobutyric acid to the hydroxylamine resin 4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (5 g, 1.1 meq / r) was placed in a peptide synthesis vessel and was suspended in dimethylformamide (40 ml). 2butyric 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 mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step C: Substitution of bromide with thioglycolate

The 2-bromo-hydroxylate resin obtained in step A (0.45 g, 1.1 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). Methyl thioglycollate (286 mg, 5.0 eq), sodium iodide (404 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7- were added.

140 yen (DBU, 0.24 ml, 3.0 eq). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2x2 ml), dimethylformamide: water 9: 1 (2x2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

(1-Hydroxycarbamoyl-propane-1-sulfanyl) acetic acid methyl ester obtained in step B (150 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and 70% tert-butyl hydroperoxide was added ( 1.0 ml) and benzenesulfonic acid (50 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

(1-Hydroxycarbamoyl-propane-1-sulfanyl) acetic acid methyl ester obtained in step B (150 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and mPCBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of (1-hydroxycarbamoylpropane-1-sulfanyl) -acetic acid methyl ester from the resin

(1-Hydroxycarbamoyl-propane-1-sulfanyl) acetic acid methyl ester obtained in step B (150 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour.

141

The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. LCMS (API electrospray) m / z 228 (M + Na) ⁺ ;

The hydroxamic acids of Examples 120 - 124 were synthesized using the appropriate starting materials and the steps of Example 119 were followed.

Example 120

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

Example 121

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

Example 122

(1-Hydroxycarbamoyl-propane-1-sulfanyl) acetic acid hydroxyamide; ¹ H NMR (DMSO-d ₆ ): δ 10.7 (brs, 1 Η), 4.03 (t, 2Η), 2.95 (q, 1H), 2.75 - 2.70 (m, 1 Η), 2.60 - 2.54 (m, 1H ), 1.74-1.66 (m, 2H), 1.58-1.55 (m, 4H), 1.32 (sextet, 2H), 0.88 (t, 3H), 0.85 (t, 3H); LCMS (APIelectrospray) m / z 264 (M + H) ⁺ .

Example 123

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

Example 124

(1-Hydroxycarbamoyl-propane-1-sulfonyl) propionic acid hydroxyamide; 100% @ 220 nm;

Example 125

2- (4-hydroxybenzenesulfanyl) -1H-hydroxy-3-phenyl-propionamide

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

142 to the hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -molin (5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). 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 mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 4-hydroxythiophenol

The 2-bromo-hydroxylate resin obtained in step A (0.33 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 4-Hydroxythiophenol (250 mg, 5.0 eq), sodium iodide (297 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7en (DBU, 0.18 ml, 3.0 eq) were added. The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2 x 2 ml), dimethylformamide: water 9: 1 (2x2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide 2- (4-hydroxybenzenesulfanyl) -N-hydroxy-3-phenylpropionamide resin obtained in step B (110 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and added 70% tert-butyl hydroperoxide (0.73 ml) and benzenesulfonic acid (36 mg). The reaction mixture was evaporated

143 shakes the orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 2- (4-hydroxybenzenesulfanyl) -N-hydroxy-3-phenylpropionamide resin obtained in step B (110 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and mPCBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of 2- (4-hydroxybenzenesulfanyl) -N-hydroxy-

3-Phenyl-propionamide from the resin

The 2- (4-hydroxybenzenesulfanyl) -N-hydroxy-3-phenylpropionamide resin obtained in step B (110 mg, 1.2 meq / r) was suspended in DCM (1.0 mL) and trifluoroacetic acid (1.0 mL) was added. the mixture was shaken at room temperature for 1 hour, then the mixture was filtered and the resin was washed with DCM (2 x 1 ml), the filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus methanol (1 ml) and the mixture were added concentrated. 84% @ 215 nm; NMR (DMSO-d _6): δ 10.41 (brs, 1 Η), 7.95 (brs, 1Η ), 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).

The hydroxamic acids of Examples 126-130 were synthesized using the appropriate starting materials and the steps of Example 125 were followed.

Example 126

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

144

Example 127 2- (4-Hydroxybenzenesulfonyl) -N-hydroxy-3-phenylpropionamide, 77% @ 215 nm. 1 H NMR (DMSO-d ₆ ): δ 10.50 (brs, 1 Η), 7.95 (brs, 1 Η), 7.68 - 7.57 (m, 2Η), 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-acetylamino-benzenesulfanyl) -N-hydroxy-3-phenylpropionamide; 86% @ 215 nm. 1 H NMR (DMSO-d ₆ ): δ 10.50 (brs, 1 Η), 10.03 (brs, 1 Η), 8.13 (brs, 1 Η), 7.56 - 7.12 (m, 9Η), 3.67 (q, 1 Η ), 3.08 (dd, 1Η), 2.84 (dd, 1H), 2.04 (s, 3H).

Example 129 2- (4-acetylamino-benzenesulfinyl) -N-hydroxy-3-phenylpropionamide; 73% @ 215 nm.

Example 130 2- (4-acetylamino-benzenesulfonyl) -N-hydroxy-3-phenylpropionamide; 95% @ 215 nm.

Example 131

4-Hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) -butyric acid methyl ester

Step A: Coupling of 2-6 Romo-3-methyl glutaric acid to a hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (4.5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). S-2bromo-5-methyl glutarate (3.87 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue) the above coupling is repeated in

144

Example 127 2- (4-Hydroxybenzenesulfonyl) -N-hydroxy-3-phenylpropionamide, 77% @ 215 nm. 1 H NMR (DMSO-d ₆ ): δ 10.50 (brs, 1 Η), 7.95 (brs, 1Η), 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-acetylamino-benzenesulfanyl) -N-hydroxy-3-phenylpropionamide; 86% @ 215 nm. ¹ H NMR (DMSO-d ₆ ): δ 10.50 (brs, 1 Η), 10.03 (brs, 1 Η), 8.13 (brs, 1 Η), 7.56 - 7.12 (m, 9Η), 3.67 (q, 1 Η ), 3.08 (dd, 1Η), 2.84 (dd, 1Η), 2.04 (s, 3H).

Example 129

2- (4-acetylamino-benzenesulfinyl) -N-hydroxy-3-phenylpropionamide; 73% @ 215 nm.

Example 130

2- (4-acetylamino-benzenesulfonyl) -1,1-hydroxy-3-phenylpropionamide; 95% @ 215 nm.

Example 131

4-Hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) -butyric acid methyl ester

Step A: Coupling of 2-bromo-3-methyl glutaric acid to a hydroxylamine resin 4-0-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (4.5 g, 1.2 meq / r) was placed in a synthesis vessel of peptides and suspended in dimethylformamide (40 ml). S-2bromo-5-methyl glutarate (3.87 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue) the above coupling is repeated in

146 room temperature 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of 4-hydroxycarbamoyl-4 (4-methanesulfanyl-phenylsulfanyl) -butyric acid methyl ester 4-hydroxycarbamoyl-4- (4-methanesulfanylphenylsulfanyl) -methylbutyric acid (3-methanesulfanyl) -butanoic acid , 1.2 meq / r), was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 77% @ 215 nm; LCMS (API electrospray) m / z 316 (M + H) ⁺ .

The hydroxamic acids of Examples 132-139 were synthesized using the appropriate starting materials and the steps of Example 131 were followed.

Example 132

4-Hydroxycarbamoyl-4- (4-methanesulfinylphenylsulfinyl) -butyric acid hydroxyamide. 77% @ 215 nm; LCMS (API electrospray) m / z 348 (M + H) ⁺ .

Example 133

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

Example 134

4-Hydroxycarbamoyl-4- (4-bromobenzenesulfanyl) -butyric acid hydroxyamide. 93% @ 215 nm.

Example 135

147

Hydroxyamide on 4-hydroxycarbamoyl-4- (4-bromo- benzenesulfinyl) -butyric acid. 80% @ 215 nm. Example 136 Hydroxyamide on 4-hydroxycarbamoyl-4- (4-bromo- benzenesulfonyl) -butyric acid. 77% @ 215 nm. Example 137

4-Hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfanyl) -butyric acid hydroxyamide. 93% @ 215 nm.

Example 138

4-Hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfinyl) -butyric acid hydroxyamide. 72% @ 215 nm.

Example 137

4-Hydroxycarbamoyl-4- (2-trifluoromethylbenzenesulfonyl) -butyric acid hydroxyamide. 90% @ 215 nm.

Example 140

2- (3-Methoxy-benzenesulfanyl) -decanecarboxylic acid hydroxyamide

Step A: Coupling of 2-bromo-decanecarboxylic acid to hydroxylamine resin 4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (4.5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). 2 Bromo-decanecarboxylic acid (4.07 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin is colored blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), with

148 methanol (2 x 20 mL) and with DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 3-methoxy-benzentiol

The 2-bromo-hydroxylate resin obtained in step A (0.22 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 3-Methoxy-benzentiol (185 mg, 5.0 eq), sodium iodide (197 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7en (DBU, 0.12 ml, 3.0 eq) were added. ). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2 x 2 ml), dimethylformamide: water 9: 1 (2x2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The hydroxyamide 2- (3-methoxy-benzenesulfanyl) decanecarboxylic acid resin obtained in step B (73 mg, 1.1 meq / r) was suspended in DCM (1.5 ml) and 70% tert-butyl hydroperoxide (0.49 ml) was added and benzenesulfonic acid (24 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The hydroxyamide 2- (3-methoxy-benzenesulfanyl) decanecarboxylic acid resin obtained in step B (73g, 1.1 meq / r) was suspended in DCM (1.5 ml) and mPCBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), c

149 dimethylformamide (2x2 ml), with methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: 2- (3-Methoxybenzenesulfanyl) decanecarboxylic acid hydroxyamide cleavage from the resin

The hydroxyamide 2- (3-methoxy-benzenesulfanyl) decanecarboxylic acid resin obtained in step B (73 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 89% @ 215 nm.

The hydroxamic acids of Examples 141-145 were synthesized using appropriate starting materials and the steps of Example 140 were followed.

Example 141

2- (3-Methoxy-benzenesulfinyl) decanecarboxylic acid hydroxyamide 96% @ 215 nm.

Example 142

2- (3-Methoxy-benzenesulfonyl) decanecarboxylic acid hydroxyamide 96% @ 215 nm.

Example 143

2- (4-Methanesulfanyl-benzenesulfanyl) decanecarboxylic acid hydroxyamide 85% @ 215 nm. LCMS (API electrospray) m / z 342 (M + H) ⁺ .

Example 144

2- (4-Methanesulfinyl-benzenesulfinyl) decanecarboxylic acid hydroxyamide 86% @ 215 nm. LCMS (API electrospray) m / z 374 (M + H) ⁴ .

Example 145

150

2- (4-Methanesulfonyl-benzenesulfonyl) decanecarboxylic acid hydroxyamide 92% @ 215 nm.

Example 146

3- Benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) propionamide

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

4- O-Methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene-resin ¹ (4.5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). S-2bromo was added. -3-Benzyloxy-propionic acid (4.2 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) The reaction mixture was shaken on an orbital shaker at room temperature 2-16 The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml), a resin sample was collected and subjected to the Kaiser test If the test showed the presence of an amine (the resin was colored blue) above eluvane was repeated, otherwise the resin was washed with DCM (3 x 20 mL), methanol (2 x 20 ml) and with DCM (2 x 20 mL). The resin was dried under vacuum at room temperature.

Step B: Substitution of the bromide with 4- (methylthio) thiophenol

The 2-bromo-hydroxylate resin obtained in step A (0.22 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 4- (methylthio) thiophenol (206 mg, 5.0 eq), sodium iodide (197 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7en (DBU, 0.12 ml, 3.0 eq) were added. .). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2 x 2 ml), dimethylformamide: water 9: 1 (2 x 2 ml), with dimethylformamide (2 ml). p

151 methanol (2 x 2 mL) and with DCM (2x2 mL). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 3-benzyloxy-1 N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) propionamide resin obtained in step B (73 mg, 1.1 meq / r) was suspended in DCM (1.5 ml) and 70% tert-added. butyl hydroperoxide (0.49 ml) and benzenesulfonic acid (24 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone 3-benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) propionamide resin obtained in step B (73 g, 1.1 meq / r) was suspended in DCM (1.5 ml). and mCBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of 3-benzyloxy-N-hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) -propionamide from the resin 3-benzyloxy-1 N -hydroxy-2- (4-methanesulfanyl-benzenesulfanyl) propionamide resin obtained in step B (73) mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 76% © 215nm. LCMS (API electrospray) m / z 350 (M + H) ⁺ .

152

The hydroxamic acids of Examples 147-151 were synthesized using the appropriate starting materials and the steps of Example 146 were followed.

Example 147

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

Example 148

3-benzyloxy-N-hydroxy-2- (4-methanesulfonyl-benzenesulfonyl) propionamide; 63% @ 215 nm. LCMS (API electrospray) m / z 414 • (M + H) ⁺ .

Example 149

3-benzyloxy-1 N-hydroxy-2- (2-chloro-benzylsulfanyl) propionamide; 90% @ 215 nm.

Example 150

3-benzyloxy-1,1-hydroxy-2- (2-chloro-benzylsulfinyl) propionamide; 70% @ 215 nm.

Example 151

3-benzyloxy-1 N-hydroxy-2- (2-chloro-benzylsulfonyl) propionamide; 72% @ 215 nm.

® Example 152

2- (2-bromo-benzenesulfanyl) -1'-1-hydroxy-3- (3H-imidazol-4-yl) propionamide

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

4- O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (4.5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). S-2bromo-3- (3H-imidazol-4-yl) -propionic acid (3.55 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) were added. The reaction mixture was shaken

153

orbital shaking machine at room temperature for 2 - 16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 2-bromothiophenol

The 2-bromo-hydroxylate resin obtained in step A (0.22 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 2-Bromothiophenol (249 mg, 5.0 eq), sodium iodide (197 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7en (DBU, 0.12 ml, 3.0 eq) were added. The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2 x 2 ml), dimethylformamide: water 9: 1 (2x2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) propionamide resin obtained in step B (73 mg, 1.1 meq / r), was suspended in DCM (1.5 ml) and 70% tert-butyl hydroperoxide (0.49 ml) and benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

154

2- (2-Bromo-benzenesulfanyl) -N-hydroxy-3- (3H-imidazol-4-yl) propionamide resin obtained in step B (73 g, 1.1 meq / r) was suspended in DCM (1.5 ml) and mCBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of 2- (2-bromo-benzenesulfanyl) -N-hydroxy-3 (3H-imidazol-4-yl) -propionamide from 2- (2-bromo-benzenesulfanyl) -1M-hydroxy-3- ( The 3H-imidazol-4-yl) propionamide resin obtained in step B (73 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 86% @ 215 nm.

The hydroxamic acids of Examples 153-154 were synthesized using the appropriate starting materials and the steps of Example 152 were followed.

Example 153

2- (4-bromo-benzenesulfinyl) -N-hydroxy-3- (3H-imidazol-4-yl) propionamide 69% @ 215 nm.

Example 154

2- (4-chloro-benzenesulfonyl) -N-hydroxy-3- (3H-imidazol-4-yl) propionamide

Example 155

2- (3-Fluorophenylsulfanyl) -5-guanidinopentanecarboxylic acid hydroxyamide

Step A: Coupling of 2-bromo-5-guanidino-pentanecarbonate

155 acid to hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (4.5 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (40 ml). S-2bromo-5-guanidino-pentanecarboxylic acid (3.85 g, 3.0 eq), HOBt (4.4 g, 6.0 eq) and DIC (3.4 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows the presence of an amine (the resin turns blue), the above coupling is repeated, otherwise the resin is washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 3-fluorothiophenol

The 2-bromo-hydroxylate resin obtained in step A (0.22 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 3-Fluorothiophenol (169 sodium iodide (197 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU, 0.12 ml, 3.0 eq) were added. The reaction mixture was shaken at room temperature 12-16 hours The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2x2 ml), dimethylformamide: water 9: 1 (2 x 2 ml), with dimethylformamide (2 ml), with methanol (2 x 2 ml) and DCM (2x2 ml) The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The hydroxyamide 2- (3-fluorophenylsulfanyl) -5-guanidinopentanecarboxylic acid resin obtained in step B (73 mg, 1.1 meq / r) was suspended in DCM (1.5 ml) and 70% tert-butyl hydroperoxide (0.49 ml) was added and benzenesulfonic acid (24 mg). The reaction mixture was shaken on an orbital shaker at

^. Lii «.- ig« * e <ia

Ml ¹⁵⁶ room temperature 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The hydroxyamide 2- (3-fluorophenylsulfanyl) -5-guanidinopentanecarboxylic acid resin obtained in step B (73 g, 1.1 meq / r) was suspended in DCM (1.5 ml) and mPCBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: 2- (3-Fluorophenylsulfanyl) -5-guanidino-pentanecarboxylic acid hydroxyamide cleavage from the resin

The hydroxyamide 2- (3-fluorophenylsulfanyl) -5-guanidinopentanecarboxylic acid resin obtained in step B (73 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 93% @ 215 nm.

The hydroxamic acids of Examples 156-159 were synthesized using the appropriate starting materials and the steps of Example 155 were followed.

Example 156

157

2- (3-Fluorophenylsulfinyl) -5-guanidinopentanecarboxylic acid hydroxyamide; 80% @ 220 nm. LCMS (API electrospray) m / z 317 (M + H) ⁺ .

Example 157

2- (2-Bromosulfanyl) -5-guanidinopentanecarboxylic acid hydroxyamide; 92% @ 220 nm. ¹ H NMR (DMSO-de): 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-guanidinopentanecarboxylic acid hydroxyamide; 79% @ 220 nm. LCMS (API electrospray) m / z 379 (M + H) ⁺ .

Example 159

2- (2-Bromosulfonyl) -5-guanidinopentanecarboxylic 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-Dichlorobenzenesulfanyl) octanecarboxylic acid hydroxyamide

Step A: Coupling of 2-bromo-octanecarboxylic acid to a hydroxylamine resin

4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% divinylbenzene) -mole ¹ (10.0 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in dimethylformamide (80 ml). 2 Bromo-octanecarboxylic acid (8.4 g, 3.0 eq), HOBt (8.8 g, 6.0 eq) and DIC (7.2 ml, 4.0 eq) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 2-16 hours. The reaction mixture was filtered and washed with dimethylformamide (3 x 20 ml). Separate the resin sample and pass the Kaiser test. If the test shows

158 the presence of an amine (the resin turns blue), the above coupling was repeated, otherwise the resin was washed with DCM (3 x 20 ml), methanol (2 x 20 ml) and DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step B: Substitution of bromide with 2,5-dichlorothiophenol

The 2-bromo-hydroxylate resin obtained in step A (0.22 g, 1.2 meq / r) was placed in a 20 ml scintillation vial and suspended in tetrahydrofuran (2 ml). 2,5-Dichlorothiophenol (483 mg, 5.0 eq), sodium iodide (404 mg, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7en (DBU, 0.24 ml, 3.0 eq) were added. ). The reaction mixture was shaken at room temperature for 12-16 hours. The reaction mixture was poured into a polypropylene syringe tank equipped with polypropylene frit, filtered and washed with dimethylforamide (2x2 ml), dimethylformamide: water 9: 1 (2 x 2 ml), dimethylformamide (2 ml), methanol (2 x 2 ml) and with DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The hydroxyamide 2- (2,5-dichlorobenzenesulfanyl) octanecarboxylic acid acid resin obtained in step B (150 mg, 1.1 meq / r) was suspended in DCM (3.0 ml) and 70% tert-butyl hydroperoxide (1.0 ml) was added and benzenesulfonic acid (50 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2x2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The hydroxyamide 2- (2,5-dichlorobenzenesulfanyl) octanecarboxylic acid resin obtained in step B (150 g,

1.1 meq / r), suspended in DCM (3.0 ml), and mCBA (180 mg) added.

159

The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step E: 2- (2,5-Dichlorobenzenesulfanyl) -octanecarboxylic acid hydroxyamide cleavage from the resin

The hydroxyamide 2- (2,5-dichlorobenzenesulfanyl) octanecarboxylic acid acid resin obtained in step B (73 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2x1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. 92% @ 215 nm. ¹ H NMR (DMSO-d ₆ ): δ 10.96 (brs, 1 Η), 9.26 (brs, 1 Η), 7.93 - 7.76 (m 3H), 4.07 (q, 1H), 2.04 - 1.85 (m, 1 Η ), 1.78 - 1.64 (m, 1Η), 1.78 - 1.64 (m, 1H), 1.32 - 1.09 (m, 8H), 0.81 (t, 3H).

The hydroxamic acids of Examples 161-167 were synthesized using the appropriate starting materials and the steps of Example 160 were followed.

Example 161

2- (2,5-Dichlorobenzenesulfonyl) octanecarboxylic acid hydroxyamide 96% @ 215 nm.

Example 162

2- (3-Methoxybenzenesulfanyl) -octanecarboxylic acid hydroxyamide 86% @ 220 nm. LCMS (API electrospray) m / z 298 + Η) ⁺ .

Example 163

2- (3-Methoxybenzenesulfonyl) -octanecarboxylic acid hydroxyamide 96% @ 220 nm.

Example 164

NMSH

160

2- (3-Methoxybenzenesulfoyl) -octanecarboxylic acid hydroxyamide 83% @ 220 nm.

Example 165

2- (3,4-Dimethoxybenzenesulfanyl) octanecarboxylic acid hydroxyamide 87% @ 215 nm. LCMS (API electrospray) m / z 328 (M + H +).

Example 166

2- (3,4-Dimethoxybenzenesulfinyl) oxanecarboxylic acid hydroxyamide 90% @ 215 nm.

Example 167

2- (3,4-Dimethoxybenzenesulfonyl) oxanecarboxylic acid hydroxyamide 87% @ 215 nm.

The hydroxamic acids of Examples 168-198 were synthesized using the appropriate starting materials and the steps of Example 160 were followed. The crude compounds were dissolved in DMSO: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described below. conditions.

Column: ODS-A, 20mm x 50mm, 5mm particle size (YMC,

Inc. Wilmington, North Carolina)

solvent gradient time water acetonitrile 0.0 95 5 25 min 5 95 flow rate: 15 ml / min

Example 168

2- (2-Benzoimidazol-2-ylsulfanyl) octanecarboxylic acid hydroxyamide 81%; @ 215 nm. LCMS (API electrospray) m / z 308 (M + H) ⁺ .

Example 169

2- (2-Benzooxazol-2-ylsulfanyl) octanecarboxylic acid hydroxyamide 72%; @ 215 nm. LCMS (API electrospray) m / z 309 (M + H) ⁺ .

Example 170

2- (2-Benzothiazol-2-ylsulfanyl) octanecarboxylic acid hydroxyamide 72%; @ 215 nm. LCMS (API electrospray) m / z 325 (M + H) ⁺ .

161

Example 171

2- (2-Pyridine-2-sulfanyl) -octanecarboxylic acid hydroxyamide 76%; @ 215 nm. LCMS (API electrospray) m / z 269 (M + H) ⁺ .

Example 172

2- (4-Phenyl-thiazole-2-sulfanyl) -octanecarboxylic acid hydroxamide 97%; @ 215 nm. LCMS (API electrospray) m / z 336 (M + H) ⁺ .

Example 173

2- (2-Pyridin-2-yl-ethylsulfanyl) octanecarboxylic acid hydroxyamide 84%; @ 215 nm. LCMS (API electrospray) m / z 297 (M + H) ⁺ .

Example 174

Octanecarboxylic acid hydroxyamide 67%; m / z 338 (M + H) ⁺ .

Example 175

Octanecarboxylic acid hydroxyamide 98%; m / z 298 (M + H) ⁺ .

Example 176

Octanecarboxylic acid hydroxyamide 66%; m / z 274 (M + H) ⁺ .

N - (2-phenyl-5H-tetrazol-5-ylsulfanyl) @ 215 nm. LCMS (API Spray)

2- (2-Pyrazin-2-yl-ethylsulfanyl) @ 215 nm. LCMS (API-electrospray) - (1-methyl-1H-tetrazol-5-ylsulfanyl) @ 215 nm. LCMS (API Spray)

Example 177

162

2- (2-Benzimidazol-2-ylsulfinyl) octanecarboxylic acid hydroxyamide 81%;

@ 215 nm.

Example 178

Acid hydroxyamide 76%; @ 215 nm.

2- (2-Pyridine-2-sulfinyl) -octanecarbonyl

Example 179

2- (4-Phenyl-thiazole-2-sulfinyl) -octanecarboxylic acid hydroxyamide 78%; @ 215 nm.

Example 180

2- (2-Pyrazin-2-yl-ethylsulfinyl) octanecarboxylic acid hydroxyamide 96%; @ 215 nm. LCMS (API electrospray) m / z 314 (M + H) ⁺ .

Example 181

2- (3-oxy-1H-benzimidazole-2-sulfonyl) octanecarboxylic acid hydroxyamide 63%; @ 215 nm. LCMS (API electrospray) m / z 356 (M + H) ⁺ .

Example 182

2- (4-Phenyl-thiazole-2-sulfonyl) -octanecarboxylic acid hydroxyamide 70%; @ 215 nm. LCMS (API electrospray) m / z 383 (M + H) ⁺ .

Example 183

2- [2- (1-oxy-pyridin-2-yl) -ethanesulfonyl] octanecarboxylic acid hydroxyamide 77%; @ 215 nm. LCMS (API electrospray) m / z 345 (M + H) ⁺

Example 184

3- (1-Hydroxycarbamoyl-heptylsulfanyl) benzoic acid hydroxyamide 100%; @ 220 nm. LCMS (API electrospray) m / z 312 (M + H) ⁺ .

Example 185

163

3- (4- (1-Hydroxycarbamoyl-heptylsulfanyl) phenyl] -propionic acid hydroxyamide 90%; @ 220 nm LCMS (API-electrospray) m / z 340 (M + H) ⁴ ·.

Example 186

2- (Thiazol-2-ylsulfanyl) -octanecarboxylic acid hydroxyamide 75%; @ 215 nm. LCMS (API electrospray) m / z 275 (M + H) ⁺

Example 187

2- (2,5-Dioxo-imidazolidin-4-ylmethylsulfanyl) -octanecarboxylic acid hydroxyamide 98%; @ 215 nm. LCMS (API electrospray) m / z 304 (M + H) ⁺ .

Example 188

3- (1-Hydroxycarbamoyl-heptylsulfinyl) benzoic acid hydroxyamide 84%; @ 220 nm. LCMS (API electrospray) m / z 328 (M + H) ⁺ .

Example 189

3- (4- (1-Hydroxycarbamoyl-heptylsulfinyl) phenyl] -propionic acid hydroxyamide 78%; @ 220 nm LCMS (API-electrospray) m / z 356 (M + H) ⁺ .

Example 190

2- (quinoline-8-sulfinyl) -octanecarboxylic acid hydroxyamide 87%; @ 220 nm. LCMS (API electrospray) m / z 335 (M + H) ⁴ .

Example 191

2- (Naphthalen-2-ylcarbamoylmethanesulfinyl) octanecarboxylic acid hydroxyamide 83%; @ 220 nm. LCMS (API electrospray) m / z 391 (M + H) ⁺ .

Example 192

3- (1-Hydroxycarbamoyl-heptylsulfonyl) benzoic acid hydroxyamide 72%; @ 215 nm.

Example 193

164

3- (4- (1-Hydroxycarbamoyl-heptylsulfonyl) phenyl] -propionic acid hydroxyamide 67%; @ 215 nm.

Example 194

2- (1H-Imidazole-2-sulfonyl) -octanecarboxylic acid hydroxyamide 95%; @ 215 nm. LCMS (API electrospray) m / z 290 (M + H) ⁺ .

Example 195

2- (Thiazol-2-ylsulfonyl) -octanecarboxylic acid hydroxyamide 91%; @ 215 nm. LCMS (API electrospray) m / z 307 (M + H) ⁺ .

Example 196

2- (quinoline-8-sulfonyl) -octanecarboxylic acid hydroxyamide 94%; @ 220 nm. LCMS (API electrospray) m / z 351 (M + H) ⁺ .

Example 197

2- (Naphthalen-2-ylcarbamoylmethanesulfonyl) octanecarboxylic acid hydroxyamide 79%; @ 220 nm. LCMS (API electrospray) m / z 407 (M + H) ⁺ .

Example 198

2- (2,5-Dioxo-imidazolidin-4-ylmethylsulfonyl) -octanecarboxylic acid hydroxyamide 97%; @ 215 nm.

Example 199

Step A: Replacement of the bromide with 4-fluorothiophenol

The 2-bromo-hydroxylate resin obtained in Example 160, step A (9.4 g, 1.2 meq / r) was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (50 ml). 4-Fluorothiophenol (6.6 g, 5.0 eq), sodium iodide (7.7 g, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU, 4.6 ml, 3.0 eq) were added. ). The reaction mixture was shaken at room temperature for 12-16 hours, filtered and washed with dimethylformamide (2 x 30 ml), dimethylformamide: water 9: 1 (2 x 30 ml), dimethylformamide (30 ml), methanol ( 2 x 50 ml) and with DCM (2 x 20 ml). The resin was dried in vacuo at room temperature.

Step B: Coupling of the hydroxyamide 2- (4165 fluorobenzenesulfanyl) -o-carboncarboxylic acid resin with benzyl alcohol

The hydroxyamide 2- (4-fluorobenzenesulfanyl) -octanecarboxylic acid resin obtained in step A (330 mg, 1.1 meq / r) was suspended in dimethylformamide (2.0 ml) and benzyl alcohol (731 mg, 15 eq) and sodium were added. hydride (237 mg, 15 eq). The reaction mixture was heated at 80 ° C for 15 hours and shaken on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with dimethylformamide (2x2 ml), dimethylformamide: water 9: 1 (2x3 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The hydroxyamide 2- (4-benzyloxy-phenylsulfanyl) octanecarboxylic acid resin obtained in step B (110 mg, 1.1 meq / r) was suspended in DCM (2.2 ml) and 70% tert-butyl hydroperoxide (0.73 ml) and benzenesulfonic acid were added. acid (36 mg). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The hydroxyamide 2- (4-benzyloxy-phenylsulfanyl) octanecarboxylic acid resin obtained in step B (110 g, 1.1 meq / r) was suspended in DCM (2.2 ml) and mPCBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x2 ml), dimethylformamide (2 x 2 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was then dried under vacuum at room temperature.

166

Step E: Cleavage of 2- (4-benzyloxyphenylsulfanyl) -octanecarboxylic acid hydroxamide from the resin Hydroxyamide 2- (4-benzyloxy-phenylsulfanyl) octanecarboxylic acid resin obtained in step B (110 mg, 1.2 meq / sec) in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in DMSO: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described above:

Column: ODS-A, 20 mm x 50 mm, 5 μm particle size (YMC, Inc. Wilmington, North Carolina)

solvent gradient time water acetonitrile 0.0 95 5 25 min 5 95 flow rate: 15 ml / min

2- (4-Benzyloxy-phenylsulfanyl) octanecarboxylic acid hydroxyamide 100% @ 215 nm. LCMS (API electrospray) m / z 374 (M + H) ⁺ .

The hydroxamic acids of Examples 200-220 were synthesized using the appropriate starting materials and following the steps of Example 199.

Example 200

2-4-Butoxy-benzenesulfanyl-octanecarboxylic acid hydroxyamide 100% @ 215 nm. LCMS (API electrospray) m / z 374 (M + H) ⁺ .

Example 201

167

2- [4- (2-Piperazin-1-yl-ethoxy) benzenesulfanyl] -octanecarboxylic acid hydroxyamide 98%; @ 215 nm. LCMS (API spray) m / z 340 (M + H) ⁺

Example 202

2- [4- (5-Hydroxy-pentyloxy) -phenylsulfanyl] octanecarboxylic acid hydroxyamide 65%; @ 215 nm. LCMS (API electrospray) m / z 370 (M + H) ⁺ .

Example 203

2- [4- (3-Pyridin-2-yl-propoxy) benzenesulfanyl] -octanecarboxylic acid hydroxyamide 95%; @ 215 nm. LCMS (API electrospray) m / z 403 (M + H) ⁺ .

Example 204

2- (4-Benzyloxy-phenylsulfinyl) octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 205

2- (4-Butoxy-phenylsulfinyl) -octanecarboxylic acid hydroxyamide 98%; @ 215 nm.

Example 206

2- [4- (2-Piperazin-1-yl-ethoxy) benzenesulfinyl] -octanecarboxylic acid hydroxyamide 98%; @ 215 nm.

Example 207

2- [4- (3-Pyridin-2-yl-propoxy) benzenesulfinyl] -octanecarboxylic acid hydroxyamide 99%; @ 215 nm.

Example 208

2- (4-Benzyloxy-phenylsulfonyl) octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 209

2- (4-Butoxy-phenylsulfonyl) -octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 210

168

2- (4- (2-Piperazin-1-yl-ethoxy) benzenesulfonyl] -octanecarboxylic acid hydroxyamide 97%; @ 215 nm.

Example 211

2- (4- (3-Pyridin-2-yl-propoxy) benzenesulfonyl] -octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 212

2- (4- (1-Methyl-pyrrolidin-3-yloxy) benzenesulfanyl] -octanecarboxylic acid hydroxyamide 91%; @ 215 nm LCMS (APIelectrospray) m / z 367 (M + H) ⁺ .

Example 213

2- (4- (1-Ethyl-propoxy) -benzenesulfanyl] octanecarboxylic acid hydroxyamide 100%; @ 215 nm LCMS (API-electrospray) m / z 354 (M + H) ⁺ .

Example 214

2- (4- (tetrahydro-pyran-4-yloxy) benzenesulfanyl] -octanecarboxylic acid hydroxyamide 97%; @ 215 nm LCMS (APIelectrospray) m / z 368 (M + H) ⁺

Example 215

2- (4- (1-Methyl-pyrrolidin-3-yloxy) benzenesulfinyl] -octanecarboxylic acid hydroxyamide 96%; @ 215 nm.

Example 216

2- (4- (1-Ethyl-propoxy) -benzenesulfinyl] octanecarboxylic acid hydroxyamide 97%; @ 215 nm.

Example 217

2- (4- (tetrahydro-pyran-4-yloxy) benzenesulfinyl] -octanecarboxylic acid hydroxyamide 97%; @ 215 nm.

Example 218

2- (4- (1-Methyl-pyrrolidin-3-yloxy) benzenesulfonyl] -octanecarboxylic acid hydroxyamide 96%; @ 215 nm.

Example 219

169

2- (4- (1-Ethyl-propoxy) -benzenesulfonyl] octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 220

2- [4- (Tetrahydro-pyran-4-yloxy) benzenesulfonyl] -ooganecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 218

2- (4- (1-Methyl-pyrrolidin-3-yloxy) benzenesulfonyl] -octanecarboxylic acid hydroxyamide 96%; @ 215 nm.

Example 221

Step A: Substitution of bromide with 4-bromothiophenol

The hydroxyamate 2-bromo-octanecarboxylic acid resin obtained in Example 160, Step A (5.0 g, 1.1 meq / r) was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (60 ml). 4-Bromothiophenol (5.2 g, 5.0 eq), sodium iodide (4.1 g, 5.0 eq) and 1,8 diazabicyclo [5.4.0] -undec-7-ene (DBU, 2.5 ml, 3.0 eq) were added. The reaction mixture was shaken at room temperature for 12-16 hours, filtered and washed with dimethylformamide (2 x 30 ml) with dimethylformamide; water 9: 1 (2 x 30 ml), with dimethylformamide (30 ml), methanol (2 x 30 ml) and DCM (2 x 30 ml). The resin was dried in vacuo at room temperature.

Step B: Oxidation of sulfide to sulfoxide

The hydroxyamide 2- (4-bromobenzenesulfanyl) -octanecarboxylic acid resin obtained in step A (4.4 g, 1.1 meq / r) was suspended in DCM (60 ml) and 70% tert-butyl hydroperoxide (30 ml) benzenesulfonic acid was added. (1.5 g). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 30 mL), dimethylformamide (2 x 30 mL), methanol (2 x 30 mL) and DCM (2 x 30 mL). The resin was then dried under vacuum at room temperature.

Step C: Oxidation of sulfide to sulfone

170

The hydroxyamide 2- (4-bromobenzenesulfanyl) -octanecarboxylic acid resin obtained in step A (4.4 g, 1.1 meq / r) was suspended in DCM (60 ml) and mPCBA (5.2 g) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 24 hours. The mixture was filtered and washed with DCM (2 x 30 ml), dimethylformamide (2 x 30 ml), methanol (2 x 30 ml) and DCM (2 x 30 ml). The resin was then dried under vacuum at room temperature.

Step D: Coupling of hydroxyamide 2- (4-bromobenzenesulfinyl) -o-carbonic acid resin with 4-chlorobenzenic acid

The hydroxyamide 2- (4-bromobenzenesulfinyl) -octanecarboxylic acid resin obtained in step B (150 mg, 1.1 meq / r) was suspended in DM E (2.0 ml) and nitrogen gas was bubbled through the suspension for 1-2 minutes. 4-Chlorobenzoic acid (51.6 mg, 2 eq), tetrakis (triphenylphosphine) palladium (O) (19.07 mg, 0.1 eq) and sodium carbonate (2 M solution, 825 ml, 10 eq) were added. The reaction mixture was heated at 80 ° C for 8 hours and shaken on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with DM E (2 x 2 ml), dimethylformamide: water 9: 1 (2x3 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step E: Separation of 2- (4'-chloro-biphenyl-4-sulfinyl) -o-carbonic acid hydroxyamide from the resin

The hydroxyamide 2- (4'-chloro-biphenyl-4-sulfinyl) octanecarboxylic acid resin obtained in step D (150 mg, 1.1 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. . The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2x1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was added

171 concentrates. The crude product was dissolved in OMvO: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described above:

Column: ODS-A, 20 mm x 50 mm, 5 μm particle size (YMC, Inc. Wilmington, North Carolina)

solvent gradient time water acetonitrile 0.0 95 5 25 min 5 95 flow rate: 15 ml / min

2- (4'-Chloro-biphenyl-4-sulfinyl) octanecarboxylic acid hydroxyamide 96% @ 215 nm. LCMS (API electrospray) m / z 394 (M + H) ⁺ .

The hydroxamic acids of Examples 222 - 224 were synthesized using appropriate starting materials and the steps of Example 221 were followed.

Example 222

2- [4- (5-Chloro-thiophen-2-yl) -benzenesulfinyl] octanecarboxylic acid hydroxyamide 100%; @ 215 nm.

Example 223

2- (4'-Chloro-biphenyl-4-sulfonyl) octanecarboxylic acid hydroxyamide 94%; @ 215 nm. LCMS (API electrospray) m / z 410 (M + H +).

Example 224

2- [4- (5-Chloro-thiophen-2-yl) -benzenesulfonyl] octanecarboxylic acid hydroxyamide 85%; @ 215 nm. LCMS (API electrospray) m / z 416 (M + H) ⁺ .

Example 225

Step A: Coupling of hydroxyamide 2- (4-bromobenzenesulfanyl) -octanecarboxylic acid resin with N (3-aminopropyl) -morpholine

172

The hydroxyamide 2- (4-bromobenzenesulfanyl) -octanecarboxylic acid resin obtained in Example 199, step A (100 mg, 1.1 meq / r) was suspended in dioxane (2.0 ml) and nitrogen gas was bubbled through the suspension for 1 - 2 minutes . 1M- (3-Aminopropyl) -morpholine (346 mg, 20 eq), tetrakis (tribenzylideneacetone) dipalladium (O) (22 mg, 0.2 eq), (S) (-) - 2,2'-bis are added. (diphenylphosphino) -1, 1'-binaphthyl ((S) -BINAP, 60 mg, 0.8 eq.) and sodium tert-butoxide (207 mg, 18 eq.). The reaction mixture was heated at 80 ° C for 8 hours and shaken on an orbital shaker. After cooling to room temperature, the mixture was filtered and washed with DM E (2 x 2 mL), dimethylformamide: water 9: 1 (2 x 3 mL), methanol (2 x 2 mL) and DCM (2x2 mL). ). The resin was dried in vacuo at room temperature.

Step B: Cleavage of 2- [4- (3-morpholin-4-ylpropylamino) -phenylsulfanyl] -octanecarboxylic acid hydroxyamide from the resin

The hydroxyamide 2- [4- (3-morpholin-4-yl-propylamino) phenylsulfanyl] -octanecarboxylic acid resin obtained in step A (100 mg, 1.1 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic was added acid (1.0 ml). The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in 0M5O: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described above:

Column: ODS-A, 20 mm x 50 mm, 5 μm particle size (YMC, Inc. Wilmington, North Carolina)

solvent gradient time water acetonitrile 0.0 95 5 25 min 5 95

173 flow rate: 15 ml / min

2- [4- (3-Morpholin-4-yl-propylamino) phenylsulfanyl] -octanecarboxylic acid hydroxyamide 88% @ 215 nm. LCMS (API electrospray) m / z 410 (M + H) ⁺ .

The hydroxamic acids of Examples 226 - 231 were synthesized using the appropriate starting materials and following the steps of this example.

Example 226

2- [4- (Biphenyl-4-ylamino) -phenylsulfanyl] octanecarboxylic acid hydroxyamide 95%; @ 215 nm. LCMS (API electrospray) m / z 435 (M + H) ⁺ .

Example 227

2- [4- (Pyridin-4-ylamino) -phenylsulfanyl] octanecarboxylic acid hydroxyamide 97%; @ 215 nm. LCMS (API electrospray) m / z 360 (M + H) ⁺ .

Example 228

2- (4-Cyclopentylamino-phenylsulfanyl] octanecarboxylic acid hydroxyamide 77%; @ 215 nm LCMS (API-electrospray) m / z 351 (M + H) ⁺ .

Example 229

2- (4-Methylamino-phenylsulfanyl) octanecarboxylic acid hydroxyamide; 99%; @ 215 nm. LCMS (API electrospray) m / z 297 (M + H) ⁺ .

Example 230

2- (4-Piperidin-1-yl-phenylsulfanyl) octanecarboxylic acid hydroxyamide; 72%; @ 215 nm. LCMS (API electrospray) m / z 351 (M + H) ⁺ .

Example 231

174

2- (4-Piperazin-1-yl-phenylsulfanyl) octanecarboxylic acid hydroxyamide; 74%; @ 215 nm. LCMS (API electrospray) m / z 352 (M + H) +.

Example 232

Step A: Replacement of the bromide with 4-hydroxythiophenol

The hydroxyamate 2-bromo-octanecarboxylic acid resin obtained in Example 160, step A (15.0 g, 1.1 meq / r) was placed in a peptide synthesis vessel and suspended in tetrahydrofuran (120 ml). 4-Hydroxythiophenol (11.3 g, 5.0 eq), sodium iodide (13.5 g, 5.0 eq) and 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU, 8.1 ml, 3.0 eq) were added. ). The reaction mixture was shaken at room temperature for 12-16 hours, filtered and washed with dimethylformamide (2 x 60 ml), dimethylformamide: water 9: 1 (2 x 30 ml), dimethylformamide (60 ml), methanol ( 2 x 60 ml) and with DCM (2 x 60 ml). The resin was dried in vacuo at room temperature.

Step B: Coupling of the hydroxyamide 2- (4-hydroxybenzenesulfanyl) -octanecarboxylic acid resin with benzene sulfonyl chloride

The hydroxyamide 2- (4-hydroxybenzenesulfanyl) octanecarboxylic acid resin obtained in step A (240 mg, 1.2 meq / r) was suspended in DCM (3.0 ml). Benzene sulfonyl chloride (225 mg, 5 eq) and triethylamine (0.06 mL, 2 eq) were added. The reaction mixture was shaken on an orbital shaker for 8 hours, filtered and washed with DME (2 x 2 ml), dimethylformamide: water 9: 1 (2 x 3 ml), methanol (2 x 2 ml) and DCM (2x2 ml). The resin was dried in vacuo at room temperature.

Step C: Oxidation of sulfide to sulfoxide

The 4- (1-hydroxycarbamoyl-heptylsulfanyl) -phenyl ester of benzenesulfonic acid obtained in step B (80 mg, 1.2 meq / r) was suspended in DCM (3 ml) and 70% tert-butyl hydroperoxide was added

175 (1 ml) benzenesulfonic acid (23 mg g). The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2x3 ml), dimethylformamide (2x3 ml), methanol (2 x 3 ml) and DCM (2 x 3 ml). The resin was then dried under vacuum at room temperature.

Step D: Oxidation of sulfide to sulfone

The 4- (1-hydroxycarbamoyl-heptylsulfanyl) -phenyl ester of the benzenesulfonic acid obtained in step B (80 mg, 1.2 meq / r) was suspended in DCM (3 ml) and mPCBA (84 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12-24 hours. The mixture was filtered and washed with DCM (2 x 3 mL), dimethylformamide (2 x 3 mL), methanol (2 x 30 mL) and DCM (2x3 mL). The resin was then dried under vacuum at room temperature.

Step E: Cleavage of benzenesulfonic acid 4- (1-hydroxycarbamoyl-heptarsulfanyl) -phenyl ester resin

The benzene sulfonic acid resin 4- (1-hydroxycarbamoyl-heptylsulfanyl) -phenyl ester obtained in step B (80 mg, 1.2 meq / r) was suspended in DCM (1.0 ml) and trifluoroacetic acid (1.0 ml) was added. The reaction mixture was shaken at room temperature for 1 hour. The mixture was then filtered and the resin was washed with DCM (2x1 ml). The filtrate and washes were combined and concentrated to dryness on Savant SpeedVac Plus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was dissolved in 0M8O: methanol (1: 1, 2 ml) and purified by reverse phase HPLC under the conditions described above:

Column: ODS-A, 20 mm x 50 mm, 5 μm particle size (YMC, Inc. Wilmington, North Carolina)

solvent gradient time water acetonitrile 0.0 95 5 25 min 5 95

176 flow rate: 15 ml / min

Benzenesulfonic acid 4- (1-hydroxycarbamoyl-heptirsulfanyl) -phenyl ester 91% @ 215 nm; LCMS (API electrospray) m / z 424 (M + H) ⁺ .

The hydroxamic acids of Examples 233 - 240 were synthesized using the appropriate starting materials and following the steps of Example 232.

Example 233

2,5-Dichloro-thiophene-3-sulfonic acid 4- (1-hydroxycarbamoyl-heptylsulfanyl) -hydroxyamide; 98% @ 215 nm; LCMS (API electrospray) m / z 498 (M + H) ⁺ .

Example 234

Ethanesulfonic acid 4- (1-hydroxycarbamoyl-heptylsulfanyl) -hydroxyamide; 72% @ 215 nm; LCMS (API electrospray) m / z 376 (M + H) ⁺ .

Example 235

5chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid 4- (1-hydroxycarbamoyl-heptylsulfinyl) -hydroxyamide; 99% @ 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% @ 215 nm; LCMS (APIelectrospray) m / z 514 (M + 1-1) +

Example 237

5-Pyridin-2-yl thiophene-2-sulfonic acid 4- (1-hydroxycarbamoyl-heptylsulfinyl) -hydroxyamide; 96% @ 215 nm; LCMS (API electrospray) m / z 523 (M + H) ⁺ .

Example 238

177

2- nitro-benzenesulfonic acid 4- (1-hydroxycarbamoyl-heptylsulfonyl) -hydroxyamide; 97% @ 215 nm; LCMS (API electrospray) m / z 501 (M + H) ⁺ .

Example 239

3bromo-2-chloro-thiophene-2-sulfonic acid 4- (1-hydroxycarbamoyl-heggylsulfonyl) -hydroxyamide; 97% @ 215 nm; LCMS (API electrospray) m / z 576 (M + H) ⁺

Example 240

4- (1-Hydroxycarbamoyl-heptylsulfonyl) -hydroxyamide of benzo [1,2,5] thiazole-4-sulfonic acid; 83% @ 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 solution of 4-methoxybenzenethiol (2.8 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in dry acetone (100 ml) in a round-bottom flask, and α-bromoethyl acetate (3.3 g, 20 mmol) was added with stirring. The reaction mixture was heated at reflux for 8 hours with good stirring. The mixture was then allowed to cool and the potassium salts filtered off and the mixture concentrated. The residue was extracted with chloroform and washed with water and a 0.5 N NaOH solution. The organic layer was extracted with chloroform and 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: 227 (M + H) ⁺ .

To a solution of 4- (methoxy-phenylsulfanyl) acetic acid ethyl ester (4.4 g, 20 mmol) and anhydrous potassium carbonate (10 g, excess) in dry acetone (100 ml) was added benzyl bromide (3.5 g, 20 mmol) with stirring. The mixture was filtered, concentrated and the residue was extracted with chloroform. Washed

178 well with water, dry and concentrate. The resulting crude product was converted to (4-benzyloxy-phenylsulfonyl) -acetic acid ethyl ester by oxidation with m-chloro perbenzoic acid as described in Example 83. Low-solids solid. Yield 6.6 g, 97%; MS: 335 (M + 1).

To a solution of bis- (2-chloro-ethyl) -benzyl amine hydrochloride (6.6 g, 24.7 mmol) 18-Crown-6 (500 mg) and anhydrous potassium carbonate (30 g, excess) in dry acetone (250 ml) in A round-bottom flask was added with stirring (4-benzyloxy-phenylsulfonyl) -acetic acid ethyl ester (8.01 g, 24 mmol) and stirred at reflux for 16 hours. The reaction mixture was then allowed to cool, the potassium salts filtered off and the mixture concentrated. The residue was extracted with chloroform and washed with water. The organic layer was washed thoroughly with water, dried over magnesium sulfate, filtered and concentrated. The dark brown residue was purified by column chromatography on silica gel eluting with 30% ethyl acetate: hexane. (4-Benzyloxy-benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid ethyl ester product was isolated as a brown oil. Yield: 6.5 g, 55%; MS: 494 (M + H) ⁺ .

(4-Benzyloxy-benzenesulfonyl) -1-benzylpiperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in methanol tetrahydrofuran (1: 1, 200 ml) and stirred at room temperature for 72 hours. The reaction mixture was then concentrated and the product was neutralized with conc. HCI when dissolved in water (200 ml). After neutralization, the reaction mixture was concentrated to dryness. Ice-cooled water (100 ml) was added to the residue and filtered. The product (4-benzyloxy-benzenesulfonyl) -1-benzylpiperidine-4-carboxylic acid was dried at 50 ° C and used in the next step without further purification. Colorless solid, mp 66-68 ° C; Yield 4.3 g, 91%; MS: 466 (M + H) ⁺ .

179

Starting from (4-benzyloxy-benzenesulfonyl) -1-benzylpiperidine-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure described in Example 83, 1.1 g of 1-benzyl-4- (4-benzyloxy) hydroxyamide was obtained. -benzenesulfonyl) -1-benzyl-piperidine-4-carboxylic acid as a colorless solid. Yield 21%, mp 89 ° C; MS: 481.1 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 2.27 (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-Bugoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide

Obtained from 2- (2-hydroxy-ethyl) - [4- (2-piperidin-1-ylethoxy) benzyl] -amine by the method of Example 83 starting from diethanolamine (15.0 g, 150) and 4- (2 -piperidin-1-yl-ethoxy) -benzyl chloride (5.9 g, 20 mmol). Yield 5.5 g, (85%); brown semi-solid; MS: 323 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - [4- (2-piperidin-1-yl-ethoxy) benzyl] -amine was prepared according to the method of Example 83 starting from 2- (2-hydroxy-ethyl) [4 - (2-piperidin-1-yl-ethoxy) benzyl] -amine (3.22 g, 10 mmol). Yield 4.0 g, (92%); brown semi-solid; MS: 361.1 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from ethyl ester of 4- 4- (Bugoxybenzenesulfonyl) -acetic acid (6.0 g, 20 mmol) and bis- (2-chloro-ethyl) [4- (2-piperidin-1-yl-ethoxy) benzyl] -amine (8.6 g, 20 mmol) . Yield 8.0 g (68%); brown oil; MS: 587.7 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid is prepared from 4- (4-butoxy-benzenesulfonyl) -1- [4- (2-Piperidin-1-yl-180 ethoxy) benzyl] piperidine-4-carboxylic acid (5.8 g, 10 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.3 g (86%). Porous brown solid mp 98 ° 0. MS: 559.6 (M + H) ⁺ .

Starting from 4- (4-butoxy-benzenesulfonyl) -1- (4- (2-piperidin-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid (5.5 g, 10 mmol) and follow the method of Example 83 yields 2.4 g of 4- (4-butoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-ylethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide as a pale yellow solid. 41% yield, m.p. 155 ° C (HCl); MS: 574 (M + H) ⁺ . * H NMR (300 MHz, DMSO-dg): δ 0.9 (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-Bugoxy-benzenesulfonyl) -1- (3- (2-morpholinyl-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide

Bis- (2-hydroxy-ethyl) - [3- (2-morpholin-1-yl-ethoxy) benzyl] -amine was prepared according to the method of Example 83 starting from diethanolamine (15.0 g, 150 mmol) and 3- (2-morpholin-1-yl-ethoxy) -benzyl chloride (5.9 g, 20 mmol). Yield 6.2 g, (95%); brown semi-solid; MS: 325 (M + H) ⁺ .

Bis- (2-chloro-ethyl) - [3- (2-morpholin-1-yl-ethoxy) benzyl] -amine was prepared according to the method of Example 83 starting from 2- (2-hydroxy-ethyl) [3 - (2-morpholin-1-yl-ethoxy) benzyl] -amine (3.24 g, 10 mmol). Yield 4.0 g, (92%); brown semi-solid; MS: 363.1 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- (3- (2-morpholinyl-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from ethyl ester

181 of 4- (butoxy-benzenesulfonyl) -acetic acid (6.0 g, 20 mmol) and bis (2-chloro-ethyl) - [3- (2-morpholin-1-yl-ethoxy) benzyl] -amine (8.6 g (20 mmol). Yield 8.5 g (72%); brown oil; MS: 589.7 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- [3- (2-morpholinyl-1-ylethoxy) benzyl] piperidine-4-carboxylic acid is obtained from 4- (4-butoxy-benzenesulfonyl) -1- (3- (2-morpholinyl-1-ylethoxy) benzyl] piperidine-4-carboxylic acid (5.8 g, 10 mmol) dissolved in tetrahydrofuran: methanol 3: 1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up. as described in Example 83. Yield 4.8 g (85%) Porous brown solid mp 98 ° C MS: 561.6 ♦ (M + H) ⁺ .

Starting from 4- (4-butoxy-benzenesulfonyl) -1- (3- (2-morpholinyl-1-yl-ethoxy) benzyl] -piperidine 4-carboxylic acid (5.6 g, 10 mmol) and follow the method of Example 83 4.02 g of 4- (4-butoxy-benzenesulfonyl) -1- [3- (2-morpholinyl-1-yl-ethoxy) benzyl] piperidine-4-carboxylic acid hydroxyamide was obtained as a pale yellow solid. Yield 62%; mp 123 ° C (HCl); MS: 574 (M + H) ⁺ . 1H NMR (300 MHz, DMSO-dg): δ 0.9 (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).

is Example 244

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

1-Methyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- ((butoxybenzenesulfonyl) -acetic acid ethyl ester (3.0 g, 10 mmol) and methyl-bis- (2-chloro-ethyl) -amine (2.2 g, 11.6 mmol). Yield 4.0 g (98%); brown low-fat substance; MS: 384 (M + H) ⁺

-methyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was obtained from 1-methyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (7.6 g, 20 mmol) ) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). 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) ⁺ .

Starting from 1-methyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid (4.0 g, 11.2 mmol) and following the method of Example 83, 3.9 g of hydroxyamide of 1-methyl-4- ( 4-Butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid as a yellow powder. Yield 85%; mp 118 ° C; MS: 371 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dg): δ 0.9 (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-boxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide

1-Ethyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (butoxy-benzenesulfonyl) -acetic acid ethyl ester (3.0 g, 10 mmol) and ethyl bis (2-chloro-ethyl) amine (2.2 g, 10.6 mmol). Yield 3.5 g (88%); brown low-fat substance; MS: 398 F ( ^{m + n} ) ⁺

1-Ethyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared from 1-ethyl-4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (7.94 g, 20 mmol) ) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). 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) ⁺ .

Starting from 1-ethyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid (3.7 g, 10 mmol) and following the procedure of Example 83, 3.2 g of hydroxyamide of 1-ethyl-4- ( 4-Butoxybenzenesulfonyl) -piperidine-4-carboxylic acid as a yellow powder.

Μ ··

183

Yield 76%; τ. τ. 98 ° C; MS: 385 (Μ + Η) ⁺ * Η NMR (300 MHz, DMSO-d6: δ 0.9 (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-Bugyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide

1-n-Butyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (butoxybenzenesulfonyl) -acetic acid ethyl ester (3.0 g , 10 mmol) and n-butyl-bis- (2-chloro-ethyl) -amine (2.0 g, 10.1 mmol). Yield 3.8 g (89%); brown low-fat substance; MS: 426 (M + H) ⁺ .

1-n-Butyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared from 1- {1- Butyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 mL) and 10 N NaOH (35 mL). 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) ⁺ .

Starting from 1-n-butyl-4- (4-butoxy-benzenesulfonyl) piperidine-4-carboxylic acid (3.9 g, 10 mmol) and following the procedure of Example 83, 1.8 g of 1- n-butyl hydroxyamide is obtained. -4- (4-Butoxybenzenesulfonyl) -piperidine-4-carboxylic acid as a yellow powder. Yield 40%; mp 121 ° C; MS: 413 (M + H) ^{+ 1} H NMR (300 MHz, DMSO-d ₆ ): δ 0.9 -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] -acetic acid ethyl ester

A mixture of 4-bromo-chlorobenzene (1.92 g, 10 mmol), (4-hydroxy-phenylsulfanyl) -acetic acid ethyl ester (2.12 g, 10 mmol),

184

sodium hydride (460 mg, 10 mmol) and copper (II) chloride (500 mg) were boiled in anhydrous pyridine (50 ml) for 12 hours. Ice-water was carefully added to the reaction mixture and acidified with concentrated HCl. The product was extracted with chloroform, washed well with water, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 30% ethyl acetate: hexane. Yield 2.5 g (77%); colorless low-solids; MS: 323 (M + H) ⁺ . Alternatively, the title compound may be prepared from 4- (4-chloro-phenoxy) -benzentiol and bromo-ethyl acetate as described in Example 83.

Example 248

[4- (4-Chloro-phenoxy) -benzenesulfonyl] -acetic acid ethyl ester

[4- (4-Chloro-phenoxy) -benzenesulfonyl] -acetic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (4-chloro-phenoxy) -phenylsulfanyl] -acetic acid ethyl ester (3.23 g, 10 mmol) and oxone (10 g). Yield 3.5 g, (99%); butter; MS: 356EI (M + H) ⁺

Example 249

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

4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -1-methylpiperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (4-chloro- phenoxy) benzenesulfonyl] -acetic acid (2.0 g, 5.6 mmol) and mechlorethamine hydrochloride (Aldrich) (1.9 g, 10 mmol). Yield 2 g (81%); brown oil; MS: 438 (M + H) ⁺ .

4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -1-methyl-piperidine-4-carboxylic acid is prepared from 4- [4- (4-chlorophenoxy) -benzenesulfonyl] -1-methyl-piperidine-ethyl ester. 4-carboxylic acid

185 (4.3 g, 10 mmol) dissolved in tetrahydrofuran methanol (3: 1 150 ml) and 10 N NaOH (100 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.5 g (86%). White solid mp 185 ° C. MS: 410 (M + H) ⁺ .

Starting from 4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -1methyl-piperidine-4-carboxylic acid (1.0 g, 2.4 mmol) and following the method of Example 83, 460 mg of hydroxyamide of 4- was obtained. [4- (4-Chlorophenoxy) -benzenesulfonyl] -1-methyl-piperidine-4-carboxylic acid as a white powder. Yield 41%; mp 52 ° C; MS: 426 (M + H) ⁺ 1 H NMR (300 MHz, DMSO-de): δ 1.3 (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] -1-ethyl-piperidine-4-carboxylic acid hydroxyamide

4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -1-ethylpiperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (4-chloro- phenoxy) benzenesulfonyl] -acetic acid (4.0 g, 11.3 mmol) and ethyl bis- (2-chloro-ethyl) -amine (2.32 g, 16.9 mmol). Yield 3.36 g (66%); brown oil; MS: 452.0 (M + H) ⁺ .

4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -1-ethyl-piperidine-4-carboxylic acid is prepared from 4- [4- (4-chlorophenoxy) -benzenesulfonyl] -1-ethyl-piperidine-ethyl ester. 4-carboxylic acid (3.02 g, 6.7 mmol) dissolved in tetrahydrofuran methanol (3: 1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.8 g (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 method of Example 83, 650 mg of hydroxyamide of 4- was obtained. [4- (4-Chloro-186 phenoxy) -benzenesulfonyl] -1-ethyl-piperidine-4-carboxylic acid, which is isolated as a white powder as HCl salt. Yield 33%; mp 158 ° C; MS: 438.9 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d ₆ ): δ 1.78 (t. J = 7.23 Hz, 3H), 2.23-2.27 (m, 2H), 2.51-2.73 (m 4H), 3.04 (m, 2H), 3.81 (d, J = 24 Hz, 2H), 7.16 - 7.27 (m, 4H), 7.50 - 7.57 (m, 2H), 7.76 (d, J = 7 Hz, 2H), 9.34 (s, 1H), 9.85 ( s, 1H).

Example 251

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

1-Butyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (4-chloro -phenoxy) benzenesulfonyl] -acetic acid (6.0 g, 18.3 mmol) and butyl-bis- (2-chloro-ethyl) -amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M + H) ⁺ .

-Butyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-4carboxylic acid is obtained from 1-butyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-4 ethyl ester -carboxylic acid (3.3 g, 6.9 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 2.08 g (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 following the method of Example 83, 630 mg of hydroxyamide of 1-butyl is obtained -4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid, which is isolated as an HCl salt as a white solid. Yield 31%; mp 212 ° C; MS: 466.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.87 (t. J = 7.3 Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, .2H), 2.50 ( ΠΊ, 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 = 9 Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).

Example 252

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

1-Benzyl-4- [4- (4-chloro-phenoxy) benzenesulfonyl] -piperidine-4-carboxylic acid ethyl ester was prepared by the general method of Example 83 starting from [4- (4-chloro-phenoxy) ethyl ester ) -benzenesulfonyl] -acetic acid (6 g, 16.9 mmol) and bis- (2-chloro-ethyl) -benzyl amine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow oil; MS: 513.9 (M + H) ⁺ .

1- Benzyl -4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid is prepared from 1-benzyl -4- (4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-ethyl ester- 4-carboxylic acid (2.11 g, 4.1 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (20 ml) 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) ⁺ .

Starting from 1-benzyl-4- [4- (4-chloro-phenoxy) benzenesulfonyl] -piperidine-4-carboxylic acid (1 g, 2.06 mmol) and following the method of Example 83, 430 mg of hydroxyamide of 1-benzyl is obtained. -4- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid, which is isolated as an HCl salt as an off-white solid. Yield 39%; mp 90.4 ° C; MS: 500.9 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-d6): 82.18-2.20 (m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, J = 4.5 Hz, 2H), 7.15 - 7.25 (m, 4H), 7.43 - 7.48 (m, 3H), 7.51 - 7.56 (m, 4H), 7.74 (d, J = 9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H) ).

Example 253

(4- (3-Methyl-boxy) -phenylsulfanyl] -acetic acid ethyl ester

188

Potassium carbonate (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) in boiling were added to a stirring solution of (4-hydroxy-phenylsulfanyl) acetic acid (2.12 g, 10 mmol). The reaction mixture was refluxed for 24 hours and cooled to room temperature, filtered and concentrated. The residue was extracted with chloroform, washed with water and concentrated. The crude product obtained was used in the next step without purification. (94%); MS: 283 (M + H) ⁺ .

Example 254

[4- (3-Methyl-boxy) -phenylsulfonyl] -acetic acid ethyl ester

[4- (3-Methyl-butoxy) -phenylsulfonyl] -acetic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (3-methyl-butoxy) -phenylsulfanyl] -acetic acid ethyl ester (2.8 g, 10 mmol) and oxone (10 g). Yield 3.0 g, (99%); butter; MS: 314EI (M + H) ⁺ .

Example 255

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

1-Benzyl-4- [4- (3-methyl-butoxy) benzenesulfonyl] -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4- (3methyl) ethyl ester -butoxy) -phenylsulfonyl] -acetic acid (6.2 g, 20 mmol) and bis- (2-chloro-ethyl) -benzyl amine (6.44 g, 24 mmol). Yield 8 g (84%); yellow oil; MS: 474 (M + H) ⁺

1-Benzyl-4- (4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid is prepared from 1-benzyl-4- (4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-ethyl ester). 4-carboxylic acid (4.7 g, 10 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (20 ml) The resulting reaction mixture was worked up as is

189 was described in Example 83. Yield 3 g (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 method of Example 83, 1.82 g of 1-benzyl hydroxyamide is obtained. -4- [4- (3-Methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid, which is isolated as an HCl salt as an off-white solid. Yield 73%; mp 106 ° C; MS: 498 (M + H) ⁺ . ^] H NMR (300 MHz, DMSO-d6): δ 0.8 (d, 6H), 1.5 (m, 1 Η), 1.6 - 2.0 (m, 6H), 2.73 - 2.81 (m, 4H), 3.5 (d, 2H), 4.28 (d, J = 4.5 Hz, 2H), 7.15 - 7.25 (m, 4H), 7.43 - 7.48 (m, 3H), 7.51 - 7.56 (m, 4H), 7.74 (d, J = 9 Hx , 2H), 9.53 (s, 1H), 10.47 (S, 1H).

Example 256

1-Bougyl-4- [4- (3-methyl-boxy) benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide

1-Butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- [4- (3 -methyl-butoxy) phenylsulfonyl] -acetic acid (6.2 g, 20 mmol) and butyl-bis- (2-chloroethyl) -amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M + H) ⁺ .

1-Butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid is prepared from 1-butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-ethyl ester. 4-carboxylic acid (4.4 g, 10 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 3.2 g (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

190 Following the method of Example 83, 1.6 g of hydroxyamide of 1-butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid is obtained, which is isolated as an HCl salt as an off-white solid . Yield 69%; mp 201 ° C; MS: 464 (M + H) ⁺ .

Example 257

[4- (2-Ethyl-boxy) -phenylsulfanyl] -acetic acid ethyl ester

To a solution of (4-hydroxy-phenylsulfanyl) acetic acid ethyl ester (2.12 g, 10 mmol) was added potassium carbonate (anhydrous, 10 g) under stirring and 1-bromo-3-ethyl butane (3 g, excess) in boiling water. acetone The reaction mixture is refluxed for 24 hours and cooled to room temperature The reaction mixture is filtered and concentrated The residue is extracted with chloroform, washed with water and concentrated The resulting crude product is used in the next step without purification Yield 2.8 g , (94%); MS: 297 (MH-H) ⁺ .

Example 258

[4- (2-Ethyl-boxy) -phenylsulfonyl] -acetic acid ethyl ester

[4- (2-Ethyl-butoxy) -phenylsulfonyl] -acetic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (2-ethyl-butoxy) -phenylsulfanyl] -acetic acid ethyl ester (2.96 g, 10 'mmol) and oxone (10 g). Yield 3.1 g, (99%); butter; MS: 329EI (M + H) ⁺ .

Example 259

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

1-Benzyl-4- [4- (2-ethyl-butoxy) -benzenesulfonyl] piperidine-4-carboxylic acid ethyl ester was prepared by the general 'method of Example 83 starting from 4- [4- ( 2-ethyl-butoxy) phenylsulfonyl] -acetic acid (6.4 g, 20 mmol) and bis- (2-chloro-ethyl) 191 benzyl amine (6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M + H) ⁺ .

-benzyl-4- [4- (2-ethyl-butxy) -benzenesulfonyl] '- piperidine-4carboxylic acid is obtained from 1-benzyl-4- [4- (2-ethyl-butoxy) -benzenesulfonyl] -piperidine- 4-carboxylic acid (4.8 g, 10 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4 g (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 method of Example 83, 1.02 g of 1-benzyl hydroxyamide is obtained. -4- [4- (2-Ethyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid, which is isolated as an HCl salt as an off-white solid. Yield 40%; mp 114 ° C; MS: 512 (M + H) ⁺ .

Example 260

4- (4-Butoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid hydroxyamide

4- [4-Butoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4-butoxybenzenesulfonyl) ethyl ester - acetic acid (20 g, 77.5 mmol) and bis- (2-chloroethyl) - (3-methoxy-benzyl) -amine (34 g, 116 mmol). Yield 9.53 g (25%); brown oil; MS: 490.2 (M + H) ⁺ .

4- [4-Butoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid is prepared from 4- [4-butoxybenzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-ethyl ester; 4-carboxylic acid (2.61 g, 5.34 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (15 ml). The reaction mixture obtained was

192 worked out as described in Example 83. Yield 1 g (41%). Brown solid mp 175 ° C. MS: 462.0 (M + H) ⁺ .

Starting from 4- [4-butoxy-benzenesulfonyl) -1- (3-methoxybenzyl) -piperidine-4-carboxylic acid (900 mg, 1.95 mmol) and following the procedure of Example 83, 200 mg of hydroxyamide of 4- [4butoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid, which is isolated as a HCl salt as a brown powder. Yield 20%; mp 137 ° C; MS: 477.0 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-dj): δ 0.96 (t, J = 7.11 Hz, 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 = 7.8 Hz, 1H), 7.64 (d, J = 9 Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).

Example 261

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

4- (4-Methoxy-benzenesulfonyl) -1- (4-thiophen-2-yl-benzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 1- (4-ethyl ester) -bromobenzyl) -4- (4-methoxy-benzenesulfonyl) -acetic acid (3 g, 6.05 mmol) and 2- (tributylstanyl) -thiophene (6.8 g, 18.14 mmol) in the presence of palladium tetrakis (0) in boiling toluene. Yield 1.58 g (52%); brown solid; MS: 500 (M + H) ⁺ .

4- (4-Methoxy-benzenesulfonyl) -1- (4-thiophen-2-yl-benzyl) piperidine-4-carboxylic acid is obtained from 4- (4-methoxy-benzenesulfonyl) -1- (4-thiophen- 2-yl-benzyl) -piperidine-4carboxylic acid (1.3 g, 2.61 mmol) dissolved in tetrahydrofuran: methanol (3: 1 150 ml) and 10 N NaOH (20 ml). 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) ⁺

193

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (4-thiophen-2-yl-benzyl) -piperidine-4-carboxylic acid (920 mg, 1.95 mmol) and following the method of Example 83, 510 mg was obtained 4- (4-Methoxy-benzenesulfonyl) -1- (4-thiophen-2-yl-benzyl) -piperidine-4-carboxylic acid hydroxyamide, which is isolated as a HCl salt as a brown solid. Yield 50%; mp 166 ° C; MS: 486.9 (M + H) ⁺ . NMR (300 MHz, DMSO-ββ): δ 2.12-2.21 (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

4- (4-Methoxy-benzenesulfonyl) -1- (4-pyridin-2-ylbenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 261 starting from 1- (4-ethyl ester) -bromobenzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid (4.65 g, 9.38 mmol) and 2- (tributylstanyl) -pyridine (12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M + H) ⁺

4- (4-Methoxy-benzenesulfonyl) -1- (4-pyridin-2-yl-benzyl) piperidine-4-carboxylic acid is prepared from 4- (4-methoxy-benzenesulfonyl) -1- (4-pyridine- ethyl) 2-yl-benzyl) -piperidine-4-carboxylic acid (1.83 g, 3.7 mmol) dissolved in THF methanol (3: 1 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.38 g (80%). Whitish solid, mp 217 ° C. MS: 466.9 (M + H) ⁺

Starting from 4- (4-methoxy-benzenesulfonyl) -1- (4-pyridin-2-yl-benzyl) -piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) and follow the procedure of Example 83 to give 480 mg of hydroxyamide 4- (4-methoxy-benzenesulfonyl) -1- (4-pyridin-2-yl-benzyl) -piperidine-4194 carboxylic acid, which was isolated as a white powder HCl salt. Yield 33%; mp 214 ° C; MS: 482.0 (M + H) ⁺ * H NMR (300 MHz, DMSO-d6): δ 2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, J = 12.5 Hz, 2H), 3.75 ( m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, J = 8.9 Hz, 2H), 7.59 - 7.74 (m, 4H), 7.84 - 7.95 (m, 3H), 8.55 (d, J = 8.1 Hz, 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-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4 ethyl ester -carboxylic acid was prepared by the general method of Example 83 starting from 4- (4-butoxy-benzenesulfonyl) -acetic acid ethyl ester (13.2 g, 44 mmol) and (3,4-dichloro-benzyl) -bis- (2-chloro -ethyl) -amine (14.3 g, mmol). Yield 14.1 g (60%); white solid; MS: 527.9 (M + H) ⁺ .

1- (3,4-Dichlorobenzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid is prepared from 1- (3,4-dichlorobenzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-ethyl ester. 4carboxylic acid (14.0 g, 26.5 mmol) dissolved in tetrahydrofuran: methanol (100: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 7.87 g (60%). Whitish solid, mp 239 ° C. MS: 501.9 (M + H) ⁺ .

Starting from 1- (3,4-dichlorobenzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid (7.7 g, 15.5 mmol) and following the procedure of Example 83, 4.05 g of hydroxyamide of 1 ( 3,4-Dichlorobenzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid, which is isolated as an HCl salt as a white solid. Yield 48%; mp 256.8 ° C; MS: 514.9 (M + H) ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.94 (t. 3H), 1.38 - 1.48 (q, 2H), 1.68 - 1.75 (q, 2H).

195

2.27 (m, 4H), 2.72 (m, 2H), 4.10 (t, 2H), 4.24 (s, 2H), 7.12 - 7.15 (d, J = 8.9 Hz, 2H), 7.51 - 7.53 (d, J = 8.1 Hz, 1H), 7.63 - 7.65 (d, J = 8.8 Hz, 2H), 7.72 - 7.75 (d, J = 9.9 Hz, 2H), 7.87 (s, 1H), 9.36 (S, 1H), 10.5 ( s, 1H), 11.2 (s, 1H).

Example 264 '

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

[4- (4-Chloro-benzyloxy) -benzenesulfonyl] -1methyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from [4- (4-chlorobenzyloxy) -benzenesulfonyl] - acetic acid (13.79 g, 37 mmol) and 4 (4-chloro-benzyloxy) -bis- (2-chloro-ethyl) -amine (8.7 g, 45 mmol). Yield 10.9 g (65%); brown oil; MS: 451.9 (M + H) ⁺ .

[4- (4-Chloro-benzyloxy) -benzenesulfonyl] -1-methylpiperidine-4carboxylic acid was obtained from [4- (4-chlorobenzyloxy) -benzenesulfonyl] -1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in tetrahydrofuran: methanol (75: 75 mL) and 10 N NaOH (20 mL). The resulting reaction mixture was worked up as described in Example 83. Yield 4.9 g (50%). Whitish solid. MS: 426.2 (M + H) ⁺ .

Starting from [4- (4-chloro-benzyloxy) -benzenesulfonyl] -1methylpiperidine-4-carboxylic acid (4.9 g, 12 mmol) and following the procedure of Example 83, 1.2 g of hydroxyamide of [4- (4- chlorobenzyloxy) -benzenesulfonyl] -1-methylpiperidine-4-carboxylic acid, which is isolated as an HCl salt as an off-white solid. Yield 24%; mp 117.8 ° C; MS: 438.9 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 2.2 (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) benzoyl-piperidine-4-carboxylic acid hydroxyamide

4- (4-Butoxy-benzenesulfonyl) -1- (3-phenoxybenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4-butoxybenzenesulfonyl) ethyl ester -acetic acid (10.1 g, 34 mmol) and 1- (3-phenoxybenzyl) -bis- (2-chloro-ethyl) -amine (18 g, 50 mmol). Yield 8.9 g (49%); brown oil; MS: 552.1 (M + H) ⁺

4- (4-Butoxy-benzenesulfonyl) -1- (3-phenoxy-benzyl) -piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (3-phenoxy-benzyl) -piperidine-ethyl ester. 4-carboxylic acid (10.7 g, 24 mmol) dissolved in tetrahydrofuran: methanol 75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 5.0 g (76%). Whitish solid. MS: 524.3 (M + H) ⁺ .

Starting from 4- (4-butoxy-benzenesulfonyl) -1- (3-phenoxybenzyl) -piperidine-4-carboxylic acid (5.9 g, 11 mmol) and following the method of Example 83, 0.39 g of hydroxyamide of 4- was obtained. (4-Butoxy-benzenesulfonyl) -1- (3-phenoxy-benzyl) -piperidine-4-carboxylic acid, which is isolated as an HCl salt as a light brown solid. Yield 11%; mp 92.5 ° C; MS: 539.1 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 0.93 - 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

[4- (4-Chloro-benzyloxy) -benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from [1- (4- chloro-97 benzyloxy) -benzenesulfonyl] -acetic acid (5.47 g, 15 mmol) and 1- (4-methyl-benzyl) -bis- (2-chloro-ethyl) -amine (5.23 g, 18 mmol). Yield 8.0 g (96%); brown oil; MS: 542.0 (M + H) ⁺ , [4- (4-chloro-benzyloxy) -benzenesulfonyl] -1- (4-methylbenzyl) piperidine-4-carboxylic acid is obtained from [4 (4-chloro- benzyloxy) -benzenesulfonyl] -1- (4-methylbenzyl) -piperidine-4carboxylic acid (7.9 g, 124 mmol) dissolved in tetrahydrofuran: methanol (50: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 4.6 g (61%). Whitish solid. Mp 204 ° C; MS: 514.2 (M + H) ⁺ .

Starting from [4- (4-chloro-benzyloxy) -benzenesulfonyl] -1- (4methylbenzyl) -piperidine-4-carboxylic acid (4.2 g, 8 mmol) and following the method of Example 83, 1.3 g of hydroxyamide was obtained. [4- (4chloro-benzyloxy) -benzenesulfonyl] -1- (4-methylbenzyl) -piperidine-4-carboxylic acid, which is isolated as the HCl salt as a yellow solid. Yield 29%; mp 172 ° C; MS: 528.9 (M + H) ⁺ .

Example 267

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

4- (4-Butoxy-benzenesulfonyl) -1- (4-methylbenzyl) piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4-butoxybenzenesulfonyl) -acetic ethyl ester acid (5.47 g, 15 mmol) and 1- (4methylbenzyl) -bis- (2-chloro-ethyl) -amine (15.3 g, 51 mmol). Yield 10.1 g (57%); white solid, mp 93 ° C; MS: 474.1 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid ethyl ester (10.0 g, 22 mmol) dissolved in tetrahydrofuran: methanol (50: 50 mL) and 10 N NaOH (20 mL). The resulting reaction mixture was worked out as is

198 was described in Example 83. Yield 7.2 g (72%). Whitish solid. 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 of Example 83, 2.06 g of 4- (4-butoxy hydroxyamide) is obtained -benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid, which is isolated as the HCl salt as a yellow solid. Yield 28%; mp 137 ° C; MS: 461.3 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-de): δ 0.91 - 0.964 (t, J = 7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, S, 3H), 2.52 (ΠΊ, 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-Bugoxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxyamide

4- (4-Butoxy-benzenesulfonyl) -1- (4-cyanobenzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4-butoxybenzenesulfonyl) ethyl ester - acetic acid (5.29 g, 17.6 mmol) and 1- (4-cyanobenzyl) -bis- (2-chloro-ethyl) -amine (6.19 g, 21 mmol). Yield 6.8 g (80%); light brown solid, mp 93 ° C; MS: 485.0 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-ethyl ester. 4-carboxylic acid (10.0 g, 124 mmol) dissolved in tetrahydrofuran: methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 0.7 g (11%). Belasnikavr solid. MS: 456.0 (M + H) ⁺ .

Starting from 4- (4-butoxy-benzenesulfonyl) -1- (4-cyanobenzyl) -piperidine-4-carboxylic acid (0.6 g, 1.2 mmol) and

199, following the method of Example 83, 0.21 g of 4- (4-butoxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxyamide is obtained, which is isolated as an HCl salt as an off-white solid. Yield 34%; mp 241.6 ° C; MS: 472.0 (M + H) ⁺ . 1 H NMR (300 MHz, DMSO-ds): δ 0.915 - 0.964 (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-Bugoxy-benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxyamide

4- (4-Butoxy-benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method of Example 83 starting from 4- (4-butoxybenzenesulfonyl) -acetic acid ethyl ester (6.0 g, 20.0 mmol) and pyridin-2ylmethyl-bis- (2-chloro-ethyl) -amine (4.89 g, 21 mmol). Yield 4.5 g (48%); brown oil; MS: 461.0 (M + H) ⁺ .

4- (4-Butoxy-benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid is prepared from 4- (4-butoxybenzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in tetrahydrofuran: methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 83. Yield 1.2 g (42%). Whitish solid. MS: 433.0 (M + H) ⁺ .

Starting from 4- (4-butoxy-benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid (0.864 mg, 2.0 mmol) and following the method of Example 83, 600 mg of 4- (4-butoxy hydroxyamide) is obtained. -benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4carboxylic acid, which is isolated as an HCl salt as an off-white solid. Yield 67%; mp 118 ° C; MS: 447.9

200 (M + H) ^{+ 1} H NMR (300 MHz, DMSO-de): δ 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 (ΠΊ, 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), 1.1.2 (br s, 1H), 11.4 (br s 1H).

Help:

¹ Rickter, LS; Desai, MC, Tetrahedron Letters, 1997, 38, 321 - 322.

The compounds of the invention are tested for biological activity according to the following procedures:

In vitro gelatinase assay

This assay is based on the cleavage of the thiopyptide substrate ((Ac-Pro-Leu-Gly- (2-MepKanTO-4-MeTnn-neHTaHonn) -Leu-Gly-OEt), Bachem Bioscience) by the gelatinase enzyme, releasing the substrate interacting product colorimetrically with DTNB ((5,5'-dithiobis (2-nitro-benzoic acid)). Enzyme activity was measured by the rate of increase in staining.

The thiopeptide substrate was made fresh as 20 mM stock 100% DMSO and DTNB was dissolved in 100% DMSO as 100 mM stock solution and stored in the dark at room temperature. Both substrate and DTNB were diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCIg) before use. Stock solution of human neutrophil gelatinase B was diluted with test buffer (50 mM HEPES pH 7.5, 5 mM CaCl ₂ , 0.02% Brij) to a final concentration of 0.15 nM.

Test buffer, enzyme, DTNB / substrate (500 µM final concentration) and vehicle or inhibitor were added to 96 well plates (total reaction volume of 200 µl) and the staining increase was detected by photrophotometry for 5 minutes at 405 nm on a reading apparatus. An increase of OD ₄₀₅ is plotted and the slope of the line is calculated, which is the response time.

201

The linearity of the reaction rate was confirmed (r ² > 0.85). The mean (x ± sem) value of control velocity was calculated and compared for statistical significance (p <-0.05) at drug velocities using Dunnett's multiple comparative test. The dose-response relationship can be obtained using multiple doses of drug and IC values of 95% CI are determined using linear regression (IPRED, NTV).

Reference: Weingarten, N. and Feder, J., Spectrophotometric assey for vertebrate collagenase, Anal. Biochem., 147, 437 - 440 (1985).

In vitro collagenase assay

The assay is based on cleavage of a peptide substrate (Dnp-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (NMa) -NH2) Peptide International, Inc.) by collagenase releasing the fluorescent NMa group, which quantitatively determines the fluorometer. Dnp Suppression There is fluorescence in the whole (unaffected) substrate. The assay was performed in a HCVB assay buffer (50 mM HEPES, pG 7.0p 5 mM Ca ⁺² , 0.02% Brij, 0.5% cysteine), with human recombinant fibroblast collagenase (truncated, MT = 18.818, WAR, Radnor). The substrate was stored frozen in buffer of 25 μM equal portions. For the assay, the substrate was dissolved in HCl buffer at a final concentration of 10 μM and collagenase to a final concentration of 5 nM. The compounds were dissolved in methanol, DMSO or HCBC to <1.0%. The compounds were added to a 96 well plate containing the enzyme, and the reaction was started by the addition of substrate.

The reaction was read (excitation 340 nm, emission 444 nm) for 10 min and the increase in fluorescence over time was plotted linearly. The slope of the line calculated m represents the reaction rate.

The linearity of the reaction rate was confirmed (r ² > 0.85). The average value (x ± sem) of the control speed is calculated

202 and compared for statistical significance (p <0.05) with drug-treated rats using Dunett's multiple comparative test. The dose-response relationship can be obtained using multiple drug doses, and IC ₅₀ values with 95% CI are determined using linear regression (IPRED, NTV).

Reference: Bickett, D. M. et al., A high throughput flourogenic substrate for intestinal collagenase (MMP-1) and gelatinase (MMP-9), Anal. Biochem., 212, 58 - 64 (1993).

Method for measuring TACE inhibition

Using 96 well microtiter plates, a solution of 10 μl TACE (Immunex, final concentration 1 μg / ml), 7 μl trisbuffer, pH 7.4, containing 10% glycerol (final concentration 1 μM, DMSO) was placed in each well. concentration (<1%) and incubated for 10 minutes at room temperature. The reaction was initiated by adding a fluorescent peptidyl substrate (final concentration 100 μM) to each well and then shaking on a shaking machine for 5 sec.

The reaction was read (excitation 340 nm, emission 420 nm) for 10 min and the increase in fluorescence over time was plotted linearly. The slope of the line is calculated and represents the reaction rate.

The linearity of the reaction rate was confirmed (r ² > 0.85). The mean value (x ± sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rats using Dunett's multiple comparative test. The dose-response relationship can be obtained using multiple doses of the drug and IC ₅₀ values with 95% CI are determined using linear regression.

The results obtained using these standard experimental tests are given in the following table.

203

Table

ΙΟδο (nM or% inhibition at 1 micromole or 10 micromole (*))

an example MMP 1 MMP 9 MM313 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% • 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 24.6 28.7 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

204

an example MMP 1 MMP 9 MM313 TACE 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% 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%

205

reamer MMP 1 MMP 9 MM313 TACE 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 1000 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 ϊ. 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

206

an example MMP 1 MMP 9 MM313 TACE 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 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 1014 44.2 4.1 50.2% 106 3788 5.1 0.9 631 107 629 29.8 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

207

an example MMP 1 MMP 9 MM313 TACE 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 a 269 2071 2.2 1.4 296

208

Table

Compounds, obtained by solid phase synthesis. Details for Examples 110 to 240 at- MMP 1 MMP 9 MMP 13% MMP 13% TACE% mayor inhibition inhibition inhibition No at 0.2 μM at 0.2 μM at 1mm (HTS) (manual) 110 75 17.6 111 10 40.4 • 112 50 33.7 113 0 13.1 114 0 0 115 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 φ 122 0 3.1 123 0 2.5 124 0 0 125 5 2.3 126 25 10.4 127 47 29.2 128 1.9 mm 213 nm 91 255 nm 19.31 129 9θ; 32.77 130 - 28 ^vols 27.9 131 71 20.73 132 71 20.76

209

at MMP 1 MMP 9 MMP 13% MMP 13% TACE% mayor inhibition inhibition inhibition No at 0.2 μM at 0.2 μM at 1mm (HTS) (manual) 133 53 22.04 134 25 -9.31 135 79 42.67 136 89 42.69 137 83 13.35 f 138 20 5.284 139 8 28.05 140 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 f 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 ^Vol -2.09 157 19 13.7 158 33 -7.48

210

at- MMP 1 MMP 9 MMP 13% MMP 13% TACE% mayor inhibition inhibition inhibition No at 0.2 μM at 0.2 μM at 1mm (HTS) (manual) 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 Table at- MMP 13% MMP 13% MMP 13 % TACE TACE% mayor inhibit- inhibition inhibition IC50nM inhibit- No not at 36 at 0.36 mm at 3.6 mm not at nm (HTS) (HTS) (HTS) 1mm 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 '38.5 178 -10 74 39 26 179 12 32 60 42.7

at- MMP 13% MMP 13% mayor inhibit- inhibition No not at 36 'nm (HTS) at 0.36 mm (HTS) 180 14 19 181 6 35 182 -9 -8 183 -6 12 184 16 24 • 185 9 0 186 -14 -4 187 -14 -12 188 -27 -24 189 -30 -18 190 -35 -28 191 -45 -3 192 -32 5 193 -32 15 194 -17 -8 ♦ 195 -9 -2 196 -18 1 197 -33 26 198 -39 -7 199 200 201 202 203 204 205 -10 -7

211

MMP 13% TACE TACE% inhibition IC50 nm inhibits at 3.6 mm not at (HTS) 1mm 45 34.4 62 15.7 7 28.6 70 34.6 44 24.8 23 7.21 35 19.5 20 85.5 4 16.2 -9 14 -13 38.3 22 2.9 61 33.2 56 14.9 5 5.4 10 27.0 11 35.7 -3 17.8 15 17.1 30 -1.0 37.9 50.9 10.6 32.8 7.75 84.0

212

at- MMP 13% MMP 13% MMP 13% TACE TACE% mayor inhibit- inhibition inhibition IC50 nm inhibit- No not at 36 4. at 0.36 mm at 3.6 mm not at nm (HTS). (HTS) (HTS) 1mm 206 89.8 207 -6.3 208 67.7 209 31.2 210 52.2 _f 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 • 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

213

at- MMP 13% MMP 13% MMP 13% TACE TACE% mayor inhibit- inhibition inhibition IC50 nm inhibit- No not at 36 at 0.36 mm at 3.6 mm not at nm (HTS) (HTS) (HTS) 1mm 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

Pharmaceutical composition

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

Applicable solid carriers may include one or more substances that may also act as flavoring agents, lubricants, solubilizers or suspending agents, fillers, sliding agents, compression-promoting agents, binders or dysfunctional agents or encapsulating material. In powders, the carrier is a finely divided solid which is mixed with the finely saturated active substance. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active substance. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium.

214 carboxime ethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of the invention may be dissolved or suspended in a pharmaceutically acceptable carrier such as water, an organic solvent or both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, sealants, colorants, viscosity regulators, stabilizers or regulators of osmosis. Suitable examples of liquid carriers for oral or parenteral administration include water (especially containing additives such as those mentioned above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monovalent alcohols and polyvalent alcohols, eg glycerols) and derivatives thereof oils (eg fractionated coconut oil and peanut butter). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used, for example, by intramuscular, peritoneal or subcutaneous injection. Sterile solutions can also be used intravenously. Orally administered can be liquid or solid forms.

The compounds of the invention may be administered rectally in the form of conventional suppositories. For administration intranasally or by intrabronchial inhalation or injection, the compounds of

215 the invention can be formulated in aqueous or partially aqueous solutions, which can then be used in the form of an aerosol.

The compounds of this invention can also be administered transdermally by using a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin and allows delivery of a systemic adsorption agent into the bloodstream through the skin. The carrier can take many different forms such as creams or ointments, gels and occlusive devices. Creams and ointments can be viscous, liquid or semi-liquid emulsions of the type oil-in-water or water-in-oil. Pastes include absorbent powders dispersed in oil or hydrophilic oil containing the active substance. Various occlusal devices can be used to release the active ingredient into the blood serum, such as a semipermeable membrane, which covers the reservoir containing the active substance with or without a carrier or matrix containing the active ingredient. Other occlusive devices are known in the literature.

The dose used in the treatment of a particular patient suffering from a disease or condition involving MMPs and TACE should be determined by the treating physician. Various dose determinants are the severity of the dysfunction, weight, age and response of the patient. Treatment is usually started at smaller doses below the optimum for the compound. The dose is then increased until the optimum condition is achieved. The exact dosages for oral, parenteral, nasal or intrabronchial administration will be determined by the physician on the basis of his or her experience with the individual patient and usual medical principles.

The pharmaceutical composition is preferably in separate dosage units, for example as tablets or capsules. In this form the composition

216 is subdivided into unit doses containing appropriate amounts of the active ingredient; the individual dosage unit may be packaged individually, for example packaged powders, ampoules, pre-filled syringes or fluid-containing cartridges. The hotel dosage form may be, for example, a capsule or tablet, or a suitable number of each of these forms may be contained in a single package.

Claims (42)

Claims A compound of formula I wherein: R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ; or heteroaryl ^ CH ^ o-e-heteroaryl wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and is optionally substituted with one or two groups selected independently from R ^5; A represents -S-, -SO- or SO ₂ -; 218 2 3 R and R taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; _C3 ^ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ^7, optionally substituted with one or two groups selected independently from R ^5; R ⁵ is H, C 1-6 aroyl, C 2-6 alkanoyl, C 1-6 alkyl, C 2- 12 alkenyl, C 1-2 alkynyl, F, Cl, Br, I, CN, CHO, C 1-4 alkoxy, aryloxy, heteroaryloxy, C 3-6 alkenyloxy, C3-6 alkynyloxy, C1-6 alkoxyaryl, alkoxyheteroaryl, C1-6alkylamino-C1-6alkoxy, C1-6 allylenedioxy, aryloxy-C1-6alkylamine, C142 perfluoroalkyl, C1-6-C4alkyl, S (O) naryl, where η means aryl 0, 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC, C 1-6 alkyl, COOaryl, CONR ⁶ R®, CONHOH, NR ⁶ R ⁶ , SO2NR ⁶ R®, NR ⁶ SO2apnn, -NR ⁶ CONR ⁶ R ⁶ , - NHSO2CF ₃ , SOjNHxeTepoapwn, SOgNHCOapnn,. COINbO2-C3-6 alkyl, CONHSC3-pnn, S0 ₂ NHCOapnn, COINvO-C2-alkyl, CONHSO ₂ apnn, NH ₂ , OH, aryl, heteroaryl, O ₃ cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or 219 bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein C 1-6 alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups selected from halogen, cyano, amino, nitro, C ^ alkyl, _C1 ^ alkoxy or hydroxy; R ⁶ represents H, C _1-8 alkyl optionally substituted with OH; C ₃ _b alkenyl, _C3 ^ alkynyl, C ^ perfluoroalkyl, B ^ p-C ^ alkyl, S (O) _n -aryl where η is 0, 1 or 2; or SOheteroaril wherein heteroaryl means 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups selected from halogen, cyano, , amino, nitro, C1-6 alkyl, C1-6 alkoxy or hydroxy; and R ⁷ represents C 1-6 aroyl, C 2-4 alkanoyl, C 1-6 perfluoroalkyl, C 1-6 -C 1-6 alkyl, B (O) n-aryl, where η is 0.1 or 2; COOC ^ alkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO2NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, CONHSO-C ^ alkyl, CONHSO ^ pnn, aryl or heteroaryl in which aryl means phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; and heteroaryl means a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from O, S or C 1 -C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from. R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; 220 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or R ^ N-C ^ alkoxyaryl-C ^ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ^ alkyl, or R ⁸ and R ⁹ together with mezhdinnopostaveniya nitrogen form a 5-7 membered saturated hetero cyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. A compound according to claim 1 wherein: R ¹ means alkyl of 1 to 18 _? carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; 221 alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ; or heteroaryl- (CH 2 - where the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; A represents -S-, -SO- or SO ₂ -; R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; . alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; 222 phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; _C3 _8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5; R ⁵ represents H, F, Cl, Br, I , CN, CHO, C7.t1 aroyl, C2 ^ alkanoyl, C ^ alkyl, S2.12alkenil, S2_12alkinil, SYbalkoksi, aryloxy, heteroaryloxy, C ^ alkenyloxy, C3-alkynyloxy, C1-6alkoxyaryl, C1-6alkoxyheteroaryl, C1-6alkylamino-C1-6alkoxy, C1-6alkylenedioxy, aryloxy-C1-6alkylamine, C1-6 perfluoroalkyl, C1-6C4alkyl, S (O) aryl, where η is 0, 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC ^ alkyl, COOaryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO2NR ^e R ⁶ , NR ^e SO2apnn, -NR ⁶ CONR ⁶ R ⁶ , NHSO2CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, CONHSO ^ C ^ anKnn, CONHSO ^ pnn, SO ₂ NHCOapnn, SOINvOg-C ^ alkyl, CONHSOgapnn, NH _2, OH, aryl, heteroaryl, C ₃ cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein the heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 to 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or hydroxy; R is H, _H8 alkyl optionally substituted by OH; C 3-6 alkenyl, C 1-6 alkynyl, C 1-6 fluoroalkyl, C 1 -C 4 alkyl or aryl, where η is 0, 1 or 2; or CO heteroaryl, where heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having _? 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups selected from halogen, cyano, amino, nitro, C 1-4 alkyl, C 1-6 alkoxy or hydroxy; 223 and R ⁷ denotes C 7-12 aroyl, C 2-4 alkanoyl, C 1-8 perfluoroalkyl, C 1-6 -C 1-4 alkyl, S (O) n-apnn, where η is 0, 1 or 2; COOalkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF _{3) C 2} MH Heteroaryl, SO ₂ NHCOapnn, COMH ₂ CO ₂ alkyl, CONHSO ₂ apnn, aryl or heteroaryl, where C 1-6 alkyl is with straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 or 2 groups independently selected from halogen, cyano, , amino, nitro, C 1-6 alkyl, alkoxy or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ; A saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or R 6 - C 1-6 alkoxyaryl-C 1-6 alkyl wherein R ⁸ and R ⁹ are independently selected from C 1-6 alkyl or R ⁸ and R ⁹ together with the intermediate nitrogen form a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, where the aryl group is phenyl or naphthyl; and pharmaceutically acceptable salts thereof. The compound of claim 2, wherein R ¹ means phenyl, naphthyl, alkyl having 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, C ₆ . ₁₀ aryloxy, heteroaryloxy, _C3 ^ alkenyloxy, C ^ alkynyloxy, halogen; or 8 (0) _n -C ^ alkyl alkoxyaryl or alkoxyheteroaryl _b6; A represents -S-, -SO- or -SO ₂ -; R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; 225 phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; _C3 ^ cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5; R ⁵ represents Η, Ο7.η aroyl, C 2-8 alkanoyl, C 12-12 KHn, C 2-12 alkenyl, C 2-12 alkynyl, F, Cl, Br, I, CN, CHO, C 1-4 alkoxy, aryloxy, heteroaryloxy, C 3-6 alkenyloxy, C3-6alkynyloxy, C1-6alkylamino-C1-6alkoxy, C1-6alkylenedioxy, aryloxy-C1-6alkylamine, C1-6 perfluoroalkyl, C 1 -C 4 alkyl, in (O) n-aryl, where η is 0.1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC ^ alkyl, COOaryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO2NR ⁶ R ⁶ , NR ⁶ SO2apnn, NR ⁶ CONR ⁶ R ⁶ , NHSO2CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, CONHSO ₂ C 1-6 alkyl, CONHSO ₂ apnn, SO ₂ NHCOapnn, COOHCO-C 1-6 alkyl, CONHSO ₂ apnn, NH ₂ , OH, aryl, heteroaryl, C 1-4 cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ where alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 to 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; R ⁶ represents H, C 1-6 alkyl optionally substituted with OH; _C3 ^ alkenyl, _C3 ^ alkynyl, C ^ perfluoroalkyl, c (O) _n alkyl or aryl where η is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having 1 _g to 3 heteroatoms selected independently from 0, S or NR ⁷ , and aryl being phenyl or naphthyl optionally substituted by 1 to 2 groups selected from halogen, cyano, amino, nitro, Cl ealkil, C _P6 alkoxy or hydroxy; 226 and R ⁷ are C 1-6 aroyl, C 2-6 alkanoyl, C 1-6 fluoroalkyl, in (O) n-alkyl, in (O) n-aryl, where η is 0, 1 or 2; COOalkyl, COOaryl, CONHR ^6, CONR ⁶ R ^6, CONHOH, SO2NR ⁶ R ^6, SO ₂ CF _3, VO ₂ MNheteroaril, SO ₂ NHCOapnn, CONHSO ₂ anKnn, CONHSO ₂ apnn, aryl or heteroaryl; wherein aryl means phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from O, S or C 1 -C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; A saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from 0, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or N ⁸ R ⁹ N-C 1-4 alkoxyaryl-C 1-4 alkyl wherein R ⁸ and R ⁹ are independently selected from C 1-6 alkyl or R ⁸ and R ⁹ together with the intermediate nitrogen form a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom where the aryl group is phenyl or naphthyl; and pharmaceutically acceptable salts thereof. The compound of claim 1, which is 1-benzyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 (4-methoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 1 (3,4-dichlorobenzyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 4 (4-methoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 4 (4-methoxy-benzenesulfonyl) -1-naphthalen-2-yl-methylpiperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1, which is hydroxyamide of 1biphenyl-4-ylmethyl-4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. 228 The compound of claim 1 which is 4 (4-methoxy-benzenesulfonyl) -1- (3-methyl-but-2-enyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 1 (4-bromo-benzyl) -4- (4-methoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 4 (4-methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof . A compound according to claim 1, which is 1-benzyl-4 ~ (4-benzyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 4 (4-butoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof . A compound according to claim 1 which is 4 (4-butoxy-benzenesulfonyl) -1- [3- (2-morpholinyl-1-yl-ethoxy) -benzyl] piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof . The compound of claim 1 which is 1-methyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 1-ethyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide, The compound of claim 1, which is 1H-butyl-4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. w 229 The compound of claim 1 which is 4 [4- (4-chloro-phenoxy) -benzenesulfonyl] -1-methyl-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 [4- (4-chloro-phenoxy) -benzenesulfonyl] -1-ethyl-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is hydroxyamide of 1-butyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is hydroxamide of 1-benzyl-4- [4- (4-chloro-phenoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 1-benzyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is 1- butyl-4- [4- (3-methyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1, which is hydroxamide of 1-benzyl-4- [4- (2-ethyl-butoxy) -benzenesulfonyl] -piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof. A compound according to claim 1 which is 4 (4-butoxy-benzenesulfonyl) -1- (3-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. A compound according to claim 1, which is 4 (4-methoxy-benzenesulfonyl) -1- (4-thiophen-2-yl-benzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 (4-methoxy-benzenesulfonyl) -1- (4-pyridin-2-yl-benzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. 230 The compound of claim 1, which is 1 (3,4-dichlorobenzyl) -4- (4-butoxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1 which is [4 (4-chloro-benzyloxy) -benzenesulfonyl] -1-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 (4-butoxy-benzenesulfonyl) -1- (3-phenoxy-benzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is [4 (4-chloro-benzyloxy) -benzenesulfonyl] -1- (4-methylbenzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 (4-butoxy-benzenesulfonyl) -1- (4-methylbenzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4 (4-butoxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is 4- (4-butoxy-benzenesulfonyl) -1-pyridin-4-ylmethyl-piperidine-4 carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. A compound according to 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- hydroxyamide 1-Butyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid carboxylic hydroxyamide acid, 231 hydroxyamide of 1-cyclooctyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic hydroxyamide piperidine-4-carboxylic hydroxyamide of acid, of 1-ethyl-4- (4-methoxy-benzenesulfonyl) acid, 1-Isopropyl-4- (4-methoxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxamide piperidine-4-carboxylic hydroxamide piperidine-4-carboxylic hydroxamide benzenesulfonyl) -piperidine-4-carboxylic 1-methyl-4- (4 -methoxy-benzenesulfonyl) acid, 1-benzyl-4- (4-butoxy-benzenesulfonyl) acid, 1- (4-fluoro-benzyl) -4- (4-methoxyacid, 1- (4-fluoro- benzyl) -4- (4-butoxybenzenesulfonyl) -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid hydroxamide, 4- ( 4-methoxy and-benzenesulfonyl) -1- (2- (4-methoxyphenyl) -ethyl] -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1- (2-phenyl-ethyl) piperidine-4-carboxylic acid acid, 4- (4-n-butoxy-benzenesulfonyl) -1- (4-methoxybenzyl) -piperidine-4-carboxylic acid hydroxamide, 4- (4-methoxy-benzenesulfonyl) -1- (3-phenoxypropyl) hydroxamide -piperidine-4-carboxylic acid, 4- (4-n-butoxy-benzenesulfonyl) -1- (3-phenoxypropyl) -piperidine-4-carboxylic acid, 4- (4-methoxy-benzenesulfonyl) -1 hydroxamide - (2-phenoxyethyl) -piperidine-4-carboxylic acid, idroksamid of 4- (4-n-butoxy-benzenesulfonyl) -1- (2-phenoxyethyl) -piperidine-4-carboxylic acid and 232 4- (4-Methoxy-benzenesulfonyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid hydroxamide. 37. A method for inhibiting pathological changes mediated by a matrix metalloproteinase in a mammal, comprising administering to the mammal in need thereof a curative effective amount of a matrix metalloproteinase inhibiting compound of the formula: wherein: R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups independently selected from R ⁵ ; aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ; or heteroaryl- (CH 2) _O- 6-wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms independently selected from 0, S 233 or N and may be optionally substituted by one or two groups selected independently from R ⁵ ; A represents -S-, -SO- or SO ₂ -; R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; C 3-8 cycloalkyl or bicycloalkyl optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono- or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , optionally substituted by one or two groups selected independently from R ⁵ ; R ⁵ denotes H, C 1-6 aroyl, C 2-4 alkanoyl, C 1-6 alkyl, C 2- 12 alkenyl, C 1-2 alkynyl, F, Cl, Br, I, CN, CHO, C 1-6 alkoxy, aryloxy, heteroaryloxy, C 2-4 alkenyloxy, C3-6 alkynyloxy, C1-6 alkoxyaryl, C1-6 alkoxyheteroaryl, C1-6 alkylamino-C1-6 alkoxy, C1-6 allylenedioxy, aryloxy-C1-6 alkylamine, CH2 perfluoroalkyl, C0-6-alkyl, S (O) aryl, S (O) aryl, denotes 0, 1 or 2; OCOO-C 1-6 alkyl, OCOOaryl, OCONR ⁶ , COOH, COOC ^ alkyl, COOaryl, CONR ⁶ R ^e , CONHOH, NR ⁶ R ⁶ , SO ² NR ⁶ R ⁶ , NR'SO 4 pnn, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NHxeTepoapnr, 234 SO ₂ NHCOapnn, CONHSO ₂ -C ₁ ^ anKnn, CONHSO ^ pnn, SO ₂ NHCOapnn, SOINBOg-C ^ alkyl, CONHSO ₂ apnn, NH _2, OH, aryl, heteroaryl, C ₃ cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein C 1-6 alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 up to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; R ⁶ denotes H, _H8 alkyl optionally substituted by OH; alkenyl, _C3 ^ alkynyl, C ^ perfluoroalkyl, in-p-C ^ alkyl, S (O) _n -apnn, where η is 0, 1 or 2; or SOheteroaril wherein heteroaryl means 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups selected from halogen, cyano, , amino, nitro, C1-6 alkyl, C1-6 alkoxy or hydroxy; and R ⁷ is C 1-6 aroyl, C 2-4 alkanoyl, C 1-8 perfluoroalkyl, C 1 -C 4 alkyl, in (O) n-aryl, where η is 0.1 or 2; COOC6alkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO2NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, CONHSO-C ^ alkyl, CONHSO ₂ apnn, aryl or heteroaryl in which aryl means phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; and heteroaryl means a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from O, S or N-C 1-6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; 235 alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ^s ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or R ⁸ R ⁹ N-C 1-6 alkoxy aryl-C 1-6 alkyl where R ⁸ and R ⁹ are independently selected from C 1-6 alkyl or R ⁸ and R ⁹ together with the intermediate nitrogen form a 5-7 membered saturated heterocyclic ring, optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. The method of claim 37, wherein the treatable condition is atherosclerosis, formation of atherosclerotic plaques, 236 reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP mediated osteopenia, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastases, tumor growth, osteoarthritis, osteoarthritis, osteoarthritis, osteoarthritis of wounds, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss due to traumatic damage to the joint, demyelinating diseases of the nervous system, qi liver rose, glomerular kidney disease, premature rupture of germ membranes, inflammatory bowel disease or periodontal disease. 39. The method of claim 37, wherein the treatment condition is age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, premature retinopathy, ocular inflammation, keratoconus, Sjogren's syndrome, ocular inflammation, ocular inflammation, ocular inflammation . 40. A method for inhibiting pathological alterations by a mammalian TNF-α converting enzyme (TACE) in a mammal, comprising administering to the mammal in need thereof a curative effective amount of a TACE inhibiting compound of the formula wherein R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; 237 alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ; or heteroaryl- (CH 2) 0-6-wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and may be optionally substituted by one or two groups selected independently from R ⁵ ; A represents -S-, -SO- or SO ₂ -; R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; MH 238 phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; C 3 -C 7 cycloalkyl or bicycloalkyl optionally substituted by one or two groups selected independently from R ⁵ ; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ^7, optionally substituted with one or two groups selected independently from R ^5; R ⁵ denotes H, C 1-6 aroyl, C 2-6 alkanoyl, C 2-8 alkyl, C 2-8 alkenyl, C 2- 12 alkynyl, F, Cl, Br, I, CN, CHO, C 1-4 alkoxy, aryloxy, heteroaryloxy, C 1-6 alkenyloxy, C 2-4 alkynyloxy, C1-6alkoxy aryl, alkoxyheteroaryl, C1-6alkylamino-C1-6alkoxy, C1-6alkylenedioxy, aryloxy-C1-6alkylamine, CM2 perfluoroalkyl, C1-6-C1-6alkyl, S (O) aryl, where η is 0, 1 or 2; OCOO-C 1-6 alkyl, OCOO aryl, OCONR ⁶ , COOH, COOC ^ alkyl, COOaryl, CONR ⁶ R ⁶ , CONHOH, NR ^e R ⁶ , SO ² NR ⁶ R ⁶ , NR 4 Ojapun, -NR ⁶ CONR ⁶ R ⁶ , NHSO 2 CF 3, SO2NHxeTepoapwn, SO2NHCOapnn, COINvO-C2-6alkyl, CONHSOgapnn, SO2NHCOapnn, COINvO-C3-6alkyl, CONHSO ^ pnn, NH2, OH, aryl, heteroaryl, C3-8 cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein C 1-6 alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 up to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or hydroxy; R ⁶ represents H, C 1-6 alkyl optionally substituted with OH; _C3 ^ alkenyl, C ^ alkynyl, C ₁ ^ perfluoroalkyl, in-p-C ^ alkyl, c (O) _n -aryl where η is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or 239 NR ⁷ and aryl is phenyl or naphthyl optionally substituted with 1 to 2 groups selected from halogen, cyano, amino, nitro, C ^ alkyl, _C1 ^ alkoxy or hydroxy; and R ⁷ is C 1-6 aroyl, C 2-4 alkanoyl, C 1-6 fluoroalkyl, C 1-4 -C 1-4 alkyl, in (O) n-aryl, where η is 0.1 or 2; COOC ^ alkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ⁶ , CONHOH, SO ₂ NR ⁶ R ⁶ , SO ₂ CF ₃ , C 0 H 3 heteroaryl, SO ₂ NHCOapnn, CONHSO-C 1-6 alkyl, CONHSO ₂ apnn, aryl or heteroaryl, in which aryl means phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; and heteroaryl means a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from 0, S or или-Ομθθπκππ; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; * 240 cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or R ⁸ R ⁹ N-C ₁ ^ alkoxyaryl-C ₁ ^ alkyl wherein R ⁸ and R ⁹ are independently selected from C ^ alkyl, or R ⁸ and R ⁹ together with mezhdinnopostaveniya nitrogen form a 5-7 membered saturated heterocyclic ring optionally containing an oxygen an atom where the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. The method of claim 40, wherein the treated condition is rheumatoid arthritis, implant rejection, cachexia, anorexia, inflammation, temperature, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory or intestinal inflammation. infection. 42. A pharmaceutical composition comprising a pharmaceutical carrier and a medicamentally effective amount of a matrix metalloproteinase or TACE inhibiting compound of formula I. wherein: R ¹ means alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; nm 241 alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; aryl of 6 to 10 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; cycloalkyl of 3 to 8 carbon atoms optionally substituted by one or two groups selected independently from R ⁵ ; a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ optionally substituted by one or two groups selected independently from R ⁵ ; or heteroaryl- (CH 2) _O- 6-wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from 0, S or N and may be optionally substituted by one or two groups selected independently from R ⁵ ; A represents -S-, -SO- or SO ₂ -; R ² and R ³ taken together with the carbon atom to which they are attached form a 5 to 7 membered heterocyclic ring containing 0, S or NR ⁷ , optionally having one or two double bonds; R ⁴ represents hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; d alkynyl 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; MMYJYSHShgtt - | «» and1Sh1 »n» tShS | J1IIMMMM 242 phenyl or naphthyl optionally substituted by one or two groups selected independently from R ⁵ ; _C3 -8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R ^5; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ^7, optionally substituted with one or two groups selected independently from R ^5; R ⁵ represents H, C 1-6 aroyl, C 2-6 alkanoyl, C 1-6 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, F, Cl, Br, I, CN, CHO, C 1-4 alkoxy, aryloxy, heteroaryloxy, C 3-6 alkenyloxy , C3-6 alkynyloxy, C1-6 alkoxyaryl, C1-6 alkoxyheteroaryl, C1-6 alkylamino-C1-6 alkoxy, C2- 2 allenedioxy, aryloxy-C1-6 alkylamine, CV12 perfluoroalkyl, C 1 -C 4 alkyl, S (O) aryl, where n is 0 , 1 or 2; COOO-C 1-6 alkyl, COOOaryl, OCONR ⁶ , COOH, COOC, C 1-6 alkyl, COOaryl, CONR ⁶ R ⁶ , CONHOH, NR ⁶ R ⁶ , SO2NR ⁶ R ⁶ , NR'SOaapwn, -NR ⁶ CONR ⁶ R ⁶ , NHSO ₂ CF ₃ , SO ₂ NHxeTepoapwi, SO ₂ NHCOapnn, COINbO-C 1 -C 6 alkyl, CONH 5 C 1-4 alkyl, SO ₂ NHCOapnn, CONHSO ^ C ^ anKnn, CONHSO ₂ apnn, NH ₂ , OH, aryl, heteroaryl, C ₃ cycloalkyl; or a saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR ⁷ , wherein C 1-6 alkyl is straight or branched, heteroaryl is a 5 to 10 membered mono or bicyclic heteroaryl group having 1 up to 3 heteroatoms selected independently from O, S or NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-4 alkoxy or hydroxy; R ⁶ represents H, C 1-6 alkyl optionally substituted with OH; _C3 ^ alkenyl, _C3 ^ alkynyl, C ^ perfluoroadkil, 3 (O) _n -C ^ alkyl, 3 (O) _n -aryl where η is 0, 1 or 2; or CO heteroaryl, wherein heteroaryl means a 5 to 10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or 243 NR ⁷ , and aryl is phenyl or naphthyl optionally substituted by 1 to 2 groups S. selected from halogen, cyano, amino, nitro, C1-6 alkyl, C1-6 alkoxy or hydroxy; and R ⁷ represents C 1-6 aroyl, C 2-4 alkanoyl, C 1-6 fluoroalkyl, S (O) C 1-6 alkyl, in (O) n-aryl, where η is 0.1 or 2; COOC ^ alkyl, COOaryl, CONHR ⁶ , CONR ⁶ R ^e , CONHOH, SO2NR ⁶ R ⁶ , SO ₂ CF ₃ , SO ₂ NHxeTepoapnn, SO ₂ NHCOapnn, CONHSO-C ^ alkyl, CONHSO ₂ apnn, aryl or heteroaryl, in which aryl means phenyl or naphthyl optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or hydroxy; and heteroaryl means a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from O, S or N-C 1-4 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted by one or two groups selected independently from R ⁵ ; alkenyl having 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted by one or two groups selected independently from R ⁵ ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted by one or two groups selected independently from R ⁵ ; arylalkyl having 7 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; heteroarylalkyl wherein alkyl has from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, S or N and optionally substituted by one or two groups selected independently from R ⁵ ; biphenylalkyl of 13 to 18 carbon atoms, wherein the biphenyl is optionally substituted by one or two groups selected independently from R ⁵ ; arylalkenyl having 8 to 16 carbon atoms, wherein aryl is optionally substituted by one or two groups selected independently from R ⁵ ; 244 cycloalkylalkyl or bicycloalkylalkyl having 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted by one or two groups selected independently from R ⁵ ; h a saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1-6 alkyl optionally substituted by one or two groups selected independently from R ⁵ ; or R ^ N-C ^ alkoxyaryl-C ^ alkyl, wherein R ⁸ and R ⁹ are independently selected from C ^ alkyl, or R ⁸ and R ⁹ together with mezhdinnopostaveniya nitrogen form a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl a group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.