AU9120198A

AU9120198A - N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

Info

Publication number: AU9120198A
Application number: AU91201/98A
Authority: AU
Inventors: Jannie Lea Baker; Jamie Marie Davis; George Theodore Grosu; Jeremy Ian Levin; Aranapakam Mudumbai Venkatesan
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1998-02-19
Filing date: 1998-08-26
Publication date: 1999-09-06
Anticipated expiration: 2018-08-26
Also published as: HRP20000543A2; IL137566A0; EA003283B1; NO20004093D0; WO1999042436A1; HUP0101837A2; EA200000849A1; GEP20022797B; JP2002503717A; KR20010041089A; NO20004093L; CN1291183A; EP1054858A1; NZ506184A; HUP0101837A3; ID25639A; TR200002423T2; AU757719B2; BG104782A; CN1213021C

Description

WO 99/42436 PCT/US98/17633 -1 N-HYDROXY-2-(ALKYL, ARYL, OR HETEROARYL SULFANYL, SULFINYL OR SULFONYL)-3-SUBSTITUTED ALKYL, ARYL OR HETEROARYLAMIDES AS MATRIX METALLOPROTEINASE INHIBITORS 5 BACKGROUND OF THE INVENTION Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement 10 membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to 15 tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor 20 growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age 25 related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and 30 M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287 1196. TNF-o converting enzyme (TACE) catalyzes the formation of TNF-a from 35 membrane bound TNF-a precursor protein. TNF-a is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestiveheart failure, inflammatory disease of the WO 99/42436 PCT/US98/17633 -2 central nervous system, inflammatory bowel disease, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti- TNF-a antibodies and transgenic animals has demonstrated that blocking the formation of TNF-a inhibits the progression of arthritis. This observation has recently 5 been extended to humans as well. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic and peptide-like compounds that one would expect to have 10 bioavailability and pharmacokinetic problems common to such compounds that would limit their clinical effectiveness. Low molecular weight, potent, long acting, orally bioavalable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states. 15 Recently, two references have appeared (U.S. 5,455,258 and European Patent Appl. 606,046) that disclose arylsulfonamido-substituted hydroxyamic acids. These documents cover compounds exemplified by CGS 27023A. These are the only non peptide matrix metalloproteinase inhibitors disclosed to date. MeO ,N S N CONHOH o/,so 20 CGS 27023A Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they 25 were tested for their fungicidal activity.

WO 99/42436 PCT/US98/17633 -3 Mannich Reaction R S ' CONHOH R/ RI (O)n (O)n HNO 1 11 N N Some sulfone carboxylic acids are disclosed in U.S. patent 4,933,367. Those compounds were shown to exhibit hypoglycemic activity. 5 SUMMARY OF THE INVENTION: The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-a converting enzyme 10 (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection. In accordance with this invention there is provided a group of compounds of general 15 formula I O R-,A OH I wherein:

R

1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups 20 selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; 25 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5

;

WO 99/42436 PCT/US98/17633 -4 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with 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 5 one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ; A is -S-, -SO- or SO 2 -;

R

2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 10 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds;

R

4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 15 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected 20 independently from R 5 ;

C

3 to C 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 O, S or NR 7 , optionally 25 substituted with one or two groups selected independently from R 5 ;

R

5 is H, C 7

-C

1 aroyl, C 2

-C

6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 12 alkenyl,

C

2

-C

12 alkynyl, F, Cl, Br, I, CN, CHO, C 1

-C

6 alkoxy, aryloxy, heteroaryloxy, C 3

-C

6 alkenyloxy, C 3

-C

6 alkynyloxy, C 1

-C

6 alkoxyaryl,

C

1

-C

6 alkoxyheteroaryl, C 1

-C

6 alkylamino-C 1

-C

6 alkoxy, C 1

-C

2 alkylene 30 dioxy, aryloxy-CI-C6 alkyl amine, Cl-C 12 perfluoro alkyl, S(O)n-Cl-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C 1

-C

6 alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1

-C

6 alkyl, COOaryl, CONR 6

R

6 , CONHOH, NR 6

R

6 ,

SO

2

NR

6

R

6 , NR 6 SO2aryl, -NR 6

CONR

6

R

6 , NHSO2CF 3

,

WO 99/42436 PCT/US98/17633 -5

SO

2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, CONHSO 2 aryl,

SO

2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or 5 NR 7 , wherein C 1

-C

6 alkyl is straight or branched, heteroaryl is a 5-10 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy; 10 R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n-C 1

-C

6 alkyl S(O)n aryl where n is 0, 1 or 2, or COheteroaryl, wherein heteroaryl is a 5-10 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 15 or 2 groups selected from halogen, cyano, amino, nitro, Cl-C 6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C 7

-C

11 aroyl, C 2

-C

6 alkanoyl, C 1

-C

1 2 perfluoro alkyl, S(O)n-C 1

-C

6 -alkyl, S(O)n-aryl where n is 0, 1 or 2; COO-C 1

-C

6 -alkyl, COOaryl, CONHR 6 ,

CONR

6

R

6 , CONHOH, SO 2

NR

6

R

6 , SO 2

CF

3 , SO2NHheteroaryl, 20 SO 2 NHCOaryl, CONHSO-C 1

-C

6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro,

C

1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms 25 selected independently from O, S or N-CI-C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; 30 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5

;

WO 99/42436 PCT/US98/17633 -6 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally 5 substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or 10 two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1

-C

6 alkyl, optionally substituted with one or two groups selected independently from R 5 ; or

R

8

R

9

N-C

1

-C

6 -alkoxyaryl-C 1

-C

6 -alkyl where R 8 and R 9 are independently 15 selected from C 1

-C

6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof. 20 A more preferred aspect of the present invention is the group of compounds of general formula (Ia): O R3 R .

N

' .R 4 R ,

R

1 A OH Ia 25 wherein:

R

1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; 30 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R 5

;

WO 99/42436 PCT/US98/17633 -7 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR 7 , optionally 5 substituted with one to 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 O, S, and N and may be optionally substituted with one or two groups selected independently from Rs; 10 A is -S-, -SO- or SO 2 -;

R

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

R

4 is hydrogen, 15 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally 20 substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;

C

3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; 25 R 5 is H, F, Cl, Br, I, CN, CHO, C 7 -CII aroyl, C 2

-C

6 alkanoyl, C 1 to C 12 alkyl,

C

2 to C 12 alkenyl, C 2

-C

12 alkynyl, C 1

-C

6 alkoxy, aryloxy, heteroaryloxy, C 3 C 6 alkenyloxy, C 3

-C

6 alkynyloxy, C 1

-C

6 alkoxyaryl, C 1

-C

6 alkoxyheteroaryl,

C

1

-C

6 -alkylamino-C 1

-C

6 alkoxy, C 1

-C

2 -alkylene dioxy, aryloxy-C 1

-C

6 alkyl amine, C 1

-C

12 perfluoro alkyl, S(O)n-C 1

-C

6 alkyl, S(O)n-aryl where n is 0, 1 30 or 2; OCOO-C 1

-C

6 alkyl, OCOOaryl, OCONR 6 , COOH, COO-C 1

-C

6 alkyl, COOaryl, CONR 6

R

6 , CONHOH, NR 6

R

6 , SO 2

NR

6

R

6 , NR 6

SO

2 aryl,

NR

6

CONR

6

R

6 , NHSO 2

CF

3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 C 1

-C

6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, WO 99/42436 PCT/US98/1 7633 -8 CONHSO2aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 ; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl 5 group having 1 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 independently from halogen, cyano, amino, nitro, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy;

R

6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 10 alkynyl, C, to C 6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1, or 2; or COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having lto 3 heteroatoms selected independently from O, S or

NR

7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 15 groups selected from halogen, cyano, amino, nitro, C 1

-C

6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C 7

-C

1 l aroyl, C 2

-C

6 alkanoyl, C 1

-C

12 perfluoro alkyl, S(O)n-alkyl, S(O)n aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6

R

6 , CONHOH, SO 2

NR

6

R

6

,SO

2

CF

3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, 20 CONHSO 2 alkyl, CONHSO 2 aryl, aryl, heteroaryl; wherein C 1

-C

6 alkyl, 25 C 1

-C

6 alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from Rs; 30 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from Rs; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5

;

WO 99/42436 PCT/US98/17633 -9 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally 5 substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected 10 independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 ;

R

8

R

9

N-C

1

-C

6 -alkoxyaryl-C1-C 6 -alkyl where R 8 and R 9 are independently 15 selected from C 1

-C

6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof. 20 The most preferred group of compounds are those of the following formula (Ib): 0 o R 4 ,T .

N .R R-A OH Ib in which 25 RI is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C 1

-C

6 alkyl, C 1

-C

6 alkoxy, C 6 -Clo aryloxy, heteroaryloxy, C 3

-C

6 alkenyloxy, C 3

-C

6 alkynyloxy, halogen; or S(0)n -- C 1

-C

6 alkyl C!-C 6 alkoxyaryl or CI-C 6 alkoxyheteroaryl; A is -S-, -SO- or -SO 2 -; 30 R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; WO 99/42436 PCT/US98/17633 -10

R

4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally 5 substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from Rs; phenyl or naphthyl optionally substituted with one or two groups selected independently from Rs; 10 C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;

R

5 is H, C 7 -Cll aroyl, C 2

-C

6 alkanoyl, CI to Cl 2 alkyl, C 2 to Cl 2 alkenyl, C 2

-C

12 alkynyl, F, Cl, Br, I, CN, CHO, C 1

-C

6 alkoxy, aryloxy, heteroaryloxy, C 3

-C

6 alkenyloxy, C 3

-C

6 alkynyloxy, C 1

-C

6 alkylamino-C-C 6 alkoxy, C 1

-C

2 15 alkylene dioxy, aryloxy-Cj-C 6 alkyl amine, C 1

-C

12 perfluoro alkyl, S(O)n-C 1 C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C 1

-C

6 alkyl, OCOOaryl,

OCONR

6 , COOH, COO C 1

-C

6 alkyl, COOaryl, CONR 6

R

6 , CONHOH,

NR

6

R

6 , SO 2

NR

6

R

6 , NR 6

SO

2 aryl, -NR 6

CONR

6

R

6 , NHSO 2

CF

3 ,

SO

2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, CONHSO 2 aryl, 20 SO 2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or

NR

7 , wherein C 1

-C

6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected 25 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

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy;

R

6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1 or 2; or 30 COheteroaryl; wherein heteroaryl is a 5-10 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 WO 99/42436 PCT/US98/17633 -11 or 2 groups selected from halogen, cyano, amino, nitro, C 1

-C

6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C 7

-C

11 aroyl, C 2

-C

6 alkanoyl, C 1

-C

R

6 , 5 CONHOH, SO 2

NR

6

R

6

,SO

2

CF

3 , SO 2 NHheteroaryl, SO2NHCOaryl,

CONHSO

2 alkyl, CONHSO 2 aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen,cyano, amino, nitro, C 1

-C

6 alkyl, CI-C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl 10 group having 1 to 3 heteroatoms selected independently from O, S or N

CI-C

6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally 15 substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 20 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 25 arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom 30 selected from O, S or NR-Cl-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 ;

R

8

R

9

N-C

1

-C

6 -alkoxyaryl-C 1

-C

6 -alkyl where R 8 and R 9 are independently selected from C 1

-C

6 alkyl or R 8 and R 9 together with the interposed nitrogen WO 99/42436 PCT/US98/17633 -12 forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; and the pharmaceutically acceptable salts thereof. 5 The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are: 1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 10 1-(3,4-dichlorobenzyl) -4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide, 4-(4-methoxy-benzenesulfonyl)- 1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide, 4-(4-methoxy-benzene-sulfonyl)- 1 -napthalene-2-yl-methylpiperidine-4-carboxylic acid 15 hydroxamide, 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide, 4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide, 20 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid 25 hydroxyamide, 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 30 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid 35 hydroxyamide, 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, WO 99/42436 PCT/US98/17633 - 13 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide, 5 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid 10 hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 15 4-(4-n-butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxyamide, 1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid 20 hydroxyamide, 4-(4-Butoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxyamide, 4-(4-Butoxy-benzenesulfonyl)- 1-[3-(2-morpholinyl- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxyamide, 25 1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-methyl-piperidine-4-carboxylic acid hydroxyamide, 30 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-ethyl-piperidine-4-carboxylic acid hydroxyamide, 1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid 35 hydroxyamide, 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, WO 99/42436 PCT/US98/17633 - 14 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 5 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-Methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid 10 hydroxyamide, 1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide, 15 4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide, [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl)-piperidine-4 carboxylic acid hydroxamide, 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4- carboxylic acid 20 hydroxamide, 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide, and 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxamide, and pharmaceutical salts thereof. 25 It is understood that the definition of the compounds of formulas I, Ia and Ib, when R 1 , R 2 , R 3 and R 4 contains asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which posses the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which 30 possesses the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. Where not stated otherwise, the term "alkyl" refers to a straight or branched C 1 -- C 6 alkyl group and aryl is phenyl or naphthyl. The pharmaceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, 35 malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.

WO 99/42436 PCT/US98/17633 - 15 The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of compound of this 5 invention and a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients. In order to obtain consistency of administration, it is preferred that a 10 composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules, and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg per kg. Such composition may be administered from 1 to 6 times a day, more usually 15 from 1 to 4 times a day. The compositions of the invention may be formulated with conventional excipients, such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner. Also according to the present invention, there are provided processes for 20 producing the compounds of the present invention. PROCESS OF THE INVENTION. The compounds of the present invention may be prepared according to one of 25 the general processes out lined below. The appropriately substituted mercaptan derivative was alkylated using either substituted (Scheme I) or unsubstituted ( Scheme 2) ct-bromo acetic acid ester derivative in refluxing acetone using K 2

CO

3 as base. The sulphide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH 2 C12 or by using Oxone in 30 methanol/ water. The sulfone obtained from the above mentioned process can be either further alkylated using variety of alkyl halides to obtain the disubstituted derivative or it can be hydrolyzed using NaOH/ MeOH at room temp. However instead of using the ethyl ester, if the tertiary butyl ester is present, the hydrolysis can be carried out with

TFA/CH

2 C1 2 at room temperature. Subsiquently, the carboxylic acid obtained was 35 converted to the hydroxamic acid derivative by reaction with oxalyl chloride/ DMX (catalytic) and hydroxyl amine/ triethyl amine.

WO 99/42436 PCT/US98/17633 -16 SCHEME 1 SYNTHESIS:

R

2 a R

R

1 -SH + R OEt a R 00 b R R 3

R

2 cR 2 Et OI OO O t

O

/

O

/

\ 0 d

SR

3

R

2

R

3

R

2 RI S O H R' S .NHOH O~OHO 0 O 0 0 0 0 0 0 a. K 2 CO3/ Acetone/ Reflux; b. m-Chloroperbenzoic acid; c. K2CO 3 / 18-Crown-6/ R 3 Br/Acetone/ Reflux/ d. NaOH/ MeOH/ THF/ RT e. (COC1) 2

/CH

2 CI2/Et 3

NINH

2 OH'HC1.

WO 99/42436 PCT/US98/17633 - 17 SCHEME 2 SYNTHESIS: a R'-SH + Br OEt R SOEt 0 b

R

2 R OEt c R1 OEt 0~SY 00 0 0O~ d

R

3

R

2 e, f R 3

R

2 RI S OEt R SNHO H a. K 2 COz/ Acetone/ Reflux; b. m-Chloroperbenzoic acid; c. K 2 CO3/ 18-Crown-6/ R 2 Br/Acetone/ Reflux/ d. R 3 Br/ 10 N NaOH/ BzN(Et)3/ CH 2

CI

2 / RT e. NaOH/ MeOH/ THF/ RT f. (COC1) 2

/CH

2 CI2/Et 3

N/NH

2 OH.HC1. As outlined in Scheme 3, the sulfide derivative can be further alkylated using 5 lithium bis(trimethyl silyl)amide in THF at 0 C. The alkylated or mono substituted compound was hydrolyzed and converted to the hydroxamic acid derivative. The sulfinyl derivatives were prepared by oxidizing the sulfide hydroxamic acid derivatives with H 2 0 2 in MeOH solution.

WO 99/42436 PCT/US98/17633 -18 SCHEME - 3 SYNTHESIS: 2

R

1 -SH + OEt a R R2 B OS OEt 0 0 b C R 3

R

2 R 3S OH R SOEt O0 d e

R

3

R

2

R

3

R

2 S NHOH R S NHOH O 0 0 a. K 2 COz/ Acetone/ Reflux; b. R 3 Br/I HMDS/ THF; c. NaOH/ MeOH/ THF/ RT d. (COCI) 2

/CH

2

CI

2 /Et 3

NINH

2 OH.HC1. e. MeOH/ H 2 0 2 1 RT The corresponding 1-substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamides were prepared starting from diethanolamine and 5 appropriately substituted alkyl or aryl halides (Scheme 4). The N-substituted diethanol amine derivatives were converted to the dichloro compounds using thionyl chloride. The corresponding dichlorides were reacted with substituted sulfonyl acetic acid ethyl ester derivatives in the presence of K 2

CO

3 /18-Crown-6 in boiling acetone. 1 substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl esters 10 thus obtained were converted to the hydroxy amide as outlined in Scheme 4.

WO 99/42436 PCT/US98/1 7633 -19 Alternatively these classes of compounds and other hetrocycles can be prepared as indicated in Scheme 5 and 6. SCHEME 4 R IN H R R I I N a N b Nc EtOOC R I-ffIEtOOCS HO OH HO OH Cl Cl 0 d a. K 2 CO31/RBr/ Acetone/ Reflux b. SOCl 2 / CH 2

C

2 R R c. R ISO 2

CH

2 COOEt /

K

2 C O 3/ N N 18-Crown-6/ Acetone/ Reflux d. NaOH/ THF/ MeOH/ RT HOHNOC HOOC , R e. (COC1) 2 / NH 2 OH. HCI/ Et 3 N HOHNOC 5 SCHEME 5 0,o COOH P HOHN . S R a HOO SR1 b HC" S'R e b e R R R N R NRR N-R COOH HOOC SR HOOC SR 1 HOHNOC Y = N orCH a. RBr/ RISH/ CHC1 3 / Reflux; b. Oxone/ MeOH; e. (COC1) 2

/NH

2 OH. HCI/Et 3 N SCHEME 6 S0 2

R

1 S0 2

R

1 b S0 2 R' a COOH b i. CONHOH -N, S, O -N, S, O -N, S, O a. LiN(TMS) 2 / THF/ 0 *C/ C0 2 ; b. (COC1) 2 / NHzOH. HCl/ Et 3 N Alternatively, Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support (P).

WO 99/42436 PCT/US98/17633 - 20 Scheme 7 0'NH2 a O-N R2 b , 1HI 0 j:r 0 ::rBr(CI) 0 0 0 O-N RR 0 O O-N H " ,r-1 H 0j \..R0 Ox 0R 1 d 0 O ~ 0-N H O 0 0 0 O-N' R2 e HO-N _ R 2 O.\' SOn SOn 0% NR1 R1 Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate 5 (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25 0 C; 2-16 hours. b) Thiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25 0 C; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25 0 C; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25 0 C; 12-24 hours. e) TFA : DCM (1:1); 25oC; 1 hour. 10 The 4-O-methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinyl benzene)-resin (hydroxylamine resin) may be coupled with a 2-halo acid to give the hydroxamate ester resin. The coupling reaction may be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. The 15 halogen group may be displaced with a thiol in the presence of a base, such as DBU, in an inert solvent such as THF at room temperature. The sulfide may be oxidized to the sulfoxide by reaction with an oxidizing agent such as tert-butylhydroperoxide 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 20 reaction with an oxidizing agent such as meta-chloroperoxybenzoic acid, in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide, or sulfone may be WO 99/42436 PCT/US98/17633 -21 treated with and acid, such as trifluoroacetic acid, in and inert solvent such as DCM to liberate the free hydroxamic acid. Scheme 8 shows a method of preparing hydroxamic acids having alkoxy groups 5 attached to the aromatic ring. Scheme 8

O

0 N H2 O- O-N ) R b I H I &. N," & Br(CI) 0 0 OO-N R2 cO O-N R 2 & 0 -a F S :: O ,alkyl d4e O OON R2 O OR R2 O~ O -N 2NR 0 1 , O alkyl oalkyl 0 0

,U,,R

2 f ON R 0j -N H HO - I H SOn - ~ H SOn n= 0, 1, 2 10 Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25oC; 2-16 hours. b) 4-Fluorobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU, 3.0 eq.); THF; 25 0 C; 12-16 hours. c) Alcohol (15.0 eq.); sodium hydride (15.0 eq.); DMF; 80 0 C; 15 hours. d) 70% tert-butylhydroperoxide (40 eq.); 15 benzenesulfonic acid (2.0 eq.); DCM; 25oC; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25°C; 12-24 hours. f) TFA : DCM (1:1); 25 0 C; 1 hour. The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by fluorobenzenethiol as previously described. The fluoro WO 99/42436 PCT/US98/17633 - 22 group may then be displaced with an alcohol in the presence of a base such as sodium hydride, in an inert solvent such as DMF at about 80 0 C. The alkoxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The free hydroxamic acids may be 5 liberated as previously described. Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, and sulfonylhydroxamic acids. 10 Scheme 9 0

OO

N H 2 a O-N -- R2 b NO . ,N.: H Br(CI) 0 0 SO-N R2 c O-N R2 S:Br B jr 0 o~S Br O Br dO-N

R

2 HO Br 0 0 e O-N R2 f HO-N R SOn H SOn NQ,% AAr Reagents and Conditions: a) 2-Halo acid (3.0 eq.); l-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25 0 C; 2-16 hours. 15 b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU, 3.0 eq.); THF; 25oC; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25oC; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25'C; 12-24 hours. e) Arylboronic acid (2.0 eq.); tetrakis(triphenyl phosphine) palladium(0) (0.1 eq.); 10% aqueous sodium carbonate (10.0 eq.); DME;; 20 80'C; 8 hours. f) TFA : DCM (1:1); 25oC; 1 hour.

WO 99/42436 PCT/US98/17633 - 23 The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described. The bromobenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The 5 bromo group may then be replaced with an aryl group by reaction with the arylboronic acid in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium(0), and a base such as sodium carbonate, in an inert solvent such as DME at about 80 0 C. The free hydroxamic acids may be liberated as previously described. 10 Scheme 10 shows a method of preparing hydroxamic acids having amine groups attached to the aromatic ring. Scheme 10 00 O,[:r ONH2 O -& O-NIT-R b 0 R 11cr-r R 2 C

)-

0 - R2 d H- R 'S N rS" NR aI 0 R6

R

2 d Hr v -N- R

R

6 15 Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25 0 C; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU, 3.0 eq.); THF; 25 0 C; 12-16 hours. c) Amine (20.0 eq.); 20 tris(dibenzylideneacetone)-dipalladium(0) (0.2 eq.); (S)-(-)-2,2'-bis(diphenyl phosphimo)-1,1'-binaphthyl ((S)-BINAP, 0.8 eq.); sodium tert-butoxide (18.0 eq.); dioxane; 80 0 C, 8 hours; d) TFA: DCM (1:1); 25 0 C; 1 hour. The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described. The bromo 25 group may then be displaced with an amine in the presence of a catalyst such as WO 99/42436 PCT/US98/17633 -24 tris(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide, in an inert solvent such as dioxane at about 80 0 C. The free hydroxamic acids may be liberated as previously described. 5 Scheme 11 shows a method of preparing hydroxamic acids having sulfonate groups attached to the aromatic ring. Scheme 11

ON

j r Br(CI) 0 OO-N, R 2 c O-~ y R "00 11 0 II OH O-j-X e o 0 O O= O SOn O SOn 00 0 alO O- -X O-§-X 0 O n = 0, 1, 2 O-n-X O O X= C 1

-C

6 alkyl, aryl O 10 Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25'C; 2-16 hours. b) 4-Hydroxybenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25 0 C; 12-16 hours. c) Sulfonyl chloride 15 (5.0 eq.); triethylamine (2.0 eq.); DCM; 25 0 C; 8 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25 0 C; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25 0 C; 12-24 hours. f) TFA : DCM (1:1); 25oC; 1 hour.

WO 99/42436 PCT/US98/17633 - 25 The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by hydroxybenzenethiol as previously described. The hydroxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The 5 hydroxy group may then be sulfonylated by reaction with a sulfonyl chloride in the presence of a base such as triethylamine, in an inert solvent such as DCM at about room temperature. The free hydroxamic acids may be liberated as previously described. The following examples are presented to illustrate rather than limit the scope of the 10 invention. HPLC purity of compounds prepared by combinatorial procedures is presented as area percentage at a prescribed wavelength (% @ nm). Example 1 15 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide To stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous

K

2

CO

3 (10 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.6 gm, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at 20 reflux for 8 hours with good stirring. At the end, reaction was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H 2 0 and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO 4 , filtered and concentrated to afford 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl 25 ester as a light yellow oil. Yield 4.5gms (94%); MS; 241 (M+H)+. To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (2.44 g, 10 mmol), in THF (100 ml) at -4 0 C, lithium bis(trimethylsilyl)amide (1 M solution, 15 ml, 15 mmol) was added slowly. The orange colored reaction mixture was stirred at 30 room temperature for 15 minutes and then it was cooled to O'C at which time it was stirred for an additional hour. The temperature of the mixture was again brought to -40'C and benzylbromide (1.72 gm, 10 mmol) was added dropwise in THF. The reaction was warmed to room temperature and stirred overnight before it was quenched with ice water, extracted with chloroform and washed with water. The organic layer 35 was dried over MgSO 4 , filtered and concentrated and chromatographed on a silica-gel column with 10% ethyl acetate:hexane to afford 2-(4-methoxy-phenylsulfanyl)-2- WO 99/42436 PCT/US98/17633 - 26 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-phenyl-propionic acid ethyl ester (4.12 g, 5 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:diethyl ether and extracted with H 2 0. The water layer was cooled with ice and acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO 4 , filtered and concentrated to 10 afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 (M+H) +. To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g, 1.65 mmol) and DMF ( 2 drops) in CH 2 C1 2 (100 ml) at O'C, oxalyl 15 chloride (1.0 gin, 8 mmol) was added in a drop-wise manner. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gin, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at O'C for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale 20 yellow residue was dissolved in 10 ml of CH 2 C1 2 and added slowly to the hydroxyl amine at OoC. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with ethyl acetate. The N-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl 25 3-phenyl-propionamide was isolated as a colorless solid. mp 88 oC; Yield, 300 mg, 57%; MS: 318 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 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 30 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide 2-(4-Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl a.-bromophenyl WO 99/42436 PCT/US98/17633 - 27 acetate (7.18 g, 31.4 mmol) and 4-methoxythiophenol (4.4 g, 31.4 mmol), 8.5 g of the product was isolated as a light yellow oil. Yield 90%; MS: 303.1 (M+H) +. 2-(4-Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared starting from 2-(4 5 methoxy-phenylsulfanyl)-phenyl-acetic 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-methoxy-phenylsulfanyl)-phenyl acetic acid (1.05 g, 3.83 mmol) 10 and following the procedure as outlined in Example 1, 154 mg of N-hydroxy-2-(4 methoxy-phenylsulfanyl)-2-phenyl-acetamide was isolated as a colorless solid. mp 155'C; Yield 14%; MS: 290 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 5 3.72 (s, 3H), 4.68 (s, 1H), 6.86-7.44 (m, 9H). 15 Example 3 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester was prepared 20 following the procedure of Example 1, second paragraph. Starting from (4-methoxy phenylsulfanyl)-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)

+. 25 2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (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 outlined in Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H) +. 30 Starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid (1.67 g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-(4 methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide was isolated as a colorless solid. mp 89 oC; Yield 94%; MS: 296 (M+H)+; IH NMR (300 MHz, 35 CDC1 3 ): 8 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).

WO 99/42436 PCT/US98/17633 - 28 Example 4 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide 5 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 butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated. Yield 99%; Light yellow oil; MS: 271 (M+H) +. 10 2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared starting from 2-(4 methoxy-phenylsulfanyl)-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 outlined in Example 1. Yield 5.0 g, 99%. Low melting solid. MS: 242 (M+H) +. 15 Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (4.39 g, 18.3 mmol) and following the procedure as outlined in Example 1, 1.5 g of N-hydroxy-2 (4-methoxy-phenylsulfanyl)-3-methyl-butyramide was isolated as a colorless solid. mp 119 oC; Yield 33%; MS: 256 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.90-1.07 20 (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 25 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and 30%

H

2 0 2 (10 ml) was added. The reaction mixture was stirred for 48 hours at room 30 temperature at which time it was cooled to 0 C and quenched with saturated Na 2

SO

3 (20 ml) solution. The reaction mixture became cloudy. It was stirred for 4 hours before it was concentrated in a room temperature water bath, diluted with water, extracted with CHC1 3 and washed with H 2 0. The organic layer was dried over MgSO 4 , filtered and concentrated. The title compound was isolated by silica gel column 35 chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg (52%); MS: 334.1 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): d 1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).

WO 99/42436 PCT/US98/17633 - 29 Example 6 2-(4-Methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide 5 Starting from 2-(4-methoxy-benzenesulfanyl)-2,5-dimethyl-hex-4-enoic hydroxamide (900 mg, 3.0 mmol) (prepared in Example 3) and following the procedure outlined in Example 5, 2-(4-methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxy amide was isolated as a colorless solid. Yield: 104 mg (10%); mp 108 oC; MS: 312 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 10 2.27-2.80 (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 15 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide Starting from N-hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide (1 g, 3.9 mmol) as prepared in Example 4, and following the procedure of Example 5, N hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyramide was isolated as a 20 colorless solid. Yield: 420mg (40%); mp 163 oC; MS: 272 (M+H)+; 1H NMR (300 MHz, DMSO-d 6 ): 8 0.89-1.12 (m, 6H), 1.63-1.74 (m, 1H), 3.13 (d, J = 7 Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H). Example 8 25 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 prepared in Example 2, and following the procedure outlined in 30 Example 5, N-hydroxy-2-(4-methoxy-benzenesulfinyl)-2-phenyl-acetamide was isolated as colorless solid. Yield: 100mg (40%); mp 135 oC; MS 304 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H) Example 9 35 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide. To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous

K

2

CO

3 (10 gm, excess) in dry acetone (100 ml), o-bromo ethyl acetate (3.3 gm, 20 40 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux WO 99/42436 PCT/US98/17633 - 30 for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H 2 0 and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO 4 , 5 filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)+. To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40 mmol) in methylene chloride (100 ml) at 00 C, (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester 10 (4.4 g, 20 mmol) in CH 2 C1 2 (15 ml) was added slowly. The reaction mixture turned cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solids were filtered off and Na 2

SO

3 solution was added to the organic layer which was stirred for at least 3 hours before the mixture was extracted with CHCl 3 and washed with H 2 0. The 15 organic layer was dried over MgSO4, 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)+. To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 20 mmol), benzyl bromide ( 1.8 gm,10 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K 2

CO

3 (10gms, excess) and the mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO 4 , filtered and concentrated. The product obtained was purified by 25 silica-gel column chromatography, eluting with 30% ethyl acetate: hexane. The product, 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was isolated as a low melting solid. Yield: 3.0 gm 86%; Low melting solid; MS: 349 (M+H)+. 30 To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348 mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. The reaction mixture was stirred at room temperature for 48 hours. At the end, the reaction mixture was concentrated and carefully neutralized with dilute HC1. The residue obtained was extracted with chloroform, washed well with water, dried and 35 concentrated. The product obtained was purified by silica-gel column chromatography WO 99/42436 PCT/US98/17633 -31 by eluting with ethyl acetate: methanol (95:5) to afford 2-(4-methoxy-benzenesulfonyl) 3-phenyl-propionic acid as a colorless oil. Yield: 250 mg, 89%; MS: 321 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200 mg, 0.625 5 mmol) and following the procedure as outlined in Example 1, 150 mg of N-hydroxy-2 (4-methoxy-benzenesulfonyl)-3-phenyl-propionamide was isolated as a brown solid. Yield: 71%; mp 180 oC; MS: 336 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 3.2 (m, 1H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 7.0-8.0 (m, 9H). 10 Example 10 2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamnide 2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the 15 general method as outlined in Example 1. Starting from ethyl 2-bromo hexanoate (7 g, 32 mmol) and 4-methoxybenzenethiol (4.2 g, 30 mmol), 8.3 g of the product was isolated. Yield 98%; Light yellow oil; MS: 283 (M+H)+. Starting from 2-(4-methoxy-phenylsulfanyl)-hexanoic acid ethyl ester. (2.8 g 10 mmol) 20 and following the procedure as outlined in Example 9, 3 g of 2-(4-methoxy-benzene sulfonyl)-hexanoic acid ethyl ester was isolated as a colorless solid. Yield: 95%; mp 62 oC; MS: 314 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (2 g, 6.3 mmol) 25 1.5 g (83%) of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 116 oC; MS: 287 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1 mmol) and 30 following the procedure as outlined in Example 1, 700 mg of 2-(4-methoxy-benzene sulfonyl)-hexanoic acid hydroxyamide was isolated as a colorless solid. Yield: 60%; mp 130 oC; MS: 302 (M+H)+; 1H NMR (300 MHz, CDC1 3 ): 8 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 = 11 Hz, 2H), 7.8 (d, J= 11 Hz, 2H), 9.3 (s, 1H), 10.9 (s, 1H). 35 WO 99/42436 PCT/US98/17633 - 32 Example 11 2-(4-Methoxy-benzene sulfonyl)-tetradecanoic hydroxyamide 5 2-(4-Methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from the corresponding ethyl -2 bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), 5.0 g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 (M+H)

+

. 10 Starting from 2

-(

4 -methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester. (3.9 g 10 mmol) and following the procedure as outlined in Example 9, 3.2 g of 2-(4-methoxy benzenesulfonyl)-tetradecanoic acid ethyl ester was isolated as a colorless solid, yield: 76%; Oil; MS: 425 (M+H)+. 15 Starting from 2

-(

4 -methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester (2.5 g, 5.9 mmol), 2.0 g (85%) of 2 -(4-methoxy-benzenesulfonyl)-tetradecanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 82 oC; MS: 397 (M+H)+. 20 Starting from 2-(4-methoxy-benzene sulfonyl)-tetradecanoic acid (1.14 g, 2.9 mmol) and following the procedure as outlined in Example 1, 670 mg of 2-(4-methoxy benzenesulfonyl)-tetradecanoic hydroxyamide was isolated as an off-white solid. Yield: 57%; mp 114 oC; MS: 414 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.85 (t, J = 7 Hz, 3H), 1.16-1.27 (min, 20 H), 1.66 (min, 2H), 3.62-3.70 (min, 1H), 3.87 (s, 3H), 7.12 25 (d, J = 15 Hz, 2H), 7.73 (d, J = 15 Hz, 2H). Example 12 30 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide 30 To a stirred solution of 2 -(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 gm, 3mmol) (example 9), methyl iodide ( 1 ml, excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K 2

CO

3 (10 gm, excess) was added and the reaction mixture was refluxed for 24 hours. At the end, the reaction mixture was filtered and 35 the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexanes to afford 2-(4-methoxy-benzenesulfonyl)- WO 99/42436 PCT/US98/1 7633 - 33 2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1.0 g, 98%; MS: 349 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl 5 ester (900 mg, 2.7 mmol), 850 mg (quantitative) of 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-phenyl-propionic acid was isolated by following the procedure as outlined in Example 9. Colorless oil, MS 335 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid (900 10 mg, 2.7 mmol) and following the procedure as outlined in Example 1,450 mg of N hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamide was isolated as a brown solid. Yield: 48%; mp 58 oC; MS: 350 (M+H)+; 1H NMR (300 MHz, CDC1 3 ): 5 1.4 (s, 3H), 3.1 (d, J=9 Hz, 1H), 3.6 (d, J= 9 Hz, 1H), 3.9 (s, 3H), 6.8 - 7.8 (m, 9H). 15 Example 13 2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide 20 Starting from 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (Example 1) (12 g; 50 mmol) and following the procedure as outlined in Example 9, 12 g of 2-(4 methoxy-benzenesulfonyl)-propionic acid ethyl ester was isolated as a semi-solid, yield 100%; MS: 256.1 (M+H) +. 25 Following the procedure as outlined in Example 12, 2-(4-methoxy-benzenesulfonyl) 2,5-dimethyl-hex-4-enoic acid ethyl ester was prepared, starting from (1 g, 3.6 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and isoprenyl bromide (1.0 g, 6 mmol). Yield 1.0 g, 81%; Colorless oil; MS: 341 (M+H) +. 30 Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (900 mg, 2.6 mmol) 800 mg (96%) of 2-(4-methoxybenzenesulfonyl)-2,5-dimethyl hex-4-enoic acid was isolated as a semi solid by following the procedure as outlined in Example 9. MS: 313 (M+H) +. 35 Starting from 2-(4-methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid (1.0 g, 3.2 mmol) and following the procedure as outlined in Example 1, 700 mg of 2-(4 methoxy-benzenesulfonyl)-2,5 dimethyl-hex-4-enoic acid hydroxyamide was isolated as a low melting solid. Yield: 67%; MS: 328 (M+H)+; 'H NMR (300 MHz, CDCl 3 ): 8 WO 99/42436 PCT/US98/17633 - 34 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 5 3-(Biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide Following the procedure as outlined in Example 12, 3-(biphenyl-4-yl)-2-(4-methoxy benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.7 10 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester 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-methoxy-benzenesulfonyl)-2-methyl propionic 15 acid ethyl ester (3 g, 6.8 mmol), 2.5 g (89%) of 3-(biphenyl-4-yl)-2-(4-methoxy benzenesulfonyl)-2-methyl propionic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 161 oC; MS: 411 (M+H) +. Starting from 3-(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic 20 acid (2.0 g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.2 g of 3-(biphenyl-4-yl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide was isolated as colorless solid. Yield: 58%; mp 177 oC; MS: 426 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 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). 25 Example 15 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid hydroxyamide 30 Following the procedure as outlined in Example 12, 2-(4-methoxy-benzenesulfonyl) 2,5,9-trimethyl-deca-4,8-dienoic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and geranyl bromide (3.0 g, 13 mmol). Yield 4.0 g, 98%; Colorless oil; MS: 409 (M+H)+. 35 Starting from 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid ethyl ester (3 g, 7.4 mmol), 2.8 g (96%) of 2-(4-methoxy-benzenesulfonyl)-2,5,9 trimethyl-deca-4,8-dienoic acid was isolated as a colorless oil by following the procedure as outlined in Example 9. MS: 379 (M-H)-.

WO 99/42436 PCT/US98/17633 - 35 Starting from 2-(4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid (2.0 g, 5.2 mmol) and following the procedure as outlined in Example 1, 1.8 g of 2 (4-methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid hydroxyamide was isolated as a colorless oil. Yield: 88%; MS: 396 (M+H)+; 1 H NMR (300 MHz, CDC1 3 ): 5 8 1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s, 3H), 1.7 (s, 3H), 2.0- 3.1 (m,6 H), 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 10 3-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide Following the procedure as outlined in Example 12, 3-cyclohexyl-2-(4-methoxy benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and bromo 15 methylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil; MS: 369 (M+H)+. Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid ethyl ester (3 g, 8.1 mmol) 2.5 g (90%) of 3-cyclohexyl-2-(4-methoxy-benzene sulfonyl)-2-methyl propionic acid was isolated as colorless solid by following the 20 procedure as outlined in Example 9. mp 116 oC; MS: 341 (M+H)+. Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.0 g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.1 g of 3 cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionamide was 25 isolated as colorless solid. Yield: 55%; mp 58 oC; MS: 356 (M+H)+; 1H NMR (300 MHz, CDC1 3 ) 8 1.4 (s, 3H), 2.3 -1.0 (m, 13 H), 3.9 (s, 3H), 7.0 (d, 8.8 Hz, 2H), 7.69 (d, 9.0 Hz, 2H). Example 17 30 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy) phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, 35 starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil; MS: 490 (M+H)+.

WO 99/42436 PCT/US98/17633 - 36 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy) phenyl]-propionic acid ethyl ester (4.0 gin, 7.9 mmol) 3.5 g (Yield: 94 %) of 2-(4 methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in 5 example 9. Mp 106 oC; 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 following the procedure as outlined in example 1, 1 g of N-hydroxy- 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2 10 piperidin- 1 -yl-ethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 98oC; MS: 477 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.2 (s, 3H), 3.5 - 1.5 (m, 16 H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5 - 7.8 (m, 8H), 10.8 (bs, 1H). Example 18 15 2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid hydroxyamide Following the procedure as outlined in example 12, 2-[4-(2-azepan-1-yl-ethoxy) benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester was prepared, 20 starting from (2.7 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 1-[2-(4-chloromethyl-phenoxy)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) 25 propionic acid ethyl ester (4.0 gm, 7.9 mmol) 3.5 g (Yield: 94 %) of 2-[4-(2-azepan 1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 476 (M+H)+. Starting from 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) 30 propionic acid (2.0 g, 4.2 mmol) and following the procedure as outlined in example 1, 1 g of 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-propionic acid hydroxyamide was isolated as colorless solid. Yield: 1.8 g, 87%; mp 68 0 C; MS: 491 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 6 1.23 (s, 3H), 3.5 - 1.7 (m, 18 H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4 - 7.89 (m, 8H), 10.9 (bs, 1H). 35 WO 99/42436 PCT/US98/17633 - 37 Example 19 2-[4-(2-Azepan- 1 -yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) pentanoic acid hydroxyamide 5 2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester (3.5 g, 11.7 mmol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8 mmol). Yield 10 2.58 g (42%); brown oil; MS: 532.4 (M+H) + . 2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid was prepared starting from 2-[4-(2-azepan- 1 -yl-ethoxy)-benzyl]-2-(4-methoxy benzenesulfonyl)-pentanoic acid ethyl ester (2 g, 3.76 mmol) dissolved in methanol 15 (300 ml) and 10 N NaOH (15 ml). The resulting mixture was worked up as outlined in example 1. Yield 830 mg (44%); brown solid; mp 55 oC; MS: 504.4 (M+H) + . Starting from 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) pentanoic acid (690 mg, 1.37 mmol) and following the procedure as outlined in 20 example 1, 240 mg of 2-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzene sulfonyl)-pentanoic acid hydroxyamide was isolated as a yellow solid. Yield 34%; mp 85 oC; MS: 519.2 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): d 0.71 (t, J = 7.3 Hz, 3H), 0.78-1.77 (m, 16 H), 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). 25 Example 20 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl amino ethoxy)-phenyl]-propionamide 30 Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[4-(2-N,N-diisopropyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 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) + . 35 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl amino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gin, 7.9 mmol) 3.5 g (Yield: 92%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl amino- WO 99/42436 PCT/US98/17633 -38 ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 68 oC; MS: 478.6 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyl 5 amino-ethoxy)-phenyl]-propionic acid (2.0 g, 4.1 mmol) and following the procedure as outlined in example 1, 1 g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2 N,N-diisopropyl amino-ethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: 1 g, 49%; mp 98 0 C (Hcl Salt); MS: 493 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 1.2 (s, 3H), 1.3 (d,6H), 1.4 (d,6H), 3.5 - 1.5 (min, 6 H), 3.9 (s, 3H), 4.4 (s, 2H), 10 6.5 - 7.8 (m, 8H), 10.8 (bs, 1H). Example 21 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino 15 ethoxy)-phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (5.5 g, 20 20 mmol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid ethyl ester (3.5 gm, 7.7 mmol) 3.0 g (Yield: 85 %) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl] 25 propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 96-98 oC; MS: 450.5 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid (2.0 g, 4.4 mmol) and following the procedure as 30 outlined in example 1, 1 g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N diethyl amino-ethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: Ig, 48%; mp 56-59°C (HCl Salt); MS: 465.5 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.1 (t, 6H), 1.3 (s,3H), 3.2 - 3.9 (min, 8 H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5 - 7.8 (min, 8H), 10.8 (bs, 1H). 35 WO 99/42436 PCT/US98/17633 - 39 Example 22 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy) phenyl]-propionamide 5 Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 3-(2-piperidin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 8.2 g, 83%; Brown oil; MS: 490 (M+H)+. 10 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy) phenyl]-propionic acid ethyl ester (6.0 gm, 12.2 mmol) 4.9 g (Yield: 79 %) of 2-(4 methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in 15 example 9. Mp 112 oC; 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 following the procedure as outlined in example 1, 1.8 g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-piperidin-1-yl 20 ethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: 1.8 g, 58%; mp 74 0 C; MS: 477 (M+H)+; 1 H NMR (300 MHz, CDC1 3 ): 8 1.25 (s, 3H), 1.6-1.8 (m, 6 H), 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 25 3-(4- { 3-[4-(3-Chloro-phenyl)-piperazin- 1 -yl]-propoxy } -phenyl)-N-hydroxy-2-(4-m ethoxy-benzenesulfonyl)-2-methyl-propionamide Following the procedure as outlined in example 12, 3-(4-{ 3-[4-(3-chloro-phenyl) piperazin- 1 -yl]-propoxy } -phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic 30 acid ethyl ester was prepared, starting from (2.72 g, 10 mmol) of 2-(4-methoxy benzenesulfonyl)-propionic acid ethyl ester and the 1-[2-(4-chloromethyl-phenoxy) ethyl]-4-(3-chloro-phenyl)-piperazine (4.2 g, 11 mmol). Yield 5.5 g, 89%; Brown oil; MS: 616 (M+H)+. 35 Starting from 3-(4- { 3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy }-phenyl)-2-(4 methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester (4.0 gm, 6.5 mmol) 3.0 g (Yield: 78 %) of 3-(4- { 3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy }-phenyl) 2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was isolated as colorless WO 99/42436 PCT/US98/17633 -40 crystals by following the procedure as outlined in example 9. Mp 196 oC; MS: 588.1

(M+H)

+. Starting from 3-(4- { 3-[4-(3-chloro-phenyl)-piperazin-1-yl]-propoxy }-phenyl)-2-(4 5 methoxy-benzenesulfonyl)-2-methyl-propionic acid (3.0 g, 5.1 mmol) and following the procedure as outlined in 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 methyl-propionamide was isolated as pale yellow solid. Yield: 1.8 g, 55%; mp 122oC (HCl Salt); MS: 640 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 5 1.2 (s, 3H), 3.4 - 1.5 10 (m, 14 H), 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] 15 hex-4-enoic acid hydroxyamide To a stirred 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) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The 20 residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl ester was isolated as a colourless oil. Yield: 3.0 g, 93%. 25 Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)-5 methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid ethyl ester was prepared, starting from (3.26 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-5 methyl-hex-4-enoic acid ethyl ester and 4-(2-morpholin-1-yl-ethoxy)-benzyl chloride 30 (3.0 g, 11 mmol). Yield 4.5 g, 82%; Brown oil; MS: 546 (M+H)+. Starting from 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl ethoxy)-benzyl]-hex-4-enoic acid ethyl ester (3.0 gm, 5.5 mmol) 2.1 g (Yield: 75 %) of 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] 35 hex-4-enoic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 518.6 (M+H)+.

WO 99/42436 PCT/US98/17633 -41 Starting from 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl ethoxy)-benzyl]-hex-4-enoic acid (1.0 g, 1.9 mmol) and following the procedure as outlined in example 1, 450 mg of 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2 morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid hydroxyamide was isolated as pale 5 yellow solid. Yield: 450 mg, 45%; mp 92oC (HCI Salt); MS: 570 (M+H)+; 1H NMR (300 MHz, CDC1 3 ): 8 1.3 (d, 3H), 1.65 (d, 2H), 3.5 - 1.8 (m, 14 H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m, 1H), 6.5 - 7.9 (m, 8H), 11.5 (bs, 1H). Example 25 10 N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionamide To a stirred solution of 4-hydroxy thiophenol (12.6 g, 100 mmol) and triethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromo ethylpropionate (18. 2 g, 100 15 mmol) was added drop wise. The reaction mixture was refluxed for 1 hr and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester was isolated as colorless oil. Yield: 22.0 g, 99%, MS: 227 (M+H). 20 To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester (11.3 g, 50 mmol), and K 2

CO

3 (50 g, excess) in acetone (300 ml) ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At the end, reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform and washed well with water. It was dried and concentrared. The product, 2-(4-ethoxy-phenylsulfanyl) 25 propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g , 98%; MS: 255 (M+H). 2-(4-Ethoxy-phenylsulfanyl)-propionic acid ethyl ester was converted to 2-(4-ethoxy phenylsulfonyl)-propionic acid ethyl ester by following the procedure as described in 30 example 9, paragraph 2. Following the procedure as outlined in example 12, 2-(4-ethoxy-benzenesulfonyl)-2 methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of 2-(4-ethoxy-benzenesulfonyl)-propionic 35 acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (3.5 g, 12.2 mmol). Yield 4.8 g, 80%; Brown oil; MS: 492.6 (M+H)+.

WO 99/42436 PCT/US98/17633 -42 Starting from 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 8.1 mmol) 3.2 g (Yield: 80 %) of 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl] propionic acid was isolated as colorless semi-solid by following the procedure as 5 outlined in example 9. MS: 464.5 (M+H) + . Starting from 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid (2.0 g, 4.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N 10 diethyl amino-ethoxy)-phenyl]-propionamide was isolated as colorless low melting solid. Yield: 1.2 g, 57%; (HCl Salt); MS: 478.5 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 6 0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s,3H), 3.2 - 3.9 (m, 8 H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5 - 7.8 (min, 8H), 10.8 (bs, 1H). 15 Example 26

(

4 E)-2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl-ethoxy) benzyl]-deca-4,8-dienoic acid hydroxyamide To a stirred solution of (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.16 g, 20 20 mmol), geranyl bromide (4.2g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gins, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO 4 , filtered and concentrated. The product obtained was purified by 25 silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2

-(

4 -methoxy-benzenesulfonyl)-5,9-dimethyl-deca-4,8-dienoic acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%. Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl) 30 5, 9 -dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoic acid ethyl ester was prepared, starting from (1.0 g, 2.5 mmol) of 2-(4-methoxy-benzenesulfonyl)-5,9 dimethyl-deca-4,8-dienoic acid ethyl ester and 4-(2-morpholin-1-yl-ethoxy)-benzyl chloride (800 mg, 2.5 mmol). Yield 1.2 g, 76%; Brown oil; MS: 614 (M+H) + . 35 Starting from 2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl ethoxy)-benzyl]-deca-4,8-dienoic acid ethyl ester (2.0 gm, 3.2 mmol) 1.5 g (Yield: 80%) of 2

-(

4 -Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl- WO 99/42436 PCT/US98/17633 -43 ethoxy)-benzyl]-deca-4,8-dienoic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 586.6 (M+H) +. Starting from 2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin-4-yl 5 ethoxy)-benzyl]-deca-4,8-dienoic acid (1.0 g, 1.7 mmol) and following the procedure as outlined in example 1, 550 mg of (4E)-2-(4-Methoxy-benzenesulfonyl)-5,9 dimethyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-deca-4,8-dienoic acid hydroxyamide was isolated as pale yellow solid. Yield: 550 mg, 53%; mp 61oC (HCI Salt); MS: 638

(M+H)

+. 10 Example 27 2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) hexanoic acid hydroxyamide 15 2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was prepared according to the general method as outlined in example 12. Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (4 g, 12.7 mmol) and [2-(4-chloromethyl-phenoxy)-ethyl]-diethylamine (3.38 g, 14 mmol). Yield 8.21 g crude (100%); brown oil; MS: 520.4 (M+H)*. 20 2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid was prepared starting from 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy benzenesulfonyl)-hexanoic acid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10 N NaOH (30 ml). The resulting mixture was worked up as outlined in 25 example 1. Yield 3.88 g crude (51%); brown oil; MS: 492 (M+H) . Starting from 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) hexanoic acid (3.88 g, 7.89 mmol) and following the procedure as outlined in example 1, 800 mg of 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl) 30 hexanoic acid hydroxyamide was isolated as a yellow powder. Yield 20%; mp 67 oC; MS: 507.4 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.75 (t, J = 7.1 Hz, 3H), 1.05 (m, 2 H), 1.23 (t, 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) 35 WO 99/42436 PCT/US98/17633 -44 Example 28 N-Hydroxy-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin- 1-yl-ethoxy) phenyl]- propionamide 5 Following the procedure as outlined in example 12, 2-(4-n-butoxy-benzenesulfonyl)-2 methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.1 g, 10 mmol) of 2-(4-n-butoxy-benzenesulfonyl)-propionic acid ethyl ester (Prepared from 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester and n butylbromide following the procedure outlined in example 27 )the 4-(2-piperidin-1-yl 10 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-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl ethoxy)-phenyl]-propionic acid ethyl ester (5.0 gin, 9.4 mmol) 4.2 g (Yield: 88 %) of 15 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin- 1-yl-ethoxy)-phenyl] propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MS: 504.6 (M+H) + Starting from 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidin-1-yl 20 ethoxy)-phenyl]-propionic acid (3.0 g, 5.9 mmol) and following the procedure as outlined in example 1, 1.3 g of 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2 piperidine- 1 -yl-ethoxy)-phenyl]-propionamide was isolated as colorless solid. MP. 65oC, Yield: 1.3 g, 42%; (HCI Salt); MS: 478.5 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 0.9 (t, 3H), 1.2 (s, 3H), 1.3 - 1.9 (m,10H), 2.8 - 4.5 (m, 12 H), 6.8 25 7.8 (m, 8H), 10.8 (bs, 1H). Example 29 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethyl amino 30 ethoxy)-phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[3-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.0 g, 18 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 3-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (4.9 g, 18 35 mmol). Yield 8.1 g, 93%; 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 gm, 16.9 mmol) 6.7 g (Yield: 88 %) of WO 99/42436 PCT/US98/17633 -45 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethyl amino-ethoxy)-phenyl] propionic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MP: 78-81; MS: 450.1 (M+H) +. 5 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid (6.7 g, 15 mmol) and following the procedure as outlined in example 1, 1.5 g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2 N,N-diethyl amino-ethoxy)-phenyl]-propionamide was isolated as colorless low melting solid. Yield: 1.5 g, 21%; (HCI Salt); MS: 450.5 (M+H)+; 1 H NMR (300 10 MHz, DMSO-d 6 ): 8 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 15 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3 [3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 20 methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 9.1 g, 93%; Brown oil; MS: 492 (M+H) +. 25 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl ethoxy)-phenyl]-propionic acid ethyl ester (10.0 gin, 20.3 mmol) 8.0 g (Yield: 86 %) of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl-ethoxy)-phenyl] propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9.; MS: 464.5 (M+H) +. 30 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin-1-yl ethoxy)-phenyl]-propionic acid (4.55 g, 9.8 mmol) and following the procedure as outlined in example 1, 440 mg of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2 morpholi-1-yl-ethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: 35 440 mg, 9%; mp 63oC; MS: 479.5 (M+H)+; 1 H NMR (300 Mhz, DMSO-d 6 ): 8 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).

WO 99/42436 PCT/US98/17633 -46 Example 31 6-(1,3-Dioxo- 1,3-dihydro-isoindol-2-yl)-2-(4-methoxy benzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide 5 Following the procedure as outlined in Example 9, 6-(1,3-Dioxo-1,3-dihydro-isoindol 2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 4-phathalimido bromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless 10 oil; MS: 474 (M+H). Starting from 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzene sulfonyl)-2-methyl-hexanoic acid ethyl ester (8.4 g, 17.7 mmol) 6.95 g (88%) of 6 (1,3-Dioxo- 1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl 15 hexanoic acid was isolated as colorless oil by following the procedure as outlined in Example 9. MS: 446 (M-H)-. Starting from 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzene sulfonyl)-2-methyl-hexanoic acid (4.9 g, 11 mmol) and following the procedure as 20 outlined in Example 1, 3.1 g of 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4 methoxy-benzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide was isolated as a light brown solid; Yield: 46%; mp 146- 148 oC; MS: 461.2 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 1.55 (s, 3H), 1.61- 3.77 (min, 8H), 3.82 (s, 3H), 6.92-8.21 (inm, 8H), 10.70 (bs,1H), 11.20 (bs,1H). 25 Example 32 3-[4-(2-Diethylamino-ethoxy)-phenyl]-2-(4-furan-2-yl-benzenesulfonyl)-N hydroxy-2-methyl-propionamide 30 To a stirred solution of 4-bromo thiophenol (19.0 g, 100 mimol) and triethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromo ethylpropionate (18. 2 g, 100 mmol) was added drop wise. The reaction mixture was refluxed for 1 hr and cooled to room temperature. The reaction mixture was washed with water, dried and concentrated. 2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was isolated as 35 colorless oil. Yield: 28.0 g, 99%, MS: 290 (M+H).

WO 99/42436 PCT/US98/17633 -47 2-(4-bromo-phenylsulfanyl)-propionic acid ethyl ester was converted to 2-(4-bromo phenylsulfonyl)-propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2. 5 A mixture of 2-(4-bromo-phenylsulfonyl)-propionic acid ethyl ester (6.4 g, 20 mmol), 2-(tributyl stannyl)furan (7.5g, 21 mmol) and (Ph 3

P)

4 Pd (500 mg) was refluxed in degassed tolune (250 ml) for 8 hrs. At the end reaction mixture was filtered through Celite and concentrated. The product was purified by silica gel column chroma tography by eluting it with 50% ethylacetate : hexane. Colorless oil. Yield: 5.9 g, 95%, 10 MS: 309 (M+H). Following the procedure as outlined in example 12, 2-(4-(2-furanyl-benzenesulfonyl) 2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.08 g, 10.0 mmol) of 2-(4-(2-furanyl-benzenesulfonyl) 15 propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride (3.5 g, 12.2 mmol). Yield 5.0 g, 97%; Brown oil; MS: 514.6 (M+H) + . Starting from 2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino ethoxy)-phenyl]-propionic acid ethyl ester (5.1 gm, 10.0 mmol) 3.8 g (Yield: 78 %) of 20 2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino-ethoxy) phenyl]-propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 58 C, MS: 486.5 (M+H) +. Starting from 2-(4-(2-furanyl-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl amino 25 ethoxy)-phenyl]-propionic acid (5.0 g, 10.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N diethyl amniino-ethoxy)-phenyl]-propionamide was isolated as colorless low melting solid. Yield: 3.2 g, 62%; (HC1 Salt); MS: 502 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q,4H), 3.0 (t, 2 H), 4.1 (t, 2H), 6.5 - 8.0 (m, 30 7H). Example 33 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl 35 ethoxy)-benzyl]-butyramide 2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)*.

WO 99/42436 PCT/US98/17633 -48 2-(4-Methoxy-benzenesulfonyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenylsulfanyl) butyric acid ethyl ester (5 g, 20 mmol). Yield 5.74 g (100%); clear oil; MS: 287.1 5 (M+H) . Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)-2 [4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyric acid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of 2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and 10 the 4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (2.34 g, 6.7 mmol). Yield 5.7 g, 100%; Brown oil; MS: 506.4 (M+H) +. Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] butyric acid ethyl ester (5.54 gin, 11 mmol) 2.9 g (Yield: 55 %) of 2-(4-Methoxy 15 benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-butyric acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 478.3

(M+H)

+. Starting from 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] 20 butyric acid (2.6 g, 5.4 mmol) and following the procedure as outlined in example 1, 510 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl ethoxy)-benzyl]-butyramide was isolated as a brown solid. Yield 2%; mp 51 oC; MS: 493.3 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.90 (t, J = 7.2 Hz, 3H), 1.69 1.96 (m, 4 H), 2.67 (t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H) 6.8 (d, J = 8.7 25 Hz, 2H), 7.14 (m, 4H), 7.73 (d, J = 4.7 Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H). Example 34 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl 30 ethoxy)-benzyl]-butyramide Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)-2 [4-(2-piperidin-1-yl-ethoxy)-benzyl]-butyric acid ethyl ester was prepared, starting from (1.0 g, 3.33 mmol) of 2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester and the 1-[2-(4-chloromethyl-phenoxy)-ethyl]-piperidine (0.85 g, 3.36 mmol). Yield 1.07 35 g, 62%; Brown oil; MS: 504.4 (M+H) +. Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl- ethoxy)-benzyl] butyric acid ethyl ester (3.7 gin, 7.3 mmol) 2.2 g (Yield: 63 %) of 2-(4-Methoxy- WO 99/42436 PCT/US98/17633 -49 benzenesulfonyl)-2-[4-(2-piperidin-1-yl- ethoxy)-benzyl]-butyric acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 476

(M+H)

+. 5 Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl- ethoxy)-benzyl] butyric acid (2.2 g, 4.63 mmol) and following the procedure as outlined in example 1, 360 mg of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-[4-(2-piperidin-1-yl-ethoxy) benzyl]-butyramide was isolated as a brown solid. Yield 16%; mp 75 'C; MS: 491.3 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.90 (t, J = 7.1 Hz, 3H), 1.36-1.96 (m, 4 10 H), 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), 10.8 (s, 1H) Example 35 15 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl ethoxy)-benzyl]-pentanoic acid hydroxyamide 2-(4-Methoxy-phenylsulfanyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromovalerate (8.23 g, 39.3 mmol) and 4-methoxythiophenol (5 g, 35.7 mmol), 10.46 g (100%); clear oil; 20 MS: 269 (M+H)*. 2-(4-Methoxy-benzenesulfonyl)-pentanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenyl sulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4 mmol). Yield 7.07 g (86%); clear oil; 25 MS: 300.9 (M+H)*. Following the procedure as outlined in example 12, 2-(4-Methoxy-benzenesulfonyl)-2 [4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid ethyl ester was prepared, starting from (3.0 g, 10.8 mmol) of 2-(4-methoxy-benzenesulfonyl)-pentanoic acid ethyl ester 30 and the 4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (3.45 g, 11.9 mmol). Yield 3.08 g, 62%; Brown oil; MS: 520.4 (M+H) +. Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] pentanoic acid ethyl ester (2.73 gin, 5.27 mmol) 1.45 g (Yield: 56 %) of 2-(4 35 methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-pentanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 492.3 (M+H)

+.

WO 99/42436 PCT/US98/17633 - 50 Starting from 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] pentanoic acid (1.01 g, 2.05 mmol) and following the procedure as outlined in example 1, 190 mg of 2-(4-methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl] pentanoic acid hydroxyamide was isolated as a brown solid. Yield 18%; mp 101 oC; 5 MS: 507.4 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.71 (t, J = 7 Hz, 3H), 1.58 1.82 (m, 4 H), 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 10 2-[4-(2-Azepan- 1 -yl-ethoxy)-benzyl]-2-(4-Methoxy benzenesulfonyl)-octanoic acid hydroxyamide 2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 15 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-benzenesulfonyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(4-methoxy-phenylsulfanyl) 20 octanoic acid ethyl ester (4.0 g, 13.6 mmol). Yield 3.7 g (83%); clear oil; MS: 343.3 (M+H)*. Following the procedure as outlined in example 12, 2-[4-(2-Azepan-1-yl-ethoxy) benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoic acid ethyl ester was prepared, starting 25 from (1.69 g, 5.18 mmol) of 2-(4-methoxy-benzenesulfonyl)-octanoic acid ethyl ester and the 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) 30 octanoic acid ethyl ester (4.8 gm, 8.37 mmol) 1.55 g (Yield: 34 %) of 2-[4-(2-Azepan 1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl)-octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 551 (M+H)+. 35 Starting from 2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl) octanoic acid (1.09 g, 2.0 mmol) and following the procedure as outlined in example 1, 300 mg of 2-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl) octanoic acid hydroxyamide was isolated as a yellow solid. Yield 27%; mp 65 oC; MS: WO 99/42436 PCT/US98/17633 -51 561.6 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 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). 5 Example 37 2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide 2-(4-Methoxy-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the 10 general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (11.8 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g (57%); clear oil; MS: 311.2 (M+H) . Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid ethyl ester (3.1 gm, 10 15 mmol) 2.55 g (Yield: 90 %) of 2-(4-Methoxy-benzenesulfanyl)-octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 283 (M+H)+. Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid (4.25 g, 16 mmol) and 20 following the procedure as outlined in example 1, 3.64 g of 2-(4-Methoxy-benzene sulfanyl)-octanoic acid hydroxyamide was isolated as colorless solid. Yield: 76%, MP: 90oC; MS: 298.2 (M+H). Example 38 25 2-(4-Fluoro-phenylsulfanyl)-octanoic acid hydroxyamide 2-(4-Fluoro-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (6.47 30 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H) . Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid ethyl ester (3.1 gm, 10 mmol) 2.89 g (Yield: 100 %) of 2-(4-fluoro-benzenesulfanyl)-octanoic acid was isolated as 35 colorless semi-solid by following the procedure as outlined in example 9. MS: 268.9 (M+H)+. Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid (2.49 g, 9.2 mmol) and following the procedure as outlined in example 1, 2.72 g of 2-(4-fluoro-benzene- WO 99/42436 PCT/US98/17633 -52 sulfanyl)-octanoic acid hydroxyamide was isolated as colorless solid. Yield: 99%, MP: 58 0 C; MS: 284(M-H). Example 39 5 2-(1-methyl-1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide 2-(1-methyl-l1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2 10 bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clear oil; MS: 285 (M+H)*. Starting from 2-(1-methyl- 1H-imidazol-2-ylsulfanyl)-octanoic acid ethyl ester (12 gin, 42.2 mmol) 10.2 g (Yield: 95 %) of 2-(1-methyl-lH-imidazol-2-ylsulfanyl)-octanoic 15 acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 95 C, MS: 257.1 (M+H) +. Starting from 2-(1-methyl-lH-imidazol-2-ylsulfanyl)-octanoic acid (7.84 g, 30.6 mmol) and following the procedure as outlined in example 1, 2.77 g of 2-( 1-methyl 20 1H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyanmide was isolated as colorless solid. Yield: 33%, MP: 125 C; MS: 272.2 (M+H). Example 40 25 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide Following the procedure as outlined in Example 9, 2-(4-methoxy-benzensulfonyl)-3 naphthalen-2-yl-propionic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 2-bromomethyl 30 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-propionoic acid ethyl ester (3.7 g, 9 mmol) 3.3g (96%) of 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2 yl-propionoic acid was isolated as colorless oil by following the procedure as outlined 35 in Example 9. MS: 369.1 (M-H)-. Starting from 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionic acid (2.2 g, 5.9 mmol) and following the procedure as outlined in Example 1, 820 mg of N hydroxy-2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2-yl-propionamide was isolated 40 as a light brown solid; Yield: 36%; mp 161- 163 oC; MS: 385.9 (M+H)+; 1 H NMR WO 99/42436 PCT/US98/17633 - 53 (300 MHz, CDC1 3 ): 8 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 (min, 11H). Example 41 5 N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2 methyl-3-phenyl propionic acid hydroxamide A mixture of 4-methoxybenzyl mercaptan ( 7.0g, 45 mmol), ethyl 2-bromopropionate 10 (8.2 g, 46 mmol) and powdered oven dried potassium carbonate ( 10g, 72 mmol) in 150 mL of acetone was heated at reflux for 18 h. The mixture was cooled, filtered, and the filtrate 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 yield 12 g (99%); colorless liquid; MS 255.1 (M+H). This product is used without 15 further purification. To an ice cold (5 °C) solution of 2-(4-methoxy-phenylmethanesulfanyl)-propionic acid ethyl ester (5.7g, 21 mmol) in 100 mL CH 2 Cl 2 was added portionwise (7.2g, 40 mmol) of m-chloroperbenzoic acid and the mixture was stirred for 1 h. The reaction 20 was diluted with hexanes (500 mL) and stirred at 25 Co for 30 minute at room temperature. The mixture was filtered and the organic layer treated with saturated aqueous sodium bisulfite (200 mL). The hexanes solution containing the product was washed with water, dried (Na 2

SO

4 ) and concentrated. Yield 5.5g (91%); colorless oil; MS 287.1 (M+H)*. 25 Following the procedure as outlined in Example 9, 2-(4-Methoxy-phenylmethane sulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester was prepared, starting from 2-(4-Methoxy-phenylmethanesulfonyl)-propionic acid ethyl ester (2g, 7 mmol) and benzyl bromide (1.3g, 7.7 mmol). Yield 3.0 g, 100%; Low melting solid; MS: 377 30 (M+H) + . 2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid was prepared starting from 2-(4-Methoxy-phenylmethanesulfonyl)-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). 35 The resulting reaction mixture was worked up as outlined in Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 C;. MS: 347 (M-H) + .

WO 99/42436 PCT/US98/17633 - 54 Starting from 2-(4-Methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl-propionic acid (2.7 g, 7.0 mmol) and following the procedure as outlined in example 1, 266 mg of N Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2-methyl-3-phenyl propionic acid hydroxamide was isolated as light colorless solid; Yield: 10%; mp 58-59 oC; MS: 364.2 5 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.28 (s, 3H), 2.84-2.88 (d, 1H), 3.75 (s, 3H), 3.81-3.86 (d, 1H), 4.59-4.63 (d, 1H), 4.69-4.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33 (d, 4H), 9.24 (s, 1H), 10.88 (s, 1H). Example 42 10 5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid hydroxyamide 5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester 15 was prepared according to general method as outlined in example 9. Starting from ethyl c-(p-tolylsulfonyl)acetate (2.9g, 10.9 mmol and 4-bromo-2-methyl butene (3.42g, 23 mmol). Yield 4.6g ; tan oil; MS 379.2 (M+H)*. 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid was 20 prepared according to general method as outlined in example 9. Starting from 5-methyl 2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester (4.5g, 11 mmol), ethanol (15 mL) and 10 N sodium hydroxide. Starting from 5-methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic 25 acid (4.1 g, 11 mmol) and following the procedure as outlined in example 1, 1.07 g of 5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl)-hex-4-enoic acid hydroxy amide was isolated as colorless solid; Yield: 30%; mp 108-110 oC; MS: 366.2 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 : 81.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 (s, 30 1H), 10.80 (s, 1H). Example 43 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid hydroxamide 35 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid ethyl ester (Prepared from 3-mercapto-2-methylfuran) was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-ylsulfanyl)-propionic acid WO 99/42436 PCT/US98/17633 - 55 ethyl ester (2.9g, 11.9 mmol), benzyl bromide (2.22g, 13 mmol) and potassium carbonate (10g) 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 5 according to the general method as outlined in example 9. Starting from 2-(2-methyl furan-3-ylsulfanyl)-propionic acid ethyl ester (4.8g, 14.3 mmol), dissolved in ethanol (25 mL and 10 N sodium hydroxide (10 mL). Yield 3.7g (84 %),, white solid, MS 307.4 (M-H). 10 Starting from 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid (3.58 g, 12 mmol) and following the procedure as outlined in example 1, 1.078 g of 2-Methyl 2-(2-methyl-furan-3-sulfonyl)-3-phenyl-propionic acid hydroxyamide was isolated as orange color solid; Yield: 29%; mp 68-70 oC; MS: 324 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.27(s, 3H), 2.81-2.86 (d, 1H), 3.33 (s, 3H), 3.61-3.66 (d, 1H), 6.66 15 (s, 1H), 7.19-7.25 (m, 5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H) Example 44 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin- 1 -yl-ethoxy)-phenyl] 20 propionic acid hydroxamide 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl] propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester 25 (2.4g, 9.8 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96g, 10.7 mmol); Yield 2.4g (92%); amber oil; MS 464.2 (M+H) . 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin- 1-yl-ethoxy)-phenyl] propionic acid was prepared according to the general method as outlined in example 1. 30 Starting from 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy) phenyl]-propionic acid ethyl ester (2.01g, 4.5 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (10 mL). The resulting mixture was worked up as outline in example 9. Yield 2.03g; amber crystals mp 66-68 oC; MS 434 (M-H). 35 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 procedure as outlined in example 1, 1.36 g of 2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl ethoxy)-phenyl]-propionic acid hydroxyamide was isolated as amber color solid; Yield: WO 99/42436 PCT/US98/17633 - 56 32%; mp 115-117 oC; MS: 451.1 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.15 1.22 (m, 2H), (1.75 (s, 3H), 1.78 (s, 3H) 2.98-3.03 (m, 2H), 3.42-3.47 (m, 2H), 3.5 (s, 3H), 6.65 (s, 1H), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H), 10.35 (s, 1H), 10.60 (s, 1H), 11.70 (s, 1H). 5 Example 45 2-Methyl-3-[4-(2-piperidin- 1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide 10 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared acording to the general method as outlined in example 9. Starting from 2-(thiophene-2-sulfonyl)-propionic acid ethyl ester( prepared from 2 mercaptothiophene and 2-bromopropionic acid ethylester) (4.4g, 17.7 mmol) and 1-[2 15 (4-chloromethylphenoxy)-ethyl]-piperidine (5.3g, 19.5 mmol); Yield (96%); semi solid; MS 466. 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared acording to the general method as outlined in example 9. Starting 20 from 2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-sulfonyl)-propionic acid ethyl ester (9.8g, 20 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (20 mL). The resulting mixture was worked up as outline in example 1. Yield 4.5g (49 %); white solid mp 170-172 oC; MS 436.3 (M-H). 25 Starting from 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2 sulfonyl)-propionic acid (3.6 g, 8.0 mmol) and following the procedure as outlined in example 1, 345 mg of 2-Methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl-2-(thiophene-2 sulfonyl)-propionic acid hydroxyamide was isolated as light colorless solid; Yield: 10%; mp 115-118 oC; MS: 451.2 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 81.29 (s, 30 3H), 1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47 (m, 2H), 3.51-3.59 (d, 1H), 4.32 (m, 2H),6.72-6.74 (d 1H), 6.87-6.96 (d, 2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84 (m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H) 10.0 (s, 1H), 10.78 (s, 1H).

WO 99/42436 PCT/US98/17633 - 57 Example 46 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]propionic acid hydroxamide 5 2-(Octane- 1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)-propionic acid ethyl ester (5.0g, 18 mmol) and 1-[2-(4-chloro methylphenoxy)-ethyl]-piperidine (5.6g, 19.7 mmol); Yield 8.9g (96%); amber oil, MS 495. 10 2-(Octane- 1 -sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2 (octane- 1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester (8.9g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide (25 mL). Yield 6.0g 15 (72 %). Starting from 2-(Octane- 1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid (3.6 g, 7.7 mmol) and following the procedure as outlined in example 1, 3.3 g of 2-(Octane- 1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid hydroxy 20 amide was isolated as tan solid; Yield: 89%; mp 69-70 oC; MS: 483.2 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 .687 (t, 3H), 1.27-1.69 (m, 15H), 2.71-2.75 (d, 1H), 3.51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89 (d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10.70 (s, 1H). 25 Example 47 3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2 sulfonyl)-propionic acid hydroxyamide 30 3-Biphenyl-4-yl-2-methyl-2-(1-methyl- 1H-imidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-(1-methyl-1H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0g, 12.2 mmol) and 4-chloromethylbiphenyl (2.97g, 15 mmol). Yield 5.0g (99 %); low melting 35 solid; MS 413 (M+H) + . 3-Biphenyl-4-yl-2-methyl-2-( 1-methyl- 1H-imidazole-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 3 biphenyl-4-yl-2-methyl2-(1-methyl-1 H-imidazole-2-sulfonyl)-propionic acid ethyl ester WO 99/42436 PCT/US98/17633 - 58 (5.0g, 11.9 mmol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2.8g (61 %); brown solid mp 119-122 oC; MS 385.2 (M+H). Starting from 3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl) 5 propionic acid (2.8 g, 7.0 mmol) and following the procedure as outlined in example 1, 112 mg of 3-Biphenyl-4-yl-2-methyl-2-(1-methyl-1H-imidazole-2-sulfonyl)-propionic acid hydroxyamide was isolated as tan colored solid; Yield: 4%; mp 112 oC; MS: 399.0 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 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 10 7.58 (d, 2H). Example 48 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide 15 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2 sulfonyl)-propionic acid ethyl ester (3.0g, 12 mmol) and benzyl bromide (2.48g, 15 mmol). Yield 5.2 g ( %); tan oil; MS 339.1 (M+H). 20 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-methyl-3-phenyl-2 (thiophen-2-sulfonyl)-propionic acid ethyl ester (5.0 g, 15 mmol), ethanol (30 mL) and 10 N sodium hydroxide (10 mL). Yield 5.6g MS 310.0 (M+H). 25 Starting from 2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid (5.0 g, 16 mmol) and following the procedure as outlined in example 1, 1.8 g of 2-Methyl-3 phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxyamide was isolated as colorless solid; Yield: 40%; mp 116-117 oC; MS: 325.9 (M+H)+; 'H NMR (300 MHz, DMSO 30 d 6 ): 8 1.29 (s, 3H), 3.33 (d, 1H), 3.69 (d 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H). Example 49 35 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 as outlined in example 9. Starting from 2-[8- WO 99/42436 PCT/US98/17633 - 59 (1-ethoxycarbonyl-ethylsulfanyl)-octylsulfanyl]-propionic acid ethyl ester (10.2g, 26 mmol) and sodium peroxymonopersulfate (64g, 104 mmol). Yield 9.87g (86%); colorless liquid; MS 442.9 (M+H). 5 2-[8-(1-Carboxy-ethanesulfonyl)-octane-1-sulfonyl]-propionic acid was prepared according to general method as outline in example 1. Starting from 2-[8-(1-carboxy ethanesulfonyl)-octane- 1 -sulfonyl]-propionic acid ethyl ester (3.0g, 6.8 mmol), ethanol (15 mL) and 10 N sodium hydroxide (15 mL). Yield 2.7g (98 %); white solid mp 99 102 oC; MS 387 (M+NH3)*. 10 Starting from 2-[8-( 1-Carboxy-ethanesulfonyl)-octane- 1-sulfonyl]-propionic acid (2.5 g, 6.5 mmol) and following the procedure as outlined in example 1, 641 mg of 2-[8-(1 Carboxy-ethanesulfonyl)-octane- 1 -sulfonyl]-propionic acid hydroxyamidewas isolated as amber coloured oil.; Yield: 23%; MS: 434.0 (M+NH4)+; 1 H NMR (300 MHz, 15 DMSO-d 6 ): 8 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-piperidine- 1-yl-ethoxy)-phenyl] 20 propionic acid hydroxamide 2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine- 1 -yl-ethoxy)-phenyl] propionic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl u-(4-bromophenyl-sulfonyl) acetate (5.0g, 16 mmol) 25 and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97g, 16 mmol). Yield 6.1g (71 %); tan oil; MS 541.1 (M+H)*. 2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine- 1-yl-ethoxy)-phenyl] propionic acid was prepared according to general method as outlined in example 9. 30 Starting from2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy) phenyl]-propionic acid ethyl ester (6.5g, 20 mmol), ethanol (30 mL) and 10 N sodium hydroxide (15 mL). Yield 6.3g (100 %); yellow solid mp 125-127 'C; MS 512.5 (M+H)*. 35 Starting from 2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl-ethoxy) phenyl]-propionic acid (6.1 g, 612 mmol) and following the procedure as outlined in example 1, 1.07 g of 2-(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine-1-yl- WO 99/42436 PCT/US98/17633 - 60 ethoxy)-phenyl]-propionic acid hydroxyamide was isolated as light yellow solid; Yield: 17%; MS: 525.4 (M+H) + . Example 51 5 3-(4-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl propionamide Following the procedure as outlined in Example 9, 3-(4-bromo-phenyl)-2-(4-methoxy 10 benzensulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (3.0 g, 11 mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4-bromo benzyl bromide (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-methyl-propionic acid was 15 prepared starting from 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid ethyl ester (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 outlined in Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H) +. 20 Starting from 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (2.7 g, 6.5 mmol) and following the procedure as outlined in example 1, 2.26 g of 3-(4-bromophenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-propion amide was isolated as light colorless solid; Yield: 81%; mp 86-88 oC; MS: 429.8 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.42 (s,3H), 1.77 (bs, 1H), 3.26 (d, J=7.0 25 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 30 N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-naphthalen-2-yl-propionic acid ethyl ester was prepared, starting from (5.4 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 2-bromo 35 methyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; Colorless crystals, mp 182 184 oC; MS: 413 (M+H)

+.

WO 99/42436 PCT/US98/17633 -61 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester (4.6 g, 11 mmol) 4.2g (98%) of 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-naphthalen-2-yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp144-146 oC; MS: 384.9 (M+H) +. 5 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid (2.4 g, 6.2 mmol) and following the procedure as outlined in Example 1, 1.6 g of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionamide was isolated as a light colorless solid; Yield: 64%; mp 185 -187 'C; MS: 400.2 10 (M+H)+; 1H NMR (300 MHz, CDC1 3 ): 8 1.56 (s,3H), 3.28 (d, J= 8.0 Hz, 1H), 3.81 (d, J=8Hz,1H), 3.93 (s,3H), 4.88 (bs, 1H), 7.02 - 7.92 (m, 11H). Example 53 15 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 as outlined in Example 1. Starting from ethyl 2-bromo 3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 20 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was isolated. 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 procedure as outlined in Example 9 for oxidation, 3 g of 25 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester was isolated as a colorless solid, yield: 99%; mp 53 oC; MS: 273 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester (3 g, 10 mmol) 2.7 g (96%) of 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid was 30 isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 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 procedure as outlined in Example 9, 590 mg of N-hydroxy-2 35 (4-methoxy-benzenesulfonyl)-3-methyl-butyramide was isolated as a colorless solid. Mp 220 oC; Yield 28%; MS: 288 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.88 (d, WO 99/42436 PCT/US98/17633 - 62 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 5 1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid hydroxyamide Following the procedure as outlined in Example 9, 1-(4-methoxy-benzenesulfonyl) cyclopentanecarboxylic acid ethyl ester was prepared, starting from (3.0 g, 11.6 mmol) 10 of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1,4-dibromobutane ( 2.4 g, 7.6 mmol). Yield 2.4 g, 78%; Colorless solid, mp 86-88 oC; MS: 313 (M+H)+. 1-(4-Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid was prepared starting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid ethyl ester (2.2 g, 15 7.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.66 g, 83%. Colorless solid; mp 112-115 oC; MS: 285 (M+H)+. Starting from 1-(4-methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid (442 mg, 20 1.5 mmol) and following the procedure as outlined in Example 1, 410 mg of 1-(4 methoxy-benzenesulfonyl)cyclopentanecarboxylic acid hydroxyamide was isolated as a colorless solid. mp 89-91 oC; Yield 88%; MS: 300 (M+H)+;IH NMR (300 MHz, CDCl 3 ): 8 1.65-1.82 (m, 4H), 2.17-2.42 (m, 4H), 3.87 (s, 3H), 7.0 (d, J= 8Hz, 2H11), 7.7 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.73 (bs, 1H). 25 Example 55 3-(2-Bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl propionamide 30 Following the procedure as outlined in Example 9, 3-(2-bromo-phenyl)-2-(4 methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.0 g, 7.3 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 2-(bromo)benzyl bromide (2.0 g, 8 mmol). Yield 3.1 g, 87%; Colorless oil; MS: 35 441 (M+H)+. 3-(2-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was prepared starting from 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl- WO 99/42436 PCT/US98/17633 - 63 propionic acid ethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 (M+H) +. 5 Starting from 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (470 mg, 1.1 mmol) and following the procedure as outlined in Example 9, 380 mg of 3-(2-bromo-phenyl)-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl propionamide was isolated as a colorless solid. mp 93-96 oC; Yield 77%; MS: 429 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.3 (s, 3H), 3.32 (d, J=7.0 Hz, 1H), 3.69 10 (d, J= 7.0 Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (min, 8H). Example 56 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide 15 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-2 methyl-5-phenyl-pent-4-enoic acid ethyl ester was prepared, starting from (3.0 g, 11 mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and cinnamyl bromide (2.1 g, 11 mmol). Yield 3.51 g, 82%; Colorless oil; MS: 389 (M+H)+. 20 2-(4-Methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic 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 outlined in Example 9. Yield 1.9 g, 25 68%; yellowish oil; MS: 361 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid (440 mg, 1.2 mmol) and following the procedure as outlined in Example 1,420 mg of 2-(4-methoxy-benzenesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid hydroxyamide 30 was isolated as a colorless solid. mp 162-164 oC; Yield 92%; MS: 376 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.41 (s, 3H), 3.0-3.16 (min, 1H), 3.30 (d, J= 11 Hz, 2H), 3.92 (s, 3H), 5.9 - 6.1 (min, 1H), 6.53 (d, J=llHz, 1H), 7.1-7.72 (min, 9H), 9.12 (bs,1H).

WO 99/42436 PCT/US98/17633 - 64 Example 57 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid hydroxyamide 5 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5 phenyl-2-(3-phenyl-propyl)-pentanoic acid ethyl ester was prepared, starting from (4.0 g, 15.8 mmol) 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 3-bromo propyl benzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; Colorless oil; MS: 495 (M+H) +. 10 2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid was prepared starting from 2 -(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl) pentanoic acid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 15 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H-H 2 0)

+

. Starting from 2

-(

4 -methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid (600 mg, 1.2 mmol) and following the procedure as outlined in Example 1,420 mg of 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid 20 hydroxyamide was isolated as a colorless solid. Mp 118-120 oC; yield 68%; MS: 482 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.52 - 1.68 (m, 2H), 1.74 - 1.92 (m, 2H), 1.98-2.20 (m, 4H), 2.58 - 2.72 (m,4H), 3.86 (s, 3H), 6.93 (d, J= 11 Hz, 2H), 7.02 7.63 (m, 10H), 7.81 (d, J=11 Hz, 2H). 25 Example 58 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide Following the procedure as outlined in Example 9, 2-allyl-2-(4-methoxy-benzene 30 sulfonyl)-pent-4-enoic acid ethyl ester was prepared, starting from (3.0 g, 11.6 mmol) 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester 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-enoic acid was prepared starting from 35 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic 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 outlined in Example 9. Yield 1.76 g, 87%; yellowish oil; MS: 311

(M+H)

+ .

WO 99/42436 PCT/US98/17633 - 65 Starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid (1.5 g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-allyl-2-(4 methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide was isolated as colorless 5 solid. Mp 114-116 'C; Yield 99%; MS: 326 (M+H)+; IH NMR (300 MHz, CDCl 3 ): 5 1.62 (s, 1H), 2.70 - 2.80 (m,4H), 3.9 (s, 3H), 5.16 -5.27 (min, 4H), 5.81-5.94 (inm, 2H), 7.12 (d,J=8 Hz,2H). Example 59 10 2-(4-methoxy-benzenesulfonyl)-2-propyl-pentanoic acid hydroxyamide 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% 15 Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 0.92 (t, J = 4.0 Hz, 6H), 1.27-1.59 (min, 4H), 1.78-2.02 (min, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d,J=9 Hz, 2H). 20 Example 60 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide 25 Following the procedure as outlined in Example 9, 2-benzyl-2-(4-methoxy-benzene sulfonyl)-3-phenyl-propionic acid ethyl ester was prepared, starting from (1.0 g, 3.8 mmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and benzylbromide (4 ml, excess). Yield 1.2 g, 72%; Yellow oil; MS: 439 (M+H) + . 30 2-Benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid was prepared starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic 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 outlined in Example 9. Yield: 580 mg, 62%; Waxy solid; MS: 409 (M-H)-. 35 Starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (410 mg, 1 mmol) and following the procedure as outlined in Example 1, 225 mg of 2 benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide was WO 99/42436 PCT/US98/17633 - 66 isolated as a waxy solid. Yield 52%; MS: 426 (M+H)+; 1H NMR (300 MHz, CDCl 3 ): 8 3.25 (d, J=14 Hz, 2H), 3.52 (d, J= 14 Hz, 2H), 3.9 (s, 3H), 6.93 (d, J=8Hz, 2H), 7.02 - 7.26 (min, 9H), 7.61 (d, J=8Hz, 2H), 7.87 (d, J=4Hz, 1H), 9.58 (bs, 1H). 5 Example 61 N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide To a stirred solution of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester (2.7 10 gm, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 mmol). and triethyl benzyl ammonium chloride (1 g) in methylene chloride (400 ml), 10 N NaOH ( 30 ml) was added. The reaction was continued at room temp for 48 hours. At the end, the organic layer was separated and washed well with water. The organic layer was dried, filtered and concentrated. The crude product obtained was purified by silica-gel column 15 chromatography. The column was eluted with 50% ethyl acetate: hexane. 2-(4 Methoxy-benzensulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid ethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS: 364 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid 20 ethyl ester (2.5 g, 6.8 mmol) 1.8 g (79%) of 2-(4-methoxy-benzenesulfonyl)-2-methyl 3-pyridin-3-yl-propionic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 58 oC; MS: 336 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid 25 (410 mg, 1 mmol) and following the procedure as outlined in Example 1, 225 mg of N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionamide was isolated as a colorless solid. Yield 52%; mp 98 oC; MS: 351 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 5 1.4 (s, 3H), 3.1 (d, J=9.0, 1H), 3.65 (d, J= 9.1, 1H), 3.9 (s, 3H), 7-8.5 (min, 8H). 30 Example 62 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid hydroxyamide 35 Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.5 g, 29 mmol) and 1-bromooctane (6.7 g, 35 mmol) 8 g of the mono octylated compound 2-(4- WO 99/42436 PCT/US98/17633 - 67 methoxy-benzenesulfonyl)-decanoic acid ethyl ester was isolated by following the procedure outlined in Example 9. Yield: 8.0 g 74%; MS: 370 (M+H) +. Following the procedure as outlined in example 29, 2-(4-methoxy-benzenesulfonyl) 5 2-pyridin-3-ylmethyl-decanoic acid ethyl ester was prepared, starting from (8.0 g, 21.6 mmol) of 2-(4-methoxy-benzenesulfonyl)-decanoic acid ethyl ester and 3-picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 6.5 g, 68%; Brown oil; MS: 462

(M+H)

+. 10 Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid ethyl ester (5.0 g, 11 mmol), 4.5g (91%) of 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3 ylmethyl-decanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 159 oC; MS: 434 (M+H) +. 15 Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid (2.5 g, 5.7 mmol) and following the procedure as outlined in Example 1, 1.4 g of 2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid hydroxyamide was isolated as colorless solid. Yield: 50%; mp 62 oC; MS: 448 (M+H)+; 1 H NMR (300 MHz, CDC1 3 ): 8 0.86 (t, 6.9 Hz, 3H), 1.25-2.17 (m, 14 H), 3.3 (d, J=14 Hz, 1H), 20 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-enoic acid 25 hydroxyamide Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5 methyl-hex-4-enoic acid ethyl ester was prepared, starting from (6.0 g, 23 mmol) 2-(4 methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenyl bromide (3.0 g, 20 30 mmol). Yield 6.52 g, 86%; Colorless oil; MS: 327 (M+H)+. Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)-5 methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid ethyl ester was prepared, starting from (4.0 g, 12.2 mmol) of 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4-enoic acid ethyl 35 ester and 3-picolylchloride hydrochloride (2.1 g, 13 mmol). Yield 4.14 g, 81%; Brown oil; MS: 418 (M+H)+.

WO 99/42436 PCT/US98/17633 - 68 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl hex-4-enoic acid ethyl ester (4.0 g, 9.5 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 5 9. Yield 3.2 g, 87%; ivory solid; mp 117-119 'C; MS: 390 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4 enoic acid (2.1 g, 5.4 mmol) and following the procedure as outlined in Example 1, 1.82 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hex-4-enoic 10 acid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp 89 - 92 'C; MS: 405 (M+H)+; 1 H NMR (300 MHz, CDCl 3 ): 8 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (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). 15 Example 64 2-Benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyramide Following the procedure as outlined in Example 29, 2-benzyl-4-diisopropylamino-2-(4 20 methoxy-benzenesulfonyl)-butyric acid ethyl ester was prepared, starting from (3.0 g, 8.5 mmol) of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 mmol). Yield 3.2 g, 79%; Ivory solid, mp 89-91 oC; MS: 476.4 (M+H)+. 25 Starting from 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid ethyl ester (3.53 gm, 7.5 mmol) 2.8 g (86%) of 2-benzyl-4-diisopropylamino-2 (4-methoxy-benzenesulfonyl)-butyric acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 136-138 oC; MS: 448.5 (M+H)+. 30 Starting from 2-benzyl-4-diisopropylamino-2-(4-methoxy-benzenesulfonyl)-butyric acid (1.85 g, 4.1 mmol) and following the procedure as outlined in Example 1, 1.3 g of 2-benzyl-4-diisopropylamino-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-butyramide was isolated as a low melting waxy solid; Yield: 68%; MS: 463.3 (M+H)+; 1H NMR 35 (300 MHz, CDC1 3 ): 8 0.98 (d, J = 11 Hz, 6H), 1.16 (d, J=ll 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).

WO 99/42436 PCT/US98/17633 - 69 Example 65 3-Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl propionamrnide 5 Following the procedure as outlined in Example 9, 3-cyclohexyl-2-(4-methoxy benzenesulfonyl)-propionic acid ethyl ester was prepared, starting from (4.0 g, 15 mmol) 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromomethyl cyclohexane (2.7 g, 15 mmol). Yield 5.0 g, 94%; Colorless oil; MS: 355 (M+H)+. 10 Following the procedure as outlined in Example 29, 3-cyclohexyl-2-(4-methoxy benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid ethyl ester was prepared, starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester(1.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g, 15 38%; Colorless oil; MS 446 (M+H)+. Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl propionic acid ethyl ester (1.3 g, 2.9 mmol) 1.0g (83%) of 3-cyclohexyl-2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid was isolated as 20 colorless crystals by following the procedure as outlined in Example 9. Mp 92 oC; 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 procedure as outlined in Example 25 1, 80 mg of 3-cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2-pyridin-3 ylmethyl-propionamide was isolated as a colorless hydrochloride salt; Yield: 71%; mp 57-60 oC; MS: 433 (M+H)+; 1 H NMR (300 MHz, CDC1 3 ): 8 0.8-2.08 (m, 13 H), 3.3 (d, J=14 Hz, 1H), 3.7 (d, J= 14 Hz, 1H), 3.9 (s, 3H), 7.0 - 8.5 (m, 8H). 30 Example 66 2-(4-Methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3 ylmethyl-pentanoic acid hydroxyamide 35 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-4 methyl-pentanoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) 2-(4 methoxy-benzenesulfonyl)-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)+.

WO 99/42436 PCT/US98/17633 - 70 Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl) 4-methyl-2-pyridin-3-ylmethyl-penanoic acid ethyl ester was prepared, starting from (3.1 g, 10 mmol) of 2-[(4-methoxy-benzenesulfonyl)-4-methyl pentanoic acid ethyl 5 ester 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)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid ethyl ester (1.2 g, 2.9 mmol) 1.0g (91%) of 2-(4-methoxy-benzenesulfonyl)-4 10 methyl-2-pyridin-3-ylmethyl-pentanoic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 188-186 oC; MS: 378 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid (800 mg, 2.1 mmol) and following the procedure as outlined in Example 1, 180 15 mg of 2-(4-methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3-ylmethyl-pentanoic acid hydroxyamide was isolated as a colorless solid; Yield: 21%; mp 78 oC; MS: 393.4 (M+H)+; IH NMR (300 MHz, CDCl 3 ): 6 0.65 (d, 6.3 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8 -8.5 (m, O10H). 20 Example 67 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamiide Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)-2 25 methyl-3-quinolin-6-yl-propionic acid ethyl ester was prepared, starting from (5.2 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and 7 bromomethyl quinoline (4.4 g, 20 mmol). Yield 4.5 g, 54%; Pale yellow solid; mp 86 0 C; MS: 414 (M+H)+. 30 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid ethyl ester ( 3.0 gm, 7.2 mmol) 2.5g (90%) of 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-quinolin-6-yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp 106-108 oC; MS: 386.4 (M+H) +. 35 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionic acid (2.0 gm, 5.2 mmol) and following the procedure as outlined in Example 1, 1.2 g of N hydroxy-2-(methoxy-benzenesulfonyl)-2-methyl-3-quinolin-6-yl-propionamide was isolated as a colorless solid; Yield: 57%; mp 206 'C; MS: 401.4 (M+H)*; 'H NMR WO 99/42436 PCT/US98/17633 -71 (300 MHz, CDCl 3 ): 5 1.4 (s, 3H), 3.19 (m, 1H), 3.8 -4.0 (m, 4H), 7.1 -8.95 (m, 12H). Example 68 5 2-(4-Methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-6 10 phenoxy-hexanoic acid ethyl ester was prepared, starting from (2.5 g, 10 mmol) 2-(4 methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromo-4-phenoxy butane ( 2.2, 10 mmol). Yield 3.8 g, 93%; Colorless oil; MS: 407 (M+H) +. Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-6 15 phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from (3.1 g, 10 mmol) 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester and 3-picolyl chloride (1.8 g, 11 mmol). Yield 3.5 g, 71%; Colorless oil; MS: 498

(M+H)

+. 20 Starting from 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl hexanoic acid ethyl ester (3.0 g, 6.0 mmol), 2.8g (Yield: Quantitative) of 2-(4 methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 148 151°C; MS: 470.5 (M+H) +. 25 Starting from 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl hexanoic acid (2.0 g, 4.3 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was isolated as a colorless solid; Yield: 72%; mp 68 oC; MS: 485.5 30 (M+H)+; 1 H NMR (300 MHz, CDC1 3 ): 8 1.5 - 2.5 (m, 8H), 3.4 (bs, 2H), 3.8 (s, 3H), 6.8 - 8.7 (m, 13H).

WO 99/42436 PCT/US98/17633 - 72 Example 69 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide 5 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5 hexanoic acid ethyl ester was prepared, starting from (10.0 g, 39 mmol) 2-(4-methoxy benzenesulfonyl)-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)+. 10 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5 methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from (6.0 g, 18 mmol) of 2-(4-methoxy-benzenesulfonyl)-5-methyl-hexanoic acid ethyl ester and picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; Brown oil; MS: 15 420 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester (3.0 g, 7.1 mmol) 2.6g (92%) of 2-(4-methoxy-benzenesulfonyl)-5 methyl-2-pyridin-3-ylmethyl-hexanoic acid was isolated as a colorless solid by 20 following the procedure as outlined in Example 9. Mp: 173 C; MS: 392 (M+H)+. Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid (1.0 g, 2.5 mmol) and following the procedure as outlined in Example 1, 800 mg of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethyl-hexanoic acid 25 hydroxyamide was isolated as a colorless solid; The hydrochloride was prepared by passing hydrogen chloride gas through methanol solution of the hydroxyamide. Yield: 72%; mp 62 oC (HCl salt); MS: 408 (M+H) ; IH NMR (300 MHz, CDC1 3 ): 8 0.76 (m, 6H), 1.2 -2.0 (m, 5H), 3.5 (bq, 2H), 7.1 - 8.8 (m, 8H), 11.1 (bs,lH). 30 Example 70 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide (4-Methoxy-phenylsulfanyl) -acetic acid tert-butyl ester was prepared according to the 35 general method as outlined in Example 1. Starting from the corresponding 1-bromo tert-butyl acetate (5.3 g, 27 mmol) and 4-methoxybenzenethiol (3.7 g, 27 mmol), 6.4 g of the product was isolated. Yield 98%; Light yellow oil; MS: 255 (M+H)+.

WO 99/42436 PCT/US98/17633 - 73 2-(4-Methoxy-benzenesulfonyl)-acetic acid tert-butyl ester was prepared according to the general method as outlined in Example 9. Starting from 2-(4-methoxy-benzene sulfanyl)-acetic acid tert-butyl ester (5.0 g, 20 mmol) and 3-chloroperoxybenzoic acid 57% (12.0g, 40 mmol), 5.3 g of the product was isolated. Yield 92%; Waxy solid; 5 MS: 287.1 (M+H) +. 2-(4-Methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4 methoxy-benzenesulfonyl)acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and 3-picolyl 10 chloride (7.28 g, 44.4 mmol), 10.5 g of the product was isolated by silica gel chromatography (50% ethyl acetate: hexane). Yield 63%; white solid; mp 93-94 'C; MS: 378.0 (M+H) +. 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester 15 was prepared according to the procedure as outlined in Example 9. Starting from 2-(4 methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester (2.0 g, 5.3 mmol) and n-butyl bromide (0.73 g, 5.3 mmol), 1.20 g of the product isolated. Yield 52%; yellowish gum; MS: 434.3 (M+H)+. 20 A mixture of the 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester (1.1 g, 2.5 mmol), in methylene chloride/ TFA (1:1 )was stirred at room temperature for about 2 hours. The solvents were then evaporated and the 2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid was purified by silica gel chromatography (30% methanol/methylene chloride). Yield 0.90 g, 94%; white 25 solid; mp 70 'C; MS: 376.1 (M-H)-. 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid (0.31 g, 0.81 mmol) 30 and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.13 g of the product isolated. Yield 37%; pale yellowish solid; mp 65 oC; MS: 392.9 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 0.80 (t, J = 7.2 Hz, 3H), 1.10-1.25 (min, 2H), 1.25-1.50 (min, 2H), 1.70 2.00 (min, 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 (min, 1H), 8.40-8.45 35 (min, 1H), 8.70-8.85 (min, 2H), 11.0 (brs, 1H); IR (KBr, cm- 1 ): 3064m, 2958s, 2871m, 1671m.

WO 99/42436 PCT/US98/17633 - 74 Example 71 2-(4-methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide. 5 The title compound was prepared according to the procedure as outlined in example 9. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-octyne (3.80 g, 20 mmol), 4.4 g of the product isolated. Yield 100%; yellowish gum; MS: 446.9 (M+H) +. 10 2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid was prepared according to the method as outlined in example 70. Starting from 2-(4-methoxy-benzenesulfonyl) 2-oct-2-ynyl-dec-4-ynoic acid tert-butyl ester (4.40 g, 10.0 mmol), 2.0 g of the product isolated. Yield 49%; white solid; mp 61oC; MS: 345.1 (M-H)-. 15 2-(4-Methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4 methoxy-benzenesulfonyl)-2-oct-2-ynyl-dec-4-ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g of the product isolated. Yield 20 62%; white solid; mp 83-84 'C; 462.0 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 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 (brd, 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; 25 Anal. Calc'd for C 25

H

35 NO5S: C, 65.05; H, 7.64; N, 3.03. Found: C, 65.26; H, 7.68; N, 2.90. Example 72 30 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4 methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo 35 2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87 oC; MS: 391.0 (M+H)+.

WO 99/42436 PCT/US98/17633 -75 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was prepared according to the procedure as outlined in example 70. Starting from 2-(4-methoxy-benzene sulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester (3.0 g, 7.7 mmol), 2.5 g of the product isolated. Yield 97%; white solid; mp 141-143 'C; MS: 333.1 (M-H)-. 5 2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4 methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. 10 Yield 89%; white solid; mp 135-137oC; MS: 349.9 (M+H)+1; 1 H NMR (300 MHz, DMSO-d 6 ) 8 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-1): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m. 15 Example 73 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester was 20 prepared according to the procedure as outlined in Example 9. Starting from 2-(4 methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 mmol), 1.90 g of the product was isolated. Yield 75%; white solid; mp 113-115 0 C; MS: 362.1 (M+H) +. 25 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-methoxy benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester (1.70 g, 4.7 mmol), 1.30 g of the product isolated. Yield 90%; white solid; mp 156oC; MS: 305.1 (M-H)-. 30 2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4-methoxy benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156oC; MS: 321.9 (M+H)+; IH NMR (300 MHz, DMSO 35 d 6 ) 8 2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J = 9.0 Hz, 2H), WO 99/42436 PCT/US98/17633 - 76 7.82 (d, J = 9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm-1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C 1 5

H

15

N

5 OsS: C, 56.07; H, 4.70; N, 4.36. Found: C, 55.65; H, 4.67; N, 4.10. 5 Example 74 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide 10 The title compound was prepared according to the procedure as outlined in Example 38. Starting from 2-(4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester (2.20 g, 5.8 mmol) and 1-bromo-2-octyne (1.14 g, 6 mmol), 2.60 gm of the product isolated. Yield 92%; yellowish gum; MS: 486.0 (M+H)+. 15 A mixture of the 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid tert-butyl ester (2.60 g, 5.35 mmol), in methylene chloride/TFA (1:1) is stirred at room temperature for about 2 hours. (Ref. example 70) The solvents are then evaporated and the 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid was purified by silica gel chromatography (-30% methanol/methylene chloride). 20 Yield: 2.0 g, 87%; White solid; mp 146 0 C; MS: 428.1 (M-H)-. 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the procedure outlined in Example 1. Starting from 2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.71 g, 1.62 25 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp 65 0 C; MS: 445.0 (M+H)

+

; 'H NMR (300 MHz, DMSO-d 6 ) 8 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 30 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; Anal. Calc'd for C 23

H

28

N

2

O

5 S-HCl-0.9H 2 0: C, 55.56; H, 6.24; N, 5.63. Found: C, 55.84; H, 6.19; N, 5.59.

WO 99/42436 PCT/US98/17633 - 77 Example 75 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide 5 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 38. Starting from 2 (4-methoxy-benzenesulfonyl)-pyridin-3-ylpropionic acid tert-butyl ester (3.77 g, 10 mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of the product was isolated. Yield 60%; yellowish solid; mp 132-133oC; MS: 416.0 (M+H)+. 10 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-methoxy benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester (2. 0 g, 4.8 mmol), 1.2 g of the product isolated. Yield 69%; white solid; mp 119-121 0 C; MS: 15 358.1 (M-H)-. 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamnide was prepared according to the method as outlined in Example 1. Starting from 2-(4 methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 20 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70 0 C; MS: 375.0 (M+H)+; 1H NMR (300 MHz, DMSO-d 6 ) 5 1.19 (brs, 1H), 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, 25 1H); IR (KBr, cm-1): 3168m, 3095s, 1670m, 1593s. Example 76 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid hydroxyamide 30 2-(4-Fluoro-benzenesulfanyl)-acetic acid tert-butyl ester was prepared according to the procedure as outlined in Example 1. Starting from 4-fluorothiophenol (30.0 g, 230 mmol) and tert-butyl bromoacetate (45.67 g, 230 mmol), 53.4 g of the product was isolated. Yield 100%; pale yellowish oil; MS: 243.1 (M+H)+. 35 2-(4-Fluoro-benzenesulfonyl)-acetic acid tert-butyl ester was prepared according to the general method as outlined in Example 9. Starting from 2-(4-fluoro-benzenesulfanyl)- WO 99/42436 PCT/US98/17633 -78 acetic acid tert-butyl ester (48.4 g, 200 mmol) and 3-chloroperoxybenzoic acid (121.3g (57%), 400 mmol ), 48.0 g of the product was isolated. Yield 88%; pale yellowish oil; MS: 275.1 (M+H) +. 5 The title compound was prepared according to the procedure as outlined in Example 70. Starting from 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-butyne (0.67 g, 5.0 mmol), 2.18 g of the product was isolated. Yield 100%; yellowish gum; MS: 419.2 (M+H) +. 10 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid was prepared according to the method as outlined in Example 38. Starting from 2-(4-fluoro benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid tert-butyl ester (2.1 g, 5.0 mmol), 1.20 g of the product was isolated. Yield 67%; off-white solid; mp 150 0 C; MS: 360.2 (M-H)-. 15 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl- hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4 fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride ( 0.70 g, 10 mmol), 0.15 g of the product was 20 isolated. Yield 45%; white solid; mp 190 0 C; MS: 377.2 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ) 8 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; 25 Anal. Calc'd for C 18

H

17 FN20 4 S-HC1. 0.5H 2 0: C, 51.24; H, 4.54; N, 6.64. Found: C, 51.21; H, 4.35; N, 6.46. Example 77 30 2

-(

4 -Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide The title compound was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-ylpropionic acid tert-butyl ester (1.83 g, 5.0 mmol) and 1-bromo-2-octyne (0.95 g, 5.0 mmol), 1.80 g of the product 35 was isolated. Yield 56%; yellowish gum; MS: 474.3 (M+H)+.

WO 99/42436 PCT/US98/17633 - 79 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid was prepared according to the method as outlined in Example 70. Starting from 2-(4-fluoro-benzene sulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid tert-butyl ester (1.80 g, 3.8 mmol), 1.40 g of the product was isolated. Yield 88%; off-white solid; mp 123-124 0 C; MS: 5 416.3 (M-H)-. 2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4 fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4-ynoic acid (0.67 g, 1.62 mmol) 10 and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.22 g of the product was isolated. Yield 29%; white solid; mp 180-182oC; MS: 433.2 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ) 8 0.84 (t, J = 6.8 Hz, 3H), 1.20-1.40 (min, 6H), 1.90-2.05 (min, 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 (min, 3H), 8.30-8.40 (m, 15 1H), 8.70-8.80 (min, 2H), 11.1 (brs, 1H); IR (KBr, cm-1): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m. Anal. Calc'd for C 2 2H 25 FN20 4 S.HC1: C, 56.34; H, 5.59; N, 5.97. Found: C, 56.18; H, 5.54; N,5.76. 20 Example 78 2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide 2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was 25 prepared according to the procedure as outlined in Example 9. Starting from 2-(4 fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2 butyne (5.36 g, 40 mmol), 6.0 g of the product was isolated. Yield 77%; white solid; mp 85 0 C; MS: 379.1 (M+H)+. 30 2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid was prepared according to the procedure as outlined in Example 70, starting from 2-(4-fluoro-benzenesulfonyl) 2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester (3.50 g, 8.47 mmol), 2.35 g of the product was isolated. Yield 79%; white solid; mp 129-131 C; MS: 642.8 (2M-H)-. 35 2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1.. Starting from 2-(4-fluoro- WO 99/42436 PCT/US98/17633 - 80 benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g of the product was isolated. Yield 77%; white solid; mp 161-163oC; MS:338.1(M+H)+; 1H NMR (300 MHz, DMSO-d 6 ) 8 1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J = 9.0, 9.0 Hz, 2H), 7.87 5 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm-1): 3336s, 3245m, 1681s, 1589m, 1493m; Anal. Calc'd for C 16

H

16

FNO

4 S: C, 56.96; H, 4.78; N, 4.15. Found: C, 56.59; H, 4.75; N, 4.04. 10 Example 79 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid hydroxyamnide 15 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5 methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenyl bromide (6.0 g, 40 mmol). Yield 7.0 g, 88%; Colorless oil; MS: 395

(M+H)

+. 20 Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4 enoic acid ethyl ester (3.5 g, 9 mmol), 3.3g (97%) of 2-(4-methoxy-benzenesulfonyl) 5-methyl-2-(3-methyl-but-2-enyl)-hex-4-enoic acid was isolated as a colorless oil by following the procedure as outlined in Example 9. MS: 365 (M-H)-. 25 Starting from 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4 enoic acid (2.6 g, 7.0 mmol) and following the procedure as outlined in Example 1, 1.36 g of 2-(4-methoxy-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-enyl)-hex-4 enoic acid hydroxyamide was isolated as a colorless solid. Yield: 67%; mp 93 - 96 oC; 30 MS: 383 (M+H)+; 'H NMR (300 MHz, CDCl 3 ): 8 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).

WO 99/42436 PCT/US98/17633 -81 Example 80 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide. 5 2-(4-Methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (13.8 g, 98%) was prepared according to the general method as outlined in example 1 starting from ethyl 2-bromo heptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6g, 42.8 mmol), as a yellow oil; MS: 297.2 (M+H)*. 10 2-(4-Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4 methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g (83%). yellow oil. MS: 267.1 (M-H). 15 Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid (2.49 g, 9.32 mmol) and following the procedure as outlined in example 1, 1.83 g of 2-4-(methoxy-phenyl sulfanyl)-heptanoic acid hydroxyamide was isolated as an off white solid. Mp 90 95oC; Yield 70%; MS: 284.0 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.826 (t, J= 6.9 Hz, 3H), 1.135-1.76 (min, 8H), 3.35 (min, 1H), 3.82 (s, 3H), 6.91-7.49 (min, 4H). 20 Example 81 (49A) 2R*-(4-methoxy-phenyl- S*- sulfinyl)-heptanoic acid hydroxyamide and 25 (49B) 2S*-(4-methoxy-phenyl- R*- sulfinyl)-heptanoic acid hydroxyamide Starting from 2-(4-methoxy-phenylsulfanyl)-heptanoic acid hydroxyamide (1.69 g, 6 mmol) and following the procedure outlined in example 5, the two diastereomers of 2 (4-methoxy-phenylsulfinyl)-heptanoic acid hydroxyamide were separated on a silica gel 30 column using 75% ethyl acetate:hexanes. The less polar isomer, 2R*-(4-methoxy phenyl- S*- sulfinyl)-heptanoic acid hydroxyamide was isolated as a white powder. Yield: 390 mg (22%); mp 115 oC; MS: 300.0 (M+H)+; 'H NMR (300 MHz, DMSO d 6 ): 0.828 (t, J= 6.2 Hz, 3H), 1.18-1.23 (min, 6H), 1.73-1.99 (min, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61 (min, 4H). The more polar isomer, 2S*-(4-methoxy 35 phenyl- R*- sulfinyl)-heptanoic acid hydroxyamide was isolated as a gray solid. Yield: 200 mg (11%); mp 112 oC; MS: 300.0 (M+H) , 'H NMR (300 MHz, DMSO-d 6 ): 8 0.754 (t, J= 6.9 Hz, 3H), 1.014-1.121 (min, 6H), 1.58-1.89 (min, 2H), 3.10-3.15 (inm, 1H), 3.834 (s, 3H), 7.13-7.65 (min, 4H).

WO 99/42436 PCT/US98/17633 - 82 Example 82 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-4-yl-ethoxy)-phenyl] 5 propionic hydroxyamide hydrochloride. Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2 methyl-3-[4-(2-morpholin- 1-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (4.0 g, 15 mmol) of 2-(4-methoxy-benzenesulfonyl)-propionic 10 acid ethyl ester and 4-(morpholin-1-yl-ethoxy)-benzyl chloride hydrochloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil; MS: 492 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gm, 8.1 mmol) 3.2 g (Yield: 84 %) of 15 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin- 1 -yl-ethoxy)-phenyl] propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 171 oC; MS: 464 (M+H) +. Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-morpholin-1-yl 20 ethoxy)-phenyl]-propionic acid (4.0 g, 8.6 mmol) and following the procedure as outlined in example 1, 2.5 g of 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2 morpholin-1-yl-ethoxy)-phenyl]-propionic hydroxyamide was isolated as colorless solid. The hydrochloride salt was prepared by reacting the free base with methanolic hydrogen chloride at 0 C. Yield: 2.5 g, 60%; mp 98oC; MS: 479 (M+H)+; 1 H NMR 25 (300 MHz, CDC1 3 ): 1.36 (s, 3H), 3.8 - 12.6 (min, 16 H), 3.9 (s, 3H), 4.1 - 4.3 (inm, 1H), 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 30 1-Benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic Acid hydroxyamide To a stirred solution of 4-methoxybenzenethiol (2.8 gm, 20 mmol) and anhydrous

K

2

CO

3 (10 gm, excess) in dry acetone (100 ml), ao-bromo ethyl acetate (3.3 gm, 20 35 mmol) was added in a round bottom flask and the reaction mixture was 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 and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H 2 0 and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO4, WO 99/42436 PCT/US98/1 7633 - 83 filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H)+. To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40 mmol) in 5 methylene chloride (100 ml) at 00 C, (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol) in CH 2 C1 2 (15 ml) was added slowly. The reaction mixture turned cloudy and was stirred at room temperature for 6 hours. The reaction mixture was then diluted with hexanes (300 ml) and stirred for 15 minutes. The solids were filtered off and Na 2

SO

3 solution was added to the organic layer which was stirred for at least 3 10 hours before the mixture was extracted with CHCl 3 and washed with H 2 0. The organic layer was dried over MgSO4, 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) + . 15 To a stirred solution of diethanol amine (10.5 g, 100 mmol), and anhydrous K 2 CO3 (30 gm, excess) in dry acetone (250 ml), benzyl bromide (17.2 gm, 100 mmol) was added in a round bottom flask and the reaction mixture was 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 and the reaction mixture was concentrated. The 20 residue was extracted with chloroform and washed with H 2 0 . The organic layer was further washed well with water, dried over MgSO 4 , 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 25 hydrochloric acid and concentrated to dryness. The hydrochloride thus formed was dissolved in methylene chloride (300 ml) and thionyl chloride (20 g, excess) was added dropwise and stirred at room temperature for 1 hr. At the end reaction mixture was concentrated to dryness and the product bis-(2-chloro-ethyl)-benzyl amine hydrochloride was used for further transformation with out any purification. Yield: 30 13.0 g, 97%; Mp: MS: 232 (M+H). To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K 2

CO

3 (30 gm, excess) in dry acetone (250 ml), (4-methoxy-phenylsulfonyl)-acetic acid ethyl ester (6.12 gm, 24 mmol) was 35 added in a round bottom flask and the reaction mixture was heated at reflux for 16 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The WO 99/42436 PCT/US98/17633 - 84 residue was extracted with chloroform and washed with H20. The organic layer was further washed well with water, dried over MgSO 4 , filtered and concentrated. The dark brown reaction mixture was purified by silica gel coumn chromatography by eluting it with 30% ethylacetate: hexane and the product 4-(4-Methoxy-benzenesulfonyl)-l 5 benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.0 g, 60%; MS: 418 (M+H). 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.9 mmol) was dissolved in MeOH/THF (1:1, 200 ml) and stirred at room 10 temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. Hcl by dissolving it in water (200 ml). After the neutralization reaction mixture was concentrated to dryness. Ice cold water (100 ml) was added to the solid and filtered. The product 4-(4-Methoxy-benzenesulfonyl)-1 benzyl-piperidine-4-carboxylic acid was dried at 50 C and taken to next step with out 15 any purification. Colorless solid. Yield: 3.2 g, 69% ; MS: 390 (M+H). To a stirred solution of 4-(4-Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4 carboxylic acid (2.0 g, 5.1 mmol) and DMF ( 2 drops) in CH 2 Cl 2 (100 ml) at OoC, oxalyl chloride (1.0 gin, 8 mmol) was added in a drop-wise manner. After the addition, 20 the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gin, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at OoC for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH 2 C1 2 and added slowly to the 25 hydroxylamine at OoC. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with chloroform the product 4-(4-Methoxy-benzene sulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a 30 colorless solid. mp 90-95 oC; Yield, 1.2 g, 48%; MS: 405 (M+H)+; 1H NMR (300 MHz, DMSO-d 6 ): 8 2.29 (min, 3H), 2.76-2.79 (min, 2H), 3.43 (min, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (min, 5H), 9.37 (s,lH), 10.53 (s,lH), 11.18 (s,lH).

WO 99/42436 PCT/US98/1 7633 - 85 Example 84 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 5 2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined 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). 10 3-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in 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)*. 15 4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.0 g, 22 mmol) and bis- (2-chloro ethyl)-(3-methoxy-benzyl)-amine (8.0 g, 23.5 mmol). Yield 2.4 g (24%); low melting solid; MS: 447.9 (M+H)*. 20 4-(4-Methoxy-benzenesulfonyl) 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl) piperidine-4-carboxylic acid ethyl ester (2.4g, 5.36 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting 25 reaction mixture was worked up as outlined in example 83. Yield 710 mg (32%). white solid mp 199 oC , MS: 419.9 (M+H) +. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4 carboxylic acid (830 mg, 1.98 mmol) and following the procedure as outlined in 30 example 83, 190 mg of 4-(4-methoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl) piperidine-4-carboxylic acid hydroxamide was isolated as a white solid. mp 130 oC; Yield 20.4%; MS: 435.0 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 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, 1HO, 10.1 (s, 1H). 35 WO 99/42436 PCT/US98/17633 - 86 Example 85 1-(3,4-dichlorobenzyl) -4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide 5 2-[(2-Hydroxy-ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamiine (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) . 10 3,4-Dichlorobenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 3,4-dichlorobenzyl diethanolamine (10.7 g, 41 mmol). Yield 99%; yellow solid mp 218-220 oC; MS: 301.8 (M+H) . 15 1-(3,4-Dichloro-benzyl)-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.9 g, 11 mmol) and 3,4-dichlorobenzyl-bis(2-chloroethyl)-amine (3.4 g, 11 mmol). Yield 5.9g (60 %); brown oil; MS: 494.5 (M+H) +. 20 1 -(3,4-Dichloro-benzyl)-4-(4-methoxy-benzenesulfulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(3,4-dichloro-benzyl)-4-(methoxy-benzenesulfonyl) piperidine-4-carboxylic acid ethyl ester (5.0 g, 10 mmol) dissolved in methanol (50 mL), 10 N sodium hydroxide (15 mL) and tetrahydrofuran (75 mL). The resulting 25 reaction mixture was worked up as outlined in example 83. Yield 2.94 g (62 %), MS: 458.3 (M+H)*. Starting from 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid (2.67g, 5.8 mmol) and following the procedure as outlined in example 30 83, .2 g of 1-(3,4-dichlorobenzyl) -4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxamide was isolated as a white solid. mp 192-195 oC; Yield 10%; MS 472.9 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 5 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=.030, 2H), 7.50-7.73 (d, J=.027, 1H), 7.65-7.68 (d, J=.029, 2H), 7.72-7.75 (d, J=.027, 2H), 7.87 (s, 1H), 35 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).

WO 99/42436 PCT/US98/17633 - 87 Example 86 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide 5 2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)- amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.8 g, 46 mmol) and 4-methylbenzyl chloride (8.5 g, 46 mmol). Yield 9.8 g (99 %); MS: 209.9 (M+H) . 10 4-Methylbenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 4-methyl-benzyl diethanolamine (6 g, 20 mmol). Yield 5.2 g (84 %); yellow solid mp 145-147 oC; MS: 245.9 (M+H)*. 15 4-(4-Methoxy-benzenesulfonyl)-1-(4-methyl-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.0 g, 27 mmol) and 4 methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol). Yield 4.64 g (63 %); low melting solid; MS: 431.9 (M+H)*. 20 4-(4-Methoxy-benzenesulfonyl) 1-(4-methyl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.3g, 9.9 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up 25 as outlined in example 83. Yield 1.6 g (40 %). white solid mp 207-208 oC, MS: 404.3 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(4-methylbenzyl)-piperidine-4 carboxylic acid (1.59g, 3.9 mmol) and following the procedure as outlined in example 30 83, .505 g of 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4 carboxylic acid hydroxamide was isolated as a white solid. mp 176-177 oC; Yield 32%; MS: 419.0 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 2.24-2.32 (min, 2H), 2.51(t, 3H), 2.73-2.80 (min, 2H), 3.35-3.50 (min, 4H), 3.87 (s, 3H), 4.24 (s, 2H), 7.13-7.17 (d, J=.039, 2H), 7.23-7.60 (d, J=.036, 2H), 7.38-7.41 (d, J=.025, 2H), 7.65-7.68 35 (d, J=.039, 2H).

WO 99/42436 PCT/US98/17633 - 88 Example 87 4-(4-methoxy-benzene-sulfonyl)- 1-napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide 5 2-[(2-Hydroxy-ethyl)-(2-napthyl-2-ylmethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (6.18 g, 59 mmol) and 2-(bromomethyl)napthalene (10 g, 45 mmol). Yield 12.7 g (96 %); yellow solid mp 162-164 oC; MS: 246.0 (M+H) +. 10 2-Napthyl-2-ylmethyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-napthyl-ylmethyl-diethanol amine (10 g, 36 mmol). Yield 9.1 g (79 %); brown solid mp 124-126 oC; MS: 281.9 (M+H) . 15 4-(4-Methoxy-benzenesulfonyl)--napthalene-ylmethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (8.4 g, 32 mmol) and 1-napthalene-ylmethyl-bis-(2-chloro-ethyl)-amine ((8.6 g, 27 mmol). Yield 6.5 g 20 (52%); low melting solid; MS: 440.0 (M+H)*. 4-(4-Methoxy-benzenesulfonyl)- 1-napthalene-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-napthalene-ylmethyl piperidine-4-carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol (30 25 mL), 10 N sodium hydroxide (30 mL) and tetrahydrofuran (30 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.3 g (36 %). yellow solid mp 226-228 oC, MS: 440.0 (M+H) +. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-napthalene-2-yl-methylpiperidine-4 30 carboxylic acid (2.18g, 5.0 mmol) and following the procedure as outlined in example 83, .753 g of 4-(4-methoxy-benzene-sulfonyl)- 1-napthalene-2-yl-methylpiperidine-4 carboxylic acid hydroxamide was isolated as a off white solid. mp 168-170 oC; Yield 31%; MS 455.0 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 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), 7.13-7.16 (d, J=.030, 35 2H), 7.56-7.64 (m, 3H), 7.65-7.68 (d, J=.030, 2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s, 1H).

WO 99/42436 PCT/US98/1 7633 - 89 Example 88 1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide 5 2-[(2-Hydroxy-ethyl)-(1-biphenyl-4-ylmethyl))-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amine (5.2 g, 49 mmol) and 4-(chloromethyl)biphenyl (10 g, 49 mmol). Yield 9.98 g (66 %); white solid mp 160-162 'C; MS: 271.9 (M+H) . This was converted to the dichloride as 10 outlined in example 83 1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.85 g, 11 mmol) 15 and 1-biphenyl-4-ylmethyl-bis-(2-chloro-ethyl)-amine (3.4 g, 11 mmol). Yield 2.1 g, (39 %); beige solid, mp 176-178 oC, MS: 494.1 (M+H)*. 1-Biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-biphenyl-4ylmethyl-(4-methoxy-benzenesulfonyl) 20 piperidine-4-carboxylic acid ethyl ester (5.7g, 12 mmol) dissolved in ethanol (20 mL), tetrahydrofuran (20 mL) and 10 N sodium hydroxide (10 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.1g (39% ) MS: 465.8

(M+H)

+

. 25 Starting from 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid (1.0g, 2.2 mmol and following the procedure as outlined in example 83, .132g of 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4 carboxylic acid hydroxamide was isolated as a tan solid. mp168 oC; Yield 20%; MS: 440.9 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 8 2.30-2.35 (m, 2H), 2.83-2.87 (m, 30 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.15-7.721 (d, J=.059 Hz, 2H), 7.49-7.65 (m, 5H), 7.68-7.74 (d, J=.06 Hz, 2H), 9.3 (s, 1H), 10.3 (s, 1H), 11.15 (s, 1H).

WO 99/42436 PCT/US98/17633 - 90 Example 89 4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide 5 2-[(2-Hydroxy-ethyl)- 1 -(3-methyl-but-2-enyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amine (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) +. 10 1-(3-methyl-but-2-enyl)]-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxy-ethyl)-1-(3 methyl-but-2-enyl)-amino]-ethanol (10.4g, 50 mmol). Yield 10.5g (99%); brown solid; MS: 210.3 (M+H) 15 4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 1. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (11.32 g, 44 mmol) and 3-methyl-but-2-enyl)-bis-(2-chloroethyl)-amine ( 10.4 g, 50 mmol). Yield 6.2 g 20 (36 %); brown oil; MS: 395.6 (M+H) . 4-(4-Methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl) piperidine-4-carboxylic acid ethyl ester (6.2g, 16 mmol) dissolved in ethanol (15 mL), 25 10 N sodium hydroxide (10 mL) and tetrahydrofuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.2 g (21 %). brown solid mp 196-197 oC, MS: 367.9 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methyl-but-2-enyl)-piperidine-4 30 carboxylic acid (1.0g. 3.0 mmol) and following the procedure as outlined in example 83, .110 mg of 4-(4-methoxy-benzene-sulfonyl)- 1-(3-methyl-but-2-enyl)piperidine-4 carboxylic acid hydroxamide was isolated as a yellow solid. mp 142-145 oC; Yield 12%; MS: 382.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.67 (s, 3H), 1.79 (s, 3H), 2.18-2.23 (m, 2H), 2.66-2.73 (m, 2 H), 3.37-3.46 (m, 2H), 3.67-3.69 (m, 35 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, J=.03, 2H), 7.67-7.70 (d, J=.030, 2H), 9.34 (s, 1H), 9.88 (s, 1H), 11.15 (s, 1H).

WO 99/42436 PCT/US98/17633 -91 Example 90 1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 5 2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (22.5 g, 150 mmol). and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66g, (99%); yellow oil; MS: 273.8 (M+H)*. 10 (4-Bromo-benzyl)-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(4-bromobenzyl)-(2-hydroxy ethyl)-amino]-ethanol (33.28 g, 122 mmol). Yield 47 g, (99%); brown solid; mp 125 0 C; MS: 309.8 (M+H) +. 15 1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (8.6 g, 33.5 mmol) and (4 bromo-benzyl)-bis-(2-chloro-ethyl)-amine (13.3 g, 38.6 mmol). Yield 17 g (44%); 20 brown oil; MS: 497.8 (M+H)*. 1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine 4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and 25 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215 oC; MS: 469.7 (M+H) +. Starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid (1.95 g, 4.2 mmol) and following the procedure as outlined in example 30 83, 1.29 g of 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 60%; mp 180 0 C; MS: 484.7 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 2.18-2.29 (m, 2H), 2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s, 2H), 7.18 (d, J = 17 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.65- 7.68 (m, 4H), 9.37 (s, 1H), 10.5 (s, 35 1H).

WO 99/42436 PCT/US98/17633 - 92 Example 91 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide 5 2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was prepared according to the general method as outlined 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)*. 10 Bis-(2-Chloro-ethyl)-(3-phenyl-propyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-hydroxy-ethyl)-(3-phenyl propyl)-amino]-ethanol (20.32 g, 90.7 mmol). Yield 24.9 g (92%); brown oil; MS: 259.8 (M+H)*. 15 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (12 g, 46.5 mmol) and bis-(2-chloro-ethyl)-(3-phenyl-propyl)-amine (24.8 g, 93.8 mmol). Yield 11.24 g 20 (54%); brown oil; MS: 446 (M+H)*. 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine 4-carboxylic acid ethyl ester (10.74 g, 24.13 mmol) dissolved in THF:methanol 3:1 25 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g (47%); off white powder; mp 203 oC; MS: 418.2 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenyl-propyl)-piperidine-4 carboxylic acid (4.37 g, 10.4 mmol) and following the procedure as outlined in 30 example 83, 1.64 g of 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenyl-propyl)-piperidine 4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 37%; mp 143'C; MS: 432.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 5 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, 7 H), 7.68, 35 (d, J = 9 Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).

WO 99/42436 PCT/US98/17633 - 93 Example 92 1-Tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 5 tert-Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 1-tert-butyl-diethanolamine (6 g, 37.2 mmol). Yield 11.15 g, (99%); white solid; MS: 197.8 (M+H) +. 10 1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) 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) . 15 1-tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.37 g 14 mmol) dissolved in methanol (300 ml) and 10 N NaOH (23 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.52 g 20 (30.6%); white powder; mp 204 oC; 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 procedure as outlined in example 83, 190 mg of 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxy 25 amide was isolated as a green solid. Yield 52%; mp 40 oC; MS: 371.1 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 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 30 1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide Butyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from N-butyldiethanolamine (6 g, 37.2 mmol). Yield 35 11.3 g, (99%); white powder; mp 165 oC; MS: 197.9 (M+H) +. 1-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4 (methoxy-benzenesulfonyl) acetic acid ethyl ester (5 g, 19.38 mmol) and butyl-bis-(2- WO 99/42436 PCT/US98/17633 - 94 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 prepared 5 starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (6.42 g 16.8 mmol) dissolved in methanol (200 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g (27%); white powder; mp 206 oC; MS: 356.4 (M+H)*. 10 Starting from 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.51 g, 4.3 mmol) and following the procedure as outlined in example 83, 200 mg of 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 9.3%; mp 75 'C; MS: 371.1 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.87 (t, J = 7.2 Hz, 3H), 1.27 (m, 2H), 1.59 (m, 15 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 20 1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide Cyclooctyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from N-cyclooctyldiethanolamine (6 g, 28 mmol). 25 Yield 10 g, (99%); off white solid; mp 158 oC; MS: 251.9 (M+H) . 1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5 g, 19.4 mmol) and cyclooctyl 30 bis-(2-chloro-ethyl)-amine (5.57 g, 19.4 mnimol). Yield 8.2 g, (96%); brown oil; MS: 438 (M+H)*. 1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4 35 carboxylic acid ethyl ester (8 g, 18.3 mmol) dissolved in methanol (200 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.36 g (32%); white powder; mp 180 oC; MS: 410 (M+H)*.

WO 99/42436 PCT/US98/1 7633 - 95 Starting from 1-Cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.26 g, 5.53 mmol) and following the procedure as outlined in example 83, 570 mg of 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a white powder. Yield 22%; mp >200 'C; MS: 425 5 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.42-1.66 (m, 14H), 1.83 (m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H) 3.88 (s, 3H) 7.17 (d, 2H), 7.66 (d, 2H). Example 95 10 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 as outlined in example 83. Starting from 4 (methoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and ethyl-bis-(2 15 chloro-ethyl)-amine (2.39g, 11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; MS: 356 (M+H)*. 1-Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl 20 ester (2.42 g, 6.8 mmol) dissolved in methanol (100 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.29 g (58%); white solid; mp 209 oC; MS: 328 (M+H)*. Starting from 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid 25 (1.23 g, 3.76 mmol) and following the procedure as outlined in example 83, 1.02 g of 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white powder. Yield 80%; mp 85 oC; MS: 343 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.926 (t, J =7.1 Hz, 3H), 1.68-1.89 (m, 4H), 2.05 2.24 (m, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H). 30 Example 96 1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 35 1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.7 g, 22.2 mmol) and isopropyl- WO 99/42436 PCT/US98/17633 - 96 bis-(2-chloro-ethyl)-amine (4.9 g, 22.2 mmol). Yield 5.64 g, (68%); low melting brown solid; MS: 370 (M+H) +. 1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared 5 starting from 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.18 g (42%); white powder; mp 204 oC; MS: 341.9 (M+H) . 10 Starting from 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.13 g, 6.25 mmol) and following the procedure as outlined in example 83, 590 mg of 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a white powder. Yield 2.4%; mp 75 'C; MS: 357 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.21 (d, J = 6.6 Hz, 6H), 2.33-3.53 (m, 15 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 20 1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4 (methoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and methyl-bis-(2 chloro-ethyl)-amine (2.2g, 11.6 mmol). Yield 3.09 g, (75%); low melting brown solid; 25 MS: 342 (M+H)*. 1-Methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8.7 g, 25.6 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 30 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.23 g (41%); white solid; mp 204 oC; 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 procedure as outlined in example 83, 1.10 g of 35 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a yellow powder. Yield 53%; mp 89 oC; MS: 329 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 1.67- 1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2.17 WO 99/42436 PCT/US98/17633 - 97 (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 5 1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 10 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 prepared 15 starting from 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210 oC; MS: 432 (M+H) . 20 Starting from 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (2.61 g, 6.06 mmol) and following the procedure as outlined in example 83, 860 mg of 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white powder. Yield 32%; mp 144 oC; MS: 446.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.94 (t, J = 7.3 Hz, 3H), 1.44 (q, J = 7.5 Hz, 2H), 25 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 30 1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl 35 ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (18.8 g, 72.8 mmol) and (4 fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (20.8 g, 73 mmol). Yield 25 g (79%); brown oil; MS: 436.9 (M+H) .

WO 99/42436 PCT/US98/17633 - 98 1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine 4-carboxylic acid ethyl ester (17.4 g, 40 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in 5 example 83. Yield 10.8 g (66%); colorlesssolid; mp 154 'C; MS: 408 (M+H) . Starting from 1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4 carboxylic acid (8.14 g, 20 mmol) and following the procedure as outlined in example 83, 4.3 g of 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4 10 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 51%; mp 176 178 'C; MS: 484.7 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 5 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, 2H), 7.14-7.19 (d, J = 17 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). 15 Example 100 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 20 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6 g, 20 mmol) and (4 fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.73 g, 20 mmol). Yield 8.2 g (86%); 25 yellow oil; MS: 478 (M+H)*. 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4 carboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N 30 NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114 oC; MS: 450 (M+H) . Starting from 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4 carboxylic acid (2.24 g, 5.0 mmol) and following the procedure as outlined in example 35 83, 200 mg of 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an off white powder. Yield 9%; mp 112 0 C; MS: 465.9 (M+H) ; 'H NMR (300 MHz, DMSO-d 6 ): 8 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), WO 99/42436 PCT/US98/17633 - 99 3.77-3.78 (m, 4H), 4.06-4.10 (m, 2H), 4.19 (s, 2H), 7.14-7.19 (d, J = 8.7, 2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.34 (s, 1H), 10.55 (s, 1H). 5 Example 101 4-(4-methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 10 2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined 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). 15 4-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 4-Methoxy-benzyl diethanolamine (10 g, 44 mmol). Yield 10 g (75 %); yellow solid mp 55 C; MS: 263.1 (M+H)*. 4-(4-Methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid 20 ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-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 melting solid; MS: 448.5 (M+H)*. 25 4-(4-Methoxy-benzenesulfonyl) 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl) piperidine-4-carboxylic acid ethyl ester (4.2g, 10 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (71 %). white solid mp 30 190 oC , MS: 420.4 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4 carboxylic acid (2.0 g, 4.7 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4 35 carboxylic acid hydroxamide was isolated as a white solid. mp 175 oC (HCI); Yield: 1.2 g, 59 %; MS: 433.0 (M+H)+; 1H NMR (300 MHz, DMSO-d 6 ): 8 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).

WO 99/42436 PCT/US98/17633 - 100 Example 102 4-(4-methoxy-benzenesulfonyl)- -[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic 5 acid hydroxyamide 2- { (2-Hydroxy-ethyl)- [2-(4-methoxy-phenyl)-ethyl]-amino } -ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amine (10.0 g, excess). and 1-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol). 10 Yield 11 g, (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 as outlined in example 83. Starting from 2- { (2-hydroxy-ethyl)- [2-(4-methoxy-phenyl)-ethyl]-amino } -ethanol (10 g, 41.8 15 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 as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 20 mmol) and bis-(2-chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-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 starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxy 25 phenyl)-ethyl]-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.0 g (85%); off white powder; mp 205oC; MS: 434.5 (M+H)*. 30 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 as outlined in example 83, 900 mg of 4-(4-methoxy-benzenesulfonyl)-1-[2-(4 methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 206 oC (HC1); MS: 449.5 (M+H)*; 'H NMR (300 35 MHz, DMSO-d 6 ): 5 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.60 (d, J = 12.3 Hz, 2H), 3.77 (s, 3H),3.99 (s, 3H), 6.9 (d, 2 H), 7.1 - 7.25, (q, 4H), 7.7 (d, 2H), 9.3 (s, 1H), 10.6 (s, 1H).

WO 99/42436 PCT/US98/17633 - 101 Example 103 4-(4-methoxy-benzenesulfonyl)- 1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide 5 2-[(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-amino]-ethanol was prepared according to the general method as outlined 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)*. 10 Bis-(2-Chloro-ethyl)-(2-phenyl-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[(2-Hydroxy-ethyl)-(2-phenyl ethyl)-amino]-ethanol (8.5 g, 40.6 mmol). Yield 11 g (95%); brown oil; MS: 247.1

(M+H)

+. 15 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 mmol) and bis-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine (5.6 g, 20 mmol). Yield 5.5 g 20 (63%); brown oil; MS: 432.5 (M+H) . 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4 carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10 N 25 NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder; mp 208 oC; MS: 404.5 (M+H) . Starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4 carboxylic acid (1.5 g, 3.7 mmol) and following the procedure as outlined in example 30 83, 900 mg of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 205oC (HC1); MS: 419.4 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 5 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m,4H), 3.9 (s, 3H),7.22 - 7.8 (m, 9H), 10.6 (s, 1H), 11.2 (bs, 1H). 35 WO 99/42436 PCT/US98/17633 -102 Example 104 4-(4-n-Butoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 5 4-(4-n-Butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(n-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 10 mmol) and bis- (2-chloro ethyl)-(4-methoxy-benzyl)-amine (3.0 g, 10 mmol). Yield 3.5 g (71 10 %); low melting solid; MS: 490.5 (M+H) . 4-(4-n-Butoxy-benzenesulfonyl) 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methoxy benzyl)piperidine-4-carboxylic acid ethyl ester (3.0g, 6.1 mmol) dissolve in methanol 15 (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined 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-methoxy-benzyl)-piperidine-4 20 carboxylic acid (1.0 g, 2.1 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-Butoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4 carboxylic acid hydroxamide was isolated as a white solid. mp 173 'C (HC1); Yield: 800 mg, 77 %; MS: 477.5 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 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), 25 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 30 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide 2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 35 151 mmol). and 3-Phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)*.

WO 99/42436 PCT/US98/17633 - 103 Bis-(2-Chloro-ethyl)-(3-phenoxy-propyl)-amine was prepared according to the general method as outlined in example 83. Starting 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) . 5 4-(4-Methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.2 g, 20 mmol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22 mmol). Yield 10 6.5 g (70%); brown oil; MS: 462.5 (M+H)*. 4-(4-Methoxy-benzenesulfonyl)- 1 -(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl) piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 15 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder; mp 195 oC; MS: 434.5 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4 20 carboxylic acid (2.5 g, 5.77 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 46%; mp 101 oC; MS: 448.5 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m 2H), 3.87 (s, 3H), 25 4.01 (t, 2H), 6.9 - 7.7 (m, 9H), 9.33 (bs, 1H), 10.28 (bs, 1H). Example 106 4-(4-n-Butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid 30 hydroxyamide 4-(4-n-Butoxy-benzenesulfonyl)- 1 -(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (3.0 g, 10 35 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)*.

WO 99/42436 PCT/US98/17633 -104 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl) piperidine-4-carboxylic acid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as 5 outlined in example 83. Yield 3.0 g (79%); off white powder; mp 191 oC; MS: 476.5 (M+H) . Starting from 4-(4-n-butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4 carboxylic acid (700 mg, 1.4 mmol) and following the procedure as outlined in 10 example 83, 300 mg of 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl) piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84 oC; MS: 491.5 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 4.1 (t, 2H), 6.9 - 7.7 (m, 9H), 10.7 15 (bs, 1H), 11.28 (bs, 1H). Example 107 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid 20 hydroxyamide 2-[(2-Hydroxy-ethyl)-(2-phenoxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.0 g, 150). and 2-chloro-phenetol (15.6 g, 100 mmol). Yield 18 g, (80%); Colorless oil; 25 MS: 226 (M+H)*. Bis-(2-Chloro-ethyl)-(2-phenoxy-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting 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 30 (M+H) . 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, 20 35 mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (6.0 g, 20 mmol). Yield 5.8 g (64%); brown oil; MS: 448.5 (M+H)*.

WO 99/42436 PCT/US98/17633 - 105 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine 4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in 5 example 83. Yield 3.0 g (63%); off white powder; mp 235 oC; MS: 420.5 (M+H)*. Starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4 carboxylic acid (2.5 g, 5.9 mmol) and following the procedure as outlined in example 83, 1.3 g of 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4 10 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 50%; mp 168 172 oC (HC1); MS: 435.4 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 2.3 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m,2H), 3.9 (s, 3H), 4.4 (m, 2H), 6.9 - 7.8 (m, 9H), 9.3 (s, 1H), 10.2 (bs, 1H), 11.3 (s, 1H). 15 Example 108 4-(4-n-Butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide 20 4-(4-Butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl ester (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)*. 25 4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy) piperidine-4-carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as 30 outlined in example 83. Yield 1.5 g (56%); off white powder; mp 204 oC; MS: 462.5 (M+H) . Starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4 carboxylic acid (1.0 g, 2.16 mmol) and following the procedure as outlined in example 35 83, 600 mg of 4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; mp 112oC (HCI); MS: 477.4 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.942 (t, 3H), WO 99/42436 PCT/US98/17633 -106 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4 (m, 4H), 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9 - 7.7 (m, 9H), 9.4 (s, 1H), 10.5 (bs, 1H), 11.3 (s, 1H). 5 Example 109 4-(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxyamide 10 Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared according to the general method as outlined in 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) +. 15 Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared according to the general method as outlined in 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) . 20 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 as outlined in example 83. Starting from from 4-(methoxy-benzenesulfonyl) acetic acid ethyl 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) +. 25 4-(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-[4-(2 piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.4 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction 30 mixture was worked up as outlined in example 83. Yield 4.0 g (77%); off white powder; mp 174 oC; 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 following the procedure as 35 outlined in example 83,1.8 g of 4-(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin-1-yl ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amidewas isolated as an pale yellow solid. Yield 49%; mp 114 oC (HC1); MS: 532 (M+H)+; 'H NMR (300 MHz, WO 99/42436 PCT/US98/17633 - 107 DMSO-d 6 ): 8 1.4-1.6 (min, 4H), 1.9 (min, 2H), 2.3 (min, 2H), 2.8 (min, 2H), 3.4 (inm, 4H), 3.9 (s, 3H), 4.2 (min, 1H), 6.9 - 7.8 (min, 8H), 9.1 (s, 1H11), 10.8 (bs, 1H). Example 110 5 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide Step A: Coupling of 2-bromo-propionic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin' 10 (2 g, 1.1 meq/g) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and suspended in DMF (20 mL). 2-Bromopropionic acid (0.6 mL, 3.0 eq.) 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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and 15 washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). (A wash consisted of addition of the solvent and agitation either by nitrogen bubbling or shaking on the orbital shaker 20 for 1-5 minutes, then filtration under vacuum). The resin was dried in vacuo at room temperature. A sample of resin (5-20 mg) was subjected to cleavage with DCM (0.5 mL) and TFA (0.5 mL) for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (1 x 1 mL). The filtrate and the washing were combined and 25 concentrated in vacuo on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The product was then characterized by H' NMR, (DMSO d-6) 8 4.54 (q, 1H1), 1.83 (d, 3H11). Step B: Displacement of bromide with 4-methoxybenzenethiol. 30 The N-Hydroxy-2-bromo-propionamide resin prepared in Step A (0.35 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 4 Methoxybenzenethiol (0.23 mL, 5.0 eq.), sodium iodide (288 mg, 5.0 eq.) and 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU, 0.17 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured 35 into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.

WO 99/42436 PCT/US98/17633 - 108 Step C: Oxidation of sulfide to sulfoxide. N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert 5 butylhydroperoxide (1.0 mL) and benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 10 Step D: Oxidation of sulfide to sulfone. N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 15 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide from 20 resin. The N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-propionamide resin prepared in Step D (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined 25 and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 84% @ 215 nm; 'H NMR (DMSO d-6) 8 10.75 (brs, 1 H), 7.95 (brs, 1 H), 7.71 (dd, 2 H), 7.16 (dd, 2 H), 3.87 (s, 3 H), 3.83 (q, 1 H), 1.26 (d, 3 H). 30 The hydroxamic acids of Examples 111-113 are synthesized using appropriate starting materials and following the steps in example 110.

WO 99/42436 PCT/US98/17633 - 109 Example 111 N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionamide. 72% @ 215 nm 5 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-propionamide. 76% @ 215 nm; 'H NMR (DMSO d-6) 6 10.90 &10.60 (brs, 1 H), 7.95 (brs, 1 H) 7.61 & 7.52 (dd, 2 H), 7.15 & 7.10 (dd, 2 H), 3.83 & 3.82 (s, 3 H), 3.42 & 3.28 (q 1H), 1.23 & 0.97 (d, 3 H). Example 112 10 N-Hydroxy-2-(3-methyl-butane-l1-sulfanyl)-propionamide. 74% @ 215 nm. N-Hydroxy-2-(3-methyl-butane-1-sulfinyl)-propionamide. 'H NMR (DMSO d-6) 8 10.8 (brs 1 H), 7.95 (brs, 1 H), 3.45 & 3.31 (q, 1 H), 2.71 -2.50 (min, 2 H), 1.71 15 1.46 (min, 3 H), 1.33 & 1.25 (d, 3 H), 0.94-0.82 (min, 6 H) Example 113 N-Hydroxy-2-(3-methyl-butane-1-sulfonyl)-propionamide. 84% @ 215 nm. 20 Example 114 N-hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide 25 Step A: Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1 %-divinylbenzene)-resin' (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.) and DIC (9.04 mL, 10.5 eq.) 30 were added. The reaction was shaken on an orbital shaker at room temperature for 2 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). 35 The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with 2-naphthalenethiol. The 2-bromo hydroxymate resin prepared in Step A (0.15 g, 1.1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 2-Naphthalenethiol (138 mg, WO 99/42436 PCT/US98/17633 -110 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 was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 5 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B (175 mg, 10 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 15 Step D: Oxidation of sulfide to sulfone. 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B (175 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 20 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyramide from 25 resin. The 2-(2-Naphthalenesulfanyl)-N-hydroxypropionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and 30 concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 83% @ 215 nm; LCMS (API-electrospray) m/z 276 (M+H)+; 1 H NMR (DMSO d-6) 8 10.7 (brs, 1 H), 7.91 (brs, 1 H), 7.91-7.81 (min, 4 H), 7.55-7.45 (m, 3 H), 3.41 (d, 1 H), 2.09-1.97 (m, 1 H), 1.05 (d, 3 H), 0.97 (d, 3 H). 35 WO 99/42436 PCT/US98/17633 -111 The hydroxamic acids of Examples 115-118 are synthesized using appropriate starting materials and following the steps in example 114: Example 115 5 N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfinyl)-butyramide. 67% @ 215 nm. Example 116 10 N-Hydroxy-3-methyl-2-(naphthalen-2-ylsulfonyl)-butyramide. 97% @ 215 nm; LCMS (API-electrospray) m/z 308 (M+H) +. Example 117 15 N-Hydroxy-3-methyl-2-phenethylsulfinyl-butyramide. 93% @ 215 nm; LCMS (API electrospray) m/z 254 (M+H) . Example 118 20 N-Hydroxy-3-methyl-2-phenethylsulfonyl-butyramide. 97% @ 215 nm; LCMS (API electrospray) m/z 286 (M+H) . Example 119 25 (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester Step A: Coupling of 2-bromobutyric acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1 %-divinylbenzene)-resin' (5 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 30 mL). 2-Bromobutyric acid (3.0 g, 3.0 eq.) HOBt (4.86 g, 6.0 eq.) and DIC (3.75 mL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, 35 otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with methyl thioglycolate. The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.1 meq/g) was placed in 40 a 20 mL scintillation vial and suspended in THF (2 mL). Methyl thioglycolate (286 mg, WO 99/42436 PCT/US98/1 7633 - 112 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.24 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 5 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. (1-Hydroxycarbamoyl-propane-l-sulfanyl)-acetic acid methyl ester resin prepared in 10 Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 15 Step D: Oxidation of sulfide to sulfone. (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature 20 for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of (1-Hydroxycarbamoyl-propane-1-sulfanyl)-acetic acid methyl ester 25 from resin The (1-Hydroxycarbamoyl-propane-l1-sulfanyl)-acetic acid methyl ester resin prepared in Step B (150 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were 30 combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. LCMS (API-electrospray) m/z 228 (M+Na) . The hydroxamic acids of Examples 120-124 are synthesized using appropriate starting 35 materials and following the steps in example 119.

WO 99/42436 PCT/US98/17633 -113 Example 120 (1-Hydroxycarbamoyl-propane-1-sulfonyl)-acetic acid hydroxyamide. LCMS (API-electrospray) m/z 224 (M+H) . 5 Example 121 (1-Hydroxycarbamoyl-propane-1-sulfinyl)-acetic acid hydroxy amide. 100% @ 220 nm; LCMS (API-electrospray) m/z 240 (M+H)*. 10 Example 122 (1-Hydroxycarbamoyl-propane-1-sulfanyl)-propionic acid hydroxyamide. 1 H NMR (DMSO d-6) 8 10.7 (brs, 1 H), 4.03 (t, 2 H), 2.95 (q, 1 H), 2.75-2.70 (min, 1 15 H), 2.60-2.54 (min, 1 H), 1.74-1.66 (min, 2 H), 1.58-1.50 (min, 4 H), 1.32 (sextet, 2 H), 0.88 (t, 3 H), 0.85 (t, 3 H); LCMS (API-electrospray) m/z 264 (M+H) . Example 123 20 (1-Hydroxycarbamoyl-propane-1-sulfinyl)-propionic acid hydroxyamide. 83% @ 220 nm; LCMS (API-electrospray) m/z 280 (M+H)*. Example 124 25 (1-Hydroxycarbamoyl-propane-1-sulfonyl)-propionic acid hydroxyamide. 100% @ 220 nm; Example 125 30 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide Step A: Coupling of 2-bromo-3-phenyl-propionic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin (5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 35 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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above WO 99/42436 PCT/US98/17633 -114 was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with 4-hydroxythiophenol. 5 The 2-bromo hydroxymate resin prepared in Step A (0.33 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 4-Hydroxythiophenol (250 mg, 5.0 eq.), sodium iodide (297 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7 ene (DBU, 0.18 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene 10 syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 15 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 20 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (132 mg) 25 was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 30 Step E: Cleavage of 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide from resin. The 2-(4-Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide resin prepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was 35 filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) WO 99/42436 PCT/US98/17633 - 115 was added and the mixture concentrated. 84% @ 215 nm; 'H NMR (DMSO d-6) 6 10.41 (brs, 1 H), 7.95 (brs (1 H), 7.30-7.15 (m, 5 H), 7.10 (dd, 2 H), 6.75 (dd, 2 H), 3.53 (q, 1 H), 3.05 (dd, 1 H), 2.79 (dd, 1 H). 5 The hydroxamic acids of Examples 126-130 are synthesized using appropriate starting materials and following the steps in example 125. Example 126 10 2-(4-Hydroxybenzenesulfinyl)-N-hydroxy-3-phenyl-propionamide. 73% @ 215 nm; Example 127 2-(4-Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 77% @ 215 nm; 15 'H NMR (DMSO d-6) 8 10.50 (brs, 1 H), 7.95 (brs, 1 H), 7.68-7.57 (m, 2 H), 7.28 7.17 (m, 3 H), 7.08-7.98 (m, 2 H), 6.95-6.87 (m, 2 H), 3.96 (t, 1 H), 3.02 (d, 2 H). Example 128 20 2-(4-Acetylamino-benzenesulfanyl)-N-hydroxy-3-phenyl-propionamide. 86% @ 215 nm; 'H NMR (DMSO d-6) 8 10.50 (brs, 1 H), 10.03 (brs, 1 H), 8.13 (brs, 1 H), 7.56-7.12 (m, 9 H), 3.67 (q, 1 H), 3.08 (dd, 1 H), 2.84 (dd, 1 H), 2.04 (s, 3 H) Example 129 25 2-(4-Acetylamino-benzenesulfinyl)-N-hydroxy-3-phenyl-propionamide. 73% @ 215 nm. Example 130 30 2-(4-Acetylamino-benzenesulfonyl)-N-hydroxy-3-phenyl-propionamide. 95% @ 215 nm; Example 131 35 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acid methyl ester Step A: Coupling of 2-bromo-5-methyl glutaric acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin' 40 (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 WO 99/42436 PCT/US98/17633 -116 mL). S-2-Bromo-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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test 5 showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with 4-hydroxythiophenol. 10 The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (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-7 ene (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene 15 syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 20 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acid methyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), 25 MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acid methyl ester 30 resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step E: Cleavage of 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl) butyric acid methyl ester from resin.

WO 99/42436 PCT/US98/17633 -117 The 4-Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)-butyric acid methyl ester resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). 5 The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 77% @ 215 nm; LCMS (API-electrospray) m/z 316 (M+H) . The hydroxamic acids of Examples 132-139 are synthesized using appropriate starting 10 materials and following the steps in example 131. Example 132 4-Hydroxycarbamoyl-4-(4-methanesulfinyl-phenylsulfinyl)-butyric acid 15 hydroxyamide. 79% @ 215 nm; LCMS (API-electrospray) m/z 348 (M+H)*. Example 133 4-Hydroxycarbamoyl-4-(4-methanesulfonyl-phenylsulfonyl)-butyric acid 20 hydroxyamide. 78% @ 215 nm; LCMS (API-electrospray) m/z 380 (M+H)*. Example 134 4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfanyl)-butyric acid hydroxyamide. 25 93% @ 215 nm. Example 135 4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfinyl)-butyric acid hydroxyamide. 30 80% @ 215 nm. Example 136 4-Hydroxycarbamoyl-4-(4-bromo-benzenesulfonyl)-butyric acid hydroxyamide. 35 77% @ 215 nm. Example 137 4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfanyl)-butyric acid 40 hydroxyamide. 93% @ 215 nm.

WO 99/42436 PCT/US98/17633 -118 Example 138 4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfinyl)-butyric acid hydroxyamide. 72% @ 215 nm. 5 Example 139 4-Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfonyl)-butyric acid hydroxyamide. 90% @ 215 nm. 10 Example 140 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide 15 Step A: Coupling of 2-bromo-decanoic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). 2-Bromo-decanoic 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 was shaken on an orbital shaker at room 20 temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. 25 Step B: Displacement of bromide with 3-methoxy-benzenethiol. The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 3-Methoxy-benzenethiol (185 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7 30 ene (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step C: Oxidation of sulfide to sulfoxide. 2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert-butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken WO 99/42436 PCT/US98/17633 -119 on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 5 Step D: Oxidation of sulfide to sulfone. 2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), 10 MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide from resin. 15 The 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added 20 and the mixture concentrated. 89% @ 215 nm. The hydroxamic acids of Examples 141-145 are synthesized using appropriate starting materials and following the steps in example 140. 25 Example 141 2-(3-Methoxy-benzenesulfinyl)decanoic acid hydroxamide. 96% @ 215 nm. Example 142 30 2-(3-Methoxy-benzenesulfonyl)decanoic acid hydroxamide. 96% @ 215 nm. Example 143 35 2-(4-methanesulfanyl-benzenesulfanyl)decanoic acid hydroxamide. 85% @ 215 nm; LCMS (API-electrospray) m/z 342 (M+H) .

WO 99/42436 PCT/US98/17633 - 120 Example 144 2-(4-methanesulfinyl-benzenesulfinyl)decanoic acid hydroxamide. 86% @ 215 nm; LCMS (API-electrospray) m/z 374 (M+H)*. 5 Example 145 2-(4-methanesulfonyl-benzenesulfonyl)decanoic acid hydroxamide. 92% @ 215 nm. 10 Example 146 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide Step A: Coupling of 2-bromo--3-benzyloxy propionic acid to hydroxylamine resin. 15 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1 %-divinylbenzene)-resin' (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). S-2-Bromo-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.) were added. The reaction was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF 20 (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. 25 Step B: Displacement of bromide with 4-(methylthio)thiophenol. The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (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-7 ene (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room 30 temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step C: Oxidation of sulfide to sulfoxide. 3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The WO 99/42436 PCT/US98/17633 - 121 reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. 5 3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried 10 in vacuo at room temperature. Step E: Cleavage of 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl) propionamide from resin. The 3-benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide 15 resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 76% @ 215 nm; LCMS 20 (API-electrospray) m/z 350 (M+H) +. The hydroxamic acids of Examples 147-151 are synthesized using appropriate starting materials and following the steps in example 146. 25 Example 147 3-Benzyloxy-N-hydroxy-2-(4-methanesulfinyl-benzenesulfinyl)-propionamide. 70% @ 215 nm; LCMS (API-electrospray) m/z 382 (M+H) +. 30 Example 148 3-Benzyloxy-N-hydroxy-2-(4-methanesulfonyl-benzenesulfonyl)-propionamide. 63% @ 215 nm; LCMS (API-electrospray) m/z 414 (M+H) +. 35 Example 149 3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfanyl)-propionamide. 90% @ 215 nm.

WO 99/42436 PCT/US98/17633 - 122 Example 150 3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfinyl)-propionamide. 70% @ 215 nm. 5 Example 151 3-Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfonyl)-propionamide. 72% @ 215 nm. Example 152 10 2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide Step A:Coupling of 2-bromo-3-(3H-imidazol-4-yl)-propionic acid to hydroxylamine resin. 15 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 mL). S-2-Bromo-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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed 20 with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. 25 Step B: Displacement of bromide with 2-bromothiophenol. The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 2-Bromothiophenol (249 mg, 5.0 eq.), sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene 30 (DBU, 0.12 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step C: Oxidation of sulfide to sulfoxide. 2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction WO 99/42436 PCT/US98/17633 - 123 mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 5 Step D: Oxidation of sulfide to sulfone. 2-(2-Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 10 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of 2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl) propionamide from resin. 15 The 2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. 20 Methanol (1 mL) was added and the mixture concentrated. 86% @ 215 nm. The hydroxamic acids of Examples 153-154 are synthesized using appropriate starting materials and following the steps in example 152. 25 Example 153 2-(4-bromo-benzenesulfinyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide. 69% @ 215 nm 30 Example 154 2-(4-chloro-benzenesulfonyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionamide. Example 155 35 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide Step A: Coupling of 2-bromo-5-guanidino-pentanic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1 %-divinylbenzene)-resin 40 (4.5 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF (40 WO 99/42436 PCT/US98/17633 - 124 mL). S-2-Bromo-5-guanidino-pentanic 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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the 5 test showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with 3-fluorothiophenol. 10 The 2-bromo hydroxymate resin prepared in Step A (0.22 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 mL). 3-Fluorothiophenol (169 mg, 5.0 eq.), 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 was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene syringe barrel 15 fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 20 2-(3-Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tert butylhydroperoxide (0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 25 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. 2

-(

3 -Fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) 30 was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step E: Cleavage of 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxy amide from resin.

WO 99/42436 PCT/US98/17633 - 125 The 2-(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the 5 washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 93% @ 215 nm. The hydroxamic acids of Examples 156-159 are synthesized using appropriate starting materials and following the steps in example 155: 10 Example 156 2-(3-Fluorophenylsulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 80% @ 220 nm; LCMS (API-electrospray) m/z 317 (M+H) . 15 Example 157 2-(2-Bromosulfanyl)-5-guanidino-pentanoic acid hydroxyamide. 92% @ 220 nm; 'H NMR (DMSO d-6) 8 10.90 (brs, 2 H), 10.41 (brs, 1H), 7.95 (brs, 1 H), 7.66-7.14 20 (m, 5 H), 3.72 (q, 1 H), 3.13 (q, 2 H), 1.90-1.66 (m, 2 H), 1.58-1.43 (2 H). Example 158 2-(2-Bromosulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 79% @ 220 nm; 25 LCMS (API-electrospray) m/z 379 (M+H)*. Example 159 2-(2-Bromosulfonyl)-5-guanidino-pentanoic acid hydroxyamide. 'H NMR (DMSO d 30 6) 8 8.03-7.45 (m, 5 H), 4.52 (q, 1 H), 3.16 (q, 2 H), 2.07-1.90 (m, 2 H), 1.66-1.59 (2 H). Example 160 35 2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide Step A: Coupling of 2-bromo-octanoic acid to hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin' (10.0 g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF WO 99/42436 PCT/US98/17633 -126 (80 mL). 2-Bromo-octanoic 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 was shaken on an orbital shaker at room temperature for 2 - 16 hours. The reaction was filtered and washed with DMF (3 x 20 mL). A sample of resin was removed and subjected to the Kaiser test. If the test 5 showed the presence of free amine (resin turned blue) the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x 20 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Displacement of bromide with 2,5-dichlorothiophenol. 10 The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1.2 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (6 mL). 2,5-Dichlorothiophenol (483 mg, 5.0 eq.), sodium iodide (404 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7 ene (DBU, 0.24 mL, 3.0 eq.) were added. The reaction was shaken at room temperature for 12 - 16 hours. The reaction mixture was poured into a polypropylene 15 syringe barrel fitted with a polypropylene frit, filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 2 mL), DMF (2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 20 2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert butylhydroperoxide (1.0 mL) benzenesulfonic acid (50 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 25 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. 2-(2,5-Dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and mCPBA (180 mg) was 30 added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 35 Step E: Cleavage of 2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide from resin.

WO 99/42436 PCT/US98/17633 - 127 The 2-(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were 5 combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. 92% @ 215 nm; 'H NMR (DMSO d-6) 8 10.96 (brs, 1 H), 9.26 (brs, 1 H), 7.93-7.76 (min, 3 H), 4.07 (q, 1 H), 2.04-1.85 (m, 1 H), 1.78-1.64 (min, 1 H), 1.32-1.09 (min, 8 H), 0.81 (t, 3 H). 10 The hydroxamic acids of Examples 161-167 are synthesized using appropriate starting materials and following the steps in example 160. Example 161 15 2-(2,5-Dichlorobenzenesulfonyl)-octanoic acid hydroxyamnide. 96% @ 215 nm. Example 162 2-(3-Methoxybenzenesulfanyl)-octanoic acid hydroxyamide 86% @ 220 nm; LCMS 20 (API-electrospray) m/z 298 (M+H)*. Example 163 2-(3-Methoxybenzenesulfinyl)-octanoic acid hydroxyamide 96% @ 220 nm. 25 Example 164 2-(3-Methoxybenzenesulfonyl)-octanoic acid hydroxyamide 83% @ 220 nm. 30 Example 165 2-(3,4-Dimethoxybenzenesulfanyl)-octanoic acid hydroxyamide 87% @ 215 ninm; LCMS (API-electrospray) m/z 328 (M+H)*. 35 Example 166 2-(3,4-Dimethoxybenzenesulfinyl)-octanoic acid hydroxyamide 90% @ 215 nm. Example 167 40 2-(3,4-Dimethoxybenzenesulfonyl)-octanoic acid hydroxyamide 87% @ 215 nm.

WO 99/42436 PCT/US98/1 7633 - 128 The hydroxamic acid compounds of Examples 168-198 are synthesized using appropriate starting materials and following the steps in example 160. The crude products are dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase 5 HPLC under the conditions described below: Column: ODS-A, 20 mm x 50 mm, 5 gm particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 10 0.0 95 5 25 min. 5 95 Flow Rate: 15 mL/min. Example 168 15 2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide 81% @ 215 nm; LCMS (API-electrospray) m/z 308 (M+H)*. Example 169 20 2-(2-Benzooxazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 nm; LCMS (API-electrospray) m/z 309 (M+H)*. Example 170 25 2-(2-Benzothiazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 nm; LCMS (API-electrospray) m/z 325 (M+H) . Example 171 30 2-(2-Pyridine-2-sulfanyl)-octanoic acid hydroxyamide 76% @ 215 nm; LCMS (API electrospray) m/z 269 (M+H)*. Example 172 35 2-(4-Phenyl-thiazole-2-sulfanyl)-octanoic acid hydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 336 (M+H)*. Example 173 40 WO 99/42436 PCT/US98/17633 - 129 2-(2-Pyridin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 84% @ 215 nmn; LCMS (API-electrospray) m/z 297 (M+H) +. Example 174 5 2-(2-Phenyl-5H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide 67% @ 215 nm; LCMS (API-electrospray) m/z 338 (M+H)*. Example 175 10 2-(2-Pyrazin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 98% @ 215 nm; LCMS (API-electrospray) m/z 298 (M+H) +. Example 176 15 2-(1-Methyl-1H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide 66% @ 215 nm; LCMS (API-electrospray) m/z 274 (M+H)*. Example 177 20 2-(2-Benzimidazol-2-ylsulfinyl)-octanoic acid hydroxyamide 81% @ 215 nm. Example 178 25 2-(2-Pyridine-2-sulfinyl)-octanoic acid hydroxyamide 76% @ 215 nm;. Example 179 2-(4-Phenyl-thiazole-2-sulfinyl)-octanoic acid hydroxyamride 78% @ 215 nm. 30 Example 180 2-(2-Pyrazin-2-yl-ethylsulfinyl)-octanoic acid hydroxyamide 96% @ 215 nm; LCMS (API-electrospray) m/z 314 (M+H) . 35 Example 181 2 -(3-Oxy-1H-benzimidazole-2-sulfonyl)-octanoic acid hydroxyamide 63% @ 215 nm; LCMS (API-electrospray) m/z 356 (M+H)

+

. 40 Example 182 2-(4-Phenyl-thiazole-2-sulfonyl)-octanoic acid hydroxyamide 70% @ 215 nm; LCMS (API-electrospray) m/z 383 (M+H)*.

WO 99/42436 PCT/US98/1 7633 -130 Example 183 2-[2-(1-Oxy-pyridin-2-yl)-ethanesulfonyl]-octanoic acid hydroxyamide 77% @ 215 5 nm; LCMS (API-electrospray) m/z 345 (M+H)*. Example 184 3-(1-Hydroxycarbamoyl-heptylsulfanyl)-benzoic acid hydroxyamide. 100% @ 220 10 nm; LCMS (API-electrospray) m/z 312 (M+H) . Example 185 3-[4-(1-Hydroxycarbamoyl-heptylsulfanyl)-phenyl]-propionic acid hydroxyamide. 15 90% @ 220 nm; LCMS (API-electrospray) m/z 340 (M+H)*. Example 186 2-(Thiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. 75% @ 215 nm; LCMS (API 20 electrospray) m/z 275 (M+H)*. Example 187 2-(2,5-Dioxo-imidazolidin-4-ylmethylsulfanyl)-octanoic acid hydroxyamide. 98% @ 25 215 nm; LCMS (API-electrospray) m/z 304 (M+H) . Example 188 3-(1-Hydroxycarbamoyl-heptylsulfinyl)-benzoicacid hydroxyamide. 84% @ 220 nm; 30 LCMS (API-electrospray) m/z 328 (M+H)*. Example 189 3-[4-(1-Hydroxycarbamoyl-heptylsulfinyl)-phenyl]-propionic acid hydroxyamide. 78% 35 @ 220 nm; LCMS (API-electrospray) m/z 356 (M+H) . Example 190 2-(Quinoline-8-sulfinyl)-octanoic acid hydroxyamide. 87% @ 220 nm; LCMS (API 40 electrospray) m/z 335 (M+H) .

WO 99/42436 PCT/US98/17633 - 131 Example 191 2-(Naphthalen-2-ylcarbamoylmethanesulfinyl)-octanoic acid hydroxyamide. 83% @ 220 nm; LCMS (API-electrospray) m/z 391 (M+H) +. 5 Example 192 3-(1-Hydroxycarbamoyl-heptylsulfonyl)-benzoic acid hydroxyamide. 72% @ 215 nm. 10 Example 193 3-[4-(1-Hydroxycarbamoyl-heptylsulfonyl)-phenyl]-propionic acid hydroxyamide. 67% @ 215 nm. 15 Example 194 2-(1H-Imidazole-2-sulfonyl)-octanoic acid hydroxyamide. 95% @ 215 nm; LCMS (API-electrospray) m/z 290 (M+H) +. 20 Example 195 2-(Thiazol-2-ylsulfonyl)-octanoic acid hydroxyamide. 91% @ 215 nm; LCMS (API electrospray) m/z 307 (M+H) . 25 Example 196 2-(Quinoline-8-sulfonyl)-octanoic acid hydroxyamide. 94% @ 220 nm; LCMS (API electrospray) m/z 351 (M+H)*. 30 Example 197 2-(Naphthalen-2-ylcarbamoylmethanesulfonyl)-octanoic acid hydroxyamide. 79% @ 220 nm; LCMS (API-electrospray) m/z 407 (M+H) . 35 Example 198 2-(2,5-Dioxo-imidazolidin-4-ylmethylsulfonyl)-octanoic acid hydroxyamide. 97% @ 215 nm.

WO 99/42436 PCT/US98/17633 - 132 Example 199 Step A: Displacement of bromide with 4-fluorothiophenol. The 2-bromo hydroxymate resin prepared in Example 160, Step A (9.4 g, 1.2 meq/g) 5 was placed in a peptide synthesis vessel and suspended in THF (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 was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2 x 30 mL), DMF:water 9:1 (2 x 30 mL), DMF (30 mL), MeOH (2 x 20 mL), and 10 DCM (2 x 20 mL). The resin was dried in vacuo at room temperature. Step B: Coupling of 2-(4-fluorobenzenesulfanyl)-octanoic acid hydroxyamide resin with benzyl alcohol. 2-(4-Fluorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step A (330 15 mg, 1.1 meq/g) was suspended in DMF (2.0 mL) and benzyl alcohol (731 mg, 15 eq.) and sodium hydride (237 mg, 15 eq.) were added. The reaction was heated to 80 0 C for 15 hours while shaking on an orbital shaker. After cooling to room temperature the mixture was filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 3 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room 20 temperature. Step C: Oxidation of sulfide to sulfoxide. 2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and 70% tert 25 butylhydroperoxide (0.73 mL) benzenesulfonic acid (36 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 30 Step D: Oxidation of sulfide to sulfone. 2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.1 meq/g) was suspended in DCM (2.2 mL) and mCPBA (132 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 35 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.

WO 99/42436 PCT/US98/17633 - 133 Step E: Cleavage of 2-(4-benzyloxy-benzenesulfanyl)-octanoic acid hydroxyamide from resin. The 2-(4-benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (110 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was 5 added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions 10 described below: Column: ODS-A, 20mm x 50 mm, 5 pm particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 15 0.0 95 5 25 min. 5 95 Flow Rate: 15 mL/min. 2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide 100% @ 215 nm; LCMS (API-electrospray) m/z 374 (M+H) . 20 The hydroxamic acid compounds of Examples 200-220 are synthesized using appropriate starting materials and following the steps in example 199: Example 200 25 2-(4-Butoxy-benzenesulfanyl)-octanoic acid hydroxyamide 100% @ 215 nm; LCMS (API-electrospray) m/z 374 (M+H) . Example 201 30 2-[4-(2-Piperazine- 1-yl-ethoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 98% @ 215 nm; LCMS (API-electrospray) m/z 340 (M+H)*. Example 202 35 2-[4-(5-Hydroxy-pentyloxy)-phenylsulfanyl]-octanoic acid hydroxyamide 65% @ 215 nm.; LCMS (API-electrospray) m/z 370 (M+H)*.

WO 99/42436 PCT/US98/17633 - 134 Example 203 2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 95% @ 215 nm; LCMS (API-electrospray) m/z 403 (M+H)*. 5 Example 204 2-(4-Benzyloxy-phenylsulfinyl)-octanoic acid hydroxyamide 100% @ 215 nm. 10 Example 205 2-(4-Butoxy-benzenesulfinyl)-octanoic acid hydroxyamide 98% @ 215 nm. Example 206 15 2-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfinyl]-octanoic acid hydroxyamide 98% @ 215 nm. Example 207 20 2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfinyl]-octanoic acid hydroxyamide 99% @ 215 nm. Example 208 25 2-(4-Benzyloxy-phenylsulfonyl)-octanoic acid hydroxyamide 100% @ 215 nm. Example 209 30 2-(4-Butoxy-benzenesulfonyl)-octanoic acid hydroxyamide 100% @ 215 nm. Example 210 2-[4-(2-Piperazine-1-yl-ethoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 35 97% @ 215 nm. Example 211 2-[4-(3-Pyridin-2-yl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 100% @ 215 nm. 40 Example 212 2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfanyl]-octanoic acid hydroxyamide 91% @ 215 nm; LCMS (API-electrospray) m/z 367 (M+H)*.

WO 99/42436 PCT/US98/17633 - 135 Example 213 2-[4-( 1-Ethyl-propoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 5 100% @ 215 nm; LCMS (API-electrospray) m/z 354 (M+H)*. Example 214 2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfanyl]-octanoic acid hydroxyamide 10 97% @ 215 nm; LCMS (API-electrospray) m/z 368 (M+H)*. Example 215 2-[4-( 1-Methyl-pyrrolidin-3-yloxy)-benzenesulfinyl]-octanoic acid hydroxyamide 15 96% @ 215 nm. Example 216 2-[4-( 1-Ethyl-propoxy)-benzenesulfinyl]-octanoic acid hydroxyamide 97% @ 215 nm. 20 Example 217 2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfinyl]-octanoic acid hydroxyamide 97% @ 215 nm. 25 Example 218 2-[4-(1-Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]-octanoic acid hydroxyamide 96% @ 215 nm. 30 Example 219 2-[4-( 1-Ethyl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 100% @ 215 nm. 35 Example 220 2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfonyl]-octanoic acid hydroxyamide 100% @ 215 nm.

WO 99/42436 PCT/US98/17633 -136 Example 221 Step A: Displacement of bromide with 4-bromothiophenol. The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160, Step A (5.0 g, 5 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in THF (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 was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2 x 30 mL), DMF:water 9:1 (2 x 30 mL), DMF (30 mL), MeOH (2 x 30 mL), and 10 DCM (2 x 30 mL). The resin was dried in vacuo at room temperature. Step B:Oxidation of sulfide to sulfoxide. 2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step A (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and 70% tert-butylhydroperoxide (30 15 mL) benzenesulfonic acid (1.5 g) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 30 mL), DMF (2 x 30 mL), MeOH (2 x 30 mL), and DCM (2 x 30 mL). The resin was dried in vacuo at room temperature. 20 Step C: Oxidation of sulfide to sulfone. 2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (4.4 g, 1.1 meq/g) was suspended in DCM (60 mL) and mCPBA (5.2 g) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 30 mL), DMF (2 x 30 25 mL), MeOH (2 x 30 mL), and DCM (2 x 30 mL). The resin was dried in vacuo at room temperature. Step D: Coupling of 2-(4-bromobenzenesulfinyl)-octanoic acid hydroxyamide resin with 4-chlorobenzeneboronic acid. 30 2-(4-Bromobenzenesulfinyl)-octanoic acid hydroxyamide resin prepared in Step B (150 mg, 1.1 meq/g) was suspended in DME (2.0 mL) and nitrogen gas bubbled through the suspension for 1-2 minutes. 4-Chlorobenzeneboronic acid (51.6 mg, 2 eq.), tetrakis(triphenylphosphine) palladium(0) (19.07 mg, 0.1 eq.) and sodium carbonate (2 M solution, 0.825 mL, 10 eq.) were added. The reaction was heated to 80 0 C for 8 35 hours while shaking on an orbital shaker. After cooling to room temperature the mixture was filtered and washed with DME (2 x 2 mL), DMF:water 9:1 (2 x 3 mL), WO 99/42436 PCT/US98/17633 - 137 MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step E: Cleavage of 2-(4'-chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide from 5 resin. The 2-(4'-chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide resin prepared in Step D (150 mg, 1.1 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were 10 combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions described below: 15 Column: ODS-A, 20mm x 50 mm, 5 gm particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 5 25 min. 5 95 20 Flow Rate: 15 mL/min. 2-(4'-Chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide 96% @ 215 nm; LCMS (API-electrospray) m/z 394 (M+H) . The hydroxamic acid compounds of Exmples 222-224 are synthesized using 25 appropriate starting materials and following the steps in example 221: Example 222 2-[4-(5-Chloro-thiophen-2-yl)-benzenesulfinyl]-octanoic acid hydroxyamide 100% @ 30 215 nm; LCMS (API-electrospray) m/z 400 (M+H)*. Example 223 2-(4'-Chloro-biphenyl-4-sulfonyl)-octanoic acid hydroxyamide 94% @ 215 nm; 35 LCMS (API-electrospray) m/z 410 (M+H) .

WO 99/42436 PCT/US98/17633 - 138 Example 224 2-[4-(5-Chloro-thiophen-2-yl)-benzenesulfonyl]-octanoic acid hydroxyamide 85% @ 215 nm; LCMS (API-electrospray) m/z 416 (M+H)*. 5 Example 225 Step A:Coupling of 2-(4-bromobenzenesulfanyl)-octanoic acid hydroxyamide resin with N-(3-aminopropyl)-morpholine. 10 2-(4-Bromobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Example 199, Step A (100 mg, 1.1 meq/g) was suspended in dioxane (2.0 mL) and nitrogen gas bubbled through the suspension for 1-2 minutes. N-(3-Aminopropyl)-morpholine (346 mg, 20 eq.), tris(dibenzylideneacetone)-dipalladium(0) (22 mg, 0.2 eq.), (S)-(-)-2,2' bis(diphenylphosphino)-1,1'-binaphthyl((S)-BINAP, 60 mg, 0.8 eq.) and sodium tert 15 butoxide (207 mg, 18 eq.) were added. The reaction was heated to 80 0 C for 8 hours while shaking on an orbital shaker. After cooling to room temperature the mixture was filtered and washed with DMF (2 x 2 mL), DMF:water 9:1 (2 x 3 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. 20 Step B:Cleavage of 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide from resin. The 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide resin prepared in Step A (100 mg, 1.1 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. 25 The reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The crude product was dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions described below: 30 Column: ODS-A, 20mm x 50 mm, 5 gm particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 5 35 25 min. 5 95 Flow Rate: 15 mL/min. 2-[4-(3-morpholin-4-yl-propylamino)-phenylsulfanyl]-octanoic acid hydroxyamide 88% @ 215 nm; LCMS (API-electrospray) m/z 410 (M+H)*.

WO 99/42436 PCT/US98/17633 - 139 The hydroxamic acid compounds of Examples 226-231 are synthesized using appropriate starting materials and following the steps in this example: 5 Example 226 2 -[4-(Biphenyl-4-ylamino)-phenylsulfanyl]-octanoic acid hydroxyamide 95% @ 215 nm; LCMS (API-electrospray) m/z 435 (M+H)*. 10 Example 227 2 -[4-(Pyridin-4-ylamino)-phenylsulfanyl]-octanoic acid hydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 360 (M+H)*. 15 Example 228 2

-(

4 -Cyclopentylamino-phenylsulfanyl)-octanoic acid hydroxyamide 77% @ 215 nm; LCMS (API-electrospray) m/z 351 (M+H)*. 20 Example 229 2-(4-Methylamino-phenylsulfanyl)-octanoic acid hydroxyamide 99% @ 215 nm; LCMS (API-electrospray) m/z 297 (M+H) . 25 Example 230 2 -(4-Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide 72% @ 215 nm; LCMS (API-electrospray) m/z 351 (M+H)*. 30 Example 231 2 -(4-Piperazin-l-yl-phenylsulfanyl)-octanoic acid hydroxyamide 74% @ 215 nm; LCMS (API-electrospray) m/z 352 (M+H) . 35 Example 232 Step A: Displacement of bromide with 4-hydroxythiophenol. The 2-bromo-octanoic acid hydroxymate resin prepared in Example 160, Step A (15.0 g, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in THF (120 40 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 WO 99/42436 PCT/US98/17633 -140 was shaken at room temperature for 12 - 16 hours, then filtered and washed with DMF (2 x 60 mL), DMF:water 9:1 (2 x 60 mL), DMF (60 mL), MeOH (2 x 60 mL), and DCM (2 x 60 mL). The resin was dried in vacuo at room temperature. 5 Step B: Coupling of 2-(4-hydroxybenzenesulfanyl)-octanoic acid hydroxyamide resin with benzene sulfonyl chloride. 2-(4-Hydroxybenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step A (240 mg, 1.2 meq/g) 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 was 10 shaken on an orbital shaker at room temperature for 8 hours, then filtered and washed with DME (2 x 2 mL), DMF:water 9:1 (2 x 3 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature. Step C: Oxidation of sulfide to sulfoxide. 15 Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL) and 70% tert butylhydroperoxide (1 mL) benzenesulfonic acid (23 mg) were added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 3 mL), DMF (2 x 3 mL), MeOH (2 x 20 3 mL), and DCM (2 x 3 mL). The resin was dried in vacuo at room temperature. Step D: Oxidation of sulfide to sulfone. Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL) and mCPBA 25 (84 mg) was added. The reaction mixture was shaken on an orbital shaker at room temperature for 12 - 24 hours. The reaction was filtered and washed with DCM (2 x 3 mL), DMF (2 x 3 mL), MeOH (2 x 3 mL), and DCM (2 x 3 mL). The resin was dried in vacuo at room temperature. 30 Step E: Cleavage of benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl) phenyl ester resin. The benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (1.0 mL) and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at room temperature. The 35 reaction was filtered and the resin washed with DCM (2 x 1 mL). The filtrate and the washing were combined and concentrated to dryness on a Savant SpeedVac Plus. Methanol (1 mL) was added and the mixture concentrated. The crude product was WO 99/42436 PCT/US98/17633 - 141 dissolved in DMSO:methanol (1:1, 2 mL) and purified by reverse phase HPLC under the conditions described below: Column: ODS-A, 20mm x 50 mm, 5 gm particle size (YMC, Inc. Wilmington, North 5 Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 5 25 min. 5 95 Flow Rate: 15 mL/min. 10 Benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester 91% @ 215 nm; LCMS (API-electrospray) m/z 424 (M+H)*. The hydroxamic acid compounds of Examples 233-240 are synthesized using appropriate starting materials and following the steps in example 232: 15 Example 233 2,5-Dichloro-thiophene-3-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfanyl) hydroxyamide 98% @ 215 nm; LCMS (API-electrospray) mn/z 498 (M+H) . 20 Example 234 Ethanesulfonic acid 4(1-hydroxycarbamoyl-heptylsulfanyl)-hydroxyamide. 72% @ 215 nm; LCMS (API-electrospray) m/z 376 (M+H)*. 25 Example 235 5-Chloro-1,3-dimethyl-l1H-pyrazole-4-sulfonic acid 4-(1-hydroxycarbamoyl-heptyl sulfinyl)-hydroxyamide 99% @ 215 nm; LCMS (API-electrospray) m/z 492 (M+H) . 30 Example 236 2,5-Dichloro-thiophene-3-sulfonic acid 4-( 1-hydroxycarbamoyl-heptylsulfinyl) hydroxyamide 96% @ 215 nm; LCMS (API-electrospray) m/z 514 (M+H) . 35 Example 237 5-Pyridin-2-yl-thiophene-2-sulfonic acid 4(1-hydroxycarbamoyl-heptylsulfinyl) hydroxy amide 96% @ 215 nm; LCMS (API-electrospray) m/z 523 (M+H) .

WO 99/42436 PCT/US98/17633 - 142 Example 238 2-Nitro-benzenesulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 5 97% @ 215 nm; LCMS (API-electrospray) m/z 501 (M+H) +. Example 239 3-Bromo-2-chloro-thiophene-2-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl) 10 hydroxyamide 97% @ 215 nm; LCMS (API-electrospray) m/z 576 (M+H) +. Example 240 Benzo[ 1,2,5]thiadiazole-4-sulfonic acid 4-(1-hydroxycarbamoyl-heptylsulfonyl) 15 hydroxyamide 83% @ 215 nm; LCMS (API-electrospray) m/z 514 (M+H)*. Example 241 1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 20 To a stirred solution of 4-methoxybenzenethiol (2.8 gin, 20 mmol) and anhydrous

K

2

CO

3 (10 gmin, excess) in dry acetone (100 ml), a-bromo ethyl acetate (3.3 gin, 20 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to cool and 25 the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H20 and 0.5 N NaOH solution. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g (100%); MS; 227 (M+H) + 30 To stirred solution of (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol), anhydrous K2CO3 (10 gm, excess) in dry acetone (100 ml) benzyl bromide (3.5 g, 20 mmol) was added and refluxed for 4 hrs. At the end, reaction mixture was filtered , concentrated and the residue was extracted with chloroform. It was washed 35 well with water, dried and concentrated. The crude product obtained was converted to (4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester by oxidaizing with m-chloro perbenzoic acid as described in the example 83. Low melting solid. Yield: 6.6 g, 97%; MS: 335 (M+1) WO 99/42436 PCT/US98/1 7633 - 143 To a stirred solution of bis-(2-chloro-ethyl)-benzyl amine hydrochloride (6.6 g, 24.7 mmol), 18-Crown-6 (500 mg), and anhydrous K2CO3 (30 gin, excess) in.dry acetone (250 ml), (4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester (8.01 gin, 24 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 16 5 hours with good stirring. At the end, the reaction mixture was allowed to cool and the potassium salts were filtered off and the reaction mixture was concentrated. The residue was extracted with chloroform and washed with H20. The organic layer was further washed well with water, dried over MgSO4, filtered and concentrated. The dark brown reaction mixture was purified by silica gel coumn chromatography by eluting it 10 with 30% ethylacetate: hexane and the product 4-(4-Benzyloxy-benzenesulfonyl)-1 benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.5 g, 55%; MS: 494 (M+H) 4-(4-Benzyloxy-benzenesulfonyl)- 1 -benzyl-piperidine-4-carboxylic acid ethyl ester 15 (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1,200 mnl) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. HC1 by dissolving it in water (200 ml). After the nuetralization reaction mixture was concentrated to dryness. Ice cold water (100 ml) was added to the solid and filtered. The product 4-(4-Benzyloxy-benzenesulfonyl)-1 20 benzyl-piperidine-4-carboxylic acid was dried at 50 C and taken to next step with out any purification. Colorless solid. MP: 66-68; Yield: 4.3 g, 91% ; MS: 466 (M+H) Starting from 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure outlined in example 83, 1.1 g of 4 (4-Benzyloxy-benzenesulfonyl)- 1-benzyl-piperidine-4-carboxylic acid hydroxyamide 25 was isolated as a colurless solid. Yield 21%; mp 89 oC; MS: 481.1 1H NMR (300 MHz, DMSO-d6): 8 2.27 (min, 3H), 2.76-2.79 (min, 2H), 3.43 (min, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (min, 5H), 9.37 (s,1H), 10.53 (s,lH), 11.18 (s,lH). Example 242 30 4-(4-Butoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl] piperidine-4-carboxylic acid hydroxyamide From 2-[(2-Hydroxy-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared 35 according to the general method outlined in 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)* WO 99/42436 PCT/US98/17633 -144 Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was prepared according to the general method outlined in example 83 starting from 2-[(2-Hydroxy ethyl)- [4-(2-piperidin-l-yl-ethoxy)-benzyl]-amine (3.22 g, 10 mmol). Yield 4.0 g (92%); brown semi-solid; MS: 361.1 (M+H) + 5 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 outlined in example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6.0 g, 20 mmol) and Bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine (8.6 10 g, 20 mmol). Yield 8.0 g (68%); brown oil; MS: 587.7 (M+H) + 4-(4-Butoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)- 1-[4-(2 piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 15 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98 oC; MS: 559.6 (M+H) + Starting from 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl] 20 piperidine-4-carboxylic acid (5.5 g, 10 mmol) and following the procedure outlined in example 83, 2.4 g of 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin- 1 -yl-ethoxy) benzyl]-piperidine-4-carboxylic acid hydroxy amidewas isolated as a pale yellow solid. Yield 41%; mp 155 oC (HC1); MS: 574 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 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, 25 8H), 4.2 (m, 2H), 6.9 - 7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H). Example 243 4-(4-Butoxy-benzenesulfonyl)-I-[3-(2-morpholinyl- 1-yl-ethoxy)-benzyl]-piperidine-4 30 carboxylic acid hydroxyamide Bis-(2-hydroxy-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine was prepared according to the general method outlined in example 83 starting from diethanolamine (15.0 g, 150). and 3-(2-morpholin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol). 35 Yield 6.2 g, (95%); Brown semi-solid; MS: 325 (M+H)

"

WO 99/42436 PCT/US98/1 7633 - 145 Bis-(2-chloro-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine was prepared according to the general method outlined in example 83 starting from Bis-(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)* 5 4-(4-Butoxy-benzenesulfonyl)- 1-[3-(2-morpholin- 1-yl-ethoxy)-benzyl]-piperidin e-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from from 4-(butoxy-benzenesulfonyl) acetic acid ethyl ester (6.0 g, 20 mmol) and Bis-(2-chloro-ethyl)-[3-(2-morpholin-1-yl-ethoxy)-benzyl]-amine 10 (8.6 g, 20 mmol). Yield 8.5 g (72%); brown oil; MS: 589.7 (M+H) + 4-(4-Butoxy-benzenesulfonyl)- 1 -[3-(2-morpholin- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[3-(2 morpholin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 15 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (85%); Spongy brown solid; MS: 561.6 (M+H)* Starting from 4-(4-butoxy-benzenesulfonyl)- 1-[3-(2-morpholin- 1-yl-ethoxy)-benzyl] 20 piperidine-4-carboxylic acid (5.6 g, 10 mmol) and following the procedure outlined in example 83, 4.02 g of 4-(4-butoxy-benzenesulfonyl)- 1-[3-(2-morpholin-1-yl-ethoxy) benzyl]-piperidine-4-carboxylic acid hydroxy amidewas isolated as a pale yellow solid. Yield 62%; mp 123 oC (HCI); MS: 576 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 5 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, 25 1H), 10.8 (bs, 1H). Example 244 1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 30 1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4 (butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and methyl-bis-(2 chloro-ethyl)-amine (2.2g, 11.6 mmol). Yield 4.0 g, (98%); low melting brown solid; 35 MS: 384 (M+H)* WO 99/42436 PCT/US98/17633 -146 1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting 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 outlined in example 83. Yield 6.0 g (84%); 5 white solid; mp 195 oC; 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 procedure outlined in example 83, 3.9 g of 1-methyl 4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated 10 as a yellow powder. Yield 85%; mp 118 oC; MS: 371 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.9 (t, 3H), 1.45 (q, 2H), 1.8 (q, 2H), 2.1 (s, 3H), 2.3 (d, J = 11.4 Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H) Example 245 15 1-Ethyl-4-(4-butoxy-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 outlined in example 83 starting from 4 20 (butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and ethyl-bis-(2 chloro-ethyl)-amine (2.2g, 10.6 mmol). Yield 3.5 g, (88%); low melting brown solid; MS: 398 (M+H) 1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared 25 starting from 1-ethyl-4-(4-butoxy-benzenesulfonyl)-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 outlined in example 83. Yield 6.5 g (88%); white solid; mp 162 oC; MS: 370 (M+H)* 30 Starting from 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (3.7 g, 10 mmol) and following the procedure outlined in example 83, 3.2 g of 1-ethyl-4 (4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a yellow powder. Yield 76%; mp 98 oC; MS: 385 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.9 (t, 3H), 1.2 (t, 3H), 1.46 (q, 2H), 1.9 (q, 2H), 2.3 (d, J = 11.4 Hz, 35 2H), 2.5-3.6 (m, O10H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H) WO 99/42436 PCT/US98/17633 -147 Example 246 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 5 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4 (butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and n-butyl-bis-(2 chloro-ethyl)-amine (2.0g, 10.1 mmol). Yield 3.8 g, (89%); low melting brown solid; MS: 426 (M+H)* 10 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-n-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 outlined in example 83. Yield 7.5 g 15 (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 outlined in example 83, 1.8 g of 1-n butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was 20 isolated as a yellow powder. Yield 40%; mp 121 oC; MS: 413 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.9-1.0 (min, 6H), 1.2-1.8 (min, 8H), 2.2-2.8 (min, 8H), 3.0-3.6 (inm, 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). 25 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) 30 acetic acid ethyl ester (2.12 g, 10 mmol), sodium hydride (460 mg, 10 mmol) and copper(II) chloride (500 mg) was refluxed in anhydrous pyridine (50 ml) for 12 hrs. The reaction mixture was carefully quenched with ice cold water and acidified with concentrated HC1. The product was extracted with choroform, washed well with water; dried and concentrated. The product was purified by silica gel column chromatography 35 by eluting with 30% ethyl acetate : hexane. Yield 2.5 g (77%); Colorless low melting solid; MS: 323 (M+H) . Alternatively the title compound may be prepared from 4-(4 chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.

WO 99/42436 PCT/US98/17633 - 148 Example 248 [4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester 5 [4-(4-Chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy) phenylsulfanyl]-acetic acid ethyl ester ( 3.23g, 10 mmol) and oxone (10 g). Yield 3.5g ( 99%); oil; MS: 356EI (M+H)* 10 Example 249 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-methyl-piperidine-4-carboxylic acid hydroxyamide 15 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]- 1 -methyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester ( 2.0g, 5.6mmol) and mechlorethanmine hydrochloride (Aldrich), (1.9g, 10mmol). Yield 2g ( 81%); brown oil; MS:438 (M+H)* 20 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]- 1-methyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]- 1 -methyl-piperidine 4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH ( 100 ml). The resulting reaction mixture was worked up as outlined 25 in example 83. Yield 3.5g (86 %); white solid; mp 185oC; MS:410(M+H) Starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-methyl-piperidine-4 carboxylic acid (1.0 g, 2.4 mmol) and following the procedure outlined in example 83, 460mg of 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-methyl-piperidine-4-carboxylic 30 acid hydroxyamide was isolated as a HCI salt, a white powder. Yield 41%; mp 52 oC; MS: 426 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 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).

WO 99/42436 PCT/US98/17633 -149 Example 250 4 -[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-ethyl-piperidine-4-carboxylic acid hydroxyamide 5 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (4 g, 11.3 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.32 g, 16.9 mmol). Yield 3.36 g (66%); brown 10 oil; MS: 452.0 (M+H) 4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-l1-ethyl-piperidine-4-carboxylic acid was prepared starting from 4 -[4-(4-chloro-phenoxy)-benzenesulfonyl]- 1-ethyl-piperidine-4 carboxylic acid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3:1 150 ml) 15 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.8 g (65%); white solid; mp 184oC; MS: 423.9 (M+H)* Starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]- 1-ethyl-piperidine-4 carboxylic acid (1.75 g, 4.14 mmol) and following the procedure outlined in example 20 83, 650 mg of 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1-ethyl-piperidine-4 carboxylic acid hydroxyamide was isolated as a HCI salt, a white powder. Yield 33%; mp 158 oC; MS: 438.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 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), 25 9.85 (s, 1H). Example 251 1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid 30 hydroxyamide 1-Butyl- 4

-[

4

-(

4 -chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [ 4

-(

4 -chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 18.3 mmol) 35 and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)* WO 99/42436 PCT/US98/17633 -150 1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4 carboxylic acid ethyl ester (3.3 g, 6.9 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in 5 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 procedure outlined in example 83, 630 mg of 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic 10 acid hydroxyamide was isolated as a HCI salt, a white solid. Yield 31%; mp 212 oC; MS: 466.9 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.87 (t, J=7.3 Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70 (q, 2H), 3.00 (m, 2H), 3.57 (d, 2H), 7.16-7.26 (m, 4H), 7.49-7.56 (m, 2H), 7.77 (d, J = 9 Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H). 15 Example 252 1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide 20 1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 16.9 mmol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow 25 oil; MS: 513.9 (M+H)* 1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine 4-carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in THF:methanol (3:1 150 30 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201 oC; MS: 485.9

(M+H)

+ Starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4 35 carboxylic acid (1 g, 2.06 mmol) and following the procedure outlined in example 83, 430 mg of 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCI salt, an off white solid. Yield 39%; mp WO 99/42436 PCT/US98/17633 - 151 90.4oC; MS: 500.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 2.18-2.30 (m, 2H), 2.73-2.81 (min, 4H), 3.36 (d, 2H), 4.28 (d, J= 4.5 Hz, 2H), 7.15-7.25 (min, 4H), 7.43 7.48 (min, 3H), 7.51-7.56 (min, 4H), 7.74 (d, J = 9 Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H). 5 Example 253 [4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester 10 To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mimol), K 2

CO

3 (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. 15 The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H) 283. Example 254 20 [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenyl sulfanyl]-acetic acid ethyl ester (2.8 g, 10 mmol) and oxone (10 g). Yield 3.0g (99%); 25 oil; MS: 314EI (M+H)* Example 255 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid 30 hydroxyamide 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and 35 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 was prepared starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine- WO 99/42436 PCT/US98/17633 - 152 4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g (67%); white solid; mp 182 oC; MS: 446 (M+H)* 5 Starting from 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4 carboxylic acid (2.2 g, 5 mmol) and following the procedure outlined in example 83, 1.82 g of 1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HC1 salt, an off white solid. Yield 73%; mp 106 oC; MS: 498 (M+H)+; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.8 (d, 6H), 1.5 (m,1H), 10 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, 4H11), 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 256 15 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl 20 ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M+H) + 25 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4 carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g (77%); white solid; mp 188 oC; MS: 412 (M+H) + 30 Starting from 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4 carboxylic acid (2.0 g, 5 mmol) and following the procedure outlined in example 83, 1.6 g of 1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCI salt, an off white solid. Yield 69%; mp 201 oC; 35 MS: 464 (M+H)

+.

WO 99/42436 PCT/US98/17633 - 153 Example 257 [4-(2-Ethyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester 5 To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K 2 C0 3 (anhydrous, 10 g) and 1-bromo-2-ethyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude 10 product obtained was taken to next step without purification. Yield 2.8 g (94%); (M+H) 297. Example 258 15 [4-(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester [4-(2-Ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(2-ethyl-butoxy)-phenyl sulfanyl]-acetic acid ethyl ester (2.96 g, 10 mmol) and oxone (10 g). Yield 3.1g ( 20 99%); oil; MS: 329EI (M+H) Example 259 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid 25 hydroxyamide 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(2-ethyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.4 g, 20 mmol) and 30 bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 8 g (82%); yellow oil; MS: 488 (M+H)* 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4 35 carboxylic ethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 mi) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined 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 40 acid (2.2 g, 5 mmol) and following the procedure outlined in example 83, 1.02 g of 1- WO 99/42436 PCT/US98/17633 - 154 Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCI salt, an off white solid. Yield 40%; mp 114 oC; MS: 512 (M+H) +. 5 Example 260 4-(4-butoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 10 4-(4-Butoxy-benzenesulfonyl)- 1 -(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acetic acid ethyl ester (20 g, 77.5 mmol) and bis (2-chloro-ethyl)-(3-methoxy-benzyl)-amine (34 g, 116 mmol). Yield 9.53 g (25%); brown oil; MS: 490.2 (M+H) 15 4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl) piperidine-4-carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture 20 was worked up as outlined in example 83. Yield 1 g (41%); brown solid; mp 175oC; MS: 462.0 (M+H)* Starting from 4-(4-butoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4 carboxylic acid (900 mg, 1.95 mmol) and following the procedure outlined in example 25 83, 200 mg of 4-(4-butoxy-benzenesulfonyl)-l1-(3-methoxy-benzyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as a HCI salt, a brown powder. Yield 20%; mp 137 oC; MS: 477.0 (M+H)+; 1'H1 NMR (300 MHz, DMSO-d 6 ): 6 0.96 (t, J=7.11 Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H11), 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 30 (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).

WO 99/42436 PCT/US98/17633 - 155 Example 261 4-(4-Methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide 5 4-(4-Methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from 1-(4-Bromo-benzyl)-4-(4-methoxy benzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2 (tributylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium 10 (0) in boiling tolune. Yield 1.58 g (52%); brown solid; mp 130'C; MS: 500 (M+H) 4-(4-Methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl benzyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in 15 THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 950 mg (77%); brown solid; mp 235oC; MS: 471.8 (M+H) Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4 20 carboxylic acid (920 mg, 1.95 mmol) and following the procedure outlined in example 83, 510 mg of 4-(4-methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine 4-carboxylic acid hydroxyamide was isolated as a HCI salt, a brown solid. Yield 50%; mp 166 oC; MS: 486.9 (M+H) ; 'H NMR (300 MHz, DMSO-d 6 ): 5 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 25 (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 30 hydroxyamide 4-(4-Methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 261. Starting from 1-(4-Bromo-benzyl)-4-(4-methoxy-benzensulfonyl)-piperidine-4 35 carboxylic acid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributylstannyl)-pyridine (12.08 g, 32.8 mmol). Yield 2.79 g (60%); brown oil; MS: 495.1 (M+H)* WO 99/42436 PCT/US98/17633 - 156 4-(4-Methoxy-benzenesulfonyl)- 1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl) piperidine-4-carboxylic acid ethyl ester (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 5 as outlined in example 83. Yield 1.38 g (80%); off white solid; mp 217 0 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 following the procedure outlined in example 10 83, 480 mg of 4-(4-methoxy-benzenesulfonyl)-l1-(4-pyridin-2-yl-benzyl)-piperidine-4 carboxylic acid hydroxyamide was isolated as a HCI salt, a white powder. Yield 33%; mp 214 'C; MS: 482.0 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 6 2.30 (m, 2H), 2.80 (min, 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 (min, 4H), 7.84-7.95 (min, 3H), 8.55 (d, J= 8.1 Hz, 15 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H) Example 263 1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine 20 4-carboxylic acid hydroxyamide 4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethyl ester (13.2g 44 mmol) (3,4 25 dichloro-benzyl)-bis-(2-chloro-ethyl)-amine (14.3g, mmol). Yield 14.1g (60%), white solid, MP 86oC; MS: 527.9 (M+H)* 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl) 30 piperidine-4-carboxylic acid ethyl ester (14.0 g, 26.5 mmol) dissolved in THF:Methanol (100: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.87 (60%); off white solid; mp 239 0 C; MS: 501.9 (M+H) 35 Starting 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (7.7g, 15.5 mmol) and following the procedure outlined in example 83, 4.05g of 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCI salt, white solid. Yield 48%; mp 256.8 oC; MS: WO 99/42436 PCT/US98/17633 - 157 514.9 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.94 (t, 3H), 1.38-1.48 (q, 2H), 1.68-1.75 (q, 2H), 2.27 (m, 4H),2.72 (m, 2H), 4.10 (t, 2h), 4.24 (s, 2H), 7.12-7.15 (d, J=8.9, 2H), 7.51-7.53 (d, J=8.1, 1H), 7.63-7.65 (d, J=8.8, 2H), 7.72-7.75 (d, J=9.9, 2H), 7.87 (s, 1H), 9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H) 5 Example 264 [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4 carboxylic acid hydroxamide 10 [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-benzyloxy)-benzenesulfonyl]-acetic acid ethyl ester (13.79g, 37 mmol) and 4-(4-chloro-benzyloxy)-bis-(2-chloro-ethyl)-amine (8.7g, 45 mmol). Yield 15 10.9 (65%); brown oil; MS: 451.9 (M+H) + [4-(4-Chloro-benzyloxy)-benzenesulfonyl- 1 -methylpiperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine 4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 75 ml) 20 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9g (50%); off white solid; MS: 426.2 (M+H)* Starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4 carboxylic acid (4.9g, 12 mmol) and following the procedure outlined in example 83, 25 1.2g of [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide was isolated as a HCI salt, off white solid. Yield 24%; mp 117.8 oC; MS: 438.9 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 8 2.2 (m, 2H), 2.49 (m, 4H), 2.5 (s, 3 H), 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) 30 Example 265 4-(4-Butoxy-benzenesulfonyl)- 1-(3-phenoxy-benzyl)-piperidine-4 carboxylic acid hydroxamide 35 4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4-(4-butoxy-benzenesulfonyl)-acetic acid ethyl ester (10.1g, 34 mmol) and 1-(3- WO 99/42436 PCT/US98/17633 - 158 phenoxy-benzyl)-bis-(2-chloro-ethyl)-amine (18g, 50 mmol). Yield 8.9 (49%); brown oil; MS: 552.1 (M+H) 4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid was 5 prepared starting from 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine 4-carboxylic ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.0g (76%); off white solid; MS: 524.3 (M+H)* 10 Starting from 4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4 carboxylic acid (5.9g, 11 mmol) and following the procedure outlined in example 83, 0.39g of 4-(4-butoxy-benzenesulfonyl)- 1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HCI salt, tan solid. Yield 11%; mp 92.5 oC; MS: 539.1 (M+H)*; 1 H NMR (300 MHz, DMSO-d 6 ): 8 0.93-0.97 (t, J=3.6, 3H), 1.49 (m, 15 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 20 [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl)-piperidine-4 carboxylic acid hydroxamide [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl)-piperidine-4 25 carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [ 1-(4-chloro-benzyloxy)-benzenesulfonyl]-acetic acid ethyl ester (5.47g, 15 mmol) and 1-(4-methyl-benzyl)-bis-(2-chloro-ethyl)-amine (5.23g, 18 mmol). Yield 8.0 (96%); brown oil; MS: 542.0 (M+H) 30 [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl)-piperidine-4 carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl] 1-(4-methylbenzyl)-piperidine-4- carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in THF:Methanol (50: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6g (61%); off 35 white solid, mp 204 oC; MS: 514.2 (M+H)* Starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl) piperidine-4-carboxylic acid (4.2g, 8 mmol) and following the procedure outlined in WO 99/42436 PCT/US98/17633 - 159 example 83, 1.3g of [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1-(4-methylbenzyl) piperidine-4-carboxylic acid hydroxamide was isolated as a HC1 salt, yellow solid. Yield 29%; mp 172 oC; MS: 528.9 (M+H)*; 'H NMR (300 MHz, DMSO-d 6 ): 8 5 Example 267 4-(4-Butoxy-benzenesulfonyl)- 1-(4-methylbenzyl)-piperidine-4 carboxylic acid hydroxamide 10 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting 4 (4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (5.47g, 15 mmol) and 1-(4-methyl benzyl)-bis-(2-chloro-ethyl)-amine (15.3g, 51 mmol). Yield 10.1 (57%); white solid, MP 93oC; MS: 474.1 (M+H)* 15 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4 carboxylic ethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in 20 example 83. Yield 7.2g (72%); off white solid, mp 244 oC; MS: 446.3 (M+H) Starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4 carboxylic acid (6.6g, 1.5 mmol) and following the procedure outlined in example 83, 2.06g of 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4-carboxylic 25 acid hydroxamide was isolated as a HCI salt, yellow solid. Yield 28%; mp 137 oC; MS: 461.3 (M+H) ; 'H NMR (300 MHz, DMSO-d 6 ): 8 0.91-0.964 (t, J=7.3, 3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, s, 3H), 2.52 (m, 2H), 2.76 (m, 2H), 3.33 (bd, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12-7.14 (d, J=8.7, 2H), 7.25-7.28 (d, J=8.1, 2H), 7.42-7.45 (d, J=7.8, 2H), 7.63 30 7.65 (d, J=8.7, 2H), 10.31 (s, 1H), 10.75 (bs, 1H) Example 268 4-(4-Butoxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4- hydroxamide 35 carboxylic acid hydroxamide 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting 4- WO 99/42436 PCT/US98/17633 -160 (4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (5.29g, 17.6 mmol) and 1-(4-cyano benzyl)-bis-(2-chloro-ethyl)-amine (6.19g, 21 mmol). Yield 6.8g (80%); tan oil; MS: 485.0 (M+H) + 5 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4 carboxylic ethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield .7g (11%); off white solid; MS: 456.0 (M+H) + 10 Starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4 carboxylic acid (.600g, 1.2 mmol) and following the procedure outlined in example 83, .21g of 4-(4-Butoxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HC1 salt, off white solid. Yield 34%; mp 241.6 oC; 15 MS: 472.0 (M+H)+; 'H NMR (300 MHz, DMSO-d 6 ): 8 .915-.964 (t, J=7.2, 3H), 1.51 (q, 2H), 1.75 (q, 2H), 2.27 (m, 2H), 2.49 (m, 4H), 4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-7.15 (d, J=8.7, 2H), 7.63-7.66 (d, J=9, 2H), 7.72-7.74 (d, J=7.8, 2H), 9.36 (s, 1H), 10.23 (s, 1H), 11.16 (s, 1H) 20 Example 269 4-(4-Butoxy-benzenesulfonyl)- 1-pyridin-4-ylmethyl-piperidine-4 carboxylic acid hydroxamide 25 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting with 4-(4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (6.0g, 20.0 mmol) and pyridin-4 ylmethyl-bis-(2-chloro-ethyl)-amine. (4.89g, 21 mmol). Yield 4.5g (48%); Brown oil; MS: 461.0 (M+H) + 30 4-(4-Butoxy-benzenesulfonyl)- 1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)- 1 -pyridin-4-ylmethyl-piperidine 4-carboxylic acid ethyl ester (3.0 g, 6.5 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in 35 example 83. Yield 1.2g (42%); off white solid; MS: 433.0 (M+H)* WO 99/42436 PCT/US98/1 7633 - 161 Starting from 4-(4-Butoxy-benzenesulfonyl)- 1-pyridin-4-ylmethyl-piperidine-4 carboxylic acid (0.864 mg, 2.0 mmol) and following the procedure as outlined in example 83, 600 mg of 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl piperidine-4-carboxylic acid hydroxyamide was isolated as a HC1 salt, off white solid. 5 Yield 67%; mp 118 oC; MS: 447.9 (M+H)*; 1H NMR (300MHz, DMSO-d6): d0.94 (t, 3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H),2.34 (min, 2H), 2.78 (m, 2H), 3.10 (min, 2H), 3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s, 2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82(d, 2H), 11.2 (br s, 1H), 11.4 (br s, 1H). 10 References: 1 Rickter, L. S.; Desai, M. C. Tetrahedron Letters, 1997, 38, 321-322. The subject compounds of the present invention were tested for biological activity according to the following procedures. 15 In Vitro Gelatinase Assay The assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu-Gly(2 mercapto-4 methyl-pentanoyl)-Leu-Gly-OEt), Bachem Bioscience) by the enzyme, 20 gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)). The enzyme activity is measured by the rate of the color increase. The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in dark at room 25 temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaC1 2 ) before use. The stock of human neutrophil gelatinase B is diluted with assay buffer (50 mM HEPES pH 7.5, 5 mM CaC1 2 , 0.02% Brij) to a final concentration of 0.15 nM. The assay buffer, enzyme, DTNB/substrate (500 pM final concentration) and vehicle or 30 inhibitor are added to a 96 well plate (total reaction volume of 200pl) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader. The increase in OD405 is plotted and the slope of the line is calculated which represents the reaction rate. The linearity of the reaction rate is confirmed (r 2 >0.85). The mean (x ± sem) of the 35 control rate is calculated and compared for statistical significance (p <0.05) with drug treated rates using Dunnett's multiple comparison test. Dose-response relationships can WO 99/42436 PCT/US98/17633 - 162 be generated using multiple doses of drug and IC 5 0 values with 95% CI are estimated using linear regression (IPRED, HTB). References: Weingarten, H and Feder, J., Spectrophotometric assay for vertebrate collagenase, Anal. Biochem. 147, 437-440 (1985). 5 In Vitro Collagenase Assay The assay is based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly-Cys(Me) His-Ala-Lys(NMa)-NH2), Peptide International, Inc.) by collagenase releasing the 10 fluorescent NMa group which is quantitated on the fluorometer. Dnp quenches the NMa fluorescence in the intact substrate. The assay is run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca +2 , 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw=18,828, WAR, Radnor). Substrate is dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase is stored 15 frozen in buffer in 25 pM aliquots. For the assay, substrate is dissolved in HCBC buffer to a final concentration of 10 pM and collagenase to a final concentration of 5 nM. Compounds are dissolved in methanol, DMSO, or HCBC. The methanol and DMSO are diluted in HCBC to < 1.0%. Compounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate. 20 The reaction is read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate. 25 The linearity of the reaction rate is confirmed (r 2 >0.85). The mean (x ±+ sem) of the control rate is calculated and compared for statistical significance (p <0.05) with drug treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC 50 values with 95% CI are estimated using linear regression (IPRED, HTB). 30 References: Bickett, D. M. et al., A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9), Anal. Biochem. 212,58-64 (1993).

WO 99/42436 PCT/US98/1 7633 - 163 Procedure for Measuring TACE Inhibition Using 96-well black microtiter plates, each well receives a solution composed of 10 pL 5 TACE (Immunex, final concentration l pg/mL), 7 0pL Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration 1pM, DMSO concentration <1%) and incubated for 10 minutes at room temperature. The reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 pM) to each well and then shaking on a 10 shaker for 5 sec. The reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the line is calculated and represents the reaction rate. The linearity of the reaction rate is confirmed (r 2 >0.85). The mean (x±sem) of the 15 control rate is calculated and compared for statistical significance (p<0.05) with drug treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC50 values with 95% CI are estimated using linear regression 20 The results obtained following these standard experimental test procedures are presented in the following table.

WO 99/42436 PCT/US98/17633 -164 IC 50 (nM or % inhibition at 1 micromolar or 10micromolar (*)) Example MMP 1 MMP 9 MMP 13 TACE 1 NT 559.6 193.3 31.62% 2 NT 10.50% 0% 403 3 NT 308.9 169.4 27.43% 4 371 22.20% 17.10% 21% 5 NT 7.7 4.7 25% 6 267 21.4 15.6 40.43% 7 844 72.9 42.1 33% 8 NT 346 307.9 47% 9 313 107 NT 20.30% 10 8% 128 64 54.75% 11 18.80% 2925 319 942 12 100 10.8 11 15.50% 13 239 11 14 626 14 158 23 8 17.18% 15 285 17 4 137 16 325 9 24 180 17 238.6 8.9 1.4 41.00% 18 540 18.9 11.5 29.2% 19 446 95.8 4.8 33.1% 20 423 14.6 18.7 31% 21 318 13.2 15.3 39% 22 219 3.2 2.5 30% 23 593 7.9 4.0 40.6% 24 413 20.9 31.3 47.5 25 262 26.7 8.0 NT 26 304.6 6.3 3.2 34.6 27 629 106 30.1 NT 28 761 3.1 2.0 30.6% 29 297 4.3 3.6 41% 30 397 8.1 5.7 25.2% 31 162 15.2 5.7 688 32 13.7 3.7 1.0 NT 33 318 53.9 18.4 23.9% 34 519.8 34.7 26.1 28.1% 35 455.8 233.6 48.2 44.9 36 622 83.8 20.7 826 37 9% 31.6% 14.3% 87 38 48.3% 1.7% 5.8% 55.1% 39 29.4% 35.2% 26.6% 69.4 40 583 197 14 160 41 100 10.8 11 15.50% 42 262 50.9 6.2 36.5 43 66.1% 34.7% 55.5% 46.6% 44 47.1% 36.9% 39.5% 14.9% WO 99/42436 PCT/US98/1 7633 - 165 Example MMP 1 MMP 9 MMP 13 TACE 45 49% 48.6% 36.7% 20.4% 46 78.9% 79.12% 84.7% 1.4% 47 17.1% 12.9% 7.12% 3.3% 48 99.1% 79.1% 85.4% 51.1% 49 10.1% 23.7% 54.6% NT 50 51.1 58.4 10.6 NT 51 178.1 10.4 13.1 48.14% 52 139.3 7.9 9.1 NT 53 647.9 27.80% 188 52.57% 54 110 66 21 55.10% 55 303 10 7 21.70% 56 299 16 12 65% 57 258 332 191 16.57% 58 211 35 39 7.70% 59 30.20% 447 141 24.86% 60 NT 184 NT 23.60% 61 258 38 22 17.21% 62 522 174 43 669 63 156 9 3 203 64 40.90% 25.60% 36.70% 29.70% 65 1000 63 13 42.21% 66 1600 131 226 42.33% 67 364 2.3 43.7 690 68 297 29 27 522 69 574.5 120.2 90 41.32% 70 1139 88.80% 127 764 71 1000 63 13 42.21% 72 117 11 1 51.64% 73 300 141 12 20.17% 74 138.1 9.2 4.3 47.86% 75 672.3 83.4 32.7 23.77% 76 805 NT 500 NT 77 205.5 NT 170 NT 78 262 560 34 24.58% 79 25 0.54 0.4 805 80 22.1% 26% 63.6% 191 81a 2036 230.9 43.9 27.1 81b 3765 154 15.7 228 82 237.6 19.4 5.1 34.5% 83 492 10.2 2.0 229 84 519 8.8 2.0 213 85 450 5.8 1.5 115 86 494 16.8 1.5 222 87 368 5.0 1.6 170.7 88 1329 12.8 3.1 610 WO 99/42436 PCT/US98/17633 -166 Example MMP 1 MMP 9 MMP 13 TACE 89 1389 38.6 7.0 49% 90 598 10.3 2.2 71.9 91 1929 13.3 10.8 503 92 59.6% 649 148 9.7 93 56.3% 452 38 15.8% 94 2640 138 28.6 22.9 95 3681 364 33.1 25.4% 96 4437 374 33.8 18.1 97 5109 484 43.7 20.20% 98 2383 3.8 1.2 154 99 656 16.2 2.4 250 100 4729 19.1 5.3 39.5% 101 642 12.3 2.1 197 102 662 33.7 1.9 53% 103 1306 45.1 8.8 470 104 2610 3.1 1.4 208 105 1214 44.2 4.1 50.2% 106 3788 5.1 0.9 631 107 629 26.8 2.5 293 108 2896 5.4 1.7 270 109 393 2.7 2.5 386 241 48.2% * 2.7 15.8 277 242 1950 2 1.3 581 243 2181 1.9 1.5 506 244 3417 9.8 1.5 594 245 7062 43.4 2.2 51.95%* 246 50.30%* 28.3 2.4 880 249 1412 2 1.6 270 250 1717 1.6 0.8 413 251 1067 0.8 0.9 301 252 801 1.1 0.9 278 255 2558 3.6 1.5 565 256 10000 7.2 2.9 43.01%* 259 3160 14.3 5.3 39%* 260 1495 2.9 1.3 272 261 513 10.9 2.7 273 262 422 6.1 2.3 298 263 3669 20.3 5.2 57.70%* 264 4293 2.9 3.1 182 265 1944 9.3 7.8 1037 266 4746 6 5.7 421 267 3620 5.4 2.3 508 268 2292 2.8 1.1 278 269 2071 2.2 1.4 296 WO 99/42436 PCT/US98/17633 - 167 Compounds prepared by solid phase synthesis Data: for Examples 110 to 240 Example MMP 1 MMP 9 MMP 13 % MMP 13 % TACE % No inhibition at 0.2 inhibition at inhibition at pM (HTS) 0.2 pM I mM (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 6.1 122 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 90 32.77 130 28 27.9 131 71 20.73 132 71 20.76 133 53 22.04 134 25 -9.31 135 79 42.67 136 89 42.69 137 83 13.35 138 20 5.284 139 8 28.05 140 29 -4.22 141 32 11.76 142 69 54.27 143 53 43.9 144 38 19.7 145 45 2.5 146 68 7.317 147 73 11.95 148 15 43.46 149 13 4.408 150 54 1.818 151 6 5.927 152 9 10.03 153 12 11.8 154 89 13.14 155 31 18.62 156 23 -2.09 WO 99/42436 PCT/US98/17633 -168 Example MMP 1 MMP 9 MMP 13 % MMP 13 % TACE % No inhibition at 0.2 inhibition at inhibition at pM (HTS) 0.2 pM 1 mM (manual) 157 19 13.7 158 33 -7.48 159 49 5.852 160 14 -3.57 161 0 12.7 162 13 0 163 84 9.515 164 74 62.69 165 71 73.7 166 9 4.16 167 27 8.961 168 21 3.688 Example MMP 13 % MMP 13 MMP 13 TACE TACE N o. inhibition at % inhibition at % inhibition at IC 5 0 nM % inhibition at 36 nM (HTS) 0.36 mM 3.6 mM (HTS) 1 mM (HTS) 169 28 40 72 41.7 170 32 49 90 25.5 171 31 38 48 16.6 172 34 32 42 29.4 173 18 46 56 25.5 174 10 19 40 27.7 175 16 20 37 32.9 176 6 5 16 26.6 177 5 1 9 38.5 178 -10 74 39 26 179 12 32 60 42.7 180 14 19 45 34.4 181 6 35 62 15.7 182 -9 -8 7 28.6 183 -6 12 70 34.6 184 16 24 44 24.8 185 9 0 23 7.21 186 -14 -4 35 19.5 187 -14 -12 20 85.5 188 -27 -24 4 16.2 189 -30 -18 -9 14. 190 -35 -28 -13 38.3 191 -45 -3 22 2.9 192 -32 5 61 33.2 193 -32 -15 56 14.9 194 -17 -8 5 5.4 195 -9 -2 10 27.0 196 -18 1 11 35.7 197 -33 -26 -3 17.8 198 -39 -7 15 17.1 199 -10 -7 30 -1.0 WO 99/42436 PCT/US98/1 7633 - 169 Example MMP 13 % MMP 13 MMP 13 TACE TACE N o. inhibition at % inhibition at % inhibition at ICso nM % inhibition at 36 nM (HTS) 0.36 mM 3.6 mM (HTS) 1 mM (HTS) 200 37.9 201 50.9 202 10.6 203 32.8 204 7.75 205 84.0 206 89.8 207 -6.3 208 67.7 209 31.2 210 52.2 211 20.7 212 56.0 213 -17.5 214 11.03 215 895 60.12 216 2.49 217 55.1 218 380 68.7 219 7.3 220 256 53.1 221 146 98.9 222 212 89.3 223 226 107.3 224 404 75.0 225 96.6 114.3 226 28 22 28 2.2 227 15 -16 -22 7.3 228 37 28 65 6.8 229 29 17 33 34.4 230 29 31 26 700 72.1 231 23 13 5 41.6 232 30 17 42 20.8 233 33 29 46 19.8 234 26 28 40 18.4 235 59 70 70 48.3 236 44 44 64 35 237 55 65 72 38.2 238 22 11 24 930 54.4 239 54 74 83 45.9 240 48 51 46 40.3 WO 99/42436 PCT/US98/17633 -170 Pharmaceutical Composition Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid. 5 Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having 10 the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes 15 and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier 20 can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferable sodium 25 carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. 30 Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form. The compounds of this invention may be administered rectally in the form of a 35 conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The WO 99/42436 PCT/US98/17633 - 171 compounds of this invention may also be administered transdermally through the use of 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 the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of 5 forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream 10 such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. The dosage to be used in the treatment of a specific patient suffering from a disease or condition in which MMIPs and TACE are involved must be subjectively 15 determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration 20 will be determined by the administering physician based on experience with the individual subject treated and standard medical principles. Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be 25 packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Claims

1. A compound according to formula I 0 O R2 ,R4 R-A OH 5 I wherein: RI is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally 10 substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 15 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from Rs; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from Rs; 20 or heteroaryl-(CH 2 )0- 6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from Rs; A is -S-, -SO- or SO 2 -; 25 R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups 30 selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 - 173 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from Rs; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; 5 C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from Rs; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; 10 R 5 is H, C 7 -C 1 aroyl, C

2 -C 6 alkanoyl, CI to C 12 alkyl, C 2 to C 12 alkenyl, C 2 -C 1 2 alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkoxyaryl, C 1 -C 6 alkoxyheteroaryl, C 1 -C 6 alkylamino-C 1 -C 6 alkoxy, C 1 -C 2 alkylene dioxy, aryloxy-CI-C 6 alkyl amine, C 1 -C 12 perfluoro alkyl, S(O)n-C 1 -C 6 alkyl, S(O)n-aryl where n is 0, 1 15 or 2; OCOO C 1 -C 6 alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6 alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, -NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 Cl-C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -CI-C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or 20 unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6 alkyl is straight or branched, heteroaryl is a 5-10 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 or 2 25 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n-C!-C 6 alkyl S(O)n aryl where n is 0, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or 30 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; WO 99/42436 PCT/US98/17633 - 174 and R 7 is C 7 -CIl aroyl, C2-C 6 alkanoyl, C 1 -C 1 2 perfluoro alkyl, S(O)n-C 1 -C 6 -alkyl, S(O)n-aryl where n is 0, 1 or 2; COO-C 1 -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, 5 where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C 1 -C 6 alkyl; 10 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Rs; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally 15 substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one ortwo groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally 20 substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; 25 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from Rs; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C I-C 6 alkyl, optionally substituted with one or 30 two groups selected independently from Rs; or R 8 R 9 N-C -C 6 -alkoxyaryl-C -C 6 -alkyl where R 8 and R 9 are independently selected from C I-C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally WO 99/42436 PCT/US98/17633 - 175 containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof. 5 2. A compound according to claim 1 wherein: RI is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; 10 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ; cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups 15 selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR 7 , optionally substituted with one to two groups selected independently from Rs; or heteroaryl-(CH 2 )0- 6 - wherein the heteroaryl group is 5 to 6 membered with 20 one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ; A is -S-, -SO- or SO 2 -; R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 25 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from Rs; 30 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from Rs; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from Rs; WO 99/42436 PCT/US98/17633 -176 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; 5 R 5 is H, F, Cl, Br, I, CN, CHO, C 7 -C11 aroyl, C 2 -C 6 alkanoyl, C 1 to C 1 2 alkyl, C 2 to C 1 2 alkenyl, C 2 -C 12 alkynyl, C 1 -C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkoxyaryl, C 1 -C 6 alkoxyheteroaryl, CI-C 6 -alkylamino-Cl-C6 alkoxy, C 1 -C 2 -alkylene dioxy, aryloxy-CI-C 6 alkyl amine, C 1 -C 1 2 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n-aryl where n is 0, 1 10 or 2; OCOO-C 1 -C 6 alkyl, OCOOaryl, OCONR 6 , COOH, COO-C 1 -C 6 alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO2 C 1 -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or 15 unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 ; wherein heteroaryl is a 5-10 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 or 2 20 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1, or 2; or COheteroaryl; 25 wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having lto 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, CI-C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; 30 and R 7 is C 7 -CII aroyl, C 2 -C 6 alkanoyl, C 1 -C 12 perfluoro alkyl, S(O)n-alkyl, S(O)n aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, S0 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, heteroaryl; wherein C 1 -C 6 alkyl is WO 99/42436 PCT/US98/17633 - 177 straight or branched, heteroaryl is a 5-10 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, 5 Cl-C 6 alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Rs; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from Rs; 10 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from Rs; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl 15 contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from Rs; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with 20 one or two groups selected independently from R 5 ; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from Rs; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom 25 selected from O, S or N-C 1 -C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 ; R 8 R 9 N-C 1 l-C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8 and R 9 are independently selected from C 1 -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally 30 containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2 wherein WO 99/42436 PCT/US98/17633 - 178 R 1 is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 1 0 aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, halogen; or S(O)n -C 1 -C 6 alkyl C 1 -C 6 alkoxyaryl or C 1 -C 6 alkoxyheteroaryl; 5 A is -S-, -SO- or -SO 2 -; R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; R 4 is hydrogen, 10 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally 15 substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; 20 R 5 is H, C 7 -C 1 l aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 12 alkenyl, C 2 -C 12 alkynyl, F, Cl, Br, I, CN, CHO, Cl-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylamino-C!-C 6 alkoxy, CI-C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, C 1 -C 12 perfluoro alkyl, S(O)n-C 1 C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C 1 -C 6 alkyl, OCOOaryl, 25 OCONR 6 , COOH, COO Ci-C 6 alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, -NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; saturated or unsaturated 5 to 10 membered 30 mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7 and aryl is phenyl or WO 99/42436 PCT/US98/17633 - 179 naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1 or 2; or 5 COheteroaryl; wherein heteroaryl is a 5-10 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; 10 and R 7 is C 7 -C 1 1 aroyl, C 2 -C 6 alkanoyl, C 1 -C 12 perfluoro alkyl, S(O)n-alkyl, S(O)n aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently 15 from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N C 1 -C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups 20 selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; 25 arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; 30 biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from Rs; arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from Rs; WO 99/42436 PCT/US98/17633 - 180 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR-C 1 -C 6 alkyl, optionally substituted with one 5 or two groups selected independently from R 5 ; R 8 R 9 N-CI-C 6 -alkoxyaryl-C-C 6 -alkyl where R 8 and R 9 are independently selected from C 1 -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or 10 naphthyl; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 which is 1-benzyl-4-(4-methoxy-benzene sulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable 15 salt thereof.

5. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(3 methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof. 20

6. A compound according to claim 1 which is 1-(3,4-dichlorobenzyl) -4-(4-methoxy benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. 25

7. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4 methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 which is 4 -(4-methoxy-benzene-sulfonyl)-1 30 napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 which is 1-biphenyl-4-ylmethyl-4-(4-methoxy benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide or a pharmaceutically 35 acceptable salt thereof. WO 99/42436 PCT/US98/17633 - 181

10. A compound according to claim 1 which is 4-(4-methoxy-benzene-sulfonyl)-1-(3 methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof. 5

11. 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.

12. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-[4 10 (2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically accepted salt thereof.

13. A compound according to claim 1 which is 1-benzyl-4-(4-benzyloxy benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt 15 thereof.

14. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-[4-(2 piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 20

15. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-[3 (2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 25

16. A compound according to claim 1 which is 1-methyl-4-(4-butoxy benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

17. A compound according to claim 1 which is 1-ethyl-4-(4-butoxy-benzenesulfonyl) 30 piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

18. A compound according to claim 1 which is 1-n-butyl-4-(4-butoxy-benzene sulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 35

19. A compound according to claim 1 which is 4-[4-(4-chloro-phenoxy) benzenesulfonyl] 1-methyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. WO 99/42436 PCT/US98/17633 - 182

20. A compound according to claim 1 which is 4-[4-(4-chloro-phenoxy)-benzene sulfonyl] 1-ethyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 5

21. A compound according to claim 1 which is 1-butyl-4-[4-(4-chloro-phenoxy) benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

22. A compound according to claim 1 which is 1-benzyl-4-[4-(4-chloro-phenoxy) 10 benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

23. A compound according to claim 1 which is 1-benzyl-4-[4-(3-methyl-butoxy) benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt 15 thereof.

24. A compound according to claim 1 which is 1-butyl-4-[4-(3-methyl-butoxy) benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 20

25. A compound according to claim 1 which is 1-benzyl-4-[4-(2-ethyl-butoxy) benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 25

26. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-l-(3 methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

27. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4 30 thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.

28. A compound according to claim 1 which is 4-(4-methoxy-benzenesulfonyl)-1-(4 pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical 35 salt thereof.

29. A compound according to claim 1 which is 1-(3,4-dichlorobenzyl)-4-(4-butoxy benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof. 40 WO 99/42436 PCT/US98/17633 - 183

30. A compound according to claim 1 which is [4-(4-chloro-benzyloxy)-benzene sulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof. 5

31. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-(3 phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.

32. A compound according to claim 1 which is [4-(4-chloro-benzyloxy)-benzene 10 sulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.

33. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-(4 methylbenzyl)-piperidine-4- carboxylic acid hydroxamide or a pharmaceutical salt 15 thereof.

34. A compound according to claim 1 which is 4-(4-butoxy-benzenesulfonyl)-1-(4 cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof. 20

35. A compound according to claim 1 which is 4-(4-Butoxy-benzenesulfonyl)-1 pyridin-4-ylmethyl-piperidine4-carboxylic acid hydroxamide or a pharmaceutical salt thereof. 25

36. A compound according to claim 1 or a pharmaceutically acceptable salt thereof which is selected from the group of compounds consisting of: 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide, 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxy 30 amide, 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxy amide, 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 35 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxy amide, 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, WO 99/42436 PCT/US98/17633 -184 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 5 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid 10 hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 15 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid 20 hydroxyamide, and 4-(4-methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxy amide.

37. A method of inhibiting pathological changes mediated by matrix metalloproteinases 25 in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula 0 RzA O R ,R4 R1,A OH I 30 wherein: R 1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 - 185 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 5 cycloalkyl of 3 to 8 carbon atoms, 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 O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; 10 or heteroaryl-(CH 2 )0- 6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from Rs; A is -S-, -SO- or SO 2 -; 15 R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups 20 selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; 25 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from Rs; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle 30 containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; R 5 is H, C 7 -C 11 aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C1 2 alkenyl, C 2 -C 12 alkynyl, F, Cl, Br, I, CN, CHO, CI-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 WO 99/42436 PCT/US98/17633 -186 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkoxyaryl, CI-C 6 alkoxyheteroaryl, C 1 -C 6 alkylamino-C 1 -C 6 alkoxy, C 1 -C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, C 1 -C 12 perfluoro alkyl, S(O)n-C 1 -C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C 1 -C 6 alkyl, OCOOaryl, OCONR 6 , COOH, COO CI-C 6 alkyl, 5 COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO2NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 C 1 -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -Cl-C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one 10 heteroatom selected from O, S or NR 7 , wherein C 1 -C 6 alkyl is straight or branched, heteroaryl is a 5-10 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, 15 C 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n-C 1 -C 6 alkyl S(O)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected 20 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 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 11 aroyl, C 2 -C 6 alkanoyl, C 1 -C 1 2 perfluoro alkyl, S(O)n-C 1 -C 6 -alkyl, S(O)n-aryl where n is 0, 1 or 2; COO-C 1 -C 6 -alkyl, COOaryl, CONHR 6 , 25 CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 -30 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C -C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 - 187 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; 5 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one ortwo groups selected independently from Rs; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; 10 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the 15 cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1 -C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 ; or 20 R 8 R 9 N-C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8 and R 9 are independently selected from C 1 -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl; 25 or a pharmaceutically acceptable salt thereof.

38. A method according to claim 37 wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the 30 central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal 35 membranes, inflammatory bowel disease, or periodontal disease. WO 99/42436 PCT/US98/1 7633 - 188

39. A method according to claim 37 wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection. 5

40. A method of inhibiting pathological changes mediated by TNF-Ca converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound of the formula O R NR4 10 R1.A OH I wherein: RI is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 15 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups 20 selected independently from R 5 ; cycloalkyl of 3 to 8 carbon atoms, 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 O, S or NR 7 , optionally 25 substituted with 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 O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ; 30 A is -S-, -SO- or SO 2 -; R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; WO 99/42436 PCT/US98/17633 - 189 R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally 5 substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; 10 C 3 to C 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 O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; 15 R 5 is H, C 7 -Cll aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 12 alkenyl, C 2 -C 12 alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkoxyaryl, C 1 -C 6 alkoxyheteroaryl, C 1 -C 6 alkylamino-C 1 -C 6 alkoxy, CI-C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, C 1 -C 1 2 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n-aryl where n is 0, 1 20 or 2; OCOO C 1 -C 6 alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6 alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 C 1 -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or 25 unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6 alkyl is straight or branched, heteroaryl is a 5-10 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 or 2 30 groups selected from halogen, cyano, amino, nitro, CI-C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C 1 to C 6 perfluoro alkyl, S(O)n-CI-C 6 alkyl S(O)n aryl where n is 0, WO 99/42436 PCT/US98/17633 -190 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 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 or 2 groups selected from halogen, cyano, 5 amino, nitro, CI-C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and R 7 is C 7 -Cll aroyl, C 2 -C 6 alkanoyl, C 1 -C 12 perfluoro alkyl, S(0)n-CI-C 6 -alkyl, S(0)n-aryl where n is 0, 1 or 2; COO-C 1 -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-Ci-C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, 10 where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-CI-C 6 alkyl; 15 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally 20 substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally 25 substituted with one or two groups selected independently from Rs; biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; 30 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 - 191 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1 -C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 ; or R 8 R 9 N-C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8 and R 9 are independently 5 selected from CI-C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms 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. 10

41. The method according to claim 40 wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection. 15

42. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula O RR 4 RA OH 20 wherein: R 1 is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally 25 substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 30 cycloalkyl of 3 to 8 carbon atoms, 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 O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 - 192 or heteroaryl-(CH 2 )0- 6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ; 5 A is -S-, -SO- or SO 2 -; R 2 and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N-R 7 optionally having one or two double bonds; R 4 is hydrogen, 10 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ; alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally 15 substituted with one or two groups selected independently from R 5 ; phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ; C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ; 20 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from Rs; R 5 is H, C 7 -ClI aroyl, C 2 -C 6 alkanoyl, C 1 to C 1 2 alkyl, C 2 to C 12 alkenyl, C 2 -C 12 alkynyl, F, Cl, Br, I, CN, CHO, CI-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 25 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkoxyaryl, C 1 -C 6 alkoxyheteroaryl, C 1 -C 6 alkylamino-CI-C 6 alkoxy, C 1 -C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, C 1 -C 12 perfluoro alkyl, S(O)n-Cl-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C 1 -C 6 alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6 alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, 30 -NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 C 1 -C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one WO 99/42436 PCT/US98/17633 - 193 heteroatom selected from O, S or NR 7 , wherein CI-C 6 alkyl is straight or branched, heteroaryl is a 5-10 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 or 2 5 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, CI 1 -C 6 alkoxy, or hydroxy; R 6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, C1 to C 6 perfluoro alkyl, S(O)n-C 1 -C 6 alkyl S(O)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or 10 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 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 1 1 aroyl, C 2 -C 6 alkanoyl, C 1 -C 12 perfluoro alkyl, S(O)n-CI-C 6 -alkyl, 15 S(O)n-aryl where n is 0, 1 or 2; COO-C1-C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, 20 Cl-C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-Ci-C 6 alkyl; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 25 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from Rs; alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ; arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with 30 one ortwo groups selected independently from R 5 ; heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ; WO 99/42436 PCT/US98/17633 -194 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ; arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ; 5 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C 1 -C 6 alkyl, optionally substituted with one or 10 two groups selected independently from Rs; or R 8 R 9 N-C 1 -C 6 -alkoxyaryl-C1-C 6 -alkyl where R 8 and R 9 are independently selected from C 1 -C 6 alkyl or R 8 and R 9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or 15 naphthyl; or a pharmaceutically acceptable salt thereof.