AU757719B2

AU757719B2 - N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted-alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

Info

Publication number: AU757719B2
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: 2003-03-06
Anticipated expiration: 2018-08-26
Also published as: BR9815781A; CN1213021C; CA2320469A1; AU9120198A; IL137566A0; SK12332000A3; HRP20000543A2; TR200002423T2; GEP20022797B; EE200000471A; KR20010041089A; EP1054858A1; CN1291183A; NO20004093L; HUP0101837A2; BG104782A; NO20004093D0; ID25639A; EA200000849A1; PL342548A1

Description

WO 99/42436 PCTIS98/17633 -1- N-HYDROXY-2-(ALKYL, ARYL, OR HETEROARYL SULFANYL, SULFINYL OR SULFONYL)-3-SUBSTITUTED ALKYL, ARYL OR HETEROARYLAMIDES AS MATRIX METALLOPROTEINASE

INHIBITORS

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 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 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 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 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: Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), Curr. Opin. Ther. Patents (1994) 7-16, Curr. Medicinal Chem. (1995) 2: 743-762, Exp. Opin.

Ther. Patents (1995) 1087-110, Exp. Opin. Ther. Patents (1995) 5(12): 1287- 1196.

TNF-a converting enzyme (TACE) catalyzes the formation of TNF-a from membrane bound TNF-a precursor protein. TNF-oa is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -2central 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 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 bioavailability and pharmacokinetic problems common to such compounds that would limit their clinical effectiveness. Low molecular weight, potent, long acting, orally bioavailable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states.

Recently, two references have appeared 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 nonpeptide matrix metalloproteinase inhibitors disclosed to date.

MeO

N

S .N CONHOH 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 were tested for their fungicidal activity.

SUBSTITUTE SHEET (RULE 26) R S CONHOH R S (0)n (O)n HN 0 Mannich Reaction 1 p Some sulfone carboxylic acids are disclosed in U.S. patent 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.

Summary of the Invention According to a first aspect, the present invention consists in a compound according to formula I

R

3 0 R4 NR 4 R: ,A OH

I

wherein: 10 R' 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 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted 15 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 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 Rs; 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 -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; P 30 R 4 is hydrogen, [R:\LIBFF] 10871 spcci.doc:njc 3a 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 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 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

R

5 is H, C 7

-C

1 aroyl, C 2

-C

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

-CI

2 alkynyl, 15 F, Cl, Br, I, CN, CHO, C 1

-C

6 alkoxy, aryloxy, heteroaryloxy, C 3

-C

6 alkenyloxy, C 3

-C

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

-C

6 alkyl, OCOOaryl, OCONR 6

COOH,

S. COO CI-C 6 alkyl, COOaryl, CONR 6

R

6 CONHOH, NR 6

R

6

SO

2

NR

6

R

6

NR

6 SO2aryl, 20 -NR 6

CONR

6

R

6

NHSO

2

CF

3

SO

2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2

-CI-C

6 alkyl,

CONHSO

2 aryl, SO 2 NHCOaryl, CONHSO 2

-C

1

-C

6 alkyl, CONHSO 2 aryl, NH 2 OH, aryl, i heteroaryl, C 3 to Cs cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one 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 form 0, 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, CI to C 6 perfluoro alkyl, S(O)n-CI-C 6 alkyl S(O)n aryl where n is 0, 1 or 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, amino, nitro, Ci-C 6 alkyl, C 1

-C

6 alkoxy, or hydroxy; and R 7 is C 7 -Cl aroyl, C 2

-C

6 alkanoyl, CI-C 1 2 perfluoro alkyl, S(O)n-Ci-C 6 -alkyl, S(O)n- RA aryl where n is 0, 1 or 2; COO-Ci-C 6 -alkyl, COOaryl, CONHR 6

CONR

6

R

6

CONHOH,

IR:\LIBFF] 10871 specidoc:njc 3b

SO

2 NR6R 6 S0 2

CF

3

SO

2 NHheteroaryl, SO 2 NHCOaryl, CONHSO-Ci-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,

CI-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-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 o0 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 one or two groups selected independently from R; 15 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 substituted with one or two groups selected independently from R 5 20 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 two groups selected independently from R 5 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-Ci-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-Ci-C 6 -alkyl where R 8 and R 9 are independently 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; with the proviso that at least one of R 2

R

3

R

4

R

5 and R 6 contains the group NR 7 wherein R 7 is a heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl RAZ contains 1 or 2 heteroatoms selected from 0, S or N and is optionally substituted with one 5 or two groups selected independently from R 5 or two groups selected independently from R5, [R:\LIBFF] 10871spci.doc:njc 3c or a pharmaceutically acceptable salt thereof.

According to a second aspect, the present invention consists in a compound selected from: 1 -benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 1 ,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 0 4-(4-methoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzene-sulfonyl)- 1 -naphthalene-2-yl-methylpiperidine-4-carboxylic :acid hydroxyamide, 1 -biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzene-sulfonyl)- 1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxyamide, 1 -(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid 20 hydroxyamide, 204-(4-methoxy-benzenesulfonyl)-1- [4-(2-piperidin- 1-yl-ethoxy)-benzyl] -piperidine- 4-carboxylic acid hydroxyamide, 1 -benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-butoxy-benzenesulfonyl)-1- [4-(2-piperidin- 1-yl-ethoxy)-benzyl] -piperidine-4 carboxylic acid hydroxyamide, 4-(4-butoxy-benzenesulfonyl)-l 1-[3-(2-morpholinyl- 1 -yl-ethoxy)-benzyl] piperidine-4 carboxylic acid hydroxyamide, 1 -methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1 -methyl-pip eridine-4-carboxylic acid hydroxyamide, [RALIBFF] 1087 1Ispccidoc:njc 3d 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1 -ethyl-piperidine-4-carboxylic acid hydroxyamide, 1 -butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide, 1 -benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 1 -benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 1 -butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid i0 hydroxyamide, 1 -benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide, :4-(4-butoxy-benzenesulfonyl)- 1 -(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 15 4-(4-methoxy-benzenesulfonyl)- 1 -(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1 -(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 201 ,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid 2o hydroxyamide, :[4-(4-chloro-benzyloxy)-benzenesulfonyl]- 1 -methylpiperidine-4-carboxylic acid hydroxamide, 4-(4-butoxy-benzenesulfonyl)- 1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide, [4-(4-chloro-benzyloxy)-benzenesulfonyl] -1-(4-methylbenzyl)-piperidine-4carboxylic acid hydroxamide, 4-(4-butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide, 4-(4-butoxy-benzenesulfonyl)- 1 -(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxyamide 4-(4-Butoxy-benzenesulfonyl)- 1 -pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxamide, 4-(4-methoxy-benzenesulfonyl)- 1-(3 -phenyl-propyl)-piperidine-4-carboxylic acid T 7 ~Nhydroxyamide, [R:\LIBFF] 1087 1 spcci.doc:njc 3e 1 -tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 1 -benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 15 i 1 -(4-fl~ioro-benzyl)-4-(4-methoxy-benzenesulfony1)-piperidine-4-carboxylic acid hydroxyamide, 1 -(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 204-(4-methoxy-benzenesulfonyl)-l1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid 2o hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-[2-(4-methoxyphenyl)-ethyl] -piperidine-4carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl) -pip eridine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, and [R:\LIBFF] 1087 1 speci.doc:njc 3f 4-(4-methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine- 4-carboxylic acid hydroxy amide, or a pharmaceutically acceptable salt of any of these.

According to a third aspect, the present invention consists in a method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula R2 3

R

4 R^rN R1 A

OH

I

10 wherein: R' 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 RS; 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 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 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 A is -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, alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected -,Ndependently from RS; 3g 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 independently from R 5

C

3 to Cs 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 Rs

R

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

-C

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

2 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 arl,

-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

-CI-C

6 alkyl, CONHSO 2 aryl, NH 2 OH, aryl, heteroaryl, C 3 to Cs cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one 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 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 1 8 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),-C 1

-C

6 alkyl aryl where n is 0, 1 or 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, amino, nitro, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy; and R 7 is C 7 -CII aroyl, C 2

-C

6 alkanoyl, C 1

-C

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

-C

6 -alkyl, S(O)naryl where n is 0, 1 or 2; COO-Ci-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, 54 CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally [R:\LIBFF]10871 speci.doc:njc 3h 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; 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 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 Sor 2 heteroatoms selected from 0, S or N and is optionally substituted with one or two 15 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 S 20 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-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or

R

8

R

9 N-C -C 6 -alkoxyaryl-Ci-C 6 -alkyl where R 8 and R 9 are independently 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; with the proviso that at least one of R 2

R

3

R

4

R

5 and R 6 contains the group NR 7 wherein R 7 is a 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 SR=A^or a pharmaceutically acceptable salt thereof.

[R:\LIBFF] 10871speci.doc:njc 3i According to a fourth aspect, the present invention consists in a method of inhibiting pathological changes mediated by TNF-a 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

3 0 R4 RIA OH

I

wherein: R' is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 o10 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 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 substituted with one or two groups 5 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 A is -SO- or SO 2

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 substituted pf, 7A with one or two groups selected independently from R 5 [R:\LIBFF]10871 speci.doc:njc 3j 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

C

3 to Cs 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, optionally substituted with one or two groups selected independently from R 5 to R 5 is H, C 7

-CI

1 aroyl, C 2

-C

6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 1 2 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, CI-C 6 alkoxyheteroaryl, CI-C 6 alkylamino-C 1 I-Cs alkoxy,

C

1

-C

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

-C

6 alkyl, OCOOaryl, OCONR 6

COOH,

COO CI-C 6 alkyl, COOaryl, CONR 6

R

6 CONHOH, NR 6

R

6

S

2

N

6

R

6 6SO2arl, -NR6CONR6R6, NHSO 2

CF

3

SO

2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2

-CI-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 Cs cycloalkyl; or 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 20 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 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; R6 is H, C 1 to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, CI to C 6 perfluoro alkyl, S(O)n-CI-C 6 alkyl S(O)n aryl where n is 0, 1 or 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, amino, nitro, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy; and R 7 is C 7 -CIl aroyl, C 2

-C

6 alkanoyl, C 1

-C

1 2 perfluoro alkyl, S(O)n-Ci-C 6 -alkyl, S(O)naryl where n is 0, 1 or 2; COO-Ci-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, where aryl is phenyl or naphthyl, optionally 2 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 [R:\LIBFF] 10871 spcci.doc:njc 3k bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, 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 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 o0 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 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted is 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 two groups selected 20 independently from R; saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or R'R9N-Cl-C 6 -alkoxyaryl-Ci-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; with the proviso that at least one of R 2

R

3

R

4

R

5 and R 6 contains the group NR 7 wherein R 7 is a 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 or a pharmaceutically acceptable salt thereof.

According to a fifth aspect, the present invention consists in a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount Sof a matrix metalloproteinase or TACE inhibiting compound according to the formula [R:\LIBFF] 10871 spci.doc:njc 31

O

R 3 N R 4 R,A OH

I

wherein: R' 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 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 10 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups S° 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 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 S 20 A is -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' 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 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 independently from R 5 [R:\LIBFF]10871speci.doc:njc 3m

C

3 to Cs 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', optionally substituted with one or two groups selected independently from is H, C 7 -C I aroyl, C 2

-C

6 alkanoyl, C 1 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-C 1

-C

6 alkyl amine, C 1

-C

2 perfluoro alkyl, S(O)n-CI-C 6 lo 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, -NR6CONR6R6, NHSO 2

CF

3

SO

2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2

-CI-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 Cs cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or S 15 is 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 groups selected from halogen, cyano, amino, nitro, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or hydroxy; R6 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, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group i 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, CI-C 6 alkoxy, or hydroxy; and R 7 is C 7 -ClI aroyl, C 2

-C

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

-C

6 -alkyl, S(O)n- 66 aryl where n is 0, 1 or 2; COO-CI-C 6 -alkyl, COOaryl, CONHR6, 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

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; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups elected independently from

R

35 \elected independently from "QZ [R:\LIBFF] 10871 speci.doc:nje 3n 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 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 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; Sarylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl 15 or bicycloalkyl group is optionally substituted with one or two groups selected independently from saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-Ci-C 6 alkyl, optionally substituted with one or two groups selected independently from Rs; or 20 R R9N-Cl-C 6 -alkoxyaryl-C 1

-C

6 -alkyl where R 8 and R 9 are independently 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; with the proviso that at least one of R 2

R

3

R

4

R

5 and R 6 contains the group

NR

7 wherein R 7 is a 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 or a pharmaceutically acceptable salt thereof.

According to a sixth aspect, the present invention consists in use of a compound of the first or second aspect in the preparation of a medicament for inhibiting pathological changes mediated by matrix metalloproteinase or TNF-a converting enzyme (TACE) in mammals.

The present invention relates to novel, low molecular weight, non-peptide inhibitors Sof matrix metalloproteinases (MMPs) and TNF-a converting enzyme (TACE) for the [R:\LIBFF]10871spcci.doc:njc treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.

There is disclosed herein a group of compounds of general formula I R2 3

NR

4

RNR

RA

OH

I

wherein: R' 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 10 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 .o 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 .ooi

C

[R:\LIBFF] 1087speci.doc:njc WO 99/42436 PCT/US98/17633 -4saturated 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 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 -SO- or SO 2

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 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

C

R

5 is H, C 7

-C

1 aroyl, C 2

-C

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

C

2

-C

1 2 alkynyl, F, Cl, Br, I, CN, CHO, CI-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-Ci-C 6 alkyl amine, C 1

-C

12 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO Ci-C 6 alkyl, OCOOaryl, OCONR 6 COOH, COO C 1

-C

6 alkyl, COOaryl, CONR 6

R

6 CONHOH, NR 6

R

6 S02NR 6

R

6

,NR

6 SO2aryl, -NR 6

CONR

6

R

6

NHSO

2

CF

3 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633

SO

2 NHheteroaryl,SO2NHCOaryl, CONHSO 2

-CI-C

6 alkyl, CONHSO 2 aryl, SO2NHCOaryl, CONHSO 2

-CI-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

NR

7 wherein 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(0)n-CI-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 or 2 groups selected from halogen, cyano, amino, nitro, C--C 6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C 7 -C aroyl, C 2

-C

6 alkanoyl, C 1

-C

12 perfluoro alkyl, S(O)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, 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 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 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, wherein aryl is optionally substituted with one or two groups selected independently from R 5 SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -6heteroarylalkyl 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 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 two groups-selected independently from R 5 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or

R

8

R

9 N-CI-C6-alkoxyaryl-CI-C6-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; and the pharmaceutically acceptable salts thereof.

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

O

3 4

R

2 N

R

R R RL/A

OH

Ia wherein: R' 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 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -7cycloalkyl 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 substituted with one to two groups selected independently from R 5 or heteroaryl-(CH 2 )0o6- 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 A is -SO- or SO 2

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 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 R 5

C

3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5

R

5 is H, F, Cl, Br, I, CN, CHO, C 7 -Ci 1 aroyl, C 2

-C

6 alkanoyl, C 1 to C 12 alkyl,

C

2 to C 1 2 alkenyl, C 2

-C

12 alkynyl, CI-C 6 alkoxy, aryloxy, heteroaryloxy, C 3

C

6 alkenyloxy, C 3

-C

6 alkynyloxy, C 1

-C

6 alkoxyaryl, CI-C 6 alkoxyheteroaryl, C -C 6 -alkylamino-C I-C 6 alkoxy, C -C 2 -alkylene dioxy, aryloxy-C -C 6 alkyl amine, C 1

-C

12 perfluoro alkyl, S(O)n-CI-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 S02NR 6

R

6

NR

6

SO

2 aryl,.

NR

6

CONR

6

R

6 NHS02CF 3

SO

2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2

C

1

-C

6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-Ci-C 6 alkyl, SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -8- CONHSOaryl, NH 2 OH, aryl, heteroaryl, C 3 to Cg 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 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, CI-C 6 alkyl, Ci-C 6 alkoxy, or hydroxy;

R

6 is H, Ci to C 1 8 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; 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, C 1

-C

6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C7-C 1 1 aroyl, C 2

-C

6 alkanoyl, CI-C 1 2 perfluoro alkyl, S(O)n-alkyl, S(0)naryl 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, heteroaryl; 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 0, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C -C 6 alkyl,

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 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, wherein aryl is optionally substituted with one or two groups selected independently from R 5 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -9heteroarylalkyl 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 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 independently from R 5 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5

R

8

R

9

N-CI-C

6 -alkoxyaryl-Ci-C 6 -alkyl where R 8 and R 9 are independently 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; and the pharmaceutically acceptable salts thereof.

The most preferred group of compounds are those of the following formula (Ib): o 3 4 R2Y 3

R

4 R/A OH Ib in which

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 -Clo aryloxy, heteroaryloxy, C 3

-C

6 alkenyloxy, C 3

-C

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

-C

6 alkyl CI-C 6 alkoxyaryl or C 1

-C

6 alkoxyheteroaryl; A is -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; SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633

R

C

R

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

-C

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

-C

1 2 alkynyl, F, Cl, Br, I, CN, CHO, CI-C 6 alkoxy, aryloxy, heteroaryloxy,

C

3

-C

6 alkenyloxy,

C

3

-C

6 alkynyloxy,

CI-C

6 alkylamino-Ci-C 6 alkoxy, Ci-C 2 alkylene dioxy, aryloxy-Cl-C 6 alkyl amine, Ci-C12 perfluoro alkyl, S(O)n-CI-

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, 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 NHS02CF 3 SO2NHheteroaryl,SO 2 NHCOaryl, CONHSO 2

-CI-C

6 alkyl, CONHSO 2 aryl,

SO

2 NHCOaryl, CONHSO2-Ci-C 6 alkyl, CONHSO 2 aryl, NH 2 OH, aryl, heteroaryl, C 3 to Cg cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one 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 groups selected from halogen, cyano, amino, nitro, CI-C 6 alkyl, CI-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(0)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 1 to 3 heteroatoms selected independently from O, S or NR 7 and aryl is phenyl or naphthyl, optionally substituted by 1 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 11 or 2 groups selected from halogen, cyano, amino, nitro, Ci-C 6 alkyl,

C

1

-C

6 alkoxy, or hydroxy; and R 7 is C 7 -C aroyl, C 2

-C

6 alkanoyl, C 1

-C

12 perfluoro alkyl, S(O)n-alkyl, S(O)naryl 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 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; 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 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 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 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 selected from O, S or NR-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5

R

8

R

9 N-Cl-C 6 -alkoxyaryl-Cl-C 6 -alkyl where R 8 and R 9 are independently selected from CI-C 6 alkyl or R 8 and R 9 together with the interposed nitrogen SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 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.

The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are: 1 -benzyl- 4 4 -methoxy-benzenesufony)piperidine4-carboxylic acid hydroxyarnide, 4 -(4-methoxy-benzenesulfonyl). 1-( 3 -methoxy-benzyl)-piperidine-4carboxylic acid hydroxyanide, 1 -(3,4-dichlorobenzyl) 4 -methoxy-benzenesulfonyl)-pipeidine-4carboxylic acid hydroxamide, 4 4 -methoxy-benzenesulfonyl)..1 4 -methylbenzyl)-piperidine-4-carboxylic acid hydroxamide, 4-(4-methoxy-benzene-sulfonyl)- 1 -napthalene-2-yl-methylpiperidine4carboxylic acid hydroxamide, 1-ihnl-lehl4(-ehx-eznsloy~ieiie4croyi acid hydroxamide, 4 4 -methoxy-benzene-sulfonyl)- 1-( 3 -methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide, 1-4boobny)4(-ehx-ezeeufnl-ieiie4croyi acid hydroxyamude, 4 -(4-methoxy-benzenesulfonyl)- 1-( 3 -phenyl-propyl)-piperidineA4-carboxylic acid hydroxyamide, 1-etbtl4(-ehx-eznsufnl-ieiie4croyi acid hydroxyarnide, l-butylA4-( 4 -methoxy-benzenesulfonyl).pipeidine-4carboxylic acid hydroxyamide, l-cyclooctylA4-( 4 -Jnethoxy-benzenesulfonyl).piperidine-4carboxylic acid hydroxyam-ide, I-ty--4mtoybneeufnl-ieiie4croyi acid hydroxyamide, l-isopropyIA4-( 4 -methoxy-benzenesufony)pipeidine-4carboxylic acid hydroxyarnide,.

l-methylA4-( 4 -methoxy-benzenesulfonyl).piperidine-4carboxylic acid hydroxyamide, 1-bny -4btx-eznslonl-ieiie4;croyi acid hydroxyamide,l-( 4 -fluoro-!benzyl)+4-methoxy-benzenesufony)piperidine-4-caboxylic acid hydroxyamide, .1(-lo~-ezl--4btx-ezeeufnl-ieiie4croyi acid hydroxyamide, SUBSTITUTE SHEET (RULE WO 99/42436PCUS8I73 PCTIUS98/17633 13 4-(4-methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyanide, 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 hydroxyanide, 4-(4-n-butoxy-benzenesulfonyl)- 1 -(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfony l)-1I-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-n-butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4carboxylic acid hydroxyanide, 1 -Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-Butoxy-benzenesulfonyl)- 1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidine-4carboxylic acid hydroxyamide, 4-(4-Butoxy-benzenesulfonyl)- 1 -[3-(2-morpholinyl- I -yl-ethoxy)-benzyl]-piperidine-4carboxylic acid hydroxyamide, 1 -Methyl-4-(4-butoxy-benzenesulfonyl)-pipenidine-4-carboxylic acid hydroxyamide, 1 -Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide, I -n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic. acid hydroxyamide, 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1 -methyl-piperidine-4-carboxylic acid hydroxyamide, 4-[4-(4-chloro-phenoxy)-benzenesulfonyl] 1 -ethyl-piperidine-4-carboxylic acid hydroxyamide, 1 -Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyarmide, 1 -Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide, 1 -Benzyl-4-[4-(3-rnethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hyditoxyamide, SUBSTITIUTE SHEET (RULE WO 99/42436 PCTIUS98fl 7633 14 1 -Butyl- 4 4 -(3-methyl-butoxy)-benzenesulfonyl]-piperidine4carboxylic acid hydroxyam-ide, 1 -Benzyl- 4 4 -(2-ethyl-butoxy)-benzenesulfonyll-piperidine.4-carboxylic acid hydroxyamide, 4-(4-butoxy-benzenesulfonyl)- 1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 4-(4-Methoxy-benzenesulfonyl)- 1 4 -thiophen-2-yl-benzyl)-piperidineA-carboxylic acid hydroxyamide, 4-(4-methoxy-benzenesulfonyl)- 1 4 -pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide, 1 3 4 -Dichlorobenzyl)-4-(4-butoxy-benzenesulfony1)-piperidine-4carboxylic acid hydroxyamide, [4-(4-Chloro-benzyloxy)-benzenesulfonyll- 1 -methylpiperidine-4-carboxylic acid hydroxainide, 4-(4-Butoxy-benzenesulfonyl)- 1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxanude, [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1 -(4-methylbenzyl)-piperidine-4carboxylic acid hydroxamnide, 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4- carboxylic acid hydroxamide, 4-(4-Butoxy-benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide, and 4-(4-Butoxy-benzenesulfonyl)-l1-pyridin-4--ylmethyl-piperidine-4-carboxylic acid hydroxamide, and pharmaceutical salts thereof.

It is understood that the definition of the compounds of formulas I, la and lb, when R 1

R

2

R

3 and R 4 contains asymmetric carbons, encompass all possible stereoisomners and mixtures thereof which posses the activity discussed below. In particular, it encompasses racemnic modifications and any optical isomers which 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, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 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 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 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 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 producing the compounds of the present invention.

PROCESS OF THE INVENTION.

The compounds of the present invention may be prepared according to one of the general processes out lined below.

The appropriately substituted mercaptan derivative was alkylated using either substituted (Scheme I) or unsubstituted Scheme c-bromo acetic acid ester derivative in refluxing acetone using K 2 CO, as base. The sulphide derivative thus obtained was oxidized using -m-chloroperbenzoic acid in CHC1, or by using Oxone in 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- at room temperature. Subsiquently, the carboxylic acid obtained was converted to the hydroxamic acid derivative by reaction with oxalyl chloride/ DMX (catalytic) and hydroxyl amine/ triethyl amine.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1I7633 16 SCHEME 1

SYNTHESIS:

R'-SH

a OEt 0 'R N -I OEt' 0 R3 R2C ,slKR3

R

e R3KRNHOH 0 0 a. K 2 C0 3 1 Acetonel Refiux; b. m-Chloroperbenzoic acid; c. K,C0 3 18-Crown-6/ R 3 Br/Acetone/ Reflux! d. NaOHI MeOIH/ THF/ RT e. (COCI) 2 /C11 2 C1 2 /Et 3

N/NH

2

OH*HCI.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/I 7633 17 SCHEME 2

SYNTHESIS:

R'-SH

O t a

B

00-Y

O

0 R1 R

C

CEt 0 "SOY /,ThO Et 0 0 R1 R 3

R

2

O

0 e, f 0a. K 2 C0 3 1 Acetone! Reflux; b. m-Chloropferbenzoic acid; c. K 2 CO3/ 18-Crown-6/ R 2 Br/Acetone/ Reflux! d. R 3 Br/ 10 N NaOHI BzN(Et)31 CH 2

CI

2 I RT e. NaOI MeOEU THF/ RT L. (COCI) 2

/CH

2

CI

2 JEt 3

NINH

2

OH.HCI.

As outlined in Scheme 3, the sulfide derivative can be further alkylated using lithium bis(trimethyl silyl)aniide in THF at O' 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.

SUBSTITUTE SHEET (RULE WO 99/42436 PCTIUS98/1 7633 SCHEME -3

SYNTHESIS:

R'-SH

2 a B; ~OEtPR 0 e-rOEt 0

R

3

R

0 c 0 e

RKY~J~NHOH

0

R

3 R 2

NHOH

0 0 a. K 2 CQI/ Acetone/ Reflux; b. R 3 Br/ HMDS/ THF; e. NaOHI MeOHI THF/ RT d. (COCI) 2

/CH

2

CI

2 IEt 3

NINH

2

OH.HCI..

e. MeOI H 2 0 2

RT

The corresponding 1 -substituted-4-(4-methoxy-benzenesulfonyl)-piperidine-4carboxylic acid hydroxyainides were prepared starting from diethanolainine and appropriately substituted alkyl or aryl halides (Scheme The N-substituted diethanol amine derivatives were converted to the dichioro. compounds using. thionyl chloride...

The corresponding dichiorides were reacted with substituted sulfonyl acetic acid ethyl ester derivatives in the presence of K 2 C0 3 /1 8-Crown-6 in boiling acetone. 1 substituted- 4 4 -methoxy-benzenesulfonyl)-piperidineA...carboxylic acid ethyl esters thus obtained were c onverte d to the hydroxy amnide as outlined in Scheme 4.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -19- Alternatively these classes of compounds and other hetrocycles can be prepared as indicated in Scheme 5 and 6.

SCHEME 4

R

N

EtOOCrS-R' e a b a. KC0 3 1 RBrI Acetone/ Reflux b. SOC1I CH,C1, c. R'SO 2 CHCOQEt/ K-C0 3 I 8-Crown-6/ Acetone/ Reflux d. NaOH THF/ MeOH/ RT e. (COCI) 2 NH20H. HCI/ Et 3

N

e SCHEME %R1 bi b

~I

HOO~ S

N

R

HOHNOC

S

e

N

I

COOH

a HOOC SR' HOOC SRI HOHNOC SRI d% e e Y=NorCH a. RBrI R'SHI CHCI 3 Reflux; b. Qxone/ MeOH; e. (COCI) 2

INH

2 OH. HCIJEt 3

N

SCHEME 6

.SO

2 R' S 2 R1

Q---CONH-OH

a. LiN(TMS) 2 /THF/O C/ C0 2 b. (COCI) 2 HCI/Et 3

N

Alternatively, Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 Scheme 7 0 ONH 2 a 00 o-N 2 0

O-N

(PO J H Br(Ci) b 0 f^-NY 2 c° 0 O R2 or0NsR, d 0

-O-O

O O

O

0 j H 1On 0 e HO-N

YR

H~k SOn "R1 Reagents and Conditions: a) 2-Halo acid (3.0 1-hydroxybenzotriazole hydrate (HOBt, 6.0 1,3-diisopropylcarbodiimide (DIC, 4.0 DMF, 25 0 C; 2-16 hours.

b) Thiol (5.0 sodium iodide (5.0 1,8-diazabicyclo[5.4.0]undec-7-ene

(DBU,

THF; 25C; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 DCM; 25°C; 12-24 hours. d) mCPBA (5.0 DCM; 12-24 hours. e) TFA DCM 25°C; 1 hour.

The 4 -O-methylhydroxylamine-phenoxymethyl-copoly(styrene-1 %-divinylbenzene)-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 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 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.

SUBSTITUTE SHEET (RULE 26) 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 attached to the aromatic ring.

preparing hydroxamic acids having alkoxy groups Scheme 8 O OeNH2 a b am.- Br(CI) &0 c &ojtx c,~J 0 0-N R S aO,alkyl 0

N'N

H

~k 11 0 ak-N Lo lalkyl

O-N

SOn n alky n 0, 1, 2O 0 f HO-N SOn I O,alkyl Reagents and Conditions: a) 2-Halo acid (3.0 1-hydroxybenzotriazole hydrate (HOBt, 6.0 1,3-diisopropylcarbodii-mide (DIC, 4.0 DMF, 25 0 C; 2-16 hours.

b) 4-Fluorobenzenethiol (5.0 sodium iodide (5.0 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 THF; 25 0 C; 12-16 hours. c) Alcohol (15.0 sodium hydride (15.0 DMF; 80 0 C; 15 hours. d) 70% tert-butylhydroperoxide benzenesulfonic acid (2.0 DCM; 25 0 C; 12-24 hours. e) mCPBA (5.0 DCM; 0 C; 12-24 hours. f) TFA DCM 25*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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -22group 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 liberated as previously described.

Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, and sulfonylhydroxamic acids.

Scheme 9 0

O.NH

2 -N R 2 b Br(CI) O-N R2 c O-N R 2 OS S Brd OBr O-N R 2

O

Br e O-N R2 f HO-N yR2 SOn c~r ArQAr Reagents and Conditions: a) 2-Halo acid (3.0 1-hydroxybenzotriazole hydrate (HOBt, 6.0 1, 3 -diisopropylcarbodiimide (DIC, 4.0 DMF, 25 0 C; 2-16 hours.

b) 4 -Bromobenzenethiol (5.0 sodium iodide (5.0 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,.3.0 THF; 25 0 C; 12-16 hours. c) 70% tert-butylhydroperoxidebenzenesulfonic acid (2.0 DCM; 25 0 C; 12-24 hours.. d) mCPBA DCM; 25 0 C; 12-24 hours. e) Arylboronic acid (2.0 tetrakis(triphenylphosphine) palladium(0) (0.1 10% aqueous sodium carbonate (10.0 DME;; 80 0 C; 8 hours. f) TFA DCM (1:1);'25 0 C; I hour.

SUBSTITUTE SHEET (RULE 26) 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 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.

Scheme 10 shows a method of preparing hydroxamic acids having amine groups attached to the aromatic ring.

Scheme A0 eO

NH

2 a O-N R 2 b (P0 j (0r H Br(CI) 0 0 O O-N V O -N 1>Br

NIB

0 R6 d HO-N T R- SN,R6 R6 Reagents and Conditions: a) 2-Halo acid (3.0 1-hydroxybenzotriazole hydrate (HOBt, 6.0 1,3-diisopropylcarbodiimide (DIC, 4.0 DMF, 25 0 C; 2-16 hours.

b) 4-Bromobenzenethiol (5.0 sodium iodide (5.0 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 THF; 25*C; 12-16 hours. c) Amine (20.0 eq.); tris(dibenzylideneacetone)-dipalladium(0) (0.2 (S)-(-)-2,2'-bis(diphenylphosphimo)- 1,l'-binaphthyl ((S)-BINAP, 0.8 sodium tert-butoxide (18.0 eq.); dioxane; 80*C, 8 hours; d) TFA DCM 25C; 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.

group may: then be displaced with an amine in the presence of a catalyst such as SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/ 7633 -24tris(dibenzylideneacetone)-dipalladiuxn(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'C. The free hydroxamnic acids may be liberated as previously described.

Scheme 11I shows a method of preparing hydroxamic acids having sulfonate groups attached to the aromatic ring.

Scheme 11 0 ONH2 a0 b 00 0 d ®~cr 0

-N

0 R2 nO 0 f HO-NkyR HSOn X= CI -C 6 alkyl, aryl 0 Reagents and Conditions: a) 2-Halo acid (3.0 1-hydroxybenzotriazole hydrate (HQBt, 6.0 l,3-diisopropylcarbodiimide (DIC, 4.0 DMF, 25'C; 2-16 hours.

4-Hydroxybeiizenethiol (5.0 -sodium iodide (5.0 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU; 3.0- .THF; 25*C; 12-16- hours. c) Sulfonyl chloride (5.0 triethylanine (2.0 DCM; 25"C; 8 hours. d) 70% tert-butylhydroperoxide (4 benzenesulfonic acid (2.0 DCM; 25*C; 12-24 hours. e) mCPBA DCM; 25*C; 12-24. hours. f) TFA -DCMi(1: 256C; 1 hour.

SUBSTrTUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 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 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 invention. HPLC purity of compounds prepared by combinatorial procedures is presented as area percentage at a prescribed wavelength nm).

Example 1 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 C0 3 (10 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.6 gm, 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, 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 ester as a light yellow oil. Yield 4.5gms MS; 241 To a stirred solution of 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (2.44 g, 10 mmol), in THF (100 ml) at lithium bis(trimethylsilyl)amide (1 M solution, ml, 15 mmol) was added slowly. The orange colored reaction mixture was stirred at -room temperature for 15 minutes and then it was cooled to 0°C at which time it was stirred for an additional hour. The temperature of the mixture was again brought to 0 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 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- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -26methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield: 860 mg, MS: 331 (M+H) 2 4 -methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12 g, 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 afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 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 C12 (100 ml) at OC, oxalyl chloride (1.0 gm, 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 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water 30 ml) at O°C 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 C12 and added slowly to the hydroxylamine at OC. 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- 3-phenyl-propionamide was isolated as a colorless solid, mp 88 Yield, 300 mg, 57%; MS: 318 1H NMR (300 MHz, CDCI 3 8 1.32 3H), 3.07 J =11 Hz, 1H), 3.23 J =11 Hz, 1H), 3.79 3H), 6.83-7.36 9H).

Example 2 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-2-phenyl-acetamide 2 4 -Methoxyphenylsulfanyl)-phenylacetic acid ethyl ester was prepared according to the general method as outlined in Example 1. Starting from ethyl o-bromophenyl SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/17633 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 2-(4-Methoxy-phenylsulfanyl)-2-phenyl acetic acid was prepared starting from 2-(4methoxy-phenylsulfanyl)-phenyl-acetic acid ethyl ester (3.0 g, 10 mmol) dissolved in methanol (50 mld) and 10 N NaQH (20 ml). The resulting reaction mixture was worked up as in Example 1. Yield 1.9 g, 70%. Low melting solid. MS: 273 Starting from 2-( 4 -methoxy-phenylsulfanyl)-phenyl acetic acid (1.05 g, 3.83 mmol) and following the procedure as outlined in Example 1, 154 mg of N-hydroxy-2-(4methoxy-phenylsulfanyl)-2-phenyl-acetamide was isolated as a colorless solid. mp 155'C; Yield 14%; MS: 290 H NMR (300 MHz, DMSO-d 6 8 3.72 (s, 3H), 4.68 1H), 6.86-7.44 (in, 9H).

Example 3 2 4 -Methoxy-phenylsulfanyl)-2,5-dimethyl-hexA-enoic acid hydroxyanude 2 4 -Methoxy-phenylsulfanyl)-2,5-dimethyl-hex.4-enoic acid ethyl ester was prepared following the procedure of Example 1, second paragraph. Starting from (4-methoxyphenylsulfanyl)-propionic acid ethyl ester (3.5 g, 14.3 mmol), and isoprenyl bromide (2.25 g, 15 mmol), 2.2 g of the product was isolated as an oil. Yield 50%; MS: 3 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 NaOil (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 Starting from 2 4 -methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4enoic acid (1 .67 g, 5.8 mmol) and following the procedure as outlined in Example 1, 1.5 g of 2-(4methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid hydroxyaniide was isolated as a colorless -solid. rnp 89 *C;'Yield 94%; MS: -296 'H NMR (300 MHz, CDCl 3 861.34 3H), 1.61 3H), 1.74'(s, 3H), 2.41'-2.58 (in, 3.80 3H), 5.17 J 7.5 Hz, lH), 6.86 J =12.4 Hz, 2H), 7.35 J 12.4 Hz, 2H).

SUBSTITUTE SHEET (RULE WO 99/42436 PCT/US98/1 7633 -28- Example 4 N-Hydroxy-2-(4-methoxy-phenylsulfanyl)-3-methyl-butyramide 2 4 -Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2 -bromo-3-methylbutanoate (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 2 4 -Methoxy-phenylsulfanyl)-3-methyl-butyric acid was prepared starting from 2-(4methoxy-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 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 Yield 33%; MS: 256 IH NMR (300 MHz, DMSO-d 6 8 0.90-1.07 6H), 1.84-1.96 1H), 3.07 J 8.8 Hz, 1H), 3.75 3H), 6.88 J Hz, 2H), 7.35 J =15 Hz, 2H).

Example N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-2-methyl-3-phenyl-propionamide N-hydroxy-2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenylpropionamide (400 mg, 1.26 mmol) (prepared in Example 1) was dissolved in methanol (100 ml) and

H

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

SO

3 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 CHCI 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 chromatography, eluting with 75% ethylacetate:hexane. Low melting solid. Yield: 220 mg MS: 334.1 IH NMR (300 MHz, CDCl 3 d 1.11 2H), 1.22 (s, 3H), 3.84 3H), 7.00-7.61 9H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 29 Example 6 2-(4-Methoxy-benzenesulfinyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide 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 hydroxyamnide was isolated as a colorless solid. Yield: 104 mg mp 108 MS: 312 1 H NMR (300 MHz, DMSO-d 6 8 0.88 3H), 1.59 3H), 1.68 3H), 2.27-2.80 (in, 2H), 5.02 J 7.5 Hz, IH), 7.09 J 9 Hz, 2H), 7.39 J 9 Hz, 2H).

Example 7 N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyraniide Starting from N-hydroxy-2-(4-inethoxy-phenylsulfanyl)-3-methyl-butyramide (1 g, 3.9 inxol) as prepared in Example 4, and following the procedure of Example 5, Nhydroxy-2-(4-methoxy-benzenesulfinyl)-3-methyl-butyraniide was isolated as a colorless solid. Yield: 420mg mp 163 MS: 272 'H NMR (300 MHz, DMSO-d 6 8 0.89-1.12 (in, 6H), 1.63-1.74 (in, 1H), 3.13 J =7 Hz, 1H), 3.83 3H), 6.94-7.65 (in, 4H).

Example 8 N-Hydroxy-2-(4-inethoxy-benzenesulfinyl)-2-phenyl.acetanmide 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 Example 5, N-hydroxy-2-(4-inethoxy-benzenesulfinyl)-2-phenyl-acetaniide was isolated as colorless solid. Yield: 100mg mp 135 MS 304 1

H

NMR (300 MHz, DMSO-d 6 8 3.75 3H), 4.38 1H), 6.92-7.69 (in, 9H) Example 9 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionamide To a stirred solution of 4-inethoxybenzenethiol (2.8 gin, 20 mmol) and anhydrous

K

2 C0 3 (10 gin, excess) in dry acetone (100 ml), cc-broino ethyl acetate+ (3.3 gin, mmol) was added- in a round bottom flask and the reaction mixture was heated at reflux SUBSTITIUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 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 filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g MS; 227 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 (4.4 g, 20 mmol) in CH 2 Cl 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 CHC1 3 and washed with H 2 0. The organic layer was dried over MgSO4, filtered and concentrated and the colorless (4methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as an oil. Yield: 100%; MS: 259.1 To stirred solution of the (4-methoxy-benzenesulfonyl)-acetic acid ethyl ester (2.5 g, 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 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)

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 HCI. The residue obtained was extracted with chloroform, washed well with water, dried and concentrated. The product obtained was purified by silica-gel column chromatography SUBSTITUTE SHEET (RULE 26) 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 Starting from 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (200 mg, 0.625 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 MS: 336 'H NMR (300 MHz, CDC13): 3.2 (m, 1H), 3.8 3H), 4.0-4.2 2H), 7.0-8.0 9H).

Example 2-(4-Methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide 2-(4-Methoxy-phenylsulfanyl)-hexanoic acid ethyl ester was prepared according to the 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 Starting from 2-(4-methoxy-phenylsulfanyl)-hexanoic acid ethyl ester. (2.8 g 10 mmol) and following the procedure as outlined in Example 9, 3 g of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester was isolated as a colorless solid. Yield: 95%; mp 62 MS: 314 (M+H) Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (2 g, 6.3 mmol) 1.5 g of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 116 MS: 287 Starting from 2-(4-methoxy-benzenesulfonyl)-hexanoic acid (1.0 g, 3.1 mmol) and following the procedure as outlined in Example 1, 700 mg of 2-(4-methoxy-benzenesulfonyl)-hexanoic acid hydroxyamide was isolated as a colorless solid. Yield: mp 130 MS: 302 'H NMR (300 MHz, CDC13): 8 0.786 J= 7.2 Hz, 3H), 1.1 -1.3 4H), 1.6 1.8 2H), 3.7 1H), 3.9 3H),7.2 J 11 Hz, 2H), 7.8 J=ll Hz, 2H), 9.3 1H), 10.9 1H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -32- Example 11 2 4 -Methoxy-benzene sulfonyl)-tetradecanoic hydroxyamide 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 -2bromomyristate (5.0 g, 14.9 mmol) and 4-methoxythiophenol (1.9 g, 13.4 mmol), g of the product was isolated. Yield 98%; Light yellow oil; MS: 393 Starting from 2 4 -methoxy-phenylsulfanyl)-tetradecanoic acid ethyl ester. (3.9 g mmol) and following the procedure as outlined in Example 9, 3.2 g of 2 -(4-methoxybenzenesulfonyl)-tetradecanoic acid ethyl ester was isolated as a colorless solid, yield: 76%; Oil; MS: 425 Starting from 2 4 -methoxy-benzenesulfonyl)-tetradecanoic acid ethyl ester (2.5 g, 5.9 mmol), 2.0 g of 2 4 -methoxy-benzenesulfonyl)-tetradecanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 82 °C; MS: 397 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-methoxybenzenesulfonyl)-tetradecanoic hydroxyamide was isolated as an off-white solid. Yield: 57%; mp 114 OC; MS: 414 IH NMR (300 MHz, DMSO-d 6 8 0.85 J 7 Hz, 3H), 1.16-1.27 20 1.66 2H), 3.62-3.70 1H), 3.87 3H), 7.12 J 15 Hz, 2H), 7.73 J 15 Hz, 2H).

Example 12 N-Hydroxy-2-(4-methxybenzenesulfonyl)-2-methyl-3-phenyl-propionamide To a stirred solution of 2 4 -methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (1.0 gm, 3mmol) (example methyl iodide 1 ml, excess) and 18-Crown-6 (500 mg) in acetone (250 ml), K 2 CO3 (10 gm, excess) was added and. the reaction 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 silica-gel column chromatography by eluting it with 30% ethyl acetate:hexanes to afford 2 4 -methoxy-benzenesulfonyl)- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/I 7633 33 2-methyl-3-phenyl-propionic acid ethyl ester as a colorless oil. Yield 1 .0 g, 98%; MS: 349 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid ethyl ester (900 mg, 2.7 mmol), 850 mg (quantitative) of 2-(4-methoxy-benzenesulfonyl)-2methyl-3-phenyl-propionic acid was isolated by following the procedure as outlined in Example 9. Colorless oil, MS 335 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid (900 mg, 2.7 mmol) and following the procedure as outlined in Example 1, 4 50mg of Nhydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-phenyl-propionamde was isolated as a brown solid. Yield: 48%; mp 58 MS: 350 H NMR (300 MHz, CDC1 3 5 1.4 3H), 3.1 J=9 Hz, 1H), 3.6 J= 9 Hz, LR), 3.9 3H), 6.8 7.8 (in, 9H).

Example 13 2-(4-Methoxy-benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid hydroxyamide Starting from 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester (Example 1) (12 g; 50 minol) and following the procedure as outlined in Example 9, 12 g of 2-(4methoxy-benzenesulfonyl)-propionic acid ethyl ester was isolated as a semi-solid, yield 100%; MS: 256.1 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 g; 6 mmol). Yield 1.0 g, 8 Colorless oil; MS: 341 Starting from 2-(4-methoxy- benzenesulfonyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (900 mng, 2.6 mmol) 800 mg of 2-(4-methoxybenzenesulfonyl)-2,5-dimethylhex-4-enoic acid was isolated as a semni solid by following the procedure as outlined in Example 9. MS: 313 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 mng of 2-(4dimethyl-hex-4-enoic acid hydroxyamide was isolated as a lo~w melting solid.-Yield. 67%; MS: 328 1H NMR (300 MHz, -CDC1 3 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/1 7633 -34- 1.3 3H), 1.5 J=6.2 Hz, 6H), 2.5 -3.0 (in, 2H), 3.9 3H), 7.0 J= 11I Hz, 2H), 7.8 J= 11 Hz, 2H).

Example 14 3-(B iphenyl- 4 -yl)-N-hydroxy-2-(4methoxybenzenesulfony)2methyl-propionamide Following the procedure as outlined in Example 12, 3-(biphenyl-4-yl)-2-(4-methoxybenzene sul fonyl)-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 4- (chloromethyl)biphenyl (2.5 g, 12 inmol). Yield 4.0 g, 91%; Colorless oil; MS: 438 Starting from 3 -(biphenyl-4-yl)-2-(4-methoxy-benzenesulfonyly2-methyl propionic acid ethyl ester (3 g, 6.8 inmol), 2.5 g of 3-(biphenyl-4-yl)-2-(4-methoxybenzenesulfonyl)-2-methyl propionic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. mp 161 MS: 411 Starting from 3 -(biphenyl- 4 -yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl.propionic acid (2.0 g, 4.8 mmol) and following the procedure as outlined in Example 1, 1.2 g of 3-bpey--l--yrx--4mtoybneeufnl--ehlpoinmd was isolated as colorless solid. Yield: 58%; mp 177 MS: 426 H NMR (300 MHz, CDCl 3 8 1.4 3H), 3.2 J=9 Hz, lH), 3.7 J= 9 Hz, IH), 3.9 (s, 3H), 7.0 7.8 (in, 13H), 9.7 (bs, 1H).

Example 2-(4-methoxy-benzenesulfonyl)-2,5 ,9-trimethyl-deca-4,8-dienoic acid hydroxyarnide Following the procedure as outlined in Example 12, 2-(4-methoxy-benzenesulfonyl)- 2,5,9-trirnethyl-deca-4,8-dienoic acid ethyl ester was prepared, starting from (2.7 g, minol) of 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and geranyl bromide (3.0 g, 13 inmol). Yield 4.0 g, 98%; Colorless oil; MS: 409 Starting from 2-(4-methoxy-benzenesulfonyl)-2,5 ,9-trimethyl-deca-4,8-dienoic acid ethyl ester (3 g, 7.4 inmol), 2.8 g 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 SUBSTITUTE SHEET (RULE WO 99/42436 PCTIUS98/1 7633 35 Starting from 2 4 -methoxy-benzenesulfonyl)-2,5,9-trimethyl-deca-4,8-dienoic acid 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 IH NMR (300 MHz, CDCl 3 81.4 3H), 1.6 3H), 1.65 3H), 1.7 3H), 2.0-.3.1 (m,6 3.9 3H), (in, 2H), 6.98 J= 9.0 Hz, 2H), 7.7 J= 9.0 Hz, 2H).

Example 16 3 -Cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-2methyl.propionride Following the procedure as outlined in Example 12, 3 -cyclohexyl-2-(4-methoxybenzenesulfonyl)-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 bromomethylcyclohexane (1.8 g, 10 mmol). Yield 3.5 g, 95%; Yellow oil; MS: 369 Starting from 3-cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid ethyl ester (3 g, 8.1 mmol) 2.5 g of 3 -cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-methyl propionic acid was isolated as colorless solid by following the procedure as outlined in Example 9. mp 116 MS: 341 Starting from 3 -cyclohexyl-2-(4-methoxy-benzenesulfony)-2-methyl-propionic acid 5.8 inmol) and following the procedure as outlined in Example 1, 1. 1 g of 3cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl).2mefiylpropionamiide was isolated as colorless solid. Yield: 55%; mp 58 MS: 356 'H NMR (300 MHz, CDCl 3 8 1.4 3H), 2.3 1.0 (in, 13 3.9 3H), 7.0 8.8 Hz, 2H), .7.69 9.0 Hz, 2H).

Example 17 N-yrx--4mtoybneeufnl--ehl3[-2pprdn 1 -yl-ethoxy)phenyll-propionamide Following the procedure as outlined in example 12, 2-(4-rnethoxy-benzenesulfonyl)-2methyl-3-[4-(2-piperidin- 1 -yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2 4 -inethoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-piperidin-l-yl-ethoxy)-benzyl chloride (2.9 g, 10 mmol). Yield 4.8 g, 98%; Brown oil: MS: 4.90 SUBSTITUTE SHEET (RULE WO 99/42436 PCTIUS98/1 7633 36 Starting from 2 4 -methoxy-benzenesulfonyl)2methyl..3.[4(2-pipeidin-1 -yl-ethoxy)phenyl]-propionic acid ethyl ester (4.0 gin, 7.9 mmol) 3.5 g (Yield: 94 of 2-(4methoxy-benzenesulfonyl)-2-methyl.3-[4(2-pipeidin-.1 -yl-ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 106 MS: 462.5 Starting from 2 4 -inethoxy-benzenesulfonyl)-2methyl3.[4(2piperidin. 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)2methyl3.[4-(2 piperidin-lI-yl-ethoxy)-phenyl]ypropionamide was isolated as colorless solid. Yield: 1 g, 48%; mp 98'C; MS: 477 1H NMR (300 MHz, CDCl 3 8 1.2 3H), 1.5 (in, 16 3.9 3H), 4.4 (in, 1H), 6.5 7.8 (in, 8H), 10.8 (bs, 1H).

Example 18 2-[4-(2-Azepan-1 lehx)bny]2(-ehoybneeufnl-rpoi acid hydroxyamide Following the procedure as outlined in example 12, 2 4 2 -azepan-1-yl-ethoxy)bezl--4mtoybneeufnl-rpoi acid ethyl ester was prepared, starting from (2.7 g, 10 mmol) of 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and the l-[ 2 4 -chloromethyl-phenoxy)ethyll-azepane (3.03 g, 10 mmol). Yield g, 90%; Brown oil; MS: 504 Starting from 2 -[4-(2-azepan- 1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl).

propionic acid ethyl ester (4.0 gmn, 7.9 mmol) 3.5 g (Yield: 94 of 2-[4-(2-azepan- 1-lehx)bnyl2(-ehoybneeufnl-rpoi acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 476 Starting from 2-[4-(2-azepan- 1 y-toy'ezl--4mehx-eznsloy) propionic acid (2.0 g, 4.2 inmol) and following the procedure as outlined in example 1, 1 g of 2 -14-(2-azepan- l-yl-ethoxy)-benzyl]-2-(4-methoxy.bezenesulfonyl)-propionic acid hydroxyarnide was isolated as colorless solid. Yield: 1.8 g, 87%; mnp 68'C; MS:.

491 'H NMR (300 MHz, CDCl 3 8 1.23 3H), 3.5 1.7 (in, 18 3.8 3H), 4.2 (in, 1H), 6.4 7.89 (in, 8H), 10.9.(bs, IH).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 37 Example 19 2-14-(2-Azepan- 1-yl-ethoxy)-benzyl] -2-(4-methoxy-benzenesulfonyl)pentanoic acid hydroxyamide 2-[4-(2-Azepan-1I-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 nimol) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (3.9 g, 12.8 mmol). Yield 2.58 g brown oil; MS: 532.4 2-14-(2-Azepan- 1-yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid was prepared starting from 2-14-(2-azepan- 1 -yl-ethoxy)-benzyl]-2-(4-methoxybenzenesulfonyl)-pentanoic acid ethyl ester (2 g, 3.76 mmol) dissolved in methanol (300 ml) and 10 N NaOH (15 ml). The resulting mixture was worked up as outlined in example 1. Yield 830 mg brown solid; mp 55 MS: 504.4 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 example 1, 240 mg of 2-14-(2-azepan- 1 -yl-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-pentanoic acid hydroxyamide was isolated as a yellow solid. Yield 34%; mp MS: 519.2 I H NMR (300 MHz, DMSO-d 6 d 0.71 J 7.3 Hz, 3H), 0.78-1.77 (in, 16 3.04-3.46 (mn, 4H), 3.87 3H), 4.26 (mn, 2H) 6.87 (d, J 8.7 Hz, 2H), 7.14 (mn, 4H), 7.71 J =9 Hz, 2H), 9.07 1H), 10 1H).

Example N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diisopropyI aminoethoxy)-phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2methyl-3-[4-(2-N,N-diisopropyl amrino-ethoxy)-phenyl] -propionic acid ethyl ester was prepared, starting from (5.4 g, 20 minol) of 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diisopropyl amino-ethoxy)-benzyl chloride (6.1 g, minol).. Yield.8.9 Yellow oil; MS: 506..5 Starting from 2-(4-methoxy-benzeniesulfonyl)-2-inethyl-3-[4-(2-N,N-diisopropy ainino-ethoxy)-phenyl]-propionic acid ethyl ester (4.0 gin, 7.9 inmol) 3.5 g (Yield: 92%) of 2-(4-methoxy-benzenesulfonyl)-2'-methyl-3- [4-(2-N,N-diisopropyl amino- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US981 7633 38 ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 68 0 C; MS: 478.6 Starting from 2 4 -methoxy-benzenesulfonyl)2methyl3-[4(2-N,N-diisopropyI arnino-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-mefiyl..3..4-(2 N,N-diisopropylanino-ethoxyy.phenyl.propionmde was isolated as colorless solid.

Yield: 1 g, 49%; mp 98'C (Hcl Salt); MS: 493 1H NMR (300 MHz, CDCI 3 1.2 3H), 1.3 1.4 3.5 1.5 (in, 6 3.9 3H), 4.4 2H), 6.5 7.8 (in, 8H), 10.8 (bs, 1H).

Example 21 N-yrx--4mtoybneeufoy)2mty--4(-,-ity aminoethoxy)-phenyl]-propionamride 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 minol) of 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 4-(2-N,N-diethyl arnino-ethoxy)-benzyl chloride (5.5 g, nunol). Yield 8.5 g, 89%; Brown oil; MS: 478.6 (M+H Starting from 2 4 -methoxy-benzenesulfonyl)2methyl34(2NNdiethyI aminoethoxy)-phenyl]-propionic acid ethyl ester (3.5 gin, 7.7 nimol) 3.0 g (Yield: 85 of 2 4 -methoxy-benzenesulfonyl)-2-methyl-3[4..(2-NN-d 4 iethyI ainino-ethoxy)-phenyl]propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 96-98 MS: 450.5 Starting from 2 4 -methoxy-benzenesulfonyl)2methyl3[4(2NNdiethyl aminoethoxy)-phenyl]-propionic acid (2.0 g, 4.4 minol) and following the procedure as outlined in example 1, 1 g of 2 4 -methoxy-benzenesulfonyl)2methyl3[4(2-N,Ndiethyl-amiino-ethoxy)phenyl]propionamide was isolated as colorless solid. Yield: 1g, 48%; mp 56-59 0 C (HCl Salt); MS: 465.5 H NMR (300 MHz, CDCl 3 8 1.-1 6H), 1.3 3.2 3.9 (mn, 8 3.9 3H), 4.3 2H), 6.5 7.8 (in, 8H), lH).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 39 Example 22 N-Hydroxy- 2 4 -methoxy-benzenesulfonyl2methyl3[3-(2-piperidin- 1 -yl-ethoxy)phenyl]-propionaxnide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2methyl-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-lI-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol). Yield 8.2 g, 83%; Brown oil; MS: 490 Starting from 2 4 -methoxy-benzenesulfonyl)-2-methyl-3-[3.(2-piperidin.1 -yl-ethoxy)phenylli-propionic acid ethyl ester (6.0 gin, 12.2 mmol) 4.9 g (Yield: 79 of 2-(4methoxy-benzenesulfonyl)-2-methylb3.[3.(2-piperidin 1 -yl-ethoxy)-phenyl]-propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 112' 0 C; MS: 462.5 Starting from 2-4mtoybneeufnl--ehl3[-2pprdn 1 -yl-ethoxy)phenylil-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-l-ylethoxy)-phenyl]-propionamide was isolated as colorless solid. Yield: 1.8 g, 58%; mp 74'C; MS: 477 H NNM (300 MHz, CDCl 3 5 1.25 3H), 1.6-1.8 (in, 6 2.5 3.7 (in, 8H), 3.9 3H), 4.4 2H), 6.7 7.8 (mn, 8H), 10.8 (bs, lH).

Example 23 4 3 -Chloro-phenyl)-piperazin- 1-yl]-propoxy)}-phenyl)-N-hydroxy-2-(4-m ethoxy-benzenesulfonyl)-2-methyl-propiona-,jde Following the procedure as outlined in example 12, [4-(3-chloro-phenyl)piperazin- 1-yl]-propoxy)}-phenyl)-2-(4-methoxy-benzenesulfonyl)-2methyl-propionic acid ethyl ester was prepared, starting from (2.72 g, 10 mmol) of 2-(4-methoxy-7 benzenesulfonyl)-propionic acid ethyl ester and the I -[2-(4-chloromethyl-phenoxy)ethyl]-4-(3-chloro-phenyl)-piperazine (4.2 g, 11I mmol). Yield 5.5 g, 89%; Brown oil; MS: 616 Starting from 3 -1 4 3 -cWoro-phenyl)-piperazin- 1-yl]-propoxy }-phenyl)-2-(4methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester (4.0 gin, 6.5 inmol) g (Yield: of 3 4 -(3-chloro-phenyl)-piperazin- 1-yl]-propoxy I-phenyl)- 2 4 -methoxy-benzenesuilfony1)-2-rnethyl-propionic acidwas isolated as colorless.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 crystals by following the procedure as outlined in example 9. Mp 196 MS: 588.1 Starting from 3 4 3 -chloro-phenyl)-piperazin- I1-yl]-propoxy) -phenyl)-2-(4methoxy-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)-2methyl-propionamide was isolated as pale yellow solid. Yield: 1.8 g, 55%; mp 122 0

C

(HCI Salt); MS: 640 IH NMR (300 MHz, CDCl 3 8 1.2 3H), 3.4 (min, 14 3.9 3H), 4.5 (min, 2H), 6.5 8.2 (min, 12H), 10.3-(bs, 1H).

Example 24 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]hex-4-enoic acid hydroxyamide To a stirred solution of 4 -methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.16 g, mmol), isoprenyl bromide (3.0 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2C03 (10 gmins, 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 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%.

Following the procedure as outlined in example 12, 2 methyl-2-[4-(2-morpholin-4-yl-ethoxy)-benzyl]ex-4-enoic acid ethyl ester was prepared, starting from (3.26 g, 10 mmol) of 2-(4-methoxy-benzenesulfonyl)-5methyl-hex-4-enoic acid ethyl ester and 4 -(2-morpholin-1-yl-ethoxy)-benzyl chloride (3.0 g, 11 mmol). Yield 4.5 g, 82%; Brown oil; MS: 546 Starting .from 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-yiethoxy)-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]hex-4-enoic acid was isolated as semi-solid by following the procedure as outlined in example 9. MS: 518.6 SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -41- Starting from 2-(4-Methoxy-benzenesulfonyl)-5-methyl-2-[4-(2-morpholin-4-ylethoxy)-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-(2morpholin-4-yl-ethoxy)-benzyl]-hex-4-enoic acid hydroxyamide was isolated as pale yellow solid. Yield: 450 mg, 45%; mp 92 0 C (HC1 Salt); MS: 570 'H NMR (300 MHz, CDCl 3 8 1.3 3H), 1.65 2H), 3.5 1.8 14 3.9 3H), 2H), 5.4 1H), 6.5- 7.9 8H), 11.5 (bs, 1H).

Example N-Hydroxy-2-(4-ethoxy-benzenesulfonyl)-2-methyl-3-[4-(2-N,N-diethyl aminoethoxy)-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 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 To stirred solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester (11.3 g, mmol), and K 2 C0 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)propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g 98%; MS: 255 2-(4-Ethoxy-phenylsulfanyl)-propionic acid ethyl ester was converted to 2-(4-ethoxyphenylsulfonyl)-propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2.

Following the procedure as outlined in example 12, 2-(4-ethoxy-benzenesulfonyl)-2methyl-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 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -42 Starting from 2 4 -ethoxy-benzenesulfony)2methyl.3-[4-(2-NNdiethyl aminoethoxy)-phenyl]ypropionic acid ethyl ester (4.0 gin, 8.1 mmol) 3.2 g (Yield: 80 of 2 4 -ethoxybenzenesulfonyl)2methyl3[4(2NNdithy amino-ethoxy).phenylppropionic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 464.5 Starting from 2-4ehx-eznsloy)2mty--4(-,-ity aminoethoxy)-phenyl]-propionic acid (2.0 g, 4.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2 4 -ethoxybenzenesulfonyl2methyl3[4(-N, diethyl amino-ethoxy)phenyl].propionmde was isolated as colorless low melting solid. Yield: 1.2 g, 57%; (HC1 Salt); MS: 478.5 'H NMR (300 MHz,

CDCI

3 8 0.9 3H), 1. 1 6H), 1.3 3.2 3.9 (in, 8 3.9 3H), 4.3 2H), 6.5 7.8 (in, 8H), 10.8 (bs, lH).

Example 26 (4)2(-ehx-eznsloy)59dmty--4(-opoi--lehx) benzyl]-deca-4,8-dienoic acid hydroxyamide To a stirred solution of 4 -methoxy-benzenesulfonyl)-acetjc acid ethyl ester (5.16 g, mmol), geranyl bromide (4.2g, 20 inmol) and 1 8-Crown-6 (500 mg) in acetone (250 ml) was added K2C03 (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 silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-4mtoybneeufnl-,-iehldc-,-ini acid ethyl ester was isolated as a colourless oil. Yield: 7.0 g, 89%.

IVollowing the procedure as outlined in example 12, 2 -(4-Methoxy-benzenesulfonyl).

5,-iehl2[-2mrhln4ylehx)bny]dc-,-ini acid ethyl ester was prepared, starting from (1.0 g, 2.5 minol) of 2 4 -methoxy-benzenesulfonyl)..s9dimethyl-deca-,8-dienoic acid ethyl ester and 4 2 -morpholiin- I-yl-ethoxy)..benzy] chloride (800 mng, 2.5 inmol). Yield 1.2 g, 76%; Brown oil; MS: 614 Starting from 2-4Mtoybneeufnl-,-dmty--4(-opoi--i .thoxy)-benzy]dec~a-8-dienoic acid ethyl ester (2.0 gin, 3.2 inmol) 1.5 g (Yield: of 2 4 -Methoxy-benzenesulfonyl)s ,9-dimethyl-2- 4 -(2-morpholin-4-yl- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -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 Starting from 2-(4-Methoxy-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholin.4-yl.

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)-5,9dimethyl-2-[4-(2-morpholin-4-yI-ethoxy)-benzyl]-deca-4,8-dienoic acid hydroxyamide was isolated as pale yellow solid. Yield: 550 mg, 53%; mp 61'C (HCI Salt); MS: 638 Example- 27 2 -f 4 -(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl).

hexanoic acid hydroxyamide 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 brown oil; MS: 520.4 2 4 -(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid was prepared starting from 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxybenzenesulfonyl)-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 example 1. Yield 3.88 g crude (5 brown oil; MS: 492 Starting from 2-[4-(2-diethylamiino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid (3.88 g, 7.89 mnnol) and following the procedure as outlined in example 1, 800 mg of 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)hexanoic acid hydroxyamide was isolated as a yellow powder. Yield 20%; mp 67 0

C;

MS: 507.4 'H NMR (300 MHz, DMSO-d 6 6 0.75 J 7.1 Hz, 3H), 1.05 (in, 2 1.23 J 7.2 Hz, 6H) 1.37-1.91 2H), 3.13 (in, 4H), 3.38-3.51 (in, 3.87 3H1), 4.3 J 4.8 Hz, 2H), 6.88 J =8.7 Hz, 2H), 7.15 (in, 4H), .7.7 (d J 9 Hz,.2H), 9.07 1H), 10.1 1H) SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,I 7633 -44- Example 28 N-Hydroxy- 2 -(4-n-butoxy-benzenesulfonyl)-2.methylp3-[4.(2-piperidinl 1 -yl-ethoxy)phenyl]- propionamide Following the procedure as outlined in example 12, 2 4 -n-butoxy-benzenesulfonyl).2methyl-3-[4-(2-piperidin- 1 -yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.1 g, 10 mmnol) of 2 4 -n-butoxy-benzenesulfonyl)-propionic acid ethyl ester (Prepared from 2 4 -hydroxy-phenylsulfanyl)-propionic acid ethyl ester and nbutylbromide following the procedure outlined in example 27 )the 4 -(2-piperidin-1I-ylethoxy)-benzyl chloride (3.0 g, 10. 1 mmol). Yield 4.5 g, 84%; Brown oil; MS: 532.7 Starting from 2 4 -n-butoxy-benzenesulfonyl)-2-methyl-3.4(2-piperidin-1 -ylethoxy)-phenyl]-propionic acid ethyl ester (5.0 gin, 9.4 inmol) 4.2 g (Yield: 88 of 2 4 -n-butoxy-benzenesulfonyl)-2-methyl314(2.piperdin- 1 -yl-ethoxy)-phenyl]propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MS: 504.6 Starting from 2-4nbtx-eznsloy) -ehl3[-2pprdn1 -ylethoxy)-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-(2piperidine- I -yl-ethoxy)-phenyl]-propionainide was isolated as colorless solid. MP.

Yield: 1.3 g, 42%; (HCl Salt); MS: 478.5 'H NMR (300 MHz,

CDCI

3 8 0.9 3H), 1.2 3H), 1.3 1.9 2.8 4.5 (in, 12 6.8 .7.8 (in, 8H), 10.8 (bs, 1H).

Example 29 N-yrx--4mtoybneisloy)2mty--3(-,-ity aminoethoxy)-phenyl]-propionamide Following the procedure as outlined in example 12, 2-(4-methoxy-benzenesulfonyl)-2methyl-3-[3-(2-N,N-diethyl aminQ-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (5.0 g, 18 inmol) of 2 -(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and the 3-(2-N,N-dieth yl amino-ethoxy)-benizyl chloride (4.9 g, 18' inmol)..Yield 8.1 g, 93%; Brown oil; MS: 478.1 Starting from 2 4 -inethoxy-benzenesulfonyl)-2-methyl3.3(2-N,N-diethyl aminoethoxy)-phenyl]-propionic acid ethyl ester (8.1 gin,.16.9 inmol) 6.7 g (Yield: 88 of SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 2 4 -methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethy am-ino-ethoxy)-phenyl]propionic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MP: 78-8 1; MS: 450.1 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-N,N-diethyl aminoethoxy)-phenyl]-propionic acid (6.7 g, 15 minol) 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 arnino-ethoxy)-phenyl]-propionamide was isolated as colorless low melting solid. Yield: 1.5 g, 21%; (HCI Salt); MS: 450.5 'H NMR (300 MHz, DMSO-d 6 6 1.21 6H), 1.26 3H), 3.18-3.24 (in, 2H), 3.38 (in, 4H), 3.43-3.46 (in, 2H), 3.80 3H), 4.30 6.76-6.78 2H), 6.84-7.2 (m,6H), 10.3 (bs, lH).

Example 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)-2methyl-3-113-(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-lI-yl-ethoxy)-benzyl chloride (6.0 g, 20 mmol).

Yield 9.1 g, 93%; Brown oil; MS: 492 Starting from 2 -(4-methoxy-benzenesulfonyl)-2-methyl-3-[3-(2-morpholin- 1-ylethoxy)-phenyl]-propionic acid ethyl ester (10.0 gin, 20.3 mmol) 8.0 g (Yield: 86 of 2-4mtoybneesloy)2mty 3[-2mrhn1 -yl-ethoxy)-phenyl]propionic acid was isolated as colorless crystals by following the procedure as outlined in example MS: 464.5 Starting from 2 -(4-methoxy-benzenesulfonyl)-2-inethyl-3-[3.(2-morpholin-1 -ylethoxy)-phenyl]-propionic acid (4.55 g, 9.8 inmol) and following the procedure as outlined in example 1, 440 mng of 2-(4-methoxy-benzenesulfonyl)-2-inethyl-3-[3-(2morpholi- 1-yl-ethoxy)-phenyll-propionamide was isolated as colorless solid. Yield: 440 ing, mp 63'C; MS: 479.5 I H NMR (300 Mhz, DMSO-d 6 8 1.26 3H), 3.18- 3.8 (in, 12H), 3.9 3H), 4.4"(in, 2H), 6.7 8.8 (in, 8H), 10.8 (bs, I H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -46 Example 31 1,3-Dioxo- 1 3 -dihydro-isoindo-2-yl)-2-(4-methoxybenzenesulfonyl)-2-methyl-hexanoic acid hydroxyamide Following the procedure as outlined in Example 9, 6&(l, 3 -Dioxo-1,3-dihydro-isoindol.

2 -yl)- 2 4 -methoxy-benzenesulfonyl)2methyl-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 oil; MS: 474 Starting from 6-(1I,3-Dioxo- 1 3 -dihydro-isoindol-2-yl)-2-(4methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester (8.4 g, 17.7 mmol) 6.95 g of 6- (1 ,3-Dioxo- l, 3 -dihydro-isoindol2y)2(4methoxy-benzenesulfonyl)-2-methylhexanoic acid was isolated as colorless oil by following the procedure as outlined in Example 9. MS: 446 Starting from 1,3-Dioxo- 1 3 -dihydro-isoindol-2-yl)-2(4methoxy-benzenesulfonyl)-2-methyl-hexanoic acid (4.9 g, 11I mmol) and following the procedure as outlined in Example 1, 3.1 g of 6 -(1,3-Dioxo-1,3-dihydro-isoindol2yl).2(4.

methoxy-benzenesulfonyl)2methyl-hexanoic acid hydroxyamide was isolated as a light brown solid; Yield: 46%; mp 146- 148 MS: 461.2 H NMR (300 MHz, DMSO-d 6 8 1.55 3H), 1.61- 3.77 (in, 8H), 3.82 3H), 6.92-8.21 (in, 8H), 10.70- (bs,1H), 11.20 (bs,1H).

Example 32 3 4 2 -Diethylaminoethoxy)pheny2(4ura-2-yl-benzensulfonyl).Nhydroxy-2-methyl-propionamide To a stirred solution of 4-bromo thiophenol (19.0 g, 100 minol) and triethyl amine (15.0 g, 150 mmol) in chloroform (400 ml) 2-bromno ethylpropionate (18. 2 g, 100 .ml) was added drop wise. -The reaction mixture was refluxed for I hr and cooled to room temperature. The reaction miuxture was washed with water, dried and concentrated. 2 4 -bromo-phenyisulfanyl):-propionic acid ethyl ester was isolated as colorless oil. Yield: 28.0 g, 99%, MS: 290 SUBSTITUT SHEET (RULE 26) WO 99/42436 PCTIUS98/'17633 -47 2 4 -bromo-phenylsulfanyl)-propionic acid ethyl ester was converted to 2-(4-bromophenylsulfonyl)-propionic acid ethyl ester by following the procedure as described in example 9, paragraph 2.

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 chromatography by eluting it with 50% ethylacetate :hexane. Colorless oil. Yield: 5.9 g, MS: 309 Following the procedure as outlined in example 12, 2 4 2 -furanyl-benzenesulfonyl).

2-methyl-3- 14-(2-N,N-diethyl amiino-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (3.08 g, 10.0 mmol) of 2 4 -(2-furanyl-benzenesulfonyl)propionic acid ethyl ester and the 4-(2-N,N-diethyl amino-ethoxy)-benzyl chloride g, 12.2 mmol). Yield 5.0 g, 97%; Brown oil; MS: 514.6 Starting from 2-4(-uay-eznslfnl -ehl3[-2NN-diethyl aminoethoxy)-phenyl]-propionic acid ethyl ester (5.1 gin, 10.0 mmol) 3.8 g (Yield: 78 of 2 4 2 -furanyl-benzenesulfonyl)-2-methyl.3[4(2N,N-diefiyI amino-ethoxy)phenyll-propionic acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 58 C, MS: 486.5 Starting -from 2 4 2 -furanyl-benzenesulfonyl)-2-methyl-3.[4(2.N,N-diethyI aminoethoxy)-phenyl]-propionic acid (5.0 g, 10.3 mmol) and following the procedure as outlined in example 1, 1.2 g of 2-4ehx-eznsloyl--ehl3[-2NN diethyl amino-ethoxy)-phenyll-propionanide was isolated as colorless low melting solid. Yield: 3.2 g, 62%; (HCI Salt); MS: 502 I H NM (300 MHz, CDCl1 3 1 1.23 6H), 1.4 2H), 2.8 3.0 2 4.1 2H), 6.5 8.0 (in, 711).

Example 33 N-Hydroxy- 2 (4methoxybenzenesulfony)2[4(2moholin-4yl ethoxy)-benzyl]-butyrarmde 2 4 -Methoxy-phenylsulfanyl)-7butyric 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 minol), 5.19 g clear oil; MS: 255.2 SUBSTITUTE SHEET (RULE 26) WO 9942436PCTJUS98/1 7633 48 2 4 -Methoxy-benzenesulfonyl).tutyric 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 clear oil; MS: 287.1 Following the procedure as outlined in example 12, 2 4 -Methoxy-benzenesulfonyl)-2 4 2 -morpholin-4-yl-ethoxy)..benzyl]ybutyic acid ethyl ester was prepared, starting from (3.5 g, 12.2 mmol) of 2 4 -methoxy-benzenesulfonyl)-butyric acid ethyl ester and the 4 2 -(chloromethyl-phenoxy)ethyll-morpholine (2.34 g, 6.7 mmol). Yield 5.7 g, 100%; Brown oil; MS: 506.4 Starting from 2-4Mtoybneeufnl--4(-opoi--lehx)bny] butyric acid ethyl ester (5.54 gin, 11 mmol) 2.9 g (Yield: 55 of 2 -(4-Methoxybeznsloy)2[-2mrhln4y-toy-ezl-uyi acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 478.3 Starting from 2-4mtoybneeufnl--4(-opoi--lehx)bny] butyric acid (2.6 g, 5.4 inmol) and following the procedure as outlined in example 1, 10 mg of N-yrx--4mtoybneeufnl--4(-opoi--l ethoxy)-benzyl]-butyranide was isolated as a brown solid. Yield mp 51 0 C; MS: 493.3 'H NMR (300 MHz, DMSO-d 6 8 0.90 J 7.2 Hz, 3H), 1.69- 1.96 (in, 4 2.67 2H), 3.34 (in, 8H), 3.87 311), 4.04 (in, 2H) 6.8 J 8.7 Hz, 2H), 7.14 (in, 4H), 7.73 J 4.7 Hz, 2H), 9.08 lH), 10.8 IH).

Example 34 N-yrx--4mtoybneesloy)2[-2pprdn 1 -ylethoxy)-benzyl]-butyranide Following the procedure as outlined in example 12, 2 4 -Methoxy-benzenesulfonyl)-2- [4(-ieii-I-lehx)bny]-uyi acid ethyl ester was prepared, starting from (1.0 g, 3.33 minol) of 2 4 -met hoxy-benzenesulfonyl)-butyric acid ethyl ester and the 1-[ 2 4 -chloromethyl-phenoxy)-ethyll-piperid-ine (0.85. g, 3.36 mmol). Yield 1.07 g, 62%; Brown oil; MS: 504.4 Starting from 2 4 -Methoxy-benzenesulfonyl)2[4-(2piperidin- I -yl- ethoxy)-benzylbutyric acid ethyl ester (3.7 gin, 7.3 miriol) 2.2 g.(Yield: 63 of 2-(4-Methoxy- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98'1 7633 -49benzenesulfonyl)-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 Starting from 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-piperidin- l-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)benzyll-butyramide was isolated as a brown solid. Yield 16%; mp 75 0 C; MS: 491.3 'H NMR (300 MHz, DMSO-d 6 8 0.90 J 7.1 Hz, 3H), 1.36-1.96 (in, 4 2.4-2.63 (in, 14H), 3.87 3H), 4.01 J 5.9 Hz, 2H) 6.8 J 8.5 Hz, 2H), 7.11 (in, 4H), 7.71 J 8.8 Hz, 2H), 9.09 LH), 10.8 1H) Example 2-(4-Methoxy-benzenesulfonyl)-2-[4-(2-morpholin-4-y[ethoxy)-benzyl]-pentanoic acid hydroxyam-ide 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 clear oil; MS: 269 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-phenylsulfanyl)-pentanoic acid ethyl ester (6.9 g, 27.4 mmol). Yield 7.07 g clear oil; MS: 300.9 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 and the 4-[2-(chloromethyl-phenoxy)-ethyl]-morpholine (3.45 g, 11.9 nixol). Yield 3.08 g, 62%; Brown oil; MS: 520.4 Starting from 2-(4 -Methoxy-benzenesulfonyl)-2-[4-(2-morpholin.4.yl-ethoxy)-benzylpentanoic acid ethyl ester (2.73 gin, 5.27 nimol) 1.45 g (Yield: 56 of 24(4methoxy-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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 50 Starting from 2 4 -methoxy-benzenesulfonyl)-2-[4-(2-morPholin4yl-ethoxy)-benzyl..

pentanoic acid (1.01 g, 2.05 mmol) and following the procedure as outlined in example 1, 190 mg of 2-4mtoybneeufnl--4(-opoi--iehx)bny] pentanoic acid hydroxyamide was isolated as a brown solid. Yield 18%; mp 101 'C; MS: 507.4 'H NMR (300 MHz, DMSO-d 6 6 0.71 J 7 Hz, 3H), 1.58- 1.82 (in, 4 3.12-3.98 (mn, 12H), 3.87 3H), 4.35 2H) 6.89 J 8.7 Hz, 2H), 7.15 (mn, 4H), 7.74 J 8.9 Hz, 2H), 9.08 1H).

Example 36 2-[4-(2-Azepan- 1-yl-ethoxy)-benzyl]-2-(4-Methoxybenzenesulfonyl)-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 g, 47.3 inmol) and 4-methoxythiophenol (6 g, 43 inmol). Yield: 7.24 g clear oil; MS: 311.2 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)octanoic acid ethyl ester (4.0 g, 13.6 inmol). Yield 3.7 g clear oil; MS: 343.3 Following the procedure as outlined in example 12, 2-[4-(2-Azepan-1I-yl-ethoxy)benzyll-2-(4-Methoxy-benzenesulfonyl).octanoic acid ethyl ester was prepared, starting from (1.69 g, 5.18 inmol) of 2 4 -methoxy-benzenesulfonyl)-octanoic acid ethyl ester and the l-[ 2 4 -chloromethyl-phenoxy)-ethyl]-azepane (1.73 g, 6.0 inmol). Yield 4.86 g, 99%; Brown oil; MS: 574.5 Starting from 2-[4-(2-Azepan-1I-yl-ethoxy)-benzyl]-2-(4-Methoxy-benzenesulfonyl).

octanoic acid ethyl ester (4.8 gin, 8.37 inmol) 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 Starting from 2-[4-(2-Azepan- 1 -yl-ethoxy)-benzylI-2-(4-Methoxy-benzenesulfony).

octanoic acid (1.09 g, 2.0 inmol) and following the pfocedure 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%; rnp 65 MS: SUBSTITIUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 -51 561.6 'H NMR (300 MHz, DMSO-d 6 8 0.81 (t7 J 6.6 Hz, 3H), 1.08- 1.82 (m,14H), 3.13-3.51 (in, 12H), 3.87 3H), 4.33 2H) 6.88 J 8.7 Hz, 2H),7.14 7.7 J=9Hz, 2H), 9.06 1H), 10.28 1H).

Example 37 2 -(4-Methoxy-benzenesuilfanyl)-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 g, 47.3 mmol) and 4-methoxythiophenol (6 g, 43 mmol). Yield: 7.24 g clear oil; MS: 311.2 Starting from 2 4 -Methoxy-benzenesulfanyl)-octanoic acid ethyl ester (3.1 gin, 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 Starting from 2-(4-Methoxy-benzenesulfanyl)-octanoic acid (4.25 g, 16 mmnol) and following the procedure as outlined in example 1, 3.64 g of 2-(4-Methoxy-benzenesulfanyl)-octanoic acid hydroxyamide was isolated as colorless solid. Yield: 76%, MP: MS: 298.2 Example 38 2-(4-Fluoro-phenylsulfanyl)-octanoic acid hydroxyanude 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 g, 24.7 inmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g clear oil; MS: 299 Starting from 2 -(4-fluoro-benzenesulfanyl)-octanoic acid ethyl ester (3.1 gin, 10 inmol) .2.89 g (Yield: 100 of 2 -(4-fluoro-benzenesulfanyl)-octanoic acid was isolated as colorless semi-solid by following the procedure as outlined in example 9. MS: 268.9 Starting from 2-(4-fluoro-benzenesulfanyl)-octanoic acid (2.49 g, 9.2 inmol) and following the procedure as outlined in example 1, 2..72 g of 2-(4-fluoro-benzene- SUBSTITIUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 52 sulfanyl)-octanoic acid hydroxyamnide was isolated as colorless solid. Yield: 99%, UP: 58'C; MS: 284(M-H).

Example 39 1-methyl- I H-imidazol-2-ylsulfanyl)-octanoic acid hydroxyarnide 1-methyl- lH-imidazol-2-ylsuifanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2bromooctanoate (12.1 g, 48 mmol) and 1-methyi-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g clear oil; MS: 285 Starting from 2-(1 1-methyl- I H-imidazoi-2-ylsulfanyl)-octanoic acid ethyl ester (12 gin, 42.2 mmol) 10.2 g (Yield: 95 of 2 -(l-methy-1IH-imidazol-2-ylsulfanyl)-octanoic acid was isolated as colorless solid by following the procedure as outlined in example 9. MP: 95 C, MS: 257.1 Starting from 2 -(l-methyl-1IH-imridazol-2-ylsulfanyl)-octanoic acid (7.84 g, 30.6 minol) and following the procedure as outlined in example 1, 2.77 g of 2-(1-methyl- 1lH-imidazol-2-ylsulfanyl)-octanoic acid hydroxyamide was isolated as colorless solid.

Yield: 33%, MP: 125 C; MS: 272.2 Example N-yrx--4mtoybneeufny)3nptae--lpoinmd Following the procedure as outlined in Example 9, 2-(4-methoxy-benzensulfonyl)-3naphthalen-2-yl-propionic acid ethyl ester was prepared, starting from (5.0 g, minol) of 2 4 -methoxy-benzenesulfonyl)-acetic acid ethyl ester and 2-bromomethyl naphthalene (4.4 g, 20 nimol). Yield 7.2 g, 9 Colorless oil; MS: 3 99 Starting from 2 4 -methoxy-benzenesulfonyl)-3-naphthalen-2yi..propionoic acid ethyl ester (3.7 g, 9 mniol) 3.3g of 2-(4-methoxy-benzenesulfonyl)-3-naphthalen-2yi-propionoic acid. was isolated as colorless oil by folio wing the procedure as outlined in Example 9. MS: 369.1 *Starting from 2 4 -methoxy-benzenesulfonyi)-3-napithalen..2.yl-propionic acid (2.2 g, 5.9 nimol) and following the procedure as outlined in Example 1, 820 mng of Nhyrx--4mtoybneeufny)3nptae--lpolnmd was isolated as a light brown solid; Yield: 36%; mp 161-- 163 MS:.385.9 1 H NMR SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -53- (300 MHz, CDCI 3 8 3.32 J=7.0 Hz, 1H), 3.69 J= 7.0 Hz, 1H), 3.82 3H), 5.02 1H), 6.92-7.89 11H).

Example 41 N-Hydroxy-2-(4-methoxy-phenylmethanesulfonyl)-2methyl-3-phenyl propionic acid hydroxamide A mixture of 4-methoxybenzyl mercaptan 7.0g, 45 mmol), ethyl 2-bromopropionate (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 colorless liquid; MS 255.1 This product is used without further purification.

To an ice cold (5 solution of 2-(4-methoxy-phenylmethanesulfanyl)-propionic acid ethyl ester (5.7g, 21 mmol) in 100 mL CH 2 C12 was added portionwise (7.2g, mmol) of m-chloroperbenzoic acid and the mixture was stirred for 1 h. The reaction was diluted with hexanes (500 mL) and stirred at 25 C° 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 colorless oil; MS 287.1 Following the procedure as outlined in Example 9, 2-(4-Methoxy-phenylmethanesulfonyl)-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 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).

The resulting reaction mixture was worked up as outlined in Example 9. Yield 930 mg, 31%. Colorless solid, mp: 106-108 MS:.347 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT1US98/17633 -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 MS: 364.2 'H NMR (300 MHz, DMSO-d 6 6 1.28 3H), 2.84-2.88 1H), 3.75 (s, 3H), 3.81-3.86 lH), 4.59-4.63 lH), 4.69-4.74 lH), 6.94-6-98 2H), 7T19 (in, 2H), 7.29-7.33 4H), 9.24 1H), 10.88 IH).

Example 42 2 -(3-methyl-but-2-enyl)2(toluene.z-sulfonyl)..hex-4-enoic acid hydroxyamide 2 3 -methyl-but-2-enyl)-2.(toluene4sulfonylhex4enoic acid ethyl ester 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 2 3 -methyl-but-2-enyl).2..toluene4-sulfony)hex-4-noic acid was prepared according to general method as outlined in examnple 9. Starting from 2 3 methyl-but-2-enyl)-2-(toluene..4-sulfonyl..hex4enoic acid ethyl ester (4.5g, 11I mmol), ethanol (15 mL) and 10 N sodium hydroxide.

Starting from 5-methyl- 2 -(3-methyl-but-2-enyl)-2-(toluene4-sulfonyl)-hexA..enoic acid (4.1 g, 11 inmol) and following the procedure as outlined in example 1, 1.07 g&of 2 3 -methyl-but-2-enyl)-2-(toluene4-sulfonyl)hex-4enoic acid hydroxyamnide was isolated as colorless solid; Yield: 30%; mp 108-110 MS: 366.2 'H NMR (300 MHz, DMSO-d 6 61.49 6H), 1.62 6H), 2.41 3H), 2.53-2.63 (in, 4H), 5.00-5.05 2H), 7.40-7.43 2H), 7.59-7.62 2H), 9.04 (s, 1H), 10.80 IH).

Example 43 2 -Methyl- 2 7(2-methyl-furan-3-sulfonyl)-3phenyl.propionic acid hydroxamide 2 -Methyl- 2 -(2-methyl-furan-3-sulfonyl)3phenyl-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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98'1 7633 ethyl ester (2.9g, 11.9 mmol), benzyl bromide (2.22g, 13 mmol) and potassium carbonate (l0g) in acetone (75 mL). Yield (99 amber oil; MS 337.1 2 -Methyl-2-(2-methyl-furan-3-sulfonyl)-3-pheny-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(2-methylfuran-3-ylsulfanyl)-propionic acid ethyl ester (4.8g, 14.3 mmol), dissolved in ethanol mL and 10 N sodium hydroxide (10 Yield 3.7g (84 white solid, MS 307.4 Starting from 2 -Methyl-2-(2-methy1-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 MS: 324 'H NMR (300 MHz, DMSO-d 6 8 1.27 3H), 2.81-2.86 1H), 3.33 3H), 3.61-3.66 1H), 6.66 1H), 7.19-7.25 (in, 5H), 7.76 1H), 9.09 1H), 10.81 1H) Example 44 2 -Methyl-2-(2-methyl-furan-3-sulfonyl)- 3-[4-(2-piperidin- 1-yl-ethoxy)-phenyl]propionic acid hydroxanide 2-ehl2(-ehlfrn3sloy)--4(-ieii-lehx)peyl 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 (2.4g, 9.8 mmol) and l-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96g, 10.7 mmol); Yield 2.4g amber oil; MS 464.2 (M+H) 4 2 -Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin- 1-yl-ethoxy)-phenyllpropionic acid was prepared according to the general method as outlined in example 1.

Starting from 2 -inethyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin- l-yl-ethoxy)phenyl]-propionic acid ethyl ester (2.01ig, 4.5 mmol), dissolved in -ethanol (20 mL) and N sodium hydroxide (10 mnL). The resulting mixture was worked up as outline in example 9. Yield 2.03g; amber crystals mp 66-68 MIS 434 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 minol) 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- l-ylethoxy)-phenyl]-propionic. acid hydroxyatrmide was isolated as amber color solid; Yield: SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT[US98/1 7633 -56- 32%; mp 115-117 MS: 45 1.1 'H NMR (300 MHz, DMSO-d 6 8 1.15- 1.22 (in, 2H), (1.75 3H), 1.78 3H) 2.98-3.03 (mn, 2H), 3.42-3.47 (in, 2H), 3H), 6.65 1H), 6.87-6.90 2H), 7.12-7.17 2H), 10.35 1H), 10.60 1H), 11.70 1H).

Example 2 -Methyl-3-[4-(2-piperidmn- I -yl-ethoxy)-pheny-2-(thliophene2sulfony)propionic acid hydroxainide 2-Methyl-3-[4-(2-piperidin- l-yl-ethoxy)-pheny12-(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 2mercaptothiophene and 2-bromopropionic acid ethylester) (4.4g, 17.7 mmol) and 14[2- 4 -chloroinethylphenoxy)-ethyl]-piperidine (5.3g, 19.5 mniol); Yield semisolid; MS 466.

2-Methyl-3-[4-(2-piperidin- 1-yl-ethoxy)-phenyl-2-(thiophene-2-sulfonyl)-propiopic acid was prepared acording to the general method as outlined in example 9. Starting 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 m1L) and 10 N sodium hydroxide mL). The resulting mixture was worked up as outline in example 1. Yield 4.5g (49 white solid mp 170-172 MS 436.3 Starting from 2-Methyl-3-[4-(2-piperidin-.1 -yl-ethoxy)-phenyl-2-(thiophene-2.

sulfonyl)-propionic acid (3.6 g, 8.0 inmol) and following the procedure as outlined in example 1, 345 mng of 2-ehl3[-2pprdn1y-ehx)pey--tipee2 sulfonyl)-propionic acid hydroxyainide was isolated as light colorless solid; Yield:.mp 115-118 MS: 451.2 'H NMR (300 MHz, DMSO-1 6 81.29 (s, 3H), -1.66-1.78 (in, 6H), 2.8 1-2.86 1H), 2.96-3.99 (mn, 4H), 3.39-3.47 (mn, 2H), 3.5.1-.3.59 1H), 4.32 (in, 2H),6.72-6.74 (d 1H), 6.87-6.96 (dC, 2H), 7.01-7.20 (mn, 3H), 7.31-7.33 (mn, 1H), 7.69-7.72 (in, 1H), 7.83-7.84 (in, lH), 8.07-8.08 (dd, lH), 8.17 (dd, 1H), 9.0 1H) 10.0 1H), 10.78 1H).

SUBSTmJTE SHEET (RULE WO 99/42436 PCT/US981 7633 57 Example 46 2-(octane- 1 -sulfonyl)- 3 -[4-(2-piperidin-yl-ethoxy)-phenyljpropionic acid hydroxan-ude 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-l-sulfonyl)-propionic acid ethyl ester (5.0g, 18 mmol) and l-12-(4-chloromethylphenoxy)-ethyl]-piperidine (5.6g, 19.7 mmol); Yield 8.9g amber oil, MS 495.

2-(Octane-l1-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- I -suifonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenylI-propionic acid ethyl ester (8.9g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide (25 mL). Yield 6.Og 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- l-sulfonyl)- 3 -[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid hydroxyamnide was isolated as tan solid; Yield: 89%; mp 69-70 MS: 483.2 'H NMR (300 MHz, DMSO-d 6 8 .687 3H), 1.27-1.69 (in, 15H), 2.71-2.75 1H), 3.51 3H), 3.65-3.69 1H), 6.86-6.89 2H), 7.08-7.11 2H), 9.16 1H), 10.70 1H).

Example 47 3-B iphenyl-4-yl-2-methyl-2-( 1-methyl-i H-imidazole-2sulfonyl)-propionic acid hydroxyamide 3-B iphenyl-4-yl-2-methyl-2-( 1-methyl-i H-imiidazole-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-methyl-( 1-methyl- 1 H-imidazolesulfonyl)-propionic acid ethyl ester Prepared from (I1-Methyl-2-mercapto imidazole and 2-bromo ethyl propionate) (3.0g, 12.2 mmol) and 4-chioromethylbiphenyl (2.97g, 15 mmol). Yield 5.Og (99 low melting solid; MS 413 3-Biphenyl-4-yl-2-methyl-2-( 1-methyl-i H-iinidazole-2-sulfonyl)-propionic acid was prepared according to the general method as outlined in example 9. Starting from 3biphenyl-4-yl-27methyl2-( 1-methyl- I H-imidazole-2-sulfonyl)-propionic acid ethyl ester SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/I 7633 58 11 .9 mmol), ethanol (15 mL) and 10 N sodium hydroxide (10 mL). Yield 2. gg (61 brown solid mp 119-122 MS 385.2 Starting from 3-Biphenyl-4-yl-2-methyl-2-( 1-methyl- I H-imidazole-2-sulfonyl)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-I H-imidazole-2-sulfonyl)-propionic acid hydroxyainide was isolated as tan colored solid; Yield: mp 112 MS: 399.0 'H NMR (300 MHz, DMSO-1 6 8 0.911 3H), 3.3 3H), 3.5 I1H), 4.2 1H), 6.8 1H), 6.9 1H), 7.18-7.66 (in, 5H), 7.30-7.33 2H), 7.55- 7.58 2H).

Example 48 2 -Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxamide 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-2sulfonyl)-propionic acid ethyl ester (3.0g, 12 mmol) and benzyl bromide (2.48g, mmol). Yield 5.2 g (ft) tan oil; MS 339.1 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 N sodium hydroxide (10 mL). Yield 5.6g MS 3 10.0 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-3phenyl-2-(thiophene-2-sulfonyl)-propionic acid hydroxyamide was isolated as colorless solid; Yield: 40%; mp 116-117 MS: 325.9 'H NMR (300 MHz, DMSOd 6 8 1.29 3H), 3.33 1H), 3.69 (d 1H), 7.18-7.30 (in, 5H), 7.74 (in, 1H), 8.22 (in, 1H), 9.13 1H), 10.80 1H).

Example 49 1-carboxy-ethanesulfonyl)-octante-l1-sulfonyl]-propionic acid hydroxyamide 2-j18-( 1-Carboxyl-ethanesulfonyl)-octane- 1-sulfonyll-propionic acid ethyl ester was prepared according to the general method as'outlined in example 9. Starting from SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 9942436PCTIUS98/ 17 633 59 (1-ethoxycarbonyl-ethylsulfanyl)-octylsulfanyl]-propionic acid ethyl ester (10.2g, 26 mimol) and sodium peroxymonopersulfate, (64g, 104 mmol). Yield 9.87g colorless liquid; MS 442.9 I-Carboxy-ethanesulfonyl)-octane- 1-sulfonylj-propionic acid was prepared according to general method as outline in example 1. Starting from 2 -[8-(l-carboxyethanesulfonyl)-octane- 1 -sulfonyl]-propionic acid ethyl ester (3.0g, 6.8 mmol), ethanol ml-) and 10 N sodium hydroxide (15 mL). Yield 2.7g (98 white solid mp 99- 102' 0 C; MIS 387 (M+NH3)'.

Starting from 1-Carboxy-ethanesulfonyl)-octane-l1-sulfonyll-propionic acid g, 6.5 mmol) and following the procedure as outlined in example 1, 641 mg of 1- Carboxy-ethanesulfonyl)-octane- 1 -sulfonyl]-propionic acid hydroxyamidewas isolated as amber coloured oil.; Yield: 23 MS: 434.0 'H NMR (300 Mffz, DMSO-d 6 5 1.27-3.23 (in, 22H), 3.33 (in, 2H), 8.9 1H), 9.28 1H).

Example 2 -(4-Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine- 1-yl-ethoxy)-phenyl]propionic acid hydroxamide 2 4 -Bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidine- 1-yl-ethoxy)-phenyllpropionic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl a-(4-bromophenyl-sulfonyl) acetate (5.0g, 16 mniol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (4.97g, 16 mmol). Yield 6. 1lg (71 tan oil; MS 54 1.1 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.

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 0 C; MS 512.5 Starting from 2-(4-Bromo-benzenesulfonyl)-2methyl3[4(2.piperidine.1 -yl-ethoxy)phenyll-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- l-yi- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 60 ethoxy)-phenyl]-propionic acid hydroxyamnide was isolated as light yellow solid; Yield: 17%; MS: 525.4 Example 51 3-4Boopey)N-yrx--4mtoy-eznsloy)2methylpropionamude Following the procedure as outlined in Example 9, 3 4 -bromo-phenyl)-2- (4-methoxy.

benzensulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (3.0 g, 11 nImol) 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4-bromobenzyl bromide (3.0 g, 12 mmol). Yield 4.67 g, 96%; Colorless oil; MS: 441 3 4 -Bromo-phenyl)-2-(4methoxybenzenesulfonyl).2-methyl-propionic acid was prepared starting from 3-4boopey)2(-ehxybneeufnl--ehl propionic acid ethyl ester (4.0 g, 9.0 nimol) 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 Starting from 3-4boopey)2(-ehx-eznsloy)2mty-rpoi acid (2.7 g, 6.5 mmol) and following the procedure as outlined in example 1, 2.26 g of 3 4 -bromophenyl)-Nhydroxy2.(4methoxybenzenesulfonyl)-2.methyljpropionamide was isolated as light colorless solid; Yield: 8 nip 86-8 8 MS: 429.8 H NMR (300 MHz, CDC1 3 8 1.42 1.77 (bs, IlH), 3.26 J=7 .0 Hz, 1H), 3.68 J= 7.0 Hz, 1H), 3.85 3H), 7.01 -7.76 9.71 9.88 (bs, I H).

Example 52 N-yrx--4mtoybneeufnl--ehl3nptae--lpoinmd Following the procedure as outlined in Example 9, 2 -(4-methoxy-benzenesulfonyl)-2methyl- 3 -naphthalen..2.yl-propionic acid ethyl ester was prepared, starting from (5.4 g, nimol) 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and 2-bromnomethyl naphthalene (4.4 g, 20 mmol). Yield 8.0 g, 97%; Colorless crystals, mnp 182- 184 0 C; MS&413 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -61- Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid ethyl ester (4.6 g, 11I mmol) 4.2g of 2-(4-methoxy-benzenesulfonyl)-2methyl-3-naphthalen-2-yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp 144-146 MS: 384.9 Starting from 2-(4-methoxy-benzenesulfonyl)-2-methyl-3-naphthalen-2-yl-propionic acid (2.4 g, 6.2 mnmol) 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 MS: 400.2 H NMR (300 MHz, CDCI 3 8 1.56 3.28 J= 8.0 Hz, I1H), 3.81 J=8Hz,1H), 3.93 4.88 (bs, 1H), 7.02 7.92 (in, I1LH).

Example 53 N-Hydroxy-2-(4-methoxy-benzenesulfonyl)-3-methyl-butyranmide 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 mmol), 30 g of 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was isolated. Yield 99%; Light yellow oil; MS: 269 Starting from 2-(4-methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester. (2.68 g inmol) and following the procedure as outlined in Example 9 for oxidation, 3 g of 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester was isolated as a colorless solid, yield: 99%; mnp 53 MS: 273. (M+H) t Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid ethyl ester (3 g, mxnol) 2.7 g of 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 96 MS: 273 Starting from 2-(4-methoxy-benzenesulfonyl)-3-methyl-butyric acid (2.0 g, 7.34 inmol) and following the procedure as outlined in Example 9, 590 mg of N-hydroxy-2- (4-methoxy-benzenesulfonyl)-3-methyl-butyrainide was isolated as a colorless solid.

Mp 220' 0 C; Yield 28%; MS: 288 'H NMR (300 MHz, DMSO-d 6 8 0.88'(d, SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 62 J 6.7 Hz, 3H), 1.07 J 6.7 Hz, 3H), 2.09-2.20 (bs, 1H), 3.53 J 9, 1H), 7.12-7.17 (in, 2H), 7.74-7.79 (in, 2H).

Example 54 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 inmol) of 2 4 -methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1 ,4-dibromobutane 2.4 g, 7.6 nimol). Yield 2.4 g, 78%; Colorless solid, mp, 86-88 0 C; MS: 313 1 4 -Methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid was prepared starting from 1 4 -methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid ethyl ester (2.2 g, 7.0 nimol) dissolved in methanol (50 ml) and 10 N NaOH (30 The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.66 g, 83%.

Colorless solid; mp 112-115 MS: 285 Starting from 1-( 4 -methoxy-benzenesulfonyl)-cyclopentanecarboxylic acid (442 mg, 1.5 inmol) and following the procedure as outlined in Example 1, 4 10 mng of 1-(4methoxy-benzenesulfonyl)cyclopentanecarboxylic acid hydroxyamide was isolated as a colorless solid. mp 89-91 Yield 88%; MS: 300 IH NMR (300 MHz, CDCl 3 8 1.65-1.82 (in, 4H), 2.17-2.42 (mn, 4H), 3.87 3H), 7.0 J= 8Hz, 2H), 7.7 (bs, lH), 7.72 J=8 Hz, 2H), 9.73 (bs, 1H).

Example 3 2 -Bromo-phenyl)-N-hydroxy-2..(4-methoxy..benzenesulfonyly..2-metylpropionamide Following the procedure as outlined in Example 9, 3-(2-bromo-phenyl)-2-(4methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester was prepared, starting from (2.0 g, 7.3 inmol) of 2 4 -methoxy-be~nzene-sulfonyl)-propionic acid ethyl ester and 2-(bromo)benzyl bromide (2.0 g, 8 minol). Yield 3.1 g, Colorless oil; MS: 441 3 2 -Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl).2-miethyl-propionic acid was prepared starting from 3 2 -bromo-phenyl)-2-(4-inethoxy-benzenesulfonyl)2-miethyl.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PTU9n73 PCTIUS98/17633 63 propionic acid ethyl ester (3.0 g, 68 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 mlJ). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.7 g, 63%. Waxy solid; MS: 414 Starting from 3-(2-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid (470 mg, 1. 1 minol) 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 Yield 77%; MS: 429 I H NMR (300 MHz, CDCl 3 8 1.3 3H), 3.32 J=7.0 Hz, 1H), 3.69 J= 7.0 Hz, 1H), 3.82 3H), 6.92-7.89 (in, 8H).

Example 56 2-(4-methoxy-benzenesulfoniyl)-2-methyl-5-phenyl-pent.4-enoic acid hydroxyamnide Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-2methyl-5-phenyl-pent-4-enoic acid ethyl ester was prepared, starting from (3.0 g, 11I mmol) 2-(4-methoxy-benzenesulfonyl)-propionic acid ethyl ester and cinnamyl bromide (2.1 g, 11I mmol). Yield 3.51 g, 82%; Colorless oil; MS: 389 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, 11I 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, 68%; yellowish oil; MS: 361 Starting from 2-(4-methoxy-benienesulfonyl)-2-methyl-5-phenyl-pent-4-enoic acid (440 mg, 1.2 minol) 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 was isolated as a colorless solid. mp 162-164 Yield 92%; MS: 376 1H NMR (300 MHz, CDCl 3 8 1.41 3H), 3.0-3.16 (in, 1H), 3.30 J= 11 Hz, 2H), 3.92. 3H), 5-.9 6.1 (in, 1H), 6.53 J=llHz, 1H), 7.1-7.72 9.12 (bs,lIH).

SUBSTITUTE SHEET (RULE WO 99/42436 PCT/US98/I 7633 -64- Example 57 2 4 -methoxy-benzenesulfonyl)5phenyl-2.(3-phenyl-propyl)-pentanoic acid hydroxyamnide Following the procedure as outlined in Example 9, 2 4 phenyl- 2 3 -phenyl-propyl)-pentanoic acid ethyl ester was prepared, starting from g, 15.8 mmol) 2 4 -methoxy-benzenesulfonyl)-acetic acid ethyl ester and 3-bromopropyl benzene (6.4 g, 32 mmol). Yield 3.7 g, 47%; Colorless oil; MS: 495 2 4 -Methoxy-benzenesulfonyl)-5-phenyl-2-(3phenyl.propyl)-pentanoic acid was prepared starting from 2 4 -methoxy-benzenesulfonyl)-5-phenyl2(3..phenyl-propyl).

pentanoic acid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 nil) and 10 N NaOH (30 The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H-H 2 Starting from 2 4 -methoxy-benzenesulfonyl)5-phenyl.2.(3phenylpropyl)pentanoic acid (600 mg, 1.2 mmol) and following the procedure as outlined in Example 1, 420 mg of 2-4mtoybneeufnl--hey--3pey-rpl-etni acid hydroxyamide was isolated as a colorless solid. Mp 118-120 yield 68%; MS: 482 H NMR (300 MHz, CDCl 3 8 1.52 1.68 (in, 2H), 1.74 1.92 (in, 2H), 1.98-2.20 (in, 4H), 2.58 2.72 3.86 3H), 6.93 J= 11I Hz, 2H), 7.02- 7.63 (mn, 1OH), 7.81 J=1Il Hz, 2H).

Example 58 2 -allyl- 2 4 -methoxy-benzenesulfonyl)-pent.4-enoic acid hydroxyamidde Following the procedure as outlined in Example 9, 2 -allyl-2-(4-inethoxy-benzenesulfonyl)-pent-4-enoic acid ethyl ester was prepared, starting from (3.0 g, 11.6 inmol) 2 4 -inethoxy-benzenesulfonyl)-acetic acid ethyl ester and allyl bromide (4 ml, excess).

Yield 3.6 g, 92%; Yellow oil; MS: 338 2 -Allyl- 2 4 -methoxy-benzenesulfonyl)pent-4enoic acid was prepared starting from 2 7allyl- 2 4 -methoxy-benzenesulfonyl-pent4enoic acid ethyl ester (2.2 g, 6.5 inmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9' Yield 1176 g, 87%; yellowish oil; MS: 311 SUBSTTUTE SHEET (RULE WO 99/42436 PCT/US98/I 7633 65 Starting from 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid (1.5 g, 4.8 mimol) and following the procedure as outlined in Example 1, 1.5 g of 2-allyl-2-(4methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyamide was isolated as colorless solid. Mp 114-116 Yield 99%; MS: 326 H NMR (300 MHz, CDCl 3 8 1.62 lH), 2.70 2.80 3.9 3H), 5.16 -5.27 (in, 4H), 5.8 1-5.94 (in, 2H), 7.12 (d,J=8 Hz,2H).

Example 59 2-(4-methoxy-benzenesulfonyl)-2-prdpyl-pentanoic acid hydroxyamide 2-allyl-2-(4-methoxy-benzenesulfonyl)-pent-4-enoic acid hydroxyarnide (326 mg, minol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 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 mng, 75%; MS: 330 'H NMR (300 MHz, CDCl 3 8 0.92 J 4.0 Hz, 6H), 1.27-1.59 (in, 4H), 1.78-2.02 (in, 4H), 3.86 3H), 6.04 (bs, 1H), 6.97 J=9Hz, 2H), 7.76 (d,J=9 Hz, 2H).

Example 2-benzyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)-3-phehyl-propionamide Following the procedure as outlined in Example 9, 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester was prepared, starting from (1.0 g, 3.8 inmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and benzylbromide (4 ml; excess). Yield 1.2 g, 72%; Yellow oil; MS' 439 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 inmol) 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 Starting from 2-benzyl-2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid (410 mg, I inmol) and following the procedure as outlined in Example 225 mg of. 2benzyl-N-hydroxy-2-(4-methox.y-benzenesulf6nyl)-3-phenyp'ropionamide was SUBSTVMJT SHEET (RULE WO 99/42436 PCT/US98/1 7633 66 isolated as a waxy solid. Yield 52%; MS: 426 IH NMR (300 MHz, CDCl 3 3.25 J=14 Hz, 2H), 3.52 J= 14 Hz, 2H), 3.9 3H), 6.93 J=8Hz, 2H), 7.02 7.26 (in, 9H), 7.61 J=8Hz, 2H), 7.87 J=4Hz, 1H), 9.58 (bs, 1H).

Example 61 N-hydroxy- 2 4 methoxybenzenesufonyl)2methyl.3.pyridin3ylpropionmde To a stirred solution of 2 4 -methoxy-benzenesulfonyl)propionic acid ethyl ester (2.7 gin, 10 mmol), 3-picolyl chloride hydrochloride (3.2 g, 20 inmol). and triethyl benzylammonium 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 chromatography. The column was eluted with 50% ethyl acetate: hexane. 2-(4- Methoxy-benzensulfonyl)-2methyl3pyridin.3-yl.propionic acid ethyl ester was isolated as brown oil. Yield 3.0 g, 82%; Brown oil; MS: 364 Starting from 2 4 -methoxy-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid ethyl ester (2.5 g, 6.8 inmol) 1.8 g 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 MS: 336 Starting from 2 4 -methoxy-benzenesulfonyl)-2-methiyl-3.pyri~jn..3yl-propionic acid (410 mg, I mmol) and following the procedure as outlined in Example 1, 225 mg of N-yrx--4mtoybneeufnl)2mty--yii--lpoinmd was isolated as a colorless solid. Yield 52%; mp 98 MS: 351 IH NMR (300 MHz, CDC1 3 8 1.4 3H), 3.1 J=9.0, 1H), 3.65 J= 9.1, 1H), 3.9 (s, 3H), 7-8.5 (in, 8H).

Example .62 2 4 -Methoxy-benzenesulfonyl)-2pyridin3ylmethyl..decanoic acid hydroxyamicle Starting from 2 4 -methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.5 g, 29 mmol) and I -bromooctane (6.7g, 35 inmol) 8 g of the mono octylated compound 2-(4- SUBSTrrumE SHEET (RULE WO 99/42436 PCTIUS98/I 7633 67 methoxy-benzenesulfonyl)-decanoic acid ethyl ester was isolated by following the procedure outlined in Example 9. Yield: 8.0 g 74%; MS: 370 Following the procedure as outlined in example 29, 2 -(4-methoxy-benzenesulfonyl)- 2-pyridin-3-ylmethyl-decanoic acid ethyl ester was prepared, starting from (8.0 g, 21.6 Inmol) 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 Starting from 2 4 -methoxy-benzenesulfonyl)-2-pyridin-3-ylmethy..decanoic acid ethyl ester (5.0 g, I11 mmol), 4.5g (91 of 2 -(4-methoxy-benzenesulfonyl)-2-pyridin-3ylmethyl-decanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp 159 MS: 434 Starting from 2 4 -methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-decanoic acid g, 5.7 mmol) and following the procedure as outlined in Example 1, 1.4 g of 2-(4mehx-eznsloy)2pyii--lehldcni acid hydroxyamide was isolated as colorless solid. Yield: 50%; mp 62 MS: 448 I H NMR (300 MHz, CDCl 3 8 0.86 6.9 Hz, 3H), 1.25-2.17 (in, 14 3.3 J= 14 Hz, I1H), 3.5 (d J= 14 Hz, 1H), 3.9 3H), 6.8 8.6 (in, 8H).

Example 63 2-4Mtoybneeufnl--ehy--yii- ymty-e--ni acid hydroxyamride Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-5methyl-hex-4-enoic acid ethyl ester was prepared, starting from (6.0 g, 23 inmol) methoxy-benzenesulfonyl)-acetic acid ethyl ester and isoprenyl bromide (3.0 g, inmol). Yield 6.52 g, 86%; Colorless oil; MS: 327 Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)-5met hyl-2-pyridin-3- ylmethyl-hex..4-enoic acid ethyl ester was prepared, starting from g, 12.2 rnmol)- Of 2 4 -methoXy-benzenesulfonyl)-5-methyl..hex.4-enoic- acid ethyl ester and 3-picolylchloride hydrochloride (2.1 g, 13. mnmol). Yield 4.14 81%; Brown oil; MS: 418 SUBSTrIUTE SHEET (RULE 26) WO 99/42436 PCT/US9 8/17633 68 2 4 -Methoxy-benzenesulfonyl)-5-methyl-2-pyridin-3-ylmethylhex-4-enoic acid was prepared starting from 2 4 -methoxy-benzenesulfonyl)-5-methyl-2-pyridin3ylmethylhex-4-enoic acid ethyl ester (4.0 g, 9.5 nimol) dissolved in methanol (50 nml) and 10 N NaCH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.2 g, 87%; ivory solid; mp 117-119 MS: 390 Starting from 2 4 -methoxy-benzenesulfonyl)-5-methyl-2-pyridin3ylmethyl..hex-4 enoic acid (2.1 g, 5.4 nimol) and following the procedure as outlined in Example 1, 1.82 g of 2 4 -methoxy-benzenesulfonyl)-5-methy-2pyrdin3ylmethyl..hex-4-noic acid hydroxyamide was isolated as a colorless solid. Yield: 82%; mp 89 92 MS: 405 I H NMR (300 MHz, CDCl 3 8 1.63 3H), 1.76 3H), 2.62-2.78 (in, 2H), 3.3 J=4.0 Hz, 1H), 3.63 J= 4.0 Hz, IH), 3.82 3H), 5.26 (mn, 11H), 7.12-7.88 (mn, 6H), 8.27-8.33 (mn, 2H).

Example 64 2 -Benzyl- 4 -diisopropylanino-N-hydroxy2(4-methoxy-benz.enesulfonyl)butyramide Following the procedure as outlined in Example 29, 2-benzyl-4-diisopropylarnino-2-(4methoxy-benzenesulfonyl)-butyric acid ethyl ester was prepared, starting from (3.0 g, nimol) of 2 4 -inethoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (Example 9) and 2-diisopropylaminoethyl chloride hydrochloride (4.0 g, 20 inmol).

Yield 3.2 g, 79%; Ivory solid, mp 89-91 MS: 476.4 Starting from 2 -benzyl- 4 -diisopropylamino-2-(4-nethoxy-benzenesulfonyl).butyric acid ethyl ester (3.53 gin, 7.5 inmol) 2.8 g 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 MS: 448.5 Starting from 2 -benzyl- 4 -diisopropylan-ino-2-(4-methoxy..benzenesulfonyl)-butyric acid (1.85 g, 4.1 rnmol) and following the procedure as outlined in Example 1, 1.3 g of 2-enzy*-ispoyain--yrx--4mtoybeznsloy)btrmd was isolated as a low melting waxy solid; Yield: 68%; MS: IlH.NMR (300 MHz, CDCI 3 80.98 J I 11 Hz, 6H), 1.t16 J= 11 Hz, 6H), 1..92 (in, 2H), 2.46 (in, 2H), 2.71 (in, 2H), 3.18 (in, lH), 3.48 (mn, 1H), 3.86 3H), 6.98 Hz, 2H), 7.18 -7.22 (mn, 5H), 7.92 J=8 Hz, 2H), 8.12 1H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 69 Example 3-ylhxlNhdoy2(-ehx-eneeufnl--yii--lehl propionamide Following the procedure as outlined in Example 9, 3-cyclohexyl-2-(4-methoxybenzenesulfonyl)-propionic acid ethyl ester was prepared, starting from (4.0 g, 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 Following the procedure as outlined in Example 29, 3 -cyclohexyl-2-(4-methoxybenzenesulfonyl)-2-pyridin-3-ylmethyl-propionic acid ethyl ester was prepared, starting from 3 -cyclohexyl- 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester(l.5 g, 4.2 mmol) and 3-picolyl chloride (1.0 g, 6 mmol). Yield 1.0 g 38%; Colorless oil; MS 446 Starting from 3 -cyclohexyl-2-(4-methoxy-benzenesulfonyl)-2-pyridin.3-ylmetiyl.

propionic acid ethyl ester (1.3 g, 2.9 mmol) 1.Og of 3-cyclohexyl-2-(4methoxy-benzenesulfony1)-2-pyridin-3-ylmethyl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 92 MS: 417.5 Starting from 3 -cyclohexyl-2-(4-methoxy-benzenesulfonyl)2pyridin3ylmeihylpropionic acid (1.0 g, 2.4 mmol) and following the procedure as outlined in Example 1, 80 mg of 3 -cyclohexyl-N-hydroxy-2-(4-methoxy-benzenesulfonyl)2pyridin-3 ylmethyl-propionamide was isolated as a colorless hydrochloride salt; Yield: 7 mp 57-60 MS: 433 'H NMR (300 MHz, CDCI 3 8 0.8-2.08 (in, 13 3.3 J= 14 Hz, IlH), 3.7 J= 14 Hz, I1H), 3.9 3H), 7.0 -8.5 Example 66 2 4 -Methoxy-benzenesulfonyl)-4-methyl-2-pyridin-3ylmethyl-pentanoic acid hydroxyamide Following. the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-4methyl-pentanoic acid ethyl ester. was prepared, starting from (5.0 g, 20 inmol) 2-(4methoxy-benzenesulfonyl)-acetic acid ethyl ester and l-bromo-2-methyl propane (2.6 g, 20 minol). Yield 6.0 g, 95%; Colorless oil; MS: 315 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 70 Following the procedure as outlined in Example 29, 2 4 -methoxy-benze nesulfonyl).

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 ester and 3-picolyl chloride hydrochloride (1.8 g, 11 mmol). Yield 3.0 g, Colorless oil; MS: 406 Starting from 2 4 -methoxy-benzenesulfonyl)A4-methyl.2pyridin.3.ylmethyl..pentanoic acid ethyl ester (1.2 g, 2.9 mmol) 1 .Og of 2-(4-methoxy-benzenesulfonyl)-4 methyl-2-pyridin-3-ylmethyl-pentanoic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. Mp 188-186 MS: 378 Starting from 2 4 -methoxy-benzenesulfonyl)-4methyl2pyridin-3ylmethyl.pentanic acid (800 mg, 2.1 mmnol) and following the procedure as outlined in Example 1, 180 mg of 2 4 -methoxy-benzenesulfonyl)4methyl2pyridin3ylmethyl-pentanoic acid hydroxyamide was isolated as a colorless solid; Yield: 21 mp 78 MS: 393.4 I H NMR (300 MHz, CDCl 3 8 0.65 6.3 Hz, 3H), 0.89 J=6.2 Hz, 3H), 1.7 (in, 1H), 2.06 (mn, 2H), 3.85 3H), 6.8 -8.5 (mn, Example 67 N-yrx--4mtoybneeufnl--ehl3qioi--ipoinmd Following the procedure as outlined in Example 29, 2-(4-methoxy-benzenesulfonyl)-2-.

methyl-3-quinolin-6-yl-propionic acid ethyl ester was prepared, starting from (5.2 g, mmol) of 2 4 -methoxy-benzenesulfonyl)-propionic ac id ethyl ester and 7broinoiethyl quinoline (4.4 g, 20 mnmol). Yield 4.5 g, 54%; Pale yellow solid; mp 86'C1 MS: 414 Starting from 2 4 -methoxy-benzenesulfonyl)-2methyl3quinolin6.yl-propionic acid ethyl ester 3.0 gin, 7.2 minol) 2.5g of 2-( 4 -methoxy-benzenesulfonyl)-2methyl-3-quinolin-6-yl-propionic acid was isolated as colorless crystals by following the procedure as outlined in Example 9. mp 106-108 MS: 386.4 Starting from 2 4 -methoxy-benzenesulfonyl)2methyl.3quinolin6YIpropionic acid gin, 5.2 minol) and following the procedure as outlined in Example 1, 1.2 g of Nhyrx--mtoybneeufnl--ehl3qioi--ipolnmd was isolated as a colorless solid; Yield: 57 mp 206 MS: 401.4. IH NM SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -71 (300 MHz, CDC1 3 6 1.4 3H), 3.19 (in, 1H), 3.8 -4.0 (mn, 4H), 7.1 -8.95 (mn, 12H).

Example 68 2 4 -Methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic acid hydroxyamnide.

Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-6phenoxy-hexanoic acid ethyl ester was prepared, starting from (2.5 g, 10 inmol) 2-(4methoxy-benzenesulfonyl)-acetic acid ethyl ester and 1-bromo-4-phenoxy butane 2.2, inmol). Yield 3.8 g, 93%; Colorless oil; MS: 407 Following the procedure as outlined in Example 9, 2-(4-methoxy-benzenesulfonyl)-6phenoxy-2-pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from (3.1 g, 10 inmol) 2 4 -inethoxy-benzenesulfonyl)-6-phenoxy-hexanoic acid ethyl ester and 3-picolyl chloride (1.8 g, 11 nmmol). Yield 3.5 g, 7 Colorless oil; MS: 498 Starting from 2-(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethylb hexanoic acid ethyl ester (3.0 g, 6.0 inmol), 2.8g (Yield: Quantitative) of 2-(4methoxy-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 Starting from 2 -(4-methoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylinethylhexanoic acid (2.0 g, 4.3 mmol) and following t he procedure as outlined in Example 1, g of 2 4 -inethoxy-benzenesulfonyl)-6-phenoxy-2-pyridin-3-ylmethyl-hexanoic.

acid hydroxyamide was isolated as a colorless solid; Yield: 72%; mp 68 MS: 485.5 'H NMR (300 MHz, CDCI 3 2.5 (mn, 8H), 3.4 (bs, 2H), 3.8 (s, 3H), 6.8 8.7 (mn, 13H).

SUBSTITUT SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 72 Example 69 2 4 -Methoxy-benzenesulfonyl)-5..methyl.2-pyridin.3.ylmethyi..hexanoic acid hydroxyamide, Following the procedure as outlined in Example 9, 2 4 hexanoic acid ethyl ester was prepared, starting from (10.0 g, 39 mmol) 2-(4-methoxybenzenesulfonyl)-acetic acid ethyl ester and I -bromo-3-methyl butane 6.0 g, mmol). Yield 8.5 g, 62%; Colorless oil; MS: 329 Following the procedure as outlined in Example 9, 2 4 methyl- 2 -pyridin-3-ylmethyl-hexanoic acid ethyl ester was prepared, starting from g1l8 minol) of 2 4 -methoxy-benzenesulfonyl).s-methyl-hexanoic acid ethyl ester and picolyl chloride hydrochloride (4.1 g, 25 mmol). Yield 4.5 g, 60%; Brown oil; MS: 420 Starting from 2 4 -methoxy-benzenesulfonyl)-5-methy12pyridin3ylmethyl-hexanoic acid ethyl ester (3.0 g, 7.1 nimol) 2.6g of 2 4 methyl-2-pyridin-3-ylmethyl-hexanoic acid was isolated as a colorless solid by following the procedure as outlined in Example 9. Mp: 173 C; MS: 392 Starting from 2 4 -methoxy-benzenesulfonyl)-5-methyl2pyridin..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)-5methyl2pyridn-3-ylmethyl-hexanoic acid hydroxyainide 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 'C (HCl salt); MS: 408 I H NMR (300 MHz, CDCI 3 8 0.76 (in, 6H), 1.2 -2.0 (in, 5H), 3.5 (bq, 2H), 7.1 8.8 (in, 8H), 11. 1 (bs,1IH).

Example 2 4 -Methoxy-benzenesulfony)2pyridin3ylmethyl-hexanoic acid hydroxyamide 4 -Methoxy-phenyisulfanyl) -acetic. acid tert-butyl ester was prepared according to the general method. as outlined in Example 1. Starting from the. corresponding 1-broino tert-butyl acetate (5.3 g, 27 inmol) and 4-inethoxybenzenethiol (3.7 g, 27 inmol), 6.4 g of the product was isolated. Yield 98%; Light yellow oil; MS: 255 SUBSTITUTE SHEET (RULE 26) 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-benzenesulfanyl)-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; MS: 287.1 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-(4methoxy-benzenesulfonyl)acetic acid tert-butyl ester (20.0 g, 70.0 mmol) and 3-picolyl 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 2 4 -Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4methoxy-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 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-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-hexanoic acid was purified by silica gel chromatography (30% methanol/methylene chloride). Yield 0.90 g, 94%; white solid; mp 70 MS: 376.1 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-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethylhexanoic acid (0.31 g, 0.81 mmol) 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 IH NMR (300 MHz, DMSO-d 6 8 0.80 J 7.2 Hz, 3H), 1.10-1.25 2H), 1.25-1.50 2H), 1.70- 2.00 2H),'3.53 J 14.4 Hz, 1H), 3.62 J 14.4 Hz, 1H), 3.88 3H), 7.15 J 8.9 Hz, 2H), 7.71 J 8.9 Hz, 2H), 7.90-8.00 8.40-8.45 1H), 8.70-8.85 2H), 11.0 (brs, 1H); IR (KBr, cnm-1): 3064m, 2958s, 2871m, 1671m.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,I 7633 74- Example 71 2 4 -methoxy-benzenesulfonyl)-2-oct-2-ynylbdec4ynoic acid hydroxyamicle.

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, mmol) and I1-bromo-2-octyne (3.80 g, 20 mmol), 4.4 g of the product isolated. Yield 100%; yellowish gum; MS: 446.9 2 4 -Methoxy-benzenesulfonyl)-2oct2ynyldec-4-pynoic 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 Inmol), 2.0 g of the product isolated. Yield 49%; white solid; mp 61'C; MS: 345.1 2 4 -Methoxy-benzenesulfonyl)-2-oct-2ynyl.dec.z-ynoic acid hydroxyamnide was prepared according to the method as outlined in example 1. Starting from 2-(4methoxy-benzenesulfonyl)2-oct2ynylbdec-4ynoic acid (0.36 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.25 g of the product isolated. Yield 62%; white solid; mp 83-84 462.0 H NMR (300 MHz, DMSO-d 6 8 0.82-0.90 (in, 6H), 1. 15-1.45 (in, 12H), 1.90-2.05 (in, 4H), 2.86 (brd, J 17.0 Hz, 2H), 3.00 (brd, J 17.0 Hz, 2H), 3.87 3H), 7.15 J 10.0 Hz, 1H), 7.71 J 10.0 Hz, lH), 9.20 (brs, IH), 10.90 (brs, 1H); IR (KBr, cm- 1 3344s, 3208m, 2930m, 2870m, 1677s, 1592s; Anal. Calc'd for C 25

H

35 N0 5 S: C, 65.05; H, 7.64; N, 3.03.

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

Example 72 2 4 -Methoxy-benzenesulfonyl)-2but2ynylhex4ynoic acid hydroxyam-ide 2 4 -Methoxy-benzenesulfonyl)2but2.ynylheX74ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4methoxy-benzenesulfonyl)..acetic acid tert~butyl ester (2.86 g, 10 inmol) and I1-bromo- 2-butyne (2.68 g, .20 inmol), 3.50 g of the productwas isolated. Yield. 90%; white solid; mp 85-87 0 C; MS: 391.0 SUBSTrruTE SHEET (RULE WO 99/42436 PCT/US981 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-benzenesulfonyl)-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 14 1-143 MS: 333.1 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-(4methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 nunol) and hydroxylamnine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated.

Yield 89%; white solid; mp 135-137*C; MS: 349.9 'H NMR (300 MHz, DMSO-d 6 8 1.67 6H), 2.70-3.10 (in, 4H), 3.88 3H), 7.15 J 10.0 Hz, 2H), 7.71 J 10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (K.Br, cm-i): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.

Example 73 2 4 -Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pentA-ynoic acid hydroxyamide 2 4 -Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent.4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.0 g, 7.0 mmol) and propargyl bromide (1.77 g, 15 nimol), 1.90 g of the product was isolated. Yield 75%; white solid; mnp I1I3-115'C; MS: 362.1 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-methoxybenzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid tert-butyl ester (1.70 g, 4.7 mmol1), 1.30 g of the product isolated. Yield 90%; white solid; mp 156'C; MS: 305.1 2 4 -Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid hydroxyamnide was prepared according to the method as outlined in Example 1. Starting from (4-methoxybenzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 mmol) and hydroxylamiune hydrochloride (0.70 g, 10 mn-ol), 0.22 +g of the product was isolated.

Yield 85%; white solid.; mp 156'C; MS: 321.9 1 H NMR (300 MHz, DMSOd 6 8 2.00-2.13 (in, 2H), 3.00-3.30 (mn, 4H), 3.90(s, 3H), 7.01 J =9.0 Hz, 2H), SUBSTITUTE SHEET (RULE 26) WO 99/42436 PTU9/73 76 7.82 J 9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, lH); IR (KBr, cm-i): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C I 5 H I 5 N0 5 S: C, 56.07; H, 4.70; N, 4.36.

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

Example 74 2 4 -Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec.4-ynoic acid hydroxyam-ide 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 Il-bromo-2-octyne 14 g, 6 nimol), 2.60 gm of the product isolated. Yield 92%; yellowish gum; MS: 486.0 A mixture of the 2 4 -methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4ynoic acid tert-butyl ester (2.60 g, 5.35 mmol), in methylene chloridelTFA 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-4ynoic acid was purified by silica gel chromatography methanollmethylene chloride).

Yield: 2.0 g, 87%; White solid; mp 146 0 C; MS: 428.1 2 4 -Methoxy-benzenesulfonyl).2-pyridin-3-ylmethyl-dec.4ynoic acid hydroxyan-ide was prepared according to the procedure outlined in Example 1. Starting from 2-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyldec-4-ynoic acid (0.7-1 g, 1.62nnnol) and hydroxylamine hydrochloride (1.39 g, 20 mmol), 0.48 g of the product was isolated. Yield 67%; off-white solid; mp, 65'C; MS: 445.0 'H NMR (300 MHz, DMSO-d 6 8 0.84 J 6.8 Hz, 3H), 1.10-1.40 (in, 6H), 1.85-2.00 (in, 2H), 2.79 J 17.9 Hz, 1H), 2.90 J 17.9 Hz, 1H), 3.50 J =13.7 Hz, 1H), 3.74 J 13.7 Hz, 1H), 3.89 3H), 7.19 J 9.0 Hz, 2H), 7.76 J Hz, 2H), 7.85-7.89 (in, I 8.37-8.40 (in, I 8.70-8.80 (in, 2H), 11.0 (brs, IlH); IR(KBr, cm-I1): 3157m, 3095m, 2954s, 2932s, 2858m, 167 im, 1593s; Anal. Calc'd for C 23

H

2 gN 2

O

5 S-HCl*0.9H 2 O: C, 55.56; H, 6.24; N, 5.63.

Found: C,-55.84; H, 6.19; N, 5.59.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/IuS98/17633 77 Example 2-( 4 -Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide 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, mmol) and propargyl bromide (1.74 g, 13 mmol), 2.50 g of the product was isolated.

Yield 60%; yellowish solid; mp 132-133'C; MS: 416.0 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-methoxybenzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid tert-butyl ester 0 g, 4.8 mimol), 1.2 g of the product isolated. Yield 69%; white solid; mp 1 19-121'C; MS: 358.1 2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pentA-ynoic acid hydroxyamnide was prepared according to the method as outlined in Example 1. Starting from 2-(4methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 mn, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70'C; MS: 375.0 'H NMR (300 MHz, DMSO-d 6 8 1.19 (brs, 1H), 2.90-3.00 (in, 2H), 3.55 J 13.8 Hz, 1H), 3.67 J 13.8 Hz, 1H), 3.89 3H), 7.18 J 9.0 Hz, 2H), 7.75 J= Hz, 2H), 7.80-7.89 (in, 1H), 8.35-8.40 (in, 1H), 8.70-8.80 (in, 2H), 11.1 (brs, 1H); IR (KIBr, cm-i): 3168mn, 3095s, 1670m, 1593s.

Example 76.

2 4 -Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid hydroxyamide 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 minol) and tert-butyl bromoacetate (45.67 g, 230 minol), 53.4 g of the product was isolated. Yield 100%; pale yellowish oil; MS: 243.1 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)- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/UJS98/1 7633 78 acetic acid tert-butyl ester (48.4 g, 200 mmol) and 3 -chloroperoxybenzoic acid 1 2 1.3g 400 mmol 48 .0 g of the product was isolated. Yield 88%; pale yellowish oil; MS: 275.1 The title compound was prepared according to the procedure as outlined in Example Starting from 2 4 -fluoro-benzenesulfonyl)y3.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 2 4 -Fluoro-benzenesulfonyl)2pyridin3ylmethyl-hex-4ynoic acid was prepared according to the method as outlined in Example 38. Starting from 2 -(4-fluorobenzenesulfonyl)-2pyridin3ylmethyl-hex-4ynoic acid tert-butyl ester (2.1 g, mmol), 1.20 g of the product was isolated. Yield 67%; off-white solid; mp 150 0 C; MS: 360.2 2 4 -Fluoro-benzenesulfonyl).2pyridin.3-ylmethyl- hex-4-ynoic acid hydroxyam-ide was prepared according to the method as outlined in Example 1. Starting from 2-(4fluoro-benzenesulfonyl)-2-pyridin.3ylmethyl-hex.4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylanune hydrochloride 0.70 g, 10 mmol), 0. 15 g of the product was isolated. Yield 45%; white solid; mp 190*C; MS: 377.2 I H NMR (300 MHz, DMSO-d 6 8 1.60 3H), 2.70-3.00 (in, 2H), 3.53 J 13.8 Hz, 1H), 3.74 J =13. 8 Hz, 1H), 7.50-7.58 (in, 2H), 7.80-7.95 (mn, 3H), 8 3 5-8.40(m, 1H), 8.74- 8.79 (in, 2H), 11. 1 (brs, I1H); IR (KBr, cm-I1): 3154mn, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s; Anal. Calc'd for C1 8

H

1 7

FN

2 0 4 S*HCI. 0.5H 2 0: C, 51.24; H, 4.54; N, 6.64.

Found: C, 51.2.1; H, 4.35; N, 6.46.

Example 77 2-4Fur-eznsloy)2prdn3ymty-e--ni acid hydroxyamide The title compound was prepared according to the procedure as outlined in Example 9.

Starting from 2 4 -fluoro-benzenesulfonyl)-3pyridin.3zylpropionic acid tert-butyl ester (1 .83 g, 5.0 minol). and. Il-broino-2-octyne (0.95 5.0 mmol), 1.80 g of the product was isolated. Yield 56%; yellowish gum; MS: 474.3 SUBSTMTIE SHEET (RULE 26) WO 99/42436 PCT/US98/I 7633 79 2 4 -Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-dec-4ynoic acid was prepared according to the method as outlined in Example 70. Starting from 2 4 -fluoro-benzenesulfonyl)-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: 416.3 2 4 -Fluoro-benzenesulfonyl)-2-pyridin..3..ylmethyl.dec4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyldec-4ynoic acid (0.67 g, 1.62 nimol) and hydroxylanine hydrochloride (1.39 g, 20 mmol), 0.22 g of the product was isolated. Yield 29%; white solid; mp 180-182 0 C; MS: 433.2 'H NMR (300 MHz, DMSO-d 6 8 0.84 J 6.8 Hz, 3H), 1.20-1.40 (in, 6H), 1.90-2.05 (mn, 2H), 2.75 J 19.9 Hz, 1H), 2.94 J 19.9 Hz, 1H), 3.54 J 13.7 Hz, lH), 3.75 J 13.7 Hz, 1H), 7.40-7.60(m, 2H), 7.70-8.00 (mn, 3H), 8.30-8.40 (in, 1 8.70-8.80 (mn, 2H), 11. 1 (brs, I1H); JR (KBr, cm-I1): 3154m, 31lO5s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631mn.

Anal. Calc'd for C 2 2H 25

FN

2

O

4 S-HC1: C, 56.34; H, 5.59; N, 5.97.

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

Example 78 2 4 -Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4.ynoic acid hydroxyamide 2 4 -Fluoro-benzenesulfonyl)-2-but-2-ynyl.hex4ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and I1-bromo-2butyne (5.36 g, 40'mmol), 6.0 g of the product was isolated. Yield white solid; mp 85"C; MS: 379.1 2 4 -Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex4ynoic 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 nimol), 2.35 g of the product was isolated. Yield 79%; white solid; mp 129-131VC; MS: 642.8 2 4 -Fluoro-benzenesulfonyl)-2-but-2-yny-hex4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US981 17633 benzenesulfonyl)-2-but2ynylhex-4ynoic acid (0.26 g, 0.81 mmrol) and hydroxylaxnine hydrochloride (0.70 g, 10 mnmol), 0.21 g of the product was isolated.

Yield 77%; white solid; mp, 161-163'C; MS:338.1I(M+H)'; 'H NMR (300 MHz, DMSO-d 6 6 1.67 6H), 2.80-3. 10 (in, 4H), 7.51 (dd, J 9.0, 9.0 Hz, 2H), 7.87 (in, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm-I): 3 336s, 3 245m, 1681is, 1589m, 1493m; Anal. Calc'd for C 16

H

16 FN0 4 S: C, 56.96; H, 4.78; N, 4.15.

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

Example 79 2 4 -Methoxybenzenesulfonyl)5methyl2(3methylbut2enyl)hex-4enoic acid hydroxyamide Following the procedure as outlined in Example 9, 2 4 -methoxy-benzenesulfonylys...

methyl- 2 -(3-methyl-but-2-enyl)-hexA..enoic acid ethyl ester was prepared, starting from (5.0 g, 20 inmol) 2 4 -methoxy-benzenesulfonyl).acetic acid ethyl ester and isoprenyl bromide (6.0 g, 40 inmol). Yield 7.0 g, 88%; Colorless oil; MS: 395 Starting from 2 4 -methoxybenzenesulfonyl)methyl2(3methylbut2enyl)-hex-4enoic acid ethyl ester (3.5 g, 9 inmol), 3.3g of 2 -(4-methoxy-benzenesulfonyl)- 2 -(3-methyl-but-2enyl)hex-4-enoic acid was isolated as a colorless oil by following the procedure as outlined in Example 9. MS: 365 Starting from 2 4 -methoxybenzenesulfonyl)smethy12(3methy1.but2enyl)-hex-4 enoic acid (2.6 g, 7.0 inmol) and following the procedure as outlined in Example 1, 1.36 g of 2 4 -methoxybenzensufony)methyl.2(3iethyl-but.2enyl).hex4enoic acid hydroxyamnide was isolated as a colorless solid. Yield: 67%; mp, 93 96 'C; MS: 383 I H NMR (300 MHz, CDCl 3 8 1.68 6H), 1.73 6H), 2.72 (in, 3.82 3H), 5.12 (in, 2H), 6.92 J=8 Hz, 2H), 7.33 (bs, 1H), 7.72 (d, J=8 Hz, 2H), 9.71 (bs, l).

SUBSTITUJTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -81 Example 2 4 -methoxy-phenylsulfanyl)-heptanoic acid hydroxyamnide.

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-bromoheptanoate (11 g, 47 mmol) and 4-methoxythiophenol (6g, 42.8 mmol), as a yellow oil, MS: 297.2 2 4 -Methoxy-phenylsulfanyl)-heptanoic acid was prepared starting with 2-(4methoxy-phenylsulfanyl)-heptanoic acid ethyl ester (4 g, 13.5 mmol) dissolved in methanol (300 ml) and- 10 N NaOH (25 The resulting reaction mixture was worked up as outlined in example 1. Yield 3 g yellow oil. MS: 267.1 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-phenylsulfanyl)-heptanoic acid hydroxyaniide was isolated as an off white solid. Mp Yield 70%; MS: 284.0 'H NMR (300 MHz, DMSQ-d6~): 8 0.826 J= 6.9 Hz, 3H), 1.135-1.76 (in, 8H), 3.35 (in, 1H), 3.82 3H), 6.91-7.49 (in, 4H).

Example 81 (49A) 2R*-(4-methoxy-phenyl- sulfinyl)-heptanoic acid hydroxyamide and (49B) 2 S*-(4-methoxy-phenyl- sulfinyl)-heptanoic acid hydroxyamide Starting from 2 4 -methoxy-phenylsulfanyl)-heptanoic acid hydroxyam-ide (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.

column using 75% ethyl acetate:hexanes. The less polar isomer, 2R*-(4-methoxyphenyl- sulfinyl)-heptanoic acid hydroxyarnide was isolated as a white powder.

Yield: 390 mng mp 115 0 C; MS: 300.0 'H NMR (300 MHz, DMSOd 6 0.828 J= 6.2 H4z, 3H), 1.18-1.23 (mn, 6H1), 1.73-1.99 (in, 2H), 3.11-3.15 (in, 1H), 3.82 3H), 7.09-7.61 (in, 4H). The. more polar isomer, 2S*-(4-inethoxy-.

phenyl- sulfinyl)-heptanoic acid hydroxyamide was isolated as a gray solid. Yield: 200 mg mp 112 MS: 300.0 'H NMR (300 MHz, DM50-l 6 ):8 0.754 J= 6.9 Hz, 3H), 1.014-1.121 (in, 6H), 1.58-1.89 (in, 2H), 3.10-3.15 (in, 1H), 3.834 3H), 7.13-7.65 (in, 4H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1,7633 82 Example 82 2 4 -methoxybenzenesulfonyl)2methyl..3j[4.2morpholin4yl-ethoxy)-phelyl]propionic hydroxyamride hydrochloride.

Following the procedure as outlined in example 12, 2 4 -methoxy-benzenesulfonyl)-2methyl-3- [4-(2-morpholin- I -yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared, starting from (4.0 g, 15 mmol) of 2 4 -methoxy-benzenesulfonyl)-propionic acid ethyl ester and 4 -(morpholin-1-yl-ethoxy)-benzyl chloride hydrochloride (2.9 g, mmol). Yield 4.8 g, 98%; Brown oil; MS: 492 Starting from 2-4mtoybneeufnl--ehl3[-2mrhln 1 -ylethoxy)-phenyll-propionic acid ethyl ester (4.0 gin, 8.1 mmol) 3.2 g (Yield: 84 of 2 4 -methoxy-benzenesulfonyl)2methyl-3-4(2-morholin-.1 -yl-ethoxy)-phenyl]propionic acid was isolated as colorless crystals by following the procedure as outlined in example 9. Mp 171 MS: 464 Starting from 2 4 -methoxy-benzenesulfonyl)-2-methyI3-[4-(2morpholin-1 -ylethoxy)-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)2methyl-3-.[4-(2 morpholin-1I-yl-ethoxy)..phenyly-propionic hydroxyamide was isolated as colorless solid. The hydrochloride salt was prepared by reacting the free base with methanolic hydrogen chloride at 0 Yield: 2.5 g, 60%; mp 98'C; MS: 479 I'H NMR (300 MHz, CDC1 3 1.36 3H), 3.8 12.6 (in, 16 3.9 3H), 4.1 4.3 (in, 1H), 6.6 J= 8 Hz, 2H), 6.96 J= 9 Hz, 2H), 7.1 8 Hz, 2H), 7.84 9 Hz, 2H), 10.8 (bs, 1H).

Example 83 1-ezl4(-ehx-eznsufnl-ieiie4croyi Acid hydroxyamide To a stirred solution of 4-inethoxybenzenethiol (2.8 gin, 20 inmol) and anhydrous

K

2 C0 3 (10 gin, excess) in dry acetone (100 ml), cx-bromo ethyl acetate (3.3 gin, mmol) was added in a round bottom flask. and the reaction mi xture. was heated at reflux for 8 hours with good stirring. At the end, the reaction mixture was allowed to Pool 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 SUBSTrru-rE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -83filtered and concentrated. (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester was isolated as pale yellow oil. Yield: 4.4 g MS; 227 To a stirred solution of 60% 3-chloroperoxybenzoic acid (14.0 gm, 40 mmol) in methylene chloride (100 ml) at 0° C, (4-methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, 20 mmol) in CH 2 C12 (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 organic layer was dried over MgSO4, filtered and concentrated and the colorless (4methoxy-phenylsulfonyl)-acetic acid ethyl ester was isolated as an oil. Yield: 100%; MS: 259.1 To a stirred solution of diethanol amine (10.5 g, 100 mmol), and anhydrous K 2 CO3 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 residue was extracted with chloroform and washed with H 2 O 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 N-Benzyldiethanolamine (9.75 g, 50 mmol) was dissolved in saturated methanolic hydrochloric acid and concentrated to dryness. The hydrochloride thus formed was dissolved in 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: 13.0 g, 97%; Mp: MS: 232 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 C0 3 (30 gm, excess) in dry acetone (250 ml), (4-methoxy-phenylsulfonyl)-acetic acid ethyl ester (6.12 gm, 24 mmol) was 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -84residue 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. 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)- 1benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.0 g, MS: 418 4 4 -Methoxy-benzenesulfonyl)-1 -benzyl-piperidine-4-carboxylic acid ethyl ester g, 11.9 mmol) was dissolved in MeOH/THF 200 ml) and stirred at room 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)- 1benzyl-piperidine-4-carboxylic acid was dried at 50 C and taken to next step with out any purification. Colorless solid. Yield: 3.2 g, 69% MS: 390 To a stirred solution of 4 4 -Methoxy-benzenesulfonyl)-1-benzyl-piperidine-4carboxylic acid (2.0 g, 5.1 mmol) and DMF 2 drops) in CH 2 C12 (100 ml) at OOC, oxalyl chloride (1.0 gm, 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 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water 30 ml) at OC for 1 hour.

At the end of I hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH 2 Cl 2 and added slowly to the hydroxylamine at OC. 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-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colorless solid, mp 90-95 Yield, 1.2 g, 48%; MS: 405 1H NMR (300 MHz, DMSO-d 6 8 2.29 3H), 2.76-2.79 2H), 3.43 4H),4.30 2H), 7.14-7.17 7.50-7.73 5H), 9.37 10.53 11.18 (s,lH).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 85 Example 84 4-(4-methoxy-benzenesulfonyl)- 1 -(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 2 -[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-aniino] -ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolarnine 3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride 5 g, 31.9 inmol). Yield 9.28 g, (99%) yellow oil; MS: 226 3-Methoxybenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 3-Methoxy-benzyl diethanolamnine (4.4 g, 20 mmol). Yield 4.5 g (93 yellow solid mp 86 -88 C; MS: 263. 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-chioro ethyl)-(3-methoxy-benzyl)-amfine (8.0 g, 23.5 mmol). Yield 2.4 g low melting solid; MS: 447.9 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 mL) 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 7 10 mg white solid mp 199 'C MS: 419.9 Starting from 4-(4-methoxy-benzenesulfonyl)- 1 -(3-methoxy-benzyl)-piperidine-4carboxylic acid (830 mg, 1.98 mmol) and following the procedure as outlined in.

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 'C; Yield 20.4%;.MS: 435.0 'H.NMR (300 MHz, DMSO-d 6 8 2.24-2.32 (in, 2H), 2.51(d, 2H), 2.73-2.83 (in, 2H), 3.37 2H), 3.76 3H), 3.88 3H), 4.32 2H), 7.01-7.77 (m,8H),*9.38 iHO, 101(s, 1 H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 86 Example 1 -(3,4-dichlorobenzyl) 4 4 -methoxy-benzenesulfonyl)-piperidne4carboxylic acid hydroxamide 2-[(2-Hydroxy-ethyl)-(3 ,4-dichloro-benzyl)-axnino]-ethanoI was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 mmol). Yield 13.8 g (99 colorless oil; MS: 264.3 3 4 -Dichlorobenzyl-bis-(2-cliloro-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 MS: 301.8 (M+H) 4 1-( 3 4 -Dichloro-benzyl)-4-(methoxy..benzenesulfonyl).piperidine4carboxylic 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 brown oil; MS: 494.5 l-( 3 4 -Dicfforobenzyl)A-(4methoxybenzenesulfulfonyl)piperidine4-carboxylic acid was prepared starting from 1 4 -dichloro-benzyl)-4-(methoxy-benzenesulfonyl).

piperidine-4-carboxylic acid ethyl ester (5.0 g, 10 mmu .ol) dissolved in methanol m1L), 10 N sodium hydroxide (15 mL) and tetrahydrofuran (75 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.94 g (62 MS: 458.3 Starting from l-( 3 4 -dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl).piperidineA..

carboxylic acid (2..67g, 5.8 mmol) and following the procedure as outlined in example 83, .2 g of 1 ,4-dichlorobenzyl) 4 4 -methoxy-benzenesulfonyl)-piperidine-4carboxylic acid hydroxamide was isolated as a white solid. mp 192-195 Yield MS 472.9 'H NMR (300 MHz, DMSO-d6): 8 2.20-2.28 (in, 2H), 2.76-2.79 (in, 2H), 3.43-3.44 (in, 4H),'4.30 2H), 7.14-7.17 J=.030, 2H), 7.50-7.73 (d, J=.027, 1H), 7.65-7.68 J=.029, 2H), 7.7-2-7.75 J='.027, 2H), 7.87 1H), 9.37 1H), 10.53 1H), 11.18 1H).

SUBSTITUTE SHEET (RULE WO 99/42436 PCTJUS98/1 7633 87 Example 86 4-(4-methoxy-benzenesulfonyl)- 1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide 2-iI(2-Hydroxy-ethyl)-(4-methyl-benzyl)- aminoJ-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 4-Methylbenzyl-bis-(2-chloro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 4-methyl-benzyl diethanolanune (6 g, mmol). Yield 5.2 g (84 yellow solid mp 145-147 MS: 245.9 4-(4-Methoxy-benzenesulfonyl) 1 -(4-methyl-benzyl)piperidine-4-carboxylic acid ethyl ester was prepared acc6rding to the general method as outlined in example 83. Starting from 4-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (7.0 g, 27 mmol) and 4methyl-bis-(2-chloro-ethyl)-amine (5.0 g, 17 mmol). Yield 4.64 g (63 low melting solid; MS: 431.9 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 mL), tetrahydrohydrofuran (20 The resulting reaction* mixture was-worked up as outlined in example 83. Yield 1.6 g (40 white solid mp 207-208 MS: 404.3 Starting from 4-(4-methoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4carboxylic acid .(1.59g, 3.9 mmol) and following the procedure as outlined in example 83'T' .505 g 'of 4 -(4-mnethoxy-:benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4carboxylic acid hydroxamide was isolated as a white solid. mp 176-177 Yield 32%; MS: 419.0 'H NMIR (300 MHz, DMSO-d 6 8 2.24-2.32 (in, 2H), 2.5 1l(t, 3H), 2.73-2.80 (mn, 2H), 3.35-3.50 (mn, 4H), 3.87 3H), 4.24 2H), 7.13-7.17 J=.039, 2H), 7.23-7.60 J=.036, 211), 7.38-7.4 1 J=.025, 2H), 7.65-7.68 2H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/1 7633 88 Example 87 4 -(4-methoxy-benzene-sulfonyl)- 1 -napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide 2 2 -Hydroxy-ethyl)-(2-napthyl-2-ylmethyl)..arriinoI 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 MS: 246.0 2 -Napthyl- 2 -ylmethyl-bis-(2-choro-etliyl)-anine was prepared according to the general method as outlined in example 83. Starting from 2-napthyl-ylmethyl-diethanol amine g, 36 mmol). Yield 9.1 g (79 brown solid mp 124-126 MS: 281.9 4 4 -Methoxy-benzenesulfonyl)--napthaleneylmethyl-piperidme-4carboxylic 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 l-napthalene-ylmethyl-bis-(2-chloro-ethyl)-anine g, 27 mimol). Yield 6.5 g low melting solid; MS: 440.0 4-(4-Methoxy-benzenesulfonyl)- 1 -napthalene-ylmethyl-piperidineA-carboxylic acid was prepared starting from 4 4 -methoxy-benzenesulfonyl)-napthalene-ylmethylpiperidine-4-carboxylic acid ethyl ester (6.3g, 13 mmol) dissolved in methanol 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 MS: 440.0 (M+H) 4 Starting from 4-(4-methoxy-benzenesulfonyl). 1 -napthalene-2-yl-methylpiperidine-4carboxylic acid (2.18g, 5.0 mmol) and following the procedure as outlined in example 83,-753 g of 4 -(4-methoxy-benzene-sulfonyl)-l1-napthalene-2-yl-methylpiperidine-4carboxylic acid hydroxamide was isolated as a off white solid. mp 168-170 Yield 3 MS 455.0 'H NMR (300 MHz, DMSO-d 6 8 2.29-2.33 2H), 2.86- 2.89 (in, 2H4), 3.42-3.46 (in, 4H), 3.85 3H), 4.46 2H), 7.13-7.16 (d,'J=.030, 2H), 7.56-7:64 (mn' 3H), 7.65-7.68 J=.030, 2H), 7.98-8.00 (in, 3H), 8.21 (s, LH), 10.70 lH), 11.20 IH).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 89 Example 88 1 -Biphenyl- 4 -ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine.4-carboxylic acid hydroxainide 2-[(2-Hydroxy-ethyl)-( I-biphenyl-4-ylmethyl))-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol amnine (5.2 g, 49 mmol) and 4-(chloromethyl)biphenyl (10 g, 49 mmol). Yield 9.98 g (66 white solid mp 160-162 MS: 271.9 This was converted to the dichloride as outlined in example 83 I-ihnl4ymty--4mtoybneeufnl-ieiie4croyi 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) and 1-biphenyl-4-ylmethyl-bis-(2-chloro-ethyl).aine (3.4 g, 11 mmol). Yield 2.1 g, (39 beige solid, mp 176-178 MS: 494.1 I -Biphenyl- 4 -ylmethyl-4-(4-methoxy-benzenesulfonyl).piperiine-4-carboxylic acid was prepared starting from 1 -biphenyl-4ylmethyl-(4-methoxy-benzenesulfonyl).

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.l1g (39% MS: 465.8 Starting from 1 -biphenyl -4-ylmethy1-4-(4-methoxybenzenesulfonyl)piperidine-4 carboxylic acid (1.0g, 2+.2 mmol and following the procedure as outlined in example 83, .1 32g of 1 -biphenyl-4-ylmethy1-4-(4-methoxy-benzenesulfonyl)piperidine-4 *carboxylic acid hydroxamide was isolated as a tan solid. mp 168 Yield 20%; MS: 440.9 'H NMR (300 MHz, DMSO-d 6 8 2.30-2.35 (in, 2H1), 2.83-2.87 (in, 2H), 3.35-3.5 (in, 4H), 3.87 3H), 7.15-7.721 J=.059 Hz, 2H), 7.49-7.65 (in, 7.68-7.74 J=.06 Hz, 2H), 9.3 1H), 10.3 1H), 11.15 1H).

SUBSTITUTrE SHEET (RULE 26) WO 99/42436 PCT/US9SI 7633 Example 89 4-(4-methoxy-benzene-sulfonyl)- 1-( 3 -methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide 2-[(2-Hydroxy-ethyl)- 1-(3-methyl-but-2-enyl)-amnino] -ethanol was prepared according to the general method as outlined in example 83. Starting from diethanol am-ine (4.1 g, 39 mmol) and 4-bromo-2-methyl-butene (6.0 g, 40 mmol). Yield 98 brown oil; MS: 173.8 1 3 -methyl-but-2-enyl)]-bis-(2-ch~oro-ethyl)-amine was prepared according to the general method as outlined in example 83. Starting from 2-[2-hydroxy-ethyl)-l-(3methyl-but-2-enyl)-amino]-ethanoI (10.4g, 50 mmol). Yield 10.5g brown solid; MS: 210.3 (M+H) 4 -(4-Methoxy-benzenesulfonyl)- 1-( 3 -methyl-but-2-enyl)-piperidine.4-.carboxylic acid ethyl ester was prepared according to the general method 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 (36 brown oil; MS: 395.6 (M+H) 4 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), 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 MS: 367,9 Starting from 4-(4-methoxy-benzenesulfonyl)- 1 -(3-methyl-but-2-enyl)-piperidine-4carboxylic 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-4carboxylic acid hydroxamide was isolated as a yellow solid. mp 142-145 Yield 12%; MS: .382.9 NMR (300 MHz, DMSO-d 6 8 1.67 3H), 1.79 (s, 3H),-2.18-2.23 2.66-2.73 (in, 3.37-3..46 (in, 3.67-3.69 (in, 2H), 5.19-5.24 (mn, lH), 7.15-7.18 J=.03, 2H), 7.67-7.70 J=.030, 2H), 9.34 1lH), 9.8 8 IlH), 11. 15 1 H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/I 7633 -91- Example 1 4 -Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethano 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 inmol). Yield 3 3.66g, yellow oil; MS: 273.8 (4-Bromo-benzyl)-bis-(2-chloro-ethyl)-anu ne was prepared according to the general method as outlined in example 83. Starting from 2-[4-bromobenzyl)-(2-hydroxyethyl)-amino]-ethanol (33.28 g, 122 mmol). Yield 47 g, brown solid; mp, 125'C; MS: 309.8 1 4 -Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidineA4-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 (4bromo-benzyl)-bis-(2-chloro-ethyl)-amine (13.3 g, 38.6 minol). Yield 17 g brown oil; MS: 497.8 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 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g tan solid; mp 215 MS: 469.7 Starting from 1 -(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4carboxylic acid (1.95 g, 4.2 mmol) and following the procedure as outlined in example 83, 1.29 g of 1 -(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4carboxylic acid hydroxyamide was isolated as an off white solid. Yield 60%; mp 180*C; MS: 484.7 H NMR (300 MHz, DMSO-d 6 8 2.18-2.29 (in, 2H1), 2.46 2H), 2.74-2.89 (in, 2H), .3.39 2H1), 3.87 3H), 4.28 2H), 7.18 (d, J 17 Hz, 2H), 7.49 J Hz, 2H), 7.65- 7.68 (in, 4H), 9.37 1H),'10.5 (s, 1H).

SUBSTrrIU-uE SHEET (RULE 26) WO 99/42436 PCTIUS98,I 7633 92 Example 91 4 4 -methoxy-benzenesulfonyl)- 1 3 -phenyl-propyl)-piperidine-4-carboxylic acid hydroxyanide 2 2 -Hydroxy-ethyl)-(3-phenylpropy).ami~no]-ethanol was p repared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and l-bromo-3-phenylpropane (20 g, 101 mmol). Yield 21.31 g, yellow oil; MS: 223.9 Bis-( 2 -Ch~oro-ethyl)-(3-phenyl.propyl).amne was prepared according to the general method as outlined in example 83. Starting from 2 2 -hydroxy-ethyl)-(3-phenyl.

propyl)-aminol-ethanol (20.32 g, 90.7 mmol). Yield 24.9 g brown oil; MS: 259.8 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)-ami~ne (24.8 g, 93.8 mmol). Yield 11.24 g brown oil; MS: 446 (M+H) 4 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 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.67 g off white powder; mp 203 0 C; MS: 418.2 Starting from 4 4 -methoxy-benzenesulfonyl)- 1 3 -phenyl-propyl)-piperidine-4carboxylic acid (4.37 g, 10.4 minol) and following the procedure as outlined in example 83, 1.64 g of 4 4 -methoxy-benzenesulfonyl)..1-(3phenylppropyl)-pipeidine- 4-carboxylic acid hydroxyan-ide was isolated as an off white solid. Yield 37%; mp 143'C; MS: 432.9 H NMR (300 MHz, DMSO-d 6 8 1.92-1.97 (in, 2H), 2.18-2.29+ (mn, 2H1), 2.47 2H), 2.58 J 7.7 Hz, 2H1), 2.6-2.73 (in, 211), 3.06 (mn, 2H), 3.60 J 12.3 Hz, 2H), 3.87 2H), 7.15-7.30 (in, 7 7.68,.

J 9 Hz;'2H), 9.3 I 10. 1 IlH).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 93 Example 92 1 -Tert-butyl-4-(4-methoxy-benzenesulfonyl)-pipendine-4-carboxylic acid hydroxyamide tert-Butyl-bis-(2-chloro-ethyl)-aniine 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, white solid; MS: 197.8 1 -tert-Butyl- 4 -(4-methoxy-benzenesulfonyl)piperidine-4carboxylic 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-butylbis-(2-chloro-ethyl)-amine (5.25 g, 22.53 mmol). Yield 5.37 g, brown oil; MS: 384 1 -tert-Butyl-4-(4-methoxy-benzenesulfonyl)-piperidine.4-carboxylic acid was prepared starting from 1 -tr-uy--4mtoybneeufnl-ieiie4croyi 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 whilte powder; mp 204 MS: 356 Starting from 1 -tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (320 mg, 0.9 mniol) and following the procedure as outlined in example 83, 190 mg of 1 -tert-butyl- 4 -(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyanide was isolated as a green solid. Yield 52%; mp 40 MS: 37 1.1 'H NMR (300 MHz, DMSO-d 6 8 1.29 9H), 1.54 (in, 2H), 1.66 (in, 2H), 2.39 (mn, 2H1), 2.98 (in, 2H), 3.88 3H), 7.18 2H), 7.67 2H).

Example 93- 1 -Butyl- 4 4 -methoxy-benzenesulfonyl)-piperidineA4-carboxylic acid hydroxyamide Butyl-bis-(2-chloro-ethyl)-amrine was prepared according to the general method as outlined in example- 83. Starting from. N-butyldiethanolamiine (6 g, 37.2 mmol. Yield 11.3 g, white powder; mp 165 MS: 197.9 1 -Butyl- 4 4 -methoxy-benzenesulfonyl)-piperidine.4carboxylic 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, -19.3 mmol) and butyl-bis-(2- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 94 chloro-ethyl)-arnine (4.52 g, 19.38 mmol). Yield 6.86 g, brown oil; MS: 384 Il-ButylA-( 4 -methoxy.benzenesulfonyl).pipeidie-4carboxylic acid was prepared starting from l-butylA4-( 4 -methoxy-benzenesulfonyl)piperidine-4carboxylic acid ethyl ester (6.42- g 16.8 mmol) dissolved in methanol (200 mld) and 10 N NaOH (20 ml).

The resulting reaction mixture was worked up as outlined in example 83. Yield 1.6 g white powder; mp 206 MS: 356.4 Starting from 1-uy--4mtoybneeufnl-ieiie4croyi acid (1.51 g, 4.3 mmol) and following the procedure as outlined in example 83, 200 mg of I btl4(-ehx-eznslfnl-ieiie4croyi acid hydroxyaiide was isolated as an off white solid. Yield mp 75 MS: 37 1.1 (M+Hr; 'H NMR (300 MHz, DMSO-d 6 5 0.87 J 7.2 Hz, 3H), 1.27 (in, 2H), 1.59 (mn, 2H), 2.27 (in, 2H), 2.45 (mn, 2H), 2.50 (in, 2H), 2.65 (in, 2H), 2.97 (in, 2H) 3.88 3H), 7.18 2H), 7.69 2H).

Example 94 1 Ccocy--4mtoybneeufnl-ieiie4croyi acid hydroxyamide Cyclooctyl-bis(2chlorothyl)amne was prepared according to the general method as outlined in example 83. Starting from N-cyclooctyldiethanolamrine (6 g, 28 inmol).

Yield 10 g, off white solid; mp 158 MS: 251.9 I Ccoey--4mtoybneeufnl-ieiie4croyi 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 nirol) and cyclooctylbis-(2-chloro-ethyl)-amine (5.57 g, 19.4 mmol). Yield 8.2 g, brown oil; MS: 438 l- CyclooctylA4-(4inethoxy-befizenesulfonyl)..pipe6idne4-carboxylic acid was prepared starting from Il-cyclooctylA-(4-rnethoxy-benzenesulfonyl)pipeiidine-4 carboxylicacid ethyl ester (8 g, 18.3 inmol) 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 white powder; rnp 180 MS: 410 (M+H)r.

SUBSTITUTE SHEET (RULE 26) 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 I -cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a white powder. Yield 22%; mp >200 MS: 425 'H NMR (300 MI-z, DMSO-d 6 8 1.42-1.66 (in, 14H), 1.83 (in, 211), 2.33 (in, 2H), 2.67 (mn, 2H), 3.30-3.5 1 (mn, 3H) 3.88 3H) 7.17 2H), 7.66 2H).

Example 1 -Ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-caxboxylic 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- (inethoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 11.6 mmol) and ethyl-bis-(2chloro-ethyl)-amine (2.39g, 11.6 inmol). Yield 3.09 g, low melting brown solid; MS: 356 1-Ethyl-4-(4-inethoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1 -ethyl-4-(4-inethoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl 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 white solid; mp 209 MS: 328 Starting from 1 -ethyl-4-(4-inethoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (1.23 g, 3.76 mmol) and following the procedure as outlined in example 83, 1.02 g of 1 -ethyl-4-(4-methox'y-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white powder. Yield 80%; mp 85 MS: 343 'H NMR (300 MHz, DMSO.-d 6 8 0.926 J =7.1 Hz, 3K), 1.68-1.89 (in, 4H), 2.05- 2.24 (in, 4H), 2.73 2H), 3.85 3H), 7.07 2H), 7.64 2H).

Example 96 1 -Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carbox .ylic acid hydroxyamide 1 -Isopropyl-4-(4-inethoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in example 83. Starting from 4-(inethoxy-benzenesulfonyl) acetic acid ethyl ester 22.2 mmnol) and isopropyl- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/JS98/, 7633 96 bis-(2-chloro-ethyl)-amune (4.9 g, 22.2 mmol). Yield 5.64 g, low melting brown solid, MS: 370 1 -Isopropyl- 4 4 -methoxy-benzenesulfonyl)..piperidine.4.carboxylic acid was prepared starting from I -isopropyl- 4 4 -methoxy-benzenesulfonyl)-piperidine-4carboxylic 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 white powder; mp 204 MS: 341.9 Starting from I -isopropyl- 4 4 -methoxy-benzenesulfonyl)-piperidine4carboxylic acid (2.13 g, 6.25 nunol) and following the procedure as outlined in example 83, 590 mg of I -isopropyl- 4 4 -methoxy-benzenesulfonyl)-piperidine.4-carboxylic acid hydroxyamide was isolated as a white powder. Yield mp 75 MS: 357 'H NMR (300 MHz, DMSO-d 6 6 1.21 J 6.6 Hz, 6H), 2.33-3.53 (in, 9H), 3.88 3H), 7.16 2H), 7.66 2H).

Example 97 1 -Methyl- 4 4 -methoxy-benzenesulfonyl)piperidine4carboxylic acid hydroxyaxnide 1 -Methyl- 4 4 -methoxy-benzenesulfonyl)-piperidine4-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 inmol) and methyl-bis-(2chloro-ethyl)-atnine (2.2g, 11.6 mmol). Yield 3.09 g, low melting brown solid; MS: 342 1 -Mty--4mtoybneeufnl-ieiie4croyi acid was prepared starting from 1 -methyl- 4 4 -methoxy-benzenesulfonyl)-.piperidine-4carboxylic acid ethyl ester (8.7 g, 25.6 minol) dissolved in methanol (300 ml) and 10 N NaOH mnl). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.23 g (41 white solid; mp, 204 MS: 313.9 Starting from Il-methyl- 4 -(4-methoxy-ben zenesulfonyl)-piperidine-4-carboxylic acid g, 6.3 8 minol) and following the procedure as outlined in example 83, 1. 10 g of 1 -methyl- 4 4 -methoxy-ben'zenesulfonyl)'-piperidine-4carboxylic acid hydroxyamide was isolated as a yellow powder. Yield 53 mp 89 0 C; MS: 329 'H NMR (300 MHz, DMSO-d 6 8 1.67- 1.76 (in, 2H), 1.85-1.96 (in, 2H), 2.05 3H), 2.17 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,1 7633 97 J 11.4 Hz, 2H), 2.57 J 10.4 Hz, 2H) 3.83 3H), 7.02 2H), 7.62 (d, 2H).

Example 98 1 -Benzyl- 4 4 -butoxy-benzenesulfonyl)-pipexidine-4carboxylic acid hydroxyamide I -Benzyl- 4 4 -butoxy-benzenesulfonyl)piperidine-4carboxylic 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 bis-(2chloro-ethyl)-benzylamine (10 g, 30 mmol). Yield 5.15 g yellow oil; MS: 460 1 -Benzyl- 4 4 -butoxy-benzenesufonyl)piperidine4carboxylic acid was prepared starting from 1 -benzyl- 4 4 -butoxy-benzenesulfonyl)piperidine4-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 off white solid; mnp 2 10 MS: 432 Starting from 1 -benzyl- 4 4 -butoxy-benzenesulfonyl)..piperidine-4carboxylic 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 MS: 446.9 'H NMR (300 MHz, DMSO-d,): 5 0.94 J =7.3 Hz, 3H), 1.44 J 7.5 Hz, 2H), 1.70 2H), 2.28-2.32 (in- 2H), 2.50 2H), 2.74-2.83 (mn, 2H), 3.35 2H), 4.08 J 6.3 Hz, 2H), 4.34 2H), 7.13 J 8.7, 2H), 7.45 7.54 (s, 2H), 7.74 J 8.7, 2H), 9.35 1H), 10.7 1H).

Example 99 1-( 4 -Fluoro-benzyl)A4-(4methoxybenzenesulfonyl)-piperidine-4carboxylic acid hydroxyamide 1-4Fur-ezl--4mtoybneeufnl-ieiie4croyi acid ethyl 'ester was prepared according to the general method as outlined in example 83. Starting from 4 -(ineth oxy -benzenesulfonyl) acetic acid ethyl ester (18.8 g, 72.8 minol) and (4fluoro-benzyl)-bis-(2-chloro-ethyl).anmjne (20.8 g, 73 minol). Yield 25 g brown oil; MS: 436.9.(M+H)'.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US 98/17633 98 1 4 -Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)pipeidine-4carboxylic acid was prepared starting from I 4 -fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine.

4-carboxylic acid ethyl ester (17.4 g, 40 mnmol) dissolved in THF:methanol 3:1 and N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 10.8 g colorlesssolid; mp 154 MS: 408 Starting from 1 4 -Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)ypiperidine-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 carboxylic acid hydroxyarnide was isolated as an off white solid. Yield 5 mp 176- 178 MS: 484.7 (M+H) 4 'H NMR (300 MHz, DMSO-d 6 5 2.12-2.20 (in, 2H), 2.64-2.79 (in, 2H), 3.32-3.45 (in, 4H1), 3.87 3H), 4.31 7.14-7.19 J 17 Hz, 2H), 7.27-7.33 J 8.1 Hz, 2H), 7.50-7.54 7.65-7.68 2H), 9.38 IH), 9.75 1H).

Examnple 100 1 4 -Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)..piperidine-4-arboxylic acid hydroxyamide 1 4 -Fluoro-benzyl)- 4 -(4-butoxy-benzenesulfony)piperidine-4-arboxylic 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 (4fluoro-benzyl)-bis-(2-chloro.ethyl)-amine (5.73 g, 20 inmol). Yield 8.2 g yellow oil; MS: 478 1-4Fur-ezl--4btx-ezeeufnl-ieiie4croyi acid was prepared starting from 1 4 -Fluoro-benzyl)A4-(4-butoxy-benzenesulfonyl).piperidineA..

carboxylic acid ethyl ester (4.77 g, 10 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 3.5 g off white solid; mnp 114 MS: 450 Starting from 1 4 -Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)piperidine-4 carboxylic acid (2.24 g, 5.0 minol) and following the procedure as outlined in example 83, 200 mg o f l-( 4 -Fluoro-benzyl)-4-(4-buitoxy-benzenesulfonyl) piperidine-4 carboxylic acid hydroxyamide was isolated as an off white powder. Yield mp 1 12'C; MS: 465.9 1 H NMR (300 MHz'.DMSO-d 6 6 0.94 J 7.3 Hz, 31j), 1.35-1.50 (mn, 2H), 1.68-1.77 (in, 2H), 2 2 0- 2 2 8 2H), 2.66-2.71 (in, SUBSTITUE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 99 3.77-3.78 (in, 4.06-4.10 (in, 2H), 4.19 2H), 7.14-7.19 J 8.7, 2H), 7.27-7.33 2H), 7.50-7.54 7.65-7.68 9.34 1H), 10.55 (s, I1H).

Example 10 1 4-(4-methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethano was prepared according to the general method as outlined in example 83. Starting from diethanolamine 12.0 g, 114 inmol) and 4-methoxybenzyl chloride 14.2 g, 100 inmol). Yield 17.5 g, (77%) yellow oil; MS: 226 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 g, 44 inmol). Yield 10 g (75 yellow solid mp 55 C; MS: 263.1 4-(4-Methoxy-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-(methoxy-benzenesulfonyl)-acetic acid ethyl ester (5.0 g, 20 mmol) and bis- (2-chioro ethyl)-(4-methoxy-benzyl)-amine (7.0 g, 22 mmol). Yield 5.0 g (56 low melting solid; MS: 448.5 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) 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.

190 "C MS: 420.4 Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4carboxylic acid (2.0 g, 4.7 mmol) and following the procedure as outlined in example 83, 1.2 g of 4-(4-inethoxy-benzenesul1fonyl)-l1-(4-methoxy-benzyl)-piperidine-4carboxylic acid hydroxamide was isolated as a white solid. mnp'175 'C (HCl); Yield: 1.2 g, 59 MS: 433.0 'H NMR (300 MHz,-DMSO-d 6 8-1.8 (mn, 4H), 2.3(mn, 2H), 2.73 (mn, 214), 3.37 2H), 3.76 3.88 6.87 2H), 7.11 2H), 7.21 2H1), 7.65. 2H), 9.2. (bs, IlH), 10.9* (bs, I H).

SUBSTITIUTE SHEET (RULE 26) WO 99/42436 PC1'1US98/I 7633 100 Example 102 4-(4-methoxy-benzenesulfonyl)- 1 2 4 -methoxyphenyl)-ethyl]-piperidine-4carboxylic acid hydroxyainide 2-1{(2-Hydroxy-ethyl)- 2 -(4-methoxy-phenyl)-ethyl]-ami no I -ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (10.0 g, excess). and 1-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol).

Yield I11 g, yellow oil; MS: 240 The corresponding dichloride, bis-( 2 -chloro-ethyl)-(4-methoxyphenyl-2ethyl).rriine was prepared according to the general method as outlined in example 83. Starting from 2- {(2-hydroxy-ethyl)- 2 -(4-methoxy-phenyl)-ethyl]-amino I}-ethanol (10 g, 41.8 mnmol). Yield 11I g brown oil; MS: 277.2 4 4 -methoxy-benzenesulfonyl)- I 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, mmol) and bis-( 2 -chloro-ethyl)-(4-methoxyphenyl-2-ethyl)-anune (6.4 g, 20 mmol).

Yield 6.0 g brown oil; MS: 462.5 4 -(4-methoxy-benzenesulfonyl)- 1 -1 2 4 -methoxyphenyl)-ethyl]-piperidineA4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)- 1 -[2-(4-methoxyphenyl)-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 off white powder; mp 205*C; MS: 434.5 Starting from 4-(4-methoxy-benzenesulfonyl)-l1-[ 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)- methoxyphenyl)-ethy1]-piperidine-4-carboxylic acid hydroxyamnide was isolated as an off white solid. Yield 58%; mp -206 0 C (HCl); MS: 449.5 'H NMR (300 MHz, DMSO-1 6 6 2.3 (in, 2.5 (in, 3H), 2.8 (in, 2H), 2.95 (in, 2H), 3-.25'(in, 2H), 3.4 3.60 J 12.3 Hz, 2H), 3.77 3H),3.99 3H4), 6.9 2 7.1 7.25, 4H), 7.7 2H), 9.3 10.6 1H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUJS98/I 7633 101 Example 103 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide 2- [(2-Hydroxy-ethyl)-(2-phenyl-ethyl)-armnoj -ethanol was prepared according to the general method as outlined in example 1. Starting from diethanolarnine (6.0 g, 57).

and 2-bromo-ethylbenzene (9.0 g, 48.3 mmol). Yield 9 g, yellow oil; MS: 210 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-phenylethyl)-am-ino]-ethanol (8.5 g, 40.6 mmol). Yield 11I g brown oil; MS: 247.1 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, nimol) and bis-(2-chloro-ethyl)-(2-phenyl-ethyl)-aniine (5.6 g, 20 inmol). Yield 5.5 g brown oil; MS: 432.5 (M+H) 4 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-4carboxylic acid ethyl ester (3.0 g, 6.9 nimol) 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 2.0 g off white powder; mp 208 MS: 404.5 Starting from 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl)-piperidine-4carboxylic acid (1.5 g, 3.7 nimol) and following the procedure as outlined in example 83, 900 mg of 4-(4-methoxy-benzenesulfonyl)- 1 -(2-phenyl-ethyl)-piperidine-4carboxylic acid hydroxyamide was isolated as an off white solid. Yield 58%; nip 205-C (HG1); MS: 419.4 'H NMR -(300 MHz, DMSO-d 6 8 2.3 (in, 2H), (mn, 3H), 2.8 (in, 2H), 2.95 (in, 2H), 3.25 (mn, 2H), 3.4 (rn,4H), 3.9 (s, .3H),7.22 7.8 (in, 9H), 10.6 1H), 11.2 (bs, IH).' SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 -102- Example 104 4 -(4-n-Butoxy-benzenesulfonyl)- I 4 -methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide 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)-aniine (3.0 g, 10 mmol). Yield 3.5 g (71 %;low melting solid; MS: 490.5 4 4 -n-Butoxy-benzenesulfonyl) 1 4 -methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4 -(4-Butoxy-benzenesulfonyl)- 1-(4-methoxybenzyl)piperidine-4-carboxylic acid ethyl ester (3.0g, 6.1 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 1.5 g white solid mp 207 'C MS: 462.5 Starting from 4 4 -n-Butoxy-benzenesulfonyl)- 1-(4-methoxy-benzyl)-piperidine-4carboxylic acid (1.0 g, 2.1 mmol) and following the procedure as outlined in example 83, 1.2 g of 4 -(4-Butoxy-benzenesulfonyl)- I -(4-methoxy-benzyl)-piperidine-4carboxylic acid hydroxamide was isolated as a white solid. mp 173 *C (HCl); Yield: 800 mg, 77 MS: 477.5 'H NMR (300 MHz, DMSO-d 6 8 0.9 3H), 1.4 (in, 2H), 1.7 2.3 (in, 2H), 2.5 (in, 2H), 2.7 (in, 2H), 3.3 (in, 2H), 3.5(m,.214), 4.1 2H), 4.3 (in, 2H), 6.97 d, 2H), 7.14 2H), 7.48 2H), 7.7 2H), 9.4 (bs, 111), 10.9 (bs, 1H).

Example 105 4 4 -Methoxy-benzenesulfonyl)- 1-( 3 -phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide 2 2 -Hydroxy-ethyl)-(3-phenoxy-propyl)..amino]-ethanoI was prepared according to the general method as outlined in example 83. Starting from diethanolanine (15.8 g, 151 inmol). and 3-Phenoxypropyl bromide (21.5 g, 100 minol). Yield 21.31 g, yellow oil; MS: 238.1 SUBSTITUJTE SHEET (RULE 26) WO 99/42436PCUS8I73 PCTIUS98/17633 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-phenoxypropyl)-amino] -ethanol (20.0 g, 84 mnmol). Yield 24.0 g (91 brown oil; MS: 277.8 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, nimol) and bis-(2-chloro-ethyl)-(3-phenoxy-propyl)-amine (7.0 g, 22 nimol). Yield 6.5 g brown oil; MS: 462.5 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 nimol) 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 3.0 g off white powder; mp 195 MS: 434.5 Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4carboxylic 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-4carboxylic acid hydroxyamide was isolated as an off white solid. Yield 46%; mp 101 0 C; MS: 448.5 'H NMR (300 MHz, DMSO-d 6 8 2.18 (in, 2H), 2.3 (mn, 2H), 2.58 (mn, 2H), 2.6-2.73 (in, 2H), 3.0-3.06 (in, 2H), 3.60 (m 2H), 3.87 3H), 4.01 2H), 6.9 7.7 (in, 9H), 9.33 (bs, 1H), 10.28 (bs, 1H).

Example 106 4-(4-n-Butoxy-benzenesulfonyl)- 1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid 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, inmol) and-bis-(2-chloro-ethyl)-(3-phenoxy-propyi)-amine (3.0 g, 11 Ininol). Yield.

g. brown oil; MS: 504.6 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -104- 4 4 -n-Butoxy-benzenesulfonyl)- l-( 3 -phenoxy-propyl)-piperidine-4carboxylic 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 TIW:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g off white powder; mp 191 0 C; MS: 476.5 Starting from 4 4 -n-butoxy-benzenesulfonyl)- 1 3 -phenoxy-propyl)-piperidine-4zcarboxylic acid (700 mg, 1.4 mmol) and following the procedure as outlined in example 83, 300 mg of 4 4 -n-butoxy-benzenesulfonyl).1.(3-phenoxy.propyl)piperidine-4-carboxylic acid hydroxyamnide was isolated as an off white solid. Yield 43%; mp 84 MS: 491.5 'H4 NMR (300 MHz, DMSO-d 6 8 0.9 311), (in, 2H), 1.8 (in, 2H4), 2.18 (in, 211), 2.3 (mn, 2H), 2.58 2H), 2.6-2.73 (mn, 2H), 3.2 (in, 2H), 3.40 (m 6H), 3.97 2H), 4.1 2H), 6.9 7.7 (in, 9H), 10.7 (bs, 114), 11.28 (bs, 111).

Example 107 4 4 -methoxy-benzenesulfonyl) l-( 2 -phenoxy-ethyl)-piperidine..carboxylic acid hydroxyanide 2-(-yrx-ty)(-hnx-ty)aio-tao 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, Colorless oil; MS: 226 (M+H) 4 Bi-2Clr-ty)(2peoyehl-mn was prepared according to the general method as outlined in example 83. Starting from 2 2 -Hydroxy-ethyl)-(2-phenoxyethyl)-amnino]-ethanol (20.0 g, 88.8 mmol). Yield 25 g brown oil; MS: 263.1 4 4 -methoxy-benzenesulfonyl.. l-( 2 -phenoxy-ethyl)-piperidine-4carboxylic acid ethyl ester was prepared according to the general method as outlined -in example 83.

Starting from from 4 -(miethoxy-benzenesulfonyl) acetic acid ethyl ester (5.0 g, mmol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-an-jne (6.0 g, 20 mmol). Yield 5'.8 g brown oil; MS: 448.5 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/I 7633 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 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g off white powder; mp 235 MS: 420.5 Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4carboxylic acid (2.5 g, 5.9 mmol) and following the procedure as outlined in example 83, 1.3 g of 4-(4-methoxy-benzenesulfonyl)- l-(2-phenoxy-ethyl)-piperidine-4carboxylic acid hydroxyamnide was isolated as an off white solid. Yield 50%; mp 168- 172 'C (HCl); MS: 435.4 'H NMR (300 MHz, DMSO-d 6 5 2.3 (in, 211), (in, 2H), 2.9 (mn, 2H), 3.4 (in, 4H), 3.5 (in, 2H), 3.7 3.9 3H), 4.4 (mn, 2H), 6.9 7.8 (in, 9H), 9.3 1H1), 10.2 (bs, 1H), 11.3 1H1).

Example 108 4-(4-n-Butoxy-benzenesulfonyl)- 1 -(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide 4-(4-Butoxy-benzenesulfonyl)-1I-(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-(inethoxy-benzenesulfonyl) acetic acid ethyl ester (2.5 g, minol) and bis-(2-chloro-ethyl)-(2-phenoxy-ethyl)-amine (2.98 g, 10 inmol). Yield g brown oil; MS: 490.6 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 minol) dissolved in THF.inethanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g off white powder; mp 204 MIS: 462.5 Starting from 4-(4-n-butoxy-benzenesulfonyl)- 1-(2-phenoxy-ethyl)-piperidine-4carboxylic acid (1.0 g, 2.16 mmol) and following the procedure as outlined in example 83, 600mg of 4-(4-butoxy-benzenesulfony1)- 1-(2-phenoxy-ethyl-piperidine-4carboxylic acid hydroxyaiide was isolated as an off white solid. Yield 58%; mp 1 12'C (HICl); MS: 477.4 'H NMR (300 MHz, DMSO-d 6 6 0.942 311), SUBSTmJUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -106- 1.4 (in, 2H), 1.7 (in, 2H), 2.3 (in, 2H), 2.5 (in, 4H), 2.8 (in, 2H), 2.9-3.4 (mn, 414), 3.3 (in, 4H), 4.2 2H), 4.4 (in, 2H), 6.9 7.7 (mn, 9H), 9.4 1H), 10.5 (bs, 1H), 11.3 1H).

Example 109 4-(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyll-piperidine-4 carboxylic acid hydroxyamide 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 diethanolam-ine (15.0 g, 150). and 4 -(2-piperidin-lI-yl-ethoxy)-benzyl chloride (5.9 g, inmol). Yield 5.5 g, Brown semi-solid; MS: 323 Bis-(2-chloro-ethyl)-[4-(2-piperidin. I-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 inmol).

Yield 4.0 g brown semi-solid; MS: 361.1 4-(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- l-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 g, 20 inmol) and Bis-(2-chloro-ethyl)-[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-amine (8.6 g, 20 mmol). Yield 6.0 g brown oil; MS: 545.7 4 -(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoyxy)-benzyl]-piperidine-4carboxylic acid was prepared starting fro m 4 4 -Methoxy-benzenesulfonyl)-1-[4-(2piperidin-l-yl-ethoxy)-benzyl]-piperidine4-carboxylic acid ethyl ester (5.4 g, inmol) dissolved in THE: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 off white powder; mp 174 MS: 517.6 Starting from -4-(4-Methoxy-benzenesulfonyl)- 1 -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]piperidine-4.-carboxylic acid (3.5 g, 6.78 inmol) and following the procedure as outlined in example 83,1.8 g of 4 -(4-Methoxy-benzenesulfonyl)- 1-[4-(2-piperidin- l-ylethoxy)-benzyl]-piperidine-4-carboxyli'c acid hydroxy amidewas isolated as an pale yellow solid. Yield 49%; mp 114 'C (HCl); MS: 532 'H4 NMR (300 MHz, SUBSTITUJTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 107- DMSO-d 6 5 1.4-1.6 4H), 1.9 2H), 2.3 2.8 2H), 3.4 (m, 4H), 3.9 3H), 4.2 1H), 6.9 7.8 8H), 9.1 1H), 10.8 (bs, 1H).

Example 110 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' (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-diisopropylcarbodiimide (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 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 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 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 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) 6 4.54 1H), 1.83 3H).

Step B:Displacement of bromide with 4-methoxybenzenethiol.

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 sodium iodide (288 mg, 5.0 eq.) and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU, 0.17 mL, 3.0 eq.) were added. The reaction.

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.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/7633 -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% tertbutylhydroperoxide (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.

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 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 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 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 7.95 (brs, 1 7.71 (dd, 2 7.16 (dd, 2 3.87 3 3.83 1 1.26 3 H).

The hydroxamic acids of Examples 111-113 are synthesized using appropriate starting materials and following the steps in example 110.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUJS98/1 7633 -109- Example I111 N-Hydroxy-2-(4-methoxy-benzenesulfanyl)-propionarrude. 72% 215 nm N-Hydroxy-2-(4-methoxy-benzenesulfinyl)-propionanuide 76% 215 nm; 'H NMR (DMS0 d-6) 5 10.90 &10.60 (brs, 1 7.95 (brs, 1 H) 7.61 7.52 (dd, 2 7.15 7.10 (dd, 2 3.83 3.82 3 3.42 3.28 (q 1H), 1.23 0.97 3 H).

Example 112 N-Hydroxy-2-(3-methyl-butane-l1-sulfanyl)-propionamride. 74% 215 nm.

N-Hydroxy-2-(3-methyl-butane-1-sulfinyl).propionamide. 'H NMR (DMSO d-6) 8 10.8 (brs 1 7.95 (brs, 1 3.45 3.31 1 2.71 -2.50 (in, 2 1.71- 1.46 (in, 3 1.33 1.25 3 0.94-0.82 (mn, 6 H) Example 113 N-Hydroxy-2-(3-methyl-butane- 1-sulfonyl)-propionamide. 84% 215 nm.

Example 114 N-hydroxy-3-methyl-2-(naphthalen-2-ylsulfanyl)-butyraniide Step A: Coupling of 2-bromo-3-methyl-butyric acid to hydroxylamine resin.

4 -O-Methylhydroxylamine-phenoxymethyl-copoly(styrene. 1 %-divinylbenzene)-resin' g, 1. 1 ineq/g) was placed in a peptide synthesis vessel and suspended in DMF mL). 2-Bromo-3-methyl-butyric acid (9.96 g, 10.0 eq.) and DIC (9.04 inL, 10.5 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, otherwise the resin,.was washed with DCM (3 x 20 mnL)-, MeOH (2 x 20 mnL), and DCM (2 x 20 mL).

The resin was dried in vacuc at room temperature.

Step B: Displacement of bromide with 2-naphthalenethiol.

The 2-bromo hydroxymate resin prepared in Step A 15 g, 1. 1 meq/g) was placed in a 20 mL scintillation vial and suspended in THF (2 inL). 2-Naphthalenethiol (13 8 mg,- SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -110sodium 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 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, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tert-butylhydroperoxide 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.

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 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-ysulfanyl)-butyramide from 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 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 'H NMR (DMSO d-6) 10.7 (brs, 1 7.91 (brs, 1 7.91-7.81 4 7.55-7.45 3 3.41 1 2.09-1.97 1 1.05 3 0.97 3 H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PTU9,I73 The hydroxamic acids of Examples 115-1 18 are synthesized using appropriate starting materials and following the steps in example 114: Example 115 N-Hydroxy-3-methyl-2.(naphthalen2ylsulfinyl)-butyrandde- 67% 215 nm.

Example 116 N-Hydroxy-3-methyl-2(naphthaen2ysulfonyl).butyrmde. 97% 215 nm; LCMS (API-electrospray) m/z 308 Example 117 N-Hydroxy-3-methyl-2phenethylsulfinylbutyramide. 93% 215 nm; LCMS (APIelectrospray) m,/z 254 Example 118 N-Hydroxy-3-methyl-2phenethylsufonylbutyrrride. 97% 215 m; LCMS (APIelectrospray) m/z 286 Example 119 (l-Hydroxycarbamnoyl-propane-l-sulfany1)-acetic acid methyl ester Step A: Coupling of 2-bromobutyric acid to hydroxylamine resin.

4 -O-Methylhydroxylamrine-phenoxymethyl-copoly(styrene- I %-divinylbenzene)-resin' g, 1. 1 meq/g) was placed in a peptide synthesis vessel and suspended in DMIF mL). 2-Bromobutyric acid (3.0 g, 3.0 eq.) HOBt (4.86 g, 6.0 eq.) and DIC (3.75 m.L, 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, otherwise the resin was washed With DCM (3 x 20 mL), MeOH (2 x 20 and DCM (2 x 20 The resin was dried in vacuo at room temperature.

Step B: Dis'lacement of bromide with methyl thioglycolate.

The 2-bromo hydroxymate resin prepared in Step A (0.45 g, 1. 1 meq/g) was placed in a 20 mL scintillation vial and suspended in THFf (2 MnL). Methyl thioglycolate (286 mg, SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -112sodium 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 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 Step B (150 mg, 1.1 meq/g) was suspended in DCM (3.0 mL) and 70% tertbutylhydroperoxide (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.

Step D: Oxidation of sulfide to sulfone.

(1-Hydroxycarbamoyl-propane-l-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 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 from resin The (1-Hydroxycarbamoyl-propane-1-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 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) 4 The hydroxamic acids of Examples 120-124 are synthesized using appropriate starting materials and following the steps in example 119.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUJS98'1 7633 113- Example 120 (1 -Hydroxycarbamoyl-propane- 1-sulfonyl)-acetic acid hydroxyamide.

LCMS (API-electrospray) m/z 224 Example 121 (1 -Hydroxycarbamoyl-propane- 1-sulfinyl)-acetic acid hydroxy amnide.

100% 220 nm; LCMS (API-electrospray) rn/z 240 Example 122 (1 -Hydroxycarbamoyl-propane- 1-sulfanyl)-propionic acid hydroxyam ide.

'H NMR (DMSO d-6) 8 10.7 (brs, 1 4.03 2 2.95 1 2.75-2.70 (in, 1 2.60-2.54 (mn, 1 1.74-1.66 (in, 2 1.58-1.50 (in, 4 1.32 (sextet, 2 H), 0.88 3 0.85 3 LCMS (API-electrospray) in/z 264 Example 123 (1 -Hydroxycarbamoyl-propane- 1 -sulfinyl)-propionic acid hydroxyam-ide.

83% 220 nm; LCMS (API-electrospray) in/z 280 Example 124 (1 -Hydroxycarbamoyl-propane- 1 -sulfonyl)-propionic acid hydroxyainide.

100% @a 220 nin; Example 125 2 4 -Hydroxybenzenesulfanyl)-N-hydroxy-3-phenyl-propionamide Step A: Coupling of 2-broino-3-phenyl-propionic acid to hyd roxylamnine resin.

4 -O-Methylhydroxylamine-phenoxymethyl-copoly(styrene. 1 %-divinylbenzene)-resin' g, 1.2 ineq/g) was placed in a peptide synthesis vessel and suspended in DMF iL). 2-Bromo-3-phenyl-propionic acid (3.5 g; 3.0 eq.) HOBt (4A g, 6.0 eq.) and DIC (3.4 inL, 4.0 eq.) were added. The reaction was shaken on an orbital shaker at room temperature for 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 turnied blue) the coupling described above SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -114was repeated, otherwise the resin was washed with DCM (3 x 20 mL), MeOH (2 x mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

Step B:Displacement of bromide with 4-hydroxythiophenol.

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 sodium iodide (297 mg, 5.0 eq.) and 1, 8 -diazabicyclo[5.4.0]undec-7ene (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 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.

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% tertbutylhydroperoxide (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.

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) 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.

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 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) SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 115was added and the mixture concentrated. 84% 215 nmn; 'H NMR (DMSO d-6) 8 10.41 (brs, I 7.95 (brs (1 7.30-7.15 (in, 5 7. 10 (dd, 2 6.75 (dd, 2 3.53 I 3.05 (dd, 1 2.79 (dd, 1 H).

The hydroxamic acids of Examples 126-130 are synthesized using appropriate starting materials and following the steps in example 125.

Example 126 2 4 -Hydroxybenzenesulfinyl)-N-hydroxy-3-phenyl-propionamide. 73% @a 215 nm; Example 127 2 -(4-Hydroxybenzenesulfonyl)-N-hydroxy-3-phenyl-propionawiide. 77% Ca- 215 nm; 'H NMR (DMSO d-6) 6 10.50 (brs, I 7.95 (brs, 1 7.68-7.57 (in, 2 7.28- 7.17 (mn, 3 7.08-7.98 (mn, 2 6.95-6.87 (mn, 2 3.96 1 3.02 2 H).

Example 128 2 4 -Acetylam-ino-benzenesulfanyl)-N-hydroxy-3-pheny1-propionam-ide. 86% 215 rum; 'H NMR (DMSO d-6) 8 10.50 (brs, I 10.03 (brs, I 8.13 (brs, 1 H), 7.56-7.12 (mn, 3.67 1 3.08 (dd, 1 2.84 (dd, 1 H4), 2.04 3 H) Example 129 2 4 -Acetylamino-benzenesulfinyl)-N-hydroxy-3-phenyl.propionaride.

73% 215 nm.

Example 130 2 4 -Acetylamino-be-nzenesulfonyl)-N-hydroxy.3-.phenyl..propionamide.

215 nm; Example 131 4 -Hydroxycarbamoyl-4-(4-inethanesuli'ariyl-phenyjsulfanyl)-bu'tyrc acid methyl ester Step A: Coupling of 2-bromo-5-methyl glutaric acid to hydroxylaniine resin.

4 -O-Methylhydroxylamine-phenoxyinethyl-copoly(styrene-l1%-divin-ylbenzene)-resin' (4.5 g, 1.2 me'q/g) was placed in a peptide synthesis vessel and suspended in DMF SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCTIUS98/17633 -116mL). 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 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 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

Step B: Displacement of bromide with 4-hydroxythiophenol.

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 sodium iodide (197 mg, 5.0 eq.) and 1, 8 -diazabicyclo[5.4.0]undec-7ene (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.

Step C: Oxidation of sulfide to sulfoxide.

4 -Hydroxycarbamoyl-4-(4-methanesul fanyl-phenylsulfanyl)-butyric acid methyl ester resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 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 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 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.

Step E: Cleavage of 4 -Hydroxycarbamoyl-4-(4-methanesulfanyl-phenylsulfanyl)butyric acid methyl ester from resin.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTUS98/'17633 -117- The 4 -Hydroxycarbamnoyl-4-(4-methanesulfanyl-phenylsulfanyl)4,utyric 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).

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 The hydroxamic acids of Examples 132-139 are synthesized using appropriate starting materials and following the steps in example 131.

Example 132 4 -Hydroxycarbamoyl-4-(4-methanesulfinyl-phenyisulfinyl)-butyric acid hydroxyamide. 79% 215 nm; LCMS (API-electrospray) m/z 348 Example 133 4 -Hydroxycarbamoy1-4-(4-methanesulfonyl-phenylsulfonyl).butyric acid hydroxyamide. 78% 215 nm; LCMS (API-electrospray) m/z 380 (M+H) 4 Example 134 4 -Hydroxycarbamoyl4-(4-bromo-benzenesulfany1)-butyric acid hydroxyamide.

93% 215 nm.

Example 135 4 -Hydroxycarbamoyl-4-(4-bromo-benzenesulfinyl)-butyric acid hydroxyamide.

8 0% @215 nm.

Example 136 4 -Hydroxycarbamnoyl-(4-bromo-benzenesulfonyl)ybutyric acid hydroxyanude.

77% 215 nm.

Example 137 4 -Hydroxycarbanloyl-4-(2-trifluoromehyl-benzenesulfanyl).b'utyric acid hydroxyamide. 93% 215 nm.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -118- Example 138 4 -Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfinyl)-butyric acid hydroxyamide. 72% 215 nm.

Example 139 4 -Hydroxycarbamoyl-4-(2-trifluoromethyl-benzenesulfonyl)-butyric acid hydroxyamide. 90% 215 nm.

Example 140 2 -(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide Step A: Coupling of 2-bromo-decanoic acid to hydroxylamine resin.

4 -O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- 1%-divinylbenzene)-resin' g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF 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 temperature for 2 16 hours. The reaction was filtered and washed with DMF (3 x 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 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

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 sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7ene (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.

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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -119on 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.

Step D: Oxidation of sulfide to sulfone.

2-(3-Methoxy-benzenesulfanyl)decanoic acid hydroxamideresin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and mCPBA (87 mg) was added.

Step E: Cleavage of 2-(3-methoxy-benzenesulfanyl)decanoic acid hydroxamide from resin.

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 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.

Example 141 2 -(3-Methoxy-benzenesulfinyl)decanoic acid hydroxamide. 96% 215 nm.

Example 142 2 3 -Methoxy-benzenesulfonyl)decanoic acid hydroxamide. 96% 215 nm.

Example 143 2 4 -methariesulfanyl-benzenesulfanyl)decanoic acid hydroxamide. 85% 215 nm; LCMS (API-electrospray) m/z 342 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/17633 -120- Example 144 2 4 -methanesulfinyl-benzenesulfinyl)decanoic acid hydroxamide. 86% 215 nm; LCMS (API-electrospray) m/z 374 Example 145 2 4 -methanesulfonyl-benzenesulfonyl)decanoic acid hydroxamide. 92% 215 nm.

Example 146 3 -benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionamide Step A: Coupling of 2-bromo--3-benzyloxy propionic acid to hydroxylamine resin.

4 -O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- %-divinylbenzene)-resin' g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF 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 (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 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

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 sodium iodide (197 mg, 5.0 eq.) and 1,8-diazabicyclo[5.4.0]undec-7ene (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 rmL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.

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 mL) and 70% tertbutylhydroperoxide (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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/I 7633 121 reaction was filtered and washed with DCM (2 x 2 mL), DMF (2 x 2 MeOR (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.

3-Benzyloxy-N-hydroxy-2-(4-methanesulfanyl-benzenesulfanyl)-propionaide 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 temperatur e 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 vacuc 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)-propionaniide 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 nmn; LCMS (API-electrospray) m/z 350 The hydroxarnic acids of Examples 147-151 are synthesized using appropriate starting materials and following the steps in example 146.

Example 147 3-Benzyloxy-N-hydroxy-2-(4-methanesulfinyl-benzenesulfinyl)-propionamide.

215 nm; LCMS (API-electrospray) m/z 382 Example 148 3 -Benzyloxy-N-.hydroxy-2-(4-methanesulfonyl-benzenesulfonyl)-propiona-de 63% *215 nm; LCMS (API-electrospray) m/z 414 Example 149.

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

SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -122- Example 150 3 -Benzyloxy-N-hydroxy-2-(2-chloro-benzylsulfinyl)-propionamide. 70% 215 nm.

Example 151 3 -Benzyloxy-N-hydroxy-2-(2-chlorobenzylsulfonyl)-propionamide 72% 215 nm.

Example 152 2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-irmidazol-4-yl)-propionamide StepA:Coupling of 2 -bromo- 3 -(3H-imidazol-4-yl)-propionic acid to hydroxylamine resin.

4 -O-Methylhydroxylamine-phenoxymethyl-copoly(styrene- I %-divinylbenzene)-resin' g, 1.2 meq/g) was placed in a peptide synthesis vessel and suspended in DMF mL). S- 2 -Bromo-3-(3H-imidazol-4-yl)-propionic acid (3.55 g, 3.0 eq.) HOBt (4.4 g, 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 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-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, 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 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.

2 2 -Bromobenzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionaide resin prepared in Step B (73 mg, 1.1 meq/g) was suspended in DCM (1.5 mL) and 70% tertbutylhydroperoxide.(0.49 mL) benzenesulfonic acid (24 mg) were added. The reaction SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1I7633 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 DMF (2 x 2 MeGH (2 x 2 mL), and DCM (2 x 2 The resin was dried in vacuo at room temperature.

Step D: Oxidation of sulfide to sulfone.

2-( 2 -Bromo-benzenesulfanyl)-N-hydroxy-3-(3H-im-idazol.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 midxture 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 MeOH (2 x 2 mL), and DCM (2 x 2 The resin was dried in vacuo at room temperature.

Step E: Cleavage of 2-(2-bromo-benzenesulfanyl)-N-hydroxy-3-(3H-in-idazol4ylypropionamide from resin.

The 2 2 -bromo-benzenesulfanyl)-N-hydroxy-3-(3H-imidazol-4-yl)-propionami~de resin prepared in Step B (73 mg, 1.2 meq/g) was suspended in DCM (1.0 ml,) and TFA (1.0 niL) was added. The reaction was shaken for 1 hour at room temperature.

Methanol (1 niL) was added and the mnixture concentrated. 86% 215 nm.

The hydroxamic acids of Examples 153-154 are synthesized using appropriate starting materials and following the steps in example 152.

Example 153 2 4 -bromo-benzenesullfinyl)-N-hydroxy-3-(3H-imijdazol-4-yl)-propionanide 69% 215 nm.

Example 154 2 4 -chloro-benzenesulfonyl)-N-hydroxy-3-(3H.imidazol.4yl)..propionarnide.

Example 155.

2 -(3-fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyanide Step A: Coupling of 2-bromo-5-guanidino-pentanic acid to hydroxylamine resin.

4 -O-Methylhydroxylaml~ne-phenoxymethyl-copoly(styrene- 1 %-divinylbenzene)-resin' (4.5 g, 1.2 meq/g)'was 'placed in a peptide, synthesis vessel and sugpended -in DMF SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -124mL). 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 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 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

Step B: Displacement of bromide with 3-fluorothiophenol.

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 -Fluorotliophenol (169 mg, 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 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.

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% tertbutylhydroperoxide (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 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) 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.

Step E: Cleavage of 2 3 -fluorophenylsulfanyl)-5-guanidino-pentanoic acid hydroxyamide from resin..

SUBSTITUTE SHEET (RULE 26) 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 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. 93% 215 nm.

The hydroxamic acids of Examples 156-159 are synthesized using appropriate starting materials and following the steps in example 155: Example 156 2 3 -Fluorophenylsulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 80% 220 nm; LCMS (API-electrospray) m/z 317 Example 157 2 -(2-Bromosulfanyl)-5-guanidino-pentanoic acid hydroxyamide. 92% 220 nm; 'H NMR (DMSO d-6) 8 10.90 (brs, 2 10.41 (brs, 1H), 7.95 (brs, 1 7.66-7.14 (min, 5 3.72 1 3.13 2 1.90-1.66 2 1.58-1.43 (2 H).

Example 158 2 2 -Bromosulfinyl)-5-guanidino-pentanoic acid hydroxyamide. 79% 220 nm; LCMS (API-electrospray) m/z 379 Example 159 2 2 -Bromosulfonyl)-5-guanidino-pentanoic acid hydroxyamide. 'H NMR (DMSO d- 6) 8 8.03-7.45 5 4.52 1 3.16 2 2.07-1.90 2 1.66-1.59 (2 H).

Example 160 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 126mL). 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 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 mL), and DCM (2 x 20 mL). The resin was dried in vacuo at room temperature.

Step B: Displacement of bromide with 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 sodium iodide (404 mg, 5.0 eq.) and 1, 8 -diazabicyclo[5.4.0]undec-7ene (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 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 ,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% tertbutylhydroperoxide (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.

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 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.

Step E: Cleavage of 2 2 ,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide from resin.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/I 7633 127 The 2 -(2,5-dichlorobenzenesulfanyl)-octanoic acid hydroxyamide resin prepared in Step B (73 mg, 1.2 meq/&) was suspended in DCM (1.0 mL) and TEA (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. 92% 215 nmn; 'H NMR (DMSO d-6) 8 10.96 (brs, 1 9.26 (brs, 1 7.93-7.76 3 4.07 1 2.04-1.85 (in, 1 1.78-1.64 (mn, 1 1.32-1.09 (in, 8 0.81 3 H).

The hydroxamnic acids of Examples 161-167 are synthesized using appropriate starting materials and following the steps in example 160.

Example 161 2 -(2,5-Dichlorobenzenesulfonyl)-octanoic acid hydroxyamide. 96% 215 nin.

Example 162 2 3 -Methoxybenzenesulfanyl)-octanoic acid hydroxyarnide 86% 220 nm; LCMS (API-electrospray) m/z 298 .Example 163 2 3 -Methoxybenzenesulfinyl)-octanoic acid hydroxyatnide 96% 220 nin.

Example 164 2 3 -Methoxybenzenesulfonyl)-octanoic acid hydroxyamide 83% 220 nin.

Example 165 2 3 4 -Diinethoxybenzenesulfanyl)-octanoic acid hydroxyamide 87% 215 rn; LCMS (API-electrospray) m/z 328 Example 166 2 3 ,4-Diinethoxybenzenes'ulfinyl)-octanoic acid hydroxyamide 90% 215 nin.

Example 167 2 3 4 -Dine thoxybenzenesulfonyl).octanoic acid hydiroxyamide 87% 215 nmn.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US9817633 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 2 mL) and purified by reverse phase HPLC under the conditions described below: Column: ODS-A, 20 mmn x 50 mm, 5 g1m particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time 0.0 min.

Water Acetonitrile 95 5 Flow Rate: 15 mL/min.

Example 168 2-(2-Benzimidazol-2-ylsulfanyl)-octanoic acid hydroxyamide 8 1% 215 nm; LCMS (API-electrospray) m/z 308 Example 169 2 2 -Benzooxazol-2-ylsulfanyl)-octanoic acid hydroxyamide 72% 215 nm; LCMS (API-electrospray) m/z 309 Example 170 2 2 -Benzothiazol-2-ylsulfanyl)-octanoic acid hydroxyarnide 72% 215 rn; LCMS (API-electrospray) m/z 325 Example 171Y 2-(2-Pyridine-2-sulfanyl)-octanoic acid hydroxyamide 76% 215 nm; LCMS (APIelectrospray) m/z 269 Example 172 2 4 -Phenyl-thiazole-2-sulfaniyl)-octanoic 'acid hydroxyamide 97%- 215 nm; LCMS (API-electrospray) m/z 336 Example 173 SUBSTITUT SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 129 2-(2-Pyridin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamnide 84% 215 nm; LCMS (API-electrospray) mlz 297 Example 174 2-(2-Phenyl-5H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyamide 67% 215 nm; LCMS (API-electrospray) m/z 338 Example 175 2-(2-Pyrazin-2-yl-ethylsulfanyl)-octanoic acid hydroxyamide 98% 215 rim; LCMS (API-electrospray) m/z 298 Example 176 1-Methyl-i H-tetrazol-5-ylsulfanyl)-octanoic acid hydroxyaniide 66% 215 rim; LCMS (API-electrospray) m/z 274 Example 177 2 2 -Benzimidazol-2-ylsulfrnyl)-octanoic acid hydroxyamnide 8 1% 215 rim.

Example 178 2-(2-Pyridine-2-sulfinyl)-octanoic acid hydroxyamide 76% 215 nm;.

Example 179 2 4 -Phenyl-thiazole-2-sulfinyl)-octatioic acid hydroxyamide 78% 215 nm.- Example 180 2 2 -Pyrazin-2-yl-ethylsulfinyl)-octanoic acid hydroxyamide 96% 215 nmn; LCMS (API-electrospray) m/z 314 Example 181 2 3 -Oxy-lH-benzimidazole-2-sulfonyl)-octanoic acid hydroxyamide63% 215 rum; LCMS (API-electrospray) m/z 356 Example 182 2 4 -Phenyl-thiazole-2-sulfonyl)-octanoic acid hydroxyamide 70% @215 rim; LCMS .(API-electrospray)mlnz 383 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUJS98/1 7633 -130- Example 183 2 2 -(l-Oxy-pyridin-2-yl)-ethanesulfony1I-octanoic acid hydroxyan-ide 77% 215 nm; LCMS (API-electrospray) m/z 345 Example 184 3 -(l-Hydroxycarbamoyl-heptylsulfanyl)-benzoic acid hydroxyamnide. 100% 220 nm; LCMS (API-electrospray) m/z 312 Example 185 3-[4-(lI -Hydroxycarbamoy1-heptylsulfanyl)-pheny1]-propionic acid hydroxyamide.

90% 220 nm; LCMS (API-electrospray) m/z 340 Example 186 2 -(Thiazol-2-ylsulfanyl)-octanoic acid hydroxyamide. 75% 215 nm; LCMS (APIelectrospray) m/z 275 Example 187 2 2 ,5-Dioxo-imidazolidin-4-ylmethylsulfany1)..octanoic acid hydroxyamide. 98% 215 nm; LCMS (API-electrospray) m/z 304 Example 188 1-Hydroxycarbamoyl-heptylsulfinyl)-benzoicacid hydroxyamide. 84% 220 rim; LCMS (API-electrospray) m/z 328 Example 189 3- 1-Hydroxycarbamoyl-heptylsulfinyl)phenyl]-proponic acid hydroxyainide. 78% 220 rim; LCMS (API-electrospray) mlz 356 Example 190 2 -(Quinoline-8-sulfinyl)-octanoic acid hydroxyamide. 87% 220 rim; LCMS (APIelectrospray) m/z 335 SUBSTITUTE SHEET (RULE WO 99/42436 PCTIUS98/1 7633 131 Example 191 2-(Naphthalen-2-ylcarbamoylmethanesulfinyl)-octanoic acid hydroxyainide. 83% 220 nm; LCMS (API-electrospray) mlz 391 Example 192 I-Hydroxycarbamoyl-heptylsulfonyl)-benzoic acid hydroxyamide. 72% 215 nm.

Example 193 1-Hydroxycarbamoyl-heptylsulfonyl)-phenyl]-propionic acid hydroxyamide.

67% 215 nm.

Example 194 2-(1H-Imiidazole-2-sulfonyl)-octanoic acid hydroxyamide. 95% 215 nm; LCMS (API-electrospray) m/z 290 Example 195 2-(Thiazol-2-ylsulfonyl)-octanoic acid hydroxyamide. 91% 215 nm; LCMS (APIelectrospray) m/z 307 Example 196 2-(Quinoline-8-sulfonyl)-octanoic acid hydroxyamide. 94% -220 -nm; LCMS (APIelectrospray) m/z 351 Example 197 2-(Naphthalen-2-ylcarbamoylmethanesulfonyl).octanoic acid hydroxyamide. 79% 220 nm; LCMS (API-electrospray) m/z 407 Example 198 2 2 ,5-Dioxo-imiudazolidin-4-ylmethylsulfonyl)-octanoic acid hydroxyamide. 97% 215 nm.

SUBSTITUTE SHEET (RULE 26) 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) was placed in a peptide synthesis vessel and suspended in THF (50 mL). 4- Fluorothiophenol (6.6 g, 5.0 sodium iodide (7.7 g, 5.0 eq.) and 1,8diazabicyclo[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 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 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 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.

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% tertbutylhydroperoxide (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.

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 2 mL), MeOH (2 x 2 mL), and DCM (2 x 2 mL). The resin was dried in vacuo at room temperature.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/17633 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 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 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 Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 min. 5 Flow Rate: 15 mL/min.

2-(4-Benzyloxy-phenylsulfanyl)-octanoic acid hydroxyamide 100% 215 nm; LCMS (API-electrospray) m/z 374 The hydroxamic acid compounds of Examples 200-220 are synthesized using appropriate starting materials and following the steps in example 199: Example 200 2-(4-Butoxy-benzenesulfanyl)-octanoic acid hydroxyamide 100% 215 nm; LCMS (API-electrospray) m/z 374 Example 201 2-[4-(2-Piperazine- 1 -yl-ethoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 98% 215 nm;.LCMS (API-electrospray) m/z 340 Example 202 2-[4-(5-Hydroxy-pentyloxy)-phenylsulfanyl]-octanoic acid hydroxyamide .215 nm.; LCMS (API-electrospray) m/z 370 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJIJS98,I 7633 -134- Example 203 2 4 3 -Pyridin- 2 -yl-propoxy)-benzenesulfanyl]yoctanoic acid hydroxyamide 215 nm; LCMS (API-electrospray) m/z 403 Example 204 2 4 -Benzyloxy-phenylsulfinyl)-octanoic acid hydroxyamide 100% 215 nm.

Example 205 2 4 -Butoxy-benzenesulfinyl)-octanoic acid hydroxyaniide 98% 215 nm.

Example 206 2 -14-(2-Piperazine-1I-yl-ethoxy)-benzenesulfinyl]-octanoic acid hydroxyamide 98% 215 nm.

Example 207 2 4 3 -Pyridin-2-y1-propoxy)-benzenesulfinyl]yoctanojc acid hydroxyamide 99% 215 nm.

Example 208 2 4 -Benzyloxy-phenylsulfonyl)-octanoic acid hydroxyamide 100% 215 nm.

Example 209 2 4 -Butoxy-benzenesulfonyl).octanoic acid hydroxyamide 100% 215 nm.

Example 210 2- [4-(2-Piperazine- 1 -yl-ethoxy)-benzenesulfonyl]-octanoic acid hydroxyam-ide 97% 215 nm.

Example 211 2 4 3 -Pyridin- 2 -yl-propoxy)-benzenesulfonyl]-octaoic acid hydroxyamide 100%@ 215 nm.

Example 212 1-Methyl-pyrrolidin-3-yloxy-benzenesulfany]-octanoic acid hydroxyaniide 9 .2.15 nm; LCMS (API-electrospray) m/z~ 367 SUBSTMJTE SHEET (RULE 26) WO 99/42436PCJS8/73 PCT/US98/17633 -135 Example 213 1-Ethyl-propoxy)-benzenesulfanyl]-octanoic acid hydroxyamide 100% 215 nm; LCMS (API-electrospray) mlz 354 Example 214 2-[4-(Tetrahydro-pyran-4-yloxy)-benzenesulfanyl]-octanoic acid hydroxyam-ide 97% 215 nm; LCMS (API-electrospray) m/z 368 Example 215 1-Methyl-pyrrolidin-3-yloxy)-benzenesulfinyl]-octanoic acid hydroxyanide 96%@9215 nm.

Example 216 2- -Ethyl-propoxy)-benzenesulfinyl] -octanoic acid hydroxyamide, 97% @4 215 nm.

Example 217 2-14-(Tetrahydro-pyran-4-yloxy)-benzenesulfinyl]-octanoic acid hydroxyamide 97% @a 215 nm..

Example 218 1-Methyl-pyrrolidin-3-yloxy)-benzenesulfonyl]-octanoic acid hydroxyamide 96% 215 nm.

Example 219 1-Ethyl-propoxy)-benzenesulfonyl]-octanoic acid hydroxyamide 100% 215 nm.

Example 22.0 2-114-Cfetrahydro-pyran-4-yloxy)-benz'nesufonyl]-octanoic acid hydroxyamide 100% 215 nm.

SUBSTrrIUTEF SHEET (RULE WO 99/42436 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, 1.1 meq/g) was placed in a peptide synthesis vessel and suspended in THF (60 mL). 4- Bromothiophenol (5.2 g, 5.0 sodium iodide (4.1 g, 5.0 eq.) and 1,8diazabicyclo[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 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 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.

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 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.

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°C for 8 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), SUBSTITUTE SHEET (RULE 26) 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 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 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 2 mL) and purified by reverse phase HPLC under the conditions described below: Column: ODS-A, 20mm x 50 mm, 5 pm particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 min. 5 Flow Rate: 15 mL/min.

2 4 '-Chloro-biphenyl-4-sulfinyl)-octanoic acid hydroxyamide 96% 215 nm; LCMS (API-electrospray) m/z 394 The hydroxamic acid compounds of Exmples 222-224 are synthesized using appropriate starting materials and following the steps in example 221: Example 222 2 4 -(5-Chloro-thiophen-2-yl)-benzenesulfinyl]-octanoic acid hydroxyamide 100% 215 nm; LCMS (API-electrospray) m/z 400 Example 223 2-(4'-Chloro-biphenyl-4-sulfonyl)-octanoic acid hydroxyamide 94% 215 nm; LCMS (API-electrospray) m/z 410 SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCTIUS98/17633 138- Example 224 2 4 -(5-Chloro-thiophen-2-yl)-benzenesulfonyl]-octanoic acid hydroxyamide 85% 215 nm; LCMS (API-electrospray) m/z 416 Example 225 StepA:Coupling of 2 -(4-bromobenzenesulfanyl)-octanoic acid hydroxyamide resin with N-(3-aminopropyl)-morpholine.

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 tris(dibenzylideneacetone)-dipalladium(0) (22 mg, 0.2 bis(diphenylphosphino)-1,1'-binaphthyl((S)-BINAP, 60 mg, 0.8 eq.) and sodium tertbutoxide (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.

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.

The reaction was filtered and the resin washed with DCM (2 x I 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 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 Carolina) Solvent Gradient .Time Water Acetonitrile .0.0 95 25 min. 5 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/1 7633 -139- The hydroxamic acid compounds of Examples 226-231 are synthesized using appropriate starting materials and following the steps in this example: Example 226 2 4 -(Biphenyl-4-ylamino)-phenylsulfanyl]yoctanoic acid hydroxyamide 95% 215 nm; LCMS (API-electrospray) m./z 435 Example 227 2 4 -(Pyridin- 4 -ylamino)-phenylsulfanyl]poctanoic acid hydroxyamide 97% 215 nm; LCMS (API-electrospray) m/z 360 Example 228 2 4 -Cyclopentylamino-phenylsulfanyl)-octanoic acid hydroxyamide 77% 215 nrn; LCMS (API-electrospray) m/z 351 Example 229 2 4 -Methylamino-phenylsulfanyl)-octanoic acid hydroxyamide 99% 215 flfl; LCMS (API-electrospray) m/z 297 Example 230 2 4 -Piperidin-1-yl-phenylsulfanyl)-octanoic acid hydroxyamide 72% 215 rn; LCMS (API-electrospray) m/z 351 Example 231 2 4 -Pi perazin-1-yl-phenylsulfanyl).octanoic acid hydroxyamide 74% Ca 215 inn; LCMS (API-electrospray) m/z 352 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 mL). 4-1-ydroxythiophenol (11.3 g, 5.0 sodium iodide (13.5 g, 5.0 eq.) and 1,8diazabicyclo[5.4.O]undec-7-ene (DBU, 8.1 mnL, 3.0 eq.) were added. The reaction SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -140was 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.

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 and triethylamine (0.06 mL, 2 eq.) were added. The reaction was 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.

Benzenesulfonic acid 4 -(l-hydroxycarbamoyl-heptylsulfanyl)-phenyl ester resin prepared in Step B (80 mg, 1.2 meq/g) was suspended in DCM (3 mL) and 70% tertbutylhydroperoxide (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 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 (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.

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 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. The crude product was SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98'1 7633 141 dissolved in DMSO:methanol 1, 2 mL) and purified by reverse phase HPLC under the conditions described below: Column: ODS-A, 20mm x 50 mm, 5 gim particle size (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 min. 5 Flow Rate: 15 mL/min.

Benzenesulfonic acid 1 -hydroxycarbamoyl-heptylsulfanyl)-phenyl ester 91 215 nm; LCMS (API-electrospray) m/z 424 The hydroxamic acid compounds of Examples 233-240 are synthesized using appropriate starting materials and following the steps in example 232: Example 233 2,5-Dichloro-thiophene-3-sulfonic acid 4-(l1-hydroxycarbamoyl-heptylsulfanyl)hydroxyarnide 98% 215 nm; LCMS (API-electrospray) m/z 498 Example 234 Ethanesulfonic acid 4(1 -hydroxycarbainoyl-heptylsuifanyl)-hydroxyarnide.

72% 215 nm; LCMS (API-electrospray) m/z 376 Example 235 1,3-dimethyl- 1H-pyrazole-4-sulfonic acid 1-hydroxycarbamoyl-heptylsulfinyl)-hydroxyamide 99% 215 nm; LCMS (API-electrospray) m/z 492 Example 236 2,5-Dichloro-thiophene-3-sulfomc acid 1-hydroxycarbamoyl-heptylsulfinyl)hydroxyamnide 96% 215 nm; LCMS (API-electrospray) m/z 514 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -142- Example 238 2-Nitro-benzenesulfonic acid 4-(1 -hydroxycarbamoyl-heptylsulfonyl)-hydroxyamide 97% 215 nm; LCMS (API-electrospray) m/z 501 (M+H) 4 Example 239 3 -Bromo-2-chloro-thiophene-2-sulfonic acid 4-(1 -hydroxycarbamoyl-heptylsulfonyl)hydroxyamide 97% 215 nm; LCMS (API-electrospray) m/z 576 Example 240 Benzo[ 1,2,5]thiadiazole-4-sulfonic acid 4-(1 -hydroxycarbamoyl-heptylsulfonyl)hydroxyamide 83% 215 nm; LCMS (API-electrospray) m/z 514 Example 241 1-Benzyl- 4 4 -benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide To a stirred solution of 4-methoxybenzenethiol (2.8 gmin, 20 mmol) and anhydrous

K

2 C0 3 (10 gm, excess) in dry acetone (100 mi), a-bromo ethyl acetate (3.3 gm, 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 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 MS; 227 To stirred solution of 4 -methoxy-phenylsulfanyl)-acetic acid ethyl ester (4.4 g, mmol), anhydrous K2C03 (10 gm, excess) in dry acetone (100 mi) benzyl bromide 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 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) SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 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 K2C03 (30 gm, excess) in.dry acetone (250 ml), (4-benzyloxy-phenylsulfonyl)-acetic acid ethyl ester (8.01 gm, 24 mmol) was 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 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 with 30% ethylacetate: hexane and the product 4-(4-Benzyloxy-benzenesulfonyl)- 1benzyl-piperidine-4-carboxylic acid ethyl ester was isolated as Brown oil. Yield: 6.5 g, MS: 494 (M+H) 4-(4-Benzyloxy-benzenesulfonyl)- 1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1,200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. HCI 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)-1benzyl-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 was isolated as a colurless solid. Yield 21%; mp 89 MS: 481.1 1H NMR (300 MHz, DMSO-d6): 6 2.27 3H), 2.76-2.79 2H), 3.43 4H),4.30 2H), 7.14-7.17 7.50-7.73 5H), 9.37 10.53 11.18 (s,1H).

Example 242 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 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, Brown semi-solid; MS: 323 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98,I 7633 -144- Bis-(2-chloro-ethyl)-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-am-ine was prepared according to the general method outlined in example 83 starting from 2 -[2-Hydroxyethyl)- 4 2 -piperidin-lI-yl-ethoxy)-benzyl]-a-une (3.22 g, 10 mmol). Yield 4.0 g brown semi-solid; MS: 361.1 4 -(4-Butoxy-benzenesulfonyl)- I-[4-(2-piperidin-1I-yl-ethoxy)-benzyll-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 g, 20 mmol) and Bis-(2-chloro-ethyl)-[4-(2-piperidin-1I-yl-ethoxy)-benzyl]-amine (8.6 g, 20 mmol). Yield 8.0 g brown oil; MS: 587.7 4 -(4-Butoxy-benzenesulfonyl)- I -[4-(2-piperidin- 1 -yl-ethoxy)-benzyl]-piperidineA...

carboxylic acid was prepared starting from 4-(4-B utoxy-benzenesulfonyl)- 1- piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, nunol) 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 Spongy brown solid; mp 98 MS: 559.6 Starting from 4-(4-butoxy-benzenesulfonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]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)benzyll-piperidine-4carboxylic acid hydroxy amidewas isolated as a pale yellow solid.

Yield 4 mp 155 'C (HCl); MS:'574 (M+H) 4 'H NMR (300 MI~z, DMSO-d 6 6 0.9 3H), 1.1-1.8 (in, 6H), 1.9 (in, 4H1), 2.3 (in, 4H), 2.8 (mn, 6H), 3.2-3.6 (in, 8H), 4.2 (in, 2H), 6.9 7.8 (in, 8H), 9.1 1H1), 10.8 (bs, 111).

Example 243 4 4 -Butoxy-benzenesulfonyl)- I-[3-(2-morpholinyl- 1-yl-ethoxy)-benzyl]-piperidine-4carboxylic acid hydroxyanide Bis-(2-hydroxy-ethyl){3 (2-inorpholin.1 -yl-ethoxy)-benzyl] -aminie was'prepared *according to the general method outlined in example 83 starting from diethanolaniine '(15.0 g, 150). and 3 2 -inorpholin-1I-yl-ethox. y)-benzyl chloride (5.9 g, 20 mmol).

Yield 6.2 g, Brown'semi-solid; MS-i 325 SUBSTITUTE SHEET (RULE 26) WO 99/42436PCIS8 73 PCTIUS98/17633 145 Bis-(2-chloro-ethyl)-[3-(2-morpholin- 1-yl-ethoxy)-benzyl]-ami ne was prepared according to the general method outlined in example 83 starting from Bis-(2-Hydroxyethyl)- [3-(2-morpholin-l-yl-ethoxy)-benzyl]-arnine (3.24 g, 10 mmol). Yield 4.0 g brown semi-solid; MS: 363.1 4-(4-Butoxy-benzenesulfonyl)- 1 -[3-(2-morpholin- 1 -yl-ethoxy)-benzyll-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 g, 20 mmol) and Bis-(2-chloro-ethyl)-[3-(2-morpholin- 1-yl-ethoxy)-benzyl]-amine (8.6 g, 20 mmol). Yield 8.5 g brown oil; MS: 589.7 4-(4-Butoxy-benzenesulfonyl)- I-[3-(2-morpholin- 1-yl-ethoxy)-benzyl]-piperidine-4carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)- 1 -13-(2morpholin- I -yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 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 Spongy brown solid; MS: 561.6 Starting from 4-(4-butoxy-benzenesulfonyl)- 1-[3-(2-morpholin- 1-yl-ethoxy)-benzyl]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]-rpiperidine-4-carboxylic acid hydroxy amidewas isolated as a pale yellow solid..

Yield 62%; mp 123 0 C (HCl); MS: 576 NMR (300 MHz, DMSO-d 6 8 0.9 3H), 1.4 (in, 2H), 1.8 2H), 2.3-4.7 (in, 24H), 7.0- 7.8 (in, 8H), 9.1 (s, l1H), 10.8 (bs, lH).

Example 244 1 -Methyl-4-(4-butoxy-benzenesulfonyl)-pipeidine-4-carboxylic acid hydroxyamide 1 -Methyl-4-(4-b utoxy-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 inmol) and -methyl-bis-(2- *chloro-ethyl)-amine (2.2g, 11.6 inmol). Yield 4.0 g, low melting brown solid; MS: 384 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -146- 1 -MethylA4-( 4 -butoxy-benzenesulfonyl)-piperidineA-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 NaOil (35 mrl). The resulting reaction mixture was worked up outlined in example 83. Yield 6.0 g white solid; mp 195 MS: 356.4 Starting from 1 -methyl-4-(4-butoxy-benzenesulfonyl)-piperidine.4-carboxylic acid 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 hydroxyainide was isolated as a yellow powder. Yield 85%; mp 118 MS: 371 'H NMR (300 MI-z, DMSO-d 6 8 0.9 3H), 1.45 2H), 1.8 2H), 2.1 3H1), 2.3 J 11.4 Hz, 2H), 2.5-3.7 (in, 8H), 4.1 2H), 7.16 2H), 7.67 2H) Example 245 1 -Ethyl- 4 4 -butoxy-benzenesulfonyl)-piperidine4..carboxylic acid hydroxyamide 1 -Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine.4carboxylic 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 inmol) and ethyl-bis-(2chloro-ethyl)-amine (2.2g, 10.6 nimol). Yield 3.5 g, low melting brown solid; MS: 398 1 -Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4.carboxylic acid was prepared starting from I -ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine.4-carboxylic acid ethyl ester (7.94 g, 20 nimol) 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 white solid; mp 162 'C MS: 370 Starting from 1 -ethylA4-(4-butoxy-benzenesulfonyl)-piperidine-4carboxylic acid (3.7 g, .10 nimol) and following the procedure outlined in example 83,-3.2.g of 1-ethyl-4- 4 -butoxy-benzenesulfonyl)-piperidine-4.carboxylic acid hydroxyamnide was isolated as a yellow powder. Yield 76%; *mp 98 0 C; MS: 385'(M+H) 4 'H NMR (300 MHz, DMSO-d 6 8 0.9 3H), 1.2 3H), 1.46 2H), 2.3 J =11.4 Hz, 2.5-3.6 (in, 10H), 4.1 2H), 7.16 2H), 7.67 2H) SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -147- Example 246 1-n-Butyl- 4 4 -butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide 1-n-Butyl- 4 4 -butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4- (butoxy-benzenesulfonyl) acetic acid ethyl ester (3 g, 10 mmol) and n-butyl-bis-(2chloro-ethyl)-amine (2.0g, 10.1 mmol). Yield 3.8 g, low melting brown solid; MS: 426 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 mi) and 10 N NaOH (35 mi).

The resulting reaction mixture was worked up as outlined in example 83. Yield 7.5 g white solid; mp 182 MS: 398 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-nbutyl- 4 4 -butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a yellow powder. Yield 40%; mp 121 MS: 413 'H NMR (300 MHz, DMSO-d 6 8 0.9-1.0 6H), 1.2-1.8 8H), 2.2-2.8 (mn, 8H), 3.0-3.6 (m, 4H), 4.2 2H), 7.16 2H), 7.67 2H), 9.3 (bs,1H), 10.3 (bs,1H), 11.1 (bs,1H).

Example 247 4 -(4-Chloro-phenoxy)-phenylsulfanyi]-acetic acid ethyl ester A mixture of 4-bromno chlorobenzene (1.92 g, 10 mmol), (4-Hydroxy-phenylsulfanyl)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 by eluting with 30% ethyl acetate hexane. Yield 2.5 g Colorless low melting solid; MS: 323 (M+H) 4 Alternatively the title compound may be prepared from 4-(4chloro-phenoxy)-benzenethiol and bromo ethyl acetate as described in example 83.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/1 7633 148 Example 248 4 4 -Chloro-phenoxy)-benzenesulfonyl] -acetic acid ethyl ester 4 4 -Chloro-phenoxy)-benzenesulfonyl]yacetic 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 Yield oil; MS: 356EI Example 249 4 -1 4 4 -choro-phenoxy)-benzenesulfonyl] I -methyl-piperidine-4-carboxylic acid hydroxyainide 4- 4 4 -Chloro-phenoxy)-benzenesulfony I -methyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4 4 -chioro-phenoxy)-benzenesulfonyl] acetic acid ethyl ester 2.0g, 5.6rnmol) and mechlorethann-une hydrochloride (Aldrich), (1.9g, l0mmol). Yield 2g 81 brown oil; MS:438 4 4 4 -Chloro-phenoxy)-benzenesulfonyl]- 1-methyl-piperidine-4-carboxylic acid was prepared starting from 4 [4-(4-chloro-phenoxy)-benzenesulfonyl] I -methyl-piperidine- 4-carboxylic acid ethyl ester (4.3 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaGH 100 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5g (86 white solid; mp 185'C; MS:410(M+H)' Starting from 4 4 4 -chloro-phenoxy)-benzenesulfonyl]- 1 -methyl-piperidine-4carboxylic 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 acid hydroxyamnide was isolated as a HCl salt, a white powder. Yield 41 mp 52 'C; MS: 426 'H NMR (300 MHz, DMSO-d 6 8 1.3 3H), 2.2 2.9 (in, 6H), (bd, 2H), 7.2 -7.9 mn, 8H), 8.1 1H), 11.0 (bs, lH).

SUBSTITUTE SHEET (RULE WO 99/42436 PCT/US98,I 7633 149 Example 250 4 4 4 -chloro-phenoxy)-benzenesulfonylI 1 -ethyl-piperidine-4-carboxylic acid hydroxyamide 4 4 4 -Chloro-phenoxy)-benzenesulfonyl]- I -ethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4 4 -chloro-phenoxy)-benzenesulfonyI ]-acetic acid ethyl ester (4 g, 11.3 mmol) and ethyl-bis-(2-chloro-ethyl).aniine (2.32 g, 16.9 mmnol). Yield 3.36 g brown oil; MS: 452.0 4 -1 4 4 -hloro-phenoxy)-benzenesulfonyl]-lI-ethyl-piperidine-4-carboxylic acid was prepared starting from 4 -[4-(4-chloro-phenoxy)-benzenesulfonyl.. 1 -ethyl-piperidine-4carboxylic acid ethyl ester (3.02 g, 6.7 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 1.8 g white solid; mp 184*C; MS: 423.9 Starting from 4 4 4 -chloro-phenoxy)-benzenesulfonyl]-l1-ethyl-piperidine-4carboxylic acid (1.75 g, 4.14 mmol) and following the procedure outlined in example 83, 650 mg of 4 4 4 -chloro-phenoxy)-benzenesulfonyl] I1-ethyl-piperidine-4carboxylic acid hydroxyamide was isolated as a HCI salt, a white powder. Yield 33%; mp 158 0 C; MS: 438.9 NMR (300 MHz, DMSO-d 6 8 1.78 J=7.23 Hz, 3H), 2.23-2.27 (in, 2H), 2.5 1-2.73 (in, 4H), 3.04 (mn, 2H), 3.81 J=24 Hz, 716-7.27 (mn, 4H), 7.50-7.57 (mn, 2H), 7.76 J =7 Hz, 2H), 9.34 1lH), 9.85 I H).

Example 251 1-ButylA4-[ 4 -(4-chlorophenoxy)-benzenesulfonyly-piperidine4-carboxylic acid hydroxyaniide l-ButyIA4-[ 4 -(4-choro-phenoxy)benenesulfonyl]Ipiperidine-4carboxylic 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 inmol) and butyl-bis-(2-chloro-ethyl).anine (5.2 g, 22 inmol). Yield 3.3 g yellow oil; MS: 480 (M+H) 4 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US9817633 -150- I-uy--4(-hoopeoy-ezeeufnl-ieiie4croyi acid was prepared starting from Il-butyl- 4 4 4 -chloro-phenoxy)-benzenesulfonyl]..piperidine-4 carboxylic acid ethyl ester (3.3 g, 6.9 nimol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (25 nil). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.08 g white solid; nip 201'C; MIS: 451.9 Starting from l-butyl- 4 4 4 -chloro-phenoxy)-benzenesulfonylI..piperidine-4 carboxylic acid (2 g, 4.43 nimol) and following the procedure outlined in example 83, 630 mg of I btl4[-4clr-hnx)bneeufnl-ieiie4croyi acid hydroxyamide was isolated as a HCI salt, a white solid. Yield 3 mp 212 *C; MS: 466.9 'H NMR (300 MHz, DMSO-d 6 8 0.87 J=7.3 Hz, 3H1), 1.32 (in, 2H), 1.60 (in, 2H), 2.21 (in, 2H), 2.50 (mn, 2H), 2.70 2H), 3.00 (mn, 2H-), 3.57 211), 7.16-7.26 (in, 4H), 7.49-7.56 (mn, 2H), 7.77 J =9 Hz, 211), 9.34 IlH), 10. 13 I1H).

Example 252 I-Benzy- 4 4 4 chlorophenoxy)benzenesulfonyl-piperidine-4carboxylic acid hydroxyamide I-ezl4[-4clr-hnx)bneeufnl-ieiie4croyi 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 mxnol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mnol). Yield 2.21 g yellow oil; MS: 513.9 l-Benzyl- 4 4 -(4-chloro-phenoxy)-benzenesulfonyl]ypiperidine-4carboxylic acid was prepared starting from l-benzyl- 4 4 4 -chloro-phenoxy)-benzenesulfonyll-piperidine- 4-carboxylic acid ethyl ester (2.11 g, 4.1 nimol) dissolved in THF:methanol (3:1 150 n-l) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1. 11 g white solid; nip 201 MS: 485.9 Starting from l-benzylA4-[ 4 -(4-chloro-phenoxy)-benzenesuilfonyl]-piperidine-4 carboxylic acid (1 g, 2.06 mmol) and following the procedure outlined in example 83, 430 mng of l-benzyl- 4 4 -(4-chborophenoxy)-benzenesulfonyly-piperidine-4carboxylic acid hydroxyaxnide was isolated as a HCl salt, an off white solid. Yield 39%; nip SUBSTITUTE SHEET (RULE 26) WO 99/42436 WO 9942436PCTIUS98/1 7633 151 90.4'C; MS: 500.9 'H1 NMR (300 MHz, DMSO-d 6 5 2.18-2.30 (in, 2H), 2.73-2.8 1 (in, 4H), 3.36 2H), 4.28 J= 4.5 Hz, 2H), 7.15-7.25 (in, 4H), 7.43- 7.48 (in, 311), 7.51-7.56 (in, 4H), 7.74 J 9 Hz, 2H), 9.53 1H), 10.47 (s, I1H).

Example 253 [4-(3-methyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, mmol), K2CO 3 (anhydrous, 10 g) and l-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.

The crude product obtained was taken to next step with out purification. Yield 2.7 g 283.

Example 254 [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)-phenylsulfanyl] -acetic acid ethyl ester (2.8 g, 10 inmol) and oxone (10 Yield 3.Og oil; MS: 314EI Example 255 1 -Benzyl-4-[4-(3-inethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide 1 -Benzyl- 4 -[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4Acarboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-ineth'yl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 imol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 minol). Yield 8 g yellow oil, ms: 474 1 -Benzyl-4- [4-(3-methyl-butoxy)-benzenesulfonyl] -piperidine-4-carboxylic acid was prepared starting from .1 -Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyll-piperidine- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/I 7633 152 4-carboxylic ethyl ester (4.7 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3 g white solid; mp 182 MS: 446 Starting from 1 ezl4[-3-ehlbtx)-eznsloyl-ieiie4 carboxylic acid (2.2 g, 5 mmol) and following the procedure outlined in example 83, 1.82 g of l-Benzyl- 4 4 3 -methyl-butoxy)-benzenesulfonyll-pipeidine-4carboxylic acid hydroxyamide was isolated as a HCl salt, an off white solid. Yield 73%; mp 106 MS: 498 'H NMR (300 MHz, DMSO-d 6 S 0.8 6H), 1.5 (m,1H), 1.6-2.0 (in, 6H), 2.73-2.81 (mn, 4H), 3.5 2H), 4.28 J= 4.5 Hz, 2H), 7.15- 7.25 (in, 4H), 7.43-7.48 (in, 3H), 7.51-7.56 (mn, 4H), 7.74 J 9 Hz, 2H), 9.53 1H), 10.47 1H).

Example 256 I-uy--4(-ehlbtx)bneeufnl-ieiie4croyi acid hydroxyarnide I-Butvl- 4 4 3 -methyl-butoxy)benzenesulfonyly-pipeidine-4carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 4 3 -iethyl-butoxy)-phenylsulfonyl..-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-anmjne (5.2 g, 22 minol). Yield 7 g yellow oil; MS: 440 I-uy--4(-ehlbtx)bneeufnl-ieiie4croyi acid was prepared starting from 1 -Butyl- 4 4 3 -methyl-butoxy)..benzenesulfonyl]-piperidine-4carboxylic ethyl ester (4.4 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.2 g white solid; mp 188 MS: 412 Starting from 1 uy--4(-ehy-uoy-eznslfnl-ieiie4 carboxylic -acid (2.0 g, 5 mmol) and following the procedure outlined in example 8 3, 1.6 g of I-uy4[-3mty-uoy-ezneufnl-ifiie4croyi acid hydroxya'mide was isolated as a HCl salt, an off white solid. Yield 69%; mp 201 *C; MS: 464 SUBSTrrIUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -153- Example 257 [4-(2-Ethyl-butoxy)-phenylsulfanyl]-acetic acid ethyl ester To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, mmol), K 2

CO,

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 product obtained was taken to next step without purification. Yield 2.8 g 297.

Example 258 [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)-phenylsulfanyl]-acetic acid ethyl ester (2.96 g, 10 mmol) and oxone (10 Yield 3.lg oil; MS: 329EI Example 259 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine4-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 bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 8 g yellow oil; MS: 488 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-4carboxylic ethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4 g Semi solid; MS: 460 Starting from 1 -Benzyl- 4 4 -(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid (2.2 g, 5 mmol) and following the procedure outlined in example 83, 1.02 g of 1- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,I 7633 154 Bezl-4(-ty-uoy-eznsloylpprdn4croyi acid hydroxyamide was isolated as a HCI salt, an off white solid. Yield 40%; mp 114 *C; MS: 512 (M+H) 4 Example 260 4 4 -butoxy-benzenesulfonyl).1 3 -methoxy-benzyl)-piperidine-4carboxylic acid hydroxyamide 4 4 -Butoxy-benzenesulfonyl).1 3 -methoxy-benzyl)-piperidine-4carboxylic 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 minol) and bis- 2 -chloro-ethyl)-(3-methoxy-benzyl)-aine (34 g, 116 mmol). Yield 9.53 g brown oil; MS: 490.2 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 was worked up as outlined in example 83. Yield 1 g (4 brown solid; mp 175'C; MS: 462.0 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 83, 200 mg of 4 4 -butoxy-benzenesulfonyl).1 3 -methoxy-benzyl)-piperidine.4carboxylic acid hydroxyamide was isolated as a HCI salt, a brown powder. Yield mp 137 MS: 477.0 'H NMR (300 MHz, DMSO-d 6 6 0.96 J=7.1 1 Hz, 3H), 1.48 (in, 2H), 1.73 (in, 2H), 2.27 (in, 2H), 2.47 (in, 2H), 2.78 (in, 2H), 3.35 (in, 2H), 3.77 2H), 4.08 J= 6.3 Hz, 3H), 4.32 2H), 7.03 2H), 7.15 (in, 3H), 7.36 J= 7.8 Hz, 1H), 7.64 J 9 Hz, 2H), 9.36 1H), 10.22 (s, 1 H).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/1 7633 -155 Example 261 4-(4-Methoxy-benzenesulfonyl)- 1 -(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyainide 4-(4-Methoxy-benzenesulfonyl)- 1 -(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared starting from l-(4-Bromo-benzyl)-4-(4-methoxybenzensulfonyl)-piperidine-4-carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2- (tnibutylstannyl)-thiophene (6.8 g, 18.14 mmol) in the presence of tetrakis palladium in boiling tolune. Yield 1.58 g brown solid; mnp 130"C; MS: 500 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-ylbenzyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 2.61 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 950 mg brown solid; mp 235"C; MS: 471.8 Starting from 4-(4-methoxy-benzenesulfonyl)- 1-(4-thiophen-2-yl-benzyl)-piperidine-4carboxylic 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 hydroxyam-ide was isolated as a HCl salt, a brown solid. Yield mp 166 MS: 486.9 'H NMR (300 Mliz, DMSO-d 6 5 2.12-2.21 (in, 2H), 2.50 (mn, 2H), 2.78 (in, 2H), 3.39 (mn, 2H), 3.87 3H), 4.29 2H), 7.17 (in, 3H), 7.54-7.75 (in, 8H), 9.36 1H), 10.07 1H) Example 262 4-(4-methoxy-benzenesulfonyl)- 1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyarnide 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 I romo-benzyl)-4-(4-methoxy-benzensulfonyl )-piperidine-4carboxylic acid ethyl ester (4.65 g, 9.38 inmol) and 2-(tributylstannyl)-pyridine (12.08 g, 32.8 inmol). Yield 2.79 g brown oil; MS: 495.1 SUBSTrrUrs SHEET (RULE 26) WO 99/42436 PCTJUS98/1 7633 -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 mrl). The resulting reaction mr~ixture was worked up as outlined in example 83. Yield 1.38 g off white solid; mp 217'C; MS: 466.9 Starting from 4 -(4-methoxy-benzenesulfonyl)-l1-( 4 -pyridin-2-y1-benzyl)-piperidine-4carboxylic acid (1.32 g, 2.83 mmol) and following the procedure outlined in example 83, 480 mg of 4-(4-methoxy-benzenesulfonyl)- 1 4 -pyridin-2-yl-benzyl)-piperidine-4carboxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%; mp 214 MS: 482.0 'H NMR (300 MHz, DMSO-d 6 8 2.30 (in, 2H), 2.80 (in, 2H), 3.42 J= 12.5 Hz, 2H), 3.75 (mn, 2H), 3.88 3H4), 4.36 2H), 7.15 J= 8.9 Hz, 2H), 7.59-7.74 (mn, 4H), 7.84-7.95 (in, 3H), 8.55 J= 8.1 Hz, 1H), 8.79 1H4), 9.14 1H), 10.68 1H), 11.17 1H) Example 263 1 3 4 -Dichlorobenzyl)-4-(4-butoxy-benzenesulfony)piperidine.

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 (1 3.2g 44 inmol) (3,4dichloro-benzyl)-bis-(2-chloro-ethyl).anine (14.3g, mmol). Yield 14. Ig white solid, MP 86'C; MS: 527.9 1 4 -dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine.4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)- 1-(3 ,4-dichloro-benzyl)piperidine-4-carboxylic acid ethyl ester (14.0 g, 26.5 minol) dissolved in THF:Methanol (100: 50 ml) and 10 N NaGH (20 ml). The resulting reaction mixture was Worked up as outlined in example 83.. Yield 7.87 off white solid;-mp 239'C; MS: 501.9 Starting 1 4 -dichlorobenzyl)-4-(4-butoxy-benzenesulfony)piperidine-4carboxyic acid (7.7g, 15.5 mmol) and following the procedure outlined in example 83, 4.05g of 1 4 -dichlorobenzyl)- 4 -(4-butoxy-benzenesulfonyl)piperidine-4carboxylic acid hydroxyamide was isolated as a HCl salt, white solid. Yield 48%; mp, 256.8-'C; M -S: SUBSTiTUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 157 14.9 'H NMR (300 MHz, DMSO-d 6 8 0.94 3H), 1.38-1.48 2H), 1.68-1.75 2H), 2.27 (in, 4H),2.72 (in, 2H), 4. 10 2h), 4.24 2H), 7.12-7.15 J=8.9, 2H), 7.5 1-7.53 J=8. 1, 1 7.63-7.65 J=8.8, 2H), 7.72-7.75 (d, J=9.9, 2H), 7.87 1H), 9.36 1H), 10.5 1H), 11.2 1H) Example 264 [4-(4-Chloro-benzyloxy)-benzenesulfonyl] -1-methylpiperidine-4carboxylic acid hydroxainide [4-(4-Chloro-benzyloxy)-benzenesulfonylj- 1 -methylpipenidine-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 inmol) and 4 -(4-chloro-benzyloxy)-bis-(2-chloro-ethyl)-amine (8.7g, 45 imol). Yield 10.9 brown oil; MS: 451.9 [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 inmol) dissolved in THF:Methanol (75: 75 ml]) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9g off white solid; MS: 426.2 Starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl- I -methylpiperidine-4carboxylic acid (4.9g, 12 inmol) and following* the procedure outlined in example 83, 1 .2g of [4-(4-Chloro-benzyloxy)-benzenesulfonyl] -1-methylpiperidine-4-carboxylic acid hydroxamide was isolated as a HC1 salt, off white solid. Yield 24%; mp 117.8 'C; MS: 438.9 'H NMR (300 MHz, DMSO-d 6 8 2.2 (in, 2H), 2.49 (in, 4H), 3 2.6 (in, 2H), 5.2 2H), 7.25-7.23 t=8.7, 2H), 7.5 t=2.7, 4H), 7.68-7.71 t=9.6, 2H), 9.3 3 I1H), 10. 11 I1H) Example 265 4-(4-Butoxy-benzenesulfonyl)- 1 -(3-phenoxy-benzyl)-piperi .dine-4carboxylic acid hydroxamide 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 inmol) and 1-(3- SUBSTmJTEu- SHEET (RULE 26) WO 99/42436 PCTIUS98/1 7633 -158 phenoxy-benzyl)-bis-(2-chloro-ethyl)-amine (18g, 50 mmol). Yield 8.9 brown oil; MS: 552.1 4-(4-Butoxy-benzenesulfonyl)- 1 3 -phenoxy-benzyl)-piperidine-4-carboxylic acid was 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 mnl) and N NaOH (20 mld). The resulting reaction mixture was worked up as outlined in example 83. Yield 5.Og off white solid; MS: 524.3 4 Starting from 4 -(4-Butoxy-benzenesulfonyl)-1I-( 3 -phenoxy-benzyl)-piperidine.4 carboxylic acid (5.9g, 11I 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 HCl salt, tan solid. Yield 11I%; mp 92.5 MS: 539.1 NMR (300 MHz, DMSO-d 6 8 0.93-0.97 J=3.6, 3H), 1.49 (in, 2H), 1.73 (in, 2H), 2.51 (mn, 4H), 4.09 2H), 4.29 (bs, 2H), 7.06-7.10 J=12, 2H), 7.13-7.15 (mn, 3H), 7.39-7.42 2H), 7.63-7.66 2H), 9.50 IH), 9.98 I1H) Example 266 4 -(4-Chloro-benzyloxy)-benzenesulfonyl].. 1 -(4-methylbenzyl)-piperidine-4carboxylic acid hydroxarride 4 4 -Chloro-benzyloxy-benzenesulfonyl.. 1 -(4-methylbenzyl)-piperidine-4carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from 1-( 4 -chloro-benzyloxy)-benzenesulfonyl]yacetic acid ethyl ester (5.47g, 15 mmuol) and l-( 4 -inethyl-benzyl)-bis-(2-chloro.ethyl)..amine (5.23g, 18 inmol). Yield 8.0 brown oil; MS: 542.0 (M+H) 4 4 -Chloro-benzyloxy)-benzenesulfonyl.. 1 4 -methylbenzyl)-piperidine-4carboxylic acid was prepared starting from 4 4 -Chloro..benzyloxy)-benzenesulfonyl]l-( 4 -inethylbenzyl)-piperidine-4. carboxylic acid ethyl ester (7.9 g, 124 inmol) dissolved in THF:Methanol (50: 50 ml) and 10 N NaQH (20 mld). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.6g off white solid, mp 204 MS: 514.2 Starting from 4 4 -Chloro-benzyloxy)-benzenesulfonyl]y 1 -(4-methylbenzyl)piperidine-4-carboxylic acid (4.2g, 8rmol) and following the procedure outlined in SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98,i 7633 -159 example 83, 1 .3g of [4-(4-Chloro-benzyloxy)-benzenesulfonyl]- 1 -(4-methylbenzyl)piperidine-4-carboxylic acid hydroxanude was isolated as a HC1 salt, yellow solid.

Yield 29%; mp 172 MS: 528.9 'H4 NMR (300 MHz, DMSO-d 6 Example 267 4-(4-Butoxy-benzenesulfony 1)-i -(4-methylbenzyl)-piperidine-4carboxylic acid hydroxamide 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-methylbenzyl)-bis-(2-chloro-ethyl)-amine (1 5.3g, 51 mmol). Yield 10. white solid, MP 93)C; MS: 474.1 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4carboxylic ethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and N NaOH (20 mlJ). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.2g off white solid, mp 244 MS: 446.3 -Starting from 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-methylbenzyl)-piperidine-4carboxylic acid (6.6g, 1.5 mmol) and following the procedure outlined in example 83, 2.06g of 4-(4-Butoxy-benzenesulfonyl)- I-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, yellow solid. Yiel *d 28%; mp 137 MS: 461.3 'H NMR (300 MHz, DMSO-d 6 6 0.91-0.964 J=7.3, 3H), 1.41 (in, 2H), 1.70 (in, 4H), 1.79 s, 3H1), 2.52 (mn, 2H), 2.76 (mn, 2H), 3.33 (bd, 2H), 4. 10 2H), 4.22 2H), 7.12-7.14 J=8.7, 2H), 7.25-7.28 J=8.1, 2H), 7.42-7.45 J=7.8, 2H), 7.63- 7.65 J=8.7, 2H), 10.31 1H1), 10.75 (bs, 1H) Example 268 4-(4-Butoxy--benzenesulfonyl)- 1-(4-cyano-benzyl)-piperidine-4- hydroxamnide 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- SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,I 7633 -160- (4-Butoxy-benzenesulfonyl)-acetic acid ethyl ester (5.29g, 17.6 mnmol) and l-(4-cyanobenzyl)-bis-(2-chloro-ethyl)-amine (6.19g, 21 mmol). Yield 6.8g tan oil; MS: 485.0 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 mnmol) dissolved in THF:Methanol (75: 50 ml) and N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield .7g off white solid; MS: 456.0 Starting from 4-(4-Butoxy-benzenesulfonyl)- 1 -(4-cyanobenzyl)-piperidine-4carboxylic acid (.600g, 1.2 mmol) and following the procedure outlined in example 83, .21 g of 4-(4-Butoxy-benzenesulfonyl)- 1 4 -cyano-benzyl)-piperidine.4-carboxylic acid hydroxanide was isolated as a HC1 salt, off white solid. Yield 34%; mp 241.6 'C; MS: 472.0 'H NMR (300 MHz, DMSO-d 6 8 .915-.964 J=7.2, 3H), 1.51 2H), 1.75 2H), 2.27 (in, 2H), 2.49 (in, 4H), 4.11-4.19 2H), 4.37 1H), 7.12-7.15 J=8.7, 2H), 7.63-7.66 J=9, 2H), 7.72-7.74 J=7.8, 2H), 9.36 1H), 10.23 1H), 11.16 1H) Example 269 4-(4-Butoxy-benzenesulfonyl)- 1 -pyridin-4-ylmethyl-piperidine-4carboxylic acid hydroxamide 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-4ylmethyl-bis-(2-chloro-ethyl)-amine.

(4.89g, 21 mmol). Yield 4.5g Brown oil; MS: 461.0 4 -(4-Butoxy-benzenesulfonyl) 1-pyridin-4-ylinethyl-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 minol) 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 1.2g off white solid; MS: 433.0 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 161 Starting from 4-(4-Butoxy-benzenesulfonyl)- 1-pyridin-4-ylmethyl-piperidine-4carboxylic acid (0.864 mg, 2.0 mmol) and following the procedure as outlined in example 83, 600 mg of 4-(4-Butoxy-benzenesulfonyl)- -pyridin-4-ylmethylpiperidine-4-carboxylic acid hydroxyamide was isolated as a HCI salt, off white solid.

Yield 67%; mp 118 MS: 447.9 1H NMR (300MHz, DMSO-d6): d0.94 (t, 3H), 1.11 1H), 1.23 1H), 1.44 1H), 1.73 1H),2.34 2H), 2.78 (m, 2H), 3.10 2H), 3.38 2H), 4.08 2H), 4.42 (br s, 2H), 7.13 2H), 7.64 2H), 7.94 2H), 8.82(d, 2H), 11.2 (br s, 1H), 11.4 (br s, 1H).

References: 1 Rickter, L. 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.

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, 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 temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl 2 before use. The stock of human neutrophil gelatinase B is diluted with assay buffer (50 mM HEPES pH 7.5, 5 mM CaCl 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 inhibitor are added to a 96 well plate (total reaction volume of 200l1) 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 The mean (x sem) of the control rate is calculated and compared for statistical significance (p <0.05) with drugtreated rates using Dunnett's multiple comparison test. Dose-response relationships can SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -162be generated using multiple doses of drug and ICso values with 95% CI are estimated using linear regression (IPRED, HTB).

References: Weingarten, H and Feder, Spectrophotometric assay for vertebrate collagenase, Anal. Biochem. 147, 437-440 (1985).

In Vitro Collagenase Assay The assay is based on the cleavage of a peptide substrate ((Dnp-Pro-Cha-Gly-Cys(Me)- His-Ala-Lys(NMa)-NH 2 Peptide International, Inc.) by collagenase releasing the 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 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 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 nM. Compounds are dissolved in methanol, DMSO, or HCBC. The methanol and DMSO are diluted in HCBC to Compounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate.

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.

The linearity of the reaction rate is confirmed (r 2 The mean (x sem) of the control rate is calculated and compared for statistical significance (p <0.05) with drugtreated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC5o values with 95% CI are estimated using linear regression (IPRED, HTB).

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).

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -163- Procedure for Measuring TACE Inhibition Using 96-well black microtiter plates, each well receives a solution composed of 10 pL TACE (Immunex, final concentration lpg/mL), 70pL Tris buffer, pH 7.4 containing glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration 1pM, DMSO concentration and incubated for 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 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 The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drugtreated 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 The results obtained following these standard experimental test procedures are presented in the following table.

SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98,I 7633 -164- IC 50 (nM or inhibition at 1 micromolar or l0micromolar Example MMP 1 MMP 9 MMP 13 TACE 1 NT 559.6 193.3 31.62T 2 NT 10.50% 0% 403 3 NT 308.9 169.4 27.43% 4 371 22.20% 17.10% 21% NT 7.7 4.7 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% 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% 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% 423 14.6 18.7 31% 21 318 13.2 15.3 39% 22 219 3.2 2.5 23 593 7.9 4.0 40.6% 24 413 20.9 31.3 47.5 262 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% 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% 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% 69.4 583 197 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% SUBSTmTT SHEET (RULE 26) WO 99/42436 PCTIUS98/17633 165 Example MMP 1 MMP 9 MMP 13 TACE 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 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% 303 10 7 21.70% 56 299 16 12 57 258 332 191 16.57% 58 211 35 39 7.70% 59 30.20% 447 141 24.86% 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% 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% 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% 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 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 2.0 213 450 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 SUBSTrrIU-u SHEET (RULE 26) WO 99/42436 WO 99/42436 PCT/US98/17633 -166- Example MMP 1 MMP 9 MMP 13 TACE 89 1389 38.6 7.0 49% 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 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -167- Compounds prepared by solid phase synthesis Data: for Examples 110 to 240 Example No MMP 1 MMP 9 MMP 13 inhibition at 0.2 pM (HTS) MMP 13 inhibition at 0.2 tpM (manual) TACE inhibition at ImM 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 1.9 mM 213 nM 75 10 50 0 0 0 0 7 24 0 31 0 0 0 0 5 25 47 91 90 28 71 71 53 25 79 89 83 20 8 29 32 69 53 38 45 68 73 15 13 54 6 9 12 89 31 23 255 nM 17.6 40.4 33.7 13.1 0 0 9.1 8.1 16.7 7.8 19.9 6.1 3.1 0 2.3 10.4 29.2 19.31 32.77 27.9 20.73 20.76 22.04 -9.31 42.67 42.69 13.35 5.284 28.05 -4.22 11.76 54.27 43.9 19.7 7.317 11.95 43.46 4.408 1.818 5.927 10.03 11.8 13.14 18.62 -2.09 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTJUS98/1I7633 -168- Example No MMP 1 MMP 9 MMP 13 inhibition at 0.2 ,iM (HTS) MMP 13 inhibition at 0.2 pM (manual) TACE inhibition at ImM 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 N o. inhibition at 36 nM (WI'S) MMP 13 inhibition at 0.36 mMv

(LITS)

MMP 13 inhibition at 3.6 mnM (HTS)

TACE

IC

50 nM

TACE

inhibition at ImM 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 28 32 31 34 18 10 16 6 5 -10 12 14 6 -9 -6 16 9 -14 -14 -27 -30 -35 -45 -32 -32 -17 -9 -18 -33 -39 -10 40 49 38 32 46 19 20 5 1 74 32 19 35 -8 12 24 0 -4 -12 -24 -18 -28 -3 5 -15 -8 -2 1 -26 -7 -7 72 90 48 42 56 40 37 16 9 39 60 45 62 7 70 4 23 35 20 4 -9 -13 22 61 56 5 10 11 -3 15 30 41.7 25.5 16.6 29.4 25.5 27.7 32.9 26.6 38.5 26 42.7 34.4 15.7 28.6 34.6 24.8 7.21 19.5 85.5 16.2 14.

38.3 2.9 33.2 14.9 5.4 27.0 35.7 17.8 17.1 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCTIUS98/17633 -169- Example MMP 13 N o. inhibition at 36 nM (HTS) MMP 13 MMP 13 inhibition at inhibition at 0.36 mnM 3.6 mnM (HTS)

(HTS)

TACE

IC

50 nrM

TACE

inhibition at ImM 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 895 380 256 146 212 226 404 96.6 700 930 37.9 50.9 10.6 32.8 7.75 84.0 89.8 -6.3 67.7 31.2 52.2 20.7 56.0 -17.5 11.03 60.12 2.49 55.1 68.7 7.3 53.1 98.9 89.3 107.3 75.0 114.3 2.2 7.3 6.8 34.4 72.1 41.6 20.8 19.8 18.4 48.3 38.2 54.4 45.9 40.3 SUBSTITUTE SHEET (RULE 26) 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.

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 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 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 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, cellulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, glycols) and their derivatives, and oils 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.

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 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 SUBSTITUTE SHEET (RULE 26) WO 99/42436 PCT/US98/17633 -171compounds 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 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 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 MMPs and TACE are involved must be subjectively 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 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, 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 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.

SUBSTITUTE SHEET (RULE 26)

Claims

08.11.02 -172- The claims defining the inventions are as follows: 1. A compound according to formula I O R2 ,R4 RI/A OH 1 wherein: R' 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 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted o,0. with one or two groups selected independently from R 5 aryl of6 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 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 2. or heteroaryl-(CH 2 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 A is -SO- or SO2-; 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 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 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ACY-33311-02-C1 AU 08.11.02 -173- C 3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 saturated cir unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR', optionally substituted with one or two groups selected independently from R 5 Rs is H, C 7 -Cll aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 1 2 alkenyl, C 2 -C 1 2 alkynyl, F, Cl, Br, I, CN, CHO, CI-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, CI-C 6 alkoxyaryl, C 1 -C 6 alkoxyheteroaryl, C 1 -C 6 alkylamino-CI-Cs alkoxy, C,-C 2 alkylene dioxy, aryloxy-Cl-C 6 alkyl amine, CI-CI2 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, 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 -CI-C 6 alkyl, CONHSO 2 aryl, SO2NHCOaryl, CONHSO 2 -CI-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 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 groups selected from halogen, cyano, amino, nitro, C 1 -C 6 alkyl, CI-C 6 alkoxy, or hydroxy; R6 is H, C, 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),-CI-C 6 alkyl aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl 21 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, Ci-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 1 aroyl, C 2 -C 6 alkanoyl, CI-C 12 perfluoro alkyl, S(O)n-C 1 -C 6 -alkyl, S(O)- aryl where n is 0, 1 or 2; COO-C i-C 6 -alkyl, C00aryl, CONHR 6 CONR 6 R 6 CONHOH, SO 2 NR 6 R 6 SO 2 CF 3 SO2NHheteroaryl, 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, CI-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 I-C 6 alkyl; ACY-33311-02-C1 AU 08.11.02
174- 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 doublk 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 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 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 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-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or R 8 R 9 N-C -C6-alkoxyaryl-C I-C 6 -alkyl where R 8 and R 9 are independently selected S: 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; with the proviso that at least one ofR', R 2 R 3 R 4 R 5 and R 6 contains the group NR 7 wherein R 7 is a 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 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 wherein: R' is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ACY-33311-02-C1 AU 08.11.02 175 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 to two groups selected independently from R 5 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 substituted with one to two groups selected independently from R 5 or heteroaryl-(CH 2 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 A is -SO- or SO 2 R 2 and R 3 taken with the carbon atom to which they are attached, form a 5 to 7 *o *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 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 .25 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 R 5 is H, F, Cl, Br, I, CN, CHO, C 7 -C 1 I aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 12 alkenyl, C 2 -C 12 alkynyl, Ci-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 C 6 alkynyloxy, CI-C 6 alkoxyaryl, CI-C 6 alkoxyheteroaryl, Ci-C 6 -alkylamino-Cl- C 6 alkoxy, Ci-C 2 -alkylene dioxy, aryloxy-Ci-C 6 alkyl amine, C -C 1 2 perfluoro alkyl, S(O)n-Ci-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO-Ci-C 6 alkyl, OCOOaryl, OCONR 6 COOH, COO-C -C 6 alkyl, COOaryl, CONR 6 R 6 CONHOH, NR 6 R 6 S0 2 NR 6 R 6 NR 6 SO 2 aryl, NR 6 CONR 6 R 6 NHS0 2 CF 3 SO2NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 -CI-C 6 alkyl, CONHSO 2 aryl, SO2NHCOaryl, CONHSO 2 ACY-33311-02-C1 AU 08.11.02
176- Ci-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 NR7; 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 independently from halogen, cyano, amino, nitro, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; R 6 is H, Ci to C 18 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, Ci 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 Shaving 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, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and R 7 is C 7 -C11 aroyl, C 2 -C 6 alkanoyl, C -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 SO2NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, heteroaryl; 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 groups selected from halogen, cyano, amino, nitro, Ci-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected .25 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 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 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 ACY-33311-02-C1 AU 08.11.02
177- 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 R 5 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 RSR 9 N-Cl-C 6 -alkoxyaryl-C -C 6 -alkyl where R 8 and R 9 are independently selected from C -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. 3. A compound according to claim 2 wherein R I is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with CI-C 6 alkyl, Ci-C 6 alkoxy, C 6 -Clo aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, halogen; or S(O) -Ci-C 6 alkyl CI-C 6 alkoxyaryl or CI-C 6 alkoxyheteroaryl; A is -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, S...alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected 2.5 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 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 R 5 is H, C 7 -C 1 aroyl, C 2 -C 6 alkanoyl, C 1 to C 1 2 alkyl, C 2 to C 12 alkenyl, C 2 -C 1 2 alkynyl, F, Cl, Br, I, CN, CHO, Ci-C 6 alkoxy, aryloxy, heteroaryloxy, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 1 -C 6 alkylamino-Ci-C 6 alkoxy, CI-C 2 alkylene ACY-33311-02-C1 AU 08.11.02 -178- dioxy, aryloxy-Ci-C 6 alkyl amine, C 1 -C 12 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n- aryl where n is 0, 1 or 2; OCOO Ci-C 6 alkyl, OCOOaryl, 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 SO2NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 -CI-C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C-C 6 alkyl, CONHSO 2 aryl, NH 2 OH, aryl, heteroaryl, C 3 to C 8 cycloalkyl; saturated or unsaturated 5 to membered mono or bicyclic heterocycle containing one 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 groups selected from halogen, cyano, amino, nitro, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; R 6 is H, Ci to C 1 8 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 'i: 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 -C 6 alkyl, Ci-C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 1 1 aroyl, C 2 -C 6 alkanoyl, C 1 -C 1 2 perfluoro alkyl, S(O)n-alkyl, S(O)n- S. 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, CONHS02alkyl, CONHSO 2 aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from 25 halogen, cyano, amino, nitro, C -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-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 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 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 ACY-3331 1-02-Cl AU 08.11.02
179- or 2 heteroatoms selected from 0, 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 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 selected from 0, S or NR-C I-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 R 8 R 9 N-C 1-C 6 -alkoxyarylCI Cc 6 -alkyl where R 8 and R 9 are independently selected from C 1 I-C 6 alkyl or R 8 and R 9 together with the interposed nitrogen formns 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. 4. A compound selected from: I bny--4mtoybneeufnl-ielie4croyi acid hydroxyamlide, 4 4 -methoxy-benzenesulfonyl) 1 -methoxy-benzyl)-piperidine-4carboxylic acid hydroxyamide, :1 4 -dichlorobenzyl)4(-methoxybenzenesulfonyl-pipefidine-4carboxylic acid -hydroxamide, 4 4 -methoxy-benzenesulfonyl). 1-( 4 -methylbenzyl)-piperidine-4carboxylic acid hydroxamide, 4 4 -methoxy-benzene-sulfonyl)- 1 -napthalene- 2 -yl-methylpipefidine4carboxylic acid hydroxamide, I -biphenyl- 4 -ylmethyl-4(4-methoxy-benzenesul fonyl)piperidine-4-carboxylic acid hydroxamide, 4 4 -methoxy-benzene-sulfonyl) 1 -methyl-but-2-enyl)piperidine4carboxylic acid hydroxamide, 1-4boobny)4(-ehx-ezeeufnl-ieiie4croyi acid hydroxyamide, 4 -(4-methoxy-benzenesul fonyl)- 1-[4-(2-piperidin- 1-yl-ethoxy)-benzyl]-piperidine-4- carboxylic acid hydroxyamide, l-benzyl- 4 4 benzyloxybenzenesulfonyl-piperidine4carboxylic acid hydroxyamide, 4 4 -butoxy-benzenesulfonyl) 1 -[4-(2-piperidin- 1-yl-ethoxy)-benzyl] -piperidine-4 ACY-333 11-02-Cl AU 08.11.02 180 carboxylic acid hydroxyamide, 4 4 -butoxy-benzenesulfonyl)- 1-[3 -(2-morpholinyl- 1-yl-ethoxy)-benzyl]-piperidine-4 carboxylic acid hydroxyamide, l-methyl- 4 4 -butoxy-benzenesulfonyl)>piperidine-4carboxylic acid hydroxyamide, 1l-ethyl- 4 4 -butoxy-benzenesulfony)piperidine-4carboxyic acid hydroxyamide, 1--uy--4btx-eznslfnl-ieiie4croyi acid hydroxyamide, 4 4 4 -chloro-phenoxy)-benzenesulfonyl]l1-methyl-piperidine-4-carboxylic acid' hydroxyamide, 4 4 4 -chloro-phenoxy)-benzenesulfonyl] I -ethyl-piperidine-4-carboxylic acid hydroxyamide, l-butyl- 4 4 4 chorophenoxy-benzenesufony]piperidine-4carboxylic acid hydroxyamide, -benzyl- 4 4 (4chlorophenoxy)benzenesulfonyl]pipeidie4cablic acid hydroxyamide, 45 1 -benzyl-4-[4-(3 -methyl-butoxy)-benzenesulfony]piperidine-4carboxylic acid hydroxyamide, I. -butyl- 4 4 -(3-methyl-butoxy)-benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide, I -benzyl-4-[4-(2-ethy1-butoxy)-benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide, 4 4 -butoxy-benzenesulfonyl)- 1-(3 -methoxy-benzyl)-piperidine-4carboxylic acid :hydroxyamide, 4 4 -methoxy-benzenesulfonyl) 1 4 -thiophen- 2 -yl-benzyl)-piperidine4carboxylic acid hydroxyamide, 4 -(4-methoxy-benzenesulfonyl) 1 4 -pyridin- 2 -yl-benzyl)-piperidine.4-carboxylic acid hydroxyamide, 1 4 -dichlorobenzyl)-4-(4butoxybenzenesulfony)>piperidine-4carboxylic acid hydroxyamide, 4 4 -chloro-benzyloxy)-benzenesulfonyl] -I -methylpiperidine-4-carboxylic acid hydroxamide, 4 -(4-butoxy-benzenesul fonyl)- 1-(3 -phenoxy-benzyl)-piperidine-4carboxylic acid hydroxainide, 4 4 -chloro-benzyloxy)-benzenesulfonyl]y I-( 4 -methylbenzyl)-piperidine-4-carboxylic acid hydroxamide, 4 -(4-butoxy-benzenesul fonyl)- 1-( 4 -methylbenzyl)-piperidine-4 carboxylic acid hydroxamide, 4 4 -butoxy-benzenesulfonyl)- 1-( 4 -cyano-benzyl)-piperidine4carboxylic acid hydroxamide ACY-3331 1-02-Cl AU 08.11.02 181 4 4 -Butoxy-benzenesulfonyl)- 1-pyridin- 4 -ylmethyl-piperidine-4carboxylic acid hydroxamide, 4 4 -methoxy-benzenesulfonyly 1 -phenyl-propyl)-piperidine-4carboxylic acid hydroxyamide, l-tert-butyl-4-(4-methoxybenzenesulfony)piperidine-4carboxylic acid hydroxyarnide, I-butyl- 4 4 -methoxy-benzenesulfony)piperidine-4carboxylic acid hydroxyamnide, I-cyclooctyl-4-(4-methoxybenzenesulfonyl)-piperidine-4carboxyic acid hydroxyamnide, I-ethylI- 4 4 -methoxy-benzenesul fony)piperidine4carboxyli c acid hydroxyarride, I-isopropyl-4-(4-methoxy-benzenesufony)piperidine-4carboxylic acid hydroxyamide, 1 -in ethyl 4 4 -rnethoxy-b enzenesu fony)p iperi d ine-4carbox y i c acid hydroxyamide, I -benizyI- 4 4 -butoxy-benzenesulfony)piperidine4carboxylic acid hydroxyamide, l-( 4 -fluoro-benzy1)-4-(4-methoxy-benzenesulfony)piperidine-4carboxylic acid hydroxyarnide, 1-( 4 -fluoro-benzyl)-4-(4butoxy-benzenesulfonyl)>piperidine-4carboxylic ai hydroxyamide, S 4 -(4-methoxy-beiizenesulfonyl)> I 4 -methoxy-benzyl)-piperidine-4carboxylic acid hydroxyamide, 4 4 -methoxy-benzenesulfonyl) -12-(4-methoxyphenyl)-ethyl] -piperidine-4-carboxylic acid hydroxyamide, 4 -(4-methoxy-benzenesulfonyly 1 2 -phenyl-ethyl)-piperidine-4-carboxylic acid hydrnbuoxyarenzee fny)I 4 -methoxy-benzyl)-piperidine-4carboxylic acid hydroxyamide, U. 4-(4-methoxy-benzenesul fonyl)- 1-(3 -phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4 4 -n-butoxy-benzenesulfonyl)- I-( 3 -phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide, 4 4 -methoxy-benzenesulfonyl) I 2 -phenoxy-ethyl)-piperidine-4carboxylic acid hydroxyamide, 4 4 -n-butoxy-benzenesulfonyl)- I 2 -phenoxy-ethyl)-piperidine-4carboxylic acid hydroxyamide, and 4 4 -methoxy-benzenesulfonyl)- 1 -[4-(2-piperidin- I -yI-ethoxy)-benzyl]-piperidine-4- carboxylic acid hydroxy amnide. or a pharmaceutically accceptable salt of any of these. ACY-33311-02-C1 AU 08.11.02
182- A method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula OH R1I^ OH *9 9 .9 9 wherein: R' 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 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 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 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 A is -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, 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 substituted with one or two groups selected independently from R 5 ACY-33311-02-C1 AU 08.11.02 -183- 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 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 R 5 is H, C 7 -C 1 aroyl, C 2 -C 6 alkanoyl, Cl to C 12 alkyl, C 2 to C 12 alkenyl, C 2 -Cl2 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, CI-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, CI-C 1 2 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO CI-C 6 alkyl, OCOaryl, OCONR 6 COOH, COO C -C 6 alkyl, C00aryl, 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 -CI-C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -CI-C 6 alkyl, CONHSO 2 aryl, Nl 2 OH, aryl, heteroaryl, C 3 to Cs cycloalkyl; or 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 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--C 6 alkyl, C 1 -C 6 alkoxy, or hydroxy; R6 is H, C 1 to Cs 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 NR7 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; and R 7 is C 7 -C 1 I aroyl, C 2 -C 6 alkanoyl, Ci-C 1 2 perfluoro alkyl, S(O)n-CI-C 6 -akyl, S(O)n- aryl where n is 0, 1 or 2; COO-CI-C 6 -alkyl, COOaryl, CONHR 6 CONR 6 R 6 CONHOH, SO 2 NR 6 R 6 SO 2 CF 3 SO2NHheteroaryl, SO2NHCOaryl, 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, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or ACY-33311-02-C1 AU 08.11.02 -184- bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N-C I-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 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 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from 0, 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 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 two groups selected independently from R 5 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-Ci-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or R 8 R 9 N-C -C6-alkoxyaryl-C1 -C 6 -alkyl where R 8 and R 9 are independently 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; with the proviso that at least one ofR', R 2 R 3 R 4 R 5 and R 6 contains the group NR 7 wherein R 7 is a 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 or a pharmaceutically acceptable salt thereof. 6. A method according to claim 5 wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic ACY-33311-02-C1 AU 08.11.02
185- plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the 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 followiig 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, or periodontal disease. 7. A method according to claim 5 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. 8. A method of inhibiting pathological changes mediated by TNF-ao 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 *R 3 OH RI OH 0 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 2 5 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 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 ACY-33311-02-C1 AU 08.11.02 -186- or heteroaryl-(CH 2 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 A is -SO- or SO2-; 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 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 phenyl or naphthyl optionally substituted with one or two groups selected 1 independently from R 5 C 3 to C 8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups S* selected independently from R 5 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from 0, S or NR 7 optionally substituted with one or two groups selected independently from R 5 R 5 is H, C 7 -CI aroyl, C 2 -C 6 alkanoyl, C 1 to C 12 alkyl, C 2 to C 1 2 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, CI-C 6 alkoxyheteroaryl, Cl-C 6 alkylamino-C -C 6 alkoxy, C 1 -C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, C -C 12 25 perfluoro alkyl, S(O)n-C -C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO Ci-C 6 alkyl, OCOOaryl, OCONR 6 COOH, COO CI-C 6 alkyl, COOaryl, CONR 6 R 6 CONHOH, NR 6 R 6 S0 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 -CI-C 6 alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 -C 1 -C 6 alkyl, CONHS02aryl, 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 C 1 I-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, Ci-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; ACY-33311-02-C1 AU 08.11.02 -187- R 6 is H, Ci to C 1 8 alkyl optionally substituted with OH; C 3 to C 6 alkenyl, C 3 to C 6 alkynyl, Ci to C 6 perfluoro alkyl, S(O)n-Ci-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 or 2 groups selected from halogen, cyano, amino, nitro, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and R 7 is C 7 -C 1 aroyl, C 2 -C 6 alkanoyl, C -Ci 2 perfluoro alkyl, S(O)n-CI-C 6 -alkyl, S(O)n- aryl where n is 0, 1 or 2; COO-Ci-C 6 -alkyl, COOaryl, CONHR 6 CONR 6 R 6 CONHOH, SO 2 NR 6 R 6 SO 2 CF 3 SO2NHheteroaryl, 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, Ci-C 6 alkyl, Ci-C 6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or 1bicyclic 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 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 S. substituted with one or two groups selected independently from R 5 S.o 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 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 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-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or ACY-33311-02-C1 AU 08.11.02
188- RSR 9 N-CI-C6-alkoxyaryl-C -C 6 -alkyl where R 8 and R 9 are independently 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; with the proviso that at least one of R 2 R 3 R 4 R 5 and R 6 contains the group NR 7 wherein R 7 is a 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 or a pharmaceutically acceptable salt thereof i 9. The method according to claim 8 wherein the condition treated is rheumatoid arthritis, S graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, 1:5 congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula 03 R 4 *2 N OH wherein: R' 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 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 ACY-33311-02-C1 AU 08.11.02
189- 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 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 A is -SO- or S02-; 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 selected independently from R 5 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted o 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 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 2 two groups selected independently from Ri; R 5 is H, C 7 -Cll aroyl, C 2 -C 6 alkanoyl, C to C 1 2 alkyl, C 2 to Cl 2 alkenyl, C 2 -C 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, Ci-C 6 alkoxyaryl, CI-C 6 alkoxyheteroaryl, Ci-C 6 alkylamino-Ci-C 6 alkoxy, Ci-C 2 alkylene dioxy, aryloxy-C 1 -C 6 alkyl amine, CI-C 1 2 perfluoro alkyl, S(O)n-CI-C 6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO Ci-C 6 alkyl, OCOOaryl, OCONR 6 COOH, COO CI-C 6 alkyl, COOaryl, CONR 6 R 6 CONHOH, NR 6 R 6 S0 2 NR 6 R 6 NR 6 SO 2 aryl, -NR 6 CONR 6 R 6 NHS02CF 3 SO2NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 -CI-C 6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO 2 -Ci-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 NR 7 wherein CI-C 6 ACY-33311-02-C1 AU 08.11.02 -190- 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 substkuted by 1 or 2 groups selected from halogen, cyano, amino, nitro, Ci-C 6 alkyl, Ci-C 6 alkbxy, or hydroxy; R 6 is H, C 1 to C 1 s 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, 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, amino, nitro, CI-C 6 alkyl, CI-C 6 alkoxy, or hydroxy; and R 7 is C 7 -CI aroyl, C 2 -C 6 alkanoyl, Ci-C 1 2 perfluoro alkyl, S(O)n-Ci-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, SO 2 NHCOaryl, CONHSO-C -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, CI-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 S* 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 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally Ssubstituted 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 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 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl ACY-33311-02-C1 AU 08.11.02 191 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-CI-C 6 alkyl, optionally substituted with one or two groups selected independently from R 5 or R 8 R 9 N-CI-C 6 -alkoxyaryl-CiC6-alkyl where R 8 and R 9 are independently 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; with the proviso that at least one ofR', R 2 R 3 R 4 R 5 and R 6 contains the group NR 7 wherein R 7 is a 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 S or a pharmaceutically acceptable salt thereof 11. A hydroxyamide according to claim 1, substantially as hereinbefore described with reference to any one of the examples. 12. A method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically S effective amount of a matrix metalloproteinase inhibiting compound according to claim 11. "2 13. A method according to claim 12 wherein the condition treated is atherosclerosis, Satherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic S plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the 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 membranes, inflammatory bowel disease, or periodontal disease. 14. A method according to claim 12 wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ACY-33311-02-Cl AU 08.11.02 -192- ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection. 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 according to claim 11. 16. A method according to claim 15 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. 17. Use of a compound as claims in any one of claims 1 to 4 or 11 in the preparation of a medicament for inhibiting pathological changes mediated by matrix metalloproteinase or *1 TNF-a converting enzyme (TACE) in mammals. 18. Use of a compound as claimed in claim 17 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 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 S of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, S.23 inflammatory bowel disease, or periodontal disease. 19. Use of a compound as claimed in claim 17 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. Use of a compound as claimed in claim 17 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. 193 Dated 12 December, 2002 American Cyanamid Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON too* to. s00*0 [R:\LIBFF] 10871 specidoc:njc