CA2244903C - Hydroxamic acid derivatives for use with the treatment of diseases related to connective tissue degradation - Google Patents

Abstract

The present invention provides novel hydroxamic acid derivatives represented by the compound of formula (I), or pharmaceutical acceptable salts thereof, wherein the compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, including collagenase, stromelysin, and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthrits, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation.

Description

HYDROXAMIC ACID DERIVATIVES FOR USE WTTH THE TREATMENT OF DISEASES RELATED
TO CONNECTIVE TTSSUE DEGRADATTON

FIELD OF THE INVENTION
The present invention relates to novel hydroxamic acid derivatives or pharmaceutically acceptable salts thereof, their preparation, and pharmaceutical compositions containing them. Particularly, the present invention relates to hydroxamic acid derivatives substituted by a series of 2-pyrrolidinones, hydanti~ons, and pyrazolidinones, which are useful in the treatment of diseases related to connective tissue degradation.
BACKGROUND OF THE INVENTION
Loss of connective tissue integrity occurs in many disease processes, including osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth) periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation. Although there is a high incidence of these diseases in the developed world, there is no treatment that prevents the tissue damage that occurs. Considerable lines of scientific evidence indicate that uncontrolled connective matrix metalloproteinase (MMPs) actavity is responsible for the damage, and as a consequence the inhibition of these enzymes has become the target for therapeutic intervention (see Matrisian, L. M., Bases, Vol. 14, pp 445--463, (1992); Emonard, H. et al., Cellular and molecular Biology, Vol. 36, pp 131-153, (1990); Docherty, A. J. P. et ai., Annals of the Rheumatic, Vol. 49, pp 469-479, ( 1990)).
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, including collagenase, stromelysin, and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to coanective tissue degradation. These compounds may also inhibit the release of cytokines including tumor necrosis factor (TNFa) and hence may also be useful in the treatment of inflammation, fever, acute infections and shock.

INFORMATION DISCLOSURE
International Publication No. W095/0984i discloses new hydroxamic acid derivatives of amino acid amide compounds useful as TNF release and matrix metalloprotease inhibitors, e.g., for treating inflammation, fever or arthritis.
International Publication No. W095/04033-A1 discloses new succinimide derivatives useful as gelatinase and collagenase inhibitors.
International Publication No. W093/21942 discloses matrix metallo protease inhibitors for promoting tumour regression by inhibiting cancer cell proliferation and angiogenesis, atherosclerosis, ovarian carcinoma, melanoma and sarcoma.
European Patent Publication 0,574,758A discloses new hydroxamic acid derivatives useful as collagenase inhibitors for the treatment of arthritis, tumours, atherosclerosis, etc.
UK Patent Application GB2,282,598A discloses hydroxysuccinyl hydroxyamines useful in the prophylaxis or treatment of diseases or conditions mediated by metalloproteinases and/or tumour necrosis factor.
SZmIiMARY OF THE INVENTION
The present invention provides novel hydroxamic acid derivatives represented by the formula I:
H Rio R
N
HO~
X
O O N~
Ra Rs I
or pharmaceutical acceptable salts thereof wherein X is a) -(CH2)-, b) -NR5-, or c) -C(=O)-;
Y is a) -(CH2)-, or b) -NR5-;
with the proviso that when X is -NR5- then Y is -(CH2)-;

WO 97!32846 PCT/CTS97/02568 Ri is a) H, b) C1-2o ~yh c) -{CH2)i Aryl, d) -(CH2)i -O-R5, e) -(CH2)i -Het, -(CH2)i -C02 R5~

g) -{CH2)I -C{=O)NHRS, h) -(CH2)i -NR.~R.~, IO i) -{CH2)i -S02 Aryl, j) -{CH2)j cycloalkyl, or k) -(CH~)j Aryl Aryh R2 is a) H, b) CI_2o alkyl, c) -(CH2)j -R8, d) -(CH2)j -ORS, e) -CHCRS=CR5R5, t? -NHR5, g) -(CH2)jNRgRq, h) -NHS02Rb, i) -(CH2)j -C(=O)NR,6R7, j) -(CH2)~ -NR.~C{=O)R~, k) -(CH2)j-NR5S02R5, or 1) -(CH2)~ -N{COR~)2;

R3 is a) H, b) C1-s alkyh c) _(CH2)j -~'Yh d) -(CH2)~ -Het, e) -(CH2)j -C3_6 cycloalkyl, or f~ -C{=O)NHR5;

' R4 is a) H, b) -C{=O)NHRS, c) -C(=O)NR6R7, -3_ d) -C(=O)NH(CH2)~NRgR7, e) -C(=O)NH(CH2)3 -Aryl, f) -C(=O)NH(CH2)k-O-(CH2)kNR6R7, g) -C(=O)NH(CH2~-S-(CH2)~NR6R7, h) -C(=O)NH(CH2)k-NHSO2-Aryl, i) C(=O)NH(CH2)k-NHSO2-NRgRq, or J) -.N~~N-RS

R5 is a) H, b) CI-6 alkyl, c) -(CH2)~ -Aryl, d) -(CH2)~ -Ar~YI - Aryl e) -(CH2)~ Aryl -(CH2)~ -Aryl, f) (CH2)~ -Het, or g) -(CH2)~ -cycloalkyl Rs and R7 may be the same or differently a) H, b) C1_6 alkyl, c) -(CH2)~ Aryl, d) Q, or e) R6 and R7 taken together with the linking N-atom form azetidinyl, pyrrolidinyl, piperazinyl, piperidinyi, or morpholinyl, optionally substituted with one or more C1~ alkyl;

R8 is a) -S-R5, b) -SO-R5, c) _S02_R5, d) -S-(CH2)~ -Het, e) -NHC02R5, fj piperidinyl, g) , ~ (Rg)~
~1) s ~ / ' I s a C~3 O R
1) ~ ~N / s N~
O~ Rs O
R
-~~N/ s ~RS
O Rs O
k) - H
O' 1) O (Rg)n - ~ ~ , or O
Il) .._N / (R9)n ;

R9 is a) halogen, b) C~_6 alkyl, c) -ORS, d) -NR5R5, e) -CONHRS, f) -S02NHR5, g) -NHSO~RS, h) -NO~, i) -C02R5, or J ) -CF3:
R14 is a) H, b) OH, c) ORS, d} NHRS, or e) -tCH2)~-ORS;
Aryl is phenyl, optionally substituted with one or more of the following:
a) halogen, b) C1-1~ alkyl, c) -ORS, d) -NR5R5, e) -CONHRS, fj -S02NF~,5, g) -NHSO2R5, h) -N02, i) -C02R5, or j) -CF3;
Het is a 5-, or 6-membered heteroaromatic moiety having one or more atoms selected from the group consisting of N, O, and S; .
Q is a saturated 5, or 6-membered heterocyclic moiety having 1-2 atoms selected .
from the group consisting of N, O, and S;
i is 1, 2, 3, 4, ~ or 6;
j is 0, i, 2, 3, or 4;
_g-WO 97/32846 PCT/iTS97/02568 k is 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
C1-6 ~3'h C1-lo~yl, or C1-2~alkyl in each of the above definitions, may be each and independently substituted with one to three halogen, hydroxy, or cyano;
and ' 5 with the proviso that when RI is methylbutyl R4 is other than H.
The present invention provides novel hydroxamic acid derivatives useful as preventatives and therapeutics for diseases related to connective tissue degradation.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum anal maximum number of carbon atoms in the moiety, i.e., the prefix Ci ~
defines the number of carbon atoms present from the integer "i" to the integer "j"
inclusive.
Thus, C1~ alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The terms "C 1-6 alkyl", "C 1-1~ alkyl" or "C 1-20 alkyl", refers to methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. and isomeric forms thereof, and preferably an alkyl group having 1 to 6 carbon atoms.
The Ci-6 alkyl group may optionally be substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, or -CN group such as, for example, fluoromethyl, difluoromethyl, fluoroethyl, cyanomethyl and the like.
The term "C3-g cycloalkyl" refers to cyciopropyl, cyclobutyl, cyclopentyi, cyclohexyl and isomeric forms thereof, and preferably an cycloalkyl group having 4 to 6 carbon atoms.
The term "halogen" refers to fluoro, chloro, bromo, or iodo, preferably ffuoro and chloro.
The term "Q" refers to a saturated 5-, or 8-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of nitrogen, oxygen, and sulfur forming such groups as, for example, dioxolane, imidazolidine, dithiolane, ogathiolane, oxazolidine, piperidinyl, piperazinyl, morpholino and thiomorpholino.
The term "Het" refers to a 5-, 6-membered heteroaromatic moiety having one or more atoms selected form the group consisting of nitrogen, oxygen, and sulfur forming such groups as, for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, ~.~-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3 pyrazinyl, 2-furanyl, 3-furanyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, I-pyrazolyl. A

preferred heteroaromatic ring within the definition is 2-thienyl and pyridyl.
Within the definition of the terms "Het", and "Q", the nitrogen atom forming the hetero rings may have a protective group such as an acetyl or hydroxyacetyl group.
The compounds of the present invention can be converted to their salts according to conventional methods.
The term "pharmaceutically acceptable salts" refers to salts useful for administering the compounds of this invention and these include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. Some of the compounds of this invention may form metal salts such as sodium, potassium, calcium and magnesium salts and these are embraced by the term "pharmaceutically acceptable salts".
I5 Certain of the hydroxamic acid derivatives of the present invention are preferred.
The preferred Rl substituent is methylpropyl.
The preferred R2 substituent is H, methyl, 2-(1,3-dihydro-I,3-dioxo-2H-isoindol-2 yl)ethyl, 2-(1,3-dihydro-I,3-dioxo-2H-naphthoisoindol-2-yl)ethyl, 2-(4,5,6,7,-tetrafluoro-i,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5,6,-dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-amino-1,3-dihydro-1,3-dioxo-2H-isoindol-yl)ethyl, 2-(4-vitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-vitro-I,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(4-fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(4,Z-diffuoro-1,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-fluoro-I,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(I,3-dihydro-1,3-dioxo-isoindol-2-yl)propyl, 2-{ 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl, 2-(2 thienylthio)propyl, or 2-(2-thienylthio)methyl.
The preferred R3 substituent is H, 2-methyipropyl, cyclohexylmethyl, benzyl, or phenyl.
The preferred R~ substituent is H or acetamide.
The preferred absolute configurations of the compounds claimed in the present invention are as represented in the structures II - VII. The absolute configurations are determined under the Cahn-Ingold-Prelog nomenclature system.
The compounds depicted in the Examples are racemic unless indicated otherwise by R or S to refer their optical activity. The pure enantiomers possess higher inhibitory activities. The racemic mixtures are useful in the same way and for the same -g_ purpose as the pure enantiomer; the difference is that more racemic material may be used to produce the same inhibitory effect. Optically pure material can be obtained '' by using chiral HPLC methods to provide the corresponding enantiomers as illustrated in Examples 2, 5, and 28. Optionally, optically pure materials can be ' S obtained chemically to provide the desired enantiomer as illustrated in Examples 29-34.
Depending on substituents, the compounds of this invention may exist ira geometric, optical and other isomeric forms and this invention embraces any of these isomers or enantiomers.
Particularly preferred compounds of this invention are as follows:
la) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1b) (3S)-N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, lc) N-Hydroxy-a-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1d) a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1e) (3S)-a-[2-( 1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, -l.f) a-[2-(1,3-Dihydro-I,3-dioxo-2H-naphthoisoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1g) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(4,5,6,7-tetraffuoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yi)ethyl]-3-pyrrolidineacetamide, 1h) a-[2-(5,6-Dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N
hydroxy-3-(2-methylgropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1i) a-[2-(5-Amino-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1j) N-Hydroxy-3-(2-methylpropyl)-a-[2-(4-vitro-1,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, ~ 1k) N-Hydroxy-3-(2-methylpropyl)-a-[2-(5-vitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1I) a-[2-(4-Fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, lm) a-[2-(4,7-Difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1n) a-[2-{5-Fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 10) a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl}propyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1p) a-[2-(1,3-Dihydro-I,3-dioxo-2H-isoindol-2-yl)methyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1q) N-Hydroxy-3-(2-methylgropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(2-thienylthio)ethyl]-3-pyrrolidineacetamide, 1r} N-Hydroxy-3-(2-methylprogyl)-2-oxo-1-(2-phenyiethyl)-a-[2-(2-thienylthio)propyl]-3-pyrrolidineacetamide, 1s) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a,-[2-(2-thienylthio)methyl]-3-pyrrolidineacetamide, 1t) N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 1u) N3-Hydroxy-N~-methyl-3-(2-methylpropyl)-2-oxo-al-(ghenylmethyl)-I,3-pyrrolidinediacetamide, 1v) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetamide, 1w) a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyi]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetamide, lx) N-Hydroxy-3-(2-methylprapyl)-2-oxo-1-(phenylmethyl)-a-[2-(4,5,6,7-tetrafluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide, 1y) 1-(3-Fluorophenyl)methyl)-a.-[2-{1,3-dihydro-1,3-dioxo-2H-isoindo1-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 1z) a3-[2-(I,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2a) N3-Hydroxy-Nl-methyl-3-(2-methylpropyl)-2-oxo-a3-[2-(4,5,6,7-tetraffuoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyl]-1,3-pyrrolidinediacetamide, 2b) [S-CR*, R*)]-N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-a1-(phenyimethyl)-1,3-pyrrolidinediacetamide, 2c} [S,R-(R*, R*)]-a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl}-1,3-pyrrolidinediacetamide, 2d) [S-(R*, R*)]-N3-Hydroxy-N~-methyl-3-(2-methylpropyl)-2-oxo-a~-(phenylmethyl)-I,3-pyrrolidinediacetamide, 2e) [S-(R*, R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-N~-(2-phenethyl)-a1-WO 97!32846 PCT/LTS97/02568 (phenylmethyl}-1,3-pyrrolidinediacetamide, 2f} [S-(R*, R*)]-N3-Hydroxy-N1-methyl-a~,3-bis (2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2g) [S-(R*, R*)]-al-(Cyclohexylmethyl)-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2h) [S-(R*, R*)]-N3-Hydroxy-Nl-methyl-3-(3-methylbutyl)-2-oxo-a1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2i) N-Hydroxy-3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2j) N-Hydroxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide, 2k) N-Hydroxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl).-4-imidazolidineacetamide, 2I) N-Hydroxyl-4-(2-methylpropyl)-5-oxo-1-(2-phenylethyl)-4-pyrazolidineacetamide monohydrochloride, 2m) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-Nl-phenyl-al-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2n) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-N1-(2-pyridinylmethyl)-I,3-pyrrolidinediacetamide, 20) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyi)-N~--(4-pyridinyl)-1,3-pyrrolidinediacetamide, 2p) [S-(R*,R*)] Nx-(4-Fluorophenyl} 1V3-hydroxy-3-(2-methylpropyl)-2-oxo-a1-(phenylmethyl}-1,3-pyrrolidinediacetamide, 2q) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-Nl-[I-(phenyimethyl)-4-piperdinyl]-1,3-gyrrolidinediacetamide, 2r) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-a1-(phenylmethyl)-N1-(4-piperdinyl)-1,3-pyrrolidinediacetamide, 2s) ~S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-N1-(4-pyridinyhnethyl)-I,3-pyrrolidinediacetamide, 2t) [S-(R*,R*)] N1-(4-Fluorophenylmethyl) 1V3-hydroxy-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyl)-I,3-pyrrolidinediacetamide, 2u) [S-(R*,R*)] N3-Hydroxy N~-methyl-3-(2-methylpropyl)-2-oxo-a~-(2-phenylethyl)-I,3-pyrrolidinediacetamide, 2v) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(2-phenylethyl)-Nl-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2w) [S-(R*,R*)] 1V3-Hydroxy-a1,3-bis(2-methylpropyl}-2-oxo NI-2-pyridinyl-WO 97!32846 PCT/US97/02568 I,3-pyrrolidinediacetamide, 2x) [S-(R*,R*)]-a1-Cyclohexyl IV3-hydroxy N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2y) [S-(R*,R*)]-a1-Cyclohexyl N3-hydroxy-3-(2-methylpropyl)-2-oxo N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 2z) [S-(R*,R*)]-3-(Cyclopentylmethyl) 1V3-hydroxy NI-methyl-2-oxo-a1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3a) CS-(R*,R*)]-3-(Cyclopentylmethyl)-N3-hydroxy N~-methyl-2-oxo-al-(phenylmethyi)-I, 3-pyrrolidinediacetamide, 3b) [3S-[1(R*),3R*(R*)]]-a3-[2-(Benzoylamino)ethyi] N3-hydroxy-Nl-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3c) [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-Nl-[2-(4-morphoiinyl)ethyl]-2-oxo-a 1-(phenylmethyl)- I, 3-pyrrolidinediacetamide, 3d) [S-(R*,R*)] N Hydroxy-3-(2-methylpropyl)-I-[2-(4-morpholinyl)-2-oxo-I-(phenylmethyl)ethyl]-2-oxo-3-pyrrolidineacetamide, 3e) [I(1S)-[1[R*(R*)], 3a,5a]]-1-[2-(3,5-Dimethyl-I-piperazinyl)-2-oxo-I-(phenylmethyl)ethyl] N hydroxy-3-(2-methylgropyl)-2-oxo-3-pyrrolidineacetamide, 3fl [S-(R*,R*)] N3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-Nl-2-pyridinyl-1,3-pyrrolidinediacetamide, 3g) [3S-[1(R*),3R*(R*)]]-a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] 1V3-hydroxy Nl-methyl-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyl)-I,3-pyrrolidinediacetamide, 3h) [S-(R*,R*)]-al-Cyclohexyl NI-cyclopropylmethyl N3-hydroxy-3-(2-methylpropyl)-2-oxo-I, 3-pyrrolidinediacetamide, 3i) [S-(R*,R*)]-a1-Cyclohexyl N1-(4-fluorophenyl) 1V3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 3j) [S-(R*,R*)]-a~-tert-Butyl N3-hydroxy N1-methyl-3-(2-methylpropyl)-2-oxo-I,3-pyrrolidinediacetamide, 3k) N Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(5-propyloxy-I,3-dihydro-1,3-dioxo-2H-isoindol-2-y!)ethyl]-3-pyrrolidineacetamide, 31) [R.-(R*,S*)]-5-Fluoro-1,3-dihydro N-hydroxy-a-[3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyxxolidinyl]-1,3-dioxo-2H isoindole-2-butanamide, 3m) a-[2-(5,6-Difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] N
hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3n) N Hydroxy-3-(2-methylpropyi)-2-oxo-1-(2-phenylethyl)-a-[2-(5--WO 97!32846 PCT/(T897/02568 trifluoromethyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineaceta.mide, 30) a-[2-(1,3,4,5,6,7-Hexahydro-I,3-dioxo-2H-isoindol-2-yl)ethyl]-N
hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3p) a-[2-(I,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] N hydroxy-3-(2~-rnethylpropyl)-2-oxo-I-(3-phenylpropyl)-3-pyrrolidineacetamide, 3q) 1-[2-(4-Fluorophenyl)ethyl]-a-[2-(1,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 3r) a-[2-(o-benzoic sulftmi.de)ethyl] N hydroxy-3-(2-methyipropyl)-2-oxo-I-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3s) Ethyl Phenyimethyl [4-(hydroxyamino)-3-[3-(2-methyipropyi)-2-oxo-I-(2-phenylethyl)-3-pyrrolidinyl]-4-oxobutyl]imidodicarbonate, 3t) S-(R*,R*)]-I,3-Dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-i-(2-phenylethyl)-3-pyrrolidinyl]-I,3-dioxo-2H isoindole-2-butanamide, 3u) i,3-Dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-[2-(4-fluorophenyl)ethyl]-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 3v) a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3w) [R-(R*,S*)-a-[2-[(3-Fiuorobenzoyl)amino]ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3x) a-[2-[(4-Fluorobenzoyi)amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3y) N Hydroxy-3-(2-methylpropyl)-a-[2-[(3-nitrobenzoy!)amino]ethyl]-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 3z) a-[2-[(3-Fluorobenzoyi)amino]ethyl] N hydroxy-3-(2-methylpropyi)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 4a) a-[2-[(3-Fluorobenzoyl)amino]ethyl]-I-[2-(4-ffuorophenyl)ethyl] N
hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 4b) a-[2-[(4-Biphenylcarbonyl)amino]ethyl] N hydroxy-3-(2-methyipropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 4c) N Hydroxy-a.-[2-[[(4-methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 4d) a-[2-[[(4-Fluorophenyl)sulfonyi]amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 4e) N Hydroxy-a-[2-[[(4-methoxyphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide, 4f) N Hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-a-[2-[(phenylsulfonyl)amino]ethyl]-3-pyrrolidineacetamide, 4g) [R-(R*,S*)]-a-[2-[[(4-Fluorophenyl)sulfonyl]amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4h) 5,6-Difluoro-I,3-dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidinyl]-I-oxo-2H isoindole-2-butanamide, 4i) 1,3-Dihydro N-hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl)-1-oxo-2H isoindole-2-butanamide, 4j) [R-(R*,S*)]-6-Fluoro-I,3-dihydro-N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-I-oxo-2I~ isoindole-2-butanamide, 4k) [R-(R*,S*)]-5-Fluoro-1,3-dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H isoindole-2-butanamide, 41) [R-(R*,S*)J-5,6-Difluoro-1,3-dihydro-.N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-I-oxo-2H-isoindole-2-butanamide, 4m) N Hydroxy-a-[[[(4-methoxyphenyl)sulfonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenyiethyl)-3-pyrrolidineacetamide (aR-diastereomer), 4n) N Hydroxy-a-[[[(4-methoxyphenyl)suifonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (aS-diastereomer), 40) a-[[(4-Fluorophenyl)sulfonyl]amino] 1V hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide (R-diastereomer), 4p) a-[[(4-Fluorophenyl)sulfonyl]amino] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (aS-diastereomer), 4q) a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N hydroxy-3-(3-hydroxypropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide, 4r) a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N hydroxy-3-(2-hydroxyethyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide, 4s) [R-(R*,S*)]-a-[2-[(3-Fluorobenzoyl)amino]ethyl] N-hydroxy-3-(3-hydroxypropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide, 4t) S-(R*,R*)] 1V3-hydroxy NI-methyl-aI-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 4u) [S-(R*,ft*)] NI-cyclopropy11Y3-hydroxy-aI-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-I,3-pyrrolidinediacetamide., 4v) [S-(R*,R*)] 1V3-hydroxy-aI-(I-meth.ylethyl)-3-(2-methylpropyl)-2-oxo-NI-phenyl-1,3-pyrrolidinediacetamide, 4w) [S-(R*,R*)] NI-(4-fluorophenyl) N3-hydroxy-aI-(I-methylethyl)-3-(2-methylpxopyl)-2-oxo-I,3-pyrrolidinediacetamide, 4x) [S-(R*,R*)J-N3-hydroxy-a~-(1-methylethyl)-3-(2-methyipropyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 4y) [S-(R*,R*)]-aI-tert-butyl N1-cyclogropyl N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 4z) [S-(R*,R*)]-aI-tert-butyl-.1V3-hydroxy-3-(2-methylpropyl)-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide, 5a) [S-(R*,R*)]-a1-tert-butyl Nl-(4-fluorophenyl) N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 5b) [S-(R*,R*)]-a1-tent-butyl N'3-hydroxy-3-(2-methylpropyl)-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6c) [S-(R*,.R*)]-al-cyclohexyl N3-hydroxy-3-(2-methylpropyl)-2-oxo N~-phenyl-1,3-pyrrolidinediacetamide, 5d) [S-(R*,R*)]-al-cyclohexyl-.N3-hydroxy-3-{2-methylpropyl)-2-oxo Nx-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 5e) [S-(R*,R*)]-3-(cyclopentylmethyl) 1V3-hydroxy NI-methyl-a1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5~ [S-(R*,R*)]-3-(cyciopentylmethyl) lV1-cyclopropyl-1V3-hydroxy-al-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5g) [S-(R*,ft*)]-3-(cyclopentylmethyl) 1V3-hydroxy-a1-(1-methylethyi)-2-oxo-N~-phenyl-1,3-pyrrolidinediacetamide, 5h) [S-(R*,R*)]-3-(cyclogentylmethyl) N1-(4-ffuoroghenyl) N3-hydroxy-a1-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5i) [S-(R*,R*)]-3-(cyclopentyimethyl) 1V3-hydroxy-al-{1-methylethyl)-2-oxo-NI-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5j) [S-(R*,R*)]-a~-tert-butyl-3-(cyciopentylmethyl) N3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide, 5k) [S-(R*,R*)]-al-tert-butyl-3-(cyclopentyhnethyl) NZ-cyclopropyl 1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5I) [S-(R*,R*)]-al-tent-butyl-3-(cyclogentyimethyl) 1V3-hydroxy-2-oxo NI-phenyl-1,3-gyrrolidinediacetamide, 5m) [S-(R*,R*)]-aI-tert-butyl-3-(cyclopentylmethyl) Nl-(4-ffuorophenyl) N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5n) [S-(R*,R*)J-al-tent-butyl-3-(cyclopentylmethyl) N3-hydroxy-2-oxo Nl-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 50) [S-(R*,R*)]-al-cyclohexyl-3-(cyciopentylmethyl) N'3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide, 5p) [S-(R*,R*))-al-cyclohexyl-3-{cyclopentylmethyl) N1-cyclopropy11V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5q) [S-(R*,R*)]-al-cyclohexyi-3-(cyclopentylmethyl) 1V3-hydroxy-2-oxo N1-phenyl-1,3-pyrrolidinediacetamide, 5r) [S-(R*,R*)]-aI-cyclohexyl-3-(cyclopentyimethyl) Nl-(4-fluorophenyl) N3- ~
hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5s) [S-(R*,R*)J-a1-cyclohexyl-3-(cyclopentylmethyl) 1V3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5t) [S-(R*,R*)J 1V3-hydrnxy N~-methyl-a1-(I-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5u) [S-(R*,R*)) Nl-cyciopropyld~-hydroxy-a3-(I-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5v) [S-(R*,R*)] 1V3-hydroxy-a1-(1-methylethyl)-2-oxo Nl-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5w) [S-(R*,R*)1 N~-(4-fluorophenyl) 1V3-hydroxy-a1-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5x) [S-(R*,R*)] 1V3-hydroxy-al-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5y) [S-(R*,R*)]-al-tent-butyl N3-hydroxy Nl-methyl-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5z) [S-(R*,R*)]-ax-tert-butyl NI-cyclopropyl lV3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, Fa) [S-(R*,R*)7-a1-tert-buty11V3-hydroxy-2-oxo Nl-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6b) [S-(R*,R*)]-al-tert-butyl N;-(4-fluorophenyl) 1V3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6c) [S-<R*,R*))-al-tent-butyl N3-hydroxy-2-oxo-3-(3-phenylpropyl) NI-(4-pyridinyl)-1,3-pyrrolidinediacetamid, 6d) [S-(R*,R*)]-al-cyclohexyl IV3-hydroxy N1-methyl-2-oxa-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, fie) [S-(R*,R*)]-al-cyclohexyl Nl-cyciopropyl N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyzxolidinediacetamide, 6f7 [S-(R*,R*)]-ai-cyclohexyl N3-hydroxy-2-oxo Nx-phenyl-3-(3- t phenylpropyl)-1,3-pyrrolidinediacetamide, 6g) [S-(R*,R*)]-aI-cyclohexyl N1-{4-fluorophenyl) N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, WO 97!32846 PCT/US97/025~58 fih) [S-(R*,R*)]-a1-cyclohexyl 1V3-hydroxy-2-oxo-3-(3-phenylpropyl) Nv-(4-pyridinyi)-1,3-pyrrolidinediacetamide, 6i) [S-(R*,R*)J-3-I3-(~-fluorophenyl)propyl]-1V3-hydroxy N~-methyl-an-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6j) [S-(R*,R*)J Nl-cyclopropyl-3-[3-(4-fluorophenyi)propyl] 1V3-hydroxy-al-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6k) [S-(R*,R*)J-3-[3-(4-fluorophenyl)propyi] 1V3-hydroxy-al-(1-methylethyl)-2-oxo N1-phenyl-1,3-pyrrolidinediacetamide, 61) [S-(R*,R*)] Nl-(4-fluorophenyi)-3-[3-(4-fluorophenyl)propyi] 1V3-hydroxy-cc1-(1-methylethyl)-2-oxo-1,3-pyrrolidinedi.acetamide, 6m) IS-(R*,R*)]-3-[3-(4-fluorophenyl)propyl] 1V3-hydroxy-a1-(1-methyiethyl)-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6n) [S-(R*,R*)]-ai-tert-butyl-3-[3-(4-fluorophenyl)propyl] 1V3-hydroxy N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 60) [S-(R*,R*)]-al-tert-butyl Nl-cyclopropyl-3-[3-(4-fluorophenyi)propylJ-N3-hydroxy--2-oxo-1,3-pyrrolidinediacetamide, 6p) [S-(R*,R*)]-a1-tert-butyl-3-[3-(4-fluorophenyl)propyi] 1V3-hydroxy-2-oxo-NI-phenyl-I,3-pyrrolidinediacetamide, 6q) [S-(R*,R*)]-al-tent-butyl Nl-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-propyl] N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 6r) [S-(R*,R*)]-a~-tert-butyl-3-[3-(4-fluorophenyl)propyi] IV3-hydroxy-2-oxo-Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6s) [S-(R*,R*)]-al-cyclohexyl-3-[3-(4-fluorophenyl)propyl] 1V3-hydroxy N~-methyl-2-oxo-1,3-pyrrolidinediacetamide, 6t) [S-(R*,R*)]-al-cyclohexyl Nl-cycloprnpyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 6u) [S-(R*,R*)1-al-cyciohexyl-3-[3-(4-fluorophenyl)propyl] N3-hydroxy-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide, 6v) [S-(R*,R*)]-al-cyclohexyl N1-(4-fluorophenyi)-3-[3-(4-fluorophenyl)propyi] N3-hydroxy-2-oxo-1,3-gyrrolidinediacetamide, 6w) [S-(R*,R*)]-al-cyciohexyl-3-(3-(4-fluorophenyl)propyl] 1V3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, fix) [S-(R*,R*))-3-[3-(biphen-4-yl)propyl] lV~-hydroxy Nl-methyl-a1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6y) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl] N~-cyclopropyi lV3-hydroxy-a1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6z) [S-(R*,R*)7-3-[3-(biphen-4-yl)propyl] N3-hydroxy-ai--(1-methylethyl)-2-oxo N~-phenyl-1,3-pyrrolidinediacetamide, 7a) [S-(R*,R*)J-3-[3-(biphen-4-yl)propyl]-N1-(4-ffuorophenyl) 1V3-hydroxy-a1-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7b) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl] N3-hydroxy-ai-(1-methylethyl)-2-oxo Nl-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 7c) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-a1-tent-buty11V3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7d) [S-(R*,.R*)]-3-[3-(biphen-4-yI)propyl]-a1-tert-butyl Nl-cyclopropyl N3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide, 7e) [S-(R*,R*)]-3-[3-(biphen-4-yI)propyl]-ai-tert-butyl N3-hydroxy-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide, 7f~ [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-aI-tert-butyi Nl-(4-ffuorophenyl)-1V3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide, 7g) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-al-tent-butyl 1V3-hydroxy-2-oxo N~-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 7h) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyi]-a1-cyclohexyl-N3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7i) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-al-cyclohexyl N~-cyclopropyl lV3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, ?j) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-a~-cyclohexyllV'~-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 7k) [S-(R*,R*)]-3-L3-(biphen..4-yl)propyl]-a1-cyclohexyllVl-(4-fluorophenyl)-N3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide, 71) [S-(R*,R*)J-3-[3-(bipheri-4-yl)propyl]-oc.~-cyclohexyl N'3-hydroxy-2-oxo-Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7m) [S-(R*,R*)1-3-[3-(4'-ffuorobiphen-4-yl)propyl]-.1V3-hydroxy N~-methyl-al-( 1-methylethyl)-2-oxo-7., 3-pyrrolidinediacetamide, 7n) [S-(R*,R*)]-3-[3-(4'-ffuorobighen-4-yl)propyl] NZ-cyclopropyl 1V3-hydroxy-al-(1-methylethyl)-2-oxo-1,3-gyrrolidinediacetamide, 70) [S-(R*,R*)]-3-[3-(4'-ffuorobiphen-4-yI)propyl]-.1V3-hydroxy-al-(1-methylethyl)-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide, 7p) [S-(R*,R*)]-3-[3-(~'-fluorobiphen-4-yl)propyl] 111-(4-fluorophenyl) N3-hydroxy-a 1-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7q) [S-(R*,R*)]-3-I3-(4'-fluorobiphen-4-yl)propyl] N3-hydroxy-a1-(1-methyiethyl)-2-oxo N~-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7r) [S-(R*,R*)3-al-tert-butyl-3-[3-(4'-fluorobiphen-4-yl~ropylJ N3-hydroxy-N~-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7s) [S-(R*,R*)]-al-tent-butyl Nl-cyclopropyi-3-[3-(4'-fluorobiphen-4-yl)propyl] N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7t) [S-(R*,R*)J-a1-tent-butyl-3-[3-(4'-fluorobiphen-4-yl~ropyl] N3-hydroxy-2-oxo NI-phenyl-1,3-pyrrolidinediacetamide, 7u) [S-(R*,R*)J-al-tent-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl] Nl-(4-ffuorophenyl) 1V3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide, ?v) [S-(R*,R*)]-al-tent-butyl-3-[3-(4'-ffuorobiphen-4-yl)propyl] IV3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7w) [S-(R*,R*)]-a1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl] N3-hydroxy-N~-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7x) [S-(R*,R*)]-aI-cyclohexyl NI-cyclopropyl-3-[3-(4'-fluorobiphen-4-yl)propyl] N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7y) [S-(R*,R*)J-ai-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propylJ 1V~-hydroxy-2-oxo Nl-phenyl-I,3-pyrrolidinediacetamide, 7z) [S-(R*,R*)J-a.l-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl] Nl-(4-fluorophenyl) N'3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8a) [S-{R*,R*)J-a~-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl] 1V3-hydroxy-2-oxo N1-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 8b) Preparation of [S-(R*,R*)J-3-heptyl 1V3-hydroxy N~-methyl-al-(I-methylethyl)-2-oxo-I,3-pyrrolidinediacetamide, 8c) Preparation of [S-(R*,R*)] Nl-cyclopropyl-3-heptyl N3-hydroxy-al-(I-methylethyl)-2-oxo-I,3-pyrrolidinediacetamide, 8d) Preparation of [S-(R*,R*)J-3-heptyl N3-hydroxy-al-(1-methylethyl)-2-oxo N~-phenyl-1,3-pyrrolidinediacetamide, 8e) Preparation of [S-(R*,R*)]-3-heptyl N~-(4-#luorophenyl) 1V3-hydroxy-al-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, Sf) Preparation of [S-{R*,R*)J-3-heptyl N3-hydroxy-al-(1-methylethyl)-2-oxo N1-(4-pyridinyl)-I,3-pyrrolidinediacetamide, 8g) Preparation of [S-(R*,R*)]-al-tert-butyl-3-heptyl lY3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide, 8h) Preparation of [S-(R*,R*)]-a~-tert-butyl N1-cyclopropyl-3-heptyl N'3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8i) Preparation of [S-(R*,R*)]-a1-tent-butyl-3-heptyl N3-hydroxy-2-oxo 1V1-phenyl-1,3-pyrroiidinediacetamide, 8j) Preparation of [S-(R*,R*)J-a.1-tert-butyl Nl-(4-fluorophenyl)-3-heptyl-1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8k) Preparation of [S-(R*,.R*)]-a1-tert-butyl-3-heptyl N3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 81) Preparation of [S-(R*,R*)J-ocl-cyclohexyl-3-heptyl-1V3-hydroxy N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 8m) Preparation of [S-(R*,R*)3-al-cyclohexyl N~-cyclopropyl-3-heptyl N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8n) Preparation of (S-(R*,R*)]-a~-cyclohexyl-3-heptyl N3-hydroxy-2-oxo N~-phenyl-I,3-pyrrolidinediacetamide, 80) Preparation of [S-(R*,R*)]-al-cyclohexyl-3-heptyl Nr-(4-ffuorophenyl)-1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, and 8p) Preparation of [S-(R*,R*)l-aI-cyclohexyl-3-heptyl N'3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
Is The compounds represented by the general formula I can be prepared by the methods of reaction in Schemes A-D.
As shown in Scheme A-1, structure 2 is readily prepared from structure 1 (commercially available) according to the procedures described in J. Am. Chem.
Soc.
Vol. 75, 3679 (1953). Atkyiation of structure 2 requires an alkyl group (R1) attached to an appropriate leaving group. The alkylation occurs in the presence of a suitabie base such as lithium diisopropylamide (LDA) at a suitable temperature in the range -78 °C to 5 °C to provide structure 3. The ester side chain of structure 4 is introduced by aikylation of 3 with an alkyl (R' = C1-s alkyl) bromoacetate in the presence of a suitable base such as LDA in a suitable solvent such as tetrahydrofuran (THF), at a suitable temperature in the range -78 °C to 0 °C.
Hydrolysis of structure 4 by the procedures well known to one of ordinary skill in the art affords structure 5, which is then converted to the hydroxamate 6 by reaction of structure 5 with hydroxylamine hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) as an acid activating agent at a suitable temperature in the range -20 °C to 20 °C.
The reaction occurs in -the presence of a catalyst such as 1-hydroxybenzotriazole hydrate (HOBT) and an appropriate acid scavenger such as N-methylmorpholine in a suitable solvent such as DMF, CH2C12 or a mixture thereof . Alternatively, alkylation of structure 4 with a halide compound I-RZ (I is halogen, R2 is defined as above) by procedures well known to one of ordinary skill in the art affords structure 7. For example, alkylation of 4 with allyl bromide introduces an allyl group on the a-position of side chain using a suitable base such as LDA in a suitable solvent such as THF at a suitable temperature in the range -78 °C to 25 °C. The resultant allyl intermediate is then converted to the corresponding alcohol by ozonelysis and reduction NaB:Ei4 or by hydroboration with 9-BBN. In many cases the alcohols are converted to a phthalimide via the Mitsunobu protocol. Alternatively, the alcohol can be converted to a leaving group (such as Ms, Ts) which is subsequently displaced with the desired nucleophile such as SR, NR2, OR, etc. The remaining synthetic steps which leads structure 7 to structure 9 is similar to that described above.
A slightly di$'erent approach is employed to prepare 16 as shown in Scheme A-2, which incorporates a terminal amide R4 (R~ is as defined above, except R4 is not hydrogen). Alkylation of commercially available 10 affords lactam 11 according to the procedures described in Fisher, M. J. and Overman, L. E., J. Org.
Chem., Vol.
55, pp 1447-1459 (1990). Lactam 1I is reacted with allyl bromide to provide 12.
I5 The yields for this reaction are generally quite high. Alkylation of 12 with ethyl bromoacetate provides ester 13. Structure 13 is then converted to the corresponding amide I4, which followed by oxidation with ruthenium tetroxide in a solvent mixture such as carbontetrachloride, water, and acetonitrile at room temperature affords pyrrolidineacetic acid 15. The step which leads from structure 15 to structure 16 is similar to that described above in Scheme A-1.
Scheme A-3 illustrates another method for preparing the compounds of formula I. As shown in Scheme A-3, reaction of structure 10 with di-tert-butyl dicarbonante in the presence of DMAP provided protected lactam 17. Alkylatio~a of 17 with alkyl or alkenyl halides in the presence of HMPA provides lactam 1$.
The ester side chain of structure 19 is introduced by alkylation of 18 with alkyl bromoacetate as described in Scheme A-1. Structure 19 can then be deprotected using magnesium methoxide in a suitable solvent according the procedure described in Tetrahedron Lett. Vol. 35, p 847 (1994) to provide structure 20.
Alteratively, alkylation of I9 with a halide compound I-R2 by procedures well known to one of ordinary skill in the art affords structure 21. Deprotection of structure 2I
affords structure 22. The R substituent can be introduced directly by N-alkylation of 2~D or 22 with a desired halide compound using a suitable base such as sodium hydride in ' a suitable solvent such as THF or DMF to provide structures 4 or 7, respectively.
If desired, lactam 20 and 22 can be resolved using chiral HPLC or chemical methods to provide the corresponding enantiomers as illustrated in Examples 2 and 28. Each antipode can be converted to the appropriate chiral analogs 20a and 22a as shown in Scheme A-4. Lactam 20 and 22, either as the racemate or a single enantiomer, are used in the alkylation steps as described in Schemes A-3 and A-4.
As shown in scheme A-4, the alkylation of lactam 20a or 22a with the tri.flate affords 24 and 28, respectively. For simplicity, only a single antipode of 20a or 22a "
and triflate 23 are presented. This chemistry can be carried out for both the racemate or a single enantiomer. Triflate 23 can be prepared following the procedure described in J. Org. Chem. Vol. 58, pp 2725-2737 (1993). A preferred approach to provide 24 involves deprotonation of 20a with a suitable base such as IO sodium hydride in a suitable solvent such as THF at a temperature in the range 20°C to 15 °C, followed by the addition of triflate 25. Warming to ambient temperature affords desired structure 24. If racemate 20 is utilized the diastereomers can be separated at this stage by silica gel chromatography or HPLC.
Hydrolysis of the methyl ester 24 with aqueous NaOH provide 25, which following the formation of an amide by the procedure outlined in Scheme A-3, affords 26.
The remaining synthetic steps which lead from structure 26 to structure 27 are similar to that described i.n Scheme A-1. In a similar fashion, the compounds represented by structure 31 are prepared.
Alternatively, an enantiospecific method can by employed to prepare a single antipode as shown in Scheme A-5. Alkylation of commercially available compound 32 requires an alkyl or allyl (RI) attached to a leaving group in the presence of a suitable base such as lithium diisopropylamide (LDA) provides structure 33 as a mixture of diastereoisomers at the C-3 position of the ring. The mixture is alkylated with allyl bromide to provide 34 in optically pure form as shown in A-5. The trityl group is removed with TFA to provide 35, which is converted to Iactol 36 following the protocol described in J. Chem. Soc. C.C. pp 1119-1122 (1989). The key cyclization step is effected quite simply by reaction of the iactol 36 with an amine 37 in the presence of sodium cyanoborohydride followed by heating the crude uncyclized intermediate at reflex in toluene to provide 38 as a single isomer. Amine 37 can be prepared thxough the conversion of a commercial available L-, or D-amino acid to the corresponding amine by procedures well known to one of ordinary skill in the art. Following the chemistry outlined in Schemes A-2, the olefin is oxidized with ruthenium tetroxide to provide 39, which is coupled with O-benzylhydroxylamine hydrochloride (CDI, THF) and then deprotected by hydrogenation with palladium on carbon to provide 41.

A series of other ring system are synthesized as shown in Schemes B-E.
Scheme B illustrates a method for preparing 2,5-dioxo pyrrolidines. Exhaustive ' ruthenium tetroxide oxydation of 4 in the presence of sodium periodate in the suitable solvent such as water/acetonitrile%arbontetrachioride at an ambient ' S temperature provides 42. In a similar fashion as described in Scheme A-1, hydroxamate 43 is prepared.
Two different synthetic routes are developed for the synthesis of the hydantoin analogs as shown in Schemes C-1 and C-2. in Scheme C-1, N-alkylation of 1-methy3hydantoin 44 with 2-bromoethylbenaene occurs in the presence of a suitable base such as sodium hydride, in a suitable solvent such as DMF, at the temperature in the range -20°C to 15 °C. Following C-alkylation with a halide compound in the presence of a suitable base such as LDA at the temperature in the range -78°C to 15 °C affords 46. Formation of the quaternary center through C-alkylation with an alkyl bromoacetate in the presence of a suitable base such as i5 LDA at the temperature in the range -78°C to 15 °C affords 47. Conversion of 47 to the hydroxamate 48 is conducted following the previously outlined procedures.
An alternative approach is developed for the synthesis of the unsubstituted (I-H) hydantoin analog of 48. Amino acid 49 can be prepared according to the procedures described in Dellaria, J. F., J. ORG. Chem. Vol. 53, p 5607 (1988). Following the general procedure of Van der Veen, J.M. at e1. J. C. S. Perkin II pp 653-658 (1979), amino acid 49 is reacted with an appropriate substituted isocyanate followed by cyclization under acidic conditions to provide hydantoin 50. The remaining synthetic steps which lead to structure 52 are similar to that described previously.
Scheme D illustrates an approach into a pyrazolidinone ring system.
Protection of pyrrazolidinone 53 by the procedures described in Perri, S. T.
at e1., J.
Org. Chem., Voi. 55, pp 6037-6047 (1990) provides 54. Following N-alkylation and C-alkylations as outlined previously, lead to structure 57. An atmosphere of hydrogen is placed over a mixture of 57 and Pearlman's catalyst in a suitable solvent such as MeOH at ambient temperature to afford the desired compound 58.
The pharmaceutical compositions of this invention may be prepared by ' combining the compounds of formula I of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically ° acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be at least one substance which may WO 97!32846 PCT/US97/02568 also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, -dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions.
For example, there may be provided solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula I according to this invention.
The quantity of active component, that is the compounds of formula I
according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.
Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
Tn therapeutic use for treating a patient, suffering from or susceptible to a diseases involving connective tissue degradation, or inhibiting various enzymes from the matrix metalloproteinase family, including collagenase, stromeiysin, and gelatinase, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the patient undergoing treatment which will be effective to inhibit such enzymes.
Generally, an effective amount of the active compound will be in the range of about 0.1 to about 100 mg/kg. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of connective tissue degradation being treated, and the particular compounds being used. A.iso, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.

WO 97/32846 PCTlUS97/02568 The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, including collagenase, stromelysin, and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, and other diseases related to connective tissue degradation. Such diseases and conditions are well known and readily diagnosed by physician of ordinary skill.
These compounds may also inhibit the release of cytokines including tumor necrosis factor (T'NFa) and hence may also be useful in inflammation, fever, acute infections and shock. In general, the preferred form of administration is orally.
Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a I5 pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5-6. Suitable buffering agents include, for example, trzsodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few. The compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mI to about 400 mg/ml. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned inhibitory effective amount of dosage. The compounds of formula I
according to this invention are advantageously administered orally in solid and liquid dosage forms.
Inhibitory activity is evaluated in one or more of the MMP enzymes (stromelysin, gelatinase, and collagenase) in vitro using a particle concentration fluorescence techniques. An inhibitor binds to M1VIF' enzymes prevents the degradation of a substrate of stromelysin, gelatinase, or collagenase. The substrate is attached with a ffuorescein and a biotin. The intact substrate then binds to ,an ' avidin-coated particle via the biotin moiety. Once the particle is washed and dried, a fluorescent signal is generated since the fluorescent group is attached to the particle. Without an inhibitor present, the substrate is degraded by MMP
enzymes and the fluorescein group is removed, therefore, no fluorescent signal can be detected. Testing compounds are dissolved in DMSO to the desired concentration, then the solutions are diluted to 1:5 with NJMP buffer (50 mM Tris-HCl, pH
7.5; 150 mM NaCl; 0.02% NaN3). Serial two-fold dilutions of each compound are prepared.
A concentrated, activated enzyme solution is transferred into each plate of the testing compounds, and the mixture is incubated at room temperature for 15 ' minutes. Thawed MMl' substrate is then added into all plates, and the plates are incubate in the dark for 1-3 hours at room temperature. At this point, the substrate mixture is reacted with 0.1% avidin-coated polystyrene particles. After 15 minutes, the inhibitory activities are evaluated by Ki assay. Inhibitory data for the compounds of this invention are shown in TABLE I. Compounds with lower Ki value are expected to be more effective as MMP inhibitors. It is expected that a compound with a Ki less than 15 1zM against any one of the M1VI1"s will display therapeutic effects in connective tissue disorders.

NBVIP Inhibition Constants (Kj, ~zM) for Hydroxamie Acid Derivatives Stromelysin Gelatinase ~ Collagenase Example No. ~ (~) Example 1 27.2 3.55 2.3 Example 2 20.2 3.29 1.04 Example 3 10.86 11.68 4.23 Example 4 0.275 0.204 5.7 Example 5 0.041 0.115 4.37 Example 6 0.491 0.082 -Example 7 1.27 1.42 -Example 8 1.14 0.734 -Example 9 0.903 0.78 14.3 Example IO 6.04 WO 97!32846 PCT/US97/02568 Stromelysin Gelatinase ~ Collagenase _ Example No. ~ ~~~ ~ ~~~ Ey ~~~

y Example 11 1.02 0.498 0.073 Example 12 0.12 0.312 -Example 13 0.334 0.28 -Example 14 0.046 0.097 0.533 Example 15 0.188 0.782 21.3 Example 16 0.0924 2.87 14.2 Example 17 2.22 4.09 -Example 18 1.47 3.04 -Example 19 2.77 2.47 -Example 20 16.6 3.103 0.579 Example 21 2.08 0.049 0.022 Example 22 1.96 i.3 2.07 Example 23 4.19 1.56 0.453 Example 24 7 - -i5 Example 25 0.649 1.28 i.9 Example 26 0.713 0.998 -Example 27 11 16.5 -Example 29 0.57 0.981 0.484 Example 30 1.05 0.024 0.016 WO 97/32846 PCT/(TS97/02568 Stromeiysin Geiatinase ' Collagenase Example No. ~ (~) ~ (~) Example 31 0.517 0.0193 0.096 Example 32 0.73 0.05 0.036 Example 33 - - 0.031 Example 34 4.14 0.031 0.022 Example 35 3.12 - -Example 36 2.4 44 Example 37 4.74 - -Example 38 31.2 14.5 13.3 Example 39 0.101 0.0759 0.00581 Example 40 1.99 0.0105 0.037 Example 41 0.014 0.0023 0.0028 Example 42 0.0255 0.0054 0.00244 Example 43 1.8 0.0023 0.00236 Example 44 4 O.OI1 0.0202 Example 45 LO1 0.017 0.0235 Example 46 2.1 0.04 0.035 Example 47 0.868 0.0853 0,0815 Example 48 0.385 0,16 0.072 Example 49 0.138 0.061 0.085 WO 97/32846 PC'd'/US97/025~68 Stromelysin Gelatinase ' Collagenase Example No. ~ (~) ~ (~) ~ (~) Example 50 0.283 0.017 0.00606 Example 51 0.084 0.023 0.0422 Example 52 O.I87 0.0011 0.0013 Example 53 0.0105 0.00106 0.00069 Example 54 0.7 0.07 0.076 Example 55 1.9 0.2Ii 0.75 Example 56 2.3 0.34 0.925 Example 57 0.075 0.0095 0.012 Example 58 0.023 0.0029 -Example 59 0.23 0.011 fl.0033 Example 60 0.019 0.0123 0.018 Example 62 0.369 0.31 55 Example 63 0.058 0.032 1.5 Example 64 0.107 0.049 0.735 Example 65 1.05 0.227 0.51 Example 66 0.39 0.75 4.7 Example 67 0.216 0.036 5 Example 68 0.35 0.16 1.46 Example 69 0.214 0.498 1.2 Staromelysin Gelatinase Collagenase Example No. ~ (~) ~ t~) ~ (~) Example 70 O.I94 0.0522 L2 Example 71 - - 0.098 Example 72 0.64 0.083 0.039 Example 74 0.052 0.021 0.026 Example 75 0.295 0.264 0.074 Example 76 10.8 3.3 0.298 Example 77 0.146 0.0319 0.0685 Example 78 0.696 0.278 0.018 Example 79 0.038 0.00177 0.339 Example 81 0.273 1.4 5.6 Example 82 0.379 0.878 2.4 Example 83 0.107 0.58 17 Example 84 1.73 3 0.385 Example 85 O.I16 0.031 0.084 I5 Example 86 0.102 0.046 0.647 Example 87 0.091 0.00488 0.23 Example 88 0.288 0.062 0.326 Example 89 0.318 0.146 2.5 Example 90 1.77 0.624 0.052 Stromeiysin Gelatinase Collagenase Example No. ~ (~) ~ (~) Example 92 0.309 0.273 0.37 Example 93 2.08 L 1 0.098 Example 94 0.016 0.0012 0.0134 Example 95 0.119 0.013 0.025 Example 96 0.0087 0.00098 0.0127 In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following experimental examples are presented, but they should not be taken as limiting.

Example I Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
N
HO~

Step 1. Preparation of 1-(2-Phenylethyl)-2-pyrrolidinone.
Following the procedure of Boekelheide and Godfrey (J. Am. Chem. Soc. 1953, 75, 3679), y butyrolactone (50.0 mL, 650 mmol) and phenethylamine (85.0 mL, 67?
mmol) are heated in a sealed reaction vessel from room temperature to 200 °C over 2.5 hours, at 280-300 °C for 2 hours, and is allowed to cool to room temperature.
The reaction mixture is distilled (1.5 mm, 130-144 °C) to yield 107 g of the title compound which solidified upon standing (mp 50.5-52.5 °C).
IR (mineral oil) 3334, 3079, 3022, 1671, 1634, 1498, 1493, 1433, 1425, 1328, 1280, 1248, 1156, 759, 707 cni 1;
~H NMR (300 MHz, CDCl3) S 7.10-7.35, 3.53, 3.25, 2.84, 2.35, L8-2.0;
MS (EI) m !z I89, 104, 98, 70.
Step 2. Preparation of 3-(2-Methylpropyl)-I-(2-phenylethyl)-2-pyrrolidinone.
A solution of 1-(2-phenyiethyl)-2-pyrrolidinone (500 mg, 2.64 mmol) and THF
(6 mL) is cooled to -78 °C. Some precipitation occurred and 2 mL of THF
is added.
A solution of lithium diisopropylamide (LDA, 1.4 mL, 2.8 mmoi, 2.0 M in heptane/THF/ethylbenzene) is added and the mixture stirred at -78° C
for 40 minutes, giving a dark brown solution. To this solution is added 1-iodo-2-methylpropane (0.37 mL, 3.2 mmol). The solution is allowed to warm from -78 °C to 5 °C over 2.5 hours. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgS04) and purification by column chromatography (20%
EtOAc/hexane) to give 642 mg (99%) of the title compound as a white solid (mp 71 °C). .
IR, (mineral oil) 3032, 3002, 1665, 1632, 1499, 1441, I425, 1303, 1271, 1168, 772, 745, 704, 619 cm 1;
IH NMR (300 MHz, CDCl3) 8 7.I5-7.40, 3.40-3.65, 3.I0-3.20, 2.84, 2.35-2.45, 6 PCT/US97/025Cu8 2.05-2.2, 1.45-L80, 1.10-1.25, 0.93, 0.89;
MS (EI) m /z 245, 189, 154, 126, 98, 54.
Step 3. Preparation of tent-Butyl 3-(2-Methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
LDA (2.0 M, 11.5 mL, 23.0 mmol) is added to a solution of 3-(2-methylpropyl)-1-(2-phenylethyl)-2-pyrrolidinone (4.70 g, 19.2 mmol) and THF (80 mL) at -78 °C.
The solution is stirred at -78 °C for 45 minutes, and tent-butyl bromoacetate (3.4 mL, 23 mmol) is added. The solution is allowed to warm to 0 °C over 2 hours and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgS04) and purification by column chromatography (10% EtOAc/5% CH2Cl2/hexane) to give 4.67 g (68%) of the title compound as a colorless ail. An analytical sample is crystallized from hexane (mp 50 °C).
IR (liq.) 2957, 2930, 2870, 1'128, 1688, 1497, 1455, 1444, 1429, 1367, 1347, 1278, 1258, 1156, 701 cni 1;
~H NMR (300 MHz, CDC13) b 7.15-7.35, 3.6-3.75, 3.35-3.5, 3.15-3.25, 2.85, 2.43, 2.05-2.2, 1.9-2.0, 1.55-1.7, 1.35-i.5, 1.42, 0.88, 0.86;
MS (EI) m/z 359, 303, 286, 268, 247, 212, I84, 166, 156, 138, 105.
Step 4. Preparation of 3-(2-Methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetic Acid.
A solution of tent-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (659 mg, 1.83 mmol), trifluoroacetic acid (6.5 mL) and CH2Ci2 (6.5 mL) is stirred at room temperature for 1 hour. The solution is concentrated from CH2C12 (3 x 50 mL), dissolved in I N NaOH (I0 mL), and the basic layer is extracted with Et20 (2 x 25 mL). The pH of the basic layer is adjusted to pH 1 with 6 N HCI. The acidic layer is extracted with CH2C12 (2 x 25 mL), the combined CH2Cl2 layers dried (MgS04), filtered and concentrated to give 511 mg (92%} of the title compound as a colorless oil.
IR (mineral oil) 3065, 3029, 1738, 1647, 1497, 1440, 1304, 1213, I183, 1171, I152, 1I12, 756, ?33, 701 cm 1;
- 1H NMR (300 MHz, CDCl3) 8 7.10-7.35, 3.50-3.70, 3.15-3.35, 2.89, 2.55, 2.05-2.15, 1.60-1.85, 1.57, 1.36, 0.91, 0.87;
MS (EI) m/z 303, 247, 213, 212, 184, 166, 156, 138, 105, 104.
Step 5. Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 451 mg, 2.35 mmol) is added to a solution of 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (595 mg, 1.96 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 281 mg, 2.08 mmol) and 4-methylmorpholine (0:26 mL, 2.4 mmol) in CH2C12 ( 19 mL) and DMF (4 mL) at 0 °C. The solution is stirred at 0 °C for 1 hour, and then a near solution of hydroxylamine hydrochloride (204 mg, 2.94 mmol) and 4-methylmorpholine (0.32 mL, 2.9 mmol) in DMF (2.? mL) is added. After stirring at room temperature overnight, the mixture is concentrated under high vacuum, and purified by column chromatography (3% MeOHJCH2Cl2). Crystallization from Et2Qlhexane provided 193 mg (31%) of the title compound as a white solid (mp 124 °C).
IR (mineral oil) 3205, 3071, 3026, 1664, 1638, 1496, 1353, 1316, 1296, 1283, 1271, 1078, 982, 751, ?05 crri 1;
1H.NMR (300 MHz, CDC13) 8 7.15-7.35, 3.55, 3.10-3.30, 2.84, 2.39, 1.85-2.20, 1.55-1.75, 1.50, 1.32, 0.88, 0.85;
MS (EI) m /z 318, 227, 21 i, 193, 182, 166, 154, 138, 110, 105.
EXAMPLE 2 Preparation of (3S)-N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl~3-pyrrolidineacetamide.
H
N~-., HO I ~~

Resolution of tent-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate. A solution of 50 mg/mL of racemic tent-butyl 3-(2-methylprnpyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3) is made in the mobile phase that consisted of 10% isopropanol in hexane (Vl~. Aliquots of 3.5 mL
rM
(175 mg) are injected onto a 2.1x25 cm Chiralgak AD column (Chiral technologies, Inc.). The column is eluted at 10 mL/min and monitored at 220 nm. The two enantiomers are collected using a peak recognition program and fractions are pooled appropriately. Each enantiomer is obtained at >99% ee. Enantiomeric excess is determined on a 0.46x25 cm Chiralpak AD column (Chiral Technologies, Tnc.), developed with the same solvent at 0.5 mLJmin and the monitor set at 220 nm.
The retention times here are I2.2 and 23.0 minutes (a = 2.61).
Following the general procedure outlined in EXAMPLE 1 (steps 4-5), and ' making non-critical variations but starting with (S)-tent-butyl 3-(2-methylpropyl)-2-oxo-I-{2-phenylethyl)-3-pyrrolidineacetate (the faster eluting enantiomer described ' S above), the title compound is obtained.
1H NMR {300 MHz, CDC13) b 7.I0-7.35, 3.40-3.70, 3.10-3.30, 2.75-2.95, 2.38, 1.15-2_20, 0.75-1.00.
EXAMPLE 3 Preparation of N-Hydroxy-a-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
to H H3C CHg N
HO~ ~C

O ~ N
15 w Step 1. Preparation of tert-Butyl a-Methyl-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate.
20 LDA (1.5 mL, 3.0 mmol, 2.0 M in heptane/THF/ethyibenzene) is added to a solution of tent-butyl 3-(2-methylpropyl)-2-oxo-I-{2-phenylethyl)-3-pyrrolidineacetate (967 mg, 2.69 mmol) and THF (I1.0 mL) at -78 °C. The solution is stirred at -78 °C
for 30 minutes and then iodomethane (0.19 mL, 3.1 mmol) is added. The solution is starred at -78 °C for 2 hours and then allowed to slowly warm to room temperature 25 overnight. Aqueous workug (EtOAc, MgS04) and purification by flash chromatography (1:1 hexane:EtOAc) gives 791 mg (79%) of the title compound as an oil.
IR. (iiq.) 2975, 2956, 2931, 2869, 1724, 1686, 1497, 1455, 1429, 1367, 1279, 1257, 1153, 1114, 700, cni 1;
30 1H NMR (300 MHz, CDCIg) 8 7.15-7.35, 3.60-3.75, 3.30-3.45, 3.25, 2.82, 2.65, 2.25-2.40, 1.50-1.80, 1.35-1.50, 1.40, 1.12, 0.86, 0.84;
M$ (El) m /z 373, 317, 300, 282, 26I, 227, 226, 152, 105, 104, 57.
Step 2. Preparation of a-Methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic Acid.
35 TFA ( 10.0 mL) is added to a solution of tert-butyl a-methyl-3-(2-methylgropyl)-2-oxo-1-{2-phenylethyl)-3-pyrrolidineacetate (780 mg, 2.09 mmol) and CH2C12 (10 mL) at 0 °C. The solution is stirred for 2.5 hours at 0 °C and 1.5 hours at room temperature. After concentration, the residue is partitioned between EtOAc and water. The organic layer is extracted several times with 10% NaOH, the combined basic layers acidified (4 N HCl), and the acidic layers extracted several times with CH2C12. The CH2C12 layers are dried (MgS04), filtered, and concentrated to provide 79 mg (12%) of the title compound as a white solid (mp 95 °C).
TR (mineral oil) 2400, 1731, 1616, 1505, 1497, 1488, 1443, 1354, 1326, 1289, 1266, 745, 736, 702, 607, ciri 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 3.65-3.85, 3.45-3.60, 3.20-3.40, 2.90, 2.59, 1.50-2.10, 1.06, 0.89, 0.85;
MS (E/) m /z 3I7, 261, 22?, 226, 216, 180, 152, 105, 104, 55.
Step 3. Preparation of N-Benzyloxy-a-methyl-3-(2-methylpropyl)-2-oxo-I-(2-phenyiethyl)-3-pyrrolidineacetamide.
CDI {39.7 mg, 0.245 mmol) is added to a solution of a-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (74.0 mg, 0.233 mmol) and CH2Cl2 (2.0 mL). The solution is stirred for 1 hour at room temperature.
To this is added O-benzylhydroxylamine~HC1 (63.2 mg, 0.396 mmol) and N-methylmorpholine (44 uL, 0.40 mmol). The resultant solution is stirred for 16 hours at room temperature. Aqueous workup (CH2C12, MgS04) and purification by flash chromatography (2:1 EtOAc:hexane) gives 88.1 mg {89%) of the title compound as an oil.
IR (iiq.) 3230, 3063, 3029, 2956, 2936, 2869, 1664, 1497, 1454, 1367, 1310, 1282, 1029, 748, 699 cm-~;
1H NMR (300 MHz, CDCl3) S 10.16, 7.10-7.45, 4.87, 3.35-3.60), 3.10-3.30, 2.81, 2.42, 2.10-2.30, 1.?5-1.90, i.35-1.70, 1.05, 0.85, 0.79;
MS (EI) rn /z 422, 300, 225, 196, 152, 105, 104, 91, 77, 69, 55.
Step 4. Preparation of N-Hydroxy-a-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
An. atmosphere of hydrogen is placed over a mixture of N-benzyloxy-a.-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide {80.0 mg, 0.189 mmol), MeOH (4.5 mL) and Pearlman's catalyst ( I5 mg). The mixture is stirred at room temperature for 4 hours. The mixture is filtered, the solids rinsed with MeOH (4 X 5 mL), and the filtrate concentrated to give 55.9 mg of an oil.
Crystallization from hexane provided 46.9 mg (75%) of the title compound as a white solid (mp 107-lob °C).
IR (mineral oil) 3227, 3044, 3026, I658, 1641, 1498, 1436, 1294, 1262, 1031, 774, 735, 713, 695, 611 cni ~;
MS (FAB) m /z 333, 332, 301, 300, 272, 105, 69, 55, 41.
EXAMPLE 4 Preparation of a-(2-(i,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyll-~.V-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

O N O CHs CHs HO~ ~C
ti O O N l I
Step 1. Preparation of tent-Butyl 3-(2-Methylpropyl)-2-oxo-1-(2-phenylethyl)-oc-(propen-2-yl)-3-pyrrolidineacetate.
LDA (2.0 M, 7.7 mL, 16 mmol) is added to a solution of tent-butyl 3-(2-methylpropyl)-2-oxo-I-(2-phenyiethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3;
4.62 g, 12.9 mmol) and THF (45 mL) at -78 °C. The solution is stirred at -78 °C for 45 minutes and allyl bromide ( 1.3 mL, 16 mmol) is added. The solution is allowed to warm to 0 °C over 2 hours, and is allowed to stir overnight at room temperature.
After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgS04) and purification by column chromatography (2:1:I7 v/v EtOAc:CH2C12:hexane) gives 4.43 g (86%) of the title compound as yellow oil which solidified upon standing (mp 54.5-56 °C).
IR, (mineral oil) 1712, 1686, 1641, 197, I432, 1298, 128I, 1270, 1250, 1237, 1205, 1155, 912, 752, 702, cxri 1;
1H NMR (300 MHz, CDCl3) 8 7.I5-7.35, 5.fi5-5.8, 4.95-5.1, 3.55-3.7, 3.3-3.45, 3.15-3.25, 2.82, 2.53, 2.2-2.5, 1.7-1.85, 1.5-1.65, L35-1.45, L40, 0.87, 0.83;
MS (EI) m /z 399,343, 326, 308, 253, 252, 234, 202, I05, 57.
Step 2. Preparation of tent-Butyl a-(2-Hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.

WO 97!32846 PCTILTS97/OZ568 Ozone is bubbled through a solution of tent-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-(propen-2-yl)-3-pyrrolidi.neacetate (555 mg, 1.39 mmol) and EtOH
( 12 mL) at -78 °C for 5 minutes. Nitrogen is then bubbled through the solution for 5 minutes. Sodium borohydride (79 mg, 2. l mmoD is added and the mixture is allowed to warm slowly and to stir at room temperature overnight. The mixture is -concentrated to near dryness, and aqueous workup (EtOAc, MgSOg) to give 511 mg (91%) of the title compound as a colorless oil.
IR (liq.) 2957, 2931, 2870, 1720, 1672, 1671, 1497, 1455, 1392, 1367, 1282, 1257, 1152, 1055, 701 cm I;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 3.55-3.75, 3.35-3.45, 3.15-3.25, 2.82, 2.61, 2.3-2.45, 1.85-2.0, 1.65-1.8, 1.35-1.60, 1.43, 0.87, 0.83;
MS (EI) m/z 403, 347, 330, 291, 270, 256, 238, 227, 202, 1$1, 105, 104.
Step 3. Preparation of tent-Butyl a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
Diethyl azodicarboxylate ( 182 uL, 1.16 mmoi) is added to a mixture of tert-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (468 mg, 1.16 mmol), triphenylphosphine (304 mg, 1.16 mmol), phthalimide (171 mg, 1. I6 mmol) and THF (10 mL) at room temperature. The mixture is allowed to stir avernight and is concentrated. Purification by column chromatography (2 columns, 5% acetone/CH2C12 and 10% EtOAclhexane) provided 327 mg (51%) of the title compound as a colorless oil.
IR. (liq.) 2956, 2932, 1773, 1716, 1685, 1467, 1454, 1438, 1397, 1368, 1299, 1255, 1152, 720, 701 cni 1;
1H NMR (300 MHz, CDC13) b 7.8-7.9, 7.65-7.75, 7.15-7.35, 3.55-3.8, 3.3-3.4, 3.15-3.25, 2.80, 2.51, 2.3-2.4, 2.0-2.15, 1.8-1.95, 1.6-1.8, 1.35-1.6, 1.46, 0.85, 0.82;
MS (EI) m/z 532, 476, 459, 441, 420, 385, 339, 311, 245, 202, 160, 105.
Step 4. Preparation of a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethylJ-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrroiidineacetic Acid.
Triffuoroacetic acid (2.0 mL) is added to a solution of tent-butyl a-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethylJ-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)- , 3-pyrrolidineacetate (282 mg, 0.507 mmol) in CH2Cl2 (4.0 mL) at 0 °C.
The solution is stirred for 1 hour at 0 °C. A second portion of trifluoroacetic acid (2.0 mL) is added, and the solution is stirred for 30 minutes at 0 °C and for 30 minutes at room temperature. Concentration and aqueous workup (CH2C12, MgS04) to give 217 mg (90%) of the title compound as a colorless oil.

IR, (mineral oil) 1711, 1606, 1509, 1498, 1485, 1445, 1403, 1359, 1295, 7.262, 1244, 1111, 704 cni 1;
' 1H NMR (300 MHz, CDCI3) 8 7.85-7.9, 7.7-7.8, 7.15, 6.9-7.0, 3.7-3.9, 3.55-3.65, 3.35-3.5, 3.25-3.35, 2.75-2.95, 2.49, 2.0-2.1, 1.80-1.95, 1.65-1.75, 1.5-1.65, 1.2-1.45, 0.91, 0.84;
MS (EI) m /z 476, 420, 385, 339, 31I, 272, 258, 202, 160, 105.
Step 5. Preparation of N-Benzyloxy-a-C2-(1,3-dihydro-1,3-dioxo-2H-isoind.ol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
CDi (82 mg, 0.51 mmol) is added to a solution of a-[2-(I,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (202 mg, 0.424 mmol) and CH2C12 (3.2 mL) at room temperature, and the solution is stirred for 1 hour at room temperature. O-Benzylhydroxylamine hydrochloride (98 mg, 0.614 mmol) and 4-methylmorpholine (84 uL, 0.76 mmol) are added in succession, and the solution is allowed to stir overnight at room temperature. Aqueous workup (CH2C12, MgS04) and purification by column chromatography (2% acetone/CH2C12) gives 120 mg (49%) of the title compound as a colorless oil.
IR. (mineral oil) 1773, I7I5, 1683, 1663, 1662, 1497, 1398, /340, 1301, 1270, 1038, 1030, 748, 699 cm: l;
1H NMR (300 MHz, CDC13) 8 7.8-7.9, 7.7-7.8, 7.05-7.55, 4.93, 3.55-3.8, 3.48, 3.1-3.2, 2.77, 2.15-2.3, 1.7-1.9, 1.35-1.65, 0.80, 0.73;
MS (FAB) m /z 582, 459, 431, 160, 105, 91.
Step 6. Preparation of a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidine-acetamide.
A mixture of N-benzyloxy-a-L2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (58 mg, 0.10 mmol) and 5% Pd/C (20 mg) is stirred for 1.5 hours at room temperature under an atmosphere of hydrogen. Palladium hydroxide on carbon (10 mg) is added and the mixture is stirred under hydrogen at room temperature for 6 hours. The mixl,-ure is filtered and the filtrate is concentrated. Purification by column chromatography (5%
MeOHIEtOAc) gives 39 mg of an oil which is crystallized from EtOAc/hexane to give 29 mg (59%) of the title compound as a white solid (mg I58-I59 °C).
IR. (mineral oil) 3212, 3101, 3087, 3005, 1773, 1711, 1659, 1495, 1444, 1401, 1310, 1292, 1040, 706 cm 1;

WO 97/32846 PCTlUS97/02568 1H NMR (300 MHz, CDC13) 8 10.19, 7.8-7.9, ?.7-7.8, ?.05-7.35, 6.9-7.0, 3.3-3.8, 3.19, 2.79, 2.39, 2.1-2.3, 1.75-2.0, 1.35-L7, 0.83, 0.76;
MS (EI) m /z 491, 459, 435, 419, 400, 375, 355, 327, 262, 261, 245, 202, 160, 105.
EXAMPLE 5 Preparation of (3S)-a-I2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyl]- "
N-hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetatnide.
/ \

HO~ ~C
O O N
Following the general procedure outlined in EXAMPLE 4, and making non-critical variations but starting with (S)-tent-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EX.AMPLE 2, faster eluting enantiomer), the title compound is obtained (mp 102-105 °C).
IR (mineral oii) 3546, 3172, 3087, 3064, 3024, 1770, 1717, 1665, 1497, 1434, 1407, 1303, 746, 725, 703 ciri 1;
IH NMR (300 MHz, CDC13) 8 7.80-7.90, 7.65-7.80, 7.05-7.35, 6.80, 3.25-3.80, 3.10-3.25, 2.79, 2.35-2.45, 2.10-2.30, 1.75-2.00, L30-1.75, 0.83, 0.76;
MS (EI) m /z 491, 459, 435, 431, 327, 262, 261, 244, 160, 105.
EX~LMPLE 6 Preparation of a-[2-(1,3-Dihydro-I,3-dioxo-2H-naphthoisoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

I
t HO~
Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-ono-I-(2-phenylethyl)-3-pyrrolidineacetate and 2,3-naphthalenedicarboximide, the title compound is obtained (mp 203-205 °C).
IR (mineral oil) 3216, 3061, 3028, 1767, 1703, 1662, 1515, 1497, 1437, 1394, 1343, 1131, 769, 765, 616 cm 1;
1H NMR (300 MHz, CDC13) 8 8.31, 7.95-8.10, 7.60-7.75, 6.90-7.35, 3.30-3.90, 3.18, 2.78, 2.35-2.50, 2.15-2.35, 1.75-2.10, 1.35-1.75, 0.82, 0.75;
MS (EI) m /z 541, 485, 262, 261, 245, 210, 202, 180, 154, I05, 56.
E~~ANR'LE 7 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(4,5,6,7-tetraffuoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyl]-3-pyrrolidineacetamide.
F F
F / \ F

H ~ CH3 N
HO~ ~C
I!
O O N
Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylprnpyl)-2-0~0-1-(2-phenylethyl)-3-pyrrolidineacetate and tetrafluorophthalimide, the title compound is obtained (mp 172.5-173.5 °C).

IR. .(mineral oil) 3216, 1724, 1712, 1664, 1639, 1514, 1503, 1418, 1341, 1301, II56, 1038, 948, 940, 754 cm 1;
1H NMR (300 MHz, CDC13) 8 8.89, 7.4?, 6.95-7.35, 3.35-3.80, 3.10-3.35, 2.79, 2.38, 1.30-2.30, 0.85, 0.80;
MS (EI) m /z 563, 507, 454, 261, 245, 202, 154, IIO, 105, 104, 55.
EXAMPLE 8 Preparation of oc-[2-(5,6-Dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-yl)ethyl-N-hydroxy-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide.
CI CI
/ \

H ~ CH3 N
HO~ ~'C
N
Following the general procedure of E~~LE 4 and making non-critical variations but starting with tert-butyl a.-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate and 4,5-dichlorophthalimide, the title compound is obtained (mp 207-208 °C).
IR (mineral oiI) 3173, 3070, 1775, 1709, 1667, 1630, I441, 1434, 1401, 1330, 1278, 1033, 749, 706, 601 cm 1;
1H NMR (300 MHz, CDC13) 8 10.18, 8.91, 7.89, 7.42, 7.00-7.40, 3.35-3.80, 3.05-3.35, 2.78, 2.38, 2.05-2.30, 1.30-2.05, 0.83, 0.78;
MS (EI) m/z 559, 505, 503, 262, 261, 245, 244, 230, 228, 202, 105.
EXAMPLE 9 Preparation of a-[2-(5-Amino-1,3-dihydro-1,3-dioxo-2H-isoindol-2 yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

WO 97/32846 PCT/US971025~68 > 5 O ~ O CHs N
HO ~ ~C
It O O N
IO
Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2~~ogo-1-(2-phenylethyl)-3-pyrrolidineacetate and 4-aminophthalimide, the title compound is obtained (mp 187-I88 °C).
15 1H NMR (300 MHz, CDCl3) 8 7.56, 7.10-7.35, 7.01, 6.83, 3.30-3.70, 3.15-3.30, 2.80, 2.35-2.50, 2.15-2.30, 1.70-1.95, 1.20-1.60, 0.83, 0.75.
EXAMPLE 10 Preparation of N-Hydroxy-3-(2-methylpropyl)-a.-[2-(4-vitro-I,3-dihydro-1,3-dioxo-2H-isoindol-2-yl?ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
t N02 N
HO~ ~C
I!
O O N
Following the general procedure of EXAMPLE 4 and making non-critical - variations but starting with tent-butyl ac-(2-hydroxyethyl)-3-(2-methyipropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidinea.cetate and 3-nitrophthalimide, the title compourxd is obtained (mp 136-138 °C):
IR, (mineral oil) 3189, 3096, 3069, 1720, 1695, 1655, 1545, 1496, 1429, 1400, 1347, 1306, 1043, 749, 707 cni I;
1H NMR (300 MHz, CDC13) 8 8.05-8.15, 7.85-7.95, 7.05-7.35, 3.35-3.85, 3.10-3.25, 2.79, 2.35-2.50, 2.10-2.25, i.75-2.05, 1.35-i.70, 0.85, 0.79; .
MS (FAB) m /z 537, 536, 523, 521, 505, 504, 475, i05, 104.
EXAMPLE 11 Preparation of N-Hydroxy-3-(2-methylpropyl)-a-[2-(5-nitro-i,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

C ~ O CH3 H CHa N
HO~ ~C
Ii O O N
i5 Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-i-(2-phenylethyl)-3-pyrrolidineacetate and 4-nitrophthalimide, the title compound is obtained (mp 161-162 °C).
IR, (mineral oil) 3158, 3106, 3060, 3027, 1707, 1664, 1543, 1496,-1434, 1411, 1344, 1132, 725, 7I9, 700 cni 1;
1H NMR (300 MHz, CDCl3) S 8.65, 8.59, 8.04, 7.05-7.35, 3.35-3.90, 3.10-3.25, 2.79, 2.35-2.50, 2.10-2.30, 1.75-2.05, 1.35-1.75, 0.84, 0.79;
MS (FAB) m/z 537, 523, 522, 504, 476, 202, 105.
FxA'~'LE 12 Preparation of a-C2-(4-Fluoro-1,3-dihydro-1,3-dioxo-2H-isoindoi-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
F

CHg HO~ ~C
II
O O N
I

Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate and 3-fiuorophthalimide, the title compound is obtained (mp 145-146 °C).
IR. (mineral oil) 3205, 3065, 3028, 1776, 1717, 1657, I61I, 1497, I483, 1399, 1349, 1303, 1255, 746, 701 cm-1;
III NMR (300 MHz, CDClg) S 7.55-7.80, 7.36, 6.80-7.35, 3.35-3.85, 3.05-3.30, 2.79, 2.30-2.55, 2.05-2.30, 1.70-2.00, 1.35-1.70, 0.83, 0.78;
MS (EI) m/z 509, 477, 453, 449, 345, 262, 261, 178, 105, 104.
EXAMPLE 13 Preparation of a-(2-(4,7-Difluoro-1,3-dihydro-I,3-dioxo-2H-isoindol-2-yI)ethyll-N-hydroxy-3-(2-methylpropyi)-2-oxo-1-<2-phenylethyl)-3-pyrrolidineacetamide.
F ~ ~ F

H ~ CHg N
HO's ~C .
ti O O N
Following the general prncedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate and 3,6-difluorophthalimide, the title compound is obtained (mp 13I-i32 °C).
IR (mineral oil) 3196, 3029, 1779, 172I, 1657, 1495, 1421, I395, 1359, 1263, 1256, 911, 908, 753, 697,cni 1;
1H NMR (300 MHz, CDCI3) 8 7.I0-7.45, 6.94, 3.35-3.80, 3.15-3.30, 2.79, 2.30-2.50, 2.00-2.30, L75-2.00, 1.35-L75, 0.85, 0.79;
MS (EI) m/z 527, 495, 47I, 467, 363, 262, 261, 202, 196, 105, 104.
EXAMPLE 14 Preparation of a-f2-(5-Fiuoro-1,3-dihydro-i,3-dioxo-2H-isoindol-2 yl)ethyi3-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineaceta.mide.

HO' Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrmlidineacetate and 4-fluorophthalimide, the title compound is obtained (mp 143-144 °C).
IR (mineral oil) 3218, 3072, 3006, 1'175, 1713, 1660, 1612, 1495, 1483, 1400, 1293, 1264, 1040, 747, 707 cni 1;
1H NMR (300 MHz, CDC13) 8 7.83, 7.50, 6.85-7.45, 3.35-3.80, 3.05-3.25, 2.79, 2.30-2.50, 2.05-2.30, 1.75-2.00, 1.30-1.70, 0.83, 0.77;
MS (EI) m /z 509, 477, 453, 449, 345, 262, 261, 178, 105, 104.
FxAMPLE 15 Preparation of a-I2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl7-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
O
H
HO~N~
Following the general procedure of EXAMPLE 4 and making non-critical variations but starting with tent-butyl a-(3-hydroxypropyl)-3-(2-methylpropyl)-2-oxo- , 1-(2-phenylethyl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 4, step 2) and phthalimide, the title compound is obtained (mp 113-114 °C).

WO 97/32846 PC~YUS97/025~68 ~R, (mineral oil) 3241, 3087, 3058, 3026, 1773, 1715, 1663, 1498, 1399, 7.352, 1320, 1298, 1067, 718, 604 cni I;
' xH NMR (300 MHz, CDC13) b 10.66, 7.75-7.85, 7.60-7.55, 6.95-7.45, 3.35-3.80, 3.10-3.25, 2.80, 2.44, 2.10-2.30, 1.85-2.00, 1.30-1.85, 0.85, 0.79;
- 5 MS (EI) m /z 505, 473, 445, 261, 245, 244, 202, 160, 105, I04.
EXAMPLE 16 Preparation of a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
O

O
CHg HO~ ~C
p O-Step 1. Preparation of tert-Butyl a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yI)methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
LDA (1.50 mL, 3.0 mmol, 2.0 M in heptane/THF'lethylbenzene) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAn~LE 1, step 3; 1.02 g, 2.84 mmol), HMPA (0.51 mL, 2.9 mmol), and THF' (10 mL) at -78 °C. The solution is stirred at -78 °C for 30 minutes and then a solution of N-(bromomethyl)phthalimide (0.887 g, 3.69 mmol) and TIC (4.0 mL) is added.
The solution is stirred at -78 °C for 1 hour and then allowed to warm slowly to room temperature overnight. Aqueous workup CEtOAc, MgS04) and purification by flash chromatography (3:1 hexane:EtOAc) gives 374 mg (25%) of the title compound as a white solid (mp 96-98 °C).
iR, (mineral oil) 1772, 1753, 1724, 1713, 1668, 1435, 1403, 1309, 1234, 1143, 1094, 737, 725, ?14, 697 cni 1;
1H NMR (300 MHz, CDC13) 8 7.70-7.90, 7.15-7.35, 4.07, 3.86, 3.55-3.70, 3.35-3.50, 3.25-3.35, 3.11, 2.84, 2.50-2.65, 1.75-i.90, 1.60-1.75, 1.20, 0.85-0.95;
MS (FAB) m /z 519, 464, 463, 445, 159, 105, 57, 41, 29.
Step 2. Preparation of a-[2-( 1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methylJ-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic Acid.
TFA (5.0 mL) is added to a solution of tent-butyl a-[2-(I,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (374 mg, 0.721 mmoi) and CH2C12 (5.0 mL) at 0 °C.
The solution is stirred for 2 hours at 0 °C and 2 hours at room temperature. The solution is concentrated and reconcentrated twice more from CH2C12 (2 X 30 mL). Aqueous workup (CH2C12, MgS04} provides 291 mg (87%) of the title compound as an oil which is carried on crude.
1H NMR (300 MHz, CDCl3) 8 7.65-7.95, ?.05-7.35, 3.90-4.05, 3.64, 3.35-3.55, 3.12, 2.80-3.05, 2.83, 2. I0-2.40, 1.50-1.80, 0.90, 0.86.
Step 3. Preparation of a-[2-(I,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyi)-3-pyrrolidineacetamide.
EDC (129 mg, 0.672 mmoi) is added to a solution of a-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-3-(2-methylgropyl)-2-oxo-I-(2-phenylethyl~3-pyrrolidineacetic acid (270 mg, 0.584 mmol), CH2C12 (5.7 mL), DMF ( 1.4 mL), HOBT (78.9 mg, 0.584 mmol), and N-methylmorpholine (74 pL, 0.67 mmol) at 0 °C.
The solution is stirred for 5 minutes at 0 °C and for 1 hour at room temperature.
Hydroxylamine hydrochloride (80.9 mg, i.16 mmol) and N-methylmorpholine (0.13 mL, 1.2 mmoi) are added and the mixture stirred overnight at room temperature.
Aqueous workug (CH2C12, MgS04) a.nd purification by flash chromatography (EtOAc) provides 160 mg of the hydroxamate as a white foam which is crystallized from ether/hexane to give 129 mg (46%) of the title compound as a white crystalline material which is a 4.25:1 mixture of diastereomers (mp 170-1? 1 °C).
IR, (mineral oil) 3194, 3105, 3050, 3028, 1773, 1709, 1665, 1644, 1496, 1434, 1409, 1393, 1309, 721, 701 crn 1;
IH NMR (300 MHz, CDC13} s 10.9?, 7.65-7.90, 7.10-7.35, 3.65-3.90, 3.20-3.55, 2.75-2.95, 2.35-2.50, 2.00-2.15, 1.50-1.85, 0.87;
MS (FAB) m /z 478 477, 445, 261, 202, 160, 105, 43.
EXAMPLE 17 Preparation of N-Hydroxy-3-(2-methylprapyl)-2-oxo-1-(2-phenylethyl)-a-[2-(2-thienylthio)ethyl]-3-pyrrolidineacetamide.

WO 97/32846 PCT/US97/025fi8 %S

N ~ CHs HO~ ~C
t~
O O N
w Step 1. Preparation of tent-Butyi a-(2-(Methanesulfonyloxy)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
Methanesuifonyl chloride (0.29 mL, 3.7 mmol) is added to a solution of tert-butyl a-(2-hydroxyethyl)-3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 4, step 2; 1.36 g, 3.37 mmol), triethylamine (0.52 mL, 3.7 mmol) and CH2CI2 (8 mL) at 0 °C. The mixture is stirred for 2 hours, washed with saturated NaHC03 (2 x 10 mL), water (10 mL), dried (MgS04 ), filtered, and concentrated to give 1.22 g (75%) of the title compound as a light yellow oil.
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 4.10-4.30, 3.55-3.70, 3.35-3.50, 3.20-3.30, 3.01, 2.82, 2.55, 2.10-2.35, 1.85-2.05, L70-2.05, 1.40-1.65, 1.44, 0.87, 0.83.
Step 2. Preparation of tent-Butyl 3-(2-Methyipropyl)-2-oxo-1-(2-phenylethyl)-a.-(2-(2-thienylthio)ethyl]-3-pyrrolidineacetate.
Sodium hydride (60%, 41 mg, 1.0 mmol) is added to a solution of thiophenethiol (118 mg, 1.02 mmol), THF (25 mL) and DMF (25 mL) at 0 °C. The mixture is stirred for 30 minutes at 0 °C and a solution of tent-butyl a-I2-(methanesulfonyloxy)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (490 mg, 1.02 mmol) in THF (15 mL) is added. The solution is allowed to warm slowly and is stirred at room temperature overnight.
Concentration, aqueous workup (EtOAc, MgS04), and purification by flash chromatography (25% EtOAc/hexane) gives 361 mg (71%) of title compound as a colorless oil.
- IR (liq.) 2956, 2930, 2868, 1720, 2685, 1497, 1454, 1428, 1367, 1276, 1258, 1217, 1147, 847, 700 cui 1;
t 1H NMR (300 MHz, CDC13) 8 7.15-7.40, 7.10-7.15, 6.90-7.00, 3.55-3.65, 3.30-3.45, 3.15-3.25, 2.75-2.90, 2.60-2.75, 2.58, 2.25-2.40, 1.80-2.00, 1.65-1.80, 1.35-1.65, 1.39, 0.84, 0.80;
MS (EI) m /z 501, 428, 386, 331, 330, 303, 247, 246, 2I2, 105, 57.

Step 3. Preparation of 3-(2-Methylpropyl)-2-oxo-1-(2-phenylethyl)-a-I2-(2-thienylthio)ethyl]-3-pyrrolidineacetic Acid.
A solution of tent-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-I2-(2- -thienylthio)ethyl]-3-pyrrolidineacetate (338 mg, 0.674 mmol), triffuoroacetic acid (3 mL), and CH2C12 (3 mL) is stirred at 0 °C for 15 minutes and at room temperature for 1.5 hour. Concentration and aqueous workup (CH2C12, MgS04) gives 287 mg (96%) of the title compound as a colorless oil.
IR. (liq.) 2958, 2931, 2870, I?36, 1683, 1620, 1498, 1480, 1465, 1454, 1444, 1263, 12I6, 746, 700 cni 1;
IO 1H NMR (300 MHz, CDCl3) 8 13.75, 7.35-7.40, 7.05-7.35, 6.95-7.05, 3.70-3.85, 3.35-3.50, 3.I5-3.35, 2.80-2.95, 2.55-2.80, 2.00-2.15, 1.35-1.90, 0.91, 0.84;
MS (EI) m/z 445, 331, 330, 258, 247, 246, 228, 212, 156, I05, 55.
Step 4. Preparation of N-Hydroxy-3-(2-methylpropyi)-2-oxo-1-(2-phenylethyl)-a-[2-(2-thienylthio)ethyl]-3-pyrrolidineacetamide.
A solution of HOBT (83 mg, 0.62 mmol) in DMF (1.3 mL) is added to a solution of 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-I2-(2-thienylthio)ethyl]-3-pyrrolidineacetic acid (259 mg, 0.58I mmol) in C~C12 (6 mL) at room temperature.
The solution is cooled to 0 °C. To this is added 4-methylmorpholine (77 N.L., 0.70 mmol) and EDC (134 mg, 0.697 mmol). The solution is stirred at 0 °C for 1 hour and then a mixture of hydroxylamine hydrochloride (57 mg, 0.87 mmol), 4-methylmorpholine (96 EtL, 7.4 mmol), and DMF (0.8 mL) is added. The mixture is stirred overnight at room temperature and concentrated. Purification of the residue by flash chromatography (50% EtOAc/hexane) and crystallization (ether/hexane) gives 95 mg (36%) of the title compound as a white solid {mp 109-11fl °C).
IR (mineral oil) 3202, 3096, 3081, 3023, 1652, 1496, 144I, 1432, 1314, 1294, 1280, 1222, 751, 717, 702 cm I;
1H NMR (300 MHz, CDC13) 8 10.55, 7.05-7.40, 6.90-7.00, 3.50-3.65, 3.05-3.25, 2.70-2.95, 2.50-2.70, 1.95-2.25, 1.35-1.95, 0.85, 0.80;
MS (EI) m /z 460 345, 284, 262, 261, 228, 105, 81, 79, 55.
EXAMPLE 18 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-I2-(2-thienylthio)propyl]-3-pyrrolidineacetamide.
a _50_ S
S
~3 H CHg HO~N~.C
O O Nl Following the general procedure of EXAMPLE 17 and making non-critical variations but starting with tent-butyl a-(3-hydroxypropyl)-3-(2-methylpropyl)-2..oxo-1-(2-phenylethyl)-3-pyrrolidineacetate, the title compound is obtained (mp 104-'C>.
IR. (mineral oil) 3211, 3101, 3069, 3028, 1667, 1653, 1497, 1428, 1399, 1310, 1298, 1293, 1249, 760, 710 c><ri 1;
1H NMR (300 MHz, CDC13) 8 6.70-7.75, 3.05-3.95, 2.50-3.05, 1.15-2.50, 0.87, 0.82;
MS (EI) m/z 474, 442, 386, 359, 326, 298, 244, 202, 105, 55.
EXAMPLE 19 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(2-thienylthio)methyl]-3-pyrrolidineacetamide.
S
~S CHg H ~ Cti3 N
HO~ ~C
I I
O O N / I
Following the general procedure of EXAMPLE 17 and making non-critical ' variations but starting with tert-butyl a-( 1-hydroxymethyl)-3-(2-methylpropyl)-2,-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate, the title compound is obtained (mp 145-:L46 oC).
IR (mineral oil) 3177, 3085, 3027, 1664, 1641, 1496, 1408, 1297, 1274, 1218, 1029, 1000, 845, 746, 702 cm-1;
1H NMR (300 MHz, CDC13) b 7.68, 7.15-7.40, 6.90-7.15, 3.35-3.70, 2.55-3.30, 2.05-2.25, 1.65-1.70, 1.25-1.60, Major diastereomer peaks. 0.80,, 0.71, Minor diastereomer peaks. 0.75, 0.61;
MS (EI) m/z 446, 246, 245, 203, 202, 154, 105. ' EXAMPLE 20 Preparation of N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
N
HO' ~NHMe O
Step 1. Preparation of 1-Trimethylsilyl-2-pyrrolidinone.
Chlorotrimethylsilane (TMSCl, 56.0 mL, 441 mmol) is added dropwise to a solution of 2-pyrrolidinone (30.4 mL, 400 mmol), triethylamine (70.0 mL, 502 mmoi) and toluene (400 mL) at room temperature. After stirring at room temperature with a mechanical stirrer for 20 minutes, the mixture is heated at 50 °C for 4 hours.
After cooling, the mixture is diluted with hexane (300 mL) and stirred fox 30 minutes at room temperature. The mixture is filtered and the filtrate concentrated.
Distillation of the residue (1 mm, 68-74 °C) gives 50.0 g (94°l0) of the title compound as an oil.
1H NMR (300 MHz, d5-pyridine) 8 3.17, 2.26, 1.70-1.85, 0.32.
Step 2. Preparation of 3-(2-methylpropyl)-2-pyrrolidinone.
26 A solution of LDA (2.0 M, lIl mL, 222 mmol) and THF (300 mL) is cooled to -78 °C and a solution of 1-trimethylsilyl-2-pyrrolidinone (29.4 g, 221 mmol) in T7KF
(145 mL) is added. After stirring for 45 minutes at -78 °C, the enolate solution is added via cannula over 1 hour to a solution of 1-iodo-2-methylpropane (42.7 g, mmol) in THF (200 mL) at -78 °C. The solution is allowed to warm slowiy and stirred at room temperature overnight. The reaction is quenched by the adclition of 50 mL of acetic acid. Aqueous workup (EtOAc, MgS04) and purification by column chromatography (30~100°lo EtOAc/hexane) gives 12.8 g of the title compound as an oii.
1H NMR (300 MHz, CDCI~) 8 6.30, 3.10-3.30, 2.05-2.35, 1.45-1.80, 1.00-1.20, 0.81, 0.76.
Step 3. Preparation of 3-(2-methylpropyl)-1-trimethylsiiyl-2-pyrrolidinone.

TMSCl (2.2 mL, 18 mmol) is added dropwise to a solution of 3-(2-methylpropyl)-2-pyrrolidinone (2.25 g, 15.9 mmol), triethylamine (2.7 mL, 19 mnzol), anal toluene (16 mL) at room temperature. The mixture is heated at 40 °C for 3 hours and diluted with hexane (50 mL}. After stirring for 10 minutes at 0 °C, the mixture is filtered and the filtrate concentrated. Distillation (1 mm, 62-68 °C) of the residue gives 2.40 g (71%) of the title compound as an oil.
~H NMR (300 MHz, CDC13) 8 3.05-3.30, 2.20-2.35, 2.05-2.20, 1.45-1.70, 1.05-1.I5, 0.82, 0.78, 0.15.
Step 4. Preparation of 3-(2-Methyipropyl)-3-(propen-2-yl)-2-pyrrolidinone.
I0 A solution of 3-(2-methylpropyl)-1-trimethylsilyl-2-pyxxolidinone ( 10.2 g, 47.8 mmol) and THF (153 mL) is cooled to -78 °C, and LDA (2.0 M, 26.3 mL, 52.6 mmol) is added. The solution is stirred at -78 °C for 30 minutes and then allyl bromide (5.0 mL, 57 mmol) is added. The solution is allowed to warm to 5 °C over 2.5 hours, and is then stirred at 5 °C for 1 hour. After quenching with saturated aqueous I5 ammonium chloride (25 mL), aqueous workup (EtOAc, MgS04) and purification by column chromatography (1:9:10 v/v CH2C12:EtOAc:hexane) provides 7.76 g (90%'0) of the title compound as an oil.
IR, (liq.) 3241, 3077, 2957, 2929, 2902, 2873, 1708, 1693, 1640, I440, 1284, 1277, 1264, 1251, 842 cna 1;
20 1H NMR (300 MHz, CDCl3) 8 6.43, 5.65-5.85, 5.00-5.15, 3.15-3.35, 2.00-2.40, 1.65-1.85, 1.40-1.60, 0.92;
MS (EI ) m /z 138, 125, 124, 98, 73, 60, 55, 45, 43, 41.
Step 5. Preparation of Ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-1-pyrrolidineacetate.
25 A solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 16.4 mL, 8.19 mmol) is cooled to 0 °C, and a solution of 3-(2-methyipropyl)-3-(propen-2-yl)-2-pyrrolidinone ( L24 g, 6.82 mmol) in THF ( 10 mL) is added dropwise over 2 minutes After stizxing at 0 °C for 40 minutes, ethyl bromoacetate (0.91 mL, 8.2 mmol) is . added. The reaction is stirred at 0 °C for 3 hours and for 1 hour at room 30 temperature. After quenching with saturated aqueous ammonium chloride (10 mL), aqueous workup (EtOAc, MgS04) and purification by column chromatography (1:9:10 v/v CH2C12:EtOAc:hexane) provided 1.66 g (9I%) of the title compound as an '' oil.
IR (liq.) 2957, 2930, 2906, 2872, 1750, 1692, 1462, 1440, 1375, 1296, 1281, 35 1252, 1196, 1028, 916 cai 1;
1H NMR (300 MHz, CDCl3) 8 5.50-5.75, 4.90-5.05, 4.00-4.15, 3.93, 3.15-3.30, WO 97/32846 PCT/US97/0256$
2.15-2.30, 2.00-2.15, 1.80-2.00, L55-L75, 1.30-1.50, 1.16, 0.82, 0.77;
MS (EI ) m /z 212, 211, 2I0, 194, 152, 138, 137, I10.
Step 6. Preparation of N-Methyl-3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-1- ' pyrrolidineacetarnide.
Ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2-yI)-I-pyrrolidineacetate (500 mg, 1.87 mmol) is stirred in a saturated solution of methylamine in EtOH (50 mL) at room temperature overnight. The solution is concentrated and purified by column chromatography (1:12:8 v/v CH2C12:EtOAc:hexane) to give 401 mg (85%) of the title compound as an oil.
IR, (liq.) 3308, 2955, 2928, 2872, 1662, 1560, 1495, 1464, 1443, 1413, 1279, 1263, 1252, 915, 842 cm'1;
1H NMR (300 MHz, CDCl3) 8 6.32, 5.50-5.75, 4.90-5.10, 3.79, 3.28, 2.67, 2.I7, 1.85-2.10, 1.55-1.75, 1.30-1.55, 0.84, 0.77;
MS (EI) m /z 252, 221, 2I0, 209, I96, 194, 166, 165, 152, 138, 124, 110, 95, 73.
Step 7. Preparation of 1-(N-Methylacetamide)-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetic Acid.
Ruthenium(I~ oxide hydrate ( I5 mg, 0.11 mmol) is added at room temperature to a mixture of sodium periodate (944 mg, 4.41 mmol) in acetonitrile (1.9 mL), carbon tetrachloride (0.9 mL) and water (2.0 mL). After stirring for minutes, sodium bicarbonate (2.32 g, 27.6 mmol) is added, followed by a solution of N-methyl-3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-I-pyrrolidineacetamide (I39 mg, 0.552 mmol) in acetonitrile (2.0 mL). Sodium periodate (approximately i50 mg) is added until the black mixture turner light green. After 5 minutes the mixture is poured into 100 mL of water. The pH of the mixture is adjusted to pH 2 (pH
paper) with concentrated HCl. The acidic solution is extracted with CH2C12 and EtOAc.
The combined organic layers are dried (MgS04), filtered, and concentrated to provide 157 mg ( 100%) of the title compound as an oil.
1H NMR (300 MHz, CDC13) b 7.09, 4.30-4.45, 3.20-3.50, 2.67, 2.63, 1.95-2.25, 1.55-1.70, 1.30-1.45, 0.84, 0.78.
Step 8. Preparation of N3-Hydroxy-NI-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
EDC (1.14 g, 5.95 mmol) is added to a solution of 1-(N-methylacetamide)-3-(2-methylpropyl)-2-oxo-3-pyrroiidineacetlc acid ( 1.34 g, 4.96 mmol), HOBT
(710 mg, 5.26 mmol) and 4-methylmorpholine (0.65 mL, 5.9 mmol) in CH~C12 (51 mL) and DMF (10 mL) at 0 °C. The solution is stirred at 0 °C for 1 hour, and then a mixture WO 97!32846 PCTIUS97/02568 of hydroxylamine hydrochloride (517 mg, 7.44 mmol) in DMF (7. mL) is added followed by 4-methylmorpholine (0.82 mL, 7.4 mmol). After stirring for 7 days at room temperature, the mixture is concentrated under high vacuum and purified by column chromatography (3% MeOH/CH2C12). Crystallization from Et20/hexan,e provides 211 mg (I5%) of the title compound as a white solid (mp 145-147 °C).
IR, (mineral oii) 3259, 3199, 3097, 3017, I662, I564, 1522, 1501, I4I2, 1405, 1313, 1297, 1275, 750, 724 sari I;
1H NMR (300 MHz, CDCI3/CD30D) 8 4.25-4.45, 3.05-3.50, 2.74, 2.32, L90-2.20, 1.55-L75, 1.30-1.50, 0.87, 0.79;
IO MS (EI) m /z 285, 254, 229, 226, 194, 180, I69, I66, 152, 138, 124, 110, 55.
EXAMPLE 21 Preparation of N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
O

O N
-CONHMe Step 1. Preparation of Ethyl 3-(2-methylpropyl)-2-oxo-a-(phenylmethyi)-3-(propen-2-yl)-1-pyrrolidineacetate.
A solution of ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2 yl)-1 pyrrolidineacetate (Example 20, step 5; L63 g, 6.I0 mmol) and THF (15 mL) is cooled to -78 °C and LDA (2.0 M, 3.2 mL, 6.4 mmol) is added. The solution is stirred at -78 °C for 30 minutes and then benzyl bromide (0.80 mL, 6.7 mmol) is added.
The solution is allowed to warm to 0 °C over 2 hours, and then stirred at 0 °C for 1 hour. After quenching with saturated aqueous ammonium chloride ( 10 mL), aqueous workug (EtOAc, MgS04) and purification by column chromatography (10%
EtOAc/hexane) provided 1.94 g (89%) of the title compound as an oil in a 1:1 mixture - of diastereomers.
IR (liq.) 2975, 2956, 2930, 2906, 1739, 1689, 1499, 1455, I425, 1266, 1207, 1192, 1032, 915, 698 cni 1;
rH NMR (300 MHz, CDC13) b 7.05-7.30, 5.55-5.75, 4.85-5.20, 4.65-4.85, 4.00-_55_ 4.20, 3.00-3.40, 2.80-2.95, 2. I2, 1.50-1.95, 1.30-1.45, 1.15-1.30, 1.00-1.
I5, 0.83, 0.79, 0.66, 0.54;
MS (EI) m /z 35?, 301, 238, 228, 284, 282, 26?, 266, 2I0, 200, 1?6, 164, 125, "
102, 91.
Step 2. Preparation of N-Methyl-3-(2-methylpropyl)-2-oxo-a-(phenylmethyl)-3-(propen-2-yl)-1-pyrrolidineacetamide.
Methylamine gas is bubbled through a solution of ethyl 3-(2-methylpropyl)-2-oxo-a-(phenylmethyl)-3-(propen-2-yl)-1-pyrrolidineacetate (3.40 g, 9.51 mmol) in EtOH ( 120 mL) far 30 minutes at room temperature, and the solution is stirred at room temperature overnight. The solution is concentrated and purified by flash chromatography (1:6:11-X1:10:9 v/v CH2C12:EtOAc:hexane) to give 3.01 g (92%) of the title compound as a solid (mp 9I-92 °C) which is a ca. 1:1 mixture of diastereomers.
IR, (mineral oil) 3315, 1684, 1654, 1584, 1562, 1499, 1442, 1414, 1296, 12?8, 1264, 1225, 913, 744, 708 cm ~;
1H NMR (300 MHz, CDCi3) 8 7.10-7.30, 6.15-6.40, 5.50-5.70, 5.10-5.30, 4.95-5.10, 4.75-4.95, 3.15-3.35, 2.90-3.10, 2.72, 2.71, 1.95-2.20, 1.50-1.95, 1.15-1.50, 0.86, 0.78, 0.74, 0.64;
MS (EI) m /z 342, 300, 284, 267, 251, 242, 200, 162, 132, 105, 91, 8I, 73, 67.
Step 3. Preparation of Nl-Methylacetamide-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-3-pyrrolidineacetic Acid.
Ruthenium(I~ oxide hydrate (29 mg, 0.22 mmol) is added to a mixture of sodium periodate (1.85 g, 8.65 mmol) in acetonitrile (3.8 mL), carbon tetrachloride (1.8 mL), and water (3.9 mL) at room temperature. After stirring for i0 minutes, sodium bicarbonate (4.55 g, 54.2 mmol) is added, followed by a solution of N-methyl-3-(2-methylpropyl)-2-oxo-a-(phenylmethyl)-3-(propen-2-yl)-1-pyrrolidineacetamide (371 mg, 1.08 mmol) in acetonitrile (4.0 mL). Sodium periodate (approximately mg) is added until the black mixture turns light green. After 5 minutes, the mixture is poured into 100 mL of water. The mixture is extracted with EtOAc (2 x 50 mL). The pH of the aqueous mixture is adjusted to pH 2 (pH paper) with concentrated HCl. The acidic mixture is extracted with CH2C12 and EtOAc, and these layers are combined with the original EtOAc extracts, dried (MgSOg), filtered, and concentrated to give 300 mg of the crude acid as a dark brown oil. This material is dissolved in 15% NaOH (10 mL) and extracted with Et20 (3 x 20 mL).
These Et20 layers are discarded. The pH of the aqueous layer is adjusted to pH

(pH paper) with concentrated HCI. The acidic layer is extracted with EtOAc (3 x 30 mL), the combined EtOAc layers dried (MgSOø), filtered, and concentrated to give WO 97!32846 PCT/US97/02568 230 mg (59 .%) of the title compound as an oil as a 1:1 mixture of diastereomers.
IR (mineral oil) 3358, 3fl87, 3064, 3029, 1721, 1649, 1550, 1498, 1441, 1413, 1297, 1272, 1233, 1192, 700 c~ri ~;
1H NMR (300 MHz, CDC13) 8 7.05-7.40, 6.55-6.70, 5.10, 4.56, 3.64, 3.20-3.55, " 5 2.70-3.05, 2.30-2.70, 1.75-2.20, 1.55-L75, L49, L05-1.40, 0.80-1.00, 0.90, 0.83, 0.69, 0.66;
MS (EI) m /z 360, 336, 303, 302, 284, 269, 256, 246, 228, 200, 162, I61, 132, 105, 91.
Step 4. Preparation of N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-aZ-(phenylmethyl)-1,3-pyrrolidinediacetamide.
EDC {1.08 g, 5.66 mmol) is added to a solution of Nl-methyiacetamide-3-{2-methylpropyl)-2-oxo-ocl-(pheny!methyl)-3-pyrrolidineacetic acid (1.70 g, 4.72 mlnol), HOBT (676 mg, 5.00 mmol) and 4-methylmorpholine (0.52 mL, 4.7 mmol) in CHZCl2 (49 mL) and DMF (10 mL) at 0 °C. The solution is stirred at 0 °C
for 1 hour and then a mixture of hydroxyiamine hydrochloride (491 mg, 7.08 mmoi) in DMF (7 mL) is added, followed by 4-methylmorpholine (0.79 mL, 7.1 mmol). The mixture is stirred at room temperature overnight and concentrated under high vacuum. The residue is dissolved in I5% NaOH ( 13 mL) and extracted with EtOAc (3 x 20 nnL).
These EtOAc layers are discarded. The pH of the aqueous layer is adjusted to pH 2 (pH paper) with 6 N HCl. The acidic Iayer is extracted with CH2C12 (3 x 30 mL), the combined CH2CI2 layers dried (MgS04), filtered, and concentrated.
Purification by column chromatography (5 % MeOHlCH2CL2) and crystallization from Et20/hexane provided 255 mg (14%) of the title compound as a white solid (mp 168 °C) as a mixture of diastereomers.
IR (mineral oil) 3373, 3199, 3087, 3064, 3027, 1686, 1667, 1634, 1546, 1498, 1404, 1356, 1303, 742, 697 cal 1;
1H NMR (300 MHz, CDCl3/CDgOD) major diastereomer, key peaks: 8 4.48, 2.76, 0.89, 0.81. Minor diastereomer, key peaks: 8 5.05, 2.82, 0.69, 0.62;
MS (EI) m /z 375, 344, 317, 316, 285, 284, 256, I32, 91.
EXAMPLE 22 Preparation of a-[2-(I,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-I-(phenylmethyl)-3-pyrrolidineacetamide.
_57_ p N p CH3 H ~CH3 N
Ho'' 'c p O N
Step 1. Preparation of N-tent-Butyloxycarbonyl-2-pyrrolidinone.
A solution of di-tert-butyl dicarbonate (28.2 g, 129 mmol) in dry CH2C12 (80 mL) is added to a stirred solution of 2-pyrrolidinone ( 10.0 g, 117 mmol) and DMAP
(200 mg, catalytic 'amount) in dry CH2C12 (230 mL) over 10 minutes. After 16 hours, the solution is diluted with H20 (150 mL) and extracted with EtOAc (4 x i00 mL). The organic layers are combined, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give a red oil. The oil is purified by silica geI
chromatography (200 g SG, 40% EtOAclhexane) to yield 20.1 g (93%) of the title compound as a gold oil.
IR (liq.) 2980, 1786, 1752, 1714, 1459, 1394, 1368, 1315, 1256, 1228, 1154, 1045, 1018, 858, 778 cni 1;
1H NMR {300 MHz, CDC13) 8 3.74, 2.50, 1.90-2.05, i.52; MS (FAB) m /z 186, 131, 130, 112, 86, 57, 41.
Step 2. Preparation of N-tent-Butyloxycarbonyl-3-(2-methylpropen-2-yl)-2-pyrrolidinone.
A solution of N-tent-butyloxyearbonyl-2-pyrrolidinone (10.0 g, 54.0 mmol) and HMPA (9.40 mL, 54.0 mmol) in dry THF (200 mL) is cooled to -78 °C and treated drop-wise over 6.5 minutes with lithium diisopropylamide (LDA, 29.7 mL, 59.4 mmol, 2 M in heptanelTHF/ethylbenzene). After 30 minutes at -78 °C, 3-bromo-2-methylpropene (6.53 mL, 64.8 mmol) is added. The solution is maintained at -78 °C
under N2 for 6 hours, and is then quenched with saturated NH4CI ( 100 mL). The solution is warmed to 0 °C and diluted with H20 (300 mL). The crude olefin is extracted into EtOAc (3 x 200 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give an oil. The oil is purified by silica gel chromatography (350 g gel; 20% EtOAc/hexane) to yield 7.75 g (60%) of the title compound as a golden oil.
_58_ WO 97132846 PCTlUS97/025G8 IR (liq.) 2980, 2934, 2903, 1785, 1''74$, 1.'716, I~57, 1394, .2368, 1322, 1295, 1251, 1227, 1155, 779 ciri 1;
1H NMR (300 MHz, CDC13) 8 4.79, 4.?1, 3.70-3.80, 3.50-3_65, 2.60-2.75, 1.95-2.20, 1.72, 1.55-1.75, 1.52;
' 5 MS (EI) m/z 239, 183, 166, 165, 139, 57.
Step 3. Preparation of tent-Butyl N-tert-Butyloxycarbonyl-3-(2-methylpropen-2-yl)-2-oxo-3-pyrrolidineacetate.
A solution of N-tent-butyloxycarbonyl-3-(2-methylpropen-2-yi)-2-pynrolidi.none (7.39 g, 30.8 mmol) in dry THF (125 mL) is cooled to -78 °C and treated drop-wise with LDA (17.0 mL, 33.9 mmol). After 30 minutes at -78 °C, tent-butyl bromoacetate (5.46 mL, 37.0 mmol) is added. The solution is maintained at -78 °C for 6 hours and then quenched with saturated NH4C1 (50 mL). The solution is warmed to 0 °C and diluted with H20 (50 mL). The crude ester is extracted into EtOAc (3 x 100 mL), dried over anhydrous Na2S04, f ltered, and concentrated under reduced pressure to give an orange oil. The material is purified by silica gel chromatography (2 columns:
250 g, 100 g SG, 10% EtOAc/hexane) to yield 7.69 g (71%) of the title compound as a golden oil.
IR (Iiq.) 2980, 2934, 2918, 1786, 1748, 1718, 1457, 1394, 1369, 1315, 1258, 1208, 1155, 965, 853 cni 1;
1H NMR (300 MHz, CDC18) 8 4.90, 4.78, 3.50-3.75, 2.53, 2.30, 2.05-2.20, 1.72, LSI, 1.42;
MS (EI) m /z 353, 297, 280, 241, 224, 223, 196, 180, 57.
Step 4. Preparation of tert-Butyl N-tert-Butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate.
A solution of tent-butyl N-tent-butyloxycarbonyl-3-(2-methylpropen-2-yl)-2-oxo-3-pyrrolidineacetate (7.90 g, 22.4 mmol) in EtOH (150 mL) is treated with 10%
palladium on carbon (1.98 g, 25% by weight) and hydrogenated in a Parr flask at 45 psi for 16 hours at room temperature. The mixture is filtered through celite;
the residual cake is washed with EtOH (2 x I00 mL), MeOH (2 x 100 mL), and CH2C12 (100 mL). The filtrate is concentrated under reduced pressure to yield 7.86 g ('99%) ~ of the title compound as a thick, cloudy oil.
IR (liq.) 2978, 2934, 1786, 1749, 1717, 1476, 1458, 1393, 1369, 1317, 1258, 1207, 1155, 1117, 969 ciri 1;
1H NMR (300 MHz, CDC13) 8 3.55-3.80, 2.53, 2.05-2.20, 1.90-2.05, 1.60-:L.80, 1.40-L60, 1.52, 1.42, 0.91, 0.90;
MS (FAB) m /z 356, 300, 244, 226, 200, 182, 154, 57.

Step 5. Preparation of tert-Butyl N-tert-Butyloxycarbonyl-3-{2-methylpropyl)-2-oxo-a-(propen-2-yl}-3-pyrrolidineacetate.
A solution of tent-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate {3.65 g, 10.3 mmol) in dry THF {45 mL) is cooled to -78 °C and treated drop-wise with LDA (5.70 mL, 11.3 mmol). After 30 minutes at -78 °C, allyl -bromide (1.10 mL, 12.4 mmol) is added. The solution is maintained at -78 °C for 3 hours, and is then allowed to slowly warm to room temperature under N2. After hours, the solution is quenched with saturated NH4C1 (10 mL) and diluted with H20 (50 mL). The crude lactam is extracted into EtOAc (3 x 100 mL). The organic extracts are combined, washed with brine (50 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give 4.72 g of gold oil.
The oil is purified by silica geI chromatography (300 g SG, 5% EtOAc/hexane) to yield 2.98 g (73%) of the title compound as a clear, pale gold oil as a mixture of diastereomers.
IR (liq.) 2979, 2961, 2934, 1785, 1748, 1719, 1457, 1393, 1369, 1315, 1257, 1207, 1156, 1125, 851 czri 1;
1H NMR (300 MHz, CDC13, key peaks of the major diastereomer): s 5.60-5.85, 4.95-5.15, 3.55-3.75, 2.64, 2.20-2.50, 1.35-1.90, 1.52, 1.42, 0.91, 0.88;
MS (FAB) m /z 396, 340, 285, 284, 266, 222, 57, 41, 29.
Step 6. Preparation of tent-Butyl 3-(2-Methylpropyl)-2-oxo-a-{propen-2-yl)-3-pyrrolidineacetate.
A solution of tent-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-a.-(propen-2-yl)-3-pyrrolidineacetate (5.40 g, 13.7 mmol) in MeOH (70 mL) is treated with magnesium methoxide (74.7 mL, 68.5 mmol, 10.3 wt % in MeOH). The resultant solution is stirred under N2 at room temperature for 16 hours. The solution is quenched with 1:1 glacial AcOHIH~O ( 100 mL). The solution is reduced to a minimal volume under reduced pressure, and the unprotected lactam is extracted into CH2Cl2 (3 x 100 mL). The organic layers are combined, washed with saturated NH4C1 ( 100 mL), brine ( 100 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give 4.75 g of a gold oil. The oil is purified by silica gel chromatography ( 100 g SG, 25% EtOAc/hexane) to yield 3.85 g (96%) of the title compound as an o~ white, Iow-melting solid.
IR (mineral oil) 3206, 3105, 1720, 1701, 1352, 1299, 1268, 1255, 1231, 1162, 1153, 1125, 923 ciri ~;
1H NMR (300 MHz, CDC13) 8 6.28, 5.65-5.85, 4.90-5.15, 3.20-3.40, 2.60, 2.20-2.60, L85-2.00, 1.65-1.80, 1.35-1.65, 1.41, 0.93, 0.9I;
MS (FAB) m /z 296, 240, 222, 194, 57.

Step 7. Preparation of tert-Butyl 3-(2-Methylpropyl)-2-oxo-1-(phenylmethyl)-a-(propen-2-yl)-3-pyrrolidineacetate.
A cold (0 °C) solution of tent-butyl 3-(2-methylpropyl)-2-oxo-a-(propen-2-yl)-3-pyrrolidineacetate (1.11 g, 3.76 mmol) in dry THF (25 mL) is treated with NaH
(60%
dispersion in mineral oil, 226 mg, 5.64 mmol) in one portion. After 30 minutes, benzyl bromide (537 p.L, 4.5I mmol) is added. The solution is allowed to slowly warm to room temperature, stirring under N2 overnight. The mixture is quenched with H20 {25 mL) and extracted with EtOAc (3 x 25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to yield 1.70 g of yellow oil. The oil is purified by silica gel chromatography (30 g SG, 10% EtOAc/hexane) to give 1.37 g (94%) of the title compound as a clear, colorless oil.
IR (liq.) 2977, 2957, 2930, 2870, 1721, 1687, 1496, 1454, 1440, 1367, 1287, 1260, 1238, 1153, 701 cm ~;
I5 1H NMR (300 MHz, CDC13) b 7.20-7.35, 5.65-5.85, 4.95-5.15, 4.41, 3.05-3.30, 2.62, 2.20-2.55, L50-1.85, 1.41, 0.89, 0.87;
MS (EI) m /z 385,329, 312, 232, 231, 188, 91, 57.
Step 8. Preparation of tert-Butyl a-(2-Hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate.
Ozone is bubbled through a cold (-78 °C) solution of tent-butyl 3-(2-methylpropyl)-2-oxo-1-(phenybnethyl)-a-(propen-2-yl)-3-gyrrolidineacetate ( 1.32 g, 3.42 mmol) in EtOH {30 mL). After purging the solution with N2, sodium borohydride (195 mg, 5.14 mmol) is added in one portion (at -78 °C).
The solution is allowed to slowly warm to room temperatuare under N2 overnight. The reactian mixture is concentrated to a white solid, diluted with H20 (10 mL) and extracted with EtOAc {3 x 25 mL). The organic extracts are combined, washed with brine (25 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to yield 1.37 g of a clear, colorless oil. The oil is purified by silica gel chromatography (50 g SG, 20% EtOAc/hexane) to give 850 mg (64%) of the title compound as a clear, colorless oil, which is a single diastereomer.
' IR, (liq.) 2956, 2930, 2870, 1771, 1720, 1684, 1497, 1464, 1454, 1441, 136.7, 1286, 1261, 1154, 701 cm 1;
t 1H NMR (300 MHz, CDC13) 8 7.20-7.40 4.42, 3.55-3.80, 3.10-3.30, 2.70, 2.35-2.50, 1.90-2.05, 1.50-1.90, 1.44, 0.88, 0.87;
MS (EI) m /z 389, 333, 287, 259, 258, 232, 230, 140, I19, 91.

Step 9. Preparation of tert-Butyl a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2 yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3 pyrrolidineacetate.
A solution of tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (435 mg, 1.12 mmol) in dry THF ( 10 mL) is "
treated with triphenyiphosphine (323 mg, 1.23 mmol), diethylazodicarboxylate (194 pL, 1.23 mmol), and phthalimide (181 mg, 1.23 mmol). The solution is allowed to stir overnight at room temperature under N2. The reaction mixture is concentrated and purified by silica gel chromatography (25 g SG, 20% EtOAc/hexane) to give mg (89%) of the title compound as an off white, amorphous solid.
IR (mineral oil) 1773, 1754, 1744, 1722, 1713, 1671, 1433, 1398, 1309, 1264, 1164, 1116, 706 cni 1;
~-H NMR (300 MHz, CDC13) 8 7.80-7.90, 7.65-7.80, 7.20-7.35, 4.41, 3.60-3.85, 3.05-3.25, 2.59, 2.30-2.50, 2.00-2.20, 1.75-1.95, 1.40-1.75, 1.48, 0.87;
MS (FAB) m /z 5I9, 464, 463, 445, 417, 230, 91, 57.
Step 10. Preparation of a-E2-(1,3-Dihydro-1,3-dioxo-2H-isoindoi-2-yl)ethyll N
hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3 pyrrolidineacetamide.
A cold (0 °C) solution of tent-butyl a-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (500 mg, 0.964 mmol) in CH2CI2 (2 ml) is treated with TFA (2 mL) and maintained at 0 °C
for 1 hour, and then at room temperature for 1 hour. The solvent is removed in vacuo to give a quantitative yield of a-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetic acid as a gelatinous solid.
IR (liq.) 2962, 1775, 1755, 1716, I6I7, 1469, 1455, 1441, 1402, 1377, 1309, ?21, ?02 cxii 1;
IH NMR (300 MHz, CDC13) 8 7.80-7.90, 7.70-7.80, 7.10-7.30, 4.44, 3.60-3.90, 3.32, 2.68, 1.80-2.25, 1.55-1.75, 0.91, 0.84;
MS (EI) m/z 462, 406, 302, 244, 232, 230, 188, 160, 91.
A cold (0 °C) solution of a-[2-(I,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyi]-3- ' (2-methylpropyl)-2-oxo-1-(phenylrnethyl)-3-pyrrolidineacetic acid (559 mg) in CH2Cl2/DMF (8 mL/2 mL) is treated with i-hydroxybenzotriazole (158 mg, 1.17 r mmol), 4-methylmorpholine ( 129 wL, 1.17 mmol), and EDC (224 mg, 1.17 mmol).
After 1 hour, additional 4-methylmorpholine ( 159 pL, L45 mmol) and hydroxylamine WO 97/32846 PCTlLTS97/02568 HCl (101 mg, 1.45 mmol) are added. The solution is allowed to.slowly warm to room temperature, stirring under N2 overnight. The reaction mixture is diluted with (25 mL) and extracted into CH2CI2 (3 x 50 mL). The organic extracts are dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and reconstituted in EtOAc (50 mL). The EtOAc layer is washed with more H20 (3 x 25 mL) and brine (25 mL). The organic layer is dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give 416 mg of white foam. The foam is purified by silica gel chromatography (50 g SG, 2°~o MeOH/CHC13) to yield 220 mg of white foam which is triturated with Et20 to give 18I mg (39°l0) of the title compound as a white solid (mp 162-164 °C).
IR (mineral oiI) 3167, 3059, 3033, 3022, 1776, 1710, 1666, 1653, 1498, 1396, 1265, 706, 696 cni 1;
1H NMR (300 MHz, CDC13) 8 7.80-7.90, 7.65-7.80, 7.05-7.40, 4.20-4.60, 3.60-4.00, 3.05-3.35, 1.40-2.75, 0.75-0.95;
MS (EI) m /z 477, 445, 421, 417, 248, 247, 188, 160, 91.
EXAMPLE 23 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetamide.

H ''CH3 N
HO~ ~C
Ii O O N
w Following the general procedure in EXAMPLE 22 and making non-critical variations but starting with tent-butyl N-tent-butyloxycarbonyl-3-(2-methylpropyl)-2-° oxo-3-pyrrolidineacetate (EXAMPLE 22, step 4), the title compound is obtained (mp 119-I20 °C).
IR (mineral oil) 326, 3164, 3065, 3029, 3016, 1658, 1519, 1494, 1305, 1291, 1260, 1063, 701, 651, 617 c~ 1;
~H NMR (300 MHz, CDC13) b 10.13, 7.60-8.30, 7.10-7.40, 4.44, 3.10-3.30, 2.48, 2.15-2.30, 1.95-2.I0, 1.35-i.85, 0.88, 0.8?;

MS (EI) m /z 304, 272, 248, 215, 188, 187, 186, 92, 91, 65.
EXAMPLE 24 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-a-[2-(4,5,6,7-tetrafluoro-1,3-dihydro-1,3-dioxo- ' 2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide.
F F
F ~ ~ F
~ N O CH

HO~ ~C
O O N
Following the general procedure in EXAMPLE 22 and making non-critical variations but starting with tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(ghenylmethyl)-3-pyrrolidineacetate (EXAMPLE 22, step 8), the title compound is obtained (mp I$3-185 °C).
IR (mineral. oil) 3221, 1724, 1713, 1694, 1672, I629, 1513, 1503, 1418, 1262, 1155, 1033, 954, 941, 754 eni 1;
~-H NMR (300 MHz, CDC13) 8 7.10-7.40, 4.25-4.55, 3.60-4.00, 3.10-3.35, 2.40-2.55, 1.40-1.35, 1.80-1.95;
MS (FAB) m/z 550, 534, 517, 489, 230, 91.
EXAMPLE 25 Preparation of 1-(3-Fluorophenyl)methyl)-a-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide.

WO 97!32846 PC.'T/CTS97/02568 / \
O N O

H ~ CH3 N
HO~ ~
O O N
F
Following the general procedure in EXAMPLE 22 and making non-cxatical variations but starting with tent-butyl 3-(2-methylpropyl)-2-oxo-a.-(propen-2-yl)-3-pyrrolidineacetate (EXAMPLE 22, step 6), the title compound is obtained (mp 163 °C).
IR. (mineral oil) 3169, 3058, 3048, 1776, 1709, 1667, 1653, 1614, 1590, 1487, 1397, 1292, 1267 cni 1;
1H NMR (300 MHz, CDC13) 8 7.75-7.90, 7.65-7.75, 7.I5-7.35, 6.80-7.00, 4.40, 3.60-3.85, 3.10-3.30, 2.30-2.65, 1.40-2.25, 0.85, 0.79;
MS (EI) m /x 495, 463, 435, 379, 322, 288, 248, 206, 160, 138, 109.
EXAMPLE 26 Preparation of a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoi.~dol-2-yl)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
/ \
o N o H ~ CHg N
HO~ ~'C

~ NHMe O
Following the general procedure in EXAMPLE 22 and making non-critical variations but starting with tent-butyl 3-(2-methylpropyl)-2-oxo-a-(propen-2-yl)-3-pyrrolidineacetate (EXAMPLE 22, step 6), the title compound is obtained (mp °C, dec).

IR, (mineral oil) 3296, 3100, 3060, 1773, 1714, 1668, 1547_, 1496, 1400, 1340, 1299, 1272, 117I, 1038 cni 1;
~I3 NMR (300 MHz, CDCl3) 8 7.80-7.90, 7.65-7.80, 6.85, 4.33, 3.60-3.95, 3.25-' 3.55, 2.81, 2.65-2.85, 2.20-2.40, 1.70-2.20, 1. I5-1.70, 0.75-0.95, 0.8I, 0.68;
MS (EI) m /z 458, 402, 340, 339, 229, 212, 185, 169, 160, 138.
EXAMPLE 27 Preparation of N3-Hydroxy-Nl-methyl-3-(2-methylprapyl)-2-oxo-a3-[2-(4,5,6,7-tetrafluoro-I,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethylJ-1,3-pyrrolidinediacetamide.
F F
F ~ ~ F

1 N ~ CH3 HO~ ~C
tt O O N
'NHMe ~O
Following the general procedure in EXANfPLE 22 and making non-critical variations but starting with tent-butyl 3-(2-methylpropyl)-2-oxo-a-(propen-2-yl)-3-pyrrolidineacetate ('F'.XAMPLE 22, step 6), the title compound is obtained (mp °C, dec).
IR (mineral oil) 3293, I785, 1723, 1668, 1550, 1514, 1500, 14I0, 1314, 1273, 1158, 1035, 944, 754 crri I;
1H NMR (300 MHz, CDCl3) 8 6.55, 4.30, 3.64-4.00, 3.20-3.55, 2.55-2.90, 1.30-1.40, 1.10-L30, 0.89, 0.78;
MS (EI) m /z 530, 498, 474, 411, 232, 212, 180, 169, 154, 152, 138.
EXA1VIPLE 28 Preparation of [S-(R*, R*)J-N3-Hydroxy-Nl-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3- ' pyrrolidinediacetamide.

H CHs HO~N~~'' OHO IV l H C'N

O
Step 1. Resolution of tent-Butyl N-tent-Butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate.
A 20 mg/mL solution of racemic tent-butyl N-tent-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate (EXAMPLE 22, step 4) is made in the mobile phase, 2% isopropanol in hexane (V/~. Aliquots of 53 mL (1.06 g) are TM
injected onto a 5.1x50 cm Chiralcel OD column (Chiral Technologies, Inc., Exton, PA
TM
19341) using a SepTech 140 HPLC (EM Separations, Inc., Wakefield, RI 02880) instrument in the automated peak shaving and recycling mode. The flow rate is mlJmin and the monitor is set at 213 nm. After four passes through the column with appropriate peak shaving, both peaks are obtained in nearly 100% yield at >99% ee for the earlier eluting enantiomer (enantiomer 1) and 96.4% ee for the later eluting enantiomer (enantiomer 2). Enantiomeric excess is determined on a 0.46 x cm Chiralcel OD-H column (Chiral Technologies, Inc.) using 5% isopropanol in hexane (V/~ at 0.5 mlJmin with the monitor set at 210 nm. Enantiomer i eluted at 8.8 minutes and enantiomer 2 eluted at 10.2 minutes (a = 1.42).
25 Step 2. Preparation of (S) tert-Butyl 3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate.
A solution of (S)-tent-butyl N-tent-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-pyrrolidineacetate (193 mg, 0.543 mmol), magnesium methoxide (3.0 mL, 6-10 wt.
%
in MeOH), and MeOH (2.7 mL) is stirred at room temperature for 16 hours. The solution is poured into water (15 mL) and the mixture acidified with acetic acid.
The mixture is extracted several times with CH2C12, the combined filtrates dried (MgS04), filtered, and concentrated to give 124 mg (89%) of the title compound as an oil.
TR (mineral oil) 3209, 3100, 3001, 1728, 1691, 1496, 1318, 1302, 1281, 1261, 1208, 1163, 1132, 1079, 969 cni l;
1H NMR (300 MHz, CDC13) 8 5.77, 3.25-3.40, 2.49, 2.20-2.40, 2.05-2.20, 1.65-WO 97/32846 PCT/US9?/02568 1.85, 1.35-1.64, 1.44, 1.42, 0.85-1.00;
MS (FA.B) m /z 256, 201, 200, 182, 154, 57, 41.
Step 3. Preparation of Methyl D-Phenyllactate.
A mixture of D-phenyllactic acid (4.79 g, 28.8 mmol), iodomethane ( 1.80 mL, 28.9 mmol), K2C03 (4.07 g, mmol), and DMF (80 mL) is stirred for I6 hours at roam -temperature. The solution is diluted with 500 mL of ether. The mixture washed with water (3 X 150 mL) and brine (150 mL). The organic layer is dried (MgS04), filtered, and concentrated to give 3.89 g (75%) of the title compound as a white solid.
1H NMR (300 MHz, CDC13) a 7.15-7.40, 4.40-4.55, 3.78, 3.13, 2.97, 2.68.
Step 4. Preparation of the Triflate of Methyl D-Phenyllactate.
Triffuoromethylsulfonic anhydride ( 1.37 mL, 8.14 mmol) is added to a solution of methyl D-phenyllactate (1.20 g, 6.66 mmol), CC14 (8.6 mL), and pyridine (0.70 mL, 8.7 mmol) at 0 °C. The mixture is stirred for 1 hour at 0 °C and then diluted with pentane (35 mL). The mixture is allowed to warm to room temperature and is filtered. The solids are washed with pentane (35 mL) and the combined filtrates concentrated. Purification by flash chromatography (4:1 hexane:EtOAc) to give 1.39 g (55%) of the title compound as an oil.
1H NMR (300 MHz, CDC13) b 7.15-7.40, 5.25, 3.84, 3.35, 3.21.
Step 5. Preparation of [S-(R*, R*)]N3-tent-Butyl-Nl-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetate.
Sodium hydride (21.4 mg, 0.535 mmol, 60% mineral oil dispersion) is added to a solution of (S) tent-butyl 3-(2-methylgropyl)-2-oxo-3-pyrrolidineacetate (124 mg, 0.486 mmol) and THF (1.65 mL) at 0 °C. The solution is stirred for 15 minutes at 0 °C and then a solution of the triflate ( 166 mg, 0.532 mmol) in 0.5 mL
of pentane is added. The solution is stirred for 2 hours at 0 °C and 1 hour at room temperature.
Aqueous workup (EtOAc, MgS04) and purification (4:1 hexane:EtOAc) provides 88.3 mg (44%) of the title compound as an oil.
IR (liq.) 2956, 2933, 1744, 1731, 1693, 1455, 1435, 1393, 1368, 1352, 1269, 1209, 1156, 1155, ?00 cm 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 5.14, 3.70, 3.20-3.45, 3.00, i.95-2.10, 2.08, 1.60-1.80, 1.45-1.55, 1.35-1.45, 1.40, 0.89, 0.86;
MS (EI) m /z 417, 361, 344, 305, 302, 271, 270, 214, 162, 132, 57.
Step 6. Preparation of [S-(R*, R*)1 3-(tert-Butylacetoxy)-3-(2-methylpropyl)-2-oxo-a1-(phenylmethyl)-1-pyrrolidineacetic Acid.
A mixture of [S-(R*, R*)]-N3-tent-butyl-N1-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetate (254 mg, 0.608 mmol), MeOH (12 mL), water (3.0 mL), and sodium hydroxide (98.4 mg, 2.46 mmol) is stirred at room temperature for 16 hours and then concentrated. The residue is diluted with water, acidified ( 10% HCl) and the aqueous layer extracted several times with CH2C12.
The organic layers are dried (MgS04), filtered, and concentrated to give 233 mg (95%) of the title compound as an oil.
IR (liq.) 2958, 2933, 2872, 1730, 1693, 1651, 1456, 1443, 1393, 1368, I273, 1258, 1207, 1155, 699 cni 1;
IH NMR (300 MHz, CDC13) 8 7.20-7.35, 4.67, 3.40, 3.20-3.35, 3.00-3.10, 2.29, 1.95-2.10, 1.80-1.95, 1.60-1.75, 1.52, 1.41, 1.31, 0.91, 0.87;
MS {EI) m/z 403, 347, 330, 303, 302, 291, 256, 200, 132, 57, 55.
Step 7. (S-(R*, R*)] tert-Butyl Nl-Methylacetamide-3-(2-methylpropyl)-2-oxo-ccl-(phenylmethyl)-3-pyrrolidineacetate.
CDI (94.3 mg, 0.582 mmol) is added to a solution of [S-(R*, R*)] 3-(tert-butylacetoxy)-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyl)-I-pyrrolidineacetic acid (224 mg, 0.555 mmol) and THF (2.5 mL). The solution is stirred for 1 hour at room temperature and then 0.27 mL of 40% aq methylamine is added. The solution is stirred at room temperature for 16 hours. Aqueous workug (EtOAc, 3% HCI, 10%
NaOH and brine washes, MgS04) gives 259 mg of crude product which is purified by flash chromatography (1:1 hexane:EtOAc) to give 198 mg (86%) of the title compound as an oil.
IR (mineral oil) 3395, 1719, 1682, 1656, 1545, 1442, 1351, I306, 1274, 1248, 1210, 11.50, 1117, 747, 703 cm 1;
IH NMR (300 MHz, CDC13) 8 7.15-7.30, 6.90-7.05, 4.25, 3.41, 3.20-3.35, 2.95-3.10, 2.82, 2.43, 1.95-2.10, 1.75-1.90, 1.50-1.70, 1.43, 1.08, 0.88, 0.81;
MS (EI) m /z 416 (M+) 360, 358, 343, 303, 302, 284, 269, 161, 132, 57.
Step 8. Preparation of [S-(R*, R*)] NI-Methylacetamide-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyl)-3-pyrrolidineacetic Acid.
TFA (3.0 mL) is added to a solution of [S-(R*, R*)] tent-butyl NI-methylacetamide-3-(2-methylpropyl)-2-oxo-a 1-(phen.ylmethyl)-3-pyrrolidineaceta~te (192 mg, 0.461 mmol) and CH2CI2 (3.0 mL) at 0 °C. The solution is stirred for 1 hour at 0 °C and for 3 hours at room temperature. The solution is concentrated which is repeated twice more from CH2Cl2 (2 X 30 mL). Aqueous workup (CH2C12, - MgS04) provides 158 mg (95%) of the title compound as an oil.
*H NMR (300 MHz, CDCl3) 8 7.15-7.35, 6.10-6.25, 4.66, 3.25-3.50, 3.17, 2.76, 2.38, 2.00-2.10, 1.60-1.85, 1.53, 1.25-i.40, 0.90, 0.84;
MS (EI) m/z 360, 303, 302, 284, 269, I61, 149, 132, 69, 57, 55.
_69-Step 9. Preparation of [S-(R*, R*)]-N3-Hydroxy-N~-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
EDC (92.2 mg, 0.481 mmol) is added to a solution of [S-(R*, R*)] Nl- -methylacetamide-3-(2-methylpropyl)-2-oxo-a1-(phenylmethyl)-3-pyrrolidineacetic acid (I5I mg, 0.419 mmol), CH2C12 (4.1 mL), DMF (1.0 mL), HOBT (56.4 mg, 0.417 mmol), and N-methyimorpholine (50 uL, 0.46 mmoi) at 0 °C. The solution is stirred for 5 minutes at 0 °C and 1 hour at room temperature. Hydroxylamine hydrochloride (57.8 mg, 0.832 mmol) and N-methylmorpholine (90 ~tL, 0.82 mmol) are added and the mixture stirred overnight at room temperature. Aqueous workup (CH2C12, MgS04) anal purification by flash chromatography (20:1 CH2C12:MeOH) provided mg of the hydroxamate as an oil which is crystallized from ether/EtOAclhexane to give 50 mg (32%) of the title compound as a white crystalline material (mp 159-°C): [a]D25 -84° (c 0.49, CHCi3).
IR (mineral oil) 3372, 3196, 3028, 1687, 1669, 1635, 1605, 1543, 1441, 1404, 1355, 1302, 1287, 747, 703 ciri 1;
MS (EI) m /z 375, 317, 316, 302, 299, 284, 200, 132, 91, 58, 55.
EXAMPLE 29 Preparation of CR,,R-(R*, R*)]-a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy-Nl-methyl-3-(2-methylprnpyl)-2-oxo-a1-(phenylmethyl)-1,3-pyrrolidinediacetamide.
O N O

H ~ CH3 HO~ ~C
OHO N /
H C-N

O

Step I. Preparation of (R) tert-Butylmethyl-3-(2-methylpropyl)-2-oxo-aZ-(phenylmethyl)-a3-(propen-2-yI)-1,3-pyrrolidinedia.cetate.
Sodium hydride (129 mg, 3.23 mmol, 60% mineral oil dispersion) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-a-(propen-2-yI)-3-pyrrolidineacetate (EXAMPLE 22, step 6; 862 mg, 2.92 mmol) and THF (10 mL) at 0 °C. The solution is stirred for 20 minutes at 0 °C and then a solution of the trifl.ate (EXAMPLE 28, step 4; 1.01 g, 3.23 mmol) ~ 2.0 mL of pentane is added. The solution is stirred for 2 hours at 0 °C and 1.5 hours at room temperature. Aqueous workup (EtOAc, MgS04) and purification (4:I hexane:EtOAc) provided 922 mg (69%) of the title compound as an oil which is a mixture of diastereomers.
IR (liq.) 2975, 2956, 2934, 1745, 1724, 1690, 1455, 1435, 1425, 1368, 1288, 1267, 1237, 1210, 1153, cni 1;
1H NMR (300 MHz, CDCl3) major peaks only 8 3.71, 3.70, L40, 1.38, 0.89, 0.83, 0.69, 0.56;
MS (EI) m l z 457, 401, 342, 310, 304, 303, 260, 200, 162, 91, 57.
Step 2. Preparation of (R) 3-(tert-Butylacetoxy)-3-(2-methylpropyl)-2-oxo-al-1 (phenylmethyl)-a3-(propen-2-yl)-1-pyrrolidineacetic Acid.
A mixture of (R.) tent-butyimethyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl) a3-(propen-2-yl)-1,3-pyrrolidinediacetate (913 mg, 2.00 mmol), MeOH (32 mL), water (8.0 mL), and sodium hydroxide (362 mg, 9.05 mmol) is stirred at room temperature for 16 hours and then concentrated. The residue is diluted with water, acidified (10% HCI), and the aqueous layer extracted several times with CH2C12. The organic layers are dried (MgS04), filtered, and concentrated to give 829 mg (93%) of the title compound as an oil.
IR, (liq.) 3003, 2974, 2959, 2932, 1725, 1692, I652, 1643, 1455, 1368, 1284, 1272, 1255, 1206, 1153 cui 1;
1H NMR (300 MHz, CDCl3) major peaks only 8 3.57, 2.99, 2.69, 1.40, 1.38, 0.89, 0.85, 0.61, 0.59;
MS (EI) m /z 443, 387, 342, 296, 290, 289, 252, 246, 200, 91, 57.
Step 3. Preparation of [R,R-(R*, R*)) and [S,R-(S*, S*)l tert-Butyl Nl-Methylacetamide-3-{2-methylpropyl)-2-oxo-a1-1-{phenylmethyl)-a3-(propen-2-yl)-3-pyrrolidineacetate.
- CDI (3I4 mg, 1.94 mmol) is added to a solution of (R) 3-(tent-butylacetoxy)-(2-methylpropyl)-2-oxo-al-1-(phenylmethyl)-a3-(propen-2-yl)-1-pyrrolidineacetic acid (821 mg, i.85 mmol) and THF (8.0 mL). The solution is stirred for 1 hour at room temperature and then 1.1 mL of 40% aq methylamine is added. The solution is WO 97!32846 PCTJUS97102568 stirred at room temperature for 16 hours. Aqueous workup (EtOAc, 3% HCl, 10%
NaOH and brine washes, MgS04) gives 921 mg of crude product which is purified by flash chromatography (1:1 hexane:EtOAc) to give 126 mg of diastereomer A. ' Further elution provided diastereomer B contaminated by diastereomer A and two minor diastereomers. Repurification of the mixture by flash chromatography (two ' collums; 1:1 hexane EtOAc) provides an additional I74 mg of diastereomer A
(total 300 mg, 36%) as an oil.
IR (mineral oil) 3376, 1702, 1685, 1667, 1538, I50I, I443, 1433, 1277, 1267, I249, I232, II56, 742, 697 cm 1;
MS (EI) m /z 456, 400, 399, 398, 343, 342, 324, 309, 200, I32, 5?.
Further elution provided 209 mg (25%) of impure diastereomer B:
IR, (liq.) 3328, 2975, 2957, 2934, 1724, I663, I554, 1498, 1455, 1438, 1368, 1292, I266, 1152, 699 cm 1;
1H NMR (300 MHz, CDC13) 8 7.I0-7.30, 6.25-6.35, 5.50-5.70, 4.90-5.10, 4.64, 3.30-3.45, 3.08, 2.80, 2.71, 2.I0-2.40, L70-L90, L30-1.65, 0.86, 0.79;
MS (EI) m /z 456, 400, 398, 343, 342, 324, 309, 259, 200, I32, 57.
Step 4. Preparation of [R,R-(R*, R*)]-tent-Butyl a3-(2-Hydroxyethyl)-Nl-methylacetamide-3-(2-methylpropyl)-2-oxo-a1-1-(phenylmethyl)-3-pyrrolidineacetate.
Ozone is passed through a solution of [R,,R-(R*, R*)]-tert-butyl N~--methylacetamide-3-(2-methyipropyl)-2-oxo-al-1-(phenylmethyi)-a3-(propen-2-yl)-pyrrolidineacetate (EXAMPLE 29, step 3, diastereomer B; 203 mg, 0.445 mmol) and EtOH (4.4 mL) at -78 °C for 4 minutes. After purging with oxygen, sodium borohydride (27 mg, 0.71 mmol) is added. The mixture is stirred at -78 °C for 1 hour and then allowed to slowly waxen to room temperature over 1 hour. After 1 hour at room temperature, sodium borohydride ( I4 mg, 0.37 mmol) is added and the mixture stirred an additional 2 hours at room temperature. Concentration and aqueous workup (EtOAc, MgS04) provided 198 mg {97%) of the title compound as an oil which is carried on crude.
IR (liq.) 3320, 2957, 2934, 1722, 1659, I455, 1437, I4I4, 1392, 1368, 1260, II52, 1057, 734, 699 cai 1;
1H NMR (300 MHz, CDCl3) 8 7. I0-7.35, 6.15-6.25, 4.64, 2.70, 1.44, 0.86, 0.79;
MS {EI) m /z 460, 346, 328, 132, 105, 91, 81, 69, 58, 57, 55.

WO 97/32846 PCT/US97I025b8 Step 5. Preparation of [R,R-{R*, R*)]-tent-Butyl a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyll-Nl-methylacetamide-3-(2-methylpropyl)-2-oxo-al-1-(phenylmethyl)-3-pyrroiidineacetate.
DEAD (73.4 uL, 0.446 mmol) is added to a solution of [R,R-(R*, R*)]-tent-butyl a3-(2-hydroxyethyl)-NI-methylacetamide-3-{2-methylpropyl)-2-oxo-al-1-(phenylmethyl)-3-pyrrolidineacetate (195 mg, 0.423 mmol), triphenylphosphine (I22 mg, 0.465 mmol), phthalimide (68.1 mg, 0.463 mmol) and THF (5.0 mL). The solution is stirred for 16 hours at rnom temperature. Concentration and purification by flash chromatography (two collums; 1:1 hexane:EtOAc) give 144 mg (58%) of the 7.0 title compound as an oil.
1H NMR (300 MHz, CDCI3) major peaks 8 7.78-7.90, 7.65-7.75, 7.10-7.35, 6.30-6.40, 4.59, 2.71, 1.49, 0.83, 0.78.
Step 6. Preparation of [R,,R-(R*, R*)]-a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-al-1-(phenylinethyl)-1,3-pyrrolidinediacetamide.
TFA (2.0 mL) is added to a solution of [R,R-(R*, R*)]-tert-butyl a3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-Nl-methylacetamide-3-(2-methylpropyl)-2-ozo-al-1-(phenylmethyl)-3-pyrrolidineacetate (144 mg, 0.244 mmol) and CH2C12 (2.0 mi~) at 0 °C. The solution is stirred for 0.5 hours at 0 °C and for i.5 hours at room temperature. The solution is concentrated which is repeated twice more from CH2Ci2 (2 X 40 mL). Aqueous workup (CH2Cl2, MgSO4) provides 127 mg (97%) of the acid intemediate as an oil.
EDC (52.7 mg, 0.275 mmol) is added to a solution of the crude acid (127 mg, 0.238 mmol), CH2C12 (2.4 mL), DMF (0.& mL), HOBT {32.2 mg, 0.238 mmol), and N-methylmorpholine (28.5 p.L, 0.259 mmoi) at 0 °C. The solution is stirred for 5 minutes at 0 °C and 1 hour at room temperature. Hydroxylamine hydrochloride (33.2 mg, 0.478 mmol) and N-methylmorpholine (51 ~ch, 0.46 mmol) are added and the mixture stirred overnight at room temperature. Aqueous workup (CH2C12, MgS04) and purification by flash chromatography (40:1 EtOAc:MeOH) provides 65.9 mg of the title compound as an oil which is crystallized from etherlhexane to give 45 ' mg (34%) of the product as a white powder material (mp 176-180°C ).
IR, (mineral oil) 1714, 1672, 1634, 1401 cni ~;
1H NMR {300 MHz, CDCI3) 8 7.70-7.90, 7.05-7.35, 6.85-7.00, 6.10-6.20, 4.68, 3.35-3.75, 3.4I, 3.23, 2.90-3.10, 2.70, 2.32, 2.10-2.35, 1.30-1.95, 0.82, 0.73;
MS (EI) m /z 548, 430, 429, 302, 259, 244, 200, 185, 160, 130, 56.

WO 97/32846 PCTlLTS97/02568 EXAMPLE 30 Preparation of [S-(R*, R*}J-N3-Hydroxy-N~-methyl-3-(2-methylpropyl)-2-oxo-a 1-(phenylmethyl)-1, 3-pyrrolidinediacetamide. ' H
N
HO~
cal-10'~ N' H CAN

O
Step 1. Preparation of (~)-a-(2-Methylpropen-2-yl)-y trityloxymethyl-y butyrolactone.
Lithium diisopropylamide (10.6 mL, 21.2 mmol, 2.0 M, .
heptane/TI~/ethylbenzene) is added to a solution of S-(+)-~-trityloxymethyl-~-butyrolactone (6.36 g, 17.6 mmol), THF (51 mL), and HNtPA (3.8 mL) at -78 °C.
After stirring for 30 minutes at -78 °C, a solution of 3-bromo-2-methylpropene (1.96 mL, 19.4 mmol) and THF { 10.0 mL) is added. The solution is allowed to stir for 4 hours at -?8 °C and is then quenched with aqueous ammonium chloride (50 mL).
After warming to room temperature, aqueous workup (EtOAc, MgS04) provides an oil which is crystallized from hexane/EtOAc (4:1) to give 3.89 g of the title compound as a white solid (mp 134-135.5°C). The filtrate is concentrated and purified by flash chromatography (4:1 hexane:EtOAc) to give additional title compound {6.I1 g total, 84%):
IR (mineral oil) 1764, 1489, 1216, 1179, 1151, 1102, 1041, 1029, 962, 902, 77I, 749, 707, 694, 636 crri 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.50, 4.81, 4.72, 4.50-4.65, 3.45, 3.I3, 2.95-3.15, 2.60-2.70, 1.85-2.25, L73; "
MS (EI) m /z 412, 335, 259, 258, 244, 243, 165, 105, 93, 77, 55.
Step 2. Preparation of (yS)-a-(2-Methylpropyl)-y-trityloxymethyl-~-butyrolactone.
A mixture of (yS)-a-(2-methyipropen-2-yl)-y-trityloxymethyl-y butyrolactone (6.10 g, 14.8 mmol), 10% Pd/C (800 mg) and EtOAc (250 mL) is hydrogenated (42 ~psi) in a Parr flask at room temperature for 18 hours. The mixture is filtered and the residue washed with EtOAc, CH2C12, and EtOAc. The filtrate is dried (MgS04), filtered, and concentrated to give 5.67 g (92%) of the title compound as an oiI which is a mixture of diastereomers.
IR (liq.) 2956, 2930, 2871, 1773, 1490, 1449, 1227, II72, 1093, 1033, 9''l4, 767, 747, 706, 633 cm 1;
1H NMR. (300 MHz, CDCl3) & 7.15-7.50, 4.50-4.65, 3.44, 3.12, 2.80-2.95, 2.I5-2.30, L85-2.00, 1.60-1.85, 1.20-1.40, 0.95, 0.91;
MS (ED m/z 414, 337, 259, 258, 244, 243, 165, I09, 105, 77, 69.
Step 3. Preparation of [S-(R*, R*)]-a-(2-Methylpropyl)-a-(propen-2-yl)-~
trityloxymethyl-~y butyrolactone.
Lithium diisopropylamide (8.3 mL, 16.6 mmol, 2.0 M, heptane/THFlethylbenzene) is added to a solution of (~yS)-a-(2-methylpropyl)-y trityloxymethyl-~butyrolactone (5.67 g, 13.7 mmol), THF (50 mL), and HMPA (2.9 mL) at -78 °C. After stirring for 30 minutes at -78 °C, a solution of allyl brom2de (L46 mL, I6.9 mmol) and THF (8.0 mL) is added. The solution is allowed to stir for 4 hours at -78 °C and is then quenched with aqueous ammonium chloride (50 ~mL).
After warming to room temperature, aqueous workup (EtOAc, MgS04) and purification by flash chromatography (6:1 hexane:EtOAc) to give 5.12 g of the title compound (82%) as a white powder (mp 84-85 °C).
TR (mineral oil) 1770, 1489, 1I84, 1119, 1089, 1070, 1034, 1027, 1002, 99I, 775, 754, 704, 632 cvi 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.50, 5.65-5.85, 5.10-5.20, 4.40-4.55, 3.15-3.35, 2.20-2.40, L90-2.15, 1.45-1.80, 0.92, 0.85;
MS (EI) m/z 454, 377, 259, 258, 244, 243, I65, 109, 105, 77, 55.
Step 4. Preparation of [S-(R*, R*)]-a.-(2-Methylpropyl)-a-(propen-2-yI)-y hydroxymethyl-y-butyrolactone.
TFA (15.0 mL) is added to a solution of [S-(R*, R*)~-a-(2-methylpropyl)-a-(propen-2-yl)-y trityloxymethyl-~butyrolactone (2.09 g, 4.60 mmol) and CH2C12 (30.0 mL) at 0 °C. The solution is stirred for 75 minutes at 0 °C and is ' concentrated. Aqueous workup (CH2C12, MgS04) and purification by flash chromatography (i:1 hexane:EtOAc) provides 684 mg (70%) of the title compound as an oil.
IR. (liq. ) 3434, 2958, 2932, 2872, 1767, 1368, 1191, 1140, 1101, I075, 1058, 1034, 998, 923, 622 cni I;
1H NMft (300 MHz, CDC13) 8 5.70-5.90, 5.I0-5.25, 4.45-4.55, 3.89, 3.60, 2.00-2.50, 1.60-1.90, 1.52, 0.96, 0.89; , MS (EI } m/z 212, 156, III, 109, 93, 81, 69, 67, 55, 43, 41.
Step 5. Preparation of [R*,R*~ a-(2-Methylpropyl)-a-(propen-2-yl)-y hydroxy-~y~- ' butyrolactone.
A mixture of [S-(R*, R*)3-a-(2-methylpropyl)-a-(propen-2-yl)-y-hydroxymethyl-' ~butyrolactone (682 mg, 3.21 mmol), NaOH (350 mg, 8.75 mmol), THF (40 mL), and H20 ( 10 mL) is stirred for 19 hours at room temperature. Additional NaOH ( mg, 2.85 mmol) is added after I6 hours. The mixture is concentrated and the residue taken up into MeOH (43 mL). A solution of sodium periodate (862 mg, 4.03 IO mmol) and H20 (4.3 mL) is added and the mixture stirred at room temperature for 3 hours. After concentration, the aqueous residue is acidified (HCI) and extracted with CH2C12 (3 X 44 mL). The organic layers are dried (MgS04), filtered, and concentrated to provide 625 mg (98%) of the title compound as a semi-solid.
IR. (liq.) 3389, 2959, 2933, 2873, 1769, 1747, 1746, I369, 1186, 1170, 1129, I5 988, 963, 944, 926 cm 1;
~H NMR (300 MHz, CDClg) 8 5.60-5.90, 5.I0-5.25, 3.30-3.50, 1.45-2.55, 0.85-1.00;
MS (EI ) mlz 142, 113, 97, 95, 67, 57, 55, 43, 41, 39.
Step 6. Preparation of L-Phenylalanine Methyl Amide.
20 CDI (545 mg, 3.36 mmol) is added to a solution of CBZ-z-phenylalanine (1.00 g, 3.34 mmol) and THF (12.5 mL). The solution is stirred for 1 hour at room temperature and then 40% aqueous methylamine (1.5 mL) is added. The solution is stirred for 16 hours at room temperature. The solution is diluted with EtOAc and is washed with NaHC03, I0% HCi, NaHC03, and brine. The organic layer is dried 25 (MgS04), filtered, and concentrated to give 983 mg (94%) of the carbamate intermediate as a white solid.
1H NMR (300 MHz, CDC13) b 7.10-7.40, 5.50-5.65, 5.25-5.40, 5.07, 4.33, 2.95-3.20, 2.70.
Ammonium formate (644 mg, 10.2 mmol) is added to a mixture of the 30 carbamate (980 mg, 3.14 mmol), MeOH (2I mL), and 10% Pd/C (104 mg). The mixture is stirred for I hour at room temperature and is filtered. The residue is "
washed with MeOH, CH2Cl2, and is concentrated. The residue is diluted with 30:1 CH2C12:MeOH (30 mL), dried (MgS04), filtered, and concentrated to provide 504 mg (90%) of the title compound as a foam which is carried on crude.
35 1H NMR (300 MHz, CDC13) 8 8.I2, 7.15-7.40, 4.07, 3.72, 3.26, 2.65-2.85, 2.78.

Step 7. Preparation of [S-(R*, R*)] Methyl-3-(2-methylpropyl)-2-oxo-a-(phenylmethyl)-3-(propen-2-yl)-1-pyrrolidineacetamide.
A solution of L-phenylalanine methyl amide (EXA.MPLE 30, step 6; 210 mg, 1.18 mmol) and MeOH (8.5 mL) is added to [R*,R*] a-(2-methylpropyl)-a-(propen-yl)-y-hydroxy-~butyrolactone (EXAMPLE 30, step 5; 200 mg, 1.01 mmol). Sodium cyanoborohydride (85.0 mg, 1.35 mmol) is added and the solution stirred for 16 hours at room temperature. Concentration and aqueous workup (20:I CHCI3:MeOH, MgS04) provided 397, mg of the uncyclized intermediate as an oil. A mixture of the crude residue, toluene (24 mL), MeOH (8.0 mL), and silica gel (800 mg) is slowly heated to reflex allowing the MeOH to boil off. The mixture is then maintained at reffux for 3 hours and is allowed to cool to room temperature. The mixture is filtered, the solids washed with 20:1 CH2C12:MeOH (3 X 40 mL), and the filtrate concentrated. Purification by flash chromatography (EtOAc) provided 218 mg (63°!0) of the title compound as an oil.
IR (liq.) 3314, 2955, 2929, 2871, 1661, 1660, 1558, 1498, 1455, 1439, 1413, 1296, 1267, 741, 698 cni 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 6.15-6.30, 5.10-5.35, 4.75-5.00, 3.15-3.40, 3.07, 2.74, 2.00-2. I5, 1.55-2.00, 1.35-1.55, 0.90, 0.81;
MS (EI) m/z 342, 311, 299, 285, 284, 162,132, 105, 91, 81, 67, 58, 55.
Step 8. Preparation of [S-(R*, R*)] N1-Methylacetamide-3-(2-methylpropyl)-2-oxo-ai-(phenylmethyl)-3-pyrrolidineacetic Acid.
Ruthenium(I~ oxide hydrate (17.3 mg, 0.130 mmol) is added to a mixture of sodium periodate (1.07 g, 5.00 mmol), H20 (14.0 mL), CH3CN (14.0 mL), and CC14 (14.0 mL). The mixture is stirred for 20 minutes at room temperature and then NaHC03 (1.32 g, 15.7 mmol) and Ii20 (7.0 mL) are added. After stirring an additional 5 minutes, a solution of [S-(R*, R*)]-methyl-3-(2-methylpropyl)-2-oxo-a-(phenylmethyl)-3-(propen-2-yl)-1-pyrrolidineacetamide (215 mg, 0.628 mmol) and CH3CN (6.0 mL) is added. After stirnng for 8 minutes at room temperature, the residue is poured into a mixture of H20 (40 mL) and EtOAc (100 mL). The aqueous layer is removed and the organic layer extracted with 10% NaOH (2 X 15 mL).
The " combined basic layers are acidified (4 N HCl) and extracted with CH2CI2 (3 X

mL). The CHZC12 layers are dried (MgS04), filtered, and concentrated to provide 109 mg (48%) of the title compound as an oil.
IR (liq.) 3347, 3029, 2957, 2872, 1724, 1657, 1552, 1498, 1455, 1440, 1413, 1296, 1271, 1193, 700 cm-1;
1H NMR (300 MHz, CDC13) 8 7.10-'1.40, 6.81, 4.54, 3.15-3.50, 2.73, 2.45, 1.80-2.05, 1.55-1.75, L40-1.55, 1.24, 0.89, 0.82;
MS (EI) m /x 360, 303, 302, 284, 269, 244, 200, 161, 132, 9I, 55.
Step 9. Preparation of [S-(R*, R*)]-N3-Benzyloxy-N1-methyl-3-(2 methylpropyl)-2-oxo-a 1-(phenylmethyl)-1, 3-pyrrolidinediacetamide.
CDI (59.0 mg, 0.364 mmol) is added to a solution of [S-(R*, R*)J N~-methylacetamide-3-(2-methylpropyl)-2-oxo-al(phenylmethyl)-3-pyrrolidineacetic acid (109 mg, 0.302 mmol) and CH2C12 (2.3 mL). The solution is stirred for 1 hour at room temperature and then O-benzylhydroxylamine hydrochloride (?0.0 mg, 0.439 mmol) and N-methylmorpholine (0.06 mL, 5.5 mmol) are added. The solution is stirred for 16 hours at room temperature. Aqueous workup (CH2C12, MgSO,~) and purification by flash chromatography (EtOAc) provides 82.4 mg (59%) of the title compound as an oil.
IR (liq.) 3213, 3031, 2957, 2872, 1662, 1545, 1498, 1455, 1441, 1412, 1368, 1295, 1280, 750, 699 cm-1;
1H NMR (300 MHz, CDCl3) 8 8.85-9.00, 7.10-7.50, 6.40-6.55, 4.75-5.00, 4.40-4.55, 3.10-3.45, 2.75, 2. I5-2.30, 1.80-2.15, 1.40-1.65, 1.10-L30, 0.87, 0.79;
MS (EI) m/z 465, 407, 284, 132, 105, 92, 91, 77, 69, 58, 55.
Step 10. Preparation of [S-(R*, R*)J-N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
An atmosphere of hydrogen is placed over a mixture of [S-(R*, R*)]-N3-benzyloxy-N1-methyl-3-(2-methylpropyl)-2-oxo-a~--(phenylmethyl)-1,3-pyrrnlidinediacetamide (79.2 mg, 0.170 mmol), MeOH (4.0 mL) and 10% Pd/C (15 mg). After stirring for 4 hours at room temperature, the mixture is filtered, the solids washed with MeOH (4 X 5 mL) and CH2C12 (5 mL), and the combined filtrate concentrated to provide 41 mg of the desired product as an oil. Trituration (ether/hexane) provides 39.4 mg (62%) of the title compound as a white powder (mp 162-165°C): [aJD25 -g6° (c 026, CHC13).
IR (mineral oil) 3372, 3195, 3028, 1687, 1669, 1636, 1605, 1542, 1441, 1405, 1355, 1302, 1287, 747, 704 cni I;
1H NMR (300 MHz, CDCl3) 8 7.15-7.40, 6.50-6.65, 4.50-4.65, 3.10-3.50, 2.78, 2.32, 1.90-2.15, 1.45-1.80, 1.20-1.35, 0.90, 0.83;
MS (EI) miz 375, 317, 302, 301, 299, 284, 244, 200, 132, 91, 55.
EXAMPLE 31 Preparation of [S-(R*, R*)J-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-NI-(2-phenethyl)-aI-(phenylmethyl)-1,3-pyrrolidinediacetamide.
_78_ CHg HO~
'' S OHO N
N
~I

Following the general procedure of EXAMPLE 30 and making non-critical variations but starting with LR .*,R*] a-(2-methylpropyl)-a-(propen-2-yl)-y hydroxy-y butyrolactone (EXAMPLE 30, Step 5) and L-phenylalanine phenethyl amide (prepared similarly to that described in EXt-LMPLE 30, Step 6), the title compomnd is obtained (mp 158-159°C).
[a]D25 -83° (c 0.35, CHC13);
IR (mineral oil) 3219, 3087, 3063, 3029, 1668, 1644, 1558, 1498, 1354, 1311, 1297, 1283, 749, 743, 701 cni 1;
~H NMR (300 MHz, CDC13) S 9.63, 7.00-7.40, 6.31, 4.59, 3.30-3.60, 3.00-3.20, 2.65-2.85, 2.14, 1.85-2.10, L40-1.?5, 1.25, 0.87, 0.80;
MS (EI) m /z 465, 318, 3I7, 316, 284, 200, 132, 105, 9I, 55. -EXANIPLE 32 Preparation of [S-(R*, R*)]-N3-Hydroxy-N~-methyl-a1,3-bis (2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.

~CH3 HO~

H3C'N\~~CH3 Following the general procedure of EXAMPLE 30 and making non-critical variations but starting with [R*,R*] a-{2-methylpropyl)-a-(propen-2-yI)-'y-hydroxy y--79_ WO 97!32846 PCT/US97/02568 butyrolactone (EXAMPLE 30, Step 5) and L-leucine methyl amide (pregared similarly to that described in EXE1MPLE 30, Step 6), the title compound is obtained Y
(mp 138-139°C).
[a]D2~ +117° (c 0.28, CHCl3);
IR (mineral oil) 3376, 3198, 3023, 1689, 1676, 1639, 1543, 1493, 1406, 1355, 1304, 1281, 1195, 1166 ciri 1;
~-H NMR (300 MHz, CDC13) 8 9.91, 6.31, 4.35-4.50, 3.30-3.55, 2.76, 2.44, 2.20-2.40, 2.00-2.15, 1.35-1.90, 0.75-1.00;
MS (EI) m /z 341, 310, 284, 283, 282, 251, 250, 222, 98, 86, 55.
EXAMPLE 33 Preparation of [S-(R*, R*)]-ai-(Cyclohexylmethyl)-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.

N ~CH3 ,,.
HO~
O
O N
MeNH
O
Following the general procedure of EX~~MPLE 30 and making non-critical variations but starting with [R*,R*J a-(2-methylpropyl)-a-(propen-2-yl)-y hydroxy y butyrolactone (EX1~1MPLE 30, Step 5) and ~-cyclohexyl-~,-alanine methyl amide (prepared similarly to that described in EXAMPLE 30 Step 6), the title compound is obtained (mp I50-152 °C).
IR (mineral oiI) 3253, 3194, 3058, 1678, 1643, 1544, 1502, 1409, 1285, 1268, 1259, 1228, 1048, 738, 647 cni I;
1H NMR (300 MHz, CDCl3) s 6.52, 4.42, 3.30-3.55, 2.77, 2.44, 2.20-2.35, 1.95-2.15, 1.98, 1.35-1.90, 0.75-1.35, 0.92, 0.86;
MS (EI) m /z 381, 324, 323, 322, 290, 208, 86, 67.

EXAMPLE 34 Preparation of [S-(R*, R*)]-N3-I3ydroxy-N~-methyl-3-(3-methylbutyl)-2-oxo-a 1-(phenylmethyl)-1, 3-pyrrolidinediacetamide.

HO
c~HO~N~
H3C~N
O
Following the general procedure of EXAMPLE 30 and making non-critical variations but starting with [R*,R*] a-(3-methyibutyl)-a-(propen-2-yl)-y hydroxy-y butyroiactone (prepared simiiariy to that described in EXAMPLE 30, Steps 1-5) and L-phenylalanine methyl amide (EXAMPLE 30, step 6), the tide compound is obtained (mp 167-168°C).
[a]25D -104° (c 0.43, CHC13);
IR. (mineral oil) 3372, 3195, 3064, 3029, 1687, 1670, 1635, 1545, 1497, 1443, 1405, 1297, 1287, 745, 701 cm 1;
1H NMR (300 MFiz, CDC13) 8 9.50-9.80, 7.10-7.40, 6.92, 4.40-4.50, 3.10-3.45, 2.79, .2.23, 1.90-2.20, 1.70-1.90, 1.05-1.55, 0.75-1.00;
MS (FAB) m/z 390, 389, 374, 357, 331, 298, 132.
EXAMPLE 35 Preparation of N-Hydroxy-3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
H
N
HO~ ~
N
w Step 1. Preparation of Ethyl 3-(2-Methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
Ruthenium(I~ oxide hydrate (27 mg, 0.20 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2-oxo-1-{2-phenylethyl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, steps 1-3; 900 mg, 2.71 mmol), sodium periodate (2.71 g, 12.7 mmol), water (27 mL), and CC14 (27 mL) at room temperature. After stirring overnight at room temperature, aqueous workup (CH2CI2, MgS04) and purification by column chromatography (20% EtOAc/hexane) gives 611 mg of the title compound (65%) as a colorless oil.
IR (Iiq.) 2959, 1775, 1733, 1704, 1455, 1438, 1403, 1368, 1346, 1255, 1218, 1193, 1165, 1030, 699 c~ 1;
1H NMR (300 MHz, CDCI3) 8 7.15-7.35, 4.09, 3.65-3.85, 2.50-3.00, 1.35-1.80, 1.22, 0.91, 0.85;
MS (EI) m /z 345, 300, 289, 259, 203, 105, I04.
Step 2. Preparation of 3-{2-Methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetic Acid.
Sodium hydroxide (283 mg, 7.08 mmol) is added to a mixture of ethyl 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetate (611 mg, 1.77 mmol), methanol (10 mL), and water (5 mL), and the mixture is allowed to stir overnight at room temperature. The mixture is partitioned with 10 ml of water and 10 mL of Et20. The layers are separated and the pH of the aqueous layer was adjusted to pH
2 (pH meter) with 1.2 N HCI. The aqueous layer is extracted with EtOAc (2 x 10 mL) and CH2CI2 (2 x i0 mL), and the combined organic layers are dried (MgS04), filtered and concentrated to give 500 mg (89%) of the title compound as a white foam which is carried on crude.
~H NMR (300 MHz, CDCl3) b 7.10-7.40, 3.30-3.85, 2.50-2.95, 1.10-1.85, 0.75-1.00.
Step 3. Preparation of N-Benzyloxy-3-(2-methylpropyl)-2,5-dioxo-1-{2-phenyiethyl)-3-pyrrolidineacetamide.
CDI ( 153 mg, 0.945 mmol) is added to a mixture of 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetlc acid (300 mg, 0.945 mmol) and (7.5 mL) at room temperature. After stirring at room temperature for 1 hour, O-benzylhydroxylamine hydrochloride ( 18I mg, 1. i3 mmol) and 4-methylmorpholine ( 124 EtL, 1.13 mmol) are added to the solution. The mixture is allowed to stir overnight at room temperature. Basic workup (CH2Cl2, NaHC03, MgS04) and _82_ purification by column chromatography (1.5% MeOH/CHC13) affordes 70 mg (18%) of the title compound as a white solid (mp 1I5-117 °C).
IR. (mineral oil) 3195, 1705, 1677, 1659, 1409, 1357, 1182, 1169, 1018, 773, 752, 707, 700, 693, 627 cni 1;
1H NMR (300 MHz, CDC13) b 8.53, 8.10-8.30, 7.I0-7.45, 4.70-4.90, 3.60-3.80, 2.65-2.95, 2.10-2.65, 1.25-1_60, 0.86, 0.79;
MS (EI) m/z 422, 389, 366, 300, 260, 229, 194, 179, 125, 105, 104, 91.
Step 4. Preparation of N-Hydroxy-3-{2-methylpropyl)-2,5-dioxo-1-{2-phenylethyl)-3-pyrrolidineacetamide.
A mixture of N-benzyloxy-3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (80 mg, O.I9 mmol), Pd/C ( 10%, 5 mg), ammonium formate (59 mg, 0.95 mmol) and EtOH (2.5 mL) is stirred at room temperature. After 2 hours, a second portion of ammonium formate (35 mg, 0.56 mmol) is added and the mixture is allowed to stir overnight at room temperature. The mixture is filtered, and the filter cake washed with MeOH (3 x I5 mL) and CHC13 (3 x 15 mL). The filtrate is concentrated, reconstituted in 100 mL of 5%MeOFi/CHCI3, dried (MgS04), filtered and concentrated to an oil. Crystallization from CH2C12/Et20/hexane gives I9 mg (31%) of the title compound as~a white solid (mp 136-137 °C).
IR (mineral oil) 3316, 3087, 3065, 3027, 1702, 1634, 1563, 1498, 1420, 1229, 1213, 1164, 1083, 1048, 698 cni I;
IH NMR (300 MHz, CDC13) 8 7.10-7.40, 5.63, 3.50, 2.65-2.90, 2.71, 2.54, 1.45-1.90, 0.92, 0.87;
MS (EI) m /z 332, 300, 276, 259, 24I, 212, i96, 184, 142, I09, I05, I04, 103, 9I.
EXAMPLE 36 Preparation of N-Hydroxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide.

H CHs HOiN N.iCH3 O O~N~O
/ \
Step 1. Preparation of 3-Methyl-I-(2-phenylethyl)hydantoin.
Sodium hydride (92i mg, 23.0 mmol, 60% mineral oiI dispersion) is addecl to a solution of 1-methylhydantoin (2.19 g, 19.2 mmol) and DMF (40 mL) at 0 °C. The mixture was stirred for 1 hour and then (2-bromoethyl)benzene (3.14 mL, 23.0 mmol) is added. The mixture is stirred at 0 °C for 1 hour and 16 hours at room ' temperature. Aqueous workup (EtOAc, MgS04) and trituration with ether provides 2.21 g (53%) of the title compound as a white solid (mp 113-I14 °C). -IR (mineral oil) 1768, 1758, 1748, 1713, 1488, 1441, 1403, 1340, 1290, 1243, 1134, 995, 989, 748, 704 cnz 1;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 3.82, 3.70-3.80, 2.99, 2.85-3.00;
MS (EI) m /x 218, 105, 104, 99, 91, 78, 65, 57, 56, 51.
Step 2. Preparation of 3-Methyl-4-(2-methylpropyl)-1-(2-phenylethyl)hydantoin.
Lithium diisopropylamide (3.45 mL, 6.90 mmol. 2.0 M, heptaneJTHF/ethyibenzene) is added to a mixture of 3-methyl-I-(2-phenylethyl)hydantoin ( L50 g, 6.87 mmol) and THF (27 m.L) at -78 °C.
After stirring for 30 minutes at -78 °C, 1-iodo-2-methylpropane (0.93 mL., 8.08 mmol) is added. The mixture is stirred at -78 °C for 30 minutes and is allowed to gradually warm to room temperature. After stirring at room temperature for 1 hour, aqueous workup (EtOAc, MgS04) and purification by flash chromatography (1:1 hexane:EtOAc) gives 467 mg of the title compound (25%) as an oil. Further elution provides 704 mg of recovered starting material (47% of product based on recovered starting material). Spectral data for the title compound.
IR (liq.) 2958, 2936, 2871, 1771, 1?12, 1498, 1454, I429, 1412, 1389, 1368, I142, 1030, 753, 701 cni ~-;
1H NMR (300 MHz, CDC13) 8 7.15-7.35, 3.65-3.85, 2.85-3.00, 2.93, 1.50-1.90, 0.91;
MS (EI) m /z 274, 218, 127, 114, 105, 104, 91, 43, 41.
Step 3. Preparation of 3-Methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic Acid.
Lithium diisopropylamide (0.84 mL, 1.7 mmol, 2.0 M, heptane/THF/ethylbenzene) is added to a solution of 3-methyl-4-(2-methylpropyl)-1-(2-phenylethyl)hydantoin (464 mg, 1.69 mmol) and THF (7.0 mL) at -78 °C. After stirring the partial solution for 30 minutes at -78 °C, ethyl bromoacetate (0.23 mL, 2.1 mmol) is added. The mixture is stirred for 1 hour at -78 °C and is then allowed to warm to room temperature. After stirring at room temperature for 1 hour, aqueous workup (EtOAc, MgS04) and purification by flash chromatography (3:1 hexane:EtOAc) gives 407 mg of a 1.25:1 mixture of starting material and the ester WO 97/32846 PCT/US97/025fa8 intermediate. The mixture could not be purified by chromatography and is carried on crude. Key spectral features for the ester intermediate: 1H NMR
(300 MHz, CDC13) 8 4.00-4.15, 2.84, 1.19, 0.81.
A mixture of the crude ester (407 mg), MeOH (12 mL), H20 (2.5 mL) anal NaOH (213 mg, 5.33 mmol) is stirred at room temperature for 16 hours and is concentrated. The residue is partitioned between EtOAc and 10% NaOH. The organic layer is dried (MgS04), filtered, and concentrated to give 250 rng of starting material. The basic layer is acidified ( 10% HCl) and extracted several times with CH2Cl2. The CH2C12 layers are dried (MgS04), filtered, and concentrated to give 117 mg (21%, 45% based on recovered starting material) of the titie compound as a white solid (mp 64-67 °C).
IR (mineral oil) 3505, 3374, 1761, 1699, 1499, 1414, 1404, 1336, 1325, 1:230, 1136, 1036, 1031, 736, 697 ctri 1;
1H NMR (300 MHz, CDC13) b 7.15-7.35, 3.70-3.80, 2.80-3.00, 2.85, 2.?8, 1.73, 1.55, 1.20-1.40, 0.84, 0.78;
MS (EI) m /z 332, 2?6, 275, 273, 241, 231, 105, 104, 91, 56.
Step 4. Preparation of N-Benzyloxy-3-methyl-4-(2-methyipropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide.
CDI (57.0 mg, 0.352 mmol) is added to a solution of 3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic acid (113 mg, 0.340 mmol) and CH2C12 (2.5 mL). The solution is stirred for 1 hour at room temperature and then O-benzyl hydroxylaminehydrochloride (67.0 mg, 0.420 mmol) and N-methylmorpholine (46 ltL, 0.42 mmol) are added. The solution is stirred for 60 hours at room temperature. Basic workup (CH2C12, NaHC03, MgS04) and purification by flash chromatography (1:1 hexane:EtOAc) provides 94.8 mg (64%) of the title compound as a white solid.
IR (mineral oiI) 3198, 3012, 1771, 1713, 1681, 1653, 1522, 1498, 1432, I4I4, 1394, 1359, 758, 738, 696 cxri 1;
1H NMR (300 MHz, CDC13) 8 8.35-8.55, 7.15-7.50, 4.70-4.90, 3.74, 2.96, 2.84, 2.60-2.90, 2.38, 1.69, 1.45-1.65, 1.20-1.40, 0.80, 0.65-0.85;
MS (EI) m /z 437, 363, 273, 231, 169, 105, 104, 92, 91, 56.
Step 5. Preparation of N-Hydroxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-" phenylethyl)-4-imidazolidineacetamide.
Ammonium form.ate (59.0 mg, 0.936 mmol) is added to a mixture of N-benzyloxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4--85_ iznidazolidineacetamide (91.0 mg, 0.208 mmol), EtOH (2.5 mL), and 10% Pd/C (15 mg). The mixture is stirred at room temperature for 5.5 hours. Additional ammonium formate (35.0 mg, 0.555 mmol) is added after 2.5 hours. The mixture is filtered, the solids washed with MeOH (3 X 15 mL) and CHC13 (3 X 15 mL), and the filtrate concentrated. The residue was taken up into CHCI3 (40 mL), dried (MgS04), filtered, and concentrated to give 64.? mg (90%) of the title compound as an oil.
Crystallization from ether/hexane provided 46.4 mg (64%) of the title compound as a white powder (mp 127-129 °C).
IR. (mineral oil) 3223, 3025, 1771, 1701, 1690, I66I, 1497, 1416, 1394, 1359, 1136, 1027, 742, 737, 698 cni 1;
1H NMR (300 MHz, CDCI3) b 9.55, 7.i0-7.30, 3.60-3.85, 2.92, 2.8I, 2.55, L45-1.75, 1.15-1.35, 0.76, 0.73;
MS (EI) m /z 347, 274, 273, 231, 169, 105, 104, 56.
EXAMPLE 37 Preparation of N-Hydroxy-4-(2-methylpropyl)-2,5-dioxo-1-{2-phenylethyl)-4-imidazolidineacetamide.
H
HO'N H
N
O p N~p Step 1. Preparation of 4-(2-Methyipropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic Acid.
Sodium hydroxide (300 mg, 7.50 mmol) is added to a solution of 2-(2 methylpropyl)-2-(propen-2-yl)glycine triffuoroacetic acid {856 mg, 3.00 mmol) which is prepared by the method described in J. Org. Chem., 1988, Vol. 53, p. 5607 and H20 (10 mL). Phenethyl isocyanate (541 mg, 3.00 mmol} is added after 5 minutes and the mixture stirred fox 1 hour at room temperature under N2. The solution is diluted with more H20 {5 mL) and acidified with 6 N HCl. The resultant solution is .
heated at reffux for 2 hours. Upon cooling to room temperature, the desired product is extracted into CH2Cl2 (3 x 50 mL) and EtOAc (2 x 50 mL). The combined organic layers are dried over anhydrous Na2SO4, filtered, and concentrated under reduced WO 97/32846 PCT/ITS97/025~68 pressure to yield 619 mg of a golden oil. The oil is purified by silica gel chromatography (50 g SG, packed and eluted with a gradient of 0-40%
EtOAc/hexane) to give 162 mg (18%) of the hydantoin intermediate as an oil.
The material is suf~.ciently pure to be carried on: ZH NMR (300 MHz, CDC13) b 7.90-8.60, 7.20-7.40, 5.75-5.95, 5.25-5.40, 3.15-3.30, 3.05-3.15, 2.60-2.90, 1.80-2.00, 0.90-1.05.
Sodium periodate (NaI04, 883 mg, 4.13 mmol) is added to a mixture of H20/CH3CNlCCl4 (3/3/2 mL, respectively) and treated with ruthenium oxide monohydrate ( 14 mg, 20 mole %). Once the black solution has turned green, NaHC03 (2.17 g, 25.8 mmol) is added, followed by the further addition of NaI04 until the solution became green again. A solution of the hydantoin intermediate (155 mg, 0.516 mmol) in 3 mL CH3CN is added to the green mixture. After 5 minutes, the reaction mixture is quenched with H20 and extracted with EtOAc several times. The aqueous layer is acidified with 6 N HCl and then extracted twice with CH2CI2 (2 x) and EtOAc (2 x). The organic layers are combined, washed again with brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to yield 79 mg of the title compound as a solid. Additional title compound is recovered by washing the original EtOAc extracts with 10% NaOH, acidifying the aqueous with 6 N HCl, and re-extracting with CH2C12 (3 x). These extracts are also combined, washed again with brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to yield an additional 64 mg of the title compound. Both crops are dissolved in CH2C12, combined, filtered through a fine frit, and concentrated under reduced pressure to give a total of 143 mg (87%) of the title compound as a solid.
1H NMR (300 MHz, CDC13) 8 7.10-7.35, 3.70-3.80, 2.95, 2.66, 1.65-1.80, 1.40-1.55, 0.88, 0.80.
Step 2. Preparation of N-Benzyloxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide.
A solution of 4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic acid (126 mg, 0.379 mmol) in dry THF (5 mL) is treated with CDg (74.0 mg, 0.455 mmol). After 1 hour, 4-methylmorpholine (417 uL, 3.79 m3no1) and O-benzyhydroxylamine hydrochloride (91.0 mg, 0.569 mmol) are added. The mixture is stirred for 12 hours at room temperature and is diluted with EtOAc.
The solution is washed with saturated NaHC03, I N HCl, saturated NaHC03, and brine. The organic layer is dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to yield 156 mg of a black oil. The oil is purified by silica gel chromatography (25 g SG, packed with hexane, eluted with 50% EtOAc/hexane) to give 47 mg (28%) of the title compound as an amorphous white solid.
IH NMR (300 MHz, CDC13) 8 8.89, 7.15-7.45, 6.67, 4.70-5.00, 3.60-3.90, 2.95, 2.15-2.40, 1.50-1.70, 1.35-1.50, 0.84, 0.75;
MS (FAB) m/z 424, 334, 318, 259, 105, 91.
Step 3. Preparation of N-Hydroxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4.-imidazolidineacetamide.
A solution of N-benzyioxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide (85.0 mg, 0.201 mmol) in 25% MeOH/EtOAc is purged with N2, treated with galladium hydroxide on carbon (17 mg, 20% by weight), and placed under a H2 atmosphere (balloon). After 2.5 hours, the reaction mixture is filtered through celite and concentrated under reduced pressure to yield 70 mg of an off white foam. The material is recrystallized from hot EtOAc/hexane to give 36 mg (54%) of the title compound as a white, powdery solid (mp I45-147 °C).
IR, (mineral oil) 3284, 3227, 1762, 1719, 1707, 1662, 1655, 1424, 1365, 699 ~ 1;
IH NMR (300 MHz, CDC13) 8 7.84, 7.I5-7.40, 3.60-3.85, 2.65-3.10, 2.35-2.55, 1.45-1.75, 0.90, 0.83;
MS (EI) m/z 333, 277, 259, 243, 229, 217, 155, 105, 104, 91.
EXAMPLE 38 Preparation of N-Hydroxyl-4-(2-methylpropyl)-5-oxo-1-(2-phenylethyl)-4-pyrazolidineacetamide monohydrochloride.

H ~ CH3 N
HO~
,NH
00 N ~HC!
Step 1. Preparation of 1-(Benzyloxycarbonyl)-2-(2-phenylethyl)pyrazolidin-3-one.
Sodium hydride (562 mg, 14.1 mmol, 60% mineral oil dispersion) is added to _88-a solution of 1-(benzyloxycarbonyl)pyrazolidin-3-one (2.81 g, 12.8 mmol, prepared similarly to that described in J. Org. Chem. 1990, 55, 6037) and DMF (37 mL) at 0 °C. The solution is stirred for 30 minutes and then (2-bromoethyl)benzene (1.90 mL, I3.9 mmol) is added. The solution is stirred at 0 °C for 1 hour and 16 hours at room temperature. Aqueous workup (EtOAc, brine, MgS04} and purification by flash chromatography (2:1 ~ 1:1 hexane:EtOAc) gives 1.58 g (38%) of the title compound as an oil.
IR. (liq.) 3029, 2954, 1709, 1498, 1455, 1412, 1378, 1314, 1214, 1184, 1110, I086, I027, 748, 699 eni 1;
IO 1H 1VMR (300 MHz, CDCl3) 8 7.38, 7.I0-7.30, 5.23, 4.02, 3.80, 2.87, 2.44;
MS (EI) m /z 324, 190, 189, 106, 105, 104, 92, 91, 79, 77, 65.
Step 2. Preparation of 1-(Benzyloxycarbonyl)-4-(2-methylpropen-2-yl}-2-(2-phenylethyl)pyrazolidin-3-one.
Lithium diisopropylamide (2.92 mL, 5.84 mmol, 2.0 M, heptanel'I'HF'/ethylbenzene) is added to a solution of 1-(benzyloxycarbonyl)-2-(2.-phenylethyl)pyrazolidin-3-one (L58 g, 4.87 mmol), THF (15 mL), and HMPA (1.,04 mL) at -78 °C. After stirring for 35 minutes at -78 °C, a solution of 3-bromo-2-methylpropene (0.54 mL, 5.4 mmol) and THF (2.6 mL) is added. The solution is allowed to stir for 6 hours at -78 °C and is then quenched with aqueous ammonium chloride (25 mL}. After warming to room temperature, aqueous workup (EtOAc, MgS04) and purification by flash chromatography (3:I hexane:EtOAc) gives 1.21 g of the title compound (66%) as an oil. Further elution provides 201 mg of recovered starting material (75% of product based on recovered sm). Spectral data fox the title compound:
IR (Iiq.) 2945, I710, 1498, 1455, 1416, 1377, 1318, 1232, 1206, 1172, 1121, 1028, 897, 748, 698 cm 1;
1H NMR (300 MHz, CDC13) 8 7.38, 7.10-7.40, 5.23, 4.71, 4.53, 4.10-4.30, 4.01, 3.80-3.95, 3.09, 2.75-2.95, 2.60-2.80, 2.35-2.45, 1.63, L53;
MS (EI) m /z 378, 244, 243, 105, 104, 92, 91, 79, 77, 65.
Step 3. Preparation of tent-Butyl 2-(Benzyloxycarbonyl)-4-(2-methylpropen-2-'' yi)-5-oxo-I-(2-phenylethyl)-4-pyrazolidinacetate.
Lithium diisopropylamide (1.70 mL, 3.40 mmol, 2.0 M, heptane~~HF/ethylbenzene) is added to a solution of 1-(benzyloxycarbonyl)-4-(2-methylpropen-2-yl)-2-(2-phenylethyl)pyrazolidin-3-one (1.20 g, 3.17 mmol), TH.F (I5.6 mL), and I~'VIPA (0.69 mL) at -78 °C. After stirring for 30 minutes at -78 °C, a solution of tert-butyl bromoacetate (0.57 mL, 3.5 mmol) and THF (1.5 mL) is added.

The solution is allowed to stir for 6 hours at -78 °C and is then quenched with aqueous ammonium chloride (25 mL). After warming to room temperature, aqueous workup (EtOAc, MgS04) and purification by flash chromatography (4:1 -~ 3:1 hexane:EtOAc) gives 4I0 mg of the title compound (26%) as an oil. Further elution provides 624 mg of recovered starting material (55% of product based on recovered "
sm). Spectral data for the title compound.
IR, (neat) 1723, 1696, 1320, 1286, 1263, 1242, 1201, 1186, 1165, II23, 906, 764, 749, 697, 604 cm I;
xH NMR (300 MHz, CDC13) 8 7.35-7.45, 7.10-7.30, 5.19, 4.74, 4.68, 4.15-4.30, 3.88, 3.75-3.95, 2.80-2.95, 2.19, 2.I7, 1.62, L41;
MS {EI) m /z 492, 302, 301, 283, 255, 105, 92, 91, 57.
Step 4. Preparation of 2-(Benzyloxycarbonyl)-4-(2-methylpropen-2-yl)-5-oxo-1-(2-phenylethyl)-4-pyrazolidineacetic Acid.
TFA {8.0 mL) is added to a solution of tent-butyl 2-(benzyloxycarbonyl)-4-(2-methylpropen-2-yl)-5-oxo-I-(2-phenylethyl)-4-pyrazolidinacetate (546 mg, 1.1l mmol) and CH2C12 (20 mL) at 0 °C. The solution is stirred for 1.5 hours at 0 °C and is concentrated. Aqueous workup (CH2Cl2, MgS04) provides 456 mg (94%) of the title compound which is isolated as an oil.
IR. (mineral oil) 3069, 3061, 3031, 1719, /651, /422, /405, 1329, 1238, 1207, 1134, 1027, 905, 755, 699, cai 1;
IH NMR (300 MHz, CDCl3) S ?.39, 7.10-7.30, 5.19, 4.75, 4.68, 4.20-4.35, 3.80-3.95, 3.77, 2.75-3.00, 2.10-2.40, L6I;
MS (EI) m /z 436, 301, 255, 105, 104, 92, 91, 79, 77, 65, 57.
Step 5. Preparation of N-Benzyloxy-2-(benzyloxycarbonyl)-4-(2-methylpropen-2-yl)-5-oxo-1-(2-phenylethyl)-4-pyrazolidineacetamide.
CDI (204 mg, 1.26 mmol) is added to a solution of 2-(benzyloxycarbonyl)-4-(2-methylpropen-2-yl)-5-oxo-I-(2-phenylethyl)-4-pyrazolidineacetic acid (453 mg, 1.04 mmol) and CH2C12 (10 mL). The solution is stirred for 1 hour at room temperature and then O-benzylhydroxylamine hydrochloride (293 mg, 1.84 mmol) and N-methylmorpholine (0.23 mL, 2.1 mmol) are added. The solution is stirred for 60 hours at room temperature. Aqueous workup (CH2Cl2, MgS04) and purification by flash chromatography ( 1:1 hexane:EtOAc) provides 468 mg {83%) of the title compound as an oil.
IR (liq.) 3031, 1724, 1701, 1498, 1455, /379, 1320, 1217, 1182, 1134, 1044, 1028, 749, 698, cm-1;
IH NMR (300 MHz, CDCl3) b 8.72, 7.05-7.45, 5.I8, 4.88, 4.73, 4.66, 4.05-4.30, WO 97/32846 PCT/U597/025Cu8 3.80-3.95, 3.57, 2.75-2.95, 1.95-2.20, 1.78, 1.57;
MS (EI) m /z 541, 407, 406, 106, 105, 104, 92, 91, 79, 77, 65.
Step 6. Preparation of N-Hydroxyl-4-{2-methylpropyl)-5-oxo-1-(2-phenylethyl}-4-pyrazolidineacetamide monohydrochloride.
An atmosphere of hydrogen is placed over a mixture of N-benzyloxy-2-(benzyloxycarboayl)-4-(2-methylpropen-2-yl)-5-oxo-I-(2-phenylethyl)-4-pyrazolidineacetamide (462 mg, 0.853 mmol), MeOH (34 mL) and Pearlman's catalyst {85 mg). After stirring for 8 hours at room temperature, the mixture is filtered, the solids washed with MeOH (3 X 10 mL}, CH2C12 (I0 mL), and the filtrates concentrated to provide 220 mg {81°fo) of the title compound as an oil.
1H NMR (300 MHz, CDCI3) S 10.3-10.5, 7.10-7.40, 3.45-3.80, 3.37, 2.80-3.00, 2.35, 1.45-1.90, 1.10-1.30, 0.88, 0.82.
The hydrochloride salt is formed (EtOAclMeOhI) and triturated with ether to provide the hydrochloride salt of the title compound as a solid (mp 51-54°C).
IR (mineral oiI) 3172, 3061, 3028, 2724, 1714, 1655, 1604, 1585, 1556, 1498, 1414, 1282, 1227, 750, 701 cai I;
MS (EI) m /z 319, 263, 245, 228, 172, 105, 104, 91, 57, 55.

WO 97/32846 PCT/LTS97l02568 Following the general procedures outlined in EXAMPLES 28,29 and making non-critical variations, the following compounds are prepared.
EXAMPLE 39 Preparation of [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-Nx-phenyl-a~-(phenylmethyl)-1,3-pyrrolidinediacetamide. -ti O ' N '~'''-~ C H
v O
H
, ' N.
mp 169-172 °C;
[a3D2~ -43° (c 0.54, MeOH);
IR (mull) 3246, 3193, 3135, 3059, 3029, 1658, 1600, 1547, 1493, 1444, 1358, 1322, 1311, 759, 698 c~ 1;
1H NMR (300 MHz, CDCl3) 8 7.48, 7.10-7.35, 7.06, 4.74, 3.30-3.55, 3.05-3.25, 1.90-2.40, L40-1.65, 1.20-1.35, 0.83, 0.75;
MS (EI) m/e 364, 321, 273, 244, 228, 200, 132.
EX.ANIPLE 40 Preparation of [S-(R*,R*)] IV3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl) N1-(2-pyridinylmethyl)-1,3-pyrrolidinediacetamide.

M 'CH3 HO'N~~"' ~ o 0 I ~ ~ I
v v mp 68-71 °C;
IA (mull) 3244, 3062, 3027, 1658, 1598, 1572, 1540, 1497, 1439, 1354, 1296, 1271, 75I, 701, 620 cni 1;
1H NMR (300 MHz, CDC13) b 8.40-8.55, 7.90-8.00, 7.75, 7.50, 7.05-7.35, 4.35-4.70, 4.10-4.25, 3.25-3.50, 2.75-2.90, 2.15-2.40, 1.75-1.90, 1.40-i.65, 1.00-1.15, 0.86, 0.81;
MS (EI) m /z 436, 379, 336, 301, 244, 200, 147, 135, 92.

EXAMPLE 41 Preparation of [S-(R*,R*)] N3-Hydroxy-3-(2-methyipropyl)-2-oxo-al-(phenylmethyi) Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

~ H ~CHg HO'N ~~~'' N / I
/ N w N~ ! O
to mp 12I-123 °C;
IR (mull) 3240, 3178, 3086, 3064, 3028, 1664, 1593, 1512, 1498, 1422, 1331, 1294, 1210, 749, 701 cni 1;
1H NMR (300 MHz, CDC13) 8 9.98, 8.25, 7.65-7.85, 7. i5-7.35, 4.15-4.25, 3.25-3.65, 15 2.65-2.85, 2.37, 1.70-1.85, 1.45-1.70, 1.10-1.20, 0.90, 0.84;
MS (EI) rn /z 438 (M+) 317, 316, 30I, 284, 200, I32, 105, 95, 91, 55.
EXAMPLE 42 Preparation of IS-(R*,R*)] Nl-(4-Fluorophenyl) 1V3-hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
20 CHs H ~CH3 HO'N ~~~'' O HO N ~ I
~N
F ['~~~ O
2s mp 181-182.5;
IR (mull) 3254, 3154, 3066, 1658, 1614, 1552, 151I, 1499, 1409, 1309, 1299, 1230, 1213, 836, 699 cnz 1;
30 1H NMR (300 MHz, CDCl3) 8 8.20-8.50, 7.46, 7.15-7.40, 6.90-7.05, 4.65-4.80, 3.15-3.50, 1.90-2.45, 1.40-1.70, 1.20-1.35, 0.87, 0.79;
MS (EI) m /z 455 (M+) 345, 344, 317, 3I6, 284, 200, 132, 131, 9I, 55.

EXAMPLE 43 Preparation of [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyl) N~--[1-(phenylmethyl)-4-piperdinyl]-1,3-pyrrolidinediacetamide.
CH3 ..
H ...T-'1 CHS
HO'N'~.
v O
H
N~N
mp 108-110 °C;
IR (mull) 3276, 3I07, 3085, 3062, 3027, 2764, 1658, 1540, 1496, 1296, 1271, 744, 72I, 700 cm's; MS (FAB) m/z 535 (MH+), 534, 533, 519, 1?2, 91, 82.
EXAMPLE 44 Preparation of [S-(R*,R*)] 1V3-Hydroxy-3-(2-methylgropyi)-2-oxo-ocI-(phenylmethyl) NI-(4-piperdinyl)-1,3-pyrrolidinediacetamide.

~CH3 H O
OHO N
N
HN~ O
mp 160-165 °C;
IR (mull) 3283, 3085, 3062, 3028, 1661, 1584, 1544, I497, 1311, 1297, 127I, 1213, 1154, 748, 700 cm I; MS (EI) m /z 444 (M+), 302, 301, 284, 132, 91, 84, 83, 82, 56, 55.

WO 97/32846 PCT/CJS97/025~58 EXAMPLE 45 Preparation of [S-(R*,R*)] N~-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl) Nl-(4-pyridinyimethyl)-1,3-pyrrolidinediacetamide.
GHg H o'N ~'''' N~ HO N
N

mp 140.5-142 °C
IH NMR (300 MHz, CDC13) 8 8.49, 8.35, 7.95-8.10, '1.10-7.35, 4.50-4.60, 4.20-4..45, 3.25-3.55, 2.80-3.10, 2. I5-2.60, 1.95-2.10, L75-L90, 1.40-L70, 1.05-1.35, 0.89, 0.83;
MS (FAB) m /z 453 (MHO'), 452, 43'1, 284, 132, 105, 93, 91.
EXANtPLE 46 Preparation of (S-(R*,R*)] N1-(4-Fluorophenylmethyl) N3-hydroxy-3-(2-methylpropyl)-2-oxo-a 1-(phenylmethyl)-1,3-pyrrolidinediacetamide.
CHg 'N ~CH3 H O
O HO N / I
I~N w O
mp 64-66 °C
1H NMR (300 MHz, CDCl3) 8 7.05-?.35, 6.90-7.05, 4.50-4.70, 4.20-4.45, 3.10-3.4.-5, 2.29, 1.80-2.10, 1.40-1.70, 1.10-1.30, 0.86, 0.80.

E~~LE 47 Preparation of IS-(R*,R*)I N3-Hydroxy NI-methyl-3-(2-methylpropyl)-2-oxo-al-(2-phenylethyl)-1,3-pyrrolidinediacetamide.
H
HO.N
H3<
mp 148-148.5 °C;
Ia]D25 -3I° (c 0.68, MeOH);
IR. (mull) 3227, 3092, 3084, 3024, 1678, 1667, 1658, 1644, 1569, 1503, 1496, 1297, 1282, 1206, 703 crri 1;
I5 iH NMR (300 MHz, CDCl3) 8 7.10-7.35, 6.29, 4.30, 3.35-3.50, 2.75, 2.45-2.65, 2.35, 2.00-2.30, 1.60-1.80, 1.35-1.60, 0.91, 0.86;
MS (EI) m /e 316, 273, 258, 91, 44.
EXAMPLE 48 Preparation of [S-(R*,R*)I N'3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(2-phenylethyl) Nl-(phenylmethyl)-1,3-pyrrolidinediacetamide.
H
HO'N
mp 59-61°C;
[aJD2~ _57° (c 0.39, CHC13);
IR (mull) 3234, 3086, 3062, 3027, 1652, 1605, 1585, 1540, 1497, 1295, 1269, 1213, 1030, 739, 699 cm-1;
1H NMR (300 MHz, CDCl3) 8 7.10-7.40, 6.40-6.55, 4.25-4.50, 3.25-3.50, 2.00-2.70, 1.25-1.?5, 0.87, 0.83; MS (EI) m/z 465 (M'~) 361, 332, 331, 330, 316, 298, 182, I17, , 91.

WO 97/32846 PcT/US97/o2s6s EXAMPLE 49 Preparation of [S-(R*,R*)] 1V3-Hydroxy-aI,3-bis(2-methylpropyl)-2-oxo Nl-2-pyridinyl-I,3-pyrrolidinediacetamide.

S H ,CHs .HO.N !l ....
O O N
H
N

N O
mp 73-75°C;
IR (mull) 3203, 2728, 1663, I600, 1579, 1532, 1494, 1435, 1298, 1279, I181, 1152, 780, 741 cui 1;
1H NMR (300 MHz, CDC13) S 8.10-8.35, 7.72, 7.05, 4.25-4.40, 3.30-3.65, 2.35-2.60, 2.00-2.20, 1.35-1.95, 1.20-1.35, 0.75-1.10;
MS (EI) m /z 404 (M+), 284, 283, 267, 250, 208, 149, 98, 56, 55.
EXAMPLE 50 Preparation of [S-(R*,R*)]-al-CyclohexyldV3-hydroxy Nl-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
CHs ,N ~CH 3 HO
HO N
H3C,N
O
mp 199-200 °C;
IR (mull) 3310, 3232, 3105, I647, I565, 1536, 1498, 1415, 1297, 1277, 1258, 1236, 1223, 1047, 722 cm 1;
1H NMR (300 MHz, CDC13) 8 6.I5-6.35, 4.01, 3.30-3.60, 2.76, 2.44, 2.20-2.40, 2.15, L 10-1.80, 0.90, 0.83;
MS (EI) m/z 367 (M+) 336, 310, 309, 308, 277, 276, 154, 95, 58, 55.
_97_ EXAMPLE 51 Preparation of [S-(R*,k*)l-al-Cyclohexyl lV3-hydroxy-3-(2-methylpropyl)-2-oxo N1-2-pyridinyl-1,3-pyrrolidinediacetamide.
CNg H '''~ C H g _ HO'N~.
H ~' N
I
N Q
mp 119-121 °C;
IR. (mull) 3254, 1665, 1596, 1579, 1532, 1497, 1434, 1301, 1279, 1270, 1186, 1172, 1151, 779, 740 cni ~-;
1H NMR (300 MHz, CDC13) 8 8.25-8.35, 8. I7, 7.65-7.80, 7.00-7.15, 4.20-4.35, 3.35-3.60, 2.00-2.75, 0.70-1.85;
MS (EI) m /z 430 (M+), 309, 294, 293, 276, 218, 154, 95, 78, 67, 55.
EXAN~LE 52 Preparation of [S-(R*,R*)~-3-(Cyclopentylm.ethyl) N3-hydroxy-N~-methyl-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
H
HO'N
H gC
mp 180-181.5 °C;
1H NMR (300 MHz, CDC13) 8 7.10-7.40, 4.41, 3.10-3.45, 2.75, 2.70-3.05, 2.00-2.35, 1.85-2.00, 1.30-1.85, 0.85-1.15;
MS (ET) m/z 401, 343, 342, 328, 3I0, 200, 132, 91, 58.
_98_ EXAMPLE 53 Preparation of [3S-[1(R*),3R*(R*)]]-a3-[2-(Benzoylamino)ethyl]-1V3-hydroxy N~-methyl-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl)-1,3-pyrrolidinediacetamide.
s H
N
HO~
H' HgC
1H NMR (300 MHz, CDC13) 8 7.70-7.85, 7.35-7.55, 7.05-7.35, 6.40, 4.80-5.00, 3.10-3.50, 2.76, 2.20-2.40, 1.20-2.00, 0.70-1.00, 0.30-0.45;
MS (FAB) m /z 523 (MH+), 522, 391, 371, 129, 105, 71, 57, 43.
EXAMPLE 54 Preparation of [S-(R*,R*)1 N3-Hy~'ox3'-3-(2-methylpropyl)-,NI-[2-(4-morpholinyl)ethyl]-2-oxo-oc1-(phenylmethyl)-I,3-pyrrolidinediacetamide.
H
HO' N II
O
F
N
c~~ O J
mp 66 °C;
[a.]D = -56° (c, 0.58; CHC13);
IR, (mull) 3223, 3086, 3063, 3027, I653, 1547, 1497, 1297, 1271, 1239, 1146, 1118, 1071, 748, 700 c~ri 1;
1H NMR (300 MHz, CDC13) 8 7.45-7.15, 3.80-3.60, 3.50-3.00, 2.70-2.00, 1.95-1.80, 1.75-L45, L35-L 15, 0.88;
MS (EI) m /z 474 (M~'), 418, 358, 345, 244, 200, 113, 100.
-99_ EXAMPLE 55 Preparation of [B-(R*,R*)] N-Hydroxy-3-(2-methylpropyl)-1-[2-(4-morpholinyl)-2-oxo-1-(phenylmethyl)ethyl]-2-oxo-3-pyrrolidiueacetamide.
H
N '~.
Ho' "
° o r~
n o N

mp 52-56 °C);
[a]D = -82° (c, 0.70; CHCl~);
IR. (mull) 3237, 3085, 3061, 3025, 1648, 1494, 1299, 1268, 1239, 1213, 1115, 1039, 1029, 75 I, 702 cm-1;
MS (EI) m /z 431 (M'~), 399, 375, 357, 344, 340, 317, 284, 114, 9I;
1H NMR (CDC13) 8 7.35-7.15, 5.30, 3.70-3.10, 3.10-2.90, 2.40-1.95, 1.85-1. I5, 0.86;
HRMS (EI) 431.2436.
EXAMPLE 56 Preparation of [I(IS)-[I[R*(R*)], 3a,5a]]-1-[2-(3,5-Dimethyl-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide.
H
N
H O' O
r mp 106 °C;
[a]D = -77° (c, 0.6082; CHCI3);
IR (mull) 3252, 3087, 3062, 3027, I649, 1493, 1323, 1263, 1193, 1157, 1110, 1084, 1033, 751, 702 cni 1;
IH NMR (300 MHz, CDCl3) 8 7.35-7.10, 5.40-5.25, 4.50-4.35, 3.95-3.65, 3.55-3.30, -3.30-2.95, 2.75-0.75;
MS (EI) m /z 458 (M~'), 402, 317, 113, 84_ EXAMPLE 57 Preparation of [S-(R*,R*)]-N'3-Hydroxy-3-(2-methyipropyi)-2-oxo-a.l-(phenylmethy1) N~-2-pyridinyl-1,3-pyrrolidinediacetamide.
Ho' o~
/ N
'N
mp 171-174 °C;
Ccc]D = -14° (c, 0.67; CHCl3);
IR (mull) 3057, 3030, 3010, 1706, 1661, 1642, 1614, 1586, 1558, 1315, 1282, 1205, 786, 753, 704 cni 1;
~H NMR (300 MHz, CDC13) S 8.40-8.30, 8.25-8.15, 7.85-7.75, 7.40-7.20, 7.20-7.05, 4.26, 3.60-3.35, 2.80-2.65, 2.55-2.25, 1.90-1.40, 1.10-1.95, 0.87;
MS (EI) m/z 438 (M+), 406, 382, 364, 347, 317, 284, 226, 200, I32, 91.
EXAMPLE 58 Preparation of L3S-[1(R*),3R*(R*)]]-oc3-C2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] 1V3-hydroxy NI-methyl-3-(2-methylpropyl)-2-oxo-aI-(phenylmethyi)-1,3-pyrrolidinediacetamide.

HO
IH NMR (300 MHz, CDC13) 8 7.65-7.95, 7.10-7.40, 6.20, 4.55-4.70, 3.05-3.75, 2.6'T, 1.15-2.30, 0.77, 0.68;
MS (FAB) m /z 549 (MH'"), 550, 549, 517, 516, 429, 160, 69, 57, 55, 43.

EXAN~LE 59 Preparation of [S-(R*,.R*)]-al-Cyclohexyl N1-cyclopropylmethyl-1V3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
H H
HO~N1C~
ii N
~N
O
mp 140-144°C;
1H NMR, (300 MHz, CDC13) 8 6.40, 3.97, 3.50-3.65, 3.30-3.45, 2.50-2.70, 2.20-2.40, 1.90-2.15, 1.10-1.90, 0.65-1.00, 0.40-0.60.
EX.ANlPLE 60 Preparation of [S-(R*,R*)]-a~-Cyclohexyl N1-(4-#luorophenyl)-1V3-hydroxy-3-(2-methyipropyl)-2-oxo-1,3-pyrrolidinediacetamide.

2O H CHg ht O ~N ~C ~~''' n O~ N
N, O \"/
F
mp 132-135 °C;
1H NMR (300 MHz, CDC13) 8 8.47, 7.40-7.50, 6.99, 4.15, 3.35-3.65, 2.57, 2.30-2.45, 2.00-2.20, 0.95-1.85, 0.86, 0.77.

~C

WO 97/32846 PCT/LTS97/025u58 Following the general procedures outlined in EXAN~LES 30-34 and making non-critical variations, the following compounds are prepared.
EXAMPLE 61 Preparation of IS-(R*,R*)]-al-tent-Butyl lV3-hydroxy N~-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.

,N -C H 3 I0 H p ~'-.
O O N
H
H3C.N
O

mp 108-110 °C;
IH NMR (300 MHz, CDC13) 8 5.80-6.00, 4.23, 4.15-4.35, 2.70-2.80, 2.45-2.70, 2.30-2.45, 1.85-2.30, 1.35-L85, 1.05, 0.75-L00;
MS (ESI) 340 (MH-).

Following the general procedures outlined in EXAMPLES 4-14 and making non-critical variations, the following compounds are prepared.
EXAMPLE 62 Preparation of N Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2- "
phenylethyl)-a-[2-(5-propyloxy-1,3-dihydro-1,3-clioxo-2I-i-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide.
OPr ~O
O N
H
N
HO~
O O N
mp 137-138 °C;
IR (mineral oil) 3211, 3085, 3028, 17?2, 1712, 1660, 1620, 1491, 1400, 1346, 1292, 1249, 1234, 749, 705 cni 1;
1H 1VMR (300 MHz, CDC13) 8 7.72, 7.05-7.40, 4.02, 3.35-3.80, 3.10-3.25, 2.78, 2.30-2.45, 2.05-2.30, 1.75-2.00, 1.35-1.70, 1.06, 0.83, 0.76;
MS (EI) m /z 549 (M''-), 493, 489, 262, 261, 245, 244, 218, 202, 176, 105.

EXAMPLE 63 Preparation of [R-(R*,S*)]-5-Fluoro-I,3-dihydro N hydrox3T-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H
isoindole-2-butanamide.
F
\ /
O N
H
N
HO' IR (mull) 3205, 3063, 3027, 1775, 1717, 1664, 1616, 1497, 1481, 1399, 1302, 1263, 1229, 747, 701 cni I;
1H NMR (300 MHz, CDC13) S 8.92, 7.83, 7.50, 7.00-7.45, 3.35-3.80, 3.25-3.35, 3.10-3.25, 2.79, 2.55-2.70, 2.30-2.50, 2.10-2.30, 1.70-2.00, 1.35-L65, 0.70-1.00;
MS (EI) m /z 509 (M+), 477, 453, 449, 345, 262, 26I, 178, 105, 104.
FXA_MPI,E 64 Preparation of oc-[2-{5,6-Diffuoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-{2-phenylethyl)-3-pyrrolidineaceta.mide.
F
~O
a N
i i HO~
IR (mull) 3340, 3187, 3062, 3028, 1777, 1720, 1678, 1654, 1505, 1406, 1354, 1277, 1261, 746, 704 czri I;
1H NMR (300 MHz, CDCl3) s 7.55-7.70, 7.40-7.55, 7.05-7.40, 3.35-3.80, 3.10-3.35, 2.70-2.85, 2.55-2.70, 2.30-2.55, 2.05-2.30, 1.70-2.05, 1.35-L70, 0.85, 0.79;
MS (EI) m /z 527 (M~), 471, 467, 363, 262, 261, 202, 196, 105, 104.

EXE1MPLE 65 Preparation of N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-(5-trifluoromethyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-pyrrolidineacetamide.

s -HO' mp 137-138 °C;
IR (mull) 1715, 1659, 1494, 1444, 1398, 1348, 1323, 1307, I295, 1266, 1I84, 1140, 15 IlOI, 750, 694 cm-1;
IH NMR (CDC13) 8 8.91, 8.05-8.15, 7.90-8.05, 7.37, 7.05-7.35, 3.35-3.85, 3.25-3.35, 3.10-3.25, 2.79, 2.55-2.70, 2.35-2.55, 2.10-2.35, 1.75-2.05, 1.30-1.70, 0.84, 0.78;
MS (EI) m/z 559 (M+), 527, 503, 499, 395, 262, 261, 228, 105, 104.
EXAMPLE 66 Preparation of a-L2-(1,3,4,5,6,7-Hexahydro-I,3-dioxo-2H-20 isoindol-2-yl)ethyl) N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
30 mp I18-119 °C;
IR (mull) 3167, 3088, 3065, 3028, 1703, 1668, 1497, 1443, 1393, 1346, 1331, 1306, I296,~ 1279, 701 cai 1;
1H NMR (300 MHz, CDCl3) 8 8.80, 7.45, 7.10-7.40, 3.35-3.65, 3.10-3.35, 2.70-2.95, .
2.50-2.70, 2.10-2.50, 1.25-2.10, 0.85, 0.79;
MS (EI) m /z 497 (M+), 465, 441, 437, 262, 261, 244, 105, 104, 81.

WO 97!32846 PCT/US97I02568 EXAMPLE 67 Preparation of a-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(3-phenylpropyl)-3-pyrrolidineacetamide.
/ \
O N O
H w HO'N

i mp 163-165 °C}:
IR, (mineral oil) 3231, 3107, 3088, 3051, 3034, 1771, 1712, 1683, 1663, 1499, 1442, 1400, less cm-'-;1 H NMR (300 MHz, CDC13) 8 7.75-7.90, 7.65-7.75, 7.10-7.30, 3.60-3.85, 3.I0-3.40, 2.56, 1.35-2.45, 0.87, 0.80;
MS (EI) m/z 505 (M'~), 387, 386, 276, 259, 258, 2I6, 185, 130, 91, 56.
EXAMPLE 68 Preparation of 1-[2-(4-Flnoropheny!)ethyl]-a-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yI)ethyI] N hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide.
/ \
o N o H
HO'N

mp I42.5-I44 °C;
IR (mineral oil) 3212, 3067, 1773, 1712, 1673, 1657, 1510, 1495, 1438, 1398, 1341, 1301, 1219, 1034 cm I;
- ZH NMR (300 MHz, CDC13) 8 7.60-7.95, 7.05-7.25, 6.85-7.05, 3.20-3.85, 3.10-3.25, 2.76, 1.30-2.50, 1.21, 0.82, 0.75;
MS (EI) m /z 509 (M'~), 477, 453, 449, 400, 220, 160, 123.

WO 97/32846 PCTlUS97/~25d8 EXAMPLE 69 Preparation of a-[2-(o-benzoic sulfimide)ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
/ \
o2s.r~ o HO ~N CH3 ' mp 144-144.5 °C;
IR, (mull) 3257, 1739, 1656, 1492, 1334, I326, 1298, 1279, 1264, II81, 1178, 1163, 1126, 752, 674 cni x;
1H NMR (304 MHz, CDC13) 8 7.75-8.15, 7.00-7.40, 3.35-4.05, 3.10-3.30, 2.70-2.90, 2.40-2.60, 1.20-2.35, 0.65-1.00;
MS (EI) m /x 527 (M+) 495, 471, 26I, 245, 244, 202, 105, 104, 81, 56.
EXAMPLE 70 Preparation of Ethyl Phenylmethyl [4-(hydroxyamino)-3-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-4-oxobutyl]imidodicarbonate.
O'I O'I CH3 O~ N~O~CH3 H ~ cH

HO~
O O. N
MS (EI) m/e 568.

WO 97/32846 PCT'/US97'/02568 Following the general procedures outlined in EXAMPLES 4-l4.and making non-critical variations, but starting with the diastereomer of tent-butyl a-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXA,MPLE 4, step 2), the following compounds are prepared.
EXAN.~'LE 71 Preparation of [S-(R*,R*)]-1,3-Dihydro N hydroxy-a-I3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide.
/ \
1d O N O
H CHs HO ~N ~CH3 CHaCHz i I

IR, (mull) 1716, 1660, 1644, 1401 cm 1;
1H NMR (300 MHz, CDC13) 8 9.84, 7.80-7.90, 7.65-7.80, 7.15-7.35, 3.70-3.80, 3.35-3.70, 3.05-3.25, 2.80, 2.40-2.56, 2.34, 1.85-2.10, 1.30-L65, 0.79, 0.71;
20 MS (EI) m/e 491, 459, 373, 245, 202, 185, 105.
EXAMPLE 72 Preparation of 1,3-Dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-[2-(4-fluorophenyl)ethyl]-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide.

H vn3 HON ~CH3 ~I
F
IR (mull) 3223, 1716, 1675, 1648, 1510, 1444, 1397, 1367, 1218, 722 crri 1;
MS (EI) m /e 509, 477. 453, 449, 400, 262, 220, 160, 123.

EXAMPLE 73 Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
F
F
HN ~O CHa CHg HO~
t Step 1. Preparation of tert-Butyl a-(2-Aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
DEAD (1.I8 mL) is added to a solution of tent-butyl a.-(2-hydroxyethyl)-3-(2-methylgropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 4, step 2;
2.74 g, 6.79 mmol), dibenzyl iminodicarboxylate (2.14 g), triphenyiphosphine (1.96 g) and THF (43 mi.). The mixture is stirred for 16 hours at room temperature. The solution is concentrated and purified by flash chromatography (3:1 hexane EtOAc) to give 3.09 g (68%) of the imide as an oil:
IR. (neat) 2957, 1799, 1751, 1723, 1686, 1498, 1455, 1387, 1367, 1335, 1331, 1287, 1213, 1188, 1153, 1108, 1092, 698 crri 3;
1H NMR (300 MHz, CDC13) 8 7.I5-7.40, 5.23, 3.55-3.90, 3.25-3.40, 3.19, 2.'79, 2.47, 2.30-2.45, 1.75-1.95, 1.50-1.70, 1.39, 0.82, 0.79;
MS (FAB) m/z 671 (MH+), 616, 572, 420, 419, 105, 92, 93, 57.
A mixture of the imide (1.01 g, 1.51 mmol), EtOH (100 mL), and 10% PdIC
(250 mg) is hydrogenated at 32 psi for 16 hours. The mixture is filtered, the solids washed with EtOH (20 mL), CH2Cl2 (20 mL), and EtOH (20 mL). The combined filtrates are concentrated to provide 549 mg (91%) of the title compound as an oil:
1H NMR (300 MHz, CDCI3) 8 7.15-?.35, 3.55-3.70, 3.30-3.45, 3.15-3.30, 2.30-2.90, 1.92, 1.35-1.85, 0.87, 0.83. "
Step 2. Preparation of tert-Butyl a-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenyiethyl)-3-pyrrolidineacetate. -To a solution of tent-butyl a-(2-aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (549 mg, 1.36 mmol), CH2C12 (8.4 mL), and diisopropylethylamine (0.29 ml, 1.6 mmol) at 0 °C is added 3,4-difluorobenzoyl -llo-WO 97!32846 PCT/US97/025~68 chloride (0.21 mL, 1.6 mmol). The solution is stirred at 0 °C for 1 hour and I6 hours at room temperature. Basic workup (CH2Ci2, NaHC03, MgS04) and gurification by flash chromatography (1:1 hexane:EtOAc) gives 477 mg (64%) of the title compound as a white solid (mp I47-148 °C):
IR, (mull) 3365, 1717, 1657, 1606, I549, 1509, 1497, 1319, 1295, 1282, 1229, 1199, 1152, 832, ?74 cni I;
~H NMR (300 MHz, CDCl3) 8 7.65-7.80, 7.50-7.60, 7.15-7.40, 6.55-6.70, 3.55-3.'T0, 3.20-3.50, 2.81, 2.50-2.60, 2.10-2.40, 1.75-1.90, 1.40-1.65, 1.43, 0.85, 0.79;
MS CEI) m /z 542 (M+} 486, 396, 395, 260, 245, 202, 141, 105, I04, 57.
Step 3. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic Acid.
A solution of tent-butyl a-[2-[(3,4-difluorobenzoy!)amino]ethyl]-3-(2-methylpropyl)-2-oxo-I-(2-pheny!ethyl)-3-pyrrolidineacetate (473 mg, 0.872 mmol), CH2Cl2 (5.0 mL), and TFA (5.0 mL) is stirred for 1 hour at 0 °C and 2 hours at room temperature. The solution is concentrated and the residue resuspended in CH~C12 and reconcentrated two additional times (2 x 20 mL). Aqueous workup (CH2C12, MgS04) provides 420 mg (99%) of the title compound as an oil:
IR (liq.) 2959, 1728, 1661, 1618, 1607, 1553, 1510, 1467, 1454, 1443, 1442, 1314, 1297, 1283, 1203 ciri I;
IH NMR (300 MHz, CDCI3) 8 7.65-7.75, 7.50-7.60, 7.I5-7.40, 6.75-6.90, 3.70-3.90, 3.60-3.70, 3.40-3.55, 3.20-3.40, 2.80-3.00, 2.52, 1.95-2.10, 1.50-L90, 1.15-L35, 0.91, 0.83;
MS (EI) m /z 486 (M~}, 395, 272, 259, 258, 247, 141, 113, 105, 104.
Step 4. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide.
EDC ( 193 mg) is added to a solution of a-[2-[(3,4-difluorobenzoyl)amino]ethyl]-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrroiidineacetic acid (411 mg, 0.865 mmol}, CH2Cl2 (8.7 mL), DMF (2.1 mL), HOBT
(118 mg), and 4-methyimorpholine (0.11 ml) at 0 °C. The solution was stirred for 5 min at 0 °C and 50 min at room temperature. Hydroxylamine hydrochloride (121 mg) and 4-methylmorpholine (0.19 mL) are added and the solution stirred for 1~6 hours at room temperature. The solution is dilated with 20 mL of water and the - mixture acidified to pH 5 with l N HCI. The mixture is extracted several times with CH2Cl2 (3 x 20 mL), the combined organic layers dried (MgS04), filtered, and concentrated. The residue is purified by flash chromatography (10:I
CH2CI2:MeOH) to give 273 mg of an oil which is crystallized from EtOAclhexane to give 164 mg WO 97!32846 PCT/LTS97/02568 (38%) of the title compound as a white powder (mp 132.5-134 °C):
IR (mull) 3264, 1674, 1666, 1649, 1512, 1497 cna 1; 1 H NMR (300 MHz, CDCi3) 8 7.60-7.80, 7.50-7.60, 7.05-7.35, 3.15-3.65, 2.81, 2.48, 1.85-2.20, 1.40-1.75, 0.85, 0.79;
MS (EI) m /e 501, 469, 262, 245, 202, 141, 105. ' Following the general procedures outlined in EXAMPLE 73 and making non-critical variations, the following compounds were prepared.
EXAMPLE 74 Preparation of CR-(R*,S*)-a-[2-[(3-Fluorobenzoyl)amino]ethyl]-N hydroxy-3-{2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetaznide.
F

N ~ CH3 HO~
O O N- /
mp 144-145 °C;
[a]D25 ,~13° (c 0.75, CHC13);
IR (mull) 3290, 3216, 3062, 3029, 1673, 1662, 1643, 1585, 1555, 1496, 1486, 1323, 1301, 1227, 698 c~ 1;
1H NMR (300 MHz, CDCl3) 8 7.45-7.60, 7.I0-7.45, 6.97, 3.35-3.70, 3.15-3.30, 2.83, 2.40-2.55, 1.80-2.05, 1.40-1.70, 0.87, 0.8fl;
MS (EI) m /z 483 (M+), 451, 262, 245, 202, 154, 123, 105, 104, 95, 56.
EXAMPLE 75 Preparation of a.-[2-[(4-Fluorobenzoyl)amino]ethyl] N-hydroxy-3-(2-methyiprogyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
F
i HN o cHs NO~
O O N / i IR {mull) 2950, 2932, I7I8, 1661, 1604, 1547, 1504, 1466, 1454, 1234 cxa 1.

WO 97!32846 PCT/US97/02568 EXAMPLE 76 Preparation of N Hydroxy-3-(2-methylpropyl)-a-I2-[(3-nitrobenzoyl)amino]ethyl]-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide.
NO~
s ~~
HN ~O CH3 IiO~
O O N_ to IR. (mull) 3270, 1664, 1633, 1556, 1532, 1454, 1447, 1351, 1310, 698 crri 1;
MS(EI)m/e510.
EXAMPLE 77 Preparation of a.-[2-[(3-Fluorobenzoyl)amino]ethyl] N-hydroxy-3-15 (2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetamide.
F
20 H ~ o C 1-f g ~Cii3 HO ~
O O N
2s mp 157-159 °C ;
IR (mull) 2954, 2925, 2868, 2855, 1645, 1624, 1586, 1552, 1465, 1455 cni 1;
MS (EI) m / a 403.

WO 97/32846 PCT/US97/025~68 EXAMPLE 78 Preparation of oc-[2-[(3-Fluorobenzoyl)amino]ethyl]-I-[2-(4-fluorophenyl)ethyl]-N hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide.
F
I
HN ~0 CH

CFig HO~
~ o N , I F
IR, (mull) 2954, 2924, 2855, 1662, 1586, 1544, 1510, 1484, 1462, 1224 cm I.
EXAMPLE ?9 Preparation of oc-[2-[(4-Biphenylcarbonyl)amino]ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
i w tiN O CHg HO~
0 o N ~ I
MS (EI) m / a MH+ 542.

E~~AMPLE 80 Preparation of N-Hydroxy-a-[2-[[(4- .
methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-~1-(2-phenylethyl)-pyrrolidineacetamide.

W
.S02 HN GHg N ~ CHa HO~
O O N

Step 1. Preparation of tent-Butyl a-L2-[[(4-Methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
Toluenesulfonyl chloride (372 mg) is added to a solution of tent-butyl a-(2-amin.oethyl)-3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (F.~~ANB'LE 73, step 1; 654 mg, 1.62 mmol), CH2Cl2 (10.0 mL), and diisopropylethylamine (0.34 mL) at 0 °C. The solution is stirred at 0 °C for 1 hour and at room temperature for 16 hours. Basic workup (CH2C12, NaHC03, MgS04) and purification by flash chromatography gives 634 mg (70%) of the title compound as a white solid (mp 136-138 °C):
IR. (mineral oil) 1? 10, 1674, 1366, 1329, 1303, 1156, 1101 c~ 1;
1H NMR (300 MHz, CDC13) 8 7.73, 7.15-7.35, 4.45-4.55, 3.50-3.70, 3.30-3.45, 3.15-3.30, 2.75-3.10, 2.42, 2.20-2.35,-1.80-1.95, 1.60-1.80, 1.30-1.60, 1.38, 0.84, 0.79;
MS (FAB) m/z 557 (MH+), 503, 502, 501, 484, 483, 105, 91, 57.
Step 2. Preparation of a-[2-[[(4-Methyiphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic Acid.
TFA (7.0 mL) is added to a solution of tert-butyl a-[2-[[(4-methylphenyl)suifonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyi)-pyrrolidineacetate (616 mg, 1.I1 mmol) and CH2C12 (7.0 mL) at 0 °C. The solution is stirred for 1 h at 0 °C and for 2 hours at room temperature. The solution is concentrated which is repeated twice more from CH2C12 (2 x 20 mL). Aqueous workup (CH2C12, MgS04) provides 463 mg (84%) of the title compound as a white foam:
IR (mineral oil) 1733, 1615, 1503, 1498, 1481, 1330, 1305, 1288, 1160, 1094, WO 97/32846 PCT1US97/025~68 cm 1; 1H NMR (300 MHz, CDClg) 8 7.70-7.80, 7.I5-7.40, 4.80-5.00, 3.70-3.90, 3.20-3.50, 2.$5-3.10, 2.50-2.65, 2.42, 1.95-2.10, 1.80-1.95, 1.50-1.80, 1.00-1.20, 0.92, 0.85;
MS (EI) m /z 500 (M+), 426, 392, 391, 334, 327, 244, I55, 105, 104, 91.
Step 3. Preparation of N Benzyloxy-a-[2-[[(4-methylphenyl)sulfonyl]amino]ethylJ-3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-pyrrolidineacetamide.
CDI (162 mg) is added to a solution of a-[2-[[(4-methylphenyl)suifonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-pyrrolidineacetic acid (453 mg) and CH2CI2 (5.0 mL). The solution is stirred for I
hour at room temperature and then O-benzylhydroxylamine hydrochloride (192 mg) and 4-methylmorpholiue (0.13 mL) are added. The solution is stirred for 16 h at room temperature. The solution is diluted with 60 mL of EtOAc which is wasihed with 10% HCl, brine, dried (MgS04), filtered, and concentrated. Purification by flash chromatography (I:1 hexane:EtOAc) provides a lactam intermediate with no evidence of O-benzylhydroxylamine incorporation:
IH NMR (300 MHz, CDC13) 8 7.86, 7.15-?.45, 3.85-4.00, 3.45-3.70, 3.18, 2.85, 2.60-2.80, 2.43, 1.80-2.I5, 1.35-L55, 0.70-0.95.
A solution of the bis-lactam intermediate (317 mg, 0.657 mmol), O-benzyihydroxylamine (500 mg) and THF (4.0 mL) is heated at reffux for 72 hours and then allowed to cool to room temperature. The residue is diluted with EtOAc which is washed with 10% HCl (2 x 10 mL) and brine (10 mL). The organic layer is dried (MgS04), filtered, and concentrated. Purification by flash chromatography (1:1 hexane:EtOAc) and crystallization from ether provides 139 mg (35%) of the title compound as a white crystalline material (mp 155-157 °C):
IR (mull) 3162, 1664, 1650, 1332, 1154, 704 ciri I;
1H NMR (300 MHz, CDC13) 8 7.71, 7.15-7.40, 4.97, 4.81, 3.35-3.65, 3.17, 2.75-3.00, 2.55-2.75, 2.30-2.45, 2.39, 1.80-2.05, L35-1.70, 0.84, 0.77;
MS(EI) m/e 605, 483, 433, 32?, 245, 202.
Step 4. Preparation of .N-Hydroxy-a-[2-[[(4-methyiphenyl)sulfonyl]amino]ethyl]-3-(2-methyipropyl)-2-oxo-I-(2-phenylethyl)-pyrrolidineacetamide.
A mixture of N-benzyloxy-a-[2-[[(4-methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide ( 133 mg, 0.220 mmoi), MeOH (8.0 mL), and Pearlman's cat (25 mg) is hydrogenated ( 1 atm) for 8 h at room temperature. The mixture is filtered, the solids washed with MeOH (2 x 5 mL), CH2C12 (5 mL), and MeOH (5 mL). The combined filtrates are.concentrated and the residue crystallized from EtOAc/hexane to give 84 mg (74%) of the title compound as a white solid (mp 166.5-167 °C) IR (mull) 3278, 3202, 3028, 1659, 1636, 1496, 1329, 1298, 129 I, 1160, 1093, I061, 816, 702, 656 cuz 1;
1H NMR (300 MHz, CDCl3) S 7.72, 7.30-7.60, 7.15-7.35, 5.82, 3.40-3.70, 3.15-3.35, 2.95-3.10, 2.70-2.95, 2.81, 2.57, 2.40, 2.10-2.25, 1.80-2.00, 1.30-1.75, 0.86, 0.80;
MS (EI) m/z 515 (M~'), 483, 391, 343, 245, 244, 202, 155, 105, 104, 91.

Following the general procedures outlined in EXAMPLE 80 and making non-critical variations, the following compounds are prepared.
EXAMPLE 81 Preparation of a-[2-[[(4-Fluorophenyl)suLfonyl]amino]ethyl] N
hydroxy-3-(2-methylprnpyl)-2-oxo-1-(2-phenyiethyl)-3-pyrrolidineacetamide.
F
W

IO H ~ °H3 'CH3 HO~
O O N

IR (mull) 3195, 3026, 1661, 1634, 1593, 1496, 1333, 1259, 1238, 1166, 1157, 1095, 1060, 844, 702 cm 1;
1H NMft (300 MHz, CDC13) 8 8.79, 7.75-7.90, 7.50-7.70, 7.43, 7.10-7.30, 3_10-3.50, 2.68, 2.40-2.75, 2.05-2.20, 1.85-2.00, 1.50-i.70, 1.30-1.50, 1.15-1.30, 0.75, 0.66;
20 MS (EI) m/a 519 (M+), 395, 245, 202, I59, 154, 3.10, 105, I04, 95, 56.
E~~AMPLE 82 Preparation of N Hydroxy-a-[2-[[(4-methoxyphenyl)sulfonyl] amino]ethyl]-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide.
25 onne I
w SOa HN~ CH3 30 H o' ° o N .~ I
35 MS (EI) m/e 532 (MH+).

EXAMPLE 83 Preparation of N Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-a-[2-[(phenylsulfonyl)amino]ethyl]-3-pyrrolidineacetamide.
r I
~
.S02 HN CHs HO'~
O O N
' IR. (mull) 2954, 2924, 2862, 2855, 1663, 1610, 1569, 1453, 1446, 1429 cm-1;
MS (EI) m /e 502 (MH+). .
EXAMPLE 84 Preparation of [R-(R*,S*)]-a-[2-[I(4-Fluorophenyl)sulfonyl]amino]ethyl] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
F
.S02 HN CH
CHg HO ~
O O N
mp 67-70 °C;
IR (mull) 3196, 3107, 3065, 3027, 1662, 1592, 1495, 1332, 1292, I237, 1166, II54, 1093, 839, 701 cni 1;
1H NMR (300 MHz, CDClg) S 7.80-7.95, 7.40-7.70, 7.10-7.40, 5.90, 3.10-3.70, -3.00-3.15, 2.70-3.00, 2.55, 2.05-2.20, 1.80-2.00, 1.20-1.80, 0.85, 0.80;
MS (FAB) m /z 520 (MH+), 519, 504, 488, 487, 343, 202, 105.

EXAMPLE 85 Preparation of 5,6-Difluoro-1,3-dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-I-(2-phenyiethyi)-3-pyrrolidinyl]-I-oxo-2H isoi.ndole-2-butanamide.
F F
O N
H !-, h~O'N
O
~ N, ~
Step I. Preparation of tent-Butyl a-[2-(3-Acetoxy-5,6-diffuoro-1,3-dihydro-1-oxo-2H-isoindol-2-yl)ethyl]-3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
Sodium borohydride (26 mg, 0.68 mmol) is added to a solution of tent-butyl a-[2-(5,6-diffuoro-1,3-dihydro-i,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXA1VIPLE 64; 384 mg, 0.675 mmol) and methanol (2.4 mL) at room temperature. The solution is stirred overnight at room temperature. Aqueous workup (EtOAc, MgS04) provides 386 mg (100°h~) of the diastereomeric mixture as a white foam. Solid 4-dimethylaminopyridine (14 mg, 0.12 mmol) is added to a solution of the crude alcohol (336 mg, 0.590 mmol), triethylamine (0.49 mL, 3.5 mmol), acetic anhydride (0.28 mL, 3.0 mmol) and CH2C12 (6.0 mL). The solution is stirred at rnom temperature for 2 hours. The reaction mixture was diluted with ether and the ether is washed with 10% HCI, saturated NaHC03, dried over MgS04, filtered, and concentrated. Column chromatography (20 -~ 50% EtOAc/hexane) provides 273 mg (76%) of the title compound as a diastereomeric mixture as an oil:
MS (EI) m/z 612 (Mf) 497, 496, 440, 406, 405, 245, 236, 202, 105, 57.
Step 2. Preparation of tent-Butyi 5,6-Diffuoro-1,3-dihydro-a-[3-(2-methyipropyi)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H isoindole-2-butyrate.
A mixture of tent-butyl a-[2-(3-acetoxy-5,6-diffuoro-1,3-dihydro-I-oxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (236 mg, 0.386 mmoi), palladium on carbon (10%, 60 mg) and acetonitrile (30 mL) is hydrogenated at 35 psi for 2 hours. The mixture was filtered and concentrated.
Aqueous workup (EtOAc, MgS04) gave 200 mg (93%) of the title compound as an oil:

WO 97/32846 PCTlUS97/02568 MS (EI) m/z 554 (M~) 499, 498, 481, 408, 407, 247, 202, I82, 105, 57.
Step 3. Following the general procedure outlined in E~~ll'LE 1, steps 4 and 5, and making non-critical variations, but starting with tart-butyl 5,6-difluoro-1,3-dihydro-a,-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinylJ-1-oxo-2FI ' isoindole-2-butyrate, the title compound is obtained: (mp I75-176 °C):
IR (mull) 3186, 3060, 3022, 1702, 1659, I51I, 1436, 1307, I290, 1265, 1219, 762, 757, 707, 699 ciri ~;
1H NMR (300 MHz, CDC13) 8 8.80, 7.45-7.60, 7.05-?.35, 4.30-4.60, 3.05-3.?5, 2.60-2.80, 1.30-2.60, 0.87, 0.78;
MS (EI) zn/z 513 (M+) 514, 5I3, 480, 423, 262, 244, 236, 202, 182, 105.

Following the general procedures outlined in EXAMPLE 85 and making non-critical variations, the following compounds are prepared.
EXAMPLE 86 Preparation of I,3-Dihydro N-hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H isoindole-2-butanamide.
O
HO'N
\ /
N
H L~
O
mp 140-144 °C;
IR, (mull) 3165, 3085, 3058, 3020, 1683, 1669, 1653, 1616, 1487, 1424, 1349, 1335, 1295, 738, 699 cm 1;
1H NMR (300 MHz, CDC13) 8 7.80, 7.35-'1.55, 7.00-7.35, 4.30-4.55, 3.10-3.85, 2.60-2.80, 1.90-2.40, 1.45-1.85, 0.87, 0.76;
MS (EI) m /z 477 (M'~), 202, 200, 189, 146, 134, 105, 104, 91, 56.
EXE1MPLE 87 Preparation of [R-(R*,S*)~-6-Fluoro-1,3-dihydro N hydroxy-a-[3-(2-methyipropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide.
F
o N
H L~
HO'N
O
N
mp 167-170 °C;
1H NMR (300 MHz, CDCl3) 8 7.48, 7.35-7.45, 7.05-7.35, 4.30-4.50, 3.10-3.80, 2.55-2.95, 1.15-2.55, 0.87, 0.77;
MS (ESI) 496 (MH+).

EXAMPLE 88 Preparation of [R-(R*,S*)]-5-Fluoro-1,3-dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenyiethyi)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-a butanamide.
F
O N
H ~~
HO-N
O
O N r !
mp 135-136 °c;
1H NMR (300 MHz, CDC13) 8 7.70-7.85, 7.44, 7.00-7.35, 4.30-4.55, 3.05-3.80;
2.55-2.80, 2.35-2.55, 1.85-2.35, 0.87, 0.76;
MS (ESI) 496 (MH+).
EXAMPLE 89 Preparation of IR-(R*,S*)]-5,6-Diffuoro-1,3-dihydro N hydroxy-a-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide.

O N
H ~'-.
HO'N
O
~ N ~ !
mp 153.5-155°C;
~H NMR (300 MHz, CDCI3) b 8.98, 7.50-7.65, 7.43, 7.00-?.35, 4.50, 3.10-3.75, 2.60-2.80, 2.45-2.60, 2.25-2.45, 1.85-2.25, 1.40-1.85, 0.87, 0.79;
MS (ESI) 514 (MH+).
,.

EXAMPLE 90 Preparation of N Hydroxy-a-[[[(4- .
methoxyphenyl)sulfonyllamino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-J
pyrrolidineacetamide (aR-diastereomer).

/ I
SOp H~N CHg H-o,N CH3 ~O N
Step 1. Preparation of tent-Butyl a-(I-Hydroxymethyi)-3-(2-methylpropyl.)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (aS-diastereomer).
A cold (-78 °C) solution of tert-butyl 3-(2-methylpropyl)-2-oxo-I-(2 phenylethyl)-3-pyrrolidineacetate (EXA1VIPLE 1, step 3; 2.00 g, 5.56 mmol) in .dry THF (20 mL) is treated with the dropwise addition of LDA (3.20 mL, 6.40 mmol, 2.0 N). The solution is maintained at -78 °C for 30 min and then warmed to -30 °C.
Gaseous formaldehyde (generated by heating 834 mg of paraformaidehyde at 160 °C
to provide approximately 28 mmol) is bubbled through the enolate solution. The solution is maintained at -30 °C for 1 hour and then quenched with saturated aqueous NH4C1 (5 mL) and diluted with H20 (20 mL). The product is extracted into EtOAc (3 x 50 mL), dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide 2.52 g of a yellow solid which is purified by silica gel chromatography (100 g SG; 25% EtOAclhexane) to give 1.43 g (83%) of the title compound as a golden oil. Another fraction containing 375 mg of a mix of both diastereomers is also recovered. Sgectral data for the title compound:
IR (liq.) 34/7, 2957, 2931, 2869, 1722, 1669, 1497, /465, 1455, 1392, 1368, 1274, 1252, II55, 701 cm I;
IH NMR (300 MHz, CDC13) b 7.I5-7.40, 3.90-4.05, 3.70-3.80, 3.55-3.70, 3.40-3.55, 3.20-3.30, 2.85, 2.75, 2.69, 2.00-2.20, 1.90-2.00, L65-L70, 1.50-1.60, 1.44, 0.90, 0.84;
MS (EI) m /z 389 (M+), 333, 316, 298, 277, 243, 242, 202, I05, 104, 57.
Step 2. Preparation of tert-Butyl a-(1-Hydroxymethyl)-3-(2-methylpropylJ-2-WO 97!32846 PCT/US97l02568 oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetate (aR-diastereomer).
A cold (-78 °C} solution of oxalyl chloride (L02 mL, 11.7 mmol) in dry (30 mL) is treated with DMSO (1.66 mL, 23.4 mmol, in 5 mL CH2C12). After 5 min, ' tent-butyl a-(1-hydroxymethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrxolidineacetate (S-isomer) (3.80 g, 9.76 mmol) is added. The solution is sfirred for an additional 15 min and then quenched with triethylamine (6.8 mL, 48.8 mmol).
The solution is maintained at -78 °C for 30 min and then allowed to warm to rnom temperature under N2. After 2.5 hours, the solution is diluted with H20 (50 mL) and extracted into EtOAc (3 X 100 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide a quantitative yield of the desired aldehyde as a ca. 1:2 mixture in favor of the R
diastereomer. Key peaks of the NMR of the crude mixture:
1H NMR (300 MHz, CDC13) 8 9.75, 9.48.
A cold (0 °C) solution of the aldehyde mixture ( 1.68 g, 4.34 mmol) in MeOH
(30 mL) is treated with sodium borohydride (246 mg, 6.51 mmol). The solution is maintained at 0 °C for 1 h, and then allowed to warm to room temperature. After 3 hours, the solution is concentrated to a yellow foam. The foam is diluted with (25 mL) and extracted with EtOAc (3 x 50 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure. The material, 1.69 g, is purified by silica gel chromatography ( 100 g SG; 20%
EtOAclhexane) to provide 562 mg (33%) of the title compound, 467 mg (28%) of the S diastereomer and 331 mg of the unreduced atdehyde. Spectral data for the title compound:
IR (mineral oil) 3542, 3006, 1704, 1672, 1499, 1396, 1313, 1265, 1160, 1124, I066, 1059, 1036, 738, 697 crri ~; 1 H NMR (300 MFiz, CDC13) 8 7.I5-7.35, 3.95, 3.75, 3.60-3.75, 3.40-3.65, 3.24, 2.87, 2.69, 1.80-2.15, 1.40-1.70, 1.45, 0.89, 0.87;
MS (FAB) m /z 390 (MH+), 335, 334, 332, 316, 298, 242, I05, 57.
Step 3. Preparation of tent-Sutyl a-(1 Azidomethyl)-3-(2-methylpropyl)-2-oxo-1-(2-pheny!ethyl)-3-pyrrolidineacetate.
Methanesulfonyl chloride (0.058 mL, 0.751. mmol) is added dropwise to a solution of tent-butyl a-( 1-hydroxymethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrroiidineacetate (aR-diastereomer) (225 mg, 0.578 mmol) and triethylamine (105 mL, 0.75I mmol) in dry CH2C12 (3 mL}. The solution is stirred overnight at rnom temperature under N2. After diluting with CH2Cl.2 (20 mL), the solution is washed with saturated NaHC03 (5 mL}, H20 (5 mL), and brine (5 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 289 mg of a gold oil. The oil is purified by silica gel chrnmatography (10 g SG;
20% EtOAcJhexane) to provide 243 mg (90%) of the mesylate as an oil:
IH NMR (300 MHz, CDC13) 8 7. I0-7.40, 4.47, 4.17, 3.35-3.70, 3.05-3.30, 2.90-3.05, 2.97, 2.84, 2.10-2.30, I_75-1.95, 1.30-L70, L46, 0.88, 0.86.
A solution of the mesylate (795 mg, L70 mmol) and sodium azide (166 mg, 2.55 mmol) in DMSO (6 m.L) is heated at 60 °C for 24 hours and then allowed to cool to room temperature under N2. The solution is diluted with Et20 (40 mL) and washed with H20 (3 x 15 mL) and brine (15 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 6'79 mg (96%) of the title compound as a clear, colorless oil:
IR. (liq.) 2958, 2932, 2870, 2101, 1725, 1682, 1498, 1455, 1393, 1368, 1276, I152, 1122, 748, 700 cni 1;
1H NMR (300 MHz, CDC13) b 7. I5-7.35, 3.10-3.80, 3.00, 2.70-2.95, 2.15-2.30, 1.30-i5 L90, 1.47, 0.85;
MS (EI) m /z 41.4 (Mf), 358, 268, 267, 246, 224, 212, 105, 104, 57.
Step 4. Preparation of tent-Butyl a-(I-Aminomethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
A mixture of tent-butyl a-{1-azidomethyl)-3-{2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate (648 mg, 1.56 mmol) and 10% palladium on carbon (163 mg) in EtOH (25 mL) is hydrogenated at 30 psi in a Parr flask for I6 hours.
The mixture is filtered, rinsing the residual solids with MeOH and CH2C12. The filtrate is concentrated and purified by silica gel chromatography ( Z5 g SG;
EtOAc, 15% MeOH/EtOAc) to prnvide 356 mg (57%) of the title compound as a partially crystalline solid:
IR (mull) 3004, 1718, 1672, 1498, 1394, 13I1, 1296, 1263, 1223, I156, 1149, 852, 738, 697, 620 cna I;
1H NMR (300 MHz, CDC13) S 7.15-7.35, 3.35-3.70, 3.05-3.30, 2.70-2.95, 2.60-2.70, 2.45-2.60, 2.20-2.40, 1.25-2.00, 1.46, 0.85 MS (FAB) m /z 389 (MH'~'), 359, 334, 333, 316, 202, 105, 57.
Step 5. Preparation of tent-Butyl a-[[[(4-Methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methyipropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate.
A cold (0 °C) solution of tent-butyl a-(1-aminomethyl)-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-gyrrolidineacetate (337 mg, 0.867 mmol) in dry CH2C12 (3 mL) is treated with diisopropylethylamine (240 uL, 1.30 mmol), and 4-methoxybenzenesulfonyl chloride (215 mg, 1.30 mmol). The solution was allowed to slowly warm to room temperature, stirring overnight under N2. After diluting with CH2C12 (25 mL), the solution is washed with dilute NaHC03 ( 10 mL), H20 ( 10 mL), and brine (10 mL). The organic layer was dried over anhydrous MgS04, fiitered, -and concentrated under reduced pressure to give 460 mg of a yellow oil. The oiI was purified by silica geI chromatography (20 g SG; 25% EtOAc/hexane) to provide mg (79%) of the desired material as a white amorphous solid:
IR (liq.) 2958, 2932, 1725, 1668, 1598, 1499, 1455, 1444, 1368, 1334, 1304, 1279, 1260, 1160, 1097 cm 1;
1H NMR (300 MHz, CDC13) 8 7.79, 7.10-7.35, 6.95, 5.45-5.60, 3.81, 3.30-3.65, 2.95-3.30, 2.60-2.90, 2.00-2.20, 1.70-1.90, 1.20-1.70, 1.43, 0.80;
M$ (EI) m /z 558 (M~), 411, 387, 287, 246, 245, 202, 17I, 107, 105, 57.
Step 6. Preparation of a-[[[(4-Methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid.
A cold (0 °C) solution of tent-butyl a-[[L(4-methoxyphenyl)sulfonyl]
amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (374 mg, 0.669 mmol) in CH2C12 (2 mL) is treated with TFA (2 mL). The solution is maintained at 0 °C for 40 min and then allowed to warm to room temperature under N2. After 1.5 hours, the solution is diluted with CH2C12 and stripped (5 x).
The residual foam is diluted with H20 (5 mL) and extracted into CH2Cl~ (3 x 20 mL).
The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide 301 mg (90%) of the title compound as a white, amorphous solid:
IR (mull) 3062, 3026, 1713, 1647, 1597, 1580, 1498, 1332, 1304, 1261, 1180, 1158, 1096, 834, 701 cni 1;
1H NMR (300 MHz, CDC13) 8 7.70-7.80, 7.15-7.35, 6.90-?.00, 5.45-5.55, 3.86, 3.45-3.75, 3.00-3.40, 2.89, 2.67, 1.95-2.25, 1.35-1.80, 0.84, 0.78;
MS (EI) m /z 502 (M'~'), 411, 287, 246, 245, 244, 202, 171, 107, 105, 77.
Step 7. Preparation of N Benzyloxy-a-[[[(4-methoxyphenyl)sulfonyl]amino]
methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
A solution of a-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (290 mg, 0.577 mmol) in dry CH2C12 (5 mL) is treated with CDI ( 112 mg, 0.692 mmol). After 1 h, 4-WO 97/32846 PCT/LTS97/025~68 methylinorpholine (0.095 mL, 0.866 mmol) and O-benzylhydroxyamine HCl (138 mg, 0.866 mmol) are added. The solution is stirred at room temperature under N2 for 65 h. The solvent had evaporated, and the residual gel is diluted with EtOAc (25 mL).
The solution is washed with 1 N HCl ( 10 mL), 1 N NaOH ( 10 mL), and brine ( IO
- 5 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 380 mg of an oil. The oil is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 249 mg (71%) of the title compound as an oil:
IR, (mull) 3205, 3028, 1658, 1597, 1498, 1331, 1304, 1287, 1261, 1157, 1096, 1027, 834, 749, 699 cni 1;
1H NMR (300 MHz, CDC13) S 7.70-7.85, 7.10-7.45, 6.85-?.00, 5.70-5.80, 4.86, 3.76, 3.40-3.55, 3.00-3.25, 2.60-3.00, 2.30-2.50, 1.80-2.00, 1.30-1.60, 0.82, 0.75;
MS (FAB) m /z 608 (MH+), 485, 298, 286, 244, 1? 1, 107, 105, 91.
Step 8. Preparation of N-Hydroxy-a-[[[(4-methoxyphenyl)suifonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-pheaylethyl)-3-pyrrolidineacetamide.
A solution of N benzyloxy-a-LI[(4-methoxyphenyl)suifonyl]amino)methyl]-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetamide (218 mg, 0.359 mmol) in EtOH (7 mL) is treated with palladium hydroxide on carbon (55 mg) and placed under a H2 atmosphere via a balloon. After 6.5 hours, the mixture is filtered, rinsing the residual solids with MeOH and CHC13. The filtrate is concentrated to give 182 mg of a white solid. The material is crystallized from hot EtOAc with a trace of MeOH, eventually dilutiag with hexane, to provide I36 mg of the title compound as a solid (mp 195-196 °C):
IR (mull) 3317, 3095, 1658, 1620, 1597, 1496, 1335, 1304, 1257, 1163, 1097, 833, 829, 805, 751 cai 1;
1H NMR (300 MHz, CDC13) 8 7.78, 7.05-7.35, 6.91, 6.20-6.35, 3.75, 3.35-3.60, 3.05-3.35, 2.60-2.90, 2.25-2.50, 1.80-2.00, 1.I5-1.70, 0.83, 0.77; MS (EI) m /z 517 (M'~'), 261, 245, 244, 202, 171, 154, 107, 105.
EXAMPLE 91 Preparation of N Hydroxy-a-[[[(4-methoxyphenyl)sulfonyl]amino]methyll-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (aS-diastereomer).

CHgO , ' ~S02 H~N' CHg H-O~N CHs 00 N l ~
mp 60-64 °C);
1H NMR (300 MHz, CDC13) 8 7.70-7.90, 7.10-7.40, 6.85-7.05, 5.40-5.60, 3.86, 3.40-3.60, 2.95-3.30, 2.70-2.85, 2.05-2.25, 1.30-1.90, 0.65-0.90.
EXAMPLE 92 Preparation of a-[[(4-Fluorophenyl)sulfonyl]amino] N hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (R-diastereomer).
F
O~!=O CH3 N H
O'~ ~CHg H O -N ~'C
O N
2s Step 1. Preparation of tent-Butyl a-Azido-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (aR-diastereomer).
Potassium bis(trimethylsilyl)amide (0.5 M in toluene, 19.9 mL, 9.93 mmol) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 1.70 g, 4.73 mmol) and THF (57 mL) at -78 .
°C. The solution is allowed to stir at -78 °C for 25 min. A
solution of trisylazide (3.66 g, 11.8 mmol) in THF (34.5 mL) is added dropwise over 5 min. The solution is stirred for an additional 2 min and acetic acid ( 1.2 mL) is added. The solution was allowed to warm slowly and stir at room temperature overnight. Aqueous workup (EtOAc, NaHC03 wash, brine wash, MgS04) and column chromatography (7.5 %

WO 97/32846 PC'F/LTS97/02568 EtOAc/hexane) provides i.34 g (71%) of the title compound as a yellow oil:
~H NMR (300 MHz, CDC13) b 7.15-7.35, 4.23, 4.12, 3.65-3.80, 3.50-3.65, 3.15-3.40, 2.75-2.90, 2.35-2.50, 2.10-2.30, 1.I5-L85, 0.75-0.95;
MS (ESI) 401 (MH+).
Step 2. Pxeparation of tert-Butyl a-Ami.no-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (aR-diastereomer).
A mixture of tent-butyl a-azido-3-(2-methylpropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate (I59 mg, 0.397 mmol), palladium on carbon (I0%, 40 mg) and EtOH (2.0 mL) is hydrogenated overnight at 30 psi. The mixture is filtered and concentrated to give 145 mg (97%) of the title compound as an oii:
1H NMR (300 MHz, CDC13) 8 7.i5-7.39, 3.55-3.75, 3.15-3.35, 2.84, 2.i5-2.30, 7..85-L95, 1.30-1.80, 1.46, 0.89, 0.84;
MS (ESI) 375 (MH'~).
Following the procedures outlined in EXAMPLE 90 (steps 5-8) and making non-critical modifications, but starting with tent-butyl a-amino-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (oGR,-diastereomer), the title compound is obtained (mp 1II-lI3 °C):
1H NMR (300 MHz, CDC13) 8 9.05, 7.80-7.90, 7.05-7.35, 6.85, 5.25-5.50, 4.50-9:.60, 3.80-3.90, 3.60-3.75, 3.05-3.60, 2.70-2.85, 2.10-2.35, 1.40-1.90, 1.55, 0.70-0.90;
MS (ESI) 492 (MH+).

Following the general procedures outlined in EXAMPLE 92 and making non-critical variations, the following compounds were prepared.
EXAMPLE 93 Preparation of a-[[(4-Fluorophenyl)sulfonyl]amino]-N hydroxy-3-{2-methylpropyl)-2-oxo-1-{2-phenylethyl)-3-pyrrolidineacetamide (ecS-diastereomer).
F
1~ p-Scp CH3 NH
Oy.CH3 H O -N ~G
O N
w E
mp 99-102 °C;
1H NMR (300 MHz, CDC13) S 7.75-7.85, 7.10-7.35, 5.06, 3.45-3.60, 3.I5-3.35, 2.85, 2.35-2.50, 1.95-2.I0, 1.15-1.60, 0.78, 0.74;
MS (ESI) 492 (MH+).
EXAMPLE 94 Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N-hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

F / i NH OH
F
H
HO'N

Step 1. Preparation of tent-Butyl a-(2-Chloroethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yI)-3-pyrrolidineacetate A cold (-78 °C) solution of tent-butyl 2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (prepared similarly to that described in EXAMPLE 1, step 3;
5.52 WO 97/32846 PCT/US971025~68 g, I6.1 mmol) in dry THF (I00 mL) is treated with the dropwise addition of LDA
(9.66 mL, 19.3 mmol, 2.0 N). The solution is stirred for 30 min, and then treated with the dropwise addition of 1-bromo-2-chloroethane (1.61 mL, i9.3 mmol).
'The solution is maintained at -78°C for 5 hours and then allowed to slowly warm to room temperature under N2 overnight. The solution is quenched with saturated NH4Cl (10 mL) and diluted with H20 (25 mL). The product is extracted with EtOAc (3 x 100 mL), dried over anhydrous MgS04, filtered, and concentrated to give 6.6 g of a brown oil. The oil is purified by silica gel chromatography (275 g SG; IO%
EtOAcJhexane) to provide 5.07 g (78%) of the title compound as a clear, yellow oil:
IR (liq.) 2977, 293I, 1721, 1685, 1496, I455, 1440, 1393, 1367, 1282, 1257, 1149, 9I7, 748, 701 cxri 1;
~H NMR (300 MHz, CDC13) 8 7.I5-7.35, 5.45-5.65, 4.95-5.15, 3.25-3.80, 3.05-3.25, 2.81, 2.71, 1.90-2.45, L65-L85, 1.43;
MS (EI) m /z 405 (M+), 370, 351, 349, 332, 314, 260, 259, 258, 105, 104, 57.
I5 Step 2. Preparation of tent-Butyl a-(2-Azidoethyl)-2-oxo-I-(2-phenylethyl)-(proper-2-yI)-3-pyrrolidineacetate A solution of tent-butyl a-(2-chloroethyl)-2-oxo-1-(2-phenylethyl)-3-(proper-2-yl)-3-pyrrolidineacetate (2.10 g, 5. I7 mmol) in DMSO ( 15 mL) is treated with sodium azide (504 mg, 7.74 mmol). The mixture is heated to 60 °C (oil bath) for i7 hours.
The resultant solution was cooled to room temperature, diluted with Et20 (100 mL), washed with H20 (3 X 50 mL) and brine (50 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide a quantitative yield of the title compound as a yellow oil:
1H NMR (300 MHz, CDC13) b 7.15-7.35, 5.40-5.65, 4.95-5.15, 3.60-3.80, 3.05-3.40, 2.8I, 2.60, 2.10-2.4fl, 1.65-2.05, 1.43.
Step 3. Preparation of tent-Butyl a-(2-Aminoethyl)-2-oxo-1-(2-phenylethyl)-3-(proper-2-yl)-3-pyrrolidineacetate.
A solution of tent-butyl a-(2-azidoethyl)-2-oxo-1-(2-phenylethyl)-3-(proper-2-yl)-3-pyrrolidineacetate (2.12 g, 5.14 mmol) and triphenylphosphine (L48 g, 5.65 mmol) in THF ( 15 mL) is stirred under N2 for 7 hours. Water ( 1 mL) is added and the solution stirred overnight at room temperature under N2. The solution is concentrated and purified by silica gel chromatography (75 g SG; EtOAc, 20%
MeOFi/EtOAc) to provide 1.94 g (97%) of the title compound as a yellow oil:
1H NMR (300 MHz, CDCl3) 8 7.15-7.35, 5.45-5.65, 4.95-5.15, 3.60-3.80, 3.05-3.40, 2.80, 2.50-2.80, 2.10-2.45, 1.60-1.90, 1.42.
Step 4. Preparation of tert-Butyl a-[2-[(3,4-Difluorobenzoyl)amino]ethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate A cold (0 °C) solution of tent-butyl a.-(2-aminoethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (1.93 g, 4.99 mmol) in dry CH2Cl2 (20 mL) is ' treated with diisopropylethylamine (1.04 mL, 5.99 mmol) and 3,4-diftuorobenzoyl chloride (691 ~tL, 5.49 mmol). The solution is allowed to warm to roam temperature, °
stirring under N2 overnight. The solution is diluted with EtOAc ( 100 mL) and washed with 1 N HCl (25 mL), 1 N NaOH (25 mL), and brine (25 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 3.60 g of a brown oil. The oil is purified by silica gel chromatography (50 g SG; 25% EtOAc/hexane) to provide 2.10 g (80%) of the title compound as a yellow, amorphous solid:
IR, (mineral oil) 3360, 1717, 1660, 1606, 1550, 1509, 1497, 1436, I315, 1295, 1281, 1199, 1154, 831, 775 cna 1;
1H NMR (300 MHz, CDC13) 8 7.65-7.75, 7.50-7.60, 7.15-7.35, 6.70, 5.45-5.65, 4.90-I5 5.10, 3.55-3.85, 3.10-3.45, 2.70-2.90, 2.62, 2.10-2.35, L65-L90, 1.43;
MS (ESI) m /z 549 (MNa+).
Step 5. Preparation of tert-Butyl a-[2-[(3,4-Diffuorobenzoyl)amino]ethyl]-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate.
A cold (0 °C) solution of tent-butyl a.-[2-[(3,4-diffuorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate ( 1.62 g, 3.07 mmol) in dry THF ( 10 mL) is treated with monochloroborane methylsulfide complex (640 p:L, 6.14 mmol). The ice bath is removed, and after 4.5 h, 3 N NaOH (7.4 mL, 22.I mmol) is added dropwise, followed by 30% H202 (2.5 mL). The solution is stirred for 1 hour at room temperature and then for 1 hour at 50 °C. After cooling to room temperature and dilution with saturated NH4C1 (5 mL) and H20 (15 mL), the product is extracted into EtOAc (3 X 50 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 1.6 g of a yellow gel. The material is purified by silica gel chromatography (75 g SG;
75%
EtOAcJhexane) to provide 713 mg (43%) of the title compound as a white, amorphous solid:
IR, (liq.) 3335, 2934, 1721, 1666, 1606, 1554, 1511, 1455, 1368, 1316, I296, 1283, .
1250, 1204, 1153 cm-1;
1H NMR (300 MHz, CDC13) 8 7.65-7.75, 7.45-7.60, 7.15-7.35, 6.60-6.75, 3.75-3.95, , 3.10-3.70, 2.70-2.90, 2.65, 2.20-2.40, 2.00-2.20, 1.42, 1.05-1.90;
MS (ESi) m /z 567 (MNa+).

WO 97/32846 PCT/US97/U2~68 Step 6. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-3-(3-hydroxypropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetic acid.
A cold (0°C) solution of tent-butyl a-[2-[(3,4-di.ffuorobenzoyl)amino]ethyl)-3-(3-hydroxypropyl)-2-oxo-I-(2-phenylethyl)-3-pyrrolidineacetate (655 mg, 1.20 mmol) in CH2C12 (3 mL) is treated with TFA (2 mL) and maintained at 0°C for 30 min. The ice bath is removed, and after 2 hours, the solution is diluted with CH2Cl2 and concentrated (3 x). The residual oil is diluted with H20 (10 mL) and extracted into CH2C12 (3 X 50 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide a quantitative yield of the title compound as a white, amorphous solid:
IR (liq.) 1785, 1724, 1644, 1619, 1605, 1557, 1511, 1455, 1442, 1322, 1297, 1284, 1207, 1171, 701 c~ 1;
IH NMR (300 MHz, CDCl3) 8 7.60-7.75, 7.50-7.60, 7.15-7.40, 6.85-7.00, 4.10-4.35, 3.50-3.80, 3.20-3.45, 2.80-3.00, 2.54, 1.20-2.00;
MB (EI) m/z 488, 470, 397, 379, 260, 246, 14I, 113.
Step 7. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N benzyloxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
A cold (0 °C) solution of a-E2-[(3,4-difluorobenzoyl)amino]ethyl]-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (586 mg, 1.20 mmol) in 2:1 CH2Cl2/DMF (7.5 mL) is treated with HOBT (195 mg, 1.44 mmol), EDC (276 mg, 2.44 mmol), and 4-methylmorpholine (158 p.L, 1.44 mmol). The ice bath is removed, and after I hour, O-benzylhydroxylamine HCl (287 mg, 1.80 mmol) and a second portion of 4-methylm.orpholine (198 p.L, L80 mmol) are added. The solution is stirred overnight at room temperature under N2. The solution is diluted wrath H20 (25 mL) and extracted into CH2C12 (3 X 50 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide an oil. The residual oil is reconstituted in EtOAc (50 mL) and washed with I N HCl (10 mL), 1 N NaOH (10 mL), H20 (10 mL), and brine (I0 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 603 mg of a white foam. The material is purified by silica gel.
chromatography (25 g SG; EtOAc) to provide 433 mg (62%) of the title compound as a white, amorphous solid:
'~ IR, (Iiq.) 3328, 2941, 1664, 1619, 1605, 1554, 15I1, 1454, 1438, 1319, 1298, 1283, 1205, 750, 700 cFri 1;
IH NMR (300 MHz, CDC13) 8 7.60-7.75, 7.45-7.60, 7.10-7.45, 6.75-6.85, 4.86, 3.35-3.70, 3.10-3.30, 2.75-2.90, 2.30-2.45, 1.10-2.15;
MS (FAB) m /z 594 (MH+), 593, 592, 531, 489, 472, 471, 453, 313, 57.
Step 8. Preparation of a-[2-[(3,4-Diffuorobenzoyi)amino]ethyl] N hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
A solution of a-[2-[(3,4-difluorobenzoyl)amino]ethyl] N-benzyloxy-3-(3- -hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (215 mg, 0.368 mmol) is dissolved in EtOH (5 mL) and purged with N2. Pearlman's catalyst (22 mg) is added and the atmosphere was replaced with H2 . After 7 hours, the mixture is filtered through celite, washing the residual solids with MeOH, EtOH, and CH2C12.
The fzltrate is concentrated to give 171 mg of a slightly brown foam. The material is crystallized from hot EtOAc (diluting with hexane). The product is isolated and dried in the vacuum oven (45 °C) overnight to provide I17 mg (63%) of the title compound as a cream-colored, powdery solid (mp 118 °C, dec.):
IR (mineral oil) 3274, 3225, 3064, 3027, 1656, 1620, 1606, 1559, 1512, 1359, 1319, 1290, 1282, 1060, 701 cm's;
~H NMR (300 MHz, CDCl3) 8 7.45-7.80, 7.10-7.40, 3.10-3.75, 2.70-2.90, 2.40-2.60, 1.15-2.25;
MS (FAB) m/z 504 (MH+), 503, 502, 488, 471, 313, 246, 141, 105.
EXA112PLE 95 Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N
hydroxy-3-(2-hydroxyethyi)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

F ~ ! NH
OH
F
H
HO'N
~ f Step 1. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetic acid A cold (0 °C) solution of tent-butyl a-[2-[(3,4-difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (EXAMPLE 94, step 4; 505 mg, 0.959 mmol) in CH2Cl2 (2 mL) is treated with TFA (2 mL) and maintained at 0 a °C for 30 min. The ice bath is removed, and after 1 h, the solution was diluted with CH2C1~ and concentrated (3 X). The residual oil is diluted with H20 (10 mL) and extracted into CH2C12 (3 X 25 mL). The extracts are combined, dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to provide mg (95%) of the title compound as a slightly yellow, amorphous solid:
IR, (Iiq.) 1727, 1662, 1641, 1619, 1606, 1554, 1510, 1454, 1441, 1316, 1298, 1283, 1203, 775, 700 cm-1;
1H NMR (300 MHz, CDCl3) 8 7.60-7.75, 7.50-7.60, 7.15-7.40, 6.75-6.90, 5.45-5.65, 5.10-5.20, 3.50-3.75, 3.15-3.35, 2.88, 2.52, 2.34, 1.70-2.05, L20-L45;
MS (ESI) m /z 469 (M').
Step 2. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl] N benzylo~cy-2-oao-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetamide.
A cold (0 °C) solution of a-[2-[(3,4-difluorobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetic acid (427 mg, 0.908 mmol) in 2:I
CH2C12IDMF (6 mL) is treated with HOBT (147 mg, 1.09 mmol), EDC (209 mg, 1.09 mmol), and 4-methylmorpholine (120 N.L, 1.09 mmol). The ice bath is removed, and after 1 hour, a second portion of 4-methylmorpholine ( 150 ~T., 1.36 mmol) and O-benzylhydroxylamine HCI (21? mg, 1.36 mmol) are added. The solution is stirred overnight at room temperature under N2. The solution is diluted with EtOAc (25 mL) and washed with 1 N HCl ( IO mL), 1 N NaOH ( 10 mL), H20 (2 X 10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 530 mg of a yellow solid. The soled is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 3?3 mg (7I%) of the title compound as a white, amorphous solid:
IR, {mineral oil) 3336, 3193, 1679, 1669, 164I, 1608, 1544, 1509, 1495, 1442, 13I1, 1296, 1275, 747, 696 ciri I;
1H NMR (300 MHz, CDCi3) 8 7.05-7.75, 6.65-6.85, 5.40-5.60, 4.80-5.I5, 3.35-3.'I0, 3.05-3.30, 2.81, L35-2.45;
MS (ESI) m /z 574 {M-).
Step 3. Preparation of a-[2-[(3,4-Diffuorobenzoyl)amino]ethyl] N benzyloxy-3-(2-hydroxyethyi)-2-oxo-1-(2-phenylethyi)-3-pyrrolidineacetamide.
a-[2-[(3,4-Difl.uornbenzoyl)amino]ethyl] N benzyloxy-2-oxo-1-(2-phenyiethyl)-3-(propen-2-yi)-3-pyrrolidineacetamide (365 mg, 0.634 mmol) is dissolved in warm EtOH {I0 mL) and cooled to -78 °C. The solution is subjected to ozone for 3.5 min and then purged with N2 for 15 min. The ozonide is quenched with NaBH4 (36 mg, 0.951 mmol) and allowed to slowly warm to room temperature under N2. After 5 hours, additional NaBH4 (36 mg, 0.951 mmol) is added and the mixture allowed to stir overnight. The mixture is concentrated, diluted with H20 (20 mL) and extracted into EtOAc (3 x 50 mL). The extracts are dried over anhydrous MgS04, filtered, and concentrated under reduced pressure to give 306 mg of a white foam.
The foam is purified by silica gel chromatography (25 g SG; EtOAc) to provide mg (34%) of the title compound as a white, amorphous solid:
IR (mineral oil) 3321, 1664, 1619, 1605, 1554, 1510, 1318, 1297, 1283, 1205, 1028, 776, 750, 699, 626 cm'1;
1H NMR (300 MHz, CDC13) S 7. I0-7.75, 6.65-6.75, 4.85, 3.10-3.70, 2.70-2.90, 2.45-2.60, 2.10-2.30, 1.50-1.95;
MS (ESI) m /z 580 (M+), 578 (M-).
Step 4. Preparation of a-[2-[(3,4-Difluorobenzoyl)amino]ethyl) 1V hydroxy-3-(2-hydroxyethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.
A solution of a-[2-[(3,4-diffuorobenzoyl)amino]ethyl) lV benzyloxy-3-(2-hydroxyethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide ( l I7 mg, 0.202 mmol) is dissolved in EtOH (3 mL) and purged with N2. Pearlman's catalyst (10 mg) is added and the atmosphere is replaced with H2. After 6 hours, the mixture is rM
filtered through celite, washing the residual solids with MeOH, EtOH, and CH2C12.
The filtrate is concentrated and resubjected to the same procedure. The recovered material (99 mg) is purified by silica gel chromatography (8 g SG; 5, 10%
MeOHlCHCI3) to give 45 mg of a white, amorphous solid. The solid is triturated with Et2Olhexane, filtered, and dried. This provides 39 mg (40%) of the title compound as a white, powdery solid (mp 135-137 °C):
IR (mineral oil) 3202, 3089, 3063, 3029, 1670, 1648, 1633, 1601, 1564;, 1515, 1499, 1435, 1331, 1320, 1299 cni 1;
1H NMR (300 MHz, DMSO-ds) 8 8.77, 8.40-8.55, ?.80-7.90, 7.65-7.75, 7.45-7.60, 7.10-7.30, 4.30-4.40, 3.00-3.50, 2.60-2.75, 2.10-2.45, 1.50-1.90;
MS (FAB) m /x 490 (MH+), 489, 474, 457, 439, 299, 246, 141, 105.
EXAMPLE 96 Preparation of [R-(R*,S*)]-a.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N hydmxy-3-(3-hydroxypropyl~2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

NH OH
H
HO.N

[odD25 = +13° {c 0.71, CHC13);
IR (mineral oil) 3233, 3085, 3064, 3026, 1662, 1586, 1547, 1497, 1484, I3I9, I299, 1271, 1225, 751, 70i cni 1;
1H NMR (300 MHz, CDC13) 8 7.45-7.60, 7.05-7.45, 3.10-3.65, 2.70-2.90, 2.45-2.60, 1. i5-2.25;
MS {EI) m /z 485 (M+), 248, 247, 202, i78, 156, 123, i05, 104, 95, 56.
Following the general procedures outlined in EXAMPLES 28-29 or 30-34 and making non-critical variations, the following compounds may be prepared.
EXAMPLE 97 Preparation of [S-(R*,.ft*)J N3-hydroxy 1V1-methyl-ocl-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-I,3-pyrrolidinediacetamide.

HO~N~C~~~'' n O ~3 N
H3C~N~C~
O
E~~AMPLE 98 Preparation of [S-(R*,R*)7 N1-cyclopropyl lV'~-hydroxy-al-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.

H ~CHg HO~N~C~'''' O~ N
N ~ ~.
C
r O

EXAMPLE 99 Preparation of [S-(R*,R*)~ N3-hydroxy-a1-(I-methyiethyl)-3-(2-methylpropyl)-2-oxo N3-phenyl-I,3-pyrrolidinediacetamide.

or H CH3 HO~N~C~~~'' i1 N
N ~ ~
w I C' Y
(O
EXAMPLE 100 Preparation of [S-(R*,R*)] N1-(4-fluorophenyl) 1V3-hydroxy-a.l-( 1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.
I5 CHs HO~N~C~~~'' i~
O~ N
N
~ ~ O
EXAMPLE 101 Preparation of [S-(R*,R*)71V'3-hydroxy-a1-(1-methylethyl)-3-{2-methylpropyl)-2-oxo NI-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

H CHs HO~N~C~~~'' ii O ~ N
N
Nw O

WO 97/32846 PCTlLTS97/025~68 EXAMPLE 102 Preparation of [S-(R*,R*)]-al-tent-butyl-.NI-cyclopropyl 1V~-hydroxy-3-(2-methylpropyl)-2-oxo-I,3-pyrrolidinediacetamide.

- .Jr H CH3 H O ~N 1'C ~~''' N
ii ~N'C~
O
FxA'MPLE 103 Preparation of [S-(R*,R*)J-a.1-tent-butyl N3-hydroxy-3-(2-methylpropyl)-2-oxo NI-phenyl-1,3-pyrrolidinediacetamide.

H ~CH3 HO~N~C~~~'' ~i N
N ~ ' C' X
EXAMPLE 104 Preparation of [S-(R*,R*)]-aI-tert-butyl N1-(4-ffuorophenyl) 1V3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide.

H CHs HO~N~C~~~'' ~i N
~. N
I
O

EXAMPLE I05 Preparation of [S-(R*,R*)]-a,1-tert-butyl N3-hydroxy-3-(2-methylpropyl)-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

H CHg HO ~N 1C ~~~~' ii N
N
~ C I
N~ O
i0 EXAIVn'LE 106 Preparation of LS-(R*,R*)]-al-cyclohexy11V3-hydroxy-3-(2-methylpropyl)-2-oxo Nl-phenyl-I,3-pyrrolidinediacetamide.
cH3 HO~N~'C~~~'' ii N
N
~ ~ o EXAMPLE 107 Preparation of [S-(R*,R*)J-aI-cyclohexyl lV3-hydroxy-3-(2-methylpropyl)-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

H 'CH3 HO~N~C~~~~' \
O~ NJ
N
N~ ( O

WO 97!32846 PCT/US97/02568 EXAMPLE 108 Preparation of [S-{R*,R*)]-3-(cyclopentylmethyl) N3-hydroxy-N1-methyl-al-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~"' i1 N
H3C~N~C~
O
EXAMPLE i09 Preparation of [S-(R*,R*)]-3-(cyclopentylmethyl) N1-cyclopropyl-N3-hydroxy-oc1-( I-methyiethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~'.
O hf N
~ N
O
EXAMPLE 110 Preparation of [S-(R*,R*)J-3-(cyclopentylmethyl) N3-hydroxy-al-( 1-methylethyl)-2-oxo N1-phenyl-i,3-pyrrolidinediacetamide.
H
HO~N~C~~~"' O ~ N, N ~ ' C
D

WO 97!32846 PCT/L1S97/02568 EXAMPLE 111 Preparation of [S-(R*,R*)]-3-(cyciopentylmethyl)-.Nl-(4-fluorophenyl) N3-hydroxy-al-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' ti N
N ~ ' C' [O
IO
EXAMPLE 112 Preparation of [S-(R*,R*)]-3-(cyclopentylmethyl) N'3-hydroxy-a1-(1-methylethyl)-2-oxo Nl-(4-pyridinyl)-I,3-pyrrolidinediacetamide.

H ""' HO',N ~C ~..'' ti N
N ~ ' C
20 N~ O
EXA1VIPLE 113 Preparation of [S-(R*,R*)]-al-tent-butyl-3-(cyclopentylmethyl)-N'3-hydroxy N1-methyl-2-oxo-1,3-pyrrolidinediacetamide.
H
HO'~N~'C'~~' tt O~ N
H3C~N'C~
O

EXANfPLE 11~ Preparation of [S-(R*,R*)]-al-tert-butyl-3-(cyclopentylinethyl)-N1-cyciopropyl N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO ~N ~'C ~~''' O I-1- N l N~ ~/
C
O
EXAMPLE 1I5 Preparation of [S-(R*,R*)~-al-tent-butyl-3-(cyclopentyliuethyl)-N3-hydroxy-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' \
Oti- Nl N
O
EXAMPLE 116 Preparation of [S-(R'~,R*)]-al-tent-butyl-3-(cyclopentylmethyl)-Nl-(4-fluorophenyl) N3-hydroxy-2-oxo-1,3-pyrrolidinediacetatnide.
H
HO~N~C~'~' ii O~ N
i N
C
O

EXAMPLE 117 Preparation of [S-(R*,.R*)]-a1-tert-butyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo N~-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H ' HO~N~C~~~'' ii O~ N
N ~ ' C
N~ II ''''O
EXAMPLE 118 Preparation of [S-(R*,R*)]-a1-cyclohexyl-3-(cyciopentylmethyl)-N3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediaceta.mide.
H
HO~N~C~~~'' if N
H3C'N~C
O
EXAMPLE 119 Preparation of [S-(R*,R*)]-al-cyclohexyi-3-(cyclopentylinethyl)-Nl-cyclopropyl 1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' 1 O~ Nl ~N~

EXAMPLE 120 Preparation of [S-(R*,R*)]-a~--cyciohexyl-3-(cyciopentylmethyl)-N3-hydroxy-2-oxo NI-phenyl-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' ' Ol-T Nl N~C
ii O
EXAMPLE 121 Preparation of [S-(R*,R*)1-al-cyclohexyl-3-(cyciopentylmethyl)-Nl-(4-ffuoropheny1) N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H '"
WO~N~C~~~'' ii N
N
F
EXAMPLE 122 Preparation of [S-(R*,R*)]-al-cyclohexyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo-Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' ti N
, N
N~ l o EXAMPLE 123 Preparation of [S-(R*,R*)] 1V3-hydroxy Nl-methyl-al-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H
N
HO~ ~C
O
H3C' ' C' O
EXAMPLE I24 Preparation of [S-(R*,R*)] N1-cyclopropyl 1V3-hydroxy-a1-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' N
~N'C~
p EXAMPLE 125 Preparation of [S-(R*,R*)] 1V3-hydroxy-a1-(1-methylethyl)-2-oxo-Nl-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H w HO~N~C~~'.
it N
i N~C
O

EXAMPLE 126 Preparation of [S-(R*,R*)] Nl-(4-fluorophenyl) 1V3-hydroxy-a~-( 1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H
HO~N~'C~~~'' tt O~ N
N~ ~ ' C' IO
EX6~MPLE 127 Preparation of [S-(R*,R*)] 1V3-hydroxy-a~-(1-methylethyl)-2-oxo-3-(3-phenylpropyl) Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~~' tt N
N

0 N~ p E~~LE 128 Preparation of [S-(R*,R*)]-a~-tert-butyl 1V3-hydroxy Nt-methyl-2-oxo-3-(3-phenyipropyl)-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~'' tt N
H3C/N'C I
O

EXAMPLE 129 Preparation of [S-(R*,R*)]-aI-tert-butyl NI-cyclopropy11V3-hydroxy-2-oxo-3-(3-phenylpropyl)-I,3-pyrrolidinediacetamide.
b f P
HO's v EXAMPLE 130 Preparation of [S-(R*,R*)]-al-tent-butyl N'3-hydroxy-2-oxo NI-phenyl-3-(3-phenylpropyl)-I,3-pyrrolidinediacetamide.
H
HO~N~C~~~~' tt O~ N
N
(' ~ O
FxAMPLE 131 Preparation of [S-(R*,R*)]-ai-tert-butyl NI-(4-fluorophenyl) 1V3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
/ ' H
HO~N~C~~'' tt O~ N
~ N, C ~ , O
a EXAMPLE I32 Preparation of [S-(R*,R*)]-al-tent-butyl-N3-hydroxy-2-oxo-3-(3-phenylpropyi) Nx-(4-pyridi.nyl)-1,3-pyrroliclinediacetamide.
-H
HO~N~C~~''' ii O~ N
N ~ ' C_ N~ ' 'O
EXAMPLE 133 Preparation of [S-(R*,R*)1-al-cyclohexyl 11T3-hydroxy Nz-methyl-2-oxo-3-(3-phenylpropyl)-I,3-pyrroliclinediacetamide.
i I
H
HO~N~C~''' ii N
H3C'N~C
EXAMPLE 134 Preparation of IS-(R*,R*)]-al-cyclohexyl N1-cyclopropyl 1V3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.

WO 97/32846 PCT/iJS97/02568 EXAMPLE 135 Preparation of [S-(R*,R*)J-a1-cyclohexyl-N3-hydroxy-2-oxo Nl-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H
N
HO ~
O
w ~ _C, O
EXAMPLE 136 Preparation of [S-(R*,R*)]-oci-cyclohexyl NI-(4-fluorophenyl) N'3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide.
H
HO'-N ~C ~.._', i~
O~ N
N
~ , o F
EXAMPLE 137 Preparation of [S-(R*,R*)I-a1-cyclohexyl N3-hydroxy-2-oxo-3-(3-phenylpropyl) N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H
HO~N~C
O
_ Nw EXAMPLE I38 Preparation of [S-(R*,R*)]-3-[3-(4-fluorophenyl)propyl] N3-hydroxy Nl-methyl-a1-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
F
' s H
H O'~ N ~ C ~~~'' tt N
H3G~N~C~
O
EXFLMPLE 139 Preparation of [S-(R*,R*)] Nl-cyclopropyl-3-[3-(4-fluorophenyl)propyl] N3-hydxoxy-a~-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
F

I
HO~
EXAMPLE 140 Preparation of [S-(R*,R*)]-3-[3-(4-ffuorophenyl)propyl] N3-hydroxy-al-(1-methylethyl)-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide.
F
HO~
C

EXAMPLE 14i Preparation of [S-(R*,R*)] NI-(4-fiuorophenyl)-3-[3-(4-fluorophenyl)propyl]-.N8-hydroxy-a,I-( 1-methylethyl)-2-oxo-i,3-pyrrolidinediacetarnide.
, F
H \ I
HO~N~C~~''' tE
N
N
~ I
F~ O
F'XAMPLE 142 Preparation of [S-(R*,R*)]-3-[3-(4-fluorophenyl)propyl] N3-hydroxy-ocl-(1-methylethyl)-2-oxo N1-(4-pyridinyl)-I,3-pyrroiidinediacetamide.

F
HO ~
r.
N
EXAMPLE 143 Preparation of [S-(R*,R*)]-a.l-tert-butyl-3-[3-(4-ffuorophenyl)propyl] N3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide.
F
H ~I
HO~N~C~~'~' p N
HsC.N.C I
O

EXAIVJPLE 144 Preparation of [S-(R*,R*)]-a~-tert-butyl N1-cyciopropyl-3-[3-(4-fluorophenyl)propyl] N3-hydroxy--2-oxo-I,3-pyrrolidinediacetamide.
F
H
HO~N~C~~~'' n O~ N
FN-~~ C
O
EXAMPLE 145 Preparation of [S-(R*,R*)]-al-tent-butyl-3-[3-(4-fluorophenyI)propyl] 1V3-hydroxy-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide.
i5 ~ F
H
HO~N~C~~''' N
N
O
FX_AMPLE 146 Preparation of [S-(R*,R*)]-al-tert-butyl NI-(4-fluorophenyl.)-3-[3-(4-fluorophenyl)propyl] 1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C
O
I
F ~ a EXAMPLE 147 Preparation of [S-(R*,R*)]-a.l-tert-butyl-3-[3-(4-ffuorophenyl)propyl]-IV3-hydroxy-2-oxo Nt-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
F
H
N
HO~ ~C
O
N~ I O
EXAMPLE 148 Preparation of [S-{R*,R*)J-oc1-cyciohexyl-3-[3-(4-ffuorophenyl)propyl] 1V3-hydroxy N~-methyl-2-oxo-1,3-pyrrolidinediacetamide.
F
ht HO~N~C
O

' EXAMPLE 149 Preparation of [S-(R*,R*)]-al-cyclohexyl N1-cyclopropyl-3-[3-(4-fluorophenyl)propyl] N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
F
H
HO~N~C~~~~' a On N
~N~C
is O

EXAMPLE 150 Preparation of [S-(R*,.R*))-a1-cyclohexyl-3-[3-(4-fluorophenyl)propyl) 1V3-hydroxy-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide.
F
WO
EXAMPLE 151 Preparation of [S-(R*,R*))-a1-cyclohexyl N1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl) N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
HO~
N
F
E~~ANIPLE 152 Preparation of [S-(R*,R*))-a~-cyclohexyl-3-[3-(4-fluorophenyl)propyl) N3-hydroxy-2-oxo Nl-(4-pyridinyl)-I,3-pyrrolidinediacetamide.

F
H
N
HO~ ~C
O
N w I _O, H
N w C ~--..
ti O N

WO 97!32846 PCT/U897/02568 Fx_AlylpLE 153 Preparation of [S-(R*,R*)J-3-[3-(biphen-4-yl)propyl] N3-hydroxy-Nl-methyl-al-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetarnide.
H
HO~N~
H3G C:
O
EXAMPLE 154 Preparation of [S-(R*,R*)]-3-(3-(biphen-4-yl)propyl] Nl-cyclopropyi 1V3-hydroxy-aZ-(1-methyiethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C
O
V
EXAMPLE 155 Preparation of [S-(R*,R*)]-3-I3-(biphen-4-yl)propylJ N3-hydroxy-al-(1-methylethyl)-2-oxo Nl-phenyl-1,3-pyrrolidinediacetamide.
H
N
HO~ ~C

I
\ V

EXAMPLE 156 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-y3)propyl] NI-(4-fluorophenyl) N'3-hydroxy-a1-(1-methylethyl)-2-oxo-I,3-pyrrolidinediacetamide.
H
N
HO~ 1C
O
n N ~ /
~ C' O
EXAMPLE 157 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl] N3-hydroxy-a1-(1-methylethyl)-2-oxo N1-(4-gyridinyl)-1,3-pyrrolidinediacetamide.
H
N
HO~ ~C
O
, N.
N I C
O
EXAMPLE 158 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-aI-tert-buty11V3-hydroxy-3V~-methyl-2-oxo-1,3-pyrrolidiaediacetamide.
H
N
HO~
H3C, _C, O

WO 97132846 PCT/iJS97/02568 EXAMPLE 159 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-a~-tert-butyl Nl-cyclopropyl 1V3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide.
H
N
HO~ ~C
O
N
N ~ ~
C- '1' 'O
EXAMPLE 160 Preparation of [S-(R*,R*)J-3-[3-(biphen-4-yl)propyl]-a~-tert-butyl 1V3-hydroxy-2-oxo NI-phenyl-1,3-pyrrolidinediacetamide.

H
N
HO~ ~C

N C N
ii O
E~~t~MPLE I61 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-al-tert-butyl NI-(4-fluorophenyl) 1V3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide.

WO 97/32846 PCTlUS971025~68 EXA1VIPLE I62 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl7-a~-tern"-butyl 1V3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H
N
HO~ ~C
O
N
N.
Nw ~
~ O
EXAMPLE I63 Preparation of [S-(R*,R*)]-3-[3-(biphen-4 yl)propyl]-a.Z-cyclohexyl-~-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide.
H
HON ~C
O
HgC' 'C' O
EXAMPLE 164 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-al cyclohexyl Nl-cyclopropyl N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HOiN~
f EXAMPLE 165 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yi)propyl]-a~-cyclohexyl 1V3-hydroxy-2-oxo Nx-phenyl-1,3-pyrrolidinediacetamide.
H
N
HO~ ~C
O
IV
N
w I
EXAMPLE 166 Preparation of [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-a~-cyclohexyl-N~-(4-fluorophenyl) N'3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C
~i 0 ~, N ~C
it F O
EXA1VIPLE 167 Preparation of [S-(R*,R*)J-3-[3-(biphen-4-yl)propyl]-al-cyclohexy11V3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H

HO~N~C
it O
r, , N~
I

N~ O

WO 97!32846 PCT/US97/02568 EXAN~'LE I68 Preparation of [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4.-yl)propyl] N3-hydroxy Nl-methyl-a~-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
F
' S
H
HO~N~C
ii O
a EXP~MPLE 169 Preparation of [S-(R*,R*)]-3-[3-(4'-fl.uorobiphen-4-yl)propyl] Nl-cyciopmpyl-N3-hydroxy-aZ-(i-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
F
H
HO~N~C

EXAMPLE 170 Preparation of [S-(R*,R*)]-3-[3-(4'-~Luorobiphen-4-yl)propyl] N3-hydroxy-aI-( 1-methylethyl)-2-oxo N1-phenyl-1,3-pyrrolidinediacetamide.
H
HON
h N.
O

EXAMPLE 171 Preparation of [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyla N~-(4-fluorophenyl) N~-hydroxy-a1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.

F

H
HO~N~C
i!

N
F~ O
~,'xAMPLE 172 Preparation of [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl]

hydroxy-al-( 1-methylethyl)-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
F
H
N
HO~ ~C

IV
N ~ ' C' N~ IO
EXAN.~'LE 173 Preparation of [S-(R*,R*)]-al-tent-butyl-3-[3-(4'-fluorobiphen-4-yl~ropyl] ~V'3-hydroxy Nl-methyl-2-oxo-1,3-pyrrolidinediacetamide.
F
H
HO~N~C
ii O
'~I 'O

EXAMPLE 174 Preparation of [S-(R*,R*)]-aI-tert-butyl N1-cyclopropyl-3-C3-(4'-ffuorobiphen-4-yI)propyl] lV3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
F
H
N
HO~ ~C
O
v EXAMPLE 175 Preparation of (S-(R*,.R*)]-al-tert-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl] 1V3-hydroxy-2-oxo NI-phenyl-1,3-pyx~olidinediacetamide.
F
H
HO~N~C
it O
I
v EXE1MPLE 176 Preparation of [S-(R*,R*)]-a1-tent-butyl-3-[3-(4'-fiuorobiphen-4-yl)propyl] Nl-(4-fluorophenyl)-1~T3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
N
HO ~ ~'C
O
y ~ rv N
F~ O
r EXAMPLE 177 Preparation of [S-(R*,R*)]-aI-tert-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl] N3-hydroxy-2-oxo N1-(4-pyridinyl)-I,3-pyrrolidinediacetamide.
F
s H
N
HO~ ~C
O
lV
N
Nw ~
O
Io EXAMPLE I78 Preparation of [S-(R*,R*)]-al-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl] 1V3-hydroxy-N1-methyl-2-oxo-I,3-pyrrolidinediacetamide.

H
N
HO~ ~C
O
HsC~N.C~

E~~AN~LE 179 Preparation of ES-(R*,R*)]-al-cyclohexyl Nl-cyclopropyl-3-I3-(4'-ffuorobiphen-4-yl)propyl] N'3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide.
F
H
N
HO~ ~C
O
IV
N'C
\VY O

WO 97/32846 PCT/US97/02~68 EXF1MPLE 180 Preparation of [S-(R*,R*)]-a1-cyciohexyi-3-[3-(4'-fluorobiphen-4-yl)propyl] lV3-hydroxy-2-oxo N1-phenyl-1,3-pyrrolidinediacetami.de.
F
H
HO~N~'C
O
N
O
EXAMPLE 181 Preparation of [S-(R*,R*)]-a1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yI)propyl] Nl-(4-fluorophenyl) N3-hydroxy-2-oxo-I,3-pyrrolidinediacetamide.
F
H
N
HO ~ ~C
O
N
C
F O
EXl-LMPLE 182 Preparation of [S-(R*,R*)J-al-cyclohexyi-3-[3-(4'-fluorobipJzen-yl)propyl] lV3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
F
H
HO~N~C
i~
' O
~ I
N

EXA112PLE 183 Preparation of [S-(R*,R*)~-3-heptyl N3-hydroxy N1-methyl-al-( I-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~'.
o~P N~
H3C~N~C
EXAMPLE I84 Preparation of [S-(R*,R*)I NI-cyclopropyl-3-heptyl N3-hydroxy-al-(I-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.

H
HO~N~C~~~~' orb N~
N
O
EXAMPLE 185 Preparation of [S-(R*,R*)1-3-heptyl N3-hydroxy-al-(I-methylethyl)-2-oxo-Nl-phenyl-1,3-pyrrolidinediacetamide.
H aw HO~N~C~~'.
Ot-f Nl N.C
O

E~~AlYll'LE I86 Preparation of [S-(R*,R*)1-3-heptyl N1-(4-fluorophenyl) N3-hydroxy-a1-( 1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~Pd~C~..,,, O~ NJ
N
O
EXAMPLE 187 Preparation of [S-(R*,R*)]-3-heptyl 1V3-hydroxy-a~-(I-methylethyl)-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

H
N
HO~
~i O
n , N. ~ ' C
O
EXANCPLE 188 Preparation of [S-(R*,.R*)]-al-tert-butyl-3-heptyl N3-hydroxy-Nl-methyl-2-oxo-1,3-gyrrolidinediacetamide.
H
HO~N~C~~'.
O~ Nl H3C.N.C
t O

EXAMPLE 189 Preparation of [S-(R*,R*)]-ocZ-tert-butyl Nl-cyclopropyl-3-heptyl-1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~~~~' o~ N~
ii ~N\C~
O
EXAMPLE 190 Preparation of [S-(R*,R*)~-ocl-tert-butyl-3-heptyl IV3-hydroxy-2-oxo N~-phenyl-i,3-pyrrolidinediacetamide.

H
HO~N~C~~~~' ' OI-f Nl N~, FxAMPLE 191 Preparation of [S-(R*,R*)]-a.l-tert-butyl N1-(4-fluorophenyl)-3-heptyl ~-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H
HO~N~C~-'.
~i O~ N
N~ ~ ' C
I 'O

WO 97/32846 PCT/US971025~68 EXAMPLE 192 Preparation of [S-(R*,R*))-a1-tent-butyl-3-heptyl N3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H uu HOiNwC~....
N~
N ~ ' C
N~ O
EXAN~LE I93 Preparation of [S-(R*,R*)7-al-cyclohexyl-3-heptyl 1V3-hydroxy-Nl-methyl-2-oxo-I,3-pyrrolidinediacetamide.
H a a HO'~N~'C~~''' o~ N~
H3C ~N ~C
O
EXAMPLE 194 Preparation of [S-(R*,R*)7-al-cyclohexyl Nl-cyclopropyl-3-heptyl N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H a HO~N~C~w.
O~ Nl ~N~
O
-I? 1-WO 97/32846 PCTlUS97/02568 EXAMPLE 195 Preparation of [S-(R*,R*)]-ai-cyclohexyl-3-h_ eptyl N3-hydroxy-2-oxo N1-phenyl-1,3-pyrrolidinediacetamide.
H
HO~N~
IO
EXAMPLE 196 Preparation of [S-(R*,R*)]-al-cyclohexyl-3-heptyl N1-(4-fluorophenyl) 1V3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide.
H uu HO~N~C~~'.

N~C
F
EXAMPLE 197 Preparation of CS-(R*,R*)]-a1-cyclohexyl-3-heptyl N3-hydroxy-2-oxo Nl-(4-pyridinyl)-1,3-pyrrolidinediacetamide.
H
HO~ N ~ C~'''-O!-i- N, N
N~ I O

SCHEME A-I
R
p- U O N O N
R R

Z~
R,O t! R~ R2 I_R2 R,O ~ Ry O
N O C
R rr'' I
R

2O HO~ Rt HO R2 R~
N
O/y i R
R
5 g iN Ri H R2 R
HO N
O HO~
N
I N
R
' R
& g R~
O' -N
H O
H

Ri Ri O N
H Et0 R~
R~ H0~1~~
\/\
O N
O
R~ R3 . H R, ~N~~
Ho R~ Rs -1?4-WO 97!32846 PCTIUS97/02a68 Y
R~
O
H BOC O
BOC

!_Rz R'O~ R~
O N
BQC O
BOC
i8 2t R Rz R'O~ ' R,a R~
O
H
H

RO R' R'O ~ R~
i "' R R

Rz R O --. R~ H CO OTf R'O R~ ., O :~ * 3 ~ .. R3 +
O N O p N
H 20a 23 H 22a R'O R i R2 ~_Rz R'O R~
IO p ---O O
H CO
3 R3 H3CO ~ R

O
O

I5 R~O~,,, R, ~2 I' R'O Ri O N
N
HO~
_ Rs HO' / R
O ~ 3 O

Rz ... R ~
RO ~ R~O R~

R4 Rs ~2 H H
HO-N R~ HO-N R~

R~ R3 R/' R3 3~

Y
R~
OG(Ph)3 ~~~ OC(Ph)3 O O
O
'' 5 R~ R~
~~/' . ~~/' .
,~~ OC(P h )3 ~~~ OH
p O O O
R, I5 R' ~/'Rs O N
O O OH H2N ~ Ra R Rs R, H R, N
HO ~~ Bn0 N O N
Ra~ R3 Ra"' Rs 2s H R, HO

Ra' _ Rs s 4t WO 97/32846 PCTlUS97/02568 SCHEME B
J
6 R,O ~ R ~ ,.
O O.i R

I5 R~o ~ R ~

O
R

N R~
N ~.!~O
R

WO 97/32846 PCTIUS97/02~68 ~ Rs r c~ ~~ ~O
H

Rs O~~O
R

R~ / R5 O~~O
R

R~O N%R5 O
R

N R jR5 Ho' ~O

R

L

2 %/~
R~

NW
o I fio R

R~
WO~~ W
20 0 ' N'~o I
R

Ri HO~ ~~NW
O N ~O
' R

r WO 97/32846 PCT/LTS97/0256$
SCHEME D
O ~NH
H
5s 0 ~NCBZ
H

O ~NCBZ
R

R~
O ~NCBZ
R

R~O R i ,NCSz O N
R

~ R~
HO ~
,NH
O N
R

Claims (29)

We claim:

1. A compound of formula I

or pharmaceutical acceptable salts thereof wherein X is a) -(CH2)-, b) -NR5-, or c) -C(=O)-;
Y is a) -(CH2)-, or b) -NR5-;
with the proviso that when X is -NR5-, then Y is -(CH2)-;
R1 is a) H, b) C1-20 alkyl, c) -(CH2)i-Aryl, d) -(CH2)i-O-R5, e) -(CH2)i-Het, f) -(CH2)i-CO2R5, g) -(CH2)i-C(=O)NHR5, h) -(CH2)i-NR6R7, i) -(CH2)i-SO2-Aryl, j) -(CH2)j cycloalkyl, or k) -(CH2)j-Aryl-Aryl;
R2 is a) H, b) C1-20 alkyl, c) -(CH2)j-R8, d) -(CH2)j-OR5, e) -CH2CR5=CR5R5 f) -NHR5, g) -(CH2)j NR6R7, h) -NHSO2R5, i) -(CH2)j-C(=O)NR6R7, j) -(CH2)j-NR5C(=O)R5, k) -(CH2)j-NR5SO2R5, or l) -(CH2)j-N(CO2R5)2;
R3 is a) H, b) C1-6 alkyl, c) -(CH2)j-Aryl, d) -(CH2)j-Het, e) -(CH2)j-C3-6 cycloalkyl, or f) -C(=O)NHR5;
R4 is a) H, b) -C(=O)NHR5, c) -C(=O)NR6R7, d) -C(=O)NH(CH2)k NR6R7, e) -C(=O)NH(CH2)j-Aryl, f) -C(=O)NH(CH2)k-O-(CH2)k NR6R7, g) -C(=O)NH(CH2)k-S-(CH2)j NR6R7, h) -C(=O)NH(CH2)k-NHSO2-Aryl, i) C(=O)NH(CH2)k-NHSO2-NR6R7, or j) R5 is a) H, b) C1-6 alkyl, c) -(CH2)j-Aryl, d) -(CH2)j-Aryl - Aryl, e) -(CH2)j-Aryl-(CH2)j-Aryl, f) (CH2)j-Het, or g) -(CH2)j-cycloalkyl R6 and R7 may be the same or differently a) H, b) C1-6 alkyl, c) -(CH2)j-Aryl, d) Q, or e) R6 and R7 taken together with the linking N-atom form azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl, optionally substituted with one or more C1-4 alkyl;
R8 is a) -S-R5, b) -SO-R5, c) -SO2-R5, d) -S-(CH2)j-Het, e) -NHCO2R5, f) piperidinyl, R9 is a) halogen, b C1-6 alkyl, c) -OR5, d) -NR5R5, e) -CONHR5, f) -SO2NHR5, g) -NHSO2R5, h) -NO2, i) -CO2R5, or j) -CF3;
R10 is a) H, b) OH, c) OR5, d) NHR5, or e) -(CH2)j-OR5;
Aryl is phenyl, optionally substituted with one or more of the following :
a) halogen, b) C1-10 alkyl, c) -OR5, d) -NR5R5, e) -CONHR5, f) -SO2NHR5, g) -NHSO2R5, h) -NO2, i) -CO2R5, or j) -CF3;
Het is a 5-, or 6-membered heteroaromatic moiety having one or more atoms selected from the group consisting of N, O, and S;
Q is a saturated 5, or 6-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S;
i is 1,2,3,4,5 or 6;
j is 0, 1, 2, 3, or 4;
k is 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
C1-6 alkyl, C1-10 alkyl, or C1-20 alkyl in each of the above definitions, may be each and independently substituted with one to three halogen, hydroxy, or cyano;
and with the proviso that when R1 is methylbutyl R4 is other than H.

2. A compound of structure II
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

3. A compound of structure III
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

4. A compound of structure IV
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

5. A compound of structure V
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

6. A compound of structure VI
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

7. A compound of structure VII
wherein R1, R2, R3, R4, X and Y are as defined in Claim 1.

8. A compound of claim 1 wherein R1 is 2-methylpropyl, or 3-methylbutyl.

9. A compound of claim 1 wherein R2 is selected from the group consisting of H, methyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(1,3-dihydro-1,3-dioxo-2H-naphthoisoindol-2-yl)ethyl, 2-(4,5,6,7,-tetrafluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5,6,-dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-amino-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(4-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(4-fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(4,7-difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(5-fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl, 2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl, 2-(2-thienylthio)propyl, and 2-(2-thienylthio)methyl.

10. A compound of claim 1 wherein R3 is selected from the group consisting of H, 2-methylpropyl, cyclohexylmethyl, benzyl, and phenyl.

11. A compound of claim 1 wherein R4 is H or acetamide.

12. A compound which is 1a) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1b) (3S)-N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1c) N-Hydroxy-.alpha.-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1d) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1e) (3S)-.alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1f) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-naphthoisoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl-3-pyrrolidineacetamide, 1g) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(4,5,6,7-tetrafluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide, 1h) .alpha.-(2-(5,6-Dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1i) .alpha.-[2-(5-Amino-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1j) N-Hydroxy-3-(2-methylpropyl)-.alpha.-[2-(4-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1k) N-Hydroxy-3-(2-methylpropyl)-.alpha.-[2-(5-nitro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1l) .alpha.-[2-(4-Fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1m) .alpha.-[2-(4,7-Difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1n) .alpha.-(2-5-Fluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1o) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1p) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1q) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(2-thienylthio)ethyl)-3-pyrrolidineacetamide, 1r) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(2-thienylthio)propyl]-3-pyrrolidineacetamide, 1s) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(2-thienylthio)methyl)-3-pyrrolidineacetamide, 1t) N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 1u) N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1v) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetamide, 1w) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetamide, 1x) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-.alpha.-[2-(4,5,6,7-tetrafluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide, 1y) 1-(3-Fluorophenyl)methyl)-.alpha.-[2-(1,3-dihydro-1,3-dioxo-2H-isoindo1-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 1z) a3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2a) N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.3-[2-(4,5,6,7-tetrafluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1,3-pyrrolidinediacetamide, 2d) [S-(R*, R*)]-N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2e) [S-(R*, R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-N1-(2-phenethyl)-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2f) [S-(R*, R*)]-N3-Hydroxy-N1-methyl-.alpha.1,3-bis (2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2g) [S-(R*, R*)]-.alpha.1-(Cyclohexylmethyl)-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2h) [S-(R*, R*)]-N3-Hydroxy-N1-methyl-3-(3-methylbutyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2i) N-Hydroxy-3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2j) N-Hydroxy-3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide, 2k) N-Hydroxy-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetamide, 2l) N-Hydroxyl-4-(2-methylpropyl)-5-oxo-1-(2-phenylethyl)-4-pyrazolidineacetamide monohydrochloride, 2m) (S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-N1-phenyl-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2n) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(2-pyridinylmethyl)-1,3-pyrrolidinediacetamide, 2o) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 2p) [S-(R*,R*)]-N1-(4-Fluorophenyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2q) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-[1-(phenylmethyl)-4-piperdinyl]-1,3-pyrrolidinediacetamide, 2r) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(4-piperdinyl)-1,3-pyrrolidinediacetamide, 2s) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(4-pyridinylmethyl)-1,3-pyrrolidinediacetamide, 2t) [S-(R*,R*)]-N1-(4-Fluorophenylmethyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2u) [S-(R*,R*)]-N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha..1-(2-phenylethyl)-1,3-pyrrolidinediacetamide, 2v) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(2-phenylethyl-N1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2w) [S-(R*,R*)]-N3-Hydroxy-.alpha.1,3-bis(2-methylpropyl)-2-oxo-N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 2x) [S-(R*,R*)]-.alpha.1-Cyclohexyl-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2y) [S-(R*,R*)]-.alpha.1-Cyclohexyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 3a) [S-(R*,R*)]-3-(Cyclopentylmethyl)-N3-hydroxy-N1-methyl-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3b) [3S-[1(R*),3R*(R*)]]-.alpha.3-[2-(Benzoylamino)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3c) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-N1-[2-(4-morpholinyl)ethyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3d) [S-(R*,R*)]-N-Hydroxy-3-(2-methylpropyl)-1-[2-(4-morpholinyl)-2-oxo-1-(phenylmethyl)ethyl]-2-oxo-3-pyrrolidineacetamide, 3e) [1(1S)-[1[R*(R*)], 3.alpha.,5.alpha.]]-1-[2-(3,5-Dimethyl-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 3f] [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 3g) [3S-[1(R*),3R*(R*)]]-.alpha.3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N3-hydroxy N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 3h) [S-(R*,R*)]-.alpha.1-Cyclohexyl-N1-cyclopropylmethyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 3i) [S-(R*,R*)]-.alpha.1-Cyclohexyl-N1-(4-fluorophenyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 3j) [S-(R*,R*)]-.alpha.1-tert-Butyl-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 3k) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(5-propyloxy-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-pyrrolidineacetamide, 3l) [R-(R*,S*)]-5-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 3m) .alpha.-[2-(5,6-Difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3n) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-(2-(5-trifluoromethyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide, 3o) .alpha.-[2-(1,3,4,5,6,7-Hexahydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3p) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(3-phenylpropyl)-3-pyrrolidineacetamide, 3r) .alpha.-[2-(o-benzoic sulfimide)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-(2-phenylethyl)-3-pyrrolidineacetamide, 3s) Ethyl Phenylmethyl [4-(hydroxyamino)-3-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-4-oxobutyl]imidodicarbonate, 3t) S-(R*,R*)]-1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 3u) 1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-[2-(4-fluorophenyl)ethyl]-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 3v) .alpha.-[2-[(3,4-Difluorobenzoyl)amino)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3w) [R-(R*,S*)-.alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3x) .alpha.-[2-[(4-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3y) N-Hydroxy-3-(2-methylpropyl)-.alpha.-[2-[(3-nitrobenzoyl)amino]ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3z) .alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4a) .alpha.-[2-[(3-Fluorobenzoyl)amino)ethyl]-1-[2-(4-fluorophenyl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 4b) .alpha.-[2-[(4-Biphenylcarbonyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4c) N-Hydroxy-.alpha.-[2-[[(4-methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4d) .alpha.-[2-[[(4-Fluorophenyl)sulfonyl]amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4e) N-Hydroxy-.alpha.-[2-[[(4-methoxyphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4f) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-[(phenylsulfonyl)amino]ethyl]-3-pyrrolidineacetamide, 4g) [R-(R*,S*)]-.alpha.-[2-[[(4-Fluorophenyl)sulfonyl]amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4h) 5,6-Difluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 4i) 1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 4j) [R-(R*,S*)]-6-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 4k) [R-(R*,S*)]-5-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 4l) [R-(R*,S*)]-5,6-Difluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 4m) N-Hydroxy-.alpha.-[[[(4-methoxyphenyl)sulfonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.R-diastereomer), 4n) N-Hydroxy-.alpha.-[[[(4-methoxyphenyl)sulfonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.S-diastereomer), 4o) .alpha.-[[(4-Fluorophenyl)sulfonyl]amino]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (R-diastereomer), 4p) .alpha.-[[(4-Fluorophenyl)sulfonyl]amino]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.S-diastereomer), 4q) .alpha.-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-N-hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4r) .alpha.-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-hydroxyethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4s) [R-(R*,S*)]-.alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 4t) S-(R*,R*)]-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 4u) [S-(R*,R*)]-N1-cyclopropyl-N3-hydroxy-.alpha.1-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide., 4v) [S-(R*,R*)]-N3-hydroxy-.alpha.1-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 4w) [S-(R*,R*)]-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 4x) [S-(R*,R*)]-N3-hydroxy-.alpha.1-(1-methylethyl)-3-(2-methylpropyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 4y) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-cyclopropyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 4z) [S-(R*,R*)]-.alpha.1-tert-butyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 5a) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-(4-fluorophenyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 5b) [S-(R*,R*)]-.alpha.1-tert-butyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5c) [S-(R*,R*)]-.alpha.1-cyclohexyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 5d) [S-(R*,R*)]-.alpha.1-cyclohexyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5e) [S-(R*,R*)]-3-(cyclopentylmethyl)-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5f) [S-(R*,R*)]-3-(cyclopentylmethyl)-N1-cyclopropyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5g) [S-(R*,R*)]-3-(cyclopentylmethyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 5h) [S-(R*,R*)]-3-(cyclopentylmethyl)-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 5i) [S-(R*,R*)]-3-(cyclopentylmethyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5j) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(cyclopentylmethyl)-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 5k) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(cyclopentylmethyl)-N1-cyclopropyl-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5l) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 5m) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(cyclopentylmethyl)-N1-(4-fluorophenyl)-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5n) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5o) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-(cyclopentylmethyl)-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 5p) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-(cyclopentylmethyl)-N1-cyclopropyl-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5q) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 5r) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-(cyclopentylmethyl)-N1-(4-fluorophenyl)-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 5s) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-(cyclopentylmethyl)-N3-hydroxy-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5t) [S-(R*,R*)]-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5u) [S-(R*,R*)]-N1-cyclopropyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5v) [S-(R*,R*)]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5w) [S-(R*,R*)]-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5x) [S-(R*,R*)]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-3-(3-phenylpropyl)-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 5y) [S-(R*,R*)]-.alpha.1-tert-butyl-N3-hydroxy-N1-methyl-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 5z) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-cyclopropyl-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6a) [S-(R*,R*)]-.alpha.1-tert-butyl-N3-hydroxy-2-oxo-N1-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6b) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-(4-fluorophenyl)-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6c) [S-(R*,R*)]-.alpha.1-tert-butyl-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamid, 6d) [S-(R*,R*)]-.alpha.1-cyclohexyl-N3-hydroxy-N1-methyl-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6e) [S-(R*,R*)]-.alpha.1-cyclohexyl-N1-cyclopropyl-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6f) [S-(R*,R*)]-.alpha.1-cyclohexyl-N3-hydroxy-2-oxo-N1-phenyl-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6g) [S-(R*,R*)]-.alpha.1-cyclohexyl-N1-(4-fluorophenyl)-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-1,3-pyrrolidinediacetamide, 6h) [S-(R*,R*)]-.alpha.1-cyclohexyl-N3-hydroxy-2-oxo-3-(3-phenylpropyl)-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6i) [S-(R*,R*)]-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl}-2-oxo-1,3-pyrrolidinediacetamide, 6j) [S-(R*,R*)]-N1-cyclopropyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6k) [S-(R*,R*)]-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 6l) [S-(R*,R*)]-N1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6m) [S-(R*,R*)]-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6n) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 6o) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-cyclopropyl-3-[3-(4-fluorophenyl)propyl]--N3-hydroxy--2-oxo-1,3-pyrrolidinediacetamide, 6p) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4-fluorophenyl)propyl)-N3-hydroxy-2-oxo--N1-phenyl-1,3-pyrrolidinediacetamide, 6q) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-propyl]-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 6r) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-2-oxo--N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6s) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4-fluorophenyl)propyl)-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 6t) [S-(R*,R*)]-.alpha.1-cyclohexyl-N1-cyclopropyl-3-[3-(4-fluoropheny)propyl]--N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 6u) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 6v) [S-(R*,R*)]-.alpha.1-cyclohexyl-N1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 6w) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4-fluorophenyl)propyl]-N3-hydroxy-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 6x) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl)-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6y) [S-(R*,R*))-3-[3-(biphen-4-yl)propyl]-N1-cyclopropyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 6z) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 7a) [S-(R*,R*))-3-[3-(biphen-4-yl)propyl]-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7b) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-N3-hydroxy-.alpha.1-(1-methylethy1)-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7c) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-tert-butyl-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7d) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-tert-butyl-N1-cyclopropyl-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7e) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-tert-butyl-N3-hydroxy-2-oxo-phenyl-1,3-pyrrolidinediacetamide, 7f) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-tert-butyl-N1-(4-fluorophenyl)--N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7g) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-tert-butyl-N3-hydroxy-2-oxo-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7h) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-cyclohexyl-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7i) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-cyclohexyl-N1-cyclopropyl-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7j) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-cyclohexyl-N3-hydroxy-2-oxo--N1-phenyl-1,3-pyrrolidinediacetamide, 7k) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-cyclohexyl-N1-(4-fluorophenyl)--N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7l) [S-(R*,R*)]-3-[3-(biphen-4-yl)propyl]-.alpha.1-cyclohexyl-N3-hydroxy-2-oxo--N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7m) [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7n) [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl]-N1-cyclopropyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7o) [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 7p) [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl)-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 7q) [S-(R*,R*)]-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 7r) [S-(R*,R*)]-.alpha.1-tert-butyl-3-(3-(4'-fluorobiphen-4-yl)propyl)-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7s) (S-(R*,R*)]-.alpha.1-tert-butyl-N1-cyclopropyl-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7t) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl)-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 7u) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl]-N1-(4-fluorophenyl)-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7v) [S-(R*,R*)]-.alpha.1-tert-butyl-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-2-oxo-N1-(4-pyridinyl )-1,3-pyrrolidinediacetamide, 7w) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl)-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 7x) [S-(R*,R*))-.alpha.1-cyclohexyl-N1-cyclopropyl-3-[3-(4'-fluorobiphen-4-yl)propyl]-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 7y) (S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl)-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 7z) (S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl]-N1-(4-fluorophenyl)-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8a) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-[3-(4'-fluorobiphen-4-yl)propyl)-N3-hydroxy-2-oxo N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 8b) [S-(R *,R * )]-3-heptyl-N3-hydroxy-N1-methyl-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 8c) [S-(R*,R*)] N1-cyclopropyl-3-heptyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 8d) [S-(R*,R*)]-3-heptyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 8e) [S-(R*,R*)]-3-heptyl-N1-(4-fluorophenyl)-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-1,3-pyrrolidinediacetamide, 8f) [S-(R*,R*)]-3-heptyl-N3-hydroxy-.alpha.1-(1-methylethyl)-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 8g) [S-(R*,R*)]-.alpha.1-tert-butyl-3-heptyl-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 8h) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-cyclopropyl-3-heptyl-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8i) [S-(R*,R*)]-.alpha.1-tert-butyl-3-heptyl-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 8j) [S-(R*,R*)]-.alpha.1-tert-butyl-N1-(4-fluorophenyl)-3-heptyl-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8k) [S-(R*,R*)]-.alpha.1-tert-butyl-3-heptyl-N3-hydroxy-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 8l) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-heptyl-N3-hydroxy-N1-methyl-2-oxo-1,3-pyrrolidinediacetamide, 8m) [S-(R*,R*)]-.alpha.1-cyclohexyl-N1-cyclopropyl-3-heptyl-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, 8n) [S-(R*,R*))-.alpha.1-cyclohexyl-3-heptyl-N3-hydroxy-2-oxo-N1-phenyl-1,3-pyrrolidinediacetamide, 8o) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-heptyl-N1-(4-fluorophenyl)-N3-hydroxy-2-oxo-1,3-pyrrolidinediacetamide, or 8p) [S-(R*,R*)]-.alpha.1-cyclohexyl-3-heptyl-N3-hydroxy-2-oxo-N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide.

13. A compound of claim 12 which is 1a) (3S)-.alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 1b) [S,S-(R*,R*)]-.alpha.3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, lc) [S-(R*, R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-N1-(2-phenethyl)-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1d) [S-(R*, R*)]-.alpha.1-(Cyclohexylmethyl)-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 1e) [S-(R*, R*))-N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1f) [S-(R*,R*))-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-N1-phenyl-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1g) [SCR*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)--N1-(2-pyridinylmethyl)-1,3-pyrrolidinediacetamide, 1h) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)--N1-(4-pyridinyl)-1,3-pyrrolidinediacetamide, 1i) [S-(R*,R*)]-N1-(4-Fluorophenyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1j) [S-(R*,R*))-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-[1-(phenylmethyl)-4-piperdinyl]-1,3-pyrrolidinediacetamide, 1k) [S-(R*,R*))-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(4-piperdinyl)-1,3-pyrrolidinediacetamide, 11) (S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-N1-(4-pyridinylmethyl)-1,3-pyrrolidinediacetamide, 1m) [S-(R*,R*))-N1-(4-Fluorophenylmethyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1n) [S-(R*,R*)] N3-Hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(2-phenylethyl)-1,3-pyrrolidinediacetamide, 10) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-.alpha.1-(2-phenylethyl)-N1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1p) [S-(R*,R*))-N3-Hydroxy-.alpha.1,3-bis(2-methylpropyl)-2-oxo N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 1q) [S-(R*,R*))-.alpha.1-Cyclohexyl-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 1r) [S-(R*,R*))-.alpha.1-Cyclohexyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 1s) [S-(R*,R*)]-3-(Cyclopentylmethyl)-N3-hydroxy-N1-methyl-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1t) [S-(R*,R*)]-3-(Cyclopentylmethyl-N3-hydroxy-N1-methyl-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1u) [3S-[1(R*),3R*(R*))]-.alpha.3-[2-(Benzoylamino)ethyl]-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1v) [S-(R*,R*)]-N3-Hydroxy-3-(2-methylpropyl)-N1-[2-(4-morpholinyl)ethyl]-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 1w) [S-(R*,R*))-N-Hydroxy-3-(2-methylpropyl)-1-[2-(4-morpholinyl)-2-oxo-1-(phenylmethyl)ethyl]-2-oxo-3-pyrrolidineacetamide, 1x) [1(1S)-[1[R*(R*)],3.alpha.,5.alpha.]]-1-[2-(3,5-Dimethyl-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 1y) [S-(R*,R*))-N3-Hydroxy-3-(2-methylpropyl)-2-oxo-al-(phenylmethyl) N1-2-pyridinyl-1,3-pyrrolidinediacetamide, 1z) [3S-[1(R*),3R*(R*)))-.alpha.3-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-.alpha.1-(phenylmethyl)-1,3-pyrrolidinediacetamide, 2a) [S-(R*,R*)]-.alpha.1-Cyclohexyl- N1-cyclopropylmethyl-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2b) [S-(R*,R*)]-.alpha.1-Cyclohexyl-N1-(4-fluorophenyl)-N3-hydroxy-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2c) [S-(R*,R*)]-.alpha.1-tert-Butyl-N3-hydroxy-N1-methyl-3-(2-methylpropyl)-2-oxo-1,3-pyrrolidinediacetamide, 2d) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(5-propyloxy-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-pyrrolidineacetamide, 2e) [R,-(R*,S*)]-5-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 2f) .alpha.-[2-(5,6-Difluoro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2g) N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-(5-trifluoromethyl-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-pyrrolidineacetamide, 2h) .alpha.-[2-(1,3,4,5,6,7-Hexahydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2i) .alpha.-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(3-phenylpropyl)-3-pyrrolidineacetamide, 2j) 1-[2-(4-Fluorophenyl)ethyl]-.alpha.-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-yl)ethyl] N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 2k) .alpha.-[2-(o-benzoic sulfimide)ethyl)-N-hydroxy-3-(2-methylpropyl)-2-oxo-(2-phenylethyl)-3-pyrrolidineacetamide, 2l) Ethyl Phenylmethyl [4-(hydroxyamino)-3-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-4-oxobutyl]imidodicarbonate, 2m) S-(R*,R*)]-1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 2n) 1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-[2-(4-fluorophenyl)ethyl]-3-pyrrolidinyl]-1,3-dioxo-2H-isoindole-2-butanamide, 2o) .alpha.-[2-[(3,4-Difluorobenzoyl)amino)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2p) [R-(R*,S*)-.alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2q) .alpha.-[2-[(4-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2r) N-Hydroxy-3-(2-methylpropyl)-.alpha.-[2-[(3-nitrobenzoyl)amino)ethyl]-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2s) .alpha.-[2-[(3-Fluorobenzoyl)amino)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2t) .alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-1-[2-(4-fluorophenyl)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetamide, 2u) .alpha.-[2-[(4-Biphenylcarbonyl)amino]ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2v) N-Hydroxy-.alpha.-[2-[[(4-methylphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2w) .alpha.-[2-[[(4-Fluorophenyl)sulfonyl]amino)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2x)-N-Hydroxy-.alpha.-[2-[[(4-methoxyphenyl)sulfonyl]amino]ethyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 2y)-N-Hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-.alpha.-[2-[(phenylsulfonyl)amino]ethyl]-3-pyrrolidineacetamide, 2z) [R-(R*,S*)]-.alpha.-[2-[[(4-Fluorophenyl)sulfonyl]amino)ethyl]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3a) 5,6-Difluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl)-1-oxo-2H-isoindole-2-butanamide, 3b) 1,3-Dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 3c) [R-(R*,S*)]-6-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 3d) [R-(R*,S*)]-5-Fluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 3e) [R-(R*,S*)]-5,6-Difluoro-1,3-dihydro-N-hydroxy-.alpha.-[3-(2-methylpropyl)-oxo-1-(2-phenylethyl)-3-pyrrolidinyl]-1-oxo-2H-isoindole-2-butanamide, 3f)-N-Hydroxy-.alpha.-[[[(4-methoxyphenyl)sulfonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.R-diastereomer), 3g)-N-Hydroxy-.alpha.-[[[(4-methoxyphenyl)sulfonyl]amino]-methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.S-diastereomer), 3h) .alpha.-[[(4-Fluorophenyl)sulfonyl]amino]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (R-diastereomer), 3i) .alpha.-[[(4-Fluorophenyl)sulfonyl]amino]-N-hydroxy-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide (.alpha.S-diastereomer), 3j) .alpha.-[2-[(3,4-Difluorobenzoyl)amino)ethyl]-N-hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, 3k) .alpha.-[2-[(3,4-Difluorobenzoyl)amino]ethyl]-N-hydroxy-3-(2-hydroxyethyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide, or 31) [R-(R*,S*)]-.alpha.-[2-[(3-Fluorobenzoyl)amino]ethyl]-N-hydroxy-3-(3-hydroxypropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetamide.

14. Use of an effective amount of a compound according to Claim 1 to inhibit matrix metalloproteinase.

15. Use of an effective amount of a compound according to Claim 1 to inhibit collagenases, stromelysins or gelatinases.

16. Use of an effective amount of a compound according to Claim 1 to treat or prevent connective tissue degradation in a human which is caused by matrix metallo endoproteinase diseases.

17. Use of an effective amount of a compound according to Claim 1 to treat or prevent a disease in a human selected from the group consisting of osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenia, osteoporosis, tumor metastasis, periodontitis, gingivitis, corneal ulceration, dermal ulceration and gastric ulceration.

18. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an amount of a compound according to Claim 1 effective to inhibit matrix metalloproteinase.

19. Oral, parenteral or topical use of a composition according to Claim 18.

20. Oral, parenteral or topical use of a composition comprising a pharmaceutically acceptable carrier and a compound according to Claim 1 to treat or prevent connective tissue degradation in a human.

21. The use of Claim 14 or 16 wherein the effective amount is about 0.1 to about 100 mg/kg of body weight/day.

22. A commercial package comprising a container containing therein a compound according to any one of Claims 1-13 and written matter which states that the compound is for use in inhibiting matrix metalloproteinase.

23. A commercial package comprising a container containing therein a compound according to any one of Claims 1-13 and written matter which states that the compound is for use in inhibiting excess collagenases, stromelysins or gelatinases.

24. A commercial package comprising a container containing therein a compound according to any one of Claims 1-13 and written matter which states that the compound is for use in treating or preventing connective tissue degradation in a human caused by matrix metallo endoproteinase diseases.

25. A commercial package comprising a container containing therein a compound according to any one of Claims 1-13 and written matter which states that the compound is for use in treating or preventing osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenia, osteoporosis, tumor metastasis, periodontitis, gingivitis, corneal ulceration, dermal ulceration or gastric ulceration in a human.

26. A commercial package comprising a container containing therein a composition comprising a compound according to any one of Claims 1-13 and a pharmaceutically acceptable carrier and written matter which states that the composition is for use in inhibiting matrix metalloproteinase.

27. A commercial package comprising a container containing therein a composition comprising a compound according to any one of Claims 1-13 and a pharmaceutically acceptable carrier and written matter which states that the composition is for use in inhibiting collagenases, stromelysins or gelatinases.

28. A commercial package comprising a container containing therein a composition comprising a compound according to any one of Claims 1-13 and a pharmaceutically acceptable carrier and written matter which states that the composition is for use in treating or preventing connective tissue degradation in a human caused by matrix metallo endoproteinase diseases.

29. A commercial package comprising a container containing therein a composition comprising a compound according to any one of Claims 1-13 and a pharmaceutically acceptable carrier and written matter which states that the composition is for use in treating or preventing osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenia, osteoporosis, tumor metastasis, periodontitis, gingivitis, corneal ulceration, dermal ulceration or gastric ulceration in a human.