CA2277105A1 - C-terminal ketone hydroxamic acid inhibitors of matrix metalloproteinases and tnfa secretion - Google Patents

Abstract

C-terminal compounds of formula (I) are potent inhibitors of matrix metalloproteinase and are useful in the treatment of diseases in which matrix metalloproteinase play a role. Also disclosed are matrix metalloproteinase inhibiting compositions and a method of inhibiting matrix metalloproteinase in a mammal.

Description

OF MATRIX METALLOPROTEINASES AND TNFA
C-TERMINAL KETONE HYDROXAMIC ACID INHIBITORS
SECRETION
Technical Field This invention relates to compounds having activity to inhibit matrix metalloproteinases and TNFa secretion, to pharmaceutical compositions comprising these compounds) and to a medical method of treatment. More particularly) this invention concerns C-terminal ketone compounds which inhibit matrix metalloproteinases and TNFa secretion, pharmaceutical compositions comprising these compounds and a method of inhibiting matrix metalloproteinases and TNFa secretion.
Background of the Inve_n_r;n., The matrix metalloproteinases (MMP's) are a class of extracellular enzymes including collagenase, stromelysin, and gelatinase which are believed to be involved in the tissue destruction which accompanies a large number of disease states varying from arthritis to cancer.
Typical connective tissue cells are embedded within an extracellular matrix of high molecular weight proteins and glycoproteins. In healthy tissue, there is a continual and delicateiy-balanced series of processes which include cell division) matrix synthesis) and matrix degradation.
In certain pathological conditions, an imbalance of these three processes can lead to improper tissue restructuring. For example) in arthritis, joint mobility can be lost when there is improper remodelling of load-bearing joint cartilage. In the case of cancer, lack of coordination of cell division and the two processes of matrix synthesis and degradation can lead to conversion of transformed cells to invasive phenotypes in which increased matrix turnover permits tumor cells to penetrate basement membranes surrounding capillaries leading to subsequent metastasis.
There has been hightened interest in discovering therapeutic agents which bind to and inhibit MMP's. The discovery of new therapeutic agents possessing this activity will lead to new drugs having a novel mechanism of action for combatting disease states involving tissue degenerative processes including, for example, rheumatoid arthritis, osteoarthritis) osteopeniax such as osteoporosis, periodontitis, gingivitis) corneal) epidermal or gastric ulceration, and tumor growth and metastasis or invasion.
Tumor Necrosis Factor a (TNFa) is a potent proinflammatory mediator which has been implicated in inflammatory conditions including arthritis) asthma) septic shock, non-insulin dependent diabetes mellitus and inflammatory bowel disease. TNFa is originally expressed as a membrane-bound protein of about 26 kD, which is proteolytically cleaved to release a soluble 17 kD fragment (TNFa processing) which combines with two other secreted TNFa molecules to - 35 form a circulating 51 kD homotrimer. Recently, several MMP inhibitors were found to inhibit TNFa processing (see Mohler, et al., Nature) 1994, 370, 218; Gearing, et al., Nature, 1994, 370, 555; and McGeehan, et al., Nature, 1994) 370, 558), leading to the hypothesis that TNFa processing is caused by an as yet uncharacterized metalloproteinase residing in the plasma membrane of cells producing TNFa. Inhibitors of this metalloproteinase would therefore be useful as therapeutics to treat disease states involving TNFa secretion.
Transforming growth factor alpha (TGFa) is a potent mitogen which ellicites its biological activity by binding to cell surface receptors, in particular epidermal growth factor (EGF) receptor.
It is known to promote angiogenesis and to stimulate epithelial cell migration and therefore has been implicated in a number of malignant disorders such as breast cancer and ovarian carcinoma.
TGFa is produced by proteolytic cleavage of a 160 amino acid membrane bound precursor.
Several cleavage sites have been identified including A1a38-Va139, similar to the cleavage site of proTNFa (Ala-76-Va177). This common cleavage site suggests that inhibitors of TNFa processing may also block the cleavage of proTGFa and therefore would be therapeutically useful in diseases mediated by TGFa.
Summarv of the Invention The present invention provides a novel class of C-terminal ketone inhibitors of matrix metalloproteinases and/or TNFa secretion.
In its principle embodiment, the present invention provides a macrocyclic compound of formula I

O R ~ R H Ra V
N
Rs or a pharmaceutically acceptable salt, ester or prodrug thereof wherein W is NHOH or -OH.
R1 and R4 are independently selected at each occurrence from hydrogen or alkyl of one to four carbon atoms.
V is O or NOR ~ .
R2 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) alkoxy of one to six carbon atoms, (d) alkyl of one to six carbon atoms, (e) alkyl of one to six carbon atoms substituted with ( I ) halogen, (2) hydroxy, (3) alkoxy of one to six carbon atoms, (4) cycloalkyl of three to eight carbon atoms) (5) alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, (6) pyridyl, (7) pyridyl substituted with alkyl of one to four carbon atoms, (8) phenoxy wherein the phenyl ring is unsubstituted or substitued with I, 2 or 3 substituents independently selected from (8a) alkyl of one to four carbon atoms, (8b)hydroxy, (8c) alkoxy of one to four carbon atoms, (8d) halogen) (8e) haloalkyl of one to four carbon atoms, (8f) cyano, (8g) cyanoallcyl, (8h) -C02R~ wherein R~ is hydrogen or alkyl of one to four carbon atoms) (8i) -CONR~R~ wherein R~ is defined above and R~ is selected from hydrogen) alkyl of one to four 1 S carbon atoms, alkanoyl of one to four carbon atoms, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms) hydroxy, alkoxy of one to four carbon atoms) halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl) -CONR'~R ) ~ wherein Ry and R ) ~ are independently selected from hydrogen and alkyl of one to four carbon atoms) and -C02R9, R' ~ O
~ 1 O~O
..( (9) ( 10 ) -S(O)AR > > wherein n is 0, 1 or 2 and R > > is selected from ( 1 Ua) alkyl of one to six carbon atoms, ( l Ob) phenyl. ( 1 Oc) phenyl substituted with 1, 2 ar 3 substituents independently selected from alkyl of one to four carbon atoms) hydroxy) alkoxy of one to four carbon atoms) halogen) haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -C02R~, -COIVR~RH) ( l Od) thienyl, 25 ( l0e) thienyl substituted with alkyl of one to four carbon atoms, ( 1 Uf) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, ( 1 Og) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, and the phenyl ring is substituted with l ) 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano) cyanoalkyl) -C02R~, and -CONR~Rg) ( 30 ( 1 Oh ) thienylalkyl wherein the alkyl portion is of one to four carbon atoms, and ( 1 Oi ) thienylalkyl wherein the alkyl portion is of one to four carbon atoms and the thienyl ring is substituted with alkyl of one to four carbon atoms, and (11) -NR12R13 wherein R12 is hydrogen or alkyl of one to four carbon atoms and R13 is selected from ( I I a) hydrogen, ( I 1 b) alkyl of one to four carbon atoms, ( 11 c) -C02R 14 wherein R ~ 4 is 35 independently selected at each occurrence from (i) alkyl of one to four carbon atoms, (ii) haloalkyl of one to four carbon atoms, (iii) phenyl, (iv) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, allcoxy of one to four carbon atoms, halogen, haloallcyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -S02NH2, -COZR~, and -CONR~Rg, (v) phenylalkyl wherein the alkylene portion is of one to four carbon atoms, (vi) phenylalkyI wherein the alkylene portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms) cyano, cyanoalkyl, -S02NH2, -C02R~, and -CONR~Rg, (vii) heteroarylalkyl wherein the alkylene portion is of one to four carbon atoms, and the heteroaryl group is selected from furyl, pyridyl, thienyl, benzimidazolyl, imidazolyl, thiazolyl, and benzothiazolyl wherein the heteroaryl group is unsubstituted or substituted with alkyl of one to four carbon atoms) and ( 11 d) -S02R 14, or R12 and R13, together with the N atoms to which they are attached define a heterocycle selected from morpholinyl) thiomorpholinyl, thiomorpholinyl sulfone, pyrrolidinyl) piperazinyl, piperidinyl, succinimidyl, maleimidyl, glutarimidyl, phthalimidyl, naphthalimidyl, H3C~ N"\ H3C~ N'\ H3C~ N' \ O' \
- H C~N~ ~3C~ - H3C
N i N- N N
0 3 ° ~c o -~cI ~o , , , , O ~ ~ O O N/
N ~ ~ N- N_ ' O
/ I
O O H O, and ~H3 ' , (f) alkenyl of two to six carbon atoms, (g) alkenyl of two to six carbon atoms substituted with 2(1 ( I ) halogen) (2) hydroxy) (3) alkoxy of one to six carbon atoms, (4) cycloalkyl of three to eight carbon atoms) (5) alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, (6) pyridyl) (7) pyridyl substituted with alkyl of one to four carbon atoms, (8) phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from (8a) alkyl of one to four carbon atoms, (8b) hydroxy, (8c) alkoxy of one to four carbon atoms) (8d) halogen, (8e) haloallcyl of one to four carbon atoms, (8f) cyano, (8g) cyanoalkyl, (8h) -C02R~, (8i) -CONR~Rg, (8j) phenyl, and (8k) phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoallcyl) -C02R9) and -CONR9R10, R' i~ ( .~ O

O

(9) , ( I0) -S(O)nR i i and 5 (11) -NR12Ri3~
R3 is selected from the group consisting of (a) alkyl of one to ten carbon atoms, (b) alkenyl of two to ten carbon atoms, (c) cycloallcyl of three to eight carbon atoms) (d) (cycloalkyl)alkyl wherein the cycloalkyl portion is of three to eight carbon atoms, and the alkylene portion is of one to six carbon atoms, (e) cycloalkylene of five to eight carbon atoms, (f) (cycloalkylene)alkyl wherein the cycloalkylene portion is of three to eight carbon atoms) and the alklene portion is of one to six carbon atoms) IS (g) phenyl wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 subsdtuents independently selected from (g 1 ) alkyl of one to four carbon atoms) (g2) allcoxy of one to four carbon atoms) (g3) halogen, (g4) haloalkyl of one to four carbon atoms) (g5) cyano, (g6) cyanoalkyl) (g7) -C02R~, (g8) -C02NR~Rg, (g9)) alkoxyalkyloxy and (gl0) phenyl substituted with 1. 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms) 2U hydroxy, alkoxy of one to four carbon atoms, halogen) haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO~R'~, and -CONR'~R i~) (h 1 phenylalkyl wherein the alkylene portion is of one to six carbon atoms, and the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from (h 1 ) alkyl of one to four carbon atoms, (h2) alkoxy of one to four carbon atoms, (h3) halogen) (h4) haloalkyl of ~5 one to four carbon atoms, (h5) cyano, (h6) cyanoall:yl) (h7) -C02R~) (h8) -C02NR~R~, (h9) phenyl, and (h10) phenyl substituted with 1) 2) or 3 substutuents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -C02R~ and -C02NR~R8) (i) -(CH2)m-T-(CH2)~-RiS wherein m and n are independently 0, 1, 2, 3 or 4) T
is O or S, - 30 and R 15 is selected from the group consisting of (i 1 ) alkyl of one to four carbon atoms, (i2) phenyl, and (i3) phenyl substituted with 1, 2) or 3 substituents selected from (i) alkyl of one to four carbon atoms) (ii) hydroxy, (iii) allcoxy of one to four carbon atoms) (iv) halogen) (v) haloalkyl of one to four carbon atoms, (vi) cyano) (vii) cyanoalkyl, (viii) -C02R~, (ix) -CONR~Rg, (x) phenyl, and (xi) phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl) -C02R~, and -CONR~RR) and (j) fluorenylalkyl wherein the alkylene portion is of one to four carbon atoms, and RS is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with (b 1 ) cycloallcyl of three to eight carbon atoms, (b2) hydroxy, (b3) alkoxy, (b4) -SRS) (b5) -NR~Rg, (b6) -C02R~, (b7) -CONR~R~, (b8) guanidyl, (b9) phenyl, (b10) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, vitro, cyano) cyanoalkyl, carboxyalkyloxy, -S(O)"R»
wherein n is 0, 1 or 2 and R16 is alkyl of one to four carbon atoms, -SOZN~-I2, -C02R~, and CONR~Rg, and (b 11 ) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy) alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (b 10) naphthyl, (b 11 ) naphthyl substituted with 1, 2, or 3 I S substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen) haloalkyl of one to four carbon atoms, (b12) indolyl, (b13) indolyl substituted with alkyl of one to four carbon atoms, hydroxy) alkoxy of one to four carbon atoms) halogen, haloalkyl of one to four carbon atoms, -S02R1~, -S02NH2, -C02R~ and -CONR~RR) (b 14) pyridyl) (b 1 S) pyridyl substituted with alkyl of one to four carbon atoms, (b 16) pyrazolyl, (b17) pyrazolyl substituted with alkyl of one to four carbon atoms, (b18) 5-oxadiazolyl, (b 19) imidazolyl) and (b-20) imidazolyl substituted with alkyl of one to four carbon atoms) (c ) phenyl and (d) phenyl substituted with 1, 2) or 3 substituents independently selected from alkyl of one to four carbon atoms) hydroxy, alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to 2_5 four carbon atoms.
R~ is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with hydroxy, alkoxy, halogen, and -C02R
wherein R 1~ is selected from hydrogen, alkyl of one to four carbon atoms and alkenyl of two to 3(1 four carbon atoms) (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from (d 1 ) alkyl of one to four carbon atoms, (d2) halogen, (d3) hydroxy, (d4) hydroxyalkyl of one to four carbon atoms, (d5) haloalkyl of one to four carbon atoms, (d6) allcoxy of one to four carbon atoms) 35 (d7) cyano, (d8) -NR~Rg, (d9) -S02NR~Rg, (d 10) -S02R ~ 6, (d 11 ) -CH2NR 1 gR 19, wherein R 1 g and R19 are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R1g and R19 together with the N atom to which they are attached define a a 5-or 6-membered heterocyclic ring selected from morpholinyl, thiomorpholinyl, thiompholinyl sulfone, pyrrolidinyl, piperazinyl, 3-ketopiperazinyl and piperidinyl, (d 12) -CONR~Rg, (d 13) -COZR~) and (d I 4) phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen) and haloalkyl of one to four carbon atoms, (e) 1,3-benzodioxole, {f) indolyl, (g) indolyl substituted with (gl) alkyl of one to four carbon atoms, (g2) halogen, (g3) haloalkyl of one to four carbon atoms) {g4) alkoxy of one to four carbon atoms) (g5) -S02NR~RR, (g6) -C02R~) (g7) alkylsulfonyl of one to four carbon atoms, and (g8) phenyl, wherein the phenyl ring may be substituted with l, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms) and alkoxy of one to four carbon atoms, (h) Pyrrolyl, (i) pyrroIyl substituted with alkyl of one to four carbon atom (j) imidazolyl, I S (k) imidazolyl substituted with alkyl of one to four carbon atoms, (1) benzimidazolyl) (m) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms) halogen and haloalkyl of one to four carbon atoms) provided that in (f)-(m) above, when the heterocycle is attached at a carbon atom, the N atom may 2l1 bear a substituent selected from the group consisting of alkyl of one to six carbon atoms) -CONR~RB, -S02NR~Rg and -S02Rt4, (n) pyridyl, (o) pyridyl substituted with alkyl of one to four carbon atoms, (p) thienyl, ='S (q) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (r) thiazolyl) (s) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms) 30 (t) oxazolyl, (u) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloallcyl of one to four carbon atoms, (v) furyl, (w) furyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to 35 four carbon atoms, (x) benzofuryl, (y) benzofuryl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (z) benzothiazolyl, and (aa) benzothiazolyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloallcyl of one to four carbon atoms.
In another aspect, the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of compound of formula I in combination with a pharmaceutically acceptable carrier.
In yet another aspect, the present invention provides a method of inhibiting matrix metalloproteinases and/or TNFa secretion in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1.
Detailed Description As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term alkyl refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tort-butyl) and the Like.
2U The term allcylsulfonyl represents an alkyl group, as defined above, attached to the parent molecular group through a S02 group.
The term "alkanoyl" represents an alkyl group, as defined above, attached to the parent molecular moiety through a carbonyl group. Alkanoyl groups are exemplified by fonmyl, acetyl, propionyl, butanoyl and the like.
The terms allcoxy and alkoxyl denote an alkyl group, as defined above, at ached to the parent molecular moiety through an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propoxy, butoxy) and the like.
The term "alkoxycarbonyl" represents an ester group; i.e. an all:oxy group) attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl) and 3() the like.
The term alkenyl as used herein refer to monovalent straight or branched chain groups of 2 to 6 carbon atoms containing a carbon-carbon double bond, derived from an alkene by the removal of one hydrogen atom and include) but are not limited to groups such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
The term alkylene denotes a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon containing by the removal of two hydrogen atoms, for example -CH2-, -CH2CH2-, -CH(CH3)CH2- and the like.

The term alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. Examples of alkenylene include -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-) -CH2CH=CHCHZ-, and the like.
The terms alkynylene refers to a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain acyclic hydrocarbon group containing at least one carbon-carbon triple bond. Examples of alkynylene include -CH_--CH-, -CH-_-_-C-CH2-, -CH-CH-CH(CHg)- and the like.
The term cycloalkyl as used herein refer to a monovalent saturated cyclic hydrocarbon group. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl) 1(1 cyclohexyl) cycloheptyl, bicyclo(2.2.I]heptane and the like.
Cycloalkylene denotes a divalent radical derived from a cycloalkane by the removal of two hydrogen atoms.
The terms "(cycIoallcyl)alkyl" and "(cycloalkenylene)alkyl" refer, respectively, to a cycloalkyl group or cycloalkenylene group as defined above attached to the parent molecular 1 S moiety through an alkylene group.
The term cyanoalkyl denotes an alkyl group) as defined above, substituted by a cyano group and includes, for example, cyanomethyl, cyanoethyl, cyanopropyl and the like.
The term haloalkyl denotes an alkyl group, as defined above, having one, two) or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, 2(I trifluoromethyl, and the like.
The term "hydroxyalkyl" represents an alkyl group) as defined above) substituted by one to three hydroxyl groups with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
The term "phenoxy" refers to a phenyl group attached to the parent molecular moiety '_'S through an oxygen atom.
By pharmaceutically acceptable salt is meant those salts which are) within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable beneflt/risk ratio. Pharmaceutically acceptable salts are well known in the art . For 3U example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J.
Pharmaceutical Sciences, 1977, 66:1 - 19 . The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, 35 camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate) hydrobromide, hydrochloride, hydroiodide) 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate) methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate) palirutate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tarnate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include 5 sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine canons) including, but not limited to ammonium, tetramethylammonium, tetraethylammoruum, methylamine, dimethylamine, trimethylamine, triethylamine) ethylamine, and the like.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which 10 hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids) particularly alkanoic) alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like) commensurate with a reasonable benefitJrisk ratio) and 2f effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A
thorough discussion is provided in T. Higuchi and V. Stella) Pro-drugs as Novel Delivery S sv terns, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible 2_5 Carriers in Drult Desien) American Pharmaceutical Association and Pergamon Press) 1987) both of which are incorporated herein by reference.
Asymmetric centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof.
Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the 30 chiral centers or by preparation of mixtures of enantiomeric products follwed by separation as, for example) by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques) or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well 35 known in the organic chemical arts.

Il Preferred Embodiments Preferred compounds of the present invention have formula I wherein R6 is defined therein; R1 and R4 are hydrogen; R2 is selected from the group consisting of (a) hydrogen) (b) hydroxy, (c) alkoxy of one to six carbon atoms, (d) alkyl of one to six carbon atoms, (e) alkyl of one to six carbon atoms substituted with R' ~ O

(1) , 1(l (2) -S(O)~RI~ wherein n is 0, 1 or 2 and R11 is selected from (2a) phenyl) (2b) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms) hydroxy, alkoxy of one to four carbon atoms) halogen, haloalkyl of one to four carbon atoms, cyano) cyanoalkyl) -C02R~, and -CONR~R~, (2c) thienyl and (2d) thienyl substituted with alkyl of one to four carbon atoms and (3) -NR 12R 1 ~ wherein R 12 and R 13 are independently selected from hydrogen and alkyl of one to four carbon atoms or R 1 Z and R 13, together with the N atoms to which they are attached define a H3C~ N' \
N
heterocycle of formula ~c o , and (f) alkenyl of two to six carbon atoms: R-~ is selected from the group consisting of (a) alkyl of one to ten carbon atoms, 2U (b) cycloalkyl of three to eight carbon atoms, and (c) phenylalkyl wherein the alkylene portion is of one to six carbon atoms, and the phenyl ring is unsubstituted or substituted with 1) 2 or 3 substituents independently selected from (cl ) alkyl of one to four carbon atoms, (c2) alkoxy of one to four carbon atoms) (c3) halogen, (c4) haloalkyl of one to four carbon atoms) (c5) cyano, (c6) cyanoalkyl) (c7) -C02R~) (c$) -C02NR~RR) (c9) phenyl, and (c10) phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyI, -C02R~ and -C02NR~Rg; and RS is selected from (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with (b 1 ) cycloalkyl of three to eight carbon atoms, (b2) -C02R~, (b3) -SRS, (b4) phenyl, and (b5) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoallryl, -S(O)nRl6 wherein n is 0, 1 or 2 and R16 is alkyl of one to four carbon atoms, -S02NH2, -C02R~, and -CONK?Rg.
More prefenred compounds have the structure immediately above wherein W is -NHOH
and V is O.
Still more preferred compounds have the structure immediately above wherein R2 is selected from the group consisting of hydrogen, hydroxy and alkenyl of two to six carbon atoms;
R3 is selected from the group consisting of isobutyl) cyclohexyl, 3-phenylpropyl, 3-(4-toIyl)propyl and biphenyloxy; RS is selected from the group consisting of alkyl of one to six carbon atoms, and alkyl of one to six carbon atoms substituted with cycloallcyl of three to eight 1 O carbon atoms, carboxy, phenyl, and hydroxyphenyl; and R~ is selected from (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with -C02R1~, (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy) hydroxyalkyl of one to four carbon atoms) haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR~Rg) cyano, -S02NR~RR, -S02R~6,~-CH2NR(8R19) -CONR~RA and -C02R~) (e) indolyl, (f) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to 2U four carbon atoms, alkoxy of one to four carbon atoms and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloallcyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (g) PYrTOIyI.
(h) pyrrolyl substituted with alkyl of one to four carbon atoms, ?_5 (i ) benzimidazolyl, (j ) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms) provided that in (e)-(j) above, when the heterocycle is attached at a carbon atom, the N atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms, -30 CONR~Rg and -S02NR~Rg, (k) thienyl, (1) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (m) thiazolyl, 35 (n) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (o) oxazolyl and (p) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms.
Still yet more preferred compounds have the structure immediately above wherein R6 is selected from the group consisting of (a) phenyl, (b) phenyl substituted with l, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy) hydroxyalkyl of one to four carbon atoms) haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms) -NR~RB, cyano) -S02NR~Rg, -S02R 1~ -1 () CH2NR I gR 19, -CONR~Rg and -C02R~, (c) indolyl, (d) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (e) pyrrolyl) (f) pyrrolyl substituted with alkyl of one to four carbon atoms) (g) benzimidazolyl, (h) benzimidazolyl substituted with 1) 2 or 3 substituents independently selected from alkyl of 2() one to four carbon atoms) halogen and haloalkyl of one to four carbon atoms, provided that in (c)-(h) above, when the heterocycle is attached at a carbon atom, the N atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms, -CONR15R» and -S02NR~SR~6) (i) thienyl, (j) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms) (k ) thiazolyl, (1) thiazolyl substituted with halogen) alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms) (m) oxazolyl and (n) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloallcyl of one to four carbon atoms.
The most preferred compounds of this invention have the structure immediately above . wherein R6 is selected from the group consisting of phenyl and phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyallcyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR~Rg, cyano, -S02NR~Rg, -S02R~6, -CH2NR~gRl9, -CONR~Rg, -C02R~, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloallcyl of one to four carbon atoms.
Determination of Stromelvsin Inhibition The efficacy of the compounds of this invention as matrix metalloproteinase inhibitors was determined by measuring the inhibition of stromelysin. The inhibition of stromelysin by the compounds of this invention was determined as follows: Recombinant truncated stromelysin (human sequence) produced in E. coli was prepared by expression and purification of the protein as described by Ye et al., Biochemistry , 1992, 31, 11231- I I 235. The enzyme was assayed by its cleavage of the thiopeptide ester substrate Ac-Pro-Leu-Gly-[2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt described by Weingarten and Feder, Anal. Biochem. . 1985,147) 437-440 ( 1985), as a substrate of vertebrate collagenase. The reported conditions were modified to allow assays to be carried out in a microtiter plate. Upon hydrolysis of the thioester bond.
the released thiol group reacts rapidly with 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB)) producing a yellow color which is measured by a microtiter plate reader set at 405 nm. The rates of cleavage of the substrate by stromelysin in the presence or absence of inhibitors are measured in a 30 min assay at ambient temperature. Solutions of the compounds in DMSO are prepared, and these are diluted at various concentrations into the assay buffer (50 mM MES/NaOH pH 6.5 with 10 mM CaCl2 and 0.2%
Pluronic F-68), which is also used for dilution of the enzyme and substrate.
The potency of the 2~ compounds [ICSp] are calculated from the inhibition/inhibitor concentration data. The compounds of this invention inhibit stromelysin as shown by the data for representative examples in Table 1.
Table 1 Inhibitory Potencies against Stromelysin of Representative Compounds Exam le ICS (nM) 1 G 2.3 3.6 5.6 7 8.0 8 8.6 9 1.2 ~

_ 12 7.8 14 1.2 18 4.5 19 1.5 2() 7.3 21 1.7 23 6.6 24 3.2 1.8 27 2.7 I

Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic 5 pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally) 10 topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to modes of administration which include intravenous, intramuscular) intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectabIe solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water) ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof) vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained> for example) by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents) emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectabie pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
in some cases, in order to prolong the effect of the drug, it is desirable to slow the 2() absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubilit)~.
The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in Iiposomes or microemulsions which are compatible with body tissues.
The injectable fotrnulations can be sterilized) for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose) glucose, mannitol, and silicic acid) b) binders such as, for example, carboxymethylcellulose, alginates, gelatin) polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol) d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example) cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay) and i) lubricants such as talc, calcium stearate) magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtwes thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only) or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate) with one or 2(1 more of the above-mentioned excipients.
Liquid dosage forms far oral administration include pharmaceutically acceptable emulsions, solutions) suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol) benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide) oils (in particular, cottonseed, groundnut, corn) germ) olive) castor, and sesame oils)) glycerol) tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents) sweetening, flavoring) and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as) for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite) agar-agar, and tragacanth, and mixtwes thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room IS
temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes.
As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or mufti-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers) preservatives, excipients) and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example) Prescott, Ed., Methods in Cell Biolo~v) Volume XIV, Academic Press, New York, N.Y. (1976), p.
33 et seq.
Dosage forms for topical administration of a compound of this invention include powders) sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a I S pharmaceutically acceptable carrier and any needed preservatives) buffers) or propellants which may be required. Opthalmic formulations) eye ointments) powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compounds) that is effective to 2() achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired 2S therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50) more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Preparation of Compounds of this Invention The compounds of this invention may be prepared by a variety of synthetic routes.
Representative procedures are outlined in the following Schemes I-3.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: THF for tetrahydrofuran; DMF for N,N-dimethylformamide; ETOAc for ethyl acetate; Et20 for diethyl ether, IPA for isopropanol; ETOH for ethanol; MeOH
for methanol; AcOH
for acetic acid; HOBT for 1-hydroxybenzotriazole hydrdate; EDC for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM for N-methylmorpholine; Bu3P for tributylphosphine;
ADDP for 1,1'-(azodicarbonyl)dipiperidine; and DMPU for 1,3-dimethyl-3,4,5,6-tetrahydro-2( 1H)-pyrimidinone.
The preparation of representative compounds of the invention, wherein Ri-R6 and W are defined above, is outlined in Scheme 1. Coupling of succinic acid derivative 1 with keto amine _2 in the presence of an tertiary amine base) hydroxybenzotriazole (HOBt), and a suitable coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI~HCl) gives 3.
Conversion of 3 to the corresponding carboxylic acid 4 is accomplished by acidic removal of the tert-butyl ester using, for example, trifluoroacetic acid or hydrogen chloride in dioxane. Treatment of this acid with hydroxylamine or a hydroxylamine equivalent such as O-tert-butyldimethylsilylhydroxylamine in the presence of a suitable coupling agent such as EDCI~HCl gives hydroxamate 5. O-Benzylhydroxylamine can also be employed in this coupling reaction.
The resulting0-benzylhydroxamate can then be treated with hydrogen and a palladium catalyst such I S as 10% palladium on carbon to produce hydroxamate 5.
Scheme 1 O R R H R O
O R~ R3 R40 ~ a t-BuO~~OH + H2N~R6 t-BuO~~~N~Rs R2 O R5 ~ R2 O R5 3_ O R' R N R40 4: W = -OH
Rs R2 O R5 ~~ W = -NHOH

Preparation of keto amine 2 is accomplished as shown in Scheme 2. Conversion of the protected amino acid 6_ to the methyl ester or N,O-dimethylamide is accomplished by known methods. Reaction of 7 with R6MgX wherein X is Br) Cl or I, or R6Li generates ketone 8_. Acidic removal of the tert-butyl protecting groups gives amino ketone 2.
Alternatively, 6 can be treated 25 with a carbon anion such as phenyllithium which gives 8 directly.

Scheme 2 t-BuOuN R4 t-BuO~N
~O H I I T P _ $ Z
P = -OCH3 or -NCH30CH3 4~
t-BuO~N~Rs H2N R4 s ' -R

$ 2 The preparation of the succiruc acid derivative _l is shown in Scheme 3.
Treatment of 5 oxazolidinone ~ with a suitable base such as lithium diisopropylamide followed by addition of tert-butyl bromoacetate and basic hydrolysis gives carboxylic acid 1_Q. This acid is treated with at least two equivalents of a strong base such as lithium diisopropylamide followed by an alkylating agent R2X wherein X is Br, Cl or I. The resulting dialkyl succinate 11 is again treated with a strong base such as lithium diisopropylamide followed by either methanol (R t = H) or an alkyl halide (R I
1 (1 = alkyl) such as methyl iodide to give substituted succinate _1.
Scheme 3 R
R3 N O R3 O H O R3 O ~ R3 t-BuO~ -" t-Bu0~0 H -''t-gu0~0 H

Ph $ ~ t~ t I5 The foregoing may be better understood by reference to the following examples which are presented for illustration and are not intended to Iimit the scope of the invention as defined in the appended claims.

ation of Succinate E ter I

t-Bu0 OH
O
1_ Step 1 O O
OH SOCK
CI
t A mixture of 4-methylvaleric acid (50.7 g) 0.43 mmol) and thionyl chloride (40 mL, 65.2 g, 0.54 mole) was stirred at ambient temperature for 18 hours. The mixture was heated to distill the excess reagent through a 10 cm Vigreux column. The acid chloride was then distilled to give i (48.43 g, 84 %), by 135-138 °C.
Step 2:

NHVO + n-BuLi + ~ CI --~.. ~ ~ p ! L ~"'/ _ I 5 To a -78 °C solution of 4S-benzyl-2-oxazoIidinone (62.2 g) U.35 mole) in THF (600 mL) was addedn-butyllithi um ( 140 mL, 2.5 M in hexane j over 1 hour. After 30 minutes i (0.359 mole ) was added over 10 minutes during which time the temperature rose to -60 °C. After 1 hour the bath was removed and the reaction mixture was warmed to 0 °C. The reaction was quenched with saturated ammonium chloride) the mixture was allowed to settle) and the supernatant was decanted and concentrated. The combined residues were partitioned between water and ethyl acetate. The organic layer was washed with water, 1 M sodium bicarbonate) water and brine) dried over sodium sulfate) filtered and concentrated. .The residue was distilled discarding a small forerun to give Z
(92.9 g) 96%), by 154-156 °C / 0.15 mm.

Step 3:
0 o ° + NaN(TMS )2 + °'' .-~ ~ °
B~~ °-t Bu t-Bu0 U
\ / ~ o \ /
To a mechanically-stirred -78 °C solution of ii (92.9 g, 0.337 mole) in THF ( 1 L) was added sodium bis(trimethylsilyl)amide (375 mL, I M in THF) over 40 minutes.
The reaction mixture was stirred for 30 minutes and t-butyl bromoacetate (55 mL, 72.6 g, 0.372 mole)was added over 30 minutes. The reaction mixture was stirred for 30 minutes and then the cold bath was removed and the mixture was warmed to 0 °C. The reaction was quenched with saturated ammonium chloride. After mixing well, the mixture was allowed to settle and the supernatant was 1 () decanted, concentrated, and recombined with the residue. This mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, 1 M sodium bicarbonate, water and brine) dried over sodium sulfate and concentrated by distillation to about 250 mL. After dilution with 750 mL hexane and cooling in an ice bath the resulting crystals were collected and washed with hexane to provide iii ( 104.6 g) mp 101-102 °C. The mother liquors were 1 S concentrated and the residue was purified by chromatography on silica gel (S - 10°lo ethyl acetate hexane) and the product fraction crystallized to yield 7.6 g more for a total of 112.2 g (85 %).
Step 4:
°
° °
t-Bu0 ° + LiOH + H~O~ -~ ° + N LJ
a t-B~o °"
i~ ° iv ° \ /
\ /
To a 0 °C solution of iii ( I I2.2 g, ().288 mole) in THF ( 1.2 L) was added water ( 100 mL) and 30 % hydrogen peroxide ( 110 mL, 36.6 g, 1.08 mole). A solution of lithium hydroxide monohydrate ( 17.8 g, 0.424 mole) in water (400 mL) was added in portions over 25 minutes and the resulting solution was stirred for 1 hour. The mixture was concentrated under a slow nitrogen stream to about 800 mL. After seeding with the chiral oxazolidinone the mixture was chilled and filtered removing a portion of the auxiliary which was washed well with water.
The fil~ate was extracted with dichloromethane (3x) to remove the balance of the chiral oxazolidinone. The combined organic extracts were washed with aqueous 0.5 N sodium hydroxide. The base layers were acidified with 1 M sulfuric acid to pH 3 and extracted with ethyl acetate. After washing with water and brine) drying over sodium sulfate, and evaporation of solvents the residue amounted to 64.9 g (98%) of R-2-(i-butyl)-succinic acid-4-t-butyl ester.
Ste~S

t-Bu0 OH + LDA + wl ~ OH
t-Bu0 iv O O
/
To a -78 °C solution of lithium diisopropylamide) prepared by the addition of n-butyllithium ( I 1.4 ml, 28.4 mmol, 2.SM in hexanes) to a solution of diisopropylamine (3.7 ml, 28.4 mmol) in 60 ml THF at -78 °C, was added a solution of iv (2.7 g, 11.8 mmol) in THF (20 mL) at -78 °C by cannula in a stream. The resulting clear, yellow solution was stirred at -78 °C for I hour and then butenyl iodide (2.58 g, 14.2 mmol) was added by syringe. This mixture was allowed to warm to ambient temperature and stir overnight. The reaction mixture was poured into l :l ether-water and the separated aqueous layer was extracted with ether (2x). The combined organic layers were washed with aq 1 M NaHS04 and brine, dried with MgSOa, filtered and concentrated. Flash chromatography (2%-5% isopropanol-hexane) gave epimeric succinates _v (2.30 g, >9: I Syn/anti) as a clear liquid.
t 6 t-Bu0 OH ~) LDA OH
2) MeOH t-Bu0 O .O
_v ~ v~
2() To a -78 °C solution of lithium diisopropylamide, prepared by the addition of n-butyllithium (7.8 ml, 19.5 mmol, 2.SM in hexanes) to a solution of diisopropylamine (2.6 ml) 19.5 mmol) in 30 ml THF at -78 °C) was added a solution of epimeric isobutyl succinate _v (2.3 g, 8. I mmol) in THF ( 10 mL) at -78 °C by cannula in a stream. The resulting clear, yellow solution was stirred at -78 °C for I hour, warmed to 0 °C and recooled to -78 °C. Methanol (1 ml) was added and the solution was warmed to 0 °C. The reaction mixture was poured into 1:1 ether-water . and the separated aqueous layer was extracted with ether (2x). The combined organic layers were washed with aq 1 M NaHS04 and brine, dried with MgS04, filtered and concentrated to give an epimeric mixture (2:1 anti/syn) of succinates vi which could be separated by flash chromatography (10-50% ethyl acetate-hexanes). .

Prev~tiQn of~uccinate Ester 2 t-Bu0 OH
~ O
The desired compound was prepared according to the method used to prepare succinate ester 1) except substituting allyl bromide for 4-bromo-1-butene.
Preparation of Succinate Ester O
t-Bu0 OH
O
The desired compound was prepared according to the method used to prepare succinate ester 1, except substituting 5-bromo-1-pentene for 4-bromo-1-butene.
Preparation of Succinate Ester 4 O
t-Bu0 OH
O

SteR 1 Br O O
H C~ + ~ OH ~ ( OH
H3(~, Vil mizture of isomers A mixture under nitrogen of 4-bromotolucne (36.9 mL, 51.3 g, 0.3 mole), 4-pentenoic acid (30.6 mL, 30.0 g, 0.3 mole), acetonitrile (500 mL)) >Tiethylamine ( 126 mL, 91.5 g, 0.90 mole), palladium acetate ( 1.35 g, 6 mmole) and tri-(o-tolyl)phosphine (4.65 g, 15 mmole) was heated slowly to a gentle reflux. (A mild exotherm was observed as reflux begins.) After 18 hours at reflux, the mixture was cooled in an ice bath and the solid was removed by filtration and rinsed well with ethyl acetate. The filtrate was concentrated to a small volume and the residue was partitioned between aqueous I M sodium carbonate and ether. The aqueous phase was extracted with ether. The combined ether layers were extracted with aqueous 1 M sodium carbonate. The basic solution was treated with charcoal and filtered. The filtrate was acidified with 3 M
hydrochloric acid. After cooling in an ice bath, the soft solid was filtered) washed with ice water, 5 and dried over sodium hydroxide to give vii (45 g) as a mixture of isomers which was used without further purification.
SteR 2 O O
OH I ~ OH
H3C ~ vii H3C
The mixtureof isomers vii was hydrogenated in 600 mL TIC over 9 g of 10%
palladium on carbon at 4 atmospheres of hydrogen for 18 hours. After filtration and concentration of the solution, the residue was crystallized from hexane to yield 5-(4-tolyl)pentanoic acid viii, 33 g) mp 77-78 °C).
Step 3 O o OH ~ ~ cl HaC ~ ~' H3C ~ 1.~
A mixture of ~0ø ( 11.02 g) 57 mmole) and l2 mL thionyl chloride was stirred at 24 °C for 2(~ 18 hours and then heated to distill most of the excess thionyl chloride.
Short path distillation gave 1 1.74 g (97 °lo) of 5-(4-tolyl)pentanoyl chloride (~, by - 110 °C at 0.35 mm).
Step 4 o O O o N VO + n-BuLi + I ~ CI -----~-H3C'v j~ H3C~ x V
To a -78 °C solution of 4S-benzyl-2-oxazolidinone ( 10.36 g, 58 mmole) in THF ( 1 SO mL) was added ra-butyllithium (23.5 mL 2.5 M) over 25 minutes. After 30 minutes, ~
(55.7 mmole) was added quickly, during which time the reaction temperature rose to -45 °C. The reaction mixture was warmed to 0 °C and the reaction was quenched with saturated aqueous ammonium chloride. The mixture was allowed to settle and the supernatant was decanted and concentrated.

The residue was partitioned between water and ethyl acetate. The organic layer was washed with water, aqueous 1 M sodium bicarbonate, water and brine. After drying over sodium sulfate the solution was concentrated and the residue was chromatographed ( 10-20 % ethyl acetate-hexane) to give ,~ ( 17.83 g, 89%).
Sten 5 O O
O
v v -N O
H ~ I / ~ ~--~ _ t-Bu0 OH
O

The desired compound was prepared using Step 4 of the preparation of succinate ester 1, except substituting x_ for "~i.
Preparation of Succinate E ter 5 O
t-Bu0 OH
O
S
The desired compound was prepared using steps 5 and 6 of the preparation of succinate ester 1, except substituting succinate ester 4 for iv.
Preparation of Succinate Ester 6 O F F
t-Bu0 O / F
F
To a cold (0°) solution of succinate ester 2_ (0.79g, 3mmol) in 10 mL
methylene chloride was added pentaflurophenol (0.65g, 3.Smmo1) and EDCI (0.698, 3.Smmol). The resulting solution was stirred for 16 hours while warming to ambient temperature. The reaction mixture was Quenched with 2N Na2C03. The organic layer was washed with 2N HCl and brine, dried (sodium sulfate) and concentrated to give succinate ester _8 (0.8 g) as a crude yellow oil, which was used without further purification.
Preparation of succinate E ter 7 O
t_Bu.O H

The desired compound was prepared using steps 1-4 of the preparation of succinate ester 1, except substituting 4- -pentenoic acid for 4-methyl valeric acid in step 1.
Preparation of succinate E ter 8 The desired compound was prepared from the succinate ester 7 using the Suzuki coupling conditions described in Example 41B.

Preparation of succinate Ester 9 II y The desired compound was prepared from succinate ester _8) using step 5 of the preparation of succinate ester I , except substituting allyl iodide for butenyl iodide.
Preparation of succinate Ester 10 O
O
t-Bu.O OH
O I () The desired compound was prepared using steps 1-4 of the preparation of succinate ester 1, except substituting 6-benzyloxyhexanoic acid for 4-methyl valeric acid in step I.
Preparation of succinate ester 1 I
f OH

~telL
OH OH
(H3Cy~S
xi S Prepared as described for 4-(trimethylsilyl)-3-butyn-1-of in Organic Syntheses 1993, Volume VIII, p. 609.
IH NMR (300 MHz, CDCl3) 8 3.68 (t, 2H)) 2.27 (t, 2H), 1.68-1.62 (m, 4H), 0.14 (s, 9H).
Ste~2 OH OH
(H3C
~3$~ (HaC)aSl O

Prepared as described in Tetrahedron Letters 1979, p. 399.
1H NMR (300 MHz, CDCl3) 8 2.50 (t, 2H)) 2.32 (t) 2H), 1.84 (t, 2H)) 0.14 (s, 9H).
st O
OH
O
O
The desired compound was prepared using steps 1-4 of the preparation of succinate ester 1, except substituting 6-(trimethylsilyl)-5-hexynoic acid for 4-methyl valeric acid in step 1.
~ H NMR (300 MHz) CDC13 ) 8 3.03-2.94 (m, 1 H)) 2.64 (dd, 1 H), 2.47 (dd, 1 H)) 2.31 (td) 2H)) 2(t 2.00 (t) 1H), 1.99-1.90 (m) 1H), 1.81-1.69 (m, IH), 1.45 (s) 9H).
MS (DCI/NH3) m/e 227 (M+I )+.

Exam In a 1 O
H
HOHN N
O
E~lhe l A
O
MeO~N
II OH
O

To a 0° C solution of L-phenylalanine (25 g) 151 mmol) in aqueous 1 N
NaOH ( I 75 mL) was added methyl chloroformate ( I S g, 159 mmol ) via syringe over several minutes. The pH was adjusted to 14 with 1 N NaOH and the resulting clear solution was stirred for 1 hour. The basic 1 () solution was extracted with ether (3x) and the organics were discarded.
The pH was adjusted to 3 with a cold phosphoric acid (~ 1 N) and the acidic solution was extracted with methylene chloride (3x). The combined organics were washed with brine, dried (Na?S04) and concentrated in vacuo to give 1a (32g) as an extremely viscous oil which was carried on without further purification.
15 Example 1 B
H O H O i MeO~N~OH MeO~N
'' II \ T
O O
/ ~ ~ /
To a 0 °C solution of la (4.9 g, 21 mmol) in anhydrous diethyl ether (250- mL) was added PCIS (5.25g) 25.Smmo1) over several minutes. The resulting suspension was allowed to stir for 1 20 hour during which time it slowly became a pale yellow solution. Solvent was removed in vacuo and the resulting acid chloride was dried under high vacuum for 1 hour. The crude acid chloride was then dissolved in methylene chloride (250 mL)) cooled to 0 °C, and indole (2.9 g, 25.2 mmol) was added over 10 minutes. AlCl3 (S.Sg, SOmmol) was then added over a period of 5 minutes, during which time the solution became a blood-red color, and the reaction mixture was allowed to warm to ambient temperature and stir for 16 hours. The reaction mixture was poured into cold water and extracted with methylene chloride. The combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo to give 7.Sg of a crude red solid.
Flash chromatography (hexane-ethyl acetate) gradient elution 3:1 to 1:1 ) gave 2.6 g of a product 1 b containing ~60% of the desired acylation product which was carried on without further purification.
Example 1 O
MeO~N ~ ~ H2 H
lU
To a solution of 1 b (2.4 g) in 3:1 MeOH/water (40 mL) was added KOH (2.1 g, 37.3 mmol). The resulting solution was heated at reflux for 18 hours) cooled and acidifed with 1 N
phosphoric acid. The acidic aqueous Iayer was extracted with ethyl acetate (3x) and the organic layer discarded. The aqueous layer was made basic with aqueous 3N NaOH
solution and extracted with methylene chloride (3x). The combined organics were washed with brine) dried (Na2S04) and concentrated in vacuo to give the desired compound i cc (482mg) as a racemic mixture.
Example 1 D
O F F O
O ~ H2 \ J O H O
t-Bu0 ~ / F + ~ N ~ t-6u0 N \ /
O H O
f / \ ~ H
1~ /
2() To a solution of ~ (0.48 g, 1.8 mmol) in DMF was added succinate ester f (0.8 g, 1.8 mmol). The reaction was allowed to stir at ambient temperature for 16 hours) then was warmed to 45 °C for 3 days. The reaction mixture was diluted with ethyl acetate and the organic layer washed with 1 N NaOH, water (4x), dried (Na2S04), filtered and concentrated to give 1 g of a tan foam.
Flash chromatography (hexane-ethyl acetate 5:1 ) gave 1 d (510 mg) as a 1:1 mixture of epimers at the Phe center.

Example 1 E
O H O
t-Bu0 HO
O L. N
H
Ester 1 d (0.5 g, 1.0 mmoi) was dissolved in cold (0°)- TFA and stirred for 5 hours while warming to ambient temperature. Solvent was removed under a stream of nitrogen and the residue was azeotroped with methylene chloride and dried on high vacuum for 16 hours to give 1 a (250 mg) as a 1:1 mixture of epimers at the Phe center.
Example 1 F
H
To a cold (0°) solution of le (0.25g, 0.54mmo1) in DMF was added- NMM
(0.08 g, 0.81 mmol, 0.09 mL), HOBT (0.08 g, 0.59 mmol) and EDCI (0.11 g) 0.59 mmol). The resulting solution was stirred for 5 minutes and tertr-butyltrimethylsilylhydroxylamine (0.09 g) 0.59 mmol ) was added in one portion. The resulting solution was warmed to ambient temperature and allowed to stand for 97 hours. The reaction mixture was diluted with EtOAc, washed with water (3x ) and brine. dried (Na2S04), filtered and concentrated in vacuo . Flash chromatography ( 1-3~7c methanol-methylene chloride) gave the desired compound (80mg) as a tan solid which was a 1:1 mixture of epimers at the Phe center. mp 18()-210° (dec). ~H NMR (3(>n MHz) DMSO-d6) 8 2U 12.02 (s, 1H)) I().4 (s) 1H), 8.64-8.17 (m, 3H), 8.22-8.17 (m, 2H), 7.48-7.13 (m, 7H), 5.42-5.39 (m, 2H), 4.82-4.52 (m) 3H), 3.12-30.7 (m, 2H), 2.97-2.91 (m) 2H), 2.41-2.38 (m, 2H), 2.0-1.94 (m, 3H), 1.30-1.25 (m, 2H), 1.10-1.01 (m, 2H), 0.8-0.56 (m, 8H). MS
(DCI/IVH3) m/e 476 (M+H)+. Anal calcd for C2gH33N304: C, 70.71; H, 6.99; N) 8.83. Found:
C, 70.50;
H) 6.99; N, 8.60.

WO 98/30541 PCTlUS98/00142 Example 1 G
O H O
HOHN N
O N
\ H
Separation of the diastereomers prepared in Example 1 F by HPLC gave the compound of Example 1G. mp 190-210 °C (dec). 1H NMR (300 MHz, DMSO-d6) 8 11.95 (s, 1H)) 10.36 (s, 1H)) 8.68 (s, 1H), 8.51-8.46 (m) 2H), 7.48-7.46 (m, 1H), 7.40-7.37 (d, 2H, J =
7.1 Hz), 7.25-7. I 0 (m, 4H), 5.44-5.33 (m, 2H), 4.82-4.67 (m, 2H)) 3.14-3.12 (dd, I H, J =
4.1, 9.4 Hz)) 2.97-2.89 (m, 1H), 2.39-2.35 (m, 1H), 1.98-1.83 (m, 2H), 1.30-1.25 (m) 2H)) 1.21-0.99 (m, 1 H), 0.85-0.77 (m, I H)) 0.67-0.65 (d, 3H, J = 6.4 Hz), 0.55-0.53 (d, 3H, J =
6.8 Hz). MS
(DCI/NH3) m/e 476 (M+N)+. Anal calcd for C2gH33N304~0.75 H20: C, 68.76; H, 7.11; N) 8.59. Found: C, 68.77; H, 6.66; N, 8.52. [a]d = -4.19° (c) 0.31 ) DMF).
Exam I» a 1 H
O
H
HOHN N
O
IS
The desired compound was isolated in the chromatography of Example 1 G. mp I70-°C (dec). IH NMR (DMSO) 8 12.03 (s, 1 H), 10.39 (s) I H), 8.71 (s, 1 H)) 8.64-8.61 (d) I H) J =
7.8 Hz)) 8.55 (s) 1 H)) 8.22-8.19 (d, I H, J = 6.4 Hz)) 7.49-7.47 (d) 1 H, J =
6.4 Hz)) 7.38-7.35 (d) 2H) J = 7.8 Hz)) 7.27-7.17 (m) SH), 5.41-5.40 (m, 2H)) 4.72-4.68 (d) 1H) J
= 7.8 Hz)) 4.56-4.50 (d, 1 H) J = 14.9 Hz)) 3.12-3.07 (m) 1 H), 2.95-2.91 (m, 1 H)) 2.42-2.41 (m, 1 H), 2.00-1.99 (m, 1 H ), 1.76-1.72 (m) 1 H ), I .26-1.25 ( m, 1 H ), 0.80-0.72 (m, 1 H ), U.62-0.5 6 (m, 6H). MS (DCI/IVH3) m/e 476 (M+H)+. Anal calcd for C2gH33N304~5/4 H20: C, 67.52; H, 7.18; N, 8.44. Found: C) 67.54; H, 6.94; N, 8.42. [a]d = 36.67° (c, 0.24, DMF).

_~xam~le 2 H
I
OH
a O
/ \ H
i ' Example 2A

/D" . dH
o / \ ~~/ H ~ ~
s To a solution of methyl carbamate 2a (63.32 g, 280 mmol) in ether ( 1 L) was added PBr3 ( 10.8 mL, 110 mmol) via syringe at ambient temperature. The solution was allowed to stir overnight. The solvent was removed in vacuo and the resulting N-carboxyanhydride ~ø (s4.2 g, 10010) was dried on under high vacuum for 2 hours. The product was carried forward without further purification.
Example 2B_ -- H
H ~ / \
To a solution of 2b (28.3s g) 148 mmol) was added indole (139.12 g, 740 mmol) in one portion. The reaction mixture was cooled to 0 °C and A1C13 (59.22 g, 445 mmol) was added slowly via solid addition funnel. Upon complete addition of AICl3, the cold bath was removed and the solution was allowed to stir for 4 hours while warming to ambient temperature. The reaction was quenched by pouring onto 250 mL ice. The pH was adjusted to 12 by the dropwise addition of NI~OH. The aqueous layer was extracted twice with CH2C12. The combined organic layers were washed with brine, dried (MgS04)) filtered, and concentrated in vacuo to a brown oil.

~5 Flash chromatography (1:2:97 to 1:3:96 NH40H-MeOH-CH2C12) gave 2c (5 g, 16%) as a tan solid.
H
.H
\ N
H
r A solution of acid succinate ester 4 (1.107 g, 3.7 mmol) in 20 mL DMF was cooled to U
°C. NMM (975 mg, 8.9 mmol) was added via syringe, followed by HOBT (602 mg, 4.5 mmol)) EDCI (856 mg, 4.5 mmol), and 2c ( 1.18 g, 4.5 mmol). The solution was allowed to stir overnight while warming to ambient temperature. The reaction was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (MgS04}, filtered, and concentrated in vacuo. The resulting orange foam was chromatographed ( 1 % MeOH-CH2C12) to give 2sl ( I .607 g, 80%).
Ex O H O _ t-Bu0 ~ ~ ~ HOH
r O N O
S
I \ H
a r The desired compound was prepared according to the method of Examples 1 E and F, except substituting ~ for ~. mp I 88 °C (dec). 1 H NMR (300 MHz, DMSO-d6) b I I .99 (d, 1 H, J = 3.0 Hz)) 10.41 (d, 1 H) J = 1.5 Hz}, 8.74 (d) 1 H, J = 1.8 Hz), 8.56-8.44 (m, 2H), 8.20-8.17 (m, IH), 7.49-7.16 (m, 8H), 5.74-5.58 (m, 1H), 5.49-5.35 (m, 1H), 4.95-4.86 (m, 2H)) 3.18-2.93 (m, 2H), 2.42-2.30 (m) 1H), 2.21-2.11 (m, IH), 1.96-1.56 (m) 3H), 1.47-0.72 (m) 6H), 0.6I (dd, 6H, J = 36.4, 6.7 Hz). MS (APCI) m/e 504 (M+1 ). Anal calcd for C3pH37N304:C, 71.54; H) 7.40; N, 8.34. Found: C, 70.72; H) 7.05; N, 7.10. [a]d = -35°.

Example 3 HOH
O
Example 3A
Bn O
H~ C02H "~ Bri f ~ O' gn 3~ .
i i To a solution of phenylalanine ( 10 g, 61 mmol) in 500 mL of H20 was added (27.6 g, 200 mmol) and benzyl bromide (24 mL) 200 mmol). The reaction mixture was heated at reflux for 2.5 days and then was quenched with I M HCl and extracted with CH2C12. The organic layer was washed with H20) 1 M NaOH and brine. The organic layer was dried (MgS04), filtered) and concentrated in vacuo. Flash chromatography (20% EtOAc-hexane) gave 3a (48%).
I 5 Example 3B
Bn 8n Bri p' Bn Bpi ~ COpH
w ~ ~ w i U
To a solutiong of 3a (5.05 g, 1.16 x 10-2 mol) in 2:1 dioxane/water (300 mL) was added KOH (0.65 g, 1.16 x 10'2 mol) and the reaction mixture was stirred for 2 days.
The reaction mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer was dried (MgS04)) filtered, and concentrated in vacuo. Flash chromatography (40% EtOAc-hexane) gave fib,.

Examl 1~
Bn Bn O
Bri ~C02H Bn~~~OMe \ ~ ~ \
/ /
To a 0 °C solution of ,~, (2.0 g, 5.8 x 10'3 mol) in 30 mL CH2Cl2 was added EDCI ( I .22 g, 6.36.x 10-3 mol), N,O-dimethylhydroxylamine hydrochloride (0.62 g, 6.36 x 10-3 mol), and NMM (0.764 mL) 6.96 x 10-3 mol) and the reaction mixture was stirred at 0 °C for 10 minutes.
The cold bath was removed and the reaction was allowed to warm to ambient temperature and stir overnight. The reaction was quenched with H20 and exuacted with CH2Cl2. The organic layer was washed with citric acid) saturated aqueous NaHC03, pH 7 buffer and brine.
The organic layer was dried (MgS04)) filtered) and concentrated in vacuo. Flash chromatography (20%
EtOAc-hexane) gave ,~c (48% yield).
Exam lie 3D
Bn Bn B~ -'OMe en 3E ~ \ ~ ~ \
/ /
IS
To a 0 °C solution in THF (20 mL) of Weinreb amide ~ (588 mg, 1.5 mmol) was added ethylmagnesium bromide (I mL, 3 mmol) via syringe. The ice bath was removed and the reaction mixuture was allowed to warm to ambient temperature and stir for 3.5 hours.
The reaction was quenched with H20 and extracted with EtOAc. The organic layer was washed with brine, dried 2U (MgS04), filtered, and concentrated in vacuo. Flash chromatography (5°!o EtOAc-hexane) gave the desired product ~ in 36% yield.

Exam lp a 3E
Bri Bn : H2N~
_ _e i To a solution of ketone ~j, (554 mg) 1.55 mmol) in 50 mL MeOH was added 20%
Pd(OH)2/C and the reaction was stirred for 24 hours. The reaction was filtered to remove the catalyst and concentrated in vacuo to give the desired product in ~g 91 %
yield.
'H\~
H HOHN N
w o \
The desired compound was prepared according to the method of Examples 1 D-F, except substituting 3e for Ic. mp 145 °C (dec). IH NMR (300 MHz) DMSO-d6) 8 10.36 (d. 1H, J =
1.7 Hz), 8.69 (d, 1 H, J = 1.7 Hz), 8.20 (d) 1 H) J = 8.8 Hz)) 7.09-7.30 (m, SH)) 5.23-5.39 (m) I H ), 4.6U-5.00 (m, 2H ), 4.46-4.57 (m, 1 H)) 2.56-2.94 (m) 2H )) 2.29-2.39 (m, 1 H)) 1.64-1.94 (m, 3H), 1.26-1.50 (m) 2H), 0.98-1.08 (m, 1H), 0.92 (t) 3H) J = 7.4 Hz), 0.84-0.96 (m) 2H), 0.7R (dd, 6H) J = 6.4, 16.6 Hz). [a]d = +30.4°
x 1 4 i H l H
s O
/ \ H
The desired compound was prepared by coupling of ~ andR-2-(i-butyl)-succinic acid-4-t-butyl ester according to the method of Example 2C, followed by hydrolysis of the ten-butyl ester using the method of Example lE. mp 110 °C (dec). IH NMR (300 MHz, DMSO-d6) 8 12.08 (s, 1 H), 11.92 (d, 1 H, J = 2.7 Hz), 8.43 (d, 1 H, J = 8.5 Hz), 8.30 (d, 1 H, J =
3.1 Hz), 8.16-8.19 (m, 1 H), 7.44-7.47 (m, 1 H), 7.1 I -7.30 (m, 8H), 5.32-5.42 (m, 1 H), 2. 87-3.19 (m, 2H)) 2.61-2.74 (m, 1 H), 2.04-2.25 (m, 2H)) 1.18-1.40 (m, 2H), 0.97-1.08 (m) I H), 0.69 (dd, 6H, J =
6.5, 16.3 Hz). MS (APCI) m/e 421 (M+1 ), 438 (M+18). Anal calcd for C25H28N204 O.SH20: C, 69.90; H) 6.80; N) 6.52. Found: C, 69.83; H) 6.80; N, 6.49. [a]d =
+7.2°.
Example 5 o HOH
O
Example SA
i O ~ O i H H \ I ~ ~ H \ I
O ~ 1 N OBn O 1 N
~H ~ ~ ~ ~H
A pH 4 solution in 1.5:1 THF-H20 of the compound of Example 4 (50 mg) 1.0 x 10-mmol) and O-benzylhydroxylamine hydrochloride (26 mg) 1.6 x 10-1 mmol) was cooled to 0 °C
and EDCI (63 mg) 3.3 x 10-1 mmol ) was added. The reaction stirred at 0 °C for 1 hour. The ice bath was removed and the reaction mixture was warmed to ambient temperature and stirred overnight. The THF was removed in vacuo and the remaining liquid was partioned between EtOAc and citric acid. The organic layer was washed with brine, dried (MgS04), filtered and concentrated in vacuo. Flash chromatography (1 % MeOH-CH2C12) gave the desired product ~ in 46% yield.

Example SB
Hog Oen O O
A mixture of benzyl hydroxamate Sa (0.266 g, 5.1 x 10-4 mol) and Pd/C (0.133 g) in 10 5 mL of THF was stirred overnight under I atm of H2. The reaction mixture was gravity filtered through a plug of celite. Solvent was removed in vacuo to give the desired product in 82% yield as a tan solid. mp 120 °C. I H NMR (300 MHz, DMSO-d6) 8 11.94 (s) 1 H), 10.33 (s) 1 H), 8.71 (s) 1H), 8.47 (d, IH, J = 8.5 Hz), 8.33 (s, IH), 8.16-8.20 (m) 1H)) 7.44-7.48 (m, 1H)) 7.11-7.31 (m, 7H)) 5.30-5.39 (m, 1 H)) 2.89-3.16 (m, 2H), 2.64-2.77 (m) I H), 1.83 (d, 2H) J = 7.4 10 Hz)) I .29-1.40 (m) 1 H), I .14-1.26 (m, I H ) ) 0.86-0.97 (m, 1 H )) 0.66 (dd, 6H) J = 6.6) 10.3 Hz). MS (CI) m/e 436 (M+1 ). Anal calcd for C25H29N304 ~ 1.00 H20: C) 66.20;
H, 6.88; N) 9.26. Found: C) 66.34; H) 6.74; N) 8.99. [a]d = -1 I.5°.
I5 Exam a 6 H
HOH

\ ~H
The desired compound was prepared by coupling of 2c and succinate ester 5 according to the method of Example 2C, followed by hydrolysis of the tert-butyl ester using the method of 20 Example 1 E, and conversion of the acid to the hydroxamate according to the method of Example 5.
mp 185 °C. 1 H NMR (300 MHz, DMSO-d6) 8 I 1.94 (d, 1 H, J = 2.6 Hz)) 10.35 (s, I H), 8.70 (s, 1 H)) 8.53 (d, 1 H, J = 8.8 Hz), 8.35 (d, 1 H, J = 3.4 Hz), 8.20-8.23 (m, 1 H), 7.46-7.51 (m, 1 H), 7.10-7.31 (m, 7H), 6.70 (dd, 4H, J = 8.1, 25.7 Hz), 5.33-5.43 (m, 1 H), 2.87-3.19 (m, 2H), 2.61-2.75 (m, 1H), 2.14-2.4.4 (m) 2H), 2.14 (s, 3H), 1.88 (d, 2H, J = 7.3 Hz), 1.11-1.42 (m, 4H). MS (CI) m/e 512 (M+1 ). Anal calcd for C31 H33N304 ~ 0.75 H20: C, 70.90; H) 6.62;
N, 8.00. Found: C, 71.20; H, 6.63; N, 7.72. [oc]d = -5.8°, Ex 7 o i \ H
r The desired compound was prepared by coupling of 2c and succinate ester 6 according to the method of Example 2C, followed by hydrolysis of the tert-butyl ester using the method of 1 () Example 1 E. I H NMR (300 MHz, DMSO-d6) 8 12.01 (d, I H, J = 3.0 Hz)) 8.63 (d) 1 H) J = 9.2 Hz), 8.49 (d, I H, J = 3.3 Hz)) 8.25-8.22 (m, 1 H)) 7.52-7.48 (m, 1 H), 7.37-7.13 (m) 7H)) 6.68 (dd, 4H, J = 34.2, 8.1 Hz), 5.7405.61 (m, 1 H), 5.52-5.45 (m, I H), 4.97-4.87 (m, 2H), 3.91 (br, 1H), 3.16-2.92 (m) 2H), 2.40-2.10 (m, 4H)) 2.15 (s, 3H)) 1.87-1.63 (m) 2H), 1.44-0.96 (m, 7H)) O.S4-0.7U (m, 1H). MS (CI) m/e 565 (M+1). Anal calcd for C36H4004N2 ~
I.5 H20:
C, 73.07; H) 7.32; N, 4.73. Found: C, 73.13; H, 6.97; N, 4.98.

Ex~ arn~lg~

o i H
HOH i o ~ N
H
The desired compound was prepared according to the method of Example 5, except substituting the compound of Example 7 for the compound of Example 4. mp 220 °C. 1 H NMR
(300 MHz) DMSO-d6) & 12.02 (s, 1H), 10.48 (s, IH), 8.77 (s) IH), 8.60 (d) 1H) J = 9.2 Hz)) 8.53 (s) 1 H )) 8.29-8.26 (m, 1 H), 7.56-7.15 (m) 8H), 6.70 (dd) 4H, J = 34.6) 7.8 Hz), 5.80-5.64 (m, 1 H), 5.55-5.44 (m) 1 H), 5.02-4.90 (m) 2H), 3.23-2.90 (m, 2H), 2.44-2.28 (m) 3H ), 2.19 (s, 3H)) 2.08-1.96 (m, IH), 1.91-1.66 (m, 2H)) 1.48-0.96 (m) 7H), 0.76-0.63 (m, IH).
1 () MS (ESI) m/e 58U (M+1 ), 602 (M+Na). Anal calcd for C36H41 N304 ~ I.25 H20: C, 71.79; H, 7.28; N) 6.97. Found: C) 71.59; H, 7.05; N) 7.06. [a]d = -20.4°.

x 9 H I
HOH ~ \
O
H
Ex~ar thehe 9A
H2 \ I

~ H
The desired compound was prepared according to the method of Examples 1 A-C, except substituting L-ten-leucine for L-phenylalanine.
I
H \ H 1 ----~ HOH
O ~ N
H ~ ~H
The desired compound was prepared according to the method of Examples 28 and C, except substituting Q~ for ~ and substituting succinate ester ~ for succinate ester _4. mp 218 °C
I 5 (dec). I H NMR (300 MHz. DMSO-d6) 8 I 1.92 (s, 1 H)) 1 U.45 (s, 1 H)) 8.73 (s) I H)) 8.36 (d) 1 H) J = 3.1 Hz), 8.17-8.21 (m, 1 H), 8. I 2 (d, 1 H, J = 8.8 Hz), 7.44-7.47 (m, 1 H), 7.13-7.25 (m) 2H), 5.54-5.70 (m, 1 H), 5.1 U (d, 1 H, J = 8.8 Hz), 4.87-4.97 (m) 2H), 2.73 (dt) 1 H, J =
2.7, 10.9 Hz), 2.23-2.37 (m, 1H), 1.98-2.20 (m) 2H), 1.28-1.39 (m) 1H), 0.96-1.16 (m, 1H), 1.00 (s) 9H)) 0.82-0.94 (m) 1 H), 0.62 (dd) 6H, J = 6.1, 40.3 Hz). MS (DCI) m/e 442 (M+H)+.
20 Anal calcd for C25H35N304 ~ 0.5 H20: C) 66.64; H) 8.05; N, 9.32. Found: C) 66.59; H, 8.01;
N, 9.10. [a]d = -55.9°.

Exam I;Re 10 O H O / I
N
HO
OH O \ NH
O OPFP H O / I
O + O N
~O O ~~ ~NH
ls~ l~ I \
Pentafluorophenol ester ~ (0.605 g) I .53 mmol), prepared as described in W094/U2446, and ~ (0.448 g) 1.70 mmol) were combined in dry DMF (6 mL). The solution was heated at 30 °C for 24 hours, then reduced in volume by rotary evaporation under high vacuum. The residue was diluted with ethyl acetate) then washed succesively with brine) pH3 buffer) aqueous Na2C03, pH7 buffer and brine. The organics were dried over Na2S04 and evaporated to give II Ob (0.764 g) as a tan solid which was carried forward without purification.
Exam Ip a l OB
O H O / I O H O / I
N ~ N
O \ ~ HO
O O ~NH OH O \ NH
\ \
IS
To a 0 °C solution in THF ( 12 mL) of dioxolanone ,~ (0.728 g, 1.5 mmol) was added 2.1 M HCl ( 12 mL) and the solution allowed to warm to ambient temperature over 18 hours. The solution was evaporated to drynessto give a tan foam (0.70 g). The crude material was purified by reverse phase HPLC to give the desired compound (0.223 g) as a white foam. 1 H
NMR (DMSO-d6) 0.65 (d, 3H) J = 6.4 Hz), 0.72 (d, 3H, J = 6.5 Hz), 1.02 (m, 1 H), 1.23 (m, 1 H), 1.41 (m, 1H), 2.62 (m, 1H), 2.94 (dd, 1H, J = 7.4, 13.9 Hz), 3.17 (dd, 1H, J = 6.5, 13.9 Hz), 3.91 (d, 1 H, J = 7.1 H z)) 5.38 (m, 1 H ), 7. 22 (m, 6H), 7.45 (dd, 1 H, J = 2.3, 6.4 Hz)) 8.16 (dd, 1 H, J =
2.3, 6.1 Hz), 8.27 (d, 1 H, J = 3.0 Hz)) 8.41 (d, 1 H, J = 3.0 Hz), 8.58 (bds, 1 H), 11.91 (d, 1 H, WO 98/30541 PCT/(JS98/00142 J = 2.7 Hz). MS (DCI/IVH3) M/e 454 (M+NH4)+, 437 (M+H)+, 419, 265. Anal. Calcd for C25 H28 N2 OS ~.75 H20: C, 66.72; H) 6.61; N, 6.22. Found: C, 66.71; H, 6.30; N, 5.90.
Exam lp a I 1 o H ~ ~ L
N \
HO
OH O ~NH
The desired compound was the slower eluting species in the chromatography described in Example I . I H NMR (DMSO-d6) 0.63 (d, 3H) J = 5.5 Hz)) 0.71 (d) 3H) J = 5.5 Hz), 0.87 10 (m, 2H), 1.27 (m, 1 H), 2.59 (m, 1 H)) 2.89 (dd, 1 H, J = 10.0, 13.6 Hz)) 3.09 (dd, 1 H) J = 4.7, 13.6 Hz), 3.83 (d, 1H, J = 7.8 Hz), 5.43 (m, 1H), 7.21 (m) 4H)) 7.32 (d, 2H, J
= 6.9 Hz), 7.46 (dd, 1 H) J = 1.8) 5.5 Hz), 8.21 (dd) 1 H, J = 2.6, 5.5 Hz), 8.47 (d) 1 H) J =
3.3 Hz), 8.64 (d) 1 H, J = 8.9 Hz), I I .98 (d) 1 H, J = 2.6 Hz). MS (DCI/NH3 ) m/e 454 (M+NI-I4 )+, 437 ( M+H )+) 265. Anal calcd for C25H28N205: C, 68.79; H, 6.47; N, 6.42. Found: C) 67.87;
H, 7.14; N, IS 5.54.
Example 12 O H O
HO N \
N _ NH
H OH O
The desired compound was prepared according to the method of Example 5) except substituting the compound of Example 10 for the compound of Example 4. mp I22-125 °C. 1 H
NMR (DMSO-d6) 0.63 (d, 3H, J = 6.8 Hz), 0.68 (d, 3H, J = 6.4 Hz), 0.85 (m) 1H), 1.08 (d, 1 H)) I .37 (m, 1 H), 2.63 (m, I H), 2.94 (dd, 1 H, J = 6.8, 13.9 Hz), 3.18 (dd) 1 H, J = 7.2, 13.9 Hz), 3.77 (dd) 1 H, J = 6.8, 8.5 Hz), 5.22 (d, 1 H, J = 6.8 Hz), 5.37 {dd, 1 H, J = 6.8, 7.2 Hz), 7.19 (m, 6H), 7.45 (dd) 1H, J = 0.7, 7.8 Hz)) 8.13 (dd, 1H, J = 2.0, 5.7 Hz), 8.25 (d, 1H, J =
2.0 Hz), 8.37 (d, 1H, J = 8.1 Hz), 8.83 (s, 1H), 10.59 (s, 1H), 11.92 {s, 1H).
MS (DCI/NH3) m/e 469 (M+NHd)+, 452 (M+H)+. Anal calcd for C25H29N305~0.33 H20: C, 65.64; H, 6.53;
N, 9.19. Found: C, 65.65; H, 6.54; N, 8.20. [ot]d = +12 ° (C = 0.95) CH3OH).
Exam l O H O / I
H O~N N \
I _ ~
H OH O ~NH
The desired compound was prepared according to the method of Example 5) except substituting the compound of Example 11 for the compound of Example 4. mp 172-175 °C. 1 H
NMR (DMSO-d6) 0.62 (d, 3H) J = 6.4 Hz), 0.69 (d) 3H, J = 6.1 Hz), 0.79 (m) 1 H)) 0.88 (m, 1 H ), 1.23 (m, 1 H ), 2.62 (m) 1 H)) 2.90 (dd, 1 H, J = 9.5, 13.9 Hz)) 3.09 (dd, 1 H, J = 4.7, 13.9 Hz)) 3.68 (dd, 1 H, J = 6.5, 8.8 Hz)) S.U 1 (d(OH), 1H, J = 6.1 Hz), 5.41 (m, 1 H), 7.22 (m) SH), 7.30 (s) 1 H), 7.31 (dd, 1 H) J = 1.7, 7.0 Hz)) 7.46 (dd) 1 H, J = 1.3, 8.5 Hz), 8.20 (dd) 1 H) J = 2.6, 8.5 Hz)) 8.44 (d, 1 H, J = 9.5 Hz)) 8.46 (s) 1 H), 8.75 (s, 1 H), 10.51 (s, 1 H), 11.92 (s) 1H). MS (DCI/NH3) m/e 469 (M+MH4)+, 452 (M+H)+) 391. Anal calcd for C25H2gN305~0.33 H20: C, 65.64; H, 6.53; N) 9.19. Found: C, 65.63; H, 6.74; N) 8.31. [
- -9.1 ° (C = 1.1, CH30H).
2« Example 14 O H O _ H O~N N
- = t Y
H OH O ~ N
H
The desired compound was prepared according to the method of Examples 10 and 12, except substituting 9a for Ic. mp 144-146 °C. 1H NMR (DMSO-d6) 0.65 (d, 3H, J = 6.8 Hz), 0.69 (d, 3H, J = 6.5 Hz), 0.89 (m, 1 H), 0.98 (s, 9H), 1.20 (m, 1 H), 1.41 (m, 1 H), 2.77 (m, 1 H)) 3.73 (t) 1 H, J = 8.2 Hz}, 5.12 (d, 1 H, J = 9.5 Hz), 5.24 (d, 1 H, J =
8.1 Hz)) 7.12 (m, 2H), 7.46 (d, 1H, J = 6.8 Hz), 7.78 (d, 1H, J = 9.4 Hz), 8.21 (dd, 1H, J =
1.7, 6.1 Hz), 8.36 (d, 1H, J = 2.7 Hz), 8.84 (bds, 1H), 10.59 (bds, 1H), 11.96 (bds, 1H). 13C NMR
(DMSO-d6) 21.58, 23.49, 25.12, 27.05) 34.42, 37.22, 47.57, 60.23, 71.47, 112.07, 116.61, 121.45, 121.68, 122.81, 125.49) 134.45) 136.59, 168.77, 172.44, 193.57 . MS (DCI/NH3) m/e 435 (M+NH4)+, 418 (M+H)+. Anal calcd for C22H31 N305'0.5 H20: C, 61.95; H, 7.56;
N, 9.95.
Found: C) 61.64; H, 7.69; N, 9.67. [a]d = -57 ° (C = 1.2, CH30H).
Fpm- I?~ a 15 O H O
HO~ N
H OH O
Example 15A

HpN
IU ~ /
The desired compound was prepared according to the method of Examples 3A-E, except substituting phenyllithium for ethylmagnesium bromide.
Example I SB

2N H 0~ H
N N
H OH O \
/
The desired compound was prepared according to the method of Examples 10 and 12) except substituting ~ for lc. IH NMR (CD30D) $ 0.78 (d, 3H, J = 6.5 Hz), 0.80 (d) 3H, J =
6.5 Hz), I .10 (m, 1 H), I .30 (m) 1 H), 1.54 (m) 1 H), 2.77 (m) 1 H)) 3.01 (dd, 1 H, J = 6.5) 13.6 Hz), 3.20 (dd, 1 H, J = 6.8) 13.9 Hz), 3.98 (d, 1 H, J = 7.1 Hz), 5.73 (t, 1 H, J = 6.8 Hz), 7.18 (m, 5H)) 7.45 (t) 2H, J = 7.8 Hz), 7.58 (m, IH)) 7.93 (d, 2H, J = 7.1 Hz). MS
(DCI1NH3) m/e 430 (M+NH4)+, 413 (M+H)+. Anal calcd for C23H28N205~O.SH20: C, 65.54; H, 6.93;
N, 6.65. Found: C, 65.57; H, 6.99; N, 6.52.

Example 16 O
H
HOHN N
O
The desired compound was prepared according to the method of Example 1, except substituting 1-methylindole for indole. ~H NMR (300 MHz, DMSO-d6) 8 10.36 (s, 1H), 8.68-8.46 (m, 3H), 8.32-8.18 (m, 1 H)) 7.56-7.18 (m, 7H), 5.43-5.33 (m, 2H), 4.82-4.6 (m, 2H), 3.88 (s, 3H), 3.12-3.07 (m) 1H), 2.95-2.90 (m, 1H)) 2.40-2.39 (m, 1H), 2.03-1.88 (m, 2H), 1.34-1.26 (m, 2H), 0.81-0.56 (m, 7H). MS (DCI/NH3) m/e 490 (M+H)+. Anal calcd for C29H35N3o4'0-25 H20: C, 70.49; H, 7.24; N, 8.42. Found: C, 70.39; H, 7.37; N, 8.35.
O H
HOHN N
O
Example 17A
O
~O~N~
'IO
To a -78 °C solution of N-Boc-phenylalanine (2.69 g) 10 mmol) in 10 mL
THF was added MeLi (22.9mL, 32mmoL, 1.4M in ether) via addition funnel over 10 minutes. The cold bath removed and the solution allowed to warm to ambient temperature and stirred 2 hours. The reaction was quenched with 25 mL of 2N HCl solution, stirred for 10 minutes, and the aqueous layer was extracted with ether (3x). The combined organics were washed with brine) dried (Na2S04) and concentrated in vacuo. Flash chromatography (hexane-ethyl acetate S: I ) gave 17a ( 1.31 g) as a waxy solid.
Example 17B
O
HCI~H2N~
A 0 °C solution of 17~ ( 1.31 g, 4.83 mmol) in 4N HCI/dioxane was stirred for 2 hours and then was diluted with diethyl ether. The residual solid was filtered and dried under high vacuum to give 17ø (U.9 g) as the HCl salt.
O
O
HC!~H2N~ O N
HOHN
O
The desired compound was prepared according to the method of Examples 1 D-F, except I S substituting 17b for 1 c. mp I 80 °C (dec). 1 H NMR (DMSO-D6) 8 1 U.37 (S, I H), 8.71 (S, 1 H)) 8.47-8.38 (D, IH) J = 8.1 Hz), 7.30-7.13 (M, SH)) 5.36-5.30 (M) 1H)) 4.80-4.U6 (M) 3H)) 3.10-3.()4 (M, 1 H), 2.72-2.64 (M, 1 H)) 2.41-2.39 (M, l H), 2.11 (S, 3H), 1.92-1.90 (M, I H)) 1.7y-1.70 (M, 1 H > I .39-1.35 (M) 2H )) 1.23-1.20 (M. 2H)) U.84-U.75 ( M) 7H). MS (DCUNH3 ) m/e 375 ( M+H ). Anal calcd for C2 ~ H 3pN~ 04C: C, 67.35; H, 8.U 1; N ) 7.48.
Found: C, 66.95;
2() H) 8.01; N) 7.31.

Examplg 18 O H O
HOHN N \
O
Examine 18A
H O
Ou N \
'OI

To a cold 0 °C solution of bromobenzene (5 g, 32 mmol) in THF was added nBuLi ( 12.8 mL, 32 mmol, 2.SM in diethyl ether) over the course of 5 minutes. The resulting yellow solution was stirred at 0 °C for 25 minutes and then was added to a -78 °C solution of N-BOC-1-10 phenylalanine (2.69 g, 10 mmol) over 25 minutes. The resulting yellow solution was allowed to warm to room temperature overnight ( 16 hours) and then was quenched with 1 N
HCl solution.
The aqueous layer was extracted with ether (3x) and the combined organics were washed with 1 N
NaHC03 and brine, dried (MgS04) and concentrated in vacuv.. Flash chromatography (hexane-ethyl acetate 6:1 ) gave 1 a (0.25 g) as a waxy solid.
Example 18B
O N O O H O
HOHN N I \
O /
1$.a The desired compound was prepared according to the method of Examples 17B and C, except substituting 18a for ~ 7a. mp 209-211 °. 1 H NMR (DMSO-d6) 8 10.39 (s, 1 H)) 8.72 (s, 1 H ) ) 8.59-8.57 (d, 1 H, J=8.5 Hz), 8/06-8.02 (d, 2H, J=8. I Hz), 7.69-7.64 (t, 1 H, J=7.1 Hz), 7.55-7.52 (t, 2H, J=8.1 Hz), 7.40-7.38 (d, 2H, J=7.4 Hz)) 7.30-7.28 (m, 2H), 7.20-7.18 (m, 1 H), 5.66-5.62 (m, 1 H), 5.44-5.35 (m, 1 H), 4.86-4.70 (m, 2H), 3.19-3.13 (dd, 1 H, J=7.9,4.1 Hz)) 2.94-2.86 (m, 1H), 2.38-2.34 (m, 1H), 1.96-1.81 (m, 2H), 1.33-1.26 (m, 2H), 0.88-0.81 (m) 2H), 0.68-0.59 (m, 6H). MS (DCI/NH4) 437 (M+1 ). Anal. Calcd for:
C26H32N204: C, 70.57; H, 7.44; N, 6.33. Found: C, 70.60; H) 7.13; N, 6.42.
Examgle 19 O H O
HOHN N
O I/
OH
Example 19A
H O
t-BuO~ N
1~
Ot-8u The desired compound was prepared according to the method of Example 18A) except substituting N-Boc-O-tBu-L-tyrosine for N-BOC-1-phenylalanine.
Exam~he 19B
O
HCI~HpN
1~ ~ \
I OH
A cold 0 °C solution of 19a ( 1.8 g, 4.7 mmol) in trifluoroacetic acid was stirred for 30 minutes. The excess TFA was removed in vacuo and the residue was taken up in 1 N HCl in Et20, allowed to stir for 30 minutes, diluted with diethyl ether, and the residual solid was filtered. The extremely hygroscopic solid was dried in a vacuum oven for several hours and then was dried under high vacuum for 16 hours to give 19b (0.48 g) as a hygroscopic) white HCI salt.

Exam In a 19C
HCI~HpN
t-Bu0'~ N
O /
OH ~ ' OH
To a 0 °C solution of succinate ester ~ (1.5 g, Smmol) in 20 mL of methylene chloride was added HOBT (0.81 g) 6 mmol) and EDCI ( 1.17 g, 6 mmol). The suspension became a clear solution after 10 minutes and was allowed to stir for 4 hours total. The solution was diluted with methylene chloride and the organics were washed with water (3x) and brine and concentrated in vacuo. The crude HOBT ester was dissolved in DMF ( l OmL) and added to a solution of 19b ( 1.7 g, 6 mmol) and NMM (1.2 g, 10 mmol) in 10 mL of DMF. The reaction stirred for 3 days and 1 () then was diluted with ethyl acetate and the organic layer was washed with water (3x) and brine) dried (Na2S04) and concentrated iia vacuo. Flash chromatography (gradient elution: methanol-methylene chloride 0-2%) gave 19c (2.45 g) as a while solid.
Example 19D
O H O O H O
t-Bu0 O N I \ HOHN O N
1~
OH ~ ' OH
The desired compound was prepared according to the method of Examples I E and F) except substituting ~ for _l~. mp 208-210 °C (dec). tH NMR (3(?0 MHz, DMSO-d6) 8 10.42 (s, 1 H ), 9. I 5 (s, 1 H), 8.71 (s) 1 H ) ) 8.49-8.47 (d, 1 H, J = 7.8 Hz), 7.99-7.97 (d, 2H, J = 7.4 Hz), 7.63-7.60 (t) 1 H, J = 7.2 Hz), 7.53-7.48 (t, 2H, J = 7.8 Hz), 7.13-7.10 (d, ZH, J = 8.2 Hz), 6.65-6.62 (d, 2H, J = 8.5 Hz), 5.73-5.64 (m, 1 H), 5.49-5.48 (m) 1 H), 4.95-4.86 (m, 2H), 3.01-2.95 (m) 1H), 2.77-2.69 (m, 1H), 2.36-2.34 (m, 1H), 1.89-1.68 (m, 3H), 1.28-I.18 (m, SH), 0.82-0.58 (m, 7H). MS (DCI/NH3) m/e 481 (M+H)+.

Exanr~le 20 O H O
HOHN N I
O
The desired compound was prepared according to the method of Example 19, except substituting N-BOC-alpha-cyclohexyl alanine for N-Boc-O-tBu-L-tyrosine. mp 209-210 °C. 1H
NMR (300 MHz) DMSO-d6) b 10.47 (s, 1 H)) 8.76 (s, 1 H), 8.54-8.52 (d, I H, J =
7.5 Hz)) 7.92-7.89 (d, 2H, J = 8. I Hz), 7.66-7.60 (t, I H, J = 8.5 Hz), 7.55-7.49 (t, 2H, J = 7.8 Hz)) 5.62-5.50 (m, 1 H), 5.33-5.29 (m, 1 H), 4.93-4.86 (m, 2H)) 2.20-2.08 (m, 2H), 1.91-1.87 (m, 2H), 1.61-1.32 (m, 7H)) 1.13-1.10 (m) 4H)) 0.9-0.80 (m, 3H)) 0.76-0.74 (d, 3H, J = 6.4 Hz), 1 () 0.67-0.65 (d) 3H) J = 6.8 Hz). MS (DCI/NH3) m/e 443 (M+H)+. Anal calcd for C2~,H3gN2p4:
C, 70.55; H, 8.65; N, 6.32. Found: C, ?0.21; H, 8.65; N) 6.32.
E~caml 1~ a 21 O ~ O
H
HOHN N /
O Phi H
Example 21 A
H O
BOCN /
Phi H
21a To a -40 °C solution under nitrogen of methylmagnesium bromide (9.54 ml, 3.0 M in Et20, 28.6 mmol) in dry toluene (20 ml) was added pyrrole (3.2 ml, 46.5 mmol) dropwise and the resulting solution was stirred at -10 °C for 10 minutes. The Grignard reagent was cannulated into a solution of BOC-L-phenylalanine-methyl ester (1.0 g, 3.58 mmol) in dry toluene (lOml) at -65 °C, the temperature was allowed to warm up to 0 °C over 4 hours, and the reaction was quenched by addition of sat. NH4C1 solution, extracted with CH2C12 (3x), dried over Na2S04, filtered and concentrated in vacuo to give 1.9 g of a crude mixture which was purified by flash chromatography(15% ethyl acetate-hexane) followed by recrystallization from Et20-hexanes to give 21 ~ (677 mg) as a white solid.
Example 21 B
H O O
BOCN / HpN
j NJ = NJ
Ph H Ph H
21a ?~
A solution of 21 a (600 mg, 1.91 mmol) in 4M HCl/dioxane (8 ml) was stirred at room temperature for 50 minutes. The solvent was evaporated to give 21 b (507 mg) as a purple solid which was used in the next step without further purification.
Example 21 C
O O O
H2N ~ N
t-Bu0 ~/~
Phi H O phi H /
21b To a 0 °C solution in DMF (20 mL) of 21 b (6(>D mg, 1.91 mmol) was added HOBT (258 mg, 1.91 mmol)) NMM(630 ltl, 1.91 mmol), succinate ester 2 (515.7 mg) 1.91 mmol) and EDC
(366 mg) 1.91 mmol) and the reaction mixture was stirred for 20 minutes at 0 °C and for 15 hours at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 2() brine-H20 (1:1 ). The aqueous wash was extracted with ethyl acetate (3x) and the combined organic extracts were washed with brine-H20 ( 1:1 ), dried over Na2S04, filtered and concentrated in vacuo to give a brown foam. Purification by chromatography on silica gel (20% ethyl acetate-hexanes to give 21c (797 mg) as a yellow foam.

Exam lp a 21 D
O H O O H O
t-Bu0 N / ----~ HO N /
O Phi H O Phi H
21~
A solution of ~ (781 mg, 1.67 mmol) in trifluoroacetic acid (8ml) was stirred at ambient temperature for 50 minutes. The ssolvent was evaporated to give 2~ (808 mg) as a yellow foam.
Exam 1e~21~
O ~ O
H O O
HO N / / HO. N N /
O Phi H H O = N
Ph H
10 To a 0 °C solution in DMF (15 mL) under nitrogen of ~Il (753 mg) 1.84 mmol} was added HOBT (273 mg) 2.02 mmol), NMM(443 ~tl) 4.04 mmol)) TBDMSONH2 (298 mg, 2.02 mmol) and EDC (387 mg. 2.02 mmol). The reaction mixture was stirred at 0 °C
for 1 hour and at ambient temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with brine-H20 ( I :1 ). The aqueous wash was extracted with ethyl acetate (3x) and the combined 15 organic extracts were washed with brine-H20 ( 1:1 ), dried over Na2S04) filtered and concentrated in vacuo to give a yellow solid. Purification by chromatography on silica gel ( 10°lo MeOH-CH2Cl2) gave the desired compound (448 mg) as a white solid. mp 2(>4-205 °C (dec). IH NMR
(300 MHz) DMSO-d6) 8 U.65 (d, 3H, J = 3 Hz), 0.77 (d) 3H) J = 3 Hz),0.83 (m, I
H), 1.13-1.38 (m) 3H), 1.77-1.98 (m) 2H), 2.41 (dt) 1 H) J = 3) 12 Hz), 2.88 (dd, 1 H) J = 3, 1 U.SHz)) 20 3.07 (dd) 1 H, J = 4.5) 15 Hz), 4.66-4.84 (m, 2H), 5.23-5.46 (m, 2H), 6.22 (m, 1 H), 7.09-7.40 (m, 7H), 8.44 (d, 1H) J = 9 Hz), 8.685 (s, 1H), 10.36 (s, 1H)) 11.88 (s, 1H).
MS (DCI/NH3) m/z 426 (M+H)+. [a]d =+19.69°(EtOH).

Example 22 O ~ O
H
HOHN N I
OPh ~NJ
Examha a 22A
H O
BOCN
Ph ~N~
To a -78 °C solution under nitrogen of n-butyl lithium (2.SM in hexanes, 21.5 ml, 53.8 mmol) in ether ( I 80m1) was added 3-bromopyridine (5.18 ml, 53.8 mmol) dropwise and the reaction mixture was stirred for I hour. A solution of BOC-L-phenylalanine methyl ester (6.U g) 21.5 mmol) in ether (25 ml) was added and the reaction mixture was stirred at -78 °C for 3 hours and 0 °C for two hours. The reaction mixture was poured onto water, extracted with CH2C12 (3x)) dried over Na2S04) filtered and concentrated in vacuo to give an orange oil which was purified by flash chromatography (3U°lo ethyl acetate-hexanes) to give 2a (1.2 g) as a yellow oil.
Example 22B
H O O O
BOCN H
HOHN N
Ph N OPh ~N~
The desired compound was prepared according to the method of Examples 21 B-E) except substituting ~ for 1 a. mp 196.3- I 97.7 °C. 1 H-NMR (300 MHz) DMSO-d6) 8 0.49-0.62 (m, 6H), 0.69-0.82 (m, 2H )) 1.04-1.28 (m, 2H), 1.66- I .80 (m, 1 H)) 1.825-1.97 (m, 1 H), 2.23-2.35 (m, 1 H ), 2.84-2.98 (m, 1 H ), 3.08-3.21 (m, 1 H ), 4.62-4.84 (m, 2H), 5.24-5.63 (m, 2H), 7.09-7.38 (m, 6H), 7.49-7.57 (m, 1H), 8.26-8.37 (1H), 8.61-8.78 (3H), 9.0?-9.I5 (1H). MS
(DCI/NH3) m/z 438 (M+H)+. a]d =-18.86° (EtOH).

Example 23 O H O
HOHN N
O Ph Example 23A
Br N
TI PS
~3a To a -78 °C solution under nitrogen of 1-triisopropylsilyIpyrrole (2.8 g, 12.6 mmol ) in THF (30 ml) was added NBS (2.23 g) 12.6 mmol) via a solid addition funnel. The reaction mixture was stirred at -78 °C for 1 hour and then was warmed to ambient temperature over 1 hour.
The reaction mixture was concentrated) carbon tetrachloride was added to precipitate the succinimide and the solid was filtered and washed with carbon tetrachloride.
The filtrate was concentrated, and the crude product was purified by flash chromatography (hexanes) to afford 3-bromo-I-triisopropylsilylpyrrole (3.18 g) as a colorless oil.
I5 Example 23B
H O
Br BOCN
N Ph ~N~
TIPS TIPS
To a -78 °C solution under nitrogen of 3-bromo-I-(triisopropylsilyl-pyrrole (3.18 g, 10.5 mmol) in dry THF (50 ml) was added n-BuLi ( 1.6 M, 6.56 ml, 10.5 mmol) and the reaction mixture was stirred for 0.5 hours. A solution of BOC-L-phenylalanine methyl ester (1.25 g, 4.2 mmol) in dry THF (2 ml) was then added and the resulting mixture was stirred at -78 °C for 1.5 hours. The reaction mixture was poured onto water) extracted with CH2C12 (3x), dried over Na2S04) filtered, and concentrated in vacuo. Chromatography on silica gel (10%
ethyl acetate-hexanes) provided ~ (268 mg) as a light yellow oil.

Example 23C
H O p H O

Ph N ~ O Ph TIPS
The desired compound was prepared according to the method of Examples 21B-E) except substituting 23b for 21a. ~H NMR (300 MHz, DMSO-d6) 8 0.53-0.88 (7H), 1.06-1.36 (m, 2H)) 1.73-2.13 (m, 2H)) 2.32-2.46 (m, 1 H), 2.70-2.91 (m, 1 H), 2.98-3.08 (m, 1 H
)) 4.65-4.85 (m, 2H), 5.18-5.54 (m, 2H)) 6.54 ( I H), 6.85 ( 1 H), 7.09-7.40 (m, SH), 7.75 ( 1 H), 8.34-8.54 ( 1 H )) 8.70 (s, I H). MS (DCI/NH3) m/z 426 (M+H)+.
Example 24 O ~ O
H

O Ph S
Exams lei 24A
H O
BOCN /

S
Ph 24a To a -78 °C solution under nitrogen of BOC-L- phenylalanine methyl ester (2.0 g, 7.16 mmol) in dry THF (80 ml) was added 2-thienyllithium ( 17.9 ml, 17.9 mmoI) and the reaction mixture stirred for 1 hour. The reaction mixture was poured onto water, extracted with CH2C12 (3x), dried over Na2S04, filtered and concentrated in vacuo to give an orange oil. Purification by chromatography on silica gel (0.5°lo acetone-CH2C12) gave 24a (882 mg) as a yellow solid.

Ex~, lp a 24B
H O O
BOCN / H O
HOHN N /
Ph S O S
Ph The desired compound was prepared according to the method of Examples 21 B-E
except substituting ~ for ~. 1 H NMR(300 MHz, DMSO-d6) 8 0.54-0.87 (m, 7H), 0.95-1.35 (m) 2H ),1.68-2.11 (m, 2.SH), 2.32-2.47 (m, O.SH), 2.83-3.15 (m, 2H)) 4.63-4.85 (m, 2H), 5.29-5.52 (m) 2H)) 7.11-7.40 (m, 6H), 8.02-8.20 (2H), 8.58-8.75 (1H), 8.73 (s, 1H).
MS
(DCI/NH3)) m/z 443 (M+H)+.
Example 25 O ~ O
HOHN N N
O p Ph Example 25A
H OH
BOCN
Ph O
~Sa To a -70 °C solution under nitrogen of oxazole (3.36 g, 48.8 mmol) in THF (80 ml) at was added n-BuLi (30.5 ml, 48.8 mmol) and the mixture was stirred at -7U °C
for 20 minutes. A
solution of N-BOC-phenylalaninal (4.86 g, 19.5 mmol) in THF (20 ml) was then added and the mixture was stirred at -50- -70 °C for 6 hours. The reaction was quenched with H20, extracted with CH2CI2 (3x), dried over Na2S04, filtered and concentrated in vacuo.
Chromatography on silica gel (40% ethyl acetate-hexanes) provided ~5 ( 1.12 g).

Example 25B
H OH H O
BOCN N BOCN
o~ \o~
Ph Ph To a 0 °C solution of ~ (969 mg, 3.05 mmol) in CH2C12 (60m1) was added KBr/H20 5 (36.3 mg, 613p1) and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (4.76 mg, 0.0305 mmol).
In another vial, NaOCI solution (10.9 ml) was adjusted to pH 8 with saturated aqueous NaHC03 solution, and the resulting solution was added to the 25a solution and the reaction mixture was stirred at 0 °C for S hours. The reaction mixture was poured into H20-brine, extracted with CH2C12 (3x), dried over Na2S04) filtered and concentrated in vacuo.
Chromatography on silica 10 gel (30%-40% ethyl acetate-hexanes) gave 25b (731 mg).
Example 25C
H O O H O
BOCN N
HOHN N
Ph O Ph O
25b 15 The desired compound was prepared according to the method of Examples 21 B-E except substituting 25b for 21 a. 1 H NMR (300 MHz, DMSO-d6) 8 0.54-0.90 (m) 7H)) I
.14-1.39 (m) 3H ), 1.75-2.06 (m, 2H)) 2.71-2.82 (m, 1H), 3.11-3.22 (m, 1H), 4.64-4.91 (m, 2H)) 5.29-5.42 (m) 2H)) 7.12-7.41 (m, SH), 8.53 (d, 1 H, J = 7.5 Hz), 8.60-8.65 ( 1 H), 8.74 (s, 1 H). 9.02-9.08 (1H)) 10.36-10.48 (1H). MS (DCI/NH3) m/z 428 (M+H)+.

Examlhe 26 O H O
HOHN N
O Ph S
Example 26A
H O
BOCN
S
Ph 26a To a -78 °C solution under nitrogen of thiazole ( 1.1 ml) 15.8 mmol) in THF (8() ml) was added n-butyl lithium (1.6M in hexanes, 9.88 ml) 15.8 mmol) and the reaction mixture was stirred for 0.5 hours. A solution of BOC-L-phenylalanine methyl ester (2.0g) 7.17 mmol) in THF (5 ml) was added and the mixture was stirred at -78 °C for 30 minutes. The reaction mixture was poured into water) extracted with CH2C12 (3x)) dried over Na2S04) filtered) and concentrated in vacuo.
Chromatography on silica gel (20% ethyl acetate-hexanes) gave 26a ( 1.95g) as a yellow solid.
Example 26B
BOCN O N HO' O H O
N N N/
Ph S H O S
~ ~ Ph The desired compound was prepared according to the method of Examples 2l B-E
except substituting 2~(a for 21a. 1H NMR (300 MHz) DMSO-d6) 8 0.55-0.92 (m, 7H)) 1.18-1.40 (m, 2H),1.80-2.29 (m) 3H), 2.75-2.90 (m, 1H), 4.66-4.95 (m) 2H), 5.30-5.76 (m, 2H)) 7.13-7.38 (m, SH)) 8.22-8.30 (2H)) 8.58-8.75 (2H). MS (DCI/NH3) m/z 444 (M+H)+.

Example 27 O H O _ HOHN~N
O H IOI
\ /
Example 27A
I' o H~OH O
O' ~ ~ O
OH O
Malic acid (53.2 g, .397 mol) was dissolved in 400 mL of HCI saturated 2-propanol and the solution was heated at reflux for 22 hours. The solution was reduced in volume by rotary evaporation, diluted with EtOAc ( I L), and extracted twice with saturated aqueous Na2C03. The 1 () organics were dried over MgS04 and concentrated to give diiso-propyl malate 27a (67g).
Example 27B
i - o'/
~o~° °
OH O OH TO
I S Diiso-propyl malate 27a, 25.6 g) 117 mmol) was added slowly to a 1 M
solution of LDA
in THF (235 mL) 235 mmol) at -78 °C. The solution was allowed to slowly warm to -50 °C over 2 hours, and then was recooled to -78 °C. Cinnamyl bromide (25.Ug) 127 mmol ) in THF (SU mL) was added dropwise, and the solution was stirred at -78 °C for 15 hours. The dry ice bath was removed and the reaction was quenched with 1 M HCI. The solution was diluted with ether and 20 extracted twice with 1 M HCI. After drying (Na2S04) and solvent removal, the crude material was chromatographed on silica gel ( I S°lo ether-hexanes) to give 27b as a 10:1 mixture of diastereomers (9.5 g).

Exam 1e~27r o _ OH O
A mixture of 27~ (9.29g) and 10% Pd/C (0.45 g) and were placed in a Parr shaker S containing 150 mL methanol, and exposed to 4 atm pressure of hydrogen for 18 hours. Filtration and solvent removal provided 27c as a yellow liquid (9.39 g).
Example 27D
i I

O _ O OH
HO
OH O ~ OH O
A solution of 27c (9.39 g) 27.9 mmol) in 20 mL dioxane was treated with 3 M
KOH (30 mL) and stirred overnight at 90 °C. The solution was poured over ice and acidified to pH 3 with concentrated HCI. The reaction mixture was extracted twice with EtOAc, and the organics were dried over MgS04. Solvent removal gave 27~ as a yellow liquid.
Example 27E
H O
To a solution of 27~c (7.U g, 28 mmol) DMF (50 mL) and 2,2-dimethoxypropane ( I 80 mL) was added Dowex-50 resin and the mixture was stirred at ambient temp for 3 days. The resin was filtered off and the solution concentrated to give a DMF solution of 27e which was used as is in the next step.

Example 27F

\ 7rZg ~ \ ?Zf Crude acid 27e (theoretical yield 28 mmol) with residual DMF was diluted with ( 1 I 0 mL) and cooled to 0 °C. Pentafluorophenol (8.33 g, 45 mmol) was added, followed by EDCI (6.49 g) 33.8 mmol). The mixture was stirred at 0 °C for 2.5 hours, then extracted succesively with saturated aqueous Na2C03 and brine. The organic phase was reduced in volume in vacuo, diluted with ethyl acetate, washed three times with brine, dried over Na2S04) filtered, and concentrated in vacuo. Chromatography on silica gel (gradient elution 10-15-20% ether-I U hexanes) gave ~ (8.88 g) as a 7:4 mixture of diastereomers.
Exam,~]e 27G
O O H O _ O OPFP HOHN ~ I
~O O O H O
/ \\
The desired compound was prepared according to the method of Example 1 (), except substituting 27f for 10a. mp 111- I I 3 °C. ~ H NMR (30() MHz, DMSO-d6) 8 1.23 ( m, 3H ). 1.37 (m, 1H). 2.25 (m) 1H)) 2.38 (m) 1H), 2.62 (m) IH), 2.90 (dd) 1H, J = 6.6) 14.() Hz), 3.21 (dd, I H, J =7.3) I 3.6 Hz)) 3.84 (dd, 1 H) J = 6.6, 8.5 Hz)) 5.24 (d, 1 H, J = 6.6 Hz), 5.44 (q, 1 H, J
= 8.1 Hz), 6.77 (dd, 2H, J = 1.5, 8.2 Hz), 6.96 (m, 3H), 7.15 (m) 3H), 7.22 (m, 6H), 7.47 (dd) 2l ) 1 H ) J = 1.9, 5.9 H z), 8.19 (dd) I H, J = 2.2, 5.9 H z), 8.32 (d, I H, J = 3.0 H z), 8.52 (d, 1 H, J =
8.4 Hz), 8.83 (bds, 1 H), 10.63 (bds, 1 H), 11.94 (d, I H, J = 2.6 Hz). 13C
NMR (CD30D) 8 30.03, 30.11, 36.55, 39.80, 50.99, 57.05, 73.04, 112.98, 1 I 6.67, 122.89, 123.37, 124.49, 126.50, 127.15, 127.50) 129.12, 129.20, 129.28, 130.45, 135.53, 138.43, 138.69, 143.14, 171.52) 175.07, 194.40. MS (APCI) m/e 514 (M+H)+, 453. Anal calcd for C3pH31 N3O5~0.8 H20: C, 68.24; H, 6.22; N, 7.96. Found: C, 68.40; H, 6.27; N, 7.56. [a]d = -129 (CH30H, c =
0.02).

Ex~l~8_ o H o _ HOHN~N
O H OII ~ N\
H
The desired compound was isolated in the purification of the compound of Example 27.
5 mp 116-118 °C. 1 H NMR (300 MHz, DMSO-d6) 8 1.18 (m, 2H), 1.28 (m, 1 H)) 1.53 (m, 1 H ), 2.0 I (m, 2H), 2.70 (m, 1 H)) 2.89 (dd, I H, J = 4. I , 13.3 Hz), 3.12 (dd, I
H, J = 4.8, I 3.3 Hz), 3.97 (t, 1 H, J = 4.9 Hz)) 5.21 (d, 1 H, J = 5.2 Hz), 5.38 (m, I H), 7.04 (d) 2H, J = 7.0 Hz). 7.1-7.3 (m, IOH)) 7.47 (m, 1H)) 8.20 (dd, 1H, J =2.3, 5.6 Hz)) 8.41 (d) 1H) J =
2.9 Hz), 8.51 (d.
1 H) J = 8.5 Hz)) 8.63 (bds) 1 H), 10.37 (bds, I H), 1 I .97 {bds, I H). MS
(APCI) m/e 514 10 (M+H)+) 453 . Anal calcd for C3pH3~N305~U.5 H20: C, 68.95; H) 6.17; N, 8.(14. Found: C, 69.11; H, 6.17; N, 7.92. [aJd = -22.3 (CH~OH) c = 0.01 ).
Example 29 O H O
HOHN N
O N
Ph Exam 1"~ 2yA
OH OH H NHp BocHN~ BocHN ~ N
COOH ---~ Ph ~ Ph 29b To a solution of 29a (0.32g, I.08 mmol) in DMF (6.0 mL) was added EDC (0.23 g, 1.I9 mmol), HOBT (0.16 g, 1.19 mmol), NMM (0.13 mL, 1,19 mmol) and 1,2-phenethyldiamine (0.12 g) 1.13 mmoI) and the reaction mixture was stirred for 6 hours. the reaction mixture was partitioned between ethyl acetate and brine. The aqueous layer was separated and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over MgS04, filtered and evaporated to dryness. The crude 29b was used for next reaction without purification.
Exam In a 29B

BocHN ~ ~ BocHN ~N
_ O - N
~ Ph ~ Ph A mixture of ~ø and camphorsulfonic acid (12 mg, mmol) in toluene (20 mL) was heated at 80 °C for 4 hours. The reaction mixture was evaporated to a small volume and partitioned between CH2C12, brine and saturated aqueous NaHC03. The aqueous layer was extracted with CH2C12. The CH2C12 layers were combined) dried (MgS04), filtered and evaporated to dryness.
Flash chromatography (40%-80% ethyl acetate-hexanes) gave (~ (261 mg) as white crystals.
Exam 1e~29r.
OH
BacHN ~ N . OH H

- N_~(~ '_' ~(N
~ Ph ~ Ph A mixture of 29c (255 mg) 0.69 mmol ) and trifuloroacetic acid ( 1.5 mL) was stirred for 30 minutes, and then was evaporated to dryness. Residual trifluoroacetic was removed by azeotropic evaporation with toluene to give 29d as brownish crystals which was used without further purification.
Example 29D
OH H
H2N~~ O ~ OH
'' '(~ ~ ~ t-Bu0 N~ O t Ph N
Ph To a solution of succinate ester 2 (U.828 mmol) in DMF (2 mL) was added EDC ( 159 mg, 0.828 mmol), HOBT( 112 mg, 0.828 mmol) and NMM (0.19 mL, 1.73 mmol). The reaction mixture was stirred at room temperature for 10 minutes and a solution of ~
(0.69 mmol) in DMF
(2 mL) was added. The reaction mixture was stirred for 10 hours and then was partitioned between ethyl acetate and brine. The aqueous layer was separated and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine) dried (MgS04), filtered and evaporated to dryness. Chromatography on silica gel (20-40 % ethyl acetate-hexanes) gave 29e ( 156 mg) as yellow crystals.
S
Example 29E
O ~ OH ~ O
t-Bu0 , \ "'.~' t_gu0 - ~ o N
O ~ ~ O
N N
Ph ~ Ph The desired compound was prepared according to the method of Example 25B, except substituting ,fig for ~.
Fxamnle 29F

t-Buo O ~ ~ ~ O
---~ HOHN -O ' N O
~ Ph ~ Ph The desired compound was prepared according to the method of Examples 21 D and E, except substituting 29f for 21c. Mixture of two stereoisomers: mp: 159.5-161.0 °C (dec). iH
NMR (3(?0 MHz, DMSO-d6) 8 0.58 (d, 3H, J = 5.6 Hz)) 0.65 (d, 3H, J = 5.6 Hz)) 0.72 (d, 3H, J = 6.2 Hz), 0.87 (d, 3H, J = 6.2 Hz), U.79-U.89 (m) I H), 0.70-0.89 (m, 1 H), 1.20-1.30 (m) 2H ), 1.3U-1.42 (m, 2H), 1.83-2.17 (m. 3H)) 1.83-2.17 (m) 3H)) 2.78-2.87 (m) I
H)) 2.78-2.87 2() (m) 1 H)) 3.4U (m) 2H), 3.45 (m, 2H), 4.7U (dd, 1 H, J = 16.5, 1.6 Hz)) 4.81 (dd) I H, J = 1 U) 1.6 Hz)) 4.88 (d) I H, J = 10.5 Hz), 4.89 (d, I H, J = I 5.8 Hz)) 5.38 (m) I
H)) 5.55 (m) I H), 5.79 (m) IH)) 5.84 (m, IH), 7.21 (m, 2H), 7.26-7.32 (m) SH)) 7.41 (m, 2H)) 7.36-7.43 (m, SH), 7.58 (d, 2H) J = 8.4 Hz), 7.89 (d, 2H, J = 8.7 Hz), 8.61 (d, 1H) J = 8.4 Hz)) 8.70 (s, IH, J = 8.2 Hz), 8.72 (s, IH), 8.72 (s, 1H), 10.40 (d, 1H, J = 1.2 Hz), 10.42 (d, IH, J = 1.2 Hz)) 13.52 (s, 1H), 13.52 (s, 1H). MS (DCl-NH3) m/e 477 (M+H)+, 433. Anal calcd for C27H32N404: C, 66.78; H, 6.84; N, 11.53. Found: C, 66.6; H, 6.69; N, I 1.25.

Example 30 ~,O
H
H~N N
OH O
I
Example 30A
I
H i H N~ i N \ ' t-Bu0 N I
t-Bu0 ~
O L--N O ~N
I ~ ,H ~ I ~ ,H
' To a solution of ~ (2.45 g, S.15 x 10-3 mol)) prepared by coupling of 2c andR-2-(i-butyl)-succinic acid-4-t-butyl ester according to the method of Example 2C) in pyridine (50 mL) was added O-methylhydroxylamine hydrochloride {0.80 g, 1.00 x 10-2 mol) in one portion and 1 U the mixture was heated at 80 °C for 3 days. The pyridine was removed in vacuo. The residue was taken up in CH2C12 and the solvent was removed in vacuo. Flash chromatography (CH2C12) gave ~(_)b as a mixture of oxime diastereomers.
Example 30B
( H ~~O i H ~p i t-Bu0 N \ ' HOHN N \

O N O N
I \ H I \ H
' '' The desired compound was prepared according to the method of Examples SA and B, except substituting 30b for the compound of Example 4. 1 H NMR (300 MHz, DMSO-db) 8 11.43 (s, 1 H), 10.37 (s, 1 H), 8.73 (s, 1 H), 8.36 (d, 1 H, J = 8.1 Hz)) 8.08 (d, 1 H, J = 7.7 Hz), 7.92 (d, 1H, J = 2.6 Hz), 7.41-6.98 (m, 8H}, 5.60-5.49 (m, 1H), 3.90 (s, 3H)) 3.20-2.98 (m, 2H), 2.81-2.69 (m, 1 H), 1.87-1.77 (m, 2H), 1.29-1.17 (m, 1 H), 1.02-0.74 (m, 2H), 0.58-0.49 (m, 6H). MS (DCI-NH3) m/e 465 (M+H)+. Anal calcd for C26H32N404~U.25 H20: C) 66.57;
H, 6.98; N, 11.94. Found: C, 66.72; H, 7.11; N, 11.85.
Examl 1~ a 31 O H O i HOHN
O ø ~ N
\C02H \H
Example 31 A
H O
HN~ H
d O8n O
OBn H
O
To a suspension in THF (25 mL) of OBn-Asp ( 1 g, 4.48 mmol) and activated charcoal (25 mg) was added diphospgene (0.416 mL) 3.45 mmol) via syringe at ambient temperature and the reaction mixture was heated at 55 °C for 1.5 hours. The solution was then filtered through celite) the filter cake was washed with EtOAc, and the solvent was removed in vacuo.
The resulting solid I S was recrysnrllized (EtOAc-Hexane) to give the desired product in 55°lo yield.
Example 31 B

O O H O i ,,,~ HO
;' -O
OBn H O
OBn N
31a ~ ~ H

-2U The desired compound was prepared according to the method of Examples 2A
and B, except substituting ~ for ~ and substituting for R-2-(i-butyl)-succinic acid-4-t-butyl estersuccinate ester 4.

Exam lp a 31 C
O H O ~ H
I
HO ~ 1 ~ HOH
O ~ OBn ~ O
H \C02H ~H
The desired compound was prepared according to the method of Example 5, except 5 substituting ~1 for the compound of Example 4.
Example 32 O H O
N
HO
O
HO
Example 32A

N~O
'O H
Cyclohexylacetic acid (25 g, 0.176 mol ) was dissolved in 5() mL thionyl chloride, and the solution was heated at reflux for 1 hour. The solution was concentrated in vacuo and placed under vacuum for 1 hour. The acid chloride was then added to a -78 °C
solution in THF (450 mL) of 1-lithio 2-(S)-benzyloxazolidinone (0.158 mol). After 10 minutes, the dry ice bath was removed, and after a further 30 minutes) the mixture was quenched with aqueous NH4CI
solution. The solution was extracted with 1 M NaOH and washed with pH 7 buffer solution. The organic phase was dried over MgS04) filtered and concentrated in vacuo to give 2a as a white solid (42 g) which was used without further purification.

Exam~he 32B

N~O
t-Bu0 O
To a -78 °C solution in THF (420 mL) of acyl oxazolidinone ~ (42 g, 140 mmol) was added sodium hexamethyldisilazide (140 mL of a 1 M soultion in THF, 140 mmol) dropwise over 40 minutes. After 30 minutes, a solution often-butyl bromoacetate (23 mL, 156 mmol) in 70 mL
THF was added dropwise over 30 minutes. One hour after the addition was begun, the dry ice bath was removed and replaced with an ice bath. After 2 hours at 0 °C) the reaction was quenched with aquesou NHqCI. The solution was concentrated, diluted with EtOAc and extracted twice with aqueous NH4Cl. After drying (Na2S04) and solvent removal, the crude material was rec,-rystallized from 3:I hexanes-EtOAc to give ~2b (31.8 g) as white needles) mp 141-142 °C.
Flash chromatography of the mother liquors provided a further 2.60 g product.
Example 32 U
f-Bu0 N O O
OH
O t-Bu0 O
To a 0 °C solution of acyloxazolidinone ~ (34.4 g, 83 mmol) in 360 mL
THF was added 30 mL water and 33 ml 3U~lo hydrogen peroxide) followed by a solution of LiOH
(5.28 g) 126 mmol) in 120 mL water. After 6.5 hours) the peroxides were quenched with NaHS03 (300 2() mmol), then KOH (300 mmol) was added. The solution volume was reduced in vacuo and the pH
adjusted to 9 with 50% aqueous NaOH. The solution was extracted twice with methylene chloride, then acidified to pH3 with concnetrated HCI. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over Na2S04) filtered and concentrated in vacuo to give 32c as a slightly yellow oil ( 10.4 g).

Exa~r le 32D
O H O
O t-Bu0 N ~ \
t-Bu0 O H O /
O
HO
The desired compound was prepared according to the method of Example 19C, except substituting 32c for succinate ester 3.
Example 32E
O H O
N O H O
t-Bu0 \ H O N \
O ~ / O
HO
HO
1 () A solution of ~ ( 1.37 g, 2.86 mmol) in 30 mL HCl saturated acetic acid was stirred for 4 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was azeotroped twice with toluene. Vacuum drying provided the desired compound as a white foam.
tH NMR (300 MHz, CD30D) 8 0.87 (m) 2H)) 1.08 (m) 2H), 1.42 (m) 3H)) 1.60 (m.
4H), 2.5 (m) 3H), 2.87 (dd, 1 H, J = 6.7, 13.9 Hz), 3.07 (dd, 1 H, J = 6.8) 13.9 Hz), 5.62 (t) 1 H, J = 6.8 Hz), 6.61 (d. 2H, J = 8.4 Hz), 6.98 (d, 2H) J = 8.5 Hz)) 7.42 (t) 2H) J = 7.4 Hz), 7.55 (m, 1 H )) 7.89 (d) 2H, J = 7.2 Hz) . t3C NMR (CD~OD) 8 27.40, 31.29, 31.66, 34.72) 37.81, 41.63) 49.11, 56.37) 116.15, 129.07, 129.61, 129.70, 131.45, 134.45) 137.18, 157.08, 176.06, 176.35, 200.32. MS (DCI/NH3) m/e 424 (M+H)+) 195.

Exa~33 . O H O
N
HOHN
O
HO
The desired compound was prepared according to the method of Example 5, except substituting the compound of Example 33 for the compound of Example 4. mp 144-145 °C. ~ H
NMR (300 MHz, DMSO-d6) 8 0.7-1.0 (bdm, SH), 1.2-1.6 (bdm, 6H), 2.01 (m, 2H), 2.58 (m) I H), 2.76 (dd) 1 H, J = 7.4, 13.9 Hz), 2.97 (dd) 1 H, J = 6.8, 13.9 Hz), 5.39 (q) 1 H, J = 7.1 Hz)) 6.59 (d) 2H) J = 8.5 Hz)) 7.01 (d, 2H, J = 8.4 Hz), 7.46 (t) 2H, J = 7.8 Hz), 7.62 (m) 1 H ), 7.88 (d, 2H) J = 7.1 Hz), 8.65 (s, IH)) 9.14 (s, 1H), 10.32 (s) 1H). MS
(DCI/NH3) m/e 456 (M+NH4)+, 439 (M+H)+. Anal calcd for C~SH3~N205~.75 HBO: C) 66.43; H, 7.02; N, 6.20.
Found: C) 66.53; H, 6.79; N) 6.22. [a]d = -12° (CH~OH, c = .013 g/mL).
Example 34 o l ~ o H O
O
IS o Example 'i4A
o HCI~H
i OH
The desired compound was prepared by adding 4-bromo-tert-butylbenzene to a 0 °C
solution of nBuLi in diethyl ether . The resulting 4-tert-butylphenyllithium solution was added to a -78 °C solution of N-BOC-tBu(OH) tyrosine in diethyl ether. The solution was stirred at -78 °C
for 30 minutes, warmed to 0° over 1 hour and quenched with an aqueous solution of NH4C1. The aqueous layer was extracted twice with diether ether and the combined organics were washed with brine, dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography gave the BOC-protected compound which was immediately taken up in 4N HCl-dioxane and stirred for 30 minutes. The resulting slurry was diluted with diethyl ether, filtered and dried for 16 hours under high vacuum, to give ~.
Exam lp a 34B
O O H O
HCI'H2N
HO N \
o I
off HO
The desired compound was prepared according to the method of Examples 19C and 32E, except substituting 34a for 19b, and substituting succinate ester 1 for succinate ester 3. 1H NMR
(300 MHz) CD~OD) 8 0.67 (d) 3H, J = 6.5 Hz), 0.75 (d, 3H, J = 6.4 Hz), 0.95 (m, 3H), 1.16 (m) 1H), 1.35 (s, 9H), 1.52 (m, IH), 1.82 (m. IH)) 1.94 (m) IH)) 2.34 (m, 1H), 2.46 (m, 1H), 2.8 I (dd, 1 H, J = 6.2, 14.2 Hz)) 3. I 1 (dd, 1 H) J = 4.7, 14.2 Hz)) 4.89 (bds) 1 H), 4.94 (m, 1 H), 5.59 (m) 1 H), 5.73 (m, 1 H)) 6.68 (d) 2H, J = 8.5 Hz), 7.1 I (d, 2H, J
= 8.4 Hz), 7.55 (d, 2H, J = 6.7 Hz), 7.97 (d) 2H, J = 6.8 Hz), 8.59 (d) 1 H, J = 5.6 Hz). MS
(DCl/NH3) m/e 508 ( M+H )+.
2O Example 35 O H O
HOHN N I \
O
HO
The desired compound was prepared according to the method of Example 1 F, except substuting the compound of Example 34 for I e. ~ H NMR (300 MHz) CD30D) 8 0.67 (d, 3H) J =
6.4 Hz), 0.74 (d, 3H, J = 6.4 Hz), 0.86 (m, 2H)) 0.95 (m, 1H), 1.14 (m) 1H), 1.34 (s, 9H), 1.42 (m, 1 H), 1.77 (m) 1 H), 2.03 (m) 1 H), 2.43 (m) I H), 2.83 (dd, 1 H, J =
9.8, 13.9 Hz), 3.10 (dd) 1H, J = 4.4, 13.9 Hz), 4.80 (m, 1H), 4.92 (m, 1H), 5.53 (m, 1H)) 5.77 (m, 1H), 6.69 (d, 2H, J = 7.6 Hz), 7.13 (d, 2H, J = 8.5 Hz), 7.54 (d, 2H, J = 8.5 Hz), 7.97 (d, 2H) J = 7.6 Hz).
13C NMR (CD30D) 8 21.46, 24.45, 26.49, 30.55, 31.45, 32.29, 36.00) 37.37, 41.63, 47.08, 49.84) 56.31, 115.63, 116.28, 126.74) 129.24, 129.70) 131.31, 134.12, 138.71, 157.17, 158.54, 172.87, 176.02, 199.57. MS (DCI/NH3) m/e 523 (M+H)+. Anal calcd for 5 C3~H42N205~0.5 H20: C, 70.03; H, 8.15; N, 5.27. Found: C, 69.92; H) 8.15; N, 5.21.
Example 36 HOHN

Example 36A
O
O
O
H O~~O
p ~ O
A suspension of succinic anhydride (4 g) 40 mmol )) allyl alcohol (2.7 mL) 40 mmol ) and 1 S DMAP (5.9 g) 48 mmol) in 200 mL toluene was refluxed for 4 hours and then cooled to ambient temperature and concentrated. The residue waspartitioned between EtOAc and brine. The aqueow layer was extracted with EtOAc and then acidified to pH 2 with 6M HCI. The acidic aqueous phase was extracted with EtOAc (3x) to give an organic layer which was washed with brine (2x)) dried (MgS04)) filtered and concentrated to afford ~ (5.96 g) as a clear liquid which was used 2U without further purification.
Example ~6B
O O
H O~~ O ~ O

25 To a solution of carboxylic acid 3~a (3 g, 19 mmoI) in 95 mL CHZC12 was added EDC
( 1.8 g, 9.5 mmol). The reaction mixture was stirred for 3 hours and then poured into a separatory funnel containing 20 mL of ice water. The organic layer was washed with ice-cold water, saturated aqueous NaHC03 and brine) dried with MgS04, filtered and concentrated in vacuo to afford 36b (2.8 g) which was used without purification.
Example 36C
° 0 0 "ZN~ a I' c.B~o °"+ ° ~ ~ t.e~o o _ ~ o \ / HCt -\ /
To a solution of R-2-(i-butyl)-succinic acid-4-t-butyl ester ( 1 g) 4.35 mmol), O-benzylphenylalanine hydrochloride salt ( 1.52 g, 5.22 mmol, Aldrich), HOBT
(704 mg, 5.22 1 () mmol) and NMM ( 1.4 mL) 13 mmol) in 22 mL DMF at 0 °C was added EDC ( 1 g, 5.22 mmol) in a single portion. The resulting solution was allowed to slowly warm to ambient temperature and then was stirred for 3 days. The reaction mixture was partitioned between water and ethyl acetate.
The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with I M NaHS04) I M NaHC03 and brine, dried with MgS04) filtered and concentrated in vacuo.
15 The residue was purified by flash clu-omatography (CH2Cl2 then 2% MeOH-CH~C12) to give 36c ( 1.96 g) as a yellow oil.
Example 36D
O o O ~ O
t.e~o a.~o ~ t_e~o Hydrogenation of benzyl ester ~r ( 1.96 g, 4.2 mmol; 20U mg 10% Pd/C;
methanol; 1 atm hydrogen) gave 36d (1.57 g) as a thick oil which was used without further purification.

WO 98/30541 PCTlUS98/00142 Example ~~F
O O~ O H O
t-Bu0 v 'O H 2 O t-Bu0 N O ~
O O ~ O \
\ / ~ / 36e To neat anhydride ~Cb. (2.7 g, 9 mmol) was added a solution of carboxylic acid ,3,~d ( 1.57 g, 4.16 mmol) in 10 mL CH2CI2, Et3N (864 uL, 6.24 mmol) and DMAP (21 mg, 9 mmol). The resulting yellow solution was refluxed in an oil bath at 50 °C for 3 hours, cooled, concentrated and then stirred in the presence of 50 mL 5% NaHC03 for 30 minutes. This mixture was diluted with EtOAc and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with 1 M NaHS04 and brine, dried with MgS04, filtered and concentrated. The residue was purified by flash chromatographed (IS% ethyl acetate-hexane then 35% ethyl acetate hexane) to give 36e (952 mg) as a yellow foam.
Example 36E

t-Bu0 ~ O~ ----~. HOHN ~ O
O O O O
/ \ /
The desired compound was prepared according to the method of Examples 1 E and F) except substituting 36e for I d. mp 126- I 29 °C. I H NMR (300 MHz) DMSO-d6) 8 0.6-1.0 (m) 8H ), 1.1-1.4 (m) 2H )) 1.8-2.2 (m, 2H)) 2.6-3.2 (m, 6H)) 4.2-4.6 (m, 3H)) 5.2-5.4 (m, 2H)) 5.8-6.0 (m) IH), 7.1-7.3 (m) SH)) 8.4-8.6 (m) 1H)) 8.45-8.55 (m) IH)) 8.70 and 8.73 (two s, IH), 10.36 and 10.40 (two s, IH). MS (DCI/NH3) m/e 433 (M+H)+, 450 (M+NH4)+.

Exam 1R a 37 HOHN ~ OH
O O
To a solution of the compound of Example 36 (329 mg, 0.76 mmol) in 6 mL THF
was S added palladium(0) bis(dibenzylideneacetone) (44 mg, 0.08 mmol), triphenylphosphine (42 mg) 0.16 mmol) and morpholine (662 uL, 7.6 mmol). The resulting clear) yellow solution was stirred for I hour and then concentrated. The residue was partitioned between CHZCl2 and HBO and the separated aqueous layer was extracted with CH2C12 (2x). The aqueous layer was concentrated, redissolved in H20, filtered and the desired compound ( 135 mg) was isolated by reverse-phase HPLC (0-30% CH3CN/H20; 2 I mm Dynamax 60A C 18 column; 12 mL/minutes). mp 120-°C. 1H NMR (300 MHz, DMSO-d6) b 0.60 (d, 3H, J = 5.4 Hz), 0.67 (d, 3H, J = 5.7 Hz), 0.8-1.0 (m, 2H), 1.1-1.3 (m, 1H), 1.91 (dd) 1H) J = 14.4,7.8 Hz)) 2.10 (dd) IH) J
= 14.4, 6.6 Hz), 2.36 (t) 2H, J = 6.3 Hz)) 2.6-2.9 (m, SH), 2.70 (t) 4H, J = 4.8 Hz)) 3.05 (dd, 1 H, J = 14.1, 4.2 Hz)) 3.52 (t, 4H, J = 4.8 Hz)) 4.4-4.5 (m) IH)) 7.1-7.3 (m) SH), 8.47 (d, 1H, J = 8.4 Hz). MS
(DCI/NH3) m/e 393 (M+H)+. Anal calcd for C2pH2gN20~~1.0 H20: C, 57.93; H, 7.90; N, 8.44.
Found: C, 57.91; H) 7.55; N, 8.76. [oc] _ +62 ° (c 0.3, MeOH).
Example 38 o H O
HOHN N
O
HO
The desired compound was prepared according to the method of Example 6 substituting succinate ester 4 for 5 and ketone 19b for 2c. ~ H NMR (300MHz, DMSO-d6) d 9.
I 8 (s, 1 H), 8.76 (s, 1H), 8.5-8.4 (m, 1H), 7.92-7.88 (d, 2H) J=7.1 Hz), 7.58-7.57 (m, IH), 7.48-7.45 (m, IH)) 7.03-6.98 (m, 3H), 6.85-6.82 (d, 2H, J=7.4 Hz), 6.61-6.58 (d, 2H, J=8.2 Hz), 5.45-5.40 (m, I H), 3.10-2.87 (m, 2H), 2.8-2.6 (m) 3H), 2.23 (s, 3H), I .88-. I 87 (m, I
H), 1.2-1.15 (m, 2H).

MS (ESI) m/e 487 (M-H)-. Anal. Calcd for: C29H32N2Og~0.75H20: C, 69.37; H, 6.72; N, 5.57. Found: C, 69.37; H, 6.74; N, 5.88.
Jrxample 39 H
HOHN - N I \
OH 0 ~ NH
The desired compound was prepared according to the method of Examples 10A, l OB and 5 except substituting 27f for l0a and 9a for lc. 1H NMR (300MHz, DMSO-d6) d 11.98 (s, 1H), I 0.63 (s, I H), 8.83 (s) I H), 8.41 (s, 1 H), 8.27-8.2 (m, 1 H), 8.01-7.98 (d) I H) J=9.5 Hz)) 7.50-7.48 (m, 1 H), 7.27-7.18 (m) 2H)) 6.98-6.85 (m, 3H), 6.76-6.74 (d, 2H, J=8.4 Hz)) 5.27-5.22 (d, 1 H, J=8.4 Hz), 5. I 8-5.1 S (d, 1 H, J=9.6 Hz)) 3.82-3.77 (t, 1 H>
J=9.5, 7.7 Hz)) 2.80-2.75 (m, 1 H)) 2.40-2.33 (m) I H)) 2.25-2.21 (m, 1 H), 1.41-1.30 (m, I H), I
.25-1.2U (m, 3H)) 1.00 (s) 9H). MS (ESI) m/e 480 (M+H)+) 478 (M-H)-. Anal. Caicd for:
C27H33N3O4~O.SOH20: C) 66.37; H. 7.01; N) 8.68. Found: C) 66.39; H) 6.96; N) 8.45.
Example 4p H
HOHN N
O
The desired compound was prepared according to the method of Example 6 substituting succinate ester _4 for ~ and ketone ~ for ~. tH NMR (300MHz, DMSO-d6) d 10.31 (s, 1H), ,20 8.61 (m, IH), 8.55-8.52 (d) 1H) J=8.1 Hz), 7.94-7.91 (d, 2H, J=8.5 Hz), 7.58-7.55 (m, 1H), 7.48-7.45 (m) 2H), 7.25-7.14 (m) SH), 7.00-6.98 (d, 2H, J=7.8 Hz), 6.85-6.82 (d, 2H, J=7.9 Hz), 5.51-5.49 (m, 1 H), 3.14-3.08 (m, 1 H ), 2.91-2.83 (m, 1 H), 2.71-2.59 (m, 1 H), 2.33-2.26 (m, 2H), 1.83-1.80 (m, 2H), 1.23-1.18 (m, 3H). MS (ESI) m/e 471 (M-H)-. Anal.
Calcd for:
C29H32N2O4~O.SOH20: C, 72.32; H, 6.90; N, 5.81. Found: C, 72.57; H, 6.88; N, 5.80.

I
-n N
H
Example 41 A

o--<

S ~ OH O
41a The desired compounds was prepared according to the method of Example 27B, except substituting allyl bromide for cinnamyl bromide.
Example 41 b 1~) OH O
A solution of 4~(S.0 g, 19.4 mmol) in THF (60 mL) at 0°C was treated with 9-BBN) stirred at ambient temperature for 1.S hours, treated sequentially with DMF, [
1) 1'-bis(diphenylphosphino)-ferrocene)dichloropalladium (790 mg) 0.97 mmol), 3,4,5-trimethoxybromobenzene (14.4 g) 58.3 mmol) and cesium carbonate (38.6 g, 118.5 mmol), 1 S stirred at 60°C for S.S hours, cooled to room temperature and diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried (Na2S04) and concentrated to an oil. The oil was purified on silica gel with 10% to 30%
ethyl acetate/hexane to provide 4.95 g (59.9%) of ~1 as a yellow oil.
MS (APCI) m/e 427 (M+H)+.
20 Exam In a 41 C
Exam lr a 41 The desired compound was prepared according to the method of Example27D and 27E, except substituting 41 j2 for ~. MS (ESI) m/e 383 (M+H)+ .
Exarrrole 41 D
' H _41d A solution of 41~ (755 mg, 1.97- mtnol) in DMF (15 mL) at 0 °C was treated sequentially with HOBT (294 mg, 2.17 mmol), NMM (477 mL) 438.8 mg, 4.35 mmol), EDC (417 mg, 2.17 mmol ) and indoleketone-ten-leucine) 1 Oa (500 mg, 2.17 mmol) , stirred at room temperature for 1 ( i 17 hours, and diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2S04), and concentrated. The residue was purified on silica gel with 50% ethyl acetate/hexane to provide 402 mg (34%) of the title compound as a pale yellow foam. MS (APCI) m/e 595 (M+H)+.
Example 41 E
_41e A solution of 4l~lc (400 mg, 0.6734 mtnol) in trifluoroacetic acid (3 mL) was stirred at room temperature for 4 hours, and concentrated. The residue was purified on silica gel with 0.1 % acetic acid in 10% MeOH/CH2C12 to provide 353.4 mg (94.7%) of title compound as a white solid. MS
(ESI) m/e 555 (M+H)+.
Example 41F
o~
-o I

H
HOHN _ N
OH O
A solution of ~1 (326 mg) 0.588 mmol) in DMF (IS mL) at 0 °C was treated sequentially with HOBT ( 103.4 mg, 0.765 mmol), NMM ( 168 mL, 154.6 mg, 1.53 mmoi), EDC ( 146.6 mg, 0.765 mmol) and O-(tert-butyldimethyl-silyl)hydroxyamine (112.6 mg) 0.765 mmol)) stirred at room temperature for 17 hours, and diluted with water) extracted with ethyl acetate. The combined organic layers were washed with water and brine) dried (Na2S04)) and concentrated. The residue was purified on silica gel with 7% MeOH/CH2Cl~ to provide 32 mg (9.56%) of the title compound as a pale pink solid. 1 H NMR (300 MHz, DMSO-d6) 8 0.979 (s) 9H)) 1.130-2.000 (m, 4H), 2.272-2.392 (m) 2H), 2.700 (m, IH). 3.546 (s, 3H)) 3.568 (s, 6H), 3.783 (t.
1H)) 5.146 (d, 1 H), 5.255 (d) 1 H)) 6.282 (s, 2H), 7.138-7.237 (m, 2H)) 7.457 (d, 1 H)) 7.909 (d, 1 H)) 8. I 82 (d. IH), 8.412 (s) IH), 8.849 (s, IH)) 10.633 (s, 1H), 11.969 (s) 1H). MS
(APCI) m/e 570 (M+H)+. High resolution MS (FAB) m!e calcd for (M+H)+ : C3~H4pN30R: 570.2815.
Found 570.2822.
Example 42 o~
-o I

H
HOHN N
OH O /
N
H
The desired compound was prepared according to the methods of Example 41, except substituting 2c for 1l 0a in Example 41 D. 1 H NMR (300 MHz, DMSO-d6) 8 1.236-1.377 (m, 4H}, 2.274-2.441 (m, 2H), 2.918-2.988 (dd, 1 H), 3.111-3.183 (dd, I H), 3.570 (s, 3H), 3.638 (s, 6H), 3.826 (t, 1 H), 5.222 (d, 1 H), 5.387 (q, 1 H), 6.343 (s, 2H), 7.118-7.276 (m, 9H), 7.439 (d, 1 H)) 8.125 (d, 1 H), 8.297 (s, 1 H), 8.435 (d, 1 H). MS (APCI) m/e 604 (M+H)+. Anal. calcd for C33H3~N3Og~HOAc: C, 63.33; H, 6.22; N, 6.33. Found: C, 63.10; H, 6.05; N, 6.05.
~x;3mnle 43 o' 'o o H o I o~
HORN - N
OH O ~ /
~xamnle 43A
0 0' BocHN
_43a A solution of Boc-tert-leucine-N-methoxyl-N'-methylamide ( I .15 g) 4.2 mmol ) in ethyl ether (70 mL) at -78°C was treated with 2-lithioanisole (prepared by addition of 2-bromoanisole ( 1.57 mL, 2.36 g, 12.6 mmol) to a solution of n-butyllithium (2.SM/hexane, 5.04 mL) 12.6 mmol ) in ethyl ether ( I S mL) at 0°C)) stirred at -30°C to -45°C for I hour and poured onto I :1 Et~O: U.1 M HCI. The aqueous layer was separated, and extracted with ether) the combined organic layers were washed with brine) dried (Na2S04), and concentrated. The residue was purified on silica get with 2%-5%-10% ethyl acetate/hexane to provide 788 mg (58%) of the title compound as a colorless oil. MS (DCI/NH3) m/e 322 (M+H)+.
Example 43B
0 0' HCI HzN
/
A solution of 43~ (786 mg, 2.45 mmol) in HCI/dioxane (4M, 6 mL) was stirred at room temperature for I hour, diluted with ether, filtered. The filtrate was washed with ether, and dried under high vacuum to provide 550.6 mg (87.3%) of the title compound as a white solid. MS
(APC1) m/e 222 (M-HCl+H)+.
Exam In a 43C

o~
'o o H o I o~
HOHN . N \
OH O
The desired compound was prepared according to the method of Examples 41 D-F, except substituting ketone 43b for II Oa. I H NMR (300 MHz) DMSO-d6) 8 0.883 (s, 9H), 1.171-1.399 (m, 4H), 2.291-2.515 (m, 2H), 2.728-2.833 (m, 1H), 3.575 (s, 3H), 3.635 (s, 6H), 3.797 (s, 3H),3.772-3.813 (m, IH), 5.199 (d, 1H), 5.304 (d) 1H), 6.388 (s, 2H), 6.960-7.009 (t, 1H), 7.104 (d, 1 H), 7.449-7.501 (t, 1 H), 7.550-7.588 (dd, 1 H), 7.929 (d) 1 H), 8.852 (s, 1 H)) 10.645 (s, 1H). MS (ES1) m/e 561 (M+H)+. Anal. calcd for C29H4pN209: C) 62.12;
H, 7.19;
N, 4.99. Found: C, 62.20; H, 7.22; N, 4.71.
Example 44 o~
'o I
O H O
HOHN , N
OH O
Example 44A

HCI HZN \ O~
/
44a The desired compound was prepared following the methods of Examples 43A and 43B, except substituting 3-lithioanisole for 2-lithio anisole. MS (ESI) m/e 222 (M-HCl+H)+.

Example 44B
o~
'o I
O H O
HOHN . N ! \
OH O
The desired compound was prepared following the methods of Example 43C, except 5 substituting 44a for 43a. IH NMR (300 MHz, DMSO-d6) 8 0.933 (s, 9H)) 1.138-1.328 (m) 4H), 2.244-2.428 (m, 2H), 2.794-2.826 (m) 1H), 3.584 (s) 3H)) 3.666 (s, 6H), 3.793 (s, 3H),3.774-3.812 (m, 1 H)) 5.223 (d, IH), 5.298 (d, 1 H), 6.339 (s) 2H)) 7.151-7. I 87 (dd, I H), 7.388-7.441 (m, 2H)) 7.571 (d, 1H), 8.137 (d) IH), 8.$59 (s, 1H), 10.655 (s, 1H). MS (ES1) m/e 561 (M+H)+. Anal. calcd for C29H4pN209~0.25H20: C) 61.63; H, 7.22; N, 4.95. Found:
1 (1 C, 61.78; H, 7.48; N) 4.58.
i ~l N
~H
Example 45 WO 98130541 PCTlUS98/00142 Exacrlple 45A
o i H
N
45a The desired compound was prepared according to the method of Example 2C, except coupling succinate 7 instead of 4 with ketone 2c. MS (ESI) m/e 461 (M + N)+.
i '~ N
H
The desired compound was prepared according to the method of Example 41 B, except using 45~
instead of 4_j,~.
Example 45B

i H°~
\ T
N
The desired compound was prepared according to the method of Examples 1 E and except substituting ~5 from above for _l~. mp 104 °C. I H NMR (300 MHz, DMSO-d~,) 11.92 (s, 1 H)) 10.35 (d) 1 H) J~.7 Hz), 8.70 (d, 1 H, J=1.4 Hz), 8.47 (d) 1 H) J=8.5 Hz), 8.36 (d, IH, J=3.0 Hz), 8.18-8.14 (m) 1H)) 7.47-7.42 (m) 1H)) 7.32-7.11 (m) 7H), 6.33 (s) 2H), 5.41-5.31 (m, 1 H)) 3.63 (s, 6H), 3.56 (s) 3H), 3. I 6-3.07 (m, 1 H), 2.98-2.88 (m) 1 H)) 2.77-2.65 (m) 1H)) 2.77-2.65 (m, 3H)) 1.93-1.R7 (m, 1H), 1.44-1.18 (m) 4H). MS (ESI) m/e 588 (M + H)+.
i "°~ \
o : \ T
\H
The desired compound was prepared according to the method of Example 45A-45C, except substituting ketone Q~ for ~ in Example 45A. mp 126 °C. t H NMR (300 MHz, DMSO-d6) I 1.96 I 5 (d, 1 H, J=2.2 Hz), 10.37 (d, 1 H, J=1.4 H z), 8.69 (d, 1 H, J= I .5 Hz), 8.39 (d, I H ) J=2.9 Hz), 8.18 (d, 1 H, J=7.4 Hz)) 8.05 (d, 1 H, J=9.2 Hz), 7.48-7.43 (m) 1 H), 7.24-7.13 (m, 2H), 6.32 (s, 2H)) 5.09 (d, 1 H, J=8.8 Hz), 3.60 (s) 6H)) 3.56 (s, 3H), 2.96-2.87 (m, 1 H), 2.47-2.27 (m) E~ple 45~
Example 46 2H), 2.22-1.98 (m, 2H)) 1.47-1.24 (m, 4H), 0.97 (s, 9H).13C NMR (300 MHz, DMSO-d6) 193.9, 174.0, 1 S2.S, 137.7, 136.6, 135.4, 134.4, 12S.S, 122.9, 121.7, 121.4, 116.9, 112.1, lOS.3, 60.3, 59.9) 41.0, 35.3, 34.2, 31.5, 28.2, 27.1. MS (APCI) m/e SS4 (M +
H)+.
S
Example 47 o Example 47A
O
HpN
The desired compound was prepared according to the method of Example 43A and 43B, except using phenyl lithium in place of 3-lithioanisole.

Examlhe 47B
o The desired compound was prepared according to the method of Example 45A-45C, except substituting ketone 47a for 2c in Example 45A. mp 146 °C. ~H NMR (300 MHz) DMSO-d6) 10.36 (s, 1 H), 8.67 (s) 1 H), 8.22 (d) 1 H) J=8.0 Hz)) 7.97-7.92 (m) 2H), 7.63-7.45 (m) 3H)) 6.38 (s, 2H), 5.27 (d, 1H) J=8.1 Hz), 3.68 (s) 6H), 3.59 (s, 3H), 2.98-2.87 (m, 1H)) 2.46-2.26 (m, 2H), 2.22-1.96 (m, 2H)) 1.44-1.30 (m, 4H)) 0.92 (s) 9H).13C NMR (300 MHz, DMSO-d~) 1 U 200.3) 174.4 , 167.6, 164.8) 152.6, 138.2, 137.8) 135.4) 133.0, 128.6) 128.0, 105.3, 59.9, 59.5) 55.7) 4U.6) 35.3, 35.2, 34.0) 31.6, 28.0) 26.9.
H
The desired compound was prepared according to the method of Example 2C and 2D, except coupling succinate _9 instead or 4 with ketone 9a instead of 2c.
x 48 1H NMR (300 MHz) DMSO-d6) 11.93 (s, 1H), 10.48 (d, 1H, J=1.7 Hz), 8.74 (d> 1H, J=1.7 Hz), 8.42 (d) 1 H, J=3.1 Hz)) 8.16 (t) 2H, 3=8.1 Hz), 7.47-7.43 (m, 1 H), 7.23-7.11 (m, 2H)) 7.23-7.11 (m, 2H), 6.28 (s, 2H), 5.76-5.56 (m, 1H), 5.14 (d, 1H, J=8.5 Hz), 4.96-4.90 (m, 2H), 3.58 (s, 6H), 3.56 (s, 3H), 2.80-2.70 (m, 1H), 2.46-2.33 (m, 1H), 2.33-2.13 (m, 3H)) 5 2.10-1.98 (m, 1H), 1.38-1.18 (m, 4H), 1.00 (s, 9H). MS (ESI) m/e 594 (M +
H)+~ Anal. Calcd for: C33 H43 N3 O7~0.50H20: C) 65.76; H) 7.35; N, 6.97. Found: C, 65.70; H, 7.46; N, 6.98.
Example 49 O \ /
O H O
HO.N N
H O
The desired compound was prepared according to the method of Example 2C and 2D, except coupling succinate _1Q instead of 4 with ketone ~ instead of _2~.
~ H NMR (DMSO-d6) 8 0.93 (s) 9H), 1.0-1.43 (m, 6H), 1.95-2.02 (m, 1 H), 2.10-2.21 (m, 1 H )) 2.78-2.90 (m, 1H), 3.21 (t, 2H, J=9 Hz), 4.34 (s, 2H), 7.28 (d) 1H, J=9 Hz).
7.21-7.36 (m) 5H)) 7.44-7.50 (m, 2H), 7.53-7.62 (m) 1 H). 7.94 (d, 2H) J=8 Hz), 8.24 (d. 1 H, J=9 Hz), 8.68 (s, 1 H ), 10.38 (s, 1 H ). MS (DCI/NH3 ) m/e 469 (M+H)+. Anal. calcd for:
C27H36N205: C, 69.20; H, 7.74; N, 5.99. Found: C) 69.35; H, 7.70; N, 6.02.
Example 50 O \
O H O
HO.N N
H O /

Example SOA
O

The desired compound was prepared according to the methods of Examples I 8A
and B, except substituting N-Boc-alpha-cyclohexyl alanine for N-Boc-phenylalanine.
Example SOB
O
O H O
HO.N N
H O /
The desired compound was prepared according to the method of Example 2C and 2D) except coupling succinate 1 () instead or 4 with ketone ()a instead of 2c. ~ H NMR
(300 MHz, DMSO-d6) 8 0.78-1.0 (m, 2H), 1.03-1.68 (m, 16H), 1.78-1.90 (m, 1 H), I .91-2.13 (m, 2H)) 2.60-2,74 (m) 1l~ 1H), 3.21-3.29 (m, 2H), 4.4 (s) 2H), 5.20-5.37 (m, IH), 7.20-7.39 (m) SH), 7.41-7.52 (m) 2H), 7.55-7.63 (m, 1 H)) 7.90 (d, 2H) J=8 Hz)) 8.38 (d) 1 H, J=8 Hz), 8.70 (s, 1 H)) 10.38 (s) I H); MS
(DCI/NH3) m/e 509 (M+H)+. Anal. calcd for: C3oH40N2OS: C) 70.83; H, 7.92; N, 5.50. Found:
C. 70.63: H, 8.13; N, 5.63.

Example 51 HO~
N
H
H
~O H ~O N , O O
H
The desired compound was prepared according to the method of Example 2C except substituting succinate ester 1 1 for 4 and ketone ~ for 2c.
~H NMR (300 MHz, DMSO-d6) 8 8.39 (s) 1H)) 8.21 (d, 1H), 8.06 (d, 1H), 7.47 (d, 1H), 7.24-7.18 t m) 2H), 5.10 (d, 1 H), 2.89-.287 (m, 1 H), 2.69 )t) 1 H), 2.45 (dd, 1 H), 2.29 (dd) 1 H), 2.07-1.91 (m, 2H)) 1.58-1.42 (m, 2H)) 1.37 )s, 9H), 0.97 (s, 9H). MS (DCI/NH3) m/e 439 (M+1 )+.
Example 51 A

Example 1 B
O~
,O
O H O O H O
O N , / '-~ N
O ~ ~NY O O I ~ /
H ~ N
Sla H
A solution of the alkyne I a (2 I 1 mg) 0.48 mmol) and 1-bromo-3,4,5-trimethoxybenzene (131 mg, 0.528 mmol) in 2:1 triethylamine/acetonitrile (4.8 mL) was degassed with N2 for 20 minutes, treated with 10% palladium on activated carbon (20 mg, 0.0192 mmol) and copper iodide (5 mg, 0.024 mmol)) heated at reflux for 24 hours) cooled to 23 °C, filtered through Celite, and concentrated to a residue. The residue was purified on silica gel with 50%
ethyl acetate/hexane to provided 13U mg of 51 b as a white solid. ~H NMR (300 MHz) DMSO-d6) b 8.41 (s) 1 H), 8.22 (d, 1 H), 8.08 (d) I H), 7.47 (d) 1 H), 7.22-7.18 (m, 2H), 6.63 (s) 2H)) 5.14 (d, 1'H), 3.73 (s, 6H), 3.63 (s, 3H), 2.96-.290 (m, 1H)) 2.37-2.10 (m, 4H), 1.65-I.55 (m, 2H), 1.38 (s) 9H)) 0.98 (s, 9H). MS (DCI/NN3) m/e 605 (M+I)+, Example 5 i c;
A solution of the alkyne ~ ( 115 mg) 0.19 mmol) in 1: I methanol/ethyl acetate (4 mL}
was treated with 10% palladium on activated carbon (20 mg, 0.019 mmol) under an atmosphere of hydrogen (H2 balloon) for 16 hours, filtered through Celite) and concentrated to provide 115 mg of Sue. 1H NMR (300 MHz, DMSO-d6) 8 8.35 (s) 1H}) 8.24 (d, 1H), 8.11 (d, 1H), 7.48 (d, 1H)) 7.24-7.14 (m, 2H), 6.29 (s, 2H), 5.12 (d) 1H), 3.69 (s, 6H), 3.57 (s, 3H), 2.82-2.81 (m, 1 H), 2.42 (dd, 1 H ), 2.20 (dd, 1 H), 2.13 (t, 1 H ) ) 1.37 ( s, 9H), 1.33-1.24 (m, 6H ), 0.98 ( s, 9H ).
MS (ESI) m/e 607 (M-1)+.
Exarr~le 51 D
\ /
H
The ester 1 c was convereted to the desired compound following the procedures described 1 () in Examples 1 E, SA and SB. ~ H NMR (300 MHz) DMSO-d~) 8 8.68 (s) 1 H), 8.36 (d, 1 H}, 8.24 (d) 1 H), 8.07 (d, 1 H)) 7.48 (d) 1 H), 7.24-7. I 4 (m) 2H)) 6.29 (s, 2H)) 5.10 (d, 1 H)) 3.69 (s, 6H), 3.57 (s, 3H), 2.82 (m, 1H), 2.21-1.98 (m, 4H), 1.40-1.18 (m, 6H)) 0.99 (s) 9H). MS
(DCl/NH3) m/e 568 (M+1)+.
Anal. calcd for C3 ~ H4 ~ N30~~H20: C, 63.57; H, 7.40: N, 7.17. Found: C) 63.52; H) 7.15; N) 1 S f~.67.
Exam lp a 52 H
HON N
H OH O ' H
Example 52A
Br o o~
20 off o The desired compound was prepared according to the method of Example 27B, except substituting 1,3-dibromo-1-propene for cinnamyl bromide.
Example S2B
NHAc O
S ~ OH O
A solution of Example 2a (3.0 g, 8.9 mmol) in DMF (100 mL) at room temperature was treated with [ 1,1 '-bis(diphenylphosphino)-ferrocene] dichloropalladium (363 mg, 0.445 mmol )) 3-acetimidobenzenoboronic acid (2.39 g, 13.35 mmol) and cesium carbonate (8.7 g, 26.7 mmol ), stirred at 60°C for 7 hours, cooled to room temperature and diluted with water, extracted with ethyl acetate, and the combined organic layers were washed with water and brine) dried (Na2S04) and concentrated to an oil. The oil was purified on silica gel with SO% ethyl acetate/hexane to provide 716.9 mg (20%) of S2b as a yellow oil. MS (ESI) m/e 392 (M+H)+.
Example S2C
NHAc r0 off o ~
The olefin 5~ was converted to the desired compound ~ following the procedure of Example S 1 C .
NHAc HO~
N
H
OH O

The desired compound was prepared according to the methods of Example 41 C-F, except substituting 52c for 41b. IH NMR (DMSO-d6) 8 0.989 (s, 9H), 1.23-1.39 (m, 4H), 1.98 (s, 3H), 2.19-2.36 (m, 2H), 2.72-2.76 (m, 1 H), 3.77-3.83 (t, 1 H, J=8.1 Hz)) 5.12-5.16 (d, 1 H, J=6 Hz), 5.26-5.29 (d, 1 H, J=7.5 Hz), 6.37-6.39 (d, 1 H, J=7.8 Hz), 6.72-6.77 {t, I H, J=7.8 Hz), 7.16-7.25 (m, 4H), 7.45-7.48 ( 1 H), 7.94-7.97 (d, 1 H, J=9.6 Hz), 8.2 I -8.24 ( I H), 8.38 (s, 1 H ), 8.80 (s, 1 H), 9.71 (s, 1 H), 10.6 {s, 1 H), 11.94 (s, 1 H). MS (ESI) 537 (M+H)+, 559 (M+Na)+.
Example 53 OMe H O
N
OH O , I N
H
The desired compound was prepared according to the method of Example 52B-D
except substituting 3-methoxybenzenoboronic acid for 3-acetimidobenzenoboronic acid.

(DMSO-d6 ) b U.99 (s, 9H), 1.22- I .27 (m) 4H)) 2.27-2.39 (m, 2H)) 2.74 (dt, 1 H), 3.59 (s, 3H), 3.76-3.8 I (t) 1 H) J=8.4 Hz), 5.13-5.16 (d, 1 H, J=9.6 Hz), 5.25-5.27 (d, I
H) J=7.2 Hz)) 6.31-6.33 (d) 1 H, J=7.2 Hz), 6.55-6.68 (2H)) 6.75-6.81 (t) I H, J=7.R Hz), 7.18-7.23 (m, 2H), 7.45-7.48 (d. 1 H. J=8.7 Hz), 7.94-?.98 (d, I H, J=9.3 Hz), 8.21-8.24 (d) 1 H, J=9.6 Hz), 8.40 (s, 1 H ), 8. R4 ( s, 1 H ), 10.63 ( s, 1 H ), 11.97 ( s, 1 H ). M S (ES 1 ) 510(M+H )+, 532 (M+Na)+.
2() Example 54 'o I
H O
N
OH O
N
I

Exam lie 54A
/ ../
/ ~ w / o\

i ~ -o 0 o i o \- o b _ 0 0 ~~ o ~ , v ~
H ~ N
SOzMe A solution of 4 ~,~ (249 mg) 0.419 mmol) in dichloromethane (5 mL) at room temperature was treated with methanesulfonyl chloride ( 144.2 mg) 97.4 ml, 1.26 mmol), and triethylamine ( 127 mg, 175 ml, 1.26 mmol), stirred for 6 hours, and quenched with water) extracted with dichloromethane, dried (Na2S04) and concentrated . The residue was purified on silica gel with 40% to 60% ethyl acetate/hexane to provide 239.4 mg (85%) of S~ as a white foam. MS (ESI) m/e 673 (M+H)+.
Example 54B
o' o~
~ I o I
O H O
N -._ HO
OH O
N
SOZMe A solution of 4a (237 mg, 0.353 mmol) in THF (4.5 mL) at 0°C was treated with I N HCl (4.5 mL), stirred at room temperature for I7 hours, and concentrated. The residue was extracted with dichloromethane, dried (Na2S04), and concentrated. The residue was purified on silica gel with 0.1 % acetic acid in 10% MeOH/CH2Cl2 to provide 177 mg (79%) of 5~ as a white solid. MS
(ESI) m/e 631 (M-H)-.

Exam 1 -o I
H
N
OH O
I~ N

SOpCH3 The desired compound was prepared according to the method of Examples 5A-B, except substituting S~ø for 4_. 1 H NMR (DMSO-d6) 8 1.004 (s, 9H), 1.247-1.347 (m, 4H), 2.269-2.418 (m, 2H), 2.800-2.833 (m) 1H), 3.554 (s, 3H), 3.593 (s, 6H)) 3.649 (s) 3H) , 3.768-3.822 ( 1 H), 5.100-5.127 (d, 1 H, J=8.1 Hz), 5.232-5.256 (d, 1H, J=7.2 Hz), 6.301 (s, 2H), 7.403-7.464 (m, 2H), 7.874-7.900 (d, 1 H, J=7.8 Hz), 8.136-8.165 (d, 1 H) J=8.7 Hz), 8.215-8.240 (d, 1 H) J=7.5 Hz), 8.634 (s, 1 H)) 8.855 (s, 1 H)) 10.652 (s) 1 H). MS (ES1 ) 648 (M+H)+, 665 (M+NH4)+.

Claims

WE CLAIM

1. A compound of formula or pharmaceutically acceptable salt, ester or prodrug thereof wherein W i s NHOH or -OH;
R1 and R4 are independently selected at each occurrence from hydrogen or alkyl of one to four carbon atoms;

V is O or NOR1;
R2 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) alkoxy of one to six carbon atoms, (d) alkyl of one to six carbon atoms, (e) alkyl of one to six carbon atoms substituted with (1) halogen, (2) hydroxy, (3) alkoxy of one to six carbon atoms, (4) cycloalkyl of three to eight carbon atoms, (5) alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, (6) pyridyl, (7) pyridyl substituted with alkyl of one to four carbon atoms, (8) phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7 wherein R7 is hydrogen or alkyl of one to four carbon atoms, -CONR7R8 wherein R7 is defined above and R8 is selected from hydrogen, alkanoyl of one to four carbon atoms, alkyl of one to four carbon atoms, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CONR9R10 wherein R9 and R10 are independently selected from hydrogen and alkyl of one to four carbon atoms, and -CO2R9, and (10) -S(O)n R11 wherein n is 0, 1 or 2 and R11 is selected from (a) alkyl of one to six carbon atoms, (b) phenyl, (c) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CONR7R8, (d) thienyl, (e) thienyl substituted with alkyl of one to four carbon atoms, (f) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, (g) phenylalkyl wherein the alkyl portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, and -CONR7R8, (h) thienylalkyl wherein the alkyl portion is of one to four carbon atoms, and (i) thienylalkyl wherein the alkyl portion is of one to four carbon atoms and the thienyl ring is substituted with alkyl of one to four carbon atoms, and (11) -NR12R13 wherein R12 is hydrogen or alkyl of one to four carbon atoms and R13 is selected from (a) hydrogen, (b) alkyl of one to four carbon atoms, (c) -CO2R14 wherein R14 is independently selected at each occurrence from alkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -SO2NH2, -CO2R7, and -CONR7R8, phenylalkyl wherein the alkylene portion is of one to four carbon atoms, phenylalkyl wherein the alkylene portion is of one to four carbon atoms, and the phenyl ring is substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -SO2NH2, -CO2R7, and -CONR7R8, heteroarylalkyl wherein the alkylene portion is of one to four carbon atoms, and the heteroaryl group is selected from furyl, pyridyl, thienyl, benzimidazolyl, imidazolyl, thiazolyl, and benzothiazolyl wherein the heteroaryl group is unsubstituted or substituted with alkyl of one to four carbon atoms, and (d) -SO2R14, or R12 and R13, together with the N atoms to which they are attached define a heterocycle selected from morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, pyrrolidinyl, piperazinyl, piperidinyl, succinimidyl, maleimidyl, glutarimidyl, phthalimidyl, naphthalimidyl, (f) alkenyl of two to six carbon atoms, (g) alkenyl of two to six carbon atoms substituted with (1) halogen, (2) hydroxy, (3) alkoxy of one to six carbon atoms, (4) cycloalkyl of three to eight carbon atoms, (5) alkanoyloxy wherein the alkyl portion is of one to four carbon atoms, (6) pyridyl, (7) pyridyl substituted with alkyl of one to four carbon atoms, (8) phenoxy wherein the phenyl ring is unsubstituted or substitued with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CONR7R8, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R9, and -CONR9R10, (10) -S(O)n R11 and (11) -NR12R13;

R3 is selected from the group consisting of (a) alkyl of one to ten carbon atoms, (b) alkenyl of two to ten carbon atoms, (c) cycloalkyl of three to eight carbon atoms, (d) (cycloalkyl)alkyl wherein the cycloalkyl portion is of three to eight carbon atoms, and the alkylene portion is of one to six carbon atoms, (e) cycloalkylene of five to eight carbon atoms, (f) (cycloalkylene)alkyl wherein the cycloalkylene portion is of three to eight carbon atoms, and the alklene portion is of one to six carbon atoms, (g) phenyl wherein the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CO2NR7R8, phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R9, and -CONR9R10, (h) phenylalkyl wherein the alkylene portion is of one to six carbon atoms, and the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CO2NR7R8, alkoxyalkyloxy, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7 and -CO2NR7R8, (i) -(CH2)m-T-(CH2)n-R15 wherein m and n are independently 0, 1, 2, 3 or 4, T is O or S, and R15 is selected from the group consisting of alkyl of one to four carbon atoms, phenyl, and phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, alkoxyalkyloxy halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, and -CONR7R8, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CONR7R8, and (j) fluorenylalkyl wherein the alkylene portion is of one to four carbon atoms.

R5 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with cycloalkyl of three to eight carbon atoms, hydroxy, alkoxy, -SR7, -NR7R8, -CO2R7, -CONR7R8, guanidyl, phenyl, phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, carboxyalkyloxy, -S(O)n R16 wherein n is 0, 1 or 2 and R16 is alkyl of one to four carbon atoms, -SO2NH2, -CO2R7, and -CONR7R8, and phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, naphthyl, naphthyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, indolyl, indolyl substituted with alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, -SO2R13, -SO2NH2, -CO2R7 and -CONR7R8, pyridyl, pyridyl substituted with alkyl of one to four carbon atoms, pyrazolyl, pyrazolyl substituted with alkyl of one to four carbon atoms, 5-oxadiazolyl, imidazolyl, and imidazolyl substituted with alkyl of one to four carbon atoms, (c) phenyl and (d) phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms;

R6 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with hydroxy, alkoxy, halogen, and -CO2R17 wherein R17 is selected from hydrogen, alkyl of one to four carbon atoms and alkenyl of two to four carbon atoms, (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, cyano, -NR7R8, -SO2NR7R8, -SO2R16.
-CH2NR18R19, wherein R18 and R19 are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R18 and R19 together with the N atom to which they are attached define a a 5-or 6-membered heterocyclic ring selected from (1) morpholinyl, (2) thiomorpholinyl, (3) thiompholinyl sulfone, (4) pyrrolidinyl, (5) piperazinyl, (6) 3-ketopiperazinyl and (7) piperidinyl, -CONR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (e) 1,3-benzodioxole, (f) indolyl, (g) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -SO2NR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (h) pyrrolyl, (i) pyrrolyl substituted with alkyl of one to four carbon atom (j) imidazolyl, (k) imidazolyl substituted with alkyl of one to four carbon atoms, (l) benzimidazolyl, (m) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms, provided that in (f)-(m) above, when the heterocycle is attached at a carbon atom, the N
atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms -CONR7R8, -SO2NR7R8 and -SO2R14, (n) pyridyl, (o) pyridyl substituted with alkyl of one to four carbon atoms, (p) thienyl, (q) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (r) thiazolyl, (s) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (t) oxazolyl, (u) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (v) furyl, (w) furyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (x) benzofuryl, (y) benzofuryl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (z) benzothiazolyl, and (aa) benzothiazolyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms.

2. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined in claim 1 wherein R6 is selected from the group consisting of (a) alkyl of one to six carbon atoms, and (b) alkyl of one to six carbon atoms substituted with hydroxy, alkoxy, halogen, and -CO2R17 wherein R17 is selected from hydrogen, alkyl of one to four carbon atoms and alkenyl of two to four carbon atoms.
3. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined in claim 1 wherein R6 is selected from the group consisting of (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, cyano, -NR7R8, -SO2NR7R8, -SO2R16, -CH2NR18R19, wherein R18 and R19 are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R18 and R19 together with the N atom to which they are attached define a a 5-or 6-membered heterocyclic ring selected from (1) morpholinyl, (2) thiomorpholinyl, (3) thiompholinyl sulfone, (4) pyrrolidinyl, (5) piperazinyl, (6) 3-ketopiperazinyl and (7) piperidinyl, -CONR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, and (e) 1,3-benzodioxole.
4. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined in claim 1 wherein R6 is selected from the group consisting of (f) indolyl, (g) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -SO2NR7R8, -CO2R7, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (h) pyrrolyl, (i) pyrrolyl substituted with alkyl of one to four carbon atom (j) imidazolyl, (k) imidazolyl substituted with alkyl of one to four carbon atoms, (l) benzimidazolyl, (m) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms, provided that in (f)-(m) above, when the heterocycle is attached at a carbon atom, the N
atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms -CONR7R8, -SO2NR7R8 and -SO2R14, (n) pyridyl, (o) pyridyl substituted with alkyl of one to four carbon atoms, (p) thienyl, (q) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (r) thiazolyl, (s) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (t) oxazolyl, (u) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (v) furyl, (w) furyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (x) benzofuryl, (y) benzofuryl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms, (z) benzothiazolyl, and (aa) benzothiazolyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, and haloalkyl of one to four carbon atoms.

. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined in claim 1 wherein R1 and R4 are hydrogen;
R2 is selected from the group consisting of (a) hydrogen, (b) hydroxy, (c) alkoxy of one to six carbon atoms, (d) alkyl of one to six carbon atoms, (e) alkyl of one to six carbon atoms substituted with (2) -S(O)nR11 wherein n is 0, 1 or 2 and R11 is selected from (a) phenyl, (b) phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CONR7R8, (c) thienyl and (d) thienyl substituted with alkyl of one to four carbon atoms and (3) -NR12R13 wherein R12 and R13 are independently selected from hydrogen and alkyl of one to four carbon atoms and or R12 and R13, together with the N atoms to which they are attached define a heterocycle of formula and (f) alkenyl of two to six carbon atoms;

R3 is selected from the group consisting of (a) alkyl of one to ten carbon atoms, (b) cycloalkyl of three to eight carbon atoms, and (c) phenylalkyl wherein the alkylene portion is of one to six carbon atoms, and the phenyl ring is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7, -CO2NR7R8, phenyl, and phenyl substituted with 1, 2, or 3 substutuents independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R7 and -CO2NR7R8; and R5 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with cycloalkyl of three to eight carbon atoms, -CO2R7, -SR7, phenyl, and phenyl substituted with 1, 2, or 3 substituents independently selected from alkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, nitro, cyano, cyanoalkyl, -S(O) n R16 wherein n is 0, 1 or 2 and R16 is alkyl of one to four carbon atoms, -SO2NH2, -CO2R7, and -CONR7R8.
6. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined by claim 5 wherein W is NHOH and V is O.
7. A compound pharmaceutically acceptable salt, ester or prodrug thereof as defined in claim 6 wherein R2 is selected from the group consisting of hydrogen, hydroxy, alkenyl of two to six carbon atoms;
R3 is selected from the group consisting of isobutyl, cyclohexyl, 3-phenylpropyl, 3-(4-tolyl)propyl) biphenyloxy) 4-(phenylmethoxy)butyl, 4-(3,4,5-trimethoxyphenyl)butyl) and 3-(3,4,5-trimethoxyphenyl)propyl;
R5 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with cycloalkyl of three to eight carbon atoms, carboxy, phenyl, and hydroxyphenyl.
8. A compound or pharmaceutically acceptable salt, ester or prodrug thereof as defined by claim 7 wherein R6 is selected from the group consisting of (a) alkyl of one to six carbon atoms, (b) alkyl of one to six carbon atoms substituted with -CO2R17, (c) phenyl, (d) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR7R8, cyano.
-SO2NR7R8, -SO2R16, -CH2NR18R19, -CONR7R8 and -CO2R7, (e) indolyl, (f) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (g) pyrrolyl, (h) pyrrolyl substituted with alkyl of one to four carbon atoms, (i) benzimidazolyl, (j) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms, provided that in (e)-(j) above, when the heterocycle is attached at a carbon atom, the N atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms, -SO2R14, -CONR7R8 and -SO2NR7R8, (k) thienyl, (L) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (m) thiazolyl, (n) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (o) oxazolyl and (p) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms.
9. A compound or pharmaceutically acceptable salt, ester or prodrug thereof as defined by claim 8 wherein R6 is selected from the group consisting of (a) phenyl, (b) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR7R8, cyano, -SO2NR7R8, -SO2R16, -CH2NR18R19, -CONR7R8 and -CO2R7, (c) indolyl, (d) indolyl substituted with alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, and alkoxy of one to four carbon atoms, (e) pyrrolyl, (f) pyrrolyl substituted with alkyl of one to four carbon atoms, (g) benzimidazolyl, (h) benzimidazolyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen and haloalkyl of one to four carbon atoms, provided that in (c)-(h) above, when the heterocycle is attached at a carbon atom, the N atom may bear a substituent selected from the group consisting of alkyl of one to six carbon atoms, -SO2R14, -CONR7R8 and -SO2NR7R8, (i) thienyl, (j) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (k) thiazolyl, (l) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (m) oxazolyl and (n) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms.

10. A compound or pharmaceutically acceptable salt, ester or prodrug thereof as defined by claim 9 wherein R6 is selected from the group consisting of (a) phenyl and (b) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, -NR7R8, cyano, -SO2NR7R8, -SO2R16, -CH2NR18R19, -CONR7R8, and -CO2R7.
11. A compound or pharmaceutically acceptable salt, ester or prodrug thereof as defined by claim 1 selected from the group consisting of 12. A method for inhibiting matrix metalloproteinases in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.

13. A composition for inhibiting matrix metalloproteinases comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.