Macrocyclic Inhibitors of Matrix Metalloproteinases and TNFα 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 macrocyclic compounds which inhibit matrix metalloproteinases and TNFa secretion, to pharmaceutical compositions comprising these compounds and to a method of inhibiting matrix metalloproteinases and TNFa secretion.

Background of the Invention 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 delicately- 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, osteopenias 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. TNFoc 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 form a circulating 51 kD homotrimer. Recently, several MMP inhibitors were found to inhibit

TNFα 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 TNFα processing is caused by an as yet uncharacterized metalloproteinase residing in the plasma membrane of cells producing TNFα. Inhibitors of this metalloproteinase would therefore be useful as therapeutics to treat disease states involving TNFα secretion.

Transforming growth factor alpha (TGFα) 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.

TGFα is produced by proteolytic cleavage of a 160 amino acid membrane bound precursor.

Several cleavage sites have been identified including Ala38-Val39, similar to the cleavage site of pro TNFα (Ala-76-Val77). This common cleavage site suggests that inhibitors of TNFα processing may also block the cleavage of pro TGFα and therefore would be therapeutically useful in diseases mediated by TGFα.

Summary of the Invention The present invention provides a novel class of macrocyclic inhibitors of matrix metalloproteinases and/or TNFα secretion.

In its principle embodiment, the present invention provides a macrocyclic compound of formula I or a pharmaceutically acceptable salt, ester or prodrug thereof wherein W is NHOH or OH.

R and R are independently selected from hydrogen or alkyl of one to four carbon atoms.

R² 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 alklene portion is of one to six carbon atoms,

(e) cycloalkenylene of five to eight carbon atoms, (f) (cycloalkenylene)alkyl wherein the cycloalkenylene portion is of five to eight carbon atoms, and the alklene portion is of one to six carbon atoms, (g) phenyl, (h) 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, cyano, cyanoalkyl, -Co2R4 wherein R4 is independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, and -CONR4R5 wherein R4 is defined above and and R5 is independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, (i) phenylalkyl wherein the alkylene portion is of one to six carbon atoms, (j) phenylalkyl wherein the alkylene portion is of one to six carbon atoms and the phenyl ring is substituted with 1, 2, or 3 substituents independently selected from alkoxyalkyloxy, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -Co2R4, -CONR4R5, 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, - Co2R4, and -CONR4R5, (k) -(CH2)m-T-(CH2)n-R6 wherein m and n are independently 0, 1, 2, 3 or 4, T is O or S, and R6 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, halogen, haloalkyl of one to four carbon atoms, cyano, cyanoalkyl, -CO2R4, -CONR4R5, 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, -Co2R4, and - CONR4R5, and (1) fluorenylalkyl wherein the alkylene portion is of one to four carbon atoms.

Y is absent or -O-.

L1 is alkylene of two to six carbon atoms.

L2 is selected from the group consisting of (a) alkylene of one to six carbon atoms, and (b) wherein D is CH or N, L3 is absent or is alkylene of one to four carbon carbon atoms, and Ra, Rb and RC are independently selected from hydrogen, alkyl of one to four

carbon atoms, hydroxy, alkoxy of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, cyano, -SO2R6 wherein R6 is alkyl of one to four carbon atoms, -SO2NH2, - CO2R4, 2-tetrazolyl, and -CONR7R8 wherein R7 and R8 are independently selected at each occurrence from hydrogen and alkyl of one to four carbon atoms, or R7 and R8 together with the N atom to which they are attached define a a 5-or 6-membered heterocyclic ring selected from the group consisting of morpholinyl, thiomorpholinyl, thiomorpholinyl sulfone, pyrrolidinyl, piperazinyl, piperidinyl, and 3-ketopiperazinyl.

A is absent or is selected from the group consisting of (a) -0-, (b) -NR9- wherein R9 is selected from the group consisting of (1) hydrogen, (2) alkyl of one to four carbon atoms, (3) -CO2R10 wherein R10 is independently selected at each occurrence from the group consisting of 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, -CO2R4, and -CONR4R5, phenylallcyl 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, -C02R4, and -CONR4R5, 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, (4) -CONR7R8, (5) -COR10, and (6) -SO2R1°, (c) -S(O),- wherein n is 0, 1, or 2, (d) -S-S- (e) -CH=CH-, (f) l wherein V is O or NoR4, wherein J is O or NR4,

wherein J is defined above and K is selected from O and NR4, provided that J and K are not simultaneously O, (i) 1 wherein L4 is alkylene of two to six carbon atoms, wherein L5 is alkylene of one to three carbon atoms, wherein R4 is defined above and R12 is selected from hydrogen, alkyl of one to four carbon atoms, -COR10, -CO2R10, and -SO2R10, (o)

(w) -J'-L4-K'- wherein J' and K' are independently selected from 0 and NR12, (x) -NR4SO2-, (y) -S02NR4-, (z) -NR4SO2NR5-, (aa) wherein T and V are independently selected from O and S and Ra is defined above, (bb)

wherein Ra, Rb, and RC are defined above, wherein Rd and Re are independently selected from hydrogen and alkyl of | one to four carbon atoms, and (ff) provided that when A is selected from (aa), (bb), (cc), (dd) and (ff) above, L² is alkylene, and further provided that when both Y and A are absent, L1 is alkylene of three to six carbon atoms.

Z is absent or is selected from the grout consisting of (a) -CO2H, (b) -CO2R10, (c) wherein R13 is hydrogen or alkyl of one to six carbon atoms, and R14 is selected from the group consisting of (1) hydrogen,

(2) alkyl of one to six carbon atoms, (3) cycloalkyl of three to eight carbon atoms, (4) (cycloalkyl)alkyl wherein the cycloalkyl portion is of three to eight carbon atoms and the alkyl portion is of one to four carbon atoms, (5) cycloalkenyl of five to eight carbon atoms, (6) (cycloalkenyl)alkyl wherein the cycloalkenyl portion is of five to eight carbon atoms and the alkyl portion is of one to four carbon atoms, (7) -S02R10, (8) -CH2CH2M(L3M)p-R4 wherein p is 1, 2 or 3, L3 is alkylene of from one to four carbon atoms and M is selected at each occurrence from 0 and S, (9) -L4-(NR4L4)q-NR7R8 wherein q is 0, 1 or 2, (10) -L4-(NR4L4)q-NR4S02NR7R8, (11) aryl wherein the aryl group is selected from (a) phenyl, (b) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, cyano, -C(o)R4, -NR4R5, -C02R4, - So2R4, -S02NR4R5, (c) naphthyl, (d) naphthyl substituted with 1, 2 or 3 substituents independently selected from alkyl of one to four carbon atoms, halogen, haloalkyl of one to four carbon atoms, hydroxy, alkoxy of one to four carbon atoms, cyano, -C(o)R4, -NR4R5, -C02R4, - S02R4, -S02NR4R5, (12) heteroaryl selected from the group consisting of (a) pyridyl, (b) thiazolyl, (c) furyl, (d) thienyl, (e) pyrrolyl, (f) tetrahydrofuryl, (g) imidazolyl, (h) phenylthiazolyl, (i) benzothiazolyl, (j) benzimidazolyl, (k) pyrazinyl, (1) pyrimidyl, (m) quinolyl, (n) piperazinyl, and (o) indolyl wherein the heteroaryl group is unsubstituted or substituted with alkyl of one to four carbon atoms, (13) arylalkyl wherein the alkylene portion is of one to four carbon atoms and the aryl group is defined above, (14) heteroarylalkyl wherein the alkylene portion is of one to four carbon atoms and the heteroaryl group is defined above, (15) (16)

wherein R15 is selected from hydrogen, hydroxy, alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and alkoxyalkyl of one to four carbon atoms, and (17) wherein RX is the side chain of a naturally occurring amino acid, or R13 and R14, together with the N atom to which they are attached define a 5-or 6-membered heterocyclic ring selected the group consisting of (1) morpholinyl, (2) thiomorpholinyl, (3) thiomorpholinyl sulfone, (4) pyrrolidinyl, (5) piperazinyl, (6) piperidinyl, (7) 3-ketopiperazinyl, and (8) wherein K16 is hydrogen or benzyl, and (d) wherein V is defined above and R17 is selected from the group

consisting of (1) alkyl of one to six carbon atoms, (2) carboxyalkyl wherein the alkylene portion is of two to six carbon atoms, (3) phenyl, (4) 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, amino, cyano, -NR4R5, -S02NR4R5. -S02R4, -CH2NR7R8, -CONR7R8. -C02R4, and phenyl, wherein the phenyl ring may be 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, (5) 1,3-benzodioxole, (6) indolyl, (7) 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, -S02NR4R5, -C02R10, and phenyl, wherein the phenyl ring may be substituted with 1, 2, or 3 substituents independently 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, (8) pyrrolyl, (9) pyrrolyl substituted with alkyl of one to four carbon atoms, (10) imidazolyl, (11) imidazolyl substituted with alkyl of one to four carbon atoms, provided that in (6)-(11) 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, -S02NR7R8 and -S02R10, (12) pyridyl, (13) pyridyl substituted with alkyl of one to four carbon atoms, (14) thienyl, (15) thienyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (16) thiazolyl, (17) thiazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (18) oxazolyl, (19) oxazolyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms, (20) furyl, (21) furyl substituted with halogen, alkyl of one to four carbon atoms, and haloalkyl of one to four carbon atoms,

(22) benzofuryl, (23) 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, (24) benzothiazolyl, (25) 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, (26) benzimidazolyl and (27) 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, (e) wherein R18 and R19 are independently selected from the group consisting of (1) alkyl of one to four carbon atoms, (2) halogen, (3) haloalkyl of one to four carbon atoms, (4) alkoxyalkyl wherein the alkoxy and alkylene portions are independently of one to six carbon atoms, (5) alkanoyl of one to six carbon atoms, (6) -CH(oH)R4, (7) -CONR4R5, (8) -C02R4, (9) phenyl, (10) phenyl substituted with 1, 2, or 3 substituents selected from alkyl of one to four carbon atoms, halogen, hydroxy, haloalkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, amino, cyano, -S02NR4R5, -S02R4, -CH2NR4R5, -CoNR4R5, and -C02R4 or R18 and R19 together with the carbon atoms to which they are attached define a fused 5-7 membered carbocyclic aryl or heterocyclic aryl ring wherein the ring may be substituted with alkyl of one to four carbon atoms or haloalkyl 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 I.

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 tert-butyl, and the like.

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 formyl, acetyl, propionyi, butanoyl and the like.

The terms alkoxy and alkoxyl denote an alkyl group, as defined above, attached 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 alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and 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=CHCH2-, and the like.

The terms aikynylene 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(CH3)- and the like.

The term "benzyloxy" as used herein refers to -O-(CH2)-phenyl.

The term cycloalkyl as used herein refers to a monovalent saturated cyclic hydrocarbon group. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1 ]heptane and the like.

Cycloalkylene denotes a divalent radical derived from a cycloalkane by the removal of two hydrogen atoms.

The terms "(cycloalkyl" and "(cycloalkenylene)alkyl" refer, respectively, to a cycloalkyl group or cycloalkenylene group as defined above attached to the parent molecular 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, 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 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 benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M Berge, et al. describe pharmaceutically acceptable salts in detail in J.

Phannaceutical 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, ben zo ate, bisulfate, borate, butyrate, camphorate, 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, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which 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 ester 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 benefit/risk ratio, and 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 Svstems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche. ed., Bioreversible Carriers in Drug Design, 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 chiral centers or by preparation of mixtures of enantiomeric products followed 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 known in the organic chemical arts.

Preferred Embodiments Preferred compounds of the present invention have formula II wherein W and L2 are defined above, Y is absent or -O-;

R and R are H; L is alkylene of two to six carbon atoms; A is selected from the group consisting of (a) -O-, (b) -NR9- wherein R9 is selected from the group consisting of (1) hydrogen, (2) alkyl of one to four carbon atoms, (3) -CO2R10 wherein R10 is independently selected at each occurrence from the group consisting of alkyl 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, - CO2R4, and -CONR4R5, 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, -CO2R4, and -CONR4R5, and (4) -SO2R10, (c) -CH=CH-, (d) wherein Rd and Re are independently selected from hydrogen and alkyl of one to four carbon atoms, provided that when A is (f) above, L² is alkylene;

R² is selected from the group consisting of isobutyl, cyclohexyl, cyclopentylmethyl, phenyl, 3-(4-tolyl)propyl, 3-(4-chlorophenyl)propyl, 2-(4-propylphenyl)ethyl, 3- <BR> <BR> <BR> <BR> benzyloxypropyl, 4-phenoxybutyl, 4-(4-butylphenoxy)butyl, 4-biphenyloxy, and<BR> 2-(4-(4'cyano)biphenyloxy)ethyl; and Z is absent or is selected from the group consisting of (a) -CO2H, (b) -CO2R10, (c) wherein R13 is hydrogen or alkyl of one to six carbon atoms, and R14 is selected from the group consisting of (1) hydrogen, (2) alkyl of one to four carbon atoms, (3) 2-phenylethyl, (4) 2-(4-aminosulfonyl)phenylethyl, (5) cyclopropyl, (6) phenyl, (7) phenylsulfonyl, (8) 2-tiomethylethyl, (9) 2-dimethylaminoethyl, (10) -(CH2)2OCH2O(CH2)2OCH3, (11) 2-morpholinylethyl, (12) 4-pyridinylethyl, (13) 2-furylmethyl, (14) 2-pyridyl, (15) 2-thiazolyl, wherein R15 is hydrogen, and or R13 and R14, together with the N atom to which they are attached define a 5-or 6-membered heterocyclic ring selected the group consisting of morpholinyl, pyrrolidinyl, piperidinyl, and

wherein R16 is hydrogen or benzyl, wherein V is defined above and R17 is selected from the group consisting of (1) phenyl, (2) phenyl substituted with alkyl of one to four carbon, methanesulfonyl or dimethylaminomethyl, (3) 3-indolyl, (4) 2-pyrrolyl, and (5) 1-dimethylaminocarbomoylindol-3-yl, (e) More preferred compounds of the present invention have formula II wherein is -NHOH.

Still more preferred compounds have formula II wherein Y, R , R , L and A are defined above; R2 is selected from isobutyl, 3-(4-tolyl)propyl, 2-(4-propylphenyl)ethyl; and Z is absent or is selected from the group consisting of -C02H, -C02CH3, -CO2benzyl, -CONHCH3, - CON(CH3)2,

Still yet more preferred compounds have the formula II wherein W is -NHOH and Z is - CONHCH3.

The most preferred compounds of the present invention have formula III

wherein W is NHOH; L1 is alkylene of two to six carbon atoms; L3 is absent or methylene; A is selected from the group consisting of (a) -O, (b) -NR9- wherein R9 is selected from hydrogen, -C02benzyl,-S02CH3, -S02-(4-tolyl), (c) -CH=CH-, and (d) -C(O)NH-; R2 is selected from isobutyl, 3-(4-tolyl)propyl, 2-(4-propylphenyl)ethyl; and Z is is selected from the group consisting of-CONHCH3, -CON(CH3)2,

Determination of Stromelysin 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, 11231-11235. 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 CaC12 and 0.2% Pluronic F-68), which is also used for dilution of the enzyme and substrate. The potency of the compounds [IC50] 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 ICso (nM) 1 6.9 2 7.2 3 5.8 4 2.4 5 9.3 6 2.6 7 ~ 3.6 8 syn 570

Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic 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 human and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, 8anti 8 3.9 9 2100 10 7.8 11 6.1 12 12 13 2.4 14 2.7 15 7.2 16 23 18 0.61 19 20 20 92 21 39 23 ~ 8.1 24 8.9 25 44 26 27 30 20 31 2.9 32 6.7 34 1.5 38 0.56 41 26

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 injectable 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 injectable 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 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 solubility.

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 liposomes or microemulsions which are compatible with body tissues.

The injectable formulations 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 mixtures 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 ingredient(s) 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 more of the above-mentioned excipients.

Liquid dosage forms for 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 mixtures 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 <BR> <BR> <BR> <BR> <BR> <BR> <BR> temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and<BR> 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 multi-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 Biology, 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 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 compound(s) that is effective to 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 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 1-10. It is understood that while the following schemes describe the preparation of macrocycles predominately derived from

tyrosine, the substitution of any of a number of both natural and unnatural amino acids will result in the formation of the desired macrocycles.

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; Et2O for diethyl ether, IPA for isopropanol; ETOH for ethanol; MeOH for methanol; AcOH for acetic acid; HOBT for 1 -hydroxybenzoniazole hydrdate; EDC for 1 -(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride; NMM for N-methylmorpholine; Bu3P for tributylphosphine; ADDP for 1 ,l'-(azodicarbonyl)dipiperidine; and DMPU for 1 ,3-dimethyl-3,4,5,6-tetrahydro- 2( lH)-pyrimidinone.

The preparation of compounds of formula 6, wherein W is -OH and 2, wherein W is - NHOH and R1, R2, R3, R13 and R14 are defined above is described in Schemes la and b.

According to Scheme la, coupling of acid 1 with amino amide 2 in the presence of an tertiary amine base, hydroxybenzotriazole (HOBt), and a suitable coupling agent such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCIHC1) provides amide 3.

Hydroboration of 3 using, for example, a tetrahydrofuran solution of borane followed by work up with aqueous hydrogen peroxide gives alcohol 4. Cyclization of 4 can be achieved using Mitsunobu conditions (Mitsunobu et al., J. Am. Chem. Soc., 1972, 94, 679). For example addition of 4 to a solution of triphenylphosphine and diethylazodicarboxylate gives macrocycle 5.

Conversion of 5 to the corresponding carboxylic acid 6 is accomplished by acidic removal of the tert-butyl ester with, 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 EDCIHC1 gives hydroxamate 7. O-Benzylhydroxylamine can also be employed in this coupling reaction.

The resultingO-benzylhydroxamate can then be treated with hydrogen and a palladium catalyst such as 10% palladium on carbon to produce hydroxamate 7.

Scheme la An alternative route to hydroxamate 7 as outlined in Scheme Ib, involves reaction of acid 1 with the benzyl ester analog of 2 under the conditions used to prepare 3. The resulting amide 8 is subjected to the cyclization conditions described above followed by hydrogenolytic removal of the benzyl ester giving carboxylic acid 9. Treatment of 9 with EDCIoHCl, HOBt, N- methylmorpholine, and a primary or secondary amine of the formula HNR13R14 gives amide 5 which can be converted to hydroxamate 7 as described above.

Scheme 1b Preparation of intermediate 2 is accomplished by treating commercially available acid 10 with the requisite amine of general formula HNR13Rl4 using, for example, EDCI-HC1, HOBt, and

N-methylmorpholine as shown in Scheme 2. The resulting amide 11 is subjected to acidic removal of the N-t-butoxycarbonyl nitrogen protecting group using trifluoroacetic acid or hydrogen chloride in dioaxane giving amide 2. Amino ketones of the general formula 15 are prepared by treating acid 12 with ethereal diazomethane to produce methyl ester 13. This compound is subsequently reacted with a anion such as R17MgX wherein X is Br, Cl or I, or R17Li to generate ketone 14. Acidic removal of the tert-butyl protecting groups gives amino ketone 15. Alternatively, carboxylic acid 12 can be treated with a carbon anion such as phenyllithium which gives 14 directly. Amino ketone 15 can be used in place of amino amide 2 in Scheme 1 for the preparation of macrocyclic compound where "Z" = -COR17.

Scheme 2 The preparation of intermediate 1 is shown in Scheme 3. Treatment of oxazolidinone 16 with a suitable base such as lithium diisopropylamide followed by addition of tert-butyl bromoacetate and basic hydrolysis gives carboxylic acid 17. This acid is treated with at least two equivalents of a strong base as lithium diisopropylamide followed by an alkenyl halide such as 4-bromo-1-butene. The resulting dialkyl succinate 18 is again treated with a strong base such as lithium diisopropylamide followed by either methanol (R = H) or an alkyl halide (R = alkyl) such as methyl iodide giving substituted succinate 1.

Scheme 3 Preparation of compounds of this invention where "Y" is -O- is shown in Scheme 4. The known acetonide 19 (British Biotechnology PCT application WO 94/02446) is first treated with a base such as potassium carbonate then with an alkenyl halide such as allyl bromide. Acidic removal of the acetonide group using, for instance, aqueous hydrogen chloride gives the corresponding hydroxy acid which is subjected to treatment with a base such as potassium carbonate and benzyl bromide giving alcohol 20. O-Allcylation of 20 using sodium hydride and allyl bromide followed by palladium catalyzed ester deprotection using, for instance, tetrakis(triphenylphosphine)palladium (0) gives allyl ether 21. Coupling of 21 with 2 followed by hybroboration and cyclization as described in Scheme 1 above provides macrocycle 22.

Hydrogenolytic removed of the benzyl ester using, for instance, hydrogen and 10% palladium on carbon gives acid 23 which can be converted to macrocyclic hydroxamate 24 as described above.

Scheme 4 Benzimidazole-containing macrocycles are prepared according to Scheme 5. o-Amino amide 25, prepared as described in Scheme 1 wherein HNR13R14 is 1 ,2-phenylenediamine, is heated with an acid such as camphor sulfonic acid to generate benzimidazole 26. Conversion of this compound to the corresponding carboxylic acid 27 and hydroxamate 28 is accomplished by analogy with the sequence shown in Scheme 1.

Scheme 5 r H2N 1 A < 26: W = -Ot-butyl II J I 22: W=-OH L iB: W=-NHOH ¼ :W= -NHOH Macrocyclic olefins such as 30 are prepared by treating aryl iodide 29 with a suitable palladium catalyst, for instance tetrakis(triphenylphosphine)pallaium (0), and an amine base such as triethylamine and heating in a solvent such as acetonitrile. Olefin 30 is converted to the corresponding acid 31 and hydroxamate 32 according to the sequence outlined in Scheme 1.

Scheme 6 R2 0 R2 I I R1 H R3 R1 Th R' 0 0) ¼¼;R3z L li:W=-OH X > E 31 W=-OH 29 32:W= NHOH Tryptophan-derived macrocycles are prepared according to Scheme 7. Alcohol 33 is converted to a suitable leaving group, for example by reaction with p-toluenesulfonyl chloride in the presence of a tertiary base such as pyridine to give tosylate 34. This compound is subjected to phase-transfer alkylation conditions using, for example, potassium hydroxide and benzyltrimethyl ammonium chloride in a mixture of water and methylene chloride. The resulting macrocyclic ester 35 is converted to the corresponding acid 36 and hydroxamate 37 according to the sequence outlined in Scheme 1.

Scheme 7 rl O R1L- H R3Z W O R1i HR3 c h o R W=-Ot-butyl 33: X = -OH Nv afi:W=-OH 34: X = -OTs ~ / 37:W= -NHOH

p-Aminophenylalanine-derived compounds of this invention are prepared as outlined in Scheme 8. Alcohol 38 is first converted to its mesylate using methanesulfonyl chloride and a tertiary amine base such as triethylamine. Hydrogenation of this material using 10% palladium on carbon and triethylamine in a solvent such as iso-propanol generates macrocyclic ester 39 directly.

Conversion to acid 40 and hydroxamate 41 is accomplished by the reaction sequence shown in Scheme 1. Alcohol 38 can also be oxidized to acid 42 using, for example, chromic acid in sulfuric acid. Hydrogenation of the aromatic nitro group is achieved using hydrogen over a palladium catalyst. Lactam formation is completed by treatment with a coupling agent such as bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP-Cl) in the presence of a tertiary amine base such as triethylamine giving 43 which is converted to the corresponding acid 44 and hydroxamate 45 as outlined in Scheme 1.

Scheme 8 r > RAf HN4Z = g HNtz A00{3z 0 : W = -OtuWI HO, :W=-OH 3B o2N H 41: W = -NHOH a E £: W R2 R1 NHR3Z J4: W = Ir""c' HO C / o ) 44:W=-OH { ° O N u X W = -NHOH H Carbamate and urea-derived macrocycles can be prepared according to Scheme 9. Alcohol 46 is treated with bromoacetyl bromide in the presence of sodium carbonate. The resulting ester 47 is subjected to hydrogenation conditions using, for example 10% palladium on carbon in the presence of a tertiary amine base such as triethylamine which gives macrocycle 48. The tert-butyl ester group of 48 can be converted to acid 49 and to hydroxamate 50 under the conditions illustrated in Scheme 1. Alcohol 46 is converted to the corresponding methanesulfonate 51 by reaction with methanesulfonyl chloride in the presence of triethylamine. Mesylate 51 is reacted with trimethylsilyl azide in the presence of tri-n-butylammonium fluoride to produce azide 52.

This compound can be subjected to hydrogen over a palladium catalyst and the resulting diamine treated with a phosgene derivative such as carbonyldiimidazole to generate urea . Conversion of

this ester to the corresponding acid 54 and hydroxamate 55 is accom,plished as described in Scheme 1.

Scheme 9 r | R R t H R3 R Rr t H R3 3/z NC,Z x ))W)oNZp W=-Ot-butyl X 0 N'O H C 49: W=-OH ~ X = -OCOCH2Br 50: W N -OCOCH2Br H R' 82 - Xf N R3 z 4fN R3z > O $ C 53: W = -Ot-butyl L 51: X = -oMsphAOJ2N N>N E 54: W = -OH L~~ 2. X- -N3 H 55: W - -NHOH The preparation of macrocyclic lactones is shown in Scheme 10. Hydrogenolysis of the benzyl ester of 55 isd achieved using hydrogen over a palladium catalyst. The resulting hydroxy acid is treated with 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine in a suitable solvent such as tetrahydrofuran to produce 56. This ester can be converted to the correspodning acid 57 and hydroxamate 58 as described in Scheme 1.

Scheme 10 o AiR2 N<,Z Xf ½ o } p ° | E h: W = W=-OH ° KPh °< E 57: W = -OH I\ 55 I 58: W=-NHOH The foregoing may be better understood by reference to the following examples which are presented for illustration and are not intended to limit the scope of the invention as defined in the appended claims.

Preparation of Succinate Ester 1 Step 1 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 <BR> <BR> the excess reagent through a 10 cm Vigreux column. The acid chloride was then distilled to give i<BR> (48.3 g, 84 %), bp 135-138 °C.

Step 2: To a -78 °C solution of 4S-benzyl-2-oxazolidinone (62.2 g, 0.35 mole) in THF (600 mL) was addedn-butyllithium (140 mL, 2.5 M in hexane) 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, 1M sodium bicarbonate, water and brine, dried over sodium sulfate, filetred and concentarted. The residue was distilled discarding a small forerun to give ii (92.9 g, 96%), bp 154-156 °C/0.15 mm.

Step 3:

To a mechanically-stirred -78 °C solution of ii (92.9 g, 0.337 mole) in THF (1L) was added solution bis(trimethylsilyl)amide (375 mL, 1M 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 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) mp 101-102 °C. The mother liquors were concentrated and the residue was purified by chromatography on silica gel (5 - 10% ethyl acetate- hexane) and the product fraction crystallized to yield 7.6 g more for a total of 112.2 g (85 %).

Step 4: To a 0 °C solution of iii (112.2 g, 0.288 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 waashed werll with water. The filtrate 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 1M 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.

Step 5 To a -78 °C solution of lithium diisopropylamide, prepared by the addition of n- butyllithium (11.4 ml, 28.4 mmol, 2.5M 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 1hour and then butenyl iodide (2.58 g, 1.42 mmol) was added by syringe. This mixture was allowed to warm to ambient temperature and stir overnight. 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 1M NaHSO4 and brine, dried with MgSO4 filtered and concentrated. Flash chromatography (2%-5% isopropanol-hexane) gave epimeric succinates v (2.30 g, >9:1 synlanti) as a clear liquid.

Step 6 To a -78 °C solution of lithium diisopropylamide, prepared by the addition of n- butyllithium (7.8 ml, 19.5 mmol, 2.5M 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 (22.3 g, 8.1 mmol) in THF (10 mL) at -78 °C by cannula in a stream. The resulting clear, yellow solution was stirred at -78 °C for 1 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 1M NaHSO4 and brine, dried with MgSO4, 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).

Preparation of Succinate Ester 2 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 3 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 Step 1 H3C - --- - °-- I mixture of isomers A mixture under nitrogen of 4-bromotoluene (36.9 mL, 51.3 g, 0.3 mole), 4-pentenoic acid (30.6 mL, 30.0 g, 0.3 mole), acetonitrile (500 mL), triethylamine (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 1 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, and dried over sodium hydroxide to give vii (45 g) as a mixture of isomers which was used without further purification.

Step 2 The mixtureof isomers vii was hydrogenated in 600 mL THE 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 (, 33 g, mp 77-78 "C).

Step 3 A mixture of 30b (11.02 g, 57 mmole) and 12mL thionyl chloride was at 24 °C for 18 hours and then heated to distill most of the excess thionyl chloride. Short path distillation gave 11.74 g (97 %) of 5-(4-tolyl)pentanoyl chloride (30c, bp ~ 110 °C at 0.35 mm).

Step 4 To a 78 °C solution of 4S-benzyl-2-oxazolidinone (10.36 g, 58 mmole) in THF (150 mL) was added n-butyllithium (23.5 mL 2.5M) over 25 minutes. After 230 minutes, 30c (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 partitioned between water and ethyl acetate. The organic was washed with water, aqueous 1M 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 30d (17.83 g, 89%).

Step 5 The desired compound was prepared using Steps 4, 5 and 6 and of the preparation of succinate ester 1, except substituting x for iii and substituting 5-bromo-1-pentene for 4-bromo-1-butene.

Preparation of Succinate Ester 5 The desired compound was prepared using step 5 of the procedure for the preparation of succinate ester 4, except substituting TBDMSO(CH2)4I (10.8g, 34.5mmol), prepared as described by Heiquist et al., Tetrahedron Lett., 1985, 26, 5393, for 5-bromo-1-pentene.

Preparation of Succinate Ester 6 Step 1 To a 0 °C solution in anhydrous mIF (100 mL) of methyl 3-butenoate (97%, 10.0 g, 96.9 mmol)was added 9-BBN (0.5 M in THF, 194 mL, 97 mmol) dropwise via dropping funnel. After the addition was completed, the reaction mixture was stirred at ambient temperature for 5 hours.

To the resulting solution was added anhydrous THF (300 mL), tetrakis(triphenylphosphine)palladium(0) (3.03 g, 2.62 mmol), 1 -bromo-4-propylbenzene (98%, 13.8 mL, 87 mmol), and powdered sodium methoxide (95%, 7.72 g, 136 mmol). The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and ported into saturated aqueous ammonium chloride. The mixture was extracted twice with ether. The combined organic extracts were washed with brine, dried with MgS O4 and concentrated to afford crude product as a light brown oil. Flash chromatography (CH2Cl2-hexane, 1:4) afforded xii (6.4 g).

Step 2 The desired compound was prepared by hydroysis of ester xiii, followed by conversion of the carboxylic acid to succinate ester 6 according to steps 3, 4 and 5 of the preparation of succinate ester 4, substituting TBDMSO(CH2)41, for 5-bromo-l -pentene.

Preparation of Succinate Ester 7 The desired compound was prepared according to the procedure used to prepare succinate ester 1, except substituting TBDMSO(CH2)4L for 4-bromo- 1 -butene.

Preparation of Succinate Ester 8 The desired compound was prepared in the same manner as succinate ester 5, except replacing acid viii with 6-benzyloxy hexanoic acid.

Preparation of Succinate Ester 9 The desired compound was prepared in the same manner as succinate ester 5, except replacing acid viii with 4-pentenoic acid.

Example 1 Example 1 A To a solution of succinate ester 1, benzyltyrosine tosylate salt (8.1 g, 18.4 mmol, Aldrich Chemical Co.), HOBT (2.5 g, 18.4 mmol) and NMM (4 mL, 36.8 mmol) in 80 mL DMF at 0°C was added EDC (3.5 g, 18.4 mmol) in a single portion. The resulting solution was allowed to slowly warm to ambient temperature and was stirred for 3 days at which time it was poured into a sepratory funnel containing water and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate (3x) and the combined organic layers were washed with aqueous 1M NaHSO4, aqueous 1M NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was flash chromatographed (CH2Cl2 to 2% methanol-CH2Cl2) to afford 8.26 g of intermediate 1b as a white foam.

Example 1B To a solution of lb (8.25 g, 15.4 mmol) dissolved in 77 mL THF at 0 "C was added BH3 solution (1 M in THF, 51.3 mL, 51.3 mmol) dropwise by syringe over 10 minutes. The resulting solution was stirred at 0 "C for 1.5 hours. Ethanol (15.4 mL) was added over 5 minutes followed by pH 7 buffer (30 mL) and 30% H2O2 solution (30 mL). After 10 minutes, the cooling bath was

removed and the cloudly mixture was stirred at ambient temperature for 2.5 hours at which time it was concentrated to half the original volume and added to a mixture of brine and and ethyl acetate.

The separated aqueous layer was extracted with ethyl acetate (3x) and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Flash chromatography (2% methanol-CH2Cl2 then 5% methanol-CH2Cl2) gave 7.62 g of intermediate 1c as a white foam.

Example 1C To a solution of 1c (4.54 g, 8.19 mmol) and Bu3P (4.1 mL, 16.4 mmol) in 800 mL benzene at ambient temperature was added ADDP (4.13 g, 16.4 mmol) in a single portion. The solution was stirred at ambient temperature for 2 hours and then concentrated in vacuo. The residue was suspended in a minimal amount of CH2Cl2 and flash chromatographed (30% ethyl acetate-hexane) to give cyclic intermediate 1d (3.1 g) as a white solid.

Example 1D A mixture of ld (3.1 g, 5.77 mmol) and 10% Pd/C catalyst (620 mg) in 30 mL methanol was stirred under a positive hydrogen pressure for 3 hours. The reaction mixture was then filtered through Celite with methanol washings. The filtrate was concentrated in vacuo to give cyclic intermediate le (2.54 g) as a white solid which was used without further purification.

Example 1E To a solution of 1e (510 mg, 1.14 mmol) dissolved in 6 mL DMF at 0 °C was added NMM (150 µL, 1.37 mmol), HOBT (185 mg, 1.37 mmol), EDC (263 mg, 1.37 mmol) and 4-(2- aminoethyl)benzenesulphonamide (274 mg, 1.37 mmol, Aldrich Chemical Co.). The resulting clear solution was stirred overnight at ambient temperature and then poured into a mixture of water and ethyl acetate. The separated aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Flash chromatography (3% methanol-CH2Cl2) afforded 1f (758 mg) as a white solid.

Example 1F A mixture of 1f(717 mg, 1.14 mmol), trifluoroacetic acid (5 mL) and CH2Cl2 (1 mL) was stirred at ambient temperature for 1 hour and then concentrated under a stream of nitrogen. The residue was dissolved in 1:1 mix of CH2Cl2-methanol and concentrated in vacuo. This was repeated until a white solid formed to give 630 mg 1a which was used without purification.<BR> <P> Example 1G To a 0 °C solution in DMF (8 mL) of la (630 mg, 1.1 mmol) was added NMM (242 uL, 2.2 mmol), HOBT (178 mg, 1.32 mmol) and EDC (253 mg, 1.32 mmol). After 15 minutes at 0

°C, O-(tert-butyldimethylsilyl)hydroxyl amine (194 mg, 1.32 mmol) was added in a single portion and the mixture was allowed to warm to ambient temperature and stir overnight. The solution was then poured into a mixture of brine and CH2Cl2. The aqueous layer was extracted twice with CH2Cl2 and the combined organic layers were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The crude solid was flash chromatographed (5% methanol-CH2Cl2) to give 183 mg of the desired compound as a white solid. mp > 270°C. H NMR (DMSO) # -0.6-(-0.4) (m, 1H), 0.6-1.0 (m, 5H), 0.71 (d, 3H, J = 6.3 Hz), 0.80 (d, 3H, J = 6.3 Hz), 1.1-1.4 (m, 2H), 1.5-1.7 (m, 3H),2.1 (dt, 1H, J = 10.8, 2.7 Hz), 2.5-2.6 (m, 1H), 2.75-2.85 (m, 2H), 3.02 (dd, 1H, J = 12.9,4.8 Hz), 3.3-3.4 (m, 2H), 3.9-4.1 (m, 2H), 4.5-4.7 (m, 1H), 6.90 (d, 2H, J = 8.7 Hz), 7.21 (t, 2H, J = 8.7 Hz), 7.29 (br s, 2H), 7.40 (d, 2H, J = 8.1 Hz), 7.75 (d, 2H, J = 8.1 Hz), 7.80 (d, 1H, J = 9.6 Hz), 7.89 (t, 1H, J = 5.7 Hz), 8.66 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) # 21.9, 24.5, 25.0, 25.3, 28.4, 28.7, 35.1, 37.0, 39.8, 41.1, 46.9, 53.8, 73.2, 121.3, 121.5, 125.9, 129.0, 129.4, 132.4, 132.7, 142.4, 143.8, 157.4, 170.4, 171.5, 173.0.

MS (CI) m/e 589 (M+1). Anal. Calcd for: C29H40N4O7S.0.4H2O: C,58.45; H, 6.90; N, 9.40.

Found: C, 58.49; H, 6.94; N, 9.20; [α] +55° (c 0.5, DMF).

Example 2 The desired compound was prepared according to the method of Examples 1E-G, except substituting phenethylamine for 4-(2-aminoethyl)benzenesulphonamide, mp>270°C. H NMR (DMSO) # -0.6-(-0.4) (m, 1H), 0.6-1.0 (m, 4H), 0.70 (d, 3H, J = 6.3 Hz), 0.80 (d, 3H, J = 6.3 Hz), 1.1-1.4 (m, 2H), 1.5-1.7 (m, 3H), 2.0-2.1 (m, 1H), 2.5-2.6 (m, 1H), 2.7-2.8 (m, 2H), 3.0-3.1 (m, 1H), 3.2-3.4 (m, 2H), 3.9-4.1 (m, 2H), 4.55-4.65 (m, 1H), 6.90 (d, 2H, J = 8.4 Hz), 7.15-7.35 (m, 7H), 7.8-7.9 (m, 2H), 8.68 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) # 21.6, 24.2, 24.7, 24.9, 28.4, 35.1, 36.7, 40.0, 40.8, 46.6, 53.5, 72.9, 120.9, 121.1, 126.0, 128.2, 128.5, 128.7, 132.0, 132.4, 139.2, 157.0, 170.0, 171.1, 172.7. MS (CI) m/e 510 (M+I). Anal. Calcd for: C29H39N3O5: C, 68.34; H, 7.71; N, 8,24. Found: C, 68.00; H, 7.78; N, 8.05. [a] +18° ( c 0.5, DMF).

Example 3 The desired compound was prepared according to the method of Examples 1E-G, except substituting cyclopropylamine for 4-(2-aminoethyl)benzenesulphonamide. mp > 270 "C. 1H NMR (DMSO) -0.6-(-0.4) (m, 1H), 0.3-0.4 (m, 2H), 0.6-0.7 (m, 2H), 0.71 (d, 3H, J = 6 Hz), 0.8 (d, 3H, J = 6 Hz), 0.7-1.0 (m, 5H), 1.1-1.3 (m, 2H), 1.5-1.7 (m, 3H), 2.04 (apparent t, 1H, J = 12 Hz), 2.5-2.7 (m, 2H), 3.04 (dd, 1H, J = 12.8,4.1 Hz), 3.9-4.1 (m, 2H), 4.5-4.6 (m, 1H), 6.90 (d, 2H, J = 8.4 Hz), 7.15-7.25 (m, 2H), 7.7-7.85 (m, 2H), 8.69 (s, 1H), 10.3 (s, 1H).

13C NMR (DMSO) 5.60, 5.83, 21.6, 22.2, 24.2, 24.7, 24.9, 28.0, 28.4, 36.5, 40.8, 46.0, 46.5, 53.4, 72.9, 120.9, 121.2, 128.6, 132.0, 132.4, 157.0, 170.0, 172.2, 172.6. MS (CI) m/e 446 (M+1). Anal. Calcd for C24H35N3O50.3H2O: C, 63.92; H, 7.96; N, 9.32. Found: C, 63.86; H, 7.96; N, 9.39. [a] +17° (c 0.5, DMF).

Example 4 The desired compound was prepared according to the method of Examples 1E-G, except substituting aniline for 4-(2-aminoethyl)benzenesulphonamide. mp > 270°C. H NMR (DMSO) # -0.5-(-0.4) (m, 1H), 0.6-1.0 (m, 4H), 0.67 (d, 3H, J = 6.3), 0.81 (d, 3H, J = 6.3 Hz), 1.1-1.4 (m, 2H), 1.5-1.65 (m, 2H), 1.69 (dt, 1H, J = 10.8, 2.4 Hz), 2.12 8 (dt, 1H, J = 10.5, 2.7 Hz), 2.69 (br t, 1H, J = 12.6 Hz), 3.9-4.0 (m, 1H), 4.0-4.1 (m, 1H), 4.75-4.90 (m, 1H), 6.9-7.0 (m, 2H), 7.07 (t, 1H, J = 7.2 Hz), 7.25-7.40 (m, 4H), 7.60 (d, 2H, J = 7.8 Hz), 7.98 (d, 1H, J = 9.6 Hz), 8.70 (s, 1H), 10.0 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) # 21.6, 24.2, 24.7, 25.0, 28.1, 28.4, 36.7, 40.8, 46.0, 46.6, 54.4, 73.0, 119.1, 121.0, 121.3, 123.3, 128.8, 132.1, 132.3, 138.8, 157.1, 170.0, 170.1, 172.9. MS (CI) m/e 482 (M+1). Anal. Calcd for

C27H35N3O5-H2O: C, 64.91; H, 7.46; N, 8.41. Found: C, 64:85; H, 7.16; N, 8.29. [a] +38° (c 0.4, MeOH).

Example 5 The desired compound was prepared according to the method of Examples 1 E-G, except substituting morpholine for 4-(2-aminoethyl)benzenesulphonamide. mp > 270 "C. 1H NMR (DMSO) -0.6-(-0.4) (m, 1H), 0.6-1.0 (m, 4H), 0.71 (d, 3H, J = 6.3 Hz), 0.78 (d, 3H, J = 6.3 Hz),1.14 (dt, 1H, J = 10.8, 2.7 Hz), 1.2-1.4 (m, 1H), 1.45-1.55 (m, 2H), 1.68 (dt, 1H, J = 11.1, 3.0 Hz), 2.10 (dt, 1H, J = 11.4, 3.3 Hz), 2.79 (t, 1H, J = 12.6 Hz), 2.9-3.0 (m, 1H), 3.4-3.8 (complex m, 8H), 3.9-4.1 (m, 2H), 5.0-5.1 (m, 1H), 6.89 (d, 2H, J = 8.4 Hz), 7.27 (t, 2H, J = 7.3 Hz),8.00 (d, 1H, J = 9.6 Hz), 8.67 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) 8 21.6, 24.0, 24.8, 25.0, 28.2, 28.5, 40.3, 40.9, 45.7, 46.5, 48.9, 66.1, 72.8, 120.7, 120.8, 129.1, 131.9, 132.2, 157.1, 169.7, 170.0, 172.5. MS (CI) m/e 476 (M+1).

Anal. Calcd for C2H37N306+0.5H2O: C, 61.96; H, 7.90; N, 8.67. Found: C, 61.86; H, 7.68; N, 7.24. [a] +65° (c 0.4, MeOH).

Example 6 The desired compound was prepared according to the method of Examples 1 E-G, except substituting 2-aminopyridine for 4-(2-aminoethyl)benzenesulphonamide. mp > 270 "C. 1H NMR (DMSO) 8 -0.6-(-0.4) (m, lH), 0.6-1.0 (m, 4H), 0.68 (d, 3H, J = 6.3 Hz), 0.83 (d, 3H, J = 6.3 Hz), 1.1-1.4 (m, 2H), 1.5-1.8 (m, 3H), 2.13 (dt, 1H, J = 10.8, 2.7 Hz), 2.66 (t, 1H, J = 12.0

Hz), 3.28 (dd, 1H, J = 12.3, 6.0 Hz), 3.9-4.0 (m, 1H), 4.0-4.1 (m, 1H), 4.8-5.0 (m, 1H), 6.9- 7.0 (m, 2H), 7.1-7.2 (m, 1H), 7.25-7.40 (m, 2H), 7.83 (dt, 1H, J = 8.1, 1.8 Hz), 7.99 (d, 1H, J = 9.6 Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.35 (dd, 1H, J = 5.4, 2.1 Hz), 10.3 (br s, 1H), 10.5 (s, 1H). 13C NMR (DMSO) # 21.6, 24.2, 24.8, 25.0, 28.4, 36.3, 40.8, 46.1, 46.7, 54.6, 73.1, 113.6, 119.6, 121.1, 121.6, 128.8, 132.2, 132.4, 139.0, 147.4, 151.4, 157.3, 170.0, 171.1, 173.2. MS (CI) m/e 483 (M+1). Anal. Calcd for C26H34N4O5.H2O: C, 62.38; H, 7.24; N, 11.19. Found: C, 62.04; H, 7.44; N, 9.70. [a] +34° (c 0.6, MeOH).

Example 7 Example 7A The desired compound was prepared using the procedure described for example 1E, except substituting 1,2-phenylenediamine for 4-(2-aminoethyl)benzenesulphonamide.

Example 7B

A solution of 7b and camphorsulfonic acid (60 mg) in 15 mL toluene and 5 mL THF was stirred at reflux for 3 hours. The resulting brown solution was cooled, concentrated and flash chromatographed (3% methanol-CH2Cl2) to afford 7c (1.0 g) as a light tan solid.

Example 7C The desired compound was prepared from 7c according to the method of Examples 1F and G. mp > 270 "C. 1H NMR (DMSO) 8 -0.5-(-0.3) (m, 1H), 0.6-1.0 (m, 4H), 0.59 (d, 3H, J = 6.3 Hz), 0.64 (d, 3H, J = 6.3 Hz), 1.1-1.4 (m, 2H), 1.6-1.8 (m, 3H), 2.0-2.1 (m, 1H), 3.07 (t, 1H, J = 12.9 Hz), 4.0-4.2 (m, 2H), 5.4-5.5 (m, 1H), 6.96 (apparent d, 2H, J = 6.3 Hz), 7.1-7.2 (m, 2H), 7.32 (br t, 2H, J = 6.9 Hz), 7.4-7.5 (m, 2H), 8.18 (d, 1H, J = 9.0 Hz), 8.69 (s, 1H), 10.3 (s, 1H), 12.2 (s, 1H). 13C NMR (DMSO) 8 21.6, 24.1, 24.7, 28.1, 28.5, 38.0, 40.9, 46.1, 46.6, 47.9, 72.9, 111.3, 118.5, 121.1, 121.2, 121.9, 128.8, 132.2, 132.5, 154.9, 157.2, 170.1, 172.6. MS (CI) m/e 479 (M+1). Anal. Calcd for C27H34N404*1.4H2O: C, 64.37; H, 7.36; N, 11.12. Found: C, 64.47; H, 7.41: N, 10.35. [a] -39" (c 0.5, DMF).

Example 8 Example 8A

To a 0°C solution in DMF (40 mL) of BOC-L-tyrosine (2.81 g, 10 mmol) and HOBT (3.70 g, 27 mmol) was added methylamine hydrochloride (675 mg, 10 mmol) and NMM (3.16 mL, 2.9 mmol) and the mixture was stirred for 30 minutes. EDC (2.76 g, 14 mmol) was added and stirring was continued for 2 hours in the ice bath and then at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous ammonium chloride and was extracted twice with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and the filtrate concentrated to a yellow oil. A minimum amount of ethyl acetate was added and the suspension heated until a solution resulted. Crystallization was allowed to occur at room temperature and 8a as a while solid was collected by filtration (1.97g, 67% yield).

Example 8B K 6:1 u o v cho 2H t-B u o )9 syn:ant u O JX CO2H t-BuO 002H t-BuO CO2H t-BuO CO2H ¼ Step 1: To a -78°C solution in THF (8 mL) of diisopropylamine (541 mg, 5.35 mmol) was added butyllithium (2 ml, 5 mmol, 2.5M in hexanes) dropwise and the solution was stirred for 15 minutes. A mixture of (R)-iso-butylsuccinic acid tert-butylester (0.5g, 2.17 mmol) in DMPU (1 mL) and THF (3 mL) was added dropwise. The resulting yellow solution was stirred for one hour at -70 "C and a solution of 4-bromo-1-butene (354 mg, 2.62 mmol) in THF (3 mL) was added dropwise over 8 minutes. The reaction mixture was stirred for 1 hour at -70 OC and a solution of Lii (35 mg, 2.62 mmol) in THF (1 mL) was added dropwise. The cold bath was removed and stirring was continued overnight at ambient temperature. The reaction mixture was poured into saturated aqueous ammonium chloride and ethyl acetate and the organic layer set aside. The aqueous layer was washed once with ethyl acetate and the organics combined, dried over MgSO4, filtered and the filtrate concentrated to a yellow oil which was purified by flash chromatography on silica gel (15% ethyl acetate-hexanes) to yield 244 mg of 8b as a yellow gum(40% yield). Isomer ratio approximately 6:1.

Step 2: To a -78 "C solution in THE (7 mL) of diisopropylamine (523 mg, 5.17 mmol) was added butyllithium (1.93 ml, 4.83 mmol, 2.5M in hexanes) dropwise and the solution was stirred for 15 minutes. A solution of 8b (611 mg, 2.15 mmol) in THF (8 mL) was added dropwise. The reaction mixture was warmed to -200C and stirred for 15 minutes before being cooled to -78C and quenched with a solution of methanol(356 mg, 11 mmol) in 2 ml THF. The reaction mixture was warmed to room temperature and mixed with saturated aqueous ammonium chloride and the pH

was adjusted to 4 with added dilute HCl. The solution was extracted twice with ethyl acetate and the organic extracts were combined, dried over MgSO4, filtered and the filtrate concentrated to a to give 8b (594 mg) as a yellow gum having an isomer ratio determined by CMR to be 1:1.5 syn: anti.

Example 8C To a solution of BOC-L-tyrosine-N-methyl amide (8a, 627 mg, 2.13 mmol) in THF (2 ml) was added 4M HCl-dioxane (6 mL) dropwise. The resulting yellow solution was stirred for 4 hours at ambient temperature and then concentrated to dryness. The residue was azeotroped twice with toluene and once with ether leaving an off-white solid which was added to an ice-bath-cooled flask containing compound 8b (561 mg, 1.97 mmol), HBOT (716 mg, 5.3 mmol), NMM (562 mg, 5.6 mmol) and DMF (8 mL). The resulting orange solution was stirred for 30 and EDC (534 mg, 2.79 mmol) was added as a solid. Stirring in the ice bath was continued for 2 hours and then at room temperature overnight. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted 3 times with ethyl acetate. The organic extracts were combined, dried, filtered and the filtrate concentrated to a yellow oil which was purified by flash chromatography(4% methanol-methylene chloride) to give 8c (783 mg, 86% yield) as a white powder.

Example 8D The desired compound 8d was prepared from 8c by hydroboration/oxidation according to the method of Example 1C.

Example 8E To a -5°C solution of triphenylphosphine (419 mg, 1.6 mmol) in methylene chloride (20 mL) was added dropwise a solution of diethylazodicarboxylate (249 mg, 1.43 mmol) in methylene chloride (20 mL) and the solution stirred for 30 minutes. A solution of 8d (465 mg, 0.97 mmol) in methylene chloride (120 mL) was added dropwise and the solution was stirred for 1 hour. The reaction mixture was poured into brine and the organic layer set aside. The aqueous phase was washed with ethyl acetate and the organic layers were combined, dried and concentrated to a yellow gum which was purified by flash chromatography (50% ethyl acetate-hexanes) to give the desired compound 8e (75 mg).

Example 8F The desired compound 8f was prepared by saponification of 8e using trifluoroacetic acid in dichloromethane according to the method of Example 1F.

Example 8G

To a 0°C solution of 8g (50 mg, 0.125 mmol) in DMF (0.8 mL) was added NMM(19 mg, 0.19 mmol),a solution of HOBT (19 mg, 0.14 mmol) in DMF (0.2 mL) and EDC (27mg, 0.14 mmol). After stirring for 15 minutes, a solution of O-tert-butyldimethylsilylhydroxylamine (21 mg, 0.14 mmol) in DMF (0.2 mL) was added and stirring was continued for 30 minutes in the ice bath and the at ambient temperature for 3 days. The reaction mixture was diluted with saturated aqueous ammonium chloride and was extracted twice with ethyl acetate. The combined organic extracts were dried and concentrated to a clear gum. The gum was mixed with diethyl ether and the resulting suspension filtered to give 32 mg of a white solid (61% yield). A portion (9.8 mg) of this material was dissolved in a mixture of 1.5 ml acetonitrile, 0.5 ml methanol and 2.0 ml water and loaded onto a C-18 reverse phase HPLC column and eluted with a gradient from 10% acetonitrile/90% water to 70% acetonitrile/30% water. The faster eluting peak was collected and concentrated to give the anti compound as a white powder (3.1 mg) and the slower eluting peak was collected and concentrated to give the syn compound as a white powder (3.4 mg).

Anti: 1H NMR (300 MHz, DMSO-d6) 6 10.41 (s, 1H), 8.69 (s, 1H), 7.79-7.87 (c, 1H), 7.69-7.76 (c, 1H), 7.51-7.67 (c, 1H), 7.16-7.28 (c, 1H), 6.87-6.96 (c, 2H), 4.53-4.64 (c, 1H), 3.88-4.13 (c, 2H), 3.01-3.11 (c, 1H), 2.54-2.69 (c, 4H), 2.00-2.13 (c, 1H), 1.51-1.73 (c, 3H), 1.12-1.36 (c, 2H), 0.84-0.95 (c, 1H), 0.80 (d, 3H, J = 6Hz), 0.71 (d, 3H, J = 6Hz), 0.50-0.67 (c, 1H). 13C NMR (300 MHz, DMSO-d6) 8 172.68, 172.65, 171.56, 157.03, 132.05, 128.64, 121.26, 120.99, 97.75, 72.97, 53.49, 46.61, 45.97, 40.83, 36.75, 28.38, 28.04, 25.45, 24.93, 24.75, 24.22, 21.60. IR, (KBr) 3300, 2950, 2940, 1640, 1530, 1510, 1210, 1190 cm-l. MS (DCI/NH3) m/e 420(m+H)+.

Syn:1H NMR (300 MHz, DMSO-d6) 8 9.90 (bs 1H), 7.94-8.01 (c, 1H), 7.40 (d, 1H, J = 6 Hz), 7.05 (dd, 1H, J = 1.5, 4.5 Hz), 6.73-6.79 (c, 2H), 6.66-6.71 (c, 1H), 5.66-5.74 (c, 1H), 3.96-4.03 (c, 1H), 3.81-3.90 (c, 1H), 2.91 (dd, 1H, J = 3, 9 Hz), 2.45 (d, 3H, J = 3 Hz), 2.23- 2.29 (c, 1H), 1.94 (d, 1H, J = 6 Hz), 1.60-1.70 (c, 1H), 1.21-1.31 (c, 2H), 1.00-1.10 (c, 1H), 0.88-1.00 (c, 2H), 0.72-0.82 (c, 1H), 0.49 (d, 3H, J = 3 Hz), 0.43 (d, 3H, J = 3 Hz), -0.01-(- 0.09) (c, 1H). 13C NMR (300 MHz, DMSO-d6) d 171.8, 171.2, 170.5, 159.5, 130.8, 130.6, 130.0, 119.2, 119.1, 70.3, 52.0, 49, 45.7, 38.5, 33.4, 30.2, 25.9, 25.4, 23.4, 22.5, 21.5, 21.4. MS (DCI/NH3) m/e 420 (M+H)+.

Example 9

The desired compound was prepared according to the method of Examples 8C-F. except substituting allyl bromide for 4-bromo-1-butene in Example 8B.

Example 10 Thde desired compound was prepared from the compound of Example 9 according to the method of Examples 8G. H NMR (300 Mz, DMSO-d6) # 10.30 (s, 1H) 8.69 (bs, 1H), 7.81 (d, 1H, J = 6 Hz), 7.62 (dd, 1H, J = 3, 3 Hz), 7.05-7.17 (c, 3H), 6.81 (dd, 1H, J = 4.5, 1.5 Hz), 4.65-4.73 ((c, 1H), 4.08-4.15 (c, 1H), 3.98-4.05 (c, 1H), 3.15 (dd, 1H, J = 3, 4.5 Hz), 2.62 (d, 3H, J = 3 Hz), 2.54 (d, 1H, J = 7.5 Hz), 2.00 (dt, 1H, J = 6, 1.5 Hz), 1.59 (dt, 1H, J = 7.5, 1.5 Hz), 1.10-1.27 (c, 4H), 0.73-0.79 (c, 7H), 0.70 (d, 2H, J = 3 Hz), 0.57-0.68 (c, 1H),- 0.61--0.72 (c, 1H). 13C NMR (300 MHz, DMSO-d6) d 172.7, 171.5, 169.6, 158.3, 132.7, 132.5, 128.9, 122.0, 120.0, 72.9, 53.0, 46.7, 46.1, 39.9, 36.7, 29.9, 29.3, 25.4, 25.1, 24.0, 21.2 IR (KBr) 3300, 2960, 2920, 1660, 1640, 1530, 1510, 1220 cm-1. MS(FAB(+)) m/e 428(M+Na)+, 406(M+H)+.

Example 11 The desired compound was prepared according to the method of Example 1A-C, F and G, except substituting succinate ester 3 for succinate ester 1, and substituting 8e for benzyltyrosine tosylate salt. mp > 300C. NMR (MHz, DMSO-d6) # -0.25-(-0.1) (m, 1H), 0.6-0.71 (m, 1H), 0.72 (d, 3H, J = 6.9 Hz), 0.82 (d, 3H, J = 6.3 Hz), 0.85-1.39 (m, 8H), 1.4-1.59 (m, 1H), 1.6-1.75 (m, 1H), 2.14-2.24 (m, 1H), 2.58-2.60 (m, 1H), 2.61 (d, 3H, J = 4.8 Hz), 2.86-2.91 (m, 1H), 4.08-4.22 (m, 2H), 4.4-4.55 (m, 1H), 6.81 (d, 1H, J = 8.1 Hz), 6.92 (1, 8.1H), 7.2- 7.24 (m, 2H), 7.71 (d, 1H, J = 4.8 Hz), 7.93 (d, 1H, J = 9 Hz), 8.69 (s, 1H), 10.3 (s, 1H). MS

(DCI/NH3) m/e 434 (M+H)+. Anal. calcd for C23H35N3O5.0.5H2O: C, 62.42; H 8.19: N, 9.49.

Found: C, 62.69; H, 8.12; N, 9.45. | a ] + 31° (c 0.3, DMF).

Example 12 Example 12A The desired compound 12a was prepared according to the method of Example 8B, except substituting 6-bromo-1-hexene for 4-bromo-1-butene.

Example 12B The desired compound was prepared according to the method of Examples IA-F, except substituting 12a for succinate ester 1.

Example 12C To a 0 °C solution of 12b (0.21, 0.49 mmol) in DMF (4 mL), was added NMM (200 pl, 1.8 mmol), HOBT (80mg, 0.59 mmol) and EDC (113mg, 0.59 mmol). After 15 minutes at 0 C O-benzylhydroxylamine hydrochloride (95mg, 0.59 mmol) was added in a single portion and the mixture was allowed to warm to room temperature with stirring overnight. The turbid solution was added to water and 5% methanol/CH2C12. The aqueous layer was extracted twice with CH2C12 and the combined organic layers were concentrated. The crude material was triturated in 5:1 ether/methanol and the solid collected by filtration to give 109mg of the O-benzylhydroxamate.

This material was dissolved in 75ml of 70:30 THF/MeOH and treated with 10mg of 10% Pd/C under 1 atm of H2 for 2hours. The catalyst was filtered off and the solution concentrated to give the desired anti isomer (35mg) as a white solid. 1H NMR (DMSO) 80.1-0.2 (m, 1H), 0.73 (d, 3H, J = 6.6 Hz), 0.75-1.15 (m, 6H), 0.85 (d, 3H, J = 6.3 Hz), 1.2-1.44 (m, 3H), 1.5-1.8 (m, 4H), 2.2-2.32 (m, 1H), 2.60 (d, 3H, J = 4.8 Hz), 2.62-2.73 (m, 1H), 2.80-2.90 (m, 1H), 4.15- 4.23 (m, 2H), 4.33-4.50 (m, 1H), 6.92 (d, 2H, J = 8.1 Hz), 7.23 (d, 2H, J = 8.4 Hz), 7.93 (d, 1H, J = 4.2 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.72 (s, 1H), 10.38 (s, 1H). MS (DCI/NH3) m/e 448 (M+H)+. Anal. calcd for C24H37N3O5.0.25H2O: C, 63.76; H, 8.36; N, 9.29. Found: C. 63.74; H, 8.32; N, 8.43. [a] +2° (c 0.2, DMF).

Example 13

Example 1 3A The desired compound 13a was prepared by coupling of 12a and p-iodo-phenylalanine-N- methylamide hydrochloride using the described above for the preparation of la.

Example 1 3B To s solution of the compound of 13a (0.65g, 1.93 mmol) in acetonitrile (25 mL) in a glass bomb was added triethylamine (1.63 ml, 16 mmol). Argon was bubbled through the solution for five minutes followed by rapid addition of tetrakis(triphenylphosphine)palladium(0) (127mg, 10 mol%). The bomb was then sealed and heated at 80 C for 2hours. After cooling, the solution was concentrated and purified by flash chromatography (40% ethyl acetate-hexanes) to give the desired compound 13b (146mg9 as a white solid.

Example 13C

The desired compound was prepared from 13b according to the method of Examples 1F and G. H NMR (DMSO) # -0.7-(-0.4) (m, 1H), 0.42-2.2 (series of m, 12H), 0.6-0.7 (narrow m, 3H). 0.8-0.9 (narrow m. 3H), 2.6-2.7 (narrow m. 3H), 3.0-3.2 (m, 3H), 4.2-5.0 (m, 3H), 7.0-8.0 (m, 6H), 8.6-8.7 (m, 1H). MS (DCI/NH3) m/e 430 (M+H)+.

Example 14 Example 14A To a 0°C solution of nBuLi (2.5M/Hexanes, 14.25 mL) in diethyl ether (5mL) was added bromobenzene (5.55g, 35.6mmol) over a few minutes. The resulting yellow solution allowed to stir cold for 45 minutes and then was cannulated into a -78°C solution of N-Boc-O-tBu-L-tyrosine (3.0g, 8.9mmol) in diethyl ether (75mL). The reaction mixture was warmed to 0°C over 1.5 hours and then was quenched with 2N citric acid. The aqueous layer was extracted twice with diethyl ether and the combined organic extracts were washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. Flash chromatography (hexane-ethyl acetate 9:1) afforded the desired compound 14a (1.84 g) which was carried on without further purification.

Example 14B

A solution of the ]4a (1.8 g. 4.7mrnol) in trifluoroacetic acid was stirred at 0@ for 30 minutes, The excess trifluoroacetic acid was evaporated in lfacus. The residue was taken up in 1N HCl in ether and stirred for 30 minutes. The mixture was diluted with diethyl either (70mL) and the resulting solid filtered. The extremely hygroscopic solid was dried in a vacuum oven for several hours, transferred into a round bottom flask and dried under high vacuum for 16 hours to give the desired compound ]4b (0.48 g) as a hygroscopic, white HCI salt.

Example 14C The desired compound was prepared from 14b and succinate ester 3 according to the method of Examples 1A-C. mp 210-220° (Dec.) H NMR (300 MHz, DMSO-d6) # 10.30 (s, 1H), 8.63 (s, 1H), 8.17-8.14 (d, 9.2H), 8.10-8.07 (d, 2H, J = 8.5 Hz), 7.66-7.63 (t, 1H, J = 7.3 Hz), 7.56-7.51 (t, 2H, J = 7.8 Hz), 7.43-7.40 (d, 1H, J = 8.5 Hz), 7.25-7.22 (d, 1H, J = 8.4 Hz), 6.96-6.94 (d, 1H, J = 8.5 Hz), 6.85-6.83 (d, 1H, J = 8.5 Hz), 5.68-5.61 (m, 2H), 3.09-3.03 (m, 1H), 2.77-2.68 (m, 1H), 2.17-2.13 (m, 1H), 1.71-1.69 (m, 1H), 1.50-1.49 (m, 1H), 1.34-1.31 (m, 2H), 1.16-1.05 (m, 3H), 0.78-0.62 (m, 5H), 0.47-0.45 (d, 3H, J = 7.3 Hz), 0.00-(-)0.08 (m, 1H). MS (DCI/NH3) m/e 481 (M+H)+. Anal calcd for C28H36N2O5.0.5H2O: C. 68.68; H, 7.61; N, 5.72. Found: C, 68.88: 1H, 7.88; N, 5.10. [α]D: +21.3°(c = 0.46, DMF).

Example 15 Example 15A

To a solution of methylmagnesium bromide (35 ml, 3.0M in Et2O, 105.6 mmol) in dry toulene(140ml) was added pyrrole (12 ml, 171.9mmol) dropwise at -40°C under nitrogen. The resulting solution was then stirred at -10 °C for 10 minutes and then was cannulated into a solution of BOC-L-tyrosine methyl ester (3.9g, 13.2mmol) in dry toluene (40ml) at -65 °C. The temperature was allowed to warm to -10 °C over 4 hours and the reaction was quenched by addition of 2N citric acid. The reaction mixture was extracted with CH2Cl2 (3x), dried over Na2SO4, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (30% ethyl acetate-hexanes) to give the desired compound 15a (2.46 g, 56%) as a light brown foam.

Example 15B Compound 15a (720mg, 2.18mmol) was dissolved in trifluoroacetic acid (5ml) and stirred at room temperature for 5 minutes. The solvent was evaporated to give 15b (900mg) as a brown oil which was used without further purification.

Ecample 15C The desired compound was prepared according to the method of Example 14C, except substituting 15b for 14b. m.p. 242 °C (dec.) H NMR (300 MHz, DMSO-d6) # -0.02-(-0.15) (m, 1H), 0.53-0.88 (m, 4H), 0.61 (d, 3H, J = 3 Hz), 0.79 (d, 3H, J = 3 Hz), 0.90-1.04 (m, 1H), 1.07-1.40 (m, 5H), 1.42-1.60 (broad, 1H), 1.65-1.76 (dt, 1H, J = 3.9 Hz), 2.19-2.30 (dt, 1H, J = 3, 12 Hz), 2.65-2.78 (1H), 3.0-3.1 (dd, 1H, J = 3, 15 Hz), 4.04-4.07 (m, 2H), 5.21- 5.32 (m, 1H), 6.24-6.28 (m, 1H), 6.81-6.88 (dd, 1H, J = 3.9 Hz), 6.91-6.99 (dd, 1H, J = 3, 9 Hz), 7.14 (1H), 7.25-7.34 (m, 2H), 7.39-7.46 (dd, 1H, J = 3, 9 Hz), 8.12 (d, 1H, J = 9 Hz), 8.69 (s, 1H), 10.31 (s, 1H), 11.93 (s, 1H). MS (DCI/NH3) m/e 470 (M+H)+. Anal calcd for

C26H35N3O5@H2O: C, 64.04; H, 7.64; N, 8.61. Found: C, 64.00; H, 7.61; N, 8.44. [α]D: +97.3°(c = 0.26. EtOH).

Example 16 Example 16A To a solution of N-tertbutoxycarbonyl p-nitro-phenylalanine (Sigma) (0.78 g, 2.51 mmol) in DMF (12-5 mL) was added EDC (0.53 g, 2.77 mmol), HOBT (0.37 g. 2.77 mmol), NMM (0.30 g, 2.77 mmol) and methylamine hydrochloride (0.19 g, 2.77 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture 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 over MgSO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography (60% ethyl acetate-hexanes) to give 16a (0.8 g, 98%).

Example 16B The desired compound was prepared by deprotection of 16a by treatment with trifluoroacetic acid according to the procedure of Example l5B, followed by coupling with succinate ester 3 and hydroboration/oxidation using the method of Examples 1A and B.

Example 1 6C To a solution of the compound 16b (207 mg, 0.397 mmol) in CH2C12 was added Jones' reagent dropwise until the orange color of the reagent was preserved, then ethyl alcohol was added dropwise to quench the excess Jones' reagent (the color changed to green). The mixture was evaporated to a small volume and partitioned between CH2C12 and brine. The aqueous phase pH was adjusted to 2. The aqueous phase was extracted with CH2C12 (3x). The combined CH2C12 extracts were dried (MgSO4), filtered and evaporated to give the desired compound 16c (209 mg) which was used without further purification.

Example 16D A mixture of 16c (205 mg, 0.383 mmol) and 10% Pd/C (40 mg) in EtOH was stirred under H2 (1atm) for 2 hours. The rection mixture was filtered through Celite and the rsidue was washed thoroughly with 10% methanol-CH2Cl2. The filtrate and washings were collected and evaporated to dryness to give 16d (193 mg) as a pale brown solid which was used without further<BR> purification.

Example 16E To a solution of 16d (190 mg, 0.376 mmol) in CH2Cl2 (4 mL) was added triethylamine (156.9 mL, 1.13 mmol) followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (43.7 mg, 0.564 mmol). After stirring at room temperature for 2 hours, the mixture was poured into CH2Cl2 and washed with saturated aqueous NaHCO3 and brine. The aqueous layer was then extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (MgSO4), filtered and evaporated to dryness. Flash chromatography (2%-5% methanol-CH2Cl2) gave 16e /87.7 mg).

Example 16F The desired compound was prepared from 16e according to the method of Example 1F and G. mp: >250 °C. H NMR (300 MHz, DMSO-d6) # -0.09 (m, 1H), 0.78 (d, 3H), J = 6.2 Hz), 0.85 (d, 3H, J = 6.2 Hz), 0.78-0.85 (m, 2H), 1.10-1.40 (m, 6H), 1.60-1.75 (m, 2H), 2.12 (m, 1H), 2.22 (m, 1H), 2.63 (d, 3H, J = 4.5 Hz), 2.74 (t, 1H, J = 13.2 Hz), 2.99 (dd, 1H, J = 13.2, 3 Hz), 4.5 (m, 1H), 7.10 (m, 2H), 7.37 (m, 2H), 7.84 (bs, 1H), 8.08 (bs, 2H), 9.09 (s, 1H), 10.15 (bs, 1H). MS (DCI-NH3) 447 (M+H)+, 429, 403, 282.

[α] = +50.0 ° (c=0.11, CH3OH).

Example 17 Example 17A To a solution of 16b (449 mg, 0.863 mmol) in CH2C12 was added triethylamine (0.18 mL, 1.29 mmol) and methanesulfonyl chloride (0.080 mL, 1.04 mmol). After stirring at room temperature for 0.5 hours, the mixture was poured into CH2C12 and washed with NaHCO3 and brine. The CH2C12 was dried (MgSO4), filtered and evaporated to dryness. Flash chromatography (40-80% ethyl acetate-hexanes) gave 17a (428 mg, 83%) as white crystals.

Example 17B A mixture of 17a (420 mg, 0.701 mmol), 10%Pd/C (50 mg) and triethylamine (0.098 mL, 0.701 mmol) in isopropanol (4 mL) was stirred under H2 (latm) for 10 hours. The reaction mixture was filtered through Celite and the residue was washed thoroughly with 10% methanol- CH2C12. The filtrate and washings were combined and evaporated to dryness. Flash chromatography (2-5% methanol-CH2C12) provided 17b (280.4 mg, 84.4%) as white crystals.

Example 17C The desired ompound was prepared from 17b according to the method of Example 1F. mp 194-196 °C (dec.) H NMR (500 MHZ, DMSO-d6, 30 °C) # 0.03 (t, 1H, J = 11 Hz), 0.74 (d, 3H, J = 6.1 Hz), 0.67-0.84 (m, 3H), 0.85 (d, 3H, J = 6.1 Hz), 1.03-1.08 (m, 4H), 1.32- 1.38 (m, 3H), 1.89 (dt, 1H, J = 11.2, 3.4 Hz), 3.0 (dt, 1H, J = 11.1, 3.4 Hz), 2.62 (d, 3H, J = 4.8 Hz), 2.66 (t. 1H. J = 12.5 Hz), 2.98 (dd, 1H, J = 12.5, 4.2 Hz), 3.17 (m, 2H), 4.5 (m, 1H), 7 (bs, 1H), 7.09 (bs, 1H), 7.18 (bs, 1H), 7.31 (bs, 1H), 7.76 (q, 1H, J = 4.8 Hz) 8.05 (d, 1H.

J = 9.1 Hz), 12.07 (bs, 1H). MS (DCI-NH3) 418 (M+H)+, 401, 229. Anal calcd for C23H35N3O4@1.8CF3COOH@1.8H2O: C, 48.83; H, 6.22; N, 6.42. Found: C, 48.68; H, 6.30; N.6.73 [α] = -10.7 ° (c=0.14, CH3OH) Example 18 Example 18A

To a solution of 17b (230mg, 0.486 mmol) in THE (4 mL) was added saturated NaHCO3 (3 mL) followed by benzyl chloroformate (0.083 mL, 0.583 mmol). The mixture was stirrined at ambient temperature for 2 hours and then was evaporated to a small volume. The residue was partitioned between CH2C12 and brine. The aqueous layer was separated and extracted with twice with CH2Cl2 and the combined CH2C12 layers were dried, filtered and evaporated to dryness.

Flash chromatography (60%-80% ethyl acetate-hexanes) yielded 18a (264 mg, 89.7%) as a white solid.

Example 18B The desired compound was prepared from 18a according to the procedure of Examples 1F and G. mp: >250 °C. 1H NMR (DMSO) 8 0.0 (m, 1H), 0.65-0.90 (m, 3H), 0.79 (d, 3H, J = 6.2 Hz), 0.89 (d, 3H, J = 6.2 Hz), 1.02-1.40 (m, 7H),1.73 (dt, 1H, J = 11.4, 3.0 Hz), 2.30 (dt, 1H, J = 11.5, 3.0 Hz), 2.68 (d 3H, J = 4.8 Hz), 2.77 (d, 1H, J = 13.2 Hz), 3.02 (dd, 1H, J = 13.2, 3 Hz), 3.71 (m, 1H), 3.93 (m, 1H), 4.57 (m, 1H), 5.14 (s, 2H), 7.16 (dd, 1H, J = 7.5, 0.6 Hz), 7.26 (m, 1H), 7.37-7.41 (m, 7H), 7.83 (q, 1H, J = 4.8 Hz), 8.13 (d, 1H, J = 9 Hz), 8.76 (s, 1H), 10.36 (s, 1H). MS (DCI-NH3) m/e 567 (M+H)+, 523, 356. Anal. calcd for C31H42N4O6@0.4H2O: C, 64.87; H, 7.51; N, 9.76. Found: C, 64.79; H, 7.32; N, 9.8. [a] = - 42.4 ° (c=0.13, CH30H) Example 19

A mixture of the compound of Example 18 (27.0 mg, 0.048 mmol) and 10% Pd/C (5 mg) in THF-MeOH (10:1, 22 mL) was stirred under H2 (latm) for 4 hours. The mixture was filtered through Celite, and the residue was washed thoroughly with 10% MeOH/CH2Cl2. The filtrate and washings were combined and evaporated to dryness. Flash chromatography (5%-8%-10% methanol-CH2Cl2) gave the desired compound (10.3 mg, 50%). mp 258-260 OC (dec). 1H NMR (500 MHz, DMSO-d6) 8-0.06 (t, 1H, J = 11 Hz), 0.72 (d, 3H, J = 6.5 Hz), 0.82 (d, 3H, J = 6.5 Hz), 0.72-0.82 (m, 4H), 0.88-1.10 (m, 3H), 1.18-1.32 (m, 2H), 1.52 (bs, 1H), 1.69 (m, 1H), 2.18 (m, 1H), 2.53 (d, 1H, J = 13 Hz), 2.60 (d, 3H, J = 4.5 Hz), 2.17 (dd, 1H, J = 13, 2.5 Hz), 3.08 (bs, 2H), 4.42 (m, 1H), 5.11 (m, 1H), 6.50 (d, 1H, J = 7.5 Hz), 6.59 (d, 1H, J = 7.5 Hz), 7.02 (t, 2H, J = 5.5 Hz), 7.60 (q, 1H, J = 4.5 Hz), 7.81 (d, 1H, J = 9 Hz), 8.64 (s, 1H), 10.27 (s, 1H). MS (DCI-NH3) m/e 433 (M+H)+, 415, 389. Anal calcd for C23H36N404-0.8 CF3COOH0.8 CH3COOH.0.8 THF: C, 56.60; H, 7.70; N, 9.23. Found: C, 56.37; H, 7.79; N, 9.09.

Example 20 Example 20A The desired compound was prepared according to the method of Examples lA-C, F and G, except substituting succinate ester @ for succinate ester 1. mp > 270 °C. 1H NMR (DMSO) 8 - 0.3-(-0.1) (m, 1H), 0.6-0.9 (m, 3H), 0.63 (d, 3H, J = 6.6 Hz), 0.72 (d, 3H, J = 6.6 Hz), 0.9- 1.0 (m, 1H), 1.0-1.6 (m, 6H), 0.6-0.7 (m, 1H), 2.19 (dt, 1H, J = 11.1, 3.3 Hz), 2.67 (t, 1H, J = 13.2 Hz), 3.2 (dd, 1H, J = 13.2, 3.3 Hz), 4.1-4.3 (m, 2H), 4.7-4.8 (m, 1H), 5.15 (apparent AB, 2H, J = 12.6 Hz), 6.8-7.0 (m, 2H), 7.22 (d, 2H, J = 8.4 Hz), 7.3-7.4 (m, 5H), 8.12 (d, 1H, J = 9.0 Hz), 8.69 (s, 1H), 10.3 (s, 1H). MS (DCI/NH3) 511 (M+H)+. Anal calcd for

C29H38N2O6@0.5H2O: C, 67.03; H, 7.56; N, 5.39. Found: C, 67.18; H, 7.57; N, 5.32. [a] +9° (c 0.4, MeOH).

Example 21 The desired compound was prepared by hydrogenation of the compound of Example 20 using the procedure of Example 1D except substituting THF for methanol. mp>250 °C. H NMR (DMSO) # -0.2-(-0.1) (m, 1H), 0.6-1,4 (m, 9H), 0.72 (d, 3H, J = 6.6 Hz), 0.83 (d, 3H, J = 6.6 Hz), 1.4-1.6 (m, 2H), 1.6-1.75 (m, 1H), 2.15-2.3 (m, 1H), 2.62 (t, 1H, J = 12.9 Hz), 3.1-3.2 (m, 1H), 4.1-4.25 (m, 2H), 4.5-4.6 (m, 1H), 6.8-7.0 (m, 2H), 7.20 (apparent t, 2H, J 8.4 Hz), 7.99 (d, 1H, J = 9.3 Hz), 8.70 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) # 21.45, 21.53, 22.0, 22.1, 24.1, 24.3, 24.5, 25.4, 28.1, 35.7, 40.9, 46.1, 46.2, 53.3, 65.9, 114.7, 117.7, 118.5, 128.3, 129.7, 130.4, 131.1, 154.0, 170.0, 173.0, 173.1. MS (DCI/NH3) m/e 421 (M+H)+. Anal calcd for C22H32N2O6@1.4H2O: C. 59.28; H, 7.87; N, 6.28. Found: C, 59.36; H, 7.51; N, 6.13. [α] +28° (c 0.3, MeOH).

Example 22 The dsired compound was prepared according to the method of Examples 1E, F and G, except substituting N,N-dimethylethylenediamine for 4-(2-aminoethyl)benzenesulphonamide. mp 121-124°C. H NMR (DMSO) # -0.6-(-0.4) (m, 1H), 0.6-1.0 (m, 3H), 0.71 (d, 3H, J = 6.6 Hz), 0.79 (d, 3H, J = 6.6 Hz), 1.1-1.4 (m, 3H), 1.5-1.7 (m, 3H), 2.0-2.2 (m, 1H), 2.62 (t, 1H, J = 13.5 Hz), 3.0-3.2 (m, 3H), 3.3-3.6 (m, 2H), 3.9-4.1 (m, 2H), 4.4 (br s, 1H), 4.6-4.7 (m, 1H), 6.92 (d, 2H, J = 8.4 Hz), 7.15-7.30 (m, 2H), 7.84 (d, 1H, J = 9.3 Hz), 8.15 (t, 1H, J =

5.7 Hz), 9.50 (br s, 1H). MS (DCI/NH3) m/e 477 (M+H)+. Anal calcd for C25H40N4O5@1.5 TFA@0.3H2O: C, 51.50; H, 6.50; N, 8.58. Found: C, 51.53; H, 6.62; N, 8.39. [α] +41° (c 0.3, H2O).

Example 23 Example 23A A solution of 23a (1.19g, 2.06 mmol, prepared according to the method of Examples 1A- E, except substituting succinate ester 3 for succinate ester 1 and substituting commercially available 2-aminoacetophenone hydrochloride for 4-(2-aminoethyl)benzenesulphonamide) and ammonium acetate (4.56g, 59.4 mmol) in 10 mL acetic acid at 115 OC was stirred for 6 hours and then cooled to ambient temperature. The acetic acid was removed under vacuum and the orange solid was redissolved in 100 mL ethyl acetate and 50 mL H2O. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered and concentrated. This material was flash chromatographed (CH2C12 then 2% MeOH/CH2Cl2) to give 23b (856 mg) as a brick-red foam.

Example 23B The desired compound was prepared as a white solid from 23b using the procedure of Examples 1F and G. mp > 250°C. H NMR (DMSO) # -0.1-0 (m, 1H), 0.6-0.9 (m, 1H), 0.68 (d, 3H, J = 6.3 Hz), 0.85 (d, 3H, J = 6.3 Hz), 0.9-1.4 (m, 7H), 1.4-1.8 (m, 3H), 2.2-2.3 (m, 1H), 2.88 (t, 1H, J = 12.9 Hz), 3.22 (dd, 1H, J = 13.5,4.2 Hz), 4.1-4.3 (m, 2H), 5.1-5.3 (m, 1H), 6.8-7.0 (m, 2H), 7.1-7.2 (m, 1H), 7.25-7.35 (m, 4H), 7.53 (d, 1H, J = 1.8 Hz), 7.76 (d, 2H, J = 6.9 Hz), 8.01 (d, 1H, J = 9.3 Hz), 8.66 (s, 1H), 10.3 (s, 1H), 11.8 (s, 1H). MS (DCI/NH3) m/e 519 (M+H)+. Anal Calcd for C30H38N4O4.1.3H2O: C, 66.47; H, 7.55; N, 10.34. Found: C, 66.60; H, 7.60; N, 10.23. [α] -35° (c 0.8, MeOH).

Example 24 The desired compound was prepared according to the method of Examples 1A-C, F and G, except substituting commercially succinate ester 3 for succinate ester L and substituting commercially-available O-benzyl-(L)-proline hydrochloride for 4-(2- aminoethyl)benzenesulphonamide. mp > 250 °C. 1H NMR (DMSO) o -0.3-(-0.1) (m, 1H), 0.6- 0.9 (m, 3H), 0.70 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.6 Hz), 0.9-1.0 (m, 1H), 1.0-1.4 (m, 5H), 1.4-1.6 (m, 1H), 1.6-1.7 (m, 1H), 1.8-2.1 (m, 3H), 2.1-2.3 (m, 2H), 2.60 (t, 1H, J = 13.2 Hz), 2.8-2.9 (m, 1H), 3.75-3.85 (m, 2H), 4.1-4.3 (m, 2H), 4.37 (dd, 1H, J = 8.7, 5.1 Hz), 4.7- 4.8 (m, 1H), 5.13 (AB pattern, 2H), 6.8-7.0 (m, 2H), 7.26 (d, 2H, J = 9.0 Hz), 7.3-7.4 (m,

5H), 8.07 (d, 1H, J = 9.0 Hz), 8.69 s, 1H), 10.3 (s, 1H). MS (DCI/NH3) m/e 608 (M+H)+.

Anal calcd for: C34H45N3O7@0.8H2O: C, 65.54; H, 7.55; N, 6.75. Found: C, 65.69; H, 7.09; N, 6.68. [α] -9 °(c 0.3, MeOH).

Example 25 The desired compound was prepared as an off-white solid from the compound of Example 24 using the hydrogenolysis procedure of Example 21. mp > 250 °C. H NMR (DMSO) # -0.2-(- 0.1) (m, 1H), 0.6-0.8 (m, 3H), 0.70 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.6 Hz), 0.9-1.0 (m, 1H), 1.0-1.4 (m, 5H), 1.4-1.6 (m, 1H), 1.6-1.7 (m, 1H), 1.8-2.1 (m, 3H), 2.1-2.3 (m, 2H), 2.65 (t, 1H, J = 13.2 Hz), 2.9-3.0 (m, 1H), 3.7-3.9 (m, 2H), 4.1-4.3 (m, 3H), 4.6-4.7 (m, 1H), 6.8-7.0 (m, 2H), 7.2-7.3 (m, 2H), 8.06 (d, 1H, J = 9.3 Hz), 8.68 (s, 1H), 10.3 (s, 1H), 12.1- 12.4 (br s, 1H). 13C NMR (DMSO) + 21.7, 22.2 24.2, 24.7, 24.9, 25.5, 28.3, 28.7, 35.1, 40.8, 46.1, 46.3, 46.6, 52.4, 58.7, 66.1, 117.9, 118.6, 128.7, 130.4, 131.4, 154.1, 169.8, 170.1, 173.0, 173.4 MS (DCI/NH3) m/e 518 (M+H)+. Anal calcd for C27H39N3O7@1.0H2O: C, 60.54; H, 7.71; N, 7.84. Found: C, 60.53; H, 7.73; N, 7.51. [α] +16° (c 0.3, MeOH).

Example 26 The desired compound was prepared as an off-white solid according to the method of Examples 1A-E, except substituting succinate ester 3 for succinate ester 1 and omitting 4-(2- aminoethyl)benzenesulphonamide and substituting methanol for DMF in Example 1E. mp > 250°C. H NMR (DMSO) # -0.25-(-0.1) (m, 1H), 0.6-1.0 (m, 4H), 0.75 (d, 3H, J = 6.6 Hz),

0.84 (d, 3H, J = 6.6 Hz), 1.0-1.2 (m, 2H), 1.2-1.4 (m, 2H), 1.4-1.6 (m, 2H), 1.6-1.7 (m, 1H), 2.22 (dt, 1H, J = 11.4, 3.3 Hz), 2.64 (t, 1H, J = 13.2 Hz), 3.1-3.2 (m, 1H), 3.65 (s, 3H), 4.1- 4.3 (m, 2H), 4.6-4.7 (m, 1H), 6.8-7.0 (m, 2H), 7.2-7.25 (m, 2H), 8.10 (d, 1H, J = 9.6 Hz), 8.71 (s, 1H), 10.33 (s, 1H). 13C NMR (DMSO) # 21.4, 22.1, 24.0, 24.3, 24.6, 25.4, 28.1, 35.4, 40.9, 46.15, 46.24, 51.8, 52.9, 65.9, 117.8, 118.6, 128.3, 129.9, 131.2, 154.1, 169.9, 170.2, 173.2. MS (DCI/NH3) (M+H)+. Anal calcd for C23H34N2O6@0.4H2O: C, 62.54; H,7.94; N, 6.34. Found: C, 62.59; H, 7.81; N, 6.22. [α] +24° (c 0.3, MeOH).

Example 27 The desired compound was prepared as a white solid according to the method of Example 1, except substituting succinate ester 3 for succinate ester 1 and substituting piperidine for 4-(2- aminoethyl)benzenesulphonamide. mp > 250°C. H NMR (DMSO) # -0.2-0 (m, 1H), 0.6-0.8 (m, 1H), 0.71 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.3 Hz), 0.9-1.05 (m, 1H), 1.05-1.8 (m, 14H), 2.1-2.2 (m, 1H), 2.7-2.8 (m, 2H), 3.2-3.3 (m, 1H), 3.5-3.7 (m, 3H), 3.75-3.85 (m, 1H), 4.0-4.3 (m, 2H), 4.9-5.0 (m, 1H), 6.8-6.9 (m, 1H), 6.9-7.0 (m, 1H), 7.2-7.3 (m, 2H), 8.03 (d, 1H, J = 9.0 Hz), 8.67 (d, 1H, J = 1.5 Hz), 10.29 (d, 1H, J = 1.5 Hz). 13C NMR (DMSO) # 21.7, 22.1, 24.1, 24.2, 4.9, 25.3, 26.3, 28.2, 35.9, 40.9, 42.5, 46.0, 46.3, 49.8, 66.0, 117.9, 118.3, 118.4, 128.8, 130.5, 131.4, 154.1, 169.5, 170.1, 172.7. MS (DCI/NH3) m/e 488 (M+H)+. Anal calcd for C27H41N3O5@0.4H2O: C, 65.54; H, 8.51; N, 8.49. Found: C, 65.64; H, 8.49; N, 8.39. [α] +78 ° (c 0.25, MeOH).

Example 28

The desired compound was prepared as a white solid according to the method of Example 1, except substituting succinate ester 3 for succinate ester 1 and substituting dimethylamine hydrochloride for 4-(2-aminoethyl)benzenesulphonamide. mp > 250 °C. H NMR (DMSO) #- 0.2-0.0 (m, 1H), 0.6-0.8 (m, 2H), 0.71 (d, 3H, J = 6.6 Hz), 0.81 (d, 3H, J = 6.3 Hz), 0.9-1.0 (m, 1H), 1.1-1.6 (m, 6H), 1.65-1.75 (m, 1H), 2.20 (dt, 1H, j = 11.1, 3.0 Hz), 2.66 (t, 1H, J = 12.9 Hz), 2.84 (s, 3H), 2.8-2.9 (m, 1H), 3.19 (s, 3H), 4.05-4.25 (m, 2H), 4.9-5.0 (m, 1H), 6.8-7.0 (m, 2H), 7.2-7.3 (m, 2H), 8.03 (d, 1H, J = 9.3 Hz) 8.67 (d, 1H, J = 2.1 Hz), 10.30 (d, 1H, J = 1.5 Hz). MS (DCI/MH3) m/e 448 (M+H)+. Anal calcd for C24H37N3O5@0.7H2O: C, 62.64; H, 8.41; N, 9.13. Found: C, 62.80; H, 8.30; N, 8.87 [α] +53° (c 0.3, MeOH).

Example 29 Example 29A 1 -tert-butvldimethvlsilvl-3-bromoindole To a cold (-78°) solution of indole (4.0g, 34mmol) in THF (120mL) was added nBuLi (2.5M/Hexanes) over 5 minutes. The solution was warmed to -100 (ice/salt bath) for 15 minutes, re-cooled to -78" and TBDMS-C1 (5.8g, 38mmol) was added in THE (30mL). The solution was held at 0° for 3 hours, cooled to -78" and N-Bromosuccinirnide (6.0g, 34mmol) was added in one portion. The solution was stirred coldfor 2 hours and then was allowed to warm to ambient temperature at which time hexane/pyridine (100mL/1mL) was added to the solution and the resulting suspension was filtered over Celite. The organics were evaporated and the residue quickly purified by flash chromatography (hexanes/methylene chloride 2: 1) giving 8.5g of the desired compound as a slightly purple solid.

Example 29B To a 0°C solution of nBuLi (2.5M/hexanes, 9.6 mL) in diethyl ether (10 mL) was added 1- tert-butyldimethylsily-3-bromoindole (7,4g, 24 mmol) in diethyl ether (5 mL). The resulting pale yellow solution was stirred cold for 25 minutes then was added to a -78°C solution of N-tert- butoxycarbony-O-tert-butyl-L-tyrosine (2.0g, 6mmol) in diethyl ether (150 mL). The solution was warmed to 0°, held for 1 hour, and quenched with saturated aqueous NH4Cl (25mL). The aqueous layer was extracted with diethyl ether (3x), and the combined organics washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Flash chromatography (gradient elution; 0.5-2% acetone/hexane) gave 0.5g of 29b as a reddish foam.

Example 29C To a solution of 29b (1.4g, 2.56mmol) in 30 mL dry THF was added 2.6mL tetrabutylammonium fluoride (1M in THF) over 1 minute. The greenish solution was stirred at ambient temperature for 1 hour and diluted with diethyl ether. The organics were washed with water (2x) and brine, dried (MgSO4), fileterd and concentrated in vacuo to give 29c (1.3 g) as a reddish foam.

Example 29D

The desired compound was prepared according to the method of Examples 14B and C, except substituting 29c for 14a. mp 250° (dec.) H NMR (DMSO-d6) # 12.00 (s, 1H), 10.28 (s, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.21-8.15 (m, 2H), 7.48-7.44 (m, 2H), 7.29-7.16 (m, 3H), 6.91-6.82 (m, 2H), 5.41-5.38 (m, 1H), 4.31-4.05 (m, 2H), 3.06-3.01 (m, 1H), 2.88-2.80 (m, 1H) 2.25-2.17 (m, 1H), 1.72-1.71 (m, 1H), 1.81-1.67 (m, 1H), 1.35-1.23 (m, 1H), 1.16-106 (m, 4H), 0.77-0.43 (m, 8H), 0.01-(-)0.06 (m, 1H). MS (DCl/NG3) m/e 520 (M+H)+.

[α]D: +12.5°(c = 0.12, DMF).

Example 30 The desired compound was prepared according to the method of Examples 1A, B, C and Fm except substituting succinate ester 4 for succinate ester 1, and substituting L-tyrosine N- methylamide hydrochloride for benzyltyrosine tosylate salt. mp >270°C. H NMR (300 MHz, DMSO-d6) # 0.02-(-0.11) (complex, 1H), 0.56-0.85 (complex, 2H), 0.91-1.56 (complex, 10H), 1.86-1.97 (m, 1H), 2.08-2.19 (m, 1H), 2.24 (s, 3H), 2.30-2.64 (complex, 3H), 2.57 (d, 3H, J = 5.1 Hz), 2.95 (dd, 1H, J = 12.9, 3.0 Hz), 4.05-4.16 (m, 1H), 4.16-4.26 (m, 1H), 4.50 (m, 1H), 6.81 (dd, 1H, J = 2.1, 8.4 Hz), 6.93 (dd, 1H, J = 2.1, 8.4 Hz), 6.98-7.07 (complex, 4H), 7.15 (m, 1H), 7.22 (m, 1H), 7.75 (m, 1H), 8.12 (d, 1H, J = 9.0 Hz), 12.08 (s, 1H). MS (DCl/NH3) 495 (M+H)+, 391. Anal calcd for C29H38N2O5: C, 70.41; H, 7.74; N, 5.66. Found: C, 70.19; H, 7.66; N, 5.85.

Example 31

The desired compound was prepared from the compound of Example 30 according to the procedure of Example 1G. mp >270°C. H NMR (300 MHz, DMSO-d6) # -0.22-(-0.12) (complex, 1H), 0.62-0.73 (complex, 2H), 0.88-1.57 (complex, 9H), 1.68-1.79 (complex, 1H) 2.14 (m, 1H), 2.23-2.37 (m, 1H), 2.25 (s, 3H), 2.41-2.64 (m, 2H), 2.54 (d, 3H, J = 4.2 hz), 2.94 (m, 1H), 4.06-4.26 (m, 2H), 4.47 (m, 1H), 6.81 (dd, 1H, J = 2.4, 7.8 Hz), 6.92 (dd, 1H, J = 2.7, 8.1 Hz), 6.99-7.07 (complex, 4H), 7.16 (dd, 1H J = 2.4, 8.7 Hz), 7.22 (dd, 1H J = 2.4, 8.7 Hz), 7.66 (m, 1H), 8.05 (d, 1H, J = 9.0 Hz), 8.70 (s, 1H), 10.33 (s, 1H). MS (APCI) 510 (m+H)+, 492, 477, 461. Anal. Calcd for C29H39N3O5: C, 68.34; H, 7.71; N, 8.24. Found: C, 68.07; H, 8.00; N, 8.16.

Example 32 Example 32A The desired compound was prepared according to the method of Example 1A, except substituting succinate ester 5 for succinate ester 1.

Example 32B To a 0°C solution of epimeric amides 32b (1.67 g, 2.24 mmol) in THF (15 mL) was added tetrabutylammonium fluoride (1.0M in THF, 6.5 mL, 6.5 mmol) dropwise via syringe over 5 minutes. After 30 minutes the cooling bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours at which time it was poured into a separatory funnel containing H2O and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4, filtered and concentrated. Flash chromatography (50-80% EtOAc-hexanes) afforded 32c (1.23 g) as an epimeric mixture of diols as a colorless foam.

Example 32D The desired compound was prepared from 32c by ring closure, hydrolysis of the tert-butyl ester, conversion to the hydroxamic acid and debenzylation according to the method of Examples 1C, F, G and D. H NMR (300 MHz, DMSO-d6) # -0.4-(0.51) (m, 1H), 0.52-0.93 (m, 3H), 1.12-1.20 (m, 2H), 1.30-1.42 (m, 1H), 1.44-1.63 (m, 3H), 1.68-1.80 (m, 1H), 1.98-2.08 (m, 1H), 2.22 (s, 3H), 2.31-2.39 (m, 1H), 2.40-2.51 (m, 1H), 2.52-2.63 (m, 1H), 3.24 (dd, 2H, H = 4.5, 4.8 Hz), 3.91-4.14 (m, 2H), 4.58-4.7 (m, 1H), 6.89 (d, 2H, J=8.1 Hz), 7.01 (s, 4H), 7,18 (d, 2H, J = 8.4 Hz), 7.96 (d, 1H, J = 9.9 Hz), 8.70 (bs, 1H), 10.4 (s, 1H). MS (DCI/NH3) m/e 483 (m+H+). [α] (MeOH) = +24° (MeOH).

Example 33 Example 33A The desired compound was prepared according to the method of example 1A, except substituting succinate ester 6 for succinate ester 1, and substituting L-tyrosine N-methylamide hydrochloride for benzyltyrosine tosylate salt.

Example 33B The desired compound was prepared from 33e by desilyation according to the method of Example 32D, followed by ring closure and saponification of the tert-butyl ester according to the method of Examples 1C and F. mp 193-195°C. H NMR (DMSO-d6) # -0.30-(-0.17) (complex, 1H), 0.61-0.78 (complex, 1H), 0.79-0.98 (complex, 2H), 0.96 (t, 3H, J = 7.4 Hz), 1.30-1.66

(complex, 6H), 1.96-2.17 (complex, 2H), 2.37 (m, 2H), 2.44-2.60 (complex, 3H), 2.64 (d, 3H, J = 5.1 Hz), 3.10 (m, 1H), 4.05 (m, 2H), 4.66 (m, 1H), 6.89-6.96 (complex, 4H), 7.05 (d, 2H, J = 8.4 Hz), 7.20 (m, 2H), 7.89 (m, 1H), 8.02 (d, 1H, J = 9.6 Hz), 12.07 (s, 1H). MS (ESI+) 495(M+H), 464, 436. Anal calcd for C29H38N2O5. 0.75 H2O: C, 68.54; H, 7.83; N, 5.51.

Found: C, 68.63; H, 7.73; N, 5.40.

Example 34 The desired compound was prepared from the product of Example 33 according to the method of Example 1G. mp >260°C. H NMR (DMSO-d6) # -0.30-(0.17) (complex, 1H), 0.61- 0.95 (complex, 3H), 0.86 (t, 3H, J = 7.5 Hz), 1.28-1.40 (complex, 2H), 1.47-1.63 (complex, 4H), 1.73-1.85 (m, 1H), 2.06-2.16 (complex, 1H), 2.26-2.40 (complex, 2H), 2.24-2.59 (complex, 3H) 2.63 (d, 3H, J = 4.7 Hz), 3.09 (m, 1H), 3.91-4.18 (m, 2H), 4.62 (m, 1H), 6.89- 6.96 (m, 4H), 7.05 (d, 2H, J = 8.1 Hz), 7.18-7.24 (complex, 2H), 7.88 (m, 1H), 8.01 (d, 1H, J = 9.1 Hz), 8.66 (s, 1H), 10.33 (s, 1H). MS (ESI+) m/e 510 (M+H)+, 477. Anal calcd for C29H39N3O5; C, 68.34; H, 7.71; N, 8.24. Found: C, 68.06; H, 7.41; N, 8.14.

Example 35

Example 35A The desired compound was prepared according to the method of Examples 8A, C and D except substituting N-α-t-BOC-N-#-Cbz-L-lysine for BOC-L-tyrosine in Example 8A and substituting succinate ester 2 for 8b.

Example 35B To a -78 °C solution of oxalyl chloride (154 ul, 224 mg, 1.765 mmol) in anhydrous CH2Cl (3 mL) was added a solution of anhydrous DMSO (251 ul, 276 mg, 3.54 mmol) in anhydrous CH2Cl2 (3 mL) dropwise. The suspension was stirred for 1 hour at -70 °C and a solution of 35a (500 mg, 0.887 mmol) in anhydrous CH2Cl2 (3 mL) was added dropwise. The reaction mixture was stirred for 6 hours at -70 °C and triethylamin (390 ul, 282 mg, 2.80 mmol) was added and the resulting yellow solution was stirred for 1 hour at ambient temperature. The reaction mixture was diluted with saturated aqueous NH4Cl and CH2Cl2. The aqueous phase was washed with 10% isopropanol-CHCl3. the combined organic layers were dried over MgSO4 and filtered and the filtrate was concentrated leaving a yellow gum was purified using flash chromatography (3% methanol-CH2Cl2) to give 35b (411 mg) as a foamy white solid (82% yield).

Example 35C The desired compound was prepared by catalytic hydrogenation of 35b (methanol, palladium hydroxide on carbon, 1 atm. H2) for 3 days.

Example 35D The desired compound was prepared according to the method of Example 18, except substituting 35e for the compound of Example 17.

Example 35E

The desired compound was prepared according to the method of Examples 1F and G, except substituting 35d for 8e. H NMR (300 MHz, DMSO-d6) # 10.55 (s, 1H), 8.80 (s, 1H), 8.31 (d, 1H, J = 12 Hz), 7.65 (d, 1H, J = 12 Hz), 7.24-7.39 (c, 5H), 4.91-5.04 (c, 2H), 4.20- 4.30 (c, 1H), 2.99-3.35 (c, 5H), 2.76-2.85 (c, 1H), 2.73 (d, 3H, J = 3 Hz), 1.94-2.04 (c, 1H), 1.06-1.72 (c, 12H), 0.72-0.95 (c, 6H). 13C NMR (DMSO-d6): 173.1, 172.0, 169.7, 155.1, 136.2, 127.7, 127.0, 126.7, 65.4, 49.9, 49.4, 48.8, 48.7, 45.0, 28.8, 28.5, 27.1, 26.8, 26.6, 24.71, 24.70, 23.4, 23.4, 22.1, 20.9. MS (ESI) m/e 527(M+Na), 522(M+NH4), 505(M+H). IR (KBr) 3420, 2940, 1630, 1540 cm-1. HRMS (ESI) Theory: 505.3026. Found: 505.3023.

Example 36 The desired compound was prepared according to the method of Example 19, except, substituting the compound of Example 35 for the compound of Example 18.

Example 37 Example 37A

To a 0°C solution in dichloromethane (18 mL) of 35a (1.0 g, 1.77 mmol) was added triethylamine (697 µl, 506 mg, 5.0 mmol) followed by the dropwise addition of methanesulfonyl chloride (310 µl, 458 mg, 4.0 mmol). The reaction mixture was stirred at 0 °C for 30 minutes and then at ambient temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and water. The aqueous phase was washed once with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give 37a as a yellow gum (1.13 g) which was used without further purification.

Example 37B The desired compound was prepared by hydrogenation of 37a (methanol, 10% palladium on carbon, 1 atm H2) for 3 days.

Example 37C To a solution of 37b (732 mg, 1.44 mmol) in dichloromethane (40 mL) was added triethylamine (418 µL, 304 mg, 3.0 mmol) and a solution of 2-nitrobenzenesulfonyl chloride (335 mg, 1.5 mmol) in dichloromethane (8 mL) was added dropwise and stirring at was continued for 3 hours. The reaction solution was washed with water, saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated to give a green-brown solid which was purified using flash chromatography (3% MeOH-dichloromethane) to give 37 c as a white solid (591mg, 59% yield).

Example 37D Compound ZL(590mg, 0.85mmo1) was dissolved in anhydrous DMF (45ml) and to that solution was added K2CO3 (235mg, 1.7mmol) as a solid and the suspension stirred at RT over 3 days.

The reaction mixture was diluted with 40ml water and extracted 1 X 400ml with ether. The organic layer was dried over MgSO4, filtered and the filtrate concentrated to a yellow solid which was purified using flash chromatography eluting with 30% EtOAc/CH2Cl2 to give a white solid (166mg, 33% yield).

Example 37E The desired compound was prepared according to the method of Examples 1F and G, except substituting 37d for if. 1H NMR (300 MHz, DMSO-d6) # 10.46(d, 1H, J = 1.5 Hz), 8.78 (d, 1H, J = 1.5 Hz), 8.29 (bd, 1H, J = 9 Hz), 7.77-7.97 (c, 4H), 7.45-7.54 (c, 1H), 4.20-4.33 (c, 1H), 2.93-3.16 (c, 2H), 2.61-2.85(c, 2H). 2.56 (d, 3H, J = 4.5 Hz), 1.97-2.07 (c, 1H), 1.21-1.81 (c, 13H), 0.81-0.94 (c, 4H), 0.78 (d. 3H J = 6 Hz). MS (APCI) m/e 573 (M+NH4)+, 556 (M+H)+

Example 38 Example 38A To a methanol solution (150 mL) of 38a (3.39 g, 5.52 mmol), prepared by ring closure of 32c using the method of Example 1C, was added dry 10%Pd/C (340 mg) and the mixture was stirred under 4 atm of hydrogen in a pressurized reaction vessel for 2 hours at room temperature.

The mixture was filtered through a Celite pad with methanol washings. The filtrate was concentrated to provide 38b (2.83 g) as a white foam.

Example 38B

The desired compound was prepared according to the method of Examples 1E, F and G, except substituting 38b for 1f and substituting N, N-dimethylethylenediamine for 4-(2- aminoethyl)benzenesulphonamide. mp >250 °C. H NMR (DMSO) # -0.4-(-0.46) (m, 1H), 0.52-0.97 (m, 3H), 1.08-1.20 (m, 2H) , 1.31-1.40 (m, 2H), 1.52-1.61 (m, 2H), 1.68-1.75 (m, 1H), 2.0-2.08 (m, 1H), 2.12 (s, 6H), 2.23 (s, 3H), 2.24-2.45 (m, 2H), 2.52-2.61 (m, 1H),

3.03-3.20 (m, 3H), 3.3-3.39 (m, 2H), 3.90-4.10 (m, 2H), 4.52-4.64 (m, 1H), 6.90 (d, 2H, J = 8.4 Hz), 6.98-7.04 (m, 4H), 7.17-7.22 (m, 2H), 7.63-7.66 (m, 1H), 7.95 (d, 1H J = 9.3 Hz), 8.69 (s, 1H), 10.34 (s, 1H), MS (ESI) m/e 553 (M+H). Anal calcd for C31H44N4O5.O.75H20: C, 65.75; H, 8.09; N, 9.89. Found: C, 65.72; H, 8.28; N, 9.80. [α] +28° ( c 1.04, MeOH).

Example 39 The desired compound was prepared according to the method of Examples 1E-G, except substituting 2-(methylthio)ethylamine for 4-(2-aminoethyl)benzenesulphonamide. mp > 270°C.

H NMR (DMSO) # -0.6-(-0.4) (m, 1H), 0.5-1.0 (m, 5H), 0.71 (d, 3H, J = 6.6 Hz), 0.80 (d, 3H, J = 6.6 Hz), 1.1-1.4 (m, 2H), 1.5-1.7 (m, 3H), 2.0-2.1 (m, 1H), 2.07 (s, 3H), 2.5-2.7 (m, 3H), 3.05-3.4 (m, 2H), 3.9-4.1 (m, 2H), 4.55-4.7 (m, 1H), 6.90 (d, 8.4H), 7.2-7.3 (m, 2H), 7.8-7.9 (m, 2H), 8.68 (d, 1H J = 1.5 Hz), 10.3 (d, 1H, J = 1.5 Hz). 13C NMR (DMSO) # 14.5, 21.6, 24.2, 24.7, 24.9, 28.0, 28.4 32.8, 37.8, 40.3, 40.8, 46.0, 46.6, 53.5, 72.9, 121.0, 121.2, 128.7, 132.0, 132.4, 157.1, 170.0, 171.1, 172.7. MS (DCl/NH3) m/e 480 (M+H)+.

Anal calcd for C24H37N3O5S.0.5H2O: C, 58.99; H, 7.84; N, 8.60. Found: C, 59.05; H, 7.65; N, 8.45.

[α] +41° (c 0.5, MeOH).

Example 40

Example 40A To a 0 °C solution of nBuLi (2.5M/hexanes, 14.2 mL) in diethyl ether (50 mL) was added 4-bromothioanisole (7.2g, 35.6mmol) over a few minutes. The resulting solution was allowed to stir cold for 25 minutes and then was added to a -78 °C solution of N-BOC-tBu(OH) tyrosine (3g, 8.9mmol) in diethyl ether (200 mL). The solution was stirred at -78 °C for 25 minutes, warmed to 0° over 1 hour and quenched with an aqueous solution of NH4Cl. The aqueous layer was extracted twice with diether ether and the combined organics were washed with brine, dried (Na2SO4), fileterd and concentrated in vacuo. Flash chromatography (8:1 hexane-ethyl acetate) gave 2.5g pf product which was immediately taken up in 10mL 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 40a (1.4 g) as a chalky-white solid.

Example 40B The desired compound was prepared as a mixture of the sulfide (n=o) and sulfone (n=2) using the procedure of Examples 1A and B, except substituting 40 a for benzyltyrosine tosylate salt.

Example 40C

To a solution of 40b (1.0g. 1.7mmol) in acetone (50 mL) was added OXONETM (potassium peroxymonosulfate, 5g, 8mmol). The resulting slurry was stirred for 3 days. The reaction was diluted with ethyl acetate and water and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (2-4% methanol-methylene chlorid) gave 40c (0.9 g) as a white foam.

Example 40D The desired compound was prepared according to the method of Examples 1C, F and G, except subsituting 40c for 1c. mp 250-250 °C (dec.) H NMR (DMSO-d6) # 10.28 (s, 1H), 8.65 (s, 1H), 8.28-8.25 (d, 2H, J = 6.8 Hz), 8.19-8.16 (d, 1H, J = 9.5 Hz), 8.07-8.04 (d, 2H, J = 6.8 Hz), 7.42-7.39 (d, 1H, J = 8.5 Hz), 7.24-7.20 (d, 1H, = 8.5 Hz), 6.97-6.93 (d, 1H, J = 8.1 Hz), 6.87-6.83 (d, 1H, J = 8.2 Hz), 5.60-5.47 (m, 1H), 4.21-4.13 (m, 2H), 3.12 (s, 3H), 3.12-3.06 (m, 1H), 2.81-2.73 (m, 1H), 2.15-2.12 (m, 1H), 1.70-1.69 (m, 1H), 1.47-1.40 (m, 1H), 1.33-1.30 (m, 1H), 1.15-0.99 (m, 4H), 0.71-0.68 (m, 3H), 0.50-0.38 (m, 7H), (-)0.02-(- )0.09 (m, 1H). Anal calcd for C29H38N2O7S.0.5H2=: C, 61.35; H, 6.92; N, 4.93. Found: C, 61.26; H, 6.83; N, 4.61. [α]D: +11.4°(c = 0.21, DMF).

Example 41 Example 41A

To a solution of (L)-p-hydroxyphenylglycine (5g, 29.9 mmol, Sigma) in 50% aqueous dioxane (100 mL) and triethylamine (8.3 mL, 59.8 mmol) at ambient temperature was added a solution of Boc-anhydride (13.7 g, 59.8 mmol) in dioxane (10 mL) over 1 minute. The resulting solution was stirred at ambient temperature for 2.5 days and then was poured into a mixture of aqueous 1M HCl (100 mL) and ether (75 mL). The aqueous layer was extracted twice with ether and the combined organic layers were washed with aqueous 1M HCl and brine, dried with MgSO4, filtered and concentrated to afford 41a (10.8 g) as a white foam which was used without further purification.

Example 41B The desired compound was prepared according to the method of Example 1E, except substituting methylamine hydrochloride for 4-(2-aminoethyl)benzenesulphonamide.

ExamDle 41C A mixture of 41b (1.13 g, 4.02 mmol), trifluoroacetic acid (10 mL) and CH2Cl2 (2 mL) was stirred at ambient temperature for 1 hour and then concentrated under a stream of nitrogen.

The residue was dissolved in a 1:1 mix of CH2Cl2 and methanol (40 mL) and concentrated in vacuo. The dissolving-concentration sequence was repeated until a white foam formed to give 41c (1.2 g) which was used without purification.

Example 41D

The desired compound was prepared according to the method of Example 1A, except substituting seccinate ester 3 for succinate ester 1, and substituting 41c for benzyltyrosine tosylate salt.

Example 41E The desired compound was prepared according to the method of examples 1B, C, F and G, except substituting 41d for 1b. mp > 270 °C. H NMR (DMSO) # -0.65-(-0.5) (m, 1H), 0.4- 1.1 (m, 6H), 0.77 (apparent, 6H, J = 6.6 Hz), 1.2-1.5 (m, 4H), 1.6-1.7 (m, 1H), 2.3-2.5 (m, 1H), 2.65 (d, 2H, J = 4.5 Hz), 4.1-4.2 (m, 2H), 5.30 (d, 1H, J = 9.3 Hz), 6.87 (dd, 1H, J = 8.1 2.4 Hz), 6.96 (dd, 1H, J = 8.1, 2.4 Hz), 7.24 (dd, 1H, J = 8.1, 2.4 Hz), 7.38 (dd, 1H, J = 8.1, 2.4 Hz), 8.0-8.1 (m, 1H), 8.19 (d, 1H, J = 9.3 Hz), 8.64 (d, 1H, J = 1.2 Hz), 10.24 (d, 1H, J = 1.5 Hz). MS (DCl/NH3) m/e 420 (M+H)+. Anal calcd for C22H33N3O5.0.1H2=: C, 62.72; H, 7.94; N, 9.97. Found: C, 62.61; H, 7.73; N, 9.73. [α] + 186° (c 0.25, DMF).

Example 42 The desired compound was prepared according to the method of Examples 1A-C, F and G, except substituting tyramine for benzyltyrosine tosylate salt. mp > 270 °C. H NMR (300 MHz, DMSO-d6) # -0.5-(-0.4) (m, 1H), 0.5-1.0 (m, 4H), 0.73 (d, 3H, J = 6.3 Hz), 0.77 (d, 3H, J = 6.3 Hz), 1.1-1.3 (m, 2H), 1.4-1.7 (m, 3H), 1.98 (dd, 1H, J = 10.5, 3.3 Hz), 2.5-2.6 (m, 1H), 2.8-3.0 (m, 2H), 3.8-4.1 (m, 3H), 6.85-6.95 (m, 2H), 7.1-7.2 (m, 2H), 7.40 (d, 9.3H), 8.67 (s, 1H), 10.3 (s, 1H). 13C NMR (DMSO) # 21.5, 24.1, 24.6 25.2, 28.1, 28.5 33.5, 38.3, 40.6, 46.6, 46.7, 72.7, 120.6, 120.9, 129.0, 131.6 133.3, 156.9, 170.3, 172.6. MS (CI NH3) m/e

363 (M+H)+. Anal calcd for C20H30N2O4.0.8H2O: C, 63.74; H, 8.45; N, 7.43. Found: C, 63.90; H, 8.53; N, 7.33. [a] +103° (c 0.3, MeOH).

Example 43 Example 43A The desired compound was prepared according to the method of Example 40A, except substituting 4-bromo-tert-butyl benzene for 4-bromothioanisole.

Example 43B The desired compound is prepared by coupling of 43a and 7, and deprotection using tetrabutylammonium fluoride according to the method of Examples 32B and C.

Example 43D

The desired compound was prepared by ring closure according to the method of Example 8E, followed by saponification of the tert-butyl ester and conversion to the hydroxamate according to the method of Examples 1F and G, except substituting 43c for 1c. mp 220-221°C. H NMR (CD3OD) # -0.26 (m, 1H), 0.50 (d, 3H, J = 5.7 Hz), 0.64 (d, 3H, J = 5.8 Hz), 0.85 (m, 4H), 1.18 (m, 3H), 1.35 (s, 9H), 1.63 (m, 1H), 1.79 (m, 2H), 2.89 (t, 1H = 12.9 Hz), 3.21 (dd, 1H, J = 4.7, 12.9 Hz), 4.08 (m, 1H), 4.18 (m, 1H), 5.93 (dd, 1H, J = 4.4 Hz), 6.90 (dd, 1H, J = 2.7, 8.1 Hz), 6.96 (dd, 1H, J = 2.7, 8.4 Hz), 7.19 (dd, 1H, J = 2.4, 8.1 Hz), 7.41 (dd, 1H, J = 1.7, 8.1 Hz), 7.55 (d, 2H, J = 8.5 Hz), 8.05 (d, 2H, J = 8.4 Hz), 8.38 (d, 1H, J = 12.2 Hz). 13C NMR (CD3OD) # 21.35, 24.75, 25.99, 29.49, 30.24, 30.67, 31.48, 36.03, 36.83, 42.44, 47.90, 48.45, 55.04, 74.40, 122.14, 122.37, 126.77, 129.80, 130.55, 133.17, 133.23, 134.16, 158.65, 159.01, 173.25, 175.25, 175.52, 192.27. MS (DCl/NH3) m/e 523 (M+H)+. Anal calcd for C31 H42 N2O5.H2O: C, 68.86; H, 8.20; N, 5.18. Found: C, 68.57; H, 8.05; N, 5.45.

Example 44 The desired compound was prepared as a white foam according to the method of Examples 1E and F, except substituting piperidine for 4-(2-aminoethyl)benzenesulphonamide, substituting 32a for 1e and substituting methanol for DMF in Example 1E. H NMR (DMSO) # -0.40-(-0.24) (m, 1H), 0.52-0.72 (m, 1H), 0.73-1.0 (m, 2H), 1.10-1.43 (m, 7H), 1.44-1.70 (m, 6H), 1.92- 2.08 (m, 2H), 2.22 (s, 3H), 2.24-2.37 (m, 1H), 2.39-2.50 (m, 1H), 2.71-2.93 (m, 2H), 3.32- 3.40 (m, 2H), 3.51-3.58 (m, 2H), 4.0-4.08 (m, 2H), 5.0-5.12 (m, 1H), 6.88 (d, 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.1 Hz), 7.03 (d, 2H, J = 8.1 Hz), 7.15 (d, 1H, J = 9.3 Hz), 7.24 (d, 1H, J = 9.2 Hz), 8.13 (d, 1H, J = 9.9 Hz). MS (DCl/NH3) 535 (M+H)+.

Example 45 The desired compound was prepared as a white solid according to the method of Example 1G, except substituting the compound of Example 44 for la. mp<250 °C. H NMR (DMSO) # -0.50-(-0.38) (m, 1H), 0.53-1.0 (m, 3H), 1.07-1.20 (m,2H), 1.22-1.43 (m, 5H), 1.45-1.64 (m, 5H), 1.65-1.81 (m, 1H), 1.98-2.10 (m, 1H), 2.23 (s, 3H), 2.25-2.31 (m, 1H), 2.38-2.45 (m, 1H), 2.71-2.90 (m, 2H), 3.30-3.42 (m, 2H), 3.50-3.62 (m, 2H), 3.94-4.10 (m, 2H), 4.97-5.10 (m, 1H), 6.87 (d, 2HH, J = 9.0 Hz), 6.93-7.07 (m, 4H), 7.15 (d, 1H, J = 7.2 Hz), 7.24 (d, 1H, J = 7.1 Hz), 8.05 (d, 1H, J = 9.3 Hz), 8.69 (s, 1H), 10.36 (s, 1H). MS (ESI-) m/e 548 (M-1).

Anal calcd for C32H43N3O5; C, 69.91; H, 7.88; N, 7.64. Found: C, 69.85; H, 7.77; N, 7.57.

[α] + 56° (c = 1.0, MeOH).

Example 46 The desired compound was prepared according to the method of Examples 1E and F, except substituting 38b for 1e, and substituting 2-aminothiazole for 4-(2- aminoethylbenzenesulphonamide. H NMR (300 MHz, DMSO-d6) # -0.34-(-0.20)(m, 1H), 0.60-0.74 (m, 1H), 0.81-0.97 (m, 2H), 1.13-1.25 (m, 2H), 1.36-1.45 (m, 2H), 1.55-1.67 (m, 2H), 1.90-2.01 (m, 1H), 2.05-2.16 (m, 1H), 2.22 (s, 3H), 2.24-2.38 (m, 1H), 2.40-2.45 (m, 1H), 2.57-2.65 (m, 3.24-3.34 (m, 1H), 3.94-4.05 (m, 1H), 4.07-4.16 (m, 1H), 4.95-5.03 (m, 1H), 6.93-7.04 (m, 7H), 7.20-7.27 (m, 1H), 7.31 (d, 1H, J = 3.6 Hz), 7.35-7.38 (m, 1H),

7.53 (d, 1H, J = 3.6 Hz), 8.22 (d, 1H, J = 9.6 Hz), 12.40 (bs, 1H). MS (DCl/NH3) m/e 550 (M+H)+.

Example 47 The desired compound was prepared according to the method of Example 1G, except substituting the compound of Example 46 for la. mp<250 °C. H NMR (300 MHz, DMSO-d6) # -0.48-)-0.33) (m, 1H), 0.60-0.93 (cm, 3H), 1.10-1.23 (m, 2H), 1.28-1.50 (m, 2H), 1.52-1.67 (m, 2H), 1.70-1.81 (m, 1H), 2.04-2.18 (m, 1H), 2.21 (s, 3H), 2.23-2.31 (m, 1H), 2.40-2.48 (m, 1H), 2.58-2.67 (m, 1H), 3.23-3.25 (m, 1H), 3.90-4.00 (m, 1H), 4.04-4.16 (m, 1H) 4.88- 4.98 (m, 1H), 6.90-7.01 (m, 6H), 7.22-7.28 (m, 1H), 7.29 (d, 1H, J = 3.9 Hz), 7.31-7.36 (m, 1H), 7.50 (d, 1H, J = 3.3 Hz), 8.12 (d, 1H, J = 9.3 Hz), 8.68 (s, 1H), 10.35 (s, 1H), 12.30 (s, 1H). MS (DCI/NH3) m/e 565 (M+H)+. Anal calcd for C30 H36N4O5S.0.5 H2O: C, 62.80; H, 6.50; N, 9.76. Found: C, 62.95; H, 6.33: N, 9.76. [α] + 26° (c = 0.9, MeOH).

Example 48

Example 48A To a solution of 17b (142mg, 0.300mmol) in CH2Cl2 (4 mL) was added triethylamine (0.059 mL, 0.420 mmol) followed by methanesulfonyl chloride (0.028 mL, 0.360 mmol). The mixture was left stirring at room temperature for 2 hours and then was poured into brine. The biphasic mixture was extracted with CH2Cl2 (3x) and the combined CH2Cl2 layers were dried (MgSO4), filtered and evaporated to dryness. Flash chromatography (2%-5% MeOH/CH2Cl2) yielded 157.7 mg (95.2%) of 48 as pale yellow crystals.

The desired compound was prepared as a white solid according to the method of Examples 1F and G, except substituting 48a for 1f. mp 242-244 °C (dec). H NMR (DMSO-D6) # -0.118 (m, 1H), 0.63 (m, 2H), 0.73 (d, 3H, J = 6.6 Hz), 0.83 (d, 3H, J = 6.6 Hz=, 0.79-1.40 (m, 7H), 1.66 (m, 1H), 2.24 (m, 1H), 2.44-2.56 (m, 1H), 2.62 (d, 3H, J = 4.5 Hz), 2.50-2.75 (m, 2H), 2.93 (s, 3H), 3.01 (dd, 1H, J = 2.7, 12 Hz), 3.60 (m, 2H), 4.52 (m, 1H), 7.17 (dd, 1H, J = 8.1, 1.8 Hz), 7.32 (dd, 1H, J = 8.1, 1.8 Hz), 7.41 (dd, 1H, J ? 8.1, 1.8 Hz), 7.38 (dd, 1H, J = 8.1, 1.8 Hz), 7.76 (q, 1H, J = 4.5 Hz), 7.06 (s, 1H, J = 9.3 Hz), 8.70 (s, 1H), 10.30 (s, 1H). MS (ESI) 1043 (m+Na)+, 1021 (2M+H)+, 533 (M+Na)+, 511 (M+H)+, 478, 215. Anal calcd for C24H38N4O6S.1.75 H2=: C, 53.16; H, 7.71: N, 10.33. Found: C, 53.14; H, 7.32; N, 9.90.

[a] = +14.6° (c=0.205, CH3OH).

Example 49 The desired compound was prepared according to the method of Example 48, except substituting p-toluenesulfonyl chloride for methanesulfonyl chloride. mp: 235-237 °C(dec). H NMR (DMSO-D6) # -0.16 (m, 1H), 0.59 (m, 3H), 0.72 (d, 3H, J = 6.6 Hz), 0.82 (d, 3H, J = 6.6 Hz), 0.95-1.26 (m, 7H), 1.64 (m, 1H), 2.22 (m, 1H), 2.61 (d, 3H, J = 4.5 Hz), 2.69 (t, 1H, J = 13.2 Hz), 2.97 (dd, 1H, J = 13.2, 2.4 Hz), 3.36 (m, 1H), 3.51 (m, 1H), 4.47 (m, 1H), 6.82 (dd, 1H, J = 1.8, 8.1 Hz), 6.97 (dd, 1H, J = 1.8, 8.1 Hz), 7.28 (m, 1H, 8.1 Hz), 7.33- 7.447.33-7.44 (m, 5H), 7.72 (q, 1H, J = 4.5 Hz), 8.05 (d, 1H, J = 8.7 Hz), 8.70 (s, 1H), 10.30 (s, 1H). MS (DCI-NH3) m/e 587 (M+H)+, 543, 447, 391, 302, 258, 215. Anal calcd for C30H42N4O6S.0.75 MeOH: C, 60,46; H, 7.42; N, 9.17. Found: C, 60.33; H, 7.40; N, 8.90.

[a] = +41.5° (c=0.065, CH3OH).

Example 50 Example 50A To a 0°C solution of N-Boc-imidazolyl-tosy-L-histide (5.0g, 12.2mmol) in dichlorormethane (125ml) was added methylamine hydrochloride (990mg, 14.7mmol), BOP-Cl (3.7g, 14.7mmol) and TEA (4ml, 29.4mmol) under nitrogen, the ice-bath was removed and the mixture was stirred at room temperature for 23 hours. The reaction mixture was diluted with brine and extracted with three portions of dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (60% ethy acetate-hexanes, then 10% MeOH/CH2Cl2) to provide 50a (1.67g, 32%) as a white solid.

Example 50B A solution of 50a in trifluoroacetic acid was stirred for 10 minutes. The trifluoroacetic acid was evaporated and the mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3.

The aqueous phase was extracetd with three portions of CH2Cl2 and the combined extracts were <BR> <BR> <BR> washed with brine, dried over sodium sulfate and concentrated in vacuo to give 50b (1.09g, 85%)<BR> as an off-white solid.

Example 50C To a 0 °C solution of succinate ester 3 (772mg, 2.59mmol) and 50b (1.0g, 3.1mmol) in dichloromethane (20ml) was added BOP-Cl )789mg, 3.1mmol) and triethylamine (862µl, 6.2mmol) under nitrogen, the ice-bath removed, and the mixture was stirred at room temperature for 23 hours. Additional 50b, BOP-Cl and triethylamine (0.8 equivalent) were then added and stirring was continued for another 48 hours. The reaction mixture was diluted with brine and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (5% MeOH-CH2Cl2) and (80% ethyl acetate-hexanes) to provide 50c (1.01g, 65%) as ayellow foam.

Example 50D The desired compound was prepared according to the method of Example 1B, except substituting 50c for 1b.

Example 50E To a 0 °C solution of 50d (156mg, 0.25mmol) in CH2Cl2(4ml) under nitrogen was added methanesulfonyl chloride(25µl, 0.325mmol), followed by NMM(41µl, 0.375mmol), the resulting mixture was stirred at 0°c for 2hr and diluted with CH2Cl2/brine, ectracted with two portions of CH2Cl2, dried over sodium sulfate, filtered, solvent was evaporated and the crude mixture was purified by flash chromatography(5% MeOH/CH2Cl2) to afford 50e (113 mg, 65%) as a white foam.

Example 50F A mixture of 50e (166mg, 0.24mmol) and HOBT (64.8mg, 0.48mmol) in THF (4ml) was stirred at room temperature for 24 hours, the solvent was evaporated, and the crude product was <BR> <BR> <BR> purified by flash chromatography(5% -10% MeOH-CH2Cl2) to afford 50f (116 mg, 89%) as a<BR> white solid.

Example 50G A mixture of 50f (137mg, 0.25mmol), LiI (50mg, 0.375mmol) and Na2CO3 (27 mg, 0.25 mmol) in acetone(5ml) was heated at 50 °C for 5 hours. The reaction mixture was then cooled to ambient temperature and stirring was continued for 17 hours. The solvent was evaporated and the crude product was purified by flash chromatography(10% MeOH-CH2Cl2) to afford 50g (71mg, 63% as a white soild.

Example 50H The desired was prepared according to the method of Examples 1F and G, except substituting 50g for 1f. NMR (300 MHz, DMSO-d6) # 0.75 (d, 3H, J = 6.2 Hz), 0.81 (d, 3H, J = 6.2 Hz), 0.80 (m, overlped, 4H,), 1.14 (m, 1H), 1.22-1.52 (m, 4H), 1.56-1.80 (m, 2H), 2.24-2.47 (m, 2H), 2.58 (d, 3H, J = 5.1 Hz), 2.63-2.79 (m, 2H), 3.63-3.76 (m, 1H), 3.87-3.96 (m, 1H), 4.35-4.48 (m, 1H), 6.92 (s, 1H), 7.46 (bs, 2H), 8.12 (d, 1H, J = 15 Hz), 8.735 (d, 1H, J = 1.5 Hz), 10.36(d, 1H, J = 1.5 Hz). MS(DCI/NH3), m/e 408 (M+H)+.

[α]D=+10.4°.(c=0.25, EtOH).

Example 51 The compound was prepared using the method of Example 43, except substituting succinate ester 5 for 7 and substituting ketone 14b for 43a. mp 211-212 °C. H NMR (300 MHz, DMSO-d6) # -0.38 (m, 1H), 0.64 (m, 1H), 0.81 (m, 1H), 0.98 (m, 4H), 1.58 (m, 1H), 1.62 (m, 1H), 1.80 (dt, 1H), 2.00 (m, 2H), 2.18 (m, 1H), (s, 3H), 2.81 (t, 1H), 3.07 (dd, 1H), 4.04 (m, 2H), 5.73 (m, 1H), 6.69 (d, 2H), 6.93 (m, 4H), 7.17 (dd, 1H), 7.38 (dd, 1H), 7.51 (t, 2H), 7.64 (t, 1H), 8.11 (m, 3H), 6.68 (s, 1H), 10.38 (s, 1H).

MS (DCI/NH3) m/e 543 (M+H)+.

Anal. calcd for C33H38N2O5@0.75 H2O: Cm 71.26; H, 7.16; N, 5.04. Found; C, 71.03; H, 7.09; N, 5.16.

Example 52 The desired compound was prepared by following the procedures described in Examples lA-C and 1F starting with succinate ester 7 and ketone 14b.

1H NMR (300MHz, DMSO-d6) 8 8.14-8.11 (d, lH, J=9.8 Hz), 8.05-8.03 (d, 2H, J=7.2 Hz), 7.66-7.64 (m, 1H), 7.54-7.51 (m, 2H), 7.41-7.38 (m, 1H), 7.21-7.18 (m, 1H), 6.98-6.89 (m, 2H), 5.82-5.75 (m, 1H), 4.13-3.99 (m, 2H). 3.15-3.09 (m, 1H), 2.87-2.79 (m, 1H), 2.00-1.91 (m, 2H), 1.69-1.67 (m, 1H), 1.59-1.58 (m, 1H), 1.3-.06 (mm, 7H), 0.55-0.37 (m, 7H), (- )0.25-(-)0.33 (m, 1H). MS (APCI) m/e 450 (M-H)-, 452 (M+H)+, 486 (M+Cl)-.

Example 53 The desired compound was prepared by according to the method of Example 1G, except substituting acid 52 for 1a. H NMR (300MHz, DMSO-d6) # 10.1 (s, 1H), 8.50 (s, 1H), 7.92- 7.85 (m, 3H), 7.52-7.47 (m, 1H), 7.39-7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.09-7.06 (m, 1H), 6.92-6.74 (m, 1H), 3.95-3.90 (m, 1H), 3.00-2.92 (m, 1H), 2.72-2.64 (m, 1H), 1.88-1.80 (m, 1H), 1.59-1.52 (m, 3H), 0.94-0.47 (bm, 5H), 0.46-023 (mm, 6H), (-)0.55-(-)0.57 (m, 1H).

MS (DCI/NH4) m/e 467 (M+H)+. Anal. Calcd for: C27H34N2O5@0.25H2O: C, 68.84; H, 7.38; N, 5.94. Found: C, 68.53; H, 7.38; N, 5.66.

Examp,e 54 Example 54A I The desired compound was prepared according to the method of Example 40A except substituting 4-bromo- 1,2- (methylenedioxy) benzene for 4-bromothioanisole.

Example 54B The desired compound was prepared according to the method of Example 43, except substituting succinate 5 for 7 and ketone 54a for 43a. H NMR (300 MHz, DMSO-d6) # 10.36 (s. 1H), 8.70 (s, 1H), 8.16-8.13 (d, 1H, J = 9.5 Hz), 7.80-7.77 (d, 1H, J = 7.7), 7.55 (s, 1H), 7.36-7.33 (d, 1H, J =6.6 Hz), 7.11-7.13 (d, 1H, J =8.1 Hz), 7.02-6.99 (d, 1H, J =8.4 Hz), 6.96-6.87 (m, 4H), 6.62-6.60 (d, 2H, J =8.1 Hz), 6.10-6.08 (d, 2H, J=4.1 Hz), 5.64-5.60 (m, 1H), 4.06-4.03 (m, 2 H), 3.04-2.98 (m, 1H), 2.87-2.78 (m, 1H), 2.21 (s, 3H), 2.07-1.96 (m, 3H), 1.84-1.80 (m, 2H), 1.70-1.60 (m, 1H), 160-1.52 (m, 1H), 1.05-0.96 (bm, 4H), 0.87-0-80 (m, 1H), 0.64-0.60 (m, 1H), (-)0.37-(-) 0.38 (m, 1H). MS (ESI) m/e (M+H)+, 585 (M-H)-.

Anal. Calcd for: C34H38N2O7@0.25H2O: C, 69.07; H, 4.70. Found: C, 68.72; H, 6.41; N, 4.64.

Example 55 Example 55A The desired compound was prepared according to the method of Example 40A, except substituting 4-bromofluorobenze for 4-bromothioanisole.

Example 55B

The desired compound was prepared according to the method of Example 43, except substituting succinate 5 for 7 and ketone 55a for 43a. H NMR (300MHz, DMSO-d6) # 10.38 (s, 1H), 8.71 (s, 1H), 8.19-8.13 (m, 3H), 7.37-7.28 (m, 3H), 7.17-7.11 (d, 1H, J=7.3 Hz), 6.95-8.88 (m, 4H), 6.59-6.57 (d, 2H, J=7.1 Hz), 5.73-6.65 (m, 2H), 4.06-4.03 (m, 2H), 3.08-3.03 (m, 1H), 2.89-2.73 (m, 2H), 2.21 (s, 3H), 2.18-2.17 (m, 1H), 2.06-1.99 (m, 2H), 1.82-1.76 (m, 1H), 1.64-1.55 (m, 2H), 1.09-0.59 (bm, 9H), -(-)0.382-)-)0.385 (m, 1H). MS (ESI) m/e 561 (M+H)+.559 (M-H)-. Anal. Calcd for: C33H37FN2O5@0.25H2O: C, 70.13; H, 6.68; N, 4.95.

Found: C, 70.01: H. 6.59: N. 5.05.

Example 56

Example 56A The desired compound was prepared according to the method of example 40A except substituting 4-benzyloxybromobenzene for 4-bromothioanisole.

Example 56B The desired compound was prepared by following the procedures described in Examples 1 A-C and 1F starting with succinate ester 5 and ketone 56a. H NMR (300MHz, DMSO-d6) # 8.21-8.18 (d, 1H. J=9.6 Hz), 8.10-8.07 (d, 2H, J=9.1 Hz), 7.44-7.31 (m, 6H), 7.16-7.11 (m, 3H), 6.96-6.88 (m, 4H), 6.64-6.61 (d, 2H, J=7.8 Hz), 5.69-5.65 (m, 1H), 5.18 )s, 2H), 4.08-4.07 (m, 2H), 3.07-3.01 (m, 1H), 2.87-2.78 (m, 1H), 2.19 (s, 3H), 2.20-1.98 (m, 3H), 1.71-1.53 (m, 2H).

1.17-0.86 (mm, 7H), -0.20- (-) 0.41 (m, 1H). MS (DCJ/NH4) m/e 634 (M+H)+.

Example 57

The desired compound was prepared by according to the method of Example 1G, except substituting acid 56 for 1a. H NMR (300MHz, DMSO-d6) # 10.38 (s, 1H), 8.70 (s, 1H), 8.16- 8.14 (m, 3H), 7.47-7.38 (m, 6H), 7.21-7.18 (m, 3H), 6.96-6.91 (m, 3H), 6.65-6.63 (d, 2H, J=7.8 Hz), 5.75-5.65 (m, 1H), 5.21 (s, 2H), 4.11-4.08 (m, 2H), 3.10-3.04 (m, 1H), 2.90-2.81 (m, 1H), 2.23 (s, 1H), 2.13-2.01 (m, 2H), 1.88-1.87 (m, 1H), 1.77-1.65 (m, 2H), 1.07-0.96 (m, 6H), 0.70-0.66 (m, 2H), -(-)0.29.-(-)0.32 (m, 1H).

Example 58 The desired compound was prepared by removing the benzyl group of example 57 using to the procedure described in Example 1D. H NMR (300MHz, DMSO-d6) # 10.42 (s, 1H), 10.35 (s, 1H), 8.69 (s, 1H), 8.11-8.08 (d, 1H, J=9.6 Hz), 8.03-8.00 (d, 2H, J=8.4 Hz), 7.36-7.33 (d, 1H, J=8.4 Hz), 7.17-7.11 (d, 1H, J=8 Hz), 6.94-6.84 (m, 6H), 6.63-6.61 (d, 2H, J=8.1 Hz), 5.66-5.59 (m, 1H), 4.06-4.00 (m, 2H), 3.03-2.97 (m, 1H), 2.84-2.76 (m, 1H), 2.12 (s, 3H), 2.08-1.96 (m, 2H), 1.82-1.78 (m, 1H), 1.63-1.55 (m, 2H), 1.04-0.61 (mm, 6H), (-)0.21-(- )0.41 (m, 1H).

MS (DCI/NH4) m/e (M+H). Anal. Calcd for: C33H38N2O6@0.25H2O: C, 70.37; H, 6.89; N, 4.97. Found: C, 70.20; H, 6.94; N, 4.86.

Example 59 The desired compound was prepared according to the method of Example 43, except substituting succinate 8 for 7 and ketone 14b for 43a. H NMR (300MHz, DMSO-d6) # 10.31 (s, 1H), 8.65 (s, 1H), 8.12-8.08 (d, 2H, J=9.8 Hz), 8.06-8.03 (d, 2H, J=7.1 Hz), 7.59-7.54 (m, 1H), 7.48- 7.43 (m, 2H), 7.38-7.22 (m, 7H), 7.18-7.14 (m, 1H), 6.95-6.87 (m, 2H), 5.75-5.69 (m, 1H), 4.29 (s, 2H), 4.07-4.03 (m, 2H), 3.13-3.07 (m, 1H), 2.98-2.75 (m, 3H), 1.93-1.88 (m, 1H), 1.82-0.56 (mm, 15H), (-) 0.036-(-) 0.030 (m, 1H). MS (ESI) 573 (M+H)+, 571 (M-H)-. Anal.

Clacd for: C34H40N2O6: V, 71.30; H, 7.04: N, 4.89. Found: C, 71.16; H, 7.14; B, 4.85.

Example 60

Example 60A The desired compound was prepared according to the method of Example 40A, except substituting 4-benzyloxymethyl bromobenzene for 4-bromothioanisole.

Example 60B The desired compound was prepared according to the methods of Examples IA, coupling succinate 5 with ketone 60A, followed by deprotection of the silyl ether as in Example 32B and subsequent cyclization as in Example 1C.

MS (DCI/NH3) m/e 720 (M+H).

Example 60C A solution of ester 60b (0.050 g, 7.0 x 10-2mmol) in 4:1 CH3CN/H2O (5 mL) was treated with ceric ammonium nitrate (0.19 g, 3.5 x 10-1 mmol) and stirred and 1.5 h. The solution was partitioned between ethyl acetate and water, the organic layer was dried (MgSO4) and concentrated <BR> <BR> <BR> <BR> <BR> to a solid. The solid was purified on silica gel with 25% ezhyl acetate/hexane ramped to 60% to<BR> provide 0.01 g(36%) of 60c.

Example 60D The desired compound was prepared according to the methods of Examples 1F, except substituting 60c for 1f.

H NMR (d6-DMSO) # 8.21 (d, 1H, J=10.3 Hz), 8.13 (d, 2H, J=8.5Hz), 7.59 (d, 2H, J=8.1 Hz), 7.38 (dd, 1H, J=1.4, 8.1 Hz), 7.15 (dd, 1H, J=8, 8.1 Hz), 7.02-6.87 (m, 4H), 6.61 (d, 2H, J=8.1 Hz), 5.83-5.69 (m, 1H), 5.48 (s, 2H), 4.07 (t, 1H,J=1.5 Hz), 3.10 (dd, 2H, J=3.7, 13.6 Hz), 2.86-2.72 (m, 2H), 2.30-1.93 (m, 2H), 2.21 (s, 3H), 1.77-1.49 (m, 2H), 1.20-0.79 (m, 7H), 0.70-0.55 (m, 2H), -0.16--0.32 (m, 1H).

MS (ESI) m/e 558 (M+H).

Example 61 Example 61A The desired compound was prepared according to the methods of Examples 1A-C, coupling succinate 1 with ketone 60A, followed by deprotection of the benzyl ether as in Example 60C.

Example 61B The desired compound was prepared according to the methods of Examples 1F-G, substituting ester 60c for 1f.

H NMR (300MHz, DMSO-d6) # 10.29 (d, 1H, J=1.7 Hz), 8.64 (d, 1H,J=1.7 Hz), 8.02-7.98 (m, 3H), 7.46-7.38 (m, 3H9, 7.22 (dd, 1H,J=8.1, 2 Hz), 6.96-6.88 (m, 2H), 5.80-5.68 (m,

1H), 5.34 (t, 1H, J=5.8 Hz), 4.57 (d, 2H, J=5.4 Hz), 4.05 (t, 2H, J=4.7 Hz). 3.10 (dd, 1H, J=13.5, 4.4 Hz), 2.79 (t, 1H, J=12.9 Hz), 2.05-1.94 (m, 1H), 1.77-1.46 (m, 3H), 1.13-0.54 (m, 6H), 0.48 (dd, 6H, J=45.1, 5 Hz), -0.34-0.50 (m, 1H). MS (ESI) m/e 497 )M + H)+.

Anal. Calcd for: C28H36N2O6@1.25H2O: C, 64.78; H, 7.47; N, 5.39. Found: C, 64.44; H, 7.23; N, 5.43.

Example 62 Example 62A The desired compound was prepared according to the methods of Examples IA, coupling succinate 9 with ketone 14b, followed by deprotection of the silyl ether as in Example 32B and subsequent cyclization as in Example 1C.

Example 62B A solution of macrocycle olefin 62a (1.544 g, 3.14 mmol) in THF (10 mL) at 0°C under argon atmosphere was treated with 9-BBN (19.5 mL of 0.5 M solution in THF, 9.75 mmol) dropwise and stirred at 0°C for 0.2 h then at ambinet temperature for 5.0 h. The resulting solution was treated wirh DMF (80 mL), [1,1'-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) , complex with dichloromethane (1:1) (0.30 g, 0.37 mmol), 3,4,5-trimethoxy-bromobenzene (2.41 g. 9.75 mmol), and cesium carbonate (6.14 g, 18.84 mmol) and stirred at 60°C for 6 h then at ambient temperature for 10 h. The solution was partitioned between ether and water, the organic layer was dried (MgSO4), and concentrated to an oil. The oil was purified on silica gel with ethyl acetate/hexanem 1:2 to provide 0.86 g (42%) of 62b. MS (ESI) m/e 660 (M+H)+.

Example 62C The desired compound was prepared according to the methods of Example 1F, except substituting 62b for lf. 1H NMR (300 MHz DMSO-d6) 12.08 (s,lH), 8.25 (d, lH, J=9.3 Hz), 8.07 (d, 2H, J=7.4 Hz), 7.66-7.61 (m, lH), 7.53-7.48 (m,2H), 7.42 (d, lH, J=8.1 Hz), 7.18 (d, 1H,

J=8.1 Hz), 6.99-6.91 (m, 2H), 6.22 (s, 2H), 5.76 (m, 1H), 4.04-4.11 (m, 2H), 3.69 (s, 6H), 3.59 (s, 3H), 3.10-3.18 (m, 1H), 2.75 (t, 1H, J=12.3 Hz), 1.98-2.30 (m, 4H), 1.53-1.74 (m, 2H), 0.80-1.21 (m, 6H), 0.58-0.74 (m, 1H), -0.16- -0.30 (m, 1H). MS (ESI) m/e 604 <BR> <BR> <BR> <BR> <BR> (M+H)+. Anal. Calcd for: C35H41NO8.0.25H2O: C, 69.11; H, 6.87; N, 2.30. Found: C,<BR> 69.01; H, 6.90; N, 2.22.

Example 63 The desired compound was prepared by according to the method of Example 1G, except substituting Example 62 62 for 1a. H NMR (300 MHz, DMSO-d6) # 10.38 (s, 1H), 8.71 (s, 1H), 8.20 (d, 1H, J=9.6 Hz), 8.08 (d, 2H, J=7.3 Hz), 7.60-7.67 (m, 1H), 7.47-7.52 (m, 2H), 7.42 (d, 1H, J=8.5 Hz), 7.20 (d, 1H, J=8.1 Hz), 6.90-6.97 (m, 2H), 6.21 (s, 2H), 5.66-5.77 (m, 1H), 3.99-4.11 (m, 2H), 3.69 (s, 6H), 3.59 (s, 3H), 3.09-3.17 (m, 1H), 2.73 (t, 1H, J=12.9 Hz), 1.98-2.29 (m, 3H), 1.74-1.84 (m, 1H), 1.50-1.70 (m, 2H), 0.59-1.13 (m, 7H), - 0.31- -0.44 (m, 1H).MS (ESI) m/e 619 (M+H)+. Anal. Calcd for:C35H42N2O8: C, 67.94; H.

6.84; N, 4.52. Found: C, 67.65; H, 6.75; N, 4.43.

Example 64 The desired compound was prepared according to the method of Examples 62-63, except substituting 3,5-dimethoxy-bromobenzene for 3,4,5-trimethoxy-bromobenzene in Example 62B.

H NMR (300 MHz, DMSO-d6) # 10.37 (s, 1H), 8.70 (s, 1H), 8.17 (d, 1H,J=9.9 Hz), 8.07 (d, 2H, J=7.4 Hz), 7.58-7.66 (m, 1H), 7.44-7.51 (m, 2H), 7.40 (dd, 1H, J=8.4, 2 Hz), 7.18 (dd, 1H, J=8.1, 2 Hz), 6.88-6.97 (m, 2H), 6.23 (t, 1H, J=2 Hz), 6.05 (d, 2H, J=2.3 Hz), 5.66-5.77 (m, 1H), 4.02-4.08 (m, 2H), 3.67 (s, 6H), 3.07-3.16 (m, 1H), 2.76 (t, 1H,J=12.6 Hz), 2.14- 2.28 (m, 1H), 1.95-2.10 (m, 2H), 1.75-1.85 (m, 1H), 1.49-1.72 (m, 2H), 0.56-1.11 (m, 7H),- 0.31--0.44 (m, 1H). MS (ESI) m/e 589 (M + H)+. Anal. Calcd for: C34H40N2O7: C, 69.36; H, 6.84; N, 4.75. Found: C, 69.27; H, 6.63; N, 4.61.

Example 65 The desired compound was prepared according to the method of Examples 62-63, except substituting 1,3,5-tribromobenzene for 3,4,5-trimethoxy-bromobenzene in Example 62B. H NMR (300 MHz, DMSO-d6) # 0.38 (s, 1H), 8.72 (s, 1H), 8.17 (d, 1H, J=9.6 Hz), 8.07 (d, 2H, J=7.7 Hz), 7.55-7.61 (m, 2H), 7.35-7.47 (m, 3H), 7.13-7.19 (m, 1H), 7.06 (d, 2H, J=1.8 Hz), 6.88-6.97 (m, 2H), 5.68-5.79 (m, 1H), 4.03-4.10 (m, 2H), 3.08-3.16 (m, 1H), 2.85 (t, 1H, J=12.7 Hz), 2.22-2.35 (m, 1H), 1.91-2.10 (m, 2H), 1.75-1.85 (m, 1H), 1.46-1.75 (m, 2H), 0.57-1.16 (m, 7H), -0.30- -0.43 (m, 1H). MS (ESI) m/e 687 (M + H)+. Anal. Calcd for: C32H34N2O5Br2: C, 55.99; H, 4.99; N, 4.08. Found: C, 56.14; H, 4.97; N, 4.01.

Example 66

Example 66A A solution of 5-methoxyresorcinol (2.52 g, 19 mmol) in DMF (25 mL) at ambient temperature was treated with K2CO3 (9.94 g, 72 mmol) and 2-bromoethyl methyl ether (1.72 mL, 18 mmol) and heated at 50°C for 16 h. The suspension was partioned between Et2O and water, the organic layer was dries (MgSO4), and concentrated to the crude product. Purification on silica gel with ethyl acetate/hexane, 1:4 provided 1.26 g (45%) of the title compound. MS (ESI) m/e 199 (M + H)+.

Example 66B The desired compound was synthesized following the procedure described in J.Org.

Chem. 141. 4102 (1976). MS (DCI/NH3) m/e 287 (M + H)+.

Example 66C The desired compound was prepared according to the method of Examples 62-63, except substituting 66b for 3,4,5-trimethoxy-bromobenzene in Example 62B. 1H NMR (300 MHz, DMSO-d6) 5 10.35 (s, 1H), 8.66 (s, lH), 8.13 (d, lH, J=9.6 Hz), 8.07 (d, 2H, J=7.5 Hz),

7.47-7.66 (m, 1H), 7.46-7.51 (m, 3H), 7.15-7.21 (m, 1H9, 6.87-6.97 (m, 2H), 6.22-6.25 (m, 1H), 6.02-6.07 (m, 2H), 5.65-5.75 (m, 1H), 4.02-4.09 (m, 2H), 3.96-4.02 (m, 2H), 3.67 (s, 3H), 3.59-3.64 (m, 2H), 3.30 (s, 3H), 3.07-3.16 (m, 1H), 2.76 (t, 1H, 12.9 Hz), 2.11-2.38 (m, 1H), 1.94-21.0 (m, 2H9, 1.73-1.85 (m, 1H), 1.48-1.72 (m, 2H), 0.58-1.10 (m, 7H), -0.30- - 0.44 (m, 1H). MS )ESI) m/e 633 (M + H)+. Anal. Calcd for: C36H44N2O8@H2O: C, 66.44; H, 7.12; N, 4.30. Found: C, 66.40; H, 6.97; N, 4.31.

Example 67 Example 67A The described compound 67a was prepared according to the method of Example 16A except substituted methylamine hydrochloride with N,O-dimetheylhydroxyamine hydrochloride.

Example 7B A solution of 67a (0.52 g, 0.35 mole) and Pd/C (52 mg) in EtOH (10 mL) was stirred under H2 for 2 hours, stirred for 30 minutes. The reaction mixture was filtered through Celite and

the residue was washed thoroughly with 10% methanol-CH2Cl2. The filtrate and washings were collected and evaporated to dryness to give 0.47 g of 67b as a off white solid (99%).

Example 67C A solution of 67b (0.47 g, 1.46 mmole) in Et2O (10 mL) at room temperature was treated with saturated aqeoud NaHCO3 (10 mL), stirred for 10 minutes, treated with benzyl chloroformate (0.25 mL, 1.75 mmol), stirred for 2 hours. The mixture was partitioned between water and ether, the aqueous layer was separated and extracted twice with ther. The etheral layer (50 mL) were combined, dried (MgSO4) and concentrated to provide 610.7 mg (92%) of 67 c.

Example 67D A solution of Example 67c (1.67 g, 3.65 mmole) in THF (40 mL) at -78°C was treated with phenyllithium (1.8 M in Et2O and cyclohexane, 7.0 mL, 36.6 g, 1.08 mmole). The mixture was warmed to -15 °C, stirred for 2 hours, and then quenched with saturated ammonium chloride.

The mixture was partitioned between EtOAc and brine, the aqueous layer was separated and extracted three times with EtOAc. The combined organic extracts (100 mL) were dried (MgSO4), and concentrated to an oil. The oil was purified on silica gel with 10-40% EtOAc/haxane to provide 1.17 g (67%) product which was taken up in HVl-dioxane (4N, 10 mL) and stirred for 3 hors. The rsulting slurry was diluted with Et2O (200 mL), filtered and dried under vacuum to give 1.0 g 67d as a white solid (98%).

Example 67E The desired compound 67e was prepared according to the methods of Examples lA, coupling succinate ~ with ketone 67d.

Example 67F A mixture of Example 67e (0.46 g, 0.608 mmol), P(o-tol)3 (37.0 mg, 0.122 mmol), Pd(OAc)2 (14.7 mg, 0.061 mmol) and 3,4,5-trimethoxy bromobenzene (224.4 mg, 0.912 mmol) in acetonitrile (8 mL) under Ar was heated at 75 "C for 14 hours. The mixture was evaporated to dryness and purified on silica gel with 10-40% EtOAc/hexane to provide 511 mg (91%) of 67f.

Example 67G

The desired compound was prepared according to the previous methods. Deprotecion of the silyl ether as in Example 32B and subsequent cyclization as in Example 17 A-B.

Example 67H A solution of Example 67 g (65.3 mg, 0.099 mole) in CH2Cl2 (4 mL) at 0 °C was treated with pyridine (0.032 mL, 0.39 mmol) followed by (0.018 mL, 0.24 mol), warmed to room temperature for 7 hours. The mixture was poured into CH2Cl2 and washed with brine and <BR> <BR> <BR> <BR> saturated aqueous NaHCO3. The organic layer was dried (MgSO4) and concentrated to give 73<BR> mg of 67h as an oil.

Example 67I A solution of 67h (73 mg, 0.099 mmol) in CH2Cl2 (10 mL) room temperature was treated with Dess-Martin reagent (46.1 mg) stirred for 1 hour. The mixture was partitioned between water and CH2Cl2, the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic extracts were washed with aqueous NaHCO3 and brine, dried (MgS04), and concentrated to an oil. The oil was purified on silica gel with 10-40io EtOAc/hexane to provide 39.1 mg (53.7% for the last two steps) product.

Example 673 The desired compound was prepared by the methods of Examples 1F and G, except substituting for 1F. h NMR (300 MHz, DMSO-d6) # -0.48 (m,1H), 0.6-0.8 (m,5H), 1.35- 1.81 (m,3H), 2.0-2.62 (m,4H), 2.73 (m,1H), 2.80 (t, 1H,J = 12.5 Hz), 3.05 (s,3H), 3.19 (dd, 1H, J1= 12.5 Hz), J2 = 4.5 Hz), 3.59 (s,3H), 3.69 (s,6H), 3.73-3.77 (m,2H), 5.73 (m, 1H), 6.23 (s,2H), 7.45 (d, 1H,J = 8.6 Hz), 7.32-7.39 (m,2H), 7.51 (t, 2H,J= 7.6 Hz), 7.56 (d, 1H,J = 8.6 Hz), 7.64 (t, 1H,J = 7.6 Hz), 8.08 (d, 2H,J Hz), 8.71 (s,1H), 10.37 (s,1H); MS (ESI) m/e 718 (M+Na)+, 696 (M+H)+.