INHIBITORS OF PROTEIN ISOPRENYL TRANSFERASES

Technical Field The present invention relates to novel compounds which are useful in inhibiting protein isoprenyl transferases (for example, protein farnesyltransferase and protein geranylgeranyltransferase) and the farnesylation or geranylgeranylation of the oncogene protein Ras and other related small g-proteins, compositions containing such compounds and methods of using such compounds.

Background of the Invention Ras oncogenes are the most frequently identified activated oncogenes in human tumors. Transformed protein Ras is involved in the proliferation of cancer cells. The Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein farnesyltransferase. Inhibition of protein farnesyltransferase, and thereby farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate. Inhibition of protein geranylgeranyltransferase and, thereby, of geranylgeranylation of Ras proteins, also results in down regulation of Ras protein function.

Activation of Ras and other related small g-proteins that are farnesylated and/or geranylated also partially mediates smooth muscle cell proliferation (Circulation, I-3: 88 (1993), which is hereby incorporated herein by reference). Inhibition of protein isoprenyl transferases, and thereby farnesylation or geranylgeranylation of the Ras protein, also aids in the prevention of intimal hyperplasia associated with restenosis and atherosclerosis, a condition which compromises the success of angioplasty and surgical bypass for obstructive vascular lesions.

There is therefore a need for compounds which are inhibitors of protein farnesyltransferase and protein geranylgeranyltransferase.

Summary of the Invention In its principle embodiment, the invention provides a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of (1) hydrogen, (2) alkenyl, (3) alkynyl, (4) alkoxy, (5) haloalkyl, (6) halogen, (7) loweralkyl, (8) thioalkoxy, (9) aryl-L2-wherein aryl is selected from the group consisting of (a) phenyl, (b) naphthyl, (c) dihydronaphthyl, (d) tetrahydronaphthyl, (e) indanyl, and (f) indenyl wherein (a)- (f) are unsubstituted or substituted with at least one of X, Y, or Z wherein X, Y, and Z are independently selected from the group consisting of alkenyl, alkynyl, alkoxy, aryl, carboxy, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, loweralkyl, nitro,

N-protected amino, and -NRR'wherein R and and R'are independently selected from the group consisting of hydrogen and loweralkyl, oxo (=O), and thioalkoxy and L2 is absent or is selected from the group consisting of -CH2-, -CH2CH2-, -CH (CH3)-, -O-, -C(O)-, -S (O) q wherein q is 0,1 or 2, and -N (R)-, and (10) heterocycle-L2-wherein L2 is as defined above and the heterocycle is unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from the group consisting of (a) loweralkyl, (b) hydroxy, (c) hydroxyalkyl, (d) halogen (e) cyano, (f) nitro, (g) oxo (=O), (h)-NRR', (i) N-protected amino, (j) alkoxy, (k) thioalkoxy, (1) haloalkyl, (m) carboxy, and (n) aryl; R2 is selected from the group consisting of

wherein L11 is selected from the group consisting of (a) a covalent bond, (b)-C (W) N (R)- wherein R is defined previously and W is selected from the group consisting of O and S, (c)-C (O)-, (d)-N (R) C (W)-, (e)-CH20-, (f)-C (O) O-, and (g)-CH2N (R)-, R12a is selected from the group consisting of (a) hydrogen, (b) loweralkyl, and (c)-C (O) OR13 wherein R13 is selected from the group consisting of hydrogen and a carboxy-protecting group, and R12b is selected from the group consisting of (a) hydrogen and (b) loweralkyl, with the proviso that R12a and Rí2b are not both hydrogen, (2) -L11-C(R14)(Rv)-C(O)OR15 wherein L I I is defined previously, Rv is selected from the group consisting of (a) hydrogen and (b) loweralkyl, R15 is selected from the group consisting of (a) hydrogen, (b) alkanoyloxyalkyl, (c) loweralkyl, and (b) a carboxy-protecting group, and Rl4 is selected from the group consisting of (a) alkoxyalkyl, (b) alkoxyarylalkyl,

(c) alkoxycarbonylalkyl, (d) alkylsulfinyalkyl, (e) alkylsulfonylalkyl, (f) alkynyl, (g) aminoalkyl, (h) aminocarbonylalkyl, (i) aminothiocarbonylalkyl, 0)aryl.

(k) arylalkyl, (1) carboxyalkyl, (m) cyanoalkyl, (n) cycloalkyl, (o) cycloalkylalkoxyalkyl, (p) cycloalkylalkyl, (q) (heterocyclic) alkyl, (r) hydroxyalkyl, (s) hydroxyarylalkyl, (t) loweralkyl, (u) sulfhydrylalkyl, (v) thioalkoxyalkyl wherein the thioalkoxyalkyl is unsubstituted or substituted with 1,2,3, or 4 substituents selected from the group consisting of halogen, (w) thioalkoxyalkylamino, and (x) thiocycloalkyloxyalkyl, wherein n is 1-3, (4)-C (O) NH-CH (RI4)-C (o) NHSo2Rl6 wherein R14 is defined previously and R16 is selected from the group consisting of (a) loweralkyl, (b) haloalkyl, (c) aryl wherein the aryl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of

loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=0), -NRR' N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl, and (d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=O), -NRR', N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl; (5)-C (O) NH-CH (Rs4)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl, (6)-L11-heterocycle,

(7)-C (O) NH-CH (RI4)-C (O) NRl7Rlg wherein R14 is defined previously and Rl7 and R18 are independently selected from the group consisting of (a) hydrogen, (b) loweralkyl, (c) arylalkyl, (d) hydroxy, and (e) dialkylaminoalkyl, (8)-C (O) OR15, and (9)-C (O) NH-CH (RI4)-heterocycle wherein R14 is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl; Li is absent or is selected from the group consisting of (1)-L4-N (R5)-L5- wherein L4 is absent or selected from the group consisting of (a) Cl-to-Clo-alkylene and (b) C2-to-C16-alkenylene, wherein the alkylene and alkenylene groups are unsubstituted or substituted with 1,2,3 or 4 substitutents independently selected from the group consisting of alkenyl, alkenyloxy, alkenyloxyalkyl, alkenyl [S (O) q] alkyl, alkoxy, alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of halogen and

cycloalkyl, alkylsilyloxy, alkyl [S (O) q], alkyl [S (O) q] alkyl, aryl wherein the aryl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of alkoxy wherein the alkoxy is unsubstituted or substituted with substituents selected from the group consisting of cycloalkyl, aryl, arylalkyl, aryloxy wherein the aryloxy is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of, halogen, nitro, and -NRR', cycloalkyl, halogen, loweralkyl, hydroxyl, nitro, -NRR', and -S02NRR', arylalkoxy wherein the arylalkoxy is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, arylalkyl, arylalkyl [S (O) q] alkyl, aryl [S (O) q], aryl [S (O) q] alkyl wherein the aryl [S (O) q] alkyl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from alkoxy and loweralkyl,

arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, and halogen, aryloxy, aryloxyalkyl wherein the aryloxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of halogen, carboxyl, -C (O) NRCRD wherein Re and RD are independently selected from the group consisting of hydrogen, loweralkyl, and alkoxycarbonyl or Rc and RD together with the nitrogen to which they are attached form a ring selected from the group consisting of morpholine, piperidine, pyrrolidine thiomorpholine, thiomorpholine sulfone, and thiomorpholine sulfoxide, wherein the ring formed by RC and RD together is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy and alkoxyalkyl, cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of alkenyl, cyclolalkoxy, cycloalkoxycarbonyl, cyclolalkoxyalkyl, cyclolalkyl wherein the cycloalkyl is unsubstituted or

substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of aryl, loweralkyl, and alkanoyl, cycloalkylalkoxy, cycloalkylalkoxycarbonyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cyclolalkyl [S (O) q] alkyl, cycloalkylalkyl [S (O) q] alkyl, fluorenyl, heterocycle wherein the heterocycle is unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from the group consisting of alkoxy wherein the alkoxy is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl and cycloalkyl, alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl and cycloalkyl, alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl and cycloalkyl, aryl wherein the aryl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of alkanoyl,

alkoxy, carboxaldehyde, haloalkyl, halogen, loweralkyl, nitro, -NRR', and thioalkoxy, arylalkyl, aryloxy, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, halogen, heterocycle, hydroxyl, loweralkyl wherein the loweralkyl is unsubstituted or substituted with 1,2,-or 3 substituents independently selected from the group consisting of heterocycle, hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, and NRR3R3'wherein RR3 and RR3'are independently selected from the group consisting of hydrogen aryl, loweralkyl, aryl, arylalkyl, heterocycle, (heterocyclic) alkyl, cycloalkyl, and cycloalkylalkyl, and

sulfhydryl, (heterocyclic) alkoxy, (heterocyclic) alkyl, (heterocyclic) alkyl [S (O) q] alkyl, (heterocyclic) oxy, (heterocyclic) alkoxyalkyl, (heterocyclic) oxyalkyl, heterocycle [S (O) q] alkyl, hydroxyl, hydroxyalkyl, imino, N-protected amino, =N-O-aryl,and =N-OH, =N-O-heterocycle wherein the heterocycle is unsubstituted or substituted with 1,2,3, or 4 substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=O), -NRR' N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl, <BR> <BR> <BR> =N-O-loweralkyl,<BR> <BR> <BR> <BR> -NRR3RR3,<BR> <BR> <BR> <BR> <BR> -NHNRcRD, -OG wherein G is a hydroxyl protecting group, -O-NH-R,

wherein J and J'are independently selected from the group consisting of loweralkyl and arylalkyl, oxo, oxyamino (alkyl) carbonylalkyl, oxyamino (arylalkyl) carbonylalkyl, oxyaminocarbonylalkyl, -S02-A wherein A is selected from the group consisting of loweralkyl, aryl, and heterocycle wherein the loweralkyl, aryl, and heterocycle are unsubstituted or substituted with 1,2,3, 4, or 5 substituents independently selected from the group consisting of alkoxy, halogen, haloalkyl, loweralkyl, and nitro, sulfhydryl, thioxo, and thioalkoxy, Ls is absent or selected from the group consisting of (a) C1-to-Cl0-alkylene and (b) C2-to-C16-alkenylene wherein (a) and (b) are unsubstituted or substituted as defined previously, and Rs is selected from the group consisting of hydrogen, alkanoyl wherein the alkanoyl is unsubstituted or substituted with substituents selected from the group consisting of aryl,

alkoxy, alkoxyalkyl, alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of aryl and halogen, alkylaminocarbonylalkyl wherein the alkylaminocarbonylalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl, (anthracenyl)alkyl, aryl, arylalkoxy, arylalkyl wherein the arylalkyl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of alkoxy, aryl, carboxyl, cyano, halogen, haloalkoxy, haloalkyl, nitro, oxo, and -1-11-C (RI4) (Rv)-C (O) OR15, (aryl) oyl wherein the (aryl) oyl is unsubstituted or substituted with substituents selected from the group consisting of halogen, aryloxycarbonyl, carboxaldehyde, -C (O) NRR', cycloalkoxycarbonyl,

cycloalkylaminocarbonyl, cycloalkylaminothiocarbonyl, cyanoalkyl, cyclolalkyl, cycloalkylalkyl wherein the cycloalkylalkyl is unsubstituted or substituted with 1 or 2 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (cyclolalkyl) oyl, (9,10-dihydroanthracenyl) alkyl wherein the (9,10-dihydroanthracenyl) alkyl is unsubstituted or substituted with 1 or 2 oxo substituents, haloalkyl, heterocycle, (heterocyclic) alkyl wherein the (heterocyclic) alkyl is unsubstituted or substituted with 1,2,3,4, or 5 substituents selected from the group consisting of loweralkyl, (heterocyclic) oyl, loweralkyl, wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of-NRR', -S02-A, and thioalkoxyalkyl; (3)-L4-S (O) m-LS-wherein L4 and L5 are defined previously and m is 0,1, or 2, (4)-L4-L6-C (W)-N (R6)-Ls-wherein L4, W, and Ls are defined previously, R6 is selected from the group consisting of (a) hydrogen, (b) loweralkyl, (c) aryl, (d) arylalkyl, (e) heterocycle,

(heterocyclic) alkyl, (g) cyclolakyl, and (h) cycloalkylalkyl, and L6 is absent or is selected from the group consisting of (a)-0-, (b)-S-, and (c)-N (R6,)-wherein R6. is selected from the group consisting of hydrogen, loweralkyl, aryl, arylalkyl, heterocycle, (heterocyclic) alkyl, cyclolakyl, and cycloalkylalkyl, (5)-L4-L6-S(O)m-N(R5)-L5-, (6)-L4-L6-N(R5)-S(O)m-L5-, (7)-L4-N (Rs)-C (W)-L7-L5-wherein L4, R5, W, and and L5 are defined previously and L7 is absent or is selected from the group consisting of-O-and-S-, (8) C1-C10-alkylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of (a) aryl, (b) arylalkyl, (c) heterocycle, (d) (heterocyclic) alkyl, (e) cyclolakyl, cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy,

(9) C2-to-C1o-alkenylene wherein the alkenylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of (a) aryl, (b) arylalkyl, (c) (aryl) oxyalkyl wherein the (aryl) oxyalkyl is unsubstituted or substituted with 1,2,3,4, or 5 substituents selected from the group consisting of halogen, (d) heterocycle, (e) (hererocycle) alkyl, (f) hydroxyalkyl, (g) cyclolakyl, (h) cycloalkylalkyl, (i) alkylthioalkyl, and (j) hydroxy, (10) C2-to-C10-alkynylene wherein the alkynylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of (a) aryl, (b) arylalkyl, (c) heterocycle, (d) (heterocyclic) alkyl, (e) cyclolakyl, cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy, (11)-L4-heterocycle-L5-, (12) a covalent bond, wherein B is selected from the group consisting of loweralkyl and arylalkyl, and

Z is selected from the group consisting of (1) a covalent bond, (2)-0-, (3)-S (O) q-, and (4)-NRz-wherein Rz is selected from the group consisting of (a) hydrogen (b) loweralkyl, (c) aryl, (d) arylalkyl, (e) heterocycle, (f) (heterocyclic) alkyl, (g) cyclolakyl, and (h) cycloalkylalkyl; R3 is selected from the group consisting of (1) hydrogen, (2) aryl, (3) fluorenyl, (4) heterocycle, wherein (2)- (4) are unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of (a) alkanoyl, (b) alkoxy wherein the alkoxy is unsubstituted or substituted with 1, 2,3,4, or 5 substituents independently selected from the group consisting of halogen, aryl, and cycloalkyl, (c) alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2,3,4 or 5 substituents independently selected from the group consisting of aryl and

cycloalkyl, (d) alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of aryl, and cycloalkyl, (e) alkylsilyloxyalkyl, (f) arylalkyl, (g) aryl wherein the aryl is unsubstituted or substituted with 1,2,3, 4, or 5 substituents independently selected from the group consisting of alkanoyl, alkoxy wherein the alkoxy is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of cycloalkyl, carboxaldehyde, haloalkyl, halogen, loweralkyl, nitro, -NRR', and thioalkoxy, (h) arylalkyl, (i) aryloxy wherein the aryloxy is unsubstituted or substituted with 1,2,3,4, or 5 substituents independently selected from the group consisting of, halogen, nitro, and -NRR', (j) (aryl) oyl, (k) carboxaldehyde, (1) carboxy, (m) carboxyalkyl, (n)-C (O) NRR" wherein R is defined previously and R"is selected from the group consisting of hydrogen, loweralkyl, and

carboxyalkyl, (o) cyano, (p) cyanoalkyl, (q) cycloalkyl, (r) cycloalkylalkyl, (s) cycloalkoxyalkyl, (t) halogen, (u) haloalkyl wherein the haloalkyl is unsubstituted or substituted with 1,2,3,4, or 5 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (v) heterocycle, (w) hydroxyl, (x) hydroxyalkyl wherein the hydroxyalkyl is unsubstituted or substituted with substitutients selected from the group consisting of aryl, (y) loweralkyl wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of heterocycle, hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, -NRR3RR3', and -P (O) (OR) (OR'), (z) nitro, (aa)-NRR', (bb) oxo, (cc)-SO2NRARg wherein RA and RB are independently selected from the group consisting of hydrogen, (aryl) oyl, loweralkyl, and heterocycle wherein the heterocycle is unsubstituted or substituted with 1,2, or 3 substituents independently selected from the group consisting of loweralkyl, (dd) sulfhydryl, and

(ee) thioalkoxy, (5) cycloalkyl wherein the cycloalkyl is unsubstituted or substituted with 1,2,3,4 or 5 substituents selected from the group consisting of (a) alkoxy, (b) aryl, (c) arylalkoxy (d) aryloxy wherein the aryloxy is unsubstituted or substituted with 1,2,3,4, or 5 substituents selected from the group consisting of halogen, (e) loweralkyl, (f) halogen, (g) NRR3RR3', (h) oxo, and (6) cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from the group consisting of (a) loweralkyl, (b) alkoxy, (c) halogen, (d) aryl, (e) aryloxy, (f) alkanoyl, and (g) NRR3RR3 wherein Xi and X2 together are cycloalkyl wherein the cycloalkyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of aryl, and (8)-P (W) RR3RR3'; and R4 is selected from the group consisting of

(1) hydrogen, (2) loweralkyl, (3) haloalkyl (4) halogen, (5) aryl, (6) arylalkyl, (7) heterocycle, (8) (heterocyclic) alkyl (9) alkoxy, and (10)-NRR' ; or Ll, Z, and R3 together are selected from the group consisting of (1) aminoalkyl, (1) haloalkyl, (2) halogen, (3) carboxaldehyde, and (4) (carboxaldehyde) alkyl, and (5) hydroxyalkyl, with the proviso that when Ll, Z, and R3 together are (1)- (5), Ri is other than hydrogen.

In a further aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.

In yet another aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of formula I in combination with another chemotherapeutic agent and a pharmaceutically acceptable carrier.

In yet another aspect of the present invention is disclosed a method for inhibiting protein isoprenyl transferases (i. e., protein farnesyltransferase and/or geranylgeranyltransferase) in a human or lower mammal, comprising administering to the patient a therapeutically effective amount of a compound compound of formula I.

In yet another aspect of the present invention is disclosed a method for inhibiting post-translational modification of the oncogenic Ras protein by protein farnesyltransferase, protein geranylgeranyltransferase or both.

In yet another aspect of the present invention is disclosed a method for treatment of conditions mediated by farnesylated or geranylgeranylated proteins, for example, treatment of Ras associated tumors in humans and other mammals.

In yet another aspect of the present invention is disclosed a method for inhibiting or treating cancer in a human or lower mammal comprising administering to the patient a

therapeutically effective amount of a compound of the invention alone or in combination with another chemotherapeutic agent In yet another aspect of the present invention is disclosed a method for treating or preventing intimal hyperplasia associated with restenosis and atherosclerosis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention. The terms"S"and"R" configuration, as used herein, are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45,13-30, which is hereby incorporated herein by reference.

Detailed Description Definitions of Terms As used herein the terms"Cys,""Glu,""Leu,""Lys,""Met,""nor-Leu," "nor-Val,""Phe,""Ser"and"Val"refer to cysteine, glutamine, leucine, lysine, methionine, norleucine, norvaline, phenylalanine, serine and valine in their L-, D-or DL forms. As used herein these amino acids are in their naturally occuring L-form.

As used herein, the term"carboxy protecting group"refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene,"Protective Groups in Organic Synthesis"pp.

152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo (for example by enzymatic hydrolysis) to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in"Pro-drugs as Novel Delivery Systems", Vol 14 of the A. C. S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields (as described in U. S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of"Bioreversible Carriers in Drug Design: Theory and Application", edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference.

Representative carboxy protecting groups are Cl to Cg loweralkyl (e. g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl. for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e. g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1- ethyl, 1-methyl-1- (propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl or cycloalkyloxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1- ethyl, and the like; alkoxycarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; aryloxycarbonyloxyalkyl, such as 2- (phenoxycarbonyloxy) ethyl, 2- (5-indanyloxycarbonyloxy) ethyl and the like; alkoxyalkylcarbonyloxyalkyl, such as 2- (1- methoxy-2-methylpropan-2-oyloxy) ethyl and like; arylalkyloxycarbonyloxyalkyl, such as 2- (benzyloxycarbonyloxy) ethyl and the like; arylalkenyloxycarbonyloxyalkyl, such as 2- (3- phenylpropen-2-yloxycarbonyloxy) ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4- methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5- (loweralkyl)-2- oxo-1,3-dioxolen-4-yl) alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen- 4-yl) methyl and the like.

Preferred carboxy-protected compounds of the invention are compounds wherein the protected carboxy group is a loweralkyl, cycloalkyl or arylalkyl ester, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, amyl ester, isoamyl ester, octyl ester, cyclohexyl ester, phenylethyl ester and the like or an alkanoyloxyalkyl, cycloalkanoyloxyalkyl, aroyloxyalkyl or an arylalkylcarbonyloxyalkyl ester.

The term"N-protecting group"or"N-protected"as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene,"Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated herein by reference. N- protecting groups comprise acyl groups such as forrnyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl)-1-methylethoxycarbonyl, a, a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,- trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term"alkanoyl"as used herein refers to R29C (O)- wherein R29 is a loweralkyl group. The alkanoyl groups of this invention can be optionally substituted.

The term"alkanoylaminoalkyl"as used herein refers to a loweralkyl radical to which is appended R71-NH-wherein R71 is an alkanoyl group. The alkanoylaminoalkyi groups of this invention can be optionally substituted.

The term"alkanoyloxy"as used herein refers to R29C (O)-O- wherein R29 is a loweralkyl group. The alkanoyloxy groups of this invention can be optionally substituted.

The term"alkanoyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended an alkanoyloxy group. The alkanoyloxyalkyl groups of this invention can be optionally substituted.

The term"alkenyl"as used herein refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenyl include-CH=CH2.-CH2CH=CH2,-C (CH3) =CH2,

-CH2CH=CHCH3, and the like. The alkenyl groups of this invention can be optionally substituted.

The term"alkenylene"as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 20 carbon atoms and also 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 alkenylene groups of this invention can be optionally substituted.

The term"alkenyloxy"as used hereiwrefers to an alkenyl group attached to the parent molecular group through an oxygen atom. The alkenyloxy groups of this invention can be optionally substituted.

The term"alkenyloxyalkyl"as used herein refers to a loweralkyl group to which is attached an alkenyloxy group. The alkenyloxyalkyl groups of this invention can be optionally substituted.

The term"alkoxy"as used herein refers to R30O-wherein R30 is loweralkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t- butoxy and the like. The alkoxy groups of this invention can be optionally substituted.

The term"alkoxyalkyl"as used herein refers to a loweralkyl group to which is attached an alkoxy group. The alkoxyalkyl groups of this invention can be optionally substituted.

The term"alkoxyalkoxy"as used herein refers to R310-R320-wherein R31 is loweralkyl as defined above and R32 is an alkylene radical. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The alkoxyalkoxy groups of this invention can be optionally substituted.

The term"alkoxyalkyl"as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. The alkoxyalkyl groups of this invention can be optionally substituted.

The term"alkoxyalkylcarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R66-C (O)-O- wherein R66 is an alkoxyalkyl group.

The term"alkoxyarylalkyl"as used herein refers to a an arylalkyl group to which is attached an alkoxy group. The alkoxyarylalkyl groups of this invention can be optionally substituted.

The term"alkoxycarbonyl"as used herein refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. The alkoxycarbonyl groups of this invention can be optionally substituted. The alkoxycarbonyl groups of this invention can be optionally substituted.

The term"alkoxycarbonylalkyl"as used herein refers to an alkoxylcarbonyl group as previously defined appended to a loweralkyl radical. Examples of. alkoxycarbonylalkyl include methoxycarbonylmethyl, 2-ethoxycarbonylethyl and the like. The alkoxycarbonylalkyl groups of this invention can be optionally substituted.

The term"alkoxycarbonylaminoalkyl"as used herein refers to a loweralkyl radical to which is appended R69-NH-wherein R69 is an alkoxycarbonyl group. The alkoxycarbonylaminoalkyl groups of this invention can be optionally substituted.

The term"alkoxycarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R63-O-wherein R63 is an alkoxycarbonyl group. The alkoxycarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"alkylamino"as used herein refers to R35NH-wherein R35 is a loweralkyl group, for example, methylamino, ethylamino, butylamino, and the like. The alkylamino groups of this invention can be optionally substituted.

The term"alkylaminoalkyl"as used herein refers a loweralkyl radical to which is appended an alkylamino group. The alkylaminoalkyl groups of this invention can be optionally substituted.

The term"alkylaminocarbonylaminoalkyl"as used herein refers to a loweralkyl radical to which is appended R70-C (O)-NH-wherein R70 is an alkylamino group. The alkylaminocarbonylaminoalkyl groups of this invention can be optionally substituted.

The term"alkylene"as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like. The alkylene groups of this invention can be optionally substituted.

The term"alkylsilyloxy"as used herein refers to a loweralkyl group to which is attached-OSiRw Rx*RyX wherein Rw, Rx, and Ry are selected from the group consisting of loweralkyl.

The term"alkylsulfinyl"as used herein refers to R33S (O)- wherein R33 is a loweralkyl group. The alkylsulfinyl groups of this invention can be optionally substituted.

The term"alkylsulfinylalkyl"as used herein refers to an alkyl group to which is attached a alkylsulfinyl group. The alkylsulfinylalkyl groups of this invention can be optionally substituted.

The term"alkylsulfonyl"as used herein refers to R34S (O) 2- wherein R34 is a loweralkyl group. The alkylsulfonyl groups of this invention can be optionally substituted.

The term"alkylsulfonylalkyl"as used herein refers to a loweralkyl radical to which is appended an alkylsulfonyl group. The alkylsulfonylalkyl groups of this invention can be optionally substituted.

The term alkylthioalkyl as used herein refers to a lower alkyl group as defined herein attached to the parent molecular moiety through a sulfur atom and an alkylene group. The alkylthioalkyl groups of this invention can be optionally substituted.

The term"alkynyl"as used herein refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include-C=CH,-CH2C_CH,-CH2C-CCH3, and the like.

The alkynyl groups of this invention can be optionally substituted.

The term"alkynylene"as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynylene include-C-C-, -CH2CzC-,-CH2CzCCH2-, and the like. The alkynylene groups of this invention can be optionally substituted.

The term"amino"as used herein refers to-NH2.

The term"aminocarbonyl"as used herein refers to an amino group attached to the parent molecular group through a carbonyl group. The aminocarbonyl groups of this invention can be optionally substituted.

The term"aminocarbonylalkyl"as used herein refers to an alkyl group to which is attached an aminocarbonyl group. The aminocarbonylalkyl groups of this invention can be optionally substituted.

The term"aminoalkyl"as used herein refers to a loweralkyl radical to which is appended an amino group. The aminoalkyl groups of this invention can be optionally substituted.

The term"aminothiocarbonyl"as used herein refers to an amino group attached to the parent molecular group through a thiocarbonylcarbonyl (C=S) group. The aminothiocarbonyl groups of this invention can be optionally substituted.

The term"aroyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended an aroyloxy group (i. e., R61-C (O) O- wherein R61 is an aryl group). The aroyloxyalkyl groups of this invention can be optionally substituted.

The term"aryl"as used herein refers to a mono-or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, sulfhydryl, nitro, cyano, carboxaldehyde, carboxy, alkoxycarbonyl, haloalkyl-C (O)-NH-, haloalkenyl-C (O)-NH-and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term"arylalkenyl"as used herein refers to an alkenyl radical to which is appended an aryl group. The arylalkenyl groups of this invention can be optionally substituted.

The term"arylalkenyloxycarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R68-O-C (O)-O-wherein R68 is an arylalkenyl group. The arylalkenyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"arylalkoxy"as used herein refers to an alkoxy group to which is attached an aryl group. The arylalkoxy groups of this invention can be optionally substituted.

The term"arylalkyl"as used herein refers to a loweralkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like. The arylalkyl groups of this invention can be optionally substituted.

The term"arylalkylcarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i. e., R62C (O) O-wherein R62 is an arylalkyl group). The arylalkylcarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"aryloxy"as used herein refers to an aryl group attached to the parent molecular group through an oxygen atom. The aryloxy groups of this invention can be optionally substituted.

The term"aryloxycarbonyl"as used herein refers to an aryloxy group attached to the parent molecular group through a carbonyl group. The aryloxycarbonyl groups of this invention can be optionally substituted.

The term"aryloyl"as used herein refers to an aryl group attached to the parent molecular group through a carbonyl group. The aryloyl groups of this invention can be optionally substituted.

The term"arylalkyloxycarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R67-0-C (O)-O- wherein R67 is an arylalkyl group. The arylalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"aryloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R65-O-wherein R65 is an aryl group. The aryloxyalkyl groups of this invention can be optionally substituted.

The term"arylalkoxy"as used herein refers to an alkoxy radical to which is appended R65-O-wherein R65 is an aryl group. The arylalkoxy groups of this invention can be optionally substituted.

The term"arylalkyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group. The arylalkyloxyalkyl groups of this invention can be optionally substituted.

The term"aryloxy"as used herein refers to R65-O-wherein R65 is an aryl group.

The aryloxy groups of this invention can be optionally substituted. The aryloxy groups of this invention can be optionally substituted.

The term" (aryl) oyl" as used herein refers to an aryl group attached to the parent molecular group through a carbonyl group. The (aryl) oyl groups of this invention can be optionally substituted.

The term"aryloxythioalkoxyalkyl"as used herein refers to a loweralkyl radical to which is appended R75-S-wherein R75 is an aryloxyalkyl group. The aryloxythioalkoxyalkyl groups of this invention can be optionally substituted.

The term"aryloxycarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R65-O-C (O)-O- wherein R65 is an aryl group. The aryloxycarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"arylsulfonyl"as used herein refers to R36S (O) 2- wherein R36 is an aryl group. The arylsulfonyl groups of this invention can be optionally substituted.

The term"arylsulfonyloxy"as used herein refers to R37S (O) 20- wherein R37 is an aryl group. The arylsulfonyloxy groups of this invention can be optionally substituted.

The term"carboxy"as used herein refers to-COOH.

The term"carboxyalkyl"as used herein refers to a loweralkyl radical to which is appended a carboxy (-COOH) group. The carboxyalkyl groups of this invention can be optionally substituted.

The term"cyanoalkyl"as used herein used herein refers to a loweralkyl radical to which is appended a cyano (-CN) group. The cyanoalkyl groups of this invention can be optionally substituted.

The term"carboxaldehyde"as used herein used herein refers to-CHO.

The term" (carboxaldehyde) alkyl" as used herein used herein refers to a carboxaldehyde group attached to a loweralkyl group. The (carboxaldehyde) alkyl groups of this invention can be optionally substituted.

The terms"cycloalkanoyl"and" (cycloalkyl) oyl" refer to a cycloalkyl group attached to the parent molecular group through a carbonyl group. The cycloalkanoyl and (cycloalkyl) oyl groups of this invention can be optionally substituted.

The term"cycloalkanoylalkyl"as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyl group (i. e., R60-C (O)- wherein R60 is a cycloalkyl group).

The cycloalkanoylalkyl groups of this invention can be optionally substituted.

The term"cycloalkylalkoxyalkyl"as used herein refers to an alkoxyalkyl group to which is attached a cycloalkyl group. The cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.

The term"cycloalkenyl"as used herein refers to an alicyclic group comprising from 3 to 10 carbon atoms and containing a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like. The cycloalkenyl groups of this invention can be optionally substituted.

The term"cycloalkoxy"as used herein refers to a cycloalkyl group attached to the parent molecular group through an oxygen atom. The cycloalkoxy groups of this invention can be optionally substituted.

The term"cycloalkoxyalkyl"as used herein refers to a loweralkyl group to which is attached a cycloalkoxy group. The cycloalkoxyalkyl groups of this invention can be optionally substituted.

The term"cycloalkoxycarbonyl"as used herein refers to a cycloalkoxy group attached to the parent molecular group through a carbonyl group. The cycloalkoxycarbonyl groups of this invention can be optionally substituted.

The term"cycloalkyl"as used herein refers to an alicyclic group comprising from 3 to 10 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like. The cycloalkyl groups of this invention can be optionally substituted. The cycloalkyl groups of this invention can be optionally substituted.

The term"cycloalkylaminocarbonyl"as used herein refers to NHR60 (O)- wherein R60 is group. cycloalkyl cycloalkylaminocarbonyl groups cycloalkylaminocarbonyl groups invention this invention optionally substituted.

The term"cycloalkylaminothiocarbonyl"as used herein refers to NHR60fC (S)- wherein R60 is defined above. The cycloalkylaminothiocarbonyl groups of this invention can be optionally substituted.

The term"cycloalkylalkoxy"as used herein refers to an alkoxy radical to which is appended a cycloalkyl group. The cycloalkylalkoxy groups of this invention can be optionally substituted.

The term"cycloalkylalkoxyalkyl"as used herein refers to an alkyl radical to which is appended a cycloalkylalkoxy group. The cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.

The term"cycloalkylalkoxycarbonyl"as used herein refers to a cycloalkylalkoxy radical attached to the parent molecular group through a carbonyl group. The cycloalkylalkoxycarbonyl groups of this invention can be optionally substituted.

The term"cycloalkylalkyl"as used herein refers to a loweralkyl radical to which is appended a cycloalkyl group. Representative examples of cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl, 2- (cyclopropyl) ethyl, adamantylmethyl and the like.

The cycloalkylalkyl groups of this invention can be optionally substituted.

The term"cycloalkyloxycarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R64-O-C (O)-O- wherein R64 is a cycloalkyl group. The cycloalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"dialkoxyalkyl"as used herein refers to a loweralkyl radical to which is appended two alkoxy groups. The dialkoxyalkyl groups of this invention can be optionally substituted.

The term"dialkylamino"as used herein refers to R3gR39N-wherein R38 and R39 are independently selected from loweralkyl, for example dimethylamino, diethylamino, methyl propylamino, and the like. The dialkylamino groups of this invention can be optionally substituted.

The term"dialkylaminoalkyl"as used herein refers to a loweralkyl radical to which is appended a dialkylamino group. The dialkylaminoalkyl groups of this invention can be optionally substituted.

The term"dialkyaminocarbonylalkyl"as used herein refers to a loweralkyl radical to which is appended R73-C (O)- wherein R73 is a dialkylamino group. The dialkyaminocarbonylalkyl groups of this invention can be optionally substituted.

The term"dioxoalkyl"as used herein refers to a loweralkyl radical which is substituted with two oxo (=O) groups. The dioxoalkyl groups of this invention can be optionally substituted.

The term"dithioalkoxyalkyl"as used herein refers to a loweralkyl radical to which is appended two thioalkoxy groups. The dithioalkoxyalkyl groups of this invention can be optionally substituted.

The term"halogen"or"halo"as used herein refers to I, Br, Cl or F.

The term"haloalkenyl"as used herein refers to an alkenyl radical, as defined above, bearing at least one halogen substituent. The haloalkenyl groups of this invention can be optionally substituted.

The term"haloalkyl"as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like. Haloalkyl can also include perfluoroalkyl wherein all hydrogens of a loweralkyl group are replaced with fluorides.

The term"heterocyclic ring"or"heterocyclic"or"heterocycle"as used herein refers to a 5-, 6-or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 5-, 6-or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent

positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-and 7-membered rings have 0-3 double bonds. The term "heterocyclic"also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like). Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl and benzothienyl. Heterocyclics also include bridged bicyclic groups wherein a monocyclic heterocyclic group is bridged by an alkylene group, for example, and the like.

Heterocyclics also include compounds of the formula wherein X* is-CH2-,-CH2O-or-O-and Y* is-C (O)- or- (C (R") 2)-wherein R"is hydrogen or Cl-C4-alkyl and v is 1,2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.

Heterocyclics can be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of a) hydroxy, b)-SH, c) halo, d) oxo (=O), e) thioxo (=S), f) amino, g)-NHOH, h) alkylamino, i) dialkylamino, j) alkoxy, k) alkoxyalkoxy, 1) haloalkyl, m) hydroxyalkyl, n) alkoxyalkyl, o) cycloalkyl which is unsubstituted or substituted with one, two, three or four

loweralkyl groups, p) cycloalkenyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, q) alkenyl, r) alkynyl, s) aryl, t) arylalkyl, u)-COOH, v) -SO3H, w) loweralkyl, x) alkoxycarbonyl, y)-C (O) NH2, z)-C (S) NH2, aa)-C (=N- OH) NH2, bb) aryl-L16-C (O)- wherein L16 is an alkenylene radical, cc)-S-L17-C (O) OR40 wherein Ljy is an alkylene radical which is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or methinylamino (=CHNR4lR42 wherein R41 is hydrogen or loweralkyl and R42 is loweralkyl) and R40 is hydrogen or a carboxy-protecting group, dd)-S-LI8-C (O) NR43R44 wherein L. o is an alkylene radical which is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or methinylamino (=CHNR4lR42 wherein R41 is hydrogen or loweralkyl and R43 and R44 are independently selected from the group consisting of hydrogen, loweralkyl and aryl, ee) -S-Llg-CN wherein L19 is an alkylene radical, ff)-S-L20-R45 wherein L20 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with oxo (=O) and R is hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, gg)-O-L21-R46 wherein L21 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or methinylamino (=CHNR4lR42 wherein R41 is hydrogen or loweralkyl and R46 is hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, hh)-O-S (0) 2-R47 wherein R47 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, ii)-S (0) 2-NH-R48 wherein R48 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, jj) alkylsulfinyl, kk) alkylsulfonyl, 11) arylsulfonyl, mm) arylsulfonyloxy, nn)-C (=NOR49) C (O) OR50 wherein R49 is hydrogen or loweralkyl and R50 is hydrogen or a carboxy-protecting group, oo) alkoxycarbonylalkyl,

pp) carboxyalkyl, qq) cyanoalkyl, rr) alkylaminoalkyl, ss) N-protected alkylaminoalkyl, tt) dialkylaminoalkyl, uu) dioxoalkyl, vv) loweralkyl-C (O)-, ww) loweralkyl-C (S)-, xx) aryl- C (O)-, yy) aryl-C (S)-, zz) loweralkyl-C (O)-O-, aaa) loweralkyl-S-C (S)- bbb) N-protected amino, ccc) aminoalkyl-C (O)-, ddd) N-protected aminoalkyl-C (O)- eee) aminoalkyl-C (S)-, fff) N-protected aminoalkyl-C (S)-, ggg) aminoalkyl, hhh) N-protected aminoalkyl, iii) formyl, jjj) cyano, kkk) nitro, 111) spiroalkyl, mmm) oxoalkyloxy, nnn) R53-L22-, wherein L22 is alkenylene or alkynylene and R53 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, ooo) aryl-NH-C (O)-, ppp) R54- N=N-wherein R54 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, qqq) =N-R55 wherein R55 is hydrogen, aryl, heterocyclic,-S (O) 2-aryl or-S (O) 2-heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, rrr) diarylalkyl-N=N-, sss) aryl- N (R56)- or arylalkyl-N (R56)- wherein R56 is hydrogen or an N-protecting group, ttt) aryl- sulfonylalkyl, uuu) heterocyclicsulfonylalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, vvv) =C (CN) (C (O) NH2), www) =C (CN) (C (O) O-loweralkyl), xxx) heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, yyy) hydroxythioalkoxy, zzz) aryloxyalkyl, aaaa) aryloxyalkylthioalkoxy, bbbb) dialkoxyalkyl, cccc) dithioalkoxyalkyl, dddd) arylalkyl-NH-L23-wherein L23 is an alkylene group, eeee) heterocyclicalkyl-NH- L24-wherein L24 is an alkylene group, ffff) aryl-S (O) 2-NH-L25- wherein L25 is an alkylene group, gggg) heterocyclic-S (O) 2-NH-L26- wherein L26 is an alkylene group, hhhh) aryl- C (O)-NH-L27- wherein L27 is an alkylene group and iiii) heterocyclic-C (O)-NH-L28- wherein L28 is an alkylene group, jjj) Ryy (CH2) n-X-Y-Z- (CH2) m wherein Ryy is cycloalkyl, aryl and loweralkyl, n amd m are independently 0-2, Z is O or absent, Y is absent, CH2, CHOH or C (O), with the proviso that when X is O, Z is absent and with the proviso that when Z is O, X is absent and with the proviso that when Y is CHOH, X and Z are absent.

The term" (heterocyclic) alkoxy" as used herein refers to an alkoxy group to which is attached a heterocycle. The (heterocyclic) alkoxy groups of this invention can be optionally substituted.

The term" (heterocyclic) alkyl" as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above. Examples of heterocyclic alkyl include 2-pyridylmethyl, 4-pyridylmethyl, 4-quinolinylmethyl and the like. The (heterocyclic) alkyl groups of this invention can be optionally substituted.

The term" (heterocyclic) oxy" as used herein refers to a heterocycle connected to the parent molecular group through an oxygen atom. The (heterocyclic) oxy groups of this invention can be optionally substituted.

The term" (heterocyclic) oxyalkyl" as used herein refers to a loweralkyl group to which is attached a (heterocyclic) oxy group. The (heterocyclic) oxyalkyl groups of this invention can be optionally substituted.

The term" (heterocyclic) alkoxyalkyl" as used herein refers to an alkoxyalkyl group to which is attached a heterocycle. The (heterocyclic) alkoxyalkyl groups of this invention can be optionally substituted.

The term"heterocycliccarbonyloxyalkyl"as used herein refers to a loweralkyl radical to which is appended R72-C (O)-O- wherein R72 is a heterocyclic group. The heterocycliccarbonyloxyalkyl groups of this invention can be optionally substituted.

The term"hydroxy"as used herein refers to-OH.

The term"hydroxyalkyl"as used herein refers to a loweralkyl radical to which is appended an hydroxy group. The hydroxyalkyl groups of this invention can be optionally substituted.

The term"hydroxyarylalkyl"as used herein refers to a arylalkyl group to which is appended a hydroxy group. The hydroxyarylalkyl groups of this invention can be optionally substituted.

The term"hydroxythioalkoxy"as used herein refers to R51S-wherein R51 is a hydroxyalkyl group. The hydroxythioalkoxy groups of this invention can be optionally substituted.

The term"loweralkyl"as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n- butyl, t-butyl, neopentyl and the like. The loweralkyl groups of this invention can be optionally substituted.

The term"N-protected alkylaminoalkyl"as used herein refers to an alkylaminoalkyl group wherein the nitrogen is N-protected. The N-protected alkylaminoalkyl groups of this invention can be optionally substituted.

The term"nitro"as used herein refers to-N02.

The term"oxo"as used herein refers to (=O).

The term"oxoalkyloxy"as used herein refers to an alkoxy radical wherein the loweralkyl moiety is substituted with an oxo (=O) group. The oxoalkyloxy groups of this invention can be optionally substituted.

The term"oxyamino (alkyl) carbonylalkyl" as used herein refers to a -O-NR-C (O)-R' group wherein R and R'are loweralkyl.

The term"oxyamino (arylalkyl) carbonylalkyl" as used herein refers to a -O-NRR3-C (O)-R group wherein RR3 is arylalkyl and R is loweralkyl.

The term"oxyaminocarbonylalkyl"as used herein refers to-O-NH-C (O)-R group wherein R is loweralkyl.

The term"spiroalkyl"as used herein refers to an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group.

The spiroalkyl groups of this invention can be optionally substituted : The term"sulfhydryl"as used herein refers to-SH.

The term"sulfhydrylalkyl"as used herein refers to a loweralkyl group to which is attached a sulfhydryl group. The sulfhydrylalkyl groups of this invention can be optionally substituted.

The term"thioalkoxy"as used herein refers to R52S-wherein R52 is loweralkyl.

Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.

The thioalkoxy groups of this invention can be optionally substituted.

The term"thioalkoxyalkyl"as used herein refers to a thioalkoxy group as previously defined appended to a loweralkyl group as previously defined. Examples of thioalkoxyalkyl include thiomethoxymethyl, 2-thiomethoxyethyl and the like. The thioalkoxyalkyl groups of this invention can be optionally substituted.

The term"thiocycloalkoxy"as used herein refers to a cycloalkyl group attached to the parent molecular group through a sulfur atom. The thiocycloalkoxy groups of this invention can be optionally substituted.

The term"thiocycloalkoxyalkyl"as used herein refers to a loweralkyl group to which is attached a thiocycloalkoxy group. The thiocycloalkoxyalkyl groups of this invention can be optionally substituted.

Preferred embodiments Preferred compounds of the invention are compounds of formula I wherein R1 is unsubstituted or substituted phenyl and R2 is-C (O) NH-CH (RI4)-C (O) OR15 or -C (O) NH-CH (RI4)-C (O) NHS02Rl6 wherein L2, R14 R15 and R16 are defined above.

More preferred compounds of the invention are compounds of formula I wherein Ru is unsubstituted or substituted phenyl and R2 is

Still more preferred compounds have formula I wherein R3 is selected from the group consisting of (a) pyridyl, (b) imidazolyl, and (c) furyl wherein the pyridyl, imidazolyl, or furyl group may be substituted with 1,2 or 3 substituents selected from the group consisting of aryl, loweralkyl, halo, nitro, haloalkyl, hydroxy, hydroxyalkyl, amino, N-protected amino, alkoxy, and thioalkoxy.

Still more preferred compounds of the invention have the structure defined immediatelv above wherein R, is unsubstituted or substituted phenyl and Ri is The most preferred compounds have the structure defined immediately above wherein R3 is unsubstituted or substituted pyridyl or imidazolyl.

Protein Farnesvltransferase Inhibition The ability of the compounds of the invention to inhibit protein farnesyltransferase or protein geranylgeranyltransferase can be measured according to the method of Moores, et al., J. Biol. Chem. 266: 14603 (1991) or the method of Vogt, et al., J. Biol. Chem.

270: 660-664 (1995). In addition, procedures for determination of the inhibition of farnesylation of the oncogene protein Ras are described by Goldstein, et al., J. Biol.

Chem., 266: 15575-15578 (1991) and by Singh in United States Patent No. 5,245,061.

In addition, in vitro inhibition of protein farnesyltransferase may be measured by the following procedure. Rat brain protein farnesyltransferase activity is measured using an Amersham Life Science commercial scintillation proximity assay kit and substituting a biotin-K Ras B fragment (biotin-Lys-Lys-Ser-Lys-Thr-Lys-Cys-Val-Ile-Met-CO2H), 0.1 mM final concentration, for the biotin-lamin substrate provided by Amersham. The enzyme is purified according to Reiss, Y., et al., Cell, 62: 81-88 (1990), utilizing steps one through three. The specific activity of the enzyme is approximately 10 nmol substrate farnesylated/mg enzyme/hour. The percent inhibition of the farnesylation caused by the compounds of the invention (at 10 x 10-6 M) compared to an uninhibited control sample is evaluated in the same Amersham test system.

The % inhibition of protein farnesyltransferase was determined for representative compounds of the invention. The results are summarized in Table 1.

Tables 1-5 In Vitro Potencies of Representative Compounds Table 1. Inhibition of farnesyltransferase % inhibition % inhibition Example at 1 X 10-5 M Example at 1X 10-5 M 200 93 674 40 350 53 676 76 351 82 678 73 352 52 680 58 353 62 683 57 354 47 684 48 355 43 685 55 356 58 686 48 357 56 687 78 358 45 688 71 359 36 689 73 360 88 690 61 361 97 692 74 362 83 699 74 363 96 700 68 364 69 701 64 365 97 702 79 366 83 704 67 367 81 705 72 368 71 706 53 369 87 707 66 370 86 708 76 371 66 709 55 372 69 710 45 373 76 711 46 374 61 712 69 375 68 713 40 376 80 714 56 377 71 715 67 378 54 717 75 380 45 718 40 381 79 750 44 382 > 50 752 58 5075355383> 5075440387> 5075544388> 390 > 50 756 47 639 44 757 58 659 55 758 46 663 43 759 49 664 75 952 > 50 9555066952 974>5067078 672 48 Table 2. Inhibition of farnesvltransferase % inhibition Nc inhibition Example at ExampleM at 1X10-6 M 5839815792 158 2 587 97 159 84 595 97 160 30 607 96 161 54 610 94 162 12 613 97 163 18 617 99 164 92 620 98 165 74 626 61 166 97 627 85 167 98 632 43 168 92 633 32 183 98 636 72 184 36 641 34 185 93 642 48 186 86 644 54 187 68 386 > 50 188 40 399 > 50 189 88 403 99 190 4 404 98 191 28 405 98 192 95 406 95 193 4 407 98 196 43 435 96 197 1 451 85 201 63 452 96 202 31 453 90 203 76 456 81 204 98 457 92 205 98 460 88 206 67 463 91 207 98 465 92 208 98 466 93 209 74 467 97 210 5 468 96 211 98 469 92 212 12 470 95 213 98 471 94 214 97 472 97 215 82 473 96 216 67 474 92 217 99 475 21 218 89 476 91 219 56 477 98 220 92 478 98 221 55 479 95 222 41 480 87 223 63 481 95 224 41 488 41 225 93 494 96 226 23 495 95 227 94 496 93 228 39 497 94 231 50 498 98 233 65 499 98 234 4 500 98 235 95 501 84 237 98 502 24 238 22 503 57 239 97 504 90 240 98 505 72 241 41 507 95 242 99 507 96 243 23 508 95 244 21 509 77 245 50 510 84 248 79 512 94 249 77 513 96 250 96 514 94 252 98 515 72 253 99 516 95 254 96 525 99 255 98 528 99 256 98 529 99 257 98 530 94 258 98 537 97 259 98 540 40 260 98 645 37 261 98 646 58 262 98 649 86 263 99 650 68 264 98 651 33 265 98 652 41 266 97 653 62 267 96 655 35 268 98 657 32 269 98 658 73 270 98 661 45 271 84 662 68 272 96 665 55 273 96 666 82 274 94 667 83 276 98 671 36 277 98 673 59 278 99 677 37 279 99 682 31 280 98 691 34 281 98 693 53 282 76 694 45 283 98 696 57 284 83 697 39 286 84 703 40 287 24 716 69 288 22 719 90 289 23 720 70 290 74 721 83 291 23 722 96 292 36 723 87 294 98 724 87 295 94 725 78 296 89 726 81 297 65 727 95 298 43 744 84 299 94 749 84 300 22 751 32 301 98 764 88 302 31 765 76 304 99 768 67 305 99 771 72 306 99 772 79 307 82 773 41 308 62 774 48 309 98 775 32 310 98 776 36 311 97 777 83 313 94 782 96 314 97 786 34 315 93 787 70 316 63 788 44 317 54 789 86 318 98 790 88 319 98 791 53 320 93 792 88 321 90 793 94 322 98 794 92 323 98 796 35 324 98 797 35 325 99 806 72 326 91 807 90 327 97 808 88 328 96 809 78 329 98 810 89 330 98 812 94 331 98 813 95 332 26 816 87 333 99 824 90 334 93 831 92 343 72 832 80 344 95 834 55 345 91 835 96 346 98 844 92 347 95 846 85 348 66 850 90 349 99 862 95 379 21 866 62 541 37 867 71 542 67 868 89 544 35 872 74 545 88 878 95 546 97 879 95 547 91 886 35 550 96 889 95 78 902 85 728 552 88 903 78 553 92 908 88 554 96 910 42 555 85 911 65 556 99 918 97 557 93 923 78 560 91 924 77 561 91 925 87 564 98 926 69 565 94 936 69 566 98 937 95 568 93 962 > 50 569 91 964 >50 572 91 979 26 575 70 982 64 576 88 987 93 577 94 988 92 9898858299 1390 Table 3. Inhibition of famesvitransferase % inhibition % inhibition Example at 1 X 1 Ov M Exam le at lux10-7 M 434 93 623 96 436 89 729 73 437 89 730 96 438 90 731 65 439 80 732 84 440 92 733 60 441 91 734 49 442 88 735 96 443 97 736 96 444 95 737 95 445 94 738 54 446 91 739 83 447 91 740 94 448 92 741 89 449 91 742 87 450 96 743 51 455 83 745 93 458 87 746 84 459 92 747 68 461 93 748 56 462 91 769 90 464 86 770 91 482 96 781 91 483 95 785 96 484 97 795 87 485 96 798 95 486 97 799 96 487 81 800 74 489 86 801 87 490 70 802 88 491 94 811 85 492 95 814 81 493 51 815 71 511 82 817 60 519 89 818 78 520 97 822 93 521 94 823 75 522 93 825 79 523 97 839 63 524 99 849 66 526 96 854 78 527 97 855 92 531 74 856 97 532 88 857 92 533 91 859 86 534 84 861 65 535 89 863 72 536 79 864 84 539 89 865 95 548 86 869 92 549 98 874 90 551 93 875 92 558 87 876 92 559 96 891 94 562 95 893 87 563 95 894 89 570 92 895 92 571 88 896 96 573 72 900 95 574 81 906 88 578 90 912 85 579 92 913 89 580 90 914 91 581 96 917 78 584 96 919 91 585 96 921 82 589 91 929 81 590 95 931 98 592 93 933 91 9357259386 594 95 940 92 597 75 941 90 600 93 945 80 601 92 947 79 602 97 948 75 604 86 949 57 609 95 950 71 611 95 951 71 615 94 959 > 50 616 95 983 66 618 89 984 86 621 98 990 84 9939062295 Table 4. Inhibition offarnesyltransferase % inhibition % inhibition Example at 1X10-8 M Example at lux10-8 M 384 91 851 82 397 50 852 79 398 > 50 853 85 400 98 858 60 401 66 860 85 408 > 95 870 91 409 84 871 94 410 94 873 97 517 92 877 68 518 90 880 95 567 69 881 69 586 90 882 79 588 68 883 91 591 82 884 94 599 86 885 95 603 94 887 92 605 68 888 86 606 93 892 59 608 91 897 76 612 96 898 82 614 92 899 88 619 95 901 84 760 95 904 85 762 84 905 86 763 92 907 79 766 95 909 79 767 97 916 96 779 70 920 96 780 71 922 96 803 95 927 74 804 95 928 84 805 96 930 66 819 76 932 60 820 66 934 71 821 75 938 61 826 92 939 72 827-77 942 58 828 87 943 79 829 92 944 88 833 78 946 52 836 95 954 > 50 837 91 958 > 50 838 92 960 > 50 840 73 985 89 841 93 986 95 842 88 991 69 843 96 992 93 845 85 994 83 847 85 995 92 848 87 996 80 Table 5. Inhibition of geranvlseranvltransferase I.

ExampleActivity 387 > 50% inhibition at 1 X 10-6 M 388 > 50% inhibition at 1 X 10-7 M 389 > 50% inhibition at 1 X 10-6 M 390 > 50% inhibition at 1 X 10-5 M 392 > 50% inhibition at 1 X 10-5 M 399 > 50% inhibition at 1 X 10-6 M 953 > 50% inhibition at 1 X 10-6 M 955 > 50% inhibition at 1 X 10-7 M 962 > 50% inhibition at 1 X 10-7 M 964 > 50% inhibition at 1 X 10-6 M 966 > 50% inhibition at 1 X 10-6 M 967 > 50% inhibition at 1 X 10-6 M 969 > 50% inhibition at 1 X 10-5 M 974 > 50% inhibition at 1 X 10-5 M 1395 Table 6. Inhibition of farnesyltransferase at concentrations of 10 mM and 1 mM unless specified as * (0.1 mM) or ** (0. 01 mM) Example % inhibition % inhibition Example % 1mM10mM1mM10mM 997 91 1199 71 120097*99879** 999 90 1201 73* 96**82*1202 1001 92** 1203 84* 120493*100282** 120555**100392* 1004 92** 1206 63** 1005 95** 1207 91* 1006 95** 1208 89* 120987*100785** 121064**100895** 1009 86** 1211 94 101090*121286* 121379**101192** 121492**101288* 121517101380* 121688**101491 121787*101559* 121854**101692* 121985**101751* 1220101897 1019 82**1221 1020 89*1222 122391**102193* 122488*102291** 122592**102389** 122669**102489** 122791102591** 122888*102674** 122966**102781** 123077**102892** 123193*102982** 123268**103092** 123377**103190** 123471**103293** 123586**103376** 1034 83**1236 123789**103576 123891**103679 123985*103788 124064**103857 124174*103989** 124275*104090** 124395*104148 124484104288 124592104390* 124682104476* 124795*104586* 124888104693 124989104795 125079**104878** 125191**104993** 125284*105062** 1051 76*1253 1052 671254 125582*105360** 125695*105489** 125793**105585** 1056 97**1258 1057 89**1259 126090**105889 126194105992* 126295106042 126385*106188* 126483**106293 126590106392** 126685*106495** 126796106578* 126895*106673** 126984**106793* 127091**106879** 127178**106974* 127273**107093** 127394*107195* 127489*107282* 127586**107393** 127688**107482 127790**107590** 127868107669** 127987**107793** 128078**107886* 128181*107990 1080 69*1282 128374*108161 128486108284* 128594108388 1084 85**1286 1085 95**1287 128869*108687* 128993108776* 129080108873* 1291108986* 1292109081** 1293109187* 1294109274** 1295109395** 1296109496** 1297109576* 129897**109686* 1097 96**1299 130097*109860* 130197*109987** 1100 93**1302 130391**110186* 130490**110284** 130591**110392* 130685**110489** 130785**110591** 130891**110667** 130996*110788** 131090**110895** 131195**110974** 91**11101312 131391**111163** 131496*111262 131586*111355 1114 78*1316 13179996111594* 1318111691** 1117 79**1319 1118 791320 1119 1321 1322112093 1323112172* 1324112292** 1325112390* 1326112490* 1327112592* 1328112687 1127 1329 1330112886* 1331112992** 1130 92**1332 1131 95*1333 1132 72**1334 1133 90*1335 133674113495** 133783**113588* 133865*113691 1339113783** 134077*113865* 134189113992* 1342114077** 134388114180* 134493**114284** 134594**114392* 134694*114476* 134781**114583* 134878**114661** 1147 92**1349 1350114879** 1149 1351 1352115092* 1353115191* 135438115296* 1153 461355 135680115493* 1155 781357 1156 1358 1359115766** 1158 98**1360 136196*115972* 136283**116083* 136388**116187* 1162 1364 1365116373** 1164 79*1366 136793*116584* 1166 92**1368 1167 94*1369 137086**116888* 137194*116977 137295**117074* 137395**117174** 137493**117238* 137580**117389** 137686**117479** 137795*117596 137868117697* 137941117719 138087**117888** 138165**117985* 138286**118093* 1181 88*1383 1182 92** 69** 138593*118379** 138688*118484** 1185 82**1387 1186 93*1392 139787**118793** 1188 93** 1398 81* 139994118974** 140095119095** 119185** 1192 91* 1193 95** 1194 78** 1195 94* 119687* 119785* 1198 86*

* % inhibition at 0.1 RM ** % inhibition at 0. 01 µM Additional methods for the measurement of in vitro inhibition of protein prenylation (i. e., inhibition of farnesyltransferase or geranygeranyltransferase) are described below.

Assays are performed using the glass fiber filter binding assay procedure with either rabbit reticulocyte lysate or FTase or GGTase I fractions isolated from bovine brains using a combination of hydrophobic and DEAE column chromatography procedures. Protein substrates are purchased from Panvera Corporation (H-ras for FTase, H-ras-CVLL for GGTase I). Tritium labeled prenyl lipid substrates (FPP or GGPP) are obtained from Amersham Life Science.

FTase 3H-Farnesyldiphosphate (final concentration 0. 6 µM), H-Ras (final concentration 5.0 RM) and the test compound (various final concentrations from a stock solution in 50% DMSO/water; final concentration DMSO < 2%) were mixed in buffer (50 mM HEPES (pH 7.5), 30 mM MgCl2,20 mM KC1,10 RM ZnCl2,5 mM DTT, 0.01% Triton X-100) to give

a final volume of 50 RL. The mixture was brought to 37 °C, enzyme was added, and the reaction is incubated for 30 minutes. 1 mL of 1 M HCl/ethanol was added to stop the reaction, and the mixture was allowed to stand for 15 minutes at room temperature then diluted with 2 mL of ethanol. The reaction mixture was filtered through a 2.5 cm glass microfiber filter from Whatman and washed with four 2 mL portions of ethanol. The glass filter was transferred to a scintillation vial and 5 mL of scintillation fluid was added. The radioisotope retained on the glass fiber filter was counted to reflect the activity of the enzymes. The ICso value was calculated by. measuring the activity of the enzyme over a suitable range of inhibitor concentrations.

GGTase I 3H-geranylgeranyldiphosphate (final concentration 0.5 ptM), H-Ras-CVLL (final concentration 5.0 M) and the test compound (various final concentrations from a stock solution in 1: 1 DMSO/water; final concentration DMSO < 2%) were mixed in buffer (50 mM Tris-Cl (pH 7. 2), 30 mM MgCl2,20 mM KC1,10 uM ZnCl2,5 mM DTT, 0.01% Triton X-100) to give a final volume of 50 RL. The mixture was brought to 37 °C, treated with enzyme, andincubated for 30 minutes. 1 mL of 1 M HCl/ethanol was added to stop the reaction, and the mixture was allowed to stand for 15 minutes at room temperature then diluted with 2 mL of ethanol. The reaction mixture was filtered through a 2.5 cm glass microfiber filter from Whatman and washed with four 2 mL portions of ethanol. The glass filter was transferred to a scintillation vial, and 5 mL scintillation fluid was added. The radioisotope retained on the glass fiber filter was counted to reflect the activity of the enzymes. The ICso value was calculated by measuring the activity of the enzyme over a suitable range of inhibitor concentrations.

Additionally, the ability of the compounds of the invention to inhibit prenylation in whole cells, inhibit anchorage-independent tumor cell growth and inhibit human tumor xenograft in mice could be demonstrated according to the methods described in PCT Patent Application No. W095/25086, published September 21,1995, which is hereby incorporated herein by reference.

Pharmaceutical Compositions The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,

hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p- toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides (such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides), dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I)- (XII) or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.

Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminum salts 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. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The compounds of the invention are useful (in humans and other mammals) for inhibiting protein isoprenyltransferases (i. e, protein farnesyltransferase and/or protein geranylgeranyltransferase) and the isoprenylation (i. e., farnesylation and/or geranylgeranylation) of Ras. These inhibitors of protein isoprenyltransferases are also useful for inhibiting or treating cancer in humans and other mammals. Examples of cancers which may be treated with the compounds of the invention include, but are not limited to, carcinomas such as lung, colorectal, bladder, breast, kidney, ovarian, liver, exocrine pancreatic, cervical, esophageal, stomach and small intestinal; sarcomas such as oesteroma, osteosarcoma, lepoma, liposarcoma, hemanioma and hemangiosarcoma; melanomas such as amelanotic and melanotic; mixed types of cancers such as carcinosarcoma, lymphoid tissue type, follicular reticulum, cell sarcoma and Hodgkins disease and leukemias, such as

myeloid, acute lymphoblastic, chronic lymphocytic, acute myloblastic and chronic mylocytic.

The ability of the compounds of the invention to inhibit or treat cancer can be demonstrated according to the methods of Mazerska Z., Woynarowska B., Stefanska B., Borowski S., Drugs Exptl. Clin. Res. 13 (6), 345-351 (1987) Bissery, M. C., Guenard F., Guerritte-Voegelein F., Lavelle F., Cancer Res. 51,4845-4852 (1991) and Rygaard J., and Povlsen C., Acta Pathol. Microbiol. Scand. 77,758 (1969), which are hereby incorporated herein by reference.

These inhibitors of protein isoprenyltransferases are also useful for treating or preventing restenosis in humans and other mammals. The ability of the compounds of the invention to treat or prevent restenosis can be demonstrated according to the methods described by Kranzhofer, R. et al. Circ. Res. 73: 264-268 (1993), Mitsuka, M. et al.

Circ. Res. 73: 269-275 (1993) and Santoian, E. C. et al. Circulation 88: 11-14 (1993), which are hereby incorporated herein by reference.

For use as a chemotherapeutic agent, the total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.01 to 500 mg/kg body weight daily, preferably in amounts from 0.1 to 20 mg/kg body weight daily and more preferably in amounts from 0.5 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

For treatment or prevention of restenosis, the total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 50 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes

subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

Injectable preparations, for example sterile injectable aqueous or oleagenous suspensions, may be formulated according to the known art using suitable dispersing or wetting and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent (as in a solution in 1,3-propanediol, for example). Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.

Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may also comprise additional substances other than inert diluents such as lubricating agents like magnesium stearate. With capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills mayalso be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants such as wetting agents, emulsifying and suspending agents and sweetening, flavoring, and perfuming agents.

The 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 dispersed in an aqueous medium. Any non-toxic, physiologically aceptable 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 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., which is hereby incorporated herein by reference.

While the compounds of the invention can be administered as the sole active pharmaceutical agent for the treatment of cancer, they can also be used in combination with one or more other chemotherapeutic agents.

Representative examples of chemotherapeutic agents are described in Holleb, et al., Clinical Oncologv, American Cancer Society, United States (1991) p 56 et seq., which is hereby incorporated herein by reference These agents include alkylating agents such as the nitrogen mustards (mechloethamine, melphalan, chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas (carmustine, lomustine, semustine, streptozocin), alkyl sulfonates (busulfan), triazines (dacarbazine) and ethyenimines (thiotepa, hexamethylmelamine); folic acid analogues (methotrexate); pyrimidine analogues (5-fluorouracil, cytosine arabinoside); purine analogues (6-mercaptopurine, 6-thioguanine); antitumor antibiotics (actinomycin D, the anthracyclines (doxorubicin), bleomycin, mitomycin C, methramycin); plant alkaloids such as vinca alkaloids (vincristine and vinblastine) and etoposide (VP-16); hormones and hormone antagonists (tamoxifen and corticosteroids); and miscellaneous agents (cisplatin, taxol and brequinar).

The above compounds to be employed in combination with the isoprenyl protein transferase inhibitor of the invention will be used in therapeutic amounts as indicated in the Physicians'Desk Reference (PDR) 47th Edition (1993), which is incorporated herein by reference or by such therapeutically useful amounts as would be known to one of ordinary skill in the art.

The compounds of the invention and the other chemotherapeutic agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.

When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

Preparation of the Compounds of the Invention In general, the compounds of the invention can be prepared by the processes illustrated in the following Schemes 1-16. In these general schemes compounds of the formula I are used to exemplify the methods, but the methods are intended to be applicable to all of the compounds of the invention.

SCHEME 1

R1 R1 A. # phosgene O # #-R2+-R2 R3NH2R3HN H2N R1a N R1R1 thiophosgeneS#B.# + -R2# R3NH2 R3HN N H2N R1a R1a R1R1 C. # SOCl2 O # S-R2+-R2 R3HNNR3NH2# H2N R1a R1a R1R1 SO2Cl2O#D.# #S-R2+-R2 R3NH2 R3HN N OH2NR1a H R1a SCHEME 2 SCHEME3 R, R R3NH, R, A-/1)vinylation 1 NaCNBH3 R2 2 oso4 I R R 2) OsO,-1 Br J R3HNCH2 R 2 ruz Rua Ph3P DEAD R1 hydrazoic B. Rl NaE3H,, acid I I R2 IJ 2 J -r J HOCH2 Ra N3Cf"2 Rta Rta D 1) triphosgene a R t 1) triphosgene R1 E 3 N Et, N R R H2NCH2 Ra R3HNC (O) HNCH2 Ra C. Ri 1) thiophosgene 2) R3NH2 J ruz H2NCH2 R1a R3HNC (S) HNCH2 ia 'R1 i) soc z f R2 2) R3NH2 ' ! L-R2 H2NCH2 R9a R3HNS (O) HNCH2 Ra 'R1 1) S02CIR1 2) R3NH2 R 2) R3NH2 CJ R2 H2NChi2 R3HNS (0) 2HNC

SCHEME 4 1) phosgene R1 A.,R R3NH2 f ;f-1 HOCH2 R1a R3HNC (O) OCH2 R1a B. Ri 1) thiophosgene Ri 2) R3NH2 ! J-R2J-}-R2 Rla 3HNC (S 2 Ria C. Ri 1) SOC12 Ri t R3NH2 R2 R2 11 J R2 II J R2 HOCH2 Ra R3HNS (O) OCH2Rla D. R1 1) SO2cl2 R 2) R3NH2 R2 R2 HOCH2 Ria R3HNS (0) 20CH2

SCHEME5 R1 1) NaNO2/H2s04 R A. je}. je 2 Ra Rta n 1)phosgene 2)R3NH2 R2 R3HNC(O) Rta B. R1 1) thiophosgene R 2) R, NH2 R2 H Rla R3HNC (S) R ta C. R1 1) SOCI2 R1 2) R3NH2 J R2 v R2 Rta R 4S (O) s Ria D. R 1) S02CI2 2)R3NH2 aJ R2--\J H R1a R3HNS (0) 2S 1a SCHEME6 Rl DTos-C! R A R 1 t) Tos-CI R 1 "t/R2naos II J R2 jl J R2 HOCH Rla HSCH2 Ria 1)phosgene 2)R3NH2 t'; R2 J R3HNC (O) SCH2 R1 a B. Ri 1) thiophosgene 2) R3NH2 R2 R2 J-R2 J--R2 HSCH2 R1 a R3HNC (S) SCH a C. Ri 1) SOCI2 Ri 2)R3NH2 HSCH2 la R3HNS (O) SCH2 R1a D./R1 1) SO2CI2 R1 2)R3NH2 R2-R2 HSCH2 Ra R3HNS (O) 2SCH2 Ria SCHEME7 , ¢Q ; "R2 R3-C°2H C (O) H 4\ »/R R2A. R, R ')-R R2 R3-CO2H H N J "cl Rta B. Ri R -R2L-R2 II \ J R2---jl \ H2NCH2 R1a R3C (O) HNCH2<R1a C. Me3SiC=CH (Ph3P) 2Pd (OAc) 2 R cul 2 R Br Ria H-C=-C B r H-C=-C' R1 R3-COCI 1| I R2 R3-C(O)-C--_ Rta D. R D. Ri Lindlar catalyst Ri -R2 H2-R2 z R R3-C(O)-HC=H \R1 a "la F R E. Rl Lindiar catalyst Ri H2 R2 R2 3 R3-C (O)-H2CH2 Ria R1a

SCHEME8 Rl A.Ri Pd (OAc) 2 Ri R, NH, Ri DPPE/CO H2N, C, \,/-I iiii-R2 Rla H02 Rla R3-HN-C (o Rla Rl 1) oxalyl chloride Rl Ri X R3NH2R1 i2 j y-R2-----j-}-R2 HO2C Ri R, CHO Ri C. R1 R3CH0 Ria NaCNBH3 \ R2 Rta R1a W Rt D. R1 R3CHO R1 R2 NaCNBH3 3 H2NCH2 J R3CH2NHCH2 Ra

SCHEME 9 R R 2) SO 2HCI R 2joxalyl chioride R1 ) \J 2 11 R2 3) R3NH R2 CIS02 R-HN-C (O) NH-SO Ri Ph3P/DEAD R 1) NH3 2)HSC (O) CH3 B. IC R2 R2 3) R nu 3 2 R2 HOCH2 CISO CH J la Ria R3NHC (O) NHS02C 2 Ria C. Ri C i) Tos-CI R1 R2 2) R30H/CuCI t'J 2 HOCH2 R R2 R30CH2 Ria D. Ru D. R1 1) phosgene R1 2)R3-OH/CuCI R2 R2 H2N. J H2N R1 a R30C (O) NH R1 a Rta E. R E. R1 1) thiophosgene R1 2)R3-OH/CuCl Ria R30C (S) NH wR1a F. ruz Ria 2) 2) R3-OH/CuCI ßR2 "IC-R2 R2 Ria R30S (O) N Ria Rta 1) S02CI2 R1 2) R3-OH/CuCI vJ 2 I i H2 Rta R30S0) 2N \J R1a

SCHEME 10 R, Rl 1) triphosgene R1 R2 2) R30H/CuCI J I- H2NCH2 Ra J R R30C (O) NHCH2 Ra B. Ri B. Ri thiophosgene Ri 'R2 2) R30H/CuCI 2) R H NCH R2 R30C (S) NHCH2 R1 a C. Ri 1) souci2 R2 30H/CuCi -R2 H2NCH2 R1a R30S (O) NHCH2 Ra D. R1 D.Ri . <, 1) SOsCt2 /'' -R2 2) R30H/CuCl R2 H2NCH2 RUZ \"j la R30S (0) 2NHCH2 Ria SCHEME 11 A. R1 A. 1) NaNO2/HBF4 R1 jRSFi/NaH H N J R2 Ria R3_ \ R1a B. Ri 1) triphosgene 2) R3SHI R2 Rua R3SC (O) NH R1a C. Ri 1) thiophosgene R 1 R22) R3SH R2 D. Ri H2N R1a R3SC (S) N \R 1a D. Ri D./R1soct2 R1. R2 2) R3sH 2 H2N Rta J R R3SS (O) NH Ria E. R1 1) S02CI2 R1 -R2 2) R3SH ' \rota

SCHEME 12 A. ri 1) thphosgene Ri 2) R3SFil 2 2 Ria 1a R3SC (O) NHCH2 R1a Rta B. R1 1) thiophosgene 2 2) R3SH H2NCH2 Ria R3SC (S) NHCH2-% Ra C. Ri i) SOC R2 2) RUSH H2NCH2 R R1a R3SS (O) NHCH2 wR1a D. Ri 1) soZC je R2 SH R H2NCH2 1a R3SS (0) 2NHCH2 1a SCHEME 13 A. RI Ri R3-X !--Rp NaH/Cu r R2 ira Rua X = halide B. Rl Ri R3-X Ru NCH B. R1 HS R J a R3S Rta 3 Ria C. R1 C. Ri R R2 pyridine J H2N Ria R3N \Rta X = halide D. R1 D. Rl R3-X Ri R2 NaH HOCH2R J 30C 2 Ria X = halide E. R1 E. R1 R-X R R2 NaH R2 HSCH2 R J HSCH2 R3SCH2 Ria X = halide

SCHEME 14 A. Pi (Ph3P) 2Pd (OAc) 2 R2 R3-X I"l R2 Hic 1 R3 C-Rta X = halide B./Rl R Lindlar catalyst . 1 HR/ R2 R3-C=-Ria R3-HC Pd Pd/C R 1 R-HCI Ra R3-H2GCH2 R ru R 1, 1'- (Ph2P) 2- 1,1'- (Ph2P) 2- D.I (2 ferrocene PdCi2 I R3-Br a . Ri Ri R3-Br Ri Ri Lindlar catalyst E. tR2 H2, HJX R2 R3-C (O) C-C Ra Rg-C (O) CH=C VRia /R'Hd/C/ R 3-C (O) C R 1 a R3-C (O) CH2-CH2 Ria SCHEME 15 A. Ri MCPBAR1 f'r'2 r Ra R3S02 R1a a R3SO B. Ri 1) R3CH2X Ri 2) MCPBA fi R2 R2 vs HS= halide R3CH2S02 R a C. MCPBA R R2 HSCH2 Ria X = halide R3SO2CH Ria Ri cr so2ci 1 R E. R2 2 Ri Ri ria R R1 /so2ci/ E. I \ J R2 J R2 R3SO2NHCH2 R

Scheme 16 illustrates an alternative method for preparing compounds wherein R2 is -C (O) NH-CH (R14)-C (O) OR15 or

as defined above.

SCHEME 16

Table 6. Amines of the Type e A(B)N-L1

Table

Tah)pKSulfonamides of the Type ASO2(B)N-L1

Table 9. Hvdrocarbons of the Type A(B)CH2-L1

Table 10. Amines of the type B-NH2

Table 11. Bromides of the type B-Br

Table 12. Amines of the type A-NH2

Table 13. Acids of the tape A-CO2H

Table 14. Aldehydes of the type A-CHO

Table 15. Alcohols of the type A-OH

Table 16. Mercaptans of the type A-SH

Table 17. Halides of the type A-Cl, A-Br, and A-I

Table 18. Sulfonyl chlorides of the type A-SO2Cl

The foregoing may be better understood by reference to the following examples which are provided for illustration and not intended to limit the scope of the inventive concept.

In Tables 2-10, the abbreviation bz=benzoyl, bn=benzyl, Ph=phenyl, BOC=t- butyloxycarbonyl and TS=p-toluenesulfonyl. <BR> <BR> <BR> <P> Compound1<BR> <BR> <BR> <BR> O-CAminomethvDbenzoyD-Met-OCHo Step A (3-(Chloromethvl) benzovl !-Met-OCHS To a solution of methionine methyl ester hydrochloride (2.0 g, 10 mmol) and 3- (chloromethyl) benzoyl chloride (2.08 g, 11.0 mmol) in methylene chloride (50 mL) was slowly added triethylamine (3.07 mL, 22.0 mmol) at ice bath temperature for 2 hours. The mixture was washed with 0.5 N HCl (50 mL x 2), brine (50 mL x 2) and water (50 mL x 2) then dried over anhydrous MgS04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% ethyl acetate in hexanes) to give the desired product (3.03 g) as a white solid: m. p. 82-83°C; 1H NMR (CDCl3) d 7. 82 (1H, s), 7.74 (1H, d, J=7.7 Hz), 7.53 (1H, d, J=7.7 Hz), 7.42 (1H, t, J=7.7 Hz), 7.06 (1H, br d, J=7.6Hz), 4.92 (lH, ddd, J=7.6,7.1,5.1 Hz), 4.59 (2H, s), 3.78 (3H, s), 2.58 (2H, t, J=7. 1Hz) 2.26 (1H, sm), 2.15 (1H, m), 2.10 (3H, s); 13C NMR (CDCl3) d 12,127.42,126.97, 52.72,52.14,45.55,31.47,30.12,15.55.

Step B (3-(Azidomethvl) benzovl)-Met-OCH3 A suspension of (3- (chloromethyl) benzoyl)-Met-OCH3 (1.58 g, 5.0 mmol) and sodium azide (1.3 g, 20.0 mmol) in DMSO (40 mL) was stirred at 80°C for 7 hours. The mixture was diluted with methylene chloride (100 mL), washed with brine (70 mL x 2) and water (70 mL x 2), and then dried over anhydrous MgS04. The solvent was evaporated under reduced pressure to give a yellow residue. Chromatography on silica gel (30% ethyl acetate in hexanes) to provide the desired product (1 : 45 g) as a colorless solid: m. p. 48-49°C; IH NMR (CDCl3) d 7.78 (2H, m), 7.49 (2H, m), 6.99 (1H, br d, J=7.4 Hz), 4.49 (1H, ddd, J=7.4,7.1,5.2 Hz), 4.42 (2H, s), 3.80 (3H, s), 2.60 (2H, t, J=7.4 Hz), 2.29 (1H, m), 2.17 (1H, m), 2.12 (3H, s); 13C NMR (CDCl3) d 97,134.06, 30.

(3-(Aminomethyl) benzoyl)-Met-ocH3 A suspension of (3-(azidomethyl) benzoyl)-Met-OCH3 (1.29 g, 4.0 mmol) and 5% palladium on carbon (0.2 g) in methanol (40 mL) was stirred under a hydrogen atmosphere (1 atm) for two days at room temperature. The catalyst was removed by filtration through celite (1.5 g) and the solvent was evaporated in vacuo. The residue was washed with water (5 mL x 2) and dried to give the desired product (1.12 g) as a colorless foam. IH NMR (CDCl3) d 7.81 (1H, s), 7.68 (1H, d, J=7.4 Hz), 7.45 (1H, d, J=6.5 Hz), 7.36 (1H, t, J=7.4 Hz), 4.91 (1H, ddd, J=7.3,7.1,5. 1#Hz), 3.90 (2H, s), 3.77 (3H, s), 3.21 (2H, br s), 2.59 (2H, t, J=7.4 Hz), 2.20 (1H, m), 2.12 (1H, m), 2.09 (3H, s).

Compound 2 (4-(Aminomethvl) benzovl)-Met-OCH3 The title compound is prepared according to the procedure used to prepare Compound 1 but replacing 3- (chloromethyl) benzoyl chloride with 4-(chloromethyl) benzoyl chloride.

Compound 3 (3-Aminobenzovl)-Met-OCH3 The title compound was prepared according to the procedure described in J. Biol. Chem.

269 12410-12413 (1994).

Compound 4 (4-Aminobenzoyl)-Met-OCH3 Step A N-BOC-4-Aminobenzoic acid 4-Aminobenzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 mL) and 0.5 M NaOH (145.8 mL). The solution was cooled to 0°C and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate. The ethyl acetate fractions were combined and washed with IN HCl to remove any unreacted starting material. The solution was dried over Na2SO4 and the solvent was removed in vacuo. The crude material was recrystallized from ethyl acetate/hexanes to provide the desired product (12.2 g): m. p. 189-190°C; IH NMR (CD30D) d 1.52 (9H, s), 7.49 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6 Hz), 9.28 (1H, s); 13C NMR (CD30D) d 70,155.00, 169.80; Anal. Calc. for C12HlNO4, C: 60.76, H: 6.37, N: 5.90; Found, C: 60.52, H: 6.43, N: 5.83; HRMS Calc. for C12HlsNO4,237.0961, Found, 237.1001.

Step B<BR> <BR> <BR> <BR> <BR> (N-BOC-4-Aminobenzovll-Met-OCH3 Into a dried, nitrogen filled flask was placed N-BOC-4-aminobenzoic acid (8.77 g, 36.97 mmol) in dry methylene chloride (148 mL) along with methionine methyl ester hydrochloride (8.12 g, 40.66 mmol). This solution was cooled in an ice bath and triethylamine (6.7 mL), EDCI (7.80 g, 40.66 mmol) and hydroxybenzotriazole (HOBT, 5.50 g, 40.66 mmol) were added. The mixture was stirred overnight, diluted with more methylene chloride and was extracted three times each with 1 M HCI, 1M NaHC03 and water. The methylene chloride was dried over MgS04 and the solvent was removed in vacuo. The resulting solid was recrystallized from ethyl acetate/hexanes to yield the desired product (9.72 g): m. p. 184-185°C; 1H NMR (CDCl3) d 1.53 (9H, s), 2.06-2.18 (4H, m), 2.23-2.33 (1H, m), 2.59 (2H, t, J=7.6 Hz), 3.80 (3H, s), 4.92 (1I3, m), 7.45 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.7 Hz); 13C NMR (CDC13) d 15,31.64, 73,127.8,128.33,141.88,152.33,166.50,172.75 ; Anal. Calc. for C, 8H26N, 05S, C: 56.53, H: 6.85, N: 7.29; Found, C: 56.47, H: 6.86, N: 7.29; m/z (EI) 382 (M).

Step C (4-Aminobenzovl)-Met-OCH3 hydrochloride N-BOC-4-aminobenzoyl-Met-OCH3 (3.53 g, 9.59 mmol) was placed into methylene chloride (30-35 mL) and to it was added 3M HCl/EtO2 (38.4 mL). After standing, a white precipitate formed. After two hours the solution was decanted and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether and dried overnight on the vacuum pump. Meanwhile, the filtrate was left to stand overnight to allow additional product to precipitate. The second fraction was washed with ether and dried overnight on the vacuum pump. The total yield of the desired product was 2.87 g: m. p. 158-164°C ; IH NMR (CDCl3) d 2.10 (3H, s), 2.12-2.29 (IH. m), 2.52- 2.71 (1H, m), 2.59 (2H, t, J=7.6 Hz), 3.75 (3H, s), 4.79 (1H, m), 7.02 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz); 13C NMR (CDCl3) d 15.23,31.43,31.53,52.91,52.43, 76,168.95,173.87; HRMS Calc. for Cl3Hl8N203S, 282.1038, Found 282.1009.

Compound 5 (4-Amino-3-methylbeyl)-Met-OCH3 Step A

N-BOC-4-Amino-3-methvlbenzoic acid 4-Amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting orange-brown solid was recrystallized from ethyl acetate and hexanes to provide the desired product (4.99 g) as tan prismatic crystals: m. p. 180-182°C; 1H NMR (CD30D) d 1.51 (9h, s), 2.27 (3H, s), 7.66 (1H, d, J=8.1 Hz), 7.79-7.82 (2H, m), 8.32 (1H, s); 13C NMR (CD30D) d 99, 33,168.70; Anal. Calc. for Cl3Hl7NO4, C: 62.15, H: 6.82, N: 5.58; Found C: 62.07, H: 6.86, N: 5.46; m/z (EI) 251; HRMS Calc. forCI3Hl7NO4,251.1158; Found, 251.1153.

Step B (N-BOC-4-Amino-3-methvlbenzovl)-Met-OCH3 N-BOC-4-amino-3-methylbenzoic acid (2.00 g, 7.96 mmol) was reacted with with methionine methyl ester hydrochloride (1.75 g, 8.76 mmol), triethylamine (1.4 mL), EDCI (1.68 g, 8.76 mmol) and hydroxybenzotriazole (HOBT, 1.18 g, 8.76 mmol) in dry methylene chloride (31.8 mL) according to the procedure described for the preparation of N- BOC-4-aminobenzoyl)-Met-OCH3. The resulting solid was recrystallized from ethyl acetate/hexanes to yield the desired product (2.61 g): m. p. 163-165°C; IH NMR (CDC13) d 1.54 (9H, s), 2.06-2.18 (4H, m), 2.23-2.34 (4H, m), 2.59 (2H, t, J=6.8 Hz), 3.80 (3H, s), 4.92 (1H, m), 6.45 (1H, s), 6.88 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=8.6 Hz), 7.66 (lH, s), 8.05 (1H, d, J=8.6 Hz); 13C NMR (CDCl3) d 61,28.22,30.03, 58, 172.66.

Step C (4-Amino-3-methvlbenzoyl)-Met-OCH3 hvdrochloride N-BOC4-Amino-3-methylbenzoyl-Met-OCH3 (0.99 g, 2.59 mmol) was dissolved in methylene chloride (15-20 mL) and precipitated with 3M HCI/Et2O (20.7 mL). A pale orange precipitate was obtained, washed with ether and dried overnight on the vacuum pump. The total yield of the desired product was 0.83 g: m. p. 157-159°C; IH NMR (CD30D) d 2.04 (3H, s), 2.11-2.25 (1H, m), 2.47 (3H, s), 2.52-2.68 (3H, m), 3.74 (3H, s), 4.75-4.80 (1H, m), 7.48 (1H, d, J=8.2 Hz), 7.81 (2H, d, J=8.2 Hz), 7.87 (1H, s); 13C NMR (CD30D) d 15.23,17.28,31.43,31.51,52.91,53.37,124.41,127.85, 63,134.14,135.65,169.05,173.84; Anal. Calc. for Cl4H21N203S, C: 50.52, H: 6.36, N: 8.42; Found C: 50.71, H: 6.40, N: 8.34.

Compound 6 (4-Amino-3-methoxvhenzoyl)-Met-ocHS Step A N-BOC4-Amino-3-methoxvbenzoic acid 4-Amino-3-methoxybenzoic acid (1 g, 5.98 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting solid was recrystallized from ethyl acetate and hexanes to provide the desired product (1.5 g) as tan crystals: m. p. 176-178°C; IH NMR (CD30D) d 1.52 (9H, s), 3.92 (3H, s), 7.56 (1H, s), 7.62 (1H, d, J=8.4Hz), 7.96 (1H, s), 8.03 (1H, d, J=8.4 Hz); 13C NMR (CD30D) d 20,125.76,133.84, 149.04,154.20,169.60; HRMS Calc. for C13Hl7NO5,267.1107; Found, 267.1103.

Step B (N-BOC-4-Amino-3-methoxvbenzovl)-Met-OCH3 N-BOC-4-amino-3-methoxybenzoic acid (0.35 g, 1.31 mmol) was reacted with with methionine methyl ester hydrochloride (0.9 g, 1.43 mmol) using EDCI according to the procedure described for the preparation of (N-BOC-4-aminobenzoyl)-Met-OCH3.

The resulting solid was recrystallized from ethyl acetate/hexanes to yield the desired product (0.36 g): m. p. 163-165°C; IH NMR (CDCl3) d 1.53 (9H, s), 2.09-2.18 (4H, m), 2.23-2.35 (1H, m), 2.60 (2H, t, J=6.9 Hz), 3.80 (3H, s), 3.93 (3H, s), 4.92 (1H, br s), 6.93 (1H, d, J=7.6 Hz), 7.25 (1H, m), 7.31 (1H, d, J=10.2 Hz), 7.44 (1H, s), 8.15 (lH, d, J=8.5 Hz); 13C NMR (CDC13) d 09,31.48,52.06,52.54,55.81, 06,109.38,116.66,119.31,131.52,147.23,152.31,166.57,172.58; m/z (FAB) 413 (M + 1).

Step C (4-Amino-3-methoxybenzoyl)-Met-OCH3hydrochloride N-BOC-4-Amino-3-methoxybenzoyl-Met-OCH3 (0.71 g, 1.79 mmol) was dissolved in methylene chloride (4 mL) and precipitated with 3M HCl/Et2O (12 mL). A reddish precipitate was obtained, washed with ether and dried overnight on the vacuum pump. The total yield of the desired product was 0.55 g: m. p. 176-177°C; I H NMR (CD30D) d 2.08 (3H, s), 2.21 (2H, m), 2.61 (2H, m), 3.74 (3H, s), 4.02 (3H, s), 4.79 (1H, m), 7.50 (1H, d, J=8.2 Hz), 7.57 (1H, d, J=4.1 Hz), 7.67 (1H, s); 13C NMR (CD30D) d 15.26, 12,112.29,121.43,124.57,124.77,136.15,153.67, 168.79,173.81.

Compound 7 (4-Amino-1-naphthovl)-Met-OCH3 Step A 4-Amino-1-naphthoic acid 4-Amino-1-naphthalenecarbonitrile (1.5 g, 8.91 mmol) was suspended in a 50% KOH solution (18 mL). The heterogeneous solution was heated at reflux for 2-3 days. Once the solution became homogeneous and TLC showed no more starting material, the deep red solution was cooled and poured over 200 mL of water. The resulting solution was then filtered and the desired product was precipitated with concentrated HC1. The resulting red crystals were filtered and the filtrate was refiltered to give pink crystals. The first fraction of crystals was treated with activated carbon to remove some of the red color. A total of 1.51 g of the desired product was obtained: m. p. 169-171°C ; IH NMR (CD30D) d 6.69 (1 H, d, J=8.2 Hz), 7.38-7.43 (1H, m), 7.48-7.54 (1H, m), 8.03 (1H, d, J=8.5 Hz), 8.13 (1H, d, J=8.2 Hz), 9.09 (1H, d, J=8.5 Hz); 13C NMR (CD30D) d 61,122.99, 04,151.35,171.44; HRMS Calc. for CIlH7NO2, 187.0633; Found, 187.0642.

Step B N-BOC-4-Amino-1-naphthoic acid 4-Amino-1-naphthoic acid (0.86 g, 4.61 mmol) was dissolved in dioxane (9.2 mL). Di-t- butyl dicarbonate (1.11 g, 5.07 mmol) was added and the mixture was stirred overnight.

The reaction mixture was worked up as described above for N-BOC-4-aminobenzoic acid to give 0.76 g of the desired product as a reddish pink solid: m. p. 194-195°C; IH NMR (CD30D) d 1.56 (9H, s), 7.53-7.62 (2H, m), 7.79 (1H, d, J=8.1 Hz), 8.12 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.18 Hz), 9.02 (1H, d, J=8.9 Hz); 13C NMR (CD30D) d 26.68, 81.62,119.06,123.40,124.57,127.03,127.37,128.49,128.77,131.8 9,133.76, 139.86,155.95,170.73; Anal. Calc. for C17Hl7NO4, C: 66.90, H: 5.96, N: 4.88; Found C: 66.49, H: 6.08, N: 4.79; m/z (EI), 289; HRMS Calc. for C16Hl7NO4,287.1158; Found, 287.1151. <BR> <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> (N-BOC-4-Amino-1-naphthovl)-Met-OCH3 N-BOC-4-Amino-naphthoic acid (0.46 g, 1.60 mmol), methionine methyl ester hydrochloride (0.35 g, 1.76 mmol), EDCI (0.43 g, 1.76 mmol), HOBT (0.24 g, 1.76 mmol) and triethylamine (0.27 mL) in methylene chloride (6.4 mL) were reacted as described above for N-BOC-4-aminobenzoyl-Met-OCH3. After workup and

recrystallization from ethyl acetate hexanes, the desired product (0.44 g) was obtained as pale pink crystals: m. p. 131-132°C; IH NMR (CDC13) d 1. 57 (9H, s), 2. 11-2. 21 (4H, m), 2.29-2.41 (1H, m), 2.65 (2H, t, J=7.1 Hz), 3.83 (3H, s), 4.99-5.06 (1H, m), 6.68 (1H, d, J=8.0 Hz), 7.02 (1H, s), 7.56-7.59 (2H, m) 7.69 (1H, d, J=7.9 Hz), 7.87-7.90 (1H, m), 8.02 (1H, d, J=7.9 Hz), 8.44-8.48 (1H, m); 13C NMR (CDCl3) d 15.56, 82,120.18,125.79,126.37,126.53, 65,152.93,169.04,172.40; HRMS Calc. for C22H28N2O5S, 432.1719; Found, 432.1702; m/z (FAB) 433 (M+1).

Step D (4-Amino-l-naphthovl)-Met-OCH3 hvdrochloride (N-BOC-4-Amino-l-naphtholyl)-Met-OCH3 (0.57 g, 1.31 mmol) was deprotected with HCI/ether to yield the desired product (0.31 g) as a white solid: m. p. 178-181°C; 1H NMR (CD30D) d 2.08-2.16 (4H, m), (1H, m) 2.57-2.75 (2H, m) 3.82 (3H, s), 4.87- 4.91 (1H, m), 7.59 (1H, d, J=7.5 Hz), 7.67 (1H, d, J=7.5 Hz) 7.71-7.80 (2H, m), 8.03 (1H, dd, J=7.1,2.0 Hz), 8.35 (1H, dd, J=6.8,1.8 Hz); 13C NMR (CD30D) d 15.23, 20,126.15,127.41,127.77,129.09,129.31,131.50, 83; m/z (FAB), 369 (M+1).

Compound 8 (4-Amino-2-phenylbenzoyl)-Met-OCH3 Step A 4-Nitro-2-phenvltoluene 2-Bromo-4-nitrotoluene (2.16 g, 10.00 mmol) and phenylboric acid (1.46 g, 12.00 mmol) were dissolved in anhydrous DMF (25 mL) under nitrogen. To this mixture was added Pd (Ph3P) 4 (0.58 g, 5%). The mixture was heated at 100°C overnight. The solution was poured onto IN HC1 and extracted with Et2O. The crude product was chromatographed on silica gel using hexanes as eluent. After recrystallization from ethanol, the desired product (1.23 g) was obtained as pale orange needles: m. p. 69-71°C; I H NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (SH, m), 8.07-8.10 (2H, m); 13C NMR (CDCl3) d 20.68,121.96,124.51,127.78,128.41,128.83,131.06,139.06,139.4 4,142.97, 143.48,146.05; Anal. Calc. for CHNO. C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (EI) 213; HRMS Calc. for C13H11NO2, 213.0790; Found, 213.0793.

Step B

4-Nitro-2-phenvlbenzoic acid 4-Nitro-2-phenyltoluene (0.5 g, 2.34 mmol) was dissolved in water (4.6 mL) and pyridine (2.3 mL). The mixture was heated to reflux and KMnO4 (1.85 g, 11.7 mmol) was added.

The reaction mixture was heated overnight and the solution was filtered and washed several times with boiling water. The aqueous solution was made acidic and the product was extracted into ethyl acetate. The ethyl acetate solution was dried over Na2SO4 and the solvent removed in vacuo to provide the desired product (0.37 g): m. p. 174-176°C, IH NMR (CD30D) d 7.38-7.48 (5H, m), 7.96 (1H, d, J=8.5 Hz), 8.21 (1H, d, J=2.3 Hz), 8.28 (1H, dd, J=8.48,2.37 Hz); 13C NMR (CD30D) d 122.95,126.09,129.27,129.42, 17,170.52; m/z (EI) 243 (M).

Step C 4-Nitro-2-phenvlbenzov-Met-OCH 4-Nitro-2-phenylbenzoic acid (0.3 g, 1.23 mmol), methionine methyl ester hydrochloride salt (0.27 g, 1.35 mmol), EDCI (0.26 g, 1.35 mmol), HOBT (0.18 g, 1.35 mmol) and triethylamine (0.19 mL) in dry methylene chloride (4.9 mL) were reacted according the procedure described above for (N-BOC-4-aminobenzoyl)-Met-OCH3. After recrystallization of the product from ethyl acetate hexanes, the desired product (0.41 g) was obtained: m. p. 98-101°C; IH NMR (CDC13) d 1.62-1.73 (1H, m), 1.79-1.88 (1H, m), 1.91 (3H, s), 1.99 (2H, t, J=7.2 Hz), 3.59 (3H, s), 4.53 (1H, m), 6.45 (1H, d, J=7.8 Hz), 7.33-7.40 (5H, m), 7.67 (1H, d, J=8.3 Hz), 8.07-8.12 (2H, m); 13C NMR (CDC13) d 52, 56,141.02,148.09,167.23,171.23 ; m/z (FAB), 389 (M+1).

Step D (4-Amino-2-phenvlbenzovl)-Met-OCH3 (4-Nitro-2-phenylbenzoyl)-Met-OCH3 (0.35 g, 0.90 mmol) was dissolved in ethyl acetate (9.0 mL). To this mixture was added SnCI2 2H2O (1.02 g, 4.5 mmol) and the reaction mixture was heated under nitrogen at reflux for one hour. The mixture was poured onto ice, the solution was made basic using NaHC03 and the product was extracted into ethyl acetate several times (7-8). The ethyl acetate solutions were combined, washed with brine and dried over Na2SO4. The solvent was removed in vacuo to the desired product (0.24 g) as a yellow solid: IH NMR (CDC13) d 1.58-1.70 (1H, m), 1.80-1.92 (1H, m), 1.98 (3H, s), 2.06 (2H, t, J=7.7 Hz), 3.62 (3H, s), 4.00 (2H, br s), 4.56-4.63 (1H, m), 5.84 (1H, d, J=7.7 Hz), 6.50 (1H, s), 6.61 (1H, d, J=8.4 Hz) 7.29-7.42 (5H, m), 7.58 (1H, d, J=8.3 Hz); 13C NMR (CDCl3) d 27,115.88,123.52, 91.

Compound 9 (4-Amino-2-(2-thienvl) benzovl)-Met-OCHß The title compound can be prepared according to the method used to prepare Compound 8, only substituting thiophene-2-boronic acid for phenyl boronic acid.

Compound 10 (4-Amino-2-(1-naphthyl)benzoyl)-Met-OCH3 The title compound can be prepared according to the method used to prepare Compound 8, only substituting 1-naphthylboronic acid for phenylboronic acid.

Compound11 4-Amino-3'-methylbiphenyl The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1- bromo-3-methylbenzene.

Compound 12 4-Amino-4'-biphenvl carboxylic acid Step A 4-Nitro-4'-methvlbiphenvl The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1- bromo-4-methylbenzene.

StepB 4-Nitro-4'-biphenvl carboxvlic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-4'-methylbiphenyl.

Step C 4-Amino4'-biphenvl carboxvlic acid The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-4'- biphenyl carboxylic acid.

Compound 13 4-Amino-3'-biphenvl carboxylic acid Step A

4-Nitro-3'-methvlbiphenvl The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1- bromo-3-methylbenzene.

StepB 4-Nitro-3'-biphenvl carboxvlic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-3'-methylbiphenyl.

Step C 4-Amino-3'-biphenvl carboxylic acid The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-3'- biphenyl carboxylic acid.

Compound 14 4-Amino-2-methoxy-3'-biphenyl carboxylic acid Step A 2-Methoxy-4-nitro-3'-methylbiphen The title compound was prepared by reaction of 1-bromo-2-methoxy-4-nitrobenzene with 3- methylphenylboronic acid in the presence of palladium acetate.

Step B 2-Methoxy-4-nitro-3'-biphenylcarboxvlic acid The title compound was prepared by KMnO4 oxidation of 2-methoxy-4-nitro-3'- methylbiphenyl.

Step C 4-Amino-2-methoxv-3'-biphenyl carboxylic acid The title compound can be prepared by palladium catalyzed hydrogenation of 2-methoxy-4- nitro-3'-biphenyl carboxylic acid.

Compound 15 4-Amino-2-isopropvloxy-3'-biphenvl carboxylic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.

Compound 16

4-Amino-2-phenvl-y 3-biphenvlcarboxvlic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.

Compound 17 (4-Amino-2-(3, 5-dimethvlphenvl) benzovl !-Met-OCH3 Step A 2-Bromo-4-nitrobenzoic acid 2-Bromo-4-nitrotoluene (5.0 g, 23.14 mmol) was dissolved in pyridine (23 mL) and water (46 mL). The heterogeneous mixture was heated to 60°C and KMnO4 (18.29 g, 115.7 mmol) was added carefully. The mixture was then heated under reflux overnight. The reaction mixture was filtered and washed with boiling water. The solution was then made acidic and extracted into ethyl acetate, dried over Na2S04 and the solvent was removed in vacuo. The crude product was dissolved in aqueous NaOH and washed with hexanes. The aqueous phase was made acidic and the product was extracted into ethyl acetate. The ethyl acetate solutions were combined and dried over Na2S04 and the solvent was removed in vacuo to provide the desired product (3.72 g): m. p. 158-160°C; IH NMR (CD30D) d 7.81 (1H, d, J=8.5 Hz), 8.08 (lH, d, J=8.5 Hz), 8.30 (1H, s); 13C NMR (CD30D) d 121.96,122.75,129.36,132.24,139.52,149.54,167.75; Anal. Calc. for C7H4BrNO4 0.1 ethyl acetate, C: 34.88, H: 1.90, N: 5.50; Found, C: 34.68, H: 1.86, N: 5.82.

Step B 3.5-Dimethylphenvlboronic acid Magnesium turnings (1.44 g, 59.43 mmol) were coverd with dry THF (18.8 mL) in a dried, nitrogen filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 mL) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reacton mixture was heated at reflux for 1-2 hours until most of the magnesium had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to an nitrogen filled flask containing triisopropyl borate (24.9 mL) at-70°C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow.

The solution was extracted with Et2O and the Et2O fractions were combined, dried over MgS04 and the solvent was removed in vacuo to provide the desired product (2.41 g): m. p. 249-251°C ; IH NMR (CDC13) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD30D) d 39,137.48.

Step C 4-Nitro-2-(3,5-dimethylphenyl)benzoicacid 2-Bromo-4-nitrobenzoic acid (0.43 g, 2.03 mmol) and 3,5-dimethylphenyl boronic acid (0.334 g, 2.23 mmol) were dissolved in anhydrous DMF (25 mL) under nitrogen. To this mixture was added Cs2CO3 (1.66 g, 5.08 mmol) followed by Pd (Ph3P) 4 (0.12 g, 5%).

The mixture was heated at 100°C overnight. The solution was poured onto IN HC1 and extracted with Et2O. It was dried over MgS04 and the solvent was removed in vacuo. The crude product was chromatographed on silica gel using a 9: 1 mixture of hexanes and ethyl acetate to provide the desired product (0.34 g): 1H NMR (CDCl3) d 2.36 (6H, s), 6.99 (2H, s), 7.07 (1H, s), 8.03 (1H, d, J=9.0 Hz), 8.23-8.25 (2H, m); 13C NMR (CDCl3) d 31,135.04,138.21, 144.74,170.75.

Step D f4-Nitro-2-f3. 5-dimethvlphenvnbenzovn-Met-OCH 4-Nitro-2- (3,5-dimethylphenyl) benzoic acid (0.15 g, 0.55 mmol), methionine methyl ester hydrochloride (0.11 g, 0.55 mmol), EDCI (0.11 g, 0.55 mmol), HOBT (0.07 g, 0.55 mmol) and triethylamine (0.08 mL) in dry methylene chloride (2.2 mL) were reacted and worked up according to the procedure for (N-BOC-4-aminobenzoyl)-Met-OCH3 as described above. After recrystallization from ethyl acetate and hexanes, the desired product was obtained (0.13 g): m. p. 122-124°C; IH NMR (CDC13) d 1.2-1.84 (1 H, m), 1.85- 1.97 (lH, m), 2.01 (3H, s), 2.05 (3H, t, J=7.7Hz), 2.38 (6H, s), 3.70 (3H, s), 4.67-4.74 (1H, m), 6.03 (1H, d, J=7.9 Hz), 7.05 (2H, s), 7.09 (1H, s), 7.84-7.87 (1H, m), 7.84- 7.87 (lH, m) 8.23-8.26 (2H, m); 13C NMR (CDC13) d 15.20,21.26,29.22,31.15, 82,140.29,141.56, 148.41,167.14,171.53.

Step E (4-Amino-2-(3,5-dimethylphenyl)benzoyl)-Met-OCH3 (4-Nitro-2- (3,5-dimethylphenyl) benzoyl)-Met-OCH3 (0. 11 g, 0.26 mmol) was dissolved in ethyl acetate (3.0 mL). To this mixture was added SnCI2 2H2O (0.3 g, 1.30 mmol) and the reacton was heated under nitrogen at reflux for 6 hours. The mixture was worked up as described above for (4-amino-2-phenylbenzoyl)-Met-OCH3 to give the desired product (0.15 g): IH NMR (CDC13) d 1.60-1.70 (1H, m), 1.80-1.90 (1H, m), 1.99 (3H, s), 2.05 (2H, t, J=7.6 Hz), 2.33 (6H, s), 3.64 (3H, s), 3.93 (2H, br s), 4.61-4.64 (1H, m), 5.82 (1H, d, J=7.7 Hz), 6.49 (1H, d, J=2.3 Hz) 6.62 (1H, dd, J=8.4,2.4 Hz), 6.98 (2H, s),

7.00 (1H, s), 7.65 (1H, d, J=8.3 Hz); 13C NMR (CDC13) d 15.08,21.17,29.28,31.49, 92, 45,172.01.

Preparation1 Anilines of the formula B-NH2 The anilines from Table 1, entries 10-126 (B-NH2) are prepared using the procedures for Compounds 1-18 with the exception that methionine methyl ester is replaced by methioninesulfone methyl ester, (S-Me) cysteine methyl ester, serine methyl ester, (O- Me) serine methyl ester, (O-Me) homoserine methyl ester, homoserine lactone, isoleucine methyl ester, leucine methyl ester, norleucine methyl ester, norvaline methyl ester, cyclohexylalanine methyl ester, phenylalanine methyl ester, or glutamic acid dimethyl ester.

Preparation 2 4-Bromo-2-phenylbenzoyl methionine methyl ester Preparation 2A 4-Bromo-2-phenvlbenzoic acid methvl ester A solution of methyl 4-amino-2-phenylbenzoic acid (1.0 equivalent) in dilute aqueous HBr is treated with NaN02 (1.1 equivalents) to form the diazonium salt. The reaction is treated with CuBr (1.1 equivalents) and heated. When judged complete by TLC analysis, the mixture is extracted into ethyl acetate which is dried and evaporated. The title arylbromide is purified by chromatography on silica gel.

Preparation 2B 4-Bromo-2-phenvlbenzoic acid To a solution of the resultant compound from Preparation 2A (1.0 equivalent) in a 3: 1 mixture of tetrahydrofuran (THF) and water is added an excess (1.5 equivalents) of LiOH.

When hydrolysis is judged complete by TLC analysis, the solvent is evaporated and the remaining aqueous layer is acidified to pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.

Preparation 2C 4-Bromo-2-phenylbenzovl methionine methyl ester To a solution of the resultant compound from Preparation 2B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and 1- (3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Preparation 2D 4-Bromo-2-phenylbenzovl methionine methyl ester alternate procedure A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous HBr is treated with NaNO2 (1.1 equivalents) to form the diazonium salt. The reaction is treated with CuBr (1.1 equivalents) and heated. When judged complete by TLC analysis, the mixture is extracted into ethyl acetate which is dried and evaporated. The title arylbromide is purified by chromatography on silica gel.

Preparation 3 Arylbromides of the formula B-Br The anilines from Table 1 (B-NH2) are reacted according to the procedures of Preparation 2 to provide the arylbromides listed in Table 2.

Example 1<BR> 4-((S)-2-Pvrrolidone-5-aminomethvlcarbonvl ! amino-2-phenvlbenzovl methionine<BR> <BR> Example 1A Methyl-4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-ph enylbenzoate

To a solution of methyl 4-amino-2-phenylbenzoate hydrochloride (1.0 equivalent) in toluene is added triphosgene (0.33 equivalent) and the mixture is heated at reflux until judged complete by TLC analysis. The intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (2.0 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with IN HC1 and brine, evaporated, and purified by chromatography on silica gel.

Example1B 4- ( (S)-2-Pvrrolidone-5-aminomethvlcarbonvl) amino-2-phenylbenzoic acid To a solution of the resultant compound from Example 1A (1.0 equivalent) in a 3: 1 mixture of tetrahydrofuran (THF) and water is added an excess (1.5 equivalents) of LiOH. When hydrolysis is judged complete by TLC analysis, the solvent is evaporated and the remaining aqueous layer is acidified to pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.

Example1C 4- ((S)-2-Pyrrolidone-5-aminomethylcarbonyl) amino-2-phenylbenzoyl methionine methylester To a solution of the resultant compound from Example 1B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and 1- (3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HC1 and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example1D 4-((S)-2-Pvrrolidone-5-aminomethvlcarbonvl) amino-2-phenvlbenzoyl((S)-2-Pvrrolidone-5-aminomethvlcarbonv l) amino-2-phenvlbenzoyl methionine methyl ester, alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and triethylamine (2.0 equivalents). The intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with IN HC1 and brine, evaporated, and purified by chromatography on silica gel.

Example IE

4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-phenylben zoylmethionine To a solution of the resultant compound from Example 1C in a 3: 1 mixture of THF and water is added an excess of LiOH (1.5 equivalents). When hydrolysis is judged complete by TLC analysis, the solvent is evaporated and the remaining aqueous layer is acidified to pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.

Example 2 <BR> <BR> 4- ( (S-2-Pvrrolidone-5-aminomethylthiocarbonylamino-2-phenylbenz oyl methionine The title compound is prepared as described in Example 1 with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 3 4- ((S)-2-Pvrrolidone-5-aminomethvlsulfinvl) amino-2-phenylbenzovl((S)-2-Pvrrolidone-5-aminomethvlsulfinv l) amino-2-phenylbenzovl methionine Example 3A 4- ( (S)-2-Pvrrolidone-5-aminomethylsulfinyllamino-2-phenvlbenzov l methionine methyl ester To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in methylene chloride is added thionyl chloride (1.0 equivalent) and triethylamine (2.0 equivalents). After the amine has fully reacted, (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is added. When the reaction is judged complete by TLC analysis, the product is isolated as described in Example 1A and purified by chromatography on silica gel.

Example 3B 4- (l. S-2-Pvrrolidone-5-aminometh lsulfinyl) amino-2-phenvlbenzovl methionine To a solution of the resultant compound from Example 3A in a 3: 1 mixture of THF and water is added an excess of LiOH (1.5 equivalents). When hydrolysis is judged complete by TLC analysis, the solvent is evaporated and the remaining aqueous layer is acidified to pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.

Example 4 4- (S)-2-Pvrrolidone-5-aminomethvlsulfonyl_) amino-2-phenylbenzoyl(S)-2-Pvrrolidone-5-aminomethvlsulfonyl _) amino-2-phenylbenzoyl methionine Example 4A 4- ( (S)-2-Pyrrolidone-5-aminometh lsulfonyl) amino-2-phenylbenzoyl methionine methyl ester To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in methylene chloride is added sulfuryl chloride (1.0 equivalent) and triethylamine (2.0 equivalents). After the amine has fully reacted, (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is added. When the reaction is judged complete by TLC analysis, the product is isolated as described in Example 1A and purified by chromatography on silica gel.

Example 4B 4- ( (S)-2-Pvrrolidone-5-aminomethvlsulfonvl) amino-2-phenylbenzovl methionine methyl ester, alternate procedure A solution of 1 equivalent of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) and sulfuryl chloride (1.0 equivalent) in acetonitrile with a catalytic amount of antimony (V) chloride is heated to reflux until judged complete by TLC analysis. The solution is then cooled, filtered, and all volatiles are removed under reduced pressure. The residue is taken up in dichloromethane and treated with triethylamine (1 equivalent and (S)- 5-aminomethyl-2-pyrrolidone (1.0 equivalent). When the reaction is judged complete by

TLC analysis, the product is isolated as described in Example 1A and purified by chromatography on silica gel.

Example 4C 4-l(S)-2-Pvrrolidone-5-aminomethvlsulfonyl) amino-2-phenbenzovl methionine methyl ester The resultant compound from Example 4A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 5 4- ( (-2-Pyrrolidone-5-methylaminosulfonyI-2-phenylbenzoyI methionine<BR> <BR> Example 5A 4-Chlorosulfonvl-2-phenvlbenzoic acid methyl ester To a solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in concentrated HC1 is added a solution of sodium nitrite (1.1 equivalents) until an excess of nitrous acid persists.

The chlorodiazonium salt is poured into a solution of sulfur dioxide (10 equivalents), copper (II) chloride (0.5 equivalent) and KCI (1.1 equivalents) in dioxane. When TLC analysis indicated that the reaction is complete, the mixture is diluted with water and extracted into benzene which is dried and evaporated to give the title sulfonyl chloride Example 5B 4- ((S)-2-Pvrrolidone-5-aminomethvl) sulfonvl)-2-phenvlbenzoic((S)-2-Pvrrolidone-5-aminomethvl) sulfonvl)-2-phenvlbenzoic acid methyl ester To a solution of the resultant compound from Example 5A (1.0 equivalent) in methylene chloride is added (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When the reaction is judged complete by TLC analysis, the solvent is evaporated and the residue is purified by chromatography on silica gel.

Example 5C 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonyl)-2-phenylbenzoic acid

The resultant compound from Example 5B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 5D 4- ((S)-2-Pvrrolidone-5-aminomethvl) sulfonvl)-2-phenvlbenzovl((S)-2-Pvrrolidone-5-aminomethvl) sulfonvl)-2-phenvlbenzovl methionine meth lv ester To a solution of the resultant compound from Example 5C (1.0 equivalent) in (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by 1N HC1 and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 5E 4- ( (S)-2-Pyrrolidone-5-aminomethvlcarbonyl) amino-2-phenvlbenzovl methionine methyl ester, alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in concentrated HC1 is added a solution of sodium nitrite (1.1 equivalents) until an excess of nitrous acid persists at which time the chlorodiazonium salt will be treated with gaseous sulfur dioxide and copper (II) chloride to give the sulfonyl chloride (0.1 equivalent). This intermediate is reacted with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent) according to the procedure of Example 5B to give the title compound.

Example 5F 4- ((S)-2-Pyrrolidone-5-aminomethvlcarbonvl) amino-2-phenvlbenzovl((S)-2-Pyrrolidone-5-aminomethvlcarbonv l) amino-2-phenvlbenzovl methionine To a solution of the resultant compound from Example 5D (1.0 equivalent) in a 3: 1 mixture of THF and water is added an excess of LiOH (1.5 equivalents). When hydrolysis is judged complete by TLC analysis, the solvent is evaporated and the remaining aqueous layer is acidified to pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.

Example 6 4-l2-nvridyloxv)-2-phenvlbenzovlmethionine Example 6A 4-Hydroxy-2-phenvlbenzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaN02 (1.1 equivalents) until an excess of nitrous acid persists to form the diazonium salt. This salt is then diluted further with water and heated. The mixture is extracted into ethyl acetate which is dried and evaporated. The title ester is purified by chromatography on silica gel.

Example 6B 4- (2-Pyridvloxy)-2-phenvlbenzoic acid methyl ester A solution of the resultant phenol from Example 6A (1.0 equivalent) is treated with 2- bromopyridine (1.0 equivalent) in the presence of a NaH (1.0 equivalent), or K2CO3 (2.0 equivalents) and copper (1.0 equivalent) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 6C 4- (2-Pyndyloxy)-2-phenvlbenzoic acid A solution of the resultant ester from Example 6B (1.0 equivalent) in aqueous methanol is treated with NaOH (2.0 equivalents) and stirred until the reaction is deemed complete by TLC analysis. The mixture is acidified, diluted with water, and extracted into ethyl acetate which is dried and evaporated. Chromatography on silica gel provides the title product.

Example 6D 4- (2-Pvridyloxy)-2-phenvIbenzovlmethionine methyl ester The resultant product from Example 6C is coupled to methionine methyl ester according to the procedure of Example 1 C to give the title compound.

Example 6E 4- (2-Pdy)-2-phenylbenzoylmethionine methvl ester, alternate procedure A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaN02 (1.1 equivalents) until an excess of nitrous acid persists to form the diazonium salt. This salt is then diluted further with water and heated to form the phenol which is purified by chromatography on silica gel. A solution of this phenol (1.0 equivalent) is treated with 3-bromopyridine (1.0 equivalent) in the presence of a

NaH (1.0 equivalent), or K2CO3 (2.0 equivalents) and copper (1.0 equivalent) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 6F 4- (2-pvridyloxy)-2-phenvlbenzoylmethionine The resultant compound from Example 6E is hydrolyzed according to the procedure of Example 1B to give the title compound.

Example 7 4-(3-pvridvlmethvlenoxv)-2-phenvlbenzovlmethionine The title compound is prepared as described in Example 6 with the exception that 2- bromopyridine is replaced by 3-chloromethylpyridine hydrochloride.

Example 8 4-((S)-2-Pyrrolidone-5-aminomethyl)carbonyloxy-2-phenylbenzo ylmethionine Example 8A 4- ((S)-2-Pvrrolidone-5-aminomethvl) carbonvloxv-2-phenylbenzovl methionine methvl((S)-2-Pvrrolidone-5-aminomethvl) carbonvloxv-2-phenylbenzovl methionine methvl ester To a solution of 4-hydroxy-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) from Example 6E in methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and p-dimethylaminopyridine (2.0 equivalents). When the reaction is judged complete by TLC analysis, the solvent is evaporated with toluene chasers. The chloroformate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone

(1.0 equivalent) and triethylamine (1.0 equivalent) in dichloromethane. When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HC1 and brine, evaporated, and purified by chromatography on silica gel.

Example 8B 4- ( (S)-2-Pyrrolidone-5-aminomethvl) carbonyloxv-2-phenylbenzoyl methionine The resultant compound from Example 8A is hydrolyzed according to the procedure of Example 1B to give the title product.

# H #<BR> <BR> <BR> <BR> O OO <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> N # H<BR> <BR> <BR> <BR> <BR> <BR> <BR> NHS OH o MeS Example 9 4- ((S)-2-Pvrrolidone-5-aminomethvl) thiocarbonvloxy-2-phenvlbenzovl((S)-2-Pvrrolidone-5-aminomet hvl) thiocarbonvloxy-2-phenvlbenzovl methionine methyl ester The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by thiophosgene.

Example 10 4-S')-2-Pyn-oIidone-5-aminomethyIulfinvloxv2-phenylbenzovlme thionine The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by thionyl chloride.

Example 11 4- ((S)-2-Pyrrolidone-5-aminomethvl) sulfonyloxv)-2-phenvlbenzovl((S)-2-Pyrrolidone-5-aminomethvl ) sulfonyloxv)-2-phenvlbenzovl methionine The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by sulfuryl chloride.

Example 12 4- 3-Pvridylmevlenthio)-2-phen, tbenzoylmethionine Example 12A 4-Mercapto-2-phenvlbenzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoic acid (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaN02 (1.1 equivalents) to form the diazonium salt. The reaction is treated with Sg (10 equivalents) and heated. The mixture is extracted into ethyl acetate which is dried and evaporated. The title thiophenol is purified by chromatography on silica gel.

Example I2B 4- (2-Pvridvlmethvlenthio)-2-phenvlbenzoic(2-Pvridvlmethvlenthi o)-2-phenvlbenzoic acid methyl ester A solution of the resultant thiophenol (1.0 equivalent) from Example 12A is treated with 2- chloromethylpyridine hydrochloride (1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2C03 (3.0 equivalent) s in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 12C<BR> 4-(2-Pvridvlthiomethvlen)-2-phenvlbenzoic acid The resultant compound from Example 12B is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 12D 4- (2-Pvidvlthiomethylen)-2-phenvlbenzovlmethionine methyl ester The resultant product from Example 12C is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 12E 4-(2-Pvridvlthiomethvlen)-2-phenvlbenzovlmethionine methvl ester(2-Pvridvlthiomethvlen)-2-phenvlbenzovlmethionine methvl ester alternate procedure 1 A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaN02 (1.1 equivalents) to form the diazonium salt. The reaction is treated with Sg (10 equivalents) and heated. The mixture is extracted into ethyl acetate which is dried and evaporated to afford 2-phenyl-4-mercaptobenzoyl-methionine methyl ester. The thiophenol is purified by chromatography on silica gel. A solution of this thiophenol (1.0 equivalent) is treated with 2-chloromethylpyridine hydrochloride (1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2CO3 (3.0 equivalents) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 12F 4- (2-PvridvlthiomethylenLphenylbevlmethionine methyl ester, alternate procedure 2 Methyl 4-amino-2-phenylbenzoate (100 mmol) is mixed in 50% sulfuric acid, and is cooled by a ice-water bath. To the above mixture with good stirring is added slowly a cold solution of sodium nitrite (110 mmol) in water, the reaction temperature is kept under 10 °C.

Powdered anhydrous sodium carbonate (100 mmol) is carefully added to the cold reaction mixture in small portions, until the reaction mixture reaches pH 7 to 8. Then, the reaction mixture is added in small portions to a solution of sodium p-methoxybenzylsulfide (prepared from reaction 110 mmol of p-methoxybenzylthiol with 55 mmol of 2.0 M NaOH aqueous solution). After completion of the addition, the reaction mixture is refluxed until judged complete by TLC analysis. The reaction mixture is then extracted with ether, and the organic extracts are washed sequentially with aqueous sodium carbonate solution, water and

brine, dried with anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel. The product thus obtained is dissolved in methanol and water, followed by addition of lithium hydroxide (200 mmol), and the mixture is refluxed until hydrolysis is judged complete by TLC analysis. The reaction mixture is then acidified with 6 N HCI, and extracted into ethyl acetate. The organic extracts are washed with brine, dried with anhydrous sodium sulfate, and concentrated in vacuo. The crude product obtained is redissolved in methylene chloride, followed by addition of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (1.1 equivalent) and 1-hydroxybenzotriazol (1.2 equivalent). The reaction is stirred until it is judged complete by TLC analysis, and then is diluted with ether. The mixture is washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.

The residue is then purified by column chromatography on silica gel. The resulting product is dissolved in trifluoroacetic acid and anisole (1.5 equivalent), and mercury diacetate (1.2 equivalent) is added. After TLC shows no starting material left, the reaction mixture is diluted with ether, washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude material is purified by column chromatography to afford 2-phenyl-4-mercaptobenzoyl-methionine methyl ester. A solution of this thiophenol (1.0 equivalent) is treated with 2-chloromethylpyridine hydrochloride (1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2C03 (3.0 equivalents) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 12G 4- (3-Pdvlthiomethylen)-2-phenylbevlmethionine The resultant compound from Example 12D is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 13 4-(2-Pvridvlthio)-2-phenvlbenzovlmethionine Example 13A 4-Fluoro-2-phenvl benzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous HBF4 is treated with NaN02 (1.1 equivalents) until an excess of nitrous acid persists. The mixture is extracted into ethyl acetate which is dried and evaporated. The title ester is purified by chromatography on silica gel.

Example 13B 4-Fluoro-2-phenvl benzoic acid The resultant compound from Example 13A is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 13C 4-Fluoro-2-phenyl benzoyl methionine methyl ester The resultant product from Example 13B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 13D 4- (2-Pyridylthio)-2-phenvl benzovl methionine methyl ester A mixture of the resultant fluorobenzoate from Example 13C (1.0 equivalent) and 2- mercaptopyridine (1.0 equivalent) is treated with K2CO3 (2.0 equivalents) or NaH (1.0 equivalent) in DMF or DMSO and is stirred until the reaction is judged complete by TLC analysis. The mixture is diluted with water and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.

Example 13E 4- (2-Pyridylthio)-2-phenyl benzoyl methionine methyl ester, alternate procedure 1 A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaN02 (1.1 equivalents) to form the diazonium salt. The

reaction is treated with S8 (10 equivalents) and heated. The mixture is extracted into ethyl acetate which is dried and evaporated. The title thiophenol is purified by chromatography on silica gel. A solution of this thiophenol (1.0 equivalent) is treated with 2-bromopyridine hydrobromide (1.0 equivalent) in the presence of a NaH (2.0 equivalent), or K2CO3 (3.0 equivalent) s in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 13F 4- (2-Pyridvlthio !-2-phenvl benzovl(2-Pyridvlthio !-2-phenvl benzovl methionine methyl ester, alternate procedure 2 A solution of the resultant thiophenol from Example 12A (1.0 equivalent) is treated with 2- bromopyridine hydrobromide (1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2CO3 (3.0 equivalents) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel. The resultant ester is hydrolyzed according to the procedure of Example 6C and then is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 13G 4- (2-Pyridvlthio)-2-phen, lbenzoylmethionine The resultant compound from Example 13D is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 14 4-(2-Pvridvlsulfonvl !-2-phenvlbenzovlmethionine Example 14A 4- (2-ridvlsulfonyl)-2-phenylbenzoic acid methyl ester A solution of 4- (2-pyridylthio)-2-phenylbenzoic acid methyl ester (Example 13F) is carefully treated with two equivalents of meta-chloroperbenzoic acid in methylene chloride at low temperature and the reaction is then quenched with aqueous Na2SO3 when judged complete by TLC analysis. The layers are separated and the organic phase is extracted with

aqueous NaHC03 to remove the m-chlorobenzoic acid. The product is isolated by removal of the solvent and is purified by chromatography on silica gel.

Example 14B 4-(2-Pyridylsulfonyl)-2-phenylbenzoicacid The resultant compound from Example 14A is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 14C 4-j2-pvridylsulfonvl)-2-phenylbenzoylmethionine methyl ester The resultant product from Example 14B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 14D 4-C2-PyridylsuIfonyI')-2-phenyIbenzoylmethionine The resultant compound from Example 14C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 15 4-f 3-Pyridylthiomethvlen)-2-phenylbenzoylmethionine The title compound is prepared from the resultant product of Example 12B using the procedures from Example 14.

Example 16 4-f (2-AminopYridyl) methylenel-2-phenylbenzoylmethionine

Example 16A<BR> 2-Phenvlterephthalic acid mono methvl ester A solution of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), Pd (OAc) 2 (0.05 equivalent) and DPPE (1.0 equivalent) is heated in DMF to 65° C under 4 atm. of carbon monoxide until TLC analysis indicates that the reaction is complete. The reaction mixture is poured into water and extracted with ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.

Example 16B 4- (Hydroxymethyl)-2-phenylbenzoic acid methyl ester The resultant acid from Example 16A (1.0 equivalent) is treated with a slight excess of N- methylmorpholine (1.1 equivalent) and isobutylchloroformate (1.0 equivalent) in THF at 0° C. The mixture is then treated with NaBH4 (1.0 equivalent) and aqueous NaHC03 and stirred at 0° C until the reaction is judged complete by TLC analysis. The mixture is poured into dilute aqueous acid and extracted into ethyl acetate which is dried and evaporated. The product is purified by chromatography on silica gel.

Example 16C 4- (Hvdroxymethvl)-2-phenvlbenzoic acid The resultant compound from Example 16B is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 16D 4- (Hvdroxvmethvl)-2-phenvlbenzovl methionine methyl ester The resultant product from Example 16C is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 16E 4-formyl-2-phenvlbenzovl methionine methyl ester A mixture of the resultant alcohol from Example 16D (1.0 equivalent), N- methylmorpholine-N-oxide (1.5 equivalents), molecular sieves, and a catalytic amount of TPAP is stirred in a CH2Cl2/acetonitrile mixture until the reaction is judged complete by TLC analysis. The mixture is diluted with ethyl ether and filtered through Si02. The product is purified by chromatography on silica gel.

Example 16F<BR> 4- !-2-phenvlbenzoyl methionine methyl ester, alternate procedure A mixture of (2-phenyl-4-bromobenzoyl) methionine methyl ester (100 mmol), 4,4,6- trimethyl-2-vinyl-1,3,2-dioxaborinane (100 mmol), tetrakis (triphenylphosphine) palladium (0) (3 mmol) in toluene and 2 M sodium carbonate in water (100 mL) is heated at 80 °C until the starting methyl ester disappears. The resulting mixture is extracted with ether, and washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel. To a solution of the resulting vinyl compound in dioxane/water (4/1) is added osmium tetraoxide (0.03 equivalent), N-methylmorpholine N-oxide (3 equivalents), and the reaction is stirred at 25 °C until TLC analysis shows the reaction to be complete. The reaction mixture is extracted with ether, which is washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to afford the title product.

Example 16G 4- (Hydroxvmethyl)-2-phenvlbenzovl methionine methyl ester, alternate procedure To a solution of the resultant compound from Example 16E in ethanol at 0 °C is added sodium borohydride (0.5 equivalent), and the reaction is stirred at 0 °C until TLC analysis shows the reaction to be complete. The reaction mixture is extracted with ether, which is washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to afford the title product.

Example 16H 4-f(2-Arninopvridvl) methvlenel-2-phenvlbenzovlmethionine methvl ester A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHC03 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.

Example161<BR> 4 j (2-Aminopyridyl) methvlenel-2-phenvlbenzovlmethionine

The resultant compound from Example 16H is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 17 4-r (3-aminomethvlpvridvl) methvlenel-2-phenvlbenzovlmethionine Using the procedures of Examples 16F-G and replacing 2-aminopyridine with 3- aminomethylpyridine affords the title product.

Example 18 4- ( (Sl-2-Pvrrolidone-5-aminomethylcarbonyl) aminomethyl-2-phenylbenzoyl methionine Example 18A 4- !-2-phenvlbenzovl methionine methyl ester To triphenylphosphine (1.0 equivalent) in tetrahydrofuran (THF) at-78° C is added diethyl azodicarboxylate (1.0 equivalent) in THF. To this mixture is added a solution of hydrazoic acid in benzene (2.0 equivalents) and then the resultant compound from Example 16D (1.0 equivalent). After one hour the mixture was warmed to room temperature, stirred until the reaction is judged complete by TLC analysis, evaporated and chromatographed on silica gel to afford the title product.

Example 18B 4- (Aminomethvl)-2-phenvlbenzovl methionine methvl(Aminomethvl)-2-phenvlbenzovl methionine methvl ester To the resultant compound from Example 18A in methanol is added triethylamine (3.0 equivalent) and propane 1,3-dithiol (3.0 equivalents). After the reaction is judged complete

by TLC analysis, the mixture is filtered and evaporated. Chromatography of the residue on silica gel provides the title product.

Example 18C 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)aminomethyl-2-phe nylbenzoylmethionine methyl ester To a solution of the resultant compound from Example 18B (1.0 equivalent) in methylene chloride is added triphosgene (0.33 equivalent) and triethyl amine (2.0 equivalents). This intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HCl and brine, evaporated, and purified by chromatography on silica gel.

Example 18D 4- ((S)-2-Pvrrolidone-5-aminomethvlcarbonvl) aminomethvl-2-phenvlbenzoVl((S)-2-Pvrrolidone-5-aminomethvlc arbonvl) aminomethvl-2-phenvlbenzoVl methionine The resultant compound from Example 18C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 19 <BR> 4- ( (S)-2-Pvrrolidone-5-aminomethylthiocarbonyl) aminomethyl-2-phenylbenzovl methionine The title compound is prepared as described in Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 20 4-((S)-2-Pyrrolidone-5-aminomethylsulfinyl)aminomethyl-2-phe nylbenzoylmethionine The title compound is prepared as described in Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by thionyl chloride (1.0 equivalent).

Example 21 <BR> 4-((S)-2-Pvrrolidone-5-aminomethvlsulfonvl) aminomethyl-2-phenylbenzovl((S)-2-Pvrrolidone-5-aminomethvls ulfonvl) aminomethyl-2-phenylbenzovl methionine Using the Procedure of Example 4 with the resultant compound from Example 18B affords the title product.

Example 22 4-((S)-Pyrrolidone-5-aminomethyl)carbonyloxymethylene)-2-phe nylbenzoylmethionine Using the procedure of Example 8 with the resultant compound from Example 16D provides the title product.

Example 23

4-((S)-2-Pyrrolidone-5-aminomethyl)thiocarbonyloxymethylene) -2-phenylbenzoyl methionine Using the procedure of Example 8 with the resultant compound from Example 16D and replacing triphosgene (0.33 equivalent) with thiophosgene (1.0 equivalent) provides the title product.

Example 24 4-(2-Aminopvridvl !-2-phenvlbenzovlmethionine Example 24A 4- (2-Aminopvridvl)-2-phenylbenzoylmethionine methyl ester 4-Amino-2-phenylbenzoyl methionine (1.0 equivalent) methyl ester and 2-bromopyridine hydrobromide (1.0 equivalent) in pyridine are heated until the reaction is judged complete by TLC analysis. The solvent is evaporated and the residue is taken up in ethyl acetate which is washed with water and brine, dried, and evaporated. Chromatography on silica gel affords the title product.

Example 24B 4-(2-Aminopvridvl)-2-phenvlbenzovlmethionine The resultant compound from Example 24A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 25 4- 3-Aminomethylpvridyl)-2-phenylbvlmethionine Example 25A 4-(3-Aminomethvlpvridvl)-2-phenvlbenzovlmethionine methvl ester

A mixture of 3-pyridinecarboxaldehyde (1.0 equivalent), 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) and NaCNBH3 (1.0 equivalent) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHC03 and extracted into ethyl acetate which is dried and evaporated.

Chromatography of the residue on silica gel affords the title compound.

Example 25B 4-(3-Aminomethylpyridyl)-2-phenylbenzoylmethionine The resultant compound from Example 25A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 26 444-aminomethylpyridyDmethylene1-2-phenyIbenzoylmethionine Using the procedures of Examples 25 with the resultant amine from Example 18B and 3- pyridinecarboxaldehyde affords the title product.

Example 27 4-(3-Pvridvloxvmethvlene)-2-phenvlbenzovlmethionine Example 27A ester4-(p-Toluenesulfonyloxy)-2-phenylbenzoylmethioninemethy l The resultant compound from Example 16D (1.0 equivalent) and p-toluenesulfonyl chloride (1.0 equivalent) in pyridine are stirred until the reaction is judged complete by TLC analysis.

The solvent is evaporated and the residue is taken up in ethyl acetate which is washed with water and brine, dried, and evaporated. Chromatography on silica gel affords the title product.

Example 27B 4-(3-Pvridvloxvmethvlene)-2-phenvlbenzovlmethionine methvl ester 3-Hydroxypyridine (1.0 equivalent) is treated with sodium hydride (1.0 equivalent) in DMSO, then the resultant compound from Example 27A (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.

Example 27C 4-(3-Pvridvloxvmethvlene)-2-phenvlbenzovlmethionine The resultant compound from Example 27B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 28 4- (3-Pvridylmethoxymethvlene)-2-phenylbenzoylmethionine Example 28A 4- (3-Pdylmethoxymethvlene)-2-phenylbenzoylmethionine methyl ester Using the procedure of Example 27B but replacing 3-hydroxypyridine with 3- hydroxymethylpyridine affords the title compound.

Example 28B 4- (3-Pvridvlmethoxymethvlene)-2-phenvlbenzoylmethionine methyl ester, alternate procedure The resultant compound from Example 16D (1.0 equivalent) is treated with sodium hydride (2.0 equivalents) in DMSO, then 3-chloromethylpyridine hydrochloride (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.

Example 28C

ester4-(3-Pyridylmethoxymethylene)-2-phenylbenzoylmethionine methyl The resultant compound from Example 28A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 29 f 2-Phenvl-4-f (thiazol-2-ylamino) carbonylthiolbenzovl-methionine Example 29A Thiazol-2-ylisocyanate A solution of 2-aminothiazol (1.0 mmol), triphosgene (0.34 mmol) and triethylamine (1.0 mmol) in toluene (10 mL) is refluxed until TLC shows no starting amine left. The solvent is then removed in vacuo, and the resulting material is used without further purification.

Example 29B f 2-Phenyl-4-[ (thiazol-2-vlamino ! carbonvlthiolbenzovl !-methionine methyl ester A solution of 2-phenyl4-mercaptobenzoyl-methionine methyl ester from example 12E or 12F (1.0 mmol) and the isocyanate prepared in example 29A (1.0 mmol) in THF is refluxed until TLC shows no thiol left. The solvent is then evaporated in vacuo, and the residue is purified by column chromatography on silica gel to give the title compound.

Example 29C f2-PhenyI-4-rfthiazol-2-ylamino) carbonylthio1benzoyH-methionine methyl ester, alternate procedure To a solution of 2-phenyl-4-mercaptobenzoyl-methionine methyl ester from example 12E or 12F (1 equivalent) in methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and p-dimethylaminopyridine (2.0 equivalents). When the reaction is judged complete by TLC analysis, the solvent is evaporated with toluene chasers. The thiochloroformate is reacted without further purification with 2-aminothiazol (1.0 equivalent) and triethylamine (1.0 equivalent) in dichloromethane. When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HC1 and brine, evaporated, and purified by chromatography on silica gel.

Example 29D {2-Phenvl-4 [(thiazol-2-ylamino) carbonvlthiolbenzovl}-methionine The resultant compound from Example 29B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 30 f2-PhenyI-4-ffthien-2-vlmethylamino) carbonylthiolbenzoyI}-methionine Using the procedure of Example 29 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example31 {2-Phenyl-4-[(thiazol-2-ylamino)thionylthio]benzoyl}-methion ine Example31 A (N-Thionyl)thiazol-2-ylamine A solution of 2-aminothiazol (1.0 mmol), in thionyl chloride is heated at reflux until the reaction is judged to be complete by TLC analysis. Then, the excess thionylchloride is distilled out in vacuo. The resulting material is used without further purification.

Example 31B L-Phenvl-4-f (thiazol-2-ylamino) thionvlthiolbenzoy}-methionine methyl ester Using the procedure of Example 29B but replacing the resultant product from Example 29A with the resultant product from Example 31A affords the title compound.

Example31C {2-Phenyl-4-r (thiazol-2-vlamino) thionvlthiolbenzoyl-methionine methvl ester, alternate procedure

Using the procedure of Example 29C but replacing phosgene in toluene with thionyl chloride affords the title compound. <BR> <BR> <P> Example 31 D<BR> t 2-Phenvl4-[(thiazol-2-vlamino) thionylthiolbenzovl i-methionine The resultant compound from Example 31B is hydrolyzed according to the procedure of Example IB to give the title product.

Example 32 {2-Phenyl-4-[(thien-2-ylmethylamino)thionylthio]benzoyl}-met hionine Using the procedure of Example 31 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 33 {2-Phenyl-4-flthiazol-2-vlamino) sulfonvlthiolbenzovll-methionine methyl ester Using the procedure of Example 31 but replacing thionyl chloride with sulfuryl chloride affords the title product. example.) 34<BR> <BR> f 2-Phenvl4-[(thien-2-vlmethvlamino) sulfonvlthiolbenzovl}-methionine Using the procedure of Example 31 but replacing 2-aminothiazol with thien-2- ylmethylamine and replacing thionyl chloride with sulfuryl chloride affords the title product.

Example 35 f 2-Phenvl4-[(thiazol-2-vlamino) thiocarbonvlthiolbenzovl}-methionine Using the procedure of Example 29 and replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol) affords the title product.

Example 36 {2-Phenyl-4-[(thien-2-ylmethylamino)thiocarbonylthio]benzoyl }-methionine Using the procedure of Example 29 and replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol) and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

Example 37 f 2-Phenyl-4-f (thiazol-2-yl) thiomethvllbenzoyl}-methionine Example 37A <2-PhenvI-4-rthiomethvnbenzovn-methionine methyl ester The resultant product from Example 27A is dissolved DMF/water (2/1), and sodium hydrosulfide (5 equivalent) is added to the reaction mixture. The reaction is stirred until TLC analysis shows that the reaction is complete. Then, the reaction mixture is acidified with 3 N HC1 to about pH 4, extracted with ether, and washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified with column chromatography on silica gel to give the title compound.

Example 37B ester,alternateprocedure{2-Phenyl-4-[(thiomethyl]benzoyl}-me thioninemethyl

To triphenylphosphine (1.2 equivalents) in THF at-78 °C is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 16D (1. equivalent) in THF. The reaction is stirred at-78 °C for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.

Example 37C {2-PhenyI-4- thiomethyllbenzovl}-methlonine methvl ester A mixture of the resultant thiol from Example 37A (1 mmol), 2-bromothiazole (1.5 mmol), and anhydrous potassium carbonate (5 mmol) in DMF is stirred at 100 °C until TLC analysis shows that the starting thiol disappeared. Then, the reaction mixture is diluted with water, extracted with ether, and washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography on silica gel to give the title compound.

(2-Phenyl-4-f (thiazoI-2-yI) thiomethyl1benzoyI}-methionine The resultant compound from Example 37C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example38 {2-Phenyl-4-[(thien-2-ylmethyl)thiomethyl]benzoyl}-methionin e Using the procedure of Example 37 and replacing 2-bromothiazole with 2- bromomethylthiophene affords the title product.

Example 39

{2-Phenvl-4-flthiazol-2-vlamino) carbonvlthiomethvllbenzov-methionine Using the procedure of Example 29 with the resultant product from Example 37A affords the title product.

Example 40 {2-Phenyl-4-[(thiazol-2-ylamino)carbonylthiomethyl]benzoyl}- methionine Using the procedure of Example 29 with the resultant product from Example 37A and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

Example 41 f 2-Phenvl4-r (thiazol-2-vlamino) thiocarbonvlthiomethvllbenzovl}-methionine Using the procedure of Example 29 with the resultant product from Example 37A and replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol) affords the title product.

Example 42 f2-Phenvl-4-f (thiazol-2-vlamino) thiocarbonvlthiometh, llbenzovl -methionine Using the procedure of Example 29 with the resultant product from Example 37A, replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol), and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

Example 43 {2-Phenyl-4-[(thiazol-2-ylamino)thionylthiomethyl]benzoyl}-m ethionine Using the procedure of Example 31 with the resultant product from Example 37A affords the title product.

Example 44 {2-Phenyl-4-[(thien-2-ylmethylamino)tionylthiomethyl]benzoyl }methionine Using the procedure of Example 31 with the resultant product from Example 37A and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

Example 45 f 2-Phenyl-4-rrthiazol-2-vlamino) sulfonylthiomethyllbenzoyl l-methionine Using the procedure of Example 31 with the resultant product from Example 37A and replacing thionyl chloride with sulfuryl chloride affords the title product. affords the title product.

Example 46 <BR> <BR> f 2-Phenyl-4-f (thien-2-ylmethylamino sulfonylthiomethlbenzoyl}-methionine

Using the procedure of Example 31 with the resultant product from Example 37A, replacing thionyl chloride with sulfuryl chloride, and replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 47 f 4-f2- (lmidazol-2-ylethynyl1-2-phenylbenzoyl} methionine Example 47A (4-EthynYl-2-phenYlbenzoYl) methionine methyl ester A mixture of (2-phenyl-4-bromobenzoyl)-methionine methyl ester (100 mmol), diethylamine (300 mmol), trimethylsilylacetylene (110 mmol), bis (triphenylphosphine) palladium diacetate (5 mmol) and copper (I) iodide (3 mmol) in toluene is heated at 60 °C until TLC analysis indicates the starting methyl ester has disappeared. The reaction mixture is concentrated in vacuo, redissolved in ether, filtered through silica gel, and concentrated.

The residue is then dissolved in THF, and is treated with tetrabutylammonium fluoride (120 mmol). After TLC analysis indicates that no starting material is left, the reaction mixture is diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified with column chromatography on silica gel to give the title product.

Example 47B f4-f2- (lmidazol-2-yl) ethynyn-2-phenylbenzoyl}-methionine methyl ester The resultant product from Example 47A (5 mmol) is mixed with 4-bromoimidazole (5 mmol), diethylamine (1 mL), bis (triphenylphosphine) palladium diacetate (0.1 mmol) and copper (I) iodide (0.1 mmol) in toluene. The mixture is stirred at 25 °C until TLC analysis indicates the reaction is complete. The reaction mixture is concentrated in vacuo, and the residue is purified with column chromatography on silica gel to give the title product.

Example 47C {4-[2-(Imidazol-2-yl)ethynyl]-2-phenylbenzoyl}-methionine The resultant compound from Example 47B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 48 f4-f2- (Imidazol-4-yl) ethenyll-2-phenvlbenzov-methionine The resultant acetylene (3 mmol) from Example 47 is mixed with Lindlar catalyst (50 mg), 5 drops of quinoline in ethyl acetate. The reaction mixture is attached to a hydrogenation apparatus, and then is detached from the apparatus after about 95% of the theoretical hydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo.

The crude product is purified with a column chromatography on silica gel to give the title compound.

Example 49 {4-[2-(Imidazol-4-yl)ethyl]-2-phenylbenzoyl}-methionine The resultant olefin (1 mmol) from Example 48 is mixed with 5% palladium on carbon (100 mg) in ethyl acetate. The reaction mixture is attached to a hydrogenation apparatus, and then is detached from the apparatus after about 95% of the theoretical hydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo. The crude product is purified with a column chromatography on silica gel to give the title compound.

Example 50 <BR> {4-f2-lImidazol-4-vlcarbonyl) ethynyl]-2-phenylbenzoy}-methionine<BR> <BR> Example50A ester{4-[2-(Imidazol-4-ylcarbonyl)ethynyl]-2-phenylbenzoyl]- methioninemethyl

A stainless autoclave containing the resultant product from Example 47A (5 mmol), 4- bromoimidazole (5 mmol), 1,1'-bis (diphenylphosphine)-ferrocenepalladium dichloride (0.1 mmol), and triethylamine (10 mL) is flushed with nitrogen, and pressurized to 20 atm with carbon monoxide. The reaction mixture is stirred at 120 °C until judged complete by TLC analysis. After cooling, the triethylamine is evaporated in vacuo, and the residue is purified by column chromatography on silica gel to give the title compound. <BR> <BR> <P> Example50B<BR> {4-j2- (Imidazol-4-vlcarbonyl) ethynyll-2-phenylbenmethionine The resultant compound from Example 50A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example51<BR> <BR> f 4-f2- (Imidazol-4-yicarbonyl) ethenyH-2-phenyIbenzoy !}-methionine Using the procedure of Example 48 with the resultant compound from Example 50 affords the title product.

Example 52 {4-[2-(Imidazol-4-ylcarbonyl)ethyl]-2-phenylbenzoyl}-methion ine Using the procedure of Example 49 with the resultant compound from Example 51 affords the title product.

Example 53 14-r4-methionine Example 53A {4-f4- (1-Methvlimidazol-4-yl-3-keto-1-butynyll-2-phenylbenzoyl}-me thionine methy ! ester To a solution of 1-methyl4-imidazoleacetic acid (5 mmol) in methylene chloride at 0 °C is added oxalyl chloride (6 mmol) and DMF (0.05 mmol). After 30 minute, the solvent is evaporated in vacuo. The residue is redissolved in dichloromethane, followed by the addition of the resultant acetylene from Example 47A (5 mmol), triethylamine (10 mmol), and copper (I) iodide (1 mmol). The reaction is stirred at 25 °C until TLC analysis indicates no starting material is left in the reaction mixture. The reaction is diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to give the title compound.

Example 53B {4-[4-(1-Methylimidazol-4-yl)-3-keto-1-butynyl]-2-phenylbenz oyl}-methionine The resultant compound from Example 53A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 54 f4-r4- (1-Methylimidazol-4-yl)-3-keto-1-butenyll-2-phenvlbenzovl 1-methionine Using the procedure of Example 48 with the resultant compound from Example 53 affords the title product.

Example 55 {4-[4-(1-Methylimidazol-4-yl)-3-keto-1-butyl]-2-phenylbenzoy l}-methionine

Using the procedure of Example 49 with the resultant compound from Example 53 affords the title product.

Example 56 (S) Pyroglutamvl- (4-amino-2-phenvl) benzoyl methionine Example 56A (S) Pyroglutamvl- (4-amino-2-phenvl) benzovl methionine methyl ester To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by pyroglutamic acid (1.0 equivalent) and 1- (3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 56B () Pyroglutamyl- (4-amino-2-phenyl) benzoyl methionine The resultant compound from Example 56A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 57 (S) Pyroglutamvl- (4-amino-2-phenvl) benzovl methionine

Using the procedure of Example 56 and replacing pyroglutamic acid with 3-pyridylacetic acid affords the title product.

Example 58 (S) Pyroglutamyl- (4-aminomethyl-2-phenyl) benzoyl methionine Example 58A (S) Pyroglutamvl- (4-aminomethyl-2-phenyl) benzovl methionine methyl ester To a solution of the resultant amine from Example 18B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by pyroglutamic acid (1.0 equivalent) and 1- (3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents) : When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HC1 and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 58B (S) methionine The resultant compound from Example 58A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 59 naming error (S) Pvroglutamvl-(4-aminomethvl-2-phenvl) benzovl methionine

Using the procedure of Example 58 and replacing pyroglutamic acid with 3-pyridylacetic acid affords the title product.

Example 60 4-f (ridin-2-ylamino) carbonyll-2-phenylbenzovl methionine Example 60A 4-Carboxy-2-phenylbenzoyl methionine methyl ester A solution of 4-bromo-2-phenylbenzoyl methionine methyl ester (1.0 equivalent), Pd (OAc) 2 (0.05 equivalent) and DPPE (1.0 equivalent) is heated in DMF to 65° C under 4 atm. of carbon monoxide until TLC analysis indicates that the reaction is complete. The reaction mixture is poured into water and extracted with ethyl acetate which is dried and evaporated.

The product is purified by chromatography on silica gel.

Example 60B 4-f (Pvridin-2-vlamino) carbonyll-2-phenylbenzovl methionine methyl ester To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3- hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1- (3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by 1N HC1 and saturated brine, and then is dried and evaporated.

The crude reaction mixture is purified by column chromatography to afford the title product.

Example 60C 4-r (Pvridin-2-vlamino ! carbonvll-2-phenvlbenzovl methionine The resultant compound from Example 60B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example61 4-((S)-2-Pyrrolidone-5-aminomethyl)carbonyl)-2-phenylbenzoyl methionine Using the procedure of Example 60 and replacing 2-aminopyridine with (S)-5-aminomethyl- 2-pyrrolidone affords the title product.

Example 62 4-f (ridin-2-vlamino) carbonylmethyll-2-phenylbenzovl methionine Example 62A 4-Diazocarbonvl-2-phenvlbenzovl methionine methvl ester The resultant acid from Example 60A (1 equivalent) in dichloromethane is treated with oxalyl chloride (1 equivalent) and DMF (0.05 equivalent). When gas evolution has ceased, the acid chloride solution is added to an ether solution of diazomethane. The reaction is stirred until judged complete by TLC analysis, and then is concentrated to give the crude title compound which is purified by chromatography on silica gel.

Example 62B 4-carboxymethyl-2-phenvlbenzoyl methionine methyl ester The resultant compound from Example 62A (1 equivalent) in dioxane is added to a slurry of sodium thiosulfate (1.1 equivalents) and silver (1) oxide (0.5 equivalent) in water. The reaction is stirred until judged complete by TLC analysis, filtered, acidified, and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title product.

Example 62C

methylester4-[(Pyridin-2-ylamino)carbonylmethyl]-2-phenylben zoylmethionine To a solution of the resultant acid from Example 62B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by 2- aminopyridine (1.0 equivalent) and 1- (3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with 1N HC1 and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 62D 4-r (,vridin-2-vlaminolcarbonvlmethyll-2-phenvlbenzovl methionine The resultant compound from Example 62C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 63 4-((S)-2-Pyrrolidone-5-aminomethyl)carbonylmethyl)-2-phenylb enzoylmethionine Using the procedure of Example 62 and replacing 2-aminopyridine with (S)-5-aminomethyl- 2-pyrrolidone affords the title product.

Example 64 4- ( (-2-Pyrrolidone-5-methoxycarbonyl) amino-2-phenylbenzoylmethionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCI (0.1 equivalent).

Example 65 4-((S)-2-Pyrrolidone-5-methoxythiocarbonyl)amino-2-phenylben zoylmethionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 66 4- ( (-Pvnolidone-5-methoxvsulfinyl) amino-2-phenyIbevl methionine The title compound is prepared as described in Example 3 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 67 4-((S)-2-Pyrrolidone-S-methoxvsulfonvl ? amino-2-phenvlbenzovl methionine

The title compound is prepared as described in Example 4 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 68 4- (Pyridin-3-ylmercaptocarbonvl) amino-2-phenvlbenzovl methionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example 69 4-(Pvridin-3-vlmercaptothiocarbonvl) amino-2-phenvlbenzovl methionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 70 4-(Pyridin-3-ylmercaptosulfinyl)amino-2-phenylbenzoylmethion ine

The title compound is prepared as described in Example 3 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example71<BR> <BR> 4-lyridin-3-ylmercaptosulfonyl) amino-2-phenvlbenzovl methionine The title compound is prepared as described in Example 4 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example 72 4- (S-2-Pvrrolidone-5-methoxvcarbonyl) aminomethyl-2-phenvlbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 73 <BR> <BR> S)-2-Pyrrolidone-5-methoxvthiocarbonvl) aminomethvl-2-phenylbenzoyl methionine

The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 74 4- ( (S)-2-PXrrolidone-5-methoxysulfinyl) aminomethvl-2-phenvlbenzovl methionine The title compound is prepared as described in Example 3 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2-pyrrolidone (1.0 equivalent) and CuCI (0.1 equivalent).

Example 75 4-y((S'1-2-Pvrrolidone-5-methoxysulfonylaminomethyl-2-phenvl benzovl methionine The title compound is prepared as described in Example 4 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2-pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 76

4- (Pvridin-3-ylmercaptocarbonvl) aminomethyl-2-phenvlbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example 77 4-lyridin-3-ylmercaptocarbonyl) aminomethyl-2-phenylbenzovl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 78 4-(Pvridin-3-vlmercaptosulfinvl) aminomethyl-2-phenvlbenzovl methionine The title compound is prepared as described in Example 3 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example 79

4-yridin-3-vlmercaptosulfonyl) aminomethyl-2-phenylbenzovl methionine The title compound is prepared as described in Example 4 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

Example 80 A-NH-CO-NH-B The procedure of Example 1 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 81 A-NH-CS-NH-B The procedure of Example 1 is used with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent), 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 82 A-NH-SO-NH-B The procedure of Example 3 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5-

aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 83 A-NH-SO ?-NH-B The procedure of Example 4 is used with the exception that 4-amino-2- phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 84 A-NH-S02-B The procedure of Example 5 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 85 A-NH-CO-O-B

The anilines from Table 1 (B-NH2) are reacted according to the procedure of Example 6E.

The resultant phenols are reacted according to the procedure of Example 8 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A- NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 86 A-NH-CS-O-B The anilines from Table 1 (B-NH2) are reacted according to the procedure of Example 6E. The resultant phenols are reacted according to the procedure of Example 8 with the exception that phosgene in toluene is replaced by thiophosgene and (S)-5- aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 87 A-NH-SO-O-B The anilines from Table 1 (B-NH2) are reacted according to the procedure of Example 6E.

The resultant phenols are reacted according to the procedure of Example 8 with the exception that phosgene in toluene is replaced by thionyl chloride and (S)-5-aminomethyl-2- pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 88 A-NH-SO2x-B The anilines from Table 1 (B-NH2) are reacted according to the procedure of Example 6E. The resultant phenols are reacted according to the procedure of Example 8 with the exception that phosgene in toluene is replaced by sulfuryl chloride and (S)-5- aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final Li OH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 89 A-NH-CHo-B The procedure of Example 16 is used with the exception that (2-phenyl-4-bromobenzoyl)- methionine methyl ester is replaced by a bromide from Table 2 (B-Br) and 2-aminopyridine is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 90 A-NH-CO-NH-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F-G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 91 A-NH-CS-NH-CH The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent) and (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 92 A-NH-SO-NH-CH2-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by thionyl chloride (1.0 equivalent) and (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 93 A-NH-S02-NH-CH-B

The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by sulfuryl chloride (1.0 equivalent) and (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 94 A-NH-CO-O-CH=B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 8 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A- NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 95 A-NH-CS-O-CH The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 8 with the exception that phosgene in toluene is replaced by thiophosgene and (5 ;)-5-aminomethyl-2- pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the

bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 96 A-NH-CO-S-B The anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to the procedure of Example 12E. These mercaptans are reacted according to the procedure of Example 29 with the exception that 2-aminothiazol is replaced by an amine from Table 3 (A- NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 97 A-NH-CS-S-B The anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to the procedure of Example 12E. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by thiophosgene and 2- aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 98 A-NH-SO-S-B The anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to the procedure of Example 12E. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by thionyl chloride and 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from

amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 99 A-NH-SO-S-B The anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to the procedure of Example 12E. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by sulfuryl chloride and 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. <BR> <BR> <P> Example 100<BR> A-NH-CO-S-CHS The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding mercaptans according to the procedures of Examples 27A and 37A. These mercaptans are reacted according to the procedure of Example 29 with the exception that 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example101<BR> A-NH-CS-S-CHS The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding mercaptans according to the procedures of Examples 27A and 37A. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by thiophosgene and 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 102 A-NH-SO-S-CH The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding mercaptans according to the procedures of Examples 27A and 37A. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by thionyl chloride and 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 103 A-NH-S02-S-CHDB The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding mercaptans according to the procedures of Examples 27A and 37A. These mercaptans are reacted according to the procedure of Example 29 with the exception that phosgene in toluene is replaced by sulfuryl chloride and 2-aminothiazol is replaced by an amine from Table 3 (A-NH2). For products

derived from amines 146-206 from Table 3, the final Li OH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206. example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 104 A-CO-NH-B The procedure of Example 56 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and pyroglutamic acid is replaced by an acid from Table 4 (A-C02H). For products derived from acids 164- 238 and 262-269 from Table 4, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 105 A-CO-NH-CHS The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding amines according to the procedures of Examples 18A-B. These amines are reacted according to the procedure of Example 58 with the exception that pyroglutamic acid is replaced by an acid from Table 4 (A-C02H). For products derived from acids 164-238 and 262-269 from Table 4, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 106 A-CO-C-C-B The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 47A.

The resultant acetylenes are reacted according to the procedure of Example 53 with the exception that l-methyl4-imidazoleacetic acid is replaced by an acid from Table 4 (A- C02H). For products derived from acids 164-238 and 262-269 from Table 4, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 107 A-CO-CH=CH-B The products from Example 106 are reacted according to the procedure of Example 54.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 108 A-CO-CHo-CH=B The products from Example 107 are reacted according to the procedure of Example 55.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the

bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 109 A-NH-CO-B The procedure of Example 60 is used with the exception that 4-bromo-2-phenylbenzoyl methionine methyl ester is replaced by a bromide from Table 2 (B-Br) and 2-aminopyridine is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final Li OH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Example110<BR> <BR> <BR> <BR> <BR> <BR> <BR> A-NH-CO-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 60A.

The resultant carbocyclic acids are reacted according to the procedure of Example 62 with the exception that 2-aminopyridine is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146- 206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 111 A-CH2-NH-B The procedure of Example 25 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an amine from Table 1 (B-NH2) and 3- pyridinecarboxaldehyde is replaced by an aldehyde from Table 5 (A-CHO). For products derived from aldehydes 360-432 and 433-440 from Table 5, the LiOH hydrolysis step is

followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Example112<BR> <BR> <BR> <BR> <BR> A-CH2.-NH-CH2-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F-G. The resultant alcohols are converted to the corresponding amines according to the procedures of Examples 18A-B. These amines are reacted according to the procedure of Example 25 with the exception that 3-pyridinecarboxaldehyde is replaced by an aldehyde from Table 5 (A-CHO). For products derived from aldehydes 360-432 and 433- 440 from Table 5, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compound comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 113 4- (rS)-2-Pvrrolidone-5-aminomethyl) sulfonvlmethvl)-2-phenvlbenzovl(rS)-2-Pvrrolidone-5-aminomet hyl) sulfonvlmethvl)-2-phenvlbenzovl methionine

Example113A<BR> <BR> <BR> <BR> <BR> <BR> 4-Thioacetoxvmethvl-2-phenylbenzoic acid methvl ester To triphenylphosphine (1.2 equivalents) in THF at-78 °C is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 16B (1. equivalent) in THF. The reaction is stirred at-78 °C for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2C03 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.

Example 113B 4-Chlorosulfonvlmethylene-2-phenvlbenzoic acid methyl ester The resultant compound from Example 113A in water is stirred vigorously while gaseous chlorine is bubbled through the mixture. When the reaction is judged to be done by TLC analysis, the reaction is extracted with dichloromethane which is dried and evaporated to afford the title product.

Example 113C 4- ( (S)-2-Ptrrrolidone-5-aminomethyl) sulfonylmethvlene-2-phenylbenzoic acid methyl ester To a solution of the resultant compound from Example 113B (1.0 equivalent) in methylene chloride is added (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When the reaction is judged complete by TLC analysis, the solvent is evaporated and the residue is purified by chromatography on silica gel.

Example 113D 4- ( (-2-Pyrrolidone-5-aminomethynsuIfonyImethylene-2-phenyIbenzo ic acid The resultant compound from Example 113C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 113E 4- ( (S)-2-Pmrolidone-5-aminomethyl) sulfonylmethvlene-2-phenylbvl methionine methylester To a solution of the resultant compound from Example 113D (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and 1- (3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged

complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 113F 4-((S)-2-Pyrolidone-5-aminomethyl)sulfonylmethylene-2-phenyl benzoylmethioinine The resultant compound from Example 113E is hydrolyzed according to the procedure of Example 1B to give the title product. <BR> <BR> <P> Example114<BR> A-NH-SCh-CH-B The procedure of Example 113 is used with the exception that (S)-5-aminomethyl-2- pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

Example 115 4-((S)-2-Pvrrolidone-5-aminomethvl) sulfonvlmethvl)-2-phenylbenzovl leucine Example 115A 4- (Hvdroxvmeyl)-2-phenrlbenzovl leucine methyl ester (2-phenyl-4-bromobenzoyl)-leucine methyl ester is reacted according to the procedures of Example 16F-G.

Example 115B 4-Thioacetoxvmeth.2-phenylbenzoyl leucine methyl ester To triphenylphosphine (1.2 equivalents) in THF at-78 °C is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 115A (1. equivalent) in THF. The

reaction is stirred at-78 °C for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.

Example 115C 4-Chlorosulfonylmethylene-2-phenylbevl leucine methyl ester The resultant compound from Example 115B in water is stirred vigorously while gaseous chlorine is bubbled through the mixture. When the reaction is judged to be done by TLC analysis, the reaction is extracted with dichloromethane which is dried and evaporated to afford the title product.

Example 115D 4- ((S)-2-Pvrrolidone-5-aminomethvl) sulfonvlmethvlene-2-phenvlbenzovl((S)-2-Pvrrolidone-5-aminom ethvl) sulfonvlmethvlene-2-phenvlbenzovl leucine methyl ester To a solution of the resultant compound from Example 11C (1.0 equivalent) in methylene chloride is added (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When the reaction is judged complete by TLC analysis, the solvent is evaporated and the residue is purified by chromatography on silica gel. <BR> <BR> <BR> <BR> <BR> <P> Example 115E<BR> <BR> <BR> <BR> 4-((S)-2-Pvrrolidone-5-aminomethvl) sulfonvlmethvlene-2-phenvlbenzoVl leucine The resultant compound from Example 115D is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 116 A-NH-SO-CHS The procedure of Example 115 is used with the exception that (2-phenyl-4-bromobenzoyl)- leucine methyl ester is replaced by a bromide from Table 2, entries 28-132 (B-Br) and (S)- 5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

Example 117 4-(2-Thiazolvl)-2-phenvlbenzovl methionine Example 117A 2-Thiazole boronic acid A solution of thiazole (1.0 equivalent) is lithiated with a slight excess of n-butyl lithium in THF (1.05 equivalents) and then treated with trimethyl borate (1.05 equivalents). The reaction mixture is quenched by the addition of aqueous HCl and the resulting boronate ester is cleaved by the addition of excess aqueous NaOH. After acidification and extraction into ethyl acetate the crude boronic acid is used without further purification.

Example 117B 4- (2-Thiazolvl)-2-phenvlbenzovl(2-Thiazolvl)-2-phenvlbenzovl methionine methyl ester A mixture of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), 2-thiazole boronic acid (1.0 equivalent) and catalytic Pd (PPh3) 4 is heated in a two phase system of toluene and aqueous Na2CO3. After cooling, the resulting biaryl compound is isolated by evaporation of the organic phase and is purified by chromatography on silica gel.

Example 117C 4-(2-Thiazolvl)-2-phenvlbenzovl(2-Thiazolvl)-2-phenvlbenzovl methionine The resultant compound from Example 117C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 118 4-l2-Thiazolvlcarbonyl-2-phenvlbenzovl methionine

Example 118A methylester4-(2-Thiazolylcarbonyl)-2-phenylbenzoylmethionine A mixture of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), 2-thiazole boronic acid from Example 117A (1.0 equivalent) and catalytic Pd (PPh3) 4 is heated in a two phase system of toluene and aqueous Na2CO3 previously purged with a large excess of carbon monoxide. The resulting diaryl ketone is isolated by evaporation of the organic phase and is purified by chromatography on silica gel.

Example 118B 4-2-Thiazolvlcarbonyl)-2-phenylbenzoyl methionine The resultant compound from Example 1 18A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 119 4-[(3-Aminopyridyl)carbonylaminosulfonyl]-2-phenylbenzoylmet hionine Example119A 4-Aminosulfonyl-2-phenylbenzoylmethionine methvl ester To a solution of 4-chlorosulfonyl-2-phenylbenzoyl methionine methyl ester from Example SE in dichloromethane is added aqueous ammonia and the mixture is stirred until the reaction is judged complete by TLC analysis. The organic phase is separated, dried and evaporated and the product is purified by chromatography on silica gel.

Example 119B 4-Isocyanatosulfonphen, lbenzovlmethionine methyl ester A mixture of the resultant sulfonamide from Example 119A in chlorobenzene is treated with with oxalyl chloride according to the procedure of Franz et al. (J. Org. Chem, 1964,29, 2592) to give the title compound.

Example119C 4-f (A-aminopyridYl) carbonylaminosulfog-2-phenylbenzovlmethionine methyl ester A mixture of the resultant isocyanate from Example 119B (1 equivalent) in dichloromethane is treated with 3-aminopyridine (1 equivalent) and stirred until the reaction is judged complete by tlc analysis. The solvent is evaporated and the product is purified by chromatography on silica gel. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Example119D<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-r (A-aminopyridyl) carbonylaminosulfonyll-2-phenvlbenzoylmethionine The resultant compound from Example 119C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 120 A-NH-CO-NH-SOß The anilines from Table 1 (B-NH2) are reacted according to the procedures of Example SE to afford the corresponding sulfonyl chlorides. These are reacted according to the procedure of Example 119 with the exception that 3-aminopyridine is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final Li OH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 121 A-NH-CO-NH-SO-CH The bromides from Table 2, entries 28-132 (B-Br) are reacted according to the procedures of Example 115A-C to afford the corresponding sulfonyl chlorides. These are reacted according to the procedure of Example 119 with the exception that 3-aminopyridine is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the

bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 122 A-O-CHffl The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 27 with the exception that 3-hydroxypyridine is replaced by an alcohol from Table 6 (A-OH). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replacedby the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 123 A-O-CO-NH-B The procedure of Example 1 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 124 A-O-CS-NH-B

The procedure of Example 1 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2), (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCI (0.1 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 125 A-O-SO-NH-B The procedure of Example 3 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCI (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 126 A-O-S02-NH-B The procedure of Example 4 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH,

1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 127 A-O-CO-NH-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyZ, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 128 A-O-CS-NH-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCI (0.1 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by

removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 129 A-O-SO-NH-CHS The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 3 with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 130 A-O-SO-NH-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 4 with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane

and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the arnino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 131 A-S-B The anilines from Table 1 (B-NH2) are reacted according to the procedures of Example 13A. The resultant fluorides are reacted according to the procedure of Example 13 with the exception that 2-mercaptopyridine is replaced by a mercaptan from Table 7 (A-SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 132 A-S-CO-NH-B The procedure of Example 1 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by a mercaptan from Table 7 (A- SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the

anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 133 A-S-CS-NH-B The procedure of Example 1 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2), (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by a mercaptan from Table 7 (A- SH), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent). For products derived from mercaptans 301-394 from Table 7, the Li OH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 134 A-S-SO-NH-B The procedure of Example 3 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (Y)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by a mercaptan from Table 7 (A- SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example135<BR> <BR> <BR> <BR> <BR> A-S-SO-NH-B The procedure of Example 4 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (J)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by a mercaptan from Table 7 (A- SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 136 A-S-CO-NH-CHv-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by a mercaptan from Table 7 (A-SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 137 A-S-CS-NH-CH2-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 18 with the

exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by a mercaptan from Table 7 (A-SH) and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds. comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 138 A-S-SO-NH-CHS The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 3 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by a mercaptan from Table 7 (A-SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 139 =A-S-S02-NH-CH2-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 4 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by a mercaptan from Table 7 (A-SH). For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting

group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 140 A-O-B The procedure of Example 6 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and 3- bromopyridine is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I). For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final E ; iOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 141 A-S-B The procedure of Example 12 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and 2- chloromethylpyridine hydrochloride is replaced by a halide from Table 8 (A-Cl, A-Br, or A- I). For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 142 A-NH-B The procedure of Example 24 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and 2- bromopyridine hydrobromide is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I).

For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 143 A-O-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 28 with the exception that 3-chloromethylpyridine hydrochloride is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I). For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 144 A-S-CH-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are reacted according to the procedure of Example 37 with the exception that 2-bromothiazole is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I).

For products derived from halides 202-239 from Table 8, the Li OH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 145 A-CC-B The procedure of Example 47 is used with the exception that (2-phenyl-4-bromobenzoyl)- methionine methyl ester is replaced by a bromide from Table 2 (B-Br) and 4- bromoimidazole is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I). For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 146 A-CH=CH-B The products from Example 145 are reacted according to the procedure of Example 48.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 147 A-CH-CH-B The products from Example 146 are reacted according to the procedure of Example 49.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 148 A-CO-CC-B The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 47A.

The resultant acetylenes are reacted according to the procedure of Example 50 with the exception that 4-bromoimidazole is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I).

For products derived from halides 202-230 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 149 A-CO-CH=CH-B The products from Example 148 are reacted according to the procedure of Example 48.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to

prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 150 A-CO-CH-CH-B The products from Example 149 are reacted according to the procedure of Example 49.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 151 A-SO-B The anilines from Table 1, entries 28-132 (B-NH2) are reacted according to the procedures of Example 13A. The resultant fluorides are reacted according to the procedure of Example 13 with the exception that 2-mercaptopyridine is replaced by a mercaptan from Table 7 (A-SH). The resultant sulfides are oxidized according to the procedure of Example 14A. For products derived from mercaptans 301-394 from Table 7, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 152 A-CH2SO=B The procedure of Example 12 is used with the exception that 4-amino-2- phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1, entries 28- 132 (B-NH2) and 2-chloromethylpyridine hydrochloride is replaced by a halide from Table 8 (A-Cl, A-Br, or A-1). The resultant sulfides are oxidized according to the procedure of Example 14A. For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting

group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 153 A-SO2-CH2-B The bromides from Table 2, entries 28-132 (B-Br) are reacted according to the procedures of Example 16F-G. The resultant alcohols are reacted according to the procedure of Example 37 with the exception that 2-bromothiazole is replaced by a halide from Table 8 (A- Cl, A-Br, or A-I). The resultant sulfides are oxidized according to the procedure of Example 14A. For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 154 f4-f (3-sulfonvlmethylpvridvl) aminol-2-phenylbenzovllmethionine Example 154A f 4-f (3-sulfonvlmethvlpvl) aminol-2-phenvlyl methionine methyl ester

A mixture of 3-chlorosulfonylmethylpyridine hydrochloride (1.0 equivalent) and (4-amino- 2-phenylbenzoyl) methionine methyl ester (1.0 equivalent) in dichloromethane is treated with triethylamine (2.2 equivalents). When judged complete by TLC analysis, the reaction is dilutedwith ethyl acetate, and then is washed with pH 4 water, saturated NaHC03, and brine. The mixture is dried and concentrated to give the crude title compound which is purified by chromatography on silica gel.

Example 154B f4-f (3-sulfonylmethylpyridylamino1-2-phenylbenzoyl} methionine The resultant compound from Example 154A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 155 A-CHS02-NH-B The procedure of Example 154 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and 3- chlorosulfonylmethylpyridine hydrochloride is replaced by a sulfonyl chloride from Table 9 (A-S02C1).

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the anilines in Table 1 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 156 A-S02-NH-CHz-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding amines according to the procedures of Examples 18A-B. These amines are reacted according to the procedure of Example 154 with the exception that-chlorosulfonylmethylpyridine hydrochloride is replaced by a sulfonyl chloride from Table 9 (A-S02C1).

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.

Example 273 f4- (2-thienvlmethoxymethyl)-2- (2-methylphenvl) benzoyllmethionine Lithium salt Example 273A 4- (2-thienylmethoxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester To a suspension in DMF (3.5 mL) of sodium hydride (60% in mineral oil, 52 mg, 1.3 mmol) was added 2-thiophenemethanol (0.135 mL, 1.4 mmol) and the reaction mixture was stirred for 1.25 hours. 4-bromomethyl-2- (2-methylphenyl) benzoic acid methyl ester (0.35 mL, 1.2 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between water and ether. The aqueous phase was extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (3% ethyl acetate-hexane) gave 4- (2-thienylmethoxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (250 mg).

Example 273B 4- (2-thienvlmethoxymethyl)-2- (2-methylphenyl) benzoic acid To a solution in 1: 1 THF-methanol (3.4 mL) was added aqueous 4N sodium hydroxide (0.34 mL) and the reaction mixture was stirred at reflux for 4.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between ether and water. Aqueous 2N HCl (1 mL) was added to the aqueous phase. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 4- (2-thienylmethoxymethyl)-2- (2-methylphenyl) benzoic acid (230 mg) as a thick oil.

Example 273C f4- (2-thienylmethoxyvl)-2- (2-methylphenvl) benzovllmethionine methyl ester The desired compound was prepared by coupling 4- (2-thienylmethoxymethyl)-2- (2- methylphenyl) benzoic acid, prepared as in Example 272C, with methionine methyl ester hydrochloride using the procedure of Example 184A.

Example 273D [4- (2-thienvlmethoxymethvl)-2- (2-methylphenyl) benzoyl1methionine lithium salt To a solution in 1: 1 THF-methanol of [4- (2-thienylmethoxymethyl)-2- (2- methylphenyl) benzoyl] methionine methyl ester, prepared as in Example 272C was added a solution of lithium hydroxide hydrate (40 mg, 0.95 mmol) in water (0.5 mL) and the reaction mixture was stirred for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and water. Aqueous 2N HCl (1 mL) was added to the aqueous phase. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give [4-(2-thienylmethoxymethyl)-2-(2-methylphenyl) benzoyl] methionine. The acid was dissolved in acetonitrile (5 mL) and a solution of lithium hydroxide hydrate (18 mg, 0.43 mmol) in water (8 mL) was added. The mixture was concentrated and the residue was dissolved in water, frozen and lyophilized to give [4- (2-thienylmethoxymethyl)-2- (2- methylphenyl) benzoyl] methionine lithium salt (204 mg) as a light-yellow solid.

IH NMR (300 MHz, DMSO-d6) 8 7.52 (d, lH), 7.50 (dd, 1H), 7.38 (dd, 1H). 7.25-7.10 (envelope, SH), 7.08 (m, 1H), 7.00 (m, 1H), 6.95 (br d, 1H), 4.70 (s, 2H), 4.60 (s, 2H), 3.70 (m, 1H), 2.20-1.80 (envelope, 8H), 1.68,1.59 (both m, total 2H).

MS (APCI) 470 (M+H) +.

Anal calcd for C25H26LiN04S2 1.0 H20: C, 60.84; H, 5.72; N, 2.84. Found: C, 61.10; H, 5.47; N, 2.73.

Example 274 14- (3-thienvlmethoxvmethvl)-2-(2-methvlphenvl) benzovllmethionine Lithium(3-thienvlmethoxvmethvl)-2-(2-methvlphenvl) benzovllmethionine Lithium salt The desired compound was prepared according to the method of Example 272, except substituting 3-thiophenemethanol for 2-thiophenemethanol.

IH NMR (300 MHz, DMSO-d6) 8 7.52 (m, 2H), 7.45 (m, 1H), 7.40 (dd, 1H), 7.22,7.10, 6.95 (all br m, total 7H), 4.59 (s, 2H), 4.55 (s, 2H), 3.68 (m, 1H), 2.20-1.80 (envelope, 8H), 1.68,1.59 (both m, total 2H).

MS (ESI) m/e 470 (M+H) +, 468 (M-H)-, Anal calcd for C25H26LiNO4S2-0.75 H20: C, 61. 40; H, 5.67; N, 2.86. Found: C, 61.10; H, 5.47; N, 2.73.

Example 287 f4- (3-tetrahvdrofurvlmethvloxymethyl)-2-phenylbenzovllmethionin e Example 287A 4-chloromethyl-2-phenylbenzoic acid methyl ester A solution of thionyl chloride (10.0 g, 84.0 mmol) in DMF (10 mL) was added dropwise to a solution of 4-hydroxymethyl-2-phenylbenzoic acid, methyl ester (12.1 g, 50 mmol), prepared as in Example 158C, and LiCI (2.33 g, 55.0 mmol) in DMF (40 mL).

After 1 hour, the reaction mixture was poured into H20 and the resulting mixture was extracted with ether (3x). The combined organic extracts were rinsed with H20 (2x), saturated aqueous NaHC03 (3x) and brine, dried (MgS04) and concentrated under reduced pressure to provide the desired compound (10.8 g, 83%) as a clear, colorless oil.

Example 287B 4- (3-tetrahydrofurylmethyloxymethyl)-2-phenylbenzoic acid methyl ester A solution of the product of Example 287A (2.09 g, 8.00 mmol) and tetrahydro-3- furanmethanol (0.990 g, 9.60 mmol) in DMF (4 mL) was added to a mixture of NaH (6.40 g, 16.0 mmol) (rinsed with THF just prior to use), KI (1.33 g, 9.00 mmol), and Bu4NBr (2.60 g, 0.800 mmol). An exothermic reaction including gas evolution was observed. The mixture was stirred for 30 minutes and then heated at 130 °C for 3.5 hours. The reaction mixture was quenched with by the addition of a few drops of methanol and then treated with H20 (50 mL). The mixture was extracted with a 2: 1 mixture of ether and ethyl acetate, followed by ether (2x). The combined organic extracts were rinsed with H20 (4x) and brine, dried (MgS04), and concentrated under reduced pressure. Flash column chromatography (20% ethyl acetate-hexane) afforded 0.406 g (14.5%) of a 1.6: 1 mixture of the methyl and tetrahydro-3-furanmethyl esters, respectively.

Example 287C

f4- (3-tetrahydrofurvlmethyloxvmethvl)-2-phenylbenzovllmethionin e methyl ester A solution of the product of Example 287B (0.406 g, 1.15 mmol) in saturated LiOH- methanol (6 mL) was heated to reflux for 15 hours. The reaction mixture was cooled to ambient temperature and treated with H20. The mixture was extracted with ether (3x). The ether extracts were discarded and the aqueous phase was made acidic with 3 M HCI. The mixture was extracted with ether (4x), and the organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The resulting amber oil was dissolved in DMF (12 mL) and the solution was treated with L-methionine, methyl ester hydrochloride (0.459 g, 2.30 mmol), 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (0.957 g, 5.75 mmol), 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide (1.12 g, 5.75 mmol), and finally N- methylmorpholine (0.822 g, 8.05 mmol). The reaction mixture was stirred at ambient temperature for 60 hours, diluted with ethyl acetate (36 mL), and extracted with 2 N HCI (3x), followed by saturated aqueous NaHC03 (3x) and brine. The organic phase was dried (MgS04) and concentrated to provide a gold oil. Flash column chromatography (30% ethyl acetate-hexane) afforded the desired compound (0.172 g, 29%).

Example 287D f4- (3-tetrahydrofurylmethyloxymethyl)-2-phenylbenzoyl1methionin e Sodium hydroxide (0.776 mL of a 0.979 M aqueous solution, 0.752 mmol) was added to a solution of the product of Example 287C (0.172 g, 0.376 mmol) in methanol (1.5 mL). After 3.5 hours, the mixture was acidified by the addition of 2 N HCI (1 mL) and then extracted with CH2Cl2 (4x). The combined organic extracts were dried (Na2SO4) and then concentrated to provide the title compound (0.126 g, 75%) as a white foam.

IH NMR (CDC13) 8 1.56-1.78 (comp, 2H), 1.85-2.16 (comp, 7H), 2.50-2.64 (m, 1H), 3.36-3.50 (comp, 2H), 3.57-3.64 (m, 1H), 3.69-3.78 (m, 1H), 3.81-3.89 (comp, 2H), 4.56 (s, 2H), 4.56-4.65 (m, 1H), 6.06 (d, J= 7.4 Hz, 1H), 7.30-7.45 (comp, 7H), 7.67 (d, J= 7.8 Hz, 1H). LRMS (CI) m/e 444 (M+H) +, 461 (M+NH4) +.

Example 288 r4-f2-tetrahvdrofurylmethyloxymethyl)-2-phenylbenzoyl1methio mne

Example 288A 4- (2-tetrahydrofurvlmethyloxvmethvl)-2-phenvlbenzoic acid methyl ester A solution of 4-hydroxymethyl-2-phenylbenzoic acid, methyl ester (1. 94 g, 8.00 mmol), prepared as in Example 158C, and tetrahydrofurfuryl chloride (1.18 g, 9.60 mmol) in DMF (4 mL) was added to a mixture of NaH (6. 40 g, 16.0 mmol) (rinsed with THF just prior to use), KI (1. 33 g, 9.00 mmol), and Bu4NBr (2.60 g, 0.800 mmol). An exothermic reaction including gas evolution was observed. The mixture was stirred 30 minutes and then heated to 130 °C for 3.5 hours. The reaction mixture was quenched by the addition of a few drops of methanol and then treated with H20. The mixture was extracted with 2: 1 ether- ethyl acetate and ether (2x). The combined organic extracts were rinsed with H20 (4x) and brine, dried (MgS04) and concentrated under reduced pressure. Flash column chromatography eluting 20% ethyl acetate-hexane) afforded the desired compound (74.9 mg) as an oil shown to be 89% pure by H NMR.

Example 288B f4- (2-tetrahydrofurylmethvloxymethyl)-2-phenylbenzomethionine The desired compound was prepared from the product of Example 288A according to the method of Examples 287C and D.

IH NMR (300 MHz, CDC13) 8 1.58-1.64 (m, 1H), 1.64-1.78 (m, 1H), 1.81-1.90 (comp, 4H), 2.00 (s, 3H), 2.04-2.12 (comp, 2H), 3.49-3.52 (comp, 2H), 3.65 (s, 3H), 3.73-3.82 (m, 1H), 3.84-3.92 (m, 1H), 4.06-4.14 (m, 1H), 4.58-4.70 (comp, 3H), 5.86 (d, 1= 7.8 Hz, 1H), 7.33-7.44 (comp, 7H), 7.70 (d, J= 7.8 Hz, 1H). LRMS (CI) m/e448 (M+H) +, 475 (M+NH4) +.

Example 299 t4- (2-furvlmethyloxymethyl)-2- (2-methylphenvl) benzoyllmethionine Example 299A

furfuryl alcohol, potassium salt Potassium hydride (35% in mineral oil) was washed three times with pentane and dried under a N2 sweep to give a grey powder (2. 6 g, 65 mmol). THF (20 mL) was added and the mixture cooled in an ice/H20 bath. A solution of furfuryl alcohol (6.4 g, 65 mmol) in THF (10 mL) was then added over 15 minutes. The ice bath was removed and the solution was allowed to warm to ambient temperature and stir for 3 hours. The solvent was removed in vacuo to give 8.6 g of a brown paste which was used as is in the next step.

Example 299B 4- (2-furvlmethyloxymethyl)-2- (2-methphenvl) benzoic acid methyl ester To a stirred solution of the 4-chloromethyl-2- (2-methylphenyl) benzoic acid methyl ester (1.12g, 4.08 mmol) in toluene (20 mL) under N2 was added the furfuryl alcohol potassium salt prepared in Example 299A (0.84 g, 6.1 mmol) followed by 18-crown-6 (1.6 g, 6.1 mmol). The solution was heated at 90 °C for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with H20 (2x), saturated NaHC03 solution (2x), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (10% ethyl acetate-hexane) to give the title compound (0.45 g, 33%) as an orange oilwhich was contaminated with-10% of the 2-furanmethyl ester.

Example 299C 4- (2-furylmethyloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester To a stirred solution of the product of Example 299B (0.51 g, 1.5 mmol) in methanol (20 mL) was added saturated LiOH (3 mL) and the resulting solution was heated at reflux for 5 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in formic acid (2 mL) and concentrated in vacuo. The residue was taken up in 3: 1 ethyl acetate-H20 and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H20 (3x), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (25%, then 50% ethyl acetate-hexane) to give the desired compound (0.42 g, 85%) as a light yellow oil.

Example 299D [4- (2-furylmethyloxymethyl)-2- (2-methyll2henyl) benzoyllmethionine methyl este To a stirred solution of the acid (0.41 g, 1.3 mmol), in DMF (6 mL) under N2 was added 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (0.23 g, 1.4 mmol), methionine methyl ester

hydrochloride (0.33 g, 1.7 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 g, 1.7 mmol) and triethylamine (-0.2 mL) to pH = 7. The mixture was stirred for 6hours. The reaction mixture was taken up in ethyl acetate and washed with H20 (Sx), saturated NaHC03 solution (2x) and brine. The organic layer was dried (MgS04) and concentrated in vacuo.

The residue was purified by flash chromatography (5% ethyl acetate-CH2Cl2) and the fractions containing product were concentrated in vacuo to give the desired compound (0.47 g, 80%) as a yellow oil.

Example 299E [4- (2-furylmethyloxymethyl)-2- (2-methylphenyl) benzoyl1methionine To a stirred solution of the ester (0.47 g, 1.0 mmol) in THF (10 mL) under N2 was added saturated LiOH (2 mL) and the resulting solution stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was azeotroped with formic acid. The residue was taken up in 3: 1 ethyl acetate-H20 and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with H20 (3x), dried (MgS04), and concentrated in vacuo to give the title compound (0.39 g, 85%) as a cloudy pale yellow oil.

I H NMR (300 MHz, CDC13) 5 7.98 (dd, 1 H, J= 11.7,8.1 Hz), 7.44 (dd, 1 H, J= 8.1,1.7 Hz), 7.41 (dd, 1 H, J= 1.7,1.0 Hz), 7.36-7.17 (m, 6 H), 6.36-6.33 (m, 2 H), 5.89 (bt, 1 H, J= 7.1 Hz), 4.60-4.53 (2s and m, 5 H), 2.14-2.01 (4s and m, 8 H), 1.96-1.89 (m, 1 H), 1.59-1.43 (m, 1 H).

MS m/z 454 (M+).

Anal. Calcd for C25H27NO5S (453.55): C, 66.21; H, 6.00; N, 3.09. Found: C, 65.92; H, N, 2.79.

Examples 321-323 Example 321 4- (2-benzothiazolyloxymeth, 1)-2- (2-methXlphenyl) benzoyllmethionine

To a solution of [4-bromomethyl-2-(2-methylphenyl) benzoyl] methionine methyl ester (160 mg, 0.36 mmol) in DMF (1.5 mL) was added 2-hydroxybenzothiazole (80 mg, 0.53 mmol) and potassium carbonate (100 mg, 0.72 mmol) and the reaction mixture was stirred overnight at ambient temperature. Aqueous workup followed by chromatography on silica gel (40% ethyl acetate-hexanes) gave [4- (2-benzoythiazolyloxymethyl)-2- (2- methylphenyl) benzoyl] methionine (70 mg, 37%). Saponification of the methyl ester using the method of Example 159 gave the title compound (67 mg).

IH NMR (300MHz, DMSO-d6) 8 7.99 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.38 (dd, IH), 7.36 (m, 2H), 7.18 (m, 4H), 7.09 (m, 2H), 5.07 (s, 2H), 4.07 (m, lH), 1.92-2.20 (m, 8H), (m, 2H).

MS (CI, NH3) m/e 524,507,489.

Anal calcd for C27H26N204S2 1.12 H20: C, 61.56; H, 5.40; N, 5.32. Found: C, 61.56; H, 5.49; N, 5.16.

Example 322 [4-! benzovllmethionine The desired compound was prepared according to the method of Example 321, except substituting 2-thiobenzoxazole for 2-hydroxybenzothiazole.

IH NMR (300MHz, DMSO-d6) 8 8.14 (bd, 1H), 7.56-7.67 (m, 3H), 7.46 (d, 1H), 7.33 (m, 3H), 7.19 (m, 2H), 7.10 (m, 2H), 4.65 (s, 2H), 4.18 (m, 1H), 1.97-2.21 (m, SH), 1.93 (s, 3H), 1.63-1.88 (m, 2H).

MS (CI, NH3) m/e 524,507,489.

Anal calcd for C27H26N204S2 0.60 H20: C, 62.67; H, 5.30; N, 5.41. Found: C, 62.67; H, N, 5.29.

Example 323 [4- (2-benzothiazolylthiomethyl)-2- (2-methylphenyl) benzoyllmethionine The desired compound was prepared according to the method of Example 321, except substituting 2-thiobenzothiazole for 2-hydroxybenzothiazole.

IH NMR (300MHz, DMSO d6) 8 8.14 (bd, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.59 (d, 1H), 7.47 (m, 2H), 7.35 (m, 2H), 7.19 (m, 2H), 7.08 (m, 2H), 4.70 (s, 2H), 4.19 (m, 1H), 1.94-2.18 (m, SH), 1.93 (s, 3H), 1.63-1.87 (m, 2H).

MS (CI, NH3) m/e 523,505.

Anal calcd for C27H26N203S3 0. 58 H20: C, 60.83; H, 5.13; N, 5.25. Found: C, 60.83; H , 5.06; N, 5.13.

Example 327 f4- (5-phenylfur-2-ylmethyloxymethyl)-2- (2-methylphenyl) benzoyl1methionine lithium salt Example 327A 5-bromo-2-hydroxymethylfuran To a solution of 5-bromofuroic acid (8.97 g, 47.0 mmol) in 200 mL of THF at 0 °C was added N-methylmorpholine (5.23 g, 51.7 mmol) followed by isobutyl chloroformate (6.74g, 49.5 mmol) and the reaction mixture was stirred for 30 minutes at 0 °C. Sodium borohydride (10.7 g, 282 mmol) was added followed by 2 mL of saturated aqueous sodium bicarbonate and the reaction mixture was stirred for 16 hours. The reaction was quenched with 4 mL of 0.5 M phosphoric acid and the reaction was evaporated to a 20 mL volume and extracted with ethyl acetate (3x), dried over Na2SO4, filtered and evaporated to an oil.

Purification by flash chromatography (50% ethyl acetate-hexanes) gave the desired compound as an oil which is unstable to oxygen at ambient temperature.

Example 327B 5-phenyl-2-hydroxymethylfuran The 5-bromo-2-hydroxymethylfuran prepared in Example 327A (1.012g, 5.72 mmol) was dissolved in 10 mL of DMF and PdCl2 (PPh3) 2 (401 mg, 0.57 mmol) was added followed by phenylboronic acid (1.39 g, 11.4 mmol) and Cs2CO3 (3.71 g, 11.4 mmol) and the reaction was heated at 80 °C under N2 for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3x) and brine (3x), dried over Na2S04, filtered and evaporated to a brown oil that was purified by flash chromatography (50% ethyl acetate- hexanes) to give the desired compound (345mg, 35%) as an oil.

Example 327C 4- (5-phenylfur-2-vlmethvloxymethyl !-2-(2-methylphenvl !(5-phenylfur-2-vlmethvloxymethyl !-2-(2-methylphenvl ! benzoic acid methyl ester

The 5-phenyl-2-hydroxymethylfuran prepared in Example 327B (345mg, 1.98 mmol) was dissolved in 5 mL of dry DMF and NaH (50 mg, 1.98 mmol) was added followed by 15-crown-5 (436 mg, 1.98 mmol) and the reaction stirred for 5 minutes at ambient temperature. To the reaction was then added 4-chloromethyl-2- (2- methylphenyl) benzoic acid methyl ester (659 mg, 2.40 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with water (3x) and brine (3x), dried over Na2SO4, filtered, evaporated and purified by flash chromatography (15% ethyl acetate-hexanes) to give the desired compound (670 mg, 82%) as an oil.

Example 327D salt[4-(5-phenylfur-2-ylmethyloxymethyl)-2-(2-methylphenyl)b enzoyl]methioninelithium The desired compound was prepared from the product of Example 327C according to the method of Examples 304E, F and G.

IH NMR (300 MHz, DMSO-d6) 8 7.65-7.68 (m, 2H), 7.54 (d, J= 7.8 Hz, 1H), 7.43-7.35 (m, 3H), 7.30-7.10 (m, 6H), 6.96 (bs, 1H), 6.91 (d, J= 3.4 Hz, 1H), 6.58 (d, J= 3.4 Hz, 1H), 4.62 (s, 2H), 4.58 (s, 2H), 3.71 (bs, 1H), 2.20-1.50 (m, 10H, includes SMe at 1.92ppm).

MS (ESI) m/e 528 (M-H)-.

Example 328 <BR> <BR> <BR> r4- (5- (4-fluorophenyl) fur-2-ylmethyloxymethvl)-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 327, except substituting 4-fluorophenylboronic acid for phenylboronic acid. lH NMR (300 MHz, DMSO-d6) 8 7.72-7.68 (m, 2H), 7.54 (d, J= 4.3 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.25-7.05 (m, 7H), 6.92 (bs, 1H), 6.88 (d, J= 3.6 Hz, 1H), 6.56 (d, J=

3.4 Hz, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 3.68 (bs, 1H), 2.20-1.46 (m, 10H, includes SMe at 1. 91 ppm).

MS (ESI) m/e 546 (M-H)-.

Example 404 4-f2- (1-adamantane) ethoxylmethvl-2 (2-methylphenyl) benzoylmethionine lithium salt.

The desired compound was prepared according to Example 273 except substituting 1- adamantaneethanol for 2-thiophenemethanol in Example 273A.

IH (DMSO-d6) 8 7.52 (d, lH), 7.37 (dd, 1H), 7.20,7.18,7.10,6.97 (all m, total 6H), 4.50 (s, 2H), 3.68 (m, 1H), 3.49 (t, 2H), 2.17,2.00,1.90 (all m, total 11H), 1.60 (m, 8H), 1.48 (m, 6H), 1.37 (t, 2H).

MS (ESI) 534 (M-H)-.

Anal calcd for C32H4oLiN04S-1.25 H20: C, 68.12; H, 7.59; N, 2.48. Found: C, 68.04; H, N, 2.87.

Example 405 4- (3-cyclohexylpropoxy) methyl-2- (2-methylphenyl) benzoylmethionine lithium salt.

The desired compound was prepared according to Example 273 except substituting 3- cyclohexylpropanol for 2-thiophenemethanol in Example 273A.

IH (DMSO-d6) 8 7.52 (d, lH), 7.37 (d, 1H), 7.20,7.18,7.10,6.97 (all m, total 6H), 4.50 (s, 2H), 3.63 (m, 1H), 3.41 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 9H), 1.17 (m, 6H), 0.82 (m, 2H).

MS (ESI) 496 (M-H)-.

Anal calcd for C29H3gLiN04S-0.85 H20: C, 67.12; H, 7.71; N, 2.70. Found: C, 67.07; H, 7.75; N, 3.00.

Example 434 N-[4-(5-Bromofuran-2-ylmethoxymethyl)-2-(2-methylphenyl)benz oyl]methioninelithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.51 (d, 1H), 7.38 (bd, 1H), 7.24-6.90 (m, 7H), 6.53 (s, 2H), 4.56 (s, 2H), 4.46 (s, 2H), 3.65 (bs, 1H), 2.16-1.50 (m, 10H, methyl signals at 2.00 and 1.91 buried in multiplet) CIMS, Calcd for C25H2605NSBr MH+, 533

Example 435 <BR> <BR> <BR> N- 4- (5-N, N-dimethylaminomethYlfuran-2-Ylmethoxymethyl)-2- (2-<BR> <BR> <BR> <BR> methylphenyl) benzoylimethionine The desired compound was prepared according to the method of Examples 157C-H OH NMR (300 MHz, D20) 6 7.62 (d, 1H), 7.47 (bd, 1H), 7.35-7.10 (m, 5H), 6.66 (d, 1H), 6.51 (d, 1H), 4.70 (s, 2H), 4.62 (s, 2H), 4.27 (s, 2H), 2.79 (s, 6H), (m, 10H); MS (CI, isobutane) m/e 511 (511 Calcd for C28H3405N2S, MH).

Example 436 N- [4-f5-3-fluorophenyl) furan-2-ylmethoxymethyl)-2-f2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.54-7.38 (m, 4H), 7.21-7.08 (m, 5H), 7.03 (d, 1H), 6.61 (d, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.70-3.60 (m, 1H), 2.16-2.14 (m, 2H), 1.99- 1.91 (m, 6H) singlet part of multiplet at 1.91,1.70-1.50 (m, 2H) HRFABMS MH+ C3lH3o05NSFLi, Calcd 554.1989, Found 554.1996.

Example 437 N-[4-(5-(2-fluorophenyl)furan-2-ylmethoxymethyl)-2-(2-methyl phenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.74 (dt, 1H), 7.54 (d, 1H), 7.42-6.95 (m, 9H), 6.83 (t, 1H), 6.65 (d, 1H), 4.63 (s, 2H), 4.58 (s, 2H), 3.70-3.60 (m, 1H), 2.16-2.10 (m, 2H), 2.02-1.91 (m, 6H) singlet at 1.91 is part of multiplet, 1.70-1.50 (m, 2H). HR FABMS MH+ C3 I H3105NSF, Calcd 548.1907, Found 548.1916.

Example 438 N- [4- (5- (2-trifluoromethylphenyl) furan-2-ylmethoxymethyl)-2- (2- methyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.84 (d, 1H), 7.79-7.71 (m, 2H), 7.60 (dd, 1H), 7.25- 7.10 (m, 5H), 6.95 (bs, 1H), 6.76 (d, 1H), 6.62 (d, 1H), 4.61 (s, 2H), 4.56 (s, 2H), 3.70 -3.60 (m, 1H), 2.15-2.10 (m, 2H), 2.01-1.90 (m, 6H), 1.70-1.50 (m, 2H). HR FABMS MH+ C32H3105NF3S, Calcd 598.1875, Found 598.1868.

Example 439 N-f4- (5- (2-methoxyphenylfuran-2-ylmethoxymethyl)-2- (2- methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H in NMR (300 MHz, d6 DMSO) 8 7.70 (dd, 1H), 7.54 (d, 1H), 7.40 (bd, 1H), 7.27 (dt, 1H), 7.25-7.08 (m, 7H), 7.00 (dt, 1H), 6.88 (d, 1H), 6.56 (d, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 3.90 (s, 3H), 3.70-3.60 (m, 1H), 2.16-2.12 (m, 2H), 2.02-1.90 (m, 6H), 1.70-1.50 (m, 2H). HR FABMS MH+ C32H3306NSLi, Calcd 566.2189, Found 566.2195.

Example 440 N-[4-(5-(3-nitrophenyl)furan-2-ylmethoxymethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 8.42 (t, 1H), 8.14-8.09 (m, 2H), 7.71 (t, 1H), 7.54 (d, 1H), 7.40 (dd, 1H), 7.22 (d, 1H), 6.66 (d, 1H), 4.64 (s, 2H), 4.59 (s, 2H), 3.70- 3.60 (m, 1H), 2.15-2.10 (m, 1H), 2.00-1.95 (m, 1H), 1.91 (s, 3H), 1.68-1.60 (m, 1H), 1.56 (s, 3H), 1.52-1.48 (m, 1H). HRMS MH+ C31H3107N2S, Calcd 575.1852, Found 575.1846.

Example 441 N- [4- (5- (3-trifluoromethyll2henyl) furan-2-ylmethoxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.98-7.95 (m, 2H), 7.68-7.64 (m, 2H), 7.53 (d, 1H), 7.40 (dd, 1H), 7.25-7.05 (m, 5H), 6.95 (bs, 1H), 6.63 (d, 1H), 4.63 (s, 2H), 4.58 (s, 2H), 3.70-3.60 (m, 1H), 2.18-2.10 (m, 2H), 2.02-1.90 (m, 6H) methyl singlet at 1.91 is part of multiplet, 1.70-1.50 (m, 2H). HR FABMS MH+ C32H3005NF3SLi, Calcd 604.1957, Found 604.1981.

Example 442 N- [4- (5- (3-methoxyphenyl) furan-2-ylmethoxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H OH NMR (300 MHz, d6 DMSO) 6 7.53 (d, 1H), 7.40 (dd, 1H), 7.32 (m, 1H), 7.23 (dt, 1H), &. 21-7.08 (m, 7H), 6.94 (d, 1H), 6.85 (ddd, 1H), 6.58 (d, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.79 (s, 3H), 3.65 (bs, 1H), 2.15-2.10 (m, 2H), 2.00-1.91 (m, 6H), 1.70- 1.55 (m, 2H). HR FABMS MH+ C32H3306NSLi, Calcd 566.2189, Found 566.2195.

Example 443 N-[4-(5-(4-chlorophenyl)furan-2-ylmethoxymethyl)-2-(2-methyl phenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.70-7.66 (m, 2H), 7.52 (d, 1H), 7.48-7.42 (m, 2H), 7.40 (dd, 1H), 7.25-7.13 (m, 5H), 6.96 (d, 1H), 6.96-6.91 (m, 1H), 6.58 (d, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.66-3.60 (m, 1H), 2.15-2.10 (m, 2H), 2.01-1.95 (m, 6H, singlet part of multiplet at 1.91), 1.70-. 150 (m, 2H) HRMS MH+ C3 I H3105NSCI, Calcd 564.1611, Found 564.1611.

Example 444 N- [4- (5- (4-methylphenyl) furan-2-ylmethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.60-7.50 (m, 3H), 7.40 (d, 1H), 7.23-7.06 (m, 7H), 7.02-6.90 (m, 1H), 6.82 (d, 1H), 6.56 (d, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 3.75-3.65 (m, 1H), 2.31 (s, 3H), 2.18-2.10 (m, 2H), 2.04-1.91 (m, 6H), 1.76-1.50 (m, 2H). HR FABMS MH+ C32H3305NSLi, Calcd 550.2239, Found 550.2247.

Example 445 N-[4-(5-(4-trifluoromethylphenyl)furan-2-ylmethoxymethyl)-2- (2- methvlphenyl) benzoYllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.92 (d, 2H), 7.74 (d, 2H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.26-7.06 (5H), 6.94 (bs, 1H), 6.64 (d, 1H), 4.58 (s, 2H), 4.48 (s, 2H), 3.69 (bs, 1H), 2.16-1.50 (m, 10H); CIMS, Calcd for C32H3005NSF3 MH+, 598.

Example 446 N- [4- ( 4-methoxyphenyl) furan-2-ylmethoxymethyl)-2- (2- saltmethylphenyl)benzoyl]methioninelithium The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.64 (d, 1H), 7.60 (d, 2H), 7.42 (bd, 1H), 7.28-7.15 (m, 5H), 6.96 (d, 2H), 6.65 (d, 1H), 6.48 (d, 1H), 4.64 (s, 2H), 4.55 (s, 2H), 3.81 (s, 3H), 2.24-2.20 (m, 2H), 2.08-1.96 (m, 6H), 1.70-1.58 (m, 2H). HR FABMS MH+ C32H3306NSLi, Calcd 566.2189, Found 566.2195

SMe O<BR> <BR> <BR> <BR> <BR> # N CO2Li<BR> <BR> <BR> #O#O# H MeS Example 447 N-f4- (5- (4-methylthiophenyl) furan-2-ylmethoxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.60 (d, 2H), 7.55 (d, 1H), 7.40 (d, 1H), 7.27 (d, 2H), 7.21-7.00 (m, SH), 6.94 (bs, 1H), 6.86 (d, 1H), 6.57 (d, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 3.70-3.62 (m, 1H), 2.18-2.10 (m, 2H), 2.02-1.90 (m, 6H), 1.70-1.50 (m, 2H) HRMS MH+ C32H3405NS2, Calcd 576.1878, Found 576.1884.

Example 448 <BR> <BR> <BR> N- [4- (5- (4-formylphenyl) furan-2-ylmethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 157C-H I H NMR (300 MHz, d6 DMSO) 8 9.16 (s, 1H), 7.93-7.86 (m, 3H), 7.54 (d, 1H), 7.40 (bd, 1H), 7.24-6.94 (m, 7H), 6.66 (d, 1H), 6.00 (d, 1H), 4.63 (s, 2H), 4.59 (s, 2H), 2.16-2.10 (m, 2H), 2.01-1.91 (m, 6H), 1.70-1.55 (m, 2H). HR FABMS MH+ C32H3106NSLi, Calcd 564.2032, Found 564.2034.

Example449 N-[4-(5-(4-acetylphenyl)furan-2-ylmethoxymethyl)-2-(2-methyl phenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Examples 157C-H IH NMR (300 MHz, d6 DMSO) 8 7.98 (d, 2H), 7.80 (d, 2H), 7.. 54 (d, 1H), 7.40 (d, 1H), 7.24-7.06 (m, 6H), 7.02-6.90 (m, 1H), 6.65 (d, 1H), 4.63 (s, 2H), 4.58 (s, 2H), 3.70- 3.60 (m, 1H), 2.59 (s, 3H), 2.16-2.10 (m, 2H), 2.02-1.91 (m, 6H) methyl singlet is part of multiplet at 1.91,1.74-1.55 (m, 2H). HR FABMS MH+ C33H3306NSLi, Calcd 578.2189, Found 578.2178.

Example 450 N-r4-5-C3-chloro-4-fluorophenyl) furan-2-ylmethoxymethyl)-2-C2- methylphenyl) benzoyllmethionine lithium The desired compound was prepared according to the method of Examples 157C-H OH NMR (300 MHz, d6 DMSO) 8 7.88 (dd, 1H), 7.66 (ddd, 1H), 7.52 (d, 1H), 7.45 (t, 1H), 7.40 (d, 1H), 7.21-7.06 (m, 6H), 7.02 (d, 1H), 6.99-6.90 (m, 1H), 6.59 (d, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.65 (bs, 1H), 2.15-2.10 (m, 2H), 2.00-1.91 (m, 6H), 1.70 -1.50 (m, 2H). HR FABMS MH+ C3 I H2905NFSCILi, Calcd 588.1599, Found 588.1613.

Example 497 N-l 4-(naphth-2-vlthio)-2-(2-methylphenvl) benzovl] methionine The desired compound was prepared according to the method of Examples 13D followed by hydrolysis of the ester.

IH NMR (CDCl3, 300 MHz) 5 1.58 (m, 1H), 1.88 (m, 1H), 2.1 (m, 8H), 4.58 (m, 1H), 5.83 (d, 1H, J = 8 Hz), 7.10 (m, 1H), 7.25 (m, 5H), 7.53 (m, 3H), 7.82 (m, 4H), 8.01 (m, 1H). MS m/e 502 (M+H) +.

Example 498 N-[4-(2-phenylethylthio)-2-(2-methylphenyl)benzoyl]methionin e The desired compound was prepared according to the method of Examples 13D followed by hydrolysis of the ester.

I H NMR (CDC13,300 MHz) 8 1.57 (m, 1H), 1.89 (m, 1H), 2.1 (m, 8H), 2.99 (m, 2H), 3.12 (m, 2H), 4.58 (m, 1H), 5.84 (t, 1H, J = 8 Hz), 7.05 (m, 1H), 7.19-7.29 (m, 10H), 7.96 (m, 1H). MS m/e 480 (M+H) +.

Example 521 <BR> N- [4-f4-isoprop-2-enylcyclohexen-1-yl') methoxymethyl-2-f2- methylphenvl) benzoyl]methionine lithium salt

The desired compound was prepared according to the method of Example 157 IH NMR (300 MHz, DMSO) 8 1.33-1.47 (m, 1H), (m, 1H), 1.68 (s, 3H), 1.70- 2.18 (m, 12H), 1.93 (s, 3H), 3.60-3.73 (m, 1H), 3.86 (s, 2H), 4.47 (s, 2H), 4.71 (s, 2H), 5.68 (brs, 1H), 6.93-7.01 (m, 2H), 7.07-7.26 (m, 5H), 7.37 (dd, J=8,1 Hz, 1H), 7.54 (d, J=8 Hz, 1H).

MS (ESI (+)) m/z 508 (M+H) +.

Anal calcd for C3oH36N04SLi'0.4OH20-0.25LiOTf: C, 66.69; H, 6.80; N, 2.55. Found: C, 66.64; H, 6.81; N, 2.58.

Example 522 N-f4- (1, 3-diphenylpropan-2-yl) oxymethyl-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (300 MHz, DMSO) 8 1.47-1.74 (m, 2H), 1.74-1.88 (m, 1H), 1.90 (s, 3H), 1.95 (m, 3H), 2.04-2.13 (m, 1H), 2.78 (m, 4H), 3.57-3.69 (brs, 1H), 3.86 (pentet, J=6 Hz, 1H), 4.43 (s, 2H), 6.82 (brs, 1H), 6.92 (m, 1H), 7.04-7.26 (m, 16H), 7.37 (d, J=8 Hz, 1H).

MS (APCI (-)) m/z 566 (M-H)-.

Anal calcd for C3sH36NO4SLi0.80H20: C, 71.48; H, 6.44; N, 2.38. Found: C, 71.51; H, 6.15; N, 2.31.

Example 525 <BR> <BR> <BR> N-f4- 3-Cyclohexvl-1-ethoxypropan-2-yl) oxymethyl-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (300 MHz, DMSO) 8 0.72-0.97 (m, 2H), 1.07 (t, J=7 Hz, 3H), 1.08 (m, 2H), 1.20-1.42 (m, 4H), 1.53-1.74 (m, 8H), 1.79-2.18 (m, 4H), 1.91 (s, 3H), 3.34-3.47 (m, 4H), 3.54-3.71 (m, 2H), 4.55 (d, J=12.9 Hz, 1H), 4.68 (d, J=12.9 Hz, 1H), 6.97 (brd, 1H), 7.06-7.23 (m, 5H), 7.36 (dd, J=8.1,1.0 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H).

MS (ESI (-)) m/z 540 (M-H)-.

Anal. calcd for C3iH42N05SLi'0. 70H20: C, 66.45; H, 7.81; N, 2.50. Found: C, 66.45; H, 7.64; N, 2.27.

Example 530 N-f4- (furan-3-vlmethoxymethyl)-2-2-methylphenyl) benzolmethionine litihium salt The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) 8 7.63 (d, 1 H, J= 22.6 Hz), 7.53 (d, 1 H, J= 8.0 Hz), 7.38 (d, 1 H, J= 8.0 Hz), 7.22-7.11 (m, 5 H), 7.03-6.95 (m, 2 H), 6.50 (s, 1 H), 4.55 (s, 2 H), 4.41 (s, 2 H), 3.69-3.58 (m, 1 H), 2.18-1.85 (m, 8 H), 1.78-1.66 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 452 (M+-1,100).

Exact mass calcd for C25H28NO5S 454.1688, found 454.1693.

Anal. Calcd for C25H26LiNO5S. H20 (477.50): C, 62.88; H, 5.91; N, 2.93. Found: C, 62.80; H, 5.72; N, 2.86.

Example 531 N- -[4-(2-furan-2-ylethoxymethyl)-2-(2-methylphenyl)benzoyl]met hionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) 5 7.52 (d, 1 H, J= 7.9 Hz), 7.46 (s, 1 H), 7.34 (d, 1 H, J= 7.9 Hz), 7.23-6.91 (m, 6 H), 6.34-6,31 (m, 1 H), 6.17-6.14 (m, 1 H), 4.57 (s, 2 H), 3.68 (t, 2 H, J= 7.9 Hz), 3.68-3.63 (m, 1 H), 2.89 (t, 2 H, J= 7.9 Hz), 2.17-1.81 (m, 8 H), 1.72-1.65 (m, 1 H), 1.59-1. 53 (m, 1 H); MS m/z 468 (M+ + 1,100).

Anal. Calcd for C26H2gLiNO5S. 0. 5 H20 (482.52): C, 64.72; H, 6.06; N, 2.90. Found: C, 64.79; H, 6.02; N, 2.78.

Example 532 N-[4-(5-methylfuran-2-ylmethoxymethyl)-2-(2-methylphenyl)ben zoyl]methioninelithium salt The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) S 7.52 (d, 1 H, J= 7.9 Hz), 7.36 (d, 1 H, J= 7.9 Hz), 7.22-6.95 (m, 6 H), 6.29 (d, 1 H, J= 3.1 Hz), 6.01 (d, 1 H, J= 3.1 Hz), 4.54 (s, 2 H), 4.41 (s, 2 H), 3.69-3.60 (m, 1 H), 2.23 (s, 3 H), 2.18-1.86 (m, 8 H), 1.78-1.65 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 468 (M+ + 1,100).

Exact mass calcd for C26H3oNO5S 468.1845, found 468.1847.

Anal. Calcd for C26H28LiNO5S. 0.67 H20 (485.52): C, 64.32; H, 6.09; N, 2.88. Found: C, 64.17; H, 5.70; N, 2.90.

Example 533 N-f4- (benzofuran-2-ylmethoxymethyl)-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157 1H NMR (DMSO-d6) 8 7.62 (d, 1 H, J = 8.0 Hz), 7.54 (d, 1 H, J = 6.1 Hz), 7.73 (d, 1 H, J = 4.9 Hz), 7.41 (d, 1 H, J = 8.0 Hz), 7.30 (dt, 1 H, J = 7.3,1.2 Hz), 7.25-7.14 (m, 6 H), 6.96-6.91 (m, 2 H), 4.68 (s, 2 H), 4.65 (s, 2 H), 3.69-3.61 (m, 1 H), 2.18-1.86 (m, 8 H), 1.78-1.65 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 504 (M+ + 1,100).

Anal. Calcd for C29H28LiNO5S. H20 (527.57): C, 66.02; H, 5.73; N, 2.65. Found: C, 65.76; H, 5.37; N, 2.73.

Example 534 N- [41-furan-2-yl-2-phenylethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) 8 7.57 (d, 1 H, J = 1.7 Hz), 7.37 (dd, 1 H, J = 7.5,1.7 Hz), 7.18- 7.01 (m, 9 H), 6.84-6.80 (m, 3 H), 6.34-6.31 (m, 2 H), 4.58 (dd, 1 H, J = 13.9,6.3 Hz),

4.40 (d, 1 H, J = 12.8 Hz), 4.31 (d, 1 H, J = 12.8 Hz), 3.62-3.60 (m, 1 H), 3.11 (ddd, 1 H, J = 5 Hz), 2.11-1.85 (m, 8 H), 1.79-1.61 (m, 1 H), 1.51-1.46 (m, 1 H); MS m/z 544 (M+ + 1,100).

Anal. Calcd for C32H32LiNOsS H2O (567.63): C, 67.71; H, 6.04; N, 2.47. Found: C, 67.84; H, 6.10; N, 2.83.

Example 535 <BR> <BR> <BR> N- [4- (5- (4-fluorophenyl) furan-2-ylethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 1H NMR (DMSO-d6) 8 7.64-7.60 (m, 1 H), 7.51-7.33 (m, 4 H), 7.19-7.09 (m, 6 H), 6.96- 6.91 (m, 1 H), 6.86 (d, 1 H, J= 3.1 Hz), 6.27 (d, 1 H, J= 3.4 Hz), 4.58 (s, 2 H), 3.76 (t, 2 H, J= 6.6 Hz), 3.68-3.58 (m, 1 H), 2.97 (t, 2 H, J= 6.6 Hz), 2.18-1.85 (m, 8 H), 1.78-1.66 (m, I H), 1.59-1.52 (m, I H); MS m/z 562 (M+ + 1,100).

Exact mass calcd for C32H33FN05S 562.2063, found 562.2068.

Example 536 <BR> <BR> <BR> N-f4- (5- (4-chlorophenyl) furan-2-ylethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) S 7.67-7.62 (m, 2 H), 7.49 (d, 1 H, J= 7.8 Hz), 7.58-7.54 (m, 1 H), 7.25-7.08 (m, 6 H), (m, 2 H), 6.78 (d, 1 H, J= 3.1 Hz), 6.26 (d, 1 H, J= 3.4 Hz), 4.58 (s, 2 H), 3.76 (t, 2 H, J= 6.4 Hz), 3.67-3.58 (m, 1 H), 2.96 (t, 2 H, J= 6.4 Hz), 2.17-1.86 (m, 8 H), 1.79-1.66 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 578 (M+ + 1,100).

Exact mass calcd for C32H33C1NO5S 578.1768, found 578.1784.

Example 539 saltN-[4-(thiazol-5-ylmethoxymethyl)-2-(2-methylphenyl)benzo yl]methioninelithium The desired compound was prepared according to the method of Example 157 IH NMR (DMSO-d6) 8 9.08 (d, 1 H, J= 0.7 Hz), 7.88 (d, 1 H, J= 1.0 Hz), 7.53 (d, 1 H, J= 7.8 Hz), 7.38 (dd, 1 H, J= 7.8,1.4 Hz), 7.21-7.12 (m, 4 H), 6.96-6.91 (m, 2 H), 4.80 (s, 2 H), 4.60 (s, 2 H), 3.72-3.64 (m, 1 H), 2.18-1.85 (m, 8 H), 1.78-1.65 (m, 1 H), 1.60-1.51 (m, 1 H); MS m/z 471 (M+ + 1,100).

Exact mass calcd for C24H27N204S2 471.1412, found 471.1420.

Example 545 saltN-[4-(3-phenylpropan-1-ol-2-ylthiomethyl)-2-phenylbenzoy l]methionine,sodium The desired compound was prepared according to the method of Example 157 IH NMR (300 MHz, d6-DMSO) 5 1.65-1.85 (m, 1H), 1.97 (s, 3H), 1.98-2.10 (m, 1H), 2.65 (dd, J=15.7,10.8 Hz, 1H), 2.82 (m, 1H), 3.01 (m, 1H), 3.17 (brd, 2H), 3.39 (m, 1H), 3.54 (dd, J=11.4,4.8 Hz, 1H), 3.75 (m, 2H), 4.90 (brm, 1H), 7.07-7.42 (m, 13H); MS (FAB) nVe (M+H) + 510, (M-H)-508.

Example 546 N- [4-geranyloxy-2- (2-methylphenvllbenzovllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F IH nmr (300 MHz, DMSO d6): 8 7.50, d, 1H; 7.20, m, 3H; 6.94, m, 2H; 6.79, m, 1H; 6.66, m, 1H; 5.43, t, 1H; 5.09, m, 1H; 4.60, d, 2H; 3.68, m, 1H; 1.88-2.23, m, 13H; 1.83, m, 1H; 1.67, s, 3H; 1.63, s, 3H; 1.58, s, 3H.

MS (APCI (+)): 494 (MH+). Calc'd for C2gH36LiNO4St2.11 H20: C 64.55, H 7.51, N 2.60: Found: C 64.56, H 6.94, N 2.60.

Example 547 N- 4-farnesvloxv-2- (2-methylphenyl) benzovllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F I H nmr (300 MHz, D20): 6 7.73, m, 1H; 7.19, m, 3H; 6.82, m, 2H; 6.52, m, 1H ; 5.24, m, 1H ; 4.90, m, 2H; 4.24, m, 3H; 1.71-2.12, m, 18H; 1.40, m, 12H.

MS (APCI (+)) 5644 (MH+). Calc'd for C34H44LiNO4St1. 67 H2O: C 68.08, H 7.96, N 2.34: Found: C 68.09, H 7.94, N 2.26.

Example 550 saltN-[4-cyclohexylthiomethyl-2-(2-methylphenyl)benzoyl]meth ionine,lithium The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, D20): 8 7.64, d, 1H; 6.98-7.37, m, 6H; 4.20, m, 1H; 3.69, s, 2H; 2.49, m, 1H; 2.07, bs, 2H; 1.99, s, 3H; 1.97, s, 3H; 1.03-1.95, m, 12H.

MS (FAB (+)) 472 (MH+); FAB (-): 470 (M-H)-. Calc'd for C26H32LiNO3S2#1. 30 H20: C 62.33, H 6.96, N 2.80: Found: C 62.33, H 6.85, N 2.60.

Example551 N-[4-naphth-2-ylthiomethyl-2-(2-methylphenyl)benzoyl]methion ine The desired compound was prepared according to the method of Example 157 1H nmr (300 MHz, DMSO d6): 8 8.12d. 1H; 7.83, m, 4H; 7.47, m, 5H ; 1.16, m, 3H; 7.06, m, 1H ; 6.99, m, 1H ; 4.42, s, 2H; 4.18, m, 1H; 1.61-2.20, m, 10H.

MS (APCI (+)) 516 (MH+). Calc'd for C3oH29N03S2'0. 82 H20: C 67.93, H 5.82, N 2.64: Found: C 67.92, H 5.64, N 2. 51.

Example 552 N- [4- (2-cyclohexylethoxy)-2- (2-methylphenvl) benzovllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F 1H nmr (300 MHz, DMSO d6): # 7.50, d, 1H; 7.20, m, 2H; 6.96, dd, 1H ; 6.79, m, 1H; 6.64, m, 1H; 4.04, t, 2H; 3.67, m, 1H; 2.16, m, 1H; 1.99, m, 2H; 1.91, s, 3H; 1.38-1.90, m, 14H; 1.18, m, 2H; 0.93, m, 2H.

MS (ESI (+)) 468 (M-H)-. Calc'd for C27H34LiN04S'L62 H20: C 64.25, H 7.44, N 2.77: Found: C 64.25, H 7.44, N 2.72.

Example 553 N- [4- (2-adamantan-1-ylethoxv)-2-l2-methylphenvl) benzovllmethionine The desired compound was prepared according to the method of Example 6E-F I H nmr (300 MHz, DMSO d6): 8 12.53, bs, 1H; 7.79, d, 1H; 7.50, d, 1H; 7.18, m, 4H; 6.99,

dd, 1H; 6.67, bs, 1H; 4.21, m, 1H; 4.06, m, 2H; 1.99-2.24, m, 3H; 1.87-1.97, m, 4H ; 1.50-1.84, m, 20H.

MS (APCI (+)) 522 (MH+).

Example 554 N- [4-benzvlthiomethvl-2- (2-methvlphenvl) benzoyllmethionine. lithium salt The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, DMSO d6): 8 7.63, d, 1H; 7.37, d, 1H; 7.25, m, 9H; 7.10, bd, 2H; 4.24, m, 1H; 3.68, s, 2H; 3.65, s, 2H; 2.26, bs, 1H; 1.57-2.13, m, 8H.

MS (APCI (+)) 480 (MH+). Calc'd for C27H2gLiNO3S2-1.67 H20: C 62.89, H 6.13, N 2.72: Found: C 62.81, H 5.35, N 3.32.

Example 555 N- [4-benzvlsulfonylmethyl-2- (2-methylphenyl) benzovllmethionine The desired compound was prepared according to the method of Example 157, employing the sodium salt of benzylsulfinic as the nucleophilic partner I H nmr (300 MHz, DMSO d6): 8 8.28, m, 1H; 7.50, m, 2H; 7.39, m, 5H; 7.22, m, 3H; 7.14, m, 2H; 4.57, s, 2H; 4.49, s, 2H; 4.22, m, 1H; 2.00,2.22, m, 5H; 1.94. s. 3H; 1.65-1.92, m, 2H.

MS (APCI (+)) 512 (MH+). Calc'd for C27H29NO5S20.26 H20: C 62.81, H 5.76, N 2.71: Found: C 62.80, H 6.01, N 2.57.

Example 556 N- [4- (4-methylbenzvl) thiomethyl-2- (2-methylphenvl) benzoyl] methionine, lithium salt The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, D20): 8 7.60, d, 1H; 6.86-7.22, m, 5H; 6.75, m, 3H; 6.66, m, 2H; 4.22, m, 1H; 3.23, s, 2H; 3.20, s, 2H; 1.60-2.09, m, 13H.

MS (APCI (+)) 494 (MH+). Calc'd for C2gH3oLiN03S2'1.34 H20: C 64.21, H 6.29, N 2.67: Found: C 64.21, H 5.74, N 2.46.

Example 557 saltN-[4-(2-methylbenzyl)thiomethyl-2-(2-methylphenyl)benzoy l]methionine,lithium The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, D20): 6 7.61, d, 1H; 7.03-7.26, m, 5H; 6.80, m, 5H; 4.22, m, 1H; 3.37, s, 2H; 3.31, s, 2H; 1.59-2.06, m, 13H.

MS (APCI (+)) 494 (MH+). Calc'd for C3oH29N03S2'0.94 H20: C 65.11, H 6.22, N Found: C 65.12, H 6.05, N 2.68.

Example 558 N- [4- (4-methoxybenzvl) thiomethyl-2- (2-methylphenyllbenzolmethionine, lithium salt

The desired compound was prepared according to the method of Example 157 1H nmr (300 MHz, D ? O): 8 7.58, d, 1H; 7.03-7.15, m, 5H; 6.93, d, 2H; 6.82, d, 1H; 6.59, d, 2H; 4.19, m, 1H; 3.48, s, 3H; 3.41, s, 2H; 3.37, s, 2H; 1.55-2.07, m, 10H.

MS (APCI (+)) 509 (MH+). Calc'd for C2gH3iLi2N06S20.73 H20: C 59.14, H 5.75, N 2.46: Found: C 59.13, H 5.80, N 2.21.

Example 559 N- [4-cvclohexvlmethylthiomethyl-2- (2-methylphenvllbenzoyl] methionine, lithium salt The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, D20): d 7.67, d, 1H; 6.95-7.34, m, 6H; 4.22, m, 1H; 3.52, m, 2H; 0.63- 2.19, m, 23H.

MS (APCI (+)) 486 (MH+). Calc'd for C27H34LiNO3S2#1. 77 H20: C 61.94, H 7.23, N 2.68: Found: C 61.94, H 7.18, N 2.53.

Example 560 N- [4- (3-phenprop-2-en-1-yloxy-2- (2-methylpheny) benzoyllmethionine The desired compound was prepared according to the method of Example 6E-F IH nmr (300 MHz, DMSO d6): d 7.89, bd, 1H; 7.48, m, 3H; 7.36, m, 2H; 7.27, m, 1H; 7.10- 7.24, m, 4H; 7.08, dd, 1H; 6.75, m, 2H; 6.51, dt, 1H; 4.82, d, 2H; 4.19, m, 1H; 1.98- 2.25, m, 5H; 1.97, s, 3H; 1.63-1.93, m, 2H.

MS (APCI (+)) 476 (MH+). Calc'd for C2gH2gNO4S*0.29 H20: C 69.95, H 6.20, N 2.91: Found: C 69.95, H 5.93, N 2.81.

Example 561 N-f4- (2-phenoxy) ethoxy-2- (2-methylphenyl') benzoyHmethionine The desired compound was prepared according to the method of Example 6E-F IH nmr (300 MHz, D20): d 7.89, d, 1H; 7.53, d, 1H; 7.30, dd, 2H; 7.10-7.25, m, 4H; 7.07, dd, 1H; 6.97, m, 3H; 6.74, bs, 1H; 4.39, m, 2H; 4.31, m, 2H; 4.22, m, 1H; 2.02-2.29, m, 5H; 1.97, s, 3H; 1.63-1.91, m, 2H.

MS (APCI (+)) 480 (MH+). Calc'd for C27H29NO5S0.67 H20: C 65.91, H 6.22, N 2.85: Found: C 65.95, H 6.14, N 3. 31.

Example 562 N- 4- (2-phenyl) ethylthiomethvl-2- (2-methylphenyl) benzoyllmethionine. lithium salt The desired compound was prepared according to the method of Example 157 IH nmr (300 MHz, D20): d 7.62, d, 1H; 7.08-7.19, m, 5H; 6.90-7.01, m, 4H; 6.83, d, 2H; 4.17, m, 1H; 3.44, s, 2H; 2.51, m, 2H; 2.38, m, 2H; 1.60-2.05, m, 10H.

MS (APCI (+)) 494 (MH+). Calc'd for C28H3lLiNO3S2'1.24 H20: C 64.31, H 6.45, N 2.68: Found: C 64.30, H 5.93, N 2.20.

Example 563 N- [4- (2-adamantan-1-ylpropox-2-l2-methylphenvl) benzovllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F 1H nmr (300 MHz, DMSO d6): 6 7.5, d, 2H; 7.17, m, 4H; 6.96, dd, 1H; 6.80, m, 1H; 6.63, bs, 1H; 3.96, t, 2H; 3.65, m, 1H; 2.17, m. 1H; 1.50-2.08, m, 29H.

MS (APCI (+)) 535 (MH+). Calc'd for C32H3gLiN04S'1.51 H20: C 67.80, H 7.29, N 2.47: Found: C 67.81, H 7.03, N 2.23.

Example 564 N-f4- (3-cyclohexylpropoxy)-2- (2-methylphenvl) benzoyllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F 1H nmr (300 MHz, D20): 5 7.72, m, 1H; 7.18, m, 3H; 6.80, m, 2H; 6.51, m, 1H; 4.22, m, 1H; 3.64, m, 2H; 0.55-2.17, m, 26H.

MS (APCI (+)) 484 (MH+). Calc'd for C2gH36LiN04S'0.87 H20: C 66.56, H 7.53, N 2.77: Found: C 66.57, H 7.75, N 2.53.

Example 565 N-l4- (2-cvClohexvloxv) ethoxv-2-(2-methvlphenyl) benzovllmethionine(2-cvClohexvloxv) ethoxv-2-(2-methvlphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 6E-F IH nmr (300 MHz, DMSO d6): 8 7.50, d, 1H; 7.20, m, 4H; 6.97, dd, 1H; 6.81, m, 1H; 6.66,

bs, 1H; 4.12, m, 2H; 3.66, m, 2H; 3.63, m, 1H; 1.11-2.24, m, 20H.

MS (APCI (+)) 486 (MH+). Calc'd for C27H34LiNO5S'1.94 H20: C 61.59, H 7.25, N 2.66: Found: C 61.59, H 6.97, N 2.556.

Example 566 N-[4-(3-phenoxy)propoxy-2-(2-methylphenyl)benzoyl]mthionine The desired compound was prepared according to the method of Example 6E-F I H nmr (300 MHz, D20): 8 7.66, m, 1H; 7.01-7.22, m, 4H; 6.80, m, 3H; 6.67, m, 4H; 4.19, m, 1H; 3.72, m, 2H; 3.60, m, 2H; 1.52-2.08, m, 12H.

MS (APCI (+)) 493 (MH+). Calc'd for C28H30LiNO5S#1. 34 H20: C 64.22, H 6.29, N 2.67: Found: C 64.23, H 6.01, N 2.38.

Example 567 N-f4- (4-cvclohexyl) butoxv-2- (2-methvlphenylbenzoyllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F IH nmr (300 MHz, DMSO d6): 8 7.50, d, 1H; 7.20, m, 4H; 6.95, dd, 1H; 6.80, m, 1H; 6.63, m, 1H; 4.00, t, 2H; 3.68, m, 1H; 0.78-2.20, m, 27H.

MS (ESI (-)) 496 (M-H)-. Calc'd for C29H38LiNO4S'1.08 H20: C 66.59, H 7.74, N 2.68: Found: C 66.60, H 7.47, N 2.52.

Example 568 N- [4- (3-phenoxy) butoxy-2- (2-methylphenyl) benzoyllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F lH nmr (300 MHz, DMSO d6): 8 7.68, m, 1H; 6.86-7.20, m, 4H; 6.77, m, 3H; 6.45, m, 4H; 4.19, m, 1H; 3.51, m, 2H; 3.39, m, 2H; 1.33-2.06, m, 14H.

MS (APCI (+)) 508 (MH+). Calc'd for C29H32LiNO5S'1.19 H20: C 65.11, H 6.48, N 2.62: Found: C 65.10, H 6.25, N 2.73 Example 571 N-f4- (benzyloxymethyl)-2- (2-methvlphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.41 (dd, 1H), 7.37,7.30,7.18,6.97 (all m, total 11H), 4.60 (s, 2H), 4.56 (s, 2H), 3.65 (m, 1H), 00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (APCI) 464 (M+H) +.

Anal calcd for C27H2gLiN04S 50 H20: C, 67.77; H, 6.11; N, 2.93. Found: C, 67.64; H, 5.93; N, 3.00.

Example 573 N-[4-(naphth-2-yloxymethyl)-2-(2-methylphenyl)benzoyl]methio nine The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 8.20 (d, 1H), 7.83 (d, 2H), 7.78 (d, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.37 (m, 2H), 7.24 (dd, 1H), 7.20 (m, 4H), 5.24 (s, 2H), 4.22 (m, 1H), 2.10 (m, 5H), 1.96 (s, 3H), 1.80 (m, 2H).

MS (APCI) 500 (M+H) +.

Anal calcd for C30H29NO4S 40 H20: C, 71.09; H, 5.93; N, 2.76. Found: C, 71.01; H, 5.83; N, 2.59.

Example 574 N-f4-naphth-1-yloxymethyl)-2- (2-methylphenyl) benzoyUmethionme The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 8.20 (m, 2H), 7.87 (m, 1H), 7.64 (d, lH), 7.50 (m, 4H), 7.42 (d, 1H), 7.39 (m, 1H), 7.21 (m, 2H), 7.15 (m, 2H), 7.09 (d, 1H), 5.40 (s, 2H), 4.22 (m, 1H), 2.10 (m, 5H), 1.96 (s, 3H), 1.80 (m, 2H).

MS (APCI) 500 (M+H) +.

Anal calcd for C3oH29NO4S-0.40 H20: C, 71.09; H, 5.93; N, 2.76. Found: C, 71.07; H, N, 2.61.

Example 575 N-f4- (benzyloxymethyl)-2-phenylbenzallmethionine The desired compound was prepared according to the method of Example 157 (DMSO-d6) b 8.53 (d, lH), 7.38 (m, 13H), 4.62 (s, 2H), 4.58 (s, 2H), 4.30 (m, 1H), 2.23 (m, 2H), 2.00 (s, 3H), 1.84 (m, 2H).

MS (APCI) 450 (M+H) +.

Anal calcd for C26H27NO4S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.15; H, 5.99; N, 3.08.

Example 576 <BR> <BR> <BR> N-2- [4- (benzvloxymethyl)-2- (2-methylphenyl) benzolamino-4-methanesulfonvlbutanoic acid lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 6 7.59 (d, lH), 7.41 (dd, 1H), 7.37,7.30,7.18,7.01 (all m, total 11H), 4.60 (s, 2H), 4.56 (s, 2H), 3.70 (m, 1H), 2.80 (s, 3H), 2.53 (m, 2H), 82 (all m, total 5H).

MS (ESI) 494 (M-H)-.

Anal calcd for C27H2gLiN06S- 1.00 H20: C, 62.42; H, 5.82; N, 2.70. Found: C, 62.19; H, N, 2.70.

Example 577 N-L4- (2-methylbenzyloxymethyl)-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.41 (dd, 1H), 7.32 (m, 1H), 7.18,6.97 (both m, total 9H), 4.61 (s, 2H), 4.57 (s, 2H), 3.68 (m, 1H), 2.25 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 2H).

MS (APCI) 478 (M+H) +.

Anal calcd for C2gH3oLiNO4S-0.75 H20: C, 67.66; H, 6.39; N, 2.82. Found: C, 67.70; H, 6.23; N, 2.79.

Example 578 N-r4- (3-methylbenzyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.40 (dd, 1H), 7.22,7.15,6.97 (all m, total 10H), 4.60 (s, 2H), 4.53 (s, 2H), 3.68 (m, 1H), 2.30 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H).

MS (APCI) 478 (M+H) +.

Anal calcd for C2gH3oLiN04S 0.75 H20: C, 67.66; H, 6.39; N, 2.82. Found: C, 67.83; H, 6.12; N, 2.82.

Example 579 N- [4- (4-methylbenzyloxymethyl)-2- (2-methylphenyl') be nzoymethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, 1H), 7.39 (dd, 1H), 7.22,7.15,6.95 (all m, total 10H), 4.59 (s, 2H), 4.50 (s, 2H), 3.68 (m, 1H), 2.28 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H).

MS (APCI) 478 (M+H) +.

Anal calcd for C28H3oLiN04S-0.75 H20: C, 67.66; H, 6.39; N, 2.82. Found: C, 67.51; H, N, 2.72.

Example 580 <BR> <BR> BenzenesulfonylN-2- [4- (benzyloxymethyl)-2- (2-methylphenyl) benzoyllamino-4-<BR> <BR> <BR> methylthiobutanamide The desired compound was prepared according to the method of Example 157. The resultant acid was reacted with 1,1'-carbonyldiimidazole and benzenesulfonamide to yield the title compound. (DMSO-d6) 8 7.75 (m, 2H), 7.52,7.40,7.37,7.30,7.15 (all m, total 16H), 4.60 (s, 2H), 4.57 (s, 2H), 4.00 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 2H).

MS (ESI) 601 (M-H)- Anal calcd for C33H34N205S2-1.00 H20: C, 63.85; H, 5.85; N, 4.51. Found: C, 63.77; H, 5.40; N, 4.37.

Example 581 <BR> <BR> <BR> 4-chlorobenzenesulfonyl N-2- [4- (benzyloxymethvl)-2- (2-methylphenyl) benzoyllamino-4-<BR> <BR> <BR> <BR> methylthiobutanamide The desired compound was prepared according to the method of Example 157. The resultant acid was reacted with 1,1'-carbonyldiimidazole and 4-chlorobenzenesulfonamide to yield the title compound. (DMSO-d6) 8 7.65 (m, 2H), 7.52,7.40,7.37,7.30,7.15 (all m, total 16H), 4.60 (s, 2H), 4.57 (s, 2H), 4.00 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 2H).

MS (ESI) 601 (M-H)- Anal calcd for C33H34N2OsS2 1.00 H20: C, 63.85; H, 5.85; N, 4.51. Found: C, 63.77; H, 5.40; N, 4.37.

Example 582 4-methylbenzenesulfonylN-2-[4-(benzyloxymethyl)-2-(2-methylp henyl)benzoyl]amino-4- methylthiobutanamide The desired compound was prepared according to the method of Example 157. The resultant acid was reacted with 1,1'-carbonyldiimidazole and 4-methylbenzenesulfonamide to yield the title compound. (DMSO-d6) 8 7.60 (m, 2H), 7.50,7.40,7.37,7.30,7.15 (all m, total 15H), 4.60 (s, 2H), 4.57 (s, 2H), 4.00 (m, 1H), 2.34 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 2H).

MS (ESI) 617 (M+H) + Anal calcd for C34H36N20SS2'0.25 H20 and 1.00 HOAc: C, 63.46; H, 5.99; N, 4.11.

Found: C, H, 5.53; N, 4.26.

Example 583 saltN-[4-(naphth-2-ylmethoxymethyl)-2-(2-methylphenyl)benzoy l]methioninelithium The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 6 7.90 (m, 4H), 7.50 (m,. SH), 7.20,6.98 (both m, total 6H), 4.72 (s, 2H), 4.65 (s, 2H), 3.70 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 2H).

MS (APCI) 514 (M+H) +.

Anal calcd for C3lH30LiNO4S 00 H20: C, 69.26; H, 6.00; N, 2.61. Found: C, 69.26; H, 5.82; N, 2.55.

Example 584 N-j4- (naphth-1-ylmethoxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 8.09 (m, 1H), 7.95 (m, 1H), 7.90 (m, 1H), 7.52 (m, 5H), 7.42 (m, 1H), 7.20,6.98 (both m, total 6H), 5.01 (s, 2H), 4.68 (s, 2H), 3.70 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 2H).

MS (APCI) 514 (M+H) +.

Anal calcd for C31H3oLiN04S- 1. 00 H20: C, 69.26; H, 6.00; N, 2.61. Found: C, 69.14; H, 5.72; N, 2.47.

Example 585 N-4- (cyclohexylmethoxymethvl)-2- 22-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.55 (d, 1H), 7.38 (dd, 1H), 7.20,7.00 (both m, total 6H), 4.50 (s, 2H), 3.72 (m, 1H), 3.25 (d, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 8H), 1.18 (m, 3H), 0.91 (m, 2H).

MS (ESI) 468 (M-H)-.

Anal calcd for C27H34LiNO4S 75 H20: C, 66.31; H, 7.32; N, 2.86. Found: C, 66.19; H, 7.36; N, 2.89.

Example 586 4-methylbenzenesulfonylN-2-[4-(benzylthiomethyl)-2-(2-methyl phenyl)benzoyl]amino-4- methylthiobutanamide The desired compound was prepared according to the method of Example 582.

(DMSO-d6) 8 7.67 (m, 2H), 7.44 (m, 1H), 7.30 (m, 14H), 4.02 (m, 1H), 3.73 (s, 2H), 3.68 (s, 2H), 2.37 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 2H).

MS (APCI) 633 (M+H) + Anal calcd for C34H36N204S3 # 2.25 H2O : C, 60.64; H, 6.06; N, 4.16. Found: C, 60.51; H, N, 4.37.

Example 587 N- [4- (2-phenylethoxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157. (DMSO-d6) 8 7.50 (d, lH), 7.33 (d, 1H), 7.20,7.05 (both m, total 11H), 4.56 (s, 2H), 3.72 (m, 1H), 3.66 (t, 2H), 2.85 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (APCI) 478 (M+H) +.

Anal calcd for C2gH30LiN04S 00 H20: C, 67.26; H, 6.43; N, 2.79. Found: C, 67.29; H, N, 2.78.

Example 588 N-f4- (2- (2-chlorophenyl) ethoxymethyl)-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.50 (d, lH), 7.38 (d, 2H), 7.31 (d, 1H), 7.20,7.05 (both m, total 8H), 4.56 (s, 2H), 3.82 (m, 1H), 3.66 (t, 2H), 3.00 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (APCI) 512/514 (M+H) +.

Anal calcd for C2gH2gClLiNO4S ¢ 0.50 H20: C, 63.81; H, 5.74; N, 2.66. Found: C, 63.84; H, 5.62; N, 2.62.

Example 589 <BR> <BR> <BR> N-f-4- (2- (2-methoxyphenyl) ethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 5 7.50 (d, lH), 7.33 (dd, 1H), 7.20,7.16,7.05,6.99 (all m, total 8H), 6.92, (m, 1H), 6.82 (ddd, 1H), 4.54 (s, 2H), 3.74 (s, 3H), 3.72 (m, 1H), 3.60 (t, 2H), 2.83 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (ESI) 506 (M-H)-.

Anal calcd for C29H32LiNO5S-0.40 H20: C, 66.88; H, 6.35; N, 2.69. Found: C, 66.90; H, N, 2.66.

Example590<BR> <BR> <BR> <BR> N- (2- (4-chlorophenyl) ethoxymethyl)-2- (2-methylphenyl) benzoyl methionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.50 (d, lH), 7.32,7.27,7.22,7.15,7.04 (all m, total 11H), 4.54 (s, 2H), 3.79 (m, 1H), 3.66 (t, 2H), 2.85 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.72 (m, 1H), 1.60 (m, 1H).

MS (ESI) 512/514 (M+H) +.

Anal calcd for C28H29CILiNO4S-1.00 H20: C, 62.74; H, 5.83; N, 2.61. Found: C, 62.83; H, 5.50; N, 2.52.

Example 591 <BR> <BR> <BR> N-r4-(2-(2s4-dichlorophenvl) ethoxymethvl)-2-(2-methvlphenYl) benzovll methionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.53 (d, 1H) 7.50 (d, 1H), 7.41 (d, 1H), 7.21,7.12,7.03 (all m, total 8H), 4.56 (s, 2H), 3.75 (m, 1H), 3.67 (t, 2H), 2.98 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (ESI) 544/546 (M-H)-.

Anal calcd for C2gH29Cl2LiN04S: C, 60.88; H, 5.11; N, 2.54. Found: C, 60.57; H, 5.19; N, 2.42.

Example 592 N- [4- (2-naphth-l-ylethoxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 6 8.09 (m, 1H), 7.90 (m, 1H), 7.78 (m, 1H), 7.48 (m, 3H), 7.42 (m, 2H), 7.31 (m, 1H), 7.22,7.10,6.98 (all m, total 6H), 4.59 (s, 2H), 3.80 (t, 2H), 3.73 (m, 1H), 3.33 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (ESI) 526 (M-H)-.

Anal calcd for C32H32LiNO4S 0.75 H20: C, 70.25; H, 6.17; N, 2.56. Found: C, 70.27; H, 6.03; N, 2.49.

Example 593 saltN-[4-(2-naphth-2-ylethoxymethyl)-2-(2-methylphenyl)benzo yl]methioninelithium The desired compound was prepared according to the method of Example 158.

(DMSO-d6) (500 MHz) 8 7.82 (d, 1H), 7.78 (m, 2H), 7.72 (s, 1H), 7.50 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H), 7.32 (d, lH), 7.20,7.10,6.98 (all m, total 6H), 4.57 (s, 2H), 3.81 (m, 1H), 3.79 (t, 2H), 3.02 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (ESI) 526 (M-H)-.

Anal calcd for C32H32LiNO4S-0.50 H20: C, 70.83; H, 6.13; N, 2.58. Found: C, 70.90; H, 5.83; N, 2.45.

Example 594 N-f4- (2-cyclohexylethoxymethyl)-2- (2-methylphenyl) benzoyl1methionme lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.55 (d, 1H), 7.38 (dd, 1H), 7.19,7.10,6.96 (all m, total 6H), 4.50 (s, 2H), 3.66 (m, 1H), 3.45 (t, 2H), 90 (all m, total 8H), 1.60 (m, 7H), 1.40 (m, 3H), 1.15 (m, 3H), 0.86 (m, 2H).

MS (ESI) 482 (M-H)-.

Anal calcd for C28H36LiNO4S-0.85 H20: C, 66.61; H, 7.53; N, 2.77. Found: C, 66.55; H, 7.56; N, 3.03.

Example 595 N-14- (3-phenvlpropoxvmethvl)-2-(2-methvlphenvl) benzoyllmethionine lithium(3-phenvlpropoxvmethvl)-2-(2-methvlphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.54 (d, lH), 7.39 (dd, 1H), 10,6.95 (all m, total 11H), 4.53 (s, 2H), 3.67 (m, 1H), 3.43 (t, 2H), 2.62 (t, 2H), 2.17,2.00,1.90,1.84 (all m, total 10H), 1.70 (m, 1H), 1.58 (m, 1H).

MS (ESI) 492 (M+H) +.

Anal calcd for C29H32LiNO4S-0.60 H20: C, H, 6.58; N, 2.75. Found: C, 68.49; H, 6.45; N, 2.77.

Example 597 N-f4- (3-cvclohexylpropoxymethyl)-2- (2-methylphenyl) benzovll-N-methylmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.37,7.20,7.10 (all m, total 7H), 4.50 (m, 1H), 4.49,4.46 (both s, total 2H), 3.42 (t, 2H), 2.62,2.45,2.17,2.00,1.90 (all m, total 11H), 1.60 (m, 8H), 1.17 (m, 7H), 0.83 (m, 2H).

MS (ESI) 510 (M-H)-.

Anal calcd for C30H40LiNO4S 50 H20: C, 68.42; H, 7.85; N, 2.66. Found: C, 68.33; H, 7.72; N, 2.82.

Example 599 <BR> <BR> N-F4-(3-adamant-l-vlpropoxvmethvl)-2-(2-methvlphenvl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.52 (d, 1H), 7.40 (m, 1H), 7.37 (dd, 1H), 7.20,7.15,7.10 (all m, total 5H), 4.50 (s, 2H), 3.86 (m, 1H), 3.40 (t, 2H), 2.17,2.00,1.90 (all m, total 10H), 1.60, 1.47,1.40 (all m, total 17H), 1.04 (m, 2H).

MS (ESI) 548 (M-H)-.

Anal calcd for C33H42LiNO4S # 0.25 H2O : C, 70.75; H, 7.65; N, 2.50. Found: C, 70.56; H, 7.69; N, 2.66.

Example 600 N-[4-(4-cyclohexylbutoxymethyl)-2-(2-methylphenyl)benzoyl]-N -methylmethionine The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 8 7.52 (d, 1H), 7.36 (d, 1H), 7.20,7.10,6.96 (all m, total 6H), 4.50 (s, 2H), 3.66 (m, 1H), 3.43 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 9H), 1.30 (m, 2H), 1.17 (m, 6H), 0.83 (m, 2H).

MS (APCI) 512 (M+H) +.

Anal calcd for C3oH4oLiN04S- 1.00 H20: C, 67.27; H, 7.90; N, 2.61. Found: C, 67.32; H, N, 2.51.

Example 601 N-[4-(4-phenylbutoxymethyl)-2-(2-methylphenyl)benzoyl]-N-met hylmethionine The desired compound was prepared according to the method of Example 157.

(DMSO-d6) 6 7.52 (d, lH), 7.37 (dd, 1H), 7.20,7.15,7.10,6.95 (all m, total 11H), 4.50 (s, 2H), 3.67 (m, 1H), 3.43 (t, 2H), 2.58 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.60 (m, 6H).

MS (APCI) 506 (M+H) +.

Anal calcd for C3oH34LiN04S 50 H20: C, 69.21; H, 6.78; N, 2.69. Found: C, 69.08; H, N, 2.78.

Example 606 N- [4- (3-cyclohexvl-1-ethylthiopropan-2-ylaminomethyl)-2- (2- Saltmethylphenyl)benzoyl]methionineLithium The desired compound was prepared according to the method of Example 157.

MS (CI/NH3) m/z: (M-H)-556; 1H NMR (DMSO-d6,300 MHz) 8 7.53 (d, J=8 Hz, 1H), 7.37 (dd, J=8,1 Hz, 1H), 7.21- 7.12 (m, 4H), 6.94 (m, 1H), 4.66 (d, J=12 Hz, 1H), 4.51 (d, J=12 Hz, 1H), 3.75-3.55 (m, 2H), 2.78-2.45 (m, 4H), 2.18-1.92 (m, 7H), 1.74-1.54 (m, 7H), 1.46-1.23 (m, 3H), 1.18-1.04 (m, 7H), 0.94-0.85 (m, 2H); Anal. Calcd for C3 H42LiN04S2'1.10 H20: C, 63.80; H, 7.63; N, 2.40. Found: C, 63.79; H, N, 2.28.

Examples 729-747 were prepared by the procedure described in Example 157

Example 795 saltN-[4-(4-phenoxyphenoxymethyl)-2-(2-methylphenyl)benzoyl] methioninelithium

The desired compound was prepared according to the method of Example 157.1H nmr (300 MHz, DMSO-d6): 5 7.58 (d, 1 H), 7.51 (d, 1 H), 7.35 (t, 2 H), 730-7.10 (m, 5 H), 7.10-6.96 (m, 7 H), 6.90 (dt, 1 H), 5.18 (s, 2 H), 2.12 (m, 2 H), 2.00 (br s, 3 H), 1.92 (br s, 3 H), 1.72 (m, 1 H), 1.58 (m, 1 H).

MS (ESI-): m/e 540 (M-H)-.

Example 807 <BR> <BR> N- [4- (1-benzylpiperidin-4-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157. IH nmr (300 MHz, DMSO-d6): 8 7.52 (d, 1 H), 7.40-7.16 (m, 10 H), 7.10 (m, 1 H), 6.95 (m, 1 H), 4.55 (s, 2 H), 3.66 (m, 1 H), 3.43 (s, 2 H), 3.40 (m, 1 H), 3.16 (s, 2 H), 2.65 (m, 2 H), 2.18-1.98 (m, 6 H), 1.91 (br s, 3 H), 1.92-1.80 (m, 2 H), 1.70-1.44 (m, 3 H).

MS (ESI-): m/e 545 (M-H)-.

Example 808 <BR> <BR> N- 4- (1-t-butoxycarbonylpiperidin-4-yloxymethy)-2- (2-methylpheny) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. IH nmr (300 MHz, DMSO-d6): 8 7.52 (d, 1 H), 7.39 (dd, 1 H), 7.25-7.10 (m, 5 H), 6.94 (m,

1 H), 4.58 (s, 2 H), 4.10 (m, 1 H), 3.70-3.50 (m, 3 H), 3.17 (m, 2 H), 3.03 (m, 2 H), 2.18 (m, 2 H), 2.00 (br s, 3 H), 1.92 (br s, 3 H), 1.90-1.45 (m, 4 H), 1.39 (s, 9 H).

MS (ESI-): m/e 555 (M-H)-.

Example 809 <BR> <BR> <BR> N-j4- (l-t-butoxycarbonyl-4-benzylpiperidin-4-yloxymethyl)-2- (2-methylphenyl) benzoyll- methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H nmr (300 MHz, DMSO-d6): 8 7.52 (d, 1 H), 7.41 (dd, 1 H), 7.25-7.10 (m, 10 H), 6.94 (m, 1 H), 4.66 (s, 2 H), 3.72-3.60 (m, 3 H), 2.95 (m, 2 H), 2.91 (s, 2 H), 2.18 (m, 2 H), 2.00 (br s, 3 H), 1.92 (br s, 3 H), 1.80-1.37 (m, 6 H), 1.35 (s, 9 H).

MS (ESI-): m/e 645 (M-H)-.

Example 816 <BR> <BR> N- [4- (l-t-butoxvcarbonyl-4-phenpiperidin-4-yloxymethyl)-2- (2-methylphenyl) benzoyll- methionine lithium salt The desired compound was prepared according to the method of Example 157. IH nmr (300 MHz, DMSO-d6): 8 7.49 (m, 3 H), 7.39 (m, 3 H), 7.30 (t, 1 H), 7.27-7.07 (m, 5 H), 6.95 (d, 1 H), 4.14 (s, 2 H), 3.85 (m, 32 H), 3.68 (m, 1 H), 3.10-3.05 (m, 2 H),

2.20-1.95 (m, 7 H), 1.92 (br s, 3 H), 1.83 (dt, 2 H), 1.70 (m, 1 H), 1.57 (m, 1 H), 1.40 (s, 9 H).

MS (ESI-): m/e 631 (M-H)-.

Example817<BR> <BR> <BR> <BR> N-f4- (4-t-butoxvcarbonylaminocyclohexyloxymethyl)-2-l2-methylphen yl) benzoyll- methionine lithium salt The desired compound was prepared according to the method of Example 157. IH nmr (300 MHz, DMSO-d6): 8 7.51 (d, 1 H), 7.36 (dd, 1 H), 7.26-7.12 (m, 3 H), 7.10 (m, 1 H), 6.94 (m, 1 H), 6.70 (d, 1 H), 4.55 (s, 2 H), 3.67 (m, 1 H), 3.30-3.12 (m, 2 H), 2.16 (m, 2 H), 2.05-1.93 (m, 5 H), 1.91 (br s, 3 H), 1.82-1.50 (m, 4 H), 1.37 (s, 9 H), 1.30- 1.10 (m, 4 H).

MS (ESI-): m/e 569 (M-H)-.

Example 818 <BR> <BR> <BR> N- [4- (5- (4-chlorophenyl) furan-2-ylmethoxymethyl)-2- (2-methylphenyl) benzoyl methionine methanesulfonimide The desired compound was prepared according to the method of Example 157.

IH NMR (300 MHz, CDC13) 8 7.99 (s, 1H), 7.57 (d, 2H), 7.48-7.40 (m, 2H), 7.36- 7.18 (m, 6H), 6.60 (d, 1H), 6.42 (d, 1H), 4.66 (s, 2H), 4.58 (s, 2H), 3.23 (s, 3H), 2.16-

1.40 (m, 10H, methyl signals at 2.16 and 2.13 buried in multiplet) CIMS, Calcd for C32H3306N2S2C1 APCI-Q1MS, MH-639 Example 819 N-[4-(5-(4-chlorophenyl)furan-2-ylmethoxymethyl)-2-(2-methyl phenyl)benzoyl]methionine benzenesulfonimide The desired compound was prepared according to the method of Example 157. lu NMR (300 MHz, d6 DMSO) # 7.89-7.28 (m, 16H), 6.96 (d, 1H), 6.58 (d, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 2.16-150 (m, 10H) Calcd for C37H35O6N2S2Cl APCI-Q1MS, MH-701 Example 820 N [4- (5- (4-isopropylphenyl) furan-2-vlmethoxvmethyl)-2- (2- methylphenyDbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (300 MHz, d6 DMSO) 8 7.59-7.51 (m, 3H), 7.40 (bd, 1H), 7.28-7.11 (m, 7H), 7.00-6.91 (m, 1H), 6.82 (d, 1H), 6.55 (d, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 3.70- 3.61 (m, 1H), 2.92 (dq, 1H), 2.16-1.50 (m, 10H, methyl signals at 2.00 and 1.91 buried in multiplet), 1.22 (d, 6H). Calcd for the acid C34H3705NS APCI-Q1MS, MH-570

Example 821 N-[4-(5-(4-N,N-dimethylaminophenyl)furan-2-ylmethoxymethyl)- 2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (300 MHz, d6 DMSO) 8 7.54-7.44 (m, 3H), 7.40 (dd, 1H), 7.21-6.90 (m, 6H), 6.74-6.71 (m, 2H), 6.47 (d, 1H), 4.60 (s, 2H), 4.51 (s, 2H), 3.70-3.61 (m, 1H), 2.93 (s, 6H), 2.16-1.50 (m, 10H, Calcd for the acid C33H3605N2S APCI-Q1MS, MH- 571 Example 822 N-[4-(5-syn(4-chlorophenyl)tetrahydrofuran-2-ylmethoxymethyl )-2-(2- methylphenyl)! benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (300 MHz, d6 DMSO) 8 7.54 (d, 1H), 7.41-7.06 (m, 9H), 7.02-6.90 (m, 1H), 4.81 (dd, 1H), 4.62 (s, 2H), 4.18 (m, 1H), 3.70-3.50 (m, 3H), 2.31-1.48 (m, 14H).

Calcd for the acid C31H34O5NSCl FT HRMS MH+ 568.1919, found 568.1921.

Example 825 N-f4- (1-furan-2-ylpentyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (DMSO-d6,) 8 7.63 (s, 1 H), 7.50 (d, 1 H, J = 8.1 Hz), 7.32 (d, 1 H, J = 7.5 Hz), 7.21-6.92 (m, 6 H), 6.43-6.40 (m, 1 H), 4.48-4.36 (m, 3 H), 3.67-3.61 (m, 1 H), 2.18-1.53 (m, 12 H), 1.28-1.14 (m, 4 H), 0.83-0.78 (m, 3 H); MS 508 (M+-1,100).

Example 826 N- [4-(1-(5-(4-chlorophenyl) furan-2-yl) pentvloxymethyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 7.69-7.65 (m, 2 H), 7.50 (d, 1 H, J = 7.8 Hz), 7.47-7.43 (m, 2 H), 7.37-7.33 (m, 1 H), 7.20-7.08 (m, 4 H), 6.96-6.92 (m, 2 H), 6.54 (dd, 1 H, J = 3.4, 1.0 Hz), 4.57-4.43 (m, 3 H), 3.65-3.60 (m, 1 H), 2.18-1.1.51 (m, 12 H), 1.37-1.23 (m, 4 H), 0.86-0.80 (m, 3 H); MS m/z 618 (M+-1,100).

Example827 N-[4-(3-(4-chlorophenyl)furan-2-ylmetoxymethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 7.67 (d, 1 H, J = 2.0 Hz), 7.47-7.41 (m, 3 H), 7.38-7.29 (m, 3 H), 7.17-7.03 (m, 5 H), 6.92-6.87 (m, 1 H), 6.75 (d, 1 H, J = 2.0 Hz), 4.54 (s, 2 H), 4.49 (s, 2 H), 3.61-3.56 (m, 1 H), 2.18-1.81 (m, 8 H), 1.74-1.64 (m, 1 H), (m, 1 H); MS m/z 562 (M+-1,100).

Example 828 <BR> <BR> N-L4- (1-thiazol-5-yl-2-phenylethoxymethyl)-2- (2-methylphenvl) benzoyllmethionine lithiun salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 5 9.06 (s, 1 H), 7.78 and 7.77 (2s, 1 H total), 7.43 (dd, 1 H, J = 7.8,2.4 Hz), 7.19-7.04 (m, 10 H), 6.97-6.88 (m, 2 H), 5.09-5.03 (m, 1 H), 4.50-4.45 (m, 1 H), 4.41-4.37 (M, 1 H), 3.68-3.59 (m, 1 H), 3.24-3.16 (m, 1 H), 3.07-2.98 (m, 1 H), 2.17-1.82 (m, 8 H), 1.73-1.64 (m, 1 H), (m, 1 H); MS m/z 559 (M+-1,100).

Example 829 N-[4-(3,4-dichloro-5-(4-chlorophenyl)furan-2-ylmethoxymethyl )-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 7.86-7.81 (m, 2 H), 7.61-7.56 (m, 2 H), 7.52 (d, 1 H, J = 7.8 Hz), 7.39 (dd, 1 H, J = 7.8,1.7 Hz), 7.21-7.10 (m, 4 H), 6.97-6.92 (m, 2 H), 4.64 (s, 2 H), 4.62 (s, 2 H), 3.67-3.61 (m, 1 H), 2.18-1.83 (m, 8 H), 1.73-1.64 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 632 (M+-1,100).

Example 868 N-r4-- (4-fluorophenyl) furan-2-ylmethoxymethyl)-2-naphth-l-ylbenzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157.

1 H NMR (CD30D-d4,500MHz) 8: 7.88 (m, 3H), 7.77 (d, J=7.5Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.60-7.44 (m, 8H), 7.34 (m, 2H), 7.01 (m, 1H), 6.60 (d, J=2.5Hz, 1H), 6.42 (d, J=2.5Hz, 1H), 4.65 (s, 2H), 4.53 (s, 2H), (m, 1H), 1.78 (s, 3H), 1.64-l. 11 (m, 4H).

MS: ESI (-) m/z: (M-H)-582

Example 869 N-f4- (5- (4-fluorophenyl) furan-2-ylmethoxymethyl)-2- (2-chloro-4-fluorophenyl)- benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1 H NMR (CD30D-d4,500MHz) 8 7.64 (m, 3H), 7.45 (m, 2H), 7.22 (m, 2H), 7.08 (m, 3H), 6.64 (d, J=2.5Hz, 1H), 6.45 (d, J=2.5Hz, 1H), 4.64 (s, 2H), 4.57 (s, 2H), 4.26 (m, 1H), 2.70-2.50 (M, 1H), 2.20 (m, 2H), 2.02 (s, 3H), 1.79 (m 1H). MS: ESI (-) m/z: (M- H)-584

Example 872 <BR> <BR> <BR> <BR> N- [4- (5- (4-fluorophenyl) furan-2-ylmethoxymethyl)-2- (2-trifluoromethylphenyl) benzol methionine Lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (CD30D-d4,500MHz) 8 7.88 (m, lH), 7.84 (m, 1H), 7.71 (m, 2H), 7.56-7.36 (m, SH), 7.12 (m, 2H), 6.67 (d, J=2.5Hz, 1H), 6.46 (d, J=2.5Hz, 1H), 4.55 (s, 4H), 2.30-2.20 (m, 2H), 2.10 (s, 3H), 2.09-2.0 (m, 2H).

MS: ESI (-) m/z: (M-H20)'582

Example 879 N- [4- (3-phenylpropoxy)-2- (2-methylphenvl) benzovllmethionine, lithium salt The desired compound was prepared according to the method of Example 6E-F lH (300 MHz, D20): 5 7.67, m, 1H; 7.00-7.23, m, 4H; 6.68-6.94, m, 6H; 6.40, s, 1H; 4.20, m, 1H; 3.51, m, 2H; 2.29, m, 2H; 1.69-2.05, m, 9H; 1.50-1.68, m, 3H.

MS (APCI (+)): 478 (MH+). Calc'd for C2gH3oLiNO4S + 1.22 (H20): C 66.53, H 6.47, N 2.77: Found: C 66.53, H 6.31, N 2.44.

Example 882 N-[4-(3-Cyclohexyl-1-methylthiopropan-2-yl)oxymethyl-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (300 MHz, DMSO) 60.70-0.95 (m, 2H), 1.00-1.15 (m, 3H), 1.30-1.50 (m, 3H), 1.50-1.70 (m, 7H), 1.93 (s, 3H), 2.00 (brs, 2H), 2.06 (s, 3H), 2.16 (brs, 2H), 2.59 (dd, J=13.5,6.3 Hz, 1H), 2.71 (dd, J=13.5,4.8 Hz, 1H), 3.60 (brs, 2H), 4.51 (d, J=12 Hz, 1H), 4.66 (d, J=12 Hz, 1H), 6.96 (brs, 1H), 7.10-7.28 (m, 5H), 7.38 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H).

MS (APCI (+)) mAz 544 (M+H); Analysis calc'd for C30H4oLiN04S20.50 H20: C, 64.49; H, 7.40; N, 2.51; found: C, H, N, 2.53.

Example 883 N- [4- (3-Cvclohexvl-1-t-butylthiopropan-2-vl) oxvmethvl-2- (2- saltmethylphenyl)benzoyl]methioninelithium The desired compound was prepared according to the method of Example 157.

1H NMR (300 MHz, DMSO) 6 0.70-0.95 (m, 2H), (m, 3H), 1.24 (s, 9H), 1.35- 1.43 (m, 3H), 1.50-1.65 (m, 7H), 1.91 (brs, 3H), 1.95-2.05 (m, 2H), 2.10-2.19 (m, 1H), 2.59 (dd, J=12.6,6.8 Hz, 1H), 2.76 (dd, J=12.6,4.8 Hz, 1H), 3.53-3.71 (m, 2H), 4.54 (d, J=12.5 Hz, 1H), 4.68 (d, J=12.6 Hz, 1H), 6.96 (brd, J=6 Hz, 1H), 7.10-7.25 (m, 5H), 7.37 (dd, J=8.0,1.4 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H).

MS (APCI (+)) m/z 586 (M+H); Analysis calc'd for C33H46LiNO4S2'1. 05H2O : C, 64.90; H, 7.94; N, 2.29; found: C, 64.88; H, 7.89; N, 2.28.

Example 884 N-[4-(3-Cyclohexyl-1-phenylthiopropan-2-yl)oxymethyl-2-(2- methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (300 MHz, DMSO) 8 0.65-0.92 (m, 2H), 0.96-1.20 (m, 3H), 1.26-1.74 (m, 10H), 1.75-1.87 (m, 1H), 1.91 (s, 3H), 1.91-2.03 (m, 2H), 2.07-2.18 (m, 1H), 2.99-3.10

(m, 1H), 3.24 (dd, J=13.2,4.7 Hz. 1H), 3.52-3.73 (m, 2H), 4.44 (d, J=12.6 Hz, 1H), 4.62 (d, J=12.6 Hz, 1H), 6.89-7.02 (m, 2H), 7.06-7.16 (m, 2H), 7.18-7.27 (m, 4H), 7.28-7.37 (m, 3H), 7.50 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/z 604 (M-1); Analysis calc'd for C3sH42LiNO4S261. 10 H20: C, 66. 56; H, 7.05; N, 2.22; found: C, 66.57; H, 6.89; N, 2.18.

Example 885 N-f4- (3-Cvclohexyl-1-morpholin-4-ylpropan-2-vl) oxymethyl-22- methylphenyl) benzoylLmethionine trifluoroacetate salt The desired compound was prepared according to the method of Example 157.

H NMR (300 MHz, DMSO) 8 (m, 2H), 1.12-1.39 (m, 5H), 1.56-1.76 (m, 8H), 1.95 (s, 3H), 2.00-2.20 (m, 5H), 3.03-3.78 (m, 7H), 3.85-3.99 (m, 2H), 4.23 (brs, 1H), 4.63 (s, 2H), 7.10-7.26 (m, 5H), 7.43 (dd, J=7.8,1.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 8.04 (m, 1H).

MS (APCI (-)) m/z 581 (M-H); Analysis calc'd for C33H46N2O5S#0.40H2O+1. 25TFA: C, 58.21; H, 6.61; N, 3.82; found: C, 58.20; H, 6.62; N, 3.80.

Example 889 N-[4-(3-Cyclohexyl-2-cyclohexylmethylpropan-2-yl)oxymethyl-2 -(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (300 MHz, DMSO) 6 0.70-0.84 (m, 4H), 0.93-1.31 (m, 13H), 1.51-1.77 (m, 14H), 1.89 (s, 3H), 1.93-2.16 (m, 4H), 3.28 (s, 2H), 3.64 (brs, 1H), 4.50 (s, 2H), 6.92- 6.98 (m, 1H), 7.09-7.24 (m, SH), 7.33 (dd, J=7.8,1.3 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H).

MS (ESI (-)) m/z 592 (M-H); Analysis calc'd for C36HsoLiNO4S0.5H20: C, 71.02; H, 8.44; N, 2.30; found: C, 70.99; H, 8.33; N, 2.20.

Example 891 N-f4- (oxazol-5-ylmethoxymethvl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (DMSO-d6,) 8 8.34 (s, 1 H), 7.53 (d, 1 H, J = 7.9 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.22-7.07 (m, 6 H), 6.96-6.91 (m, 1 H), 4.59 (s, 2 H), 4.58 (s, 2 H), 3.73-3.69 (m, 1 H), 2.18-1.82 (m, 8 H), 1.74-1.64 (m, 1 H), 1.59-1.53 (m, 1 H); MS m/z 453 (M+-1,100).

Exact mass calcd for C24H27N205S 455.1629, found 455.1635.

Example 892 N-[4-(2-(2-chlorophenyl)oxazol-5-ylmethoxymethyl)-2-(2- methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 5 8.49 (s, 1 H), 7.52-7.31 (m, 5 H), 7.26-7.22 (m, 5 H), 6.92-6.87 (m, 2 H), 4.53 (s, 2 H), 4.50 (m, 2 H), 3.68-3.62 (m, 1 H), 2.18-1.80 (m, 8 H), 1.77- 1.65 (m, 1 H), (m, 1 H); MS m/z 563 (M+-1,100).

Exact mass calcd for C3oH3oClN205S 565.1564, found 565.1578.

Example 893 N-[4-(2-(3-chlorophenyl)oxazol-5-ylmethoxymethyl)-2-(2- methvlphenyl ! benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 8.49 (s, 1 H), 7.74-7.72 (m, 1 H), 7.64-7.61 (m, 1 H), 7.53 (d, 1 H, J = 7.8 Hz), 7.48-7.38 (m, 3 H), 7.21-7.12 (m, 5 H), 6.99-6.94 (m, 1 H), 4.76 (s, 2 H), 4.64 (m, 2 H), 3.68-3.62 (m, 1 H), 2.15-1.80 (m, 8 H), 1.77-1.64 (m, 1 H), 1.58- 1.52 (m, 1 H); MS m/z 563 (M+-1,100).

Exact mass calcd for C3oH3oClN205S 565.1564, found 565.1588.

Example 894 N-l 4-(2-(4-chlorophenyl) oxazol-5-ylmethoxvmethyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 8.46 (s, 1 H), 7.71-7.67 (m, 2 H), 7.54-7.46 (m, 3 H), 7.40-7.37 (m, 1 H), 7.21-7.12 (m, 5 H), 6.99-6.94 (m, 1 H), 4.74 (s, 2 H), 4.64 (m, 2 H), 3.68- 3.62 (m, 1 H), 2.17-1.79 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.52 (m, 1 H) ; MS m/z 563 (M+-1,100).

Exact mass calcd for C30H30ClN2O5S 565.1564, found 565.1578.

Example 895 N- ! benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157.

H NMR (DMSO-d6,) 8 7.60 (s, 1 H), 7.53 (d, 1 H, J = 7.8 Hz), 7.38 (dd, 1 H, J = 7.8, 1.4 Hz), 7.21-7.11 (m, 5 H), 6.97-6.93 (m, 1 H), 4.72 (s, 2 H), 4.59 (m, 2 H), 3.68-3.62 (m, 1 H), 2.18-1.80 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H), 1.35 (s, 9 H); MS m/ 525 (M+-1,100).

Exact mass calcd for C28H35N204S2 527.2033, found 527.2037.

Example 896 N-f4- (2-methoxvthiazol-5-ylmethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. lH NMR (DMSO-d6,) # 7.53 (d, 1 H, J = 8.0 Hz), 7.37 (d, 1 H, J = 7.9 Hz), 7.22-7.06 (m, 6 H), 6.97-6.87 (m, 1 H), 4.60 (s, 2 H), 4.56 (s, 2 H), 3.99 (s, 3 H), 3.71-3.64 (m, 1 H), 2.17-1.79 (m, 8 H), 1.73-1.64 (m, 1 H), 1.59-1.53 (m, 1 H); MS m/z 501 (M+ + 1,100).

Example 897 N- [4- (2- (2-chlorophenyl) thiazol-5-ylmethoxymethyl)-2- (2- methylphenvl ! benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) S 8.19-8.14 (m, 1 H), 7.96 (s, 1 H), 7.67-7.61 (m, 1 H), 7.56-7.47 (m, 3 H), 7.41 (dd, 1 H, J = 7.8,1.4 Hz), 7.21-7.15 (m, 5 H), 6.98-6.95 (m, 1 H), 4.86 (s, 2 H), 4.66 (m, 2 H), 3.69-3.63 (m, 1 H), 2.18-1.82 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H); MS m/z 579 (M+-1,100).

Exact mass calcd for C3oH3oClN204S2 581.1336, found 581.1316.

Example 898 N-[4-(2-(3-fluorophenyl)thiazol-5-ylmethoxymethyl)-2-(2-meth ylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6.) 5 7.90 (s, 1 H), 7.79-7.70 (m, 2 H), 7.59-7.52 (m, 2 H), 7.42-7.40 (m, 1 H), 7.37-7.31 (m, 1 H), 7.21-7.14 (m, 5 H), 6.98-6.95 (m, 1 H), 4.83 (s, 2 H), 4.64 (m, 2 H), 3.69-3.63 (m, 1 H), 2.17-1.79 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H); MS m/z 563 (M+-1,100).

Exact mass calcd for C3oH30FN204S2 565.1631, found 565.1624.

Example 899 N-[4-(2-(3-chlorophenyl)thiazol-5-ylmethoxymethyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. tH NMR (DMSO-d6,) â 7.96-7.94 (m, 1 H), 7.91 (s, 1 H), 7.90-7.86 (m, 1 H), 7.56-7.53 (m, 3 H), 7.43-7.40 (m, 1 H), 7.21-7.14 (m, 5 H), 6.98-6.96 (m, 1 H), 4.83 (s, 2 H), 4.64 (m, 2 H), 3.69-3.63 (m, 1 H), 2.17-1.79 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H); MS m/z 579 (M+-1,100).

Exact mass calcd for C30H30ClN2O4S2 581.1336, found 581.1339.

Example 900 N-[4-(2-(4-fluorophenyl)thiazol-5-ylmethoxymethyl)-2-(2-meth ylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

IH NMR (DMSO-d6,) 8 8.00-7.95 (m, 2 H), 7.85 (s, 1 H), 7.54 (d, 1 H, J = 7.7 Hz), 7.42-7.39 (m, 1 H), 7.37-7.31 (m, 2 H), 7.22-7.13 (m, 5 H), 6.98-6.95 (m, 1 H), 4.81 (s, 2 H), 4.63 (m, 2 H), 3.69-3.63 (m, 1 H), 2.17-1.79 (m, 8 H), 1. 77-1.63 (m, 1 H), 1.60- 1.53 (m, 1 H); MS m/z 563 (M+-1,100).

Exact mass calcd for C3oH29LiFN204S2 571.1708, found 571.1707.

Example 901 N-l 4-(2-(4-chlorophenyl) thiazol-5-ylmethoxymethvl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (DMSO-d6,) 8 7.97-7.92 (m, 2 H), 7.88 (s, 1 H), 7.58-7.53 (m, 3 H), 7.42-7.40 (m, 1 H), 7.22-7.13 (m, 5 H), 6.98-6.96 (m, 1 H), 4.82 (s, 2 H), 4.64 (m, 2 H), 3.69- 3.62 (m, 1 H), 2.17-1.79 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H); MS m/z 579 (M+-1,100).

Example904<BR> <BR> <BR> <BR> N-4- (4- (4-chlorophenyl) furan-2-ylmethoxymethvl)-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H NMR (DMSO-d6,) 8 8.20 (s, 1 H), 7.64-7.60 (m, 2 H), 7.55-7.52 (m, 1 H), 7.44-7.38 (m, 3 H), 7.21-7.11 (m, 5 H), 6.96-6.93 (m, 2 H), 4.60 (s, 2 H), 4.52 (s, 2 H), 3.71-3.64 (m, 1 H), 2.18-1.82 (m, 8 H), 1.74-1.64 (m, 1 H), 1.59-1.53 (m, 1 H); MS m/z 562 (M+-l, 100).

Example 923 N-f 5-Benzyl-4-benzyloxymethyl-2- (2-methylphenyl) benzoyllmethionine The desired compound was prepared according to the method of Example 343 using 9-benzyl-9-BBN as the coupling partner. 1H (300MHz, DMSO-d6,8) 12.55 (1H, bs), 8.00 (1H, bd, J=12Hz), 7.40-7.25 (8H, m), 7.25-7.10 (8H, m), 4.59 (2H, s), 4.50 (2H, s), 4.18 (1H, m), 4.07 (2H, s), 2.25-1.95 (4H, m), 1.93 (3H, s), 1.90-1.60 (3H, m). m/z (ESI) 554 (MH+) Anal. calc. for C34H35NO4S C 73.75, H 6.37, N 2.53 Found C 73.47, H 6.12, N 2.27

Example 924 N-r5-Benzyl-4-(furan-2-vlOxymethyl)-2-(2-methylphenvl) benzOyllmethionine The desired compound was prepared according to the method of Example 343 using 9-benzyl-9-BBN as the coupling partner. 1H (300MHz, DMSO-d6,8) 12.55 (1H, bs), 7.98 (1H, bd, J=12Hz), 7.63 (1H, m), 7.40-7.25 (4H, m), 7.25-7.00 (7H, m), 6.41 (2H, m), 4.47 (2H, s), 4.50 (2H, s), 4.18 (1H, m), 4.04 (2H, s), 2.25-1.90 (5H, m), 1.92 (3H, s), 1.90-1.60 (2H, m). m/z (ESI) 544 (MH+) Anal. calc. for C32H33N05S'0.50 H20 C 69.54, H 6.20, N 2.53 Found C 69.57, H 6.69, N 2.57

Example 925 N-[5-Benzyl-4-(2-phenylethoxymethyl)-2-(2-methylphenyl)benzo yl]methionine The desired compound was prepared according to the method of Example 343 using 9-benzyl-9-BBN as the coupling partner. 1H (300MHz, DMSO-d6,8) 7.40-7.00 (16H, m), 6.86 (1H, bd, J=lOHz), 4.51 (2H, s), 4.18 (2H, s), 3.62 (1H, m), 3.41 (2H, t, J=8Hz), 2.59 (2H, t, J=8Hz), 2.25-1.95 (4H, m), 1.94 (3H, s), 1.80 (2H, m) 1.80-1.60 (3H, m). m/z (ESI) 580 (MH-) Anal. calc. for C36H38LiNO4S#1. 70 H20 C 69.93, H 6.75, N 2.27 Found C 69.61, H 6.30, N 2.06

Example 930 N-f4- (2-chlorobenzyloxvmethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.56 (m, 2H), 7.43 (m, 2H), 7.35 (m, 2H), 7.18,6.97 (both m, total 8H), 4.65 (s, 2H), 4.61 (s, 2H), 3.70 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.68,1.59 (both m, total 2H).

MS (ESI) 498/500 (M+H) +.

Anal calcd for C27H27ClLiN04S-0.25 H20: C, 63.78; H, 5.45; N, 2.75. Found: C, 63.75; H, 5.41; N, 2.70.

Example 931 N-F4- (2-methoxybenzyloxvmethyl)-2-(2-methylphenyl ! benzoyllmethionine(2-methoxybenzyloxvmethyl)-2-(2-methylphen yl ! benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.40 (dd, 1H), 7.36 (dd, 1H), 7.26 (m, 1H), 7.18,7.10 (both m, total 6H), 6.98 (d, 1H), 6.93 (ddd, 1H), 4.62 (s, 2H), 4.53 (s, 2H), 3.75 (m, 1H), 3.74 (s, 3H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 2H).

MS (ESI) 492 (M-H)-.

Anal calcd for C2gH3oLiNO5S 50 H20: C, 66.13; H, 6.14; N, 2.75. Found: C, 65.99; H, 5.99; N, 2.66.

Example 932 N- [4- (3-methoxybenzyloxymethyl)-2-22-methylphenyl) benzoyl methionine lithium lithium The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.41 (dd, 1H), 7.25,7.18,7.12,6.97,6.93 (all m, total 9H), 6.84 (m, 1H), 4.60 (s, 2H), 4.54 (s, 2H), 3.74 (s, 3H), 3.72 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 2H).

MS (ESI) 492 (M-H)-.

Anal calcd for C2gH3oLiNOsS 50 H20: C, 66.13; H, 6.14; N, 2.75. Found: C, 66.27; H, 5.82; N, 2.63.

Example 933 N-r4- (4-chlorobenzyloxymethyl)-2-(2-methylphenyl) benzoyllmethionine(4-chlorobenzyloxymethyl)-2-(2-methylpheny l) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (D2O) 8 7.60 (d, 1H), 7.25,7.13,6.94,6.88 (all m, total 11H), 4.20 (m, 5H), 2.05,1.97,1.90, 1.80,1.70 (all m, 10H).

MS (ESI) 498/500 (M+H) +.

Anal calcd for C27H27ClLiN04S-0.25 H20: C, 63.78; H, 5.45; N, 2.75. Found: C, 63.52; H, 5.33; N, 2.72.

Example 934 N- [4- (3-chlorobenzyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, 1H), 7.41 (m, 2H), 7.35 (m, 2H), 7.17,6.97 (both m, total 7H), 4.61 (s, 2H), 4.58 (s, 2H), 3.69 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.68,1.59 (both m, total 2H).

MS (ESI) 498/500 (M+H) +.

Anal calcd for C27H27ClLiN04S-0.25 H20: C, 63.78; H, 5.45; N, 2.75. Found: C, 63.72; H, 5.30; N, 2.71.

Example 935 N- [4- (4-methoxybenzyloxymethyl)-2- (2-methylphenvl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.39 (dd, 1H), 7.27 (dd, 2H), 7.20,7.10,6.97 (all m, total 7H), 6.90 (dd, 1H), 4.57 (s, 2H), 4.46 (s, 2H), 3.74 (s, 3H), 3.69 (m, 1H), 2.17,2.00, 1.90 (all m, total 8H), 1.63 (m, 2H).

MS (ESI) 492 (M-H)-.

Anal calcd for C28H3oLiNO5S-0.50 H20: C, 66.13; H, 6.14; N, 2.75. Found: C, 66.21; H, 5.93; N, 2.72.

Example 937 N-f4- (2- (4-methoxyphenyl) ethoxymethyl)-2- (2-methylphenvllbenzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.51 (d, lH), 7.32 (dd, 1H), 7.20,7.07,6.97 (all m, total 5H), 7.13 (dd, 2H), 6.80 (dd, 1H), 4.55 (s, 2H), 3.70 (s, 3H), 3.70 (m, 1H), 3.60 (t, 2H), 2.79 (t, 2H), 2.17,2.00,1.90 (all m, total 8H), 1.63 (m, 2H).

MS (ESI) 506 (M-H)-.

Anal calcd for C29H32LiNO5S-0.50 H20: C, 66.65; H, 6.36; N, 2.68. Found: C, 66.73; H, 6.33; N, 2.65.

Example 938 saltN-[4-(2-isopropylbenzyloxymethyl)-2-(2-methylphenyl)benz oyl]methioninelithium The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.40 (d, 1H), 7.30,7.20,7.13,6.98 (all m, total 10H), 4.61 (s, 2H), 4.59 (s, 2H), 3.70 (m, 1H), 3.18 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H), 1.15 (d, 6H).

MS (ESI) 504 (M-H)-.

Anal calcd for C3oH34LiN04S-0.85 H20: C, 68.38; H, 6.83; N, 2.66. Found: C, 68.04; H, 6.50; N, 3.06.

Example 939 N-f4- (3-isopropylbenzyloxymethyl)-2- (2-methylphenyl) benzoyl methionine lithium lithium The desired compound was prepared according to the method of Example 157 (DMSO-d6) 5 7.55 (d, lH), 7.40 (d, 1H), 15,6.98 (all m, total 10H), 4.60 (s, 2H), 4.54 (s, 2H), 3.64 (m, 1H), 2.85 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H), 1.19 (d, 6H).

MS (ESI) 504 (M-H)-.

Anal calcd for C3oH34LiN04S 00 H20: C, 68.04; H, 6.85; N, 2.64. Found: C, 68.21; H, N, 2.85.

Example 940 N-f4- (4-isopropylbenzyloxymethvl)-2- (2-methvlphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.40 (dd, 1H), 00 (all m, total 10H), 4.59 (s, 2H), 4.52 (s, 2H), 3.70 (m, 1H), 2.85 (m, 1H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H), 1.19 (d, 6H).

MS (ESI) 504 (M-H)-.

Anal calcd for C3oH34LiNO4S-0.50 H20: C, 69.21; H, 6.78; N, 2.69. Found: C, 69.26; H, N, 2.71.

Example 941 N- [4- (3-N, N-dimethvlaminobenzyloxvmeth-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 8 7.55 (d, lH), 7.40 (dd, 1H), 7.27 (dd, 2H), 7.20,7.15,6.98 (all m, total 7H), 6.69 (m, 1H), 6.64 (dd, 2H), 4.49 (s, 2H), 4.54 (s, 2H), 3.69 (m, 1H), 2.85 (s, 6H), 2.17,2.00,1.90 (all m, total 8H), 1.62 (m, 2H).

MS (ESI) 505 (M-H)-.

Anal calcd for C29H33LiN204S-0.33 H20: C, 67.17; H, 6.54; N, 5.40. Found: C, 66.87; H, 6.13; N, 5.28.

Example 942 N- [4-(nonan-5-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) S 7.55 (d, lH), 7.37 (d, 1H), 7.20,7.10,6.97 (all m, total 6H), 4.53 (s, 2H), 3.66 (m, 1H), 3.35 (m, 1H), 2.17,2.00,1.90,1.60,1.44,1.25 (all m, total 16H), 0.84 (m, 6H).

MS (ESI) 498 (M-H)-.

Anal calcd for C29H4oLiNO4S-0.50 H20: C, 67.68; H, 8.03; N, 2.72. Found: C, 67.84; H, 8.22; N, 2.63.

Example 943 N-[4-(1-(2-chlorophenyl)hexan-2-yloxymethyl)-2-(2-methylphen yl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157 (DMSO-d6) 6 7.45 (dd, 1H), 7.36 (m, 2H), 7.20,6.96 (both m, total 9H), 4.54 (d, 1H), 4.44 (d, 1H), 3.66 (m, 2H), 2.98 (m, 1H), 2.85 (m, 1H), 2.17-1.20 (envelope, 16H), 0.83 (m, 3H).

MS (ESI) 566 (M-H)-.

Anal calcd for C32H37ClLiN04S-0.75 H20: C, 65.41; H, 6.60; N, 2.34. Found: C, 65.41; H, 6.25; N, 2.38.

Example 975 2-N- 4- (N-benzyloxyacetamidoxy)-2-phenylbenzovllamino-4-methanesulf onvlbutanoic acid Example 975A Methyl4-Benzyloxy-2-phenylbenzoate The methoxy group of compound methyl 4-methoxy-2-phenylbenzoate was deprotected to give methyl 4-hydroxy-2-phenylbenzoate by using the method described previously (EtSH-AlCl3). The crude product (7.83 g, 34.3 mmol) was dissolved in 200 mL of acetone. To this solution was added benzylbromide (5.87 g, 34.3 mmol) and potassium

carbonate (9.47 g, 2.0 eq). The mixture was refluxed for 12 hr. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ether and washed with IN HCl and IN NaOH solution. The ether solution was evaporated. The pale yellow solid was recrystallized from 5% ethyl acetate in hexane to give the title compound as white crystals (7.53 g, yield 87%).

IH NMR (CDC13) 8 7.87 (d, J = 8.6 Hz, 1H), 7.27-7. 44 (m, 10H), 6.98 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 5.13 (s, 2H), 3.61 (s, 3H).

Example 975B N- [4-Benzyloxy-2-phenylbenzoyllmethionine methyl este The compound prepared in Example 975A was hydrolyzed with IN aqueous NaOH and the carboxylic acid was coupled with (L)-methionine methyl ester by using coupling reagents.

After flash column chromatography (1.5: 1 = hexane/ethyl acetate), the desired compound was obtained (82% yield).

H NMR (CDC13) 8 7.69 (d, J = 8.5 Hz, 1H), 7.28-7.41 (m, 10H), 6.97 (d, J = 8.5 Hz, 1H), 6.94 (s, 1H), 6.02 (d, J = 7.7 Hz, 1H), 5.09 (s, 2H), 4.64 (ddd, J = 5.1 and 7.7 Hz, 1H), 3.64 (s, 3H), 2.09 (t, J = 7.6 Hz, 2H), 2.00 (s, 3H), 1.86-1.96 (m, 1H), 1.68-1.77 (m, 1H); 13C NMR (CDC13) 5 2, 7,51.3,30.7,29.0,14.7.

Example 975C Methyl N-[4-benZvloxv-2-phenvlbenzoyllamino-4-methanesulfonvlbutanO ate The compound resulting from Example 975B (2.07 g, 4.67 mmol) was dissolved in a mixture of 60 mL of acetone and 15 mL of water. To this solution was added 4- methylmopholine-N-oxide (1.64 g, 3.0 eq) and 1.0 mL (0.019 eq) of Os04 solution (2.5% in tert-butanol). The mixture was stirred at r. t for 5 hr. The solvents were evaporated and the residue was extracted with ethyl acetate and water. After evaporation of solvents, the desired compound was obtained (2.22 g, 100% yield).

1H NMR (CDC13) 8 7.71 (d, J = 8.6 Hz, 1H), 7.34-7.48 (m, 10 H), 7.02 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 5.88 (d, J = 7.4 Hz, 1H), 5.13 (s, 2H), 4.65 (ddd, J = 5.1 and 7.4 Hz, 1H), 3.67 (s, 3H), 2.85 (s, 3H), 2.62-2.82 (m, 2H), 2.20-2.28 (m, 1H), 1.88-1.98 (m, 1H).

Example 975D <BR> <BR> <BR> Methyl 2-N-E4-(benZvloxvcarbonvlmethoxv)-2-phenvlbenzovleamino-4-&l t;BR> <BR> <BR> <BR> <BR> methanesulfonvlbutanoate

The compound resulting from Example 975C (2. 44 g, 4.25 mmol) was hydrogenated at I atm in THF-CH30H to remove the benzyl group (yield 100%). The resulting compound (1.66 g, 4.25 mmol) was reacted with benzyl bromoacetate (1.07 g, 4.67 mmol) in acetone in the presence of K2CO3 (1.22 g, 8.84 mmol). After stirring at r. t for 10 hrs, the reaction mixture was worked up. The crude product was purified by recrystalization from 20% of ethyl acetate in hexane to give the title compound (2.17 g, 95% yield for 2 steps).

1H NMR (CDC13) 8 7.68 (d, J = 8.7 hz, 1H), 7.41-7.47 (m, 3H), 7.31-7.39 (m, 7H), 6.92 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 5.87 (d, J = 7.5 Hz, 1H), 5.24 (s, 2H), 4.73 (s, 2H), 4.64 (ddd, J = 5.1 and 7.5 Hz, 1H), 3.67 (s, 3H), 2.84 (s, 3H), 2.62-2.81 (m, 2H), 2.22- 2.28 (m, 1H), 1.92-2.00 (m, 1H).

Example 975E 2-N- [4- (N-benzyloxyacetamidoxv)-2-phenvlbenzoyl] amino-4-methanesulfonylbutanoic acid The compound resulting from Example 975D (279 mg, 0.50 mmol) was suspended in 6 mL of methanol and 2.0 mL of 0.5 N LiOH solution. After stirring at 0 °C for 2 hr and at r. t for 2 hr, the solvents were evaporated and the residue was dissolved in 20 mL of water.

The aqueous solution was filtered and the filtrate was acidified with 1 N HCl solution. The white precipitate was collected (263 mg, 97% yield).

IH NMR (CDC13 and 1 drop of CD30D) 8 8.92 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.40- 7.47 (m, 3H), 7.26-7.38 (m, 7H), 6.85 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.00 (d, J = 7.5 Hz, lH), 4.93 (s, 2H), 4.60-4.67 (m, 3H), 2.84 (s, 3H), 2.64-2.78 (m, 2H), 2.20-2.24 (m, 1H), 1.90-1.95 (m, 1H).

Example 976 <BR> 2-A-r4-W-hydroxyacetamidoxy)-2-phenyIbenzoyI]amino-4-methane suIfonyIbutanoicacid The compound resulting from Example 975D (279 mg, 0.50 mmol) was suspended in 6 mL of methanol and 2.0 mL of 0.5 N LiOH solution. After stirring at 0 °C for 2 hr and at r. t for 2 hr, the solvents were evaporated and the residue was dissolved in 20 mL of water.

The aqueous solution was filtered and the filtrate was acidified with 1 N HCl solution. The

white precipitate was collected (263 mg, 97% yield). TLC showed this compound was pure (Rf = 0.50,30 : 3: 1 = CH2C12/CH30H/HOAc). This compound (176 mg) was dissolved in 4 mL of THF and 4 mL of methanol. The solution was hydrogenated at 1 atm in the presence of catalytic amount of Pd/C. After 1 hr, the reaction mixture was filtered. The filtrate was evaporated to dryness. The residue was dissolved in 10 mL of water and the aqueous solution was lyophilized to give the title compound as a white solid (141 mg, 96% yield). in NMR (CD30D) 8 7.52 (d, J = 8.4 Hz, 1H), 7.35-7.45 (m, 5H), 7.04 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 4.62 (s, 2H), 4.44 (dd, J = 4.6 and 9.2 Hz, 1H), 2.88 (s, 3H), 2.77- 2.82 (m, 1H), 2.59-2.68 (m, 1H), 2.21-2.29 (m, 1H), 1.96-2.00 (m, 1H); 13C NMR (CD30D) 8 1, 3,67.3,52.6,51.8,40.7,25.3.

Example 981 N-f4- (1, 3-dicvclohexylpropan-2-yloxymethyl)-2- (2-methvlphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 IH NMR (300 MHz, CDC13) 8 0.81-1.00 (m, 6H), 1.09-1.78 (m, 20H), 1.86 (2.20, J=m Hz, 3H), 2.08 (s, 3H), 2.16 (m, 3H), 3.58 (m, 1H), 4.50-4.59 (m, 3H), 5.84-5.96 (m, 1H), 7.18 (brs, 1H), 7.26-7.47 (m, 6H), 7.94-8.02 (m, 1H).

MS (DCI (NH3)) m/z 580 (M+H); Analysis calc'd for C35H4gN04SLi+1.0LiOTf+0.25H20: C, 69.30; H, 7.68; N, 2.69; found: C, 62.60; H, 6.93; N, 1.96.

Example 985 N-E4-(2-thiazol-S-ylbut-2-oxymethyl)-2-(2-methylphenyl) benzovllmethionine The desired compound was prepared according to the method of Example 157 1 H nmr (300 MHz, DMSO d6): 8 12.57, bs, 1H ; 9.08, s, 1H; 8.09, bd, 1H ; 7.86, d, 1H ; 7.50, d, 1H ; 7.33, dd, 1H; 7.20, m, 2H; 7.07-7.17, m, 3H; 4.78, t, 1H; 4.45, q (AA'), 2H; 4.23, ddd, 1H; 2.00-2.24, m, 4H; 1.97, s, 3H; 1.62-1.95, m, 4H; 1.24, m, 4H; 0.82, t, 1.5H; 0.81, t, 1.5H.

MS (ESI (-)): 525 (M-H); (ESI (+)): 527. Calc'd for C28H34N204S2: C 63.85, H 6.51, N 5.32: Found: C 63.62, H 6.54, N 5.16.

Example 987 N- [4 l-benzylpyrrolidin-3-oxymethyl)-2- (2-methylphenyl) benzo, ] methionine The desired compound was prepared according to the method of Example 157 1H nmr (300 MHz, DMSO d6): 8 8.05, m, 2H; 7.49, d, 1H ; 7.38, m, 1H ; 7.03-7.26, m, 8H; 6.99, m, 2H; 4.50, m, 2H; 4.07-4.31, m, 4H; 3.20-3.75, m. 2H; 2.53-2.96, m, 2H; 1.62-2.24, m, 12H.

MS (ESI (-)): 531 (M-H); (ESI (+)): 533. Calc'd for C3lH36N204S + 1.40 H20: C 68.72, H 7.01, N 5.02: Found: C 66.73, H 6.28, N 4.59.

Example 994 N-[4-(1-t-butylthio-3-phenylprop-2-oxymethyl)-2-(2-methylphe nyl)benzoyl]methionine The desired compound was prepared according to the method of Example 157 IH (300MHz, DMSO-d6,8) 7.43 (1H, d, J=8Hz), 7.24 (1H, d, J=3Hz), 7.22-7.10 (9H, m), 7.10 (1H, bs), 6.92 (1H, m), 4.63 (1H, d, J=12Hz), 4.52 (1H, d, J=12Hz), 3.75 (1H, m), 3.67 (1H, m), 2.86 (2H, m), 2.64 (2H, m), 2.20-1.95 (4H, m), 1.90 (3H, s), 1.80-1.50 (3H, m), 1.20 (9H, s). m/e (ESI) 578 (MH-) Anal. calc. for C33H40LiNO4S2 1.00 H20 C 65.65, H 7.01, N 2.32 Found C 65.65, H 6.73, N 2.22

Example 1042 <BR> N- [4- (2-hydroxymethylphenoxymethyl)-2- (2-methylphenyl) benzoyllmethionine, lithium salt

Example 1042A 2-hydroxymethyltert-butvldimethylsiloxvbenzene To a solution of methyl salycilate (1. Og) in DMF (15mL) was added imidazole (0.56g) and TBDMS-Cl (1. lg). After 21h, the reaction was diluted with water (150mL) and extracted into hexane (lOOmL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated to give a colorless oil (1.77g). A portion of this product (0.5g) was dissolved in THF (5mL), and 1M LiAlH4 (THF, 1.4mL) was added at -78°C. The reaction was warmed immediately to 0°C. After 15min, the reaction was quenched by addition of 10% sodium potassium tartrate (20mL). After stirring vigorously for 5min, the mixture was extracted with EtOAc/hexane (1: 1,2XSOmL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to afford a colorless oil (250mg).

MS (ESI (-)) m/e (M-H)-237.

Example 1042B

4- (2-tert-butvldimethylsiloxvmethylphenoxvmethvl)-2- (2-methylphenvl) benzoic acid. methvlester 2-Hydroxymethyltert-butyldimethylsiloxybenzene (250mg) was converted to the title compound by the procedure in Example 1308F. The product was purified by silica gel chromatography eluting with 5% EtOAc/hexane to afford a colorless oil (400mg).

MS (ESI (+)) m/e (M+NH4) + 494.

Example 1042C <BR> <BR> <BR> N-14-(2-hvdroxvmethvlphenoxvmethvl)-2-(2-methvlphenvl) benzovllmethionine, methvl ester <BR> <BR> <BR> 4- (2-tert-butyldimethylsiloxymethylphenoxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (400mg) was dissolved in THF (3mL), and 1M TBAF (THF, lmL) was added.

After 15min, the reaction was diluted with EtOAC (50mL), and washed with water. The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated to give a light yellow oil. This material was converted to the title compound by the procedure in examples 608C and D. The product was isolated as a colorless glassy foam (0.336g).

MS (APCI (+) m/e (M+H) + 494, MS (APCI (-) m/e (M-H)-492.

Example 1042D N-[4-(2-hydroxymethylphenoxymethyl)-2-(2-methylphenyl)benzoy l]methionine,lithium salt

N- [4- (2-Hydroxymethylphenoxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester (330mg) was converted into the title compound by the procedure in example 608E. The product was isolated as a white powder (320mg).

IH NMR (300 MHz, DMS O) 5 1.48-1.70 (m, 4H), 1.92 (s, 3H), 1.95-2.15 (m, 3H), 3.58-3.70 (m, 1H), 4.56 (brs, 2H), 4.97-5.06 (m, 1H), 5.19 (brs, 2H), 6.90-7.03 (m, 3H), 7.14-7.25 (m, 6H), 7.39 (brd, J=7 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 1H).

MS (APCI (-)) m/e 478 (M-H); Analysis calc'd for C27H2gLiNO5S3.45H20: C, 59.21; H, 6.42; N, 2.56; found: C, 59.14; H, 5.92; N, 2.51.

Example 1043 N-f4- (2-hydroxvmethvlbenzvloxymethyl)-2- (2-methylphenvl) benzovllmethionine, lithium salt Example 1043A methylester4-(2-hydroxymethylbenzyloxymethyl)-2-(2-methylphe nyl)benzoicacid, The title compound was prepared in 74% yield according to the procedure described in example 1308F.

MS (ESI) 394 (M+NH4) +.

Example 1043B <BR> <BR> N- [4- (2-hydroxymethylbenzyloxymethyn-2- (2-methylphenvlbenzoyl1methionine. methyl ester The title compound was prepared from 4- (2-hydroxymethylbenzyloxymethyl)-2- (2- methylphenyl) benzoic acid methyl ester according to the procedures in examples 608C and D.

MS (APCI (+) m/e (M+H) + 508, MS (APCI (-) m/e (M-H)-506.

Example 1043C N-L (2-hvdroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine,(2-hvdroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine, lithium salt N- [4- (2-Hydroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

IH NMR (300 MHz, DMS O) 8 1.50-1.87 (m, 4H), 1.91 (s, 3H), 1.94-2.19 (m, 3H), 3.60-3.72 (m, 1H), 4.56 (brs, 2H), 4.59 (s, 4H), 5.07-5.14 (m, 1H), 6.91-7.00 (m, 1H), 7.09-7.46 (m, 10H), 7.54 (d, J=8.1 Hz, 1H).

MS (APCI (-)) m/e 492 (M-H); Analysis calc'd for C2gH3oLiNO5S'0.75H20: C, 65.55; H, 6.19; N, 2.73; found: C, 65.56; H, 6.22; N, 2.69.

Example 1044 N- [4- (3-hydroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyllmethionine, lithium salt Example 1044A methylester4-(3-hydroxymethylbenzyloxymethyl)-2-(2-methylphe nyl)benzoicacid, The title compound was prepared according to the procedure described in example 1308F.

MS (ESI) 394 (M+NH4) +.

Example 1044B N-[4-(3-hydroxymethylbenzyloxymethyl)-2-(2-methylphenyl)benz oyl]methionine,methyl ester The title compound was prepared from 4- (3-hydroxymethylbenzyloxymethyl)-2- (2- methylphenyl) benzoic acid methyl ester according to the procedures in examples 608C and D.

MS (APCI (+) m/e (M+H) + 508, MS (APCI (-) m/e (M-H)-506.

Example 1044C <BR> <BR> <BR> N-f4- (3-hvdroxymethylbenzvloxymethyl)-2- (2-methylphenyl) benzovllmethionine, lithium salt N- [4- (3-Hydroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

H NMR (300 MHz, DMS O) 6 1.48-1.87 (m, 4H), 1.93 (s, 3H), 1.95-2.18 (m, 3H), 3.60-3.72 (m, 1H), 4.48 (brs, 2H), 4.52 (s, 2H), 4.59 (s, 2H), 5.20 (brs, 1H), 6.90-7.00 (m, 1H), 7.09-7.26 (m, 5H), 7.29 (s, 4H), 7.40 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 492 (M-H); Analysis calc'd for C2gH3oLiNO5S'1. 05H20: C, 64.87; H, 6.24; N, 2.70; found: C, H, 6.16; N, 2.62.

Example 1045 N- [4- (4-hydroxymethvlbenzyloxymethyl)-2- (2-methylphenyllbenzoyllmethionine, lithium salt Example 1045A methylester4-(4-hydroxymethylbenzyloxymethyl)-2-(2-methylphe nyl)benzoicacid,

The title compound was prepared according to the procedure described in example 1308F.

MS (ESI) 394 (M+NH4) +.

Example 1045B <BR> N-[4-(4-hydroxymethylbenzyloxymethyl)-2-(2-methylphenyl)benz oyl]methionine,methy@ ester The title compound was prepared from 4- (4-hydroxymethylbenzyloxymethyl)-2- (2 methylphenyl) benzoic acid methyl ester according to the procedures in examples 608C anc D.

MS (APCI (+) m/e (M+H) + 508, MS (APCI (-) m/e (M-H)-506.

Example 1045C N-[4-(4-hydroxymethylbenzyloxymethyl)-2-(2-methylphenyl)benz oyl]methionine,lithium salt N- [4- (4-Hydroxymethylbenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

IH NMR (300 MHz, DMS O) 8 1.50-1.87 (m, 4H), 1.92 (s, 3H), 1.95-2.19 (m, 3H), 3.60-3.72 (m, 1H), 4.48 (d, J=6 Hz, 2H), 4.54 (s, 2H), 4.60 (s, 2H), 5.20 (t, J=6.0 Hz, 1H), 6.91-7.00 (m, 1H), 7.09-7.24 (m, 7H), 7.30 (d, J=14.7 Hz, 1H), 7.30 (s, 1H), 7.41 (dd, J=7.8,1.2 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 492 (M-H).

Example 1046 N-f4- (4-hydroxybenzyloxvmethyl)-2- (2-methylphenyl) benzoyllmethionine, lithium salt Example 1046A 4-hydroxymethyltert-butyldimethylsiloxybenzene The title compound was prepared according to the procedure in example 1042A, replacing methyl salycilate with methyl 4-hydroxybenzoate, and was isolated as a colorless oil.

IH NMR (300 MHz, CDC13) 8 0.19 (s, 6H), 0.98 (s, 9H), 4.61 (s, 2H), 6.82 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H).

Example 1046B methyl4-(4-tert-butyldimethylsiloxybenzyloxymethyl)-2-(2-met hylphenyl)benzoicacid, ester The title compound was prepared according to the procedure described in example 1308F, and was isolated as a colorless oil.

MS (APCI (+)) 494 (M+NH4) +.

MS (APCI (-)) m/e 475 (M-H)-.

Example 1046C <BR> <BR> N-f4- (4-hvdroxybenzyloxvmethyl-2-2- (2-methylphenyl) benzoyllmethionine, methyl ester The title compound was prepared from 4- (4-tert- butyldimethylsiloxybenzyloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedures in examples 608C and D.

MS (APCI (+) m/e (M+H) + 494, MS (APCI (-) m/e (M-H)-492.

Example 1046D saltN-[4-(4-hydroxybenzyloxymethyl)-2-(2-methylphenyl)benzoy l]methionine,lithium N- [4- (4-hydroxybenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

IH NMR (300 MHz, DMS O) 8 1.50-1.76 (m, 4H), 1.91 (s, 3H), 1.95-2.16 (m, 3H), 3.62-3.74 (m, 1H), 4.39 (brd, J=5 Hz, 2H), 5.03-5.09 (m, 1H), 5.17 (s, 2H), 6.93-7.00 (m, 3H), 7.13-7.26 (m, 7H), 7.48 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 478 (M-H); Analysis calc'd for C27H2gLiNOsSvl. 30H2O: C, 63.72; H, 6.06; N, 2.75; found: C, 63.66; H, 5.89; N, 2.57.

Example1049<BR> N- 4- (3-cyclohexyl-l-hydroxyprop-2-yloxymethyl)-2- (2- saltmethylphenyl)benzoyl]methionine,lithium

Example 1049A methyl4-(3-cyclohexyl-1-hydroxyprop-2-yloxymethyl)-2-(2-meth ylphenyl)benzoicacid, ester To a solution of N- [4- (3-cyclohexyl-1- (4-methoxybenzyloxy) prop-2-yloxymethyl)- 2- (2-methylphenyl) benzoic acid methyl ester (Example 1051B, 360mg) in dichloromethane (2mL) was added water (5 drops), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (190mg). After 50min, the reaction was diluted with EtOAc/hexane (1: 1, 10mL), dried (MgS04), and filtered through a pad of silica gel. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluting with 20%-30% EtOAc/hexane to give the title compound (230mg, 90%) as a colorless oil.

MS (DCI/NH3) 414 (M+NH4) +.

Example 1409B <BR> <BR> <BR> N-l 4-(3-cyclohexyl-1-hydroxyprop-2-yloxymethyl)-2-(2-<BR> <BR> <BR> <BR> methvlphenyl ! benzovllmethionine. methyl ester The title compound was prepared from 4- (3-cyclohexyl-1-hydroxyprop-2- yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure described in examples 608C and D, and was isolated as a colorless oil.

MS (APCI (+)) 528 (M+H) + MS (APCI (-)) 526 (M+H)-, 562 (M+Cl)-, 586 (M+CH3COO)-.

Example 1049C N- [4-(3-cyclohexvl-1-hvdroxyprop-2-yloxymethvl)-2-(2- saltmethylphenyl)benzoyl]methionine,lithium The title compound was prepared from N- [4- (3-cyclohexyl-l-hydroxyprop-2- yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to example 608E, and was isolated as a white powder.

H NMR (300 MHz, DMS O) 8 0.70-0.94 (m, 2H), (m, 15H), 1.91 (s, 3H), 1.95-2.19 (m, 3H), 3.36-3.48 (m, 3H), 3.60-3.70 (m, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.52-4.61 (m, 1H), 4.69 (d, J=12.9 Hz, 1H), 6.89-6.98 (m, 1H), 7.08-7.24 (m, 5H), 7.37 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 512 (M-H); Analysis calc'd for C29H38LiNO5S#1.25H2O : C, 64.25; H, 7.53; N, 2.58; found: C, 64.28; H, 7.29; N, 2.50.

Example 1050 <BR> N-f4- (3-cvclohexyl-1- (2-methoxyethoxymethyleneoxv) prop-2-yloxymethvl)-2- (2- saltmethylphenyl)benzoyl]methionine,lithium Example1050A

(S)-3-cyclohexvl-2- (4-methoxybenzyloxv)-l-methoxvethoxvmethyleneoxvpropane To a solution of (S)-3-cyclohexyl-2- (4-methoxybenzyloxy)-l-propanol (Example 1316B, 425mg) in dichloromethane (SmL) at ambient temperature was added diisopropylethylamine (0.533mL), then methoxyethoxymethylchloride (0.21mL). After 6h, additional methoxyethoxymethyl chloride (0.04mL) was added. After a total of 8h, the reaction was concentrated and the residue was purified by silica gel chromatography eluting with 30% EtOAc/hexane to give the title compound as a colorless oil (450mg, 80%).

1H NMR (300 MHz, CDC13) # 0.70-0.95 (m, 2H), 1.08-1.70 (m, 11H), 3.40 (s, 3H), 3.54-3.73 (m, 7H), 3.80 (s, 3H), 4.47 (d, J=11.4 Hz, 1H), 4.62 (d, J=11.4 Hz, 1H), 4.75 (s, 2H), 6.86 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H).

MS (DCI/NH3) m/e 384 (M+NH4) +.

Example1050B<BR> <BR> <BR> <BR> (S)-3-cvclohexyl-l-methoxyethoxymethyleneoxv-2-propanol To a solution of (S)-3-cyclohexyl-2- (4-methoxybenzyloxy)-1- methoxyethoxymethyleneoxy propane (450mg) in methylenechloride (4mL) was added water (0.4mL) and 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (335mg). After 2h, the reaction was diluted with EtOAc/hexane (1: 1,40mL), dried (MgS04), and filtered through a pad of silica gel. The solution was concentrated, and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexane to afford the title compound as a colorless oil (280mg, 92%).

MS (DCI/NH3) 264 (M+NH4) +.

Example1050C 4- ! prop-2-yloxymethyl)-2-(2- methylphenyltbenzoic acid. methyl ester

The title compound was prepared from (S)-3-cyclohexyl-1- methoxyethoxymethyleneoxy-2-propanol according to the procedure in example 1308F.

MS (DCI/NH3) 502 (M+NH4) +. exampleiuDuL) N-[4-(3-cyclohexyl-1-(2-methoxyethoxymethyleneoxy)prop-2-ylo xymethyl)-2-(2- methylphenyl) benzovllmethionine, methyl ester The title compound was prepared from 4- (3-cyclohexyl-1- (2- methoxyethoxymethyleneoxy) prop-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in examples 608C and D.

MS (APCI (+)) 616 (M+H) +.

MS (APCI (-)) 614 (M+H)-.

Example1050E<BR> <BR> <BR> <BR> N- [4- (3-cyclohexyl-l-C2-methoxyethoxymethyleneoxy) prop-2-yloxymethyl)-2- (2- methvlphenyl ! benzoyljmethionine. lithium salt The title compound was prepared from N- [4- (3-cyclohexyl-l- (2- methoxyethoxymethyleneoxy) prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 608E, and was isolated as a white powder.

IH NMR (300 MHz, DMS O) 5 0.72-1.87 (m, 17H), 1.91 (s, 3H), 1.98-2.16 (m, 3H), 3.21 (s, 3H), 3.39-3.43 (m, 2H), 3.49-3.57 (m, 4H), 3.58-3.73 (m, 2H), 4.53 (d, J=12.6 Hz, 1H), 4.61 (s, 2H), 4.68 (d, J=12.6 Hz, 1H), 6.90-6.98 (m, 1H), 7.08-7.24 (m, 5H), 7.35 (brd, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 600 (M-H); Analysis calc'd for C33H46LiNO7S'0.8H20: C, H, N, 2. 25; found: C, 63.72; H, 7.66; N, 2.08.

Example 1051 N-[4-(3-cyclohexyl-1-(4-methoxybenzyloxy)prop-2-yloxymethyl) -2-(2- methylphenyl) benzoyllmethionine. lithium salt Example1051 A 3-cyclohexyl-1- (4-methoxybenzyloxy)-2-propanol The title compound was prepared according to example 1308D, replacing n-butanol with 4-methoxybenzyl alcohol.

MS (CI/NH3) 296 (M+NH4) +.

Example1051B

N-f4- (3-cvclohexyl-4-methoxybenzyloxv) prop-2-vloxymethvl)-2- (2- methvlphenyl) benzoic acid, methyl ester The title compound was prepared from 3-cyclohexyl-1-(4-methoxybenzyloxy)-2- propanol according to example 1308F.

MS (CI/NH3) 534 (M+NH3) +.

Example1051 C<BR> <BR> <BR> <BR> N- [4- (3-cyclohexyl- 1- (4-methoxybenzyloxy) prol2-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, methyl ester The title compound was prepared from N-[4-(3-cyclohexyl-1-(4- methoxybenzyloxy) prop-2-yloxymethyl)-2-(2-methylphenyl) benzoic acid methyl ester according to the procedures in examples 608C and D.

MS (APCI (+)) 648 (M+H) +.

MS (APCI (-)) 646 (M-H)-.

Example1051D N-[4-(3-cyclohexyl-1-(4-methoxybenzyloxy)prop-2-yloxymethyl) -2-(2- methylphenyl) benzoyllmethionine, lithium salt The title compound was prepared from N- [4- (3-cyclohexyl-1- (4- methoxybenzyloxy) prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 608E, and was isolated as a white powder.

H NMR (300 MHz, DMS O) 5 0.70-0.93 (m, 2H), 1.02-1.87 (m, 15H), 1.91 (s, 3H), 1.95-2.18 (m, 3H), (m, 2H), 3.57-3.70 (m, 2H), 3.72 (s, 3H), 4.39 (ABq, Au) AB=24Hz, JAB=11. 7 Hz, 2H), 4.53 (d, J=12.6 Hz, 1H), 4.67 (d, J=12.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.92-6.99 (m, 1H), 7.07-7.20 (m, SH), 7.21 (d, J=8.4 Hz, 2H), 7.34 (dd, 9 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H).

MS (APCI (-)) m/e 632 (M-H); Analysis calc'd for C37H46LiN06SO. 5H20: C, 68.50; H, 7.30; N, 2.16; found: C, 68.50; H, N, 2.09.

Example 1052 <BR> N- [4- (3-cyclohexyl-N-piperidin-1-ylpropion-2-yloxymethy)-2- (2- methylphenyl) benzoyllmethionine, lithium salt Example 1052A (S)-3-cyclohexyl-2-hydroxy-N-piperidin-1-ylpropionamide To a solution of (S)-3-cyclohexyllactic acid (Example 1308A, 260mg) in DMF (8mL) was added piperidine (0.326mL), 1-hydroxybenzotriazole (222mg), and l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (344mg). After stirring at ambient temperature for 6h, the reaction was poured into EtOAc (lOOmL), washed with water (2XSOmL), and brine (lOmL). The organic solution was dried (MgSO4), filtered and concentrated to afford a light yellow oil which was purified by silica gel chromatography eluting with 40% EtOAc/hexane to give a white solid (399mg, 94%).

H NMR (300 MHz, CDC13) 8 0.80-1. 03 (m, 2H), (m, 5H), (m, 12H), 1.91-2.00 (m, 1H), 3.30 (m, 2H), 3.51-3. 68 (m, 2H), 3.79 (brd, J=6 Hz, 1H), 4.41 (m, 1H).

MS (DCI/NH3) m/e 240 (M+H) +.

Example 1052B 4-(3-cyclohexyl-N-piperidin-1-ylpropion-2-yloxymethyl)-2-(2- methylphenyl)benzoicacid, methyl ester The title compound was prepared from (S)-3-cyclohexyl-2-hydroxy-N-piperidin-l- ylpropionamide according to the procedure in example 1308F as a colorless oil.

MS (APCI (+)) 478 (M+H) +.

Example 1052C N-r4-(3-cvclohexyl-N-piperidin-1-ylpropion-2-yloxvmethvl)-2- (2- methylphenyl) benzoyllmethionine, methyl ester The title compound was prepared from 4- (3-cyclohexyl-N-piperidin-l-ylpropion-2- yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in example 608C and D as a colorless oil.

MS (APCI (+)) 609 (M+H) +.

MS (APCI (-)) 607 (M-H)-.

Example 1052D N-[4-(3-cyclohexyl-N-piperidin-1-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, lithium salt The title compound was prepared from N- [4- (3-cyclohexyl-N-piperidin-l- ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 608E as a white powder.

1H NMR (300 MHz, DMS O) 8 0.64-0.93 (m, 2H), 1.02-1.14 (m, 3H), 1.32-1.70 (m, 14H), 1.73-2.18 (m, 7H), 1.91 (s, 3H), 3.37-3.50 (m, 4H), 3.62-3.74 (m, 1H), 4.32 (dd, J=9,2.4 Hz, 1H), 4.37 (d, J=1-2.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 6.92-6.99 (m, 1H), 7.09-7.24 (m, 5H), 7.35 (dd, J=7.8,1 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H).

MS (APCI (-)) m/e 593 (M-H); Analysis calc'd for C34H45LiN205S'1.60H20: C, 64.87; H, 7.72; N, 4.45; found: C, 64.87; H, 7.61; N, 4.46.

Example 1053 <BR> N- [4- (3-cyclohexvl-N-morpholin-4-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, lithium salt

Example 1053A (S)-3-cyclohexyl-2-hydroxy-N-morpholin-1-ylpropionamide The title compound was prepared as a colorless oil according to example 1052A, substituting morpholine for piperidine.

MS (DCI/NH3) 242 (M+H) +.

Example1053B 4-(3-cyclohexyl-N-morpholin-4-ylpropion-2-yloxymethyl)-2-(2- methylphenyl)benzoic acid. methyl ester The title compound was prepared from (S)-3-cyclohexyl-2-hydroxy-N-morpholin- 1-ylpropionamide as a colorless oil according to the procedure in example 1308F.

MS (APCI (+)) 480 (M+H) +.

Example 1053C <BR> N-f4- (3-cyclohexvl-N-morpholin-4-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, methyl ester

The title compound was prepared from 4- (3-cyclohexyl-N-morpholin-4-ylpropion- 2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in examples 608C, and D.

MS (APCI (+)) 611 (M+H) +.

MS (APCI (-)) 609 (M-H)-.

Example 1053D N- [4- (3-cyclohexyl-N-morpholin-4-ylpropion-2-yloxymethyl)-2- (2- methvlphenyl) benzoyllmethionine lithium salt N- [4- (3-Cyclohexyl-N-morpholin-4-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyl] methionine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder.

IH NMR (300 MHz, DMS O) 8 0.75-0.97 (m, 2H), (m, 3H), 1.33-1.46 (m, 2H), (m, 6H), 1.75-2.20 (m, 7H), 1.91 (s, 3H), 3.41-3.49 (m, 2H), 3.50-3.58 (m, 6H), 3.62-3.73 (m, 1H), 4.33 (dd, J=8.9,3 Hz, 1H), 4.39 (d, J=12.6 Hz, 1H), 4.57 (d, J=12.3 Hz, 1H), 6.92-7.02 (m, 1H), 7.08-7.24 (m, SH), 7.36 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H).

MS (APCI (-)) m/e 595 (M-H); Analysis calc'd for C33H43N206SLi'1. 85H20: C, 62.32; H, 7.40; N, 4.40; found: C, H, 7.29; N, 4.43.

Example 1054 <BR> N- [4- (3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, lithium salt

Example 1054A (S)-3-cyclohexyl-2-hydroxy-N-thiomorpholin-1-yipropionamide The title compound was prepared as a colorless oil according to example 1052A, substituting thiomorpholine for piperidine.

MS (DCI/NH3) 258 (M+H) +.

Example 1054B <BR> <BR> 4- (3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid,methyl ester The title compound was prepared from (S)-3-cyclohexyl-2-hydroxy-N- thiomorpholin-1-ylpropionamide as a colorless oil according to the procedure in example 1308F.

MS (APCI (+)) 496 (M+H) +.

Example 1054C N-[4-(3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl )-2-(2- estermethylphenyl)benzoyl]methionine,methyl The title compound was prepared from 4- (3-cyclohexyl-N-thiomorpholin-4- ylpropion-2-yloxymethyl)-2- (2-methylphenyl)(2-methylphenyl) benzoic acid methyl ester according to the procedure in examples 608C, and D.

MS (APCI (+)) 627 (M+H) +.

MS (APCI (-)) 625 (M-H)-.

Example 1054D N-f4- (3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyn-2- (2- methylphenyl) benzoyl_lmethionine, lithium salt N- [4- (3-Cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl)-2- (2- methylphenyl) benzoyl] methionine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMS O) 8 0.76-0.98 (m, 2H), 1.03-1.19 (m, 2H), 1.32-1.74 (m, 9H), 1.75-2.18 (m, 7H), 1.92 (s, 3H), 2.52-2.59 (m, 4H), 3.60-3.82 (m, 5H), 4.32 (dd, J=9.1,3.8 Hz, 1H), 4.39 (d, J=12.3 Hz, 1H), 4.57 (d, J=12.3 Hz, 1H), 6.92-6.98 (m, 1H), 7.08-7.23 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H).

MS (APCI (-)) m/e 611 (M-H);

Analysis calc'd for C33H43N3O5S2Li#2.05H2O : C, 60.45; H, 7.24; N, 4.27 ; found: C, 60.48; H, 7.16; N, 4.22.

Example 1055 <BR> N- [4- (3-cyclohexyl-N-thiomorpholin-S-oxide-4-ylpropion-2-yloxymI) -2- (2- methvlphenyl) benzoyllmethionine. lithium salt

Example 1055A 4- 3-cyclohexyl-N-thiomorpholin-S-oxide-4-ylpropion-2-yloxymeth yl)-2- (2- methylphenyl) benzoic acid, methyl ester To a solution of 4- (3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (example 1054B, 250mg) in dichloromethane (2.5mL) at 0°C was added m-chloroperbenzoic acid (174mg, 55% pure). After 1.5h at 0°C, the reaction was quenched by the addition of dilute aqueous sodium sulfite. The reaction was diluted with ether (50mL), and washed with 1M NaOH (2X5mL), and brine (2X5mL).

The organic solution was dried (MgS04), filtered and concentrated to afford a light yellow oil which was purified by silica gel chromatography eluting with 2.5%-5.0% MeOH/EtOAc to give a colorless oil (240mg, 94%).

MS (APCI (+)) 512 M+H) +.

Example 1055B N-f4- (3-cyclohexyl-N-thiomorpholin-S-oxide-4-ylpropion-2-yloxymet hyl)-2- (2- methylphenyl) benzoyllmethionine. methyl ester The title compound was prepared from 4- (3-cyclohexyl-N-thiomorpholin-S-oxide- 4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in examples 608C, and D.

MS (APCI (+)) 643 (M+H) +.

MS (APCI (-)) 641 (M-H)-.

Example1055C N-4- (3-cyclohexyl-N-thiomorpholin-S-oxide-4-ylpropion-2-yloxymet hyl)-2- (2- methylphenyl) benzoylmethionine, lithium salt N- [4- (3-Cyclohexyl-N-thiomorpholin-S-oxide-4-ylpropion-2-yloxymet hyl)-2- (2- methylphenyl) benzoyl] methionine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder. lH NMR (300 MHz, DMS O) 8 0.76-0.97 (m, 2H), 1.04-1.18 (m, 3H), 1.34-1.74 (m, 8H), 1.75-2.18 (m, 7H), 1.92 (s, 3H), 2.68-2.90 (m, 4H), 3.40-3.70 (m, 2H), 3.77-4.06 (m, 2H), 4.16-4.27 (m, 1H), 4.32-4.41 (m, 2H), 4.54-4.67 (m, 1H), 6.97 (brs, 1H), 7.11-7.26 (m, 5H), 7.39 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H).

MS (ESI (-)) m/e 627 (M-H);

Analysis calc'd for C33H43N206S2Li'2.1OH20: C58.93,58.90; H, 7.07; N, 4.16; found: C58.93,; H, 7.01; N, 4.01.

Example 1084 N- [4- (2- (4-chlorobenzyloxy) ethoxymethyl')-2- (2-methylphenyl) benzoyl1methionine lithium salt Example 1084A To a stirred solution of p-chlorobenzaldehyde (7.0 g, 50 mmol) in toluene (100 mL) was added ethylene glycol (3.1 mL, 55 mmol) and p-toluenesulfonic acid (0.1 g). The solution was refluxed overnight and the water collected in a Dean-Stark trap. The reaction was cooled and concentrated in vacuo. The residue was taken up in EtOAc (150 mL) and washed with water (3 x 50 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (hexane EtOAc 19: 1) to give 8.1 g (89 %) of a colorless liquid; MS m/z 185 (M+ + 1,100).

Example 1084B To a stirred suspension of zirconium (IV) chloride (5.1 g, 22 mmol) in ether (100 mL) was added a 1 M solution of LAH in ether (10.9 mL, 10.9 mmol) and the resulting black mixture stirred for 30 min. A solution of the acetal (2.0 g, 11 mmol) in ether (20 mL) was then added and the mixture refluxed overnight. The reaction was cooled and a solution

of 10% aqueous K2CO3 (50 mL) was added carefully over 20 min and stirred for 45 min.

The reaction was filtered thru Celite and the bed was washed well with ether. The ether layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 7: 3) to get 0.17 g (8%) of a colorless liquid; MS m/z 204 (M+ + 18,100).

Example 1084C To an ice-cooled suspension of sodium hydride (0.032 g, 1.4 mmol) in DMF (3 mL) was added 15-crown-5 (0.2 mL, 1 mmol) and the core benzyl bromide (see example 1178D) (0.34 g, 1.1 mmol) and the resulting mixture stirred for 30 min. The reaction was quenched with H20 (2 mL) and taken up in EtOAc (30 mL). The organic layer was washed with H20 (5 x 10 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 9: 1) to give 0.124 g (33%) of a colorless oil; MS m/z 442 (M+ + 18,100).

Example 1084D N- [4- (2- (4-chlorobenzyloxy) ethoxymethyl)-2- (2-methylphenyl) benzoyllmethionine, methyl ester To a solution of the ester (0.115 g, 0.271 mmol) in MeOH (5 mL) was added a saturated solution of LiOH in H20 (1 mL) and the resulting solution heated to 60 °C overnight. The reaction was concentrated in vacuo and the residue taken up in 1: 1 EtOAc/H20 (30 mL) and acidified to pH = 3 with 1N HCI. The layers were separated and the organic washed with

H20 (2 x 10 mL), dried (MgS04) and concentrated in vacuo to give 0.105 g (95%) of a colorless oil which was used as is in the following coupling.

To a stirred solution of the acid (0.105 g, 0.255 mmol) in DMF (3 mL) was added L-methionine methyl ester hdrochloride (0.066 g, 0.33 mmol), 1-hydroxybenzotriazole hydrate (0.045 g, 0.33 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g, 0.33 mmol) and triethylamine to pH = 7 and the resulting mixture stirred overnight at rt. The reaction was poured into EtOAc (20 mL) and washed with H20 (5 x 20 mL) and saturated aqueous NaHC03 (2 x 20 mL). The organic layer was dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 3: 1) to give 0.129 g (91 %) of a colorless oil; MS m/z 556 (M+ + 1,100).

Example 1084E N- [4- (2- (4-chlorobenzyloxy) ethoxymethyl)-2- (2-methylphenyl) benzo, ] methionine lithium salt To a stirred solution of the ester (0.124 g, 0.223 mmol) in THF (5 mL) was added a solution of LiOH-H20 (0.0103 g, 0.245 mmol) in H20 (1 mL) and the resulting solution stirred for 3h at rt. The reaction was concentrated in vacuo and lyopholized to give 0.122 g (100%) of a white powder: I H NMR (DMS O-d6,) 8 7.53 (d, 1 H, J = 7.8 Hz), 7.38-7.29 (m, 5 H), 7.22-7.12 (m, 5 H), 6.97-6.93 (m, 1 H), 4.57 (s, 2 H), 4.48 (s, 2 H), 3.73-3.60 (m, 5 H), 2.17-1.79 (m, 8 H), 1.68-1.63 (m, 1 H), 1.59-1.53 (m, 1 H); MS m/z 540 (M+-1,100).

Example1090<BR> <BR> <BR> [4- (2- (5-cyclohexylfuranyl) methoxymethyl)-2- (2-methylphenyl)- benzoyl] methionine, lithium salt

Example 1090A To a stirred solution of dichloroethane (70 mL) cooled-20 °C was added aluminum chloride (23 g, 0.17 mol) and cyclohexane carbonyl chloride (25 g, 0.17 mol) and the resulting mixture stirred for 10 min. Allyl chloride (15 mL, 0.18 mol) was added over 15 min, keeping the temperature between-15 to-25 °C, and the resulting mixture stirred lh at -20 °C. The reaction was quenched with IN Hcl (200 mL) very carefully. The layers were separated and the aqueous extracted with ether (2 x 50 mL). The combined organic layers were washed with H20 (200 mL), 5% aqueous NaHC03 (150 mL), dried (MgS04) and the solvent removed by distillation up to 85 °C. The residue was put under vacuum (30 mmHg) and heated to 70 °C for-30 min. The residue was purified by flash chromatography (hexane) and the solvent removed by distillation to give 5 g (20%) of a colorless liquid; I H NMR (CDC13) 8 7.29-7.28 (m, 1 H), 6.28-6.26 (m, 1 H), 5.95-5.93 (m, 1 H), 2.65- 2.57 (m, 1 H), 2.06-1.96 (m, 2 H), 1.82-1.66 (m, 3 H), 1.43-1.19 (m, 5 H).

Example 1090B To a stirred solution of the cyclohexyl furan (0.75 g, 5.0 mmol) in DMF (1.6 mL, 20 mmol) was added phosphorus oxychloride (1.9 mL, 20 mmol) and the mixture heated to 90 °C for 2.5h. The reaction was cooled, poured onto ice, and brought to pH = 8 with 6N NaOH. The solution was extracted with ether (2 x 50 mL) and the combines ether layers were washed with H20 (25 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 20: 1 then 10: 1) to give 0.48 g (54 %) of a yellow liquid; I H NMR (CDC13) 8 9.52 (s, 1 H), 7.17 (d, 1 H, J = 3.5 Hz), 6.20 (dd, 1 H, J = 3.5,0.7 Hz), 2.79-2.68 (m, 1 H), 2.12-2.05 (m, 2 H), 1.86-1.69 (m, 3 H), 1.53-1.21 (m, 5 H).

Example1090C To a stirred solution of the aldehyde (0.48 g, 2.7 mmol) in MeOH (10 mL) at 0 °C was added sodium borohydride (0.20 g, 5.3 mmol) portionwise and the resulting solution stirredfor lh. The reaction was quenched with IN HC1 (10 mL) and concentrated in vacuo.

The residue was taken up in EtOAC (25 mL) and washed with H20 (15 mL), dried (MgS04) and concentrated in vacuo. the residue was purified by flash chromatography (hexane/EtOAc 6: 1) to give 0.30 g (63%) of a colorless liquid; MS m/z 181 (M+ + 1,100).

Example 1090D The alcohol (0.30 g, 1.7 mmol) was coupled to the core benzyl bromide (see example 1178 D) by procedure 1084 C. Flash chromatography (hexane/EtOAc 20: 1) gave 0.48 g (68 %) of a colorless oil; MS m/z 436 (M+ + 18,100).

Example 1090E The ester (0.47 g, 1.1 mmol) was hydrolyzed as in example 1084 D and coupled to L-methionine methyl ester hydrochloride as in example 1084 D. Flash chromatography (hexane/EtOAc 3: 1) gave 0.37 g (60 %) of an yellow oil; MS m/z 550 (M+ + 1,100).

Example 1090F The ester (0.37 g, 0.67 mmol) was hydrolyzed as in example 1084 E to give 0.37 g of a white powder; IH NMR (DMS O-d6,) 8 7.52 (d, 1 H, J = 7.8 Hz), 7.35 (d, 1 H, J = 7.8 Hz), 7.21-7.07 (m, 5 H), 7.00-6.92 (m, 1 H), 6.31 (d, 1 H, J = 3.1 Hz), 5 99 (d, 1 H, J = 3.1 Hz), 4.54 (s, 2 H), 4.41 (s, 2 H), 3.72-3.66 (m, 1 H), 2.17-1.14 (m, 21 H); MS m/z 534 (M+-1,100).

Example 1091 N-[4-(1-furan-2-yl-3-cyclohexylpropoxymethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt Example 1091 A

To a stirred suspension of magnesium (0.55 g, 23 mmol) in ether (20 mL) was added cyclohexylethyl bromide (3.6g, 19 mmol) and a crystal of iodine and the reaction was stirred 90 min. In another flask a stirred solution of 2-furanaldehyde (1.5 g, 16 mmol) in 1: 1 THF/ether (20 mL) was cooled in an ice/MeOH bath. The Grignard solution was added to the aldehyde and stirred for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) and the reaction concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with H20 (2 x 15 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 6: 1) to give 1.5 g (45 %) of a yellow oil; MSm/z208 (M++ 1,100).

Example 1091B The alcohol (0.50 g, 2.4 mmol) was coupled to the core benzyl bromide (see example 1178 D) by procedure 1084 C. Flash chromatography (hexane/EtOAc 20: 1) gave 0.60 g (60 %) of a colorless oil; MS m/z 446 (M+ + 1,100).

Example1091C N- [4- ( 1-furan-2-vl-3-cyclohexylpropoxymethvl)-2- (2-methylphenvl) benzoYllmethionine methyl ester The ester (0.59 g, 1.3 mmol) was hydrolyzed as in example 1084 D and coupled to L-methionine methyl ester hydrochloride as in example 1084 D. Flash chromatography (hexane/EtOAc 6: 1) gave 0.51 g (67 %) of a colorless oil; MS m/z 565 (M+ + l, 100).

Example1091D<BR> <BR> <BR> <BR> N- [4- (l-furan-2-yl-3-cyclohexylpropoxymethyl)-2- (2-methvlphenyl) benzoyl] methionine lithium salt The ester (0.51 g, 0.90 mmol) was hydrolyzed as in example 1084 E to give 0.50 g of a light pink powder; 1H NMR (DMS O-d6,) 8 7.62 (s, 1 H), 7.50 (d, 1 H, J = 7.8 Hz), 7.32-7.30 (m, 1 H), 7.21-6.91 (m, 6 H), 6.42-6.39 (m, 2 H), 4.48-4.34 (m, 3 H), 3.72-3.65 (m, 1 H), 2.18- 1.52 (m, 17 H), 1.27-1.02 (m, 6 H), 0.85-0.75 (m, 2 H); MS m/z 562 (M+-1,100).

Example 1092

N-F4-(1-(5-(4-chlorophenvl) furan-2-v1)-2-cvclohexylethOxvmethvl)-2-(2- methylphenyl) benzoyllmethionine lithium salt Example 1092A To a stirred suspension of LAH (0.78 g, 21 mmol) in THF (10 mL) was added a solution of 5- (4-chlorophenyl)-2-furoic acid (3.8 g, 17 mmol) in THF (30 mL) at a rate to maintain a gentle reflux. The reaction was stirred for 2h at rt and heated to 50 °C for 30 min. The reaction was cooled in an ice bath and quenched with H20 (0.8 mL), 15 % NaOH (0.8 mL), and H20 (2.1 mL). The reaction was filtered and concentrated in vacuo.

The residue was taken up in EtOAc (50 mL) and washed with H20 (25 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2) to give 1.3 g (36 %) of a yellow oil; MS m/z 208 (M+ + 1,100).

Example 1092B To a stirred solution of the alcohol (1.3 g, 6.2 mmol) in 9: 1 CH2C12/CH3CN (20 mL) was added powdered sieves (6 g), N-methylmorpholine N-oxide (1.1 g, 9.3 mmol), and tetrapropylammonium perruthenate (0.11 g, 0.31 mmol) and stirred for 2h at rt. The reaction was filtered through a silica gel bed, eluting with EtOAc (25 mL). The filtrate was concentrated in vacuo to give 1.0 g (78 %) of a pink powder; MS m/z 206 (M+ + 1,100).

Example 1092C A Grignard reaction was run on the aldehyde (1.0 g, 4.9 mmol) as in example 1091 A using cyclohexylmethyl bromide. Flash chromatography (hexane/EtOAc 9: 1) gave 0.73 g (48%) of an orange oil; MS m/z 304 (M+ + 1,100).

Example 1092D The alcohol (0.79 g, 2.6 mmol) was coupled to the core benzyl bromide (see example 1178 D) by procedure 1084 C. Flash chromatography (hexane/EtOAc 20: 1) gave 0.50 g (36 %) of a colorless oil; MS m/z 543 (M+ + 1,100).

Example 1092E <BR> N-f4- (1- (5- (4-chlorophenyl) furan-2-yl)-2-cvclohexylethoxymethyl)-2- (2-<BR> <BR> methylphenyl) benzoyllmethionine, methyl este The ester (0.50 g, 0.92 mmol) was hydrolyzed as in example 1084 D and coupled to L-methionine methyl ester hydrochloride as in example 1084 D. Flash chromatography (hexane/EtOAc 3: 1) gave 0.37 g (59 %) of colorless oil; MS m/z 674 (M+ + 1,100).

Example 1092F N- [4- (l- (5- (4-chlorophenvl) furan-2-yl)-2-cyclohexylethoxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The ester (0.35 g, 0.52 mmol) was hydrolyzed as in example 1084 E to give 0.35 g of a white powder; I H NMR (DMS O-d6,) 8 7.68 (dd, 2 H, J = 8.8,3.3 Hz), 7.50 (d, 1 H, J = 7.8 Hz), 7.46 (dd, 2 H, J = 8.8,2.6 Hz), 7.33 (d, 1 H, J = 8.1 Hz), 7.21-7.09 (m, 5 H), 6.97-6.87 (m, 2 H), 6.56 (dd, 1 H, J = 3.3,0.73 Hz), 4.56-4.42 (m, 3 H), 3.74-3.66 (m, 1 H), 2.17- 0.83 (m, 23 H); MS m/z 658 (M+-1,100).

Example 1093 N-[4-(1-oxazol-5-yl-3-cyclohexylpropoxymethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt

Example 1093A To a stirrred solution of toluenesulfonyl chloride (500 g, 2.6 mol) in quinoline (900 g) at 75 °C was added slowly N-methylformamide (100 g, 1.69 mol). The product distills from the reaction and is collected in a dry ice/acetone cooled receiving flask. Heating was discontinued and the addition was added at a rate to maintain a pot temperature of 75-80 °C.

After the addition was complete the reaction was stirred until distillation ceased. The distillate contained 48 g (69 %) of a colorless liquid which was used as is in the next step.

To a stirred solution of methyl isocyanate (48 g, 1.17 mol) in THF (800 mL) in a dry ice/EtOH bath was added a 1.6M BuLi solution (730 mL) over 90 min, and the reaction was stirred an additional 20 min. A solution of ethyl diethoxyacetate (206 g, 1.17 mol) in THF (200 mL) was then added over 1 h. The reaction was allowd to warm to-10 °C over 90 min. Cool in an ice bath and quench with glacial AcOH (75 mL) and stir overnight. The reaction was concentrated in vacuo, taken up in EtOAc (300 mL) and washed with H20 (2 x 100 mL), dried (MgS04) and concentrated in vacuo. Flash chromatography (hexane/EtOAc 4: 1) gave 94 g (47 %) of a golen liquid which was used as is in the next step.

To a flask containing the acetal (1 lg, 64 mmol) in an ice bath was added a 1: 1 mixture of TFA/CH2Cl2 (70 mL) followed by H20 (4 mL) and the solution stirred for 2h.

The reaction was concentrated in vacuo. Flash chromatography (hexane/EtOAc 7: 3) gave 7.1 g of a brown liquid which was used as is in the next step.

A Grignard reaction was run on the aldehyde (0.59 g, 6.1 mmol) as in example I using cyclohexylethyl bromide. Flash chromatography (CH2Cl2/EtOAc 9: 1) gave 0.15 g (13 %) of a yellow powder; MS m/z 209 (M+ + 1,100).

Example1093B The alcohol (0.15 g, 0.75 mmol) was coupled to the core benzyl bromide (see example 1178 D) by procedure 1084 C. Flash chromatography (hexane/EtOAc 6: 1) gave 0.20 g (61 %) of a colorless oil; MS m/z 448 (M+ + l, 100).

Example 1093C N-[4-(1-oxazol-5-yl-3-cyclohexylpropoxymethyl)-2-(2-methylph enyl)benzoyl]methionine, methyl ester The ester (0.19 g, 0.44 mmol) was hydrolyzed as in example 1084 D and coupled to L-methionine methyl ester hydrochloride as in example 1084 D. Flash chromatography (hexane/EtOAc 3: 2) gave 0.20 g (84 %) of colorless oil; MS m/z 579 (M+ + l, 100).

Example 1093D <BR> <BR> N-44- (1-oxazol-5-yl-3-cyclohexylpropoxymethyl)-2- (2-methylphenyl) benzovllmethionine lithium salt The ester (0.18 g, 0.31 mmol) was hydrolyzed as in example 1084 E to give 0.18 g of a white powder; I H NMR (DMS O-d6,) 5 8.34 (d, 1 H, J = 1.1 Hz), 7.52 (d, 1 H, J = 8.1 Hz), 7.33 (dd, 1 H, J = Hz), 7.22-6.95 (m, 7 H), 4.53-4.40 (m, 3 H), 3.74-3.63 (m, 1 H), 2.18- 1.52 (m, 17 H), 1.29-1.02 (m,'6 H), 0.88-0.75 (m, 2 H); MS m/z 563 (M+-1,100).

Example 1095 N-[4-(1-(4-methylthiazol-5-yl)pentyloxy)methyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt Step 1: 2-amino-4-methyl-thiazole ethyl ester A 50 mL round-bottom flask was charged with ethylthioacetate (6.4 mL, 50 mmol) and water (25 mL). Bromine (2.8 mL, 51 mmol) was added over 30 min. An orange

solution was formed. The reaction was added to Et20 (100 mL). The organic layer was dried over MgS04 and solvent removed under vacuum. The orange gel was added to a refluxing solution of thiourea (8.95 g, 117.5 mL) in ethanol (25 mL). The reaction was refluxed for about 2 h, then cooled slightly and poured into 50 mL of ice water. The pH was adjusted to 7-9 with NH3 (aq.). A thick white precipitate formed. The mixture was filtered to collect the solid. The product was recrystalized from 95% EtOH. Yield: 7.3 g (78%), white fluffy crystalline solid.

I H NMR (5, CDCI3): 5.4 (2H), 4.25 (3H), 2.55 (3H), 1.35 (2H). Mass spec (DCI): 187 (M+1).<BR> <BR> <P> Step 2: 4-methvlthiazole ethyl ester A 50 mL round-bottom flask was charged with 4 N H2SO4 (80 mL) and 2-amino-4- methyl-thiazole ethyl ester (2.23 g, 12 mmol). The reaction was cooled to-5°C. Sodium nitrite (0.99 g, 14.4 mmol) in 5 mL H20, was added over 5 min. The reaction was stirred for about 30 min. 50% (by wt) H3PO2 (15.84 mL, 120 mmol) was slowly added. A thick orange foam formed. The reaction was allowed to stir about 3 h until the foam had subsided. 50 mL of water was added. The pH was adjusted to 4-5 with potassium hydrogen phosphate tribasic. The reaction was extracted with Et20 (3 x 50 mL), dried over Na2S04 and concentrated under vacuum. Purified by silica gel column (3: 1 Hexane/EtOAc). Yield: 1.50 g (67%), orange oil.

IH NMR (8, CDCl3) : 8.8 (1H), 4.35 (3H), 2.8 (3H), 1.4 (2H). <BR> <BR> <P> N-f4- (l- (4-methylthiazo !-5-yl) pentyloxy) methyl')-2- (2-methylphenyl) benzoyl1methionine lithium salt Steps 3-9: Follow Steps 1-7 in example 1098. Yield: 30.6 mg, pale peach solid.

IH NMR (8, DMS O): 8.95 (1H), 6.8-7.6 (7H), 7.2 (1H), 4.4 (2H), 3.7 (1H), 2.32 (3H), 2.3 (3H), 0.7-2.2 (17H) Mass spec (ESI): 541 (M+1), 539 (M-1) C29H3sLiN204S2l4.30 H20 Calc'd.: C 55.81 H 7.04 N 4.49 Found: C 55.82 H 6.16 N 3.86

Example 1096 N-[4-(1-(2,4-dimethylthiazol-5-yl)-2-cyclohexylethoxy)methyl )-2-(2- methylphenvl) benzoyllmethionine lithium salt Procedure: Follow step 1-7 in example 1098 except in step 3 use cyclohexylmagnesium bromide (1 M in Et20) instead of n-butylmagnesium bromide. Yield: 286.7 mg, pale yellow fluffy solid.

IH NMR (8, DMS O): 6.85-7.6 (7H), 4.7 (1H), 4.4 (2H), 3.68 (1H), 2.56 (3H), 2.22 (3H), 2.2 (3 H), 1.9 (3H), 0.7-1.85 & 1.95-2.19 (18H) Mass spec (ESI): 595 (M+1), 593 (M-1) C33H4 LiN204S2@2.00 H20 Calc'd: C 62. 24 H 7. 12 N 4.40 Found : C 62.21 H 6.75 N 4.23 Example 1097 N-[4-(1-(4-methylthiazol-5-yl)-2-cyclohexylethoxy)methyl)-2- (2- methvlphenvl) benzovllmethionine lithium salt Procedure: Follow step 1-7 in example 1095 except use cyclohexylmagnesium bromide (1 M in Et20) instead of n-butylmagnesium bromide. Yield: 122.1 mg, pale yellow fluffy solid.

lH NMR (8, CDC13): 8.7 (1H), 6.8-7.4 (7H), 5.7 (1H), 4.38 (2H), 4.1 (1H), 2.95 (3H), 2.9 (3H), 0.8-2.6 (21H) Mass spec (ESI): 581 (M+l), 579 (M-1) C32H39LiN204S2'3.45 H20 Calc'd.: C 59.23 H 7.13 N 4.32 Found: C 59.19 H 6.98 N 4.38 Example 1098 N-[4-(1-(2,4-dimethylthiazol-5-yl)pentyloxy)methyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt Step 1: 2.4-dimethylthiazole-5-methanol A 3-neck 100 mL round-bottom flask under N2 atmosphere was charged with ethyl- 2,4-dimethylthiazole-5-carboxylate (1.85 g, 10 mmol) in anhydrous CH2C12 (20 mL). The mixture was cooled to-78°C. 22 mL of di-isobutylaluminum hydride (1.0 M in CH2C12) was added dropwise via syringe. The reaction was allowed to warm to room temperature slowly and stirred for 14 h. TLC (1: 1 Hexane/EtOAc) showed no starting material. The reaction was cooled to 0°C. MeOH (2 mL) and then 1 M HCl (10 mL) were slowly added.

The bath was removed and the reaction stirred for 20 min. Extract with Et20 (3 x 10 mL).

Wash the combined organic layers with brine (10 mL). Dry over MgS04, filter and remove solvent under vacuum. Yield: 1.363 g (95%), orange oil.

H NMR (6, CDC13): 2.65 (3H), 2.36 (3H), 2.05 (1H), 1.7 (2H).

Step 2: 2.4-dimethylthiazole-5-carbaldehyde A 3-neck 100 mL round-bottom flask was charged with anhydrous CH2Cl2 (20 mL) and oxalyl chloride (1.0 mL, 11.25 mmol) under N2 atmosphere. The mixture was cooled

to-78°C. Anhydrous DMS O (1.1 mL, 15 mmol) was slowly added. The reaction was allowed to stir for 30 min. 2,4-dimethylthiazole-5-methanol (1.181 g, 7.5 mmol) in CH2Cl2 (5 mL) was slowly added. The reaction was allowed to stir for about 3 h, until TLC (1: 1 EtOAc/Hexane) showed no starting material. The reaction was quenched with triethylamine (4.3 mL, 30 mmol) and stirred for 10 min. before warming to room temperature. The reaction was poured into Et20 (100 mL) and then extracted with water (2 x 25 mL). The organic phase was washed with NaHC03 (aq) (25 mL) and brine (25 mL).

Dry over MgS04 and concentrated under vacuum. The product was stored in the freezer.

Yield: 1.04 g (89%) orange crystalline solid.

IH NMR (o, CDC13): 10.0 (1H), 2.72 (d, 6H).

Step 3: 2.4-dimethylthiazol-5-pentanol A 3-neck 100 mL round-bottom flask was charged with 2,4-dimethylthiazole-5- carbaldehyde (1.164 g, 7.5 mmol) and anhydrous THF (20 mL) under N2 atmosphere.

The reaction was cooled to-10 °C. n-Butylmagnesium chloride (7.5 mL, 2.0 M (in THF)) was added dropwise. The reaction was stirred for 1 h, then warmed to room temperature and stirred for an additional 3 h. The reaction was quenched with 4 mL MeOH/1 M HCl (1: 1). The aqueous and organic layers were separated. The pH of the aqueous layer was adjusted to 3 with 1 M HCI. The aqueous layer was extracted with EtOAc (3 x 10 mL). All organic layers were combined and washed with brine (10 mL), dried over MgS04 and concentrated under vacuum. Purify by silica gel column (1: 1 EtOAc/Hexane). Yield: 1.76 g, orange oil.

H NMR (8, CDC13): 2.65 (3H), 2.35 (3H), 1.2-2.0 (7H), 0.9 (3H). <BR> <BR> <BR> <BR> <BR> <P> Step 4: 4- (1- (2, 4-dimethylthiazol-5-, yllpentyloxy) methyl)-2- (2-methylphenvl) benzoic acid A 50-mL round-bottom flask was charged with 2,4-dimethylthiazol-5-pentanol (523.2 mg, 2.4 mmol), 4-bromomethyl-2- (2-methylphenyl) benzoic acid, methyl ester (639.3 mg, 2 mmol) (as prepared by examples 1178A-1178D) and anhydrous dmf (3 mL).

The reaction was cooled to 0°C. Sodium hydride (60% dispersion in mineral oil) (126.9 mg, 3 mmol) was added. After stirring at 0°C for 15 min., the bath was removed and the reaction was allowed to stir at ambient temperature for 2 h. After the TLC showed no 4- bromomethyl-2- (2-methylphenyl) phenylacetate was present, the reaction was quenched with 6 M H3PO4 buffer (2 mL). Extract with Et20 (3 x 10 mL). The pH of the aqueous layer was adjusted to 3 with 1 M H3PO4 and then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgS04, filtered and concentrated under vacuum. The product was redissolved in EtOH (10

mL) and 4 N NaOH (4 mL, 16 mmol) was added. The reaction was refluxed for 2 h, then allowed to cool. Water (10 mL) was added and the mixture was extracted with Et-) (3 x 10 mL). The pH of the aqueous layer was adjusted to 3 with 1 M H3PO4 and then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum. Yield: 309 mg (35 %), orange solid.

IH NMR (8, CDC13): 7.0-7.4 (7H), 4.35 (d, 1H), 2.65 (3H), 2.25 (3H), 2.1 (3H), 1.2- 2.0 (6 H), 0.85 (3H). <BR> <BR> <BR> <BR> <BR> <BR> <P> Step 5: N- [4-1- (2, 4-dimethylthiazol-5-yl) pentyloxy) methyl-2- (2-<BR> <BR> <BR> <BR> <BR> methvlphenvl) benzovllmethionine A 50 mL round-bottom flasks was charged with 4- (1- (2,4-dimethylthiazol-5- yl) pentyloxy) methyl)-2- (2-methylphenyl) benzoic acid (174.9 mg, 0.4 mmol), 1- (3- dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDAC) (85.7 mg, 0.44 mmol), L-methionine methyl ester hydrochloride (106.6 mg, 0.52 mmol), 1-hydroxybenzotriazole (61.0 mg, 0.44 mmol) and dmf (3 mL). The reagents were stirred until completely dissolved and then triethylamine (0.11 mL, 0.72 mmol) was added. The reaction was stirred about 48 h until no starting material was present. Water (2 mL) and EtOAc (2 mL) were added to dissolve the precipitate. The mixture was extracted with EtOAc (3 x 10 mL).

The combined organic layers were washed with 2 M Na2CO3 (10 mL), water (10 mL) and brine (10 mL), dried over MgS04, filtered and concentrated under vacuum. Yield: 74.7 mg (33 %), yellow oil.

1H NMR (8, CDC13): 7.0-7.4 (7H), 4.55 (2H), 4.33 (1H), 3.75 (3H), 2.95 (3H), 2.65 (3H), 2.0-2.4 (5H), 0.8-2.0 (9H). Mass spec (ESI): 569 (M+1), 567 (M-1).

Step 6: N- [4-1- (2, 4-dimethylthiazol-5-yl) pentyloxy) methyl-2- (2-methylphenyl) benzoyllmethionine carboxylic acid A 25 mL round-bottom flask was charged with N- [4-1- (2,4-dimethylthiazol-5- yl) pentyloxy) methyl-2- (2-methylphenyl) benzoyl] methionine (74.7 mg, 0.13 mmol) and 3 mL of MeOH/THF (1: 1). The flask was cooled to 0°C and 1 M lithium hydroxide (0.260 mL, 0.26 mmol) was added. The bath was removed and the reaction stirred for about 3 h, monitoring by TLC (1: 1 EtOAc/Hexane). The solvent was removed under vacuum and the reaction diluted with water. The mixture was extracted with EtOAc (3 x 10 mL), washed with brine (10 mL), dried over MgS04, filtered and concentrated under vacuum. Yield: 59.1 mg (81%), yellow oil.

IH NMR (8, CDC13): 7.1-7.5 (7H), 4.55 (2H), 4.35 (1H), 2.65 (3H), 2.3 (3H), 1.8-2.2 (5H), 0.8-2.0 (9H). Mass spec (ESI): 555 (M+1), 553 (M-1).

Step 7: 7: N-[4-1-(2,4-dimethylthiazol-5-yl)pentyloxy)methyl-2-(2- methylphenyl) benzoyllmethionine lithium salt A 25 mL round-bottom flask was charged with N- [4-1- (2,4-dimethylthiazol-5- yl) pentyloxy) methyl-2- (2-methylphenyl) benzoyl) methionine-carboxylic acid (53.1 mg, 0.095 mmol) and 2 mL MeOH/H20 (1: 1). 1 M lithium hydroxide (0.110 mL, 0.105 mmol) was added. The reaction was allowed to stir for a few minutes and then the solvent was removed under vacuum. The reaction was frozen at-78°C and lyophilized to dryness.

Yield: 48.5 mg, white fluffy powder.

IH NMR (o, DMS O): 6.8-7.6 (7H), 4.62 (1H), 4.4 (2H), 3.65 (1H), 2.56 (3H), 2.22 (3H), 2.2 (3H), 1.9 (3 H), 0.7-1.85 & 1.92-2.8 (14H) Mass spec (ESI): 555 (M+l), 553 (M-1) C30H37LiN2O4S2#4.45H2O Calc'd.: C 56.23 H 7.22 N 4.37 Found: C 56.23 H6.25 N 3.75 Example 1113 Example 1113A 1-(5-thiazolyl)-3-cyclohexylpropan-1-ol

A solution of thiazole-5-carboxaldehyde (2.31 g, 20.4 mmol) in 20 mL of in THF was added to a cold (0°C) solution of 2-cyclohexylethylmagnesium bromide (prepared from 2-bromoethylcyclohexane (7.88 g) and magnesium turnings (1.22 g)) in 30 mL of ethyl ether and the mixture stirred 30 minutes. The cold bath was removed and the mixture stirred for 2 hours more and then quenched by the addition of 3N aqueous HCI. The solution was stirred until 2 clear phases resulted and then the layers were separated. The pH of the aqueous phase was adjusted to 4 with 2M aqueous sodium carbonate and then extracted with 3 portions of ethyl acetate. All the organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (125 g, 50% ethyl acetate/hexanes) to provide 2.69 g (58%) of the title compound.

MS (DCI, NH3): 226 (MH+); 243 (M+NH4) +.

Example1113B 4- (1-thiazol-5-yl-3-cvclohexvlpropoxy) methvl)-2- (2-methylphenvl) benzoic acid A solution of example 1113A (270 mg, 1.2 mmol) and example 1178D (319 mg, 1.0 mmol) in 1 mL of DMF were cooled in an ice bath and treated with sodium hydride (60%, 60 mg, 1.5 mmol). The bath was removed and the mixture stirred for 1 hour and quenched by the addition of water. The mixture was diluted with water and the pH adjusted to-2 with phosphoric acid. The mixture was extracted with 3 portions of ethyl acetate.

The combined organic fractions were washed with water and brine, dried filtered and concentrated. The residue was dissolved in 10 mL of ethanol and treated with 2 mL of 4N aqueous sodium hydroxide and then heated to reflux for 2 hours. The solution was cooled to room temperature and concentrated to dryness. The residue was dissolved in water and extracted with 2 portions of ethyl ether. The ether extracts were combined and washed with water. The pH of the combined aqueous phases was adjusted to-4 with phosphoric acid and then the mixture was extracted with three portions of ethyl acetate. The combined ethyl

acetate layers were washed with water and brine, dried, filtered and concentrated to provide 369 mg (82%) of the title compound.

MS (DCI, NH3): 450 (MH+).

Example1113C O-cyclopropvlmethvl-N-t-butoxvcarbonvl-L-serine, methyl ester A solution example 1109A (268 mg, 1.09 mmol) in 5 mL of ether was treated with ethereal diazomethane until a light yellow color persisted. The excess diazomethane was removed in a stream of nitrogen and the solution of the methyl ester was treated with palladium (II) acetate (12 mg, 0.05 mmol) and excess ethereal diazomethane was added in portions over 1 hour and stirring continued for an additional 30 minutes. The resulting dark mixture was filtered through alumina and alumina pad washed well with ether. The filtrate was concentrate to provide 273 mg (92%) of the title compound.

MS (DCI, NH3): 274 (MH+).

Example 1128 <BR> N-f4- (N-benzyloxycarbonpyrrolin-2-vlmethoxymethyl)-2- (2- methvlphenyl) benzovllmethionine lithium salt Example 1128A

N-Benzyloxycarbonyl-2(S)-hydroxymethylpryrrolidine 2 (S)-hydroxymethylpyrrolidine (1. 01 g, 10.00 mmol) was dissolved in 10 mL of methylene chloride and cooled in an ice bath. The solution was treated with 10 mL of 2M sodium carbonate and vigorously stirred while a solution of benzylchloroformate (1.6 mL, 11.0 mmol) in 5 mL of methylene chloride was added dropwise. The mixture was stirred overnight during which time the ice bath melted. The layers were separated and the aqueous layer extracted with methylene chloride. The combined organic extracts were dried, filtered and concentrated to provide 2.35 g (100%) of the title compound.

MS (DCI, NH3): 236 (MH) +; 253 (M+NH4) +.

Example 1128B <BR> N-f4- (N-benzyloxycarbonylpyrrolin-2-ylmethoxymethyl)-2- ('2-methyIphenylbenzoic acid Following the procedure described in example 1113B, example 1128A (265 mg.

1.2 mmol) provided 363 mg (77%) of the title compound.

MS (ESI+): 460 (MH+): (ESI-): 458 (M-H).

Example 1128C N-[4-(N-benzyloxycarbonylpyrrolin-2-ylmethoxymethyl)-2-(2- estermethylphenyl)benzoyl]methioninemethyl Following the procedure of example 1178I, example 1128B (300 mg, 0.65 mmol) provided 280 mg (71%) of the title compound.

MS (ESI+): 605 (MH+): (ESI-): 603 (M-H).

Example 1128D N- [4- (N-benzyloxycarbonylpyrrolin-2-ylmethoxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt Using the procedure described in example 1178J, example 1128C (270 mg, 0.45 mmol) provided 226 mg of the title compound.

I H nmr (300 MHz., dmso d6): 6 7.52, d, 1H; 12H; 5.03, s, 2H; 4.51, d, 2H; 33.93, m, 1H; 3.68, m, 1H; 3.23-3.59, m, 4H; 1.46-2.18,14H.

MS (ESI+): 591 (MH+): (ESI-): 589 (M-H).

Calc'd for C33H37LiN206S'1.20 H20; C H 6.42; N 4.53; Found: C 64.10; H 6.23; N 4.38.

Example 1129 N- [4- (N-cyclohexylmethoxycarbonylpyrrolin-2-ylmethoxymethyl)-2- (2- methvlphenvl ! benzovllmethionine Sodium salt Following the procedure of example 1128 and substituting cyclohexylmethylchloroformate for benzylchloroformate in example A, the title compound was prepared. Additionally, sodium hydroxide was was substituted for lithium hydroxide prior to lyphilization.

1H nmr (300 MHz., dmso d6): 8 7.52, d, 1H; 7.36, dd, 1H; 6.94-7.26, m, 5H ; 6.92, m, 1H; 4.53, s, 2H; 3.88, m, 1H; 3.75, d, 2H; 3.67, m, 1H; 3.51, m, 1H; 3.40, m, 1H; 3.25, m, 1H; 2.15, bs, 2.00, bs, 1.5H; 1.91, s, 3H; 1.43-1.97,17H; 1.12, bm, 3H; 0.92, m, 2H.

MS (ESI+): 597 (MH+): (ESI-): 595 (M-H).

Calc'd for C33H43NaN2O6S#1. 65 H2O; C 61.12; H 7.20; N 4.32; Found: C 61.13; H 7.02 ; N 4.18.

Example 1131 N-[4-(2-cyclohexyl-1-thiazol-5-ylethoxymethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt Example1131 A 1-(5-thiazolyl)-2-cyclohexylethanol Using the procedure of example 1113A and substituting cyclohexymethylmagnesium bromide, 0.98 g (46%) of the title compound was prepared.

MS (DCI, NH3): 212 (MH) +; 229 (M+NH4) +.

Example1131B

N-r4-(2-cvCloheXvl-l-thiazol-5-vlethoxvmethvl)-2-(2-methvlph envllbenzOic(2-cvCloheXvl-l-thiazol-5-vlethoxvmethvl)-2-(2-m ethvlphenvllbenzOic acid Following the procedure of example 1113B, example 1131A (0.96 g, 4.54 mmol) provided 1.48 g (90%) of the title compound.

MS (DCI, NH3): 212 (MH) +.

Example1131C N-[4-(2-cyclohexyl-1-thiazol-5-ylethoxymethyl)-2-(2-methylph enyl)benzoyl]methionine methyl ester Following the procedure of example 11781, example 1131 B (1.48 g, 3.48 mmol) provided 1.64 g (81%) of the title compound.

MS (ESI+): 581 (MH+): (ESI-): 579 (M-H).

Example 1131D <BR> <BR> <BR> N-4- (2-cyclohexyl-l-thiazol-5-ylethoxymethyl')-2- (2-methylphenyl) benzoyl] methionine lithium salt Following the procedure of example 1178J, example 1131C (1.63 g, 2.80 mmol) provided 1.61 g (89%) of the title compound.

1H nmr (300 MHz., dmso d6): # 9.08, s, 1H; 7.89, s, 1H; 7.52, d, 1H; 7.33, dd, 1H; 7.10-7.26, m, 4H; 7.07, bs, 1H; 6.96, bs, 1H; 4.88, m, 1H; 4.42, q, 2H; 3.71, m, 1H; 1.95-2.20, m, 4H; 1.92, s, 3H; 1.81, bm, 2H; 1.57, bm, 8H; 1.32, m, 1H; 1.07, m, 3H; 0.89, m, 2H.

MS (ESI+): 567 (MH+): (ESI-): 575 (M-H).

Calc'd for C31H37LiN2O4S2#1. 35 H2O ; C 62.37; H 6.70; N 4.69; Found: C 62.37; H N 4. 57.

Example 1132 <BR> N- 4- (3-cyclohexvl-1-thiazol-5-ylpropoxvmethyl)-2- (2-methylphenyl) benzoyllmethioninf lithium salt Example 1132A N-[4-(3-cyclohexyl-1-thiazol-5-ylpropoxymethyl)-2-(2-methylp henyl)benzoyl]methionine methy ! ester Following the procedure of example 11781, example 1113B (0.36 g, 0.80 mmol) provided 0.41 g (87%) of the title compound.

MS (ESI+): 595 (MH+): (ESI-): 593 (M-H).

Example 1132B <BR> <BR> <BR> N- [4- (3-cyclohexyl-l-thiazol-5-ylpropoxymethyl)-2- (2-methylphenyl) benzoyl1methionine lithium salt Following the procedure of example 1178J, example 1132A (405 mg, 0.68 mmol) provided 362 mg (91%) of the title compound.

IH nmr (300 MHz., dmso d6): 8 9.08, s, 1H; 7.87, s, 1H; 7.51, d, 1H; 7.32, d, 1H; 7.19, bm, 4H; 7.08, bs, 1H; 6.95, m, 1H; 4.74, t, 1H; 4.43, q, 2H; 3.69, m, 1H; envelope 1.78 -2.20,8H; 1.62, bm, 8H; 1.11, bm, 6H; 0.79, m, 2H.

MS (ESI+): 581 (MH+): (ESI-): 579 (M-H).

Calc'd for C32H3gLiN204S2@1.15 H20; C 63.27; H 6.85; N 4.61; Found: C 63.30; H 6.64; N 4.50.

Example 1133 <BR> <BR> N-f4- (3-cvclohexyl-1-thiazol-5-ylpropoxymethyll-2- (2-methylpheny) benzoyllserine lithium salt

Example 1133A <BR> N- 4- (3-cvclohexvl-1-thiazol-5-ylpropoxymethyl)-2- (2-methvlphenl) benzoyllserine methyl ester Using the procedure described in example 1178I and substituting L-serine methyl ester for L-methionine methyl ester, example 1113B provided the title compound.

Example 1133B N-[4-(3-cyclohexyl-1-thiazol-5-ylpropoxymethyl)-2-(2-methylp henyl)benzoyl]serine lithium salt Using the procedure described in example 1178J, example 1133A provided the title compound.

Example1152<BR> N- 4- (cvclohexyvcarbonvlethyl)-2- (2-methylphenvl) benzolmethionine Example 1152A <BR> <BR> <BR> N- [4- (cyclohexyloxycarbonylethyl')-2- (2-methylphenyl') benzoyl1methionine tert-butyl ester The procedures descriped in the Example 1147C were used here to convert 1147B (50 mg) to the title diester (35 mg, 55%).'HNMR (300 MHz, CDCl3) 5 7.82 (2 d's, 1 H), 7.31- 7.15 (m, 5 H), 7.03 (br s, 1 H), 5.85 (br d, 1 H), 4.75 (m, 1 H), 4.50 (m, 1 H), 3.00 (t, 2 H), 2.63 (t, 2 H), 2.20-1.90 (m, 8 H), 1.90-1.20 (m, 12 H), 1.40 (s, 9 H).

MS (CI/NH3) m/z: 554 (M+H) +.

Example 1152B N-[4-(cyclohexyloxycarbonylethyl)-2-(2-methylphenyl)benzoyl] methionine The intermediate 1152A (30 mg) was stirred with HCl (4.0 N in dioxane, 1.0 mL) in DCM (1 mL) at room temperature for 15 hours. Solvent was then evaporated to give the title compound without purification. lHNMR (300 MHz, CDCl3) 5 7.96 (2 d's, 1 H),

7.37-7.15 (m, 5 H), 7.05 (br s, 1 H), 5.87 (m, 1 H), 4.75 (m, 1 H), 4.52 (m, 1 H), 3.01 (t, 2 H), 2.64 (t, 2 H), 2.20-2.00 (m, 8 H), 2.00-1.20 (m, 12 H).

MS (ESI-) m/z: 496 (M-H)-.

Example 1153 N-4- (cvclohexvlmethoxvcarbonylethyl)-2- (2-methylphenyl) benzolmethionine The procedures descriped in the Example 1152A and 1152B were used here to 1147B (50 mg) to the title compound (33 mg, 56%). 1HNMR (300 MHz, CDC13) 5 7.96 (2 d's, 1 H), 7.37-7.15 (m, 5 H), 7.05 (br s, 1 H), 5.87 (m, 1 H), 4.60 (m, 1 H), 3.87 (d, 2 H), 3.01 (dt, 2 H), 2.64 (t, 2 H), 2.20-1.97 (m, 8 H), 1.80-0.85 (m, 13 H).

MS (ESI-) m/z: 510 (M-H).

Example1156

Example 1156A l-t-butoxycarbonyl-4-hydroxy-4-phenvlpiperidine To a solution of 4-hydroxy-4-phenylpiperidine (1.77 g, 10.0 mmol) and triethylamine (2 mL) in DCM (40 mL) was addede di-tert-butyl dicarbonate (2.29 g, 10.5 mmol). After 15 hopurs at room temperature, the reaction mixture was then partitioned between ether (80 mL) and water (20 mL). The organic layer was washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated.

The residue was purified by column chromatography with 90: 10: 5 of hexane: ethyl acetate: chloroform to give the title compound (1.01 g, 36%).'HNMR (300 MHz, CDCl3) 6 7.48 (dq, 2 H), 7.37 (tt, 1 H), 7.30 (dt, 1 H), 4.02 (br loop, 2 H), 3.15 (br t, 2 H), 2.01 (br dt, 2 H), 1.74 (dq, 2 H), 1.48 (s, 9 H).

MS (CI/NH3) m/z: 278 (M+H) +.

Example 1156B <BR> <BR> <BR> Methyl 4-(N-t-butoxvCarbonyl-4-phenvlpiperidin-4-vloxvmethyl !-2-(2-<BR> <BR> <BR> <BR> methylphenyl) benzoate To a suspension of of sodium hydride (95%, 22 mg, 0.85 mmol) in DMF (1.5 mL) was added 1156A (208 mg, 0.75 mmol). After 15 min., a solution of 4-bromomethyl-2- (2- methylphenyl) benzoic acid, methyl ester (example 1178D, 160 mg, 0.50 mmol), 15-crown- 5 (22 mg), and tetrabutylammonium iodide (37 mg) in DMF (2 mL) was added to the reaction mixture through a cannula. After 3 hours, the reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified wibyth column chromatography with 20% ethyl acetate in hexane to give the title compound (145 mg, 56%). 1HNMR (300 MHz, CDC13) 8 7.94 (d, 1 H), 7.46-7.19 (m, 9 H), 7.18 (d, 1 H), 7.07 (br d, 1 H), 4.18 (s, 2 H), 4.02 (br loop, 2 H), 3.60 (s, 3 H), 3.25 (br loop, 2 H), 2.15 (m, 2 H), 2.066 (s, 3 H), 1.93 (m, 2 H), 1.47 (s, 9 H).

MS (CI/NH3) m/z: 533 (M+NH4) +.

Example 1156C N- [4(N-t-butoxycarbonyl-4-phenpiperidin-4-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine methyl ester The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate 1156B (411 mg, 0.80 mmol) to the title methyl ester (275 mg, 53%).

1HNMR (300 MHz, CDCl3) 8 7.94 (2 d's, 1 H), 7.43 (2 d's, 1 H), 7.36-7.25 (m, 9 H), 7.18 (m, 1 H), 5.88 (br d, 1 H), 4.62 (m, 1 H), 4.61 (s, 2 H), 3.77 (m, 2 H), 3.66 (s, 3 H), 3.12 (m, 2 H), 2.20-2.00 (m, 9 H), 1.87 (m, 3 H), 1.61 (m, 2 H), 1.46 (s, 9 H).

MS (CI/NH3) m/z: 664 (M+ NH4) +.

Example 1156C N-f4- (N-t-butoxvcarbonyl-4-phenpiperidin-4-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The procedure descriped in the Example 403I was used here to convert the intermediate 1156B (265 mg) to the title lithium salt (264 mg, 100%).

H nmr (300 MHz, DMS O-d6): 8 7.49 (m, 3 H), 7.39 (m, 3 H), 7.30 (t, 1 H), 7.27-7.07 (m, 5 H), 6.95 (d, 1 H), 4.14 (s, 2 H), 3.85 (m, 32 H), 3.68 (m, 1 H), 3.10-3.05 (m, 2 H), 2.20-1.95 (m, 7 H), 1.92 (br s, 3 H), 1.83 (dt, 2 H), 1.70 (m, 1 H), 1.57 (m, 1 H), 1.40 (s, 9 H).

MS (ESI-): m/e 631 (M-H)-.

Example 1192 N- [4-f 1-Cyclohexylheptan-3-yloxymethyl-2- (2-methylphenyl') benzoyl1methionine lithium salt Example1192A<BR> 1-Cyclohexylheptan-3-ol The alcohol was prepared using the method described in Example 1206A starting with 3-cyclohexylpropyl carboxaldehyde (prepared by Swern oxidation of 3-cyclohexyl-1- propanol) and butylmagnesium chloride.

Example 1192B methylester4-(1-Cyclohexylheptan-3-yloxymethyl-2-(2-methylph enyl)benzoicacid

The ether was prepared using the method described in Example 1205B starting with the compound from Example 1192A and 4-bromomethyl-2-(2-methylphenyl) benzoic acid methyl ester, prepared as in Example 1132A-D. m/e (ESI) 437 (MH+)

Example 1192C 4-(1-Cyclohexylheptan-3-yloxymethyl-2-(2-methylphenyl)benzoi cacid The acid was prepared using the method described in Example 1205C starting with the compound from Example 1192B.

Example 1192D <BR> N-f4- (1-Cyclohexylheptan-3-vloxymethyl-2- (2-methylphenyl) benzoyllmethionine methyl ester The compound was prepared using the method described in Example 1132G starting with the compound from Example 1192C. m/e (ESI) 566 (MH-)

Example 1192E N-[4-(1-Cyclohexylheptan-3-yloxymethyl-2-(2-methylphenyl)ben zoyl]methioninelithium salt The desired compound was prepared according to the method of Example 1132H starting with the compound from Example 1192D. 1H (300MHz, CDCl3, d) (rotamer) 8.00 (7.96) (1H, d, J=9Hz), 7.44 (1H, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.87 (1H, m), 4.57 (2H, s), 4.56 (1H, m), 3.36 (1H, m), 2.20-2.00 (8H, m), 1.91 (1H, m), 1.67 (4H, m), 1.53 (4H, m), 1.30 (6H, m), 1.20 (6H, m), 0.88 (5H, m). m/e (ESI) 552 (MH-) Anal. calc. for C33H46LiNO4S 1.25 H20 C 68.07, H 8.40, N 2.41 Found C 68.19, H 8.22, N 2.48 Example 1205 N-[4-(2-(2-chlorophenyl)hexan-1-yloxymethyl)-2-(2-methylphen yl)benzoyl]methionine lithium salt Example 1205A

2-(2-chlorophenvl) hexan-l-ol THF (45 mL) was cooled to-10 °C, then 1.5M LDA*THf in cyclohexane was added followed by 1.7 g (10 mmol) 2-chlorophenylacetic acid in THF (15 mL) which was added dropwise. Stirred reaction at-10 °C under N2 for 30 min., warmed to RT over 30 min., then recooled to-10 °C. Added 5.5 g (3.4 mL, 30 mmol) 1-iodobutane, then allowed reaction to warm to RT overnight. Next day filtered through celite, then added the filtrate to 2N HCl and Et20. Washed organic layer with brine, extracted combined aqueous layers with Et20, then dried combined organic layers over Na2SO4. After filtration and concentration had 1.9 g dark brown oil that was reduced without purification.

That oil was dissolved in THF (10 mL), cooled to-10 °C, then 1. OM BH3 in THF was added dropwise under N2. After allowing the reaction to warm to RT overnight, it was cooled to 0 °C, and 1 N NaOH (17 mL) was added dropwise. The reaction was stirred for 15 min., then partitioned between water and Et20. Washed organic layer with brine, extracted combined aqueous layers with Et20, then dried combined organic layers over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 88/12 hex/EtOAc. Recovered 0.72 g (34% from 2- chlorophenylacetic acid). tH NMR (CDC13) õ 7.40 (d, 1H), 7.28 (m, 2H), 7.17 (m, 1H), 3.79 (t, 2H), 3.48 (m, 1H), 1.79 (m, 1H), 1.64 (m, 1H), 1.29 (m, 4H), 0.86 (t, 3H).

Example 1205B 4- (2- (2-chlorophenyl) hexan-1-yloxymethyl)-2- (2-methphenyl) benzoic acid methyl ester The alcohol described in Example 1205A (240 mg, 1.13 mmol) and the bromide described ih Example 1178D (315 mg, 1.00 mmol) were dissolved in DMF (0.5 mL), then 45 mg 60% NaH (1.12 mmol) was added. After stirring at RT overnight, the reaction was partitioned between EtOAc and water. The organic layer was washed with brine, then dried over Na2S04. After filtration and concentration the crude material was purified by chromatography using 98/2 hex/EtOAc. Recovered 170 mg (38%).

MS (APCI) 451/453 (M+H) +.

Example 1205C 4- (2-(2-chlorophenvl) hexan-1-vloxvmethyl !-2-(2-methvlphenvl)(2-(2-chlorophenvl) hexan-1-vloxvmethyl !-2-(2-methvlphenvl) benzoic acid The title compound was prepared from the compound described in Example 1205B by the method described in Example 1178H.

MS (APCI) 454/456 (M+H+NH3) +.

Example 1205D N-[4-(2-(2-chlorophenyl)hexan-1-yloxymethyl)-2-(2-methylphen yl)benzoyl]methionine methylester The compound described in Example 1205D (148 mg, 0.34 mmol) was dissolved in DMF (1.5 mL), then 74 mg (0.37 mmol) HClMet-OMe, 70 mg (0.37 mmol) EDCI#HCl, 54 mg (0.35 mmol) HOBT#H2O, and 38mg (41u. L, 0.37 mmol) N-methylmorpholine were added.

The reaction was stirred at RT overnight, then partitioned between 2N HCl and EtOAc. The organic layer was washed with saturated aqueous NaHC03 and brine, then dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 4/1 hex/EtOAc. Recovered 160 mg (81%).

MS (APCI) 582/584 (M+H) +.

Example 1205E <BR> <BR> <BR> N-f4- (2- (2-chlorophenyl) hexan-1-yloxvmethyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1205D according to the method of Example 1178J.

I H NMR (DMS O-d6) 6 7.47 (d, 1H), 7.37 (m, 2H), 7.20,6.96 (both m, total 9H), 4.50 (dd, 2H), 3.66 (m, 1H), 3.60 (d, 2H), 3.45 (m, 1H), 97,1.90,1.75,1.58 (all m, total 12H), 1.18 (m, 4H), 0.79 (m, 3H).

MS (ESI) 566/568 (M-H)-.

Anal calcd for C32H37ClLiN04S 50 H20: C, 65.91; H, 6.46; N, 2.40. Found: C, 65.85; H, 6.57; N, 2.40.

Example 1206 N-[4-(1-(3-chlorophenyl)pentan-1-yloxymethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt

Example 1206A 1-(3-chlorophenvl) pentan-1-ol A solution of 3-chlorobenzaldehyde (1.4 g, 10 mmol) in THF (10 mL) was cooled to-10 °C, then 2.0M n-butylmagnesium chloride (10 mL) was added. The reaction was allowed to warm to RT under N2 overnight. Next day the reaction was cooled to 0-5° C, water (5 mL) was added, followed by 2N HCl-Et2O partition. The organic layer was washed with brine, then dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 9/1 hex/EtOAc. Recovered 1.25 g (63%). lH NMR (CDCl3) õ 7.37 (m, 1H), 7.23 (m, 3H), 4.43 (ddd, 1H), 1.82 (d, 1H), 1.72 (m, 2H), 1.35 (m, 4H), 0.90 (t, 3H).

Example 1206B methylester4-(1-(3-chlorophenyl)pentan-1-yloxymethyl)-2-(2-m ethylphenyl)benzoicacid The title compound was prepared from the compound described in Example 1206A and the bromide described in Example 1178D using the method of Example 1205B.

MS (DCI/NH3) 454/456 (M+H+NH3) +.

Example 1206C 4-(1-(3-chlorophenyl)pentan-1-yloxymethyl)-2-(2-methylphenyl )benzoicacid The title compound was prepared from the compound described in Example 1206B using the method of Example 1178H.

MS (APCI) 440/442 (M+H+NH3) +.

Example 1206D N-[4-(1-(3-chlorophenyl)pentan-1-yloxymethyl)-2-(2-methylphe nyl)benzoyl]methionine methylester The title compound was prepared from the compound described in Example 1206C using the method of Example 1205D.

MS (APCI) 568/570 (M+H) +.

Example 1206E <BR> <BR> <BR> N- [4- (l- (3-chlorophenyl) pentan-l-yloxymethvl)-2- (2-methylphenyl) benzovI1methioniM lithium salt The above compound was prepared from the compound described in Example 1206D according to the method of Example 1178J.

I H NMR (DMS O-d6) 8 7.50 (d, 1H), 7.37 (m, 5H), 7.20,7.08,6.96 (all m, total 6H), 4.40 (m, 3H), 3.66 (m, 1H), 2.17,2.00,1.90,1.75,1.60 (all m, total 12H), 1.23 (m, 4H), 0.80 (m, 3H).

MS (ESI) 552 (M-H)-.

Anal calcd for C31H35ClLiNO4S-0. 50 H20: C, 65.43; H, 6.38; N, 2.46. Found: C, 65.35; H, 6.19; N, 2.42.

Example 1207 N-[4-(1-(3-chlorophenyl)-3-cyclohexylpropan-1-yloxymethyl)-2 -(2- saltmethylphenyl)benzoyl]methioninelithium Example 1207A 2-cvclohexylethvl bromide The title compound was prepared from the alcohol by the method of Example 1178D.

IH NMR (CDC13) 8 3.63 (t, 2H), 1.75 (m, 7H), 1.45 (m, 1H), 1.22 (m, 3H), 0.90 (m, 2H).

Example 1207B 1-(3-chlorophenyl)-3-cyclohexylpropan-1-ol The bromide described in Example 1207A was converted to the Grignard reagent, then reacted with 3-chlorobenzaldehyde using the method of Example 1206A to give the title compound.

1H NMR (CDC13) 8 7.37 (s, 1H), 7.23 (m, 3H), 4.42 (m, 1H), 1.70 (m, 8H), 1.20 (m, 6H), 0.88 (m, 2H).

Example 1207C 4-ll- (3-chlorophenyl)-3-cyclohexylpropan-1-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1207B and the bromide described in Example 1178D using the method of Example 1205B.

MS (APCI) 491/493 (M+H) +.

Example 1207D <BR> 4- (1- (3-chloropheny-3-cyclohexylpropan-1-yloxymethyl')-2- (2-methylphenyl) benzoic acid The title compound was prepared from the compound described in Example 1207C using the method of Example 1178H.

MS (APCI) 475/477 (M-H)-.

Example 1207E N-[4-(1-(3-chlorophenyl)-3-cyclohexylpropan-1-yloxymethyl)-2 -(2- estermethylphenyl)benzoyl]methioninemethyl The above compound was prepared from the compound described in Example 1207D using the method of Example 1205D.

MS (APCI) 622/624 (M+H) +.

Example 1207F N-f4- (l- (3-chlorophenyl)-3-cyclohexylpropan-l-yloxymethyl')-2- (2- methylphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1207E according to the method of Example 1178J.

I H NMR (DMS O-d6) 5 7.50 (d, 1H), 7.37 (m, 5H), 7.20,7.08,6.96 (all m, total 6H), 4.40 (m, 3H), 3.66 (m, 1H), 2.20-1.50 (envelope, 17H), 1.10 (m, 6H), 0.80 (m, 2H).

MS (ESI) 606 (M-H)-.

Anal calcd for C3sH4lClLiNO4S # 0.75 H20: C, 66.97; H, 6.82; N, 2.23. Found: C, 66.84; H, 6.42; N, 1.81.

Example 1208 N-[4-(1-(3-Methoxyphenyl)pentan-1-yloxymethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt

Example 1208A 1-3-Methoxyphenyllpentan-l-ol The title compound was prepared from 3-methoxybenzaldehyde using the method of Example 1206A.

IH NMR (CDC13) 8 7.26 (m, 1H), 6.94 (m, 2H), 6.82 (m, 1H), 4.63 (m, 1H), 3.82 (s, 3H), 1.82 (d, 1H), 1.75 (m, 2H), 1.35 (m, 4H), 0.90 (t, 3H).

Example 1208B methyl4-(1-(3-Methoxyphenyl)pentan-1-yloxymethyl)-2-(2-methy lphenyl)benzoicacid ester The title compound was prepared from the compound described in Example 1208A and the bromide described in Example 1178D using the method of Example 1205B.

MS (DCI/NH3) 450 (M+H+NH3) +.

Example 1208C

4-(l-(3-Methoxvphenvl) pentan-1-vloxymethvl)-2-(2-methvlphenvl) benzoic(l-(3-Methoxvphenvl) pentan-1-vloxymethvl)-2-(2-methvlphenvl) benzoic acid The title compound was prepared from the compound described in Example 1208B using the method of Example 1178H.

MS (APCI) 436 (M+H+NH3) +.

Example 1208D N-[4-(1-(3-Metoxyphenyl)pentan-1-yloxymethyl)-2-(2-methylphe nyl)benzoyl]methionine methyl ester The title compound was prepared from the compound described in Example 1208C using the method of Example 1205D.

MS (APCI) 564 (M+H) +.

Example 1208E <BR> <BR> N-f4- (1- (3-Methoxyphenyl) pentan-1-ylvl)-2- (2-methvlphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1208D according to the method of Example 1178J.

IH NMR (DMS O-d6) 8 7.39 (d, 1H), 7.20-6.68 (envelope, 11H), 4.22 (m, 2H), 4.18 (m, 1H), 3.60 (s, 3H), 3.56 (m, 1H), 2.20-1.40 (envelope, 12H), 1.10 (m, 4H), 0.65 (m, 3H).

MS (ESI) 548 (M-H)-.

Anal calcd for C32H3gClLiNO5S 65 H20: C, 67.74; H, 6.98; N, 2.47. Found: C, 67.76; H, 6.95; N, 2.42.

Example 1209 saltN-[4-(3-(1-Propoxy)benzyloxymethyl)-2-(2-methylphenyl)be nzoyl]methioninelithium Example 1209A 3-(1-Propoxy ! benzoic acid propvl(1-Propoxy ! benzoic acid propvl ester 3-Hydroxybenzoic acid (2.88 g, 20.9 mmol) and potassium carbonate (14.0 g, 101 mmol) were slurried in DMF (50 mL), then 1-bromopropane (8.0 mL, 10.8 g, 88 mmol) was added. The reaction was stirred at RT overnight, then partitioned between water and Et20. The organic layer was washed with brine, then dried over Na2SO4. After filtration and concentration recovered 4.6 g (100%).

IH NMR (CDCl3) 8 7.62 (m, 1H), 7.57 (m, 1H), 7.33 (dd, 1H), 7.09 (m, 1H), 4.26 (t, 2H), 3.98 (t, 2H), 1.80 (m, 4H), 1.05 (t, 3H), 1.04 (t, 3H).

Example 1209B 3- (1-Propoxy) benzyl alcohol The compound described in Example 1209A (2.2 g, 10 mmol) was dissolved in THF (10 mL), then added to 1. OM LAH in THF (10.5 mL). Stirred reaction at RT for Ih, cooled in an ice-water bath, then successively added water (0.6 mL), 15% NaOH (0.6 mL), and water (1.8 mL). The bath was removed, and after 15 min. stirring added Et20 (60 mL) and MgS04. Stirred reaction for another 15 min., then filtered through a plug (10-15 g) of silica gel, rinsing the plug with Et20 (200 mL). Concentrated filtrate to give 1.5 g (83%) of the title compound.

1H NMR (CDC13) 8 7.27 (dd, 1H), 6.90 (m, 2H), 6.82 (m, 1H), 4.63 (s, 2H), 3.91 (t, 2H), 1.95 (s, 1H), 1.80 (m, 2H), 1.04 (t, 3H).

Example 1209C 4-(3-(1-Propoxy)benzyloxymethyl)-2-(2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1209B and the bromide described in Example 1178D using the method of Example 1205B.

MS (DCI/NH3) 422 (M+H+NH3) +.

Example 1209D 4-(3-(1-Propoxy)benzyloxymethyl)-2-(2-methylphenyl)benzoicac id The title compound was prepared from the compound described in Example 1209C using the method of Example 1178H.

MS (DCI/NH3) 408 (M+H+NH3) +.

Example 1209E N- [4- (3- (l-Propoxy) benzyIoxymethyl)-2-f2-methyIphenyI) benzoynmethionine methyl ester The title compound was prepared from the compound described in Example 1209D using the method of Example 1205D.

MS (APCI) 536 (M+H) +.

Example 1209F <BR> <BR> <BR> <BR> N- [4- (3- (l-Propoxy) benzyIoxymethyl)-2- (2-methylphenyl) benzoyl1methionine lithium salt The above compound was prepared from the compound described in Example 1209E according to the method of Example 1178J.

I H NMR (DMS O-d6) 8 7.55 (d, lH), 7.40 (d, 1H), 7.20,7.07 (both m, total 7H), 6.90 (m, 2H), 6.82 (m, 1H), 4.60 (s, 2H), 4.54 (s, 2H), 3.90 (t, 2H), 3.78 (m, 1H), 2.17, 2.00,1.90 (all m, total 8H), 1.70 (m, 3H), 1.60 (m, 1H), 0.96 (t, 3H).

MS (ESI) 520 (M-H)-.

Anal calcd for C3oH34LiNO5S: C, 68.30; H, 6.50; N, 2.65. Found: C, 67.90 ; H, 6.55; N, 2.68.

Example 1210 N-[4-(3-cyclohexylmethyloxybenzyloxymethyl)-2-(2-methylpheny l)benzoyl]methionine lithium salt Example 1210A 3- (cyclohexylmethyloxy) benzoic acid cyclohexylmethyl ester The above compound was prepared from 3-hydroxybenzoic acid and bromomethylcyclohexane using the method of Example 1209A, except with this bromide

the compound had to be purified by chromatography using 97/3 hex/EtOAc which gave a 9% yield.

MS (DCI/NH3) 331/348 (M+H) +/ (M+H+NH3) +.

Example 1210B 3-(cyclohexylmethyloxy)benzylalcohol The title compound was prepared from the compound described in Example 1210A using the method of Example 1209B.

MS (DCI/NH3) 221/238 (M+H) +/ (M+H+NH3) +.

Example 1210C 4- (3-cyclohexylmethyloxybenzyloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1210B and the bromide described in Example 1178D using the method of Example 1205B.

MS (DCI/NH3) 476 (M+H+NH3) +.

Example 1210D 4-(3-cyclohexylmethyloxybenzyloxymethyl)-2-(2-methylphenyl)b enzoicacid The title compound was prepared from the compound described in Example 1210C using the method of Example 1178H.

MS (DCI/NH3) 462 (M+H+NH3) +.

Example 1210E <BR> N- 4- (3-cvclohexylmethyloxybenzyloxymethylL2- (2-methylphenyl) benzoyllmethionine methyl ester The title compound was prepared from the compound described in Example 1210D using the method of Example 1205D.

MS (APCI) 590 (M+H) +.

Example1210F<BR> <BR> <BR> <BR> N- [4- (3-cyclohexylmethyloxybenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine lithium salt The above compound was prepared from the compound described in Example 1210E according to the method of Example 1178J.

I H NMR (DMS O-d6) 8 7.55 (d, lH), 7.40 (dd, 1H), 7.20,6.97 (both m, total 7H), 6.90 (m, 2H), 6.82 (m, 1H), 4.60 (s, 2H), 4.52 (s, 2H), 3.73 (d, 2H), 4.48 (m, 1H), 2.17, 2.00,1.90 (all m, total 7H), 1.70 (m, 9H), 1.20 (m, 3H), 1.03 (m, 2H).

MS (ESI) 574 (M-H)-.

Anal calcd for C34H40LiNO5S# 0. 70 H20: C, 68.71; H, 6.84; N, 2.17. Found: C, 68.70; H, 7.02; N, 2.36.

Example 1221 N-14- (Pvridazin-4-vlmethoxvmethvl)-2-(2-methvlphenyl) benzovllmethionine(Pvridazin-4-vlmethoxvmethvl)-2-(2-methvlp henyl) benzovllmethionine lithium salt Example 1221 A 3,6-Dichlopvridazine-4-carboxylic acid ethyl ester 3,6-Dichloropyridazine-4-carboxylic acid was preapared by the methods in JACS, 76,2201 (1954) and Chem. Pharm. Bull., 5,587 (1957). That acid (9.15 g, 47.4 mmol) was dissolved in THF (50 mL), then EtOH (6.5 mL, 5.1 g, 111 mmol), EDCI'HCI (10.0 g, 52.5 mmol), and DMAP (0.64 g, 5.2 mmol) were added. The reaction was stirred at RT overnight, concentrated, and partitioned between EtOAc and water. The organic layer washed with 2M aq. Na2CO3, then water several times to clarify the organic layer. The combined aqueous layers were extracted with EtOAc, then the combined organic layers were dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using 4/1 hex/EtOAc. Recovered 6.45 g (61%). MS (DCI/NH3) 221/223 (M+H) + and 238/240 (M+H+NH3) +.

Example 1221B 3.6-Dichlopyridazine-4-methanol The compound descibed in Example 1221A (5.4 g, 24 mmol) was dissolved in toluene (75 mL), cooled to-10 °C, then 1.5M DIBAL in toluene (32 mL) was added dropwise, keeping the reaction temperature under 0 °C (the addition took ca. 15 min.).

After another 5 min. saturated aqueous Rochelle's salt (25 mL) was added carefully. That mixture was stirred cold for 20 min., at RT for 20 min., then Na2SO4 was added. That slurry was stirred for 30 min., then filtered through celite. The solids on top of the celite were partitioned between 2N HCl (to dissolve Al salts) and EtOAc. Solid NaHC03 was used to adjust the aqueous layer to pH 7-8, twice extracted with EtOAc, then the combined EtOAc layers were washed with brine, combined with the toluene filtrate from the celite filtration, and dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography (had to dissolve the 4.2 g crude solids in CHC13/MeOH and preadsorb on 12 g silica gel) using 65/35 hex/EtOAc. Recovered 1.8 g (41%). MS (DCI/NH3) 179/181 (M+H) + and 196/198 (M+H+NH3) +.

Example1221C<BR> <BR> <BR> Pvridazine-4-methanol The compound descibed in Example 1221B (1.8 g, 10 mmol) was dissolved in absolute EtOH (65 mL), then 10% palladium on carbon (335 mg) and triethylamine (6.0 mL, 4.4 g, 43 mmol) were added. The slurry was stirred at RT under H2 balloon for 3h, then filtered through celite and concentrated. The 3.5 g solids were slurried in EtOAc (100 mL), and mechanically stirred at RT overnight. The slurry was filtered, the filtrate concentrated, and that material was purified by chromatography using EtOAc/EtOH 9/1.

Recovered 0.83 g (75%) MS (DCI/NH3) 111 (M+H) + and 128 (M+H+NH3) +.

Example1221D<BR> <BR> <BR> <BR> 4-(Pvridazin-4-vlmethoxvmethvl)-2-(2-methvlphenyl) benzoic acid methvl(Pvridazin-4-vlmethoxvmethvl)-2-(2-methvlphenyl) benzoic acid methvl ester The bromide described in Example 1178D (230 mg, 0.72 mmol) was dissolved in DMF (0.8 mL), cooled to-10 °C, then added 29 mg 60% NaH (so 17 mg, 0.72 mmol NaH), followed by the alcohol described in Example 1221C (79 mg, 0.72 mmol). Stired the reaction at-10 °C for 45 min., then partitioned between EtOAc and water. The EtOAc layer was washed with brine, the combined aqueous layers extracted with EtOAc, then the combined organic layers were dried over Na2SO4. After filtration and concentration the crude material was purified by chromatography using EtOAc. Recovered 150 mg (60%).

MS (APCI) 349 (M+H) +.

Example1221E 4-(Pyridazin-4-ylmethoxymethyl)-2-(2-methylphenyl)benzoicaci d Starting with the compound described in Example 1221D, the title compound was prepared by the method of Example 1178H, except that during the work-up, the aqueous layer was water and enough 2N HCl to get pH 3-4. MS (ESI) 333 (M-H)-.

Example1221F<BR> <BR> <BR> este@N-[4-(Pyridazin-4-ylmethoxymethyl)-2-(2-methylphenyl)be nzoyl]methioninemethyl Starting with the compound described in Example 1221E, the title compound was prepared by the method of Example 1205D, except that during the work-up, the 2N HCl wash was eliminated, and the chromatography used successively hex/EtOAc 1/3, EtOAc, EtOAc/EtOH 98/2. MS (APCI) 480 (M+H) +.

Example1221G N-f4- (Pvridazin-4-vlmethoxymethyl2-methylphenl) benzoyllmethionine lithium salt Starting with the compound described in Example 1221F, the title compound was prepared by the method of Example 1178J. IH NMR (DMSO-d6) 8 9.22 (m, 1H), 9.18 (dd, 1H), 7.65 (m, 1H), 7.55 (d, 1H), 7.45 (d, 1H), 7.20,6.95 (both m, total 6H), 4.69 (s, 2H), 4.66 (s, 2H), 3.68 (m, 1H), 2.15-1.50 (envelope, 10H). MS (ESI) 464 (M-H)-.

HRMS (FAB+) calcd for C25H27LiN304S: 472.1882. Found: 472.1898.

Example 1223 N-[4-(1-(Isothiaz-5-yl)-3-cyclohexylpropan-1-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt Example 1223A 1- !-3-cvclohexvlpropan-1-ol Isothiazole was made from propynal (prepared using the procedure in Org. Syn., Coll. Vol. IV, 813) by the method in Can. J. Chem., 44,1324 (1966), then converted to isothiazole-5-carboxaldehyde by the method in JCS, 446 (1964). That aldehyde was used to make the title compound by the method described in Example 1207B. MS (APCI) 226 (M+H) +.

Example 1223B 4-(1-(Isothiaz-5-yl)-3-cyclohexylpropan-1-yloxymethyl)-2-(2- methylphenyl)benzoicacid methyl ester The title compound was prepared from the compound described in Example 1223A and the bromide described in Example 1178D using the method of Example 1205B. MS (APCI) 464 (M+H) +.

Example 1223C 4- (1- (Isothiaz-5-yl)-3-cvclohexylpropan-1-yloxvmethyl)-2- (2-methylphenyl) benzoic acid The title compound was prepared from the compound described in Example 1223B using the method of Example 1178H. MS (ESI) 450 (M+H) +.

Example 1223D <BR> <BR> N- [4- (1- (Isothiaz-5-yl)-3-cyclohexylpropan-1-yloxymethyl-2- (2-<BR> methylphenyDbenzoyMmethionine methy} ester The title compound was prepared from the compound described in Example 1223C using the method of Example 1205D. MS (APCI) 595 (M+H) +.

Example 1223E N- [4- (l- (Isothiaz-5-yl)-3-cvclohexylpropan-1-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1223D according to the method of Example 1178J. IH NMR (DMSO-d6) b 8.50 (m, 1H), 7.54 (d, 1H), 7.37 (d, 1H), 7.33 (m, 1H), 7.20,7.00 (both m, total 6H), 4.90 (t, 1H), 4,56 (dd, 2H), 3.70 (m, 1H), 2.17,2.00,1.91,1.80,1.60 (all m, total 17H), 1.17 (m, 6H), 0.80 (m, 2H). MS (ESI) 579 (M-H)-. Anal calcd for C32H39LiN204S2-1.00 H20: C, 63.56; H, 6.83; N, 4.63. Found: C, 63.41; H, 6.77; N, 4.54.

Example 1224 N-[4-(1-(1-Methyl-1,2,4-triaz-5-yl)-3-cyclohexylpropan-1-ylo xymethyl)-2-(2- methylphenyl') benzoyl] methionine lithium salt

Example 1224A 1-Methvl-1.2.4-triazole Sodium (1.9g, 83 mmol) was dissolved in MeOH (35 mL), allowed to cool to RT, then 1,2,4-triazole (5.7 g, 83 mmol) was added. The solution was cooled in an ice-water bath, then iodomethane (5.1 mL, 11.6 g, 82 mmol) was added dropwise. The reaction was allowed to warm to RT, stoppered, then heated at 38 °C overnight. The reaction was concentrated, then treated with hot benzene (25 mL) which resulted in the formation of white solids. Those solids were slurried in hot CHC13 (25 mL) and filtered off. The CHC13 slurry was repeated twice, the three filtrates combined, concentrated, and distlled (37-40 °C/8 mm). Recovered 2.6 g (38%). IH NMR (CDC13) 8 8.05 (s, 1H), 7.93 (s, 1H), 3.96 (s, 3H).

Example 1224B 3-Cvclohexvlpropanal 3-Cyclohexylpropan-1-ol was oxidized to the aldehyde using the method of Example 403G. IH NMR (CDCl3) 8 9.77 (t, 1H), 2.42 (dt, 2H), 1.67 (m, 5H), 1.52 (m, 2H), 1.20 (m, 4H), 0.90 (m, 2H).

Example 1224C 4- (1- (1-Methyl-1. 2. 4-triaz-5-yl)-3-cyclohexylpropan-1-ol The compound described in Example 1224A (500 mg, 6.0 mmol) was dissolved in THF (25 mL), cooled to-77 °C, then 2.5M BuLi in hexanes (2.5 mL) was added slowly, keeping the reaction temperature under-66 °C. After stirring at-78 °C for lh the compound described in Example 1224B (0.86 g, 6.1 mmol) was added via syringe. The reaction was stirred cold for 30 min., then allowed to warm to RT, whereupon water was added, and the reaction was extracted with EtOAc. The organic layer washed with brine, dried over Na2S04, then filtered and concentrated. Purification by chromatography using hex/EtOAc 1/3, then EtOAc gave 748 mg (56%). MS (DCI/NH3) 224 (M+H) +.

Example 1224D 4- (1- ( 1-Methyl-1, 2. 4-triaz-5-yl)-3-cyclohexylpropan-1-yloxvmethyl)-2-(2- methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1224C and the bromide described in Example 1178D using the method of Example 1205B. MS (APCI) 462 (M+H) +.

Example 1224E 4-(1-(1-Methyl-1,2,4-triaz-5-yl)-3-cyclohexylpropan-1-yloxym ethyl)-2-(2- methylphenyllbenzoic acid The title compound was prepared from the compound described in Example 1224D using the method of Example 1178H. MS (ESI) 448 (M+H) +.

Example 1224F N- [4- (l- (l-Methyl-1. 2. 4-triaz-5-yl')-3-cyclohexylpropan-l-yloxymethyl)-2- (2- methvlphenyl) benzoyllmethionine methvl ester The title compound was prepared from the compound described in Example 1224E using the method of Example 1205D. MS (APCI) 593 (M+H) +.

Example 1224G N-[4-(1-(1-Methyl-1,2,4-triaz-5-yl)-3-cyclohexylpropan-1-ylo xymethyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1224F according to the method of Example 1178J. lH NMR (DMSO-d6) 5 7.70 (s, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 7.19,7.08,6.95 (all m, total 6H), 4.74 (t, 1H), 4.43 (dd, 2H), 3.86,3.85 (both s, total 3H), 3.70 (m, 1H), 2.20-1.50 (envelope, 17H), 1.20 (m, 6H), 0.80 (m, 2H). MS (ESI) 577 (M-H)-. Anal calcd for C32H41LiN404S 0.60 H20: C, 64.54; H, 7.14; N, 9.41. Found: C, 64.54; H, 7.33; N, 9.37.

Example 1225 <BR> N-14-(1-(1-Methvl-1 2*3-triaz-5-yl !-3-cyclohexylpropan-1-yloxvmethvl)-2-(2- methylphenyl) benzoyllmethionine lithium salt Example 1225A 1-Methyl-1,2,3-triazole Starting with 1,2,3-triazole the title compound was prepared by the method of Example 1224A, except the reaction was stirred at RT overnight. Dist. (88-90 °C/7 mm).

IH NMR (CDC13) 8 7.73 (s, 1H), 7.37 (s, 1H), 4.15 (s, 3H).

Example 1225B 4-(1-(1-Methyl-1,2,3-triaz-5-yl)-3-cyclohexylpropan-1-ol Starting with the compound described in Example 1225A, the title compound was prepared by the method of Example 1224C, except the reaction was 1.5 times more dilute, and was stirred at-55 °C instead of-78 °C (this lithium salt less soluble in THF than the one in Example 1224C). MS (DCI/NH3) 224 (M+H) +.

Example 1225C 4-(1-(1-Methyl-1,2,3-triaz-5-yl)-3-cyclohexylpropan-1-yloxym ethyl)-2-(2- methylphenylbenzoic acid methyl ester The title compound was prepared from the compound described in Example 1225B and the bromide described in Example 1178D using the method of Example 1205B. MS (APCI) 462 (M+H) +.

Example 1225D 4-(1-(1-Methyl-1,2,3-triaz-5-yl)-3-cyclohexylpropan-1-yloxym ethyl)-2-(2- methylphenyl) benzoic acid The title compound was prepared from the compound described in Example 1225C using the method of Example 1178H. MS (ESI) 448 (M+H) +.

Example 1225E N- [4-n-d-Methyl-1. 2. 3-triaz-5-yl)-3-cyclohexylpropan-1-yloxymethyl)-2- (2- methylphenyl) methionine methyl ester The title compound was prepared from the compound described in Example 1225D using the method of Example 1205D. MS (APCI) 593 (M+H) +.

Example 1225F N-[4-(1-(1-Methyl-1,2,3-triaz-5-yl)-3-cyclohexylpropan-1-ylo xymethyl)-2-(2- methylphenyl) benzoyllmethionine lithium salt The above compound was prepared from the compound described in Example 1225E according to the method of Example 1178J. IH NMR (DMSO-d6) õ 7.68 (s, 1H), 7.51 (d, 1H), 7.33 (dd, 1H), 7.19,7.08,6.95 (all m, total 6H), 4.72 (t, 1H), 4.43 (dd, 2H), 3.97,3.98 (both s, total 3H), 3.68 (m, 1H), 2.20-1.50 (envelope, 17H), 1.20 (m, 6H), 0.82 (m, 2H). MS (ESI) 577 (M-H)-. Anal calcd for C32H41LiN404S-0. 25 H20: C, 65.23; H, 7.10; N, 9.51. Found: C, 65.02; H, 7.17; N, 9.21.

Example 1226 N- [4-(3,5-trifluorobenzyloxymethyl)-2-(2-methylphenyl)benzoyl] methionine lithium salt Example 1226A Prepared according to the procedure of example 1290D from the reaction between example 3,5-difluorobenzyl alcohol and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester. NMR (CDCl3) 7.95-8.00 (m, 1H); 7.42-7.48 (m, 1H); 7.10-7.30 (m, 4H); 7.05-7.10 (m, 2H); 6.73-6.80 (m, 1H); 4.65 (s, 2H); 4.55 (s, 2H); 3.60 (s, 3H); 2.06 (s, 3H). (DCI/NH3)/MS: 383 (M+H) +; 400 (M+NH4) +.

Example 1226B N- [4- (3, 5-trifluorobenzyloxymethyl)-2- (2-methphenvl) benzovllmethionine, methvl ester Prepared according to the procedure of example 1258C from 1226A. NMR (CDCl3) 7.82-8.02 (m, 1H); 7.40-7.50 (m, 1H); 7.18-7.40 (m, 5H); 6.80-6.92 (m, 1H); 6.68-6.80 (m, 1H); 5.90-5.96 (m, 1H); 4.65 (s, 2H); 4.56 (s, 2H); 3.65 (s, 3H); 2.00-2.20 (m, 8H); 1.70-2.00 (m, 1H); 1.50-1.70 (m, 1H). (DCI/NH3)/MS: 514 (M+H) +; 531 (M+NH4) +.

Example 1226C N-14- (3, 5-trifluorobenzyloxvmethyl)-2-(2 methvlphenvl) benzovllmethionine(3, 5-trifluorobenzyloxvmethyl)-2-(2 methvlphenvl) benzovllmethionine lithium salt Prepared according to the procedure of example 1178J from 1226B. NMR 1H (d4- MeOH): 7.67-7.77 (1H, m); 7.45-7.5 (1H, m); 7.1-7.35 (6H, m); 6.9-7.0 (2H, m); 6.8- 6.9 (1H, m); 4.65 (2H, s); 4.6 (2H, s); 4.1 (1H, m) 2.2 (1H, s); 1.75-2.1 (8H, m); 1.6- 1.75 (1H, m).. ESI (-)/MS: 498 (M-Li).

Example 1252 <BR> N-4- (1- (4- (N-phenylsulfonyl) piperidinyl) benzyloxymethyl-2- (2- methylphenyl) benzovllmethionine lithium salt.

Example 1252A A mixture of ethyl 1-piperazinecarboxylate (3.14 g, 20 mmol), benzenesulfonyl chloride (3.53 g, 20 mmol), and triethylamine (4.05 g, 40 mmol) in methylene chloride was stirred for 12 hours. The reaction mixture was washed by 10% HCI, brine, and dried over anhydrous MgS04. Evaporation of methylene chloride afforded 5.8 g of the title compound (98%). NMR (CDCl3) 7.75-7.8 (m, 2H); 7.4-7.6 (m, 3H); 4.3-4.1 (m, 2H); 3.5-3.6 (m, 2H); 2.6-2.7 (m, 2H); 2.2-2.3 (m, 1H); 1.9-2.1 (m, 2H); 1.7-1.9 (m, 2H); (m, 3H). (DSI/NH3)/MS: 298 (M+H) +.

Example 1252B 1252A (2. 97 g, 10 mmol) in 20 ml of anhydrous toluene was treated with 1.0 M DiBAL toluene solution (10 ml, 10 mmol) at-78°C. The reaction mixture was stirred for 3 hours at-78°C. The reaction was quenched with 30 ml of 4 N NaOH solution. The organic layer was diluted with 20 ml of EtOAc, washed with brine, and dried over anhydrous MgS04. Flash chromatography of the residue eluting with 1: lEtOAc/Hexane afforded 2.01 g of the title compound. NMR (CDCl3) 9.58 (s, 1H); 7.75-7.8 (m, 2H); 7.4- 7.6 (m, 3H); 3.5-3.6 (m, 2H); 2.6-2.7 (m, 2H); 2.2-2.3 (m, 1H); 1.9-2.1 (m, 2H); 1.7-1.9 (m, 2H). (DSI/NH3)/MS: 254 (M+H) +; 271 (M+NH4) +.

Example 1252C 1252B (0.56 g, 2.2 mmol) in 15 ml of anhydrous THF was treated with 3.0 M phenylmagesium bromide solution (1.6 ml, 4.8 mmol) at 0°C. The reaction was stirred for 2 hours. The reaction was then quenched with saturated NH4Cl solution. 10 ml of EtOAc was added to the solution, and the organic layer was washed with brine, dried over anhydrous MgS04. Flash chromatography of the residue eluting with 1: 1/EtOAc/Hexane afforded o. 48 g of the title compound (65%). NMR (CDC13) 7.7-7.82 (m, 2H); 7.4-7.6 (m, 3H); 7.2-7.4 (m, 5H); 4.3-4.4 (m, 1H); 3.7-3.95 (m, 2H); 2.0-2.3 (m, 4H); 1.92 (m, 1H); 1.2-1.6 (m, 4H). (DSI/NH3)/MS: 332 (M+H) +; 349 (M+NH4) +.

Example 1252D A mixture of 1252C (0.465 g, 1.40 mmol) and 4-bromomethyl-2- (2- methylphenyl) benzoic acid methyl ester (0.45 g, 1.40 mmol) in 1.4 ml of anhydrous DMF was treated with sodium hydride (0.102 g, 4.2 mmol) at 0°C under N2. The reaction mixture was stirred for another 2 hours. The reaction was quenched with 20 ml of water, extracted with EtOAc, washed with brine, and dried over MgS04. Flash chromatography of the residue eluting with 3: 7/EtOAc/Hexane afforded 0.53 of the title compound (67%).

NMR (CDCl3) 7,90-7.98 (m, 1H); 7.70-7.78 (m, 2H); 7.25-7.40 (m, 3H); 7.20-7.38 (m, 4H); 7.00-7.10 (m, 2H); 4.20-4.45 (m, 2H); 3.96-4.02 (m, 1H); 3.70-3.90 (m, 2H); 3.60 (s, 3H); 2.10-2.20 (m, 2H); 2.08 (3H, m); 1.40-1.60 (m, 3H). (DSI/NH3)/MS: 587 (M+NH4)+.

Example 1252E <BR> <BR> <BR> N-r4-(1-(4-(N-phenylsulfonYl ! piperidinvl) benzvloxvmethvl-2-(2-<BR> <BR> <BR> <BR> methvlphenvllbenzoyllmethionine, methvl ester.

Prepared according to the procedure of example 1258C from 1252D. NMR (CDCl3) 7,82-7.98 (m, 1H); 7.70-7.78 (m, 2H); 7.23-7.40 (m, 3H); 7.20-7.38 (m, 5H); 7.10 (s, 1H); 5.88-5.92 (m 2H); 4.55-4.70 (m, 1H); 4.20-4.45 (m, 2H); 3.96-4.02 (m, 1H); 3.70- 3.90 (m, 2H); 3.60 (s, 3H); 2.00-2.20 (m, 10H); 1.80-2.00 (m, 1H); 1.40-1.70 (m, 4H).

DSI/NH3)/MS: 701 (M+H) + ; 718 (M+NH4) +.

Example 1252F

N-[4-(1-(4-(N-phenylsulfonyl)piperidinyl)benzyloxymethyl-2-( 2- methylphenyl) benzoyllmethionine lithium salt.

Example 1253 N-[4-(2-phenyl-1-(4-(N-phenylsulfonyl)piperidinyl)ethyloxyme thyl-2-(2- methylphenyl) benzoyllmethionine lithium salt.

Example 1253A Prepared according to the procedure of example 1291C from the reaction between example 1252B and benzylmagesium bromide. NMR (CDC13) 7.75-7.62 (m, 2H); 7.50- 7.66 (m, 3H); 7.15-735 (m, 5H); 3.93-3.98 (m, 2H); 3.50-3.70 (m, 1H); 2.80-2.90 (m, 1H); 2.50-2.60 (m, 1H); 2.20-2.30 (m, 2H); 1.90-2.00 (m, 1H); 1.70-1.84 (m, 1H); 1.30- 170 (m, 3H). DSI/NH3)/MS: 345 (M+H) +; 363 (M+NH4) +.

Example 1253B

Prepared according to the procedure of example 1290D from the reaction between example 1253A and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester.

NMR (CDC13) 7.85-7.90 (m, 2H); 7.70-7.80 (m, 3H); 7.05-7.45 (m, 9H); 6.94-7.05 (m, 2H); 4.30-4.40 (m, 2H); 3.80-3.95 (m, 2H); 3.60 (s, 3H); 3.50-3.70 (m, 1H); 2.70-2.90 (m, 2H); 2.11-2.23 (m, 2H); 2.05 (s, 3H); 1.80-1.95 (m, 1H); 1.70-1.84 (m, 1H); 1.30- 170 (m, 3H). DSI/NH3)/MS: 601 (M+NH4) +.

Example 1253C Prepared according to the procedure of example 1258C from 12953B.

NMR (CDC13) 7.82-7.95 (m, 1H); 7.70-7.80 (m, 2H); 7.50-7.65 (m, 3H); 7.10-7.40 (m, 10); 6.95 (m, 1H); 5.85-5.92 (m, 1H); 4.55-4.65 (m, 1H); 4.30-4.40 (m, 2H); 3.80-3.95 (m, 2H); 3.64 (s, 3H); 3.50-3.70 (m, 1H); 2.70-2.90 (m, 2H); 1.2-2.3 (m, 13H).

(DSI/NH3)/MS: 715 (M+NH4) +.

Example 1253D N-[4-(2-phenyl-1-(4-(N-phenylsulfonyl)piperidinyl)ethyloxyme thyl-2-(2- methylphenyl) methionine lithium salt.

Prepared according to the procedure of example 1178J from 1252E. NMR 1H (d4- MeOH): 7.4-7.8 (8H, m); 7.0-7.4 (1OH, m); 4.1-4.55 (3H, s); 4.0 (1H, m) 3.6-3.8 (2H, s); 1.1-2.3 (17H, m). ESI (-)/MS: 685 (M-Li); 693 (M+H).

Example 1274A Prepared according to the procedure of example 1290D from the reaction between example 2- (3-fluorophenyl) ethanol and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester. NMR (CDCl3) 7.92-7.98 (m, 1H); 6.84-7.32 (m, 10H); 4.68 (s, 2H); 3.70- 3.76 (t, 2H); 3.60 (s, 3H); 2.90-3.00 (t, 2H); 2.05 (s, 3H). (DCI/NH3)/MS: 379 (M+H) +; 396 (M+NH4) +.

Example 1274B <BR> <BR> <BR> N- [4- (2- (3-fluorophenyl, !) ethyloxymethyl-2- (2-methylphenyl benzoyl] methionine, methyl ester Prepared according to the procedure of example 1178J from 1274B. NMR (CDCl3) 7.82-8.00 (m, 1H); 7.05-7.40 (m, 7H); 6.80-7.00 (m, 2H); 5.83-5.94 (m, 1H); 4.55-4.70 (m, 2H); 3.70-3.78 (t, 2H); 3.64 (s, 3H); 2.90-2.96 (t, 2H); 2.00-2.20 (m, 8H); 1.78-2.00 (m, 1H); 1.50-1.66 (m, 1H). DCI/NH3)/MS: 510 (M+H) +; 527 (M+NH4) +.

Example1274 (A-250000)

N- 4- (2- (3-fluorophenyly) ethvloxymethyl-2- (2-methylphenvl) benzovllmethionine lithium salt ° Prepared according to the procedure of example 1178J from 1274B. NMR 1 H (d4- MeOH): 7.6-7.7 (1H, m); 6.9-7.4 (10H, m); (1H, m); 4.6 (2H, s); 4.1 (1H, m) 3.7-3.75 (2H, s); 2.9-2.95 (2H, s); 1.5-2.2 (1OH, m). ESI (-)/MS: 494 (M-Li).

Example 1282 A Prepared according to the procedure of example 1291C from the reaction between example 1279B andn-butylmagesium bromide. NMR (CDCl3) 3.93-4.10 (m, 2H); 3.30- 3.42 (m, 3H); 1.20-1.80 (m, 11H); 0.95-1.00 (t, 3H). (DCI/NH3)/MS: 173 (M+H) +; 190 (M+NH4) +.

Example 1282B Prepared according to the procedure of example 1290D from the reaction between example 1282A and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester.

NMR (CDCl3) 7.93-7.98 (m 1H); 7.40-7.45 (m, 1H); 7.20-7.30 (m, 4H); 7.08-7.12 (m, 1H); 4.50-4.65 (m 2H); 3.95-4.05 (m, 2H); 3.60 (s, 3H); 3.30-3.45 (m, 3H); 3.12-3.30 (m, 2H); 2.06 (s, 3H); 1.30-1.80 (m, 11H); 0.92-0.96 (t, 3H). (DCI/NH3)/MS: 411 (M+H) +; 428 (M+NH4) +.

Example 1282C N-[4-(1-(4-tetrahydropyranyl)pentyloxymethyl-2-(2-methylphen yl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1282B. NMR (CDCl3) 7.82-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.15-7.36 (m, 5H); 5.83-5.92 (m, 1H); 4.50-4.65 (m, 2H); 4.50-4.68 (m, 3H); 3.94-4.02 (m, 2H); 3.65 (s, 3H); 3.25-3.42 (m, 2H); 3.10- 3.20 (m, 1H); 1.22-2.00 (m, 18H); 0.88-0.92 (t, 3H). (DCI/NH3)/MS: 542 (M+H) +; 559 (M+NH4) +.

Example 1282 (A-241617) N-[4-(1-(4-tetrahydropyranyl)pentyloxymethyl-2-(2-methylphen yl)benzoyl]methionine lithium salt.

Prepared according to the procedure of example 1178J from 1282C. NMR 1H (d4- MeOH): 7.6-7.7 (1H, m); 7.4-7.5 (1H, m); 7.05-7.4 (6H, m); 4.5-4.7 (2H, m); 4.25 (1H, m) 3.9-4.0 (2H, m); 3.2-3.4 (3H, m); (3H, s); 2.25 (1H, s); 1.3-2.2 (20H, m); 0.85-0.95 (3H, m). ESI (-)/MS: 526 (M-Li).

Example 1283A Prepared according to the procedure of example 1291C from the reaction between example 1279B and phenylmagesium bromide. NMR (CDC13) 7.20-7.30 (m, 5H); 4.36- 4.41 (m, 1H); 3.83-4.08 (m, 2H); 3.22-3.42 (m, 2H); 1.05-2.00 (m, 5H).

(DCI/NH3)/MS: 193 (M+H) +; 210 (M+NH4) +.

Example 1283B Prepared according to the procedure of example 1290D from the reaction between example 1283A and 4-bormome. thyl-2- (2-methylphenyl) benzoic acid methyl ester.

NMR (CDCl3) 7.20-7.30 (m, 5H); 4.36-4.41 (m, 1H); 3.83-4.08 (m, 2H); 3.22-3.42 (m, 2H); 1.05-2.00 (m, 5H). (DCI/NH3)/MS: 193 (M+H) +; 210 (M+NH4) +.

Example 1283C N-[4-(1-(4-tetrahydropyranyl)benzyloxymethyl-2-(2-methylphen yl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1258C from 1283B. NMR (CDC13) 7.92-7.92 (m, 1H); 7.13-7.41 (m, 10H); 7.12 (s, 1H); 5.88-5.96 (m, 1H); 4.53-4.70 (m, 1H); 4.22-4.50 (m, 2H); 3.80-4.02 (m, 3H); 3.65 (s, 3H); 3.20-3.42 (m, 2H); 1.02-2.20 (m 15H). (DCI/NH3)/MS: 562 (M+H) +; 579 (M+NH4) +.

Example 1283 fA-241616) N-[4-(1-(4-tetrahydropyranyl)benzyloxymethyl-2-(2-methylphen yl)benzoyl]methionine lithium salt.

Prepared according to the procedure of example 1178J from 1282C. NMR 1H (d4- MeOH): 7.6-7.7 (1H, m); 7.1-7.4 (12H, m); 4.3-4.5 (2H, dd); 4.2-4.3 (1H, m); 4.1 (1H, m); 3.8-4.0 (2H, dd); (2H, s); 2.15 (1H, s); 1.75-2.1 (9H, m); 1.6-1.65 (1H, m); 1.2-1.65 (2H, m); (1H, m). ESI (-)/MS: 546 (M-Li).

Example 1288A <BR> <BR> <BR> N- [4- (I- (4-piperidinyl) pentyloxymethyl-2- (2-methylphenyl) benzoyllmethionine, methyl ester.

A solution of 1289E (0.40 g, 0.625 mmol) 100 ml of methanol was saturated with anhydrous hydrochloride gas. The resulted solution was stirred for 10 hours at room temperature. After methanol was removed under vacuum, the residue was treated with saturated NaHC03, then extracted with EtOAc, washed with brine, and dried over MgSO4.

Evaporation of the solvent afforded 0.32 g of the title compound (95%). NMR (CDCl3) 7.82-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.24 (m, 4H); 7.18 (s, 1H); 5.83-5.93 (m, 1H); 4.50-4.70 (m, 3H); 4.10-4.20 (m, 2H); 3.65 (s, 3H); 3.18-3.22 (m, 1H); 2.57-2.70 (m, 2H); 1.20-2.20 (m, 21H); 0.88-0.94 (t, 3H). (DSI/NH3)/MS: 541 (M+H) +.

Example 1288 (A-245500) N- 4- (1- (4-piperidinyl) pentyloxymethyl-2- (2-methphenvl) benzoyllmethionine lithium salt.

Prepared according to the procedure of example 1178J from 1288E. NMR IH (d4- MeOH): 7.6-7.7 (1H, m); 7.4-7.5 (1H, m); 7.1-7.3 (6H, m); 4.84 (2H, s); 4.2-4.3 (1H, m) 3.3 (1H, m); 3.1-3.2 (2H, m); 3.55-3.7 (2H, m); 2.15 (1H, s); 1.5-2.1 (16H, m); 1.3- 1.5 (SH, m); 0.9-0.95 (3H, m). ESI (-)/MS: 587 (M+H) 533.

Example1289A A mixture of ethyl 1-piperazinecarboxylate (7.85 g, 50 mmol), di-tert-butyl- dicarbonate (13.1 g, 60 mmol) in 60 ml of THF was treated by sodium hydroxide (2.4 g, 60 mmol) in 15 ml of water. After 30 min, TLC indicated that there was no any ethyl 1- piperazinecarboxylate left. The reaction mixture was diluted with 100 ml of ethyl ether, washed by NaHC03 solution, and then dried over anhydrous MgS04. Vacuum distillation of the residue afforded 10.2 g of the title product (80%). NMR (CDC13) 4.10-4.20 (q, 2H); 3.94-4.10 (m, 2H); 2.78-2.90 (m, 2H) 1 2.38-2.50 (M, 1H); 1.80-1.94 (m, 2H); 1.50-1.70 (m, 1H); 1.45 (s, 9H); 1.20-1.28 (t, 3H). (DSI/NH3)/MS: 258 (M+H) +; 275 (M+NH4) +.

Example 1289B Prepared according to the procedure of example 1291B from example 1291A.

NMR (CDC13) 9.84 (s, 1H); 3.92-4.10 (m, 2H); 2.82-3.00 (m, 2H); 2.18 (m, 2.48 (m,

1H); 1.93 (m, 2H); 1.50 1.70 (m, 2H); 1.45 (s, 9H). (DSI/NH3)/MS: 214 (M+H) + ; 23 1 (M+NH4) +.

Example 1289C Prepared according to the procedure of example 1291C from the reaction between example 1289B and butylmagesium bromide. NMR (CDC13) 4.10-4.28 (m, 2H); 3.34- 3.44 (m, 1H); 2.60-2.70 (m, 2H); 1.15-1.80 (m, 20H); 0.88-0.94 (t, 3H). (DSI/NH3)/MS: 272 (M+H) +; 287 (M+NH4) +.

Example 1289D Prepared according to the procedure of example 1290D from the reaction between example 1289C and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester.

NMR (CDCl3) 7.94-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.24 (m, 4H); 7.05-7.10 (m, 1H); 4.50-4.68 (m, 2H); 4.10-4.20 (m, 2H); 3.60 (s, 3H); 3.18-3.22 (m, 1H); 2.57-2.70 (m, 2H); 2.04 (s, 3H). 1.15-1.80 (m, 20H); 0.88-0.94 (t, 3H). (DSI/NH3)/MS: 510 (M+H) +; 527 (M+NH4) +.

Example 1289E N-[4-(1-(4-(N-t-butoxycarbonyl)piperidinyl)pentyloxymethyl-2 -(2- methylphenyl) benzoyllmethionine, methyl ester Prepared according to the procedure of example 1258C from 1289D. NMR (CDCl3) 7.82-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.24 (m, 4H); 7.18 (s, 1H); 5.83-5.93 (m, 1H); 4.50-4.70 (m, 3H); 4.10-4.20 (m, 2H); 3.65 (s, 3H); 3.18-3.22 (m, 1H); 2.57-2.70 (m, 2H); 1.20-2.20 (m, 30H); 0.88-0.94 (t, 3H). (DSI/NH3)/MS: 640 (M+H) +; 657 (M+NH4) +.

Example 1289 (A-245499)<BR> <BR> <BR> <BR> N-[4-(1-(4-(N-t-butoxvcarbonvl) piperidinyl) pentvloxvmethvl-2-(2- methylphenyltbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1289E. NMR 1H (d4- MeOH): 7.6-7.7 (1H, m); 7.4-7.5 (1H, m); 7.1-7.3 (6H, m); 4.84 (2H, m); 4.2-4.3 (1H, m); 4.1-4.2 (2H, m); 3.2 (1H, m); 2.6-2.8 (2H, m); 2.15 (1H, s); 1.2-2.1 (30H, m); 0.9- 0.95 (3H, m). ESI (-)/MS: 633 (M+H).

Example1290A

Prepared according to the procedure of example 1291C from the reaction between example 1291B and t-butylmagesium bromide. NMR (CDCl3) (m, 2H); 7.10- 7.30 (m, 3H); 3.88-3.90 (m, 2H); 3.05-3.10) m, 1H); 2.20-2.35 (m, 2H); 1.60-1.85 (m, 8H); 0.90 (s, 9H). DSI/NH3)/MS: 312 (M+H) +; 329 (M+NH4) +.

Example 1290B Prepared according to the procedure of example 1290D from the reaction between example 1290A and 4-bormomethyl-2- (2-methylphenyl) benzoic acid methyl ester.

NMR (CDC13) 7.92-7.99 (m, 1H); 7.72-7.80 (m, 2H); 7.45-7.62 (m, 3H); 7.38-7.42 (m, 1H); 7.10-7.28 (m, 6H); 4,50-4.70 (m, 2H); 3.88-3.90 (m, 2H); 3.60 (s, 3H); 2.80-2.84 (m, 1H); 2.10-2.30 (m, 2H); 2.05 (s, 3H); 1.60-1.85 (m, 8H); 0.90 (s, 9H).

DSI/NH3)/MS: 567 (M+NH4) +.

Example 1290C <BR> N- [4- (2. 2-dimethyl-l- (4- (N-phenylsulfonyl) piperidinyl) propyloxymethyl-2- (2- methyiphenyDbenzoyIlmethionine. methyl ester.

Prepared according to the procedure of example 1258C from 1290B. NMR (CDC13) 7.92-7.99 (m, 1H); 7.72-7.80 (m, 2H); 7.45-7.62 (m, 3H); 7.38-7.42 (m, 1H); 7.10-7.28 (m, 6H); 5.90-5.95 (m, 1H); 4,50-4.72 (m, 3H); 3.78-3.90 (m, 2H); 3.65 (s, 3H); 2.80- 2.84 (m, 1H); 2.00-2.30 (m, 10H); 1.7-2.0 (m, 2H); 1.60-1.85 (m, 4H); 0.90 (s, 9H).

DSI/NH3)/MS: 681 (M+H) + ; 698 (M+NH4) +.

Example 1290 (A-241624) N-[4-(2,2-dimethyl-1-(4-(N-phenylsulfonyl)piperidinyl)propyl oxymethyl-2-(2- methylphenyl) benzoyllmethionine lithium salt.

Prepared according to the procedure of example 1178J from 1290E. NMR IH (d4- MeOH): 7.7-7.8 (2H, m); 7.5-7.7 (4H, m); 7.2-7.4 (7H, m); 4.84 (2H, m); 4.2-4.3 (1H, m); 3.8 (2H, s); 2.9 (1H, s); 1.6-2.3 (18H, m); 0.9 (9H, s). ESI (-)/MS: 665 (M-Li).

Example 1303 (A-229042 ! N-f4- (1-Cyclohexyl-2-hexyloxymethyl)-2- (2-methylphenyi') benzoylmethionine Lithium Salt Example 1303A 1-Cvclohexylhexan-2-ol A solution of 2.0M propylmagnesium chloride in Et20 (2.0 mL, 4.0 mmol) was added to a solution of the product from Example 1308C (463 mg, 3.3 mmol), copper (I) chloride (33 mg, 0.3 mmol) and chlorotrimethylsilane (460 L, 3.6 mmol) in THF (11 mL)

at 0 °C. After 15 min of stirring, a solution of 2N HCI was added to the reaction vessel and the mixture was extracted with EtOAc (2X). The organic phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; hexanes/EtOAc, 1: 20) to afford the title compound as a clear oil. MS (CI/NH3) m/z: (M+NH4) + 202.

Example 1303B N- 4- (1-Cyclohexvl-2-hexyloxymethyl)-2- (2-methylphenyl) benzovllmethionine methvl ester The product from Example 1303A (355 mg, 1.9 mmol) in DMF (250 tL), the product from Example 1308E (845 mg, 2.3 mmol) in DMF (500 1L), and NaH, 60% dispersion in mineral oil, (85 mg, 2.1 mmol) in DMF (250 RL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 40) to afford the title compound as a clear oil (170 mg, 21%). MS (CI/NH3) m/z: (M+H) + 423.

Example 1303C N-[4-(1-Cyclohexyl-2-hexyloxymethyl)-2-(2-methylphenyl)benzo yl]methioninemethyl ester The product from Example 1303B (170 mg, 0.4 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (95 mg, 0.5 mmol), Hobt (55 mg, 0.4 mmol), (L)-methionine methyl ester hydrochloride (83 mg, 0.4 mmol) and NMM (70 RL, 0.6 mmol) in DMF (1.5 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 5) to afford the title compound as a clear oil (96 mg, 43%). MS (CI/NH3) m/z: (M+H) + 554.

Example 1303D N-[4-(1-Cyclohexyl-2-hexyloxymethyl)-2-(2-methylphenyl)benzo yl]methionineLithium Salt The product from Example 1303C (91 mg, 0.16 mmol) was allowed to react with lithium hydroxide monohydrate (7 mg, 0.17 mmol) in a manner similar to that described in Example 608E to afford the title compound. lH NMR (DMSO-d6,300 MHz) 8 0.81-0.90 (m, 5H), 1.05-1.70 (m, 21H), 1.91-2.03 (m, 5H), 2.16 (m, 1H), 3.41 (m, partially buried under water peak 1H), 3.63 (m, 1H), 4.47 (d, J=12.5 Hz 1H), 4.57 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.08-7.25 (m, 4H), 7.36 (d, J=8.5 Hz 1H), 7.51 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-538; Anal. Calcd for C32H44LiNO4S'1.50 H20: C, 67.11; H, 8.27; N, 2.45. Found: C, 67.13; H, 7.84; N, 2.22.

Example 1304 (A-260016 !

N-[4-(3-Cyclohexyl-1-methoxyprop-2-yloxymethyl)-2-(2- methylphenvl) benzovllmethionine Lithium Salt Example 1304A 3-Cyclohexvlpropan-2-ol The product from Example 1308C (600 mg, 4.3 mmol) in DMF (4.0 mL) was added to a solution of DMF (4.5 mL) and I. OM lithium methoxide in MeOH (4.5 mL, 4.5 mmol) at ambient temperature. The mixture was heated at 65 °C for 18 hours and then allowed to cool to ambient temperature. A solution of 2N HCl was added to the mixture followed by extration with EtOAc (2X). The organic phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 10) to afford a clear oil (505 mg, 68%). 1H NMR (CDC13, 300 MHz) 8 0.77-1.00 (m, 2H), 1.11-1.84 (m, 8H), 3.20 (dd, J=8.9.5 Hz, 1H), 3.38 (dd, J=3,9.5 Hz, 1H), 3.39 (s, 3H), 3.90 (m, 1H).

Example 1304B <BR> <BR> <BR> N-14-(3-Cvclohexvl-1-methoxvprop-2-vloxvmethvl)-2-(2-<BR& gt; <BR> <BR> <BR> methylphenvl) benzoyllmethionine methyl ester The product from Example 1304A (250 mg, 1.4 mmol) in DMF (1.4 mL), the product from Example 1308E (622 mg, 1.4 mmol) in DMF (1.5 mL), and NaH, 60% dispersion in mineral oil, (70 mg, 1.7 mmol) in DMF (4 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 20) to afford the title compound as a clear oil (201 mg, 34%). MS (CI/NH3) m/z: (M+H) + 411.

Example 1304C N-[4- (3-Cyclohexyl-l-methoxyprop-2-yloxymethyl)-2- (2 methylphenyl) benzoyllmethionine methyl ester The product from Example 1304B (193 mg, 0.47 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (126 mg, 0.66 mmol), Hobt (70 mg, 0.52 mmol), (L)-methionine methyl ester hydrochloride (113 mg, 0.56 mmol) and NMM (95 RL, 0.85 mmol) in DMF (2.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 3) to afford the title compound as a clear oil (204 mg, 80%). MS (CI/NH3) m/z: (M+H) + 542.

Example 1304D N-14-(3-Cvclohexvl-l-methoxvprop-2-vloxvmethvl)-2-(2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1304C (195 mg, 0.36 mmol) was allowed to react with lithium hydroxide monohydrate (16 mg, 0.38 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 80.72-1.41 (m, 9H), 1.50-1.77 (m, 9H), 1.80-2.03 (m, 6H), 2.15 (m, 1H), 3.24 (s, 3H), 3.55-3.75 (m, 2H), 4.53 (d, J=12.5 Hz 1H), 4.68 (d, J=12.5 Hz 1H), 6.96 (m, 1H), 7.10-7.27 (m,

4H), 7.36 (d, J=8 Hz 1H), 7.52 (d, J8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-526; Anal.

Calcd for C30H40LiNO5S#0. 90 H20: C, 65.53; H, 7.66; N, 2.55. Found: C, 65.49; H, 7.43; N, 2.46.

Example 1305 (A-257312) <BR> <BR> N-j4- (3-Cyclohexyl-l-propoxyprop-2-yloxymethyl1)- (2- methylphenyl) benzoyllmethionine Lithium Salt Example1305A 3-Cvclohex,1-propoxypropan-2-ol The product from Example 1308C (600 mg, 4.3 mmol) in DMF (4.5 mL), n- propanol (336 RL, 4.5 mmol) in DMF (4.5 mL) and NaH, 60% dispersion in mineral oil, (200 mg, 5.0 mmol) in DMF (10 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1 : 10) to afford a light yellow oil (581 mg, 67%). MS (CI/NH3) m/z: (M+NH4) + 218.

Example 1305B N-[4-(3-Cyclohexyl-1-propoxyprop-2-yloxymethyl)-2-(2- methylphenyl) benzoyl] methionine methyl ester The product from Example 1305A (300 mg, 1.5 mmol) in DMF (1.5 mL), the product from Example 1308E (650 mg, 1.8 mmol) in DMF (2.5 mL), and NaH, 60% dispersion in mineral oil, (75 mg, 1.8 mmol) in DMF (4 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 20) to afford the title compound as a clear oil (344 mg, 52%). MS (CI/NH3) m/z: (M+NH4) + 456.

Example 1305C N-f4- ('3-CyclohexyI-1-propoxyprop-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine methyl ester The product from Example 1306B (334 mg, 0.8 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (215 mg, 1.1 mmol), Hobt (120 mg, 0.9 mmol), (L)-methionine methyl ester hydrochloride (192 mg, 1.0 mmol) and NMM (160 µL, 1.4 mmol) in DMF (3.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 4) to afford the title compound as a clear oil (223 mg, 49%). MS (CI/NH3) m/z: (M+H) + 570.

Example 1305D N- [4-f3-CycIohexyI-l-propoxyprop-2-yIoxymethyl)-2- (2- methylphenyl) )benzoyl]methionine Lithium Salt The product from Example 1305C (218 mg, 0.38 mmol) was allowed to react with lithium hydroxide monohydrate (18 mg, 0.40 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 5 0.74-0.92 (m, 5H), 1.00-1.74 (m, 16H), 1.78-2.03 (m, 6H), 2.15 (m, 1H), 3.29-3.45 (m, 4H), 3.55-3.70 (m, 2H), 4.55 (d, J=12.5 Hz 1H), 4.69 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.35 (d, J=7.5 Hz 1H), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M- H)-554; Anal. Calcd for C32H44LiNO5S'1.25 H20: C, 65.79; H, 8.02; N, 2.40.

Found: C, 65.79; H, 7.72; N, 2.30.

Example1306fA-2573in<BR> N-f4-rlS)-3-Cyclohexvl-1- (1-methylethoxy) prop-2-ylvl]-2- (2- methylphenyl) benzoyllmethionine Lithium Salt

Example 1306A (S)-3-Cyclohexyl-1-(1-methylethoxy)propan-2-ol The product from Example 1308C (600 mg, 4.3 mmol) in DMF (4.5 mL), 2- propanol (348 lL, 4.5 mmol) in DMF (4.5 mL) and NaH, 60% dispersion in mineral oil, (200 mg, 5.0 mmol) in DMF (10 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 12) to afford a clear oil (312 mg, 34%). MS (CI/NH3) m/z: (M+NH4) + 218.

#<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> O<BR> <BR> <BR> <BR> <BR> <BR> #OMe<BR> <BR> <BR> <BR> <BR> <BR> <BR> O<BR> <BR> <BR> O Example 1306B <BR> <BR> <BR> 4- [ (S)-3-Cvclohexvl-1- l-methvlethoxprop-2-yloxymethyll-2- (2-methylphenyl) benzoic acid. methyl ester The product from Example 1306A (300 mg, 1.5 mmol) in DMF (4.5 mL), the product from Example 1308E (659 mg, 1.8 mmol) in DMF (4.5 mL), and NaH, 60% dispersion in mineral oil, (72 mg, 1.8 mmol) in DMF (3 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 20) to afford the title compound as a clear oil (356 mg, 54%). MS (CI/NH3) m/z: (M+H) + 439.

Example 1306C N-[4-[(S)-3-Cyclohexyl-1-(1-methylethoxy)prop-2-yloxymethyl] -2-(2- methyIphenyDbenzoyIlmethionine methyl ester The product from Example 1306B (350 mg, 0.8 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (215 mg, 1.1 mmol), Hobt (120 mg, 0.9 mmol), (L)-methionine methyl ester hydrochloride (192 mg, 1.0 mmol) and NMM (160 RL, 1.4 mmol) in DMF (2.5 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 4) to afford the title compound as a clear oil (176 mg, 38%). MS (CI/NH3) m/z: (M+H) + 570.

Example 1306D N-[4-[(S)-3-Cyclohexyl-1-(1-methylethoxy)prop-2-yloxymethyl] -2-(2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1306C (166 mg, 0.29 mmol) was allowed to react with lithium hydroxide monohydrate (13 mg, 0.31 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 8 0.73-1.44 (m, 16H), 1.50-1.74 (m, 6H), 1.78-2.03 (m, 6H), 2.15 (m, 1H), 3.30-3.59 (m, 4H), 3.67 (m, 1H), 4.55 (d, J=12.5 Hz 1H), 4.69 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.35 (d, J=7 Hz 1H), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-554; Anal. Calcd for C32H44LiNoss0.70 H2O: C, 66.92; H, 7.97 ; N, 2.44. Found: C, 66.97; H, N, 2.31.

Example1307A<BR> <BR> <BR> <BR> <BR> <BR> (S)-l- (tert-B utoxy)-3-cyclohexvl-propan-2-ol (S)-l-(tert-Butoxy)-3-cyclohexyl-propan-2-ol was prepared according to the procedure described by Alan Armstrong et al., Tetrahedron Letters 1988,29: 2483-2486.

Three drops of boron trifuoride etherate were added to a solution of (S)-3-cylcolhexyl 1,2- propanediol (540 mg, 3.4 mmol) and tert-butyl 2,2,2-trichloroacetamide (670 u. L, 3.8 mmol) in cyclohexane (7 mL) at ambient temperature. After stirring for 21 hours, a saturated solution of NaHC03 was added to the reaction mixture and the mixture was extracted with EtOAc (2X). The EtOAc phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 10) to afford a clear oil (235 mg, 32%). IH NMR (CDC13,300 MHz) 8 0.79-1.01 (m, 2H), 1.12-1.53 (m, 6H), 1.20 (s, 9H) 1.58-1.84 (m, 5H), 3.12 (dd, J=9,9 Hz, 1H), 3.35 (dd, J=3,9 Hz, 1H), 3.81 (m, 1H); MS (CI/NH3) m/z: (M+H) + 215.

Example 1307B <BR> 4-f (S)-l-tert-Butoxy-3-cvclohexylprop-2-yloxymethl-2- (2-methylphenyl) benzoic aci methyl ester The product from Example 1307A (226 mg, 1.0 mmol) in DMF (1.0 mL), the product from Example 1308E (460 mg, 1.3 mmol) in DMF (3.0 mL), and NaH, 60% dispersion in mineral oil, (51 mg, 1.3 mmol) in DMF (3 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 15) to afford the title compound as a clear oil (185 mg, 39%). MS (CI/NH3) m/z: (M+H) + 470.

Example 1307C N-[4-[(S)-1-tert-Butoxy-3-cyclohexylprop-2-yloxymethyl]-2-(2 - estermethylphenyl)benzoyl]methioninemethyl The product from Example 1307B (180 mg, 0.40 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (110 mg, 0.56 mmol), Hobt (60 mg, 0.44 mmol), (L)-methionine methyl ester hydrochloride (100 mg, 0.48 mmol) and NMM (80 u. L, 0.72 mmol) in DMF (2.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 6) to afford the title compound as a clear oil (84 mg, 36%). MS (CI/NH3) m/z: (M+H) + 584.

Example 1307D <BR> N-r4-f<'S)-l-tert-Butoxy-3-cyclohexylprop-2-yloxymethyl1- 2-C2- methylphenyl) benzoyl]methionine Lithium Salt

The product from Example 1307C (77 mg, 0.13 mmol) was allowed to react with lithium hydroxide monohydrate (6 mg, 0.14 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 80.75-1.20 (m, 19H), 1.57-1.74 (m, 6H), 1.80-2.03 (m, 6H), 2.15 (m, 1H), 3.26-3.41 (m, 2H), 3.50 (m, 1H), 3.67 (m, 1H), 4.55 (d, J=13 Hz 1H), 4.70 (d, J=13 Hz 1H), 6.95 (m, 1H), 7.12-7.25 (m, 4H), 7.35 (m, 1H), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-568; Anal. Calcd for C33H46LiNO5S'1.80 H20: C, 65.17; H, 8.22; N, 2.30. Found: C, 65.12; H, 7.77; N, 2.34.

Example 1308 (A-260015)<BR> <BR> N- [4- (3-Cvclohexvl-1-butoxyprop-2-yloxymethyl-2- (2-methylpheny) benzol] methionine Lithium Salt Example 1308A (S)-3-Cyclohexyllacticacid To a solution of (S)-3-phenyllactic acid (20g) in ethanol (250mL) was added 5% rhodium on alumina (2.5g), and the reaction was shaken under 4atm H2 for 24h. The reaction was filtered, and concentrated to give product as a white solid (=20g). 1H NMR (300 MHz, CDC13) 8 0.86-1.07 (m, 2H), 1.08-1.39 (m, 3H), 1.54-1.91 (m, 9H), 4.33 (dd, J=9.3,3.6 Hz, 1H). MS (CI/NH3) m/e: (M+NH4) + 190.

Example 1308B (S)-3-Cyclohexyl-1,2-propanediol To a solution of (S)-3-cyclohexyllactic acid (15g) in THF (lOOmL) at 0°C was added 1M BH3-THF (130mL), and the reaction was warmed to ambient temperature. After 5h, the reaction was quenched cautiously with aqueous THF (1: 1,100mL), then with 1M KOH (lOOmL). The reaction was concentrated, diluted with water (200mL), and washed with EtOAc (3X150mL). The organic extracts were washed with brine (lOOmL), dried (MgS04), filtered and concentrated to give a colorless oil (14g). IH NMR (300 MHz, CDC13) 5 0.80-1.04 (m, 2H), 1.05-2.00 (m, 13H), 3.41 (dd, J=10.8,7.5 Hz, 1H), 3.64 (dd, J=10.8,2.7 Hz, 1H), 3.84 (m, 1H). MS (CI/NH3) m/e: (M+NH4) + 176.

Example 1308C (S)-Cyclohexylmethyloxirane To a solution of (S)-3-cyclohexyl-1,2-propanediol in CH2Cl2 was added triethylamine (6.6mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5g), and DMAP (0.386g). After 14h, the reaction was diluted with ether, chilled to 0°C, filtered through celite and concentrated. The residue was dissolved in ethanol (lOOmL), and 1M NaOH was added (32mL). After 30min, the reaction was carefully concentrated, diluted with water (lOOmL) and extracted into ether (3X50mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated to give a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5% EtOAc/hexane, then by bulb-to-bulb distillation under reduced pressure to give a colorless aromatic oil (3.3g, 75%). 1H NMR (300 MHz, CDC13) 8 0.90-1.09 (m, 2H), 1.10-1.85 (m, 11H), 2.43 (dd, J=5.1,2.7 Hz, 1H), 2.75 (dd, J=5.1,4.5 Hz, 1H), 2.94 (m, 1H).

Example 1308D (S)-3-Cvclohexvl-1-butoxv-2-propanol n-Butanol (2.2mL) was dissolved in DMF (50mL) followed by addition of NaH (0. 49g of a 60% oil dispersion). After gas evolution ceased, (S)-cyclohexylmethyloxirane (example 1308C, 0.86g) was added, and the reaction was stirred at ambient temperature overnight. The reaction was warmed to 60°C for one hour, then cooled and quenched by pouring into water (500mL). The mixture was washed with ether/hexane (1: 1,3X150mL), and the organic extracts were washed with brine (lOOmL), dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 7.5% EtOAc/hexane to afford a colorless oil (1.07g, 81%). 1H NMR (300 MHz, CDCl3) 6 0.80- 1.02 (m, 2H), 0.92 (t, J=7.5 Hz, 3H), 1.06-1.83 (m, 16H), 2.27 (brd, J=2.4 Hz, 1H),

3.20 (dd, J=9.6,8.1 Hz, 1H), 3.38-3.53 (m, 3H), 3.82-3.92 (m, 1H). MS (CI/NH3) m/e: (M+NH3) + 232.

Example 1308E 4-Iodomethvl-2- (2-methvlphenvl)(2-methvlphenvl) benzoic acid. methyl ester Triphenylphosphine (5.16g), and imidazole (1.34g) were dissolved in 3: 1 ether: acetonitrile (80mL), and the reaction was cooled to 0°C. Iodine (5.0g) was added with vigorous stirring, and the reaction was warmed to ambient temperature. After Ih, the reaction was recooled to 0°C and 4-hydroxymethyl-2- (2-methylphenyl) benzoic acid, methyl ester (example 1178C, 4.6g) was added as a solution in ether (20mL). After 4h at ambient temperature, the reaction was diluted with hexane/ether (1: 1,200mL) and filtered. The filtrate was washed with a dilute solution of Na2SO3 until colorless, then with water (2X50mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give a light yellow oil (4.7g) which slowly crystalizes in the freezer. IH NMR (300MHz, CDC13) 8 2.06 (s, 3H), 3.60 (s, 3H), 4.45 (ABq, JAB=9.7Hz, AuAg=6.7Hz, 2H), 7.03 (brd, J=6.6Hz, IH), 7.17-7.29 (m, 4H), 7.41 (dd, J=8.1, 1.6Hz, 1H), 7.90 (d, J=8.1Hz, 1H)). MS (CI/NH3) m/e: (M+NH4) + 384.

Example 1308F methyl4-(3-Cyclohexyl-1-butoxyprop-2-yloxymethyl)-2-(2-methy lphenyl)benzoicacid, ester To a solution of (S)-3-cyclohexyl-1-butoxy-2-propanol (example 1308D, l. 0g) in DMF (15mL) was added NaH (0.184g of a 60% oil dispersion). After 15min, the reaction was chilled to 0°C, and 4-iodomethyl-2- (2-methylphenyl) benzoic acid, methyl ester

(example 1308E, 1.54g) was added. After 45min, the reaction was poured into water (150mL), and extracted with EtOAc (2X75mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane to give a colorless oil (1.18g, 62%).

1H NMR (300 MHz, CDC13) 5 0.80-0. 95 (m, 2H), 0.90 (t, J=7.5 Hz, 3H), 1.06-1.71 (m, 15H), 2.06 (s, 3H), 3.38-3.49 (m, 4H), 3.61 (s, 3H), 3.67 (m, 1H), 4.62 (d, J=12.6 Hz, 1H), 4.79 (dd, J=12.6,1.6 Hz, 1H), 7.07 (dt, J=7.2,0.9 Hz, 1H), 7.16-7.28 (m, 4H), 7.42 (dd, J=7.8,1.5 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H). MS (CI/NH3) m/e: (M+NH4) + 470.

Example130Ci <BR> <BR> <BR> N- [4- (3-Cvclohexyl-l-butoxyprop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl methionine methyl ester 4- (3-Cyclohexyl-1-butoxyprop-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid, methyl ester (l. lg) was converted into the title compound by the procedure in examples 608C and D. Product was isolated as a colorless oil (1.06g). I H NMR (300 MHz, CDCl3) 8 0.80-0.95 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 1.07-1.72 (m, 15H), 1.80-1.93 (m, 2H), 2.00-2.20 (m, 8H), 3.37-3.52 (m, 4H), 3.65 (s, 3H), 3.65-3.71 (m, 1H), 4.56-4.68 (m, 1H), 4.62 (d, J=12.6 Hz, 1H), 4.78 (d, J=12.6 Hz, 1H), 5.89 (brd, J=6.3 Hz, 1H), 7.16- 7.47 (m, 5H), 7.44 (brd, J=6.9 Hz, 1H), 7.94 ("dd", J=15.6,7.8 Hz, 1H). MS (APCI (+)) m/e: (M+H) + 584, MS (APCI (-)) m/e: (M-H)-582.

Example13081

N- [4- ('3-Cvclohexvl-l-hutoxyprop-2-vloxvmethyl)-2- ('2-methylphenvl) benzoyl1methionine Lithium Salt N- [4- (3-Cyclohexyl-l-butoxyprop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester (1.05g) was converted to the title compound by the procedure in example 608E. Product was isolated as a white powder (1.02g). 1 H NMR (DMSO-d6, 300 MHz) 5 7.52 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, lH), 7.25-7.10 (m, 4H), 6.95 (m, 1H), 4.69 (d, J=13 Hz 1H), 4.55 (d, J=13 Hz 1H), 3.71-3.53 (m, 2H), 3.45-3.31 (m, 4H), 2.15 (m, 1H), 2.04-1.52 (m, 14H), 1.49-1.00 (m, 10H), 0.95-0.75 (m, 2H), 0.84 (t, J=7 Hz, 3H); MS (CI/NH3) m/z: (M-H)-568; Anal. Calcd for C33H46LiNO5S'I-15 H20: C, 66.45; H, 8.16; N, 2.35. Found: C, 66.43; H, 7.90; N, 2.19.

Example1309fA-237810) N-[4-(3-Cyclohexyl-1-(3,3-dimethylbut-1-yloxy)prop-2-yloxyme thyl0-2-(2- Saltmethylphenyl)benzoyl]methionineLithium Example 1309A (S)-3-Cyclohexyl-1-(3,3-dimethylbut-1-yloxy)propan-2-ol The product from Example 1308C (435 mg, 3.1 mmol) in DMF (2.0 mL), 3,3- dimethylbutanol (400 gel, 3.3 mmol) in DMF (3.0 mL) and NaH, 60% dispersion in mineral oil, (145 mg, 3.6 mmol) in DMF (7.0 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes,, 1: 20) to afford a light yellow oil (458 mg, 57%). 1H NMR (CDC13,300 MHz) 8 0.78-1. 01 (m, 2H), 0.92 (s, 9H), 1.11-1.57 (m, 8H), 1.62-1.85 (m, SH), 3.21 (dd, J=8,9 Hz, 1H), 3.40-3.66 (m, 3H), 3.89 (m, 1H); MS (CI/NH3) m/z: (M+NH4) + 260.

Example 1309B 4- (S-3-Cyclohexvl-l-(3.3-dimethylbut-l-yIoxyprop-2-vloxymethvI 1-2-f2- methvlphenyl) benzoic acid. methvl ester The product from Example 1309A (450 mg, 1.9 mmol) in DMF (2.0 mL), the product from Example 1308E (817 mg, 2.2 mmol) in DMF (5.0 mL), and NaH, 60% dispersion in mineral oil, (90 mg, 2.2 mmol) in DMF (5 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 15) to afford the title compound as an amber oil (563 mg, 63%). 1H NMR (CDC13,300 MHz) 8 0.80-0.95 (m, 2H), 0.90 (s, 9H), 1.08-1.72 (m, 13H), 2.06 (s, 3H), 3.35-3.50 (m, 4H), 3.61 (s, 3H), 3.65 (m, 1H) 4.62 (d, J=13 Hz, 1H), 4.78 (d, J=13 Hz, 1H), 7.05 (d, J=7 Hz, 1H), 7.16-7.27 (m, 4H), 7.43 (dd, J=1,8 Hz, 1H), 7.95 (d, J=8 Hz, 1H); MS (CI/NH3) m/z: (M+H) + 481.

Example 1309C

N-f4- (3-Cyclohexvl-l- 3. 3-dimethylbut-1-vloxv) prop-2-vloxvmethvl)-2- (2- methylphenyl) benzoyllmethionine methyl ester The product from Example 1309B (555 mg, 1. 1 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (310 mg, 1.6 mmol), Hobt (170 mg, 1.3 mmol), (L)-methionine methyl ester hydrochloride (275 mg, 1.4 mmol) and NMM (230 µL, 2.1 mmol) in DMF (5.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 8) to afford the title compound as a clear oil (184 mg, 26%). 1 H NMR (CDC13,300 MHz) 8 0.80-0.95 (m, 2H), 0.89 (s, 9H), 1.07- 1.72 (m, 16H), 1.85 (m, 1H), 1.98-2.10 (m, 6H), 3.37-3.50 (m, 4H), 3.65 (s, 3H), 3.66 (m, 1H) 4.61 (m, 1H), 4.62 (d, J=12.5 Hz, 1H), 4.78 (d, J=12.5 Hz, 1H), 5.89 (d, J=8 Hz, 1H), 7.19 (d, J=2 Hz, 1H), 7.24-7.33 (m, 3H), 7.44 (dd, J=2,8 Hz, 1H), 7.94 (dd, J=8,16 Hz, 1H); MS (CI/NH3) m/z: (M+H) + 612.

Example 1309D N- [4- (3-Cyclohexyl-l- (3, 3-dimethylbut-1-yloxy) prop-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1309C (172 mg, 0.28 mmol) was allowed to react with lithium hydroxide monohydrate (12 mg, 0.29 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 8 0.75-0.94 (m, 2H) 0.85 (s, 9H), 1.05-1.44 (m, 8H), 1.50-1.70 (m, 8H), 1.77-2.04 (m, 6H), 2.15 (m, 1H), 3.35-3.45 (m, 4H), 3.53-3.71 (m, 2H), 4.55 (d, J=12.5 Hz 1H), 4.68 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.35 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-596; Anal. Calcd for C35H5oLiNO5S'1.05 H20: C, 67.51; H, 8.43; N, 2.25. Found: C, 67.53; H, 8.38; N, 2.04.

Example 1310 (A-240191) <BR> N- [4- (3-Cvclohexvl-l-ethvlsulfenylprop-2-yloxymethy)-2- (2- methylphenyl)! benzoyllmethionine Lithium Salt Example1310A<BR> <BR> <BR> <BR> (S)-3-Cyclohexyl-l-ethylthiopropan-2-ol Ethanethiol (317 uJL, 4.3 mmol) was added to a 60% dispersion in mineral oil NaH (180 mg, 4.5 mmol) slurry in DMF (26 mL) at ambient temperature. After stirring for 15 min, the product from Example 1308C (300 mg, 2.1 mmol) in DMF (2.0 mL) was added to the reaction vessel. After stirring for 30 min, a solution of saturated NH4CI was added to the mixture followed by extraction with EtOAc (2X). The organics were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes 1: 20) to afford a light yellow oil (347 mg, 80%). 1H NMR (CDCl3, 300 MHz) # 0. 80- 1.00 (m, 2H), 1.12-1.32 (m, 7H), 1.39-1.75 (m, 6H), 1.81 (m, 1H), 2.42 (dd, J=9,14 Hz, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.74 (dd, J=3,14 Hz, 1H), 3.76 (m, 1H); MS (CI/NH3) m/z: 203 (M+H) +.

Example1310B 4-[(S)-3-Cyclohexyl-1-ethylthioprop-2-yloxymethyl]-2-(2-meth ylphenyl)benzoicacid, methylester The product from Example 1310A (347 mg, 1.7 mmol) in DMF (0.85 mL), the product from Example 1308E (685 mg, 1.9 mmol) in DMF (1.0 mL), and NaH, 60% dispersion in mineral oil, (85 mg, 2.1 mmol) in DMF (4 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 30) to afford the title compound as an amber oil (290 mg, 39%). IH NMR (CDC13,300 MHz) 8 0.80-1.02 (m, 2H), 1.10-1.30 (m, 6H), 1.42-1.93 (m, 8H), 2.06 (s, 3H), 2.56 (q, J=7 Hz, 2H), 2.64 (dd, J=6,13 Hz, 1H), 2.75 (dd, J=5,13 Hz, 1H), 3.61 (s, 3H), 3.65 (m, 1H) 4.56 (d, J=12 Hz, 1H), 4.71 (d, J=12 Hz, 1H), 7.05 (d, J=7 Hz, 1H), 7.16-7.27 (m, 4H), 7.43 (dd, J=1.5,8 Hz, 1H), 7.96 (d, J=8 Hz, 1H); MS (CI/NH3) m/z: (M+NH4) + 458.

Example 1310C<BR> <BR> N-[4-(3-Cyclohexvl-l-ethvlsulfenylprop-2-vloxvmethvl)-2-(2- methylphenyl) benzoyllmethionine methyl ester The product from Example 1310B (220 mg, 0.5 mmol) in MeOH (4 mL) was combined with a saturated solution of LiOH (2 mL) and heated at reflux for 90 min. The reaction mixture was allowed to cool to ambient temperature and concentrated HCl was added to the reaction vessel. The mixture was extracted with EtOAc. The organic phase was dried (MgS04) and concentrated to give the crude acid.

The crude acid was immersed in THF (2 mL) at ambient temperature and a solution of 30% hydrogen peroxide (51 l, uL) was added to the reaction vessel. After stirring for 72 hours, a solution of 10% sodium thiosulfate (2 mL) was added to the reaction mixture followed by concentrated HCI. The mixture was extracted with CH2CI2 (2X). the organic phases were combined, dried (MgS04) and conctrated to dryness to afford the crude sulfoxide.

The crude sulfoxide was then allowed to react with EDCI (135 mg, 0.7 mmol), Hobt (75 mg, 0.55 mmol), (L)-methionine methyl ester hydrochloride (120 mg, 0.6 mmol) and NMM (100 RL, 0.9 mmol) in DMF (2.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc) to afford the title compound as a clear oil (92 mg, 3 1%). MS (CI/NH3) m/z: (M+H) + 588.

Example'1310D<BR> <BR> <BR> <BR> <BR> <BR> N- [4- (3-Cyclohexyl- I-ethylsulfenylprop-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1310A (80 mg, 0.14 mmol) was allowed to react with lithium hydroxide monohydrate (6 mg, 0.14 mmol) in a manner similar to that described in Example 608E to afford the title compound. lH NMR (DMSO-d6, 300 MHz) 6 0.73-0.95 (m, 2H), 1.05-1.25 (m, 6H), 1.32-1.75 (m, 12H), 1.80-2.18 (m, 7H), 1.60-2.85 (m, 2H), 2.95 (m, 1H), 3.68 (m, 1H), 3.92 (m, 1H), 4.49 (d, J=12.5 Hz 1H), 4.64 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.38 (d, J=8 Hz, lH), 7.53 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-572; Anal. Calcd for C3lH42LiNO5S2-3.45 H20: C, 58.01; H, 7.68; N, 2.18. Found: C, 58.02; H, 7.19; N, 1.96.

Example 1311 (A-228419) <BR> N-f4- (3-Cyclohexyl-1-ethylsulfonylprop-2-yloxymethyl)-2- (2- methylphenyllbenzoyllmethionine Lithium Salt Example 1311 A N-[4-(3-Cyclohexyl-1-ethylsulfonylprop-2-yloxymethyl)-2-(2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1310B (285 mg, 0.65 mmol) in MeOH (2.5 mL) was combined with a solution of saturated LiOH (0.75 mL) and heated at reflux for 2 hours.

The mixture was allowed to cool to ambient temperature and concentrated HCl was added to the reaction vessel. The mixture was extracted with CH2C12 (2X). The organic phases were combined, dried (MgS04) and concentrated. MS (CI/NH3) m/z: 444 (M+NH4).

The crude acid and 3-chloroperoxybenzoic acid (460 mg, 2.6 mmol) were immersed in CH2Cl2: EtOH (3.0 mL: 1.0 mL) at ambient temperature and allowed to stir for 24 hours.

A solution of 10% sodium thiosulfate was added to the reaction vessel followed by concentrated HCI. The organic phase was separated, dried (MgS04) and concentrated.

The crude sulfone was then allowed to react with EDCI (180 mg, 0.9 mmol), Hobt (100 mg, 0.7 mmol), (L)-methionine methyl ester hydrochloride (160 mg, 0.8 mmol) and

NMM (130 RL, 1.2 mmol) in DMF (2.5 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 2) to afford the title compound as an oil (178 mg, 44%). IH NMR (CDC13,300 MHz) 8 0.85-1.03 (m, 2H), 1.06-1.94 (m, 17H), 1.98-2.10 (m, 7H), 2.96-3.08 (m, 3H), 3.26 (dd, J=9,15 Hz, 1H), 3.66 (s, 3H), 4.16 (m, 1H), 4.57-4.69 (m, 3H), 5.90 (d, J=8 Hz, 1H), 7.16 (s, lH), 7.25-7.38 (m, 3H), 7.43 (dd, J=l, 8 Hz, 1H), 7.95 (dd, J=8,16.5 Hz, 1H).

Example1311B<BR> <BR> <BR> <BR> N-f4- (3-Cvclohexvl-l-ethylsulfonylprop-2-vloxvmethvn-2- (2- methylphenyl) benzovllmethionine Lithium Salt The product from Example 1311A (169 mg, 0.28 mmol) was allowed to react with lithium hydroxide monohydrate (13 mg, 0.29 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR 97 (m, 2H), 1.03-1.30 (m, 8H), 1.37-2.04 (m, 16H), 2.16 (t, J=7 Hz, 2H), 3.05 (q, J=7 Hz, 2H), 3.67 (m, 1H), 4.55 (s, 2H), 5.30 (m, 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.36 (d, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-588; Anal. Calcd for C3iH42LiN06S2'1. 80 H20: C, 59.27; H, 7.32; N, 2.23. Found: C, 59.25; H, 7.02; N, 2.17.

Example1312 (A-264870)<BR> N- [-(1-Butylthio-3-cvclohexylprop-2-yloxymethyl)-2- (2- methylphenyllbenzoylmethionine Lithium Salt Example 1312A (S)-l-Butylthio-3-cvclohexylpropan-2-ol Butanethiol (765) iL, 7.1 mmol), the product from Example 1308C (500 mg, 3.6 mmol) in DMF (3.0 mL), and NaH, 60% dispersion in mineral oil, (305 mg, 7.6 mmol) in DMF (40 mL) were allowed to react in a manner similar to that described in Example 1310A. The residue was chromatographed (silica gel; EtOAc/hexanes 1: 40) to afford a clear oil (641 mg, 77%). lH NMR (CDC13,300 MHz) 8 0.80-1.00 (m, 2H), 0.92 (t, J= 7 Hz, 3H), 1.08-1.34 (m, 4H), 1.37-1.75 (m, 10H), 1.81 (m, 1H), 2.42 (dd, J=9,13.5 Hz, 1H), 2.53 (t, J=7 Hz, 2H), 2.72 (dd, J=3,13.5 Hz, 1H), 3.76 (m, 1H); MS (CI/NH3) m/z: 231 (M+H) +.

. Example 1312B 4-f (S)-1-Butylthio-3-cvc ! ohexvlprop-2-vloxymethyl1-2- (2-methylphenvl) benzoic acid. methyl ester The product from Example 1312A (308 mg, 1.3 mmol) in DMF (1.5 mL), the product from Example 1308E (588 mg, 1.6 mmol) in DMF (2.5 mL), and NaH, 60% dispersion in mineral oil, (65 mg, 1.6 mmol) in DMF (2.5mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 30) to afford the title compound as an amber oil (361 mg, 59%). MS (CI/NH3) m/z: (M+NH4) + 486.

Example 1312C N- 4- (l-Butylthio-3-cyclohexylprop-2-yoxymethyl)-2- (2- methylphenyl) benzoylmethionine methyl ester The product from Example 1312B (350 mg, 0.75 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (201 mg, 1.0 mmol), Hobt (111 mg, 0.8 mmol), (L)-methionine methyl ester hydrochloride (180 mg, 0.9 mmol) and NMM (150 RL, 1.4 mmol) in DMF (3.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 6) to afford the title compound as a clear oil (252 mg, 56%). lH NMR (CDC13,300 MHz) 8 0.82-0.97 (m, 2H), 0.89 (t, J=7 Hz, 3H), 1.08-1.72 (m, 17H), 1.85 (m, 1H), 1.98-2.10 (m, 7H), 2.53 (t, J=7 Hz, 2H), 2.63 (dd, J=6,13 Hz, 1H), 2.73 (dd, J=5,13 Hz, 1H), 3.64 (m, 1H), 3.66 (s, 3H), 4.55 (d, J=12 Hz, 1H), 4.62 (m, 1H), 4.71 (d, J=12 Hz, 1H), 5.90 (d, J=7.5 Hz, 1H), 7.19 (s, 1H), 7.26-7.34 (m, 3H), 7.44 (dd, J=2,8 Hz, 1H), 7.95 (dd, J=8,16 Hz, 1H).

Example 1312D N- [4- (l-Butylthio-3-cyclohexprop-2-yvmethyl)-2- (2- methylphenyl)! benzovllmethionine Lithium Salt The product from Example 1312C (242 mg, 0.4 mmol) was allowed to react with lithium hydroxide monohydrate (18 mg, 0.42 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 8 0.73-0.93 (m, 2H), 0.82 (t, J=7 Hz, 3H), 1.02-1.74 (m, 20H), 1.77-2.02 (m, 6H), 2.15 (m, 1H), 2.59 (dd, J=6.5,13 Hz, 1H), 2.72 (dd, J=4.5,13 Hz, 1H), 3.55-3.73 (m, 2H), 4.51 (d, J=12.5 Hz, 1H), 4.65 (d, J=12.5 Hz, 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.37 (d, J=7.5 Hz, lH), 7.53 (d, J=8 Hz, 1H) ; MS (APCI (-)) m/z: (M-H)-584; Anal. Calcd for C33H46LiNO4S2#0. 85 H20: C, 65.29; H, 7.92; N, 2.31. Found: C, 65.29; H, 7.45; N, 2.15.

Example 1314 (A-265088) <BR> N-f4- (3-Cvclohexyl-2-hydroxyprop-1-yloxymethvl)-2- (2- methylphenyl) benzovllmethionine Lithium Salt

Example 1314A (3S)-3-Cvclohexyl-2- (4-methoxyphenyl)-1, 3-dioxolane To a solution of (S)-3-cyclohexyl-1,2-propanediol (example 1308B, 5.0g) in toluene (60mL) was added p-anisaldehyde (4.6mL), magnesium sulfate (7.6g), and p- toluenesulfonic acid hydrate (600mg). After stirring 16h at ambient temperature, the reaction was diluted with diethyl ether (lOOmL), filtered through infusorial earth, and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane to give the title compound (an inseparable mixture of diastereomers at the acetal center) as a colorless oil (6.5g, 85%). IH NMR (300 MHz, CDCl3) b 0.85-1.08 (m, 2H), 1.10-1.84 (m, 11H), 3.56 (t, J=7.3 Hz, 0.4H), 3.61 (t, J=7.2 Hz, 0.6H), 3.81 (s, 3H), 4.23-4.38 (m, 2H), 5.75 (s, 0.6H), 5.86 (s, 0.4H), 6.90 (d, J=8.4 Hz, 2H), 7.38- 7.43 (m, 2H). MS (DCI/NH3) m/e 277 (M+H) +.

Example 1314B 3-Cyclohexyl-2- (4-methoxybenzyloxy) propan-1-ol The product from Example 1314A (1.9 g, 7.0 mmol) and a solution of 1. OM borane THF complex (7.7 mL, 7.7 mmol) were combined in THF (20 mL) and heated at reflux for 2 hours. The reaction mixture was allowed to cool to ambient temperature and a solution of saturated NaHC03 was added to the reaction vessel. After stirring for 2 hours the mixture was extracted with EtOAc (2X). The organic phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 4) to afford a clear oil (1.1 g, 56%). 1H NMR (CDC13,300 MHz) 8 0.80-0.97 (m, 2H), 1.10-1.92 (m, 5H), 1.52-1.90 (m, 6H), 3.47 (dd, J=6,11 Hz, 1H), 3.58 (m, 1H), 3.70 (dd, J=3,11 Hz, 1H), 3.81 (s, 3H), 4.48 (d, J=ll Hz, 1H), 4.54 (d, J=ll Hz, 1H), 6.89 (d, J=9 Hz, 2H), 7.27 (d, J=9 Hz, 2H); MS (CI/NH3) m/z: 296 (M+NH4) +.

Example 1314C 4- [ (S)-3vclohexy4-methoxybenzvloxy) prop-1-yloxymethyll-2- (2- methylphenyl) benzoic acid, methyl este The product from Example 1314B (717 mg, 2.6 mmol) in DMF (2.5 mL) was added to NaH, 60% dispersion in mineral oil, (110 mg, 2.7 mmol) in DMF (4 mL) at ambient temperature. After stirring for 20 min, the mixture was cooled to 0 °C and the product from Example 1308E (900 mg, 2.5 mmol) in DMF (3.0 mL) was added to the reaction vessel. After 2.5 hours, water was added to the reaction mixture the mixture was extracted with EtOAc (2X). The organic phases were combined, washed with brine, dried (MgS04) and concentrated. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 20) to afford the title compound as a light yellow oil (584 mg, 46%). MS (CI/NH3) m/z: 534 (M+NH4) +.

Example 1314D <BR> <BR> <BR> 4-1 (S)-3-Cvclohexvl-2-hvdroxvprop-1-vloxvmethvll-2-(2-methvlphe nyl) benzoic acid. methyl ester (182 mg, 0.8 mmol) was added to a solution of the product from Example 1314C (343 mg, 0.7 mmol) in CH2Cl2 (2.5 mL) at ambient temperature. After stirring for 2.5 hours, a solution of EtOAc: hexanes (1: 1) (20 mL) was added to the reaction vessel. The reaction mixture was filtered through celite and the filtrate concentrated. The residue was chronmatographed (silica gel; EtOAc/hexanes, 1: 4) to afford a yellow oil (197 mg, 75%). MS (CI/NH3) m/z: 397 (M+H) +.

Example 1314E N-[4-(3-Cyclohexyl-2-hydroxyprop-1-yloxymethyl)-2-(2- methylphenvl) benzoyllmethionine methyl ester The product from Example 1314D (191 mg, 0.5 mmol) was saponified in a manner similar to that described in Example 608C. The crude acid was then allowed to react with EDCI (130 mg, 0.7 mmol), Hobt (70 mg, 0.5 mmol), (L)-methionine methyl ester hydrochloride (115 mg, 0.6 mmol) and NMM (95, uL, 0.9 mmol) in DMF (2.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 2) to afford the title compound as a clear oil (173 mg, 68%). MS (CI/NH3) m/z: (M+H) + 528.

Example 1314F N-f 4- (3-Cyclohexyl-2-hydroxyprop-1-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1314E (161 mg, 0.31 mmol) was allowed to react with lithium hydroxide monohydrate (13.5 mg, 0.32 mmol) in a manner similar to that described in Example 608E to afford the title compound. lH NMR (DMSO-d6,300 MHz) 8 0.70- 0.94 (m, 2H), 1.06-1.28 (m, 5H), 1.36-2.00 (m, 15H), 2.15 (m, 1H), 3.25-3.36 (m, 2H), 3.63-3.76 (m, 2H), 4.54 (s, 2H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.38 (dd, J=8,1 Hz, lH), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-512; Anal. Calcd for C29H38LiNO5S'1.40 H20: C, 63.93; H, 7.55; N, 2.57. Found: C, 63.95; H, 7.31; N, 2.47.

Example 1315 (A-237785) N- [4- (2-Cyclohexylmethylhex-1-yloxymethyl)-2-2-methphenyl) benzoyl] methionine

Example1315A N-(1-Hydroxy-1-phenylprop-2-yl)-N-methyl-3-cyclohexylpropion amide Thionyl chloride (3.5 mL, 48 mmol) was added to a solution of cyclohexanepropionic acid (5.5 mL, 32 mmol) in CH2Cl2 (60 mL). The mixture was heated at reflux for 60 min and then allowed to cool to ambient temperature and the solvent removed. The residue was redissolved in THF (50 mL) and (1R, 2R) pseudoephedrine (4.8 g, 29 mmol) in THF (60 mL) was added to the reaction mixture at 0 °C. After stirring for 30 min, a solution of saturated NaHC03 was added to the mixture which was then extracted with EtOAc. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes 1: 1) to afford an oil which solidified when placed in the refrigerator over night (8.2 g, 94%). MS (CI/NH3) m/z: 304 (M+H) +.

Example1315B<BR> <BR> N- (l-Hydroxphenylprop-2-yl)-N-methvl-2-butyl-3-cyclohexylpropi onamide

A solution of 2.5M nBuLi in hexanes (5.8 mL, 14.5 mmol), diisopropylamine (2.0 mL, 14.5 mmol), lithium chloride (1.6 g, 39 mmol), iodobutane (130 LL, 6.4 mmol) and the product from Example 1315A (2.0 g, 6.4 mmol) were allowed to react in a manner similar to that described by A. G. Myers et al., Journal of the American Chemical Society 1994,116: 9361-9362. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 4) to afford the title compound as a yellow oil (1.2 g, 53%). MS (CI/NH3) m/z: 360 (M+H) +.

Example 1315C 2-Cyclohexylmethvlhexan-1-ol A solution of 1.6M nBuLi (8.5 mL, 13.6 mmol), lithium amidotrihydroborane (470 mg, 13.6 mmol) and the product from Example 1315B (1.2 g, 3.4 mmol) were allowed to react in a manner similar to that described by A. G. Myers et al., Tetrahedron Letters 1996, 37: 3623-3626. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 8) to afford the title compound as a clear oil (595 mg, 89%).

Example 1315D (R) 4- (2-Cyclohexylmethylhex-1-yloxymethyl)-2- (2-methylphenyl) benzoic acid, methyl ester The product from Example 1315C (185 mg, 0.9 mmol) in DMF (1.0 mL), the product from Example 1308E (380 mg, 1.0 mmol) in DMF (1.0 mL), and NaH, 60% dispersion in mineral oil, (45 mg, 1.1 mmol) in DMF (2 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 50) to afford the title compound as a clear oil (82 mg, 20%). MS (CI/NH3) m/z: (M+H) + 437.

Example 1315E <BR> <BR> <BR> N-l (R) 4-(2-Cyclohexylmethvlhex-1-yloxymethyl-2-(2-methylphenyl) benzovl] methionine methylester The product from Example 1315D (77 mg, 0.2 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (75 mg, 0.4 mmol), Hobt (40 mg, 0.3 mmol), (L)-methionine methyl ester hydrochloride (65 mg, 0.3 mmol) and NMM (55 RL, 0.5 mmol) in DMF (1.0 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 6) to afford the title compound as a clear oil (56 mg, 36%). MS (CI/NH3) m/z: (M+H) + 568.

Example 1315F <BR> <BR> N-r4- (2-Cyclohexylmethylhex-1-yloxymethyl)-2- (2-methylphenyl) benzoyl1methionine Lithium Salt The product from Example 1315E (48 mg, 0.08 mmol) was allowed to react with lithium hydroxide monohydrate (4 mg, 0.09 mmol) in a manner similar to that described in Example 608E to afford the title compound. MS (APCI (-)) m/z: (M-H)-552; IH NMR (DMSO-d6,300 MHz) 8 0.74-0.86 (m, 5H), (m, 12H), 1.54-2.02 (m, 15H), 2.15 (m, 1H), 3.26-3.32 (m, 2H), 3.65 (m, 1H), 4.50 (s, 2H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.34 (d, J=8, Hz, lH), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-552; Anal. Calcd for C33H46LiNO4S'1.30 H20: C, 67.97; H, 8.40; N, 2.40. Found: C, 67.92; H, 8.06; N, 2.35.

Example1316 (A-264976)<BR> N- [4- (3-Cvclohexyl-2-4-methoxybenzyloxylprop-loxvmethyll-2- (2- Saltmethylphenyl)benzoyl]methionineLithium Example1316A N-[4-(3-Cyclohexyl-2-(4-methoxybenzyloxy)prop-1-yloxymethyl) -2-(2- methylphenyl) benzoyl_lmethionine methyl ester The product from Example 1314C (188 mg, 0.4 mmol) was saponified in a manner similar to that described in Example 608C. The crude acid was then allowed to react with EDCI (97 mg, 0.5 mmol), Hobt (55 mg, 0.4 mmol), (L)-methionine methyl ester hydrochloride (86 mg, 0.4 mmol) and NMM (75, uL, 0.6 mmol) in DMF (1.5 mL) in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 4) to afford the title compound as a clear oil (120.5 mg, 52%). MS (CI/NH3) m/z: (M+H) + 648.

Example 1316B N-[4-(3-cyclohexyl-2-(4-methoxybenzyloxy)prop-1-yloxymethyl) -2-(2- methylphenyl) benzoylmethionine Lithium Salt The product from Example 1316A (107 mg, 0.26 mmol) was allowed to react with lithium hydroxide monohydrate (7 mg, 0.17 mmol) in a manner similar to that described in Example 608E to afford the title compound. IH NMR (DMSO-d6,300 MHz) 8 0.66-0.91 (m, 2H), 1.02-1.40 (m, 6H), 1.48-2.16 (m, 15H), 3.43-3.71 (m, 4H), 3.72 (s, 3H), 4.38 (d, J=11.5 Hz, 1H), 4.53 (d, J=11.5 Hz, 1H), 4.57 (s, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.95 (m, 1H), 7.10-7.25 (m, 6H), 7.37 (d, J=8, Hz, 1H), 7.53 (d, J=8 Hz, 1H) ; MS (APCI (-)) m/z: (M-H)-632; Anal. Calcd for C37H46LiNO6S#1. 25 H20: C, 67.10; H, N, 2.11. Found: C, 67.09; H, 6.95; N, 1.92.

Example 1343 <BR> <BR> N-f4- (3-hydroxybenzyloxymethyl-2- (2-methylphenyl) benzoyl] methionme. Lithium Salt Example 1343A 4-Hydroxymethyl-tert-butyldimethylsiloxybenzene The title compound was prepared according to the procedure in example 1042A, replacing methyl salycilate with methyl 3-hydroxybenzoate, and was isolated as a colorless oil. 1H NMR (300 MHz, CDC13) 8 0.20 (s, 6H), 0.99 (s, 9H), 4.64 (brs, 2H), 6.76 (ddd, J=8.3,2.4,0.9 Hz, 1H), 6.86 (t, J=1.5 Hz, 1H), 6.94 (dm, J=7.2 Hz, 1H), 7.91 (tus J=7.8 Hz, 1H).

Example 1343B <BR> <BR> 4- (3-tert-ButyIdimethylsiloxvbenzyl)-2- (2-methylphenvl) benzoic acid, Methyl Ester The title compound was prepared from 4-hydroxymethyl-tert- butyldimethylsiloxybenzene according to the procedure described in example 1308F, and was isolated as a colorless oil. MS (APCI (+)) m/e 494 (M+NH4) +. MS (APCI (-)) m/e 475 (M-H)-.

Example 1343C EsterN-[4-(3-Hydroxybenzyloxymethyl)-2-(2-methylphenyl)benzo yl]methionine,Methyl The title compound was prepared from 4- (3-tert- butyldimethylsiloxybenzyloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in example 1308G. MS (APCI (+) m/e (M+H) + 494, MS (APCI (-) m/e (M-H)-492.

Example 1343D SaltN-[4-(3-hydroxybenzyloxymethyl)-2-(2-methylphenyl)benzoy l]methionine,Lithium N- [4- (3-hydroxybenzyloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted to the title compound by the procedure in example 1308H. The product

was isolated as a white powder. 1H NMR (300 MHz, DMSO) 8 1.49-1.75 (m, 4H), 1.90 (s, 3H), 1.95-2.15 (m, 3H), 3.60-3.72 (m, 1H), 4.44 (d, J=5 Hz, 2H), 5.13-5.19 (m, 3H), 6.82-6.90 (m, 2H), 6.94-6.98 (m, 2H), 7.10-7.25 (m, 6H), 7.47 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H). MS (APCI (-)) m/e 478 (M-H); Analysis calc'd for C27H28LiNO5S#1.20H20 : C, 63.95; H, 6.04; N, 2.78; found: C, 63.97; H, 5.90; N, 2.66.

(27017 1) Example 1344<BR> N- [4- (- I-sec-Butoxy-3-cyclohexylprop-2-yloxymethyl)-2- (2- methylphenvl ! benzoyllmethionine Lithium Salt Example 1344A l-sec-Butoxy-3-cvclohexylpropan-2-ol The product from Example 1308C (420 mg, 3.0 mmol) in DMF (3.0 mL), 2-butanol (1.1 mL, 12.0 mmol) in DMF (6.0 mL) and NaH, 60% dispersion in mineral oil, (240 mg, 6.0 mmol) in DMF (12 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 12) to afford a clear oil (355 mg, 55%). MS (CI/NH3) m/z: (M+NH4) + 232.

Example 1344B <BR> <BR> <BR> N-f4- (l-sec-Butoxy-3-cyclohexylprop-2-hyl)-2- (2-<BR> <BR> <BR> <BR> methylphenyl) benzoyllmethionine methyl este The product from Example 1344A (345 mg, 1.6 mmol) in DMF (1.6 mL), the product from Example 1308E (560 mg, 1.5 mmol) in DMF (1.5 mL), and NaH, 60% dispersion in mineral oil, (68 mg, 1.7 mmol) in DMF (3.2 mL) were allowed to react in a manner similar to that described in Example 1308F. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 30) to afford the title compound as a clear oil (289 mg, 42%). MS (CI/NH3) m/z: (M+H) + 453.

Example 1344C N-[4- (1-sec-Butoxy-3-Cyclohexylprop-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine methyl este The product from Example 1344B (280 mg, 0.62 mmol) was saponified in a manner similar to that described in Example 1308G. The crude acid was then allowed to react with EDCI (166 mg, 0.88 mmol), Hobt (92 mg, 0.68 mmol), (L)-methionine methyl ester hydrochloride (150 mg, 0.74 mmol) and NMM (125 fiL, 1.1 mmol) in DMF (1.5 mL) in a manner similar to that described in Example 1308G. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 6) to afford the title compound as a clear oil (168 mg, 46%). MS (CI/NH3) m/z: (M+H) + 584.

Example 1344D N-[4-(1-sec-Butoxy-3-cyclohexylprop-2-yloxymethyl)-2-(2- methylphenyl) benzoyllmethionine Lithium Salt The product from Example 1344C (153 mg, 0.26 mmol) was allowed to react with lithium hydroxide monohydrate (12 mg, 0.27 mmol) in a manner similar to that described in Example 1308H to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 8 0.75-1.68 (m, 25H), 1.78-2.02 (m, SH), 2.15 (m, 1H), 3.25-3.58 (m, 4H), 3.65 (m, 1H), 4.55 (d, J=12.5 Hz 1H), 4.69 (d, J=12.5 Hz 1H), 6.95 (m, 1H), 7.10-7.24 (m, 4H), 7.36 (d, J=7 Hz 1H), 7.52 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-568; Anal. Calcd for C33H46LiNO5S-0.70 H20: C, 67.37; H, 8.12; N, 2.38. Found: C, 67.33; H, 7.79; N, 2.13.

Example 1345 <BR> N-f4- (3-Cyclohexyvclobutoxyprop-2-yloxvmethyl)-2- (2- methylphenyl) benzoyllmethionine, Lithium Salt

Example 1345A (S)-3-Cyclohexyl-1-cyclobutoxv-2-propanol The title compound was prepared according to example 1308D, replacing n-butanol with cyclobutanol. MS (CI/NH3) m/e 230 (M+NH4) +.

Example 1345B <BR> <BR> N-f4- (3-Cvclohexyl-l- (cyclobutoxyprop-2-ymethyl)-2- (2-methylphenvl) benzoic acid, MethylEster The title compound was prepared from (S)-3-cyclohexyl-1-cyclobutoxy-2-propanol according to example 1308F. MS (APCI (+)) m/e 451 (M+H) +, 468 (M+NH4) +.

MS (APCI (-)) m/e 449 (M-H)-.

Example 1345C <BR> N-f4- (3-Cyclohexvl-1-cvclobutoxyprop-2-yloxyYl)-2- (2- Estermethylphenyl)benzoyl]methionine,Methyl

The title compound was prepared from N- [4- (3-cyclohexyl-l-cyclobutoxyprop-2- yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in example 1308G. MS (APCI (+)) m/e 582 (M+H) +. MS (APCI (-)) m/e 580 (M-H)-.

Example 1345D N- [4- (3-Cyclohexyl-l-cyclobutoxyprop-2-yloxymethyl)-2- (2- methylphenvl) benzoy, methionine, Lithium Salt The title compound was prepared from N- [4- (3-cyclohexyl-l-cyclobutoxyprop-2- yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 1308H, and was isolated as a white powder. 1H NMR (300 MHz, DMSO) 8 0.70-0.95 (m, 2H), 1.00-2.18 (m, 24H), 1.91 (s, 3H), 2.27-3.32 (m, 1H), 3.52-3.71 (m, 2H), 3.86 (quintet, J=7.2 Hz, 1H), 4.54 (d, J=12.6 Hz, 1H), 4.67 (d, J=12.6 Hz, 1H), 6.89-6.98 (m, 1H), 7.07-7.26 (m, 5H), 7.36 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H). MS (APCI (+)) m/e 586 (M+H) +, MS (APCI (-)) 586 (M-H)- ; Analys calc'd for C33H44LiNOsS0.30H20: C, 68.44; H, 7.76; N, 2.42; found: C, 68.44; H, 7.53; N, 2.35.

Example 1346

N-[4-(3-Cyclohexyl-1-(2,2-dimethyl-1,3-dioxolan-4-methanoxy) prop-2-yloxymethyl)-2-(2- methylphenvl) benzovllmethioninez Lithium Salt Example 1346A 3-Cyclohexyl-1- (2, 2-dimethyl-1, 3-dioxolan-4-methanoxy)-2-propanol The title compound was prepared according to example 1308D, replacing n-butanol with ()-2,2-dimethyl-1,3-dioxolane-4-methanol. MS (CI/NH3) m/e 290 (M+NH4) +.

Example1346B N-[4-(3-Cyclohexyl-1-(2,2-dimethyl-1,3-dioxolan-4-methanoxy) -prop-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid. Methvl Ester The title compound was prepared from 3-cyclohexyl-1- (2, 2-dimethyl-1,3-dioxolan- 4-methanoxy)-2-propanol according to example 1308F. MS (APCI (+)) m/e 511 (M+H) +, 528 (M+NH4) +.

Example 1346C N-[4-(3-Cyclohexyl-1-(2,2-dimethyl-1,3-dioxolan-4-methanoxy) -prop-2-yloxymethyl)-2- (2-methylphenyl ! benzoyl] methionine Methvl Ester The title compound was prepared from N- [4- (3-cyclohexyl-l- (2, 2-dimethyl-1,3- dioxolan-4-methanoxy)-prop-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in example 1308G. MS (APCI (+)) m/e 642 (M+H) +.

MS (APCI (-)) m/e 640 (M-H)-.

Example 1346D <BR> <BR> <BR> N-f4- (3-Cyclohexvl-1- (2, 2-dimethyl-1, 3-dioxolan-4-methanoxv)-prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyllmethionine, Lithium Salt The title compound was prepared from N- [4- (3-cyclohexyl-1- (2, 2-dimethyl-1,3- dioxolan-4-methanoxy)-prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 1308H, and was isolated as a white powder. 1H NMR (300 MHz, DMSO) 8 0.70-0.95 (m, 2H), 1.04-1.68 (m, 11H), 1.24 (s, 3H), 1.28 (s, 3H), 1.74-1.89 (m, 2H), 1.90-2.20 (m, SH), 1.92 (s, 3H), 3.28-3.73 (m, 7H), 3.93 (t, J=7.5 Hz, 1H), 4.14 (quintet, J=6.0 Hz, 1H), 4.54 (d, J=12.6 Hz, 1H), 4.70 (d, J=12.6 Hz, 1H), 6.90-6.98 (m, 1H), 7.09-7.26 (m, SH), 7.36 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H). MS (APCI (+)) m/e 628 (M+H) +, MS (APCI (-)) 626 (M-

H)- ; Analysis calc'd for C35H48LiNO7S-0-65H20: C, 65.13; H, 7.70; N, 2.17; found: C, 65.13; H, 7.44; N, 2.10.

Example 1347 N-[4-(3-Cyclohexyl-1-(2,3-dihydroxy-1-propoxy)-prop-2-yloxym ethyl)-2-(2- methylpheny benzoyllmethionine. Lithium Salt Example 1347A N- [4- (3-Cyclohexyl-l- (2. 3-dihydroxy-l-propoxy)-prop-2-yloxymethyl)-2- (2- methylphenyl) benzoyllmethionine, Methyl Ester To a solution of N- [4- (3-cyclohexyl-1- (2, 2-dimethyl-1,3-dioxolan-4-methanoxy)- prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester (example 1346C, 330mg) in methanol (2mL) was added p-toluenesulfonic acid hydrate (lOmg). After 3h, the solvent was removed under a stream of dry nitrogen, and the residue was purified by silica gel chromatography eluting with 50%-100% EtOAc/hexane to give the title compound (230mg, 75%) as a colorless oil. MS (APCI (+)) m/e 602 (M+H) +. MS (APCI (-)) m/e 600 (M-H)-.

Example 1347B N- [4- 3-Cvclohexyl-l- (2, 3-dihvdroxv-l-propoxy)-prop-2-yloxvmethvl)-2- (2- methylphenyl) benzoyllmethionine, Lithium Salt The title compound was prepared from N- [4- (3-cyclohexyl-l- (2, 3-dihydroxy-1- propoxy)-prop-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 1308H, and was isolated as a white powder. I H NMR (300 MHz, DMSO) 8 0.70-0.94 (m, 2H), 1.02-1.74 (m, 11H), 1.74-2.18 (m, 7H), 1.91 (s, 3H), 3.23-3.68 (m, 9H), 4.49-4.55 (m, 1H), 4.54 (d, J=12.6 Hz, 1H), 4.65 (dd, J=4.8,3.3 Hz, 1H), 4.70 (d, J=12.3 Hz, 1H), 6.89-6.97 (m, 1H), 7.06-7.23 (m, 5H), 7.37 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H). MS (APCI (+)) m/e 588 (M+H) +, (APCI (+)) 586 (M-H)- ; Analysis calc'd for C32H44LiNO7SH2O: C, 63.49; H, 7.54; N, 2.31; found: C, 63.48; H, 7.24; N, 2.24.

Example 1348 <BR> N- 4- (3-cyclohexvl-N-thiomorpholin-S. S-dioxide-4-vlpropion-2-yloxymethyll-2- (2- methylphenyl) benzoylmethionine, Lithium Salt

Example 1348A 4- (3-Cyclohexvl-N-thiomorpholin-S. S-dioxide-4-ylpropion-2-yloxymethvl--2- (2- methylphenyDbenzoic acid. Methyl Ester To a solution of 4- (3-cyclohexyl-N-thiomorpholin-4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (example 1054B, 170mg) in dichloromethane (2.0mL) at ambient temperature was added m-chloroperbenzoic acid (207mg, 55% pure).

After 15min, the reaction was quenched by the addition of dilute aqueous sodium sulfite.

The reaction was diluted with ether (50mL), and washed with 1M NaOH (2X5mL), and brine (2X5mL). The organic solution was dried (MgS04), filtered and concentrated to afford a light yellow oil which was purified by silica gel chromatography eluting with 30%- 50% EtOAc/hexane to give a colorless oil (150mg, 84%). MS (APCI (+)) m/e 528 (M+H) +.

Example 1348B <BR> N-r4- (3-Cyclohexyl-N-thiomorpholin-S. S-dioxide-4-ylpropion-2-yloxymethvl)-2- (2-<BR> <BR> methylphen3rl) benzoyllmethionines Methyl Ester The title compound was prepared from 4- (3-cyclohexyl-N-thiomorpholin-S, S- dioxide-4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester according to the procedure in example 1308G. MS (APCI (+)) m/e 659 (M+H) +. MS (APCI (-)) m/e 657 (M-H)-.

Example 1348C N-f4- (3-Cyclohexvl-N-thiomorpholin-S, S-dioxide-4-ylpropion-2-yloxymethvl)-2- (2- methylphenyl) benzoyl1methionine. Lithium Salt N- [4- (3-Cyclohexyl-N-thiomorpholin-S, S-dioxide-4-ylpropion-2-yloxymethyl)-2- (2-methylphenyl) benzoyl] methionine methyl ester was converted into the title compound according to the procedure in example 1308H, and was isolated as a white powder. IH NMR (300 MHz, DMSO) 8 0.76-0.99 (m, 2H), 1.02-1.22 (m, 3H), 1.36-1.75 (m, 8H), 1.75-2.29 (m, 7H), 1.92 (s, 3H), 3.11-3.22 (m, 4H), 3.61-3.73 (m, 1H), 3.74-3.86 (m, 2H), 3.90-4.02 (m, 3H), 4.34-4.37 (m, 1H), 4.41 (d, J=12.3 Hz, 1H), 4.62 (d, J=12.3 Hz, 1H), 6.96 (brs, 1H), 7.12-7.27 (m, 5H), 7.38 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H). MS (APCI (-)) m/e 643 (M-H); Analysis calc'd for C33H43LiN207S2'1.9H20: C, 57.86; H, 6.89; N, 4.09; found: C, 57.90; H, 6.89; N, 4.07.

Example 1349-A Pyridazine-4-carboxaldehyde Starting with the compound described in Example 1221C, the title compound was prepared by a Swern oxidation as outlined in Example 1224B, except after warming to RT and diluting with Et20, there was no aqueous work-up. Instead, the Et20 slurry was filtered through celite, the filtrate concentrated, and the material purified by chromatography using EtOAc. MS (DCI/NH3) 109 (M+H) + and 126 (M+H+NH3) +.

Example 1349-B 1-!-3-cvclohexvlpropan-1-ol The bromide described in Example 1207A was converted to the Grignard reagent, resulting in a THF solution ca. 0.8M. That solution (3.5 mL, 2.8 mmol) was added to a mechanically stirred solution of the compound described in Example 1349-A (300 mg, 2.8 mmol) in THF (30 mL) at-44 °C (dry ice-CH3CN bath). The reaction was stirred at-44 °C for 50 min., then water was added and the reaction allowed to warm to RT. Used 2N HCl to adjust to pH 3, then extracted with EtOAc. The EtOAc solution was dried over Na2SO4, filtered, concentrated, and the residue purified by chromatography using EtOAc/EtOH 98/2.

Recovered 74 mg (12%). MS (DCI/NH3) 221 (M+H) + and 238 (M+H+NH3) +.

Example 1349C <BR> <BR> 4- (1- (Pvridazin-4-yl)-3-cyclohexvlpropan-1-yloxymethvl)-2- (2-methylphenvl) benzoic acid methyl ester The bromide described in Example 1132D and the alcohol described in Example 1349-B were reacted to give the title compound using the method of Example 1221D. MS (APCI) 459 (M+H) +.

Example1349D 4-(1-(Pyridazin-4-yl)-3-cyclohexylpropan-1-yloxymethyl)-2-(2 -methylphenyl)benzoicacid Starting with the compound described in Example 1349-C, the title compound was prepared by the method of Example 1205C, except that during the work-up, the aqueous layer was water and enough 2N HCl to get pH 3-4. MS (ESI) 443 (M-H)-.

Example 1349E <BR> <BR> N- 4- (l- (Pvridazin-4-y)-3-cvclohexylpropan-l-oxymethvl)-2- (2-methvlphenvl) benzoyl] methionine methyl ester Starting with the compound described in Example 1349-D, the title compound was prepared by the method of Example 1205D, except that during the work-up, the 2N HCl wash was eliminated, and the chromatography used hex/EtOAc 3/7. MS (APCI) 590 (M+H) +.

Example 1349F N-[4-(1-(Pyridazin-4-yl)-3-cyclohexylpropan-1-yloxymethyl)-2 -(2- methvlphenvltbenzovllmethionine lithium salt Starting with the compound described in Example 1349-E, the title compound was prepared by the method of Example 1132H. IH NMR (DMSO-d6) 8 9.22 (s, 1H), 9.18 (d, 1H), 7.63 (m, 1H), 7.51 (d, 1H), 7.36 (m, 1H), 7.20,7.12,6.94 (all m, total 6H), 4.50, 4.40 (both m, total 3H), 3.68, (m, 1H), 2.20-1.50 (envelope 17H), 1.10 (m, 6H), 0.79 (m, 2H). MS (ESI) 574 (M-H)-. Anal calcd for C33H40LiN304S 0.80 H20: C, 66.49; H, 7.03; N, 7.05. Found: C, 66.47; H, 7.02; N, 6.94.