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 Ri 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 L I I 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)-, R I 2a 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 R12b are not both hydrogen, (2)-Ll I-C (RI4) (RV)-C (O) ORIs wherein Lll 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 R14 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, (j) 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 (=O), -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 (Rz4)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl, (6)-Ll l-heterocycle,

(7)-C (O) NH-CH (RI4)-C (O) NR} 7Ri8 wherein R14 is defined previously and Rl7 and R 18 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-CI6-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 RC 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 Ré 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 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> <BR> -NRR3RR3',<BR> <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, L5 is absent or selected from the group consisting of (a) Cl-to-Clo-alkylene and (b) C2-to-cl6-alkenylene wherein (a) and (b) are unsubstituted or substituted as defined previously, and R5 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 -LI l-C (Rl4) (Rv)-C (o) oRl5 (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-L5- wherein L4 and Ls are defined previously and m is 0,1, or 2, (4)-L4-L6-C (W)-N (R6)-L5- wherein L4, W, and L5 are defined previously, R6 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, 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 (R5)-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-Clo-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, (f) cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy,

(9) C2-to-c I o-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-CI0-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, (f)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)-O-, (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, (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)-SO2NRAeRg wherein RAE and Ra 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 L1, 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 L1, Z, and R3 together are (1)- (5), Rl 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, l-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 formyl, 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 alkanoylaminoalkyl 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 herein refers 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 R 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 Ry 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-, -CH2C-C-,-CH2C-CCH2-, 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 R65-0-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 R7-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 a cycloalkyl group. The cycloalkylaminocarbonyl groups of this invention can be optionally substituted.

The term"cycloalkylaminothiocarbonyl"as used herein refers to NHR60C (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 R. 4-0-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) -S03H, 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-LI7-C (O) OR40 wherein L17 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-L18-C (O) NR43R44 wherein L18 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-L19-CN wherein L19 is an alkylene radical, ff)-S-L20-R45 wherein L2 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)-0-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 (=CHNR41R42 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 (O) 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, m) 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-L2g- wherein L28 is an alkylene group, jjjj) 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 Ri is unsubstituted or substituted phenyl and R2 is-C (O) NH-CH (RI4)-C (O) OR15 or -C (O) NH-CH (RI4)-C (O) NHSo2Rl6 wherein L2, R14 R15 and R16 are defined above.

More preferred compounds of the invention are compounds of formula I wherein Ri 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 immediately above wherein R. is unsubstituted or substituted phenyl and R2 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 1X10-5 M Example at 1xi-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 58 383 > 50 753 55 387 > 50 754 40 388 > 50 755 44 390 > 50 756 47 639 44 757 58 659 55 758 46 663 43 759 49 664 75 952 > 50 669 52 955 50 670 78 974 > 50 672 48 Table 2. Inhibition of farnesvltransferase % inhibition % inhibition Example at lX10-6 M 157 92 583 98 158 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 78731593 78831663 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 139o Table 3. Inhibition of farnesyltransferase % inhibition % inhibition Example at ExampleM at 1X10-7 M 6239643493 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 84 622 95 993 90 Table 4. Inhibition of farnesyltransferase % inhibition % inhibition Example at 1X10-8 MExample at IX10-8 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 geranylgeranyltransferase I.

Example Activity 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 % inhibition % inhibition 1mM10mM1mM10mM 11997199791** 998 79** 1200 97* 120173*99990 1000 82* 1202 96** 92** 1203 84* 1002 82** 1204 93* 1003 92* 1205 55** 1004 92** 1206 63** 1005 95** 1207 91* 1006 95** 1208 89* 120987*100785** 1008 95** 1210 64** 1009 86** 1211 94 1010 90* 1212 86* 121379**101192** 121492**101288* 121517101380* 1014 88**1216 1015 87*1217 1016 54**1218 121985**101751* 1220101897 122182**101970 122289*102039 122391**102193* 122488*102291** 1023 89** 1225 92** 1024 69**1226 1025102591** 91 122888*102674** 122966**102781** 123077**102892** 123193*102982** 1030 68**1232 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** 125184*105062** 1051 76*1253 125467105291** 125582*105360** 125693*105489** 125793**105585** 1056 97**1258 125989**105782* 126090**105889 126194105992* 126295106042 126385*106188* 126483**106293 126590106392** 1064 85*1266 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 128685**108476** 128795**108593* 128869*108687* 128993108776* 129080108873* 1291108986* 1292109081** 1293109187* 1294109274** 1295109395** 1296109496** 1297109576* 129897**109686* 129996**109780** 130097*109860* 130197*109987** 130293**110082** 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 131678*111483** 13179996111594* 1116 1318 131979**111792* 1118 86* 1320 79 1321111984** 1120 93 1322 1323112172* 1324112292** 1123 90* 1325 1326112490* 1327112592* 1328112687 1329112790* 1128 1330 1129 92** 1331 133292**113088** 1131 96** 1333 95* 133472**113297* 1133 75* 1335 90* 1134 95** 1336 74 1135 83**1337 133865*113691 1339113783** 134077*113865* 134189113992* 1342114077** 134388114180* 1142 84** 1344 93** 1143 92* 1345 94** 134694*114476* 134781**114583* 134878**114661** 1147 92**1349 1350114879** 1351114994* 1150 92* 1352 1353115191* 135438115296* 1153 461355 135680115493* 135778115591* 1358115687 1157 66** 1359 136098**115875 72* 1361 96* 136283**116083* 136388**116187* 1162 84* 1364 1163 73** 1365 1164 94 1366 79* 1165 84* 1367 93* 1166 74** 1368 92** 1167 91* 1369 94* 137086**116888* 1169 77 1371 94* 137295**117074* 1171 74** 1373 95** 137493**117238* 137580**117389** 137686**117479** 1175 96 1377 95* 1176 97* 1378 68 1177 19 1379 41 138087**117888** 1179 85* 1381 65** 138286**118093* 138388*118182* 138469**118292** 138593*118379** 1184 84** 1386 88* 138782**118585** 1186 93** 1392 93* 1187 93** 1397 1188 93** 1398 81* 139994118974** 1190 95** 1400 95 1191 85** 119291* 119395** 1194 78** 119594* 1196 87* 119785% 1198 86*

* % inhibition at 0.1 RM * * % inhibition at 0.0 1 4M 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 µM) 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 KCl, 10, uM ZnC12,5 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 RM), H-Ras-CVLL (final concentration 5.0 RM) 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-HCl (pH 7.2), 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, 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 Oncology, 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

RltD A// phosgene O + I'"I R3NH2 HR2 R R, ta Ria 3H'N Ruz thiophosgene +-R2 ! L-R2 H N R HN'' ff R °'9 r C. R, RI C. H ria 2 s r'-R '9 r R3NH2 + < R2 R3HNo sN< » J H la OH"la R NH + I R so2Ci2 p T R 3 2 H2N \ ; a R3HN N I R 2 1a SCHEME 2 R Ri A. Rl 1) NaNO2/HCI Ri R, 1I J R2 I1 R2 R3NH2 I R2 H2N Ria C102s,, R3HN02 Ria Ria Ri 1) phosgene Ri B. 1) NaNO2/H2S04/1 2) R3NH2 g R2r p,. t.- la Ri Dthiophosgene Ri C. 1) NaNO,/H2SO, Rl 2) R, NH2 2) H20 R2 R2 -Ri R J R3HN (S) CO ta H R1a 1a D..X l) NaNOSO,."1 2)N R2 2 I 1 R2 I J R2 H2N R J R3HN (O) SO ia HO R1a Rta "1a e. Ri a Dso, a, Ri E. R NaNOSO<"1 2) F<3NH2 z l R2 ad---I-2.J H R J R3HNS (0) 20 Ria SCHEME3 BrAa R RsNHz R1 1) vinyiabon NaCNE3H3 2) ost, R IC :-L-R 2 OHC R ia Ph3P R DEAD R B. R hydrazoic Nabi, acid -R2 J HOCHp R1a N3CH2 R1a OH RUA 1 HS (CHZSHR 1 2 R3N 9ene Et3 N Et, \J R2. \J H2NCH2 Ra R3HNC (O) HNCH2 Ra C. Ri 1) thiophosgene Ri 2) R3NH2 R2 R2 H2NCH2 R1a R3HNC (S) HNCH2 1a D. R1 1) SOCI nu Vu H2NCH2 Ra R3HNS (O) HNCH2 1a E. i) SOUCI Ri 2) R3NH2 1 H. \J R3HNS (0) 2HNJ R2 H2NCFi2 Ra R3HNS (O) 2HNCH2 Ra

SCHEME 4 1) phosgene A. || j R2. || S R2 J y-R2j! y-R2 Ria 3HNC (O 2 Ria B. R 1) thiophosgene 2) R3NH2 HOCH2 R1a R3HNC OCH2 R ia C'R1 1) SOCI2 R1 2) R3NH2 il-R2 R2 i-R2 R2 \ J R J HOCH 2 Ria R3HNS (O) OCH2 Ra D. Rl l) so2C'2 R 2) R3NH2 -R2 R2 HOCH HOCH2 Ria R3HNS (0) 20CHi Ria

SCHEME5 A R1 l) NaNOz/H2SO A. 2) S, I-R2 R2 H2 I \ J R2---H I \J R2 Rua rota n 1)phosgene 2)R3NH2 I R3HNC(O) ta B. R, 1) thiophosgene 2)R3NH2 J Ria R3HNC (S) Ra C. R1 1) SOCI2 R1 11) 300. Ri 2)R3NH2 "I R2 Ra R3HNS (O) S Ria D. R1 1) SO2CI2 R 2)R3NH2 Zizi R2 R1a R3HNS (0) 2S'J SCHEME6 A. R1 1) Tos-CI R1 2) NaHS R2 R HOCH2 Ra HSCH2 1a 1)phosgene R1 2)R3NH2 J R3HNC (O) SCH2 Rla B.thiophosgene 2) R3NH2 1 ---I R2 HSCH H Ria R3HNC (S) SCHp ira /''i 1) 300. Ri C zR1 1) SOCI2 xR1 2)R3NH2 2 HASCH HSCH2 Rla R3HNS (O) SCH2 Ria D. R1 1) Pi 2) R3NH2 HOCH HSCH2 Ria R3HNS (0) 2SCH2--C-\FRi a

SCHEME7 A. Rl Ri \1/R, A.C02Fi I 1 R2 H N J H2N R R3C (O) HN Ria B. Ri Ri « R 2 H2NCH2 Ria 2 Ria Me3SiC=CH (Ph3P) 2Pd (OAc) 2 R2 Cul R2 J Ru tu R1 R3-COCI I Rz R3-C(O)-C--- D R D. R1 Lindlar ratalyst R1 I J R2 H2 I R2 R E. R 1 Lindiar catalyst Ri R2 H2 R2 _ _ R3 C (O) HC=H R3-C R3-C (O)-H2CH2 Ria SCHEME8 n Pd (OAc) 2 R3NH2 DPPE/CO R2 DPPE/CO \ ;-R2--R2 R H02 Ria R3-HN-C (O Rta R11) oxalyl chloride R R B. CH 2) CH2N2R R3NH2R1 1---I1 B. R-R2 R Hv2., Ria 2CCH2 Ria N-C (O) CH2 Ria c. Ri Ri R3CHO R2 NaCNBH3 HX R 2 ria Rua D. R D. Ri R3CHO Rl D. R 1 R3CHO R 1zNaCNBH3 2-R H2NCH2 Rta R3CHpNHCH2 Ria

SCHEME 9 D A. 1) NaNO2/HCI Ri 1) NH3 R , Z 2) oxalyl chlohde R2 3) R NH L-R2 CIS02"C\ R-HN-C (O) NH-SO2 R1 1) Ph3P/DEAD R 1) NH3 2) HSC (O) CH3 2) oxalyl chloride Ri -_, 11/1 1 3 CI IJ R2 3) RsNH2 J HOCH2 CISO CH Rta 2CH2 R1a R3NHC (O) NHS02CH2 R1a C. Ri C « 1) Tos-CI R1 R 2) R30H/CuCl 2 R2 LOCH2 RIVA La D. R1 D. RI 1) ft R 2) R3-OH/CuCi R2 R H2N J R1 a R30C (O) NH Rua E. R1 E. R1 1) thiophosgene R1 I.'1 R 2) R3-OH/CuCI R2 R H2N 2 H2N R1a R3OC (S) NH Rua F. R F. Ri 1) SOC'2 R 1 f)R3-OH/CuCI I, H2N Ra R30S (O) N Riz ) so2C2 2 2) R3-OH/CuCI I-R2 H2 Ria R30S (0) 2NHCN-

SCHEME 10 1) triphosgene R2 2) R30H/CuCl R2 H2NCH2 Ra J B. Ri B. R1 1) thiophosgene R1 vs R R30H/CuCI -R2 R30C (S) NHCH2 R a C. Ri C. R1 1) SOCI/R R2 2) R30H/CuCl -1 R H2NCH2 \R a 1 \ J R R R30S (O) NHCH2-Ra D. Ri y so2Ci2 /1-R2 2) R30H/CUC' R2 H2NCH2 R1a J R R30S (0) 2NHCH2 R1 a SCHEME 11 A. Ri Ri 1) NaN02/HBF,, R22) RgSH/NaH Rua B. ri B. R1 1) triphosgene 2) R ra RgSC (O) NH R1a C. Ri 1)thiophosgene R1 R2 2) R3SH . \J H2N Ria R3SC (S) N Ria D. Ri D. R1 H2N."C\ R2 Rua 2 Rta R3SS (O) NH Ria E. R1 R ) so2C2 Jl \J R2 2) R3SH R2 2 Ra R3SS (0) 2N ta SCHEME 12 A. Pi- 1) triphosgene Ri 2) R3SHI H2NCH2 1a R3SC (O) NHCH2 R1a B. Ri p, t) thiophosgene R2 2) R, SH H--R2 2NCH2 Ria R3SC (S) NHCH2 Rla C. Ri R 2) R3SH R2 2) RSH H2NCH2R 2 2 a 1a R3SS (O) NHCH2 1a D. Ri Ri 2) R3SH D. < R1 < 'J 2 la R3SS (O) 2NHCH2 1a

SCHEME 13 A. Ri 3-X R2NaH/Cu r) J- H 0 2 Rua X = halide B. RI Ri R3-X Ho ra R3S Ria X = halide C. Rl R3-X Rp pydine J R2 X = halide D.. ru ri Rs-x/1 R2 NaH Rl R2 NaH "RaOCHR R30CH2 R1a X = halide E. R1 Ruz ah Na HSCHp Rya J R 2 X = halide

SCHEME 14 A. R1 Ri R RPhXP) 2Pd (OAc) 2 )-R2 HC-Rla R3 HC-\Ra I R Ra X = halide B./R R Hndlar catalyst -R2 H2-R2 Rs-C=C'R,-HC=CH C° Ria R3-HC ira 'Pcuc C. I R2 R-HC=CJ i-J C. H R2 H2 R3-H2C-CH29 R1 R . Pi p D. t S R2 fenocenePdCI2 C R2 2 HC=C Ria CO R3-C (O) C= R3-Br Ru ri Lindlar catalyst E. H2 R2 R3-C (O) C_C a R3-C (O) CH=C a . Pi-. Pi . Pc R3-C (O) CH=C Rta R3W0) CH2-CHRa

SCHEME 15 A. Ri MCPBA R1 2 Rua R3S02 Ra R 2) MCPBA I R 2) MCPBA R2 X = halide R1 a 1) R, CH2X C. R2 2) MCPBA J R2 ,-R2 HASCH HSCH2 R1a X= halide R3S02CH2 R1 a Ruz cso2ci A H2 Rt a Ri tX R2 RiRi R2 H2NCH2 Rya R3S02NHCH2 R1 a 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 A(B)N-L1

Table 7. Ethers of the Type A-OL1

Table 8. Sulfonamides of the ASO2(B)N-L1

Table 9. theTypeA(B)CH2-L1of

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 type A-CO2H

Table 14. Aldehydes of the type A-CHO

/-c<BR> <BR> 0/-CHO/-CHO/-CHO0/-CHO'y-N0<BR> 0 °m C0<BR> 225 226 227 228"<BR> <BR> <BR> <BR> <BR> <BR> <BR> 229<BR> <BR> <BR> <BR> <BR> <BR> <BR> CHO CHO r-CHO°\<BR> <BR> CHOHOBr <BR> #### <BR> N N N N<BR> H H H<BR> 232233230231 <BR> <BR> <BR> <BR> MeONCHOCHO <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> CHOOCHO <BR> #S#NH##ON <BR> S S N<BR> S S N<BR> <BR> s S*y N<BR> <BR> PhO S#N<BR> NH-CHO<BR> 234 235 236 238<BR> <BR> <BR> <BR> 237<BR> CHOCHOCHOHO <BR> HSCHO <BR> <BR> <BR> <BR> <BR> # # # N<BR> OHNSNSONO#N <BR> <BR> <BR> <BR> <BR> <BR> <BR> HF3COH <BR> 241242239240 <BR> H CHO CHO CHO O2N CHO O2N CHO<BR> #NNNN# <BR> <BR> <BR> <BR> <BR> <BR> <BR> OHONNH###ON <BR> H NN <BR> H<BR> 243 244 245 246 247<BR> <BR> <BR> HO<BR> CHO CHO # CHO N CHO CHO <BR> <BR> <BR> <BR> <BR> #NO#N# <BR> YNH0,N-oY'OH<BR> 250251OH248249 <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 252<BR> CHOHSCHOCHOCHOCHOCHO <BR> N N<BR> ###### NNNSSOO 253 254 255 256 257 258

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> (3-(Aminomethvl) benzoyl !-Met-OCH3 Step A (3-(Chloromethvl) benzoyl)-Met-OCH3 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; IH NMR (CDCI3) 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 (1H, 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 (CDC13) d 97, 12,15.55. <BR> <BR> <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> (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; I H 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 (CDC13) d 177.50.166.54,135.97,134.06, 84,126.71,54.09,52.47,51.95,31.38,30.00,15.30.

(3-(Aminomethvl) benz°Vl)-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 (CDC13) 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-! 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-Aminobenzovl)-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 HCI to remove any unreacted starting material. The solution was dried over Na2S04 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 54,125.30,131.81,145.70,155.00, 169.80; Anal. Calc. for C12Hl5NO4, C: 60.76, H: 6.37, N: 5.90; Found, C: 60.52, H: 6.43, N: 5.83; HRMS Calc. for C12Hl5NO4,237.0961, Found, 237.1001.

Step B<BR> <BR> <BR> <BR> <BR> <BR> (N-BOC4-Aminobenzovl)-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 desire product (9.72 g): m. p. 184-185°C; IH NMR (CDC13) 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 (1H, m), 7.45 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.7 Hz); 13C NMR (CDCl3) d 64, 73,81.20,117.73,127.8,128.33,141.88,152.33,166.50,172.75; Anal. Calc. for C18H26N205S, 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-Aminobenzoyl)-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 HCI/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 (1H, 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 (CDC13) d 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-methvlbenzovl)-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 12,127.05,129.14,130.65,132.99, 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. for C13Hl7NO4,251.1158; Found, 251.1153. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (N-BOC-4-Amino-3-methvlbenzoyl)-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 (1H, s), 8.05 (1H, d, J=8.6 Hz); 13C NMR (CDC13) d 22,30.03, 89,152.34,166.58, 172.66. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> (4-Amino-3-methvlbenzovl)-Met-OCH3 hvdrochloride N-BOC-4-Amino-3-methylbenzoyl-Met-OCH3 (0.99 g, 2.59 mmol) was dissolved in methylene chloride (15-20 mL) and precipitated with 3M HCl/Et20 (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; 1H 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 41,127.85, 05,173.84; Anal. Calc. for C14H2lN203s, C: 50.52, H: 6.36, N: 8.42; Found C: 50.71, H: 6.40, N: 8.34.

Compound 6 (4-Amino-3-methoxybenzovl)-Met-OCHa Step A N-BOC-4-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; 1H 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 01,118.58,124.20,125.76,133.84, 149.04,154.20,169.60; HRMS Calc. for C13Hl7NO5,267.1107; Found, 267.1103.

Step B (N-BOC-4-Amino-3-methoxybenzoyl)-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 (1H, d, J=8.5 Hz); 13C NMR (CDC13) d 23,30.09,31.48,52.06,52.54,55.81, 57,172.58; m/z (FAB) 413 (M + 1). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> (4-Amino-3-methoxvbenzovl)-Met-OCHßydrochloride 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 ; IH 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, 31.34,31.42,52.95,53.38,57.12,112.29,121.43,124.57,124.77,13 6.15,153.67, 168.79,173.81.

Compound 7 (4-Arnino-l-naphthovl)-Met-OCHS Step A 4-Amino-l-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 ; 1H NMR (CD30D) d 6.69 (1H, 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, 48,135.04,151.35,171.44; HRMS Calc. for CIlH7NO2, 187.0633; Found, 187.0642.

Step B N-BOC4-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; 1H 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, 76, 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 C 16H I 7NO4,287.1158; Found, 287.1151. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> (N-BOC-4-Arnino-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 (CDCl3) 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, 28.31,30.19,31.65,52.06,52.64,81.17,115.82,120.18,125.79,126 .37,126.53, 93,169.04,172.40; HRMS Calc. for C22H28N2O5S, 432.1719; Found, 432.1702; m/z (FAB) 433 (M+1).

Step D (4-Amino-1-naphthoyl)-Met-OCH3hydrochloride (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; IH NMR (CD30D) d 2.08-2.16 (4H, m), 2.20-2.30 (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, 33,119.90,122.20,126.15,127.41,127.77,129.09,129.31,131.50, 77,173.83; m/z (FAB), 369 (M+1).

Compound 8 (4-Amino-2-phenylbenzoyl)-Met-OCH., StepA 4-Nitro-2-phenyltoluene 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 1N HCl 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; IH NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (5H, m), 8.07-8.10 (2H, m); 13C NMR (CDC13) 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 C13H1 tNO2, 213.0790; Found, 213.0793.

StepB

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 Na2S04 and the solvent removed in vacuo to provide the desired product (0.37 g): m. p. 174-176°C, I H NMR (CD30D) d 7.38-7.48 (SH, 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 42, 129.49,131.56,139.26,140.42,144.41,150.17,170.52; m/z (EI) 243 (M).

Step C (4-Nitro-2-phenvlbenzovl)-Met-OCH3 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 (SH, m), 7.67 (1H, d, J=8.3 Hz), 8.07-8.12 (2H, m); 13C NMR (CDCI3) d 14.92,29.11,30.67,51.51,52.29,121.86,124.74,128.27,128.60,12 8.69,129.52, 09,167.23,171.23; m/z (FAB), 389 (M+1). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step D<BR> <BR> <BR> <BR> <BR> <BR> (4-Amino-2-phenvlbenzovl)-Met-OCH (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: 1H NMR (CDCl3) 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 (CDC13) d 25,51.57,52.15,113.27,115.88,123.52, 127.56,128.37,128.44,130.92,140.66,141.44,148.53,168.58,171. 91.

Compound 9 (4-Amino-2-(2-thienyl)benzoyl)-Met-OCH3 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- benzovl !-Met-OCH ; The title compound can be prepared according to the method used to prepare Compound 8, only substituting 1-naphthylboronic acid for phenylboronic acid.

Compound 11 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-Amino4'-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.<BR> <BR> <P> Step B 4-Nitro-4'-biphenyl carboxvlic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-4'-methylbiphenyl.

Step C 4-Amino-4'-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 carboxvlic acid Step A

4-Nitro-3'-methvlbiphenv ! 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'-biphenyl carboxvlic 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 carboxyl acid Step A 2-Methoxv-4-nitro-3'-methvlbiphenvl 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'-biphenylcarboxylicacid The title compound was prepared by KMnO4 oxidation of 2-methoxy-4-nitro-3'- methylbiphenyl.

StepC 4-Amino-2-methoxv-3'-biphenvl 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-isopropvloxv-3'-biphenvl carboxvlic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.

Compound 16

4-Amino-2-phenvl-3'-biphencarbox lic 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-OCHS 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 Na2SO4 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 Na2SO4 and the solvent was removed in vacuo to provide the desired product (3.72 g): m. p. 158-160°C; lH NMR (CD30D) d 7.81 (1H, d, J=8.5 Hz), 8.08 (1H, d, J=8.5 Hz), 8.30 (1H, s); 13C NMR (CD30D) d 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-Dimethvlphenvlboronic 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; I H NMR (CDC13) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD30D) d 48.

StepC<BR> <BR> <BR> <BR> <BR> 4-Nitro-2-(35-dimethvlphenvl) benzoic acid 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 1N HCl 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): IH 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 (CDC13) d 19,131.31,135.04,138.21, 144.74,170.75.

StepD (4-Nitro-2-(3. 5-dimethvlphenvl ! benzovl !-Met-OCH3 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 (1H, m), 1.85- 1.97 (1H, 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 (1H, m) 8.23-8.26 (2H, m); 13C NMR (CDCl3) d 15.20,21.26,29.22,31.15, 11,126.27,130.03,130.53,137.77,138.82,140.29,141.56, 148.41,167.14,171.53.

Step E (4-Amino-2-(3 *5-dimethvlphenvl) benzovl)-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 SnCl2 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 (CDCl3) 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 (CDCl3) d 49, 30,115.94,123.55,126.36,129.32,131.23,138.15,140. 72,141.92, 148.40,168.45,172.01.

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-phenvlbenzovl methionine methyl ester Preparation 2A 4-Bromo-2-phenylbenzoic acid methyl 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-phenvlbenzoyl 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 HCI 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 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 3 Arvlbromides 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 ! 4- fS)-2-Pvrrolidone-5-aminomethvlcarbonyl) amino-2-phenylbenzoyl methionine<BR> <BR> Example1A Methyl 4-(fS)-2-Pvrrolidone-5-aminomethvlcarbonvl) arnino-2-phenvlbenzoate

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 equivalent)andtriethylamine(1.0 (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.

Example 1B 4- (. S-2-Pvrrolidone-5-aminomethvlcarbonyl) 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.

Example 1C 4- ( (S)-2-Pyrrolidone-5-aminomethylcarbony ) amino-2-phen, lbenzoyl methionine methyl ester 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.

Example 1 D 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-ammomethyl-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 1E

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 4-((S)-2-Pyrrolidone-5-aminomethylthiocarbonyl)amino-2-pheny lbenzoylmethionine 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-Pyrrolidone-5-aminomethylsulfinyl)amino-2-phenylben zoylmethionine Example 3A 4-ffS2-PyrroIidone-5-aminomethvIsulfinvlamino-2-phenylbenzov lmethionine 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-((S)-2-Pyrrolidone-5-aminomethylsulfinyl)amino-2-phenylben zoylmethionine 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-aminomethylsulfony ) amino-2-phenvlbenzovl methionine Example 4A 4- amino-2-phenvlbenzovl methionine methvl 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 1 A and purified by chromatography on silica gel.

Example 4B 4- ! amino-2-phenvlbenzovl 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- ( (S)-2-Pvrrolidone-5-aminomethylsulfonvl) amino-2-phenylbenzovl 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-yS)-2-Pyrrolidone-5-methylaminosulfonyl)-2-phenylbenzoyl methionine Example 5A 4-Chlorosulfonyl-2-phenvlbenzoic acid methyl ester To a solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in concentrated HCI 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) sulfonvll-2-phenvlbenzoic((S)-2-Pvrrolidone-5-aminomethvl) sulfonvll-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-((5)-2-Pvrrolidone-S-aminomethvl) sulfonvl !-2-phenvlbenzoic 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 methionine methvl 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-Pxrrolidone-5-aminomethylcarbonvl) amino-2-phenylbenzoyl 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- ( (y)-2-Pyrrolidone-5-aminomethylcarbonyl) amino-2-phenyIbenzoyI 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- (2-pyridyloxv)-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-Pvyloxv)-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-Pvridvloxv !-2-phenvlbenzoic(2-Pvridvloxv !-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-Pyridyloxy)-2-phenylbenzoylmethionine methyl ester The resultant product from Example 6C is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 6E 4- (2-PyYloxy)-2-phenylbvlmethionine 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-pyridvloxv)-2-phenvlbenzovlmethionine The resultant compound from Example 6E is hydrolyzed according to the procedure of Example 1B to give the title compound.

Example 7 4- (3-pyridylmethylenoxy-2-phenylbenzoylmethionine 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-Pvrrolidone-5-aminomethvl) carbonvloxv-2-phenvlbenzoVl methionine Example 8A 4- ( S-2-Pyrrolidone-5-aminomethyl) carbonyloxy-2-phenylbenzoyl methionine methyl 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 IN HC1 and brine, evaporated, and purified by chromatography on silica gel.

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

MeS Example 9 methyl4-((S)-2-Pyrrolidone-5-aminomethyl)thiocarbonyloxy-2-p henylbenzoylmethionine 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- (YS-2-Pyrrolidone-5-aminomethyI) suIfinyloxy-2-phenylbenzoyl methionine 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-aminomethyl)sulfonyloxy)-2-phenylbenz oylmethionine The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by sulfuryl chloride. <BR> <BR> <BR> <BR> <BR> <BR> <P> # #<BR> <BR> <BR> NS<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> #<BR> CONHMet Example 12 4-l3-Pyridvlmethvlenthio)-2-phenylbenzoylmethionine 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 12B 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 4- (2-Pyridylthiomethylen)-2-phenylbenzoic 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-Pvridvlthiomethvlen)-2-phenvlbenzovlmethionine methvl 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-Pvridvlthiomethv)-2-phenylbenzovlmethionine 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 NaNO2 (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 K2C03 (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-Pyridvlthiomethvlen)-2-phenvlbenzovlmethionine methvl 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 HC1, 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-Pyridylthiomethylen)-2-phenylbenzovlmethionine The resultant compound from Example 12D is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 13 4- (2-Pvridylthio)-2-phenylbenzovlmethionine Example 13A 4-Fluoro-2-phenyl 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-phenyI benzovl 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 benzoyl methionine methyl ester A mixture of the resultant fluorobenzoate from Example 13C (1.0 equivalent) and 2- mercaptopyridine (1.0 equivalent) is treated with K2C03 (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-Pyridvlthio)-2-phenvl benzovl(2-Pyridvlthio)-2-phenvl benzovl 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-Pvridvlthio)-2-phenvl benzovl(2-Pvridvlthio)-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 1 C to give the title compound.

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

Example 14 4-l2-Pvridvlsulfonyl)-2-phenylbenzoylmethionine Example 14A 4- (2-Pyridylsulfonyl)-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- ridvlsulfonvl)-2-phenvlbenzoic acid The resultant compound from Example 14A is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 14C 4- (2-pyridyIsulfonyl)-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- (2-Pyridylsulfonyl)-2-phenylbenzoylmethionine The resultant compound from Example 14C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 15 4-f3-Pvridvlthiomethylen-2-phenylbenzoylmethionine The title compound is prepared from the resultant product of Example 12B using the procedures from Example 14.

Example 16 4-[(2-Aminopyridyl)methylene]-2-phenylbenzoylmethionine

Example 16A 2-Phenvlterephthalic acid mono methyl 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- (Hvdroxvmethvl)-2-phenvlbenzoic(Hvdroxvmethvl)-2-phenvlbenzo ic 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- (Hvdroxymethyl)-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-(Hydroxymethyl)-2-phenylbenzoyl 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-formvl-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 CH2CI2/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.

Example16F 4-!-ormvl)-2-phenylbenzovl 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-(Hydroxymethyl)-2-phenylbenzoyl 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-r (2-AminopvridvlEmethvlenel-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.

Example 16I 4-f (2-Aminopyridvl) methylenel-2-phenylbenzovlmethionine

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

Example 17 4- [3-aminomethvlpvridyl) methylenel-2-phenvlbenzovlmethionine Using the procedures of Examples 16F-G and replacing 2-aminopyridine with 3- aminomethylpyridine affords the title product.

Example 18 4- ( (S-2-Pyrrolidone-5-aminomethvlcarbonvl) aminomethyl-2-phenylbenzoyl methionine Example 18A 4- (Azidomethvl)-2-phenylbenzovl(Azidomethvl)-2-phenylbenzovl 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(Aminomethvl)-2-phenvlbenzovl methionine methyl 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-Pvrrolidone-5-aminomethvlcarbonvl) aminomethvl-2-phenvlbenzovl((S)-2-Pvrrolidone-5-aminomethvlc arbonvl) aminomethvl-2-phenvlbenzovl methionine 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 IN HC1 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 4-((S)-2-Pyrrolidone-5-aminomethylthiocarbonyl)aminomethyl-2 -phenylbenzoylmethionine 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 4-lf S)-2-Pvrrolidone-5-aminomethylsulfonyl) aminomethyl-2-phenylbenzoyl methionine Using the Procedure of Example 4 with the resultant compound from Example 18B affords the title product.

Example 22 <BR> 4-! carbonyloxymethylene)-2-phenylbenzoyl methionine 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-Aminopyridyl)-2-phenylbenzoylmethionine Example 24A 4- (2-Aminopyl)-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-Aminopyridyl)-2-phenylbenzovlmethionine The resultant compound from Example 24A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 25 4-(3-Aminomethylpyridyl)-2-phenylbenzoylmethionine Example 25A 4-l3-Aminomethvlpvd_vl)-2-phenvlbenzovlmethionine methyl 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-Aminomethylpvridvl)-2-phenvlbenzoylmethionine The resultant compound from Example 25A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 26 4-E (4-aminomethvlpvridvl) methvlenel-2-phenvlbenzovlmethionine Using the procedures of Examples 25 with the resultant amine from Example 18B and 3- pyridinecarboxaldehyde affords the title product.

Example 27 4-(3-Pvridyloxvmethylene)-2-phenYlbenzovlmethionine Example 27A 4- methyl ester 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-L'Yridyloxymethylene)-2-phenylbenzoylmethionine methyl este 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-Pyridyloxymethylene)-2-phenvIbenzovlmethionine The resultant compound from Example 27B is hydrolyzed according to the procedure of Example 1B to give the title product.

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

Example 28B 4- (3-Pvridvlmethoxvmethvlene)-2-phenvlbenzovlmethionine methvl ester(3-Pvridvlmethoxvmethvlene)-2-phenvlbenzovlmethionine methvl 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

4- (3-Pvridvlmethoxymethvlene)-2-phenvlbenzoylmethionine methvly ester The resultant compound from Example 28A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 29 (2-Phenvl-4-r (thiazol-2-vlamino) carbonvlthiolbenzovl}-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 {2-Phenvl-4-r (thiazol-2-vlamino) carbonvlthiolbenzovl}-methionine methvl ester A solution of 2-phenyl-4-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 2-Phenyl-4-f (thiazol-2-vlamino) carbonylthiolbenzovll-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 f2-Phenyl-4-(thiazol-2-vlamino) carbonvlthiolbenzoyl-methionine The resultant compound from Example 29B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 30 j 2-Phenvl-4-f (thien-2-ylmvlamino) carbonvlthiolbenzovl ?-methionine Using the procedure of Example 29 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 31 tt-methionine Example 31 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 f 2-Phenvl-4-ffthiazol-2-vlamino) thionvlthiolbenzovl?-methionine methvl 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.

Example 31C ester,alternate{2-Phenyl-4-[(thiazol-2-ylamino)thionylthio]b enzoyl)-methioninemethyl procedure

Using the procedure of Example 29C but replacing phosgene in toluene with thionyl chloride affords the title compound.

Example 31D {2-Phenyl4-F (thiazol-2-vlamino) thionvlthiolbenzovl}-methionine The resultant compound from Example 31B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 32 {2-Phenvl-4-f (thien-2-ylmvlamino) thionvlthiolbenzoyl}-methionine Using the procedure of Example 31 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 33 ester{2-Phenyl-4-[(thiazol-2-ylamino)sulfonylthio]benzoyl}-m ethioninemethyl Using the procedure of Example 31 but replacing thionyl chloride with sulfuryl chloride affords the title product.

Example 34 (2-Phenvl-4-flthien-2-ylmethvlamino) sulfonvlthiolbenzoyl j-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 {2-Phenyl-4-[(thiazol-2-ylamino)thiocarbonylthio]benzoyl}-me thionine 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-Phenvl-4-f (thien-2-ylmvlamino) thiocarbonvlthiolbenzoy}-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 f2-Phenvl4-[(thiazol-2-vl) thiomethvllbenzovl T-methionine Example 37A {2-Phenvl4-[thiomethvllbenzovl ?-methionine methvl 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 12-Phenyl-4-fthiomethyllbenzoyl I-methionine methyl ester, alternate procedure

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 f 2-Phenvl4-f (thiazol-2-vl) thiomethvllbenzovl T-methionine 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-Phenvl-4-f (thiazol-2-yl) thiomethlbenzovl-methionine The resultant compound from Example 37C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 38 {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-Phenyl-4-[(thiazol-2-ylamino)carbonylthiomethyl]benzoyl}- 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 {2-Phenvl-4-[(thiazol-2-vlamino ! thiocarbonvlthiomethvllbenzoyl}-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 {2-Phenvl-4-f (thiazol-2-vlamino) thiocarbonvlthiomethvllbenzoyl)-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 J 2-Phenvl-4-f (thiazol-2-vlamino) thionvlthiomethvllbenzoyl-methionine Using the procedure of Example 31 with the resultant product from Example 37A affords the title product.

Example 44 f 2-Phenyl-4-f (thien-2-ylmethylamino) thionylthiomethyllbenzoyl I 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 {2-Phenyl-4-[(thiazol-2-ylamino)sulfonylthiomethyl]benzoyl}- 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> {2-Phenvl-4-r (thien-2-vlmethvlamino) sulfonvlthiomethvllbenzovl}-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-f 2- (Imidazol-2-yl) ethynyll-2-phenylbenzoyl_1 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 (4-r2- (Imidazol-2-vlethvnvM-2-phenvlbenzovlt-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 f 4-r2-(Imidazol4-vl) ethenvll-2-phenvlbenzovl}-methionine 'he resultant acetylene (3 mmol) from Example 47 is mixed with Lindlar catalyst (50 mg), 5 lrops of quinoline in ethyl acetate. The reaction mixture is attached to a hydrogenation Lpparatus, and then is detached from the apparatus after about 95% of the theoretical Iydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo.

, he crude product is purified with a column chromatography on silica gel to give the title ompound.

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

Example 50 {4-[2-(Imidazol-4-ylcarbonyl)ethynyl]-2-phenylbenzoyl}-methi onine Example 50A 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.

Example 50B (4-f 2- (Imidazol-4-ylcarbonyl) ethynyll-2-phenvlbenzovl}-methionine The resultant compound from Example 50A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 51 f4-f2- (Imidazol-4-ylcarbonyl) ethenyll-2-phenylbenzovl 1-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) ethyll-2-phenylben}-methionine Using the procedure of Example 49 with the resultant compound from Example 51 affords the title product.

Example 53

{4-[4-(1-Methylimidazol-4-yl)-3-keto-1-butynyl]-2-phenylbenz oyl}methionine Example 53A {4-f4- (1-Methvlimidazol-4-vl)-3-keto-1-butvnvll-2-phenylbenzoyl_-m ethionine methyl ester To a solution of 1-methyl-4-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-f4- (1-Methylimidazol-4-yl)-3-keto-1-butynyll-2-phenylbenzoyl-me thionine The resultant compound from Example 53A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 54 {4-f4- (1-Methylimidazol-4-yl)-3-keto-1-butenyll-2-phenylbenzoyl}-m ethionine Using the procedure of Example 48 with the resultant compound from Example 53 affords the title product.

Example 55 <BR> f 4-f4- (1-Methvlimidazol-4-yl)-3-keto-1-butyll-2-phenvlbeyl-methion ine

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

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

Example 57 (S) roglutamyl- (4-amino-2-phenyl) benzovl methionine

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

Example 58 methionine(S)Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl Example 58A (S) roglutamvl- (4-aminomethvl-2-phenvl) 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 HCI 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) Pvroglutamvl- 4-aminomethyl-2-phenvl) benzovl 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) Pvroglutamyl-(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 (Pyridin-2-vlamino) carbonyll-2-phenylbenzovl methionine Example 60A methylester4-Carboxy-2-phenylbenzoylmethionine 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- [ (yridin-2-vlamino) carbonyl]-2-phenylbenzoyl methionine methyl ester To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3- hydroxy-l, 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 HCI 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-f (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.

Example 61 4-((S)-2-Pvrrolidone-5-aminomethvl) carbonvl)-2-phenvlbenzovl methionine Using the procedure of Example 60 and replacing 2-aminopyridine with (S)-5-aminomethyl- 2-pyrrolidone affords the title product.

Example 62 4-E (Pvridin-2-vlamino) carbonvlmethyll-2-phenvlbenzoyl methionine Example 62A 4-Diazocarbonvl-2-phenvlbenzovl methionine methyl 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-carboxvmethvl-2-phenylbenzoyl 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 (I) 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

4-1 (Pyridin-2-vlamino) carbonvlmethvll-2-phenvlbenzovl methionine methyl ester 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-[(Pyridin-2-ylamino)carbonylmethyl]-2-phenylbenzoylmethion ine 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-Pvrrolidone-5-aminomethylcarbonvlmethyl)-2-phenylbenzov l methionine Using the procedure of Example 62 and replacing 2-aminopyridine with (S)-5-aminomethyl- 2-pyrrolidone affords the title product.

Example 64 4- (S)-2-Pvrrolidone-5-methoxycarbonyl) amino-2-phenylbenzovl 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 (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (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 (5)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCI (0.1 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 66 4-((S)-2-Pyrrolidone-5-methoxysulfinyl)amino-2-phenylbenzoyl 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 <BR> <BR> 4-((S)-2-Pvrrolidone-5-methoxvsulfonvl) amino-2-phenYlbenzovl 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- (ridin-3-vlmercaptocarbonyl) amino-2-phenylbevl 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-ylmercaptothiocarbonvl) amino-2-phenylbenzoyl 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-f,. ridin-3-ylmercaptosulfinyl) amino-2-phenylbenzovl methionine

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

Example 71 4-(Pvridin-3-vlmercaptosulfonvl) 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-Pyrrolidone-5-methoxycarbonyl)aminomethyl-2-phenylb enzoylmethionine 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 CuCI (0.1 equivalent).

Example 73 4- ( (Sl-2-Pvrrolidone-5-methoxythiocarbonyl) aminomethyl-2-phenylbevl 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-l (Sl-2-Pyrrolidone-5-methoxysulfinyl) 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 (S)-5-hydroxymethyl-2-pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 75 4-((S)-2-Pvrrolidone-5-methoxvsulfonvl) aminomethvl-2-phenvlbenzovl 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 CuCI (0.1 equivalent).

Example 76

4- (ridin-3-vlmercaptocarbonvl) aminomethvl-2-phenvlbenzovl 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-(Pyridin-3-ylmercaptocarbonyl)aminomethyl-2-phenylbenzoylm ethionine 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-vlmercaptosulfinyl ! 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 3-mercaptopyridine (1.0 equivalent).

Example 79

4-(Pvridin-3-vlmercaptosulfonvl) aminomethvl-2-phenvlbenzovl 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 (Y)-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-S02-0-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 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 89 A-NH-CH-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-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 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-SO2-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-CHz_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-CHS 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 (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 96 A-NH-CO-S-B The 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-S02-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.

Example 100 A-NH-CO-S-CH-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 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.

Example 101 A-NH-CS-S-CH-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 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-CHß 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-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 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 LiOH 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-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 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-CH2-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 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 110 A-NH-CO-CH2-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.

Example 112 A-CH2-NH-CH9-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 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 113 4-((5)-2-Pvrrolidone-5-aminomethvl) sulfonvlmethvl)-2-phenylbenzovl methionine

Example 113A 4-Thioacetoxvmethyl-2-phenvlbenzoic 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 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.

ExampleI 13B 4-Chlorosulfonylmethylene-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-Pvrrolidone-5-aminomethvl) sulfonvlmethvlene-2-phenvlbenzoic((S)-2-Pvrrolidone-5-aminom ethvl) sulfonvlmethvlene-2-phenvlbenzoic 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-((5)-2-Pvrrolidone-S-arninomethvl ! sulfonvlmethvlene-2-phenvlbenzoic acid The resultant compound from Example 113C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example113E 4-((S)-2-Pvrrolidone-5-aminomethyl) sulfonvlmethylene-2-phenvlbenzovl methionine methyl ester 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

: omplete 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. <BR> <BR> <P> Fxample 113F<BR> 4-((S)-2-Pyrrolidone-5-aminomethvl) sulfonvlmethvlene-2-phenvlbenzovl methionine The resultant compound from Example 113E is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 114 A-NH-SO_-CHß 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-Pyrrolidone-5-aminomethyl)sulfonylmethyl)-2-phenylb nzoylleucine Example 115A 4- vmethvll-2-phenylbenzovl leucine methyl ester (2-phenyl-4-bromobenzoyl)-leucine methyl ester is reacted according to the procedures of Example 16F-G.

Example 115B 4-Thioacetoxymethyl-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 11 5A (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-phenylbenzovl 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 4S)-2-Pyrrolidone-5-aminomethyl) sulfonylmethylene-2-phenylbenzovl leucine methyl ester To a solution of the resultant compound from Example 115C (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 115E 4--2-Pvrrolidone-5-aminomethvnsulfonvlmethvlene-2-phenvlbenz ovl 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-CH 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(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-Thiazolyl)-2-phenylbenzoyl 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-Thiazolyl)-2-phenylbenzoylmethionine The resultant compound from Example 117C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example118 <BR> 4 (2-Thiazolvlcarbonyl)-2-phenvlbenzo3rl methionine

Example118A 4- (2-Thiazolvlcarbonylphenvvl methionine methvi ester 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-phenvlbeyl methionine The resultant compound from Example 118A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 119 4-f (3-Aminopyridvl) carbonvlaminosulfonvll-2-phenylbenzovlmethionine Example 119A ester4-Aminosulfonyl-2-phenylbenzoylmethioninemethyl To a solution of 4-chlorosulfonyl-2-phenylbenzoyl methionine methyl ester from Example 5E 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-Isocyanatosulfonyl-2-phenvlbenzovlmethionine 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.

Example 119C 4-flA-aminopvridyl) carbonvlaminosulfonyll-2-phenvlbenzoylmethionine methvl ester A mixture of the resultant isocyanate from Example 119B (1 equivalent) in dichloromethane is treated with 3-aminopyridine (I 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.

Example 119D 4-(lA-aminopvridvl) carbonylaminosulfonylv_l-2-phenylbenzovlmethionine 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-S02-B The anilines from Table 1 (B-NH2) are reacted according to the procedures of Example 5E 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 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 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-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 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 replaced by 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 (5)-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 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 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 127 A-O-CO-NH-CHS 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). 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 128 A-O-CS-NH-CH2 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-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 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-S02-NH-CHa-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 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 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 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 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 (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 135 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 (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 136 A-S-CO-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). 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-CH2nB 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 L ; 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 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 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 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-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 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-CH2-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-S02-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-CH2S02-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-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 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-SO_-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 <4-rf3-sulfonvlmethvlpvndvIamino1-2-phenv ! benzovHmethionine Example 154A ester{4-[(3-sulfonylmethylpyridyl)amino]-2-phenylbnzoyl}meth ioninemethyl

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 diluted with 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-sulfonvlmethylpyndyaminol-2-phenylbenzoynmethionine The resultant compound from Example 154A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 155 A-CH2S02-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-SO-NH-CH-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-S02CI).

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 173 <BR> <BR> <BR> [4- ( (2S. 5S)-1. 4-diazabicyclo (2. 2. 1octan-1-yl)-2-phenylbenzoyl1methionine hydrochloride To a solution of 74mg (0.13 mmol) of 2-phenyl-4-[(2S, SS)-4-Boc-1,4- diazabicyclo (2,2,1) octan-l-yl] benzoylmethionine methyl ester, prepared as in Example 172A, in 5 ml of THF was added 0.4 ml (0.4 mmol) of 1 N LiOH in an ice bath. The reaction mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the solvent was evaporated. The residue was partitioned with dichloromethane and water, and extracted 3 times with dichloromethane.

The combined organic solution was washed with 1 N HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 60 mg of the resulting free acid as a oily residue. To a 2 ml of a 1: 1 solution of TFA and dichloromethane was added 60 mg of the acid. After 30 min, The reaction mixture was thoroughtly evaporated in high vacuum to give an oily residue. The residue was triturated with 0.3 ml of 3 M anhydrous HCl-ether in 5 ml of ether and the white solid was collected by filtration to give 43 mg (66 %) of [4- ((2S,5S)-1, 4-diazabicyclo (2,2,1) octan-l-yl)-2-phenylbenzoyl] methionine hydrochloride: HPLC 95% (purity); IH NMR (300 MHz, CD30D) 8 7.49-7.36 (m, 6H), 6.73 (dd, 1H, J=2.2,8.4 Hz), 6.60 (d, 1H, J=2.1 Hz), 4.77 (s, 1H), 4.50 (m, 12H), 3.73 (m, 2H), 3.32 (m, 2H), 2.31-1.85 (m, 6H); 13C NMR (CD30D) 8 175.0,173.1,148.5,143.7,142.4, 8,37.1, 31.9,31.1,15.8.

Example 224 L4-(2. 4-dioxohexahvdro-l, 35-triazin-2-vl)-2-phenvlbenzoyllmethionine Example 224A (4-carboxymethylamino-2-phenylbenzovl) methionine methyl ester A mixture of (4-amino-2-phenylbenzoyl) methionine methyl ester (compound 8,1.51 g, 4.21 mmol), glyoxylic acid monohydrate (466 mg, 5.06 mmol), sodium cyanoborohydride (1.0 M in THF, 4.2 mL), sodium acetate (0.5 g) and acetic acid (0.5 mL) in methanol (10 mL) was stirred for 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous potassium dihydrogenphosphate, water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate, then 3% methanol-ethyl acetate) to give (4-carboxymethylamino-2-phenylbenzoyl) methionine methyl ester (1.46 g, 83%). 1H NMR (300 MHz, CDC13) 8 7.67 (d, 1H), 7.39 (m, 5H), 6.54 (dd, 1H), 6.45 9d, 1H), 5.96 (br d, 1H), 4.63 (m, lH), 3.88 (d, 2H), 3.67 (s, 3H), 2.04 (m, 2H), 2.00 (s, 3H), 1.86 (m, 1H), 1.67 (m, 1H). MS (APCI+) m/e 417 (M+H) +.

Example 224B <BR> <BR> <BR> <BR> <BR> 14-(N-rert-butoxyCarbonylamino ! carboxamidomethvlamino-2-phenvlbenzovllmethionine methyl ester A mixture of the (4-carboxymethylamino-2-phenylbenzoyl) methionine methyl ester prepared in Example 224A (1.04 g, 2.50 mmol), tert-butylcarbazate (661 mg, 5.0 mmol), 3-hydroxy1,2,3-benzotriazin-4 (3H)-one (489 mg, 3.0 mmol) and 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide (576 mg, 3.0 mmol) in dichloromethane (10 mL) was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to give [4- (N- tertbutoxycarbonylamino) carboxamidomethylamino-2-phenylbenzoyl] methionine methyl ester (671 mg, 51%). lH NMR (300 MHz, CDC13) 8 8.16 (d, 1H), 7.69 (d, 1H), 7.40 (m, 5H), 6.64 (dd, 1H), 6.53 (d, 1H), 6.45 (m, 1H), 5.96 (br d, 1H), 4.63 (m, 1H), 3.97 (d, 2H), 3.67 (s, 3H), 2.99 (m, 4H), 2.06 (m, 2H), 2.00 (s, 3H), 1.88 (m, 1H), 1.68 (m, 1H), 1.46 (s, 9H). MS (APCI+) m/e 531 (M+H) +.

Example 224C [4- (N-tertbutoxvcarbonvlamino) carboxamidomethN-chloroformv) amino-2- phenylbenzovllmethionine methyl ester To a-78 °C solution of the [4- (N--tert- butoxycarbonylamino) carboxamidomethylamino-2-phenylbenzoyl] methionine methyl ester prepared in Example 224B (258 mg, 0.481 mmol) in dichloromethane (3 mL) was added phosgene (1.93 M in toluene, 0.38 mL, 0.74 mmol), followed by triethylamine (0.20 mL, 1.5 mmol). The reaction was then left to warm to ambient temperature over 14 hours. The reaction mixture was then filtered through silica gel (10 g), rinsed with ethyl acetate, and concentrated in vacuo. The residue was purified by column chromatography (40% ethyl acetate-hexane) to give [4- (N-tertbutoxycarbonylamino) carboxamidomethyl- (N- chloroformyl) amino-2-phenylbenzoyl] methionine methyl ester (171 mg, 60%). 1H NMR (300 MHz, DMSO-d6) 8 8.24 (d, 1H), 7.33 (m, 5H), 7.28 (d, 1H), 6.68 (m, 3H), 4.39 (m, 2H), 4.30 (m, 1H), 3.62 (s, 3H), 2.25 (m, 2H), 2.00 (s, 3H), 1.83 (m, 2H), 1.51 (s, 9H).

Example 224D ester[4-(2,4-dioxohexahydro-1,3,5-triazin-2-yl)-2-phenylbenz oyl]methioninemethyl To a solution of the [4-(N-tertbutoxycarbonylamino) carboxamidomethyl-(N- chloroformyl) amino-2-phenylbenzoyl] methionine methyl ester prepared in Example 224C (70 mg, 0.118 mmol) in dichloromethane (2 mL) was added 2-mercaptoethanol (5 drops) and trifuoroacetic acid (1 mL). After 1.5 hour, the solvent was evaporated in vacuo and the residue was purified by column chromatography (30% ethyl acetate-hexane) to give [4- (2,4- dioxohexahydro-1,3,5-triazin-2-yl)-2-phenylbenzoyl] methionine methyl ester (43 mg, 80%). 1H NMR (300 MHz, CDC13) 8 8.86 (br s, 1H), 8.69 (d, 1H), 7.40 (m, 5H), 6.69 (dd, 1H), 6.56 (d, 1H), 5.76 (br d, 1H), 4.63 (m, lH), 4.32 (s, 2H), 3.65 (s, 3H), 2.99 (m, 4H), 2.09 (t, 2H), 2.01 (s, 3H), 1.89 (m, 1H), 1.68 (m, 1H). MS (CI+) m/e 457 (M+H) +.

Example 224E 14-(2. 4-dioxohexahvdro-l *35-triazin-2-vl)-2-phenvlbenzovllmethionine

The desired compound was prepared by saponification of the product of Example 224D using the procedure of Example 211. in NMR (300 MHz, DMSO-d6) 8 7.32 (m.

5H), 7.23 (d, 1H), 6.79 (d, 1H), 6.63 (dd, 1H), 6.56 (d, 1H), 6.38 (m, 1H), 4.00 (m, lH), 3.50 (s, 2 H), 2.07 (m, 2H), 1.97 (s, 3H), 1.79 (m, 2H). MS (APCI+) m/e 465 (M+Na) +.

Example 289 [4- 4-methylpiperazinylmethyl)-2-phenylbenzoyllmethionine Example 289A f4- (4-methylpiperazinylmethyl)-2-phenylbenzoyl1methionine methyl ester A solution of 4-chloromethyl-2-phenylbenzoic acid methyl ester (0.521 g, 2.00 mmol), prepared as in Example 286A, 1-methylpiperazine (0.607 g, 6.00 mmol), K2CO3 (0.663 g, 4.80 mmol), KI (0.332 g, 2.00 mmol), and Bu4NBr (0.032 g, 0.10 mmol) in DMF (5 mL) was stirred for 2 hours at ambient temperature and then concentrated under reduced pressure. The residue was treated with a saturated LiOH-methanol (10 mL) and then heated at reflux for 5 hours. The mixture was concentrated and the residue was dissolved in H20. This solution was extracted with ethyl acetate (5x), and the aqueous phase was then acidified by the addition of 3 M HCl and lyopholized. The resulting white foam was dissolved in DMF (20 mL) and the solution was treated with L-methionine, methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.33 g, 8.00 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (1.56 g, 8.00 mmol), and N-methylmorpholine (1.23 g, 12.0 mmol). The reaction mixture was stirred at ambient temperature for 20 hours, diluted with ethyl acetate, and extracted with a 2: 1 mixture of H20 and saturated aqueous NaHC03 (2x), 1: 1 mixture of the same (2x) and brine (2x). The organic phase was dried (MgS04) and concentrated to provide a gold oil.

Radial chromatography (30% methanol-ethyl acetate) afforded the desired compound (0.321 g, 35%).

Example 289 f4- (4-methylpiperazinylmethyl)-2-phenylbenzoyllmethionine Saponification of the product of Example 289A using the procedure of Example 287D gave the desired compound as a white foam as the bis-hydrochloride, mono-sodium chloride. lH NMR (d6-DMSO) 8 1.76-1.95 (comp, 2H), 2.00 (s, 3H), 2.17-2.36 (comp, 2H), 2.52 (br, 3H), 3.18-3.80 (br, 8H), 4.28-4.60 (br, 3H), 7.30-7.42 (comp, 3H), 7.47- 7.55 (comp, 3H), 7.67-7.73 (m, 1H), 7.74-7.80 (br, 1H), 8.63 (d, J= 7.8 Hz, 1H).

LRMS (CI): 442 (M+H) +.

Example 290 (4-piperazinylmethyl-2-phenymethionine Example 290A 4-N-tert-butoxycarbonylpiperazinylmethyl-2-phenvlbenzoic acid A solution of 4-chloromethyl-2-phenylbenzoic acid methyl ester (0.521 g, 2.00 mmol), prepared as in Example 286A, piperazine (1.39 g, 16.0 mmol), K2CO3 (0.663 g, 4.80 mmol), KI (0.332 g, 2.00 mmol), and Bu4NBr (0.032 g, 0.10 mmol) in DMF (7 mL) was stirred for 2 hours at ambient temperature and then concentrated under reduced pressure. The residue was treated with saturated LiOH-methanol (10 mL) and then heated at reflux for 5 hours. The mixture was concentrated and the residue was dissolved in H20.

This solution was extracted with ethyl acetate (Sx), and the aqueous phase was then acidified by the addition of 3 M HCl and lyopholized. The resulting white foam was dissolved in a 1: 1 mixture of H20 and 0.979 M NaOH (86 mL), and the solution was treated with di-tert-butyldicarbonate (6.68 g, 30.0 mmol). The reaction mixture was stirred at ambient temperature for 15 hours and then concentrated to remove THF. The mixture was treated with H20 and saturated aqueous NaHC03 and then extracted with a ether (4x).

The aqueous phase was acidified to pH 3 by the addition of 3 M HC1 and then extracted with 4: 1 CHC13-methanol (lOx). The combined organic extracts were dried twice with saturated aqueous Na2SO4 and concentrated to provide the desired compound (0.544 g, 69%) as an amber wax.

Example 290B (4-N-tert-butoxyCarbonylpiperazinylmethyl-2-phenylbenzoyl) methionine methvl ester A solution of the product of Example 290A (0.544 g, 1.37 mmol), L-methionine, methyl ester hydrochloride (0.553 g, 2.74 mmol), 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.14 g, 6.85 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (1.34 g, 6.85 mmol), and N-methylmorpholine (0.980 g, 9.59 mmol) in DMF (14 mL) was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate and then extracted with a 2: 1 mixture of H20 and saturated aqueous NaHC03 (2x), a 1: 1 mixture of the same (2x) and brine (2x). The organic phase was dried (MgS04) and concentrated to provide an amber oil. Radial chromatography (1: 1 hexane-ethyl acetate) afforded the desired compound (0.356 g, 48%) as an amber oil.

Example 290C (4-piperazinvlmethvl-2-phenylbenzoyl) methionine The desired compound was prepared from the product of Example 290B according to the method of Example 286E. IH NMR (300 MHz, DMSO-d6) 8 1.75-1.96 (comp, 2H), 2.00 (s, 3H), 2.17-2.35 (comp, 2H), 3.3-3.7 (br, 8H), 4.28-4.38 (m, 1H), 4.28- 4.38 (m, 1H), 4.38-4. 54 (br, 2H), 7.30-7.44 (comp, 3H), 7.46-7.56 (comp, 3H), 7.70 (d, J= 7.3 Hz, 1H), (br, 1H), 8.66 (d, J= 7.7 Hz, 1H), 9.86-10.06 (br, 1H), 12.30-12.70 (br, 1H). LRMS (CI) m/e 248 (M+H) +.

Example 291

f4- (3-hydroxypvrrolidinvl)-2-phenvlbenzoyllmethionine Example 291 A f4- 3-hydroxypyrrolidinyl)-2-phen lbenzovlltnethionine methyl ester A solution of 4-chloromethyl-2-phenylbenzoic acid methyl ester (0.521 g, 2.00 mmol), prepared as in Example 286A, 3-pyrrolidinol (0.178 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and Bu4NI (0.0754 g, 0.20 mmol) in CH3CN (5 mL) was stirred for 15 hours, treated with LiOHH2O (0.506 g, 12.0 mmol), and then heated at reflux for 5 hours.

The solution was cooled to ambient temperature and added to a mixture of L-methionine methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-1,2,3-benzotriazin-4 (3H)-one (1.66 g, 10.00 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (1.96 g, 10.00 mmol), and triethylamine hydrochloride (2.81 g, 20 mmol) in CH3CN (15 mL). After 12 days the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was extracted with a 1: 1 mixture of H20 and saturated aqueous NaHC03 (4x) and brine. The organic phase was dried (MgS04) and concentrated to provide a gold oil. Radial chromatography (12% methanol-ethyl acetate) afforded the desired compound (0.494 g, 56%).

Example 291B [4-(3-hydroxYpyrrolidinyl)-2-phenvlbenzovllmethionine Saponification of the product of Example 289A using the procedure of Example 287D gave the desired compound as a white foam as the bis-hydrochloride, mono-sodium chloride. NMR (300 MHz, DMSO-d6) 8 1.77-2.06 (comp, 5H), 2.16-2.36 (comp, 2H), 2.94-3.04 (m, 1H), 3.12-3.34 (comp, 2H), 3.34-3.56 (comp, 2H), 4.28-4.37 (m, 1H), 4.37-4.60 (comp, 2H), 4.60-5.50 (br, 2H), 7.32-7.43 (comp, 3H), 7.45-7.56 (comp, 3H), 7.65-7.80 (comp, 2H), 8.68 (d, J= 7.8 Hz, 1H), 11.2-11.9 (m, 1H). LRMS (CI) m/e 429 (M+H) +.

Example 349 [4- (5-cyclohexylmethyloxazolid-2-on-1-vlmethyl)-2- (2-methylphenyl) benzovllmethionine

f4-methionine A mixture of [4-formyl-2- (2-methylphenyl) benzoyl] methionine ethyl ester (614 mg, 1.54 mmol), prepared according to Example 158F except substituting [4-hydroxmethyl-2- (2-methylphenyl) benzoic acid for 4-hydroxymethyl-2-phenylbenzoic acid in Example 158E, (S)-(+)-2-amino-3-cyclohexyl-I-propanol hydrochloride (357 mg, 1.84 mmol) and diisopropylethylamine (0.135 mL, 0.77 mmol) in toluene was refluxed for 5 hours using a Dean-Stark apparatus. The reaction mixture was cooled to ambient temperature and diluted with ethanol. Sodium cyanoborohydride (145 mg) and o-bromocresol green was added.

The reaction mixture was stirred while acidity was maintained using HCl-ethanol. The reaction was quenched with saturated aqueous potassium carbonate and the mixture was extracted with dichloromethane (2x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (5% methanol-chloroform) gave the desired compound (840 mg).

Example 349B <BR> <BR> <BR> <BR> [4- (l-hydroxy-3-cyclohexyIprop-2-yl-A-ethoxycarbonyIaminomethyl )-2- (2-<BR> <BR> <BR> <BR> methylphenyi) benzoyllmethionine To a solution in THF of the product of Example 348A (173 mg, 0.32 mmol) and diisopropylethylamine (66 RL, 0.38 mmol) was added ethyl chloroformate (40 J. L, 0.38 mmol) and the reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was poured into ethyl acetate and the organic phase was washed with aqueous 2N HCI, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the desired compound as a clear oil which was used without further purification.

Example 349C <BR> <BR> <BR> <BR> [4- (5-cyclohexylmethyl-2-oxazolidon-l-vlmethvl)-2- (2-methylphenvl) benzovl1methionine To a 100 °C solution of the product of Example 348B in toluene was added sodium ethoxide (21% in ethanol, 30 µL) and the reaction mixture was stirred for 10 minutes. The reaction mixture was cooled to ambient temperature and diluted with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (33% ethyl acetate-hexane) gave the title compound as the ethyl ester.

Saponification of the ethyl ester using lithium hydroxide gave the title compound. I H NMR (DMSO-d6,300 MHz) 8 8.13 (m, 1H), 7.41 (d, J= 7 Hz, 1H), 7.25 (d, J= 7 Hz, 1H), 7.11-7.02 (m, 4H), 4.45 (d, J= 15 Hz, 1H), 4.34 (dd, J= 9,8 Hz, 1H), 4.19 (d, J= 15 Hz, 1H), 4.10 (m, 1H), 3.84 (dd, J= 8,8 Hz, 1H), 3.58 (m, 1H), 2.10-1. 83 (m, 5H), 1.85 (s, 3H), 1.47-1.37 (m, 8H), 1.10-0.92 (m, 5H), 0.85-0.57 (m, 2H). MS (DCI- NH3) m/e 539 (M+H) +, 556 (M+NH4) +.

Example 452 N- [4-(2-(2-phenylphenyl) ethyl)-2-(2-methvlphenyl) benzovllmethionine[4-(2-(2-phenylphenyl) ethyl)-2-(2-methvlphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Examples 210-212 1H nmr (300 MHz, DMSO-d6): 8 7.2-7.04 (m, 15 H), 6.89 (dd, 1 H), 6.54 (br d, 1 H), 4.12 (m, 1 H), 2.81 (t, 2 H), 2.63 (t, 2 H), 2.00 (m, 1 H), 1.88-1.87 (br s, 6 H), 1.73 (m, 2 H), 1.56 (m, 1 H). MS (ESI-): m/e 522 (M-H)-.

Example 453 N- 4- (2- (2-phenoxyphen) ethen-1-Xl)-2- (2-methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210 and 211..'Hnmr (300MHz. DMSO-d6): # 7. 88 (br d, 1 H), 7.55 (m, 2 H), 7.40-7.17 (m, 11 H), 7.10 (t, 1 H), 6.96 (m, 4 H), 3.65 (m, 1 H), 2.15 (m, 1 H), 2.00 (m, 1 H), 1.91 (br s, 6 H), 1.75-1.55 (m, 2 H). MS (APCI-): m/e 536 (M-H)-.

Example 454 N-[4-(2-(2-phenoxyphenyl)ethenyl)-2-(2-methylphenyl)benzoyl] -2-amino-4- methylsulfinylbutanoic acid lithium salt The desired compound was prepared according to the method of Examples 210 and 211.. 1 H nmr (300 MHz, DMSO-d6): 3 7.88 (br d, 1 H), 7.62-7.50 (m, 2 H), 7.40-7.17 (m, 11 H), 7.10 (t, 1 H), 6.98 (m, 4 H), 3.90 (m, 1 H), 2.45 (s, 3 H), 2.39,2.36 (2 s's, 3 H), 2.10-1.64 (m, 4 H). MS (ESI-): m/e 552 (M-H)-.

Example 455 saltN-[4-(2-(2-phenoxyphenyl)ethyl)-2-(2-methylphenyl)benzoy l]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 7.45-6.90 (m, 17 H), 3.65 (m, 1 H), 2.88 (br s, 4 H), 2.18-2.00 (m, 2 H), 1.91 (br s, 6 H), 1.70-1.50 (m, 2 H). MS (APCI-): m/e 538 (M- H)-.

Example 456 N-4- (2- (2-phenoxyphenylethvl)-2- (2-methylphenvl) benzovll-2-amino-4- methylsulfinylbutanoic acid lithium salt The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 5 7.43 (m, 1 H), 7.34 (m, 3 H), 7.25-7.00 (m, 9 H), 6.95 (m, 1 H), 6.85 (m, 3 H),. 3.90 (m, 1 H), 2.88 (br s, 4 H), 2.41-2.37 (4 s's, 6 H), 2.10-1.64 (m, 4 H). MS (ESI-): m/e 554 (M-H)-.

Example 457 N- 4- (2-benzylphen ethenyl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, DMSO-d6): 8 7.70 (m, 1 H), 7.59 (m, 1 H), 7.51 (m, 2 H), 7.34- 7.10 (m, 14 H), 6.96 (br s, 1 H). 4.17 (br s, 2 H), 3.63 (m, 1 H), 2.19 (m, 1 H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.73-1.52 (m, 2 H). MS (APCI-): m/e 534 (M-H)-.

Example 458 saltN-[4-(2-(2-benzylphenyl)ethenyl)-2-(2-methylphenyl)benzo yl]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 7.60-7.40 (m, 3 H), 7.25-7.07 (m, 12 H), 7.00- 6.80 (m, 2 H), 3.97 (s, 2 H), 3.61 (m, 1 H), 2.83 (m, 2 H), 2.72 (m, 2 H), 2.08 (m, 1 H), 1.97 (m, 1 H), 1.96,1.91 (2 br s's, 6 H), 1.80-1.52 (m, 2 H). MS (APCI-): m/e 536 (M- H)-.

Example 459 saltN-[4-(2-(3-phenoxyphenyl)ethyl)-2-(2-methylphenyl)benzoy l]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 7.44 (d, 1 H), 7.35 (tt, 2 H), 7.25 (dt, lH), 7.19 (m, 4 H), 7.10 (tt, 2 H), 6.98 (dt, 1 H), 6.96-6.83 (m, 5 H), 6.79 (ddd, 1 H), 3.64 (m, 1 H), 2.91 (br s, 4 H), 2.08 (m, 1 H), 1.95 (m, 1 H), 1.91 (br s, 6 H), 1.73-1.52 (m, 2 H).

MS (APCI-): m/e 538 (M-H)-.

Example 460 N-[4-(2-(3-phenoxyphenyl)ethyl)-2-(2-methylphenyl)benzoyl]-2 -amino-4- methylsulfinylbutanoic acid lithium salt The desired compound was prepared according to the method of Examples 210- 212.. nmr (300 MHz, DMSO-d6): 7.44 (dd, 1 H), 7.35 (tt, 2 H), 7.25 (dt, 1 H), 7.19 (m, 4 H), 7.10 (tt, 2 H), 6.98 (dt, 1 H), 6.96-6.83 (m, 5 H), 6.79 (ddd, 1 H), 3.90 (m, 1 H), 2.91 (br s, 4 H), 2.45 (s, 3 H), 36 (2 s's, 3 H), 2.20-1.54 (m, 4 H). MS (ESI -): m/e 554 (M-H)-.

Example461 saltN-[4-(2-(4-cyclohexylphenyl)ethyl)-2-(2-methylphenyl)ben zoyl]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 7.45 (d, 1 H), 7.29 (dd, 1 H), 7.25-7.05 (m, 8 H), 6.88 (m, 2 H), 3.64 (m, 1 H), 2.88 (m, 4 H), 2.44 (m, 1 H), 2.10-1.30 (m, 14 H), 1.91 (br s, 6 H). MS (APCI-): m/e 528 (M-H)-.

Example 462 saltN-[4-(2-(4-phenoxyphenyl)ethyl)-2-(2-methylphenyl)benzoy l]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 7.45 (d, 1 H), (m, 3 H), 7.25-7.12 (m, 7 H), 7.10 (tt, 1 H), 6.98-6.87 (m, 5 H), 8 3.67 (m, 1 H), 2.91 (br s, 4 H), 2.16-1.95 (m, 2 H), 1.91 (br s, 6 H), 1.73-1.52 (m, 2 H). MS (APCI-): m/e 538 (M-H)-.

Example 463 N-[4-(2-(4-phenoxyphenyl)ethyl)-2-(2-methylphenyl)benzoyl]-2 -amino-4- methylsulfinylbutanoic acid lithium salt The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 7.66-6.87 (m, 17 H), 3.70 (m, 1 H), 2.92 (br s, 4 H), 2.40-2.37 (4 s's, 6 H), 2.20-1.54 (m, 4 H). MS (ESI-): m/e 554 (M-H)-.

Example 464 N-f4- (2-fluoren-4-vlet112- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 7.84 (d, 1 H), 7.77 9d, 1 H), 7.56 (d, 1 H), 7.45 (d, 1 H), 7.44 (s, 1 H), 7.40-6.86 (m, 10 H), 3.86 (s, 2 H), 3.64 (m, 1 H), 2.98 (br s, 4 H), 2.08 (m, 1 H), 1.95 (m, 1 H), 1.91 (br s, 6 H), 1.73-1.52 (m, 2 H). MS (APCI-): m/e 538 (M-H)-.

Example 465 N-[4-(2-naphth-2-ylethenyl)-2-(2-methylphenyl)benzoyl]methio nine The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, CDCl3): 8: 8 8.07 (dd, 1 H), 7.90-7.80 (m, 4 H), 7.74 (dd, I H), 7.66 (dd, 1 H), 7.51 (m, 2 H), 7.42-7.31 (m, 6 H), 7.25 (m, 1 H), 5.94 (t, 1 H), 4.60 (m, 1 H), 2.20-2.00 (4 s's, 6 H), 2.12 (m, 1 H), 2.03 (m, 1 H), 1.94 (m, 1 H), 1.58 (m, 1 H). MS (CI +): m/e 496 (M+H) +.

Example 466 N-f4- (2-naphth-1-lethen)-2- (2-methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210 and 211.. lH nmr (300 MHz, MeOD-d4): 8 8.28 (d, 1 H), 8.12 (dd, 1 H), 7.90-7.72 (m, 5 H), 7.63-7.42 (m, 5 H), 7.35-7.10 (m, 5 H), 4.25 (m, 1 H), 2.98 (br s, 4 H), 2.30 (m, 1 H), 2.10 (m, 1 H), 2.02-1.97 (4 s's, 6 H), 1.84 (m, 1 H), 1.68 (m, 1 H). MS (ESI-): m/e 494 (M-H)-.

Example 467 saltN-[4-(2-naphth-1-ylethyl)-2-(2-methylphenyl)benzoyl]meth ioninelithium The desired compound was prepared according to the method of Examples 210- 212.. nmr (300 MHz, MeOD-d4): b 8.08 (d, 1 H), 7.85 (dd, 1 H), 7.70 (d, 1 H), 7.63- 7.38 (m, 4 H), 7.37-7.15 (m, 6 H), 7.05-6.83 (m, 2 H), 4.24 (m, 1 H), 3.42 (t, 2 H), 3.12 (t, 2 H), 2.27-2.05 (m, 2 H), 2.00 (br s, 6 H), 1.90-1.60 (m, 2 H). MS (ESI-): m/e 496 (M-H)-.

Example 468 saltN-[4-(2-naphth-1-ylethyl)-2-(2-methylphenyl)benzoyl]meth ioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, MeOD-d4): 8 7.66 (m, 3 H), 7.45 (m, 2 H), 7.31 (m, 2 H), 7.24 (dd, 1 H), 7.20 (dd, 1 H), 7.13-7.00 (m, 4 H), 6.80 (br d, 1 H), 4.13 (m, 1 H), 3.01 (t, 4 H), 1.91,1.88,1.81 (3 br s's, 6 H), 1.95-1.48 (m, 4 H). MS (ESI-): m/e 496 (M-H)-.

Example 469 N-f4- 3phenylprop-l-enyl l-2(2-methylphenyl) benzoyl_] methionine (1: 1 mixture of olefin isomers) The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, CDC13): 8 8.00,7.96 (2 d's, from each of the isomers, 1 H), 7.48- 7.08 (11 H), 6.52-6.30 (m, 2 H), 5.88 (m, 1 H), 4.56 (m, 1 H), 3.60 (2 d's, from each of the isomers, 2 H), 2.20-2.00 (m, 8 H), 1.90 (M, 1 H), 1.52 (m, 1 H). MS (CI +) m/e 460 (M+H) +.

Example 470 saltN-[4-(3-naphth-2-ylpropyl)-2-(2-methylphenyl)benzoyl]met hioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, MeOD-d4): 8 7.68 (t, 1 H), 7.65 (t, 1 H), 7.51 (m, 2 H), 7.34- 7.06 (m, 9 H), 6.93 (m, 1 H), 4.17 (m, 1 H), 2.73 (t, 2 H), 2.66 (t, 2 H), 1.96 (m, 1 H), 1.99 (m, 3 H), 89 (2 br s's, 6 H), 1.72 (m, 1 H), 1.53 (m, 1 H). MS (ESI-): m/e 510 (M-H)-.

Example 471 N-f4- (3-cyclohexylprop-1-envl-2- (2-methylphenyl) benzoyl1methionine lithium salt The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, DMSO-d6): 8 7.46 (m, 2 H), 7.25-7.09 (m, 6 H), 6.96 (m, 1 H), 6.40 (m, 1 H), 3.64 (m, 1 H), 3.18 (m, 2 H), 2.2-2.05 (m, 2 H), 2.03-1.92 (3 br s's, 6 H), 1.75-0.90 (m, 13 H). MS (ESI-): m/e 464 (M-H)-.

Example 472 N-f4- (4-phenylbut-l-enyl)-2- (2-methvlphenyl) benzoyllmethionine The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, CDC13): 8 7.98 (m, 1 H), 7.50-7.10 (m, 12 H), 6.41 (m, 1 H), 5.88 (m, 1 H), 4.57 (m, 1 H), 2.82 (m, 2 H), 2.57 (m, 2 H), 2.20-2.00 (m, 8 H), 1.92 (m, 1 H), 1.52 (m, 1 H). MS (CI +) m/e 474 (M+H) +.

Example 473 saltN-[4-(4-naphth-2-ylbut-4-on-1-yl)-2-(2-methylphenyl)benz oyl]methioninelithium The desired compound was prepared according to the method of Examples 210- 212.. 1H nmr (300 MHz, DMSO-d6): 8 8.61 (s, 1 H), 8.10 (br d, 1 H), 7.98 (m, 2 H), 7.63 (m, 2 H), 7.46 (m, 2 H), 7.31 (m, 1 H), 7.23-6.87 (m, 6 H), 3.44 (m, 1 H), 3.20 (m, 2 H), 2.75 (m, 2 H), 2.30-1.97 (m, 4 H), 1.95 (br s, 3 H), 1.91 (br s, 3 H), 1.90-1.56 (m, 2 H). MS (ESI-): m/e 538 (M-H)-.

Example 474 N-[4-(4-naphth-2-ylbut-4-ol-1-enyl)-2-(2-methylphenyl)benzoy l]methionine The desired compound was prepared according to the method of Examples 210 and 211. 1H nmr (300 MHz, DMSO-d6): 8 7.95-7.83 (m, 4 H), 7.56 (dd, 1 H), 7.48 (m, 3 H), 7.43 (m, 1 H), 7.25-7.08 (m, 5 H), 7.00-6.85 (m, 1 H), 6.45 (m, 1 H), 4.86 (t, I H), 3.64 (m, 1 H), 2.63 (br t, 2 H), 2.17 (m, 1 H), 1.98,1.91 (2 br s's, 6 H), 1.95 (m, 1 H), 1.90- 1.56 (m, 2 H). MS (ESI-): m/e 538 (M-H)-.

Example 478 N-f4- (4-cvclohexylbutyl)-2- (2-methylphenyl) benzoyl] methionine sodium salt The desired compound was prepared according to the method of Examples 210- 212.. nmr (300 MHz, DMSO-d6): 8 7.45 (d, 1 H), 7.27-7.10 (m, 5 H), 6.96 (m, 1 H), 6.89 (br s, 1 H), 3.67 (m, 1 H), 2.62 (t, 2 H), 2.15 (m, 1 H), 1.98,1.91 (2 br s's, 6 H), 1.97 (m, 1 H), 1.70-0.75 (m, 19 H). MS (ESI-): m/e 480 (M-H)-.

Example 480 N-[4-(5-phenylpent-1-enyl)-2-(2-methylphenyl)benzoyl]methion ine The desired compound was prepared according to the method of Examples 210 and 211.. 1H nmr (300 MHz, CDC13): 6 8.00 (tt, 1 H), 7.43 (dt, 1 H), 6.38-7.15 (m, 11 H), 6.39 (m, 1@ H), 5.85 (m, 1 H), 4.52 (m, 1 H), 2.70 (m, 2 H), 2.19 (m, 1 H), 2.20-2.00 (4 s's, 6 H), 2.10 (m, 3 H), 1.90-1.50 (m, 4 H). MS (CI +): m/e 488 (M+H) +.

Example 493 saltN-[4-(2-pyrimidin-5-ylethynyl)-2-(2-methylphenyl)benzoyl ]methioninelithium The desired compound was prepared according to the method of Examples 210-211 1H nmr (300 MHz, DMSO-d6): # 9.20 (s, 1 H), 9.04 (s, 2 H), 7.63 (m, 3 H), 7.42 (m, 1 H), 7.30-7.18 (m, 4 H), 7.16-7.00 (m, 2 H), 3.48 (m, 1 H), 2.18 (m, 1 H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H).

Example 494

saltN-[4-(2-pyrimidin-5-ylethen-1-yl)-2-(2-methylphenyl)benz oyl]methioninelithium The desired compound was prepared according to the method of Examples 210-211 1H nmr (300 MHz, DMSO-d6): # 9.06 (s, 1 H), 9.04 (s, 2 H), 7.67 (br d, I H), 7.00 (m, 2 H), 7.47 (m, 1 H), 7.38 (d, 1 H), 7.30-7.15 (m, 3 H), 7.10-6.97 (m, 2 H), 3.66 (m, 1 H), 2.20 (m, 1 H), 2.03 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 446 (M-H)-.

Example 495 N- benzoyl] methionine lithium salt The desired compound was prepared according to the method of Examples 210-211 lH nmr (300 MHz, DMSO-d6): 8 8.78 (s, 1 H), 8.63 (dd, 1 H), 8.51 (d, 1 H), 7.82 (d, 1 H), 7.76 (dd, 1 H), 7.59 (d, 1 H), 7.52 (m, 2 H), 7.30-7.10 (m, 4 H), 7.02 (m, 1 H), 3.68 (m, 1 H), 2.20 (m, 1 H), 2.03 (m, 1 H), 1.93 (br s, 16 H), 1.70 (m, 1 H), 1.58 (m, 1 H).

MS (ESI-): m/e 446 (M-H)-.

Example 496 saltN-[4-(3-naphth-2-ylprop-1-enyl)-2-(2-methylphenyl)benzoy l]methioninelithium (1: 1 mixture of olefin isomers) The desired compound was prepared according to the method of Examples 210-211 lu nmr (300 MHz, MeOD-d4): 8 7.85-7.58 (m, 5 H), 7.51-7.36 (m, 4 H), 7.32-7.10 (m, 5 H), 6.61 (m, 1 H), 4.24 (m, 1 H), 3.72,3.67 (2 d's, 2 H, 1 : 1 ratio), 2.24 (m, 1 H), 2.08- 1.95 (4 s's, 6 H), 1.99 (m, 1 H), 1.90-1.60 (m, 2 H). MS (ESI-) m/e 508 (M-H)-.

Example 572 saltN-[4-(2,3-diphenylpropan-1-yl)-2-(2-methylphenyl)benzoyl ]methioninelithium The desired compound was prepared according to the method of Examples 210-212 (DMSO-d6) 8 7.38 (d, lH), 7.10,6.90,6.73 (all m, total 17H), 3.75 (m, 1H), 2.98 (m, 5H), (envelope, 10H). MS (ESI) 536 (M-H)-. Anal calcd forC34H34LiN03S- 0.25 H20: C, 74.50; H, 6.34; N, 2.56. Found: C, 7.10; H, 5.95; N, 2.53.

Example 768 <BR> <BR> <BR> N-4- (N-Benzyl-N-phenylaminosulfonyll-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 5E. IH (d6-DMSO): 8 7.7-7.9 (4H, m); 7.3-7.1 (13H, m); 4.84 (2H, s); 4.1 (1H, m) 3.2 (3H, s); 1.9 (3H, s); 2.1-1.6 (4H, m). ESI (-)/MS: 587 (M-Li)

Example 772 N-f4- (N-2-cvclohex. vlethylaminosulfonyl)-2-phenylbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 5E. IH (CD30D): 7.85-7.9 (1H, d); 7.7-7.8 (, 1H, d); 7.6-7.7 (1H, s); 7.2-7.3 (4H, m); 4.2-4.3 (1 H, m); 2.8-2.9 (2H, t); 2.05-2.1 (2H, m); 2.0 (3H, s); 1.9 (3H, s); 1.6-1.7 (6H, m) 1.1- 1.4 (7H, m); 1.7-1.86 (2H, m). ESI (-)/MS: 521 (M-Li); 487,459.

Example 773 saltN-[4-(1-Benzylylpiperidin-4-ylaminosulfonyl)-2-phenylben zoyl]methioninelithium The desired compound was prepared according to the method of Example 5E. l H (CD30D): 7.82-7.94 (1H, d); 7.75-7.81 (1H, d); 7.62-7.72 (1H, s); 7.1-7.38 (9H, m); 4.2- 4.3 (1H, m); 3.1 (2H, s); 3.0-3.1 (1H, m); 2.7-2.8 (2H, d) ; 2.42-2.54 (2H, t); 1.78-2.3 (l IH, m); 1.6-1.78 (3H, m); 1.4-1.6 (2H, m). ESI (-)/MS: 594 (M-Li).

Example 774

N-f4-N- (2-piperidin-lyleyl) aminosulfonvll-2-phenvlbenzovllmethionine lithium salt The desired compound was prepared according to the method of Example 5E. 1 H (CD30D): 7.82-7.94 (1H, d); 7.75-7.81 (1H, d); 7.62-7.72 (1H, s); 7.1-7.38 (4H, m) ; 4.18-4.3 (1H, m); 3.1 (2H, m); 2.34-2.5 (5H, m); 2.2-2.35 (2H, m); 2.05-2.2 (2H; m) ; 1.93-2.05 (3H, s); 1.8-1.95 (4H, m); 1.6-1.7 (2H, m); 1.55-1.6 (3H, m); (2H, m).

ESI (-)/MS: 532 (M-Li); 488; 357.

Example 775 <BR> <BR> <BR> N- [4-N- (2-morpholin-lylethyi) aminosulfonyn-2-phenylbenzoynmethionine lithium salt The desired compound was prepared according to the method of Example 5E. IH (CD30D): 7.9-8.1 (1H, d); 7.8-7.9 (1H, d); 7.67-7.8 (1H, s); 7.1-7.4 (4H, m); 4.2-4.3 (1H, m); 3.4-3.7 (4H, m); 3.4-3.2 (4H, m); 2.9-3.2 (2H, t); 1.6-2.6 (12H, m) ESI (-)/MS: 534 (M-Li); 490; 462.

Example 776 N-f4- (2- (3. 4-dimethoxyphenvl) ethvlaminosulfonvl)-2-phenylbenzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 5E.

IH (MeOH-d4): 8 7.78-7.9 (2H, m); 7.62-7.7 (lH, s); 7.1-7.3 (4H, m); 6.78-6.82 (1H, d); 6.72-6.78 (1H, d); 6.65-6.72 (1H, q); 4.2-4.3 (1H, m); 3.75-3.8 (6H, s); 3.08-3.18 (2H, m); 2.58-2.7 (2H, t); (10H, m). ESI (-)/MS: 585 (M-Li); 541; 410.

Example 777 N-f4- (3-imidazol-1-ylpropvlaminosulfonyl)-2-phenylbenzoyllmethion ine lithium salt The desired compound was prepared according to the method of Example 5E, tH (MeOH-d4): 8 7.78-7.9 (2H, dd); 7.5-7.6 (2H, m); 7.1-7.3 (4H, m); 7.1 (1H, s); 6. 92 (IH, s); 4.2-4.3 (1H, m); 4.05-4.18 (2H, t); 2.8-2.9 (2H, t); 1.6-2.3 (12H, m). ESI (-)/MS: 529 (M-Li); 281 ; 255.

Example 778 N-[4-(3-(2-methylpiperidin-1-yl)propylaminosulfonyl)-2-pheny lbenzoyl]methioninelithium salt The desired compound was prepared according to the method of Example 5E.

I H (MeOH-d4): 8 7.8-7.94 (2H, dd); 7.6-7.7 (1H, s); 7.1-7.4 (4H, m); 4.2-4.3 (1 H, m); 2.84-2.94 (2H, t); 2.7-2.87 (2H, m); (13H, m); 1.4-1.8 (6H, m); 1.24-1.349 (2H, m); 1. 0-1. 1 (3H, m). ESI (-)/MS: 560 (M-Li); 385; 281.

Example 783 N-[4-iodo-2-(2-methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 21 OC.'H nmr (300 MHz, CDC13): b 7.83 (dd, 1 H), 7.72 (dd, 1 H), 7.60 (s, 1 H), 7.39-7.16 (m, 4 H), 5.89 (m, 1 H), 4.58 (m, 1 H), 2.20-2.00 (m, 8 H), 1.96 (m, 1 H), 1.58 (m, 1 H). MS (CI +) m/e 452 (M+H) +.

Example 784 N-r4-N(t-Butylcarbazatocarbonylmethyl) amino-2-phenylbenzoyllmethionine The desired compound was prepared according to the method of Example 57, except t-Butylcarbazatocarbonylmethyl bromide was used as the alkylating agent. nmr (300 MHz, DMSO-d6): 8 9.79 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, 1 H), 7.47-7.29 (m, 6 H), 6.65 (br d, 1 H), 6.56 (d, 1 H), 6.43 (t, 1 H), 4.30 (m, 1 H), 3.81 (d, 2 H), 2.32 (m, 2 H), 2.05 (br s, 6 H), 1.90 (m, 2 H), 1.47 (s, 9 H). MS (APCI +) m/e 517 (M+H) +.

Example 785 saltN-[4-(2-thiazol-5-yl)ethen-1-yl)-2-(2-methylphenyl)benzo yl]methioninelithium The desired compound was prepared according to the method of Examples 210- 211. 1 H nmr (300 MHz, DMSO-d6): 8 9.01 (s, 1 H), 7.98 (s, 1 H), 7.67 (d, 1 H), 7.63 (m, 1 H), 7.55 (d, 1 H), 7.42 (m, 1 H), 7.30-7.15 (m, 4 H), 3.65 (m, 1 H), 2.18 (m, 2 H), 2.02 (br s, 3 H), 1.92 (br s, 3 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 451 (M-H)-.

Example 786 N- (4- (2-phenylphenyl)-2-l2-methylphenyl) benzoyllmethionine(4- (2-phenylphenyl)-2-l2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210- 211.'H nmr (300 MHz, DMSO-d6): # 7.96 (s, 1 H), 7.83 (d, 1 H), 7.77 (d, 2 H), 7.74 (d, 1 H), 7.66 (t, 2 H), 7.56 (t, 2 H), 7.48 (t, 2 H), 7.38 (t, 1 H), 7.24 (m, 3 H), 7.02 (m, 1 H), 3.66 (m, 1 H), 2.22 (m, 2 H), 2.05 (br s, 3 H), 1.93 (br s, 3 H), 1.77 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 494 (M-H)-.

Example 787 A [4- (3-phenylphenyn-2- (2-methylphenyi) benzoyl] methionine lithium salt The desired compound was prepared according to the method of Examples 210- 211.'H nmr (300 (300 MHz, DMSO-d6): 8 7.7.54-7.44 (m, 4 H), 7.51 (m, 1 H), 7.38 (m, I H), 7.34-7.22 (m, 3 H), 7.19-7.00 (m, 5 H), 6.90-6.85 (m, 2 H), 6.66 (m, 1 H), 3.62 (m, 1 H), 2.22 (m, 2 H), 2.05 (br s, 3 H), 1.93 (br s, 3 H), 1.77 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 494 (M-H)-.

Example 788 saltN-[4-(4-phenylphenyl)-2-(2-methylphenyl)benzoyl]methioni nelithium The desired compound was prepared according to the method of Examples 210- 211. IH nmr (300 MHz, DMSO-d6): b 7.87-7.80 (m, 3 H), 7.78 (t, 2 H), 7.73 (d, 2 H), 7.65 (d, 1 H), 7.49 (m, 3 H), 7.39 (m, 1 H), 7.33-7.15 (m, 4 H), 7.02 (m, 1 H), 3.66 (m, 1 H), 2.22 (m, 2 H), 2.05 (br s, 3 H), 1.93 (br s, 3 H), 1.77 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 494 (M-H)-.

Example 789 saltN-[4-(4-phenylcyclohexylidenyl)-2-(2-methylphenyl)benzoy l]methioninelithium The desired compound was prepared according to the method of Examples 210- 211. in nmr (300 MHz, CD30D): 8 7.56 (m, 1 H), 7.25-6.94 (m, 10 H), 6.27 (s, 1 H), 4.16 (m, 1 H), 2.60 (m, 1 H), 2.40 (m, 2 H), 2.17 (m, 2 H), 2.00-1.70 (m, 13 H), 1.58 (m, 1 H). MS (ESI-): m/e 522 (M-H)-.

Example 790 N-f4-svn- (4-phenylcyclohexylmethyl-2- (2-methylphenyl) benzovllmethionine(4-phenylcyclohexylmethyl-2- (2-methylphenyl) benzovllmethionine lithium salt The desired compound was prepared according to the method of Examples 210- 212. nmr (300 MHz, CD30D): 8 7.53 (m, 2 H), 7.22-6.92 (m, 10 H), 4.15 (m, I H), 2.73 (br d, 2 H), 2.52 (m, 1 H), 2.15 (m, 2 H), 2.02-1.90 (m, 6 H), 1.75 (m, 5 H), 1.57 (m, 5 H). MS (ESI-): m/e 514 (M-H)-.

Example 791 N-[4-(2-phenylethen-1-yl)-2-(2-methylphenyl)benzoyl]methioni ne The desired compound was prepared according to the method of Examples 210- 211. 1 H nmr (300 MHz, CDCl3): 8 8.03 (dd, 1 H), 7.61 (dd, 1 H), 7.52 (m, 2 H), 7.40- 7.22 (m, 8 H), 7.20 (d, 1 H), 7.10 (d, 1 H), 5.93 (m, 1 H), 4.59 (m, 1 H), 2.20-2.00 (m, 8 H), 1.96 (m, 1 H), 1.56 (m, 1 H). MS (CI +) m/e 446 (M+H) +.

Example 792 saltN-[4-(2-(3-phenylphenyl)ethen-1-yl)-2-(2-methylphenyl)be nzoyl]methioninelithium The desired compound was prepared according to the method of Examples 210- 211. 1H nmr (300 MHz, CD30D): 8 7.83-7.10 (m, 18 H), 4.27 (m, 1 H), 2.30 (m, 1 H), 2.15-1.95 (m, 8 H), 1,88 (m, 1 H), 1.69 (m, 1 H). MS (ESI-): m/e 520 (M-H)-.

Example 793 N- [4- (2- (3-phenylphenyl)yl)-2- (2-methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples210-212.

I nmr (300 MHz, CD30D): # 7.60 (br d, 1 H), 7.51 (br d, 2 H), 7.45-7.20 (m, 12 H), 6.98 (m, 1 H), 4.23 (m, 1 H), 3.04 (br s, 4 H), 2.12 (m, 2 H), 2.03-1.91 (m, 6 H), 1.83 (m, 1 H), 1.65 (m, 1 H). MS (ESI-): m/e 522 (M-H)-.

Example 794 saltN-[4-(2-(3-phenylphenyl)ethen-1-yl)-2-(2-methylphenyl)be nzoyl]methioninelithium The desired compound was prepared according to the method of Examples 210- 211. 1H nmr (300 MHz, DMSO-d6): 8 7.85 (dd, 1 H), 7.54-7.30 (m, 9 H), 7.30-7.10 (m, 6 H), 7.10 (d, 1 H), 6.95 (m, 1 H), 3.67 (m, 1 H), 2.16 (m, 2 H), 2.02 (br s, 3 H), 1.91 (br s, 3 H), 1.70 (m, 1 H), 1.57 (m, 1 H). MS (ESI-): m/e 521 (M-H)-.

Example 810 N-f 4- (2- (3-phenoxvpvridazin-6-vl) ethen-l-vl)-2- (2-methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210- 211. nmr (300 MHz, DMSO-d6): 8 8.08 (d, 1 H), 7.76 (dd, 1 H), 7.59 (d, 1 H), 7.52 (d, 1 H), 7.52-7.43 (m, 4 H), 7.31-7.10 (m, 7 H), 7.00 (m, 1 H), 2.18 (m, I H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 538 (M-H)-.

Example 811 N-f4- (2- (3-phenoxypvridazin-6=yl) ethvl)-2- (2-methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Examples 210- 211. 1H nmr (300 MHz, DMSO-d6): 8 7.65 (d, 1 H), 7.46 (d, 1 H), 7.44 (d, 1 H), 7.38- 7.10 (m, 9 H), 6.94 (m, 1 H), 6.88 (m, 1 H), 6.75 (m, 1 H), 3.65 (m, 1 H), 3.19 (t, 2 H), 3.07 (t, 2 H), 2.18 (m, 1 H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 540 (M-H)-. example siz N- [4- (2- (2-phenoxypyridazin-5-y) ethen-1-yll- (2-methylphenylbenzoyl methionine lithium salt The desired compound was prepared according to the method of Examples 210- 211.1 H nmr (300 MHz, DMSO-d6): 8 8.51 (s, 1 H), 8.33 (s, 1 H), 7.64 (m, 1 H), 7.53-

7.38 (m, 6 H), 7.30-7.15 (m, 7 H), 7.00 (m, 1 H), 3.65 (m, 1 H), 2.18 (m, I H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 538 (M-H)-.

Example 813 saltN-[4-(2-(2-phenoxypyridazin-5-yl)ethyl)-2-(2-methylpheny l)benzoyl]methioninelithium The desired compound was prepared according to the method of Examples 210- 212. nmr (300 MHz, DMSO-d6): 8 8.26 (s, 1 H), 8.21 (s, 1 H), 7.50-7.30 (m, 6 H), 7.30-7.10 (m, 5 H), 7.00 (m, 1 H), 3.65 (m, 1 H), 2.97 (m, 4 H), 2.18 (m, 1 H), 2.02 (m, 1 H), 1.92 (br s, 6 H), 1.70 (m, 1 H), 1.58 (m, 1 H). MS (ESI-): m/e 540 (M-H)-.

Example 824 N-[4-(2-benzyloxymethylpyrrolidin-1-ylmethyl)-2-(2-methylphe nyl)benzoyl]methionine The desired compound was prepared according to the method of Example 157. 1H nmr (300 MHz, DMSO d6): 5 8.13, d, 1H ; 7.47, d, 1H ; 7.37, d, 1H ; 7.13-7.32, m, 10H; 4.48, s, 2H; 4.21, m 2H; 3.51, m, 2H; 3.38, m, 2H; 2.89, m, 2H; 1.99-2.40 m, 7H ; 1.98, s, 3H; 1.50-1.96, m, 4H. MS (ESI (-)): 545 (M-H); (ESI (+)): 547. Calc'd for C32H38N204S+0. 70H20: C 68.72, H 7.10, N 5.01: Found: C 68.71, H 6.6.88, N 4.92.

Example 854 N-[4-(2-(4-(2-chlorophenoxy)phenyl)ethen-1-yl)-2-(2-methylph enyl)benzoyl]methionine The desired compound was prepared according to the method of Examples 210-21 l.

MS m/e 570 (M-H)-. lH NMR (CDC13,300 MHz) 8 1.58 (m, 1H), 1.95 (m, lH), 2.1 (m, 8H), 4.59 (m, 1H), 5.91 (m, 1H), 6.91-7.62 (m, 16H), 8.03 (m, 1H).

Example 855 N-[4-(2-(4-(2-chlorophenoxy)phenyl)ethyl)-2-(2-methylphenyl) benzoyl]methionine The desired compound was prepared according to the method of Examples 210- 21 l. MS m/e 574 (M+H) +. IH NMR (CDC13,300 MHz) 8 1.53 (m, 1H), 1.93 (m, 1H), 2.1 (m, 8H), 2.95 (m, 4H), 4.59 (m, 1H), 5.83 (m, 1H), 6.83-7.50 (m, 14H), 7.97 (m, 1H).

Example 856

N-[4-(2-(4-(2-nitrophenoxy)phenyl)ethen-1-yl)-2-(2-methylphe nyl)benzoyl]methionine The desired compound was prepared according to the method of Examples 210- 211. MS m/e 583 (M+H) +. 1H NMR (CDCl3, 300 MHz) 8 1.57 (m, 1H), 1.93 (m, 1H), 2.1 (m, 8H), 4.58 (m, 1H), 5.90 (m, 1H), 6.65 (m, 2H), 6.90-7.50 (m, 14H), 7.96 (m, 1H).

Example 857 N-[4-(2-(4-(2-aminophenoxy)phenyl)ethyl)-2-(2-methylphenyl)b enzoyl]methionine The title compound was prepared in an analogous manner Example 212 except that the final compound was extracted out of pH 7 buffer after the final hydrolysis. MS m/e 555 (M+H) +. in NMR (CDCl3, 300 MHz) b 1.49 (m, lH), 1.91 (m, 1H), 2.1 (m, 8H), 2.95 (m, 4H), 4.56 (m, 1H), 5.84 (m, 1H), 6.68-7.38 (m, 14H), 7.97 (m, 1H).

Example 858 N-[4-(2-(4-(3-chlorophenoxy)phenyl)ethen-1-yl)-2-(2-methylph enyl)benzoyl]methionine The desired compound was prepared according to the method of Examples 210- 21 l. MS m/e 570 (M-H)-. IH NMR (CDC13,300 MHz) 8 1.57 (m, 1H), 1.95 (m, 1H), 2.1 (m, 8H), 4.59 (m, 1H), 5.91 (m, 1H), 6.91-7.62 (m, 16H), 8.04 (m, 1H).

Example 859 N-[4-(2-(4-(3-chlorophenoxy)phenyl)ethyl)-2-(2-methylphenyl) benzoyl]methionine The desired compound was prepared according to the method of Examples 210- 212. MS m/e 572 (M-H)-. lH NMR (CDCl3, 300 MHz) S 1.49 (m, 1 H), 1.93 (m, 1H), 2.1 (m, 8H), 2.97 (m, 4H), 4.55 (m, 1H), 5.84 (m, 1H), 6.81-7.37 (m, 14H), 7.98 (m, 1H).

Example 860 N-[4-(2-(4-(4-chlorophenoxy)phenyl)ethyl)-2-(2-methylphenyl) benzoyl]methionine The desired compound was prepared according to the method of Examples 2 10- 212. MS m/e 574 (M+H) +. I H NMR (d6-DMSO, 300 MHz) 8 1.75 (m, 2H), 1.94 (m, 6H), 2.06 (m, 2H), 2.94 (m, 4H), 4.13 (m, 1H), 6.92-7.48 (m, 12H), 7.66 (m, 2H), 7.97 (m, 1 H).

Example 861

N-[4-(2-(4-(3-nitrophenoxy)phenyl)ethen-1-yl)-2-(2-methylphe nyl)benzoyl]methionine The desired compound was prepared according to the method of Examples 2 10- 211. MS m/e 583 (M+H) +. I H NMR (CDC13,300 MHz) b 1.54 (m, 1H), 1.92 (m, 1H), 2.1 (m, 8H), 4.58 (m, 1H), 5.91 (m, 1H), 6.7-7.6 (m, 16H), 8.02 (m, 1H).

Example 866 N-f 4- (4-t-butoxycarbonylpiperazin-1-ylmethyl)-2- (2-methvlphenyl) benzoyllmethionine The desired compound was prepared according to the method of Example 158. in NMR (CDCl3, 300 MHz) 8 1.45 (s, 9H), 1.60 (m, 1H), 1.82 (m, 1H), 2.05 (m, 8H), 2.53 (m, 4H), 3.46 (m, 4H), 3.62 (m, 2H), 4.38 (m, 1H), 6.00 (m, 1H), 7.10-7.50 (m, 6H), 7.86 (m, 1H). MS m/e 540 (M-H)-.

Example 867 N-[4-(4-phenylpiperazin-1-ylmethyl)-2-(2-methylphenyl)benzoy l]methionine The desired compound was prepared according to the method of Example 15 8. 1 H NMR (CDC13,300 MHz) b 1.47 (m, 1H), 1.82 (m, 1H), 2.0 (m, 8H), 2.75 (m, 4H). 3.21 (m, 4H), 3.65 (m, 2H), 4.30 (m, 1H), 6.11 (m, 1H), 6.89 (m, 2H), 7.22 (m, 8H), 7.40 (m, 1H), 7.82 (m, 1H). MS m/e 516 (M-H)-.

Example 888 N-[4-N-(1,3-Diphenylpropan-2-yl)iminooxymethyl-2-(2-methylph enyl)benzoyl]-methionine lithium salt The desired compound was prepared according to the method of Example 157. in NMR (300 MHz, DMSO) 8 1.50-1.62 (m, 1H), 1.63-1.76 (m, 1H), 1.92 (s, 3H), 1.95- 2.15 (m, 5H), 3.38 (s, 2H), 3.53 (s, 2H), 3.69 (brs, 1H), 5.18 (s, 2H), 6.98 (d, J=6.4 Hz, lH), 7.04-7.28 (m, 15H), 7.36 (dd, J=7.8,1.7 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H). MS (ESI) m/z 587 (M+H); Analysis calc'd for C35H35LiN204S'1. 0H2O : C, 69.52 ; H, 6.17 ; N, 4.63; found: C, 69.47; H, 6.09; N, 4.58.

Example 929 N-f4-(N-Hept-4-vlaminooxymethy-2- (2-methylphenyl) benzoyl] methionine The desired compound was prepared according to the method of Example 157 1 H (300MHz, DMSO-d6,8) 7.52 (1H, d, J=8Hz), 7.37 (1H, dd, J=9&2Hz), 7.30-7.10 (4H, m), 7.10 (1H, bs), 6.97 (1 H, m), 6.33 (1H, bd, J=lOHz), 4.63 (2H, s), 3.68 (1H, m), 2.74 (1H, m), 2.20-1.95 (3H, m), 1.92 (3H, s), 1.90-1.40 (4H, m), 1.40-1.20 (8H, m), 0.83 (6H, t, J=8Hz). m/z (ESI) 485 (MH-) Anal. calc. for C27H37LiN204S 0.25 H20 C 65.24, H 7.60, N 5.64 Found C 65.14, H 7.81, N 5.33

Example988 N- 4- 3-benzyloxypyrrolidin-1-ylmethvll-2- (2-methylpheny, benzoyllmethionine The desired compound was prepared according to the method of Example 158 1H nmr (300 MHz, DMSO d6): 8 8.08, d, 1H ; 7.47, d, 1H ; 7.37, dd, 1H; 7.29, m, 5H ; 7.20. m, 2H; 7.14, m, 3H; 4.40, q (AA'), 2H; 4.21, m, 1H ; 4.11, m, 1H ; 3.68, q (AA'), 2H ; 2.41-2.76, m, 4H; 1.98-2.23, m, 6H; 1.97, s, 3H; 1.64-1.93, m, 3H. MS (ESI (-)): 531 (M-H); (ESI (+)): 533. Calc'd for C3lH36N204S: C 69.90, H 6.81, N 5.26: Found: C 69.21, H 6.86, N 5.06 Example 989 N-[4-(3-benzyloxypiperidin-1-ylmethyl)-2-(2-methylphenyl)ben zoyl]methionine The desired compound was prepared according to the method of Example 158 lH nmr (300 MHz, DMSO d6): 8 8.09, d, 1H ; 7.49, d, 1H; 7.37, dd, 1H ; 7.23-7.34, m, 5H ; 7.22, m, 2H; 7.12, m, 3H; 4.48, s, 2H; 4.23, ddd, 1H ;'3.60, m, 2H; 3.46, m, 1H ; 3.30, m, 2H; 2.95, m, 1H; 2.64, m, 1H; 2.00-2.24, m, 6H; 1.98, s, 3H; 1.63-1.96, m, 3H; 1.42, m, 1H ; 1.22, m, 1H. MS (ESI (-)): 545 (M-H); (ESI (+)): 547. Calc'd for C32H38N204S + 0.37 H20: C 69.46, H 7.06, N 5.06: Found: C 69.45, H 7.14, N 4.76.

Example 990 N-[4-(3-cyclohexylmethoxypiperidin-1-ylmethyl)-2-(2-methylph enyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158 l H nmr (300 MHz, DMSO d6): 8 7.98, d, 0.5H; 7.97, d, 0.5H; 7.37, d, 1H; 7.25, d, 1H; 7.09, m, 2H; 7.02, m, 3H; 4.10, m, 1H; 3.44, s, 2H; 3.15, m, 2H; 3.05, m, 2H; 2.77, m, 1H ; 2.52, m, 1H ; 1.88-2.13, m, 5H; 1.60-1.82, m, 3H; 1.51, m, 5H ; H; 1.85, s, 3H; 1.30, m, 2H; 0.90-1.16, m, 4H; 0.75, m, 2H. MS (ESI (-)): 551 (M-H); (ESI (+)): 553.

Calc'd for C32H44N204S + 1. 13 H20: C 67.06, H 8.14, N 4.89: Found: C 67.06, H 7.88, N 4.80.

Example 991 N-f4-4(2-phenoxvmethylpvrrolidin-1 ; lv methvl)-2- (2-methylphenyl) benzoyllmethionine The desired compound was prepared according to the method of Example 158 t H nmr (300 MHz, DMSO d6): 8 8.10, d, 1H ; 7.48, d, 1H; 7.40, d, 1H; 7.01-7.30, m, 6H; 6.90, m, 3H; 4.22, m, 2H; 4.01, m, 1H; 3.85, m, IH; 3.59, m, 1H ; 3.34, m, 1H ; 3.03, m, 1H ; 2.91, m, 1H ; 2.36, m, 1H; 1.98-2.24, m, 6H; 1.96, s, 3H; 1.60-1.90, m, 4H. MS (ESI (-)): 531 (M-H); (ESI (+)): 533. Calc'd for C3lH36N204S + 0.87 H20: C 67.90, H 6.94, N 5.11 : Found: C 67.90, H 6.95, N 4.87.

Example 992 N-L4- (2-cyclohexylmethoxymethylpyrrolidin-1 ;ylmethyl)-2-l2- methylphenyl) benzoyllmethionine The desired compound was prepared according to the method of Example 158 l H nmr (300 MHz, DMSO d6): 6 8.11, d, 1H; 7.47, d, 1H; 7.38, d, 1H; 7.21, m, 2H; 7.16, m, 3H; 4.21, m, 2H; 3.53, m, 1H; 3.25-3.46, m, 3H; 3.18, dq (AA'), 2H; 2.87, m, 2H; 2.30, m, 1H; 1.99-2.24, m, 6H; 1.97, s, 3H; 1.77-1.95, m, 2H ; 1.56- 1.76, m, 6H; 1.40-1.55, m, 2H; 1.51, m, 3H; 0.88, m, 2H. MS (ESI (-)): 551 (M-H); (ESI (+)): 553. Calc'd for C32H4N2O4S + 0.74 H2O : C 67.90, H 8.10, N 4.95: Found: C 67.89, H 7.83, N 4.79.

Example 993 <BR> <BR> <BR> N-f4- (2-benzyloxymethylpyrrolidin-1-ylmethyl)-2- (2-methylphenyl) benzoYllmethionine The desired compound was prepared according to the method of Example 158 1H nmr (300 MHz, DMSO d6): 8 8.12, d, 1H ; 7.49, d, 1H ; 7.39, d, 1H ; 7.30, m, 5H ; 7.21, m, 2H; 7.15, m, 3H; 4.48, s, 2H; 4.22, m, 2H; 3.53, m, 2H; 3.40, m, 2H; 2.89, m, 2H; 2.23-2.40, m, 1H; 2.00-2.22, m, 5H ; 1.98, s, 3H; 1.50-1.94, m, 6H. MS (ESI (-)):

545 (M-H); (ESI (+)): 547. Calc'd for C32H3gN204S + 1. 60 H2O: C 66.78, H 7.22. N 4.87: Found: C 66.79, H 6.88, N 4.70.

Example 1016 N-[4-(2-(4-(4-chlorophenoxy)phenyl)ethen-1-yl)-2-(2-methylph enyl)benzoyl]methionine lithium salt Prepared as in Example 210. MS m/e 570 (M-H)-. lH NMR (d6-DMSO, 300 MHz) 8 1.5-2.2 (m, 10H), 3.65 (m, 1H), 6.95 (m, 1H), 7.02-7.69 (m, 17H).

Example 1035 N-[4-(4-benzylpiperazin-1-ylmethyl)-2-(2-methylphenyl)benzoy l]methionine Prepared similarly. MS m/e 530 (M-H)-. IH NMR (CDCl3, 300 MHz) 5 1.65 (m, IH), 1.95 (m, 1H), 2.08 (m, 8H), 2.75 (m, 8H), 3.71 (m, 4H), 4.42 (m, 1H), 6.21 (m, 1H), 7.3 (m, 11H), 7.79 (m, 1H).

Example 1036

N-[4-(4-benzylpiperidin-1-ylmethyl)-2-(2-methylphenyl)benzoy l]methionine Prepared similarly. MS m/e 529 (M-H)-. NMR (CDC13,300 MHz) 8 1.65 (m, 5H), 1.95 (m, 1H), 2.06 (m, 8H), 2.41 (m, 1H), 2.56 (m, 2H), 3.30 (m, 2H), 3.55 (m, 1H), 3.71 (m, 2H), 4.13 (m, 1H), 4.42 (m, 1H), 6.30 (m, 1H), 7.18 (m, 10H), 7.47 (m, 1H), 7.77 (m, 1H).

Example 1037 A- [4- (4- (4-chlorophenyl)-4-hydroxypiperidin-l-ylmethyl)-2- (2- methylphenyl) benzoyllmethionine Prepared similarly. MS m/e 565 (M-H)-. IH NMR (d6-DMSO, 300 MHz) 8 1.61 (m, 4H), 1.80 (m, 1H), 1.93 (m, 1H), 1.99 (s, 3H), 2.15 (m, 5H), 2.48 (m, 2H), 2.69 (m, 2H), 3.63 (s, 2H), 4.18 (m, 1H), 4.92 (s, 1H), 6.95 (m, 2H), 7.45 (m, 8H), 7.95 (m, 1H).

Example 1038 N-f4- (4-cyclohexylpiperazin-l-ylmethyl)-2- (2-methylphenyl) benzoyl1methionine Prepared similarly. MS m/e 522 (M-H)-. 1H NMR (CDCl3, 300 MHz) 5 1.29 (m, 6H), 1.68 (m, 1H), 1.88 (m, 5H), 2.05 (m, 8H), 2.71 (m, 4H), 2.89 (m, 1H), 3.58 (m, 6H), 4.38 (m, 1H), 6.42 (m, 1H), 7.2-7.5 (m, 6H), 7.74 (m, 1H).

Example 1083 (2S)SaltLithium Example 1083A (2S) Methyl Ester To a solution of N- [4-formyl-2- (2-methylphenyl) benzoyl] methionine methyl ester ( example 403G, 340mg) and 1,2-dihydroxyethylbenzene (134mg) in toluene (3mL) was added p-toluenesulfonic acid hydrate (17mg), and magnesium sulfate (212mg). After 7h at ambient temperature, the reaction was filtered through infusorial earth and concentrated. The residue was purified by silica gel chromatography eluting with 30% EtOAc/hexane to give the title compound as a colorless oil (330mg, 74%). MS (APCI (+)) m/e 506 (M+H) +. MS (APCI (-)) m/e 540 (M+Cl)-.

Example 1083B (2S) 2-14- (4-phenyl-1. 3-dioxolan-2-yl)-2-l2-methylpheny_) benzolmethionine, Lithium Salt The title compound was prepared from (2S) 2- [4- (4-phenyl-1, 3-dioxolan-2-yl)-2- (2- methylphenyl) benzoyl] methionine methyl ester according to the procedure in example 608E, and was isolated as a white powder. 1H NMR (300 MHz, DMSO) 5 1.51-1.88 (m, 4H), 1.92 (s, 3H), 1.98-2.20 (m, 3H), 3. 62-3.73 (m, 1H), 3.76 (t, J=7.8 Hz, 0. 5H), 3.85 (t, J=7.2 Hz, 0.5H), 4.38 (t, J=7.2 Hz, 0.5H), 4.56 (ddd, J=8.4,6.6,1.8 Hz, 0.5H), 5.25 (t, J=6.9 Hz, 1H), 6.20 (s, 0.5H), 6.22 (s, 0. 5H), 7.00-7.12 (m, 1H), 7.25-7.47 (m, 10H), 7.59 (d, J=6 Hz, 2H). MS (APCI (+)) m/e 492 (M+H); Analysis calc'd for C2gH2gLiNO5S'1. 30H20: C, 64.56; H, 5.92; N, 2.69; found: C, 64.56; H, 5.69; N, 2.54 Example 1099 N-[4-(1-benzyltetrazol-5-ylmethyl)-2-(2-methylphenyl)benzoyl ]methionine Step 1: 4-nitrilemethyl-2- (2-methylphenyl) phenylacetate A 100 mL round-bottom flask was charged with 4-bromomethyl-2- (2- methylphenyl) phenylacetate (798.0 mg, 2.5 mmol and MeOH (23 mL)/H20 (2 mL).

Potassium cyanide (489.4 mg, 7.5 mmol) was added and allowed to stir at room

temperature for 12 h, then heated to reflux for 1 h, monitoring by TLC (1: 1 EtOAc/hexane).

The reaction was cooled and solvent was removed under vacuum. It was then diluted with water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum. The product was purified by silica gel column (1: 1 EtOAc/Hexane). Yield: 597.3 mg (90%), off-white solid.

I H NMR (5, CDC13): 8.0 (2H), 7.0-7.5 (SH), 2.83 (2H), 3.6 (3H), 2.05 (3H), 1.55 (1H).

Mass spec (ESI): 266 (M+1), 264 (M-1).

Step 2: 4-tetrazol-5-ylmethyl-2- (2-methylphenphenylacetate A 100 mL 3-neck round-bottom flask was charged with 4-nitrilemethyl-2- (2- methylphenyl) phenylacetate (533.3 mg, 2 mmol) and dmf (25 mL) under N2 purge.

Sodium azide (910.1 mg, 12 mmol) and triethylamine hydrochloride (1.3780 g, 10 mmol) were added. The reaction was heated at 100 °C for 48 h. After cooling, 1 M NaHC03 (50 mL) was added. The reaction was extracted with Et20 (3 x 25 mL). The aqueous layer was acidified with 1 M H3PO4 to pH = 3. Then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over MgS04, filtered and concentrated under vacuum. The product was purified by silica gel column (CHCl3/MeOH/HOAc (95: 5: 1)). Yield: 691.2 mg, yellow oil. Mass spec (ESI): 309 (M+1), 307 (M-1).

Step 3: 4- (l-benzvltetrazol-5-vlmethvl)-2-(2-methvlphenvl) benzoate (A) and 4- (2- benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoate (B) A 25 mL round-bottom flask was charged with 4-tetrazol-5-ylmethyl-2- (2- methylphenyl) phenylacetate (618.1 mg, 2 mmol) in CH3CN (9.5 mL)/water (0.5 mL).

Benzyl bromide (0.36 mL, 3 mmol) and potassium hydrogen carbonate (1 g) were added.

The reaction was stirred for 4 h and then diluted with water. The mixture was extracted with Et20 (3 x 10 mol). The organic layer was washed with water (10 mL) and brine (10 mL), dried over MgS04, filtered and concentrated under vacuum. The two regioisomers were separated by silica gel column (40% EtOAc/Hexane). Yield: 255.7 mg (product A) and 277.6 mg (product B). Product A: I H NMR (8, CDC13): 7.9 (2H), 7.0-7.4 (l0H), 5.7 (2H), 4.27 (2H), 3.6 (3H), 2.0 (3H). Mass spec (ESI): 399 (M+1), 397 (M-1).

Product B: H NMR (8, CDC13): 7.9 (2H), 6.9-7.4 (lOH), 5.4 (2H), 4.2 (2H), 3.6 (3H), 2.0 (3H). Mass spec (ESI): 399 (M+1), 397 (M-1).

Step 4: 4- (l-benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoic acid

A 50 mL round-bottom flask was charged with 4- (1-benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoate (A) (205.8 mg, 0.52 mmol) and ethanol (10 mL). 4 N sodium hydroxide (l. 1 mL, 4.16 mmol) was added. The reaction was refluxed for 2 h and then cooled. The solvent was removed under vacuum and then diluted with water. The reaction was extracted with Et20 (3 x 10 mL). The pH of the aqueous layer was adjusted to 2 with I M H3PO4. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated under vacuum. Yield: 205.1 mg, white solid. IH NMR (8, CDCl3) : 8.0 (2H), 7.0-7.4 (10H), 5.7 (2H), 4.3 (2H), 2.0 (3H).

Step 5: N-[4-(L-benzvltetrazol-5-vlmethvl)-2-(2-methvlphenvlZbenzovl l methioníne A 50 mL round-bottom flasks was charged with 4-(1-benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoic acid (205.1 mg, 0.52 mmol), 1- (3-dimethylaminopropyl-3- ethylcarbodiimide hydrochloride (EDAC) (110.1 mg, 0.0.572 mmol), L-methionine methyl ester hydrochloride (135.0 mg, 0.676 mmol), 1-hydroxybenzotriazole (78.6 mg, 0.572 mmol) and dmf (3 mL). The reagents were stirred until completely dissolved and then triethylamine (0.14 mL, 0.936 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: 273.0 mg, yellow solid. 1H NMR (8, CDC13): 8.0 (2H), 7.0-7.4 (lOH), 5.85 (1H), 5.7 (2H), 4.6 (1H), 4.3 (2H), 3.65 (3H), 1.95-2.2 (6H), 1.5-1.9 (4H).

Step 6: N-[4-(1-benzyltetrazol-5-ylmethyl)-2-(2-methylphenyl)benzoyl ]methionine- carboxylic acid A 25 mL round-bottom flask was charged with N- [4- (l-benzyltetrazol-5-ylmethyl)- 2- (2-methylphenyl) benzoyl] methionine (273.0 mg, 0.53 mmol) and 3 mL of MeOH/THF (1: 1). The flask was cooled to 0°C and 1 M lithium hydroxide (1.1 mL, 1.07 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: 176.2 mg yellow solid.

IH NMR (8, CDC13): 7.9 (2H), 7.0-7.4 (10H), 5.9 (1H), 5.7 (2H), 4.57 (1H), 4.3 (2H), 2.0-2.2 (6H), 1.9 (2H), 1.5 (2H)

Mass spec (ESI): 516 (M+l), 514 (M-1) C28H29N5O3S#1. 30 H20 Anal. Calc'd.: C 62.39 H 5.91 N 12.99. Found: C 62.43 H 5.64 N 12.83 Example 1100 N-[4-(1-cyclohexylmethyltetrazol-5-ylmethyl)-2-(2-methylphen yl)benzoyl]methionine Procedure: Follow example 1102 (product B). Yield: 105.7 mg, pale yellow solid.

N- [4- (l-cyclohexylmethyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoyl] methionine. lu NMR (6, CDC13): 7.95 (1H), 7.0-7.4 (5H), 5.9 (1H), 4.55 (1H), 4.3 (2H), 4.0 (2H), 2.9 (3H), 0.8-2.2 (20H) Mass spec (ESI): 522 (M+l), 520 (m-1) C28H35NsO3S0.90 H2O0.05 CH3CN Anal Calc'd.: C 62.51 H 6.90 N 13.10 Found: C 62.51 H 6.43 N 12.92 Example 1101 N-f4- (2-benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoyllmethionine Procedure: Follow example 1099 (product B). Yield: 176.2 mg.

N- [4- (2-benzyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoyl] methionine.

IH NMR (8, CDC13): 7.92 (2H), 6.8-7.4 (lOH), 5.9 (1H), 5.4 (2H), 4.55 (1H), 4.2 (2H), 2.0-2.2 (6H), 1.9 (2H), 1.55 (2H) Mass spec (ESI): 516 (M+1), 514 (M-1) C28H29N5O3S#1.30H2O Anal. calc'd.: C 62.39 H5.91 N 12.99 Found: C 62.43 H 5.65 N 12.53

Example 1102 N-f4- (2cyclohexvlmtrazol-5-ylmethvl)-2- (2-methylphenyl) benzoyllmethionine Procedure: Follow example 1099, except use bromomethylcyclohexane instead of benzylbromide (product A). Yield: 220.2 mg, pale yellow solid. N- [4- (2cyclohexylmethyltetrazol-5-ylmethyl)-2- (2-methylphenyl) benzoyl] methionine IH NMR (8, CDC13): 7.95 (1H), 7.0-7.5 (5H), 5.9 (1H), 4.55 (1H), 4.4 (2H), 4.3 (2H), 2.9 (3H), 0.9-2.2 (20H) Mass spec (ESI): 522 (M+l), 520 (M-1) C28H35N5O3S#0.50H2O Anal. Calc'd.: C 63.37 H 6.84 N 13.20 Found: C 63.58 H 6.54 N 12.80 Example 1109 <BR> N- (S)-cyclohexvlmethoxymethylmorpholin-4-ylmethyl)-2- (2-<BR> <BR> methvlphenvnbenzovll methionme Example 1109A O-Allyl-N-t-butoxycarbonyl-L-serine Serine (5.13 g, 25.0 mmol) in 60 mL of DMF was cooled in an ice bath and treated with sodium hydride (60%, 3.30 g, 82.5 mmol) in 3 portions over-15 minutes and the mixture stirred until the ceasation of bubbling (-20 minutes). The mixture was treated with allyl bromide (2.4 mL, 27.5 mmol) and after 5 minutes, the ice bath was removed. The

mixture was stirred for 1.5 hours at ambient temperature and then quenched by the careful addition of water. The pH of the solution was adjusted to 2 with 1M aqueous phosphoric acid and extracted with 3 portions of ethyl acetate. The combined organic fractions were extrated with 3-30 mL portions of IN aqueous sodium hydroxide and the combined aqueous phases washed with ether. The pH of the aqueous phase was adjusted to 2 with IM aqueous phosphoric acid and extracted with 3 portions of ethyl acetate. The combined organic fractions were washed with water and brine, dried, filtered and concentrated to provide 6.10 g (99%) of the title compound. MS (DCI, NH3): 246 (MH+); 263 (M+NH4) +.

Example 1109B O-Allyl-N-t-butoxycarbonyl-L-serine,methyl ester A solution of example 1109A (6.09 g, 24.8 mmol) in 30 mL of 50% aqueous DMF was treated with cesium carbonate (8.09,24.8 mmol) and the mixture stirred 30 minutes.

Methyl iodide (3.1 mL, 49.7 mmol) was added and the mixture stirred for 60 hours at ambient temperature. The mixture was diluted with water and extracted with 3 portions of ethyl ether. The combined organic extracts were washed with water, IN aqueous sodium hydroxide and brine, dried filtered and concentrated to provide 1.51 g (23%) of the title compound. MS (DCI, NH3): 260 (MH+); 277 (M+NH4) +.

Example 1109C 3 (S)-Methoxycarbonvl-4-t-butoxycarbonvl-5-hydrox,morpholine Ozone was passed through a solution of example 1109B (1.50 g, 5.8 mmol) in 20 mL of 1: 1 methanol/methylene chloride cooled in a dry ice/acetone bath until the solution turned blue. Nitrogen was passed through the cold solution until the blue color was discharged and then dimethyl sulfide (3 mL) was added and the cooling bath removed and the mixture stirred overnight and concentrated. The residue was dissolved in ether and washed with water, brine, dried, filtered and concentrated to provide 1.5 g of the title compound that was used directly.

Example1109D 3 (Su-Methoxvcarbonvl-4-t-butoxvcarbonvlmorpholine A solution of example 1109C (522 mg, 2.0 mmol) in 4 mL of methylene chloride was cooled in an ice/acetone bath and triethylsilane (1.6 mL, 10.0 mmol) was added. The solution was then treated with a solution of boron trifluoride etherate (0.27 mL, 2.2 mmol) in 1 mL of methylene chloride. After stirring 30 minutes, the bath was removed and stirring continued for 30 minutes and the mixture was quenched by the addition of 2M aqueous sodium carbonate. The mixture was diluted with water and methylene choride and the layers separated. The aqueous layer was extracted with 2 portions of methylene chloride and the combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (40 g, 20% ethyl acetate/hexanes) to provide 200 mg (41%) of the title compound. MS (DCI, NH3): 246 (MH+); 263 (M+NH4) +.

Example 1109E 3 (S)-Hydroxymethyl-4-t-butoxvcarbonvlmorpholine A solution of example 1109D (376 mg, 1.53 mmol) in 4 mL of ethanol was treated with calcium chloride (310 mg, 3.06 mmol) nad the mixture stirred until a clear solution resulted. The solution was diluted with 2 mL of THF and then treated with sodium borohydride (232 mg, 6.13 mmol) and the mixture stirred for 4 hours. The reaction was quenched by the addition of water, diluted with 2M aqueous sodium carbonate and extracted with 3 portions of methylene chloride. The combined organic fraactions were dried, filtered and concentrated to provide 268 mg (83%) of the title compound. MS (DCI, NH3): 218 (MH+); 235 (M+NH4) +.

Example1109F<BR> <BR> 3 (S)-Benzvloxymethvl-4-t-butoxvcarbonylmorpholine A solution of example 1109E (261 mg, 1.2 mmol) and benzyl bromide (0.18 mL, 1.44 mmol) in 1 mL of DMF was cooled in an ice bath and treated with sodium hydride (60%, 72 mg, 1.80 mmol) and the mixture stirred for 15 minutes. The cooling bath was removed and stirring continued for 6 hours and then the mixture was quenched by the addition of water. The mixture was partitioned between water and 3 portions of ethyl

acetate. The combined organic extracts were washed with water, brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (20 g, 25% ethyl acetate/hexanes) to provide 275 mg (74%) of the title compound. MS (DCI, NH3): 308 (MH+); 325 (M+NH4) +.

Example 1109G 3 (S)-Cyclohexvlmethyloxymethvl-4-t-butoxycarbonylmorpholine A solution of example 1109F (270 mg, 0.88 mmol) in 15 mL of methanol was treated with 135 mg of 5% rhodium on alumina and stirred under 4 atmospheres of hydrogen gas for 24 hours. The mixture was filtered and concentrated to provide 274 mg (99%) of the title compound. MS (DCI, NH3): 314 (MH+).

Example 1109H 3 (S)-Cyclohexylmethyloxymethylmorpholine Using the procedure of example 1106C, example 1109G (265 mg, 0.84 mmol) was converted to the title compound. MS (DCI, NH3): 214 (MH+).

Example 11091 N- [4- 3 (S)-cyclohexylmethoxvmethvlmorpholin-4-,llth l) (2- estermethylphenyl)benzoyl]methionine,methyl Using the procedure described in example 1106C, part 1, example 1109H (204 mg, 0.82 mmol) provided 29 mg (10%) of the title compound. MS (ESI+): 583 (MH+): (ESI-): 581 (M-H).

Example 1109J N-[4-(3(S)-cyclohexylmethoxymethylmorpholin-4-ylmethyl)-2-(2 - methylphenyl) benzoyllmethionine Prepared according to the procedure of example 1104D. H nmr (300 MHz., CD30D): 8 7.64, d, 1H; 7.48, d, 1H ; 7.14-7.34, m, 5H; 4.41, m, 1H ; 4.28, bd, 1H ; 3.85, dd, 1H ; 3.76, m, 1H; 3.49,3.70, m, 6H ; 3.23, d, 2H; 2.82, m, 2H; 2.51, m, 1H ; 2.06-2.24, m, 5H; 1.99, s, 3H; 1.93, m, 2H; 1.70, m, 6H; 1.55, m, 1H; 1.09-1.32, m, 4H; 0.92, m, 2H. MS (ESI+): 569 (MH+): (ESI-): 567 (M-H). Calc'd for C32H44N205S0.40 H2O ; C 66.73; H 7.84; N 4.86; Found: C 66.72; H 7.82 ; N4. 71.

Example 111 IF N-[4-(3(R)-cyclohexylmethoxymethylthiomorpholin-4-ylmethyl)- 2-(2- methvlphenvl ! benzovllmethionine Example 1111A 3 (S)-cyclohexylmethoxy-2-t-butoxycarbonylaminopropan-l-ol Following the procedure of example 1109G, example 1108A (1.00g, 3.55 mmol) was converted to 0.85 g (83%) of the title compound. MS (DCI, NH3): 288 (MH+).

Example1111B<BR> <BR> R-f2-t-butoxycarbonYlamino-3-cyclohexvlmethypropylmercaptoac etic acid, ethyl ester Following the procedure described in example 1106B (and substituting the potassium salt of ethyl mercaptoacetate for sodium thiomethoxide), example t I I I A (0.84 g, 2.91 mmol) was converted to 0.89 g (78% overall) the title compound. MS (DCI, NH3): 390 (MH+).

Example I I I I C 3-Oxo-5 (R)-cyclohexylmethyloxymethvl-thiomorpholine Example 1111B (0.88 g, 2.24 mmol) was dissolved in 4 mL of 4N HCl/dioxane and the mixture stirred overnight and concentrated. The residue was dissolved in 5 mL of acetonitrile and diisopropylethylamine (0.80 ml, 4.48 mmol) was added. The mixture was stirred for 1 hour at room temperature and 4 days at 65°C. The mixture was cooled to room temperature, diluted with water and exatracted with 3 portions of ethyl ether. The combined organic extracts were washed with 1M aqueous phosphoric acid, water, brine, dried, filtered and concentrated. The residue was purified by cloumn chromatography on silica gel (30 g, 40%-100% ethyl acetate/hexanes) to provide 0.35 g (65%) of the title compound. MS (DCI, NH3): 244 (MH+); 261 (M+NH4) +.

Example 1111D 5 (R !-cyclohexvlmethvloxymethvl-thiomorpholine Following the procedure of example 1178F, example 1111C (0.34 g, 1.40 mmol) provided 0.34 g (100%) of the title compound. MS (DCI, NH3): 230 (MH+).

Example 111 1E N-f4- (3- (R) cyclohexvlmethoxymethylthiomorpholin-4-ylmethyl)-2- (2- methylphenynbenzoyllmethionine. methyl ester Following the procedure of example 1103C, example 1111D (172 mg, 0.75 mmol) was converted to 67 mg (11%) of the title compound. MS (ESI+): 599 (MH+): (ESI-): 597 (M-H).

Example 111 IF N-[4-(3(R)-cyclohxylmethoxymethylthiomorpholin-4-ylmethyl)-2 -(2- methylphenyl) benzoyllmethionine Following the procedure of example 1104D, the title compound was prepared. H nmr (300 MHz., CD30D): 8 7.65, d, 1H ; 7.48, d, 1H ; 7.14-7.32, m, 5H; 4.40, m, 1H ; 4.10, d, 1H ; 3.91, d, 1H; 3.80, dt, 1H; 3.24, dd, 2H; 3.16, m, 2H; 2.84, m, 2H; 2.56- 2.77, m, 3H; 2.05-2.13, m, 5H ; 2.00, s, 3H; 1.93, m, 2H; 1.69, m, 6H; 1.55, m, IH; 1.09-1.32, m, 4H; 0.94, m, 2H. MS (ESI+): 585 (MH+): (ESI-): 583 (M-H). Calc'd for C32H40N2O4S2#0.30 H2O; C 65.12; H 7.62; N 4.75; Found: C 65.14; H 7.72; N 4.60.

Example 1114 <BR> N-r4-(2 (S)-cyclohexvlmethoxvmethvlazetidin-l-vlmethvl)-2-(2-<BR& gt; <BR> methylphenvl) benzovllmethionine Example1114A<BR> <BR> <BR> N-t-Butoxvcarbonvl-2(S)-hydroxymethylazetidine Azetidine-2-carboxylic acid (1.25 g, 12.4 mmol) was dissolved in 10 mL of 2M aqueous sodium carbonate and a solution of di-tert-butyldicarbonate in 10 mL of THF was added and the mixture was stirred overnight. The mixture was diluted with water and ether and the layers were separated. The ether layer was washed with water and pH of the combined aqueous phases adjusted to with phosphoric acid. The mixture was extracted with 4 portions of 20% isopropanol/chloroform and the combined organic phases were dried, filtered and concentrated. The residue was dissolved in 15 mL of THF and cooled in an ice bath. The solution was treated with 25 mL of borane in THF (1M, 25 mmol) and stirring was continued for 1 hour. The ice bath was removed and the solution stirred for 2 hours and then quenched by the careful addition of 25 mL of 4: 1 THF/water. The mixture was stirred for 15 minutes, carefully treated with 25 mL of 1N aqueous HCI, and diluted with ethyl acetate. The layers wre separated and the aqueous layer extracted with 2 additional portions of ethyl acetate. The combined organic fractions were washed with 2M aqueous sodium carbonate, water, brine, and dried, filtered and concentrated to provide 2.18 g (94%) of the title compound. MS (DCI, NH3): 188 (MH+).

Example 1114B

N-t-Butoxycarbonyl-2 (S)-benzyloxymethylazetidine Following the procedure of example 1109F, example 1114A (0.94 g, 5 mmol) was converted to the crude product. The crude residue was purified by chromatography on silica gel (50 g, 20% ethyl acetate/hexanes) to provide 0.44 g, (32%) of the title compound. MS (DCI, NH3): 278 (MH+).

Example 1114C N-t-Butoxycarbonyl-2(S)-cyclhexylmethyloxymethylazetidine Following the procedure described in example 1109G, example 1114B (0.43 g, 1.56 mmol) provided 0.42 g, (95%) of the title compound. MS (DCI, NH3): 284 (MH+).

Example 1114D 2 (S)-cylmethYloxymethylazetidine, hydrochloride salt Following the procedure described in example 1106C, example 1114C (0.42 g, 1.48 mmol) was converted to 0.32 g (100%) of the title compound. MS (DCI, NH3): 184 (MH+).

Example1114E<BR> <BR> N-f 4- (2 (S)-cvclohexylmethoxmethvlazetidin-1-ylmethyl)-2- (2-<BR> <BR> methylphenvl) benzoyllmethionine, methyl ester Following the procedure described in example 1106D, part 1, example 1114D (220 mg, 1.0 mmol) provided 145 mg (53%) of the title compound. MS (ESI+): 553 (MH+): (ESI-): 551 (M-H).

Example 1114F N-f4- (2 (S)-cyclohexylmethoxymethylazetidin-1-ylmethyl)-2- (2- methylphenyl) benzoyllmethionine Following the procedure of example 1104D, example 114E (100 mg, 0.18 mmol) provided 92 mg (95%) of the title compound. H nmr (300 MHz., dmso d6): 6 8.10, bd, 1H ; 7.47, d, 1H ; 7.33, d, 1H; 7.20, m, 2H; 7.11, m, 3H; 4.21, m, 1H; 3.83, d, 1H ; 3.54, d, 1H; envelope 3.07-3.48, m, 4H; 2.84, m, 1H; 1.98-2.22, m, 5H ; 1.97, s, 3H; envelope, 0.77-1.95,17H. MS (ESI+): 539 (MH+): (ESI-): 537 (M-H). Calc'd for C3 90 H2O; C 67.09; H 7.96; N 5.05; Found: C 67.09; H 7.84; N 5.00.

Example 1115 N-[4-(2(S)-(3,5-difluorophenoxy)methylpyrrolidin-1-ylmethyl) -2-(2- methylphenyl ! benzoyllmethionine Example 1115A N-t-Butoxycarbonyl-2 (SL- (3, 5-difluorophenoxy) pyrrolidine A solution of N-t-butoxycarbonyl-2-hydroxymethylpyrrolidine (0.40 g, 2.00 mmol), triphenylphosphine (1.05 g, 4.00 mmol), and 3,5-diflurorophenol (0.52 g, 4.00

mmol) in 5 mL of 1,2-dichloroethane was cooled in an ice bath and treated with a solution of diethylazodicarboxylate (0.63 mL, 4.00 mmol) in 3 mL of toluene. The cooling bath was removed and the solution was stirred for 70 hours at ambient temperature. The mixture was diluted with ether and extracted with 4N aqueous sodium hydroxide, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (30 g, 10% ethyl acetate/hexanes) provided 0.49 g, (80%) of the title compound. MS (DCI, NH3): 314 (MH+).

Example 1115B 2 (S)- (3. 5-difIuorophenoxy) pyrrolidine. hydrochloride salt Following the procedure of example 1106C, example 1115A (0.48 g, 1.53 mmol) was provided 0.35 g (91%) of the title compound. MS (DCI, NH3): 214 (MH+), 231 (M+NH4) +.

Example 1115C N-[4-(2(S)-(3,5-difluorophenoxy)methylpyrrolidin-1-ylmethyl) -2-(2- methylphenyDbenzoyl] methionine. methyl ester Following the procedure of example 1106C, part 1, example 1115B (0.19 g, 0.75 mmol) provided 0.22 g (76%) of the title compound. MS (ESI+): 583 (MH+): (ESI-): 581 (M-H).

Example1115D N-f4- (2 (Sl- (3 5-difluorophenoxv) methylpyrrolidin-1-ylmethvl)-2- (2- methylphenyl) benzovl] methionine Following the procedure of example 1104D, example 1115C (0.21 g, 0.36 mmol) provided the title compound. H nmr (300 MHz., CD30D): 5 7.69, d, 1H; 7.53, dd, 1H ; 7.33, m, 1H; 7.05-7.29, m, 4H; 6,48-6,62, m, 3H; 4.48, m, IH; 4.34, m, 1H ; 4.12,111, 3H; 3.65, m, 1H; 3.31, m, 1H; 2.96, m, 1H ; envelope 1.82-2.41,13H; 1.68, m, IH. MS (ESI+): 569 (MH+): (ESI-): 567 (M-H). Calc'd for C31H34F2N2O4S#0. 35 H2O ; C 64.76; H 6.08; N 4.87; Found: C 64.72; H 5.97; N 4.75.

Example 1116 N-[4-(2(S)-cyclohexyloxymethylpyrrolidin-1-ylmethyl)-2-(2- methvlphenvnbenzovnmethionine Example1116A N-t-Butoxvcarbon(S)-phenoxymethylpyrrolidine Following the procedure of example 1115 A, N-t-butoxycarbonyl-2- hydroxymethylpyrrolidine (0.80 g, 4.00 mmol) and phenol (1.13 g, 12.00 mmol) provided 0.99 g (89%) of the title compound. MS (DCI, NH3): 278 (MH+).

Example 1116B N-t-Butoxycarbonyl-2(S)-cyclohexyloxymethylpyrrolidine

Following the procedure of example 1109G, example 1116A (0.56 g, 2.00 mmol) provided 0.55 g (96%) of the title compound. MS (DCI, NH3): 284 (MH+).

Example 1116C 2 (S)-cvclohexyloxymethylpvrrolidine hvdrochloride salt Following the procedure of example 1106C, example 1116B (0.54 g, 1.90 mmol) provided 0.41g (99%) of the title compound. MS (DCI, NH3): 184 (MH+); 201 (M+NH4) +.

Example 1116D N-[4-(2(S)-cyclohexyloxymethylpyrrolidin-1-ylmethyl)-2-(2- methylphenvl) benzoyllmethionine, methyl ester Following the procedure of example 1106D, part 1, example 1116C (0.22 g, 1.00 mmol) provided 0.22 g (83%) of the title compound. MS (ESI+): 553 (MH+): (ESI-): 551 (M-H).

Example 1116E N- [(2 (S)-cyclohexyloxymethylpyrrolidin-1-vlmethvl)-2- (2- methylphenyl) benzoyllmethionine Following the procedure of example 1104D, example 1116D (0.22 g, 0.40 mmol) provided 0.18 g (81%). 1H nmr (300 MHz., dmso d6): 8 8.09, bd, 1H; 7.48, d, 1H ; 7.36,

d, 1H ; 7.21, m, 2H; 7.13, m, 3H; 4.21, m, 2H ; 3.49, d, 1H ; envelope ; 2.84, m, 1H ; 2.70, m, 1H ; 2.00-2.29, m, 7H; 1.96, s, 3H; 1.34-1.94, m, 8H ; 1.18, m.

6H. MS (ESI+): 539 (MH+): (ESI-): 537 (M-H). Calc'd for C31H42N2O4S#0. 50 H2O ; C 67.98; H N 5. 11; Found: C 67.95; H N 5.05.

Example 1117 <BR> <BR> N-14-(2 (S)-cvclohexvlmethvloxvmethvl-4*4-difluoropvrrolidin-l-vlmet hvl)-2-(2- methylphenyl) benzoyl] methionine

Example 1117A N-t-butoxycarbonyl-2 (S)-hydroxymethyl-4 (R)-benzyloxypyrrolidine A solution of trans-N-t-butoxycarbonyl-4-benzyloxy-L-proline (3.32 g, 10.3 mmol) in 20 mL of THF was cooled in an ice/acetone bath and a solution of borane in THF (1 M, 20.6 mL, 20.6 mmol) was added dropwise. The solution was stirred for 2 hours then the cooling bath was removed and the mixture stirred overnight. The reaction was quenched by the careful addition of water followed by the addition of 20 mL of IN aqueous HCl and then <BR> <BR> <BR> poured into ethyl acetate. The layers were separated and the aqueous layer extracted with 2 portions of ethyl acetate. The combined organic extracts were 2M aqueous sodium carbonate, water and brine, dried, filtered and concentrated to provide 3.19 g (100%) of the title compound. MS (DCI, NH3): 308 (MH+).

Example 1117B N-t-butoxvcarbonyl-2 (s)-ethoxvmethvloxvmethvl-4 (R)-benzVloxvpvrrolidine A solution of example 1117A (2.14 g, 7.00 mmol) in 15 mL of methylene chloride was cooled in an ice bath and treated with diisopropylethylamine (1.87 mL, 10.50 mmol) followed by the addition of chloromethylethyl ether (0.97 mL, 10.50 mmol). The cooling bath was removed, the mixture stirred for 24 hours and then poured into 100 mL of ethyl ether. The organic phase washed with water, aqueous HCI, brine, dried, filtered and concentrated to provide 2.32 g (94%) of the title compound. MS (DCI, NH3): 366 (M + NH4) +.

Example 1117C N-t-butoxycarbonyl-2 (S)-ethoxymethyloxymethyl-4 (R)-hydroxypyrrolidine A solution of exaomple 1117B (2.29 g, 6.50 mmol) in 20 mL of degassed methanol was treated with Perleman's catalyst (0.40 g) and then the mixture was stirred under a balloon of hydrogen gas overnight. The mixture was diluted with ethyl acetate and filtered through a plug of silica gel. The silica gel plug was washed well with ethyl acetate and the filtrated concentrated to provide 1.77 g (99%) of the title compound. MS (DCI, NH3): 276 (MH+).

Example 1117D N-t-butoxvcarbonyl-2(S)-ethoxvmethyloxvmethvl-4-oxopvrrolidi ne A solution of example 1117C (0.99 g, 3.59 mmol) in 20 mL of 10% acetonitrile/methylene chloride was treated with powdered, activated 4A molecular sieves (I g), 4-methylmorpholine-4-oxide (0.63 g, 5.38 mmol) and the mixture stirred for 30 minutes. The suspension was treated with tetrapropylammonium perruthenate (0.04g, 0.11 mmol) and the resulting black mixture stirred for 30 minutes. The mixture was treated with -3 g of celite and diluted with 30 mL of ether and stirred for 20 minutes. The suspension was then filtered through a pad of silica gel (which was washed well with ether) and the

filtrate conecentrated to provide 0.91 g (93%) of the title compound. MS (DCI, NH3): 274 (MH+); 291 (M+NH4) +.

Example1117E<BR> <BR> <BR> N-t-butoxycarbonvl-2 (S)-ethoxymethvlvl-4, 4--difluoropvrrolidine A solution of example 1117D (0.90 g, 3.30 mmol) in 20 mL of methylene chloride was cooled in an dry ice/acetone bath and treated with DAST (1.80 mL, 13.20 mmol). The bath was removed and the mixture stirred for 48 hours, cooled in an ice bath and carefully quenched by the addition of 2M aqueous sodium carbonate. The layers were separated and the aqueous layer was extracted with 2 additional portions of methylene chloride and the combined organic fractions were dried, filtered and concentrate. The residue was purified by column chromatography on silica gel (40 g, 15% ethyl acetate/hexanes) provided 0.70 g (72%) of the title compound. MS (DCI, NH3): 296 (MH+) ; 313 (M+NH4) +.

Example 1117F N-t-butoxycarbonyl-2 (S)-hydroxymethyl-4. 4-difluoropyrrolidine A solution of example 1117E (0.69 g, 2.30 mmol) in 10 mL of methanol was treated with 0.5 mL of concentrated aqueous HCl and the mixture stirred overnight. The yellow solution was poured into 2M aqueous sodium carbonate and concentrated to remove the methanol. The mixture was diluted with THF and g of di-t-butyldicarbonate was added and the mixture stirred for 3 hours and diluted with ethyl ether. The phasees were separated and the aqueous phase was extracted with 3 portions of methylene chloride. The combined organic phases were dried, filtered and concentrated to provide 0.48 g (88%) of the title compound. MS (DCI, NH3): 238 (MH+); 255 (M+NH4) +.

Example 1117G

N-t-butoxvCarbonyl-2 (s)-benzvloxvmethyl-4s4--difluoropvrrolidine Following the procedure of example 1109F, example 1117G (0.24 g, 1.00 mmol) provided 0.26 g (78%) of the title compound. MS (DCI, NH3): 328 (MH+).

Example 1117H N-t-butoxycarbonyl-2(S)-cyclohexylmethyloxymethyl-4,4-difluo ropyrrolidine Following the procedure of example 1109G, example 1117G (0.25 g, 1.10 mmol) provided 0.22 s (87%) of the title compound. MS (DCI, NH3) : 334 (MH+).

Example 1117I 2 (S)-cvclohexylmethyloxvmethyl-4. 4--difluoropvrrolidine. hvdrochloride salt Following the procedure of example 1106C, example 1117H (0.22 g, 0.92 mmol) provided 0.17 g (98%) of the title compound. MS (DCI, NH3): 234 (MH+).

Example 1117J N-[4-(2(S)-cyclohexylmethyloxymethyl-4,4-difluoropyrrolidin- 1-ylmethyl)-2-(2- methylphenyl) benzoyllmethionine, methyl ester Following the procedure of example 1106D, part 1, example 1117I (0.16 g, 0.60 mmol) provided 0.13 g (43%) of the title compound. MS (ESI+): 603 (MH+): (ESI-): 601 (M-H).

Example11 17K N-[4-(2(S)-cyclohexylmethyloxymethyl-4,4-difluoropyrrolidin- 1-ylmethyl)-2-(2- methvlphenyDbenzovllmethionine Following the procedure of example 1104D, example 1117J (123 mg, 0.20 mmol) provided 116 mg (98%) of the title compound. H nmr (300 MHz., CD30D): 8 7.62, d, 1H; 7.43, d, 1H; 7.13-7.32, m, 5H; 4.44, m, 1H; 4.26, d, 1H; 3.56, d, 1H; 3.54, dd, 1H; 3.48, dd, 1H; 3.24, m, 2H; 3.10, m, 1H; 2.71, m, 1H; 2.37, m, 1H; 2.03-2.25, m, 6H; 2.00, s, 3H; 1.87-2.00, m, 1H; 1.68, m, 5H; 1.53, m, 1H; 1.18, m, 3H; 0.90, m, 2H.

MS (ESI+): 589 (MH+): (ESI-): 587 (M-H). Calc'd for C32H42F2N2O4S; C 65. 28; H 7.19; N 4.76; Found: C 64.99; H 7.16; N 4.54.

Example 1118 <BR> N-14-(2-methoxvmethvl-5-benzylpvrrolidin-1-vlmethvl)-2-(2- methylphenyl) benzoyllmethionine Example 1118A 5 (S)-t-butyldimethyIsiIoxvmethyl-2-pyrroIidinone A stirred solution of 5 (S)-hydroxymethyl-2-pyrrolidinone (5.00 g, 0.043 mol) in 20 mL of DMF was treated with imidazole (6.81 g,. 10 mol) and then t- butyldimethylchlorosilane (7.20 g, 0.047 mol) and the mixture stirred for 2 hours. The thick mixture was diluted with water and extracted with 3 portions of ethyl acetate. The combined ethyl acetate layer were washed with water, brine, dried filtered and concentrated to provide 7.50 g (75%) of the title compound. MS (DCI, NH3): 230 (MH+); 247 (M+NH4) +.

Example 1118B N-t-butoxvcarbonyl-5 (S)-t-butyldimethylsiloxymethyl-2-pyrrolidinone A stirred solution of example 1118A (1.65 g, 7.20 mmol) in 5 mL of acetonitrile at rt was treated with DMAP (0.15 g, 1.25 mmol) and ditertbutyldicarbonate (1.09 g, 7.20 mmol) and the mixture stirred at ambient temperature for 48 hours at which time an additional 0.80 g of ditertbutyldicarbonate was added. The mixture was stirred an additional 6 hours and then diluted with 80 mL of ether and washed with 1M aqueous phosphoric acid, water, brine, dried filtered and concentrated. The residue was purified by column chromatography on silica gel (100 g, 15% ethyl acetate/hexanes) to provide 1.50 g (63%) of the title compound.

MS (DCI, NH3): 347 (M+NH4) +.

Example 1118C N-t-butoxycarbonyl-2 (S)-hydroxymethyl-5 (S)-benzylpyrrolidine A solution of example 1118C (1.05 g, 3.17 mmol) in 10 mL of toluene was cooled in a dry ice/acetone bath and treated with diisobutylaluminum hydride (3.2 mL of a 1.5M solution in toluene, 4.75 mmol) and the mixture stirred for 1 hour. The dry ice bath was replaced with an ice/acetone bath and the mixture stirred for an additional hour and then quenched with the careful addition of methanol (0.25 mL) and stirring continued until the evolution of gas ceased. The solution was then treated with IN aqueous HCl and ethyl acetate and the mixture stirred until 2 clear phases resulted. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with IN HCI, saturated sodium bicarbonate, brine, dried, filtered and concentrated. The residue was dissolved in 10 mL of methylene chloride and cooled in a dry ice/acetone bath and then treated with boron

trifluoride etherate (0.41 mL, 3.34 mmol) followed by benzylmagnesium chloride (4 mL of a 2. OM solution in THF, 8.00 mmol) and the mixture stirred for 1.5 hours and quenched by the addition of saturated sodium bicarbonate. The cooling bath was removed and the mixture allowed to reach room temperature. The mixture was diluted with ether and extracted with water and then 3N aqueous HCI. The combined organic layers were back extracted with ether and the combined organic extracts dried, filtered and concentrated. The residue was diluted with THF (10 mL) and treated with TBAF (10 mL of a 1. OM THF solution, 10.0 mmol) and the mixture stirred overnight. The mixture was diluted with water and extracted with 3 portions of ethyl acetate. The combined organic fractions were washed with water, brine, dried, filtered and concentrated. The rsidue was purified by column chromatography on silica gel (50 g, 30% ethyl acetate/hexanes) to provide 0.15 g (16%) of the title compound. MS (DCI, NH3): 292 (MH) +.

Example 1118D N-t-butoxycarbonyl-2 (S)-methoxymethyl-5-benzylpyrrolidine A solution of example 1118C (224 mg, 0.77 mmol) in 1 mL of DMF wa treated with methyl iodide (96 uL, 1.54 mmol) and cooled in an ice bath. The mixture was treated with sodium hydride (60%, 62 mg, 1.54 mmol) and after 10 minutes the cooling bath removed and stirring continued for 2 hours. The reaction was quenched by the addition of water and the the mixture diluted with water and extracted with 3 portions of ethyl ether. The combined organic fractions were washed with water, brine, dried filtered and concentrated. The residue was purified by column chromatography on silica gel (20 g, 20% ethyl acetate/hexane) to provide 158 mg (67%) of the title compound. MS (DCI, NH3): 306 (MH) +.

Example 1118E 2 (S)-methoxvmethvl-5-benzvlpvrrolidine, hvdrochloride salt Following the procedure of example 1106C, example 1118D (152 mg, 0.5 mmol) provided 110 mg, (91%) of the title compound. MS (DCI, NH3): 306 (MH) +.

Example 1118F N-f4- (2-methoxvmethyl-5-benzylpyrrolidin-1-ylmethyl)-2- (2- methylphenyl) benzoyl methionine. methyl ester Following the procedure of example 1106D, part 1, example 1118E (106 mg, 0.44 mmol) provided 95 mg (41%) of the title compound. MS (ESI+): 575 (MH+): (ESI-): 573 (M-H).

Example 1118G N-[4-(2-methoxymethyl-5-benzylpyrrolidin-1-ylmethyl)-2-(2- methylphenyl)benzoyl] methionine Following the procedure of example 1105D, example 1118F (88 mg, 0.15 mmol) provided 50 mg (60%) of the title compound. H nmr (300 MHz., dmso d6): 8 8.11, d, 1H ; 7.48, m, 2H; 7.19, m, 8H; 7.03, d, 2H; 4.22, m, 1H ; 4.08, d, 1H; 3.93, d, 1H ; 3.22, s, 3H; 3.09, m, 2H; 2.94, dd, 1H; 2.37, dd, 1H; 1.99-. 22, m, 4H; 1.97, s, 3H; 1.78, bm, 2H; 1.56, m, 2H; 1.42, m, 2H. MS (ESI+): 561 (MH+): (ESI-): 559 (M-H). Calc'd for C33H4oN204S'0.43 H2O ; C 69.72; H 7.24; N 4.93; Found: C 69.72; H 7. 11 ; N 4.78.

Example1119 <BR> N- 4- (2-cyclohexylmethoxymethylpvrrolidin-1-ylmethyl)-2- (2-<BR> <BR> methvlphenyl) benzoY methionine Example 1119A N-t-Butoxycarbonyl-2 (R)-benzyloxvmethylpyrrolidine Following the procedure of example 1109F, N-t-butoxycarbonyl-2 (R)- hydroxymethylpyrrolidine (1.06 g, 5.00 mmol) provided 1.20 g (82%) of the title compound. MS (DCI, NH3): 292 (MH) +.

Example 1119B N-t-Butoxycarbonyl-2 (R)-cvclohexylmethoxvmethylpvrrolidine Following the procedure of example 1109G, example 1119A (0.60 g, 2.06 mmol) provided 0.59 g (97%) of the title compound. MS (DCI, NH3): 298 (MH) +.

Example 1119C 2 (R)-cvclohexvlmethoxymethylpyrrolidine, hydrochloride salt Following the procedure of example 1106C, example 1119B (573 mg, 1.93 mmol) provided 467 mg (100%) of the title compound. MS (DCI, NH3): 198 (MH) +.

Example 1119D N-j4- (2-cvclohexvlmethoxymethylpyrrolidin-l- lmethyl)-2- (2- methylphenyl) benzovllmethionine, methyl ester Following the procedure of example 1106C, example 1119C (175 mg, 0.75 mmol) provided 181 mg (64%) of the title compound. MS (ESI+): 567 (MH+): (ESI-): 565 (M- H).

Example 1119E N-[4-(2-cyclohexylmethoxymethylpyrrolidin-1-ylmethyl)-2-(2- methyll2henyl) benzoyllmethionine Following the procedure of example 1104D, example 1119D (174 mg, 0.31 mmol) provided 163 mg (95%) of the title compound.. H nmr (300 MHz., dmso d6): 8 8.10, d, 1H ; 7.47, d, 1H; 7.36, d, 1H; 7.20, m, 2H; 7.11, m, 3H; 4.21, m, 1H; 4.17, d, 1H ; 3.48, d, 1H ; 3.18, m, 2H; 2.85, m, 1H; 2.76, m, 1H; 1.98-2.30, m, 7H; 1.97, s, 3H; 1.70- 1.90, m, 3H; 1.62, m, 7H; 1.49, m, 2H; 1.10, m, 4H; 0.88, m, 2H. MS (ESI+): 553 (MH+): (ESI-): 551 (M-H). Calc'd for C32H44N204S*0.50 H2O; C 68.42; H 8.07; N 4.99; Found: C 68.47; H 7.82; N 4.77.

Example 1120 <BR> N- 4- (2-benzyloxymethvl-4-methoxypyrrolidin-1-ylmethvl)-2- (2- methylphenyl)benzoyl]methionine Example1120A N-t-Butoxycarbonyl-2(S)-ethoxymethyloxymethyl-4(R)-methoxypy rrolidine Following the procedure of example 1118D, example 1117C (0.76g, 2.76 mmol) provided 0.64 g (80%) of the title compound. MS (DCI, NH3): 290 (MH) +.

Example 1120B N-t-Butoxycarbonyl-2 (S)-hydroxymethyl-4 (R)-methoxypvrrolidine Following the procedure of example 1117F, example 1120A (0.64g, 2.21 mmol) provided 0.39 g (77%) of the title compound. MS (DCI, NH3): 232 (MH) +.

Example1120C N-t-Butoxycarbonyl-2 (S)-Benzyloxymethyl-4 (R)-methoxypyrrolidine Following the procedure of example 1109F, example 1120B (0.39 g, 1.68 mmol) provided 0.42 g (78%) of the title compound. MS (DCI, NH3): 332 (MH) +.

Example 1120D 2 (S)-Benzyloxvmethvl-4 (R)-methoxypvrrolidine, hydrochloride salt

Following the procedure of example 1106C, example 1120C (0.41 g, 1.28 mmol) provided 0.32 g (97%) of the title compound. MS (DCI, NH3): 232 (MH) +.

Example 1120E <BR> <BR> N-f4- (2-benzyloxymeXl-4-methoxypvrrolidin-1-, lmethyl)-2- (2-<BR> <BR> <BR> methylphenvl) benzoyllmethionine, methyl ester Following the procedure of example 1106D, part 1, example 1120D (0.26 g, 1.00 mmol) provided 0.21 g (70%) of the title compound. MS (ESI+): 591 (MH+): (ESI-): 589 (M-H).

Example 1120F N-[4-(2-benzyloxymethyl-4-methoxypyrrolidin-1-ylmethyl)-2-(2 - methvlphenyllbenzoyllmethionine Following the procedure of example 1104D, example 1120E (197 mg, 0.33 mmol) provided 163 mg (86%) of the title compound. H nmr (300 MHz., dmso d6): 6 8.12, d, 1H; 7.48, d, 1H; 7.36, dd, 1H; 7.27, m, 5H ; 7.20, m, 2H; 7.13, m, 3H; 4.48, s, 2H; 4.21, m, 2H; 3.82, m, 1H; 3.53, m, 2H; 3.42, m, 2H; 3.14, s, 3H; 1.99-2.30, m, 6H; 1.96, s, 3H; 1.64-1.90, m, 4H. MS (ESI+): 577 (MH+): (ESI-): 575 (M-H). Calc'd for C33H40N205S*0.55 H2O; C 67.56; H 7.06; N 4.77; Found: C 67.56; H 7.02; N 4.80.

Example 1121

N-[4-(2-benzyloxymethyl-4-methoxypyrrolidin-1-ylmethyl)-2-(2 - methylphenyl) benzovllmethionine Example1121 A<BR> N-t-Butoxycarbonyl-4 (S)-methyoxy-L-proline, methyl ester Following the procedure of example 1118D, N-t-butoxycarbonyl-4 (S)-hydroxy-L- proline, methyl ester (1.22 g. 5.00 mmol) provided 1.04 g (80%) of the title compound.

MS (DCI, NH3): 260 (MH+); 277 (M+NH4) +.

Example 1121B N-t-Butoxycarbonyl-2 (S)-hydroxymethyl-4 (S)-methyoxypyrrolidine Following the procedure of example 1109E, example 1121A (1.03 g, 3.97 mmol) provided 0.83 g (90%) of the title compound. MS (DCI, NH3): 232 (MH+).

Example 1121C N-t-Butoxycarbonyl-2 (S)-benzyloxymethyl-4 (S)-methyoxypyrrolidine Following the procedure of example 1109F, example 1121B (0.41 g, 1.78 mmol) provided 0.46 g (80%) of the title compound. MS (DCI, NH3): 322 (MH+).

Example 1121D 2 (SZbenzyloxymethyl-4(S)-methyoxypvrrolidine, hydrochloride salt Following the procedure of example 1106C, example 1121C (228 mg, 0.71 mmol) provided 183 mg (100%) of the title compound. MS (DCI, NH3): 222 (MH+).

Example 1121E N-[4-(2-benzyloxymethyl-4-methoxypyrrolidin-1-ylmethyl)-2-(2 - methylphenyl) benzoyllmethionine, methyl ester Following the procedure of example 1106D, part 1, example 1121D (178 mg, 0.69 mmol) provided 210 mg (71%) of the title compound. MS (ESI+): 591 (MH+): (ESI-): 589 (M-H).

Example 1121F N (2-benzyloxymethyl-4-methoxypyrrolidin-l-ylmethyl')-2- (2- methylphenyl) benzoyllmethionine Following the procedure used in example 1104D, example 1121E (204 mg, 0.34 mmol) provided 195 mg (99%) of thetitle comppound. H nmr (300 MHz., dmso d6): 6 8.08, d, 1H ; 7.45, d, 1H; 7.33, d, 1H; 7.28, m, 5H ; 7.21, m, 2H; 7.14, m, 3H; 4.49, s, 2H; 4.22, m, IH; 4.18, m, 1H; 3.79, m, 1H; 3.56, dd, 1H ; 3.43, dd, 1H ; 3.09, s, 3H; 2.90, d, 1H; 2.75, m, 1H; envelope 1.97, s, 3H; 1.78, bm, 2H; 1.51, ddd, lH. MS (ESI+): 577 (MH+): (ESI-): 575 (M-H). Calc'd for C33H40N2O5S#0.45 H20; C 67.77; H 7.05; N 4.79; Found: C 67.80; H 6.93; N 4.62.

Example 1122 N-[4-(2-cyclohexyloxymethyl-5-propylpyrrolidin-1-ylmethyl)-2 -(2- methvlphenxl) benzovllmethionine

Example 1122A N-t-Butoxvcarbonyl-2 (R. S)-hydroxy-5 (S)-t-butyldimethylsiloxymethylpyrrolidine Example 1118B (3.10 g, 9.36 mmol) was dissolved in 20 mL of toluene and cooled in a dry ice/acetone bath. The cold solution was treated with diisobutylaluminum hydride (9.4 mL of a 1.5M toluene solution, 14.0 mmol), the dry ice bath was removed and the mixture stirred for 2 hours. The mixture was cooled in an ice/acetone bath and quenched by the careful addition of 10 mL of a 10% methanol/toluene solution. After the ceasation of bubbling, the mixture was treated with 75 mL of IN aqueous HCl and 100 mL of ether and vigorously stirred for 30 minutes and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with 2 portions of ether and the combined organic fractions were washed with IN HCI, water and brine, dried, filtered and concentrated to provide 2.93 g (94%) of the title compound. MS (DCI, NH3): 332 (MH+) ; 314 (M+NH4) +-H20.

Example 1122B N-t-Butoxycarbonyl-5(S)-allyl-2(S)-hydroxymethylpyrrolidine

A solution of example 1122A (663 mg, 2 mmol) and allyltrimethylsilane (1. 2 mol, 8 mmol) in 12 mL methylene chloride was cooled in a dry ice/acetone bath and treated with boron trifluoride etherate (0.49 mL, 4.00 mmol) dropwise. The solution was stirred for 30 minutes and then the dry ice bath was replaced with an ice/acetone bath and the mixture stirred an additional 30 minutes and quenched by the addtion of 2M sodium carbonate. The mixture was diluted with water and methylene chloride and the layers separated. The aqueous phase was extracted with 2 additional portions of methylene chloride and the combined organic fractions were dried, filtered and concentrated. The residue was dissolved in 4 mL of THF and treated with TBAF (4 mL of a I. OM THF solution, 4 mmol) and the mixture stirred overnight. The reaction was partitioned between water and 3 portions of ethyl acetate. The combined organic extracts were washed with water, brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (25 g, 30% ethyl acetate/hexanes) to provide 227 mg (47%) of the title compound. MS (DCI, NH3): 242 (MH+).

Example 1122C N-t-Butoxycarbonyl-5 (S)-allyl-2 (S)-benzyloxymethylpvrrolidine Following the procedure of example 1109F, example 1122B (223 mg, 0.92 mmol) provided 250 mg (82%) of the title compound. (DCI, NH3): 332 (MH+).

Example 1122D N-t-Butoxvcarbonyl-S(R)-propyl-2 (S)-cyclohexylmethyvmethpvrrolidine Following the procedure of example 1109G, example 1122C (245 mg, 0.74 mmol) provided 246 mg (100%) of the title compound. (DCI, NH3): 340 (MH+).

Example 1122E salt5(R)-propyl-2(S)-cyclohexylmethyloxymethylpyrrolidine,hy drochloride Following the procedure of example 1106C, example 1122D (245 mg, 0.74 mmol) provided 204 mg (100%) of the title compound. (DCI, NH3): 240 (MH+).

Example 1122F N- [4- (2 (S)-cvclohexylmethyloxymethyl-5 (R)-propylpyrrolidin-1-ylmethyl)-2- (2- methylphenyl) benzoyllmethionine, methyl este Following the procedure of example 1106D, part 1, example 1122E (204 mg, 0.74 mmol) provided 110 mg (36%) of the title compound. MS (ESI+): 609 (MH+): (ESI-): 607 (M-H).

Example 1122G <BR> N-r4- (2-cyclohexyloxymethyl-5-propylpyrrolidin-1-ylme)-2- (2- methylphenyl)benzoyl]methionine

Following the procedure of example 1104D, example 1122F (104 mg, 0.17 mmol) provided 87 mg (86%) of the title compound. H nmr (300 MHz., dmso d6): b 8.04, d.

1H ; 7.46, d, 1H; 7.35, d, 1H; 7.20, m, 2H; 7.13, m, 3H; 4.22, m, 1H; 3.83, dd, 2H; 3.08, m, 2H; 3.04, d, 2H; 2.88, pentet, 1H; 2.63, m, 1H; 1.99-2.24, m, 6H; 1.96, s, 3H; 1.77, bm, 4H; 1.59, m, 6H; envelope 11H ; 0.81, m, 5H. MS (ESI+): 595 (MH+): (ESI-): 593 (M-H). Calc'd for C35H50N2O4S#0. 55 H2O ; C H 8.52; N 4.63 ; Found: C 69.54; H 8.32; N 4.58.

Example 1123 <BR> <BR> N-14-(2 (S)-cvclohexylmethoxvmethvl-4 (R)-methoxvpvrrolidin-l-ylmethyl)-2-(2- methy benzovllmethionine Example 1123A N-t-ButoxXcarbonyl-2 (S)-cvclohexymethyloxymethyl-4 (S)-methvoxypXrrolidine Following the procedure of example 1109G, example 1112C (227 mg, 0.71 mmol) provided 232 (100%) of the title compound. (DCI, NH3): 328 (MH+).

Example 1123B salt2(S)-cyclohexymethyloxymethyl-4(S)-methyoxypyrrolidine,h ydrochloride Following the procedure of example 1106C, example 1123 A (232 mg, 0.71 mmol) provided 187 mg (100%) of the title compound. (DCI, NH3): 228 (MH+).

Example 1123C N-[4-(2(S)-cyclohexylmethoxymethyl-4(R)-methoxypyrrolidin-1- ylmethyl)-2-(2- methylphenyl) benzoyllmethionine, methyl este Following the procedure of example 1106D, part 1, example 1123B (181 mg, 0.69 mmol) provided 196 mg (66%) of the title compound. MS (ESI+): 597 (MH+): (ESI-): 595 (M-H).

Example 1123D <BR> <BR> <BR> N-j4(2 (S)-cyclohexylmethoxymethyl-4 (R)-methoxyvrrolidin-1-,llvl)-2- (2-<BR> <BR> <BR> <BR> methylphenynbenzovllmethionine Following the procedure of example 1104D, example 1123C (190 mg, 0.32 mmol) provided 174 mg (93%) of the title compound. H nmr (300 MHz., dmso d6): 8 8.12, d, 1H; 7.46, d, 1H; 7.35, dd, 1H; 7.19, m, 2H; 7.13, m, 3H; 4,18, m, 2H; 3.78, m, 1H; 3.45, dd, 1H; 3.29, d, 1H; 3.17, dd, 1H; 3.15, dd, 1H ; 3.08, s, 3H; 2.89, bd, 1H ; 2.72, m, 1H ; 2.29, m, 1H; envelope 1.97-2.25,6H; 1.96. s, 3H; 1.77, bm, 2H; 1.62, m, 5H ; 1.47, m, 2H; 1.12, m, 3H; 0.86, bq, 2H. MS (ESI+): 583 (MH+): (ESI-): 581 (M-H).

Calc'd for C33H46N205SH20; C 68.01; H 7.96; N 4.81; Found: C 67.96; H 7.96; N 4.81.

Example 1124 N-[4-(3-cyclohexylmethoxy-2-methoxymethylpyrrolidin-1-ylmeth yl)-2-(2- methvlphenvl) benzovllmethionine Example 1124A N-t-Butoxycarbonyl-2(S)-methoxymethyl-4(S)-benzyloxypyrrolid ine Following the prodedure of example 1118D, example 1117A (922 mg, 3.00 mmol) provided 0.64 g (67%) of the title compound. (DCI, NH3): 322 (MH+).

Example1124B<BR> <BR> N-t-Butoxycarbonyl-2 (S)-methoxvmethvl-4 llmethylovpvrrolidine Following the procedure of example 1109G, example 1124A (0.63 g, 1.96 mmol) provided o. 63 g (99%) of the title compound. (DCI, NH3): 328 (MH+).

Example1124C 2 (S)-methoxymethyl-4 (S)-cyclohexylmethyloxypyrrolidine. hydrochloride salt Following the procedure of example 1106C, example 1124B (627 mg, 1.91 mmol) provided 511 mg (101%) of the title compound. (DCI, NH3): 228 (MH+).

Example1124D N- 4- (3-cyclohexylmethoxy-2-methoxvmethylpyrrolidin-1-ylmethvl)-2 - (2- methylphenyl) benzoyllmethionine, methyl ester Following the procedure of example 1106D, part 1, example 1124C (264 mg, 1.50 mmol) provided 209 mg (70%) of the title compound. MS (ESI+): 597 (MH+): (ESI-): 595 (M-H).

Example 1124E N- [4- 3-cyclohexylmethoxv-2-methoxypvrrolidin-1-ylmethyl)-2- (2- methylphenyl)methionine Following the procedure of example 1104D, example 1124D (197 mg, 0.33 mmol) provided 176 mg (92%) of the title compound. H nmr (300 MHz., dmso d6): 5 8.14, d, 1H ; 7.47, d, 1H ; 7.38, d, 1H; 7.22, m, 2H; 7.13, m, 3H; 4.23, m, 1H; 4.13, bd, 1H; 3.87, m, 1H; 3.55, bm, 1H; 3.42, dd, 2H; 3.27, dd, 1H; 3.23, s, 3H; 3.11, dd, 1H;; envelope 1.98-2.24,6H; 1.96, s, 3H; envelope 1.55-1.93,8H; 1.43, bm, 1H ; 1.12-1.30, m, 4H ; 0.86. bq, 2H. MS (ESI+): 583 (MH+): (ESI-): 581 (M-H). Calc'd for C33H46N205S'0.50 H20; C 66.97; H 8.00; N 4.73; Found: C 67.04; H 7.97; N 4. 51.

Example 1125 <BR> <BR> N-f4- (2-piperidin-1-ylmethyvrrolidin-l-ylmethyl)-2- (2-methylphenyl) benzovllmethionine

Example 1125A N-t-Butoxycarbonyl-2 (S)-phen lsulfonvloxvmethvlpyrrolidine A solution of N-t-Butoxycarbonyl-2 (S)-hydroxymethylpyrrolidine (2.01 g, 10.00 mmol) and triethyl amine (1.70 mL, 12.00 mmol) in 10 mL of methylene chloride was cooled in an ice bath and treated with benzenesulfonylchloride (1.96 g, 11.00 mmol) and the mixture placed in a refridgerator overnight. The mixture was allowed to reach room temperaure and partioned between ethyl ether and water. The aqueous phase was extracted with ether and the combined organic layers washed with water IN HCI, saturated sodium bicarbonate, brine, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g, 25% ethyl acetate/hexanes) to provide 2.82 g (83%) of the title compound. MS (DCI, NH3): 359 (M+NH4) +.

Example1125B<BR> N-t-Butoxycarbonyl-2 (S)-piperidinylmethylpyrrolidine Example 1125B (341 mg, 1.00 mmol) was dissolved in 1 mL of piperidine and the mixture heated in a screw-cap vial to 100°C for 16 hours. The mixture was cooled to room temperature and concentrated. The residue was partitioned between water and 3 portions of ethyl acetate. The combined organic layers were washed with water, brine, dried filtered

and concentrated to provide 234 mg (87%) of the title compound. (DCI, NH3): 269 (MH+).

Example1125C ester2(S)-piperidinylmethylpyrrolidine,methyl Using the procedure of example 1106C, example 1125C (230 mg, 0.85 mmol) provided 195 mg (100%) of the title compound. (DCI, NH3): 159 (MH+).

Example 1125D <BR> <BR> N-f4- (2iperidin-1-ylmethylpyrrolidin-1 vlmethyl)-2- (2-methylphenylv_) benzovllmethionine. methylester Using the procedure described in example 1106D, part 1, example 1125C (195 mg, 0.86 mmol) provided 206 mg (77%) of the title compound. MS (ESI+): 538 (MH+) ; (ESI- ): 536 (M-H).

Example 1125E N-[4-(2-piperidin-1-ylmethylpyrrolidin-1-ylmethyl)-2-(2-meth ylphenyl)benzoyl]methionine Following the procedure of example 1104D, example 1125D (195 mg, 0.36 mmol) provided 117 mg of the title compound. 1H nmr (300 MHz., dmso d6): # 8.12, d, 1H;

7.43, d, 1H ; 7.21, m, 2H; 7.14, m, 3H; 4.22, m, 2H; 3.55, d, 1H ; 3.06, m.

1H ; 2.90, m, 6H; 2.75, m, 1H ; 2.41, m, 1H ; 1.97-2.24, m, 6H; 1.96, s, 3H; 1.74, bm, 4H; 1.62, m, 4H; 1.45, m, 2H. MS (ESI+): 524 (MH+): (ESI-): 522 (M-H). Calc'd for C3oH41N303S'0.65 H2O*1. 00TFA; C 59.50; H 6.77; N 6.71; Found: C 60.10; H 6.89; N 6.46.

Example 1126 N-[4-(2-morpholin-4-ylmethylpyrrolidin-1-ylmethyl)-2-(2-meth ylphenyl)benzoyl]methionine Prepared according to the procedure of example 1125 by substituting morpholine for piperidine in example 1125B. H nmr (300 MHz., dmso d6): 8 8.17, d, 1H; 7.53, d, 1H ; 7.48, d, 1H ; 7.28, m, 1H ; 7.23, m, 2H; 7.15, m, 2H; 4.39, d, IH; 4.23, m, IH; envelope 2.58, m, 1H; 2.51, m, 3H; 2.42, m, 4H; 1.97-2.24, m, 6H; 1.96, s, 3H ; 1.79, bm, 3H; 1.62, m, 1H. MS (ESI+): 524 (MH+): (ESI-): 526 (M-H). Calc'd for C29H39N304S'0.65 H2O0.55 TFA; C 60.24; H 6.86; N 7.00; Found: C 60.26; H 6.94; N 6.87.

Example 1127 N-[4-(2-(N-cyclohexyl-N-methylamino)methylpyrrolidin-1-ylmet hyl)-2-(2- methylphenyl) benzoyllmethionine Prepared according to the procedure of example 1125 by substituting N- methylcyclohexyamine for piperidine in example 1125B. H nmr (300 MHz., dmso d6): 8

8.00, d, IH; 7.49, d, IH; 7.40, d, IH; 7.20, m, 3H; 7.13, m, 2H; 4.22, m, 1H ; 4.18, d, 1H ; 3.47, d, 1H; envelope 2.60-2.95.3H; 2.50, s, 3H; 2.42, s, 2H; 2.33, m, 1H ; envelope 1.96, s, 3H; 1.75, bm, 6H; 1.56, m, 2H; envelope 0.95-1.35, 6H. MS (ESI+): 552 (MH+): (ESI-): 550 (M-H). Calc'd forC32H45N303S0. 75 H2O#0. 50 TFA; C 63.69; H 7.61; N 6.75; Found: C 63.69; H 7.66; N 6.67.

Example 1130 N-[4-(3-cyclohexyloxymethylisoxazolidin-2-ylmethyl)-2-(2- methylphenvl ! benzovlSmethionine Example 1130A 4-N-Hydroxyaminomethyl-2-(2-methylphenyl)benzoic estermethyl A solution of example 1178D (1.76 g (5.50 mmol) and N, O-bis-t- butoxoycarbonylhydroxylamine (1.09 g, 5.00 mmol) in 10 mL of DMF were cooled in an ice bath and treated with sodium hydride (60%, 0.24 g, 6.00 mmol). After stirring for 4 hours, the mixture was quenched by the addition of pH 6 phosphate buffer and partitioned between water and 3 portion of ethyl ether. The combined organic fractions were washed with water and brine, dried, filtered and concentrated. The residue was dissolved in 10 mL of 4N HCl/dioxane and stirred overnight. The mixture was diluted with ethyl ether and placed in a freezer for 3 days. The precipitate was collected, wshed with ether and dried under vacuum to provide 1.17 g (74%) of the title compound. MS (DCI, NH3): 272 (MH) +; 289 (M+NH4) +.

Example1130B<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4- (N-Oxy-2-cyclohexyoxvacetaldoximinomethvl)-2- (2-methvlphenyl) benzoic acid, methyl ester A solution of example 1130A (1.15 g, 4.29 mmol) and 2-cyclohexyloxyacetaldehyde (0.55 g, 3.90 mmol) in 10 mL of acetonitrile was treated with powdered, activated 4A molecular sieves (0.50 g) and potassium hydrogen carbonate (0.47 g. 4.70 mmol) and stirred overnight. The mixture was filtered throught a plug of silica gel (prewetted with ether) and the pad washed well with ether. The filtrate was concentrated to provide 0.82 g (55%) of the title compound. MS (DCI, NH3): 272 (MH) +.

Example 1130C N-I4- (3-cyclohexyloxvmethvlisoxazolidin-2-ylmethyl)-2- (2-methylphenylbenzoic acid methylester A solution of example 1130B (0.81 g, 2.05 mmol) in 30 mL of chloroform was heated to 75°C under 640 psi of ethylene for 72 hours. The mixture was cooled to room temperature and vented. The chloroform was evaporated and the residue purified by column chromatograhy on silica gel (40 g, 15% ethyl acetate/hexanes) to provide 363 mg (40%) of the title compound. MS (ESI+): 424 (MH+).

Exam. ple 1130D<BR> <BR> <BR> <BR> N- 4- (3-cvclohexyloxymethylisoxazolidin-2-vlmeth lv 1-2-2-methylphenyl) benzoic acid A mixture of example 1130C (355 mg, 0.84 mmol) and sodium hydroxide (1 mL of a 4N aqueous solution, 4 mmol) in 4 mL of ethanol was heated to reflux for 6 hours and then cooled to room temperature. The mixture was diluted with water and the pH adjusted to 5 with aqueuos phosphoric acid. The mixture was extracted with 3 portions of ethyl acetate and the combined organic fractions were washed with water and brine, dried, filtered and concentrated to provide 270 mg (78%) of the title compound. MS (ESI+): 410 (MH+).

Example1130E N-f4- (3-cyclohexyloxymethylisoxazolidin-2-ylmethyl)-2- (2- estermethylphenyl)benzoyl]methionine,methyl Following the procedure of example 1178I, example 1130D (265 mg, 0.65 mmol) provided 147 mg (41%) of the title compound. MS (ESI+): 555 (MH+): (ESI-): 553 (M- H).

Example 1130F <BR> <BR> <BR> <BR> N- [4- (3-cyclohexyloxymethylisoxazolidin-2-ylmethyl)-2-f2-<BR&g t; <BR> <BR> <BR> <BR> <BR> <BR> methvlphenyl) benzovl] methionine Following the procedure of example 1104, example 1130E (140 mg, 0.25 mmol) provided 78 mg (70%) after preparative HPLC purification. 1H nmr (300 MHz., CDC13): # 7.91, m, 1H; 7.56, m, 1H; 7.13-7.35, m, 5H; 5.99, d, 1H; 4.62, m, 2H; 4.41, m, III ; 4.24, m, IH; 4.05, m, 1H ; 3.91, m, 1H ; 3.52, m, 1H; 3.33, m, 1H; 2.40, m, 1H ; 2.29, m, IH; 2.00-2.28, m, 7H; 2.02, s, 3H; 1.89, bm, 3H; envelope, 1.43-1.75, 5H ; 1.26, bm, 5H.

MS (ESI+): 541 (MH+): (ESI-): 539 (M-H). Calc'd for C30H40N2OsS*l 10 TFA; C 58.06; H 6.22; N 4. 21; Found: C 57.97; H 6.28; N 4.17 Example 1135 Example11J3A Methyl4-(tert-Butoxycarbonylethyl)-2-(2-methylphenyl)benzoat e To a solution of (t-butoxycarbonylmethyl) triphenylphosphonium bromide (10.98 g, 24.0 mmol) in THF (150 mL) at 0 °C was added potassium t-butoxide (1.0 M in THF, 24 mL) over 5 min. After 2 h, the aldehyde in THF (10 mL) was added slowly over 5 min., and the reaction was further stirred for 30 min. The reaction mixture was diluted with <BR> <BR> <BR> <BR> <BR> hexane (200 mL), and the resulting muddy mixture was filtered through silica gel (200 g), rinsed with ether, and concentrated to give an intermediate olefin.'H NMR (300 MHz, CDC13) 8 7.97 (d, 1 H), 7.59 (d, 1 H), 7.54 (dd, 1 H), 7.37 (d, 1 H), 7.30-7.27 (m, 3 H), 7.06 (d, 1 H), 6.44 (d, 1 H), 3.61 (s, 3 H), 2.06 (s, 3 H), 1.52 (s, 9 H). MS (CI/NHl) m/z: 353 (M+H) +, 370 (M+NH4) +.

That intermediate was mixed with palladium on carbon (10%, 2.0 g) in ethanol (30 mL), and was stirred under a hydrogen balloon overnight. The mixture was then filtered through Celiez (5 g), and the filtrate was concentrated. The residue was then redesolved in ether (100 mL) and the solution was filtered through silica gel (30 g). Concentration of the filtrate afforded the title compound (7.27 g, 99% for 2 steps). 1H NMR (300 MHz, CDC1,)

8 7.91 (d, 1H), 7.28-7.15 (m, 4 H), 7.07-7.03 (m, 2 H), 3.60 (s, 3 H), 2.97 (t. 2 H), 2.57 (t, 2 H), 2.05 (s, 3 H), 1.40 (s, 9 H). MS (CI/NH3) m/z: 355 (M+H) +, 372 (M+NH4).

Example 1135B <BR> <BR> <BR> <BR> A-f4- (2-t-butoxycarbonyl-3-f3. 5-difluorophenyl) propyl)-2- (2-<BR> <BR> <BR> <BR> <BR> <BR> <BR> methylphenyl)benzoyllmethionine Methyl Este To a-78 °C solution of intermediate 1135A (487 mg, 1.32 mmol) in THF (5 mL) was added sodium hexamethyldisilylazide (NaHMDS, 1.0 M in THF, 1.6 mL). After 30 min., 3,5-difluorobenzyl bromide (329 mg, 1.59 mmol) was added to the reaction, and the reaction mixture was then gradually warmed to room temperature over 2 h. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 8% ethyl acetate in hexane (the product and starting material had identical Rf on TLC) in to give the methyl ester intermediate.

The product obtained from the previous step was stirred with saturated aquous LiOH (2 mL) in MeOH (3 mL) at 50 °C overnight. Then, the reaction mixture was carefully adjusted to pH 3 to 4, and extracted with ethyl acetate (100 mL). The organic layer was rinsed once with brine (15 mL), an dried with anhydrous magnesium sulfate, filtered, and concentrated. The crude monoacid obtained this way was stirred with L-methionine methyl ester hydrochloride (383 mg, 2 mmol), 1-hydroxybenzotriazole (266 mg, 2.0 mmol), triethylamine (303 mg, 3.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (400 mg, 2.0 mmol) in DMF for 5 h. 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 by column chromatography with 20% ethyl acetate in hexane to give the title compound (277 mg, 34% for 3 steps).'H NMR (300 MHz, CDCl3) 8 7.92 (2 d's, I H), 7.37-7.12 (m, 5 H), 7.02 (d, 1 H), 6.75-6.60 (m, 3 H), 5.90 (br d, 1 H), 4.62 (m, I

H), 3.66 (s, 3H), 3.05-2.72 (m, 5 H), 2.00 (4 s's, 6 H), 2.03 (m, 2 H), 1.95 (m, 1 H), 1.60 (m, 1 H), 1.22 (3 s's, 9 H). MS (CI/NH3) m/z: 612 (M+H)+.

Example 1135C N-[4-(2-t-butoxycarbonyl-3-(3,5-difluorophenyl)propyl)-2-(2- methyIphenyDbenzoyl] methionine Lithium Salt The procedure descriped in the Example 403I was used here to convert the intermediate 1135B (66 mg) to the title lithium salt (65 mg, 100%). 1H NMR (300 MHz, MeOD-d4) 8 7.52 (br s, 1 H), 7.35-7.21 (m, 5 H), 7.06 (m, 1 H), 6.87-6.72 (m, 3 H), 4.24 (m, 1 H), 3.00-2.85 (m, 5 H), 2.08-1.93 (m, 8 H), 1.84 (m, 1 H), 1.65 (m, 1 H), 1.18-1.12 (3 s's, 9 H). MS (ESI-) m/z: 596 (M-H)-.

Example 1138 Example1138A

Methyl4-(N-Cyclohexylmethylaminosulfonylmethyl)-2-(2-methylp henyl)benzoate To a room temperature solution of 1178D (1. 21 g, 3.79 mmol) in THF (10 mL) was added potassium thioacetate (0.48 g, 4.2 mmol). After 5 hours, NaOH (3.5 M in water, 3 mL) was added, and the reaction mixture was stirred another 30 min. Reaction mixture was then acidified with HCl (1.0 M, 15 mL), and partitioned between ethyl acetate (100 mL) and water (10 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated.

The residue desolved acetic acid (5 mL) and hydrogen peroxide (30%, 5 mL), and heated at 80 °C for 16 hours. The reaction mixture was diluted with brine (10 mL), and extrated with ethyl acetate (3 X 30 mL). The combined extrats were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude sulfonic acid. MS (ESI-) m/z: 319 (M-H)-.

The crude sulfonic acid was then refluxed with thionyl chloride (5 mL) and DMF (0.5 mL) for 8 hours. Solvent was then evaporated, and the residue was dried under high vacuum (5 mmHg) for 3 hours. The sulfonyl chloride obtained this way was then desolved in DCM (10 mL), and to it was added cyclohexylmethylamine (0.5 g) and triethylamine (2 mL). Afte 20 min., the reaction was diluted with ether (20 mL), filtered through silica gel (20 g), rinsed with ether (50 mL), and concentrated. The residue was purified by column chromatography with hexane: chloroform: ethyl acetate (50: 50: 10) to give the title compound (61 mg, 3.9%, 3 steps). 7.97 (d, 1 H), 7.46 (dd, 1 H), 7.30-7.15 (m, 5 H), 7.05 (br d, 1 H), 4.30 (s, 2 H), 3.61 (s, 3 H), 2.83 (t, 2 H), 2.07 (s, 3 H), 1.80-0.90 (m, 11 H). MS (CI/NH3) m/z: 433 (M+NH4) +.

Example 1138B <BR> <BR> <BR> N-[4-(N-CvCloheXylmethylaminosulfonylmethvl)-2-(2-methylphen yl) benzovllmethionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate 1138A (45 mg) to the title methyl ester (37 mg, 63%).'HNMR (300 MHz, CDC13) 8 7.97 (2 d'd, 1 H), 7.48 (d, 1 H), 7.37-7.22 (m, 5 H), 5.93 (d, 1 H), 4.63

(m, 1 H), 4.29 (s, 2 H), 3.67 (s, 3 H), 2.87 (t, 2 H), 2.20-2.00 (m, 8 H), 2.86 (m, 1 H), 2.80-0.80 (m, 12 H). MS (ESI-) m/z: 545 (M-H)-.

Example 1138C N-[4-(N-Cyclohexylmethylaminosulfonylmethyl)-2-(2-methylphen yl)benzoyl]methionine Lithium Salt The procedure descriped in the Example 403I was used here to convert the intermediate 1135B (32 mg) to the title lithium salt (32 mg, 100%). 1H NMR (300 MHz, dmso-d6) 8 7.46 (d, 1 H), 7.36 (m, 1 H), 7.20-6.92 (m, 6 H), 7.08 (m, 1 H), 4.30 (s, 2 H), 3.58 (m, 1 H), 2.64 (br d, 2 H), 2.00-1.80 (m, 8 H), 1.80-0.68 (m, 13 H). MS (ESI-) m/z: 531 (M-H)-.

Example1162 Example1162A Methyl4-[2-t-Butoxycarbonyl-3-hydroxy-3-(thiazol-5-yl)propyl ]-2-(2- methylphenyi) benzoate

To a-78 °C solution of intermediate 1135A (1.75 g, 4.94 mmol) in THF (20 mL) was added sodium hexamethyldisilylazide (1. 0 M in THF, 5.9 mL). After 10 min, 5- thiazolcarboxaldehyde (838 mg, 7.41 mmol) in THF (10 mL) was added to the reaction, and the reaction mixture was then gradually warmed to room temperature over 2 h. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL).

The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 50% ethyl acetate in hexane to give the title intermediate as a mnixture of diastereomers (1.41 g, 61%, ratio of diastereomers, 2.5: 1). IH NMR (300 MHz, CDC13) 8 8.90 (2 br s's, 1 H), 7.91 (2 d's, 1 H), 7.80 (2 br s's, 1 H), 7.31-7.25 (m, 5 H), 7.05 (m, 2 H), 5.30,5.05 (2 m'm, 1 H), 3.60 (s, 3 H), 3.14-3.00 (m, 3 H), 2.05 (4 s's, 3 H), 19,1.18 (3 s's, 9 H). MS (CI/NH3) m/z: 468 (M+H) +.

Example 1162B <BR> <BR> <BR> Methyl 4- vcarbonyl-3- (thiazol-5-yl_ prop-2-enyll-2- (2-methylphenyl) benzoate To a solution of intermediate 1162A (267 mg, 0.57 mmol) in 1,2-dichloroethane (10 mL) was added pyridine (0.5 mL), POCl3 (0.2 mL) and DBU (5 drops) in that order. After 4 hours at room temperature, the reaction mixture was diluted with ether (10 mL), filtered through silica gel (30 g), rinsed with ether (2 X 20 mL), and concentrated. The residue was purified by column chromatography with 30% ethyl acetate in hexane to give the title compound as a single isomer (230 mg, 90%).'H NMR (300 MHz, CDC13) 8 8. 81 (s, 1 H), 8.02 (s, 1 H), 7.96 (s, 1 H), 7.89 (d, 1 H), 7.26-7.15 (m, 5 H), 7.02 (m, 2 H), 4.06 (br s, 2 H), 3.59 (s, 3 H), 2.00 (s, 3 H), 1.43 (s, 9 H). MS (CI/NH3) m/z: 450 (M+H) +.

Example1162C

Methyl 4-fE-2-Hvdroxymethy3- (thiazol-5-yl) rrop-2-enyll-2- (2-methvlphenyl) benzoate A mixture of intermediate 1162B (205 mg, 0.456 mmol) and HCI (anhydrous, 4.0 M in 1,4-dioxane, 2 mL) was stirred for 16 h at room temperature. The reaction mixture was then concentrated to dryness, and the residue was desolved in THF (3 mL) and cooled to 0 °C. To it was added isobutyl chloroformate (0.089 mL, 0.685 mmol) and N- methylmorpholine (0.15 mL, 1.4 mmol). After 15 min. at 0 °C, sodium borohydride (53 mg, 1.4 mmol) was added to the reaction, followed by addition of methanol (1 mL). The reaction was then stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (5 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 50% ethyl acetate in hexane to give the title compound (69.7 mg, 40%).'H NMR (300 MHz, CDCl3) 8 8.70 (s, 1 H), 7.90 (d, 1 H), 7.81 (s, 1 H), 7.27-7.15 (m, 4 H), 7.05 (m, 2 H), 6.93 (s, 1 H), 4.21 (d, 2 H), 3.85 (s, 2 H), 3.59 (s, 3 H), 2.02 (s, 3 H). MS (CI/NH3) m/z: 380 (M+H) +.

Example1162 D N-{4-[E-2-Hydroxymethyl-3-(thiazol-5-yl)prop-2-enyl]-2-(2- methvlphenvl ! benzoyl) methionine Methvl Ester The procedures descriped in the Example 403E and 403F were used here to convert the intermediate 1162D (69 mg) to the title methyl ester (74 mg, 80%).'H NMR (300 MHz, CDC13) 8 8.78 (s, 1 H), 7.95-7.81 (m, 2 H), 7.35-7.15 (m, 5 H), 7.01 (s, 1 H), 6.94 (s, 1 H), 5.86 (m, 1 H), 4.62 (m, 1 H), 4.22 (s, 2 H), 3.84 (s, 2 H), 3.77 (s, 3 H), 2.14-2.00 (m, 8 H), 1.87 (m, 1 H), 1.60 (m, 1 H). MS (CI/NH3) m/z: 511 (M+H) +.

Example1162 E

N-[4-[E-2-Hydroxymethyl-3-(thiazol-5-yl)prop-2-enyl]-2-(2- methylphenyl) benzoYllmethionine Lithium Salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1162D (20.2 mg) to the title lithium salt (20 mg, 100%). 1H NMR (300 MHz, dmso-d6) 8 8.97 (s, 1 H), 7.90 (s, 1 H), 7.47 (d, 1 H), 7.25 (dd, 1 H), 7.22-7.07 (m, 4 H), 6.92 (m, 2 H), 6.89 (m, 1 H), 5.42 (t, 1 H), 3.99 (d, 2 H), 3.75 (s, 2 H), 3.60 (m, 1 H), 2.08 (m, 1 H), 1.95 (m, 1 H), 1.90 (br s, 6 H), 1.68 (m, 1 H), 1.55 (m, I H).

MS (ESI-) m/z: 495 (M-H)-..

Example 1163 Example 1163A N-{4-[E-2-(3,5-difluorophenoxy)methyl-3-(thiazol-5-yl)prop-2 -enyl]-2-(2- methylphenyl) benzoyl} methionine Lithium Salt To a 0°C solution of triphenylphosphine (55 mg, 0.21 mmol) in DCM (1 mL) was added diethyl azodicarboxylate (36 mg, 0.21 mmol). After 10 min., the solution thus prepared was transfered to a 0 °C solution of intermediate 1162D (35.1 mg, 0.069 mmol) and 3,5-difluorophenol (27.3 mg, 0.21 mmol) in DCM (1 mL). After the reaction mixture was stirred at room temperature for 15 hours, it eas diluted with ether (5 mL), filtered through silica gel (5 g), rinsed with ether (10 mL), and concentrated. The residue was purified twice by column chromatography with 30% ethyl acetate in hexane to give the title methyl ester (13.2 mg, 31%). 1H NMR (300 MHz, CDC13) 8 8.78 (s, 1 H), 7.95-7.85 (m, 2 H), 7.35-7.05 (m, 9 H), 7.02 (s, 1 H), 6.97 (s, 1 H), 5.88 (m, 1 H), 4.62 (m, 1 H),

4.49 (s, 2 H), 3.92 (s, 2 H), 3.66 (s, 3 H), 2.17-1.98 (m, 8 H), 1.87 (m, 1 H), 1.60 (m, 1 H). MS (CI/NH3) m/z: 623 (M+H) +.

Example 1163B N-f4-rE-2- (3. 5-diflourophenoxy) methvl-3- (thiazol-5-3rl) prop-2-envll-2- (2- methylphenyl) benzoyl I methionine Lithium Salt The procedure descriped in the Example 403I was used here to convert the intermediate 1163A (13.2 mg) to the title lithium salt (13.0 mg, 100%).'H NMR (300 MHz, dmso-d6) 8 9.05 (s, 1 H), 7.98 (s, 1 H), 7.47 (d, 1 H), 7.25 (dd, 1 H), 7.22-7.07 (m, 5 H), 6.95 (m, 1 H), 6.87 (m, 1 H), 6.80-6.70 (m, 4 H), 4.62 (s, 2 H), 3.87 (s, 2 H), 3.60 (m, 1 H), 2.10-1.92 (m, 2 H), 1.90 (br s, 6 H), 1.68 (m, 1 H), 1.55 (m, 1 H).

MS (ESI-) m/z: 607 (M-H)-.

Example 1176 Example 1176A 4-Phthalimidoyloxymeth, vl-2- (2-methylphenyl) benzoic acid methyl ester To a stirred solution at 0°C under N2 of 4-hydroxymethyl-2- (2- methylphenyl) benzoic acid methyl ester (5.00 g, 19.5 mmol), prepared as in Example 1178A-C, N-hydroxyphthalimide (3.19 g, 19.5 mmol), and triphenylphosphine (5.12 g,

19.5 mmol) in anhydrous THF (150 mL) was added diethyl azodicarboxylate (3.38 mL, 21.5 mmol). Cooling bath removed and reaction warmed to 50°C overnight. Solvents concentrated in vacuo, and residue taken up in ether and washed with 2M Na2CO3 (3x), water, and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.

Residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/Hexanes to afford the desired product as a white solid (3.32 g, 41%). IH (300MHz, CDC13, #) 7.99 (1H, d, J=8Hz), 7.79 (4H, m), 7.63 (1H, dd, J=7&2Hz), 7.38 (1H, d, J=2Hz), 7.30-7.10 (3H, m), 7.02 (1H, dd, J=8&2Hz), 5.26 (2H, s), 3.62 (3H, s), 1.99 (3H, s).

Example 1176B <BR> <BR> 4-(N-(3*5-difluorobenzvlidenovl ! aminooxvmethyl)-2-(2-methvlphenyl) benzoic acid methvI ester To a solutuon under N2 of 4-phthalimidoyloxymethyl-2- (2-methylphenyl) benzoic acid methyl ester (575 mg, 1.43 mmol), prepared as in Example 1176A, in boiling EtOH (10 mL) was added while hot 55% hydrazine hydrate (0.089 mL, 1.58 mmol). Reaction allowed to cool to ambient temperature, and to this mixture was added 3,5- difluorobenzaldehyde (0.172 mL, 1.58 mmol). Reaction stirred overnight at ambient temperature. Solvents concentrated in vacuo, and residue stirred with CC14 (30 mL) and MgS04 for 15 minutes at ambient temperature. Mixture filtered through celite, and filtrate concentrated in vacuo. Residue was purified by flash chromatography on silica gel eluting with 10% EtOAc/Hexanes to afford the desired product as a pale yellow solid (551 mg, 97%). m/e (ESI) 396 (MH+)

Example1176C<BR> <BR> <BR> <BR> <BR> 4- (7V- (3. 5-difluorobenzyl) aminooxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester To a stirred solution at room temperature under N2 of 4- (N- (3,5- difluorobenzylidenoyl) aminooxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (551 mg, 1.40 mmol), prepared as in Example 1176B, in MeOH (5 mL) was added sodium cyanoborohydride (263 mg, 4.18 mmol) and bromocresol green indicator. To this was added a 1: 1 solution of conc. HCI/MeOH dropwise to maintain a yellow-orange color (pH less than 3). After reaction mixture remained yellow, it was allowed to stir 30 minutes at room temperature. Reaction quenched with 1. OM NaHC03, and product extracted out with EtOAc (2x). Extracts washed with 1. OM NaHC03 (2x) and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Residue was purified by flash chromatography on silica gel eluting with 25% EtOAc/Hexanes to afford the desired product. (254 mg, 46%). m/e (ESI) 398 (MH+)

Example 1176D<BR> <BR> 4-(N-Butvl-N-(3Æ5-difluorobenzvl) aminooxvmethyl)-2-(2-methvlphenvl) benzoic acid methyl ester To a stirred solution at ambient temperature under N2 of 4- (N- (3,5- difluorobenzyl) aminooxymethyl)-2- (2-methylphenyl) benzoic acid methyl ester (254 mg, 0.640 mmol), prepared as in Example 1176 C, in DMF (2 mL) was added potassium carbonate (265 mg, 1.92 mmol) and 1-iodobutane (0.146 mL, 1.28 mmol). Reaction stirred

vigorously at 80°C overnight. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue was purified by flash chromatography on silica gel eluting with 7% EtOAc/Hexanes to 30% EtOAc/Hexanes to afford the desired product. (44 mg, 15%). m/e (ESI) 454 (MH+) Example 1176E 4-(N-Butyl-N-(3,5-difluorobenzyl)aminooxymethyl)-2-(2-methyl phenyl)benzoicacid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 1176D.

Example 1176F<BR> N-f[4-N--Butvl-N- (3. 5-difluorobenzyl) aminooxymethyl-2- (2-<BR> <BR> methvlphenyl) benzoyllmethionine methyl ester The desired product was prepared using the method described in Example 403F starting with the compound prepared in Example 1176E.

Example1176G N-[4-N--Butyl-N-(3,5-difluorobenzyl)aminooxymethyl-2-(2- methylphenvl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 403I starting with the compound from Example 1176F. 1 H (300MHz, CDC13,8) 7.70 (1 H, m), 7.30-7.00 (6H, m), 6.94 (1H, m), 6.85 (1H, dd, J=7&2Hz), 6.65 (1H, m), 4.53 (2H, bs), 4.03 (1H, m), 3.80 (2H, bs), 2.72 (2H, t, J=8Hz), 2.30-1.90 (5H, m), 1.80 (3H, s), 1.58 (2H, m), 1.50-1.20 (4H, m), 0.87 (3H, t, J=8Hz). m/e (ESI) 569 (MH-) Example 1186 ExamplellsoA

4-N- (CyclohexyImethylidene) aminooxvmethvl-2- (2-methylphenyl) benzoic acid methyl ester The desired product was prepared using the method described in Example 1176B starting with 4-phthalimidoyloxymethyl-2- (2-methylphenyl) benzoic acid methyl ester, prepared as in Example 1176A and cyclohexanecarboxaldehyde. m/e (ESI) 366 (MH+) Example1186B 4-N- (Cvclohexylmethyl) aminooxymethvl-2- (2-methylphenyl) benzoic acid methyl ester The desired product was prepared using the method described in Example 1 176C starting with the compound in Example 1186A. m/e (ESI) 368 (MH+) Example1186C N-[4-N--Butyl-N-(cyclohexylmethyl)aminooxymethyl-2-(2-methyl phenyl)benzoicacid methyl ester The desired product was prepared using the method described in Example 1176D starting with the compound in Example 1186B. m/e (ESI) 424 (MH+) Example 1186D

N-[4-N--Butyl-N-(cyclohexylmethyl)aminooxymethyl-2-(2-methyl phenyl)benzoicacid The desired product was prepared using the method described in Example 403E starting with the compound in Example 1186C.

Example 1186E N-[4-N--Butyl-N-(cyclohexylmethyl)aminooxymethyl-2-(2- methylphen, ) benzoyllmethionine methyl ester The desired product was prepared using the method described in Example 403F starting with the compound in Example 1186D. m/e (ESI) 555 (MH+) Example 1186F N-j4-N--Butyl-N- (cyclohexylmethyl) aminooxymethyl-2- (2- methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 403I starting with th compound in Example 1186E. 1 H (300MHz, DMSO-d6,8) 7.53 (l H, d, J=9Hz), 7.37 (1H, dd, J=7&2Hz), 7.30-7.05 (5H, m), 6.96 (1H, m), 4.63 (2H, s), 3.68 (1H, m), 2.62 (2H, t, J=8Hz), 2.42 (2H, d, J=8Hz), 2.25-1.95 (5H, m), 1.92 (3H, s), (7H, m), 1.42 (3H, m), 1.26 (2H, m), 1.13 (3H, m), 0.85 (5H, t, J=8Hz). m/e (ESI) 539 (MH-) Anal. calc. for C31H43LiN204S 0.75 H20 C 66.46, H 8.01, N 5.00 Found C 66.43, H 8.02, N 4.88

Example 1211 N-[4-(Benzylphenyl(oxophosphinyl)methyl)-2-(2-methylphenyl)b enzoyl]methionine Example1211 A<BR> <BR> <BR> <BR> Benzvlphosphonic acid monoethvl ester Diethyl benzylphosphonate (5.0 mL, 5.5 g, 24 mmol) was dissolved in absolute EtOH (25 mL), then 50% NaOH (3 mL) was added. The reaction was heated under reflux overnight, allowed to cool to RT, then partitioned between 2N HCl and EtOAc. Washed organic layer with brine, extracted combined aqueous layers with EtOAc, dried combined organic layers over Na2SO4. After filtration and concentration recovered 4.5 g (93%). MS (DCI/NH3) 201/218 (M+H) +/ (M+H+NH3) +.

Example1211B Benzylphenylphosphinic acid ethyl ester The compound described in Example 1211A (2.5 g, 12.5 mmol) was dissolved in CH2C12 (100 mL), cooled to 0-5 °C, then added DMF (50 uL) and oxalyl chloride (1.25 mL, 1.82 g, 14.3 mmol). After 15 min. removed the bath, and let the reaction warm to RT over 1 h. The reaction was then concentrated, dissolved in toluene, reconcentrated, dissolved in Et20 (8 mL), and cooled to-10 °C. Under N2,3.0M phenylmagnesium chloride (3.3 mL) was added dropwise (removed bath after ca. 7 mL had been added

because the reaction was too thick to stir). Stirred the reaction at RT for 3 h, then partitioned between 2N HCl and Et20. Washed organic layer with water and brine, then dried over Na2S04. After filtration and concentration the compound was purified by chromatography using 1/4 hex/EtOAc. Recovered 1.38 g (42%). MS (DCI/NH3) 261/278 (M+H) +/ (M+H+NH3) +.

Example 1211C 4-(Benzylphenyl(oxophosphinyl)methyl)-2-(2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1211 B and the bromide described in Example 1178D using the method found in JACS, 94,1774 (1972).

After chromatography using 1/2 hex/EtOAc the product still contained 35-40% (wt.) starting ethyl phosphinate. MS (APCI) 455 (M+H) + & 261 (M+H) + (for starting material).

Example1211 D<BR> 4-CBenzylphenyl (oxophosphinylmethyl)-2- (2-methylphenylbenzoicacid The title compound was prepared from the compound described in Example 1211C by the method of Example 1178H. The title compound was seperated from the phosphinic acid by chromatography using 98/2/0.5 CHC13/MeOH/CH3CO2H. MS (ESI) 439 (M-H)-.

Example 1211 1E N-[4-(Benzylphenyl(oxophosphinyl)methyl)-2-(2-methylphenyl)b enzoyl]methioninemethyl ester The title compound was prepared from the compound described in Example 1211D using the method of Example 1205D, except the chromatography used 1.5% EtOH in EtOAc. MS (APCI) 586 (M+H) +.

Example 1211F N-14-(Benzylphenyl (oxophosphinvl ! methvl)-2-(2-methylphenyl) benzoyllmethionine The above compound was prepared from the compound described in Example 1211E according to the method of Example 1178J, except the lithium salt was not made. 1H NMR (DMSO-d6) # 8.08 (m, 1H), 7.68 (m, 2H), 7.45 (m, 4H), 7.36 (d, 1H), 10, 82 (all m, total 10H), 4.19 (m, 1H), 3.50 (m, 4H), 95,1.80 (all m, total 10H). MS (ESI) 570 (M-H)-. Anal calcd for C33H34NO4PS 0.15 CHC13: C, 67.53; H, 5.84 ; N, 2.38. Found: C, 67.55; H, 5.90; N, 2.24.

Example1212<BR> N-f4- ( (Cylohexylmeth3rl methyl (oxophosphinyl) methyl)-2- (2- methylphenyl) methjonine Example 1212A Cyclohexylmethylphosphonic acid dimethyl ester Using the Grignard reagent made from bromomethyl cyclohexane and dimethyl phosphochloridate, the title compound was prepared by the method found in Engel, Robert, <BR> <BR> ed. Synthesis of Carbon-Phosphorous Bonds, p. 179. Boca Raton, FL: CRC Press, 1988.

The compound was purified by chromatography using EtOAc. MS (DCI/NH3) 207/224 (M+H) +/ (M+H+NH3) +.

Example 1212B Cyclohexylmethylphosphonic acid monomethyl ester The title compound was prepared from the compound described in Example 1212A by the method of Example 1211A. MS (DCI/NH3) 193/210 (M+H) +/ (M+H+NH3) +.

Example 1212C (Cyclohexylmethyl) methylphosphinic acid methyl ester The title compound was prepared from the compound described in Example 1212B and methylmagnesium bromide by the method of Example 1211B. MS (DCI/NH3) 191/208 (M+H) +/ (M+H+NH3) +.

Example 1212D 4-((cyclohexylmethyl)methyl(oxophosphinyl)methyl)-2-(2-methy lphenyl)benzoicacid methyl ester The title compound was prepared from the compound described in Example 1212C and the bromide described in Example 1178D using the method found in JACS, 94,1774 (1972), followed by purification with chromatography using EtOAc/EtOH 93/7. MS (DCI/NH3) 399/416 (M+H) +/ (M+H+NH3) +.

Example 1212E 4- ( (Cylohexylmethyl) methYl (oxophosphinyl) methyl)-2- (2-methylphenylbenzoic acid The title compound was prepared from the compound described in Example 1212D using the method of Example 1178H. MS (DCI/NH3) 385/402 (M+H) +/ (M+H+NH3) +.

Example 1212F N-[4-((Cylohexylmethyl)methyl(oxophosphinyl)methyl)-2-(2- methylphenynbenzoynmethionine methyl ester The above compound was prepared from the compound described in Example 121.2E according to the method of Example 1205D. MS (APCI) 530 (M+H) +.

Example 1212G N-[4-((Cyclohexylmethyl)methyl(oxophosphinyl)methyl)-2-(2- methylphenyl)benzoyllmethionine The above compound was prepared from the compound described in Example 1212F according to the method of Example 1178J, except the lithium salt was not made. I H NMR (DMSO-d6) 8 8.08 (d, lH), 7.46 (d, 1H), 7.30 (d, 1H), 7.20,7.10 (both m, total 5H), 4.21 (m, 1H), 3.20 (dd, 2H), 2.10 (m, 5H), 1.95 (s, 3H), 1.80,1.60 (both m, total 10H), 1.30 (d, 3H), 00 (both m, total 5H). MS (ESI) 514 (M-H)-. Anal calcd for C28H38N04PS: C, 65.22; H, 7.43; N, 2.72. Found: C, 64.86; H, 7.44; N, 2.60.

Example 1213 N-[4-((cyclohexylmethyl)butyl(oxophosphinyl)methyl)-2-(2- methylphenyl)benzoyl]methionine Example 1213A (Cyclohexylmethyl) butylphosphinic acid methyl ester

The title compound was prepared from the compound described in Example 1212B and butylmagnesium chloride by the method of Example 1211B. MS (DCI/NH3) 233/250 (M+H) +/ (M+H+NH3) +.

Example 1213B 4- ((Cylohexylmethvl) butyl (oxophosphin, methyl)-2- (2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1213A and the bromide described in Example 1178D using the method of Examplel212D. MS (DCI/NH3) 441/458 (M+H) +/ (M+H+NH3) +.

Example 1213C 4-((Cylohexylmethyl)butyl(oxophosphinyl)methyl)-2-(2-methylp henyl)benzoicacid The title compound was prepared from the compound described in Example 1213B using the method of Example 1178H. MS (DCI/NH3) 427/444 (M+H) +/ (M+H+NH3) +.

Example 1213D <BR> <BR> N-14-((Cylohexylmethel) butvl (oxophosphinyl) methvl)-2-(2-<BR> <BR> <BR> methylphenYl) benzoyllmethionine methyl ester The above compound was prepared from the compound described in Example 1213C according to the method of Example 1205D. MS (APCI) 572 (M+H) +.

Example 1213E N-[4-((cyclohexylmethyl)butyl(oxophosphinyl)methyl)-2-(2- methylphenyl) benzoyl1 methionine The above compound was prepared from the compound described in Example 1213D according to the method of Example 1178J, except the lithium salt was not made. I H NMR (DMSO-d6) 8 8.08 (d, 1H), 7.46 (d, 1H), 7.30 (d, 1H), 10 (both m, total 5H), 4.21 (m, 1H), 3.20 (d, 2H), 2.10 (m, SH), 1.97 (s, 3H), 1.85-0.90 (envelope 21H), 0.85 (t, 3H). MS (ESI) 556 (M-H)-. Anal calcd for C31H44N04PS: C, 66.76; H, 7.95; N, 2.51. Found: C, 66.73; H, 8.00; N, 2.42.

Exemple 1214 N-[4-(Di(cclohexylmethyl)(oxophosphinyl)methyl)-2-(2-methylp henyl)benzoyl]methionine Example 1214A Difcvclohexvlmethvnphosphinicacid Using the Grignard reagent made from bromomethyl cyclohexane, the title compound was prepared by the method found in JACS, 72,5508 (1950). MS (DCI/NH) 259/276 (M+H) +/ (M+H+NH3) +.

Example 1214B Di (cyclohexylmethyl) phosphinic acid methyl ester Using the compound described in Example 1214A, the title compound was prepared by the method found in JOC, 59,7616 (1994)-specifically Method B on p. 7623. MS (DCI/NH3) 273/290 (M+H) +/ (M+H+NH3) +.

Example 1214C 4- (Di (cylohexylmethyl) (oxophosphinyl) methyl)-2- (2-methylphenyl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1214B and the bromide described in Example 1178D using the method of Example 1212D. MS (APCI) 481 (M+H) +.

Example 1214D 4-(Di(cyclohexylmethyl)(oxophosphinyl)methyl)-2-(2-methylphe nyl)benzoicacid The title compound was prepared from the compound described in Example 1214C using the method of Example 1178H. MS (APCI) 467 (M+H) +.

Example 1214E N-[4-(Di(cyclohexylmethyl)(oxophosphinyl)methyl)-2-(2-methyl phenyl)benzoyl]methionine methyl ester

The above compound was prepared from the compound described in Example 1214D according to the method of Example 1205D. MS (APCI) 612 (M+H) +.

Example 1214F <BR> <BR> N-f4- (Di (cylohexylmethyl) (oxophosphinyl) methyl)-2- (2-methylphenvlbenzovllmethionine The above compound was prepared from the compound described in Example 1214E according to the method of Example 1178J, except the lithium salt was not made. 1H NMR (DMSO-d6) õ 8.04 (d, 1H), 7.46 (d, 1H), 7.30 (d, 1H), 7.20,7.10 (both m, total 5H), 4.21 (m, 1H), 3.20 (d, 2H), 2.10 (m, 5H), 1.97 (s, 3H), 1.80,1.60 (both m, total 18H), 1.20 (m, 6H), 0.95 (m, 4H). MS (ESI) 596 (M-H)-. Anal calcd for C34H48N04PS: C, H, 8.09; N, 2.34. Found: C, 68.20; H, 8.19; N, 2.36.

Example 1215 N-[4-(Di(cyclohexylmethyl)(thiaphosphinyl)methyl)-2-(2-methy lphenyl)benzoyl]methionine

Example1215A methyl4-(Di(cyclohexylmethyl)(thiaphosphinyl)methyl)-2-(2-me thylphenyl)benzoicacid ester The compound described in Example 1214C (390 mg, 0.81 mmol) was dissolved in CH3CN (15 mL), then Lawesson's reagent (1.57 g, 3.88 mmol) was added. The reaction was heated under reflux for 3 h, then stirred at RT overnight. After filtration through celite and concentration of the filtrate, purification by chromatography using hex/EtOAc 85/15 gave 335 mg (83%) of the title compound. MS (APCI) 497 (M+H) +.

Example 1215B 4-(Di(cylohexylmethyl)(thiaphosphinyl)methyl)-2-(2-methylphe nyl)benzoicacid The title compound was prepared from the compound described in Example 1215A using the method of Example 1178H. MS (ESI) 483 (M+H) +.

Example 1215C

N-[4-(Di(cyclohexylmethyl)(thiaphosphinyl)methyl)-2-(2-methy lphenyl)benzoyl]methionine methylester The above compound was prepared from the compound described in Example 1215B according to the method of Example 1205D. MS (APCI) 628 (M+H) +.

Example 1215D <BR> <BR> N- [4- (Di (cylohexylmethyl) (thiaphosphinyl) methyl_l-2(2-methynhenYl) benzoyllmethionine The above compound was prepared from the compound described in Example 1215C according to the method of Example 1178J, except the lithium salt was not made. IH NMR (DMSO-d6) b 8.14 (d, 1H), 7.46 (d, 1H), 7.38 (d, 1H), 7.20,7.14 (both m, total 5H), 4.21 (m, 1H), 3.40 (d, 2H), 2.10 (m, 5H), 1.97 (s, 3H), 1.80,1.60 (both m, total 18H), 1.20,1.00 (both m, total 10H). MS (ESI) 612 (M-H)-. Anal calcd for C34H4gNO3PS2: C, 66.53; H, 7.88; N, 2.28. Found: C, 66.26; H, 7.86; N, 2.19.

Example 1219 N-[4-(Di(2-cylohexylethyl)(oxophosphinyl)methyl)-2-(2-methyl phenyl)benzoyl]methionine

Example 1219A Di (2-cylohexylethyl) phosphinic acid The bromide described in Example 1207A was converted to the Grignard reagent, then used to prepare the title compound by the method of Example 1214A. MS (DCI/NH3) 287/304 (M+H) +/ (M+H+NH3) +.

Example 1219B Di (2-cvlohexylethyl) phosphinic acid methyl ester Using the compound described in Example 1219A, the title compound was prepared by the method of Example 1214B. MS (DCI/NH3) 301/318 (M+H) +/ (M+H+NH3) +.

Example 1219C methyl4-(Di(2-cyclohexylethyl)(oxophosphinyl)methyl)-2-(2-me thylphenyl)benzoicacid ester The title compound was prepared from the compound described in Example 1219B and the bromide described in Example 1178D using the method of Example 1212D. MS (APCI) 509 (M+H) +.

Example 1219D 4-fDif2-cvlohexvlethvl) (oxophosphinvl) methvl)-2-l2-methvlphenvl) benzoic acid The title compound was prepared from the compound described in Example 1219C using the method of Example 1178H. MS (APCI) 495 (M+H) +.

Example 1219E N-[4-(Di(2-cylohexylethyl)(oxophosphinyl)methyl)-2-(2-methyl phenyl)benzoyl]methionine methyl ester The above compound was prepared from the compound described in Example 1219D according to the method of Example 1205D. MS (APCI) 640 (M+H) +.

Example 1219F N- [4- (Di (2-cylohexylethyl) (oxophosphinyl) methyl)-2- (2-methylphenyl) benzoyllmethionine The above compound was prepared from the compound described in Example 1219E according to the method of Example 1178J, except the lithium salt was not made. 1H NMR (DMSO-d6) 8 8.07 (d, lH), 7.46 (d, 1H), 7.30 (d, 1H), 7.20,7.10 (both m, total 5H), 4.21 (m, 1H), 3.20 (d, 2H), 2.10 (m, 5H), 1.97 (s, 3H), 1.80,1.60 (both m, total 16H), 1.32 (m, 4H), 1.15 (m, 8H), 0.83 (m, 4H). MS (ESI) 624 (M-H)-. Anal calcd for C36H52NO4PS: C, 69.09; H, 8.37; N, 2.24. Found: C, 68.98; H, 8.33; N, 2.20.

Example 1222 <BR> N-f4- (Dibutyl (oxophosphinylmethyl)-2- (2-methylphenyl) benzoyl) methionine Example 1222A Dibutytphosphinic acid

Using butylmagnesium chloride, the title compound was prepared by the method of Example 1214A. MS (DCI/NH3) 179/196 (M+H) +/ (M+H+NH3) +.

Example 1222B Dibutylphosphinic acid methyl ester Using the compound described in Example 1222A, the title compound was prepared by the method of Example 1214B. MS (DCI/NH3) 193/210 (M+H) +/ (M+H+NH3) +, Example 1222C 4- (Dibutvl (oxophosphinyl ! methvl)-2-(2-methylphenvl) benzoic(Dibutvl (oxophosphinyl ! methvl)-2-(2-methylphenvl) benzoic acid methyl ester The title compound was prepared from the compound described in Example 1222B and the bromide described in Example 1178D using the method of Example 1212D. MS (DCI/NH3) 401/418 (M+H) +/ (M+H+NH3) +.

Example 1222D 4- (Dibutyl (oxophosphinyl) methyl)-2- (2-methylphenvl) benzoic acid The title compound was prepared from the compound described in Example 1222C using the method of Example 1178H. MS (DCI/NH3) 387/404 (M+H) +/ (M+H+NH3) +.

Example 1222E esterN-[4-(Dibutyl(oxophosphinyl)methyl)-2-(2-methylphenyl)b enzoyl]methioninemethyl The above compound was prepared from the compound described in Example 1222D according to the method of Example 1205D. MS (APCI) 532 (M+H) +.

Example 1222F N-r4-(Dibutyl (oxophosphinvl) methvl)-2-(2-methvlphenvlZbenzovllmethionine The above compound was prepared from the compound described in Example 1222E according to the method of Example 1178J, except the lithium salt was not made. l H NMR (DMSO-d6) 8 8.15 (d, 1H), 7.46 (d, 1H), 7.31 (d, 1H), 7.20,7.10 (both m, total 5H), 4.21 (m, 1H), 3.20 (d, 2H), 2.10 (m, 5H), 1.97 (s, 3H), 1.80 (m, 2H), 1.60 (m, 4H), 1.40 (m, 8H), 0.85 (t, 6H). MS (ESI) 516 (M-H)-. Anal calcd for C2gH40N04PS: C, 64.97; H, 7.79; N, 2.71. Found: C, 64.87; H, 7.83; N, 2.72.

Example 1278 N-f4-phenyl-butylaminosulfonXl)-2-phenvlbenzoyllmethionine lithium salt.

Example 1278A 4-amino-2- (2-methylphenyl) benzoic acid methyl ester (4.5 g, 0.018 mol) in an excess of concentrated (38%) hydrochloric acid (25 ml), was diazotized at 0 C with sodium nitrite (1.45 g, 0.0216 mol). The solution of diazonium chloride was added with stirring to a mixture of sulfur dioxide (40 g), 1,2-dichlorobenzene (10 ml), copper (II) chloride (1.4 g), and potassium chloride (1.4 g) in dioxane (20 ml), and heated to 40-50°C. After the evolution of nitrogen was complete (about 30 min.), water (200 ml) was added and the sulfonyl chloride was extracted with methylene chloride. The organic layer was washed quickly with 10% sodium hydroxide (3*50 ml), followed by washing with water. After drying over anhydrous magnesium sulfate, the organic solvents were removed under reduced pressure. A brown liquid of the title compound (4.8 g, 82%) was obtained. l H NMR: 2.09 (3H, s), 3.65 (3H, s), 7.0-7.1 (1H, d), 7.2-7.4 (3H, m), 7.9-8.0 (1H, d), 8.1- 8.2 (2H, m). 13C NMR: 20.0 (CH3), 52.6 ( OCH3), 4,129.2,130.0, 131.0,135.0,135.0,138.6,144.2,146.0,166.0. (DSI/NH3) MS: 324 (M+NH4) +.

Example 1278B A mixture of 1278B (0.32 g, 1.0 mmol), 4-phenylbutylamine (0.223 g, 1.5 mmol), and 0.2 ml of pyridine in 5 ml of anhydrous methylene chloride was stirred for 12 hours.

The reaction mixture was washed by 10% HC1, brine, and dried over anhydrous MgS04.

Flash chromatography of the residue eluting with 4: 6EtOAc/Hexane afforded 0.205 g of the title compound. NMR (CDC13) 8.00-8.05 (m, 1H); 7.85-7.92 (m, 1H); 7.73 (s, 1H); 7.00-

7.30 (m, 8H); 4.35-4.45 (m, 1H); 3.65 (s, 3H); 2.95-3.08 (t, 2H); 2.55-2.62 (t, 2) : 2.08 (s, 3H); 1.4-1.67 (m, 4H). (DSI/NH3) MS : 455 (M+NH4) +.

Example 1278C Prepared according to the procedure of example 1258C from 1278B NMR (CDCl3) 8.00-8.10 (m, 1H); 7.88-7.94 (m, 1H); 7.73 (s, 1H); 7.10-7.40 (m, 8H); 5.93-6.00 (m, 1H); 4.52-4.60 (m, 1H); 4.32-4.40 (m, 1H); 3.70 (s, 3H); 2.95-3.08 (t, 2H); 2.55-2.62 (t, 2); 2.0-2.2 (m, lOH); 1.70-2.00 (m, 1H); 1.50-1.70 (m, 4H). (DSI/NH3) MS : 569 (M+H) + ; 586 (M+NH4) +.

Example 1278 N-f4-phenvl-butvlaminosulfonyl)-2-phenylbenzovllmethionine lithium salt.

Prepared according to the procedure of example 1178J from 1296C. NMR 1H (MeOH-d4): 7.8-7.9 (2H, m); 7.7 (1H, s); 7.1-7.3 (13H, m); 4.2-4.3 (1H, m); 2.85- 2.95 (2H, m); 2.5-2.6 (2H, m); 1.6-2.3 (14H, m). ESI (-)/MS: 553 (M-Li).

Example 1299 <BR> N-f4- (2- (2-CyclohexylethylY)-1-hydroxyprop-3-vl)-2- (2-methylphenyl) benzovllmethionine Lithium Salt

Example 1299A tert-Butvl4-cyclohexylbutyrate 4-Cyclohexylbutyric acid (1.8 g, 10.6 mmol), isobutylene (25 mL) and concentrated sulfuric acid (0.3 mL) were combined in CH2C12 (25 mL) in a pressure bottle. After shaking for 8 days, the pressure bottle was placed in a-78 °C bath and a saturated solution of NaHC03 was added and the phases separated. The organic phase was dried (MgS04) and concentrated to afford crude ester as a clear oil (2.3 g). 1H NMR (CDCI3,300 MHz) b 0.81- 0.94 (m, 2H), 1.14-1.25 (m, 6H), 1.44 (s, 9H) 1.55-1.74 (m, 7H), 2.18 (t, J=7.5 Hz, 2H); MS (CI/NH3) m/z: (M+H) + 227.

Example 1299B <BR> <BR> <BR> 4- (2- (2-Cyclohexylethyl) t-butylpropion-3-yl1-2- (2-methylphenyl) benzoic acid, methyl ester A 1.6M solution of n-BuLi in hexanes (1.7 mL, 2.7 mmol) was added to a solution of diisopropylamine (385 RL, 2.7 mmol) at ambient temperature. After 10 minutes of stirring, the solution was cooled to-78 °C and the product from Example 1299A (600 mg, 2.6 mmol) in THF (2.5 mL) was added to the reaction mixture. After stirring for 15 min, the cold bath was removed. After 30 min of stirring, the mixture was recooled to-78 °C and the product from Example 1308E (1.0 g, 2.7 mmol) in THF (2.0 mL) was added to the reaction mixture. The mixture was allowed to gradually warm to ambient temperature and stir over night. A solution of 2N HCl was added and the mixture extracted with EtOAc (2X). The organic phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 40) to afford a clear oil (572 mg, 47%).

MS (CI/NH3) m/z: (M+H) + 465.

Example 1299C 4-f2- (2-Cyclohexylethyl')-l-hydroxyprop-3-yn-2- (2-methylphenyl) benzoic acid. methyl ester Trifluoroacetic acid (3 mL) was added to a solution of the product from Example 1299B (448 mg, 1.0 mmol) in CH2C12 (3 mL) at ambient temperature. After stirring for 90 min, solvent was evaporated to dryness. MS (CI/NH3) m/z: (M+H) + 409.

A 1. OM solution of borane THF complex (2.1 mL, 2.1 mmol) was added to a solution of the crude product described above in THF (3 mL) at ambient temperature. After stirring for 6 hours, a 2N solution of HCl was added to the reaction mixture. After 90 min of stirring, 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: 8) to afford a clear oil (256 mg, 68%). MS (CI/NH3) m/z: (M+H) + 395.

Example 1299D <BR> <BR> <BR> N-r4-f2-(2-Cyclohexvlethvl)-1-hydroxvprop-3-yl]-2-(2-methylp henyl) benzovllmethionine methyl ester The product from Example 1299C (97 mg, 0.25 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (55 mg, 0.28 mmol), Hobt (30 mg, 0.22 mmol), (L)-methionine methyl ester hydrochloride (48 mg, 0.24 mmol) and NMM (40, uL, 0.36 mmol) in DMF (1 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 (66 mg, 63%). MS (CI/NH3) m/z: (M+H) + 526.

Example 1299E <BR> <BR> N- [4-(2- (2-Cyclohexylethyl-l-hydroxyprop-3-yl)-2- (2-methylphenvl) benzolmethionine Lithium Salt The product from Example 1299D (60 mg, 0.11 mmol) was allowed to react with lithium hydroxide monohydrate (5 mg, 0.12 mmol) in a manner similar to that described in Example 608E to afford the title compound. IH NMR (DMSO-d6,300 MHz) 8 0.72-0.88 (m, 2H), 1.03-1.30 (m, 8H), 1.52-1.70 (m, 9H), 1.88-2.03 (m, 6H), 2.15 (m, 1H), 2.47 (m, partially buried under DMSO peak 1H), 2.70 (m, 1H0, 3.32 (d, partially buried under water peak 2H), 4.42 (m, 1H), 6.90 (d, J=6 Hz, 1H), 6.94 (s, 1H), 7.10-7.25 (m, 4H), 7.46 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-510; Anal. Calcd for C30H40LiNO4S*2.1 H20: C, 64.87; H, 8.02; N, 2.52. Found: C, 64.89; H, 7.37; N, 2.37.

Example 1300 <BR> N- (4- (2- (2-Cyclohexvlethyl)-l-ethylthioprop-3-yl)-2- (2-methylphenv) benzoyl] methionine Lithium Salt

Example 1300A <BR> <BR> <BR> 4- [2(2-Cyclohexylethyl)-l-methylsulfonyloxyprop-3-yl]-2-l2-met hrlphenyl) benzoic acid. methyl ester Methanesulfonyl chloride (33 u, L) was added to a solution of the product from Example 1299C (149 mg, 0.38 mmol) and triethylamine (60 µL, 0.42 mmol) in THF (1 mL) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stir for 3 hours. A solution of 2N HCl was added to the mixture which was then extracted with EtOAc. The organic phase was separated, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 8) to afford a clear oil (111 mg, 62%).

1H NMR (CDCl3, 300 MHz) 8 0.75-0.90 (m, 2H), 1.07-1.27 (m, 6H), 1.35-1.43 (m, 2H), 1.60-1.66 (m, 5H), 2.04 (m, 1H), 2.05 (s, 3H), 2.66-2.81 (m, 2H), 2.96 (s, 3H), 3.61 (s, 3H), 4.10 (d, J=5 Hz, 2H), 7.04-7.07 (m, 2H), 7.18-7.29 (m, 4H), 7.92 (d, J=8 Hz, 1H); MS (CI/NH3) m/z: (M+H) + 473.

Example 1300B 4-r2-(2-CyclohexYlethYI)-l-ethYlthioprop-3-v1]-2-(2-methylph enyl) benzoic acid methvl ester Ethanethiol (50 µL, 0.66 mmol) was added to a 60% dispersion in mineral oil NaH (27 mg, 0.68 mmol) slurry in THF (0.7 mL) at ambient temperature. After stirring for 40 min, the product from Example 1300A (105 mg, 0.22 mmol) in THF (0.7 mL) was added to the reaction mixture followed by heating at reflux for 90 min. The mixture was allowed to cool to ambient temperature and a solution of 2N HCl was added to the reaction vessel. 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: 10) to afford a clear oil (83 mg, 86%). MS (CI/NH3) m/z: 439 (M+H) +.

Example 1300C <BR> <BR> N-14- (2-Cyclohexylethyl)-1-ethylthioprop-3-yll-2- (2-methylphenyl) benzoyl] methionine methylester The product from Example 1300B (78 mg, 0.18 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (48 mg, 0.25 mmol), Hobt (27 mg, 0.20 mmol), (L)-methionine methyl ester hydrochloride (43 mg, 0.22 mmol) and NMM (35 RL, 0.32 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: 8) to afford the title compound as a clear oil (46.5 mg, 45%).

Example1300D<BR> <BR> <BR> <BR> N- [4-- (2-Cyclohexyletl)-1-ethylthioprop-3-yl)-2- (2-methylphenyl) benzoyllmethionine LithiumSalt The product from Example 1300C (46.5 mg, 0.08 mmol) was allowed to react with lithium hydroxide monohydrate (4 mg, 0.08 mmol) in a manner similar to that described in Example 608E to afford the title compound. I H NMR (DMSO-d6,300 MHz) 8 0.75-0.88 (m, 2H), 1.08-1.38 (m, 10H), 1.53-2.01 (m, 14H), 2.15 (m, 1H), 2.39-2.49 (m, 4H),

2.57-2.75 (m, 2H), 3.32 (d, partially buried under water peak 2H), 3.66 (m, 1H), 6.86 (d, J=6 Hz, 1H), 6.95 (m, 1H), 7.12-7.26 (m, 4H), 7.47 (d, J=8 Hz, 1H); MS (APCI (-)) m/z: (M-H)-554; Anal. Calcd for C32H44LiNO3S2'1.75 H20: C, 64.78; H, 8.07; N, 2.36.

Found: C, 64.75; H, 7.40; N, 2.20.

Example 1301 <BR> <BR> N-f4- (2-l2-cyclohexvlethyl) t-butvropion-3-yl)-2-l2-methylphenyl) benzovllmethionine Lithium Salt Example1301 A<BR> <BR> <BR> <BR> N-f4-l2-Cvclohexylethyllt-butylpropion-3-y)-2- (2-methylphenvl) benzoyllmethionine methylester The product from Example 1299B (99 mg, 0.21 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (56 mg, 0.29 mmol), Hobt (31 mg, 0.23 mmol), (L)-methionine methyl ester hydrochloride (50 mg, 0.25 mmol) and NMM (42 µL, 0.38 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) to afford the title compound as a clear oil (62 mg, 49.5%).

Example1301B N-[4-(2-(2-Cyclohexylethyl)t-butylpropion-3-yl)-2-(2-methylp henyl)benzoyl]methionine Lithium Salt The product from Example 1301A (61 mg, 0.10 mmol) was allowed to react with lithium hydroxide monohydrate (4.5 mg, 0.08 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- 0.90 (m, 2H), 1.05-1.35 (m, 15H), 1.45-2.03 (m, 17H), 2.15 (m, 1H), 2.75-2.80 (m, 2H), 3.65 (m, 1H), 6.86-7.00 (m, 2H), 7.07-7.25 (m, 4H), 7.46 (d, J=8 Hz, I H); MS (APCI (-)) m/z: (M-H)-580; Anal. Calcd for C34H46LiNO5S-1.70 H20: C, 66.04; H, 8.05; N, 2.26. Found: C, H, 7.54; N, 2.27.

Example 1302 <BR> N- [4-(4-Cyclohexvl-2-phenvlsulfonvlbut-1-vl)-2-(2-methYlphenvl ) benzovll methionine Lithium Salt Example 1302A sulfone3-Cyclohexylpropylphenyl

A solution of 2. 5M nBuLi in hexanes (1.9 mL, 4.7 mmol) was added to a solution of diisopropylamine (660 RL, 4.7 mmol) in THF (9.0 mL) at ambient temperature. After 10 min, the mixture was cooled to-78 °C and methyl phenyl sulfone (700 mg, 4.5 mmol) was added to the reaction vessel. The cold bath was removed and after stirring for 30 min, I- bromo-2-cyclohexylethane (1.3 g, 6.7 mmol) was added to the reaction mixture. The mixture was allowed to warm to ambient temperature and stir for 18 hours. A solution of 2N HCI was added to the reaction mixture followed by extraction with EtOAc (2X). The organic phases were combined, dried (MgS04) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1: 8) to afford a clear oil (620 mg, 52%). 1H NMR (CDC13, MHz) b 0.75-0.91 (m, 2H), 1.07-1.26 (m, 6H), 1.58-1.76 (m, 7H), 3.06 (t, J=8 Hz, 2H), 7.55-7.70 (m, 3H), 7.92 (m, 2H); MS (CI/NH3) m/z: (M+NH4) + 284.

Example 1302B N-f4- 4-Cyclohexyl-2-phenvlsulfonylbut-1 ; l)-2- (2-methylphenyl) benzolmethionine methylester The product from Example 1302A (200 mg, 0.75 mmol) was allowed to react with diisopropylamine (110 RL, 0.79 mmol), 1.6M nBuLi in hexanes (495, uL, 0.79 mmol) and the product from Example 1308E (302 mg, 0.82 mmol) in a manner similar to that described under Example 1302A. The crude residue was chromatographed (silica gel; EtOAc/hexanes, 1: 8) to afford a clear oil (179 mg, 47%). 1 H NMR (CDC13, MHz) 8 0.60-0.75 (m, 2H), 0.90-1.15 (m, 6H), 1.43 (m, 1H), 1.50-1.64 (m, 5H), 1.84 (m, 1H), 2.02 (s, 3H), 2.78 (m, 1H), 3.22 (m, 1H), 3.38 (m, 1H), 3.60 (s, 3H), 6.95-7.02 (m, 2H), 7.14-7.29 (m, 4H), 7.53-7.88 (m, 3H), 7.86-7.93 (m, 3H); MS (CI/NH3) m/z: (M+NH4) + 522.

Example 1302C N-f4- (4-Cyclohexyl-2-phenvlsulfonvlbut-1-rl)-2- (2-methylphenyl) benzoyl methionine methylester The product from Example 1302B (168 mg, 0.33 mmol) was saponified in a similar manner as that described in Example 608C. The crude acid was then allowed to react with EDCI (90 mg, 0.46 mmol), Hobt (50 mg, 0.36 mmol), (L)-methionine methyl ester hydrochloride (80 mg, 0.39 mmol) and NMM (65 uL, 0.39 mmol) in DMF (1.3 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 (117 mg, 56%).

Example 1302D <BR> <BR> <BR> N-f4- (4-Cyclohex,2-phenylsulfonylbut-1-vl)-2- (2-methylphenybenzoyllmethionine Lithium Salt The product from Example 1302C (107 mg, 0.17 mmol) was allowed to react with lithium hydroxide monohydrate (8 mg, 0.18 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6,300 MHz) 8 0.54-0.70 (m, 2H), 0.85-1.10 (m, 6H), 1.30-2.04 (m, 16H), 2.14 (m, 1H), 2.80 (m, 1H), 3.16 (m, lH), 3.60-3.73 (m, 2H), 6.85-7.26 (m, 6H), 7.43 (d, J=8 Hz, 1H), 7.62-7.68 (m, 2H), 7.75 (m, 1H), 7.93 (d, J=7 Hz, 2H); MS (APCI (-)) m/z: (M-H)-620; Anal. Calcd for C35H42LiNO5S2#3. 20 H20: C, 61.33; H, 7.12; N, 2.04. Found: C, 61.31; H, 6.63; N, 1.70