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

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

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

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

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

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

N-protected amino, and -NRR' wherein R and and R' are independently selected from the group consisting of hydrogen and loweralkyl, oxo (=0), and thioalkoxy and L2 is absent or is selected from the group consisting of -CH2-, <BR> <BR> <BR> -Cli2CH2-, <BR> <BR> <BR> <BR> <BR> -CH(CH3)-, <BR> <BR> <BR> <BR> <BR> <BR> -0-, 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 (=0), (h) -NRR', (i) N-protected amino, (j) alkoxy, (k) thioalkoxy, (1) haloalkyl, (m) carboxy, and (n) aryl; R2 is selected from the group consisting of

wherein L11 is selected from the group consisting of (a) a covalent bond, (b) -C(W)N(R)- wherein R is defined previously and W is selected from the group consisting of 0 and S, (c) -C(O)-, (d) -N(R)C(W)-, (e) -CH2O-, (f) -C(O)O-, and (g) -CH2N(R)-, R12a is selected from the group consisting of (a) hydrogen, (b) loweralkyl, and (c) -C(O)OR13 wherein R13 is selected from the group consisting of hydrogen and a carboxy-protecting group, and R12b is selected from the group consisting of (a) hydrogen and (b) loweralkyl, with the proviso that R12a and R12b are not both hydrogen, (2) -L1 i-C(R14)(Rv)-C(O)0R15 wherein L1l 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, (l) 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(R14)-C(O)NHSO2R16 wherein R14 is defined previously and R16 is selected from the group consisting of (a) loweralkyl, (b) haloalkyl, (c) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently

selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=0), -NRR' N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl, and (d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=0), -NRR', N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl; (5) -C(O)NH-CH(R14)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl, (6) -L1 1-heterocycle,

(7) -C(O)NH-CH(R1 4)-C(O)NR1 7R18 wherein R14 is defined previously and R17 and R18 are independently selected from the group consisting of (a) hydrogen, (b) loweralkyl, (c) arylalkyl, (d) hydroxy, and (e) dialkylaminoalkyl, (8) -C(O)OR15, and (9) -C(O)NH-CH(R14)-heterocycle wherein R14 is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl; L1 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) C1-to-Cl0-alkylene and (b) C2-to-C,6-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 Re 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

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

cycloalkylalkyl, and sulfhydryl, (heterocyclic) alkoxy, (heterocyclic)alkyl, (heterocyclic)alkyl[S(O)q]alkyl, (heterocyclic)oxy, (heterocyclic)alkoxyalkyl, (heterocyclic)oxyalkyl, heterocycle[S(O)q]alkyl, hydroxyl, hydroxyalkyl, imino, N-protected amino, =N-O-aryl, and =N-OH, =N-O-heterocycle wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, cyano, nitro, oxo (=0), -NRR' N-protected amino, alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl, =N-O-loweralkyl, NRR3RR3, -NHNRCRD, -OG wherein G is a hydroxyl protecting group,

-O-NH-R, wherein J and J' are independently selected from the group consisting of loweralkyl and arylalkyl, oxo, oxyamino(alkyl)carbonylalkyl, oxyamino(arylalkyl)carbonylalkyl, oxyaminocarbonylalkyl, -S02-A wherein A is selected from the group consisting of loweralkyl, aryl, and heterocycle wherein the loweralkyl, aryl, and heterocycle are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkoxy, halogen, haloalkyl, loweralkyl, and nitro, sulfhydryl, thioxo, and thioalkoxy, Ls is absent or selected from the group consisting of (a) C1-to-C10-alkylene and (b) C2-to-C16-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 ofaryl, (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 -L1 1-C(R,4)(Rv)-C(O)0R15, (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, (9,1 O-dihydroanthracenyl)alkyl wherein the (9,1 O-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; (2) -L4-O-L5-, (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 Ls 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, Rg, W, and and Ls are defined previously and L7 is absent or is selected from the group consisting of -0- 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-C10-alkenylene wherein the alkenylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of (a) aryl, (b) arylalkyl, (c) (aryl)oxyalkyl wherein the (aryl)oxyalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, (d) heterocycle, (e) (hererocycle)alkyl, (f) hydroxyalkyl, (g) cyclolakyl, (h) cycloalkylalkyl, (i) alkylthioalkyl, and (j) hydroxy, (10) C2-to-C10-alkynylene wherein the alkynylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of (a) aryl, (b) arylalkyl, (c) heterocycle, (d) (heterocyclic)alkyl, (e) cyclolakyl, (f) cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy, (11) -L4-heterocycle-Ls-, (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, (f) (heterocyclic)alkyl, (g) cyclolakyl, and (h) cycloalkylalkyl; R3 is selected from the group consisting of (1) hydrogen, (2) aryl, (3) fluorenyl, (4) heterocycle, wherein (2)-(4) are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of (a) alkanoyl, (b) alkoxy wherein the alkoxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, aryl, and cycloalkyl, (c) alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2, 3, 4 or 5 substituents independently selected from the group consisting of

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

loweralkyl, and carboxyalkyl, (o) cyano, (p) cyanoalkyl, (q) cycloalkyl, (r) cycloalkylalkyl, (s) cycloalkoxyalkyl, (t) halogen, (u) haloalkyl wherein the haloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (v) heterocycle, (w) hydroxyl, (x) hydroxyalkyl wherein the hydroxyalkyl is unsubstituted or substituted with substitutients selected from the group consisting of aryl, (y) loweralkyl wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of heterocycle, hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, -NRR3RR3, and -P(O)(OR)(OR'), (z) nitro, (aa) -NRR', (bb) oxo, (cc) -SO2NRARB wherein RAT and RIB 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 X1 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), R1 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 C1 to C8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1- ethyl, 1 -methyl- I -(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 methyl 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- I ,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, <BR> <BR> 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 R31o-R32o- wherein R31 is loweralkyl as defined above and R32 is an aikylene radical. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The alkoxyalkoxy groups of this invention can be optionally substituted.

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

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

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

The term "alkoxycarbonyl" as used herein refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of

alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. The alkoxycarbonyl groups of this invention can be optionally substituted. The alkoxycarbonyl groups of this invention can be optionally substituted.

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

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

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

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

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

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

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

The term "alkylsilyloxy" as used herein refers to a loweralkyl group to which is attached -OSiRweRxsRyfi wherein Row', Rx, and Rye 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 -CeCH, -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-O-C(O)-O- wherein R67 is an arylalkyl group. The arylalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.

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

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

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

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

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

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

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

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

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

The term "arylsulfonyloxy" as used herein refers to R37S(O)2O- 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,C(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 NHR60,C(S)- wherein R60 is defined above. The cycloalkylaminothiocarbonyl groups of this invention can be optionally substituted.

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

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

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

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

The cycloalkylalkyl groups of this invention can be optionally substituted.

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

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

The term "dialkylamino" as used herein refers to R38R39N- 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 (=0) 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 -0- and Y* is -C(O)- or -(C(R")2)v - 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 (=0), e) thioxo (=S), f) amino,g) -NHOH, h) alkylamino, i) dialkylamino, j) alkoxy, k) alkoxyalkoxy, 1) haloalkyl, m) hydroxyalkyl, n) alkoxyalkyl, o) cycloalkyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, p) cycloalkenyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, q) alkenyl, r) alkynyl, s) aryl, t) arylalkyl, u) -COOH, v) -SO3H, w) loweralkyl, x) alkoxycarbonyl, y) -C(O)NH2, z) -C(S)NH2, aa) -C(=N- OH)NH2, bb) aryl-Ll6-C(O)- wherein L16 is an alkenylene radical, cc) -S-L17-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 (=0) or methinylamino (=CHNR41R42 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 (=0) or methinylamino (=CHNR41R42 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 L20 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with oxo (=0) and R45 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 (=0), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, gg) -O-L21-R46 wherein L21 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=0) 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 (=0), 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 (=0), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, ii) -S(O)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 (=0), 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 (=0), 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 (=0), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, qqq) =N-R55 wherein R55 is hydrogen, aryl, heterocyclic, -S(O)2-aryl or -S(0)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 (=0), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, rrr) diarylalkyl-N=N-, sss) aryl- N(R56)- or arylalkyl-N(R56)- wherein R56 is hydrogen or an N-protecting group, ttt) aryl- sulfonylalkyl, uuu) heterocyclicsulfonylalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=0), 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 (=0), 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(0)2-NH-L25- wherein L25 is an alkylene group, gggg) heterocyclic-S(0)2-NH-L26- wherein L26 is an alkylene group, hhhh) aryl- C(O)-NH-L27- wherein L27 is an alkylene group and iiii) heterocyclic-C(O)-NH-L28-

wherein L28 is an alkylene group, 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)-0- 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 -NO2.

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 (=0) group. The oxoalkyloxy groups of this invention can be optionally substituted.

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

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

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

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

The spiroalkyl groups of this invention can be optionally substituted.

The term "sulfhydryl" as used herein refers to -SH.

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

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

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

The thioalkoxy groups of this invention can be optionally substituted.

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

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

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

Preferred embodiments

Preferred compounds of the invention are compounds of formula I wherein R1 is unsubstituted or substituted phenyl and R2 is -C(O)NH-CH(RI4)-C(O)ORl5 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 R1 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 R1 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 Farnesyltransferase 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 famesyltransferase 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 lX10-5 M Example at lX10-5 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 farnesyltransferase % inhibition % inhibition Example at 1X10-6 M Example at lx 10-6 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 34 315 93 787 70 316 63 788 44 317 54 789 86 318 98 790 88 319 98 791 53 320 93 792 88 321 90 793 94 322 98 794 92 323 98 796 35 324 98 797 35 325 99 806 72 326 91 807 90 327 97 808 88 328 96 809 78 329 98 810 89 330 98 812 94 331 98 813 95 332 26 816 87 333 99 824 90 334 93 831 92 343 72 832 80 344 95 834 55 345 91 835 96 346 98 844 92 347 95 846 85 348 66 850 90 349 99 862 95 379 21 866 62 541 37 867 71 542 67 868 89 544 35 872 74 545 88 878 95 546 97 879 95 547 91 886 35 550 96 889 95 78 902 85 728 552 88 903 78 553 92 908 88 554 96 910 42 555 85 911 65 556 99 918 97 557 93 923 78 560 91 924 77 561 91 925 87 564 98 926 69 565 94 936 69 566 98 937 95 568 93 962 > 50

569 91 964 > 50 572 91 979 26 575 70 982 64 576 88 987 93 577 94 988 92 582 99 989 88 Table 3. Inhibition of farnesyltransferase % inhibition % inhibition Example at 1X10-7 M Example at 1X10-7 M 434 93 623 96 436 89 729 73 437 89 730 96 438 90 731 65 439 80 732 84 440 92 733 60 441 91 734 49 442 88 735 96 443 97 736 96 444 95 737 95 445 94 738 54 446 91 739 83 447 91 740 94 448 92 741 89 449 91 742 87 450 96 743 51 455 83 745 93 458 87 746 84 459 92 747 68 461 93 748 56 462 91 769 90 464 86 770 91 482 96 781 91 483 95 785 96 484 97 795 87 485 96 798 95 486 97 799 96 487 81 800 74 489 86 801 87 490 70 802 88 491 94 811 85 492 95 814 81 493 51 815 71 511 82 817 60 519 89 818 78 520 97 822 93 521 94 823 75 522 93 825 79 523 97 839 63 524 99 849 66 526 96 854 78 527 97 855 92 531 74 856 97 532 88 857 92 533 91 859 86 534 84 861 65 535 89 863 72 536 79 864 84 539 89 865 95 548 86 869 92 549 98 874 90 551 93 875 92 558 87 876 92 559 96 891 94 562 95 893 87 563 95 894 89 570 92 895 92 571 88 896 96 573 72 900 95 574 81 906 88 578 90 912 85 579 92 913 89 580 90 914 91 581 96 917 78 584 96 919 91 585 96 921 82 589 91 929 81 590 95 931 98 592 93 933 91 593 86 935 72 594 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 M Example at 1X10-8 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 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 10mM 1 mM 10 mM 1 mM 997 91** 1199 71 998 79** 1200 97* 999 90 1201 73* 1000 82* 1202 96** 1001 92** 1203 84* 1002 82** 1204 93* 1003 92* 1205 55** 1004 92** 1206 63** 1005 95** 1207 91* 1006 95** 1208 89* 1007 85** 1209 87* 1008 95** 1210 64** 1009 86** 1211 94 1010 90* 1212 86* 1011 92** 1213 79** 1012 88* 1214 92** 1013 80* 1215 17 1014 91 1216 88** 1015 59* 1217 87* 1016 92* 1218 54** 1017 51* 1219 85** 1018 97 1220 1019 70 1221 82** 1020 39 1222 89* 1021 93* 1223 91** 1022 91** 1224 88* 1023 89** 1225 92** 1024 89** 1226 69** 1025 91** 1227 91 1026 74** 1228 88* 1027 81** 1229 66** 1028 92** 1230 77** 1029 82** 1231 93* 1030 92** 1232 68** 1031 90** 1233 77** 1032 93** 1234 71** 1033 76** 1235 86** 1034 77 1236 83** 1035 76 1237 89** 1036 79 1238 91** 1037 88 1239 85* 1038 57 1240 64** 1039 89** 1241 74* 1040 90** 1242 75* 1041 48 1243 95* 1042 88 1244 84 1043 90* 1245 92 1044 76* 1246 82 1045 86* 1247 95* 1046 93 1248 88 1047 95 1249 89 1048 78** 1250 79** 1049 93** 1251 91** 1050 62** 1252 84* 1051 79** 1253 76* 1052 91** 1254 67 1053 60** 1255 82* 1054 89** 1256 95* 1055 . 85** 1257 93** 1056 75** 1258 97** 1057 82* 1259 89** 1058 89 1260 90** 1059 92* 1261 94 1060 42 1262 95 1061 88* 1263 85* 1062 93 1264 83** 1063 92** 1265 90 1064 95** 1266 85* 1065 78* 1267 96 1066 73** 1268 95* 1067 93* 1269 84** 1068 79** 1270 91** 1069 74* 1271 78** 1070 93** 1272 73** 1071 95* 1273 94* 1072 82* 1274 89* 1073 93** 1275 86** 1074 82 1276 88** 1075 90** 1277 90** 1076 69** 1278 68 1077 93** 1279 87** 1078 86* 1280 78** 1079 | 90 1281 81* 1080 87 1282 69* 1081 61 1283 74* 1082 84* 1284 86 1083 88 1285 94 1084 76** 1286 85** 1085 93* 1287 95** 1086 87* 1288 69* 1087 76* 1289 93 1088 73* 1290 80 1089 86* 1291 1090 81** 1292 1091 87* 1293 1092 74** 1294 1093 95** 1295 1094 96** 1296 1095 76* 1297 1096 86* 1298 97** 1097 80** 1299 96** 1098 60* 1300 97* 1099 87** 1301 97* 1100 82** 1302 93** 1101 86* 1303 91** 1102 84** 1304 90** 1103 92* 1305 91** 1104 89** 1306 85** 1105 91** 1307 85** 1106 67** 1308 91** 1107 88** 1309 96* 1108 95** 1310 90** 1109 74** 1311 95** 1110 1312 91** 1111 63** 1313 91** 1112 62 1314 96* 1113 55 1315 86* 1114 83** 1316 78* 1115 94* 1317 99 96 1116 91** 1318 1117 92* 1319 79** 1118 86* 1320 79 1119 84** 1321 1120 93 1322 1121 72* 1323 1122 92** 1324 1123 90* 1325 1124 90* 1326 1125 92* 1327 1126 87 1328 1127 90* 1329 1128 86* 1330 1129 92** 1331 1130 88** 1332 92** 1131 96** 1333 95* 1132 97* 1334 72** 1133 75* 1335 90* 1134 95** 1336 74 1135 88* 1337 83** 1136 91 1338 65* 1137 83** 1339 1138 65* 1340 77* 1139 92* 1341 89 1140 77** 1342 1141 80* 1343 88 1142 84** 1344 93** 1143 92* 1345 94** 1144 76* 1346 i 94* 1145 83* 1347 81** 1146 61** 1348 78** 1147 93* 1349 92** 1148 79** 1350 1149 94* 1351 1150 92* 1352 1151 91* 1353 1152 96* 1354 38 1153 89* 1355 46 1154 93* 1356 80 1155 91* 1357 78 1156 87 1358 1157 66** 1359 1158 75 1360 98** 1159 72* 1361 96* 1160 83* 1362 83** 1161 87* 1363 88** 1162 84* 1364 1163 73** 1365 1164 94 1366 79* 1165 84* 1367 93* 1166 74** 1368 92** 1167 91* 1369 94* 1168 88* 1370 86** 1169 77 1371 94* 1170 74* 1372 95** 1171 74** 1373 95** 1172 38* 1374 93** 1173 89** 1375 80** 1174 79** 1376 86** 1175 96 1377 95* 1176 97* 1378 68 1177 19 1379 41 1178 88** 1380 87** 1179 85* 1381 65** 1180 93* 1382 86** 1181 82* 1383 88* 1182 92** 1384 69** 1183 79** 1385 93* 1184 84** 1386 88* 1185 85** 1387 82** 1186 93** 1392 93* 1187 93** 1397 87** 1188 93** 1398 81* 1189 74** 1399 94 1190 95** 1400 95 1191 85** 1192 91* 1193 95** 1194 78** 1195 94* 1196 87* 1197 85* 1198 86* * % inhibition at 0.1 RM ** % inhibition at 0.01 us 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 uM), 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 RM ZnCl2, 5 mM DTT, 0.01% Triton X-100) to give

a final volume of 50 uL. 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 IC5o 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 uM), H-Ras-CVLL (final concentration 5.0 uM) 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 KCl, 10 RM ZnCl2, 5 mM DTT, 0.01% Triton X-100) to give a final volume of 50 uL. 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 IC5o 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. WO95/25086, 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 Biologv, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., which is hereby incorporated herein by reference.

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

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

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

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

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

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

SCHEME 1 R1 ,R1 A. R3NH2 + ~~~ phosgene RaHD½0NH)½)Rll1 R2 R3NH2 H2N/ K B. R1 thiophosgene R1 thiophosgene R3NH2 + N<\J 2 S R2 R2 R3H NH Ria CR3NH2 H N04wJR1 R R HN,SXN4R1 2 R3NH2 H NJQ a 2 R3HN-f NHJQ SCHEME 2 A. " +< 2.R3NH2 R1 A. 7 SO,/CUCI, 7Ri 7 R2 2) SQicuol2 ~~~R2 R3HNO2 Ria H2N Ria c102 - Ria R1 l) phosgene R1 B. 7 1) NaNQ2/H2SO4 1 2) R3NH2 7 Iy R2 2) H20 HO 4'J 2 R3HN(O)CO oil H2N Ria HO \kiaR2 R3HN(O)CO Ria R1 1) thiophosgene R1 C. 7 1) NaNOH2SO4 R1 2) R3NH2 7 R2 2)H20 7 IviR2 H2N Ria HO R2 ----t R3HN(S)CO Ria R1 /R1 R 1)SOCl2 R1 D. 7 1) NaNO2/H2S04 R1 2) R3NH2 C H2N/ 2) H20 j¼)1R2 R3HN(O)SO I\iR2 H2N<\ HO Ria Ria Ri 1)so2c12 R1 E./R1 R1 2)H20 ~~~ E. ) R2 1) NaNO2/H2S04 R 2) R,NH, R2 R2 - H2N Ria 2)H20 HO Ria SCHEME 3 A. 7R1 i)vinylation R R3NH2 7R1 ll R2 2)0504 7 R2 R2 Br Ria Ria R3HNCH2 OHC Ria Ph3P 7 hydrazoic R1 B. R1 NaBH4 R1 acid ¼yR2 JYR2 R2 ~~~~~~~ OHM RIP HOCH2 Ria N3CH2 R1a HS(0H2)3sH R1 1) triphosgene R Et3N )R2 2)B3NH2 4)) R2 H2NCH2 Ria R3HNC(O)HNCH2 Ria C. R1 1) thiophosgene R R2 2) R3NH2 ,4 H2NCH2 Ria R3HNC(S)HNCH2 Ria D. R1 1)socl2 /R1 t R 2) R3NH2 C R2 H2NCH2 Ria R3HNS(O)HNCH2 Ria E. R1 R1 4)1) R 2) R3NH2 4)') R2 H2NCH2 Ria R3HNS(0)2HNCH2/9R1a

SCHEME 4 R1 1) phosgene R1 HoC,/I R2 2)R3NH2 4))m R2 a Ria B. R1 1) thiophosgene I3HNC(S)OCH ,tQJ 4))m R2 2) R3NH2 4) R2 HOCH2 Ria R3HNC(S)OCH2 Ria R1 R1 R1 HOCH2 R2 2) R3NH2 4)) R2 HOCH2 Ria R3HNS(O)OCH2 Ria D. R1 1)so2cl2 R1 , X R2 R3NH2 4)) R2 R2 HOCH2 Ria R3HNS(O)2OCH2 Ria SCHEME 5 A. «qRa 1) NaNO2/H2SO4 R1 2)Ss Dy) ia H 'Ria 1) phosgene R1 2)R3NH2 R3HNC(0 IR1a B. R1 1) thiophosgene R1 I 2) R3NH, II R2 2) R3HNC(S)S<R1a C. R1 i)S0cI2 R1 R,NH, HS' 'R1, R3NH2 ~~~R2 'ia R3HNS(O)S ia D. R1 1)SO2Ci2 D. R i)so2cl2 ; R R1a 'R1, R3HNS(0)2 Ria

SCHEME 6 A. R1 1) Tos-Ol R1 2)NaHS 7 HOCH wiz CH2)ia R2 Ria HS 1 ) phosgene R3HNC(O)SCH R1 2) R3NH2 4)) R2 R3HNC(O)SCH2 Ria B. R1 1) thiophosgene << R2 2) R3NH2 4) R2 HSCH2 Ria R3HNC(S)SCH2 Ria C. Ri isoci2 Ri 4)) R 2) R3NH2 C/q- R2 HSCH2 Ria R2 4)) R3HNS(O)SCH2 Ria D. / R1 1)so2cl2 /R1 2) R 2) R3NH2 8 R2 HSCH2/ Ria 3 R3HNS(0)2SCH2 Ria

SCHEME 7 A. 7R1 Ri H2N I? R3-CO2H Rla Ria R3C(O)HNVR$a B. R1 R1 R2 R2 H2NCH2 Ria R3C(O)HNCH2 Ria F C. (Ph3P)2Pd(OAc)2 R1 R2 {Puhi8P)2Pd(OA)2 Cul R2 Br Ria H-C--C R1, R1 R3-COCI a 4 R2 R3-C(O)-C~ 1 R2 Ria D. z R1 Lindlar catalyst C R2 R3-C(O)-C~- 1 a R3-C(O)-HC=H R2 E. //R1 Lindlar catalyst ,R1 R3-C(O)-HC=H a Ria R3-C(O)-H2CH2' R2 SCHEME 8 g Pd(OAC)2 R1 R3NH2 R A. R2 DPPEICO H2N R2 he 'J R3-HN-C(O A R1a R1 1) oxalyl chloride .R1 R3NH2 R B. 2) CH,N, R2 HBO2C½)m R2 ffi½2N2 4)) R2 4)) R2 Ria HO2CCH2 Ria R3-HN-C(O)CH2 Ria C. R3OHO R H2N/ .R2 NaCNBH, H2N s\R R8CH2NVkia R2 R1, D. R1 D. NaCNBH3 R1 R2 H2NCH2/ R3CH2NHCH2/%9R1 R3CH2NHCH2 Ria

SCHEME 9 A. A- 1)NaNO2/HCl 7Ri 1 2)oxalyl chloride R1 H2N Ria 2) 502 - J R2 R3NH2 R2 CISO2 Ria R3-HN-C(O)NH-S02 Ria R1 1)Ph3P/DEAD R 1) NH3 R1 B. 2 2) HSc(o)CH3 CH2/ a 2) oxalyl chloride 3) FizzR2 ll j R2 R3NH2 ll R2 HOCH2 \ Ria 3)C12 CISO2CH2 Ria R3NHC(O)NHSO2CH2 Ria C. R1 C- « 1) 1)Tos-CIR1 R1 J R2 2) R30H/CuCI C R HOCH2 Ria R3OCH24)$1aR2 D. ,R1 Ri 1) 2) phosgene t R2 2) 1)phosgene )¼;)NRiR2 H2N Ria R3OC(O)NH Ria E.8 1) thiophosgene / R1 4)ft 2 2) R3-OHICuCl ~~~R2 H2N R1 a R30C(S)NH wR1 F. R1 .RI 7 1) SOCK, 4 2 2) 2)R3-OH/CuCI < 2 H2N Ria R30S(O)NH 1a G. H2N'4)) 1 1)502012 Dy R R2 1 1)SO,CI, CZ 1R2 R1, Ras R30S(0)2N H » Rla SCHEME 10 A. R1 7Th i)triphosgene R1 R2 =-R2 2) R3OH/CuCl 4) R2 H2NCH2 Ria R3OC(O)NHCH2 Ria B. z Ri i)thiophosgene R1 H NCH < \»J C - R2 2 2 Ria R3oC(S)NHCH2 Ria C. R1 C. /8 R 1)sock2 | 8 R2 H2NCH24)) R2 1)SOCH, 4))Ri 2) R3OH/CuCl 2) cos(o)NHCH,/ D. R1 R1 7 1) 502012 4)) R2 R2 R2 2) R30H/CuCI H2NCH2 Ria R3OS(O)2NHCH2 Ria

SCHEME 11 A. R1 A. << 1) NaNO2/HBF4 R1 H2NJ4\;'J , R3SH/NaH R IIR2 Ria B. ,R1 1) triphosgene R1 i)triphosgene R1 H2N'aR3SC(O)NH Ria C. AR1 1 )thiophosgene R1 H2N Ria 2) R3SH ~~~ R2 R3SC(S)N Ria D. R1 D. .R R2 2)R3SH R1 1) R2 Ria R3SS(O)NH Ria E. R1 4)) R2 21))SR03s2H0l2 Dy R1R2 H2N Ria R3SS(O)2N Ria

SCHEME 12 A. z R1 4))rn 3S C ( O ) N H C H H2NCHi R2 2) R,SHI R3SC(O)N B. R1 I)thiophosgene B1 2) R2 i)thIO%hO5 4)) R2 H2NCH2 Ria R3SC(S)NHCH2 Ria C. R1 R1 4)) B2 2) R3SH R H2NCH2 Ria R3SS(O)NHCH2 Ria D. R1 X SO2Ci2 B1 H2NCH2 R2 2) R3SS(0)2NHCH2 R1a SCHEME 13 A. R1 R8-X R R2 NaH/Cu 1 HO -R2 R30 R2 Ria X = halide B. R1 R R "XvJ R2 R8-X ¼?R2 R3S Ria X = halide C. R1 R3-X R C- < - R2 pyridine 1 R2 pyridine ";R1 R,-X -RR2 H2N flia X = halide R3N Ria D. H; R1 R3-X R1 HOCH2 R2 NaH 4))R2 X= halide E. 4)) Ri2 N%HX R1 HSCH2 Ria R3SCH2 Ria X = halide

SCHEME 14 A. Ph3P)2Pd(OAc) R1 ½ R2 (Ph,P),Pd(OAc), 7R1 .R2 R,-X R2 191a X = halide B. R1 Lindlar catalyst i| t R1 R3-C- R2 H2 R3HCC < R2 Ria R1 R1 C. ½ Pd/C I R2 H,;il R2 R3-HC=C Ria R3-H2C-CH2 Ria ,R1 1,1 1,1'-SPh2P)2- R1 R2 J4R2 ferrocene PdOl2 ,44 Ria co R-C(O)C=1- R3-Br Ria R,-Br RiR2 Lndlar catalyst i½ R1 R2 R3-C(O)CaaC Ria R3-C(O)CH=CH R3C(O)CC 4 Pd/C < RF3C(O)CH=CH.4¼ RiR2 H2 4))Ri Ria R3-C(O)CH2-CH2 Ria SCHEME 15 A. S $ MCPBA '; R1 RS/a MCPBA 3SO R2 Ria R3SO2 Ria B. R1 1) R3cX R1 R2 2) MCPBA 4) R2 HRia X halide R3CH2SO2 Ria C. ½R1 1) RaCHiX zJXR2 HSCH2 R2 MCPBA ~~~R2 halide RAS Ria R1 7 cH2so2cl R1 ~~~~~~~ R2 H2 Ria R3SO2W 'R1 a E. ½) Ri R2 SQCl 4)))Ri R2 H2NCH2 P.3SO2CI 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 Tvpe A(B)N-L1

Table 8. Ethers of the Type A-OL1

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

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

Table 10. Amines of the type B-NH2

Table 11. Bromides of the type B-Br

Table 12. Amines of the type A-NH2

Table 13. Acids of the type A-CO2H

Table 14. Aldehydes of the type A-CHO

Table 15. Alcohols of the type A-OH

Table 16. Mercaptans of the type A-SH

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

Table 18. Sulfonyl chlorides of the type A-SO2Cl

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

In Tables 2-10, the abbreviation bz=benzoyl, bn=benzyl, Ph=phenyl, BOC=t- butyloxycarbonyl and TS=p-toluenesulfonyl.

Compound 1 (3-(Aminomethvl)benzovl)-Met-OCH3 Step A (3-(Chloromethyl)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 MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (30% ethyl acetate in hexanes) to give the desired product (3.03 g) as a white solid: m.p. 82-83°C; 1H NMR (CDC13) 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 (211, s), 3.78 (311, s), 2.58 (2H, t, J=7.1Hz) 2.26 (1H, sm), 2.15 (1H, m), 2.10 (3H, s); 13C NMR (CDC13) d 172.59, 166.54, 138.13, 134.25, 131.95, 129.12, 127.42, 126.97, 52.72, 52.14, 45.55, 31.47, 30.12, 15.55.

Step B (3 -(Azidomethvl)benzoyl)-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 800C 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 MgSO4. 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; 111 NMR (CDC13) d 7.78 (2H, m), 7.49 (211, 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 (211, t, J=7.4 Hz), 2.29 (1H, m), 2.17 (1H, m), 2.12 (311, s); 13C NMR (CDC13) d 177.50. 166.54, 135.97, 134.06, 131.18, 128.89, 126.84, 126.71, 54.09, 52.47, 51.95, 31.38, 30.00,15.30.

Step C

(3-(Aminomethvl)benzovl)-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. 1H NMR (CDCl3) d 7.81 (1H, s), 7.68 (1H, d, J=7.4 Hz), 7.45 (1H, d, J=6.5 Hz), 7.36 (1H, t, J=7.4 Hz), 4.91 (1H, ddd, J=7.3, 7.1, 5.1 Hz), 3.90 (2H, s), 3.77 (3H, s), 3.21 (2H, br s), 2.59 (2H, t, J=7.4 Hz), 2.20 (1H, m), 2.12 (1H, m), 2.09 (3H, s).

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

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

269 12410-12413 (1994).

Compound 4 (4-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 OOC 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 1N HC1 to remove any unreacted starting material. The solution was dried over Na2SO4 and the solvent was removed in vacuo. The crude material was recrystallized from ethyl acetate/hexanes to provide the desired product (12.2 g): m.p. 189-190"C; 1H 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 28.59, 81.29, 118.54, 125.30, 131.81, 145.70, 155.00,

169.80; Anal. Calc. for C12H15NO4, C: 60.76, H: 6.37, N: 5.90; Found, C: 60.52, H: 6.43, N: 5.83; HRMS Calc. for C12HlsNO4, 237.0961, Found, 237.1001.

Step B N-B OC-4-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 HCl, 1M NaHCO3 and water. The methylene chloride was dried over MgSO4 and the solvent was removed in vacuo. The resulting solid was recrystallized from ethyl acetate/hexanes to yield the desired product (9.72 g): m.p. 184-185"C; 1H NMR (CDCl3) d 1.53 (9H, s), 2.06-2.18 (4H, m), 2.23-2.33 (1H, m), 2.59 (2H, t, J=7.6 Hz), 3.80 (3H, s), 4.92 (1H, m), 7.45 (2H, d, J=8.7 Hz), 7.77 (2H, d, J=8.7 Hz); 13C NMR (CDCl3) d 15.59, 28.34, 30.15, 31.64, 52.10, 52.73, 81.20, 117.73, 127.8, 128.33, 141.88, 152.33, 166.50, 172.75; Anal. Caic. 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-Aminobenzovl)-Met-OCH3 hvdrochloride N-BOC-4-aminobenzoyl-Met-OCH3 (3.53 g, 9.59 mmol) was placed into methylene chloride (30-35 mL) and to it was added 3M HCl/EtO2 (38.4 mL). After standing, a white precipitate formed. After two hours the solution was decanted and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether and dried overnight on the vacuum pump. Meanwhile, the filtrate was left to stand overnight to allow additional product to precipitate. The second fraction was washed with ether and dried overnight on the vacuum pump. The total yield of the desired product was 2.87 g: m.p. 158-164°C; 1H 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 (CDCl3) d 15.23, 31.43, 31.53, 52.91, 52.43, 124.35, 130.56, 135.31, 135.76, 168.95, 173.87; HRMS Calc. for C13Hl8N203S, 282.1038, Found 282.1009.

Compound 5 (4-Amino-3-methylbenzovl-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 17.98, 28.62, 81.47, 123.12, 127.05, 129.14, 130.65, 132.99, 142.45, 155.33, 168.70; Anal. Calc. for C13H17NO4, 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. forC13H17NO4, 251.1158; Found, 251.1153.

Step B (N-B OC4-Amino-3-methylbenzoyl)-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; 1H NMR (CDCl3) 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 15.47, 17.61, 28.22, 30.03, 31.55, 51.93, 52.57, 81.04, 118.73, 125.62, 127.66, 129.54, 139.89, 152.34, 166.58, 172.66.

Step C (4-Amino-3-methvlbenzovl)-Met-OCH3 hydrochloride 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/Et2O (20.7 mL). A pale orange precipitate was obtained, washed with ether and dried overnight on the vacuum pump. The total yield of the desired product was 0.83 g: m.p. 157-159"C; 1H NMR (CD3OD) d 2.04 (3H, s), 2.11-2.25 (1H, m), 2.47 (3H, s), 2.52-2.68 (3H, m), 3.74 (3H, s), 4.75-4.80 (1H, m), 7.48 (1H, d, J=8.2 Hz), 7.81 (2H, d, J=8.2 Hz), 7.87 (1H, s); 13C NMR (CD30D) d 15.23, 17.28, 31.43, 31.51, 52.91, 53.37, 124.41, 127.85,

131.99, 133.63, 134.14, 135.65, 169.05, 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 -methoxvbenzoyl-Met-OCH3 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 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS Calc. for C13Hl7NOs, 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; 1H 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 15.47, 28.23, 30.09, 31.48, 52.06, 52.54, 55.81, 80.82, 98.06, 109.38, 116.66, 119.31, 131.52, 147.23, 152.31, 166.57, 172.58; m/z (FAB) 413 (M + 1).

Step C (4-Amino-3-methoxvbenzovl)-Met-OCH3 hvdrochloride 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; 1H 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, 136.15, 153.67, 168.79, 173.81.

Compound 7 (4-Amino-1-naphthoyl)-Met-OCH3 Step A 4-Amino-1-naphthoic acid 4-Amino-1-naphthalenecarbonitrile (1.5 g, 8.91 mmol) was suspended in a 50% KOH solution (18 mL). The heterogeneous solution was heated at reflux for 2-3 days. Once the solution became homogeneous and TLC showed no more starting material, the deep red solution was cooled and poured over 200 mL of water. The resulting solution was then filtered and the desired product was precipitated with concentrated HCl. 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 107.39, 114.61, 122.99, 123.92, 125.21, 127.40, 128.48, 135.04, 151.35, 171.44; HRMS Calc. for C1lH7NO2, 187.0633; Found, 187.0642.

Step B N-BOC-4-Amino-1-naphthoic acid 4-Amino-l-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, 81.62, 119.06, 123.40, 124.57, 127.03, 127.37, 128.49, 128.77, 131.89, 133.76, 139.86, 155.95, 170.73; Anal. Calc. for C17H17NO4, C: 66.90, H: 5.96, N: 4.88; Found C: 66.49, H: 6.08, N: 4.79; m/z (EI), 289; HRMS Calc. for C16Hl7NO4, 287.1158; Found, 287.1151.

Step C

(N-B OC-4-Amino- 1 -naphthoyl!-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; 1H 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, 127.18, 131.02, 135.65, 152.93, 169.04, 172.40; HRMS Calc. for C22H28N205S, 432.1719; Found, 432.1702; m/z (FAB) 433 (M+1).

Step D (4-Amino- 1 -naphthovl)-Met-OCH3 hydrochloride (N-BOC-4-Amino-1-naphtholyl)-Met-OCH3 (0.57 g, 1.31 mmol) was deprotected with HCl/ether to yield the desired product (0.31 g) as a white solid: m.p. 178-181"C; 1H NMR (CD3OD) 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, 31.40, 53.01, 53.33, 119.90, 122.20, 126.15, 127.41,127.77, 129.09, 129.31, 131.50, 132.33, 135.64, 171.77, 173.83; m/z (FAB), 369 (M+1).

Compound 8 (4-Amino-2-phenylbenzovl)-Met-OCH3 Step A 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; 1H NMR (CDCl3) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (SH, m), 8.07-8.10 (2H, m); 13C NMR (CDCl3)

d 20.68, 121.96, 124.51, 127.78, 128.41, 128.83, 131.06, 139.06, 139.44, 142.97, 143.48, 146.05; Anal. Calc. for C13HllNO2, C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (EI) 213; HRMS Calc. for C13H11NO2, 213.0790; Found, 213.0793.

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

The reaction mixture was heated overnight and the solution was filtered and washed several times with boiling water. The aqueous solution was made acidic and the product was extracted into ethyl acetate. The ethyl acetate solution was dried over Na2SO4 and the solvent removed in vacuo to provide the desired product (0.37 g): m.p. 174-176"C, 1H NMR (CD30D) d 7.38-7.48 (5H, m), 7.96 (1H, d, J=8.5 Hz), 8.21 (1H, d, J=2.3 Hz), 8.28 (1H, dd, J=8.48, 2.37 Hz); 13C NMR (CD30D) d 122.95, 126.09, 129.27, 129.42, 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; 1H NMR (CDCl3) d 1.62-1.73 (1H, m), 1.79-1.88 (1H, m), 1.91 (3H, s), 1.99 (2H, t, J=7.2 Hz), 3.59 (3H, s), 4.53 (1H, m), 6.45 (1H, d, J=7.8 Hz), 7.33-7.40 (5H, m), 7.67 (1H, d, J=8.3 Hz), 8.07-8.12 (2H, m); 13C NMR (CDC13) d 14.92, 29.11, 30.67, 51.51, 52.29, 121.86, 124.74, 128.27, 128.60, 128.69, 129.52, 137.50, 140.56, 141.02, 148.09, 167.23, 171.23; m/z (FAB), 389 (M+1). <BR> <BR> <BR> <BR> <BR> <BR> <P> StepD <BR> <BR> <BR> <BR> (4-Amino-2-phenvlbenzovl)-Met-OCH3 (4-Nitro-2-phenylbenzoyl)-Met-OCH3 (0.35 g, 0.90 mmol) was dissolved in ethyl acetate (9.0 mL). To this mixture was added SnCl2 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 NaHCO3 and the product was extracted into ethyl acetate several times (7-8). The ethyl acetate solutions were combined, washed with brine and

dried over NSO4. 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 (CDCl3) d 15.02, 29.25, 31.25, 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-(1 -naphthvl)benzovl!-Met-OCH3 The title compound can be prepared according to the method used to prepare Compound 8, only substituting 1-naphthylboronic acid for phenylboronic acid.

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

Step B 4-Nitro-4'-biphenyl carboxylic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-4'-methylbiphenyl.

Step C 4-Amino-4'-biphenyl carboxylic acid

The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-4'- biphenyl carboxylic acid.

Compound 13 4-Amino-3 '-biphenyl carboxylic acid Step A 4-Nitro-3 '-methylbiphenyl The title compound was prepared by Suzuki coupling of 1-bromo-4-nitrobenzene and 1- bromo-3 -methylbenzene.

Step B 4-Nitro-3'-biphenvl carboxylic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-3'-methylbiphenyl.

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

Compound 14 4-Amino-2-methoxv-3'-biphenvl carboxylic acid Step A 2-Methoxy-4-nitro-3 '-methylbiphenyl The title compound was prepared by reaction of l-bromo-2-methoxy-4-nitrobenzene with 3- methyiphenylboronic acid in the presence of palladium acetate.

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

Step C 4-Amino-2-methoxy-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 carboxylic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.

Compound 16 4-Amino-2-phenvl-3'-biphenvlcarboxylic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.

Compound 17 (4-Amino-2-(3 5-dimethylphenyl)benzovl )-Met-OCH3 Step A 2-Bromo-4-nitrobenzoic acid 2-Bromo-4-nitrotoluene (5.0 g, 23.14 mmol) was dissolved in pyridine (23 mL) and water (46 mL). The heterogeneous mixture was heated to 600C 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; 1H 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 121.96, 122.75, 129.36, 132.24, 139.52, 149.54, 167.75; Anal. Calc. for C7H4BrNO4 0.1 ethyl acetate, C: 34.88, H: 1.90, N: 5.50; Found, C: 34.68, H: 1.86, N: 5.82.

Step B 3 .5-Dimethylphenylboronic 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 -700C. 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 MgSO4 and the solvent was removed in vacuo to provide the desired product (2.41 g): m.p.249-251°C; 1H NMR (CDCl3) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD30D) d 21.36, 133.28, 134.39, 137.48.

Step C 4-Nitro-2-(3.5-dimethvlphenyl!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 1000C overnight. The solution was poured onto 1N HCl and extracted with Et2O. It was dried over MgSO4 and the solvent was removed in vacuo. The crude product was chromatographed on silica gel using a 9:1 mixture of hexanes and ethyl acetate to provide the desired product (0.34 g): 1H NMR (CDCl3) d 2.36 (6H, s), 6.99 (2H, s), 7.07 (1H, s), 8.03 (1H, d, J=9.0 Hz), 8.23-8.25 (2H, m); 13C NMR (CDCl3) d 21.28, 121.68, 123.68, 125.74, 126.07, 130.22, 131.19, 131.31, 135.04, 138.21, 144.74, 170.75.

Step D (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; 1H NMR (CDCl3) 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 (CDC13) d 15.20, 21.26, 29.22, 31.15, 51.79, 52.57, 122.07, 125.11, 126.27, 130.03, 130.53, 137.77, 138.82, 140.29, 141.56, 148.41, 167.14, 171.53. <BR> <BR> <BR> <BR> <BR> <BR> <P> Step E <BR> <BR> <BR> <BR> <BR> (4-Amino-2-(3 .5 -dimethvlphenyl)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): 1H 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 15.08, 21.17, 29.28, 31.49, 51.70, 52.18, 113.30, 115.94, 123.55, 126.36, 129.32, 131.23, 138.15, 140.72, 141.92, 148.40, 168.45, 172.01.

Preparation 1 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, (0- Me)serine methyl ester, (O-Me)homoserine methyl ester, homoserine lactone, isoleucine methyl ester, leucine methyl ester, norleucine methyl ester, norvaline methyl ester, cyclohexylalanine methyl ester, phenylalanine methyl ester, or glutamic acid dimethyl ester.

Preparation 2 4-Bromo-2-phenylbenzoyl methionine methvl 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 NaNO2 (1.1 equivalents) to form the diazonium salt. The reaction is treated with CuBr (1.1 equivalents) and heated. When judged complete by TLC analysis, the mixture is extracted into ethyl acetate which is dried and evaporated. The title arylbromide is purified by chromatography on silica gel.

Preparation 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-phenvlbenzovl methionine methvl 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 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

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

Preparation 3 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 1 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-phenylben wyl methionine Example 1A Methvl 4-((5)-2-Pvrrolidone-5-aminomethvlcarbonyl?amino-2-pkenylben zoate To a solution of methyl 4-amino-2-phenylbenzoate hydrochloride (1.0 equivalent) in toluene is added triphosgene (0.33 equivalent) and the mixture is heated at reflux until judged complete by TLC analysis. The intermediate is reacted without further purification with (S)- 5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (2.0 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HC1 and brine, evaporated, and purified by chromatography on silica gel.

Example 1B 4-((S)-2-Pvrrolidone-S-aminomethYlcarbonyl!amino-2-phenvlben zoic acid To a solution of the resultant compound from Example 1 A (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-Pvrrolidone-5 -aminomethylcarbonylamino-2-phenylbenzoyl 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 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 1D 4-((S!-2-Pyrrolidone-5-aminomethvlcarbonyl!amino-2-phenylben zoyl methionine methyl ester alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and triethylamine (2.0 equivalents). The intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with 1N HCl and brine, evaporated, and purified by chromatography on silica gel.

Example 1E 4-((£)-2-Pvrrolidone-5-aminomethvlcarbonylamino-2-phenylben zoyl methionine 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-aminomethylthiocarbonvl)amino-2-pheny lbenzoyl methionine The title compound is prepared as described in Example 1 with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 3

4-((S )-2-Pvrrolidone-5-aminomethvlsulfinylamino2phenvlbenzovl methionine Example 3A 4-((S)-2-Pvrrolidone-5-aminomethvlsulfinvl)amino-2-phenvlben zovl methionine methyl ester To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in methylene chloride is added thionyl chloride (1.0 equivalent) and triethylamine (2.0 equivalents). After the amine has fully reacted, (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is added. When the reaction is judged complete by TLC analysis, the product is isolated as described in Example lA and purified by chromatography on silica gel.

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

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

Example 4B 4-((S)-2-Pyrrolidone-5-aminomethylsulfonyl)amino-2-phenylben zoyl 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 lA and purified by chromatography on silica gel.

Example 4C 4-((S)-2-Pyrrolidone-5-aminomethylsulfonyl)amino-2-phenylben zoyl 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-((5)-2-Pvrrolidone-5-methvlaminosulfonvl!-2-phenvlbenzovl methionine Example SA 4-Chlorosulfonyl-2-phenylbenzoic acid methyl ester To a solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in concentrated HCl 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 KCl (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-Pyrrolidone-5-aminomethyl)sulfonyl)-2-phenylbenzoic acid methyl ester To a solution of the resultant compound from Example SA (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-((Si-2-Pvrrolidone-5-aminomethylsulfonvl)-2-phenylbenzoic acid The resultant compound from Example SB is hydrolyzed according to the procedure of Example IB to give the title product.

Example SD 4-((S)-2-Pvrrolidone-5-aminomethvl)sulfonvl)-2-phenvlbenzovl methionine methvl ester To a solution of the resultant compound from Example SC (1.0 equivalent) in (DMF) is added 3-hydroxy- l ,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 HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example SE 4-((&)-2-Pvrrolidone-5-aminomethvlcarbonylamino-2-phenylbenz oyl methionine methyl ester. alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in concentrated HCl 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 SB to give the title compound.

Example SF 4-( (S)-2-Pvrrolidone-5-aminomethylcarbonylamino-2-phenvlbenzoyl methionine

To a solution of the resultant compound from Example SD (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-pyridvloxv)-2-phenvlbenzovlmethionine Example 6A 4-Hydroxy-2-phenylbenzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaNO2 (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-Pvridvloxv)-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-Pyridvloxy!-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-phenvlbenzovlmethionine methyl ester The resultant product from Example 6C is coupled to methionine methyl ester according to the procedure of Example lC to give the title compound.

Example 6E 4- (2-Pyridvloxv)-2-phenylbenzoylmethionine methyl ester. alternate procedure A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaNO2 (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 removai of the solvent and chromatography on silica gel.

Example 6F 4-(2-pyridyloxy)-2-phenylbenzoylmethionine The resultant compound from Example 6E is hydrolyzed according to the procedure of Example lB 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-S-aminomethvl)carbonyloxy-2-phenylbenzo yl methionine Example 8A 4-((S)-2-Pyrrolidone-5-aminomethyl )carbonvloxv-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 HCl and brine, evaporated, and purified by chromatography on silica gel.

Example 8B 4-((S)-2-Pvrrolidone-5-aminomethyl)carbonyloxv-2-phenvlbenzo vl methionine The resultant compound from Example 8A is hydrolyzed according to the procedure of Example lB to give the title product.

Example 9 4-((£)-2-Pyrrolidone-5-aminomethvl)thiocarbonyloxy-2-phenvl benzoyl methionine methvl ester The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by thiophosgene.

Example 10 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfinyloxy)-2-phenylbenz oyl 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 oyl methionine The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by sulfuryl chloride.

Example 12 4-(3-Pyridylmethvlenthio-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 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. The title thiophenol is purified by chromatography on silica gel.

Example 12B 4-(2-Pvridvlmethvlenthio)-2-phenvlbenzoic acid methvl ester A solution of the resultant thiophenol (1.0 equivalent) from Example 1 2A is treated with 2- chloromethylpyridine hydrochloride (1.0 equivalent) in the presence of a NaH (2.0 equivalents), 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 12C 4-(2-Pvridylthiomethvlen)-2-phenvlbenzoic acid The resultant compound from Example 12B is hydrolyzed according to the procedure of Example 6C to give the title acid.

Example 12D 4-(2-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-Pyridylthiomethylen)-2-phenvlbenzoylmethionine 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 K2CO3 (3.0 equivalents) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

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

Powdered anhydrous sodium carbonate (100 mmol) is carefully added to the cold reaction mixture in small portions, until the reaction mixture reaches pH 7 to 8. Then, the reaction mixture is added in small portions to a solution of sodium p-methoxybenzylsulfide (prepared from reaction 110 mmol of p-methoxybenzylthiol with 55 mmol of 2.0 M NaOH aqueous solution). After completion of the addition, the reaction mixture is refiuxed 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 HCl, 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 l-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 K2CO3 (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-Pvridylthiomethylen)-2-phenvlbenzovlmethionine

The resultant compound from Example 12D is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 13 4-(2-Pvridvlthio)-2-phenvlbenzovlmethionine Example 13A 4-Fluoro-2-phenvl benzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous HBF4 is treated with NaNO2 (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 1 3B 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-phenvl benzoyl methionine methyl ester The resultant product from Example 1 3B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.

Example 13D 4-(2-Pvridvlthio)-2-phenvl benzoyl methionine methyl ester A mixture of the resultant fluorobenzoate from Example 1 3C (1.0 equivalent) and 2- mercaptopyridine (1.0 equivalent) is treated with K2CO3 (2.0 equivalents) or NaH (1.0 equivalent) in DMF or DMSO and is stirred until the reaction is judged complete by TLC analysis. The mixture is diluted with water and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.

Example 13E 4-(2-Pvridvlthio)-2-phenyl 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 NaNO2 (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 K2C03 (3.0 equivalent)s in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.

Example 1 3F 4-(2-Pvridylthio)-2-phenyl 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 lC to give the title compound.

Example 13G 4-(2-Pvridvlthio)-2-phenvlbenzovlmethionine The resultant compound from Example 13D is hydrolyzed according to the procedure of Example lB to give the title product.

Example 14 4-(2-Pvridvlsulfonvl)-2-phenylbenzovlmethionine Example 14A 4-(2-Pvridvlsulfonvl)-2-phenvlbenzoic acid methvl 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 NaHCO3 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-Pvridvlsulfonyl)-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-pyridvlsulfonvl)-2-phenvlbenzovlmethionine methyl ester The resultant product from Example 14B is coupled to methionine methyl ester according to the procedure of Example 1 C to give the title compound.

Example 14D 4-(2-Pvridvlsulfonvl)-2-phenvlbenzovlmethionine The resultant compound from Example 14C is hydrolyzed according to the procedure of Example lB to give the title product.

Example 15 4-(3-Pvridvlthiomethvlen!-2-phenvlbenzoylmethionine The title compound is prepared from the resultant product of Example 12B using the procedures from Example 14.

Example 16 4- [(2-Aminopvridvl)methvlenel -2-phenvlbenzovlmethionine

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 atom. 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 acid methvl ester The resultant acid from Example 1 6A (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 NaHCO3 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-(Hvdroxvmethvl)-2-phenvlbenzoic acid The resultant compound from Example 16B is hydrolyzed according to the procedure of Example 6C to give the title acid.

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

Example 16E 4-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 CH2Cl2/acetonitrile mixture until the reaction is judged complete by TLC analysis. The mixture is diluted with ethyl ether and filtered through SiO2. The product is purified by chromatography on silica gel.

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

Example 16G 4-(Hvdroxvmethyl)-2-phenvlbenzovl methionine methyl ester, alternate procedure To a solution of the resultant compound from Example 16E in ethanol at 0 OC is added sodium borohydride (0.5 equivalent), and the reaction is stirred at 0 OC 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-Aminopvridvl)methvlenel-2-phenvlbenzovlmethionine methvl ester A mixture of the resultant aldehyde from Example 16E (1.0 equivalent), 2-aminopyridine (1.0 equivalent) and NaCNBH3 (1.5 equivalents) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.

Example 161 4-1 (2-Aminopvridvl)methvlenel-2-phenvlbenzovlmethionine

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

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

Example 18 4-((Si-2-Pvrrolidone-S-aminomethvlcarbonyl)aminomethvl-2-phe nvlbenzovl methionine Example 18A 4-(Azidomethvl)-2-phenvlbenzovl methionine methyl ester To triphenylphosphine (1.0 equivalent) in tetrahydrofuran (THF) at -780 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 1 6D (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-phenylbenzoyl methionine methvl ester To the resultant compound from Example 18A in methanol is added triethylamine (3.0 equivalent) and propane 1,3-dithiol (3.0 equivalents). After the reaction is judged complete

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

Example 18C 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)aminomethyl-2-phe nylbenzoyl 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 1N HCl and brine, evaporated, and purified by chromatography on silica gel.

Example 18D 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)aminomethyl-2-phe nylbenzoyl 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 -phenylbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 20 4-( (5)-2-Pvrrolidone-S-aminomethylsulfinyl )aminomethyl-2-phenvlbenzovl methionine 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-((S)-2-Pyrrolidone-5-aminomethylsulfonyl)aminomethyl-2-phe nylbenzoyl methionine Using the Procedure of Example 4 with the resultant compound from Example 18B affords the title product.

Example 22 4-((S)-2-Pyrrolidone-5-aminomethylsulfonyl)aminomethyl-2-phe nylbenzoyl methionine Using the procedure of Example 8 with the resultant compound from Example 16D provides the title product. Example 23

4-((S)-2-Prrolidone-5-aminomethyl)thiocatbonyloxymethylene)- 2-phenylbenzoyl methionine Using the procedure of Example 8 with the resultant compound from Example l 6D and replacing triphosgene (0.33 equivalent) with thiophosgene (1.0 equivalent) provides the title product.

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

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

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

A mixture of 3-pyridinecarboxaldehyde (1.0 equivalent), 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) and NaCNBH3 (1.0 equivalent) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 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 lB to give the title product.

Example 26 4-r(4-aminomethylpvridvl)methvlenel-2-phenylbenzovlmethionin e Using the procedures of Examples 25 with the resultant amine from Example 18B and 3- pyridinecarboxaldehyde affords the title product.

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

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

Example 28 4-(3-PvridylmethoxvmethYlene!-2-phenvlbenzovlmethionine Example 28A 4-(3-Pvridvlmethoxvmethvlene)-2-phenvlbenzovlmethionine methvl ester Using the procedure of Example 27B but replacing 3-hydroxypyridine with 3- hydroxymethylpyridine affords the title compound.

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

Example 29 f 2-Phenvl-4-[(thiazol-2-ylamino!carbonylthiolbenzovl I -methionine Example 29A Thiazol-2-ylisocvanate 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-Phenyl-4-l (thiazol-2-vlamino!carbonvlthiolbenzoyl } -methionine methyl 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- [(thiazol-2-ylamino)carbonvlthiolbenzovl 1 -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 HCl and brine, evaporated, and purified by chromatography on silica gel.

Example 29D (2-Phenvl-4-r(thiazol-2-vlamino)carbonvlthio Ibenzovl I -methionine The resultant compound from Example 29B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 30 {2-Phenyl-4-[(thien-2-ylmethylamino)carbonylthio]benzoyl}-me thionine Using the procedure of Example 29 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 31 2-Phenyl-4- [(thiazol-2-ylamino)thionylthio]benzoyl I -methionine Example 31A (N-Thionvl)thiazol-2-vlamine 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 {2-Phenyl-4-[(thiazol-2-ylamino)thionylthio]benzoyl}-methion ine methyl ester Using the procedure of Example 29B but replacing the resultant product from Example 29A with the resultant product from Example 31 A affords the title compound.

Example 31C {2-Phenyl-4-[(thiazol-2-ylamino)thionylthio]benzoyl}-methion ine methyl ester, alternate procedure

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

Example 31D {2-Phenyl-4-[(thiazol-2-ylamino)thionylthio]benzoyl}-methion ine The resultant compound from Example 31B is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 32 f 2-Phenvl-4-F(thien-2-vlmethvlamino)thionvlthiolbenzovl )-methionine Using the procedure of Example 31 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.

Example 33 f 2-Phenvl-4-l (thiazol-2-vlamino)sulfonvlthiolbenzovl )-methionine methyl ester Using the procedure of Example 31 but replacing thionyl chloride with sulfuryl chloride affords the title product.

Example 34 {2-Phenyl-4-[(thien-2-ylmethylamino)sulfonylthio]benzoyl}-me thionine 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-Phenyl-4-[(thien-2-ylmethylamino)thiocarbonylthio]benzoyl }-methionine Using the procedure of Example 29 and replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol) and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

Example 37 2-Phenyl-4- r(thiazol-2-vl)thiomethvllbenzovl )-methionine Example 37A {2-Phenyl-4-[thiomethyl]benzoyl}-methionine methyl ester The resultant product from Example 27A is dissolved DMF/water (2/1), and sodium hydrosulfide (5 equivalent) is added to the reaction mixture. The reaction is stirred until TLC analysis shows that the reaction is complete. Then, the reaction mixture is acidified with 3 N HCl 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 {2-Phenyl-4-[thiomethyl]benzoyl}-methionine methvl 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 l h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on silica gel to afford the title product.

Example 37C {2-Phenyl-4-[(thiazol-2-yl)thiomethyl]benzoyl 1 -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 OC until TLC analysis shows that the starting thiol disappeared. Then, the reaction mixture is diluted with water, extracted with ether, and washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography on silica gel to give the title compound.

{2-Phenyl-4-[(thiazol-2-yl)thiomethyl]benzoyl}-methionine The resultant compound from Example 37C is hydrolyzed according to the procedure of Example lB to give the title product.

Example 38 2-Phenyl-4- r(thien-2-vlmethvl)thiomethvllbenzovl -methionine Using the procedure of Example 37 and replacing 2-bromothiazole with 2- bromomethylthiophene affords the title product. Example 39

2-Phenyl-4- {(thiazol-2-vlamino)carbonylthiomethyllbenzovl I -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-Phenyl-4-[(thiazol-2-ylamino)thiocarbonylthiomethyl]benzo yl}-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-Phenyl-4-[(thiazol-2-ylamino)thiocarbonylthiomethyl]benzo yl}-methionine Using the procedure of Example 29 with the resultant product from Example 37A, replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol), and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.

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

Example 44 {2-Phenyl-4-[(thien-2-ylmethylamino)thionylthiomethyl]benzoy l}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}-m ethionine 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 2-Phenyl-4-[(thien-2-ylmethylamino)sulfonylthiomethyl]benzoy l}-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 4- [2-(Imidazol-2-yl)ethynyl}-2-phenylbenzoyl 1 methionine Example 47A (4-Ethvnvl-2-phenylbenzovl)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 {4-12-(Imidazol-2-vl)ethYnvll-2-phenvlbenzovll-methionine methvl ester The resultant product from Example 47A (5 mmol) is mixed with 4-bromoimidazole (5 mmol), diethylamine ( 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 {4-[2-Imidazol-4-yl)ethenyl]-2-phenylbenzoyl}-methionine The resultant acetylene (3 mmol) from Example 47 is mixed with Lindlar catalyst (50 mg), 5 drops of quinoline in ethyl acetate. The reaction mixture is attached to a hydrogenation apparatus, and then is detached from the apparatus after about 95% of the theoretical hydrogen has been absorbed. The reaction mixture is filtered and concentrated in vacuo.

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

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

Example 50 {4-[-(imidazol-4-ylcarbonyl)ethynyl]-2-phenylbenzoyl}-methio nine Example 50A {4-[2-(Imidazol-4-ylcarbonyl)ethynyl]-2-phenylbenzoyl}-methi onine methyl ester

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 OC 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-[2-(Imidazol-4-ylcarbonyl)ethynyl]-2-phenylbenzoyl}-methi onine The resultant compound from Example 50A is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 51 { 4-L2-(Imidazol-4-ylcarbonvl)ethenvll-2-phenYlbenzoYl ) -methionine Using the procedure of Example 48 with the resultant compound from Example 50 affords the title product.

Example 52 {4-[2-(Imidazol-4-ylcarbonyl)ethyl]-2-phenylbenzoyl}-methion ine Using the procedure of Example 49 with the resultant compound from Example 51 affords the title product. Example 53

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

Example 54 4- [4-( 1 -Methylimidazol-4-vl)-3-keto- 1 -butenvll -2-phenylbenzoyl -methionine Using the procedure of Example 48 with the resultant compound from Example 53 affords the title product.

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

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

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

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

Example 57 (S) Pyrnglutamvl-(4-amino-2-phenvl)benzoyl methionine

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

Example 58 (S') Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl methionine Example 58A (S) Pyroglutamyl-(4-aminomethyl-2-phenvl)benzoyl 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 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 58B (S') Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl 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) Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl methionine Using the procedure of Example 58 and replacing pyroglutamic acid with 3-pyridylacetic acid affords the title product.

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

The product is purified by chromatography on silica gel.

Example 60B 4- [(Pvridin-2-vlamino)carbonvll -2-phenvlbenzoyl methionine methvl 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 HCl and saturated brine, and then is dried and evaporated.

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

Example 60C 4-[(Pyridin-2-ylamino)carbonyl]-2-phenylbenzoyl 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-aminomethyl)carbonyl)-2-phenylbenzovl methionine Using the procedure of Example 60 and replacing 2-aminopyridine with (S)-5-aminomethyl- 2-pyrrolidone affords the title product.

Example 62 4- f(Pyridin-2-vlamino)carbonylmethyll -2-phenylbenzoyl methionine Example 62A 4-Diazocarbonvl-2-phenylbenzovl 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-carboxymethyl-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-r(Pvridin-2-ylarnino)carbonvlmethvll-2-phenvlbenzoyl methionine methvl ester To a solution of the resultant acid from Example 62B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-1,2,3-benzotraizin-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 lN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 62D 4- I (Pvridin-2-vlamino jcarbonvlmethvll-2-phenvlbenzovl methionine The resultant compound from Example 62C is hydrolyzed according to the procedure of Example lB to give the title product.

Example 63 4-( (Y)-2-Pyrrolidone-5-aminomethyl)carbonvlmethvl)-2-phenvlbenz oyl 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-Pyrrolidone-5-methoxycarbonyl)amino-2-phenylbenzoy l 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 CuCI (0.1 equivalent).

Example 65 4-((S')-2-Pyrrolidone-5-methoxythiocarbonyl)amino-2-phenylbe nzoyl 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), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 66 4-((S')-2-Pyrrolidone-5-methoxysulfinyl)amino-2-phenylbenzoy l 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 CuC1 (0.1 equivalent).

Example 67 4-C (S)-2-Pvrrolidone-5-methoxysulfonyl)amino-2-phenvlbenzovl methionine

The title compound is prepared as described in Example 4 with the exception that (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0. 1 equivalent).

Example 68 4-(Pvridin-3-vlmercaptocarbonyl)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 3-mercaptopyridine (1.0 equivalent).

Example 69 4-(Pyridin-3-ylmercaptothiocarbonyl)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 3-mercaptopyridine (1.0 equivalent), and triphosgene (0.33 equivalent) is replaced by thiophosgene (1.0 equivalent).

Example 70 4-(Pvridin-3-vlmercaptosulfinvl)amino-2-phenvlbenzovl methionine

The title compound is prepared as described in Example 3 with the exception that (5)-S- 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-phenyl benzoyl 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 CuC1 (0.1 equivalent).

Example 73 4-((S')-2-Pyrrolidone-5-methoxythiocarbonyl)aminomethyl-2-ph enylbenzoyl methionine

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

Example 74 4-((S')-2-Pyrrolidone-5-methoxysulfinyl)aminomethyl-2-phenyl benzoyl 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-Pyrrolidone-5-methoxysulfonyl)aminomethyl-2-phenyb enzoyl methionine The title compound is prepared as described in Example 4 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2-pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).

Example 76

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

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

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

Example 79

4-(pyridin-3-ylmercaptosulfonvl)aminomethyl-2-phenvlbenzovl methionine The title compound is prepared as described in Example 4 using the resultant amine from Example 1 8B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).

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

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

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

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

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

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

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

Example 83 A-NH-SO2-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-SO2-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 (5)-S- 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-SOs-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 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~7-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-terrninal 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-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 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-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 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-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 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-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 8 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A- NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

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

Example 95 A-NH-CS-O-CH~2-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 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 anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to the procedure of Example 12E. These mercaptans are reacted according to the procedure of Example 29 with the exception that 2-aminothiazol is replaced by an amine from Table 3 (A- NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

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

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

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

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

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

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

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

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

Example 100 A-NH-CO-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 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-CHo-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-CH2 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-SO~-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-CO2H). 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-CO2H). 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-methyl-4-imidazoleacetic acid is replaced by an acid from Table 4 (A- CO2H). 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-CH9 C 2-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-CH~-B The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 60A.

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

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

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

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

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

Example 112 A-CH,-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 25 with the exception that 3-pyridinecarboxaldehyde is replaced by an aldehyde from Table 5 (A-C HO). 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-( (£)-2-Pvrrolidone-5-aminomethyl)sulfonvlmethvl)-2-phenylben zovl methionine

Example 113A 4-Thioacetoxvmethvl-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.

Example 11 3B 4-Chlorosulfonvlmethylene-2-phenvlbenzoic acid methvl 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 1 13C 4-((S)-2-Pvrrolidone-5-aminomethvl)sulfonvlmethvlene-2-phenv lbenzoic acid methyl ester To a solution of the resultant compound from Example 1 13B (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-((S)-2-Pvrrolidone-5-aminomethvl)sulfonvlmethvlene-2-phenv lbenzoic acid The resultant compound from Example 11 3C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 113E 4-((S)-2-Pvrrolidone-S-aminomethyl)sulfonvlmethvlene-2-phenv lbenzoal methionine methyl ester To a solution of the resultant compound from Example 11 3D (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy- I ,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 lN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.

Example 113F 4-((S').2.PyrrOlidone-5-aminomethyl)sulfonylmethylene-2-phen ylbenzoyl 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~,-CH2-B The procedure of Example 113 is used with the exception that (S)-5-aminomethyl-2- pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products derived from amines 146-206 from Table 3, the final LiOH hydrolysis step also hydrolyzes the ester on the fragment of the final compound that is derived from amines 146-206.

Example 115 4-( (£)-2-Pvrrolidone-5-aminomethyl)sulfonylmethyl)-2-phenylben zovl leucine Example 115A 4-(Hvdroxvmethvl!-2-phenvlbenzovl leucine methyl ester (2-phenyl-4-bromobenzoyl)-leucine methyl ester is reacted according to the procedures of Example 16F-G.

Example 1 15B 4-Thioacetoxvmethvl-2-phenvlbenzovl leucine 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 115A (1. equivalent) in THF. The

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

Example 115C 4-Chlorosulfonylmethvlene-2-phenvlbenzovl leucine methyl ester The resultant compound from Example 1 15B 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 11 SD 4-((S)-2-Pyrrolidone-5-aminomethyl)sullonylmethylene-2-pheny lbenzoyl leucine methyl ester To a solution of the resultant compound from Example 1 15C (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-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylene-2-pheny lbenzoyl 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~-CH2-B 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-phenylbenzoyl 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 1 17B 4-(2-Thiazolvl)-2-phenvlbenzovl methionine methvl 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-phenvlbenzoyl methionine The resultant compound from Example 1 17C is hydrolyzed according to the procedure of Example 1B to give the title product.

Example 118 4-(2-Thiazolylcarbonvl)-2-phenvlbenzoyl methionine

Example 1 18A 4-(2-Thiazolylcarbonyl)-2-phenvlbenzoyl methionine methyl ester A mixture of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), 2-thiazole boronic acid from Example 1 17A (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-Thiazolvlcarbonvl!-2-phenvlbenzovl methionine The resultant compound from Example 118A is hydrolyzed according to the procedure of Example lB to give the title product.

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

Example 1 19B 4-Isocvanatosulfonvl-2-phenvlbenzovlmethionine methyl ester A mixture of the resultant sulfonamide from Example 1 19A 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 1 19C 4-{(A-aminopyridyl)carbonvlaminosullonyll-2-phenylbenzoylmet hionine methyl ester A mixture of the resultant isocyanate from Example 1 19B (1 equivalent) in dichloromethane is treated with 3-aminopyridine (1 equivalent) and stirred until the reaction is judged complete by tic analysis. The solvent is evaporated and the product is purified by chromatography on silica gel.

Example 11 9D 4-[(A-aminopvridyl)carbonylaminosulfonyll-2-phenvlbenzovlmet hionine The resultant compound from Example 119C is hydrolyzed according to the procedure of Example lB 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~-CH2 B 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 (S)-5- aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1:1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

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

Example 124 A-O-CS-NH-B

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

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

Example 126 A-O-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 an alcohol from Table 6 (A-OH,

1.0 equivalent) and CuCl (0. 1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert- butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1:1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

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

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

This example also encompasses compounds comprising a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the bromides in Table 2 are replaced by the corresponding ethyl, 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 CuCl (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-CH The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 3 with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by an alcohol from Table 6 (A-OH, 1.0 equivalent) and CuCl (0.1 equivalent). For products derived from alcohols 280-359 and 408-431 from Table 6, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1:1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

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

Example 130 A-O-SO~-NH-CH2 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 methfonine 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-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 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-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 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-SO~-NH-CH~-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18A-B. The resultant amines are reacted according to the procedure of Example 4 with the exception that (S)-5-aminomethyl-2-pyrrolidone 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 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 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-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 28 with the exception that 3-chloromethylpyridine hydrochloride is replaced by a halide from Table 8 (A-Cl, A-Br, or A-I). For products derived from halides 202-239 from Table 8, the LiOH hydrolysis step is followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirring the resultant compound from the LiOH hydrolysis step in a 1:1 mixture of dichloromethane and trifluoroacetic acid until TLC analysis indicates that the reaction is complete. The solvent is evaporated and the residue is purified by chromatography on silica gel.

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

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

For products derived from halides 202-239 from Table 8, the 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-C-C-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-CH2-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-CH2SO2 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-SO2-CHs 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-[(3-sulfonylmethylpvridvl)aminol-2-phenvlbenzoyl 1 methionine Example 154A <BR> <BR> t 4- 1 r(3-sulfonvlmethvlDvridvl)aminol -2-phenylbenzoyl t methionine methyl ester

A mixture of 3-chlorosulfonylmethylpyridine hydrochloride (1.0 equivalent) and (4-amino- 2-phenylbenzoyl)methionine methyl ester (1.0 equivalent) in dichloromethane is treated with triethylamine (2.2 equivalents). When judged complete by TLC analysis, the reaction is diluted with ethyl acetate, and then is washed with pH 4 water, saturated NaHCO3 and brine. The mixture is dried and concentrated to give the crude title compound which is purified by chromatography on silica gel.

Example 1 54B { 4-l (3-sulfonvlmethvlpvridvl)aminol-2-phenvlbenzovl } methionine The resultant compound from Example 154A is hydrolyzed according to the procedure of Example lB to give the title product.

Example 155 A-CH2SO9-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-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 154 with the exception that -chlorosulfonylmethylpyridine hydrochloride is replaced by a sulfonyl chloride from Table 9 (A-SO2Cl).

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 162 4-(thiazo-4-vlmethylcarbonvl)amino-2-phenvlbenzovllmethionin e Example 162A Thioformamide To a mechanically-stirred solution of formamide (4.0 mL, 100 mmol) in THF (45 mL) was added P4SIo (4.5 g, 10.1 mmol) while the reaction mixture was maintained at <37 °C using an ice-water bath. The reaction mixture was then stirred for 5.5 hours at ambient temperature. The reaction mixture was filtered through a pad of celite and the filter cake was washed with THF. The filtrate was concentrated and in vacuo and then under high vacuum for 4 hours to give thioformamide which was used without further purification.

Example 162B Ethvl 4-bromoacetoacetate To a mechanically-stirred solution of ethyl acetoacetate (59 mL, 463 mmol) in ether (75 mL) was added bromine (23.5 mL, 912 mmol) while the reaction temperature was maintained below 23 °C using an ice-water bath. The yellow-orange solution was stirred for 5 hours with cooling and then was stirred overnight at ambient temperature. Ice (60 g) was added and the reaction mixture was extracted with ether. The organic phase was washed twice with aqueous NaHCO3 saturated with NaCl and once with brine. The ether solution was stirred for 1 day over CaCl2 and then was filtered through celite. The filter cake was rinsed withdichloromethane. The filtrate was concentrated in vacuo to give ethyl 4- bromoacetoacetate (71.5 g) which was stored in the dark and stabilized with BaCO3 (300 mg).

Example 162C Ethvl 4-Thiazolvlacetate To a solution in absolute ethanol (18 mL) of ethyl 4-bromoacetoacetate (7.0 mL, 10.4 g, 49.7 mmol), prepared as in Example 162B, was added a solution in absolute ethanol/dioxane/toluene of thioformamide (4 g, 65 mmol), prepared as in Example 162A,

while the reaction temperature was maintained below 35 "C using an ice-water bath. The reaction mixture was stirred at reflux for 30 minutes, and then was cooled to ambient temperature. The reaction mixture was poured into aqueous 2N HCl (210 mL) and extracted twice with ether. The organic extracts were discarded and the aqueous phase was taken to ph 7-8 with NaHCO3. The aqueous phase was extracted twice with ether. The ether extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 4.7 g of a dark oil. The oil was distilled at 20 mm Hg to give ethyl 4-thiazolylacetate (2.5 g, bp 111-122 "C) as light- yellow oil.

Example 162D 4-Thiazoylacetic acid A mixture of ethyl 4-thiazolylacetate (2.4 g, 14 mmol), prepared as in Example 162C, and aqueous 10% NaOH was stirred for 10 minutes at ambient temperature. The reaction mixture was cooled to 0 "C and taken to pH 2-3 with concentrated HC1. The resulting white solid was filtered, washed with water and dried under high vacuum in the presence of P205 to give 4-thiazoylacetic acid (905 mg).

Example 162E {4-(thiazo4-vlmethylcarbonvl)amino-2-phenylbenzovllmethionin e methyl ester To a suspension in dichloromethane (10 mL) of 4-thiazolylacetic acid (460 mg, 3.22 mmol), prepared as in Example 162D was added oxalyl chloride (300 uL, 3.44 mmol) and DMF (5 mL). The mixture was stirred for 1.5 hours after bubbling ceased, and then was added over 5 minutes to a 5 "C 2-phase mixture of 4-amino-2-phenylbenzoyl methionine methyl ester (compound 8, 1.2 g, 3.2 mmol) in diclhloromethane (12 mL) and saturated aqueous NaHCO3 (15 mL). The cold bath was removed and the reaction mixture was stirred for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a dark-brown residue (1.0 g). Chromatography on silica gel (10% ethyl acetate hexane) gave [4-(thiazo-4-ylmethylcarbonyl)amino-2-phenylbenzoyl]methioni ne methyl ester (581 mg) as a light-yellow powder.

Example 162F 14-(thiazo-4-ylmethylcarbonvl)amino-2-phenylbenzovllmethioni ne The desired compound was prepared by saponification of [4-(thiazo-4- ylmethylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 162E, using lithium hydroxide hydrate according to the method of Example 159. 1H NMR (300 MHz, DMSO-d6) 6 10.42 (s, 1H), 9.06 (d, 1H), 8.43 (d, 1H), 7.70 (d, lH), 7.63

(dd, 1H), 7.52 (d, 1H), 7.40 (d, 1H.), 7.35 (m, SH), 4.28 (m, 1H), 3.90 (s, 2H), 2.25 (m.

2H), 2.00 (s, 3H), 1.86 (m, 2H); MS (DCI-NH3) m/e 470 (M+H)+. Anal calcd for C23H23N304S2: C, 58.83; H, 4.94; N, 8.95. Found: C, 58.44; H, 4.87; N, 8.58.

Example 163 [4-(thiazoi-2-vlmethylcarbonyl)amino-2-phenylbenzoylmethioni ne Example 1 63A 3-bromosuccinaldehydic acid ethyl ester To a 0-5 "C mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3:9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101 "C) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%).

Example 163B Ethvl 2-thiazolyl acetate To a slurry of thioformamide (3.9 g, 64 mmol) in diethyl ether (40 mL) and tetrahydrofuran (15 mL) was added 3-bromo-succinaldehydic acid ethyl ester (10.6 g, 51 mmol), prepared as in Example 163A. The reaction mixture was heated at reflux for 30 minutes, then ethanol (50 mL) was added, 30-40 mL of ether was distilled off, and the reaction mixture was heated at reflux for one hour. The reaction mixture was cooled to ambient temperature and aqueous 2N HCl (200 mL) was added. The mixture was extracted twice with ether. The aqueous phase was taken to pH 7-8 with NaHCO3 (40 g) and was extracted with ether and twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil which was purified by distillation (3 mm Hg, bp 109-111 "C) to give ethyl 2-thiazolyl acetate (2.15 g).

Example 163C 2-Thiazolvl acetic acid

Ethyl 2-thiazolyl acetate (2.35 g, 13.7 mmol), prepared as in Example 163B, was added to 10% aqueous KOH. After about 10 minutes all of the uil dissolved to give a clear, bright-yellow solution. The reaction mixture was cooled to 0 °C and the pH was adjusted to 2-3 using concentrated HCI. The resulting solids were filtered off, rinsed with water, and dried over P2O5 under high vacuum to give 2-thiazolyl acetic acid (1.44 g).

Example 163D [4-(thiazo-2-ylmethylcarbonyl)amino-2-phenylbenzoyl]methioni ne methyl ester To a solution in DMF (4 mL) of 2-thiazolyl acetic acid (300 mg, 2. 1 mmol), prepared as in Example 163C, was added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (373 mg, 2.3 mmol) followed by ethyl dimethylaminopropyl carbodiimide hydrochloride (442 mg, 2.3 mmol), and a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (compound 8, 760 mg, 2.0 mmol) in dichloromethane (3 mL) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed saturated aqueous NaHCO3 (2x) and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a brown solid (1.12 g).

Chromatography on silica gel (ethyl acetate) gave [4-(thiazol-2-ylmethylcarbonyl )amino-2- phenylbenzoyl]methionine methyl ester (600 mg).

Example 163E [4-(thiazol-2-ylmethylcarbonyl)amino-2-phenylbenzoyl]methion ine The desired compound was prepared by. saponification of [4-(thiazo-2- ylmethylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 163D) using the procedure of Example 159. 1H NMR (300 MHz, DMSO-d6) 6 10.50 (s, lH), 9.00 (d, lH), 8.45 (d, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 7.42 (d, 1H), 7.38 (m, 5H), 4.28 (m, 1H), 4.01 (s, 2H), 2.25 (m, 2H), 2.00 (s, 3H), 1.86 (m, 2H); MS (DCI-NH3) m/e 470 (M+H)+. Anal calcd for C23H23N304S2 H2O: C, 56.66; H, 517; N, 8.62. Found: C, 56.75; H, 4.96; N, 8.45.

Example 164 [4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methi onine methyl ester hvdrochloride Example 164A N-tert-butoxvcarbonvl-(R!-(-!thiazolidine-4-carboxvlic acid To a solution of (R)-(-)-thiazolidine-4-carboxylic acid (1.0 g, 7.5 mmol) in aqueous lN NaOH (9 mL) and THF (9 mL) was added a solution of di-tert-butyldicarbonate (1.62 g, 7.4 mmol) in THF (9 mL). An additional 2 mL of aqueous NaOH was added and the reaction mixture was stirred overnight at ambient temperature. Additional aqueous NaOH was added to make a clear solution and the reaction mixture was washed with hexanes (3x).

The hexane extracts were washed twice with saturated aqueous NaHCO3. The combined aqueous layers were acidified to pH 2 with 1.1 M NaHSO4 and extracted twice with ether.

The combined ether layers were dried over Na2SO4, filtered, and concentrated in vacuo to give N-tert-butoxycarbonyl-(R)-(-)thiazolidine-4-carboxylic acid (1.3 g) which was used without further purification.

Example 164B <BR> <BR> <BR> 14-(N-tert-butoXvcarbonel-(R!-thiazolidin-4-ylcarbonyl!amino -2-phenVlbenzovllmethionine methyl ester The desired compound was prepared by coupling of N-tert-butoxycarbonyl-(R)-(- )thiazolidine-4-carboxylic acid, prepared as in Example 164A with [4-amino-2- phenylbenzoyl]methionine methyl ester (compound 8) according to the method of Example 163D.

Example 164C [4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methi onine methyl ester hvdrochloride To a mixture of [4-(N-tert-butoxyCarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino -2- phenylbenzoyl]methionine methyl ester (270 mg, 0.47 mmol) and thiophenol (0.1 mL, 0.97 mmol) was added 4N HCl-dioxane (10 mL) and the reaction mixture was stirred for 45

minutes at ambient temperature. The reaction mixture was partitioned between water and ether. The aqueous phase was extracted with ether. The organic extracts were discarded and the aqueous phase was lyophilized to give [4-((R)-thiazolidin-4-ylcarbonyl)amino-2- phenylbenzoyl] methionine methyl ester hydrochloride (150 mg). 1H NMR (300 MHz, DMSO-d6) 6 10.53 (s, 1H), 8.45 (d, 1H), 7.68 (m, 2H), 7.42 (dd, lH), 7.37 (m, SH), 4.27 (m, 4H), 3.70, 3.25, 3.12 (all m, total 3H), 2.24 (m, 2H), 2.00 (s, 3H), 1.85 (m, 2H); MS (APCI) m/e 474 (M+H)+. Anal calcd for C23H28C1N304S2. 1 .4H2O: C, 51.61; H, 5.80; N, 7.85. Found: C, 51.67; H, 5.55; N, 7.28.

Example 165 [4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methi onine To a 0 °C solution in methanol (4.3 mL) of [4-((R)-thiazolidin-4-ylcarbonyl)amino-2- phenylbenzoyl]methionine methyl ester hydrochloride (75 mg, 0.15 mmol) was added a solution of lithium hydroxide hydrate (18 mg, 0.43 mmol) in water (0.5 mL). The reaction mixture was stirred for 1.5 hours, then the cold bath was removed and stirring was continued overnight at ambient temperature. The reaction mixture was concentrated in vacuo and aqueous 2N HCl was added to the residue. The cloudy solution was extracted with ethyl acetate and chloroform-isopropanol. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4[-((R)-thiazolidine-4- carbonyl)amino-2-phenylbenzoyl]methionine (67 mg). tH NMR (300 MHz, DMSO-d6) 611.10(s, 1H), 8.60 (d, 1H), 7.70 (s, 1H), 7.68 (dd, 1H), 7.44 (dd, 1H), 7.37 (m, 5H), 4.63 (m, 1H), 4.37 (m, 3H), 3.70 (m, 1H), 3.63 (s, 3H), 3.40 (m, 1H), 2.24 (m, 2H), 2.00 (s, 3H), 1.85 (m, 2H); MS (APCI) m/e 460 (M+H)+. Anal calcd for C22H25N3O4S20.8 HCl: C, 54.06; H, 5.32; N, 8.60. Found: C, 54.21; H, 5.34; N, 8.00.

Example 166 14-((R)-thiazolidin-4-ylmethvl!amino-2-phenYlbenzoYllmethion ine hvdrochloride Example 166A N-tert-butoxvcarbonyl-(R)-(-)thiazolidine-4-carboxYlic acid-N-methoxy-N-methvl amide To a solution in DMF (10 mL) of N-tert-butoxycarbonyl-(R)-(-)thiazolidine-4- carboxylic acid (777 mg, 3.33 mmol), prepared as in Example 164A, 3-hydroxy-1,2,3- benzotriazin-4(3H)-one (602 mg, 3.69 mmol), and ethyl dimethylaminopropyl carbodiimide hydrochloride (709 mg, 3.70 mmol) was added N, O-dimethylhydroxylamine hydrochloride (357 mg, 3.66 mmol) and 4-methylmorpholine (0.44 mL, 4.01 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and extracted with aqueous 1M H3PO4 (2x), saturated aqueous NaHCO3 (2x), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo.

Chromatography on silica gel 1 hexane-ethyl acetate) gave N-tert-butoxycarbonyl-(R)-(- )thiazolidine-4-carboxylic acid-N-methoxy-N-methyl amide (605 mg) as a thick yellow oil.

Example 1 66B N-tert-butoxvcarbonvl-(R!-(-!thiazolidine-4-carboxaldehyde To a -78 "C solution in THF (6 mL) of N-tert-butoxycarbonyl-(R)-(-)thiazolidine-4- carboxylic acid-N-methoxy-N-methyl amide (550 mg, 2.0 mmol) was added lithium aluminum hydride (1.0 M in THF, 3.0 mL, 3.0 mmol) and the reaction mixture was stirred for 2.5 hours. The reaction was quenched with 10% aqueous citric acid (30 mL) and warmed ambient temperature. The mixture was warmed to ambient temperature and extracted with ether (3x). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-tert-butoxycarbonyl-(R)-(- )thiazolidine-4-carboxaldehyde (440 mg) which was used without further purification.

Example 166C [4-(N-tert-butoxycarbonyl-(R)-thiazolidin-4-ylmethyl)amino-2 -phenylbenzoyl]methionine methvl ester N-tert-butoxycarbonyl-(R)-(-)thiazolidine-4-carboxaldehyde was reductively aminated with 4-amino-2-phenylbenzoyl methionine methyl ester (compound 8) according to the procedure of Example 158B.

Example 166C [4-((R)-thiazolidinA-vlmethyl)amino-2-phenylbenzoyllmethioni ne methvl ester The desired compound was prepared according to the method of Example 164C, except substituting [4-(N-tert-butoxycarbonyl-(R)-thiazOlidin-4-ylmethyl)amino-2 - phenylbenzoyl]methionine methyl ester, prepared as in Example 166B, for [4-(N-tert- butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbe nzoyl]methionine methyl ester.

Example 166D [4-((R)-thiazolidin-4-yLmethyl)amino-2-phenylbenzoyl]methion ine hydrochloride The desired compound was prepared by saponification of [4-((R)-thiazolidin-4- ylmethyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example l66C according to the procedure of Example 165. 1H NMR (300 MHz, DMSO-d6) 68.03 (d, 1H), 7.33 (m, 6H), 6.69 (dd, 1H), 6.59 (d, 1H), 4.30 (dd, 2H), 4.23 (m, 1H), 3.86 (m, 1H), 3.46 (dd, 2H), 3.22 (dd, 1H), 2.91 (m, 1H), 2.24 (m, 2H), 2.00 (s, 3H), 1.85 (m, 2H); MS (APCI) m/e 446 (M+H)+, 444 (M-H)-. Anal calcd for C22H27N303S2HC10.25H2O: C, 54.31; H, 5.90; N, 8.64. Found: C, 54.20; H, 6.07; N, 8.35.

Example 169 14-(4-hvdroxv-prolinvl!amino-2-phenvlbenzovllmethionine trifluoroacetate Example 169A

N-Boc-4-(t-butyldimethylsilyl)hydroxyproline To a solution of 1.3 g (3.6 mmol) of N-Boc-4-(t-butyldimethylsilyloxy)proline methyl ester, prepared as described by Rosen et al., J. Med. Chem. 1988, 31, 1598, in 10 ml methanol was added 5 ml (5 mmol) of l N LiOH in an ice bath. The reaction mixture was stirred for 30 min. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned between 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 1.05 g (96 %) of N-Boc-4-(t- butyldimethylsilyl-oxy)proline as a foamy solid which was used without further purification.

Example 169B 4- [N-Boc-4-(t-butyldimethylsilyloxy)prolinyl]amino-2-phenylben zoyl )methionine methyl ester To a solution in dichloromethane (15 mL) of N-Boc-4-(t- butyldimethylsilyloxy)proline (1.0 g, 3.29 mmol), prepared as in Example 169A, was added 550,u 1(3.9 mmol) of triethylamine in an ice bath under argon, followed by 470,u 1(3.6 mmol) of isobutyl chlroformate. The reaction mixture was stirred for 40 minutes. At this time TLC showed the absence of the starting material. To this solution, 1.07 g (2.97 mmol) of [2-phenyl-4-aminobenzoyl]methionine methyl ester (compound 8) in 10 ml of dichloromethane was introduced. The reaction mixture was stirred overnight, during which time the ice bath expired. The reaction mixture was washed with 1 N HCl, 5 % sodium bicarbonate, and water, dried over magnesiun sulfate, and solvent was removed. The residue was flash-chromatographed on silica gel (7:3 hexanes-ethyl acetate) to yield 1.92 g (94 %) of {4-[N-Boc-4-(t-butyldimethylsilyl)hydroxyprolinyl]-2- phenylaminobenzoyl}methionine methyl ester as a foamy solid. mp 83 OC; [(X]25D -36.2 (c=0.63, CHC13); 1H NMR (300 MHz, CDCl3) 6 9.94 (s, 1H), 7.53-7.26 (m, 8H), 6.41 (d, 1H, J=6 OHz), 4.55 (m, 4H), 3.63 (s, 3H), 3.57 (m, 1H), 3.32 (m, 1H), 2.30 (m, lH), 2.05 (m, 2H), 1.94 (s, 3H), 1.83 (m, 1H), 1.73 (m, 1H), 1.45 (s, 9H), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (CDC13) 6 171.8, 170.7, 169.3, 155.6, 140.0, 129.7, 129.0, 128.5, 128.2, 127.4, 120.2, 117.7, 80.7, 77.2, 70.1, 59.5, 54.7, 52.1, 51.7, 38.0, 30.9, 29.5, 28.2, 25.5, 17.7, 15.1, 4.9; HRMS (EI) calculated for C35H51N3O7SSi: 685.9498, found: 685.3217.

Example 169C [4-(N-Boc-4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine methyl ester

To a solution of 1.82 g (2.65 mmol) of {4-[N-Boc-4-(t-butyldimethylsilyloxy)- prolinyl]amino-2-phenylbenzoyl}methionine methyl ester, prepared as in Example 169B, in 20 ml of THF was added 3 ml (3 mmol) of 1 M tetra-n-butylammoniun floride in THF. The reaction mixture was stirred overnight, diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo.

The crude product was purified by flash chromatography on silica gel (ethyl acetate) to obtain 864 mg (57 %) of [4-(N-Boc -4-hydroxyprolinyl)amino-2-phenylbenzoyl] methionine methyl ester as a white solid: mp 121-123 OC; [ol]25D-53.3 (c=0.43, CHCl3); 1H NMR (300 MHz, CDCl3) 6 9.84 (s, lH), 7.60-7.38 (m, 8H), 6.35 (br s, lH), 4.58-4.51 (br s, 4H), 3.64 (s, 3H), 3.57 (m, 1H), 3.48 (m, lH), 2.63 (m, lH), 2.44 (br s, lH), 2.07 (m, 2H), 1.98 (s, 3H), 1.86 (m, 1H), 1.72 (m, lH), 1.44 (s, 9H); HRMS (EI) calculated for C29H37N3O7S: 571.6872, found: 571.2352.

Example 169D 14-(4-hvdroxvprolinvl)amino-2-phenvlbenzovllmethionine trifluoroacetate To a solution of 358 mg (0.62 mmol) of [4-(N-Boc-4-hydroxyprolinyl)amino-2- phenylbenzoyl]methionine methyl ester, prepared as in Example 169C, in 6 ml of methanol was added 1 ml (1 mmol) of 1 N LiOH in an ice bath and the reaction mixture was stirred for 4 hours. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned between chloroform and water and extracted 3 times with chloroform. The combined organic solution was washed with 1 N HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 317 mg (92 %) of [4-(4-hydroxyprolinyl)amino-2- phenylbenzoyl]methionine as a white solid. To a 5 ml of 1:1 solution of TFA and dichloromethane was added 306 mg (0.54 mmol) of the acid. After 3 hours, the reaction mixture was thoroughtly evaporated under high vacuum to give an oily residue. The residue was triturated with anhydrous ether and the white solid was collected by filtration to give 254 mg (72%) of [4-(4-hydroxyprolinyl)amino-2-phenylbenzoyli methionine trifluoroacetate: HPLC 90 % (purity); mp 127 (sub.), 154-157 OC (dec.); 1H NMR (300 MHz, CDCl3 + CD3OD) 6 7.53-7.29 (m, 8H), 4.67 (m, 1H), 4.58 (s, 1H), 4.50 (m, 1H), 2.57 (m, 1H), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, 1H), 1.76 (m, 1H); 13C NMR (CD30D) 6 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 119.3, 71.2, 60.6, 55.2, 52.9, 39.9, 31.4, 30.9, 15.0.

Example 170 [4-((2S,4S)-4-mercaptopyrrolidin-2-carboxy)amino-2- phenylbenzoyllmethionine trifluoroacetate Example 170A <BR> <BR> <BR> 14-((2S*4S)- l-Boc-4-acetvlthiopvrrolidin-2-carboxv)amino-2-phenvlbenzovl lmethionine methyl ester To a solution of 140 mg (0.22 mmol) of {4-[N-Boc-4-(t-butyldimethylsilyloxy)- prolinyl]amino-2-phenylbenzoyl methionine methyl ester, prepared as in Example 169C, in 10 ml of THF was added 128 mg (0.48 mmol) of triphenylphosphine, followed by 96 1(0.49 mmol) of diisopropyl azodicarboxylate at 0 OC under argon atmosphere. The reaction mixture was stirred for 40 minutes and 35 ul (0.49 mmol) of thiolacetic acid was added to this mixture at the same temperature. The reaction mixture was stirred overnight, during which time the ice bath expired. The solvent was removed, and a 3:1 solution of hexanes and ethyl acetate was introduced to the resulting residue to precipitate the insoluble by-products. After removal of by-products, the solution was concentrated. The crude product was chromatographed on silica gel (3:1 hexanes-ethyl acetate) to yield 123 mg (89 %) of [4-((2S,4S)-l-Boc-4-acetylthiopyrrolidin-2-carboxy)amino-s- phenylbenzoyl]methionine methyl ester as a foamy solid: mp 97 OC; [α]D25 -105.2 (c=0.27, CHCl3); IH NMR (300 MHz, CDC13) 9.87 (s, 1H), 7.68-7.38 (m, 8H), 6.37 (s, 1H), 4.58 (br s, 4H), 4.02 (m, 1H), 3.64 (s, 311), 3.33 (br s, 1H), 2.52 (br s, 1H), 2.30 (s, 3H), 2.03 (t, 2H, J=7.8Hz), 1.99 (s, 3H), 1.90 (m, 1H), 1.74 (m, 1H), 1.45 (s, 9H); 13C NMR (CDC13) 6 195.5, 172.2, 169.9, 169.3, 169.0, 155.3, 140.3, 140.0, 130.2, 129.2, 128.7, 128.4, 127.7, 120.6, 117.9, 81.6, 60.2, 53.2, 52.3, 51.9, 39.3, 34.0, 31.2, 30.5, 29.6, 28.3, 15.2; MS (EI) m/z (relative intensity) 629 (M+, 6), 571 (25), 529 (45), 196 (100).

Example 170B [4-((2S,4S)-4-mercaptopyrrolidin-2-carboxy)amino-2-phenylben zoyl]methionine trifluoroacetate

To a solution of 120 mg (0.19 mmol) of [4-((2S,4S)-1-Boc-4-acetylthiopyrrolidin-2- carboxy)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 170A, in 5 ml of THF was added 1 ml (1 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 between 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 105 mg (94 %) of [4-((2S,4S)-4-thiopyrrolidin-2- carboxy)amino-2-phenylbenzoyl]methionine as a white solid. To 5 ml of a 1:1 solution of TFA and dichloromethane were added 105 mg (0.17 mmol) of the acid, followed by a few drops of triethylsilane. After 30 minutes, the reaction mixture was thoroughtly evaporated in high vacuum to give an oily residue. The residue was triturated with anhydrous ether and the white solid was collected by filtration to give 90 mg (80%) of [4-((2S,4S)-4-thiopyrrolidin- 2-carboxy)amino-2-phenylbenzoyl]methionine trifluoroacetate: HPLC 86 % (purity); mp 169 OC (dec.); 1H NMR (300 MHz, CD30D) 6 7.59-7.28 (m, 8H), 4.39 (m, 2H), 3.53 (m, lH), 3.38 (m, lH), 3.22-3.12 (m, 2H), 2.87 (m, 1H), 2.12 (m, 1H), 2.00-1.92 (m, SH), 1.72 (m, lH); 13C NMR (CD30D) 5 175.0, 172.7, 167.5, 142.6, 140.7, 133.4, 130.2, 129.8, 129.7, 129.0, 122.5, 119.5, 61.8, 55.3, 53.2, 41.1, 36.2, 31.6, 31.1, 15.3.

Example 171 [4-((2S,4R)-4-hydroxypyrrolidin-2-ylmethyl)amino-2-phenylben zoyl]methionine hvdrochloride Example 171A (2S,4R)-1-Boc-4-[[t-butyldimethylsilyloxy]-2-(hydroxymethyl) pyrrolidine A suspension of calcium chloride (780 mg, 7 mmol) and 530 mg (14 mmol) of sodium borohydride in 25 ml of THF was stirred at ambient temperature for 5 hours. To this suspension was added 2.5 g (7 mmol) of (2S,4R)-1-Boc-4-[(t-butyldimethylsilyl)oxy]-2- (carbomethoxy)pyrrolidine methyl ester in 5 ml of THF and the reaction mixture was stirred overnight. Excess hydride was destroyed by adding hydrated sodium sulfate. The white

precipitate was removed by suction filtration through a pad of Celite, and the filtrate was dried over magnesium sulfate and concentrated to give 2.25 g (97 %) of (2S,4R)-l-Boc-4- [(t-butyldimethylsilyl)oxy]-2-(hydroxymethyl)pyrrolidine as an colorless oil: 1H NMR (CDCl3) 5 0.05 (s, 6H), 0.85 (s, 9H), 1.47 (s, 9H), 1.90 (m, 1H), 3.27-4.25 (complex m, 7H), 4.89 (br d, lH, J=6.6 Hz): MS (EI) m/z 332 (M+), 258.

Example 171B (2S,4R)- 1 -Boc-4- {t-butyldimethvlsilvloxvlpyrrolidin-2-aldehvde To a solution of 1 ml (14.1 mmol) of DMSO in 7 ml of dichloromethane were added 1.48 ml (10.4 mmol) of trifluoroacetic anhydride in 3.5 ml of dichloromethane at -78 OC under a slight stream of argon. After 10 min, 2.35 g (7 mmol) of (2S,4R)- 1-Boc-4-{t- butyldimethylsilyloxy]-2-(hydroxymethyl)pyrrolidine, prepared as in Example 171A, in 7 ml of dichloromethane was added to this mixture at the same temperature. The reaction mixture was stirred for 1 hour. To this solution was added 3 ml (21.5 mmol) of triethylamine. The reaction mixture was stirred for 1 hour at -78 OC, slowly warmed to room temperature, and concentrated. The residue was chromatographed on silica gel (9:1 hexanes-ethyl acetate to yield 1.08 g (47 %) of (2S,4R)- 1-Boc-4-[t-butyldimethylsilyloxy]-pyrrolidin-2-aldehyde as an oil: 1H NMR (300 MHz, CDC13) 9.39 (s, 1H), 4.33 (m, 1H), 4.17 (m, 1H), 3.48 (m, 1H), 3.35 (m, 1H), 1.93 (m, 2H), 1.41 (s, 9H), 0.82 (s, 9H), 0.07 (s, 6H).

Example 171C [4-[(2S,4R)-1-Boc-t-butyldimethysilyloxy]pyrrolidin-2-ylmeth yl)amino-2- phenylbenzoyl]methionine methyl ester To a solution of 0.75 g (2.09 mmol) of [2-phenyl-4-aminobenzoyl]methionine methyl ester (compound 8) and 0.7 g (2.1 mmol) of (2S,4R)-1-Boc-4-[t- butyldimethylsilyloxy]-pyrrolidin-2-aldehyde, prepared as in Example 171B, in 10 ml of methanol were added 1 ml of acetic acid, followed by 0.2 g (3.1 mmol) of sodium cyanoborohydride. The reaction mixture was stirred overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5 % sodium bicarbonate, and extracted 3 times with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesiun sulfate, and solvent was removed. The residue was flash- chromatographed on silica gel (2:1 hexanes-ethyl acetate) to yield 261 mg (74 %) of (4- [(2S,4R)- 1 -Boc-4-(t-butyldimetylsilyl)oxypyrrolidin-2-ylmethyl] amino-2- phenylbenzoyl}methionine methyl ester as a white solid: mp 48 OC; [α]D25 -15.6 (c=1.03, CHCl3); 1H NMR (300 MHz, CDCl3) 5 7.67 (d, 1H, J=8.5 Hz), 7.37 (m, 6H), 6.57 (1, 1H), 6.37 (s, 1H), 5.60 (br s, 2H), 4.60 (m, 1H), 4.31 (m, 2H), 3.77 (s, 3H), 3.61-3.10 (m, 5H), 2.06 (t, 2H, J=8.2 Hz), 1.98 (s, 3H), 1.85 (m, 1H), 1.60 (m, 1H), 1.43 (s, 9H);

0.84 (s, 9H), 0.03 (s, 6H); HRMS (EI) calculated for C35H53N306SSi: 671.3424, found: 671.3424.

Example 171D [4-((2S,4R)-N-Boc-4-hydroxy]pyrrolidin-2-ylmethyl)amino-2-ph enylbenzoyl]methionine methyl ester To a solution of 770 mg (1.14 mmol) of (4-[(2S,4R)-1-Boc-4-(t- butyldimethylsilyloxy)-pyrrolidin-2-ylmethyl]amino-2-phenylb enzoyl}methionine methyl ester, prepared as in Example 171C, in 10 ml of THF was added 2 ml (2 mmol) of 1 M tetra- n-butylammoniun fluoride in THF. The reaction mixture was stirred for 15 minutes at ambient temperature, diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (ethyl acetate) to obtain 467 mg (73 %) of 2-[4-((2S,4R)-N-Boc-4-hydroxypyrrolidin-2-ylmethyl)amino-2- phenylbenzoyl]methionine methyl ester as a foamy solid: mp 81 OC; [OC]24D -15.9 (c=0.74, CHCl3); 1H NMR (300 MHz, CDC13) 6 7.63 (d, lH, J=9.0 Hz), 7.35 (m, 6H), 6.57 (br s, 1H), 6.38 (br s, lH), 5.67 (d, lH, J=7.6 Hz), 5.54 (br s, 1H), 4.55 (m, 1H), 4.09 (m, 2H), 3.59 (s, 3H), 3.37-3.16 (m, 5H), 2.71 (br s, lH), 2.04(m, 2H), 1.96 (s, 3H), 1.80 (m, 1H), 1.60 (m, lH), 1.40 (s, 9H); 13C NMR (CDC13) 6 172.0, 168.5, 156.4, 150.0, 141.7, 141.1, 131.3, 128.6, 127.7, 121.8, 113.5, 110.8, 80.2, 69.5, 69.1, 60.3, 55.3, 54.8, 52.2, 51.7, 49.0, 38.6, 31.5, 29.4, 28.3, 25.5, 15.2; HRMS (EI) calculated for C29H39N306S: 557.2559, found: 557.2559.

Example 171E 14-((2S!4R)-N-Boc-4-hvdroxvpvrrolidin-2-vlmethvl)amino-2-phe nvlbenzovllmethionine hvdrochloride To a solution of 125mg (0.22 mmol) of [4-((2S,4R)-N-Boc-4-hydroxypyrrolidin-2- ylmethyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 171D, in 5 ml of THF was added 0.5 ml (0.5 mmol) of 1 N LiOH in an ice bath. The reaction mixture was stirred for 5 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 50 mg (42 %) of the resulting free acid as a solid.

To a 2 ml of 1:1 solution of TFA and dichloromethane was added 50 mg (0.09 mmol) of the acid. After 30 minutes, 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 35 mg (74 %) of [4- ((2S ,4R)-N-Boc-4-hydroxypyrrolidin-2-ylmethyl)amino-2-phenylbenz oyl] methionine hydrdchloride: HPLC 72 % (purity). 1H NMR (300 MHz, CD30D) 6 7.71-7.30 (m, 6H), 6.76 (dd, 1H, J= 8.4, 2.4 Hz), 6.69 (d, lH, J= 2.2 Hz), 4.55 (d, 1H, J= 4.0 Hz), 4.44 (dd, 1H, J= 9.3, 4.2 Hz), 4.12 (m, 1H), 3.62-3.19 (m, 4H), 2.02 (s, 3H), 2.21-1.75 (m, 6H).

Example 172 [4-((2S,4S)-4-thiopyrrolidin-2-yl-methylamino)-2-phenylbenzo yl]methionine hydrochloride Example 172A [4-((2S,4S)-N-Boc-4-acetylthiopyrrolidin-2-yl-methylamino)-2 -phenylbenzoyl]methionine methyl ester and [4-((2S,5S)-4-Boc-1,4-diazabicyclo(2.2.1)octan-1-yl)-2-pheny l)benzoyl]methionine methyl ester To a solution of 153 mg (0.27 mmol) of 2-Phenyl-4-[(2S,4R)-N-Boc-4- hydroxylpyrrolidine-2-methyl] aminobenzoylmethionine methyl ester, prepared as in Example 171D, in 10 ml of THF were added 142 mg (0.54 mmol) of triphenylphosphine, followed by 107 ul (0.54 mmol) of diisopropyl azodicarboxylate at 0 OC under argon atmosphere. The mixture was stirred for 30 minutes and 40 ul (0.56 mmol) of thiolacetic acid was added at the same temperature. The reaction mixture was stirred overnight, during which time the ice bath expired. The solvent was removed, and a 3:1 solution of hexanes and ethyl acetate was introduced to the residue to precipitate the insoluble by-products. After removal of by-products, the solution was concentrated. The crude products were chromatographed on silica gel (1:1 hexanes-ethyl acetate) to give 106 mg (63 %) of [4- ((2S ,4S)-N-Boc-4-acetylthiopyrrolidin-2-yl-methylamino)-2-phenyl benzoyl]methionine methyl ester and 35 mg (24 %) of the bicyclic [4-((2S,5S)-4-Boc-1,4- diazabycyclo(2,2,1)octan-1-yl)-2-phenyl)benzoyl]methionine methyl ester as white solids.

[4-((2S,4S)-N goc-4-acetylthiopyrrolidin-2-yl-methylamino)-2- phenylbenzoyl]methionine methyl ester: 1H NMR (300 MHz, CDC13) 8 7.65 (d, 1H, J=8.4 Hz), 7.37 (m, 6H), 6.60 (br s, 1H), 6.41 (br s, lH), 5.66 (d, 1H, J=7.8 Hz), 5.53 (br s, 1H), 4.58 (m, 1H), 4.23 (br s, 1H), 4.02 (br s, 1H), 3.87 (m, 1H), 3.60 (s, 3H), 3.38- 3.12 (br s, 2H), 3.12 (dd, 1H, J=6.7, 11.4 Hz), 2.52 (m, lH), 2.30 (s, 3H), 2.05 (t, 2H, J=7.6 Hz), ), 1.97 (s, 3H), 1.82 (m, 1H), 1.62 (m, lH), 1.41 (s, 9H); 13C NMR (CDCl3) 8 195.0, 172.1, 168.5, 155.8, 150.0, 141.8, 141.4, 131.5, 128.8, 128.6, 127.8, 122.2, 113.7, 111.0, 80.7, 60.4, 56.5, 52.3, 51.8, 49.2, 39.3, 36.0, 31.7, 30.6, 29.6, 28.4, 15.3; HRMS (EI) calculated for C31H4lN3o6S2: 615.2436, found: 615.2436.

[4-((2S,SS)-4-Boc- 1 ,4-diazabicyclo(2,2, 1 )octan- 1 -yl)-2-phenyl)benzoyl]methionine methyl ester: 1H NMR (300 MHz, CDCl3) 8 7.75 (d, 1H, J=8.6 Hz), 7.54-7.40 (m, 6H), 6.57 (d, 1H, J=9.0 Hz), 6.36 (s, 1H), 5.68 (br s, 1H), 4.63 (m, 2H), 4.42 (br s, 1H), 3.63 (s, 3H), 3.58-3.17 (m, SH), 2.10 (m, 2H), 1.98 (s, 3H), 1.86 (m, lH), 1.66 (m, 1H), 1.41 (s, 9H); 13C NMR (CDCl3) 6 172.2, 168.5, 154.2, 148.7, 142.0, 141.4, 132.1, 131.7, 129.0, 128.8, 128.1, 122.1, 113.7, 111.2, 80.0, 57.4, 56.4, 52.5, 52.0, 37:9, 37.4, 31.9, 29.7, 28.7, 15.5; HRMS (EI) calculated for C29H37N3O5S: 539.2454, found: 539.2453.

Example 172B [4-((2S,4S)-4-thiopyrrolidin-2-yl-methylamino)-2-phenylbenzo yl]methionine hydrochloride To a solution of 86 mg (0.14 mmol) of [4-((2S,4S)-N-Boc-4-acetylthiopyrrolidin- 2yl-methylamino)-2-phenylbenzoyl]methionine methyl ester in 2 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 resulting residue was partitioned between 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 67 mg (85 %) of the resulting free acid as a white solid. To 2 ml of 1:1 solution of TFA and dichloromethane were added 67 mg (0.12 mmol) of the acid, followed by a few drops of triethylsilane. After 30 minutes, The reaction mixture was thoroughtly evaporated under high vacuum to give an oily residue. The residue was triturated with anhydrous ether and the white solid was collected by filtration to give 62 mg (97 %) of [4- ((2S,4S)-4-thiopyrrolidin-2yl-methylamino)-2-phenylbenzoyl]m ethionine hydrochloride: HPLC 83% (purity); 1H NMR (300 MHz, CD30D) 8 7.46-7.35 (m, 6H), 6.76 (d, 1H, J=8.4 Hz), 6.70 (s, 1H), 4.45 (m, 1H), 3.91 (m, 1H), 3.68-3.30 (m, SH), 3.15 (m, 1H), 2.66 (m, 1H), 2.20 (m, 1H), 2.10 (m, 1H), 2.01 (s, 3H), 1.79 (m, 2H); 13C NMR

(CD30D) 6 175.0, 173.3, 150.5, 143.5, 142.3, 131.3, 129.9, 129.6, 128.7, 125.9, 115.9.

112.5, 60.9, 54.6, 53.3, 45.8, 40.3, 35.4, 31.8, 31.0, 15.3.

Example 182 14-( 1 H-benzimidazol-S-ylcatoxyamino)-2-phenvlbenzoyllmethionine trifluoroacetate Example 1 82A (1 H- 1 -p-Toluenesulfonylbenzimidazol-S-yl)carboxylic acid 5-Benzimidazolecarboxylic acid (1.0 g, 6.2 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.2mmol) were suspended in 10 mL of distilled water. Aqueous 1N sodium hydroxide was added periodically to maintain a pH of approximately 9 over a period of 4 hours. The reaction mixture was washed with methylene chloride (3X50 mL.) and was adjusted to pH 3 with 1N hydrochloric acid. The precipitate which formed was collected by vacuum filtration, washed with distilled water and hexanes and air dried to give (1H- l-p- toluenesulfonylbenzimidazol-5-yl)carboxylic acid (0.75 g, 38%) as a white solid.

Example 182B [4-(1H-1-p-Toluenesulfonylbezimidazol-5-ylcarboxyamino)-2-ph enylbenzoyl]methionine methvl ester To 50 mL of methylene chloride containing [4-amino-2-phenylbenzoyl]methionine methyl ester hydrochloride (compound 8, 0.65 g, 1.64 mmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.34 g, 1.8 mmol) was added (lH-1-p-toluenesulfonylbenzimidazol-5-yl)carboxylic acid (0.52 g, 1.64 mmol), prepared as in Example 182A, and the mixture was cooled to OOC. Triethylamine (0.16 g, 1.64 mmol) was slowly added to the stirred solution. After 1 hour, the ice bath was removed and the reaction was stirred for an additional 96 hours. The organic layer was washed with distilled water, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (4: 1 ethyl acetate/hexanes) to give [4-( 1 H- l-p- toluenesulfonylbenzimidazol-5-ylcarboxyamino)-2-phenylbenzoy l]methionine methyl ester (0.63 g, 59%) as a white solid.

Example 182C [4-(1H-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methio nine trifluoroacetate [4-( 1H- 1 -p-Toluenesulfonylbenzimidazol-5-ylcarboxyamino)-2- phenylbenzoyl]methionine methyl ester (0.2 g, 0.3 mmol), prepared as in Example 182B, was added to 5 mL of tetrahydrofuran (THF) and the mixture was cooled to OOC. Lithium hydroxide (5 mL., 0.5M) was slowly added and the reaction mixture was stirred for 2 hours.

The THF was removed by evaporation and 0.5M HCl was added to adjust the pH to between 2 and 3 and the precipitate which formed was collected by vacuum filtration. The solid was purified by reverse phase preparative HPLC (Waters 25X10 cm, C-18 column, 220 nm UV detector, flow rate 15 mL./min, linear gradient from 5% acetonitrile and 95% water containing 0.1% TFA to 60% acetonitrile in 40 minutes) and pure fractions were pooled and lyophilized to give [4-(1H-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methio nine trifluoroacetate as a white solid (0.146 g, 87%). 1H NMR (300 MHz, DMSO-d6) 6 10.56 (s, lH), 9.05 (s, lH), 8.47 (d, lH, J= 7.8 Hz), 8.40 (s, 1H), 8.04 (d, 1H, J= 8.1 Hz), 7.88-7.89 (m, 2H), 7.33-7.48 (m, 6H), 4.30 (m, 1H), 2.16-2.29 (m, 2H), 2.06 (5, 3H), 1.84-2.00 (m, 2H). MS m/e 489 (M+H)+.

Example 185 [4-(piperidin-2-ylcarboxyamino)-2-phenylbenzoyl]methionine hydrochloride Example 185A di-tert-butoxycarbonylpiperidine-2-carboxylic acid Di-tert-butyl dicarbonate (15.5 g, 70.2 mmol) was added to a solution of piperazine- 2-carboxylic acid (4.85 g, 23.4 mmol) and NaOH (98 mL of a 1 M aqueous solution, 98 mmol) in THF (100 mL). The cloudy mixture was stirred for 16 hours and then concentrated under reduced pressure to remove THF. The residue was saturated with solid NaHCO3 and extracted with ether (2 x 30 mL). The aqueous layer was cooled to 0 OC and then adjusted to pH = 3 with 2 M aqueous HCl. A precipitate developed. The mixture was

extracted with CH2C12 (3 x 75 mL), and the organic extracts were dried over MgSO4. filtered, and concentrated under reduced pressure to provide 7.61 g (98%) of di-tert- butoxycarbonylpiperidine-2-carboxylic acid as a tan solid. 1H NMR (CDCl3) 6 1.45 (s, 18 H), 2.80-2.98 (br, 1 H), 3.04-3.36 (br comp, 2 H), 3.70-3.83 (br, 1 H), 3.94-4.05 (br, I H), 4.44-4.65 (br comp, 2 H), 4.80-4.95 (br, 1 H). LRMS (CI): 292, 331 (M+1)+, 348 (M+NH4)+.

Example 1 85B 14-(di-tert-butoxyCarbonYlpiperidin-2-vlcarboxvamino)-2-phen Vlbenzovllmethionine methvl ester.

The desired compound was prepared by coupling di-tert-butoxycarbonylpiperidine-2- carboxylic acid with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the procedure of Example 184A.

Example 185C [4- (di-tert-butoxvcarbonylpiperidin-2-vlcarboxvamino)-2-phenvlb enzovll methionine.

Lithium hydroxide hydrate (0.411 g, 9.60 mmol) was added to a solution of [4-(di- tert-butoxycarbonylpiperidin-2-yl)carboxyamino-2-phenylmethi onine methyl ester (ca 0.8 g, 1.20 mmol), prepared in Example 185B, in THF/H2O (4:1,12 mL). The solution was stirred for 20 hours and then treated with 1 M aqueous HC1 (10 mL). The mixture was extracted with ethyl acetate (5 x 10 mL), and the organic extracts were rinsed with 1:1 brine/l N HCl (10 mL), dried over Na2SO4, and concentrated under reduced pressure to provide [4- (di-tert-butoxycarbonylpiperidin-2-yl)carboxyamino-2-phenylm ethionine (0.72 g) as a white foam ( est. 89%). IHNMR (CD30D) 6 1.3-1.5 (br, 18 H), 1.7-1.9 (br comp, 2 H), 2.0 (br s, 3 H), 2.1-2.3 (br comp, 2 H), 2.9-4.8 (br comp, 8 H), 7.3-7.5 (br comp, 6 H), 7.5- 7.6 (br m, 1 H), 7.6-7.7 (br m, 1 H). LRMS (CI): 657 (M+1)+, 457, 330.

Example 185D 14-(piperidin-2-vlcarboxyamino)-2-phenylbenzovllmethionine hvdrochloride.

[4-(di-tert-butoxycarbonylpiperidin-2-ylcarboxyamino)-2-phen ylbenzoyl]methionine (0.72 g, 1.07 mmol), prepared in Example 185C, was treated with HCl (9.6 mL of a 4 M solution in dioxane, 38.5 mmol) and the solution was stirred for 5 minutes, at which time a pink precipitate was observed. The mixture was treated with pentane (10 mL) and the precipitate was isolated by filtration to afford [4-(piperidin-2-yl)carboxyamino-2- phenylbenzoyl]methionine hydrochloride (0.448 g, 86%). 1H NMR (CD30D) 6 1.73-1.88 (m, 1 H), 1.93-2.05 (comp, 4 H), 2.05-2.14 (m, 1 H), 2.14-2.26 (m, 1 H), 3.32-3.64

(comp, 5 H), 3.68-3.85 (comp, 2 H), 3.97 (dd, 1 H), 4.13 (dd, 1 H), 4.73 (dd, 1 H), 7.35- 7.50 (comp, 5 H), 7.51-7.59 (m, l H), 7.74-7.80 (m, 1 H). LRMS (CI): 457 (M+l)+.

Example 202 [4-(2-pvrrolidinone-5-vlcarbonvlamino)-2-phenvlbenzoVlmethio nine Example 202A 14-(2-pvrrolidinone-5-vlcarbonvlamino!-2-phenvlbenzovllmethi onine methvl ester To a solution of L-pyroglutamic acid (49mg, 0.38 mmol) in 5 mL of DMF was added 3-hydroxy 1 ,2,3-benzotriazin-4(3H)-one ( 62mg, 0.38 mmol), (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5 8mg, 0.30 mmol) and [4-amino-2-phenylbe nzoyl-L- methionine methyl ester (9Omg, 0.38 mmol), prepared as in Example 192B, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with 10 mL 1N HCl, 5 mL satd aqueous NaHCO3 and brine (3 x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. Purification by radial chromatography (2-5% methanol-ethyl acetate gradient) to give [4-(2-pyrrolidinone-5- ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester (92mg, 79%) as a white solid.

Example 202B [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methi onine LiOH monohydrate (29mg, 0.69 mmol) was dissolved in 1 mL H2O and added to a solution of [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methi onine methyl ester, prepared as in Example 202A, (108mg, 0.23 mmol) in 3 mL of THF and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was evaporated and 2 mL of 1N HCl was added to the aqueous residue. The resulting precipitate was filtered and dried under vacuum to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methi onine (96 mg, 91%). H NMR (300 mHz, CD30D) 6 7.70 - 7.60 (m, 3H), 7.45 - 7.30 (m, 5H), 4.40 (bs, 1H), 2.60 - 2.10 (m, 7H), 2.00 (s, 3H), 1.90 - 1.80 (m, 2H).CIMS MH+ 456.

Example 219 1 4-(5-pVrimidvlcarboxvamino!-2-phenvlbenzovllmethionine Example 219A 5-pvrimidinecarboxvlic acid methyl ester A mixture of 5-bromopyrimidine (1.59 g, 10 mmol), 1-propanol (1.5 mL, 20 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.50 mmol) and tributylamine (3.72 g, 20 mmol) in DMF was stirred at 90 OC under a carbon monoxide balloon for 10 hours.

The reaction mixture was diluted with ethyl acetate (100 mL), washed with potassium dihydrogenphosphate (1.0 M, 20 mL, twice), water, and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacua. The residue was then purified by column chromatography (50:50: 10 hexane-dichloromethane-ether) to give 3- pyrimidinecarboxylic acid methyl ester (715 mg, 52%). 1H NMR (300 MHz, CDC13) 6 9.38 (s, 1H), 9.30 (s, 2H), 4.36 (t, 2H), 1.83 (sextet, 2H), 1.05 (t, 3H).

Example 219B -(S-pvrimidvlcarboxyamino)-2-phenvlbenzoyl1methionine methyl ester A mixture of the 5-pyrimidinecarboxylic acid methyl ester prepared in Example 219A (682 mg, 4.94 mmol) and aqueous sodium hydroxide solution (4.0 M, 2.5 mL) in THF was heated at 60 °C for 1.5 hours. Hydrochloric acid (6.0 N, 2 mL) was added to the reaction mixture, and the solvent was evaporated in vacua. The residue was dried under high vacuum at 50 °C for 1 hour, and the redesolved in to THF. To the acid solution was added (4-amino-2-phenylbenzoyl)methionine methyl ester (compound 8, 1.97 g, 5.0 mmol), 3- hydroxy 1 ,2,3-benzotriazin-4(3H)-one (0.978 g, 6.0 mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (1.15 g, 6.0 mmol) and triethylamine (2.8 mL, 20 mmol). After 14 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 vacua. The residue was then purified by column chromatography (50% ethyl acetate-hexane, then ethyl acetate) to give [4-(3-pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine methyl ester (0.937 g, 41%). 1H NMR (300 MHz, CDCl3) 6 9.34 (s, 1H), 9.19 (s, 2H), 9.01 (s, 1H), 7.64 (d, 1H), 7.52 (d, 1H), 7.42 (dd, 1H), 7.33 (m, SH), 6.20 (br d, 1H), 4.66 (m, 1H),

3.69 (s, 3H), 2.14 (t, 2H), 2.02 (s, 3H), 1.95 (m, lH), 1.78 (m, lH). MS (CI+) m/e 465 (M+H)+.

Example 219C 14-(5-pyrimidvlcarboxyamino)-2-phenylbenzovllmethìonine To a solution of the [4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine methyl ester prepared in Example 210B (324 mg, 0.70 mmol) in methanol (2 mL) was added aqueous sodium hydroxide (2.0 N, 1.0 mL). After 14 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed twice with potassium dihydrogenphosphate (1.0 M, 20 mL each), water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by column chromatography (ethyl acetate, then 95:5:0.5 ethyl acetate-methanol-acetic acid)to give [4-(3- pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine (265 mg, 84%). 1H NMR (300 MHz, DMSO-d6) # 10.80 (s, 1H), 9.38 (s, 1H), 9.30 (s, 2H), 8.51 (d, lH), 7.83 (m, 2H), 7.50 (d, 1H), 7.39 (m, SH), 4.29 (m, 1H), 2.28 (m, 2H), 2.00 (s, 3H), 1.86 (m, 2H). MS (APCI+) m/e 451 (M+H)+.

Example 231 {4- (3-piperidinecarboxyamino)-2-phenylbenzoyl} methionine hvdrochloride Example 231A 1-tert-butoxycarbonylpiperidin-3-carboxylic acid To a mixture of piperidine-3-carboxylic acid (1.29 g, 10 mmol) in THF (20 mL) was added aqueous 4N sodium hydroxide (5 mL) and di-tert-butyldicarbonate (2.62 g, 12 mmol) and the reaction mixture was stirred for 6 hours. The reaction mixture was acidified with 3N HCl (7 mL) and extracted three times with ethyl acetate. The combined organic extracts were washed with water (2x) and brine, dried, filtered, and concentrated in vacuo to give 1-tert- butoxycarbonylpiperidine-3-carboxylic acid (2.11 g) as a white solid.

Example 231B

[4-(1-tert-butoxycarbonylpiperidin-3-ylcarboxyamino)-2-pheny lbenzoyl]methionine methyl ester The desired compound was prepared by coupling of the product of Example 231A and (4-amino-2-phenylbenzoyl)methionine methyl ester (compound 8) according to the method of Example 186C.

Example 231C [4-(1-tert-butoxycarbonylpiperidin-3-ylcarboxyamino)-2-pheny lbenzoyl]methionine The desired compound was prepared by saponification of the product of Example 231B according to the procedure of Example 159.

Example 231D 14-(3-piperidinecarboxvamino)-2-phenvlbenzovllmethionine hvdrochloride The product of Example 231C was deprotected with 4N HCl-dioxane using the procedure of Example 229B. 1H nmr (300 MHz, D2O) 6 7.37 - 7.60 (m, 8H), 4.44 (dd, 1H), 3.46 (dd, 1H), 3.31 (m, 2H), 1.14 (m, 1H), 3.02 (m, 1H), 1.71 - 2.11 m, 8H), 2.02 (s, 3H). MS (CI NH3) M/e 456 (M+H+, 438, 408, 339, 307, 196. Anal calcd for C24H30ClN304S*2.54 H2O: C, 53.60; H, 6.57; N, 7.59. Found: C, 53.60; H, 6.19; N 7.59.

Example 283 <BR> <BR> 14-( lH-4-trifluoromethvl- l .2-dihydropvrid-3-vlcarbonvlamino)-2-phenylbenzovll methionine sodium salt Example 283A (4-nitro-2-phenvlbenzovl)methionine 2-trimethvlsilvlethvl ester A mixture of (4-nitro-2-phenylbenzoyl)methionine methyl ester (7.69 g, 30 mmol), prepared as in Example 192A and aqueous saturated lithium hydroxide (20 mL) in methanol (50 mL) was refluxed for 6 hours. The reaction mixture was carefully acidified with

concentrated hydrochloric acid (10 mL), and extracted with ethyl acetate (4x). The combine extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and THF (10 mL) and 2-trimethylsilylethanol (3.72 g, 31.5 mmol), l,3-diisopropylcarbodiimide (5.17 mL, 33 mmol) and 4-dimethylaminopyridine (30 mg) were added sequentially. After 4 hours, aqueous hydrochloric acid (0. 1 N, 0.5 mL) was added and the reaction mixture was stirred for another 2 hours. The reaction mixture was then filtered through silica gel (40 g), and the filtrate was concentrated in vacua. The residue was purified by column chromatography (5% ethyl ether-hexane) to give the title compound (8.90 g, 87%).

Example 283B (4-amino-2-phenvlbenzovl)methionine 2-trimethvlsilvlethvl ester A mixture of the product of Example 283A (8.85 g, 25.8 mmol), ammonium formate (4.88 g, 77.4 mmol) and palladium (10%) on carbon (1 g) in methanol was refluxed for 5 hours. The mixture was then filtered through Celite and rinsed with ethyl acetate. The filtrate was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound which was used without further purification.

Example 283C 4-(4-trifluoromethylpyrid-3-ylcarbonylamino)-2-phenvlbenzoic acid 2-trimethvlsilvlethvl ester A mixture of 4-trifluoromethylnicotinic acid (472 mg, 2.46 mmol), the product of Example 283B (771 mg, 2.46 mmol), 3-hydroxyl ,2,3-benzotriazin-4(3H)-one (481 mg, 2.95 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (566 mg, 2.95 mmol) in DMF (8 mL) was stirred 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 (30% ethyl acetate-hexane) to give the title compound (1.04 g, 87%).

Example 283D 4-(lH-4-trifluoromethVl-12-dihvdropvrid-3-vlcarbonvlamino)-2 -phenvlbenzoic acid 2- trimethvlsilvlethvl ester A solution of the product of Example 283C (1.02 g, 2.09 mmol), tetrabutylammonium borohydride (539 mg, 2.1 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 OC for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over anhydrous magnesium

sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate-hexane) to give the title compound (247 mg, 24%).

Example 283E [4-(1H-4-trifluoromethyl-1,2-dihydropyrid-3-ylcarbonylmino)- 2-phenylbenzol]methonine methvl ester A solution of the product of Example 283D (227 mg, 0.48 mmol) and tetrabutylammonium fluoride (261 mg, 1.0 mmol) in dioxane was heated at 80 °C for 90 min. The solvent was then evaporated, and the residue was further dried under high vacuum (2 mmHg) for l hour. To the residue was added L-methionine methyl ester hydrochloride (115 mg, 0.58 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (163 mg, 1.0 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 1.0 mmol), DMF (5 mL) and triethylamine (0.3 mL). After 15 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (50% ethyl acetate-hexanes) to give the title compound (179 mg, 69%).

Example 283F [4-(1H-4-trifluoromethyl-1,2-dihydropyrid-3-ylcarbonylamino) -2-phenylbenzoylmethionine sodium salt The desired compound was prepared by saponification of the product of Example 283E using the procedure of Example 276. H NMR (300 MHz, DMSO-d6) 6, 9.67 (s, 1H), 8.87 (br s, 1H), 7.68 (m, 2H), 7.54 (s, 1H), 7.41-7.30 (m, 6H), 7.03 (dd, 1H), 6.51 (d, 1H), 4.67 (t, 1H), 4.48 (m, 1H), 3.78 (m, 1H), 2.14 (m, 2H), 1.96 (s, 3H), 1.77 (m, 2H).

MS (APCI+) m/e 520 (M+H)+.

Example 286 <BR> <BR> 1 4-(2-piperazinvlmethylamino)-2-phenylbenzovl]methionine Example 286A

di-tert-butvoxvcarbonylpiperidine-2-carboxYlic acid Di-tert-butyl dicarbonate (15.5 g, 70.2 mmol) was added to a solution of piperazine- 2-carboxylic acid (4.85 g, 23.4 mmol) and NaOH (98 mL of a l M aqueous solution, 98 mmol) in THF (100 mL). The cloudy mixture was stirred for 16 hours and then was concentrated under reduced pressure to remove THF. The aqueous solution was saturated with NaHCO3 (s) and then extracted with ether (2x). The aqueous layer was cooled to 0 "C and then adjusted to pH 3 with 2 M aqueous HCl during which time a precipitate formed.

The mixture was extracted with CH2Cl2 (3x), and the organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide the desired compound (7.61 g, 98% as a tan solid.

Example 286B di-tert-butyoxvcarbonvlpiperidine-2-carboxylic acid N-methvl N-methoxv amide Triethylamine (1.75 g, 17.1 mmol) was added dropwise to a solution of N, O- dimethylhydroxylamine hydrochloride (0.741 g, 7.44 mmol), the product of Example 286A (2.46 g, 7.44 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.61 g, 9.67 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.89 g, 9.67 mmol) in DMF (75 mL).

The reaction mixture was stirred at ambient temperature for 20 hours and then concentrated under reduced pressure (50 "C, 0. 1 mm Hg). The residue was dissolved in ethyl acetate (70 mL), and the solution was extracted with saturated aqueous NaHCO3 (3x) and brine. The organic phase was dried (MgS04) and concentrated to provide a golden wax. Flash column chromatography (20% ethyl acetate-hexane) afforded the desired compound (2.29 g) which was shown to be 78% pure by 1H NMR.

Example 286C di-tert-butvoxvcarbonylpiperidine-2-carboxaldehyde A solution of the product of Example 286B (0.971 g, 2.81 mmol) in THF (4 mL) was added dropwise to a slurry of LAH (0.112 g, 2.81 mmol) in THF (4 mL) at -50 "C.

After 10 minutes the bath temperature was adjusted to -10 "C for 10 min and then returned to -50 "C. The addition of saturated aqueous KHS04 (8 mL) produced vigorous gas evolution, after which reaction mixture was allowed to warm to ambient temperature over 20 minutes and then filtered through Celite. The filtrate was extracted with 1 N HCl (2x), saturated aqueous NaHCO3 (2x) and finally brine. The organic phase was dried (MgSO4) and concentrated to provide the desired compound (0.304 g, 41%) as an amber oil.

Example 286D

[4-(di-tert-butoxycarbonylpiperazin2ylmethylamino)2-phenvlbe nzovl1methionine methyl ester The aldehyde prepared in Example 286C (0.599 g, 1.71 mmol) was added to a solution of N-(4-amino-2-phenylbenzoyl)methionine methyl ester hydrochloride (1.01 g, 2.05 mmol), prepared as in Example 192B, sodium acetate (0.425 g, 5.13 mmol) and acetic acid (0.205 g, 3.42 mmol) in isopropanol (7 mL). After 1 hour, Na(CN)BH3 (0.147 g, 2.22 mmol) was added in two portions and the mixture was stirred for 15 hours before concentration under reduced pressure provided a waxy residue. Flash column chromatography (hexane-ethyl acetate-triethylamine 60:38:2) followed by radial chromatography eluting with 40% ethyl acetate-hexane) afforded the title compound (0.344 g, 31%) as a white foam. 1H NMR (CDCl3): d 1.35-1.52 (comp, 18H), 1.52-1.71 (m, 1 H), 1.71-1.93 (m, 1 H), 2.02 (s, 3 H), 2.02-2.20 (comp, 2 H), 2.80-3.12 (comp, 2 H), 3.12-3.33 (br, 1 H), 3.33-3.50 (br, 1 H), 3.64 (s, 3 H), 3.83-4.28 (br, 3 H), 4.28-4.45 (br, 1 H), 4.60-4.72 (br, 1 H), 5.63-5.74 (br, 1 H), 6.44-6.58 (br, l H), 6.58-6.80 (br, l H), 7.33-7.52 (comp, 5 H), 7.72 (d, 1 H). LRMS (CI): 657 (M+l)+.

Example 286E 1 4-(2-piperazinvlmethvlamino)-2-phenylbenzovllmethionine Sodium hydroxide (0.642 mL of a 0.979 M aqueous solution, 0.629 mmol) was added to a solution of the product of Example 286D (0.344 g, 0.524 mmol) in methanol (2 mL). After 5 hours the mixture was lyopholized, and the resulting white foam was treated with HCl (4.7 mL of a 4 M dioxane solution, 18.8 mmol). After 7 hours, pentane was added and the yellow precipitate was isolated by filtration to afford the desired compound (79.3 mg, 24%) as the bis-hydrochloride, mono-sodium chloride salt. 1H NMR (300 MHz, CD30D) d 1.71-1.85 (m, 1H), 1.91-2.00 (m, 1H), 2.02 (s, 3H), 2.02-2.15 (m, 1H), 2.15-2.27 (m, 1H), 3.32-3.56 (comp, 3H), 3.56-3.75 (comp, 4H), 3.75-3.96 (br, 2H), 4.45 (dd, 1H), 6.73 (s, 1H), 6.81 (d, 1H), 7.30-7.50 (comp, 6H). LRMS (CI) m/e 443 (M+H)+. Example 302

14-(2-furylmethvlaminomethvl)-2-phenvlbenzovlJmethionine lithium salt Example 302A 4-(2-furylmethylaminomethyl)-2-phenylbenzoic acid methyl ester To a stirred soltuion of 4-carboxaldehyde-2-phenylbenzoic acid methyl ester (0.73 g, 3.0 mmol), prepared as in Example 160B, in methanol (15 mL) was added furfurylamine (0.33 g, 3.4 mmol), sieves ( Ig), NaBH3CN (0.29 g, 4.6 mmol) and acetic acid (-0.3 mL) to pH = 6. The mixture was stirred for 3 hours at ambient temperature. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate and filtered through a short bed of silica gel. The bed was washed with ethyl acetate and the filtrate concentrated in vacuo. The residue was purified by flash chromatography ( CH2Cl2-ethyl acetate 9: 1) to give the desired compound (0.72 g, 73%) as an opaque yellow paste.

Example 302B [4-( 2-furylmethvlaminomethyl)-2-phenylbenzoyll methionine methyl ester The desired compound was prepared by saponification of the product of Example 302A, followed by coupling with methionine methyl ester hydrochloride according to the method of Examples 299C and D.

Example 302C [4-(2-furvlmethylaminomethyl)-2-phenylbenzovli methionine methvl ester To a stirred solution of the product of Example 302B (56 mg, 0.12 mmol) in THF (2 mL) was added a solution of LiOH.H2O (5.5 mg, 0.13 mmol) in H2O (1 mL) and the resulting solution stirred for 3 hours at ambient temperature. The reaction was concentrated in vacuo, diluted with H2O, filtered and lyopholized to give the title compound (57 mg, 97%) as a white powder. 1H NMR (300 MHz, DMSO-d6, 90 °C) 6 7.48-7.24 (m, 9H), 7.07-7.04 (m, 1H), 6.37-6.34 (m, 1H), 6.24-6.20 (m, 1H), 3.76-3.69 (m, SH), 2.43-2.16 (m, 3H), 2.00-1.66 (m, SH). MS m/z 439 (M+ 1)+. Anal calcd for C24H25LiN2O4S.2 H2O (480.50): C, 59.99; H, 6.08; N, 5.83. Found: C, 59.83; H, 5.83; N, 5.74.

Examples 350-357 All reactions were performed either in a Manual solid phase synthesis flask using a 120O rotary shaker or on an Advanced ChemTech Model 396 Multiple Peptide Synthesizer (Advanced ChemTech Inc.; Louisville, Kentucky) at ambient temperature.

After the reactions were performed the finished compounds were cleaved from the resin. Usually, 80-90 mg of the dried resin containing the desired amide; urea; or secondary amine was treated with a 1.50 mL solution of 95/5 (v:v) trifluoroacetic acid/water for 1.5 hat ambient temperature. The spent resin was removed by filtration and the resulting cleavage solution evaporated in-vacuo. In most cases, 5- 20 mg of crude compound was obtained.

Compounds obtained had the desired MW as determined by electrospray mass spectroscopy and had an HPLC purity of 40-90%, or were further purified by partition chromatography to afford compounds of 40-60% HPLC purity. Two types of gradients were used for the reverse phase HPLC. For the amides and ureas a gradient starting with 100% water-O.1% <BR> <BR> <BR> Trifluoroacetic acid and finishing with 100% acetonitrile-0. 1% Trifluoracetic acid during a 30 minute period was used. For the secondary amines a gradient beginning with 100% water- Smmol ammonium acetate and finishing with 80% acetonitrile-water-Smmol ammonium acetate during 25 minutes was used.

80 mg of resin (substitution 0.40 mmol/g) containing [4-amino-2- phenylbenoyl]methionine-Wang-polystyrene resin was shaken for 3 min. with 1.0 mL. of N-methylpyrrolidone (NMP). The solvent was drained and the resin was treated 2x (3 min) with 1 mL. NMP. To the now swollen resin were then added 0.20 mL NMP; 0.20 mL of a 1.92 M diisopropylethylamine (DIEA)/NMP solution (15 eq.); 1.00 mL of a 0.180 mM/NMP solution of the desired carboxylic acid ( S eq.); and finally 0.20 mL of a 0.90 M Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrop; 5 equiv.) 1 /NMP solution. The reaction slurry was then mixed for 6 h and drained. The resin was then washed with NMP (3x; 1.0 mL; 3 min. ea); isopropanol (IPA; Sx; 1.0 mL; 3 min. ea.); NMP (3x; 1.0 mL; 3 min. ea.); methanol (MEOH; 2x; 1.0 mi; 3 min. ea.); and finally diethyl ether (2x; 1.0 mL; 3 min. ea.). The resin was then dried and subjected to cleavage conditions described above. Example B3L1 MS (M+H)+ 354 z HN 531 H 0 355 eN H 451 o

356 H2N NH s 519 H 0 Examples 358 90 mg of resin (substitution 0.39 mmol/g.) containing [4-amino-2- phenylbenzoyl]methionine-Wang-polystyrene resin was shaken with 1.0 mL. dimethylformamide (DMF) for 3 min. The solvent was drained and the resin was then washed with DMF (3x; 1.0 mL; 3 min. ea.); tetrahydrofuran (THF; 4x; 1.0 mL: 3 min. ea.); THF/dichloromethane (DCM) 1:1 (v:v) (4x; 1.0 mL; 3 min. ea.). The resin was then treated with 0.20 mL of DCM/THF (1:1) and a 1.0 mL solution of 0.50 M p- Nitrophenylchloroformate/0 .50 M DEA in a 1:1 solvent mixture of DCM/THF. The resin suspension was then shaken for 15 min. and to the suspension was then added .020 mL of neat DIEA. After shaking for an additional 15 min.; the solvents were drained away and the resin was then washed with DCM/THF (1:1) (4x; 1.0 mL; 3 min. ea.) The resin was then treated with 0.20 mL of DMF and 1.0 mL of a DMF solution containing 0.50 M of the desired primary or secondary amine and 0.50 M of DEA. The suspension was shaken for 30 min. The solvent was drained off and the resin was then washed with DMF (4x; 1.0 mL; 3 min. ea); THF (4x; 1.0 mL; 3 min. ea.); DCM/THF (4x; 1.0 mL; 3 min. ea); diethyl ether (4x; 1.0 mL; 3 min. ea.). The resin was then dried and subjected to cleavage from the resin as described above. Example B3L1 MS (M+H)+ 358 (s-?, ) H 460 N N 0

Examples 360-362 Examples 364-366 Examples 369-374 Examples 377-378 Example 381 Typically 80 mg of resin (substitution of 0.40 mmol/g) containing 4-formyl-2- phenylbenzamide-L-Methionine-Wang-polystyrene resin was swollen with 1.0 mL of dimethyl acetamide (DMA) for 3 min. The solvent was drained and the resin was then washed with additional DMA ( 2x; 1.0 mL; 3 min. ea.). The resin was then suspended in 0.20 mL of DMA and to the suspension was then added a 1.0 mL solution containing 0.48 mM of the desired primary amine (10 eq.) in a 3:1 (v:v) solution of DMA/acetic acid. The resin was shaken for 2 h and was then treated with 0.25 mL of a 2.4 mM solution of sodium cyanoborohydride (10 eq.) in DMA. The resin-slurry was shaken for an additional 2 h. The solvents were drained and the resin was then washed with DMA ( 6x; 1.0 mL; 3 min. ea.); DMF ( 6x; 1.0 mL; 3 min. ea.); IPA (6x; 1.0 mL; 3 min. ea.); DMF ( 6x; 1.0 mL; 3 min. era.); MEON( 6x; 1.0 mL; 3 min. ea.); diethyl ether (6x; 1.0 mL; 3 min. ea.). The resin was dried and then subjected to cleavage as described above. Example RE~I MS (M+HA+ 360 tN 455 H 361 t N 439 \8 I N 362 t~HN 471 CH3

364 H3CA z 498 N H3C - N 2 O H 365 0 9 473 S/N N H 366 z 471 N H 369 > 470 370 w$/,NH 425 N-N H 37l N' N H 458 H3C H 372 H3C < N 441 O-N 373 H3CN\, 457 N-S 374 ,S H 443 4 N>~">s~,N 378 2 N 573 377 ocy H 487 381 kO- I: 481 377 H 487 N 378 ;cNH 573 381 )#HN 481 H Examples 395 and Example 398 The following compounds were prepared using the materials and methods described above.

Example Example 403 [4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methy lphenyl)benzoyl] methionine.

The desired compound was prepared according to the method of Example 349A except substituting (S)-(+)- 1 -ethylthio-3-cyclohexyl-2-propylamine hydrochloride for (S)- (+)-2-amino-3-cyclohexyl- 1-propanol hydrochloride. 1H NMR (DMSO-d6, 300 MHz) 6 8.02 (m, 1H), 7.50-7.38 (m, 2H), 7.22-7.05 (m, 4H), 4.21 (m, 1H), 3.88-3.78 (m, 2H), 2.74-2.60 (m, 2H), 2.51 (s, 3H), 2.44 (q, J=7.5 Hz, 2H), 2.22-1.95 (m, SH), 1.88-1.50 (m, 7H), 1.45-1.25 (m, 4H), 2.21-1.02 (m, 3H), 1.12 (t, J=7.5 Hz, 3H), 0.90-0.70 (m, 2H). MS (CI/NH3) m/e: 557 (M+H)+ Anal calcd for C31H44N2o3S2 1.15 M2O: C, 64.47; H, 8.08; N, 4.85. Found: C, 64.48; H, 7.84; N, 4.72.

Example 406 4-(N-benzyl-N-phenyl)-aminomethyl-2-(2-methylphenyl)benzoylm ethionine The desired compound was prepared according to Example 273 except substituting N-benzylaniline for 2-thiophenemethanol in Example 273A.

IH NMR (CD30D): 5 1.62-1.77 (m, 1 H), 1.86-2.07 (comp, 7 H), 2.07-2.18 (comp, 2 H), 4.37-4.47 (br, 1 H), 4.70-4.84 (comp, 4 H), 6.68-6.89 (br, 3 H), 7.08-7.32 (comp, 13 H), 7.35-7.40 (m, 1 H), 7.56-7.62 (m, 1 H). LRMS (CI): 539 (M+1)+.

Examples 411-417 The following compounds are prepared according to the method of Example 407 except substituting the desired N-benzyl- or N-cyclolhexylmethylaminopiperazine for N- benzyl-3-aminopyridine.

Example 475 N-[4-(2,2-dibenzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)b enzoyl]methionine sodium salt The desired compound was prepared according to the method of Examples 25A -25B 1H nmr (300 MHz, DMSO-d6): 67.40 (d, 1 H), 7.25-7.10 (m, 15 H), 6.65 (m, 1 H), 6.27 (d, I H), 6.08 (m, 1 H), 4.84 (m, 1 H), 3.70 (m, 1 H), 3.17 (br s, 2 H), 3.03 (br s, 2 H), 2.80 (AB q, 4 H), 2.18 (m, 1 H), 1.99,1.91 (2 br s's, 6 H), 1.97 (m, 1 H), 1.70-1.50 (m, 2 H). MS (APCI +) m/e 597 (M+H)+.

Example 476 N-[4-N-(2-benzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)ben zoyl]methionine sodium salt The desired compound was prepared according to the method of Examples 25A -25B 1H nmr (300 MHz, DMSO-d6): 6 7.35 (d, 1 H), 7.28-7.10 (m, 10 H), 6.50 (m, 1 H), 6.16 (d, 1 H), 6.05 (m, 1 H), 4.55 (m, 1 H), 3.64 (m, 1 H), 3.39 (m, 2 H), 2.62 (m, 2 H), 2.38

(m, 1 H), 2.15 (m, I H), 1.97,1.91 (2 br s's, 6 H), 1.95 (m, 2 H), 1.70-1.50 (m, 2 H) (note: the methylene protons adjacent to the NH group might be buried in the residue water pk of DMSO). MS (APCI +) m/e 506 (M+H)+.

Example 479 <BR> <BR> <BR> N-14-N-(2-cvclohexvlmethvl-3-hvdroxvpropvl)amino-2-(2- <BR> <BR> <BR> <BR> <BR> <BR> <BR> methylphenyl)benzoyll methionine The desired compound was prepared according to the method of Examples 25A -25B 1H nmr (300 MHz, DMSO-d6): 6 7.37 (d, 1 H), 7.16 (m, 3 H), 7.02 (d, 1 H), 6.93 (m, 1 H), 6.58 (m, 1 H), 6.00 (m, 1 H), 4.45 (m, 1 H), 3.65 (m, 1 H), 3.38 (m, 2 H), 2.19 (m, 1 H), 2.03,1.97,1.93,1.92 (4 s's, 6 H), 1.96 (M, 1 H), 1.90-0.75 (m's, 14 H). MS (ESI -): rv/e 511 (M-H)-.

Example 481 N-[4-n-(4-trifluoromethylnicotinyl)amino-2-(2-methylphenyl)b enzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 57. 1H nmr (300 MHz, DMSO-d6): 6 11.04 (br s, 1 H), 9.05 (s, 1 H), 8.98 (d, 1 H), 7.90 (d, 1 H), 7.69 (br d, l H), 7.57 (m, 2 H), 7.23 (m, 4 H), 6.97 (m, 1 H), 3.70 (m, 1 H), 2.20 (m, 1 H), 2.03 (m, 1 H), 1.91 (br s, 6 H), 1.70 (m, 1 H ), 1.58 (m, 1 H). MS (ESI -): m/e 530 (M-H)-.

Example 502 N- [4-N-2-hvdroxyethvlamino-2-phenvlbenzovllmethionine The desired compound was prepared according to the method of Example 57, employing t-butyl bromoacetate. The resultant t-butyl ester was treated with TFA, and then reduced with borane. 1H NMR (CD30D): 6 1.68-1.81 (m, 1 H), 1.89-2.10 (m. l H), 2.01 (s, 3 H), 2.02-2.24 (comp, 2 H), 3.28 (t, J= 5.9 Hz, 2 H), 3.72 (t, J= 5.9 Hz, 2 H), 4.44 (dd, J= 4.4, 9.2 Hz, 1 H), 6.57 (d, J= 2.3 Hz, 1 H), 6.65 (dd, J= 2.4, 8.5 Hz. 1 H), 7.28- 7.44 (comp, 6 H). LRMS (CI): 389 (M+1)+ Example 503 N-[4-(N-2-amino-3-benzyloxypropionyl)amino-2-phenylbenzoyl)m ethionine The desired compound was prepared according to the method of Example 57 1H NMR (CD30D): 8 1.71-1.88 (m, 1 H), 1.90-2.28 (comp, 6 H), 3.65-3.72 (m, 1 H), 3.86- 3.94 (comp, 2 H), 4.24-4.31 (m, 1 H), 4.44-4.56 (m, 1 H), 4.62 (dd, J= 12.2, 29.2 Hz, 2 H), 7.23-7.58 (comp, 11 H), 7.62-7.70 (comp, 2 H). LRMS (CI): 522 (M+1 of free base)+

Example 504 <BR> <BR> <BR> <BR> N-L4-N-(furan-2-vlmethyl!-N-benzvlaminomethyl-2-(2-methylphe nvl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (CD30D): 6 1.57-1.70 (m, 1 H), 1.75-1.92 (comp, 2 H), 1.94-2.01 (comp, 6 H), 2.01-2.09 (br, 1 H), 3.56-3.67 (comp, 6 H), 4.17-4.29 (br, 1 H), 6.20-6.23 (m, 1 H), 6.33-6.36 (m, 1 H), 7.07-7.33 (comp, 8 H), 7.33-7.40 (comp, 2 H), 7.42-7.49 (comp, 2 H), 7.60-7.67 (m, 1 H). LRMS (CI): 543 (M+1 of protonated acid)+.

Example 505 N-f4-N-phenvl-N-benzvlaminomethyl-2-phenvlbenzovllmethionine The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.73-1.96 (comp, 2 H), 1.99 (s, 3 H), 2.12-2.32 (comp, 2 H), 5.53- 3.66 (comp, 2 H), 3.72-3.76 (br s, 1 H), 4.24-4.33 (comp, 2 H), 4.57-4.61 (br s, 1 H), 4.72 (s, 2 H), 6.58-6.96 (comp, 3 H), 7.06-7.19 (comp, 2 H), 7.25-7.42 (comp, 8 H), 8.53 (d, J= 7.7 Hz, 1 H). LRMS (CI): 479 (M+1)+.

Example 506 N-[4-N-(2-benzylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl ]methionine The desired compound was prepared according to the method of Example 157 1H NMR (CD30D): 6 1.63-1.80 (br, 1 H), 1.87-2.07 (br, 7 H), 2.07-2.23 (comp, 2 H), 4.02 (s, 2 H), 4.38-4.51 (comp, 3 H), 6.87-6.93 (br, 1 H), 6.96-7.44 (comp, 14 H), 7.58-7.64 (m, 1 H). LRMS (CI): 539 (M+1)+, 556 (M+NH4)+.

Example, 507 N-[4-N-(2-phenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylpheny l)benzoyl]methionine The desired compound was prepared according to the method of Example 157 1H NMR (CD30D): 8 1.55-1.68 (m, 1 H), 1.71-2.12 (comp, 9 H), 2.92 (t, 2 H), 3.63-3.71 (m, 2 H), 4.16-4.27 (br, 1 H), 4.52 (s, 2 H), 6.64 (t, 1 H), 6.74 (d, 2 H), 6.99-7.30 (comp, 13 H), 7.60 (d, 1 H). LRMS (ESI-): 551 (M-1)-.

Example 508 N-[4-N-(3-phenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylpheny l)benzoyl]methionine

The desired compound was prepared according to the method of Example 157 1H NMR (CD30D): 6 1.45-1.62 (m, 1 H), 1.63-2.05 (comp, 11 H), 2.52-2.61 (m, 1 H), 3.30- 3.39 (m, 2 H), 4.08-4.19 (br, 1 H), 4.50 (s, 2 H), 6.49-6.56 (comp, 3 H), 6.92-7.23 (comp, 13), 7.49-7.56 (m, 1 H). LRMS (ESI-): 565 (M-l)-.

Example 509 <BR> <BR> <BR> N-[4-N-(2,2-diphenvl)ethyl-N-phenyl)aminomethyl-2-(2-methvlp henyl)benzoyll methionine The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.46-2.02 (comp, 10 H), 3.38-3.42 (m, 1 H), 3.61-3.73 (br ,1 H), 4.16 (d, J= 7.3 Hz, 2 H), 4.31 (s, 2 H), 4.40-4.47 (m, 1 H), 6.55-6.67 (comp, 3 H), 6.78 (s, 1 H), 6.82-6.94 (br, 1 H), 7.05-7.21 (comp, 8 H), 7.22-7.30 (comp, 4 H), 7.35-7.41 (comp, 5 H). LRMS (CI): 629 (M+1)+.

Example 510 N-[4-(adamantan-1-ylmethyl)-N-phenyl)aminomethyl-2-(2- methylphenyl)benzoylmethionine The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.48-2.20 (br, comp, 25 H), 3.16-3.31 (br m, 1 H), 3.40-4.30 (br comp, 4 H), 4.65-4.74 (br m, 1 H), 6.49-6.57 (br m, 1 H), 6.68-6.75 (br comp, 2 H), 6.85-7.12 (br comp, 3 H), 7.14-7.25 (br comp, 5 H), 7.45 (d, J= 8.0 Hz, 1 H). LRMS (CI): 597 (M+1)+.

Example 511 N- 14-N-(2-adamantan- 1 -ylethyl)-N-phenyl)aminomethyl-2-(2- methylphenvl)benzoyllmethionine The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.28-1.37 (comp, 2 H), 1.47-1.71 (comp, 15 H), 1.88-2.10 (comp, 11 H), 3.33-3.47 (br comp, 2 H), 3.61-3.69 (br m, 1 H), 4.54 (s, 2 H), 6.55 (t, J= 7.1 Hz, 1 H), 6.63 (d, J= 8.1 Hz, 2 H), 6.88-6.94 (br m, 1 H), 6.97 (d, J= 1.3 Hz, 1 H), 7.07- 7.21 (comp, 5 H), 7.27 (dd, J= 1.7, 7.8 Hz, 1 H), 7.49 (d, J= 8.2 Hz, 1 H). LRMS (ESI- ): 609 (M-l)-.

Example 512 N-[4-N,N-dibenzylaminomethyl-2-(2-methylphenyl)benzoyl]methi onine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (d6-DMSO): 6 1.44-2.17 (comp, 10 H), 3.33-3.77 (comp, 7H), 6.90-7.56 (comp, 17 H). LRMS (ESI-): 551 (M-1 of protonated acid)-.

Example 513 N-[4-N-(2-phenylethyl)-N-benzylaminomethyxl-2-(2-methylpheny l)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (d6-DMSO): 6 1.65-1.90 (comp, 2 H), 1.96 (s, 3 H), 1.98-2.24 (comp, 5 H), 3.04- 3.20 (comp, 4 H), 4.17-4.32 (br, 1 H), 4.36-4.56 (br, 4 H), 7.03-7.34 (comp, 12 H), 7.43-7.53 (br, 3 H), 7.54-7.63 (comp, 2 H), 7.67-7.76 (comp, 2 H), 7.76-7.84 (m, 1 H), 8.32 (d, J= 7.3 Hz, 1 H), 11.42-11.64 (br, 1 H), 12.35-12.55 (br, 1 H). LRMS (CI): 567 (M+1)+.

Example 514 N-[4-N-(3-phenoxybenzyl)-N-benzylaminomethyl-2-(2-methylphen yl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (d6-DMSO): 6 1.65-1.90 (comp, 2 H), 1.95 (s, 3 H), 1.96-2.22 (comp, 5 H), 3.42- 3.58 (br, 2 H), 4.15-4.39 (comp, 5 H), 6.88-7.62 (comp, 19 H), 7.64-7.71 (m, 1 H), 8.05-8.22 (m, 1 H), 11.30-11.44 (br, 1 H). LRMS (CI): 645 (M+1)+.

Example 515 N-[4-N-(2-hydroxyethyl)-N-benzylaminomethyl-2-phenylbenzoyl] methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (d6-DMSO): 6 1.75-1.97 (comp, 2 H), 2.00 (s, 3 H), 2.15-2.34 (comp, 2 H), 3.00- 3.11 (br m, 2 H), 3.79-3.87 (br m, 2 H), 4.28-4.51 (comp, 5 H), 7.32-7.43 (comp, 3 H), 7.43-7.55 (comp, 6 H), 7.64-7.79 (comp, 4 H), 8.66 (d, J= 7.7 Hz, 1 H). LRMS (CI): 493 (M+1)+.

Example 516 N-[4-N-methyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (d6-DMSO): 6 1.65-1.91 (comp, 2 H), 1.96 (s, 3 H), 1.99-2.28 (comp, 5 H), 2.75 (s, 1 H), 3.05-3.25 (comp, 2 H), 3.25-3.44 (comp, 2 H), 4.17-4.30 (br, 1 H), 4.30-4.40 (m, 1 H), 4.46-4.56 (m, 1 H), 7.07-7.38 (comp, 9 H), 7.47-7.60 (comp, 2 H), 7.68-7.75 (m, 1 H), 8.33 (d, J= 7.0 Hz, 1 H), 11.10-11.26 (br, 1 H), 12.50-12.86 (br, 1 H). LRMS (CI): 491 (M+1)+.

Example 517 N-[4-N-benzvl-N-pyrazin-2-vlaminomethyl-2-(2-methylphenyl)be nzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.46-2.09 (comp, 10 H), 3.59-3.70 (br, 1 H), 4.83-4.95 (comp, 4 H), 6.90-6.95 (br, 1 H), 7.00 (s, 1 H), 7.04-7.34 (comp, 10 H), 7.49 (d, J= 8. 1 Hz, 1 H), 7.80 (d, J= 2.6 Hz, 1 H), 8.04-8.05 (m, 1 H), 8.07-8.10 (m, 1 H). LRMS (ESI-): 539 (M- 1 of protonated acid)-.

Example 518 N-14-N-(2-phenvethvl)-N-pvrimidin-5-vlaminomethvl-2-(2- methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157 1H NMR (d6-DMSO): 6 1.46-2.05 (comp, 10 H), 2.88 (t, J= 7.5 Hz, 2 H), 3.56-3.65 (br, 1 H), 3.73 (t, J= 7.5 Hz, 2 H), 4.66 (s, 2 H), 6.90-7.01 (br comp, 2 H), 7.05-7.31 (comp, 10 H), 7.49 (d, J= 7.8 Hz, 1 H), 8.23 (s, 2 H), 8.41 (s, 1 H). LRMS (ESI-): 553 (M-l of protonated acid)-.

Example 519 N-[4-N-(2-indol-3-ylethyl)aminomethyl-2-(2-methylphenyl)benz oyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 1.48-1.75 (m, 2H), 1.75-1.97 (m, 3H), 1.93 (s, 3H), 1.99 (m, 2H), 2.06-2.15 (m, 2H), 2.74-2.87 (m, 4H), 3.65 (brs, 1H), 3.79 (m, 2H), 6.88-6.93 (m, 1H), 6.93 (ddd, J=6.8, 6.8, 1.0 Hz, 1H), 7.03 (ddd, J=6.8, 6.8, 1 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.10-7.23 (m, SM), 7.30 (d, J=8 Hz, 1H), 7.36 (dd, J=8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H). MS (ESI(+)) m/z 516 (M+H)+. Anal calcd for C30H32N3O3SLi.1.30H2O: C, 66.1 1; H, 6.40; N, 7.71. Found: C, 66.15; H. 6.38; N, 7.64.

Example 520 N-[4-N-(2-cyclohexyl-1-ethan-1-ol-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 60.93-1.19 (m, 6H), 1.35-1.77 (m, 4H), 1.77-2.06 (m, 7H), 1.91 (s, 3H), 2.18 (brs, 1H), 2.26 (m, 3H), 3.40-3.48 (m, 1H), 3.59-3.70 (m, 1H), 3.73 (d, J=14.2 Hz, 1H), 3.81 (d, J=13.9 Hz, 1H), 4.36 (brs, 1H), 6.87-7.00 (m, 1H), 7.11- 7.27 (m, SH), 7.36 (d, J=8 Hz, 1H), 7.47 (d, J=8 Hz, 1H). MS (ESI(+)) m/z 499 (M+H)+. Anal calcd for C28H37N2O4SLi.0.75H2O: C, 64.91; H, 7.49; N, 5.41. Found: C, 64.92; H, 7.39; N, 5.21.

Example 523 N-[4-N-(1,3-diphenylpropan-2-yl)aminomethyl-2-(2-methylpheny l)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 1.48-1.74 (m, 2H), 1.74-2.02 (m, 3H), 1.93 (s, 3H), 2.03- 2.14 (m, 2H), 2.54-2.73 (m, 4H), 2.97 (pentet, J=6.5 Hz, 1H), 3.63-3.72 (brs, lH), 3.78 (s, 2H), 6.90 (brs, 2H), 7.05-7.26 (m, 16H), 7.37 (d, J=7.8 Hz, 1H). MS (ESI(+)) m/z 567 (M+H)+. Anal calcd for C3sH37N203SLi0.90H2O: C, 71.38; H, 6.64; N, 4.76.

Found: C, 71.40; H, 6.28; N, 4.69.

Example 524 N-[4-(1,3-dicyclohexylpropan-2-yl)aminomethyl-2-(2-methylphe nyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 60.70-0.88 (m, 4H), 1.01-1.17 (m, 8H), 1.20-1.38 (m, 4H), 1.46-1.64 (m, 12H), 1.64-1.75 (m, 2H), 1.92 (s, 3H), 1.94-2.02 (m, 2H), 2.13-2.18 (m, 2H), 3.60-3.76 (m, 3H), 6.84-6.97 (m, 1H), 7.04-7.24 (m, SM), 7.36 (dd, J=8, 1 Hz, 1H), 7.45 (d, J=8 Hz, 1H). MS (ESI(+)) m/z 579 (M+H)+. Anal calcd for

C35H49N2O3SLi.0.75H2O: C, 70.26; H, 8.51; N, 4.68. Found: C, 70.25; H, 8.52; N.

4.57.

Example 526 N-[4-N-(1-Cyclohexyl-6-methylhept-3-en-2-yl)aminomethyl-2-(2 - methvlDhenvl)benzovlImethionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 1.74-0.86 (m, 7H), 1.02-1.19 (m, 4H), 1.27-1.38 (m, 2H), 1.46-1.87 (m, 14H), 1.93 (s, 3H), 1.99 (s, 3H), 2.17 (m, 1H), 3.51-3.82 (m, 3H), 5.11 (m, 1H), 5.43 (m, 1H), 6.83-6.96 (m, 1H), 7.00-7.24 (m, SH), 7.24-7.36 (m, lH), 7.47 (d, J=7 Hz, 1H). MS (APCI(+)) m/z 565 (M+H)+. Anal calcd for C34H47N2O2SLi.2.02H2O: C, 67.20; H, 8.48; N, 4.61. Found: C, 67.24; H, 8.35; N, 4.47.

Example 527 N-[4-N-(1-Cyclohexyl-6-methylheptan-2-vl!aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 0.80 (d, J=5 Hz, 3H), 0.82 (d, J=5 Hz, 3H), 1.02-1.40 (m, 12H), 1.40-1.65 (m, 12H), 1.75-1.83 (m, 1H), 1.92 (s, 3H), 1.99 (m, 1H), 2.16 (m, 1H),

2.43 (m, lH), 3.60-3.77 (m, 3H), 6.86-6.95 (m, 1H), 7.08-7.22 (m, SH), 7.35 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H). MS (APCI(+)) m/z 567 (M+H)+. Anal calcd for C34H49N2O3SLi.1.15H2O: C, 66.99; H, 8.48; N, 4.60. Found: C, 67.03; H, 8.62; N, 4.49.

Example 528 N-[4-N-(1-Cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl)amino methyl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 0.72-1.35 (m, 10H), 0.85 (d, J=7 Hz, 3H), 0.87 (d, J=7 Hz, 3H), 1.43-1.76 (m, 6H), 1.82-2.14 (m, 4H), 2.00 (s, 3H), 2.06 (s, 3H), 3.07 (brs, 1H), 3.58 (s, lH), 3.96-4.14 (m, 2H), 4.40-4.59 (m, 2H), 4.99-5.23 (m, 4H), 6.08-6.10 (m, 1H), 7.17-7.35 (m, SH), 7.55 (m, 1H), 7.74 (m, 1H), 8.80 (brs, 0.5H), 9.25 (brs, 0.5H).

MS (DCI/NH3) m/z 599 (M+H)+. Anal. calcd for C34H50N2O5S.1.55H2O.1.05tfa: C, 55.70; H, 6.90; N, 3.51. Found: C, 55.72; H, 6.91; N, 3.38.

Example 529 N-[4-N-(1-Cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl) aminomethyl-2-(2-methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 6 0.80-1.40 (m, 16H), 1.45-1.77 (m, 6H), 2.00 (s, 3H), 2.04 (s, 3H), 1.80-2.13 (m, 4H), 3.20-3.40 (m, 1H), 3.59 (m, 1H), 3.39-4.10 (m, lH), 4.38-4.55 (m, 1H), 4.60-4.90 (m, 4H), 6.10 (m, 1H), 7.20-7.40 (m, SH), 7.55 (m, 1H), 7.80 (m, 1H), 9.0 (brs, lH). MS (DC1/NH3) m/z 599 (M+H)+. Anal calcd for C34H50N2O5S.1.00H2O.1.85TFA: C, 54.70; H, 6.56; N, 3.38. Found: C, 54.70; H, 6.59; N, 3.27.

Example 537 N-[4-(3-furan-2-yl-2-phenylprop-2-en-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Examples 158 IH NMR (MeOH-d4) # 7.69-7.61 (m, 1 H), 7.40-7.29 (m, 3 H), 7.22-7.17 (m, 9 H), 6.70 (dd, 1 H, J= 8.7, 2.6 Hz), 6.48 (bs, 1 H), 6.41-6.38 (m, 1 H), 6.15-6.13 (m, 1 H), 5.44 (d, 1 H, J= 3.4 Hz), 4.46-4.38 (m, 1 H), 4.10 (d, 2 H, J= 1.3 Hz), 2.18-1.85 (m, 8 H), 1.79-1.66 (m, 1 H), 1.59-1.52 (m, 1 H); MS m/z 541 (M+ + 1, 100).

Example 538 N-[4-(3-furan-2-yl-2-phenylprop-2-en-1-ylaminomethyl)-2-(2- methylphenyl)benzovllmethionine methvl ester The desired compound was prepared according to the method of Example 158 IH NMR (CDCl3) 6 7.93 (dd, 1 H, J= 17.7, 8.6 Hz), 7.42-7.27 (m, 6 H), 7.22-7.19 (m, 4 H), 6.67 (dd, 1 H, J= 8.8, 2.4 Hz), 6.52 (bs, 1 H), 6.33 (d, 1 H, J= 2.4 Hz), 6.15 (dd, 1 H, J= 3.4, 1.7 Hz), 5.70 (t, 1 H, J= 8.7 Hz), 5.52 (d, 1 H, J= 3.4 Hz), 4.62-4.55 (m, I H), 4.30-4.27 (m, 1 H), 4.14-4.11 (m, 2 H), 3.63 (s, 3 H), 2.18-2.00 (m, 8 H), 1.88-1.76 (m, 1 H), 1.56-1.48 (m, 1 H); MS m/z 555 (M+ + 1,100).

Example 540 N-[4-N-phenylacetylamino-2-(2-methylphenyl)benzoyl]methionin e lithium salt The desired compound was prepared according to the method of Example 57 1H NMR (DMSO-d6) 6 10.42 (s, 1 H), 7.60 (d, 1 H, J = 8.5 Hz), 7.51 (d, 1 H, J = 8.5 Hz), 7.47 (bs, 1 H), 7.34-7.28 (m, 3 H), 7.25-7.16 (m, 6 H), 6.97-6.85 (m, 1 H), 3.68-3.65 (m and s, 3 H total), 2.15-1.85 (m, 8 H), 1.78-1.64 (m, 1 H), 1.59-1.51 (m, 1 H); MS m/z 477 (M+ + 1, 100).

Example 541 N-[4-N-(4'-methyphenylacetyl)amino-2-(2-methylphenyl)benzoyl ]methionine lithium salt The desired compound was prepared according to the method of Example 57 l H NMR (DMSO-d6) 6 10.40 (s, 1 H), 7.60 (d, 1 H, J= 7.9 Hz), 7.51 (d, 1 H, J= 8.5 Hz), 7.46 (bs, 1 H), 7.22-6.83 (m, 9 H), 3.71-3.62 (m, 1 H), 3.60 (s, 2 H), 2.27 (s, 3 H), 2.23-1.86 (m, 8 H), 1.71-1.64 (m, 1 H), 1.60-1.52 (m, 1 H); MS m/z 491 (M+ + 1, 100).

Example 542 N-[4-N-(4'-methyphenylacetyl)amino-2-(2-methylphenyl)benzoyl ]methionine lithium salt The desired compound was prepared according to the method of Example 57 1H NMR (DMSO-d6) 6 7.67-7.63 (m, 2 H), 7.50-7.45 (m, 1 H), 7.26-7.09 (m, 6 H), 6.89- 6.85 (m. 2 H), 6.81-6.77 (m, 1 H), 4.24-4.20 (m, 1 H), 3.77 and 3.74 (2s, 3 H total), 3.62 and 3.39 (2s, 2 H total), 2.23-1.95 (m, 8 H), 1.89-1.78 (m, 1 H), 1.66-1.59 (m, 1 H); MS m/ 507 (M+ + 1, 100).

Example 543

N- [4-N-(3-phenylpropionyl)amino-2-(2-methylphenyl)benzoyl]meth ionine lithium salt The desired compound was prepared according to the method of Example 57 H NMR (DMSO-d6) 6 10.17 (bs, 1 H), 7.60 (d, 1 H, J= 7.9Hz), 7.51 (d, 1 H, J= 8.6Hz), 7.45 (bs, 1 H), 7.29-6.85 (m, 10 H), 3.71-3.65 (m, 1 H), 2.90 and 2.69 (2t, 2 H total, J= 7.9 Hz), 2.64 and 2.15 (2t, 2 H total, J= 7.9Hz), 2.17-1.83 (m, 8 H), 1.71-1.64 (m, l H), 1.59-1.53 (m, 1 H); MS m/z 491 (M+ + 1, 100).

Example 544 N- [4-N-(3-(2-methoxyphenyl)propionyl)amino-2-(2-methylphenyl)b enzoyl 1 methionine lithium salt The desired compound was prepared according to the method of Example 57 1H NMR (DMSO-d6) 6 10.10 (bs, 1 H), 7.59 (d, 1 H, J= 7.9Hz), 7.50 (d, 1 H, J= 8.6Hz), 7.45 (bs, 1 H), 7.22-7.09 (m, 6 H), 6.96 (d, 1 H, J= 7.9 Hz), 6.89-6.79 (m, 3 H), 3.78 and 3.76 (2s, 3 H total), 2.86 and 2.69 (2t, 2 H total, J= 7.9 Hz), 2.59 and 2.07 (2t, 2 H total, J= 7.9Hz), 2.17-1.84 (m, 8 H), 2.71-2.63 (m, 1 H), 1.58-1.53 (m, 1 H); MS m/z 521 (M+ + 1, 100).

Example 548 N- 4-N-benzvl-N-(thiazol-2-vlmethvl!aminomethvl-2-(2-methvlphen vl)benzovllmethionine The desired compound was prepared according to the method of Example 158 1H nmr (300 MHz, DMSO d6): 6 8.09, d, 1H; 7.72, d, 1H; 7.66, d, 1H; 7.50, m, 2H; 7.38,

m, 4H; 7.23, m, 4H; 7.14, m, 2H; 4.20, ddd, 1H; 3.89, s, 2H; 3.70, s, 2H; 3.68, s, 2H: 2.09, m, 4H; 1.96, s, 3H; 1.63 - 1.90, m, 2H. MS (APCI(+)) 560 (MH+). Calc'd for C3lH33iN303S2*0.32 H2O: C 65.84, H 6.00, N 7.43: Found: C 65.85, H 5.75, N 7.34 Example 549 N-[4-N-benzly-N-(thiazol-5-ylmethyl9aminomethyl-2-(2-methylp henyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158 1H nmr (300 MHz, DMSO d6): 6 12.45, bs, 1H; 9.03, s, 1H; 8.12, d, 1H; 7.79, s, 1H; 7.48, dd, 2H; 7.35, m, 4H; 7.04 - 7.28, m, 6H4.21, ddd, 1H; 3.81, s, 2H; 3.61, s, 2H; 3.58, s, 1H; 1.98 - 2.21, 5H; 1.96, s, 3H; 1.61 - 1.89, m, 2H. MS (APCI(+)) 560 (MH+). Calc'd for C31H33iN303S2O0.78 H2O: C 64.89, H 6.07, N 7.32: Found: C 64.89, H 5.71, N 7.29 Example 596 N-[4-N-(4-trans-pentafluorophenyloxycyclohexyl)aminomethyl-2 -(2~ methylphenylbenzoyl1 methionine A solution of trans-4-aminocylohexanol (3.03 g, 20.0 mmol) and diisopropylethylamine (7.4 mL, 42.0 mmol) in methylene chloride (30 mL) was treated with t-butyl dicarbonate (4.37 g, 20.0 mmol) over 5 minutes. The reaction stirred overnight at room temperature and was washed with 1 M HCl, 5% NaHCO3, and brine to give the Boc-

amine in nearly quantitative yield. A portion of this product (215 mg, 1.0 mmol) was combined with hexafluorobenzene (223 mg, 1.2 mmol) and 15-crown-5 (44 mg, 0.2 mmol) in DMF (3 mL) at room temperature. NaH (60% in oil, 4.4 mg, 1.2 mmol was added and stirred overnight. Standard aqueous workup provided 149 mg of the protected pentafluorophenyl ether which was treated with excess TFA in methylene chloride. stripped to dryness, and reductively alkylated and saponified in a manner analogous to Example 158 to provide 160 mg of the title compound. MS m/e 635 (M-H)-. 1H NMR (CDCl3, 300 MHz) 6 1.5 (m, 4H), 1.79 (m, 1H), 2.05 (m, 12H), 2.81 (m, lH), 4.05 (m, 4H), 6.25 (m, lH), 6.81 (m, 2H), 7.1-7.7 (m, 7H).

Example 598 <BR> <BR> N,-F4-(N-2-phenethvl-N-butanesulfonylaminomethvl)-2-(2- <BR> <BR> <BR> methvlphenyl)benzoyljmethionine The desired compound was prepared according to the method of Example 157. 1H (300MHz, DMSO-d6, 6) 7.62 (1H, d, J=7Hz), 7.52 (1H, dd, J=7&2Hz), 7.20-7.10 (10H, m), 7.14 (1H, bd, J=7Hz), 4.65 (2H, bs), 3.76 (1H, m), 3.00 (2H, m), 2.78 (2H, m), 2.25-2.00 (SH, m), 1.99 (3H, s), 1.90-1.70 (4H, m), 1.62 (2H, m), 1.37 (2H, m), 0.92 (3H, t, J=8Hz). m/e (ESI) 595 (MH-) Anal.calc. for C32H39LiN205S20.50 H2O C 62.83, H 6.59, N 4.38 Found C 62.59, H 6.59, N 4.44 Example 604

N-14-(2-cvclohexylethan- 1 -ol-2-ylaminomethyl)-2-(2-methvlphenvl)benzovll methionine Lithium Salt The desired compound was prepared according to the method of Example 158. 1H NMR (DMSO-d6, 300 MHz) 6 7.48 (d, J=8 Hz, 1H), 7.37 (dd, J=8, 1 Hz, lH), 7.20-7.08 (m, 4H), 6.90 (m, 1H), 4.40 (t, J=5 Hz, 1H), 3.82-3.65 (m, 3H), 3.46 (m, lH), 3.31 (m, 1H), 2.28-2.12 (m, 2H), 2.02-1.80 (m, 7H), 1.77-1.37 (m, 8H), 1.18-0.92 (m, SH); Anal.

Calcd for C2gH37LiN204S1.35 H2O: C, 63.58; H, 7.57; N, 5.30. Found: C, 63.55; H.

7.31; N, 4.89.

Example 605 N-[4-(N-benzyl-N-(2-cyclohexyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158. MS (C1/NH3) m/z: (M-H)- 571; 1H NMR (DMSO-d6, 300 MHz) 6 7.50 (d, J=8 Hz, lH), 7.38- 7.12 (m, 10H), 6.92 (d, J=6 Hz, 1H), 3.69 (m, 1H), 3.56 (s, 2H), 3.53 (s, 2H), 2.38 (t, J=7 Hz, 2H), 2.15-1.95 (m, 4H), 1.91 (s, 3H), 1.58-1.42 (m, 7H), 1.38-1.02 (m, 7H), 0.81-0.68 (m, 2H); Anal. Calcd for C35H43LiN2O3S.1.75 H2O: C, 68.89; H, 7.68; N, 4.59. Found: C, 68.85; H, 7.44; N, 4.37. Example 607

N-[4-(N-2-cyclohexyethylaminomethyl)-2-(2-methylphenyl)benzo yl)methionine Trifluoroacetate Salt The desired compound was prepared according to the method of Example 158. MS (Cl/NH3) m/z: (M+H)+ 483; 1H NMR (DMSO-d6, 300 MHz) 6 8.09 (m, 1H), 7.49-7.42 (m, 2H), 7.26 (m, 1H), 7.16-6.98 (m, 3H), 4.14 (m, 1H), 4.11(s, 2H), 2.87-2.80 (m, 2H), 2.11-1.90 (m, SH), 1.86 (s, 3H), 1.78-1.47 (m, 7H), 1.45-1.37 (m, 2H), 1.26-1.00 (m, 4H), 0.87-0.72 (m, 2H); Anal. Calcd for C28H38N203S'C2HF302' 1.45 H2O: C, 57.76; H, 6.93; N, 4.49. Found: C, 57.69; H, 6.51; N, 4.48.

Example 608 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl phenyl)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158. MS (Cl/NH3) m/z: (M+H)+ 497; 1H NMR (DMSO-d6, 300 MHz) 6 7.49 (d, J=8 Hz, 1H), 7.32 (dd, J=8, 1 Hz, 1H), 7.25-7.06 (m, 4H), 6.93 (d, J=6 Hz, 1H), 3.73-3.64 (m, 1H), 3.49 (s, 2H), 2.32 (t, J=7 Hz, 2H), 2.15 (m, 1H), 2.12 (s, 3H), 2.06-1.80 (m, 3H), 1.92 (s, 3H), 1.74-1.50 (m, 7H), 1.35-1.05 (m, 7H), 0.90-0.76 (m, 2H); Anal. Calcd for C29H39LiN203St1.05 H2O: C, 66.78; H, 7.94; N, 5.37. Found: C, 66.81; H, 7.75; N, 5.07. Example 609

N-[4-(N-acetyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methyl phenyl)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 607. The resultant amine was reacted with acetic anhydride - lithium carbonate under Schotten- Baumann conditions. MS (CIJNH3) m/z: (M-H)- 523; 1H NMR (DMSO-d6, 300 MHz) 7.59 minor conformer 7.53 major conformer (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.25- 7. 14 (m, 3H), 7.07-6.96 (m, 2H), 4.63 minor conformer 4.57 major conformer (s, 2H), 3.80 (m, lH), 3.33-3.25 (m, 2H), 2.21-1.85 (m, 10H), 1.77-1.56 (m, 7H), 1.44-1.30 (m, 3H), 1.25-1.07 (m, 4H), 0.95-0.83 (m, 2H); Anal. Calcd for C30H39LiN204S1.45 H2O: C, 64.72; H, 7.59; N, 5.03. Found: C, 64.75; H, 7.40; N, 4.71.

Example 610 N-[4-(N-(N,N-dimethylaminocarbonyl)-N-(2-cyclohexylethyl)ami nomethyl)-2-(2~ methvlohenvl)benzovl1 methionine The compound resulting from Example 607 was treated with dimethyl carbamoyl chloride under Schotten-Baumann conditions to yield the title compound. MS (CI/NH3) m/z: (M+H)+ 554; 1H NMR (DMSO-d6, 300 MHz) 68.18 (d, J=8 Hz, lH), 7.54 (d, J=8 Hz, 1H), 7.38 (dd, J=8, 2 Hz, 1H), 7.29-7.13 (m, 4H), 4.40 (s, 2H), 4.28 (m, 1H), 3.13- 3.06 (m, 2H), 2.80 (s, 6H), 2.29-2.06 (m, SH), 2.02 (m, 3H), 1.94-1.62 (m, 6H), 1.47- 1.15 (m, 7H), 0.96-0.84 (m, 2H); Anal. Calcd for C3lH43N3O4SO.45 H2O: C, 66.27; H, 7.88; N, 7;48. Found: C, 66.37; H, 8.10; N, 6.88.

Example 611 B-[4-(N-(2-cyclohexylethyl)-N-methanesulfonylaminomethyl)-2- (2- methylphenyl)benzoyl]methionine Lithium Salt The compound resulting from Example 607 was treated with methanesulfonyl chloride under Schotten-Baumann conditions to yield the title compound. MS (CVNH3) m/z: (M-H)- 559; 1H NMR (DMSO-d6, 300 MHz) 6 7.54 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.25-7.13 (m, 4H), 6.97 (d, J=7 Hz, 1H), 4.36 (s, 2H), 3.67 (m, 1H), 3.17-3.12 (m, 2H), 2.96 (s, 3H), 2.17-1.91 (m, 6H), 1.70-1.48 (m, 9H), 1.31-1.04 (m. 6H), 0.82- 0.69 (m, 2H); Anal. Calcd for C2gH3gLiN2OsS22.75 H2O: C, 56.52; H. 7.28; N, 4.55.

Found: C, 56.72; H, 6.49; N, 3.92.

Example 612 N-[4-(N-benzenesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2- (2- methylphenyl)benzoyl]methionine Lithium Salt The compound resulting from Example 607 was treated with benzenesulfonyl chloride under Schotten-Baumann conditions to yield the title compound. MS (Cl/NH3) m/z: (M-H)- 621; 1H NMR (DMSO-d6, 300 MHz) 6 7.86 (m, 1H), 7.72-7.59 (m, 4H), 7.51 (d, J=8 Hz, 1H), 7.36 (m, 1H), 7.26-7.07 (m, 4H), 6.96 (d, J=6 Hz, 1H), 4.36 (s, 2H), 3.66 (m, 1H), 3.10 (m, 2H), 2.16-1.92 (m, 5H), 1.70-1.40 (m, 7H), 1.30-0.99 (m, 6H), 0.90-0.61 (m, SH); Anal. Calcd for C34H41LiN2OsS251.25 H2O: C, 62.70; H, 6.73; N, 4.30. Found: 63.10; H, 6.72; N, 3.52.

Example 613 N-[4-(3-cyclohexylpropan-2-ylaminomethyl)-2-(2-methylphenyl) benzoyl]methionine The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+ 497; 1H NMR (DMSO-d6, 300 MHz) 67.63 (m, 1H), 7.52-7.43 (m, 2H), 7.25-7.04 (m, 4H), 4.06 (m, 1H), 3.97 (d, J= 14 Hz, 1H), 3.89 (d, J= 14 Hz, 1H), 2.85 (m, 1H), 2.17-1.94 (m, SH), 1.94 (s, 3H), 1.84-1.52 (m, 7H), 1.50-1.02 (m, 9H), 0.90-0.77 (m, 2H); Anal. Calcd for C2gH40N203S*1.55 H2O: C, 66.39; H, 8.28; N, 5.34. Found: 66.39; H, 7.89; N, 5.11.

Example 614 N- [4-(4-cyclohexylbutan-3-ylaminomethyl)-2-(2-methylphenyl)ben zoyl] methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (Cl/NH3) m/z: (M+H)+ 511; 1H NMR (DMSO-d6, 300 MHz) 67.48 (d, J=8 Hz, 1H), 7.36 (d, J=6 Hz, 1H), 7.25-7.09 (m, 4H), 7.00-6.85 m, 1H), 3.80-3.65 (m, 3H), 2.42 (m, 1H), 2.20-1.50 (m, 15H), 1.41-1.06 (m, 8H), 0.90-0.70 (m, 2H), 0.79 (t, J=7 Hz, 3H); Anal. Calcd for C30H41LiN2O3S.1.25 H2O: C, 66.83; H, 8.13; N, 5.20. Found: 66.86; H, 7.91; N, 4.93.

Example 615 N-[4-(6-cyclohexylhexan-5-ylaminomethyl)-2-(2-methylphenyl)b enzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M-H)- 537; 1H NMR (DMSO-d6, 300 MHz) 6 7.47 (d, J=8 Hz, 1H), 7.36 (dd, J=8, 1 Hz, 1H), 7.24-7.07 (m, 4H), 6.90 (m, 1H), 3.75-3.62 (m, 3H), 2.45 (m, 1H), 2.18-1.50 (m, l5H), 1.40-1.07 (m, 12H), 0.88-0.75 (m, SH); Anal. Calcd for C32H45LiN203S1.05 H2O: C, 68.19; H, 8.42; N, 4.97. Found: 68.19; H, 8.25; N, 4.77.

Example 616 N-[4-(1,2-dicyclohexylethylaminoethyl)-2-(2-methylphenyl)ben zoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CVNH3) m/z: (M+H)+ 565; 1H NMR (DMSO-d6, 300 MHz) 6 7.47 (d, J=8 Hz, 1H), 7.36 (m, 1H), 7.23-7.12 (m, 4H), 6.91 (m, 1H), 3.77-3.63 (m, 3H), 2.30 (m, 1H), 2.15 (m, 1H), 2.03-1.85 (m, 6H), 1.80-1.40 (m, 12H), 1.30-0.65 (m, 15H); Anal. Calcd for C34H47LiN203S-2.25 MeOH: C, 67.05; H, 8.15; N, 4.60. Found: 67.37; H, 7.69; N, 4.46.

Example 617 N- [4-(3-cyclohexylpropan- 1 -ol-2-vlaminomethvl)-2-(2-methvlphenvl)benzovl]methionine The desired compound was prepared according to the method of Example 158 MS (CVNH3) m/z: (M+H)+ 513; 1H NMR (DMSO-d6, 300 MHz) 67.85 (m, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=7 Hz, 1H), 7.23-7.05 (m, 4H), 4..18-4.12 (m, 2H), 3.92-3.84 (m, 2H), 3.45 (m, 1H), 2.65 (m, 1H), 2.18-2.00 (m, 4H), 1.85-1.55 (m, 6H), 1.38-1.08 (m, 10 H), 0.89-0.77 (m, 3H); Anal. Calcd for C29H40N2O4S.1.65 H2O: C, 64.21; H, 8.05; N, 5.16. Found: 64.26; H, 7.64; N, 4.77.

Example 618 N-[4-(3-cyclohexylpropan-1-o[-2-ylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine Trifluoroacetate Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+ 513; 1H NMR (DMSO-d6, 300 MHz) 67.85 (m, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=7 Hz, 1H), 7.23-7.05 (m, 4H), 4..18-4.12 (m, 2H), 3.92-3.84 (m, 2H), 3.45 (m, 1H), 2.65 (m, 1H), 2.18-2.00 (m, 4H), 1.85-1.55 (m, 6H), 1.38-1.08 (m, 10 H), 0.89-0.77 (m, 3H); Anal. Calcd for C29H40N2O4S.C2HF3O2.1.70 H2O: C, 56.64; H, 6.81; N, 4.26. Found: 56.67; H, 6.89; N, 4.11.

Example 619 N-[4-(2-cyclohexylprop-1-en-2-ylaminomethyl)-2-(2-methylphen yl)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M-H)- 507; 1H NMR (DMSO-d6, 300 MHz) 6 7.47 (d, J=8 Hz, lH), 7.32 (m, 1H), 7.25-7.07 (m, 4H), 6.93 (m, 1H), 5.52 (ddd, J=17, 10, 8 Hz, 1H), 5.05 (dd, J=10, 2 Hz, 1H), 4.97 (dd, J=17, 2 Hz, 1H), 3.77 (d, J=15 Hz, 1H), 3.70 (m, 1H), 3.57 (d, J=15 Hz, 1H), 2.94 (m, 1H), 2.17-1.50 (m, 15H), 1.38-1.06 (m, 6H), 0.90-0.77 (m, 2H); Anal. Calcd for C30H39LiN2O3S.1.90 H2O: C, 65.65; H, 7.86; N, 5.10. Found: 65.64; H, 7.34; N, 4.80.

Example 620 N-[4-(3-cyclohexyl-1-ethylsulfonylpropan-2-ylaminomethyl)-2- (2- methylphenyl)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+589; 1H NMR (DMSO-d6, 300 MHz) 6 7.52 (d, J=8 Hz, 1H), 7.38 (dd, J=8, 1 Hz, 1H), 7.27-7.10 (m, 4H), 6.97 (m, 1H), 3.83-3.68 (m, 3H), 3.33 (m, 1H), 3.20-3.07 (m, 3H), 2.97 (dd, J=14, 5Hz, 1H), 2.28-1.81 (m, 8H), 1.78-1.08 (m, 16H), 0.92-0.75 (m, 2H); Anal. Calcd for C31H43LiN2O5S2.4.25 H2O: C, 55.46; H, 7.73; N, 4.17. Found: 55.43; H, 6.94; N, 4.03.

Example 621 N-[4-(3-cyclohexyl-1-ethylsulfonylpropan-2-ylaminomethyl)-2- (2-methylphenyl)benzoyl]-2- amino-4-methanesulfonvlbutanoic acid Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M-H)-619; 1H NMR (DMSO-d6, 300 MHz) 6 7.53 (d, J=8 Hz, 1H), 7.37 (d, J=8 Hz, 1H), 7.25-7.09 (m, 4H), 6.97 (m, 1H), 3.78-3.65 (m, 3H), 3.25 (m, lH), 3.21-2.91 (m, 4H), 2.80 (s, 3H), 2.28-1.07 (m, 21H), 0.92-0.84 (m, 2H); Anal. Calcd for C31H43LiN207S2O1.25 H2O: C, 57.35; H, 7.06; N, 4.31. Found: 57.35; H. 7.03; N, 4.11.

Example 622 N-[4-(3-cyclohexyl-1-t-butylthiopropan-2-ylaminomethyl)-2-(2 - methylphenvl)benzovllmethionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CVNH3) m/z: (M+H)+584; 1H NMR (DMSO-d6, 300 MHz) 6 7.7.47 (d, J=8 Hz, 1H), 7.37 (dd, J=8, 1 Hz, 1H), 7.23-7.13 (m, 4H), 6.97 (m, 1H), 3.87-3.72 (m, 2H), 3.65 (m, 1H), 2.63 (m, 1H), 2.18-1.77 (m, 8H), 1.74-1.00 (m, 24 H), 0.91-0.68 (m, 2H); Anal.

Calcd for C33H47LiN203S2-4.50 EtOH: C, 59.39; H, 7.78; N, 4.70. Found: 59.65; H, 7.43; N, 3.91.

Example 623 N-[4-(3-cyclohexyl-1-phenylthiopropan-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+605; 1H NMR (DMSO-d6, 300 MHz) 6 7.7.46 (d, J=8 Hz, 1H), 7.34-6.85 (m, 11H), 3.86-3.65 (m, 3H), 3.11 (dd, J=13, 5 Hz, 1H), 2.87 (m, 1H), 2.67 (m, 1H), 2.17-0.60 (m, 23H); Anal. Calcd for C35H43LiN203S2O1.20 H2O: C, 66.47; H, 7.24; N, 4.43. Found: 66.43; H, 7.27; N, 4.49.

Examples 626-668 and Examples 669-758 Compounds 626-667, 669-722, and 723-727 were synthezised by reductive amination of the compound described in Example 625, by the procedure described in Example 158 R1 = Ph Example R3L1 MS(M+H)+ HSCH2 419 H 627 5N ,CH2 475 H 628 HO,N'CH2 417 H 629 \ 629 431 HO HN,CH2 N CH2 H 630 HJffi$NHCH2 445 445 HO s NH ,CH2

631 zH S 2,CH2 417 632 HO N,CH2 433 HO H 633 MeS/\ 477 HO, rY2 ,N'vl 634 HO N ,CH2 445 H 635 Th 458 N H,CH2 H 636 Y 486 N CH2 H 637 N'^ - N ,CH2 444 I H 638 J H,CH2 472 H 639 NYN,CH2 472 I H 640 ,Ns z N CH2 458 H 641 H 456 N ,,CH2 642 tF 453 H 643 CO2H 479 ,CH2 H 644 ° 478 NH2 vN,CH2 645 O z 527 ,CH2 H 646 EtO2 9 507 N OH2 H 647 HO <CO2H 495 N OH2 H 648 HO2CCN$HH2 459 H 649 vNXHCN 502 650 ¼¼MHN{CH2 479 H 651 < N ,CH2 450 NH2 652 MeO N N ,CH2 479 H 653 N N ,CH2 464 H2N 654 <° zN ,CH2 493 H 655 ,CH2 509 MeO OMe 656 MeOmN,CH2 539 MeO OMe 657 -OH 479 H 658 OH CH2 658 zor 479 HN- CH2 659 OMe 643 OMe HN 660 0 542 II 'CH2 660 MN 495 H2N'S..CH2 661 ,CH2 HO H 662 <e NCH2 662 Cl ,,,CH2 H 663 MN 469 663 < 469 H 664 -4'/, 495 664 ,,CH2 H H 665 1 551 H N,CH2 666 551 1<1 F\ H 667 H 495 N CH2 669 HONCH2 457 Pentyl 670 ½;:H,CH2 435 669 HO ,CH2 457 Pentyl 670 eOH 435 vN ,CH2 671 mOH 479 OH N ,CH2 671 H 478 CH2 H N u N ,CH2 674 < 449 < N ,CH2 551 675 FFF)½L CH2 F n 451 HO < N,CH2 H 677 < N H 561 H 678 519 519 F3CO v H ,CH2 679 < 493 MeO2Cv H ,CH2 H 465 HOX N ,CH2 H 681 477 H N 477 H H 682 MN 478 H2N ,CH2 H 683 z 478 N1h CH2 684 MN 493 HO2C ,,CH2 H 685 CO2H""' 507 ,,CH2 H 686 n 527 PhO/CH2 H 687 F >n 453 N ,CH2 H 688 19 561 N ,CH2 NH 689 HO s< 451 )½$NCH2 H 690 MeO 465 NN N CH2 H 691 F3CO >< 519 N N ,CH2 H 692 1 477 N N CH2 H 693 HOF3C 601 F3C 9 NoCH2 H 694 MN 479 OH 9 CH2 H 695 0 536 U ,CH2 CO2H H 696 OEt 585 EtO, N CI 585 O < N,CH2 H 697 \0- 518 N > NvCH2 H 698 O 9 520 v N N'CH2 H 699 < 517 < N-CH2 H 700 < 511 u N CH2 H 701 C > Ho 2 527 H 702 R 539 OH2 H 703 SN½¼HNPH2 568 704 N'C 463 N OH2 H 705 MN 475 ,CH2 H 706 523 N ,CH2 H 706 X H,CH2 523 707 < 601 NCH2 Br 708 /N N,CH2 486 H 709 )½NHCH2 1 463 463 NCH2 710 CO2H 523 HO2CAH ,CH2 H 711 02NCH2 538 712 Clam H ,CH2 517 H 713 ,CH2 509 N OH HO 714 ,,,, OH 493 1N ,CH2 H 715 OH 585 JN-CHP H D H H6 H 716 n 585 OH H HO H 717 0 601 N ,CH2 HO H H 718 N 491 Ph-(CH2)4" CH2 R1 = 2-MeC6H4- Example \ ,R3L1 MS (M+H)+ 719 HON'CH2 461 HO Me 720 0 459 CH2 Me 721 ¼;;;H 483 /N'CH2 723 1 <N-N 485 S H 2 H 724 43s N ,CH2 513 MeO2C H 725 MeO 549 H CH2 H 726 0 623 ,S. - H N 727 tN HNCH2 506

Examples 748-758 were prepared by the procedure described in Example 57 R1 = Ph Example R3LI MS (M+H)+ 748 H2N¼( NH 402 0 749 H > 416 750 H2N f NH 416 0 751 OMNH 511 752 z 492 Me2N NH 0 753 .OMe 513 753 NH 0 754 Br 558 MeO )t NH 0 HO. 489 755 HeI¼½ 489 NH 0 756 OMe 635 +NH I 0 757 ,NH No02

758 MeC OH 489 N H 0 758 MeO<OH ANH 489 Example 759 (2S)-2-N-[4-(N-benzyl-N-3-pyridylaminomethyl)-2-(2-methylphe nyl)benzoyl]amino-4- methanesulfonylbutanoic acid.

The desired compound was prepared according to the method of Example 157. H (300 MHz., DMSO d6): 6 12.8, (1H, s), 8.18, (1H, d J=8.Hz). 7.50 (2H, d, J-8Hz), 7.38 - 7.09 (14H. m). 4.83 (2H, s), 4.78 (2H, s), 4.21 (1H, s), 2.91 (3H, s), 2,76 (1H, m), 2.02. (1H, m), 2.00, (3fi, s), 1.85 (2H, m). MS (DCl - NH3) m/z 572 (MH+); Anal calcd for C32H33N3O5.1H2O: C. 65.18. H, 5.98. N, 7.13 Found: C. 65.54; H, 5.73; N, 6.82.

Example 762 N-[4-N-Benzoyl-N-2-cyclohexylaminomethyl-2-(2-methylphenyl)b enzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 607. The resultant amine was reacted with benzoyl chloride - lithium carbonate under Schotten- Baumann conditions. MS (CI/NH3) m/z: (M-H)- 585; 1H NMR (DMSO-d6, 300 MHz) 6 7.53 (m, 1H), 7.45-7.32 (m, 6H), 7.25-7.08 (m, 4H), 6.94 (m, 1H), 4.73-4.68 (m, 2H),

3.67-3.61 (m, 1H), 3.18-3.10 (m, 2H), 2.17-1.94 (m, 7H), 1.70-1.15 (m, 14H), 0.68- 0.55 (m, 2H); Anal. Calcd for C35H41LiN2O4S.1.80 H2O: C, 67.25; H, 7.19; N, 4.48.

Found: C, 67.23; H, 6.78; N, 4.28.

Example 763 N-[4-N-t-Butyloxycarbonvl-N-2-cvolohexylethylaminomethyl-2-( 2- methylphenvl)benzoyll methionine lithium salt The desired compound was prepared according to the method of Example 607. The resultant amine was reacted with di-t-butyl dicarbonate under Schotten-Baumann conditions.

MS (C1/NH3) m/z: (M-H)- 581; 1H NMR (DMSO-d6, 300 MHz) 7.51 (m, 1H), 7.31- 6.93 (m, 6H), 4.41 (s, 2H), 3.69-3.61 (m, 1H), 3.25-3.13 (m, 2H), 2.14 (m, 1H), 2.02- 1.91 (m, 2H), 1.91 (s, 3H), 1.66-1.51 (m, 8H), 1.45-1.05 (m, 16H), 0.88-0.75 (m, 2H); Anal. Calcd for C23H45LiN205S1.70 H2O: C, 64.00; H, 7.88; N, 4.52. Found: C, 63.99; H, 7.49; N, 4.33.

Example 764 Pivaloyloxymethyl N-[4-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl)-N-methylaminome thyl-2- (2-methylphenvl!benzovll-methionine hvdrochloride salt The desired compound was prepared by reaction of the compound resulting from Example 763 under conditions described in Example 500, followed by treatment with 4N HCl - dioxane. MS (CI/NH3) m/z: (M+H)+ 671; 1H NMR (DMSO-d6, 300 MHz) 8 8.42 (d, J=7.5 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.49-7.42 (m, 1H),

7.26-7.06 (m, 3H), 5.73 (d, J=5.8 Hz, 1H), 5.65 (d, J=5.8 Hz, 1H), 4.29 (brs. 2H), 3.25- 3.17 (m, lH), 3.04-2.97 (m, 1H), 2.86-2.77 (m, 1H), 2.24-2.02 (m, 6H), 1.94 (s, 3H), 1.83-1.40 (m, 12H), 1.25-1.07 (m, 6H), 1.13 (s, 9H), 0.93-0.77 (m, 2H); Anal. Calcd for C37HSSClN2OSS2: C, 62.82; H, 7.84; N, 3.96. Found: C, 62.71; H, 8.03; N, 3.90.

Example 765 N-[4-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl)-N-methylaminome thyl-2-(2- methylphenyl)benzoyl]-N-methylmethionine lithium salt The desired compound was prepared according to the method of Example 158. MS (C1/NH3) m/z: (M-H)- 569; 1H NMR (DMSO-d6, 300 MHz) 8 7.38 (d, J=7.8 Hz, 1H), 7.24-7.04 (m, 6H), 4.53-4.45 (m, 1H), 3.85-3.67 (m, 2H), 2.67-2.59 (m, 2H), 2.50-2.38 (m, SH), 2. 2.18-1.92 (m, SH), 1.87 (s, 3H), 1.70-1.05 (m, 17H), 0.93-0.72 (m, 2H); Anal.

Calcd for C32H4sLiN203S2*1.20 H2O: C, 64.23; H, 7.98; N, 4.68. Found: C, 64.27; H, 7.97; N, 4.66.

Example 766 N-[4-N-(2-Cyclohexyl-1-cyclohexylthiopropan-2-yl)-N-methylam inomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158. MS (CVNH3) m/z: (M-H)- 609; 1H NMR (DMSO-d6, 300 MHz) 8 7.48 (d, J=7.7 Hz, 1H), 7.34 (m, 1H), 7.21-7.06 (m, 4H), 6.96-6.88 (m, 1H), 3.83-3.66 (m, 3H), 2.64-2.54 (m,

2H), 2.15-1.90 (m, 4H), 1.90 (s, 3H), 1.87-1.02 (m, 26H), 0.87-0.75 (m, 2H); Anal.

Calcd for C3SH49LiN2O3S2.l.OS H2001.60 TFA: C, 56.08; H, 6.49; N, 3.42. Found: C.

56.05; H, 6.50; N, 3.49.

Example 767 <BR> <BR> N-{4-N-(3-Cyclohexyl- I -(2-methylphenyl)thiopropan-2-vl)-N-methylaminomethyl-2-(2- methylphenyl)benzoyl)methionine lithium salt The desired compound was prepared according to the method of Example 158. MS (CI/NH3) m/z: (M-H)- 617; 1H NMR (DMSO-d6, 300 MHz) 6 7.45 (d, J=7.8 Hz, 1H), 7.32-6.85 (m, 10H), 3.82-3.64 (m, 3H), 3.06 (dd, J=12.5, 4.4 Hz, 1H), 2.88-2.78 (m, 1H), 2.74-2.62 (m, 1H), 2.23 (s, 3H), 2.16-2.08 (m, 2H), 1.97-1.90 (m, 2H), 1.92 (s, 3H), 1.85-0.98 (m, 14H), 0.90-0.63 (m, 2H); Anal. Calcd for C36H45LiN2O3S2.1.0 H2O: C, 67.16; H, 7.51; N, 4.35. Found: C, 67.17; H, 7.30; N, 4.24.

Example 769 N-[4-N-(N-phenyl-N-benzenesulfonylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(CD3OD): 6 7.6-7.7 (2H, m); 7.5-7.6 (2H, m); 7.3-7.4 (1H, m); 7.3-7.1 (1OH, m);

6.9-7.1 (2H, m); 4.9 (2H, s); 4.1-4.3 (lH, m); 2.1-1.5 (lOH, m). ESI(-)/MS: 587(M-Li); 407.

Example 770 N-[4-N-(N-phenyl-N-toluenesulfonylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(CD3OD): 8 7.6-7.7 (2H, m); 7.5-7.6 (2H, m); 7.3-7.4 (lH, m); 7.3-7.1 (lOH, m); 6.9-7.1 (2H, m); 4.9 (2H, s); 4.1-4.3 (1H, m); 2.4 (3H, m); 1.5-2.1 (lOH, m). ESI(-)/MS: 601(M-Li); 421 Example 779 N-[4-N-(N-phenyl-N-(3-methoxybenzyl9aminomehyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(MeOH-d4): 8 7.6-7.7 (1H, d); 7.3-7.4 (1H, d); 7.0-7.3 (8H, m); 6.6-6.85 (6H, m); 4.7 (2H, s); 4.65 (2H, s); 4.18-4.3 (1H, m); 3.65 (3H, s); 1.5-2.2 (10H, m). ESI(-)/MS: 567(M-Li); 447; 366; 281.

Example 780 N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzenesulfonyl)aminome thyl)-2-(2-methylphenyl)- benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(MeOH-d4): 8 7.8-7.95 (4H, m); 7.5-7.6 (lH, d), 7.3-7.4 (1H, d); 7.1-7.3 (7H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (lH, m); 1.7-2.1 (lOH, m); 1.5-1.7 (lH, m).

ESI(-)/MS: 655(M-Li); 475. 431.

Example 781 N-[4-(N-phenyl-N-(4-chlorobenzyl)aminomethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(MeOH-d4): 8 7.6-7.7 (1H, d); 7.3-7.4 (1H, d); 7.18-7.30 (6H, m); 7.0-7.2 (4H, m); 6.6-6.78 (4H, m); 4.71 (2H, s); 4.64 (2H, s); 4.2-4.3 (1H, m); 1.55-2.2 (1 OH, m). ESI(- )/MS: 571(M-Li); 367, 255.

Example7 82 N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzyl)aminomethyl)-2-( 2-methylphenyl)- benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.

1H(MeOH-d4): 8 7.55-7.7 (3H, m); 7.3-7.5 (3H, m); 7.2-7.3 (3H, m); 7.0-7.18 (4H, m); 4.8 (4H, d); 4.18-4.3 (lH, m); 1.6-2.2 (lOH, m).

ESI(-)/MS: 605(M-Li); 367; 283.

Example 784 N-[4-N(t-Butylcarbazatocarbonylmethyl)amino-2-phenylbenzoyl] methionine The desired compound was prepared according to the method of Example 57, except t-Butylcarbazatocarbonylmethyl bromide was used as the alkylating agent. l H nmr (300 MHz, DMSO-d6): 8 9.79 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, l 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 806 N-[4-(1-ethoxycarbonylpiperidin-4-ylaminomethyl)-2-(2-methyl phenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 1H nmr (300 MHz, DMSO-d6): 8 7.48 (d, 1 H), 7.38 (dd, 1 H), 7.26-7.10 (m, 5 H), 6.90 (m, 1 H), 4.00 (q, 2 H), 3.88-3.73 (m, 4 H), 3.66 (m, 1 H), 2.85 (m, 2 H), 2.56 (m, 1 H), 2.18 (m, 2 H), 2.00 (m, 5 H), 1.92 (br s, 3 H), 1. 80 (m, 1 H), 1.76 (m, 1 H), 1.68 (m, 1 H), 1.58 (m, 1 H), 1.16 (t, 3 H). MS (ESI -): m/e 526 (M-H)-.

Example 830 <BR> <BR> <BR> N- F4-(N- 13-methylthio- 1 -carboxyprop-2-yl}aminocarbonyl)-2-phenylbenzoyllmethionine The desired compound was prepared according to the method of Example 451. 1H NMR (d6-DMSO): 8 1.64-1.91 (comp, 2 H), 1.93 (s, 3 H), 1.98-2.22 (comp, 10 H), 2.46- 2.62 (comp, 2 H), 4.18-4.28 (m, 1 H), 4.49-4.58 (m, 1 H), 7.14-7.26 (comp, 4 H), 7.58 (d, J= 7.8 Hz, 1 H), 7.74-7.79 (br s, 1 H), 7.96 (dd, J= 1.7, 7.8 Hz, 1 H), 8.24-8.32 (br, 1 H), 8.74 (d, J= 7.4 Hz, 1 H), 12.50-12.93 (br, 2 H). LRMS (ESI-): 517 (M-1)-.

Example 831 N-[4-(furan-2-ylmethyl)-N-isopropylaminomethy-2-(2-methylphe nyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158. tH NMR (d6-DMSO): 6 1.00 (d, J= 6.6 Hz, 6 H), 1.50-1.63 (m, 1 H), 1.63-1.76 (m, 1 H), 1.77-2.18 (comp, 8 H), 2.89 (sept, J= 6.6 Hz, 1 H), 3.56 (s, 2 H), 3.63 (s, 2 H), 3.66- 3.80 (br, 1 H), 6.23 (d, J= 2.9 Hz, 1 H), 6.35 (dd, J= 1.8, 3.3 Hz, 1 H), 6.93 (d, J= 6.2 Hz, 1 H), 7.10-7.26 (br comp, 4 H), 7.37 (d, J= 8.1 Hz, 1 H), 7.48 (d, J= 7.7 Hz, 1 H), 7.53 (dd, J= 0.7, 1.8 Hz, 1 H). LRMS (ESI-): 493 (M-l)-.

Example 832 N-[4-(furan-3-ylmethyl)-N-isopropylaminomethy-2-(2-methylphe nyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158. 1H NMR (d6-DMSO): 8 1.00 (d, J= 6.6 Hz, 6 H), 1.49-1.76 (comp, 2 H), 1.76-2.19 (comp, 8 H), 2.88 (sept, J= 6.6 Hz, 1 H), 3.37 (s, 2 H), 3.57 (s, 2 H), 3.68-3.78 (br, 21 H), 6.36 (s, 1 H), 6.93 (d, J= 6.2 Hz, 1 H), 7.08-7.26 (comp, 4 H), 7.39 (d, J= 8.1 Hz, 1 H), 7.48 (d, J= 7.6 Hz, 1 H), 7.52-7.57 (comp, 2 H). LRMS (ESI-): 493 (M-1)-.

Example 833 N-[4-N-benzyl-N-2-methoxyphenylaminomethyl-2-(2-methylphenyl )benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-2.10 (comp, 10 H), 3.60 (s, 3 H), 3.64-3.74 (br, 1 H), 4.69 (s, 2 H), 4.75 (s, 2 H), 6.15-6.18 (br comp, 2 H), 6.20 (d, J= 1.9Hz, 1 H), 6.29 (dd, J= 2.3, 9.2 Hz, 1 H), 6.90-7.03 (comp, 3 H), 7.08-7.34 (comp, 9 H), 7.50 (d, J= 7.7 Hz, 1 H).

LRMS (ESI-): 467 (M-l)-.

Example 834 N-[4-N,N-dibenzylaminomethyl-2-phenylbenzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158. 1H NMR (d6-DMSO): 6 1.74-1.95 (comp, 2 H), 1.99 (s, 3 H), 2.15-2.34 (comp, 2 H), 4.17- 4.37 (comp, 6 H), 7.21-7.55 (comp, 14 H), 7.60-7.75 (comp, 4 H), 8.57 (d, J= 7.8 Hz, 1 H). LRMS (CI+): 539 (M+1)+.

Example 835 N- 14-N-(2-phenvlethvl )-N-isopropylaminomethvl-2-(2-methylpbenyl jbenzovllmethionine lithium salt The desired compound was prepared according to the method of Example 158. 1H NMR (d6-DMSO): 8 0.94 (d, J= 6.3 Hz, 6 H), 1.50-1.77 (comp, 2 H), 1.77-2.20 (comp, 8 H), 2.56-2.66 (comp, 4 H), 2.92 (sept, J= 6.3 Hz, 1 H), 3.66 (s, 2 H), 3.70-3.81 (br, 1 H), 6.94 (d, J= 5.9 Hz, 1 H), 7.07-7.26 (comp, 9 H), 7.32 (d, J= 7.7 Hz, 1 H), 7.46 (dd, J= 1.8, 7.7 Hz, 1 H). LRMS (ESI-): 517 (M-1)-.

Example 836 N-[4-N-benzyl-N-pyrimidin-5-ylaminomethyl-2-(2-methylphenyl) benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 6 1.48-1.74 (br comp, 2 H), 1.86-2.08 (br comp, 8 H), 3.62-3.74 (br, 1 H), 4.83 (s, 2 H), 4.89 (s, 2 H), 6.92-7.03 (br, 1 H), 7.04-7.38 (comp, 11 H), 7.52 (d, J= 8.1 Hz, 1 H), 8.22 (s, 2 H), 8.42 (s, 1 H). LRMS (ESI-): 539 (M-l)-.

Example 837 N-[4-N-(1,3-benzodiox-5-yl)-N-pyrimidin-5-ylaminomethyl-2-(2 -methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.46-1.76 (br comp, 2 H), 1.84-2.05 (br comp, 8 H), 3.56-3.67 (br, 1 H), 4.71 (s, 2 H), 4.86 (s, 2 H), 6.77 (dd, J= 1.6, 7.8 Hz, 1 H), 6.83-6.88 (comp, 2 H), 6.90-6.98 (br comp, 2 H), 7.0 (s, 1 H), 7.07-7.24 (br comp, 3 H), 7.33 (dd, J= 1.9, 8.1 Hz, 1 H), 7.51 (d, J= 7.7 Hz, l H), 8.23 (s, 2 H), 8.42 (s, 1 H). LRMS (ESI-): 583 (M- 1)-.

Example 838 N-[4-N-(1,3-benzodiox-5-yl)-N-pyrimidin-2-ylaminomethyl-2-(2 -methylphenyl) benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.49-1.72 (comp, 2 H), 1.88-2.06 (comp, 8 H), 3.60-3.71 (br, 1 H), 4.75-4.80 (br, 2 H), 4.90 (s, 2 H), 5.96 (s, 2 H), 6.75 (dd, J= 1.7, 7.8 Hz, 1 H), 6.80- 6.83 (comp, 2 H), 6.90-6.96 (comp, 3 H), 7.05-7.22 (br, 3 H), 7.29 (dd, J= 1.7, 8.2 Hz, 1 H), 7.49 (d, J= 7.8 Hz, 1 H), 7.80 (d, J= 2.4 Hz, 1 H), 8.03-8.09 (comp, 2 H).

Example 839 N-[4-(N-benzyl-N-(2-methoxyphenyl)aminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.47-1.75 (comp, 2 H), 1.76-2.05 (comp, 8 H), 3.66-3.77 (br, 1 H), 3.83 (s, 3 H), 4.22 (s, 2 H), 4.26 (s, 2 H), 6.68-6.74 (m, 1 H), 6.81-6.98 (comp, 4 H), 7.02-7.08 (br, 1 H), 7.10-7.37 (comp, 9 H), 7.44 (d, J= 7.8 Hz, 1 H).

Example 840 N-[4-(N-benzyl-N-(4-methoxyphenyl)aminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.49-1.62 (m, 1 H), 1.62-1.75 (m, 1 H), 1.78-2.08 (comp, 8 H), 3.61 (s, 3 H), 3.64-3.76 (br, 1 H), 4.58 (s, 2 H), 4.64 (s, 2 H), 6.62-6.74 (comp, 4 H), 6.89- 6.96 (m, 1 H), 7.01 (s, 1 H), 7.08-7.33 (comp, 9 H), 7.47 (d, J= 7.8 Hz, 1 H).

Example 841 N-[4-(N-benzyl-N-(4-acetylphenyl)aminomethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-1.63 (m, 1 H), 1.63-1.75 (m, 1 H), 1.78-2.10 (comp, 8 H), 2.38 (s, 3 H), 3.66-3.76 (br, 1 H), 4.82 (s, 2 H), 4.88 (s, 2 H), 6.74 (d, J= 8.8 Hz, 2 H), 6.95 (d, J= 6.1 Hz, 1 H), 7.02 (s, l H), 7.08-7.36 (comp, 9 H), 7.52 (d, J= 8.1 Hz, 1 H), 7.72 (d, J= 8.8 Hz, 2 H).

Example 842 N-[4-(N-benzyl-N-(3-nitrophenyl)aminomethyl)-2-(2-methylphen yl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.49-1.76 (comp, 2 H), 1.77-2.08 (comp, 8 H), 3.67-3.76 (br, 1 H), 4.85 (s, 2 H), 4.90 (s, 2 H), 6.92-7.01 (br, 1 H), 7.05-7.43 (comp, 14 H), 7.53 (d, J= 7.8 Hz, 1 H).

Example 843 N- {4-(N-benzvl-N-(4-nitrophenvl)aminomethyl )-2-(2-methvlphenvl)benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-1.62 (m, 1 H), 1.62-1.74 (m, 1 H), 1.76-2.10 (comp, 8 H), 3.64-3.73 (br, 1 H), 4.90 (s, 2 H), 4.95 (s, 2 H), 6.82 (d, J= 9.5 Hz, 2 H), 6.94 (d, J= 6.1 Hz, 1 H), 7.02 (s, 1 H), 7.08-7.38 (comp, 9 H), 7.53 (d, J= 7.8 Hz, 1 H), 8.00 (d, J= 9.5 Hz, 2 H).

Example 844 N- [4-N-(N-benzyl-N-(2-acetylphenyl)aminomethyl)-2-(2-methvlphe nyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.45-1.70 (br comp, 2 H), 1.86-2.04 (comp, 8 H), 2.60 (s, 3 H), 3.56-3.66 (br, 1 H), 4.21 (app s, 4 H), 6.82-6.94 (br comp, 2 H), 6.99 (t, J= 7.4 Hz, 1 H), 7.08 (d, J= 7.7 Hz, 1 H), 7.16-7.34 (comp, 10 H), 7.39 (dd, J= 1.9, 7.7 Hz, 1 H), 7.45 (d, J= 8.0 Hz, 1 H).

Example 845 N-[4-N-(N-benzyl-N-(3-acetylphenyl)aminomethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-1.74 (br comp, 2 H), 1.85-2.08 (comp, 8 H), 2.43 (s, 3 H), 3.62-3.74 (br, 1 H), 4.78 (s, 2 H), 4.84 (s, 2 H), 6.90-7.04 (comp, 2 H), 7.07-7.36 (comp, 13 H), 7.51 (d, J= 7.8 Hz, 1 H) Example 846 N-[4-N-(N-benzyl-N-(2-chlorophenyl)aminomethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 1H NMR (d6-DMSO): 6 1.46-1.64 (br comp, 2 H), 1.76-2.03 (comp, 8 H), 3.15-3.19 (br, l H), 4.23 (s, 2 H), 4.26 (s, 2 H), 6.84-7.47 (comp, 16 H).

Example 847

N-[4-N-(N-benzyl-N-(3-chlorophenyl)aminomethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR(d6-DMSO): 8 1.48-1.75 (br comp, 2 H), 1.88-2.10 (comp, 8 H), 3.64-3.75 (br, 1 H), 4.74 (s, 2 H), 4.79 (s, 2 H), 6.57-6.66 (comp, 3 H), 6.90-7.36 (comp, 12 H), 7.52 (d, J= 7.7 Hz, 1 H).

Example 848 N-[4-N-(N-benzyl-N-(4-chlorophenyl)aminomethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 6 1.47-1.76 (br comp, 2 H), 1.89-2.10 (comp, 8 H), 3.65-3.77 (br, 1 H), 4.71 (s, 2 H), 4.77 (s, 2 H), 6.62-6.89 (comp, 2 H), 6.90-7.34 (comp, 13 H), 7.51 (d, J= 7.8 Hz, 1 H).

Example 849 <BR> <BR> N-r4-(N-benzvl-N-(2-nitrophenvl)aminomethvl)-2-(2-methvlphen vl!benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.46-1.71 (br comp, 2 H), 1.86-2.20 (br comp, 8 H), 3.58-3.70 (br, 1 H), 4.25 (s, 2 H), 4.27 (s, 2 H), 6.85-6.95 (br, 1 H), 6.98-7.36 (comp, 12 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.75 (dd, J = 1.7, 8.2 Hz, 1 H).

Example 850 N-[4-(N-benzyl-N-(2-methylthiophenyl)aminomethyl)-2-(2- methvlDhenvl)benzovlImethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-1.72 (br comp, 2 H), 1.86-2.03 (br comp, 8 H), 2.40 (s, 3 H), 3.58-3.68 (br, 1 H), 4.09 (s, 2 H), 4.13 (s, 2 H), 6.83-6.91 (br, 1 H), 6.95-7.31 (comp, 11 H), 7.33-7.44 (comp, 4 H).

Example 851 N-4-(N-benzvl-N-(3-methvlthiophenyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 1H NMR (d6-DMSO): 8 1.48-1.72 (br comp, 2 H), 1.89-2.09 (br comp, 8 H), 2.27 (s, 3 H), 3.62-3.71 (br, 1 H), 4.71 (s, 2 H), 4.77 (s, 2 H), 6.45-6.49 (comp, 3 H), 6.91-7.35 (comp, 12 H), 7.50 (d, J = 8.1 Hz, 1 H).

Example 852 N- r4-(N-benzvl-N-(4-methylthiophenvl)aminomethvl)-2-(2- methvlphenvl!benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.45-1.74 (br comp, 2 H), 1.88-2.08 (br comp, 8 H), 2.33 (s, 3 H), 3.58-3.67 (br, 1 H), 4.70 (s, 2 H), 4.76 (s, 2 H), 6.64 (d, J = 8.8 Hz, 2 H), 6.88-6.94 (br, 1 H), 7.00 (s, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.16-7.34 (comp, 9 H), 7.50 (d, J = 7.8 Hz, 1 H).

Example 853 N-[4-(N-benzyl-N-(4-trifluoromethylphenyl)aminomethyl)-2-(2- methylphenvl)benzovll methionine lithium salt The desired compound was prepared according to the method of Example 157. 1H NMR (d6-DMSO): 8 1.48-1.75 (br comp, 2 H), 1.90-2.06 (br comp, 8 H), 3.64-3.74 (br, 1 H), 4.81 (s, 2 H), 4.86 (s, 2 H), 6.79 (d, J = 8.8 Hz, 2 H), 6.90-7.35 (comp, 11 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 1 H).

Example 862 N-[4-N-(4-piperidin-1-ylphenyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine The desired compound was prepared according to the method of Example 158 MS m/e 530 (M-H)-. 1H NMR (CDC13, 300 MHz) # 1.55 (m, 3H), 1.78 (m, 4H), 1.85 (m, 1H), 2.0 (m, 8H), 3.03 (m, 4H), 4.3 (m, 3H), 6.13 (m, 1H), 6.54 (m, 2H), 6.98 (m, 2H), 7.10-7.52 (m, 6H), 7.74 (m, 1H).

Example 863 N-[4-N-(4-morpholin-1-ylphenyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine The desired compound was prepared according to the method of Example 158. MS m/e 534 (M+H)+. 1H NMR (CDC13, 300 MHz) 8 1.48 (m, 1H), 1.83 (m, 1H), 2.0 (m, 8H), 3.00 (m, 4H), 3.85 (m, 4H), 4.35 (m, 3H), 6.03 (m, 1H), 6.58 (m, 2H), 6.80 (m, 2H), 7.22 (m, 6H), 7.85 (m, 1H).

Example 864 N-14-N-(4-phenoxyphenvl)aminomethvl-2-(2-methvlphenyl)benzov llmethionine The desired compound was prepared according to the method of Example 158. MS m/e 539 (M-H)-. 1H NMR (CDC13, 300 MHz) 8 1.42 (m, 1H), 1.75 (m, 1H), 2.0 (m, 8H), 4.21 (m, 1H), 4.31 (s, 2H), 6.15 (m, 1H), 6.54 (m, 2H), 6.86 (m, 4H), 6.99 (m, 2H), 7.2 (m, 7H), 7.76 (m, 1H).

Example 875 N-[4-N-(benzyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methylp henyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158. 1H (300 MHz, DMSO d6): 8 9.08, d, 1H; 8.13, d, 1H; 7.58, d, 1H; 7.49, s, 2H; 7.40, d, 2H; 7.31, t, 2H; 7.22, m, 4H; 7.11, m, 2H; 4.21, m, 1H; 3.77, s, 2H; 3.67, s, 2H; 3.62, s, 2H; 1.98 - 2.23, m, 5H; 1.97, s, 3H; 1.63 - 1.90, m, 2H. MS (ESI(-)): 558 (M-H). Calc'd for C31H33N303S2 + 0.49 H2O: C 65.49, H 6.02, N 7.39: Found: C 65.49, H 5.86, N 7.27.

Example 876 N- 14-N-(benzvl-N-thiazol-5 -vlmethvl) aminomethyl-2-phenylbenzoyll methionine The desired compound was prepared according to the method of Example 158. 1H (300 MHz, DMSO d6): 8 9.04, s, lH; 8.46, d. lH; 7.82, s, 1H; 7.3, m, 13H; 4.27, ddd, 1H; 3.83, s, 2H; 3.64, s, 2H; 3.60, s, 2H; 2.21, m, 2H; 1.99, s, 3H; 1.84, m, 2H. MS (ESI(-)): 544 (M-H). Calc'd for C30H31N303S2: C 66.03, H 5.72, N 7.70: Found: C 65.65, H 5.81, N 7.50.

Example 877 N-[4-N-(tolueneslfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2 -methylphenyl)- benzovllmethionine The desired compound was prepared according to the method of Example 157. 1H (300 MHz, DMSO d6): 6 12.62, bs, 1H; 8.94, s, 1H; 8.08, bs, 1H; 7.79, d, 2H; 7.59, s, lH; 7.41, m, 3H; 7.20, m, 4H; 7.03, bs, lH; 6.90, bs, lH; 4.59, s, 2H; 4.38, s, 2H; 4.21, m, lH; 2.51, s, 3H; 2.40, s, 3H; 2.18, m, 2H; 1.98, s, 3H; 1.78, m, 2H. MS (ESI(-)): 622 (M-H). Calc'd for C31H33N3OsS3: C 59.69, H 5.33, N 6.74: Found: C 59.41, H 5.19, N 6.57.

Example 878 N-[4-N-(methanesulfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-( 2-methylphenyl)- benzoyllmethionine The desired compound was prepared according to the method of Example 157. 1H (300 MHz, DMSO d6): 89.00, s, 1H; 8.11, bs, 1H; 7.52, s, 1H; 7.46, d, 1H; 7.39, dd, 1H; 7.00 - 7.22, m, 5H; 4.63, s, 2H; 4.42, s, 2H; 4.21, m, 1H; 3.02, s, 3H; 1.98 - 2.23, m, 5H; 1.97, s, 3H; 1.64 - 1.91, m, 2H. MS (ESI(-)): 546 (M-H); (ESI(+)): 548. Calc'd for C25H29N3O5S3: C 54.82, H 5.34, N 7.67: Found: C 54.60, H 5.32, N .49.

Example 880 <BR> <BR> N-14-(N-2-Cyclohexvlethyl-N-cyclopropylaminomethyl!-2-(2 <BR> <BR> <BR> methylphenvl)benzoyllmethionine The desired compound was prepared according to the method of Example 158. 1H (300 MHz, DMSO d6): 8 8.06, d, lH; 7.47, d, lH; 7.31, dd, lH; 7.20, m, 2H; 7.02 - 7.17, m, 3H; 4.21, m, 1H; 3.71, s, 2H; 2.50, m, 2H; 1.98 - 2.23, m, 6H; 1.97, s, 3H; 1.68 - 1.90, m, 3H; 1.50 - 1.66, m, 4H; 1.37, m, 2H; 1.03 - 1.14, m, 4H; 0.81, m, 2H; 0.44, m, 2H; 0.30, m, 2H. MS (ESI(-)): 521 (M-H); ESI((+)): 523 (MH+). Calc'd for C31H42N303S: C 71.23, H 8.10, N 5.36: Found: C 70.25, H 8.05, N 5.31.

Example 881 N-[4-(N-tetrahydrothiopvran4-vl-N-thiazol-5-vlaminometbvl)-2 -(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 158. 1H (300 MHz, DMSO d6): 8 8.97, s, 1H; 8.08, d, 1H; 7.78, s, 1H; 7.44, dd, 2H; 7.00 - 7.25, m, SH; 4.20, ddd, 1H; 3.89, s, 2H; 3.71, s, 2H; 2.38 - 2.70, m, SH; 1.98 - 2.23, m,7H; 1.97, s, 3H; 1.59 - 1.91, m, 4H. MS (ESI(-)): 5688 (M-H); ESI((+)): 570. Calc'd for C29H35N303S3 + 0.45 H2O: C 60.27, H 6.26, N 7.27: Found: C 60.27, H 6.32, N 7.17.

Example 886 N-[4-N-t-Butyloxycarbonyl-N-(1,3-dicyclohexylpropan-2-yl)ami nomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158, followed by treatment with di-t-butyl dicarbonate, and hydrolysis. 1H NMR (300 MHz, DMSO) # 0.68-0.87 (m, 4H), 0.95-1.10 (m, 13H), 1.28 (s, 3H), 1.40 (s, 6H), 1.50-1.70 (m, 13H), 1.94 (s, 3H), 1.97-2.18 (m, 5H), 3.55-3.70 (m, lH), 4.20-4.40 (m, 3H), 6.85- 6.95 (m, 1H), 7.01-7.27 (m, SH), 7.30-7.42 (m, 1H), 7.42-7.53 (m, 1H). MS (APCI(+)) m/z 679 (M+H); Analysis calc'd for C40H57LiN2O5S.0.75H2O: C, 68.79; H, 8.44; N, 4.01; found: C, 68.77; H, 8.33; N, 4.04.

Example 887 N- [4-N-(3-Cvclohexyl- I -oxo- 1 -piperidin- 1 -vlpropan-2-yl)aminomethyl-2-(2- methylphenyl)benzovll -methionine lithium salt The desired compound was prepared according to the method of Example 158. 1H NMR (300 MHz, DMSO) # 0.65-0.90 (m, 2H), 1.00-1.24 (m, 10H), 1.30-1.70 (m, 15H), 1.90 (s, 3H), 1.92-2.18 (m, SH), 3.35-3.80 (m, 3H), 6.85-6.95 (m, 1H), 7.06-7.23 (m, SH), 7.32 (d, J=7.8 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H). MS (ESI(-)) m/z 592 (M-H); Analysis calc'd for C34H46-LiN3O4S.1.30H2O: C, 65.53; H, 7.86; N, 6.74; found: C, 65.53; H, 7.36; N, 6.41.

Example 890 N-[4-(N-(furan-2-ylmethyl)aminomethyl-2-phenylbenzoyl]methio nine lithium salt The desired compound was prepared according to the method of Example 158. H NMR (DMSO-d6, 90 °C) 6 7.48-7.24 (m, 9 H), 7.07-7.04 (m, 1 H), 6.37-6.34 (m, 1 H), 6.24-6.20 (m, 1 H), 3.76-3.69 (m, 5 H), 2.43-2.16 (m, 3 H), 2.00-1.66 (m, 5 H); MS m/z 439 (M+ + 1, 100). Anal. Calcd for C24H25LiN204S .2H2O (480.50): C, 59.99; H, 6.08; N, 5.83. Found: C, 59.83; H, 5.83; N, 5.74.

Example 902 N-[4-N-(thiazol-5-ylmethoxycarbonyl)amino-2-(2-methylphenyl) benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 57. H NMR (DMSO-d6,) # 9.93 (s, 1 H), 9.04 (s, 1 H), 7.93 (s, 1 H), 7.44 (s, 2 H), 7.19-7.06 (m, 4 H), 6.92-6.88 (m, 1 H), 6.78-6.74 (m, 1 H), 5.34 (s, 2 H), 3.61-3.56 (m, 1 H), 2.10-1.79 (m, 8 H), 1.77-1.63 (m, 1 H), 1.60-1.53 (m, 1 H); MS miz 498 (M+ - 1, 100).

Exact mass calcd for C24H26N305S2 500.1303, found 500.1308.

Example 905 N-[4-N-(1-ethylthio-4-methylpentan-2-yl)aminomethyl-2-(2-met hylphenyl)benzoyl]- methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, CDCl3, 6) 7.70 (1H, m), 7.43 (1H, d, J= 10Hz), 7.30-7.00 (5H, m), 6.25 (1H, m), 4.38 (lH, m), 4.06 (1H, m), 3.91 (lH, bd, J=12Hz), 3.01 (lH, m), 2.82 (lH, dd, J= 15&3Hz), 2.67 (1H, m), 2.45 (2H, q, J=8Hz), 2.05 (3H, s), 2.00 (3H, s), 2.00-1.80 (4H, m), 1.67 (lH, m), 1.53 (3H, m), 1.20 (3H, t, J=8Hz), 0.92 (3H, d, J=8Hz), 0.85 (3H, d, J=8Hz). m/z (ESI) 517 (MH+) Anal.calc. for C28H40N2o3S2 C 65.08, H 7.80, N 5.42 Found C 65.37, H 7.86, N 5.38

Example 906 N-[4-(N-(1-ethylthio-4-methylpentan-2-yl)-N-methylaminomethy l)-2-(2- methylphenyl)benzoyl]-methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, CDC13, b) (rotamer) 7.70 (lH, m), 7.52 (lH, d, J=lOHz), 7.40-7.10 (5H, m), 6.08 (1H, m), 4.43 (1H, m), 3.88 (2H, m), 3.15 (lH, m), 2.87 (lH, dd, J=15&3Hz), 2.60 (lH, m), 2.51 (2H, q, J=8Hz), 2.38 (2.36) (3H, s), 2.06 (2.13) (3H, s), 2.00 (3H, s), 2.00-1.60 (4H, m), 1.60-1.40 (3H, m), 1.22 (3H, t, J=8Hz), 0.92 (3H, d, J=8Hz), 0.88 (3H, d, J=8Hz). m/z (ESI) 531 (MH+) Analcalc. for C29H42N2O3S2.0.25 H2O C 65.07, H 8.00, N 5.23 Found C 65.01, H 7.84, N 5.14 Example 907 N-[4-(N-(1,3-Dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2 -(2-methylphenyl)- benzoyl]-methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, DMSO-d6, o) 7.50 (lH, d, J=12Hz), 7.33 (lH, m), 7.25-7.10 (3H, m), 7.08 (lH, m), 6.98 (lH, m), 3.82 (lH, m), 3.55 (2H, m), 2.20-2.00 (3H, m), 2.08 (3H, s), 1.93 (3H, s), 1.82 (3H, s), 1.75-1.40 (12H,m), 1.40-1.20 (5H, m), 1.20-0.90 (9H, m), 0.90-0.70 (3H, m). m/z (ESI) 593 (MH+)

Example 908 N-[4-(N-(1,3-Dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2 -(2-methylphenyl)- benzoyl]methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, DMSO-d6, o) (rotamer) 7.65 (1H, m), 7.49 (1H, bd, J=12Hz), 7.33 (1H, dd, J=12&2Hz), 7.30-7.00 (4H, m), 4.50 (2H, m), 4.10 (1H, m), 3.53 (lH, m), 3.20 (1H, m), 2.58 (lH, m), 2.20-2.00 (6H, m), 1.97 (1.92) (3H, s), 1.80-1.40 (14H,m, 1.40-1.20 (4H, m), 1.20-0.90 (8H, m), 0.90-0.60 (9H, d, J=9Hz). m/z (ESI) 635 (MH+) Anal.calc. for C39H58N2O3S.1.00 H2O C 71.74, H 9.26, N 4.29 Found C 71.60, H 8.90, N 4.27 Example 909 N-[4-(N-acetyl-N-(1,3-Dicyclohexylpropan-2-yl)aminomethyl)-2 -(2-methylphenyl)- benzoyllmethionine The desired compound was prepared according to the method of Example 158, followed by Schotten-Baumann acylation and subsequent hydrolysis 1H (300MHz, DMSO- d6, o) (rotamer) 12.60 (1H, m), 8.05 (1H, m), 7.48 (1H, m), 7.35 (1H, bd, J=12Hz), 7.20-6.90 (4H, m), 4.50 (2H, bd, J=18Hz), 4.22 (1H, m), 3.87 (1H, m), 3.10 (1H, m), 2.20-2.00 (4H, m), 2.08 (3H, s), 1.96 (1.94) (3H, s), 1.80 (3H,m), 1.60-1.30 (9H, m), 1.30-1.00 (14H, m), 0.80-0.60 (3H, m). m/z (ESI) 621 (MH+) Anal.calc. for C37H52N2O4S.0.50 H2O C 70.55, H 8.48, N 4.45 Found C 70.67, H 8.42, N 4.36\

Example 910 N-[4-(N-benzoyl-N-(1,3-Dicyclohexylpropan-2-yl)aminomethyl)- 2-(2-methylphenyl)- benzovllmethionine The desired compound was prepared according to the method of Example 909. 1H (300MHz, DMSO-d6, 8)12.60 (1H, m), 8.05 (lH, bd, J=12Hz), 7.47 (4H, m), 7.33 (2H, m), 7.25-7.10 (5H, m), 4.62 (2H, bs), 4.21 (lH, m), 3.82 (1H, m), 3.10 (lH, m), 2.20- 2.00 (4H, m), 1.96 (3H, s), 1.80 (3H,m), 1.60-1.30 (9H, m), 1.30-1.00 (14H, m), 0.80- 0.60 (3H, m). m/z (ESI) 683 (MH+) Anal.calc. for C42H54N204S 0.75 H2O C 72.43, H 8.03, N 4.02 Found C 72.24, H 7.72, N 3.93 Example 911 N-[4-(N-Benzenesulfoyl-N-(1,3-Dicyclohexylpropan-2-yl)aminom ethyl)-2-(2- methvlDhenvl)-benzovIlmethionine The desired compound was prepared according to the method of Example 157. 1H (300MHz, DMSO-d6, b) 7.83 (2H, bd, J=12Hz), 7.80-7.55 (3H, m), 7.49 (2H, m), 7.30- 7.00 (5H, m), 4.43 (2H, m), 4.22 (1H, m), 3.78 (1H, m), 3.20 (1H, m), 2.25-2.00 (4H, m), 1.97 (3H, s), 1.90-1.70 (3H,m), 1.60-1.40 (9H, m), 1.30-0.90 (14H, m), 0.80-0.40

(3H, m). m/z (ESI) 719 (MH+) Anal.calc. for C41H54N2O5S2.0.50 H2O C 67.64, H 7.61, N 3.85 Found C 67.74, H 7.48, N 3.79 Example 912 N-[4-(N-(N,N-dibutylacetamido)aminomethyl)-2-(2-methylphenyl )benzoyl]methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, DMSO-d6, 6) 7.96 (1H, m), 7.48 (1H, d, J=1OHz), 7.39 (lH, dd, J=12&2Hz), 7.25-7.00 (4H, m), 4.17 (1H, m), 3.80 (2H, s), 3.23 (2H, t, J=8Hz), 3.16 (2H, t, J=8Hz), 2.20-2.00 (5H, m), 1.96 (3H, s), 1.90-1.60 (2H,m), 1.41 (4H, m), 1.22 (4H, m), 0.85 (6H, q, J=8Hz). m/z (DCI, NH3) 542 (MH+) Anal.calc. for C30H43N3O4S.0.75 H2O C 64.89, H 8.08, N 7.57 Found C 64.83, H 7.94, N 7.33 Example 913 N-[4-(N-(N,N-dibutylacetamido)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyll methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, DMSO-d6, o) 7.53 (1H, d, J=1OHz), 7.38 (1H, dd, J=12&2Hz), 7.25-7.00 (4H, m), 4.23 (1H, m), 3.64 (2H, s), 3.48 (1H, m), 3.35-3.16 (4H, m), 3.14 (1H, m), 2.22 (3H, s), 2.20-2.00 (5H, m), 1.96 (3H, s), 1.90-1.60 (2H,m), 1.42 (4H, m), 1.19 (4H, m), 0.86 (6H, q, J=8Hz). m/z (ESI) 556 (MH+) Anal.calc. for C31H45N304S C 66.99, H 8.16, N 7.56 Found C 66.65, H 8.20, N 7.23

Example 914 N-[4-(N-(N,N-dibenzylacetamido)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, DMSO-d6, b) (rotamer) 7.76 (lH, m), 7.40 (1H, d, J=9Hz), 7.30-7.00 (15H, m), 4.41 (4H, d, J=12Hz), 4.10 (lH, m), 3.73 (2H, s), 3.41 (2H, s), 2.20-1.90 (5H, m), 1.87 (1.83) (3H, s), 1.80-1.50 (2H,m). m/z (ESI) 610 (MH+) Example 915 N-[4-(N-(2-Cyclohexylethyl)-N-isopropylaminomethyl)-2-(2-met hylphenyl)- benzovllmethionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, CDCl3, 6) 7.80-7.60 (2H, m), 7.30-7.00 (5H, m), 6.50 (1H, d, J=8Hz), 4.38 (1H, m), 4.03 (2H, m), 3.67 (1H, m), 2.88 (2H, m), 2.20-2.00 (7H, m), 2.00 (3H, s), 1.80-1.40 (8H, m), 1.33 (6H, d, J=7Hz), 1.30-1.00 (3H, m), 1.00-0.80 (2H, m). m/z (ESI) 525 (MH+) Anal.calc. for C3lH44N203S 0.50 H2O C 69.76, H 8.50, N 5.25 Found C 69.90, H 8.26, N 5.57

Example 916 N-[4-(N-Butanesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-( 2-methylphenyl)- benzoyllmethionine The desired compound was prepared according to the method of Example 157. 1H (300MHz, CDCl3, o) 7.99 (lH, m), 7.45 (1H, dd, J=9&2Hz), 7.40-7.10 (SH, m), 5.92 (1H, m), 4.56 (1H, m), 4.44 (2H, s), 3.20 (2H, m), 2.96 (2H, m), 2.20-2.05 (5H, m), 2.02 (3H, s), 2.00-1.70 (3H, m), 1.70-1.30 (lOH, m), 1.30-1.00 (4H, m), 0.95 (3H, t, J=8Hz), 0.83 (2H, m). m/z (ESI) 603 (MH+) Anal.calc. for C32H46N2O5S2.0.25 H2O C 63.28, H 7.72, N 4.61 Found C 63.27, H 7.73, N 4.50 Example 917 N-[4-(N,N-Dibutylaminomethyl)-2-(2-methylphenyl)benzoyl]meth ionine The desired compound was prepared according to the method of Example 158. 1H (300MHz, CDCl3, 6) 7.75 (lH, d, J=9Hz), 7.67 (1H, m), 7.30-7.10 (5H, m), 6.33 (1H, m), 4.42 (1H, m), 4.13 (2H, m), 2.95 (4H, m), 2.20-2.00 (5H, m), 2.00 (3H, s), 2.00- 1.80 (2H,m), 1.68 (4H, m), 1.33 (4H, m), 0.93 (6H, q, J=8Hz). m/z (DCI, NH3) 485 (MH+) Anal.calc. for C28H40N2o3S 1.00 H2O C 66.90, H 8.42, N 5.57 Found C 66.73, H 8.23, N 5.40

Example 927 N-f4-(N-Butanesulfonyl-N-(3-phenylpropyl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 157 1H (300MHz, CDC13, a) 7.97 (lH, m), 7.40 (lH, dd, J=9&2Hz), 7.35-7.10 (8H, m), 7.04 (1H, d, J=2Hz), 7.03 (1H, s), 5.89 (1H, m), 4.60 (lH, m), 4.43 (2H, s), 3.22 (2H, t, J=8Hz), 2.96 (2H, t, J=8Hz), 2.55 (2H, t, J=8Hz), 2.20-2.05 (2H, m), 2.05 (3H, s), 2.02 (3H, s), 2.00-1.70 (5H, m), 1.57 (lH, m), 1.42 (2H, m), 0.94 (3H, t, J=8Hz). m/z (ESI) 609 (MH-) Anal.calc. for C33H42N205S2 C 64.89, H 6.93, N 4.59 Found C 64.61, H 6.90, N 4.52 Example 928 N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine The desired compound was prepared according to the method of Example 157 1H (300MHz, CDC13, a) 7.78 (1H, d, J=9Hz), 7.60 (1H, bd, J=8Hz), 7.40-7.20 (SH, m), 7.20-7.00 (SH, m), 6.27 (1H, m), 4.43 (1H, m), 4.20-4.00 (2H, m), 3.20-2.80 (6H, m), 2.20-2.05 (SH, m), 1.98 (3H, s), 1.90 (1H, m), 1.63 (3H, m), 1.32 (2H, m), 0.93 (3H, t, J=8Hz). m/z (ESI) 533 (MH+) Anal.calc. for C32H40N2O3S.1.00 H2O C 69.79, H 7.69, N 5.09 Found C 70.04, H 7.48, N 4.96

Example 936 N- {4-(N-benzylaminomethyl)-2-phenylbenzovllmethionine hydrochloride salt The desired compound was prepared according to the method of Example 158 (DMSO-d6) 88.61 (d,lH), 7.61 (m,lH), 7.58 (m, 3H), 7.40 (m, 9H), 4.32 (m, 1H), 4.22 (s, 2H), 4.18 (s, 2H), 2.27 (m, 2H), 2.00 (s, 3H), 1.88 (m, 2H). MS (DCVNH3) 449 (M+H)+. Anal calcd for C26H29C1N203S 0.80 H2O: C, 62.53; H, 6.18; N, 5.61.

Found: C, 62.59; H, 6.31; N, 5.57.

Example 944 N-[4-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl)-N-methylaminome thyl-2-(2- methylphenvl)benzoyll-methionine hvdrochloride salt The desired compound was prepared according to the method of Example 158 (DMSO-d6) 88.23 (m, 1H), 7.75 (m, lH), 7.59, 7.50 (both m, total 2H), 7.22, 7.15 (both m, total 4H), 4.50, 4.38 (both m, total 2H), 4.22 (m, lH), 3.10, 2.90, 2.70 (all m, total SH), 2.40, 2.10 (both m, total 7H), 1.98 (s, 3H), 1.90-1.40 (envelope, total 10H), 1.15, 1.00, 0.82 (all m, total 7H). MS (ESI) 569 (M-H)-. Anal calcd for C32H47C1N203S2 : C, 63.29; H, 7.80; N, 4.61. Found: C, 63.07; H, 7.79; N, 4.51.

Example 945 N-[4-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl)-N-isobutylamino methyl-2-(2- methylphenvl)benzoyl l -methionine The desired compound was prepared according to the method of Example 158 (DMSO-d6) 8 8.05 (d, lH), 7.55 (d, 1H), 7.42 (d, 1H), 7.22, 7.20 (both m, total SH), 4.27 (m, 1H), 3.73 (d, 1H), 3.60 (d, 1H), 2.90 (dd, lH), 2.77 (m, 1H), 2.45 (q, 2H), 2.30, 2.10 (both m, total 8H), 2.00 (s, 3H), 1.97-1.25 (envelope, llH), 1.19 (t, 3H), 1.19-0.70 (envelope, 12H), MS (ESI) 611 (M-H)-. Anal calcd for C33H52N2O3S2.0.25 H2O: C, 68.09; H, 8.57; N, 4.54. Found: C, 67.96; H, 8.53; N, 4.49.

Example 946 N-[4-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl)-N-formylaminome thyl-2-(2- methylphenvl!benzoyllmethionine The desired compound was prepared according to the method of Example 607, followed bt Schotten-Baumann acylation. (DMSO-d6) 8 8.40, 8.27 (both s, total lH), 8.03, 7.97 (both d, total 1H), 7.45 (m, 2H), 7.20, 7.15 (both m, total SH), 4.40 (m, 2H), 4.21 (m, 1H), 3.70 (m, 1H), 2.62, 2.46 (both m, total 4H), 2.18, 2.05 (both m, total SH), 1.96 (s, 3H), 1.90-1.20 (envelope, 9H), 1.10, 1.00, 0.75 (all m, total 9H). MS (ESI) 585 (M- H)-. Anal calcd for C32H44N204S2: C, 65.72; H, 7.58; N, 4.79. Found: C, 65.47; H, 7.53; N, 4.74.

Example 947 <BR> <BR> <BR> N- l4-N-acetvl-N-(3-Cvclohexyl- 1 -ethylthiopropan-2-yl)aminomethyl-2-(2-methylphenyl )- benzovllmethionine The desired compound was prepared according to the method of Example 946 (DMSO-d6) 88.12, 8.00 (both d, total 1H), 7.55, 7.45, 7.40 (all m, total 2H), 7.20, 7.10, 7.06 (all m, total SH), 4.65, 4.58 (both m, total 2H), 4.30, 4.20, 3.94 (all m, total 2H), 2.79, 2.60, 2.48 (all m, total 4H), 2.10, 1.97 (m, s, total llH), 1.90-1.20 (envelope, 9H), 1.15, 1.10, 0.80 (all m, total 9H). MS (ESI) 597 (M-H)-. Anal calcd for C33H46N204S2: C, 66.19; H, 7.74; N, 4.68. Found: C, 66.02; H, 7.68; N, 4.56.

Example 948 N-[4-N-t-Butyloxycarbonyl-N-(3-cyclohexyl-1-ethylthiopropan- 2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method of Example 946 (DMSO-d6) 7.95 (m, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.20, 7.10 (both m, total 5H), 4.40, 4.30, 4.20 (all m, total 4H), 2.60, 2.47 (both m, total 4H), 2.10 (m, 5H), 1.97 (s, 3H), 1.90-1.00 (envelope, 25H), 0.78 (m, 2H). MS (ESI) 655 (M-H)-. Anal calcd for C36H52N2O5S2: C, 65.82; H, 7.98; N, 4.26. Found: C, 65.56; H, 7.99; N, 4.20.

Example 949 N-14-N-Benzoyl-N-(3-Cvclohexyl- l -ethylthiopropan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine The desired compound was prepared according to the method of Example 946 (DMSO-d6) 6 8.10 (d, lH), 7.44 (m, 7H), 7.20 (m, 5H), 4.77, (d, 1H), 4.57 (d, lH), 4.22 (m, lH), 3.82 (m, 1H), 2.82 (m, 1H), 2.62 (m, lH), 2.23, 2.10 (both m, total 7H), 1.97 (s, 3H), 1.80 (m, 2H), 1.48, 1.38 (both m, total 5H), 1.06, 0.65 (both m, total 11H).

MS (ESI) 659 (M-H)-. Anal calcd for C38H48N2O4S2: C, 69.06; H, 7.32; N, 4.24.

Found: C, 68.94; H, 7.31; N, 4.17.

Example 950 N-[4-N-Butanesulfoyl-N-(3-Cyclohexyl-1-ethylthiopropan-2-yl) aminomethyl-2-(2- methvlphenyl)-benzovllmethionine The desired compound was prepared according to the method of Example 157 (DMSO-d6) 6 8.08 (d, 1H), 7.57 (s, 2H), 7.35, 7.25, 7.18 (all m, total SH), 4.44 (m, 2H), 4.28 (m, 1H), 3.87 (m, 1H), 3.10 (m, 2H), 2.77, 2.64, 2.55 (all m, total 4H), 2.10 (m, 5H), 2.00 (s, 3H), 1.95-1.50 (envelope, 8H), 1.42, 1.30, 1.20, 1.10 (m, m, t, m, total 12H), 0.90 (t, 3H), 0.80 (m, 2H). MS (ESI) 675 (M-H)-. Anal calcd for C35H52N2OsS3 C, 62.10; H, 7.74; N, 4.14. Found: C, 61.86; H, 7.57; N, 4.18.

Example 951 N-[4-N-Benzenesulfonyl-N-(3-cyclohexyl-1-ethylthiopropan-2-y l)aminomethyl-2-(2- methvlphenyl)-benzoyllmethionine The desired compound was prepared according to the method of Example 157 (DMSO-d6) 6 8.07 (d, lH), 7.86 (d, 2H), 7.70 (m, lH), 7.64 (m, 2H), 7.50 (s, 2H), 7.20 (m, SH), 4.50 (m, 2H), 4.22 (m, lH), 3.72 (m, 1H), 2.50-2.00 (envelope, 10H), 1.98 (s, 3H), 1.80 (m, 2H), 1.42, 1.20, 1.06, 0.90, 0.63 (m, m, t, m, m, total 15H). MS (ESI) 695 (M-H)-. Anal calcd for C37H48N2O5S3: C, 63.76; H, 6.94; N, 4.02. Found: C, 63.63; H, 6.93; N, 3.94.

Example 952 N-{4-(4-hydroxyprolinylamino)-2-phenylbenzoyl}methionine Example 952A N-[4-N-(N-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-L-proli nyl)amino-2-phenylbenzoyl]- methionine methyl ester To a solution of N-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-L-proline methyl ester (1.3 g, 3.6 mmol) in methanol (10 mL) was added 1N LiOH (5 mL) in an ice-bath. The reaction mixture was stirred for 30 min. The reaction mixture was adjusted to pH2-3 with 1N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned with dichloromethane and water, and extracted 3 times with dichloromethane. The combined organic solution was washed with 1N HCl and water, dried over anhydrous

magnesium sulfate, and concentrated in vacuo to give the corresponding acid 2 (1.05 g, 96 %) as a foamy solid. Without any purification, 2(1.0 g, 3.29 mmol) was dissolved in 15 ml of dichloromethane. To this solution was added triethylamine (550 uL, 3.9 mmol) in an ice- bath under argon, followed by IBCF (470 pL, 3.6 mmol). The reaction mixture was allowed to stir for 40 min. At this time TLC showed the absence of the starting material. To this solution 4-amino-2-phenylbenzoyl methionine methyl ester2 3 (1.07 g, 2.97 mmol) in dichloromethane (10 mL) was introduced. The reaction mixture was stirred overnight, during which time the ice-bath expired. The reaction mixture was washed with lN HCl, 5% sodium bicarbonate, and water, dried over magnesiun sulfate, and solvent was removed. The residue was flash-chromatographed on silica gel using a 7:3 solution of hexanes and EtOAc to yield 4 (1.92 g, 94 %) as a foamy solid: mp 830C; [ot]25D -36.2 (c=0.63, CHCl3); 1H NMR (300 MHz, CDCl3) 69.94 (s, lH), 7.53-7.26 (m, 8H), 6.41 (d, 1H, J=6.0Hz), 4.55 (m, 4H), 3.63 (s, 3H), 3.57 (m, 1H), 3.32 (m, lH), 2.30 (m, 1H), 2.05 (m, 2H), 1.94 (s, 3H), 1.83 (m, lH), 1.73 (m, lH), 1.45 (s, 9H), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3) 8 171.8, 170.7, 169.3, 155.6, 140.0, 129.7, 129.0, 128.5, 128.2, 127.4, 120.2, 117.7, 80.7, 77.2, 70.1, 59.5, 54.7, 52.1, 51.7, 38.0, 30.9, 29.5, 28.2, 25.5, 17.7, 15.1, 4.9; HRMS (EI) calculated for C35H51N307SSi: 685.9498, found: 685.3217. 1H NMR (300 MHz, CDC13+CD30D) 7.53-7.29 (m, 8H), 4.67 (m, 1H), 4.58 (s, 1H), 4.50 (m, lH), 2.57 (m, 1H), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, 1H), 1.76 (m, 1H); 13C NMR (CD30D) 6 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 119.3, 71.2, 60.6, 55.2, 52.9, 39.9, 31.4, 30.9, 15.0.

Example 952B N-[4-N-(N-t-butoxycarbonyl-4-hydroxy-L-prolinyl)amino-2-phen ylbenzoyl]methionine methyl ester To a solution of the above compound (1.82 g, 2.65 mmol) in THF (20 mL) was added 1M TBAF (3 mL). The reaction mixture was stirred for overnight, diluted with EtOAc, and washed 3 times with water. The combined aqueous washings were extracted 3 times with EtOAc. The combined organic fractions were dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using ethyl acetate as an eluent to obtain 5 (864 mg, 57%) as a white solid: mp 121-1230C; [a]25D -53.3 (c=0.43, CHCl3); 1H NMR (300 MHz, CDCl3) 6 9.84 (s, 1H), 7.60-7.38 (m, 8H), 6.35 (br s, 1H), 4.58-4.51 (br s, 4H), 3.64 (s, 3H), 3.57 (m, 1H), 3.48 (m, 1H), 2.63 (m, 1H), 2.44 (br s, 1H), 2.07 (m, 2H), 1.98 (s, 3H), 1.86 (m, 1H), 1.72 (m, 1H), 1.44 (s, 9H); HRMS (EI) calculated for C29H37N307S: 571.6872, found: 571.2352.

Example 952C

N-r4-N-(4-hydroxv-L-prolinvl)amino-2-phenvlbenzovllmethionin e trifluoroacetate (FTI- 2103) To a solution of the above compound (358 mg, 0.62 mmol) in methanol (6 mL)was added lN LiOH (1 mL) in an ice bath. The reaction mixture was stirred for 4 hr. The reaction mixture was adjusted to pH=2-3 with IN HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned with chloroform and water, and extracted 3 times with chloroform. The combined organic solution was washed with iN HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the resulting free acid (317 mg, 92 %) as a white solid. To a 5 ml of 1:1 solution of TFA and dichloromethane was added the acid (306 mg, 0.54 mmol). After 3 h, The reaction mixture was thoroughtly evaporated in high vacumm to give an oily residue. The residue was triturate with anhydrous ether and the white solid was collected by filtration to give 6 (254 mg, 72%): HPLC 90% (purity); mp 127 (sub.), 154-157 OC (dec.); 1H NMR (300 MHz, CDCl3+CD30D) 6 7.53- 7.29 (m, 8H), 4.67 (m, 1H), 4.58 (s, 1H), 4.50 (m, lH), 2.57 (m, 1H), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, lH), 1.76 (m, lH); 13C NMR (CD30D) 5 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 119.3, 71.9, 60.6, 55.2, 52.9, 39.9, 31.4, 30.9, 15.0.

Example 959 N-[4-((2S,4S)-4-thiolpyrrolidin-2-ylmethylamino)-2-phenylben zoyl]methionine Example 959A N- [4-N-((2R.3R)- 1 -t-butvloxvcarbonvl-3-t-butvldimethvlsilvloxvpvrrolidin-2- ylmethvlamino)-2-phenylbenzoyllmethionine methvl ester To a solution of N-[4-amino-2-phenylbenzoyl]methionine methyl ester (238 mg, 0.66 mmol) and (2R,3R)-1-t-butyloxycarbonyl-3-t-butyldimethylsilyloxypyrrol idine-2- carboxaldehyde (158 mg, 0.48 mmol) in methanol (5 mL) was added acetic acid (0.5 mL), followed by sodium cyanoborohydride (65 mg, 1 mmol). The reaction mixture stirred overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5%

sodium bicarbonate, and extracted 3 times with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesiun sulfate, and the solvent was removed. The residue was flash-chromatographed on silica gel using a 7:3 solution of hexanes and ethyl acetate to yield the title compound (284 mg, 88 %) as a white solid: 1H NMR (300 MHz, CDC13) 7.68 (d, lH, J=8.4 Hz), 7.40 (m, 6H), 6.62 (d, lH), 6.44 (br s, lH), 5.65 (d, 1H), 5.43 (s, 1H), 4.61 (m, 1H), 4.41 (br s, lH), 4.08 (br s, 1H), 3.64 (s, 3H),3.58-3.14 (m, SH), 2.10 (t, 2H, J=7.7 Hz), 2.01 (s, 3H), 1.88 (m, lH), 1.64 (m, lH), 1.43 (s, 9H); 0.88 (s, 9H), 0.07 (s, 6H); HRMS (EI) calculated for C35H53N3O6SSi: 671.3424, found: 671.3415.

Example 959B N-[4-N-((2R,3R)- l -t-butyloxvcarbonyl-3-hydroxypvrrolidin-2-vlmethylamino)-2- phenylbenzoyl]methionine methyl ester To a solution of the compound prepared in Example 959A (98 mg, 0.14 mmol) in THF (2 mL) was added 1M TBAF-THF (0.18 mL). The reaction mixture was stirred for 15 min at OOC, diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a 3:1 solution of ethyl acetate and hexanes to obtain the title compound (60 mg, 76.8 %) as a white solid: mp 67 OC; [ot]25D +6.32 (c=O.19, CHCl3); 1H NMR (300 MHz, CDCl3) 7.61 (d, 1H, J=8.3 Hz), 7.30 (m, 6H), 6.59 (dd, 1H, J=1.2, 8.3 Hz), 6.43 (d, 1H, J=2.1 Hz), 5.74 (d, 1H, J=7.6 Hz), 5.44 (br s, lH), 4.57 (m, 1H), 4.40 (m, 1H), 4.07 (br s, 2H), 3.59 (s, 3H), 3.37-3.16 (m, SH), 2.04(m, 2H), 1.96 (s, 3H), 1.87 (m, 1H), 1.65 (m, lH), 1.43 (s, 9H); HRMS (EI) calculated for C29H39N306S: 557.2559, found: 557.2544.

Example 959C N-[4-N-((2R.3S)- 1 -t-butvloxycarbonvl-3-acetylthiopyrrolidin-2-vlmethvlamino)- 2- phenylbenzoyl]methionine methyl ester To a solution of the compound prepared in Example 959B (300 mg, 0.53 mmol) in THF (10 mL) were added TPP (278 mg, 1.06 mmol), followed by DIAD (208 uL, 1.06 mmol) at 0° C under argon. The mixture was allowed to stir for 30 min and thiolacetic acid (76 CULL, 1.06 mmol) was added to this mixture at the same temperature. The reaction mixture was stirred overnight, during which time the ice-bath expired. The solution was concentrated. The crude products were chromatographed on silica gel using a 1:1 solution of hexanes and ethyl acetate to give the desired compound (211 mg, 64 %): 1H NMR (300 MHz, CDC13) 7.68 (d, 1H, J=8.2 Hz), 7.39 (m, 6H), 6.64 (br s, 1H), 6.44 (br s, 1H),

5.66 (d, 1H, J=7.4 Hz), 5.39 (br s, lH), 4.60 (m, lH), 4.03-3.87 (m, 2H), 3.62 (s, 3H), 3.42-3.11 (m, SH), 2.33 (s, 3H), 2.07 (t, 2H, J=7.6 Hz), 1.99 (s, 3H), 1.87 (m, lH), 1.64 (m, 1H), 1.43 (s, 9H); HRMS (EI) calculated for C31H41N3O6S2: 615.2436, found: 615.2437.

Example 959D N-[4-N-((2R,3S)-3-acetylthiopyrrolidin-2-ylmethylamino)-2-ph enylbenzoyl]methionine hvdrobromide To a solution of the compound prepared in Example 959C (106 mg, 0.17 mmol) in dichloromethane (10 mL) was added lM boron tribromide-dichloromethane (2.58 mL) at 0° C under argon. The mixture was allowed to stir for 1 hr at the same temperature.

Additionally the reaction mixture was stirred 4 hr at room temperature, and quenched by dropwise addition of water ( 5 mL). The solvent was removed to give crude residue.The residue was taken up with a 1:1 solution (1 mL) of water and THF, and purified by Prep- HPLC to give the desired 11(83 mg, 73.7 %) as a white power: 1H NMR (300 MHz, CD30D) 6 7.48-7.35 (m, 6H), 7.01 (d, 1H, J= 8.6Hz), 6.64 (s, 1H), 4.45 (dd, lH, J=4.1, 9.2 Hz), 3.92-3.81 (m, 2H), 3.69-3.65 (m, 1H), 3.55-3.40 (m, 4H), 2.55 ( m, 1H), 2.32 (s, 3H),2.22 (m, 1H), 2.09 (m, lH), 2.05 (s, 3H),1.97 (m, lH), 1.79 (m, lH).

Example 959E N-[4-((2S,4S)-4-thiolpyrrolidin-2-ylmethylamino)-2-phenylben zoyl]methionine To a solution of the compound described in Example 959D (80 mg, 0.12. mmol) in TFA (2 mL) was added mercuric acetate (0.38 g, 1.2 mmol) at OO C under argon. The reaction mixture was allowed to stir for 30 min at the same temperature. This solution was evaporated and the resulting solid was suspended in methanol ( 10 mL). Gaseous hydrogen sulfide was bubbled into the reaction mixture for 15 min. The black precipitate was removed <BR> <BR> <BR> by filtration. After removing methanol, the residue was taken up with a 1:1 solution ( mL) of water and THF, and purified by Prep-HPLC to afford the desired 12 (7.7 mg, 10.3 %) as a white powder: 1H NMR (300 MHz, CD30D) 8 7.45-7.39 (m, 6H), 6.74 (br s, 1H), 6.70 (br s, 1H), 4.44 (br s, 1H), 3.72-3.30 (m, 7H), 2.56 (br s, 1H), 2.18 (m, 1H), 2.02-1.96 (m, 2H), 2.01 (s, 3H), 1.80 (m, 1H).

Example 960 N-[4-((2S,4R)-4-thiolpyrrolidin-2-ylmethylamino)-2-phenylben zoyl]methionine Example 960A (2R,3S)-1-Boc-2-t-butyldimethylsilyloxymethyl-3-benzoyloxypy rrolidine To a solution of (2R,3S)-1 -Boc-2-t-butyldimethylsilyloxymethyl-3- hydroxypyrrolidine (1.52 g, 4.59 mmol) in THF (20 mL) was added TPP (2.41 g, 9.2 mmol), followed by dropwise addition of DIAD (1.82 mL, 9.2 mmol) in THF (10 mL) at 0°C under argon atmosphere. The mixture was allowed for 40 min and benzoic acid (1.12 g, 9.2 mmol) was added dropwisely to this mixture at the same temperature. The reaction mixture was stirred overnight, during which time the ice bath expired. The solvent was removed, and a 3:1 solution of hexanes and ethyl acetate was introduced to the resulting residue to precipitate the insoluble by-products. After removal of by-products, the solution was concentrated. The crude product was chromatographed on silica gel using a 9:1 solution of hexanes and ethyl acetate to yield 14 (1.3 g, 65 %) as a foamy solid: 1H NMR (300 MHz, CDCl3) 6 7.55-7.32 (m, SH), 5.49 (dd, 1H, J= 4.2, 11.7 Hz), 3.98-3.52 (m, SH), 2.40 (m, 1H), 2.07 (m, 1H), 1.47 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); MS (EI) m/z (relative intensity) 379 ([M-C4H8]+, 15), 322 (50), 154 (50), 105 (90), 77 (80).

Example 960B (2R.3S) 1 -Boc-2-t-butvldimethylsilvloxvmethvl-3-hvdroxypyrrolidine To a solution of the compound prepared in Example 960A (1.25 g, 2.86 mmol) in methanol (5 mL) was added 1N LiOH (3 mL) in an ice-bath. The reaction mixture was stirred for 2 hr. The reaction mixture was adjusted to pH2-3 with 1N HCl at the same temperature and the solvent was evaporated. The resulting residue was partitioned with dichloromethane and water, and extracted 3 times with dichloromethane. The combined organic fractions were dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a 3:1 solution of hexanes and ethyl acetate to obtain the desired compound (275 mg, 30%) as a white solid: mp 1 180C; [(x]22D -46.7 (c=0.47, CHCl3); 1H NMR (300 MHz, CDCl3) 6 4.34 (s, 1H), 3.77 (dd, 1H,

J= 3.0, 9.8 Hz), 3.66-3.29 (m, 4H), 2.54 (d, lH, J= 8.5 Hz), 2.09 (m, lH), 1.79 (m, 1H), 1.42 (s, 9H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (Cell3, minor isomer) 6 154.8, 79.7 (79.3), 74.6 (74.1), 67.0 (67.1), 63.2 (62.5), 44.7 (45.2), 31.7 (32.5), 28.7, 26.0, 18.3, -5.2; MS (EI) m/z (relative intensity) 275 ([M-C4H8]+, 20), 259 (85), 218 (100), 86 (40), 75 (55). 57 (90).

Example 960C (2R,3S) 1-Boc-2-t-butyldimethylsilyloxymethyl-3-t-butyldimethylsilyl oxypyrrolidine To a solution of the compound prepared in Example 960B (198 m g, 0.59 mmol) in dry DMF (2 mL) were added tert-butyldimethylsilyl chloride (110 mg, 0.71 mmol) and imidazole (102 mg, 1.5 mmol). The reaction mixture was stirred for 5 hr and then diluted with ether (20 mL).The reaction mixture was washed with brine, 1M HCl, and 5 % sodium bicarbonate. The organic layer was dried over magnesium sulfate, and concentrated in vacuo.

The crude product was purified by flash chromatography on silica gel using a 9:1 solution of hexanes and ethyl acetate to obtain the title compound (235 mg, 88%): 1H NMR (300 MHz, CDCl3) 8 4.27 (m, lH), 3.62-3.20 (m, SH), 1.88 (m, 1H), 1.62 (m, 1H), 1.36 (s, 9H), 0.78 (s, 18H), -0.03 (s, 12H); MS (CI, isobutane) m/z (relative intensity) 446 ([M+H]+, 60), 390 (10), 346 (100).

Example 960D (2R.3S) l-Boc-2-hvdroxvmethyl-3-t-butvldimethvlsilvloxvpvrrolidine To a solution of the compound prepared in Example 960C (229 m g, 0.51 mmol) in THF (2 mL) at 0°C were added water (2 mL) and acetic acid (6 mL). The reaction mixture was stirred for overnight at room temperature. After this time, the reaction mixture was concentrated under reduced pressure. The exess water was removed by azeotroping with toluene. The crude product was purified by flash chromatography on silica gel using a 9:1 solution of hexanes and ethyl acetate to obtain the title compound (96 mg, 56.8%): 1H NMR (300 MHz, CDC13) 4.41 (br s, 1H), 4.00 (s, 1H), 3.66-3.27 (m, SH), 1.88 (m, lH), 1.70 (m, lH), 1.42 (s, 9H), 0.83 (s, 9H), 0.03 (s, 6H).

Example 960E N-4-[(2R,3S) 1-Boc-3-t-butyldimethylsilyloxypyrrolidin-2-ylmethyl]amino)- 2- phenvlbenzoyll methionine methyl ester To a solution of DMSO (42 uL, 0.58 mmol) in dichloromethane (2 mL) were added trifluoroacetic anhydride (62 ul, 0.43 mmol) via syringe at -78 OC under the slight stream of argon. After 10 min, the compound prepared in Example 960D (96 mg, 0.29 mmol) in dichloromethane (2 mL) was added to this mixture at the same temperature. The reaction

mixture was stirred for 1 hr. To this solution was added triethylamine (122 ul, 0.87 mmol).

The reaction mixture was allowed for 1 hr at -780C, slowly warmed to room temperature and concentrated. After usual work-up, the crude aldehyde was used for the next step without purification. To a solution of N-[4-amino-2-phenylbenzoyl]methionine methyl ester hydrochloride (172 mg, 0.29 mmol) and the aldehyde in methanol (5 mL) were added acetic acid (0.5 mL), followed by sodium cyanoborohydride (38 mg, 0.58 mmol). The reaction mixture was allowed to react for overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5% sodium bicarbonate, and extracted 3 times with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesiun sulfate, and the solvent was removed. The residue was flash-chromatographed on silica gel using a 1:1 solution of hexanes and ethyl acetate to yield the title compound (142 mg, 73 %) as a oily residue: 1H NMR (300 MHz, CDCl3) 6 7.64 (d, lH, J=8.0 Hz), 7.35 (m, 6H), 6.55 (d, lH, J= 8.2 Hz), 6.37 (br s, lH), 5.67 (d, 1H, J=7.6 Hz), 5.55 (s, lH), 4.56 (m, lH), 4.21-3.15 (m, 7H), 3.59 (s, 3H), 2.04 (t, 2H, J=7.7 Hz), 1.95 (s, 3H), 1.83 (m, 1H), 1.60 (m, lH), 1.42 (s, 9H); 0.82 (s, 9H), -0.03 (s, 6H); 13C NMR (CDC13 minor isomer) 8 172.1, 168.6, 156.6, 155.0, 150.1 (149.6), 147.7 (141.4), 131.4,128.8 (128.6), 127.7, 122.6 (122.5), 113.5 (113.7), 110.9, 79.9 (80.2), 74.5, 64.9 (64.7), 60.4, 52.3, 51.8, 47.6, 45.2 (44.8), 33.1, 31.6 (31.9), 29.5, 28.4, 25.7, 21.0, 18.0, 15.3, 14.2, -4.6.

Example 960F <BR> <BR> <BR> N-4- f (2R,3 S) 1 -Boc-3-hydroxypyrrolidin-2-ylmethyllamino)-2-phenylbenzoyll methionine methyl ester To a solution of the compound prepared in Example960E (140 mg, 0.20 mmol) in THF (3 mL) was added 1M TBAF-THF (0.3 mL). The reaction mixture was stirred for 30 min at OOC and then quenched with saturated ammonium chloride. The reaction mixture was diluted with ethyl acetate, and washed 3 times with water. The combined aqueous washings were extracted 3 times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a 1:1 solution of ethyl acetate and hexanes to obtain the desired compound (85 mg, 76 %) as a oily residue: 1H NMR (300 MHz, CDCl3) 8 7.55 (d, lH, J=8.3 Hz), 7.30 (m, 6H), 6.45 (d, 1H, J=8.5 Hz), 6.31 (br s, 1H), 5.75 (br s, 1H), 5.54 (br s, 1H), 4.51 (m, 1H), 4.15-3.82 (m, 3H), 3.56 (s, 3H), 3.59-2.98 (m, 5H), 2.00 (m, 2H), 1.92 (s, 3H), 1.80 (m, 1H), 1.56 (m, 1H), 1.38 (s, 9H).

Example 960G

N-4-[(2R,3R) 1-Boc-3-acetylthiopyrrolidin-2-ylmethyl]amino)-2-phenylbenzo yl]methionine methyl ester To a solution of the compound prepared in Example 960F (85 mg, 0.15 mmol) in THF (3 mL) were added TPP (80 mg, 0.30 mmol), followed by DIAD (60 CULL, 0.30 mmol) at OO C under argon. The mixture was allowed to stir for 30 min and thiolacetic acid (22 COIL, 0.31 mmol) was added to this mixture at the same temperature. The reaction mixture was stirred overnight, during which time the ice-bath expired. The solution was concentrated.

The crude products were chromatographed on silica gel using a 1:1 solution of hexanes and ethyl acetate to give the desired compound (80 mg, 86.6 %) as a oily residue: 1H NMR (300 MHz, CDCl3) 8 7.65 (d, 1H, J=9.0 Hz), 7.37 (s, SH), 6.55 (d, 1H, J= 7.7 Hz), 6.37 (s, 1H), 5.66 (d, 1H, J=7.3 Hz), 5.44 (br s, 1H), 4.58 (m, lH), 4.40-3.98 (m, 3H), 3.60 (s, 3H), 3.38-3.06 (m, 3H), 2.32 (s, 3H), 2.21 (m, 1H), 2.07 (t, 2H, J=7.6 Hz), 1.99 (s, 3H), 1.87 (m, 1H), 1.64 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) 8 194.4, 172.2, 168.5, 156.0, 150.1, 141.8, 141.4, 131.4, 128.8, 128.7, 127.8, 122.2, 113.4, 111.0, 80.5, 60.4, 57.6, 52.4, 51.8, 46.3, 45.1, 44.8, 42.3, 31.7, 30.7, 29.5, 28.4, 15.3, 14.7; HRMS (EI) calculated for C31H41N3O6S2: 615.2436, found: 615.2436.

Example 960H N-4-[(2R,3R) 3-thiopyrrolidin-2-ylmethyl]amino)-2-phenylbenzoyl]methionin e hvdrobromide To a solution of the compound prepared in Example 960G (78 mg, 0.12 mmol) in dichloromethane (5 mL) was added 1M boron tribromide-dichloromethane (1.2 mL) at Oo C under argon. The mixture was allowed to stir for 1 hr at the same temperature. Additionally the reaction mixture was stirred 4 hr at room temperature, and quenched by dropwise addition of water ( 5 mL). The solvent was removed to give crude residue. Without purification, the crude thioacetate was dissolved in TFA (2 mL). To this solution, mercuric acetate (0.1 g, 0.31 mmol) was added at OO C under argon. The reaction mixture was allowed to stir for 30 min at the same temperature. This solution was evaporated and the resulting solid was suspended in methanol ( 10 mL). Gaseous hydrogen sulfide was bubbled into the reaction mixture for 5 min. The black precipitate was removed by filtration. After removing methanol, the residue was taken up with a 1:1 solution ( 1 mL) of water and THF, and purified by Prep-HPLC to afford the desired compound (17 mg, 23 %) as a white powder: 1H NMR (300 MHz, CD30D) 6 7.46-7.34 (m, 6H), 6.74 (m, 1H), 6.66 (s, lH), 4.46 (m, lH), 4.10-3.91 (m, 2H), 3.75-3.31 (m, 4H), 2.56-2.40 (m, 2H), 2.20-1.78 (m, 4H), 2.01 (s, 3H).

Example 979 N-[4-(N-2-chloroethoxycarbonyl)amino-2-phenylbenzoyl]methion ine The desired compound was prepared according to the method of Example 57 H NMR (CD30D): 6 1.68-1.82 (m, 1 H), 1.86-2.03 (comp, 4 H), 2.03-2.26 (comp, 2 H), 3.28 (m, 2 H), 3.72 (t, J= 5.8 Hz, 2 H), 4.44 (dd, J= 4.4, 9.2 Hz, 1 H), 6.58 (d, J= 2.3 Hz, 1 H), 6.66 (dd, J= 2.3, 8.5 Hz, 1 H), 7.27-7.46 (comp, 8 H). LRMS (CI): 389 (M- 62, loss of COCl)+.

Example 980 N-[4-(N-5-(4-Chlorophenyl)furan-2-ylmethyl-N-isopropylaminom ethyl)-2-(2- methylphenyl)benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, d6 DMSO) 8 7.59 - 7.55 (m, 2H), 7.44 (d, lH), 7.42 - 7.36 (m, 3H), 7.24 - 7.06 (m, SH), 6.88 (d, 1H), 6.36 (d, 1H), 3.69 (s, 2H), 3.65 (s, 2H), 2.96 (m, 1H), 2.16 - 1.50 (m, 1 lH) 1.04 (d, 6H) Calcd for the acid C34H3604N2SC1 APCI -Q1MS, MH- 603.

Example 982 N- F4-(N-Methvl-N-(l.l -dimethyl-2-phenvlethyl)aminomethyl)-2-(2-methvlphenvl)- benzovllmethionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 8 1.02 (s, 6H), 1.52-1.76 (m, 4H), 1.94 (s, 3H), 1.96-2.04 (m, 3H), 2.17 (s, 3H), 2.78 (s, 2H), 3.64-3.73 (m, 3H), 6.92 (d, J=5.0 Hz, 1H), 7.05-7.23 (m, 10H), 7.34 (dd, J=7.8, 1.5 Hz, 1H), 7.47 (d, J=7.8 Hz, lH). MS (APCI(+)) m/z 518 (M+H); Analysis calc'd for C3lH37LiN203S+0.85H2O: C, 68.96; H, 7.22; N, 5.19; found: C, 68.86; H, 6.60; N, 5.25.

Example 983 N-[4-(N-Methyl-N-(1,1-dimethyl-2-cyclohexylethyl)aminomethyl )-2-(2-methylphenyl)- benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 1H NMR (300 MHz, DMSO) 80.85-1.17 (m, 6H), 1.03 (brs, 6H), 1.30-1.35 (m, 2H), 1.51- 1.77 (m, 10H), 1.93 (s, 3H), 1.97-2.18 (m, 3H), 2.02 (s, 3H), 3.56 (brs, 2H), 3.59-3.74 (m, 1H), 6.92 (d, J=5.0 Hz, 1H), 7.11-7.23 (m, SH), 7.34 (d, J=7.7 Hz, 1H), 7.46 (d, J=7.8 Hz, lH). MS (APCI(+)) m/z 525 (M+H); Analysis calc'd for C31H43LiN2O3S+0.80H2O: C, 68.31; H, 8.25; N, 5.14; found: C, 68.29; H, 8.23; N, 5.04.

Example 986 <BR> <BR> N-14-(N-2-CvclohexVlethvl-N-thiazol-S-vlmethylaminomethvl)-2 -(2-methvlphenvl)benzoyll- methionine The desired compound was prepared according to the method of Example 157 1H nmr (300 MHz, DMSO d6): 8 9.02, s, 1H; 8.09, d, 1H; 7.76, s, 1H; 7.48, d, 1H; 7.37, dd, 1H; 7.21, m, 2H; 7.15, m, 3H; 4.21, m, 1H; 3.83, s, 2H; 3.61, s, 2H; 2.42, t, 2H; 1.98 - 2.23, m, 6H; 1.96, s, 3H; 1.65- -1.90, m, 2H; 1.55, m, 5H; 1.01 - 1.43, m, 6H; 0.80, m, 2H. MS (ESI(-)): 578 (M-H); (ESI(+)): 580. Calc'd for C32H41N303S2: C 66.29, H 7.13, N 7.43: Found: C 65.82, H 7.03, N 7.34.

Example 995 N-[4-(1-ethylthio-4-phenylbut-2-oxymethyl)-2-(2-methylphenyl )benzoyl]methionine The desired compound was prepared according to the method of Example 158 1H (300MHz, CDC13, o) 7.70 (1H, m), 7.38 (1H, dd, J=6&2Hz), 7.30-7.20 (6H, m), 7.20- 7.05 (3H, m), 7.04 (lH, bs), 6.12 (1H, m), 6.00-5.40 (2H, m), 4.38 (1H, m), 4.01 (1H, m), 3.85 (1H, d, J=12Hz), 3.00-2.50 (SH, m), 2.37 (2H, m), 2.20-2.00 (6H, m), 1.98 (3H, s), 1.86 (2H, m), 1.57 (1H, m), 1.07 (3H, t, J=8Hz). m/e (ESI) 565 (MH+) Anal.calc. for C32H40N2O3S2.0.50 H2O C 66.98, H 7.20, N 4.88 Found C 67.02, H 7.24, N 4.80

Example 996 <BR> <BR> <BR> <BR> N- [4-(N-cyclohexvlmethvl-N-butanesulfonvlaminomethyl)-2-(2- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> methvlphenvl)benzovll methionine The desired compound was prepared according to the method of Example 157 1H (300MHz, DMSO-d6, o) 7.54 (1H, m), 7.42 (1H, m), 7.30-7.10 (SH, m), 6.96 (1H, m), 4.40 (2H, m), 3.63 (lH, m), 3.08 (2H, m), 2.99 (2H, m), 2.17 (2H, m), 1.99 (2H, m), 1.90 (3H, s), 1.80-1.40 (10H, m), 1.37 (4H, m), 1.00 (2H, m), 1.87 (3H, t, J=8Hz), 1.73 (2H, m). m/e (ESI) 587 (MH-) Example 997 N-[4-N-benzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine, lithium salt Example 997A A solution of 4-aminobenzonitrile (2.41 g, 20.0 mmol) and benzaldehyde (2.14 g, 20.0 mmol) in dichloroethane solvent (30 mL) was treated with Na(OAc)3BH (6.69 g, 30.0 mmol) [CAUTION! - exothermic]. After 16 h the reaction mixture was carefully quenched by the addition of saturated aqueous NaHCO3 (60 mL), and the resulting biphasic mixture was extracted with ethyl acetate (60 mL + 2 x 30 mL). The combined organic extracts were rinsed with brine (30 mL), dried over MgS04, and concentrated under reduced pressure to provide an amber oil. Flash column chromatography eluting with hexane and ethyl acetate

using an elution gradient of 90:10 to 80:20 afforded 3.56 g of 997A as a white solid (86% yield).

1H NMR (CDCl3):8 4.37 (d, J = 5.4 Hz, 2 H), 2.58-4.66 (br, 1 H), 6.58 (d, J = 8.8 Hz, 2 H), 7;26-7.42 (comp, 7 H). LR MS (CI+): (M+H)+ calc for C14Hl3N2: 209; found: 209.

Example 997B A solution of 1 178C (2.50 g, 9.75 mmol) and lithium chloride (0.537 g, 12.7 mmol) in dimethyl formamide solvent (10 mL) was treated dropwise with a solution of thionyl chloride (1.78 g, 14.6 mmol) in dimethyl formamide solvent (5 mL). After 15 h the reaction mixture was poured into water (125 mL), and the resulting solution was extracted with diethyl ether (3 x 25 mL). The combined organic extracts were rinsed sequentially with water (2 x 20 mL), saturated aqueous sodium bicarbonate (3 x 20 mL), and then brine (20 mL). The organic portion was dried over MgSO4 and concentrated under reduced pressure to provide a colorless oil. Flash column chromatography eluting with hexane and ethyl acetate using an elution gradient of 96:4 to 94:6 afforded 2.63 g of 997B as a colorless oil (98% yield).

IH NMR (CDCl3):8 2.06 (s, 3 H), 3.61 (s, 3 H), 4.62 (s, 2 H), 7.07 (d, J = 7.0 Hz, 1 H), 7.17-7.31 (comp, 4 H), 7.45 (dd, J = 1.5, 8.1 Hz, 1 H), 7.97 (d, J = 8.1 Hz, l H). LR MS (CI+): (M+H)+ calc for C16H15C1O2: 274; found: 274; (M+NH4)+ calc for C16H18ClNO2: 292; found: 292.

Example 997C A heterogeneous mixture of 997A (0.466 g, 2.0 mmol), 4-chloromethyl-2-(2- methylphenyl)benzoic acid, methyl ester, 997B (0.550 g, 2.00 mmol), K2CO3 (0.553 g, 4.00 mmol), and tetrabutylammonium iodide (0.0754 g, 0.200 mmol) in acetonitrile solvent (5 mL) was heated to 70 OC. After 16 h the reaction mixture was returned to room

temperature, diluted with dimethylformamide (DMF) solvent (5 mL) and treated with solid LiOH (0.514 g, 12.0 mmol), and then heated to 90 OC for 10 h. The reaction mixture was returned to room temperature and diluted with additional DMF (10 mL). Triethylamine hydrochloride (1.40 g, 10.0 mmol) was added, followed by methionine methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy- 1,2,3-benzotriazin-4(3H)-one (HOOBT) (1.66 g, 10.0 mmol), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.96 g, 10.0 mmol). The mixture was heated to 60 OC for 18 h, cooled to room temperature, diluted with ethyl acetate (80 mL), and extracted with 2:1:1 H2O: saturated aqueous NaHCO3: brine (50 mL + 2 x 20 mL), followed by brine (10 mL). The organic layer was dried over MgSO4, filtered through silica gel with 1:1 hexane: ethyl acetate rinses, and concentrated under reduced pressure to yield an amber oil. Radial chromatography eluting with hexane and ethyl acetate using an elution gradient of 80:20 to 50:50 afforded 0.0365 g of 997C as a colorless oil (3.2So yield).

1H NMR (d6-DMSO):8 1.52-1.65 (m, 1 H), 1.79-1.91 (m, 1 H), 1.98-2.12 (comp, 8 H), 3.66 (s, 3 H), 4.56-4.67 (m, 1 H), 4.72 (s, 2 H), 4.75 (s, 2 H), 5.81-5.90 (br, 1 H), 6.69 (d, J = 8.9 Hz, 2 H), 7.00 (d, J = 1.7 Hz, 1 H), 7.15-7.88 (comp, 10 H), 7.42 (d, J = 8.9 Hz, 2 H), 7.93 (dd, J = 8.1, 13.2 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H36N303S: 578; found: 578. LR MS (ESI-): (M-H)- calc for C35H34N303S: 576; found: 576.

Example 997D N-[4-N-benzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine, lithium salt A solution of 997C (0.0375 g, 0.0649 mmol) in methanol solvent (0.3 mL) was treated with LiOH (0.078 mL of a 1 M aqueous solution, 0.078 mmol) to afford a cloudy, white mixture which gradually became clear and colorless. After 8 h the reaction mixture was diluted with H2O (2 mL) and extracted with diethyl ether (2 x 1 mL). The aqueous phase was lyophilized to provide 0.0332 g of 997D as a white solid (90% yield).

'H NMR (d6-DMSO):8 1.48-1.76 (comp, 2 H), 1.88-2.08 (comp, 8 H), 3.59-3.72 (br, l H), 4.83 (s, 2 H), 4.89 (s, 2 H), 6.76 (d, J = 9.1 Hz, 2 H), 6.90-6.96 (m, 1 H), 7.00 (s, 1 H), 7.07-7.37 (comp, 10 H), 7.47-7.53 (comp, 3 H). HR MS (FAB): (M+H)+ calc for C34H34N303S: 564.2321; found: 564.2325 (0.8 ppm error).

Example 998 N- 14-N-benzvl-N-(4-carboxamidophenvl)aminomethvl-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 998A Compound 998A was prepared in the same fashion as 997A (69% yield).

1H NMR (d6-DMSO):8 4.32 (d, J = 5.9 Hz, 2 H), 6.55 (d, J = 8.6 Hz, 2 H), 6.78-6.92 (br comp, 2 H), 7.20-7.26 (m, 1 H), 7.28-7.38 (comp, 4 H), 7.49-7.59 (br, 1 H), 7.60 (d, J = 8.6 Hz, 2 H). LR MS (CI+): (M+H)+ calc for C14H15N2: 227; found: 227.

Example 998B Compound 998B was prepared in the same fashion as 997C (5.7% yield).

1H NMR (d6-DMSO):8 1.70-1.85 (comp, 2 H), 1.96 (s, 3 H), 1.97-2.24 (comp, 5 H), 3.58 (s, 3 H), 4.23-4.33 (br, 1 H), 4.80 (s, 2 H), 4.85 (s, 2 H), 6.68 (d, J = 9.2 Hz, 2

H), 6.86-6.94 (br, 1 H), 7.04-7.36 (comp, 14 H), 7.48 (d, J = 8.2 Hz, 1 H), 7.50-7.60 (br, 1 H), 7.63 (d, J = 8.8 Hz, 2 H), 8.30 (d, J = 7.8 Hz, 1 H): LR MS (ESI+): (M+H)+ calc for C35H38N304S: 596; found: 596. LR MS (ESI-): (M-H)- calc for C35H36N304S: 594; found: 594.

Example 998C N-[4-N-benzyl-N-(4-carboxyamidophenyl)aminomethyl-2-(2- methylphenvl)benzovllmethionine, lithium salt Compound 998C was prepared in the same fashion as 997D (100% yield).

1H NMR (d6-DMSO):6 1.47-1.61 (m, 1 H), 1.62-1.73 (m, 1 H), 1.87-2.08 (comp, 8 H), 3.59-3.70 (m, 1 H), 4.78 (s, 2 H), 6.67 (d, J = 8.9 Hz, 2 H), 6.86-6.94 (br comp, 2 H), 7.01 (s, l H), 7.05-7.35 (comp, 8 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.54-7.61 (m, 1 H), 7.62 (d, J = 8.9 Hz, 1 H). HR MS (FAB): (M+Li)+ calc for C34H35LiN304S: 588.2508; found: 588.2502 (-1.0 ppm error).

Example 999 N- r4-N-benzvl-N-(4-sulfonamidophenvl)aminomethvl-2-(2- methylphenyl)benzoyl]methionine, lithium salt

Example 999A Compound 999A was prepared in the same fashion as 997A (51% yield).

1H NMR (d6-DMSO):6 4.34 (d, J = 6.3 Hz, 2 H), 6.63 (d, J = 8.8 Hz, 2 H), 6.90-6.94 (br, 2 H), 7.00-7.06 (m, 1 H), 7.20-7.26 (m, 1 H), 7.32-7.34 (comp, 4 H), 7.48 (d, J = 8.8 Hz, 2 H). LR MS (CI+): (M+H)+ calc for C13H15N2O2S: 263; found: 263.

Example 999B Compound 999B was prepared in the same fashion as 997C (1.3% yield).

1H NMR (CDCl3):8 1.51-1.63 (m, 1 H), 1.78-1.91 (m, 1 H), 1.95-2.16 (comp. 8 H), 3.63 (app d, J = 4.0 Hz, 3 H), 4.14-4.20 (m, 2 H), 4.37 (d, J = 5.1 Hz, 2 H), 4.52-4.83 (comp, 3 H), 5.83-5.91 (m, 1 H), 6.59 (dd, J = 2.6, 8.8 Hz, 2 H), 7.07 (d, J = 8.1 Hz, 1 H), 7.24-7.40 (comp, 9 H), 7.61 (app t, J = 7.4 Hz, 2 H), 7.85 (dd, J = 7.8, 18.0 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C34H38N3O5S: 632; found: 632. LR MS (ESI-): (M.)- calc for C34H37N3O5S: 631; found: 631.

Example 999C N-[4-N-benzyl-N-(4-sulfonamidophenyl)aminomethyl-2-(2- methvlphenvl)benzovllmethionine, lithium salt Compound 999C was prepared in the same fashion as 997D (90% yield).

1H NMR (d6-DMSO):8 1.46-1.82 (comp, 2 H), 1.86-2.16 (comp, 8 H), 3.59-3.73 (m, l H), 3.99 (s, 2 H), 4.31 (app d, J = 5.9 Hz, 2 H), 6.55 (d, J = 8.0 Hz, 2 H), 6.74-7.37 (comp, 14 H), 7.72-7.80 (br, 1 H). HR

MS (FTMS): (M+H)+ calc for C33H36N303S2: 618.2087; found: 618.2091 (-0.7 ppm error).

Example 1000 N-[4-N-benzyl-N-(4-N-benzoylsulfonamidophenyl)aminomethyl-2- (2- methvlphenvl)benzovllmethionine lithium salt Example 1000A Compound 1000A was prepared in the same fashion as 997A (81% yield).

1H NMR (CDCl3):8 4.39 (d, J = 4.7 Hz, 2 H), 4.67-4.73 (br, 1 H), 6.62-6.67 (m, 2 H), 7.29-7.42 (comp, 5 H), 7.43-7.47 (comp, 2 H), 7.53-7.59 (m, 1 H), 7.74-7.79 (m, 2 H), 7.92-7.95 (m, 2 H), 8.46-8.80 (br, 1 H). LR MS (CI+): (M+H)+ calc for C20H19N2O2S: 367; found: 367.

Example 1000B Compound 1000B was prepared in the same fashion as 997C (5.6% yield).

1H NMR (CDC13):6 1.52-1.66 (m, 1 H), 1.79-1.91 (m, 1 H), 1.99-2.10 (comp, 8 H), 3.65 (s, 3 H), 4.56-4.66 (m, 1 H), 4.72 (s, 2 H), 4.75 (s, 2 H), 5.86-5.93 (br, 1 H), 6.60-6.78 (comp, 2 H), 7.12-7.37 (comp, 9 H), 7.37-7.45 (comp, 3 H), 7.50-7.57 (m, 1 H), 7.87 (d, J = 7.8 Hz, 2 H), 7.86-7.94 (comp, 5 H), 8.02 (s, 1 H), 9.38 (s, 1 H), 10.70-10.86 (br, 1 H). LR MS (ESI+): (M+H)+ calc for C41H42N3O6S: 736; found: 736. LR MS (ESI-): (M-H)- calc for C41H40N3o6S: 734 found: 734.

Example 1000C N- [4-N-benzvl-N-(4-N-benzovlsulfonamidophenvl)aminomethvl-2-(2 - methylphenvl)benzovll methionine. lithium salt Compound 1000C was prepared in the same fashion as 997D (77% yield).

1H NMR (d6-DMSO):o 1.48-1.76 (comp, 2 H), 1.89-2.06 (comp, 8 H), 3.67-3.77 (br, 1 H), 4.29 (d, J = 5.9 Hz, 1 H), 4.74 (s, 2 H), 4.79 (s, 2 H), 6.49 (d, J = 8.9 Hz, 1 H), 6.60-6.66 (m, 2 H), 6.95-7.35 (comp, 15 H), 7.47-7.58 (comp, 2 H), 7.86 (d, J = 7.2 Hz, 2 H). LR MS (ESI-): (M-H)- calc for C40H38N306S2: 720; found: 720.

Example 1001 N-[4-N-benzyl-N-(4-propionylphenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1001A Compound 1001A was prepared in the same fashion as 997A (89% yield).

1H NMR (CDC13):6 0.97 (t, J = 7.4 Hz, 3 H), 1.73 (tq, J = 7.3, 7.4 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H), 4.39 (d, J = 4.0 Hz, 2 H), 4.56-4.63 (br, l H), 6.59 (d, J = 9.0 Hz, 2 H), 7.25-7.35 (comp, 5 H), 7.82 (d, J = 9.0 Hz, 2 H). LR

MS (CI+): (M+H)+ calc for C,7H20NO: 254; found: 254.

Example 1001B Compound 1001B was prepared in the same fashion as 997C (49% yield).

1H NMR (CDCl3):8 0.97 (t, J = 7.5 Hz, 3 H), 1.52-1.66 (m, 1 H), 1.73 (app q, J = 7.5 Hz, 2 H), 1.78-1.91 (m, 1 H), 1.99-2.13 (comp, 8 H), 2.82 (t, J = 7.5 Hz, 2 H), 3.66 (s, 3 H), 4.53-4.67 (m, 1 H), 4.73 (s, 2 H), 4.76 (s, 2 H), 5.84-5.90 (m, 1 H), 6.71 (d, J = 8.9 Hz, 2 H), 7.04 (d, J = 1.7 Hz, 1 H), 7.14-7.37 (comp, 10 H), 7.82 (d, J = 8.9 Hz, 2 H), 7.92 (dd, J = 8.1, 13.2 Hz, l H). LR MS (ESI+): (M+H)+ calc for C38H43N204S: 623; found: 623. LR MS (ESI-): (M-H)- calc for C28H41N2O4S: 621; found: 621.

Example 1001C N-f4-N-benzyl-N-(4-propionvlphenyl)aminomethyl-2- (2- methvlphenvl)benzovllmethionine lithium salt Compound 1001C was prepared in the same fashion as 997D (98% yield).

1H NMR (d6-DMSO):8 0.88 (t, J = 7.3 Hz, 3 H), 1.50-1.63 (comp, 3 H), 1.63-1.78 (m, 1 H), 1.79-2.11 (comp, 8 H), 2.78 (t, J = 7.3 Hz, 2 H), 3.72-3.81 (br, 1 H), 4.82 (s, 2 H), 4.87 (s, 2 H), 6.74 (d, J = 9.2 Hz, 2 H), 6.94-7.02 (br, 1 H), 7.02 (s, 1 H), 7.09-7.36 (comp, 10 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 9.2 Hz, 2 H). HR MS (FAB): (M+2Li-H)+ calc for C37H39Li2N204S: 621.2951; found: 621.2966 (2.4 ppm error).

Example 1002 N-[4-N-benzyl-N-(4-benzoylphenyl)aminomethyl-2-(2-methylphen yl)benzoyl]methionine, lithium salt Example 1002A Compound 1002A was prepared in the same fashion as 997A (63% yield).

1H NMR (d6-DMSO):6 3.37 (s, 1 H), 4.38 (d, J = 6.2 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 7.22-7.28 (m, 1 H), 7.31-7.38 (comp, 4 H), 7.46-7.62 (comp, 7 H). LR MS (ESI+): (M+H)+ calc for C20H18NO: 288; found: 288. LR MS (ESI-): (M-H)- calc for C20H16NO: 286; found: 286.

Example 1002B Compound 1002B was prepared in the same fashion as 997C (30% yield).

1H NMR (CDCl3):8 1.52-1.68 (m, 1 H), 1.79-1.93 (m, 1 H), 1.98-2.16 (comp, 8 H), 3.67 (s, 3 H), 4.56-4.70 (m, 1 H), 4.76 (s, 2 H), 4.78 (s, 2 H), 5.85-5.92 (m, 1 H), 6.74 (d, J = 9.2 Hz, 2 H), 7.05 (s, 1 H), 7.14-7.38 (comp, 10 H), 7.40-7.48 (comp, 2 H), 7.69-7.78 (comp, 4 H), 7.94 (dd, J = 8.1, 13.3 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C41H41N204S: 657; found: 657. LR MS (ESI-): (M-H)- calc for C41H39N204S: 655; found: 655.

Example 1002C <BR> <BR> N-[4-N-benzvl-N-(4-benzovlphenyl!aminomethvl-2-(2-methylphen vl)benzovllmethionine, lithium salt Compound 1002C was prepared in the same fashion as 997D (86% yield).

1H NMR (d6-DMSO):6 1.49-1.63 (m, 1 H), 1.63-1.77 (m, 1 H), 1.78-2.10 (comp, 8 H), 3.68-3.76 (br, 1 H), 4.84 (s, 2 H), 4.89 (s, 2 H), 6.81 (d, J = 9.1 Hz, 2 H), 6.96 (d, J = 5.4 Hz, 1 H), 7.03 (s, 1 H), 7.08-7.37 (comp, 11 H), 7.46-7.61 (comp, 7 H). HR MS (FAB): (M+Li)+ cale for C40H38LiN204S: 649.2712; found: 649.2723(1.6 ppm error).

Example 1003 N-[4-N-benzyl-N-(4-(6-methylbenzthiazol-2yl)phenyl)aminometh yl-2-(2- methvlphenvl)benzovllmethionine lithium salt Example 1003A

Compound 1003A was prepared in the same fashion as 997A (38% yield).

1H NMR (CDC13):6 2.47 (s, 3 H), 4.41 (app s, 3 H), 6.65-6.70 (m, 2 H), 7.22-7.38 (comp, 6 H), 7.62 (s, 1 H), 7.83-7.91 (comp, 3 H). LR MS (ESI+): (M+H)+ calc for C21H19N2S: 330; found: 330. LR MS (ESI-): (M-H)- calc for C21H17N2S: 329; found: 329.

Example 1003B Compound 1003B was prepared in the same fashion as 997C (16% yield).

1H NMR (CDC13):o 1.52-1.72 (br m, 1 H), 1.80-1.92 (m, 1 H), 1.99-2.14 (comp, 8 H), 2.48 (s, 2 H), 3.66 (s, 3 H), 4.56-4.68 (m, 1 H), 4.74 (s, 2 H), 4.77 (s, 2 H), 5.84-5.90 (m, 1 H), 6.79 (d, J = 8.8 Hz, 2 H), 7.07 (s, 1 H), 7.24-7.38 (comp, 11 H), 7.62 (s, 2 H), 7.85-7.98 (comp, 4 H). LR MS (ESI+): (M+H)+ calc for C42H42N303S2: 698; found: 698. LR MS (ESI-): (M-H)- calc for C42H40N303S2: 700; found: 700.

Example 1003C N-[4-N-benzyl-N-(4-(6-methylbenzthiazol-2yl)phenyl)aminometh yl-2-(2- methylphenyl)benzoyllmethionine. lithium salt Compound 1003C was prepared in the same fashion as 997D (93% yield).

1H NMR (d6-DMSO):8 1.48-1.62 (m, 1 H), 1.62-1.73 (m, 1 H), 1.80-2.11 (comp, 8 H), 2.41 (s, 3 H), 3.64-3.73 (br, 1 H), 4.82 (s, 2 H), 4.87 (s, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.95 (d, J = 5.8 Hz, 1 H), 7.04 (s, 1 H), 7.08-7.37 (comp, 11 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.76-7.82 (comp, 4 H). HR MS (FAB): (M.)+ calc for C41 H38N303S2: 685.2433; found: 685.2421 (-1.8 ppm error).

Example 1004 N-[4-N-2,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzovllmethionine. lithium salt Example 1004A A heterogeneous mixture of 4-bromomethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1178D) (0.638 g, 2.00 mmol), 4-aminobenzonitrile (0.241 g, 2.0 mmol), K2CO3 (1.11 g, 8.00 mmol), and tetrabutylammonium iodide (0.0754 g, 0.200 mmol) in acetonitrile solvent (5 mL) was heated to 70 OC for 18 h. Next, 2,5-difluorobenzyl bromide (0.507 g, 2.40 mmol) was added, and the reaction mixture was returned to 70 OC. After 16 h the reaction mixture was cooled to room temperature, diluted with DMF solvent (5 mL) and treated with solid LiOH (0.514 g, 12.0 mmol), and then heated to 90 OC for 14 h. The reaction mixture was cooled to room temperature and diluted with additional DMF (20 mL).

Triethylamine hydrochloride (1.40 g, 10.0 mmol) was added, followed by methionine methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-1 ,2,3-benzotriazin-4(3H)-one (HOOBT) (1.66 g, 10.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.96 g, 10.0 mmol), and finally, triethylamine (1.02 g, 10.0 mmol). The mixture was

heated to 60 "C for 8 h, cooled to roorn temperature, diluted with ethyl acetate (80 mL). and extracted with 2:1:1 H2O: saturated aqueous NaHCO3: brine (50 mL + 2 x 20 mL), followed by brine (10 mL). The organic layer was dried over MgS04, filtered through silica gel with 1:1 hexane: ethyl acetate rinses, and concentrated under reduced pressure to yield an amber oil. Radial chromatography eluting with hexane and ethyl acetate using an elution gradient of 70:30 to 50:50 afforded 0.142 g of 1004A as a colorless oil (12% yield).

1H NMR (CDCl3):8 1.53-1.66 (m, 1 H), 1.80-1.92 (m, 1 H), 1.98-2.12 (comp, 8 H), 3.66 (s, 3 H), 4.56-4.67 (m, 1 H), 4.71 (s, 2 H), 4.75 (s, 2 H), 5.86-5.96 (m, 1 H), 6.69 (d, J = 9.0 Hz, 2 H), 6.78-6.89 (comp, 2 H), 7.00 (s, 1 H), 7.04-7.37 (comp, 6 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.93 (dd, J = 8.1, 13.5Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H34F2N303S: 614; found: 614. LR MS (ESI-): (M-H)- calc for C35H32F2N303S: 612; found: 612.

Example 1004B N-[4-N-2,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzoyllmethionine. lithium salt Compound 1004B was prepared in the same fashion as 997D (93% yield).

1H NMR (d6-DMSO):6 1.50-1.80 (comp, 2 H), 1.90-2.12 (comp, 8 H), 3.64-3.81 (m, 1 H), 4.84-5.00 (comp, 4 H), 6.75-6.88 (comp, 2 H), 6.89-7.08 (comp, 3 H), 7.11-7.40 (comp, 6 H), 7.48-7.63 (comp, 3 H). HR MS (FAB): (M+H)+ calc for C34H32F2N303S: 600.2132; found: 600.2139(1.1 ppm error).

Example 1005 N-[4-N-2,4-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzoyl]methionine, lithium salt Example 1005A Compound 1005A was prepared starting from 4-bromomethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 1178D) in the same fashion as 1004A (14% yield).

1H NMR (CDCl3):o 1.53-1.66 (m, 1 H), 1.80-1.92 (m, 1 H), 1.98-2.12 (comp. 8 H), 3.66 (s, 3 H), 4.56-4.67 (m, 1 H), 4.71 (s, 2 H), 4.75 (s, 2 H), 5.86-5.92 (m, 1 H), 6.69 (d, J = 9.0 Hz, 2 H), 6.79-6.89 (comp, 2 H), 7.00 (s, 1 H), 7.04-7.37 (comp, 6 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.93 (dd, J = 8.1, 13.5Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H34F2N303S: 614; found: 614. LR MS (ESI-): (M-H)- calc for C35H32F2N303S: 612; found: 612.

Example 1005B N-[4-N-2,4-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzoyl]methionine, lithium salt Compound 1005B was prepared in the same fashion as 997D (80% yield).

1H NMR (d6-DMSO):6 1.48-1.62 (m, 1 H), 1.62-1.73 (m, 1 H), 1.89-2.07 (comp, 8 H), 3.62-3.72 (br, 1 H), 4.82-4.88 (comp, 4 H), 6.79 (d, J = 9.1 Hz, 2 H), 6.90-7.32 (comp, 10 H), 7.48-7.54 (comp, 3 H). HR MS (FAB): (M+H)+ calc for C34H32F2N303S: 600.2132; found: 600.2144 (2.0 ppm error).

Example 1006 N-[4-N-3,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzovllmethionine, lithium salt Example 1006A Compound 1006A was prepared starting from 4-bromomethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 1178D) in the same fashion as 1004A (28% yield).

1H NMR (CDCl3):8 1.53-1.65 (m, 1 H), 1.80-1.91 (m, 1 H), 1.98-2.12 (comp, 8 H), 3.66 (s, 3 H), 4.56-4.66 (m, 1 H), 4.67 (s, 2 H), 4.76 (s, 2 H), 5.88 (d, J = 7.2 Hz, 1 H), 6.64-6.76 (comp, 5 H), 7.00 (d, J = 1.3 Hz, 1 H), 7.13-7.36 (comp, 5 H), 7.44 (d, J = 8.8 Hz, 2 H), 7.94 (dd, J = 8.1, 13.2 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H34F2N303S: 614; found: 614. LR MS (ESI-): (M-H)- calc for C35H32F2N303S: 612; found: 612. Example 1006B

N-[4-N-3,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2- methylphenyl) benzoyl]methionine, lithium salt Compound 1006B was prepared in the same fashion as 997D (82% yield).

1H NMR (d6-DMSO):6 1.48-1.75 (comp, 2 H), 1.90-2.07 (comp, 8 H), 3.66-3.76 (br, 1 H), 4.86 (s, 2 H), 4.92 (s, 2 H), 6.76 (d, J = 8.8 Hz, 2 H), 6.92-7.00 (comp, 4 H), 7.07- 7.24 (comp, 5 H), 7.30 (dd, J = 1.5, 8.12 Hz, 1 H), 7.50-7.55 (comp, 3 H). HR MS (FAB): (M+H)+ calc for C34H32FoN303S: 600.2132; found: 600.2140 (1.2 ppm error).

Example 1007 N-[4-N-3,5-difluorobenzyl-N-(4-vinylphenyl)aminomethyl-2-(2- methylphenyl) benzoyl]methionine, lithium salt Example 1007A Compound 1007A was prepared starting from 4-bromomethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 1178D) in the same fashion as 1004A (11% yield).

1H NMR (CDCl3):8 1.52-1.65 (m, 1 H), 1.80-1.91 (m, 1 H), 1.95-2.12 (comp, 8 H), 2.50 (s, 3 H), 3.67 (s, 3 H), 4.56-4.67 (m, 1 H), 4.70 (s, 2 H), 4.78 (s, 2 H), 5.89 (dd, J = 2.5, 7.7 Hz, 1 H), 6.65-6.77 (comp, 5 H), 7.04 (s, 1 H), 7.13-7.36 (comp, 5 H), 7.83 (d, J = 9.2 Hz, 2 H), 7.94 (dd, J = 8.1, 13.8 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C36H37F2N204S: 631; found: 631. LR

MS (ESI-): (M-H)- calc for C36H35F2N204S: 629; found: 629.

Example 1007B A solution of 1007A (0.147 g, 0.233 mmol) in 1:1 tetrahydrofuran: methanol solvent (2 mL) was treated with NaBH4 (0.0315 g, 0.815 mmol). After 1 h the mixture was quenched by the addition of H2O (2 mL), followed by a few drops of 3 M HCl. The reaction mixture was then extracted with ethyl acetate (4 x 2 mL), and the combined organic extracts were rinsed with brine (1 mL), dried over MgSO4, filtered through silica gel with ethyl acetate rinses, and concentrated under reduced pressure to afford an amber oil. Radial chromatography eluting with hexane and ethyl acetate using an elution gradient of 60:40 to 30:70 afforded 0.0097 g of 1007B as a colorless oil (6.8% yield). lH NMR (CDC13):o 1.52-1.62 (comp, 2 H), 1.80-1.91 (m, 1 H), 1.99-2.14 (comp, 8 H), 3.66 (s, 3 H), 4.58-4.66 (comp, 3 H), 4.70 (s, 2 H), 5.04 (d, J = 11.1 Hz, 1 H), 5.53 (d, J = 17.6 Hz, 1 H), 5.84-5.90 (m, 1 H), 6.55-6.67 (comp, 3 H), 6.67-6.79 (comp, 2 H), 7.05 (s, 1 H), 7.23-7.34 (comp, 8 H), 7.92 (dd, J = 8.1, 13.6 Hz, 1 H). LR MS (ESI+): (M+H)+ cale for C36H37F2N203S: 615; found: 615. LR MS (ESI-): (M-H)- calc for C36H35F2N203S: 613; found: 613.

Example 1007C N-[4-N-3,5-difluorobenzyl-N-(4-vinylphenyl)aminomethyl-2-(2- methylphenyl) benzoyllmethionine lithium salt Compound 1007C was prepared in the same fashion as 997D (72% yield).

1H NMR (d6-DMSO):8 1.60-1.70 (br m, 1 H), 1.70-1.83 (br m, 1 H), 1.88-2.06 (br comp, 8 H), 3.58-3.68 (br, 1 H), 4.65-4.77 (br comp, 1 H), 4.75 (s, 2 H), 4.81 (s, 2 H),

4.96 (d, J = 11.0 Hz, 1 H), 5.51 (dd; J = 1.2, 17.7 Hz, 1 H), 6.54 (dd, J = 11.0, 17.7 Hz, 1 H), 6.65 (d, J = 9.2 Hz, 2 H), 6.89-7.00 (comp, 4 H), 7.01-7.22 (comp, 4 H), 7.23 (d, J = 9.2 Hz, 2 H), 7.30-7.33 (m, 1 H), 7.51 (d, J = 7.9 Hz, 1 H). LR MS (ESI-): (M-H)- calc for C35H32F2LiN303S: 599; found: 599.

1008 N-[4-N-3,5-difluorobenzyl-N-(4-acetylphenyl)aminomethyl-2-(2 -methylphenyl) benzoyl]methionine, lithium salt Compound 1008 was prepared in the same fashion as 997D (86% yield).

1H NMR (d6-DMSO):8 1.46-1.61 (m, 1 H), 1.61-1.73 (m, 1 H), 1.86-2.08 (comp, 8 H), 2.38 (s, 3 H), 3.58-3.68 (br, 1 H), 4.85 (s, 2 H), 4.90 (s, 2 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.90-7.00 (comp, 5 H), 7.05-7.20 (comp, 5 H), 7.30 (dd, J = 1.7, 7.8 Hz, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.74 (d, 9.0 Hz, 2 H). HR MS (FAB): (M+H)+ calc for C35H35F2N204S: 617.2286; found: 617.2277 (-1.5 ppm error).

Example 1009 N-[4-N-3,5-difluorobenzyl-N-(4-(1-hydroxyethyl)phenyl)aminom ethyl-2-(2-methylphenyl) benzoyllmethionine. lithium salt

Example 1009A Compound 1009A was prepared starting from 4-chloromethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 997B) in the same fashion as 1004A (17% yield).

1H NMR (CDC13):o 1.52-1.65 (m, 1 H), 1.79-1.91 (m, 1 H), 2.00-2.14 (comp, 8 H), 2.52 (s, 3 H), 2.67 (s, 3 H), 4.56-4.66 (m, 1 H), 4.66 (s, 2 H), 4.74 (s, 2 H), 5.85-5.91 (m, 1 H), 6.64-6.81 (comp, 3 H), 6.86 (d, J = 8.1 Hz, 1 H), 7.05 (s, l H), 7.14-7.35 (comp, 8 H), 7.92 (dd, J = 8.1, 14.0 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C36H37F2N204S: 631; found: 631. LR MS (ESI-): (M-H)- calc for C36H35F2N204S: 629; found: 629.

Example 1009B Compound 1009B was prepared in the same fashion as 1007B (10% yield).

1H NMR (CDCl3):8 1.41 (d, J = 6.5 Hz, 3 H), 1.52-1.65 (comp, 2 H), 1.77 (d, J = 2.7 Hz, 1 H), 1.79-1.91 (m, 1 H), 1.99-2.15 (comp, 8 H), 3.66 (s, 3 H), 4.56-4.65 (comp, 3 H), 4.69 (s, 2 H), 4.73-4.82 (m, 1 H), 5.85-5.91 (m, 1 H), 6.59 (dd, J = 2.4, 8.2 Hz, 1 H), 6.64-6.80 (comp, 5 H), 7.06 (d, J = 1.3 Hz, 1 H), 7.15-7.19 (m, 1 H), 7.21-7.36 (comp, 5 H), 7.92 (dd, J = 8.1, 14.3 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C36H39F2N204S: 633; found: 633. LR MS (ESI-): (M-H)- calc for C36H37F2N204S: 631; found: 631.

Example 1009C N-[4-N-3,5-difluorobenzyl-N-(4-(1-hydroxyethyl)phenyl)aminom ethyl-2-(2-methylphenyl) benzovllmethionine. lithium salt Compound 1009C was prepared in the same fashion as 997D (76% yield).

1H NMR (d6-DMSO):6 1.18 (d, J = 6.1 Hz, 3 H), 1.47-1.60 (m, 1 H), 1.60-1.73 (m, 1 H), 1.88-2.09 (comp, 8 H), 3.59-3.68 (m, 1 H), 4.89-4.57 (m, 1 H), 4.71 (s, 2 H), 4.78 (s, 2 H), 4.99 (d, J = 4.1 Hz, 1 H), 6.50 (dd, J = 2.3, 8.4 Hz, 1 H), 6.61 (d, J = 7.4 Hz, 1 H), 6.70 (s, 1 H), 6.89-7.03 (comp, 4 H), 7.03-7.21 (dd, J = 1.3, 7.8 Hz, 1 H), 7.51 (d, J = 9.8 Hz, 1 H). HR MS (FAB): (M+H)+ calc for C35H36F2N304S: 618.2364; found: 618.2366 (0.4 ppm error).

Example 1010 N-[4-N-3,5-difluorobenzyl-N-(4-(1-hydroxy-1-phenylmethyl)phe nyl)aminomethyl- 2-(2-methylphenyl)benzoyl]methionine, lithium salt

Example 1010A Compound 1010A was prepared starting from 4-chloromethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 997B) in the same fashion as 1004A (5.4% yield).

IH NMR (CDCl3):8 1.53-1.66 (m, 1 H), 1.80-1.91 (m, 1 H), 2.00-2.13 (comp, 8 H), 3.66 (s, 3 H), 4.55-4.66 (m, 1 H), 4.71 (s, 2 H), 4.79 (s, 2 H), 5.86-5.92 (m. 1 H), 6.68- 6.78 (comp, 5 H), 7.05 (d, J = 1.6 Hz, 1 H), 7.14-7.35 (comp, 6 H), 7.40-7.47 (comp, 2 H), 7.49-7.55 (m, 1 H), 7.70-7.77 (comp, 4 H), 7.94 (dd, J = 8.2, 13.3 Hz, 1 H;). LR MS (ESI-): (M-H)- calc for C41H37F2N204S: 691; found: 691.

Example 1010B Compound 1010B was prepared in the same fashion as 1007B (6.5% yield).

1H NMR (CDCl3):8 1.52-1.64 (comp, 2 H), 1.78-1.91 (m, 1 H), 1.99-2.11 (comp, 8 H), 3.66 (s, 3 H), 4.55-4.65 (comp, 3 H), 4.68 (s, 2 H), 5.70 (d, J = 2.9 Hz, 1 H), 5.86 (t, J = 6.4 Hz, 1 H), 6.63 (d, J = 8.5 Hz, 2 H), 6.67-6.72 (m, 1 H), 6.75 (d, J = 6.2 Hz, 2 H), 7.04 (s, 1 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.19-7.41 (comp, 10 H), 7.91 (dd, J = 8.0, 21.3 Hz, 1 H). LR MS (ESI+): (M-OH)+ calc for C41H39F2N203S: 677; found: 677. LR MS (ESI-): (M-H)- calc for C41H39F2N204S: 693; found: 693.

Example 1010C N- [4-N-3 .5-difluorobenzvl-N-(4-( 1 -hydroxy- 1 -phenylmethyl)phenyl)aminomethyl- 2-(2-methylphenyl)benzoyl]methionine, lithium salt Compound 1010C was prepared in the same fashion as 997D (100% yield).

1H NMR (d6-DMSO):8 1.50-1.59 (br m, 1 H), 1.62-1.70 (br m, 1 H), 1.88-2.23 (br comp, 8 H), 4.68 (s, 2 H), 4.77 (s, 2 H), 6.66 (d, J = 8.5 Hz, 2 H), 6.92-6.95 (comp, 3 H), 7.02-7.07 (comp, 3 H), 7.11-7.26 (comp, 5 H), 7.27-7.32 (comp, 5 H), 7.49 (d, J = 8.0 Hz, 1 H). LR MS (ESI-): (M-H)- calc for C40H37F2LiN204S: 678; found: 678.

Example 1011 N-[4-N-3,5-difluorobenzyl-N-(4-(2-hydroxyethyl)phenyl)aminom ethyl- 2-(2-methylphenyl)benzoyl]methionine, lithium salt Example 1012

N-[4-N-3,5-difluorobenzyl-N-(4-(2-hydroxyethyl)phenyl)aminom ethyl- 2-(2-methylphenyl)benzovll methionine. lithium salt Example 1011A andExample 1012A Compound 1012A was prepared starting from 4-chloromethyl-2-(2- methylphenyl)benzoic acid, methyl ester, 997B, in the same fashion as 1004A (4.1% yield).

Compound 1011A was isolated from the crude reaction mixture as a side-product (15% yield).

1H NMR (CDCl3):8 1.44-1.50 (br, 1 H), 1.52-1.65 (m, 1 H), 1.80-1.91 (m, 1 H), 1.99- 2.12 (comp, 8 H), 2.76 (t, J = 6.4 Hz, 2 H), 3.66 (s, 3 H), 3.80 (br t, J = 6.4 Hz, 2 H), 4.58-4.68 (comp, 5 H), 5.84-5.90 (m, 1 H), 6.64 (d, J = 8.5 Hz, 2 H), 6.66-6.72 (m, 1 H), 6.77 (d, J = 5.7 Hz, 2 H), 7.04 (d, J = 8.8 Hz, 2 H), 7.07 (s, 1 H), 7.20-7.34 (comp, 5 H), 7.91 (dd, J = 8.2, 13.6 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C36H39F2N204S: 633; found: 633. LR MS (ESI-): (M-H)- calc for C36H37F2N204S: 631; found: 631. 1012A: 1H NMR (CDCl3):8 -0.04 (s, 6 H), 0.86 (s, 9 H), 1.52-1.64 (m, 1 H), 1.79-1.91 (m, 1 H), 1.99-2.12 (comp, 8 H), 2.71 (t, J = 7.2 Hz, 2 H), 3.65 (s, 3 H), 3.73 (t, J = 7.2 Hz, 2 H), 4.56 (s, 2 H), 4.60-4.70 (comp, 3 H), 5.83-5.89 (m, 1 H), 6.62 (d, J = 8.4 Hz, 2 H), 6.65-6.71 (m, 1 H), 6.76 (d, J = 6.1 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 7.06 (d, J = 1.7 Hz, 1 H), 7.20-7.34 (comp, 5 H), 7.90 (dd, J = 8.1, 13.2 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C42H53F2N204SiS: 747; found: 747. LR MS (ESI-): (M-H)- calc for C42H51F2N204SiS: 745; found: 745.

Example 1011B N- [4-N-3 z5-difluorobenzyl-N-(4-(2-hvdroxyethvl!phenyl)aminomethVl- 2-(2-methvlphenvl)benzovllmethionine lithium salt Compound 1011B was prepared in the same fashion as 997D (76% yield).

IH NMR (d6-DMSO):o 1.48-1.74 (br comp, 2 H), 1.90-2.06 (br comp, 8 H), 2.56 (t, J = 7.2 Hz, 2 H), 3.48 (t, J = 7.2 Hz, 2 H), 3.64-3.76 (br, 1 H), 4.69 (s, 2 H), 4.75 (s, 2 H), 6.58 (d, J = 8.5 Hz, 2 H), 6.90-7.22 (br comp, 10 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 1 H). HR MS (FAB): (M+H)+ calc for C35H36F2LiN204S: 625.2524; found: 625.2542 (2.8 ppm error).

(258473) Example 1012B N-[4-N-3,5-difluorobenzyl-N-(4-(2-hydroxyethyl)phenyl)aminom ethyl- 2-(2-methylphenyl)benzoyl]methionine, lithium salt Compound 1012B was prepared in the same fashion as 997D (64% yield).

1H NMR (d6-DMSO):6 -0.12 (s, 6 H), 0.79 (s, 9 H), 1.48-1.74 (br comp, 2 H), 1.89- 2.08 (br comp, 8 H), 2.56 (t, J = 6.9 Hz, 2 H), 3.65 (t, J = 6.9 Hz, 2 H), 4.69 (s, 2 H), 4.76 (s, 2 H), 6.58 (d, J = 8.9 Hz, 2 H), 6.88-7.22 (comp, 10 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.49 (d, J = 7.7 Hz, 1 H). HR MS (FAB): (M+H)+ calc for C41H50F2LiN204SiS: 739.3389; found: 739.3389 (0.1 ppm error). Example 1013

N- {4-N-3 .5-difluorobenzyl-N-( 1 -ethvlthio-3-cvclohexvlprop-2-vl)aminomethvl-2-(2- methylphenvl)benzovll methionine.

Example 1013A Compound 1013A was prepared starting from 4-bromomethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 1178D) in the same fashion as 1004A (10% yield).

1H NMR (CDC13):6 0.70-0.93 (comp, 2 H), 1.06-1.71 (comp, 16 H), 1.30-1.92 (m, 1 H), 1.99-2.10 (comp, 7 H), 2.19 (s, 1 H), 2.39-2.48 (comp, 3 H), 2.77-2.89 (comp, 2 H), 3.58-3.71 (comp, 7 H), 4.56-4.70 (m, 1 H), 5.89 (d, J = 7.4 Hz, 1 H), 6.61-6.70 (m, 1 H), 6.94 (d, J = 8.1 Hz, 2 H), 7.15-7.22 (m, 1 H), 7.22-7.37 (comp, 9 H), 7.50 (d, J = 8.1 Hz, 1 H), 7.92 (dd, J = 8.1, 15.1 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C39H51F2N2O3S2: 697; found: 697. LR MS (ESI-): (M-H)- calc for C39H49F2N203S2: 695; found: 695.

Example 1013B N-[4-N-3,5-difluorobenzyl-N-(1-ethylthio-3-cyclohexylprop-2- yl)aminomethyl-2-(2- methvlphenvl)benzovll methionine.

Compound 1013B was prepared in the same fashion as 997D (76% yield).

H NMR (d6-DMSO):6 0.59-0.74 (m, 1 H), 0.74-0.91 (m, 1 H), 0.97-1.18 (comp, 4 H), 1.21-1.33 (comp, 2 H), 1.36-1.75 (comp, 8 H), 1.76-1.87 (m, 1 H), 1.88-1.96 (comp, 2 H), 1.96-2.02 (comp, 2 H), 2.15-2.22 (br, 1 H), 2.34-2.45 (comp, 3 H), 2.60-2.70 (br, 1 H), 2.94 (dd, J = 5.9, 12.9 Hz, 1 H), 3.32-3.45 (comp, 4 H), 3.57-3.74 (br comp, 5 H),

6.93 (d, J = 6.3 Hz, 1 H), 7.03-7.25 (comp, 7 H), 7.38 (d, J = 7.3 Hz, 1 H), 7.50 (d, J = 7.7 Hz, l H). HR MS (FAB): (M+H)+ calc for C38H49F2N203S2: 683.3153; found: 683.3132 (-3.0 ppm error j.

Example 1014 N-r4- (2-N-oioeridin-l -vlaminoethenvl)-2-(2-methvlDhenvl)benzo methionine. lithium salt Example 1014A A solution of (methoxymethyl)triphenylphosphonium chloride (15.6 g, 45.6 mmol) in tetrahydrofuran solvent (35 mL) was treated with sodium bis(trimethylsilyl)amide (45 mL of a 1 M tetrahydrofuran solution, 45 mmol), and the resulting deep red solution was treated with 4-formyl-2-(2-methylphenyl)benzoic acid, methyl ester, 1332A (7.30 g, 28.7 mmol).

After 18 h the reaction mixture was diluted with diethyl ether solvent (100 mL) and filtered through silica gel with additional diethyl ether rinses. Flash column chromatography eluting with hexane and ethyl acetate using an elution gradient of 98:2 to 94:6 afforded 6.62 g of 1014A as a white solid (82% yield).

1H NMR (CDC13):6 2.06 (s, 3 H), 3.59 (s, 3 H), 3.70 (s, 3 H, E isomer), 3.79 (s, 3 H, Z isomer), 5.24 (d, J = 7.1 Hz, 1 H, Z isomer), 5.81 (d, J = 13.2 Hz, 1 H, E isomer), 6.23 (d, J = 7.1 Hz, 1 H, Z isomer), 7.06-7.10 (comp, 2 H), 7.16-7.64 (comp, 5 H), 7.90 (dd, J = 2.3, 8.4 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C18H19O3: 283; found: 283.

Example 1014B A solution of 1014A (2.42 g, 8.57 mmol) in saturated methanolic LiOH (10 mL) was heated to reflux for 16 h. The reaction mixture was poured into H2O (90 mL), and the resulting mixture was extracted with diethyl ether (3 x 30 mL). The aqueous layer was cooled to 0 "C with vigorous stirring and was slowly and carefully neutralized and then acidified to pH 4 by the addition of 3 M HCl. The cloudy solution was extracted with diethyl ether (3 x 30 mL), and the combined organic extracts were dried over MgSO4 and then concentrated under reduced pressure to provide 1.81 g of 1014B as a white foam (79% yield). LR MS (ESI+): (M+H)+ cale for C17H17Q3: 269; found: 269. LR MS (ESI-): (M-H)- calc for C17H15O3: 267; found: 267.

Example 1014C A heterogeneous mixture of 1014B (1.81 g, 6.75 mmol), methionine methyl ester hydrochloride (2.72 g, 13.5 mmol), l-hydroxybenzotriazole hydrate (HOBT) (4.56 g, 33.8 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (6.60 g, 33.8 mmol) in DMF solvent (40 mL) was treated with triethylamine (3.45 g, 33.8 mmol). The mixture was heated to 50 OC for 60 h, cooled to room temperature, diluted with ethyl acetate (200 mL), and extracted with 2:1:1 H2O: saturated aqueous NaHCO3: brine (200 mL + 2 x 100 mL), followed by brine (50 mL). The organic layer was dried over MgSO4 and then concentrated under reduced pressure to yield an amber oil. Flash column chromatography eluting with hexane and ethyl acetate using an elution gradient of 80:20 to 70:30 afforded 2.55 g of 1014C as a colorless oil (91% yield).

1H NMR (CDC13):6 1.51-1.63 (m, 1 H), 1.79-1.91 (m, 1 H), 1.99-2.21 (comp, 8 H), 3.65 (s, 3 H), 3.70 (s, 3 H, E isomer), 3.79 (s, 3 H, Z isomer), 4.56-4.67 (m, 1 H), 5.24 (d, J = 7.1 Hz, 1 H, E isomer), 5.82 (d, J = 12.9 Hz, 1 H, E isomer), 5.83-5.89 (m, 1 H), 7.00-7.36 (comp, 6 H), 7.12 (d, J = 12.9 Hz, 1 H, E isomer), 7.63-7.96 (comp, l H). LR MS (ESI+): (M+H)+ calc for C23H28O4S: 414; found: 414.

Example 1014D A solution of 1014C (8.0 mL of a 0.1 M dioxane solution, 0.800 mmol) and H2O (1.6 mL) was treated with p-toluenesulfonic acid hydrate (0.0309 g, 0.160 mmol). After 17 h the mixture was diluted with additional H2O (12 mL) and then extracted with ethyl acetate (10 mL + 3 x 5 mL). The combined organic extracts were rinsed with brine (5 mL), dried over MgS04, and concentrated under reduced pressure to provide a pale yellow oil. The oil was dissolved in benzene solvent (4 mL) and treated with Na2SO4 (0.454 g, 3.20 mmol), followed by 1-aminopiperidine (0.0991 g, 0.960 mmol), resulting in a bright yellow solution. After 18 h the reaction mixture was filtered through silica gel with ethyl acetate rinses and then concentrated under reduced pressure. Radial chromatography eluting with hexane and ethyl acetate using an elution gradient of 70:30 to 30:70 afforded 0.0342 g of 1014D as a colorless oil (8.9% yield).

1H NMR (CDC13):6 1.44-1.53 (comp, 2 H), 1.54-1.74 (comp, 5 H), 1.79-1.91 (m, 1 H), 1.99-2.10 (comp, 5 H). 2.18 (s, 1 H), 2.95 (app t, J = 5.6 Hz, 4 H), 3.62-3.67 (comp, 5 H), 4.56-4.67 (m, 1 H), 5.88 (d, J = 7.8 Hz, 1 H), 6.93-6.99 (m, 1 H), 7.06 (s, 1 H), 7.16-7.35 (comp, 6 H), 7.91 (dd, J = 8.2, 15.6Hz, 1 H). LR MS (ESI+): (M+H)+ cale for C27H36N203S: 482; found: 482. LR MS (ESI-): (M-H)- calc for C27H34N303S: 480; found: 480.

Example 1014E N-14-(2-N-piperidin-1-vlaminoethenvl!-2-(2-methvlphenvl)benz ovllmethionine. lithium salt Compound 1014E was prepared in the same fashion as 997D (39% yield).

1H NMR (d6-DMSO):6 1.36-1.45 (comp, 2 H), 1.50-1.76 (comp, 6 H), 1.76-2.20 (comp, 8 H), 2.84-2.90 (comp, 4 H), 3.53 (d, J = 5.8 Hz, 1 H), 3.62-3.72 (br, 1 H), 6.92 (d, J = 5.8 Hz, 1 H), 6.96-7.03 (comp, 2 H), 7.10-7.24 (comp, 4 H), 7.27 (dd, J = 1.4, 7.8 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1 H). HR

MS (FAB): (M+Li)+ calc for C26H33LiN3o3S: 474.2403; found: 474.2386 (-3.6 ppm error).

Example 1015 N-[4-(2-N-2-methoxymethylpyrrolidin-1-ylaminoethenyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1015A Compound 1015A was prepared in the same fashion as 1014D (11% yield).

1H NMR (CDCl3):8 1.52-1.64 (m, 1 H), 1.71-2.20 (comp, 14 H), 2.72-2.84 (m, 1 H), 3.31-3.67 (comp, 12 H), 4.56-4.68 (m, 1 H), 5.88 (d, J = 7.3 Hz, 1 H), 6.64-6.70 (m, 1 H), 7.07 (s, 1 H), 7.17-7.35 (comp, 6 H), 7.91 (dd, J = 7.7, 15.4 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C28H38N304S: 512; found: 512. LR MS (ESI-): (M-H)- calc for C28H36N302S: 510; found: 510. Example 1015B

N-[4-(2-N-2-methoxvmethvlpvrrolidin- 1 -vlaminoethenvl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Compound 1015B was prepared in the same fashion as 997D (50% yield).

1H NMR (d6-DMSO):8 1.49-1.72 (comp, 3 H), 1.76-2.20 (comp, 10 H), 2.62-2.72 (m, l H), 3.19-3.55 (comp, 2 H), 3.62-3.74 (br, 1 H), 6.66 (app t, J = 5.5 Hz, 1 H), 6.89-6.94 (d, J = 5.5 Hz, 1 H), 7.02 (s, 1 H), 7.12-7.30 (comp, 5 H), 7.49 (d, J = 8.1 Hz, 1 H).

HR MS (FAB): (M+Li)+ calc for C27H35LiN304S: 504.2508; found: 504.2509 (1.2 ppm error).

Example 1017 N- [4-N-(4-trans-pentafluorophenoxvcyclohexyl)aminomethvl-2-(2- methylphenyl)benzoyll methionine A solution of trans-4-aminocylohexanol (3.03 g, 20.0 mmol) and diisopropylethylamine (7.4 mL, 42.0 mmol) in methylene chloride (30 mL) was treated with t-butyl dicarbonate (4.37 g, 20.0 mmol) over 5 minutes. The reaction stirred overnight at room temperature and was washed with 1 M HCl 5% NaHCO3, and brine to give the Boc- amine in nearly quantitative yield. A portion of this product (215 mg, 1.0 mmol) was combined with hexafluorobenzene (223 mg, 1.2 mmol) and 15-crown-5 (44 mg, 0.2 mmol) in DMF (3 mL) at room temperature. NaH (60% in oil, 4.4 mg, 1.2 mmol was added and stirred overnight. Standard aqueous workup provided 149 mg of the protected pentafluorophenyl ether which was treated with excess TFA in methylene chloride, stripped to dryness, and reductively alkylated and saponified as described previously to provide 160 mg of the title compound.

MS m/e 635 (M-H)-.

1H NMR (CDC13, 300 MHz) 6 1.5 (m, 4H), 1.79 (m, 1H), 2.05 (m, 12H), 2.81 (m, lH), 4.05 (m, 4H), 6.25 (m, 1H), 6.81 (m, 2H), 7.1-7.7 (m, 7H).

Example 1018 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl phenyl)benzoyl]glutamine Trifluoroacetic Acid salt The compound was made by standard amino acid coupling of 4-(N-(2- cyclohexy lethyl)-N-methylaminomethyl)-2-(2-methylphenyl)benzoic acid and L-Glu-OtBu followed by treatment with TFA.

MS m/e 492 (M-H)-.

IH NMR (d6-DMSO, 300 MHz) 8 0.91 (m, 2H), 1.1 (m, 4H), 1.63 (m, 9H), 1.9 (m, 3H), 2.1 (m, 3H), 2.71 (s, 3H), 3.1 (m, 2H), 4.09 (m, 1H), 4.29 (m, lH), 4.43 (m, 1H); 6.74 (s, lH), 7.1-7.22 (m, 3H), 7.39 (s, lH), 7.60 (m, 2H), 8.32 (m, 2H), 9.62 (bs, lH).

Example 1019 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]homocysteine, lithium salt Prepared in a manner analogous to Example 1018 using L-homocysteine thiolactone and opening the resulting thiolactone with 1 equivalent of LiOH.

MS m/e 481 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 6 0.84 (m, 2H), 1.11 (m, 3H), 1.32 (m, 5H), 1.6 (m, 7H), 2.18 (m, 7H), 3.48 (s, 3H), 3.82 (m, 1H), 3.97 (m, 1H), 6.95 (m, 1H), 7.0-7.34 (m, 4H), 7.5 (m, 1H), 7.65 (m, 1H), 8.39 (m, 1H).

Example 1020 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl phenyl)benzoyl]histidine Triflloroacetic Acid salt Prepared in a manner analogous to Example 1018 using L-His(trt)-OMe.HCl, removing the methyl ester with LiOH, and removing the im-trityl group with TFA/triethylsilane .

MS m/e 497 (M+H)+.

1H NMR (d6-DMSO, 300 MHz) 6 0.90 (m, 2H), 1.17 (m, 4H), 1.63 (m, 8H), 1.99 (m, 6H), 2.1 (m, 3H), 2.73 (m, 3H), 3.0 (m, 2H), 4.3 (m, lH), 4.4 (m, lH), 4.56 (m, 2H), 7.08 (m, lH), 7.15-7.42 (m, 3H), 7.58 (m, 2H), 8.62 (m, lH), 8.97 (s, lH).

Example 1021 N-[4-(N-cyclohexylmethylaminoethyl)-2-(2-methylphenyl)benzoy l]methionine, lithium salt N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benz oyl methionine methyl ester (84 mg, 0.17 mmol) was treated with LiOH (1 M, 85 µL) in methanol to provide the title compound.

MS m/e 481 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 6 0.83 (m, 2H), 1.15 (m, 4H), 1.36 (m, 1H), 1.62 (m, 9H), 1.98 (m, 10H), 3.7 (m, 2H), 4.27 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.1-7.3 (m, 4H), 7.44 (m, 1H), 8.24 (m, 1H).

N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benz oyl methionine methyl ester

Methyl 4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoat e hydrochloride (1.33 g, 3.31 mmol) was treated with sat. LiOH (1.3 mL, 6.95 mmol) in 50 mL methanol at 60 °C until no starting material remained by tlc. The solution was evaporated to dryness and treated with Met-OMe-HCl (0.99 g, 4.96 mmol), EDAC (1.26 g, 6.6 mmol), HOBt (1.5 g, 9.9 mmol), and TEA (to pH 6-7) in 25 mL DMF. Standard aqueous workup followed by flash chromatography (100 % EtOAc) provided 1.5 g of the title compound.

MS m/e 497 (M-H)-.

1H NMR (CDCl3, 300 MHz) 6 0.88 (m, 2H), 1.2 (m, 4H), 1.6 (m, 8H), 2.1 (m, 8H), 2.47 (m, 2H), 2.9 (m, 4H), 3.68 (s, 3H), 4.63 (m, 1H), 5.89 (d, 1H, J = 7 Hz), 7.04 (s, 1H), 7.19 (m, 1H), 7.3 (m, 4H), 7.91 (m, 1H).

Methvl 4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoat e Methyl 4-(propan-3-al)-2-(2-methylphenyl)benzoate (5.0 g, 18.6 mmol) and cyclohexylmethylamine (2.32 g, 10.5 mmol) were dissolved in 250 mL 1 % acetic acid in methanol. After 10 minutes, sodium cyanoborohydride (1.76 g, 28 mmol) was added. The mixture stirred overnight at room temperature before evaporating to dryness. The residue was dissolved in ether and washed with 5 % NaHCO3, water, and brine, dried over Na2SO4, and treated with anh. HCl. The oily product was crystalized from methanol and ether.

MS m/e 366 (M+H)+.

1H NMR (CDC13, 300 MHz) 8 0.88 (m, 2H), .1.2 (m, 4H), 1.6 (m, 6H), 2.06 (s, 3H), 2.48 (d, 2H, J = 7 Hz), 2.92 (s, 4H), 3.61 (s, 3H), 7.06 (m, 1H), 7.23 (m, 5H), 7;92 (m, 1H).

Methyl 4-(propan-3-al)-2-(2-methylphenyl)benzoate Methyl 4-(prop-2-enyl)-2-(2-methylphenyl)benzoate (5.23 g, 19.6 mmol), osmium tetroxide (0.02 mmol/mL t-BuOH, 29.5 mL), and sodium periodate (10.5 g, 49.1 mmol) were combined in 200 mL acetone with 50 mL water. After stirring at ambient temperature for 1 hour, the mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2SO4 to give the desired product which was used directly in the next step.

MS m/e 286 (M+NH4)+.

1H NMR (CDC13, 300 MHz) 82.06 (m, 3H), 3.61 (s, 3H), 3.8 (m, 2H), 7.1 (m, 1H), 7.25 (m, 5H), 7.95 (m, 1H), 9.80 (m, 1H).

Methyl 4-(prop-2-enyl)-2-(2-methylphenyl)benzoate

Methyl 4-iodo-2-(2-methylphenyl)benzoate (10.0 g, 28.4 mmol), allyltributyl tin (11.3 g, 34.1 mmol), and dichlorobis(triphenylphosphine)palladium (II) (1.0 g, 1.42 mmol) were combined in 50 mL toluene and 20 mL NMP and heated at 125 "C for 18 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and chromatographed (5 % EtOAc in hexanes) to provide the title compound in 74 % yield.

MS m/e 284 (M+NH4)+.

1H NMR (CDCl3, 300 MHz) 82.06 (s, 3H), 3.45 (d, 2H, J = 7 Hz), 3.61 (s, 3H), 5.1 (m, 2H), 5.97 (m, 1H), 7.08 (m, 1H), 7.23 (m, SH), 7.94 (m, 1H).

Example 1022 N-[4-(N,N-di-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl )benzoyl]methionine, lithium salt N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benz oyl methionine methyl ester (300 mg, 0.60 mmol) and cyclohexylcarboxaldehyde (140 mg, 1.21 mmol) were dissolved in 1 % acetic acid in methanol (5 mL) and treated with sodium cyanoborohydride (76 mg, 1.21 mmol). Standard workup followed by flash chromatography (20 % ethyl acetate in hexane) provided 320 mg which was subsequently saponified with LiOH to the title compound.

MS m/e 577 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 6 0.75 (m, 4H), 1.10 (m, 8H), 1.30 (m, 2H), 1.61 (m, 9H), 2.0 (m, 10H), 2.6 (m, 2H), 2.7 (m, 2H), 3.3 (m, 1H), 3.68 (m, 1H), 6.90 (m, 2H), 7.1 (m, SH), 7.44 (m, 1H).

Example 1023 N-[4-(N-cyclohexylmethyl-N-phenylacetylaminoethyl)-2-(2- methvlphenyl)benzoyllmethionine. lithium salt N-[4-(N-cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzo yl methionine methyl ester (75 mg, 0.11 mmol), phenacetyl chloride (26 mg, 0.17 mmol), and triethylamine (17 mg, 0.15 mmol) were stirred in DMF (0.5 mL) for 18 hours at ambient temperature. The reaction was diluted with EtOAc, washed with 5 % NaHCO3, water, and brine, dried over Na2SO4, and chromatographed (50 % EtOAc/hexanes) to provide 66 mg of the methyl ester of the title compound. This was subsequently saponified with LiOH in quantitative yield to the title compound.

MS m/e 599 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 8 0.83 (m, 2H), 1.15 (m, 4H), 1.6 (m, 9H), 1.98 (m, 8H), 2.8 (m, lH), 3.1 (m, 2H), 3.5 (m, 3H), 3.7 (m, 2H), 7.0 (m, 2H), 7.1-7.3 (m, 9H), 7.45 (m, 1H).

Example 1024 N- 4-(N-cyclohexylmethyl-N- 1 -adamantanoylaminoethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023 using 1- adamantanecarbonyl chlroide.

MS m/e 643 (M-H)-.

'H NMR (d6-DMSO, 300 MHz) 6 0.87 (m, 8H), 1.15 (m, 4H), 1.6 (m, 14H), 1.9 (m, 12H), 2.85 (m, 1H), 3.18 (m, 2H), 3.6 (m, 2H), 6.91 (m, 1H), 7.02 (m, lH), 7.2 (m, SH), 7.48 (m, 1H).

Example 1025 N-[4-(N-cyclohexylmethyl-N-t-butoxycarbonylaminoethyl)-2-(2- methvlPhenvl)benzovl1 methionine. lithium salt This compound was prepared in a manner analogous to Example 1023 using di-t- butyldicarbonate.

MS m/e 581 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 6 0.83 (m, 2H), 1.15 (m, 4H), 1.38 (s, 9H), 1.6 (m, 9H), 1.95 (m, 6H), 2.18 (m, 2H), 2.8 (m, 4H), 3.7 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, SH), 7.45 (m, 1H).

Example 1026 N-[4-(N-cyclohexylmethyl-N-2-ethylhexyloxycarbonylaminoethyl )-2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023 using 2- ethylhexyl chloroformate.

MS m/e 637 (M-H)-.

H NMR (d6-DMSO, 300 MHz) # 0.83 (m, 4H), 1.15 (m, 4H), 1.23 (m, 9H), 1.6 (m, 9H), 1.95 (m, 8H), 2.83 (m, 2H), 3.0 (m, 2H), 3.5 (m, 3H), 3.6 (m, 1H), 3.89 (m, 2H), 4.29 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, SH), 7.45 (m, 1H).

Example 1027 N-[4-(N-cyclohexylmethyl-N-2,2,2-trichloroethoxycarbonylamin oethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023.

MS m/e 683 (M-H)-.

H NMR (d6-DMSO, 300 MHz) 80.84 (m, 2H), 1.17 (m, 4H), 1.6 (m, SH), 1.9 (m, 14H), 2.9 (m, 3H), 3.03 (m, 1H), 3.5 (m, 3H), 3.6 (m, 1H), 4.28 (m, 1H), 6.9 (m, 1H), 7.0 (m, 2H), 7.2 (m, SH), 7.45 (m, 1H).

Example 1028 N-[4-(N-cyclohexylmethyl-N-cyclohexyloxycarbonylaminoethyl)- 2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023.

MS m/e 607 (M-H)-.

H NMR (d6-DMSO, 300 MHz) 8 0.84 (m, 4H), 1.17 (m, 4H), 1.3 (m, 6H), 1.6 (m, 10H), 1.95 (m, 8H), 2.17 (m, 1H), 2.9 (m, 4H), 3.6 (m, 1H), 4.53 (m, 1H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, SH), 7.47 (m, 1H).

Example 1029 N-[4-(N-cyclohexylmethyl-N-adamantyloxycarbonylaminoethyl)-2 -(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023.

MS m/e 659 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 8 0.83 (m, 6H), 1.16 (m, 6H), 1.6 (m, 13H), 2.0 (m, 12H), 2.82 (m, 3H), 2.95 (m, 1H), 3.65 (m, 2H), 6.95 (m, 2H), 7.2 (m, SH), 7.47 (m, 1H).

Example 1030 N- 14-(N-cvclohexvlmethvl-N-phenoxvcarbonvlaminoethvl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023.

MS m/e 601 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 8 0.91 (m, 2H), 1.19 (m, 4H), 1.63 (m, 9H), 1.98 (m, 6H), 2.15 (m, 2H), 2.97 (m, 1H), 3.11 (m, 1H), 3.5 (m, 1H), 3.7 (m, 2H), 6.85-7.39 (m, 12H), 7.48 (m, 1H).

Example 1031 N-[4-(N-cyclohexylmethyl-N-benzyloxycarbonylaminoethyl)-2-(2 - methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023.

MS m/e 615 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 6 0.83 (m, 2H), 1.13 (m, 4H), 1.6 (m, 6H), 1.95 (m, 6H), 2.14 (m, 2H), 2.83 (m, 2H), 2.99 (m, 2H), 3.40 (m, 2H), 3.65 (m, 2H), 5.04 (m, 2H), 6.9-7.3 (m, 12H), 7.43 (m, 1H).

Example 1032 N-[4-(N-cyclohexylmethyl-N-adamant-1-aminocarbonylaminoethyl )-2-(2- methylphenyl)benzoyl]methionine, lithium salt This compound was prepared in a manner analogous to Example 1023 using adamantyl isocyanate.

MS m/e 658 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 0.83 (m, 6H), 1.13 (m, 6H), 1.6 (m, 13H), 1.95 (m, 12H), 2.18 (m, 1H), 2.79 (m, 2H), 2.91 (m, 2H), 3.65 (m, 2H), 6.9 (m, 1H), 7.0 (m, 1H), 7.2 (m, SH), 7.46 (m, 1H).

Example 1033 N-14-(N-cvclohexvlmethvl-N-adamant- 1 -aminothiocarbonvlaminoethvl)-2-(2- methvlphenvl)benzovllmethionine, lithium salt This compound was prepared in a manner analogous to Example 1023 using adamantyl isothiocyanate.

MS m/e 674 (M-H)-.

H NMR (d6-DMSO, 300 MHz) 8 0.85 (m, 6H), 1.15 (m, 6H), 1.6 (m, 13H), 2.0 (m, 12H), 2.2 (m, 1H), 2.74 (m, 2H), 2.91 (m, 2H), 3.62 (m, 2H), 6.9-7.5 (m, 8H).

Example 1041 N- [4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methvlphenvl)benzovllglutaminitrile, lithium salt Boc-Gln (2.0 g, 8.11 mmol) and acetic anhydride (0.92 mL, 9.7 mmol) were combined in dry pyridine (10 mL) and stirred at room temperature overnight. The solution was evaporated to dryness and partitioned between EtOAc and 10 % citric acid. The organic layer was washed with 10 % citric acid, water, and brine, dried over Na2SO4, and evaporated to dryness. The residue was dissolved in MeOH (5 mL) and treated with trimethylsilyldiazomethane (2.0 M in hexanes, excess). The mixture was evaporated and chromatographed (50 % EtOAc in hexanes) to give 0.92 g of Boc-glutaminitrile methyl ester. The nitrile (0.24 g, 1 mmol) was treated with excess 50 % trifluoroacetic acid in methylene choride, evaporated and coupled to 4-(2-cyclohexylethyl-N-methylaminomethyl)- 2-(2-methylphenyl)benzoic acid via standard techniques, followed by standard lithium hydroxide saponification to provide the title compound.

MS m/e 474 (M-H)-.

1H NMR (d6-DMSO, 300 MHz) 80.82 (m, 2H), 1.11 (m, 3H). 1.32 (m, SH), 1.6 (m, 7H), 2.18 (m, 6H), 2.32 (m, 1H), 2.58 (m, 1H), 2.75 (m, 1H), 3.53 (m, 2H), 6.9-7.5 (m, 7H), 7.83 (m, 1H).

Example 1047 N-[4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine, lithium salt Example 1047A 4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2-methylpheny l)benzoic acid, Methyl Ester To a solution of N-methyl-p-toluenesulfonamide (203mg) and 4-hydroxymethyl-2- (2-methylphenyl)benzoic acid methyl ester (example 1178C, 255mg) in THF (3mL) at 0°C was added triphenylphosphine (315mg) and diethyl azodicarboxylate (0. 19mL). The reaction was warmed, and stirred at ambient temperature for 30h. The reaction was concentrated, and the residue was purified by silica gel chromatography eluting with a gradient from 20% EtOAc/hexane to 100% EtOAc. The product was isolated as a colorless oil (170mg, 40%).

MS (DCI/NH3) 441 (M+NH4)+.

Example 1047B N-F4-(N-p-Toluenesulfonyl-N-methvlaminomethvl)-2-(2- methvlphenyl)benzovllmethionine. Methvl Ester 4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2-methylpheny l)benzoic acid methyl ester was converted to the title compound according to the procedures in examples 608C and D.

MS (APCI(+) m/e (M+H)+ 555, MS (APCI(-) m/e (M-H)- 553.

Example 1047C %N-[4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2-methylp henyl)benzoyl]methionine, lithium salt N- [4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

IH NMR (300 MHz, DMSO) 8 1.50-1.88 (m, 4H), 1.92 (s, 3H), 1.95-2.14 (m, 3H), 2.41 (s, 3H), 2.59 (s, 3H), 3.58-3.70 (m, 1H), 4.18 (s, 2H), 6.96 (brd, J=5.4 Hz, 1H), 7.02- 7.26 (m, 5H), 7.35 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H).

MS (ESI(-)) m/e 539 (M-H); Analysis calc'd for C28H31LiN2O5S21.5OH2O: C, 58.63; H, 5.97; N, 4.88; found: C, 58.61; H, 5.66; N, 4.51.

Example 1048 <BR> <BR> <BR> N-14-(N-(4-BenzyloxYbenzyl!-N-(N-2-methvl-2-phenvlpropvlacet amido)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt Example 1048A N-(2-Methyl-2-phenylpropyl)-N-tert-butoxycarbonyl-2-aminoace tamide To a slurry of NaH (10g of a 60% dispersion in mineral oil) in dry THF (300mL) was added benzylcyanide (10g) by means of a dropping funnel. Cautious addition of methyl iodide (13mL) caused rapid gas evolution and an increase in temperature which was moderated with an ice bath. After stirring at ambient temperature for 12h, the reaction was quenched cautiously with water (100mL). The mixture was diluted with ether (500mL) and the layers were separated. The ether layer was washed with water (100mL) containing a small amount of Na2SO3 to eliminate the iodine color, then washed with brine (50mL). The organic solution was dried (MgS04), filtered and concentrated to afford an oil. This material was added neat to a solution of 1M LiAlH4 (85mL, THF) in ether (100mL). If necessary, the reduction was initiated after a small amount of starting material was added by warming with a heat gun. The starting material was then added at a rate which maintained a gentle reflux. After addition was complete, the reaction was stirred without heating or cooling for lh. The reaction was cautiously quenched with vigorous stirring by the addition of water (3.2mL), 15%NaOH (3.2mL), and more water (lOmI,). The suspension was filtered through celite, which was rinsed with ether. The filtrate was concentrated to give an oil (ca.

20g) which contained mineral oil from the sodium hydride dispersion. A portion of this material (3.3g) was dissolved in DMF (67mL) along with N-(tert-butoxycarbonyl)glycine (3.5g), followed by addition of N-methylmorpholine (3.3mL), 1-hydroxybenzotriazole (3.0g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.0g). After stirring at ambient temperature for 15h, the reaction was poured into ether (500mL), washed with water

(2X100mL), 1M HCl (2Xl00mL), saturated NaHCO3 (2X50mL), and brine (lOOmL). The organic solution was dried (MgS04), filtered and concentrated to afford a residue which partly solidified. The residue was triturated with hexane, and filtered to give 4.5g of the title compound. MS(DCI/NH3) 307 (M+H)+.

Example 1048B N-(2-Methvl-2-phenylprnpvl)-N-(4-benzyloxybenzyl)-2-aminoace tamide To a solution of N-(2-methyl-2-phenylpropyl)-N-tert-butoxycarbonyl-2- aminoacetamide (4.5g) in dichloromethane (50mL) was added trifluroracetic acid (lOmL).

After 1.5h at ambient temperature, the reaction was concentrated, then the residue was evaporated from toluene to afford a light tan solid (4.4g). This material was stirred with 4- benzyloxybenzaldehyde (3.27g) in 1:1 THF:EtOH (30mL). Bromcresol green (1 mg) was added, and the reaction was adjusted to pH=3 with 15%NaOH. The reaction was warmed briefly to reflux to complete dissolution of starting material, then cooled to ambient temperature. Sodium cyanoborohydride (1SmL, 1M THF) was added, and the reaction color was held at a light green by addition of a 2:1 ethanol:HCl mixture. After starting aldehyde was consumed (TLC), the reaction was concentrated, dissolved in EtOAc (200mL), and washed with saturated NaHCO3 (2X50mL), water (SOniL), and brine (50mL). The organic solution was dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography to give the title compound (1.96g) along with a significant amound of double alkylation product. MS(ESI) 403 (M+H)+.

Example 1048C

4-(N-(4-Benzyloxybenzyl)-N-(N-2-methyl-2-phenylpropylacetami do)aminomethyl)-2-(2- methylphenvl)benzoic acid. Methvl Ester The title compound was prepared by the procedure in example 608B, replacing N- methylcyclohexylethylamine with N-(2-methyl-2-phenylpropyl)-N-(4-benzyloxybenzyl)-2- aminoacetamide. MS(APCI(+)) 641 (M+H)+. MS(APCI(-)) 675 (M+Cl)-.

Example 1048D N-[4-(N-(4-Benzyloxybenzyl)-N-(N-2-methyl-2-phenylpropylacet amido)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, MethylEster 4-(N-(4-Benzyloxybenzyl)-N-(N-(2-methyl-2- phenylpropylamino)acetylaminomethyl)-2-(2-methylphenyl)benzo ic acid methyl ester was converted to the title compound according to the procedures in examples 608C and D.

MS(APCI(+)) 772 (M+H)+. MS(APCI(-)) 806 (M+Cl)-.

Example 1048E N-[4-(N-(4-Benzyloxybenzyl)-N-(N-2-methyl-2-phenylpropylacet amido)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt N-[4-(N-(4-Benzyloxybenzyl)-N-(N-(2-methyl-2- phenylpropylamino)acetylaminomethyl)-2-(2-methylphenyl)benzo yl]methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder.

1H NMR (300 MHz, DMSO) 6 1.15 (s, 3H), 1.16 (s, 3H), 1.50-1.84 (m, SH), 1.92 (s, 3H), 1.95-2.16 (m, 3H), 2.88 (s, 2H), 3.28 (s, 2H), 3.39 (s, 2H), 3.47 (s, 2H), 3.60-

3.68 (m, 1H), 5.07 (s, 2H), 6.87 (d, J=9 Hz, 2H), 6.93 (d, J=9 Hz, 2H), 6.93-7.48 (m, 17H). Analysis calc'd for C46H50LiN3O5S#1.95H2O: C, 69.15; H, 6.80; N, 5.26; found: C, 69.11; H, 6.50; N, 5.13.

Example 1056 <BR> <BR> N-r4-(N-(2-Cvclohexenvlethvl)-N-methvlaminomethvl!-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1056A N-Methvl-2-(l -cvclohexenvl)ethvlamine To a solution of 2-(1-cyclohexenyl)ethylamine (4.0g) in 1,4-dioxane (40mL) was added di-tert-butyldicarbonate (7.7g). After gas evolution ceased (=2h) the reaction was concentrated. A portion of the residue (2g) was dissolved in THF (lOmL) followed by addition of LiAlH4 (lOmL, 1M THF), which caused an exotherm. After 3h, more LiAlH4 solution was added (4mL), and the reaction was warmed to reflux. After lh, the reaction was cooled, and quenched cautiously with vigorous stirring by the addition of water (0.57mL), 1M NaOH (0.6mL), and more water (1.5mL). The suspension was filtered through celite, which was washed with ether. The organic solution was concentrated to give the desired product as a volatile oil (0.8g).

1H NMR (300 MHz, CDC13) 1.52-1.67 (m, 4H), 1.89-2.04 (m, 4H), 2.14 (brt, J=7 Hz, 2H), 2.42 (s, 3H), 2.63 (t, J=7 Hz, 2H), 5.45 (m, 1H).

Example 1056B 4-(N-(2-Cyclohexenylethyl)-N-methylaminomethyl)-2-(2-methylp henyl)benzoic acid, Methvl Ester The title compound was prepared from N-methyl-2-( 1 -cyclohexenyl)ethylamine according to the procedure in example 608B.

MS (DCI/NH3) 378 (M+H)+.

Example 1056C N-L4-(N-(2-Cyclohexenvlethvl!-N-methylaminomethyl)-2-(2- methylphenyl)benzoylimethionine. Methyl Ester The title compound was prepared from 4-(N-(2-cyclohexenylethyl)-N- methylaminomethyl)-2-(2-methylphenyl)benzoic acid methyl ester according to the procedure in examples 608C and D. MS(APCI(+)) 509 (M+H)+. MS(APCI(-)) 543 (M+Cl)-.

Example 1056D <BR> <BR> N- 14-(N-(2-Cyclohexenylethvl )-N-methylaminomethvl)-2-(2- methvlphenyl)benzovll methionine. lithium salt

N-[4-(N-(2-cyclohexenylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted into the title compound by the procedure in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 1.38-1.75 (m, 4H), 1.80-2.13 (m, 13H), 1.91 (s, 3H), 2.14 (s, 3H), 2.36-2.45 (m, 2H), 3.50 (s, 2H), 3.56-3.67 (brs, 1H), 5.32-5.36 (m, lH), 6.88-6.92 (m, lH), 7.05-7.23 (m, SH), 7.32 (d, J=8.1 Hz, 1H), 7.48 (d, J=8.1 Hz, lH).

MS (APCI(-)) m/e 493 (M-H); Analysis calc'd for C2gH37LiN203Sl. l5H2O: C, 66.81; H, 7.60; N, 5.37; found: C, 66.86; H, 7.34; N, 5.19.

Example 1057 <BR> <BR> N-t4-(N-(2-Cvclohexvlethvl)-N-methylaminomethyl)-2-phenylben zoyllmethioniner lithium salt Example 1057A 4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl-2-phenylbenzoic acid. Methyl Ester The title compound was prepared according to the procedure in example 608B, replacing 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester with 4-bromomethyl- 2-phenylbenzoic acid methyl ester (example 228B).

MS (DCI/NH3) 366 (M+H)+.

Example 1057B N- F4-(N-(2-Cyclohexylethyl)-N-methvlaminomethvl)-2-phenvlbenzo vllmethionine. Methvl Ester The title compound was prepared from 4-(N-(2-cyclohexylethyl)-N- methylaminomethyl)-2-phenylbenzoic acid methyl ester according to the procedure in examples 608C and D. MS(APCI(+)) 497 (M+H)+. MS(APCI(-)) 531 (M+Cl)-.

Example 1057C N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-phenylben zoyl]methionine, lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-phenylben zoyl]methionine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 6 0.76-0.92 (m, 2H), 1.06-1.38 (m, SH), 1.53-1.67 (m, 6H), 1.67-1.89 (m, 2H), 1.97 (s, 3H), 1.98-2.20 (m, 2H), 2.14 (s, 3H), 2.36 (t, J=6 Hz, 2H), 3.51 (s, 2H), 3.76-3.82 (m, 1H), 7.16 (d, J=6 Hz, 1H), 7.27-7.41 (m, 8H).

MS (APCI(-)) m/e 481 (M-H); Analysis calc'd for C28H37LiN2O3SO.95H2O: C, 66.50; H, 7.75; N, 5.54; found: C, 66.53; H, 7.58; N, 5.47.

Example 1058 (2S) 2-N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt Example 1058A (2S) 2-N-14-(N-(2-Cyclohexylethyl)-N-methalaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoic acid. Methvl Ester To a solution of N-[4-(N-(-2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl] methionine methyl ester (example 608D, 100mg) in dichloromethane (2mL) at ambient temperature was added trifluoroacetic acid (0.023ml), and the salt solution was cooled to OOC. Hydrogen peroxide (30%, 0.050mL) was added with vigorous stirring.

After 42h at ambient temperature, the reaction was concentrated and the residue was purified by silica gel chromatography eluting with 2.5%-5.0%-10.0% MeOH/CH2Cl2, to give two products which were both colorless oils. The more mobile product is (2S) 2-N-[4-(N-(2- cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)benz oyl]amino-4- methylsulfonylbutanoic acid methyl ester (35mg, 33%). MS(APCI(+)) 543 (M+H)+.

MS(APCI(-)) 577 (M+Cl)-. The less mobile product is the title compound (SOmg, 48%).

MS(APCI(+)) 527 (M+H)+. MS(APCI(-)) 561 (M+C1)-.

Example 1058B (2S) 2-N-14-(N-(2-Cyclohexylethyl)-N-methvlaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt (2S) 2-N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoic acid methyl ester was converted to the title compound according to the procedure in example 608E, with the exception that the product was isolated as a white powder after trituration of the concentrated reaction residue with diethyl ether and drying under vacuum.

IH NMR (300 MHz, DMSO) 80.76-0.90 (m, 2H), 1.04-1.37 (m, SH), 1.53-1.65 (m, 6H), 1.66-1.90 (m, 2H), 1.95-2.22 (m, SH), 2.13 (s, 3H), 2.32 (t, J=7.2 Hz. 2H), 2.37 (s, 1.5H), 2.39 (s, 1.5H), 3.49 (s, 2H), 3.64-3.77 (m, 1H), 6.99 (d, J=6 Hz, 1H), 7.06- 7.26 (m, 5H), 7.32 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.1 Hz, 0.5H), 7.51 (d, J=8.1 Hz, 0.5H).

MS (ESI(-)) m/e 511 (M-H).

Example 1059 (2S) 2-N- [4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl )-2-(2- methylphenvl)benzovllamino-4-methvlsulfonvlbutanoate, lithium salt (2S) 2-N- [4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl] amino-4-methylsulfonylbutanoic acid methyl ester (example 1058A) was converted to the title compound according to the procedure in example 608E, with the exception that the product was isolated as a white powder after trituration of the concentrated reaction residue with diethyl ether and drying under vacuum.

H NMR (300 MHz, DMSO) # 0.76-0.91 (m, 2H), 1.08-1.37 (m, SH), 1.53-1.67 (m, 6H), 1.72-1.93 (m, 2H), 1.95-2.20 (m, 3H), 2.16 (s, 3H), 2.36 (t, J=7.2 Hz, 2H), 2.42- 2.56 (m, 2H), 2.83 (s, 3H), 3.52 (s, 2H), 3.64-3.77 (m, 1H), 6.98 (d, J=6 Hz, 1H), 7.04-7.28 (m, 5H), 7.34 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H).

MS (ESI(-)) m/e 527 (M-H); Analysis calc'd for C29H39LiN2O5S#0.15H2O#0.40HoAc: C, 60.32; H, 6.82; N, 4.74; found: C, 60.25; H, 6.97; N, 4.92.

Example 1060 N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenvl)benzoyllnorleucine. lithium salt Example 1060A N- 14-(N-(2-Cyclohexylethyl)-N-methylaminomethvl)-2-(2- methylphenvl)benzoyll norleucine. Methyl Ester The title compound was prepared according to example 608D, substituting L- norleucine methyl esterHCl for L-methionine methyl ester HCl. MS(APCI(+)) 493 (M+H)+. MS(APCI(-)) 491 (M-H)-.

Example 1060B N-14-(N-(2-Cyclohexylethvl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]norleucine, lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]norleucine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 0.62-0.90 (m, 7H), 0.97-1.44 (m, 10H), 1.52-1.64 (m, 5H), 1.95-2.18 (m, 3H), 2.13 (s, 3H), 2.33 (t, J=6 Hz, 2H), 3.48 (s, 2H), 3.56-3.66 (m, 1H), 6.80-6.89 (m, 1H), 7.01-7.22 (m, 5H), 7.30 (d, J=7.8 Hz, 1H), 7.46 (d. J=7.8 Hz, 1H).

MS (ESI(-)) m/e 477 (M-H); Analysis calc'd for C30H41LiN2O3O.9H2O: C, 71.95; H, 8.61; N, 5.59; found: C, 72.00; H, 8.36; N, 5.50.

Example 1061 N-[4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, Internal salt Example 1061A N,N-Dimethyl-2-cyclohexylethylamine

The title compound was prepared from N-methylcyclohexylethylamine (example 608A) according to the procedure described in example 1056A.

1H NMR (300 MHz, CDC13) 0.80-0.95 (m, 2H), 1.10-1.39 (m, 6H), 1.60-1.74 (m, SH), 2.20 (s, 6H), 2.23-2.28 (m, 2H).

MS (DCl/NH3) m/e 156 (M+H)+.

Example 1061B 4-Iodomethyl-2-(2-methylphenyl)benzoic acid, methyl ester Triphenylphosphine (5. l6g), and imidazole (1.34g) were dissolved in 3:1 ether:acetonitrile (80mL), and the reaction was cooled to 0°C. Iodine (5.0g) was added with vigorous stirring, and the reaction was warmed to ambient temperature. After lh, the reaction was recooled to 0°C and 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1178C, 4.6g) was added as a solution in ether (20mL). After 4h at ambient temperature, the reaction was diluted with hexane/ether (1:1, 200mL) and filtered. The filtrate was washed with a dilute solution of Na2SO3 until colorless, then with water (2X50mL). The organic extracts were washed with brine (20mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give a light yellow oil (4.7g) which slowly crystalizes in the freezer.

1H NMR (300MHz, CDC13) 2.06 (s, 3H), 3.60 (s, 3H), 4.45 (ABq, JAB=9.7Hz, uAB=6.7Hz, 2H), 7.03 (brd, J=6.6Hz, 1H), 7.17-7.29 (m, 4H), 7.41 (dd, J=8.1, 1.6Hz, 1H), 7.90 (d, J=8.1Hz, 1H)). MS(CI/NH3) m/e: (M+NH4)+ 384.

Example 1061C 4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2-methy lphenyl)benzoic acid, Methvl Ester. Iodide

To a solution of 4-iodomethyl-2-(2-methylphenyl)benzoic acid methyl ester ( 0.5g) in dichloromethane (I mL) was added N,N-dimethyl-2-cyclohexylethylamine (0.233mg), and the reaction was stirred at ambient temperature for 2h. The reaction was concentrated to give a light yellow foam (760mg, 100%).

1H NMR (300 MHz, CDCl3) 8 0.89-1.44 (m, 6H), 1.60-1.73 (m, 7H), 2.06 (s, 3H), 3.34 (s, 6H), 3.55-3.63 (m, 2H), 3.64 (s, 3H), 5.14 (ABq, A1)AB=56 Hz, JAB=12.7 Hz, 2H), 7.01 (d, J=7.5 Hz, 1H), 7.17-7.32 (m, 3H), 7.39 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.1, 1.8 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H).

Example 1061D 4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2-methy lphenyl)benzoate, Internal salt To a solution of 4-(N-(2-cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoic acid methyl ester, iodide (700mg) in methanol (3mL) was added 5M LiOH (0.54mL). The reaction was refluxed for lh, then stirred at ambient temperature overnight. The reaction was diluted with water (30mL), and purified by preparative reverse- phase medium pressure chromatography, eluting with a gradient of methanol/water/TFA (0.1%) to give a tan syrup (711mg).

1H NMR (300 MHz, DMSO) 8 0.90-1.03 (m, 2H), 1.10-1.28 (m, SH), 1.57-1.73 (m, 6H), 2.06 (s, 3H), 2.97 (s, 6H), 3.24-3.35 (m, 2H), 4.53-4.57 (m, 2H), 7.07 (d, J=6.9 Hz, 1H), 7.18-7.30 (m, 3H), 7.43 (d, J=1.5 Hz, 1H), 7.64 (dd, J=8.1, 1.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H).

MS (ESI) m/e 380 (M+H)+.

Example 1061E N-[4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, Methyl Ester. Triflate To a solution of 4-(N-(2-cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoate internal salt (771mg) in dichloromethane (5mL) at ambient temperature was added oxalyl chloride (5mL of a 2M solution in CH2Cl2). As gas evolution slowed, DMF (5 drops) was added. After stirring at ambient temperature for 20min, the reaction was warmed to reflux for 2h, then cooled, and the solvent was removed under a stream of dry nitrogen to give a tan solid. To a solution of the acid chloride dissolved in dry dichloromethane (lOmL) at 0°C was added triethylamine (0.47mL), and L-methionine methyl ester'HCl (320mg). After stirring at ambient temperature overnight, the reaction was concentrated, dissolved in 1:1 methanol/water (30mL), and purified by preparative reverse- phase medium pressure chromatography, eluting with a gradient of methanol/water/TFA (0.1%) to give a tan foam (330mg). lH NMR (300 MHz, CDCl3) 8 0.88-1.40 (m, 7H), 1.60-1.76 (m, 6H), 1.82-1.95 (m, 2H), 2.00-2.19 (m, 8H), 3.21 (brs, 6H), 3.29-3.37 (m, 2H), 3.68 (s, 3H), 4.58-4.65 (m, 3H), 6.09 (d, J=6 Hz, 1H), 7.13-7.40 (m, 6H), 7.57 (brd, J=7.8 Hz, 1H), 8.00 ("t", J=7.8 Hz, 1H).

MS (ESI(-)) m/e 637 (M-H)-, 751 (M+TFA-H)-.

Example 1061F N-[4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, Internal salt N-[4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester triflate (330mg) was dissolved in methanol (2mL), and 5M LiOH (0.21mL, 2eqiv) was added. After stirring at ambient temperature overnight, the reaction was diluted with water (lOmL), and purified by preparative reverse- phase medium pressure chromatography, eluting with a gradient of methanol/water/TFA (0.1%) to give a tan powder (1 68mg) after lyophylization from acetonitrile-water.

1H NMR (300 MHz, DMSO) 6 0.87-1.04 (m, 2H), 1.08-1.33 (m, 4H), 1.59-1.92 (m, 10H), 1.96 (s, 3H), 2.00-2.24 (m, 4H), 2.97 (brs, 6H), 3.24-3.35 (m, 2H), 4.20-4.30 (m, 1H), 4.56 (brs, 2H), 7.13-7.27 (m, 5H), 7.43 (brs, 1H), 7.62 (brs, 2H), 8.30 (brd, J=5 Hz, 1H).

MS (ESI(+)) m/e 511 (M+H); Analysis calc'd for C30H42N2O3S#0.65H2O# 1.30TFA: C, 58.38; H, 6.70; N, 4.18; found: C, 58.35; H, 6.67; N, 4.26.

Example 1062 (2S) 2-N-t4-(N-(2-Cyclohexvlethvl!-N-butvlaminomethvl!-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt Example 1062A (2S) 2-N-r4-(N-(2-Cvclohexvlethvl!-N-butvlaminomethvl!-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, Methyl Ester To a solution of N-[4-(N-(2-cyclohexylethyl)-N-butylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester (example 11781, 90mg) in dichloromethane (ill) at 0°C was added trifluoroacetic acid (0.023mL), then 30% hydrogen peroxide (0.05mL). After 2h, the reaction was quenched by addition of sodium sulfite (lOOmg). The reaction was filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 2.5%-5.0% methanol/dichloromethane to give the title compound as a colorless oil (75mg, 79%). MS(APCI(+)) 569 (M+H)+. MS(APCI(-)) 603 (M+Cl)-.

Example 1062B (2S) 2-N-l4-(N-(2-Cvclohexvlethvl!-N-butvlaminomethvl)-2-(2- methvlphenvl)benzovllamino-4-methvlsulfenvlbutanoate lithium salt (2S) 2-N- [4-(N-(2-Cyclohexylethyl)-N-butylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate methyl ester was converted to the title compound according to the procedure in example 608E, with the exception that the product was isolated as a colorless foam after trituration with dichloromethane and removal of the solvent under reduced pressure.

1H NMR (300 MHz, DMSO) 6 0.76-0.87 (m, 5H), 1.02-1.44 (m, 9H), 1.52-1.88 (m, 8H), 1.92-2.24 (m, 6H), 2.33-2.43 (m, 6H), 3.54 (brs, 2H), 3.64-3.75 (m, 1H), 6.97 (brd, J=5.1 Hz, 1H), 7.06-7.25 (m, SH), 7.32 (brd, J=7.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 0.5H), 7.51 (d, J=7.5 Hz, 0.5H).

MS (ESI(-)) m/e 553 (M-H).

Example 1063 N-[4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)- 2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1063A 2-Cvclohexvlethvlamine

Phenethylamine (50g) was dissolved in 1000mL of glacial acetic acid in a pressure vessel, followed by addition of platinum oxide (15g). After shaking under 4atm of hydrogen for 48h, the reaction was filtered and the acetic acid was removed under reduced pressure. The residue was taken up in water (1000mL), basified with SN NaOH, and washed with ether (5X250mL). The ether extracts were washed with brine (250mL), dried (MgSO4), filtered and concentrated to afford a light yellow oil which was purified by fractional distillation at atmospheric pressure (bp 185°C, 49.5g, 94%).

1H NMR(CDCl3, 300MHz) 6 0.83-0.95 (m, 2H), 1.00-1.38 (m, 8H), 1.60-1.73 (m, SH), 2.71 (dd, J=8.1, 7.2Hz, 2H).

Example 1063B N-2-Cyclohexylethyl-p-toluenesulfonamide To a solution of p-toluenesulfonyl chloride (210mg), and diisopropylethylamine (0.35mL) in dichloroethane (3mL) was added 2-cyclohexylethylamine (0. 15mL, 1.0mmol).

After 6h, the reaction was diluted with 1:1 EtOAc/hexane (25mL), washed with water (5mL), 1M HCl (2XSmL) and brine (5mL). The organic solution was dried (MgSO4), filtered and concentrated to afford a colorless crystalline solid (300mg).

1H NMR (300 MHz, CDC13) 6 0.75-0.91 (m, 2H), 1.06-1.27 (m, 4H), 1.33 (q, J=6.9 Hz, 2H), 1.59-1.70 (m, SH), 2.43 (s, 3H), 2.95 (q, J=6.9 Hz, 2H), 4.21 (brt, J=5.9 Hz, 1H), 7.31 (d, J=7.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H).

MS (DCl/NH3) m/e 299 (M+NH4)+.

Example 1063C 4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-( 2-methylphenyl)benzoic acid, Methyl Ester

To a solution of N-2-Cyclohexylethyl-p-toluenesulfonamide (300mg) in DMF (5mL) was added NaH (56mg of a 60% dispersion in mineral oil). After gas evolution subsided, 4- bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (example 1178D, 266mg) was added. After stirring at ambient temperature for l.5h, the reaction was quenched by addition of water (lOmL), and diluted with 50% EtOAc/hexane (S0mL). The organic solution was washed with water (lOmL), brine (2XlOmL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give the title compound as a colorless oil (250mg, 70%).

1H NMR (300 MHz, CDCl3) # 0.64-0.81 (m, 2H), 1.00-1.15 (m, 4H), 1.16-1.27 (m, 2H).

1.42-1.64 (m, SH), 2.03 (s, 3H), 2.41 (s, 3H), 3.12 (dd, J=9.3, 7.5 Hz, 2H), 3.61 (s, 3H), 4.35 (s, 2H), 7.00 (brd, J=7.2 Hz, 1H), 7.08 (d, J=1.5 Hz, 1H), 7.16-7.27 (m, 3H), 7.28 (d, J=8.1 Hz, 2H), 7.37 (dd, J=8.1, 1.5 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.42 (d, J=7.1 Hz, 1H).

Example 1063D N-[4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)- 2-(2- methvlphenvl)benzovllmethionine. Methvl Ester 4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-( 2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil.

1H NMR (300 MHz, CDC13) 0.68-0.82 (m, 2H), 1.00-1.28 (m, 4H), 1.43-1.66 (m, 7H), 1.78-1.92 (m, 2H), 1.98-2.17 (m, 8H), 2.41 (s, 3H), 3.13 (t, J=7.8 Hz, 2H), 3.66 (s, 3H), 4.36 (s, 2H), 4.55-4.67 (m, 1H), 5.88 (brd, J=7.5 Hz, 1H), 7.08-7.37 (m, 8H), 7.71 (d, J=8.4 Hz, 2H), 7.90 ("dd", J=15, 8.4 Hz, 1H). MS(APCI(+)) 651 (M+H)+.

MS(APCI(-)) 649 (M-H)-.

Example 1063E N-[4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)- 2-(2- methylphenyl)benzoyl]methionine, lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)- 2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 6 0.60-0.78 (m, 2H), 0.98-1.20 (m, 6H), 1.38-1.60 (m, 6H), 1.70-1.95 (m, 4H), 1.81 (s, 3H), 1.96-2.18 (m, 3H), 3.03-3.12 (m, 2H), 3.60-3.73 (m, 1H), 4.35 (s, 2H), 6.95 (d, J=6.3 Hz, 1H), 7.0-7.27 (m, SH), 7.35 (d, J=7.5 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.50 (d, J=7.8 Hz, 1H), 7.73 (s, J=6.6 Hz, 2H).

MS (APCI(-)) m/e 635 (M-H); Analysis calc'd for C35H43LiN2O5S2#0.80H2O: C, 63.96; H, 6.84; N, 4.26; found: C, 63.98; H, 6.68; N, 4.09.

Example 1064 N- [4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2- (2- methvlPhenvl)benzovlmethionine lithium salt Example 1064A

N-2-Cvclohexvlethvl-m-toluenesulfonamide The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with m-toluenesulfonyl chloride to afford a colorless oil.

MS (DCI/NH3) m/e 299 (M+NH4)+.

Example 1064B 4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-( 2-methylphenyl)benzoic acid. Methvl Ester N-2-Cyclohexylethyl-m-toluenesulfonamide was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCI/NH3) m/e 537 (M+NH4)+.

Example 1064C N-r4-(N-(2-Cvclohexylethvl)-N-m-toluenesulfonvlaminomethyl)- 2-(2- methylphenyl)benzovll methionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-( 2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(APCI(+)) 651 (M+H)+. MS(APCI(-)) 649 (M-H)-.

Example 1064D N-[4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)- 2-(2- methylphenyl)benzoyll methionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)- 2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 0.60-0.77 (m, 2H), 1.00-1.20 (m, 6H), 1.40-1.89 (m, 10H), 1.93 (s, 3H), 1.95-2.14 (m, 3H), 2.39 (s, 3H), 3.05-3.15 (m, 2H), 3.60-3.72 (m, 1H), 4.38 (s, 2H), 6.94 (d, J=5.7 Hz, 1H), 7.02-7.27 (m, SH), 7.36 (d, J=8.1 Hz, 1H), 7.44-7.54 (m, 3H), 7.60-7.69 (m, 2H).

MS (ESI(-)) m/e 635 (M-H); Analysis calc'd for C35H43LiN2O5S2l.30H2O: C, 63.10; H, 6.90; N, 4.20; found: C, 63.06; H, 6.53; N, 4.18.

Example 1065 N-[4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylami nomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt

Example 1065A N-2-Cyclohexylethvl-p-tert-butylbenzenesulfonamide The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-tert-butylbenzenesulfonyl chloride to afford a white crystalline solid.

MS (DCI/NH3) m/e 341 (M+NH4)+.

Example 1065B 4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminom ethyl)-2-(2- methvlphenvl)benzoic acid. Methyl Ester N-2-Cyclohexylethyl-p-tert-butylbenzenesulfonamide (300mg) was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCI/NH3) m/e 579 (M+NH4)+.

Example 1065C N-[4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylami nomethyl)-2-(2- methylphenyl)benzoyllmethionine. Methvl Ester 4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminom ethyl)-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(ESI(+)) 693 (M+H)+. MS(ESI(-)) 691 (M-H)-.

Example 1065D N-[4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylami nomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylami nomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 6 0.60-0.75 (m, 2H), 0.96-1.20 (m, 6H), 1.33 (s, 9H), 1.38- 1.88 (m, 10H), 1.93 (s, 3H), 1.95-2.18 (m, 3H), 3.04-3.13 (m, 2H), 3.59-3.70 (m, 1H), 4.37 (s, 2H), 6.95 (d, J=5.7 Hz, 1H), 7.10-7.28 (m, 5H), 7.35 (d, J=7.8 Hz, lH), 7.50 (d, J=6.3 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H).

MS (ESI(-)) nile 677 (M-H); Analysis calc'd for C38H49LiN2O5S21.SSH2O: C, 64.03; H, 7.37; N, 3.93; found: C, 63.98; H, 7.15; N, 3.92.

Example 1066 N-[4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1066A

N-2-CyclohexYlethYl-p-bromobenzenesulfonamide The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-bromobenzenesulfonyl chloride to afford a white crystalline solid.

MS (DCIJNH3) m/e 363 (M(79Br)+NH4)+, 365 (M(81Br)+NH4)+.

Example 1066B 4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl )-2-(2- methvlphenyl)benzoic acid. Methvl Ester N-2-Cyclohexylethyl-p-bromobenzenesulfonamide (3OOmg) was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCZ/NH3) m/e 601 (M(79Br)+NH4)+, 603 (M(81Br)+NH4)+.

Example 1066C N-[4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyllmethionine. Methvl Ester 4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl )-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(APCI(+)) 715 (M(79Br)+H)+, 717 (M(81Br)+H)+. MS(APCI(-)) 749 (M(79Br)+Cl)-, 751 (M(8 1Br)+Cl)-.

Example 1066D N-[4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

'H NMR (300 MHz, DMSO) 8 0.60-0.75 (m, 2H), 0.94-1.21 (m, 6H), 1.38-1.88 (m, 10H), 1.93 (s, 3H), 1.95-2.15 (m, 3H), 3.06-3.15 (m, 2H), 3.55-3.67 (m, 1H), 4.36 (s, 2H), 6.96 (d, J=6 Hz, 1H), 7.03-7.26 (m, 5H), 7.37 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.76-7.85 (m, 4H).

MS (ESI(-)) m/e 699 (M(79Br)+H)+, 701 (M(8lBr)+H)+; Analysis calc'd for C34H40BrLiN2O5S20.9SH2O: C, 56.34; H, 5.83; N, 3.86; found: C, 56.33; H, 5.66; N, 3.48.

Example 1067 N-[4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminom ethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt

Example 1067A N-2-Cyclohexylethyl-p-methoxybenzenesulfonamide The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-methoxybenzenesulfonyl chloride to afford a colorless oil.

MS (DCI/NH3) m/e 315 (M+NH4)+.

Example 1067B 4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonvlaminometh yl)-2-(2- methvlphenyl)benzoic acid. Methyl Ester N-2-Cyclohexylethyl-p-methoxybenzenesulfonamide (300mg) was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCI/NH3) m/e 553 (M+NH4)+.

Example 1067C N-[4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminom ethyl)-2-(2- methylphenyl)benzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminometh yl)-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(APCI(+)) 667 (M+H)+. MS(APCI(-)) 701 (M+Cl)-.

Example 1067D N- {4-(N-(2-Cvclohexvlethyl)-N-p-methoxybenzenesulfonylaminomet bvl )-2-(2- methylphenvl)benzovllmethionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminom ethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 0.62-0.78 (m, 2H), 1.00-1.22 (m, 6H), 1.37-1.85 (m, 10H), 1.90 (s, 3H), 1.90-2.16 (m, 3H), 3.01-3.10 (m, 2H), 3.58-3.67 (m, 1H), 3.83 (s, 3H), 4.32 (s, 2H), 6.94 (d, J=6 Hz, 1H), 7.04-7.26 (m, 5H), 7.11 (d, J=8.7 Hz, 2H), 7.35 (dd, J=8.1, 1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H).

MS (APCI(-)) m/e 651 (M-H); Analysis calc'd for C35H43LiN2O6S2#1.85H2O: C, 61.35; H, 6.87; N, 4.09; found: C, 61.36; H, 6.48; N, 3.91.

Example 1068 N-[4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1068A

N-2-Cvclohexvlethyl-p-nitrobenzenesulfonamide The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-nitrobenzenesulfonyl chloride to afford a colorless oil.

MS (DCI/NH3) m/e 330 (M+NH4)+.

Example 1068B 4-(N-(2-Cyclohexyletbyl)-N-p-nitrobenzenesulionylaminomethyl )-2-(2- methvlphenvl)benzoic acid. Methvl Ester N-2-Cyclohexylethyl-p-nitrobenzenesulfonamide (300mg) was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCI/NH3) m/e 568 (M+NH4)+.

Example 1068C N-[4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomethyl )-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(APCI(+)) 682 (M+H)+. MS(APCI(-)) 716 (M+Cl)-.

Example 1068D N-[4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomet hyl)-2-(2- methylphenvl)benzovll methionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomet hyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

H NMR (300 MHz, DMSO) 8 0.63-0.76 (m, 2H), 1.00-1.26 (m, 6H), 1.40-1.70 (m, 10H), 1.92 (s, 3H), 1.95-2.15 (m, 3H), 3.12-3.20 (m, 2H), 3.59-3.65 (m, lH), 4.43 (s, 2H), 6.96 (d, J=6.3 Hz, 1H), 7.0-7.25 (m, SH), 7.36 (d, J=8.1 Hz, lH), 7.52 (d, J=7.8 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H), 8.37 (d, J=8.4 Hz, 2H).

MS (APCI(-)) m/e 667 (M-); Analysis calc'd for C34H40LiN307S2O1.2H2O: C, 58.73; H, 6.15; N, 6.04; found: C, 58.73; H, 5.82; N, 5.92.

Example 1069 <BR> <BR> N-[4-(N-(2-Cyclohexyl-2-methvlpropyl)-N-methylaminomethyl)-2 -(2- methylphenyl)benzovll methionine. lithium salt Example 1069A N-Methyl-2-cyclohexyl-2-methylpropylamine

Treatment of 2-phenyl-2-methylpropylamine (example 1048A, Sg) with di-tert- butyldicarbonate according to example 1 056A afforded N-tert-butoxye arbonyl-2-phenyl-2 - methylpropylamine (10g crude) as a colorless oil. To portion of this material (Sg) in methanol (lOOmL) was added platinum oxide (lg), and the reaction was shaken under hydrogen gas (4atm) for 24h. The reaction was concentrated, diluted with water (lOOni), and extracted with chloroform (3X50mL). The organic extracts were washed with brine (20mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to afford a colorless oil (1.0g). This material was reduced with LiA1H4 according to the procedure described in example 1056A to afford the title compound (0.8g), as a colorless oil.

1H NMR (300 MHz, CDCl3) 6 0.83 (s, 6H), 0.87-1.29 (m, 6H), 1.60-1.82 (m, SH), 2.36 (s, 2H), 2.42 (s, 3H).

MS (APCI(+)) m/e 170 (M+H)+.

Example 1069B <BR> <BR> <BR> 4-(N-(2-Cyclohexvl-2-methylpropyl)-N-methylaminomethvl)-2-(2 -methylphenvl )benzoic acid. Methvl Ester The title compound was prepared according to the procedure in example 608B, subsitiuting N-methyl-2-cyclohexyl-2-methylpropylamine for N- methylcyclohexylethylamine, and was isolated as a colorless oil. MS(ESI(+)) m/e 408 (M+H)+. Example 1069C

N-[4-(N-(2-Cyclohexyl-2-methylpropyl)-N-methylaminomethyl)-2 -(2- methvlphenyl)benzovllmethionine, Methvl Ester The title compound was prepared from 4-(N-(2-cyclohexyl-2-methylpropyl)-N- methylaminomethyl)-2-(2-methylphenyl)benzoic acid methyl ester according to the procedures described in examples 608C, and D, and was isolated as a colorless oil.

MS(ESI(+)) m/e 539 (M+H)+. MS(ESI(-)) m/e 537 (M-H)-.

Example 1069D N-[4-(N-(2-Cyclohexyl-2-methylpropyl)-N-methylaminomethyl)-2 -(2- methylphenyl)benzoyllmethionine. lithium salt The title compound was prepared from N-[4-(N-(2-cyclohexyl-2-methylpropyl)-N- methylaminomethyl)-2-(2-methylphenyl)benzoyl] methionine methyl ester according to the procedure in example 608E, and was isolated as a white powder.

H NMR (300 MHz, DMSO) 6 0.79 (s, 6H), 0.80-1.27 (m, SH), 1.50-1.74 (m, 6H), 1.75-2.95 (m, 7H), 1.92 (s, 3H), 2.19 (s, 3H), 2.24 (s, 2H), 3.56 (s, 2H), 3.62-3.72 (m, lH), 6.92 (d, J=6 Hz, 1H), 7.08-7.25 (m, SH); 7.36 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H).

MS (ESI(-)) m/e 523 (M-H); Analysis calc'd for C31H43LiN203S*1.3H2O: C, 67.70; H, 8.29; N, 5.06; found: C, 67.15; H, 8.08; N, 4.97.

Example 1070 N-[4-(3-Cyclohexyl-1-methoxyprop-2-ylaminomethyl)-2-(2- methylphenvl)benzoyllmethionine. lithium salt

Example 1070A (S)-3-Cyclohexyl- l-methoxy-2-propylamine To a solution of (S)-3-phenyl-l-methoxy-2-propylamine hydrochloride (0.5g) in ethanol (loom) was added concentrated HCl (0.32mL), and platinum oxide (0.5g), and the reaction was shaken under hydrogen gas (4atm) for 18h. The reaction was filtered, concentrated, diluted with water (SOmL) and neutralized with lM NaOH (to pH#11. The mixture was washed with chloroform (3X50mL), and the organic extracts were washed with brine (20mL), dried (MgSO4), filtered and concentrated to give a colorless oil (400mg).

1H NMR (300 MHz, CDCl3) #0.76-1.00 (m, 2H), 1.10-1.48 (m, 6H), 1.61-1.81 (m, SH), 3.01-3.14 (m, 2H), 3.30-3.35 (m, lH), 3.36 (s, 3H).

Example 1070B N-[4-(3-Cyclohexyl-1-methoxyprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, Methyl Ester The title compound was prepared from (S)-3-cyclohexyl-1-methoxy-2-propylamine according to the procedure described in example 403H to afford a colorless oil.

MS(APCI(+)) 541 (M+H)+. MS(APCI(-)) 539 (M-H)-.

Example 1070C

N- {4-(3-Cvclohexyl- 1 -methoxvprop-2-vlaminomethyl)-2-(2- methvlphenyl)benzoyllmethionine. lithium salt N-[4-(3-Cyclohexyl-1-methoxyprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted into the title compound according to the procedure described in example 608E, affording a white powder.

1H NMR (300 MHz, DMSO) 8 0.65-0.88 (m, 2H), 1.00-1.88 (m, 15H), 1.91 (s, 3H), 1.95-2.19 (m, 3H), 2.61-2.68 (m, lH), 3.20 (s, 3H), 3.20-3.26 (m, 2H), 3.62-3.84 (m, 3H), 6.85-7.00 (m, 2H), 7.09-7.24 (m, 5H), 7.36 (d, J=7.8 Hz, 1H), 7.48 (d, J=7.8 Hz. lH).

MS (APCI(-)) m/e 525 (M-H); Analysis calc'd for C30H41LiN2O4SO.60H2O: C, 66.30; H, 7.83; N, 5.15; found: C, 66.29; H, 7.69; N, 5.15.

Example 1071 <BR> <BR> N-14-( 1 -Ethylsulfenyl-3-cvclohexvlprop-2-vlaminomethvl)-2- (2- methvlDhenvl)benzovlImethionine, lithium salt Example 1071A 4-Formyl-2-(2-methylphenyl)benzoic acid methyl ester To a solution of 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid methyl ester (example 1178C, 1.0g) in dichloromethane (10mL) was added infusorial earth (2g) then at 0°C was added pyridinium chlorochromate (1.7g). After 10min, the reaction was warmed to ambient temperature. After lh, the reaction was diluted with ether (50mL), and filtered through infusorial earth. The solution was concentrated, and the residue was purified by

silica gel chromatography eluting with 20% EtOAc/hexanes to afford the title compound as a colorless oil (0.842g, 85%).

1H NMR (300 MHz, CDC13) 6 2.08 (s, 3H), 3.63 (s, 3H), 7.07 (brd, J=6.6 Hz, 1H), 7.19-7.30 (m, 3H), 7.76 (d, J=1.8 Hz, 1H), 7.93 (dd, J=8.1, 1.6 Hz, lH), 8.06 (d, J=8.1 Hz, lH), 10.09 (s, lH).

MS (DC1/NH3) m/e 255 (M+H)+.

Example 1071B 4-N-(3-Cyclohexyl-1-ethylthioprop-2-yl)aminomethyl-2-(2-meth ylphenyl)benzoic acid, Methyl Ester The title compound was prepared according to example 403H, substituting 4-formyl- 2-(2-methylphenyl)benzoic acid methyl ester for N-[4-formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester, to afford a colorless oil in 70% yield.

MS(APCI(+)) 440 (M+H)+. MS(APCI(-)) 438 (M-H)-.

Example 107 1C 4-N-tert-Butoxycarbonyl-N-(3-cyclohexyl-1-ethylthioprop-2-yl )aminomethyl-2-(2- methvlphenvl)benzoic acid. Methvl Ester To a solution of 4-N-(3-cyclohexyl- 1-ethylthioprop-2-yl)aminomethyl-2-(2- methylphenyl)benzoic acid methyl ester (497mg) in dichloromethane (4mL) was added di- tert-butyldicarbonate (300mg). After 16h at ambient temperature, the reaction was concentrated, and the residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give the title compound as a colorless oil (605mg). MS(APCI(-)) 538 (M- H)-.

Example 1071D 4-N-tert-Butoxycarbonyl-N-(1-ethylsulfenyl-3-cyclohexylprop- 2-ylaminomethyl)-2-(2- methylphenyl)benzoic acid. Methyl Ester To a solution of 4-N-tert-Butoxycarbonyl-N-(3-cyclohexyl- l-ethylthioprop-2- yl)aminomethyl-2-(2-methylphenyl)benzoic acid methyl ester (600mg) in dichloromethane (SmL) at -78°C was added m-chloroperbenzoic acid (280mg@75%). After 1.5h, the reaction was warmed to 0°C, and after 30min, the reaction was quenched with dilute aqueous sodium sulfite. The product was extracted into EtOAc (30mL), and washed with sodium bicarbonate (3X5mL). The organic extracts were washed with brine (lOniL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 50%-100% EtOAc/hexane to afford a white foam (460mg,75%). MS(APCI(+)) 556 (M+H)+. MS(APCI(-)) 590 (M+Cl)-.

Example 1071E N-tert-Butoxycarbonyl-N-[4-(1-ethylsulfenyl-3-cyclohexylprop -2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine. Methyl Ester The title compound was prepared from 4-(1-ethylsulfenyl-3-cyclohexylprop-2- ylaminomethyl)-2-(2-methylphenyl)benzoic acid methyl ester according to the procedure described in examples 608C and D to afford a colorless oil which was purified by silica gel chromatography eluting with 5% methanol/dichloromethane. MS(APCI(+)) 687 (M+H)+.

MS(APCI(-)) 721 (M+Cl)-.

Example 1071F N-[4-(1-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2 - methylphenyl)benzoyl]methionine, Methyl Ester To a solution of N-tert-butoxycarbonyl-N-[4-( l-ethylsulfenyl-3-cyclohexylprop-2- ylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester (200mg) in dioxane (lmL) chilled to its melting point, was added HCl (0.75mL, 4M in dioxane). After lh, the reaction was quenched with excess aqueous sodium bicarbonate, and extracted into dichloromethane. The solution was concentrated, and the residue was purified by silica gel chromatography eluting with 5% methanol/dichloromethane to afford the title compound as a colorless oil (72mg, 42%). MS(APCI(+)) 587 (M+H)+. MS(APCI(-)) 621 (M+Cl)-.

Example 1071G N-[4-(1-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2 - methylphenyl)benzoyl]methionine, lithium salt N- [4-( 1 -Ethylsulfenyl- 3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted into the title compound according to the procedure described in example 608E. lH NMR (300 MHz, DMSO) 80.67-0.93 (m, 2H), 1.00-1.90 (m, 13H), 1.11 (t, J=7.5 Hz, 3H), 1.94-2.20 (m, 6H), 2.34-2.45 (m, SH), 2.56-2.67 (m, 2H), 3.62-3.83 (m, 3H), 6.98 (brd, J=6 Hz, 1H), 7.10-7.24 (m, SH), 7.38 (brd, J=7.8 Hz, 1H), 7.49 (d, J=7.8 Hz, 0.5H), 7.5 (d, J=7.8 Hz, 0.5H).

MS (ESI(-)) m/e 571 (M-H).

Example 1072 (2S) 2-N-F4-( 1 -ethylsullenvl-3-cyclohexylprop-2-vlaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt Example 1072A (2S) N-tert-Butoxycarbonyl-2-N-[4-(1-ethylsulfenyl-3-cyclohexylpr op-2-ylaminomethyl)-2- (2-methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, Methyl Ester To a solution of N-tert-butoxycarbonyl-N-[4-( l-ethylsulfenyl-3-cyclohexylprop-2- ylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine methyl ester (example 1071 E, 320mg) in dichloromethane (2mL) at -780C was added m-chloroperbenzoic acid (120mg@75%). After 1.5h, the reaction was warmed to -50°C, and after 30min, the reaction was quenched with dilute aqueous sodium sulfite. The product was extracted into EtOAc (30mL), and washed with sodium bicarbonate (3X5mL). The organic extracts were washed with brine (10mL), dried (MgS04), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% methanol/dichloromethane to afford a white foam (31 lmg, 95%). MS(APCI(+)) 703 (M+H)+. MS(APCI(-)) 737 (M+Cl)-.

Example 1072B (2S) 2-N-[4-(1-Ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2- (2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, Methyl Ester The title compound was prepared from (2S) N-tert-butoxycarbonyl-2-N-[4-(1- <BR> <BR> ethylSulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylp henyl)benzOyl]amino-4- methylsulfenylbutanoate methyl ester according to the procedure described in example 1071F in 58% yield. The product was purified by silica gel chromatography eluting with 5%-10% methanol/dichloromethane, and was isolated as a white foam. MS(APCI(+)) 603 (M+H)+. MS(APCI(-)) 637 (M+Cl)-.

Example 1072C (2S) 2-N-[4-(1-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2- (2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt (2S) 2-N- [4-( 1 -Ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate methyl ester was converted into the title compound according to the procedure described in example 608E, and was isolated as a yellow powder.

H NMR (300 MHz, DMSO) 8 0.72-0.90 (m, 2H), 1.03-1.20 (m, SH), 1.20-1.90 (m, 11H), 1.94-2.23 (m, SH), 2.36 (s, 3H), 2.57-2.80 (m, 4H), 2.98 (brs, 1H), 3.64-3.82 (m, 3H), 6.95-7.00 (m, 1H), 7.09-7.23 (m, SH), 7.33-7.41 (m, 1H), 7.49 (d, J=8.1 Hz, 0.5H), 7.50 (d, J=8.1 Hz, 0.5H).

MS (ESI(-)) m/e 587 (M-H).

Example 1073 <BR> <BR> N-14-(N-(3-cvclohexvlpropyl)-N-benzenesulfonylaminomethyl!-2 -(2- methylphenyl)benzovll methionine. lithium salt Example 1073A N-3-Cvclohexylpropylbenzenesulfonamide The title comound was prepared according to example 1063A (replacing phenethylamine with 3-phenylpropylamine, and example 1063B, replacing p-toluenesulfonyl chloride with benzenesulfonyl chloride to afford a colorless oil.

MS (DCI/NH3) m/e 299 (M+NH4)+.

Example 1073B 4-(N-(3-cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2-(2 -methylphenyl)benzoic acid, Methyl Ester N-3-Cyclohexylpropylbenzenesulfonamide was converted into the title compound according to the procedure in example 1063C to afford a colorless oil.

MS (DCI/NH3) m/e 537 (M+NH4)+.

Example 1073C N-f4-(N-(3-cyclohexylpropvl)-N-benzenesulfonylaminomethyl)-2 -(2- methvlphenyl)benzoyllmethionine. Methvl Ester 4-(N-(3-Cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2-(2 - methylphenyl)benzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. MS(ESI(+)) 651 (M+H)+. MS(ESI(-)) 649 (M-H)-.

Example 1073D N- F4-(N-(3-cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2-( 2- methylphenyl)benzoyll methionine, lithium salt N-[4-(N-(3-Cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2 -(2- methylphenyl)benzoyl]methionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 0.59-0.73 (m, 2H), 0.88-1.88 (m, 17H), 1.94 (s, 3H), 1.95-2.16 (m, 3H), 3.00-3.08 (m, 2H), 3.59-3.68 (m, 1H), 4.39 (s, 2H), 6.96 (d, J=6 Hz, 1H), 7.04-7.28 (m, 5H), 7.36 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.56-7.70 (m, 3H), 7.85 (d, J=6.9 Hz, 2H).

MS (ESI(-)) m/e 635 (M-H); Analysis calc'd for C35H43LiN2O5S2#1.65H2O: C, 62.51; H, 6.94; N, 4.17; found: C, 62.48; H, 6.79; N, 4.07.

Example 1074 N-[4-(N-glucosaminomethyl)-2-(2-methylphenyl)benzoyl]methion ine, lithium salt Example 1074A N-[4-(N-glucosaminomethyl)-2-(2-methylphenyl)benzoyl]methion ine, Methyl Ester A 1M solution of glucosamine was prepared by dissolving glucosamine.HCl (10g) in lM NaOH (47mL). This solution (0.31 1mL) was added to N-[4-formyl-2-(2- methylphenyl)benzoyl] methionine methyl ester (example 403G, 100mg), in ethanol (3mL).

Once dissolution was complete, the reaction was degassed, and 10% palladium on carbon (330mg) was added, followed by blanketing the reaction with a hydrogen atmosphere (1 atm). After 4h, the reaction was filtered and concentrated, and the residue was purified by silica gel chromatography eluting with 20% methanol/dichloromethane to give the title compound as a colorless syrup (SOmg, 35%). MS(ESI(+)) 549 (M+H)+, 571 (M+Na)+.

Example 1074B N-[4-(N-glucosaminomethyl)-2-(2-methylphenyl)benzoyl]methion ine, lithium salt The title compound was prepared from N-[4-(N-Glucosaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester according to the procedure described in example 608E, and was isolated as a fluffy white powder.

IH NMR (300 MHz, CD30D) 8 1.60-1.90 (m, 4H), 1.95-2.09 (m, 6H), 2.26 (brs, 2H), 2.41 (brt, J=9.3 Hz, lH), 2.54 (dd, J=10.2, 3.3 Hz, lH), 3.22-3.30 (m, 2H), 3.58-4.03 (m, SH), 4.13-4.28 (m, 2H), 4.58 (d, J=7.8 Hz, lH), 5.17-5.22 (m, lH), 7.07-7.30 (m, 6H), 7.42-7.47 (m, 1H), 7.61-7.67 (m, 1H).

MS (ESI(-)) m/e 533 (M-H).

Example 1079 (2S) 2-N-f4-(N-2-Cyclohexylethyl-N-methvlaminomethvl)-2-(2- methylphenyl)benzoyl]amino-4-difluoromethylthiobutanoate, lithium salt Example 1079A N-tert-Butoxycarbonylhomocysteine thiolactone To a solution of L-homocysteinethiolactone hydrochloride (560mg) in dioxane (lOmL) was added triethylamine (0.6mL), and di-tert-butyldicarbonate (874mg). After 20h, the reaction was diluted with EtOAc (100mL), washed with water (20mL), lM HCl (20mL), and again with water (2X20mL). The organic extracts were washed with brine (20mL), dried (MgSO4), filtered and concentrated to give a white crystalline solid.

H NMR (300 MHz, CDC13) 1.45 (s, 9H), 1.97 (ddd, J=25, 11.7, 6.6 Hz, 1H), 2.86 (m, 1H), 3.23 (dd, J=11.4, 1.5 Hz, 1H), 3.32 (ddd, J=11.4, 11.4, 5.1 Hz, 1H), 4.28 (m, 1H), 4.98 (brs, 1H).

Example 1079B N-tert-Butoxycarbonvl-S-difluoromethylhomocvsteine To a solution of N-tert-butoxycarbonylhomocysteine thiolactone hydrochloride (400mg) in THF (2mL) at 0°C was added 1M NaOH (6mL). After stirring for 20min, this solution was added to chlorodifluoromethane (#0.25mL) at -780C in a pressure tube. The vessel was sealed, and warmed to 60°C for 14h. The reaction was chilled to -78°C, opened, and warmed to ambient temperature. The aqueous solution was neutralized with 1M HCl, and extracted into dichloromethane (30mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated to give the title compound as a syrup (490mg).

1H NMR (300 MHz, CDCl3) 6 1.45 (s, 9H), 1.95-2.36 (m, 2H), 2.63 (q, J=7.4 Hz, 1H), 2.90 (ddd, J=7.6, 7.6, 2.7 Hz, lH), 4.46 (brs, 1H), 5.05 (brs, 1H), 6.82 (t, J=56 Hz, 1H).

MS (ESI(+)) m/e 308 (M+Na)+.

MS (ESI(-)) m/e 285 (M-H)-.

Example 1079C N-tert-Butoxycarbonyl-S-difluoromethylhomocysteine, Methyl Ester To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine in diethyl ether ( lmL) was added a solution of diazomethane in ether until a faint yellow color persisted. The excess reagent was quenched by addition of glacial acetic acid, and the reaction was concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to afford a colorless oil (400mg).

1H NMR (300 MHz, CDC13) 6 1.45 (s, 9H), 1.90-2.30 (m, 2H), 2.85 (t, J=7.5 Hz, 2H), 3.77 (s, 3H), 4.42 (brs, 1H), 5.08 (brs, 1H), 6.81 (t, J=56.1 Hz, 1H).

MS (ESI(+)) m/e 322 (M+Na)+.

MS (ESI(-)) m/e 298 (M-H)-.

Example 1079D S-difluoromethvlhomocvsteine. Methyl Ester, Trifluoroacetate To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine methyl ester (400mg) in dichloromethane (2mL) was added trifluoroacetic acid (lmL). After stirring 18h at ambient temperature, the reaction was concentrated, and the residue was triturated with toluene and evaporated to give the title compound as a tan solid (515mg).

1H NMR (300 MHz, CDC13) 6 2.20-2.40 (m, 2H), 3.00 (t, J=7.5 Hz, 2H), 3.84 (s, 3H), 4.22 (t, J=6.9 Hz, 1H), 6.83 (t, J=55.8 Hz, 1H).

Example 1079E (2S) 2-N-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenvl)benzovl amino-4-difluoromethylthiobutanoate. Methvl Ester The title compound was prepared according to the procedure in example 608D, relpacing L-methionine methyl ester-HCl with S-difluoromethylhomocysteine methyl ester, trifluoroacetate, and was isolated as a colorless oil.

1H NMR (300 MHz, CDC13) # 0.80-0.94 (m, 2H), 1.10-1.70 (m, 11H), 1.90-2.18 (m, SH), 2.20 (s, 3H), 2.30-2.41 (m, 4H), 3.53 (s, 2H), 3.67 (s, 3H), 4.57-5.66 (m, 1H), 5.83-5.90 (m, 1H), 6.73 ("dt", J=2.7, 56 Hz, 1H), 7.14-7.41 (m, SH), 7.39 (brd, J=7.5 Hz, 1H), 7.90 ("dd", J=14.4, 8.1 Hz, 1H).

MS (ESI(+)) m/e 547 (M+H)+.

MS (ESI(-)) m/e 545 (M-H)-.

Example 1079F (2S) 2-N-14-(N-2-Cvclohexylethyl-N-methylaminomethvl)-2-(2- methylphenyl)benzoyl]amino-4-difluoromethylthiobutanoate, lithium salt The title compound was prepared from (2S) 2-N-[4-(N-2-cyclohexylethyl-N- methylaminomethyl)-2-(2-methylphenyl)benzoyl]amino-4-difluor omethylthiobutanoate methyl ester according to the procedure described in example 608E with the following exceptions: The crude lithium salt was found to be substantially impure by analytical HPLC, and was therefore purified by preparative reverse-phase medium pressure liquid chromatography eluting with a gradient of methanol/water/0. 1 %TFA. The appropriate fractions were concentrated, dissolved in water (lOmL), neutralized (pH=6) with sodium bicarbonate solution, then extracted into chloroform (30mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated. The free amino acid was dissolved in water, the lithium salt was prepared by addition of one equivalent of SM LiOH, and the solution was frozen (-78"C) and lyophylized to give the title compound as a light yellow powder.

1H NMR (300 MHz, DMSO) 6 0.75-0.90 (m, 2H), 1.06-1.38 (m, 6H), 1.53-1.80 (m, 9H), 1.94-2.16 (m, 3H), 2.13 (s, 3H), 2.34 (t, J=6 Hz, 2H), 3.49 (s, 2H), 3.60-3.75 (m, 1H), 6.91-7.23 (m, 7H), 7.23 (d, J=7.8 Hz, lH), 7.50 (d, J=7.8 Hz, 1H).

MS (ESI(-)) m/e 531 (M-H).

Example 1080

(25) 2-N-r4-(N-2-cyclohexylethyl-N-methvlaminomethyl)-2-(2 methylphenyl)benzoyl]amino-5-methoxypentanoate, lithium salt Example 1080A Methyl (2S)-N-2-Carbobenzyloxyamino-5-hydroxypentanoate To a solution of N-carbobenzylozy-L-glutamic acid l-methyl ester (commercial, 1.0g) in 3.5mL THF at 0°C was added 1M BH3THF (6.7mL). After lh, the reaction was quenched by addition of 1M sodium bisulfate (lOmL), and concentrated. The reaction was diluted with water (20mL) and the product was extracted into EtOAc (SOmL). The organic extracts were washed with brine (20mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 100% EtOAc to afford a colorless oil (SOOmg).

MS (ESI(+)) m/e 282 (M+H)+, 299 (M+NH4)+.

MS (ESI(-)) m/e 280 (M-H)-.

Example 1080B Methyl (2S)-N-2-Carbobenzyloxyamino-5-hydroxypentanoate Methyl (2S)-N-2-carbobenzyloxyamino-5-hydroxypentanoate (SOOmg) was dissolved in ether (lOmL), followed by addition of silica gel (2g). Diazomethane solution in ether was added (=20mL), without observing the persistence of the yellow color of the reagent. The reaction was filtered and concentrated, and the above procedure was repeated.

The residue was purified by silica gel chromatography eluting with 50% EtOAc/hexane to afford a colorless oil (236mg, 45%). The yield reflects the poor conversion of the reaction.

1H NMR (300 MHz, CDC13) 6 1.59-2.00 (m, 4H), 3.31 (s, 3H), 3.38 (t, J=6 Hz, 2H), 3.74 (s, 3H), 4.34-4.44 (m, 1H), 5.11 (s, 2H), 5.43 (brd, J=7.8 Hz, 1H), 7.32-7.40 (m, <BR> <BR> 5H). <BR> <BR> <BR> <BR> <BR> <P>MS (ESI(+)) m/e 296 (M+H)+, 318 (M+Na)+.

MS (ESI(-)) m/e 294 (M-H)-.

Example 1080C Methvl (2S)-2-amino-5-methoxvpentanoate Methyl (2S)-N-2-carbobenzyloxyamino-5-methoxypentanoate (230mg) was dissolved in methanol (2.5mL) at ambient temperature, followed by addition of ammonium formate (196mg), and 10% palladium on carbon (20mg). The reaction was refluxed for 30min, then cooled, filtered and concentrated. The residue was partitioned between dichloromethane and dilute NaOH. The organic extracts were washed with brine (10mL), dried (MgS04), filtered and concentrated to give the title compound (99mg, 78%) as a light yellow syrup.

MS (ESI(+)) m/e 162 (M+H)+.

Example 1080D (2S) 2-N-E4-(N-2-Cyclohexvlethvl-N-methvlaminomethvl)-2-(2- methylphenyl)benzoyl]amino-5-methoxypentanoate, Methyl Ester The title compound was prepared according to example 608D, replacing L- methionine methyl ester HCl with methyl (2S)-2-amino-5-methoxypentanoate, and was isolated as a colorless oil.

MS (ESI(+)) m/e 509 (M+H)+.

MS (ESI(-)) m/e 507 (M-H)-.

Example 1080E (2S) 2-N-14-(N-2-Cvclohexylethyl-N-methvlaminomethyl)-2-(2- methylphenyl)benzoyl]amino-5-methoxypentanoate, lithium salt (2S) 2-N- [4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-5-methoxypentanoate methyl ester was converted to the title compound according to the procedure in example 608E, and was isolated as a white powder.

IH NMR (300 MHz, DMSO) 6 0.74-0.90 (m, 2H), 0.92-1.66 (m, 15H), 1.93-2.14 (m, 3H), 2.13 (s, 3H), 2.34 (t, J=6 Hz, 2H), 3.04-3.12 (m, 2H), 3.17 (s, 3H), 3.49 (s, 2H), 3.58-3.67 (m, lH), 6.88-6.93 (m, 1H), 7.03-7.23 (m, SH), 7.30 (d, J=8.1 Hz, lH), 7.48 (d, J=8.1 Hz, 1H).

MS (ESI(-)) m/e 493 (M-H); Analysis calc'd for C30H41LuN2O4#75H2O: C, 70.09; H, 8.33; N, 5.45; found: C, 7.0.4; H, 8.20; N, 5.38.

Example 1081 (2S) 2-N-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]aminopent-4-ynoate, lithium salt

Example 1081A (2S) 2-N-[4-(N-2-Cyclohexvlethvl-N-methvlaminomethyl)-2-(2- methylphenyl)benzoyl]aminopent-4-ynoate, Methyl Ester The title compound was prepared according to example 608D, replacing L- methionine methyl ester.HCl with L-propargylalanine methyl esterHCl, and was isolated as a colorless oil.

MS (ESI(+)) m/e 475 (M+H)+.

MS (ESI(-)) m/e 473 (M-H)-.

Example 1081B (2S) 2-N-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]aminopent-4-ynoate, lithium salt (2S) 2-N- [4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]aminopent-4-ynoate methyl ester was converted to the title compound according to the procedure in example 608E, and was isolated as a white powder.

1H NMR (300 MHz, DMSO) 8 0.74-0.92 (m, 2H), 1.06-1.38 (m, 6H), 1.53-1.66 (m, 5H), 2.04 (s, 3H), 2.10 (m, 1H), 2.14 (s, 3H), 2.32 (t, J=6 Hz, 2H), 2.36-2.43 (m, 2H), 3.49 (s, 2H), 3.56-3.63 (m, 1H), 7.00-7.28 (m, 6H), 7.31 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H).

MS (ESI(-)) m/e 459 (M-H); Analysis calc'd for C29H35LiN2O31.9OH2O: C, 69.56; H, 7.81; N, 5.59; found: C, 69.49; H, 7.33; N, 5.57.

Example 1082 2-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2-methylph enyl)benzoyl]oxy-4- methylthiobutanoate. lithium salt Example 1082A DL. 2-Hydroxy-4-methylmercaptobutyric acid. Methyl Ester A solution of DL, 2-hydroxy-4-methylmercaptobutyric acid calcium salt (2.2g) in 0.5M HC1 (50mL) was saturated with sodium chloride, extracted exhaustively with EtOAc, which was dried (MgS04), filtered and concentrated. The residue was dissolved in methanol (lOmL) and trimethylsilyldiazomethane (2M in hexane) was added until the yellow color persisted for 30min. The reaction was quenched by addition of glacial acetic acid and concentrated. The residue was purified by silica gel chromatography eluting with 30% EtOAc/hexane to give the title compound as a light yellow oil (1.37g).

1H NMR (300 MHz, CDCl3) 8 1.86-1.98 (m, 1H), 2.04-2.16 (m, 1H), 2.11 (s, 3H), 2.63 (d, J=7.8 Hz, 1H), 2.65 (dd, J=7.8, 1.5 Hz, 1H), 2.88 (brs, 1H), 3.81 (s, 3H), 3.34 (dd, J=7.8, 3.9 Hz, 1H).

Example 1082B 2-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2-methylph enyl)benzoyl]oxy-4- methylthiobutanoate. Methvl Ester

To a solution of DL, 2-hydroxy-4-methylmercaptobutyric acid methyl ester (72mg) and N-[4-(N-(2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylp henyl)benzoic acid (example 608C, 150mg) in THF (1.OmL) was added triphenylphosphine (127mg) and diethyl azodicarboxylate (0.075mL). After 6h, the reaction was concentrated, and the residue was purified by silica gel chromatography eluting with 20% EtOAc/hexane to give the title compound as a colorless oil (9Omg, 43%). MS(APCI(+)) 512 (M+H)+.

Example 1082C 2-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2-methylph enyl)benzoyl]oxy-4- methvlthiobutanoate. lithium salt 2-[4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]oxy-4-methylthiobutanoate methyl ester (180mg) was dissolved in methanol (1.2mL) and 5M LiOH (0.088mL) was added, followed by addition of THF (0.5mL) to homogenize the reaction. After 4h, additional 5M LiOH (0.088mL) was added.

After 1.5h, the reaction was concentrated, and the residue was dissolved in water (40mL).

The aqueous solution was washed once with ether (20mL), then acidified, and the product was extracted into chloroform (3X20mL). The organic extracts were washed with brine (20mL), dried (MgS04), filtered and concentrated to give an oily foam (123mg). This residue was dissolved in 1:1 acetonitrile/water (30mL), and 5M LiOH (0.05mL) was added.

The solution was frozen (-78°C) and lyophylized to afford the title compound as a very hygroscopic white powder (104mg).

1H NMR (300 MHz, DMSO) 6 0.76-0.89 (m, 2H), 1.06-1.37 (m, 6H), 1.53-1.68 (m, 7H), 1.93-2.10 (m, 7H), 2.13 (s, 3H), 2.32 (t, J=7.2 Hz, 2H), 3.52 (s, 2H), 4.56-4.66 (m, 1H), 6.93-7.02 (m, 1H), 7.02-7.24 (m, 5H), 7.36-7.41 (m, 1H), 7.82 (d, J=7.8 Hz, 0.3H), 7.87 (d, J=7.8 Hz, 0.7H).

MS (APCI(-)) m/e 496 (M-H); Analysis calc'd for C29H38NO4SLi#1.65H2O: C, 65.31; H, 7.80; N, 2.63; found: C, 65.36; H, 7.76; N, 2.57.

Example 1085 N-[4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropy laminomethyl)-2-(2- methvlphenvlAbenzovllmethionine. lithium salt Example 1085A 5-(4-chlorophenyl)-2-furoic acid. methyl ester To a solution of 5-(4-chlorophenyl)-2-furoic acid (5.0 g, 22 mmol) in MeOH (50 mL) was added conc. H2SO4 (4 drops) and the resulting solution heated to 50 OC for 4 days.

The reaction was cooloed and concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2 x 20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash cjromatography (hexane/EtOAc 19:1) to give 3.8 g (72%) of a cream powder; MS m/z 254 (M+ + 18, 100).

Example 1085B 5-(4-chlorophenyl)-4-bromo-2-furoic acid. methyl ester To a stirred solution of the ester (3.53 g, 14.9 mmol) in CHCl3 (40 mL) was added a 4.2 M solution of Br2 in CHC13 (4.3 mL, 17.9 mmol) and the resulting solution heated to 50 °C overnight. The reaction was concentrated in vacuo and the residue was purified by falsh chromatography (hexane EtOAc 19:1) to give 3.0 g (64%) of a white powder; MS m/z 334 (M+ + 18, 100).

Example 1085C The ester (1.37 g, 4.34 mmol) was hydrolyzed as in example 1084 D (for 1 hour at rt) and coupled to isopropylamine as in example 1084 D to give 1.31 g (88 %) of a beige powder; MS m/z 361 (M+ + 18, 100).

Example 1085C To a stirred solution of the amide (1.12 g, 3.27 mmol) in dichloroethane (50 mL) was added tetrabutylammonium borohydride (2,5 g, 9.8 mmol) and the resulting solution heated to 50 OC overnight. The reaction was concentrated in vacuo and the residue taken up in EtOAc (50 mL) and quenched with water (20 mL). The layers were separated and the organic layer washed with H2O (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (hexane/EtOAc 2:1) to give 0.49 g (46%) of a light yellow oil; MS m/z 330 (M+ + 1, 100).

Example 1085D To a stirred solution of the amine (0.485 g, 1.48 mmol) in acetonitrile (10 mL) was added the core benzyl bromide (see example 1178D) (0.472 g, 1.48 mmol), tetrabutylammonium iodide (0.055 g, 0.15 mmol), and K2CO3 (0.41 g, 3.0 mmol) and the resulting solution heated to 70 "C overnight. The reaction was cooled and concentrated in vacuo. The residue was taken up in EtOAc (30 mL) and washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL),brine (10 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc 19: 1) to give 0.63 g (75%) of a light yellow oil; MS m/z 568 (M+ + 1, 100).

Example 1085E N-[4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropy laminomethyl)-2-(2- methylphenyl)benzovll methionine, methvl ester The ester (0.61 g, 1.1 mmol) was hydrolyzed as in example 1084 D and coupled to L-methionine methyl ester hydrochloride as in example 1084 D. Flash chromatography (hexane/EtOAc 4:1) gave 0.57 g (77 %) of an orange oil; MS m/z 697 (M+ + 1, 100).

Example 1085 F N-[4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropy laminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt The ester (54 mg, 0.077 mmol) was hydrolyzed as in example 1084 E to give 53 mg of a beige powder; 1H NMR (DMSO-d6,) 6 7.72-7.67 (m, 2 H), 7.45-7.29 (m, 4 H), 7.11-6.82 (m, 6 H), 6.51 (s, 1 H), 3.63-3.48 (m, 5 H), 2.92-2.88 (m, l H), 2.04-1.73 (m, 8 H), 1.65-1.59 (m, 1 H), 1.53-1.47 (m, 1 H), 1.01-0.97 (m, 6 H); MS m/z 683 (M* - 1, 100). Example 1086

N-[4-(N-(5-phenyl-(4-chlorophenyl)furan-2-ylmethyl-N-isoprop ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1086A N-14-(N-(S-phenvl-(4-chlorophenyl)furan-2-vlmethvl-N-isoprop vlaminomethvl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester To a solution of the bromo ester (60 mg, 0.086 mmol) in DME (5 mL) was added benzeneboronic acid (21 mg, 0.17 mmol), CsF (39 mg, 0.26 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (7 mg, 0.009 mmol) and the resulting mixture heated to 80 OC overnight. The reaction was cooled and the reaction filtered through Celite, washing the bed with EtOAc. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (hexane EtOAc 4:1) to give 31 mg (52%) of a yellow oil; MS m/z 695 (M+ + 1, 100).

Example 1086B N-[4-(N-(5-phenyl-(4-chlorophenyl)furan-2-ylmethyl-N-isoprop ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt The ester (30 mg, 0.04 mmol) was hydrolyzed as in example 1084 E to give 30 mg of a cream powder; 1H NMR (DMSO-d6,) 6 7.47-6.85 (m, 17 H), 6.47 (s, 1 H), 3.73-3.58 (m, 5 H), 3.06- <BR> <BR> <BR> 3.01 (m, l H), 2.11-1.77 (m, 8 H), 1.63-1.57 (m, 1 H), 1.51-1.43 (m, l H), 1.05-1.01 (m, 6 H); MS m/z 679 (M+ - 1, 100).

Example 1087 N-[4-(N-(5-(3-methoxyphenyl-(4-chlorophenyl)furan-2-ylmethyl -N- isopropylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt Example 1087A N-[4-(N-(5-(3-methoxyphenyl-(4-chlorophenyl)furan-2-ylmethyl -N- isopropylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, methyl ester The bromo ester (62 mg, 0.088 mmol) was coupled to m-methoxybenzeneboronic acid as in example 1086 A. Flash chromatography (hexane/EtOAc 4: 1) gave 38 mg (55%) of an oil; MS m/z 725 (M+ + 1, 100).

Example 1087B N-[4-(N-(5-(3-methoxyphenyl-(4-chlorophenyl)furan-2-ylmethyl -N- isopropylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt The ester (38 mg, 0.054 mmol) was hydrolyzed as in example 1084 E to give 38 mg of a beige powder; 1H NMR (DMSO-d6.) 8 7.69-7.02 (m, 12 H), 6.84-6.79 (m, 4 H), 6.42 (s, 1 H), 3.65- 3.48 (m, 8 H), 2.97-2.93 (m, 1 H), 2.04-1.75 (m, 8 H), 1.63-1.57 (m, 1 H), 1.51-1.43 (m, 1 H), 1.03-0.98 (m, 6 H); MS m/z 709 (M+ - 1, 100).

Example 1088 N-[4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropy laminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1088A N-[4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropy laminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester The bromo ester (80 mg, 0.11 mmol) was coupled to p-chlorobenzeneboronic acid as in example 1086 A. Flash chromatography (hexane/EtOAc 4:1) gave 38 mg (46 %) of an oil; MS m/z 729 (M+ + 1, 100).

Example 1088B N-[4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropy laminomethyl)-2-(2- methvlDhenvl)benzovlImethionine, lithium salt The ester (31 mg, 0.042 mmol) was hydrolyzed as in example 1084 E to give 31 mg of a cream powder; 1H NMR (DMSO-d6.) 8 7.47-7.29 (m, 11 H), 7.22-7.03 (m, 4 H), 6.89-6.87 (m, 1 H) 6.48 (s, 1 H), 3.73-3.62 (m, 5 H), 3.03-2.97 (m, 1 H), 2.08-1.83 (m, 8 H), 1.68-1.63 (m, 1 H), 1.57-1.51 (m, | H), l.ll-1.05 (m, 6 H);

MS m/z 713 (M+ - 1, 100).

Example 1089 N-[4-(N-(5-thien-3-yl-(4-chlorophenyl)furan-2-yl)methyl)-N-i sopropylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt Example 1089A N-[4-(N-(5-thien-3-yl-(4-chlorophenyl)furan-2-yl)methyl)-N-i sopropylaminomethyl)-2-(2- methvlphenyl)benzovllmethionine. methvl ester The bromo ester (56 mg, 0.084 mmol) was coupled to 2-thiopheneboronic acid as in example 1086 A. Flash chromatography (hexane/EtOAc 4: 1) gave 41 mg (73 %) of an oil; MS m/z 701 (M+ + 1, 100).

Example 1089B <BR> <BR> <BR> N-14-(N-(S-thien-3-yl-(4-chlorophenyl!furan-2-vl)methyl)-N-i sopropvlaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt The ester (38 mg, 0.054 mmol) was hydrolyzed as in example 1084 E to give 37 mg of a yellow powder; 1H NMR (DMSO-d6) # 7.46-7.32 (m, 7 H), 7.11-6.99 (m, 7 H), 6.84-6.82 (m, 1 H), 6.43 (s, 1 H), 3.65-3.60 (m, 5 H), 2.96-2.92 (m, 1 H), 2.03-1.75 (m, 8 H), 1.63-1.58 (m, 1 H), 1.52-1.47 (m, 1 H), 1.02-0.99 (m, 6 H);

MS m/z 385 (M+ - 1, 100).

Example 1094 <BR> <BR> N-{4-(N-(2-cyclohexylethvl)-N-2-fluoroethylaminomethvl)-2-(2 - <BR> <BR> methylphenyl)benzoyl lmethionine Example 1094A N-(2-Fluoroethyl)-2-cyclohexylacetamide Following the procedure of example 1178E, 2-fluoroethylamine-HCl (1.00 g, 10.00 mmol) provided 1.58 g (84%) of the title compound.

MS (DCI, NH3): 188 (MH+).

Example 1094B N-(2-Fluoroethyl)-N-2-cyclohexylethylamine Following the procedure of example 1 178F, example 1094A (1.54 g, 8.2 mmol) provided 1.30 g (92%) of the title compound.

MS (DCI, NH3): 172 (MH+).

Example 1094C N-14-(N-(2-cvclohexvlethvl)-N-2-fluoroethylaminomethyl)-2-(2 -methYlphenVl)benzoic acid methyl ester Following the procedure of example 1 178G and substituting potassium phosphate for diisopropylethylamine, and heating at 600C for 60 hours, example 1094B (188 mg, 1.10 mmol) provided 288 mg (70%) of the title compound.

MS (ESI +): 410 (M + NH4+ -F-).

Example 1094D N-f4-(N-(2-cvclohexylethyl)-N-2-fluoroethylaminomethyl)-2-(2 -methylphenyl)benzoic acid Following the procedure of example 1 178H, example 1094C (0.28 g, 0.68 mmol) provided 0.25 g (93%) of the title compound.

MS (DCI, NH3): 398 (MH+).

Example 1094E <BR> <BR> N-r4-(N-(2-cyclohexvlethvl)-N-2-fluoroethvlaminomethvl)-2-(2 - methylphenyl)benzoyllmethionine. methyl ester

Following the procedure of example 1178 I, example 1094D (245 mg, 0.62 mmol) provided 257 mg (77%) of the title compound. MS: (ESI+): 541 (MH)+: (ESI-); 539 (M-H).

Example 1094F N-[4-(N-(2-cyclohexylethyl)-N-2-fluoroethylaminomethyl)-2-(2 - methylphenvl)benzovllmethionine Following the procedure of example 1 104D, example 1094E (250 mg, 0.46 mmol) provided 240 mg of the title compound.

1H NMR (o ,CDC13): 7.75 (2H), 7.0-7.4 (4H), 6.4 (1H), 3.8-4.6 (9H), 2.9-3.3 (4H), 0.8-2.3 (21H). MS: (ESI+): 527 (MH)+: (ESI-); 525 (M-H). Calc'd for C30H41FN2O3SO.9OH2O: C 66.12 H 7.92 N 5.14; Found: C 66.13 H 7.77 N 4.86.

Example 1103 N-[4-(N-(2-cyclohexylethyl)-N-2,2,2-trifluoroethylaminomethy l)-2-(2- methvlphenvl)benzovllmethionine lithium salt Example 1103A N-trifluoroacetyl-2-cyclohexylethyl amide Cyclohexylethyamine (1.27 g, 10 mmol) was dissolved in 10 mL of methylene chloride and pyridine (1.8 mL, 15.0 mol) was added and the mixture cooled to -10° C in an

ice/acetone bath. The solution was treated with trifluoroacetic anhydride (1.7 mL, 12.0 mmol) in 5 mL of methylene chloride dropwise. After stirring for 2 hours at OOC the mixture was diluted with 100 mL of ether and extracted with water, 1M aqueous phosphoric acid and satureaed aqueous sodium bicarbonate, dried, filtered and concentrated to give a white solid (2.07g, 92%).

MS (DCI, NH3): 241 (M+NH4)+.

Example 1 103B N-2-trifluoroethvl-2-cyclohexylethyl amine A solution of lithium aluminum hdydride (9 mL of a 1M solution in THF, 9 mmol) was added to a solution of example 1 103A (0.67 g, 3.0 mmol) and the mixture was heated to reflux for 2 hours and then cooled to room temperature. The reaction was quenched by the same procedure as example 1 178F to provide 0.58 g (92%) of the title compound.

MS (DCI, NH3): 228 (M+NH4)+.

Example 1 103C N- [4-(N-(2-cyclohexylethvl)-N-2 .2,2-trifluoroethvlaminomethvl)-2-(2 - methvlphenyl)benzovllmethionine methvl ester A solution of example 1 103B (210 mg, 1.0 mmol) and the aldehyde from example 403G (192 mg, 0.5 mmol) in 3 mL of 1,2 dichoroethane was treated with acetic acid (0.14 mL, 2.5 mmol) and the mixture stirred for 10 minutes. The mixture was treated with sodium triacetoxyborohydride (213 mg, 1.0 mmol) and the mixture stirred overnight. The work-up was the same as that of example 11 34E. The crude product was purified by chromatography on silica gel (20 g, 20% ethyl acetate/hexanes) to provide 96 mg (33%) of the title compound.

1H NMR (300 MHz., CDC13): 87.91, dd, 1H; 7.42, dd, 1H; 7.18 - 7.36, m, 4H; 7.15, bs, 1H; 5.88, bd, lH' 4.63, m, 1H; 3.83, s, 2H; 3.65, s, 3H; 3.09, q, 2H; 2.64, t, 2H; 2.18,

s, 1.5 H (o-tolyl); 2.07, s, l.SH (o-tolyl); 2.05, m, 1H; 2.03, s, l.SH (MeS); 2.01, s, l.5H (MeS); 1.87, m, 1H; 1.61, bm, 6H; 1.35, m, 2H; 1.20, m 2H; 1.14, m, 2H; 0.85, m, 2H.

MS (ESI+): 579 (MH+): (ESI-): 577 (M-H).

Prepared according to the procedure of example 1 178J.

H NMR (300 MHz., dmso d6): 6 7.52, d, 1H; 7.35, d, 1H; 7.23, m, 3H; 7.12, m, 3H; 6.91, d, 1H; 3.81, s, 2H; 3.66, m, 1H; 3.38, q, 2H; 2.56, t, 2H; 2.06, m, lH; 2.00, bs, 3H; 1.92, s, 3H; 1.58, m, 7H; 1.00 - 1,38, m, 6H; 0.80, m, 2H.

MS (ESI+): 587; 571; 565 (MH+): (ESI-): 563 (M-H). Calc'd for C30H38LiN203S1.75 H2O; C 59.84; H 6.95; N 4.65; Found: C 59.86; H 6.57; N 4.45.

Example 1104 N-[4-(N-(2-cyclohexylethyl)-N-2-methoxyethylaminomethyl)-2-( 2- methylphenyl)benzoyl]methionine Example l 104A N-(2-methoxvethvl)-2-cvclohexvlacetamide The acid chloride from example 1178E (1.60 g, 10 mmol) in 10 mL of methylene chloride was added dropwise to a cold (0°C) solution of 2-methoxyethylamine (1.3 mL, 15 mmol) and pyridine (1.9 mL, 22 mmol) in 10 mL of methylene chloride and the mixture was stirred overnight. The mixture was diluted with ethyl ether and washed with water, 1M aqueous phosphoric acid , 2M aqueous sodium carbonate and brine, dried, filtered and concentrated to provide 1.70 g (85%) of the title compound as a white solid.

1H NMR (300 MHz., CDC13): 8 5.89, bs, 1H; 3.46, m, 4H; 3.37, s, 3H; 2.05, d, 2H; 1.79, m, 1H; 1.70, bm, 6H; 1.24, m, 2H; 1.17, m, 1H; 0.95, m, 2H.

MS (DCI, NH3): 200 (MH+).

Example 1104B N-(2-methoxyethyl)-N-2-cyclohexylethylamine Using the procedure of example 1178F, example 1 104A (1.70 g, 8.54 mmol) provided the title compound (1.56 g, 100%).

MS (DCI, NH3): 186 (MH+).

Example 1104C N-[4-(N-(2-cyclohexylethyl)-N-2-methoxyethylaminomethyl)-2-( 2- methylphenvl)benzovllmethionine, methyl ester Using the procedure of example 1 103C, example 1 104B (186 mg, 1.0 mmol) and example 403G (192 mg, 0.5 mmol) were combined to provide 78 mg (28%) of the title compound.

H NMR (300 MHz., CDCl3): 6 7.91, dd, 1H; 7.42, dd, 1H; 7.18 - 7.37, m, 4H; 7.17, bs, lH; 5.89, bd, 1H; 4.64, m, 1H; 3.68, s, 2H; 3.66, s, 3H; 3.45, t, 2H; 3.31, s, 3H; 2.66, t, 2H; 2.50, t, 2H; 2.19, s, 1.5H (o-tolyl); 2.07, s, l.SH (o-tolyl); 2.05, m, 1H; 2.03, s, 1.5H (SMe); 2.01, s, 1.5H (SMe); 1.85, m, 1H; 1.63, bm, 6H; 1.34, m, 2H; 1.06 - 1.29, m, 4H; 0.88, m, 2H.

MS (ESI+): 555 (MH+): (ESI-): 553 (M-H). Example 1104D

N-[4-(N-2-cyclohexylethyl)-N-2-methoxyethylaminomethyl)-2-(2 - methvlphenvl)benzoyllmethionine A solution of example 1 104C (73 mg, 0.13 mmol) in 2 mL of 3:1 THF/methanol was cooled in an ice bath and treated with lithium hydroxide (0.26 mL of a lM aqueous solution, 0.26 mmol) and the mixture stirred overnight and then concentrated. The solid was diluted with water and the pH adjusted to 4.5 with lM aqueous phosphoric acid and then extracted with 3 portions of ethyl acetate. The combined organic fractions were washed with brine, dried filtered and concetrated. The residue was lyophilized to provide 70 mg of the title compound.

1H NMR (300 MHz., CD30D): 87.74, d, 1H; 7.58, d, lH; 7.37, m, 1H; 7.10 - 7.31, m, 4H; 4.50, m, 3H; 3.66, t, 2H; 3.37, s, 3H; 3.22, t, 2H; 3.04, m, 2H; 2.22, bs, lH; 2.10, m, 3H; 1.97, s, 3H; 1.90, m, 2H; 1.53 - 1.77, m, 8H; 1.14 - 1.38, m, 4H; 0.96. m, 2H.

MS (ESI+): 541 (MH+): (ESI-): 539 (M-H). Calc'd for C31H44N204S0.85 H2O; C 66.96; H 8.28; N 5.04; Found: C 66.97; H 8.34; N 4.87.

Example 1105 N-[4-(N-2-cyclohexylethyl)-N-2-methylthioethylaminomethyl)-2 -(2- methvlphenyl)benzoyll methionine Example 1105A N-(2-methylthioethyl)-2-cyclohexylacetamide Following the procedure of example 1104A, 2-methylthioethylamine (1.0 g, 11 mmol) was converted to the title compound (1.77 g, 89%).

MS (DCI, NH3): 216 (MH+); 233 (M+NH4)+.

Example 1105B N-(2-methylthioethyl)-2-cyclohexylethylamine Using the procedure of example 1178F, example 1105A (1.75 g, 8.44 mmol) was converted into the title compound (1.63 g, 100%).

MS (DCI, NH3): 202 (MH+).

Example 1105C N- K-(N-(2-cyclohexvlethyl)-N-2-methvlthioethylaminomethyl)-2- (2- methylphenyl)benzoyl]methionine, methyl ester Using the procedure of example 1 103C, example 1 105B (201 mg, 1.0 mmol) and example 403G (192 mg, 0.5 mmol) were combined to provide 151 mg (53%) of the title compound.

1H NMR (300 MHz., CDC13): 6 7.91, dd, 1H; 7.42, dd, 1H; 7.18 - 7.37, m, 4H; 7.17, bs, 1H; 5.89, bd, 1H; 4.63, m, 1H; 3.66, s, 3H; 3.63, s, 2H; 2.68, m, 2H; 2.59, m, 2H; 2.48, t, 2H; 1.99 - 2.21, m, 10H; 1.85, m, 1H; 1.62, bm, 6H; 1.36, m, 2H; 1.06 - 1.30, m, 4H; 0.87, m, 2H.

MS (ESI+): 571 (MH+): (ESI-): 569 (M-H).

Example 1105D

N-[4-(N-(2-cyclohexylethyl)-N-2-methylthioethylaminomethyl)- 2-(2- methylphenyl)benzoyl]methionine A solution of example 1 105C (145 mg, 0.25 mmol) in 2 mL of 3:1 THF/methanol was cooled in an ice bath and treated with lithium hydroxide (0.5 mL of a 1M aqueous solution, 0.5 mmol) and the mixture stirred overnight. The solution was concentrated to dryness and diluted with water and the pH adjusted to 4.5 with 1M aqueous phosphoric acid.

The solid collected was by filtration and dried in the air to provide 130 mg (93%) of the title compound.

1H NMR (300 MHz., CD30D): 87.71, d, 1H; 7.57, d, 1H; 7.35, d, 1H; 7.10 - 7.31, m, 4H; 4.32, m, lH; 4.17, s, 2H; 3.10, m, 2H; 2.94, m, 2H; 2.76, m, 2H; 2.22, bs, 1H; 2.02 - 2.09, m, 3H; 2.10, s, 3H; 1.99, s, 3H; 1.89, m, 2H; 1.68, m, 6H; 1.56, m, 2H; 1.09 - 1.26, m, 4H; 0.93, m, 2H.

MS (ESI+): 557 (MH+): (ESI-): 555 (M-H). Calc'd for C3lH44N203S2l0.50 H20; C 65.80; H 8.02; N 4.95; Found: C 65.79; H 7.89; N 4.79.

Example 1106 N-[4-(N-(2-cyclohexylethyl)-N-1-methyl-2(S)-methylthioethyla minomethyl)-2-(2- methylphenyl)benzoyl]methionine HO NHBOC Example 1106A 2(S)-N-t-butoxycarbonylaminopropan-1-ol A stirred solution of 2(S)-amino-1-propanol (1.0 g, 13.3 mmol) in 20 mL of methylene chloride was treated with di-tertbutyldicarbonate (3.19 g, 14.6 mmol) in 5 mL of methylene chloride and then the solution was treated with 10 mL of 2M aqueous sodium carbonate and stirred for 2 hours. The biphasic mixture was diluted with water and the layers were separated. The aqueous layer was extracted with methylene chloride and the combined organic layers were dried, filtered and concentrated to provide 2.35 g (105%) of the title compound.

IH NMR (300 MHz., CDC13): 6 4.59, bs, 1H; 3.77, m, lH; 3.64, dd, lH; 3.52, dd, lH; 2.42, bs, 1H; 1.44, s, 9H; 1.14, d, 3H.

MS (DCI, NH3): 176 (MH)+; 193 (M+NH4)+.

Example 1 106B 1 -Methylthio-2(S )-N-t-butoxvcarbonvlaminopropane A stirred solution of example 1 106A (350 mg, 2.0 mmol) in 6 mL of methylene chloride was cooled in an ice/acetone bath and sequentially treated with triethylamine (0.34 mL, 2.4 mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) and the mixture stirred for 2 hours and then diluted with ether, extracted with water, 1M aqueousphosphoric acid, brine, dried filterd and concentrated to provide a yellow oil that was used directly. The mesylate was dissolved in 2 mL of DMF and added to a mixture of sodium thiomethoxide (280 mg, 4.0 mmol) and 5 mL of DMF and the mixture was stirred for 2 hours. The reaction was quenched by the addition of water and the mixture diluted with water and ethyl acetate.

The layers were separated and the mixture was extracted with 2 additional portions of ethyl acetate and the combined organic layers washed with water and brine, dried, filtered and concentrated to provide 328 mg (80% overall) of the title compound.

1H NMR (300 MHz., CDC13): 6 3.86, bs, 1H; 2.65, dd, 1H; 2.56, dd, 1H; 2.14, s, 3H; 1.45, s, 9H; 1.22, d, 3H.

MS (DCI, NH3): 206 (MH)+; 223 (M+NH4)+.

Example 1 106C I -Methylthio-2(S)-aminopropane hvdrochloride salt Example 1 106B (320 mg, 1.56 mmol) was dissolved in 2 mL of 4N HCl/dioxane and stirred for 1 Hour. The mixture was diluted with ether and filtered to provide 103 mg (53%) of the title compound as a white solid.

1H NMR (300 MHz., CDC13): 8 8.56, bs, 3H; 3.51, m, 1H; 2.89, dd, 1H; 2.78, dd, 1H; 2.17, s, 3H; 1.54, d, 3H.

MS (DCI, NH3): 123 (M+NH4)+.

Example 1106D N-[4-(N-(2-cyclohexylethyl)-N-1-methyl-2(S)-methylthioethyla minomethyl)-2-(2- methvlphenvl)benzovllmethionine methyl ester Part 1. Following the general procedure of example 403H, example 1106C (98 mg, 0.69 mmol), example 403G (243 mg, 0.63 mmol), diisopropylethylamine (0.12 mL, 0.69 mmol) and acetic acid (0.18 mL, 3. 14 mmol) were stirred in 4 mL of 1 ,2-dichloroethane for 2 hours and then treated with sodium triacetoxyborohydride (263 mg, 1.26 mmol). This procedure yielded 332 mg of material that was used in the next step.

Part 2. The amine prepared in part 1 was treated with 2-cyclohexylacetaldehyde (159 mg, 1.26 mmol), acetic acid (0.36 mL, 6.3 mmol) and sitrred for 2 hours. This solution was treated with sodium triacetoxyborohydride (263 mg, 1.26 mmol) and the mixture stirred overnight. The mixture was quenched and worked-up as described in example 403H. The residue obtained was purified by cloumn chromatography on silica gel (20 g, 20% ethyl acetate/hexanes) to provide 225 mg (61% overall) of the title compound.

1H NMR (300 MHz., CDC13): 8 7.89, dd, 1H; 7.47, d, 1H; 7.15 - 7.37, m, 5H; 5.87, bd, 1H; 4.63, m, 1H; 3.67, d, 1H; 3.65, s, 3H; 3.55, d, 1H; 2.96, m, 1H; 2.75, dd, 1H; 2.44, m, 2H; 2.37, dd, 1H; 1.99 - 2.22, m, 10H; 1.84, m, 1H; 1.60, m, 6H; 1.09 - 1.33, m, 6H; 1.08, d, 3H; 0.72 - 1.00, m, 2H.

MS (ESI+): 585 (MH+): (ESI-): 583 (M-H).

Example 1106 N-[4-(N-(2-cyclohexylethyl)-N-1-methyl-2(S)-methylthioethyla minomethyl)-2-(2- methylphenyl)benzoyl]methionine

Following the procedure of example 1 105D, example 1 106D (210 mg, 0.36 mmol) provided 110 mg (53%) of the title compound.

IH NMR (300 MHz., CD3OD): 67.69, d, 1H; 7.56, bd, 1H; 7.37, bd, 1H; 7.09 - 7.32, m, 4H; 4.33, m, 1H; 4.16, m, 1H; 4.00, m, 1H; 3.32, dt, lH; 2.89, m, 3H; 2.64, m, 1H; 2.23, bs, 1H; 2.06, m, 2H; 2.04, s, 3H; 1.98, s, 3H; 1.89, m, 2H; 1.65, m, 6H; 1.44, m, 2H; 1.32, d, 3H; 1.28, m, 3H; 0.88, m, 2H.

MS (ESI+): 571 (MH+): (ESI-): 569 (M-H). Calc'd for C32H46N203S2; C 67.33; H 8.12; N 4.91; Found: C 67.12; H 8.10; N 4.70.

Example 1107 <BR> <BR> N-14-(N-(2-cvclohexvletbyl)-N-2-N.N-dimethvlaminomethyl)-2-( 2- methvlphenvl)benzovll methionine Example 1107A N-[4-(N-(2-cyclohexylethyl)-N-2-N,N-dimethylaminomethyl)-2-( 2- methvlphenvl)benzovllmethionine, methyl ester Part 1. Following the procedure of example 1106D, part 1, example 403G (550 mg, 1.43 mmol) and 2-N,N-dimethylaminoethylamine (0.31 mL, 2.86 mmol) and acetic acid (0.82 mL, 14.3 mmol) gave the coressponding secondary amine (673 mg).

Part 2. Following the procedure of example 1 106D part 2, the amine produced in example 1107A, part 1 (660 mg, 1.44 mmol) and 2-cyclohexyacetaldehyde (364 mg, 2.88 mmol) gave a material that was purified by column chromatography on silica gel (25 g, ethyl

acetate then 90/10/0.1 ethyl acetate/methanoUconc. aq. ammonia) providing 498 mg (60% overall) of the title compound.

1H NMR (300 MHz., CDC13): 6 790, dd, 1H; 7.41, dd, 1H; 7.18 - 7.34, m, 4H; 7.16, bs, 1H; 5.88, bs, 1H; 4.62, m, 1H; 3.65, s, 3H; 3.63, s, 2H; 2.57, m, 2H; 2.47, m, 2H; 2.39, m, 2H; 2.21, s, 6H; 1.99, 2.28, m, 7H; 1.86, m, 1H; 1.63, bm, 6H; 1.35, m, 2H; 1.20 m, 2H; 1.14, m, 2H; 0.85, m, 2H.

MS (ESI+): 568 (MH+): (ESI-): 566 (M-H).

Example 1107B N-[4-(N-(2-cyclohexylethyl)-N-2-N,N-dimethylaminomethyl)-2-( 2- methylphenyl)benzoyl]methionine Following the procedure of example 1 104D, example 1 107A (485 mg, 0.85 mmol) provided 382 mg (81%) of the title compound as a white lyophilate.

IH NMR (300 MHz., CD30D): 7.66, d, 1H; 7.46, d, 1H; 7.05 - 7.33, m, 5H; 4.35, m, 1H; 3.74, s, 2H; 3.17, t, 1H; 2.82, t, 2H; 2.75, s, 6H; 2.60, m, 2H; .24, bs, 1H; 1.94 - 2.12, m, 6H; 1.85, m, 2H; 1.67, m, 6H; 1.45, m, 2H; 1.21, m, 4H; 0.92, m, 2H.

MS (ESI+): 554 (MH+): (ESI-): 552 (M-H). Calc'd for C32H47N303S1.00 H2O; C 67.22; H 8.64; N 7.35; Found: C 67.23; H 8.43; N 7.26.

Example 1108 <BR> <BR> N-f4-(N-( 1 -benzvloxvmethvl-2(S)-ethvlthioethvlaminomethvl!-2-(2- methylphenyl)benzoyl]methionine

Example 1 108A 1 -benzyloxy-2(S )-t-butoxycarbonylamino-3-hvdroxvpropane N-BOC-O-benzylserine (5.0 g, 16.9 mmol) in 30 mL dimethoxyethane was treated with 4-methylmorpholine (2.0 mL, 18.6 mmol) and cooled to 0°C. The solution was treated with isobutylchloroformate ( 2.3 mL, 17.8 mmol) and the resulting suspension stirred for 15 minutes, then filtered. The solids collected were washed with 2 portions of dimethoxyethane and the washings combined with the original filtrate. This material was cooled in an ice bath and treated with a cold solution of sodium borohydride (1.93 g, 50.8 mmol) in 40 mL 1/2 saturated sodium bicarbonate and the reaction stirred for 2 hours. The mixture was diluted with water and extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried, filtered and concentrated to provide the title compound.

MS (DCI, NH3): 282 (MH+); 299 (M+NH4)+.

Example 1108B 1 -benzyloxv-2(S )-t-butoxycarbonylamino-3-ethylthiopropane Following the procedure described in example 1 106B (and substituting potassium thioethoxide for sodium thiomethoxide), example 1108A (322 mg, 1.5 mmol) was converted to 342 mg (70% overall) the title compound.

MS (DCI, NH3): 326 (MH+); 343 (M+NH4)+.

Example 1 108B 1 -benzyloxy-2(S )-amino-3-ethylthiopropane hvdrochloride salt Following the procedure described in example 1106C, example 1 108B (342 mg, 1.05 mmol) was converted to 244 mg (89%) of the title compound.

MS (DCI, NH3): 226 (MH+).

Example 1108C N-[4-(N-(1-benzyloxymethyl-2(S)-ethylthioethylaminomethyl)-2 -(2- methvlphenyl)benzovllmethionine methvl ester Following the procedure described in example 1106D, part 1, example 1108C (144 mg, 0.55 mmol), example 403G (192 mg, 0.50 mmol), diisopropylethylamine (0.098 mL, 0.55 mmol) and acetic acid (0.14 mL, 2.5 mmol) and sodium triacetoxyborohydride (213 mg, 1.0 mmol) provided 196 mg (66%) of the title compound after chromatography (silica gel, 20 g, 50% ethyl acetate/hexanes).

MS (ESI+): 595 (MH+): (ESI-): 593 (M-H).

Example 1108D N- [4- (N-(1 -benzyloxymethyl-2(S )-ethylthioethylaminomethyl)-2- (2- methylphenyl)benzoyll methionine Following the procedure of example 1 104D, example 1 108C (187 mg, 0.31 mmol) provided 175 mg of the title compound.

1H NMR (300 MHz., CD30D): 6 7.70, d, 1H; 7.50, d, 1H; 7.08 - 7.39, m, 10H; 4.59, s, 2H; 4.29, m, 1H; 4.20, s, 2H; 3.70, d, 2H; 3.37, m, 1H; 2.85, d, 2H; 2.49, m, 2H; 2.21, bs, 1.5H; 2.08, s, 1.5H; 2.03, m, 1H; 1.98, s, 3H; 1.87, m, 2H; 1.68, m, 1H; 1.20, t, 3H.

MS (ESI+): 581 (MH+): (ESI-): 579 (M-H). Calc'd for C32H40N304S2; C 66.18; H 6.94; N 4.82; Found: C 65.52; H 6.76; N 4.58.

Example 1110 <BR> <BR> N-l 4-(N-(2-CvclohexVlethvl)-N-methylaminomethyl)-2-(2-methylphe nYl)benzovllornithine * Trifluoroacetate salt Example 1110A N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl phenyl)benzoyl]-N'- carbobenzyloxvornithine. Methvl Ester The title compound was prepared according to the procedure in example 608D, replacing L-methionine methyl ester'HCl with L-N'-carbobenzyloxyornithine methyl esterHCl, and was isolated as a colorless oil.

MS (ESI(+)) m/e 628 (M+H)+.

MS (ESI(-)) m/e 626 (M-H)-.

Example 1110B N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl phenyl)benzoyl]ornithine, Trifluoroacetate salt

To a solution of N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]-N'-carbobenzyloxyornithine methyl ester (270mg) in methanol (1.4mL) was added 5M LiOH (0. 103mL). After 4h, the reaction was concentrated and the residue was dissolved in ethanol (3mL), followed by the addition of freshly distilled cyclohexene (0.1mL), then 10% palladium on carbon (50mg). The reaction vessel was tightly sealed and warmed to 800C for lh. Analytical HPCL analysis indicates ca. 30% conversion to the title compound. The reaction was filtered and concentrated, and the hydrogenation protocol was repeated twice. Analytical HPCL analysis of the resulting mixture still indicated low conversion. The reaction was filtered and concentrated, and the residue was dissolved in a minimum of 10%methanol/water, and purified by preparative reverse-phase medium pressure liquid chromatography, eluting with a gradient of methanol/water/0.1%TFA. Lyophylization of the appropriate fractions afforded the title compound as a light yellow powder (38mg).

1H NMR (300 MHz, DMSO) 80.83-0.97 (m, 2H), 1.08-1.83 (m, 15H), 2.07-2.14 (m, 4H), 2.62-2.73 (m, 4H), 2.95-3.24 (m, 2H), 4.09-4.17 (m, 1H), 4.22-4.49 (m, 2H), 7.09-7.27 (m, 4H), 7.40 (s, lH), 7.54-7.73 (m, 5H), 8.40 (brd, J=5 Hz, 1H), 9.68 (brs, 1H).

MS (APCI(-)) m/e 478 (M-H).

Example 1112 N-[4-(N-(2-cyclohexylethyl)-N-2-N-methylaminomethyl)-2-(2-me thylphenyl)benzoyl]thien- 2-vlalanine Example 1112A 3-(2-thienyl)-L-alanine. methylester hvdrochloride

A solution of 3-(2-thienyl)-L-alanine (200 mg, 1.17 mmol) in 3 mL of methanol was treated with chlorotrimethylsilane (0.73 mL, 5.84 mmol) and the mixture heated to reflux for 60 hours. The solution was then concentrated to provide 257 mg (99%) of the title compound.

MS (DCI, NH3): 186 (MH+); 203 (M+NH4)+.

Example 1112B N-[4-(N-(2-cyclohexylethyl)-N-2-N-methylaminomethyl)-2-(2-me thylphenyl)benzoyl]thien- 2-vlalanine Following the procedure of example 608D, example 11 12A (122 mg, 0.55 mmol) and example 608C (183 mg, 0.5 mmol) were converted to 154 mg (58%) of the title compound.

MS (ESI+): 533 (MH+): (ESI-): 531 (M-H).

Example 1112C N- r4-(N-(2-cvclohexvlethvl)-N-2-N-methvlaminomethYl)-2-(2-meth YlphenYl!benzoYllthien- 2-vlalanine Following the procedure of example 1105D, example 11 12C (150 mg, 0.28 mmol) provided 124 mg (85%) of the title compound.

1H NMR (300 MHz., CD30D): 8 7.69, m, 1H; 7.52, dd, 1H; 7.31, bs, 1H; 7.21, m, 2H; 7.14, m, 3H; 6.85, bt, 1H; 6.72, m, 1H; 4.40, m, 1H; 4.24, bd, 2H; 3.10 - 3.27, m, 2H; 3.06, m, 2H; 2,72, s, 3H; 2.08, s, 3H; 1.56 - 1.76, m, 7H; 1.13 - 1.37, m, 4H; 0.96, m, 2H.

MS (ESI+): 519 (MH+): (ESI-): 517 (M-H). Calc'd for C31H38N2O3S.0.75 H2O; C 69.96; H 7.48; N 5.26; Found: C 70.01; H 7.38; N 5.19.

Example 1134 <BR> <BR> N- {4-( 1 -ethylthio-3 -cyclohexylprop-2-ylaminomethyl).-5-fluoro-2-(2- <BR> <BR> methylphenyl)benzoyll methionine Example 11 34A Dimethyl 2-(2-Methylphenyl)-5-fluoroterephthalate A stirred solution of the product from example 319B (2.99 g, 10.00 mmol) in in 30 ml of dioxane was cooled in an ice bath and 6.5 ml of a 48% aqueous solution of tetrafluoroboric acid was added. The resulting solution was treated with t-butylnitrite such that the internal temperature did not exceed 10°C and stirring was continued for 30 minutes further. The mixture was carefully diluted with ether (-200 mL) and the solid collected by filtration. The dried solid was suspended in 20 mL of isooctane and heated to reflux overnight and then diluted with 5 mL of dioxane and heating continued for 1 hour more. The resulting dark mixture was cooled to ambient temperature and concentrated. The residue was purified by column chromatography on silica gel (50g, 5% ethyl acetate/hexanes) to provide 0.87 g (29%) of the title compound.

1H NMR (300 MHz., CDCl3): 6 7.73, d, 1H; 7.72, d, 1H; 7.15 - 7.32, m, 3H; 7.06, d, 1H; 3.94, s, 3H; 3.65, s, 3H; 2.07, s, 3H.

MS (DCI-NH3): 320 (M+NH4H+).

Example 11 34B 2-(2-Methvlphenvl)-4-carboxv-5-fluorobenzoic acid, methvl ester A solution of example 1 134A (0.87 g, 2.88 mmol) in 10 mL of 4:1 THF/methanol was treated with 3 mL of lM aqueous lithium hydroxide and the mixture stirred at ambient temperature for 60 hours. The solution was made acidic by the addition of excess 3N aqueous HCl and then extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried, filtered and concentrated to provide 0.77 g (92%) ofthe title compound sufficiently pure to use in the next step.

1H NMR (300 MHz., CD30D): 8 7.7.74, d, 1H; 7.69, d, 1H; 7.15 - 7.28, m, 3H; 7.03, q, 1H; 3.61, s, 3H; 2.07, s, 3H.

MS (DCI, NH3): 306 (M+ NH4+).

Example 11 34C 2-(2-Methylphenyl)-4-hvdroxymethyl-5-fluorobenzoic acid. methyl ester A solution of example 1 134B (760 mg, 2.64 mol) in 5 mL of dimethoxyethane was treated with 4-methylmorpholine (0.32 mL, 2.90 mmol) and the mixture cooled in an ice bath. The clear solution was then treated with isobutylchloroformate (0.36 mL, 2.77 mmol) and the suspension stirred for 30 minutes. The mixture was filtered and the solids washed with 2 portions of THF and the combined filtrates recooled in an ice bath. The cold solution was treated with a mixture of sodium borohydride (300 mg, 7.92 mmol) in 3 mL of 1/2 saturated sodium bicarbonate and the mixture stirred for 2 hours. The mixture was diluted with water and extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried, filtered and concentrated. The residue was purified by column chromatography of silica gel (35 g, 25% ethyl acetate/hexanes) to provide 527 mg (73%) of the title compound.

1H NMR (300 MHz., CDC13): 8 7.67, d, 1H; 7.44, d, lH; 7.15 - 7.28, m, 3H; 7.05, d, 1H; 4.83, d, 1H; 3.62, s, 3H; 2.07, s, 3H; 1.94, bt, 1H.

MS (DCI, NH3): 292 (M+ NH4+).

Example 1134D 2-(2-Methylphenyl)-4-formyl-5-fluorobenzoic acid, methvl ester A stirred solution of example 11 34C (515 mg, 1.79 mmol) in 2 mL of methylene chloride was treated with KBr (21 mg, 0.18 mmol), 2 mL of water and sodium bicarbonate (0.5 g) and then cooled in an ice bath. The mixture was treated with TEMPO (3 mg, 0.02 mmol) and then commercial bleach (Chlorox, 3.1 mL) was added such that the temperature did not exceed 5°C. The mixture was stirred for 10 minutes at which time an additional 1.5 mL of Chlorox was added. After stirring a further 10 minutes, the mixture was diluted with water and layers were separated. The aqueous phase was extracted with 1 portion of methylene chloride and the combined organic phases were extracted with 5% aqueous sodium bisulfite, dried, filtered and concentrated to give 478 mg (93%) of the title compound.

1H NMR (300 MHz., CDC13): 8 10.43, s, 1H; 7.77, d, 1H; 7.73, d, 1H; 7.17 - 7.31, m, 3H; 7.05, m, 1H; 3.63, s, 3H; 2.06, s, 3H.

MS (DCI, NH3): 290 (M+ NH4+).

Example 1134E <BR> <BR> N- 14-( 1 -ethylthio-3-cvclohexylprop-2-ylaminomethyl)-5-fluoro-2-(2-m ethylphenvl)benzoic acid methyl ester

Example 1 134D (143 mg, 0.5 mmol) was dissolved in 2 mL of l,2-dichloroethane and the amine hydrochloride salt from example 403D (178 mg, 0.75 mmol), diisopropylethylamine (0.13 mL, 0.75mmol) and acetic acid (0.15 mL, 2.50 mmol) were sequentially added. The mixture was stirred at ambient temperature for 4 hours and then treated with sodium triacetoxyborohydride (213 mg, 1.0 mmol) and the mixture stirred overnight. The reaction was quenched by the addition of 2 mL of 2M aqueous sodium carbonate and the mixture stirred vigorously for lhour and then diluted with water and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic layers dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (20g, 15% ethyl acetate/hexanes) to provide 165 mg (72%) of the title compound.

1H NMR (300 MHz., CDC13): 8 7.67, d, 1H; 7.16 - 7.31, m, SH; 7.04, bd, lH; 3.93, s, 2H; 3.63, s, 3H; 2.76, m, 2H; 2.57, m, 1H; 2.46, q, 2H; 2.06, s, 3H; 1.63, bm, 6H; 1.37, bm, 3H; 1.22, t, 3H; 1.13, m, 2H; 0.87, m, 2H.

MS (ESI +): 458 (MH+); (ESI-) 456 (M-H).

Example 11 34F N- [4-( 1 -ethylthio-3-cyclohexvlprop-2-vlaminomethyl)-S-fluoro-2-(2-m ethvlphenyl)benzoic acid Example 1 134E (160 mg, 0.35 mmol) was dissolved in 1.5 mL of ethanol and aqueous sodium hydroxide was added (1.75 mL of a 4N solution) and the mixture heated to reflux for 3 hours. The cooled solution was concentrated to dryness and dissoved in water and the pH adjusted to - 4 with 1M aqueous phosphoric acid. The mixture was extracted with 3 portions of ethyl acetate and the combined organic extracts were washed with brine, dried, filtered and concentrated to provide 164 mg (105%) of the title compound.

1H NMR (300 MHz., CD30D): 8 7.78, d, 1H; 7.43, d, 1H; 7.15 - 7.27, m, 3H; 7.06, bd, 1H; 4.42, m, 2H; 3.48, m, 1H; 3.00, dd, 1H; 2.93, dd, 1H; 2.58, q, 2H; 2.09, s, 3H; 1.63 -0 1.79, m, 7H; 1.45, bm, 2H; 1.14 - 1.36, m, 6H; 0.84 - 1.09, m, 2H.

Example 1134G N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-fluoro -2-(2- methylphenvl)benzovllmethionine. methvl ester According to the procedure described in example 11781, example 11 34F (160 mg, 0.35 mmol) provided 140 mg (68%) of the title compound after column chromatographic purification on silica gel (20 g, 35% ethyl acetate/hexanes).

1H NMR (300 MHz., CDCl3): 8 7.70, dd, 1H; 7.14 - 7.38, m, 5H; 5.91, bd, lH; 4.60, m, 1H; 3.94, s, 2H; 3.66, s, 3H; 2.77, m, 2H; 2.58, m, 1H; 2.46, q, 2H; 2.28, s, 1.5 H(o- tolyl rotamer); 2.07, s, 1.SH (o-tolyl rotamer); 1.95 - 2.10, m, 5H; 1.84, m, 2H; 1.50 - 1.72, m, 6H; 1.26 - 1.48, m, 3H; 1.21, t, 3H; 1.04- 1.26, m, 3H; 0.88, m, 2H. MS: (ESI-): 587 (M-H).

Example 11 34H N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-fluoro -2-(2- methylphenvl)benzoyllmethionine Following the procedure of example 11 05D, example 11 34G (130 mg, 0.22 mmol) provided 94 mg (75%) of the title compound.

1H NMR (300 MHz., CD30D): 8 7.52, d, 1H; 7.39, m, 1H; 7.10 - 7.30, m, 4H; 4.29, m, 1H; 4.25, q, 2H; 3.24, m, 1H; 2.89, dd, 1H; 2.78, dd, 1H; 2.52, q, 2H; 2.22, bs, 1.5H; 2.08, bs, 1.5H; 2.05, m, 1H; 1.98, s, 3H; 1.89, m, 2H; 1.69, m, 6H; 1.58, t, 2H; 1.43, m, 1H; 1.25, m, 1H; 1.22, t, 3H; 0.90, m, 2H.

MS (ESI+): 575 (MH+): (ESI-): 573 (M-H). Calc'd for C31H43FN203S2'035 H2O; C 64.07; H 7.58; N 4.82; Found: C 64.08; H 7.54; N 4.65.

Example 1136 N-[4-(N-butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt Example 1136A Methvl 4-(N-Buvtylaminomethyl)-2-(2-methylphenyl)benzoate To aO C solution of intermediate 1178B (1.0 g, 3.71 mmol) in DCM (10 mL) was added oxallyl chloride (2.0 M in DCM, 3.7 mL), and a drop of DMF. The reaction was stirred at room temperature for 2 hours, and was then evaporated to dryness. The residue was redesolved in DCM (10 mL), and was cooled to 0 C. To it was slowly added butylamine (0.5 mL). The reaction mixture was stirred for 5 min., and then was filtered through silca gel (10 g), rinsed with ethyl acetate, and concentrted. The solid was desolved in THF (10 ML), and to it was added borane (1.0 M in THF, 5.0 mL), and the reaction mixture was reluxed for 15 hours. Methanol (0.5 mL) was added dropwisly to the reaction, followed by concentrated HCl (1 mL), and the mixture was heated at 60 °C for 1 hour.

Then it was cooled to room temperature, the reaction mixture was adjusted to pH about 12- 14 with sodium carbonate (2.0 M in water). 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 (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate amine. The amine was used without further purification.

Example 1136B Methvl 4- IN-butvl-N-(4-cvclohexylbenzvlcarbonyl)aminomethvll -2-(2- methvlphenvl)benzoate To a 0 °C solution of 4-cyclohexylbenzoic acid (204 mg, 1.0 mmol) in DCM (3 mL) was added oxallyl chloride (2.0 A in DCM, 1.0 mL), and a drop of DMF. The reaction was stirred at room temperature for 2 hours, and was then evaporated to dryness. The residue was redesolved in DCM (10 mL), and was cooled toO °C. To it was slowly added the intermediate 1136A (156 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) in DCM (3 mL). The reaction mixture was stirred for 5 min., and then was filtered through silca gel (10 g), rinsed with ether, and concentrted. The residue was purified by column chromatography with 20% ethyl acetate in to give the title compound (165 mg, 66%).

HNMR (300 MHz, CDC13) 87.95 (d, 1 H), 7.32-7.16 (m, 9 H), 7.05 (br d, 1 H), 5.85- 5.55 (loop, 2 H), 3.61 (s, 3 H), 3.47-3.17 (broad loop, 2 H), 2.49 (m, 1 H), 2.06 (s, 3 H), 1.90-0.70 (m, 17 H). MS(CI/NH3) m/z: 498 (M+H)+.

Example 1136C Methyl 4-(N-Butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylpheny l)benzoate To a solution of intermediate 1136B (93 mg) in THF (2 ML) was added borane (1.0 M in THF, 1.0 mL), and the reaction mixture was reluxed for 15 hours. Methanol (0.5 mL) was added dropwisly to the reaction, followed by concentrated HCl (0.5 mL), and the mixture was heated at 60 °C for 1 hour. Then it was cooled to room temperature, and was adjusted to pH about 12-14 with sodium carbonate (2.0 M in water). 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 (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give the title amine (88 mg, 94%). 'HNMR (300 MHz, CDCl3)

87.90 (d, 1 H), 7.42 (dd, 1 H), 7.30-7.15 (m, 4 H), 7.12 (m, 2 H), 7.06 (m, 1 H), 3.59 (s, 2 H), 3.57 (br s, 2 H), 3.53 (br s, 2 H), 2.47 (m ,1 H), 2.41 (t, 2 H), 2.05 (s, 3 H), 1.90-1.20 (m, 14 H), 0.94 (t, 3 H). MS(CI/NH3) m/z: 484 (M+H)+.

Example 1 136D <BR> <BR> N-[4-(N-Butvl-N-4-cvclohexvlbenzvlaminomethYl)-2-(2-methvlph envl)benzovllmethionine Methvl Ester The procedures descriped in the Example 403E and 403F were used here to convert above intermediate 1136C (85 mg) to the title methyl ester 1136D (73 mg, 68%). 'HNMR (300 MHz, CDC13) 6 7.90 (2 d's 1 H), 7.45 (br d, 1 H), 7.35-7.22 (m, 6 H), 7. 19 (br s, 1 H), 7.13 (br d, 2 H), 5.85 (m, 1 H), 4.62 (m, 1 H), 3.65 (s, 3 H), 3.57 (s, 2 H). 3.53 (s, 2 H), 2.48 (m, 1 H), 2.41 (t, 2 H), 2.20-2.00 (4 s's, 6 H), 2.05 (m, 2 H), 1.92-1.20 (m, 16 H), 0.82 (t, 3 H). MS(CVNH3) m/z: 615 (M+H)+.

Example 1136E N-[4-(N-butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1136D (64 mg) to the title lithium salt (64 mg, 100%). 'H NMR (300 MHz, dmso-d6) 6 7.49 (d, 1 H), 7.37 (br d, 1 H), 7.25-7.09 (m, 9 H), 6.91 (d, 1 H), 3.63 (m, 1 H), 3.56 ( br s, 2 H), 3.47 (br s, 2 H), 2.45 (m, 1 H), 2.37 (t, 2 H), 2.17-1.98 (m, 8 H), 1.81-1.17 (m, 16 H), 0.76 (t, 3 H). MS(ESI-) m/z: 599 (M-H)-.

Example 1137 N-[4-(N-Butyl-N-4-cyclohexylbenzoylaminomethyl)-2-(2-methylp henyl)benzoyl]methionine lithium salt Example 1137A N- 14-(N-butyl-N-4-cvclohexvlbenzovlaminomethYl)-2-(2-methvlphe nvl!benzovllmethionine Methvl Ester The procedures descriped in the Example 403E and 403F were used here to convert intermediate 1136B (63 mg) to the title methyl ester 1137A (72 mg, 90%). HNMR (300 MHz, CDCl3) 8 7.94 (2 d's 1 H), 7.37-7.15 (m, 10 H), 5.89 (m, 1 H), 4.80 (m, 1 H), 4.61 (br. loop, 2 H), 3.66 (s, 3 H), 3.43,3.22 (2 br loops, 2 H), 2.50 (m, 1 H), 2.20-2.00 (m, 8 H), 1.92-1.00 (m, 16 H), 0.96-0.70 (2 br loops, 3 H). MS(Cl/NH3) m/z: 629 (M+H)+ Example 1137B <BR> <BR> <BR> N-F4-(N-Butvl-N-4-cvclohexvlbenzovlaminomethvl)-2-(2-methYlp henYl)benzovllmethionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1137B (68 mg) to the title lithium salt (67 mg, 100%). H NMR (300 MHz,

dmso-d6) 6 7.53 (br d, 1 H), 7.42-7.08 (m, 9 H), 6.97 (m, 1 H), 6.95 (br d, 1 H), 4.72,4.57 (2 br. loops, 2 H), 3.65 (m, 1 H), 3..17 (br loop, 2 H), 2.50 (m, l H), 2.20- 1.88 (m, 8 H), 1.86-0.95 (m, 16 H), 0.88,0.67 (2 br loops, 3 H). MS(ESI-) m/z: 613 (M-H) Example 1139 N-[4-(N-Cyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benz oyl]methionine lithium salt Example 1139 A N-[4-(N-Cyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benz oyl]methionine lithium salt The procedures descriped in the Example 403E and 403F were used here to convert intermediate 1 144C (127 mg) to the title methyl ester (141 mg, 83%). HNMR (300 MHz, CDCl3) 6 7.89 (2 d's, 1 H), 7.32-7.24 (m, 4 H), 7.95 (br d, 1 H), 7.03 (br s, 1 H), 5.86 (br d, 1 H), 5.16 (m, 1 H), 4.62 (m, 1 H), 3.75 (m, 1 H), 3.02 (t, 2 H), 2.45 (t, 2 H), 2.20-2.00 (m, 8 H), 1.92-0.97 (m, 12 H).

Example 1139B N-[4-(N-Cyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benz oyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1 139A (134 mg) to the title lithium salt (121 mg, 93%). H NMR (300 MHz, dmso-d6) 8 7.67 (d, 1 H), 7.45 (d, 1 H), 7.27-7.08 (m, 5 H), 6.97 (m, 1 H), 6.88 (m, 1 H), 3.66 (m, 1 H), 2.85 (t, 2 H), 2.36 (t, 2 H), 2.00-1.90 (m, 8 H), 1.88-0.98 (m, 12 H).

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

Example 1140 N-[4-(N-cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylpheny l)benzoyl]methionine lithium salt Example 1140A Methyl 4-(Ethoxycarbonylmethyl)-2-(2-methylphenyl)benzoate A solution of intermediate 1178D (397 g, 1.24 mmol), palladium(II) acetate (22 mg), 1 ,3-bis(diphenylphosphino)propane (42 mg), N,N-diisopropylethylamine (0.5 mL) in ethanol (1 mL) and DMF (5 mL) was stirred at 80 C under carbon monoxide balloon for 4 hours. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 5% ethyl acetate in hexane to give the title compound (233 mg, 58%). HNMR (300 MHz, CDCl3) 6 7.94 (d, 1 H), 7.35 (dd, 1 H), 7.30-7.17 (m, 3

H), 7.16 (d, 1 H), 7.07 (br d, 1 H), 4.16 (q, 2 H), 3.67 (s, 2 H), 3.61 (s, 3 H), 2.06 (s, 3 H), 1.25 (t, 3 H). MS(Cl/NH3) m/z: 330 (M+NH4)+ Example 1140B Methyl 4-(Carboxymethyl)-2-(2-methylphenyl)benzoate To the solution of intermediate 1 140A (213 mg, 0.682 mmol) in methanol (3 mL) was added NaOH (0.979 M in water, 0.697 mL). After 2 hours, the reaction mixture was acidified with HCl (1.0 A 1 mL), and 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 used witout further purification.

Example 1140C N-Butvlcvclohexvmethylamine The procedures descriped in the Example 1178E and 1178F were used here to convert cyclohexylacetyl chloride (1.47 g, 10 .0 mmol) and butylamine to the title amine in 85% yield. The amine was not purified before it was used.

Example 1140D Methyl 4-(N-Cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2-methy lphenyl)benzoate

The procedure described in example 1144C was used here to combine intermediate 1140B (311 mg, 1.10 mmol) and intermediate 1140C (205 mg) to give the title compound (247 mg, 52%). 'HNMR (300 MHz, CDCl3) 87.94 (d, 1 H), 7.33 (M, 1 H), 7.25-7.15 (m, 3 H), 7.13,7.11 (2 d's, 1 H), 7.05 (m, 1 H), 3.76,3.75 (2 s's, 2 H), 3.60 (s, 3 H), 3.35-3.05 (m, 4H), 2.05,2.04 (2 s's, 3 H), 1.80-1.10 (m, 15 H), 0.91,0.89 (2 t's, 3 H).

MS(CI/NH3) m/z: 436 (M+H)+.

Example 1140E Methyl 4-(N-Cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylphenyl)b enzoate A solution of intermediate 1140D (118 mg, 0.271 mmol) and borane (1.0M in THF, 0.54 mL) in THF was reluxed for 15 hours. Methanol (0.5 mL) was added dropwisly to the reaction, followed by concentrated HCl (0.5 mL), and the mixture was heated at 60 C for 1 hour. The it was cooled to room temperature, The reaction mixture was adjusted to pH about 12-14 with sodium carbonate (2.0 M in water). 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 (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate amine 1140E. The amine was used without further purification. 'HNMR (300 MHz, CDCl3) 87.90 (d, 1 H), 7.28-7.17 (m, 4 H), 7.05 (m, 2 H), 3.60 (s, 3 H), 2.75 (m, 2 H), 2.66 (m, 2 H), 2.40 (t, 2 H), 2.19 (d, 2 H), 2.06 (s, 3 H), 1.80-1.10 (m, 15 H), 0.88 (t, 3 H). MS(CI/NH3) m/z: 422 (M+H)+

Example 1140F N-[4-(N-Cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylpheny l)benzoyl]methionine Methvl Ester The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate amine 1140E to the title methyl ester (113 mg, 76%, 3 steps from 1140D). HNMR (300 MHz, CDC13) 7.90 (2 d's, 1 H), 7.34-7.18 (m, 5 H), 7.01 (s, 1 H), 5.87 (br d, 1 H), 4.62 (m, 1 H), 3.65 (s, 3 H), 2.75 (m, 2 H), 2.66 (m, 2 H), 2.41 (t, 2 H), 2.20 (d, 2 H), 2.19-1.98 (m, 8 H), 1.87 (m, 1 H), 1.80-1.10 (m, 16 H), 0.88 (t, 3 H). MS(CVNH3) m/z: 553 (M+H)+ Example 1140G N-[4-(N-cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylpheny l)benzoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1140F (107 mg) to the title lithium salt (91 mg, 87%). H NMR (300 MHz, dmso-d6) 6 7.51 (d, 1 H), 7.33-7.13 (m, 5 H), 7.05 (br s, 1 H), 6.95 (m, 1 H), 3.71 (m, 1 H), 2.76 (m, 2 H), 2.67 (m, 2 H), 2.42 (t, 2 H), 2.21 (d, 2 H), 2.10-1.82 (m, 8 H), 1.80- 1.10 (m, 17 H), 0.88 (t, 3 H). MS(ESI-) m/z: 537 (M-H)-.

Example 1141

N- {4-(N-Cyclohexylmethvl-N-butylaminocarbonvlmethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1141A N-[4-(N-Cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2- methylphenyl)benzoyl]methionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert the intermediate 1140D (101 mg) to the title methyl ester (127 mg, 97%). HNMR (300 MHz, CDCl3) # 7.92 (m, 1 H), 7.37-7.22 (m, 4 H), 7.19 (m, 1 H), 7.11 (br d, 1 H), 5.88 (br d, 1 H), 4.61 (m, 1 H), 3.76,3.75 (2 s's, 2 H), 3.65 (s, 3 H), 3.37-2.04 (m, 4 H), 2.00-1.97 (m, 8 H), 1.95-1.10 (m, 17 H), 0.92,0.88 (2 t's, 3 H). MS(CI/NH3) m/z: 567 (M+H)+ Example 1141B N- r4-(N-Cvclohexvlmethvl-N-butvlaminocarbonvlmethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1141A (119 mg) to the title lithium salt (102 mg, 86%). 'H NMR (300 MHz, dmso-d6) 8 7.48 (2 d's, 1 H), 7.30 (m, 1 H), 7.25-7.08 (m, 4 H), 7.03 (br s, 1 H), 5.95 (m, 1 H), 3.74,3.72 (2 s's, 2 H), 3.69 (m, 1 H), 3.23 (t, 2 H), 3.11 (m, 2 H), 2.20-1.90

(m. 8 H), 1.85 (m, 1 H), ), 1.79-1.00 (m, 17 H), 0.86,0.83 (2 t's, 3 H). MS(ESI-) m/z: 551 (M-H?.

Example 1142 N-[4-(N-Cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)b enzoyl]methionine lithium salt Example 1 142A Methvl 4-(N-Butvlaminocarbonvlmethvl)-2-(2-methvlphenvl)benzoate The procedure described in example 1 144C was used here to combine intermediate 1140B (200 mg, 0.70 mmol) and butylamine to give the title compound (171 mg, 69%).

'HNMR (300 MHz, CDC13) 6 7.95 (d, 1 H), 7.34 (dd, 1 H), 7.30-7.17 (m, 3 H), 7.13 (d, 1 H), 7.05 (d, 1 H), 5.36 (m, 1 H), 3.61 (s, 3 H), 3.60 (s, 2 H), 3.24 (q, 1 H), 2.07 (s, 3 H), 1.42 (m, 2 H), 1.27 (m, 2 H), 0.88 (t, 3 H).

Example 1142B Methyl N-[4-(N-Cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)b enzoate The procedures described in 1143B was used here to convert 1142A (102 mg, 0.36 mmol) to the title compound (137 mg, 87%). IHNMR (300 MHz, CDCl3) 8 7.92 (2 d's, 1 H), 7.30-7.17 (m, 4 H), 7.05 (m, 2 H), 3.61 (2 s's, 3 H), 3.52 (m, 2 H), 3.07,3.06 (2 t's, 2 H), 2.90 (t, 2 H), 2.37 (m, 1 H), 2.07,2.04 (2s's, 3 H), 2.00-1.15 (m, 14 H), 0.92,0.90 (2 t's, 3 H). MS(CVNH3) m/z: 436 (M+H)+.

Example 1142C N-[4-(N-Cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)b enzoyl]methionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate 1142B (130 mg) to the title methyl ester (112 mg, 66%). HNMR (300 MHz, CDC13) 6 7.91 (2 d's, 1 H), 7.37-7.15 (m, 5 H), 7.06,6.99 (2 br s's, 1 H), 6.90 (br d, 1 H), 4.61 (m, 1 H), 3.66,2.65 (2 s's, 3 H), 3.52 (m, 2 H), 3.19,2.92 (2 m's, 4 H), 2.30-2.00 (m, 9 H), 1.86 (m, 1 H), 1.80,1.10 (m, 15 H), 0.94,0.91 (2 t's, 3 H).

MS(CVNH3) m/z: 567 (M+H)+.

Example 1 142D N-[4-(N-Cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)b enzoyl]methionine lithium salt

The procedure descriped in the Example 4031 was used here to convert the intermediate 1142C (103 mg) to the title lithium salt (99 mg, 97%). 'H NMR (300 MHz, dmso-d6) 6 6 7.48 (2 d's, 1 H), 7.31-6.86 (m, 7 H), 3.63 (m, 1 H), 3.48 (m, 2 H), 3.10,2.95 (2 m's, 2 H), 2.82 (2 t's, 2 H), 2.25-1.90 (m, 9 H), 1.80 (m, 1 H), 1.75-1.07 (m, 15 H), 0.84,0.80 (2 t's, 3 H). MS(ESI-) m/z: 551 (M-H)-.

Example 1143 N-[4-(N-Cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt Example 1143A Methyl 4-(N-Cyclohexylmethylaminocarbonylmethyl)-2-(2-methylphenyl) benzoate The procedure described in example 1144C was used here to combine intermediate 1140B (301 mg, 1.05 mmol) and cyclohexylmethylamine to give the title compound (266 mg, 67%). HNMR (300 MHz, CDC13) 6 7.97 (d, 1 H), 7.35 (dd, 1 H), 7.27-7.17 (m, 3 H), 7.15 (d, 1 H), 7.05 (d, 1 H), 5.41 (m, 1 H), 3.62 (2 overlapped s's, 5 H), 3.07 (t, 2 H), 2.06 (s, 3 H), 1.85-0.87 (m, 11 H). MS(CI/NH3) m/z: 380 (M+H)+

Example 1143B Methyl 4-(N-Cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylpheny l)benzoate To a solution of intermediate 1143A (108 mg, 0.285 mmol) in THF (2 ML) was added borane (1.0 A in THF, 0.5 mL), and the reaction mixture was stirred at room temperature for 7 hours. Methanol (0.5 mL) was added dropwisly to the reaction, followed by concentrated HCl (0.5 mL), and the mixture was heated at 60 C for 1 hour. Then it was cooled to room temperature, and was adjusted to pH about 12-14 with sodium bicarbonate (2.0 M in water). The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (5 mL). While still in the separatory funnel, butyryl chloride (0.5 mL) was added to the organic layer, followed by additon of sodium bicarbonate (saturated in water, 5 mL), and the mixture was well shaked. The mixture was washed with NaOH (1 0 M 10 mL), water (2 X 10 mL), brine (10 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 to give the title amine (113 mg, 91%). HNMR (300 MHz, CDCl3) 7.94 (2d'd, 1 H), 7.31-7.18 (m, 4 H), 7.10-7.02 (m, 2 H), 3.62,3.61 (2 s's, 3 H), 3.52 (m, 2 H), 3.00-2.85 (m, 4 H), 2.26,2.18 (2 t's, 2 H), 2.06,2.05 (2 s's, 3 H), 1.80-0.80 (m, 13 H), 0.94,0.91 (2 t's, 3 H). MS(CI/NH3) m/z: 436 (M+H)+ Example 1143C N-[4-(N-Cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylph enyl)benzoyl]methionine Methvl Ester

The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate 1143B (130 mg, 0.300 mmol) to the title methyl ester (112 mg, 66%). 'HNMR (300 MHz, CDC13) 6 7.90 (m, 1 H), 7.35-7.21 (m, 4 H), 7.19 (m, 1 H), 7.03 (br d, 1 H), 5.89 (br d, 1 H), 4.61 (m, 1 H), 3.65 (s, 3 H), 3.52 (m, 2 H), 3.30,3.07 (2 m's, 2 H), 2.90 (t, 2 H), 2.40-1.97 (m, 10 H), 1.90-1.10 (m, 15 H), 0.92,0.90 (2 t's, 3 H). MS(Cl/NH3) m/z: 567 (M+H)+.

Example 1143D N-[4-(N-Cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1143C (104 mg) to the title lithium salt (95 mg, 100%). H NMR (300 MHz, dmso-d6) 6 7.48 (2 d's, 1 H), 7.31-7.10 (m, 5 H), 7.10-6.87 (m, 2 H), 3.66 (m, 1 H), 3.57-3.39 (m, 2 H), 3.22,3.09 (2 m's, 2 H), 2.85,2.79 (2 t's, 2 H), 2.40,2.25 (2 m's, 2 H), 2.20-1.90 (m, 8 H), 1.83 (m, 1 H), 1.75-1.06 (m, 14 H), 0.87,0.85 (2 t's, 3 H).

MS(ESI-) m/z: 551 (M-H) .

Example 1144 N-[4-(N-Cyclohexylpropyl)-2-(2-methylphenyl)benzoyl]methioni ne lithium salt

Example 1144A Methvl 4-(tert-Butoxvcarbonvlethvl)-2-(2-methylphenvl)benzoate 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 from example 1171A (20 mmol) 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 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, CDCl3) 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/NH3) 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 Celite (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). H NMR (300 MHz, CDCl3) 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 1144B Methvl 4-(2-Carboxvethvl)-2-(2-methylphenyl)benzoate A solution of intermediate 1 144A (5.00 g) in trifluoroacetic acid (20 mL) and methyl sulfide (3 mL) was stirred at room temperature for 7 hours. Sovlent was then evaporated to give an off-white solid, which was used without further purification.

Example 1144C Methyl 4-(2-Cyclohexylcarbomoylethyl)-2-(2-methylphenvl)benzoate To a solution of intermediate 1144B (150 mg, 0.50 mmol), oxallyl chloride (2.0 M in DCM, 0.5 mL) in DCM (2 mL) was added a small drop of DMF. After 2 hours at room temperature ,the reaction was concentrated to drynees, and redeolved in DCM (3 mL). To it was added cyclohexylamine (99 mg, 1 mmol) and triethylamine (100 mg, 1 mmol). After 15 min., HCl (1.0 M in ether, 2.0 mL) was added to the reaction mixture, and it was filtered through silica gel (5 g). The residue after concentration of the filtrate was purified by column chromatography with 20% ethyl acetate in hexane to give the title compound (152 mg, 80%).

'H NMR (300 MHz, CDCl3) 8 7.90 (d, 1 H), 7.28-7.15 (m, 4 H), 7.07-7.02 (m, 2 H), .5.16 (m, 1 H), 3.72 (m, 1 H), 3.60 (s, 3H), 3.02 (t, 2 H), 2.45 (t, 2 H), 2.05 (s, 3 H), 1.85 (m, 2 H), 1.70-1.55 (m, 3 H), 1.40-0.95 (m, 6 H). MS(CI/NH3) m/z: 380 (M+H)+, 397 (M+NH4)*.

Example 1144D N-(4-(N-Cyclobexylprnpvl)-2-(2-methylphenyl)benzoyl 1 methionine A solution of intermediate 1144C (150 mg, 0.40 mmol) and borane (1.0 M in THF, 1.0 mL) in THF (1 mL) was reluxed for 15 hours. Methanol (0.5 mL) was added dropwisly to the reaction, followed by concentrated HCl (0.5 mL), and the mixture was heated at 60 C for 1 hour. The reaction mixture was cooled to room temperature, and was adjusted to pH about 12-14 with sodium carbonate (2.0 M in water). 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 (20 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated to give the intermediate amine. The amine was used without further purification. MS(CI/NH3) m/z: 366 (M+H) +.

The procedures descriped in the Example 403E and 403F were used here to convert the abbve intermediate amine to the title methyl ester (58%, 3 steps).

Example 1 144E N- K-(N-Cvclohexylpropvl)-2-(2-methylphenyl)benzoyl}methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1144D (121 mg) to the title lithium salt (107 mg, 100%). H NMR (300 MHz, dmso-d6) 6 7.45 (d, 1 H), 7.27-7.08 (m, 4 H), 7.02-6.93 (m, 2 H), 6.90 (m, 1 H), 3.80 (m, 1 H), 3.65 (m, 1 H), 3.30 (m, 2 H), 2.64 (t, 2 H), 2.20-1.80 (m, 10 H), 1.80-1.45 (m, 7 H), 1.30-0.88 (m, 6 H). MS(ESI-) m/z: 481 (M-H) .

Example 1145 N-[4-(N-Cyclohexyl-N-propanoylaminopropyl)-2-(2-methylphenyl )benzoyl]methionine To s stirred mixture of 1144E (70 mg, 0.14 mmol) in THF (1 mL) and saturated aqueous sodium bicarbonate (1 mL) was added propionyl chloride (0.10 mL). After 10 min, the reaction mixture was adjusted to pH 4-5, and it 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 heated at 60 C under high vacuum for 5 hours to give the title compound (59 mg, 78%). 'H NMR (300 MHz, dmso-d6) 6 7.47 (m, 1 H), 7.32-6.97 (m, 7 H), 4.25 (m, 1 H),

3.57 (m, 1 H), 3.35 (m, 2 H), 2.80-2.60 (m, 2 H), 2.30-1.85 (m, 12 H), 1.85-1.45 (m, 7 H), 1.30-0.88 (m, 9 H). MS(ESI-) m/z: 537 (M-H)-.

Example 1146 N-[4-(N-Cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyl)ben zoyl]methionine lithium salt Example 1146A N-Butylcyclohexaylamine The procedures descriped in the Example 1178E and 1178F were used here to convert butyric chloride and cyclohexylamine to the title amine in 86% yield. H NMR (300 MHz, CDC13) 6 2.62 (t, 2 H), 2.41 (m, 1 H), 1.95-1.00 (m, 15 H), 0.92 (t, 3 H).

MS(CI/NH3) m/z: 156 (M+H)+.

Example 1146B Methyl N-[4-(N-Cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyl)ben zoate The procedure descriped in the Example 1144C was used here to convert the intermediate 1144B (298 mg) and N-butylcyclohexylamine (intermediate 1146A, 310 mg, 2.0 mmol) to the title methyl ester (233 mg, 54%). H NMR (300 MHz, CDC13) 8 7.90 (2 d's, 1 H), 7.30-7.15 (m, 4 H), 7.07 (m, 2 H), 4.25 (m, 1 H), 3.60 (s, 3 H), 3.18 (m, 1

H), 3.05 (m, 3 H), 2.62 (m, 2 H), 2.06 (2s's, 3 H), 1.85-1.05 (m, 14 H), 0.90 (2 t's, 3 H). MS(CI/NH3) m/z: 436 (M+H)+.

Example 1 146C N-[4-(N-Cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyl)ben zoyl]methionine Methyl Ester The procedure descriped in the Example 1 144C was used here to convert the intermediate 1 146B (230 mg) to the title methyl ester (184 mg, 63%). 'H NMR (300 MHz, CDCl3) 7.90 (2 d's, 1 H), ), 7.35-7.19 (m, 4 H), 7.03 (m, 1 H), 5.89 (m, l H). 4.62 (m, 1 H), 3.66 (s, 3 H), 3.05 (m, 1 H), 2.66 (t, 2 H), 2.46 (t, 2 H), 2.41 (t, 2 H), 2.20- 2.00 (4 s's, 6 H), 2.05 (m, 2 H), 1.90-1.00 (m, 18 H), 0.90 (t, 3 H). MS(Cl/NH3) m/z: 553 (M+H)+.

Example 1 146D N-[4-(N-Cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyl)ben zoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1146C (179 mg) to the title lithium salt (153 mg, 81%). H NMR (300 MHz, dmso-d6) 7.46 (m, 1 H), 7.35-7.08 (m, 4 H), 7.07-6.90 (m, 2 H), 3.70 (m, 1 H), 3.05 (m, 1 H), 2.64 (t, 2 H), 2.37 (m, 4 H), 2.20-1.90 (m, 8 H), 1.90-0.95 (m, 18 H), 0.85 (t, 3 H). MS(ESI-) m/z: 537 (M-H)-.

Example 1147 <BR> <BR> N-r4-(N-Cvclohexvl-N-methylaminocarbonvlethvl)-2-(2-methvlph envl)benzovllmethionine lithium salt Example 1 147A [4-(2-Trimethylsilylethoxycarbonylethyl)-2-(2-methylphenyl)b enzoyl]methionine tert-Butyl Ester A solution of intermediate 1 144A (875 mg, 2.38 mmol) and LiOH (5.3 A in water, 2.0 mL) in methanol (5 mL) was refluxed 15 hours. The mixture was then acidified with concentrated HCl (1 mL) to pH<3. The reaction mixture was then partitioned between ethyl acetate (100 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting white solid was desolved in DMF (10 mL). To it was added 2-trimethylsilylethanol (0.357 mL, 2.49 mmol), and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (545 mg, 2.84 mmol), and DMAP (10 mg).

After 2 hours, triethylamine (809 mg, 8.0 mmol) L-methionine tert-butyl ester hydrochloride (725 mg, 3.0 mmol), 1-hydroxybenzotriazole (400 mg, 3.0 mmol) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (577 mg, 3.0 mmol). After 15 hours at room temperature, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (10 mL). The organic layer was washed with water (3 X 15 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 10% ethyl acetate in hexane to give the title compound (859 mg, 68%). 1H NMR (300 MHz, CDC13) 8 7.83 (2 d'd, 1 H), 7.33-7.15 (m, 5 H), 7.04 (br s, 1 H), 5.85 (br d, 1 H), 4.50 (m, 1 H), 4.16 (t, 2 H), 3.00 (t, 2 H), 2.63 (t, 2 H),

2.17,2.07,2.03,2.02 (4 s's, 6 H), 2.00 (m, 2 H), 1.80 (m, 1 H), 1.55 (m, 1 H), 1.40 (s, 9 H), 0.95 (t, 2 H), 0.03 (s, 9 H). MS(Cl/NH3) m/z: 572 (M+H)+ Example 1147B r4-(2-Carboxvethvl)-2-(2-methvlphenvl!benzovllmethionine tert-B utyl Ester A solution of intermediate 1147A (841mg, 1.57 mmol), tetrabutylammomium fluoride (820 mg, 3.14 mmol) in DMF (5 mL) was stirred overnight. The reaction mixture was then adjusted to pH 3-5, and was partitioned between ethyl acetate (100 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 to give the title compound. The crude product was used without further purification. H NMR (300 MHz, CDCl3) 8 7.83 (2 d'd, 1 H), 7.33-7.15 (m, 5 H), 7.05 (br s, 1 H), 5.87 (m, 1 H), 4.50 (m, 1 H), 3.01 (t, 2 H), 2.71 (t, 2 H), 2.20-2.02 (4 s's, 6 H), 2.00 (m, 2 H), 1.80 (m, 1 H), 1.59 (m, 1 H), 1.40 (s, 9 H). MS(Cl/NH3) m/z: 472 (M+H)+.

Example 1147C <BR> <BR> N-r4-(N-Cvclohexvl-N-methvlaminocarbonvlethvl!-2-(2-methvlph envl)benzovllmethionine tert-Butvl Ester A solution of intermediate 1147B (50 mg, 0.115 mmol), triethylamine (100 mg), 1- hydroxybenzotriazole (31 mg, 0.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol), and N-methylcyclohexylamine (26 mg, 0.23 mmol) in DMF (2 mL) was stirred 15 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (5 mL), The organic layer was washed with water (3 X 5 mL), brine (5 mL), dried over anhydrous magnesium sulfate, filtered and

concentrated. The residue was purified by column chromatography with 40% ethyl acetate in hexane to give the title compound (44 mg, 68%). H NMR (300 MHz, CDCl3) 8 7.84 (m, 1 H), 7.33-7.15 (m, 5 H), 7.05 (br s, 1 H), 5.84 (m, 1 H), 4.47 (m, 2 H), 3.02 (t, 2 H), 2.81,2.77 (2s's, 3 H), 2.62 (m, 2 H), 2.20-1.97 (m, 8 H), 1.90-1.25 (m, 12 H), 1.40 (s, 9 H). MS(CI/NH3) m/z: 567 (M+H)+ Example 1147D <BR> <BR> N-14-(N-Cvclohexvl-N-methvlaminocarbonvlethvl)-2-(2-methylph enYl)benzovllmethionine lithium salt The intermediate 1 147C (40 mg) was stirred with HCl (4.0 N in dioxane, 1.0 mL) in DCM (1 mL) at room temperature for 15 hours. Solvent was then evaporated, and the residue was desolved in acetonitrile (1 mL), treated with 1.1 equivalent of LiOH (1.0 M in water, 0.078 mL), and freeze-dried to give the title compound (37 mg, 100%). HNMR (300 MHz, dmso-d6) 7.44 (d, 1 H), 7.30 (m, 1 H), 7.25-7.08 (m, 4 H), 7.03 (m, 1 H), 6.87 (m, 1 H), 4.23 (m, 1 H), 3.66 (m, 1 H), 2.87 (m, 2 H), 2.74,2.66 (2s's, 3 H), 2.62 (m, 2 H), 2.20-1.90 (m, 8 H), 1.90-1.25 (m, 12 H). MS(ESI-) m/z: 509 (M-H)-.

Example 1148 N-[4-(N-Cyclohexyl-N-butylaminocarbonylethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt

Example 1148A N-[4-(N-Cyclohexyl-N-butylaminocarbonylethyl)-2-(2-methylphe nyl)benzoyl]methionine Methvl ester The procedures descriped in the Example 403E and 403F were used here to convert the intermediate 1 146B (102mg) to the title methyl ester (117 mg, 90%). HNMR (300 MHz, CDC13) 6 7.91 (2 d's, 1 H), 7.35-7.15 (m, 5 H), 7.06 (br s, 1 H), 6.88 (m, 1 H), 4.61 (m, 1 H), 3.49 (m, 1 H), 3.66 (s, 3 H), 3.20-3.00 (m, 4 H), 2.66-2.50 (m, 2 H), 2.20-2.00 (m, 8 H), 1.90-0.95 (m, 16 H), 0.91 (t, 3 H). MS(CL/NH3) m/z: 566 (M+H) + Example 1 148B N-[4-(N-Cyclohexyl-N-butylaminocarbonylethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1 148A (108 mg) to the title lithium salt (91 mg, 83%). HNMR (300 MHz, dmso-d6) 6 7.44 (d, 1 H), 7.27 (t, 1 H), 7.23-7.05 (m, 3 H), 7.04-6.91 (m, 2 H), 6.89 (d, 1 H), 4.07 (m, 1 H), 3.65 (m, 1 H), 3.06 (m, 2 H), 2.88 (m, 2 H), 2.65,2.57 (2 t't, 2 H), 2.20-1.90 (m, 8 H), 1.90-0.95 (m, 16 H), 0.84 (t, 3 H). MS(ESI-) m/z: 537 (M-H) .

Example 1149 N-[4-(N,N-dicyclohexylaminocarbonylethyl)-2-(2-methylphenyl) benzoyl]methionine lithium salt The procedures descriped in the Example 1 147C and 1 147D were used here to convert 1 147B (50 mg) to the title lithium salt (30 mg, 45%, 2 steps). 'HNMR (300 MHz, dmso-d6) 6 7.44 (d, 1 H), 7.30 (m, 1 H), 7.25-7.08 (m, 4 H), 7.03 (m, 1 H), 6.87 (m, l H), 4.18 (m, 1 H), 3.66 (m, 1 H), 2.87 (t, 2 H), 2.60 (t, 2 H), 2.20-1.90 (m, 8 H), 1.75- 1.00 (m, 22 H). MS(ESI-) m/z: 577 (M-H) .

Example 1150 N-[4-(N-adamant-1-ylaminocarbonylethyl)-2-(2-methylphenyl)be nzoyl]methionine lithium salt The procedures descriped in the Example 1147C and 1147D were used here to convert 1147B (50 mg) to the title lithium salt (40 mg, 62%, 2 steps). IHNMR (300 MHz, dmso-d6) 8 7.63 (d, 1 H), 7.44 (d, 1 H), 7.27-7.05 (m, 5 H), 6.98 (m, 1 H), 6.88 (m, 1 H), 3.80 (m, 1 H), 3.64 (m, 1 H), 2.87 (m, 2 H), 2.50 (m, 2 H), 2.20-1.80 (m, 17 H), 1.77-1.45 (m, 8 H). MS(ESI-) m/z: 547 (M-H)-.

Example 1151 N-[4-(N-adamant-1-ylaminocarbonylethyl)-2-(2-methylphenyl)be nzoyl]methionine lithium salt The procedures descriped in the Example 1 147C and 1 147D were used here to convert 1147B (50 mg) to the title lithium salt (41 mg, 64%, 2 steps). HNMR (300 MHz, dmso-d6) 7.44 (m, 1 H), 7.30-7.05 (m, 6 H), 7.00 (m, 1 H), 6.88 (m, 1 H), 3.67 (m, 1 H), 2.82 (m, 2 H), 2.35 (m, 2 H), 2.20 -1.45 (m, 25 H). MS(ESI-) m/z: 547 (M- H)-.

Example 1154 N-[4-(N-adamant-1-ylmethylaminocarbonylethyl)-2-(2-methylphe nyl)benzoyl]methionine lithium salt The procedures descriped in the Example 1147C and 1147D were used here to convert 1147B (50 mg) to the title lithium salt (47 mg, 72%, 2 steps). 'HNMR (300 MHz, dmso-d6) 7.61 (t, 1 H), 7.44 (d, 1 H), 7.25 (dd, 1 H), 7.24-7.08 (m, 4 H), 6.99 (br s, 1 H), 6.88 (m, 1 H), 3.62 (m, 1 H), 2.82 (t, 2 H), 2.73 (d, 2 H), 2.45 (t, 2 H), 2.20-1.90 (m, 8 H), 1.75-1.48 (m, 11 H), 1.35 (d, 6 H). MS(ESI-) m/z: 561 (M-H)-.

Example 1155 N-[4-(N-Mytanylmethylaminocarbonylethyl)-2-(2-methylphenyl)b enzoyl]methionine lithium salt The procedures descriped in the Example 1147C and 1147D were used here to convert 1147B (50 mg) to the title lithium salt (45 mg, 70%, 2 steps). 'H NMR (300 MHz, dmso-d6) 8 7.60 (t, 1 H), 7.44 (d, 1 H), 7.28-7.08 (m, 5 H), 6.99 (br s, 1 H), 6.88 (m, 1 H), 3.66 (m, 1 H), 3.00 (m, 2 H), 2.83 (t, 2 H), 2.39 (t, 2 H), 2.33-1.20 (m, 19 H), 1.13 (s, 3 H), 0.97 (s, 3 H). MS(ESI-) m/z: 549 (M-H)-.

Example 1157 N-[4-(N-Cyclooctanylaminocarbonylethyl)-2-(2-methylphenyl)be nzoyl]methionine lithium salt The procedures descriped in the Example 1147C and 1147D were used here to convert 1147B (50 mg) to the title lithium salt (31 mg, 51%, 2 steps). 'HNMR (300 MHz, dmso-d6) 7.67 (d, 1 H), 7.44 (d, 1 H), 7.25-7.08 (m, S H), 6.96 (br s, 1 H), 6.88 (m, 1 H), 3.72 (m, 1 H), 3.63 (m, 1 H), 2.85 (t, 2 H), 2.36 (t, 2 H), 2.20-1.90 (m, 8 H), 1.90- 1.30 (m, 16 H). MS(ESI-) m/z: 523 (M-H)-.

Example 1158 Example 1158A Methyl 2-(tert-butoxycarbonylmethyl)-4-methylthiobutyrate To a -78 C solution of methyl 4-methylthiobutyrate (1.48 g, 10.0 mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11 mL). After 30 min, tert-butyl bromoacetate (2.34 g, 12.0 mmol) was added to the reaction, and the reaction mixture was gradually warmed to the room temperature over 6 hours. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (2 X 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 5% ethyl acetate in hexane to give the title compound (1.21 g, 46%).

HNMR (300 MHz, CDCl3) 8 3.75 (s, 3 H), 2.71 (t, 2 H), 2.51 (t, 2 H), 2.32 (m, 1 H), 2.06 (s, 1 H), 1.89 (t, 1 H), 1.41 (s, 9 H). MS(CI/NH3) m/z: 263 (M+H)+ Example 1158B To a solution of the acid from example 608C (530 mg, 1.32 mmol) in DCM (2 mL) was added oxallyl chloride (2.0 M in DCM, 1.5 mL), followed by a small drop of DMF.

After 2 hours at room temperature , the solvent was removed, and the residue was further dried under high vacuum (1 mmHg) for 1 hour. The solid (acid chloride) was redesolved in THF (5 mL).

To a -78 C solution of 1158A (1.21 g, 4.61 mmol) in THF (10 mL) in a separate flask was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 5.28 mL). After 30 min.. the acid chloride solution was added slowly to the reaction mixture via a cannula. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) at - 78"C. After it reached the room temperature, the reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with sodium bicarbonate (saturated in water, 10 mL), water (2 X 10 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 30% ethyl acetate in hexane to give the title compound (430 mg, 53%). HNMR is messy because of 4 diastereomers exist. MS(Cl/NH3) m/z: 610 (M+H)+.

Example 1158C Methyl 3-[4-(N-cyclohexyl-N-methylaminomethyl)-2-(2-methylphenyl)be nzoylmethyl]-4- methvlthiobutvrate A solution of 1158B (420 mg, 0.69 mmol) in HC1 (4.0 M in 1,4-dioxane, 5 mL) was heated at 80 C for 2 hours. Solvent was evaporated, and the residue was redesolved in ethyl acetate (100 mL). The mixture was then washed with sodium bicarbonate (saturated in water, 20 mL), water (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 30% ethyl acetate in hexane to give the title compound (121 mg, 34%). HNMR (300 MHz, CDC13) 8 7.62 (d, 1 H), 7.40 (br d, 1 H), 7.31-7.12 (m, 4 H), 7.07 (br d, 1 H), 3.62 (s, 3 H), 3.54 (br s, 2 H), 2.85 (m, 1 H), 2.71 (m, 1 H), 2.40 (m, 2 H), 2.35-2.00 (m, 12 H), 1.80-0.80 (m, 15 H). MS(CI/NH3) m/z: 510 (M+H)+.

Example 1158D

3-[4-(N-Cyclohexyl-N-methylaminomethyl)-2-(2-methylphenyl)be nzoylmethyl]-4- methvlthiobutvric acid The intermediate 1 158C (112 mg) in MeOH (2 ML) and lithium hydroxide (1.0 M in water, 0.7 mL) was heated at 50 C for 5 hours. The reaction mixture was then adjusted to pH 4-5 with KH2PO4 (saturated in water), and extracted with ethyl acetate (3 X 20 mL).

The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (110 mg, 100%). 'H NMR (300 MHz, dmso-d6) 8 7.77 (m, 1 H), 7.61 (br d, 1 H), 7.40 (m, 1 H), 7.35-7.15 (m, 3 H), 7.07 (m, 1 H), 4.15 (br loop, 2 H), 2.88 (m, 2 H), 2.69 (m, 1 H), 2.28 (m, 2 H), 2.22-1.96 (m, 11 H), 1.72-0.80 (m, 15 H). MS(ESI-) m/z: 494 (M-H)-. Example 1159 Example 1159A N-[4-(N-butylaminocarbonylmethyl)-2-(2-methylphenyl)benzoyl] methionine lithium salt The procedures descriped in the Example 403E and 403F were used here to convert intermediate 1 142A (61 mg, 0.18 mmol) to the title methyl ester (70 mg, 83%). IHNMR (300 MHz, CDCl3) 8 7.95 (2 d's, 1 H), 7.39-7.15 (m, 5 H), 7.12 (br s, 1 H), 5.91 (br d, 1 H), 5.35 (m, 1 H), 4.63 (m, 1 H), 3.67 (s, 3 H), 3.61 (s, 2 H), 3.24 (q, 1 H), 2.20-1.99 (m, 8 H), 1.85 (m, 1 H), 1.60 (m, 1 H), 1.42 (m, 2 H), 1.27 (m, 2 H), 0.88 (t, 3 H).

MS(CI/NH3) m/z: 471 (M+H)+.

Example 1159B N-[4-(N-butylaminocarbonylmethyl)-2-(2-methylphenyl)benzoyl] methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1 159A (63 mg) to the title lithium salt (62 mg, 100%). H NMR (300 MHz, dmso-d6) 8 8.10 (t, 1 H), 7.57 (d, 1 H), 7.40 (br d, 1 H), 7.37-7.20 (m, 4 H), 7.17 (br s, 1 H), 7.04 (br d, 1 H), 3.75 (m, 1 H), 3.54 (s, 2 H), 3.13 (q, 2 H), 2.28-1.85 (m, 8 H), 1.78 (m, 1 H), 1.64 (m, 1 H), 1.47 (m, 2 H), 1.35 (m, 2 H), 0.93 (t, 3 H). MS(ESI-) m/z: 455 (M-H) .

Example 1160 N-[4-(N-(2,2,4,4-tetramethylbutylamino)carbonylethyl)-2-(2- methvlphenyl)benzovllmethionine lithium salt The procedures descriped in the Example 1 147C and 1147D were used here to convert 1147B (50 mg) to the title lithium salt (50 mg, 81%, 2 steps). 'HNMR (300 MHz, dmso-d6) 7.44 (d, 1 H), 7.26 (br s, 1 H), 7.25-7.08 (m, 5 H), 6.98 (br s, 1 H), 6.88 (m, 1 H), 3.63 (m, 1 H), 2.82 (t, 2 H), 2.32 (t, 2 H), 2.20-1.90 (m, 8 H), 1.75-1.50 (m, 2 H), 1.67 (s, 2 H), 1.23 (s, 6 H), 0.89 (s, 9 H). MS(ESI-) m/z: 525 (M-H).

Example 1161 Example 1161A Methyl 4-(N,N-Dibutylaminocarbonylethyl)-2-(2-methylphenvl)benzovl The procedure descriped in the Example 1 144C was used here to convert the intermediate 1144B (150 mg, 0.5 mmol) and dibutylamine (129 mg, 1 mmol) to the title methyl ester (203 mg, 99%). H NMR (300 MHz, CDCl3) 6 7.90 (d, 1 H), 7.29-7.16 (m, 4 H), 7.06 (m, 2 H), 3.60 (s, 3 H), 3.30 (dt, 2 H), 3.14 (t, 2 H), 3.05 (t, 2 H), 2.61 (t, 2 H), 2.05 (s, 3 H), 1.46 (m, 2 H), 1.27 (m, 2 H), 0.90 (t, 6 H). MS(CI/NH3) m/z: 410 (M+H)+.

Example 1161B N-[4-(N,N-Dibutylaminopropyl)-2-(2-methylphenyl)benzoyl]meth ionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate 1 161A (195 mg, 0.48 mmol) to the title methyl ester (165 mg, 66%).

H NMR (300 MHz, CDC13) 6 7.90 (2 d'd, 1 H), 7.35-7.19 (m, 5 H), 7.02 (br s, 1 H), 5.88 (br d, 1 H), 4.61 (m, 1 H), 3.65 (s, 3 H), 2.66 (t, 2 H), 2.40 (m, 6 H), 2.20-2.00 (m, 8 H), 1.90-1.70 (m, 3 H), 1.59 (m, 1 H), 1.45-1.20 (m, 8 H), 0.89 (t, 6 H). MS(CI/NH3) m/z: 520 (M+H)+.

Example 1161C N-[4-(N,N-Dibutylaminopropyl)-2-(2-methylphenyl)benzoyl]meth ionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1 161B (156 mg) to the title lithium salt (151 mg, 98%). 'H NMR (300 MHz, dmso-d6) 7.46 (d, 1 H), 7.34-7.08 (m, 5 H), 6.97 (m, 2 H), 3.75 (m, 1 H), 2.63 (t, 2 H), 2.32 (m, 6 H), 2.20-1.80 (m, 9 H), 1.70 (m, 3 H), 1.60 (m, 1 H), 1.38-1.20 (m, 8 H), 0.84 (t, 6 H). MS(ESI-) m/z: 511 (M-H)-.

Example 1164 Example 1 164A N-[4-N-(2-Ethylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compound described inExample 403G and 2-ethylaniline. m/e (ESI) 489 (MH-) Example 11 64B N-[4-N-(2-Ethylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine

The desired compound was prepared according to the method of Example 4031 starting with compound prepared inExample 1 164A.1H (300MHz, CDCl3, o) 7.96 (1H, t, J=9Hz), 7.48 (lH, bd, J=8Hz), 7.20-7.00 (8H, m), 6.77 (1H, t, J=9Hz), 6.57 (1H, bd, J=8Hz), 5.89 (1H, bd, J=8Hz), 4.58 (1H, m), 4.46 (2H, s), 2.55 (2H, q, J=8Hz), 2.20- 2.00 (8H, m), 1.90 (1H, m), 1.57 (1H, m), 1.25 (3H, t, J=8Hz). m/e (ESI) 475 (MH-) Anal.calc. for C28H32N203S0.25 H2O C 69.90, H 6.81, N 5.82 Found C 69.64, H 6.66, N 5.65 Example 1165 Example 1165A N- [4-N-(2-Propylphenyl)aminomethyl-2-(2-methylphenyl)benzoyllm ethionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compound described inExample 403G and 2-propylaniline. m/e (ESI) 503 (MH-) Example 1165B N-[4-N-(2-Propylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl ]methionine

The desired compound was prepared according to the method offixample 4031 starting with compound prepared inExample 1 165A.1H (300MHz, CDCl3, 6) 7.98 (1H, t, J=9Hz), 7.47 (1H, dd, J=8&2Hz), 7.40-7.10 (6H, m), 7.03 (2H, m), 6.72 (1H, t, J=9Hz), 6.57 (1H, m), 5.86 (1H, bd, J=8Hz), 4.58 (1H, m), 4.44 (2H, s), 2.48 (2H, t, J=8Hz), 2.20-2.00 (8H, m), 1.91 (1H, m), 1.65 (2H, q, J=8Hz), 1.57 (lH, m), 1.01 (3H, t, J=8Hz). m/e (ESI) 489 (MH-) Anal.calc. for C2gH34N203S0.25 H2O C 70.34, H 7.02, N 5.66 Found C 70.33, H 6.88, N 5.44 Example 1166 Example 1 166A N-[4-N-(2-Butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compound described in Example 403G and 2-butylaniline. m/e (ESI) 517 (MH-) Example 11 66B N-[4-N-(2-Butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine

The desired compound was prepared according to the method Example 4031 starting with compound prepared inExample 1166A.1H (300MHz, CDC13, o) 7.97 (lH, t, J=9Hz), 7.45 (lH,bd, J=8), 7.40-7.10 (6H, m), 6.98 (2H, d, J=8Hz), 6.73 (1H, t, J=9Hz), 6.57 (1H, m), 5.87 (1H, bd, J=8Hz), 4.58 (1H, m), 4.45 (2H, s), 2.50 (2H, t, J=8Hz), 2.20-2.00 (8H, m), 1.91 (1H, m), 1.70-1.50 (3H, m), 1.40 (2H, q, J=8Hz), 0.93 (3H, t, J=8Hz). m/e (ESI) 503 (MH-) Anal.calc. for C30H36N203S0.50 H2O C 70.14, H 7.26, N 5.45 Found C 70.39, H 7.08, N 5.24 Example 1167 Example 1167A N-[4-N-(4-Butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compound described inExample 403G and 4-butylaniline. m/e (ESI) 517 (MH-) Example 1167B N-[4-N-(4-Butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl] methionine

The desired compound was prepared according to the method of Example 4031 starting with compound prepared inExample 1167A.1H (300MHz, CDCl3, o) 7.98 (1H, t, J=9Hz), 7.47 (1H,bd, J=8), 7.40-7.10 (6H, m), 7.04 (2H, d, J=9Hz), 6.56 (2H, d, J=9Hz), 5.88 (1H, bd, J=8Hz), 4.57 (1H, m), 4.40 (2H, s), 2.48 (2H, t, J=8Hz), 2.20- 2.00 (8H, m), 1.90 (1H, m), 1.53 (3H, m), 1.32 (2H, m), 0.92 (3H, t, J=8Hz). m/e (ESI) 503 (MH-) Anal.calc. for C30H36N2O3S.0.25 H2O C 70.76, H 7.23, N 5.50 Found C 70.77, H 7.07, N 5.35 Example 1168 Example 1 168A 4-N-(2-Butylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid methvl ester The desired compound was prepared using the method described inExample 11 69A starting with 2-butylaniline, 3,5-difluorobenzylbromide, and 4-bromomethyl-2-(2- methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A-D. m/e (ESI) 514 (MH+)

Example 1168B 4-N-(2-Butylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1168A.

Example 1168C N- [4-N-(2-Butalphenvl)-N-(35-difluorobenzvl)aminomethvl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1168B. m/e (ESI) 645 (MH+) Example 1168D N-[4-N-(2-Butylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-( 2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1168C.1H (300MHz, CDC13, o) 7.92 (1H, m), 7.40-6.90 (10H, m), 6.81 (2H, bd, J=8Hz), 6.66 (1H, m), 5.84 (1H, m), 4.55 (1H, m), 4.12 (2H, s), 4.04 (2H, s), 2.72 (2H, bt, J=9Hz), 2.20-1.80 (9H, m), 1.52 (3H, m), 1.36

(2H. m), 0.87 (3H, t, J=8Hz). m/e (ESI) 629 (MH-) Anal.calc. for C37H40F2N203S C 70.45, H 6.39, N 4.40 Found C 70.10, H 6.27, N 4.35 Example 1169 Example 1169A <BR> <BR> 4-N-(2.6-Diethylphenyl)-N- (3 .5-difluorobenzyl)aminomethyl-2- (2-methylphenvl)benzoic acid methyl ester 4-Bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (100 mg, 0.31 mmol), prepared as inExample 1178A-D, 2,6-diethylaniline (0.062 mL, 0.38 mmol), and diisopropylethylamine (0.084 mL, 0.470 mmol) were dissolved in DMF (5 mL), and solution stirred overnight at room temperature. To this mixture was then added diisopropylethylamine (0.084 mL, 0.470 mmol) and ot-bromo-3,5-difluorotoluene (0.100 mL, 0.760 mmol), and reaction heated at 800C for 3 days. Solvents concentrated in vacuo, and residue purified by flash chromatography on silica gel eluting with 2% EtOAc/Hexanes to afford the desired compound as a yellow oil (72 mg, 45%). m/e (ESI) 514 (MH+)

Example 1169B 4-N-(2,6-Diethylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2- (2-methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1169A.

Example 1169C N-[4-N-(2,6-Diethylphenyl)-N-(3,5-difluorobenzyl)aminomethyl -2-(2- methvlphenvl!benzovllmethionine methvl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1169B. m/e (ESI) 645 (MH+) Example 1169D N-[4-N-(2,6-Diethylphenyl)-N-(3,5-difluorobenzyl)aminomethyl -2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method offixample 4031 starting with the compound fromExample 11 69C.1 H (300MHz, DMSO, o) 7.43 (1 H, d, J=9Hz), 7.30-7.00 (9H, m), 6.85 (4H, m), 4.21 (2H, s), 4.18 (2H, s), 3.65 (1H, m), 2.60-2.40 (4H, m), 2.10-1.50 (10H, m), 1.03 (6H, t, J=8Hz). m/e (ESI) 629 (MH-) Anal.calc. for C37H3gF2LiN203S 1.50 H2O C 66.95, H 6.38, N 4.22 Found C 66.79, H 6.34, N 3.93

Example 1170 Example 1170A N-[4-N-(2-Butylphenyl)-N-(cyclohexylmethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compound described in Example 1166A and cyclohexanecarboxaldehyde. m/e (ESI) 613 (MH-) Example 1170B N-[4-N-(2-Butylphenyl)-N-(cyclohexylmethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method Example 4031 starting with compound prepared inExample 1170A.1H (300MHz, DMSO, o) 7.47 (1H, d, J=9Hz), 7.29 (1H, m), 7.25-6.95 (9H, m), 6.90 (1H, m), 3.97 (2H, s), 3.16 (1H, m), 2.70 (4H, m), 2.10-1.85 (7H, m), 1.70 (3H, m), 1.60-1.40 (6H, m), 1.40-1.15 (4H, m), 1.05 (3H, m), 0.79 (SH, t, J=8Hz). m/e (ESI) 599 (MH-) Anal.calc. for C37H47LiN203S 1.00 H2O C 71.13, H 7.90, N 4.48 Found C 71.01, H 7.93, N 4.14

Example 1171 Example 1171A N-(2-Cve lohexvlethvl)-N-(3 -methvlphenvl)amine To a stirred solution at ambient temperature of cyclohexylacetic acid (500 mg, 3.52 mmol) and 3-methylaniline (0.45 mL, 4.22 mmol) in DMF (10 mL) was added l-ethyl-3- (3-dimethylaminopropyl)carbodiimide (809 mg, 4.22 mmol). Reaction stirred overnight at ambient tenperature. Reaction diluted with EtOAc and washed with water, 1 .OM NaHCO3 (2x), 1N H3PO4 (2x), and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. To a solution at ambient temperature under N2 of this residue in anhydrous THF (3 mL) was added a 1 .OM lithium aluminum hydride solution (7.00 mL, 7 mmol) in THF. Reaction refluxed overnight. Reaction cooled to OOC and quenched with successive addition of water (0.27 mL), 15% aqueous NaOH (0.27 mL), and water (0.80 mL). Mixture stirred 30 minutes at ambient temperature, and solids filtered off through celite and washed with EtOAc. Filtrate dried with Na2SO4, filtered, and concentrated in vacuo to produce a colorless oil. m/e (DCI/NH3) 218 (MH+) Example 1171B

N-[4-N-(2-Cyclohexylethyl)-N-(3-methylphenyl)aminomethyl-2-( 2- methylphenyl)benzoyll methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compounds described inExample 403G andExample 1171A. m/e (ESI) 585 (MH-) Example 1171C N-[4-N-(2-Cyclohexylethyl)-N-(3-methylphenyl)aminomethyl-2-( 2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method Example 4031 starting with compound prepared inExample 1171B. 1H (300MHz, CDCl3, o) 7.92 (lH, t, J=9Hz), 7.40-7.00 (8H, m), 6.47 (2H, m), 5.86 (1H, d, J=8Hz), 4.51 (4H, m), 3.39 (2H, m), 2.25 (3H, s), 2.15-1.80 (8H, m), 1.70 (SH, m), 1.50 (3H, m), 1.40-1.05 (4H, m), 0.96 (2H, m). m/e (ESI) 571 (MH-) Anal.calc. for C3sH44N203S- 1.00 H2O C 71.15, H 7.85, N 4.74 Found C 70.91, H 7.89, N 4.46 Example 1172 Example 1172A N-(2-Butylphenyl)-N-(2-cyclohexylethyl)amine

The desired amine was prepared using the method described inExample 1171 A starting with cyclohexylacetic acid and 2-butylaniline. m/e (DCI/NH3) 260 (MH+) Example 1172B N-[4-N-(2-Butylphenyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2 - methylphenyl)benzoyl]methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compounds described inExample 403G andExample 1172A. m/e (ESI) 627 (MH-) Example 1172C N-[4-N-(2-Butylphenyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2 - methylphenyl)benzoyl]methionine The desired compound was prepared according to the method Example 4031 starting with compound prepared inExample 1 172B. 1H (300MHz, CDCl3, 6) 7.94 (1H, t, J=9Hz), 7.41 (lH, bd, J=8HZ), 7.40-7.00 (9H, m), 5.85 (1H, dd, J=8&2Hz), 4.55 (1H, m), 4.07 (2H, s), 2.91 (2H, m), 2.68 (2H, m), 2.20-1.80 (9H, m), 1.70-1.40 (8H, m), 1.40-1.00 (8H, m), 0.86 (3H, t, J=8Hz), 0.79 (2H, m). m/e (ESI) 613 (MH-) Anal.calc. for C38HSON203S 0.25 H2O C 73.69, H 8.22, N 4.52 Found C 73.74, H 8.17, N 4.30

Example 1173 Example 1173A N-(2-Butylphenyl)-N-(2-(3,5-difluoro)phenylethyl)amine The desired amine was prepared using the method described inExample 1171A starting with 3,5-difluorophenylacetic acid and butylamine. m/e (DCI/NH3) 214 (MH+) Example 1173B N-[4-N-Butyl-N-(2-(3,5-difluoro)phenylethyl)aminomethyl-2-(2 - methylphenyl)benzoyl]methionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compounds described inExample 403G andExample 1173A. m/e (ESI) 581 (MH-)

Example 1173C N-[4-N-Butyl-N-(2-(3,5-difluoro)phenylethyl)aminomethyl-2-(2 - methylphenyl)benzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1 173B. 1H (300MHz, CDC13, 6) 7.80 (1H, d, J=9Hz), 7.54 (1H, m), 7.40-7.00 (5H, m), 6.80-6.60 (3H, m), 6.17 (lH, m), 4.43 (lH, m), 4.00 (2H, m), 2.98 (4H, m), 2.81 (2H, m), 2.20-1.80 (9H, m), 2.60 (3H, m), 1.30 (2H, m), 0.92 (3H, t, J=8Hz). m/e (ESI) 567 (MH-) Anal.calc. for C32H38F2N2O3S.- 0.50 H2O C 66.53, H 6.80, N 4.85 Found C 66.67, H 6.67, N 4.69 Example 1174 Example 1 174A N-(Butanesulfonyl)-N-(2-phenylethyl)amine To a stirred solution at ambient temperature of phenethylamine (200 mg, 1.65 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.35 mL, 2.48 mmol) and butanesulfonyl chloride (0.24 mL, 1.82 mmol). After 4 hours of stirring at ambient temperature, the reaction was diluted with EtOAc and washed with water, 1 .OM NaHCO3, and brine.

Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.

Example 1174B 4-(N-ButanesulfonVl-N-(2-phenvlethvl)aminomethvl)-2-(2-methv lphenVl)benzoic acid methyl ester To a stirred mixture in anhyrous DMF ( l mL) at room temperature under N2 of 60inc sodium hydride suspension in mineral oil (30 mg, 0.752) was added N-(butanesulfonyl)-N- (2-phenylethyl)amine (181 mg, 0.752 mmol), prepared as inExample 1174A. Reaction stirred 20 minutes, and then, a solution of 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (200 mg, 0.627 mmol), prepared as inExample 1178A-D, in anhydrous DMF (5 mL) was added. Reaction stirred overnight at room temperature. Reaction quenched with 1N H3PO4 and diluted with EtOAc. Organic layer separated, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel (15% EtOAc/Hexanes) to afford the desired product as a pale yellow oil (293 mg, 98%). m/e (ESI) 480 (MH+) Example 1 174C 4-(N-Butanesulfonyl-N-(2-phenylethyl)aminomethyl)-2-(2-methy lphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1174B.

Example 1174D N-r4-N-Butanesulfonyl-N-(2-phenvlethvl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1174C. m/e (ESI) 480 (MH-) Example 1174E N-[4-N-Butanesulfonyl-N-(2-phenylethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method Example 4031 starting with compound prepared inExample 1 174D. 1H (300MHz, DMSO-d6, o) 7.62 (1H, d, J=7Hz), 7.52 (1H, dd, J=7&2Hz), 7.20-7.10 (10H, m), 7.14 (lH, bd, J=7Hz), 4.65 (2H, bs), 3.76 (1H, m), 3.00 (2H, m), 2.78 (2H, m), 2.25-2.00 (5H, m), 1.99 (3H, s), 1.90-1.70 (4H, m), 1.62 (2H, m), 1.37 (2H, m), 0.92 (3H, t, J=8Hz). m/e (ESI) 595 (MH-) Anal.calc. for C32H39LiN2O5S2.0.50 H2O C 62.83, H 6.59, N 4.38 Found C 62.59, H 6.59, N 4.44

Example 1175 N-[4-N-Benzyloxy-N-butylaminomethyl-2-(2-methylphenyl)benzoy l]methionine lithium salt Example 1175A N-t-Butoxycarbonyl-O-benzylhydroxylamine To a stirred solution at 0°C of O-benzylhydroxylamine hydrochloride in THF was added diisopropylethylamine (2.5 equiv.) and di-t-butyldicarbonate (1.2 equiv.). Reaction stirred one hour at 0°C and overnight at ambient temperature. Reaction concentrated in vacuo. Residue taken up in EtOAc and washed with water, 1.OM NaHCO3, lN H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated.

Example 1 175B N-t-Butoxycarbonyl-N-butyl-O-benzylhydroxylamine To a stirred solution at 0°C of N--t-Butoxycarbonyl-O-benzylhydroxylamine, prepared as in Example 1175A, in anhydrous THF was added portionwise a 60% dispersion of sodium hydride (1.2 equiv.) in mineral oil. Mixture stirred 30 minutes ar 0°C, and then, l-iodobutane (1.2 equiv.) was added dropwise. Reaction stirred one hour at 0°C, and than, overnight at room temperature. Reaction concentrated in vacua. Residue taken up in EtOAc and washed with water, 1.OM NaHCO3, 1N H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated.

Example 1175C N-Butyl-O-benzelhvdroxylamine hvdrochloride salt The desired compound was prepared using the method described in Example 403D starting with the compound prepared in Example 1175B.

Example 1175D N-[4-N-Benzyloxy-N-butylaminomethyl-2-(2-methylphenyl)benzoy l]methionine methyl ester The desired ester was prepared using the method described in Example 403H starting with the compound prepared in Example 1 175C and N-[4-Formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G. m/e (ESI) 547 (MH-) Example 1175E N-[4-N-Benzyloxy-N-butylaminomethyl-2-(2-methylphenyl)benzoy l]methionine lithium salt The desired compound was prepared according to the method of Example 4031 starting with the compound in Example 1175D. 1H (300MHz, DMSO-d6, b) 7.52 (1H, d, J=9Hz), 7.40 (1H, dd, J=7&2Hz), 7.30-7.10 (10H, m), 6.96 (1H, bd, J=7Hz), 4.46 (2H, bs), 3.87 (2H, bs), 3.71 (1H, m), 2.68 (2H, t, J=8Hz), 2.25-1.95 (SH, m), 1.93 (3H, s), 1.90-l.60-(2H, m), 1.50 (2H, m), 1.30 (2H, m), 0.83 (3H, t, J=8Hz). m/e (ESI) 533 (MH-) Anal.calc. for C31H37LiN204S 0.75 H2O C 67.19, H 7.00, N 5.05 Found C 67.19, H 6.91, N 4.96

Example 1177 Example 1177 N-[4-N-(2-Cyclohexylethyl)-N-methylaminomethyl-2-(2-methylph enyl)benzoyl]3- aminotetrahydrofuran-2-one The desired compound was prepared using the method of Example 403F starting with 4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphe nyl)benzoic acid, prepared as in Example 608C, and ot-amino-y-butyrolactone hydrobromide.

1H (300MHz, CDCl3, 6) (rotamer) 7.91 (1H, t, J=9Hz), 7.41 (1H, bd, J=8HZ), 7.35- 7.20 (4H, m), 7.19 (1H, d, J=2Hz), 5.72 (1H, m), 4.49 (1H, m), 4.33 (1H, bt, J=8Hz), 4.17 (1H, m), 3.53 (2H, s), 2.62 (1H, m), 2.39 (2H, t, J=8Hz), 2.20 (3H, s), 2.15 (2.07) (3H, s), 1.80-1.50 (7H, m), 1.38 (2H, m), 1.30-1.10 (3H, m), 0.89 (2H, m). m/e (ESI) 447 (MH-) Anal.calc. for C28H36N2O3.1.00 H2O C 72.07, H 8.21, N 6.00 Found C 72.12, H 8.03, N 5.76 Example 1178

N-[4-(N-(-2-cyclohexylethyl)-N-butylaminomethyl)-2-(2-methyl phenyl)benzoyl]methionine, Lithium Salt Example 1178A Dimethyl-(2-methylphenyl)terephthalate A mixture of dimethyliodoterephthalate (278 g, 0.87 mol), 2-methylphenylboronic acid (141 g, 1.04 mol) palladium (II) acetate (1.95 g, 0.0087 mol) and triphenylphosphine (9.1 g, 0.035 mol) in 2.2 L of toluene and 2.2 L of 2M sodium carbonate was degassed with nitrogen and heated to 800C for 1.5 hours and cooled to ambient temperature. The layers were separated and the organic layer filtered through a plug of silica gel (600g) prewetted with methyl t-butylether (MTBE, 1.2 L). The frit was washed with 5 L of MTBE. The mixture was then concentrated to provide 237 g (96%) of the title compound. 1H NMR (CDCl3) 6 8.09, dd, 1H; 8.02, d, 1H; 7.95, d, 1H; 7.20 - 7.34, m, 3H; 7.10, bd, 1H; 3.96, s, 3H; 3.64, s, 3H; 2.08, s, 3H. MS (DCI/NH3) 302 (M + NH4)+.

Example 1178B 2-(2-methvlphenvl)-4-carboxvbenzoic acid. methyl ester A solution of example 1178A (194 g, 0.68 mol) in 2:1 THF/methanol (-0.3M) was cooled to 0°C and lithium hydroxide (0.38 L of a 2.2 M aqueous solution, 0.82 mol) was added such that the reaction temperature remained below 10°C. The cooling bath was removed and the mixture allowed to warm to 1 10C overnight and then warmed to - 20°C over 4 hours. The mixture was concentrated to a volume of - 1.2 L and then diluted to 5.6 L with water. The mixture was extracted with hexanes and the aqueous layer filtered through celite (-200 g) and the celite pad washed with water. The mixture was diluted with ethyl acetate (6 L) and the pH of the aqueous phase adjusted to 5.5 by the addition of 3M aqueous HCl ( 250 mL). The organic phase was removed and concentrated to provide 171 g (93%) of the

title compound. The material was - 87% pure. An analytical sample was obtained by recrystallization from aqueous ethanol. 1H NMR (CDC13) 88.14, dd, 1H; 8.03, d, lH; 8.01, d, 1H; 7.28 - 7.42, m, 3H; 7.09, bd, 1H; 3.64, s, 3H; 2.08, s, 3H. MS (DCI/NH3): 271 (MH)+; 288 (M + NH4)+.

Example 1 178C 4-hvdroxvmethvl-2-(2-methvlphenvl)benzoic, methvl ester A solution of example 1 178B (4.67g, 17.3 mmol) in 35 mL of THF was cooled in an ice bath and treated with borane (0.88M in THF, 39 mL, 34.6 mmol) such that the internal temperature remained below 10°C. The cooling bath was removed and the solution stirred for 3 hours and then cooled in an ice bath. The reaction was quenched by the careful addition of 8 mL of water (vigorous evolution of hydrogen gas) keeping the temperature below 10°C. An additional 8 mL of water was added and the mixture partitioned between ethyl acetate and 2N sodium hydroxide. The layers were separated and the organic layer was extracted with water, dried, filtered and concentrated. The residue was purified by column chromatography on silica gel to provide 3.90 g (88%) of the title compound. 1H NMR (CDCl3) 8 7.98, d, 1H; 743, dd, 1H; 7.16 - 7.28, m, 4H; 7.07, bd, lH; 4.77, s, 2H; 3.62, s, 3H; 2.05, s, 3H; 1.78, bs, lH. MS (DCI/NH3): 257 (MH)+; 274 (M + NH4)+.

Example 1178D 4-bromomethyl-2-(2-methylphenyl)benzoic, methyl ester A solution of 36 g (140 mmol) of example 1178C and 13.4 g (154 mmol) lithium bromide in DMF (150 mL) was chilled in an ice-water bath, then 40.3 g (14.0 mL, 149 mmol) phosphorous tribromide was added, followed by more DMF (50 mL). After 15 minutes the reaction was partitioned between water (1200 mL) and Et2O (600 mL). The aqueous layer was extracted with Et2O (2 x 150 mL), then the combined Et2O layers were

washed with brine, and dried over Na2SO4. After filtration and concentration, recovered 44.5 g (97.5%) slightly cloudy, almost colorless oil that was 2% DMF by weight (determined by NMR). 1H NMR (CDC13) 6 7.84 (d, 1H), 7.44 (dd, 1H), 7.24 (m, 4H), 7.07 (br d, 1H), 4.50 (s, 2H), 3.62 (s, 3H), 2.07 (s, 3H). MS (DCI/NH3) 336/338 (M+H+NH3)+.

Example 1178E N-butvl-N-2-cvclohexvlacetamide 2-Cyclohexylacetic acid (42.66 g, 0.30 mol) was dissolved in 85 mL of thionyl chloride and the mixture heated to reflux for 2 hours. After cooling to room temperature, the yellow solution was concentrated. Toluene was added and the solution was concentrated again and the acid chloride used directly. The acid chloride was diluted with 100 mL of methylene chloride and this solution added to a biphasic mixture of butylamine (60 mL, 0.60 mol) in 100 mL of methylene chloride and 2M aqueous potassium carbonate (150 mL) and the mixture was stirred overnight at ambient temperature. An additional 30 mL of butylamine was added and stirring continued for 2 hours and then the mixture was poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with 1 portion of methylene chloride and the combined organic extracts were dried, filtered and concentrated to an off white solid. This material was suspended in 400 mL of 1:1 ether/hexanes and filtered. The solid was washed with 2 additional portions of 1:1 ether/hexanes. The filtrates were extracted with 3 portions of aqueous HCl, dried, filtered and concentrated to a volume of - 200 mL. The solid that formed was collecterd by filtration and combined with the previous solid material and dried under vacuum to give the title compound (49.50 g, 88%). H nmr (300 MHz., CDCl3): 8 5.35, bs, 1H; 3.24, q, 2H; 2.02, d, 2H; 1.70, bm, 6H; 1.47, m, 2H; envelope 1.06 - 1.42, 5H; 0.91, m, 5H. MS (DCI-NH3): 198 (MH+); 215 (M+NH4+).

Example 1178F N-butvl-N-2-cvclohexvlethvlamine A stirred suspension of lithium aluminum hydride (23.74 g, 0.63 mol) in THF (400 mL) was cooled in an ice bath and treated with a solution of example 1 178E (49.50 g, 0.26 mol) in THF (300 mL). The ice bath was removed and the mixture heated to gentle reflux for 20 hours. The solution was cooled in an ice bath and quenched by the careful addition of 24 mL of water in 100 mL of THF, followed by 24 mL of 15% aqueous sodium hydroxide, followed by an additional 72 mL of water. The thick slurry was vigorously stirred for 15 minutes at which time 600 mL of methylene chloride and excess sodium sulfate were sequentially added. The mixture was stirred for 1 hour and then filtered through celite. The celite pad was washed well with methylene chloride and the filtrate concentrated to give the title compound (47.80 g, 100%) which was sufficiently pure for the next step. H nmr (300 MHz., CDCl3): 82.61, m, 4H; 1.69, m, 5H; envelope 1.05 - 1.53, l lH; 0.91, m, 5H.

MS (DCI-NH3): 184 (MH+).

Example 1178G 4-(N-(-2-cyclohexylethvl-N-butvlaaminomethy1)-2-(2-methylphe nyl)benzoic acid, methyl ester A solution of example 1178D (22.2 g, 0.070mol) and diisopropylethylamine (15.7 mL, 0.090 mol) in 100 mL of acetonitrile was treated with N-butyl-N-2- cyclohexylethylamine (15.3 g, 0.084 mol). The cloudy mixture was stirred for two hours and then briefly warmed to 450C. After cooling to ambient temperature, the mixture was concentrated to remove the acetonitrile and then diluted with 400 mL of water. The pH of the mixture was brought to >10 with solid potassium phosphate and extracted with 3 portions of ethyl ether. The combined ether extracts were extracted with 1 portion of water and two portions of brine, dried, filtered and concentrated. The residue obtained (34.4 g, 117%) was used directly. An analytical sample was obtained by column chromatography on silica gel (3% ethyl acetate/hexanes) to provide pure material. 1H nmr (300 MHz., CDCl3): 8 7.92, d, 1H; 7.48, dd, 1H; 7.16 - 7.28, m, 4H; 7.07, bd, 1H; 3.62, s, 3H; 3.57, s, 2H; 2.41,

quartet, 4H; 2.06, s, 3H; 1.62, bm, 5H; envelope 1.05 - 1.48, 10H; 0.85, bm, 5H. MS (ESI+): 422 (MH+): (ESI-): 420 (M-H).

Example 1 178H N-l4-(N-(-2-cVclohexvlethvl!-N-butvlaminomethvl)-2-(2-methvl phenvl)benzoic acid A solution of 1 178G (34.35 g, 0.081 mol) in 210 mL of ethanol was treated with aqueous sodium hydroxide (4N, 70 mL, 0.28 mol) and the mixture heated to reflux until judged complete by tIc analysis. After cooling to room temperature, the mixture was concentrated to remove the ethanol. The resulting solid was partially dissolved by adding water and the mixture extracted with ethyl ether. The ether layer was then washed with water and then with 1M aqueous phosphoric acid which resulted in an oily precipitate. The precipitate was dissolved by extracting with 3 portions of ethyl acetate and the combined ethyl acetate layer were washed with water, 0.5M aqueous phosphoric acid, brine and then dried, filtered and concentrated to give 24.5 g, (86% yield for the two steps) as a cream colored solid. H nmr (300 MHz., CD30D): 8 7.96, d, 1H; 7.64, dd, 1H; 7.37, d, lH; 7.22, m, 2H; 7.18, m, 1H; 7.07, d, 1H; 4.41, bs, 2H; 3.12, m, 4H; 2.10, s, 3H; 1.18, bm, 9H; 1.37, sextet, 2H; 1.23, m, 3H; 0.96, t, 3H; 0.94, m, 2H. MS (ESI+): 408 (MH+): (ESI-): 406 (M-H).

Example 1178I N-[4-(N-Butyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylp henyl)benzoyl]methionine methyl ester Partitioned 13.2 g (66.1 mmol) L-methionine methyl ester, hydrochloride salt between saturated aqueous NaHCO3 (80 mL) and CH2Cl2 (75 mL). Added the organic

layer to the following solution: 24.5 g (60.2 mmol) acid from Example 1 178H, 10.0 g (65.3 mmol) HOBT-H2o, and 12.6 g (65.7 mmol) EDCI*HCl in DMF (150 mL). After stirring at RT overnight partitioned the reaction between saturated aqueous NaHCO3 (500 mL) and EtOAc (1200 mL). The organic layer was washed with water and brine, then dried over Na2SO4. After filtration and concentration, recovered 30 g orange oil that was purified by chromatography using hex/EtOAc 3/1. Recovered 22.9 g (69%) of the title compound. 1H NMR (CDCl3) 8 7.90 (m, lH), 7.40 (d, 1H), 7.30, 7.20, 7.16 (all m, total 5H), 5.88 (br d, lH), 4.62 (m, lH), 3.66 (s, 3H), 3.57 (s, 2H), 2.41 (m, 4H), 2.18, 2.13, 2.04 (s, m, m, total 9H), 1.85 (m, 1H), 1.62 (m, 5H), 1.50-1.10 (envelope, 10H), 0.87 (m, 5H). MS (APCI) 553 (M+H)+.

Example 1178J N-[4-(N-(-2-cyclohexylethyl-N-butylaminomethyl)-2-(2-methylp henyl)benzoyl]methionine, Lithium Salt A solution of example 11781(22.9 g, 0.041 mol), in 200 mL of 3:1 THF methanol was cooled in an ice bath and then tretaed with aqueous lithium hydroxide (1M, 83 mL, 0.083 mol) dropwise. The ice bath was removed and the mixture was stirred for 20 hours.

The solution was concentrated to remove the organics and the resulting thick slurry diluted with water until a clear solution resulted (1.2 L). The pH of the solution was carefully adjusted to pH-5 with 1M aqueous phosphoric acid and stirred for 1 hour. The solid was collected by filtration and dried under vacuum over phosphorous pentoxide to provide 19.93 g of a cream colored solid. This material was dissolved in 200 mL of THF and treated with a solution of 1.55 g (0.037 mol) of lithium hydroxide in 75 mL of water. The mixture was stirred for 15 minutes and the THF removed under vacuum on a rotary evaporator. The mixture was diluted with 500 mL of water and lyophilized to give 20.10 g (89% overall) of the title compound. H nmr (300 MHz., CD30D): 8 7.64, m, 1H; 7.41, d, 1H; 7.05 - 7.32, m, SH; 4.25, m, 1H; 3.69, s, 2H; 2.52, m, 4H; 2.51, s, 1.5H (1/2 o-tolyl); 2.06, s, 1.5 H (1/2 o-tolyl); 1.98, s, 3H; 1.97, m, 1H; 1.73, m, 2H; 1.64, bm, 6H; envelope 1.04 - 1.56, 10H; 0.90, m, 5H. MS (ESI+): 539 (MH+): (ESI-): 537 (M-H). Calc'd for C32H45N203SLiv0.60 H2O; C 69.19; H 8.38; N 5.04; Found: C 69.25; H 8.50; N 4.99.

Example 1179 Example 1179 N-[4-N-Butyl-N-(2-cyclohexylethyl)aminomethyl-2-(2-methylphe nyl)benzoyl]methionine 4-methylphenylsulfonimide N- [4-(N-Butyl-N-(2-Cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine (500 mg, 0.929 mmol), prepared as inExample 1178, p- toluenesulfonamide (429 mg, 2.51 mmol), 4-dimethylaminopyridine (57 mg, 0.465 mmol), and 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (214 mg, 1.12 mmol) were dissolved in CH2C12 (10 mL) at room temperature and stirred overnight. Reaction diluted with water and CHCl3 and layers separated. Aqueous layer extracted with CHCl3 (2x), and combined extracts dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 300:1 EtOAc/25: 1:1 EtOAc, H2O, AcOH to afford the desired compound as a white solid (284 mg, 44%).1H (300MHz, MeOD, 6) (rotamer) 7.73 (2H, d, J=9Hz), 7.62 (1H, d, J=8Hz), 7.48 (1H, bd, J=8Hz), 7.30-7.00 (7H, m), 4.22 (1H, m), 4.02 (2H, bs), 2.81 (4H, m), 2.39 (3H, s), 2.21(2.03) (3H, bs), 1.90 (3H, s), 1.85-1.40 (13H, m), 1.40-1.10 (6H, m), 0.93 (SH, t, J=8Hz). m/e (ESI) 690 (MH-) Anal.calc. for C3gH53N304S21.25 H2O C 65.56, H 7.83, N 5.88 Found C 65.41, H 7.52, N 5.61

Example 1180 Example 11 80A N-Butyl-N-( 1 -phenyltetrazol-5-vl)amine 5-Chloro-l-phenyl-lH-tetrazole (1.00 g, 5.54 mmol), butylamine (0.547 mL, 5.54 mmol), and diisopropylethylamine (1.48 mL, 8.31 mmol) were dissolved in DMF (5 mL), and stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 35% EtOAc/Hexanes to afford the desired product as a white solid (625 mg, 52%). m/e (DCI) 218 (MH+) Example 1180B 4-N-Butyl-N-(1-phenyltetrazol-5-yl)aminomethyl-2-(2-methylph enyl)benzoic acid methyl ester

The desired compound was prepared according to the method of Example 11 74B starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester. prepared as in Example 1178A-D, and the compound from Example 1180A.

Example 1180C 4-N-Butyl-N-(1-phenyltetrazol-5-yl)aminomethyl-2-(2-methylph enyl)benzoic acid The desired acid was prepared using the method described inExample 403E starting with the product fromExample 1180B. m/e (ESI) 440 (MH-) Example 1180D N- 14-N-Butvl-N-( 1 -phenyltetrazol-5-yl)aminomethyl-2-(2- methylphenyl)benzovllmethionine methvl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1180C. m/e (ESI) 587 (MH+)

Example 1180E N- [4-N-Butyl-N-( 1 -phenyltetrazol-5-vl)aminomethvl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1180D. 1H (300MHz, CDCl3, 6) 7.93 (1H, m), 7.60-7.40 (5H, m), 7.40-7.10 (5H, m), 7.03 (1H, d, J=2Hz), 5.89 (1H, m), 4.55 (lH, m), 4.52 (2H, s), 3.11 (2H, bt, J=8Hz), 2.20-2.00 (8H, m), 1.90 (1H, m), 1.56 (1H, m), 1.43 (2H, m), 1.06 (2H, m), 0.74 (3H, t, J=8Hz). m/e (ESI) 571 (MH+) Anal.calc. for C31H36N6°3S C 65.01, H 6.34, N 14.67 Found C 64.77, H 6.33, N 14.70 Example 1181 Example 1181A N-t-Butyl-N-(2-cyclohexylethyl)amine The desired amine was prepared using the method described inExample 1171A starting with cyclohexylacetic acid and t-butylamine. m/e (DCI/NH3) 184 (MH+)

Example 1181B 4-(N-t-Butvl-N-(2-cyclohexylethyl)aminomethl)-2-(2-methvIphe nvI)benzoic acid methyl ester The desired compound was prepared using the method described inExample 1 178G starting with N-t-butyl-N-(2-cyclohexylethyl)amine, prepared as inExample 1181A, and 4- bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A- D. m/e (ESI) 422 (MH+) Example 1181C 4-(N-t-Butyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylph enyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 1181B.

Example 1181D N-[4-N-t-Butyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methyl phenyl)benzoyl]methionine methvl ester The desired product was prepared using the method described inExample 403F starting with the compound prepared inExample 1181C. m/e (ESI) 553 (MH+)

Example 1181E <BR> <BR> N-14-N-t-Butal-N-(2-cyclohexylethyl)aminomethvl-2-(2-methvlp henyl)benzovllmethionine The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1 181D. 1H (300MHz, CDC13, o) 7.78 (1H, m), 7.67 (1H, m), 7.40-7.00 (SH, m), 6.21 (1H, m), 4.38 (1H, m), 4.13 (2H, m), 2.93 (2H, m), 2.20-2.00 (7H, m), 2.00 (3H, s), 1.60 (4H, m), 1.43 (12H, bs), 1.40-0.90 (4H, m), 0.75 (2H, m). m/e (ESI) 537 (MH+) Anal.calc. for C32H46N203S 0.75 H2O C 69.59, H 8.67, N 5.07 Found C 69.78, H 8.65, N 4.89 Example 1182 Example 1182A (2S)-t-Butoxycarbonylaminopentan-1-ol The desired product was prepared using the methods described in Example 1183A starting with L-norvaline.

Example 1 182B (2S)-t-Butoxycarbonvlamino- 1 -ethylthiopentane The desired product was prepared using the methods described in Example 403B and 403C starting with the compound prepared in Example 1182A.

Example 11 82C (2R)-Aminopentane hydrochloride salt The desired product was prepared using the methods described in Example 1183C starting with the compound prepared in Example 1182B.

Example 1182D N-(2-Cyclohexylethyl)-N-(pent-2-yl)amine The desired amine was prepared using the method described inExample 1171A, except triethylamine was added, starting with cyclohexylacetic acid and the compound fromExample 1182C. m/e (DCI) 198 (MH+) Example 1182E N- [4-N-(2-Cyclohexylethyl)-N-(pent-2-vl)aminomethyl-2-(2- methylphenyl)benzoyllmethionine methyl ester The desired product was prepared using the method described inExample 403H starting with the compound prepared inExample 1182D and N-[4-formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G. m/e (ESI) 567 (MH+)

Example 1182F <BR> <BR> <BR> N-14-N-(2-Cvclohexylethyl)-N-(pent-2-vl)aminomethvl-2-(2- <BR> <BR> <BR> <BR> <BR> methylphenvl)benzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound prepared inExample 1 182E. 1H (300MHz, CDC13, o) 7.74 (1H, m), 7.62 (1H, m), 7.40-7.00 (5H, m), 6.46 (1H, m), 4.37 (1H, m), 3.94 (2H, m), 3.37 (1H, m), 2.90 (2H, m), 2.20-1.80 (8H, m), 1.80-1.60 (6H, m), 1.55-1.25 (6H, m), 1.25-1.00 (8H, m), 0.91 (3H, t, J=8Hz), 0.82 (2H, m). m/e (ESI) 551 (MH-) Anal.calc. for C33H4gN203S 0.50 H2O C 70.55, H 8.79, N 4.99 Found C 70.55, H 8.71, N 4.87 Example 1183 Example 1183A (2R)-t-Butoxycarbonylaminopentan-1-ol To a stirred solution at ambient temperature of D-norvaline (5.00 g, 42.7 mmol) in THF (100 mL) was added an aqueous 4N NaOH solution (21 mL, 84 mmol), di-t-butyl dicarbonate (11.2 g, 51.2 mmol), and tetrabutylammonium bromide (1.0 g). Two-phase solution stirred overnight at ambient temperature. Reaction neutralized with aqueous 3N HCl to pH 6 and extracted with CHC13 (3x). Extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a colorless oil. To a stirred solution at 0°C under N2 of the

crude residue in anhydrous THF (80 mL) was added dropwise via addition funnel a 1 .OM borane-THF complex (100 mL, 100 mmol) in THF. After stirring overnight at ambient temperature, reaction cooled back to 0°C and quenched with an aqueous 4N NaOH solution (50 mL). Mixture stirred one hour at ambient temperature, and then, extracted with CH2Cl2 (3x). Extracts dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 30% EtOAc/Hexanes to afford the alcohol as a pale yellow oil (3.87 g, 45%). m/e (DCI) 204 (MH+) Example 11 83B (2R)-t-Butoxvcarbonvlamino- 1 -ethylthiopentane The desired product was prepared using the methods described inExample 403B and 403C starting with the compound prepared inExample 1183A. m/e (DCI) 248 (MH+) Example 1183C (2S)-Aminopentane hvdrochloride salt To a stirred solution at ambient temperature of f2R)-t-butoxycarbonylamino- l - ethylthiopentane (655 mg, 2.65 mmol), prepared as in Example 1183B, in EtOH (5 mL) was added a 50% slurry of Raney Nickel (2.65 g) in water. Mixture stirred vigorously at 80"C for 2 days. Reaction filtered through celite, and celite and catalyst washed with EtOAc.

Filtrate concentrated in vacuo to produce a colorless liquid. Residue taken up in a solution of 4N HCl in dioxane (5 mL), and reaction stirred overnight at ambient temperature. Ether added until a solid precipitated. Solid filtered off, washed with ether, and dried to produce the desired compound as a white solid (167 mg, 59%).

Example 1183D <BR> <BR> N-(2-Cvclohexvlethvl)-N-(pent-2-vl)amine

The desired amine was prepared using the method described inExample 1171 A. except triethylamine was added, starting with cyclohexylacetic acid and the compound fromExample 1183C. 1H NMR (CDC13, 300 MHz) 8 2.70-2.50 (m, 4H), 1.80-1.60 (m, 6H), 1.50-1.00 (m, 8H), 1.04 (d, 3H, J=8Hz), 1.00-0.80 (m, 5H) Example 1183E N-[4-N-(2-Cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2-met hylphenyl)benzoic acid methvl ester The desired compound was prepared using the method described inExample 1 178G starting with N-(2-cyclohexylethyl)-N-( 1 -methylbutyl)amine, prepared as inExample 1183D, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A-D. m/e (ESI) 436 (MH+) Example 1183F N-[4-N-(2-Cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2-met hylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 1183E.

Example 1183G N-[4-N-(2-Cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired product was prepared using the method described inExample 403F starting with the compound prepared inExample 1183F. m/e (ESI) 567 (MH+) Example 1183H N- 14-N-(2-Cyclohexylethyl!-N-(pent-2-yl)aminomethyl-2-(2- methvlphenvl)henzovllmethionine The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1183G. 1H (300MHz, CDCl3, o) 7.69 (2H, m), 7.40-7.00 (SH, m), 6.46 (1H, m), 4.38 (lH, m), 4.05 (2H, m), 3.41 (1H, m), 2.90 (2H, m), 2.20-1.75 (9H, m), 1.75-1.50 (7H, m), 1.50-1.00 (12H, m), 0.90 (SH, m). m/e (ESI) 551 (MH-) Anal.calc. for C33H48N2O3S.0.50 H2O C 70.55, H 8.79, N 4.99 Found C 70.65, H 8.63, N 4.93 Example 1184 Example 1184A

N-Propoxvphthalimide The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and 1-propanol. m/e (DCI) 223 (MH+NH3+) Example 1184B O-Propyl-2-cvclohexylacetaldoxime The desired product was prepared using the method described in Example 1176B starting with the compound from Example 1184 A and cyclohexylacetaldehyde.

Example 1184C N--(2 -Cyclohexylethyl )-N-propvloxyamine The desired product was prepared using the method described in Example 1 176C starting with the compound from Example 1184B. m/e (DCI) 186 (MH+) Example 1184D N-f4-N--(2-Cyclohexylethyl)-N-propyloxyaminomethyl-2-(2- methylphenyl )benzoyllmethionine methvl ester The desired product was prepared using the method described in Example 403H starting with the compound from Example 1184C and N-[4-Formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G. m/e (ESI) 553 (MH-)

Example 1184E N-14-N--(2-Cvclohexvlethvl)-N-propvloxvaminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 4031 starting with th compound from Example 1 184D.1H (300MHz, DMSO-d6, o) 7.53 (1H, d, J=9Hz), 7.38 (1H, dd, J=7&2Hz), 7.30-7.00 (5H, m), 6.92 (lH, m), 3.82 (2H, bs), 3.71 (1H, m), 3.41 (2H, m), 2.67 (2H, bt, J=8Hz), 2.25-1.95 (5H, m), 1.91 (3H, s), 1.90-1.50 (7H, m), 1.37 (SH, m), 1.15 (3H, m), 0.86 (2H, m), 0.76 (3H, t, J=8Hz). m/e (ESI) 539 (MH-) Anal.calc. for C31H43LiN2O4S.0.50 H2O C 67.00, H 7.98, N 5.04 Found C 66.82, H 7.75, N 4.92 Example 1185 Example 1185A N-Cyclohexylmethoxyphthalimide The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and cyclohexylmethanol.

Example 11 85B N-(Cyclohexvlmethyloxy)aminomethvlidene-2-(2-methvlphenyl)be nzoic acid methyl ester The desired product was prepared using the method described in Example 1176B starting with the compound from Example 1 185A and N-[4-Formyl-2-(2- methylphenyl)benzoic acid methyl ester, prepared using the method of Example 403G and starting with the alcohol prepared in Example 1178C.

Example 1185C N-(Cvclohexvlmethyloxy)aminomethvl-2-(2-methvlphenvl)benzoic acid methyl ester The desired product was prepared using the method described in Example 1176C starting with the compound in Example 1185B. m/e (ESI) 368 (MH+) Example 1 185D N-[4-N--Butyl-N-(cyclohexylmethyloxy)aminomethyl-2-(2-methyl phenyl)benzoic acid methvl ester The desired product was prepared using the method described in Example 1 176D starting with the compound in Example 1185C. m/e (ESI) 424 (MH+)

Example 1185E N-[4-N--Butyl-N-(cyclohexylmethyloxy)aminomethyl-2-(2-methyl phenyl)benzoic acid The desired product was prepared using the method described in Example 403E starting with the compound in Example 1185D.

Example 1185F N-[4-N--Butyl-N-(cyclohexylmethyloxy)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired product was prepared using the method described in Example 403F starting with the compound in Example 1185E. m/e (ESI) 555 (MH+) Example 1185G N-t4-N--Butyl-N-(cyclohexylmethyloxy)aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 4031 starting wiyh the compound in Example 1 185F.1H (300MHz, DMSO-d6, 6) 7.51 (1H, d, J=9Hz), 7.37 (1H, bd), 7.30-7.05 (SH, m), 6.94 (1H, m), 3.82 (2H, bs), 3.68 (1H, m), 3.25 (2H, m), 2.64 (2H, t, J=8Hz), 2.25-1.95 (SH, m), 1.93 (3H, s), 1.90-1.40 (9H, m),

1.31 (3H, m), 1.06 (3H, m), 0.85 (3H, t, J=8Hz), 0.73 (2H, m). m/e (ESI) 539 (MH-) Anal.calc. for C31H43LiN2O4S.2.00 H2O C 63.90, H 8.13, N 4.81 Found C 63.63, H 7.68, N 4.62 Example 1187 Example 1 187A N-(2-Cyclohexylethyl)-N-propanesulfonylamine The desired product was prepared using the method described in Example 1174A starting with cyclohexylethylamine and l-propanesulfonyl chloride.

Example 11 87B 4-(N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl)-2-(2- methylphenyl)benzoic acid methvl ester The desired product was prepared using the method described inExample 1 174B starting with N-(2-cyclohexylethyl)-N-propanesulfonylamine, prepared as inExample 1187A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A-D. m/e (ESI) 472 (MH+)

Example 1187C 4-(N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl)-2-(2- methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1187B Example 1187D N-[4-N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2 - methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1187C. m/e (ESI) 601 (MH-) Example 1187E N-[4-N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2 - methylphenyl)benzovllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound prepared inExample 1 187D. 1H (300MHz, CDCl3, b) 8.00 (1H, dd, J=8&7Hz), 7.43 (1H, dd, J=7&2Hz), 7.40-7.10 (SH, m), 5.90 (lH, m), 4.58 (1H, m), 4.42 (2H, s), 3.20 (2H, m), 2.94 (2H, m), 2.20-2.00 (7H, m), 2.00-1.80 (4H,

m), 1.60 (6H, m), 1.38 (2H, m), 1.15 (4H, m), 1.05 (3H, t, J=8Hz), 0.86 (2H, m). m/e (ESI) 587 (MH-) Anal.calc. for C31H44N2O5S2.0.25 H2O C 62.75, H 7.56, N 4.72 Found C 62.75, H 7.56, N 4.49 Example 1188 Example 118A N-[Bromomethyl-2-(2-methylphenyl)benzoyl]methionine methyl ester To a stirred solution at -10°C under N2 of N-[4-hydroxymethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester (200 mg, 0.517 mmol ), prepared as in Example 403F, and carbon tetrabromide (189 mg, 0.568 mmol) in CH2Cl2 (5 mL) was added triphenylphosphine (163 mg, 0.620 mmol). Reaction stirred one hour at - 100C, and then, solvents concentrated in vacuo to produce a colorless glass. The residue could not be stored, and so, was used directly in the reaction in Example 1188B.

Example 1188B N- -N-(3-Chloropropanesulfonvl)-N-(2-cyclohexvlethyl)aminomethv l-2-(2- methylphenvl)benzoyll methionine methyl ester

The desired compound was prepared using the method described inExample 1174B (except reaction run at -400C) starting with the product fromExample 1188A and N-(3- chloropropanesulfonyl)-N-(2-cyclohexylethyl)amine, prepared as inExample 1189A using the method described inExample 1174A. m/e (ESI) 635 (MH-) Example 1188C N-[4-N-(3-Chloropropanesulfonyl)-N-(2-cyclohexylethyl)aminom ethyl-2-(2- methylphenvl)benzoyllmethionine The desired compound was prepared according to the method offixample 4031 starting with the compound fromExample 1188B. 1H (300MHz, CDCl3, 6) 8.01 (1H, bt, J=8Hz), 7.46 (1H, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.90 (1H, m), 4.59 (lH, m), 4.45 (2H, s), 3.68 (2H, t, J=8Hz), 3.22 (2H, bt, J=7Hz), 3.12 (2H, t, J=8Hz), 2.31 (2H, m), 2.20-2.05 (4H, m), 2.03 (3H, s), 1.92 (2H, m), 1.60 (6H, m), 1.40 (2H, m), 1.30-1.00 (4H, m), 0.85 (2H, m). m/e (ESI) 621 (MH-) Anal.calc. for C31H43Cl1N2O5S2.0.50 H2O C 58.89, H 7.01, N 4.43 Found C 58.96, H 7.04, N 4.40 Example 1189 Example 1189A <BR> <BR> N-(3-Chloropropanesulfonvl)-N-(2-cyclohexylethvl)amine

The desired compound was prepared using the method described in Example 1 174A starting with cyclohexylethylamine and 3-chloropropanesulfonyl chloride.

Example 11 89B 4-N-(3-Chloropropanesulfonyl)-N-(2-cyclohexylethyl)aminometh yl-2-(2- methvlphenvl)benzoic acid methvl ester The desired product was prepared using the method described inExample 1 174B starting with the compound fromExample 1 189A and 4-bromomethyl-2-(2- methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A-D. nile (ESI) 506 (MH+) Example 11 89C N-[4-N-(2-Cyclohexylethyl)-N-(3-ethoxypropanesulfonyl)aminom ethyl-2-(2- methylphenyl)benzoic acid The acid was prepared using the method described in Example 403E starting with the product from Example 1189B. Chloride was displaced by ethoxide ion.

Example 1189D

N-[4-N-(2-Cyclohexylethyl)-N-(3-ethoxypropanesulfonyl)aminom ethyl-2-(2- methvlphenvl)benzovllmethionine methvl ester The compound was prepared using the method described inExample 403F starting with the product fromExample 1189C. m/e (ESI) 645 (MH-) Example 1189E N-[4-N-(2-Cyclohexylethyl)-N-(3-ethoxypropanesulfonyl)aminom ethyl-2-(2- methvlphenvl)benzovllmethionine lithium salt The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1189D. 1H (300MHz, DMSO-d6, b) 7.54 (lH, d, J=8Hz), 7.41 (1H, dd, J=7&2Hz), 7.30-7.10 (SH, m), 6.97 (1H, d, J=7Hz), 4.42 (2H, bs), 3.68 (1H, m), 3.43 (2H, q, J=7Hz), 3.40 (2H, m), 3.16 (4H, m), 2.20-1.95 (SH, m), 1.95 (3H, s), 1.90-1.65 (3H, m), 1.55 (6H, m), 1.27 (2H, m), 1.10 (7H, bt, J=8Hz), 0.78 (2H, m). m/e (ESI) 631 (MH-) Anal.calc. for C33H47LiN206S2-0.50 H2O C 61.18, H 7.47, N 4.32 Found C 61.15, H 7.53, N 4.15 Example 1190 Example 1 190A <BR> <BR> N-(2-Cvclohexylethyl)-N-(3-trifluoromethylpropanesulfonyl)am ine

To a stirred solution at 0°C under N2 of 4,4,4-trifluoro-l-bromobutane (2.00 g, 10.5 mmol) in anhydrous DMF (10 mL) was added dropwise a slurry of t-butanethiol sodium salt (1.29 g, 11.5 mmol) in anhydrous DMF (25 mL) such that the temperature was maintained below 5"C. Mixture stirred one hour at OOC, and then, diluted with water and extracted with ether. Extracts dried with Na2SO4, filtered, and concentrated in vacuo.

Residue dissolved in 1:1 water/EtOH at OOC, and to this was bubbled in chlorine gas for 45 minutes. After the chlorine addition, N2 was bubbled into the black-green mixture until the green color disappeared (30 minutes). The mixture was made a more homogeneous solution by addition of CH2Cl2, and to this was added carefully an aqueous 2M Na2CO3 solution until mixture was basic (pH 10). Cyclohexylethylamine (1.14 g, 9.00 mmol) was added, and this two-phase solution was stirred at room temperature overnight. Reaction diluted with water and extracted with CHC13 (2x). Extracts dried with Na2SO4, filtered, and concentrated. Residue purified by flash chromatography on silica gel eluting with 20% EtOAc/Hexanes to afford the desired product as a light brown oil (1.02 g, 32%). m/e (DCI) 319 (MH+NH3+) Example 1 190B 4-(N-(2-Cyclohexylethyl)-N-(3-trifluoromethylpropanesulfonyl )aminomethyl)-2-(2- methvlphenvl)benzoic acid methyl ester The desired product was prepared using the method described in Example 1 174B starting with N-(2-cyclohexylethyl)-N- (3-trifluoromethylpropanesulfonyl)amine, prepared as in Example 1190A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D.

Example 1190C 4-(N-(2-Cyclohexylethyl)-N-(3-trifluoromethylpropanesulfonyl )aminomethyl)-2-(2- methvlphenyl)benzoic acid The desired acid was prepared using the method described inExample 403E starting with the product fromExample 1190B. m/e (ESI) 524 (MH-) Example 1 190D N-[4-N-(2-Cyclohexylethyl)-N-(3-trifluoromethylpropanesulfon yl)aminomethyl)-2-(2- methvlphenvl)benzovl1 methionine methvl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1190C. m/e (ESI) 669 (MH-) Example 1 190E N-[4-N-(2-Cyclohexylethyl)-N-(3-trifluoromethylpropanesulfon yl)aminomethyl)-2-(2- methylphenyl)henzoyl 1 methionine The desired compound was prepared according to the method Example 4031 starting with the compound inExample 1190D. 1H (300MHz, CDCl3, b) (rotamer) 8.01(7.98) (1H, d, J=8Hz), 7.46 (1H, dd, J=7&2Hz), 7.40-7.10 (SH, m), 5.92 (1H, m), 4.80 (1H, bs), 4.58 (1H, m), 4.45 (2H, s), 3.22 (2H, bt, J=7Hz), 3.03 (2H, t, J=8Hz), 2.30 (2H, m), 2.20-2.00 (10H, m), 1.92 (1H, m), 1.62 (6H, m), 1.40 (2H, m), 1.30-1.00 (4H, m), 0.87 (2H, m). m/e (ESI) 655 (MH-) Anal.calc. for C32H43F3N205S2 C 58.52, H 6.60, N 4.26 Found C 58.27, H 6.63, N 4.13

Example 1191 Example 1191A 4-Azidomethvl-2-(2-methvlphenyl)benzoic acid methyl ester To a stirred mixture at OOC under N2 of sodium azide (1.47 g, 22.6 mmol) in anhydrous DMF (30 mL) was added a solution of 4-bromomethyl-2-(2- methylphenyl)benzoic acid methyl ester (6.00 g, 18.8 mmol), prepared as in Example 1178A-D, in anhydrous DMF (10 mL). Reaction stirred overnight at room temperature.

Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.

Example 1191B 4-Aminomethyl-2-(2-methylphenyl)benzoic acid methyl ester To a flask at ambient temperature under N2 containing 10% palladium on carbon catalyst (1.0 g) was added a solution of 4-azidomethyl-2-(2-methylphenyl)benzoic acid methyl ester (5.00 g, 17.8 mmol), prepared as inExample 1191A, in MeOH (75 mL). Two drops of conc. HCl added, and reaction stirred vigorously overnight under an atmosphere of H2. Catalyst filtered off through celite and washed with MeOH. Filtrate concentrated in vacuo, and residue taken up in an aqueous 4N NaOH solution. Aqueous solution extracted with CHC13 (3x), and extracts dried with Na2SO4, filtered, and concentrated in vacuo to afford the desired product (1.37 g, 30%). m/e (DCI) 256 (MH+)

Example 1191C 4-N-Butanesulfonylminomethyl-2-(2-metbylphenyl)benzoic acid methyl ester The desired compound was prepared using the method described inExample 1174A starting with 4-aminomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1191B, and butanesulfonyl chloride. m/e (ESI) 374 (MH-) Example 1191D 1-Bromo-3-cyclohexylpropane The desired compound was prepared according to the method of Example 1 178D starting with 3-cyclohexyl-1-propanol. 1H (300MHz, CDC13, o) 3.40 (2H, t, J=8Hz), 1.85 (2H, m), 1.80-1.50 (6H, m), 1.40-1.10 (SH, m), 0.90 (2H, m).

Example 1191E <BR> <BR> N-E4-N-(Butanesulfonyl)-N-(3-cvclohexylpropvlBaminomethvl-2- (2-methvlphenvl)benzoic acid methyl ester The desired compound was prepared using the method described inExample 1174B starting with the compounds fromExample 1 191C andExample 1191D. m/e (ESI) 500 (MH+)

Example 1191F N-[4-N-(Butanesulfonyl)-N-(3-cyclohexylpropyl)aminomethyl)-2 -(2-methylphenyl)benzoic acid The acid was prepared using the method described in Example 403E starting with the compound from Example 1191E.

Example 1191G N-[4-N-(Butanesulfonyl)-N-(3-cyclohexylpropyl)aminomethyl)-2 -(2- methylphenyl)benzoyl]methionine methyl ester The compound was prepared using the method described inExample 403F starting with the compound fromExample 1 1191F. m/e (ESI) 629 (MH-) Example 1191H N-[4-N-(Butanesulfonyl)-N-(3-cyclohexylpropyl)aminomethyl)-2 -(2- methylphenyl)benzovll methionine lithium salt The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1 191G.1H (300MHz, DMSO-d6, 6) 7.54 (1H, d, J=8Hz), 7.41 (1H, bd, J=7Hz), 7.30-7.05 (SH, m), 6.97 (1H, d, J=7Hz), 4.42 (2H, s), 3.68 (1H, m), 3.10 (4H, bt, J=7Hz), 2.20-1.95 (SH, m), 1.91 (3H, s), 1.90-1.45 (9H, m), 1.45-1.20 (4H, m), 1.20-0.90 (6H, m), 0.88 (3H, t, J=8Hz), 0.73 (2H, m). m/e (ESI) 615 (MH-) Anal.calc. for C33H47LiN2O5S2O.75 H2O C 62.29, H 7.68, N 4.40 Found C 62.18, H 7.75, N 4.36

Example 1193 Example 1 193A (2S)-t-Butoxvcarbonvlamino-4-cvclohexylbutanoic acid To a solution of Boc-homophenylalanine (3.00 g, 10.8 mmol) in CH2Cl2 at room temperature was added a solution of 4N HCl in dioxane (20 mL, 80 mmol), and mixture stirred overnight. Solvents concentrated, and white powder that resulted was reduced under high pressure (4 atm. H2) using platinum/HCl. The white solid that resulted from the reduction was mixed with aqueous 4N NaOH (30 mL), water (30 mL), and THF (50 mL) at room temperature, and to this was added di-t-butyl dicarbonate (3.5 g, 16 mmol). Reaction heated at 700C overnight. Reaction cooled to 0°C, and an aqueous solution of 3N HCl added until the pH reached 6. Product extracted out with CHCl3, and extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a white solid (3.24 g, 106%). m/e (DCI) 286 (MH+) Example 1193B <BR> <BR> <BR> (2S)-t-Butoxycarbonylamino-4-cvclohexvlbutan- l -ol

To a solution at -5°C under N2 of (2S)-t-butoxycarbonylamino-4- cyclohexylbutanoic acid (3.24 g, 10.8 mmol), prepared as inExample 1193A, in anhydrous THF (20 mL) was added dropwise a 1.OM borane-THF complex (32.3 mL, 32.3 mmol) in THF. After addition, reaction stirred overnight at room temperature. Reaction cooled to 0°C and quenched with an aqueous 4N NaOH solution. Stirred 30 minutes at room temperature, and then, extracted with CH2C12 (3x). Extracts dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 30% EtOAc/Hexanes to afford the desired product as a colorless oil (696 mg, 23%). m/e (DCI) 272 (MH+) Example 1 193C (2S)-t-Butoxvcarbonvlamino-4-cvclohexvl- 1 -ethylthiobutane The desired compound was prepared using the method described inExample 403B and 403C starting with the product fromExample 1193B. m/e (DCI) 316 (MH+) Example 1 193D (2 )-Amino4-cyclohexyl- 1-ethylthiobutane hydrochloride salt The desired compound was prepared using the method described in Example 403D starting with the product from Example 1193C.

Example 1193E N-[4-N-(4-Cyclohexyl-1-ethylthiobutan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with the product fromExample 1193D and N-[4-formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G. m/e (ESI) 585 (MH+) Example 1193F N-[4-N-(4-Cyclohexyl-1-ethylthiobutan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1193E.1H (300MHz, CDCl3, o) 7.72 (1H, m), 7.45 (1H, m), 7.40-7.00 (SH, m), 6.18 (1H, m), 4.36 (1H, m), 4.00 (2H, m), 2.95 (1H, m), 2.82 (1H, m), 2.73 (1H, m), 2.44 (2H, m), 2.20-2.00 (7H, m), 1.98 (3H, bs), 1.90- 1.40 (7H, m), 1.20 (9H, t, J=8Hz), 0.87 (3H, nE). m/e (ESI) 569 (MH-) Anal.calc. for C32H46N2O3S2.0.75 H2O C 65.77, H 8.19, N 4.79 Found C 65.74, H 8.08, N 4.69 Example 1194 Example 1194A

1 -Bromo-4-cvclohexvlbutane The desired compound was prepared according to the method of Example 1 178D starting with 4-cyclohexyl-1-butanol. 1H (300MHz, CDCl3, o) 3.40 (2H, t, J=8Hz), 1.83 (2H, m), 1.80-1.50 (6H, m), 1.42 (2H, m), 1.30-1.10 (SH, m), 0.85 (2H, m).

Example 1 194B 4-N-(Butanesulfonyl)-N-(4-cyclohexylbutyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid methyl ester The desired compound was prepared using the method described inExample 11 74B starting with the compounds fromExample 1 191C andExample 1194A. m/e (ESI) 514 (MH+) Example 1 194C 4-N-(Butanesulfonyl)-N-(4-cyclohexylbutyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid The acid was prepared using the method described in Example 403E starting with the compound from Example 1194B.

Example 1 194D

N-[4-N-(Butanesulfonyl)-N-(4-cvclohexvlbutyl)aminomethyl-2-( 2- methylphenyl)benzoyl]methionine methyl ester The compound was prepared using the method described in Example 403F starting with the compound from Example 1194C. 1H (300MHz, CDC13, o) 7.96 (1H, m), 7.43 (lH, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.90 (1H, bd, J=7Hz), 4.62 (1H, m), 4.44 (2H, s),3.64 (3H, s), 3.18 (2H, m), 2.96 (2H, m), 2.20-1.85 (8H, m), 1.75-1.50 (9H, m), 1.50-1.30 (4H, m), 1.25-1.00 (8H, m), 0.94 (3H, t, J=8Hz), 0.82 (2H, m).

Example 1194E N-[4-N-(Butanesulfonyl)-N-(4-cyclohexylbutyl)aminomethyl-2-( 2- methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1194D. 1H (300MHz, DMSO-d6, b) 7.56 (lH, d, J=8Hz), 7.41 (1H, dd, J=7&2Hz), 7.30-7.05 (SH, m), 6.98 (1H, d, J=7Hz), 4.42 (2H, bs), 3.68 (1H, m), 3.13 (4H, m), 2.20-1.95 (5H, m), 1.92 (3H, s), 1.90-1.45 (9H, m), 1.45-1.20 (4H, m), 1.20-0.90 (8H, m), 0.88 (3H, t, J=8Hz), 0.78 (2H, m). m/e (ESI) 629 (MH-) Anal.calc. for C34H49LiN2O5S2.0.75 H2O C 62.79, H 7.83, N 4.31 Found C 62.69, H 7.84, N 4.24 Example 1195

Example 1 195A N-Butvl-N-quinolin-2-vlamine 2-Chloroquinoline (500 mg, 3.06 mmol), butylamine (0.90 rnL, 9.16 mmol), and diisopropylethylamine (0.82 mL, 4.58 mmol) were dissolved in acetonitrile (5 mL), and solution refluxed 2 days. Reaction cooled and diluted with EtOAc. Reaction washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.

Residue purified by flash chromatography on silica gel eluting with 15% EtOAc/Hexanes to afford the desired product as a pale yellow oil (188 mg, 31%). m/e (DCI) 201 (MH+) Example 1195B 4-N-Butyl-N-quinolin-2-vlaminomethyl-2-(2-methylphenyl)benzo ic acid methyl ester The desired compound was prepared according to the method of Example 1 174B starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D, and the compound from Example 1195A.

Example 1195C 4-N-Butvl-N-guinolin-2-vlaminomethyl-2-(2-methylphenyl)benzo ic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1195B.

Example 1195D <BR> <BR> <BR> N-r4-N-Butvl-N-quinolin-2-vlaminomethvl-2-(2-methylphenvlZbe nzovllmethionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1195C. m/e (ESI) 570 (MH+) Example 1195E N-[4-N-Butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenyl)be nzoyl]methionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1 195D.1H (300MHz, CDCl3, o) 7.95-7.80 (3H, m), 7.72 (1H, m), 7.60-7.40 (2H, m), 7.37 (1H, dd, J=7&2Hz), 7.30-7.00 (SH, m), 6.84 (1H, d, J=9Hz), 6.03 (1H, m), 5.03 (2H, bs), 4.44 (1H, m), 3.62 (2H, m), 2.20-2.00 (5H, m), 1.96 (3H, s), 1.85 (1H, m), 1.65 (2H, m), 1.51 (1H, m), 1.37 (2H, m), 0.93 (3H, t, J=8Hz). m/e (ESI) 554 (MH-) Anal.calc. for C33H37N303S 0.40 H2O C 70.41, H 6.77, N 7.46 Found C 70.62, H 6.68, N 7.07 Example 1196

Example 1196A N-[4-(N-(2-piperidin-1-ylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and 1-(2-aminoethyl)piperidine. m/e (ESI) 498-(MH+) Example 1196B N- F4-(N-Butyl-N-(2-piperidin- 1 -ylethyl )aminomethyl )-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with the compound prepared inExample 1196A and butyraldehyde. m/e (ESI) 552 (MH-) Example 1196C N-[4-(N-Butyl-N-(2-piperidin-1-ylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine

The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1196B.1H (300MHz, CDCl3, b) 7.62 (1H, d, J=8Hz), 7.30-7.10 (SH, m), 7.09 (1H, bs), 6.42 (1H, m), 4.35 (lH, m), 3.63 (2H, m), 3.05-2.75 (8H, m), 2.42 (2H, bt, J=7Hz), 2.20-1.90 (9H, m), 1.90-1.60 (SH, m), 1.55 (2H, m), 1.40 (2H, m), 1.22 (2H, m), 0.83 (3H, t, J=8Hz). m/e (ESI) 538 (MH+) Anal.calc. for C31H45N303S0.75 H2O C 67.30, H 8.47, N 7.59 Found C 67.21, H 8.39, N 7.52 Example 1197 Example 1197A N-(1-Morpholinocarbonyl!butylamine hydrochloride salt To a stirred solution at room temperature of Boc-L-norvaline (500 mg, 2.30 mmol) and piperidine (0.27 mL, 2.76 mmol) in DMF (5 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (530 mg, 2.76 mmol). Reaction stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue mixed with a 4N HCl solution (10 mL, 40 mmol) in dioxane at room temperature overnight. Solvents concentrated in vacuo to afford the desired compound (222 mg, 44%). m/e (DCI) 185 (MH+)

Example 1197B N- f4-N-( (1 -Morpholinocarbonyl)butyl)aminomethyl-2-(2- methylphenvl)benzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and the compound prepared inExample 1197A. m/e (ESI) 554 (MH+) Example 1197C N-[4-N-((1-Morpholinocarbonyl)butyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared using the method described inExample 4031 starting with the compound fromExample 1 197B.1H (300MHz, CDCl3, o) 7.82 (1H, m), 7.43 (lH, dd, J=7&2Hz), 7.40-7.20 (4H, m), 7.17 (1H, d, J=2Hz), 6.08 (1H, m), 5.97 (lH, m), 4.43 (1H, m), 4.20-3.80 (2H, m), 3.69 (2H, m), 3.60-3.30 (3H, m), 2.20-1.90 (8H, m), 1.91 (2H, m), 1.66 (4H, m), 1.57 (4H, m), 1.30 (2H, m), 0.89 (3H, t, J=8Hz). m/e (ESI) 538 (MH+) Anal.calc. for C30H41N3O4S.0.75 H2O C 65.13, H 7.74, N 7.59 Found C 65.40, H 7.44, N 7.26

Example 1198 Example 1 198A N-[4-(N-(2-Morpholin-4-ylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]nethionine methyl ester The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and 4-(2-aminoethyl)morpholine. m/e (ESI) 500 (MH+) Example 1198B N- 4-N-Butvl-N-(2-morpholin-4-ylethyl)aminomethyl-2-(2- methylphenvl)benzoyll methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with the compound prepared inExample 1198A and butyraldehyde. m/e (ESI) 554 (MH-)

Example 1198C N- 14-N-Butvl-N-(2-morpholin-4-ylethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method offixample 4031 starting with the compound fromExample 1198B.1H (300MHz, CDCl3, b) 7.71 (1H, d, J=9Hz), 7.43 (1H, bd, J=8Hz), 7.30-7.10 (SH, m), 6.25 (1H, m), 4.39 (lH, m), 3.83 (2H, bs), 3.72 (4H, m), 2.89 (2H, m), 2.80-2.50 (8H, m), 2.20-1.80 (9H, m), 1.62 (1H, m), 1.50 (2H, m), 1.27 (2H, m), 0.88 (3H, t, J=8Hz). m/e (ESI) 540 (MH+) Anal.calc. for C30H43N3O4S.0.50 H2O C 65.42, H 8.05, N 7.63 Found C 65.22, H 7.92. N 7.47 Example 1199 Example 1199A N-[4-(N-(Fluoren-9-yl)aminomethyl)-2-(2-methylphenyl)benzoyl ]nethionine methyl ester

The desired compound was prepared using the method described inExample 403H starting with N- [4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and 9-aminofluorene hydrochloride salt m/e (ESI) 551 (MH+) Example 1 199B N-[4-N-Butyl-N-(fluoren-9-yl)aminomethyl-2-(2-methylphenyl)b enzoyl]nethionine methyl ester The desired compound was prepared using the method described inExample 403H starting with the compound prepared inExample 1199A and butyraldehyde. m/e (ESI) 605 (MH-) Example 1199C N-[4-N-Butyl-N-(fluoren-9-yl)aminomethyl-2-(2-methylphenyl)b enzoyl]nethionine The desired compound was prepared according to the method olExample 4031 starting with the compound fromExample 1 199B.1H (300MHz, CDCl3, o) 7.91 (1H, m), 7.67 (3H, m), 7.47 (1H, bd, J=8Hz), 7.40-7.10 (10H, m), 5.84 (1H, m), 5.00 (lH, bs), 4.52 (1H, m), 3.53 (2H, bs), 2.64 (2H, m), 2.20-1.95 (8H, m), 1.90 (1H, m), 1.52 (3H, m), 1.32 (2H, m), 0.83 (3H, bt, J=8Hz). m/e (ESI) 591 (MH-) Anal.calc. for C37H40N203S 0.50 H2O C 73.85, H 6.87, N 4.65 Found C 74.07, H 6.70, N 4.63

Example 1200 Example 1200A N-(2-Cyclohexylethyl)-N-(furan-2-ylmethyl)amine The desired amine was prepared using the method described inExample 1171 A starting with cyclohexylethylamine and 2-furoic acid. m/e (DCl/NH3) 208 (MH+) Example 1200B N-[4-N-(2-Cyclohexylethyl)-N-(furan-2-ylmethyl)aminomethyl-2 -(2- methylphenyl)benzoyll methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and N-(2-Cyclohexylethyl)-N-(furan-2-ylmethyl)amine, prepared as inExample 1200A. m/e (ESI) 577 (MH+)

Example 1200C N-[4-N-(2-Cyclohexylethyl)-N-(furan-2-ylmethyl)aminomethyl-2 -(2- methylphenyl)benzoyl]methionine The desired compound was prepared according to the method Example 4031 starting with the compound inExample 1200B.1H (300MHz, CDCl3, o) 7.81 (1H, d, J=8Hz), 7.56 (1H, m), 7.42 (lH, d, J=2Hz), 7.30-7.10 (5H, m), 6.37 (2H, bs), 6.15 (1H, d, J=8Hz), 4.45 (1H, m), 4.10-3.80 (4H, m), 2.67 (2H, m), 2.20-2.05 (5H, m), 2.00 (3H, s), 1.90 (1H, m), 1.80-1.40 (8H, m), 1.30-1.00 (4H, m), 0.88 (2H, m). m/e (ESI) 561 (MH-) Anal.calc. for C33H42N2O4S.1.00 H2O C 68.25, H 7.64, N 4.82 Found C 67.94, H 7.34, N 4.65 Example 1201 Example 1201A N-[4-(N-(2-Pyrrolidin-1-ylethyl)aminomethyl)-2-(2-methylphen yl)benzoyl]methionine methyl ester

The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and 1-(2-aminoethyl)pyrrolidine m/e (ESI) 484 (MH+) Example 1201B N-[4-N-Butyl-N-(2-pyrrolidin-1-ylethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403H starting with the compound prepared inExample 1201A and butyraldehyde. m/e (ESI) 540 (MH+) Example 1201C N-[4-N-Butvl-N-(2-pvrrolidin- 1 -vlethvl)aminomethvl-2-(2- methvlphenvl)benzovllmethionine The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1201B.1H (300MHz, CDCl3, o) 7.66 (1H, d, J=8Hz), 7.35-7.10 (5H, m), 7.09 (1H, bs), 6.37 (1H, m), 4.36 (1H, m), 3.63 (2H, s), 3.16 (4H, m), 3.03 (2H, m), 2.84 (2H, m), 2.43 (2H, bt, J=8Hz), 2.20-1.80 (13H, m), 1.65 (1H, m), 1.41 (2H, m), 1.23 (2H, m), 0.85 (3H, t, J=8Hz). m/e (ESI) 524 (MH+) Anal.calc. for C30H43N303S 1.00 H2O C 66.27, H 8.34, N 7.73 Found C 65.92, H 8.29, N 7.59

Example 1202 Example 1 202A 5-Thiazolecarboxaldehvde The desired compound was prepared according to the method of Example 403G starting with 5-hydroxymethylthiazole. 1H (300MHz, CDC13, o) 10.13 (1H, s), 9.12 (1H, s), 8.54 (1H, s).

Example 1202B N-(2-Butylphenyl)-N-(thiazol-5-ylmethyl)amine The desired compound was prepared according to the method Example 403H starting with 2-butylaniline and the aldehyde fromExample 1202A. m/e (DCI) 247 (MH+) Example 1202C 4-N-(2-Butylphenyl)-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid methyl ester

The desired compound was prepared according to the method of Example 11 74B starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1 178A-D, and the compound from Example 1202B.

Example 1202D 4-N-(2-Butylphenyl)-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-m ethylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1202C.

Example 1202E N-[4-N-(2-Butylphenyl)-N-(thiazol-5-ylmethyl)aminomethyl-2-( 2- methylphenyl)benzoyl]methionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1202D. m/e (ESI) 614 (MH-) Example 1202F <BR> <BR> N- r4-N- (2-Butylphenyl)-N-(thiazol-5-vlmethvl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine

The desired compound was prepared according to the method ofExample 403I starting with the compound fromExample 1202E. 1H (300MHz, CDCl3, o) 8.73 (1H, s), 7.91 (1H, bt, J=8Hz), 7.66 (1H, bs), 7.40-7.15 (SH, m), 7.15-6.90 (SH, bs), 5.88 (1H, d, J=8Hz), 4.57 (1H, m), 4.29 (2H, s), 4.13 (2H, s), 2.72 (2H, bt, J=8Hz), 2.20-1.80 (9H, m), 1.55 (3H, m), 1.35 (2H, m), 0.88 (3H, t, J=8Hz). m/e (ESI) 600 (MH-) Anal.calc. for C34H39N303S2 C 67.86, H 6.53, N 6.98 Found C 67.57, H 6.43, N 6.71 Example 1203 Example 1203A N-14-N-((2-Ethvlthio)- 1.3 .4-thiadiazol-S-vl)aminomethyl-2-(2- methylphenyl)benzovll methionine ethvl ester 2-Amino-5-(ethylthio)-1,3,4-thiadiazole (419 mg, 2.60 mmol) and N-[4-formyl-2- (2-methylphenyl)benzoyl]methionine methyl ester (1.00 g, 2.60 mmol), prepared as inExample 403G, were mixed with toluene (4 mL) and refluxed under N2 with a Dean- Stark trap overnight. Reaction diluted with EtOAc and washed with water and brine.

Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. To a solution of this residue in EtOH (8 mL) at 0°C under N2 was added sodium borohydride (98 mg, 2.60 mmol), and mixture stirred vigorously at ambient temperature for 3 hours. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting

with 60% EtOAc/Hexanes to afford the desired product as a pale yellow oil (347 mg, 95%). m/e (ESI) 543 (MH-) Example 1203B N-[4-N-((2-Ethylthio)-1,3,4-thiadiazol-5-yl)aminomethyl-2-(2 - methylphenyl)benzoyl]methionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1203A.1H (300MHz, CDCl3, #) 7.88 (1H, m), 7.46 (1H, m), 7.30-7.00 (SH, m), 5.94 (2H, m), 4.58 (1H, m), 4.42 (2H, bd, J=8Hz), 3.13 (2H, q, J=8Hz), 2.20-1.80 (9H, m), 1.67 (1H, m), 1.39 (3H, t, J=8Hz). m/e (ESI) 515 (MH-) Anal.calc. for C24H28N4O3S3.0.50 H2O C 54.83, H 5.56, N 10.66 Found C 54.86, H 5.41, N 11.04 Example 1204

Example 1204A N-[4-N-Butyl-N-((2-ethylthio)-1,3,4-thiadiazol-5-yl)aminomet hyl-2-(2- methvlphenyl)benzovllmethionine methvl ester The desired compound was prepared using the method described inExample 403H starting with the compound prepared as inExample 1203A (methyl ester) and butyraldehyde. m/e (ESI) 587 (MH+) Example 1204B <BR> <BR> N-14-N-Butvl-N-((2-ethvlthio)- 1 .3,4-thiadiazol-5-vl)aminomethvl-2-(2- <BR> <BR> <BR> methvlphenvl)benzovllmethionine The desired compound was prepared according to the method Example 4031 starting with the compound fromExample 1204A.1H (300MHz, CDCl3, o) 7.81 (1H, m), 7.43 (1H, bd, J=8Hz), 7.30-7.10 (SH, m), 6.00 (1H, d, J=8Hz), 5.38 (2H, m), 4.48 (1H, m), 3.17 (2H, m), 3.02 (2H, q, J=8Hz), 2.20-1.80 (9H, m), 1.60 (3H, m), 1.32 (SH, t, J=8Hz), 0.88 (3H, t, J=8Hz). m/e (ESI) 571 (MH-) Anal.calc. for C28H36N4O3S3.0.50 H2O C 57.80, H 6.41, N 9.63 Found C 57.79, H 6.11, N 9.52 Example 1216 N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl )benzoyl]methionine p- tolylsulfonimide hvdrochloride salt

Example 1216A N-(tert-Butoxvcarbonvl)-methionine p-tolvlsulfonimide N-(tert-Butoxycarbonyl)-methionine (960 mg, 3.85 mmol) was dissolved in CH2Cl2 (50 mL), then added EDCI'HCl (1.12 g, 5.85 mmol), DMAP (287 mg, 2.35 mmol), and p-toluenesulfonamide (1.71 g, 10.0 mmol). The reaction was stirred at RT overnight, concentrated, dissolved in EtOAc (130 mL), then washed with water, 2N HCl, water, and brine. After drying over Na2SO4, filtration, and concentration, the compound was purified by chromatography using 1/1 hex/ EtOAc, then EtOAc. Recovered 635 mg (41%). MS (APCI) 403 (M+H)+.

Example 1216B Methionine p-tolvlsulfonimide hvdrochloride salt The compound described in Example 1216A (610 mg, 1.52 mmol) was dissolved in 4N HCl in dioxane (10 mL), stirred at RT for 45 min., then diluted with Et2O. The resultant solids were filtered off, and washed with Et2O to give 465 mg (90%) white solids.

MS (DCI/NH3) 303 (M+H)+.

Example 1216C N-Butyl-2-phenylethylamine 2-Phenethylamine (12.5 mL, 12.1 g, 99.5 mmol), butyraldehyde (13.2 mL, 10.8 g, 150 mmol), and 3A molecular sieves were stirred at 50 "C for 1 h, then at RT for 5.5 h.

The reaction was then diluted with CH2C12, filtered through celite, then concentrated to an oil. That oil was dissolved in absolute EtOH (150 mL-previously cooled to 0 "C), and NaBH4 (5.7 g, 150 mmol) was added. The reaction was stirred at RT overnight, concentrated, partitioned between water and Et2O, then the organic layer was washed with

water and brine. After drying over NaSO4, filtration, and concentration, the compound was purified by vacuum distillation using a 6" Vigeraux column (98-100 "C/ 9 mm).

Recovered 8.2 g (46%). 1H NMR (CDC13) b 7.30 (m, 2H), 7.20 (m, 3H), 2.84 (m, 4H), 2.61 (dd, 2H), 1.43 (m, 2H), 1.32 (m, 2H), 1.08 (br s, 1H), 0.88 (t, 3H).

Example 1216D 4-(N-Butyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl)be nzoic acid methvl ester The title compound was prepared from the compound described in Example 121 6C and the bromide described in Example 1 178D using the method of Example 1 178G. MS (APCI) 416 (M+H)+.

Example 1216E 4-(N-Butyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl)be nzoic acid The title compound was prepared from the compound described in Example 1216D using the method of Example 1 178H. MS (ESI) 402 (M+H)+. Example 1216F

N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine p- tolvlsulfonimide hydrochloride salt The above compound was prepared according to the method of Example 1205D using the compounds described in Examples 1216B and 1216E, except the order of the aqueous work-up was saturated NaHCO3, 2N HCl, brine, and the chromatography used 98/2/0.5 CHCl3/MeOH/CH3CO2H. 1H NMR (CDC13) 8 7.85 (m, 4H),7.26 (m, 12H), 6.47 (m, 1H), 4.60 (m, 1H), 4.30 (m, 2H), 3.20 (m, 6H), 2.43 (s, 3H), 2.08 (m, 3H), 1.90 (m, 7H), 1.83, 1.60 (both m, total 4H), 0.95 (m, 3H). MS (ESI) 684 (M-H)-. Anal calcd for C39H48C1N304S2 : C, 64.84; H, 6.70; N, 5.82; Cl, 4.91. Found: C, 64.62; H, 6.82; N, 5.69; Cl, 4.62.

Example 1217 N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine 4- (aminomethyl)phenylsulfonimide dihvdrochloride salt Example 1217A 4-r(tert-Butoxvcarbonvl)aminomethvllphenvlsulfonamide 4-(Aminomethyl)phenylsulfonamide hydrochloride salt hemihydrate (1.0 g, 4.3 mmol) was dissolved in CH2C12 (20 mL), then triethylamine (0.66 mL, 0.48 g, 4.8 mmol) and di-tert-butyl-dicarbonate (0.95 g, 4.3 mmol) were added. The reaction was stiired at RT overnight, then concentrated and partitioned between water and EtOAc. The organic layer was washed with 2N HCl, saturated aqueous NaHCO3 and brine, then dried over Na2SO4.

After filtration and concentration recovered 1.3 g tacky white solids. MS (DCI/NH3) 304 (M+H+NH3)+.

Example 1217B N-(9-Fluorenylmethoxycarbonyl)-methionine 4-[((tert-butoxycarbonyl)aminomethyl] phenylsulfonimide Using N-(9-Fluorenylmethoxycarbonyl)-methionine and the compound described in Example 1217A, the title compound was prepared by the method of Example 1216A. MS (ESI) 638 (M-H)-.

Example 1217C <BR> <BR> N-14-(N-Butyl-N-(2-phenylethyl)aminomethyl!-2-(2-methVlphenY l)benzoyl1methionine 4- [(tert-butoxycarbobyl)aminomethyl]phenylsulfonimide The compound described in Example 1217B was treated with piperidine in CH2Cl2 to give the free amine which was not purified, but directly reacted with the compound decribed in Example 1216E by the method of Example 1216F to give the title compound.

MS (ESI) 801 (M+H)+.

Example 1217D N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine 4- (aminomethvl)phenvlsulfonimide dihvdrochloride salt

Starting with the compound described in Example 1217C, the title compound was prepared by the method of Example 1216B.1H NMR (CD30D) 6 8.05 (d, 2H), 7.66 (m, 4H), 7.45 (br s, 1H), 7.25 (m, 10H), 4.53 (d, 2H), 4.25 (m, 1H), 4.24 (s, 2H), 3.33 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 2.10 (m, SH), 1.97 (s, 3H), 1.80 (m, 3H), 1.60 (m, 1H), 1.40 (m, 2H), 0.98 (t, 3H). MS (ESI) 699 (M-H)-. Anal calcd for C39H50Cl2N4o4S2- 1.50 H2O : C, 68.49; H, 6.67; N, 7.00. Found: C, 58.41; H, 6.61; N, 6.70.

Example 1218 N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine isopropylsulfonimide Example 1218A N-(tert-Butoxycarbonyl)-methionine isopropylsulfonimide The title compound was prepared by the method of Example 1216A using isopropylsulfomamide. MS (DCI/NH3) 372 (M+H+NH3)+.

Example 1218B Methionine isopropylsulfonimide hydrochloride salt

Starting with the compound described in Example 1218the title compound was prepared by the method of Example 1216B, except the product was isolated as a tan foam after strippng off the dioxane. MS (DCI/NH3) 255 (M+H)+.

Example 121 8C N-[4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine isopropylsulfonimide The above compound was prepared according to the method of Example 1205D using the compounds described in Examples 1218B and 1216E, except the order of the aqueous work-up was saturated NaHCO3, 2N HCl, brine, and the chromatography used 98/2/0.5 CHCl3/MeOH/CH3CO2H. 1H NMR (CDCl3) 6 7.91 (m, 1H), 7.43 (d, 1H), 7.32 (m, 3H), 7.18 (m, 7H), 5.83 (d, 1H), 4.43 (m, 1H), 3.77 (s, 2H), 3.65 (m, lH), 2.80 (br s, 4H), 2.59 (m, 2H), 2.15, 2.02 (both m, total 8H), 1.82 (m, 1H), 1.50, 1.38, 1.28 (all m, total 1 lH), 0.86 (t, 3H). MS (ESI) 636 (M-H)-. Anal calcd for C35H47N304S2: C, 65.90; H, 7.43 N, 6.59. Found: C, 66.01; H, 7.36; N, 6.30.

Example 1227 <BR> <BR> N-L4-N-(N-phenvl-N-(4-fluorobenzovl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Example 1227A N-[4-N-(N-phenyl-N-(4-fluorobenzoyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester A mixture of 4-fluorobenzoyl chloride (0.053 g, 0.33 mmol), 1236C (0.103 g, 0.22 mmol), and 0.2 ml of pyridine in 5 ml of CH2Cl2 was stirred for 12 hours. The mixture was washed with 10% HCl and brine respectively, dried over MgS04. Flash chromatography of the residue eluting with 1:1 EtOAC/Hexane afforded 0.13 g of the title compound (99%).

NMR(CDCl3) 7.84-7.94 (m, 1H); 7.38-7.48 (m, 1H); 7.05-7.38 (m, 10H); 5.85-5.92 (m, 1H); 5.10-5.27 (m, 2H); 4.56-4.67 (m, 1H); 3.62 (s, 3H); 1.95-2.20 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 585(M+H)+ ; 604 (M+NH4)*.

Example 1227B N-[4-N-(N-phenyl-N-(4-fluorobenzoyl)aminomethyl)-2-(2- methvlhenvl)benzovlImethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1227A. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.3-7.5 (3H, m); 6.9-7.3 (14H, m); 5.18-5.38(2H, m); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 569(M-Li).

Example 1228 <BR> <BR> <BR> N-r4-N-(N-phenyl-N-(n-butanesulfonyl!aminomethyl)-2-12- methylphenvl)benzoyll methionine lithium salt Example 1228A N-[4-N-(N-phenyl-N-(n-butanesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyllmethionine. methvl ester Prepared to the procedure of example 1229A from the reaction between 1236C and butanesulfonyl chloride. NMR(CDCl3) 7.80-7.90 (m, 1H); 7.12-7.38 (m, 10H); 7.05-7.11 (m, 1H); 5.8-5.9 (m, 1H); 4.78 (s, 2H); 4.5-4.65 (m, 1H); 3.62 (s, 3H); 3.0-3.08 (m, 2H); 1.5-2.15 (m, 14H); 0.92-0.98 (m, 3H). (DSI/NH3)/MS: 583(M+H)+; 600(M+NH4)+ Example 1228B N-r4-N-lN-phenyl-N-ln-butanesulfonYl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1228A. NMR 1H(MeOH-d4): 7.5-7.62 (1H, m); 7.1-7.4 (12H, m); 4.95 (2H, s); 4.1-4.22 (1H, m); 3.1- 3.2 (2H, t); 1.7-2.1 (12H, m); 1.4-1.5 (2H, m); 0.9-1.0 (3H, t). ESI(-)/MS: 567(M-Li).

Example 1229 N-[4-N-(N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyl)-2-(2 - methylphenyl)benzovl1methionine lithium salt Example 1229A N- [4-N- (N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester A mixture of 3-nitrophenylsulfonyl chldride (0.076 g, 0.34 mmol), 1236C (0.106 g, 0.23 mmol), and 0.2 ml of pyridine in 3 ml of CH2Cl2 was stirred for 12 hours. The mixture was washed with 10% HCl and brine respectively, dried over MgSO4. Flash chromatography of the residue eluting with 1:1 EtOAC/Hexane afforded 0.12 g of the title compound (80%). NMR(CDCl3) 8.56 (m, 1H); 8.40-8.48 (m, 1H); 7.9-7.95 (m, 1H); 7.8- 7.91 (m, 1H); 7.68-7.76 (m, 1H); 7.10-7.35 (m, 8H); 7.05 (m, 1H); 6.95-7.01 (m, 2H); 5.8-5.9 (m, 1H); 4.81 (s, 2H); 4.5-4.65 (m, 1H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSVNH3)/MS: 648(M+H)+; 665(M+NH4)+.

Example 1229B N-[4-N-(N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyl)-2-(2 - methylphenyl)benzoyll methionine lithium salt Prepared according to the procedure of example 1 178J from 1229A. NMR 1H(MeOH-d4): 8.35-8.45 (2H, m); 7.78-7.85 (2H, m), 7.5-7.6 (1H, m); 7.3-7.4 (lH, m); 7.1-7.3 (8H, m); 6.95-7.15 (3H, m); 4.9 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (lOH, m).

ESI(-)/MS: 632(M-Li).

Example 1230 N-[4-N-(N-phenyl-N-(4-fluorobenzenesulfonyl)aminomethyl)-2-( 2- methylphenyl)benzoyl]methionine lithium salt Example 1230A N-f4-N-(N-phenyl-N-(4-fluorobenzenesulfonvl)aminomethyl)-2-( 2- methylphenyl)benzoyl]methionine. methyl ester Prepared according to the procedure of example 1229A from reaction between 1236C and 4-fluorophenylsulfonyl chloride. NMR(CDCl3) 7.78-7.82 (m, 1H); 7.58-7.68 (m, 2H); 7.25-7.32 (m, 10H); 7.08 (m, 1H); 6.95-7.01 (m, 2H); 5.8-5.9 (m, 1H); 4.79 (s, 2H); 4.5-4.65 (m, 1H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 621(M+NH4)+; 638(M+NH4)+.

Example 1230B N-[4-N-(N-phenyl-N-(4-fluorobenzenesulfonyl)aminomethyl)-2-( 2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1230A. NMR 1H(MeOH-d4): 7.65-7.8 (2H, m); 7.5-7.6 (IH, m); 7.1-7.3 (11H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (1OH, m). ESI(-)/MS: 605(M-Li).

Example 1231 N-[4-N-(N-phenyl-N-(4-ethylbenzenesulfonyl)aminomethyl)-2-(2 - methylphenvl)benzovl1methionine lithium salt Example 1231A N-T4-N- (N-Dhenvl-N-(4-ethvlbenzenesulfonvl )aminomethvl)-2-(2- methylphenyl)benzoyl]methionine. methyl ester Prepared according to the procedure of example 1229A from reaction between 1236C and 4-ethylphenylsulfonyl chloride. NMR(CDCl3) 7.78-7.82 (m, 1H); 7.55-7.60 (m, 2H); 7.25-7.32 (m, 10H); 7.08 (m, 1H); 6.95-7.01 (m, 2H); 5.8-5.9 (m, 1H); 4.76 (s,

2H); 4.5-4.65 (m, 1H); 3.62 (s, 3H); 2.7-2.78(m, 2H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, lH); 1.5-1.7 (m, lH); 1.2-1.35(m, 3H). (DSI/NH3)/MS: 631(M+H)+; 648(M+NH4)+ Example 1231 N-{4-N-(N-phenvl-N-(4-ethvlbenzenesulfonvl)aminomethvl)-2-(2 - methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1231A. NMR 1H(MeOH-d4): 7.5-7.6 (3H, m); 7.1-7.4 (9H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1- 4.22 (1H, m); 2.7 (2H, q)1.7-2.1 (1OH, m) (1H, m); 1.25 (3H, t). ESI(-)/MS: 615(M-Li).

Example 1232 N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyl)-2-(2 - methylphenyl)benzoyl]methionine lithium salt Example 1232A N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyl)-2-(2 - methvlphenvl)benzovllmethionine methyl ester

Prepared according to the procedure of example 1229A from reaction between 1236C and 4-nitrophenylsulfonyl chloride. NMR(CDC13) 8.56 (m, lH); 8.40-8.48 (m, 1H); 7.9-7.95 (m, 1H); 7.8-7.91 (m, 1H); 7.68-7.76 (m, 1H); 7.10-7.35 (m, 8H); 7.05 (m, 1H); 6.95-7.01 (m, 2H); 5.8-5.9 (m, 1H); 4.81 (s, 2H); 4.5-4.65 (m, 1H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSl/NH3)/MS: 648(M+H)+; 665(M+NH4)+ Example 1232B N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyl)-2-(2 - methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1232A. NMR 1H(MeOH-d4): 8.45-8.55 (1H, m); 8.35-8.38 (1H, m); 8.0-8.1 (1H, m); 7.8-7.9 (1H, m); 7.5-7.7 (1H, m); 7.3-7.4 (1H, m); 7.1-7.3 (8H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 632(M-Li).

Example 1233 N-[4-N-(N-phenyl-N-(4-dichlorobenzenesulfonyl)aminomethyl)-2 -(2- methylphenyl)benzoyl]methionine lithium salt

Example 1233A N-[4-N-(N-phenyl-N-(2,3-dichlorobenzenesulfonyl)aminomethyl) -2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1229A from reaction between 1236C and 3,4-dichlorophenylsulfonyl chloride. NMR(CDCl3) 7.6-7.7 (m, 1H); 7.5-7.55 (m, 1H); 7.55-7.6 (m, 1H); 7.40-7.43 (m, 1H); 7.15-7.36 (m, 8H); 7.08 (m, 1H); 6.95- 7.01 (m, 2H); 5.8-5.9 (m, 1H); 4.78 (s, 2H); 4.5-4.65 (m, 1H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 671(M+NH4)+ Example 1233B N-[4-N-(N-phenyl-N-(2,3-dichlorobenzenesulfonyl)aminomethyl) -2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1233A. NMR 1H(MeOH-d4): 7.7-7.8 (2H, m); 7.5-7.6 (2H, m), 7.1-7.3 (9H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 655(M-Li).

Example 1234 N-[4-N-(N-3,4-(methylenedioxy)-N-(4-fluorobenzyl)aminomethyl )-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Example 1234A Prepared according to the procedure of example 1236A. Instead of using aniline, 3,4-(methylenedioxy)aniline was used to make the title compound. NMR(CDCl3) 7.90-7.96 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.30 (m, 4H); 7.00-7.18 (m, 1H); 6.80-6.83 (m, 1H); 6.22-6.26 (m, 1H); 6.00-6.08 (m, 1H); 5.82 (s, m); 4.32-4.39 (m, 2H); 3.95-4.00 (m, 1H); 3.60 (s, 3H); 2.05 (s, 3H). (DSI/NH3)/MS: 376(M+H)+; 373(M+NH4)+ Example 1234B Prepared according to the procedure of example 1 178H from 1234A. NMR(CDCl3) 7.90-7.96 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.30 (m, 4H); 7.00-7.18 (m, 1H); 6.80-6.83 (m, 1H); 6.22-6.26 (m, 1H); 6.00-6.08 (m, 1H); 5.82 (s, 2H); 4.32-4.39 (m, 2H); 3.95- 4.00 (m, 1H); 2.05 (s, 3H). (DSVNH3)/MS: 362(M+H)+; 351(M+NH4)+.

Example 1234C Prepared according to the procedure of example 11781 from 1234B. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.18-7.30 (m, 6H); 7.00-7.18 (m, 1H); 6.6-6.65 (m, lH); 6.35-6.40 (m, 1H); 6.10-6.20 (m, 1H); 5.82 (m, 3H); 4.5-4.70 (m, 3H); 3.61 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSl/NH3)/MS: 507(M+H)+; 324(M+NH4)+ Example 1234D N-[4-N-(N-(3,4-methylenedioxy)phenyl-N-(4-fluorobenzyl)amino methyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1235C and benzyl bromide. NMR(CDC13) 7.85-7.95 (m, 1H); 7.18-7.30 (m, 10H); 7.02- 7.18 (m, 1H); 6.6-6.65 (m, 1H); 6.35-6.40 (m, 1H); 6.15-6.20 (m, 1H); 5.82 (m, 3H); 4.59-4.70 (m, 3H); 4.57 (s, 2H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5- 1.7 (m, 1H). (DSI/NH3)/MS: 597(M+H)+.

Example 1234E N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)amino methyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Prepared according to the procedure of example 1 178J from 1234D. NMR 1H(MeOH-d4): 7.5-7.6 (1H, m); 7.2-7.25 (1H, m); 7.0-7.2 (9H, m); 6.9-7.0 (2H, m); 6.5-6.57 (1H, m); 6.3 (1H, m); 6.1 (1H, m); 5.75 (2H, s); 4.45 (2H, s); 4.4 (2H, s); 4.1- 4.2 (1H, m); 1.7-2.1 (1OH, m). ESI(-)/MS: 581(M-Li).

Example 1235 N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)amino methyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1235A N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)amino methyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1234C and 4-fluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, 1H); 7.18-7.61 (m, 7H); 6.92-7.18 (m, 3H); 6.6-6.65 (m, 1H); 6.35-6.40 (m, 1H); 6.15-6.20 (m, 1H); 5.82 (m, 3H); 4.57-4.65 (m, 1H); 4.53 (s, 2H); 4.50 (s, 2H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7- 2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 614(M+H)+.

Example 1235B N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)amino methyl)-2-(2- methylphenvl)benzovllmethionine lithium salt Prepared according to the procedure of example 1 178J from 1235A. NMR 1H(MeOH-d4): 7.5-7.6 (1H, m); 7.2-7.25 (1H, m); 7.0-7.2 (8H, m); 6.9-7.0 (2H, m); 6.5-6.57 (1H, m); 6.3 (1H, m); 6.1 (1H, m); 5.75 (2H, s); 4.45 (2H, s); 4.4 (2H, s); 4.1- 4.2 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 599(M-Li).

Example 1236 N-[4-N-(N-phenyl-N-(2-fluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1236A 4-(N-phenyl)aminomethyl-2-(2-methylphenyl)benzoic acid, methyl ester A mixture of 4-Bromomethyl-2-(2-methylphenyl)benzoic acid, methyl ester (6.12 g, 20 mmol), aniline (1.68 g, 20 mmol), NaHCO3 (1.68 g, 40 mmol), and Bu4N+I- (0.74g, 2

mmol) in 50 ml of DMF was heated at 75°C under N2 for 12 hours. The reaction mixture was quenched by adding 400 ml of water. The solution was then extracted by 300 ml of EtOAc, washed by brine and dried over MgSO4. Flash chromatography of residue on silica gel eluting with 80:20 EtOAc/Hexane afforded 6.1 g of pure product(96%). NMR(CDCl3) 7.85-7.95 (m, 1H); 7.40-7.45 (m, 1H); 7.0-7.36 (m, 7H); 6.68-6.78 (m, 1H); 6.58-6.65 (m, 2H); 4.2 (s, 2H); 4.05-4.2 (m, 1H); 3.58 (s, 3H); 2.05 (s, 3H). (DSI/NH3)/MS: 332(M+H)+, 349(M+NH4)+ Example 1236B 4-(N-phenyl)aminomethyl-2-(2-methylphenyl)benzoic acid Prepared according to the procedure of example 1 178H from 1236A. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.40-7.45 (m, 1H); 7.0-7.36 (m, 7H); 6.68-6.78 (m, 1H); 6.58-6.65 (m, 2H); 4.2 (s, 2H); 4.05-4.2 (m, 1H); 2.05 (s, 3H). (DSI/'NH3)/MS: 318(M+H)+, 335(M+NH4)+.

Example 1236C N-4-[(N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methion ine, methyl ester Prepared according to the procedure of example 11781 from 1236B. NMR(CDC13) 7.85-7.95 (m, 1H); 7.41-7.47 (m, 1H); 7.1-7.36 (m, 7H); 6.68-6.78 (m, 1H); 6.58-6.65 (m, 2H); 5.85-5.95 (m, 1H); 4.56-4.68 (m, 1H); 4.2 (s, 2H); 4.05-4.2 (m, 1H); 3.62 (s, 3H); 2.05 (s, 3H); 2.0-2.15 (m, 8H), 1.7-2.0 (m, 1H), 1.5-1.7 (m, 1H).. (DSl/NH3)/MS: 463(M+H)+, 480(M+NH4)+.

Example 1236D N-14-N-(N-phenyl-N-(2-fluorobenzvl)aminomethvl)-2-(2- methvlphenvl)benzoyllmethionine. methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 2- fluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, lH); 7.0-7.4 (m, 12H); 6.65-6.78 (m, 3H); 5.8-5.9 (m, 1H); 4.75 (m, 4H); 4.58-4.65 (m, 1H); 3.65 (s, 3H), 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). MS/(DSI/NH3 ): 571(M+H)* Example 1236E N-[4-N-(N-phenyl-N-(2-fluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J for making lithium salt.

NMR 1H(MeOH-d4): 7.6-7.7 (1H, d); 7.3-7.4 (1H, d); 7.0-7.4 (9H, m); 6.6-6.85 (6H, m); 4.7 (2H, s); 4.65 (2H, s); 4.2-4.3 (1H, m); 1.5-2.2 (10H, m). ESI(-)/MS: 555(M-Li).

Example 1237

N-[4-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1237A N-[4-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 3- fluorobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, lH); 6.9-7.4 (m, 12H); 6.75-6.8 (m, 3H); 5.8-5.9 (m, 1H); 4.70 (s, 2H); 4.58-4.65 (m, 3H); 3.62 (s, 3H); 2.0-2.15 (m, H), 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 571(M+H)* Example 1237B N-r4-N-(N-phenvl-N-(3-fluorobenzvl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1237A. NMR 1H(MeOH-d4): 7.6-7.7 (2H, m); 6.86-7.4 (10H, m); 6.6-6.85 (4H, m); 4.75-4.85 (4H, m); 4.18-4.3 (1H, m); 1.6-2.2 (10H, m). ESI(-)/MS: 555(M-Li).

Example 1238 <BR> <BR> N-14-N-(N-phenvl-N-(4-fluorobenzYl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1238A N-[4-N-(N-phenyl-N-(4-fluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 4- fluorobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.15-7.4 (m, 9H); 6.95-7.15 (m, 3H); 6.7-6.8 (m, 3H); 5.8-5.9 (m, 1H); 4.70 (s, 2H); 4.58-4.65 (m, 3H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 571(M+H)+.

Example 1238B N- F4-N-(N-phenyl-N-(4-fluorobenzvl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1238A. NMR 1H(MeOH-d4): 7.6-7.7 (2H, m); 6.86-7.4 (10H, m); 6.6-6.85 (4H, m); 4.65-4.85 (4H, m); 4.18-4.3 (1H, m); 1.6-2.2 (10H, m). ESI(-)/MS: 555(M-Li).

Example 1239 N-[4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyl)-2-(2- methvlphenvl)benzoyllmethionine lithium salt Example 1239A N-[4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyl)-2-(2- methvlphenvl)benzovllmethionine methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-bormobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, 1H); 7.05-7.48 (m, 12H); 6.65-6.78 (m, 3H); 5.8-5.9 (m, 1H); 4.75 (s, 2H); 4.55-4.65 (m, 3H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 631(M+H)+ Example 1239B N-[4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt

Prepared according to the procedure of example 1 178J from 1239A. NMR 1H(MeOH-d4): 7.58-7.67 (1H, d); 7.38-7.46 (2H, d); 7.3-7.39 (H, d); 7.0-7.3 (llH, m); 6.6-6.8 (3H, m); 4.75 (2H, s); 4.65 (2H, s); 4.18-4.3 (1H, m); 1.5-2.2 (10H, m). ESI(- )/MSf 615(M-Li), 573.

Example 1240 N-[4-N-(N-phenyl-N-(4-cyanobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1240A N-[4-N-(N-phenyl-N-(4-cyanobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-cyanobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.58-7.65 (m, 2H); 7.1-7.4 (m, 10H); 6.65-6.80 (m, 3H); 5.8-5.9 (m, 1H); 4.65 (m, 4H); 4.58-4.64 (m, 1H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 578(M+H)+

Example 1240B N-[4-N-(N-phenvl-N-(4-cvanobenzyl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine lithium salt Prepared according to the procedure of example 1 178J from 1240A. NMR 1H(MeOH-d4): 7.6-7.7 (3H, m); 7.4-7.5 (2H, m); 7.35-7.4 (1H, m); 7.02-7.3 (lOH, m); 6.6-6.7 (3H, m) 4.9 (2H, s); 4.75 (2H, s); 4.18-4.3 (1H, m); 1.5-2.2 (lOH, m). ESI(- )/MS: 562(M-Li).

Example 1241 N-[4-N-(N-phenyl-N-(4-methoxybenzyl)aminomethyl)-2-(2- methvlphenvl)benzoyllmethionine lithium salt Example 1241A N-r4-N-(N-phenyl-N-(4-methoxvbenzvl)aminomethvl!-2-(2- methylphenyl]benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-methoxybenzyl bromide. NMR(CDC13) 7.85-7.95 (m, 1H); 7.15-7.4 (m,

12H); 6.8-6.9 (m, 1H); 6.7-6.8 (m, 2H); 5.8-5.9 (m, 1H); 4.65 (m, 3H); 4.60 (s, 2H); 3.81 (s, m); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H).

(DSI/NH3)/MS: 583(M+H)+ Example 1241B N-r4-N-lN-phenvl-N-(4-methoxvbenzvl)aminomethvl)-2-12- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1241A. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.0-7.3 (10H, m); 6.6-6.85 (6H, m); 4.68 (2H, s); 4.58 (2H, s); 4.18-4.3 (1H, m); 3.88 (3H, s); 1.5-2.2 (10H, m). ESI(-)/MS: 567(M-Li); 445.

Example 1242 N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2- (2- methylphenyl)benzoyl]methionine lithium salt Example 1242A

N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2- (2- methylphenyl)benzoyll methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-trifluoromethoxybenzyl bromide. NMR(CDC13) 7.85-7.95 (m, 1H); 7.15-7.4 (m, 12H); 6.8-6.9 (m, 1H); 6.7-6.8 (m, 2H); 5.8-5.9 (m, 1H); 4.65 (m, 3H); 4.60 (s, 2H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 636(M+H)+.

Example 1242B N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2- (2- methylphenyl)benzovllmethionine lithium salt Prepared according to the procedure of example 1 178J from 1242A. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.3-7.4 (3H, d), 7.05-7.25 (9H, m); 6.7-6.8 (2H, m); 6.6-6.7 (1H, m); 4.7-4.8 (4H, m); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 621 (M-Li).

Example 1243 N-[4-N-(N-phenyl-N-(4-nitrobenzyl)aminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt

Example 1243A N-[4-N-(N-phenyl-N-(4-nitrobenzyl)aminomethyl)-2-(2-methylph enyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-nitrobenzyl bromide. NMR(CDCl3) 8.15-8.20 (m, 2H); 7.85-7.95 (m, 1H); 7.1-7.45 (m, 10H); 6.75-6.81 (m, 1H); 6.65-6.71 (m, 2H); 5.78-5.88 (m, 1H); 4.7-4.8 (ss, 4H); 4.6-4.75 (m, 1H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, lH); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 598(M+H)+; 615 (M+NH4)+ Example 1243B N-[4-N-(N-phenyl-N-(4-nitrobenzyl)aminomethyl)-2-(2-methylph enyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1243A. NMR 1H(MeOH-d4): 8.15-8.2 (2H, m); 7.6-7.7 (1H, m), 7.48-7.56 (2H, m); 7.35-7.41 (1H, m); 7.15-7.3 (8H, m); 6.65-6.78 (3H, m), 4.78-4.85(4H, m); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 582(M-Li).

Example 1244

N-[4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, dilithium salt Example 1244A N-[4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- methvlphenvl)benzovllmethionine. dimethyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and methyl 4-(bromomethyl) benzyolate. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.18- 7.40 (m, 12H; 6.7-6.85 (m, 3H); 5.8-5.9 (m, 1H); 4.7 (s, 4H); 4.58-4.68 (m, 1H); 3.90 (s, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H).

(DSI/NH3)/MS: 628(M+NH4)+.

Example 1244B N-[4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, dilithium salt Prepared according to the procedure of example 1 178J from 1244A. NMR 1H(MeOH-d4): 7.9-8.0 (2H, m); 7.6-7.7 (1H, m), 7.3-7.4 (2H, m); 7.1-7.28 (9H, m); 6.7-6.75 (2H, m); 6.6-6.7 (1H, m); 4.78 (2H, s); 4.70 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (lOH, m). ESI(-)/MS: 595(M-Li).

Example 1245 <BR> <BR> N-r4-N-(N-phenyl-N-(4-phenvlbenzYl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1245 A N-[4-N-(N-phenyl-N-(4-phenylbenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1 236A from reaction between 1236C and 4-phenylbenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.1-7.45 (m, 17H); 6.75-6.81 (m, 1H); 6.65-6.7 (m, 3H); 5.8-5.9 (m, 1H); 4.7-4.8 (ss, 4H); 4.6-4.75 (m, 1H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 629(M+H)+ Example 1245B <BR> <BR> <BR> N-t4-N-(N-phenyl-N-(4-phenylbenzyl!aminomethyl)-2-(2- methylphenyl)benzoyl)methionine lithium salt

Prepared according to the procedure of example 1 178J from 1245A. NMR 1H(MeOH-d4): 7.1-7.7 (19H, m); 6.7-6.8 (2H, m); 6.6-6.7 (1H, m); 4.7-4.8 (4H, m); 4.1-4.22 (1H, m); 1.7-2. (10H, m). ESI(-)/MS: 613(M-Li).

Example 1246 <BR> <BR> N-T4-N-(N-Dhenvl-N-(4-N-carboxvmethionin )aminomethvl-2-(2- methylphenyl)benzoyl]methionine dilithium salt, Example 1246A 4-(chloromethyl)-benzoylmethionine, methyl ester A mixture of 4-(chloromethyl)-benzoyl chloride (0.189 g, 1 mmol), methionine methyl ester hydrochloride (0.199 g, 1 mmol), and 0.5 ml of pyridine in 5 ml of chloroform was stirred for 12 hours. The organic solution was washed with 10 % HCl, brine, and dried over MgSO4. Flash chromatography of the residue afforded 0.20 g of desired product (64%). NMR(CDC13) 7.80-7.85 (m, 2H); 7.28-7.32 (m, 2H; 6.9-7.0 (m, 1H); 4.9-5.0 (m, 1H); 4.60 (s, 2H); 3.80 (s, 3H); 3.68 (s, 3H); 2.35-2.45 (m, 2H); 2.12-2.35 (m, 1H); 2.1- 2.2 (m, 1H). (DSI/NH3)/MS: 316(M+H)+; 333(M+NH4)*.

Example 1246B N-[4-N-(N-phenyl-N-(4-N-carboxymethionine)benzyl)aminomethyl )-2-(2- methylphenyl)benzoyl]methionine, dimethyl ester Prepared according to the procedure of example 1236A from the reaction between 1236C and 1246A. NMR(CDC13) 7.85-7.95 (m, 1H); 7.75-7.80 (m, 2H); 7.18-7.35 (m, 9H); 7.10 (s, 1H); 6.9-6.95 (m, 1H); 6.68-6.78 (m, 3H); 5.8-5.9 (m, 1H); 4.81(s, 2H); 4.5-4.65 (m, 1H); 3.80 (s, 3H); 3.68 (s, 3H); 2.35-2.45 (m, 2H); 2.12-2.35 (m, 1H); ); 2.0-2.15 (m, 9H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSl/NH3)/MS: 742(M+H)+ Example 1246C N-[4-N-(N-phenyl-N-(4-N-carboxymethionine)benzyl)aminomethyl )-2-(2- methylphenyl)benzovllmethionine dilithium salt.

Prepared according to the procedure of example 1 178J from 1246B. NMR 1H (d4- MeOH): 7.8-7.9 (2H, m); 7.6-7.7 (1H, m); 7.3-7.4 (4H, m); 7.2 (4H, m); 7.1 (4H, m); 6.7-6.75 (2H, m); 6.6-6.7 (1H, m); 4.8 (4H, m); 4.5-4.6 (1H, m); 4.2-4.3 (1H, m); (2.5- 2.65 (2H, m); 1.6-2.3 15H, m). ESI(-)/MS: 711 (M-Li); 733 (M+Na-2H).

Example 1247 N-[4-N-(N-phenyl-N-(2-naphthyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine lithium salt

Example 1247A N-[4-N-(N-phenyl-N-(2-naphthyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 2-bromomethyl-naphthalene. NMR(CDCl3) 7.68-7.95 (m, SH); 7.18-7.45 (m, 11H); 7.1 (s, 1H); 6.7-6.85 (m, 3H); 5.8-5.9 (m, 1H); 4.80 (s, 2H); 4.76 (s, 2H); 4.56- 4.7 (m, 1H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H).

(DSl/NH3)/MS: 603(M+H)+ Example 1247B N-[4-N-(N-phenyl-N-(2-naphthyl)aminomethyl)-2-(2-methylpheny l)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1247A. NMR 1H(MeOH-dq): 7.78-7.84 (2H, m); 7.6-7.8 (3H, m), 7.3-7.5 (4H, d); 7.0-7.25 (8H, m); 6.8-7.0 (2H, m); 6.75-6.82 (2H, m); 6.6-6.6 (1H, m); 4.8 (2H, s); 4.85 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 587(M-Li).

Example 1248 N-[4-N-(N-phenyl-N-(9-methyl-anthracene-yl)aminomethyl)-2-(2 - methylphenvl)benzovllmethionine lithium salt Example 1248A N-[4-N-(N-phenyl-N-(9-methyl-anthracene-yl)aminomethyl)-2-(2 - methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 9-bromomethyl-anthracene. NMR(CDCl3) 8.4 (s, 1H); 8.1-8.2 (m, 2H); 7.9- 8.0 (m, 2H); 7.0-7.65 (m, 12H); 7.1 (s, 1H); 6.8-6.95 (m, 3H); 5.8-5.9 (m, 1H); 5.45 (s, 2H); 4.68 (m, 1H); 4.25 (s, 2H); 3.60 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5- 1.7 (m, 1H). (DSI/NH3)/MS: 653(M+H)+ .

Example 1248B N-14-N-(N-phenvl-N-(9-methyl-anthracene-vl)aminomethvl)-2-(2 - methylphenvl)benzoyll methionine lithium salt Prepared according to the procedure of example 1 178J from 1248A. NMR 1H(MeOH-d4): 8.45 (1H, s); 8.17-8.22 (2H, m), 7.9-8.05 (2H, m); 7.1-7.5 (13H, m),

6.8-6.95 (3H, m); 6.5-6.67 (1H, m); 5.45 (2H, s); 4.5 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 637(M-Li).

Example 1249 N-[4-N-(N-phenyl-N-(2-methyl-anthraquinone-yl)aminomethyl)-2 -(2- methylphenyl)benzoyl]methionine lithium salt Example 1249A N-[4-N-(N-phenyl-N-(2-methyl-anthraquinone-yl)aminomethyl)-2 -(2- methylphenyl)benzovllmethionine. methvl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 2-bromomethyl-anthraquinone. NMR(CDCl3) 8.4 (s, 1H); 8.0-8.35 (m, 3H); 7.9-8.0 (m, 2H); 7.0-7.65 (m, llH); 6.8-6.95 (m, 3H); 5.8-5.9 (m, 1H); 4.8 (s, 2H); 4.78 (s, 2H); 4.56-4.7 (m, 1H); 3.63 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSVNH3)/MS: 683(M+H)+.

Example 1249B N-{4-N-(N-phenyl-N-(2-methyl-anthraquinone-vl)aminomethvl)-2 -(2- methvlphenvl)benzovllmethionine lithium salt Prepared according to the procedure of example 1 178J from 1249A. NMR 1H(MeOH-d4): 8.1-8.3 (4H, m); 7.8-7.9 (2H, m), 7.7-7.8 (1H, m); 7.6-7.7 (1H, m); 7.25-7.35 (1H, m); 7.0-7.3 (8H, m); 6.75-6.8 (2H, m); 6.6-6.7 (1H, m); 4.9 (2H, s); 4.8 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (1OH, m). ESI(-)/MS: 667(M-Li).

Example 1250 <BR> <BR> N-14-N-(N-phenvl-N-(2,3-difluorobenzvl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine lithium salt Example 1250A N-[4-N-(N-phenyl-N-(2,3-difluorobenzyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, methyl ester

Prepared according to the procedure of example 1236A from reaction between 1236C and 2,3-difluorobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 6.95-7.40 (m, I lH); 6.68-6.8 (m, 3H); 5.8-5.9 (m, 1H); 4.75 (s, 2H); 4.70 (s, 2H); 4.60-4.70 (m, 1H); 3.70 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 589(M+H)+ Example 1250B N-14-N-(N-phenvl-N-(2.3-difluorobenzvl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1250A. NMR 1H(MeOH-d4): 7.7-7.8 (1H, m); 7.3-7.4 (1H, m), 7.0-7.28 (11H, m); 6.65-6.75 (3H, m); 4.8-4.85 (4H, m); 4.1-4.22 (1H, m); 1.7-2.1 (1 OH, m). ESI(-)/MS: 573(M-Li).

Example 1251 N-[4-N-(N-phenyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzovllmethionine lithium salt

Example 1251A N-[4-N-(N-phenyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzovllmethionine. methvl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 2,4-difluorobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.18-7.40 (m, 9H); 7.1 (s, 1H); 6.7-6.85 (m, 4H); 5.8-5.9 (m, 1H); 4.7 (s, 2H); 4.68 (m, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 589(M+H)+ Example 1251B N-F4-N-(N-phenyl-N-(2.4-difluorobenzvl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1251A. NMR 1H(MeOH-d4): 7.6-7.68 (1H, m); 7.3-7.4 (1H, m), 7.3-7.4 (1H, d); 7.0-7.3 (9H, m); 6.8-7.0 (2H, m); 6.6-6.8 (3H, m); 4.70 (2H, s); 4.75 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 573(M-Li).

Example 1255 N- F4-N-(N-phenyl-N-(2-thiophenesulfonyl)aminomethyl )-2-C2- methylphenyl)benzoyll methionine lithium salt

Example 1255A N-[4-N-(N-phenyl-N-(2-thiophenesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1229A from reaction between 1236C and 2-thiophenesulfonyl chloride. NMR(CDCl3) 7.75-7.82 (m, 1H); 7.60-7.62 (m, 1H); 7.39-7.42 (m, 1H); 7. 12-7.38 (m, 9H); 7.05-7.11 (m, 2H); 6.95-7.05 (m, 2H); 5.8- 5.9 (m, 1H); 4.78 (s, 2H); 4.5-4.65 (m, 1H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 609(M+H)+; 626(M+NH4)+ Example 1255B N-[4-N-(N-phenyl-N-(2-thiophenesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1255A. NMR 1H(MeOH-d4): 7.8-7.9 (1H, m); 7.5-7.6 (1H, m), 7.42-7.45 (1H, m); 7.1-7.3 (9H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 593(M- Li).

Example 1256 N-[4-N-(N-phenyl-N-(2-methyl-4-methylenethiazolyl)aminomethy l)-2-(2- methylphenyl)benzoyllmethionine lithium salt Example 1256A N-[4-N-(N-phenyl-N-(2-methyl-4-methylenethiazolyl)aminomethy l-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-methyl-2-(bromomethyl)-thiazole. NMR(CDCl3) 7.82-7.95 (m, lH); 7.10- 7.40 (m, 9H); 6.8 (s, 1H); 6.7-6.8 (m, 2H); 5.8-5.9 (m, 1H); 4.78 (s, 2H); 4.75 (s, 2H); 4.56-4.7 (m, 1H); 3.68 (s, 3H); 2.67 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, lH); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 574(M+H)*.

Example 1256B N-[4-N-(N-phenyl-N-(2-methyl-4-methylenethiazolyl)aminomethy l)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from 1256A. NMR 1H(MeOH-d4): 7.6-7.68 (1H, m); 7.32-7.4 (1H, m), 7.0-7.28 (9H, m); 6.7-6.8 (2H, m); 6.6-6.7 (1H, m); 4.78 (2H, s); 4.70 (2H, s); 4.1-4.22 (1H, m); 2.62 (3H, s); 1.7-2.1 (10H, m). ESI(-)/MS: 558(M-Li).

Example 1257 <BR> <BR> <BR> N- 14-N-(N-3 ,5-difluorophenyl-N-(5-thiazolvlmethvl)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt, Example 1257A Prepared according to the procedure of example 1258A from reaction between 3,5- difluoroaniline and 5-thizaolecarboxaldehyde. NMR(CDCl3) 8.85 (s, 1H); 7.82 (s, 1H); 6.10-6.30 (m, 3H); 4.56 (s, 2H); 4.05-4.50 (m, 1H). DSI/'NH3)/MS: 227(M+H)+; 244(M+NH4)+ Example 1257B Prepared according to the procedure of example 1287B from reaction between 1257A and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR(CDCl3) 8.75-8.80 (s, 1H); 7.82-8.00 (m, 1H); 7.75 (s, 1H); 7.12-7.38 (m, 4H); 7.00-7.10 (m, 2H); 6.20-6.27 (m, 3H); 4.80 (s, 2H); 4.60 (s, 2H); 3.60 (s, 3H); 2.03 (s, 3H).

DSI/NH3)/MS: 465(M+H)+; 482(M+NH4)+.

Example 1257C N-[4-N-(N-3,5-difluorophenyl-N-(5-thiazolylmethyl)aminomethy l)-2-(2- methylphenyl)benzoyl]methionine, methyl ester.

Prepared according to the procedure of example 1258C from 1257B. NMR(CDCl3) 8.75-8.80 (s, 1H); 7.80-7.90 (m, 1H); 7.65-7.80 (m, 1H); 7.12-7.38 (m, SH); 6.93 (s, 1H); 6.10-6.20 (m, 3H); 4.68 (s, 2H); 4.48-4.60 (m, 3H); 3.57 (s, 3H); 1.90-2.10 (m, 8H); 1.60-1.90 (m, 1H); 1.45-1.60 (m, 1H). DSI/NH3)/MS: 596(M+H)+ Example 1257D N-[4-N-(N-3,5-difluorophenyl-N-(5-thiazolylmethyl)aminomethy l)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1257C. 1H NMR (MeOH-d4): 8.9 (1H, s); 7.8 (1H, s); 7.6-7.7 (1H, m); 7.3-7.4 (1H, m); 7.1-7.3 (3H, m); 7.0-7.1 (1H, s); 6.3-6.45 (2H, m); 6.2-6.3 (1H, s); 4.95 (2H, s); 4.7 (2H, s); 4.1-4.22 (1H, m); 1.6-2.2 (lOH, m). ESI(-)/MS: 580(M-Li). Anal. Calcd for C30H28F2N3O3S2Li.1.73H2O: C, 58.23; H, 5.12; N, 6.79. Found: C, 58.24; H, 4.90; N, 6.54.

Example 1258 N-[4-N-(N-(5-thiazolylmethyl)-N-(3,5-difluorobenzyl)aminomet hyl)-2-(2- methylphenyl)benzoyllmethionine lithium salt.

Example 1258A A mixture of 3,5-difluorobenzyl amine (2.0 g, 14.2 mmol), 4-formyl-2-(2- methylphenyl)benzoic acid methyl ester (3.6 g, 14.2 mmol), and sodium triacetoxyborohydride (6.0 g, 28.8 mmol) in 50 ml of 1,2-dichloroethane was stirred for 24 hours. The reaction mixture was washed with 4N NaOH and with brine, then dried over anhydrous MgSO4. Flash chromatography of the reside from evaporation of the organic solution eluting with 1:1 EtOAc/Hexane afforded 4.01 g of the title compound. (74%).

NMR(CDC13) 7.95-8.00 (m, 1H); 7.38-7.45 (m, 1H); 7.18-7.30 (m, 4H); 7.05-7.15 (m, 1H); 6.85-6.92 (m, 2H); 6.63-6.72 (m, 1H); 3.88 (s, 2H); 3.80 (s, 2H); 3.62 (s, 3H); 2.05 (s, 3H). (DSI/NH3)/MS: 382(M+H)+; 399(M+NH4)+. Example 1258B

Prepared according to the procedure of example 1258A from reaction between 1258A and 5-thiazolealdehyde. NMR(CDCl3) 8.80 (s, 1H); 7.95-8.00 (m, lH); 7.72 (s, lH); 7.50-7.55 (m, 1H); 7.10-7.32 (m, 4H); 7.0-7.1 (m, 1H); 6.9-7.0 (m, 2H); 6.68-6.72 (m, lH); 4.62-4.70 (m, 2H); 3.60 (s, SH); 2.07 (s, 3H). (DSI/NH3)/MS: 479(M+H)+; 496(M+NH4)+ Example 1258C A mixture of 1258B (0.304 g, 0.63 mmol) and lithium hydroxide (0.076 g, 3.15 mmol) in 30 ml of 1:1 water/methanol was refluxed for 12 hours. After cooling to room temperature, the reaction mixture was neutralized to PH= 5-6 carefully by 1.0 M NaHSO4.

The precipitate from neutralization was extracted into 40 ml of EtOAc. The organic solution was then washed by brine, and dried over anhydrous MgSO4. Evaporation of the solvent afforded pure corresponding acid which was used directly for methionine coupling reaction.

A mixture of the acid(0.30g, 0.63 mmol) from previous Step, L-methionine methyl ester hydrochloride (0.252g, 1.26 mmol), 1-hydroxybenzotriazole hydrate (0.43 g, 3.15 mmol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (0.61 g, 3.15 mmol), and triethylamine hydrochloride (0.43 g, 3.15 mmol) in 15 ml of anhydrous DMF was heated under N2 at 750C for 20 hours. After cooling to room temperature, the solution was diluted with 50 ml of EtOAc, then was put to 200 ml of water. The aqueous solution was extracted with another portion of 50 ml of EtOAC. Combined organic solution was washed with 30 ml of saturated NaHCO3 twice, then with 50 mi of brine, finally dried over anhydrous MgSO4. Flash chromatography of the residue from evaporation of the EtOAc solution eluting with 70:30 EtOAc/Hexane afforded 0.235 g of the title compound. (61%).

NMR(CDC13) 8.78 (s, 1H); 7.90-8.00 (m, 1H); 7.72 (s, 1H); 7.50-7.55 (m, 1H); 7.20- 7.38 (m, SH); 6.9-7.0 (m, 2H); 6.68-6.72 (m, 1H); 5.88-5.92 (m, 2H); 4.58-4.70 (m, 1H); 3.88 (s, 2H); 4.62-4.70 (m, SH); 3.60 (s, 2H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 610(M+H)+.

Example 1258D N-[4-N-(N-(5-thiazolylmethyl)-N-(3,5-difluorobenzyl)aminomet hyl)-2-(2- methylphenyl)benzovllmethionine lithium salt.

Prepared according to the procedure of example of 1 178J from example 1258C.

NMR 1H(MeOH-d4): 8.95 (1H, s); 7.78 (1H, s); 7.6-7.7 (1H, m); 7.4-7.5 (1H, m), 7.05-7.3 (SH, m); 6.95-7.05(2H, m); 6.85-6.95 (1H, m); 4.95 (2H, s); 4.1-4.22 (1H, m); 3.9 (2H, s); 4.7 (2H, m); 4.6 (2H, s); 2.25 (2H, s); 1.6-2.1 (8H, m). ESI(-)/MS: 594(M- Li).

Example 1259 N-[4-N-(N-phenyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Example 1259A <BR> <BR> N-{4-N-(N-phenvl-N-(3.5-difluorobenzvl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine. methyl ester

Prepared according to the procedure of example 1236A from reaction between 1236C and 3,5-difluorobenzyl bromide. NMR(CDCl3) 7.85-7.95 (m, 1H); 7.18-7.40 (m, 9H); 7.1 (s, 1H); 6.75-6.8 (m, 2H); 6.65-6.75 (m, 2H); 5.8-5.9 (m, 1H); 4.7 (s, 2H); 4.6 (m, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H).

(DSI/NH3)/MS: 589(M+H)+ Example 1259B N-r4-N-(N-phenvl-N-(3 .5-difluorobenzvl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine lithium salt Prepared according to the procedure of example 1 178J from 1259A. NMR 1H(MeOH-d4): 7.7-7.8 (1H, m); 7.3-7.4 (1H, d), 7.0-7.3 (7H, d); 6.8-6.9 (3H, m); 6.6- 6.8 (4H, m); 4.88 (2H, s); 4.85 (2H, s); 4.1-4.22 (1H, m); 1.7-2.1 (10H, m). ESI(-)/MS: 573(M-Li).

Example 1260 N-[4-N-(N-(4-acetonitrilephenyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt,

Example 1260A Prepared according to the procedure of example 1236A from reaction 3,5- difluorobenzyl bromide, 4-bromomethyl-2-)2-methylphenyl)benzoic methyl ester, and 4- aminobenzyl cyanide. NMR(CDCl3) 7.95-8.00 (m, 1H); 7.02-7.35 (m, 8H); 6.62-6.80 (m, SH); 4.75 (s, 2H); 4.65 (s, 2H); 3.65 (s, 2H); 3.60 (s, 3H); 2.01 (s, 3H). (DSI(NH3)/MS: 497(M+H)+; 514(M+NH4)+ Example 1260B N-[4-N-(N-(4-acetonitrilephenyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from example 1260A.

NMR(CDCl3) 7.85-7.95 (m, 1H); 7.05-7.38 (m, 7H); 7.05 (s, 1H); 6.6-6.80 (m, SH); 5.80-5.90 (m, 1H); 4.70 (s, 2H); 4.60 (s, 2H); 3.65 (s, 2H); 3.61 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSI/NH3)/MS: 628(M+H)+; 645(M+NH4)+ Example 1260C N-[4-N-(N-(4-acetonitrilephenyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methvlphenyl)benzoyll methionine lithium salt.

Prepared according to the procedure of example 1 178J from example 1260B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.3-7.4 (1H, m), 7.0-7.3 (8H, m); 6.65-6.9 (SH, m); 4.78 (2H, s); 4.7 (3H, s); 4.1-4.22 (1H, m); 3.7 (2H, s); 1.7-2.1 (10H, m). ESI(-)/MS: 612(M-Li). Anal. Calcd for C35H32F2N3O3SLi.1.64 H20: C, 64.76; H, 5.48; N, 6.47.

Found: C, 64.75; H, 5.19; N, 6.16.

Example 1261 N-[4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl)aminomethyl)-2-( 2- methylphenyl)benzoyl]methionine lithium salt, Example 1261A N-[4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl)aminomethyl)-2-( 2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 3-methoxy-Snitrobenzyl bromide. NMR(CDCl3) 8.1-8.2 (m, 2H); 8.0 (s, 1H); 7.68-7.95 (m, lH); 7.1-7.40 (m, 8H); 6.9-6.95 (m, 1H); 6.7-6.8 (m, 1H); 6.6-6.7 (m, 2H); 5.8-5.9 (m, 1H); 4.78 (s, 2H); 4.6 (m, 3H); 3.92 (s, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSVNH3)/MS: 628(M+H)+

Example 1261B N-[4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl))aminomethyl)-2- (2- methylphenvl)benzovll methionine lithium salt.

Prepared according to the procedure of example 1 178J from 1261A. NMR 1H(MeOH-d4): 8.1-8.2 (1H, m); 7.9-8.0 (1H, m), 7.6-7.7 (1H, m); 7.3-7.4 (lH, m); 7.0- 7.3 (9H, m); 6.6-6.75 (3H, m); 4.8(2H, s); 4.72 (2H, s); 4.1-4.22(1H, m); 3.95 (3H, s); 1.7-2.1 (1OH, m). ESI(-)/MS: 612(M-Li).

Example 1262 <BR> <BR> N-r4-N-(N-(4-nitrophenvl-N-(4-methoxvbenzvl)aminomethyl)-2-( 2- methylphenyl)benzovllmethionine lithium salt.

Example 1262A Prepared according to the procedure of example 1236A. Instead of using aniline, 4- nitroaniline was used to make the title compound. NMR(CDC13) 8.08-8.11 (m, 2H); 7.94- 8.00 (m, 1H); 7.38-7.42 (m, lH); 7.18-7.24 (m, SH); 7.0-7.18 (m, 1H); 6.55-6.60 (m,

2H); 4.95 (m. 1H); 4.52 (s, 2H); 3.60 (s, 3H); 2.00 (s, 3H). (DSI/NH3)/MS: 394(M+NH4)+ Example 1262B Prepared according to the procedure of example 1 178H from 1262A. NMR(CDCl3) 8.08-8.11 (m, 2H); 7.94-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.18-7.24 (m, SH); 7.0-7.18 (m, 1H); 6.55-6.60 (m, 2H); 4.95 (m, 1H); 4.52 (s, 2H); 2.00 (s, 3H). (DSI/NH3)/MS: 3 80(M+NH4)+ Example 1262C Prepared according to the procedure of example 11781 from 1262B. NMR(CDC13) 8.08-8.11 (m, 2H); 7.94-8.00 (m, 1H); 7.38-7.42 (m, 1H); 7.20-7.38 (m, SH); 7.18-7.20 (m, 1H); 6.55-6.60 (m, 2H); 5.89-5.95 (m, 1H); 4.95-5.00(m, 1H); 4.58-4.70 (m, 1H); 4.55 (m, 2H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, lH); 1.5-1.7 (m, 1H).

(DSI/NH3)/MS: 508(M+H)+; 525(M+NH4)+.

Example 1262D

N-[4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyl)-2-( 2- methylphenyl)benzovllmethionine. methvl ester Prepared according to the procedure of example 1236A from reaction between 1262C and 4-methoxybenzyl bromide. NMR(CDCl3) 8.08-8.11 (m, 2H); 7.94-8.00 (m, lH); 7.38-7.42 (m, 1H); 7.11-7.40 (m, 6H); 7.00 (m, lH); 6.85-6.95 (m, 3H); 6.55-6.60 (m, 2H); 5.89-5.95 (m, lH); 4.80 (s, 2H); 4.70(s, 2H); 4.60-4.70 (m, 1H); 3.80 (s, 3H); 3.67 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H). (DSVNH3)/MS: 628(M+H)+.

Example 1262E N-[4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyl)-2-( 2- methvlphenyl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1262D. NMR 1H(MeOH-d4): 8.0-8.05 (2H, m); 7.4-7.5 (1H, m), 7.3-7.4 (1H, m); 7.18-7.3 (7H, m); 7.0 (1H, m); 6.8-6.9 (4H, m); 4.8-4.85 (4H, m); 4.1-4.22 (lH, m); 3.88 (3H, s); 1.7-2.1 (10H, m). ESI(-)/MS: 612(M-Li).

Example 1263 <BR> <BR> N-[4-N-(N-butvl-N-(3 .5-difluorobenzvl)aminomethvl)-2-(2- methylphenvl)benzovllmethionine lithium salt.

Example 1263A Prepared according to the procedure of example 1258A from reaction between 1258A and butyraldehyde. NMR(CDC13) 7.92-7.98 (m, 1H); 7.38-7.45 (m, 1H); 7.10- 7.32 (m, 4H); 7.0-7.1 (m, 1H); 6.8-6.95 (m, 2H); 6.60-6.75 (m, 1H); 3.58-3.63 (m, 5H); 3.55 (s, 2H); 2.38-2.48 (t, 2H); 2.07 (s, 3H); 1.4-1.6 (m, 2H); 1.2-1.4 (m, 2H); 0.8-0.9 (t, 3H). (DSI/NH3)/MS: 437(M+H)+.

Example 1263B N-[4-N-(N-butyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1263A. NMR(CDCl3) 7.9-8.00 (m, 1H); 7.40-7.46 (m, 1H); 7.20-7.40 (m, 4H); 7.20 (s, 1H); 6.7-6.85 (m, 2H); 6.60-6.75 (m, 1H); 5.82-5.92 (m, 1H); 4.58-4.70 (m, lH); 3.65 (s, 3H); 3.60 (s, 2H); 3.55 (s, 2H); 2.40-2.48 (t, 2H); 2.20 (s, 3H); 1.8-1.96(m, 1H); 1.55-1.65 (m, 1H); 1.45- 1.55 (m, 2H); 1.2-1.4 (m, 2H); 0.8-0.9 (t, 3H). (DSVNH3)/MS: 569(M+H)+.

Example 1263C N-[4-N-(N-butyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt, Prepared according to the procedure of example 1 178J from 1263B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.4-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 3.65 (2H, s); 3.58 (2H, s); 2.4-2.5 (2H, m); 2.21 (1H, m); 1.8-2.1 (1OH, m); 1.4-1.5 (2H, m); 1.22-1.4 (2H, m); 0.8-0.9 (3H, m). ESI(- )/MS: 553(M-Li). Anal. Calcd for C31H35F2N2O3SLi.1.5 LiOH0.26H20: C, 62.04; H, 6.05; N, 4.48. Found: C, 62.04; H, 6.05; N, 4.67.

Example 1264 N-[4-N-(N-(4,4,4-trifluorobutyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methvlphenyl!benzovllmethionine lithium salt.

Example 1264A Prepared according to the procedure of example 1258A from reaction between 1258A and 4,4,4-trifluorobutyraldehyde. NMR(CDC13) 7.92-7.98 (m, 1H); 7.38-7.45 (m, 1H); 7.10-7.32 (m, 4H); 7.0-7.1 (m, 1H); 6.8-6.92 (m, 2H); 6.62-6.78 (m, 1H); 3.58- 3.63 (m, SH); 3.55 (s, 2H); 2.43-2.55 (t, 2H); 2.00-2.1 (m, SH); 1.7-1.82 (m, 2H).(DSI/NH3)/MS: 492(M+H)+.

Example 1264B N-[4-N-(N-(4,4,4-trifluorobutyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1264A. NMR(CDCl3) 7.9-8.00 (m, 1H); 7.40-7.46 (m, 1H); 7.20-7.40 (m, 4H); 7.20 (s, 1H); 6.7-6.85 (m, 2H); 6.60-6.75 (m, 1H); 5.82-5.92 (m, 1H); 4.58-4.70 (m, 1H); 3.65 (s, 3H); 3.61 (s. 2H); 3.55 (s, 2H); 2.40-2.48 (t, 2H); 1.5-2.16 (m, 14H). (DSI/NH3)/MS: 623(M+H)+ Example 1264C N-[4-N-(N-(4,4,4-trifluorobutyl-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Prepared according to the procedure of example 11 78J from 1264B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.4-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 3.65 (2H, s); 3.6 (2H, s); 2.5-2.6 (2H, m); 1.6-2.25 (14H, m); 1.4-1.5 (2H, m); 1.22-1.4 (2H, m); 0.8-0.9 (3H, m). ESI(-)/MS: 609(M-Li).

Anal. Calcd for C31H30F5N2O3SLi.1.21H2O: C, 58.70; H, 5.15; N, 4.42. Found: C, 58.69; H, 5.16; N, 4.18.

Example 1265 <BR> <BR> N- T4-N-(N-cvclohexvl-N-(3 .5-difluorobenzvi)aminomethvl)-2-(2- methylphenyl)benzoyl]methionine lithium salt, Example 1265A.

Prepared according to the procedure of example 1258A from reaction between 1258A and cyclohexanone. NMR (CDC13) 7.90-7.95 (m, 1H); 7.40-7.45 (m, 1H); 7.18- 7.38 (m, 4H); 7.00-7.09 (m, 1H); 6.84-6.94 (m, 2H); 6.58-6.68 (m, 1H); 3.68 (s, 2H); 3.62 (m, SH); 2.40-2.50 (m, 1H); 2.08 (s, 3H); 1.75-1.96 (m, 4H); 1.05-1.65 (m, 6H).

(DSl/NH3)/MS: 464(M+H)+.

Example 1265B N-[4-N-(N-cyclohexyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2 - methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1265A. NMR (CDCl3) 7.85-7.95 (m, 1H); 7.38-7.45 (m, 1H); 7.18-7.38 (m, 4H); 7.2 (s, 1H); 6.84-6.94 (m, 2H); 6.58-6.68 (m, 1H); 5.85-5.93 (m, 1H); 4.56-4.65 (m, 1H); 3.70 (s, 2H); 3.65 (s,

2H); 3.61 (s, 3H); 2.40-2.50 (m, lH); 1.96-2.18 (m, 7H); 1.71-1.96 (m, 6H); 1.55-1.68 (m ,lH); 1.05-1.52 (m, 6H). (DSI/NH3)/MS: 595(M+H)+ Example 1265C N-[4-N-(N-cyclohexyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2 - methylphenyl)benzoyllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1265B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.35-7.45 (1H, m), 7.0-7.35 (SH, m); 6.9-7.0 (2H, m); 6.7-6.8 (lH, m); 4.1-4.22 (1H, m); 3.7 (3H, s); 3.65 (3H, s); 2.4-2.52 (1H, m); 2.1 (lH, m); 1.7-2.1 (11H, m); 1.5-1.7 (2H, m); 1.23-1.5 (2H, m); 1.05-1.25 (3H, m). ESI(-)/MS: 579(M-Li).

Example 1266 N-[4-N-(N-(4-cyclohexanoyl)-N-(3,5-difluorobenzyl)aminomethy l)-2-(2- methylphenyl)benzoyllmethionine lithium salt. Example 1266A

N-[4-N-(N-(4-cyclohexanoyl-N-(3,5-difluorobenzyl)aminomethyl )-2-(2- methylphenyl)benzoyl]methionine, methyl ester A mixture of 1267B (0.42 g, 0.604 mmol) and 10 ml of 10% of HCl in 35 ml of acetone was refluxed until all 1267B disappeared. Solvents were removed under vacuum.

The residue was treated with 20 ml of 2N Na2CO3, then extracted by 50 ml of EtOAc. The organic solution was then washed with brine, dried over anhydrous MgSO4. The crude product was purified by flash chromatography eluting with 1:1 EtOAc/Hexane to afforded 0.25 g of the title compound. NMR (CDC13) 7.82-7.95 (m, 1H); 7.40-7.49 (m, 1H); 7.18- 7.40 (m, SH); 6.82-6.92 (m, 2H); 6.58-6.68 (m, 1H); 5.82-5.91 (m, lH); 4.58-4.68 (m, lH); 3.61-3.75 (m, 7H); 2.95-3.05 (m, 1H); 1.5-2.5 (m, 18H). (DSI/NH3)/MS: 609(M+H)+; 626(M+NH4)*.

Example 1266B N-[4-N-(N-(4-cyclohexanoyl)-N-(3,5-difluorobenzyl)aminomethy l)-2-(2- methylphenyl)benzoylimethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1266A. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.4-7.5 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 3.75 (2H, s); 3.7 (2H, s); 2.1-2.3 (3H, m); 1.76-2.1 (14H, m); 1.5-1.78 (2H, m). ESI(-)/MS: 593(M-Li). Anal. Calcd for C33H35F2N2O4SLi.1.73H2O.1.5LiOH: C, 60.32; H, 5.95; N, 4.26. Found: C, 60.33; H, 5.62; N, 4.04.

Example 1267 N-[4-N-(N-(4-(2,2-dimethyltrimethylene ketal)-cyclohexyl)-N-(3,5- difluorobenzyl )aminomethyl)-2-(2-methylphenvl)benzovlimethionine lithium salt.

Example 1267A Prepared according to the procedure of example 1258A from reaction between 1258A and 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal. NMR (CDCl3) 7.82-7.92 (m, 1H); 7.36-7.42 (m, lH); 7.18-7.38 (m, 4H); 7.20 (s, lH); 6.82-6.92 (m, 2H); 6.58-6.68 (m, 1H);3.68 (s, 2H); 3.60 (s, 3H); 3.59 (s, 2H); 3.48 (s, 2H); 3.42 (s, 2H); 2.50-2.60 (m, 1H); 2.22-2.38 (m, 2H); 1.80-2.20 (m, 6H); 1.2-1.3 (m, 2H); 0.95 (s, 6H). (DSVNH3)/MS: 564(M+H)+.

Example 1267B N-[4-N-(N-(4-(2,2-dimethyltrimethylene ketal)-cyclohexyl)-N-(3,5- difluorobenzyl)aminomethyl)-2-(2-methylphenyl)benzoyl]methio nine, methyl ester Prepared according to the procedure of example 1258C from 1267A. NMR (CDCl3) 7.82-7.92 (m, 1H); 7.36-7.42 (m, 1H); 7.18-7.38 (m, 4H); 7.20 (s, 1H); 6.82-6.92 (m, 2H); 6.58-6.68 (m, 1H); 5.82-5.91 (m, 1H); 4.58-4.68 (m, 1H); 3.68 (s, 2H); 3.60 (s, 3H); 3.59 (s, 2H); 3.48 (s, 2H); 3.42 (s, 2H); 2.50-2.60 (m, 1H); 2.22-2.38 (m, 2H); 1.50-2.2 (m, 14H); 1.2-1.3 (m, 2H); 0.95 (s, 6H). (DSI/NH3)/MS: 695(M+H)+.

Example 1267C N-[4-N-(N-(4-(2,2-dimethyltrimethylene ketal)-cyclohexyl)-N-(3,5- difluorobenzvl)aminomethyl)-2-(2-methylphenvl)benzoyl imethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1267B. NMR 1H(MeOH-d4): 7.55-7.65 (1H, m); 7.38-7.48 (1H, m), 7.0-7.35 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 3.7 (2H, s); 3.65(2H, s); 3.45 (4H, s); 2.5-2.65 (1H, m); 2.26-2.4 (2H, m); 2.2 (1H, s); 1.5-2.1 (13H, m); 1.1-1.3 (2H, m); 0.95 (6H, s).

ESI(-)/MS: 686.79(M-Li). Anal. Calcd for C38H45F2N2O5SLi.0.99H2O.1.0LiOH: C, 62.65; H, 6.64; N, 3.84. Found: C, 62.65; H, 6.33; N, 3.71.

Example 1268 N-[4-N-(N-cyclohexylmethyl-N-(2,4-difluorobenzyl)aminomethyl )-2-(2- methylphenvl)benzovllmethionine lithium salt. Example 1268A

Prepared according to the procedure of example 1258A from the reaction between 2,4-difluorobenzyl amine and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR (CDCl3) 7.22-7.30 (m, 2H); 6.85-6.90 (m, 3H); 3.88 (s, 2H); 2.40-2.45 (m, 2H); 1.6-1.8 (m, 5H); 1.38-1.60 (m, 2H); 1.05-1.40 (m, 3H); 0.8-1.0 (m, 2H). (DSI/NH3)/MS: 240(M+H) + Example 1268B Prepared according to the procedure of example 1258A from reaction between 1268A and cyclohexanecarboxaldehyde. NMR (CDCl3) 7.90-7.95 (m, 1H); 7.38-7.47 (m, 2H); 7.20-7.35 (m, 4H); 7.0-7.10 (m, 1H); 6.75-6.85 (m, 2H); 3.60(s, 3H); 3.55 (s, 2H); 3.52 (s, 2H); 2.20-2.23 (m, 2H); 2.05 (s, 3H); 1.72-1.83 (m, 2H); 1.52-1.72 (m, 4H); 1.10-1.30 (m, 3H); 0.6-0.8 (m, 2H). (DSI/NH3)/MS: 478(M+H)+ Example 1268C N-[4-N-(N-cyclohexylmethyl-N-(2,4-difluorobenzyl)aminomethyl )-2-(2- methylphenyl )benzoyll methionine. methvl ester Prepared according to the procedure of example 1258C from 1268B. NMR (CDCl3) 7.85-7.95 (m, 1H); 7.20-7.47 (m, 6H); 7.18 (s, 1H); 6.75-6.85 (m, 2H); 5.85-5.92 (m, 1H); 4.56-4.67 (m, 1H); 3.67(s, 3H); 3.57 (s, 2H); 3.55 (s, 2H); 2.18-2.23 (m, 4H); 2.00-2.11 (m, 6H); 1.72-1.83 (m, 3H); 1.52-1.72 (m, 4H); 1.10-1.30 (m, 3H); 0.6-0.8 (m, 2H). (DSI/NH3)/MS: 609(M+H)+.

Example 1268D N-[4-N-(N-cyclohexylmethyl-N-(2,4-difluorobenzyl)aminomethyl )-2-(2- methvlphenyl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1267C. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.38-7.48 (2H, m), 7.0-7.28 (6H, m); 6.8-6.95 (2H, m); 4.1-4.22 (lH, m); 4.58 (4H, s); 2.2-2.3 (4H, m); 1.76-2.1 (9H, m); 1.5-1.78 (SH, m); 1.1-1.3 (3H, m); 0.7-0.82 (2H, m). ESI(-)/MS: 593(M-Li).

Example 1269 <BR> <BR> N-14-N-(N-cvclohexvlmethvl-N-(3.5-difluorobenzvl)aminomethvl )-2-(2- methylphenvl)benzovlgmethionine lithium salt. Example 1269A

Prepared according to the procedure of example 1258A from reaction between 1258A and cyclohexanecarboxaldehyde. NMR (CDCl3) 7.95-8.05 (m, 1H); 7.40-7.47 (m, 1H); 7.15-7.35 (m, SH); 7.04-7.11 (m, 1H); 6.75-6.85 (m, 2H); 6.60-6.70 (m, 1H); 3.60(s, 3H); 3.55 (s, 2H); 3.45 (s, 2H); 2.18-2.25 (m, 2H); 2.05 (s, 3H); 1.72-1.83 (m, 2H); 1.52-1.72 (m, 4H); 1.10-1.30 (m, 3H); 0.6-0.8 (m, 2H). (DSI/NH3)/MS: 478(M+H)+.

Example 1269B N-[4-N-(N-cyclohexylmethyl-N-(3,5-difluorobenzyl)aminomethyl )-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1269A. NMR (CDCl3) 7.79-7.95 (m, 1H); 7.40 -7.48 (m, 1H); 7.20-7.41 (m, SH); 7.18 (s, 1H); 6.75-6.85 (m, 2H); 6.60-6.70 (m, 1H); 5.85-5.92 (m, 1H); 4.56-4.67 (m, 1H); 3.67(s, 3H); 3.57 (s, 2H); 3.45 (s, 2H); 2.18-2.23 (m, 4H); 2.00-2.11 (m, 6H); 1.72-1.83 (m, 3H); 1.52-1.72 (m, 4H); 1.10-1.30 (m, 3H); 0.6-0.8 (m, 2H). (DSI/NH3)/MS: 609(M+H)+ Example 1269C N-[4-N-(N-cvclohexylmethvl-N-(3 ,5-difluorobenzvl)aminomethvl)-2-(2- methvlphenyl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1269B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.38-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 4.6 (2H, s); 4.55 (2H, s); 2.2-2.3 (4H, m); 1.76-2.1

(9H, m); 1.5-1.78 (SH, m); 1.1-1.3.(3H, m); 0.7-0.82 (2H, m). ESI(-)/MS: 593(M-Li).

Anal. Calcd for C31H30F5N2O3SLi.1.0LiOH: C, 65.38; H, 6.45; N, 4.48 Found: C, 65.43; H, 6.17; N, 4.40.

Example 1270 N-F4-N-(N-(4-cvanobenzvl)-N-(3 .5-difluorobenzvl)aminomethvl)-2-( 2- methvlphenvl)benzovllmethionine lithium salt.

Example 1270A Prepared according to the procedure of example 1258A from reaction between 1258A and 4-cyanobenzaldehyde. NMR(CDC13) 7.95-8.00 (m, 1H); 7.60-7.65 (m, 2H); 7.40-7.56 (m, 3H); 7.20-7.38 (m, 4H); 7.00-7.10 (m, 1H); 6.85-6.95 (m, 2H); 6.65-6.75 (, 1H); 3.58-3.65 (m, 7H); 3.54-3.58 (m, 2H); 2.05 (s, 3H). (DSI/NH3)/MS: 585(M+H)+ ; 497 (M+NH4)+. 514 (M+NH4)+.

Example 1270B N-[4-N-(N-(4-cyanobenzyl)-N-(3,5-difluorobenzyl)aminomethyl) -2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1270A. NMR(CDCl3) 8.00-8.18 (m, 1H); 7.76-7.80 (m, 2H); 7.48-7.76 (m, 3H); 7.10-7.38 (m, SH); 7.00-7.11 (m, 2H); 6.80-6.85 (m, 1H); 5.95-6.05 (m, 1H); 4.70-4.81 (m, 1H); 3.70-3.90 (m, 9H); 3.54-3.58 (m, 2H); 1.95-2.20 (m, 8H); 1.7-2.0 (m, 1H); 1.5-1.7 (m, 1H).

(DSI/NH3)/MS: 628(M+H)+; 645(M+NH4)+ Example 1270C N-r4-N-(N-(4-cvanobenzvl)-N-(3 .5-difluorobenzvl)aminomethvi)-2-(2- methylphenyl)benzoyllmethionine lithium salt.

Prepared according to the procedure of example 1178J from 1270B. NMR 1H(MeOH-d4): 8.78 (IH, s); 7.6-7.7 (2H, m); 7.5-7.6 (2H, m), 7.5-7.55 (1H, m); 7.0- 7.3 (6H, m); 6.9-7.0 (2H, m); 6.77-6.82 (1H, m); 4.1-4.22 (1H, m); 3.7 (2H, s); 3.65 (2H, s,); 3.6 (2H, s); 1.5-2.2 (lOH, m).ESI(-)/MS: 612(M-Li).

Example 1271 N- [4-N-(N-(3 .5-difluorobenzvl)-N-(4-N-carboxvmethionine)benZvl)aminometh vl-2-(2- methvlphenvl)benzovllmethionine dilithium salt.

Example 1271A Prepared according to the procedure of example 1236A from reaction between 1258A and 4-bromomethyl-benzoic methyl ester. NMR(CDCl3) 7.75-7.90 (m, 1H); 7.75- 7.85 (m, 2H); 7.40-7.50 (m, 2H); 7.20-7.40 (m, SH); 7.18 (s, 1H); 6.88-6.95 (m, 2H); 6.70-6.80 (m, 1H); 585-5.95 (m, 1H); 4.58-4.70 (m, 1H); 3.80 (s, 3H); 3.65 (s, 3H); 3.60 (s, 2H); 3.55 (s, 2H).(DSI/NH3)/MS: 530(M+H)+. Example 1271B

N-[4-N-(N-(3,5-difluorobenzyl)-N-(4-N-carboxymethionine)benz yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine dimethyl ester.

Prepared according to the procedure of example 1258C from 1271A. NMR(CDC13) 7.75-?.90 (m, 1H); 7.75-7.85 (m, 2H); 7.40-7.50 (m, 2H); 7.20-7.40 (m, SH); 7.18 (s, 1H); 6.88-6.95 (m, 3H); 6.70-6.80 (m, lH); 5.85-5.95 (m, 1H); 4.90-4.95 (m, 1H); 4.58- 4.70 (m, 1H); 3.80 (s, 3H); 3.65 (s, 3H); 3.60 (s, 2H); 3.55 (s, 2H); 2.58-2.70 (m, 2H); 2.0-2.15 (m, 10H); 1.7-2.0 (m, 3H); 1.5-1.7 (m, 2H). (DSI/NH3)/MS: 792(M+H)+ Example 1271C N-[4-N-(N-(3,5-difluorobenzyl)-N-(4-N-carboxymethionine)benz yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine dilithium salt, Prepared according to the procedure of example 1 178J from 1271B. NMR 1H (d4- MeOH): 7.8-7.9 (2H, m); 7.6-7.7 (1H, m); 7.45-7.55 (4H, m); 7.1-7.3 (6H, m); 6.9-7.05 (2H, m); 6.75-6.85 (1H, m); 4.5-4.6 (1H, m); 4.2-4.3(1H, m); 3.4-3.5 (6H, m); 2.5-2.6 (2H, m); 1.5-2.3 (15H, m). ESI(-)/MS: 762 (M-Li); 764(M+H); 781(M+NH4).

Example 1272 N-[4-N-(N-(2-cyclohexylethyl-N-(3,5-difluorobenzyl)aminometh yl)-2-(2- methylphenyl)benzovlZmethionine lithium salt.

Example 1272A Prepared according to the procedure of example 1258A from reaction between 3,5- difluorobenzaldehyde and 2-cyclohexyle-1-aminoethane. NMR(CDCl3) 6.78-6.95 (m, 2H); 6.65-6.80 (m, 3H); 3.78 (s, 2H); 2.58-2.68 (m, 2H); 1.00-1.75 (m, 11H); 0.8-1.0- (m, 2H). (DSI/NH3)/MS: 254(M+H)* ; 271(M+NH4)*.

Example 1272B Prepared according to the procedure of example 1226A from the reaction between 1272A and 4-Bromomethyl-2-(2-methylphenyl)benzoic acid, methyl ester. NMR(CDC13) 7.91-7.98 (m, lH); 7.38-7.45 (m, 1H); 7.10-7.30 (m, 4H); 7.05-7.15 (m, lH); 6.83-6.95 (m, 2H); 6.60-6.78 (m, 1H); 3.60 (s, SH); 3.55 (s, 2H); 2.40-2.50 (m, 2H); 2.05 (s, 3H); 1.50-1.75 (m, SH); 1.30-1.47 (m, 2H); 1.00-1.38 (m, 4H); 0.74-0.90 (m, 2H).

(DSI/NH3)/MS: 492(M+H)+.

Example 1272C N-[4-N-(N-(2-cyclohexylethyl-N-(3,5-difluorobenzyl)aminometh yl)-2-(2- methvlphenvl)benzovljmethionine. methyl ester

Prepared according to the procedure of example 1258C from 1272B. NMR(CDCl3) 7.81-7.98 (m, 1H); 7.38-7.45 (m, 2H); 7.20-7.40 (m, 3H); 7.18 (s, 1H); 6.83-6.95 (m, 2H); 6.60-6.78 (m, 1H); 5.81-5.90 (m, lH); 4.58-4.70 (m, lH); 3.67 (s, 3H); 3.60 (s, 2H); 3.55 (s, 2H); 2.40-2.50 (m, 2H); 2.00-2.20 (m, 8H); 1.70-2.00 (m, 1H); 1.50-1.70 (m, SH); 1.30-1.50 (m, 2H); 1.10-1.38 (m, 4H); 0.74-0.90 (m, 2H). (DSl/NH3)/MS: 623(M+H)+ .

Example 1272D N-[4-N-(N-p(2-cyclohexylethyl-N-(3,5-difluorobenzyl)aminomet hyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt, Prepared according to the procedure of example 1 178J from 1272C. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.4-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 3.65 (2H, s); 3.58 (2H, s); 2.4-2.5 (2H, m); 2.21 (1H, m); 1.1-2.1 (20H, m); 0.8-0.9 (2H, m). ESI(-)/MS: 607(M-Li).

Example 1273 N-[4-N-(N-p(3-methylthiopropyl)-N-(3,5-difluorobenzyl)aminom ethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Example 1273A Prepared according to the procedure of example 1258A from reaction between 1258A and 3-(methylthio)propionaldehyde. NMR(CDCl3) 7.91-7.98 (m, 1H); 7.38-7.45 (m, 1H); 7.20-7.30 (m, 4H); 7.04-7.10 (m, 1H); 6.83-6.90 (m, 2H); 6.60-6.74 (m, 1H); 3.60 (s, SH); 3.55 (s, 2H); 2.50-2.60 (t, 2H); 2.42-2.50 (t, 2H); 2.10 (s, 3H); 2.05 (s, 3H); 1.70-1.84 (m, 2H). (DSI/NH3)/MS: 470(M+H)+.

Example 1273B N-[4-N-(N-(3-methylthiopropyl)-N-(3,5-difluorobenzyl)aminome thyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1273A. NMR(CDCl3) 7.81-7.98 (m, 1H); 7.38-7.45 (m, 2H); 7.20-7.40 (m, 3H); 7.18 (s, 1H); 6.83-6.95 (m, 2H); 6.60-6.78 (m, 1H); 5.81-5.90 (m, 1H); 4.58-4.70 (m, 1H); 3.67 (s, 3H); 3.63 (s, 2H); 3.55 (s, 2H); 2.50-2.60 (t, 2H); 2.42-2.50 (t, 2H); 1.92-2.20 (m, 9H); 1.65-1.95 (m, 4H); 1.5-1.65 (m, 2H). (DSI/NH3)/MS: 601(M+H)+.

Example 1273C N-[4-N-(N-(3-methylthiopropyl-N-(3,5-difluorobenzyl)aminomet hyl)-2-(2- methvlphenvl)benzovl Imethionine lithium salt.

Prepared according to the procedure of example 1178J from 1273B. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.4-7.48 (1H, m), 7.0-7.3 (6H, m); 6.9-7.0 (2H, m);

6.7-6.8 (1H, m); 4.1-4.22 (1H, m); 4.65 (2H, s), 4.60 (2H, s); 2.5-2.6 (2H, m); 2.4-2.5 (2H, m); 1.8-2.3 (13H, m). ESI(-)/MS: 585(M-Li).

Example 1275 N-[4-N-(N-cyclopropyl-N-(2-(3,5-difluorophenyl)ethyl)aminome thyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Example 1275A Prepared according to the procedure of example 1 279A from the reaction between 2,4-difluorobenzaldehyde and (Methoxymethyl)triphenylphosphonium chloride. NMR.

7.18-7.21 (m, 2H); 6.80-6.94 (m, 3H); 6.06 (s, 1H); 5.84 (s, 1H); 3.78 (s, 3H).

DSI/NH3)MS: 17 1(M+H)+; 188(M+NH4)+.

Example 1275B Prepared according to the procedure of example 1279B from example 1275A.

NMR. 9.78 (s, lH); 7.18-7.21 (m, 2H) 6.60-6.70 (m, 2H); ; 3.75 (s, 2H). DSI/NH3)MS: 157(M+H)+; 174(M+NH4)+.

Example 1275C Prepared according to the procedure of example 1258A from the reaction between example 1275B and cyclopropylamine. NMR(CDC13) 7.18-7.21 (m, 1H); 6.74-6.82 (m, 2H); 2.80-2.90 (m, 2H); 2.80-2.90 (m, 2H); 1.80-1.98 (m, 1H); 0.40-0.60 (m, 4H); (DSI/NH3)MS: 198(M+H)+ Example 1275D Prepared according to the procedure of example of 1258A from the reaction between example 1275C and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR 7.94- 8.00 (m, 1H); 7.00-7.40 (m, 7H); 6.74-6.82 (m, 2H); 3.83 (s, 2H); 3.60 (s, 3H); 2.70- 2.90 (m, 4H); 2.05 (s, 3H); 1.80-2.00 (m, 1H); 0.40-0.60 (m, 4H); (DSI/NH3)MS: 436(M+H)*.

Example 1275E N-[4-N-(N-cyclopropyl-N-(2,4-difluorophenyl)ethyl)aminomethy l)-2-(2- methvlphenyl)benzovllmethionine. methvl ester.

Prepared according to the procedure of example 1258C from 1275D. NMR 7.94- 7.80 (m, 1H); 7.00-7.40 (m, 7H); 6.74-6.82 (m, 2H); 5.90-5.94 (m 1H); 4.60-4.70 (m, lH); 3.83 (s, 2H); 3.75 (s, 3H); 2.80-3.00 (m, 2H); 2.00-2.00 (m, 8H); 1.80-2.00 (m, 2H); 1.50-1.70 (m, 2H); 0.40-0.60 (m, 4H); (DSI/NH3)MS: 567(M+H)+.

Example 1275F N-[4-N-(N-cyclopropyl-N-(2-(3,5-difluorophenyl)ethyl)aminome thyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1275E. NMR II(MeOH-d4): 7.5-7.6 (1H, m); 7.25-7.35 (lH, m); 7.0-7.25 (7H, m); 6.7-6.8 (2H, m); 4.1-4.25 (1H, m); 3.8 (2H, s); 2.65-2.85 (4H, m); 1.65-2.2 (11H, m); 1.5-1.65 (1H, m); 0.4-0.5 (2H, m); 0.3-0.4 (2H, m). ESI(-)/MS: 551(M-Li). Anal. Calcd for C31H33N2O3SLi.0.32H2O.1.0LiOH: C, 63.29; H, 5.93; N, 4.76. Found: C. 63.30; H, 5.77; N, 4.67.

Example 1276 [4-N-(N-2-methylbutyl-N-(2-(2,4-difluorophenyl)ethyl)aminome thyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Example 1276A Prepared according to the procedure of example 1275C from example 1275B and 3- methylbutylamine. NMR(CDC13) 7.14-7.22 (m, 1H); 6.74-6.82 (m, 2H); 2.78-2.90 (m,

4H); 2.60-2.68 (m, 2H); 1.50-1.70 (m, 1H); 1.30-1.50 (m, 2H); 0.9 (d, 6H).

(DSI/NH3)MS: 228(M+H)+ Example 1276B Prepared according to the procedure of example of 1258A from the reaction between example 1276A and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR 7.94- 8.00 (m, lH); 7.00-7.40 (m, 7H); 6.74-6.82 (m, 2H); 3.83 (s, 2H); 3.60 (s, 3H); 2.60- 2.90 (m, 4H); 2.50-2.60 (m, 2H); 2.05 (s, 3H); 1.40-1.60 (m, 1H); 1.24-1.48 (m, 2H); 0.90 (d, 6H). (DSI/NH3)MS: 466(M+H)+.

Example 1276C [4-N-(N-2-methylbutyl-N-(2-(2.4-difluorophenvl)ethyl)aminome thyl)-2-(2- methylphenvl)benzovllmethionine methvl ester.

Prepared according to the procedure of example 1258C from 1276B. NMR 7.85- 7.95 (m, 1H); 7.00-7.40 (m, 7H); 6.67-6.82 (m, 2H); 5.91-5.97 (m, 1H); 4.56-4.70 (m, 1H); 3.63 (s, SH); 2.65-2.80 (m, 4H); 2.46-2.55 (m, 2H); 2.00-2.20 (m, 8H); 1.70-2.00 (m, 1H); 1.45-1.70 (m 2H); 1.30-1.40 (m, 2H); 0.90 (d, 6H). (DSI/NH3)MS: 597(M+H)+.

Example 1276D [4-N-(N-2-methylbutyl-N-(2-(2,4-difluorophenyl)ethyl)aminome thyl)-2-(2- methylphenyl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1276C. NMR 1H(MeOH-d4): 7.5-7.6 (1H, m); 7.2-7.3 (1H, m); 7.0-7.25 (7H, m); 6.7-6.8 (2H, m); 4.1-4.25 (lH, m); 3.8 (2H, s); 2.65-2.75 (2H, m); 2.55-2.65 (2H, m); 2.4-2.5 (2H, m); 2.1 (lH, s); 1.85-2.0 (6H, m); 1.55-1.85 (2H, m); 1.5-1.65 (1H, m); 1.38-1.5 (lH, m); 1.2-1.38 (2H, m); 0.75 )6H, d). ESI(-)/MS: 581(M-Li). Anal. Calcd for C33H39N2O3SLi.0.25H2O.1.8LiOH: C, 63.30; H, 5.54; N, 4.40. Found: C. 63.30; H, 6.17; N, 4.24.

Example 1277 [4-N-(N-butyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2- (2- methvlphenvl)benzoyllmethionine lithium salt.

Example 1277A Prepared according to the procedure of example 1275C from example 1275B and butylamine. NMR(CDCl3) 7.14-7.22 (m, 1H); 6.74-6.82 (m, 2H); 2.78-2.90 (m, 4H);

2.60-2.68 (m, 2H); 1.50-1.70 (m, 2H); 1.20-1.50 (m, 2H); 0.9 (d, 3H). (DSl/NH3)MS: 2 14(M+H)+.

Example 1277B Prepared according to the procedure of example of 1258A from the reaction between example 1277A and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR 7.94- 8.00 (m, 1H); 7.00-7.40 (m, 7H); 6.74-6.82 (m, 2H); 3.83 (s, 2H); 3.60 (s, 3H); 2.60- 2.90 (m, 4H); 2.50-2.60 (m, 2H); 2.05 (s, 3H); 1.40-1.60 (m, 2H); 1.24-1.48 (m, 2H); 0.90 t, 3H). (DSl/NH3)MS: 452(M+H)+.

Example 1277C [4-(N-(N-butyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2 -(2- methvlphenyl)benzoyl Imethionine. methyl ester.

Prepared according to the procedure of example 1258C from 1277B. NMR 7.85- 7.95 (m, 1H); 7.00-7.40 (m, 7H); 6.67-6.82 (m, 2H); 5.91-5.97 (m, 1H); 4.56-4.70 (m, lH); 3.63 (s, SH); 2.65-2.80 (m, 4H); 2.46-2.55 (m, 2H); 2.00-2.20 (m, 8H); 1.70-2.00 (m, 2H); 1.45-1.70 (m 2H); 1.30-1.40 (m, 2H); 0.90 (t, 3H). (DSI/NH3)MS: 583(M+H)+.

Example 1277D 14-N-(N-bUtvl-N-(2-(2 .4-difluorophenyl)ethyl)aminomethvl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1 178J from 1277C. NMR 1H(MeOH-d4): 7.45-7.55 (lH, m); 7.2-7.5 (lH, m); 7.0-7.25 (7H, m); 6.65-6.75 (2H, m); 4.1-4.25 (lH, m); 3.8 (2H, s); 2.65-2.75 (2H, m); 2.55-2.65 (2H, m); 2.35-2.45 (2H, m); 2.1 (1H, s); 1.8-2.0 (6H, m); 1.65-1.85 (2H, m); 1.4-1.6 (lH, m); 1.25-1.5 (3H, m); 1.1-1.25 (2H, m); 0.75 (3H, t). ESI(-)/MS: 567(M-Li). Anal. Calcd for C33H39N203SLi1.7H2O: C, 63.50; H, 6.73; N, 4.63. Found: C, 63.50; H, 6.41; N, 4.29.

Example 1279 N-[4-N-(N-(4-methyltetrahydropyran-yl)-N-(3,5-difluorobenzyl )aminomethyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Example 1279A (Methoxymethyl)triphenylphosphonium chloride (25.71 g, 75 mmol) in 200 ml of anhydrous THF was treated 1.0 M sodium bis(trimethylsilyl)amide solution (75 ml, 75 mmol) at 0°C in 10 min. under N2. The resulted deep red solution was then stirred at 0°C for another 1 hour. To this solution, tetrahydro-4-H-pyran-4-one (5.0 g, 50 mmol) in 10 ml of anhydrous THF was added. After being stirred at 0°C for another 1 hour, the solution was brought up to boiling for 12 hours. The reaction mixture was concentrated under vacuum, then diluted by 1: lether/hexane solution, filtrated through a pack of silica gel, and washed by another 200 ml of 1: lether/hexane solution The filtrate was then concentrated.

Vacuum distillation of the residue afforded 3.91 g of the title compound (64%).

NMR(CDCl3) 5.83 (s, 1H); 3 3.4-3.5 (m, 4H); 3.58 (s, 3H); 2.29-2.35 (m, 2H); 2.05-2.15 (m, 2H). DSI/'NH3)/MS: 129(M+H)t; 146(M+NH4)+ Example 1279B 1279A (0.9 g, 7 mmol) in 15 ml of 88% formic acid plus 5 ml of water was refluxed for 3 hours under N2. After the solvents were removed by rotavapor, the residue was purified by flash chromatography eluting 3:7 EtOAc/hexane to afford 0.60 g of title compound (75%). NMR(CDCl3) 9.62 (s, lH); 3.85-3.92 (m, 2H); 3.30-3.40 (m, 2H); 1.60-1.85 (m, 3H); 1.05-1.20 (m, 2H). DSI/NH3)/MS: 115(M+H)+; 132(M+NH4)+.

Example 1279C Prepared according to the procedure of example 1258A from reaction between 1258A and 1279B. NMR(CDC13) 7.92-7.99 (m, 1H); 7.35-7.45 (m, lH); 7.20-7.30 (m, 4H); 7.05-7.10 (m, 1H); 6.82-6.90 (m, 2H); 6.62-6.73 (m, 1H); 3.88-3.98 (m, 2H); 3.61 (s, 3H); 3.59 (s, 2H); 3.52 (s, 2H); 3.25-3.40 (m, 2H); 2.25-2.31 (m, 2H); 2.05 (s, 3H); 1.60-1.90 (m, 3H); 1.00-1.20 (m, 2H). DSI/NH3)/MS: 480(M+H)+. Example 1279D

N-[4-N-(N-(4-methyltetrahydropyran-yl)-N-(3,5-difluorobenzyl )aminomethyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Prepared according to the procedure of example 1258C from 1279C. NMR(CDCl3) 7.88-7.99 (m, 1H); 7.35-7.45 (m, 1H); 7.18-7.30 (m, SH); 6.80-6.90 (m, 2H); 6.62-6.73 (m, 1H); 5.85-5.92 (m, 1H); 4.52-4.70 (m, lH); 3.88-3.98 (m, 2H); 3.61 (s, 3H); 3.60 (s, 2H); 3.50 (s, 2H); 3.30-3.40 (m, 2H); 2.20-2.31 (m, 2H); 2.0-2.2 (m, 9H); 1.78-1.98 (m, 2H); 1.55-1.78 (m, 3H); 1.00-1.20 (m, 2H). DSI/NH3)/MS: 611(M+H)+ Example 1279E N-[4-N-(N-(4-methyltetrahydropyran-yl)-N-(3,5-difluorobenzyl )aminomethyl)-2-(2- methvlphenvl!benzovllmethionine lithium salt.

Prepared according to the procedure of example 1178J from 1279D. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.38-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.78-6.88 (1H, m); 4.1-4.22 (1H, m); 3.8-3.9 (2H, m); 3.8 (2H, s); 3.75 (2H, s); 3.4 (,2H, m); 2.3-2.38 (2H, m); 2.25 (1H, s); 1.76-2.1 (14H, m); 1.0-1.2 (2H, m). ESI(- )/MS: 595(M-Li).Anal. Calcd for C33H37F2N2O4SLi.0.52H2O: C, 64.76; H, 6.26; N, 4.58. Found: C, 64.76; H, 6.01; N, 4.45.

Example 1280 N-[4-N-(N-(4-methyltetrahydrothiopyran-yl)-N-(3,5-difluorobe nzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt.

Example 1280A Prepared according to the procedure of example 1279A from tetrahydrothiopyran-4- one. NMR(CDCl3) 5.82 (s, 3H); 3.58 (s, 3H); 2.38-2.43 (m, 4H); 2.30-2.38 (m, 2H); 2.05-2.12 (m, 2H). DSI/NH3)/MS: 145(M+H)*.

Example 1280B Prepared according to the procedure of example 1279B from 1280A. NMR(CDC13) 9.65 (s, 1H); 2.60-2.80 (m, 4H); 2.20-2.40 (m, 2H); 1.70 1.88 (m, 2H). DSI/NH3)/MS: 131(M+H)+ Example 1280C Prepared according to the procedure of example 1258A from reaction between 1258A and 1280B. NMR(CDC13) 8.00-8.08 (m, 1H); 7.40-7.46 (m, 1H); 7.10-7.30 (m, 4H); 7.05-7.10 (m, 1H); 6.80-6.90 (m, 2H); 6.85-6.73 (m, 1H); 3.60 (S, SH); 3.50 (s, 2H); 2.50-2.70 (m, 4H); 2.20-2.30 (m, 2H); 2.00-2.20 (m, SH); 1.40-1.70 (m, 3H); 1.12- 1.30 (m, 2H). DSI/NH3)/MS: 496(M+H)+.

Example 1280D N-[4-N-(N-(4-methyltetrahydrothiopyran-yl)-N-(3,5-difluorobe nzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester.

Prepared according to the procedure of example 1258C from 1280C. NMR(CDC13) 7.85-8.00 (m, 1H); 7.1-7.45 (m, 6H); 6.80-6.90 (m, 2H); 6. 65-6.76 (m, lH); 5.84-5.94 (m, lH); 4.55-4.70 (m, 1H); 3.65 (s, 3H); 3.52 (s, 2H); 3.45 (s, 2H); 2. 50-2.70 (m, 4H); 2.00-2.30 (m, 13H); 1.78-2.00 (m, 1H); 1.50-1.65 (m, 2H); 1.05-1.30 (m, 2H).

DSI/NH3)/MS: 626(M+H)+.

Example 1280E N-[4-N-(N-(4-methyltetrahydrothiopyran-yl)-N-(3,5-difluorobe nzyl)aminomethyl)-2-(2- methylphenyl)benzoylimethionine lithium salt.

Prepared according to the procedure of example 1 178J from example 1280D. NMR 1H(MeOH-d4): 7.6-7.7 (1H, m); 7.38-7.48 (1H, m), 7.0-7.35 (6H, m); 6.9-7.0 (2H, m); 6.75-6.85 (1H, m); 4.1-4.22 (1H, m); 3.6 (2H, s); 3.55(2H, s); 3.35 (2H, s); 2.4-2.65 (4H, m); 2.2-2.3 (3H, m); 1.78-2.1 (8H, m); 1.6-1.78 (2H, m); 1.05-1.2 (2H, m). ESI(- )/MS: 593(M-Li).Anal. Calcd for C33H37F2N2O4S2Li.1.21H2O.1.0LiOH: C, 59.65; H, 6.13; N, 4.22. Found: C, 59.65; H, 5.85; N, 3.89.

Example 1281 N-[4-N-(N-(4-tetrahydropyran-yl)-N-(3,5-difluorobenzyl)amino methyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt.

Example 1281A Prepared according to the procedure of example 1258A from reaction between 1258A and tetrahydro-4-H-pyran-4-one. NMR(CDCl3) 7.80-7.95 (m, 1H); 7.35-7.45 (m, 1H); 7.15-7.30 (m, 4H); 7.04-7.10 (m, 1H); 6.80-6.89 (m, 2H); 6.58-6.70 (m, lH); 3.95- 4.03 (m, 2H); 3.70 (s, 2H); 3.65 (s, 2H); 3.60 (s, 3H); 3.20-3.35 (m, 2H); 2.65-2.80 (m, 1H); 2.05 (s, 3H); 1.60-1.80 (m, 4H). (DSI/NH3)/MS: 466(M+H)+.

Example 1281B N-[4-N-(N-(4-tetrahydropyran-yl)-N-(3,5-difluorobenzyl)amino methyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Prepared according to the procedure of example 1258C from 1281A. NMR(CDCl3) 7.81-7.98 (m, 1H); 7.38-7.45 (m, 1H); 7.20-7.40 (m, 4H); 7.18 (s, 1H); 6.83-6.91 (m, 2H); 6.60-6.70 (m, 1H); 5.81-5.90 (m, 1H); 4.58-4.70 (m, 1H); 3.95-4.02 (m, 2H); 3.70 (s, 2H); 3.63 (s, 2H); 3.60 (s, 2H); 3.20-3.38 (m, 1H); 2.55-2.80 (m, 1H); 1.92-2.20 (m,

8H); 1.75-1.95 (m, lH); 1.61-1.78 (m, 3H). 1.50-1.65 (m, 2H); (DSI/NH3)/MS: 597(M+H)+ .

Example 1281C B-[4-N-(N-(4-tetrahydropyran-yl)-N-(3,5-difluorobenzyl)amino methyl)-2-(2- methylphenyl)benzyl]methionine lithium salt.

Prepared according to the procedure of example 1178J from 1281B. NMR 1H(MeOH-d4): 7.58-7.68 (1H, m); 7.38-7.48 (1H, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.78-6.88 (1H, m); 4.1-4.22 (1H, m); 3.9-4.0 (2H, m); 3.75 (2H, s); 3.7 (2H, s); 3.3 (,2H, m); 2.7-2.85 (1H, m); 2.2 (1H, s); 1.76-2.1 (14H, m). ESI(-)/MS: 586(M-Li). Anal.

Calcd for C32H35F2N2O4SLi.2.07H2O: C, 61.41; H, 6.30; N, 4.37. Found: C, 61.40; H, 6.05; N, 4.37.

Example 1313 N-r4-(N-(3-Cvclohexvl- 1 -ethylthioprop-2-yl)aminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfonylbutanoate Lithium Salt Example 1313A 2-Amino-3-cvclohexyl- l-ethylthiopropane

Trifluoroacetic acid (3 mL) was added to a solution of the product from Example 403C (274 mg, 0.9 mmol) in CH2Cl2 (3 mL) at ambient temperature. After 30 min of stirring, solvent was removed and the residue redissolved in CH2Cl2, washed with a solution of saturated K2CO3, dried (MgSO4) and concentrated. The crude product was chromatographed (silica gel; CHCl3/MeOH, 90: 10) to afford a clear oil (162 mg, 75%): 1H NMR (CDCl3, 300 MHz) 6 2.97 (m, 1H), 2.68 (dd, J=13, 4 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.34 (dd,J=13, 8.5 Hz, 1H), 1.80-1.61 (m, SH), 1.50-1.10 (m, 6H), 1.26 (t, J=7.5 Hz, 3H), 1.00-0.90 (m, 2H); MS (CI/NH3) m/z: 202 (M+H)+.

Example 1313B <BR> <BR> <BR> Methyl-N- r4-hvdroxvmethvl-2-(2-methvlDhenvi)benzo -2-amino-4- <BR> <BR> <BR> <BR> <BR> methylsulfonvlbutanoate The product from Example 1178C (1.0 g, 4.1 mmol) in MeOH (12 mL) was combined with a solution of saturated LiOH (4.0 mL) and heated at reflux for 3.5 hours.

The mixture was allowed to cool to ambient temperature and then extracted with Et2O. The phases were separated and concentrated HCl added to the aqueous phase which was extracted with EtOAc (2X). The EtOAc phases were combined, dried (MgS04) and concentrated to dryness to afford the crude acid as a white solid. MS (CI/NH3) m/z: 243 (M+H)+. The crude acid, EDCI (940 mg, 4.5 mmol), Hobt (1.1 g, 8.2 mmol), (L)- methionine sulfone methyl ester hydrochloride (1.0 mg, 4.5 mmol) and DIEA (2.1 mL, 12.3 mmol) in DMF (15 mL) were allowed to react in a manner similar to that described in Example 608 D. The crude residue was chromatographed (silica gel; MeOH/CHCl3, 5:95) to afford the title compound (963 mg, 56%).

Example 1313C Methyl-N-[4-formyl-2-(2-methylphenyl)benzoyl]-2-amino-4-meth ylsulfonylbutanoate

Dimethylsulfoxide (325 uL, 4.6 mmol) was added to a solution of oxalyl chloride (200 RL, 2,5 mmol) at -78 OC. After stirring for 5 min, the product from Example 1313B (955 mg, 2.3 mmol) in CH2Cl2 (2.5 mL) was added to the reaction vessel. After 15 min, TEA (950 StL, 6.8 mL) was added to the reaction mixture and the cold bath was removed.

After stirring for 30 min, a solution of 2N HCl was added to the mixture and the phases separated. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3, 2:98) to afford a clear oil (866 mg, 91%). 1H NMR (CDCl3, 300MHz) 8 1.88 (m, lH), 2.11-2.30 (m, 4H), 2.47-2.73 (m, 2H), 2.71 (s, 3H), 3.71 (s, 3H), 4.65 (m, lH), 6.12 (dd, J=8 8 Hz, 1H), 7.20 (d, J=7 Hz, 1H), 7.27-7.41 (m, 2H), 7.76 (s, 1H), 7.95-8.06 (m, 2H), 10.10 (s, 1H); MS (CI/NH3) m/z: 418 (M+H)+.

Examplel3 13D Methyl-N-[4-(N-(3-Cyclohexyl-1-ethylthioprop-2-yl)aminomethy l)-2-(2- methvlphenyl)benzovl 1 amino-4-methylsulfonylbutanoate The product from Example 1313A (285 mg, 1.4 mmol), the product from Example 1313C (618 mg, 1.5 mmol) and sodium triacetoxyborohydride (415 mg, 2.0 mmol) were combined in 1,2-dichloroethane (6 mL) at ambient temperature and allowed to stir for 18 hours. A solution of saturated NaHCO3 was added and the mixture was extracted with EtOAc (2X). The EtOAc phases were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3, 2:98) to afford a clear oil (753 mg, 89%). MS (CVNH3) m/z: 418 (M+H)+.

Example 1313E

N-[4-(N-(3-Cyclohexyl-1-ethylthioprop-2-yl)aminomethyl)-2-(2 - methvlohenvl)benzovl1 amino-4-methvlsulfonvlbutanoate Lithium Salt The product from Example 1313D (748 mg, 1.2 mmol) was allowed to react with lithium hydroxide monohydrate (55 mg, 1.3 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) 6 0.70-0.91 (m, 2H), 1.12-1.65 (m, 14H), 1.75-2.20 (m, SH), 2.35-2.67 (m, 7H), 2.82 (s, 3H), 3.66- 3.86 (m, 3H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.38 (d, J=8 Hz,lH), 7.53 (d, J=8 Hz, lH); MS (APCI(-)) m/z: (M-H)- 587; Anal. Calcd for C3 lH43LiN2o5S2 1.90 H2O: C, 59.20; H, 7.50; N, 4.45. Found: C, 59.22; H, 7.16; N, 4.36.

Example 1317 Example 1319 N-[4-(N-Methyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methvlphenvl)benzoyllmethionine p-tolylsulfonimide The above compound was prepared from the compound described in Example 608E and p-toluenesulfonamide by the method of Example 1216A, except the reaction was

worked up by diluting with CHC13 (instead of EtOAc), there was no HCl wash, and the chromatography was done with EtOAc/water/CH3CO2H 19/0.5/0.5, then 18/1/1. 1H NMR (CDCl3) 7.80 (m, 3H), 7.58 (dd, 1H), 7.22 (m, 7H), 6.18 (m, 1H), 4.20 (m, lH), 3.98 (s, 2H), 2.80 (m, 2H), 2.55 (s, 3H), 2.40 (s, 3H), 2.00 (m, 8H), 1.60 (m, 8H), 1.40, 1.20. 0.90 (all m, total 7H). MS (ESI) 648 (M-H)-. Anal calcd for C36H47N304S2 1.00 H2O: C, 64.74; H, 7.39; N, 6.29. Found: C, 64.53; H, 7.22; N, 6.06.

Example 1332 N-[4-N-(N-(trans--hydroxycyclohexyl)-N-(3,5-difluorobenzyl)a minomethyl)-2-(2- methvlphenvl)benzovllmethionine lithium salt Example 1332A A mixture of 1 ,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (1.98 g, 10 mmol), and sodium borohydride (0.757 g, 20 mmol) in 100 mi of methanol was stirred for 12 hours. The methanol was removed under reduced pressure. The residue was taken into ethyl acetate, washed by 10 % NaOH and brine respectively, and the dried over anhydrous MSG. Yield: 1.60 g (80%). (SDl/NH3) MS: 201(M+H)+; 218(M+NH4)+. Example 1332B

Prepared according to the procedure of example 1252 from the reaction between example 1332A and benzyl bromide. NMR(CDCl3) 7.20-7.35 (m, 5H); 4.57 (s, 2H); 3.45- 3.55 (m, 6H); 2.00-2.15 (m, 2H); 1.50-1.82 (m, 5H). (SDI/NH3) MS: 291(M+H)+; 308(M+NH4)+ Example 1332C Prepared according to the procedure of example of example 1266A from the reaction of example 1232B and HCl. NMR(CDCl3) 7.23-7.40 (m, 5H); 4.60 (s, 2H); 3.78-4.08 (m, lH); 2.55-2.70 (m, 2H); 2.20-2.35 (m, 2H); . 2.10-2.20 (m, 2H); 1.90-2.01 (m, 2H).

(SDI/NH3) MS: 222(M+H)+; 239(M+NH4)+.

Example 1332D Prepared according to the procedure of example 1279A from the reaction between example 1232C and (Methoxymethyl)triphenylphosphonium chloride. NMR(CDCl3) 7.23- 7.40 (m, 5H); 5.85 (s, 1H); 4.60 (s, 2H); 3.63-3.75 (m, 5H); 2.58-2.70 (m, 1H); 2.10- 2.30 (m, 1H); 1.4-2.0 (m, 5H). (SDI/NH3) MS: 233(M+H)+; 250(M+NH4)+.

Example 1332E Example 1332D was hydrolyzed in formic acid according to the example 1279B to give corresponding aldehyde, which was used to react with example 1258A to give two isomers. One is example 1232E, the other is example 1233A. NMR(CDCl3) 7.90-7.95 (m, 1H); 7.38-7.44 (m, 1H); 7.13-7.39 (m, 9H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60- 6.70 (m, lH); 4.55 (s, 2H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, lH); 2.18-2.21 (m, 2H); 2.0-2.18 (m, 4H); 1.80-2.00 (m, 2H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). (SDI/NH3) MS: 584(M+H)+.

Example 1332F A mixture of 1332D (0.07 g, 0.12 mmol) and 0. l ml of trimethylsiliy iodide in 2 ml of methylene chloride was stirred until TLC indicated that there was no starting material left.

Flash chromatography of the residue afforded 0.042 g of the title compound (71%).

NMR(CDC13) 7.90-7.95 (m, 1H); 7.40-7.44 (m, lH); 7.13-7.39 (m, 4H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60-6.70 (m, lH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 2.0-2.18 (m, 4H); 1.80-2.00 (m, 2H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). (SDI/NH3) MS: 494(M+H)+ Example 1332G Prepared according to the procedure of example 1258C from example 1232F.

NMR(CDCl3) 7.83-7.95 (m, 1H); 7.40-7.44 (m, 1H); 7.13-7.40 (m, 4H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60-6.70 (m, 1H); 5.84-5.90 (m, 1H); 4.55-4.67 (m, 1H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 1.80-2.25 (m, 16H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). (SDVNH3) MS: 624(M+H)+.

Example 1332H N-[4-N-(N-(trans-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl) aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1 178J from example 1332G.

NMR(CDCl3) 7.60-7.70 (m, 1H); 7.40-7.44 (n, 1H); 7.13-7.40 (m, 5H); 6.83-7.00 (m, 2H); 6.68-6.72 (m, lH); 4.20-4.30 (m, 1H); 3.60 (m, 2H); 3.55 (m, 2H); 3.18-4.30 (m, lH); 2.18-2.21 (m, 2H); 1.80-2.25 (m, 16H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). ESI(-)/MS: 609(M-Li). Anal. Calcd for C34H39F2N204SLi2.00 LiOH: C, 61.45; H, 6.22; N, 4.22. Found: C, 61.56; H, 5.88; N,3.94.

Example 1333 N-[4-N-(N-(cis-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)am inomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt

Example 1333A Prepared according to the procedure of example 1332E. NMR(CDCl3) 7.90-7.95 (m, 1H); 7.38-7.44 (m, 1H); 7.13-7.39 (m, 9H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60-6.70 (m, lH); 4.55 (s, 2H); 3.90-4.00 (m, 1H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 2.0-2.18 (m, 3H); 1.80-2.00 (m, 2H); 1.40- 1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). (SDI/NH3) MS: 584(M+H)+ Example 1333B Prepared according to the procedure of example 1332F from the reaction between 1333B and trimethylsilyl iodide. NMR(CDCl3) 7.90-7.95 (m, 1H); 7.40-7.44 (m, 1H); 7.13-7.39 (m, 4H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60-6.70 (m, 1H); 3.90-4.00 (m, 1H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 2.0-2.18 (m, 3H); 1.80-2.00 (m, 2H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67- 0.83 (m, 2H). (SDI/NH3) MS: 494(M+H)+.

Example 1333C Prepared according to the procedure of example 1258C from example 1333B.

NMR(CDC13) 7.83-7.95 (m, lH); 7.40-7.44 (m, 1H); 7.13-7.40 (m, 4H); 7.02-7.10 (m, 1H); 6.83-6.92 (m, 2H); 6.60-6.70 (m, 1H); 5.84-5.90 (m, 1H); 4.55-4.67 (m, lH); 3.92- 4.02 (m, 1H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 1.80-2.25 (m, 15H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H).

(SDI/NH3) MS: 624(M+H)+.

Example 1333D N-[4-N-(N-(cis-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)am inomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt Prepared according to the procedure of example 1178J from example 1333C.

NMR(CDCl3) 7.60-7.70 (m, 1H); 7.40-7.44 (m, 1H); 7.13-7.40 (m, 5H); 6.83-7.00 (m, 2H); 6.68-6.72 (m, 1H); 4.20-4.30 (m, 1H); 3.92-4.01 (m, 1H); 3.60 (m, 2H); 3.55 (m, 2H); 3.18-4.30 (m, 1H); 2.18-2.21 (m, 2H); 1.80-2.25 (m, 15H); 1.40-1.60 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). ESI(-)/MS: 609(M-Li). Anal. Calcd for C34H39F2N2O4SLi.2.50 LiOH.0.57H2O: C, 62.58; H, 6.26; N, 4.29. Found: C, 61.61; H, 5.99 N,3.92.

Example 1334 (2S) 2-N-14-( l-ethvlthio-3-cvclohexvlprop-2-vlaminomethvl)-2-(2- methviphenvl)benzovl1 amino-4-methvlsulfenvlbutanoate Lithium Salt Example 1334A (2S) 2-N-[4-formyl-2-(2-methylphenyl)benzoyl]amino-4-methylsulfen ylbutanoate, Methyl Ester The title compound was prepared from N-[4-formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester (example 403G) according to the procedure in example 1071D, and was isolated as a light yellow oil. MS(APCI(+)) 402 (M+H)+.

MS(APCI(-)) 436 (M+Cl)-, 400 (M-H)-.

Example 1334B (2S) 2-N- [4-( l-ethvlthio-3-cvclohexvlprop-2-vlaminomethvl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, Methyl Ester The title compound was prepared according to example 403H. substituting (2S) 2-N- [4-formyl-2-(2-methylphenyl)benzoyl]amino-4-methylsulfenylbu tanoate methyl ester for N-

[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester. MS(APCI(+)) 587 (M+H)+. MS(APCI(-)) 621 (M+CI)-.

Example 1334C (2S) 2-N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate. Lithium Salt The title compound was prepared from (2S) 2-N-[4-(1-ethylthio-3-cyclohexylprop- 2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]amino-4-methylsul fenylbutanoate methyl ester according to the procedure in example 608E, with the exception that the product was isolated as a light yellow foam after concentrating a methanolic solution under reduced pressure. 1H NMR (300 MHz, DMSO) 6 0.66-0.90 (m, 2H), 1.02-1.80 (m, 13H), 1.10 (t, J=7.2 Hz, 3H), 1.96-2.21 (m, SH), 2.36 (s, 1.5H), 2.39 (s, l.5H), 2.41 (q, J=7.2 Hz, 2H), 2.56-2.67 (m, 3H), 3.60-3.84 (m, 4H), 6.98 (brd, J=6 Hz, 1H), 7.08-7.23 (m, 5H), 7.38 (d, J=8.4 Hz, 1H), 7.49 (d, J=7.8 Hz, 0.5H), 7.51 (d, J=7.8 Hz, 0.5H). MS (APCI(-)) m/e 571 (M-H).

Example 1335 <BR> <BR> N-[4-(N-(2-( 1 3-dioxan-2- vlethvl)-N-butvlaminomethvl -2-(2- methylphenyl)benzoyl]methionine

Examplel335A 4-Formvl-2-(2-methvlphenvl)benzoic acid methvl ester Following the procedure of example 1 134D, example 1178 C (3.30 g, 11.82 mmol) provided 3.00 g 100%) of the title compound. MS (DCI, NH3): 255 (MH+).

Example 1335B 4-n-Butvlaminomethvl-2-(2-methvlphenyl)benzoic acid methyl ester Following the procedure of example 1 106D, part l example 1335A (1.27 g, 5.00 mmol) and butyl amine (0.99 mL, 10.00 mmol) provided 1.45 g (94%) of the title compound. MS (DCI, NH3): 312 (MH+).

Example 1335C 4-(N-(2-(1,3-dioxan-2-vlethyl)-N-butvlaminomethvl)-2-(2-meth vlphenvl)benzoic acid. methyl ester A solution of example 1335B (359 mg 1.15 mmol), 2-bromoethyl-1,3-dioxane (164 COIL, 1.2 mmol), TBAI (443 mg, 1.2 mmol) and diiospropylethylamine (260 uL, 1.5 mmol) in 3 mL of DMF were heated to 600C for 72 hours. The cooled reaction mixture was diluted with water and extracted with 3 portions of ethyl ether. 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, 25% ethyl acetate/hexanes) provided 330 mg (78%) of the title compound. MS: (ESI+) 426 (MH+).

Example 1335D 4-(N-(2-(1,3-dioxan-2-ylethyl)-N-butylaminomethyl)-2-(2-meth ylphenyl)benzoic acid, Following the procedure of example 1 130D, example 1335C (310 mg, 0.72 mmol) provided 222 mg (75%) of the title compound. MS (ESI+): 412 (MH+): (ESI-): 410 (M- H).

Example 1335E N-[4-(N-(2-(1,3-dioxan-2-ylethyl)-N-butylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, methyl ester Following the procedure of example 11781, examplel335D (85 mg, 0.25 mmol) provided 57 mg (50%) of the title compound. MS (ESI+): 557 (MH+): (ESI-): 555 (M- H).

Example 1335F N-[4-(N-(2-(1,3-dioxan-2-ylethyl)-N-butylaminomethyl)-2-(2- methylphenyl)benzoylimethionine Following the procedure of example 1104D, example 1335 E (55 mg (0.10 mmol) provided 30 mg of the title compound. H nmr (300 MHz., CD30D): 8 7.64, d, lH; 7.49, dd, lH; 7.29, m, lH; 7.02 - 7.22, m, 4H; 4.64, t, 1H; 4.29, m, 3H; 3.91, ddd, 2H; 3.66, dt, 2H; 3.22, m, 2H; 3.03, m, 2H; envelope 1.74 - 2.16, m, 12H; 1.62, m, 3H; 1.18 - 1.36, mn, 3H; 0.88, t, 3H. MS (ESI+): 543 (MH+): (ESI-): 541 (M-H). Calc'd for C31H43N205Sv1.30 H2O; C 63.64; H 7.94; N 4.95; Found: C 63.63; H 7.37; N 5.07.

Example 1336 N-E4-(N-(2-cvclohexvlethvl)-N-methvlaminomethyl)-2-(2- methvlphenvl)benzovllthioglutamine Lithium Salt N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]thioglutamine methyl ester (12 mg, 22.9 umol) was saponified using the standard LiOH procedure, evaporated, and lyophilized from water to provide 9.8 mg of the title compound. MS m/e 514 (M-H)-.

Example 1336B N- 4- (N-(2-cvclohexvlethyl)-N-methvlaminomethyl)-2-(2- methylphenyl)benzoyl]zhioglutamine Methyl Ester N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]glutaminitrile methyl ester, see Example 1041, (139 mg, 0.28 mmol) was dissolved in 5 mL pyridine with TEA (0.5 mL). Excess H2S was bubbled into the solution which was then sealed and stirred at room temperature for 18 hours. The reaction was evaporated to dryness, dissolved in EtOAc, washed with water and brine, and chromatographed (50 % EtOAc/hexanes) to give 13 mg of the methyl ester. MS m/e 524 (M+H)+. 1H NMR (CDC13, 300 MHz) 6 0.82 (m, 2H), 1.11 (m, 3H), 1.32 (m, 5H), 1.6 (m, 7H), 2.18 (m, 6H), 2.32 (m, 1H), 2.58 (m, lH), 2.75 (m, 1H), 3.53 (m, 2H), 3.72 (s, 3H), 6.9-7.5 (m, 9H), 7.83 (m, 1H).

Example 1337 N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methox y-2-(2- methylphenyl)benzoyllmethionine

Example 1337A 2-(2-Methvlphenvl)-4-formvl-5-methoxvbenzoic acid, methyl ester A solution of example 1 134D (180 mg, 0.63 mmol) in 2 mL of DMF was treated with sodium methoxide (102 mg, 1.89 mmol) and the mixture stirred for 3 hours. The solution was diluted with water and extracted with 3 portions of ethyl acetate. The combined organic extracts were wased with water, brine, dried filtered and concentrated.

The residue was purified by column chromatography to provide 40g (22%) of the title compound. MS (DCI, NH3): 302 (M+ NH4+).

Example 1337B 4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2 -(2-methylphenyl)benzoic acid. methyl ester Using the procedure of example 1134E, example 1337A provided the title compound. MS (ESI +): 470 (MH+); (ESI-) 468 (M-H).

Example 1337C <BR> <BR> <BR> 4-(1-ethvlthio-3-cyclohexylprop-2-vlaminomethyl!-5-methoxy-2 -(2-methvlphenvl!benzoic acid Using the procedure of example 1 134F, example 1337B provided the title compound. MS (ESI +): 456 (MH+); (ESI-) 454 (M-H).

Example 1337D N-f4-( 1 -ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2-(2- methylphenyl)benzoyl]methionine, methyl ester According to the procedure described in example 11781, example 1137C (55 mg, 0.12 mmol) provided 39 mg (54%) of the title compound. MS (ESI +): 601 (MH+); (ESI-) 599 (M-H).

Example 1337 N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methox y-2-(2- methylphenyl)benzoyllmethionine Following the procedure of example 1105D, example 1137D (39 mg, 0.065 mmol) provided the title compound. 1H NMR (300 MHz, DMSO): 6 7.9 (1H), 7.0-7.3 (SH), 4.1 (1H), 3.9 (lH), 3.3 (3H), 2.7 (1H), 2.4 (3H), 2.0-2.3 (6H), 1.95 (3H), 0.8- 1.9 (22H).

Mass spec (ESI): 587 (M+H), 585 (M-H) Example 1338

N-l4-( l-ethvlthio-3-cyclohexYlprop-2-vlaminomethyl)-5-NlNl-dimeth- ylamino-2-(2 methvlphenyl)benzovll methionine Example 1338A 2-(2-Methvlphenvl)-4-formyl-5-N.N-dimethvlaminobenzoic acid, methyl ester A solution of example 1 134D (146 mg, 0.50 mmol) in 1 mL of DMF was treated with 2 mL of 40% aqueous dimethylamine and the mixture heated at 700C for 2days. The cooled reaction mixture was diluted with water and the pH of the mixture adjusted to 5. The solution was extracted with 3 portions of ethyl acetate adnt he combined organic extracts were washed with wate and brine, dried, filtered and concentrated. The residue was dissolved in ethyl acetate and treated with ethereal diazomethane until tIc analysis indicated no more acid present. This solution was concentrated and the residue purified by column chromatography on silica gel (25 g, 15% ethyl acetate/hexanes) to provide 124 mg (87%) of the title compound. MS (DCI, NH3): 298 (MH+).

Example 1338B 4-(1-ethvlthio-3-cvclohexvlprop-2-vlaminomethvlA-5-N'N'-dime thvlamino-2-(2- methvlphenvl)benzoic acid. methyl ester Using the procedure of example 1134E, example 1338A provided the title compound. MS (ESI +): 483 (MH+); (ESI-) 481 (M-H).

Example 1338C 4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N',N'-dim ethylamino-2-(2- methylphenyflbenzoic acid Following the procedure of example 11 34F, example 11 38B provided the title compound. MS (ESI +): 469 (MH+); (ESI-) 467 (M-H).

Example 1338D N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N'N'-d imethylamino-2-(2- methylphenyl)benzoyl]methionine, methyl ester According to the procedure described in example 1178I, example 1138C (93 mg, 0.20 mmol) provided 69 mg (56%) of the title compound. MS (ESI +): 614 (MH+); (ESI-) 612 (M.-H).

Example 1338E N-[4-(1-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N'N'-d imethylamino-2-(2- methylphenyl)benzoyl]methionine

Following the procedure of example 1 105D, example 1 138D (69 mg, 0.11 mmol) provided the title compound. 1H NMR (300 MHz., DMSO): 6 7.9 ( lH), 7.0-7.3 (SH), 4.2 (1H), 3.9 (lH), 2.72 (6H), 2.45 (3H), 2.0-2.2 (6H), 1.9 (3H),0.7-1.85 (22H). Mass spec (ESI): 600 (M+H), 598 (M-H).

Example 1339 Pittsburg example, waiting for experimental data and other information.

Examplel340 Example 1340A N-[4-N-(6-Fluorobenzothiazol-2-yl)aminomethyl-2-(2-methylphe nyl)benzoyl]methionine methvl ester The desired compound was prepared according to the method of Example 1203A starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 2-amino-6-fluorobenzothiazole. m/e (ESI) 538 (MH+)

Example 1340B N-[4-N-(6-Fluorobenzothiazol-2-yl)aminomethyl-2-(2-methylphe nyl)benzoyl]methionine The desired compound was prepared according to the method of Example 4031 starting with the compound in Example 1340A.1H (300MHz, CDCl3, 6) 7.91 (1H, m), 7.51 (1H, m), 7.34 (2H, m), 7.30-7.15 (4H, m), 7.05 (3H, m), 5.99 (1H, m), 4.59 (1H, m), 4.48 (2H, bd, J=8Hz), 2.20-1.80 (9H, m), 1.72 (1H, m). m/e (ESI) 522 (MH-) Anal.calc. for C27H26FN303S2 0.25 H2O C 61.40, H 5.06, N 7.96 Found C 61.38, H 4.56, N 7.73 Example 1341 Example 1341A N--Butyl-N-(furan-2-ylmethyl)amine The desired amine was prepared using the method described in Example 1171A starting with 2-furoic acid and butylamine. m/e (DCI/NH3) 154 (MH+) Example 1341B

4-(N-Butyl-N-(furan-2-ylmethyl)aminomethyl)-2-(2-methylpheny l)benzoic acid methyl ester The desired compound was prepared using the method described in Example 1178G starting with N--Butyl-N-(furan-2-ylmethyl)amine, prepared as in Example 1341A, and 4- bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A- D. m/e (ESI) 392 (MH+) Example 1341C 4-(N-Butyl-N-(furan-2-ylmethyl)aminomethyl)-2-(2-methylpheny l)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 1341B.

Example 1341D N-[4-N-Butyl-N-(furan-2-ylmethyl)aminomethyl-2-(2-methylphen yl)benzoyl)benzoyl]methionine methyl ester The desired product was prepared using the method described in Example 403F starting with the compound prepared in Example 1341C. m/e (ESI) 523 (MH+) Example 1341E <BR> <BR> N-14-N-Butvl-N-(furan-2-ylmethvl)aminomethvl-2-(2-methvlphen vl)benzovllmethionine The desired compound was prepared according to the method of Example 403I starting with compound prepared in Example 1341D.1H (300MHz, CDCl3, 6) 7.81 (lH,

d, J=8Hz), 7.57 (1H, m), 7.42 (1H, d, J=2Hz), 7.30-7.10 (SH, m), 6.35 (2H, m), 6.15 (lH, bd, J=8Hz), 4.43 (lH, m), 3.98 (2H, m), 3.90-3.75 (2H, m), 2.62 (2H, m), 2.20- 2.00 (SH, m), 1.99 (3H, s), 1.95 (lH, m), 1.60 (3H, m), 1.29 (2H, m), 0.88 (3H, t, J=8Hz). m/e (ESI) 509 (MH+) Anal.calc. for C29H36N2O4S.0.50 H2O C 67.28, H 7.20, N 5.41 Found C 67.42, H 6.96, N 5.44.