WO1998050029A1 - Inhibitors of protein isoprenyl transferases - Google Patents

Inhibitors of protein isoprenyl transferases Download PDF

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Publication number
WO1998050029A1
WO1998050029A1 PCT/US1998/009296 US9809296W WO9850029A1 WO 1998050029 A1 WO1998050029 A1 WO 1998050029A1 US 9809296 W US9809296 W US 9809296W WO 9850029 A1 WO9850029 A1 WO 9850029A1
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WIPO (PCT)
Prior art keywords
methionine
benzoyl
methylphenyl
lithium salt
aminomethyl
Prior art date
Application number
PCT/US1998/009296
Other languages
French (fr)
Inventor
Said M. Sebti
Andrew D. Hamilton
David J. Augeri
Kenneth J. Barr
Bernard G. Donner
Stephen A. Fakhoury
David A. Janowick
Douglas M. Kalvin
John J. Larsen
Gang Liu
Stephen J. O'connor
Saul H. Rosenberg
Wang Shen
Rolf E. Swenson
Bryan K. Sorensen
Gerard M. Sullivan
Bruce G. Szczepankiewicz
Andrew S. Tasker
James I. Wasick
Martin Winn
Original Assignee
University Of Pittsburgh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Pittsburgh filed Critical University Of Pittsburgh
Priority to JP54848098A priority Critical patent/JP2002518985A/en
Priority to AT98922122T priority patent/ATE546139T1/en
Priority to EP98922122A priority patent/EP0986384B1/en
Priority to AU74733/98A priority patent/AU7473398A/en
Priority to CA2288330A priority patent/CA2288330C/en
Priority to ES98922122T priority patent/ES2387211T3/en
Publication of WO1998050029A1 publication Critical patent/WO1998050029A1/en

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    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Definitions

  • the present invention relates to novel compounds which are useful in inhibiting protein isoprenyl transferases (for example, protein famesyltransferase 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.
  • protein isoprenyl transferases for example, protein famesyltransferase and protein geranylgeranyltransferase
  • farnesylation or geranylgeranylation of the oncogene protein Ras and other related small g-proteins compositions containing such compounds and methods of using such compounds.
  • 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 famesyltransferase. Inhibition of protein famesyltransferase, 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.
  • Ras and other related small g-proteins that are farnesylated and/or geranylated also partially mediates smooth muscle cell proliferation (Circulation, 1-3: 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.
  • the invention provides a compound having the formula:
  • R j is selected from the group consisting of
  • aryl-L2- wherein aryl is selected from the group consisting of (a) phenyl,
  • R 2 is selected from the group consisting of 105 (1) wherein Li i is selected from the group consisting of
  • 115 R 12a is selected from the group consisting of
  • Li 1 is defined previously, R v is selected from the group consisting of (a) hydrogen and 130 (b) loweralkyl,
  • R 15 is selected from the group consisting of
  • R 1 is selected from the group consisting of
  • R 14 is defined previously and R.6 is selected from the group consisting of (a) loweralkyl, 170 (b) haloalkyl,
  • N-protected amino 200 alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl;
  • L j is absent or is selected from the group consisting of (1) - -N(R 5 )-L 5 - wherein L 4 is absent or selected from the group consisting of
  • arylalkoxy is unsubstituted or 275 substituted with substituents selected from the group consisting of alkoxy, arylalkyl, arylalkyl[S(O) q ]alkyl, aryl[S(O) q ], 280 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, 285 arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, and halogen, 290 aryloxy, aryloxyalkyl wherein the aryloxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, and halogen, 290 aryloxy, ary
  • 410 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,
  • G is a hydroxyl protecting group, -O-NH-R,
  • J and J' are independently selected from the group consisting of 435 loweralkyl and arylalkyl, oxo, oxyamino(alkyl)carbonylalkyl, oxyamino(arylalkyl)carbonylalkyl, 440 oxyaminocarbonylalkyl,
  • A is selected from the group consisting of loweralkyl, aryl, and 445 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 450 alkoxy, halogen, haloalkyl, loweralkyl, and nitro, 455 sulfhydryl, thioxo, and thioalkoxy
  • L5 is absent or selected from the group consisting of (a) C j -to-C jQ -alkylene and 460 (b) C 2 -to-C 16 -alkenylene wherein (a) and (b) are unsubstituted or substituted as defined previously, and R 5 is selected from the group consisting of hydrogen, 465 alkanoyl wherein the alkanoyl is unsubstituted or substituted with substituents selected from the group consisting of aryl, alkoxy
  • (anthracenyl)alkyl aryl, arylalkoxy, arylalkyl wherein the arylalkyl is unsubstituted or 485 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkoxy, aryl, 490 carboxyl, cyano, halogen, haloalkoxy, haloalkyl, 495 nitro, oxo, and
  • (aryl)oyl wherein the (aryl)oyl is unsubstituted or substituted with substituents selected from the 500 group consisting of halogen, aryloxycarbonyl, carboxaldehyde, -C(O)NRR', cycloalkoxycarbonyl, 505 cycloalkylaminocarbonyl, cycloalkylaminothiocarbony 1 , cyanoalkyl, cyclolalkyl, cycloalkylalkyl wherein the cycloalkylalkyl is 510 unsubstituted or substituted with 1 or 2 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (cyclolalkyl)oyl, 515 (9,10-dihydroanthracenyl)alkyl wherein the
  • (9,10-dihydroanthracenyl)alkyl is unsubstituted or substituted with 1 or 2 oxo substituents, haloalkyl, heterocycle, 520 (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, 525 loweralkyl, wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of -NRR', -SO 2 -A, and thioalkoxyalkyl;
  • R6 is selected from the group consisting of
  • L 6 is absent or is selected from the group consisting of
  • 550 consisting of hydrogen, loweralkyl, aryl, arylalkyl, 555 heterocycle,
  • L 7 is absent or is selected from the group consisting of -O- and -S-,
  • Ci-Cio-alkylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from 570 the group consisting of
  • alkenylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
  • Z is selected from the group consisting of 620 (1) a covalent bond
  • R z is selected from the group consisting of
  • R 3 is selected from the group consisting of (1) hydrogen, 635 (2) aryl,
  • alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2, 3, 4 or 5 substituents independently selected from the group consisting of 650 aryl and cycloalkyl,
  • alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of 655 aryl, and cycloalkyl,
  • aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 660 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 665 consisting of cycloalkyl, carboxaldehyde, haloalkyl, halogen, loweralkyl, 670 nitro,
  • RA ' and R ⁇ ' re independently selected from the group consisting of hydrogen, (aryl)oyl, loweralkyl, and 720 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 725 (ee) thioalkoxy,
  • cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of (a) loweralkyl, 745 (b) alkoxy,
  • Xj 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 755
  • compositions which comprise a compound of formula I in combination with a 780 pharmaceutically acceptable carrier.
  • compositions which comprise a compound of formula I in combination with another chemotherapeutic agent and a pharmaceutically acceptable carrier.
  • a method for inhibiting 785 protein isoprenyl transferases i.e., protein famesyltransferase and/or geranylgeranyltransferase
  • a human or lower mammal comprising administering to the patient a therapeutically effective amount of a compound compound of formula I.
  • a method for treatment of conditions mediated by farnesylated or geranylgeranylated proteins for example, treatment of Ras associated tumors in humans and other mammals.
  • a method for inhibiting or 795 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
  • intimal hyperplasia associated with restenosis and atherosclerosis in a mammal 800 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.
  • 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 805 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
  • Cys 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.
  • 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.
  • 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
  • carboxy protecting groups are Cj to Cs loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted 835 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, l-(propionyloxy)-l -ethyl, l-(pivaloyloxyl)-l- 840 ethyl, 1 -methyl-methyl
  • alkoxyalkylcarbonyloxyalkyl such as 2-(l- 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 855 t-butyloxycarbonylaminomethyl and the like
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like
  • alkanoylaminoalkyl such as acetylaminomethyl and the like
  • heterocycliccarbonyloxyalkyl such as 4- methylpiperaziny
  • Preferred carboxy-protected compounds of the invention are compounds wherein the protected carboxy group is a loweralkyl, cycloalkyl or arylalkyl ester, for example, methyl 865 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 protected carboxy group is a loweralkyl, cycloalkyl or arylalkyl ester, for example, methyl 865 ester, ethyl ester, propyl ester, isoprop
  • N-protecting group or “N-protected” as used herein refers to those
  • N- protecting 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 inco ⁇ orated herein by reference.
  • N- protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • alkanoyl refers to R 29 C(O)- wherein R 29 is a loweralkyl group.
  • the alkanoyl groups of this invention can be optionally substituted.
  • alkanoylaminoalkyl refers to a loweralkyl radical to which is appended R 71 -NH- wherein R 71 is an alkanoyl group.
  • the alkanoylaminoalkyl groups of this invention can be optionally substituted.
  • alkanoyloxy refers to R 29 C(O)-O- wherein R 29 is a loweralkyl group.
  • the alkanoyloxy groups of this invention can be optionally substituted.
  • alkanoyloxyalkyl refers to a loweralkyl radical to which is appended an alkanoyloxy group.
  • alkanoyloxyalkyl groups of this invention can be optionally substituted.
  • alkenyl groups of this invention can be optionally substituted.
  • alkenylene refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 20 carbon atoms and also 910 containing at least one carbon-carbon double bond.
  • the alkenylene groups of this invention can be optionally substituted.
  • alkenyloxy refers to an alkenyl group attached to the parent molecular group through an oxygen atom.
  • the alkenyloxy groups of this invention 915 can be optionally substituted.
  • alkenyloxy alkyl refers to a loweralkyl group to which is attached an alkenyloxy group.
  • alkenyloxyalkyl groups of this invention can be optionally substituted.
  • alkoxy refers to R30O- wherein R 30 is loweralkyl as
  • alkoxy groups include methoxy, ethoxy, t- butoxy and the like.
  • the alkoxy groups of this invention can be optionally substituted.
  • alkoxyalkyl refers to a loweralkyl group to which is attached an alkoxy group.
  • the alkoxyalkyl groups of this invention can be optionally substituted.
  • alkoxy alkoxy refers to R3 1 O-R32O- wherein R3 1 is loweralkyl as defined above and R3 2 is an alkylene radical.
  • Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • the alkoxyalkoxy groups of this invention can be optionally substituted.
  • alkoxyalkyl refers to an alkoxy group as previously 930 defined appended to an alkyl group as previously defined.
  • alkoxyalkyl include, but are not limited to, methoxy methyl, methoxyethyl, isopropoxymethyl and the like.
  • the alkoxyalkyl groups of this invention can be optionally substituted.
  • alkoxyalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended R 66 -C(O)-O- wherein R 66 is an alkoxyalkyl group.
  • alkoxy arylalkyl refers to a an arylalkyl group to which is attached an alkoxy group.
  • the alkoxy arylalkyl groups of this invention can be optionally substituted.
  • alkoxycarbonyl refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • examples of 940 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.
  • alkoxycarbonylalkyl refers to an alkoxylcarbonyl group as previously defined appended to a loweralkyl radical.
  • alkoxycarbonylalkyl 945 include methoxycarbonylmethyl, 2-ethoxycarbonylethyl and the like.
  • the alkoxycarbonylalkyl groups of this invention can be optionally substituted.
  • alkoxycarbonylaminoalkyl refers to a loweralkyl radical to which is appended R 69 -NH- wherein R 69 is an alkoxycarbonyl group.
  • the alkoxycarbonylaminoalkyl groups of this invention can be optionally substituted.
  • alkoxycarbonyloxy alkyl refers to a loweralkyl radical to which is appended R63-O- wherein R 63 is an alkoxycarbonyl group.
  • the alkoxycarbonyloxyalkyl groups of this invention can be optionally substituted.
  • alkylamino refers to R35NH- wherein R35 is a loweralkyl group, for example, methylamino, ethylamino, butylamino, and the like.
  • the alkylamino 955 groups of this invention can be optionally substituted.
  • alkylaminoalkyl refers a loweralkyl radical to which is appended an alkylamino group.
  • the alkylaminoalkyl groups of this invention can be optionally substituted.
  • alkylaminocarbonylaminoalkyl refers to a loweralkyl 960 radical to which is appended R 70 -C(O)-NH- wherein R 7Q is an alkylamino group.
  • the alkylaminocarbonylaminoalkyl groups of this invention can be optionally substituted.
  • alkylene 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, 965 2,2-dimethylpropylene, and the like.
  • the alkylene groups of this invention can be optionally substituted.
  • alkylsilyloxy refers to a loweralkyl group to which is attached -OSiR ⁇ y'R ⁇ 'R ⁇ ' wherein R y', Rx, and R ⁇ ] are selected from the group consisting of loweralkyl. 970
  • alkylsulfinyl refers to R 33 S(O)- wherein R 33 is a loweralkyl group.
  • the alkylsulfinyl groups of this invention can be optionally substituted.
  • alkylsulfinylalkyl refers to an alkyl group to which is attached a alkylsulfinyl group.
  • the alkylsulfinylalkyl groups of this invention can be optionally substituted.
  • alkylsulfonyl refers to R 34 S(O) 2 - wherein R 34 is a loweralkyl group.
  • the alkylsulfonyl groups of this invention can be optionally substituted.
  • alkylsulfonylalkyl refers to a loweralkyl radical to which is appended an alkylsulfonyl group.
  • alkylsulfonylalkyl groups of this invention can be optionally substituted.
  • 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.
  • alkynylene 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-, 990 -CH 2 C ⁇ C-, -CH 2 C ⁇ CCH2-, and the like. The alkynylene groups of this invention can be optionally substituted.
  • amino refers to -NH2.
  • aminocarbonyl refers to an amino group attached to the parent molecular group through a carbonyl group.
  • the aminocarbonyl groups of this 995 invention can be optionally substituted.
  • aminocarbonylalkyl refers to an alkyl group to which is attached an aminocarbonyl group.
  • the aminocarbonylalkyl groups of this invention can be optionally substituted.
  • aminoalkyl refers to a loweralkyl radical to which is 1000 appended an amino group.
  • the aminoalkyl groups of this invention can be optionally substituted.
  • the aminothiocarbonyl groups of this invention can be optionally substituted.
  • aroyloxyalkyl refers to a loweralkyl radical to which is appended an aroyloxy group (i.e., R 61 -C(O)O- wherein R 61 is an aryl group).
  • the aroyloxyalkyl groups of this invention can be optionally substituted.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, 1010 tetrahydronaphthyl, indanyl, indenyl and the like.
  • 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.
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group. The arylalkenyl groups of this invention can be optionally substituted.
  • arylalkenyloxycarbonyloxyalkyl refers to a loweralkyl 1020 radical to which is appended R 68 -O-C(O)-O- wherein R 68 is an arylalkenyl group.
  • R 68 is an arylalkenyl group.
  • the arylalkenyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
  • arylalkoxy refers to an alkoxy group to which is attached an aryl group.
  • the arylalkoxy groups of this invention can be optionally substituted.
  • arylalkyl refers to a loweralkyl radical to which is 1025 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.
  • arylalkylcarbonyloxyalkyl refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R 62 C(O)O- wherein R 62 is an
  • arylalkylcarbonyloxyalkyl groups of this invention can be optionally substituted.
  • aryloxy 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.
  • aryloxycarbonyl 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.
  • aryloyl refers to an aryl group attached to the parent molecular group through a carbonyl group.
  • the aryloyl groups of this invention can be 1040 optionally substituted.
  • arylalkyloxycarbonyloxy alkyl refers to a loweralkyl radical to which is appended R 67 -O-C(O)-O- wherein R 67 is an arylalkyl group.
  • R 67 is an arylalkyl group.
  • the arylalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
  • aryloxyalkyl refers to a loweralkyl radical to which is 1045 appended Rg5-O- wherein R 65 is an aryl group.
  • R 65 is an aryl group.
  • the aryloxyalkyl groups of this invention can be optionally substituted.
  • arylalkoxy refers to an alkoxy radical to which is appended g5"O- wherein R 65 is an aryl group.
  • the arylalkoxy groups of this invention can be optionally substituted.
  • arylalkyloxy alkyl refers to a loweralkyl radical to which is appended an arylalkoxy group.
  • the arylalkyloxyalkyl groups of this invention can be optionally substituted.
  • aryloxy refers to g5"O- wherein R 65 is an aryl group.
  • the aryloxy groups of this invention can be optionally substituted.
  • the aryloxy groups of 1055 this invention can be optionally substituted.
  • (aryl)oyl 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.
  • aryloxy thioalkoxy alkyl refers to a loweralkyl radical to 1060 which is appended R75-S- wherein R 75 is an aryloxyalkyl group.
  • R 75 is an aryloxyalkyl group.
  • the aryloxythioalkoxyalkyl groups of this invention can be optionally substituted.
  • aryloxycarbonyloxy alkyl refers to a loweralkyl radical to which is appended R 65 -O-C(O)-O- wherein R 65 is an aryl group.
  • the aryloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
  • arylsulfonyl refers to R 36 S(O) 2 - wherein R 36 is an aryl group.
  • the arylsulfonyl groups of this invention can be optionally substituted.
  • arylsulfonyloxy refers to R 37 S(O) 2 O- wherein R 37 is an aryl group.
  • the arylsulfonyloxy groups of this invention can be optionally substituted.
  • carboxy refers to -COOH. 1070
  • carboxy alkyl refers to a loweralkyl radical to which is appended a carboxy (-COOH) group.
  • carboxyalkyl groups of this invention can be optionally substituted.
  • cyanoalkyl refers to a loweralkyl radical to which is appended a cyano (-CN) group.
  • cyanoalkyl groups of this invention can be 1075 optionally substituted.
  • carboxydehyde refers to -CHO.
  • (carboxaldehyde)alkyl refers to a carboxaldehyde group attached to a loweralkyl group.
  • the (carboxaldehyde)alkyl groups of this invention can be optionally substituted.
  • 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.
  • cycloalkanoylalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyl group (i.e., R 60 -C(O)- wherein R 60 is a cycloalkyl group).
  • cycloalkanoylalkyl groups of this invention can be optionally substituted.
  • cycloalkylalkoxyalkyl refers to an alkoxyalkyl group to which is attached a cycloalkyl group.
  • the cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.
  • cycloalkenyl refers to an alicyclic group comprising from 1090 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.
  • cycloalkoxy refers to a cycloalkyl group attached to the parent molecular group through an oxygen atom.
  • the cycloalkoxy groups of this invention 1095 can be optionally substituted.
  • cycloalkoxyalkyl refers to a loweralkyl group to which is attached a cycloalkoxy group.
  • the cycloalkoxyalkyl groups of this invention can be optionally substituted.
  • cycloalkoxycarbonyl refers to a cycloalkoxy group 1100 attached to the parent molecular group through a carbonyl group.
  • the cycloalkoxycarbonyl groups of this invention can be optionally substituted.
  • cycloalkyl 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 1105 be optionally substituted.
  • the cycloalkyl groups of this invention can be optionally substituted.
  • cycloalkylaminocarbonyl refers to NHR60'C(O)- wherein R60' is a cycloalkyl group.
  • the cycloalkylaminocarbonyl groups of this invention can be optionally substituted.
  • cycloalkylaminothiocarbonyl refers to NHR60'C(S)- wherein R60 ' is defined above.
  • the cycloalkylaminothiocarbonyl groups of this invention can be optionally substituted.
  • cycloalkylalkoxy refers to an alkoxy radical to which is appended a cycloalkyl group.
  • the cycloalkylalkoxy groups of this invention can be 1115 optionally substituted.
  • cycloalkylalkoxyalkyl refers to an alkyl radical to which is appended a cycloalkylalkoxy group.
  • the cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.
  • cycloalkylalkoxycarbonyl refers to a cycloalkylalkoxy 1120 radical attached to the parent molecular group through a carbonyl group.
  • the cycloalkylalkoxycarbonyl groups of this invention can be optionally substituted.
  • cycloalkylalkyl 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. 1125
  • the cycloalkylalkyl groups of this invention can be optionally substituted.
  • cycloalkyloxycarbonyloxyalkyl refers to a loweralkyl radical to which is appended R 64 -O-C(O)-O- wherein R ⁇ is a cycloalkyl group.
  • the cycloalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
  • dialkoxyalkyl refers to a loweralkyl radical to which is 1130 appended two alkoxy groups.
  • the dialkoxyalkyl groups of this invention can be optionally substituted.
  • dialkylamino 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 1135 substituted.
  • dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
  • the dialkylaminoalkyl groups of this invention can be optionally substituted.
  • dialkyaminocarbonylalkyl refers to a loweralkyl radical to 1140 which is appended R 73 -C(O)- wherein R 73 is a dialkylamino group.
  • the dialkyaminocarbonylalkyl groups of this invention can be optionally substituted.
  • the dioxoalkyl groups of this invention can be optionally substituted.
  • dithioalkoxy alkyl refers to a loweralkyl radical to which is appended two thioalkoxy groups.
  • the dithioalkoxyalkyl groups of this invention can be optionally substituted.
  • halogen or halo as used herein refers to I, Br, Cl or F.
  • haloalkenyl refers to an alkenyl radical, as defined above, 1150 bearing at least one halogen substituent.
  • the haloalkenyl groups of this invention can be optionally substituted.
  • haloalkyl 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 1155 hydrogens of a loweralkyl group are replaced with fluorides.
  • 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
  • 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
  • 1170 cyclopentene ring and another monocyclic heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like).
  • 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,
  • Heterocyclics also include bridged bicyclic groups wherein a monocyclic heterocyclic group is bridged by an alkylene group, for example,
  • Heterocyclics also include compounds of the formula
  • X* is -CH 2 -, -CH 2 O- or -O- and Y* is -C(O)- or -(C(R") 2 ) V - wherein R" is hydrogen or C ⁇ -C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
  • L 22 is alkenylene or alkynylene and R 53 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from
  • L 24 - wherein L 24 is an alkylene group, ffff) aryl-S(O) 2 -NH-L 2 5- wherein L 25 is an alkylene group, gggg) heterocyclic-S(O) 2 -NH-L 26 - wherein L 26 is an alkylene group, hhhh) aryl- C(O)-NH-L 27 - wherein L 27 is an alkylene group and iiii) heterocyclic-C(O)-NH-L 28 - wherein L 28 is an alkylene group, jjjj) Ryy(CH2)n-X-Y-Z-(CH2)m wherein Ryy is 1265 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 pro
  • (heterocyclic)alkoxy refers to an alkoxy group to which is 1270 attached a heterocycle.
  • the (heterocyclic)alkoxy groups of this invention can be optionally substituted.
  • heterocyclic alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocyclic alkyl examples include 2-pyridylmethyl, 4-pyridylmethyl, 4-quinolinylmethyl and the like.
  • the 1275 (heterocyclic)alkyl groups of this invention can be optionally substituted.
  • (heterocyclic)oxy 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.
  • (heterocyclic)oxy alkyl refers to a loweralkyl group to which is 1280 attached a (heterocyclic)oxy group.
  • the (heterocyclic)oxyalkyl groups of this invention can be optionally substituted.
  • (heterocyclic)alkoxyalkyl refers to an alkoxyalkyl group to which is attached a heterocycle.
  • the (heterocyclic)alkoxyalkyl groups of this invention can be optionally substituted.
  • heterocycliccarbonyloxyalkyl refers to a loweralkyl radical to which is appended R 72 -C(O)-O- wherein R 72 is a heterocyclic group.
  • the heterocycliccarbonyloxyalkyl groups of this invention can be optionally substituted.
  • hydroxy as used herein refers to -OH.
  • hydroxyalkyl refers to a loweralkyl radical to which is 1290 appended an hydroxy group.
  • the hydroxyalkyl groups of this invention can be optionally substituted.
  • hydroxyarylalkyl refers to a arylalkyl group to which is appended a hydroxy group.
  • the hydroxyarylalkyl groups of this invention can be optionally substituted.
  • hydroxythioalkoxy refers to R 51 S- wherein R 51 is a hydroxyalkyl group.
  • the hydroxythioalkoxy groups of this invention can be optionally substituted.
  • loweralkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n- 1300 butyl, t-butyl, neopentyl and the like.
  • the loweralkyl groups of this invention can be optionally substituted.
  • N-protected alkylaminoalkyl refers to an alkylaminoalkyl group wherein the nitrogen is N-protected.
  • the N-protected alkylaminoalkyl groups of this invention can be optionally substituted. 1305
  • nitro refers to -NO2.
  • oxoalkyloxy groups of this invention can be optionally substituted. 1310
  • oxyamino(alkyl)carbonylalkyl refers to a
  • oxyamino(arylalkyl)carbonylalkyl refers to a -O-NR R 3-C(O)-R group wherein R R 3 is arylalkyl and R is loweralkyl.
  • oxy aminocarbonylalkyl refers to -O-NH-C(O)-R group 1315 wherein R is loweralkyl .
  • spiroalkyl 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.
  • sulfhydryl refers to -SH. 1320
  • sulfhydrylalkyl refers to a loweralkyl group to which is attached a sulfhydryl group.
  • the sulfhydrylalkyl groups of this invention can be optionally substituted.
  • thioalkoxy refers to R52S- wherein R52 is loweralkyl.
  • examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. 1325
  • the thioalkoxy groups of this invention can be optionally substituted.
  • thioalkoxyalkyl 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. 1330 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.
  • thiocycloalkoxyalkyl refers to a loweralkyl group to which is attached a thiocycloalkoxy group.
  • the thiocycloalkoxyalkyl groups of this 1335 invention can be optionally substituted.
  • Preferred compounds of the invention are compounds of formula I wherein R j is unsubstituted or substituted phenyl and R 2 is -C(O)NH-CH(R 14 )-C(O)OR 15 or -C(O)NH-CH(R 14 )-C(O)NHSO 2 Ri6 wherein L 2 , R 14 R15 and R 16 are defined above.
  • More preferred compounds of the invention are compounds of formula I wherein R j is unsubstituted or substituted phenyl and R 2 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 1350 group consisting of aryl, loweralkyl, halo, nitro, haloalkyl, hydroxy, hydroxyalkyl, amino, N-protected amino, alkoxy, and thioalkoxy.
  • Still more preferred compounds of the invention have the structure defined immediately above wherein R j is unsubstituted or substituted phenyl and R 2 is
  • Protein Famesyltransferase Inhibition The ability of the compounds of the invention to inhibit protein famesyltransferase
  • in vitro inhibition of protein famesyltransferase 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-C ⁇ 2H), 0.1 mM final concentration, for the biotin-lamin substrate provided by Amersham.
  • 1375 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.
  • 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
  • Protein substrates are purchased from Panvera Co ⁇ oration (H-ras for FTase, H-ras-CVLL for GGTase I).
  • Tritium labeled prenyl lipid substrates FPP or GGPP are obtained from Amersham Life Science.
  • H-Farnesyldiphosphate final concentration 0.6 ⁇ M
  • H-Ras final concentration 5.0 ⁇ M
  • test compound test compound
  • buffer 50 mM HEPES (pH 7.5)
  • 30 M MgCl 2 20 mM KCl, 10 ⁇ M ZnCl 2 , 5 mM DTT, 0.01% Triton X-100
  • the mixture was brought to 37 °C, enzyme was added, and the reaction is incubated for 30 minutes.
  • H-geranylgeranyldiphosphate (final concentration 0.5 ⁇ M), H-Ras-CVLL (final concentration 5.0 ⁇ M) and the test compound (various final concentrations from a stock solution in 1 : 1 DMSO/water; final concentration DMSO ⁇ 2%) were mixed in buffer (50 mM Tris-HCl (pH 7.2), 30 mM MgCl 2 , 20 mM KCl, 10 ⁇ M ZnCl 2 , 5 mM DTT, 0.01%
  • 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,
  • 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.
  • 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.
  • 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.
  • 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 famesyltransferase and/or protein geranylgeranyltransferase) and the isoprenylation (i.e., farnesylation and/or
  • 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 1485 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. 1490
  • 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.
  • 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. 1500 Circ. Res. 73: 269-275 (1993) and Santoian, E.C. et al. Circulation 88: 11-14 (1993), which are hereby inco ⁇ orated herein by reference.
  • 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 1505 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.
  • 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 1510 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.
  • any particular patient 1515 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, 1520 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.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion
  • 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
  • a solution in 1,3-propanediol for example.
  • acceptable vehicles and solvents water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • 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 drag 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.
  • 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,
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • 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.
  • the dosage forms may also comprise buffering agents. Tablets and pills may also 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.
  • 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.
  • 1555 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.
  • chemotherapeutic agents are described in Holleb, et al.,
  • alkylating agents such as the nitrogen mustards (mechloethamine, melphalan, chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas (carmustine, lomustine, semustine, strep tozocin), alkyl sulfonates (busulfan), triazines (dacarbazine) and ethyenimines (thiotepa, hexamethylmelamine); folic
  • nitrogen mustards mechloethamine, melphalan, chlorambucil, cyclophosphamide and ifosfamide
  • nitrosoureas carmustine, lomustine, semustine, strep tozocin
  • alkyl sulfonates busulfan
  • triazines diacarbazine
  • ethyenimines thiotepa, hexamethylmelamine
  • 1570 acid analogues metalhotrexate
  • 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,
  • 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
  • the therapeutic agents 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.
  • the compounds of the invention can be prepared by the processes illustrated in the following Schemes 1-16.
  • Schemes 1-16 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 16 illustrates an alternative method for preparing compounds wherein R2 is -C(O)NH-CH(R 14 )-C(O)OR 15 or

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Abstract

Compounds having formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) lower alkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl -L2-, and (i) heterocyclic -L2-; R2 is selected from (a) formula (1), (b) -C(O)NH-CH(R14)-C(O)OR15, (c) formula (2), (d) -C(O)NH-CH(R14)-C(O)NHSO2R16, (e) -C(O)NH-CH(R14)-tetrazolyl, (f) -C(O)NH-heterocyclic, and (g) -C(O)NH-CH(R14)-C(O)NR17R18; R3 is substituted or unsubstituted heterocyclic or aryl, substituted or unsubstituted cycloalkyl or cycloalkenyl, formula (3), and -P(W)R?R3RR3'; R¿4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylalkyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) -L4-N(R5)-L5-, (b) -L4-O-L5-, (c) -L4-S(O)n-L5-, (d) -L4-L6-C(W)-N(R5)-L5-, (e) -L4-L6-S(O)m-N(R5)-L5-, (f) -L4-N(R5)-C(W)-L7-L5-, (g) -L4-N(R5)-S(O)p-L7-L5-, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, (j) optionally substituted alkynylene, (k) a covalent bond, (1) formula (4), and (m) formula (5) are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.

Description

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 famesyltransferase 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 famesyltransferase. Inhibition of protein famesyltransferase, 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, 1-3: 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 famesyltransferase and protein geranylgeranyltransferase.
Summary of the Invention
In its principle embodiment, the invention provides a compound having the formula:
Figure imgf000004_0001
I or a pharmaceutically acceptable salt thereof, wherein Rj is selected from the group consisting of
(1) hydrogen,
(2) alkenyl,
(3) alkynyl,
(4) alkoxy, (5) haloalkyl,
(6) halogen,
(?) 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 75 loweralkyl, oxo (=O), and thioalkoxy and L2 is absent or is selected from the group consisting of
-CH2-,
80 -^n2 n2"'
-CH(CH3)-,
-O-,
-C(O)-
-S(O)q , wherein q is 0, 1 or 2, and
85 -N(R)- , and
(10) heterocycle-L-; ,- 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,
90 (b) hydroxy,
(c) hydroxyalkyl,
(d) halogen
(e) cyano,
( ) nitro,
95 (g) oxo (=O),
( ) -NRR',
0) N-protected amino,
(j) alkoxy,
(k) thioalkoxy,
100 0) haloalkyl,
(m) carboxy, and
(n) aryl;
R2 is selected from the group consisting of 105 (1)
Figure imgf000006_0001
wherein Li i is selected from the group consisting of
(a) a covalent bond,
(b) -C(W)N(R)- wherein R is defined previously and W is selected from the group consisting of O and S, 110 (c) -C(O)-,
(d) -N(R)C(W)-,
(e) -CH2O-,
(f) -C(O)O-, and
(g) -CH2N(R)-,
115 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 120 hydrogen and a carboxy-protecting group, and R12b is selected from the group consisting of
(a) hydrogen and
(b) loweralkyl,
125 with the proviso that R12a and R12b are not both hydrogen,
(2) -Li ι-C(Rj4)(Rv)-C(O)OR15 wherein Li 1 is defined previously, Rv is selected from the group consisting of (a) hydrogen and 130 (b) loweralkyl,
R15 is selected from the group consisting of
(a) hydrogen,
(b) alkanoyloxyalkyl,
(c) loweralkyl, and
135 (b) a carboxy-protecting group, and
R1 is selected from the group consisting of
(a) alkoxyalkyl,
(b) alkoxyarylalkyl,
- 4 - (c) alkoxycarbonylalkyl,
140 (d) alkylsulfiny alky 1 ,
(e) alkylsulfonylalkyl,
( ) alkynyl,
(g) aminoalkyl,
(h) aminocarbonylalkyl,
145 (i) aminothiocarbonylalkyl,
(j) aryl,
(k) arylalkyl,
(1) carboxyalkyl,
(m) cyanoalkyl,
150 (n) cycloalkyl,
(o) cycloalkylalkoxyalkyl,
(P) cycloalkylalkyl,
(q) (heterocyclic)alkyl,
(r) hydroxyalkyl,
155 (s) hydroxyarylalkyl,
(t) loweralkyl,
( ) sulfhydrylalkyl,
(v) thioalkoxyalkyl wherein the thioalkoxyalkyl is unsubstituted or substituted with 1, 2, 3, or 4
160 substituents selected from the group consisting of halogen,
(w) thioalkoxyalkylamino, and
(x) thiocycloalkyloxyalkyl,
165 (3)
Figure imgf000007_0001
wherein n is 1-3,
(4) -C(O)NH-CH(R14)-C(O)NHSO2Ri6 wherein R14 is defined previously and R.6 is selected from the group consisting of (a) loweralkyl, 170 (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, 175 hydroxy, hydroxyalkyl, halogen, cyano, nitro, 180 oxo (=O),
-NRR'
N-protected amino, alkoxy, thioalkoxy, 185 haloalkyl, carboxy, and aryl, and (d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently 190 selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, 195 cyano, nitro, oxo (=O),
-NRR',
N-protected amino, 200 alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl;
205
(5) -C(O)NH-CH(Ri4)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl,
(6) -Li i -heterocycle, 210
(7) -C(O)NH-CH(R14)-C(O)NRπRi8 wherein R14 is defined previously and R17 and Ris are independently selected from the group consisting of
(a) hydrogen, 215 (b) loweralkyl,
(c) arylalkyl,
(d) hydroxy, and
(e) dialkylaminoalkyl,
220 (8) -C(O)ORi5, and
(9) -C(O)NH-CH(Ri4)-heterocycle wherein R14 is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl; 225
Lj is absent or is selected from the group consisting of (1) - -N(R5)-L5- wherein L4 is absent or selected from the group consisting of
(a) Cj-to-CjQ-alkylene and 230 (b) C2-to-C16-alkenylene, wherein the alkylene and alkenylene groups are unsubstituted or substituted with 1 , 2, 3 or 4 substitutents independently selected from the group consisting of alkenyl, 235 alkenyloxy, alkenyloxy alkyl, alkenyl[S(O)q]alkyl, alkoxy, alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or 240 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 3 245 substituents independently selected from the group consisting of halogen and cycloalkyl, alkylsilyloxy, 250 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 255 alkoxy wherein the alkoxy is unsubstituted or substituted with substituents selected from the group consisting of cycloalkyl, aryl, arylalkyl, 260 aryloxy wherein the aryloxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of, halogen, 265 nitro, and
-NRR', cycloalkyl, halogen, loweralkyl, 270 hydroxyl, nitro,
-NRR', and -SO2NRR\ arylalkoxy wherein the arylalkoxy is unsubstituted or 275 substituted with substituents selected from the group consisting of alkoxy, arylalkyl, arylalkyl[S(O)q]alkyl, aryl[S(O)q], 280 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, 285 arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, and halogen, 290 aryloxy, aryloxyalkyl wherein the aryloxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of halogen, carboxyl, 295 -C(O)NRCRD wherein Re and RD are independently selected from the group consisting of hydrogen, loweralkyl, and alkoxycarbonyl or 300 R and RD together with the nitrogen to which they are attached form a ring selected from the group consisting of morpholine, piperidine, 305 pyrrolidine thiomorpholine, thiomorpholine sulfone, and thiomorpholine sulfoxide, wherein the ring formed by Rc and RD 310 together is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy and alkoxyalkyl, 315 cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of alkenyl, cyclolalkoxy, cycloalkoxycarbonyl, 320 cyclolalkoxy alkyl, cyclolalkyl wherein the cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl, 325 loweralkyl, and alkanoyl, cycloalkylalkoxy, cycloalky lalkoxy carbonyl , cycloalkylalkoxyalkyl, 330 cycloalkylalkyl, cyclolalkyl[S(O)q]alkyl, cycloalkylalkyl[S(O)q]alkyl, fluorenyl, heterocycle wherein the heterocycle is unsubstituted or 335 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 340 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 345 the group consisting of aryl and cycloalkyl, alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1 or 2 350 substituents independently selected from the group consisting of aryl and cycloalkyl, aryl wherein the aryl is unsubstituted or 355 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkanoyl, alkoxy, 360 carboxaldehyde, haloalkyl, halogen, loweralkyl, nitro, 365 -NRR', and thioalkoxy, arylalkyl, aryloxy, cycloalkoxy alkyl , 370 cycloalkyl, cycloalkylalkyl, halogen, heterocycle, hydroxyl, 375 loweralkyl wherein the loweralkyl is unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from the group consisting of heterocycle, 380 hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, and -NRR3R3' wherein RR3 and RR3' are 385 independently selected from the group consisting of hydrogen aryl, loweralkyl, 390 aryl, arylalkyl, heterocycle, (heterocyclic)alkyl, cycloalkyl, and 395 cycloalkylalkyl, and sulfhydryl,
(heterocyclic) alkoxy ,
(heterocyclic)alkyl,
(heterocyclic)alkyl[S(O)q]alkyl,
400 (heterocyclic)oxy,
(heterocyclic)alkoxyalkyl,
(heterocyclic)oxyalkyl, heterocycle [S (O)q] alkyl, hydroxyl,
405 hydroxyalkyl, imino,
N-protected amino,
=N-O-aryl, and
=N-OH,
410 =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,
415 hydroxy, hydroxyalkyl, halogen, cyano, nitro,
420 oxo (=O),
-NRR'
N-protected amino, alkoxy, thioalkoxy,
425 haloalkyl, carboxy, and aryl,
=N-O-loweralkyl , _NRR3RR3';
430 -NHNRCRD,
-OG wherein G is a hydroxyl protecting group, -O-NH-R,
-0-N=
J wherein J and J' are independently selected from the group consisting of 435 loweralkyl and arylalkyl, oxo, oxyamino(alkyl)carbonylalkyl, oxyamino(arylalkyl)carbonylalkyl, 440 oxyaminocarbonylalkyl,
-SO2-A wherein A is selected from the group consisting of loweralkyl, aryl, and 445 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 450 alkoxy, halogen, haloalkyl, loweralkyl, and nitro, 455 sulfhydryl, thioxo, and thioalkoxy, L5 is absent or selected from the group consisting of (a) Cj-to-CjQ-alkylene and 460 (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, 465 alkanoyl wherein the alkanoyl is unsubstituted or substituted with substituents selected from the group consisting of aryl, alkoxy, alkoxyalkyl, 470 alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of aryl and 475 halogen, alkylaminocarbonylalkyl wherein the alkylaminocarbonylalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting 480 of aryl,
(anthracenyl)alkyl , aryl, arylalkoxy, arylalkyl wherein the arylalkyl is unsubstituted or 485 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkoxy, aryl, 490 carboxyl, cyano, halogen, haloalkoxy, haloalkyl, 495 nitro, oxo, and
-Ln-C(R14)(Rv)-C(O)OR15,
(aryl)oyl wherein the (aryl)oyl is unsubstituted or substituted with substituents selected from the 500 group consisting of halogen, aryloxycarbonyl, carboxaldehyde, -C(O)NRR', cycloalkoxycarbonyl, 505 cycloalkylaminocarbonyl, cycloalkylaminothiocarbony 1 , cyanoalkyl, cyclolalkyl, cycloalkylalkyl wherein the cycloalkylalkyl is 510 unsubstituted or substituted with 1 or 2 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (cyclolalkyl)oyl, 515 (9,10-dihydroanthracenyl)alkyl wherein the
(9,10-dihydroanthracenyl)alkyl is unsubstituted or substituted with 1 or 2 oxo substituents, haloalkyl, heterocycle, 520 (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, 525 loweralkyl, wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of -NRR', -SO2-A, and thioalkoxyalkyl;
530
(2) -L4-O-L5-,
(3) -L,4-S(O)m-L5- wherein L4 and L5 are defined previously and m is 0, 1, or 2,
535
(4) -L,4-L6-C(W)-N(R6)-L5- wherein L4. W, and L5 are defined previously, R6 is selected from the group consisting of
(a) hydrogen,
(b) loweralkyl, 540 (c) aryl,
(d) arylalkyl, (e) heterocycle,
(f) (heterocyclic)alkyl,
(g) cyclolakyl, and
545 (h) cycloalkylalkyl, and
L6 is absent or is selected from the group consisting of
(a) -O-,
(b) -S-, and
(c) -N(R6 - wherein R6. is selected from the group
550 consisting of hydrogen, loweralkyl, aryl, arylalkyl, 555 heterocycle,
(heterocyclic) alkyl , cyclolakyl, and cycloalkylalkyl,
560 (5) -L4-L6-S(O)m-N(R5)-L5-,
(6) -L4-L6-N(R5)-S(O)m-L5-,
(7) -L4-N(R5)-C(W)-L7-L5- wherein L4, R5, W, and and L5 are
565 defined previously and L7 is absent or is selected from the group consisting of -O- and -S-,
(8) Ci-Cio-alkylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from 570 the group consisting of
(a) aryl,
(b) arylalkyl,
(c) heterocycle,
(d) (heterocyclic)alkyl, 575 (e) cyclolakyl,
(f) cycloalkylalkyl,
(g) alkylthioalkyl, and (h) hydroxy, 580 (9) C2-to-CjQ-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,
585 (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,
590 (e) (hererocycle)alkyl,
(f) hydroxyalkyl,
(g) cyclolakyl,
(h) cycloalkylalkyl, (i) alkylthioalkyl, and 595 (j) hydroxy,
(10) C2-to-C,0-alkynylene wherein the alkynylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of 600 (a) aryl,
(b) arylalkyl,
(c) heterocycle,
(d) (heterocyclic)alkyl,
(e) cyclolakyl,
605 (f) cycloalkylalkyl,
(g) alkylthioalkyl, and (h) hydroxy,
(11) -L4-heterocycle-L5-, 610
(12) a covalent bond,
. B J
(13) ' wherein B is selected from the group consisting of loweralkyl and 615 arylalkyl, and
Figure imgf000020_0001
Z is selected from the group consisting of 620 (1) a covalent bond,
(2) -O-,
(3) -S(O)q-, and
(4) -NRZ- wherein Rz is selected from the group consisting of
(a) hydrogen 625 (b) loweralkyl,
(c) aryl,
(d) arylalkyl,
(e) heterocycle,
(f) (heterocyclic)alkyl, 630 (g) cyclolakyl, and
(h) cycloalkylalkyl;
R3 is selected from the group consisting of (1) hydrogen, 635 (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 640 (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, 645 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 650 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 655 aryl, and cycloalkyl,
(e) alky lsilyloxy alkyl,
(f) arylalkyl,
(g) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 660 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 665 consisting of cycloalkyl, carboxaldehyde, haloalkyl, halogen, loweralkyl, 670 nitro,
-NRR', and thioalkoxy, (h) arylalkyl,
(i) aryloxy wherein the aryloxy is unsubstituted or 675 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of, halogen, nitro, and -NRR', 680 (j) (aryl)oyl,
(k) carboxaldehyde, (1) carboxy, (m) carboxyalkyl,
(n) -C(O)NRR" wherein R is defined previously and R" is 685 selected from the group consisting of hydrogen, loweralkyl, and carboxyalkyl, (o) cyano, 690 (p) cyanoalkyl,
(q) cycloalkyl, (r) cycloalkylalkyl, (s) cycloalkoxy alkyl, (t) halogen, 695 (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, 700 (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 705 with substituents selected from the group consisting of heterocycle, hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, 710 -NRR RR3', and
-P(OXORXOR'), (z) nitro, (aa) -NRR', (bb) oxo, 715 (cc) -SO2NRA'RB' wherein RA' and Rβ' re independently selected from the group consisting of hydrogen, (aryl)oyl, loweralkyl, and 720 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 725 (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, 730 (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, 735 (e) loweralkyl,
(f) halogen,
(g) NRR3RR3',
Figure imgf000023_0001
740
(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, 745 (b) alkoxy,
(c) halogen,
(d) aryl,
(e) aryloxy,
(f) alkanoyl, and 750 (g) NRR3RR3',
x χ 2
(7)
Figure imgf000023_0002
wherein Xj 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 755
(8) -P(W)RR RR3'; and R4 is selected from the group consisting of
(1) hydrogen,
760 (2) loweralkyl,
(3) haloalkyl
(4) halogen,
(5) aryl,
(6) arylalkyl,
765 (7) heterocycle,
(8) (heterocyclic)alkyl
(9) alkoxy, and
(10) -NRR'; or
770 Li, Z, and R3 together are selected from the group consisting of
(1) aminoalkyl,
(1) haloalkyl,
(2) halogen,
(3) carboxaldehyde, and
775 (4) (carboxaldehyde)alkyl, and
(5) hydroxyalkyl, with the proviso that when Li, Z, and R3 together are (l)-(5), Ri is other than hydrogen.
In a further aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of formula I in combination with a 780 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 785 protein isoprenyl transferases (i.e., protein famesyltransferase 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 famesyltransferase, 790 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 795 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 800 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 805 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.
810 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
815 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.
820 152-186 (1981), which is hereby incoφorated 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
825 Series, American Chemical Society (1975), which is hereby incoφorated 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 incoφorated herein by reference). Examples of esters
830 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 incoφorated herein by reference. Representative carboxy protecting groups are Cj to Cs loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted 835 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, l-(propionyloxy)-l -ethyl, l-(pivaloyloxyl)-l- 840 ethyl, 1 -methyl- l-(propionyloxy)-l -ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxy methyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 845 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl or cycloalkyloxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-l- ethyl, and the like; alkoxycarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl, such as methoxycarbonyloxy methyl , t-buty loxycarbonyloxy methyl , 1 -ethoxycarbonyloxy- 1 -ethyl , 1-cyclohexyloxycarbonyloxy-l -ethyl and the like; aryloxycarbonyloxyalkyl, such as 2- 850 (phenoxy carbonyloxy)ethyl,
2-(5-indanyloxycarbonyloxy)ethyl and the like; alkoxyalkylcarbonyloxyalkyl, such as 2-(l- 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 855 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- 860 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-l,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-l,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 865 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
870 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 incoφorated herein by reference. N- protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-
875 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-
880 bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzy loxycarbonyl , 2 ,4-dimethoxy benzyloxycarbonyl ,
4-methoxybenzyloxy carbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
885 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,
890 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. 895 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. 900 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 905 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 910 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 915 can be optionally substituted.
The term "alkenyloxy alkyl" 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
920 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. 925 The term "alkoxy alkoxy" as used herein refers to R31O-R32O- wherein R31 is loweralkyl as defined above and R32 is an alkylene radical. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The alkoxyalkoxy groups of this invention can be optionally substituted.
The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously 930 defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxy methyl, 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.
935 The term "alkoxy arylalkyl" as used herein refers to a an arylalkyl group to which is attached an alkoxy group. The alkoxy arylalkyl 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 940 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 945 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. 950 The term "alkoxycarbonyloxy alkyl" 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 955 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 960 radical to which is appended R70-C(O)-NH- wherein R7Q 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, 965 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 -OSiR\y'Rχ'Rγ' wherein R y', Rx, and Rγ] are selected from the group consisting of loweralkyl. 970 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. 975 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. 980 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 985 bond. Examples of alkynyl include -C≡CH, -CH2C=CH, -CH2C≡CCH3, and the like. The alkynyl groups of this invention can be optionally substituted.
The term "alkynylene" as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynylene include -C≡C-, 990 -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 995 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 1000 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. 1005 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, 1010 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 1015 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 1020 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 1025 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
1030 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. 1035 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 1040 optionally substituted.
The term "arylalkyloxycarbonyloxy alkyl" 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 1045 appended Rg5-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 g5"O- wherein R65 is an aryl group. The arylalkoxy groups of this invention can be optionally substituted. 1050 The term "arylalkyloxy alkyl" 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 g5"O- wherein R65 is an aryl group.
The aryloxy groups of this invention can be optionally substituted. The aryloxy groups of 1055 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 "aryloxy thioalkoxy alkyl" as used herein refers to a loweralkyl radical to 1060 which is appended R75-S- wherein R75 is an aryloxyalkyl group. The aryloxythioalkoxyalkyl groups of this invention can be optionally substituted.
The term "aryloxycarbonyloxy alkyl" 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. 1065 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. 1070 The term "carboxy alkyl" 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 1075 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. 1080 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).
1085 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 1090 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 1095 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 1100 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 1105 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. 1110 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 1115 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 1120 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. 1125 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 R^ 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 1130 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 1135 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 1140 which is appended R73-C(O)- wherein R73 is a dialkylamino group. The dialkyaminocarbonylalkyl groups of this invention can be optionally substituted.
The term "dioxoalkyl" as used herein refers to a loweralkyl radical which is substituted with two oxo (=O) groups. The dioxoalkyl groups of this invention can be optionally substituted. 1145 The term "dithioalkoxy alkyl" 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, 1150 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 1155 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
1160 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;
1165 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
1170 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,
1175 moφholinyl, thiomoφholinyl, 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,
1180 benzofuranyl and benzothienyl. Heterocyclics also include bridged bicyclic groups wherein a monocyclic heterocyclic group is bridged by an alkylene group, for example,
Figure imgf000035_0001
and the like. 1185 Heterocyclics also include compounds of the formula
Figure imgf000035_0002
wherein X* is -CH2-, -CH2O- or -O- and Y* is -C(O)- or -(C(R")2)V - wherein R" is hydrogen or Cι-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like. 1190 Heterocyclics can be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of a) hydroxy, b) -SH, c) halo, d) oxo (=O), e) thioxo (=S), f) amino,g) -NHOH, h) alkylamino, i) dialkylamino, j) alkoxy, k) alkoxyalkoxy, 1) haloalkyl, m) hydroxyalkyl, n) alkoxyalkyl, o) cycloalkyl which is unsubstituted or substituted with one, two, three or four
1195 loweralkyl groups, p) cycloalkenyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, q) alkenyl, r) alkynyl, s) aryl, t) arylalkyl, u) -COOH, v) -SO3H, w) loweralkyl, x) alkoxycarbonyl, y) -C(O)NH2, z) -C(S)NH2, aa) -C(=N- OH)NH2, bb) aryl-L16-C(O)- wherein L16 is an alkenylene radical, cc) -S-L17-C(O)OR40 wherein L17 is an alkylene radical which is unsubstituted or substituted with one or two
1200 substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or methinylamino (=CHNR41R42 wherein R41 is hydrogen or loweralkyl and R42 is loweralkyl) and R40 is hydrogen or a carboxy-protecting group, dd) -S-Ll g-C(O)NR43R44 wherein L18 is an alkylene radical which is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or 1205 methinylamino (=CHNR 1R 2 wherein R41 is hydrogen or loweralkyl and R43 and R^ 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 (=O) and R45 is
1210 hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, gg) -O-L21-R46 wherein L21 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the 1215 alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of alkanoyl, oxo (=O) or methinylamino (=CHNR41R42 wherein R41 is hydrogen or loweralkyl and R46 is hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group 1220 consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, hh) -O-S(O)2-R 7 wherein R47 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- 1225 protected amino, alkoxy, thioalkoxy and haloalkyl, ii) -S(O)2-NH-R48 wherein R 8 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, jj) alkylsulfinyl, kk) alkylsulfonyl, 11)
1230 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
1235 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) 53" 22-, 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
1240 the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, ooo) aryl-NH-C(O)-, ppp) R54- N=N- wherein R54 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-
1245 protected amino, alkoxy, thioalkoxy and haloalkyl, qqq) =N-R55 wherein R55 is hydrogen, aryl, heterocyclic, -S(O)2-aryl or -S(O)2-heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, rrr) diarylalkyl-N=N-, sss) aryl-
1250 N(R56)- or arylalkyl-N(R56)- wherein R56 is hydrogen or an N-protecting group, ttt) aryl- sulfonylalkyl, uuu) heterocyclicsulfonylalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N- protected amino, alkoxy, thioalkoxy and haloalkyl, vvv) =C(CN)(C(O)NH2), www)
1255 =C(CN)(C(O)O-loweralkyl), xxx) heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (=O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, yyy) hydroxythioalkoxy, zzz) aryloxyalkyl, aaaa) aryloxyalkylthioalkoxy, bbbb) dialkoxyalkyl, cccc) dithioalkoxyalkyl,
1260 dddd) arylalkyl-NH-L23- wherein L23 is an alkylene group, eeee) heterocyclicalkyl-NH-
L24- wherein L24 is an alkylene group, ffff) aryl-S(O)2-NH-L25- wherein L25 is an alkylene group, gggg) heterocyclic-S(O)2-NH-L26- wherein L26 is an alkylene group, hhhh) aryl- C(O)-NH-L27- wherein L27 is an alkylene group and iiii) heterocyclic-C(O)-NH-L28- wherein L28 is an alkylene group, jjjj) Ryy(CH2)n-X-Y-Z-(CH2)m wherein Ryy is 1265 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 1270 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 1275 (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)oxy alkyl" as used herein refers to a loweralkyl group to which is 1280 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. 1285 The term "heterocycliccarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended R72-C(O)-O- wherein R72 is a heterocyclic group. The heterocycliccarbonyloxyalkyl groups of this invention can be optionally substituted. The term "hydroxy" as used herein refers to -OH.
The term "hydroxyalkyl" as used herein refers to a loweralkyl radical to which is 1290 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. 1295 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- 1300 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. 1305 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 (=O) group. The oxoalkyloxy groups of this invention can be optionally substituted. 1310 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 "oxy aminocarbonylalkyl" as used herein refers to -O-NH-C(O)-R group 1315 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. 1320 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. 1325 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. 1330 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 1335 invention can be optionally substituted.
Preferred embodiments Preferred compounds of the invention are compounds of formula I wherein R j is unsubstituted or substituted phenyl and R2 is -C(O)NH-CH(R14)-C(O)OR15 or -C(O)NH-CH(R14)-C(O)NHSO2Ri6 wherein L2, R14 R15 and R16 are defined above.
1340
More preferred compounds of the invention are compounds of formula I wherein Rj is unsubstituted or substituted phenyl and R2 is
Figure imgf000040_0001
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 1350 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 Rj is unsubstituted or substituted phenyl and R2 is
(a)
Figure imgf000040_0002
1355
H
A N._.CONHS02R16 o
(c) SCH3
Figure imgf000041_0001
1360 The most preferred compounds have the structure defined immediately above wherein R3 is unsubstituted or substituted pyridyl or imidazolyl.
Protein Famesyltransferase Inhibition The ability of the compounds of the invention to inhibit protein famesyltransferase
1365 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.
1370 In addition, in vitro inhibition of protein famesyltransferase 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-Cθ2H), 0.1 mM final concentration, for the biotin-lamin substrate provided by Amersham. The enzyme
1375 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.
1380 The % inhibition of protein famesyltransferase was determined for representative compounds of the invention. The results are summarized in Table 1.
Tables 1-5 In Vitro Potencies of Representative Compounds able 1. Inhibition of famesyltransferase
% inhibition % inhibition
Example at 1X10-5 M Example at 1X10-5 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
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 famesyltransferase
% inhibition % inhibition
Example at lX10'6 M Example at lX10"6 M
157 92 583 98
158 2 587 97
159 84 595 97
160 30 607 96
161 54 610 94
162 12 613 97
163 18 617 99
164 92 620 98
165 74 626 61
166 97 627 85
167 98 632 43
168 92 633 32
183 98 636 72
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
569 91 964 >50
572 91 979 26
575 70 982 64
576 88 987 93
577 94 988 92
582 99 989 88
1390
Table 3. Inhibition of famesyltransferase
% inhibition % inhibition
Example at lX10"7 M Example at lX10'7 M
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
Figure imgf000051_0001
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 famesyltransferase
% 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
1395
Table 6. Inhibition of famesyltransferase at concentrations of 10 mM and 1 mM unless s ecified as * (0.1 mM or ** (0.01 mM)
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
* % inhibition at 0.1 μM ** % inhibition at 0.01 μM
1400
Additional methods for the measurement of in vitro inhibition of protein prenylation (i.e., inhibition of famesyltransferase 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
1405 combination of hydrophobic and DEAE column chromatography procedures. Protein substrates are purchased from Panvera Coφoration (H-ras for FTase, H-ras-CVLL for GGTase I). Tritium labeled prenyl lipid substrates (FPP or GGPP) are obtained from Amersham Life Science.
1410 FTase
3H-Farnesyldiphosphate (final concentration 0.6 μM), H-Ras (final concentration 5.0 μM) and the test compound (various final concentrations from a stock solution in 50% DMSO/water; final concentration DMSO < 2%) were mixed in buffer (50 mM HEPES (pH 7.5), 30 M MgCl2, 20 mM KCl, 10 μM ZnCl2, 5 mM DTT, 0.01% Triton X-100) to give 1415 a final volume of 50 μL. 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
1420 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 IC50 value was calculated by measuring the activity of the enzyme over a suitable range of inhibitor concentrations.
1425 GGTase I
3H-geranylgeranyldiphosphate (final concentration 0.5 μM), H-Ras-CVLL (final concentration 5.0 μM) 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 μM ZnCl2, 5 mM DTT, 0.01%
1430 Triton X-100) to give a final volume of 50 μL. 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
1435 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 IC50 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
1440 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 incoφorated herein by reference.
1445 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,
1450 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-
1455 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-
1460 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.
1465 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
1470 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
1475 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 famesyltransferase and/or protein geranylgeranyltransferase) and the isoprenylation (i.e., farnesylation and/or
1480 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,
1485 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. 1490 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 incoφorated 1495 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. 1500 Circ. Res. 73: 269-275 (1993) and Santoian, E.C. et al. Circulation 88: 11-14 (1993), which are hereby incoφorated 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 1505 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 1510 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 1515 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, 1520 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
1525 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
1530 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 puφose, 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.
1535 Suppositories for rectal administration of the drag 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,
1540 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.
1545 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.
1550 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
1555 liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et 1560 seq., which is hereby incoφorated 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.,
1565 Clinical Oncology. American Cancer Society, United States (1991) p 56 et seq., which is hereby incoφorated herein by reference These agents include alkylating agents such as the nitrogen mustards (mechloethamine, melphalan, chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas (carmustine, lomustine, semustine, strep tozocin), alkyl sulfonates (busulfan), triazines (dacarbazine) and ethyenimines (thiotepa, hexamethylmelamine); folic
1570 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,
1575 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 incoφorated herein by reference or by such therapeutically useful amounts as would be known to one of ordinary
1580 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
1585 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.
1590 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.
1595 SCHEME 1
Figure imgf000067_0001
thiophosgene
Figure imgf000067_0002
Figure imgf000067_0003
Figure imgf000067_0004
Figure imgf000067_0005
SCHEME 2
Figure imgf000068_0001
SCHEME 3
Figure imgf000069_0001
1) thiophosgene
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000069_0004
SCHEME 4
Figure imgf000070_0001
SCHEME 5
Figure imgf000071_0001
Figure imgf000071_0002
SCHEME 6
Figure imgf000072_0001
Figure imgf000072_0002
1610
SCHEME 7
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000073_0003
SCHEME 8
Figure imgf000074_0001
Figure imgf000074_0002
1615
SCHEME 9
Figure imgf000075_0001
SCHEME 10
Figure imgf000076_0001
SCHEME 11
Figure imgf000077_0001
1625
SCHEME 12
Figure imgf000078_0001
SCHEME 13
Figure imgf000079_0001
X = ha de
Figure imgf000079_0002
X = halide
Figure imgf000079_0003
X = hahde
Figure imgf000079_0004
X = hahde
Figure imgf000079_0005
X = hahde
1630
SCHEME 14
Figure imgf000080_0001
SCHEME 15
Figure imgf000081_0001
Scheme 16 illustrates an alternative method for preparing compounds wherein R2 is -C(O)NH-CH(R14)-C(O)OR15 or
Figure imgf000081_0002
as defined above. SCHEME 16
Figure imgf000082_0001
Figure imgf000082_0002
1645 Table 6. Amines of the Type ACBIN-Lj^
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
1655
Figure imgf000084_0001
10 11 12
Figure imgf000084_0002
1660 13 14 15
Figure imgf000084_0003
16 17 18
Figure imgf000084_0004
19 20 21
Figure imgf000085_0001
22 23 24
1670
Figure imgf000085_0002
25 26 27
Figure imgf000085_0003
1675 28 29 30
Figure imgf000086_0001
31 32 33
Figure imgf000086_0002
34 35 36
Figure imgf000086_0003
37 38 39
1685
Figure imgf000086_0004
40 41 42
Figure imgf000087_0001
1690 43 44 45
Figure imgf000087_0002
46 47 48
Figure imgf000087_0003
49 50 51
Figure imgf000088_0001
52 53 54
1700
Figure imgf000088_0002
55 56 57
Figure imgf000088_0003
1705 58 59 60
Figure imgf000088_0004
61 62 63
Figure imgf000089_0001
64 65 66
Figure imgf000089_0002
67 68 69
1715
Figure imgf000089_0003
70 71 72
Figure imgf000090_0001
1720 73 74 75
Figure imgf000090_0002
76 77 78
Figure imgf000090_0003
Figure imgf000091_0001
82 83 84
1730
Figure imgf000091_0002
1735 88 89 90
Figure imgf000092_0001
91 92 93
Figure imgf000092_0002
1740
94 95 96
Figure imgf000092_0003
97 98 99
1745
Figure imgf000093_0001
101 102
Figure imgf000093_0002
104 105
Figure imgf000093_0003
Figure imgf000094_0001
109 110 111
Figure imgf000094_0002
112 113 114
1760
Figure imgf000094_0003
Figure imgf000095_0001
1765 118 119 120
Figure imgf000095_0002
121 122 123
Figure imgf000095_0003
Figure imgf000096_0001
127 128 129
Figure imgf000096_0002
130 131 132
Figure imgf000096_0003
133 134 135
1780
Figure imgf000097_0001
136 137 138
Figure imgf000097_0002
139 140 141
Figure imgf000097_0003
142 143 144
Figure imgf000098_0001
145 146 147
Figure imgf000098_0002
148 149 150
Figure imgf000098_0003
151 152 153
Figure imgf000099_0001
1800 154 155 156
Figure imgf000099_0002
158 159
Figure imgf000099_0003
160 161 162
Figure imgf000100_0001
163 164 165
1810
Figure imgf000100_0002
166 167 168
Figure imgf000100_0003
1815 169 170 171
Figure imgf000101_0001
172 173 174
Figure imgf000101_0002
175 176 177
Figure imgf000101_0003
178 179 180
1825
Figure imgf000102_0001
181 182 183
Figure imgf000102_0002
184 185 186
Figure imgf000102_0003
187 188 189
Figure imgf000103_0001
190 191 192
Figure imgf000103_0002
193 194 195
1840
Figure imgf000103_0003
196 197 198
Figure imgf000104_0001
1845 199 200 201
Figure imgf000104_0002
202 203 204
Figure imgf000104_0003
205 206 207
Figure imgf000105_0001
208 209 210
1855
Figure imgf000105_0002
211 212 213
Figure imgf000105_0003
1860 214 215 216
Figure imgf000106_0001
217 218 219
Figure imgf000106_0002
220 221 222
Figure imgf000106_0003
223 224 225
1870
Figure imgf000107_0001
226 227 228
Figure imgf000107_0002
229 230 231
Figure imgf000107_0003
232 233 234
Figure imgf000108_0001
235 236 237
Figure imgf000108_0002
238 239 240
1885
Figure imgf000108_0003
241 242 243
Figure imgf000109_0001
247 248 249
Figure imgf000109_0002
Figure imgf000110_0001
253 254 255
1900
Figure imgf000110_0002
256 257 258
Figure imgf000110_0003
Figure imgf000111_0001
262 263 264
Figure imgf000111_0002
265 266 267
Figure imgf000111_0003
268 269 270
1915
Figure imgf000112_0001
271 272 273
Figure imgf000112_0002
274 275 276
Figure imgf000112_0003
277 278 279
Figure imgf000113_0001
280 281 282
Figure imgf000113_0002
283 284 285
1930
Figure imgf000113_0003
286 287 288
Figure imgf000114_0001
1935 289 290 291
Figure imgf000114_0002
292 293 294
Figure imgf000114_0003
295 296
Figure imgf000114_0004
297 298
1945
Figure imgf000115_0001
299 300
Figure imgf000115_0002
1950 301 302
Figure imgf000115_0003
303 304
Figure imgf000115_0004
306
Figure imgf000115_0005
307 308
1960
Figure imgf000116_0001
309 310
Figure imgf000116_0002
1965 311 312
Figure imgf000116_0003
313 314
Figure imgf000116_0004
315 316
Figure imgf000116_0005
317 318 1975
Figure imgf000117_0001
319 320
Figure imgf000117_0002
1980 321 322
Figure imgf000117_0003
325 326
Figure imgf000117_0004
327 328
1990
Figure imgf000118_0001
329 330
Figure imgf000118_0002
1995 331 332
Figure imgf000118_0003
333 334
Figure imgf000118_0004
335 336
Figure imgf000118_0005
337 338
2005
Figure imgf000119_0001
339 340
Figure imgf000119_0002
2010 341 342
Figure imgf000119_0003
343 344
Figure imgf000119_0004
345 346
Figure imgf000119_0005
347 348
2020
Figure imgf000120_0001
349 350
Figure imgf000120_0002
2025 351 352
Figure imgf000120_0003
353 354
Figure imgf000120_0004
355 356
Figure imgf000121_0001
35" 358
2035
Figure imgf000121_0002
359 360
Figure imgf000121_0003
2040 361 362
Figure imgf000121_0004
363 364
Figure imgf000122_0001
365 366
Figure imgf000122_0002
367 368
2050
Figure imgf000122_0003
369 370
Figure imgf000122_0004
2055 371 372
Figure imgf000123_0001
373 374
Figure imgf000123_0002
375 376
Figure imgf000123_0003
377 378
2065
Figure imgf000123_0004
379 380 Table 7. Ethers of the Tvpe A-OI^
2070
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000124_0003
2080
Figure imgf000124_0004
Figure imgf000125_0001
10
Figure imgf000125_0002
2090 11 12
Figure imgf000125_0003
13 14
2095
Figure imgf000125_0004
15 16
2100
Figure imgf000126_0001
17 18
Figure imgf000126_0002
2105 19 20
Figure imgf000126_0003
21 22
2110
Figure imgf000126_0004
23 24
2115
Figure imgf000126_0005
25 26
Figure imgf000127_0001
27 28
Figure imgf000127_0002
2125 29 30
Figure imgf000127_0003
31 32
2130
Figure imgf000127_0004
33 34
2135
Figure imgf000128_0001
35 36
Figure imgf000128_0002
37 38
Figure imgf000128_0003
39 40
2145
Figure imgf000128_0004
41 42
2150
Figure imgf000128_0005
43 44
Figure imgf000129_0001
45 46
Figure imgf000129_0002
2160 47 48
Figure imgf000129_0003
49 50
2165
Figure imgf000129_0004
51 52
2170
Figure imgf000130_0001
53 54
Figure imgf000130_0002
55 56
Figure imgf000130_0003
2180 57 58
Figure imgf000130_0004
59 60
2185
Figure imgf000131_0001
61 62
2190
Figure imgf000131_0002
63 64
Figure imgf000131_0003
67 68
2200
Figure imgf000131_0004
Figure imgf000132_0001
OL 69
96260/86Sfl/X3d 62005/86 OΛV
Figure imgf000133_0001
96260/86SnXDd 62005/86 OΛV
Figure imgf000134_0001
91 92
Figure imgf000134_0002
93 94
2240
Figure imgf000134_0003
95 96
Figure imgf000134_0004
Figure imgf000135_0001
Figure imgf000135_0002
103 104
2255
Figure imgf000135_0003
105 106
Figure imgf000135_0004
2260 107 108
Figure imgf000135_0005
109 110
Figure imgf000136_0001
111 112
Figure imgf000136_0002
113 114
2270
Figure imgf000136_0003
115 116
Figure imgf000136_0004
2275 117 118
Figure imgf000136_0005
119 120
Figure imgf000137_0001
96260/86Sπ/X3d 62005/86 OΛV
Figure imgf000138_0001
131 132
Figure imgf000138_0002
133 134
2300
Figure imgf000138_0003
135 136
Figure imgf000138_0004
2305 137 138
Figure imgf000138_0005
Figure imgf000139_0001
141 142
Figure imgf000139_0002
143 144
2315
Figure imgf000139_0003
145 146
Figure imgf000139_0004
2320 147 148
Figure imgf000140_0001
0/86Sll/X3d 62005/86 OΛV -
Figure imgf000141_0001
891 Z.91 0£C2
Figure imgf000141_0002
091 6SI
Figure imgf000141_0003
96260/86SlT/X3d 62005/86 OΛV
Figure imgf000142_0001
169 170
Figure imgf000142_0002
171 172
Figure imgf000142_0003
173 174
2360
Figure imgf000142_0004
175 176
Figure imgf000142_0005
2365 177 178
Figure imgf000143_0001
179 180
Figure imgf000143_0002
181 182
Figure imgf000143_0003
183 184
2375
Figure imgf000143_0004
185 186
Figure imgf000143_0005
2380 187 188
Figure imgf000144_0001
189 190
Figure imgf000144_0002
191 192
Figure imgf000144_0003
193 194
2390
Figure imgf000144_0004
195 196
Figure imgf000144_0005
2395 197 198
Figure imgf000145_0001
199 200
Figure imgf000145_0002
201 202
Figure imgf000145_0003
203 204
2405
Figure imgf000145_0004
205 206
Figure imgf000145_0005
Figure imgf000146_0001
209 210
Figure imgf000146_0002
211 212
Figure imgf000146_0003
21 214
2420
Figure imgf000146_0004
215 216
Figure imgf000147_0001
2425 217 218
Figure imgf000147_0002
219 220
Figure imgf000147_0003
221 222
Figure imgf000147_0004
223 224
2435
Figure imgf000148_0001
Figure imgf000148_0002
833 LZZ 0tΦ2
a
Figure imgf000148_0003
933 S33
2os^A
Figure imgf000148_0004
96260/86SO/X3d 62005/86 OΛV Table 8. Sulfonamides of the Tvpe ASQ2(,B N-L1
Figure imgf000149_0001
2445
Figure imgf000149_0002
Figure imgf000149_0003
Figure imgf000149_0004
2455
Figure imgf000149_0005
-8W -
Figure imgf000150_0001
01 6
96260/86Sn/XOd 62005/86 OΛV 6W
Figure imgf000151_0001
96260/86SHX3d 62005/86 OΛV
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000153_0001
lTzϊlD{WY 9dΛχ am jo suoqjuoopΛH 69W^1
96260/86Sl/X3d 62005/86 OΛV
Figure imgf000154_0001
Figure imgf000154_0002
01
Figure imgf000154_0003
96260/86Sπ/XOd 62005/86 OΛV i
Figure imgf000155_0001
L\
Figure imgf000155_0002
96260/86Sn/XDd 62005/86 OΛV 2520 Table 10. Amines of the type B-NH2
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000157_0002
Figure imgf000157_0003
Figure imgf000157_0005
Figure imgf000157_0004
Figure imgf000157_0006
Figure imgf000157_0007
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
96260/86Sn/X3d 62005/86 OΛV
Figure imgf000161_0001
ΘIΛJOO' ΘIΛIOO ^ θ|Λ|3O0'
Figure imgf000161_0002
aiΛIO
Figure imgf000161_0003
Figure imgf000161_0004
96260/86Sfl/X3d 62005/86 OΛV Table 11. Bromides of the type B-Br
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000163_0001
ΘIΛIS £/_.£2
Figure imgf000163_0002
96260/86SHX3d 62005/86 OΛV
Figure imgf000164_0001
θlΛ|sOθ"
Figure imgf000164_0002
96260/86SflLXDd 62005/86 OΛV
Figure imgf000165_0001
0/86SflX3d 62005/86 OΛV
Figure imgf000166_0001
Figure imgf000166_0002
96260/86SO/X3d 62005/86 OΛV
Figure imgf000167_0001
ΘIΛIOO'
Figure imgf000167_0002
0/86SnX3d 62005/86 OΛV Table 12. Amines of the type A-NH2
Figure imgf000168_0001
,NH2 ,NH 2 ,NH 2 ,NH2 ,NH2
Figure imgf000168_0002
29 30 31 32 33 34 35 36
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
2695
Figure imgf000173_0002
Figure imgf000174_0001
Figure imgf000174_0002
2705 221 222 223 224
Figure imgf000174_0003
CCHH2oNNHH2,
Figure imgf000174_0004
Figure imgf000174_0005
229 230 231 232 233
2710
Figure imgf000174_0006
234 235 236 237
Figure imgf000175_0001
2720
Figure imgf000175_0002
2725 33 34 35
Figure imgf000176_0001
,C02H H
A/N"Ac
55
Figure imgf000177_0001
2740
Figure imgf000177_0002
COpH .COpH C02H C02H H yC02H HC C02H
69 s 70 S 71 S 72 s 73 s 74
Figure imgf000177_0003
2750
H C02H H C02H O C02H H C02H H O02H H C02H
&PO sPχ Cs s oPp OPQA sXp
94 95 96 97 98 99
Figure imgf000177_0004
Figure imgf000178_0001
2765
Figure imgf000178_0002
C02H
Figure imgf000178_0003
2H
Figure imgf000179_0001
Figure imgf000180_0001
, H „O__,„. NH-Boc NH-Boc
Figure imgf000180_0003
Figure imgf000180_0002
Figure imgf000180_0004
NH-Boc NH-Boc
Figure imgf000180_0006
Figure imgf000180_0005
c
Figure imgf000181_0001
239 240 241 242 243 \PXC°2 C02H 244
2815
Figure imgf000182_0001
2820
Figure imgf000182_0002
262 263 264 265
Figure imgf000182_0003
270 271 272 273
Figure imgf000182_0004
274 275
2830 Table 14. Aldehydes of the type A-CHO
Figure imgf000183_0001
3 4
2835
2840
Figure imgf000183_0002
Figure imgf000183_0003
Figure imgf000183_0004
2845
Figure imgf000184_0001
Figure imgf000184_0002
Figure imgf000185_0001
Figure imgf000186_0001
104 105 106 107 108 109
2875
Figure imgf000186_0002
Figure imgf000186_0003
2885 CHO Cl CHO CHO HO CHO HP CHO
N NH NsN^NH N<s .NH N A, NH HN M nBu nBu Ph Ph Ύ Ph 134 135 136 137 138
Figure imgf000187_0001
2895
Figure imgf000187_0002
Figure imgf000188_0001
189
Figure imgf000188_0002
Figure imgf000189_0001
Figure imgf000189_0002
2915
Figure imgf000189_0003
Figure imgf000189_0004
Figure imgf000189_0005
2925
Figure imgf000190_0001
253 254 255 256 257 258
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000193_0002
Figure imgf000194_0001
354
2985
Figure imgf000194_0002
361 362 363
Figure imgf000194_0003
364 365 366
NH-Boc
Figure imgf000194_0004
Figure imgf000194_0005
2995
Figure imgf000195_0001
381 382
Figure imgf000195_0002
NH-Boc
3010
Figure imgf000196_0001
Figure imgf000196_0002
433 434 435 436 3025
Figure imgf000197_0001
441 442 443 444
Figure imgf000197_0002
445 446
Table 15. Alcohols of the type A-OH
Figure imgf000198_0001
Figure imgf000199_0001
3055
Figure imgf000200_0001
Figure imgf000200_0002
MeP EtO. Λ Λnu A Me χ A A. \ ^ 0H ^ OH r= OH Y=( OH TOHrCOH ψ« -y V"" ^'
Br N02 .__ SMe SP2Me
104 105 106
102 103 107 108
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000203_0002
Figure imgf000203_0003
Figure imgf000204_0001
3125
Figure imgf000205_0001
Figure imgf000206_0001
3140 290
Figure imgf000206_0002
Figure imgf000206_0003
Figure imgf000207_0001
Figure imgf000208_0001
375
Figure imgf000208_0002
377 378 379 380 381 382
Figure imgf000208_0003
3180 383 384 385 386 387 388
Figure imgf000209_0001
Figure imgf000209_0002
BOC
Figure imgf000210_0001
424 425 426 427
3200
Figure imgf000210_0002
432 433 434 435
Figure imgf000210_0003
436 437
3205 Table 16. Mercaptans of the type A-SH
3210
3215
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
3245
3250
Figure imgf000214_0001
93 94 95 96
3255
Figure imgf000214_0002
Figure imgf000215_0001
117 118 119 120
3265
Figure imgf000215_0002
Figure imgf000216_0001
135 136 137 138 139 140 141 142
Figure imgf000216_0002
3275
Figure imgf000216_0003
148 149 150
Figure imgf000216_0004
Figure imgf000216_0005
3285
Figure imgf000217_0001
177 178 179 180 181 182 183
Figure imgf000217_0002
196 197 198 199 200
Figure imgf000217_0003
3300
3305
Figure imgf000218_0001
Figure imgf000218_0002
3315
Figure imgf000219_0001
250 251 252 253 254
Figure imgf000219_0002
269 270 271 272 273
Figure imgf000219_0003
274 275 276 277 278
3325
Figure imgf000220_0001
279 280 281 282 283 284 285
Figure imgf000220_0002
286 287 288 289 290 291
Figure imgf000220_0003
292 293
3330 294 295 296 297
Figure imgf000220_0004
298 299 300
HS
Figure imgf000220_0005
3335
H2SH
Figure imgf000220_0006
Figure imgf000220_0007
Figure imgf000221_0001
3355
Figure imgf000222_0001
364 365 367 368
3365
Figure imgf000222_0002
H 2 SH BOC
Figure imgf000223_0001
BOC
Figure imgf000223_0002
385 386 387 388
Figure imgf000223_0003
HS. ς HS H J \ / \
Y ASH Y SH °ri "ZSH sri ZSH
BocHN BocHN^^ OH OH
393 394 395 396
CH2SH
Figure imgf000223_0004
397 398 399 400
3380
Table 17. Halides of the type A-Cl, A-Br, and A-I
Figure imgf000224_0001
3385
Figure imgf000224_0002
18 19
Figure imgf000224_0003
Figure imgf000225_0001
3395
Figure imgf000225_0002
3400
Figure imgf000225_0003
Figure imgf000225_0004
43 44 45 46
Figure imgf000225_0005
3405
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
3445
Figure imgf000229_0001
142 143 144
Figure imgf000229_0002
Figure imgf000229_0003
3455
Figure imgf000230_0001
c
Figure imgf000230_0002
169 P 170. ςγ 171 <X 172γ, 173.
Figure imgf000230_0003
Figure imgf000231_0001
Figure imgf000232_0001
385 386 387 388
Figure imgf000232_0002
393 394 395 396
Figure imgf000233_0001
397 398 399 400
3495
Table 18. Sulfonyl chlorides of the type A-SO2Cl
Figure imgf000234_0001
6
Figure imgf000234_0002
7 8 10 11
3500
Figure imgf000234_0003
13 14 15
Figure imgf000234_0004
16 17 18
Figure imgf000234_0005
3510
Figure imgf000235_0001
29 30 31 32
Figure imgf000235_0002
3515 38 39 40 41 42
Figure imgf000235_0003
48 49 50 51 52
3520
Figure imgf000235_0004
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. 3525 In Tables 2-10, the abbreviation bz=benzoyl, bn=benzyl, Ph=phenyl, BOC=t- butyloxycarbonyl and TS=p-toluenesulfonyl.
Compound 1 3-(Aminomethyl benzoylVMet-OCH3
3530 Step A
( -fChloromethvnbenzoyl>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 3535 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;
JH NMR (CDC13) d 7.82 (IH, s), 7.74 (IH, d, 7=7.7 Hz), 7.53 (IH, d, 7=7.7 Hz), 7.42
3540 (IH, t, 7=7.7 Hz), 7.06 (IH, br d, 7=7.6Hz), 4.92 (IH, ddd, 7=7.6, 7.1, 5.1 Hz), 4.59 (2H, s), 3.78 (3H, s), 2.58 (2H, t, 7=7.1 Hz) 2.26 (IH, sm), 2.15 (IH, m), 2.10 (3H, s); 13C NMR (CDCI3) 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.
3545 Step B
(3-(AzidomethyDbenzoyl -Met-OCH2 A suspension of (3-(chloromethyl)benzoyl)-Met-OCH3 (1.58 g, 5.0 mmol) and sodium azide (1.3 g, 20.0 mmol) in DMSO (40 mL) was stirred at 80°C for 7 hours. The mixture was diluted with methylene chloride (100 mL), washed with brine (70 mL x 2) and water
3550 (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; *H NMR (CDCI3) d 7.78 (2H, m), 7.49 (2H, m), 6.99 (IH, br d, 7=7.4 Hz), 4.49 (IH, ddd,
7=7.4, 7.1, 5.2 Hz), 4.42 (2H, s), 3.80 (3H,s), 2.60 (2H, t, 7=7.4 Hz), 2.29 (IH, m), 3555 2.17 (IH, m), 2.12 (3H, s); 1 C 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-(Αminomethy benzoyl)-Met-OCH3 3560 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. l NMR 3565 (CDC13) d 7.81 (IH, s), 7.68 (IH, d, 7=7.4 Hz), 7.45 (IH, d, 7=6.5 Hz), 7.36 (IH, t,
7=7.4 Hz), 4.91 (IH, ddd, 7=7.3, 7.1, 5.1 Hz), 3.90 (2H, s), 3.77 (3H, s), 3.21 (2H, br s), 2.59 (2H, t, 7=7.4 Hz), 2.20 (IH, m), 2.12 (IH, m), 2.09 (3H, s).
Compound 2 3570 f4-fAminomethvDbenzoyl)-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 3575 G-AminobenzovD-Met-OCH
The title compound was prepared according to the procedure described in J. Biol. Chem. 269 12410-12413 (1994).
Compound 4 3580 (4-Aminobenzoyl)-Met-OCH3
Step A N-BOC-4-Aminobenzoic acid 4-Aminobenzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 mL) 3585 and 0.5 M NaOH ( 145.8 mL). The solution was cooled to 0°C and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate. The ethyl acetate fractions were combined and washed with IN HCl to remove any unreacted starting material. The solution was dried 3590 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; !H NMR (CD3OD) d 1.52 (9H, s), 7.49 (2H, d, 7=8.6 Hz), 7.91 (2H, d, 7=8.6 Hz), 9.28 (IH, s); 13C NMR (CD3OD) 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: 3595 6.43, N: 5.83; HRMS Calc. for C12H15NO4, 237.0961, Found, 237.1001.
Step B fN-BOC-4-Aminobenzovn-Met-OCH3
Into a dried, nitrogen filled flask was placed N-BOC-4-aminobenzoic acid (8.77 g, 36.97 3600 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 3605 water. The methylene chloride was dried over MgSO 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; Η NMR (CDC13) d 1.53 (9H, s), 2.06-2.18 (4H, m),
2.23-2.33 (IH, m), 2.59 (2H, t, 7=7.6 Hz), 3.80 (3H, s), 4.92 (IH, m), 7.45 (2H, d, 7=8.7 Hz), 7.77 (2H, d, 7=8.7 Hz); 13C NMR (CDC13) d 15.59, 28.34, 30.15, 31.64,
3610 52.10, 52.73, 81.20, 117.73, 127.8, 128.33, 141.88, 152.33, 166.50, 172.75;
Anal. Calc. for C18H26N2O5S, C: 56.53, H: 6.85, N: 7.29; Found, C: 56.47, H: 6.86, N:
7.29; m/z (El) 382 (M).
Step C 3615 (4-AminobenzoylVMet-OCH3 hydrochloride
N-BOC-4-aminobenzoyl-Met-OCH3 (3.53 g, 9.59 mmol) was placed into methylene chloride (30-35 mL) and to it was added 3M HCl/EtO2 (38.4 mL). After standing, a white precipitate formed. After two hours the solution was decanted and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether 3620 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; lH NMR (CDC13) d 2.10 (3H, s), 2.12-2.29 (IH, m), 2.52-
2.71 (IH, m), 2.59 (2H, t, 7=7.6 Hz), 3.75 (3H, s), 4.79 (IH, m), 7.02 (2H, d, 7=8.6 3625 Hz), 7.55 (2H, d, 7=8.6 Hz); 13C NMR (CDC13) 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 C13H18N2O3S, 282.1038, Found 282.1009.
Compound 5 3630 (4-Amino-3-methylbenzoylVMet-OCH3 Step A N-BOC-4-Amino-3-methylbenzoic acid
4-Amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same 3635 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; IH NMR (CD3OD) d 1.51 (9h, s), 2.27 (3H, s), 7.66 (IH, d, 7=8.1 Hz), 7.79-7.82 (2H, m), 8.32 (IH, s);
13C NMR (CD3OD) d 17.98, 28.62, 81.47, 123.12, 127.05, 129.14, 130.65, 132.99, 3640 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 (El) 251; HRMS Calc. for C13H17NO4, 251.1158;
Found, 251.1153.
Step B 3645 fN-BOC-4-Amino-3-methylbenzoylVMet-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- 3650 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; lH NMR (CDC13) d 1.54 (9H, s), 2.06-2.18 (4H, m), 2.23-2.34 (4H, m), 2.59 (2H, t, 7=6.8 Hz), 3.80 (3H, s), 4.92 (IH, m), 6.45 (IH, s), 6.88 (IH, d, 7=7.5 Hz), 7.63 (IH, d, 7=8.6 Hz), 7.66 (IH, s), 8.05 (IH, d, 7=8.6 Hz); 13C NMR (CDC13) d 15.47, 17.61, 28.22, 30.03,
3655 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-methylbenzoyl)-Met-OCH3 hydrochloride 3660 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/Et2θ (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; lU NMR (CD3OD) d 2.04 (3H, s), 2.11-2.25 (IH, m), 2.47 (3H, s), 2.52-2.68 (3H, m), 3.74 (3H,
3665 s), 4.75-4.80 (IH, m), 7.48 (IH, d, 7=8.2 Hz), 7.81 (2H, d, 7=8.2 Hz), 7.87 (IH, s); 13C NMR (CD3OD) 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 C14H21N2O3S, C: 50.52, H: 6.36, N: 8.42; Found C: 50.71, H: 6.40, N: 8.34.
3670 Compound 6
(4-Amino-3-methoxybenzoyl)-Met-OCH3
Step A N-BOC-4-Amino-3-methoxybenzoic acid 3675 4-Amino-3-methoxybenzoic acid (1 g, 5.98 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting solid was recrystallized from ethyl acetate and hexanes to provide the desired product (1.5 g) as tan crystals: m.p. 176-178°C; iH NMR (CD3OD) d 1.52 (9H, s), 3.92
(3H, s), 7.56 (IH, s), 7.62 (IH, d, 7=8.4Hz), 7.96 (IH, s), 8.03 (IH, d, 7=8.4 Hz); 13C 3680 NMR (CD3OD) 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 C13H17NO5, 267.1107; Found, 267.1103.
Step B (N-BOC-4-Amino-3-methoxybenzoylVMet-OCH3
3685 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; lK NMR (CDC13) d 1.53 (9H, s), 2.09-2.18 (4H, m),
3690 2.23-2.35 (IH, m), 2.60 (2H, t, 7=6.9 Hz), 3.80 (3H, s), 3.93 (3H, s), 4.92 (IH, br s), 6.93 (IH, d, 7=7.6 Hz), 7.25(1H, m), 7.31 (IH, d, 7= 10.2 Hz), 7.44 (IH, s), 8.15 (IH, d, 7=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, 1 19.31, 131.52, 147.23, 152.31, 166.57, 172.58; m/z (FAB) 413 (M + 1). 3695
Step C (4- Amino-3 -methoxybenzoy IV Met-OCH3 hydrochloride 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
3700 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; *H NMR (CD3OD) d 2.08
(3H, s), 2.21 (2H, m), 2.61 (2H, m), 3.74 (3H, s), 4.02 (3H, s), 4.79 (IH, m), 7.50 (IH, d, 7=8.2 Hz), 7.57 (IH, d, 7=4.1 Hz), 7.67 (IH, s); 13C NMR (CD3OD) 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, 3705 168.79, 173.81.
Compound 7 (A- Amino- 1 -naρhthovD-Met-OCH3
3710 Step A
4-Amino-l-naphthoic acid 4-Amino-l-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
3715 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; ]H NMR (CD3OD) d 6.69 (IH, d,
3720 7=8.2 Hz), 7.38-7.43 (IH, m), 7.48-7.54 (IH, m), 8.03 (IH, d, 7=8.5 Hz), 8.13 (IH, d, 7=8.2 Hz), 9.09 (IH, d, 7=8.5 Hz); 13C NMR (CD3OD) d 107.39, 114.61, 122.99, 123.92, 125.21, 127.40, 128.48, 135.04, 151.35, 171.44; HRMS Calc. for CπH7NO2, 187.0633; Found, 187.0642.
3725 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
3730 give 0.76 g of the desired product as a reddish pink solid: m.p. 194-195°C; lU NMR
(CD3OD) d 1.56 (9H, s), 7.53-7.62 (2H, m), 7.79 (IH, d, 7=8.1 Hz), 8.12 (IH, d, 7=8.0 Hz), 8.22 (IH, d, 7=8.18 Hz), 9.02 (IH, d, 7=8.9 Hz); 13C NMR (CD3OD) 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 3735 C: 66.49, H: 6.08, N: 4.79; m/z (El), 289; HRMS Calc. for C16H17NO4, 287.1158; Found, 287.1151.
Step C (N-B OC-4- Amino- 1 -naphthoyl VMet-OCH3 3740 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 3745 pale pink crystals: m.p. 131-132°C; Η NMR (CDC13) d 1.57 (9H, s), 2.11-2.21 (4H, m), 2.29-2.41 (IH, m), 2.65 (2H, t, 7=7.1 Hz), 3.83 (3H, s), 4.99-5.06 (IH, m), 6.68 (IH, d, 7=8.0 Hz), 7.02 (IH, s), 7.56-7.59 (2H, m) 7.69 (IH, d, 7=7.9 Hz), 7.87-7.90 (IH, m), 8.02 (IH, d, 7=7.9 Hz), 8.44-8.48 (IH, m); 13C NMR (CDC13) 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, 3750 127.18, 131.02, 135.65, 152.93, 169.04, 172.40; HRMS Calc. for C22H28N2O5S,
432.1719; Found, 432.1702; m/z (FAB) 433 (M+l).
Step D (4- Amino- 1 -naphthoyl)-Met-OCH3 hydrochloride 3755 (N-BOC-4-Amino-l-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; lU NMR (CD3OD) d 2.08-2.16 (4H, m), 2.20-2.30 (IH, m) 2.57-2.75 (2H, m) 3.82 (3H, s), 4.87-
4.91 (IH, m), 7.59 (IH, d, 7=7.5 Hz), 7.67 (IH, d, 7=7.5 Hz) 7.71-7.80 (2H, m), 8.03 (IH, dd, 7=7.1, 2.0 Hz), 8.35 (IH, dd, 7=6.8, 1.8 Hz); 13C NMR (CD3OD) d 15.23,
3760 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+l).
Compound 8 ("4-Amino-2-phenylbenzoyl)-Met-OCH3
3765
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 3770 Pd(Ph3P)4 (0.58 g, 5%). The mixture was heated at 100°C overnight. The solution was poured onto IN HCl and extracted with Et^O. 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; lU NMR (CDC13) d 2.36 (3H, s), 7.29-7.40 (2H, m), 7.41-7.49 (5H, m), 8.07-8.10 (2H, m); 13C NMR (CDC13) 3775 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 C13HπNO2, C: 73.26, H: 5.20, N: 6.57; Found, C: 73.10, H: 5.12, N: 6.50; m/z (El) 213; HRMS Calc. for C13HnNO2, 213.0790; Found, 213.0793.
3780 Step B
4-Nitro-2-phenylbenzoic 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 3785 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, ]H NMR (CD3OD) d 7.38-7.48 (5H, m), 7.96 (IH, d, 7=8.5 Hz), 8.21 (IH, d, 7=2.3 Hz), 8.28 (IH, dd, 7=8.48, 2.37 Hz); 13C NMR (CD3OD) d 122.95, 126.09, 129.27, 129.42, 3790 129.49, 131.56, 139.26, 140.42, 144.41, 150.17, 170.52; m/z (El) 243 (M).
Step C f4-Nitro-2-phenylbenzoyl -Met-OCH3
4-Nitro-2-phenylbenzoic acid (0.3 g, 1.23 mmol), methionine methyl ester hydrochloride 3795 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. 98-10PC; *H NMR (CDC13) d 1.62-1.73 (IH, m), 1.79-1.88 (IH, m),
3800 1.91 (3H, s), 1.99 (2H, t, 7=7.2 Hz), 3.59 (3H, s), 4.53 (IH, m), 6.45 (IH, d, 7=7.8
Hz), 7.33-7.40 (5H, m), 7.67 (IH, d, 7=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+l).
3805 Step D
(4-Amino-2-phenylbenzoyl)-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, 3810 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 Na2SO4. The solvent was removed in vacuo to the desired product (0.24 g) as a yellow solid: 'H NMR (CDC13) d 1.58-1.70 (IH, m), 1.80-1.92 (IH, m), 1.98 (3H, s), 2.06 (2H, t, 7=7.7 Hz), 3.62 (3H, s), 4.00 (2H, br s), 4.56-4.63 (IH, m), 5.84 (IH, d, 3815 7=7.7 Hz), 6.50 (IH, s), 6.61 (IH, d, 7=8.4 Hz) 7.29-7.42 (5H, m), 7.58 (IH, d, 7=8.3 Hz); * C NMR (CDC13) 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 3820 (4-Amino-2-f2-thienyl')benzoyD-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 3825 (4- Amino-2-( 1 -naphthv benzovD-Met-OCH-,
The title compound can be prepared according to the method used to prepare Compound 8, only substituting 1-naphthylboronic acid for phenylboronic acid.
Compound 11 3830 4-Amino-3'-methylbiphenyl
The title compound was prepared by Suzuki coupling of l-bromo-4-nitrobenzene and 1- bromo-3-methylbenzene.
Compound 12 3835 4-Amino-4'-biphenyl carboxylic acid
Step A 4-Nitro-4'-methylbiphenyl The title compound was prepared by Suzuki coupling of l-bromo-4-nitrobenzene and 1- 3840 bromo-4-methylbenzene.
Step B 4-Nitro-4'-biphenyl carboxylic acid The title compound was prepared by KMnO4 oxidation of 4-nitro-4'-methylbiphenyl.
3845
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. 3850
Compound 13 4-Amino-3'-biphenyl carboxylic acid
Step A 3855 4-Nitro-3 '-methylbiphenyl
The title compound was prepared by Suzuki coupling of l-bromo-4-nitrobenzene and 1- bromo-3-methylbenzene.
Step B 3860 4-Nitro-3'-biphenyl carboxylic acid
The title compound was prepared by KMnO4 oxidation of 4-nitro-3'-methylbiphenyl.
Step C 4-Amino-3'-biphenyl carboxylic acid 3865 The title compound can be prepared by palladium catalyzed hydrogenation of 4-nitro-3'- biphenyl carboxylic acid.
Compound 14 4-Amino-2-methoxy-3'-biphenyl carboxylic acid
3870
Step A 2-Methoxy-4-nitro-3'-methylbiphenyl The title compound was prepared by reaction of l-bromo-2-methoxy-4-nitrobenzene with 3- methylphenylboronic acid in the presence of palladium acetate.
3875
Step B 2-Methoxy-4-nitro-3'-biphenylcarboxylic acid The title compound was prepared by KMnO oxidation of 2-methoxy-4-nitro-3'- methylbiphenyl.
3880
Step C 4-Amino-2-methoxy-3'-biphenyl carboxylic acid The title compound can be prepared by palladium catalyzed hydrogenation of 2-methoxy-4- nitro-3'-biphenyl carboxylic acid. 3885
Compound 15 4-Amino-2-isopropyloxy-3'-biphenyl carboxylic acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.
3890
Compound 16 4- Amino-2-phenyl- 3 '-bipheny lcarboxy lie acid The title compound can be prepared by methods analogous to those used to prepare Compound 14.
3895
Compound 17 (4-Amino-2-f3.5-dimethylphenyl benzoyl)-Met-OCH3
Step A 3900 2-Bromo-4-nitrobenzoic acid
2-Bromo-4-nitrotoluene (5.0 g, 23.14 mmol) was dissolved in pyridine (23 mL) and water (46 mL). The heterogeneous mixture was heated to 60°C and KMnO4 (18.29 g, 115.7 mmol) was added carefully. The mixture was then heated under reflux overnight. The reaction mixture was filtered and washed with boiling water. The solution was then made 3905 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 Na-,SO4 and the solvent was removed in vacuo to provide the desired product (3.72 g): m.p. 158-160°C; Η NMR (CD3OD) d 3910 7.81 (IH, d, 7=8.5 Hz), 8.08 (IH, d, 7=8.5 Hz), 8.30 (IH, s); 13C NMR (CD3OD) 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
3915 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
3920 mixture was heated at reflux for 1-2 hours until most of the magnesium had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to an nitrogen filled flask containing triisopropyl borate (24.9 mL) at -70°C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. 3925 The solution was extracted with Et^O and the Et^O 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; iH NMR (CDC13) d 2.44 (6H, s), 7.23 (IH, s), 7.84 (2H, s); 13C NMR (CD3OD) d 21.36, 133.28, 134.39, 137.48.
3930 Step C
4-Nitro-2-(3.5-dimethylphenyl 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%).
3935 The mixture was heated at 100°C overnight. The solution was poured onto IN HCl and extracted with Et^. 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): *H NMR (CDC13) d 2.36 (6H, s), 6.99 (2H, s), 7.07 (IH, s), 8.03 (IH, d, 7=9.0 Hz), 8.23-8.25 (2H, m); 13C NMR (CDC13) d
3940 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 f4-Nitro-2- .5-dimethylphenyl benzoyl)-Met-OCH3
3945 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 3950 was obtained (0.13 g): m.p. 122-124°C; *H NMR (CDC13) d 1.2-1.84 (IH, m), 1.85-
1.97 (IH, m), 2.01 (3H, s), 2.05 (3H, t, 7=7.7Hz), 2.38 (6H, s), 3.70 (3H, s), 4.67-4.74 (IH, m), 6.03 (IH, d, 7=7.9 Hz), 7.05 (2H, s), 7.09 (IH, s), 7.84-7.87 (IH, m), 7.84- 7.87 (IH, 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, 3955 148.41, 167.14, 171.53.
Step E (4-Amino-2-f3.5-dimethylphenvDbenzoylVMet-OCH3 (4-Nitro-2-(3,5-dimethylphenyl)benzoyl)-Met-OCH3 (0.11 g, 0.26 mmol) was dissolved in 3960 ethyl acetate (3.0 mL). To this mixture was added SnCl2 2H2O (0.3 g, 1.30 mmol) and the reacton was heated under nitrogen at reflux for 6 hours. The mixture was worked up as described above for (4-amino-2-phenylbenzoyl)-Met-OCH3 to give the desired product (0.15 g): IH NMR (CDC13) d 1.60-1.70 (IH, m), 1.80-1.90 (IH, m), 1.99 (3H, s), 2.05 (2H, t, 7=7.6 Hz), 2.33 (6H, s), 3.64 (3H, s), 3.93 (2H, br s), 4.61-4.64 (IH, m), 5.82 3965 (IH, d, 7=7.7 Hz), 6.49 (IH, d, 7=2.3 Hz) 6.62 (IH, dd, 7=8.4, 2.4 Hz), 6.98 (2H, s), 7.00 (IH, s), 7.65 (IH, d, 7=8.3 Hz); 13C NMR (CDC13) 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.
3970 Preparation 1
Anilines of the formula B-NH? The anilines from Table 1, entries 10-126 (B-NH2) are prepared using the procedures for Compounds 1-18 with the exception that methionine methyl ester is replaced by methioninesulfone methyl ester, (S-Me)cysteine methyl ester, serine methyl ester, (O-
3975 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.
Figure imgf000248_0001
Preparation 2
4-Bromo-2-phenylbenzoyl methionine methyl ester
Preparation 2A 3985 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 3990 purified by chromatography on silica gel. Preparation 2B 4-Bromo-2-phenylbenzoic acid To a solution of the resultant compound from Preparation 2A (1.0 equivalent) in a 3: 1 3995 mixture of tetrahydrofuran (THF) and water is added an excess (1.5 equivalents) of Li OH. 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.
4000 Preparation 2C
4-Bromo-2-phenylbenzoyl methionine methyl ester To a solution of the resultant compound from Preparation 2B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and l-(3-
4005 dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
4010 Preparation 2D
4-Bromo-2-phenylbenzoyl 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
4015 analysis, the mixture is extracted into ethyl acetate which is dried and evaporated. The title arylbromide is purified by chromatography on silica gel.
Preparation 3 Arylbromides of the formula B-Br 4020 The anilines from Table 1 (B-NH2) are reacted according to the procedures of Preparation 2 to provide the arylbromides listed in Table 2.
Figure imgf000250_0001
4025 Example 1
4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl amino-2-phenylbenzoyl methionine
Example 1A Methyl 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-phenylbenzoate 4030 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 (5)- 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 4035 IN HCl and brine, evaporated, and purified by chromatography on silica gel.
Example IB 4-((,S)-2-Pyrrolidone-5-aminomethylcarbonyDamino-2-phenylbenzoic acid To a solution of the resultant compound from Example 1 A (1.0 equivalent) in a 3: 1 mixture 4040 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.
4045 Example 1C
4-((S -2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-phenylbenzoyl methionine methyl ester To a solution of the resultant compound from Example IB (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5
4050 equivalents) followed by methionine methyl ester (1.0 equivalent) and l-(3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
4055 Example ID 4-f("S)-2-Pyπolidone-5-aminomethylcarbonyl)amino-2-phenylbenzoyl methionine methyl ester, alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in 4060 methylene chloride is added a solution of phosgene in toluene (1.0 equivalent) and triethylamine (2.0 equivalents). The intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) and triethylamine (1.0 equivalent). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with IN HCl and brine, evaporated, and purified by chromatography on silica gel. 4065
Example IE 4- rS)-2-Pyrrolidone-5-aminomethylcarbonyl)amino-2-phenylbenzoyl 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 4070 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.
Figure imgf000251_0001
Example 2 4-((S -2-Pyrrolidone-5-aminomethylthiocarbonyl)amino-2-phenylbenzoyl 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).
4080
Figure imgf000251_0002
Example 3 4-f(S)-2-Pyrrolidone-5-aminomethylsulfιnyl)amino-2-phenylbenzoyl methionine
4085
Example 3 A 4-frS -2-Pyrrolidone-5-aminomethylsulfinyl)amino-2-phenylbenzoyl methionine methyl ester To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester ( 1.0 equivalent) in 4090 methylene chloride is added thionyl chloride (1.0 equivalent) and triethylamine (2.0 equivalents). After the amine has fully reacted, (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is added. When the reaction is judged complete by TLC analysis, the product is isolated as described in Example 1A and purified by chromatography on silica gel.
4095 Example 3B
4-(("S)-2-Pyrrolidone-5-aminomethylsulfιnyl)amino-2-phenylbenzoyl methionine To a solution of the resultant compound from Example 3 A 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
4100 pH = 3 and extracted into ethyl acetate which is dried and evaporated prior to purification by chromatography on silica gel.
Figure imgf000252_0001
4105 Example 4
4-(('S )-2-Pyrrolidone-5-aminomethylsulfonyl')amino-2-phenylbenzoyl methionine
Example 4A 4-((SV2-Pyrrolidone-5-aminomethylsulfonyl)amino-2-phenylbenzoyl methionine methyl 4110 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 4115 isolated as described in Example 1 A and purified by chromatography on silica gel. Example 4B 4-((S)-2-Pyrrolidone-5-aminomethylsulfonyl)amino-2-phenylbenzoyl methionine methyl ester, alternate procedure 4120 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)- 4125 5-aminomethyl-2-pyrrolidone (1.0 equivalent). When the reaction is judged complete by TLC analysis, the product is isolated as described in Example 1A and purified by chromatography on silica gel.
Example 4C 4130 4-((S -2-Pyrrolidone-5-aminomethylsulfonyl)amino-2-phenylbenzoyl methionine methyl ester The resultant compound from Example 4A is hydrolyzed according to the procedure of Example IB to give the title product.
4135
Figure imgf000253_0001
Example 5 4-((S')-2-Pyrrolidone-5-methylaminosulfonyl)-2-phenylbenzoyl methionine
4140 Example 5A
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
4145 (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 4150 4-((S)-2-Pyrrolidone-5-aminomethvDsulfonylV2-phenylbenzoic acid methyl ester
To a solution of the resultant compound from Example 5A (1.0 equivalent) in methylene chloride is added (S)-5-aminomethyl-2-pyrrolidone ( 1.0 equivalent) and triethylamine ( 1.0 equivalent). When the reaction is judged complete by TLC analysis, the solvent is evaporated and the residue is purified by chromatography on silica gel.
4155
Example 5C 4-(('S)-2-Pyrrolidone-5-aminomethyl)sulfonyl)-2-phenylbenzoic acid The resultant compound from Example 5B is hydrolyzed according to the procedure of Example IB to give the title product.
4160
Example 5D 4-(('S)-2-Pyrrolidone-5-aminomethyl')sulfonyπ-2-phenylbenzoyl methionine methyl ester To a solution of the resultant compound from Example 5C (1.0 equivalent) in (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by methionine 4165 methyl ester (1.0 equivalent) and l-(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 IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product. 4170
Example 5E 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl')amino-2-phenylbenzoyl methionine methyl ester, alternate preparation To a solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in 4175 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 5B to give the title 4180 compound.
Example 5F 4-((S -2-Pyrrolidone-5-aminomethylcarbonyl')amino-2-phenylbenzoyl methionine To a solution of the resultant compound from Example 5D ( 1.0 equivalent) in a 3: 1 mixture 4185 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.
4190
Figure imgf000255_0001
Example 6 4-(2-pyridyloxy>2-phenylbenzoylmethionine
4195 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
4200 extracted into ethyl acetate which is dried and evaporated. The title ester is purified by chromatography on silica gel.
Example 6B 4-(2-Pyridyloxy')-2-phenylbenzoic acid methyl ester 4205 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.
4210 Example 6C
4-(2-PyridyloxyV2-phenylbenzoic 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
4215 which is dried and evaporated. Chromatography on silica gel provides the title product.
Example 6D 4-(2-PyridyloxyV2-phenylbenzoylmethionine ethyl ester The resultant product from Example 6C is coupled to methionine methyl ester according to 4220 the procedure of Example 1C to give the title compound.
Example 6E 4-(2-PyridyloxyV2-phenylhenzoylmethionine methyl ester, alternate procedure A solution of 4-amino-2-phenylbenzoyl methionine methyl ester ( 1.0 equivalent) in dilute
4225 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
4230 pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.
Example 6F 4-(2-pyridyloxy)-2-phenylbenzoylmethionine 4235 The resultant compound from Example 6E is hydrolyzed according to the procedure of Example IB to give the title compound.
Figure imgf000256_0001
4240
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.
4245
Figure imgf000256_0002
Example 8 4250 4-((S)-2-Pyrrolidone-5-aminomethyl)carbonyloxy-2-phenylbenzoyl methionine
Example 8A 4-((S -2-Pyrrolidone-5-aminomethyl carbonyloxy-2-phenylbenzoyl methionine methyl ester To a solution of 4-hydroxy-2-phenylbenzoyl methionine methyl ester ( 1.0 equivalent) from
4255 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
4260 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-Pyrrolidone-5-arhinomethyl')carbonyloxy-2-phenylbenzoyl methionine 4265 The resultant compound from Example 8A is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000257_0001
4270
Example 9 4-((S)-2-Pyrrolidone-5-aminomethyl')thiocarbonyloxy-2-phenylbenzoyl methionine methyl ester The title compound is prepared as described in Example 8 with the exception that phosgene 4275 in toluene is replaced by thiophosgene.
Figure imgf000258_0001
4280 Example 10
4-ffS -2-Pyrrolidone-5-aminomethyl)sulfιnyloxyV2-phenylbenzoyl methionine The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by thionyl chloride.
4285
Figure imgf000258_0002
Example 11 4ASV2-Pyrrolidone-5-aminomethyl)sulfonyloxyV2-phenylbenzoyl methionine 4290 The title compound is prepared as described in Example 8 with the exception that phosgene in toluene is replaced by sulfuryl chloride.
Figure imgf000258_0003
4295
Example 12 4-(3-Pyridylmethylenthio)-2-phenylbenzoylmethionine
Example 12A 4300 4-Mercapto-2-phenylbenzoic 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 4305 gel.
Example 12B 4-(2-PyridylmethylenthioV2-phenylbenzoic acid methyl ester 4310 A solution of the resultant thiophenol (1.0 equivalent) from Example 12A is treated with 2- chloromethylpyridine hydrochloride (1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2CO3 (3.0 equivalents in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel.
4315
Example 12C 4-(2-Pyridylthiomethylen')-2-phenylbenzoic acid The resultant compound from Example 12B is hydrolyzed according to the procedure of Example 6C to give the title acid.
4320
Example 12D 4-(2-Pyridylthiomethylen)-2-phenylbenzoylmethionine methyl ester The resultant product from Example 12C is coupled to methionine methyl ester according to 4325 the procedure of Example 1C to give the title compound.
Example 12E 4-(2-PyridylthiomethylenV2-phenylbenzoylmethionine methyl ester, alternate procedure 1
4330 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 Sβ (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
4335 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. 4340
Example 12F
4-(2-PyridylthiomethylenV2-phenylbenzoylmethionine 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
4345 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
4350 aqueous solution). After completion of the addition, the reaction mixture is refluxed until judged complete by TLC analysis. The reaction mixture is then extracted with ether, and the organic extracts are washed sequentially with aqueous sodium carbonate solution, water and brine, dried with anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel. The product thus obtained
4355 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,
4360 followed by addition of 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.1 equivalent) and 1-hydroxybenzotriazol (1.2 equivalent). The reaction is stirred until it is judged complete by TLC analysis, and then is diluted with ether. The mixture is washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel. The resulting product
4365 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
4370 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.
4375 Example 12G
4-(3-Pyridylthiomethylen)-2-phenylbenzoylrnethionine The resultant compound from Example 12D is hydrolyzed according to the procedure of Example IB to give the title product.
4380
Figure imgf000262_0001
Example 13 4-(2-Pyridylthio)-2-phenylbenzoylmethionine
4385
Example 13A 4-Fluoro-2-phenyl benzoic acid methyl ester A solution of methyl 4-amino-2-phenylbenzoate (1.0 equivalent) in dilute aqueous HBF4 is treated with NaNO2 (1.1 equivalents) until an excess of nitrous acid persists. The mixture 4390 is extracted into ethyl acetate which is dried and evaporated. The title ester is purified by chromatography on silica gel.
Example 13B 4rFluoro-2-phenyl benzoic acid 4395 The resultant compound from Example 13A is hydrolyzed according to the procedure of Example 6C to give the title acid.
Example 13C 4-Fluoro-2-phenyl benzoyl methionine methyl ester 4400 The resultant product from Example 13B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Example 13D 4-(2-PyridylthioV2-phenyl benzoyl methionine methyl ester 4405 A mixture of the resultant fluorobenzoate from Example 13C ( 1.0 equivalent) and 2- mercaptopyridine (1.0 equivalent) is treated with K2CO3 (2.0 equivalents) or NaH (1.0 equivalent) in DMF or DMSO and is stirred until the reaction is judged complete by TLC analysis. The mixture is diluted with water and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
4410
Example 13E 4-(2-Pyridylthio)-2-phenyl benzoyl methionine methyl ester, alternate procedure 1 A solution of 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) in dilute aqueous H2SO4 is treated with NaNO2 (1.1 equivalents) to form the diazonium salt. The 4415 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. A solution of this thiophenol ( 1.0 equivalent) is treated with 2-bromopyridine hydrobromide ( 1.0 equivalent) in the presence of a NaH (2.0 equivalent), or K2CO3 (3.0 equivalents in DMF or pyridine. The product is isolated by removal of the solvent and
4420 chromatography on silica gel.
Example 13F 4-(2-Pyridylthio)-2-phenyl benzoyl methionine methyl ester, alternate procedure 2 A solution of the resultant thiophenol from Example 12A (1.0 equivalent) is treated with 2- 4425 bromopyridine hydrobromide ( 1.0 equivalent) in the presence of a NaH (2.0 equivalents), or K2CO3 (3.0 equivalents) in DMF or pyridine. The product is isolated by removal of the solvent and chromatography on silica gel. The resultant ester is hydrolyzed according to the procedure of Example 6C and then is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
4430
Example 13G 4-(2-Pyridylthio -2-phenylbenzoylmethionine The resultant compound from Example 13D is hydrolyzed according to the procedure of Example IB to give the title product.
4435
Figure imgf000263_0001
Example 14 4440 4-(2-Pyridylsulfonyl -2-phenylbenzoylmethionine
Example 14A 4-('2-Pyridylsulfonyl -2-phenylbenzoic acid methyl ester A solution of 4-(2-pyridylthio)-2-phenylbenzoic acid methyl ester (Example 13F) is 4445 carefully treated with two equivalents of metα-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 NaHCO to remove the m-chlorobenzoic acid. The product is isolated by removal of the solvent and is purified by chromatography on silica gel.
4450
Example 14B 4-(2-Pyridylsulfonyl -2-phenylbenzoic acid The resultant compound from Example 14A is hydrolyzed according to the procedure of Example 6C to give the title acid.
4455
Example 14C 4-(2-pyridylsulfonyl')-2-phenylbenzoylmethionine methyl ester The resultant product from Example 14B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
4460
Example 14D 4-(2-Pyridylsulfonyl -2-phenylbenzoylmethionine The resultant compound from Example 14C is hydrolyzed according to the procedure of Example IB to give the title product.
4465
Figure imgf000264_0001
Example 15 4470 4-(3-PyridylthiomethylenV2-phenylbenzoylmethionine
The title compound is prepared from the resultant product of Example 12B using the procedures from Example 14.
Figure imgf000264_0002
Example 16 4- \(2- Aminopyridy Dmethylenel -2-phenylbenzoylmethionine 4480 Example 16A
2-Phenylterephthalic acid mono methyl ester A solution of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), Pd(OAc)2 (0.05 equivalent) and DPPE ( 1.0 equivalent) is heated in DMF to 65° C under 4 atm. of carbon monoxide until TLC analysis indicates that the reaction is complete. The reaction mixture is
4485 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-(Ηydroxymethyl)-2-phenylbenzoic acid methyl ester 4490 The resultant acid from Example 16A ( 1.0 equivalent) is treated with a slight excess of N- methylmorpholine ( 1.1 equivalent) and isobutylchloroformate (1.0 equivalent) in THF at 0° C. The mixture is then treated with NaBH4 (1.0 equivalent) and aqueous NaHCθ3 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 4495 product is purified by chromatography on silica gel.
Example 16C 4-(Hydroxymethyl -2-phenylbenzoic acid The resultant compound from Example 16B is hydrolyzed according to the procedure of 4500 Example 6C to give the title acid.
Example 16D 4-(HydroxymethylV2-phenylbenzoyl methionine methyl ester The resultant product from Example 16C is coupled to methionine methyl ester according to 4505 the procedure of Example 1C to give the title compound.
Example 16E 4-formyl-2-phenylbenzoyl methionine methyl ester 4510 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 CH2θ2/acetonitrile mixture until the reaction is judged complete by TLC analysis. The mixture is diluted with ethyl ether and filtered through Siθ2- The product is purified by chromatography on silica gel. 4515 Example 16F 4-(formyl)-2-phenylbenzoyl methionine methyl ester, alternate procedure A mixture of (2-phenyl-4-bromobenzoyl) methionine methyl ester (100 mmol), 4,4,6-
4520 trimethyl-2-vinyl-l,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
4525 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
4530 column chromatography on silica gel to afford the title product.
Example 16G 4-(Hydroxymethyl -2-phenylbenzoyl methionine methyl ester, alternate procedure 4535 To a solution of the resultant compound from Example 16E in ethanol at 0 °C is added sodium borohydride (0.5 equivalent), and the reaction is stirred at 0 °C until TLC analysis shows the reaction to be complete. The reaction mixture is extracted with ether, which is washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel 4540 to afford the title product.
Example 16H 4- r(2-Aminopyridyl methylenel-2-phenylbenzoylmethionine methyl ester 4545 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.
4550
Example 161 4-r(2-Aminopyridyl methylenel-2-phenylbenzoylmethionine The resultant compound from Example 16H is hydrolyzed according to the procedure of 4555 Example IB to give the title product.
Figure imgf000267_0001
4560 Example 17
4-[(3-aminomethylpyridyl methylenel-2-phenylbenzoylmethionine Using the procedures of Examples 16F-G and replacing 2-aminopyridine with 3- aminomethylpyridine affords the title product.
4565
Figure imgf000267_0002
Example 18 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl aminomethyl-2-phenylbenzoyl methionine
4570
Example 18A 4-(Azidomethyl -2-phenylbenzoyl methionine methyl ester To triphenylphosphine (1.0 equivalent) in tetrahydrofuran (THF) at -78° C is added diethyl azodicarboxylate (1.0 equivalent) in THF. To this mixture is added a solution of hydrazoic 4575 acid in benzene (2.0 equivalents) and then the resultant compound from Example 16D (1.0 equivalent). After one hour the mixture was warmed to room temperature, stirred until the reaction is judged complete by TLC analysis, evaporated and chromatographed on silica gel to afford the title product.
4580 Example 18B
4-(Aminomethyl)-2-phenylbenzoyl methionine methyl ester To the resultant compound from Example 18A in methanol is added triethylamine (3.0 equivalent) and propane 1,3-dithiol (3.0 equivalents). After the reaction is judged complete by TLC analysis, the mixture is filtered and evaporated. Chromatography of the residue on 4585 silica gel provides the title product.
Example 18C 4-((S)-2-Pyrrolidone-5-aminomethylcarbonyl)aminomethyl-2-phenylbenzoyl methionine methyl ester 4590 To a solution of the resultant compound from Example 18B ( 1.0 equivalent) in methylene chloride is added triphosgene (0.33 equivalent) and triethyl amine (2.0 equivalents). This intermediate is reacted without further purification with (S)-5-aminomethyl-2-pyrrolidone ( 1.0 equivalent) and triethylamine (1.0 equivalent). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate and washed with IN HCl and brine, 4595 evaporated, and purified by chromatography on silica gel.
Example 18D 4-((_S -2-Pyrrolidone-5-aminomethylcarbonyl)aminomethyl-2-phenylbenzoyl methionine The resultant compound from Example 18C is hydrolyzed according to the procedure of 4600 Example IB to give the title product.
Figure imgf000268_0001
4605 Example 19
4-((5^-2-Pyπolidone-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).
4610
Figure imgf000268_0002
Example 20 4-((S)-2-Pyrrolidone-5-aminomethylsulfinyl)aminomethyl-2-phenylbenzoyl methionine
4615 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).
Figure imgf000269_0001
4620
Example 21 4-((_S1-2-Pyrrolidone-5-aminomethylsulfonyl')aminomethyl-2-phenylbenzoyl methionine Using the Procedure of Example 4 with the resultant compound from Example 18B affords the title product.
4625
Figure imgf000269_0002
Example 22 4630 4-((S)-2-Pyrrolidone-5-aminomethyl)carbonyloxymethylene)-2-phenylbenzoyl methionine Using the procedure of Example 8 with the resultant compound from Example 16D provides the title product.
Figure imgf000269_0003
4635 Example 23 4-((S)-2-Pyrrolιdone-5-amιnomethyl)thιocarbonyloxymethylene)-2-phenylbenzoyl methionme Using the procedure of Example 8 with the resultant compound from Example 16D and replacing triphosgene (0 33 equivalent) with thiophosgene (1 0 equivalent) provides the title 4640 product
Figure imgf000270_0001
Example 24 4645 4-(2-Amιnopyπdyl -2-phenylbenzoylmethιonιne
Example 24A 4-(2-Amιnopyπdyl)-2-phenylbenzoylmethιonιne methyl ester 4-Amιno-2-phenylbenzoyl methionine (1 0 equivalent) methyl ester and 2-bromopyπdιne 4650 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
4655 Example 24B
4-(2-Amιnopyπdyl)-2-phenylbenzoylmethιonιne The resultant compound from Example 24A is hydrolyzed according to the procedure of Example IB to give the title product
4660
Figure imgf000270_0002
Example 25 4-(3-AmιnomethylpyπdylV2-phenylbenzoylmethιonιne
4665 Example 25 A
4-(3-AmιnomethylpyπdylV2-phenylbenzoylmethιonιne methyl ester A mixture of 3-pyridinecarboxaldehyde (1.0 equivalent), 4-amino-2-phenylbenzoyl methionine methyl ester ( 1.0 equivalent) and NaCNBH3 ( 1.0 equivalent) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured 4670 into aqueous NaHCθ3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Example 25B 4-(3-Aminomethylpyridyl)-2-phenylbenzoylmethionine 4675 The resultant compound from Example 25A is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000271_0001
4680
Example 26 4-r(4-aminomethylpyridyl methylene1-2-phenylbenzoylmethionine Using the procedures of Examples 25 with the resultant amine from Example 18B and 3- pyridinecarboxaldehyde affords the title product.
4685
Figure imgf000271_0002
Example 27 4690 4-(3-Pyridyloxymethylene)-2-phenylbenzoylmethionine
Example 27A 4-(/7-Toluenesulfonyloxy -2-phenylbenzoylmethionine methyl ester The resultant compound from Example 16D (1.0 equivalent) and p-toluenesulfonyl chloride 4695 ( 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. 4700 Example 27B
4-(3-PyridyloxymethyleneV2-phenylbenzoylmethionine methyl ester 3-Hydroxypyridine ( 1.0 equivalent) is treated with sodium hydride ( 1.0 equivalent) in DMSO, then the resultant compound from Example 27 A (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the
4705 organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.
Example 27C 4-(3-Pyridyloxymethylene -2-phenylbenzoylmethionine 4710 The resultant compound from Example 27B is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000272_0001
4715 Example 28
4-(3-Pyridylmethoxymethylene)-2-phenylbenzoylmethionine
Example 28A 4-(3-Pyridylmethoxymethylene)-2-phenylbenzoylmethionine methyl ester 4720 Using the procedure of Example 27B but replacing 3-hydroxypyridine with 3- hydroxymethylpyridine affords the title compound.
Example 28B 4-(3-PyridylmethoxymethyleneV2-phenylbenzoylmethionine methyl ester, alternate 4725 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 4730 by chromatography on silica gel.
Example 28C 4-(3-PyrιdylmethoxymethyleneV2-phenylbenzoylmethιomne methyl ester The resultant compound from Example 28A is hydrolyzed according to the procedure of 4735 Example IB to give the title product
Figure imgf000273_0001
Example 29 4740 ( 2-Pheny 1-4A thιazol-2-ylamιno)carbonylthιolbenzoyl } -methionine
Example 29A Thιazol-2-ylιsocyanate A solution of 2-amιnothιazol (1 0 mmol), triphosgene (0 34 mmol) and triethylamine (1 0 4745 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-[(thιazol-2-ylanuno)carbonylthιolbenzoyl . -methionine methyl ester 4750 A solution of 2-phenyl-4-mercaptobenzoyl-methιonιne methyl ester from example 12E or
12F (1 0 mmol) and the isocyanate prepared in example 29 A (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
4755 Example 29C
( 2-Phenyl-4-rfthιazol-2-ylamιno)carbonylthιolbenzoyl } -methionine methyl ester, alternate procedure To a solution of 2-phenyl-4-mercaptobenzoyl-methιonιne methyl ester from example 12E or 12F ( 1 equivalent) in methylene chloride is added a solution of phosgene in toluene ( 1 0
4760 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-amιnothιazol (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
4765 brine, evaporated, and purified by chromatography on silica gel Example 29D ■ 2-Phenyl-4-f(thiazol-2-ylar no)carbonylthiolben7.oyl I -methionine The resultant compound from Example 29B is hydrolyzed according to the procedure of 4770 Example IB to give the title product.
Figure imgf000274_0001
4775 Example 30
( 2-Pheny 1-4- r(thien-2-ylmethylamino)carbonylthiolbenzoy 1 } -methionine Using the procedure of Example 29 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.
4780
Figure imgf000274_0002
Example 31 f 2-Phenyl-4-r(thiazol-2-ylamino thionylthiolbenzoyl} -methionine
4785 Example 31 A
(N-Thiony thiazol-2-ylamine A solution of 2-aminothiazol (1.0 mmol), in thionyl chloride is heated at reflux until the reaction is judged to be complete by TLC analysis. Then, the excess thionylchloride is distilled out in vacuo. The resulting material is used without further purification.
4790
Example 3 IB f 2-Phenyl-4- IYthiazol-2-y lamino fhionylthiolbenzoy 1 } -methionine methyl ester Using the procedure of Example 29B but replacing the resultant product from Example 29 A with the resultant product from Example 31 A affords the title compound.
4795
Example 31C ■ 2-Phenyl-4-f(thiazol-2-ylamino thionylthio1benzoyl} -methionine methyl ester, alternate procedure Using the procedure of Example 29C but replacing phosgene in toluene with thionyl 4800 chloride affords the title compound.
Example 3 ID f 2-Phenyl-4-rf thiazol-2-ylamino)thionylthiolbenzoyl 1 -methionine The resultant compound from Example 3 IB is hydrolyzed according to the procedure of 4805 Example IB to give the title product.
Figure imgf000275_0001
4810 Example 32 f 2-Phenyl-4-r(thien-2-ylmethylamino)thionylthiolbenzoyl 1 -methionine Using the procedure of Example 31 but replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.
4815
Figure imgf000275_0002
Example 33 { 2-Phenyl-4-[(thiazol-2-ylamino)sulfonylthiolbenzoyl } -methionine methyl ester Using the procedure of Example 31 but replacing thionyl chloride with sulfuryl chloride 4820 affords the title product.
Figure imgf000275_0003
Example 34 ( 2-Phenyl-4- (thien-2-ylmethylamino)sulfonylthio]benzoyl } -methionine 4825 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.
Figure imgf000276_0001
4830 Example 35
( 2-Pheny 1-4- F(thiazol-2-ylamino thiocarbonylfhiolbenzoyl } -methionine Using the procedure of Example 29 and replacing triphosgene (0.34 mmol) or a solution of phosgene in toluene (1.0 equivalent) with thiophosgene (1.0 mmol) affords the title product.
Figure imgf000276_0002
Example 36 ( 2-Phenyl-4-r(thien-2-ylmethylamino)thiocarbonylthio1benzoyl 1 -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 4840 replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.
Figure imgf000276_0003
Example 37 4845 ( 2-Phenyl-4-r(thiazol-2-yl)thiomethyllbenzoyl } -methionine
Example 37A f 2-Phenyl-4-rthiomethyllbenzoyl} -methionine methyl ester The resultant product from Example 27 A is dissolved DMF/water (2/1), and sodium 4850 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.
4855
Example 37B f 2-Phenyl-4-rfhiomethyl"|benzoyl} -methionine methyl ester, alternate procedure To triphenylphosphine (1.2 equivalents) in THF at -78 °C is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added
4860 followed by the resultant compound from Example 16D (1. equivalent) in THF. The reaction is stirred at -78 °C for 1 h and then at ambient temperature until it is judged to be complete by TLC analysis. The mixture is evaporated and the residue is taken up in methanol and is treated with K2CO3 (2 equivalents). When the reaction is judged to be complete by TLC analysis, the solvent is evaporated and the residue is chromatographed on
4865 silica gel to afford the title product.
Example 37C { 2-Pheny l-4-[(thiazol-2-yl)thiomethyllbenzoy 1 } -methionine methyl ester A mixture of the resultant thiol from Example 37A (1 mmol), 2-bromothiazole ( 1.5 mmol), 4870 and anhydrous potassium carbonate (5 mmol) in DMF is stirred at 100 °C until TLC analysis shows that the starting thiol disappeared. Then, the reaction mixture is diluted with water, extracted with ether, and washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography on silica gel to' give the title compound.
4875
{ 2-Phenyl-4-r(thiazol-2-yl thiomethyl1benzoy 1 } -methionine The resultant compound from Example 37C is hydrolyzed according to the procedure of Example IB to give the title product.
4880
Figure imgf000277_0001
Example 38 { 2-Phenyl-4-r(thien-2-ylmethyl)thiomethyl1benzoyl I -methionine Using the procedure of Example 37 and replacing 2-bromofhiazole with 2- 4885 bromomethylthiophene affords the title product.
Figure imgf000277_0002
Example 39 4890 {2-Phenyl-4-r(thiazol-2-ylamino carbonylthiomethyllhenzoyl ) -methionine
Using the procedure of Example 29 with the resultant product from Example 37A affords the title product.
Figure imgf000278_0001
Example 40 { 2-Phenyl-4- (thiazol-2-ylamino carbonylthiomethyllbenzoyl ) -methionine Using the procedure of Example 29 with the resultant product from Example 37 A and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.
4900
Figure imgf000278_0002
Example 41 f 2-Phenyl-4-r(thiazol-2-ylamino thiocarbonylthiomethyl]benzoyl ) -methionine 4905 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.
Figure imgf000278_0003
Example 42 ( 2-Phenyl-4- (thiazol-2-ylamino thiocarbonylthiomethyllbenzoyl I -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 4915 thiophosgene ( 1.0 mmol), and replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.
Figure imgf000279_0001
4920 Example 43
( 2-Phenyl-4-r(thiazol-2-ylamino thionylthiomethyl"lbenzoyl ) -methionine Using the procedure of Example 31 with the resultant product from Example 37 A affords the title product.
4925
Figure imgf000279_0002
Example 44 (2-Phenyl-4-[(thien-2-ylmethylamino)thionylthiomethyllbenzoyl} methionine Using the procedure of Example 31 with the resultant product from Example 37 A and
4930 replacing 2-aminothiazol with thien-2-ylmethylamine affords the title product.
Figure imgf000279_0003
Example 45 4935 { 2-Phenyl-4- (thiazol-2-ylamino sulfonylthiomethyl1benzoyl } -methionine
Using the procedure of Example 31 with the resultant product from Example 37A and replacing thionyl chloride with sulfuryl chloride affords the title product, affords the title product.
4940
Figure imgf000279_0004
Example 46 f 2-Phenyl-4- (thien-2-ylmethylamino)sulfony lthiomethy llbenzoy 1 } -methionine Using the procedure of Example 31 with the resultant product from Example 37 A, replacing 4945 thionyl chloride with sulfuryl chloride, and replacing 2-aminothiazol with thien-2- ylmethylamine affords the title product.
Figure imgf000280_0001
4950 Example 47
( 4- f2-f Imidazol-2-yl ethynyl1-2-pheny„benzoyl I methionine
Example 47A (4-Ethynyl-2-phenylbenzoylN)methionine methyl ester
4955 A mixture of (2-phenyl-4-bromobenzoyl)-methionine methyl ester (100 mmol), diethylamine (300 mmol), trimethylsilylacetylene (1 10 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.
4960 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.
4965
Example 47B ( 4-12-fImidazol-2-yl ethynyl~l-2-phenylbenzoyl 1 -methionine methyl ester The resultant product from Example 47A (5 mmol) is mixed with 4-bromoimidazole (5 mmol), diethylamine ( 1 mL), bis(triphenylphosphine) palladium diacetate (0.1 mmol) and
4970 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 4975 { 4-[2-(Imidazol-2-yl')ethynyll-2-phenylbenzoyl 1 -methionine
The resultant compound from Example 47B is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000281_0001
Example 48 f 4-[2-(Imidazol-4-yl ethenyll-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 4985 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.
4990
Figure imgf000281_0002
Example 49 ( 4-r2-(Imidazol-4-yl ethyl1-2-phenylbenzoyl ) -methionine The resultant olefin (1 mmol) from Example 48 is mixed with 5% palladium on carbon (100
4995 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.
5000
Figure imgf000281_0003
Example 50 { 4- 2-(Imidazol-4-y lcarbonyl ethynyl]-2-phenylbenzoyl } -methionine
Example 50A
5005 (4-[2-(Imidazol-4-ylcarbonyl)ethynyl"l-2-phenylbenzoyl) -methionine methyl ester A stainless autoclave containing the resultant product from Example 47A (5 mmol), 4- bromoimidazole (5 mmol), l,l'-bis(diphenylphosphine)-ferrocenepalladium dichloride (0.1 mmol), and triethylamine (10 mL) is flushed with nitrogen, and pressurized to 20 atm with carbon monoxide. The reaction mixture is stirred at 120 °C until judged complete by TLC
5010 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 5015 { 4-[2-(Imidazol-4-ylcarbonyl ethynyn-2-phenylbenzoyl I -methionine
The resultant compound from Example 50A is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000282_0001
5020 Example 51
{4-r2-(Imidazol-4-ylcarbonyl ethenyll-2-phenylbenzoyll -methionine Using the procedure of Example 48 with the resultant compound from Example 50 affords the title product.
5025
Figure imgf000282_0002
Example 52 ( 4-r2-dmidazol-4-ylcarbonyl')ethyn-2-phenylbenzoyl } -methionine Using the procedure of Example 49 with the resultant compound from Example 51 affords
5030 the title product.
Figure imgf000282_0003
Example 53 5035 (4-r4-(l-Methylimidazol-4-yl)-3-keto-l-butvnyl1-2-phenylbenzoyl } methionine
Example 53 A ( 4-"f4-( 1 -Methylimidazol-4-yD-3-keto- l-butynyll-2-phenylbenzoyl I -methionine methyl ester 5040 To a solution of l-methyl-4-imidazoleacetic acid (5 mmol) in methylene chloride at 0 °C is added oxalyl chloride (6 mmol) and DMF (0.05 mmol). After 30 minute, the solvent is evaporated in vacuo. The residue is redissolved in dichloromethane, followed by the addition of the resultant acetylene from Example 47A (5 mmol), triethylamine (10 mmol), and copper(I) iodide (1 mmol). The reaction is stirred at 25 °C until TLC analysis indicates 5045 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.
5050 Example 53B
( 4- [4-f 1 -Methylimidazol-4-yl)-3-keto- 1 -butynyll-2-phenylbenzoyl } -methionine The resultant compound from Example 53A is hydrolyzed according to the procedure of Example IB to give the title product.
5055
Figure imgf000283_0001
Example 54 ( 4-f4-( 1 -Methylimidazol-4-yl)-3-keto- l-butenyll-2-phenylbenzoyl } -methionine Using the procedure of Example 48 with the resultant compound from Example 53 affords
5060 the title product.
Figure imgf000283_0002
Example 55
5065 { 4-14-( 1 -Methylimidazol-4-yl'. -3-keto- 1 -butyll-2-phenylbenzoyl } -methionine Using the procedure of Example 49 with the resultant compound from Example 53 affords the title product.
Figure imgf000284_0001
Example 56
(S) Pyroglutamyl-(4-amino-2-phenyl)benzoyl methionine
Example 56A
5075 (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-l,2,3-benzotriazin-4(3H)-one ( 1.5 equivalents) followed by pyroglutamic acid (1.0 equivalent) and l-(3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged
5080 complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Example 56B 5085 (S) Pyroglutamyl-(4-amino-2-phenyl)benzoyl methionine
The resultant compound from Example 56A is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000284_0002
Example 57 (S) Pyroglutamyl-(4-amino-2-phenyl benzoyl methionine Using the procedure of Example 56 and replacing pyroglutamic acid with 3-pyridylacetic acid affords the title product.
5095
Figure imgf000285_0001
Example 58 (S) Pyroglutamyl-(4-aminomethyl-2-phenyl benzoyl methionine
5100
Example 58A (S) Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl methionine methyl ester To a solution of the resultant amine from Example 18B (1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one ( 1.5 5105 equivalents) followed by pyroglutamic acid (1.0 equivalent) and l-(3- dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
51 10
Example 58B (S) Pyroglutamyl-(4-aminomethyl-2-phenyl benzoyl methionine The resultant compound from Example 58 A is hydrolyzed according to the procedure of Example IB to give the title product.
51 15
Figure imgf000285_0002
Example 59 naming error(S) Pyroglutamyl-(4-aminomethyl-2-phenyl)benzoyl methionine 5120 Using the procedure of Example 58 and replacing pyroglutamic acid with 3-pyridylacetic acid affords the title product.
Figure imgf000286_0001
5125 Example 60
4- (Pyridin-2-ylamino carbonyll-2-phenylbenzoyl methionine
Example 60A 4-Carboxy-2-phenylbenzoyl methionine methyl ester 5130 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. 5135
Example 60B 4-r(Pyridin-2-ylamino)carbonyll-2-phenylbenzoyl methionine methyl ester To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3- hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 5140 equivalent) and l-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
5145 Example 60C
4- (Pyridin-2-yla ino carbonvn-2-phenylbenzoyl methionine The resultant compound from Example 60B is hydrolyzed according to the procedure of Example IB to give the title product.
5150
Figure imgf000287_0001
Example 61 4-((S)-2-Pyrrolidone-5-aminomethyl carbonyl -2-phenylbenzoyl methionine Using the procedure of Example 60 and replacing 2-aminopyridine with (5)-5-aminomethyl- 5155 2-pyrrolidone affords the title product.
Figure imgf000287_0002
Example 62 5160 4-[(Pyridin-2-ylamino carbonylmethyl1-2-phenylbenzoyl methionine
Example 62A 4-Diazocarbonyl-2-phenylbenzoyl methionine methyl ester The resultant acid from Example 60A ( 1 equivalent) in dichloromethane is treated with 5165 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.
5170 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
5175 into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title product.
Example 62C 4-[(Pyridin-2-ylamino)carhonylmethyn-2-phenylbenzoyl methionine methyl ester 5180 To a solution of the resultant acid from Example 62B ( 1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2- aminopyridine (1.0 equivalent) and l-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried 5185 and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
. Example 62D 4-r(Pyridin-2-ylamino carbonylmethyl1-2-phenylbenzoyl methionine 5190 The resultant compound from Example 62C is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000288_0001
5195 Example 63
4-((S)-2-Pyrrolidone-5-aminomethyl carbonylmethyl)-2-phenylbenzoyl methionine Using the procedure of Example 62 and replacing 2-aminopyridine with (5)-5-aminomethyl- 2-pyrrolidone affords the title product.
5200
Figure imgf000288_0002
Example 64 4-((S)-2-Pyrrolidone-5-methoxycarbonyl)amino-2-phenylbenzoyl methionine The title compound is prepared as described in Example 1 with the exception that (S)-5- 5205 aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).
Figure imgf000289_0001
5210 Example 65
4-((S)-2-Pyrrolidone-5-methoxythiocarbonyl)amino-2-phenylbenzoyl methionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent), and triphosgene (0.33 equivalent) is
5215 replaced by thiophosgene ( 1.0 equivalent).
Figure imgf000289_0002
Example 66 5220 4-((S)-2-Pyrrolidone-5-methoxysulfinyl)amino-2-phenylbenzoyl methionine
The title compound is prepared as described in Example 3 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).
5225
Figure imgf000289_0003
Example 67 4-((S~)-2-Pyrrolidone-5-methoxysulfonyl)amino-2-phenylbenzoyl methionine The title compound is prepared as described in Example 4 with the exception that (S)-5- 5230 aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by (S)-5-hydroxyme fhyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).
Figure imgf000290_0001
5235 Example 68
4-(Pyridin-3-ylmercaptocarbonyl)amino-2-phenylbenzoyl methionine The title compound is prepared as described in Example 1 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by 3-mercaptopyridine ( 1.0 equivalent).
5240
Figure imgf000290_0002
Example 69 4-(Pyridin-3-ylmercaptothiocarbonyl)amino-2-phenylbenzoyl methionine 5245 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).
5250
Figure imgf000290_0003
Example 70 4-(Pyridin-3-ylmercaptosulfinylN)amino-2-phenylbenzoyl methionine The title compound is prepared as described in Example 3 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 5255 equivalent).
Figure imgf000291_0001
Example 71 5260 4-(Pyridin-3-ylmercaptosulfonyl)amino-2-phenylbenzoyl methionine
The title compound is prepared as described in Example 4 with the exception that (5)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by 3-mercaptopyridine ( 1.0 equivalent).
5265
Figure imgf000291_0002
Example 72 4-((S)-2-Pyrrolidone-5-methoxycarbonyl)aminomethyl-2-phenylbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- 5270 aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent).
Figure imgf000291_0003
5275 Example 73
4-((5V2-Pyrrolidone-5-methoxythiocarbonyDaminomethyl-2-phenylbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by (S)-5-hydroxymethyl-2- pyrrolidone (1.0 equivalent) and CuCl (0.1 equivalent), and triphosgene (0.33 equivalent) is 5280 replaced by thiophosgene ( 1.0 equivalent).
Figure imgf000292_0001
Example 74 5285 4-((S)-2-Pyrrolidone-5-methoxysulfιnyl aminomethyl-2-phenylbenzoyl 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).
5290
Figure imgf000292_0002
Example 75 4-((S)-2-Pyrrolidone-5-methoxysulfonyl)aminomethyl-2-phenylbenzoyl methionine The title compound is prepared as described in Example 4 using the resultant amine from 5295 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).
Figure imgf000292_0003
5300 Example 76 4-(Pyridin-3-ylmercaptocarbonyl aminomethyl-2-phenylbenzoyl methionine The title compound is prepared as described in Example 18 with the exception that (S)-5- aminomethyl-2-pyrrolidone ( 1.0 equivalent) is replaced by 3-mercaptopyridine ( 1.0 equivalent).
5305
Figure imgf000293_0001
Example 77 4-(Pyridin-3-ylmercaptocarbonyl aminomethyl-2-phenylbenzoyl methionine 5310 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).
Figure imgf000293_0002
Example 78
4-(Pyridin-3-ylmercaptosulfinyl)aminomethyl-2-phenylbenzoyl 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
5320 replaced by 3-mercaptopyridine (1.0 equivalent).
Figure imgf000293_0003
Example 79 5325 4-(Pyridin-3-ylmercaptosulfonyl aminomethyl-2-phenylbenzoyl methionine
The title compound is prepared as described in Example 4 using the resultant amine from Example 18B with the exception that (S)-5-aminomethyl-2-pyrrolidone (1.0 equivalent) is replaced by 3-mercaptopyridine (1.0 equivalent).
5330
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-
5335 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
5340 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
5345 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
5350 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-
5355 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 82 A-NH-SO-NH-B 5360 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. 5365 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.
5370
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
5375 (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
5380 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.
5385 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 (S)-5- aminomethyl-2-pyrrolidone is replaced by an amine from Table 3 (A-NH2). For products
5390 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-
5395 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 85 A-NH-CO-Q-B The anilines from Table 1 (B-NH2) are reacted according to the procedure of Example 6E.
5400 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.
5405 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.
5410 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-
5415 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
5420 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
5425 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
5430 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-
5435 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. Example 88
Figure imgf000297_0001
5440 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
5445 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.
5450
Example 89 A-NH-CH2-B The procedure of Example 16 is used with the exception that (2-phenyl-4-bromobenzoyl)-
5455 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
5460 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.
5465 Example 90
A-NH-CO-NH-CH -B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F-G. The resultant alcohols are reacted according to the procedure of Example 18 with the exception that (S)-5-aminomethyl-2-pyrrolidone is replaced by an amine from 5470 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 5475 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
5480 A-NH-CS-NH-CH -B
The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G The resultant alcohols are reacted according to the procedure of Example 18 with the exception that triphosgene (0 33 equivalent) is replaced by thiophosgene ( 1 0 equivalent) and (S)-5-amιnomethyl-2-pyrrohdone is replaced by an amine from Table 3 (A-NH2) For
5485 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 compπsing a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the
5490 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
Figure imgf000298_0001
5495 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 (5)-5-amιnomethyl-2-pyrrohdone 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
5500 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-
5505 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 93 A-NH-Sθ2-NH-CH -B 5510 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
5515 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,
5520 butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 94 A-NH-CO-O-CH2-B
5525 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
5530 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.
5535
Example 95 A-NH-CS-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
5540 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
5545 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 5550 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
5555 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-
5560 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 97 A-NH-CS-S-B
5565 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
5570 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.
5575
Example 98
A-NH-SO-S-B
The anilines Table 1 (B-NH2) are converted into the corresponding mercaptans according to
5580 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. 5585 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.
5590
Example 99
A-NH-SO2-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 5595 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 5600 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.
5605 Example 100
A-NH-CO-S-CH -B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the corresponding mercaptans according to the procedures of Examples 27 A and 37 A. These mercaptans are reacted according to the
5610 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
5615 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. 5620 Example 101
A-NH-CS-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 27 A and 37A. These mercaptans are reacted according to the
5625 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.
5630 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.
5635 Example 102
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 37 A. These mercaptans are reacted according to the
5640 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
5645 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.
5650 Example 103
A-NH-SO2-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
5655 procedure of Example 29 with the exception that phosgene in toluene is replaced by sulfuryl chloride and 2-amιnothιazol 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 5660 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
5665 Example 104
A-CO-NH-B The procedure of Example 56 is used with the exception that 4-amιno-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-
5670 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 trom the LiOH hydrolysis step in a 1 1 mixture of dichloromethane and tπfluoroacetic acid until TLC analysis indicates that the reaction is complete The solvent is evaporated and the residue is purified by chromatography on silica gel
5675 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
5680
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
5685 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-CO H) 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
5690 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 5695 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
5700 A-CO-CC-B
The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 47A. The resultant acetylenes are reacted according to the procedure of Example 53 with the exception that l-methyl-4-imidazoleacetic acid is replaced by an acid from Table 4 (A- CO H). For products derived from acids 164-238 and 262-269 from Table 4, the LiOH
5705 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.
5710 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.
5715
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 5720 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.
5725 Example 108
A-CO-CH2-CH2-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 5730 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
5735 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
5740 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.
5745
Example 110 A-NH-CO-CH2-B
The bromides from Table 2 (B-Br) are reacted according to the procedure of Example 60A.
5750 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.
5755 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.
5760
Example 111 A-CH.-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- 5765 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
5770 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.
5775
Example 112 A-CH2-NH-CH2-B
The bromides from Table 2 (B-Br) are reacted according to the procedures of 5780 Example 16F-G. The resultant alcohols are converted to the corresponding amines according to the procedures of Examples 18A-B. These amines are reacted according to the procedure of Example 25 with the exception that 3-pyridinecarboxaldehyde is replaced by an aldehyde from Table 5 (A-CHO). For products derived from aldehydes 360-432 and 433- 440 from Table 5, the LiOH hydrolysis step is followed by removal of the tert- 5785 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, 5790 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.
5795
Figure imgf000306_0001
Example 113 4-(('S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethyl -2-phenylbenzoyl methionine Example 113 A 5800 4-Thioacetoxymethyl-2-phenylbenzoic acid methyl ester
To triphenylphosphine (1.2 equivalents) in THF at -78 °C is added diethylazodicarboxylate (1.2 equivalents) in THF. After 10 min thiolacetic acid (1.3 equivalents) in THF is added followed by the resultant compound from Example 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 5805 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.
5810 Example 113B
4-Chlorosulfonylmethylene-2-phenylbenzoic acid methyl ester The resultant compound from Example 1 13 A 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
5815 afford the title product.
Example 113C 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylene-2-phenylbenzoic acid methyl ester To a solution of the resultant compound from Example 113B ( 1.0 equivalent) in methylene 5820 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 5825 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylene-2-phenylbenzoic acid
The resultant compound from Example 113C is hydrolyzed according to the procedure of Example IB to give the title product.
Example 1 13E 5830 4-((S)-2-Pyrrolidone-5-aminomethyl')sulfonylmethylene-2-phenylbenzoyl methionine methyl ester To a solution of the resultant compound from Example 113D ( 1.0 equivalent) in dimethylformamide (DMF) is added 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by methionine methyl ester (1.0 equivalent) and l-(3- 5835 dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed with IN HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
5840 Example 1 13F
4-((S)-2-Pyrrolidone-5-aminomethy sulfonylmethylene-2-phenylbenzoyl methionine The resultant compound from Example 1 13E is hydrolyzed according to the procedure of Example IB to give the title product.
5845
Example 114 A-NH-SO2-CH7-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 5850 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.
Figure imgf000308_0001
5855 Example 115
4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylV2-phenylbenzoyl leucine
Example 115A 4-(Hydroxymethyl')-2-phenylbenzoyl leucine methyl ester 5860 (2-phenyl-4-bromobenzoyl)-leucine methyl ester is reacted according to the procedures of Example 16F-G.
Example 115B 4-Thioacetoxymethyl-2-phenylbenzoyl leucine methyl ester 5865 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 5870 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 5875 4-Chlorosulfonylmethylene-2-phenylbenzoyl leucine methyl ester
The resultant compound from Example 115B in water is stirred vigorously while gaseous chlorine is bubbled through the mixture. When the reaction is judged to be done by TLC analysis, the reaction is extracted with dichloromethane which is dried and evaporated to afford the title product. 5880
Example 1 15D 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylene-2-phenylbenzoyl leucine methyl ester To a solution of the resultant compound from Example 115C (1.0 equivalent) in methylene 5885 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 5890 4-((S)-2-Pyrrolidone-5-aminomethyl)sulfonylmethylene-2-phenylbenzoyl leucine
The resultant compound from Example 115D is hydrolyzed according to the procedure of Example IB to give the title product.
5895 Example 116
A-NH-SO2-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
5900 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.
Figure imgf000310_0001
5905 Example 117
4-(2-Thiazolyl -2-phenylbenzoyl methionine
Example 117 A 2-Thiazole boronic acid 5910 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.
5915
Example 117B 4-(2-Thiazolyl)-2-phenylbenzoyl methionine methyl ester A mixture of 4-bromo-2-phenylbenzoic acid methyl ester (1.0 equivalent), 2-thiazole boronic acid (1.0 equivalent) and catalytic Pd(PPh3)4 is heated in a two phase system of 5920 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-phenylbenzoyl methionine 5925 The resultant compound from Example 117C is hydrolyzed according to the procedure of Example IB to give the title product.
Figure imgf000310_0002
5930 Example 118
4-(2-Thiazolylcarbonyl)-2-phenylbenzoyl methionine Example 1 18A 4-(2-Thiazolylcarbonvπ-2-phenylbenzoyl methionine methyl ester 5935 A mixture of 4-bromo-2-phenylbenzoic acid methyl ester ( 1.0 equivalent), 2-thiazole boronic acid from Example 117A (1.0 equivalent) and catalytic Pd(PPh3)4 is heated in a two phase system of toluene and aqueous Na2CO3 previously purged with a large excess of carbon monoxide. The resulting diaryl ketone is isolated by evaporation of the organic phase and is purified by chromatography on silica gel.
5940
Example 1 18B 4-(2-ThiazolylcarbonylV2-phenylbenzoyl methionine The resultant compound from Example 1 18A is hydrolyzed according to the procedure of Example IB to give the title product.
5945
Figure imgf000311_0001
Example 119 4-[(3-Aminopyridyπcarbonylaminosulfonyll-2-phenylbenzoylmethionine
5950
Example 119A 4-Aminosulfonyl-2-phenylbenzoylmethionine methyl ester To a solution of 4-chlorosulfonyl-2-phenylbenzoyl methionine methyl ester from Example 5E in dichloromethane is added aqueous ammonia and the mixture is stirred until the 5955 reaction is judged complete by TLC analysis. The organic phase is separated, dried and evaporated and the product is purified by chromatography on silica gel.
Example 119B 4-Isocyanatosulfonyl-2-phenylbenzoylmethionine methyl ester 5960 A mixture of the resultant sulfonamide from Example 119A in chlorobenzene is treated with with oxalyl chloride according to the procedure of Franz et al. (7. Org. Chem, 1964, 29, 2592) to give the title compound. Example 1 19C 5965 4-r(A-aminopyridyl)carbonylaminosulfonyll-2-phenylbenzoylmethionine methyl ester
A mixture of the resultant isocyanate from Example 119B (1 equivalent) in dichloromethane is treated with 3-aminopyridine ( 1 equivalent) and stirred until the reaction is judged complete by tic analysis. The solvent is evaporated and the product is purified by chromatography on silica gel.
5970
Example 119D 4- (A-aminoρyridyl)carbonylaminosulfonyll-2-phenylbenzoylmethionine The resultant compound from Example 119C is hydrolyzed according to the procedure of Example IB to give the title product.
5975
Example 120 A-NH-CO-NH-SO2-B
The anilines from Table 1 (B-NH2) are reacted according to the procedures of Example 5E 5980 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. 5985 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.
5990 Example 121
A-NH-CO-NH-SO2-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
5995 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 6000 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
6005 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-hydroxypyπdιne 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
6010 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 moietv , in which
6015 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
6020 A-O-CO-NH-B
The procedure of Example 1 is used with the exception that 4-amιno-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5- amιnomethyl-2-pyrrolιdone (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
6025 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
6030 This example also encompasses compounds compπsing 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6035 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,
6040 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
6045 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-
6050 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
6055 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
6060 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
6065 anilines in Table 1 are replaced by the coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 126 6070 A-O-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-pyπolidone (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 6075 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 6080 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6085
Example 127 A-O-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
6090 exception that (S)-5-amιnomethyl-2-pyπohdone (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 stiπing the resultant compound from the LiOH hydrolysis step in a 1 1 mixture of dichloromethane and
6095 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-
6100 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 128 A-O-CS-NH-CH -B
6105 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-amιnomethyl-2-pyπohdone ( 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
6110 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 stimng 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 6115 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
6120
Example 129 A-O-SO-NH-CH2-B The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18 A-B The resultant amines are reacted according to the procedure of Example 3
6125 with the exception that (S)-5-amιnomethyl-2-pyπohdone (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
6130 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 compπsing 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-
6135 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 130 A-O-SO2-NH-CH2-B
6140 The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18 A-B The resultant amines are reacted according to the procedure of Example 4 with the exception that (S)-5-amιnomethyl-2-pyπohdone (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
6145 followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stirnng 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 6150 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6155 Example 131
A-S-B The anilines from Table 1 (B-NH2) are reacted according to the procedures of Example 13 A. 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
6160 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 stiπing 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.
6165 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6170
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-
6175 aminomethyl-2-pyπolidone (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 stiπing 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
6180 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- 6185 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 133 A-S-CS-NH-B
6190 The procedure of Example 1 is used with the exception that 4-amιno-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2), (S)-5- amιnomefhyl-2-pyπohdone (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
6195 followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stiπing 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
6200 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6205 Example 134
A-S-SO-NH-B The procedure of Example 3 is used with the exception that 4-amιno-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (5)-5- amιnomethyl-2-pyπohdone ( 1 0 equivalent) is replaced by a mercaptan from Table 7 (A-
6210 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 stiπing 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
6215 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6220 Example 135 A-S-SO -NH-B The procedure of Example 4 is used with the exception that 4-amino-2-phenylbenzoyl methionine methyl ester is replaced by an aniline from Table 1 (B-NH2) and (S)-5-
6225 aminomethyl-2-pyπolidone ( 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 stiπing 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
6230 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-
6235 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 136 A-S-CO-NH-CH2-B
6240 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-pyπolidone 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
6245 group by stiπing 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
6250 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 137 6255 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-aminome.hyl-2-pyπolidone is replaced by a mercaptan from Table 7 (A-SH) and triphosgene (0.33 equivalent) is replaced by thiophosgene ( 1.0 equivalent).
6260 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 stiπing 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.
6265 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6270
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 18 A-B. The resultant amines are reacted according to the procedure of Example 3
6275 with the exception that (S)-5-aminomethyl-2-pyπolidone 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 stiπing 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
6280 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-
6285 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 139 A-S-SO2-NH-CH2-B
6290 The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G and 18 A-B. The resultant amines are reacted according to the procedure of Example 4 with the exception that (S)-5-aminomethyl-2-pyπolidone 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 6295 group by stiπing 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
6300 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6305 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
6310 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 stiπing 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.
6315 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6320
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-
6325 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 stiπing 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
6330 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl," isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6335
Example 142 A-NH-B The procedure of Example 24 is used with the exception that 4-amino-2-phenylbenzoyl
6340 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 stiπing the resultant compound from the LiOH hydrolysis step in a 1: 1 mixture of dichloromethane
6345 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-
6350 butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 143 A-O-CH2-B
6355 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
6360 group by stiπing 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
6365 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. 6370 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).
6375 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.
6380 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 coπesponding ethyl, propyl, isopropyl. butyl; sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6385
Example 145 A-O -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-
6390 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 stiπing 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
6395 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
6400
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 6405 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6410 Example 147
A-CH2-CH -B The products from Example 146 are reacted according to the procedure of Example 49 This example also encompasses compounds compπsing a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to prepare the
6415 bromides in Table 2 are replaced by the coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 148
6420 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-bromoιmιdazole 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
6425 followed by removal of the tert-butyloxycarbonyl (Boc) amine protecting group by stiπing 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-terrmnal ester moiety,
6430 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Example 149 6435 A-CO-CH=CH-B
The products from Example 148 are reacted according to the procedure of Example 48
This example also encompasses compounds compπsing a C-terminal ester moiety, in which case the final LiOH step is eliminated and the amino acid methyl esters used to 6440 prepare the bromides in Table 2 are replaced by the coπesponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 150 A-CO-CH2-CH2-B
6445 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 coπesponding ethyl, propyl, isopropyl,
6450 butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 151 A-SO2-B The anilines from Table 1, entries 28-132 (B-NH2) are reacted according to the 6455 procedures of Example 13 A. 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 6460 stiπing 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, 6465 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 coπesponding ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 152 6470 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 6475 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 stiπing the resultant compound from the LiOH hydrolysis step in a 1 1 mixture ot 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
6480 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
6485
Example 153 A-SO2-CH2-B The bromides from Table 2, entries 28-132 (B-Br) are reacted according to the procedures
6490 of Example 16F-G The resultant alcohols are reacted according to the procedure of
Example 37 with the exception that 2 -bromo thiazole 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
6495 group by stiπing 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 puπfied by chromatography on silica gel This example also encompasses compounds comprising a C-terminal ester moiety, in which
6500 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters
Figure imgf000326_0001
6505 Example 154
(4-r(3-sulfonylmethylpyπdyl)amιnol-2-phenylbenzoyl . methionine
Example 154A f4- (3-sulfonylmethylpyπdyl amιnol-2-phenylbenzoyl}methιonιne methyl ester 6510 A mixture of 3-chlorosulfonylmethy Ipyridine hydrochloride ( 1.0 equivalent) and (4-amino- 2-phenylbenzoyl)methionine methyl ester ( 1.0 equivalent) in dichloromethane is treated with triethylamine (2.2 equivalents). When judged complete by TLC analysis, the reaction is diluted with ethyl acetate, and then is washed with pH 4 water, saturated NaHC03, and brine. The mixture is dried and concentrated to give the crude title compound which is
6515 purified by chromatography on silica gel.
Example 154B (4-[(3-sulfonylmethylpyridyl)aminol-2-phenylbenzoyl . methionine The resultant compound from Example 154A is hydrolyzed according to the procedure of 6520 Example IB to give the title product.
Example 155 A-CH2SO -NH-B
The procedure of Example 154 is used with the exception that 4-amino-2-phenylbenzoyl 6525 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-SO2CI).
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 6530 anilines in Table 1 are replaced by the coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters.
Example 156 A-SO2-NH-CH2-B
6535 The bromides from Table 2 (B-Br) are reacted according to the procedures of Example 16F- G. The resultant alcohols are converted to the coπesponding amines according to the procedures of Examples 18 A-B. These amines are reacted according to the procedure of Example 154 with the exception that -chlorosulfonylmethy Ipyridine hydrochloride is replaced by a sulfonyl chloride from Table 9 (A-SO2CI).
6540 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 coπesponding ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, isoamyl, hexyl, octyl, cyclohexyl or phenethyl esters. 6545
Figure imgf000328_0001
Example 162 [4-(thιazo-4-ylmethylcarbonyl)amιno-2-phenylbenzoyllmethιonιne
6550 Example 162 A
Thioformamide To a mechanically-stiπed solution of formamide (4 0 mL, 100 mmol) in THF (45 mL) was added P4S10 (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 stiπed for 5 5 hours at ambient 6555 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
6560 Ethyl 4-bromoacetoacetate
To a mechanically-stiπed 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 stiπed for 5 hours with cooling and then was stiπed overnight at ambient temperature Ice (60 g) was
6565 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 stiπed for 1 day over CaC and then was filtered through celite The filter cake was rinsed with" dichloromethane 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
6570 mg)
Example 162C Ethyl 4-Thιazolylacetate To a solution in absolute ethanol (18 mL) of ethyl 4-bromoacetoacetate (7 0 mL, 104 6575 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 162 A, while the reaction temperature was maintained below 35 °C using an ice-water bath. The reaction mixture was stiπed 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
6580 twice with ether. The organic extracts were discarded and the aqueous phase was taken to ph 7-8 with NaHCU3. 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 1 11- 122 °C) as light- yellow oil.
6585
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 stiπed for 10 minutes at ambient temperature. The
6590 reaction mixture was cooled to 0 °C and taken to pH 2-3 with concentrated HCl. The resulting white solid was filtered, washed with water and dried under high vacuum in the presence of P2O5 to give 4-thiazoylacetic acid (905 mg).
Example 162E
6595 [4-(thiazo-4-ylmethylcarbonyl amino-2-phenylbenzoyllmethionine 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 μL, 3.44 mmol) and DMF (5 mL). The mixture was stiπed 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
6600 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 stiπed 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
6605 acetate hexane) gave [4-(thiazo-4-ylmethylcarbonyl)amino-2-phenylbenzoyl] methionine methyl ester (581 mg) as a light-yellow powder.
Example 162F r4-(thiazo-4-ylmethylcarbonyl amino-2-phenylbenzoyllmethionine 6610 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. Η NMR (300 MHz, DMSO-d6) δ 10.42 (s, IH), 9.06 (d, IH), 8.43 (d, IH), 7.70 (d, IH), 7.63 (dd, IH), 7.52 (d, IH), 7.40 (d, IH), 7.35 (m, 5H), 4.28 (m, IH), 3.90 (s, 2H), 2.25 (m. 6615 2H), 2.00 (s, 3H), 1.86 (m, 2H); MS (DCI-NH3) m/e 470 (M+H)+. Anal calcd for C23H23N3O4S2: C, 58.83; H, 4.94; N, 8.95. Found: C, 58.44; H, 4.87; N, 8.58.
Figure imgf000330_0001
6620 Example 163 4-(thiazol-2-ylmethylcarbonyl amino-2-phenylbenzoyllmethionine
Example 163 A 3-bromosuccinaldehydic acid ethyl ester 6625 To a 0-5 °C mechanically-stiπed 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 stiπed 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%). 6630
Example 163B Ethyl 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 6635 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 6640 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 6645 2-Thiazolyl 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 oil 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 HCl. The resulting solids were filtered off, rinsed with water, and 6650 dried over P2O5 under high vacuum to give 2-thiazolyl acetic acid ( 1.44 g).
Example 163D [4-(thiazo-2-ylmethylcarbonyl amino-2-phenylbenzoyllmethionine methyl ester To a solution in DMF (4 mL) of 2-thiazolyl acetic acid (300 mg, 2.1 mmol), prepared 6655 as in Example 163C, was added 3-hydroxy-l,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 stiπed overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and 6660 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).
6665 Example 163E r4-(thiazol-2-ylmethylcarbonyl)amino-2-phenylbenzoyllmethionine 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. *H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 6670 IH), 9.00 (d, IH), 8.45 (d, IH), 7.79 (d, IH), 7.67 (d, IH), 7.61 (dd, IH), 7.42 (d, IH), 7.38 (m, 5H), 4.28 (m, IH), 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 C23H23N3O4S2 H2O: C, 56.66; H, 517; N, 8.62. Found: C, 56.75; H, 4.96; N, 8.45.
6675
Figure imgf000332_0001
Example 164 [4-(rRVthiazolidin-4-ylcarbonyl amino-2-phenylbenzoyllmethionine methyl ester hydrochloride
6680
Example 164 A N-tert-butoxycarbonyl-(R -(- thiazolidine-4-carboxylic acid To a solution of (R)-(-)-thiazolidine-4-carboxylic acid (1.0 g, 7.5 mmol) in aqueous IN ΝaOH (9 mL) and THF (9 mL) was added a solution of di-tert-butyldicarbonate (1.62 g, 6685 7.4 mmol) in THF (9 mL). An additional 2 mL of aqueous ΝaOH was added and the reaction mixture was stiπed overnight at ambient temperature. Additional aqueous ΝaOH 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 ΝaHCU3. The combined aqueous layers were acidified to pH 2 with 1.1 M NaHSO4 and extracted twice with ether. 6690 The combined ether layers were dried over Na2SO4, filtered, and concentrated in vacuo to give N-rerf-butoxycarbonyl-(R)-(-)thiazolidine-4-carboxylic acid (1.3 g) which was used without further purification.
Example 164B 6695 r4-(N-rgr?-butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyllmethionine 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 6700 163D.
Example 164C [4-((R -thiazolidin-4-ylcarbonyl amino-2-phenylbenzoyllmethionine methyl ester hydrochloride 6705 To a mixture of [4-(N-tert-butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2- phenylbenzoyljmethionine methyl ester (270 mg, 0.47 mmol) and thiophenol (0.1 mL, 0.97 mmol) was added 4Ν HCl-dioxane (10 mL) and the reaction mixture was stiπed 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
6710 the aqueous phase was lyophilized to give [4-((R)-thιazohdιn-4-ylcarbonyl)amιno-2- phenylbenzoyl] methionine methyl ester hydrochloride (150 mg) 'H NMR (300 MHz, DMSO-d6) δ 10 53 (s, IH), 8 45 (d, IH), 7.68 (m, 2H), 7 42 (dd, IH). 7 37 (m, 5H), 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 C23H28CIN3O4S2 1 4H20 C, 51 61 , H,
6715 5 80, N, 7 85 Found. C, 51 67, H, 5.55, N, 7.28.
Figure imgf000333_0001
Example 165
6720 14-((R)-thιazohdιn-4-ylcarbonyl')anιιno-2-phenylbenzoyllmethιonιne
To a 0 °C solution in methanol (4.3 mL) of [4-((R)-thιazohdιn-4-ylcarbonyl)amιno-2- phenylbenzoyljmethiomne 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 stiπed for 1.5 hours, then the cold bath was removed and stiπing was
6725 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)-thιazohdιne-4- carbonyl)amιno-2-phenylbenzoyl]methιonιne (67 mg) lH NMR (300 MHz, DMSO-d6)
6730 δl l 10 (s, IH), 8.60 (d, IH), 7.70 (s, IH), 7.68 (dd, IH), 7 44 (dd, IH), 7 37 (m, 5H), 4 63 (m, 1Η), 4.37 (m, 3H), 3.70 (m, IH), 3.63 (s, 3H), 3.40 (m, IH), 2 24 (m, 2H), 2.00 (s, 3H), 1.85 (m, 2H); MS (APCI) m/e 460 (M+H)+ Anal calcd for C22H25N3O4S2 0 8 HCl: C, 54.06; H, 5.32; N, 8.60 Found. C, 54.21 ; H, 5.34, N, 8.00
6735
Figure imgf000334_0001
Example 166 [4-(fR)-tMazolidin-4-ylmethyl amino-2-phenylbenzoyl1methionine hydrochloride
6740 Example 166 A
N-tert-butoxycarbonyl-(R)-(-)thiazolidine-4-carboxylic acid-N-methoxy- V-methyl 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
6745 hydrochloride (709 mg, 3.70 mmol) was added N, 0-dimethylhydroxylamine hydrochloride (357 mg, 3.66 mmol) and 4-methylmorpholine (0.44 mL, 4.01 mmol) and the reaction mixture was stiπed overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and extracted with aqueous 1M H3PO4 (2x), saturated aqueous ΝaHCO3 (2x), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo.
6750 Chromatography on silica gel (2: 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 166B N-tert-butoxycarbonyl-(RA- thiazolidine-4-carboxaldehyde
6755 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 to ambient temperature. The mixture was warmed to ambient temperature and
6760 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 6765 r4-(N-tert-butoxycarbonyl-("R -thiazolidin-4-ylmethyl)amino-2-phenylbenzovnmethionine methyl 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.
6770
Example 166C [4-((R)-thiazolidin-4-ylmethyl)amino-2-phenylbenzoyllmethionine methyl 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- 6775 phenylbenzoyl] methionine methyl ester, prepared as in Example 166B, for [4-(N-tert- butoxycarbonyl-(R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine methyl ester.
Example 166D
6780 r4-((R)-thiazolidin-4-ylmethyl)amino-2-phenylbenzoyllmethionine hydrochloride
The desired compound was prepared by saponification of [4-((R)-thiazolidin-4- ylmethyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 166C according to the procedure of Example 165. »H ΝMR (300 MHz, DMSO-d6) δ 8.03 (d, IH), 7.33 (m, 6H), 6.69 (dd, IH), 6.59 (d, IH), 4.30 (dd, 2H), 4.23 (m, IH), 3.86 (m,
6785 IH), 3.46 (dd, 2H), 3.22 (dd, IH), 2.91 (m, IH), 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
C22H27Ν3O3S2ΗCI O.25H2O: C, 54.31; H, 5.90; N, 8.64. Found: C, 54.20; H, 6.07; N, 8.35.
6790
Figure imgf000335_0001
Example 169 r4-(4-hydroxy-prolinyl)amino-2-phenylbenzoyl1methionine trifluoroacetate
6795 Example 169 A N-Boc -4-ft-butyldimetylsilvDhydroxyproline 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., 7. Med. Chem. 1988, 31, 1598, in 10 ml of methanol was added 5 ml (5 mmol) of 1 Ν LiOH in an ice bath. The reaction mixture
6800 was stiπed for 30 min. The reaction mixture was adjusted to pH 2-3 with 1 Ν 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 Ν HCl and water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 1.05 g (96 %) of N-Boc-4-(t-
6805 butyldimethylsilyl-oxy)proline as a foamy solid which was used without further purification.
Example 169B (4-[N-Boc-4-(t-butyldimethylsilyloxy)prolinyllamino-2-phenylbenzoyl} methionine methyl ester
6810 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 μ 1(3.9 mmol) of triethylamine in an ice bath under argon, followed by 470 μ 1(3.6 mmol) of isobutyl chlroformate. The reaction mixture was stiπed for 40 minutes. At this time TLC showed the absence of the starting material. To this solution, 1.07 g (2.97 mmol)
6815 of [2-phenyl-4-aminobenzoyl]methionine methyl ester (compound 8) in 10 ml of dichloromethane was introduced. The reaction mixture was stiπed overnight, during which time the ice bath expired. The reaction mixture was washed with 1 Ν 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
6820 (94 %) of {4-[N-Boc-4-(t-butyldimetylsilyl)hydroxyprolinyl]-2- phenylaminobenzoyl} methionine methyl ester as a foamy solid, mp 83 °C; [α]25 D -36.2 (c=0.63, CHCI3); IH ΝMR (300 MHz, CDCI3) δ 9.94 (s, IH), 7.53-7.26 (m, 8H), 6.41 (d, IH, 7=6 0Hz), 4.55 (m, 4H), 3.63 (s, 3H), 3.57 (m, IH), 3.32 (m, IH), 2.30 (m, IH), 2.05 (m, 2H), 1.94 (s, 3H), 1.83 (m, IH), 1.73 (m, IH), 1.45 (s, 9H), 0.86 (s, 9H), 0.05
6825 (s, 6H); 13C ΝMR (CDCI3) δ 171.8, 170.7, 169.3, 155.6, 140.0, 129.7, 129.0, 128.5, 128.2, 127.4, 120.2, 1 17.7, 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 (El) calculated for C35H5 iΝ3θ7SSi: 685.9498, found: 685.3217.
6830 Example 169C r4-(N-Boc-4-hydroxyprolinyl a_τuno-2-phenylbenzovHmethionine 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
6835 reaction mixture was stiπed 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
6840 ester as a white solid: mp 121-123 °C; [α]25 D -53.3 (c=0.43, CHCI3); JH ΝMR (300 MHz, CDCI3) δ 9.84 (s, IH), 7.60-7.38 (m, 8H), 6.35 (br s, IH), 4.58-4.51 (br s, 4H), 3.64 (s, 3H), 3.57 (m, IH), 3.48 (m, IH), 2.63 (m, IH), 2.44 (br s, IH), 2.07 (m, 2H), 1.98 (s, 3H), 1.86 (m, IH), 1.72 (m, IH), 1.44 (s, 9H); HRMS (El) calculated for C29H37Ν3O7S: 571.6872, found: 571.2352.
6845
Example 169D r4-(4-hydroxyprolinyl)amino-2-phenylbenzoyllmethionine trifluoroacetate To a solution of 358 mg (0.62 mmol) of [4-(N-Boc-4-hydroxyprolinyl)amino-2- phenylbenzoyljmethionine methyl ester, prepared as in Example 169C, in 6 ml of methanol
6850 was added 1 ml (1 mmol) of 1 Ν 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 Ν 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 Ν HCl and water, dried over anhydrous magnesium sulfate, and concentrated
6855 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
6860 mg (72%) of [4-(4-hydroxyprolinyl)amino-2-phenylbenzoyl]methionine trifluoroacetate: HPLC 90 % (purity); mp 127 (sub.), 154-157 °C (dec); iH ΝMR (300 MHz, CDCI3 + CD3OD) δ 7.53-7.29 (m, 8H), 4.67 (m, IH), 4.58 (s, IH), 4.50 (m, IH), 2.57 (m, IH), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, IH), 1.76 (m, IH); 13C ΝMR (CD3OD) δ 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 1 19.3,
6865 71.2, 60.6, 55.2, 52.9, 39.9, 31.4, 30.9, 15.0.
Figure imgf000338_0001
Example 170 6870 [4-((2S.4S)-4-mercaptopyπolidin-2-carboxy)amino-2- phenylbenzoyllmethionine-trifluoroacetate
Example 170 A [4-((2S,4S)-l-Boc-4-acetylthiopyπolidin-2-carboxy)amino-2-phenylbenzoyl]methionine
6875 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 μl(0.49 mmol) of diisopropyl azodicarboxylate at 0 °C under argon atmosphere. The
6880 reaction mixture was stiπed for 40 minutes and 35 μl (0.49 mmol) of thiolacetic acid was added to this mixture at the same temperature. The reaction mixture was stiπed 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
6885 product was chromatographed on silica gel (3: 1 hexanes-ethyl acetate) to yield 123 mg (89 %) of [4-((2S,4S)- l-Boc-4-acetylthiopyπolidin-2-carboxy)amino-s- phenylbenzoyljmethionine methyl ester as a foamy solid: mp 97 °C; [α]25 D -105.2 (c=0.27, CHCI3); !H ΝMR (300 MHz, CDCI3) δ 9.87 (s, IH), 7.68-7.38 (m, 8H), 6.37 (s, IH), 4.58 (br s, 4H), 4.02 (m, IH), 3.64 (s, 3H), 3.33 (br s, IH), 2.52 (br s, IH), 2.30 (s,
6890 3H), 2.03 (t, 2H, 7=7.8Hz), 1.99 (s, 3H), 1.90 (m, IH), 1.74 (m, IH), 1.45 (s, 9H); 13C ΝMR (CDCI3) δ 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 (El) m/z (relative intensity) 629 (M+, 6), 571 (25), 529 (45), 196 ( 100).
6895
Example 170B r4-((2S.4S -4-mercaptopyπolidin-2-carboxy)amino-2-phenylbenzoyllmethionine trifluoroacetate To a solution of 120 mg (0.19 mmol) of [4-((2S,4S)-l-Boc-4-acetylthiopyrrolidin-2-
6900 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
6905 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-thiopyπolidin-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
6910 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-thiopyπolidin- 2-carboxy)amino-2-phenylbenzoyl]methionine trifluoroacetate: HPLC 86 % (purity); mp 169 °C (dec); 'H NMR (300 MHz, CD3OD) δ 7.59-7.28 (m, 8H), 4.39 (m, 2H), 3.53 (m, IH), 3.38 (m, IH), 3.22-3.12 (m, 2H), 2.87 (m, IH), 2.12 (m, IH), 2.00- 1.92 (m, 5H),
6915 1.72 (m, IH); 13C NMR (CD3OD) δ 175.0, 172.7, 167.5, 142.6, 140.7, 133.4, 130.2, 129.8, 129.7, 129.0, 122.5, 1 19.5, 61.8, 55.3, 53.2, 41.1, 36.2, 31.6, 31.1 , 15.3.
Figure imgf000339_0001
6920 Example 171
[4-((2S.4R)-4-hydroxypyπolidin-2-ylmethyl amino-2-phenylbenzoyllmethionine hydrochloride
Example 171 A 6925 (2S.4R -l-Boc-4-r(t-butyldimethylsilyloxy1-2-(hydroxymethy pyπolidine
A suspension of calcium chloride (780 mg, 7 mmol) and 530 mg (14 mmol) of sodium borohydride in 25 ml of THF was stiπed at ambient temperature for 5 hours. To this suspension was added 2.5 g (7 mmol) of (2S,4R)-l-Boc-4-[(t-butyldimethylsilyl)oxy]-2- (carbomethoxy)pyπolidine methyl ester in 5 ml of THF and the reaction mixture was stiπed 6930 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)pyπolidine as an colorless oil: Η NMR (CDC13) δ 0.05 (s, 6H), 0.85 (s, 9H), 1.47 (s, 9H), 1.90 (m, IH), 3.27-4.25 (complex m, 6935 7H), 4.89 (br d, IH, 7=6.6 Hz): MS (El) m/z 332 (M+), 258.
Example 17 IB (2S.4R)-l-Boc-4-rt-butyldimethylsilyloxylpyπolidin-2-aldehyde To a solution of 1 ml (14.1 mmol) of DMSO in 7 ml of dichloromethane were added 6940 1.48 ml (10.4 mmol) of trifluoroacetic anhydride in 3.5 ml of dichloromethane at -78 °C under a slight stream of argon. After 10 min, 2.35 g (7 mmol) of (2S,4R)-l-Boc-4-[t- butyldimethylsilyloxy]-2-(hydroxymethyl)pyπolidine, prepared as in Example 171 A, in 7 ml of dichloromethane was added to this mixture at the same temperature. The reaction mixture was stiπed for 1 hour. To this solution was added 3 ml (21.5 mmol) of triethylamine. The 6945 reaction mixture was stiπed for 1 hour at -78 °C, 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)-l-Boc-4-[t-butyldimethylsilyloxy]-pyπolidin-2-aldehyde as an oil: JH NMR (300 MHz, CDCI3) δ 9.39 (s, IH), 4.33 (m, IH), 4.17 (m, IH), 3.48 (m, IH), 3.35 (m, IH), 1.93 (m, 2H), 1.41 (s, 9H), 0.82 (s, 9H), 0.07 (s, 6H). 6950
Example 171C ■ 4-rf2S.4Ryi-Boc-4-t-butyldimethylsilyloxy1pyπolidin-2-ylmethyDamino-2- phenylbenzoyl) methionine methyl ester To a solution of 0.75 g (2.09 mmol) of [2-phenyl-4-aminobenzoyl]methionine 6955 methyl ester (compound 8) and 0.7 g (2.1 mmol) of (2S,4R)-l-Boc-4-[t- butyldimethylsilyloxy]-pyπolidin-2-aldehyde, prepared as in Example 17 IB, 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 stiπed overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5 % sodium bicarbonate, and 6960 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)-l-Boc-4-(t-butyldimetylsilyl)oxypyπolidin-2-ylmethyl]amino-2- phenylbenzoyl } methionine methyl ester as a white solid: mp 48 °C; [α]25 D -15.6 (c=1.03, 6965 CHCI3); IH NMR (300 MHz, CDCI3) δ 7.67 (d, IH, 7=8.5 Hz), 7.37 (m, 6H), 6.57 (1 , IH), 6.37 (s, IH), 5.60 (br s, 2H), 4.60 (m, IH), 4.31 (m, 2H), 3.77 (s, 3H), 3.61-3.10 (m, 5H), 2.06 (t, 2H, 7=8.2 Hz), 1.98 (s, 3H), 1.85 (m, IH), 1.60 (m, IH), 1.43 (s, 9H); 0.84 (s, 9H), 0.03 (s, 6H); HRMS (El) calculated for C35H53N3θ6SSi: 671.3424, found: 671.3424.
6970
Example 17 ID [4-((2S,4R)-N-Boc-4-hydroxylpyπolidin-2-ylmethyl)amino-2-phenylbenzoyllmethionine methyl ester To a solution of 770 mg (1.14 mmol) of {4-[(2S,4R)-l-Boc-4-(f-
6975 butyldimethylsilyloxy)-pyπolidin-2-ylmethyl]amino-2-phenylbenzoyl } 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 stiπed 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
6980 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-hydroxypyπolidin-2-ylmethyl)amino-2- phenylbenzoyljmethionine methyl ester as a foamy solid: mp 81 °C; [ ]24 D -15.9 (c=0.74, CHCI3); *H NMR (300 MHz, CDCI3) δ 7.63 (d, IH, 7=9.0 Hz), 7.35 (m, 6H), 6.57 (br
6985 s, IH), 6.38 (br s, IH), 5.67 (d, IH, 7=7.6 Hz), 5.54 (br s, IH), 4.55 (m, IH), 4.09 (m, 2H), 3.59 (s, 3H), 3.37-3.16 (m, 5H), 2.71 (br s, IH), 2.04(m, 2H), 1.96 (s, 3H), 1.80 (m, IH), 1.60 (m, IH), 1.40 (s, 9H); 13C NMR (CDCI3) δ 172.0, 168.5, 156.4, 150.0, 141.7, 141.1, 131.3, 128.6, 127.7, 121.8, 1 13.5, 1 10.8, 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 (El) calculated for
6990 C29H39N3O6S: 557.2559, found: 557.2559.
Example 17 IE [4-((2S,4R -N-Boc-4-hydroxypyπolidin-2-ylmethyl amino-2-phenylbenzoyllmethionine hydrochloride 6995 To a solution of 125mg (0.22 mmol) of [4-((2S,4R)-N-Boc-4-hydroxypyπolidin-2- ylmethyl)amino-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 17 ID, 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 stiπed 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 7000 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 7005 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-hydroxypyπolidin-2-ylmethyl)amino-2-phenylbenzoyl]methionine hydrochloride: HPLC 72 % (purity). Η NMR (300 MHz, CD3OD) δ 7.71-7.30 (m, 6H), 6.76 (dd, IH, 7= 8.4, 2.4 Hz), 6.69 (d, IH, 7= 2.2 Hz), 4.55 (d, IH, 7= 4.0 Hz), 4.44
7010 (dd, IH, 7= 9.3, 4.2 Hz), 4.12 (m, IH), 3.62-3.19 (m, 4H), 2.02 (s, 3H), 2.21- 1.75 (m, 6H).
Figure imgf000342_0001
7015 Example 172 r4-(r2S.4S -4-thiopyπolidin-2-yl-methylamino -2-phenylbenzoyllmethionine hydrochloride
Example 172 A r4-((2S.4SVN-Boc-4-acetylthiopyπolidin-2-yl-methylamino)-2-phenylbenzoyllmethionine 7020 methyl ester and r4-((2S,5S -4-Boc-1.4-diazabicyclo(2.2,l)octan-l-yl)-2-phenyl benzoyllmethionine methyl ester To a solution of 153 mg (0.27 mmol) of 2-Phenyl-4-[(2S,4R)-N-Boc-4- hydroxy]pyπolidine-2-methyl]aminobenzoylmethionine methyl ester, prepared as in 7025 Example 17 ID, 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 °C under argon atmosphere. The mixture was stiπed for 30 minutes and 40 ul (0.56 mmol) of thiolacetic acid was added at the same temperature. The reaction mixture was stiπed overnight, during which time the ice bath expired. The solvent was removed, and a 3: 1 solution of hexanes 7030 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-acetylthiopyπolidin-2-yl-methylamino)-2-phenylbenzoyl]methionine methyl ester and 35 mg (24 %) of the bicyclic [4-((2S,5S)-4-Boc-l,4- 7035 diazabicyclo(2,2,l)octan-l-yl)-2-phenyl)benzoyl]methionine methyl ester as white solids. [4-((2S,4S)-N-Boc-4-acetylthiopyπolidin-2-yl-methylamino)-2- phenylbenzoyljmethionine methyl ester: Η NMR (300 MHz, CDCI3) δ 7.65 (d, IH, 7=8.4 Hz), 7.37 (m, 6H), 6.60 (br s, IH), 6.41 (br s, IH), 5.66 (d, IH, 7=7.8 Hz), 5.53 (br s, IH), 4.58 (m, IH), 4.23 (br s, IH), 4.02 (br s, IH), 3.87 (m, IH), 3.60 (s, 3H), 3.38-
7040 3.12 (br s, 2H), 3.12 (dd, IH, 7=6.7, 1 1.4 Hz), 2.52 (m, IH), 2.30 (s, 3H), 2.05 (t, 2H, 7=7.6 Hz), ), 1.97 (s, 3H), 1.82 (m, IH), 1.62 (m, IH), 1.41 (s, 9H); 13C NMR (CDCI3) δ 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, 1 1 1.0, 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 (El) calculated for C31H41N3O6S2: 615.2436, found: 615.2436.
7045 [4-((2S,5S)-4-Boc- 1 ,4-diazabicyclo(2,2, 1 )octan- 1 -yl)-2-phenyl)benzoyl]methionine methyl ester: !H NMR (300 MHz, CDCI3) δ 7.75 (d, IH, 7=8.6 Hz), 7.54-7.40 (m, 6H), 6.57 (d, IH, 7=9.0 Hz), 6.36 (s, IH), 5.68 (br s, IH), 4.63 (m, 2H), 4.42 (br s, IH), 3.63 (s, 3H), 3.58-3.17 (m, 5H), 2.10 (m, 2H), 1.98 (s, 3H), 1.86 (m, IH), 1.66 (m, IH), 1.41 (s, 9H); 13C NMR (CDCI3) δ 172.2, 168.5, 154.2, 148.7, 142.0, 141.4, 132.1 ,
7050 131.7, 129.0, 128.8, 128.1, 122.1 , 1 13.7, 1 1 1.2, 80.0, 57.4, 56.4, 52.5, 52.0, 37.9,
37.4, 31.9, 29.7, 28.7, 15.5; HRMS (El) calculated for C29H37N3O5S: 539.2454, found: 539.2453.
Example 172B
7055 r4-((2S,4S -4-thiopyπolidin-2yl-methylamino -2-phenylbenzoyllmethionine hydrochloride To a solution of 86 mg (0.14 mmol) of [4-((2S,4S)-N-Boc-4-acetylthioρyπolidin- 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 stiπed for 2 hours. The reaction mixture was adjusted to pH 2-3 with 1 N HCl at the same temperature and the
7060 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
7065 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-thiopyπolidin-2yl-methylamino)-2-phenylbenzoyl]methionine hydrochloride: HPLC 83% (purity); Η NMR (300 MHz, CD3OD) δ 7.46-7.35 (m, 6H), 6.76 (d, IH,
7070 7=8.4 Hz), 6.70 (s, IH), 4.45 (m, IH), 3.91 (m, IH), 3.68-3.30 (m, 5H), 3.15 (m, IH), 2.66 (m, IH), 2.20 (m, IH), 2.10 (m, IH), 2.01 (s, 3H), 1.79 (m, 2H); 13C NMR (CD3OD) δ 175.0, 173.3, 150.5, 143.5, 142.3, 131.3, 129.9, 129.6, 128.7, 125.9, 1 15.9. 1 12.5, 60.9, 54.6, 53.3, 45.8, 40.3, 35.4, 31.8, 31.0, 15.3.
7075
Figure imgf000344_0001
Example 182 f 4-( 1 H-benziιτudazol-5-ylcarboxyamino -2-phenylbenzoyl]methionine trifluoroacetate
7080 Example 182 A
( lH-l-/ Toluenesulfonylbenzimidazol-5-yl)carboxylic acid 5-Benzimidazolecarboxylic acid (1.0 g, 6.2 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.2 mmol) were suspended in 10 mL of distilled water. Aqueous IN sodium hydroxide was added periodically to maintain a pH of approximately 9 over a period of 4 7085 hours. The reaction mixture was washed with methylene chloride (3X50 mL.) and was adjusted to pH 3 with IN hydrochloric acid. The precipitate which formed was collected by vacuum filtration, washed with distilled water and hexanes and air dried to give (lH-l-p- toluenesulfonylbenzimidazol-5-yl)carboxylic acid (0.75 g, 38%) as a white solid.
7090 Example 182B f4-( 1 H- 1 -p-Toluenesulfonylbenzimidazol-5-ylcarboxyamino -2-phenylbenzoyllmethionine methyl 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 l-(3- 7095 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.34 g, 1.8 mmol) was added (lH-l-/?-toluenesulfonylbenzimidazol-5-yl)carboxylic acid (0.52 g, 1.64 mmol), prepared as in Example 182 A, and the mixture was cooled to 0°C. Triethylamine (0.16 g, 1.64 mmol) was slowly added to the stiπed solution. After 1 hour, the ice bath was removed and the reaction was stiπed for an additional 96 hours. The organic layer was 7100 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-(lH-l-/?- toluenesulfonylbenzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methionine methyl ester (0.63 g, 59%) as a white solid. 7105 Example 182C r4-(lH-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyllmethionine trifluoroacetate [4-( IH- 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 0°C. Lithium
7110 hydroxide (5 mL., 0.5M) was slowly added and the reaction mixture was stiπed 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
71 15 containing 0.1% TFA to 60% acetonitrile in 40 minutes) and pure fractions were pooled and lyophilized to give [4-( lH-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methionine trifluoroacetate as a white solid (0.146 g, 87%). Η NMR (300 MHz, DMSO-d6) δ 10.56 (s, IH), 9.05 (s, IH), 8.47 (d, IH, 7= 7.8 Hz), 8.40 (s, IH), 8.04 (d, IH, 7= 8.1 Hz), 7.88-7.89 (m, 2H), 7.33-7.48 (m, 6H), 4.30 (m, IH), 2.16-2.29 (m, 2H), 2.06 (s, 3H),
7120 1.84-2.00 (m, 2H). MS m/e 489 (M+H)+.
Figure imgf000345_0001
Example 185 7125 r4-(piperidin-2-ylcarboxyamino)-2-phenylbenzoyllmethionine hydrochloride.
Example 185 A di-rert-butoxycarbonylpiperidine-2-carboxylic acid Di-tert-butyl dicarbonate (15.5 g, 70.2 mmol) was added to a solution of piperazine- 7130 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 stiπed 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 °C and then adjusted to pH = 3 with 2 M aqueous HCl. A precipitate developed. The mixture was 7135 extracted with CH2CI2 (3 x 75 mL), and the organic extracts were dried over MgS04, filtered, and concentrated under reduced pressure to provide 7.6-1 g (98%) of di-tert- butoxycarbonylpiperidine-2-carboxylic acid as a tan solid. lU NMR (CDCI3) δ 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, 1 H), 4.44-4.65 (br comp, 2 H), 4.80-4.95 (br, 1 H). LRMS (CI): 292, 331 (M+l)+, 348
7140 (M+NH4)+.
Example 185B r4-(di-tert-butoxycarbonylpiperidin-2-ylcarboxyamino -2-phenylbenzoyl1methionine methyl ester. 7145 The desired compound was prepared by coupling di-te/ -butoxycarbonylpiperidine-2- carboxylic acid with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the procedure of Example 184 A.
Example 185C
7150 r4-(di-fert-butoxycarbonylpiperidin-2-ylcarboxyamino -2-phenylbenzoyllmethιonine.
Lithium hydroxide hydrate (0.411 g, 9.60 mmol) was added to a solution of [4-(di- tert-butoxycarbonylpiperidin-2-yl)carboxyamino-2-phenylmethionine methyl ester (ca 0.8 g, 1.20 mmol), prepared in Example 185B, in THF H2O (4: 1, 12 mL). The solution was stiπed for 20 hours and then treated with 1 M aqueous HCl (10 mL). The mixture was
7155 extracted with ethyl acetate (5 x 10 mL), and the organic extracts were rinsed with 1: 1 brine/ 1 N HCl (10 mL), dried over Na2SO4, and concentrated under reduced pressure to provide [4- (di-tert-butoxycarbonylpiperidin-2-yl)carboxyamino-2-phenylmethionine (0.72 g) as a white foam ( est. 89%). JH NMR (CD3OD) δ 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-
7160 7.6 (br m, 1 H), 7.6-7.7 (br m, 1 H). LRMS (CI): 657 (M+l)+, 457, 330.
Example 185D r4-(piperidin-2-y lcarboxy amino)-2-pheny lbenzoy 11 methionine hydrochloride . [4-(di-tert-butoxycarbonylpiperidin-2-ylcarboxyamino)-2-phenylbenzoyl]methionine 7165 (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 stiπed 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%). 'H NMR (CD3OD) δ 1.73-1.88 7170 (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, 1 H), 7.74-7.80 (m, 1 H). LRMS (CI): 457 (M+l )+.
Figure imgf000347_0001
7175 Example 202 4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoylmethionine
Example 202A r4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoyllmethionine methyl ester
7180 To a solution of L-pyroglutamic acid (49mg, 0.38 mmol) in 5 mL of DMF was added
3-hydroxyl,2,3-benzotriazin-4(3/f)-one ( 62mg, 0.38 mmol), (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (58mg, 0.30 mmol) and [4-amino-2-phenylbenzoyl-L- methionine methyl ester (90mg, 0.38 mmol), prepared as in Example 192B, and the reaction mixture was stiπed at 25 °C for 12 hours. The reaction mixture was taken up in ethyl acetate
7185 and washed with 10 mL IN 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-pyπolidinone-5- ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester (92mg, 79%) as a white solid.
7190 Example 202B
[4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine LiOH monohydrate (29mg, 0.69 mmol) was dissolved in 1 mL H2O and added to a solution of [4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 202A, (108mg, 0.23 mmol) in 3 mL of THF and the reaction
7195 mixture was stiπed at 25 °C for 1 hour. The reaction mixture was evaporated and 2 mL of IN HCl was added to the aqueous residue. The resulting precipitate was filtered and dried under vacuum to give [4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine (96 mg, 91%). Η NMR (300 mHz, CD3OD) δ 7.70 - 7.60 (m, 3H), 7.45 - 7.30 (m, 5H), 4.40 (bs, IH), 2.60 - 2.10 (m, 7H), 2.00 (s, 3H), 1.90 - 1.80 (m, 2H).CIMS MH+ 456.
7200
Figure imgf000348_0001
Example 219 [4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyllmethionine
7205
Example 219A 5 -pyrimidinecarboxylic 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
7210 g, 20 mmol) in DMF was stiπed at 90 °C 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 vacuo. The residue was then purified by column chromatography (50:50: 10 hexane-dichloromethane-ether) to give 3-
7215 pyrimidinecarboxylic acid methyl ester (715 mg, 52%). !H NMR (300 MHz, CDCI3) δ 9.38 (s, IH), 9.30 (s, 2H), 4.36 (t, 2H), 1.83 (sextet, 2H), 1.05 (t, 3H).
Example 219B [4-(5-pyrimidylcarboxyamino)-2-phenylbenzoynmethionine methyl ester
7220 A mixture of the 5-pyrimidinecarboxylic acid methyl ester prepared in Example 219 A
(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 vacuo. 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
7225 (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), l-(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 vacuo. The
7230 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%). lΗ NMR (300 MHz, CDCI3) δ 9.34 (s, IH), 9.19 (s, 2H), 9.01 (s, IH), 7.64 (d, IH), 7.52 (d, IH), 7.42 (dd, IH), 7.33 (m, 5H), 6.20 (br d, IH), 4.66 (m, IH), 3.69 (s, 3H), 2.14 (t, 2H), 2.02 (s, 3H), 1.95 (m, IH), 1.78 (m, IH). MS (CI+) m/e 465 7235 (M+H)+.
Example 219C r4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyllmethionine To a solution of the [4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine 7240 methyl ester prepared in Example 21 OB (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 7245 acetate, then 95:5:0.5 ethyl acetate-methanol-acetic acid)to give [4-(3- pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine (265 mg, 84%). H NMR (300 MHz, DMSO-d6) δ 10.80 (s, IH), 9.38 (s, IH), 9.30 (s, 2H), 8.51 (d, IH), 7.83 (m, 2H), 7.50 (d, IH), 7.39 (m, 5H), 4.29 (m, IH), 2.28 (m, 2H), 2.00 (s, 3H), 1.86 (m, 2H). MS (APCI+) m/e 451 (M+H)+. 7250
Figure imgf000349_0001
Example 231 r4-(3-piperidinecarboxyamino -2-phenylbenzoyllmethionine hydrochloride
7255
Example 231 A l-tert-butoxycarbonylpiperidine-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) 7260 and the reaction mixture was stiπed 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.
7265 Example 23 IB 4-("l-tert-butoxycarhonylpiperidin-3-ylcarboxyamino)-2-phenylhenzovnmethionine methyl ester The desired compound was prepared by coupling of the product of Example 231 A and (4-amino-2-phenylbenzoyl)methionine methyl ester (compound 8) according to the 7270 method of Example 186C.
Example 231C 4-(l-fert-butoxycarbonylpiperidin-3-ylcarboxyamino)-2-phenylbenzoyllmethionine The desired compound was prepared by saponification of the product of Example 7275 23 IB according to the procedure of Example 159.
Example 23 ID r4-(3-piperidinecarboxyamino -2-phenylbenzoyllmethionine hydrochloride The product of Example 231C was deprotected with 4N HCl-dioxane using the 7280 procedure of Example 229B. JH nmr (300 MHz, D2O) δ 7.37 - 7.60 (m, 8H), 4.44 (dd,
IH), 3.46 (dd, IH), 3.31 (m, 2H), 1.14 (m, IH), 3.02 (m, IH), 1.71 - 2.1 1 ι m, 8H), 2.02 (s, 3H). MS (CI NH3) M/e 456 (M+H+, 438, 408, 339, 307, 196. Anal calcd for C24H30C1N3O4S»2.54 H2O: C, 53.60; H, 6.57; N, 7.59. Found: C, 53.60; H, 6.19; N 7.59. 7285
Figure imgf000350_0001
Example 283 [4-( lH-4-trifluoro methyl- 1.2-dihydropyrid-3-ylcarbonylamino -2-phenylbenzoyl1methionine 7290 sodium salt
Example 283A (4-nitro-2-phenylbenzoyl methionine 2-trimethylsilylethyl ester A mixture of £4-nitro-2-phenylbenzoyl)methionine methyl ester (7.69 g, 30 mmol), 7295 prepared as in Example 192 A 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
7300 mL) and 2-trimethylsilylethanol (3.72 g, 31.5 mmol), 1 ,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 vacuo. The residue was purified by column
7305 chromatography (5% ethyl ether-hexane) to give the title compound (8.90 g, 87%).
Example 283B (4-amino-2-phenylbenzoyl)methionine 2-trimethylsilylethyl ester A mixture of the product of Example 283A (8.85 g, 25.8 mmol), ammonium formate 7310 (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. 7315
Example 283C 4-(4-trifluoromethylpyrid-3-ylcarbonylamino)-2-phenylbenzoic acid 2-trimethylsilylethyl ester A mixture of 4-trifluoromethylnicotinic acid (472 mg, 2.46 mmol), the product of 7320 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 stiπed 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 7325 chromatography (30% ethyl acetate-hexane) to give the title compound (1.04 g, 87%).
Example 283D 4-( lΗ-4-trifluoro methyl- 1.2-dihydropyrid-3-ylcarbonylamino -2-phenylbenzoic acid 2- trimethylsilylethyl ester 7330 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 °C 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 7335 chromatography (30% ethyl acetate-hexane) to give the title compound (247 mg, 24%).
Example 283E |"4-( lH-4-trifluoromethyl-1.2-dihydropyrid-3-ylcarbonylamino)-2-phenylbenzoyll methionine methyl ester 7340 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 1 hour. To the residue was added -methionine methyl ester hydrochloride (1 15 mg, 0.58 mmol), 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (163 mg, 1.0 mmol), l-(3- 7345 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%). 7350
Example 283F [4-(lΗ-4-trifluoromethyl-1.2-dihydropyrid-3-ylcarbonylamino)-2-phenylbenzoyllmethionine sodium salt The desired compound was prepared by saponification of the product of Example 7355 283E using the procedure of Example 276. !H .NMR (300 MHz, DMSO-d6) δ 9.67 (s, IH), 8.87 (br s, IH), 7.68 (m, 2H), 7.54 (s, IH), 7.41-7.30 (m, 6H), 7.03 (dd, IH), 6.51 (d, IH), 4.67 (t, IH), 4.48 (m, IH), 3.78 (m, IH), 2.14 (m, 2H), 1.96 (s, 3H), 1.77 (m, 2H). MS (APCI+) m/e 520 (M+H)+.
7360
Figure imgf000352_0001
Example 286 4-(2-piperazinylmethylaminoV2-phenylbenzoyllmethionine
7365 Example 286A J -tgrt-butvoxycarbonylpiperidine-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 stiπed for 16 hours and then was
7370 concentrated under reduced pressure to remove THF. The aqueous solution was saturated with NaHCU3 (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 CH2CI2 (3x), and the organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide the desired compound (7.61 g, 98% as
7375 a tan solid.
Example 286B J.-fert-butyoxycarbonylpiperidine-2-carboxylic acid /V-methyl /V-methoxy amide Triethylamine (1.75 g, 17.1 mmol) was added dropwise to a solution of N,0- 7380 dimethylhydroxylamine hydrochloride (0.741 g, 7.44 mmol), the product of Example 286A (2.46 g, 7.44 mmol), 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (1.61 g, 9.67 mmol), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.89 g, 9.67 mmol) in DMF (75 mL). The reaction mixture was stiπed at ambient temperature for 20 hours and then concentrated under reduced pressure (50 °C, 0.1 mm Ηg). The residue was dissolved in ethyl acetate (70 7385 mL), and the solution was extracted with saturated aqueous NaΗCU3 (3x) and brine. The organic phase was dried (MgSO4) 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 lU NMR.
7390 Example 286C
J -tert-butyoxycarbonylpiperidine-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
7395 -50 °C. The addition of saturated aqueous KHSO4 (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.
7400
Example 286D r4-(J -terr-butoxycarhonylpiperazin-2-ylmethylamino)-2-phenylbenzoyllmethionine methyl ester The aldehyde prepared in Example 286C (0.599 g, 1.71 mmol) was added to a
7405 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, Νa(CΝ)BH3 (0.147 g, 2.22 mmol) was added in two portions and the mixture was stiπed for 15 hours before concentration under reduced pressure provided a waxy residue. Flash column
7410 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. Η NMR (CDC13): 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
7415 (br, 1 H), 4.60-4.72 (br, 1 H), 5.63-5.74 (br, 1 H), 6.44-6.58 (br, 1 H), 6.58-6.80 (br, 1 H), 7.33-7.52 (comp, 5 H), 7.72 (d, 1 H). LRMS (CI): 657 (M+l)+.
Example 286E r4-(2-piperazinylmethylamino)-2-phenylbenzoyllmethionine
7420 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
7425 (79.3 mg, 24%) as the bis-hydrochloride, mono-sodium chloride salt. !H NMR (300 MHz, CD3OD) d 1.71-1.85 (m, IH), 1.91-2.00 (m, IH), 2.02 (s, 3H), 2.02-2.15 (m, IH), 2.15-2.27 (m, IH), 3.32-3.56 (comp, 3H), 3.56-3.75 (comp, 4H), 3.75-3.96 (br, 2H), 4.45 (dd, IH), 6.73 (s, IH), 6.81 (d, IH), 7.30-7.50 (comp, 6H). LRMS (CI) m/e 443 (M+H)+.
7430
Figure imgf000354_0001
Example 302 r4-(2-furylmethylamιnomethyl)-2-phenylbenzoyllmethιonιne lithium salt 7435
Example 302A 4-(2-furylmethylamιnomethyl)-2-phenylbenzoιc acid methyl ester To a stiπed soltuion of 4-carboxaldehyde-2-phenylbenzoιc acid methyl ester (0 73 g, 3 0 mmol), prepared as in Example 160B, in methanol (15 mL) was added furfurylamine 7440 (0 33 g, 3 4 mmol), sieves (~ lg), NaBH3CN (0 29 g, 4 6 mmol) and acetic acid (~0 3 mL) to pH = 6. The mixture was stiπed 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 7445 give the desired compound (0 72 g, 73%) as an opaque yellow paste
Example 302B r4-(2-furylmethylamιnomethyl)-2-phenylbenzoyllmethιonιne methyl ester The desired compound was prepared by saponification of the product of Example 7450 302A, followed by coupling with methionine methyl ester hydrochloride according to the method of Examples 299C and D.
Example 302C r4-(2-furylmethylamιnomethyl)-2-phenylbenzoyllmethιonιne methyl ester
7455 To a stiπed solution of the product of Example 302B (56 mg, 0.12 mmol) in THF (2 mL) was added a solution of L1OH H2O (5.5 mg, 0.13 mmol) in H2O ( 1 mL) and the resulting solution stiπed for 3 hours at ambient temperature. The reaction was concentrated in vacuo, diluted with H2O, filtered and lyophohzed to give the title compound (57 mg, 97%) as a white powder. lH NMR (300 MHz, DMSO-d6, 90 °C) δ 7 48-7 24 (m, 9H),
7460 7 07-7 04 (m, IH), 6.37-6.34 (m, IH), 6.24-6.20 (m, IH), 3 76-3 69 (m, 5H), 2 43-2.16 (m, 3H), 2.00-1.66 (m, 5H) MS m/z 439 (M+ 1)+ Anal calcd for C24H25L1N2O4S 2 H2O (480.50)- C, 59.99; H, 6 08; N, 5.83. Found: C, 59.83; H, 5 83; N, 5.74.
Figure imgf000355_0001
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.
7470 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 h at 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.
7475 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-0.1% Trifluoroacetic acid and finishing with 100% acetonitrile-0.1 % Trifluoracetic acid during a 30
7480 minute period was used. For the secondary amines a gradient beginning with 100% water- 5mmol ammonium acetate and finishing with 80% acetonitrile-water-5mmol 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
7485 N-methylpyπolidone (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 ( 5 eq.); and finally 0.20 mL of a 0.90 M Bromo-tris-pyπolidino-phosphonium hexafluorophosphate (PyBrop; 5 equiv.) l/NMP
7490 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; 5x; 1.0 mL; 3 min. ea.); NMP (3x; 1.0 mL; 3 min. ea.); methanol (MEOH; 2x; 1.0 ml; 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.
7495
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000357_0002
Examples 358
7500 90 mg of resin (substitution 0 39 mmol/g.) containing [4-amιno-2- phenylbenzoyl]methιonιne-Wang-polystyrene resin was shaken with 1.0 mL dimethylformamide (DMF) for 3 mm. 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 (vv) (4x; 1.0 mL; 3 min. ea.) The resin was then treated
7505 with 0.20 mL of DCM THF (1: 1) and a 1.0 mL solution of 0.50 M p-
Nιtrophenylchloroformate/0.50 M DIEA 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
7510 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 DIEA. 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
7515 as described above.
Figure imgf000357_0003
Figure imgf000358_0001
7520 Examples 360-362
Examples 364-366 Examples 369-374 Examples 377-378 Example 381 7525 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 7530 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. 7535 ea.); MEOH ( 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 R3 1 MS (M+H)±
Figure imgf000358_0002
Figure imgf000359_0001
370 425
N-N
H
371 tl 458 N' N^
H3C ri
372 H3C^ 441
II O-N 373 H- 457
N-S 374 S H N^- N. 443
U
377 O^ 487
Figure imgf000359_0002
7540
Examples 395 and Example 398 The following compounds were prepared using the materials and methods described above. 7545
Example
Figure imgf000360_0001
Figure imgf000360_0002
Example 403 7550 \4-( 1 -ethylthio-3-cyclohexylprop-2-ylaminomethyl -2-(2-methylphenyl)benzoyll methionine. The desired compound was prepared according to the method of Example 349A except substituting (S)-(+)-l-ethylthio-3-cyclohexyl-2-propylamine hydrochloride for (S)- (+)-2-amino-3-cyclohexyl-l-propanol hydrochloride. lU NMR (DMSO-d6, 300 MHz) δ 8.02 (m, IH), 7.50-7.38 (m, 2H), 7.22-7.05 (m, 4H), 4.21 (m, IH), 3.88-3.78 (m, 2H), 7555 2.74-2.60 (m, 2H), 2.51 (s, 3H), 2.44 (q, 7=7.5 Hz, 2H), 2.22- 1.95 (m, 5H), 1.88-1.50 (m, 7H), 1.45-1.25 (m, 4H), 2.21-1.02 (m, 3H), 1.12 (t, 7=7.5 Hz, 3H), 0.90-0.70 (m, 2H). MS (CI/NH3) m/e: 557 (M+H)+ Anal calcd for C31H44N2O3S2 • 1.15 H2O: C, 64.47; H, 8.08; N, 4.85. Found: C, 64.48; H, 7.84; N, 4.72.
7560
Figure imgf000361_0001
Example 406 4-(N-benzyl-N-phenyl)-aminomethyl-2-(2-methylphenyl')benzoylmethionine The desired compound was prepared according to Example 273 except substituting
7565 N-benzylaniline for 2-thiophenemethanol in Example 273A.
!H NMR (CD3OD): δ 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+l)+.
7570
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.
7575
Figure imgf000361_0002
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000363_0002
Example 475 7580 N-[4-N-(2.2-dibenzyl-3-hydroxypropyl amino-2-(2-methylphenyl)benzoyllmethionine sodium salt The desired compound was prepared according to the method of Examples 25 A -25B JH nmr (300 MHz, DMSO-d6): δ 7.40 (d, 1 H), 7.25-7.10 (m, 15 H), 6.65 (m, 1 H), 6.27 (d, 1 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), 7585 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)+.
Figure imgf000363_0003
7590 Example 476
N-[4-N-(2-benzyI-3-hydroxypropyl amino-2-(2-methylphenyl')benzoyllmethionine sodium salt The desired compound was prepared according to the method of Examples 25 A -25B lH nmr (300 MHz, DMSO-d6): δ 7.35 (d, 1 H), 7.28-7.10 (m, 10 H), 6.50 (m, 1 H), 6.16 7595 (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, 1 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)+.
7600
Figure imgf000364_0001
Example 479 N-[4-N-(2-cyclohexylmethyl-3-hydroxypropyl)amino-2-(2- methylphenyDbenzoyllmethionine
7605 The desired compound was prepared according to the method of Examples 25 A -25B lH nmr (300 MHz, DMSO-d6): δ 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 -): m/e 51 1 (M-H)-.
7610
Figure imgf000364_0002
Example 481 N-[4-N-(4-trifluoromethylnicotinoyl amino-2-(2-methylphenyl')benzoyllmethionine 7615 lithium salt
The desired compound was prepared according to the method of Example 57. 'H nmr (300 MHz, DMSO-d6): δ 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, 1 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 7620 530 (M-H)-.
Figure imgf000365_0001
Example 502 7625 N-[4-N-2-hvdroxyethylamino-2-phenylbenzoynmethionine
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. Η NMR (CD3OD): δ 1.68-1.81 (m, 1 H), 1.89-2.10 (m. 1 H), 2.01 (s, 3 H), 2.02-2.24 (comp, 2 H), 3.28 (t, 7= 5.9 Hz, 2 H), 3.72 (t, 7= 5.9 Hz, 2 H), 4.44 7630 (dd, 7= 4.4, 9.2 Hz, 1 H), 6.57 (d, 7= 2.3 Hz, 1 H), 6.65 (dd, 7= 2.4, 8.5 Hz. 1 H), 7.28- 7.44 (comp, 6 H). LRMS (CI): 389 (M+l)+
Figure imgf000365_0002
7635 Example 503
N-[4-(N-2-amino-3-benzyloxypropionyl amino-2-phenylbenzoyl]methionine The desired compound was prepared according to the method of Example 57 ^H NMR (CD3OD): δ 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, 7= 12.2, 29.2 Hz, 2 7640 H), 7.23-758 (comp, 1 1 H), 7.62-7.70 (comp, 2 H). LRMS (CI): 522 (M+l of free base)+
Figure imgf000366_0001
Example 504 7645 N- 4-N-(furan-2-ylmethyl)-N-benzylaminomethyl-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 Η NMR (CD3OD): δ 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), 7650 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+l of protonated acid)+.
Figure imgf000366_0002
7655 Example 505
N-r4-N-phenyl-N-benzylaminomethyl-2-phenylbenzoynmethionine The desired compound was prepared according to the method of Example 157 JH NMR (d6-DMSO): δ 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), 7660 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, 7= 7.7 Hz, 1 H). LRMS (CI): 479 (M+l)+.
Figure imgf000367_0001
7665 Example 506
N-[4-N-(2-benzylphenyl)aminomethyl-2-(2-methylphenyl')benzoyllmethionine The desired compound was prepared according to the method of Example 157 Η NMR (CD3OD): δ 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 7670 (m, 1 H). LRMS (CI): 539 (M+l)+, 556 (M+NH4)+.
Figure imgf000367_0002
Example 507
7675 N-r4-N-(2-phenyl)ethyl-N-phenyl aminomethyl-2-(2-methylphenyl)benzoyl1methionine The desired compound was prepared according to the method of Example 157 !H NMR (CD3OD): δ 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 (ESL): 551 (M-l)-.
7680
Figure imgf000367_0003
Example 508 N-r4-N-(3-phenylN)propyl-N-phenyl)aminomethyl-2-(2-methylphenyl benzoyllmethionine 7685 The desired compound was prepared according to the method of Example 157 'H
NMR (CD3OD): δ 1.45- 1.62 (m, 1 H), 1.63-2.05 (comp, 1 1 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 (ESL): 565 (M-l)-.
7690
Figure imgf000368_0001
Example 509 N-r4-N-(2,2-diphenyl')ethyl-N-phenylN)aminomethyl-2-(2-methylphenyl)benzoyllmethionine
The desired compound was prepared according to the method of Example 157 lH
7695 NMR (d6-DMSO): δ 1.46-2.02 (comp, 10 H), 3.38-3.42 (m, 1 H), 3.61-3.73 (br , 1 H), 4.16 (d, 7= 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+l)+.
7700
Figure imgf000368_0002
Example 510 N- 4-N-(adamantan-l-ylmethyl)-N-phenyl aminomethyl-2-(2- methylphenyDbenzoyllmethionine
7705 The desired compound was prepared according to the method of Example 157 Η NMR (d6-DMSO): δ 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, 7= 8.0 Hz, 1 H). LRMS (CI): 597 (M+l)+.
7710
Figure imgf000369_0001
Example 511 N-[4-N-(2-adamantan-l-ylethyl)-N-phenyl)aminomethyl-2-(2- 7715 methy lpheny Dbenzoy 11 methionine
The desired compound was prepared according to the method of Example 157 Η NMR (d6-DMSO): δ 1.28-1.37 (comp, 2 H), 1.47-1.71 (comp, 15 H), 1.88-2.10 (comp, 1 1 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, 7= 7.1 Hz, 1 H), 6.63 (d, 7= 8.1 Hz, 2 H), 6.88-6.94 (br m, 1 H), 6.97 (d, 7= 1.3 Hz, 1 H), 7.07- 7720 7.21 (comp, 5 H), 7.27 (dd, 7= 1.7, 7.8 Hz, 1 H), 7.49 (d, 7= 8.2 Hz, 1 H). LRMS (ESL ): 609 (M-1)-.
Figure imgf000369_0002
7725 Example 512 N-[4-N.N-dibenzylaminomethyl-2-(2-methylphenyl benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158 Η NMR (d6-DMSO): δ 1.44-2.17 (comp, 10 H), 3.33-3.77 (comp, 7H), 6.90-7.56 (comp, 17 H). LRMS (ESI-): 551 (M-l of protonated acid)-.
7730
Figure imgf000370_0001
Example 513 N-[4-N-(2-phenylethyl -N-benzylaminomethyl-2-(2-methylphenyl)benzoyllmethionιne 7735 lithium salt
The desired compound was prepared according to the method of Example 158 ^H NMR (d6-DMSO): δ 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), 7740 8.32 (d, 7= 7.3 Hz, 1 H), 1 1.42-1 1.64 (br, 1 H), 12.35-12.55 (br, 1 H). LRMS (CI): 567 (M+l)+.
Figure imgf000370_0002
7745 Example 514
N-r4-N-(3L-phenoxybenzyl)-N-benzylaminomethyl-2-(2-methylphenyl)benzoynmethionine lithium salt The desired compound was prepared according to the method of Example 158 *H NMR (d6-DMSO): δ 1.65-1.90 (comp, 2 H), 1.95 (s, 3 H), 1.96-2.22 (comp, 5 H), 3.42- 7750 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+l)+.
Figure imgf000371_0001
7755 Example 515
N-[4-N-('2-hydroxyethyl)-N-benzylaminomethyl-2-phenylbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 ]H NMR (d6-DMSO): δ 1.75-1.97 (comp, 2 H), 2.00 (s, 3 H), 2.15-2.34 (comp, 2 H), 3.00- 3.1 1 (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), 7760 7.43-7.55 (comp, 6 H), 7.64-7.79 (comp, 4 H), 8.66 (d, 7= 7.7 Hz, 1 H). LRMS (CI): 493 (M+l)+.
7765 Example 516
N- 4-N-methyl-N-(2-phenyethyl aminomethyl-2-(2-methylphenyl')benzoyl1methionine lithium salt The desired compound was prepared according to the method of Example 158 'H NMR (d6-DMSO): δ 1.65-1.91 (comp, 2 H), 1.96 (s, 3 H), 1.99-2.28 (comp, 5 H), 2.75 7770 (s, 1 H), 3O5-3.25 (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, 7= 7.0 Hz, 1 H), 11.10-11.26 (br, 1 H), 12.50-12.86 (br, 1 H). LRMS (CI): 491 (M+l)+.
7775
Figure imgf000372_0001
Example 517 N-r4-N-benzyl-N-pyrazin-2-ylaminomethyl-2-(2-methylphenyl benzoyllmethionine lithium salt 7780 The desired compound was prepared according to the method of Example 157 'H
NMR (d6-DMSO): δ 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, 7= 8.1 Hz, 1 H), 7.80 (d, 7= 2.6 Hz, 1 H), 8.04-8.05 (m, 1 H), 8.07-8.10 (m, 1 H). LRMS (ESL): 539 (M- 1 of protonated acid)-. 7785
Figure imgf000372_0002
Example 518 N-r4-N-(2-phenyethyl -N-pyrimidin-5-ylaminomethyl-2-(2- 7790 methylphenyDbenzoyllmethionine lithium salt
The desired compound was prepared according to the method of Example 157 !H NMR (d6-DMSO): δ 1.46-2.05 (comp, 10 H), 2.88 (t, 7= 7.5 Hz, 2 H), 3.56-3.65 (br, 1 H), 3.73 ( 7= 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, 7= 7.8 Hz, 1 H), 8.23 (s, 2 H), 8.41 (s, 1 H). LRMS (ESL): 553 (M-l of 7795 protonated acid)-.
Figure imgf000373_0001
Example 519
7800 N-[4-N-(2-indol-3-ylethyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 *H NMR (300 MHz, DMSO) δ 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, IH), 3.79 (m, 2H), 6.88-6.93 (m, IH), 6.93 (ddd, 7=6.8, 6.8, 1.0 Hz, IH), 7.03 (ddd, 7=6.8, 6.8, 1 Hz, IH), 7.10 (d,
7805 7=2.1 Hz, IH), 7.10-7.23 (m, 5H), 7.30 (d, 7=8 Hz, IH), 7.36 (dd, 7=8 Hz, IH), 7.46 (d, 7=7.8 Hz, IH), 7.47 (d, 7=7.8 Hz, IH). MS (ESI(+)) m/z 516 (M+H)+. Anal calcd for C30H32N3O3SL .3OH2O: C, 66.1 1 ; H, 6.40; N, 7.71. Found: C, 66.15; H, 6.38; N, 7.64.
7810
Figure imgf000373_0002
Example 520 N-r4-N-(2-cyclohexyl-l-ethan-l-ol-2-yl aminomethyl-2-(2- methylphenyllbenzoyllmethionine lithium salt
7815 The desired compound was prepared according to the method of Example 158 ^H NMR (300 MHz, DMSO) δ 0.93-1.19 (m, 6H), 1.35-1.77 (m, 4H), 1.77-2.06 (m, 7H), 1.91 (s, 3H), 2.18 (brs, IH), 2.26 (m, 3H), 3.40-3.48 (m, IH), 3.59-3.70 (m, IH), 3.73 (d, 7= 14.2 Hz, IH), 3.81 (d, 7= 13.9 Hz, IH), 4.36 (brs, IH), 6.87-7.00 (m, IH), 7.1 1- 7.27 (m, 5H), 7.36 (d, 7=8 Hz, IH), 7.47 (d, 7=8 Hz, IH). MS (ESI(+)) m/z 499
7820 (M+H)+. Anal calcd for C28H37N2θ4SLi»0.75H2O: C, 64.91; H, 7.49; N, 5.41. Found: C, 64.92; H, 7.39; N, 5.21.
Figure imgf000374_0001
7825 Example 523
N- F4-N-C 1.3-diphenylpropan-2-yl aminomethy l-2-(2-methylphenyl)benzoynmethionine lithium salt The desired compound was prepared according to the method of Example 158 ^H NMR (300 MHz, DMSO) δ 1.48-1.74 (m, 2H), 1.74-2.02 (m, 3H), 1.93 (s, 3H), 2.03- 7830 2.14 (m, 2H), 2.54-2.73 (m, 4H), 2.97 (pentet, 7=6.5 Hz, IH), 3.63-3.72 (brs, IH), 3.78 (s, 2H), 6.90 (brs, 2H), 7.05-7.26 (m, 16H), 7.37 (d, 7=7.8 Hz, IH). MS (ESI(+)) m/z 567 (M+H)+. Anal calcd for C35H37N2θ3SLi»0.90H2O: C, 71.38; H, 6.64; N, 4.76. Found: C, 71.40; H, 6.28; N, 4.69.
7835
Figure imgf000374_0002
Example 524 N-[4-N-(1.3-dicyclohexylpropan-2-yl aminomethyl-2-(2-methylphenyl benzoynmethionine lithium salt
7840 The desired compound was prepared according to the method of Example 158 *H NMR (300 MHz, DMSO) δ 0.70-0.88 (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, IH), 7.04-7.24 (m, 5H), 7.36 (dd, 7=8, 1 Hz, IH), 7.45 (d, 7=8 Hz, IH). MS (ESI(+)) m/z 579 (M+H)+. Anal calcd for 7845 C35H49N2θ3SLi.0.75H2O: C, 70.26; H, 8.51 ; N, 4.68. Found: C, 70.25; H, 8.52; N. 4.57.
Figure imgf000375_0001
7850 Example 526 N-r4-N-(l-Cyclohexyl-6-methylhept-3-en-2-yl aminomethyl-2-(2- methylphenyDbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 H NMR (300 MHz, DMSO) δ 1.74-0.86 (m, 7H), 1.02-1.19 (m, 4H), 1.27-1.38 (m, 2H),
7855 1.46- 1.87 (m, 14H), 1.93 (s, 3H), 1.99 (s, 3H), 2.17 (m, IH), 3.51-3.82 (m, 3H), 5.1 1 (m, IH), 5.43 (m, IH), 6.83-6.96 (m, IH), 7.00-7.24 (m, 5H), 7.24-7.36 (m, IH), 7.47 (d, 7=7 Hz, IH). MS (APCI(+)) m/z 565 (M+H)+. Anal calcd for
C34H47N2O3SLi«2.02H O: C, 67.20; H, 8.48; N, 4.61. Found: C, 67.24; H, 8.35; N, 4.47.
7860
Figure imgf000375_0002
Example 527 N-[4-N-(l-Cyclohexyl-6-methylheptan-2-yl)aminomethyl-2-(2- 7865 methylphenyl benzoyl]methionine lithium salt
The desired compound was prepared according to the method of Example 158 H NMR (300 MHz, DMSO) δ 0.80 (d, 7=5 Hz, 3H), 0.82 (d, 7=5 Hz, 3H), 1.02-1.40 (m, 12H), 1.40-1.65 (m, 12H), 1.75-1.83 (m, IH), 1.92 (s, 3H), 1.99 (m, IH), 2.16 (m, IH), 2.43 (m, IH), 3.60-3.77 (m, 3H), 6.86-6.95 (m, IH), 7.08-7.22 (m, 5H), 7.35 (d, 7=8.0
7870 Hz, IH), 7.47 (d, 7=8.0 Hz, IH). MS (APCI(+)) m/z 567 (M+H)+. Anal calcd for C34H49N2O3SLM .15H2O: C, 66.99; H, 8.48; N, 4.60. Found: C, 67.03; H, 8.62; N, 4.49.'
Figure imgf000376_0001
Example 528 N-r4-N-(l-Cyclohexyl-2.3-dihydroxy-6-methylheptan-2-yl)aminomethyl-2-(2- methylphenyDbenzoyllmethionine The desired compound was prepared according to the method of Example 158 H
7880 NMR (300 MHz, DMSO) δ 0.72-1.35 (m, 10H), 0.85 (d, 7=7 Hz, 3H), 0.87 (d, 7=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, IH), 3.58 (s, IH), 3.96-4.14 (m, 2H), 4.40-4.59 (m, 2H), 4.99-5.23 (m, 4H), 6.08-6.10 (m, IH), 7.17-7.35 (m, 5H), 7.55 (m, IH), 7.74 (m, IH), 8.80 (brs, 0.5H), 9.25 (brs, 0.5H). MS (DCI/NH3) m/z 599 (M+H)+. Anal, calcd for C34H5θN2θ5S»1.55H2O«1.05TFA: C,
7885 55.70; H, 6.90; N, 3.51. Found: C, 55.72; H, 6.91; N, 3.38.
Figure imgf000377_0001
Example 529 7890 N-r4-N-(l-Cvclohexyl-2.3-dihvdroxy-6-methylheptan-2-yl) aminomethyl-2-(2-methylphenyl benzoyllmethionine The desired compound was prepared according to the method of Example 158 ^H NMR (300 MHz, DMSO) δ 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, IH), 3.59 (m, IH), 3.39-4.10 (m, IH), 4.38-4.55 7895 (m, IH), 4.60-4.90 (m, 4H), 6.10 (m, IH), 7.20-7.40 (m, 5H), 7.55 (m, IH), 7.80 (m, IH), 9.0 (brs, IH). MS (DCI/NH3) m/z 599 (M+H)+. Anal calcd for C34H50N2O5S .OOH2OA85TFA: C, 54.70; H, 6.56; N, 3.38. Found: C, 54.70; H, 6.59; N, 3.27.
7900
Figure imgf000377_0002
Example 537 N- 4-("3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl)-2-(2- methylphenyDbenzoyll methionine lithium salt
7905 The desired compound was prepared according to the method of Examples 158 Η NMR (MeOH-^) δ 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, 7= 3.4 Hz), 4.46-4.38 ( , 1 H), 4.10 (d, 2 H, 7= 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).
7910
Figure imgf000378_0001
Example 538 N-[4-(3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl -2-(2- 7915 methylphenyDbenzoyllmethionine methyl ester
The desired compound was prepared according to the method of Example 158 Η NMR (CDCI3) δ 7.93 (dd, 1 H, 7= 17.7, 8.6 Hz), 7.42-7.27 (m, 6 H), 7.22-7.19 (m, 4 H), 6.67 (dd, 1 H, 7= 8.8, 2.4 Hz), 6.52 (bs, 1 H), 6.33 (d, 1 H, 7= 2.4 Hz), 6.15 (dd, 1 H, 7= 3.4, 1.7 Hz), 5.70 (t, 1 H, 7= 8.7 Hz), 5.52 (d, 1 H, 7= 3.4 Hz), 4.62-4.55 (m, 1 7920 H), 4.30-4.27 (m, 1 H), 4.14-4.1 1 (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).
Figure imgf000378_0002
7925 Example 540
N- [4-N-pheny lacety lamino-2-f 2-methylphenyl)benzoy 11 methionine lithium salt The desired compound was prepared according to the method of Example 57 Η NMR (DMSO- 5) δ 10.42 (s, 1 H), 7.60 (d, 1 H, 7 = 8.5 Hz), 7.51 (d, 1 H, 7 = 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 7930 and s, 3 H otal), 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).
Figure imgf000379_0001
7935 Example 541
N- 4-N-(4,-methylphenylacetyl)amino-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 57 IH NMR (DMSO-J6) δ 10.40 (s, 1 H), 7.60 (d, 1 H, 7= 7.9 Hz), 7.51 (d, 1 H, 7= 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), 7940 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).
Figure imgf000379_0002
Example 542 7945 N-[4-N-(4'-methoxyphenylacetyl amino-2-(2-methylphenyl benzoyUmethionine lithium salt The desired compound was prepared according to the method of Example 57 !H NMR (DMSO-J6) δ 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 7950 m/z 507 (M+ + 1, 100).
Figure imgf000379_0003
Example 543 7955 N-r4-N-(3-phenylpropionoyl)amino-2-(2-methylphenyπbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 57 'H NMR (DMSO-J6) δ 10.17 (bs, 1 H), 7.60 (d, 1 H, 7= 7.9 Hz), 7.51 (d, 1 H, 7= 8.6 Hz), 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, 7= 7.9 Hz), 2.64 and 2.15 (2t, 2 H total, 7= 7.9 Hz), 2.17-1.83 (m, 8 H), 1.71- 1.64 (m, 1 H),
7960 1.59- 1.53 (m, 1 H); MS m/z 491 (M+ + 1, 100).
Figure imgf000380_0001
Example 544 7965 N-r4-N-(3-(2-methoxyphenyl)propionoyl amino-2-(2-methylphenyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 57 'H NMR (DMSO-J6) δ 10.10 (bs, 1 H), 7.59 (d, 1 H, 7= 7.9 Hz), 7.50 (d, 1 H, 7= 8.6 Hz), 7.45 (bs, 1 H), 7.22-7.09 (m, 6 H), 6.96 (d, 1 H, 7= 7.9 Hz), 6.89-6.79 (m, 3 H), 3.78 7970 and 3.76 (2s, 3 H total), 2.86 and 2.69 (2t, 2 H total, 7= 7.9 Hz), 2.59 and 2.07 (2t, 2 H total, 7= 7.9 Hz), 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).
Figure imgf000380_0002
Example 548 N-r4-N-benzyl-N-(thiazol-2-ylmethyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine
The desired compound was prepared according to the method of Example 158 Η nmr (300 MHz, DMSO d6): δ 8.09, d, IH; 7.72, d, IH; 7.66, d, IH; 7.50, m, 2H; 7.38, 7980 m, 4H; 7.23, m, 4H; 7.14, m, 2H; 4.20, ddd, IH; 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 C3 iH33iN3θ3S2'0.32 H2O: C 65.84, H 6.00, N 7.43: Found: C 65.85, H 5.75, N 7.34
Figure imgf000381_0001
Example 549
N-r4-N-benzyl-N-(thiazol-5-ylmethyl aminomethyl-2-(2-methylphenyl)benzoyllmethionine
The desired compound was prepared according to the method of Example 158 ' H nmr (300 MHz, DMSO d6): δ 12.45, bs, IH; 9.03, s, IH; 8.12, d, IH; 7.79, s, IH; 7.48,
7990 dd, 2H; 7.35, m, 4H; 7.04 - 7.28, m, 6H4.21 , ddd, IH; 3.81 , s, 2H; 3.61, s, 2H; 3.58, s,
IH; 1.98 - 2.21, 5H; 1.96, s, 3H; 1.61 - 1.89, m, 2H. MS (APCI(+)) 560 (MH+). Calc'd for C3iH33iN3O3S2»0.78 H2O: C 64.89, H 6.07, N 7.32: Found: C 64.89, H 5.71, N
7.29
7995
Figure imgf000381_0002
Example 596 N-r4-N-(4-trans-pentafluoropheynyloxycyclohexyl)aminomethyl-2-(2- methy lpheny Dbenzoy 11 methionine 8000 A solution of tran_?-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 stiπed 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 8005 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 stiπed 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 8010 to provide 160 mg of the title compound. MS m/e 635 (M-H)-. 'H NMR (CDC13, 300
MHz) δ 1.5 (m, 4H), 1.79 (m, IH), 2.05 (m, 12H), 2.81 (m, IH), 4.05 (m, 4H), 6.25 (m, IH), 6.81 (m, 2H), 7.1-7.7 (m, 7H).
Figure imgf000382_0001
Example 598 N-r4-(N-2-phenethyl-N-butanesulfonylaminomethyl)-2-(2- methylpheny benzoyllmethionine 8020 The desired compound was prepared according to the method of Example 157. XH
(300MHz, DMSO-d6, δ) 7.62 (IH, d, J=7Hz), 7.52 ( IH, dd, J=7&2Hz), 7.20-7.10 (10H, m), 7.14 ( IH, bd, J=7Hz), 4.65 (2H, bs), 3.76 (IH, 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 C32H39LiΝ2θ5S2-0.50 H2O C 8025 62.83, H 6.59, N 4.38 Found C 62.59, H 6.59, N 4.44
Figure imgf000382_0002
Example 604 N- [4-(2-cvclohexylethan- 1 -ol-2-ylaminomethyl)-2-(2-methylphenyl)benzoyll methionine 8030 Lithium Salt
The desired compound was prepared according to the method of Example 158. ^H NMR (DMSO-d6, 300 MHz) δ 7.48 (d, 7=8 Hz, IH), 7.37 (dd, 7=8, 1 Hz, IH), 7.20-7.08 (m, 4H), 6.90 (m, IH), 4.40 (t, 7=5 Hz, IH), 3.82-3.65 (m, 3H), 3.46 (m, IH), 3.31 (m, IH), 2.28-2.12 (m, 2H), 2.02-1.80 (m, 7H), 1.77- 1.37 (m, 8H), 1.18-0.92 (m, 5H); Anal. 8035 Calcd for C28H37LiN2θ4S- 1.35 H2O: C, 63.58; H, 7.57; N, 5.30. Found: C, 63.55; H, 7.31 ; N, 4.89.
Figure imgf000383_0001
8040 Example 605
N-[4-(N-benzyl-N-(2-cyclohexylethyl aminomethyl -2-(2-methylphenyl)benzoyllmethionine
Lithium Salt The desired compound was prepared according to the method of Example 158. MS (CI/NH3) m/z: (M-H)" 571 ; NMR (DMSO-d6, 300 MHz) δ 7.50 (d, 7=8 Hz, IH), 7.38- 8045 7.12 (m, 10H), 6.92 (d, 7=6 Hz, IH), 3.69 (m, IH), 3.56 (s, 2H), 3.53 (s, 2H), 2.38 (t, 7=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 C35H43LiN2θ3S-1.75 H2O: C, 68.89; H, 7.68; N, 4.59. Found: C, 68.85; H, 7.44; N, 4.37.
8050
Figure imgf000383_0002
Example 607 N-[4-(N-2-cvclohexylethylaminomethylV2-('2-methylphenyl benzoyllmethionine
Trifluoroacetate Salt 8055 The desired compound was prepared according to the method of Example 158. MS
(CI/NH3) m/z: (M+H)+ 483; *H NMR (DMSO-d6, 300 MHz) δ 8.09 (m, IH), 7.49-7.42 (m, 2H), 7.26 (m, IH), 7.16-6.98 (m, 3H), 4.14 (m, IH), 4.1 1 (s, 2H), 2.87-2.80 (m, 2H), 2.1 1-1.90 (m, 5H), 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 C28H38N2θ3S«C2HF3θ2» l -45 H2O: C, 8060 57.76; H, 6.93; N, 4.49. Found: C, 57.69; H, 6.51 ; N, 4.48.
Figure imgf000384_0001
Example 608 8065 N-[4-("N-(2-cyclohexylethyl -N-methylaminomethyl)-2-(2-methylphenyl)benzoyl1methionine
Lithium Salt The desired compound was prepared according to the method of Example 158. MS (CI/NH3) m/z: (M+H)+ 497; l NMR (DMSO-d6, 300 MHz) δ 7.49 (d, 7=8 Hz, IH), 7.32 (dd, 7=8, 1 Hz, IH), 7.25-7.06 (m, 4H), 6.93 (d, 7=6 Hz, IH), 3.73-3.64 (m, IH), 8070 3.49 (s, 2H), 2.32 (t, 7=7 Hz, 2H), 2.15 (m, IH), 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 C29H39LiN2θ3S»1.05 H2O: C, 66.78; H, 7.94; N, 5.37. Found: C, 66.81 ; H, 7.75; N, 5.07.
8075
Figure imgf000384_0002
Example 609 N-f4-(N-acetyl-N-(2-cyclohexylethyl)aminomethylV2-('2-methylphenyl)benzoyllmethionine
Lithium Salt
8080 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 (CI/NH3) m/z: (M-H)" 523; ^H NMR (DMSO-d6, 300 MHz) δ 7.59 minor conformer 7.53 major conformer (d, 7=8 Hz, IH), 7.31 (d, 7=8 Hz, IH), 7.25- 7.14 (m, 3H), 7.07-6.96 (m, 2H), 4.63 minor conformer 4.57 major conformer (s, 2H),
8085 3.80 (m, IH), 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 C3θH39LiN2θ4S« 1.45 H2O: C, 64.72; H, 7.59; N, 5.03. Found: C„ 64.75; H, 7.40; N, 4.71.
Figure imgf000385_0001
Example 610
N-[4-(N-(N.N-dimethylaminocarbonyl)-N-(2-cyclohexylethyl)aminomethyl -2-(2- methylphenyDbenzoyllmethionine The compound resulting from Example 607 was treated with dimethyl carbamoyl 8095 chloride under Schotten-Baumann conditions to yield the title compound. MS (CI/NH3) m/z: (M+H)+ 554; Ifϊ NMR (DMSO-d6, 300 MHz) δ 8.18 (d, 7=8 Hz, IH), 7.54 (d, 7=8 Hz, IH), 7.38 (dd, 7=8, 2 Hz, IH), 7.29-7.13 (m, 4H), 4.40 (s, 2H), 4.28 (m, IH), 3.13- 3.06 (m, 2H), 2.80 (s, 6H), 2.29-2.06 (m, 5H), 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 C3 iH43N3θ4S«0.45 H2O: C, 66.27; H, 8100 7.88; N, 7.48. Found: C, 66.37; H, 8.10; N, 6.88.
Figure imgf000386_0001
Example 611 8105 N-r4-(N-(2-cvclohexylethyl -N-methanesulfonylaminomethyl)-2-(2- methylphenyDbenzoyllmethionine Lithium Salt The compound resulting from Example 607 was treated with methanesulfonyl chloride under Schotten-Baumann conditions to yield the title compound. MS (CI/NH3) m/z: (M-H)" 559; iH NMR (DMSO-d6, 300 MHz) δ 7.54 (d, 7=8 Hz, IH), 7.41 (d, 7=8 8110 Hz, IH), 7.25-7.13 (m, 4H), 6.97 (d, 7=7 Hz, IH), 4.36 (s, 2H), 3.67 (m, IH), 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 C29H39LiN2OsS2*2.75 H2O: C, 56.52; H, 7.28; N, 4.55. Found: C, 56.72; H, 6.49; N, 3.92.
81 15
Figure imgf000386_0002
Example 612 N-r4-(N-benzenenesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine Lithium Salt 8120 The compound resulting from Example 607 was treated with benzenesulfonyl chloride under Schotten-Baumann conditions to yield the title compound. MS (CI/NH3) m/z: (M-H)" 621; 1H NMR (DMSO-d6, 300 MHz) δ 7.86 (m, IH), 7.72-7.59 (m, 4H), 7.51 (d, 7=8 Hz, IH), 7.36 (m, IH), 7.26-7.07 (m, 4H), 6.96 (d, 7=6 Hz, IH), 4.36 (s, 2H), 3.66 (m, IH), 3.10 (m, 2H), 2.16-1.92 (m, 5H), 1.70-1.40 (m, 7H), 1.30-0.99 (m, 8125 6H), 0.90-0.61 (m, 5H); Anal. Calcd for C34H4iLiN2θ5S2*1.25 H2O: C, 62.70; H, 6.73; N, 4.30. Found: 63.10; H, 6.72; N, 3.52.
Figure imgf000387_0001
8130 Example 613
N-r4-(3-cyclohexylpropan-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl1methionine The desired compound was prepared according to the method of Example 158 MS (CI/ H3) m/z: (M+H)+ 497; 1_H NMR (DMSO-d6, 300 MHz) δ 7.63 (m, IH), 7.52-7.43 (m, 2H), 7.25-7.04 (m, 4H), 4.06 (m, IH), 3.97 (d, 7= 14 Hz, IH), 3.89 (d, 7= 14 Hz, 8135 IH), 2.85 (m, IH), 2.17-1.94 (m, 5H), 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 C29H40N2O3SA55 H2O: C, 66.39; H, 8.28; N, 5.34. Found: 66.39; H, 7.89; N, 5.1 1.
Figure imgf000387_0002
Example 614 N- r4-(4-cyclohexylbutan-3-ylaminomethyl 2-(2-methylphenyl)benzoyl1 methionine Lithium
Salt The desired compound was prepared according to the method of Example 158 MS
8145 (CI/NH3) m/z: (M+H)+ 511; *H NMR (DMSO-d6, 300 MHz) δ 7.48 (d, 7=8 Hz, IH), 7.36 (d, 7=6 Hz, IH), 7.25-7.09 (m, 4H), 7.00-6.85 m, IH), 3.80-3.65 (m, 3H), 2.42 (m, IH), 2.20-1.50 (m, 15H), 1.41-1.06 (m, 8H), 0.90-0.70 (m, 2H), 0.79 (t, 7=7 Hz, 3H); Anal. Calcd for C3θH4lLiN2θ3S« 1.25 H2O: C, 66.83; H, 8.13; N, 5.20. Found: 66.86; H, 7.91 ; N, 4.93.
8150
Figure imgf000388_0001
Example 615 N-[4-(6-cyclohexylhexan-5-ylaminomethyl')-2-(2-methylphenylN)benzoyl1methionine Lithium 8155 Salt
The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M-H)" 537; Y\ NMR (DMSO-d6, 300 MHz) δ 7.47 (d, 7=8 Hz, IH), 7.36 (dd, 7=8, 1 Hz, IH), 7.24-7.07 (m, 4H), 6.90 (m, IH), 3.75-3.62 (m, 3H), 2.45 (m, IH), 2.18- 1.50 (m, 15H), 1.40- 1.07 (m, 12H), 0.88-0.75 (m, 5H); Anal. Calcd for 8160 C32H45LiN2θ3S»1.05 H2O: C, 68.19; H, 8.42; N, 4.97. Found: 68.19; H, 8.25; N, 4.77.
Figure imgf000388_0002
Example 616 8165 N-[4-( 1 ,2-dicyclohexylethylaminomethyl -2-(2-methylphenyl)benzoyl1methionine Lithium
Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+ 565; H NMR (DMSO-d6, 300 MHz) δ 7.47 (d, 7=8 Hz, IH), 7.36 (m, IH), 7.23-7.12 (m, 4H), 6.91 (m, IH), 3.77-3.63 (m, 3H), 2.30 (m, IH), 2.15 8170 (m, IH), 2.03-1.85 (m, 6H), 1.80-1.40 (m, 12H), 1.30-0.65 (m, 15H); Anal. Calcd for C34H47LiN2θ3S»2.25 MeOH: C, 67.05; H, 8.15; N, 4.60. Found: 67.37; H, 7.69; N, 4.46.
Figure imgf000389_0001
Example 617 N-[4-(3-cyclohexylpropan-l-ol-2-ylaminomethyl)-2-(2-methylphenyl benzoyl1methionine The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+ 513; *H NMR (DMSO-d6, 300 MHz) δ 7.85 (m, IH), 7.49 (d, 8180 7=7 Hz, IH), 7.42 (d, 7=7 Hz, IH), 7.23-7.05 (m, 4H), 4..18-4.12 (m, 2H), 3.92-3.84 (m, 2H), 3.45 (m, IH), 2.65 (m, IH), 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 C29H40N2O4SA65 H2O: C, 64.21; H, 8.05; N, 5.16. Found: 64.26; H, 7.64; N, 4.77.
8185
Figure imgf000389_0002
Example 618 N-r4-(3-cyclohexylpropan-l-ol-2-ylaminomethyl)-2-(2-methylphenyI)benzoyllmethionine
Trifluoroacetate Salt
8190 The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+ 513; *H NMR (DMSO-d6, 300 MHz) δ 7.85 (m, IH), 7.49 (d, 7=7 Hz, IH), 7.42 (d, 7=7 Hz, IH), 7.23-7.05 (m, 4H), 4..18-4.12 (m, 2H), 3.92-3.84 (m, 2H), 3.45 (m, IH), 2.65 (m, IH), 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 C29H4θN2θ4S-C2HF3θ2»1.70 H2O: C,
8195 56.64; H, 6.81 ; N, 4.26. Found: 56.67; H, 6.89; N, 4.11.
Figure imgf000390_0001
Example 619 8200 N- 4-(2-cyclohexylprop-l-en-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl1methionine
Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI NH3) m/z: (M-H)" 507; *H NMR (DMSO-d6, 300 MHz) δ 7.47 (d, 7=8 Hz, IH), 7.32 (m, IH), 7.25-7.07 (m, 4H), 6.93 (m, IH), 5.52 (ddd, 7= 17, 10, 8 Hz, IH), 5.05 (dd, 8205 7= 10, 2 Hz, IH), 4.97 (dd, 7= 17, 2 Hz, IH), 3.77 (d, 7= 15 Hz, IH), 3.70 (m, IH), 3.57 (d, 7= 15 Hz, IH), 2.94 (m, IH), 2.17-1.50 (m, 15H), 1.38-1.06 (m, 6H), 0.90-0.77 (m, 2H); Anal. Calcd for C3()H39LiN2θ3S«1.90 H2O: C, 65.65; H, 7.86; N, 5.10. Found: 65.64; H, 7.34; N, 4.80.
8210
Figure imgf000390_0002
Example 620 N- 4-(3-cyclohexyl-l-ethylsulfonylpropan-2-ylaminomethyl)-2-(2- methylphenyDbenzoyllmethionine Lithium Salt
8215 The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+589; *H NMR (DMSO-d6, 300 MHz) δ 7.52 (d, 7=8 Hz, IH), 7.38 (dd, 7=8, 1 Hz, IH), 7.27-7.10 (m, 4H), 6.97 (m, IH), 3.83-3.68 (m, 3H), 3.33 (m, IH), 3.20-3.07 (m, 3H), 2.97 (dd, 7= 14, 5Hz, IH), 2.28-1.81 (m, 8H), 1.78-1.08 (m, 16H), 0.92-0.75 (m, 2H); Anal. Calcd for C3 iH43LiN2OsS2»4.25 H2O: C, 55.46; H, 7.73; N,
8220 4.17. Found: 55.43; H, 6.94; N, 4.03.
Figure imgf000391_0001
Example 621 8225 N- 4-(3-cyclohexyl- l-ethylsulfonylpropan-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]-2- amino-4-methanesulfonylbutanoic acid Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M-H)"619; ! H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, 7=8 Hz, IH), 7.37 (d, 7=8 Hz, IH), 7.25-7.09 (m, 4H), 6.97 (m, IH), 3.78-3.65 (m, 3H), 3.25 (m, IH), 8230 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 C3 iH43LiN2θ7S2* l-25 H2O: C, 57.35; H, 7.06; N, 4.31. Found: 57.35; H, 7.03; N, 4.1 1.
Figure imgf000391_0002
Example 622 N-[4-(3-cyclohexyl- 1 -t-butylthiopropan-2-ylaminomethy l)-2-(2- methylphenyDbenzoyllmethionine Lithium Salt The" desired compound was prepared according to the method of Example 158 MS
8240 (CI/NH3) m/z: (M+H)+584; *H NMR (DMSO-d6, 300 MHz) δ 7.7.47 (d, 7=8 Hz, IH), 7.37 (dd, 7=8, 1 Hz, IH), 7.23-7.13 (m, 4H), 6.97 (m, IH), 3.87-3.72 (m, 2H), 3.65 (m, IH), 2.63 (m, IH), 2.18-1.77 (m, 8H), 1.74-1.00 (m, 24 H), 0.91-0.68 (m, 2H); Anal. Calcd for C33H47L.N2O3S2-4.5O EtOH: C, 59.39; H, 7.78; N, 4.70. Found: 59.65; H, 7.43; N, 3.91.
8245
Figure imgf000392_0001
Example 623 N-r4-(3-cyclohexyl-l-phenylthiopropan-2-ylaminomethyl)-2-(2-
8250 methylphenyDbenzoyll methionine Lithium Salt The desired compound was prepared according to the method of Example 158 MS (CI/NH3) m/z: (M+H)+605; ^H NMR (DMSO-d6, 300 MHz) δ 7.7.46 (d, 7=8 Hz, IH), 7.34-6.85 (m, 1 1H), 3.86-3.65 (m, 3H), 3.1 1 (dd, 7= 13, 5 Hz, IH), 2.87 (m, IH), 2.67 (m, IH), 2.17-0.60 (m, 23H); Anal. Calcd for C35H43LiN2θ3S2«1.20 H2O: C, 66.47; H,
8255 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
8260 compound described in Example 625, by the procedure described in Example 158
Rl = Ph
Figure imgf000392_0002
627 -CH2
X 475
Figure imgf000392_0003
Figure imgf000393_0001
632 -CH2
HO' 433
HO
Figure imgf000393_0002
634 -CH
HO' 'N' 445 H
Figure imgf000393_0003
637 -CH
~N' 444
638 -CH2
"N' 472
639 -CH2 472
"N'
Figure imgf000393_0004
Figure imgf000394_0001
Figure imgf000395_0001
664 yA 495
-CH2
Figure imgf000395_0002
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Rl=2-MeC6H4-
8265
Example MS (M+H)
-CHc
719 HO' 'N' 461 Me
HO
Figure imgf000401_0001
Examples 748-758 were prepared by the procedure desόribed in Example 57
Figure imgf000402_0001
Example E3L1 MS (M+HY1
Figure imgf000402_0002
749 NH 416
H S
Figure imgf000402_0003
Figure imgf000403_0001
8275
Figure imgf000403_0002
Example 759 (2S)-2-N-[4-(N-bcnzy]-Λf-3-pyridylaminomcthyl)-2-(2-methylphenyl)bcn7θylJamιno-4- 8280 mcthanesult'onylbutanoic acid .
The desired compound was prepared according to the method of Example 157. 'II (300 MHz., DMSO d6): δ 12.8, (I H, s), 8. 18, ( IH, 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 ( IH, s). 2.91 (311, s). 2.76 (IH, m), 2.02. (1 H. m), 2.00, (311, s), 1.85 (211, m). MS (DC1 - ΝH ; m/z 572 (MH+); Anal 8285 calcd for C32II33N3O. H2O: C 65.18. II. 5.98. N, 7 13 Found: C 65.54; 11, 5.73: N, 6.82.
Figure imgf000403_0003
8290 Example 762
N-r4-N-Benzoyl-N-2-cyclohexylethylaminomethyl-2-(2-methylphenyl)benzoyllmethionine 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- 8295 Baumann conditions. MS (CI/ΝH3) m/z: (M-H)" 585; 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (m, IH), 7.45-7.32 (m, 6H), 7.25-7.08 (m, 4H), 6.94 (m, IH), 4.73-4.68 (m, 2H), 3.67-3.61 (m, IH), 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 C35H4lLiN2θ4S«1.80 H2O: C, 67.25; H, 7.19; N, 4.48. Found: C, 67.23; H, 6.78; N, 4.28.
8300
Figure imgf000404_0001
Example 763 N-[4-N-t-Butyloxycarbonyl-N-2-cyclohexylethylaminomethyl-2-(2- 8305 methylphenyDbenzoyllmethionine 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 (CI/ΝH3) m/z: (M-H)" 581; *H NMR (DMSO-d6, 300 MHz) δ 7.51 (m, IH), 7.31- 6.93 (m, 6H), 4.41 (s, 2H), 3.69-3.61 (m, IH), 3.25-3.13 (m, 2H), 2.14 (m, IH), 2.02- 8310 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 C23H45LiN2θ5S«1.70 H2O: C, 64.00; H, 7.88; N, 4.52. Found: C, 63.99; H, 7.49; N, 4.33.
Figure imgf000404_0002
Example 764 Pivaloyloxymethyl N-|"4-N-(3-Cyclohexyl- 1 -ethyIthiopropan-2-yl)-N-methylaminomethyl-2- (2-methylphenyl)benzoyll-methionine hydrochloride salt The desired compound was prepared by reaction of the compound resulting from
8320 Example 763 under conditions described in Example 500, followed by treatment with 4Ν HCl - dioxane. MS (CI/NH3) m/z: (M+H)+ 671; NMR (DMSO-d6, 300 MHz) δ 8.42 (d, J=7.5 Hz, IH), 7.65 (d, J=8.1 Hz, IH), 7.55 (d, J=7.5 Hz, IH), 7.49-7.42 (m, IH), 7.26-7.06 (m, 3H), 5.73 (d, J=5.8 Hz, IH), 5.65 (d, J=5.8 Hz, IH), 4.29 (brs, 2H), 3.25- 3.17 (m, IH), 3.04-2.97 (m, IH), 2.86-2.77 (m, IH), 2.24-2.02 (m, 6H), 1.94 (s, 3H),
8325 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 C37H55CIN2O5S2: C, 62.82; H, 7.84; N, 3.96. Found: C, 62.71; H, 8.03; N, 3.90.
Figure imgf000405_0001
8330 Example 765
N-[4-N-(3-Cyclohexyl-l-ethylthiopropan-2-yD-N-methylaminomethyl-2-(2- methylphenyl benzoyll-N-methylmethionine lithium salt The desired compound was prepared according to the method of Example 158. MS (CI/ΝH3) m/z: (M-H)" 569; 1H NMR (DMSO-d6, 300 MHz) δ 7.38 (d, J=7.8 Hz, IH), 8335 7.24-7.04 (m, 6H), 4.53-4.45 (m, IH), 3.85-3.67 (m, 2H), 2.67-2.59 (m, 2H), 2.50-2.38 (m, 5H), 2.18-1.92 (m, 5H), 1.87 (s, 3H), 1.70-1.05 (m, 17H), 0.93-0.72 (m, 2H); Anal. Calcd for C32H45LiN2θ3S2«1.20 H2O: C, 64.23; H, 7.98; N, 4.68. Found: C, 64.27; H, 7.97; N, 4.66.
8340
Figure imgf000405_0002
Example 766 N-r4-N-(3-Cyclohexyl-l-cyclohexylthiopropan-2-yl)-N-methylaminomethyl-2-(2- methylphenyDbenzoyllmethionine lithium salt
8345 The desired compound was prepared according to the method of Example 158. MS (CI/ΝH3) m/z: (M-H)" 609; *H NMR (DMSO-d6, 300 MHz) δ 7.48 (d, J=7.7 Hz, IH), 7.34 (m, IH), 7.21-7.06 (m, 4H), 6.96-6.88 (m, IH), 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 C35H49LiN2θ3S2*1.05 H2OA6O TFA: C, 56.08; H, 6.49; N, 3.42. Found: C,
8350 56.05; H, 6.50; N, 3.49.
Figure imgf000406_0001
Example 767 8355 N- 4-N-(3-Cyclohexyl-l-(2-methylphenyl thiopropan-2-yl -N-methylaminomethyl-2-(2- methylphenyDbenzoyll methionine lithium salt The desired compound was prepared according to the method of Example 158. MS (CI/ΝH3) m/z: (M-H)" 617; *H NMR (DMSO-d6, 300 MHz) δ 7.45 (d, J=7.8 Hz, IH), 7.32-6.85 (m, 10H), 3.82-3.64 (m, 3H), 3.06 (dd, J=12.5, 4.4 Hz, IH), 2.88-2.78 (m, 8360 IH), 2.74-2.62 (m, IH), 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 C36H45LiN2θ3S2*l-0 H2O: C, 67.16; H, 7.51 ; N, 4.35. Found: C, 67.17; H, 7.30; N, 4.24.
Figure imgf000406_0002
Example 769 N-[4-N-(N-phenyl-N-benzenesulfonylaminomethyl)-2-(2-methylphenyl)benzoyl1methionine lithium salt The desired compound was prepared according to the method of Example 157.
8370
Figure imgf000406_0003
δ 7.6-7.7 (2H, m); 7.5-7.6 (2H, m); 7.3-7.4 (IH, m); 7.3-7.1 (10H, m); 6.9-7.1 (2H, m); 4.9 (2H, s); 4.1-4.3 (IH, m); 2.1-1.5 (10H, m). ESI(-)/MS: 587(M-Lι); 407.
Figure imgf000407_0001
Example 770
N-r4-N-(N-phenyl-N-toluenesulfonylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. 8380 ^(CDsOD): δ 7.6-7.7 (2H, m); 7.5-7.6 (2H, m); 7.3-7.4 (IH, m); 7.3-7.1 ( 10H, m);
6.9-7.1 (2H, m); 4.9 (2H, s); 4.1-4.3 (IH, m); 2.4 (3H, m); 1.5-2.1 ( 10H, ). ESI(-)/MS: 601(M-Li); 421
Figure imgf000407_0002
Example 779
N-r4-N-(N-phenyl-N-(3-methoxybenzyl)aminomethy0-2-(2- methylphenyPbenzoy 11 methionine lithium salt The desired compound was prepared according to the method of Example 157. 8390 lH(MeOH-d4) δ 7.6-7.7 (IH, d); 7.3-7.4 ( IH, 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 (IH, m); 3.65 (3H, s); 1.5-2.2 (10H, m). ESI(-)/MS: 567(M-Li); 447; 366; 281.
Figure imgf000408_0001
Example 780 Λ/-r4-N-(N-phenyl-N-(4-trifluoromethylbenzenesulfonyl)aminomethyl)-2-(2-methylphenyl)- benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.
8400 lH(MeOH-d4): δ 7.8-7.95 (4H, m); 7.5-7.6 (IH, d), 7.3-7.4 (IH, d); 7.1-7.3 (7H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 ( IH, m); 1.7-2.1 ( 10H, m); 1.5-1.7 ( IH, m). ESI(-)/MS: 655(M-Li); 475. 431.
Figure imgf000408_0002
Example 781 N-[4-N-(N-phenyl-N-(4-chlorobenzylΝ)aminomethyl -2-('2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157.
8410 ^(MeOH-^): δ 7.6-7.7 (IH, d); 7.3-7.4 (IH, 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 (IH, m); 1.55-2.2 (10H, m). ESI(- )/MS: 571(M-Li); 367, 255.
Figure imgf000409_0001
Example782 N-14-N-(N-phenyl-N-(4-trifluoromethylbenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyll methionine lithium salt The desired compound was prepared according to the method of Example 157.
8420 ^(MeOH-^): δ 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 ( IH, m); 1.6-2.2 ( 10H, m). ESI(-)/MS: 605(M-Lι); 367; 283.
Figure imgf000409_0002
Example 784 N-r4-N(t-Butylcarbazatocarbonylmethyl amino-2-phenylbenzoyllmethionine The desired compound was prepared according to the method of Example 57, except Butylcarbazatocarbonylmethyl bromide was used as the alkylating agent. Η nmr (300
8430 MHz, DMSO-d6): δ 9.79 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, 1 H), 7.47-7.29 (m, 6 H), 6.65 (br d, 1 H), 6.56 (d, 1 H), 6.43 (t, 1 H), 4.30 (m, 1 H), 3.81 (d, 2 H), 2.32 (m, 2 H), 2.05 (br s, 6 H), 1.90 (m, 2 H), 1.47 (s, 9 H). MS (APCI +) m/e 517 (M+H)+.
Figure imgf000410_0001
8435 Example 806
N-r4-(l-ethoxycarbonylpiperidin-4-ylaminomethyl)-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158 Η nmr (300 MHz, DMSO-d6): δ 7.48 (d, 1 H), 7.38 (dd, 1 H), 7.26-7.10 (m, 5 H), 6.90 (m, 8440 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)-.
Figure imgf000410_0002
Example 830 N-r4-(N-r3-methylthio-l-carboxyprop-2-yllaminocarbonyl)-2-phenylbenzoyllmethionine The desired compound was prepared according to the method of Example 451. ^H ΝMR (d6-DMSO): δ 1.64-1.91 (comp, 2 H), 1.93 (s, 3 H), 1.98-2.22 (comp, 10 H), 2.46-
8450 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, 7= 7.8 Hz, 1 H), 7.74-7.79 (br s, 1 H), 7.96 (dd, 7= 1.7, 7.8 Hz, 1 H), 8.24-8.32 (br, 1 H), 8.74 (d, 7= 7.4 Hz, 1 H), 12.50-12.93 (br, 2 H). LRMS (ESL): 517 (M-l)-.
Figure imgf000411_0001
Example 831 N-[4-N-(furan-2-ylmethyl -N-isopropylaminomethyl-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158. Η 8460 ΝMR (d6-DMSO): δ 1.00 (d, 7= 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, 7= 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, 7= 2.9 Hz, 1 H), 6.35 (dd, 7= 1.8, 3.3 Hz, 1 H), 6.93 (d, 7= 6.2 Hz, 1 H), 7.10-7.26 (br comp, 4 H), 7.37 (d, 7= 8.1 Hz, 1 H), 7.48 (d, 7= 7.7 Hz, 1 H), 7.53 (dd, 7= 0.7, 1.8 Hz, 1 H). LRMS (ESL): 493 (M-l)-. 8465
Figure imgf000411_0002
Example 832 N-l"4-N-(furan-3-ylmethyl)-N-isopropylaminomethyl-2-(2-methylphenyl benzoyllmethionine 8470 lithium salt
The desired compound was prepared according to the method of Example 158. X ΝMR (d6-DMSO): δ 1.00 (d, 7= 6.6 Hz, 6 H), 1.49-1.76 (comp, 2 H), 1.76-2.19 (comp, 8 H), 2.88 (sept, 7= 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, 7= 6.2 Hz, 1 H), 7.08-7.26 (comp, 4 H), 7.39 (d, 7= 8.1 Hz, 1 H), 7.48 8475 (d, 7= 7.6 Hz, 1 H), 7.52-7.57 (comp, 2 H). LRMS (ESL): 493 (M-l)-.
Figure imgf000412_0001
Example 833 8480 N-[4-N-benzyl-N-3-methoxyphenylaminomethyl-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. Η ΝMR (d6-DMSO): δ 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, 7= 1.9 Hz, 1 H), 6.29 (dd, 7= 2.3, 8485 9.2 Hz, 1 H), 6.90-7.03 (comp, 3 H), 7.08-7.34 (comp, 9 H), 7.50 (d, 7= 7.7 Hz, 1 H). LRMS (ESI-): 467 (M-l)-.
Figure imgf000412_0002
8490 Example 834
N-[4-ΝN-dibenzylaminomethyl-2-phenylbenzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 158. JH ΝMR (d6-DMSO): δ 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, 7= 7.8 Hz, 1 8495 H). LRMS (CI+): 539 (M+l)+.
Figure imgf000413_0001
Example 835 8500 N-[4-N-(2-phenylethyl -N-isopropylaminomethyl-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158. H ΝMR (d6-DMSO): δ 0.94 (d, 7= 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, 7= 6.3 Hz, 1 H), 3.66 (s, 2 H), 3.70-3.81 (br, 1 8505 H), 6.94 (d, 7= 5.9 Hz, 1 H), 7.07-7.26 (comp, 9 H), 7.32 (d, 7= 7.7 Hz, 1 H), 7.46 (dd, 7= 1.8, 7.7 Hz, 1 H). LRMS (ESL): 517 (M-l)-.
Figure imgf000413_0002
8510 Example 836
N-r4-N-benzyl-N-pyrimidin-5-ylaminomethyl-2-(2-methylphenyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. *H ΝMR (d6-DMSO): δ 1.48-1.74 (br comp, 2 H), 1.86-2.08 (br comp, 8 H), 3.62-3.74 (br, 1 8515 H), 4.83 (s, 2 H), 4.89 (s, 2 H), 6.92-7.03 (br, 1 H), 7.04-7.38 (comp, 1 1 H), 7.52 (d, 7= 8.1 Hz, 1 H), 8.22 (s, 2 H), 8.42 (s, 1 H). LRMS (ESL): 539 (M-l)-.
Figure imgf000414_0001
8520 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. 'H
ΝMR (d6-DMSO): δ 1.46-1.76 (br comp, 2 H), 1.84-2.05 (br comp, 8 H), 3.56-3.67 (br,
8525 H), 4.71 (s, 2 H), 4.86 (s, 2 H), 6.77 (dd, 7= 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, 7= 1.9, 8.1
Hz, 1 H), 7.51 (d, 7= 7.7 Hz, 1 H), 8.23 (s, 2 H), 8.42 (s, 1 H). LRMS (ESL): 583 (M- i)-.
8530
Figure imgf000414_0002
Example 838 N-|"4-N-d.3-benzodiox-5-yl -N-pyridizin-2-ylaminomethyl-2-(2-methylphenyl) benzoyllmethionine lithium salt
8535 The desired compound was prepared according to the method of Example 157. !H ΝMR (d6-DMSO): δ 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, 7= 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, 7= 1.7, 8.2 Hz, 1 H), 7.49 (d, 7= 7.8 Hz, 1 H), 7.80 (d, 7= 2.4 Hz, 1 H), 8.03-8.09 (comp, 2 H).
8540
Figure imgf000415_0001
Example 839 N-[4-(N-benzyl-N-(2-methoxyphenyl)aminomethyl)-2-(2-methylphenyl)benzoynmethionine
8545 lithium salt The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): δ 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, 7= 7.8 Hz, 1 H).
8550
Figure imgf000415_0002
Example 840 N-[4-(,N-benzyl-N-(4-methoxyphenyl aminomethyl -2-(2-methylphenyl benzoyl]methionine
8555 lithium salt The desired compound was prepared according to the method of Example 157. 'H ΝMR (d6-DMSO): δ 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, 7= 7.8 Hz, 1 H).
8560
Figure imgf000416_0001
Example 841 N-[4-('N-benzyl-N-(4-acetylphenyl)aminomethyl)-2-(2-methylphenyl)benzoyllmethionine 8565 lithium salt
The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): δ 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, 7= 8.8 Hz, 2 H), 6.95 (d, 7= 6.1 Hz, 1 H), 7.02 (s, 1 H), 7.08-7.36 (comp, 9 H), 7.52 (d, 7= 8.1 Hz, 1 H), 7.72 8570 (d, 7= 8.8 Hz, 2 H).
Figure imgf000416_0002
Example 842 8575 N-[4-(N-benzyl-N-(3-nitrophenyl)aminomethyl')-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 'H ΝMR (d6-DMSO): δ 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, 7= 7.8 8580 Hz, 1 H).
Figure imgf000417_0001
Example 843 8585 N-[4-(N-benzyl-N-(4-nitrophenyl aminomethyl)-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 'H ΝMR (d6-DMSO): δ 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, 7= 9.5 Hz, 2 H), 6.94 (d, 7= 6.1 8590 Hz, 1 H), 7.02 (s, 1 H), 7.08-7.38 (comp, 9 H), 7.53 (d, 7= 7.8 Hz, 1 H), 8.00 (d, 7= 9.5 Hz, 2 H).
Figure imgf000417_0002
8595 Example 844
N-[4-N-(N-benzyl-N-(2-acetylphenyl aminomethyl)-2-(2-methylphenyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): δ 1.45-1.70 (br comp, 2 H), 1.86-2.04 (comp, 8 H), 2.60 (s, 3 H), 8600 3.56-3.66 (br, 1 H), 4.21 (app s, 4 H), 6.82-6.94 (br comp, 2 H), 6.99 (t, 7= 7.4 Hz, 1 H), 7.08 (d, 7= 7.7 Hz, 1 H), 7.16-7.34 (comp, 10 H), 7.39 (dd, 7= 1.9, 7.7 Hz, 1 H), 7.45 (d, 7= 8.0 Hz, 1 H).
Figure imgf000418_0001
Example 845 N-r4-N-(N-benzyl-N-(3-acetylphenyl)aminomethyl)-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. X
8610 ΝMR (d6-DMSO): δ 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, 7= 7.8 Hz, 1 H)
Figure imgf000418_0002
Example 846 N-r4-N-(N-benzyl-N-(2-chlorophenyl)aminomethyl')-2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. Η
8620 ΝMR (d6-DMSO): X ΝMR (d6-DMSO): δ 1.46-1.64 (br comp, 2 H), 1.76-2.03 (comp, 8 H), 3.15-3.19 (br, 1 H), 4.23 (s, 2 H), 4.26 (s, 2 H), 6.84-7.47 (comp, 16 H).
Figure imgf000418_0003
8625 Example 847 N-[4-N-(N-benzyl-N-('3-chlorophenyl)aminomethyl)-2-(2-methylphenyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 'H ΝMR (d6-DMSO): δ 1.48-1.75 (br comp, 2 H), 1.88-2.10 (comp, 8 H), 3.64-3.75 (br, 1 8630 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, 7= 7.7 Hz, 1 H).
Figure imgf000419_0001
8635 Example 848
N-r4-N-(N-benzyl-N-(4-chlorophenyl aminomethyl -2-(2-methylphenyl)benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): δ 1.47-1.76 (br comp, 2 H), 1.89-2.10 (comp, 8 H), 3.65-3.77 (br, 1 8640 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, 7= 7.8 Hz, 1 H).
Figure imgf000419_0002
8645 Example 849
N-[4-(N-benzyl-N-(2-nitrophenyl aminomethyl)-2-(2-methylphenyl)benzovnmethionine lithium salt The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): δ 1.46-1.71 (br comp, 2 H), 1.86-2.20 (br comp, 8 H), 3.58-3.70 (br, 1 8650 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).
Figure imgf000420_0001
8655 Example 850
N-f4-(N-benzyl-N-('2-methylthiophenyl aminomethyl)-2-(2- methylphenyl benzoyl]methionine lithium salt The desired compound was prepared according to the method of Example 157. Η ΝMR (d6-DMSO): δ 1.48-1.72 (br comp, 2 H), 1.86-2.03 (br comp, 8 H), 2.40 (s, 3 H), 8660 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, 1 1 H), 7.33-7.44 (comp, 4 H).
Figure imgf000420_0002
8665 Example 851
N-[4-(N-benzyl-N-(3-methylthiophenyl aminomethylV2-('2- methylphenyllbenzoyll methionine lithium salt The desired compound was prepared according to the method of Example 157. X ΝMR (d6-DMSO): 'H ΝMR (d6-DMSO): δ 1.48-1.72 (br comp, 2 H), 1.89-2.09 (br comp, 8670 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).
Figure imgf000421_0001
8675 Example 852
N-r4-(N-benzyl-N-(4-methylthiophenyl)aminomethyl -2-(2- methylphenyDbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 157. 'H ΝMR (d6-DMSO): δ 1.45-1.74 (br comp, 2 H), 1.88-2.08 (br comp, 8 H), 2.33 (s, 3 H), 8680 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).
Figure imgf000421_0002
Example 853 N-r4-(N-benzyl-N-(4-trifluoromethylphenyl aminomethyl)-2-(2- methylphenyDbenzoyll methionine lithium salt The desired compound was prepared according to the method of Example 157. *H
8690 ΝMR (d6-DMSO): δ 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, 1 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 1 H).
Figure imgf000422_0001
Example 862 N- 4-N-(4-piperidin-l-ylphenyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine The desired compound was prepared according to the method of Example 158 MS m/e 530 (M-H)". 'H NMR (CDC13, 300 MHz) δ 1.55 (m, 3H), 1.78 (m, 4H), 1.85 (m,
8700 IH), 2.0 (m, 8H), 3.03 (m, 4H), 4.3 (m, 3H), 6.13 (m, IH), 6.54 (m, 2H), 6.98 (m, 2H), 7.10-7.52 (m, 6H), 7.74 (m, IH).
Figure imgf000422_0002
8705 Example 863
N-r4-N-(4-morpholin-l-ylphenyl aminomethyl-2-('2-methylphenyl)benzoynmethionine The desired compound was prepared according to the method of Example 158. MS m/e 534 (M+H)+. iH NMR (CDCI3, 300 MHz) δ 1.48 (m, IH), 1.83 (m, IH), 2.0 (m, 8H), 3.00 (m, 4H), 3.85 (m, 4H), 4.35 (m, 3H), 6.03 (m, IH), 6.58 (m, 2H), 6.80 (m, 8710 2H), 7.22 (m, 6H), 7.85 (m, IH).
Figure imgf000423_0001
Example 864
8715 N-r4-N-(4-phenoxyphenyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine
The desired compound was prepared according to the method of Example 158. MS m/e 539 (M-H)-. X NMR (CDC13, 300 MHz) δ 1.42 (m, IH), 1.75 (m, IH), 2.0 (m, 8H),
4.21 (m, IH), 4.31 (s, 2H), 6.15 (m, IH), 6.54 (m, 2H), 6.86 (m, 4H), 6.99 (m, 2H), 7.2
(m, 7H), 7.76 (m, IH).
8720
Figure imgf000423_0002
Example 875 N-[4-N-(benzyl-N-thiazol-2-ylmethyl aminomethyl-2-f2-methylphenyl)benzoyllmethionine 8725 The desired compound was prepared according to the method of Example 158. X
(300 MHz, DMSO d6): δ 9.08, d, IH; 8.13, d, IH; 7.58, d, IH; 7.49, s, 2H; 7.40, d, 2H; 7.31, t, 2H; 7.22, m, 4H; 7.1 1, m, 2H; 4.21, m, IH; 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 C31H33N3O3S2 + 0.49 H2O: C 65.49, H 6.02, N 7.39: Found: C 65.49, H 5.86, N 8730 7.27.
Figure imgf000424_0001
Example 876 8735 N-r4-N-(benzyl-N-thiazol-5-ylmethyl)aminomethyl-2-phenylbenzoyllmethionine
The desired compound was prepared according to the method of Example 158. X (300 MHz, DMSO d6): δ 9.04, s, IH; 8.46, d. IH; 7.82, s, IH; 7.3, m, 13H; 4.27, ddd, IH; 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 C30H31N3O3S2: C 66.03, H 5.72, N 7.70: Found: C 8740 65.65, H 5.81, N 7.50.
Figure imgf000424_0002
Example 877 8745 N-r4-N-(toluenesulfonyl-N-thiazol-2-ylmethy aminomethyl-2-(2-methylphenyl - benzoyll methionine The desired compound was prepared according to the method of Example 157. X (300 MHz, DMSO d6): δ 12.62, bs, IH; 8.94, s, IH; 8.08, bs, IH; 7.79, d, 2H; 7.59, s, IH; 7.41, m, 3H; 7.20, m, 4H; 7.03, bs, IH; 6.90, bs, IH; 4.59, s, 2H; 4.38, s, 2H; 4.21 , 8750 m, IH; 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 C31H33N3O5S3: C 59.69, H 5.33, N 6.74: Found: C 59.41, H 5.19, N 6.57.
Figure imgf000425_0001
Example 878 N-[4-N-(methanesulfonyl-N-thiazol-2-ylmethyl aminomethyl-2-(2-methylphenyl)- benzoyll methionine The desired compound was prepared according to the method of Example 157. X 8760 (300 MHz, DMSO d6): δ 9.00, s, IH; 8.11, bs, IH; 7.52, s, IH; 7.46, d, IH; 7.39, dd, IH; 7.00 - 7.22, m, 5H; 4.63, s, 2H; 4.42, s, 2H; 4.21, m, IH; 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.
8765
Figure imgf000425_0002
Example 880 N-[4-(N-2-Cyclohexylethyl-N-cyclopropylaminomethyl)-2-(2- methylphenyDbenzoyπmethionine 8770 The desired compound was prepared according to the method of Example 158. X
(300 MHz, DMSO d6): δ 8.06, d, IH; 7.47, d, IH; 7.31, dd, IH; 7.20, m, 2H; 7.02 - 7.17, m, 3H; 4.21, m, IH; 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 8775 C31H42Ν3O3S: C 71.23, H 8.10, N 5.36: Found: C 70.25, H 8.05, N 5.31.
Figure imgf000426_0001
Example 881 8780 N-|"4-(N-tetrahydrothiopyran-4-yl-N-thiazol-5-ylaminomethyl)-2-(2- methy lphenyDbenzoy 11 methionine The desired compound was prepared according to the method of Example 158. X (300 MHz, DMSO d6): δ 8.97, s, IH; 8.08, d, IH; 7.78, s, IH; 7.44, dd, 2H; 7.00 - 7.25, m, 5H; 4.20, ddd, IH; 3.89, s, 2H; 3.71, s, 2H; 2.38 - 2.70, m, 5H; 1.98 - 2.23, m, 7H; 8785 1.97, s, 3H; 1.59 - 1.91, m, 4H. MS (ESI(-)): 5688 (M-H); ESI((+)): 570. Calc'd for
C29H35Ν3O3S3 + 0.45 H2O: C 60.27, H 6.26, N 7.27: Found: C 60.27, H 6.32, N 7.17.
Figure imgf000426_0002
8790 Example 886 N-[4-N-t-Butyloxycarbonyl-N-(1.3-dicyclohexylpropan-2-yl)aminomethyl-2-(2- methylphenylVbenzoyll 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. X ΝMR (300 MHz,
8795 DMSO) δ 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, IH), 4.20-4.40 (m, 3H), 6.85- 6.95 (m, IH), 7.01-7.27 (m, 5H), 7.30-7.42 (m, IH), 7.42-7.53 (m, IH). MS (APCI(+)) m/z 679 (M+H); Analysis calc'd for C4oH57LiΝ2O5S»0.75H2O: C, 68.79; H, 8.44; N, 4.01 ; found: C, 68.77; H, 8.33; N, 4.04.
8800
Figure imgf000427_0001
Example 887 N- ["4-N-(3-Cyclohexyl- 1 -oxo- 1 -piperidin- 1 -ylpropan-2-yl aminomethy l-2-(2- 8805 methylphenyPbenzoyn-methionine lithium salt
The desired compound was prepared according to the method of Example 158. ΝMR (300 MHz, DMSO) δ 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, 5H), 3.35-3.80 (m, 3H), 6.85-6.95 (m, IH), 7.06-7.23 (m, 5H), 7.32 (d, 7=7.8 Hz, IH), 7.46 (d, 7=7.8 Hz, IH). MS (ESI(-)) m/z 592 (M-H); 8810 Analysis calc'd for C34H46LiΝ3θ4S'1.30H2O: C, 65.53; H, 7.86; N, 6.74; found: C, 65.53; H, 7.36; N, 6.41.
Figure imgf000427_0002
8815 Example 890
N-r4-(N-(furan-2-ylmethyl aminomethyl -2-phenylbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 158. Η NMR (DMSO-J6, 90 °C) δ 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 8820 439 (M+ + 1, 100). Anal. Calcd for C24H25L1N2O4S -2H2O (480.50): C, 59.99; H, 6.08; N, 5.83. Found: C, 59.83; H, 5.83; N, 5.74.
Figure imgf000428_0001
8825 Example 902
N-[4-N-(thiazol-5-ylmethoxycarbonyπamino-2-(2-methylphenyl benzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 57. NMR (DMSO-J6,) δ 9.93 (s, 1 H), 9.04 (s, 1 H), 7.93 (s, 1 H), 7.44 (s, 2 H), 7.19-7.06 8830 (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 m/z 498 (M+ - 1, 100). Exact mass calcd for C24H26N3O5S2 500.1303, found 500.1308.
Figure imgf000428_0002
Example 905 N-14-(N-(l-ethylthio-4-methylpentan-2-yl aminomethyl')-2-(2-methylphenyl)benzoyl1- methionine The desired compound was prepared according to the method of Example 158. ^H 8840 (300MHz, CDCI3, δ) 7.70 (IH, m), 7.43 (IH, d, 7= 10Hz), 7.30-7.00 (5H, m), 6.25 (IH, m), 4.38 (IH, m), 4.06 (IH, m), 3.91 (IH, bd, 7= 12Hz), 3.01 (IH, m), 2.82 (IH, dd, 7= 15&3Hz), 2.67 (IH, m), 2.45 (2H, q, 7=8Hz), 2.05 (3H, s), 2.00 (3H, s), 2.00-1.80 (4H, m), 1.67 (IH, m), 1.53 (3H, m), 1.20 (3H, t, 7=8Hz), 0.92 (3H, d, 7=8Hz), 0.85 (3H, d, 7=8Hz). m/z (ESI) 517 (MH+) Anal.calc for C28H40Ν2O3S2 C 65.08, H 7.80, 8845 N 5.42 Found C 65.37, H 7.86, N 5.38
Figure imgf000429_0001
Example 906 8850 N-[4-(N-(l-ethylthio-4-methylpentan-2-yl)-N-methylaminomethyl)-2-(2- methylphenyDbenzoyll-methionine The desired compound was prepared according to the method of Example 158. ^H (300MHz, CDCI3, δ) (rotamer) 7.70 (IH, m), 7.52 (IH, d, 7= 10Hz), 7.40-7.10 (5H, m), 6.08 (IH, m), 4.43 (IH, m), 3.88 (2H, m), 3.15 ( IH, m), 2.87 (IH, dd, 7= 15&3Hz), 2.60 8855 (IH, m), 2.51 (2H, q, 7=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, 7=8Hz), 0.92 (3H, d, 7=8Hz), 0.88 (3H, d, 7=8Hz). m/z (ESI) 531 (MH+) Anal.calc for C29H42Ν2O3S2O.25 H2O C 65.07, H 8.00, N 5.23 Found C 65.01, H 7.84, N 5.14
8860
Figure imgf000429_0002
Example 907 N-[4-('N-(1.3-Dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyllmethionine
8865 The desired compound was prepared according to the method of Example 158. ^H (300MHz, DMSO-d6, δ) 7.50 (IH, d, 7= 12Hz), 7.33 (IH, m), 7.25-7.10 (3H, m), 7.08 (IH, m), 6.98 (IH, m), 3.82 (IH, 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+)
8870
Figure imgf000430_0001
Example 908 N- 4-(N-(1.3-Dicyclohexylpropan-2-yl -N-methylaminomethyl -2-(2-methylphenyl)- 8875 benzoyllmethionine
The desired compound was prepared according to the method of Example 158. ^H (300MHz, DMSO-d6, δ) (rotamer) 7.65 (IH, m), 7.49 (IH, bd, 7= 12Hz), 7.33 (IH, dd, 7= 12&2Hz), 7.30-7.00 (4H, m), 4.50 (2H, m), 4.10 (IH, m), 3.53 ( IH, m), 3.20 (IH, m), 2.58 (IH, m), 2.20-2.00 (6H, m), 1.97 (1.92) (3H, s), 1.80-1.40 (14H,m), 1.40-1.20 8880 (4H, m), 1.20-0.90 (8H, m), 0.90-0.60 (9H, d, 7=9Hz). m/z (ESI) 635 (MH+) Anal.calc. for C39H58Ν2O3S- 1.00 H2O C 71.74, H 9.26, N 4.29 Found C 71.60, H 8.90, N 4.27
Figure imgf000430_0002
8885 Example 909
N-r4-(N-acetyl-N-(l,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 *H (300MHz, DMSO- 8890 d6, δ) (rotamer) 12.60 (IH, m), 8.05 (IH, m), 7.48 (IH, m), 7.35 (IH, bd, 7= 12Hz),
7.20-6.90 (4H, m), 4.50 (2H, bd, 7= 18Hz), 4.22 (IH, m), 3.87 (IH, m), 3.10 (IH, 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 C37H52Ν2O4SO.5O H2O C 70.55, H 8.48, N 4.45 Found C 70.67, H 8.42, N 4.36\ 8895
Figure imgf000431_0001
Example 910 N-[4-( V-benzoyl-N-(1.3-Dicyclohexylpropan-2-yl)aminomethyl -2-(2-methylphenyl)- 8900 benzoyllmethionine
The desired compound was prepared according to the method of Example 909. ^H (300MHz, DMSO-d6, δ) 12.60 (IH, m), 8.05 (IH, bd, 7= 12Hz), 7.47 (4H, m), 7.33 (2H, m), 7.25-7.10 (5H, m), 4.62 (2H, bs), 4.21 (IH, m), 3.82 (IH, m), 3.10 ( IH, 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- 8905 0.60 (3H, m). m/z (ESI) 683 (MH+) Anal.calc. for C42H54Ν2O4SO.75 H2O C 72.43, H 8.03, N 4.02 Found C 72.24, H 7.72, N 3.93
Figure imgf000431_0002
8910 Example 911
N-r4-(N-Benzenesulfoyl-N-(1.3-Dicyclohexylpropan-2-yl)aminomethyl)-2-(2- methylphenyD-benzoyllmethionine The desired compound was prepared according to the method of Example 157. ^H (300MHz, DMSO-d6, δ) 7.83 (2H, bd, 7= 12Hz), 7.80-7.55 (3H, m), 7.49 (2H, m), 7.30- 8915 7.00 (5H, m), 4.43 (2H, m), 4.22 (IH, m), 3.78 (IH, m), 3.20 (IH, 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 C4iH54N2OsS2-0.50 H2O C 67.64, H 7.61, N 3.85 Found C 67.74, H 7.48, N 3.79
8920
Figure imgf000432_0001
Example 912 N-[4-(N-(N,N-dibutylacetamido aminomethyl)-2-(2-methylphenyl)benzoynmethionine The desired compound was prepared according to the method of Example 158. ^H 8925 (300MHz, DMSO-d6, δ) 7.96 (IH, m), 7.48 (IH, d, 7= 10Hz), 7.39 (IH, dd, 7= 12&2Hz), 7.25-7.00 (4H, m), 4.17 (IH, m), 3.80 (2H, s), 3.23 (2H, t, 7=8Hz), 3.16 (2H, t, 7=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, 7=8Hz). m/z (DCI, ΝH3) 542 (MH+) Anal.calc for C30H43N3O4SO.75 H2O C 64.89, H 8.08, N 7.57 Found C 64.83, H 7.94, N 7.33 8930
Figure imgf000432_0002
Example 913 N-r4-(N-(N.N-dibutylacetamido)-N-methylaminomethyl)-2-(2- 8935 methylphenyDbenzoyllmethionine
The desired compound was prepared according to the method of Example 158. ^H (300MHz, DMSO-d6, δ) 7.53 (IH, d, 7= 10Hz), 7.38 (IH, dd, 7= 12&2Hz), 7.25-7.00 (4H, m), 4.23 (IH, m), 3.64 (2H, s), 3.48 (IH, m), 3.35-3.16 (4H, m), 3.14 (IH, 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 8940 (4H, m), 0.86 (6H, q, 7=8Hz). m/z (ESI) 556 (MH+) Anal.calc. for C31H45Ν3O4S C 66.99, H 8.16, N 7.56 Found C 66.65, H 8.20, N 7.23
Figure imgf000433_0001
8945 Example 914
N-r4-(N-(N.N-dibenzylacetamido aminomethyl)-2-(2-methylphenyπbenzoyllmethionine The desired compound was prepared according to the method of Example 158. *H (300MHz, DMSO-d6, δ) (rotamer) 7.76 ( IH, m), 7.40 (IH, d, 7=9Hz), 7.30-7.00 (15H, m), 4.41 (4H, d, 7= 12Hz), 4.10 (IH, m), 3.73 (2H, s), 3.41 (2H, s), 2.20-1.90 (5H, m), 8950 1.87 (1.83) (3H, s), 1.80-1.50 (2H,m). m/z (ESI) 610 (MH+)
Figure imgf000433_0002
Example 915 8955 N- 4-(N-(2-Cyclohexylethyl -N-isopropylaminomethyl)-2-(2-methylphenyl)- benzoyllmethionine The desired compound was prepared according to the method of Example 158. ^H (300MHz, CDCI3, δ) 7.80-7.60 (2H, m), 7.30-7.00 (5H, m), 6.50 (IH, d, 7=8Hz), 4.38 ( IH, m), 4.03 (2H, m), 3.67 (IH, m), 2.88 (2H, m), 2.20-2.00 (7H, m), 2.00 (3H, s), 8960 1.80-1.40 (8H, m), 1.33 (6H, d, 7=7Hz), 1.30-1.00 (3H, m), 1.00-0.80 (2H, m). m/z (ESI) 525 (MH+) Anal.calc. for C31H44Ν2O3SO.50 H2O C 69.76, H 8.50, N 5.25 Found C 69.90, H 8.26, N 5.57
Figure imgf000434_0001
Example 916
N-r4-(N-Butanesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyll methionine
The desired compound was prepared according to the method of Example 157. ^H
8970 (300MHz, CDC13, δ) 7.99 ( IH, m), 7.45 (IH, dd, 7=9&2Hz), 7.40-7.10 (5H, m), 5.92
(IH, m), 4.56 (IH, 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 ( 10H, m), 1.30-1.00 (4H, m), 0.95 (3H, t,
7=8Hz), 0.83 (2H, m). m/z (ESI) 603 (MH+) Anal.calc. for C32H46Ν2O5S2 O.25 H2O C
63.28, H 7.72, N 4.61 Found C 63.27, H 7.73, N 4.50
8975
Figure imgf000434_0002
Example 917 8980 N-r4-(N,N-Dibutylaminomethyl)-2-(2-methylphenyl)benzoyllmethionine
The desired compound was prepared according to the method of Example 158. *H (300MHz, CDCI3, δ) 7.75 (IH, d, 7=9Hz), 7.67 (IH, m), 7.30-7.10 (5H, m), 6.33 (IH, m), 4.42 (IH, 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, 7=8Hz). m/z (DCI, ΝH3) 485 8985 (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
Figure imgf000435_0001
8990 Example 927 N-14-(N-Butanesulfonyl-N-(3-phenylpropyl aminomethyl -2-(2- methylphenyDbenzoyllmethionine The desired compound was prepared according to the method of Example 157 ^H (300MHz, CDCI3, δ) 7.97 ( IH, m), 7.40 (IH, dd, 7=9&2Hz), 7.35-7.10 (8H, m), 7.04
8995 (IH, d, 7=2Hz), 7.03 (IH, s), 5.89 (IH, m), 4.60 ( IH, m), 4.43 (2H, s), 3.22 (2H, t, 7=8Hz), 2.96 (2H, t, 7=8Hz), 2.55 (2H, t, 7=8Hz), 2.20-2.05 (2H, m), 2.05 (3H, s), 2.02 (3H, s), 2.00-1.70 (5H, m), 1.57 (IH, m), 1.42 (2H, m), 0.94 (3H, t, 7=8Hz). m/z (ESI) 609 (MH-) Anal.calc. for C33H42Ν2O5S2 C 64.89, H 6.93, N 4.59 Found C 64.61, H 6.90, N 4.52
9000
Figure imgf000435_0002
Example 928 N-r4-(N-Butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl benzoyllmethionine 9005 The desired compound was prepared according to the method of Example 157 H
(300MHz, CDCI3, δ) 7.78 (IH, d, 7=9Hz), 7.60 (IH, bd, 7=8Hz), 7.40-7.20 (5H, m), 7.20-7.00 (5H, m), 6.27 (IH, m), 4.43 (IH, m), 4.20-4.00 (2H, m), 3.20-2.80 (6H, m), 2.20-2.05 (5H, m), 1.98 (3H, s), 1.90 (IH, m), 1.63 (3H, m), 1.32 (2H, m), 0.93 (3H, t, 7=8Hz). m/z (ESI) 533 (MH+) Anal.calc. for C32H40Ν2O3SAOO H2O C 69.79, H 7.69, 9010 N 5.09 Found C 70.04, H 7.48, N 4.96
Figure imgf000436_0001
Example 936 9015 N-[4-(N-benzylaminomethyl -2-phenylbenzoyllmethionine hydrochloride salt
The desired compound was prepared according to the method of Example 158 (DMSO-d6) δ 8.61 (d.lH), 7.61 (m, lH), 7.58 (m, 3H), 7.40 (m, 9H), 4.32 (m, IH), 4.22 (s, 2H), 4.18 (s, 2H), 2.27 (m, 2H), 2.00 (s, 3H), 1.88 (m, 2H). MS (DCI/ΝH3) 449 (M+H)+. Anal calcd for C26H29CIN2O3S 0.80 H2O: C, 62.53; H, 6.18; N, 5.61. 9020 Found: C, 62.59; H, 6.31 ; N, 5.57.
Figure imgf000436_0002
Example 944 9025 N-[4-N-(3-Cyclohexyl-l-ethylthiopropan-2-yl)-N-methylaminomethyl-2-(2- methylphenyDbenzoyfl-methionine hydrochloride salt The desired compound was prepared according to the method of Example 158 (DMSO-d6) δ 8.23 (m, IH), 7.75 (m, IH), 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, IH), 3.10, 2.90, 2.70 (all m, total 9030 5H), 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 C32H47CIΝ2O3S2 : C, 63.29; H, 7.80; N, 4.61. Found: C, 63.07; H, 7.79; N, 4.51.
Figure imgf000437_0001
Example 945 N-r4-N-(3-Cvclohexyl-l-ethylthiopropan-2-yl)-N-isobutylaminomethyl-2-(2- methylphenyr. benzoyl! -methionine The desired compound was prepared according to the method of Example 158
9040 (DMSO-d6) δ 8.05 (d, IH), 7.55 (d, IH), 7.42 (d, IH), 7.22, 7.20 (both m, total 5H), 4.27 (m, IH), 3.73 (d, IH), 3.60 (d, IH), 2.90 (dd, IH), 2.77 (m, IH), 2.45 (q, 2H), 2.30, 2.10 (both m, total 8H), 2.00 (s, 3H), 1.97-1.25 (envelope, 1 1H), 1.19 (t, 3H), 1.19-0.70 (envelope, 12H). MS (ESI) 611 (M-H)". Anal calcd for C33H52Ν2O3S2 0.25 H2O : C, 68.09; H, 8.57; N, 4.54. Found: C, 67.96; H, 8.53; N, 4.49.
9045
Figure imgf000437_0002
Example 946 N-[4-N-(3-Cyclohexyl-l-ethylthiopropan-2-yl -N-formylaminomethyl-2-(2- 9050 methylphenyDbenzoyllmethionine
The desired compound was prepared according to the method of Example 607, followed bt Schotten-Baumann acylation. (DMSO-d6) δ 8.40, 8.27 (both s, total IH), 8.03, 7.97 (both d, total IH), 7.45 (m, 2H), 7.20, 7.15 (both m, total 5H), 4.40 (m, 2H), 4.21 (m, IH), 3.70 (m, IH), 2.62, 2.46 (both m, total 4H), 2.18, 2.05 (both m, total 5H), 1.96 9055 (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 C32H44Ν2O4S2 : C, 65.72; H, 7.58; N, 4.79. Found: C, 65.47; H, 7.53; N, 4.74.
Figure imgf000438_0001
Example 947 N-r4-N-acetyl-N-(3-Cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoy 11 methionine The desired compound was prepared according to the method of Example 946
9065 (DMSO-d6) δ 8.12, 8.00 (both d, total IH), 7.55, 7.45, 7.40 (all m, total 2H), 7.20, 7.10, 7.06 (all m, total 5H), 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 11H), 1.90-1.20 (envelope, 9H), 1.15, 1.10, 0.80 (all m, total 9H). MS (ESI) 597 (M-H)". Anal calcd for C33H46Ν2O4S2 : C, 66.19; H, 7.74; N, 4.68. Found: C, 66.02; H, 7.68; N, 4.56.
9070
Figure imgf000438_0002
Example 948 N- 4-N-t-Butyloxycarbonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2- 9075 methylphenyl)benzoyl]methionine
The desired compound was prepared according to the method of Example 946 (DMSO-d6) δ 7.95 (m, IH), 7.46 (m, IH), 7.38 (m, IH), 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 9080 C36H52Ν2O5S2 : C, 65.82; H, 7.98; N, 4.26. Found: C, 65.56; H, 7.99; N, 4.20.
Figure imgf000439_0001
Example 949 9085 V-r4-N-Benzoyl-N-(3-Cvclohexyl-l-ethylthiopropan-2-ylN)aminomethyl-2-(2-methylphenyl)- benzoyll methionine The desired compound was prepared according to the method of Example 946 (DMSO-d6) δ 8.10 (d, IH), 7.44 (m, 7H), 7.20 (m, 5H), 4.77, (d, IH), 4.57 (d, IH), 4.22 (m, IH), 3.82 (m, IH), 2.82 (m, IH), 2.62 (m, IH), 2.23, 2.10 (both m, total 7H), 9090 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 C38H48Ν2O4S2 : C, 69.06; H, 7.32; N, 4.24. Found: C, 68.94; H, 7.31 ; N, 4.17.
Figure imgf000439_0002
Example 950 N-r4-N-Butanesulfoyl-N-(3-Cyclohexyl-l-ethylthiopropan-2-yPaminomethyl-2-(2- methylphenyP-benzoyllmethionine The desired compound was prepared according to the method of Example 157
9100 (DMSO-d6) δ 8.08 (d, IH), 7.57 (s, 2H), 7.35, 7.25, 7.18 (all m, total 5H), 4.44 (m, 2H), 4.28 (m, IH), 3.87 (m, IH), 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 C35H52Ν2O5S3
: C, 62.10; H, 7.74; N, 4.14. Found: C, 61.86; H, 7.57; N, 4.18.
9105
Figure imgf000440_0001
Example 951 N-r4-N-Benzenesulfonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2- 9110 methylphenyP-benzoyllmethionine
The desired compound was prepared according to the method of Example 157 (DMSO-d6) δ 8.07 (d, IH), 7.86 (d, 2H), 7.70 (m, IH), 7.64 (m, 2H), 7.50 (s, 2H), 7.20 (m, 5H), 4.50 (m, 2H), 4.22 (m, IH), 3.72 (m, IH), 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) 9115 695 (M-H)'. Anal calcd for C37H48Ν2O5S3 : C, 63.76; H, 6.94; N, 4.02. Found: C, 63.63; H, 6.93; N, 3.94.
Figure imgf000440_0002
9120 Example 952
N-[4-(4-hydroxyprolinylamdnoy2-phenylbenzoyllmethionine
Example 952A N-r4-N-(N-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-L-prolinyPamino-2-phenylbenzoyll- 9125 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 IN LiOH (5 mL) in an ice-bath. The reaction mixture was stiπed for 30 min. The reaction mixture was adjusted to pH2-3 with IN HCl at the same temperature and the solvent was evaporated. The resulting residue was 9130 partitioned with dichloromethane and water, and extracted 3 times with dichloromethane. The combined organic solution was washed with IN 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 μL, 3.9 mmol) in an ice-
9135 bath under argon, followed by IBCF (470 μL, 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 stiπed overnight, during which time the ice-bath expired. The reaction mixture was washed with IN HCl, 5% sodium
9140 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 83°C; [α]25 D -36.2 (c=0.63, CHCI3); 'H NMR (300 MHz, CDCI3) δ 9.94 (s, IH), 7.53-7.26 (m, 8H), 6.41 (d, IH, 7=6.0Hz), 4.55 (m, 4H), 3.63 (s, 3H), 3.57 (m, IH), 3.32 (m, IH), 2.30 (m, IH), 2.05 (m, 2H), 1.94 (s, 3H), 1.83
9145 (m, IH), 1.73 (m, IH), 1.45 (s, 9H), 0.86 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCI3) δ 171.8, 170.7, 169.3, 155.6, 140.0, 129.7, 129.0, 128.5, 128.2, 127.4, 120.2, 1 17.7, 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 (El) calculated for C35H5 iN3θ7SSi: 685.9498, found: 685.3217. ^H NMR (300 MHz, CDCI3+CD3OD) δ 7.53-7.29 (m, 8H), 4.67 (m, IH), 4.58 (s, IH), 4.50 (m, IH),
9150 2.57 (m, IH), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, IH), 1.76 (m, IH); 13C NMR
(CD3OD) δ 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 1 19.3, 71.2, 60.6, 55.2, 52.9, 39.9, 31.4, 30.9, 15.0.
Example 952B 9155 N-r4- V-(N-t-butoxycarbonyl-4-hydroxy-L-prolinyPamino-2-phenylbenzoynmethionine 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 stiπed for overnight, diluted with EtOAc, and washed 3 times with water. The combined aqueous washings were extracted 3 9160 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 121-123°C; [α]25 D -53.3 (c=0.43, CHCI3); X ΝMR (300 MHz, CDCI3) δ 9.84 (s, IH), 7.60-7.38 (m, 8H), 6.35 (br s, IH), 4.58-4.51 (br s, 4H), 3.64 (s, 3H), 3.57 (m, IH), 3.48 (m, IH), 9165 2.63 (m, IH), 2.44 (br s, IH), 2.07 (m, 2H), 1.98 (s, 3H), 1.86 (m, IH), 1.72 (m, IH), 1.44 (s, 9H); HRMS (El) calculated for C29H37Ν3O7S: 571.6872, found: 571.2352.
Example 952C N-r4-N-(4-hvdroxy- -prolinyPamino-2-phenylbenzoyllmethionine trifluoroacetate (FTI-
9170 2103)
To a solution of the above compound (358 mg, 0.62 mmol) in methanol (6 mL)was added IN LiOH (1 mL) in an ice bath. The reaction mixture was stiπed 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
9175 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
9180 ether and the white solid was collected by filtration to give 6 (254 mg, 72%): HPLC 90% (purity); mp 127 (sub.), 154-157 °C (dec); X ΝMR (300 MHz, CDCI3+CD3OD) δ 7.53- 7.29 (m, 8H), 4.67 (m, IH), 4.58 (s, IH), 4.50 (m, IH), 2.57 (m, IH), 2.14 (m, 2H), 2.01 (s, 3H), 1.96 (m, IH), 1.76 (m, IH); 13C ΝMR (CD3OD) δ 174.8, 172.6, 168.1, 142.4, 141.2, 140.6, 133.2, 130.0, 129.6, 129.5, 128.8, 122.2, 1 19.3, 71.2, 60.6, 55.2,
9185 52.9, 39.9, 31.4, 30.9, 15.0.
Figure imgf000442_0001
Example 959 9190 N-[4-((2S.4S -4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyllmethionine
Example 959A N-[4-Ν-(('2R.3R)-l-t-butyloxycarbonyl-3-t-butyldimethylsilyloxypyπolidin-2- ylmethylamino -2-phenylbenzoynmethionine methyl ester 9195 To a solution of N-[4-amino-2-phenylbenzoyl]methionine methyl ester (238 mg,
0.66 mmol) and (2R,3R)-l-t-butyloxycarbonyl-3-t-butyldimethylsilyloxypyπolidine-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 stiπed overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5% 9200 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: [H NMR (300 MHz, CDC13) δ 7.68 (d, IH, 7=8.4 Hz), 7.40 (m, 6H), 6.62 (d, IH), 6.44 (br
9205 s, IH), 5.65 (d, IH), 5.43 (s, IH), 4.61 (m, IH), 4.41 (br s, IH), 4.08 (br s, IH), 3.64 (s, 3H),3.58-3.14 (m, 5H), 2.10 (t, 2H, 7=7.7 Hz), 2.01 (s, 3H), 1.88 (m, IH), 1.64 (m, IH), 1.43 (s, 9H); 0.88 (s, 9H), 0.07 (s, 6H); HRMS (El) calculated for C35H53N3θόSSi: 671.3424, found: 671.3415.
9210 Example 959B
N-r4-N-((2R,3R -l-t-butyloxycarbonyl-3-hydroxypyπolidin-2-ylmethylamino)-2- phenylbenzoyllmethionine methyl ester To a solution of the compound prepared in Example 959 A (98 mg, 0.14 mmol) in THF (2 mL) was added 1M TBAF-THF (0.18 mL). The reaction mixture was stirred for 15
9215 min at 0°C, 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 °C; [α] 5o
9220 +6.32 (c=0.19, CHCI3); *H NMR (300 MHz, CDCI3) δ 7.61 (d, IH, 7=8.3 Hz), 7.30 (m, 6H), 6.59 (dd, IH, 7=1.2, 8.3 Hz), 6.43 (d, IH, 7=2.1 Hz), 5.74 (d, IH, 7=7.6 Hz), 5.44 (br s, IH), 4.57 (m, IH), 4.40 (m, IH), 4.07 (br s, 2H), 3.59 (s, 3H), 3.37-3.16 (m, 5H), 2.04(m, 2H), 1.96 (s, 3H), 1.87 (m, IH), 1.65 (m, IH), 1.43 (s, 9H); HRMS (El) calculated for C29H39N3O6S: 557.2559, found: 557.2544.
9225
Example 959C N-r4-N-((2R.3S)-l-t-butyloxycarbonyl-3-acetylthiopyπolidin-2-ylmethylamino)-2- phenylbenzoyllmethionine methyl ester To a solution of the compound prepared in Example 959B (300 mg, 0.53 mmol) in 9230 THF ( 10 mL) were added TPP (278 mg, 1.06 mmol), followed by DIAD (208 μL, 1.06 mmol) at 0° C under argon. The mixture was allowed to stir for 30 min and thiolacetic acid (76 μL, 1.06 mmol) was added to this mixture at the same temperature. The reaction mixture was stiπed 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 9235 hexanes and ethyl acetate to give the desired compound (211 mg, 64 %): X NMR (300 MHz, CDCI3) δ 7.68 (d, IH, 7=8.2 Hz), 7.39 (m, 6H), 6.64 (br s, IH), 6.44 (br s, IH), 5.66 (d, IH, 7=7.4 Hz), 5.39 (br s, IH), 4.60 (m, IH), 4.03-3.87 (m, 2H), 3.62 (s, 3H), 3.42-3.1 1 (m, 5H), 2.33 (s, 3H), 2.07 (t, 2H, 7=7.6 Hz), 1.99 (s, 3H), 1.87 (m, IH), 1.64 (m, IH), 1.43 (s, 9H); HRMS (El) calculated for C31H41N3O6S2: 615.2436, found:
9240 615.2437.
Example 959D N-r4-N-((2R.3S)-3-acetylthiopyπolidin-2-ylmethylamino -2-phenylbenzoyllmethionine hydrobromide 9245 To a solution of the compound prepared in Example 959C (106 mg, 0.17 mmol) in dichloromethane (10 mL) was added 1M boron tribromide-dichloro methane (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 stiπed 4 hr at room temperature, and quenched by dropwise addition of water ( 5 mL). The solvent was removed to give crude residue.The 9250 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: X NMR (300 MHz, CD3OD) δ 7.48-7.35 (m, 6H), 7.01 (d, IH, 7= 8.6Hz), 6.64 (s, IH), 4.45 (dd, IH, 7=4.1 , 9.2 Hz), 3.92-3.81 (m, 2H), 3.69-3.65 (m, IH), 3.55-3.40 (m, 4H), 2.55 ( m, IH), 2.32 (s, 3H),2.22 (m, IH), 2.09 (m, IH), 2.05 (s, 3H),1.97 (m, IH), 1.79 (m, IH). 9255
Example 959E N-r4-(('2S.4S -4-thiolpyπolidin-2-ylmethylamino -2-phenylbenzoynmethionine 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 0° C under argon. The 9260 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 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 12 (7.7 mg, 10.3 %) as 9265 a white powder: X ΝMR (300 MHz, CD3OD) δ 7.45-7.39 (m, 6H), 6.74 (br s, IH), 6.70 (br s, IH), 4.44 (br s, IH), 3.72-3.30 (m, 7H), 2.56 (br s, IH), 2.18 (m, IH), 2.02- 1.96 (m, 2H), 2.01 (s, 3H), 1.80 (m, IH).
Figure imgf000445_0001
Example 960
N-14-((2S.4R -4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyllmethionine
Example 960A
9275 (2R.3S)-l-„9oc-2-t-butyldimethylsilyloxymethyl-3-benzoyloxypyrrolidine
To a solution of (2R,3S)-l-βøc-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
9280 g, 9.2 mmol) was added dropwisely to this mixture at the same temperature. The reaction mixture was stiπed 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
9285 of hexanes and ethyl acetate to yield 14 (1.3 g, 65 %) as a foamy solid: 'H ΝMR (300 MHz, CDC13) δ 7.55-7.32 (m, 5H), 5.49 (dd, IH, 7= 4.2, 1 1.7 Hz), 3.98-3.52 (m, 5H), 2.40 (m, IH), 2.07 (m, IH), 1.47 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); MS (El) m/z (relative intensity) 379 ([M-C4H81+, 15), 322 (50), 154 (50), 105 (90), 77 (80).
9290 Example 960B
(2R.3S l-_9oc-2-t-butyldimethylsilyloxymethyl-3-hydroxypyπolidine To a solution of the compound prepared in Example 960A (1.25 g, 2.86 mmol) in methanol (5 mL) was added IN LiOH (3 mL) in an ice-bath. The reaction mixture was stiπed for 2 hr. The reaction mixture was adjusted to pH2-3 with IN HCl at the same
9295 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 118°C;
9300 [α]2 D -46.7 (c=0.47, CHCI3); X ΝMR (300 MHz, CDCI3) δ 4.34 (s, IH), 3.77 (dd, IH, 7= 3.0, 9.8 Hz), 3.66-3.29 (m, 4H), 2.54 (d, IH, 7= 8.5 Hz), 2.09 (m, IH), 1.79 (m, IH), 1.42 (s, 9H), 0.85 (s, 9H), 0.01 (s, 6H); 13C NMR (CDC , minor isomer) δ 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 (El) m/z (relative intensity) 275 ([M-C4H8]+, 20), 259 (85), 218 (100), 86 9305 (40), 75 (55). 57 (90).
Example 960C (2R.3S) l-βoc-2-t-butyldimethylsilyloxymethyl-3-t-butyldimethylsilyloxypyπolidine To a solution of the compound prepared in Example 960B (198 m g, 0.59 mmol) in 9310 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 stiπed 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 9315 hexanes and ethyl acetate to obtain the title compound (235 mg, 88%): X NMR (300 MHz, CDC13) δ 4.27 (m, IH), 3.62-3.20 (m, 5H), 1.88 (m, IH), 1.62 (m, IH), 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).
9320 Example 960D
(2R.3S l-5oc-2-hydroxymethyl-3-t-butyldimethylsilyloxypyπolidine 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 stiπed for overnight at room temperature. After this time, the reaction mixture was 9325 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%): *H NMR (300 MHz, CDCI3) δ 4.41 (br s, IH), 4.00 (s, IH), 3.66-3.27 (m, 5H), 1.88 (m, IH), 1.70 (m, IH), 1.42 (s, 9H), 0.83 (s, 9H), 0.03 (s, 6H). 9330
Example 960E N-4-K2R.3S l-Boc-3-t-butyldimethylsilyloxypyπolidin-2-ylmethyllamino)-2- phenylbenzoyll methionine methyl ester To a solution of DMSO (42 μL, 0.58 mmol) in dichloromethane (2 mL) were added 9335 trifluoroacetic anhydride (62 μl, 0.43 mmol) via syringe at -78 °C 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 stiπed for 1 hr. To this solution was added triethylamine ( 122 μl, 0.87 mmol). The reaction mixture was allowed for 1 hr at -78°C, slowly warmed to room temperature and
9340 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
9345 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: X NMR (300 MHz, CDC1 ) δ 7.64 (d, IH, 7=8.0 Hz), 7.35
9350 (m, 6H), 6.55 (d, IH, 7= 8.2 Hz), 6.37 (br s, IH), 5.67 (d, IH, 7=7.6 Hz), 5.55 (s, IH), 4.56 (m, IH), 4.21-3.15 (m, 7H), 3.59 (s, 3H), 2.04 (t, 2H, 7=7.7 Hz), 1.95 (s, 3H), 1.83 (m, IH), 1.60 (m, IH), 1.42 (s, 9H); 0.82 (s, 9H), -0.03 (s, 6H); 13C NMR (CDCI3, minor isomer) δ 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,
9355 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 N-4-IY2R.3S) l-Boc-3-hydroxypyπolidin-2-ylmethyl1amino -2-phenylbenzoyllmethionine
9360 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 stiπed for 30 min at 0°C 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
9365 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: X NMR (300 MHz, CDCI3) δ 7.55 (d, IH, 7=8.3 Hz), 7.30 (m, 6H), 6.45 (d, IH, 7=8.5 Hz), 6.31 (br s, IH), 5.75 (br s, IH),
9370 5.54 (br s, IH), 4.51 (m, IH), 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, IH), 1.56 (m, IH), 1.38 (s, 9H).
Example 960G N-4-1Y2R.3R) l-Boc-3-acetylthiopyπolidin-2-ylmethyllamino -2-phenylbenzoyllmethionine
9375 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 μL, 0.30 mmol) at 0° C under argon. The mixture was allowed to stir for 30 min and thiolacetic acid (22 μL, 0.31 mmol) was added to this mixture at the same temperature. The reaction mixture was
9380 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: X NMR (300 MHz, CDC13) δ 7.65 (d, IH, 7=9.0 Hz), 7.37 (s, 5H), 6.55 (d, IH, 7= 7.7 Hz), 6.37 (s, IH), 5.66 (d, IH, 7=7.3 Hz), 5.44 (br s, IH), 4.58 (m, IH), 4.40-3.98 (m, 3H), 3.60 (s,
9385 3H), 3.38-3.06 (m, 3H), 2.32 (s, 3H), 2.21 (m, IH), 2.07 (t, 2H, 7=7.6 Hz), 1.99 (s,
3H), 1.87 (m, IH), 1.64 (m, IH), 1.43 (s, 9H); 13C NMR (CDCI3) δ 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, 1 1 1.0, 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 (El) calculated for C31H41N3O6S2: 615.2436, found: 615.2436.
9390
Example 960H N-4-IY2R.3R 3-thiopyπolidin-2-ylmethyllamino)-2-phenylbenzoyllmethionine hydrobromide To a solution of the compound prepared in Example 960G (78 mg, 0.12 mmol) in
9395 dichloromethane (5 mL) was added IM boron tribromide-dichloromethane (1.2 mL) at 0° C under argon. The mixture was allowed to stir for 1 hr at the same temperature. Additionally the reaction mixture was stiπed 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
9400 acetate (0.1 g, 0.31 mmol) was added at 0° 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,
9405 and purified by Prep-HPLC to afford the desired compound (17 mg, 23 %) as a white powder: X NMR (300 MHz, CD3OD) δ 7.46-7.34 (m, 6H), 6.74 (m, IH), 6.66 (s, IH), 4.46 (m, IH), 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).
9410
Figure imgf000449_0001
Example 979 N-r4-(N-2-chloroethoxycarbonyPamino-2-phenylbenzoyllmethionine The desired compound was prepared according to the method of Example 57 X 9415 NMR (CD OD): δ 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, 7= 5.8 Hz, 2 H), 4.44 (dd, 7= 4.4, 9.2 Hz, 1 H), 6.58 (d, 7= 2.3 Hz, 1 H), 6.66 (dd, 7= 2.3, 8.5 Hz, 1 H), 7.27-7.46 (comp, 8 H). LRMS (CI): 389 (M- 62, loss of COCl)+.
9420
Figure imgf000449_0002
Example 980 N- 4-(N-5-(4-ChlorophenyPfuran-2-ylmethyl-N-isopropylaminomethyπ-2-(2- methylphenyPbenzoyllmethionine lithium salt
9425 The desired compound was prepared according to the method of Example 158 X NMR (300 MHz, d6 DMSO) δ 7.59 - 7.55 (m, 2H), 7.44 (d, IH), 7.42 - 7.36 (m, 3H), 7.24 - 7.06 (m, 5H), 6.88 (d, IH), 6.36 (d, IH), 3.69 (s, 2H), 3.65 (s, 2H), 2.96 (m, IH), 2.16 - 1.50 (m, 1 IH) 1.04 (d, 6H) Calcd for the acid C34H36O4N2SCI APCI -QIMS, MH- 603.
9430
Figure imgf000450_0001
Example 982 N- 4-(N-Methyl-N-( 1. l-dimethyl-2-phenylethyl)aminomethyP-2-(2-methylphenyP- 9435 benzoyllmethionine lithium salt
The desired compound was prepared according to the method of Example 158 X ΝMR (300 MHz, DMSO) δ 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, IH), 7.05-7.23 (m, 10H), 7.34 (dd, J=7.8, 1.5 Hz, IH), 7.47 (d, J=7.8 Hz, IH). MS (APCI(+)) m/z 518 9440 (M+H); Analysis calc'd for C31H37L1Ν2O3S+O.85H2O: C, 68.96; H, 7.22; N, 5.19; found: C, 68.86; H, 6.60; N, 5.25.
Figure imgf000450_0002
9445 Example 983 N-r4-(N-Methyl-N-(l,l-dimethyl-2-cyclohexylethyPaminomethyP-2-(2-methylphenyP- benzoy 11 methionine lithium salt The desired compound was prepared according to the method of Example 158 X ΝMR (300 MHz, DMSO) δ 0.85-1.17 (m, 6H), 1.03 (brs, 6H), 1.30-1.35 (m, 2H), 1.51-
9450 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, IH), 6.92 (d, J=5.0 Hz, IH), 7.11-7.23 (m, 5H), 7.34 (d, J=7.7 Hz, IH), 7.46 (d, J=7.8 Hz, IH). MS (APCI(+)) mAz 525 (M+H); Analysis calc'd for C31H43L1Ν2O3S+O.8OH2O: C, 68.31; H, 8.25; N, 5.14; found: C, 68.29; H, 8.23; N, 5.04.
9455
Figure imgf000451_0001
Example 986 N-r4-(N-2-Cyclohexylethyl- V-thiazol-5-ylmethylaminomethyP-2-(2-methylphenyl)benzoyll- 9460 methionine
The desired compound was prepared according to the method of Example 157 X nmr (300 MHz, DMSO d6): δ 9.02, s, IH; 8.09, d, IH; 7.76, s, IH; 7.48, d, IH; 7.37, dd, IH; 7.21, m, 2H; 7.15, m, 3H; 4.21, m, IH; 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, 9465 2H. MS (ESI(-)): 578 (M-H); (ESI(+)): 580. Calc'd for C32H41Ν3O3S2: C 66.29, H 7.13, N 7.43: Found: C 65.82, H 7.03, N 7.34.
Figure imgf000451_0002
9470 Example 995
N- 4-(l-ethylthio-4-phenylbut-2-oxymethyP-2-(2-methylphenyl)benzoyllmethionine The desired compound was prepared according to the method of Example 158 ^H (300MHz, CDCI3, δ) 7.70 (IH, m), 7.38 (IH, dd, J=6&2Hz), 7.30-7.20 (6H, m), 7.20- 7.05 (3H, m), 7.04 (IH, bs), 6.12 (IH, m), 6.00-5.40 (2H, m), 4.38 (IH, m), 4.01 (IH, 9475 m), 3.85 (IH, d, J=12Hz), 3.00-2.50 (5H, m), 2.37 (2H, m), 2.20-2.00 (6H, m), 1.98 (3H, s), 1.86 (2H, m), 1.57 (IH, m), 1.07 (3H, t, J=8Hz). m/e (ESI) 565 (MH+) Anal.calc. for C32H40Ν2O3S2 .5O H2O C 66.98, H 7.20, N 4.88 Found C 67.02, H 7.24, N 4.80
9480
Figure imgf000452_0001
Example 996 N-[4-(N-cvclohexylmethyl-N-butanesulfonylaminomethyl)-2-(2- methy lphenvPbenzoy 11 methionine 9485 The desired compound was prepared according to the method of Example 157 ^H
(300MHz, DMSO-d6, δ) 7.54 (IH, m), 7.42 (IH, m), 7.30-7.10 (5H, m), 6.96 (IH, m), 4.40 (2H, m), 3.63 (IH, 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") 9490
Figure imgf000452_0002
Example 997 9495 Ν-[4-Ν-benzyl-Ν-('4-cyanophenyPaminomethyl-2-(2-methylphenyl)benzoyllmethionine. lithium salt
Figure imgf000452_0003
Example 997A 9500 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 9505 rinsed with brine (30 mL), dried over MgSO4, 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 997 A as a white solid (86% yield).
X NMR (CDCl3):δ 4.37 (d, J = 5.4 Hz, 2 H), 2.58-4.66 (br, 1 H), 6.58 (d, J = 8.8 Hz, 2 9510 H), 7.'26-7.42 (comp, 7 H). LR
MS (CI+): (M+H)+ calc for C14H13N2: 209; found: 209.
Figure imgf000453_0001
Example 997B
9515 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
9520 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).
9525 X NMR (CDCl3):δ 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, 1 H). LR MS (CI+): (M+H)+ calc for Cι65ClO2: 274; found: 274; (M+NH4)+ calc for Cι68ClNO2: 292; found: 292.
Figure imgf000453_0002
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 9535 (5 mL) was heated to 70 °C. 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 °C 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
9540 hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-l,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 °C for 18 h, cooled to room temperature, diluted with ethyl acetate (80 mL), and extracted with 2: 1: 1 H2O: saturated aqueous NaHC03: brine (50 mL + 2 x 20 mL), followed by brine (10 mL). The organic layer was dried over
9545 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 (3.2% yield). X NMR (d6-DMSO):δ 1.52-1.65 (m, 1 H), 1.79-1.91 (m, 1 H), 1.98-2.12 (comp, 8 H),
9550 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 C35H36N3O3S: 578; found: 578. LR MS (ESI-): (M-H)- calc for C35H34N3O3S: 576; found: 576.
9555
Figure imgf000454_0001
Example 997D N-r4-N-benzyl-N-(4-cyanophenyPaminomethyl-2-(2-methylphenyPbenzoynmethionine, lithium salt 9560 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). 9565 X NMR (d6-DMSO):δ 1.48-1.76 (comp, 2 H), 1.88-2.08 (comp, 8 H), 3.59-3.72 (br, 1 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, H), 7.07-7.37 (comp, 10 H), 7.47-7.53 (comp, 3 H). HR MS (FAB): (M+H)+ calc for C34H34N3O3S: 564.2321 ; found: 564.2325 (0.8 ppm error).
9570
Figure imgf000455_0001
Example 998
N- 4-N-benzyl-N-(4-carboxamidophenyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine, lithium salt
9575
Figure imgf000455_0002
Example 998A Compound 998A was prepared in the same fashion as 997A (69% yield). X NMR (d6-DMSO):δ 4.32 (d, J = 5.9 Hz, 2 H), 6.55 (d, J = 8.6 Hz, 2 H), 6.78-6.92
9580 (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.
Figure imgf000455_0003
9585 Example 998B Compound 998B was prepared in the same fashion as 997C (5.7% yield). X NMR (d6-DMSO):δ 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 9590 (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 C35H38N3O4S: 596; found: 596. LR MS (ESI-): (M-H)- calc for C35H36N3O4S: 594; found: 594.
Figure imgf000456_0001
9595 Example 998C N- 4-N-benzyl-N-(4-carboxamidophenyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine. lithium salt Compound 998C was prepared in the same fashion as 997D (100% yield). X NMR (d6-DMSO):δ 1.47-1.61 (m, 1 H), 1.62-1.73 (m, 1 H), 1.87-2.08 (comp, 8 H),
9600 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, 1 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 C34H35LiN3O4S: 588.2508; found: 588.2502 (-1.0 ppm error).
9605
Figure imgf000456_0002
Example 999
N-[4-N-benzyl-N-(4-sulfonamidophenyl)aminomethyl-2-(2-
9610 methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000456_0003
Example 999A Compound 999A was prepared in the same fashion as 997A (51% yield). 9615 'H NMR (d6-DMSO):δ 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.
Figure imgf000457_0001
Example 999B Compound 999B was prepared in the same fashion as 997C (1.3% yield). X NMR (CDCl3):δ 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
9625 (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.
9630
Figure imgf000457_0002
Example 999C N-r4-N-benzyl-N-(4-sulfonamidophenyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine. lithium salt
9635 Compound 999C was prepared in the same fashion as 997D (90% yield). X NMR (d6-DMSO):δ 1.46-1.82 (comp, 2 H), 1.86-2.16 (comp, 8 H), 3.59-3.73 (m, 1 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 C33H36N3O3S2: 618.2087; found: 618.2091 (-0.7 ppm 9640 error).
Example 1000 N-r4-N-benzyl-N-C4-N-henzoylsulfonamidophenyPaminomethyl-2-(2- 9645 methylphenvPbenzoyllmethionine. lithium salt
Figure imgf000458_0001
Example 1000 A Compound 1000A was prepared in the same fashion as 997 A (81% yield). 9650 iH NMR (CDCl ):δ 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.
Figure imgf000458_0002
Example 1000B Compound 1000B was prepared in the same fashion as 997C (5.6% yield).
X NMR (CDCl3):δ 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), 9660 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. 9665
Figure imgf000459_0001
Example 1000C N-r4-N-benzyl-N-('4-N-benzoylsulfonamidophenyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine. lithium salt
9670 Compound 1000C was prepared in the same fashion as 997D (77% yield). X NMR (d6-DMSO):δ 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
9675 MS (ESI-): (M-H)- calc for C4oH38N3θ6S2: 720; found: 720.
Figure imgf000459_0002
Example 1001 9680 N-r4-N-benzyl-N-(4-propionylphenyl)aminomethyl-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000459_0003
Example 1001A 9685 Compound 1001 A was prepared in the same fashion as 997 A (89% yield).
X NMR (CDCl3):δ 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, 1 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 C17H20NO: 254; found: 254.
9690
Figure imgf000460_0001
Example 100 IB Compound 100 IB was prepared in the same fashion as 997C (49% yield). X NMR (CDCl3):δ 0.97 (t, J = 7.5 Hz, 3 H), 1.52-1.66 (m, 1 H), 1.73 (app q, J = 7.5
9695 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, 1 H). LR
MS (ESI+): (M+H)+ calc for C38H43N2O4S: 623; found: 623. LR
9700 MS (ESI-): (M-H)- calc for C28H4iN2O4S: 621; found: 621.
Figure imgf000460_0002
Example 1001C N-r4-N-benzyl-N-(4-propionylphenyPaminomethyl-2-(2- 9705 methylphenyPbenzoyll methionine. lithium salt
Compound 1001C was prepared in the same fashion as 997D (98% yield). X NMR (d6-DMSO):δ 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 9710 (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 C37H39L12N2O4S: 621.2951; found: 621.2966 (2.4 ppm error).
Figure imgf000461_0001
Example 1002 N-[4-N-benzyl-N-(4-benzoylphenyPaminomethyl-2-(2-methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000461_0002
Example 1002 A Compound 1002A was prepared in the same fashion as 997A (63% yield). X NMR (d6-DMSO):δ 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 9725 MS (ESI+): (M+H)+ calc for C2oHι8NO: 288; found: 288. LR MS (ESI-): (M-H)- calc for C20H16NO: 286; found: 286.
Figure imgf000461_0003
Example 1002B 9730 Compound 1002B was prepared in the same fashion as 997C (30% yield).
Η NMR (CDCl3):δ 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 9735 MS (ESI+): (M+H)+ calc for C41H41N2O4S: 657; found: 657. LR MS (ESI-): (M-H)- calc for C4ιH39N2O4S: 655; found: 655.
Figure imgf000462_0001
Example 1002C 9740 N- 4-N-benzyl-N-(4-benzoylphenyPaminomethyl-2-(2-methylphenyl)benzoyllmethionine, lithium salt Compound 1002C was prepared in the same fashion as 997D (86% yield). X NMR (d6-DMSO):δ 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 = 9745 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)+ calc for CH38LiN2O4S: 649.2712; found: 649.2723 ( 1.6 ppm error). .
Figure imgf000462_0002
Example 1003
N-r4-N-benzyl-N-(4-(6-methylbenzthiazol-2yPphenyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000462_0003
Example 1003 A Compound 1003A was prepared in the same fashion as 997A (38% yield). X NMR (CDCl3):δ 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
9760 MS (ESI+): (M+H)+ calc for C21H19N2S: 330; found: 330. LR MS (ESI-): (M-H)- calc for C21H17N2S: 329; found: 329.
Figure imgf000463_0001
Example 1003B
9765 Compound 1003B was prepared in the same fashion as 997C ( 16% yield).
'H NMR (CDCl3):δ 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
9770 MS (ESI+): (M+H)+ calc for C42H42N3O3S2: 698; found: 698. LR MS (ESI-): (M-H)- calc for C42H40N3O3S2: 700; found: 700.
Figure imgf000463_0002
Example 1003C
9775 N-r4-N-benzyl-N-(4-(6-methylbenzthiazol-2yl)phenyPaminomethyl-2-(2- methylphenyPbenzoy 11 methionine. lithium salt Compound 1003C was prepared in the same fashion as 997D (93% yield). X NMR (d6-DMSO):δ 1.48- 1.62 (m, 1 H), 1.62-1.73 (m, 1 H), 1.80-2.1 1 (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 9780 H), 6,95 (d, J = 5.8 Hz, 1 H), 7.04 (s, 1 H), 7.08-7.37 (comp, 1 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.76-7.82 (comp, 4 H). HR MS (FAB): (M»)+ calc for C4iH38N3O3S2: 685.2433; found: 685.2421 (- 1.8 ppm error).
Figure imgf000464_0001
Example 1004 N-[4-N-2.5-difluorobenzyl-N-(4-cyanophenyPaminomethyl-2-(2-methylphenyl) benzoy 11 methionine. lithium salt
Figure imgf000464_0002
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
9795 acetonitrile solvent (5 mL) was heated to 70 °C for 18 h. Next, 2,5-difluorobenzyl bromide (0.507 g, 2.40 mmol) was added, and the reaction mixture was returned to 70 °C. 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 °C for 14 h. The reaction mixture was cooled to room temperature and diluted with additional DMF (20 mL).
9800 Triethylamine hydrochloride (1.40 g, 10.0 mmol) was added, followed by methionine methyl ester hydrochloride (0.807 g, 4.00 mmol), 3-hydroxy-l,2,3-benzotriazin-4(3H)-one (HOOBT) (1.66 g, 10.0 mmol), l-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 room temperature, diluted with ethyl acetate (80 mL), and 9805 extracted with 2: 1: 1 H2O: saturated aqueous NaHCθ3: 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 70:30 to 50:50 afforded 0.142 g of 1004A as a colorless oil (12% yield). 9810 'H NMR (CDCl3):δ 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 , 13.5 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H34F2N3O3S: 614; found: 614. LR 9815 MS (ESI-): (M-H)" calc for C35H32F2N3O3S: 612; found: 612.
Figure imgf000465_0001
Example 1004B N-r4-N-2.5-difluorobenzyl-N-f4-cyanophenyPaminomethyl-2-(2-methylphenyl) 9820 benzoyllmethionine. lithium salt
Compound 1004B was prepared in the same fashion as 997D (93% yield). X NMR (d6-DMSO):δ 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), 7.1 1-7.40 (comp, 6 H), 7.48-7.63 (comp, 3 H). HR 9825 MS (FAB): (M+H)+ calc for C34H32F2N3θ3S: 600.2132; found: 600.2139 ( 1.1 ppm error).
Figure imgf000465_0002
9830 Example 1005 N-[4-N-2.4-difluorohenzyl-N-(4-cvanophenvPaminomethyl-2-(2-methylphenyP benzoyllmethionine. lithium salt
Figure imgf000466_0001
9835 Example 1005 A Compound 1005A was prepared starting from 4-bromomethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 1178D) in the same fashion as 1004 A (14% yield).
Η NMR (CDCl3):δ 1.53-1.66 (m, 1 H), 1.80-1.92 (m, 1 H), 1.98-2.12 (comp. 8 H),
9840 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, 13.5 Hz, 1 H). LR MS (ESI+): (M+H)+ calc for C35H34F2N3O3S: 614; found: 614. LR MS (ESI-): (M-H)- calc for C35H32F2N3O3S: 612; found: 612.
9845
Figure imgf000466_0002
Example 1005B N-r4-N-2.4-difluorobenzyl-N-(4-cyanophenyPaminomethyl-2-(2-methylphenyl) benzoyllmethionine. lithium salt
9850 Compound 1005B was prepared in the same fashion as 997D (80% yield). X NMR (d6-DMSO):δ 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 C34H32F2N3O3S: 600.2132; found: 600.2144 (2.0 ppm
9855 error).
Figure imgf000467_0001
Example 1006
9860 N-[4-N-3.5-difluorobenzyl-N-(4-cyanophenyPaminomethyl-2-(2-methylphenyl) benzoyllmethionine. lithium salt
Figure imgf000467_0002
Example 1006 A 9865 Compound 1006A was prepared starting from 4-bromomethyl-2-(2- methylphenypbenzoic acid, methyl ester (example 1178D) in the same fashion as 1004A
(28% yield).
X NMR (CDCl3):δ 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), 9870 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 C35H34F2N3O3S: 614; found: 614. LR
MS (ESI-): (M-H)- calc for C35H32F2N3O3S: 612; found: 612.
Figure imgf000467_0003
Example 1006B N-r4-N-3.5-difluorobenzyl-N-(4-cvanophenyl)aminomethy1-2-(2-methylphenyl) benzoyllmethionine, lithium salt Compound 1006B was prepared in the same fashion as 997D (82% yield).
9880 X NMR (d6-DMSO):δ 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 C34H32F2N3O3S: 600.2132; found: 600.2140 ( 1.2 ppm error).
9885
Figure imgf000468_0001
Example 1007 N-14-N-3.5-difluorobenzyl-N-(4-vinylphenyl)aminomethyl-2-(2-methylphenyl)
9890 benzoyllmethionine. lithium salt
Figure imgf000468_0002
Example 1007A Compound 1007 A was prepared starting from 4-bromomethyl-2-(2- 9895 methylphenyPbenzoic acid, methyl ester (example 1178D) in the same fashion as 1004A (11% yield).
X NMR (CDCl3):δ 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 9900 (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 C36H37F2N2O4S: 631; found: 631. LR MS (ESI-): (M-H)- calc for C36H35F2N2O4S: 629; found: 629.
Figure imgf000469_0001
9905 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
9910 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). X NMR (CDCl3):δ 1.52-1.62 (comp, 2 H), 1.80-1.91 (m, 1 H), 1.99-2.14 (comp, 8 H),
9915 3.66 (s, 3 H), 4.58-4.66 (comp, 3 H), 4.70 (s, 2 H), 5.04 (d, J = 1 1.1 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)+ calc for C36H37F2N2O3S: 615; found: 615. LR MS (ESI-): (M-H)- calc for C36H35F2N2O3S: 613; found: 613.
9920
Figure imgf000469_0002
Example 1007C N-r4-N-3.5-difluorobenzyl-N-(4-vinylphenyPaminomethyl-2-(2-methylphenyl) benzoyllmethionine. lithium salt 9925 Compound 1007C was prepared in the same fashion as 997D (72% yield).
X NMR (d6-DMSO):δ 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 = 1 1.0 Hz, 1 H), 5.51 (dd-, J = 1.2, 17.7 Hz, 1 H), 6.54 (dd, J = 1 1.0, 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
9930 (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 C35H32F2LiN3O3S: 599; found: 599.
Figure imgf000470_0001
9935 1008 N-r4-N-3.5-difluorobenzyl-N-(4-acetylphenyPaminomethyl-2-(2-methylphenyl) benzoyllmethionine. lithium salt Compound 1008 was prepared in the same fashion as 997D (86% yield). *H NMR (d6-DMSO):δ 1.46-1.61 (m, 1 H), 1.61-1.73 (m, 1 H), 1.86-2.08 (comp, 8 H),
9940 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 C35H35F2N2O4S: 617.2286; found: 617.2277 (-1.5 ppm error).
9945
Figure imgf000470_0002
Example 1009 N-r4-N-3.5-difluorobenzyl-N-(4-(l-hvdroxyethyl)phenyPaminomethyl-2-(2-methylphenyP
9950 benzoyllmethionine. lithium salt
Figure imgf000471_0001
Example 1009A Compound 1009 A was prepared starting from 4-chloromethyl-2-(2- 9955 methylphenyPbenzoic acid, methyl ester (example 997B) in the same fashion as 1004A (17% yield). X NMR (CDCl3):δ 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, 1 H), 7.14-7.35 9960 (comp, 8 H), 7.92 (dd, J = 8.1, 14.0 Hz, 1 H). LR
MS (ESI+): (M+H)+ calc for C36H37F2N2O4S: 631; found: 631. LR MS (ESI-): (M-H)- calc for C36H35F2N2O4S: 629; found: 629.
Figure imgf000471_0002
9965 Example 1009B
Compound 1009B was prepared in the same fashion as 1007B (10% yield). X NMR (CDCl3):δ 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
9970 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 C36H39F2N2O4S: 633; found: 633. LR MS (ESI-): (M-H)- calc for C36H37F2N2O4S: 631; found: 631.
Figure imgf000472_0001
Example 1009C N-)"4-N-3.5-difluorobenzyl-N-('4-('l-hydroxyethyl)phenyPaminomethyl-2-(2-methylphenyl) benzoyllmethionine, lithium salt Compound 1009C was prepared in the same fashion as 997D (76% yield).
9980 X NMR (d6-DMSO):δ 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
9985 MS (FAB): (M+H)+ calc for C35H36F2N3O4S: 618.2364; found: 618.2366 (0.4 ppm error).
Figure imgf000472_0002
9990 Example 1010
N-r4-N-3.5-difluorobenzyl-N-(4-(,l-hydroxy-l-phenylmethyPphenyPaminomethyl- 2-(2-methylphenyl)benzoy 11 methionine. lithium salt
Figure imgf000473_0001
9995 Example 1010A
Compound 1010A was prepared starting from 4-chloromethyl-2-(2- methylphenyl)benzoic acid, methyl ester (example 997B) in the same fashion as 1004 A
(5.4% yield).
X NMR (CDCl3):δ 1.53-1.66 (m, 1 H), 1.80-1.91 (m, 1 H), 2.00-2.13 (comp, 8 H), 10000 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 C41H37F2N2O4S: 691 ; found: 691.
10005
Figure imgf000473_0002
Example 1010B Compound 1010B was prepared in the same fashion as 1007B (6.5% yield). X NMR (CDCl3):δ 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
10010 = 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 C41H39F2N2O3S: 677; found: 677. LR MS (ESI-): (M-H)- calc for C41H39F2N2O4S: 693; found: 693.
10015
Figure imgf000474_0001
Example 1010C N-r4-N-3.5-difluorobenzyl-N-(4-(l-hydroxy-l-phenylmethyPphenyl)aminomethyl- 2-(2-methylphenyPbenzoyllmethionine, lithium salt 10020 Compound 1010C was prepared in the same fashion as 997D ( 100% yield).
X NMR (d6-DMSO):δ 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), 7.1 1-7.26 (comp, 5 H), 7.27-7.32 (comp, 5 H), 7.49 (d, J = 8.0 Hz, 1 H). LR 10025 MS (ESI-): (M-H)- calc for C4oH37F2LiN2O4S: 678; found: 678.
Figure imgf000474_0002
Example 1011
10030 N-r4-N-3.5-difluorobenzyl-N-f4-(2-hydroxyethyl)phenyPaminomethyl-
2-(2-methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000474_0003
Example 1012 10035 N-[4-N-3.5-difluoroben7.yl-N-r4-(2-hvdroxyethyπphenyPaminomethyl- 2-(2-methylphenvPbenzoyllmethionine. lithium salt
Figure imgf000475_0001
Example 1011A andExample 1012A 10040 Compound 1012A was prepared starting from 4-chloromethyl-2-(2- methylphenyPbenzoic 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).
X NMR (CDCl3):δ 1.44-1.50 (br, 1 H), 1.52-1.65 (m, 1 H), 1.80-1.91 (m, 1 H), 1.99- 10045 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 C36H39F2N2O4S: 633; found: 633. LR 10050 MS (ESI-): (M-H)- calc for C3.5H37F2N2O4S: 631; found: 631. 1012A:
*H NMR (CDCl3):δ -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 10055 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 C42H53F2N2O4SiS: 747; found: 747. LR
MS (ESI-): (M-H)- calc for C42H5iF2N2θ4SiS: 745; found: 745.
Figure imgf000475_0002
10060 Example 101 IB
N-r4-N-3.5-diflυoroben7yl-N-(4-(2-hvdroxyethyPphenyπaminomethyl-
2-(2-methylphenvPbenzoyllmethionine. lithium salt
Compound 101 IB was prepared in the same fashion as 997D (76% yield).
X NMR (d6-DMSO):δ 1.48-1.74 (br comp, 2 H), 1.90-2.06 (br comp, 8 H), 2.56 (t, J =
10065 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 C35H36F2LiN2θ4S: 625.2524; found: 625.2542 (2.8 ppm error).
10070
Figure imgf000476_0001
(258473) Example 1012B N-[4-N-3.5-difluorobenzyl-N-('4-(2-hydroxyethyPphenyPaminomethyl- 2-(2-methylphenyl)benzoyllmethionine. lithium salt
10075 Compound 1012B was prepared in the same fashion as 997D (64% yield). X NMR (d6-DMSO):δ -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
10080 MS (FAB): (M+H)+ calc for C4iH5oF2LiN2O4SiS: 739.3389; found: 739.3389 (0.1 ppm error).
Figure imgf000476_0002
10085 Example 1013 N-r4-N-3.5-difluoroben7.yl-/V-( l-ethylthio-3-cvclohexylρrop-2-yl)aminomethyl-2-(2- methylphenvPbenzoyll methionine.
Figure imgf000477_0001
EtS' 10090 Example 1013 A
Compound 1013 A was prepared starting from 4-bromomethyl-2-(2- methylphenyPbenzoic acid, methyl ester (example 1178D) in the same fashion as 1004 A ( 10% yield). X ΝMR (CDCl3):δ 0.70-0.93 (comp, 2 H), 1.06-1.71 (comp, 16 H), 1.30-1.92 (m, 1 H),
10095 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 C39H51F2Ν2O3S2: 697; found: 697. LR
10100 MS (ESI-): (M-H)- calc for C39H49F2N2O3S2: 695; found: 695.
Figure imgf000477_0002
EtS
Example 1013B N- 4-N-3.5-difluorobenzyl-N-(l-ethylthio-3-cyclohexylprop-2-yl)aminomethyl-2-(2- 10105 methylphenyPbenzoyll methionine.
Compound 1013B was prepared in the same fashion as 997D (76% yield). X NMR (d6-DMSO):δ 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 10110 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, 1 H). HR
MS (FAB): (M+H)+ calc for C38H49F2N2O3S2: 683.3153; found: 683.3132 (-3.0 ppm error).
101 15
Figure imgf000478_0001
Example 1014 N-r4-(2-N-piperidin-l-ylaminoethenyP-2-(2-methylphenyl)benzoyllmethionine. lithium salt
10120
Figure imgf000478_0002
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
10125 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
10130 1014A as a white solid (82% yield).
X NMR (CDCl3):δ 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
10135 MS (ESI+): (M+H)+ calc for Cι89O3: 283; found: 283.
Figure imgf000478_0003
Example 1014B A solution of 1014A (2.42 g, 8.57 mmol) in saturated methanolic LiOH ( 10 mL)
10140 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 stiπing 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
10145 then concentrated under reduced pressure to provide 1.81 g of 1014B as a white foam (79% yield). LR
MS (ESI+): (M+H)+ calc for C17H17O3: 269; found: 269. LR MS (ESI-): (M-H)- calc for C17H15O3: 267; found: 267.
Figure imgf000479_0001
Example 1014C
A heterogeneous mixture of 1014B (1.81 g, 6.75 mmol), methionine methyl ester hydrochloride (2.72 g, 13.5 mmol), 1 -hydro xybenzotriazole hydrate (HOBT) (4.56 g, 33.8 mmol), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (6.60 g, 33.8. mmol) in
10155 DMF solvent (40 mL) was treated with triethylamine (3.45 g, 33.8 mmol). The mixture was heated to 50 °C 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
10160 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).
'H NMR (CDCl3):δ 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),
10165 7.00-7.36 (comp, 6 H), 7.12 (d, J = 12.9 Hz, 1 H, E isomer), 7.63-7.96 (comp, 1 H). LR MS (ESI+): (M+H)+ calc for C23H28O4S: 414; found: 414.
Figure imgf000480_0001
Example 1014D
10170 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 MgSO4, and concentrated under reduced pressure to provide a pale yellow oil. The oil
10175 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
10180 1014D as a colorless oil (8.9% yield).
X NMR (CDCl3):δ 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, 15.6 Hz, 1 H). LR
10185 MS (ESI+): (M+H)+ calc for C27H36N2O3S: 482; found: 482. LR MS (ESI-): (M-H)- calc for C27H34N3O3S: 480; found: 480.
Figure imgf000480_0002
Example 1014E 10190 N-14-(2-N-piperidin-l-ylaminoethenyP-2-(2-methylphenyl)benzoyllmethionine. lithium salt Compound 1014E was prepared in the same fashion as 997D (39% yield). ]H NMR (d6-DMSO):δ 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, 10195 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).
Figure imgf000481_0001
Example 1015
N-r4-(2-N-2-methoxymethylpyπolidin-l-ylaminoethenyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000481_0002
Example 1015A Compound 1015 A was prepared in the same fashion as 1014D (1 1% yield). X NMR (CDCl3):δ 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 10210 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 C28H38N3O4S: 512; found: 512. LR MS (ESI-): (M-H)- calc for C28H36N3O2S: 510; found: 510.
Figure imgf000481_0003
10215 Example 1015B N-f4-(2-N-2-methoxymethylpyπolidin- 1 -ylaminoethenyl)-2-(2- methylphenyPhenzoyllmethionine. lithium salt Compound 1015B was prepared in the same fashion as 997D (50% yield). X NMR (d6-DMSO):δ 1.49-1.72 (comp, 3 H), 1.76-2.20 (comp, 10 H), 2.62-2.72 (m, 1 10220 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 C27H35LiN3O4S: 504.2508; found: 504.2509 ( 1.2 ppm error). 10225
Figure imgf000482_0001
Example 1017 N-[4-N-(4-trans-pentafluorophenoxycyclohexyPaminomethyl-2-(2- 10230 methylphenyPbenzoyll 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 stiπed overnight at room temperature and was washed with 1 M HCl, 5% NaHCO3, and brine to give the Boc- 10235 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 stiπed overnight. Standard aqueous workup provided 149 mg of the protected pentafluorophenyl ether which was treated with excess TFA in methylene chloride, stripped 10240 to dryness, and reductively alkylated and saponified as described previously to provide 160 mg of the title compound.
MS m/e 635 (M-H)-. X NMR (CDC13, 300 MHz) δ 1.5 (m, 4H), 1.79 (m, IH), 2.05 (m, 12H), 2.81 (m, IH), 4.05 (m, 4H), 6.25 (m, IH), 6.81 (m, 2H), 7.1-7.7 (m, 7H). 10245
Figure imgf000483_0001
Example 1018
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyP-2-(2-methylphenyPbenzoyllglutamine 10250 Trifluoroacetic Acid salt
The compound was made by standard amino acid coupling of 4-(N-(2- cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)benzoic acid and L-Glu-OtBu followed by treatment with TFA.
MS m/e 492 (M-H)". 10255 X NMR (d6-DMSO, 300 MHz) δ 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, IH), 4.29 (m, IH), 4.43 (m, IH), 6.74
(s, IH), 7.1-7.22 (m, 3H), 7.39 (s, IH), 7.60 (m, 2H), 8.32 (m, 2H), 9.62 (bs, IH).
Figure imgf000483_0002
Example 1019 N-|"4-(N-(2-cyclohexylethyl)-N-methylaminomethyP-2-("2- methylphenyPbenzoyllhomocysteine. lithium salt Prepared in a manner analogous to Example 1018 using L-homocysteine thiolactone
10265 and opening the resulting thiolactone with 1 equivalent of LiOH. MS m/e 481 (M-H)-.
'H NMR (d6-DMSO, 300 MHz) δ 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, IH), 3.97 (m, IH), 6.95 (m, IH), 7.0-7.34 (m, 4H), 7.5 (m, IH), 7.65 (m, IH), 8.39 (m, IH).
10270
Figure imgf000484_0001
Example 1020 N-r4-(N-(2-cyclohexylethvP-N-methylaminomethyP-2-(2-methylphenyl)benzoyllhistidine 10275 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)+. 10280 iH NMR (d6-DMSO, 300 MHz) δ 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, IH), 4.4 (m, IH), 4.56 (m, 2H), 7.08 (m, IH), 7.15-7.42 (m, 3H), 7.58 (m, 2H), 8.62 (m, IH), 8.97 (s, IH).
Figure imgf000484_0002
Example 1021
N- 4-(N-cyclohexylmethylaminoethyP-2-(2-methylphenyPbenzoyllmethionine. lithium salt
N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoyl methionine methyl ester (84 mg, 0.17 mmol) was treated with LiOH (1 M, 85 μL) in methanol to 10290 provide the title compound. MS m/e 481 (M-H)".
X NMR (d6-DMSO, 300 MHz) δ 0.83 (m, 2H), 1.15 (m, 4H), 1.36 (m, IH), 1.62 (m, 9H), 1.98 (m, 10H), 3.7 (m, 2H), 4.27 (m, IH), 6.90 (m, IH), 7.00 (m, IH), 7.1-7.3 (m, 4H), 7.44 (m, IH), 8.24 (m, IH).
10295
N-[4-(N-(cvclohexylmethyPaminoethyP-2-(2-methylphenyPbenzoyl methionine methyl ester Methyl 4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoate hydrochloride (1.33 g, 3.31 mmol) was treated with sat. LiOH (1.3 mL, 6.95 mmol) in 50
10300 mL methanol at 60 °C until no starting material remained by tic. The solution was evaporated to dryness and treated with Met-OMe»HCl (0.99 g, 4.96 mmol), ED AC ( 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.
10305 MS m/e 497 (M-H)-.
X NMR (CDC13, 300 MHz) δ 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, IH), 5.89 (d, IH, J = 7 Hz), 7.04 (s, IH), 7.19 (m, IH), 7.3 (m, 4H), 7.91 (m, IH).
10310 Methyl 4-(N-(cyclohexylmethyl)aminoethyP-2-(2-methylphenyPbenzoate
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 stiπed overnight at room temperature before evaporating to dryness. The residue 10315 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)+.
X NMR (CDCI3, 300 MHz) δ 0.88 (m, 2H), .1.2 (m, 4H), 1.6 (m, 6H), 2.06 (s, 3H), 10320 2.48 (d, 2H, J = 7 Hz), 2.92 (s, 4H), 3.61 (s, 3H), 7.06 (m, IH), 7.23 (m, 5H), 7.92 (m,
IH).
Methyl 4-(propan-3-al)-2-(2-methylphenyPbenzoate Methyl 4-(prop-2-enyl)-2-(2-methylphenyl)benzoate (5.23 g, 19.6 mmol), osmium
10325 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.
10330 MS m/e 286 (M+NH4)+.
X NMR (CDCI3, 300 MHz) δ 2.06 (m, 3H), 3.61 (s, 3H), 3.8 (m, 2H), 7.1 (m, IH), 7.25 (m, 5H), 7.95 (m, IH), 9.80 (m, IH).
Methyl 4-(prop-2-enyP-2-('2-methylphenyPbenzoate 10335 Methyl 4-iodo-2-(2-methylphenyl)benzoate (10.0 g, 28.4 mmol), allyltributyl tin
( 1 1.3 g, 34.1 mmol), and dichlorobis(triphenylρhosphine)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
10340 % yield.
MS m/e 284 (M+NH4)+.
X NMR (CDC13, 300 MHz) δ 2.06 (s, 3H), 3.45 (d, 2H, J = 7 Hz), 3.61 (s, 3H), 5.1
(m, 2H), 5.97 (m, IH), 7.08 (m, IH), 7.23 (m, 5H), 7.94 (m, IH).
10345
Figure imgf000486_0001
Example 1022 N- 4-(N.N-di-(cyclohexylmethyPaminoethyP-2-(2-methylphenyl)benzoyllmethionine. lithium salt 10350 N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoyl 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 10355 saponified with LiOH to the title compound. MS m/e 577 (M-H)".
X NMR (d6-DMSO, 300 MHz) δ 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, IH), 3.68 (m, IH), 6.90 (m, 2H), 7.1 (m, 5H), 7.44 (m, IH). 10360
Figure imgf000487_0001
Example 1023 N-r4-(N-cvclohexylmethyl-N-phenylacetylaminoethyl)-2-(2- 10365 methylphenyPbenzoy 11 methionine, lithium salt
N-[4-(N-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoyl methionine methyl ester (75 mg, 0.11 mmol), phenacetyl chloride (26 mg, 0.17 mmol), and triethylamine (17 mg, 0.15 mmol) were stiπed in DMF (0.5 mL) for 18 hours at ambient temperature. The reaction was diluted with EtOAc, washed with 5 % NaHCO3, water, and 10370 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)-.
•H NMR (d6-DMSO, 300 MHz) δ 0.83 (m, 2H), 1.15 (m, 4H), 1.6 (m, 9H), 1.98 (m, 10375 8H), 2.8 (m, IH), 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, IH).
Figure imgf000487_0002
10380 Example 1024
N- 4-('N-cyclohexylmethyl-N-l-adamantanoylaminoethyP-2-('2- methylphenyPbenzoyllmethionine. lithium salt This compound was prepared in a manner analogous to Example 1023 using 1- adamantanecarbonyl chlroide. 10385 MS m/e 643 (M-H)-. X NMR (d6-DMSO, 300 MHz) δ 0.87 (m, 8H), 1.15 (m, 4H), 1.6 (m, 14H), 1.9 (m, 12H), 2.85 (m, IH), 3.18 (m, 2H), 3.6 (m, 2H), 6.91 (m, IH), 7.02 (m, IH), 7.2 (m, 5H), 7.48 (m, IH).
10390
Figure imgf000488_0001
Example 1025 N-r4-(N-cyclohexylmethyl-N-t-butoxycarbonylaminoethyP-2-(2- methylphenyPbenzoyll methionine. lithium salt 10395 This compound was prepared in a manner analogous to Example 1023 using di-t- butyldicarbonate. MS m/e 581 (M-H)".
X NMR (d6-DMSO, 300 MHz) δ 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, IH), 6.9 (m, IH), 7.0 (m, IH), 10400 7.2 (m, 5H), 7.45 (m, IH).
Example 1026 10405 N-r4-(N-cyclohexylmethyl-N-2-ethylhexyloxycarbonylaminoethyl)-2-(2- methylphenyPbenzoy 11 methionine. lithium salt This compound was prepared in a manner analogous to Example 1023 using 2- ethylhexyl chloroformate. MS m/e 637 (M-H)-. 10410 X NMR (d6-DMSO, 300 MHz) δ 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, IH), 3.89 (m, 2H), 4.29 (m, IH), 6.9 (m, IH), 7.0 (m, IH), 7.2 (m, 5H), 7.45 (m, IH).
Figure imgf000489_0001
Example 1027 N- 4-(N-cyclohexylmethyl-N-2.2,2-trichloroethoxycarbonylaminoethyl)-2-(2- methylphenyPbenzoyllmethionine. lithium salt This compound was prepared in a manner analogous to Example 1023. 10420 MS m/e 683 (M-H)-.
X NMR (d6-DMSO, 300 MHz) δ 0.84 (m, 2H), 1.17 (m, 4H), 1.6 (m, 5H), 1.9 (m, 14H), 2.9 (m, 3H), 3.03 (m, IH), 3.5 (m, 3H), 3.6 (m, IH), 4.28 (m, IH), 6.9 (m, IH), 7.0 (m, 2H), 7.2 (m, 5H), 7.45 (m, IH).
10425
Figure imgf000489_0002
Example 1028 N-r4-(N-cyclohexylmethyl-N-cyclohexyloxycarbonylaminoethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt 10430 This compound was prepared in a manner analogous to Example 1023.
MS m/e 607 (M-H)-.
X NMR (d6-DMSO, 300 MHz) δ 0.84 (m, 4H), 1.17 (m, 4H), 1.3 (m, 6H), 1.6 (m, 10H), 1.95 (m, 8H), 2.17 (m, IH), 2.9 (m, 4H), 3.6 (m, IH), 4.53 (m, IH), 6.9 (m, IH), 7.0 (m, IH), 7.2 (m, 5H), 7.47 (m, IH). 10435
Figure imgf000490_0001
Example 1029 N-r4-(N-cyclohexylmethyl-N-adamantyloxycarbonylaminoethyl)-2-(2- 10440 methylphenyPbenzoyllmethionine. lithium salt
This compound was prepared in a manner analogous to Example 1023. MS m/e 659 (M-H)-.
'H NMR (d6-DMSO, 300 MHz) δ 0.83 (m, 6H), 1.16 (m, 6H), 1.6 (m, 13H), 2.0 (m, 12H), 2.82 (m, 3H), 2.95 (m, IH), 3.65 (m, 2H), 6.95 (m, 2H), 7.2 (m, 5H), 7.47 (m, 10445 I H) .
Figure imgf000490_0002
Example 1030 10450 N-r4-(N-cyclohexylmethyl-N-phenoxycarbonylaminoethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt This compound was prepared in a manner analogous to Example 1023. MS m/e 601 (M-H)-.
X NMR (d6-DMSO, 300 MHz) δ 0.91 (m, 2H), 1.19 (m, 4H), 1.63 (m, 9H), 1.98 (m, 10455 6H), 2.15 (m, 2H), 2.97 (m, IH), 3.1 1 (m, IH), 3.5 (m, IH), 3.7 (m, 2H), 6.85-7.39 (m, 12H), 7.48 (m, IH).
Figure imgf000491_0001
10460 Example 1031
N-[4-(N-cyclohexylmethyl-N-benzyloxycarbonylaminoethyl)-2-(2- methylphenyPbenzoyllmethionine. lithium salt This compound was prepared in a manner analogous to Example 1023. MS m/e 615 (M-H)-. 10465 X NMR (d6-DMSO, 300 MHz) δ 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, IH).
Figure imgf000491_0002
Example 1032 N-[4-(N-cyclohexylmethyl-N-adamant-l-aminocarbonylaminoethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt This compound was prepared in a manner analogous to Example 1023 using 10475 adamantyl isocyanate. MS m/e 658 (M-H)-.
X NMR (d6-DMSO, 300 MHz) δ 0.83 (m, 6H), 1.13 (m, 6H), 1.6 (m, 13H), 1.95 (m, 12H), 2.18 (m, IH), 2.79 (m, 2H), 2.91 (m, 2H), 3.65 (m, 2H), 6.9 (m, IH), 7.0 (m, IH), 7.2 (m, 5H), 7.46 (m, IH). 10480
Figure imgf000492_0001
Example 1033 N-r4-(N-cyclohexylmethyl-N-adamant-l-aminothiocarbonylaminoethyl)-2-(2- 10485 methylphenyPbenzoyllmethionine. lithium salt
This compound was prepared in a manner analogous to Example 1023 using adamantyl isothiocyanate. MS m/e 674 (M-H)-.
X NMR (d6-DMSO, 300 MHz) δ 0.85 (m, 6H), 1.15 (m, 6H), 1.6 (m, 13H), 2.0 (m, 10490 12H), 2.2 (m, IH), 2.74 (m, 2H), 2.91 (m, 2H), 3.62 (m, 2H), 6.9-7.5 (m, 8H).
Figure imgf000492_0002
Example 1041 10495 N-r4-(N-(2-cvclohexylethvP-N-methylaminomethyP-2-(2- methylphenyPbenzoyllglutaminitrile. 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 stiπed at room temperature overnight. The solution was evaporated to dryness and partitioned between EtOAc and 10 % citric acid. The organic 10500 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 10505 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)-. X NMR (d6-DMSO, 300 MHz) δ 0.82 (m, 2H), 1.11 (m, 3H). 1.32 (m, 5H), 1.6 (m. 10510 7H), 2.18 (m, 6H), 2.32 (m, IH), 2.58 (m, IH), 2.75 (m, IH), 3.53 (m, 2H), 6.9-7.5 (m, 7H), 7.83 (m, IH).
Figure imgf000493_0001
10515 Example 1047
N-[4-(N-p-Toluenesulfonyl-N-methylaminomethyP-2-(2-methylphenyl)benzoyllmethionine, lithium salt
Figure imgf000493_0002
10520 Example 1047 A
4-(N-p-Toluenesulfonyl-N-methylaminomethyP-2-(2-methylphenyl)benzoic acid. Methyl
Ester To a solution of N-methyl-p-toluenesulfonamide (203 mg) and 4-hydroxymethyl-2- (2-methylphenyl)benzoic acid methyl ester (example 1178C, 255mg) in THF (3mL) at 0°C 10525 was added triphenylphosphine (315mg) and diethyl azodicarboxylate (0.19mL). The reaction was warmed, and stiπed 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%). 10530 MS (DCI/NH3) 441 (M+NH4)+.
Figure imgf000494_0001
Example 1047B N-r4-(N-p-Toluenesulfonyl-N-methylaminomethyP-2-(2-
10535 methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2-methylphenyl)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,
10540 MS (APCI(-) m/e (M-H)- 553.
Figure imgf000494_0002
Example 1047C N-14-(N-p-Toluenesulfonyl-N-methylaminomethyP-2-(2-methylphenyPbenzoyllmethionine,
10545 lithium salt N-[4-(N-p-Toluenesulfonyl-N-methylaminomethyl)-2-(2- rnethylphenyl)benzoyl]methionine methyl ester was converted to the title compound by the procedure in example 608E. The product was isolated as a white powder. 'H NMR (300 MHz, DMSO) δ 1.50-1.88 (m, 4H), 1.92 (s, 3H), 1.95-2.14 (m, 3H), 2.41
10550 (s, 3H), 2.59 (s, 3H), 3.58-3.70 (m, IH), 4.18 (s, 2H), 6.96 (brd, J=5.4 Hz, IH), 7.02- 7.26 (m, 5H), 7.35 (d, J=8.1 Hz, IH), 7.44 (d, J=7.8 Hz, 2H), 7.52 (d, J=8.1 Hz, IH), 7.72 (d, J=7.8 Hz, 2H).
MS (ESI(-)) m/e 539 (M-H); Analysis calc'd for C28H3iLiN2O5S2»1.50H2O: C, 58.63; H, 5.97; N, 4.88; found: C, 58.61; H, 5.66; N, 4.51.
10555
Figure imgf000495_0001
Example 1048 N-r4-(N-(4-BenzyloxybenzyP-N-(N-2-methyl-2-phenylpropylacetamido)aminomethyP-2- 10560 (2-methylphenyPbenzoyll methionine, lithium salt
Example 1048 A N-(2-Methyl-2-phenylpropyP-N-tert-butoxycarbonyl-2-aminoacetamide
10565 To a slurry of NaH ( lOg of a 60% dispersion in mineral oil) in dry THF (300mL) was added benzylcyanide (lOg) 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 stiπing at ambient temperature for 12h, the reaction was quenched cautiously with water (lOOmL). The mixture was diluted with ether (500mL) and
10570 the layers were separated. The ether layer was washed with water ( lOOmL) containing a small amount of Na2SO3 to eliminate the iodine color, then washed with brine (50mL). The organic solution was dried (MgSO4), filtered and concentrated to afford an oil. This material was added neat to a solution of IM LiAlH4 (85mL, THF) in ether (lOOmL). If necessary, the reduction was initiated after a small amount of starting material was added by warming
10575 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 stiπed 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 ( lOmL). The suspension was filtered through celite, which was rinsed with ether. The filtrate was concentrated to give an oil (ca.
10580 20g) which contained mineral oil from the sodium hydride dispersion. A portion of this material (3.3g) was dissolved in DMF (67 mL) along with N-(tert-butoxycarbonyl)glycine (3.5g), followed by addition of N-methylmorpholine (3.3mL), 1 -hydro xybenzotriazole (3.0g), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.0g). After stiπing at ambient temperature for 15h, the reaction was poured into ether (500mL), washed with water 10585 (2X100mL), IM HCl (2X100mL), saturated NaHCO (2X50mL), and brine (lOOmL). The organic solution was dried (MgSO4), 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)+.
Figure imgf000496_0001
Example 1048B N-(2-Methyl-2-phenylpropyP-N-('4-benzyloxybenzyP-2-aminoacetamide To a solution of N-(2-methyl-2-phenylpropyl)-N-tert-butoxycarbonyl-2- aminoacetamide (4.5g) in dichloromethane (50mL) was added trifluroracetic acid ( lOmL).
10595 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 (lmg) 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
10600 temperature. Sodium cyanoborohydride (15mL, IM THF) was added, and the reaction color was held at a light green by addition of a 2: 1 ethanohHCl mixture. After starting aldehyde was consumed (TLC), the reaction was concentrated, dissolved in EtOAc (200mL), and washed with saturated NaHCO3 (2X50mL), water (50mL), and brine (50mL). The organic solution was dried (MgSO4), filtered and concentrated, and the residue
10605 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)+.
Figure imgf000496_0002
Example 1048C 10610 4-(N-(4-BenzyloxybenzyP-N-CN-2-methyl-2-phenylpropylacetamido)aminomethyP-2-(2- e.thylphenvPbenzoic acid. Methyl 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)".
10615
Figure imgf000497_0001
Example 1048D N-|"4-(N-(4-BenzyloxybenzyP-N-(N-2-methyl-2-phenylpropylacetamido)aminomethyP-2- (2-methylphenyPbenzoyllmethionine. Methyl Ester
10620 4-(N-(4-Benzyloxybenzyl)-N-(N-(2-methyl-2- phenylpropylamino)acetylaminomethyl)-2-(2-methylphenyl)benzoic 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)-.
Figure imgf000497_0002
Example 1048E N-r4-(N-(4-Benzyloxybenzyl)-N-('N-2-methyl-2-phenylpropylacetamido)aminomethyP-2- (2-methylphenyPbenzoyllmethionine. lithium salt N-[4-(N-(4-Benzyloxybenzyl)-N-(N-(2-methyl-2-
10630 phenylpropylarnino)acetylaminomethyl)-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.
X NMR (300 MHz, DMSO) δ 1.15 (s, 3H), 1.16 (s, 3H), 1.50-1.84 (m, 5H), 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- 10635 3.68 (m, IH), 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 C46H5oLiN3θ5S«1.95H2O: C, 69.15; H, 6.80; N, 5.26; found: C, 69.1 1 ; H, 6.50; N, 5.13.
Figure imgf000498_0001
Example 1056
N- 4-(N-(2-CyclohexenylethvP-N-methylaminomethyP-2-(2- methylphenyPbenzoy 11 methionine. lithium salt
Figure imgf000498_0002
Example 1056 A
N-Methy 1-2-C 1 -cyclohexenyPethylamine
To a solution of 2-(l -cyclohexenyPethylamine (4.0g) in 1,4-dioxane (40mL) was added di-tert-butyldicarbonate (7.7g). After gas evolution ceased (=2h) the reaction was 10650 concentrated. A portion of the residue (2g) was dissolved in THF (lOmL) followed by addition of LiAlH4 (lOmL, IM THF), which caused an exotherm. After 3h, more LiAlI ; 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),
IM NaOH (0.6mL), and more water (1.5mL). The suspension was filtered through celite, 10655 which was washed with ether. The organic solution was concentrated to give the desired product as a volatile oil (0.8g).
'H NMR (300 MHz, CDC13) δ 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, IH).
Figure imgf000499_0001
Example 1056B
4-("N- 2-CyclohexenylethyP-N-methylaminomethyl)-2-(2-methylphenyPbenzoic acid.
Methyl Ester
The title compound was prepared from N-methyl-2-( 1 -cyclohexenyPethylamine
10665 according to the procedure in example 608B.
MS (DCI/NH3) 378 (M+H)+.
Figure imgf000499_0002
Example 1056C
10670 N-r4-tN-r2-CyclohexenylethvP-N-methylaminomethvP-2-(2- methylphenyPbenzoyllmethionine. 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 10675 (M+Cl)".
Figure imgf000499_0003
Example 1056D N-r4-(N-(2-CvclohexenylethvP-N-methylaminomethvP-2-(2- 10680 methylphenvPbenzoyllmethionine. lithium salt N-[4-(N-(2-Cyclohexenylethyl)-N-methylaminomethyl)-2-(2- me thy lphenypbenzoyl] methionine methyl ester was converted into the title compound by the procedure in example 608E, and was isolated as a white powder. IH NMR (300 MHz, DMSO) δ 1.38-1.75 (m, 4H), 1.80-2.13 (m, 13H), 1.91 (s, 3H), 10685 2.14 (s, 3H), 2.36-2.45 (m, 2H), 3.50 (s, 2H), 3.56-3.67 (brs, IH), 5.32-5.36 (m, IH), 6.88-6.92 (m, IH), 7.05-7.23 (m, 5H), 7.32 (d, J=8.1 Hz, IH), 7.48 (d, J=8.1 Hz, IH). MS (APCI(-)) m/e 493 (M-H); Analysis calc'd for C29H37LiN2θ3S'1.15H2O: C, 66.81 ; H, 7.60; N, 5.37; found: C, 66.86; H, 7.34; N, 5.19.
10690
Figure imgf000500_0001
Example 1057 N-f4-(N-(2-Cyclohexylethyl)-N-methylaminomethyP-2-phenylbenzoyllmethionine, lithium salt
10695
Figure imgf000500_0002
Example 1057 A 4-(N-(2-CyclohexylethyP-N-methylaminomethyP-2-phenylbenzoic acid. Methyl Ester The title compound was prepared according to the procedure in example 608B, 10700 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)+.
Figure imgf000501_0001
10705 Example 1057B
N- 4-(N-(2-CyclohexylethvP-N-methylaminomethyl)-2-phenylbenzoyllmethionine. Methyl
Ester The title compound was prepared from 4-(N-(2-cyclohexylethyl)-N- methylaminomethyl)-2-phenylbenzoic acid methyl ester according to the procedure in 10710 examples 608C and D. MS(APCI(+)) 497 (M+H)+. MS(APCI(-)) 531 (M+Cl)-.
Figure imgf000501_0002
Example 1057C N- 4-(N-(2-CyclohexylethyP-N-methylaminomethyl)-2-phenylbenzoyllmethionine. lithium 10715 salt
N-[4-(N-(2-CyclohexylethyP-N-methylaminomethyl)-2-phenylbenzoyl]methionine methyl ester was converted into the title compound according to the procedure in example 608E, and was isolated as a white powder.
X NMR (300 MHz, DMSO) δ 0.76-0.92 (m, 2H), 1.06-1.38 (m, 5H), 1.53-1.67 (m, 10720 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, IH), 7.16 (d, J=6 Hz, IH), 7.27-7.41 (m, 8H). MS (APCI(-)) m/e 481 (M-H); Analysis calc'd for C28H37LiN2θ3S-0.95H2O: C, 66.50; H, 7.75; N, 5.54; found: C, 66.53; H, 7.58; N, 5.47.
10725
Figure imgf000502_0001
Example 1058
(2S) 2-N-14-(N-(2-CyclohexylethvP-N-methylaminomethvP-2-(2- methylphenvPbenzoyllamino-4-methylsulfenylbutanoate. lithium salt
10730
Figure imgf000502_0002
Example 1058A (2S 2-N-r4-(N-(2-CvclohexylethvP-N-methylaminomethvP-2-(2- methylphenyl)benzoyllamino-4-methylsulfenylbutanoic acid. Methyl Ester 10735 To a solution of N-[4-(N-(-2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyPbenzoyljmethionine methyl ester (example 608D, lOOmg) in dichloromethane (2mL) at ambient temperature was added trifluoroacetic acid (0.023ml), and the salt solution was cooled to 0°C. Hydrogen peroxide (30%, 0.050mL) was added with vigorous stiπing. After 42h at ambient temperature, the reaction was concentrated and the residue was purified 10740 by silica gel chromatography eluting with 2.5%-5.0%-10.0% MeOH/CH2θ2, 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)benzoyl]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 (50mg, 48%). 10745 MS(APCI(+)) 527 (M+H)+. MS(APCI(-)) 561 (M+Cl)-.
Figure imgf000503_0001
Example 1058B r2S 2-N-r4-(N-r2-CvclohexylethvP-N-methylaminomethyl)-2-(2- 10750 methylphenvPbenzoyllamino-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 10755 with diethyl ether and drying under vacuum.
X NMR (300 MHz, DMSO) δ 0.76-0.90 (m, 2H), 1.04-1.37 (m, 5H), 1.53- 1.65 (m, 6H), 1.66-1.90 (m, 2H), 1.95-2.22 (m, 5H), 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, IH), 6.99 (d, J=6 Hz, IH), 7.06- 7.26 (m, 5H), 7.32 (d, J=7.5 Hz, IH), 7.50 (d, J=8.1 Hz, 0.5H), 7.51 (d, J=8.1 Hz, 10760 0.5H).
MS (ESI(-)) m/e 51 1 (M-H).
Figure imgf000503_0002
10765 Example 1059
(2S) 2-N-14-(N-(2-CvclohexylethvP-N-methylaminomethvP-2-(2- methylphenyPbenzoyllamino-4-methylsulfonylbutanoate. lithium salt (2S) 2-N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfonylbutanoic acid methyl ester (example 1058A) 10770 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. X NMR (300 MHz, DMSO) δ 0.76-0.91 (m, 2H), 1.08-1.37 (m, 5H), 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- 10775 2.56 (m, 2H), 2.83 (s, 3H), 3.52 (s, 2H), 3.64-3.77 (m, IH), 6.98 (d, J=6 Hz, IH), 7.04-7.28 (m, 5H), 7.34 (d, J=8.1 Hz, IH), 7.54 (d, J=8.1 Hz, IH). MS (ESI(-)) m/e 527 (M-H); Analysis calc'd for C29H39LiN2θ5S«0.15H2θ«0.40HoAc: C, 60.32; H, 6.82; N, 4.74; found: C, 60.25; H, 6.97; N, 4.92.
10780
Figure imgf000504_0001
Example 1060
N-r4-(N-(2-CvclohexylethvP-N-methylaminomethvP-2-(2- methylphenyPbenzoyllnorleucine. lithium salt
10785
Figure imgf000504_0002
Example 1060 A N-r4-('N-(2-CyclohexylethyP-N-methylaminomethylV2-('2- methylphenyPbenzoyllnorleucine. Methyl Ester 10790 The title compound was prepared according to example 608D, substituting L- norleucine methyl ester»HCl for L-methionine methyl ester-HCl. MS(APCI(+)) 493 (M+H)+. MS(APCI(-)) 491 (M-H)".
Figure imgf000505_0001
10795 Example 1060B
N-r4-(N-(2-CvclohexylethvP-N-methylaminomethvP-2-(2- methylphenyPbenzoyllnorleucine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]norleucine methyl ester was converted into the title compound 10800 according to the procedure in example 608E, and was isolated as a white powder.
X NMR (300 MHz, DMSO) δ 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, IH), 6.80-6.89 (m, IH), 7.01-7.22 (m, 5H), 7.30 (d, J=7.8 Hz, IH), 7.46 (d. J=7.8 Hz, IH). 10805 MS (ESI(-)) m/e 477 (M-H); Analysis calc'd for C3oH41LiN2θ3»0.9H2θ: C, 71.95; H, 8.61 ; N, 5.59; found: C, 72.00; H, 8.36; N, 5.50.
Figure imgf000505_0002
10810 Example 1061
N-r4-('N-(2-CvclohexylethvP-N.N-dimethylaminomethylV2-('2- methylphenyPbenzoyllmethionine. Internal salt
Figure imgf000505_0003
10815 Example 1061 A N.N-Dimethyl-2-cyclohexylethylamine The title compound was prepared from N-methylcyclohexylethylamine (example 608A) according to the procedure described in example 1056A. X NMR (300 MHz, CDCI3) δ 0.80-0.95 (m, 2H), 1.10-1.39 (m, 6H), 1.60-1.74 (m, 10820 5H), 2.20 (s, 6H), 2.23-2.28 (m, 2H). MS (DCI/NH3) m/e 156 (M+H)+.
Figure imgf000506_0001
Example 106 IB 10825 4-Iodomethyl-2-(2-methylphenyl)benzoic acid, methyl ester
Triphenylphosphine (5.16g), and imidazole (1.34g) were dissolved in 3: 1 ether: acetonitrile (80mL), and the reaction was cooled to 0°C. Iodine (5.0g) was added with vigorous stiπing, 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 10830 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% 10835 EtOAc hexane to give a light yellow oil (4.7g) which slowly crystalizes in the freezer. X NMR (300MHz, CDCI3) δ 2.06 (s, 3H), 3.60 (s, 3H), 4.45 (ABq, JAB=9-7HZ, ΔυAB=6-7Hz, 2H), 7.03 (brd, J=6.6Hz, IH), 7.17-7.29 (m, 4H), 7.41 (dd, J=8.1 , 1.6Hz, IH), 7.90 (d, J=8.1Hz, IH)). MS(CI/NH3) m/e: (M+NH4)+ 384.
Figure imgf000506_0002
Example 1061C 4-(N-(2-Cyclohexylethyl)-N.N-dimethylaminomethyP-2-(2-methylphenyPbenzoic acid.
Methyl Ester. Iodide To a solution of 4-iodomethyl-2-(2-methylphenyl)benzoic acid methyl ester ( 0.5g) in 10845 dichloromethane ( lmL) was added N,N-dimethyl-2-cyclohexylethylamine (0.233mg), and the reaction was stiπed at ambient temperature for 2h. The reaction was concentrated to give a light yellow foam (760mg, 100%).
IH NMR (300 MHz, CDC13) δ 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, ΔυAB=56 Hz, JAB=12-7 Hz, 2H),
10850 7.01 (d, J=7.5 Hz, IH), 7.17-7.32 (m, 3H), 7.39 (d, J=1.8 Hz, IH), 7.88 (dd, J=8.1 , 1.8 Hz, IH), 8.02 (d, J=8.1 Hz, IH).
Figure imgf000507_0001
Example 106 ID 10855 4-(N-(2-CyclohexylethyP-N.N-dimethylaminomethyl)-2-(2-methylphenyPbenzoate, Internal salt To a solution of 4-(N-(2-cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- methylphenypbenzoic acid methyl ester, iodide (700mg) in methanol (3mL) was added 5M LiOH (0.54mL). The reaction was refluxed for lh, then stiπed at ambient temperature 10860 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).
X NMR (300 MHz, DMSO) δ 0.90-1.03 (m, 2H), 1.10-1.28 (m, 5H), 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, 10865 IH), 7.18-7.30 (m, 3H), 7.43 (d, J=1.5 Hz, IH), 7.64 (dd, J=8.1, 1.5 Hz, IH), 7.96 (d, J=8.1 Hz, IH).
MS (ESI) m/e 380 (M+H) +
Figure imgf000507_0002
10870 Example 106 IE
N-r4-(N-('2-Cvclohexylethvn-N.N-dimethylaminomethvP-2-(2- methylphenypbenzoyllmethionine. 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
10875 temperature was added oxalyl chloride (5mL of a 2M solution in CH2CI2). As gas evolution slowed, DMF (5 drops) was added. After stiπing 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 (0.47 mL), and L-methionine methyl
10880 ester-HCl (320mg). After stiπing 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, CDCI3) δ 0.88-1.40 (m, 7H), 1.60-1.76 (m, 6H), 1.82- 1.95 (m, 2H),
10885 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, IH), 7.13-7.40 (m, 6H), 7.57 (brd, J=7.8 Hz, IH), 8.00 ("t", J=7.8 Hz, IH). MS (ESI(-)) m/e 637 (M-H)", 751 (M+TFA-H)-.
Figure imgf000508_0001
Example 106 IF N-r4-fN-(2-CvclohexylethvP-N.N-dimethylaminomethylv2-f2- methylphenyPbenzoyllmethionine. Internal salt N-[4-(N-(2-Cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2- 10895 methylphenyl)benzoyl]methionine methyl ester triflate (330mg) was dissolved in methanol (2mL), and 5M LiOH (0.2 lmL, 2eqiv) was added. After stiπing 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 (168mg) after lyophylization from acetonitrile- water. 10900 X NMR (300 MHz, DMSO) δ 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, IH), 4.56 (brs, 2H), 7.13-7.27 (m, 5H), 7.43 (brs, IH), 7.62 (brs, 2H), 8.30 (brd, J=5 Hz, IH). MS (ESI(+)) m/e 51 1 (M+H); Analysis calc'd for C3oH42N2θ3S*0.65H2θ« 1.30TFA: C,
10905 58.38; H, 6.70; N, 4.18; found: C, 58.35; H, 6.67; N, 4.26.
Figure imgf000509_0001
Example 1062
10910 (2S 2-N-r4-(N-(2-CyclohexylethvP-N-butylaminomethyP-2-(2- methylphenyPbenzoyllamino-4-methylsulfenylbutanoate. lithium salt
Figure imgf000509_0002
Example 1062 A 10915 (2S 2-N-14-(N-f2-CvclohexylethylVN-butylaminomethvP-2-(2- methylphenyPbenzoyllamino-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 (lmL) at 0°C was added trifluoroacetic acid (0.023mL), then 30% hydrogen peroxide 10920 (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)-.
Figure imgf000510_0001
Example 1062B (2S 2-N-r4-(N-(2-CvclohexylethvP-N-butylaminomethvP-2-('2- methylphenyPbenzoyllamino-4-methylsulfenylbutanoate. lithium salt (2S) 2-N-[4-(N-(2-Cyclohexylethyl)-N-butylaminomethyl)-2-(2-
10930 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.
X NMR (300 MHz, DMSO) δ 0.76-0.87 (m, 5H), 1.02-1.44 (m, 9H), 1.52- 1.88 (m,
10935 8H), 1.92-2.24 (m, 6H), 2.33-2.43 (m, 6H), 3.54 (brs, 2H), 3.64-3.75 (m, IH), 6.97 (brd, J=5.1 Hz, IH), 7.06-7.25 (m, 5H), 7.32 (brd, J=7.5 Hz, IH), 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).
10940
Figure imgf000510_0002
Example 1063
N-r4-(N-(2-CyclohexylethyP-N-p-toluenesulfonylaminomethyP-2-(2- methylphenyPbenzoyll methionine. lithium salt
10945
Figure imgf000510_0003
Example 1063 A 2-Cvclohexylethylamine Phenethylamine (50g) was dissolved in lOOOmL of glacial acetic acid in a pressure 10950 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 (lOOOmL), basified with 5N 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 10955 fractional distillation at atmospheric pressure (bp 185°C, 49.5g, 94%).
X NMR(CDC13, 300MHz) δ 0.83-0.95 (m, 2H), 1.00-1.38 (m, 8H), 1.60- 1.73 (m, 5H), 2.71 (dd, J=8.1, 7.2Hz, 2H).
Figure imgf000511_0001
10960 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, l.Ommol).
After 6h, the reaction was diluted with 1:1 EtOAc/hexane (25mL), washed with water 10965 (5mL), IM HCl (2X5mL) and brine (5mL). The organic solution was dried (MgSO4), filtered and concentrated to afford a colorless crystalline solid (300mg).
X NMR (300 MHz, CDC13) δ 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, 5H), 2.43 (s, 3H), 2.95 (q, J=6.9 Hz, 2H), 4.21 (brt, J=5.9 Hz, IH),
7.31 (d, J=7.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H). 10970 MS (DCI/NH3) m/e 299 (M+NH4)+.
Figure imgf000511_0002
Example 1063C 4-(N-(2-CyclohexylethyP-N-p-toluenesulfonylaminomethyP-2-(2-methylphenyl)benzoic 10975 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 stiπing at ambient temperature for 1.5h, the reaction was quenched by addition
10980 of water (lOmL), and diluted with 50% EtOAc/hexane (50mL). The organic solution was washed with water ( lOmL), brine (2X10mL), 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%). X NMR (300 MHz, CDC13) δ 0.64-0.81 (m, 2H), 1.00-1.15 (m, 4H), 1.16-1.27 (m, 2H),
10985 1.42-1.64 (m, 5H), 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, IH), 7.08 (d, J=1.5 Hz, IH), 7.16-7.27 (m, 3H), 7.28 (d, J=8.1 Hz, 2H), 7.37 (dd, J=8.1, 1.5 Hz, IH), 7.71 (d, J=8.4 Hz, 2H), 7.42 (d, J=7.1 Hz, IH).
Figure imgf000512_0001
Example 1063D N-14-(N-f2-Cvclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-(2- 10995 methylphenyPbenzoic acid methyl ester was converted into the title compound according to the procedures described in examples 608C and D to afford a colorless oil. X NMR (300 MHz, CDCI3) δ 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, IH), 5.88 (brd, J=7.5 Hz, IH), 7.08-7.37 (m, 8H), 7.71 11000 (d, J=8.4 Hz, 2H), 7.90 ("dd", J=15, 8.4 Hz, IH). MS(APCI(+)) 651 (M+H)+. MS(APCI(-)) 649 (M-H)".
Figure imgf000513_0001
Example 1063E 1 1005 N- 4-(N-(2-CvclohexylethyP-N-p-toluenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. 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. 11010 IH NMR (300 MHz, DMSO) δ 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, IH), 4.35 (s, 2H), 6.95 (d, J=6.3 Hz, IH), 7.0-7.27 (m, 5H), 7.35 (d, =7.5 Hz, IH), 7.40 (d, J=8.1 Hz, 2H), 7.50 (d, J=7.8 Hz, IH), 7.73 (s, J=6.6 Hz, 2H). MS (APCI(-)) m/e 635 (M-H); Analysis calc'd for C35H43L.N2O5S2O.8OH2O: C, 63.96; 11015 H, 6.84; N, 4.26; found: C, 63.98; H, 6.68; N, 4.09.
Figure imgf000513_0002
Example 1064 11020 N-[4-(N-(2-Cyclohexylethyl -N-m-toluenesulfonylaminomethyl)-2-(2- me thy lphenyPbenzoy 11 methionine. lithium salt
Figure imgf000513_0003
Example 1064 A 1025 N-2-Cyclohexylethyl-rn-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)+.
Figure imgf000514_0001
Example 1064B
4-('N-(2-CyclohexylethyP-N-m-toluenesulfonylaminomethyP-2-(2-methylphenyPbenzoic acid. Methyl Ester
N-2-Cyclohexylethyl-m-toluenesulfonamide was converted into the title compound
1 1035 according to the procedure in example 1063C to afford a colorless oil.
MS (DCI/NH3) m/e 537 (M+NH4)+.
Figure imgf000514_0002
Example 1064C 1 1040 N-r4-(N-('2-CyclohexylethvP-N-m-toluenesulfonylaminomethyP-2-r2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic 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(+)) 11045 651 (M+H)+. MS(APCI(-)) 649 (M-H)-.
Figure imgf000515_0001
Example 1064D N-r4-(N-(2-CyclohexylethyP-N-m-toluenesulfonylaminomethyl)-2-(2-
1 1050 methylphenyPbenzoyllmethionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyljmethionine methyl ester was converted to the title compound according to the procedure described in example 608E, and was isolated as a white powder. X NMR (300 MHz, DMSO) δ 0.60-0.77 (m, 2H), 1.00-1.20 (m, 6H), 1.40-1.89 (m,
1 1055 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, IH), 4.38 (s, 2H), 6.94 (d, J=5.7 Hz, IH), 7.02-7.27 (m, 5H), 7.36 (d, J=8.1 Hz, IH), 7.44-7.54 (m, 3H), 7.60-7.69 (m, 2H).
MS (ESI(-)) m/e 635 (M-H); Analysis calc'd for C35H43LiN2θ5S2»1.30H2θ: C, 63.10; H, 6.90; N, 4.20; found: C, 63.06; H, 6.53; N, 4.18.
1060
Figure imgf000515_0002
Example 1065
N-r4-("N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyP-2-(2-
1065 methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000515_0003
Example 1065 A N-2-Cvclohexylethyl-p-tert-butylbenzenesulfonamide 1070 The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-teit-butylbenzenesulfonyl chloride to afford a white crystalline solid.
MS (DCI/NH3) m/e 341 (M+NH4) +
Figure imgf000516_0001
Example 1065B
4-(N-(2-CyclohexylethyP-N-p-tert-butylbenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic acid. Methyl Ester
N-2-Cyclohexylethyl-p-tert-butylbenzenesulfonamide (300mg) was converted into
1 1080 the title compound according to the procedure in example 1063C to afford a colorless oil.
MS (DCI/NH3) m/e 579 (M+NH4)+.
Figure imgf000516_0002
Example 1065C 11085 N- 4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic 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 11090 (M+H)+. MS(ESI(-)) 691 (M-H)-.
Figure imgf000517_0001
Example 1065D N-r4-(N-(2-CyclohexylethyP-N-p-tert-butylbenzenesulfonylaminomethyP-2-(2-
1 1095 methylphenyPbenzoyllmethionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyl)-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. X NMR (300 MHz, DMSO) δ 0.60-0.75 (m, 2H), 0.96-1.20 (m, 6H), 1.33 (s, 9H), 1.38-
. 100 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, IH), 4.37 (s, 2H), 6.95 (d, J=5.7 Hz, IH), 7.10-7.28 (m, 5H), 7.35 (d, J=7.8 Hz, IH), 7.50 (d, J=6.3 Hz, IH), 7.63 (d, J=8.4 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H). MS (ESI(-)) m e 677 (M-H); Analysis calc'd for C38H49LiN2O5S2«1.55H2O: C, 64.03; H, 7.37; N, 3.93; found: C, 63.98; H, 7.15; N, 3.92.
11 105
Figure imgf000517_0002
Example 1066
N-[4-fN-(2-CyclohexylethyP-N-p-bromobenzenesulfonylaminomethyl)-2-(2- i 10 methylphenyPbenzoy 11 methionine. lithium salt
Figure imgf000517_0003
Example 1066 A N-2-Cyclohexylethyl-p-bromobenzenesulfonamide 15 The title comound was prepared according to example 1063B, replacing p- toluenesulfonyl chloride with p-bromobenzenesulfonyl chloride to afford a white crystalline solid.
MS (DCI/NH3) m/e 363 (M(79Br)+NH4)+, 365 (M(8 lBr)+NH4)+.
Figure imgf000518_0001
Example 1066B 4-(N-(2-CyclohexylethyP-N-p-bromobenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoic acid. Methyl Ester N-2-Cyclohexylethyl-p-bromobenzenesulfonamide (300mg) was converted into the 11125 title compound according to the procedure in example 1063C to afford a colorless oil. MS (DCI/NH3) m/e 601 (M(79Br)+NH4)+, 603 (M(81Br)+NH4)+.
Figure imgf000518_0002
Example 1066C 11130 N-r4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic 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(+)) 11135 715 (M(79βr)+H)+, 717 (M(81Br)+H)+. MS(APCI(-)) 749 (M(79Br)+Cl)-, 751 (M(81Br)+Cl)-.
Figure imgf000519_0001
Example 1066D 140 N-r4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl)-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. 145 X NMR (300 MHz, DMSO) δ 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, IH), 4.36 (s, 2H), 6.96 (d, J=6 Hz, IH), 7.03-7.26 (m, 5H), 7.37 (d, J=8.1 Hz, IH), 7.54 (d, J=8. 1 Hz, IH), 7.76-7.85 (m, 4H).
MS (ESI(-)) m/e 699 (M(79Br)+H)+, 701 (M(81Br)+H)+; Analysis calc'd for 1 150 C34H4oBrLiN2θ5S2*0.95H2θ: C, 56.34; H, 5.83; N, 3.86; found: C, 56.33; H, 5.66; N, 3.48.
Figure imgf000519_0002
1 155 Example 1067
N-[4-(N-(2-CyclohexylethyP-N-p-methoxybenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000519_0003
11160 Example 1067 A
N-2-Cyclohexylethyl-p-methoxybenzenesulfonamide The titie comound was prepared according to example 1063B, replacing p- tolueriesulfonyl chloride with p-methoxybenzenesulfonyl chloride to afford a colorless oil. MS (DCI/NH3) m/e 315 (M+NH4)+.
1 1 165
e
Figure imgf000520_0001
Example 1067B 4-(N-(2-CyclohexylethyP-N-p-methoxybenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic acid. Methyl Ester 11170 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)+.
Figure imgf000520_0002
11175 Example 1067C
N-r4-(N-('2-CyclohexylethyP-N-p-methoxybenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to 11180 the procedures described in examples 608C and D to afford a colorless oil. MS(APCI(+)) 667 (M+H)+. MS(APCI(-)) 701 (M+Cl)-.
Figure imgf000521_0001
Example 1067D 1 185 N-[4-(N-(2-CyclohexylethyP-N-p-methoxybenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoy 11 methionine. lithium salt N-[4-(N-(2-Cyclohexylethyl)-N-p-methoxybenzenesulfonylaminomethyl)-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. 1 190 X NMR (300 MHz, DMSO) δ 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, IH), 3.83 (s, 3H), 4.32 (s, 2H), 6.94 (d, J=6 Hz, IH), 7.04-7.26 (m, 5H), 7.1 1 (d, J=8.7 Hz, 2H), 7.35 (dd, J=8.1 , 1 Hz, IH), 7.51 (d, J=8.1 Hz, IH), 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; 1 195 H, 6.87; N, 4.09; found: C, 61.36; H, 6.48; N, 3.91.
Figure imgf000521_0002
Example 1068 1200 N-r4-(N-(2-CyclohexylethyP-N-p-nitrobenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000521_0003
Example 1068 A 1205 N-2-Cyclohexylethyl-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)+.
Figure imgf000522_0001
Example 1068B 4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminornethyP-2-(2- methylphenyPbenzoic acid. Methyl Ester N-2-Cyclohexylethyl-p-nitrobenzenesulfonamide (300mg) was converted into the 11215 title compound according to the procedure in example 1063C to afford a colorless oil. MS (DCI/NH3) m/e 568 (M+NH4)+.
Figure imgf000522_0002
Example 1068C 11220 N-|ι4-(N-(2-CyclohexylethyP-N-p-nitrobenzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(2-Cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoic 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(+)) 11225 682 (M+H)+. MS(APCI(-)) 716 (M+Cl)".
Figure imgf000523_0001
Example 1068D N-[4-(N-(2-CvclohexylethyP-N-p-nitrobenzenesulfonylaminomethyl)-2-(2-
1230 methylphenyPbenzoyllmethionine. lithium salt N-[4-(N-(2-CyclohexylethyP-N-p-nitrobenzenesulfonylaminomethyl)-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. X NMR (300 MHz, DMSO) δ 0.63-0.76 (m, 2H), 1.00-1.26 (m, 6H), 1.40- 1.70 (m,
1 1235 10H), 1.92 (s, 3H), 1.95-2.15 (m, 3H), 3.12-3.20 (m, 2H), 3.59-3.65 (m, IH), 4.43 (s, 2H), 6.96 (d, J=6.3 Hz, IH), 7.0-7.25 (m, 5H), 7.36 (d, J=8.1 Hz, IH), 7.52 (d, =7.8 Hz, IH), 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 C34H4oLiN3θ7S2»1.2H2θ: C, 58.73; H, 6.15; N, 6.04; found: C, 58.73; H, 5.82; N, 5.92.
1240
Figure imgf000523_0002
Example 1069
N-[4-(N-(2-Cyclohexyl-2-methylpropyP-N-methylaminomethyP-2-(2-
. 1245 methylphenyPbenzoy 11 methionine. lithium salt
Figure imgf000523_0003
Example 1069 A N-Methyl-2-cyclohexyl-2-methylpropylamine 1 1250 Treatment of 2-phenyl-2-methylpropylamine (example 1048A, 5g) with di-tert- butyldicarbonate according to example 1056A afforded N-tert-butoxycarbonyl-2-phenyl-2- methylpropylamine (lOg crude) as a colorless oil. To portion of this material (5g) 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 (lOOmL),
1 1255 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 (l.Og). This material was reduced with LiAl£_4 according to the procedure described in example 1056 A to afford the title compound (0.8g), as a colorless oil.
1 1260 X NMR (300 MHz, CDC13) δ 0.83 (s, 6H), 0.87-1.29 (m, 6H), 1.60-1.82 (m, 5H), 2.36 (s, 2H), 2.42 (s, 3H). MS (APCI(+)) m/e 170 (M+H)+.
Figure imgf000524_0001
11265 Example 1069B
4-(N-(2-Cyclohexyl-2-methylpropyP-N-methylaminomethyP-2-(2-methylphenyl)benzoic acid. Methyl Ester The title compound was prepared according to the procedure in example 608B, subsitiuting N-methyl-2-cyclohexyl-2-methylpropylamine for N- 11270 methylcyclohexylethylamine, and was isolated as a colorless oil. MS(ESI(+)) m/e 408 (M+H)+.
Figure imgf000524_0002
Example 1069C 1275 N-r4-(N-(2-Cvclohexyl-9-methylpropyl)-N-methylaminomethvP-2-(2- methylphenyPhenzoyllmethionine. Methyl 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. 1280 MS(ESI(+)) m/e 539 (M+H)+. MS(ESI(-)) m/e 537 (M-H)-.
Figure imgf000525_0001
Example 1069D N-r4-(N-(2-Cyclohexyl-2-methylpropyl)-N-methylaminomethyP-2-(2-
. 1285 methylphenyPbenzoyllmethionine. 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. X NMR (300 MHz, DMSO) δ 0.79 (s, 6H), 0.80- 1.27 (m, 5H), 1.50- 1.74 (m, 6H),
1 1290 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, IH), 6.92 (d, J=6 Hz, IH), 7.08-7.25 (m, 5H); 7.36 (d, J=7.8 Hz, IH), 7.49 (d, J=7.8 Hz, I H).
MS (ESI(-)) m/e 523 (M-H); Analysis calc'd for C3ιH43LiN2θ3S» 1.3H2θ: C, 67.70; H, 8.29; N, 5.06; found: C, 67.15; H, 8.08; N, 4.97.
. 1295
Figure imgf000525_0002
Example 1070
N-r4-(3-Cyclohexyl-l-methoxyprop-2-ylaminomethvP-2-(2-
1300 methylphenyPbenzoy 11 methionine. lithium salt
Figure imgf000526_0001
Example 1070 A (S)-3-Cyclohexyl-l-methoxy-2-propylamine 1305 To a solution of (S)-3-phenyl- l-methoxy-2-propylamine hydrochloride (0.5g) in ethanol (100ml) 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 (50mL) and neutralized with IM NaOH (to pHA 1). The mixture was washed with chloroform (3X50mL), and the organic extracts were washed 1310 with brine (20mL), dried (MgSO4), filtered and concentrated to give a colorless oil (400mg).
X NMR (300 MHz, CDC13) δ 0.76-1.00 (m, 2H), 1.10- 1.48 (m, 6H), 1.61- 1.81 (m, 5H), 3.01-3.14 (m, 2H), 3.30-3.35 (m, IH), 3.36 (s, 3H).
. 1315
Figure imgf000526_0002
Example 1070B N-f 4-("3-Cyclohexyl- 1 -methoxyprop-2-ylaminomethyl)-2-(2- methylphenyPbenzoy 11 methionine. Methyl Ester The title compound was prepared from (S)-3-cyclohexyl-l-methoxy-2-propylamine [ 1320 according to the procedure described in example 403H to afford a colorless oil. MS(APCI(+)) 541 (M+H)+. MS(APCI(-)) 539 (M-H)-.
Figure imgf000526_0003
Example 1070C 1 1325 N-[4-(3-Cyclohexyl-l-methoxyprop-2-ylaminomethvP-2-(2- methylphenyPbenzoyllmethionine. lithium salt N-[4-(3-Cyclohexyl-l-methoxyprop-2-ylaminomethyl)-2-(2- methylphenyPbenzoyl] methionine methyl ester was converted into the title compound according to the procedure described in example 608E, affording a white powder.
11330 X NMR (300 MHz, DMSO) δ 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, IH), 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, IH), 7.48 (d, J=7.8 Hz, IH). MS (APCI(-)) m/e 525 (M-H); Analysis calc'd for C3oH4ιLiN2θ4S»0.60H2O: C, 66.30; H,
1 1335 7.83; N, 5.15; found: C, 66.29; H, 7.69; N, 5.15.
Figure imgf000527_0001
Example 1071
1340 N-r4-(l-Ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000527_0002
Example 1071 A 1 1345 4-Formyl-2-(2-methylphenyl)benzoic acid methyl ester
To a solution of 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid methyl ester (example 1178C, l.Og) in dichloromethane (lOmL) was added infusorial earth (2g) then at 0°C was added pyridinium chlorochromate (1.7g). After lOmin, the reaction was warmed to ambient temperature. After lh, the reaction was diluted with ether (50mL), and filtered 11350 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%).
X NMR (300 MHz, CDC13) δ 2.08 (s, 3H), 3.63 (s, 3H), 7.07 (brd, J=6.6 Hz, IH),
7.19-7.30 (m, 3H), 7.76 (d, J= 1.8 Hz, IH), 7.93 (dd, J=8.1 , 1.6 Hz, IH), 8.06 (d, J=8. 1
1355 Hz, IH), 10.09 (s, IH).
MS (DCI/NH3) m/e 255 (M+H)+.
Figure imgf000528_0001
"SEt Example 107 IB 1 1360 4-N-(3-Cyclohexyl-l-ethylthioprop-2-yPaminomethyl-2-(2-methylphenyl)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. 1 1365 MS( APCI(+)) 440 (M+H)+. MS(APCI(-)) 438 (M-H)".
Figure imgf000528_0002
"SEt Example 1071C 4-N-tert-Butoxycarbonyl-N-f3-cyclohexyl-l-ethylthioprop-2-yPaminomethyl-2-(2- 11370 methylphenyPbenzoic acid. Methyl Ester
To a solution of 4-N-(3-cyclohexyl-l-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% 11375 EtOAc/hexane to give the title compound as a colorless oil (605mg). MS(APCI(-)) 538 (M- H)-.
Figure imgf000529_0001
;SEt
I
O Example 107 ID 1 1380 4-N-tert-Butoxycarbonyl-N-d-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyPbenzoic 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 (5mL) at -78°C was added m-chloroperbenzoic acid (280mg@75%). After 1.5h, the 1 1385 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 ( lOmL), 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(+)) 1 1390 556 (M+H)+. MS(APCI(-)) 590 (M+Cl)".
Figure imgf000529_0002
^SEt
I
O
Example 107 IE N-tert-Butoxycarbonyl-N-r4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2- 1 1395 methylphenyPbenzoy 11 methionine. Methyl Ester
The title compound was prepared from 4-( l-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)+. 11400 MS(APCI(-)) 721 (M+Cl)-.
Figure imgf000530_0001
"S I Et
O
Example 107 IF N- 4-( l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyP-2-(2- 1405 methylphenyPbenzoyllmethionine. 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 1410 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)-.
Figure imgf000530_0002
"SEt
I
O 1 1415 Example 1071G
N-[4-( l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt N-[4-(l-Ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine methyl ester was converted into the title compound 11420 according to the procedure described in example 608E.
X NMR (300 MHz, DMSO) δ 0.67-0.93 (m, 2H), 1.00- 1.90 (m, 13H), 1.1 1 (t, J=7.5 Hz, 3H), 1.94-2.20 (m, 6H), 2.34-2.45 (m, 5H), 2.56-2.67 (m, 2H), 3.62-3.83 (m, 3H), 6.98 (brd, J=6 Hz, IH), 7.10-7.24 ( , 5H), 7.38 (brd, J=7.8 Hz, IH), 7.49 (d, J=7.8 Hz, 0.5H), 7.5 (d, J=7.8 Hz, 0.5H). 11425 MS (ESI(-)) m/e 571 (M-H).
Figure imgf000531_0001
Example 1072
1430 (2S) 2-N-r4-( l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyP-2-(2- methylphenyl)benzoyllamino-4-methylsulfenylbutanoate. lithium salt
Figure imgf000531_0002
Example 1072A
11435 (2S) N-tert-Butoxycarbonyl-2-N- 4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-
(2-methylphenyPbenzoyllamino-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 107 IE,
320mg) in dichloromethane (2mL) at -78°C was added m-chloroperbenzoic acid
11440 (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 (lOmL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% methanol/dichloromethane to afford a
11445 white foam (31 lmg, 95%). MS(APCI(+)) 703 (M+H)+. MS(APCI(-)) 737 (M+Cl)-.
Figure imgf000532_0001
"SEt
I
O
Example 1072B (2S) 2-N-[4-(l-Ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyP-2-(2- 1 1450 methylphenvPbenzoyllamino-4-methylsulfenylbutanoate. Methyl Ester
The title compound was prepared from (2S) N-tert-butoxycarbonyl-2-N-[4-(l- ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]amino-4- methylsulfenylbutanoate methyl ester according to the procedure described in example 107 IF in 58% yield. The product was purified by silica gel chromatography eluting with 11455 5%-10% methanol/dichloromethane, and was isolated as a white foam. MS(APCI(+)) 603 (M+H)+. MS(APCI(-)) 637 (M+Cl)".
Figure imgf000532_0002
Et O
Example 1072C
. 1460 (2S 2-N-14-(l-ethylsulfenyl-3-cvclohexylprop-2-ylaminomethyP-2-(2- methylphenyPbenzoyllamino-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
11465 yellow powder.
X NMR (300 MHz, DMSO) δ 0.72-0.90 (m, 2H), 1.03-1.20 (m, 5H), 1.20-1.90 (m,
11H), 1.94-2.23 (m, 5H), 2.36 (s, 3H), 2.57-2.80 (m, 4H), 2.98 (brs, IH), 3.64-3.82
(m, 3H), 6.95-7.00 (m, IH), 7.09-7.23 (m, 5H), 7.33-7.41 (m, IH), 7.49 (d, J=8.1 Hz,
0.5H), 7.50 (d, J=8.1 Hz, 0.5H).
11470 MS (ESI(-)) m/e 587 (M-H).
Figure imgf000533_0001
Example 1073 1475 N- 4-(N-(3-cvclohexylpropyP-N-benzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyll methionine. lithium salt
Figure imgf000533_0002
Example 1073 A 11480 N-3-Cyclohexylpropylbenzenesulfonamide
The title comound was prepared according to example 1063 A (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+NH4A 1 1485
Figure imgf000533_0003
Example 1073B 4-(N-(3-cyclohexylpropyl)-N-benzenesulfonylaminomethyP-2-(2-methylphenyPbenzoic acid. Methyl Ester 11490 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)+.
Figure imgf000534_0001
1495 Example 1073C
N-r4-('N-f3-cyclohexylpropyP-N-benzenesulfonylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. Methyl Ester 4-(N-(3-Cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoic acid methyl ester was converted into the title compound according to 1500 the procedures described in examples 608C and D to afford a colorless oil. MS(ESI(+)) 651 (M+H)+. MS(ESI(-)) 649 (M-H)-.
Figure imgf000534_0002
Example 1073D 1505 N-r4-(N-(3-cyclohexylpropyl)-N-benzenesulfonylaminomethyP-2-(2- methylphenyPbenzoyll 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. 1 1510 iH NMR (300 MHz, DMSO) δ 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, IH), 4.39 (s, 2H), 6.96 (d, J=6 Hz, IH), 7.04-7.28 (m, 5H), 7.36 (d, J=7.8 Hz, IH), 7.51 (d, J=7.8 Hz, IH), 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 C35H43LiN2θ5S2« 1.65H2θ: C, 62.51 ; H, 11515 6.94; N, 4.17; found: C, 62.48; H, 6.79; N, 4.07.
Figure imgf000535_0001
Example 1074
1520 N-[4-(N-glucosaminomethyP-2-(2-methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000535_0002
Example 1074 A N- r4-(N-glucosaminomethyP-2-(2-methylphenyPbenzoyllmethionine. Methyl Ester
1525 A IM solution of glucosamine was prepared by dissolving glucosamine»HCl ( lOg) in
IM NaOH (47mL). This solution (0.31 lmL) was added to N-[4-formyl-2-(2- methylphenyl)benzoyl] methionine methyl ester (example 403G, lOOmg), 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
11530 (latm). 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 (50mg, 35%). MS(ESI(+)) 549 (M+H)+, 571 (M+Na)+.
Figure imgf000535_0003
11535 Example 1074B N-r4-(N-glucosaminomethvP-2-(2-methylphenyl)benzoyllmethionine. lithium salt The title compound was prepared from N-[4-(N-Glucosaminomethyl)-2-(2- me thy lphenyl)benzoyl] methionine methyl ester according to the procedure described in example 608E, and was isolated as a fluffy white powder. 11540 IH NMR (300 MHz, CD3OD) δ 1.60-1.90 (m, 4H), 1.95-2.09 (m, 6H), 2.26 (brs, 2H), 2.41 (brt, J=9.3 Hz, IH), 2.54 (dd, J=10.2, 3.3 Hz, IH), 3.22-3.30 (m, 2H), 3.58-4.03 (m, 5H), 4.13-4.28 (m, 2H), 4.58 (d, J=7.8 Hz, IH), 5.17-5.22 (m, IH), 7.07-7.30 (m, 6H), 7.42-7.47 (m, IH), 7.61-7.67 (m, IH). MS (ESI(-)) m/e 533 (M-H).
1 1545
Figure imgf000536_0001
Example 1079 (2S 2-N-r4-(,N-2-Cvclohexylethyl-N-methylaminomethvP-2-(2- .1550 methylphenyPbenzoyllamino-4-difluoromethylthiobutanoate. lithium salt
Figure imgf000536_0002
Example 1079 A N-tert-Butoxycarbonylhomocysteine thiolactone
11555 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 (lOOmL), washed with water (20mL), IM 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.
11560 X NMR (300 MHz, CDC13) δ 1.45 (s, 9H), 1.97 (ddd, J=25, 11.7, 6.6 Hz, IH), 2.86 (m, IH), 3.23 (dd, J=1 1.4, 1.5 Hz, IH), 3.32 (ddd, J=1 1.4, 1 1.4, 5.1 Hz, IH), 4.28 (m, IH), 4.98 (brs, IH).
Figure imgf000537_0001
11565 Example 1079B
N-tert-Butoxycarbonyl-S-difluoromethylhomocysteine To a solution of N-tert-butoxycarbonylhomocysteine thiolactone hydrochloride
(400mg) in THF (2mL) at 0°C was added IM NaOH (6mL). After stiπing for 20min, this solution was added to chlorodifluoromethane ( 3.25mL) at -78°C in a pressure tube. The 11570 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 IM HCl, and extracted into dichloromethane (30mL). The organic extracts were washed with brine
(20mL), dried (MgSO4), filtered and concentrated to give the title compound as a syrup
(490mg). 11575 X NMR (300 MHz, CDC13) δ 1.45 (s, 9H), 1.95-2.36 (m, 2H), 2.63 (q, J=7.4 Hz, IH),
2.90 (ddd, J=7.6, 7.6, 2.7 Hz, IH), 4.46 (brs, IH), 5.05 (brs, IH), 6.82 (t, J=56 Hz,
IH).
MS (ESI(+)) m/e 308 (M+Na)+.
MS (ESI(-)) m/e 285 (M-H)-. 1 1580
Figure imgf000537_0002
Example 1079C N-tert-Butoxycarbonyl-S-difluoromethylhomocysteine. Methyl Ester To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine in diethyl 1585 ether (ImL) 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).
X NMR (300 MHz, CDCI3) δ 1.45 (s, 9H), 1.90-2.30 (m, 2H), 2.85 (t, J=7.5 Hz, 2H), 11590 3.77 (s, 3H), 4.42 (brs, IH), 5.08 (brs, IH), 6.81 (t, J=56.1 Hz, IH). MS (ESI(+)) m/e 322 (M+Na)+. MS (ESI(-)) m/e 298 (M-H)-.
Figure imgf000538_0001
"OTf 11595 Example 1079D
S-difluoromethylhomocysteine, Methyl Ester. Trifluoroacetate To a solution of N-tert-butoxycarbonyl-S-difluoromethylhomocysteine methyl ester (400mg) in dichloromethane (2mL) was added trifluoroacetic acid (ImL). After stiπing 18h at ambient temperature, the reaction was concentrated, and the residue was triturated with 11600 toluene and evaporated to give the title compound as a tan solid (515mg).
X NMR (300 MHz, CDC13) δ 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, IH), 6.83 (t, J=55.8 Hz, IH).
Figure imgf000538_0002
11605 Example 1079E
(2S 2-N-r4-(N-2-Cvclohexylethyl-N-methylaminomethvP-2-(2- methylphenyPbenzoy 11 amino-4-difluoromethylthiobutanoate. Methyl Ester The title compound was prepared according to the procedure in example 608D, relpacing L-methionine methyl ester-HCl with S-difluoromethylhomocysteine methyl ester, 11610 trifluoroacetate, and was isolated as a colorless oil.
X NMR (300 MHz, CDCI3) δ 0.80-0.94 (m, 2H), 1.10-1.70 (m, 1 1H), 1.90-2.18 (m, 5H), 2.20 (s, 3H), 2.30-2.41 (m, 4H), 3.53 (s, 2H), 3.67 (s, 3H), 4.57-5.66 (m, IH), 5.83-5.90 (m, IH), 6.73 ("dt", J=2.7, 56 Hz, IH), 7.14-7.41 (m, 5H), 7.39 (brd, J=7.5 Hz, IH), 7.90 ("dd", J=14.4, 8.1 Hz, IH). 11615 MS (ESI(+)) m/e 547 (M+H)+. MS (ESI(-)) m/e 545 (M-H)-.
Figure imgf000539_0001
Example 1079F
11620 (2S) 2-N-r4-('N-2-Cvclohexylethyl-N-methylaminomethvP-2-(2- methylphenvPbenzoyllamino-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-difluoromethylthiobutanoate methyl ester according to the procedure described in example 608E with the following
11625 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
11630 washed with brine (20mL), dried (MgSO4), filtered and concentrated. The free amino acid was dissolved in water, the lithium salt was prepared by addition of one equivalent of 5M LiOH, and the solution was frozen (-78°C) and lyophylized to give the title compound as a light yellow powder. X NMR (300 MHz, DMSO) δ 0.75-0.90 (m, 2H), 1.06-1.38 (m, 6H), 1.53-1.80 (m,
1 1635 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, IH), 6.91-7.23 (m, 7H), 7.23 (d, J=7.8 Hz, IH), 7.50 (d, J=7.8 Hz, IH). MS (ESI(-)) m/e 531 (M-H).
Figure imgf000539_0002
Example 1080 (2S 2-N-[4-(N-2-Cvclohexylethyl-N-methylaminnmethvP-2-(2- methylphfinyπhenzoyllamino-5-methoxypentanoate. lithium salt
Figure imgf000540_0001
Example 1080A Methyl (2S -N-2-Carbobenzyloxyamino-5-hydroxypentanoate To a solution of N-carbobenzylozy-L-glutamic acid 1 -methyl ester (commercial, l.Og) in 3.5mL THF at 0°C was added IM BH3»THF (6.7mL). After lh, the reaction was 1650 quenched by addition of IM sodium bisulfate (lOmL), and concentrated. The reaction was diluted with water (20mL) and the product was extracted into EtOAc (50mL). 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 (500mg). 1655 MS (ESI(+)) m/e 282 (M+H)+, 299 (M+NH4)+. MS (ESI(-)) m/e 280 (M-H)-.
Figure imgf000540_0002
Example 1080B 11660 Methyl (2S -N-2-Carbobenzyloxyamino-5-methoxypentanoate
Methyl (2S)-N-2-carbobenzyloxyamino-5-hydroxypentanoate (500mg) 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. 11665 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. X NMR (300 MHz, CDC13) δ 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, IH), 5.11 (s, 2H), 5.43 (brd, J=7.8 Hz, IH), 7.32-7.40 (m, 5H). 11670 MS (ESI(+)) m/e 296 (M+H)+, 318 (M+Na)+. MS (ESI(-)) m/e 294 (M-H)-.
Figure imgf000541_0001
Example 1080C 11675 Methyl f2S -2-amino-5-methoxypentanoate
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 11680 dichloromethane and dilute NaOH. The organic extracts were washed with brine ( lOmL), dried (MgSO4), filtered and concentrated to give the title compound (99mg, 78%) as a light yellow syrup.
MS (ESI(+)) m/e 162 (M+H) +
Figure imgf000541_0002
Example 1080D
(2S) 2-N-r4-(N-2-Cvclohexylethyl-N-methylaminomethvP-2-(2- methylphenyl)benzoyllamino-5-methoxypentanoate. Methyl Ester
The title compound was prepared according to example 608D, replacing L-
1690 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)-.
Figure imgf000542_0001
Example 1080E
(2S 2-N-r4-(N-2-Cyclohexylethyl-N-methylaminomethvP-2-(2- methylphenyPbenzoyllamino-5-methoxypentanoate. lithium salt
(2S) 2-N- [4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2-
11700 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.
X NMR (300 MHz, DMSO) δ 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),
11705 3.58-3.67 (m, IH), 6.88-6.93 (m, IH), 7.03-7.23 (m, 5H), 7.30 (d, J=8.1 Hz, IH), 7.48
(d, J=8.1 Hz, IH).
MS (ESI(-)) m/e 493 (M-H); Analysis calc'd for C3oH4ιLiN2θ4«0.75H2θ: C, 70.09; H,
8.33; N, 5.45; found: C, 7.0.4; H, 8.20; N, 5.38.
1 1710
Figure imgf000542_0002
Example 1081
('2S 2-N-r4-rN-2-Cyclohexylethyl-N-methylaminomethvP-2-('2- methylphenyPbenzoyllaminopent-4-ynoate. lithium salt
11715
Figure imgf000543_0001
Example 1081 A
(2S) 2-N-r4-rN-2-Cvclohexylethyl-N-methylaminomethyl)-2-(2- methylphenyPbenzoyllaminopent-4-ynoate. Methyl Ester
1 1720 The title compound was prepared according to example 608D, replacing L- methionine methyl ester-HCl with L-propargylalanine methyl ester»HCl, and was isolated as a colorless oil.
MS (ESI(+)) m/e 475 (M+H)+. MS (ESI(-)) m/e 473 (M-H)".
1 1725
Figure imgf000543_0002
Example 108 IB (2S) 2-N-r4-(N-2-Cyclohexylethyl-N-methylaminomethvP-2-(2- methylphenyPbenzoyllaminopent-4-ynoate. lithium salt
1730 (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. X NMR (300 MHz, DMSO) δ 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, IH), 2.14 (s, 3H), 2.32 (t, J=6 Hz, 2H), 2.36-2.43 (m, 2H),
1735 3.49 (s, 2H), 3.56-3.63 (m, IH), 7.00-7.28 (m, 6H), 7.31 (d, J=7.8 Hz, IH), 7.52 (d, J=7.8 Hz, IH).
MS (ESI(-)) m/e 459 (M-H); Analysis calc'd for C29H35LiN2θ3»1.90H2θ: C, 69.56; H, 7.81 ; N, 5.59; found: C, 69.49; H, 7.33; N, 5.57.
1740
Figure imgf000544_0001
Example 1082 2-r4-(N-2-Cvclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyl)benzoylloxy-4- methvlthiobutanoate, lithium salt
1745
Figure imgf000544_0002
Example 1082 A DL. 2-Hydroxy-4-methylmercaptobutyric acid. Methyl Ester A solution of DL, 2-hydroxy-4-methylmercaptobutyric acid calcium salt (2.2g) in 11750 0.5M HCl (50mL) was saturated with sodium chloride, extracted exhaustively with EtOAc, which was dried (MgSO4), 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% 11755 EtOAc/hexane to give the title compound as a light yellow oil (1.37g).
X NMR (300 MHz, CDC13) δ 1.86-1.98 (m, IH), 2.04-2.16 (m, IH), 2.1 1 (s, 3H), 2.63 (d, J=7.8 Hz, IH), 2.65 (dd, J=7.8, 1.5 Hz, IH), 2.88 (brs, IH), 3.81 (s, 3H), 3.34 (dd, J=7.8, 3.9 Hz, IH).
Figure imgf000544_0003
Example 1082B 2-r4-(N-2-Cyclohexylethyl-N-methylaminomethyP-2-(2-methylphenyPbenzoylloxy-4- methylthiobutanoate. Methyl Ester To a solution of DL, 2-hydroxy-4-methylmercaptobutyric acid methyl ester (72mg) 1765 and N-[4-(N-(-2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylρhenyl)benzoic acid (example 608C, 150mg) in THF (LOmL) 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 (90mg, 43%). MS(APCI(+)) 512 (M+H)+.
1770
Figure imgf000545_0001
Example 1082C 2-r4-(N-2-Cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyl)benzoylloxy-4- methylthiobutanoate, lithium salt
11775 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).
11780 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 (MgSO4), 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
11785 hygroscopic white powder ( 104mg) .
X NMR (300 MHz, DMSO) δ 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, IH), 6.93-7.02 (m, IH), 7.02-7.24 (m, 5H), 7.36-7.41 (m, IH), 7.82 (d, J=7.8 Hz, 0.3H), 7.87 (d, J=7.8 Hz, 0.7H).
11790 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.
Figure imgf000546_0001
1795 Example 1085
N-r4-(N-f5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000546_0002
1 1800 Example 1085 A
5-(4-chlorophenyP-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 cone H2SO4 (4 drops) and the resulting solution heated to 50 °C for 4 days. The reaction was cooloed and concentrated in vacuo. The residue was taken up in EtOAc 1 1805 (100 mL) and washed with saturated aqueous NaHCO3 (2 x 20 mL), dried (MgSU4) 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).
Figure imgf000546_0003
Example 1085B 5-(4-chlorophenyl)-4-bromo-2-furoic acid, methyl ester To a stiπed solution of the ester (3.53 g, 14.9 mmol) in CHCI3 (40 mL) was added a 4.2 M solution of Br2 in CHCI3 (4.3 mL, 17.9 mmol) and the resulting solution heated to 50
1815 °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).
Figure imgf000546_0004
11820 Example 1085C
The ester (1.37 g, 4.34 mmol) was hydrolyzed as in example 1084 D (for 1 hour at it) 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). 11825
Figure imgf000547_0001
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,
1830 9.8 mmol) and the resulting solution heated to 50 °C overnight. The reaction was concentrated in vacuo and the residue taken up in EtOAc (50 L) and quenched with water (20 mL). The layers were separated and the organic layer washed with H2O (20 L) and brine (20 mL), dried (MgSOα) and concentrated in vacuo. The residue was purified by flash chromatography
1835 (hexane/EtOAc 2:1) to give 0.49 g (46%) of a light yellow oil; MS m z 330 (M+ + 1, 100).
Figure imgf000547_0002
Example 1085D
11840 To a stiπed 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 ovemight. The reaction was cooled and concentrated in vacuo. The residue was taken up in EtOAc (30 mL) and washed with H2O (10 mL),
11845 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).
Figure imgf000548_0001
Example 1085E N-|"4-(N-(5-bromo-(4-chlorophenyPfuran-2-ylmethyl-N-isopropylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester The ester (0.61 g, 1.1 mmol) was hydrolyzed as in example 1084 D and coupled to
1855 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).
Figure imgf000548_0002
11860 Example 1085 F
N-r4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropylaminomethyP-2-(2- me thy lphenyPbenzoy 11 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; 11865 X NMR (DMSO-d6,) δ 7.72-7.67 (m, 2 H), 7.45-7.29 (m, 4 H), 7.1 1-6.82 (m, 6 H), 6.51
(s, 1 H), 3.63-3.48 (m, 5 H), 2.92-2.88 (m, 1 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).
1 1870
Figure imgf000548_0003
Example 1086 N-f4-(N-(5-phenyl-('4-chlorophenyPfuran-2-ylmethyl-N-isoprnpylaminomethyl)-2-(2- methylphenyPhenzoyllmethionine. lithium salt
1875
Figure imgf000549_0001
Example 1086 A N-[4-(N-(5-pheήyl-(4-chlorophenyPfuran-2-ylmethyl-N-isopropylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester
. 1880 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)feπocene]dichloropalladium(II), complex with dichloromethane ( 1: 1) (7 mg, 0.009 mmol) and the resulting mixture heated to 80 °C overnight. The reaction was cooled and the reaction filtered through Celite, washing the bed with EtOAc. The filtrate was
1 1885 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).
Figure imgf000549_0002
1890 Example 1086B
N-[4-(N-(5-phenyl-(4-chlorophenyPfuran-2-ylmethyl-N-isopropylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. lithium salt The ester (30 mg, 0.04 mmol) was hydrolyzed as in example 1084 E to give 30 mg of a cream powder; 1 1895 X NMR (DMSO-d6>) δ 7.47-6.85 (m, 17 H), 6.47 (s, 1 H), 3.73-3.58 (m, 5 H), 3.06- 3.01 (m, 1 H), 2.11-1.77 (m, 8 H), 1.63-1.57 (m, 1 H), 1.51-1.43 (m, 1 H), 1.05-1.01 (m, 6 H); MS m/z 679 (M+ - 1, 100).
1 1900
Figure imgf000550_0001
Example 1087
N-[4-(N-(5-(3-methoxyphenyP-(4-chlorophenyl)furan-2-ylmethyl)-N- isopropylaminomethyP-2-('2-methylphenyl)benzoyllmethionine. lithium salt
1905
Figure imgf000550_0002
Example 1087A N-F4-(N-(5-(3-methoxyphenyP-(4-chlorophenyPfuran-2-ylmethyl)-N- isopropylaminomethyP-2-(2-methylphenyPbenzoyllmethionine. methyl ester
1 1910 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).
Figure imgf000550_0003
Example 1087B N-r4-(N-f5-(3-methoxyphenyP-(4-chlorophenyl)furan-2-ylmethyP-N- isopropylaminomethyl)-2-(2-methylphenyPbenzoynmethionine. lithium salt The ester (38 mg, 0.054 mmol) was hydrolyzed as in example 1084 E to give 38 mg
1 1920 of a beige powder;
*H NMR (DMSO-d6,) δ 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).
1 1925
Figure imgf000551_0001
Example 1088
N-)"4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropylaminomethyP-2-(2-
1 1930 methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000551_0002
Example 1088A
N-r4-(N-(4.5-di(4-chlorophenyPfuran-2-yl)methyP-N-isopropylaminomethyP-2-(2-
1 1935 methylphenyPbenzoyllmethionine. 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).
Figure imgf000551_0003
Example 1088B N-_"4-(N-(4.5-di(4-chlorophenyPfuran-2-yPmethyl)-N-isopropylaminomethyP-2-(2- methylphenyPbenzoyllmethionine. lithium salt The ester (31 mg, 0.042 mmol) was hydrolyzed as in example 1084 E to give 31 mg
1 1945 of a cream powder;
X NMR (DMSO-d6,) δ 7.47-7.29 (m, 1 1 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, 1 H), 1.11-1.05 (m, 6 H); MS m/z 713 (M+ - 1, 100).
1950
Figure imgf000552_0001
Example 1089
N- 4-(N-(5-thien-3-yl-(4-chlorophenyPfuran-2-vPmethyP-N-isopropylaminomethyl)-2-(2-
1955 methylphenyPbenzoyllmethionine. lithium salt
Figure imgf000552_0002
Example 1089 A N- 4-(N-(5-thien-3-yl-(4-chlorophenyPfuran-2-yPmethyP-N-isopropylaminomethyl)-2-(2- 1960 methylphenyPbenzoyllmethionine. methyl 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+ + l, 100).
Figure imgf000552_0003
Example 1089B N-r4-(N-(5-thien-3-yl-(4-chlorophenyPfuran-2-yPmethyP-N-isopropylaminomethyP-2-(2- methylphenyPbenzoyll methionine. lithium salt The ester (38 mg, 0.054 mmol) was hydrolyzed as in example 1084 E to give 37 mg
11970 of a yellow powder;
X NMR (DMSO-d6) δ 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). 1975
Figure imgf000553_0001
Example 1094
N- 4-(N-(2-cyclohexylethyP-N-2-fluoroethylaminomethyP-2-(2-
1980 methylphenyPbenzoyllmethionine
Figure imgf000553_0002
Example 1094 A N-(2-FluoroethyP-2-cvclohexylacetamide 1985 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+).
Figure imgf000553_0003
1990 Example 1094B N-(2-FluoroethyP-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+).
1 1995
Figure imgf000554_0001
Example 1094C N-r4-(N-(2-cvclohexylethyP-N-2-fluoroethylaminomethyP-2-(2-methylphenyl)benzoic acid methyl ester 12000 Following the procedure of example 1178G and substituting potassium phosphate for diisopropylethylamine, and heating at 60°C for 60 hours, example 1094B (188 mg, 1.10 mmol) provided 288 mg (70%) of the title compound. MS (ESI +): 410 (M + NH4+ -P).
Figure imgf000554_0002
Example 1094D N-[4-(N-(2-cyclohexylethyP-N-2-fluoroethylaminomethyP-2-(2-methylphenyPbenzoic 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.
12010 MS (DCI, NH3): 398 (MH+).
Figure imgf000554_0003
Example 1094E
N-r4-('N-(2-cvclohexylethvP-N-2-fluoroethylaminomethvP-2-('2-
12015 methylphenyPbenzoyllmethionine. 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).
Figure imgf000555_0001
12020 Example 1094F
N-r4-(N-f2-cyclohexylethyl)-N-2-fluoroethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine Following the procedure of example 1 104D, example 1094E (250 mg, 0.46 mmol) provided 240 mg of the title compound. 12025 X NMR (δ ,CDC13): 7.75 (2H), 7.0-7.4 (4H), 6.4 (IH), 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 C3oH4ιFN2θ3S»0.90H2O: C 66.12 H 7.92 N 5.14; Found: C 66.13 H 7.77 N 4.86.
Figure imgf000555_0002
Example 1103
N-r4-rN-(2-cyclohexylethvP-N-2.2.2-trifluoroethylaminomethvP-2-r2- methylphenyPbenzoy 11 methionine. lithium salt
FaC^O
Figure imgf000555_0003
Example 1103 A 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 12040 ice/acetone bath. The solution was treated with trifluoroacetic anhydride ( 1.7 mL, 12.0 mmol) in 5 mL of methylene chloride dropwise. After stiπing for 2 hours at 0°C the mixture was diluted with 100 mL of ether and extracted with water, IM aqueous phosphoric acid and satureaed aqueous sodium bicarbonate, dried, filtered and concentrated to give a white solid (2.07g, 92%).
12045 MS (DCI, NH3): 241 (M+NH4)+.
3C.
Figure imgf000556_0001
Example 1103B N-2-trifluoroethyl-2-cyclohexylethyl amine 12050 A solution of lithium aluminum hdydride (9 mL of a IM 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 1178F to provide 0.58 g (92%) of the title compound. MS (DCI, NH3): 228 (M+NH4)+.
12055
Figure imgf000556_0002
Example 1103C N-r4-rN-(2-cyclohexylethvP-N-2.2.2-trifluoroethylaminomethvP-2-('2- me thy lphenyPbenzoy 11 methionine methyl ester 12060 A solution of example 1103B (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 stiπed for 10 minutes. The mixture was treated with sodium triacetoxyborohydride (213 mg, 1.0 mmol) and the mixture stiπed overnight. The work-up was the same as that of example 1134E. The crude product was purified by chromatography 12065 on silica gel (20 g, 20% ethyl acetate/hexanes) to provide 96 mg (33%) of the title compound.
X NMR (300 MHz., CDC13): δ 7.91, dd, IH; 7.42, dd, IH; 7.18 - 7.36, m, 4H; 7.15, bs, IH; 5.88, bd, IH' 4.63, m, IH; 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, 1.5H (o-tolyl); 2.05, m, IH; 2.03, s, 1.5H (MeS); 2.01, s, 1.5H 12070 (MeS); 1.87, m, IH; 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 1178J. X NMR (300 MHz., dmso d6): δ 7.52, d, IH; 7.35, d, IH; 7.23, m, 3H; 7.12, m, 3H; 12075 6.91, d, IH; 3.81, s, 2H; 3.66, m, IH; 3.38, q, 2H; 2.56, t, 2H; 2.06, m, IH; 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 C30H38LiN2O3SA75 H2O; C 59.84; H 6.95; N 4.65; Found: C 59.86; H 6.57; N 4.45.
12080
Figure imgf000557_0001
Example 1104
N-r4-(N-(2-cyclohexylethyP-N-2-methoxyethylaminomethyP-2-(2- methylphenyPbenzoyllmethionine
12085
Figure imgf000557_0002
Example 1104 A N-(2-methoxyethyP-2-cvclohexylacetamide The acid chloride from example 1178E (1.60 g, 10 mmol) in 10 mL of methylene 12090 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 stiπed ovemight. The mixture was diluted with ethyl ether and washed with water, IM 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. 12095 X NMR (300 MHz., CDC13): δ 5.89, bs, IH; 3.46, m, 4H; 3.37, s, 3H; 2.05, d, 2H; " 1.79, m, IH; 1.70, bm, 6H; 1.24, m, 2H; 1.17, m, IH; 0.95, m, 2H. MS (DCI, NH3): 200 (MH+).
Figure imgf000558_0001
12100 Example 1104B
N-(2-methoxyethyP-N-2-cyclohexylethylamine Using the procedure of example 1178F, example 1104A (1.70 g, 8.54 mmol) provided the title compound (1.56 g, 100%). MS (DCI, NH3): 186 (MH+).
12105
Figure imgf000558_0002
Example 1104C N-[4-(N-(2-cyclohexylethyP-N-2-methoxyethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester 12110 Using the procedure of example 1103C, example 1104B (186 mg, 1.0 mmol) and example 403G (192 mg, 0.5 mmol) were combined to provide 78 mg (28%) of the title compound.
X NMR (300 MHz., CDC13): δ 7.91, dd, IH; 7.42, dd, IH; 7.18 - 7.37, m, 4H; 7.17, bs, IH; 5.89, bd, IH; 4.64, m, IH; 3.68, s, 2H; 3.66, s, 3H; 3.45, t, 2H; 3.31, s, 3H; 2.66, t, 12115 2H; 2.50, t, 2H; 2.19, s, 1.5H (o-tolyl); 2.07, s, 1.5H (o-tolyl); 2.05, m, IH; 2.03, s,
1.5H (SMe); 2.01, s, 1.5H (SMe); 1.85, m, IH; 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).
Figure imgf000558_0003
Example 1104D N-[4-(N-f2-cycloheχylethvP-N-2-methoxyethylaminomethyl)-2-(2- methylphenvPbenzoyllmethionine A solution of example 1 104C (73 mg, 0.13 mmol) in 2 mL of 3: 1 THF/methanol was 12125 cooled in an ice bath and treated with lithium hydroxide (0.26 mL of a IM aqueous solution, 0.26 mmol) and the mixture stiπed ovemight and then concentrated. The solid was diluted with water and the pH adjusted to 4.5 with IM 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 12130 compound.
X NMR (300 MHz., CD3OD): δ 7.74, d, IH; 7.58, d, IH; 7.37, m, IH; 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, IH; 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 C31H44N2O4S»0.85 H2O; C 66.96; 12135 H 8.28; N 5.04; Found: C 66.97; H 8.34; N 4.87.
Figure imgf000559_0001
Example 1105 12140 N-r4-(N-(2-cvclohexylethvP-N-2-methylthioethylaminomethvP-2-(2- methylphenyPbenzoyllmethionine
Figure imgf000559_0002
Example 1105 A 12145 N-(2-methylthioethyl)-2-cyclohexylacetamide
Following the procedure of example 1104 A, 2-methylthioethylamine (1.0 g, 1 1 mmol) was converted to the title compound (1.77 g, 89%). MS (DCI, NH3): 216 (MH+); 233 (M+NH4)+.
Figure imgf000560_0001
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%). 12155 MS (DCI, NH3): 202 (MH+).
Figure imgf000560_0002
Example 1105C N-r4-(N-(2-cyclohexylethyl)-N-2-methylthioethylaminomethyl)-2-(2- 12160 methylphenyPbenzoyllmethionine. methyl ester
Using the procedure of example 1103C, example 1105B (201 mg, 1.0 mmol) and example 403G (192 mg, 0.5 mmol) were combined to provide 151 mg (53%) of the title compound.
X NMR (300 MHz., CDC13): δ 7.91, dd, IH; 7.42, dd, IH; 7.18 - 7.37, m, 4H; 7.17, bs, 12165 IH; 5.89, bd, IH; 4.63, m, IH; 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, IH; 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).
Figure imgf000560_0003
Example 1105D N-r4-(N-('2-ryclohexylethvP-N-2-methylthioethylaminomethvP-2-(2- methylphenvPbenzoyllmethionine' A solution of example 1 105C (145 mg, 0.25 mmol) in 2 mL of 3: 1 THF/methanol 12175 was cooled in an ice bath and treated with lithium hydroxide (0.5 mL of a IM aqueous solution, 0.5 mmol) and the mixture stiπed overnight. The solution was concentrated to dryness and diluted with water and the pH adjusted to 4.5 with IM aqueous phosphoric acid. The solid collected was by filtration and dried in the air to provide 130 mg (93%) of the title compound. 12180 'H NMR (300 MHz., CD3OD): δ 7.71, d, IH; 7.57, d, IH; 7.35, d, IH; 7.10 - 7.31, m,
4H; 4.32, m, IH; 4.17, s, 2H; 3.10, m, 2H; 2.94, m, 2H; 2.76, m, 2H; 2.22, bs, IH; 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 C3 ^44^0382*0.50 H2O; C 12185 65.80; H 8.02; N 4.95; Found: C 65.79; H 7.89; N 4.79.
Figure imgf000561_0001
Example 1106 12190 N-r4-(N-(2-cyclohexylethyP-N-l-methyl-2('S)-methylthioethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine
Figure imgf000561_0002
Example 1106 A 12195 2(SVN-t-butoxycarbonylaminopropan- 1 -ol
A stiπed solution of 2(S)-amino-l-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 stiπed for 2 hours. The biphasic mixture was diluted with water and the layers 12200 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. X NMR (300 MHz., CDCI3): δ 4.59, bs, IH; 3.77, m, IH; 3.64, dd, IH; 3.52, dd, IH; 2.42, bs, IH; 1.44, s, 9H; 1.14, d, 3H. 12205 MS (DCI, NH3): 176 (MH)+; 193 (M+NH4)+-
Figure imgf000562_0001
Example 1106B l-Methylthio-2(S)-N-t-butoxycarbonylaminopropane
12210 A stiπed solution of example 1106A (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, IM aqueousphosphoric acid, brine, dried filterd and concentrated to provide a yellow oil that was used directly. The
12215 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 stiπed 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
12220 concentrated to provide 328 mg (80% overall) of the title compound.
X NMR (300 MHz., CDCI3): δ 3.86, bs, IH; 2.65, dd, IH; 2.56, dd, IH; 2.14, s, 3H;
1.45, s, 9H; 1.22, d, 3H.
MS (DCI, NH3): 206 (MH)+; 223 (M+NH4)+.
12225
Figure imgf000562_0002
Example 1106C l-Methylthio-2(S)-aminopropane hydrochloride salt Example 1 106B (320 mg, 1.56 mmol) was dissolved in 2 mL of 4N HCl/dioxane and stiπed for 1 Hour. The mixture was diluted with ether and filtered to provide 103 mg 12230 (53%) of the title compound as a white solid.
X NMR (300 MHz., CDCI3): δ 8.56, bs, 3H; 3.51, m, IH; 2.89, dd, IH; 2.78, dd, IH;
2.17, s, 3H; 1.54, d, 3H.
MS (DCI, NH3): 123 (M+NH4)+.
Figure imgf000563_0001
Example 1106D
N-r4-(N-(2-cvclohexylethvP-N-l-methyl-2(S -methylthioethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester
Part 1. Following the general procedure of example 403H, example 1 106C (98 mg,
12240 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 stiπed 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
12245 mg, 1.26 mmol), acetic acid (0,36 mL, 6.3 mmol) and sitπed for 2 hours. This solution was treated with sodium triacetoxyborohydride (263 mg, 1.26 mmol) and the mixture stiπed 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.
12250 'H NMR (300 MHz., CDC13): δ 7.89, dd, IH; 7.47, d, IH; 7.15 - 7.37, m, 5H; 5.87, bd,
IH; 4.63, m, IH; 3.67, d, IH; 3.65, s, 3H; 3.55, d, IH; 2.96, m, IH; 2.75, dd, IH; 2.44, m, 2H; 2.37, dd, IH; 1.99 - 2.22, m, 10H; 1.84, m, IH; 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).
12255
Figure imgf000563_0002
Example 1106 N-r4-fN-r2-cyclohexylethyl -N-l-methyl-2(SVmethylthloethylaminomethvP-2-(2- methylphenyPbenzoyllmethionine 12260 Following the procedure of example 1 105D, example 1 106D (210 mg, 0.36 mmol) provided 110 mg (53%) of the title compound.
X NMR (300 MHz., CD3OD): δ7.69, d, IH; 7.56, bd, IH; 7.37, bd, IH; 7.09 - 7.32, m,
4H; 4.33, m, IH; 4.16, m, IH; 4.00, m, IH; 3.32, dt, IH; 2.89, m, 3H; 2.64, m, IH;
2.23, bs, IH; 2.06, m, 2H; 2.04, s, 3H; 1.98, s, 3H; 1.89, m, 2H; 1.65, m, 6H; 1.44, m, 12265 2H; 1.32, d, 3H; 1.28, m, 3H; 0.88, m, 2H.
MS (ESI+): 571 (MH+): (ESI-): 569 (M-H). Calc'd for C32H46N2O3S2; C 67.33; H 8.12;
N 4.91 ; Found: C 67.12; H 8.10; N 4.70.
Figure imgf000564_0001
Example 1107
N-r4-(N-(2-cyclohexylethyP-N-2-N.N-dimethylaminomethyP-2-(2- methy lphenvPbenzoy 11 methionine
Figure imgf000564_0002
Example 1107 A
N-r4-(N-(2-cvclohexylethvP-N-2-N.N-dimethylaminomethvP-2-(2- methylphenyPbenzoyll methionine. methyl ester
Part 1. Following the procedure of example 1106D, part 1 , example 403G (550 mg,
12280 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 1106D part 2, the amine produced in example 1107 A, 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 12285 acetate then 90/10/0.1 ethyl acetate/methanol/conc. aq. ammonia) providing 498 mg (60% overall) of the title compound.
X NMR (300 MHz., CDC13): δ 790, dd, IH; 7.41, dd, IH; 7.18 - 7.34, m, 4H; 7.16, bs, IH; 5.88, bs, IH; 4.62, m, IH; 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, IH; 1.63, bm, 6H; 1.35, m, 2H; 1.20 m,
12290 2H; 1.14, m, 2H; 0.85, m, 2H.
MS (ESI+): 568 (MH+): (ESI-): 566 (M-H).
Figure imgf000565_0001
Example 1107B 12295 N-r4-(N-r2-cvclohexylethvP-N-2-N.N-dimethylaminomethvP-2-(2- methylphenyPbenzoyllmethionine Following the procedure of example 1104D, example 1107A (485 mg, 0.85 mmol) provided 382 mg (81%) of the title compound as a white lyophilate. X NMR (300 MHz., CD3OD): δ 7.66, d, IH; 7.46, d, IH; 7.05 - 7.33, m, 5H; 4.35, m, 12300 IH; 3.74, s, 2H; 3.17, t, IH; 2.82, t, 2H; 2.75, s, 6H; 2.60, m, 2H; .24, bs, IH; 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 C32H47N3O3S*1.00 H2O; C 67.22; H 8.64; N 7.35; Found: C 67.23; H 8.43; N 7.26.
12305
Figure imgf000565_0002
Example 1108 N-14-(N-(l-benzyloxymethyl-2(S)-ethylthioethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine
12310
Figure imgf000566_0001
Example 1108A l-benzyloxy-2(S -t-butoxycarbonylamino-3-hydroxypropane N-BOC-O-benzylserine (5.0 g, 16.9 mmol) in 30 mL dimethoxyethane was treated 12315 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 12320 saturated sodium bicarbonate and the reaction stiπed 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)+.
12325
Figure imgf000566_0002
Example 1108B l-benzyloxy-2(S)-t-butoxycarbonylamino-3-ethylthiopropane Following the procedure described in example 1106B (and substituting potassium 12330 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)+.
Figure imgf000566_0003
12335 Example 1108B l-benzyloxy-2(S)-amino-3-ethylthiopropane hydrochloride salt Following the procedure described in example 1106C, example 1108B (342 mg, 1.05 mmol) was converted to 244 mg (89%) of the title compound. MS (DCI, NH3): 226 (MH+). 12340
Figure imgf000567_0001
Example 1108C N-r4-(N-f l-benzyloxymethyl-2(SVethylthioethylaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester 12345 Following the procedure described in example 1106D, part 1 , example 1 108C ( 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). 12350 MS (ESI+): 595 (MH+): (ESI-): 593 (M-H).
Figure imgf000567_0002
Example 1108D N-r4-(N-d-benzyloxymethyl-2(S -ethylthioethylaminomethyP-2-(2- 12355 methylphenyPbenzoyllmethionine
Following the procedure of example 1104D, example 1 108C (187 mg, 0.31 mmol) provided 175 mg of the title compound.
X NMR (300 MHz., CD3OD): δ 7.70, d, IH; 7.50, d, IH; 7.08 - 7.39, m, 10H; 4.59, s, 2H; 4.29, m, IH; 4.20, s, 2H; 3.70, d, 2H; 3.37, m, IH; 2.85, d, 2H; 2.49, m, 2H; 2.21, 12360 bs, 1.5H; 2.08, s, 1.5H; 2.03, m, IH; 1.98, s, 3H; 1.87, m, 2H; 1.68, m, IH; 1.20, t, 3H.
MS (ESI+): 581 (MH+): (ESI-): 579 (M-H). Calc'd for C32H40N3O4S2; C 66.18; H 6.94; N 4.82; Found: C 65.52; H 6.76; N 4.58.
12365
Figure imgf000568_0001
Example 1 1 10 N-r4-(N-(2-CvclohexylethyP-N-methylaminomethyP-2-(2-methylphenyl)benzoyllomithine.
Trifluoroacetate salt
12370
Figure imgf000568_0002
Example 1110 A N-r4-rN-(,2-CyclohexylethyP-N-methylaminomethyP-2-(2-methylphenyl)benzoyll-N'- carbobenzyloxyornithine. Methyl Ester
12375 The title compound was prepared according to the procedure in example 608D, replacing L-methionine methyl ester-HCl with L-N'-carbobenzyloxyornithine methyl ester*HCl, and was isolated as a colorless oil. MS (ESI(+)) m/e 628 (M+H)+. MS (ESI(-)) m/e 626 (M-H)-.
12380
Figure imgf000568_0003
Example 1110B N-r4-(N-(2-CyclohexylethyP-N-methylaminomethyP-2-('2-methylphenyPbenzoyllomithine.
Trifluoroacetate salt 12385 To a solution of N- [4-(N-(2-cyclohexy lethyl)-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 (O.lmL), then 10% palladium on carbon (50mg). The reaction vessel was
12390 tightly sealed and warmed to 80°C 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
12395 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).
X NMR (300 MHz, DMSO) δ 0.83-0.97 (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, IH), 4.22-4.49 (m, 2H),
12400 7.09-7.27 (m, 4H), 7.40 (s, IH), 7.54-7.73 (m, 5H), 8.40 (brd, J=5 Hz, IH), 9.68 (brs, IH). MS (APCI(-)) m/e 478 (M-H).
Figure imgf000569_0001
Example 1112 N- 4-(N-(2-cyclohexylethyP-N-2-N-methylaminomethyl)-2-(2-methylphenyl)benzoyllthien-
2-ylalanine
Figure imgf000569_0002
Example 1112A 3-(2-thienvP-L-alanine. methylester hydrochloride 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 12415 60 hours. The solution was then concentrated to provide 257 mg (99%) of the titie compound. MS (DCI, NH3): 186 (MH+); 203 (M+NH4)+-
Figure imgf000570_0001
12420 Example 1112B
N-r4-(N-(2-cyclohexylethyP-N-2-N-methylaminomethyl)-2-r2-methylphenyl)benzoynthien-
2-ylalanine Following the procedure of example 608D, example 1112A (122 mg, 0.55 mmol) and example 608C (183 mg, 0.5 mmol) were converted to 154 mg (58%) of the title 12425 compound.
MS (ESI+): 533 (MH+): (ESI-): 531 (M-H).
Figure imgf000570_0002
Example 1112C 12430 N-r4-(N-(2-cyclohexylethyP-N-2-N-methylaminomethyP-2-(2-methylphenyPbenzoyllthien-
2-ylalanine Following the procedure of example 1105D, example 1112C (150 mg, 0.28 mmol) provided 124 mg (85%) of the title compound.
X NMR (300 MHz., CD3OD): δ 7.69, m, IH; 7.52, dd, IH; 7.31, bs, IH; 7.21, m, 2H; 12435 7.14, m, 3H; 6.85, bt, IH; 6.72, m, IH; 4.40, m, IH; 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 H20; C 69.96; H 7.48; N 5.26; Found: C 70.01 ; H 7.38; N 5.19.
12440
Figure imgf000571_0001
Example 1134 N- 4-("l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-fluoro-2-(2- 12445 methylphenyPbenzoy 11 methionine
Figure imgf000571_0002
Example 1134A
Dimethyl 2-(2-MethylphenyP-5-fluoroterephthalate
12450 A stiπed 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 stiπing was continued for 30 minutes further. The mixture was carefully diluted with ether (-200 mL) and the solid collected by
12455 filtration. The dried solid was suspended in 20 mL of isooctane and heated to reflux ovemight 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 titie compound.
12460 X NMR (300 MHz., CDC13): δ 7.73, d, IH; 7.72, d, IH; 7.15 - 7.32, m, 3H; 7.06, d, IH; 3.94, s, 3H; 3.65, s, 3H; 2.07, s, 3H. MS (DCI-NH3): 320 (M+NH4H+).
Figure imgf000572_0001
12465 Example 1134B
2-(2-Methylphenyl)-4-carboxy-5-fluorobenzoic acid, methyl 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 IM aqueous lithium hydroxide and the mixture stiπed at ambient temperature for 60 hours. The solution was made acidic by the addition of excess 3N 12470 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.
X NMR (300 MHz., CD3OD): δ 7.7.74, d, IH; 7.69, d, IH; 7.15 - 7.28, m, 3H; 7.03, q, IH; 3.61, s, 3H; 2.07, s, 3H. 12475 MS (DCI, NH3): 306 (M+ NH4+).
Figure imgf000572_0002
Example 1134C 2-(2-MethylphenyP-4-hydroxymethyl-5-fluorobenzoic acid, methyl ester 12480 A solution of example 1134B (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 stiπed 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 12485 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 stiπed 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 12490 (73%) of the title compound. X NMR (300 MHz., CDC13): δ 7.67, d, IH; 7.44, d, IH; 7.15 - 7.28, m, 3H; 7.05, d, IH; 4.83, d, IH; 3.62, s, 3H; 2.07, s, 3H; 1.94, bt, IH. MS (DCI, NH3): 292 (M+ NH4+).
e
12495
Figure imgf000573_0001
Example 1134D
2-(2-MethylphenyP-4-formyl-5-fluorobenzoic acid, methyl ester
A stiπed solution of example 1134C (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
12500 (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 stiπed for 10 minutes at which time an additional 1.5 mL of Chlorox was added. After stiπing a further 10 minutes, the mixture was diluted with water and layers were separated. The aqueous phase was extracted with 1 portion of
12505 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.
*H NMR (300 MHz., CDC13): δ 10.43, s, IH; 7.77, d, IH; 7.73, d, IH; 7.17 - 7.31, m, 3H; 7.05, m, IH; 3.63, s, 3H; 2.06, s, 3H.
12510 MS (DCI, NH3): 290 (M+ NH4+).
Figure imgf000573_0002
Example 1134E N-r4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-fluoro-2-(2-methylphenyPbenzoic 12515 acid methyl ester Example 1134D (143 mg, 0.5 mmol) was dissolved in 2 mL of 1 ,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 stiπed at ambient temperature for 4 hours and then
12520 treated with sodium triacetoxyborohydride (213 mg, 1.0 mmol) and the mixture stiπed overnight. The reaction was quenched by the addition of 2 mL of 2M aqueous sodium carbonate and the mixture stiπed 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
12525 column chromatography on silica gel (20g, 15% ethyl acetate/hexanes) to provide 165 mg (72%) of the title compound.
X NMR (300 MHz., CDC13): δ 7.67, d, IH; 7.16 - 7.31, m, 5H; 7.04, bd, IH; 3.93, s, 2H; 3.63, s, 3H; 2.76, m, 2H; 2.57, m, IH; 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.
12530 MS (ESI +): 458 (MH+); (ESI-) 456 (M-H).
Figure imgf000574_0001
Example 1134F N-14-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-fluoro-2-(2-methylphenyPbenzoic
12535 acid Example 1134E (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 IM aqueous phosphoric acid. The mixture was extracted
12540 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. •H NMR (300 MHz., CD3OD): δ 7.78, d, IH; 7.43, d, IH; 7.15 - 7.27, m, 3H; 7.06, bd, IH; 4.42, m, 2H; 3.48, m, IH; 3.00, dd, IH; 2.93, dd, IH; 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.
12545
Figure imgf000575_0001
Example 1134G N-r4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-fluoro-2-(2- methylphenyPbenzoyllmethionine, methyl ester
12550 According to the procedure described in example 11781, example 1 134F (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).
X NMR (300 MHz., CDC13): δ 7.70, dd, IH; 7.14 - 7.38, m, 5H; 5.91, bd, IH; 4.60, m, IH; 3.94, s, 2H; 3.66, s, 3H; 2.77, m, 2H; 2.58, m, IH; 2.46, q, 2H; 2.28, s, 1.5 H(o-
12555 tolyl rotamer); 2.07, s, 1.5H (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).
Figure imgf000575_0002
12560 Example 1134H
N-14-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-fluoro-2-(2- methylphenyPbenzoyllmethionine Following the procedure of example 1105D, example 1134G (130 mg, 0.22 mmol) provided 94 mg (75%) of the title compound. 12565 X NMR (300 MHz., CD3OD): δ 7.52, d, IH; 7.39, m, IH; 7.10 - 7.30, m, 4H; 4.29, m, IH; 4.25, q, 2H; 3.24, m, IH; 2.89, dd, IH; 2.78, dd, IH; 2.52, q, 2H; 2.22, bs, 1.5H; 2.08, bs, 1.5H; 2.05, m, IH; 1.98, s, 3H; 1.89, m, 2H; 1.69, m, 6H; 1.58, t, 2H; 1.43, m, IH; 1.25, m, IH; 1.22, t, 3H; 0.90, m, 2H.
MS (ESI+): 575 (MH+): (ESI-): 573 (M-H). Calc'd for C31H43FN2O3S2*0.35 H2O; C 12570 64.07; H 7.58; N 4.82; Found: C 64.08; H 7.54; N 4.65.
Figure imgf000576_0001
12575 Example 1136
N-[4-(N-butyl-N-4-cvclohexylbenzylaminomethyl)-2-(2-methylphenyl)benzoynmethionine lithium salt
Figure imgf000576_0002
12580 Example 1136 A
Methyl 4-(N-BuytylaminomethyP-2-(2-methylphenyl)benzoate To a O °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 stiπed at room temperature for 2 hours, and was then evaporated to dryness. The residue
12585 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 stiπed 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,
12590 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
12595 to give the intermediate amine. The amine was used without further purification.
Figure imgf000577_0001
Example 1136B Methyl 4- rN-butyl-N-(4-cyclohexylbenzylcarbonyl)aminomethyll-2-(2- 12600 methylphenyPbenzoate
To a 0 °C solution of 4-cyclohexylbenzoic acid (204 mg, 1.0 mmol) in DCM (3 mL) was added oxallyl chloride (2.0 M in DCM, 1.0 mL), and a drop of DMF. The reaction was stiπed 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 12605 the intermediate 1136A (156 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) in DCM (3 mL). The reaction mixture was stiπed 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%). 1HNMR (300 MHz, CDC13) δ 7.95 (d, 1 H), 7.32-7.16 (m, 9 H), 7.05 (br d, 1 H), 5.85- 12610 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)+.
Figure imgf000577_0002
Example 1136C
12615 Methyl 4-(N-Butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylphenyPbenzoate
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
12620 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%). 1HNMR (300 MHz, CDC13) δ 7.90 (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 12625 (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)+.
Figure imgf000578_0001
Example 1136D 12630 N-r4-("N-Butyl-N-4-cyclohexylbenzylaminomethyP-2-(2-methylphenyl)benzoyl1methionine
Methyl 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) δ 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 12635 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(CI/NH3) m/z: 615 (M+H)+.
Figure imgf000578_0002
12640 Example 1136E
N-r4-(N-butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylphenyPbenzoyllmethionine 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%). lH NMR (300 MHz, 12645 dmso-d6) δ 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)~.
Figure imgf000579_0001
Example 1137 N-[4-(N-Butyl-N-4-cyclohexylbenzoylaminomethyl)-2-(2-methylphenyPbenzoynmethionine lithium salt
Figure imgf000579_0002
Example 1137 A N- 4-(N-butyl-N-4-cyclohexylbenzoylaminomethyl)-2-(2-methylphenyPbenzoyllmethionine
Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert
12660 intermediate 1136B (63 mg) to the title methyl ester 1137 A (72 mg, 90%). 'HNMR (300 MHz, CDC13) δ 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(CI/NH3) m/z: 629 (M+H)+.
Figure imgf000579_0003
Example U37B
N-r4-(N-Butyl-N-4-cyclohexylbenzoylaminomethyP-2-("2-methylphenyPbenzoyllmethionine lithium salt
The procedure descriped in the Example 4031 was used here to convert the
12670 intermediate 1137B (68 mg) to the title lithium salt (67 mg, 100%). Η NMR (300 MHz, dmso-d6) δ 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, 1 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)"
12675
Figure imgf000580_0001
Example 1139 N-[4-(N-CyclohexylaminocarbonylethyP-2-(2-methylphenyl)benzoyllmethionine lithium salt
12680
Figure imgf000580_0002
Example 1139 A N-[4-(N-CyclohexylaminocarbonylethyP-2-(2-methylphenyPbenzoynmethionine lithium salt
The procedures descriped in the Example 403E and 403F were used here to convert
12685 intermediate 1144C (127 mg) to the title methyl ester (141 mg, 83%). 'HNMR (300 MHz, CDC13) δ 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).
Figure imgf000580_0003
■ Example 1139B N-[4-(N-CvclohexylaminocarhonylethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt
The procedure descriped in the Example 4031 was used here to convert the intermediate 1139A (134 mg) to the title lithium salt (121 mg, 93%). Η NMR (300 MHz, 12695 dmso-d6) δ 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)".
Figure imgf000581_0001
Example 1140 N-r4-(N-cyclohexylmethyl-N-butylaminoethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt
Figure imgf000581_0002
Example 1140A Methyl 4-(EthoxycarbonylmethyP-2-(2-methylphenyPbenzoate A solution of intermediate 1178D (397 g, 1.24 mmol), palladium(II) acetate (22 mg), l,3-bis(diphenylphosphino)propane (42 mg), N,N-diisopropylethylamine (0.5 mL) 12710 in ethanol (1 mL) and DMF (5 mL) was stiπed 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 12715 mg, 58%). 'HNMR (300 MHz, CDC13) δ 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(CI/NH3) m/z: 330 (M+NH4)+.
H
Figure imgf000582_0001
12720 Example 1140B
Methyl 4-(CarboxymethyP-2-(2-methylphenvPbenzoate To the solution of intermediate 1140A (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 M, 1 mL), and was then partitioned between ethyl acetate (80 mL) 12725 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.
Figure imgf000582_0002
12730 Example 1140C
N-Butylcyclohexymethylamine 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.
12735
Figure imgf000582_0003
Example 1140D Methyl 4-(N-Cyclohexylmethyl-N-butylaminocarbonylmethyP-2-(2-methylphenyPbenzoate The procedure described in example 1144C was used here to combine intermediate 12740 1 HOB (311 mg, 1.10 mmol) and intermediate 1140C (205 mg) to give the title compound (247 mg, 52%). 1HNMR (300 MHz, CDC13) δ 7.94 (d, 1 H), 7.33 (M, 1 H), 7.25-7.15 (m, 3'H), 7.13,7.1 1 (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)+.
12745
Figure imgf000583_0001
Example 1140E Methyl 4(N-Cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylphenyPbenzoate A solution of intermediate 1140D (118 mg, 0.271 mmol) and borane ( 1.0 M in 12750 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 12755 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. 1HNMR (300 MHz, CDC13) δ 7.90 (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)+.
12760
Figure imgf000583_0002
Example 1 140F N-[4-(N-Cvclohexylmethyl-N-hutylaminoethyP-2-(2-methylphenvPbenzoyllmethionine
Methyl Ester 12765 The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate amine 1140E to the title methyl ester (1 13 mg, 76%, 3 steps from 1 140D). 'HNMR (300 MHz, CDC13) δ 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 12770 H). MS(CI/NH3) m/z: 553 (M+H)+.
Figure imgf000584_0001
Example 1140G N-r4-(N-cyclohexylmethyl-N-butylaminoethyP-2-(2-methylphenvPbenzoyllmethionine 12775 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%). Η NMR (300 MHz, dmso-d6) δ 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- 12780 1.10 (m, 17 H), 0.88 (t, 3 H). MS(ESI-) m/z: 537 (M-H)".
Figure imgf000584_0002
Example 1141 12785 N-f4-fN-Cyclohexylmethyl-N-butylaminocarhonylmethvP-2-(2- methylphenvPbenzoyllmethionine lithium salt
Figure imgf000585_0001
Example 1 141 A 12790 N-|"4-(N-Cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2- methylphenyPbenzoyllmethionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert the intermediate 1 HOD ( 101 mg) to the title methyl ester (127 mg, 97%). 1HNMR (300 MHz, CDC13) δ 7.92 (m, 1 H), 7.37-7.22 (m, 4 H), 7.19 (m, 1 H), 7.1 1 (br d, 1 H), 5.88 12795 (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)+.
Figure imgf000585_0002
12800 Example 1 14 IB
N-r4-(N-Cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2- methylphenyPbenzoyll methionine lithium salt The procedure descriped in the Example 4031 was used here to convert the intermediate 1 141A (1 19 mg) to the title lithium salt ( 102 mg, 86%). Η NMR (300 MHz, 12805 dmso-d6) δ 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-Hf.
12810
Figure imgf000586_0001
Example 1142 N-[4-(N-Cyclohexanoyl-N-butylaminoethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt
12815
Figure imgf000586_0002
Example 1142 A Methyl 4-(N-ButylaminocarbonylmethyP-2-(2-methylphenyPbenzoate The procedure described in example 1144C was used here to combine intermediate
12820 1 HOB (200 mg, 0.70 mmol) and butylamine to give the title compound (171 mg, 69%). 'HNMR (300 MHz, CDC13) δ 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).
Figure imgf000586_0003
Example 1142B Methyl N-14-(N-Cycloheχanoyl-N-butylaminoethyP-2-(2-methylphenvPbenzoate The procedures described in 1 H3B was used here to convert 1142A (102 mg, 0.36 mmol) to the title compound (137 mg, 87%). 1HNMR (300 MHz, CDC13) δ 7.92 (2 d's, 1
12830 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(CI/NH3) m/z: 436 (M+H)+.
Figure imgf000587_0001
12835 Example 1142C
N-r4-rN-Cyclohexanoyl-N-butylaminoethyP-2-(2-methylphenyPbenzoyllmethionine 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%). 1HNMR 12840 (300 MHz, CDC13) δ 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(CI/NH3) m/z: 567 (M+H)+.
Figure imgf000587_0002
Example 1142D N- 4-(N-Cyclohexanoyl-N-butylaminoethyl)-2-('2-methylphenyPbenzoyllmethionine lithium salt The procedure descriped in the Example 4031 was used here to convert the 12850 intermediate 1142C (103 mg) to the title lithium salt (99 mg, 97%). Η NMR (300 MHz, dmso-d6) δ δ 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)".
12855
Figure imgf000588_0001
Example 1143 N-H-(N-Cyclohexylmethyl-N-butanoylaminoethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt
12860
Figure imgf000588_0002
Example 1143 A Methyl 4-(N-CyclohexylmethylaminocarbonylmethyP-2-(2-methylphenyPbenzoate The procedure described in example 1144C was used here to combine intermediate 12865 1 HOB (301 mg, 1.05 mmol) and cyclohexylmethylamine to give the title compound (266 mg, 67%). 'HNMR (300 MHz, CDC13) δ 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)+. e
Figure imgf000589_0001
Example 1143B
Methyl 4-(N-Cvclohexylmethyl-N-butanoylaminoethyP-2-(2-methylphenyPbenzoate
To a solution of intermediate 1143A (108 mg, 0.285 mmol) in THF (2 ML) was added borane ( 1.0 M in THF, 0.5 mL), and the reaction mixture was stiπed at room
12875 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 carbonate (2.0 M i 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
12880 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
12885 MHz, CDC13) δ 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)+.
Figure imgf000589_0002
12890 Example 1143C
N-r4-(N-Cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylphenyPbenzoyllmethionine
Methyl 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 titie methyl ester (1 12 mg, 12895 66%). 'HNMR (300 MHz, CDC13) δ 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(CI/NH3) m/z: 567 (M+H)+.
Figure imgf000590_0001
Example 1143D N-[4-rN-Cyclohexylmethyl-N-butanoylaminoethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt The procedure descriped in the Example 4031 was used here to convert the 12905 intermediate 1143C (104 mg) to the title lithium salt (95 mg, 100%). Η NMR (300 MHz, dmso-d6) δ 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)". 12910
Figure imgf000590_0002
Example 1144 N-H-(N-CyclohexylpropyP-2-(2-methylphenyl)benzoyllmethionine lithium salt
12915
Example 1144 A Methyl 4-(tert-ButoxycarbonylethvD-2-(2-methylphenyDbenzoate To a solution of (t-butoxycarbonylmethyl)triphenylphosphonium bromide ( 10.98 g, 12920 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 1171 A (20 mmol) in THF ( 10 mL) was added slowly over 5 min., and the reaction was further stiπed 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. 12925 Η NMR (300 MHz, CDC13) δ 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 stiπed under a hydrogen balloon overnight. The mixture was then filtered 12930 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). Η NMR (300 MHz, CDC13) δ 7.91 (d, IH), 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+NH4f. 12935
Figure imgf000591_0002
Example 1144B Methyl 4-(2-Carboxyethyl)-2-(2-methylphenyPbenzoate A solution of intermediate 1144 A (5.00 g) in trifluoroacetic acid (20 mL) and methyl 12940 sulfide (3 mL) was stiπed at room temperature for 7 hours. Sovlent was then evaporated to give an off-white solid, which was used without further purification.
Figure imgf000592_0001
Example 1144C
12945 Methyl 4-(2-CyclohexylcarbomoylethyP-2-(2-methylphenyl)benzoate
To a solution of intermediate 1 144B (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
12950 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%). Η NMR (300 MHz, CDC13) δ 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),
12955 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)+.
Figure imgf000592_0002
Example 1144D 12960 N- 4-("N-CyclohexylpropyP-2-C2-methylphenyPbenzoyllmethionine
A solution of intermediate 1 144C (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 12965 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)+. 12970 The procedures descriped in the Example 403E and 403F were used here to convert the above intermediate amine to the title methyl ester (58%, 3 steps).
Figure imgf000593_0001
Example 1 144E 12975 N-r4-(N-Cyclohexylpropyl)-2-(2-methylphenyPbenzoyllmethionine lithium salt
The procedure descriped in the Example 4031 was used here to convert the intermediate 1 144D (121 mg) to the title lithium salt ( 107 mg, 100%). Η NMR (300 MHz, dmso-d6) δ 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, 12980 7 H), 1.30-0.88 (m, 6 H). MS(ESI-) m/z: 481 (M-H)".
Figure imgf000593_0002
Example 1 145 12985 N-r4-(N-Cyclohexyl-N-propanoylaminopropyP-2-(2-methylphenyl)benzoyllmethionine
To s stiπed 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 12990 (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%). Η NMR (300 MHz, dmso-d6) δ 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)".
12995
Figure imgf000594_0001
Example 1 146 N- 4-("N-Cvclohexyl-N-butylaminopropyP-2-(2-methylphenyPbenzoyllmethionine lithium
13000 salt
Figure imgf000594_0002
Example 1 146 A N-Butylcvclohexaylamine 13005 The procedures descriped in the Example 1 178E and 1 178F were used here to convert butyric chloride and cyclohexylamine to the title amine in 86% yield. H NMR (300 MHz, CDC13) δ 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)+.
e
Figure imgf000594_0003
Example 1 146B Methyl N-r4-(N-Cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyPbenzoate The procedure descriped in the Example 1 144C was used here to convert the intermediate 1144B (298 mg) and N-butylcyclohexylamine (intermediate 1 146A, 310 mg,
13015 2.0 mmol) to the title methyl ester (233 mg, 54%). Η NMR (300 MHz, CDC13) δ 7.90 (2 d's, 1 H), 7.30-7.15 (m, 4 H), 7.07 ( , 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)+.
Figure imgf000595_0001
Example 1146C
N-r4-(N-Cyclohexyl-N-butylaminopropyP-2-('2-methylphenyPbenzoyllmethionine Methyl
Ester
The procedure descriped in the Example 1144C was used here to convert the
13025 intermediate 1 146B (230 mg) to the title methyl ester (184 mg, 63%). Η NMR (300 MHz,
CDC13) δ 7.90 (2 d's, 1 H), ), 7.35-7.19 (m, 4 H), 7.03 (m, 1 H), 5.89 (m, 1 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(CI/NH3) m/z:
553 (M+H)+.
13030
Figure imgf000595_0002
Example 1146D N-r4-(N-Cyclohexyl-N-butylaminopropyP-2-(2-methylphenyPbenzoyllmethionine lithium salt 13035 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%). 1H NMR (300 MHz, dmso-d6) δ 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)". 13040
Figure imgf000596_0001
Example 1 147 N-[4-(N-Cyclohexyl-N-methylaminocarbonylethyl)-2-(2-methylphenyPbenzoyllmethionine 13045 lithium salt
Figure imgf000596_0002
r4-(2-TrimethylsilylethoxycarbonylethyP-2-(2-methylphenyPbenzoyllmethionine tert-Butyl
13050 Ester
A solution of intermediate 1 144A (875 mg, 2.38 mmol) and LiOH (5.3 M 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
13055 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-
13060 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
13065 mg, 68%). X NMR (300 MHz, CDC13) δ 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(CI/NH3) m/z: 572 (M+H)+.
Figure imgf000597_0001
Example 1147B F4-(2-CarboxyethyP-2-(2-methylphenyl)benzoyllmethionine tert-Butyl Ester A solution of intermediate 1147 A (841mg, 1.57 mmol), tetrabutylammomium fluoride (820 mg, 3.14 mmol) in DMF (5 mL) was stiπed ovemight. The reaction mixture 13075 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, CDC1 ) δ 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, 13080 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(CI/NH3) m/z: 472 (M+H)+.
Figure imgf000597_0002
Example 1147C 13085 N-f4-(N-Cvclohexyl-N-methylaminocarbonylethyP-2-(2-methylphenyPbenzoyllmethionine tert-Butyl Ester A solution of intermediate 1147B (50 mg, 0.115 mmol), triethylamine (100 mg), 1- hydroxybenzotriazole (31 mg, 0.23 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol), and N-methylcyclohexylamine (26 mg, 0.23 mmol) in DMF (2 mL) 13090 was stiπed 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%). Η NMR (300 MHz, CDC13) δ 7.84 (m, 1 13095 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)+.
Figure imgf000598_0001
13100 Example 1147D
N-r4-(N-Cyclohexyl-N-methylaminocarbonylethyl)-2-(2-methylphenyPbenzoyllmethionine lithium salt The intermediate 1 147C (40 mg) was stiπed 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
13105 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) δ 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)".
131 10
Figure imgf000598_0002
Example 1148 N-r4-(N-Cyclohexyl-N-butylaminocarbonylethyP-2-(2-methylphenyPbenzoyllmethionine 13115 lithium salt
Figure imgf000599_0001
Example 1148A N-r4-(N-Cyclohexyl-N-butylaminocarbonylethvP-2-(2-methylphenyl)benzoyllmethionine 13120 Methyl ester
The procedures descriped in the Example 403E and 403F were used here to convert the intermediate 1146B (102mg) to the title methyl ester (117 mg, 90%). 1HNMR (300 MHz, CDC13) δ 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), 13125 2.20-2.00 (m, 8 H), 1.90-0.95 (m, 16 H), 0.91 (t, 3 H). MS(CI/NH3) m/z: 566 (M+H)+.
Figure imgf000599_0002
Example 1148B N-[4-(N-Cyclohexyl-N-butylaminocarbonylethvP-2-('2-methylphenyPbenzoyllmethionine 13130 lithium salt
The procedure descriped in the Example 4031 was used here to convert the intermediate 1148A (108 mg) to the title lithium salt (91 mg, 83%). lHNMR (300 MHz, dmso-d6) δ 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 ft, 2 H), 13135 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)".
Figure imgf000600_0001
Example 1149 13140 N-f4-(N.N-dicyclohexylaminocarbonylethyP-2-(2-methylphenvPbenzoyllmethionine lithium salt The procedures descriped in the Example 1 H7C and 1147D were used here to convert 1 147B (50 mg) to the title lithium salt (30 mg, 45%, 2 steps). 'HNMR (300 MHz, dmso-d6) δ 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 13145 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)".
Figure imgf000600_0002
13150 Example 1150
N-H-fN-adamant- 1 -ylaminocarbonylethyP-2-(2-methylphenyPbenzoyllmethionine 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). 'HNMR (300 MHz, 13155 dmso-d6) δ 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)". 13160
Figure imgf000601_0001
Example 1 151
N-r4-(N-adamant-2-ylaminocarbonylethyP-2-('2-methylphenyPbenzoyllmethionine lithium salt
The procedures descriped in the Example 1 147C and 1 147D were used here
13165 to convert 1147B (50 mg) to the title lithium salt (41 mg, 64%, 2 steps). lHNMR (300
MHz, dmso-d6) δ 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)".
13170
Figure imgf000601_0002
Example 1154 N- 4-(N-adamant-l-ylmethylaminocarbonylethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt 13175 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 (47 mg, 72%, 2 steps). 1HNMR (300 MHz, dmso-d6) δ 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, 1 1 H), 1.35 (d, 6 H). MS(ESI-) m/z: 561 (M-H)". 13180
Figure imgf000602_0001
Example 1155 N-r4-(N-MytanylmethylaminocarbonylethyP-2-(2-methylphenyPbenzoyllmethionine lithium 13185 sak
The procedures descriped in the Example 1147C and 1147D were used here to convert 1 147B (50 mg) to the title lithium salt (45 mg, 70%, 2 steps). Η NMR (300 MHz, dmso-d6) δ 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 13190 (s, 3 H), 0.97 (s, 3 H). MS(ESI-) m/z: 549 (M-H)".
Figure imgf000602_0002
Example 1157 13195 N- [4-(N-Cyclooctanylaminocarbony lethyl)-2-(2-methylphenyPbenzoy 11 methionine lithium salt The procedures descriped in the Example 1147C and 1147D were used here to convert 1 147B (50 mg) to the title lithium salt (31 mg, 51%, 2 steps). 'HNMR (300 MHz, dmso-d6) δ 7.67 (d, 1 H), 7.44 (d, 1 H), 7.25-7.08 (m, 5 H), 6.96 (br s, 1 H), 6.88 (m, 1 13200 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)".
Figure imgf000603_0001
13205 Example 1158
Figure imgf000603_0002
Example 1158 A Methyl 2-(tert-butoxycarbonylmethyP-4-methylthiobutyrate
13210 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
13215 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%). 1HNMR (300 MHz, CDC13) δ 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)+.
13220
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.
13225 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..
13230 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
13235 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(CI/NH3) m/z: 610 (M+H)+.
Figure imgf000604_0001
Example 1158C Methyl 3-[4-(N-cyclohexyl-N-methylaminomethyP-2-(2-methylphenyPbenzoylmethyll-4- methylthiobutyrate A solution of 1158B (420 mg, 0.69 mmol) in HCl (4.0 M in 1,4-dioxane, 5 mL) 13245 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, 13250 34%). 'HNMR (300 MHz, CDC13) δ 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)+.
Figure imgf000604_0002
13255 Example 1158D 3-r4-(N-Cvclohexy1-N-methyla inomethyl)-2-(2-methylphenyPbenzoylmethyll-4- methylthiobutyric acid The intermediate 1158C (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 13260 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%). Η NMR (300 MHz, dmso-d6) δ 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, 1 1 13265 H), 1.72-0.80 (m, 15 H). MS(ESI-) m/z: 494 (M-H)".
Figure imgf000605_0001
Example 1159
13270
Figure imgf000605_0002
Example 1159 A N-r4-(N-butylaminocarbonylmethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt The procedures descriped in the Example 403E and 403F were used here to convert 13275 intermediate 1142A (61 mg, 0.18 mmol) to the title methyl ester (70 mg, 83%). 'HNMR
(300 MHz, CDC13) δ 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)+. 13280
Figure imgf000606_0001
Example 1 159B N-[4-(N-butylaminocarbonylmethyl)-2-(2-methylphenvPbenzoyllmethionine lithium salt The procedure descriped in the Example 4031 was used here to convert the
13285 intermediate 1159 A (63 mg) to the title lithium salt (62 mg, 100%). Η NMR (300 MHz, dmso-d6) δ 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)".
13290
Figure imgf000606_0002
Example 1160 N-r4-(,N-("2.2.4.4-tetramethylbutylamino carbonylethvP-2-(2-
13295 methylphenyPbenzovπ 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 (50 mg, 81%, 2 steps). 1HNMR (300 MHz, dmso-d6) δ 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),
13300 1.67 (s, 2 H), 1.23 (s, 6 H), 0.89 (s, 9 H). MS(ESI-) m/z: 525 (M-H)~.
Figure imgf000606_0003
Example 1161
13305
Figure imgf000607_0001
Example 1161 A Methyl 4-(N.N-Dibutylaminocarbonylethyl)-2-(2-methylphenvPbenzoyl The procedure descriped in the Example 1144C was used here to convert the 13310 intermediate 1144B (150 mg, 0.5 mmol) and dibutylamine (129 mg, 1 mmol) to the title methyl ester (203 mg, 99%). Η NMR (300 MHz, CDC13) δ 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)+.
13315
Figure imgf000607_0002
Example 116 IB N-|"4-(N.N-DibutylaminopropyP-2-(2-methylphenyPbenzoyllmethionine Methyl Ester The procedures descriped in the Example 403E and 403F were used here to convert 13320 the above intermediate 1 161A (195 mg, 0.48 mmol) to the title methyl ester (165 mg, 66%). Η NMR (300 MHz, CDC13) δ 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)+.
13325
Figure imgf000607_0003
Example 1161C N-r4-(N.N-Dibut.ylaminopropyP-2-('2-methylphenyl)benzoyllmethionine lithium salt The procedure descriped in the Example 4031 was used here to convert the 13330 intermediate 1161B (156 mg) to the title lithium salt (151 mg, 98%). Η NMR (300 MHz, dmso-d6) δ 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: 51 1 (M-H)".
13335
Figure imgf000608_0001
Example 1164
Figure imgf000608_0002
13340 Example 1164 A
N-r4-N-(2-EthylphenyPaminomethyl-2-(2-methylphenyl)benzoyllmethionine 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")
Figure imgf000608_0003
Example 1164B N-r4-N-(2-Ethylphenyl)aminomethyl-2-(2-methylphenyPbenzoyllmethionine The desired compound was prepared according to the method of Example 4031 starting with compound prepared inExample 1 164A. !H (300MHZ, CDCI3, δ) 7.96 ( IH, t,
13350 J=9Hz), 7.48 (IH, bd, J=8Hz), 7.20-7.00 (8H, m), 6.77 (IH, t, J=9Hz), 6.57 ( IH, bd, J=8Hz), 5.89 (IH, bd, J=8Hz), 4.58 (IH, m), 4.46 (2H, s), 2.55 (2H, q, J=8Hz), 2.20- 2.00 (8H, m), 1.90 (IH, m), 1.57 (IH, m), 1.25 (3H, t, J=8Hz). m/e (ESI) 475 (MH") Anal.calc. for C28H32N2O3SO.25 H2O C 69.90, H 6.81, N 5.82 Found C 69.64, H 6.66, N 5.65
13355
Figure imgf000609_0001
Example 1165
Figure imgf000609_0002
Example 1165 A N- 4-N-(2-PropylphenyPaminomethyl-2-(2-methylphenyPbenzoynmethionine 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")
13365
Figure imgf000609_0003
Example 1165B N-[4-N-(2-PropylphenyPaminomethyl-2-(2-methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 13370 starting with compound prepared inExample 1165A. iH (300MHz, CDCI3, δ) 7.98 ( IH, t, J=9Hz), 7.47 (IH, dd, J=8&2Hz), 7.40-7.10 (6H, m), 7.03 (2H, m), 6.72 (IH, t, J=9Hz), 6.57 (IH, m), 5.86 (IH, bd, J=8Hz), 4.58 (IH, m), 4.44 (2H, s), 2.48 (2H, t, J=8Hz), 2.20-2.00 (8H, m), 1.91 (IH, m), 1.65 (2H, q, J=8Hz), 1.57 ( IH, m), 1.01 (3H, t, J=8Hz). m/e (ESI) 489 (MH") Anal.calc. for C29H34N2O3SO.25 H2O C 70.34, 13375 H 7.02, N 5.66 Found C 70.33, H 6.88, N 5.44
Figure imgf000610_0001
Example 1166
13380
Figure imgf000610_0002
Example 1166A N-r4-N-(2-Butylphenyl)aminomethyl-2-("2-methylphenyPbenzoyllmethionine methyl ester The desired ester was prepared using the method described inExample 403H starting
13385 with the compound described in Example 403G and 2-butylaniline. m/e (ESI) 517 (MH")
Figure imgf000610_0003
Example 1166B N-r4-N-(2-ButylphenyPaminomethyl-2-(2-methylphenyl)benzoyllmethionine 13390 The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1 lόόA. iH (300MHz, CDCI3, δ) 7.97 ( IH, t, J=9Hz), 7.45 (lH,bd, J=8), 7.40-7.10 (6H, m), 6.98 (2H, d, J=8Hz), 6.73 (IH, t, J=9Hz), 6.57 (IH, m), 5.87 (IH, bd, J=8Hz), 4.58 (IH, m), 4.45 (2H, s), 2.50 (2H, t, J=8Hz), 2.20-2.00 (8H, m), 1.91 (IH, m), 1.70-1.50 (3H, m), 1.40 (2H, q, J=8Hz),
13395 0.93 (3H, t, J=8Hz). m/e (ESI) 503 (MH") Anal.calc. for C30H36N2O3SO.5O H2O C 70.14, H 7.26, N 5.45 Found C 70.39, H 7.08, N 5.24
Figure imgf000611_0001
Example 1167
13400
Figure imgf000611_0002
Example 1167 A
N-|"4-N-(4-ButylphenyPaminomethyl-2-(2-methylphenyPbenzoyllmethionine methyl ester
The desired ester was prepared using the method described inExample 403H starting with
13405 the compound described inExample 403G and 4-butylaniline. m/e (ESI) 517 (MH")
Figure imgf000611_0003
Example 1167B N-[4-N-f4-ButylphenyPaminomethyl-2-(2-methylphenyPbenzoyllmethionine 13410 The desired compound was prepared according to the method of Example 4031 starting with compound prepared inExample 1167 A. X (300MHz, CDCI3, δ) 7.98 ( IH, t, J=9Hz), 7.47 (lH,bd, J=8), 7.40-7.10 (6H, m), 7.04 (2H, d, J=9Hz), 6.56 (2H, d, J=9Hz), 5.88 ( IH, bd, J=8Hz), 4.57 (IH, m), 4.40 (2H, s), 2.48 (2H, t, J=8Hz), 2.20- 2.00 (8H, m), 1.90 (IH, m), 1.53 (3H, m), 1.32 (2H, m), 0.92 (3H, t, J=8Hz). m/e
13415 (ESI) 503 (MH") Anal.calc. for C30H36N2O3SO.25 H2O C 70.76, H 7.23, N 5.50 Found C 70.77, H 7.07, N 5.35
Figure imgf000612_0001
13420 Example 1168
e
Figure imgf000612_0002
Example 1168 A 4-N-(2-ButylphenyP-N-(3.5-difluorobenzyPaminomethyl-2-(2-methylphenyPbenzoic acid
13425 methyl ester The desired compound was prepared using the method described inExample 1169A 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+)
13430
Figure imgf000613_0001
Example 1168B 4-N-(2-ButylphenvP-N-(3.5-difluorobenzyPaminomethyl-2-(,2-methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting
13435 with the product from Example 1168 A.
Figure imgf000613_0002
Example 1168C N-r4-N-(2-ButylphenylVN-f3.5-difluorobenzyPaminomethyl-2-(2- 13440 methylphenyPbenzoyllmethionine methyl ester
The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1168B. m/e (ESI) 645 (MH+)
Figure imgf000613_0003
13445 Example 1168D
N-r4-N-(2-ButylphenylVN-(3.5-difluorobenzyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine
The desired compound was prepared according to the method ofExample 4031 starting with the compound frornExarnpie 1 lόβC^H (300MHz, CDCI3, δ) 7.92 (IH, m),
13450 7.40-6.90 (10H, m), 6.81 (2H, bd, J=8Hz), 6.66 (IH, m), 5.84 (IH, m), 4.55 (IH, 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 C37H40F2N2O3S C 70.45, H 6.39, N 4.40 Found C 70.10, H 6.27, N 4.35
13455
Figure imgf000614_0001
13460 Example 1169 A 4-N-(2.6-DiethylphenyP-N-(3.5-difluorobenzyPaminomethyl-2-(2-methylphenyPbenzoic 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
13465 diisopropylethylamine (0.084 mL, 0.470 mmol) were dissolved in DMF (5 mL), and solution stiπed ovemight at room temperature. To this mixture was then added diisopropylethylamine (0.084 mL, 0.470 mmol) and α-bromo-3,5-difluorotoluene (0.100 mL, 0.760 mmol), and reaction heated at 80°C for 3 days. Solvents concentrated in vacuo, and residue purified by flash chromatography on silica gel eluting with 2% EtOAc/Hexanes
13470 to afford the desired compound as a yellow oil (72 mg, 45%). m/e (ESI) 514 (MH+)
Figure imgf000614_0002
Example 1 169B 4-N-(2.6-DiethylphenyP-N-f3.5-difluorobenzyl)aminomethyl-2-C2-methylphenyPbenzoic 13475 acid
The desired acid was prepared using the method described in Example 403E starting with the product from Example 1169A.
Figure imgf000615_0001
13480 Example 1 169C N-l"4-N-(2.6-DiethylphenvP-N-(3.5-difluorobenzyl)aminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1169B. m/e (ESI) 645 (MH+)
13485
Figure imgf000615_0002
Example 1169D N-r4-N-(2.6-DiethylphenyP-N-f3.5-difluorobenzvPaminomethyl-2-(2- methylphenyPbenzoyllmethionine lithium salt
13490 The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1169C.1H (300MHz, DMSO, δ) 7.43 (IH, d,
J=9Hz), 7.30-7.00 (9H, m), 6.85 (4H, m), 4.21 (2H, s), 4.18 (2H, s), 3.65 (IH, 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 C37H39F2L.N2O3S l.5O H2O C 66.95, H 6.38, N 4.22 Found C 66.79, H
13495 6.34, N 3.93
Figure imgf000616_0001
Example 1170
13500
Figure imgf000616_0002
Example 1 170 A N-r4-N-(2-ButylphenyP-N-(cyclohexylmethyPaminomethyl-2-(2- methylphenyPbenzoyll methionine methyl ester
13505 The desired ester was prepared using the method described inExample 403H starting with the compound described in Example 1 166A and cyclohexanecarboxaldehyde. m/e (ESI) 613 (MH-)
Figure imgf000616_0003
13510 Example 1170B
N-r4-N-f2-ButylphenyP-N-(cyclohexylmethyPaminomethyl-2-('2- methylphenyPbenzoyllmethionine lithium salt The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1170A.iH (300MHz, DMSO, δ) 7.47 (IH, d, 13515 J=9Hz), 7.29 (IH, m), 7.25-6.95 (9H, m), 6.90 (IH, m), 3.97 (2H, s), 3.16 (IH, 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 (5H, t, J=8Hz). m/e (ESI) 599 (MH") Anal.calc. for C37H.47LiN2O3S- l.OO H2O C 71.13, H 7.90, N 4.48 Found C 71.01, H 7.93, N 4.14 13520
Figure imgf000617_0001
Example 1171
Figure imgf000617_0002
13525 Example 1171 A
N-(2-CyclohexylethyP-N-(3-methylphenyl)amine To a stiπed 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 stiπed overnight at
13530 ambient tenperature. Reaction diluted with EtOAc and washed with water, l.OM NaHCO3 (2x), IN 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 l.OM lithium aluminum hydride solution (7.00 mL, 7 mmol) in THF. Reaction refluxed ovemight. Reaction cooled to 0°C and quenched with
13535 successive addition of water (0.27 mL), 15% aqueous NaOH (0.27 mL), and water (0.80 mL). Mixture stiπed 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+)
Figure imgf000617_0003
Example 117 IB N-r4-N-t2-Cyclohexylethvn-N-(3-methylphenyl)aminomethyl-2-(2- methylphenyπhenzoyllmethionine methyl ester The desired ester was prepared using the method described inExample 403H starting 13545 with the compounds described inExample 403G andExample 1171 A. m/e (ESI) 585 (MH~)
Example 1171C N-[4-N-(2-CyclohexylethyP-N-(3-methylphenyPaminomethyl-2-(2- 13550 methylphenyPbenzoyllmethionine
The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 117 IB. iH (300MHz, CDCI3, δ) 7.92 (IH, t, J=9Hz), 7.40-7.00 (8H, m), 6.47 (2H, m), 5.86 (IH, d, J=8Hz), 4.51 (4H, m), 3.39 (2H, m), 2.25 (3H, s), 2.15-1.80 (8H, m), 1.70 (5H, m), 1.50 (3H, m), 1.40-1.05 (4H, 13555 m), 0.96 (2H, m). m/e (ESI) 571 (MH") Anal.calc. for C35H44N2O3SAOO H2O C 71.15, H 7.85, N 4.74 Found C 70.91, H 7.89, N 4.46
Figure imgf000618_0002
13560 Example 1172
Figure imgf000618_0003
Example 1172 A N-(2-ButylphenyP-N-(2-cyclohexylethyPamine 13565 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+)
Figure imgf000619_0001
Example 1172B 13570 N-r4-N-(2-ButylphenvP-N-(2-cvclohexylethvPaminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester The desired ester was prepared using the method described inExample 403H starting with the compounds described inExample 403G andExample 1172 A. m/e (ESI) 627 (MH")
Figure imgf000619_0002
Example 1172C
N-[4-N-(2-ButylphenyP-N-(2-cvclohexylethvPaminomethyl-2-(2- methylphenyPbenzoy 11 methionine The desired compound was prepared according to the method ofExample 4031 13580 starting with compound prepared inExample 1 172B.1H (300MHz, CDCI3, δ) 7.94 (IH, t, J=9Hz), 7.41 (IH, bd, J=8HZ), 7.40-7.00 (9H, m), 5.85 (IH, dd, J=8&2Hz), 4.55 ( IH, 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 C38H50N2O3SO.25 H2O C 73.69, H 8.22, N 4.52 Found C 73.74, H 8.17, N 4.30
13585
Figure imgf000620_0001
Example 1173
Figure imgf000620_0002
Example 1173 A N-(2-ButylphenyP-N-(2-(3.5-difluoro phenylethyl)amine The desired amine was prepared using the method described inExample 1 171 A starting with 3,5-difluorophenylacetic acid and butylamine. m/e (DCI/NH3) 214 (MH+)
13595
Figure imgf000620_0003
Example 1173B N-r4-N-Butyl-N-(2-(3.5-difluoro phenylethvParmnomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester
13600 The desired ester was prepared using the method described inExample 403H starting with the compounds described inExample 403G andExample 1173 A. m/e (ESI) 581 (MH")
Figure imgf000621_0001
F
Example 1173C 13605 N-[4-N-Butyl-N-(2-(3.5-difluoro phenylethvPaminomethyl-2-(2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1173B. iH (300MHz, CDCI3, δ) 7.80 (IH, d, J=9Hz), 7.54 (IH, m), 7.40-7.00 (5H, m), 6.80-6.60 (3H, m), 6.17 ( IH, m), 4.43 ( IH, 13610 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
Figure imgf000621_0002
Example 1174
-
Figure imgf000621_0003
Example 1174 A 13620 N-(ButanesulfonyP-N-(2-phenylethyPamine
To a stiπed solution at ambient temperature of phenethylamine (200 mg, 1.65 mmol) in CH2CI2 (2 mL) was added triethylamine (0.35 mL, 2.48 mmol) and butanesulfonyl chloride (0.24 mL, 1.82 mmol). After 4 hours of stiπing at ambient temperature, the reaction was diluted with EtOAc and washed with water, l.OM NaHCO3, and brine. 13625 Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.
Figure imgf000622_0001
Example 1174B 4-(N-Butanesulfonyl-N-(2-phenylethyPaminomethyP-2-(2-methylphenyl)benzoic acid 13630 methyl ester
To a stiπed mixture in anhyrous DMF ( 1 mL) at room temperature under N2 of 60% 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 1 174A. Reaction stiπed 20 minutes, and then, a solution of 4-bromomethyl-2-(2-methylphenyl)benzoic acid 13635 methyl ester (200 mg, 0.627 mmol), prepared as inExample 1178A-D, in anhydrous DMF (5 mL) was added. Reaction stiπed overnight at room temperature. Reaction quenched with IN 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, 13640 98%). m/e (ESI) 480 (MH+)
Figure imgf000622_0002
Example 1174C 4-(N-Butanesulfonyl-N-("2-phenylethyPaminomethyP-2-(2-methylphenyPbenzoic acid 13645 The desired acid was prepared using the method described in Example 403E starting with the product from Example 1174B.
Figure imgf000623_0001
Example 1174D 13650 N-r4-N-Butanesulfonyl-N-(2-phenylethvPaminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1174C. m/e (ESI) 480 (MH")
Figure imgf000623_0002
Example 1174E N-14-N-Butanesulfonyl-N-(2-phenylethyPaminomethyl-2-(2- methylphenyPbenzoy 11 methionine lithium salt The desired compound was prepared according to the method ofExample 4031
13660 starting with compound prepared inExample 1174D.iH (300MHz, DMSO-d6, δ) 7.62 ( IH, d, J=7Hz), 7.52 (IH, dd, J=7&2Hz), 7.20-7.10 (10H, m), 7.14 ( IH, bd, J=7Hz), 4.65 (2H, bs), 3.76 (IH, 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 C32H39L1N2O5S2 .5O H2O C 62.83, H 6.59, N 4.38 Found C
13665 62.59, H 6.59, N 4.44
Figure imgf000623_0003
Example 1 175 13670 N-[4-N-Benzyloxy-N-butylaminomethyl-2-(2-methylphenyPbenzoyllmethionine lithium salt
Figure imgf000624_0001
Example 1 175 A 13675 N— t-Butoxycarbonyl- -benzylhydroxylamine
To a stiπed 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 ovemight at ambient temperature. Reaction concentrated in vacuo. Residue taken up in EtOAc and washed with water, l .OM ΝaHCθ3, IN H3PO4, 13680 and brine. Organic layer dried with Na2SO4, filtered, and evaporated.
Figure imgf000624_0002
Example 1175B N— t-Butoxycarbonyl-N-butyl-O-benzylhydroxylamine 13685 To a stiπed solution at 0°C of N—t-Butoxycarbonyl- -benzylhydroxylamine, prepared as in Example 1 175A, in anhydrous THF was added portionwise a 60% dispersion of sodium hydride (1.2 equiv.) in mineral oil. Mixture stiπed 30 minutes ar 0°C, and then, 1-iodobutane (1.2 equiv.) was added dropwise. Reaction stiπed one hour at 0°C, and than, ovemight at room temperature. Reaction concentrated in vacuo. Residue taken up 13690 in EtOAc and washed with water, l.OM ΝaHC03, IN H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated.
Figure imgf000624_0003
Example 1 175C 13695 N-Butyl-0-benzylhydroxylamine hydrochloride salt
The desired compound was prepared using the method described in Example 403D starting with the compound prepared in Example 1175B.
Figure imgf000625_0001
13700 Example 1175D
N-r4-N~Benzyloxy-N-butylaminomethyl-2-(2-methylphenyPbenzoynmethionine methyl ester The desired ester was prepared using the method described in Example 403H starting with the compound prepared in Example 1175C and N-[4-Formyl-2-(2- 13705 methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G. m/e (ESI) 547 (MH")
Figure imgf000625_0002
Example 1175E 13710 N44-N-- Benzyloxy-N-butylaminomethyl-2-('2-methylphenyPbenzoyllmethionine lithium salt The desired compound was prepared according to the method of Example 4031 starting with the compound in Example 1175D. iH (300MHz, DMSO-d6, δ) 7.52 (IH, d, J=9Hz), 7.40 (IH, dd, J=7&2Hz), 7.30-7.10 (10H, m), 6.96 (IH, bd, J=7Hz), 4.46 (2H, 13715 bs), 3.87 (2H, bs), 3.71 (IH, m), 2.68 (2H, t, J=8Hz), 2.25-1.95 (5H, m), 1.93 (3H, s), 1.90-1.60 (2H, m), 1.50 (2H, m), 1.30 (2H, m), 0.83 (3H, t, J=8Hz). m/e (ESI) 533 (MH") Anal.calc. for C31H37L1Ν2O4SO.75 H2O C 67.19, H 7.00, N 5.05 Found C 67.19, H 6.91, N 4.96
13720
Figure imgf000626_0001
Example 1177
Figure imgf000626_0002
13725 Example 1 177
N-r4-N-(2-CyclohexylethyP-N-methylaminomethyl-2-(2-methylphenyl)benzoyll3- aminotetrahydrofuran-2-one The desired compound was prepared using the method of Example 403F starting with 4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)benzoic acid, 13730 prepared as in Example 608C, and α-amino-γ-butyrolactone hydrobromide. lU (300MHz, CDCI3, δ) (rotamer) 7.91 (IH, t, J=9Hz), 7.41 ( IH, bd, J=8HZ), 7.35- 7.20 (4H, m), 7.19 (IH, d, J=2Hz), 5.72 (IH, m), 4.49 (IH, m), 4.33 ( IH, bt, J=8Hz), 4.17 ( IH, m), 3.53 (2H, s), 2.62 (IH, 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) 13735 447 (MH") Anal.calc. for C28H36N2O3 I .OO H2O C 72.07, H 8.21 , N 6.00 Found C 72.12, H 8.03, N 5.76
Figure imgf000626_0003
13740 Example 1178 N-[4-(N-(-2-cvclohexylethyP-N-butylaminomethvP-2-f2-methylphenvPbenzoyllmethionine,
Lithium Salt
Figure imgf000627_0001
13745
Example 1178 A Dimethyl-(2-methylphenyl)terephthalate A mixture of dime thy liodoterephthalate (278 g, 0.87 mol), 2-methylphenylboronic acid (141 g, 1.04 mol) palladium (II) acetate ( 1.95 g, 0.0087 mol) and triphenylphosphine 13750 (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 80°C 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) pre wetted 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. iH ΝMR 13755 (CDCI3) δ 8.09, dd, IH; 8.02, d, IH; 7.95, d, IH; 7.20 - 7.34, m, 3H; 7.10, bd, IH; 3.96, s, 3H; 3.64, s, 3H; 2.08, s, 3H. MS (DCI/ΝH3) 302 (M + NH4)+.
Figure imgf000627_0002
Example 1178B 13760 2-(2-methylphenyP-4-carboxybenzoic 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 11°C ovemight and then warmed to ~ 20°C over 13765 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 13770 title compound. The material was ~ 87% pure. An analytical sample was obtained by recrystallization from aqueous ethanol. iH NMR (CDCI3) δ 8.14, dd, IH; 8.03, d, IH; 8.01, d, IH; 7.28 - 7.42, m, 3H; 7.09, bd, IH; 3.64, s, 3H; 2.08, s, 3H. MS (DCI/NH3):
271 (MH)+; 288 (M + NH4)+.
Figure imgf000628_0001
Example 1178C 4-hydroxymethyl-2-(2-methylphenyPbenzoic. methyl ester A solution of example 1178B (4.67g, 17.3 mmol) in 35 mL of THF was cooled in an 13780 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 stiπed 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 13785 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. iH NMR (CDCI3) δ 7.98, d, IH; 743, dd, IH; 7.16 - 7.28, m, 4H; 7.07, bd, IH; 4.77, s, 2H; 3.62, s, 3H; 2.05, s, 3H; 1.78, bs, IH. MS (DCI/NH3): 257 (MH)+; 274 (M + NH4)+. 13790
Figure imgf000628_0002
Example 1178D 4-bromomethyl-2-(2-methylphenyPbenzoic. methyl ester A solution of 36 g (140 mmol) of example 1178C and 13.4 g (154 mmol) lithium 13795 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 Et2θ (600 mL). The aqueous layer was extracted with Et2θ (2 x 150 mL), then the combined Et2θ layers were washed with brine, and dried over Na2SO4- After filtration and concentration, recovered 13800 44.5 g (97.5%) slightly cloudy, almost colorless oil that was 2% DMF by weight
(determined by NMR). 1H NMR (CDCI3) δ 7.84 (d, IH), 7.44 (dd, IH), 7.24 (m, 4H), 7.07 (br d, IH), 4.50 (s, 2H), 3.62 (s, 3H), 2.07 (s, 3H). MS (DCI/NH3) 336/338 (M+H+NH3)+.
Figure imgf000629_0001
Example 1178E N-butyl-N-2-cyclohexylacetamide 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
13810 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 stiπed ovemight at ambient temperature. An additional 30 mL of butylamine
13815 was added and stiπing continued for 2 hours and then the mixture was poured into a separatory funnel. The layers were separated aηd 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
13820 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., CDC13): δ 5.35, bs, IH; 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
13825 (DCI-NH3): 198 (MH+); 215 (M+NH4+).
Figure imgf000629_0002
Example 1 178F N-hnryl-N-2-cvclohexylethylarnine
13830 A stiπed 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 1178E (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,
13835 followed by an additional 72 mL of water. The thick slurry was vigorously stiπed for 15 minutes at which time 600 mL of methylene chloride and excess sodium sulfate were sequentially added. The mixture was stiπed 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
13840 MHz., CDC13): δ 2.61, m, 4H; 1.69, m, 5H; envelope 1.05 - 1.53, 1 1H; 0.91, m, 5H. MS (DCI-NH3): 184 (MH+).
Figure imgf000630_0001
Example 1178G 13845 4-(N-(-2-cyclohexylethyP-N-butylaminomethyP-2-(2-methylphenyl)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 Ν-butyl-Ν-2- cyclohexylethylamine (15.3 g, 0.084 mol). The cloudy mixture was stiπed for two hours 13850 and then briefly warmed to ~45°C. 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 13855 used directly. An analytical sample was obtained by column chromatography on silica gel (3% ethyl acetate/hexanes) to provide pure material. H nmr (300 MHz., CDC13): δ 7.92, d, IH; 7.48, dd, IH; 7.16 - 7.28, m, 4H; 7.07, bd, IH; 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).
13860
Figure imgf000631_0001
Example 1178H N-r4-(N-('-2-cyclohexylethyP--V-butylaminomethyP-2-(2-methylphenyPbenzoic acid A solution of 1178G (34.35 g, 0.081 mol) in 210 mL of ethanol was treated with
13865 aqueous sodium hydroxide (4Ν, 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 IM aqueous phosphoric acid which resulted in an oily precipitate. The
13870 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., CD3OD): δ 7.96, d, IH; 7.64, dd, IH; 7.37, d, IH; 7.22, m, 2H; 7.18, m, IH; 7.07, d, IH; 4.41, bs, 2H; 3.12, m, 4H; 2.10, s, 3H; 1.18, bm,
13875 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).
Figure imgf000631_0002
Example 11781 13880 N-r4-(N-Butyl-N-(2-cyclohexylethyPaminomethyP-2-(2-methylphenyPbenzoyllmethionine methyl ester Partitioned 13.2 g (66.1 mmol) L-methionine methyl ester, hydrochloride salt between saturated aqueous NaHCO3 (80 mL) and CH2CI2 (75 mL). Added the organic layer to the following solution: 24.5 g (60.2 mmol) acid from Example 1 178H, 10.0 g 13885 (65.3 mmol) HOBTΗ2O, and 12.6 g (65.7 mmol) EDCI*HC1 in DMF (150 mL). After stiπing at RT ovemight 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 13890 compound. lH NMR (CDCI3) δ 7.90 (m, IH), 7.40 (d, IH), 7.30, 7.20, 7.16 (all m, total 5H), 5.88 (br d, IH), 4.62 (m, IH), 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, IH), 1.62 (m, 5H), 1.50-1.10 (envelope, 10H), 0.87 (m, 5H). MS (APCI) 553 (M+H)+.
Figure imgf000632_0001
Example U78J
N-r4-(N-(-2-cyclohexylethyl)-N-butylaminomethyP-2-(2-methylphenyPbenzoyllmethionine.
Lithium Salt
A solution of example 11781 (22.9 g, 0.041 mol), in 200 mL of 3: 1 THF methanol
13900 was cooled in an ice bath and then tretaed with aqueous lithium hydroxide (IM, 83 mL,
0.083 mol) dropwise. The ice bath was removed and the mixture was stiπed 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 IM aqueous phosphoric acid and stiπed for 1 hour. The solid was
13905 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 stiπed 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
13910 the title compound. lH nmr (300 MHz., CD3OD): δ 7.64, m, IH; 7.41, d, IH; 7.05 -
7.32, m, 5H; 4.25, m, IH; 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, IH; 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 C32H45Ν2O3SLi*0.60 H2O; C 69.19; H 8.38; N 5.04; Found: C 69.25; H 8.50; N 4.99. 13915
Figure imgf000633_0001
Example 1179
Figure imgf000633_0002
Example 1179
N-[4-N-Butyl-N-(2-cyclohexylethyPaminomethyl-2-(2-methylphenyPbenzoyllmethionine
4-methylphenylsulfonimide
N-[4-(N-Butyl-N-(2-Cyclohexylethyl)aminomethyl)-2-(2-
13925 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 l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (214 mg, 1.12 mmol) were dissolved in CH2CI2 (10 mL) at room temperature and stiπed ovemight. Reaction diluted with water and CHCI3 and layers separated. Aqueous layer extracted with CHCI3 (2x), and combined
13930 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%). ^H (300MHz, MeOD, δ) (rotamer) 7.73 (2H, d, J=9Hz), 7.62 (IH, d, J=8Hz), 7.48 (IH, bd, J=8Hz), 7.30-7.00 (7H, m), 4.22 (IH, m), 4.02 (2H, bs), 2.81 (4H, m), 2.39 (3H, s), 2.21(2.03) (3H, bs),
13935 1.90 (3H, s), 1.85-1.40 (13H, m), 1.40-1.10 (6H, m), 0.93 (5H, t, J=8Hz). m/e (ESI) 690 (MH") Anal.calc. for C39H53N3O4S2A25 H2O C 65.56, H 7.83, N 5.88 Found C 65.41, H 7.52, N 5.61
Figure imgf000634_0001
Example 1180
Figure imgf000634_0002
Example 1180A 13945 N-Butyl-N-(l-phenyltetrazol-5-yPamine
5 -Chloro-1 -phenyl- IH-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 stiπed ovemight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. Residue
13950 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+)
e
Figure imgf000634_0003
Example 1180B
13955 4-N-Butyl-N-f 1 -phenyltetrazol-5-yPaminomethyl-2-("2-methylphenyPbenzoic 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 1 178A-D, and the compound from Example 1180A.
13960
Figure imgf000635_0001
Example 1180C 4-N-Butyl-N-( 1 -phenyltetrazol-5-yPaminomethyl-2-(2-methy IphenyPbenzoic acid The desired acid was prepared using the method described inExample 403 E starting
13965 with the product fromExample 1180B. m/e (ESI) 440 (MH")
Figure imgf000635_0002
Example 1180D N-r4-N-Butyl-N-(l-phenyltetrazol-5-yl')aminomethyl-2-f2- 13970 methylphenyPbenzoyllmethionine methyl ester
The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1180C. m/e (ESI) 587 (MH+)
Figure imgf000636_0001
13975 Example 1180E
N-|"4-N-Butyl-N-( l-phenyltetrazol-5-yPaminomethyl-2-(2- methylpheny Pbenzoyll methionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1180D. *H (300MHz, CDCI3, δ) 7.93 (IH, m), 13980 7.60-7.40 (5H, m), 7.40-7.10 (5H, m), 7.03 (IH, d, J=2Hz), 5.89 (IH, m), 4.55 ( IH, m), 4.52 (2H, s), 3.1 1 (2H, bt, J=8Hz), 2.20-2.00 (8H, m), 1.90 (IH, m), 1.56 ( IH, m), 1.43 (2H, m), 1.06 (2H, m), 0.74 (3H, t, J=8Hz). m/e (ESI) 571 (MH+) Anal.calc. for C31H36N6O3S C 65.01, H 6.34, N 14.67 Found C 64.77, H 6.33, N 14.70
13985
Figure imgf000636_0002
Example 1181
Figure imgf000636_0003
13990 Example 1181 A
N-t-Butyl-N-(2-cyclohexylethyPamine The desired amine was prepared using the method described inExample 1171 A starting with cyclohexylacetic acid and t-butylamine. m/e (DCI/NH3) 184 (MH+) e
Figure imgf000637_0001
Example 118 IB 4-(N-t-Butyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyl)benzoic acid methyl ester The desired compound was prepared using the method described inExample 1 178G
14000 starting with N-t-butyl-N-(2-cyclohexylethyl)amine, prepared as inExample 1 181 A, and 4- bromomethyl-2-(2-methy IphenyPbenzoic acid methyl ester, prepared as inExample 1178 A- D. m/e (ESI) 422 (MH+)
Figure imgf000637_0002
14005 Example 1181C
4-(N-t-Butyl-N-(2-cyclohexylethyPaminomethyl)-2-(2-methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 118 IB.
Figure imgf000637_0003
Example 118 ID N-[4-N-t-Butyl-N-(2-cyclohexylethyPaminomethyl-2-(2-methylphenyl)benzoyllmethionine methyl ester The desired product was prepared using the method described inExample 403F
14015 starting with the compound prepared inExample 1181C. m/e (ESI) 553 (MH+)
Figure imgf000638_0001
Example 118 IE N-r4-N-t-Butyl-N-r2-cyclohexylethyPaminomethyl-2-('2-methylphenyPbenzoyllmethionine
14020 The desired compound was prepared according to the method ofExample 4031 starting with compound prepared inExample 1 181D. iH (300MHz, CDCI3, δ) 7.78 (IH, m), 7.67 (IH, m), 7.40-7.00 (5H, m), 6.21 (IH, m), 4.38 (IH, 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 C32H46N2O3SO.75 H2O C
14025 69.59, H 8.67, N 5.07 Found C 69.78, H 8.65, N 4.89
Figure imgf000638_0002
Example 1182
14030
Boc-NH,
"O H
Example 1182 A (2S)-t-Butoxycarbonylaminopentan-l-ol The desired product was prepared using the methods described in Example 1183 A
14035 starting with L-norvaline.
Boc-NH.
"SEt Example 1182B (2S Vt-Butoxycarbonylamino- 1 -ethylthiopentane 14040 The desired product was prepared using the methods described in Example 403B and 403C starting with the compound prepared in Example 1182A.
Figure imgf000639_0001
Example 1 182C 14045 (2R)-Aminopentane hydrochloride salt
The desired product was prepared using the methods described in Example 1183C starting with the compound prepared in Example 1182B.
Figure imgf000639_0002
14050 xample 1182D
N-(2-Cyclohexylethyl)-N-(pent-2-yPamine The desired amine was prepared using the method described inExample 1 171 A, except triethylamine was added, starting with cyclohexylacetic acid and the compound fromExample 1182C. m/e (DCI) 198 (MH+) 14055
Figure imgf000639_0003
Example 1182E N-r4-N-(2-CvclohexylethyP-N-(pent-2-yl)aminomethyl-2-('2- methylphenyPbenzoyllmethionine methyl ester 14060 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+)
Figure imgf000640_0001
Example 1 182F N-r4-N-r2-CvclohexylethvP-N-(pent-2-vPaminomethyl-2-(2- methy lpheny Pbenzoyll methionine The desired compound was prepared according to the method ofExample 4031
14070 starting with the compound prepared inExample 1182E. iH (300MHz, CDCI3, δ) 7.74 ( IH, m), 7.62 (IH, m), 7.40-7.00 (5H, m), 6.46 (IH, m), 4.37 (IH, m), 3.94 (2H, m), 3.37 (IH, 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 C33H48N2O3S-0.50 H2O C 70.55, H 8.79, N 4.99 Found C 70.55, H 8.71 , N 4.87
14075
Figure imgf000640_0002
Example 1183
Figure imgf000640_0003
Example 1183 A (2R)-t-Butoxycarbonylaminopentan- 1 -ol To a stiπed 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
14085 dicarbonate (11.2 g, 51.2 mmol), and tetrabutylammonium bromide (1.0 g). Two-phase solution stiπed overnight at ambient temperature. Reaction neutralized with aqueous 3N HCl to pH 6 and extracted with CHCI3 (3x). Extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a colorless oil. To a stiπed solution at 0°C under N2 of the crude residue in anhydrous THF (80 mL) was added dropwise via addition funnel a 1.OM 14090 borane-THF complex ( 100 mL, 100 mmol) in THF. After stiπing ovemight at ambient temperature, reaction cooled back to 0°C and quenched with an aqueous 4N NaOH solution (50 mL). Mixture stiπed one hour at ambient temperature, and then, extracted with CH2CI2 (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 14095 a pale yellow oil (3.87 g, 45%). m/e (DCI) 204 (MH+)
Figure imgf000641_0001
Example 1183B (2R)-t-Butoxycarbonylamino-l-ethylthiopentane 14100 The desired product was prepared using the methods described inExample 403B and
403C starting with the compound prepared inExample 1183 A. m/e (DCI) 248 (MH+)
Figure imgf000641_0002
Example 1183C
14105 (2S -Aminopentane hydrochloride salt
To a stiπed solution at ambient temperature of (2R)-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 stiπed vigorously at 80°C for 2 days. Reaction filtered through celite, and celite and catalyst washed with EtOAc.
14110 Filtrate concentrated in vacuo to produce a colorless liquid. Residue taken up in a solution of 4N HCl in dioxane (5 mL), and reaction stiπed ovemight 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%).
Figure imgf000641_0003
Example 1183D N-("2-CyclohexylethyP-N-(pent-2-yPamine The desired amine was prepared using the method described inExample 1 171 A, except triethylamine was added, starting with cyclohexylacetic acid and the compound 14120 fromExample 1 183C. iH NMR (CDCI3, 300 MHz) δ 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)
Figure imgf000642_0001
Example 1183E 14125 N- 4-N-(2-CyclohexylethvP-N-('pent-2-yPaminomethyl-2-(2-methylphenyPbenzoic acid methyl ester The desired compound was prepared using the method described inExample 1178G starting with N-(2-cyclohexylethyl)-N-(l-methylbutyl)amine, prepared as inExample 1183D, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as 14130 inExample 1178A-D. m/e (ESI) 436 (MH+)
Figure imgf000642_0002
Example U83F N-r4-N-(2-Cyclohexylethyl)-N-('pent-2-yPaminomethyl-2-(2-methylphenyPbenzoic acid 14135 The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 1183E.
Figure imgf000642_0003
.Example 1183G 14140 N-r4-N-(-?-CvclohexylethvP-N-(pent-2-yl)aminomethyl-2-(2- methylphenvPbenzoyllmethionine methyl ester The desired product was prepared using the method described inExample 403F starting with the compound prepared inExample 1 183F. m/e (ESI) 567 (MH+)
Figure imgf000643_0001
Example 1183H N-r4-N-(2-CvclohexylethvP-N-(pent-2-vPaminomethyl-2-(2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031
14150 starting with the compound fromExample 1 183G. iH (300MHz, CDC13, δ) 7.69 (2H, m), 7.40-7.00 (5H, m), 6.46 (IH, m), 4.38 (IH, m), 4.05 (2H, m), 3.41 (IH, 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 (5H, m). m/e (ESI) 551 (MH") Anal.calc. for C33H48N2O3SO.50 H2O C 70.55, H 8.79, N 4.99 Found C 70.65, H 8.63, N 4.93
14155
Figure imgf000643_0002
Example 1184A N-Propoxyphthalimide The desired product was prepared using the method described in Example 1 176 A starting with N-hydoxyphthalimide and 1-propanol. m/e (DCI) 223 (MH+NH3+)
14165
Figure imgf000644_0001
Example 1 184B O-Propyl-2-cyclohexylacetaldoxime The desired product was prepared using the method described in Example 1 176B 14170 starting with the compound from Example 1184 A and cyclohexylacetaldehyde.
Figure imgf000644_0002
Example 1184C N— (2-CyclohexylethyP-N-propyloxyamine 14175 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+)
Figure imgf000644_0003
Example 1184D 14180 N-r4-N--(2-Cyclohexylethyl)-N-propyloxyaminomethyl-2-(2- methylphenyPbenzoy 11 methionine methyl 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) 14185 553 (MH-)
Figure imgf000645_0001
Example 1184E N-r4-N-(2-CyclohexylethyP-N-propyloxyaminomethyl-2-(2- 14190 methylphenyPbenzoy 11 methionine lithium salt
The desired compound was prepared according to the method of Example 4031 starting with th compound from Example 1 184D. iH (300MHZ, DMSO-d6, δ) 7.53 (IH, d, J=9Hz), 7.38 (IH, dd, J=7&2Hz), 7.30-7.00 (5H, m), 6.92 ( IH, m), 3.82 (2H, bs), 3.71 (IH, m), 3.41 (2H, m), 2.67 (2H, bt, J=8Hz), 2.25-1.95 (5H, m), 1.91 (3H, s), 14195 1.90-1.50 (7H, m), 1.37 (5H, m), 1.15 (3H, m), 0.86 (2H, m), 0.76 (3H, t, J=8Hz). m/e (ESI) 539 (MH") Anal.calc. for C3 iH43LiN2θ4S-0.50 H2O C 67.00, H 7.98, N 5.04 Found C 66.82, H 7.75, N 4.92
Figure imgf000645_0002
Example 1185
Figure imgf000645_0003
Example 1185 A 14205 N-Cyclohexylmethoxyphthalimide
The desired product was prepared using the method described in Example 1176 A starting with Ν-hydoxyphthalimide and cyclohexylmethanol.
Figure imgf000646_0001
14210 Example 1 185B
N-(Cyclohexylmethyloxy)aminomethylidene-2-(2-methylphenyPbenzoic acid methyl ester
The desired product was prepared using the method described in Example 1176B starting with the compound from Example 1 185 A and N-[4-Formyl-2-(2- methylphenyPbenzoic acid methyl ester, prepared using the method of Example 403G and
14215 starting with the alcohol prepared in Example 1178C.
Figure imgf000646_0002
Example 1185C N-(Cyclohexylmethyloxy)aminomethyl-2-(2-methylphenyPbenzoic acid methyl ester 14220 The desired product was prepared using the method described in Example 1 176C starting with the compound in Example 1185B. m/e (ESI) 368 (MH+)
e
Figure imgf000646_0003
Example 1185D 14225 N-T4-N— Butyl-N-(cyclohexylmethyloxy)aminomethyl-2-(2-methylphenyPbenzoic acid methyl ester The desired product was prepared using the method described in Example 1176D starting with the compound in Example 1185C. m/e (ESI) 424 (MH+)
Figure imgf000647_0001
Example 1185E N-H-N-- Butyl-N-(cyclohexylmethyloxy aminomethyl-2-(2-methylphenyPbenzoic acid The desired product was prepared using the method described in Example 403E starting with the compound in Example 1185D.
14235
Figure imgf000647_0002
Example 1185F N-r4-N-Butyl-N-(cyclohexylmethyloxy aminomethyl-2-(2- methylphenyPbenzoy 11 methionine methyl ester
14240 The desired product was prepared using the method described in Example 403F starting with the compound in Example 1 185E. m/e (ESI) 555 (MH+)
Figure imgf000647_0003
Example 1185G 14245 N-r4-N-Butyl-N-('cyclohexylmethyloxy aminomethyl-2-('2- me thy lphenyPbenzoy 11 methionine lithium salt The desired compound was prepared according to the method of Example 4031 starting wiyh the compound in Example 1 185F.iH (300MHz, DMSO-d6, δ) 7.51 (IH, d, J=9Hz), 7.37 (IH, bd), 7.30-7.05 (5H, m), 6.94 (IH, m), 3.82 (2H, bs), 3.68 (IH, m), 14250 3.25 (2H, m), 2.64 (2H, t, J=8Hz), 2.25-1.95 (5H, 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 C3 iH43LiN2θ4S-2.00 H2O C 63.90, H 8.13, N 4.81 Found C 63.63, H 7.68, N 4.62
14255
Figure imgf000648_0001
Example 1187
Figure imgf000648_0002
14260 Example 1187 A
N-(2-CyclohexylethyP-N-propanesulfonylamine The desired product was prepared using the method described in Example 1 174 A starting with cyclohexylethylamine and 1-propanesulfonyl chloride.
Figure imgf000648_0003
Example 1187B 4-(N-('2-CyclohexylethyP-N-propanesulfonylaminomethyP-2-(2-methylphenyPbenzoic acid methyl ester The desired product was prepared using the method described inExample 1174B 14270 starting with N-(2-cyclohexylethyl)-N-propanesulfonylamine, prepared as inExample 1187 A, and 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as inExample 1178A-D. m/e (ESI) 472 (MH+)
Figure imgf000649_0001
14275 Example 1187C
4-(N-(2-CyclohexylethvP-N-propanesulfonylaminomethyP-2-(2-methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1 187B.
Figure imgf000649_0002
Example 1187D
N-14-N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester
The desired compound was prepared using the method described inExample 403F
14285 starting with the product fromExample 1187C. m/e (ESI) 601 (MH")
Figure imgf000649_0003
Example 1187E N-r4-N-(2-Cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2- 14290 methylphenyPbenzoyllmethionine
The desired compound was prepared according to the method ofExample 4031 starting with the compound prepared inExample 1187D.iH (300MHz, CDCI3, δ) 8.00 (IH, dd, J=8&7Hz), 7.43 (IH, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.90 (IH, m), 4.58 (IH, m), 4.42 (2H, s), 3.20 (2H, m), 2.94 (2H, m), 2.20-2.00 (7H, m), 2.00-1.80 (4H, 14295 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 C3 iH44N2θ5S2"0.25 H2O C 62.75, H 7.56, N 4.72 Found C 62.75, H 7.56, N 4.49
Figure imgf000650_0001
Example 1 188
Figure imgf000650_0002
Example 1 188 A 14305 N-rBromomethyl-2-(2-methylphenyl)benzoyl1methionine methyl ester
To a stiπed 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 CH2CI2 (5 mL) was added triphenylphosphine (163 mg, 0.620 mmol). Reaction stiπed one hour at -10°C, and 14310 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.
Figure imgf000650_0003
Example 1188B
14315 N-r4-N-(,3-ChloropropanesulfonyP-N-('2-cyclohexylethyPaminomethyl-2-('2- methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 1 174B (except reaction run at -40°C) starting with the product fromExample 1 188A and N-(3- chloropropanesulfonyl)-N-(2-cyclohexylethyl)amine, prepared as inExample 1189 A using 14320 the method described inExample 1174A. m/e (ESI) 635 (MH")
Figure imgf000651_0001
Example 1188C N- 4-N-(3-ChloropropanesulfonyP-N-(2-cvclohexylethyl)aminomethyl-2-(2- 14325 methylphenyPbenzoyllmethionine
The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1 188B. iH (300MHz, CDCI3, δ) 8.01 (IH, bt, J=8Hz), 7.46 (IH, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.90 (IH, m), 4.59 ( IH, 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), 14330 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 C31H43CI1N2O5S2O.5O H2O C 58.89, H 7.01, N 4.43 Found C 58.96, H 7.04, N 4.40
Figure imgf000651_0002
14335 Example 1189
Figure imgf000651_0003
Example 1189 A N-(3-ChloropropanesulfonyD-N-(2-cyclohexylethyl)amine 14340 The desired compound was prepared using the method described in Example 1 174 A starting with cyclohexylethylamine and 3-chloropropanesulfonyl chloride.
e
Figure imgf000652_0001
Example 1189B 14345 4-N-(3-ChloropropanesulfonyP-N-(2-cyclohexylethyl)aminomethyl-2-(2- methylphenyPbenzoic acid methyl ester The desired product was prepared using the method described inExample 1174B starting with the compound fromExample 1189 A and 4-bromomethyl-2-(2- methy IphenyPbenzoic acid methyl ester, prepared as inExample 1178A-D. m/e (ESI) 506 14350 (MH+)
Figure imgf000652_0002
Example 1189C N-r4-N-(2-CyclohexylethyP-N-(3-ethoxypropanesulfonyPaminomethyl-2-(2- 14355 methylphenyPbenzoic 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.
Figure imgf000652_0003
14360 Example 1189D N-r4-N-(2-Cvclohexylethyl)-N-(3-ethoxypropanesulfonyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester The compound was prepared using the method described inExample 403F starting with the product fromExample 1189C. m/e (ESI) 645 (MH")
14365
Figure imgf000653_0001
Example 1189E N-r4-N-(2-CyclohexylethyP-N-(3-ethoxypropanesulfonyl)aminomethyl-2-(2- methylphenyPbenzoyllmethionine lithium salt 14370 The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1189D. iH (300MHz, DMSO-d6, δ) 7.54 ( IH, d, J=8Hz), 7.41 (IH, dd, J=7&2Hz), 7.30-7.10 (5H, m), 6.97 (IH, d, J=7Hz), 4.42 (2H, bs), 3.68 (IH, m), 3.43 (2H, q, J=7Hz), 3.40 (2H, m), 3.16 (4H, m), 2.20-1.95 (5H, 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), 14375 0.78 (2H, m). m/e (ESI) 631 (MH") Anal.calc. for C33H47L1N2O6S2 .5O H2O C 61.18, H 7.47, N 4.32 Found C 61.15, H 7.53, N 4.15
Figure imgf000653_0002
14380 Example 1190
Figure imgf000653_0003
Example 1190A N-(2-CyclohexylethyP-N-(3-trifluoromethylpropanesulfonyPamine 14385 To a stiπed 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, 1 1.5 mmol) in anhydrous DMF (25 mL) such that the temperature was maintained below 5°C. Mixture stiπed one hour at 0°C, and then, diluted with water and extracted with ether. Extracts dried with Na2SO4, filtered, and concentrated in vacuo.
14390 Residue dissolved in 1 : 1 water/EtOH at 0°C, 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 CH2CI2, 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,
14395 and this two-phase solution was stiπed at room temperature overnight. Reaction diluted with water and extracted with CHCI3 (2x). Extracts dried with Na2SO4, filtered, and concentrated. Residue purified by flash chromatography on silica gel eluting with 20% EtOAcΗexanes to afford the desired product as a light brown oil (1.02 g, 32%). m/e (DCI) 319 (MH+NH3+)
14400
Figure imgf000654_0001
Example 1190B 4-(N-(2-CyclohexylethyP-N-(3-trifluoromethylpropanesulfonyPaminomethyP-2-(2- methylphenyPbenzoic acid methyl ester 14405 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.
Figure imgf000654_0002
■ Example 1190C 4-(N-(2-Cvclohexylethyl)-N-r3-trifluoromethylpropanesulfonyPaminomethyl)-2-(2- methylphenvPbenzoic acid The desired acid was prepared using the method described inExample 403E starting 14415 with the product fromExample 1190B. m/e (ESI) 524 (MH")
Figure imgf000655_0001
Example 1190D N-r4-N-(2-Cyclohexylethyl)-N-("3-trifluoromethylpropanesulfonyl)aminomethyl-2-(2- 14420 methylphenyPbenzoy 11 methionine methyl ester
The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1190C. m/e (ESI) 669 (MH")
Figure imgf000655_0002
14425 Example 1190E
N-r4-N-(2-CyclohexylethyP-N-("3-trifluoromethylpropanesulfonyl)aminomethyl-2-(2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound inExample 1190D. H (300MHz, CDCI3, δ) (rotamer) 14430 8.01(7.98) (IH, d, J=8Hz), 7.46 (IH, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.92 (IH, m), 4.80 (IH, bs), 4.58 (IH, 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 (IH, 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 C32H43F3N2O5S2 C 58.52, H 6.60, N 4.26 Found C 58.27, H 6.63, N 4.13 14435
Figure imgf000656_0001
Example 1191
14440
Figure imgf000656_0002
Example 1191 A 4-Azidomethyl-2-(2-methylphenyl)benzoic acid methyl ester To a stiπed mixture at 0°C under N2 of sodium azide (1.47 g, 22.6 mmol) in 14445 anhydrous DMF (30 mL) was added a solution of 4-bromomethyl-2-(2- methylphenyPbenzoic acid methyl ester (6.00 g, 18.8 mmol), prepared as in Example 1178A-D, in anhydrous DMF (10 mL). Reaction stiπed ovemight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo. 14450
Figure imgf000656_0003
Example 119 IB 4-Aminomethyl-2-(2-methylphenyl)benzoic acid methyl ester To a flask at ambient temperature under N2 containing 10% palladium on carbon 14455 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 1191 A, in MeOH (75 mL). Two drops of cone HCl added, and reaction stiπed 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 14460 with CHCI3 (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+)
Figure imgf000657_0001
Example 1191C 14465 4-N-Butanesulfonylminomethyl-2-(2-methylphenyPbenzoic acid methyl ester
The desired compound was prepared using the method described inExample 1174 A starting with 4-aminomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 119 IB, and butanesulfonyl chloride, m/e (ESI) 374 (MH")
Figure imgf000657_0002
Example 1191D l-Bromo-3-cvclohexylpropane The desired compound was prepared according to the method of Example 1178D starting with 3-cyclohexyl-l-propanol. *H (300MHz, CDCI3, δ) 3.40 (2H, t, J=8Hz), 14475 1.85 (2H, m), 1.80-1.50 (6H, m), 1.40-1.10 (5H, m), 0.90 (2H, m).
e
Figure imgf000657_0003
Example 119 IE N- 4-N-("Butanesulfonyl)-N-(3-cyclohexylpropyPaminomethyl-2-(2-methylphenyPbenzoic 14480 acid methyl ester
The desired compound was prepared using the method described inExample 1174B starting with the compounds fromExample 1191C andExample 1191D. m/e (ESI) 500 (MH+)
Figure imgf000658_0001
Example 119 IF
N-[4-N-(ButanesulfonvP-N-(3-cyclohexylpropyl)aminomethyl-2-(2-methylphenyl)benzoic acid
The acid was prepared using the method described in Example 403E starting with
14490 the compound from Example 119 IE.
Figure imgf000658_0002
Example 1191G N-[4-N-(ButanesulfonyP-N-(3-cyclohexylpropyl)aminomethyl-2-(2- 14495 methylphenyPbenzoyllmethionine methyl ester
The compound was prepared using the method described inExample 403F starting with the compound fromExample 1191F. m/e (ESI) 629 (MH-)
Figure imgf000658_0003
14500 Example 1191H
N-r4-N-(ButanesulfonyP-N-(3-cyclohexylpropyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine lithium salt The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1191G.iH (300MHz, DMSO-d6, δ) 7.54 (IH, 14505 d, J=8Hz), 7.41 (IH, bd, J=7Hz), 7.30-7.05 (5H, m), 6.97 (IH, d, J=7Hz), 4.42 (2H, s), 3.68 (IH, m), 3.10 (4H, bt, J=7Hz), 2.20-1.95 (5H, 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 C33H47L1N2O5S2 .75 H2O C 62.29, H 7.68, N 4.40 Found C 62.18, H 7.75, N 4.36 14510
Figure imgf000659_0001
Example 1193
Figure imgf000659_0002
Example 1193 A
(2S -t-Butoxycarbonylamino-4-cyclohexylbutanoic acid To a solution of Boc-homophenylalanine (3.00 g, 10.8 mmol) in CH2CI2 at room temperature was added a solution of 4N HCl in dioxane (20 mL, 80 mmol), and mixture
14520 stiπed 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 70°C ovemight. Reaction cooled to 0°C, and an aqueous solution of 3N HCl added
14525 until the pH reached 6. Product extracted out with CHCI3, and extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a white solid (3.24 g, 106%). m/e (DCI) 286 (MH+)
Boc-NH H
Figure imgf000659_0003
14530 Example 1193B
(2SV t-Butoxycarbonylamino-4-cyclohexylbutan- 1 -ol To a solution at -5°C under N of (2S)-t-butoxycarbonylamino-4- cyclohexylbutanoic acid (3.24 g, 10.8 mmol), prepared as inExample 1 193A, in anhydrous THF (20 mL) was added dropwise a l.OM borane-THF complex (32.3 mL, 32.3 mmol) in
14535 THF. After addition, reaction stiπed ovemight at room temperature. Reaction cooled to 0°C and quenched with an aqueous 4N NaOH solution. Stiπed 30 minutes at room temperature, and then, extracted with CH2CI2 (3x). Extracts dried with Na2SO4t filtered, and concentrated in vacuo. Residue purified by flash chromatography on silica gel eluting with 30% EtOAcΗexanes to afford the desired product as a colorless oil (696 mg, 23%). m/e
14540 (DCI) 272 (MH+)
Boc-NH Et
Figure imgf000660_0001
Example 1193C (2S)-t-Butoxycarbonylamino-4-cyclohexyl- 1 -ethylthiobutane 14545 The desired compound was prepared using the method described inExample 403B and 403C starting with the product fromExample 1193B. m/e (DCI) 316 (MH+)
HC.-NH2 Et
Figure imgf000660_0002
Example 1193D 14550 (2S -Amino-4-cyclohexyl-l -ethylthiobutane hydrochloride salt
The desired compound was prepared using the method described in Example 403D starting with the product from Example 1193C.
Figure imgf000660_0003
14555 Example 1 193E
N-r4-N-r4-Cvclohexyl-1 -ethylthiobutan-2-yl)aminr>methyl-2-(2- methylphenyPbenzoyllmethionine 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- 14560 methylphenyPbenzoyl] methionine methyl ester, prepared as inExample 403G. m/e (ESI) 585 (MH+)
Figure imgf000661_0001
Example 1193F 14565 N-H-N-H-Cvclohexyl- 1 -ethylthiobutan-2-yPaminomethyl-2-('2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExamβie 1 193E. H (300MHz, CDCI3, δ) 7.72 ( IH, m), 7.45 ( IH, m), 7.40-7.00 (5H, m), 6.18 ( IH, m), 4.36 (IH, m), 4.00 (2H, m), 2.95 ( IH, 14570 m), 2.82 ( IH, m), 2.73 (IH, 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, rft). 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
Figure imgf000661_0002
Example 1 194
Figure imgf000661_0003
Example 1194 A 14580 1 -Bromo-4-cvclohexylbutane
The desired compound was prepared according to the method of Example 1 178D starting with 4-cyclohexyl-l -butanol. lH (300MHz, CDCI3, δ) 3.40 (2H, t, J=8Hz), 1.83 (2H, m), 1.80-1.50 (6H, m), 1.42 (2H, m), 1.30-1.10 (5H, m), 0.85 (2H, m).
Figure imgf000662_0001
Example 1194B 4-N-(ButanesulfonyP-N-(4-cyclohexylbutyPaminomethyl-2-(2-methylphenyPbenzoic acid methyl ester The desired compound was prepared using the method described inExample 1174B
14590 starting with the compounds fromExample 119 IC andExample 1194A. m/e (ESI) 514 (MH+)
Figure imgf000662_0002
Example 1194C 14595 4-N-(ButanesulfonyP-N-(4-cyclohexylbutyPaminomethyl-2-('2-methylphenyPbenzoic acid The acid was prepared using the method described in Example 403E starting with the compound from Example 1194B.
Figure imgf000662_0003
14600 Example 1194D N-r4-N-(ButanesulfonyP-N-C4-cvclohexylbutyPaminomethyl-2-(2- methylphenyPbenzoyll methionine methyl ester The compound was prepared using the method described in Example 403F starting with t e compound from Example 1194C. lH (300MHz, CDCI3, δ) 7.96 (IH, m), 7.43
14605 ( IH, dd, J=7&2Hz), 7.40-7.10 (5H, m), 5.90 (IH, bd, J=7Hz), 4.62 (IH, 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).
Figure imgf000663_0001
Example 1194E N- 4-N-(ButanesulfonyP-N-(4-cyclohexylbutyPaminomethyl-2-f2- methylphenyPbenzoy 11 methionine lithium salt The desired compound was prepared according to the method ofExample 4031
14615 starting with the compound fromExample 1194D. iH (300MHz, DMSO-d6, δ) 7.56 ( IH, d, J=8Hz), 7.41 (IH, dd, J=7&2Hz), 7.30-7.05 (5H, m), 6.98 (IH, d, J=7Hz), 4.42 (2H, bs), 3.68 (IH, 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 C34H49LiN2θ5S2-0.75 H2O C 62.79, H 7.83, N 4.31 Found
14620 C 62.69, H 7.84, N 4.24
Figure imgf000663_0002
Example 1195
14625
Figure imgf000664_0001
Example 1195 A N-Butyl-N-quinolin-2-ylamine 2-Chloroquinoline (500 mg, 3.06 mmol), butylamine (0.90 mL, 9.16 mmol), and
14630 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+)
14635
Figure imgf000664_0002
Example 1195B 4-N-Butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenyl)benzoic acid methyl ester The desired compound was prepared according to the method of Example 1174B
14640 starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1178A-D, and the compound from Example 1195A.
Figure imgf000664_0003
Example 1195C 14645 4-N-Butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenvPbenzoic acid
The desired acid was prepared using the method described in Example 403E starting with the product from Example 1195B.
Figure imgf000665_0001
14650 Example 1195D N-[4-N-Butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403F starting with the product fromExample 1195C. m/e (ESI) 570 (MH+)
14655
Figure imgf000665_0002
Example 1195E N- 4-N-Butyl-N-quinolin-2-ylaminomethyl-2-('2-methylphenyl)benzoyl1methionine The desired compound was prepared according to the method ofExample 4031
14660 starting with the compound fromExampie 1 195D. iH (300MHz, CDCI3, δ) 7.95-7.80 (3H, m), 7.72 (IH, m), 7.60-7.40 (2H, m), 7.37 (IH, dd, J=7&2Hz), 7.30-7.00 (5H, m), 6.84 (IH, d, J=9Hz), 6.03 (IH, m), 5.03 (2H, bs), 4.44 (IH, m), 3.62 (2H, m), 2.20-2.00 (5H, m), 1.96 (3H, s), 1.85 (IH, m), 1.65 (2H, m), 1.51 (IH, m), 1.37 (2H, m), 0.93 (3H, t, J=8Hz). m/e (ESI) 554 (MH") Anal.calc. for C33H37N3O3S O.4O H2O C 70.41,
14665 H 6.77, N 7.46 Found C 70.62, H 6.68, N 7.07
Figure imgf000665_0003
Example 1196
Figure imgf000666_0001
Example 1196 A N-r4-(N-(2-piperidin-l-ylethyl)aminomethvP-2-(2-methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403H
14675 starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and l-(2-aminoethyl)piperidine. m/e (ESI) 498 (MH+)
Figure imgf000666_0002
Example 1196B
14680 N-r4-fN-Butyl-N-f2-piperidin-l-ylethvPaminomethvP-2-r2- methylphenyPbenzoyllmethionine 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")
14685
Figure imgf000666_0003
Example 1196C
N-r4-fN-Butyl-N-r2-piperidin-l-ylethvPaminomethyD-2-f2- methy lpheny Pbenzoy 11 methionine 14690 The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1 196B. !H (300MHZ, CDCI3, δ) 7.62 (IH, d, J=8Hz), 7.30-7.10 (5H, m), 7.09 (IH, bs), 6.42 (IH, m), 4.35 ( IH, 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 (5H, m), 1.55 (2H, m), 1.40 (2H, m), 1.22 (2H, m), 0.83 (3H, t, J=8Hz). m/e (ESI) 538 (MH+)
14695 Anal.calc for C31H45N3O3SO.75 H2O C 67.30, H 8.47, N 7.59 Found C 67.21, H 8.39, N 7.52
Figure imgf000667_0001
14700 Example 1197
Figure imgf000667_0002
N-(l-Mo holinocarbonyPbutylamine hydrochloride salt
14705 To a stiπed 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- dimethylaminopropyPcarbodiimide (530 mg, 2.76 mmol). Reaction stiπed ovemight 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
14710 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+)
Figure imgf000668_0001
14715 Example U97B
N-[4-N-((l-MoφholinocarbonvPbutyPaminomethyl-2-("2- methylphenyPbenzoyllmethionine 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
14720 inExample 403G. and the compound prepared inExample 1197A. m/e (ESI) 554 (MH+)
Figure imgf000668_0002
Example 1197C N-r4-N-((l-MorpholinocarbonyPbutyl)aminomethyl-2-(2- 14725 methy lpheny Pbenzoy 11 methionine
The desired compound was prepared using the method described inExample 4031 starting with the compound fromExample 1197B.1H (300MHz, CDCI3, δ) 7.82 (IH, m), 7.43 ( IH, dd, J=7&2Hz), 7.40-7.20 (4H, m), 7.17 (IH, d, J=2Hz), 6.08 (IH, m), 5.97 (IH, m), 4.43 (IH, m), 4.20-3.80 (2H, m), 3.69 (2H, m), 3.60-3.30 (3H, m), 2.20-1.90 14730 (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 O.75 H2O C 65.13, H 7.74, N 7.59 Found C 65.40, H 7.44, N 7.26
Figure imgf000669_0001
Example 1 198
Figure imgf000669_0002
Example 1198 A
14740 N-r4-(N-(2-Moφholin-4-ylethyPaminomethyP-2-(2-methylphenyl)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 4-(2-aminoethyl)moφholine. m/e (ESI) 500 (MH+)
14745
Figure imgf000669_0003
Example 1198B N-r4-N-Butyl-N-r2-moφholin-4-ylethvPaminomethyl-2-(2- methylphenyPbenzoyllmethionine methyl ester
14750 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")
Figure imgf000670_0001
14755 Example 1198C
N-[4-N-Butyl-N-(2-moφholin-4-ylethyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1198B. H (300MHz, CDCI3, δ) 7.71 (IH, d, 14760 J=9Hz), 7.43 (IH, bd, J=8Hz), 7.30-7.10 (5H, m), 6.25 (IH, m), 4.39 ( IH, 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 (IH, m), 1.50 (2H, m), 1.27 (2H, m), 0.88 (3H, t, J=8Hz). m/e (ESI) 540 (MH+) Anal.calc. for C30H43N3O4SO.5O H2O C 65.42, H 8.05, N 7.63 Found C 65.22, H 7.92, N 7.47
14765
Figure imgf000670_0002
Example 1199
Figure imgf000670_0003
14770 Example 1199 A
N- 4-(N-(Fluoren-9-yl)aminomethyl)-2-(2-methylphenyPbenzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403H starting with N-[4-formyl-2-(2-methylρhenyl)benzoyl]methionine methyl ester, prepared as inExample 403G, and 9-aminofluorene hydrochloride salt m/e (ESI) 551 (MH+)
14775
Figure imgf000671_0001
Example 1 199B N- 4-N-Butyl-N-(fluoren-9-yl)aminomethyl-2-(2-methylphenyPbenzoyllmethionine methyl ester
14780 The desired compound was prepared using the method described inExample 403H starting with the compound prepared inExample 1199 A and butyraldehyde. m/e (ESI) 605 (MH")
Figure imgf000671_0002
14785 Example 1199C
N-f4-N-Butyl-N-(fluoren-9-yPaminomethyl-2-(2-methylphenyPbenzoyl1methionine The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1 199B. H (300MHz, CDCI3, δ) 7.91 (IH, m), 7.67 (3H, m), 7.47 ( IH, bd, J=8Hz), 7.40-7.10 ( 10H, m), 5.84 ( IH, m), 5.00 ( IH, bs), 14790 4.52 ( IH, m), 3.53 (2H, bs), 2.64 (2H, m), 2.20- 1.95 (8H, m), 1.90 (IH, m), 1.52 (3H, m), 1.32 (2H, m), 0.83 (3H, bt, J=8Hz). m/e (ESI) 591 (MH') Anal.calc. for C37H40N2O3SO.5O H2O C 73.85, H 6.87, N 4.65 Found C 74.07, H 6.70, N 4.63
Figure imgf000672_0001
Example 1200
Figure imgf000672_0002
14800 Example 1200 A
N-(2-Cyclohexylethyl)-N-(furan-2-ylmethyPamine The desired amine was prepared using the method described inExample 1 171 A starting with cyclohexylethylamine and 2-furoic acid, m/e (DCI/NH3) 208 (MH+)
Figure imgf000672_0003
Example 1200B N-14-N-(2-CyclohexylethyP-N-(furan-2-ylmethyPaminomethyl-2-(2- methylphenyPbenzoy 11 methionine methyl ester The desired compound was prepared using the method described inExample 403H
14810 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 1200 A. m/e (ESI) 577 (MH+)
Figure imgf000673_0001
14815 Example 1200C N44-N-(2-Cyclohexylethyl -N-(furan-2-ylmethyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine The desired compound was prepared according to the method ofExample 4031 starting with the compound inExample 1200B. iH (300MHz, CDCI3, δ) 7.81 (IH, d,
14820 J=8Hz), 7.56 (IH, m), 7.42 (IH, d, J=2Hz), 7.30-7.10 (5H, m), 6.37 (2H, bs), 6.15 (IH, d, J=8Hz), 4.45 (IH, m), 4.10-3.80 (4H, m), 2.67 (2H, m), 2.20-2.05 (5H, m), 2.00 (3H, s), 1.90 (IH, m), 1.80-1.40 (8H, m), 1.30-1.00 (4H, m), 0.88 (2H, πp. 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
14825
Figure imgf000673_0002
Example 1201
Figure imgf000673_0003
Example 1201 A N-r4-(N-(2-Pyπolidin-l-ylethyl)aminomethyP-2-(2-methylphenyl)benzoyllmethionine methyl ester The desired compound was prepared using the method described inExample 403H 14835 starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as inExample 403G. and l-(2-aminoethyl)pyπolidine. m/e (ESI) 484 (MH+)
Figure imgf000674_0001
Example 1201B 14840 N-[4-N-Butyl-N-(2-pyπolidin- 1 -ylethyl)aminomethyl-2-(2- methylphenyPbenzoyll 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+)
14845
Figure imgf000674_0002
Example 1201C N-H-N-Butyl-N-f 2-pyrtolidin- 1 -ylethyPaminomethyl-2-f 2- methylphenyPbenzoyllmethionine 14850 The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1201B. H (300MHz, CDCI3, δ) 7.66 (IH, d, J=8Hz), 7.35-7.10 (5H, m), 7.09 (IH, bs), 6.37 (IH, m), 4.36 (IH, 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 (IH, m), 1.41 (2H, m), 1.23 (2H, m), 0.85 (3H, t, J=8Hz). m/e (ESI) 524 (MH+) 14855 Anal.calc for C30H43N3O3S I.OO H2O C 66.27, H 8.34, N 7.73 Found C 65.92, H 8.29, N 7.59
Figure imgf000675_0001
14860 Example 1202
Figure imgf000675_0002
Example 1202 A 5-Thiazolecarboxaldehyde 14865 The desired compound was prepared according to the method of Example 403G starting with 5-hydroxymethylthiazole. *H (300MHz, CDCI3, δ) 10.13 ( IH, s), 9.12 ( IH, s), 8.54 ( IH, s).
Figure imgf000675_0003
14870 Example 1202B
N-(2-ButylphenyP-N-(thiazol-5-ylmethyPamine The desired compound was prepared according to the method ofExample 403H starting with 2-butylaniline and the aldehyde fromExample 1202A. m/e (DCI) 247 (MH+)
e
Figure imgf000675_0004
Example 1202C 4-N-(2-Butylphenyl)-N-(thiazol-5-ylmethyPaminomethyl-2-(2-methylphenyPbenzoic acid methyl ester The desired compound was prepared according to the method of Example 1 174B 14880 starting with 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 1 178A-D, and the compound from Example 1202B.
Figure imgf000676_0001
Example 1202D 14885 4-N-(2-ButylphenyP-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-methylphenyl)benzoic acid The desired acid was prepared using the method described in Example 403E starting with the product from Example 1202C.
Figure imgf000676_0002
14890 Example 1202E
N-["4-N-(2-Butylphenyl -N-(thiazol-5-ylmethyl)aminomethyl-2-(2- methylphenyPbenzoy 11 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")
14895
Figure imgf000676_0003
Example 1202F
N-r4-N-(2-ButylphenyP-N-(thiazol-5-ylmethvPaminomethyl-2-(2- methylpheny Pbenzoyll methionine 14900 The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1202E. iH (300MHz, CDCI3, δ) 8.73 ( IH, s), 7.91 (IH, bt, J=8Hz), 7.66 (IH, bs), 7.40-7.15 (5H, m), 7.15-6.90 (5H, bs), 5.88 ( IH, d, J=8Hz), 4.57 (IH, 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")
14905 Anal.calc. for C34H39N3O3S2 C 67.86, H 6.53, N 6.98 Found C 67.57, H 6.43, N 6.71
Figure imgf000677_0001
Example 1203
14910
Figure imgf000677_0002
Example 1203 A N-l"4-NA2-Ethylthio)- 1.3.4-thiadiazol-5-vPaminomethyl-2-(2- methylphenyPbenzoyllmethionine ethyl ester 14915 2-Amino-5-(ethylthio)-l,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 ovemight. 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 14920 residue in EtOH (8 mL) at 0°C under N2 was added sodium borohydride (98 mg, 2.60 mmol), and mixture stiπed 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, 25%). 14925 m/e (ESI) 543 (MH")
Figure imgf000678_0001
Example 1203B N44-N-f (2-Ethylthio 1 ■3.4-thiadiazol-5-yl)aminomethyl-2-(2- 14930 methylphenyPbenzoy 11 methionine
The desired compound was prepared according to the method ofExample 4031 starting with the compound fromExample 1203A. iH (300MHz, CDCI3, δ) 7.88 (IH, m), 7.46 (IH, m), 7.30-7.00 (5H, m), 5.94 (2H, m), 4.58 (IH, m), 4.42 (2H, bd, J=8Hz), 3.13 (2H, q, J=8Hz), 2.20-1.80 (9H, m), 1.67 (IH, m), 1.39 (3H, t, J=8Hz). m/e (ESI) 14935 515 (MH") Anal.calc. for C24H28N4O3S3O.5O H2O C 54.83, H 5.56, N 10.66 Found C 54.86, H 5.41, N 11.04
Figure imgf000678_0002
14940 Example 1204
Figure imgf000678_0003
Example 1204 A N-r4-N-Butyl-N-r(2-ethylthioV 1.3.4-thiadiazol-5-vnaminomethyl-2-(2- 14945 methylphenyPhenzoyllmethionine methyl 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+)
Figure imgf000679_0001
Example 1204B
N-r4-N-Butyl-N-((2-ethylthio)-1.3.4-thiadiazol-5-yPaminomethyl-2-(2- methy lpheny Pbenzoy 11 methionine The desired compound was prepared according to the method ofExample 4031 14955 starting with the compound fromExample 1204A.iH (300MHz, CDCI3, δ) 7.81 (IH, m), 7.43 (IH, bd, J=8Hz), 7.30-7.10 (5H, m), 6.00 (IH, d, J=8Hz), 5.38 (2H, m), 4.48 (IH, m), 3.17 (2H, m), 3.02 (2H, q, J=8Hz), 2.20-1.80 (9H, m), 1.60 (3H, m), 1.32 (5H, t, J=8Hz), 0.88 (3H, t, J=8Hz). m/e (ESI) 571 (MH") Anal.calc. for C28H36N4O3S3O.50 H2O C 57.80, H 6.41, N 9.63 Found C 57.79, H 6.11, N 9.52 14960
Figure imgf000679_0002
Example 1216 N- 4-(N-Butyl-N-(2-phenylethyl)aminomethyP-2-(2-methylphenyPbenzoyl]methionine p- 14965 tolylsulfonimide hydrochloride salt
Figure imgf000680_0001
Example 1216A N-(tert-ButoxycarbonvP-methionine p-tolylsulfonimide 14970 N-(tert-Butoxycarbonyl)-methionine (960 mg, 3.85 mmol) was dissolved in
CH C12 (50 mL), then added EDCI*HC1 (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 ovemight, concentrated, dissolved in EtOAc (130 mL), then washed with water, 2N HCl, water, and brine. After drying over Na2SO4, filtration, and concentration, the compound 14975 was purified by chromatography using 1/1 hex/ EtOAc, then EtOAc. Recovered 635 mg (41%). MS (APCI) 403 (M+H)+.
Figure imgf000680_0002
Example 1216B 14980 Methionine p-tolylsulfonimide hydrochloride salt
The compound described in Example 1216A (610 mg, 1.52 mmol) was dissolved in 4N HCl in dioxane (10 mL), stiπed at RT for 45 min., then diluted with Et2θ. The resultant solids were filtered off, and washed with Et2θ to give 465 mg (90%) white solids. MS (DCI/NH3) 303 (M+H)+. 14985
Figure imgf000680_0003
Example 1216C N-Butyl-2-phenylethylamine 2-Phenethylamine (12.5 mL, 12.1 g, 99.5 mmol), butyraldehyde (13.2 mL, 10.8 g, 14990 150 mmol), and 3 A molecular sieves were stiπed at 50 °C for 1 h, then at RT for 5.5 h.
The reaction was then diluted with CH2CI2, 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 stiπed at RT overnight, concentrated, partitioned between water and Et2θ, then the organic layer was washed with 14995 water and brine. After drying over Na2SO4, 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%). X NMR (CDCI3) δ 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, IH), 0.88 (t, 3H).
Figure imgf000681_0001
Example 1216D 4-(N-Butyl-N-(2-phenylethyl)aminomethyP-2-(2-methylphenyPbenzoic acid methyl ester The title compound was prepared from the compound described in Example 1216C and the bromide described in Example 1178D using the method of Example 1 178G. MS
15005 (APCI) 416 (M+H)+.
Figure imgf000681_0002
Example 1216E 4-(N-Butyl-N-(2-phenylethyPaminomethyl)-2-(2-methylphenyl)benzoic acid
15010 The title compound was prepared from the compound described in Example 1216D using the method of Example 1178H. MS (ESI) 402 (M+H)+.
Figure imgf000681_0003
Example 1216F 15015 N-[4-(N-Butyl-N-r2-phenylethvπaminomethyl)-2-(2-methylphenvπbenzoyllmethionine p- rolylsulfonimide 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
15020 98/2/0.5 CHCl3/MeOH/CH3CO2H. X NMR (CDCI3) δ 7.85 (m, 4H),7.26 (m, 12H), 6.47 (m, IH), 4.60 (m, IH), 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 C39H48CIN3O4S2 : 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.
15025
Figure imgf000682_0001
Example 1217 N- 4-(N-Butyl-N-(2-phenylethyPaminomethyl)-2-(2-methylphenyPbenzoyl1methionine 4- 15030 (aminomethyPphenylsulfonimide dihydrochloride salt
Figure imgf000682_0002
Example 1217 A 4-[(tert-ButoxycarbonyPaminomethyllphenylsulfonamide 15035 4-(Aminomethyl)phenylsulfonamide hydrochloride salt hemihydrate (1.0 g, 4.3 mmol) was dissolved in CH2CI2 (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 ovemight, 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. 15040 After filtration and concentration recovered 1.3 g tacky white solids. MS (DCI/NH3) 304 (M+H+NH3)+.
Figure imgf000683_0001
Example 1217B 15045 N-(9-FluorenylmethoxycarbonyP-methionine 4-r(tert-butoxycarbonyl)aminomethyll 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)". 15050
Figure imgf000683_0002
Example 1217C N-r4-(N-Butyl-N-(2-phenylethyPaminomethyP-2-(2-methylphenyl)benzoynmethionine 4- [(tert-butoxycarbonyPaminomethyllphenylsulfonimide 15055 The compound described in Example 1217B was treated with piperidine in CH2CI2 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)+.
Figure imgf000683_0003
Example 1217D
N-[4-('N-Butyl-N-(2-phenylethyPaminomethvP-2-(2-methylphenyPbenzoyllmethionine 4-
(aminomethyPphenylsulfonimide dihydrochloride salt Starting with the compound described in Example 1217C, the title compound was 15065 prepared by the method of Example HlόB.Η NMR (CD3OD) δ 8.05 (d, 2H), 7.66 (m, 4H), 7.45 (br s, IH), 7.25 (m, 10H), 4.53 (d, 2H), 4.25 (m, IH), 4.24 (s, 2H), 3.33 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 2.10 (m, 5H), 1.97 (s, 3H), 1.80 (m, 3H), 1.60 (m, IH), 1.40 (m, 2H), 0.98 (t, 3H). MS (ESI) 699 (M-H)". Anal calcd for C39H50C12N4O4S2- 1.50 H2O : C, 68.49; H, 6.67; N, 7.00. Found: C, 58.41 ; H, 15070 6.61 ; N, 6.70.
Figure imgf000684_0001
Example 1218 15075 N-r4-(N-Butyl-N-f2-phenylethyPaminomethyP-2-(2-methylphenyPbenzoyllmethionine isopropylsulfonimide
Figure imgf000684_0002
Example 1218A 15080 N-(tert-ButoxycarbonyP-methionine isopropylsulfonimide
The title compound was prepared by the method of Example 1216A using isopropylsulfomamide. MS (DCI/NH3) 372 (M+H+NH3)+.
Figure imgf000684_0003
15085 Example 1218B
Methionine isopropylsulfonimide hydrochloride salt Starting with the compound described in Example 1218A,the 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)+.
15090
Figure imgf000685_0001
Example 1218C N-[4-(N-Butyl-N-(2-phenylethyPaminomethyP-2-("2-methylphenyl)benzoyllmethionine isopropylsulfonimide 15095 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/CH3C02H. X NMR (CDCI3) δ 7.91 (m, IH), 7.43 (d, IH), 7.32 (m, 3H), 7.18 (m, 7H), 5.83 (d, IH), 4.43 (m, IH), 3.77 (s, 2H), 3.65 (m, IH), 2.80 (br 15100 s, 4H), 2.59 (m, 2H), 2.15, 2.02 (both m, total 8H), 1.82 (m, IH), 1.50, 1.38, 1.28 (all m, total 1 IH), 0.86 (t, 3H). MS (ESI) 636 (M-H)". Anal calcd for C35H47N3O4S2: C, 65.90; H, 7.43 N, 6.59. Found: C, 66.01; H, 7.36; N, 6.30.
Figure imgf000685_0002
Example 1227
N-[4-N-(N-phenyl-N-(4-fluorobenzoyl)aminomethyl)-2-(,2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000686_0001
Example 1227 A N-H-N-fN-phenyl-N-(4-fluorobenzoyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester A mixture of 4-fluorobenzoyl chloride (0.053 g, 0.33 mmol), 1236C (0.103 g, 0.22
151 15 mmol), and 0.2 ml of pyridine in 5 ml of CH2C12 was stiπed 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 EtOAGΗexane afforded 0.13 g of the title compound (99%). NMR(CDC13) 7.84-7.94 (m, IH); 7.38-7.48 (m, IH); 7.05-7.38 (m, 10H); 5.85-5.92 (m, IH); 5.10-5.27 (m, 2H); 4.56-4.67 (m, IH); 3.62 (s, 3H); 1.95-2.20 (m, 8H); 1.7-2.0 (m,
15120 IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 585(M+H)+ ; 604 (M+NH4)+.
Figure imgf000686_0002
Example 1227B N-r4-N-(N-phenyl-N-f4-fluorobenzoyl)aminomethyP-2-(2- 15125 methylphenyPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1178J from 1227 A. NMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.3-7.5 (3H, m); 6.9-7.3 (14H, m); 5.18-5.38(2H, m); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 569(M-Lp.
15130
Figure imgf000687_0001
Example 1228
N-[4-N-(N-phenyl-N-(n-butanesulfonyl)aminomethyl)-2-(2- methylphenyPbenzoy 11 methionine lithium salt
15135
Figure imgf000687_0002
Example 1228 A
N-r4-N-(N-phenyl-N-(n-butanesulfonyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester
15140 Prepared to the procedure of example 1229A from the reaction between 1236C and butanesulfonyl chloride. NMR(CDC13) 7.80-7.90 (m, IH); 7.12-7.38 (m, 10H); 7.05-7.1 1
(m, IH); 5.8-5.9 (m, IH); 4.78 (s, 2H); 4.5-4.65 (m, IH); 3.62 (s, 3H); 3.0-3.08 (m,
2H); 1.5-2.15 (m, HH); 0.92-0.98 (m, 3H). (DSI/NH3)/MS: 583(M+H)+; 600(M+NH4)+.
Figure imgf000687_0003
Example 1228B N-r4-N-(N-phenyl-N-(n-butanesulfonvPaminomethyP-2-(2- methylphenyPbenzoy 11 methionine lithium salt Prepared according to the procedure of example 1178J from 1228A. NMR 15150 lH(MeOH-d4): 7.5-7.62 (IH, m); 7.1-7.4 (12H, m); 4.95 (2H, s); 4.1-4.22 (IH, 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-Lp.
Figure imgf000688_0001
15155 Example 1229
N-r4-N-(N-phenyl-N-(3-nitrobenzenesulfonyPaminomethyl)-2-(2- methylphenyPbenzoyl]methionine lithium salt
Figure imgf000688_0002
15160 Example 1229 A
N-[4-N-(N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyP-2-f2- methylphenyPbenzoyllmethionine. methyl ester A mixture of 3-nitrophenylsulfonyl chloride (0.076 g, 0.34 mmol), 1236C (0.106 g, 0.23 mmol), and 0.2 ml of pyridine in 3 ml of CH2C12 was stiπed for 12 hours. The 15165 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(CDC13) 8.56 (m, IH); 8.40-8.48 (m, IH); 7.9-7.95 (m, IH); 7.8- 7.91 (m, IH); 7.68-7.76 (m, IH); 7.10-7.35 (m, 8H); 7.05 (m, IH); 6.95-7.01 (m, 2H); 5.8-5.9 (m, IH); 4.81 (s, 2H); 4.5-4.65 (m, IH); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 15170 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 648(M+H)+; 665(M+NH4)+.
Example 1229B N-14-N-(N-phenyl-N-('3-nitrobenzenesulfonyl)aminomethyP-2-(2- 15175 methylphenvPbenzoyll methionine lithium salt
Prepared according to the procedure of example 1178J from 1229A. NMR lH(MeOH-d4): 8.35-8.45 (2H, m); 7.78-7.85 (2H, m), 7.5-7.6 ( IH, m); 7.3-7.4 ( IH, m); 7.1-7.3 (8H, m); 6.95-7.15 (3H, m); 4.9 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 ( 10H, πp. ESI(-)/MS: 632(M-Lp.
15180
Figure imgf000689_0001
Example 1230 N-r4-N-(N-phenyl-N-(4-fluorobenzenesulfonyl)aminomethyP-2-(2- 15185 methylphenyPbenzoy 11 methionine lithium salt
Figure imgf000689_0002
Example 1230A N-f4-N-(N-phenyl-N-f4-fluorobenzenesulfonyl)aminomethyP-2-(2- 15190 methylphenyPbenzoyllmethionine. methyl ester
Prepared according to the procedure of example 1229 A from reaction between 1236C and 4-fluorophenylsulfonyl chloride. NMR(CDC13) 7.78-7.82 (m, IH); 7.58-7.68 (m, 2H); 7.25-7.32 (m, 10H); 7.08 (m, IH); 6.95-7.01 (m, 2H); 5.8-5.9 (m, IH); 4.79 (s, 2H); 4.5-4.65 (m, IH); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, 15195 IH). (DSI/NH3)/MS: 621(M+NH4)+; 638(M+NH4)+.
Figure imgf000690_0001
Example 1230B N-[4-N-(N-phenyl-N-(,4-fluorobenzenesulfonyl)aminomethvP-2-(2- 15200 methylphenyPbenzoy 11 methionine lithium salt
Prepared according to the procedure of example 1178J from 1230A. NMR iH(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 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 605(M-Li).
15205
Figure imgf000690_0002
Example 1231
N- 4-N-(N-phenyl-N-(4-ethylbenzenesulfonyPaminomethyP-2-f2- me thy lphenyPbenzoy 11 methionine lithium salt
15210
Figure imgf000690_0003
Example 1231 A N-r4-N-(N-phenyl-N-(4-ethylbenzenesulfonyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester 15215 Prepared according to the procedure of example 1229 A from reaction between
1236C and 4-ethylphenylsulfonyl chloride. NMR(CDC13) 7.78-7.82 (m, IH); 7.55-7.60 (m, 2H); 7.25-7.32 (m, 10H); 7.08 (m, IH); 6.95-7.01 (m, 2H); 5.8-5.9 (m, IH); 4.76 (s, 2H); 4.5-4.65 (m, IH); 3.62 (s, 3H); 2.7-2.78(m, 2H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH); 1.2- 1.35(m, 3H). (DSI/NH3)/MS: 631(M+H)+; 648(M+NH4)+.
15220
Figure imgf000691_0001
Example 1231
N-r4-N-(N-phenyl-N-(4-ethylbenzenesulfonyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
15225 Prepared according to the procedure of example 1178J from 1231 A. NMR iH(MeOH-d4): 7.5-7.6 (3H, m); 7.1-7.4 (9H, m); 6.95-7.1 (3H, ); 4.9 (2H, s); 4.1-
4.22 ( IH, m); 2.7 (2H, q) 1.7-2.1 (10H, m) (IH, m); 1.25 (3H, t). ESI(-)/MS: 615(M-Lp.
Figure imgf000691_0002
Example 1232
N-r4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)armnomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000691_0003
Example 1232 A
N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1229 A from reaction between 15240 1236C and 4-nitrophenylsulfonyl chloride. NMR(CDC13) 8.56 (m, IH); 8.40-8.48 (m, IH); 7.9-7.95 (m, IH); 7.8-7.91 (m, IH); 7.68-7.76 (m, IH); 7.10-7.35 (m, 8H); 7.05 (m, IH); 6.95-7.01 (m, 2H); 5.8-5.9 (m, IH); 4.81 (s, 2H); 4.5-4.65 (m, IH); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 648(M+H)+; 665(M+NH4)+.
15245
Figure imgf000692_0001
Example 1232B N-r4-N-(N-phenyl-N-(4-nitrobenzenesulfonyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt 15250 Prepared according to the procedure of example 1178J from 1232 A- NMR iH(MeOH-d4): 8.45-8.55 (IH, m); 8.35-8.38 (IH, m); 8.0-8.1 (IH, m); 7.8-7.9 (IH, m); 7.5-7.7 (IH, m); 7.3-7.4 (IH, m); 7.1-7.3 (8H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 632(M-Li).
15255
Figure imgf000692_0002
Example 1233
N-r4-N-(N-phenyl-N-(2.3-dichlorobenzenesulfonyl)aminomethyP-2-(2- methylphenyPbenzoyll methionine lithium salt
15260
Figure imgf000693_0001
Example 1233 A N-r4-N-(N-phenyl-N-f2.3-dichlorobenzenesulfonyl)aminomethyP-2-(2- methylphenyPbenzoyll methionine. methyl ester
15265 Prepared according to the procedure of example 1229A from reaction between 1236C and 3,4-dichlorophenylsulfonyl chloride. NMR(CDC13) 7.6-7.7 (m, IH); 7.5-7.55 (m, IH); 7.55-7.6 (m, IH); 7.40-7.43 (m, IH); 7.15-7.36 (m, 8H); 7.08 (m, IH); 6.95- 7.01 (m, 2H); 5.8-5.9 (m, IH); 4.78 (s, 2H); 4.5-4.65 (m, IH); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 671(M+NH4)+.
15270
Figure imgf000693_0002
Example 1233B
N-[4-N-('N-phenyl-N-f2.3-dichlorobenzenesulfonyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
15275 Prepared according to the procedure of example 1178J from 1233A. NMR H(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 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 655(M-Lp.
Figure imgf000693_0003
Example 1234
N-[4-N-(N-3.4-rm ihylenedioxy)phenvi-N-(4-fluorobenzvPaminomethvP-2-(2- methylphenvPbenzoyllmethionine lithium salt.
Figure imgf000694_0001
Example 1234 A Prepared according to the procedure of example 1236A. Instead of using aniline, 3,4-(methylenedioxy)aniline was used to make the title compound. NMR(CDCp) 7.90-7.96 (m, IH); 7.38-7.42 (m, IH); 7.18-7.30 (m, 4H); 7.00-7.18 (m, IH); 6.80-6.83 (m, IH);
15290 6.22-6.26 (m, IH); 6.00-6.08 (m, IH); 5.82 (s, m); 4.32-4.39 (m, 2H); 3.95-4.00 (m, IH); 3.60 (s, 3H); 2.05 (s, 3H). (DSI/NH3)/MS: 376(M+H)+; 373(M+NH4)+.
Figure imgf000694_0002
Example 1234B 15295 Prepared according to the procedure of example 1178H from 1234A. NMR(CDC13)
7.90-7.96 (m, IH); 7.38-7.42 (m, IH); 7.18-7.30 (m, 4H); 7.00-7.18 (m, IH); 6.80-6.83 (m, IH); 6.22-6.26 (m, IH); 6.00-6.08 (m, IH); 5.82 (s, 2H); 4.32-4.39 (m, 2H); 3.95- 4.00 (m, IH); 2.05 (s, 3H). (DSI/NH3)/MS: 362(M+H)+; 351(M+NH4)+.
Figure imgf000695_0001
Example 1234C Prepared according to the procedure of example 1 1781 from 1234B. NMR(CDC13) 7.85-7.95 (m, IH); 7.18-7.30 (m, 6H); 7.00-7.18 (m, IH); 6.6-6.65 (m, IH); 6.35-6.40 (m, IH); 6.10-6.20 (m, IH); 5.82 (m, 3H); 4.5-4.70 (m, 3H); 3.61 (s, 3H); 2.0-2.15 (m,
15305 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 507(M+H)+; 324(M+NH4)+.
Figure imgf000695_0002
Example 1234D N-f4-N-(N-(3.4-methylenedioxy phenyl-N-(4-fluorobenzyPaminomethyl)-2-(2- 15310 methylphenyPbenzoyllmethionine. methyl ester
Prepared according to the procedure of example 1236A from reaction between 1235C and benzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.18-7.30 (m, 10H); 7.02- 7.18 (m, IH); 6.6-6.65 (m, IH); 6.35-6.40 (m, IH); 6.15-6.20 (m, IH); 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, IH); 1.5- 15315 1.7 (m, IH). (DSI/NH3)/MS: 597(M+H)+.
Figure imgf000695_0003
Example 1234E N-r4-N-(N-3.4-(methylenedioxy phenyl-N-(4-fluorobenzyPaminomethyl)-2-(2-
15320 methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1178J from 1234D. NMR lH(MeOH-d4): 7.5-7.6 (IH, m); 7.2-7.25 (IH, m); 7.0-7.2 (9H, m); 6.9-7.0 (2H, m); 6.5-6.57 ( IH, m); 6.3 (IH, m); 6.1 (IH, m); 5.75 (2H, s); 4.45 (2H, s); 4.4 (2H, s); 4.1- 4.2 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 581(M-Lp.
15325
Figure imgf000696_0001
Example 1235
N-[4-N-(N-3.4-(methylenedioxy phenyl-N-(4-fluorobenzyl)aminomethyl)-2-(2-
15330 me thy lphenyPbenzoy 11 methionine lithium salt
Figure imgf000696_0002
Example 1235 A N-r4-N-(N-3.4-(methylenedioxy phenyl-N-(4-fluorobenzyPaminomethyP-2-(2- 15335 methylphenyPbenzoyllmethionine. 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, IH); 7.18-7.61 (m, 7H); 6.92-7.18 (m, 3H); 6.6-6.65 (m, IH); 6.35-6.40 (m, IH); 6.15-6.20 (m, IH); 5.82 (m, 3H); 4.57-4.65 (m, IH); 4.53 (s, 2H); 4.50 (s, 2H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7- 15340 2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 6H(M+H)+.
Figure imgf000697_0001
Example 1235B N-r4-N-(N-3.4-(methylenedioxy)phenyl-N-(4-fluorobenzyPaminomethyP-2-(2-
15345 me thy lphenyPbenzoyll methionine lithium salt Prepared according to the procedure of example 1178J from 1235A. NMR iH(MeOH-d4): 7.5-7.6 (IH, m); 7.2-7.25 (IH, m); 7.0-7.2 (8H, m); 6.9-7.0 (2H, m); 6.5-6.57 (IH, m); 6.3 (IH, m); 6.1 (IH, m); 5.75 (2H, s); 4.45 (2H, s); 4.4 (2H, s); 4.1- 4.2 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 599(M-Lp.
15350
Figure imgf000697_0002
Example 1236
N-[4-N-(N-phenyl-N-(2-fluorobenzyPaminomethyP-2-(2-
15355 methylphenyPbenzoyllmethionine lithium salt
Figure imgf000697_0003
Example 1236A 4-(N-phenyPaminomethyl-2-(2-methylphenyPbenzoic acid, methyl ester
15360 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 15365 gel eluting with 80:20 EtOAc/Hexane afforded 6.1 g of pure product(96%). NMR(CDC13) 7.85-7.95 (m, IH); 7.40-7.45 (m, IH); 7.0-7.36 (m, 7H); 6.68-6.78 (m, IH); 6.58-6.65 (m, 2H); 4.2 (s, 2H); 4.05-4.2 ( , IH); 3.58 (s, 3H); 2.05 (s, 3H). (DSI/NH3)/MS: 332(M+H)+ , 349(M+NH4)+.
Figure imgf000698_0001
Example 1236B
4-(N-phenyPaminomethyl-2-(2-methylphenyl)benzoic acid
Prepared according to the procedure of example 1178H from 1236A. NMR(CDC13)
7.85-7.95 (m, IH); 7.40-7.45 (m, IH); 7.0-7.36 (m, 7H); 6.68-6.78 (m, IH); 6.58-6.65
15375 (m, 2H); 4.2 (s, 2H); 4.05-4.2 (m, IH); 2.05 (s, 3H). (DSI/NH3)/MS: 318(M+H)+ ,
335(M+NH4)+.
Figure imgf000698_0002
Example 1236C 15380 N-4-r("N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine. methyl ester
Prepared according to the procedure of example 11781 from 1236B. NMR(CDC13) 7.85-7.95 (m, IH); 7.41-7.47 (m, IH); 7.1-7.36 (m, 7H); 6.68-6.78 (m, IH); 6.58-6.65 (m, 2H); 5.85-5.95 (m, IH); 4.56-4.68 (m, IH); 4.2 (s, 2H); 4.05-4.2 (m, IH); 3.62 (s, 3H); 2.05 (s, 3H); 2.0-2.15 (m, 8H), 1.7-2.0 (m, IH), 1.5-1.7 (m, IH).. (DSI/NH3)/MS: 15385 463(M+H)+ , 480(M+NH4)+.
Figure imgf000699_0001
Example 1236D N-r4-N-(N-phenyl-N-(2-fluorobenzyl)aminomethyP-2-(2-
15390 methylphenvPbenzoyllmethionine. methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 2- fluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.0-7.4 (m, 12H); 6.65-6.78 (m, 3H); 5.8-5.9 (m, IH); 4.75 (m, 4H); 4.58-4.65 (m, IH); 3.65 (s, 3H), 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). MS/(DSI/NH3 ): 571(M+H)+.
15395
Figure imgf000699_0002
Example 1236E
N-r4-N-(N-phenyl-N-(2-fluorobenzyDaminomethyP-2-(2- methylphenvPbenzoyllmethionine lithium salt
15400 Prepared according to the procedure of example 1 178J for making lithium salt.
NMR lH(MeOH-d4): 7.6-7.7 (IH, d); 7.3-7.4 (IH, 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 (IH, m); 1.5-2.2 (10H, m). ESI(-) MS: 555(M-Li).
Figure imgf000699_0003
Example 1237 N-r4-N-rN-phenyl-N-f3-fluorobenzyPaminomethyP-2-(2- methylphenvDbenzoyllmethionine lithium salt
Figure imgf000700_0001
Example 1237 A N-14-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyP-2-(2- methylphenyPbenzoyll methionine. methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 3- 15415 fluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 6.9-7.4 (m, 12H); 6.75-6.8 (m, 3H); 5.8-5.9 (m, IH); 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, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 571(M+H)+ .
Figure imgf000700_0002
15420 Example 1237B
N-r4-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1237 A. NMR iH(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, 15425 m); 4.18-4.3 (IH, m); 1.6-2.2 (10H, m). ESI(-)/MS: 555(M-Lp.
Figure imgf000701_0001
Example 1238
15430 N-[4-N-fN-phenyl-N-(4-fluorobenzyl)aminomethyP-2-(2- methylphenyPbenzoy 11 methionine lithium salt
Figure imgf000701_0002
Example 1238 A 15435 N-r4-N-(N-phenyl-N-f4-fluorobenzvPaminomethyP-2-('2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of 1236A from reaction between 1236C and 4- fluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.15-7.4 (m, 9H); 6.95-7.15 (m, 3H); 6.7-6.8 (m, 3H); 5.8-5.9 (m, IH); 4.70 (s, 2H); 4.58-4.65 (m, 3H); 3.62 (s, 3H); 15440 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 571(M+H)+ .
Figure imgf000701_0003
Example 1238B N-[4-N-(N-phenyl-N-H-fluorobenzyPaminomethyP-2-(2- 15445 methylphenyPbenzoy 11 methionine lithium salt
Prepared according to the procedure of example 1178J from 1238A. NMR ^(MeOH^): 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 (IH, m); 1.6-2.2 (10H, m). ESI(-)/MS: 555(M-Lp. 15450
Figure imgf000702_0001
Example 1239
N-r4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
15455
Figure imgf000702_0002
Example 1239A N-r4-N-(N-phenyl-N-(4-bromobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester
15460 Prepared according to the procedure of example 1236 A from reaction between 1236C and 4-bormobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.05-7.48 (m, 12H); 6.65-6.78 (m, 3H); 5.8-5.9 (m, IH); 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, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 631(M+H)+ .
Figure imgf000702_0003
Example 1239B
N-[4-N-(N-phenyl-N-(4-bromobenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1239A. NMR 15470 lH(MeOH-d4): 7.58-7.67 (IH, d); 7.38-7.46 (2H, d); 7.3-7.39 (H, d); 7.0-7.3 ( 1 1H, m); 6.6-6.8 (3H, m); 4.75 (2H, s); 4.65 (2H, s); 4.18-4.3 (IH, m); 1.5-2.2 (10H, m). ESK- )/MS:' 615(M-Li), 573.
Figure imgf000703_0001
Example 1240
N-r4-N-(N-phenyl-N-(4-cyanobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000703_0002
Example 1240A
N-r4-N-fN-phenyl-N-(4-cyanobenzyPaminomethyP-2-(2- methylphenyPbenzoyll methionine. methyl ester
Prepared according to the procedure of example 1236A from reaction between
15485 1236C and 4-cyanobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.58-7.65 (m, 2H);
7.1-7.4 (m, 10H); 6.65-6.80 (m, 3H); 5.8-5.9 (m, IH); 4.65 (m, 4H); 4.58-4.64 (m, IH);
3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS:
578(M+H)+ .
Figure imgf000704_0001
Example 1240B N-r4-N-(N-phenyl-N-(4-cyanobenzyl)aminomethyP-2-(2- methylphenvPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1240A. NMR
15495 H(MeOH-d4): 7.6-7.7 (3H, m); 7.4-7.5 (2H, m); 7.35-7.4 (IH, m); 7.02-7.3 (10H, m); 6.6-6.7 (3H, m) 4.9 (2H, s); 4.75 (2H, s); 4.18-4.3 (IH, m); 1.5-2.2 ( 10H, m). ESI(- )/MS: 562(M-Lp.
Figure imgf000704_0002
Example 1241
N- 4-N-(N-phenyl-N-(4-methoxybenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000704_0003
Example 1241 A N-r4-N-(N-phenyl-N-(4-methoxybenzyPaminomethyP-2-('2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between
15510 1236C and 4-methoxybenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.15-7.4 (m, 12H); 6.8-6.9 (m, IH); 6.7-6.8 (m, 2H); 5.8-5.9 (m, IH); 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, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 583(M+H)+ .
Figure imgf000705_0001
Example 124 IB
N-[4-N-(N-phenyl-N-H-methoxybenzvPaminomethyl)-2-(2- methylphenyPbenzoy 11 methionine lithium salt
Prepared according to the procedure of example 1178J from 1241 A. NMR
15520 iH(MeOH-d4): 7.6-7.7 (IH, 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 (IH, m); 3.88 (3H, s); 1.5-2.2 (10H, m). ESI(-) MS: 567(M-Li); 445.
Figure imgf000705_0002
15525 Example 1242
N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000705_0003
15530 Example 1242 A N-r4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2-(2- methylphenvπbenzoyllmethionine. 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, IH); 7.15-7.4 15535 (m, 12H); 6.8-6.9 (m, IH); 6.7-6.8 (m, 2H); 5.8-5.9 (m, IH); 4.65 (m, 3H); 4.60 (s, 2H); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 636(M+H)+ .
Figure imgf000706_0001
15540 Example 1242B
N-r4-N-(N-phenyl-N-(4-trifluoromethoxybenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1242A. NMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.3-7.4 (3H, d), 7.05-7.25 (9H, m); 6.7-6.8 (2H, m); 15545 6.6-6.7 (IH, m); 4.7-4.8 (4H, m); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 621(M-Lp.
Figure imgf000706_0002
15550 Example 1243
N-[4-N-(N-phenyl-N-(4-nitrobenzyPaminomethyP-2-("2-methylphenyl)benzoyl1methionine lithium salt
Figure imgf000707_0001
15555 Example 1243A
N-r4-N-(N-phenyl-N-(4-nitrobenzyPaminomethvP-2-(2-methylphenyl)benzoyllmethionine. methyl ester Prepared according to the procedure of example 1236 A from reaction between 1236C and 4-nitrobenzyl bromide. NMR(CDC13) 8.15-8.20 (m, 2H); 7.85-7.95 (m, IH); 15560 7.1-7.45 (m, 10H); 6.75-6.81 (m, IH); 6.65-6.71 (m, 2H); 5.78-5.88 (m, IH); 4.7-4.8
(ss, 4H); 4.6-4.75 (m, IH); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5- 1.7 (m, IH). (DSI7NH3)/MS: 598(M+H)+ ; 615 (M+NH4)+.
Figure imgf000707_0002
15565 Example 1243B
N-r4-N-(N-phenyl-N-(4-nitrobenzyPaminomethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1243 A. NMR iH(MeOH-d4): 8.15-8.2 (2H, m); 7.6-7.7 (IH, m), 7.48-7.56 (2H, m); 7.35-7.41 ( IH, 15570 m); 7.15-7.3 (8H, m); 6.65-6.78 (3H, m), 4.78-4.85(4H, m); 4.1-4.22 (IH, m); 1.7-2.1 ( 10H, m). ESI(-)/MS: 582(M-Li).
Figure imgf000707_0003
15575 Example 1244 N-[4-N-(N-phenyl-N-H-carboxylic acid benzyPaminomethyl)-2-(2- methylphenvPbenzoyllmethionine. dilithium salt
Figure imgf000708_0001
15580 Example 1244 A
N-r4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- methylphenvPbenzoyllmethionine. dimethyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and methyl 4-(bromomethyl) benzyolate. NMR(CDC13) 7.85-7.95 (m, IH); 7.18- 15585 7.40 (m, 12H; 6.7-6.85 (m, 3H); 5.8-5.9 (m, IH); 4.7 (s, 4H); 4.58-4.68 (m, IH); 3.90 (s, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 628(M+NH4)+ .
Figure imgf000708_0002
15590 Example 1244B
N-[4-N-(N-phenyl-N-H-carboxylic acid benzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. dilithium salt Prepared according to the procedure of example 1178J from 1244A. NMR iH(MeOH-d4): 7.9-8.0 (2H, m); 7.6-7.7 (IH, m), 7.3-7.4 (2H, m); 7.1-7.28 (9H, m); 15595 6.7-6.75 (2H, m); 6.6-6.7 (IH, m); 4.78 (2H, s); 4.70 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 595(M-Li).
Figure imgf000709_0001
15600 Example 1245
N-r4-N-(N-phenyl-N-f4-phenylbenzyl aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000709_0002
15605 Example 1245 A
N-f4-N-(N-phenyl-N-(4-phenylbenzyPaminomethyl)-2-(2- methylphenyPbenzoy 11 methionine. methyl ester Prepared according to the procedure of example 1236 A from reaction between 1236C and 4-phenylbenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.1-7.45 (m, 17H); 15610 6.75-6.81 (m, IH); 6.65-6.7 (m, 3H); 5.8-5.9 (m, IH); 4.7-4.8 (ss, 4H); 4.6-4.75 (m, IH); 3.65 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 629(M+H)+ .
Figure imgf000709_0003
15615 Example 1245B
N-[4-N-(N-phenyl-N-(4-phenylbenzyl)aminomethyP-2-(2- methylphenyPbenzoy 11 methionine lithium salt Prepared according to the procedure of example 1178J from 1245A. NMR lH(MeOH-d4): 7.1-7.7 (19H, m); 6.7-6.8 (2H, m); 6.6-6.7 (IH, m); 4.7-4.8 (4H, m); 15620 4.1-4.22 (IH, m); 1.7-2.1 ( 10H, m). ESI(-)/MS: 613(M-Li).
Figure imgf000710_0001
Example 1246
15625 N-r4-N-(N-phenyl-N-(4-N-carboxymethionine)benzyl)aminomethyl-2-(2- methylphenyPbenzoyll methionine dilithium salt.
Figure imgf000710_0002
Example 1246 A 15630 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 stiπed 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 15635 (64%). NMR(CDC13) 7.80-7.85 (m, 2H); 7.28-7.32 (m, 2H; 6.9-7.0 (m, IH); 4.9-5.0 (m, IH); 4.60 (s, 2H); 3.80 (s, 3H); 3.68 (s, 3H); 2.35-2.45 (m, 2H); 2.12-2.35 (m, IH); 2.1- 2.2 (m, IH). (DSI/NH3)/MS: 316(M+H)+; 333(M+NH4)+ .
Figure imgf000710_0003
15640 Example 1246B
N-r4-N-("N-php.nyl-N-(4-N-carboxymethionine)benzyPaminomethyl-2-(2- methylphenvPbenzoyllmethionine. dimethyl ester Prepared according to the procedure of example 1236A from the reaction between 1236C and 1246A. NMR(CDC13) 7.85-7.95 (m, IH); 7.75-7.80 (m, 2H); 7.18-7.35 (m, 15645 9H); 7.10 (s, IH); 6.9-6.95 (m, IH); 6.68-6.78 (m, 3H); 5.8-5.9 (m, IH); 4.81 (s, 2H); 4.5-4.65 (m, IH); 3.80 (s, 3H); 3.68 (s, 3H); 2.35-2.45 (m, 2H); 2.12-2.35 (m, IH); ); 2.0-2.15 (m, 9H); 1.7-2.0 (m, IH); 1.5- 1.7 (m, IH). (DSI/NH3)/MS: 742(M+H)+.
Figure imgf000711_0001
15650 Example 1246C
N-r4-N-(N-phenyl-N-(4-N-carboxymethionine benzyl)aminomethyl-2-(2- methylphenyPbenzoyllmethionine dilithium salt. Prepared according to the procedure of example 1178J from 1246B. NMR H ( _t- MeOH): 7.8-7.9 (2H, m); 7.6-7.7 (IH, m); 7.3-7.4 (4H, m); 7.2 (4H, m); 7.1 (4H, m); 15655 6.7-6.75 (2H, m); 6.6-6.7 (IH, m); 4.8 (4H, m); 4.5-4.6 (IH, m); 4.2-4.3 (IH, m); (2.5- 2.65 (2H, m); 1.6-2.3 (15H, m). ESI(-)/MS: 711 (M-Li); 733 (M+Na-2H).
Figure imgf000711_0002
15660 Example 1247
N-14-N-(N-phenyl-N-(2-naphthvPaminomethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt
Figure imgf000712_0001
15665 Example 1247 A
N-[4-N-(N-phenyI-N-(2-naphthyPaminomethyl)-2-(2-methylphenyPbenzoyl1methionine. methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 2-bromomethyl-naphthalene. NMR(CDC13) 7.68-7.95 (m, 5H); 7.18-7.45 (m, 15670 11H); 7.1 (s, IH); 6.7-6.85 (m, 3H); 5.8-5.9 (m, IH); 4.80 (s, 2H); 4.76 (s, 2H); 4.56- 4.7 (m, IH); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 603(M+H)+ .
Figure imgf000712_0002
15675 Example 1247B
N-r4-N-(N-phenyl-N-(2-naphthyl)aminomethyP-2-('2-methylphenyPbenzoynmethionine lithium salt Prepared according to the procedure of example 1178J from 1247 A. NMR iH(MeOH-d4): 7.78-7.84 (2H, m); 7.6-7.8 (3H, m), 7.3-7.5 (4H, d); 7.0-7.25 (8H, m); 15680 6.8-7.0 (2H, m); 6.75-6.82 (2H, m); 6.6-6.6 (IH, m); 4.8 (2H, s); 4.85 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 587(M-Lp.
Figure imgf000713_0001
Example 1248
N-[4-N-(N-ρhenyI-N-(9-methyl-anthracene-yl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000713_0002
Example 1248 A N-r4-N-(N-phenyl-N-(9-methyl-anthracene-yPaminomethyl)-2-(2- methylphenvPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between
15695 1236C and 9-bromomethyl-anthracene. ΝMR(CDC13) 8.4 (s, IH); 8.1-8.2 (m, 2H); 7.9- 8.0 (m, 2H); 7.0-7.65 (m, 12H); 7.1 (s, IH); 6.8-6.95 (m, 3H); 5.8-5.9 (m, IH); 5.45 (s, 2H); 4.68 (m, IH); 4.25 (s, 2H); 3.60 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5- 1.7 (m, IH). (DSI/NH3)/MS: 653(M+H)+ .
Figure imgf000713_0003
Example 1248B N-r4-N-(N-phenyl-N-(9-methyl-anthracene-yl)aminomethyP-2-(2- methylphenyPbenzoyll methionine lithium salt Prepared according to the procedure of example 1178J from 1248 A. ΝMR
15705 ^(MeOH^): 8.45 (IH, 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 ( IH, m); 5.45 (2H, s); 4.5 (2H, s); 4.1-4.22 ( IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 637(M-Li).
Figure imgf000714_0001
Example 1249
N- 4-N-(N-phenyl-N-(2-methyl-anthraquinone-yPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000714_0002
Example 1249 A N-r4-N-(N-phenyl-N-(2-methyl-anthraquinone-yl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between
15720 1236C and 2-bromomethyl-anthraquinone. ΝMR(CDC13) 8.4 (s, IH); 8.0-8.35 (m, 3H); 7.9-8.0 (m, 2H); 7.0-7.65 (m, 11H); 6.8-6.95 (m, 3H); 5.8-5.9 (m, IH); 4.8 (s, 2H); 4.78 (s, 2H); 4.56-4.7 (m, IH); 3.63 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 683(M+H)+ .
Figure imgf000715_0001
Example 1249B N-r4-N-(N-phenyI-N-(2-methyl-anthraquinone-yl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1249A. ΝMR
15730 iH(MeOH-d4): 8.1-8.3 (4H, m); 7.8-7.9 (2H, m), 7.7-7.8 (IH, m); 7.6-7.7 ( IH, m); 7.25-7.35 (IH, m); 7.0-7.3 (8H, m); 6.75-6.8 (2H, m); 6.6-6.7 (IH, m); 4.9 (2H, s); 4.8 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 ( 10H, m). ESI(-)/MS: 667(M-Li).
Figure imgf000715_0002
Example 1250
N-r4-N-fN-phenyl-N-f2.3-difluorobenzyDaminomethvD-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000715_0003
Example 1250A
N-r4-N-(N-phenyl-N-f2.3-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between 15745 1236C and 2,3-difluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 6.95-7.40 (m, 1 1H); 6.68-6.8 (m, 3H); 5.8-5.9 (m, IH); 4.75 (s, 2H); 4.70 (s, 2H); 4.60-4.70 (m, IH); 3.70 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS:
589(M+H)+ .
Figure imgf000716_0001
Example 1250B
N-r4-N-(N-phenyl-N-(2.3-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Prepared according to the procedure of example 1178J from 1250A. ΝMR
15755 iH(MeOH-d4): 7.7-7.8 (IH, m); 7.3-7.4 (IH, m), 7.0-7.28 (11H, m); 6.65-6.75 (3H, m);
4.8-4.85 (4H, m); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 573(M-Lp.
Figure imgf000716_0002
15760 Example 1251
N-[4-N-(N-phenyl-N-(2.4-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000716_0003
15765 • Example 1251 A
N-[4-N-f/v/-phenyl-N-(2.4-difluorobenzyl)aminomethyP-2-(2- methylphe.nyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 2,4-difluorobenzyl bromide. ΝMR(CDC13) 7.85-7.95 (m, IH); 7.18-7.40 (m, 15770 9H); 7.1 (s, IH); 6.7-6.85 (m, 4H); 5.8-5.9 (m, IH); 4.7 (s, 2H); 4.68 (m, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 589(M+H)+ .
Figure imgf000717_0001
Example 125 IB 15775 N-r4-N-(N-phenyl-N-(2.4-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoy 11 methionine lithium salt Prepared according to the procedure of example 1178J from 1251 A. ΝMR H(MeOH-d4): 7.6-7.68 ( IH, m); 7.3-7.4 ( IH, m), 7.3-7.4 ( IH, 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 ( IH, m); 1.7-2.1 15780 ( 10H, m). ESI(-)/MS: 573(M-Li).
Figure imgf000717_0002
Example 1255 15785 N-H-N-('N-phenyl-N-('2-thiophenesulfonvPaιninomethvP-2-(2- methylphenyPbenzoy 11 methionine lithium salt
Figure imgf000718_0001
Example 1255 A 15790 N-r4-N-(N-phenyl-N-(2-thiophenesulfonyPaminomethyl)-2-(2- methylphenvPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1229 A from reaction between 1236C and 2-thiophenesulfonyl chloride. ΝMR(CDC13) 7.75-7.82 (m, IH); 7.60-7.62 (m, IH); 7.39-7.42 (m, IH); 7.12-7.38 (m, 9H); 7.05-7.1 1 (m, 2H); 6.95-7.05 (m, 2H); 5.8- 15795 5.9 (m, IH); 4.78 (s, 2H); 4.5-4.65 (m, IH); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 609(M+H)+; 626(M+NH4)+.
Figure imgf000718_0002
Example 1255B
15800 N-r4-N-(N-phenyl-N-(2-thiophenesulfonyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1255 A. ΝMR iH(MeOH-d4): 7.8-7.9 (IH, m); 7.5-7.6 (IH, m), 7.42-7.45 (IH, m); 7.1-7.3 (9H, m); 6.95-7.1 (3H, m); 4.9 (2H, s); 4.1-4.22 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 593(M- 15805 Li).
Figure imgf000718_0003
Example 1256 15810 N-r4-N-(N-phenyl-/V-(2-methvi-4-methylenethiazolyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000719_0001
Example 1256 A 15815 Λ^g4-N-(N-phenyl-N-(2-methyl-4-methylenethiazolyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 4-methyl-2-(bromomethyl)-thiazole. ΝMR(CDC13) 7.82-7.95 (m, IH); 7.10- 7.40 (m, 9H); 6.8 (s, IH); 6.7-6.8 (m, 2H); 5.8-5.9 (m, IH); 4.78 (s, 2H); 4.75 (s, 2H); 15820 4.56-4.7 (m, IH); 3.68 (s, 3H); 2.67 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 574(M+H)+ .
Figure imgf000719_0002
Example 1256B 15825 N-r4-N-(,N-phenyl-N-(,2-methyl-4-methylenethiazolyPaminomethvP-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from 1256A. ΝMR iH(MeOH-d4): 7.6-7.68 (IH, m); 7.32-7.4 (IH, m), 7.0-7.28 (9H, m); 6.7-6.8 (2H, m); 6.6-6.7 (IH, m); 4.78 (2H, s); 4.70 (2H, s); 4.1-4.22 (IH, m); 2.62 (3H, s); 1.7-2.1 15830 (10H, m). ESI(-)/MS: 558(M-Li).
Figure imgf000720_0001
Example 1257
15835 V- 4-N-(N-3.5-difluorophenyI-N-(5-thiazolylmethyl)aminomethyl)-2-(2- methylphenyPbenzoy 11 methionine lithium salt.
Figure imgf000720_0002
Example 1257 A 15840 Prepared according to the procedure of example 1258A from reaction between 3,5- difluoroaniline and 5-thizaolecarboxaldehyde. ΝMR(CDC13) 8.85 (s, IH); 7.82 (s, IH); 6.10-6.30 (m, 3H); 4.56 (s, 2H); 4.05-4.50 (m, IH). DSI/NH3)/MS: 227(M+H)+ ; 244(M+NH4)+.
Figure imgf000720_0003
Example 1257B Prepared according to the procedure of example 1287B from reaction between 1257 A and 4-bromomethyl-2-(2-methy IphenyPbenzoic acid methyl ester. NMR(CDC13) 8.75-8.80 (s, IH); 7.82-8.00 (m, IH); 7.75 (s, IH); 7.12-7.38 (m, 4H); 7.00-7.10 (m,
15850 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)+.
Figure imgf000721_0001
Example 1257C 15855 N-|"4-N-(N-3.5-difluorophenyl-N-(5-thiazolylmethyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester. Prepared according to the procedure of example 1258C from 1257B. ΝMR(CDC1 ) 8.75-8.80 (s, IH); 7.80-7.90 (m, IH); 7.65-7.80 (m, IH); 7.12-7.38 (m, 5H); 6.93 (s, IH); 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, 15860 8H); 1.60- 1.90 (m, IH); 1.45- 1.60 (m, IH). DSI/NH3)/MS: 596(M+H)+ .
Figure imgf000721_0002
Example 1257D N-r4-N-(N-3.5-difluorophenyl-N-(5-thiazolylmethyPaminomethyP-2-(2- 15865 methylphenvPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1 178J from 1257C. X ΝMR (MeOH-d4): 8.9 ( IH, s); 7.8 ( IH, s); 7.6-7.7 (IH, m); 7.3-7.4 (IH, m); 7.1-7.3 (3H, m); 7.0-7.1 ( IH, s); 6.3-6.45 (2H, m); 6.2-6.3 ( IH, s); 4.95 (2H, s); 4.7 (2H, s); 4.1 -4.22 (IH, m); 1.6-2.2 (10H, m). ESI(-)/MS: 580(M-Lp. Anal. Calcd for 15870 C3θH28F2Ν3θ3S2Li* 1.73H2θ: C, 58.23; H, 5.12; N, 6.79. Found: C, 58.24; H, 4.90; N, 6.54.
Figure imgf000722_0001
15875 Example 1258
N- 4-N-(N-(5-thiazolylmethyP-N-(3.5-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
e
Figure imgf000722_0002
15880 Example 1258 A A mixture of 3,5-difluorobenzyl amine (2.0 g, 14.2 mmol), 4-formyl-2-(2- methylphenyPbenzoic 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 stiπed for 24 hours. The reaction mixture was washed with 4Ν NaOH and with brine, then dried over
15885 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, IH); 7.38-7.45 (m, IH); 7.18-7.30 (m, 4H); 7.05-7.15 (m, IH); 6.85-6.92 (m, 2H); 6.63-6.72 (m, IH); 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)+.
15890
e
Figure imgf000722_0003
Example 1258B Prepared according to the procedure of example 1258A from reaction between 1258A and 5-thiazolealdehyde. NMR(CDC13) 8.80 (s, IH); 7.95-8.00 (m, IH); 7.72 (s, 15895 IH); 7.50-7.55 (m, IH); 7.10-7.32 (m, 4H); 7.0-7.1 (m, IH); 6.9-7.0 (m, 2H); 6.68-6.72 (m, IH); 4.62-4.70 (m, 2H); 3.60 (s, 5H); 2.07 (s, 3H). (DSI/NH3)/MS: 479(M+H)+; 496(M+NH4)+.
Figure imgf000723_0001
15900 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
15905 was then washed by brine, and dried over anhydrous MgSO4. Evaporation of the solvent afforded pure coπesponding 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), l-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (0.61 g, 3.15 mmol), and
15910 triethylamine hydrochloride (0.43 g, 3.15 mmol) in 15 ml of anhydrous DMF was heated under N2 at 75°C 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 EtO AC. Combined organic solution was washed with 30 ml of saturated NaHCO3 twice, then with 50 ml of brine, finally dried over anhydrous
15915 MgSO . 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, IH); 7.90-8.00 (m, IH); 7.72 (s, IH); 7.50-7.55 (m, IH); 7.20- 7.38 (m, 5H); 6.9-7.0 (m, 2H); 6.68-6.72 (m, IH); 5.88-5.92 (m, 2H); 4.58-4.70 (m, IH); 3.88 (s, 2H); 4.62-4.70 (m, 5H); 3.60 (s, 2H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH);
15920 1.5-1.7 (m, IH). (DSI/NH3)/MS: 610(M+H)+.
Figure imgf000724_0001
Example 1258D N-r4-N-(N-(5-thiazolylmethyP-N-(3.5-difluorobenzyPaminomethyl)-2-(2- 15925 methylphenyPbenzoy 11 methionine lithium salt.
Prepared according to the procedure of example of 1178J from example 1258C. ΝMR iH(MeOH-d4): 8.95 ( IH, s); 7.78 ( IH, s); 7.6-7.7 (IH, m); 7.4-7.5 ( IH, m), 7.05-7.3 (5H, m); 6.95-7.05(2H, m); 6.85-6.95 ( IH, m); 4.95 (2H, s); 4.1-4.22 ( IH, 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- 15930 Li).
Figure imgf000724_0002
Example 1259
15935 N-r4-N-fN-phenyl-N-(3.5-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoy 11 methionine lithium salt
Figure imgf000724_0003
Example 1259 A
15940 N-14-N-fN-phenyl-N-f3.5-difiuorobenzvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine, methyl ester Prepared according to the procedure of example 1236A from reaction between 1236C and 3,5-difluorobenzyl bromide. NMR(CDC13) 7.85-7.95 (m, IH); 7.18-7.40 (m, 9H); 7.1 (s, IH); 6.75-6.8 (m, 2H); 6.65-6.75 (m, 2H); 5.8-5.9 (m, IH); 4.7 (s, 2H); 4.6
15945 (m, 3H); 3.68 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3) MS: 589(M+H)+ .
Figure imgf000725_0001
Example 1259B 15950 N-r4-N-(N-phenyl-N-('3.5-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoy 11 methionine lithium salt Prepared according to the procedure of example 1178J from 1259A. ΝMR lH(MeOH-d4): 7.7-7.8 (IH, m); 7.3-7.4 (IH, 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 (IH, m); 1.7-2.1 (10H, m). ESI(-)/MS: 15955 573(M-Lp.
Figure imgf000725_0002
Example 1260
15960 N- 4-N-(N-(4-acetonitrilephenyl-N-(3.5-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000726_0001
Example 1260A
15965 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(CDC13) 7.95-8.00 (m, IH); 7.02-7.35 (m, 8H); 6.62-6.80 (m, 5H); 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)+; 5 H(M+NH4)+.
15970
Figure imgf000726_0002
Example 1260B N- 4-N-(N-(4-acetonitrilephenyl-N-(3.5-difluorobenzyPaminomethyP-2-('2- methylphenyPbenzoyllmethionine. methyl ester
15975 Prepared according to the procedure of example 1258C from example 1260A. ΝMR(CDC13) 7.85-7.95 (m, IH); 7.05-7.38 (m, 7H); 7.05 (s, IH); 6.6-6.80 (m, 5H); 5.80-5.90 (m, IH); 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, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 628(M+H)+; 645(M+NH4)+.
Figure imgf000726_0003
Example 1260C
N-r4-N-(N-(4-acetonitrilephenyl-N-(3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoy 11 methionine lithium salt. Prepared according to the procedure of example 1178J from example 1260B. NMR 15985 lH(MeOH-d4): 7.6-7.7 (IH, m); 7.3-7.4 (IH, m), 7.0-7.3 (8H, m); 6.65-6.9 (5H, m); 4.78 (2H, s); 4.7 (3H, s); 4.1-4.22 (IH, m); 3.7 (2H, s); 1.7-2.1 (10H, m). ESI(-)/MS: 612(M-Lp. Anal. Calcd for C35H32F2N3θ3SLi»1.64 H2O: C, 64.76; H, 5.48; N, 6.47. Found: C, 64.75; H, 5.19; N, 6.16.
15990
Figure imgf000727_0001
Example 1261 N-14-N-(N-phenyl-N-G-methoxy-5-nitrobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt. 15995
Figure imgf000727_0002
Example 1261 A N-r4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester 16000 Prepared according to the procedure of example 1236 A from reaction between
1236C and 3-methoxy-5nitrobenzyl bromide. ΝMR(CDC13) 8.1-8.2 (m, 2H); 8.0 (s, IH); 7.68-7.95 (m, IH); 7.1-7.40 (m, 8H); 6.9-6.95 (m, IH); 6.7-6.8 (m, IH); 6.6-6.7 (m, 2H); 5.8-5.9 (m, IH); 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, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 628(M+H)+ .
Figure imgf000728_0001
Example 126 IB N- 4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyPaminomethyl)-2-(2- methylphenyPbenzoyll methionine lithium salt. Prepared according to the procedure of example 1178J from 1261 A. ΝMR
16010 iH(MeOH-d4): 8.1-8.2 (IH, m); 7.9-8.0 (IH, m), 7.6-7.7 (IH, m); 7.3-7.4 (IH, 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 (10H, m). ESI(-)/MS: 612(M-Lp.
Figure imgf000728_0002
Example 1262 N-[4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
e
Figure imgf000728_0003
Example 1262 A 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, IH); 7.38-7.42 (m, IH); 7.18-7.24 (m, 5H); 7.0-7.18 (m, IH); 6.55-6.60 (m, 16025 2H); 4.95 (m. IH); 4.52 (s, 2H); 3.60 (s, 3H); 2.00 (s, 3H). (DSI/NH3)/MS: 394(M+NH4)+.
Figure imgf000729_0001
Example 1262B 16030 Prepared according to the procedure of example 1178H from 1262 A. NMR(CDC13)
8.08-8.1 1 (m, 2H); 7.94-8.00 (m, IH); 7.38-7.42 (m, IH); 7.18-7.24 (m, 5H); 7.0-7.18 (m, IH); 6.55-6.60 (m, 2H); 4.95 (m, IH); 4.52 (s, 2H); 2.00 (s, 3H). (DSI/NH3)/MS: 380(M+NH4)+.
Figure imgf000729_0002
Example 1262C Prepared according to the procedure of example 11781 from 1262B. NMR(CDC1 ) 8.08-8.1 1 (m, 2H); 7.94-8.00 (m, IH); 7.38-7.42 (m, IH); 7.20-7.38 (m, 5H); 7.18-7.20 (m, IH); 6.55-6.60 (m, 2H); 5.89-5.95 (m, IH); 4.95-5.00(m, IH); 4.58-4.70 (m, IH);
16040 4.55 (m, 2H); 3.62 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3) MS: 508(M+H)+; 525(M+NH4)+.
Figure imgf000729_0003
Example 1262D 16045 N-r4-N-(Λ/-('4-nitrophepyl-N-('4-methoxyhen7.ynaminomethyl)-2-f2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1236A from reaction between 1262C and 4-methoxybenzyl bromide. ΝMR(CDC13) 8.08-8.1 1 (m, 2H); 7.94-8.00 (m, IH); 7.38-7.42 (m, IH); 7.1 1-7.40 (m, 6H); 7.00 (m, IH); 6.85-6.95 (m, 3H); 6.55-6.60 16050 (m, 2H); 5.89-5.95 (m, IH); 4.80 (s, 2H); 4.70(s, 2H); 4.60-4.70 (m, IH); 3.80 (s, 3H); 3.67 (s, 3H); 2.0-2.15 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 628(M+H)+.
Figure imgf000730_0001
16055 Example 1262E
N-r4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1 178J from 1262D. ΝMR !H(MeOH-d4): 8.0-8.05 (2H, m); 7.4-7.5 ( IH, m), 7.3-7.4 ( IH, m); 7.18-7.3 (7H, m); 16060 7.0 (IH, m); 6.8-6.9 (4H, m); 4.8-4.85 (4H, m); 4.1-4.22 ( IH, m); 3.88 (3H, s); 1.7-2.1 (10H, m). ESI(-)/MS: 612(M-Li).
Figure imgf000730_0002
16065 Example 1263
N-r4-N-(N-butyl-N-f3.5-difluorobenzyDaminomethvD-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000731_0001
16070 Example 1263 A
Prepared according to the procedure of example 1258A from reaction between 1258A and butyraldehyde. NMR(CDC13) 7.92-7.98 (m, IH); 7.38-7.45 (m, IH); 7.10- 7.32 (m, 4H); 7.0-7.1 (m, IH); 6.8-6.95 (m, 2H); 6.60-6.75 (m, IH); 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
16075 (t, 3H). (DSI/NH3)/MS: 437(M+H)+.
Figure imgf000731_0002
Example 1263B N-[4-N-rN-butyl-N-(3.5-difluorobenzyPaminomethyl)-2-(2- 16080 methylphenyPbenzoyllmethionine. methyl ester
Prepared according to the procedure of example 1258C from 1263 A. ΝMR(CDC13) 7.9-8.00 (m, IH); 7.40-7.46 (m, IH); 7.20-7.40 (m, 4H); 7.20 (s, IH); 6.7-6.85 (m, 2H); 6.60-6.75 (m, IH); 5.82-5.92 (m, IH); 4.58-4.70 (m, IH); 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, IH); 1.55-1.65 (m, IH); 1.45- 16085 1.55 (m, 2H); 1.2-1.4 (m, 2H); 0.8-0.9 (t, 3H). (DSI/NH3)/MS: 569(M+H)+.
Figure imgf000731_0003
Example 1263C N-H-N-f V-hι.fyl-.V-(3.5-difluorobenzvPaminomethyl)-2-(2- 16090 methylphenvPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1178J from 1263B. ΝMR lH(MeOH-d4): 7.6-7.7 ( IH, m); 7.4-7.48 ( IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.65 (2H, s); 3.58 (2H, s); 2.4-2.5 (2H, m); 2.21 (IH, m); 1.8-2.1 (10H, m); 1.4-1.5 (2H, m); 1.22-1.4 (2H, m); 0.8-0.9 (3H, m). ESI(- 16095 )/MS: 553(M-Li). Anal. Calcd for C3 lH35F2Ν2θ3SLi*1.5 LiOH*0.26H2O: C, 62.04; H, 6.05; N, 4.48. Found: C, 62.04; H, 6.05; N, 4.67.
Figure imgf000732_0001
16100 Example 1264
N-r4-N-(N-(4.4.4-trifluorobutyl-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenvPbenzoy 11 methionine lithium salt.
e
Figure imgf000732_0002
16105 Example 1264 A
Prepared according to the procedure of example 1258 A from reaction between 1258A and 4,4,4-trifluorobutyraldehyde. ΝMR(CDC13) 7.92-7.98 (m, IH); 7.38-7.45 (m, IH); 7.10-7.32 (m, 4H); 7.0-7.1 (m, IH); 6.8-6.92 (m, 2H); 6.62-6.78 (m, IH); 3.58- 3.63 (m, 5H); 3.55 (s, 2H); 2.43-2.55 (t, 2H); 2.00-2.1 (m, 5H); 1.7-1.82 (m,
16110 2H).(DSI/NH3)/MS: 492(M+H)+.
Figure imgf000733_0001
Example 1264B N-r4-N-(N-(4.4.4-trifluorobutyl-N-(3.5-difluorobenzvPaminomethyl)-2-(2-
161 15 methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1258C from 1264A. ΝMR(CDC13) 7.9-8.00 (m, IH); 7.40-7.46 (m, IH); 7.20-7.40 (m, 4H); 7.20 (s, IH); 6.7-6.85 (m, 2H); 6.60-6.75 (m, IH); 5.82-5.92 (m, IH); 4.58-4.70 (m, IH); 3.65 (s, 3H); 3.61 (s, 2H); 3.55 (s, 2H); 2.40-2.48 (t, 2H); 1.5-2.16 (m, HH). (DSI/NH3)/MS: 623(M+H)+.
16120
Figure imgf000733_0002
Example 1264C N-r4-N-(N-(4.4.4-trifluorobutyl-N-(3.5-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
16125 Prepared according to the procedure of example 1178J from 1264B. ΝMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.4-7.48 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.65 (2H, s); 3.6 (2H, s); 2.5-2.6 (2H, m); 1.6-2.25 (HH, m); 1.4-1.5 (2H, m); 1.22-1.4 (2H, m); 0.8-0.9 (3H, m). ESI(-)/MS: 609(M-Lp. Anal. Calcd for C31H30F5Ν2O3SLM.2IH2O: C, 58.70; H, 5.15; N, 4.42. Found: C,
16130 58.69; H, 5.16; N, 4.18.
Figure imgf000734_0001
Example 1265
16135 N-r4-N-(N-cyclohexyl-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
e
Figure imgf000734_0002
Example 1265 A.
16140 Prepared according to the procedure of example 1258A from reaction between 1258A and cyclohexanone. ΝMR (CDC13) 7.90-7.95 (m, IH); 7.40-7.45 (m, IH); 7.18- 7.38 (m, 4H); 7.00-7.09 (m, IH); 6.84-6.94 (m, 2H); 6.58-6.68 (m, IH); 3.68 (s, 2H); 3.62 (m, 5H); 2.40-2.50 (m, IH); 2.08 (s, 3H); 1.75-1.96 (m, 4H); 1.05-1.65 (m, 6H). (DSI/ΝH3)/MS: 464(M+H)+.
16145
Figure imgf000734_0003
Example 1265B N-r4-N-(N-cyclohexyl-N-(3.5-difluorobenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester
16150 Prepared according to the procedure of example 1258C from 1265A. ΝMR (CDC13) 7.85-7.95 (m, IH); 7.38-7.45 (m, IH); 7.18-7.38 (m, 4H); 7.2 (s, IH); 6.84-6.94 (m, 2H); 6.58-6.68 (m, IH); 5.85-5.93 (m, IH); 4.56-4.65 (m, IH); 3.70 (s, 2H); 3.65 (s, 2H); 3.61 (s, 3H); 2.40-2.50 (m, IH); 1.96-2.18 (m, 7H); 1.71- 1.96 (m, 6H); 1.55- 1.68 (m ,1H); 1.05-1.52 (m, 6H). (DSI/NH3)/MS: 595(M+H)+.
16155
Figure imgf000735_0001
Example 1265C
N-r4-N-(N-cyclohexyl-N-(3.5-difluorobenzvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
16160 Prepared according to the procedure of example 1178J from 1265B. ΝMR
1H(MeOH-d4): 7.6-7.7 (IH, m); 7.35-7.45 (IH, m), 7.0-7.35 (5H, m); 6.9-7.0 (2H, m);
6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.7 (3H, s); 3.65 (3H, s); 2.4-2.52 (IH, m); 2.1 ( IH, 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).
16165
Figure imgf000735_0002
Example 1266
N- 4-N-fN-f4-cyclohexanonyP-N-(3.5-difluorobenzyPaminomethyP-2-(2-
16170 methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000735_0003
Example 1266 A N-[4-N-(N-r4-cyclohexanonvP-N-(3,5-difluorobenzyPaminomethvP-2-(2-
16175 methylphenvPbenzoyllmethionine. 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 2Ν Na2CO , then extracted by 50 ml of EtOAc. The organic solution was then washed with brine, dried over anhydrous MgSO4. The crude
16180 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, IH); 7.40-7.49 (m, IH); 7.18- 7.40 (m, 5H); 6.82-6.92 (m, 2H); 6.58-6.68 (m, IH); 5.82-5.91 (m, IH); 4.58-4.68 (m, IH); 3.61-3.75 (m, 7H); 2.95-3.05 (m, IH); 1.5-2.5 (m, 18H). (DSI/NH3)/MS: 609(M+H)+; 626(M+NH4)+.
16185
Figure imgf000736_0001
Example 1266B N-[4-N-(N-(4-cyclohexanonylVN-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
16190 Prepared according to the procedure of example 1178J from 1266 A. ΝMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.4-7.5 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.75 (2H, s); 3.7 (2H, s); 2.1-2.3 (3H, m); 1.76-2.1 (HH, m); 1.5-1.78 (2H, m). ESI(-)/MS: 593(M-Lp. Anal. Calcd for C33H35F2Ν2θ4SLi*1.73H2θ*1.5LiOH: C, 60.32; H, 5.95; N, 4.26. Found: C, 60.33;
16195 H, 5.62; N, 4.04.
Figure imgf000736_0002
. Example 1267
16200 N-r4-N-fN-(4-(2.2-dimethyltrimethylene ketaP-cyr.1ohexyl)-N-(3.5- difluorobenzvPaminomethvP-2-(2-methylphenvPbenzoyllmethionine lithium salt.
Figure imgf000737_0001
Example 1267 A
16205 Prepared according to the procedure of example 1258 A from reaction between
1258A and 1 ,4-cyclohexanedione mønø-2,2-dimethyltrimethylene ketal. ΝMR (CDC13) 7.82-7.92 (m, IH); 7.36-7.42 (m, IH); 7.18-7.38 (m, 4H); 7.20 (s, IH); 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, IH); 2.22-2.38 (m, 2H); 1.80-2.20 (m, 6H); 1.2-1.3 (m, 2H); 0.95 (s,
16210 6H). (DSI/ΝH3)/MS: 564(M+H)+.
Figure imgf000737_0002
Example 1267B N-r4-N-(N-(4-r2.2-dimethyltrimethylene ketaP-cvcIohexyP-N-(3.5- 16215 difluorobenzyPaminomethyP-2-('2-methylphenyPbenzoyl1methionine. methyl ester
Prepared according to the procedure of example 1258C from 1267A. ΝMR (CDC13) 7.82-7.92 (m, IH); 7.36-7.42 (m, IH); 7.18-7.38 (m, 4H); 7.20 (s, IH); 6.82-6.92 (m, 2H); 6.58-6.68 (m, IH); 5.82-5.91 (m, IH); 4.58-4.68 (m, IH); 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, IH); 2.22-2.38 (m, 2H); 16220 1.50-2.2 (m, HH); 1.2-1.3 (m, 2H); 0.95 (s, 6H). (DSI/ΝH3)/MS: 695(M+H)+.
Figure imgf000738_0001
Example 1267C 16225 N-r4-N-rN-(4-(2.2-dimethyltrimethylene ketaP-cvclohexyP-N-(3.5- difluorobenzyPaminomethyP-2-(2-methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1178J from 1267B. ΝMR lH(MeOH-d4): 7.55-7.65 (IH, m); 7.38-7.48 (IH, m), 7.0-7.35 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.7 (2H, s); 3.65(2H, s); 3.45 (4H, s); 2.5-2.65 16230 (IH, m); 2.26-2.4 (2H, m); 2.2 (IH, 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 C38H45F2Ν2θ5SLi*0.99H2θ*1.0LiOH: C, 62.65; H, 6.64; N, 3.84. Found: C, 62.65; H, 6.33; N, 3.71.
Figure imgf000738_0002
Example 1268 N-r4-N-(N-cyclohexylmethyl-N-(2.4-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyll methionine lithium salt.
e
Figure imgf000738_0003
Example 1268 A 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 (CDCI3) 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
16245 (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)+.
e
Figure imgf000739_0001
Example 1268B
16250 Prepared according to the procedure of example 1258A from reaction between 1268A and cyclohexanecarboxaldehyde. NMR (CDC13) 7.90-7.95 (m, IH); 7.38-7.47 (m, 2H); 7.20-7.35 (m, 4H); 7.0-7.10 (m, IH); 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)+.
16255
Figure imgf000739_0002
Example 1268C N-r4-N-(N-cyclohexylmethyl-N-(2.4-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester
16260 Prepared according to the procedure of example 1258C from 1268B. ΝMR (CDC13) 7.85-7.95 (m, IH); 7.20-7.47 (m, 6H); 7.18 (s, IH); 6.75-6.85 (m, 2H); 5.85-5.92 (m, IH); 4.56-4.67 (m, IH); 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/ΝH3)/MS: 609(M+H)+.
16265
Figure imgf000740_0001
Example 1268D N-[4-N-(N-cyclohexylmethyl-N-r2.4-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt. 16270 Prepared according to the procedure of example 1178J from 1267C. ΝMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.38-7.48 (2H, m), 7.0-7.28 (6H, m); 6.8-6.95 (2H, m); 4.1-4.22 (IH, m); 4.58 (4H, s); 2.2-2.3 (4H, m); 1.76-2.1 (9H, m); 1.5- 1.78 (5H, m); 1.1-1.3 (3H, m); 0.7-0.82 (2H, m). ESI(-)/MS: 593(M-Lp.
16275
Figure imgf000740_0002
Example 1269
N-r4-N-fN-cyclohexylmethyl-N-("3.5-difluorobenzyPaminomethyP-2-(2- methylphenyDbenzoyllmethionine lithium salt.
16280
Figure imgf000740_0003
Example 1269A Prepared according to the procedure of example 1258A from reaction between 1258A and cyclohexanecarboxaldehyde. NMR (CDC13) 7.95-8.05 (m, IH); 7.40-7.47 (m, 16285 IH); 7.15-7.35 (m, 5H); 7.04-7.11 (m, IH); 6.75-6.85 (m, 2H); 6.60-6.70 (m, IH);
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)+.
Figure imgf000741_0001
Example 1269B N- 4-N-(N-cyclohexylmethyl-N-(3.5-difluorobenzyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1258C from 1269A. ΝMR (CDC13)
16295 7.79-7.95 (m, IH); 7.40 -7.48 (m, IH); 7.20-7.41 (m, 5H); 7.18 (s, IH); 6.75-6.85 (m, 2H); 6.60-6.70 (m, IH); 5.85-5.92 (m, IH); 4.56-4.67 (m, IH); 3.67(s, 3H); 3.57 (s, 2H); 3.45 (s, 2H); 2.18-2.23 (m, 4H); 2.00-2.1 1 (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/ΝH3)/MS: 609(M+H)+.
Figure imgf000741_0002
Example 1269C
N-r4-N-(N-cyclohexylmethyl-N-f3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1178J from 1269B. ΝMR
16305 1H(MeOH-d4): 7.6-7.7 (IH, m); 7.38-7.48 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m);
6.7-6.8 (IH, m); 4.1-4.22 (IH, 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 (5H, m); 1.1- 1-3 (3H, m); 0.7-0.82 (2H, m). ESI(-) MS: 593(M-Li). Anal. Calcd for C3 iH3θF5N2θ3SLi*1.0LiOH: C, 65.38; H, 6.45; N, 4.48 Found: C,
65.43; H, 6.17; N, 4.40.
16310
Figure imgf000742_0001
Example 1270
N-H-N-(N-(4-cyanobenzyP-N-(3.5-difluorobenzyl)aminomethyP-2-(2-
16315 methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000742_0002
Example 1270 A Prepared according to the procedure of example 1258A from reaction between 16320 1258A and 4-cyanobenzaldehyde. ΝMR(CDC13) 7.95-8.00 (m, IH); 7.60-7.65 (m, 2H); 7.40-7.56 (m, 3H); 7.20-7.38 (m, 4H); 7.00-7.10 (m, IH); 6.85-6.95 (m, 2H); 6.65-6.75 (, IH); 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)+. 16325
Figure imgf000743_0001
Example 1270B N- 4-N-(N-(4-cyanobenzyl)-N-(3.5-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyll methionine. methyl ester Prepared according to the procedure of example 1258C from 1270A. ΝMR(CDC13) 16330 8.00-8.18 (m, IH); 7.76-7.80 (m, 2H); 7.48-7.76 (m, 3H); 7.10-7.38 (m, 5H); 7.00-7.11 (m, 2H); 6.80-6.85 (m, IH); 5.95-6.05 (m, IH); 4.70-4.81 (m, IH); 3.70-3.90 (m, 9H); 3.54-3.58 (m, 2H); 1.95-2.20 (m, 8H); 1.7-2.0 (m, IH); 1.5-1.7 (m, IH). (DSI/NH3)/MS: 628(M+H)+ ; 645(M+NH4)+.
Figure imgf000743_0002
Example 1270C N-[4-N-(N-(4-cyanobenzyP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoy 11 methionine lithium salt. Prepared according to the procedure of example 1178J from 1270B. ΝMR
16340 H(MeOH-d4): 8.78 (IH, s); 7.6-7.7 (2H, m); 7.5-7.6 (2H, m), 7.5-7.55 (IH, m); 7.0- 7.3 (6H, m); 6.9-7.0 (2H, m); 6.77-6.82 (IH, m); 4.1-4.22 (IH, m); 3.7 (2H, s); 3.65 (2H, s,); 3.6 (2H, s); 1.5-2.2 (10H, m).ESI(-)/MS: 612(M-Lp.
Figure imgf000744_0001
Example 1271
N-[4-N-(N-(3.5-difluorobenzyl)-N-(4-N-carboxymethionine)benzyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine dilithium salt.
Figure imgf000744_0002
Example 1271 A Prepared according to the procedure of example 1236A from reaction between 1258A and 4-bromomethyl-benzoic methyl ester. ΝMR(CDC13) 7.75-7.90 (m, IH); 7.75- 7.85 (m, 2H); 7.40-7.50 (m, 2H); 7.20-7.40 (m, 5H); 7.18 (s, IH); 6.88-6.95 (m, 2H);
16355 6.70-6.80 (m, IH); 585-5.95 (m, IH); 4.58-4.70 (m, IH); 3.80 (s, 3H); 3.65 (s, 3H); 3.60 (s, 2H); 3.55 (s, 2H).(DSI/NH3)/MS: 530(M+H)+.
Figure imgf000744_0003
Example 127 IB 16360 N- 4-N-(N-(3.5-diflιιorobenzyP- V-(4-N-carboxymethionine1henzvPaminomethyl-2-("2- methylphenvPbenzoyllmethionine dimethyl ester. Prepared according to the procedure of example 1258C from 1271 A. ΝMR(CDC13) 7.75-7.90 (m, IH); 7.75-7.85 (m, 2H); 7.40-7.50 (m, 2H); 7.20-7.40 (m, 5H); 7.18 (s, IH); 6.88-6.95 (m, 3H); 6.70-6.80 (m, IH); 5.85-5.95 (m, IH); 4.90-4.95 (m, IH); 4.58- 16365 4.70 (m, IH); 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)+.
Figure imgf000745_0001
Example 1271C 16370 N- 4-N-(N-(3.5-difluorobenzyl)-N-(4-N-carboxymethionine)benzyPaminomethyl-2-(2- methylphenyPbenzoyllmethionine dilithium salt. Prepared according to the procedure of example 1178J from 127 IB. ΝMR iH (d4- MeOH): 7.8-7.9 (2H, m); 7.6-7.7 (IH, m); 7.45-7.55 (4H, m); 7.1-7.3 (6H, m); 6.9-7.05 (2H, m); 6.75-6.85 (IH, m); 4.5-4.6 (IH, m); 4.2-4.3(lH, m); 3.4-3.5 (6H, m); 2.5-2.6 16375 (2H, m); 1.5-2.3 (15H, m). ESI(-)/MS: 762 (M-Lp; 764(M+H); 781(M+ΝH4).
Figure imgf000745_0002
Example 1272
16380 N-r4-N-(N-(2-cyclohexylethyl-N-(3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000746_0001
Example 1272A 16385 Prepared according to the procedure of example 1258A from reaction between 3,5- difluorobenzaldehyde and 2-cyclohexyle-l-aminoethane. NMR(CDCp) 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, 1 1H); 0.8-1.0- (m, 2H). (DSI/NH3)/MS: 254(M+H)+ ; 271(M+NH4)+.
e
Figure imgf000746_0002
Example 1272B Prepared according to the procedure of example 1226 A from the reaction between 1272A and 4-Bromomethyl-2-(2-methy IphenyPbenzoic acid, methyl ester. NMR(CDC1 ) 7.91-7.98 (m, IH); 7.38-7.45 (m, IH); 7.10-7.30 (m, 4H); 7.05-7.15 (m, IH); 6.83-6.95
16395 (m, 2H); 6.60-6.78 (m, IH); 3.60 (s, 5H); 3.55 (s, 2H); 2.40-2.50 (m, 2H); 2.05 (s, 3H); 1.50-1.75 (m, 5H); 1.30-1.47 (m, 2H); 1.00-1.38 (m, 4H); 0.74-0.90 (m, 2H). (DSI/NH3)/MS: 492(M+H)+ .
Figure imgf000746_0003
16400 Example 1272C
N-("4-N-(N-(2-cyclohexylethyl-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1258C from 1272B. NMR(CDC13) 7.81-7.98 (m, IH); 7.38-7.45 (m, 2H); 7.20-7.40 (m, 3H); 7.18 (s, IH); 6.83-6.95 (m, 16405 2H); 6.60-6.78 (m, IH); 5.81-5.90 (m, IH); 4.58-4.70 (m, IH); 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, IH); 1.50- 1.70 (m, 5H); 1.30-1.50 (m, 2H); 1.10-1.38 (m, 4H); 0.74-0.90 (m, 2H). (DSI/NH3)/MS: 623(M+H)+ .
Figure imgf000747_0001
Example 1272D N-14-N-(N-f2-cvclohexylethyl-N-f3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1178J from 1272C. ΝMR
16415 iHCMeOH-cU): 7.6-7.7 (IH, m); 7.4-7.48 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 (IH, m); 4.1-4.22 (IH, m); 3.65 (2H, s); 3.58 (2H, s); 2.4-2.5 (2H, m); 2.21 (IH, m); 1.1-2.1 (20H, m); 0.8-0.9 (2H, m). ESI(-)/MS: 607(M-Lp.
Figure imgf000747_0002
Example 1273 N-[4-N-(N-(3-methylthiopropyiyN-f3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000748_0001
Example 1273 A Prepared according to the procedure of example 1258 A from reaction between 1258A and 3-(methylthio)propionaldehyde. NMR(CDC13) 7.91-7.98 (m, IH); 7.38-7.45 (m, IH); 7.20-7.30 (m, 4H); 7.04-7.10 (m, IH); 6.83-6.90 (m, 2H); 6.60-6.74 (m, IH);
16430 3.60 (s, 5H); 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)+ .
Figure imgf000748_0002
Example 1273B 16435 N-r4-N-rN-r3-methylthiopropyP-N- .5-difluorobenzyPaminomethvP-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1258C from 1273A. ΝMR(CDC13) 7.81-7.98 (m, IH); 7.38-7.45 (m, 2H); 7.20-7,40 (m, 3H); 7.18 (s, IH); 6.83-6.95 (m, 2H); 6.60-6.78 (m, IH); 5.81-5.90 (m, IH); 4.58-4.70 (m, IH); 3.67 (s, 3H); 3.63 (s, 16440 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)+ .
Figure imgf000748_0003
Example 1273C
16445 N-14-N-(N-(3-methylthiopropyP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenvPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1178J from 1273B. ΝMR !H(MeOH-d4): 7.6-7.7 (IH, m); 7.4-7.48 (IH, m), 7.0-7.3 (6H, m); 6.9-7.0 (2H, m); 6.7-6.8 ( IH, m); 4.1-4.22 ( IH, m); 4.65 (2H, s), 4.60 (2H, s); 2.5-2.6 (2H, m); 2.4-2.5 16450 (2H, m); 1-8-2.3 (13H, m). ESI(-)/MS: 585(M-Lp.
Figure imgf000749_0001
Example 1275
16455 N-I4-N-(N-cyclopropyl-N-(2-(3.5-difluorophenyl)ethyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000749_0002
Example 1275 A
16460 Prepared according to the procedure of example 1279 A from the reaction between 2,4-difluorobenzaldehyde and (Methoxymethyl)triphenylphosphonium chloride. ΝMR. 7.18-7.21 (m, 2H); 6.80-6.94 (m, 3H); 6.06 (s, IH); 5.84 (s, IH); 3.78 (s, 3H). DSI/ΝH3)MS: 171(M+H)+; 188(M+NH4)+.
Figure imgf000749_0003
Example 1275B Prepared according to the procedure of example 1279B from example 1275 A. NMR. 9.78 (s, IH); 7.18-7.21 (m, 2H) 6.60-6.70 (m, 2H); ; 3.75 (s, 2H). DSI7NH3)MS: 157(M+H)+; 174(M+NH4)+.
Figure imgf000750_0001
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, IH); 6.74-6.82 (m,
16475 2H); 2.80-2.90 (m, 2H); 2.80-2.90 (m, 2H); 1.80-1.98 (m, IH); 0.40-0.60 (m, 4H); (DSI/NH3)MS: 198(M+H)+.
e
Figure imgf000750_0002
Example 1275D
16480 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, IH); 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, IH); 0.40-0.60 (m, 4H); (DSI/NH3)MS: 436(M+H)+.
Figure imgf000750_0003
Example 1275E N-f4-N-(N-cyclopropyl-N-(2-(2.4-difluorophenyl)ethyl)aminomethyP-2-(2- methylphenyPbenzoyllmethionine. methyl ester. 16490 Prepared according to the procedure of example 1258C from 1275D. ΝMR 7.94-
7.80 (m, IH); 7.00-7.40 (m, 7H); 6.74-6.82 (m, 2H); 5.90-5.94 (m IH); 4.60-4.70 (m, IH); 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/ΝH3)MS: 567(M+H)+.
Figure imgf000751_0001
Example 1275F N-r4-N-(N-cyclopropyl-N-(2-(3.5-difluorophenyl)ethyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1 178J from 1275E. ΝMR
16500 ^(MeOH^): 7.5-7.6 (IH, m); 7.25-7.35 ( IH, m); 7.0-7.25 (7H, m); 6.7-6.8 (2H, m); 4.1-4.25 (IH, m); 3.8 (2H, s); 2.65-2.85 (4H, m); 1.65-2.2 (11H, m); 1.5- 1.65 (IH, m); 0.4-0.5 (2H, m); 0.3-0.4 (2H, m). ESI(-)/MS: 551(M-Li). Anal. Calcd for C3 lH33Ν2θ3SLi*0.32H2θ*1.0LiOH: C, 63.29; H, 5.93; N, 4.76. Found: C, 63.30; H, 5.77; N, 4.67.
16505
Figure imgf000751_0002
Example 1276 f4-N-rN-2-methylbutyl-N-(,2-(2.4-difluorophenyPethyl)aminomethyP-2-(2-
16510 methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000751_0003
Example 1276A Prepared according to the procedure of example 1275C from example 1275B and 3-
16515 methylbutylamine. ΝMR(CDC13) 7.14-7.22 (m, IH); 6.74-6.82 (m, 2H); 2.78-2.90 (m, 4H); 2.60-2.68 (m, 2H); 1.50-1.70 (m, IH); 1.30-1.50 (m, 2H); 0.9 (d, 6H). (DSI/NH3)MS: 228(M+H)+.
Figure imgf000752_0001
16520 Example 1276B
Prepared according to the procedure of example of 1258 A from the reaction between example 1276A and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR 7.94- 8.00 (m, IH); 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, IH); 1.24-1.48 (m, 2H);
16525 0.90 (d, 6H). (DSI/NH3)MS: 466(M+H)+.
Figure imgf000752_0002
Example 1276C I4-N-(N-2-methylbutyl-N-(2-(2.4-difluorophenvPethvPaminomethvP-2-(2- 16530 methylphenyPbenzoyllmethionine. methyl ester.
Prepared according to the procedure of example 1258C from 1276B. ΝMR 7.85- 7.95 (m, IH); 7.00-7.40 (m, 7H); 6.67-6.82 (m, 2H); 5.91-5.97 (m, IH); 4.56-4.70 (m, IH); 3.63 (s, 5H); 2.65-2.80 (m, 4H); 2.46-2.55 (m, 2H); 2.00-2.20 (m, 8H); 1.70-2.00 (m, IH); 1.45-1.70 (m 2H); 1.30-1.40 (m, 2H); 0.90 (d, 6H). (DSI/ΝH3)MS: 16535 597(M+H)+.
Figure imgf000753_0001
Example 1276D r4-N-fN-2-methylbutyl-N-(2-(2.4-difluorophenyl)ethvPaminomethvP-2-r2- 16540 methylphenyPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1178J from 1276C. ΝMR iH(MeOH-d4): 7.5-7.6 (IH, m); 7.2-7.3 (IH, m); 7.0-7.25 (7H, m); 6.7-6.8 (2H, m);
4.1-4.25 (IH, 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 ( IH, s); 1.85-2.0 (6H, m); 1.55-1.85 (2H, m); 1.5-1.65 (IH, m); 1.38-1.5 ( IH, m);
16545 1.2- 1.38 (2H, m); 0.75 )6H, d). ESI(-)/MS: 581(M-Lp. Anal. Calcd for
C33H39Ν2θ3SLi*0.25H2θ*1.8LiOH: C, 63.30; H, 5.54; N, 4.40. Found: C, 63.30; H, 6.17; N, 4.24.
Figure imgf000753_0002
Example 1277 r4-N-fN-butyl-N-(2-(2.4-difluorophenvPethvPaminomethvP-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000753_0003
Example 1277 A Prepared according to the procedure of example 1275C from example 1275B and butylamine. ΝMR(CDC13) 7.14-7.22 (m, IH); 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). (DSI/NH3)MS:
16560 2H(M+H)+.
Figure imgf000754_0001
Example 1277B Prepared according to the procedure of example of 1258A from the reaction between 16565 example 1277A and 4-formyl-2-(2-methylphenyl)benzoic acid methyl ester. NMR 7.94- 8.00 (m, IH); 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). (DSI/NH3)MS: 452(M+H)+.
Figure imgf000754_0002
Example 1277C r4-N-(N-butyl-N-(2-('2.4-difluorophenvPethvPaminomethvP-2-(2- methylphenvPbenzoyllmethionine. methyl ester.
Prepared according to the procedure of example 1258C from 1277B. ΝMR 7.85-
16575 7.95 (m, IH); 7.00-7.40 (m, 7H); 6.67-6.82 (m, 2H); 5.91-5.97 (m, IH); 4.56-4.70 (m,
IH); 3.63 (s, 5H); 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/ΝH3)MS: 583(M+H)+.
Figure imgf000754_0003
16580 Example 1277D r4-N-f/V-hntyl-Λ-(2-('2.4-difluorophenvPethvPaminomethvP-2-(2- methylphenyPbenzoyll methionine lithium salt. Prepared according to the procedure of example 1178J from 1277C. ΝMR iH(MeOH-d4): 7.45-7.55 ( IH, m); 7.2-7.5 (IH, m); 7.0-7.25 (7H, m); 6.65-6.75 (2H, 16585 m); 4.1-4.25 (IH, 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 (IH, s); 1.8-2.0 (6H, m); 1.65-1.85 (2H, m); 1.4-1.6 (IH, 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 C33H39Ν2θ3SLi« 1.7H2θ: C, 63.50; H, 6.73; N, 4.63. Found: C, 63.50; H, 6.41; N, 4.29. 16590
Figure imgf000755_0001
Example 1279 N-14-N-(N-(4-methyltetrahydropyran-yP-N-(3.5-difluorobenzyPaminomethyP-2-(2- 16595 methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000755_0002
Example 1279 A (MethoxymethyPtriphenylphosphonium chloride (25.71 g, 75 mmol) in 200 ml of 16600 anhydrous THF was treated 1.0 M sodium bis(trimethylsilyl)amide solution (75 ml, 75 mmol) at 0°C in 10 min. under Ν2. The resulted deep red solution was then stiπed 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 TΗF was added. After being stiπed at 0°C for another 1 hour, the solution was brought up to boiling for 12 hours. The reaction mixture was concentrated under 16605 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(CDC13) 5.83 (s, IH); 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)+ ; H6(M+NH4)+.
16610
Figure imgf000756_0001
Example 1279B 1279 A (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
16615 was purified by flash chromatography eluting 3:7 EtOAc/hexane to afford 0.60 g of title compound (75%). NMR(CDC13) 9.62 (s, IH); 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: 1 15(M+H)+ ; 132(M+NH4)+.
e
Figure imgf000756_0002
16620 Example 1279C
Prepared according to the procedure of example 1258 A from reaction between 1258A and 1279B. NMR(CDC13) 7.92-7.99 (m, IH); 7.35-7.45 (m, IH); 7.20-7.30 (m, 4H); 7.05-7.10 (m, IH); 6.82-6.90 (m, 2H); 6.62-6.73 (m, IH); 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);
16625 1.60-1.90 (m, 3H); 1.00-1.20 (m, 2H). DSI/NH3)/MS: 480(M+H)+ .
Figure imgf000756_0003
Example 1279D N- 4-N-('N-(4-methyltetrahvdropyran-vP-N-(3.5-difluorobenzvPaminomethvP-2-(2- 16630 methylphenvPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1258C from 1279C. ΝMR(CDC13) 7.88-7.99 (m, IH); 7.35-7.45 (m, IH); 7.18-7.30 (m, 5H); 6.80-6.90 (m, 2H); 6.62-6.73 (m, IH); 5.85-5.92 (m, IH); 4.52-4.70 (m, IH); 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 16635 (m, 2H); 1.55-1.78 (m, 3H); 1.00-1.20 (m, 2H). DSI/NH3)/MS: 61 1(M+H)+ .
Figure imgf000757_0001
Example 1279E N-r4-N-(N-(4-methyltetrahydropyran-yP-N-('3.5-difluorobenzyl)aminomethyP-2-('2- 16640 methylphenyPbenzoyllmethionine lithium salt.
Prepared according to the procedure of example 1178J from 1279D. ΝMR iH(MeOH-d4): 7.6-7.7 (IH, m); 7.38-7.48 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, m); 6.78-6.88 (IH, m); 4.1-4.22 (IH, 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 (IH, s); 1.76-2.1 (HH, m); 1.0-1.2 (2H, m). ESI(- 16645 )/MS: 595(M-Lp.Anal. Calcd for C33H37F2Ν2θ4SLi*0.52H2θ: C, 64.76; H, 6.26; N, 4.58. Found: C, 64.76; H, 6.01 ; N, 4.45.
Figure imgf000757_0002
16650 Example 1280
N-r4-N-(N-(4-methyltetrahydrothiopyran-yP-N-(3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt.
Figure imgf000758_0001
16655 Example 1280 A
Prepared according to the procedure of example 1279 A from tetrahydrothiopyran-4- one. NMR(CDC13) 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: H5(M+H)+ .
Figure imgf000758_0002
16660 Example 1280B
Prepared according to the procedure of example 1279B from 1280A. NMR(CDC13) 9.65 (s, IH); 2.60-2.80 (m, 4H); 2.20-2.40 (m, 2H); 1.70 1.88 (m, 2H). DSI/NH3)/MS: 131(M+H)+ .
Figure imgf000758_0003
Example 1280C
Prepared according to the procedure of example 1258 A from reaction between
1258A and 1280B. NMR(CDC13) 8.00-8.08 (m, IH); 7.40-7.46 (m, IH); 7.10-7.30 (m,
4H); 7.05-7.10 (m, IH); 6.80-6.90 (m, 2H); 6.85-6.73 (m, IH); 3.60 (S, 5H); 3.50 (s,
16670 2H); 2.50-2.70 (m, 4H); 2.20-2.30 (m, 2H); 2.00-2.20 (m, 5H); 1.40-1.70 (m, 3H); 1.12-
1.30 (m, 2H). DSI/NH3)/MS: 496(M+H)+ .
Figure imgf000759_0001
Example 1280D 16675 V-14-N-(N-(4-methyltetrahydrothiopyran-yP-N-(3,5-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester. Prepared according to the procedure of example 1258C from 1280C. ΝMR(CDC13) 7.85-8.00 (m, IH); 7.1-7.45 (m, 6H); 6.80-6.90 (m, 2H); 6. 65-6.76 (m, IH); 5.84-5.94 (m, IH); 4.55-4.70 (m, IH); 3.65 (s, 3H); 3.52 (s, 2H); 3.45 (s, 2H); 2. 50-2.70 (m, 4H); 16680 2.00-2.30 (m, 13H); 1.78-2.00 (m, IH); 1.50-1.65 (m, 2H); 1.05-1.30 (m, 2H). DSI/NH3)/MS: 626(M+H)+ .
Figure imgf000759_0002
Example 1280E 16685 N-r4-N-(N-(4-methyltetrahydrothiopyran-yP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoy 11 methionine lithium salt. Prepared according to the procedure of example 1178J from example 1280D. ΝMR H(MeOH-d4): 7.6-7.7 (IH, m); 7.38-7.48 (IH, m), 7.0-7.35 (6H, m); 6.9-7.0 (2H, m); 6.75-6.85 (IH, m); 4.1-4.22 (IH, m); 3.6 (2H, s); 3.55(2H, s); 3.35 (2H, s); 2.4-2.65 16690 (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-Lp.Anal. Calcd for C33H37F2Ν2θ4S2Li*1.21H2θ*1.0LiOH: C, 59.65; H, 6.13; N, 4.22. Found: C, 59.65; H, 5.85; N, 3.89.
Figure imgf000760_0001
Example 1281
N-r4-N-('N-(4-tetrahydropyran-yP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenvPbenzoyllmethionine lithium salt.
Figure imgf000760_0002
Example 1281 A Prepared according to the procedure of example 1258A from reaction between 1258A and tetrahydro-4-H-pyran-4-one. ΝMR(CDC13) 7.80-7.95 (m, 1Η); 7.35-7.45 (m, 1Η); 7.15-7.30 (m, 4Η); 7.04-7.10 (m, IH); 6.80-6.89 (m, 2H); 6.58-6.70 (m, IH); 3.95-
16705 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, IH); 2.05 (s, 3H); 1.60-1.80 (m, 4H). (DSI/NH3)/MS: 466(M+H)+ .
Figure imgf000760_0003
Example 128 IB 16710 N-r4-N-(N-(4-tetrahydropyran-yP-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyllmethionine. methyl ester Prepared according to the procedure of example 1258C from 1281 A. ΝMR(CDC13) 7.81-7.98 (m, IH); 7.38-7.45 (m, IH); 7.20-7.40 (m, 4H); 7.18 (s, IH); 6.83-6.91 (m, 2H); 6.60-6.70 (m, IH); 5.81-5.90 (m, IH); 4.58-4.70 (m, IH); 3.95-4.02 (m, 2H); 3.70 16715 (s, 2H); 3.63 (s, 2H); 3.60 (s, 2H); 3.20-3.38 (m, IH); 2.55-2.80 (m, IH); 1.92-2.20 (m, 8H); 1.75-1.95 (m, IH); 1.61- 1.78 (m, 3H). 1.50-1.65 (m, 2H); (DSI/NH3)/MS:
597(M+Hy
Figure imgf000761_0001
16720 Example 1281C
N-[4-N-(N-(4-tetrahydropyran-yP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt. Prepared according to the procedure of example 1178J from 128 IB. ΝMR H(MeOH-d4): 7.58-7.68 (IH, m); 7.38-7.48 (IH, m), 7.0-7.28 (6H, m); 6.9-7.0 (2H, 16725 m); 6.78-6.88 (IH, m); 4.1-4.22 (IH, m); 3.9-4.0 (2H, m); 3.75 (2H, s); 3.7 (2H, s); 3.3 (,2H, m); 2.7-2.85 (IH, m); 2.2 (IH, s); 1.76-2.1 (HH, m). ESI(-)/MS: 586(M-Li). Anal. Calcd for C32H35F2Ν2θ4SLi*2.07H2θ: C, 61.41; H, 6.30; N, 4.37. Found: C, 61.40; H, 6.05; N, 4.37.
16730
Figure imgf000761_0002
Example 1313
N-r4-(N-('3-Cvclohexyl-l-ethylthioprop-2-vPaminomethvP-2-(2- methylphenyPbenzoynamino-4-methylsulfonylbutanoate Lithium Salt
16735
Figure imgf000761_0003
Example 1313A 2-Amino-3-cyclohexyl- 1 -ethylthiopropane Trifluoroacetic acid (3 mL) was added to a solution of the product from Example 16740 403C (274 mg, 0.9 mmol) in CH2CI2 (3 mL) at ambient temperature. After 30 min of stiπing, solvent was removed and the residue redissolved in CH2CI2, 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%): iH NMR (CDCI3, 300 MHz) δ 2.97 (m, IH), 2.68 (dd, J=13, 4 Hz, IH), 2.55 (q, J=7.5 Hz, 16745 2H), 2.34 (dd,J=13, 8.5 Hz, IH), 1.80-1.61 (m, 5H), 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)+.
Figure imgf000762_0001
Example 1313B 16750 Methyl-N-[4-hydroxymethyl-2-(2-methylphenyl)benzoyl1-2-amino-4- methylsulfonylbutanoate 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 Et2θ. The 16755 phases were separated and concentrated HCl added to the aqueous phase which was extracted with EtOAc (2X). The EtOAc phases were combined, dried (MgSO4) and concentrated to dryness to afford the crude acid as a white solid. MS (CI/ΝH3) 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, 16760 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%).
Figure imgf000762_0002
16765 Example BBC
Methyl-N-r4-formyl-2-(2-methylphenyPbenzoyll-2-amino-4-methylsulfonylbutanoate Dimethylsulfoxide (325 μL, 4.6 mmol) was added to a solution of oxalyl chloride (200 μL, 2,5 mmol) at -78 °C. After stiπing for 5 min, the product from Example B (955 mg, 2.3 mmol) in CH2CI2 (2.5 mL) was added to the reaction vessel. After 15 min,
16770 TEA (950 μL, 6.8 mL) was added to the reaction mixture and the cold bath was removed. After stiπing 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%). *H NMR (CDCI3, 300 MHz) δ 1.88 (m, IH), 2.11-2.30 (m, 4H), 2.47-2.73 (m, 2H), 2.71
16775 (s, 3H), 3.71 (s, 3H), 4.65 (m, IH), 6.12 (dd, J=8 8 Hz, IH), 7.20 (d, J=7 Hz, IH), 7.27-7.41 (m, 2H), 7.76 (s, IH), 7.95-8.06 (m, 2H), 10.10 (s, IH); MS (CI/NH3) m/z: 418 (M+H)+.
Figure imgf000763_0001
16780 Example 1313D Methyl-N- 4-(N-(3-Cyclohexyl-l-ethylthioprop-2-yPaminomethyP-2-(2- methylphenyPbenzoynamino-4-methylsulfonylbutanoate The product from Example 13 BA (285 mg, 1.4 mmol), the product from Example B BC (618 mg, 1.5 mmol) and sodium triacetoxyborohydride (415 mg, 2.0 mmol) were
16785 combined in 1,2-dichloroethane (6 mL) at ambient temperature and allowed to stir for 18 hours. A solution of saturated ΝaHC03 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 (CI/NH3) m/z: 418 (M+H)+.
16790
Figure imgf000763_0002
SEt Example 13 BE N-r4-('N-f3-Cvclohexyl-1-ethylthioprop-2-vPaminomethvP-2-(2- methylphenvPbenzoyllamino-4-methylsulfonylbutanoate Lithium Salt 16795 The product from Example 13 BD (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 titie compound, lH ΝMR (DMSO-d6, 300 MHz) δ 0.70-0.91 (m, 2H), 1.12- 1.65 (m, HH), 1.75-2.20 (m, 5H), 2.35-2.67 (m, 7H), 2.82 (s, 3H), 3.66- 3.86 (m, 3H), 6.95 (m, IH), 7.10-7.25 (m, 4H), 7.38 (d, J=8 Hz.lH), 7.53 (d, J=8 Hz, 16800 IH); MS (APCI(-)) m/z: (M-H)" 587; Anal. Calcd for C3lH43LiΝ2θ5S2« 1.90 H2O: C, 59.20; H, 7.50; N, 4.45. Found: C, 59.22; H, 7.16; N, 4.36.
Figure imgf000764_0001
16805 Example 1317
Figure imgf000764_0002
Figure imgf000764_0003
16810 Example 1319
N-r4-(N-Methyl-N-(2-cyclohexylethyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine 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 16815 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. X NMR (CDCI3) δ 7.80 (m, 3H), 7.58 (dd, IH), 7.22 (m, 7H), 6.18 (m, IH), 4.20 (m, IH), 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 C36H47N3O4S2* 1-00
16820 H2O: C, 64.74; H, 7.39; N, 6.29. Found: C, 64.53; H, 7.22; N, 6.06.
Figure imgf000765_0001
Example 1332 16825 N-r4-N-(N-(tr n^-4-hydroxycyclohexyP-N-("3.5-difluorobenzyPaminomethyl)-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000765_0002
Example 1332A
16830 A mixture of 1 ,4-cyclohexanedione mσrcø-2,2-dimethyltrimethylene ketal (1.98 g,
10 mmol), and sodium borohydride (0.757 g, 20 mmol) in 100 ml of methanol was stiπed for 12 hours. The methanol was removed under reduced pressure. The residue was taken into ethyl acetate, washed by 10 % ΝaOH and brine respectively, and the dried over anhydrous MSG. Yield: 1.60 g (80%). (SDI/ΝH3) MS: 201(M+H)+; 218(M+NH4)+.
16835
Figure imgf000765_0003
Example 1332B Prepared according to the procedure of example 1252 from the reaction between example 1332A and benzyl bromide. NMR(CDC13) 7.20-7.35 (m, 5H); 4.57 (s, 2H); 3.45- 16840 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)+.
Figure imgf000766_0001
Example 1332C 16845 Prepared according to the procedure of example of example 1266A from the reaction of example 1232B and HCl. NMR(CDC13) 7.23-7.40 (m, 5H); 4.60 (s, 2H); 3.78-4.08 (m, IH); 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)+.
Figure imgf000766_0002
Example 1332D Prepared according to the procedure of example 1279 A from the reaction between example 1232C and (Methoxymethyl)triphenylphosphonium chloride. NMR(CDC13) 7.23- 7.40 (m, 5H); 5.85 (s, IH); 4.60 (s, 2H); 3.63-3.75 (m, 5H); 2.58-2.70 (m, IH); 2.10- 16855 2.30 (m, IH); 1.4-2.0 (m, 5H). (SDI/NH3) MS: 233(M+H)+; 250(M+NH4)+.
Figure imgf000766_0003
Example 1332E Example 1332D was hydrolyzed in formic acid according to the example 1279B to 16860 give coπesponding aldehyde, which was used to react with example 1258A to give two isomers. One is example 1232E, the other is example 1233A. NMR(CDC13) 7.90-7.95 (m, IH); 7.38-7.44 (m, IH); 7.13-7.39 (m, 9H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60- 6.70 (m, IH); 4.55 (s, 2H); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 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 16865 (m, 2H); 0.67-0.83 (m, 2H). (SDI/NH3) MS: 584(M+H)+. e
Figure imgf000767_0001
Example 1332F A mixture of 1332D (0.07 g, 0.12 mmol) and 0.1 ml of trimethylsiliy iodide in 2 ml 16870 of methylene chloride was stiπed 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, IH); 7.40-7.44 (m, IH); 7.13-7.39 (m, 4H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60-6.70 (m, IH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 2.18-2.21 (m, 2H); 2.0-2.18 (m, 4H); 1.80-2.00 (m, 2H); 1.40-1.60 16875 (m, 2H); 1.09-1.32 (m, 2H); 0.67-0.83 (m, 2H). (SDI/NH3) MS: 494(M+H)+.
Figure imgf000767_0002
Example 1332G Prepared according to the procedure of example 1258C from example 1232F.
16880 NMR(CDC13) 7.83-7.95 (m, IH); 7.40-7.44 (m, IH); 7.13-7.40 (m, 4H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60-6.70 (m, IH); 5.84-5.90 (m, IH); 4.55-4.67 (m, IH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 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). (SDI/NH3) MS: 624(M+H)+.
16885
Figure imgf000768_0001
Example 1332H N-r4-N-(N-(trαn_v-4-hydroxycyclohexyP-N-(3.5-difluorobenzyl)aminomethyl)-2-(2- methylphenyPbenzoy 11 methionine lithium salt 16890 Prepared according to the procedure of example 1178J from example 1332G.
ΝMR(CDC13) 7.60-7.70 (m, IH); 7.40-7.44 (p IH); 7.13-7.40 (m, 5H); 6.83-7.00 (m, 2H); 6.68-6.72 (m, IH); 4.20-4.30 (m, IH); 3.60 (m, 2H); 3.55 (m, 2H); 3.18-4.30 (m, IH); 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-Lp. Anal. Calcd for C34H39F2N2θ4SLi*2.00 16895 LiOH: C, 61.45; H, 6.22; N, 4.22. Found: C, 61.56; H, 5.88; N,3.94.
Figure imgf000768_0002
Example 1333 16900 N-r4-N-(N-(c »-4-hydroxycyclohexyP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt
Figure imgf000769_0001
Example 1333 A
16905 Prepared according to the procedure of example 1332E. NMR(CDC13) 7.90-7.95 (m, IH); 7.38-7.44 (m, IH); 7.13-7.39 (m, 9H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60-6.70 (m, IH); 4.55 (s, 2H); 3.90H.00 (m, IH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 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)+.
16910
Figure imgf000769_0002
Example 1333B Prepared according to the procedure of example 1332F from the reaction between 1333B and trimethylsilyl iodide. NMR(CDC13) 7.90-7.95 (m, IH); 7.40-7.44 (m, IH);
16915 7.13-7.39 (m, 4H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60-6.70 (m, IH); 3.90-4.00 (m, IH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 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)+.
Figure imgf000770_0001
Example 1333C Prepared according to the procedure of example 1258C from example 1333B. NMR(CDC13) 7.83-7.95 (m, IH); 7.40-7.44 (m, IH); 7.13-7.40 (m, 4H); 7.02-7.10 (m, IH); 6.83-6.92 (m, 2H); 6.60-6.70 (m, IH); 5.84-5.90 (m, IH); 4.55-4.67 (m, IH); 3.92-
16925 4.02 (m, IH); 3.60 (s, 3H); 3.55 (m, 2H); 3.50 (m, 2H); 3.18-4.30 (m, IH); 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)+.
Figure imgf000770_0002
16930 Example 1333D N-f4-N-(N-(c^-4-hydroxycyclohexyP-N-(3.5-difluorobenzyPaminomethyP-2-(2- methylphenyPbenzoyllmethionine lithium salt Prepared according to the procedure of example 1178J from example 1333C. ΝMR(CDC13) 7.60-7.70 (m, IH); 7.40-7.44 (m, IH); 7.13-7.40 (m, 5H); 6.83-7.00 (m,
16935 2H); 6.68-6.72 (m, IH); 4.20-4.30 (m, IH); 3.92-4.01 (m, IH); 3.60 (m, 2H); 3.55 (m, 2H); 3.18-4.30 (m, IH); 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-Lp. Anal. Calcd for C34H39F2N2θ4SLi*2.50 LiOH«0.57H2O: C, 62.58; H, 6.26; N, 4.29. Found: C, 61.61; H, 5.99 N,3.92.
16940
Figure imgf000771_0001
Example 1334 (2S) 2-N-r4-(l-ethylthio-3-cvclohexylprop-2-ylaminomethvP-2-(2- methylphenyPbenzoyllamino-4-methylsulfenylbutanoate Lithium Salt
16945
Figure imgf000771_0002
Example 1334 A (2S 2-N-r4-formyl-2-(2-methylphenyPbenzoynamino-4-methylsulfenylbutanoate. Methyl
Ester
16950 The title compound was prepared from N-[4-formyl-2-(2- methylphenyl)benzoyl]methionine methyl ester (example 403G) according to the procedure in example 107 ID, and was isolated as a light yellow oil. MS(APCI(+)) 402 (M+H)+. MS(APCI(-)) 436 (M+Cl)", 400 (M-H)".
16955
Figure imgf000771_0003
Example 1334B (2S 2-N- 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyPbenzoyllamino-4-methylsulfenylbutanoate. Methyl Ester The title compound was prepared according to example 403H, substituting (2S) 2-N- 16960 [4-formyl-2-(2-methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate methyl ester for N- [4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester. MS(APCI(+)) 587 (M+H)+. MS(APCI(-)) 621 (M+Cl)".
Figure imgf000772_0001
16965 Example 1334C
(2S 2-N-r4-d-ethylthio-3-cvclohexylprop-2-ylaminomethvP-2-(2- methylphenyPbenzoyllamino-4-methylsulfenylbutanoate. Lithium Salt The titie compound was prepared from (2S) 2-N-[4-(l-ethylthio-3-cyclohexylprop- 2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate methyl 16970 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. H NMR (300 MHz, DMSO) δ 0.66-0.90 (m, 2H), 1.02-1.80 (m, BH), 1.10 (t, J=7.2 Hz, 3H), 1.96-2.21 (m, 5H), 2.36 (s, 1.5H), 2.39 (s, 1.5H), 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, IH), 7.08-7.23 (m, 5H), 16975 7.38 (d, J=8.4 Hz, IH), 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).
Figure imgf000772_0002
16980 Example 1335
N-\4-(N-(2-( 1.3-dioxan-2-ylethvP-N-butylaminomethyP-2-C2- methylphenyPbenzoyllmethionine
Figure imgf000773_0001
16985 Example 1335 A
4-Formyl-2-(2-methylphenyl)benzoic acid methyl ester Following the procedure of example 1 134D, example 1 178 C (3.30 g, 1 1.82 mmol) provided 3.00 g 100%) of the title compound. MS (DCI, NH3): 255 (MH+).
Figure imgf000773_0002
Example 1335B
4-n-Butylaminomethyl-2-(2-methylphenyl)benzoic acid methyl ester
Following the procedure of example 1106D, part 1 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
16995 (DCI, NH3): 312 (MH+).
e
Figure imgf000773_0003
Example 1335C 4-(N-(2-( 1.3-dioxan-2-ylethyP-N-butylaminomethyl)-2-(2-methylphenyPbenzoic acid. methyl ester 17000 A solution of example 1335B (359 mg 1.15 mmol), 2-bromoethyl-l,3-dioxane (164 μL, 1.2 mmol), TBAI (443 mg, 1.2 mmol) and diiospropylethylamine (260 μL, 1.5 mmol) in 3 mL of DMF were heated to 60°C 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 17005 column chromatography on silica gel (25 g, 25% ethyl acetate/hexanes) provided 330 mg (78%) of the title compound. MS: (ESI+) 426 (MH+).
Figure imgf000774_0001
Example 1335D 4-(N-(2-( 1.3-dioxan-2-ylethyl)-N-butylaminomethyP-2-(2-methylphenyl)benzoic acid.
17010 Following the procedure of example 1 BOD, example 1335C (310 mg, 0.72 mmol) provided 222 mg (75%) of the title compound. MS (ESI+): 412 (MH+): (ESI-): 410 (M- H).
Figure imgf000774_0002
17015 Example 1335E
N- 4-(N-(2-( 1.3-dioxan-2-ylethvP-N-butylaminomethyP-2-(2- methylpheny benzoyllmethionine. methyl ester Following the procedure of example 11781, exampleB35D (85 mg, 0.25 mmol) provided 57 mg (50%) of the title compound. MS (ESI+): 557 (MH+): (ESI-): 555 (M- 17020 H) .
Figure imgf000774_0003
Example 1335F N- 4-(N-(2-( 1.3-dioxan-2-ylethvP-N-butylaminomethvP-2-r2- methylphenyPbenzoyllmethionine 17025 Following the procedure of example 1104D, examplel335 E (55 mg (0.10 mmol) provided 30 mg of the titie compound. H nmr (300 MHz., CD3OD): δ 7.64, d, IH; 7.49, dd, IH; 7.29, m, IH; 7.02 - 7.22, m, 4H; 4.64, t, IH; 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 17030 C31H43Ν2O5S*1.30 H2O; C 63.64; H 7.94; N 4.95; Found: C 63.63; H 7.37; N 5.07.
Figure imgf000775_0001
Example 1336 N-[4-(N-("2-cyclohexylethvP-N-methylaminomethyP-2-(2- 17035 methylphenyPbenzoyllthioglutamine Lithium Salt
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]thioglutamine methyl ester (12 mg, 22.9 μmol) 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)'.
17040
Example 1336B N-r4-(N-(2-cyclohexylethyP-N-methylaminomethyP-2-(2- methylphenyPbenzoyllthioglutamine Methyl Ester N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- 17045 methylphenyPbenzoyllglutaminitrile 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 stiπed 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 17050 (M+H)+. X ΝMR (CDC13, 300 MHz) δ 0.82 (m, 2H), 1.1 1 (m, 3H), 1.32 (m, 5H), 1.6 (m, 7H), 2.18 (m, 6H), 2.32 (m, IH), 2.58 (m, IH), 2.75 (m, IH), 3.53 (m, 2H), 3.72 (s, 3H), 6.9-7.5 (m, 9H), 7.83 (m, IH).
Figure imgf000775_0002
Example 1337 N-14-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2-(2- methylphenyPbenzoyllmethionine O
17060
Figure imgf000776_0001
Example 1337 A 2-(2-MethylphenvP-4-formyl-5-methoxybenzoic 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 stiπed for 3 hours. The
17065 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 titie compound. MS (DCI, NH3): 302 (M+ NH4 +).
Figure imgf000776_0002
Example 1337B 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-methoxy-2-(2-methylphenyl)benzoic acid, methyl ester Using the procedure of example 1134E, example 1337 A provided the titie 17075 compound. MS (ESI +): 470 (MH+); (ESI-) 468 (M-H).
Example 1337C 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2-(2-methylphenyPbenzoic acid
17080 Using the procedure of example 1134F, example 1337B provided the title compound. MS (ESI +): 456 (MH+); (ESI-) 454 (M-H).
Figure imgf000777_0001
Example 1337D
17085 N-r4-( l-ethylthio-3-cyclohexylprop-2-ylaminomethvP-5-methoxy-2-(2- methylphenyPbenzoyllmethionine. methyl ester
According to the procedure described in example 11781, example 1 137C (55 mg,
0.12 mmol) provided 39 mg (54%) of the title compound. MS (ESI +): 601 (MH+); (ESI-)
599 (M-H).
17090
Figure imgf000777_0002
Example 1337 N- 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-methoxy-2-(2- methylphenyPbenzoyllmethionine 17095 Following the procedure of example 1 105D, example 1 137D (39 mg, 0.065 mmol) provided the title compound. X ΝMR (300 MHz, DMSO): δ 7.9 (IH), 7.0-7.3 (5H), 4.1 (IH), 3.9 ( IH), 3.3 (3H), 2.7 (IH), 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)
17100
Figure imgf000777_0003
Example 1338 N-|"4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethylV5-N'N'-dimethylamino-2-(2- methy lphenvPbenzoy 11 methionine
17105
Figure imgf000778_0001
Example 1338 A
2-(2-Methylphenyl)-4-formyl-5-N.N-dimethylaminobenzoic acid, methyl ester
A solution of example 1134D (146 mg, 0.50 mmol) in 1 mL of DMF was treated
17110 with 2 mL of 40% aqueous dimethylamine and the mixture heated at 70°C 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
17115 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+).
e
Figure imgf000778_0002
17120 Example 1338B 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-N'.N'-dimethylamino-2-(2- methylphenyPbenzoic acid, methyl ester Using the procedure of example 1134E, example 1338A provided the title compound. MS (ESI +): 483 (MH+); (ESI-) 481 (M-H).
17125
Figure imgf000779_0001
Example 1338C 4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethvP-5-N'.N'-dimethylamino-2-(2- methylphenvPbenzoic acid
17130 Following the procedure of example 1134F, example 1138B provided the title compound. MS (ESI +): 469 (MH+); (ESI-) 467 (M-H).
Figure imgf000779_0002
Example 1338D
17135 N-14-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyP-5-N'N'-dimethylamino-2-(2- methylphenyPbenzoyll methionine. methyl ester According to the procedure described in example 11781, example 1138C (93 mg, 0.20 mmol) provided 69 mg (56%) of the title compound. MS (ESI +): 614 (MH+); (ESI-) 612 (M-H).
17140
Figure imgf000779_0003
Example 1338E N-r4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N'N'-dimethylamino-2-(2- methylphenyPbenzoyllmethionine 17145 Following the procedure of example 1 105D, example 1 138D (69 mg, 0.1 1 mmol) provided the title compound. *H NMR (300 MHz., DMSO): 8 7.9 ( IH), 7.0-7.3 (5H), 4.2 ( IH), 3.9 ( IH), 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).
17150
Example 1339 Pittsburg example, waiting for experimental data and other information.
Figure imgf000780_0001
Example 1340
Figure imgf000780_0002
Example 1340A
17160 N-r4-N-("6-FIuorobenzothiazol-2-yPaminomethyl-2-(2-methylphenyl)benzoynmethionine methyl ester The desired compound was prepared according to the method of Example 1203 A starting with N-[4-formyl-2-(2-methylphenyl)benzoyllmethionine methyl ester, prepared as in Example 403G, and 2-amino-6-fluorobenzothiazole. m/e (ESI) 538 (MH+)
17165
Figure imgf000781_0001
Example 1340B N-[4-N-(6-Fluorobenzothiazol-2-yPaminomethyl-2-(2-methylphenyl)benzoyl1methionine The desired compound was prepared according to the method of Example 4031 starting with
17170 the compound in Example B40A.1H (300MHz, CDCI3. δ) 7.91 (IH, m), 7.51 (IH, m), 7.34 (2H, m), 7.30-7.15 (4H, m), 7.05 (3H, m), 5.99 (IH, m), 4.59 (IH, m), 4.48 (2H, bd, J=8Hz), 2.20- 1.80 (9H, m), 1.72 (IH, m). m/e (ESI) 522 (MH") Anal.calc. for C27H26FΝ3O3S2O.25 H2O C 61.40, H 5.06, N 7.96 Found C 61.38, H 4.56, N 7.73
17175
Figure imgf000781_0002
Example 1341
O'
17180 Example 1341 A
N— Butyl-N-(furan-2-ylmethyPamine The desired amine was prepared using the method described in Example 1171 A starting with 2-furoic acid and butylamine. m/e (DCI/ΝH3) 154 (MH+)
Figure imgf000781_0003
4-(N-Butyl-N-(furan-2-ylmethyPaminomethvP-2-(2-methylphenyl)benzoic acid methyl ester
The desired compound was prepared using the method described in Example 1 178G starting 17190 with N-Butyl-N-(furan-2-ylmethyl)amine, prepared as in Example 1341 A, and 4- bromomethyl-2-(2-methy IphenyPbenzoic acid methyl ester, prepared as in Example 1 178A- D. m/e (ESI) 392 (MH+)
Figure imgf000782_0001
17195 Example 134 IC
4-(N-Butyl-N-ffuran-2-ylmethyPaminomethyP-2-(2-methylphenyPbenzoic acid The desired acid was prepared using the method described in Example 403E starting with the compound prepared in Example 134 IB.
Figure imgf000782_0002
Example 134 ID N-[4-N-Butyl-N-(furan-2-ylmethyPaminomethyl-2-("2-methylphenyPbenzoyllmethionine methyl ester The desired product was prepared using the method described in Example 403F starting 17205 with the compound prepared in Example 1341C. m/e (ESI) 523 (MH+)
Figure imgf000782_0003
Example 134 IE N-r4-N-Butyl-N-(furan-2-ylmethyl)aminomethyl-2-(2-methylphenyPbenzoyl1methionine 17210 The desired compound was prepared according to the method of Example 4031 starting with compound prepared in Example B41D. iH (300MHz, CDCI3, δ) 7.81 (IH, d, J=8Hz), 7.57 (IH, m), 7.42 (IH, d, J=2Hz), 7.30-7.10 (5H, m), 6.35 (2H, m), 6.15 ( IH, bd, J=8Hz), 4.43 (IH, m), 3.98 (2H, m), 3.90-3.75 (2H, m), 2.62 (2H, m), 2.20- 2.00 (5H, m), 1.99 (3H, s), 1.95 (IH, m), 1.60 (3H, m), 1.29 (2H, m), 0.88 (3H, t, 17215 I=8Hz). m/e (ESI) 509 (MH+) Anal.calc. for C29H36N2O4SO.5O H2O C 67.28, H 7.20, N 5.41 Found C 67.42, H 6.96, N 5.44.

Claims

WHAT IS CLAIMED TS- 17220 1 . A compound having Formula I or a pharmaceutically acceptable salt thereof, wherein 17225 Rj is selected from the group consisting of (1) hydrogen, (2) alkenyl, (3) alkynyl, (4) alkoxy, 17230 (5) haloalkyl, (6) halogen, (7) loweralkyl, (8) thioalkoxy, (9) aryl-L2- wherein aryl is selected from the group consisting of 17235 (a) phenyl, (b) naphthyl, (c) dihydronaphthyl, (d) tetrahydronaphthyl, (e) indanyl, and 17240 (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, 17245 alkynyl, alkoxy, aryl, carboxy, cyano, 17250 halogen, haloalkyl, hydroxy, hydroxyalkyl, loweralkyl, 17255 nitro, N-protected amino, and -NRR' wherein R and and R' are independently selected from the group consisting of hydrogen and 17260 loweralkyl, oxo (=O), and thioalkoxy and L2 is absent or is selected from the group consisting of 17265 -CH2CH2-, -CH(CH3)-, -O-, -C(O)-, -S(O)α wherein q is 0, 1 or 2, and 17270 -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, 17275 (b) hydroxy, (c) hydroxyalkyl, (d) halogen (e) cyano, (f) nitro, 17280 (g) oxo (=O), (h) -NRR', (i) N-protected amino, (j) alkoxy, (k) thioalkoxy, 17285 (1) haloalkyl, (m) carboxy, and (n) aryl; R2 is selected from the group consisting of 17290 (1) wherein L-n is selected from the group consisting of (a) a covalent bond, (b) -C(W)N(R)- wherein R is defined previously and W is selected from the group consisting of O and S, 17295 (c) -C(O)-, (d) -N(R)C(W)-, (e) -CH O-, (f) -C(O)O-, and (g) -CH2N(R)-, 17300 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 17305 hydrogen and a carboxy-protecting group, and R12b is selected from the group consisting of (a) hydrogen and ' (b) loweralkyl, 17310 with the proviso that R12a and R12b are not both hydrogen, (2) -Li ι-C(R14)(Rv)-C(O)OR15 wherein Li 1 is defined previously, Rv is selected from the group consisting of (a) hydrogen and 17315 (b) loweralkyl, Rj5 is selected from the group consisting of (a) hydrogen, (b) alkanoyloxyalkyl, (c) loweralkyl, and 17320 (b) a carboxy-protecting group, and R14 is selected from the group consisting of (a) alkoxyalkyl, (b) alkoxyarylalkyl, (c) alkoxycarbonylalkyl, 17325 (d) alkylsulfinyalkyl, (e) alkylsulfonylalkyl, (0 alkynyl, (g) aminoalkyl, (h) aminocarbonylalkyl, 17330 (P aminothiocarbonylalkyl, (j) aryl, ( ) arylalkyl, (1) carboxyalkyl, (m) cyanoalkyl, 17335 (n) cycloalkyl, (o) cycloalkylalkoxyalkyl, (P) cycloalkylalkyl, (q) (heterocyclic)alkyl, (r) hydroxyalkyl, 17340 (s) hydroxyarylalkyl, (P loweralkyl, (u) sulfhydrylalkyl, (v) thioalkoxyalkyl wherein the thioalkoxyalkyl is unsubstituted or substituted with 1, 2, 3, or 4 17345 substituents selected from the group consisting of halogen, (w) thioalkoxyalkylamino, and (x) thiocycloalkyloxyalkyl, 17350 (3) wherein n is 1-3, (4) -C(O)NH-CH(R14)-C(O)NHSO2Ri6 wherein Ri4 is defined previously and Ri6 is selected from the group consisting of (a) loweralkyl, 17355 (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, 17360 hydroxy, hydroxyalkyl, halogen, cyano, nitro, 17365 oxo (=O), -NRR' N-protected amino, alkoxy, thioalkoxy, 17370 haloalkyl, carboxy, and aryl, and (d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently 17375 selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halogen, 17380 cyano, nitro, oxo (=O), -NRR', N-protected amino, 17385 alkoxy, thioalkoxy, haloalkyl, carboxy, and aryl; 17390 (5) -C(O)NH-CH(Rι )-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl, (6) -L 1 1 -heterocycle, 17395 (7) -C(O)NH-CH(R14)-C(O)NRι7Rι8 wherein R14 is defined previously and Rn and Ris are independently selected from the group consisting of (a) hydrogen, 17400 (b) loweralkyl, (c) arylalkyl, (d) hydroxy, and (e) dialkylaminoalkyl, 17405 (8) -C(O)ORι5, and (9) -C(O)NH-CH(Rι4)-heterocycle wherein Rι4 is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl; 17410 Lj 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) C , -to-C j 0-alkylene and 17415 (b) C2-to-C16-alkenylene, wherein the alkylene and alkenylene groups are unsubstituted or substituted with 1, 2, 3 or 4 substitutents independently selected from the group consisting of alkenyl, 17420 alkenyloxy, alkenyloxyalkyl, alkenyl[S(O)q]alkyl, alkoxy, alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or 17425 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 17430 substituents independently selected from the group consisting of halogen and cycloalkyl, alkylsilyloxy, 17435 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 17440 alkoxy wherein the alkoxy is unsubstituted or substituted with substituents selected from the group consisting of cycloalkyl, aryl, arylalkyl, 17445 aryloxy wherein the aryloxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of, halogen, 17450 nitro, and -NRR', cycloalkyl, halogen, loweralkyl, 17455 hydroxyl, nitro, -NRR', and -SO2NRR', arylalkoxy wherein the arylalkoxy is unsubstituted or 17460 substituted with substituents selected from the group consisting of alkoxy, arylalkyl, arylalkyl[S(O)q]alkyl, aryl[S(O)q], 17465 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, 17470 arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of alkoxy, and halogen, 17475 aryloxy, aryloxyalkyl wherein the aryloxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of halogen, carboxyl, 17480 -C(O)NRCRD wherein Rc and RD are independently selected from the group consisting of hydrogen, loweralkyl, and alkoxycarbonyl or 17485 R and RD together with the nitrogen to which they are attached form a ring selected from the group consisting of morpholine, piperidine, 17490 pyπolidine thiomorpholine, thiomorpholine sulfone, and thiomorpholine sulfoxide, wherein the ring formed by Rc and RD 17495 together is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy and alkoxyalkyl, 17500 cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of alkenyl, cyclolalkoxy, cycloalkoxycarbonyl, 17505 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, 17510 loweralkyl, and alkanoyl, cycloalkylalkoxy, cycloalkylalkoxycarbonyl, cycloalkylalkoxyalkyl, 17515 cycloalkylalkyl, cyclolalkyl[S(O)q]alkyl, cycloalkylalkyl[S(O)q]alkyl, fluorenyl, heterocycle wherein the heterocycle is unsubstituted or 17520 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 17525 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 17530 the group consisting of aryl and cycloalkyl, alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1 or 2 17535 substituents independently selected from the group consisting of aryl and cycloalkyl, aryl wherein the aryl is unsubstituted or 17540 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkanoyl, alkoxy, 17545 carboxaldehyde, haloalkyl, halogen, loweralkyl, nitro, 17550 -NRR', and thioalkoxy, arylalkyl, aryloxy, cycloalkoxyalkyl, 17555 cycloalkyl, cycloalkylalkyl, halogen, heterocycle, hydroxyl, 17560 loweralkyl wherein the loweralkyl is unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from the group consisting of heterocycle, 17565 hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon, and -NRR3R3' wherein RR3 and RR3' are 17570 independently selected from the group consisting of hydrogen aryl, loweralkyl, 17575 aryl, arylalkyl, heterocycle, (heterocyclic)alkyl, cycloalkyl, and 17580 cycloalkylalkyl, and sulfhydryl, (heterocyclic) alkoxy , (heterocyclic)alkyl, (heterocyclic)alkyl[S(O)q]alkyl, 17585 (heterocyclic)oxy, (heterocyclic)alkoxyalkyl, (heterocyclic)oxyalkyl, heterocycle[S(O)q]alkyl, hydroxyl, 17590 hydroxyalkyl, imino, N-protected amino, =N-O-aryl, and =N-OH, 17595 =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, 17600 hydroxy,. hydroxyalkyl, halogen, cyano, nitro, 17605 OXO (=O), -NRR' N-protected amino, alkoxy, thioalkoxy, 17610 haloalkyl, carboxy, and aryl, =N-O-loweralkyl, -NRR3RR3', 17615 -NHNRCRD, -OG wherein G is a hydroxyl protecting group, -O-NH-R, -0-N=< J wherein J and J' are independently selected from the group consisting of 17620 loweralkyl and arylalkyl, oxo, oxyamino(alkyl)carbonylalkyl, oxyamino(arylalkyl)carbonylalkyl, 17625 oxyaminocarbonylalkyl, -SO2-A wherein A is selected from the group consisting of loweralkyl, aryl, and 17630 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 17635 alkoxy, halogen, haloalkyl, loweralkyl, and nitro, 17640 sulfhydryl, thioxo, and thioalkoxy, L5 is absent or selected from the group consisting of (a) Cj-to-CjQ-alkylene and 17645 (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, 17650 alkanoyl wherein the alkanoyl is unsubstituted or substituted with substituents selected from the group consisting of aryl, alkoxy, alkoxyalkyl, 17655 alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from the group consisting of aryl and 17660 halogen, alkylaminocarbonylalkyl wherein the alkylaminocarbonylalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting 17665 of aryl, (anthracenyl)alkyl, aryl, arylalkoxy, arylalkyl wherein the arylalkyl is unsubstituted or 17670 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkoxy, aryl, 17675 carboxyl, cyano, halogen, haloalkoxy, haloalkyl, 17680 nitro, oxo, and -Lιι-C(R14)(Rv)-C(O)OR15, (aryl)oyl wherein the (aryl)oyl is unsubstituted or substituted with substituents selected from the 17685 group consisting of halogen, aryloxycarbonyl, carboxaldehyde, -C(O)NRR', cycloalkoxycarbonyl, 17690 cycloalkylaminocarbonyl, cycloalkylaminothiocarbonyl, cyanoalkyl, cyclolalkyl, cycloalkylalkyl wherein the cycloalkylalkyl is 17695 unsubstituted or substituted with 1 or 2 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon, (cyclolalkyl)oyl, 17700 (9,10-dihydroanthracenyl)alkyl wherein the (9,10-dihydroanthracenyl)alkyl is unsubstituted or substituted with 1 or 2 oxo substituents, haloalkyl, heterocycle, 17705 (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, 17710 loweralkyl, wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of -NRR', -SO -A, and thioalkoxyalkyl; 17715 (2) -L4-O-L5- (3) -L4-S(O)m-L5- wherein L4 and L5 are defined previously and m is 0, 1 , or 2, 17720 (4) -L4-L6-C(W)-N(R6)-L5- wherein L4> W, and L5 are defined previously, R is selected from the group consisting of (a) hydrogen, (b) loweralkyl, 17725 (c) aryl, (d) arylalkyl, (e) heterocycle, (f) (heterocyclic)alkyl, (g) cyclolakyl, and 17730 (h) cycloalkylalkyl, and L6 is absent or is selected from the group consisting of (a) -O-, (b) -S-, and (c) -N(R6,)- wherein R6, is selected from the group 17735 consisting of hydrogen, loweralkyl, aryl, arylalkyl, 17740 heterocycle, (heterocyclic)alkyl, cyclolakyl, and cycloalkylalkyl, 17745 (5) -L4-L6-S(O)m-N(R5)-L5-, (6) -L4-L6-N(R5)-S(O)m-L5-, (7) -L4-N(R5)-C(W)-L7-L5- wherein L4, R5, W, and and L5 are 17750 defined previously and L7 is absent or is selected from the group consisting of -O- and -S-, (8) Ci-C lo- alkylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from 17755 the group consisting of (a) aryl, (b) arylalkyl, (c) heterocycle, (d) (heterocyclic)alkyl, 17760 (e) cyclolakyl, (f) cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy, 17765 (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, 17770 (c) (aryl)oxy alkyl wherein the (ary poxy alkyl is unsubstituted or substituted with 1 , 2, 3, 4, or 5 substituents selected from the group consisting of halogen, (d) heterocycle, 17775 (e) (hererocycle)alkyl, (f) hydroxyalkyl, (g) cyclolakyl, (h) cycloalkylalkyl, (i) alkylthioalkyl, and 17780 (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 , 17785 (a) aryl, (b) arylalkyl, (c) heterocycle, (d) (heterocyclic)alkyl, (e) cyclolakyl, 17790 (f) cycloalkylalkyl, (g) alkylthioalkyl, and (h) hydroxy, ( 1 1) -L4-heterocycle-L5-, 17795 (12) a covalent bond, . B . ( 13) * ^^ 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)£ , and (4) -NRZ- wherein Rz is selected from the group consisting of (a) hydrogen (b) loweralkyl, (c) aryl, (d) arylalkyl, (e) heterocycle, ω (heterocyclic)alkyl, (g) cyclolakyl, and (h) cycloalkylalkyl; R3 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) fluorenyl,
(4) heterocycle, with the proviso that the heterocycle is other than imidazole and pyridine, 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 17835 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 17840 aryl, and cycloalkyl,
(e) alky lsilyloxy alkyl,
(f) arylalkyl,
(g) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 17845 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 17850 consisting of cycloalkyl, carboxaldehyde, haloalkyl, halogen, loweralkyl, 17855 nitro,
-NRR', and thioalkoxy, (h) arylalkyl,
(i) aryloxy wherein the aryloxy is unsubstituted or 17860 substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of, halogen, nitro, and -NRR', 17865 (j) (aryl)oyl,
(k) carboxaldehyde, (1) carboxy, (m) carboxyalkyl,
(n) -C(O)NRR" wherein R is defined previously and R" is 17870 selected from the group consisting of hydrogen, loweralkyl, and carboxyalkyl, (o) cyano,
17875 (p) cyanoalkyl, (q) cycloalkyl, (r) cycloalkylalkyl, (s) cycloalkoxyalkyl, (t) halogen,
17880 (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,
17885 (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
17890 with substituents selected from the group consisting of heterocycle, hydroxyl, with the proviso that no two hydroxyls are attached to the same carbon,
17895 -NRR3RR3', and
-P(O)(OR)(OR'), (z) nitro, (aa) -NRR', (bb) oxo,
17900 (cc) -SO2NRA'RB' wherein R/y and Rβ' are independently selected from the group consisting of hydrogen,
(aryl)oyl, loweralkyl, and
17905 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
17910 (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, 17915 (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, 17920 (e) loweralkyl,
(f) halogen,
(g) NRR3RR3',
Figure imgf000803_0001
17925
(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, 17930 (b) alkoxy,
(c) halogen,
(d) aryl,
(e) aryloxy,
(f) alkanoyl, and 17935 (g) NRR3RR3',
(7)
Figure imgf000803_0002
wherein Xj 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 17940
(8) -P(W)RR3RR3'; and R4 is selected from the group consisting of
( 1) hydrogen,
17945 (2) loweralkyl,
(3) haloalkyl
(4) halogen,
(5) aryl,
(6) arylalkyl,
17950 (7) heterocycle,
(8) (heterocyclic)alkyl
(9) alkoxy, and
(10) -NRR'; or
17955 Lι, Z , and R3 together are selected from the group consisting of
(1) aminoalkyl,
(1) haloalkyl,
(2) halogen,
(3) carboxaldehyde, and
17960 (4) (carboxaldehyde)alkyl, and
(5) hydroxyalkyl, with the proviso that when Li, Z, and R3 to gether are (l)-(5), Ri is other than hydrogen.
2. A compound according to claim 1 wherein Lj is selected from the group consisting of
( 1) -L4-N(R5)-L5-,
(2) -L4-L6-C(W)-N(R6)-L5-, and
(3) -L4-N(R5)-C(W)-L7-L5- and
Z is a covalent bond or -O-.
3. A compound according to claim 1 of formula
Figure imgf000804_0001
wherein R3 is selected from the group consisting of (1) hydrogen,
(2) aryl,
(3) heterocycle, (3) fluorenyl, wherein (2)-(4) are unsubstituted or substituted as defined previously, (4) cycloalkyl wherein the cycloalkyl is unsubstituted or substituted as defined previously, and (5) cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted as defined previously;
Lj is selected from the group consisting of
(1) -L4-N(R5)-L5-,
(2) -L4-L6-C(W)-N(R6)-L5-, and
(3) -L4-N(R5)-C(W)-L7-L5-; and
Z is a covalent bond or -O-.
4. A compound according to claim 1 of formula
Figure imgf000805_0001
wherein
R3 is selected from the group consisting of (1) hydrogen,
(2) aryl,
(3) fluorenyl, wherein (2) and (3) are unsubstituted or substituted as defined previously,
(4) cycloalkyl wherein the cycloalkyl is unsubstituted or substituted as defined previously, and
(5) cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted as defined previously;
Lj is selected from the group consisting of (1) -L4-N(R5)-L5-,
(2) -L4-L6-C(W)-N(R6)-L5-, and (3) -L4-N(R5)-C(W)-L7-L5-; and
Z is a covalent bond or -O-.
5. A compound according to claim 4 selected from the group consisting of
[4-(thiazo-4-y lmethy lcarbony l)amino-2-phenylbenzoy 1] methionine ,
[4-(thiazol-2-ylmethylcarbonyl)amino-2-phenylbenzoyl]methionine,
[4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine, methyl ester, hydrochloride,
[4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine,
[4-((R)-thiazolidin-4-ylmethyl)amino-2-phenylbenzoyl]methionine, hydrochloride,
[4-(4-hydroxy-prolinyl)amino-2-phenylbenzoyl]methionine, trifluoroacetate, [4-((2S,4S)-4-mercaptopyπolidin-2-carboxy)amino-2-phenylbenzoyl]- methionine, trifluoroacetate,
[4-((2S,4R)-4-hydroxypyπolidin-2-ylmethyl)amino-2-phenylbenzoyl]- methionine, hydrochloride,
[4-((2S,4S)-4-thiopyπolidin-2-yl-methylamino)-2-phenylbenzoyll-methionine, hydrochloride,
[4-(lH-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methionine, trifluoroacetate,
[4-(piperidin-2-ylcarboxyamino)-2-phenylbenzoyl]methionine, hydrochloride, [4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoylmethionine,
[4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyllmethionine,
[4-(3-piperidinecarboxyamino)-2-phenylbenzoyl]methionine, hydrochloride,
[4-( 1 H-4-trifluoromethy 1- 1 ,2-dihydropyrid-3-ylcarbonylamino)-2- phenylbenzoyl] methionine, sodium salt,
[4-(2-piperazinylmethylamino)-2-phenylbenzoyl]methionine,
[4-(2-furylmethylaminomethyl)-2-phenylbenzoyl]methionine lithium salt,
N-[4-N-2-hydroxyethylamino-2-phenylbenzoyl]methionine,
N-[4-(N-2-amino-3-benzyloxypropionyl)amino-2-phenylbenzoyl]methionine, N-[4-N-phenyl-N-benzylaminomethyl-2-phenylbenzoyl]methionine,
N-[4-N-(2-hydroxyethyl)-N-benzylaminomethyl-2- phenylbenzoyl]methionine, lithium salt, N-[4-N-(t-butylcarbazatocarbonylmethyl)amino-2-phenylbenzoyl]methionine, N-[4-N,N-dibenzylaminomethyl-2-phenylbenzoyllmethionine, lithium salt, N-[4-N-(benzyl-N-thiazol-5-ylmethyl)aminomethyl-2-phenylbenzoyl]- methionine,
N-[4-(N-benzylaminomethyl)-2-phenylbenzoyl]methionine, hydrochloride salt, N-[4-(4-hydroxyprolinylamino)-2-phenylbenzoyl]methionine, N-[4-((2S,4S)-4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyl]methionine, N-[4-((2S,4R)-4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyl]methionine, and
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-phenylbenzoyl]- methionine, lithium salt.
6. A compound according to claim 1 of formula
Figure imgf000807_0001
wherein R3 is selected from the group consisting of (1) hydrogen,
(2) aryl,
(3) fluorenyl,
(4) heterocycle wherein (2)-(4) are unsubstituted or substituted as defined previously, (5) cycloalkyl wherein the cycloalkyl is unsubstituted or substituted as defined previously, and (6) cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted as defined previously;
Lj is selected from the group consisting of
(1) -L4-N(R5)-L5-,
(2) -L4-L6-C(W)-N(R6)-L5-, and
(3) -L4-N(R5)-C(W)-L7-L5-;
Z is a covalent bond or -O-; and
X is selected from the group consisting of alkoxy, aryl, carboxy, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, loweralkyl, nitro,
N-protected amino,
-NRR, oxo (=O), and thioalkoxy.
A compound according to claim 1 of formula
Figure imgf000808_0001
wherein R3 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) fluorenyl, wherein (2) and (3) are unsubstituted or substituted as defined previously,
(4) cycloalkyl wherein the cycloalkyl is unsubstituted or substituted as defined previously, and
(5) cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted as defined previously;
Lj is selected from the group consisting of
(1) -L4-N(R5)-L5-,
(2) -L4-L6-C(W)-N(R6)-L5-, and
(3) -L4-N(R5)-C(W)-L7-L5-;
Z is a covalent bond or -O-; and X is selected from the group consisting of alkoxy, aryl, carboxy, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, loweralkyl, nitro,
N-protected amino,
-NRR, oxo (=O), and thioalkoxy.
8. A compound according to claim 6 wherein X is selected from the group consisting of loweralkyl, halogen, and haloalkyl.
9. A compound according to claim 8 selected from the group consisting of [4-( l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyP- benzoyl]methionine, 4-(N-benzyl-N-phenyl)-aminomethyl-2-(2-methylphenyl)benzoylmethionine, N-[4-N-(2,2-dibenzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)benzoyl]- methionine, sodium salt,
N-[4-N-(2-benzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)benzoyl]- methionine, sodium salt,
N-[4-N-(2-cyclohexylmethyl-3-hydroxypropyl)amino-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(furan-2-ylmethyl)-N-benzylaminomethyl-2-(2-methylphenyl)benzoyll- methionine, lithium salt,
N-[4-N-(2-benzylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-phenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(3-phenyl)propyl-N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(2,2-diphenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, N-[4-N-(adamantan- l-ylmethyl)-N-phenyPaminomethyl-2-(2-methylphenyp- benzoyl]methionine, N-[4-N-(2-adamantan- l-ylethyP-N-phenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N,N-dibenzylaminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(2-phenylethyl)-N-benzylarr_inomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(3-phenoxybenzyl)-N-benzylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-methyl-N-(2-phenyethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-pyrazin-2-ylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(2-phenyethyl)-N-pyrimidin-5-ylaminomethyl-2-(2-methylphenyp- benzoyl] methionine, lithium salt,
N-[4-N-(2-indol-3-ylethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(2-cyclohexyl-l-ethan-l-ol-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-(l,3-diphenylpropan-2-yl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-6-methylhept-3-en-2-yl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-6-methylheptan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl)aminomethyl-
2-(2-methylphenyl)benzoyl]methionine, N-[4-N-(l-cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl)aminomethyl-
2-(2-methylphenyl)benzoyl]methionine,
N-[4-(3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, methyl ester, N-[4-N-phenylacetylamino-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(4'-methylphenylacetyl)amino-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(4'-methoxyphenylacetyl)amino-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(3-phenylpropionoyl)amino-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(3-(2-methoxyphenyl)propionoyl)amino-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-(thiazol-2-ylmethyl)aminomethyl-2-(2-methylphenyP- benzoyl]methionine,
N-[4-N-benzyl-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, N- [4-(2-cyclohexy lethan- 1 -ol-2-y laminomethy l)-2-(2-methylpheny pbenzoy 1] - methionine, lithium salt,
N-[4-(N-benzyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-(N-2-cyclohexylethylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, trifluoroacetate salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-acetyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt, N-[4-(N-(N,N-dimethylaminocarbonyl)-N-(2-cyclohexylethyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methanesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-benzenenesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt,
N-[4-(3-cyclohexylpropan-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(4-cyclohexylbutan-3-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, N-[4-(6-cyclohexylhexan-5-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(l,2-dicyclohexylethylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(3-cyclohexylpropan- l-ol-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- 95 methionine,
N-[4-(3-cyclohexylpropan-l-ol-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, trifluoroacetate salt,
N-[4-(2-cyclohexylprop- l-en-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, 100 N-[4-(3-cyclohexyl-l-ethylsulfonylpropan-2-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(3-cyclohexyl-l-ethylsulfonyipropan-2-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]-2-amino-4-methanesulfonylbutanoic acid, lithium salt,
N-[4-(3-cyclohexyl-l-t-butylthiopropan-2-ylaminomethyl)-2-(2-methylphenyl)- 105 benzoyl]methionine, lithium salt,
N-[4-(3-cyclohexyl-l-phenylthiopropan-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzoyl-N-2-cyclohexylethylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, 110 N-[4-N-t-butyloxycarbonyl-N-2-cyclohexylethylaminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, pivaloyloxymethyl N-[4-N-(3-cyclohexyl- 1 -ethylthiopropan-2-yl)-N-methyl- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, hydrochloride salt,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)-N-methylaminomethyl-2- 115 (2-methylphenyl)benzoyl]-N-methylmethionine, lithium salt,
N-[4-N-(3-cyclohexyl-l-cyclohexylthiopropan-2-yl)-N-methylamino- methyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(3-cyclohexyl-l-(2-methylphenyl)thiopropan-2-yl)-N-methyl- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt, 120 N- [4-N-(N-phenyl-N-benzenesulfonylaminomethy l)-2-(2-methy lphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-toluenesulfonylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-methoxybenzyl)aminomethyl)-2-(2-methylphenyl)- 125 benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzenesulfonyl)aminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-chlorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 130 N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzyl)aminomethyl)-2-(2- methylphenyl)-benzoyl]methionine, lithium salt,
N-[4-N(t-butylcarbazatocarbonylmethyl)amino-2-phenylbenzoyl]methionine,
N- [4-( 1 -ethoxycarbonylpiperidin-4-ylaminomethy l)-2-(2-methy lpheny 1- benzoyl]methionine, lithium salt, 135 N-[4-(N-[3-methylthio- l-carboxyprop-2-yl]aminocarbonyl)-2-phenylbenzoyl]- methionine,
N-[4-N-(furan-2-ylmethyl)-N-isopropylaminomethyl-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-N-(furan-3-ylmethyl)-N-isopropylaminomethyl-2-(2-methylphenyp- 140 benzoyl] methionine, lithium salt,
N-[4-N-benzyl-N-3-methoxyphenylaminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(2-phenylethyl)-N-isopropylaminomethyl-2-(2-methylphenyp- benzoyl] methionine, lithium salt, 145 N-[4-N-benzyl-N-pyrimidin-5-ylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,'
N-[4-N-(l,3-benzodiox-5-yl)-N-pyrimidin-5-ylaminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(l,3-benzodiox-5-yl)-N-pyridizin-2-ylaminomethyl-2-(2-methylphenyl)- 150 benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(2-methoxyphenyl)aminomethyl)-2-(2-methylphenyp- benzoyl] methionine, lithium salt,
N-[4-(N-benzyl-N-(4-methoxyphenyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt, 155 N-[4-(N-benzyl-N-(4-acetylphenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(3-nitrophenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(4-nitrophenyl)aminomethyl)-2-(2-methylphenyl)-benzoyl]- 160 methionine, lithium salt,
N-[4-N-(N-benzyl-N-(2-acetylphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-benzyl-N-(3-acetylphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 165 N-[4-N-(N-benzyl-N-(2-chlorophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-(N-benzyl-N-(3-chlorophenyl)aminomethyP-2-(2-methylphenyp- benzoyljmethionine, lithium salt, N-[4-N-(N-benzyl-N-(4-chlorophenyl)aminomethyl)-2-(2-methylphenyl)-
170 benzoyl] methionine, lithium salt,
N-[4-(N-benzyl-N-(2-nitrophenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(2-methylthiophenyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt, 175 N-[4-(N-benzyl-N-(3-methylthiophenyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(4-methylthiophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-benzyl-N-(4-trifluoromethylphenyl)aminomethyl)-2-(2-methylphenyl)- 180 benzoyl] methionine, lithium salt,
N-[4-N-(4-piperidin- l-ylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(4-morpholin-l-ylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, 185 N-[4-N-(4-phenoxyphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(benzyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methylphenyP- benzoyl]methionine,
N-[4-N-(toluenesulfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methyl- 190 phenyl)benzoyl]methionine,
N-[4-N-(methanesulfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-2-cyclohexylethyl-N-cyclopropylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, 195 N-[4-(N-tetrahydrothiopyran-4-yl-N-thiazol-5-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-t-butyloxycarbonyl-N-( l,3-dicyclohexylpropan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(3-cyclohexyl- 1 -oxo- 1 -piperidin- 1 -ylpropan-2-yl)aminomethyl-2-(2- 200 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(l-ethylthio-4-methylpentan-2-yl)aminomethyP-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-(l-ethylthio-4-methylpentan-2-yl)-N-methylaminomethyl)-2-(2- methylphenyPbenzoyl] methionine, 205 N-[4-(N-( 1 ,3-dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(l,3-dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-acetyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2-methyl- 210 phenyl)benzoyl]methionine,
N-[4-(N-benzoyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2-methyl- pheny Pbenzoy 1] methionine ,
N-[4-(N-benzenesulfoyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, 215 N-[4-(N-(N,N-dibutylacetamido)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(N-(N,N-dibutylacetamido)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-(N,N-dibenzylacetamido)aminomethyl)-2-(2-methylphenyl)benzoyl]- 220 methionine,
N-[4-(N-(2-cyclohexylethyP-N-isopropylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-butanesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, 225 N-[4-(N,N-dibutylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-butanesulfonyl-N-(3-phenylpropyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, 230 N-[4-N-(3-cyclohexyl- 1 -ethylthiopropan-2'-yl)-N-methylaminomethyl-2-
(2-methylphenyl)benzoyl]methionine, hydrochloride,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)-N-isobutylaminomethyl-
2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)-N-formylaminomethyl-2- 235 (2-methylphenyl)benzoyl]methionine,
N-[4-N-acetyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine,
N-[4-N-t-butyloxycarbonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine, 240 N-[4-N-benzoyl-N-(3-cyclohexyl- 1 -ethylthiopropan-2-yl)aminomethyl-2-(2- methylphenyl)-benzoyl]methionine,
N-[4-N-butanesulfoyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-benzenesulfonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- 245 methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-5-(4-chlorophenyl)furan-2-ylmethyl-N-isopropylaminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-methyl-N-(l,l-dimethyl-2-phenylethyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 250 N-[4-(N-methyl-N-( 1 , l-dimet yl-2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)-benzoyl]methionine, lithium salt,
N-[4-(N-2-cyclohexylethyl-N-thiazol-5-ylmethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(l-ethylthio-4-phenylbut-2-oxymethyl)-2-(2-methylphenyl)-benzoyl]- 255 methionine,
N-[4-N-benzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-(4-carboxamidophenyl)aminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt, 260 N-[4-N-benzyl-N-(4-sulfonamidophenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-N-benzoylsulfonamidophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-propionylphenyl)aminomethyl-2-(2-methylphenyl)- 265 benzoyl] methionine, lithium salt,
N-[4-N-benzyl-N-(4-benzoylphenyl)aminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-benzyl-N-(4-(6-methylbenzthiazol-2yl)phenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt, 270 N-[4-N-2,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-2,4-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- 275 phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-vinylphenyl)aminomethyl-2-(2-methyl- pheny Pbenzoy 1] methionine, lithium salt, N-[4-N-3,5-difluorobenzyl-N-(4-acetylphenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 280 N-[4-N-3,5-difluorobenzyl-N-(4-(l-hydroxyethyl)phenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-3 ,5-difluorobenzyl-N-(4-( 1 -hydroxy- 1 -phenylmethyPphenyl)- aminomethyl-2-(2-methylρhenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-(2-hydroxyethyPphenyl)aminomethyl-2-(2- 285 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-(2-tert-butyldimethylsiloxyethyl)phenyl)- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(l-ethylthio-3-cyclohexylprop-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine, 290 N-[4-(2-N-piperidin-l-ylaminoethenyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(2-N-2-methoxymethylpyπolidin-l-ylaminoethenyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(4-trans-pentafluorophenoxycyclohexyl)aminomethyl-2-(2-methyl- 295 phenyl)benzoyl]methionine,
N-f4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyP- benzoyPglutamine, trifluoroacetic acid salt,
N-[4-(N-(2-cyclohexylethyP-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]homocysteine, lithium salt, 300 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]histidine, trifluoroacetic acid salt,
N-[4-(N-cyclohexylmethylaminoethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N,N-di-(cyclohexylmethyl)aminoethyl)-2-(2-methylphenyl)benzoyl]- 305 methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-phenylacetylaminoethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-l-adamantanoylaminoethyl)-2-(2-methylphenyP- benzoyl]methionine, lithium salt, 310 N-[4-(N-cyclohexylmethyl-N-t-butoxycarbonylaminoethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-2-ethylhexyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl] methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-2,2,2-trichloroethoxycarbonylaminoethyl)-2-(2- 315 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-cyclohexyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamantyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 320 N-[4-(N-cyclohexylmethyl-N-phenoxycarbonylaminoethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-benzyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamant-l-aminocarbonylaminoethyl)-2-(2- 325 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamant-l-aminothiocarbonylaminoethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]glutaminitrile, lithium salt, 330 N-[4-(N-p-toluenesulfonyl-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-(4-benzyloxybenzyl)-N-(N-2-methyl-2-phenylpropylacetamido)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexenylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- 335 benzoyl] methionine, lithium salt,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyPbenzoyl] amino-4-methy lsulfony lbutanoate, lithium salt, 340 N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]norleucine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-butylaminomethyp-2-(2-methylphenyP- 345 benzoyl]amino-4-methylsulfenylbutanoate, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 350 N-[4-(N-(2-cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-(N-(2-cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-methoxybenzenesulfonylaminomethyl)-2- 355 (2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-ρ-nitrobenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexyl-2-methylpropyl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 360 N-[4-(3-cyclohexyl- 1 -methoxyprop-2-y laminomethy l)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
(2S)-2-N-[4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methyl- 365 pheny Pbenzoy l]amino-4-methylsulfenylbutanoate, lithium salt,
N-[4-(N-(3-cyclohexylpropyl)-N-benzenesulfonylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-glucosaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, 370 (2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl]amino-4-difluoromethylthiobutanoate, lithium salt,
(2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]amino-5-methoxypentanoate, lithium salt,
(2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- 375 benzoyl]aminopent-4-ynoate, lithium salt,
2-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]oxy-4-methylthiobutanoate, lithium salt,
N-[4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropyl-amino- methyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, 380 N-[4-(N-(5-phenyl-(4-chlorophenyl)furan-2-ylmethyl-N-isopropyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(5-(3-methoxyphenyl)-(4-chlorophenyl)furan-2-ylmethyl)-N- isopropylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropylamino-methyl)- 385 2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(5-thien-3-yl-(4-chlorophenyl)furan-2-yl)methyl)-N-isopropyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-fluoroethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, . 390 N-[4-(N-(2-cyclohexylethyl)-N-2,2,2-trifluoroethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-methoxyethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-2-methylthioethylaminomethyl)-2-(2-methyl- 395 phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-l-methyl-2(S)-methylthioethylaminomethyl)-2-
(2-methylphenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-2-N,N-dimethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, 400 N-[4-(N-( l-benzyloxymethyl-2-(S)-ethylthioethylaminomethyl)-2-(2-methyl- pheny pbenzoy 1] methionine ,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]ornithine, trifluoroacetate salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-N-methylaminomethyl)-2-(2-methylphenyl)- 405 benzoyl]thien-2-ylalanine,
N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-fluoro-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, 410 N- [4-(N-buty l-N-4-cyclohexy lbenzoy laminomethyl)-2-(2-methy lpheny 1)- benzoyl] methionine, lithium salt,
N-[4-(N-cyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylphenyl)benzoyl]- 415 methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, 420 N- [4-(N-cyclohexy lmethyl-N-butanoylaminoethyl)-2-(2-methy lphenyl)benzoy 1] - methionine lithium salt,
N-[4-(N-cyclohexylpropyl)-2-(2-methylphenyl)benzoyl]methionine, Uthium salt,
N-[4-(N-cyclohexyl-N-propanoylaminopropyl)-2-(2-methylphenyl)benzoyl]- methionine, 425 N- [4-(N-cyclohexyl-N-butylaminopropy l)-2-(2-methy lphenyl)benzoyl] - methionine, lithium salt,
N-[4-(N-cyclohexyl-N-methylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexyl-N-butylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- 430 methionine, lithium salt,
N-[4-(N,N-dicyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-adamant-l-ylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt, 435 N-[4-(N-adamant-2-ylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-adamant-l-ylmethylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-mytanylmethylaminocarbonylethyl)-2-(2-methyiphenyl)benzoyl]- 440 methionine, lithium salt,
N-[4-(N-cyclooctanylaminocarbonylethyl)-2-(2-methylphenyl)-benzoyl]-methionine, lithium salt,
3-[4-(N-cyclohexyl-N-methylaminomethyl)-2-(2-methylphenyl)benzoylmethyl]-
4-methylthiobutyric acid, 445 N-[4-(N-butylaminocarbonylmethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2,2,4,4-tetramethylbutylamino)carbonylethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N,N-dibutylaminopropyl)-2-(2-methylphenyl)benzoyl]methionine, lithium 450 salt,
N-[4-N-(2-ethylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-propylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(4-butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine, 455 N-[4-N-(2-butylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(2,6-diethylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(2-butylphenyl)-N-(cyclohexylmethyl)aminomethyl-2-(2-methylphenyl)- 460 benzoyl]methionine, lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-(3-methylphenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, N-[4-N-(2-butylphenyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, 465 N-[4-N-butyl-N-(2-(3,5-difluoro)phenylethyl)aminomethyl-2-(2-methylphenyP- benzoyl]methionine,
N-[4-N-butanesulfonyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-methylaminomethyl-2-(2-methylphenyl)- 470 benzoyl]-3-aminotetrahydrofuran-2-one,
N-[4-(N-(-2-cyclohexylethyl)-N-butylaminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-N-butyl-N-(2-cyclohexylethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine 4-methylphenylsulfonimide, 475 N-[4-N-butyl-N-(l-phenyltetrazol-5-yPaminomethyl-2-(2-methylphenyp- benzoyl]methionine,
N-[4-N-t-butyl-N-(2-cyclohexylethyl)aminomethyl-2-(2-methylphenyP- benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2-methylphenyl)- 480 benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2-methylphenyp- benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-propyloxyaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 485 N-[4-N-(2-cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(3-chloropropanesulfonyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-(3-ethoxypropanesulfonyl)aminomethyl-2-(2- 490 methylphenyl)benzoyl]methionine lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-(3-trifluoromethylpropanesulfonyl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(butanesulfonyl)-N-(3-cyclohexylpropyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, 495 N-[4-N-(4-cyclohexyl-l-ethylthiobutan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(butanesulfonyl)-N-(4-cyclohexylbutyl)aminomethyl-2-(2-methyl- pheny Pbenzoy 1] methionine, lithium salt,
N-[4-N-butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenyl)benzoyl]- 500 methionine,
N-[4-(N-butyl-N-(2-piperidin-l-ylethyl)aminomethyP-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-((l-no holinocarbonyl)butyl)aminomethyl-2-(2-methylphenyl)- benzoyl] methionine , 505 N-[4-N-butyl-N-(2-moφholin-4-ylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-butyl-N-(fluoren-9-yl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(2-cyclohexylethyl)-N-(furan-2-ylmethyl)aminomethyl-2-(2-methyl- 510 henyl)benzoyl]methionine,
N- [4-N-butyl-N-(2-pyπolidin- 1 -ylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(2-butylphenyl)-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, 515 N-[4-N-((2-ethylthio)-l,3,4-thiadiazol-5-yPaminomethyl-2-(2-methylphenyp- benzoy 1] me thionine ,
N-[4-N-butyl-N-((2-ethylthio)-l,3,4-thiadiazol-5-yl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- 520 methionine p-tolylsulfonimide, hydrochloride salt,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine 4-(aminomethyl)phenylsulfonimide, dihydrochloride salt,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, isopropylsulfonimide, 525 N-[4-N-(N-phenyl-N-(4-fluorobenzoyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(n-butanesulfonyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyl)-2-(2-methyl- 530 phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-fluorobenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-ethylbenzenesulfonyl)aminomethyl)-2-(2-methyl- pheny Pbenzoy 1] methionine, lithium salt, 535 N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-ρhenyl-N-(2,3-dichlorobenzenesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-3,4-(methylenedioxy)ρhenyl-N-(4-fluorobenzyl)-aminomethyl)-2- 540 (2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-3,4-(methylenedioxy)ρhenyl-N-(4-fluorobenzyl)-aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt, 545 N-[4-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyl)-2-(2-methylphenyl)- 550 benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-cyanobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-methoxybenzyl)aminomethyP-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 555 N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-nitrobenzyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- 560 methylphenyl)benzoyl]methionine, dilithium salt,
N-[4-N-(N-phenyl-N-(4-phenylbenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-N-carboxymethionine)benzyl)aminomethyl-2-
(2-methylphenyl)benzoyl]methionine, dilithium salt, 565 N-[4-N-(N-phenyl-N-(2-naphthyl)aminomethyl)-2-(2-methylphenyP- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(9-methyl-anthracene-yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-methyl-anthraquinone-yl)aminomethyl)-2-(2- 570 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2,3-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 575 N-[4-N-(N-phenyl-N-(2-thiophenesulfonyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-methyl-4-methylemethiazolyl)aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-3,5-difluorophenyl-N-(5-thiazolylmethyl)aminomethyl)-2- 580 (2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(5-thiazolylmethyl)-N-(3,5-difluorobenzypaminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, 585 N-[4-N-(N-(4-acetonitrilephenyl-N-(3,5-difluorobenzyl)aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyl)-2-(2- 590 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-butyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4,4,4-trifluorobutyl-N-(3,5-difluorobenzyl)aminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt, 595 N-[4-N-(N-cyclohexyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-cyclohexanonyl)-N-(3,5-difluorobenzyl)aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-(2,2-dimethyltrimethylene ketal)-cyclohexyl)-N-(3,5- 600 difluorobenzyl)aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-cyclohexylmethyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-cyclohexylmethyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- 605 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-cyanobenzyl)-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(3,5-difluorobenzyl)-N-(4-N-carboxymethionine)benzyl)- aminomethy l-2-(2-methylpheny benzoy 1] methionine, dilithium salt, 610 N-[4-N-(N-(2-cyclohexylethyl-N-(3,5-difluorobenzyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(3-methylthiopropyl)-N-(3,5-difluorobenzyl)aminomethyl)- 2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-cyclopropyl-N-(2-(3,5-difluorophenyl)ethyl)aminornethyl)-
615 2-(2-methylphenyl)benzoyl]methionine, lithium salt,
[4-N-(N-2-methylbutyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, [4-N-(N-butyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
620 N-[4-N-(N-(4-methyltetrahydropyran-yl)-N-(3,5-difluorobenzyl)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-methyltetrahydrothiopyran-yl)-N-(3,5-difluorobenzyl)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-tetrahydropyran-yl)-N-(3,5-difluorobenzyl)aminomethyP-2-(2-
625 methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(3-cyclohexyl-l-ethylthioprop-2-yl)aminomethyl)-2-(2- methylphenyl)benzoyl] amino-4-methylsulfony lbutanoate, lithium salt, N-[4-(N-methyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, p-tolylsulfonimide,
630 N-[4-N-(N-(trans-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)aminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(cis-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)-aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, (2S) 2-N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2-
635 methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt,
N-[4-(N-(2-(l,3-dioxan-2-ylethyP-N-butylaminomethyl)-2-(2-methylphenyP- benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]thioglutamine, lithium salt,
640 N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2-(2- methylphenyl)benzoyl] methionine,
N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N'N'-dimethyl- amino-2-(2-methylphenyl)benzoyl]methionine, N-[4-N-(6-fluorobenzothiazol-2-yl)aminomethyl-2-(2-methylphenyl)-
645 benzoyl]methionine, and
N-[4-N-butyl-N-(furan-2-ylmethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine.
0. A compound selected from the group consisting of
[4-(thiazo-4-ylmethylcarbonyl)amino-2-phenylbenzoyl]methionine,
[4-(thiazol-2-ylmethylcarbonyl)amino-2-phenylbenzoyl]methionine,
[4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine, methyl ester, hydrochloride,
[4-((R)-thiazolidin-4-ylcarbonyl)amino-2-phenylbenzoyl]methionine,
[4-((R)-thiazolidin-4-ylmethyl)amino-2-phenylbenzoyl]methionine, hydrochloride,
[4-(4-hydroxy-prolinyl)amino-2-phenylbenzoyl]methionine, trifluoroacetate,
[4-((2S,4S)-4-mercaptopyπolidin-2-carboxy)amino-2-phenylbenzoyl]- methionine, trifluoroacetate,
[4-((2S,4R)-4-hydroxypyπolidin-2-ylmethyl)amino-2-phenylbenzoyl]- methionine, hydrochloride,
[4-((2S,4S)-4-thiopyπolidin-2-yl-methylamino)-2-phenylbenzoyl]-methionine, hydrochloride,
[4-(lH-benzimidazol-5-ylcarboxyamino)-2-phenylbenzoyl]methionine, trifluoroacetate,
[4-(piperidin-2-ylcarboxyamino)-2-phenylbenzoyl]methionine, hydrochloride,
[4-(2-pyπolidinone-5-ylcarbonylamino)-2-phenylbenzoylmethionine,
[4-(5-pyrimidylcarboxyamino)-2-phenylbenzoyl]methionine,
[4-(3-piperidinecarboxyamino)-2-phenylbenzoyl]methionine, hydrochloride,
[4-(lH-4-trifluoromethyl-l,2-dihydropyrid-3-ylcarbonylamino)-2- phenylbenzoyl]methionine, sodium salt,
[4-(2-piperazinylmethylamino)-2-phenylbenzoyl]methionine,
[4-(2-furylmethylaminomethyl)-2-phenylbenzoyl]methionine lithium salt,
N-[4-N-2-hydroxyethylamino-2-phenylbenzoyl]methionine,
N-[4-(N-2-amino-3-benzyloxypropionyl)amino-2-phenylbenzoyl]methionine,
N-[4-N-phenyl-N-benzylaminomethyl-2-phenylbenzoyl]methionine,
N-[4-N-(2-hydroxyethyl)-N-benzylaminomethyl-2- phenylbenzoyl] methionine, lithium salt,
N-[4-N-(t-butylcarbazatocarbonylmethyl)amino-2-phenylbenzoyl]methionine,
N-[4-N,N-dibenzylaminomethyl-2-phenylbenzoyl]methionine, Uthium salt,
N-[4-N-(benzyl-N-thiazol-5-ylmethyl)aminomethyl-2-phenylbenzoyl]- methionine, N-[4-(N-benzylaminomethyl)-2-phenylbenzoyl]methionine, hydrochloride salt,
N-[4-(4-hydroxyprolinylamino)-2-phenylbenzoyl]methionine,
N-[4-((2S,4S)-4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyl]methionine,
N-[4-((2S,4R)-4-thiolpyπolidin-2-ylmethylamino)-2-phenylbenzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-phenylbenzoyl]- methionine, lithium salt,
[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyP- benzoyl]methionine,
4-(N-benzyl-N-phenyl)-aminomethyl-2-(2-methylphenyl)benzoylmethionine,
N-[4-N-(2,2-dibenzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)benzoyl]- methionine, sodium salt,
N-[4-N-(2-benzyl-3-hydroxypropyl)amino-2-(2-methylphenyl)benzoyl]- methionine, sodium salt,
N-[4-N-(2-cyclohexylmethyl-3-hydroxypropyl)amino-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(furan-2-ylmethyl)-N-benzylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(2-benzylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-phenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(3-phenyl)propyl-N-phenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(2,2-diphenyl)ethyl-N-phenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(adamantan-l-ylmethyl)-N-phenyl)aminomethyl-2-(2-methylphenyP- benzoyl]methionine,
N-[4-N-(2-adamantan-l-ylethyl)-N-phenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N,N-dibenzylaminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(2-phenylethyl)-N-benzylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(3-phenoxybenzyl)-N-benzylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-methyl-N-(2-phenyethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-pyrazin-2-ylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(2-phenyethyl)-N-pyrimidin-5-ylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(2-indol-3-ylethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N- [4-N-(2-cyclohexy 1- 1 -ethan- 1 -ol-2-yl)aminomethyl-2-(2-methy lphenyp- benzoyl] methionine, lithium salt,
N-[4-N-(l,3-diphenylpropan-2-yl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-6-methylhept-3-en-2-yl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-6-methylheptan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(l-cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl)aminomethyl-
2-(2-methylphenyl)benz'oyl]methionine,'
N-[4-N-(l-cyclohexyl-2,3-dihydroxy-6-methylheptan-2-yl)aminomethyl-
2-(2-methylphenyl)benzoyl]methionine,
N-[4-(3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(3-furan-2-yl-2-phenylprop-2-en-l-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, methyl ester,
N-[4-N-phenylacetylamino-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(4'-methylphenylacetyl)amino-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(4'-methoxyphenylacetyl)amino-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(3-phenylpropionoyl)amino-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(3-(2-methoxyphenyl)propionoyl)amino-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-(thiazol-2-ylmethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-benzyl-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-methylphenyl)- benzoy 1] methionine , N-[4-(2-cyclohexylethan-l-ol-2-ylaminomethyl)-2-(2-methylρhenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-2-cyclohexylethylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, trifluoroacetate salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-acetyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-(N,N-dimethylaminocarbonyl)-N-(2-cyclohexylethyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methanesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-benzenenesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine lithium salt,
N-[4-(3-cyclohexylpropan-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(4-cyclohexylbutan-3-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(6-cyclohexylhexan-5-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(l,2-dicyclohexylethylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(3-cyclohexylpropan-l-ol-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(3-cyclohexylpropan-l-ol-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, trifluoroacetate salt,
N-[4-(2-cyclohexylprop-l-en-2-ylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(3-cyclohexyl-l-ethylsulfonylpropan-2-ylaminomethyl)-2-(2-methyl- pheny Pbenzoy 1] methionine, lithium salt,
N-[4-(3-cyclohexyl-l-ethylsulfonylpropan-2-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]-2-amino-4-methanesulfonylbutanoic acid, lithium salt,
N-[4-(3-cyclohexyl-l-t-butylthiopropan-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(3-cyclohexyl-l-phenylthiopropan-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzoyl-N-2-cyclohexylethylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-t-butyloxycarbonyl-N-2-cyclohexylethylaminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt, pivaloyloxymethyl N-[4-N-(3 -cyclohexyl- 1 -ethylthiopropan-2-yl)-N-methyl- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, hydrochloride salt,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)-N-methylaminomethyl-2-
(2-methylphenyl)benzoyl]-N-methylmethionine, lithium salt,
N-[4-N-(3-cyclohexyl-l-cyclohexylthiopropan-2-yl)-N-methylamino- methyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(3-cyclohexyl-l-(2-methylphenyl)thiopropan-2-yl)-N-methyl- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-benzenesulfonylaminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-toluenesulfonylaminomethyl)-2-(2-methylphenyp- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-methoxybenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzenesulfonyl)aminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-chlorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoy I] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-trifluoromethylbenzyl)aminomethyl)-2-(2- methylphenyl)-benzoyl]methionine, lithium salt,
N-[4-N(t-butylcarbazatocarbonylmethyl)amino-2-phenylbenzoyl]methionine,
N-[4-(l-ethoxycarbonylpiperidin-4-ylaminomethyl)-2-(2-methylphenyl- benzoyl]methionine, lithium salt,
N-[4-(N-[3-methylthio-l-carboxyprop-2-yl]aminocarbonyl)-2-phenylbenzoyl]- methionine,
N-[4-N-(furan-2-ylmethyl)-N-isopropylaminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(furan-3-ylmethyl)-N-isopropylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-3-methoxyphenylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(2-phenylethyl)-N-isopropylaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-pyrimidin-5-ylanιinomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-(l,3-benzodiox-5-yl)-N-pyrimidin-5-ylaminomethyl-2-(2-methyl- phenyPbenzoyl] methionine, lithium salt,
N-[4-N-(l,3-benzodiox-5-yl)-N-pyridizin-2-ylaminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-benzyl-N-(2-methoxyphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(4-methoxyphenyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(4-acetylphenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(3-nitrophenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(4-nitrophenyl)aminomethyl)-2-(2-methylphenyl)-benzoyl]- methionine, lithium salt,
N-[4-N-(N-benzyl-N-(2-acetylphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-benzyl-N-(3-acetylphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-benzyl-N-(2-chlorophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-benzyl-N-(3-chlorophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-benzyl-N-(4-chlorophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(2-nitrophenyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-benzyl-N-(2-methylthiophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-benzyl-N-(3-methylthiophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(4-methylthiophenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-benzyl-N-(4-trifluoromethylphenyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-(4-piperidin-l-ylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(4-moφholin-l-ylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(4-phenoxyphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(benzyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(toluenesulfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(methanesulfonyl-N-thiazol-2-ylmethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-2-cyclohexylethyl-N-cyclopropylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-tetrahydrothiopyran-4-yl-N-thiazol-5-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-t-butyloxycarbonyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N- [4-N-(3 -cyclohexyl- 1 -oxo- 1 -piperidin- 1 -y lpropan-2-y l)aminomethy l-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N- [4-(N-( 1 -ethylthio-4-methylpentan-2-yl)aminomethyl)-2-(2-methy lpheny 1)- benzoyl]methionine,
N-[4-(N-(l-ethylthio-4-methylpentan-2-yl)-N-methylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine,
N-[4-(N-(l,3-dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(l,3-dicyclohexylpropan-2-yl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-acetyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-benzoyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-benzenesulfoyl-N-(l,3-dicyclohexylpropan-2-yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine,
N-[4-(N-(N,N-dibutylacetamido)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(N-(N,N-dibutylacetamido)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-(N,N-dibenzylacetamido)aminomethyl)-2-(2-methylρhenyl)benzoyl]- methionine,
N-[4-(N-(2-cyclohexylethyl)-N-isopropylaminomethyl)-2-(2-methylphenyP- benzoyl] methionine,
N-[4-(N-butanesulfonyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N,N-dibutylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-butanesulfonyl-N-(3-phenylpropyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)-N-methylaminomethyl-2-
(2-methylphenyl)benzoyl]methionine, hydrochloride,
N- [4-N-(3-cyclohexyl- 1 -ethylthiopropan-2-yl)-N-isobutylaminomethy 1-
2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(3-cyclohexyl-l-ethylthiopropan-2-yP-N-formylaminomethyl-2-
(2-methylphenyl)benzoyl]methionine,
N-[4-N-acetyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine,
N-[4-N-t-butyloxycarbonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-benzoyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)aminomethyl-2-(2- methylphenyl)-benzoyl]methionine,
N-[4-N-butanesulfoyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-benzenesulfonyl-N-(3-cyclohexyl-l-ethylthiopropan-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(N-5-(4-chlorophenyl)furan-2-ylmethyl-N-isopropylaminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-methyl-N-( 1 , l-dimethyl-2-phenylethyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-methyl-N-(l,l-dimethyl-2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)-benzoyl]methionine, lithium salt,
N-[4-(N-2-cyclohexylethyl-N-thiazol-5-ylmethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N- [4-( 1 -ethylthio-4-pheny lbut-2-oxy methy l)-2-(2-methylphenyl)-benzoy 1] - methionine,
N-[4-N-benzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-N-benzyl-N-(4-carboxamidophenyl)aminomethyl-2-(2-methylphenyl)- benzoyllmethionine, lithium salt,
N-[4-N-benzyl-N-(4-sulfonamidophenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-N-benzoylsulfonamidophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-propionylphenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-benzoylphenyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-benzyl-N-(4-(6-methylbenzthiazol-2yl)phenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-2,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-2,4-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-cyanophenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-vinylphenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-acetylphenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-(l-hydroxyethyl)phenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-3,5-difluorobenzyl-N-(4-(l-hydroxy-l-phenylmethyl)phenyp- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-3,5-difluorobenzyl-N-(4-(2-hydroxyethyl)phenyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-3,5-difluorobenzyl-N-(4-(2-tert-butyldimethylsiloxyethyl)phenyl)- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-3,5-difluorobenzyl-N-(l-ethylthio-3-cyclohexylprop-2-yl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-(2-N-piperidin-l-ylaminoethenyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-(2-N-2-methoxymethylpyπolidin-l-ylaminoethenyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-(4-trans-pentafluorophenoxycyclohexyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]glutamine, trifluoroacetic acid salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]homocysteine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]histidine, trifluoroacetic acid salt,
N-[4-(N-cyclohexylmethylaminoethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N,N-di-(cyclohexylmethyl)aιninoethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-phenylacetylaminoethyl)-2-(2-methylphenyP- benzoyl] methionine, lithium salt,
N- [4-(N-cyclohexylmethyl-N- 1 -adamantanoylaminoethy l)-2-(2-methylpheny 1)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-t-butoxycarbonylaminoethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-2-ethylhexyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-2,2,2-trichloroethoxycarbonylaminoethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-cyclohexyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamantyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-phenoxycarbonylaminoethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-benzyloxycarbonylaminoethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamant-l-aminocarbonylaminoethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-adamant-l-aminothiocarbonylaminoethyl)-2-(2- me thy lpheny Pbenzoy 1] methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyP-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyPglutaminitrile, lithium salt, N-[4-(N-p-toluenesulfonyl-N-methylaminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-(N-(4-benzyloxybenzyl)-N-(N-2-methyl-2-phenylpropylacetamido)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexenylethyl)-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl] methionine, lithium salt,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyllamino-4-methylsulfenylbutanoate, lithium salt,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2- methylphenyPbenzoyl] amino-4-methylsulfonylbutanoate, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyp- benzoyl]norleucine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N,N-dimethylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
(2S) 2-N-[4-(N-(2-cyclohexylethyl)-N-butylaminomethyl)-2-(2-methylphenyP- benzoyl]amino-4-methylsulfenylbutanoate, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-toluenesulfonylaminomethyl)-2-(2-methyl- pheny Pbenzoy 1] methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-m-toluenesulfonylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-tert-butylbenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-bromobenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-methoxybenzenesulfonylaminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-p-nitrobenzenesulfonylaminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexyl-2-methylpropyl)-N-methylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(3-cyclohexyl-l-methoxyprop-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
(2S)-2-N-[4-(l-ethylsulfenyl-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methyl- phenyl)benzoyl]amino-4-methylsulfenylbutanoate, lithium salt, N-[4-(N-(3-cyclohexylρropyl)-N-benzenesulfonylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-glucosaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
(2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl]amino-4-difluoromethylthiobutanoate, lithium salt,
(2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl]amino-5-methoxypentanoate, lithium salt,
(2S)-2-N-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl]aminopent-4-ynoate, lithium salt,
2-[4-(N-2-cyclohexylethyl-N-methylaminomethyl)-2-(2-methylphenyP- benzoyl]oxy-4-methylthiobutanoate, lithium salt,
N-[4-(N-(5-bromo-(4-chlorophenyl)furan-2-ylmethyl-N-isopropyl-amino- methyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(5-phenyl-(4-chlorophenyl)furan-2-ylmethyl-N-isopropyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(5-(3-methoxyphenyl)-(4-chlorophenyl)furan-2-ylmethyl)-N- isopropylaminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(4,5-di(4-chlorophenyl)furan-2-yl)methyl)-N-isopropylamino-methyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(5-thien-3-yl-(4-chlorophenyl)furan-2-yl)methyl)-N-isopropyl- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-fluoroethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-2,2,2-trifluoroethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-methoxyethylaminomethyl)-2-(2-methyl- pheny Pbenzoy 1] methionine,
N-[4-(N-(2-cyclohexylethyl)-N-2-methylthioethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-l-methyl-2(S)-methylthioethylaminomethyl)-2-
(2-methylphenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-2-N,N-dimethylaminomethyl)-2-(2-methyl- pheny pbenzoy 1] methionine ,
N-[4-(N-(l-benzyloxymethyl-2-(S)-ethylthioethylaminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]ornithine, trifluoroacetate salt,
N-[4-(N-(2-cyclohexylethyl)-N-2-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]thien-2-ylalanine,
N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-fluoro-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-butyl-N-4-cyclohexylbenzylaminomethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-butyl-N-4-cyclohexylbenzoylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N-cyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-butylaminoethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-butylaminocarbonylmethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-(N-cyclohexanoyl-N-butylaminoethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexylmethyl-N-butanoylaminoethyl)-2-(2-methylphenyl)benzoyl]- methionine lithium salt,
N-[4-(N-cyclohexylpropyl)-2-(2-methylphenyl)benzoyl]methionine, Uthium salt,
N-[4-(N-cyclohexyl-N-propanoylaminopropyl)-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(N-cyclohexyl-N-butylaminopropyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexyl-N-methylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclohexyl-N-butylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N,N-dicyclohexylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-adamant-l-ylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-adamant-2-ylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-adamant-l-ylmethylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-mytanylmethylaminocarbonylethyl)-2-(2-methylphenyl)benzoyl]- methionine, lithium salt,
N-[4-(N-cyclooctanylaminocarbonylethyl)-2-(2-methylphenyl)-benzoyl]-methionine, lithium salt,
3-[4-(N-cyclohexyl-N-methylaminomethyl)-2-(2-methylphenyl)benzoylmethyl]-
4-methylthiobutyric acid,
N-[4-(N-butylaminocarbonylmethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(2,2,4,4-tetramethylbutylamino)carbonylethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-(N,N-dibutylaminopropyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(2-ethylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-propylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(2-butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(4-butylphenyl)aminomethyl-2-(2-methylphenyl)benzoyllmethionine,
N-[4-N-(2-butylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(2,6-diethylphenyl)-N-(3,5-difluorobenzyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(2-butylphenyl)-N-(cyclohexylmethyl)aminomethyl-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-(3-methylphenyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(2-butylphenyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-butyl-N-(2-(3,5-difluoro)phenylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-butanesulfonyl-N-(2-phenylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-methylaminomethyl-2-(2-methylphenyl)- benzoyl]-3-aminotetrahydrofuran-2-one,
N-[4-(N-(-2-cyclohexylethyl)-N-butylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-butyl-N-(2-cyclohexylethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine 4-methy lpheny lsulf onimide ,
N-[4-N-butyl-N-(l-phenyltetrazol-5-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, N-[4-N-t-butyl-N-(2-cyclohexylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, N-[4-N-(2-cyclohexylethyP-N-(pent-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-(pent-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-propyloxyaminomethyl-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-propanesulfonylaminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-(3-chloropropanesulfonyl)-N-(2-cyclohexylethyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine,
N-[4-N-(2-cyclohexylethyl)-N-(3-ethoxypropanesulfonyl)aminomethyl-2-(2- methylphenyl)benzoyl]methionine lithium salt,
N-[4-N-(2-cyclohexylethyl)-N-(3-trifluoromethylpropanesulfonyl)amino- methyl-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(butanesulfonyl)-N-(3-cyclohexylpropyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(4-cyclohexyl-l-ethylthiobutan-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl] methionine ,
N-[4-N-(butanesulfonyl)-N-(4-cyclohexylbutyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-butyl-N-quinolin-2-ylaminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-(N-butyl-N-(2-piperidin-l-ylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-((l-noφholinocarbonyl)butyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-butyl-N-(2-moφholin-4-ylethyl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-N-butyl-N-(fluoren-9-yl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine,
N-[4-N-(2-cyclohexylethyl)-N-(furan-2-ylmethyl)aminomethyl-2-(2-methyl- henyl)benzoyl]methionine,
N- [4-N-butyl-N-(2-pyπolidin- 1 -y lethyl)aminomethy l-2-(2-methy lphenyl)- benzoyl]methionine,
N-[4-N-(2-butylphenyl)-N-(thiazol-5-ylmethyl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-N-((2-ethylthio)-l,3,4-thiadiazol-5-yl)aminomethyl-2-(2-methylphenyp- benzoyl]methionine,
N-[4-N-butyl-N-((2-ethylthio)-l,3,4-thiadiazol-5-yl)aminomethyl-2-(2-methyl- phenyl)benzoyl]methionine,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)benzoyl]- methionine p-tolylsulfonimide, hydrochloride salt,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine 4-(aminomethyl)phenylsulfonimide, dihydrochloride salt,
N-[4-(N-butyl-N-(2-phenylethyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, isopropylsulfonimide,
N-[4-N-(N-phenyl-N-(4-fluorobenzoyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(n-butanesulfonyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-nitrobenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-fluorobenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-ethylbenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-nitrobenzenesulfonyl)aminomethyl)-2-(2-methyl- phenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2,3-dichlorobenzenesulfonyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)-aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-3,4-(methylenedioxy)phenyl-N-(4-fluorobenzyl)-aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-fluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-bromobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, N-[4-N-(N-phenyl-N-(4-cyanobenzyl)aminomethyl)-2-(2-methylphenyp- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-methoxybenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-trifluoromethoxybenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-nitrobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-carboxylic acid benzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, dilithium salt,
N-[4-N-(N-phenyl-N-(4-phenylbenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl] methionine, lithium salt,
N-[4-N-(N-phenyl-N-(4-N-carboxymethionine)benzyl)aminomethyl-2- (2-methylphenyl)benzoyl]methionine, dilithium salt, N-[4-N-(N-phenyl-N-(2-naphthyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(9-methyl-anthracene-yl)aminomethyl)-2-(2- methylphenyPbenzoyPmethionine, lithium salt, N-[4-N-(N-phenyl-N-(2-methyl-anthraquinone-yl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2,3-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-thiophenesulfonyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(2-methyl-4-methylemethiazolyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-3,5-difluorophenyl-N-(5-thiazolylmethyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(5-thiazolylmethyl)-N-(3,5-difluorobenzyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-phenyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-acetonitrilephenyl-N-(3,5-difluorobenzyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-phenyl-N-(3-methoxy-5-nitrobenzyl)aminomethyl)-2-(2- methylphenyPbenzoyl] methionine, lithium salt, N-[4-N-(N-(4-nitrophenyl-N-(4-methoxybenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-butyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4,4,4-trifluorobutyl-N-(3,5-difluorobenzyl)aminomethyl)- 2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-cyclohexyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-cyclohexanonyl)-N-(3,5-difluorobenzyPaminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-(2,2-dimethyltrimethylene ketal)-cyclohexyl)-N-(3,5- difluorobenzyl)aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-cyclohexylmethyl-N-(2,4-difluorobenzyl)aminomethyl)-2-(2- me thy lpheny Pbenzoy 1] methionine, lithium salt,
N-[4-N-(N-cyclohexylmethyl-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(4-cyanobenzyl)-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(3,5-difluorobenzyl)-N-(4-N-carboxymethionine)benzyl)- aminomethyl-2-(2-methylphenyl)benzoyl]methionine, dilithium salt, N-[4-N-(N-(2-cyclohexylethyl-N-(3,5-difluorobenzyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(3-methylthiopropyl)-N-(3,5-difluorobenzyl)aminomethyl)- 2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-cyclopropyl-N-(2-(3,5-difluorophenyl)ethyl)aminomethyp- 2-(2-methylphenyl)benzoyl]methionine, lithium salt, [4-N-(N-2-methylbutyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2- (2-methylphenyl)benzoyl]methionine, lithium salt, [4-N-(N-butyl-N-(2-(2,4-difluorophenyl)ethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-methyltetrahydropyran-yl)-N-(3,5-difluorobenzyl)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-methyltetrahydrothiopyran-yl)-N-(3,5-difluorobenzyl)- aminomethyl)-2-(2-methylphenyl)benzoyl]methionine, lithium salt, N-[4-N-(N-(4-tetrahydropyran-yl)-N-(3,5-difluorobenzyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, lithium salt,
N-[4-(N-(3-cyclohexyl-l-ethylthioprop-2-yl)aminomethyP-2-(2- methylpheny l)benzoyl] amino-4-methylsulfonylbutanoate, lithium salt,
N-[4-(N-methyl-N-(2-cyclohexylethyl)aminomethyl)-2-(2- methylphenyl)benzoyl]methionine, p-tolylsulfonimide,
N-[4-N-(N-(trans-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)aminomethyl)-
2-(2-methylphenyl)benzoyl]methionine, lithium salt,
N-[4-N-(N-(cis-4-hydroxycyclohexyl)-N-(3,5-difluorobenzyl)-aminomethyl)-2-
(2-methylphenyl)benzoyl]methionine, lithium salt,
(2S) 2-N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2- methylphenyl)benzoyl]amino-4-methylsulfenylbutanoate, Uthium salt,
N-[4-(N-(2-(l,3-dioxan-2-ylethyl)-N-butylaminomethyl)-2-(2-methylphenyP- benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]thioglutamine, lithium salt,
N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-methoxy-2-(2- methylphenyl)benzoyl]methionine,
N-[4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-5-N'N'-dimethyl- amino-2-(2-methylphenyl)benzoyl]methionine,
N-[4-N-(6-fluorobenzothiazol-2-yl)aminomethyl-2-(2-methylphenyl)- benzoyl]methionine, and
N-[4-N-butyl-N-(furan-2-ylmethyl)aminomethyl-2-(2-methylphenyl)benzoyl]- methionine.
1 1. A compound according to claim 10 selected from the group consisting of [4-(l-ethylthio-3-cyclohexylprop-2-ylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine,
N-[4-(N-(2-cyclohexylethyl)-N-methylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt, and
N-[4-(N-(-2-cyclohexylethyl)-N-butylaminomethyl)-2-(2-methylphenyl)- benzoyl]methionine, lithium salt.
12. A method of inhibiting protein isoprenyl transferases in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
13. A composition for inhibiting protein isoprenyl transferases comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.
14. A method for inhibiting or treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 alone or in combination with another chemotherapeutic agent.
15. A composition for the treatment of cancer comprising a compound of claim 1 in combination with another chemotherapeutic agent and a pharmaceutically acceptable carrier.
16. A method for inhibiting post-translational modification of the oncogenic Ras protein by protein famesyltransferase, protein geranylgeranyltransferase, or both in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
17. A composition for inhibiting post-translational modification of the oncogenic Ras protein by protein famesyltransferase, protein geranylgeranyltransferase, or both comprising a compound of claim 1 in combination with a pharmaceutical caπier.
18. A method for treating or preventing intimal hypeφlasia associated with restenosis and atherosclerosis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
19. A composition for treating or preventing restenosis in a mammal comprising a compound of claim 1 in combination with a pharmaceutically acceptable caπier.
PCT/US1998/009296 1997-05-07 1998-05-07 Inhibitors of protein isoprenyl transferases WO1998050029A1 (en)

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EP98922122A EP0986384B1 (en) 1997-05-07 1998-05-07 Inhibitors of protein isoprenyl transferases
AU74733/98A AU7473398A (en) 1997-05-07 1998-05-07 Inhibitors of protein isoprenyl transferases
CA2288330A CA2288330C (en) 1997-05-07 1998-05-07 Benzoyl amino acid derivatives useful as inhibitors of protein isoprenyl tranferases
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WO1998050030A1 (en) 1998-11-12
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WO1998050031A1 (en) 1998-11-12
CA2288330C (en) 2014-02-11
EP0986384B1 (en) 2012-02-22
PH11998001072B1 (en) 2006-11-21
CA2288330A1 (en) 1998-11-12
JP5490481B2 (en) 2014-05-14
ATE546139T1 (en) 2012-03-15
JP2002518985A (en) 2002-06-25
ES2387211T3 (en) 2012-09-18
TW541302B (en) 2003-07-11
PH11998001073B1 (en) 2007-07-23
AU7371998A (en) 1998-11-27
AU7473398A (en) 1998-11-27
MX211764B (en) 2002-12-03
TW492955B (en) 2002-07-01
AR015649A1 (en) 2001-05-16
EP0986384A1 (en) 2000-03-22

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