THIOAMIDE DERIVATIVES

Abstract: Compounds of formula (1): and the pharmaceutically acceptable salts and esters thereof wherein X and Y are as defined in the specification, inhibit the binding of VCAM-1 to VLA-4 and are useful in treating inflammation associated with chronic inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), asthma, and inflammatory bowel disease (I/BD).

Description: THIOAMIDE DERIVATIVES Vascular cell adhesion molecule- 1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is expressed on activated, but not resting, endothelium. The integrin VLA-4 (a_tbι), which is expressed on many cell types including circulating lymphocytes, eosinophils, basophils, and monocytes, but not neutrophils, is the principal receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 can block the adhesion of these mononuclear leukocytes, as well as melanoma cells, to activated endothelium in vitro. Antibodies to either protein have been effective at inhibiting leukocyte infiltration and preventing ~ tissue damage in several animal models of inflammation. Anti-VLA-4 monoclonal antibodies have been shown to block T-cell emigration in adjuvant-induced arthritis, prevent eosinophil accumulation and bronchoconstriction in models of asthma, and reduce paralysis and inhibit monocyte and lymphocyte infiltration in experimental autoimmune encephalitis (EAE). Anti-VCAM-1 monoclonal antibodies have been shown to prolong the survival time of cardiac allografts. Recent studies have demonstrated that anti-VLA-4 mAbs can prevent insulitis and diabetes in non-obese diabetic mice, and significantly attenuate inflammation in the cotton-top tamarin model of colitis. Thus, compounds which inhibit the interaction between rxj-containing integrins and VCAM-1 will be useful as therapeutic agents for the treatment of inflammation resulting from chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis (MS), asthma, and inflammatory bowel disease (IBD). In one embodiment the present invention is directed to compounds of the formula: wherein X is a group of the formula wherein: Rj5 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy; Rl6 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio; or X is a group of formula X-2 wherein Het is a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N,0, and S, or Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1 , 2, 3 or 4 heteroatoms selected from O, S, and N; Rl5 and Ri6 are as in X- l above; R 30 is hydrogen or lower alkyl; and p is an integer from 0 to 1; or or X is a group of formula X-3 wherein: Ri g is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl Ri 9 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and R20 is substituted or unsubstituted lower alkanoyl or aroyl; and Y is a group of formula Y- l wherein: R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen; or Y-2 is a group of the formula: R, Het 1 Y-2 [ R 3θ]p Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R 30 and R 3 i are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R 30 and R 31 is adjacent to the point of attachment, p is an integer of 0 or 1 or Y is a group of formula Y-3 wherein: R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R 26~ (CH 2 ) e - , R26 is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio , lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R 26 is a group of formula -NR 8R29> wherein R28 i H or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R28 and R29 taken together form a 4, 5 or 6-membered saturated carbocyclic ring optionally containing one heteroatom selected from O, S, and N; with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen, Q is -(CH 2 )f 0-, -(CH 2 )f S-, -(CH 2 )f N(R27)-, -(CH 2 )f- or a bond; R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, e is an integer from 0 to 4, f is an integer from 1 to 3, and the dotted bond is optionally hydrogenated; and pharmaceutically acceptable salts and esters thereof. As used in this specification, the terms are defined as follows: The term "halogen" means bromine, chlorine, fluorine, or iodine, and the term "halo" means a halogen substituent. The term "perfluoro" means complete substitution of all hydrogen atoms with fluoro substituted, as in perfluoro lower alkyl, perfluoroloweralkanoyl and perfluoroalkanoylamino. An example is trifluoromethyl. The term "lower alkyl", alone or in combination (for example as part of lower alkanoyl, below), means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl, tert. butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl (preferably phenyl or pyridyl), hydroxy (lower alkylhydroxy or hydroxylower alkyl), halogen, cyano, lower alkoxy (alkoxy lower alkyl or lower alkyl alkoxy). lower alkanoyl, lower alkylthio (lower alkylthio lower alkyl) sulfinyl (lower alkyl sulfinyl), sulfinyl lower alkyl (lower alkyl sulfinyl lower alkyl) sulfonyl (lower alkyl sulfonyl), sulfonyl lower alkyl (lower alkyl sulfonyl lower alkyl) perfluoro (perfluoro lower alkyl) and substituted amino such as aminosulfonyl (lower alkyl aminosulfonyl) or aminocarbonyl (lower alkyl aminocarbonyl). Examples of substituted lower alkyl groups include 2-hydroxylethyl, 3-oxobutyl, cyanomethyl, and 2-nitropropyl. The term "lower alkylthio" means a low r er alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group. The term "cycloalkyl" means an unsubstituted or substituted 3- to 7-membered carbacyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino. The term "lower alkoxy" means a lower alkyl group as defined above, bonded through an oxygen atom. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. The term "lower alkenyl" means a nonaromatic partially unsaturated hydrocarbon chain containing at least one double bond, which is preferably 1 -10 and more preferably 1 -6 carbons in length. The group may be unsubstituted, or substituted with conventional substituents, preferably fluoro Examples are v inyl, all> l dimethylallyl, butenyl, isobutenyl, pentenyl The term "an l" means a mono- or bicvhe aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted bv conventional substituent groups Preferred substituents are low er alky 1, lower alkow , h\ drow lower alky 1, hydroxy, hvdroxyalkoxy, halogen, lower alkylthio, lower alk\ lsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalk\ l, alkanoyl, arovl, arvl alkvnyl, low er alkynyl, aminoalkylcarbonyl (arvlaminocarbonyl) and lower alkanoylamino The especially preferred substituents are low er alkyl, hvdroxv, and perfluoro low er alkyl Examples of aryl groups that ma\ be used in accordance w ith this lm ention are phenyl, p-toly l, p-metho\vphenyl, p-chlorophenyl, m-hvdroxy phenyl, m- methylthiophenyl, 2-methyl-5-nιtrophen\ l, 2,6 dichlorophem l, 1 -naphthy l and the hke The term "arylalkyl" means a lower alky l group as hereinbefore defined in w hich one or more hydrogen atoms is/are replaced by an aryl group as herein defined Any conventional aralkyl may be used in accordance with this invention, such as benzyl and the like Similarly, the term "heteroarylalkyl" is the same as an arylalkyl group except that there is a heteroaryl group as defined below in place of an aryl group Either of these groups may be unsubstituted, or may be substituted on the ring portion with co entional substituents such as The term "heteroai l" means an unsubstituted or substituted 5- oi 6-membered monocychc hetereoaromatic ring or a 9- or 10-membered bicychc hetereoaromatic ring containing 1, 2, 3 or 4 hetereoatoms which are independently N, S or O Examples of hetereoaryl rings are pyπdine, benzimidazole, indole, lmidazole, thiophene, lsoquinohne, quinzohne and the like Substituents as defined above for "aryl" apply equally here in the definition of heteroaryl The term "heteroaromatiL πng" may be used interchangeabh w ith the term heteroaryl The term "lo er alkoxycarbonyl" means a lo er alkoxy group bonded via a carbonyl group Examples of alkowcarbonyl groups are ethoxvcarbonyl and the The term "low τ er alkylcarbonyloxy" means lower alkylcarbonvloxy groups bonded via an oxygen atom, for example an acetoxy group The term "lower alkanoyl" means lower alkyl groups bonded via a carbonyl group and embraces in the sense of the foregoing definition groups such as acetyl, propionyl and the like. Lower alkanoyl groups may be unsubstituted, or substituted with conventional substituents such as alkoxy, lower alkyl, hydroxy, aryl, and hetereoaryl. The term "lower alkylcarbonylamino" means lower alkylcarbonyl groups bonded via a nitrogen atom, such as acetylamino. The term "aroyl" means an mono- or bicyclic aryl or heteroaryl group bonded via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, 2- naphthyl and the like. Aroyl groups may be unsubstituted, or substituted with conventional substituents such as The term "aryloxy" means an aryl group, as hereinbefore defined, which is bonded via an oxygen atom. The preferred aryloxy group is phenoxy. The term "electron-deficient substituent" means a substituent on an aromatic or heteroaromatic ring which has a positive Hammett sigma valus as defined for example in Jerry March, Advanced Organic Chemistry, 2 n Edition, McGraw Hill, 1977, page 246-253. Typical electron withdrawing groups are cyano, nitro, chloro, alkoxycarbonyl lower alkyl sulfonyl, and aminocarbonyl. In the compound of formula 1 , Y is preferably the group Y- 1 whereby the invention comprises a compound of the formula: wherein X, R 2 2> ^23 an< ^ ^24 are as above. In the group Y-l, preferably R 22 is hydrogen, halogen, lower alkyl, perfluoroalkyl (especially trifluoromethyl), R 23 is halogen, lower alkyl, perfluoro- alkyl (especially trifluoromethyl), R 2 is hydrogen, lower alkyl, lower alkoxy or halogen; more preferably R 22 and R 23 are lower alkyl, trifluoromethyl, or halogen, most preferably R 22 and R 23 are lower alkyl or halogen and R 24 is preferably hydrogen. Preferred groups Y- l , where R23 is lower-alkyl or halogen, are When Y is a group Y-2, "Het" is preferably a 6 membered heteroaromatic ring, preferably the one, two or three heteroatoms being N, with the Y-2 groups being most preferred. When Y is a group Y-3, Q is preferably -(CH 2 )f O-, -(CH )f S-, -(CH 2 )f N(R 7)- or-(CH )f-, more preferably -(CH 2 )f-; more particular Y is preferably: wherein Q is as above and the dotted bond can be optionally hydrogenated, preferably Q is (CH 2 )f and the dotted bond is hydrogenated, R 5 is R 26 -(CH 2 )e-; e is 0-4, preferably 2-4, and R 26 azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lovver alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, lower alkylthio, phenyl or phenyl substituted by alkoxy or halogen, preferably azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio, or R 26 is NHR 29 where R 29 is lower alkanoyl, lower alkoxycarbonyl or lower alkylamino carbonyl. More particularly, Y-3 is a four to five or four to six membered cycloalkyl ring (Q is (CH 2 )f, f is 1, 2 or 3), R 2 .s is R 26 -(CH ) e )e, e is 0-4, preferably 2-4, and R 2 6 is alkoxy, lower alkyl sulfonyl, loweralkylthio, phenyl or phenyl substituted by alkoxy or halogen, preferably alkoxy, lower alkyl sulfonyl or loweralkylthio, or R 26 is NHR 2 where R 29 is lower alkanoyl, loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. Most preferably, Y-3 is a group of the formula Within X- l the groups R 15 and R 16 are preferably hydrogen, lower alkyl, nitro, cyano, halogen, loweralkylsulfonyl, loweralkylthio or perfluoroloweralkyl, more preferably R 15 is lower alkyl, nitro, cyano, halogen, loweralkylsulfonyl, or perfluoroloweralkyl, and R i6 is hydrogen, lower alkyl, nitro, halogen (especially chloro or fluoro), perfluoroalkyl, loweralkylthio or cyano. Particularly, Rι ? is lower alkyl, nitro, cyano, halogen, loweralkylthio, perfluoroloweralkyl (especially trifluoromethyl) and R 16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, loweralkylthio or perfluoroloweralkyl (especially trifluoromethyl). Most preferred, R 15 and Rι 0 are independently chloro or fluoro. Moreover, it is preferred that groups selected as Rι 5 , or R 15 and R 16 , be electron-deficient as defined above. The especially preferred groups X- l are of the formula: Within the group X-2 "Het" is preferably a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. When Het is a bicyclic heteroaromatic ring, it preferably contains from 1 to 3 nitrogens as the heteroatoms. R15 is preferably, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl (especially unsubstituted phenyl); Ri 6 is preferably hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R30, when present, is preferably hydrogen or lower alkyl. More particular in X-2 Het is a 6 membered monocyclic heteroaromatic ring containing 1 or 2 nitrogens, preferably pyridine or pyrimidine, or a 10 membered bicyclic heteroaromatic ring containing one nitrogen, R 15 is lower alkyl or perfluoroalkyl and Rι 6 is hydrogen, lower alkyl, or perfluoroalkyl, and R 30 is absent. The especially preferred groups X-2 are of the formula: Within X-3 Ri g is preferably phenyl. Ri 9 is preferably lower alkyl, which is unsubstituted or substituted by pyridyl or phenyl. R 2 o is preferably substituted or, preferably, unsubstituted lower alkanoyl, with acetyl being most preferred. In a preferred combination Rι 8 is phenyl, R J9 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl and R 2 o is lower alkanoyl. In another embodiment of X-3 Rι 8 is phenyl which is unsubstituted or substituted by halogen or lower alkoxy; Rι is phenyl lower alkyl which is unsubstituted or substituted by lower alkoxy, pyridyl lower alkyl, or lower alkyl; and R 2 o is substituted or, preferably, unsubstituted lower alkanoyl with acetyl being most preferred. The especially preferred groups X-3 are of the formula: The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention. Further embodiments which define particular embodiments of the compounds of formula 1 are set forth below. 1.1. In one embodiment of a compound of formula 1 above X is a group of the formula and Y, R 15 and Riβ are as defined above, particularly wherein R ]5 is lower alkyl, nitro, halogen, perfluoromethyl, or cyano, and R !6 is hydrogen, lower alkyl, nitro, halogen, perfluoromethyl, or cyano, more particularly wherein Rι 5 and R i6 are independently chloro or fluoro, most preferably wherein X- l is selected from the group of 1.2. In another embodiment of a compound of formula I X is a group of the formula X-2 and p, Y, Rι 5 , Rι 6 , and R 30 are as defined, particularly wherein Het is a 5- or 6-membered monocyclic heteroaromatic ring containing 1 , 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen or wherein Het is a bicyclic heteroaromatic ring containing from 1 to 3 nitrogens; more particularly wherein Rl5 is nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl (especially unsubstituted phenyl), particular Rι 5 is unsubstituted phenyl, and wherein R]g is hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R 3 o is hydrogen or lower alkyl. Within this embodiment Het is in another particular embodiment a 6 membered monocyclic heteroaromatic ring containing 1 or 2 nitrogens or a 10 membered bicyclic heteroaromatic ring containing one nitrogen, R 15 is lower alkyl or perfluoroalkyl, and Rι 6 is hydrogen, lower alkyl, or perfluoroalkyl, and R30 is absent. Most preferred X-2 is selected from the group of 1.3. In yet another embodiment of a compound of formula I X is a group of formula X-3 and Y, Ris, Rι 9 , and R 2 o are as defined above, particularly wherein Ri g is phenyl, or particularly wherein Ri 9 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl, or particularly wherein R20 is substituted or unsubstituted lower alkanoyl. In more preferred embodiments Rι 8 is phenyl, Rι is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl and R 2 o is lower alkanoyl, or Rι is phenyl which is unsubstituted or substituted by halogen or lower alkoxy, Rj is phenyl lower alkyl which is unsubstituted or substituted by lower alkoxy, pyridyl lower alkyl, or lower alkyl and R 2 o is substituted or unsubstituted lower alkanoyl; with the X-3 groups being most preferred. 1.4. In another embodiment of a compound of formula 1 Y is a group of formula and X, R 2 , R 23 , and R 24 are as defined above; particularly wherein R 22 is hydrogen, lower alkyl, trifluoromethyl or halogen, R 23 is lower alkyl, trifluoromethyl, or halogen and R 24 is hydrogen, lower alkyl, lower alkoxy, or halogen; more particularly wherein R 22 and R 23 are lower alkyl, trifluoromethyl, or halogen and R 4 is hydrogen, lower alkyl, lower alkoxy, or halogen; more preferably wherein Y- l is selected from the group of 1.5. In an further embodiment of a compound of formula 1 Y is a group of the formula Y-2 and p, X, Het, R 30 and R 1 , are as defined above, particularly wherein Het is a 6 membered heteroaromatic ring, particularly wherein the heteroatom is N. Most preferred Y-2 is selected from the group of 1.6. In yet another embodiment of a compound of formula I wherein Y is a group of formula Y-3 and Y, R 23 and Q are as defined above, and the dotted bond can be optionally hydrogenated, more particularly Y-3 is selected from the group of 1.7. In further specific embodiments of a compound of formula I as defined above X is a group of formula X- 1 and Y is a group of formula Y- 1 , Y-2 or Y-3; or X is a group of formla X-2 and Y-3 is a group of formula Y-l, Y-2 or Y-3; or X is a group of formula X-3 and Y is a group of formula Y- l, Y-2 or Y-3 wherein X- l, X-2, X-3, Y-l, Y-2 and Y-3 are an defined in any of the embodiments above. More specifically an embodiment of a compound of formula 1 is preferred wherein X is a group of the formula X-l wherein R16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl, and Y is a group of the formula Y- l where R22 is hydrogen, halogen, trifluoroalkyl, or lower alkyl and R23 is halogen, trifluoroalky , or lower alkyl, and R24 is hydrogen or Y is a group of the formula Y-3 wherein Q is as above and the dotted bond can be optionally hydrogenated, R 2? is R 2 6-(CH 2 )e-; e is 2-4 and R 26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio or R__s is NHR 29 where R y is lower alkanoyl or lower alkylamino carbonyl; more particularly wherein X is a group of the formula X- l wherein R i6 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R 15 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, perfluoroloweralkyl; and Y is a group of the formula Y- l where R 22 is hydrogen, halogen, or lower alkyl and R 23 is halogen or lower alkyl, and R24 is hydrogen; more particularly wherein R i6 is hydrogen or halogen and Ris is halogen, R22 is hydrogen, halogen, ethyl, or methyl and R :3 is halogen , ethyl, or methyl; particularly wherein R 15 is in the ortho position and R 13 and R16 are both chlorine, and R 2 is methyl and R 23 is chlorine or ethyl; especially a compound which is 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [ (2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine; or more particularly wherein X is a group of the formula X- 1 wherein R 16 is in the ortho position and is hydrogen, lower alkyl, nitro, cyano, halogen, lower alkylthio, perfluoroloweralkyl and R i 5 is lower alkyl, nitro, cyano, halogen, lower alkylsulfonyl, and perfluoroloweralkyl, and Y is a group of the formula Y-3 which is a four to six membered cycloalkyl ring R25 is R26-(CH2)e-; e is 2-4 and R26 is azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or lower alkylthio, and the dotted bond is hydrogenated; particularly wherein Ri6 is halogen and R 15 is hydrogen or halogen; and Y-3 is a four or five membered ring and R 26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio; more particularly wherein R15 is in the ortho position and R 1 5 and Ri6 are both chlorine, and R 6 is lower alkyl sulfonyl or lower alkylthio; especially a compound which is 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [ [ l- [(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine; or more particularly wherein X is a group of the formula X-l where R 16 is hydrogen or halogen and R 15 is halogen and Y is a group of the formula Y- l where R 22 is hydrogen, halogen, ethyl, or methyl and R 23 is halogen, ethyl, or methyl and R 24 is hydrogen or Y is a group of the formula Y-3 where Y-3 is a four or five membered ring and R 2? is R 26 -(CH 2 ) e -; e is 2-4 and R26 is lower alkoxy, lower alkyl sulfonyl, lower alkyl sulfinyl, or lower alkylthio, and the dotted bond is hydrogenated, particularly wherein R] 5 is in the ortho position and R 15 and R J6 are both chlorine, and when Y is Y- l then R 22 is methyl and R 3 is chlorine or ethyl and when Y is Y-3, Y-3 is a four or five membered ring and R 26 is lower alkyl sulfonyl or lower alkylthio. In another embodiment of compounds of formula 1 Y is as in formula 1 and X is X- l where R 15 is ortho and is halogen, lower alkyl, or perfluoroalkyl and Rj 6 is hydrogen, halogen, lower alkyl, or perfluoroalkyl; particularly wherein R 15 is chlorine and Rι 6 is hydrogen or chlorine. In this embodiment Y is particularly Y-l where R 2 _ is hydrogen or lower alkyl, R 23 is halogen, lower alkyl, or perfluoro- alkyl, and R 2 is hydrogen; particularly wherein R[ 5 is chlorine and R 16 is hydrogen or chlorine; especially the compounds 4-[ [(2,6-dichlorophenyl)- carbonyl] amino] -N- [(2-bromophenyl)thioxomethyl] -L-phenylalanine, 4- [ [(2,6,- dichlorophenyl)carbonyl] amino] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] )- L-phenylalanine, 4- [ [(2,6,-dichlorophenyl)carbonyl]amino]-N- [(2- fluorophenyl)thioxomethyl] -L-phenylalanine, or 4- [ [ (2,6,-dichlorophenyl)- carbonyl] amino] -N-[ [2- (trifluoromethy'l)phenyl] thioxomethyl ]-L- phenylalanine. Alternatively Y is within this embodiment Y-3 which is a four to six membered cycloalkyl ring, R 25 is R & -(CH 2 )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio; preferably R 20 is methoxy, methyl sulfonyl, or methyl thio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated; especially a compound selected from 4-[ [2,6-dichlorophenyl)carbonyl]amino-N-[ [ l -[2- (acetylamino)ethyl] cyclopentyl]thioxomethyl] -L-phenylalanine, [ [ l- [2- [ [(methylamino)carbonyl] amino] ethyl] cyclopentyl] thioxomethyl] -4- [ [ (2,6- dichlorophenyl)carbonyl] amino] L-phenylalanine, 4-[ [(2,6,-dichloro- phenyl)carbonyl]amino]-N- [ [ l-(2-methoxyethyl)cyclopentyl]thioxomethyl]-L- phenylalanine, 4- [ [ (2,6,-dichlorophenyl)carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine, 4- [ [ (2,6,- dichlorophenyl)carbonyl] amino] -N- [ [ 1 - (3-methylthio)propyl] cyclobutyl] - thioxomethyl] -L-phenylalanine, or 4- [ [(2,6,-dichlorophenyl)carbonyl]amino] - N- [ [ l -(3-methylsulfonyl)propyl] cyclobutyl]thioxomethyl] -L-phenylalanine. In another embodiment of a compound of formula 1 Y is as in formula 1 and X is X-2 X-2 where Het is pyridine or pyrimidine and R 15 is lower alkyl, or perfluoroalkyl and Ri 6 , and R 20 are hydrogen, lower alkyl, or perfluoroalkyl. In this embodiment Y is particularly Y- l where IX is hydrogen or lower alkyl, R 23 is halogen, low r er alkyl, or perfluoroalkyl, and R 24 is hydrogen. Alternatively Y is in this embodiment Y-3 Y-3 which is a four to six membered cycloalkyl ring, R 25 is R 26 -(CH:)e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, preferably methoxy, methyl sulfonyl, or methyl thio, or NHR 29 where R 29 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated, especially a compound selected from 4- [ (2,6-dimethyl-3-pyridinylcarbonyl)amino] -N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine, 4- [ ' [4- (trifluoromethyl)-5-pyrimidinyl]carbonyl] amino] -N- [ [ l -(4-methylsulfonyl <- butyl] cyclobutyl]thioxomethyl] -L-phenylalanine, or 4- [ [ (2,4-dimethyl-6- trifluoromethyl-3-pyridinyl)carbonyl]amino]-N- [ [ l - [ (4-methylsulfonyl)butyT - cyclobutyl] thioxomethyl] -L-phenylalanine. In another embodiment of a compound of formula 1 Y is as in formula 1 and X is X-3 where R 19 is pyridinyl lower alkyl or phenyl lower alkyl, R 0 is lower alkanoyl, and R18 is phenyl. Particularly Y is in this embodiment Y- l where R 22 is hydrogen or lower alkyl, R 2 is halogen, lower alkyl, or perfluoroalkyl, and R 24 is hydrogen; especially 4- [ (2S, 4R)-3-acetyl-2-phenyl-4- [ (3-pyridinyl)methyl] -5-oxo-imidazolidin- l-yl] -N- [ (2-ethyl-6- methylphenyl) thioxomethyl] -L-phenylalanine. Alternatively, Y is in this embodiment Y-3 which is a four to six membered cycloalkyl ring, R 5 is R 2t ,-(CH )e-, e is 2-4, and R 26 is alkoxy, lower alkyl sulfonyl, loweralkylthio, preferably methoxy, methyl sulfonyl, or methyl thio, or R 25 is NHR where R 2 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated; especially a compound selected from 4-[(2S,4R)-3-acetyl-2-phenyl-4- [(3-phenyl)methyl]-5- oxo-imidazolidin- 1 -yl] -N- [ [ (4-methylsulfonyl)butyl ] cyclopentyl] thioxomethyl] - L-phenylalanine, or 4- [(2R,4R)-3-acetyl-2-phenyl-4- [ (3-phenyl)methyl] -5-oxo- imidazolidin-l -yl] -N-[ [ (4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl ] -L- phenylalanine. In another embodiment of a compound of formula 1 X is as in formula 1 and Y is Y- l where R 22 is hydrogen or lower alkyl, R 23 is halogen, lower alkyl, or perfluoroalkyl, and R24 is hydrogen, particularly wherein R 22 is hydrogen or methyl and R 23 is halogen, ethyl, or trifluoromethyl. Other preferred compounds of formula 1 are wherein X is as in formula 1 and Y is Y-3 which is a four to six membered cycloalkyl ring, R 2. s is R 6 -(CH )e-, e is 2-4, and R 2& is alkoxy, low er alkyl sulfonyl, loweralkylthio, preferably methoxy, methyl sulfonyl, or methylthio, or R 25 is NHR 29 where R 2 is loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. The compounds of the invention inhibit the binding of VCAM- 1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes ("VLA-4-expressing cells"). The binding of VCAM- 1 and fibronectin to VLA-4. on such cells is known to be implicated in certain disease states, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and particularly in the binding of eosinophils to pulmonary endothelium which contributes to the cause of the pulmonary inflammation which occurs in asthma. Thus, the compounds of the present invention would be useful a medicaments, especially for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and, especially, asthma. On the basis of their capability of inhibiting binding of VCAM- 1 and fibronectin to VLA-4 on circulating lymphocytes, eosinophils, basophils, and monocytes, the compounds of the invention can be used as medicament for the treatment of disorders which are known to be associated with such binding. Examples of such disorders are rheumatoid arthritis, multiple sclerosis, asthma, and inflammatory bowel disease. The compounds of the invention are preferably used in the treatment of diseases which involve pulmonary inflammation, such as asthma. The pulmonary inflammation, which occurs in asthma, is related to eosinophil infiltration into the lungs wherein the eosinophils bind to endothelium which has been activated by some asthma-triggering event or substance. Furthermore, compounds of the invention also inhibit the binding of VCAM- 1 and MadCAM to the cellular receptor alpha4-beta7, also known as LPAM, which is expressed on lymphocytes, eosinophils and T-cells. While the precise role of alpha4-beta7 interaction with various ligands in inflammatory conditions such as asthma is not completely understood, compounds of the invention which inhibit both alpha4-betal and alpha4-beta7 receptor binding are particularly effective in animal models of asthma. Furthermore w τ ork with monoclonal antibodies to alpha4-beta7 indicate that compounds which inhibit alpha4-beta7 binding to MadCAM or VCAM are useful for the treatment of inflammatory bowel disease. They would also be useful in the treatment of other diseases in which such binding is implicated as a cause of disease damage or symptoms. The compounds of the invention can be administered orally, rectally, or parentally, e.g., intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations, or as an aerosol in the case of pulmonary inflammation. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms. Intravenous, intramuscular, oral or inhalation administration is a preferred form of use. The dosages in which the compounds of the invention are administered in effective amounts depending on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. Thus, the invention further comprises a method of treating a host suffering from a disease in which VCAM- 1 of fibronectin binding to VLA-4-expressing cells is a causative factor in the disease symptoms or damage by administering an amount of a compound of the invention sufficient to inhibit VCAM- 1 or fibronectin binding to VLA-4-expressing cells so that said symptoms or said damage is reduced. In general, dosages of about 0.1- 100 mg/kg body weight per day are preferred, with dosages of 1-25 mg/kg per day being particularly preferred, and dosages of 1 -10 mg/kg body weight per day being especially preferred. The invention further comprises in another embodiment pharmaceutical compositions which contain a pharmaceutically effective amount of a compound of the invention, including salts and esters thereof, and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. In this regard the present invention relates in a further embodiment to a process for the production of a pharmaceutical preparation, especially a pharmaceutical preparation for the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma comprising bπnging one or more compounds according to the present invention or a pharmaceutically acceptable salt or ester thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with a compatible pharmaceutical carrier material Tablets or granulates can contain a series of binders, fillers, carriers or diluents Liquid compositions can be, for example, in the form of a sterile water-misαble solution Capsules can contain a filler or thickener in addition to the active ingredient Furthermore, ing additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and othei additives can also be present The previously mentioned carrier materials and diluents tan comprise am conventional pharmaceutically acceptable organic or inorganic substances, e g water, gelatin, lactose, starch, magnesium stearate, talc, gum arabl , polyalk\lene glycols and the like Oral unit dosage forms, such as tablets and capsules, preferabh contain from 25 mg to 1000 mg of a compound of the invention The compounds of the present invention may be prepared by any conventional means In reaction Scheme 1, a 4-nιtro-L-phenvlalanme dern atn e of formula 1 in which Ri is lower alkyl, w hich is a known compound or readih prepared by conv entional means, is acylated with a benzoic acid derivative of formula 2 in which R 2 hydrogen, lower alkyl, low er alkoxy, cycloalkv l, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower l sulfoml, lower alkanoyl, halogen, or perfluorolower alkyl, R 3 is hydrogen, halogen or lower alkyl and R4 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen, using conventional means for amide bond formation For example, a compound of formula 2 may be conv erted to the corresponding acid chloride and condensed with a compound of formula 1 in the presence of a proton acceptor such as a tertiary alkylamine Alternativeh compound 1 can be coupled with a carboxyhc acid of formula 2 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0 °C and room temperature to give a compound of formula 3 Conversion of the compound of formula 3 to the corresponding thioamide of formula 4 can be carried out by treatment with Lawesson s reagent hich is [2 bιs(4-methoxvphenyl)- l ,3-dιfhιa-2,4-dιphosphetane-2,4-dιsulfide] The procedure is standard and has been described in detail See for example, Scheibey, S , Pedersen, B S , Lawesson, S -O Bull Soc Chim Belg 1978 87, 229 and Cava, M P , Levinson, M I , Tetrahedron 1985, 41, 5061 The nitro group of the compound of formula 4 may be reduced to the corresponding amine by an\ of the conventional means which are compatible with thioamides One convenient procedure employs zinc dust as the reducing agent in the presence of methanol, ammonium chloride and water at a temperature of from 35 to 60 °C to give a compound of formula 5 Acvlation of this compound w ith an aryl- or heteroaryl carboxylic acid of formula 6 using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0 °C and room temperature gives a compound of formula 7 In certain cases, for example with hindered carboxylic acids 6, it may be advantageous to form the corresponding acid hahde and react it with the amine of formula 5, typically in the presence of a slight excess of a base such as a tertiary amine or 4-(dιmethylamιno)pyπdιne The carboxylic acid of formula 6 may be substituted by halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, alkylthio lower alkyl, alkylsulfinyl lower alkyl, alkylsufonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxv Where appropriate, it may also incorporate suitably protected reactive functionalities which must be removed to permit final conversion into compounds of the invention The choice and use of such groups will be apparent to those skilled in the art Guidance for the selection and use of protecting groups is provided in standard reference works, for example. "T W Green and P. G M Wuts, Protective Groups in Organic Synthesis, 2 nd edition, Wiley Interscience, New York, 19 1. The ester moiety of compound 7 can generally be cleaved to the corresponding carboxylic acid by treatment with an alkali metal hdvroxide, for example, lithium hydroxide in aqueous methanol at a temperature of from room temperature to 50 °C Depending on the nature of Ri, alternative procedures may be preferred The choice of conditions for ester cleav ge in the presence of functionalities such as thioamides is well known to those skilled in the art Scheme 1 Ortho-substituted benzoic acid derivatives which are not commercially available can be prepared by conventional means. For example ortho-substituted aryl iodides or triflates may be carbonylated in the presence of carbon monoxide and a suitable palladium catalyst. The preparation of such iodide or triflate intermediates is dependent on the particular substitution pattern desired and they may be obtained by direct iodination or diazotization of an aniline followed by treatment with a source of iodide for example, potassium iodide. Triflates may be derived from the corresponding phenols by conventional means such as treatment with trifluoromethane sulfonic anhydride in the presence of a base such as triethylamine or diisopropylethylamine in an inert solvent. Other means of obtaining ortho-substituted benzoic acids involves treatment of an 2- mefhoxyphenyloxazoline derivative such as 9 with an alkyl Grignard reagent followed by hydrolysis of the oxazoline ring following the general procedure described by Meyers, A. I., Gabel, R., Mihelick, E. D, I. Org. Chem. 1978, 43, 1372-1379., to give an acid of formula 10. 2- or 2,6-Disubstituted benzonitriles also serve as convenient precursors to the corresponsing benzoic acids. In the case of highly hindered nitriles, for example 2-chloro-6-methylbenzonitrile, conventional hydrolysis under acidic or basic conditions is difficult and better results are obtained by DIBAL reduction to the corresponding benzaldehyde followed by oxidation using a sodium chlorite/hydroperoxide oxidizing reagent. Scheme 2 10 Employing essentially the same procedures described in Scheme 1 , utilizing a heteroaromatic carboxylic acid in place of 2, one can prepare compounds of formula 11. For the synthesis of analogues a branched chain or cycloalkyl moiety, a similar procedure to that described in scheme 1 can be employed starting with the appropriate branched chain or cycloalkyl carboxylic acid of formula 12. In this case, R 6 represents is lower alkyl, unsubstituted or fluorine substituted low τ er alkenyl, or a substituted lower alkyl group wherein the substituents may be chosen from aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkyl sulfonyl, perfluoro lower alkanoyl, nitro, or a protected amino group. The amine protecting group must be chosen to be compatible with the reagents needed to convert carboxamides to thioamides. Carbamates, for example, the tert-butoxycarbonyl moiety are suitable. As appropriate, these protecting groups may be removed by conventional means later in the synthesis and the resulting free amine can be further functionalized utilizing standard methods. For example, the amine can be acylated by treatment with the appropriate anhydride, isocyanate or acid halide. 12 The synthesis of imidazolidinones of formula 21 is described in reaction scheme 3. An aminophenylalanine derivative of structure 13 in which Rg is aryl, heteroaryl, branched chain alkyl or derived from a compound of formula 12, and R7 is lower alkyl, is coupled with a N-protected D-amino acid of formula 14, in which Rg can be a natural or unnatural, D- or L-α-amino acid side chain and R9 is a nitrogen protecting group of the type conventionally used in peptide chemistry, for example, a Fmoc group, using standard peptide coupling conditions, for example HBTU in the presence of DIPEA in a polar, aprotic solvent such as DMF at a temperature between 0 °C and room temperature to give a compound of formula 15. Depending on the nature of protecting group R9, an appropriate deprotection method is employed to give compound of formula 16. In the case of the protecting group R9 is Fmoc group, it may be removed from 15 using standard base treatment well known to those practicing peptide chemistry, for example with piperidine in DMF, to afford an amine of formula 16. The compound 16 can then react with an aldehyde 17, in which R J Q is lower alkyl, aryl, or aryl lower alkyl, in the presence of a water scavenger such as 4A molecular sieves in an appropriate solvent such as dichloromethane or THF at 25-60 °C to ςive an imine of formula 18. The imine 18 mav then be treated with an acylating agent such as the acyl chloride of formula 19 in which Rl 1 can be an alkyl or aryl group in the presence of a base such DIPEA or DBL ' in an appropriate solvent such as dichloromethane or THF at 25-60 °C to give an acyl imidazolidinone of formula 20. Alternatively, other reactive acylating groups such as acid anhydrides or mixed anhydrides may be employed in this reaction. Compound 20 may be converted to a compound of the invention by an appropriate hydrolysis procedure, for example by hydrolysis by treatment with an alkali metal hydroxide, for example sodium hydroxide in aqueous alcohol to give, after acidification, a carboxylic acid of formula 21. Scheme 3 General Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. Optical rotations were determined with a Perkin-Elmer model 241 polarimeter. H-NMR spectra were recorded with Varian XL-200 and Unityplus 400 MHz spectrometers, using tetramethylsilane (TMS) as internal standard. Electron impact (EI, 70 ev) and fast atom bombardment (FAB) mass spectra were taken on VG Autospec or VG 70E-HF mass spectrometers. Silica gel used for column chromatography was Mallinkrodt SiliCar 230-400 mesh silica gel for flash chromatography; columns were run under a 0-5 psi head of nitrogen to assist flow. Thin layer chromatograms were run on glass thin layer plates coated with silica gel as supplied by E. Merck (E. Merck # 1.05719) and were visualized by viewing under 254 nm UV light in a view box, by exposure to I 2 vapor, or by spraying with either phosphomolybdic acid (PMA) in aqueous ethanol, or after exposure to Cb, with a 4,4'-tetramethyldiaminodiphenylmethane reagent prepared according to E. Von Arx, M. Faupel and M Brugger, /. Chromatography, 1976, 120, 224-228. Reversed phase high pressure liquid chromatography (RP-HPLC) was carried out using either a Waters Delta Prep 4000 employing a 3 x 30 cm, Waters Delta Pak 15 μM C- 18 column at a flow of 40 mL/min employing a gradient of acetonitrile:water (each containing 0.75% TFA) typically from 5 to 95% acetonitrile over 35-40 min or a Rainin HPLC employing a 41.4 x 300 mm, 8 μM, Dynamax 1 M C- 18 column at a flow of 49 mL/min and a similar gradient of acetonitrile:water as noted above. HPLC conditions are typically described in the format (5-95-35-214); this refers to a linear gradient of from 5% to 95% acetonitrile in water over 35 min while monitoring the effluent with a UV detector set to a wavelength of 214 nM. Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, ether, and methanol, were Fisher reagent grade and were used without additional purification except as noted, acetonitrile was Fisher hplc grade and was used as is. Definitions: THF is tetrahydrofuran, DMF is N,N-dimethylformamide, HOBT is 1 -hydroxybenzotriazole, BOP is [ (benzotriazole- l -yl)oxy]tris-(dimethylamino)phosphonium hexafluorophosphate, HATU is O-(7-azabenzotriazol- l -yl)- l ,l ,3,3-tetramethyluronium hexafluorophosphate HBTU is 0-benzotriazole-N,N,N',N',-tetramethyluronium hexafluorophosphate, DIPEA is diisopropylethylamine, DMAP is 4-(N,N-dimethylamino)pyridine DPPA is diphenylphosphoryl azide DPPP is l ,3-bis(diphenylphosphino)propane DBU is l,8-diazabicyclo[5.4.0] undec-7-ene NaH is sodium hydride brine is saturated aqueous sodium chloride solution TLC is thin layer chromatography LDA is lithium diisopropylamide BOP-Cl is bis(2-oxo-3-oxazolidinyl)phosphinic chloride NMP is N-methyl pyrrolidinone Lawesson's reagent is [2,4-bis(4-methoxyphenyl)- l ,3-dithia-2,4-diphosphetane- 2,4-disulfide] Examples Example 1. N-[[l-(2-methoxyethyl)cyclopentyl] thioxomethyl] -4-nitro-L- phenylalanine methyl ester. Lawesson " s Reaaent Toluene.50 °C. ISh C l9 H 26 N 2 0 6 C] 9 H- 6 N ' D^S Mol. Wt.: 378.42 Mol. \Vt.: 394.49 To a solution of [[l-(2-methoxyethyl)cyclopentyl]carbonyl]-4-nitro-L- phenylalanine methyl ester (4.30 g, 11.4 mmol) in toluene (20 mL) was added Lawesson's reagent (2.60 g, 6.27 mmol). The resultant mixture was warmed to 50 °C and stirred for 18 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification by flash column chromatography, eluting with hexane-ethyl acetate (9:1 then 8:1), afforded N- [[l-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (2.44 g, 54%; 70% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 395.1639. Calcd. mass, 395.1640 (M+H). Example 2.4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[l-(2-(methoxyethyl cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester. C26H30CI2N2O4S Mol. Wt.: 537.50 To a suspension of N-[[l-(2-methoxyethyl)cyclopentyl]thioxomethyl]-4-nitro- L-phenylalanine methyl ester (4.58 g, 11.6 mmol), zinc dust (7.50 g, 116 mmol) and ammonium chloride (9.20 g, 174 mmol) in methanol (200 mL) was added H 2 0 ( lOOmL) slowly over 5 min. After stirring for 20 min., the reaction mixture was diluted with ethyl acetate (400 mL) and sat. ammonium chloride solution ( 150 mL) and the organic layer was separated. The aqueous layer was back- extracted with ethyl acetate (3x100 mL) and the organic layers were combined, dried over Na 2 Sθ4, filtered and concentrated in vacuo. The oil was dried under high vacuum for 2 h to give crude 4-amino-N-[ [ l-(2-methoxyethyl)cyclopentyl] - thioxomethyl] -L-phenylalanine methyl ester (4.5 g). To a solution of the crude amine obtained above (3.40 g, -8.77 mmol based on 94% purity) and diisopropylethylamine ( 1.70 mL, 9.65 mmol) in CH 2 C1 2 ( 15 mL) was added a solution of 2,6-dichlorobenzoyl chloride ( 1.9 g, 9.21 mmol) in CH 2 Cb (5 mL). The resultant mixture was stirred overnight. The reaction mixture was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate ( 150 mL) and water (40 mL). The aqueous layer w τ as separated and back extracted with ethyl acetate ( 1 x 50 mL). The combined organic layer was washed with a sat. solution of Na2Cθ3 followed by sat. brine, dried over MgSθ4, filtered and concentrated in vacuo. Purification by silica gel flash column chromatography, eluting with hexane-ethyl acetate (3: 1 ), afforded 4-[ [(2,6-dichlorophenyl)carbonyl]amino] -N-[ [ l-(2- methoxyethyl)cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (4.50 g, 95%). HR MS: Obs. mass, 559.1201. Calcd. mass, 559.1201 (M+Na). Example 3. 4- [ [(2,6-dichlorophenyl)carbonyl]amino] -N- [ [ l -( 2-methoxy- ethyl)cyclopentyl] thioxomethyl] -L-phenylalanine. To a solution of 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- ; [ l -(2- methoxyethyl) cyclopentyl]thioxomethyl] -L-phenylalanine methyl ester (4.00 g, 7.44 mmol) in MeOH ( 18 mL) was added a solution of NaOH (421 mg, 10.5 mmol) in water (3 mL). The mixture was stirred for 2 h and then acidified (pH - 1 -2) with 0.5M HCl. The reaction mixture was poured into a separatory funnel containing ethyl acetate ( 150 mL) and water (25 mL). The aqueous layer was separated and back extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed w r ith sat. brine, dried over MgS04, filtered and concentrated in vacuo. Purification by reversed-phase HPLC, using a 15-95% acetonitrile-water gradient over 25 min., provided 4- [ [(2,6-dichlorophenyl)- carbonyl]amino] -N- [ [ l -(2-methoxyethyl)cyclopentyl]thioxomethyl]-L- phenylalanine (3.05 g, 78%). HR MS: Obs. mass, 545.1043. Caled. mass, 545.1045 (M+Na). Example 4. l -(2-azidoethyl)cyclopentane carboxylic acid. To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF (85 mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0 °C for 30 min, cooled to a bath temperature of -65 °C and ethyl cyclopentane carboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 h, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at -65 °C for 3 h and allowed to warm to room temperature overnight. The reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate ( 100 mL). The combined extracts were washed with 1 :1 brine:water (250 mL) and were dried (Na2Sθ4). The solution was filtered and concentrated, diluted with toluene ( 100 mL) and concentrated. The dilution and concentration was repeated twice to give ethyl l-(2-bromoethyl)cyclopentane carboxylate (52.5 g). A solution of the above bromide (52.5 g, 0.21 1 mol) and sodium azide (54 g, 0.831 mol) in DMF (200 mL) was stirred at 50 °C for 5 h under a nitrogen atmosphere and was filtered. The filtrate was concentrated to near dryness, diluted with ethyl acetate (500 mL), filtered and concentrated to give crude ethyl l-(2-azidoethyl)cyclopentane carboxylate (40.9 g) as a brown oil. This material was combined with product from a previous run (total 63.5 g) and was purified by chromatography over 250 g of silica gel, eluting with 5% ethyl acetate in hexane to give 50.3 g of product as a light brown oil. The oil from above (50.3 g, 0.238 mol) was dissolved in THF (750 mL) and methanol (375 mL) and a solution of LiOH hydrate ( 15 g, 0.357 mol) in water (300 mL) was added. The resulting solution was stirred at 40 "C overnight and concentrated. The residue was dissolved in 2 L of water containing 40 mL of IN NaOH and was washed with hexane ( 1 L). The aqueous layer was acidified with 1 N HCl (375 mL) and was extracted with ether (2 x 1 L). The combined extracts were dried (Na2Sθ4) and concentrated to give l-(2-azidoethyl)cyclopentane carboxylic acid (37.5 g) as an amber liquid. Example 5. N-[ [ l-(2-azidoethyl)cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester. Cιr j Hi2N 2 0 4 C18H 2 3 5O5 Mol. Wt.: 224.21 Mol. Wt.: 389.41 A solution of 4-nitro-L-phenylalanine methyl ester hydrochloride (3.0 g, 1 1.5 mmol), l -(2-azidoethyl)cyclopentane carboxylic acid (2.3g, 12.7 mmol) and BOP (5.34 g, 12.1 mmol) in dichloromethane (6 mL) and DMF (4 mL) was treated with diisopropylethylamine (4.2 mL, 24.2 mmol). The mixture was stirred overnight at which time TLC ( 1:1 hexane:ethyl acetate) indicated no more starting material. The mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with water and saturated brine and were dried over sodium sulfate. Filtration and evaporation afforded a residue which was purified by chromatography over silica gel eluting with 3: 1 hexane:ethyl acetate to afford 4.26 g of N- [ [ l-(2-azidoethyl)cyclopentyl]carbonyl] -4-nitro-L- phenylalanine methyl ester. Example 6. N-[ [ l- [2-[ [ ( l,l-dimethylethoxy)carbonyl]amino]ethyl]- cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester. a. A solution of N-[ [ l -(2-azidoethyl)cyclopentyl]carbonyl]-4-nitro-L- phenylalanine methyl ester ( 1.92 g, 4.93 mmol) in THF (20 mL) was treated dropwise with a 1 M solution of trimethylphosphine in THF. After the addition was complete, the mixture was stirred for 20 min and water (0.17 mL) was added. The reaction was stirred a further 2 h, a little TFA was added and the mixture was dried over sodium sulfate and concentrated. b. To a solution of N-[ [ l-(2-aminoethyl)cyclopentyl]carbonyl] -4-nitro-L- phenylalanine methyl ester trifluoroacetic acid salt (2.35 g, 4.93 mmol) in dioxane (25 mL) was added diisopropylethylamine (0.860 mL, 4.93 mmol) and di-tert-butyl dicarbonate (1.08 g, 4.93 mmol). The resultant mixture was stirred for 18 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification by silica gel flash column chromatography, eluting with hexane-ethyl acetate (3: 1 ), afforded N-[ [ l-[2- [ [( 1,1 -dimethylethoxy)carbonyl] amino] ethyl] cyclopentyl] carbonyl] -4-nitro-L- phenylalanine methyl ester (2.20 g, 95%). HR MS: Obs. mass, 464.2397. Calcd. mass, 464.2397 (M+H). Example 7. N- [ [ 1 - [2- [ [ ( 1 , 1 -dimethylethoxy)carbonyl ] amino] ethyl] cyclopentyl] thioxomethyl] -4-nitro-L-phenylalanine methyl ester. To a solution of N- [ [ 1 - [2- [ [ ( 1 , 1 -dimethylethoxy)carbonyl] amino] ethyl] - cyclopentyl]carbonyI] -4-nitro-L-phenylalanine methyl ester ( 1.00 g, 2.16 mmol) in toluene/dioxane ( 1:1 , 10 mL) was added Lawesson's reagent (0.524 g, 1.29 mmol). The resultant mixture was warmed to 50 °C and was stirred for 24 h. The reaction mixture was filtered through a sintered glass funnel and the filtrate was concentrated in vacuo. Purification by silica gel flash column chromatography, eluting with hexane-ethyl acetate (6: 1 then 4: 1 ), afforded N- [ [ 1 - [2- [ [ ( 1 , 1 -dimethylethoxy)carbonyl] amino ] ethyl] cyclopentyl] thioxomethyl] - 4-nitro-L-phenylalanine methyl ester (460 mg, 44%; 65% based on recovered starting material) as a light yellow oil. HR MS: Obs. mass, 478.2014. Calcd. mass, 478.2012 (M-H). Example 8. N-[ [ l - [2- (acetylamino)ethyl [ cyclopentyl ] thioxomethyl] -4-nitro-L- phenylalanine methyl ester. 23H33N3O6S Mol. Wt.: 479.59 C20H2 7 N3O5S Mol. Wt.: 421.51 To a solution of N- [ ( 1 - [2- [ [ ( 1 , 1 -dimethylethoxy)carbonyl] amino] ethyl] - cyclopentyl] thioxomethyl] -4-nitro-L-phenylalanine methyl ester ( 1.26 g, 2.63 mmol) in methylene chloride ( 15 mL) was added dropwise TFA (7 mL) and the resultant mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo to afford the TFA salt of crude N- [ [ l -(2-aminoethyl)- cyclopentyl]thioxomethyl] -4-nitro-L-phenylalanine methyl ester as a yellow oil ( 1-4 g). To a solution of the salt obtained above ( 1.4 g, -2.63 mmol) in methylene chloride ( 10 mL) was added diisopropylethylamine ( 1.37 mL, 7.88 mmol) and acetic anhydride (0.250 mL, 2.63 mmol). The resultant mixture was stirred overnight. The reaction mixture was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate ( 100 mL) and water (40 mL). The aqueous layer was separated and back extracted with ethyl acetate ( 1 x 50 mL). The combined organic layer was washed with brine, dried over MgSθ4, filtered and concentrated in vacuo. Purification by flash column chromatography, using methylene chloride-acetone (5:1 ), afforded N-[ [ l - [2- (acetylamino)ethyl] cyclopentyl] thioxomethyl] -4-nitro-L-phenylalanine methyl ester (743 mg, 67%). HR MS: Obs. mass, 422.1744. Calcd. mass, 422.1750 (M+H). Example 9. 4-amino-N-[ [ l-[2-acetylamino)ethyl [cyclopentyl ] thioxomethyl] -L- phenylalanine methyl ester. C20H 27 N3O5S Mol. Wt.: 421.51 C 2 0H29N3O3S Mol. Wt.: 391.53 To a suspension of N- [ [ l - [2-(acetylamino)ethyl]cyclopentyl] thioxomethyl] -4- nitro-L-phenylalanine methyl ester (740 mg, 1.75 mmol), zinc dust ( 1.14 g, 17.5 mmol) and ammonium chloride ( 1.41 g, 26.3 mmol) in methanol (20 mL) was added H2O ( 10 mL) slowly over 5 min. After stirring for 20 min., the reaction mixture was diluted with ethyl acetate (80 mL) and sat. ammonium chloride solution (25 mL) and the organic layer was separated. The aqueous layer was back-extracted with ethyl acetate (3 x 25 mL) and the organic layers were combined, dried over Na2Sθ4, filtered and concentrated in vacuo. The oil was dried under high vacuum for 2 h to give the crude amine (750 mg). Purification by flash silica gel column chromatography, eluting with methylene chloride- acetone (2: 1 ), afforded 4-amino-N- [ [ l - [2- acetylamino)ethyl] cyclopentyl]thioxomethyl] -L-phenylalanine methyl ester (650 mg, 95%). HR MS: Obs. mass, 392.2016. Calcd. mass, 392.2008 (M+H). Example 10. 4- [ [(2,6-dichlorophenyl)carbonyl]amino] -N- [ [ l - [2-(acetylamino) ethyl] cyclopentyl] thioxomethyl] -L-phenylalanine. To a solution of 4-amino-N- [ [ l- [2-(acetylamino)ethyl]cyclopentyl]thioxo- methyl] -L-phenylalanine methyl ester ( 195 mg, 0.498 mmol) and diisopropylethylamine (0.0950mL, 0.548 mmol) in CH2CI2 ( 1 mL) was added a solution of 2,6-dichlorobenzoyl chloride ( 1 10 mg, 0.523 mmol) in CH2CI2 ( 1 mL). The resultant mixture was stirred overnight. The reaction mixture was concentrated in vacuo and transferred to a separatory funnel containing ethyl acetate (50 mL) and water ( 10 mL). The aqueous layer was separated and back extracted with ethyl acetate ( 1 x 25 mL). The combined organic layer was washed with a sat. solution of Na2Cθ3 followed by sat. brine, dried over MgSθ4, filtered and concentrated in vacuo to provide crude 4- [ [(2,6-dichlorophenyl)carbonyl] - amino] -N- [ [ l - [2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-L- phenylalanine methyl ester (300 mg). To a solution of the above methyl ester (300 mg, -0.498 mmol) in MeOH ( 1 mL) was added a solution of NaOH (64 mg, 14.9 mmol) in water ( 1 mL). The mixture was stirred for 2 h and then acidified (pH - 1-2) with 0.5M HCl. The reaction mixture was poured into a separatory funnel containing ethyl acetate (50 mL) and water ( 10 mL). The aqueous layer was separated and back extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with sat. brine, dried over MgSθ4, filtered and concentrated in vacuo. Purification by reversed-phase HPLC, using a 15-95% acetonitrile-water gradient over 25 min and lyophylization of the product containing fractions., provided 4- [ [(2,6- dichlorophenyl)carbonyl]amino]-N- [ [ l - [2-(acetylamino)ethyl]cyclopentyl - thioxomethyl] -L-phenylalanine ( 126 mg, 46%) as a white solid. HR MS: Obs. mass, 550.1330. Calcd. mass, 550.1334 (M+H). Example 1 1. [ [ 1 - [2- [ [ (Methylamino)carbonyl] amino] ethyl] cyclopentyl] - thioxomethyl] -4- [ [(2,6-dichlorophenyl)carbonyl[ amino] -L-phenylalanine. C 23 H 33 N 3 0 6 S C 2 oH 28 0 5 S Mol. Wt.: 479.59 Mol. Wt.: 436.53 C 26 H 3 oCl2N 4 0 4 S Mol. Wt.: 565.51 [ [ l - [2-[ [ (Meth ylamino)carbonyl] amino] ethyl] cyclopentyl ] thioxomethyl] -4- [ [(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine was prepared from N- [ [ l-[2- [ [ ( l ,l -dimethylethoxy)carbonyl] amino]ethyl]cyclopentyl] thioxometh 'l ! 4-nitro-L-phenylalanine methyl ester and methyl isocyanate using the general procedure described in examples 8 to 10. HR MS: Obs. mass, 565.1436. Calcd. mass, 565.1443 (M+H). Example 12. 2-chloro-6-methylbenzaldehyde. C 8 H 6 CIN C 8 H 7 CIO Mol. Wt.: 151 .60 Mol. Wt.: 154.60 A 500 mL, three-necked, round bottomed flask equipped with a magnetic stirrer, thermometer, additional funnel, and argon inlet was charged with 75 g (494 mmol) of 2-chloro-6-methylbenzonitrile and 400 mL of toluene (stored over 4 A molecular sieves). The mixture was cooled to -2 °C (ice + acetone) and a solution of DIBAL-H (593 mmol, 593 mL, 1.0N) in hexanes was added dropwise over a period of 30 min while maintaining the temperature below 0 °C. After the addition, the reaction mixture was stirred for 1 h at 0 °C and then allowed to warm to room temperature. After 2 h at room temperature, TLC analysis indicated the absence of starting material (4: 1 hexane:ether, phosphomolybdic acid spray, as analysis by UV fluorescence was misleading). The reaction mixture was poured into an ice (2000 g) and concentrated sulfuric acid (50 mL) and was stirred for overnight. The precipitated solids were collected by filtration and the filtrate was extracted with ether (2 X 200 mL). The combined extracts were washed with brine solution and dried over MgSO . Filtration of the drying agent and concentration of the solution gave the crude aldehyde, which was combined with the above solid to afford 71.31 g (93%) of light yellow solid suitable for use in the next step. Example 13. 2-chloro-6-methylbenzoic acid. C 8 H 7 CIO C 8 H 7 CI0 2 Mol. Wt.: 154.60 Mol. Wt.: 170.60 A 1000 mL, three-necked, round bottomed flask equipped with a magnetic stirrer, thermometer, additional funnel, and argon inlet was charged with 71.31 g (461 mmol, crude obtained from the above experiment) of 2-chloro-6- methylbenzaldehyde and 750 mL of acetonitrile. To this suspension, a solution of monobasic sodium phosphate ( 1 15 mmol, 15.9 g, 0.25 eq.) in water 240 mL) was added followed by hydrogen peroxide (50 mL, 30%) at room temperature. Then, a solution of sodium chlorite (73.5 g, 81 1 mmol, 1.76 eq.) in water (700 mL) was added dropwise at 0 °C while maintaining the temperature below 3 "C. After addition, the yellow suspension was stirred for 15 h at 0 °C to room temperature at which time TLC analysis of the mixture indicated the absence of aldehyde. Then, a solution of sodium bisulfite (73 g, 701 mmol, 1.52 eq.) in water (200 mL) was added dropwise at 0 °C until the yellow color disappear (Kl-paper positive). Cooling is essential to control the exothermic reaction. The solvent was removed under vacuum to afford a white solid. The solid was collected by filtration and the filtrate was extracted with ether (200 mL). The above solid also dissolved in this ether solution and was washed with 10% NaOH solution (2 x 200 mL). The basic aqueous solution was neutralized with 10% HCl to pH ~ 1. The precipitated white solid was collected by filtration and dried at air to afford 54.88 g (65%, overall in two steps) of 2-chloro-6-methylbenzoic acid as a white solid. Example 14. N-(2-chloro-6-methylphenylcarbonyl) -4-nitro-L-phenylalanine methyl ester. To a solution of 4-nitro-L-phenylalanine methyl ester hydrochloride salt (7.44 mmol, 1.94 g), 2-chloro-6-methylbenzoic acid (8.2 mmol, 1.4 g) and HBTU (8.2 mmol, 3.11 g) in DMF (27 mL) was added diisopropylethylamine ( 18.6 mmol, 3.24 mL) at room temperature. The clear solution was stirred for 48 h at room temperature and was diluted with 100 mL of ethyl acetate. The ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2 x 50 mL), saturated sodium bicarbonate solution (2 x 50 mL), brine solution ( 100 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave 2.67 g (95%) of N-(2-chloro-6-methylbenzoyl)- 4-nitro-L-phenylalanine methyl ester as a white solid: mp 120- 123 °C. HRMS: Obs. mass, 376.4274. Calcd. mass, 376.4238 (M+H). Example 15. N- [ (2-chloro-6-methylphenyl)thioxomethyl] -4-nitro-L- phenylalanine methyl ester. Lawesson's reagent toluene, 90-100 °C, 24 h C 18 H 17 CIN 2 θ5 C 18 H 17 CIN 2 0 4 S Mol. Wt.: 376.79 Mol. Wt.: 392.86 To a mixture of N-(2-chloro-6-methylphenylcarbonyl)-4-nitro-L-phenylalanine methyl ester (9.66 mmol, 3.64 g) and Lawesson's reagent (6.0 mmol, 2.46 g, 0.62 equiv.) was added toluene ( 15 mL, which had been stored over 4 A molecular sieves) at room temperature. The suspension was heated to 90- 100 °C and was stirred for 24 h (by this time it gave a clear solution) at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded the crude compound which was purified by careful silica gel column chromatography eluting with hexane:ethyl acetate (4: 1 to 2:1) to obtain 1.52 g (40%) of N- [ (2-chloro-6-methylphenyl)thioxomethyl] -4-nitro-L- phenylalanine methyl ester as a yellow solid: mp 150- 153 °C (triturated from ether and hexane 3:1 ratio). HRMS: Obs. mass, 393.0685. Calcd. mass, 393.0677 (M+H). Example 16. 4-amino-N- [(2-chloro-6-methylphenyl)thioxomethyl] -L- phenylalanine methyl ester. C 18 H 17 CIN 2 0 4 S C 18 H 19 CIN 2 0 2 S Mol. Wt.: 392.86 Mol. Wt.: 362.87 To a mixture of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L- phenylalanine methyl ester (3.86 mmol, 1.52 g), zinc dust (-325 mesh, 39.0 mmol, 2.55 g, 10 equiv.) and ammonium chloride (58.0 mmol, 3.09 g, 15 equiv.) was added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, an exothermic reaction ensued and the temperature rose to 45 to 50 °C. The suspension was stirred for 2 h at a bath temperature of 50-60 °C at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The filtrate was concentrated under vacuum to remove methanol and the product was extracted into ethyl acetate (2 x 50 mL). The combined extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave 1.3 g (92%) of 4-amino-N-[(2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester as an amorphous yellow solid, which was used directly for next step. HRMS: Obs. mass, 363.0932. Calcd. mass, 363.0934 (M+H). Example 17. 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [ (2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester. C 18 H 19 CIN 2 0 2 S Mol. Wt.: 362.87 C 25 H 21 Cl3N 2 0 3 S Mol. Wt.: 535.87 To a solution of4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl] -L- phenylalanine methyl ester (3.57 mmol, 1.296 g) and 2,6-dichlorobenzoyl chloride (3.75 mmol, 0.785 g) in dichloromethane (20 mL) was added diisopropylethylamine (5.35 mmol, 0.93 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water (30 mL) and the two layers were separated. The aqueous phase was extracted with dichloromethane (20 mL) and the combined extracts were washed with brine solution (50 mL). After drying over anhydrous magnesium sulfate, the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with hexane:ethyl acetate (4: 1 to 1 : 1 ) to obtain 1.91 g (83%) of 4- [ [ (2,6- dichlorophenyl)carbonyl] amino] -N- [ (2-chloro-6-methylphenyl)thioxomethyl] - L-phenylalanine methyl ester as an amorphous white solid. HRMS: Obs. mass, 535.0399. Calcd. mass, 535.0416 (M+H). Example 18. 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine. C25H21 CI3N2O3S C H-|gCl3N2θ 3 S Mol. Wt: 535.87 Mol. Wt.: 521.84 To a suspension of 4-[ [(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6- methylphenyl)thioxomethyl]-L-phenylalanine methyl ester (2.89 mmol, 1.55 g) in ethanol (8 mL) was added aqueous 1.0N sodium hydroxide (5 mL) at room temperature. The mixture was heated to 50-55 °C and the resulting clear solution was stirred for 3-4 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated to remove ethanol, was diluted with 15 mL of water and extracted with 25 mL of ether to remove any neutral impurities. The aqueous layer was acidified with IN HCl and the precipitated white solid was extracted into ethyl acetate (2 x 30 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solution gave 1.45 g (96%) of 4-[ [(2,6-dichlorophenyl)carbonyl]amino]-N-[(2- chloro-6-methylphenyl)thioxomethyl] -L-phenylalanine as an amorphous white solid. HRMS: Obs. mass, 521.0241. Calcd. mass, 521.0260 (M+H). Example 19. 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ ( 2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine sodium salt. C2 Hi9CI 3 N2θ 3 S C2 H 18 CI 3 N2Naθ3S Mol. Wt.: 521.84 Mol. Wt.: 543.83 4-[ [(2,6-Dichlorophenyl)carbonyl]amino]-N-(2-chloro-6-methylphenyl- thioxomethyl] -L-phenylalanine (2.77 mmol, 1.45 g) was dissolved in water ( 10 mL) containing 1.5 equivalents of aqueous l.ON sodium hydroxide (4.2 mL) at room temperature. The solution was loaded into a reverse phase column size of 8 inches length with 1.5 inches diameter containing C-18 silica gel and eluted with water to remove excess base. The product was eluted with 5-20% methanol in water. The combined fractions were concentrated and the residue was taken up in 50 mL water and lyophilized to afford 1.3 g of sodium salt as a white amorphous solid. HRMS: Obs. mass, 543.0076. Calcd. mass, 543.0079 (M+H). Example 20. 2-ethyl-6-methylbenzoic acid. Pd(OAc) 2 , dppp, CO CH 3 CN, H 2 0, NEt 3 , 83 °C, 15 h 9H 1 1 I C 1 0H 12 O2 Mol. Wt.: 246.09 Mol. Wt.: 164.20 A 250 mL pressure bottle was charged with 2-ethyl-6-methyliodobenzene (30.07 mmol, 7.4 g), Pd(OAc) 2 ( 1.43 mmol, 334 mg) and dppp ( 1.43 mmol, 620 mg). The flask was closed with a septum and evacuated three times with argon. Then, acetonitrile (96 mL), triethylamine ( 189 mmol, 19.0 g, 26.25 mL) and water (19.1 mL) were added successively by the aid of syringe. Then, the rubber septum was replaced with teflon lined cap connected to a carbon monoxide source. The flask was now pressurized with carbon monoxide (40 psi) and the excess pressure was released. This process was repeated three times and finally the mixture was stirred for 5 min under 40 psi carbon monoxide pressure. The flask was then disconnected from the carbon monoxide cylinder and immersed in a preheated oil bath (83-85 °C). The reaction mixture turned black in 1 h and was stirred for another 14 h at this temperature. Then, the reaction mixture was cooled to room temperature and the pressure was released. The resulting mixture was diluted with ether (200 mL) and l.ON NaOH (20 mL). The formed acid was extracted into water (2 x 100 mL). The combined water extracts were neutralized with l .ON HCl and the acid was extracted into dichloromethane (3 x 100 mL). The combined dichloromethane extracts were washed with brine solution and dried over MgS0 4 . Filtration of the drying agent and removal of solvent under vacuum gave 3.58 g (72.5%) of a viscous brown oil which slowly solidified overnight. HR MS: Obs. mass, 164.0833. Calcd. mass, 164.0837 (M+). Example 21. N-[(2-ethyl-6-methylphenyl)carbonyl] -4-nitro-L-phenylalanine methyl ester. C20H22N2O5 Mol. Wt.: 370.40 Using the procedure described in example 14, N-[(2-ethyl-6-methylphenyl)- carbonyl] -4-nitro-L-phenylalanine methyl ester was prepared in 72% yield as a white solid: mp 119-121 °C. HR MS: Obs. mass, 371.1610. Calcd. mass, 371.1607 (M+H). Example 22. N-[(2-ethyl-6-methylphenyl)thioxomethyl] -4-nitro-L- phenylalanine methyl ester. C20H22N2O5 2θH22^2 , 4S Mol. Wt.: 370.40 Mol. Wt.: 386.47 Using the procedure described in example 15, N-[(2-ethyl-6- methylphenyl)thioxomethyl] -4-nitro-L-phenylalanine methyl ester was prepared in 47% yield as an amorphous w τ hite solid. HR MS: Obs. mass, 387.1383. Calcd. mass, 387.1378 (M+H). Example 23. 4-amino-N- [ (2-ethyl-6-methylphenyl)thioxomethyl] - L- phenylalanine methyl ester. 20H22N2O4S 20H24N2O2S Mol. Wt.: 386.47 Mol. Wt.: 356.48 Using the general procedure described in example 16, 4-amino-N-[(2-ethyl-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester was prepared in 94% yield as an amorphous white solid. HR MS: Obs. mass, 357.1640. Calcd. mass, 357.1638 (M+H). Example 24. 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [(2-ethyl-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester. C27H26CI2 2O3S Mol. Wt.: 529.48 Using the procedure described in example 17, 4- [ [(2,6-dichlorophenyl)- carbonyl] amino] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine methyl ester was prepared in 70% yield as an amorphous white solid. HR MS: Obs. mass, 529.1094. Calcd. mass, 529.1 119 (M+H). Example 25. 4- [ [(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6- methylphenyl)thioxomethyl] -L-phenylalanine. C27H26CI2N2O3S C26H2 4 CI 2 2O3S Mol. Wt.: 529.48 Mol. Wt.: 515.45 Using the procedure described in example 18, 4-[ [(2,6-dichlorophenyl)- carbonyl] amino] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine was prepared in 77% yield as an amorphous white solid. HR MS: Obs. mass, 515.0942. Calcd. mass, 515.0963 (M+H). Example 26. 4-[ [(2R)-2-(Fmoc-amino)-3-(3-pyridyl)-l-oxopropyl]amino]-N- [(2-ethyl-6-methylphenyl)thioxomethylj -L-phenylalanine methyl ester. C 43 H 42 N 4 0 5 S Mol. Wt.: 726.88 C2 O ^ 2 N2O2S Mol. Wt.: 356.48 Using the procedure described in example 1, 4-[[(2R)-2-(Fmoc-amino)-3-(3- pyridyl)-l-oxopropyl]amino]-N-[(2-ethyl-6-methylphenyl)thioxomethyl]-L- phenylalanine methyl ester was prepared in 72% yield as an amorphous white solid. HR MS: Obs. mass, 727.2973. Calcd. mass, 727.2954 (M+H). Example 27. 4-[[(2R)-2-amino-3-(3-pyridyl)-l-oxopropyl]amino]-N-[(2-ethyl- 6-methylphenyl)thioxomethyl] -L-phenylalanine methyl ester. C 43 H 42 N 4 0 5 S C2 8 H32N 4 0 3 S Mol. Wt.: 726.88 Mol. Wt.: 504.64 The product from example 26 (0.308 mmol, 224 mg) was treated with 25% piperidine in NMP (3 mL) and the solution was stirred for 1 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with hexane (25 mL) and the two layers were separated. The bottom yellow layer was diluted with hexane and separated. Then, the bottom yellow layer was diluted with water and extracted with ethyl acetate and THF (2:1, 3 x 25 mL). The combined extracts were washed with water (50 mL), brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave a product which dried under high vacuum to afford 126 mg (81%) of4-[ [(2R)-2-amino-3-(3-pyridyl)-l-oxopropyl]amino]-N-[(2-ethyl-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester as an amorphous white solid. HR MS: Obs. mass, 505.2270. Calcd. mass, 505.2274 (M+H). Example 28. 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl] -5-oxo- imidazolidin- 1 -yl] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine methyl ester. C 28 H 32 N 4 θ 3 S Mol. Wt.: 504.64 C 37 H 38 N 4 0 4 S Mol. Wt.: 634.79 To a solution of 4-[ [(2R)-2-amino-3-(3-pyridyl)-l-oxopropyl]amino]-N-[(2- ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine methyl ester (0.224 mmol, 113 mg) in dichloromethane (0.75 mL) and CH(OMe) (0.75 mL) was added benzaldehyde (0.25 mmol, 27.5 mg). The resulting light yellow solution was stirred for 3 days at room temperature and the reaction mixture was heated to 90 °C (oil bath temperature). Then, excess acetic anhydride (2.0 mmol, 0.21 mL) was introduced via a syringe and the solution was stirred at 1 10- 120 °C (oil bath temperature) for 6 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude residue was purified by reverse phase HPLC to obtain 95 mg (67%) of 4- [(2S,4R)-3-acetyl-2-phenyl-4- [ (3-pyridinyl)methyl] -5-oxo-imidazolidin- 1 -yl] -N- [ (2-ethyl-6- methylphenyl)thioxomethyl] -L-phenylalanine methyl ester as an amorphous white solid. HR MS: Obs. mass, 635.2672. Calcd. mass, 635.2692 (M+H). Another isomer was formed in very minor amount by HPLC (<5%) and not attempted to isolate it. Example 29. 4- [(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl] -5-oxo- imidazolidin- 1 -yl] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine. C 3 7H 38 N 4 0 4 S C 3S H 3 6N 4 0 4 S Mol. Wt.: 634.79 Mol. Wt.: 620.76 The hydrolysis was carried out using the general procedure described in example 18, and the product was purified by reversed-phase HPLC, using a 5-95% acetonitrile-water gradient over 30 min and the required fraction was collected. The acetonitrile was removed under vacuum and the product was extracted into ethyl acetate:THF (3: 1 ) (2 x 25 mL). The combined fractions were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated and the residue was dried under high vacuum to obtain 4- [ (2S,4R)-3-acetyl-2-phenyl-4- [ (3-pyridinyl)methyl] -5- oxo-imidazolinidin- 1 -yl] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L- phenylalanine in 30% yield as an amorphous white solid. HR MS: Obs. mass, 621.2520. Calcd. mass, 621.2535 (M+H). Example 30. N- [ (2-fluorophenyl)carbonyl] -4-nitro-L-phenylalanine methyl ester. C 17 H 15 FN 2 0 5 Mol. Wt.: 346.31 Using the general procedure described in example 14, starting with 2- fluorobenzoic acid, N- [ (2-fluorophenyl)carbonyl] -4-nitro-L-phenylalanine methyl ester was prepared in 99% yield as a white solid: mp 137- 139 °C. HR MS: Obs. mass, 346.0977. Calcd. mass, 346.0980, M+. Example 31 N- [ (2-fluorophenyl)thioxomethyl] -4-nitro-L-phenylalanine methyl ester. C 17 H 15 FN 2 0 5 C 17 H 15 FN 2 0 4 S Mol. Wt.: 346.31 Mol. Wt.: 362.38 Using the general procedure described in example 15, starting with N- [ (2- fluorophenyl)carbonyl] -4-nitro-L-phenylalanine methyl ester, N-[(2- fluorophenyl)thioxomethyl] -4-nitro-L-phenylalanine methyl ester was prepared in 99% yield as an amorphous white solid. HR MS: Obs. mass, 363.0816. Calcd. mass, 363.0815 (M+H). Example 32. 4-amino-N- [(2-fluorophenyl)thioxomethyl] -L-phenylalanine Using the general procedure described in example 16, starting with N-[(2- fluorophenyl)thioxomethyl] -4-nitro-L-phenylalanine methyl ester, 4-amino-N- [(2-fluorophenyl)thioxomethyl] -L-phenylalanine methyl ester was prepared in 87% yield as an amorphous white solid. HR MS: Obs. mass, 332.1042. Calcd. mass, 332.1046, (M+H). Example 33. 4-[ [(2,6-dichlorophenyl)carbonyl]amino] -N-[(2-fluorophenyl)- thioxomethyl] -L-phenylalanine methyl ester. C 24 H 19 Cl 2 FN 2 θ 3 S Mol. Wt.: 505.39 Using the general procedure described in example 17, starting with 4-amino-N- [(2-fluorophenyl)thioxomethyl]-L-phenylalanine methy r l ester, 4-[ [(2,6- dichlorophenyl)carbonyl] amino] -N-[ (2- fluorophenyl) thioxomethyl] -L- phenylalanine methyl ester was prepared in 74% yield as an amorphous white solid. HR MS: Obs. mass, 505.0561. Calcd. mass, 505.0555, (M+H). Example 34. 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [(2-fluorophenylj- thioxomethyl] -L-phenylalanine. C2 4 H 1 9CI 2 FN2O3S C 2 3H 1 7CI2FN 2 O3S Mol. Wt.: 505.39 Mol. Wt.: 491.36 Using the general procedure described in example 18, starting with 4- [ [ (2,6- dichlorophenyl)carbonyl]amino] -N-[(2-fluorophenyl)thioxomethyl] -L- phenylalanine methyl ester, 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ (2- fluorophenyl)thioxomethyl] -L-phenylalanine was prepared in 89% yield as an amorphous white solid. HR MS: Obs. mass, 491.0407. Calcd. mass, 491.0399 (M+H). Example 35. 4-nitro-N- [ [(2-(trifluoromethyl)phenyl] carbonyl] -L-phenylalanine methyl ester. C 10 H 13 CIN 2 O 4 M Mol. Wt.: 260.71 C ι 8 H 15 F 3 N 2 θ5 Mol. Wt.: 396.32 Using the general procedure described in example 14, starting with 2- trifluoromethylbenzoic acid, 4-nitro-N- [ [ (2-(trifluoromethyl)phenyl] carbonyl j - L-phenylalanine methyl ester was prepared in 69% yield as a white solid: mp 152- 154 °C. HR MS: Obs. mass, 397.1017. Calcd. mass, 397.101 1 (M+H). Example 36. 4-nitro-N- [ [2-(trifluoromethyl)phenyl]thioxomethyl] -L- phenylalanine methyl ester CiδHi5F 3 N2θ5 Ci8Hi5 3 2 0 4 S Mol. Wt.: 396.32 Mol. Wt.: 412.38 Using the general procedure described in example 15, starting with 4-nitro-N- [ [ (2-(trifluoromethyl)phenyl] carbonyl] -L-phenylalanine methyl ester, 4-nitro- N- [ [2-(trifluoromethyl)phenyl]thioxomethyl] -L-phenylalanine methyl ester was prepared in 67% yield as an amorphous white solid. HR MS: Obs. mass, 412.0752. Calcd. mass, 412.0757 (M+H). Example 37. 4-amino-N- [ [2-(trifluoromethyl)phenyl]thioxomethyl] -L- phenylalanine methyl ester. Cι 8 Hι 5 F 3 N 2 0 4 S C 18 H 17 F 3 N 2 θ2S Mol. Wt.: 412.38 Mol. Wt.: 382.40 Using the general procedure described in example 16, starting with 4-nitro-N- [ [2-(trifluoromethyl)phenyl]thioxomethyl] -L-phenylalanine methyl ester, 4- amino-N- [ [ 2- (trifluoromethyl)phenyl] thioxomethyl] -L-phenylalanine methyl ester was prepared in 98% yield as an amorphous white solid. HR MS: Obs. mass, 382.1072. Calcd. mass, 382.1078, (M+H). Example 38. 4- [ [ (2, 6-dichlorophenyl)carbonyl] amino] -N- [ [2- (trifluoromethyl) phenyl] thioxomethyl] -L-phenylalanine methyl ester. C 2 5 H 1 gCl2F 3 N 2 0 3 S Mol. Wt.: 555.40 Using the general procedure described in example 17, starting with 4-amino-N- [ [2-(trifluoromethyl)phenyl]thioxomethyl] -L-phenylalanine methyl ester, 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ [2-(trifluoromethyl)phenyl]- thioxomethyl] -L-phenylalanine methyl ester was prepared in 98% yield as an amorphous w r hite solid. HR MS: Obs. mass, 555.0511. Calcd. mass, 555.0524, (M+H). Example 39. 4-(2,6-dichlorophenylcarbonylamino)-N- [ [2-(trifluoromethyl) phenyl] thioxomethyl] -L-phenylalanine. 25H19 I2F3 2O3S C2 H 17 Cl2F 3 N 2 0 3 S Mol. Wt.: 555.40 Mol. Wt.: 541 .37 Using the general procedure described in example 18, starting with 4-(2,6- dichlorophenylcarbonylamino)-N- [ [2- (trifluoromethyl)phenyl] thioxomethyl ] - L-phenylalanine methyl ester, 4-[ [ (2,6-dichlorophenyl)carbonyl]amino]-N-[ [2- (trifluoromethyl)phenyl] thioxomethyl] -L-phenylalanine was prepared in 99% yield as an amorphous white solid. HR MS: Obs. mass, 541.0358. Calcd. mass, 541.0367, (M+H). Example 40. l-(4-bromobutyl)cyclopentane carboxylic acid methyl ester.. 1 ) LDA, THF, -70 °C to -60 °C, 1 h 2) 1 ,4-dibromobutane, -70 °C, 1 h 7H12O2 then r.t., 15 h r w Rr n M i v i oυl i . W vvt i . ■ . 1 n2-8α.1 i 7 Mo Cl.n WHt 1 . 9 : B 2r6U32.17 To a solution of diisopropylamine ( 150 mmol, 21 mL) in THF ( 100 mL) was added dropwise a solution of H-butyl lithium ( 145 mmol, 58 L, 2.5M) in hexanes at -10 °C while maintaining the temperature below 0 °C. After addition, the solution was stirred for 30 min at 0 °C. To this, a solution of methyl cyclopentane carboxylate ( 100 mmol, 13.1 g) in THF (20 mL) was added dropwise at -70 °C maintaining the internal temperature between -60 to -70 °C. After addition, the reaction mixture was stirred for 1 h at -50 to -60 °C. Then, a solution of 1,4-dibromobutane ( 100 mmol, 21.59 g) in THF (20 mL) was added dropwise and the light brown suspension was stirred for 1 h at -60 to -70 °C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (200 mL) and the organic compound was extracted into ether (2 x 100 mL). The combined extracts were washed with a saturated solution of sodium chloride ( 150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 120- 133 °C/2.5 mm Hg to obtain 12.8 g (48%) of l-(4- bromobutyl)cyclopentane carboxylic acid methyl ester as a colorless oil. HR MS: Obs. mass, 262.0565. Calcd. mass, 262.0568, (M+). Example 41. l - [4-(methylthio)butyl]cyclopentane carboxylic acid methyl ester. NaSMe, DMF, r.t., 15 h C -| iH-|gBrθ2 C 12 H2 C2S Mol. Wt.: 263.17 Mol. Wt.: 230.37 To a solution of l -(4-bromobutyl) cyclopentane carboxylic acid methyl ester (38 mmol, 10 g) in DMF ( 100 mL) was added sodium thiomethoxide (72.6 mmol, 5.09 g). After the addition, an exothermic reaction ensued and the mixture turned to a light brown cloudy solution. The mixture was stirred for 15 h at room temperature and was poured into water (200 mL). The organic compound was extracted into diethyl ether (2 x 150 mL). The combined extracts were washed with a saturated solution of sodium chloride ( 150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography to afford 4.43 g (51%) of methyl l - [4-(methylthio)butyl] cyclopentane carboxylic acid methyl ester as a colorless oil. HR MS: Obs. mass, 230.1343. Calcd. mass, 230.1341 , (M+). Example 42. l - [4-(methylsulfonyl)butyl]cyclopentane carboxylic acid methyl ester. C 12 H 2 2O 2 S C 12 H 2 2θ 4 S Mol. Wt : 230.37 o wt - : 262 - 37 To a solution of l - [4-(methylthio)butyl]cyclopentane carboxylic acid methyl ester ( 19.2 mmol, 4.43 g) in AcOH (20 mL) was added 30% hydrogen peroxide ( 10 mL). The reaction mixture was heated to 70 °C and stirred for 15 h at which time the TLC of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was concentrated under vacuum. The residue was poured into saturated sodium bicarbonate solution and was extracted with ether (3 x 100 mL). The combined extracts were washed with a saturated solution of sodium chloride (200 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under vacuum and the resulting residue was purified by silica gel column chromatography to afford 4.94 g (98%) as a colorless oil. LR MS (C12H2204S ): 263 (M+H). Example 43. l - [4-(methylsulfonyl)butyl]cyclopentane carboxylic acid To a solution of l-[4-(methylsulfonyl)butyl]cyclopentane carboxylic acid methyl ester ( 18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL). The mixture was heated to 50-55 °C for 15 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and the mixture was allowed to cool to room temperature. The solvent was removed under vacuum and the residue was diluted with water ( 100 mL) and extracted with ether (2 x 50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2 x 75 mL). The combined extracts were washed with brine solution and dried over anhydrous sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 4.31 g (92%) of the title compound as a low melting white solid. LR MS (Cl lH20O4S): 249 (M+H). Example 44. l -[4-(methylthio)butyl] cyclopentane carboxylic acid. Na0 50 H -'5 T 5 H °C F ', M 15 e0 h H Cι 2 H 22 0 2 S C 1 1 H20Q2S Mol. Wt.: 230.37 Mol. Wt.: 216.34 To a solution of l - [4-(methylthio)butyl]cyclopentane carboxylic acid methyl ester ( 18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL). The mixture was heated to 50-55 °C for 15 h at which point TLC analysis of the reaction mixture indicated the absence of starting material. After cooling to room temperature, the solvent was removed under vacuum, the residue was diluted with water ( 100 mL) and was extracted with ether (2 x 50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2 x 75 mL). The combined extracts were washed with brine solution and dried over anhydrous sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 4.31 g (92%) of l - [4-(methylthio)butyl] - cyclopentane carboxylic acid as a low melting white solid. HR MS: Obs. mass, 216.1181. Calcd. mass, 216.1 184, M+. Example 45. N- [ [ 1 - [ (4-methylthio)butyl] cyclopentyl] carbonyl] -4-nitro-L- phenylalanine methyl ester. C 10 H 13 N 2 O 4 CI C 1 1 H 2C 2S Mol. Wt.: 260.72 Mol. Wt.: 216.34 C2 1 H 30 N2θ 5 S Mol. Wt.: 422.54 To a suspension of 4-nitro-L-phenylalanine methyl ester hydrochloride salt ( 181.84 mmol, 47.41 g), l - [(4-methylthio)butyl]cyclopentane carboxylic acid ( 177.17 mmol, 38.33 g) in DMF (470 mL) were added HBTU ( 177.17 mmol, 67.2 g) and diisopropylethylamine (443 mmol, 77 mL) at room temperature. The clear solution was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting materials. The reaction mixture was diluted with 600 mL of ethyl acetate. The ethyl acetate layer was washed successively with 0.5N hydrochloric acid (2 x 250 mL), saturated sodium bicarbonate solution (2 x 250 mL), brine solution (300 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave a crude product which was purified by silica gel column chromatography to afford 58.5 g (78%) of N- [ [ l - [ (4-methylthio)butyl] - cyclopentyl]carbonyl] -4-nitro-L-phenylalanine methyl ester as an amorphous white solid. HRMS: Obs. mass, 423.1940. Calcd. mass, 423.1953 (M+H). Example 46. 4-nitro-N- [ [ l- [ (4-methylsulfonyl)butyl]cyclopentyl]carbonyl] -L- phenylalanine methyl ester. C21 H30N2O5S C 2 ι H 3 oN 2 0 7 S Mol. Wt.: 422.54 Mol. Wt.: 454.54 To a solution of N- [ [ l - [ (4-methylthio)butyl]cyclopentyl]carbonyl] -4-nitro-L- phenylalanine methyl ester ( 138.4 mmol, 58.5 g) in CH 2 C1 2 ( 1.2 L) was added m- chloroperbenzoic acid (415 mmol, 71.7 g) at -5 °C (ice-salt bath). The suspension was stirred for 30 min at 0 °C and allowed to warm to room temperatur and was stirred for another 5 h at which time TLC analysis of the mixture indicated the absence of starting material. The solid was filtered and the filtrate was concentrated under vacuum to afford a white residue. This white residue was dissolved in ethyl acetate (600 mL) and was washed with saturated sodium bicarbonate solution (3 x 300 mL). TLC analysis showed the presence of m- chloroperbenzoic acid. Thus, the ethyl acetate layer was washed with saturated sodium bisulfite solution (20 g in 150 mL of water) and saturated sodium bicarbonate solution (200 mL), brine solution (300 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave a crude product, which was dissolved in ethyl acetate; ether and hexane were added to precipitate an oily residue. Some of the solvent was removed under reduced pressure to obtain a white suspension. The suspension was further diluted with ether and the solid was collected by filtration and was washed with hexane. After drying, 53.9 g (86%) of N- [ [ l- [ (4- methylsulfonyl)butyl] cyclopentyl] carbonyl] -4-nitro-L-phenylalanine methyl ester was obtained as a white low melting solid, mp: 40-44 °C. HRMS: Obs. mass, 455.1854. Calcd. mass, 455.1852 (M+H). Example 47. N- [ [ l - [ (4-methylsulfonyl)butyl] cyclopentyl]thioxomethyl)-4-nitro- L-phenylalanine methyl ester. C 2 ι H 30 N 2 θ S C 2 ι H 3 oN 2 OeS 2 Mol. Wt.: 454.54 Mol. Wt.: 470.60 To a solution of N- [ [ l - [(4-methylsulfonyl)butyl]cyclopentyl]carbonyl]-4-nitro- L-phenylalanine methyl ester (33 mmol, 15 g) in toluene ( 100 mL, stored over 4 A molecular sieves) and freshly distilled THF (50 mL) was added Lawesson's reagent (33 mmol, 13.35 g, 1.0 equiv.) at room temperature. The solution was heated to 60-65 °C and was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3 x 150 mL). An oil formed in the aqueous layer, which was separated, diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution (200 mL), brine solution (300 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded a light brown syrup which was purified bv a silica gel column chromatography eluting with hexanerethyl acetate ( 1 : 1 ) to obtain 6.87 g (44%) of N- [ [ l - [(4-methylsulfonyl)butyl]cyclopentyl] thioxo- methyl] -4-nitro-L-phenylalanine methyl ester as a fluffy yellow solid. HRMS: Obs. mass, 493.1438. Calcd. mass, 493.1443 (M+Na). Example 48. 4-amino-N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclopentyl] thioxo- methyl)-L-phenylalanine methyl ester. C 2 ιH 3 oN 2 θ6S C 2 ι H3 2 2 0 4 S 2 Mol. Wt.: 470.60 Mol. Wt.: 440.62 The poorly soluble N- [ [ l - [ (4-methylsulfonyl)butyl]cyclopentyl]thioxomethyT - 4-nitro-L-phenylalanine methyl ester ( 19.3 mmol, 9.07 g) was dissolved in methanol ( 150 mL) and THF (20 mL) by gentle heating with a heat gun. To this solution, zinc dust (-325 mesh, 193 mmol, 12.62 g, 10 equiv.) and ammonium chloride (289.5 mmol, 15.5 g, 15 equiv.) were added followed by water (75 mL) at room temperature. After addition of water, an exothermic reaction ensued and the temperature rose to 45 to 50 °C. The suspension was stirred for 1 h, at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered and the filter cake was washed with methanol (200 mL) and THF ( 100 mL). The methanol and THF were removed under vacuum and the organic residue was extracted into ethyl acetate (2 x 200 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave 8.37 g (98%) of 4-amino-N-[ [ l-[(4-methylsulfonyl)butyl]cyclopentyl]- thioxomethyl) -L-phenylalanine methyl ester as a white gum which was used directly for next step. HRMS: Obs. mass, 441.1884. Calcd. mass, 441.1882 (M+H). Example 49. 4-[ [(2,6-dichlorophenyl)carbonyl]amino]-N-[ [ l-[(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine methyl ester. To a solution of 4-amino-N-[ [ l-[(4-methylsulfonyl)butyl]cyclopentyl]thioxo- methyl] -L-phenylalanine methyl ester ( 19.0 mmol, 8.37 g) and 2,6- dichlorobenzoyl chloride (21 mmol, 4.4 g) in dichloromethane (90 mL) was added diisopropylethylamine (32.3 mmol, 5.6 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, it was diluted with water ( 100 mL) and the two layers were separated. The aqueous phase was extracted with dichloromethane ( 100 mL) and the combined extracts were washed with brine solution (200 mL). After drying over anhydrous magnesium sulfate, the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with hexane:ethyl acetate:CH 2 Cl 2 ( 1 : 1: 1 ) to obtain 11.54 g (99%) of 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ [ l - [(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine methyl ester as a white solid mp: 200-202 °C. HRMS: Obs. mass, 613.1367. Calcd. mass, 613.1363 (M+H). Example 50. 4-[ [(2,6-dichlorophenyl)carbonyl]amino] -N-[ [ l -[(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine. 28H3 4 I2N2O5S2 2 H32CI 2 N2O5S2 Mol. Wt.: 613.62 Mol. Wt.: 599.59 To a solution of 4- [ [ (2,6-dichlorophenyl)carbonyl]amino] -N- [ [ l - [ (4- methylsulfonyl)butyl] cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (25.86 mmol, 15.87 g) in ethanol (75 mL) was added aqueous l .ON sodium hydroxide (60 mL) at 50 °C . The mixture was heated to 50-55 °C and the resulting clear light brown solution was stirred for 22 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water and allowed to cool to room temperature and was filtered to remove a small amount of solid. The filtrate was concentrated and the residual aqueous solution was washed with ether (2 x 75 mL). The basic aqueous layer was acidified with 3. ON HCl to form a cloudy suspension and was extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with brine solution (200 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was concentrated. The residue was taken up in dichloromethane and diuted with efheπhexane ( 1: 1 ) to obtain a solid which was collected by filtration. This solid was triturated with hot ethyl acetate (-100 mL) to get a suspension which was diluted with ether (-50 mL). The solid was collected by filtration. The above process was repeated to afford 10.89 g (70%) of 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ [ 1 - [ (4-methylsulfonyl)butyl] - cyclopentyl]thioxomethyl] -L-phenylalanine as a white solid. HR MS: Obs. mass, 599.1 193. Calcd. mass, 599.1208 (M+H). Example 51. 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[ l-[(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine sodium salt. C2 H32 I2N205S2 C2 7 H 31 CI 2 N 2 Na0 5 S2 Mol. Wt.: 599.59 Mol. Wt.: 621.57 A suspension of 4-(2,6-dichlorophenylcarbonylamino)-N-[ [ l -[(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine (16.49 mmol, 9.89 g) in water (100 mL) was treated with aqueous l.ON sodium hydroxide (16.4 mmol, 16.4 mL) at room temperature. The mixture was heated to 40-45 °C and some acetonitrile (-15 mL) was added to give a clear solution containing a small amount of suspended solid. The solution was filtered and the filtrate was lyophilized to afford 10.1 g of sodium salt as a white solid. HRMS: Obs. mass, 621.1023. Calcd. mass, 621.1027 (M+H). Example 52. 4- [ [ (2,4-dimethyl-3-pyridinyl)carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine methyl ester. C29H3 9 N3O5S2 Mol. Wt.: 573.77 To an ice cold solution of 2,4-dimethyl-3-pyridinecarboxylic acid (0.3 mmol, 45 mg) in dichloromethane (2 mL) and one drop of DMF, was added oxalyl chloride (0.39 mmol, 49.5 mg) at 0 °C. The reaction mixture was stirred for 30 min at this temperature, was allowed to warm to room temperature and was stirred for an additional 2 h. The solution was concentrated and the residue was dried under high vacuum. To a mixture of above acid chloride and 4-amino-N- [ [ l- [(4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine methyl ester (0.2 mmol, 88 mg) in dichloromethane (3 mL) was added diisopropylethylamine ( 1 mmol, 0.175 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. It was diluted with water (20 mL) and dichloromethane (20 mL) and the two layers were separated. The aqueous phase was extracted with dichloromethane ( 10 mL) and the combined extracts were washed with brine solution (20 mL). After drying over anhydrous magnesium sulfate, the solution was concentrated under vacuum and the residue was purified by reverse phase HPLC to obtain a pure 74 mg (65%) of 4- [ [(2,4-dimethyl-3-pyridinyl)carbonylj - amino] -N- [ [ l- [(4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L- phenylalanine methyl ester as an amorphous white solid. HRMS: Obs. mass, 574.2389. Calcd. mass, 574.2409 (M+H). Example 53. 4- [ (2,6-dimethyl-3-pyridylcarbonyl)amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine TFA salt. C29H39N3O5S2 C28H3 7 N305S2 Mol. Wt.: 573.77 Mol. Wt.: 559.74 To a solution of 4- [ [ (2,4-dimethyl-3-pyridinyl)carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (0.118 mmol, 68 mg) in ethanol (4 mL) was added aqueous l.ON sodium hydroxide (3 mL) at room temperature. The mixture was heated to 45-50 °C and the resulting clear solution was stirred for 3 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated and the crude mixture was purified by reverse phase HPLC to afford 54.5 mg (82%) of 4- [ [ (2,4-dimethyl-3-pyridinyl)carbonyl]amino] -N- [(2- fluorophenyl)thioxomethyl]-L-phenylalanine TFA salt as an amorphous white solid. HR MS: Obs. mass, 560.2240. Calcd. mass, 560.2253 (M+H). Example 54. ethyl l-(4-bromobutyl) cyclobutane carboxylate. 1 ) LDA, THF, -70 to -50 °C, 30 min 2) 1 ,4-dibromobutane, -70 to -50 °C C Η 12 02 1 h then warm to r.t., 15 h C -| -)Hi9Brθ2 Mol. Wt.: 128.17 Mol. Wt.: 263.17 Using the general procedure described in example 40, starting with cyclobutane carboxylic acid ethyl ester, l-(4-bromobutyl)cyclobutane carboxylic acid ethyl ester was prepared in 58% yield as a colorless oil. HR MS: Obs. mass, 263.0563. Calcd. mass, 263.0568, M+. Example 55. l-[4-(methylthio)butyl]cyclobutane carboxylic acid ethyl ester. NaSMe, DMF, r.t, 15 h C i iH-]gBr02 C 12 H22O2S Mol. Wt.: 263.17 Mol. Wt.: 230.37 Using the general procedure described in example 41, starting with l-(4- bromobutyl)cyclobutane carboxylic acid ethyl ester, l- [4-(methylthio)butyl] cyclobutane carboxylic acid ethyl ester was prepared in 87% yield as a colorless oil. HR MS: Obs. mass, 230.1339. Calcd. mass, 230.1340, M+. Example 56. ethyl l-[4-(methylsulfonyl)butyl]cyclobutane carboxylic acid ethyl ester. Using the general procedure described in example 46, starting with l-[4- (methylthio)butyl]cyclobutane carboxylic acid ethyl ester, l-[4-(methylsulfonyl)- butyl] cyclobutane carboxylic acid ethyl ester was prepared in 92% yield as a colorless oil. HR MS: Obs. mass, 262.1231. Calcd. mass, 262.1238, M+. Example 57. l-[4-(methylsulfonyl)butyl] cyclobutane carboxylic acid. Ci ι H2c0 S ιoHι s0 4 S Mol. Wt.: 248.34 Mol. Wt.: 234.31 Using the general procedure described in example 43, starting with l-[4- (methylsulfonyl)butyl] cyclobutane carboxylic acid ethyl ester, l-[4- (methylsulfonyl)butyl] cyclobutane carboxylic acid was prepared in 92% yield as a low melting white solid. HR MS: Obs. mass, 234.0921. Calcd. mass, 234.0918, (M+). Example 58. N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclobutyl] carbonyl] -4-nitro-L- phenylalanine methyl ester. C 2θ H28N 2 0 S Mol. Wt.: 440.51 Using the general procedure described in example 45, starting with l-[4- (methylsulfonyl)butyl] cyclobutane carboxylic acid, N-[[ l-[(4-methylsulfonyl)- butyl] cyclobutyl] carbonyl] -4-nitro-L-phenylalanine methyl ester was prepared in 89% yield as a yellow gum. HR MS: Obs. mass, 441.1700. Calcd. mass, 441.1696 (M+H). Example 59. N-[ [ l-[(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl)-4-nitro- L-phenylalanine methyl ester. C oH2 8 2 0 7 S C 2 oH 28 N 2 θ6S 2 Mol. Wt.: 440.51 Mol. Wt.: 456.58 Using the general procedure described in example 47, starting with 4-nitro-N- [[l-[(4-methylsulfonyl)butyl]cyclobutyl]carbonyl] -L-phenylalanine methyl ester, N-[ [ l -[(4-mεthylsulfonyl)butyl]cyclobutyl]thioxomethyl)-4-nitro-L- phenylalanine methyl ester was prepared in 80% yield as a w τ hite solid: mp 150- 152 °C. HR MS: Obs. mass, 457.1464. Calcd. mass, 457.1467, (M+H). Example 60. 4-amino-N- [ [ 1- [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl)- L-phenylalanine methyl ester. C20H28N2O6S2 20H30N2O4S2 Mol. Wt.: 456.58 Mol. Wt.: 426.60 Using the general procedure described in example 48, starting with N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl)-4-nitro-L-phenylalanine methyl ester, 4-amino-N- [ [ 1- [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl)-L- phenylalanine methyl ester was prepared in 94% yield as a hydroscopic solid. HR MS: Obs. mass, 427.1720. Calcd. mass, 427.1725, (M+H). Example 61. 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl]cyclobutyl]thioxomethyl] -L-phenylalanine methyl ester. Using the procedure described in example 49, starting with 4-amino-N- [[ l-[(4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl)-L-phenylalanine methyl ester, 4- [ [(2,6-dichlorophenyl)carbonyl]amino]-N-[ [l-[(4-methylsulfo- nyl)butyl]cyclobutyl]thioxomethyl]-L-phenylalanine methyl ester was obtained in 92% yield as an amorphous white solid. HR MS: Obs. mass, 599.1207. Calcd. mass, 599.1208 (M+H). Example 62. 4- [ [ (2,6-dichlorophenyl)carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine. 27H32 I2N2O5S2 26H30 I2N2O5S2 Mol. Wt.: 599.59 Mol. Wt.: 585.56 Using the general procedure described in example 50, starting with 4- [ [(2,6- dichlorophenyl)carbonyl] amino] -N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclobutyl] - thioxomethyl] -L-phenylalanine methyl ester, 4-[ [(2,6-dichlorophenyl)carbonyl]- amino] -N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L- phenylalanine was prepared in 99% yield as an amorphous white solid. HR MS: Obs. mass, 585.1038. Calcd. mass, 585.1051 (M+H). Example 63. 4-[[ [4- (trifluoromethyl) -5-pyrimidinyl ] carbonyl ] amino] -N-[ [ 1- [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester. C2 0 H 30 2O 4 S2 Mol. Wt.: 426.60 C2 6 H 3l F 3 N 4 θ 5 S2 Mol. Wt.: 600.68 Using the general procedure described in example 45, starting with 4-amino-N- [ [ l- [(4-methylsulfonyl)butyl]cyclobutyl] thioxomethyl) -L-phenylalanine methyl ester, 4- [ [ [2-(trifluoromethyl)-5-pyrimidinyl] carbonyl] amino] -N- [ [ 1 - [ (4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester was prepared in 32% yield as an amorphous white solid. HR MS: Obs. mass, 601.1766. Calcd. mass, 601.1766 (M+H). Example 64. 4- [ [ [4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino] -N-[ [ l - [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine. C 2 6H3iF 3 N 4 θ5S2 25H29F3N 4 θ5S2 Mol. Wt.: 600.68 Mol. Wt.: 586.65 Using the general procedure described in example 50, starting with the product of example 63, 4- [ [ [2- (trifiuoromethyl)-5-pyrimidinyl] carbonyl] amino] -N- [ [ 1 - [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine was prepared in 22% yield as an amorphous white solid. HR MS: Obs. mass, 587.1619. Calcd. mass, 587.1609 (M+H). Example 65. ethyl l-(3-bromopropyl) cyclobutane carboxylate 7 Η12O 2 CιrjHi7B r θ2 Mol. Wt.: 128.17 Mol. Wt.: 249.14 Using the general procedure described in example 40, starting with cyclobutane carboxylic acid ethyl ester, l-(3-bromopropyl) cyclobutane carboxylic acid ethyl ester was prepared in 33% yield as a colorless oil. HR MS: Obs. mass, 248.0416. Calcd. mass, 248.0412 (M+). Example 66. ethyl l - [3-(methylthio)propyl] cyclobutane carboxylate. (Ro 28- 1367/000, 29156-271 -3) and l -[3-(methylthio)propyl] cyclobutane carboxylic acid. ιoHi7Brθ2 Ci 1 H2o0 2 S C9H 1 6O2S Mol. Wt.: 249.14 Mol. Wt.: 216.34 Mol. Wt.: 188.29 Using the general procedure described in example 41 , starting with l-(3- bromopropyl) cyclobutane carboxylic acid ethyl ester, l - [3-(methylthip)propyl] - cyclobutane carboxylic acid ethyl ester was prepared in 58% yield as a colorless oil. HR MS: Obs. mass, 216.1182. Calcd. mass, 216.1184 (M+). Also, l- [3- (methylthio)propyl] cyclobutane carboxylic acid was obtained in 16% yield as a colorless oil. HR MS: Obs. mass, 188.0872. Calcd. mass, 188.0871 (M+). Example 67. N- [ [ 1 - [ (3-methylthio)propyl] cyclobutyl] carbonyl] -4-nitro-L- phenylalanine methyl ester. C ι g H 26 N 2 0 5 S Mol. Wt.: 394.49 Using the general procedure described in example 45, starting with 4-nitro-L- phenylalanine methyl ester hydrochloride salt, N- [ [ l- [ (3-methylthio)propyl] - cyclobutyl] carbonyl] -4-nitro-L-phenylalanine methyl ester was prepared in 92% yield as an yellow viscous oil. HR MS: Obs. mass, 395.1638. Calcd. mass, 395.1640 (M+H). Example 68. N- [ [ 1 - [ (3-methylthio)propyl] cyclobutyl] thioxomethyl] -4-nitro-L- phenylalanine methyl ester. C 1 9H26 2O5S C- | gH26 2 0 4 S 2 Mol. Wt.: 394.49 Mol. Wt.: 410.55 Using the general procedure described in example 47, starting with 4-nitro-N- [ [ l - [ (3-methylthio)propyl] cyclobutyl] carbonyl] -4-nitro-L-phenylalanine methyl ester, N- [ [ 1 - [ (3-methylthio)propyl] cyclobutyl] thioxomethyl] -4-nitro-L- phenylalanine methyl ester was prepared in 95% yield as a colorless viscous oil. HR MS: Obs. mass, 41 1.1408. Calcd. mass, 41 1.1412 (M+H). Example 69. 4-amino-N-[ [ l - [(3-methylthio)propyl]cyclobutyl]thioxomethyl]-L- phenylalanine methyl ester. CιgH26N2θ 4 S2 Cι gH2 8 2θ 2 S2 Mol. Wt.: 410.55 Mol. Wt.: 380.57 Using the general procedure described in example 48, starting with N- [ [ l - [(3- methylthio) propyl] cyclobutyl] thioxomethyl] -4-nitro-L-phenylalanine methyl ester, 4-amino-N- [ [ 1 - [ (3-methylthio)propyl] cyclobutyl] thioxomethyl] -L- phenylalanine methyl ester was prepared in 97% yield as an hygroscopic yellow- solid. HR MS: Obs. mass, 381.1660. Calcd. mass, 381.1671 (M+H). Example 70. 4- [ (2,6-dichlorophenylcarbonyl)amino] -N- [ [ 1 - [ (3-methylthio) propyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester. Mol Wt 380 57 C26H30CI2N2O3S2 Mol Wt 553.57 Using the general procedure described in example 49, starting with 4-(amino)-N- [ [ l - [ (3-methylthio)propyl]cyclobuty 7 l]thioxomethyl] -L-phenylalanine methyl ester, 4- [ (2,6-dichlorophenylcarbonyl)amino] -N- [ [ 1 - [ (3-methylthio)propyl] - cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester was prepared in 83% yield as a white solid: mp 184- 186 °C. HR MS: Obs. mass, 553.1139. Calcd. mass, 553.1153 (M+H). Example 71. 4- [ (2,6-dichlorophenylcarbonyl)amino] -N- [ [ 1 - [ (3-methylthio)- propyl] cyclobutyl] thioxomethyl] -L-phenylalanine. 2 &H3oCI 2 N 2 θ3S 2 25 H 28 CI 2 N 2 θ3S Mol. Wt.: 553.57 Mol. Wt.: 539.54 Using the general procedure described in example 50, starting with 4- [ (2,6- dichlorophenyl-carbonyl)amino] -N- [ [ 1 - [ (3-methylthio)propyl] cyclobutyl] - thioxomethyl] -L-phenylalanine methyl ester, 4- [ (2,6-dichlorophenylcarbonyl)- amino] -N- [ [ l - [(3-methylthio)propyl]cyclobutyl] thioxomethyl] -L-phenylalanine was prepared in 97% yield as a white solid: mp 186- 188 °C. HR MS: Obs. mass, 539.0986. Calcd. mass, 539.0996 (M+H). Example 72. l -(3-(methylsulfonyl)propyl) cyclobutane carboxylic acid ethyl ester. Mol Wt.: 216.34 Mol. Wt.: 248.34 Using the general procedure described in example 46, starting with ethyl l -(3- (methylthio)propyl) cyclobutane carboxylate, ethyl l -(3-(methylsulfonyl)propyl) cyclobutane carboxylate was prepared in 87% yield as a colorless oil. HR MS: Obs. mass, 248.1084. Calcd. mass, 248.1082 (M+). Example 73. l - [3-(methylsulfonyl)propyl]cyclobutane carboxylic acid ethyl ester. Cι ι H C 0 4 S C 9 Hi6θ 4 S Mol. Wt.: 248.34 Mol. Wt.' 220.29 Using the general procedure described in example 43, starting with ethyl l -(3- (methylsulfonyl)propyl) cyclobutane carboxylate, l - [3-(methylsulfonyl)propyl] cyclobutane carboxylic acid was prepared in 76% yield as a white solid: mp 1 13- 1 16 °C. HR MS: Obs. mass, 220.0770. Calcd. mass, 220.0769 (M+). Example 74. 4-(nitro)-N- [ [ 1 - [ (3-methylsulfonyl)propyl] cyclobutyl] carbonyl] -L- phenylalanine methyl ester. C 19 H 26 N2O 7 S Mol Wt 426 49 Using the general procedure described in example 45, N- [ [ l-[(3-methylsulfonyl) propyl]cyclobutyl] carbonyl] -4-nitro-L-phenylalanine methyl ester was prepared in 76% yield as a white amorphous solid. HR MS: Obs. mass, 427.1526. Calcd. mass, 427.1539 (M+H). Example 75. N- [ [ l- [ (3-methylsulfonyl)propyl] cyclobutyl] thioxomethyl] -4-nitro- L-phenylalanine methyl ester. CιgH gN 2 0 7 S C 19 H26N2θ 6 S2 Mol. Wt.: 426.49 Mol. Wt.: 442.55 Using the general procedure described in example 47, starting with N- [ [ l-[ (3- methyl-sulfonyl)propyl] cyclobutyl] carbonyl] -4-nitro-L-phenylalanine methyl ester, N- [ [ l- [ (3-methylsulfonyl)propyl]cyclobutyl] thioxomethyl] -4-nitro-L- phenylalanine methyl ester was prepared in 88% yield as an yellow sticky solid. HR MS: Obs. mass, 443.1309. Calcd. mass, 443.1310 (M+H). Example 76. 4-amino-N- [ [ 1 - [ (3-methylsulfonyl)propyl] cyclobutyl] - thioxomethyl] -L-phenylalanine methyl ester. Mol. Wt.: 442.55 Mol. Wt.: 412.57 Using the general procedure described in example 48, starting with N- [ [ l - [(3- methylsulfonyl) propyl] cyclobutyl] thioxomethyl] -4-nitro-L-phenylalanine methyl ester, 4-amino-N- [ [ 1 - [ (3-methylsulfonyl)propyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester was prepared in 97% yield as an hygroscopic yellow solid. HR MS: Obs. mass, 413.1556. Calcd. mass, 413.1570 (M+H). Example 774-[[(2,6-dιchlorophenyl]carbonyl]amιno]-N-[[l-[(3- methyl ester Using the general procedure described in example 49, starting with 4-amιno-N- [[l-[(3-methylsulfonyl)propyl]cyclobutyl] thioxomethyl] -L-phenvlalanme methyl ester, 4-[[(2,6-dιchlorophenyl)carbonvl]amιno]-N-[[l-[(3- methylsulfonyl)propyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester was prepared in 82% yield as a white amorphous solid HR MS Obs mass, 5851056 Calcd mass, 5851051 (M+H) Example 784-[(2,6-dιchlorophenylcarbonyl)amιno]-N-[[l- -methylsulfonyl) propyl] cyclobutyl] thioxomethyl] -L-phenylalanine C 2 6H 3 oCI 2 N 05S C 2 5H2 8 CI 2 N 2 0 5 S2 Mol Wt 58556 Mol Wt 57154 Using the general procedure described in example 50, starting w ith 4- [ [ (2,6- dichlorophenyl) carbonyl]amιno]-N-[[l-[(3-methylsulfon\l)propyl] cyclobutyl] - thioxomethyl] -L-phenylalanine methyl ester, 4-[(2,6-dιchlorophenylcarbonyl)- amino]-N-[[l-[(3-methylsulfonyl)propyl] cyclobutyl] thioxomethyl ]-L- phenylalamne was prepared in 87% yield as an amorphous white solid HR MS Obs mass, 571.0894 Calcd mass, 5710895 (M+H) Example 79. 2-chloro-5-(trifluoromethyl)phenol triflate C 7 H 4 CIF 3 0 C 8 H 3 CIF 6 0 3 S Mol. Wt.: 196.55 Mol. Wt.: 328.62 To a solution of 2-chloro-5-(trifluoromethyl)phenol (24.4 mmol, 4.8 g) in CH 2 C1 2 ( 160 mL) was added DMAP (54.0 mmol, 6.7 g) at -70 °C followed by triflic anhydride (36.6 mmol, 10.32 g, 6.16 mL) at -70 °C. After addition, the suspension was stirred for 30 min at this temperature and then warmed to room temperature and stirred for another 3 h, at which time TLC of the reaction mixture indicated the absence of starting material. The mixture was diluted with H 2 O ( 100 mL) and the two layers w-ere separated. The aqueous layer was extracted with CH 2 C1 2 ( 100 mL). The combined dichloromethane extracts were washed with brine solution and dried over MgS0 4 . Filtration of the drying agent and removal of solvent under vacuum gave a white suspension which was purified by silica gel column chromatography eluting with hexane:ether (4:1 ) to obtain 6.8 g (85%) of a colorless oil .HR MS: Obs. mass, 327.9388. Calcd. mass, 327.9392 (M+). Example 80. 2-Chloro-5-(trifluoromethyl)benzoic acid. Pd(OAc) 2 , dppp, CO CH 3 CN, H 2 0, N Et 3 , 83 * C, 3 h C 8 H 3 CIF 6 0 3 S C 8 H 4 CIF 3 0 2 Mol. Wt.: 328.62 Mol. Wt.: 224.56 A 250 mL pressure bottle was charged with 2-chloro-5-(trifluoromethyl)phenol triflate (20.6 mmol, 6.76 g), Pd(OAc) 2 ( 1.71 mmol, 384 mg) and dppp ( 1.71 mmol, 701 mg). The flask was closed with a septum and evacuated three times with argon. Acetonitrile ( 1 14 mL), triethylamine (225.3 mmol, 30.7 mL) and water (22.2 mL) were added successively with the aid of a syringe. The rubber septum was replaced with a teflon lined lid. The flask was pressurized with carbon monoxide (40 psi) and the gas was released This process was repeated three times and finally it was stirred for 5 mm under pressure The flask was then disconnected from the gas cylinder, immersed in a preheated oil bath (83-85 °C) and stirred for 2 h. The flask was repressuri/ed with carbon monoxide and stirred for another 1 h Then, the reaction mixture w as cooled to room temperature and the pressure was released and diluted with ether (250 mL) and 25 mL of 1 0 N NaOH The acid was extracted into water (2 x 100 mL) The combined water extracts w r ere neutralized with 1 0 N HCl and again the acid was extracted into ether (3 x 100 mL). The combined ether extracts were washed with brine solution and dried over MgS0 4 . Filtration of the drying agent and removal of solvent under vacuum gave the crude light yellow solid This solid was dissoh ed in ether ( 100 mL) and extracted with 1.0 N NaOH solution (2 x 50 mL) Then, the aqueous layer was acidified and extracted with ether (2 x 100 mL) The combined extracts were washed with brine solution ( 100 mL) and dried over MgS0 4 After filtration and concentration of the solution, 1 6 g (35%) of the 2-chloro-5- (tπfluoromethyl)ben7oιc acid was obtained as a white solid: mp 82-83.5 °C HR MS: Obs mass, 223 9852 Calcd mass, 223.9851 (M+) Example 81 4- [ [ [(2-chloro-5-(tπfluoromethyl)phenyl] carbonyl]ammo]-N- [ [ : [ (4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl ] -L-phenylalanιne methyl ester. Using the general procedure described in example 52, starting with 4-amιno-N- [ [ l - [(4-methylsulfonyl) butyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester, 4- [ [ [ (2-chloro-5- (trifluoromethyl) phenyl]carbonyl] amιno] -N- [ [ l-[ (4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalamne methyl ester was prepared in 97% yield as a white amorphous solid HR MS: Obs mass, 633.1477. Calcd. mass, 633.1471 (M+H). Example 82.4- [ [ [ (2-chloro-5-(trifluoromethyl)phenyl] carbonyl] amino] -N- [ [ 1 - [(4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine. C28H32CIF3N2O5S2 C 27 H3oCIF 3 N 2 θ5S2 Mol Wt.633.14 Mol Wt:61912 Using the general procedure described in example 50, starting with 4-[[[(2- chloro-5-(trifluoromethyl) phenyl] carbonyl] amino] -N-[ [l-[(4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine methyl ester, 4- [[[(2-chloro-5-(trifluoromethyl)phenyl]carbonyl]amino]-N-[[l-[(4- methylsulfonyl) butyl]cyclobutyl]thioxomethyl]-L-phenylalanine was prepared in 75% yield as an amorphous white solid. HR MS: Obs. mass, 619.1315. Calcd. mass, 619.1318 (M+H). Example 83.4- [[(2,4-dimethy4-6-trifluoromethyl-3-pyridinyl)carbonyl] amino] - N-[[l-[(4-methylsulfony])butyl]cyclobutyl]thioxomethyl] -L-phenylalanine methyl ester. To suspension of 2,4-dimethyl-6-trifluoromethyl-3-pyridine carboxylic acid (0.84 mmol, 184 mg) in dichloromethane (10 mL) and DMF (3-drops) was added dropwise oxalyl chloride (1.14 mmol, 146 mg, 0.1 mL) at 0 °C for 2-3 min. After addition, it was stirred for 30 min at 0 °C and then allowed to warm to room temperature. The clear solution was stirred for another 2 h at room temperature The solvent was removed under -acuum and the residue was dried under high vacuum for 1 h To a mixture of 4-amιno-N-[[l-[(4- methylsulfonyl)butvl] cyclobutyl] thioxomethyl] -L-pheny lalamne methvl ester (07 mmol, 298 mg) and amberlyst A-21 (14 mmol, 900 mg) in ethyl acetate (10 mL, stored o\ er 4A molecular sιe\ es) in 4-necked sonicator flask w as added the above prepared acid chloride in ethyl acetate (6 mL) at room temperature The mixture was subjected for somcation for 30 min and was diluted with water (100 mL) and ethvl acetate (100 mL) and the two layers were separated The aqueou layer was extracted with ethvl acetate (50 mL) and the combined extracts were washed with brine solution (100 mL) and dried o\er anhydrous magnesium sulfate After filtration of the drying agent, the solution as concentrated under vacuum and the residue was purified by re\ ersed phase HPLC to obtain 139 mg (32%) of 4-[[(2,4-dιmeth\l-6-tπfluoromethvl-3-p\πdιnyl)carbon\l]amιno]-\- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclobutyl] thioxometh l] -L-pheny lalamne meth\ 1 ester as an amorphous white solid HRMS Obs mass, 6282122 Calcd mass, 6282127 (M+H) Example 844-[[(2,4-dιmethyl-6-tπfluoromethyl-3-pyπdιnvl)carbonyl]amιno]- N- [ [ 1 - [ (4-methylsulfonyl)butyl] cyclobutvl] thioxomethyl] lalamne To a suspension of 4-[[[(2,4-dιmethyl)(6-tπfluoromethvl)-3 p\πd\l]carbonvl]- amino] -N- [ [ 1 - [ (4 methylsulfonyl)butyl] c\ phem lalamne methyl ester (02 mmol, 125 mg) in ethanol (7 mL) was added a 10M solution of sodium hydroxide (50 mL) at room temperature Within few minutes it become a clear solution and this was heated to 45-50 °C and stirred for 4 hr, at which time TLC analysis of the mixture indicated the absence of starting material Then, it was cooled to room temperature and the ethanol was removed in vacuo The residue was purified by reversed phase HPLC to obtain 675 mg (55%) of 4-[[(2,4-dιmethyl-6-tπfluoromethyl-3-pvπdιnvl)carbon\l]amιno]-N- [[l-[(4-methvlsulfonyl) butyl] cyclobutyl] thioxomethyl] -L-phenv lalamne as an amorphous white solid HRMS Obs mass, 6141970 Calcd mass, 6141970 (M+H) Example 85. 4- [ [(2,6-dichlorophenyl)carbonyl]amino] -N- [(2-bromophenyl)- thioxomethyl] -L-phenylalanine. Using the method described in examples 35 to 39, and starting w-ith 2- bromobenzoic acid, the title compound was prepared. HRMS Obs. mass, 550.9593. Calcd mass, 550.9598 (M+H). Example 86. 4- [ (2S,4R)-3-acetyl-2-phenyl-4- [ (3-phenyl)methyl] -5-oxo- imidazolidin- l -yl] -N- [ [ (4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L- phenylalanine and 4- [(2R,4R)-3-acetyl-2-phenyl-4- [ (3-phenyl)methyl] -5-oxo- imidazolidin- 1 -yl] -N- [ [ (4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L- phenylalanine. C 36 H 41 N,0BS M 1ool. Wt.: 627.7 79 Using the procedure described in examples 26 to 29, the title compounds were prepared. The isomers were separated by chromatography at the methyl ester stage. For the 2S,4R isomer, HRMS, obs. mass, 650.2670. Calcd mass, 650.2665 (M+Na). For the 2R,4R isomer, HRMS, obs. mass, 650.2679. Calcd. mass, 650.2665 (M+Na). Assays: 1. VLA-4 / VCAM- 1 Screening Assay VLA-4 antagonist activity, defined as ability to compete for binding to immobilized VCAM- 1 , was quantitated using a solid-phase, dual antibody ELISA. VLA-4 (α4β 1 integrin) bound to VCAM- 1 is detected by a complex of anti-integrin βl antibody: HRP-conjugated anti-mouse IgG: chromogenic substrate (K-Blue). Initially, this entailed coating 96 well plates (Nunc Maxisorp) with recombinant human VCAM- 1 (0.4 μg in 100 μl PBS), sealing each plate and then allowing the plates to stand at 4°C for " 18 hr. The VCAM-coated plates were subsequently blocked with 250 μl of 1% BSA/0.02% NaN3 to reduce nonspecific binding. On the day of assay, all plates are washed twice with VCAM Assay Buffer (200 μl/well of 50 mM Tris-HCl, 100 mM NaCl, 1 mM MnCb, 0.05% Tween 20; pH 7.4). Test compounds are dissolved in 100% DMSO and then diluted 1:20 in VCAM Assay Buffer supplemented with lmg/mL BSA (i.e., final DMSO = 5%). A series of 1:4 dilutions are performed to achieve a concentration range of 0.005 nM - 1.563 μM for each test compound. 100 μl per well of each dilution is added to the VCAM-coated plates, followed by 10 μl of Ramos cell-derived VLA-4. These plates are sequentially mixed on a platform shaker for 1 min, incubated for 2 hr at 37 °C, and then washed four times with 200 μl/well VCAM Assay Buffer. 100 μl of mouse anti-human integrin β l antibody is added to each well (0.6 μg/mL in VCAM Assay Buffer + 1 mg/mL BSA) and allowed to incubate for 1 hr at 37°C. At the conclusion of this incubation period, all plates are washed four times with VCAM Assay Buffer (200 μl/well). A corresponding second antibody, HRP-conjugated goat anti-mouse IgG ( 100 μl per well @ 1 :800 dilution in VCAM Assay Buffer + 1 mg/mL BSA), is then added to each well, followed by a 1 hr incubation at room temperature and concluded by three washes (200μl/well) with VCAM Assay Buffer. Color development is initiated by addition of 100 μl K-Blue per well ( 15 min incubation, room temp) and terminated by addition of 100 μl Red Stop Buffer per well. All plates are then read in a UV/Vis spectrophotometer at 650 nM. Results are calculated as % inhibition of total binding (i.e., VLA-4 + VCAM- 1 in the absence of test compound). Selected data for compounds of this invention are shown in the table below: 2. Ramos (VLA-4) / VCAM- 1 Cell-Based Screening Assay Protocol Materials: Soluble recombinant human VCAM- 1 (mixture of 5- and 7-Ig domain) was purified from CHO cell culture media by immunoaffinity chromatography and maintained in a solution containing 0.1 M Tris-glycine (pH 7.5), 0.1 M NaCl, 5 mM EDTA, 1 mM PMSF, 0.02% 0.02% NaN3 and 10 μg/mL leupeptin. Calcein- AM was purchased from Molecular Probes Inc. Methods: VLA-4 (α4β l integrin) antagonist activity, defined as ability to compete with cell-surface VLA-4 for binding to immobilized VCAM- 1 , was quantitated using a Ramos-VCAM- 1 cell adhesion assay. Ramos cells bearing cell-surface VLA-4, were labeled with a fluorescent dye (Calcein-AM) and allowed to bind VCAM- 1 in the presence or absence of test compounds. A reduction in fluorescence intensity associated with adherent cells (% inhibition) reflected competitive inhibition of VLA-4 mediated cell adhesion by the test compound. Initially, this entailed coating 96 well plates (Nunc Maxisorp) with recombinant human VCAM- 1 ( 100 ng in 100 μl PBS), sealing each plate and allowing the plates to stand at 4°C for " 18 hr. The VCAM-coated plates were subsequently washed twice with 0.05% Tween-20 in PBS, and then blocked for lhr (room temperature) with 200 μl of Blocking Buffer ( 1 % BSA/0.02% thimerosal) to reduce non-specific binding. Following the incubation with Blocking Buffer, plates were inverted, blotted and the remaining buffer aspirated. Each plate was then washed with 300 μl PBS, inverted and the remaining PBS aspirated. Test compounds were dissolved in 100% DMSO and then diluted 1:25 in VCAM Cell Adhesion Assay Buffer (4 mM CaCl2, 4 mM MgCb in 50 mM TRIS-HC1, pH 7.5) (final DMSO = 4%). A series of eight 1:4 dilutions were performed for each compound (general concentration range of 1 nM - 12,500 nM). 100 μl/well of each dilution was added to the VCAM-coated plates, followed by 100 μl of Ramos cells (200,000 cells/well in 1% BSA/PBS). Plates containing test compounds and Ramos cells were allowed to incubate for 45 min at room temperature, after which 165 μl/well PBS was added. Plates were inverted to remove non-adherent cells, blotted and 300 μl/well PBS added. Plates were again inverted, blotted and the remaining buffer gently aspirated. 100 μl Lysis Buffer (0.1% SDS in 50 mM TRIS-HC1, pH 8.5) was added to each well and agitated for 2 min on a rotary shaking platform. The plates were then read for fluorescence intensity on a Cytofluor 2300 (Millipore) fluorescence measurement system (excitation = 485 nm, emission = 530 nm). 3. MadCAM RPMI 8866 cell Based Assay MadCAM binding activity was quantified using an RPMI 8866 cell-based assay. RPMI 8866 cells bearing cell surface MadCAM were labelled with fluorescent dye (calcein AM) and and allowed to bind MadCAM in the presence or absence of test compounds. A reduction in fluoresence intensity associated with adherent cells (% inhibition) reflects competitive inhibition of MadCAM mediated cell adhesion by the test compound. Initially, this entailed coating 96 well plates (Nunc F96 Maxisorp) with 25 ng/well of MadCAM ( 100 μl/well in coating buffer: lOmλl carbonate/bicarbonate buffer, 0.8 g/L sodium carbonate, 1.55 g/L sodium bicarbonate, adjusted to pH 9.6 with IN HCL), sealing and wrapping each plate and refrigerating the plates for at least 24 hrs. The MadCAM-coated plates were subsequently washed twice with 0.05% Tween-20 in PBS, and then blocked for at least lhr. at room temperature with of blocking buffer ( 1% nonfat dry milk in PBS) to reduce non-specific binding. Following the incubation with blocking buffer, plates were washed with PBS, hand blotted, and the remaining liquid aspirated. RPMI 8866 cells (2 x 10 cells/ml x 10 ml. per plate x number of plates) were transferred to a 50 ml centrifuge tube filled with PBS and spun at 200 x g for 8 minutes, after which the PBS is poured off and the pellet resuspended to 10 x 10 cells/ml in PBS. Calcein (diluted with 200 μl DMSO from a 5 mg/ml frozen stock) was added to the cells at 5 μl/ml PBS. After incubation at 37 degrees C for 30 min. in the dark, the cells were washed in PBS and resuspended at 2 x 106 cells/ml in cell buffer (RPMI 1640 medium (no additives)). Test compounds were dissolved in 100% DMSO and then diluted 1 :25 in binding buffer ( 1.5 mM CaCb, 0.5 mM MnCb in 50 mM TRIS-HC1, adjusted to pH 7.5 with NaOH). Remaining dilutions were into dilution buffer (4% DMSO in binding buffer -- 2% DMSO final when diluted 1:2 in wells). A series of dilutions were performed for each compound tested. 129 μl of binding buffer was placed in the first row of wells in the MadCAM-coated plates. 100 μl/well of dilution buffer was added to the remaining wells, followed by 5.4 μl of each test compound in the appropriate dilution (in triplicate). 100 μl of cells (200,000 cells/well) were added. Control wells contained 100 μl dilution buffer + 100 μl cell buffer, and 100 μl dilution buffer + 100 μl cell buffer. Plates were allowed to incubate for 45 min at room temperature, after which 150 μl/well PBS was added. Plates were inverted to remove non-adherent cells, blotted and 200 μl/well PBS added. Plates were again inverted, blotted and the remaining buffer gently aspirated. 100 μl PBS was added to each well. The plates were then read for fluorescence intensity on a fluorescence measurement system (excitation = 485 nm, emission = 530 nm, sensitivity = 2). A linear regression analysis was performed to obtain the IC 50 of each compound. The results are shown in the following table: [Example 4. Acute airway inflammation in the atopic primate. Airway inflammation in the monkey was determined using a modification of the protocol described by Turner et al. (Turner et al., 1994). Adult male cynomolgus monkeys (Macaca fascicularis, Hazelton Labs, Denver, PA) weighing between 3.6 - 5.8 kg were used in these studies. All animals exhibited positive skin and airway responses to Ascaris suutn antigen and had at least a 3-fold increase in the sensitivity to methacholine (MCh) when subjected to an aerosol of ascaris extract. On the day of each experiment the animals were anesthetized with ketamine hydrochloride, 12 mg/kg, and xylazine, 0.5 mg/kg, intubated with a cuffed endotracheal tube (3 mm, Mallinckrodt Medical, St. Louis, MO), then seated in an upright position in a specially designed Plexiglass chair (Plas-Labs, Lansing, MI). The endotracheal tube was connected to a heated Fleisch pneumotachograph. Airflow was measured via a Validyn differential pressure transducer (DP 45-24) that was attached to the pneumotachograph. Transpulmonary pressure was measured via a second Validyne transducer (DP 45-24) connected between a sidearm of the tracheal cannula and a 18-gauge intrapleural needle inserted in the intercostal space located below the left nipple. Recordings of pressure and flow and the calculation of R were made using the Modular Instruments data acquisition system as described above. Baseline R was measured for all animals on the day of each experiment and had an average value of about 0.04 cmH 2 0/ml/sec. Protocol Airway inflammation was induced by exposing the animal to an aerosol of A. Suum extract for 60 sec. The aerosol was delivered via a nebulizer (De Vilbiss Model 5000, Healt Care Inc., Somerset, PA) that was attached to the endotracheal tube. The concentration of extract w τ as predetermined for each animal (500 to 50,000 PNU) and caused at least a doubling in the airway resistance. At 24 hour after the antigen challenge, the animals were anesthetized as described previously and placed on a stainless steel table. Airway inflammation was assessed by inserting a pediatric bronchoscope into the airway lumen down to about the 4 or 5 1 generation bronchi and gently lavaging with 3 X 2 ml aliquots of sterile Hanks Balanced Salt Solution. The recovered lavage fluid then was analyzed for the total cell and differential cell counts using standard hematological techniques. Drug Treatment The animals received drug or a vehicle, p.o., administered 2 hours prior to antigen challenge. The compound of example 1 caused a significant decrease in the number and percent of inflammatory cells present in the lavage fluid relative to vehicle treated control animals.

Claims: Claims 1. A compound of the formula: wherein X is a group of the formula wherein: R 5 is halogen, nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, lower alkyl aminosulfonyl, perfluorolower alkyl, lower alkylthio, hydroxy lower alkyl, alkoxy lower alkyl, lower alkylthio lower alkyl, lower alkylsulfinyl lower alkyl, lower alkylsulfonyl lower alkyl, lower alkylsulfinyl, lower alkanoyl, aroyl, aryl, aryloxy; Rl6 is hydrogen, halogen, nitro, cyano, lower alkyl, OH, perfluorolower alkyl, or lower alkylthio; or X is a group of formula X-2 wherein Het is a 5- or 6-membered heteroaromatic rinζ containin g 1 , 2 or 3 heteroatoms selected from N,0, and S, or Het is a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, and N; Rl5 and R\ are as in X- l above; R 30 is hydrogen or lower alkyl; and p is an integer from 0 to 1 ; or X is a group of formula X-3 wherein: Rl8 is aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl Ri 9 is substituted or unsubstituted lower alkyl, aryl, heteroaryl, arylalkyl, heteroaryl alkyl, and R20 is substituted or unsubstituted lower alkanoyl or aroyl; and Y is a group of formula Y-l wherein: R22 and R23 are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluorolower alkyl and at least one of R22 and R23 is other than hydrogen, and R24 is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen; or Y-2 is a group of the formula: R 31 — ~ - Het 1 V, Het is a five or six membered heteroaromatic ring bonded via a carbon atom wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and R 30 and R 31 are independently hydrogen, lower alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of R 30 and R 1 is adjacent to the point of attachment, p is an integer of 0 or 1. or Y is a group of formula Y-3 wherein: R25 is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula H 2 g (CH 2 ) e - ) j^g is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio , lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R 26 is a group of formula -NR2δR29> wherein R28 is H or lower alkyl, R29 is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl, or R28 an d R29 taken together form a 4, 5 or 6-membered saturated carbocyclic ring optionally containing one heteroatom selected from O, S, and N; with the carbon atoms in the ring being unsubstituted or substituted by lower alkyl or halogen, Q is -(CH 2 )f 0-, -(CH 2 )f S-, -(CH 2 )f N(R27)-. -(CH 2 )f- or a bond, R27 is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, e is an integer from 0 to 4, f is an integer from 1 to 3, and the dotted bond is optionally hydrogenated; and pharmaceutically acceptable salts and esters thereof. 2. A compound of claim 1 wherein X is a group of the formula and Y, R 1 5 and R] 6 are as in claim 1. 3. A compound of claim 2 wherein R !? is lower alkyl, nitro, halogen, lower alkylsulfonyl, perfluoroloweralkyl, or cyano and Rι 6 is hydrogen, lower alkyl, nitro, halogen, lower alkylthio, perfluoroloweralkyl, or cyano. 4. A compound of claim 2 or claim 3 wherein R 15 and Rι 6 are independently chloro or fluoro. 5. A compound of claim 3 wherein X- l is selected from the group of 6. A compound of claim 1 wherein X is a group of the formula X-2 and p, Y, R 15 , Rι 6 , and R 30 are as in claim 1. 7. A compound of claim 6 wherein Het is a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2 or 3 nitrogens, or a nitrogen and a sulfur, or a nitrogen and an oxygen. 8. A compound of claim 6 wherein Het is a bicyclic heteroaromatic ring containing from 1 to 3 nitrogens. 9. A compound of claim 6 wherein R15 is nitro, lower alkyl sulfonyl, cyano, lower alkyl, lower alkoxy, perfluorolower alkyl, lower alkylthio, lower alkanoyl, or aryl. 10. A compound of claim 9 wherein Rι 5 is unsubstituted phenyl. 11. A compound of claim 6 wherein R\ is hydrogen, halogen, nitro, cyano, lower alkyl, perfluoro lower alkyl; and R 30 is hydrogen or lower alkyl. 12. A compound of claim 6 wherein Het is a 6 membered monocyclic heteroaromatic ring containing 1 or 2 nitrogens or Het is a 10 membered bicyclic heteroaromatic ring containing one nitrogen, Rι 5 is lower alkyl or perfluoroalkyl and Ri 6 is hydrogen, lower alkyl, or perfluoroalkyl, and R 30 is absent. 13. A compound of claim 6 wherein X-2 is selected from the group of 14. A compound of claim 1 wherein X is a group of formula X-3 and Y, Ris, Rι 9 , and R 2 o are as in claim 1. 15. A compound of claim 14 wherein R13 is phenyl. 16. A compound of claim 14 wherein R j 9 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl. 17. A compound of claim 13 wherein R20 is substituted or unsubsituted lower alkanoyl. 18. A compound of claim 14 wherein R 18 is phenyl, Rj 9 is lower alkyl which is unsubstituted or substituted by pyridyl or phenyl and R 2 o is lower alkanoyl. 19. A compound of claim 14 wherein R i8 is phenyl which is unsubstituted or substituted by halogen or lower alkoxy; R J is phenyl lower alkyl which is unsubstituted or substituted by lower alkoxy, pyridyl lower alkyl, or lower alkyl; and R 2 o is substituted or unsubstituted lower alkanoyl. 20. A compound of claim 19 wherein X-3 is selected from the group of 21. A compound of claim 1 wherein Y is a group of formula and X, R 22 , R 23 , and R 2 are as in claim 1. 22. A compound of claim 21 wherein R 22 is hydrogen, lower alkyl, perfluoroalkyl or halogen, R 23 is lower alkyl, perfluoroalkyl, or halogen and R 24 is hydrogen, lower alkyl, lower alkoxy, or halogen. 23. A compound of claim 22 wherein Y- l is selected from the group of 24. A compound of claim 1 wherein Y is a group of the formula Y-2 R 31 Het Y-2 [ R 3θ]p and p, X, Het, R 30 and R 3i , are as in claim 1. 25. A compound of claim 24 wherein Het is a 6 membered heteroaromatic ring. 26. A compound of claim 25 wherein the heteroatom is N. 27. A compound of claim 26 wherein Y-2 is selected from the group of 28. A compound of claim 1 wherein Y is a group of formula Y-3 and Y, R 25 and Q are as in claim 1 , and the dotted bond can be optionally hydrogenated. 29. A compound of claim 28, wherein in Y-3 R 25 is R 26 -(CH ) e )e, e is 0-4, and R 2 6 is alkoxy, lower alkyl sulfonyl, loweralkylthio, phenyl or phenyl substituted by alkoxy or halogen, or NHR 29 where R 29 is lower alkanoyl, loweralkoxycarbonyl or loweralkylaminocarbonyl, and the dotted bond is hydrogenated. 30. A compound of claim 28 wherein Y-3 is selected from the group of 31. A compound according to claim 1 selected from the group consisting of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6- methylphenyl)thioxomethyl] -L-phenylalanine, < 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[l-[(4-methylsulfonyl)- butyl] cyclopentyl] thioxomethyl] -L-phenylalanine, 4-[[(2,6-dichlorophenyl)carbonyl]aminoj-N-[(2-bromophenyl)thioxo- methyl] -L-phenylalanine, 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-methylphenyl)- thioxomethyl] )-L-phenylalanine, 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[(2-fluorophenyl)thioxo- methyl] -L-phenylalanine, 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[2-(trifluoromethyl)- phenyl] thioxomethyl] -L-phenylalanine, 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-oxo-imidazolidin- 1 -yl] -N- [ (2-ethyl-6-methylphenyl)thioxomethyl] -L-phenylalanine, 4-[[2,6-dichlorophenyl)carbonyl]amino-N-[[l-[2-(acetylamino)- ethyl] cyclopentyljthioxomethyl] -L-phenylalanine, [[l-[2-[[(methylamino)carbonyl] amino] ethyl] cyclopentyl] thioxomethyl] -4- [[(2, 6-dichlorophenyl)carbonyl] amino] L- phenylalanine, 4- [ [ (2,6,-dichlorophenyl)carbonyl] amino] -N- [ [ 1 -(2-methoxyethyl)- cyclopentyl] thioxomethyl] -L-phenylalanine, 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[l-[(4-methylsulfonyl)- butyl] cyclobutyl] thioxomethyl] -L-phenylalanine, 4- [ [ (2,6,-dichlorophenyl)carbonyl] amino] -N- [ [ 1 -(3-methylthio)propyl] - cyclobutyl] thioxomethyl] -L-phenylalanine, 4-[[(2,6,-dichlorophenyl)carbonyl]amino]-N-[[l-(3-methylsulfonyl)- propyl] cyclobutyl] thioxomethyl] -L-phenylalanine, 4-[(2,6-dimethyl-3-pyridinylcarbonyl)amino] -N- [ [ l- [(4-methylsulfonyl)- butyl] cyclopentyl] thioxomethyl] -L-phenylalanine, 4- [ [ [4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino] -N- [ [ l-(4- methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine, 4- [ [ (2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl] amino] -N- [ [ 1 - ](4-methylsulfonyl)butyl] cyclobutyl] thioxomethyl] -L-phenylalanine, 4- [(2S,4R)-3-acetyl-2-phenyl-4- [(3-phenyl)methyl] -5-oxo-imidazolidin- 1 - yl] -N- [ [ (4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine or 4- [(2R,4R)-3-acetyl-2-phenyl-4- [ (3-phenyl)methyl] -5-oxo-imidazolidin- 1- yl]-N- [ [(4-methylsulfonyl)butyl] cyclopentyl] thioxomethyl] -L-phenylalanine. 32. A compound according to any one of claims 1 -31 for use as a medicament, especially in the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. 33. A pharmaceutical preparation, especially a pharmaceutical preparation for the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma, comprising a compound according to any one of claims 1-31 or a pharmaceutically acceptable salt or ester thereof together with a compatible pharmaceutical carrier material. 34. A process for the production of a pharmaceutical preparation, especially a pharmaceutical preparation for the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma, which process comprises bringing one or more compounds according to any one of claims 1 to 31 or a pharmaceutically acceptable salt or ester thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with a compatible pharmaceutical carrier material. 35. The use of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt or ester thereof in the treatment or prophylaxis of illnesses, especially in the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma. 36. The use of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt or ester thereof for the manufacture of a medicament comprising as active ingredient a compound according to any one of claims 1 -31 or a pharmaceutically acceptable salt or ester thereof for the treatment or prophylaxis of illnesses, especially for the treatment or prophylaxis of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma. 37. The new compounds, medicaments, processes and uses substantially as hereinbefore described.

Inventors: HULL KENNETH GREGORY, SIDDURI ACHYTHARAO, TILLEY JEFFERSON WRIGHT, HULL, KENNETH, GREGORY, SIDDURI, ACHYTHARAO, TILLEY, JEFFERSON, WRIGHT
Applicants: HOFFMANN LA ROCHE, F. HOFFMANN-LA ROCHE AG
Application year: 2000
Main classification: C07C327
IPC codes: A61K31, A61P1, A61P11, A61P29, A61P43, C07C327, C07D213, C07D233, C07D239, C07D401