Background of Invention The integrin (Xvp3 has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue (Sefton et al.. Proc. Natl. Acad. Sci, USA. 1992, 89,1557-1561) and to protect these cells against natural cell death cycle (apoptosis) (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1994,91,8856-8860). Vitronectin receptor (avß3) antagonists have been shown to inhibit the growth of various solid tumors of human origin (Brooks et al.. Cell. More recently, αvß3 has been shown to be involved in liver metastasis (Yun et al., Cancer Res., 1996, 56,3103-3111).

Although angiogenesis is an important and natural process in growth and wound healing, it is now appreciated that a variety of clinically relevant conditions are pathologically related to these processes, and that the integrin avp3 is involved. For example, (Xvp3 was shown to be expressed on human wound tissue but not on normal skin (Brooks, et al., Science, and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of (Xvp3 promote tumor regression by inducing apoptosis of the tumor cells (Brooks et al., Cell, 1994,79,1157-1164). This process of neovascularization which is critical for tumor growth and metastasis, is also an important event in ocular tissue, leading to diabetic retinopathy, glaucoma and blindness (Adonis et al., Am. J. Ophthal., 1994,118,445-450; Hammes et al., Nature Med., 1996,2,529-533; Friedlander, et al., Natl. Acad. Sci. U. S. A., 1996,93,9764-

9769) and in joints, promoting rheumatoid arthritis (Peacock et al., J. Exp. Med., 1992,175,1135-1138).

αvß3 has been shown to play a pivotal role in the proliferation and migration of- smooth muscle and vascular endothelial cells, a pathological process leading to restenosis after balloon angioplasty (Choi et al., J. Vasc. Surgery, 1994,19,125-134; Matsumo et al., Circulation, 1994,90,2203-2206). At least one type of virus (adenovirus) has been shown to utilize (Xyp3 for entering host cells (White et al., Current Biology, 1993,596-599.

Various bone diseases involve bone resorption which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells <BR> <BR> <BR> <BR> initially bind to bone, a process well known to be mediated by CCVß3 (Davies et al., J.

Cell. Biol., 1989 109,1817-1826; Helfrich et al., J Bone Mineral Res., 1992.7,335- <BR> <BR> <BR> <BR> 343). It is also well known that blockade of (Xyp3 with antibodies or RGD containing<BR> <BR> <BR> <BR> <BR> peptides block osteoclast cell adhesion and bone resorption in vitro (Horton et al., Exp. Cell Res. 1991,195,368-375) and that echistatin, an RGD containing protein, inhibits bone resorption in vivo (Fisher et al., Endocrinology, 1993,132, 1411-1413).

More recently, an RGD peptidomimetic has likewise been shown to inhibit osteoclasts in vitro and, by i. v. administration in vivo prevents osteoporosis (Engleman et al., J.

Clin. Invest., 1997,99,2284-2292).

αvß3 also plays an important role in autoimmune diseases such as psoriasis and rheumatoid arthritis. Peacock, et al., supra.

Numerous patents/applications have claimed various non-peptide (Xvp3 inhibitors for some or all of the above applications (e. g. EP92307157.5A, EP92307156.7A, W09708145, W09532710, W096/00730, W09637492, W09626190, W09606087, W097/23451, W09724119, W09724122, W09724124, W096-US20744961220, EP796855, W09733887, W097/34865, W097/35615, W097/36859, W097/35615, W097/08145, US5668159, W098/08840, W098/14192).

W09532710 teaches compounds for inhibiting bone resorption. Among the preferred compounds are compounds having a 4-alkyloxy substituted benzoic acid core coupled to an (a-phenylsulfonylamino-3-amino propanoic acid) terminus. None of the exemplary compounds teach a 2-hydroxy substitution of the benzoyl core. The lead compound of W09532710 exhibited limited bioavailability in vivo. (VnR symposium Abstracts, 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996).) W09708145 discloses certain meta-guanidine, urea, thiourea and azacyclic amino substituted benzoic acid derivitaves as integrin antagonists.

European patent application number EP0320032 broadly claims certain 2- aminoalkoxy-substituted pyridazine derivatives. The compounds disclosed do not comprise an acid functionality.

W09513262 teaches certain 2-hydroxy-4-heteroarylmethoxy benzamide derivatives are endothelin inhibitors.

Detailed Description of the Invention According to the present invention are provided novel compounds of Formula I: wherein G is

R'and R2 are independently, hydrogen, alkyl of 1 to 6 carbon atoms, mono or bicyclic aralkyl of 6 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having I to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms; R3 is hydrogen, mono or bicyclic aryl of 6 to 10 carbon atoms, 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O; R4 is hydrogen, NHR9, OR9, NHCOR9, NHCONHR9, NHCOR9or NHSO2R9; provided that R3 and R4 are not both hydrogen; R5 is hydrogen or alkyl of 1 to 6 carbon atoms which may optionally be substituted with a terminal group which serves as a prodrug. For example, the alkyl group may be substituted with an acid, alcohol or amino functionality to form an alkylamino, carboxyalkyl or alkanol group; R6 and R 7are independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or aralkoxy of 6 to 10 carbon atoms;

R8 and R9 are independently hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbons, alkynyl of 2 to 10 carbons, mono or polycycloalkyl of 3-12 carbon atoms, mono or polycycloalkyl-alkyl of 4-12 carbon atoms, mono or bicyclic aryl of 6 to 10- carbon atoms, 6 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O, mono or bicyclic aralkyl of 7 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms; n is an integer from 1 to 4; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present invention G is is 6- aminopyridin-2yl, pyridin-2yl, pyrimidyl, tetrahydropyrimidyl tetrahydropyrimid-4- one, dihydroimidazolyl, amino (imino)-, pyridyl-urea, benzyl-urea, or imidazolidinyl.

In a still more preferred embodiment of the present invention G is 6-amino- pyridin-2-yl, pyridin-2yl, dihydroimidazolyl, 5-amino 1,2,4-triazol-4yl (and/or all tautomers thereof) or tetrahydropyrimidyl, R3 is H, and n is 2 or 3.

In some preferred aspects of the invention R9 is methyl, ethyl, n-propyl. i- propyl, allyl, homoallyl, propargyl, pentyl, n-hexyl, octyl, neopentyl, trichloroethyl, n- butyl, i-butyl, butynyl, phenyl, methylphenyl, dimethylphenyl, halophenyl, methoxy- phenyl, acetylphenyl, biphenyl, naphthyl, benzyl, phenethyl, cyclohexyl, cyclohexyl- methyl, trimethylcyclopropyl, phenylcyclopropyl, adamantyl, adamantylmethyl. cinnamic, pyridyl or dimethylfuranyl.

"Alkyl", whether used alone or as part of a group such as"alkoxy", means a branched or straight chain having from 1 to 10 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

Lower alkyl refers to alkyl having from 1 to 4 carbon atoms. Alkyl groups may be substituted.

"Cycloalkyl"as used herein refers to mono or polycyclic alkyl groups of 3-12 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclohexyl and adamantyl. Cycloalkyl groups may be substituted. One preferred substitution is phenyl.

"Aryl"whether used alone or as part of a group such as"aralkyl", means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl. The aryl may be substituted with one or more substituents. Substituents include halogen, lower alkyl, alkoxy. alkylthio, amino, nitro, cyano, carboxy, carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy and phenyl. One preferred aryl group is phenyl.

"Heterocycloalkyl"whether used alone or as part of a group such as "heterocycloalkyl-alkyl"means a stable, saturated or unsaturated 5 to 10 membered mono or bicyclic ring having from 1 to 3 heteroatoms selected from N, O and S.

Exemplary heterocycloalkyls include pyrazinyl, pyrazolyl, tetrazolyl. mranyl. thienyl, pyridyl, imidazolyl. pyrimidinyl, tetrahydropyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl. indolyl, isoquinolinyl, oxazolyl and oxadiazolyl. Preferred heteroaryl groups include pyrimidinyl, tetrahydropyrimidinyl, pyridyl. and imidazolyl.

Most preferred heteroaryls include pyridin-2yl, and tetrahydropyrimidine. The heteroaryl may also be substituted with one or more substituents. Substituents include halogen, lower alkyl, alkoxy, alkylthio, amino, nitro, cyano, carboxy. carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy and phenyl. Preferred substituents include amino and oxy. Preferred substituted heterocycloalkyls include 6 aminopyridin-2yl and tetrahydropyrimid-4-one.

"Aralkyl"means an aryl-alkyl group in which the aryl and alkyl are as previously described. Exemplary aralkyl groups include benzyl and phenethyl. Use in this context, the alkyl group may include one or more double bonds.

"Heterocycloalkyl-alkyl"means an heterocycloalkyl group in which the heterocycloalkyl and alkyl are as previously described. Use in this context, the alkyl group may include one or more double bonds. Exemplary heterocycloalkyl-alkyls

include pyridylmethyl, pyridylethyl, thienylethyl, thienylmethyl, indolylmethyl, and furylmethyl.

"Alkoxy"means an alkyl-0 group in which the alkyl group is as previously, described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.

"Aralkoxy"means an aryl-alkoxy group in which aryl and alkoxy are as previously described.

"Halogen"includes fluorine, chlorine, iodine and bromine.

"Prodrug", as used herein means a compound which is convertible ira vivo by metabolic means (e. g. by hydrolysis) to a compound of Formula I.

NMR and IR spectra indicate the 2-hydroxy substitution of Formula I is strongly H-bonded to the adjacent carbonyl, effectively forming a six-membered ring which conformationally restricts the amide residue bearing the carboxy terminus.

Thus, the 2-hydroxy substitution of the phenyl core of Formula I plays a significant role in integrin receptor selectivity.

In addition, the 2-hydroxy compounds of the invention are believed to obviate at least two of the three hydrating water molecules which are known to form intermolecular hydrogen bonds with secondary amide functionalities. The energy needed to desolvate water molecules for efficient transport across cell membranes is thus reduced in compounds of the present invention and is believed to contribute to the markedly improved plasma concentrations seen with compounds of the present invention.

Preferred compounds include: (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino)-2- [(methoxycarbonyl) amino] propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino)-2- [ (propoxycarbonyl) amino] propanoic acid,

(2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy]benzoyl}amino-2-[(isopropoxycarbonyl)amino] propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-2-{ [(allyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(1 , 4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl)amino) propanoic acid, (2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- { [ (octyloxy) carbonyl] amino} propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, ethoxy] benzoyl}- amino)-2-{[(neopentyloxy)carbonyl]amino}propanoicacid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethOxy] benzoyl}- amino)-2-{[(2, 2,2-trichloroethoxy) carbonyl] amino} propanoic acid, (2S)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(butoxycarbonyl) amino] propanoic[(butoxycarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(isobutoxycarbonyl) amino] propanoic[(isobutoxycarbonyl) amino] propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}propanoicacid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl]amino) propanoic acid, (2S)-2-{ [(butylamino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(hexylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(octylamino)carbonyl]amino}propanoicacid, (2S)-2-{[(allylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1,4 ,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid,

(2S)-2-{ [(1-adamantylamino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(1,4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-[(anilinocarbonyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5, 6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2{[(cyclohexylamino)carbonyl]amino}-3-({2-hydroxy-4-[2- (1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(benzylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydrox-4-[2-(1, ethoxy] benzoyl}- amino)-2- [ (4-toluidinocarbonyl) amino] propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (2-toluidinocarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(2-methoxyanilino)carbonyl]amino}propanoicacid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- { [(4-methoxyanilino) carbonyl] amino} propanoic acid, (2S)-2-{[(2-chloroanilino)carbonyl]amino}-3-([2-hydroxy-4-[2 -(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(2-bromoanilino)carbonyl]amino}-3-({2-hydroxy-4-[2- (1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[([1,1'-biphenyl]-2-ylamino) carbonyl] amino}-3- ( {2-hydroxy-4- [2- ( 1,4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(4-chloroanlino)carbonyl]amino}-3-({2-hydroxy-4-[2- (1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(1-nahthylamino) carbonyl] amino} propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-( { [(2-phenylethyl) amino] carbonyl} arnino)( { [(2-phenylethyl) amino] carbonyl} arnino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-(isobutyrylamino)propanoicacid,

(2S)-2-(hexanoylamino)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy]- benzoyl} amino)-2- (pent anoylamino) propanoic acid, (2S)-2-[(3,3-diemthylbutanoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-[(cyclohexylcarbonyl) amino]-3-( {2-hydroxy-4- [2-(1,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl amino)-2- [(2-phenylacetyl) amino] propanoic acid, <BR> <BR> <BR> <BR> (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (3-phenylpropanoyl) amino] propanoic acid, (2S)-2-[(2-cyclohexylacetyl)amino]-3-({2-hydroxy-4-[2-(1,4,5 ,6-tetrahydropyrimdin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(E)-3-phenylprop-2-enoyl]amino}propanoicacid, (2S)-2-[(2-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (2-methylbenzoyl) amino] propanoic acid, -(2S)-3-( {2-hydroxy-4-[2-(1,(2S)-3-( {2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(2-methoxybenzoyl) amino][(2-methoxybenzoyl) amino] propanoic acid, (2S)-2-[(4-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylami no)ethoxy]benzoyl}- arnino)-2- [ (4-methylbenzoyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (4-methoxybenzoyl) amino] propanoic acid, (2S)-2-[(2,5-dimethyl-3-furoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid,

(2S)-2-[(2-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-[(4-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-- ylamino) ethoxy] benzoyl} amino) propanoic acid (2S)-2- [ (2,3-dimethylbenzoyl) amino]-3- ( {2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2- [(3-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimdin-2-ylamino) ethoxy] benzoyl} amino)-2- [(phenoxycarbonyl)amino]propanoicacid, (2S)-2-{[(benzoyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyr imidin-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [(isobutoxycarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(4- methoxyphenoxy) carbonyl] arnino} propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- { [ (octyloxy) carbonyl] amino} propanoic acid, (2S)-2- [ (butoxycarbonyl) amino]-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy]- benzoyl} amino) propanoic acid, (2S)-3- (f 2-hydroxy-4- [2- (pyrirrdin-2-ylamino) ethoxy] benzoyl} amino)-2- { [(2,2,2- trichloroethoxy) carbonyl] amin}propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- {[(neopentyloxy) carbonyl] amino} propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-([{(4- nitrobenzyl) oxy] carbonyl} amino) propanoic acid, (2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrim idin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(prop-2- ynyloxy) carbonyl] amino} propanoic acid,

(2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} aniino)-2-f [ (4- methylphenoxy) carbonyl] amino} propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [(methoxycarbonyl) amino] propanoic acid, (2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(pyrimidin -2-ylamino)- ethoxy] benzoyl}amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [ (propoxycarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2- [(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrim idin-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-[(anilinocarbonyl)amino]-3-({2-hydroxy-4-[2-(pyrimidi n-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(tert-butylamino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimdin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(butylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyr imidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(4 methoxyanilino) carbonyl] amino} propanoic acid, (2S)-2- { [ (2-ethylanilino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(allylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyr imdin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(2,4-dichloroanilino)carbonyl]amino}-3-({2-hydroxy- 4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-[(2- toluidinocarbonyl)amino]propanoicacid,

(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(2- methoxyanilino) carbonyl] amino} propanoic acid, (2S)-2-{ [(2-chloroanilino) carbonyl] amino 3-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{ [(2-bromoanilino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(1,1'-biphenyl]-2-ylamino)carbonyl]amino]-3-({2-hyd roxy-4-[2-(pyrimdin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-[(4- toluidinocarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-({[4- (trifluoromethyl) anilino] carbonyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-({[4- (trifluoromethoxy) anilino] carbonyl} amino) propanoic acid, (2S)-2-{[(4-chloroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(4-fluoroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{ [(4-acetylanilino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(4-(ethoxycarbonyl)anilino]carbonyl}amino)-3-({2-hy droxy-4-[2-(pyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(cyclohexylamino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(1- naphthylamino) carbonyl] amino} propanoic acid, (2S)-2-{[(benzylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(py rimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-({[(2- phenylethyl) amino] carbonyl} amino) propanoic acid,

(2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} arnino)-2- {[(octylamino) carbonyl] amino} propanoic acid, (2S)-3-{[(benzyloxy)carbonyl]amino]-3-({4-[2-(4,5-dihydro-1H -imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3-({4-[2-(4,5-dihyro-1H-imiidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2- [ (methoxycarbonyl) aminoJpropanoic acid, (2S)-3-({4-[2-(4,5-dihyro-1H-imiidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-[(ethoxycarbonyl) amino] propanoic[(ethoxycarbonyl) amino] propanoic acid, (2S)-3-({4-[2-(4,5-dihyro-1H-imiidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-[(propoxycarbonyl)amino]propanoicacid, (2S)-3-({4-[2-(4,5-dihyro-1H-imiidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-[(isopropoxycarbonyl) amino] propanoic[(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-({4-[2-(4,5-dihydro-1H- imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({4-[2-(4,5-dihydr o-1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl}amino)-2-{[(prop-2-ynyloxy) carbonyl] amino} propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl}amino)-2-{[(hexyloxy)carbonyl]amino}propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl} amino)-2-{[(octyloxy) carbonyl] amino} propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2- hydroxybenzol-2-ylamino)- carbonyl] amino} propanoic acid, (2S)-2-{[(butoxycarbonyl)amino]-3-({4-[2-(4,5-dihydro-1H-imi dazol-2- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3-( {4-[2-(4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoica cid, (2S)-2-{[(butylamino)carbonyl]amino}-3-({4-[2-(4,5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid,

(2S)-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(hexylamino)carbonyl]amino]propanoicacid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(octylamino) carbonyl] amino} propanoic acid, (2S)-2-{[(allylamino)carbonyl]amino]-3-({4-[2-(4,5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(cyclohexylamino)carbonyl]amino}-3-4-[2-(4,5-dihydr o-1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(benzylamino)carbonyl]amino}-3-({4-[2-(4,5-dihydro- 1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> 3- ( {4- [2- (2, 5-dihydro-1 H-imidazol-4-ylamino) ethoxy]-2-hydroxybenzoyl) amino)-N- { [ (IS, 2R)-2-phenylcyclopropyl] amino) carbonyl) alanine, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-{[(2-methoxyanilino)carbonyl]amino}propanoicacid, (2S)-2-{[([1,1'-biphenyl]-2-ylamino)carbonyl]amino}-3-({4-[2 -(4,5-dihydro-1H- imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-({[(2-phenylethyl)amino]carbonyl}amino)propanoicaci d, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2-(isobutyrylamino)(isobutyrylamino) propanoic acid, (2S)-2- (butyrylamino)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl} amino) propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- (hexanoylamino) propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- (pentanoylamino) propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (3,3-dimethylbutanoyl) amino] propanoic acid, (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- { [ (2,2,3,3-tetramethylcyclopropyl)-carbonyl] amino} propanoic acid,

(2S)-2-{[2-(1-adamantyl)acetyl]amino}-3-({4-[2-(4,5-dihydro- 1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, <BR> <BR> <BR> <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- (pent-4-ynoylamino) propanoic acid, (2S)-2-[(cyclohexylcarbonyl]amino}-3-({4-[2-(4,5-dihydro-1H- imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, <BR> <BR> <BR> <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- arnino)-2-[(2-phenylacetyl) amino] propanoic[(2-phenylacetyl) amino] propanoic acid, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2- [ (3-phenylpropanoyl) amino] propanoic acid, (2S)-2-[(2-cyclohexylacetyl]amino}-3-({4-[2-(4,5-dihydro-1H- imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(E)-3-phenylprop-2-enoyl]amino}propanoicacid, (2S)-2- [ (2-chlorobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-[(2-methylbenzoyl)[(2-methylbenzoyl) amino] propanoic acid, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2- [ (2-methoxybenzoyl) amino] propanoic acid, <BR> <BR> <BR> <BR> <BR> (2S)-2- [ (4-chlorobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2- [ (4-methylbenzoyl) amino] propanoic acid, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2- [ (4-methoxybenzoyl) amino] propanoic acid, (2S)-3- {4-[2-(4, 5-dihydro-l H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (2, 5-dimethyl-3-furoyl) amino] propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-2- [ (2-bromobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid,

(2S)-2- [ (4-bromobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethyoxy]-2- hydroxybenzoyl]- amino)-2- [ (2,3-dimethylbenzoyl) amino] propanoic acid, (2S)-2- [ (3-chlorobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3, 4,5,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-[(methoxycarbonyl)amino]propanoicacid, <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin- 7-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- amino)-2-[(propoxycarbonyl) amino] propanoic[(propoxycarbonyl) amino] propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-[(isopropoxycarbonyl)[(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5 ,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( 3-, 2H-azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}propanoicacid, (2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5 ,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl)- amino)-2-{[(octyloxy)carbonyl]amino}propanoicacid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-{[(neopentyloxy)carbonyl]amino}propanoicacid, (2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylam ino)ethoxy]benzoyl}- amino)-2- { [ (2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid,

(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-t etrahydro-2H-azepin- 7-ylamino)ethoxy]benzoyl}amino)propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2- [ (isobutoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- {[(benzyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (methoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(ethoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(propoxycarbonyl)amino]propanoicacid, (2S)-3-{[4-(2-[{amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-{[4-(2-{[amino(imino)me thyl]amino}ethoxy-2- hydroxybenzoyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(but-3-enyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [(butoxycarbonyl) arnino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- {[ (2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- {[(neropentyloxy) carbonyl] amino} propanoic acid, (2S)-3-1 [4- (2- f [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(hexyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(prop-2-ynyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [([1, 1'-biphenyl]-2-ylmethoxy) carbonyl] amino} propanoic acid,

(2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- ( { [(4-bromobenzyl) oxy] carbonyl} amino) propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [(4-fluorobenzyl) oxy] carbonyl} amino) propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [(2-bromobenzyl) oxy] carbonyl} amino) propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [({[4-(trifluoromethyl)benzyl]oxy}carbonyl}amino]propanoicac id, (2S)-3-{ [4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(2-toluidinocarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(2-methoxyanilino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(2-chloroanilino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(2-bromoanilino)carbonyl]amino} propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [ ( [1, 1'-biphenyl]-2-ylamino) carbonyl] amino} propane ic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [ (4-toluidinocarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [4-(trifluoromethoxy) anilino] carbonyl} amino) propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [ (4-chloroanilino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [ (4-fluoroanilino) carbonyl] amino} propanoic acid, (2S)-2-{[4-acetylanilino)carbonyl]amino}-3-{[4-(2-{[amino-(i mino)methyl]amino}- ethoxy)-2-hydroxybeznoyl]amino}propanoicacid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(cyclohexylamino) carbonyl] amino} propanoic acid

(2S)-3-{ [4-(2- { [arnino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(l-naphthylamino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [ (benzylamino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [(2-phenylethyl) amino] carbonyl} amino) propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(octylamino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(4-methoxyanilino) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [(anilinocarbonyl)amino]propanoicacid, (2S)-3-{[4-(2-{ [amino (imino) methyl) amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (isobutyrylamino) propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl) amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (butyrylamino) propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (hexanoylamino) propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- (pentanoylamino) propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (3,3-dimethylbutanoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [ (2,2,3,3-tetramethylcyclopropyl) carbonyl] amino) propanoic acid, (2S)-2-{ [2-(1-adamantyl) acetyl] amino}-3-{ [4-(2-{ [amino (imino) methyl]- amino} ethoxy)-2-hydroxybenzoyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (pent-4-ynoylamino) propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-3-{ [4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (cyclohexylcarbonyl) amino] propanoic acid,

(2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(2- phenylacetyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(3- phenylpropanoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- cyclohexylacetyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- { [(E)-3-phenylprop-2-enoyl]amino} propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- chlorobenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(2- methylbenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(2- methoxybenzoyl) amino] propanoic acid, (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (4- chlorobenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(4- methylbenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(4- methoxybenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(pyridin-3-ylcarbonyl) amino] propanoic acid, (2S)-3-{ [4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (isonicotinoylamino) propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (2,5-dimethyl-3-furoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(2- bromobenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(4- bromobenzoyl) amino] propanoic acid,

(2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [(2, 3-dimethylbenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (3-chlorobenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (benzoylamino) propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2-[(4- ethylbenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (4- butoxybenzoyl) amino] propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- { [(benzyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[(benzylamino) carbonyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(methoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- [(ethoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- [(propoxycarbonyl) amino] propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- [(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-{[4-(2-{[(benzylamino)c arbonyl]amino}- ethoxy)-2-hydroxybenzoyl] amino} propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- {[(but-3-enyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- {[(prop-2-ynyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- {[(hexyloxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[(benzylamino) carbonyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(octyloxy) carbonyl] amino} propanoic acid,

(2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- {[(neopentyloxy)carbonyl]amino}propanoicacid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- { [(2, 2, 2-trichloroethoxy) carbonyl] amino} propanoic acid, (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy-2-hydroxyben zoyl]amino}-2- [(butoxycarbonyl)amino]propanoicacid, (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy-2-hydroxy benzoyl]amino}-2- [(isobutoxycarbonyl) arnino] propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(p yridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}amino)ethoxy]- benzoyl}amino)-2-[(methoxycarbonyl)amino]propanoicacid, (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2- [(propoxycarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2- [(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(py ridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( {[(pyridin-3- ylmethyl) amino) carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}amino)- ethoxy]benzoyl]amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}pro panoicacid, (2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(py ridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl]amino) propanoic acid, (2S)-3-{(2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}amino)- ethoxy] benzoyl} amino)-2- { [(octyloxy) carbonyl] amino} propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( { [ (pyridin-3-ylmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2-{[(neopentyloxy)carbonyl]amino} propanoic acid,

(2S)-3-({2-hydroxy-4-[2-({[pyridin-3-ylmethyl)amino]carbonyl }amino)ethoxy]- benzoyl}amino)-2-{[(2-, 2,2-trichloroethoxy) carbonyl] amino} propanoic acid, <BR> <BR> <BR> <BR> <BR> <BR> (2S)-2-[(butoxycarbonyl) amino]-3-({2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl) arnino]- carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-3-ylmethyl)amino]carbonyl }amino)- ethoxy] benzoyl} arnino)-2-[(isobutoxycarbonyl)[(isobutoxycarbonyl) amino] propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[py ridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2-[(methoxycarbonyl) amino] propanoic acid, (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-3-ylmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2- [ (propoxycarbonyl) amino] propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-4-ylmethyl)amino]carbonyl }amino)- ethoxy] benzoyl} amino)-2- [(isopropoxycarbonyl) amino] propanoic acid, (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[pyr idin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( {[pyridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-4-ylmethyl)amino]carbonyl }amino)- ethoxy] benzoyl} amino)-2- { [(prop-2-ynyloxy) carbonyl] amino} propanoic acid, (2S)-2-{ [(hexyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3- ( {2-hydroxy-4- [2- ( { [ (pyridm-4-yLmethyl) amino] carbonyl} amino)- ethoxy] benzoyl} amino)-2-{[(octyloxy)carbonyl]amino}propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-4-ylmethyl)amino]carbonyl }amino)- ethoxy] benzoyl}amino)-2-{[(neopentyloxy)carbonyl]amino} propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-4-ylmethyl) amino] carbonyl} amino)- ethoxy]benzoyl}amino)-2-{[(2, 2,2-trichloroethoxy) carbonyl] amino} propanoic acid,

(2S)-2-[(butoxycarbonyl)amino}-3-({2-hydroxy-4-[2-({[pyridin -4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-3-({2-hydroxy-4-[2-({[pyridin-4-ylmethyl)amino]carbonyl }amino)- ethoxyJbenzoyl} amino)-2- [ (isobutoxycarbonyl) amino] propanoic acid, (2S)-2-[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(4- methylbenzyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(4- methylbenzyl)- amino] carbonyl} amino) ethoxy) benzoyl} amino) propanoic acid, (2S)-2-[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(4-chlorobenz yl)amino]carbonyl}- amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-[(benzyloxy)carbonyl]amino}-3-({4-{2-[({[4-(dimethyla mino)benzyl]amino}- carbonyl) amino] ethoxy}-2-hydroxybenzoyl) amino] propanoic acid, (2S)-3-[(4- {2-[( { [4-(aminosulfonyl) benzyl] amino} carbonyl) amino] ethoxy}-2- hydroxybenzoyl)amino]-2-{[(benzyloxy)carbonyl]amino}propanoi cacid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2-hydroxy-4-{2-[({[4 -(trifluoromethoxy)- benzyl] amino) carbonyl) amino] ethoxy} benzoyl) amino] propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2-chloroben zyl)amino]carbonyl}- amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(2 -methylbenzyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2-bromobenz yl)amino]- carbonyl} amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2,4-dichlor obenzyl)amino]- carbonyl} amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid, (2S)-3-({4-[2-({[(2-aminobenzyl)amino]carbonyl}amino)ethoxy] -2-hydroxybenzoyl}- amino)-2-{[(benzyloxy)carbonyl]amino}propanoicacid, (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(p yridin-2-ylmethyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid, (2S)-2-Benzenesulfonylamino-3- (2-hydroxy-4- [3- (1,4,5,6-tetrahydropyrimidin-2- ylamino)-propoxy]-benzoylamino)-propionic acid,

(2S)-2-Benzenesulfonylamino-3- (2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino)-ethoxy]-benzoylamino}-propionic acid tert-butyl ester, (2S)-2-Benz4enesulfonylamino-3-{2-hydroxy-5-[4-(pyrimidin-2- ylamino)- butoxy]-benzoylamino}-propionic acid, 3- {2-Hydroxy-5- [3- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino)-propoxyl- benzoylamino)-3-phenyl-propionic acid ethyl ester, (2S)-2-Benzenesulfonylamino-3- {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydro- pyrimidin-2-ylamino)-ethoxy]-benzoylamino}-propionic acid 2-(2-tert-butoxy- carbonylamino-ethoxy)-ethyl ester, (2S)-2-Benzenesulfonylamino-3- {2-hydroxy-5-[4-(1, 4,5,6- tetrahydropyrimidin-2-ylamino)-butoxy]-benzoylamino}-propion ic acid ethyl ester, (2S)-2-Benzenesulfonylamino-3-{2-hydroxy-4- [3- (pyrimidin-2-ylamino)- propoxy]-benzoylamino}-propionic acid, 3-{2-Hydroxy-5-[3-(pyrimidin-2-ylamino)-propxoyl]-benzoylami no]-3-phenyl- propionic acid, (2S)-2- {Adamantan-1-yloxycarbonylamino)-3- {2-hydroxy-4-[2-(1,4,5, 6- tetrahydro-pyrimidin-2-ylamino)-ethoxy]-benzoylamino)-propio nic acid, (2S)-2-Benzenesulfonylamino-3-(2-hydroxy-4-[3-(1, 2-ylamino)-propoxy]-benzoylamino)-propionic acid ethyl ester, 3- {2-Hydroxy-5- [3- (pyrimidin-2-ylamino)-propoxy)-benzoylamino)-3-phenyl- propionic acid ethyl ester, (2S)-2-(Adamantan-1-ylmethoxycarbonylamino)-3-{2-hydrox-4-[2 -(1, 4,5,6- tetrahydro-pyrimidin-2-ylamino)-ethoxy]-benzoylamino}-propio nicacid, (2S)-2-Benzenesulfonylamino-3- {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydro- pyrimidin-2-ylamino)-ethoxy]-benzoylamino}-propionic acid isopropyl ester, (2S)-2-tert-Butoxycarbonylamino-3-{2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrirnidin-2-ylamino)-ethoxy]-benzoylamino}-propionic acid, (2S)-2-Benzenesulfonylamino-3- {2-hydroxy-5- [4- (1,4,5,6-tetrahydro- pyrimidin-2-ylamino)-butoxy]-benzoylamino}-propionic acid,

2 (S)-Benzenesulfonylamino-3- [2-hydroxy-4- (2-pyrimidin-2-ylamino) ethoxy]- benzoylamino] propionic acid ethyl ester, 2 (S)-Benzenesulfonylamino-3- [2-hydroxy-4- (2-pyrimidin-2-ylamino) ethoxy]- benzoylamino] propionic acid, 2 (S)-Benzenesulfonylamino-3- [2-hydroxy- 4- [2- (3,4,5,6-tetrahydropyrimidin- 2-ylamino) ethoxy] benzoylamino] propionic acid hydrochloride, 2 (S)-Benzenesulfonylamino-3- [2-hydroxy-4-(2-pyrimidin-2-ylamino) ethoxy]- benzoylamino] propionic acid ethyl ester hydrochloride, 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro- pyrirnidin-2-ylamino) ethoxy] benzoylamino] propionic acid ethyl ester hydrochloride, 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoylamino] propionic acid hydrochloride, 3- [4- (2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoi c acid ethyl ester hydrochloride, 3- [4- (2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoi c acid hydrochloride, 3- [2-hydroxy-4- [2- (pyrimidin-2-ylamino)-ethoxy] benzoylamino]-3-pyridin-3- yl-propanoic acid ethyl ester, 3- [2-hydroxy-4- [2- (pyrimidin-2-ylamino)-ethoxy] benzoylamino]-3-pyridin-3- yl-propanoic acid, 3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro-pyrimidin-2-ylamino) ethoxy] benzoyl- amino]-3-pyridin-3-yl-propanoic acid ethyl ester dihydro-chloride, 3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro-pyrimidin-2-ylarnino) ethoxy] benzoyl- amino]-3-pyridin-3-yl-propanoic acid, 3- [4- (2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid ethyl ester dihydrochloride,

3- [4- (2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid, 3- [2-hydroxy-4- [2- (pyrimidin-2-ylamino)-ethoxy] benzoyl-amino]-3-phenyl- propanoic acid ethyl ester, 3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy] benzoyl-amino]-3-phenyl- propanoic acid hydrochloride, 3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro-pyrimidin-2-ylamino) ethoxy]- benzoylamino]-3-phenyl-propanoic acid ethyl ester hydrochloride, 3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro-pyrimidin-2-ylamino) ethoxy]- benzoylamino]-3-phenyl-propanoic acid, 3- [2-hydroxy-5- [3- (pyrimidin-2-ylamino)-propoxy]-benzoylamino]-3-phenyl- propanoic acid ethyl ester, 3- [2-hydroxy-5- [3- (pyrimidin-2-ylamino)-propoxy]-benzoylamino]-3-phenyl- propanoic acid, 3- [2-hydroxy-5- [3- (3,4,5,6-tetrahydro-pyrimidin-2-ylamino) propoxy]- benzoylamino]-3-phenyl-propanoic acid ethyl ester hydrochloride, <BR> <BR> <BR> <BR> <BR> <BR> 3- [2-hydroxy-5- [3- (3,4,5,6-tetrahydro-pyrimidin-2-ylamino) propoxy]-<BR> <BR> <BR> <BR> <BR> <BR> <BR> benzoylamino]-3-phenyl-propanoic, 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (pyrimidin-2- ylamino) ethoxy]-benzoylamino] propionic acid ethyl ester hydro-chloride, 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (pyrimidin-2- ylamino) ethoxy]-benzoylamino] propionic acid methyl ester, 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (pyrimidin-2- ylamino) ethoxy]-benzoylamino] propionic acid, 2 (S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-methyl-pyrimidin- 2-ylamino)- ethoxy] benzoylamino] propionic acid, and

2-Amino-3- [2-hydroxy-4- [2- (3,4,5,6-tetra-hydropyrimidin-2-ylamino) ethoxy]- benzoylamino] propionic acid dihydrochloride, or pharmaceutical salts thereof.

It is understood that the definition of compounds of Formula (I) include racemates, (racemic mixtures) and individual enantiomers or diastereomers. AH asymmetric forms, individual isomers and combinations thereof are within the scope of the present invention.

Optically active isomers may be prepared, for example by resolving the racemic mixtures. The resolution can be carried out by methods known to those skilled in the art such as in the presence of resolving agent, by chiral chromatography, or combinations thereof.

Compounds of Formula I are useful in methods of selectively inhibiting or antagonizing an integrin receptor such as avb3. More specifically, methods of the present invention include but are not limited to methods of inhibiting cancer (tumor metastasis, tumorgenesis/tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone matastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and viral infection by administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The compounds of this invention are prepared in accordance with the solid phase combinatorial library synthesis methods or solution phase synthesis methods.

Generally, to prepare the compounds via combinatorial methodology, the starting acylresorcinol ester is condensed with an alkylene chain bearing a terminal primary amino group which is suitably blocked/protected. Methods for this condensation include, but are not limited to selective alkylation of one (the non-H- bonded hydroxyl group) of the resorcinol hydroxy groups, using standard procedures such as the Gabriel synthesis (Angew Chem. Int. Ed. Engl. 7,1968,919-930 (1968) or Mitsunobu reaction (Synthesis, 1981,1-28). After conventional deprotection of the N-

terminus and the acid, the amine 2-2 was protected as fluorenylmethyloxy carbamate (Fmoc) 2-6. On the other hand, in the case of G = pyrimidine 2-3, the primary amine 2-2 was activated with trimethylsilyl chloride in the presence of 2-bromopyrimidine in refluxing (anhydrous) 1,4-dioxane. The carboxylic acid 2-3 was activated as pentafluorophenyl ester 2-5. The carboxylic acid 2-3 was also hydrogenated under catalytic hydrogenation conditions to obtain the tetrahydropyrimidine derivative 2-4.

Orthogonally protected 2,3-diamino propionic acid 1-1 was used for carboxylic acid terminus and was immobilized on polymer support with linkers like but not limited to Wang. The 2-amino group of the 2,3-diaminopropionic acid was Fmoc protected, while the 3-amino group was dde (4,4-dimethyl-2,6-dioxocyclohex-1- ylideneethyl) protected. The 2-amino group was deprotected and further derivatized to and 1-7 using various acylating agents including but not limitted to chloroformates, isocyanates, sulfonyl chlorides, carboxylic acids/chlorides. The 3- amino group was deprotected to give 1-8,1-9,1-10 and 1-11 and coupled with the resorcinol acid derivatives 2-4,2-5 or 2-6.

N-terminus derivatives such as dihydroimidazole 5-3, azepine 5-4, guanidine 6- 3, and ureas 6-4 were prepared from common primary amine intermediate 4-2.

Schemes 1-6, below, demonstrate the solid phase synthesis practice of this invention as it relates to the examples specified. Detailed synthetic procedures for representative compounds of this invention follow.

Throughout the Examples data for LC (@254 nM) were obtained under the following conditions. HP 1100,23oC, 10RL injected; Column: YMC-ODS-A 4.6 x 50 5,; Gradient A: 0.05% TFA/Water, B: 0.05% TFA/Acetonitrile Time 0 & 1 min: 98% A &2% B; 7 min: 10% A & 90% B; 8 mm: 10% A & 90% B; 8.9 min: 98% A & 2% B; Post time 1 min; Flow rate 2.5 mL min.; Detection: 215 and 254 nm, DAD.

Scheme 1 0 0 OH + N'-OH NHFmoc 1-1 HOBT,HBTU DIEA, DMF 0 O O y "NHFmoc dde, Xf zoo O 20% Piperidine DMF (CH3) 3CCH2OCOCI 9 PhCOOH, DIC Et3N, CH2C12 H e < DMAP, DMF FO H NH2 0 O O dde, ddeN+°o> PhNCO hSO2CI ddesN<sOmx HN°/Et3 XEt3N HN>O 0 0 0 1-7 Ph O p Ph dde. N^ O dde, N 0.. 2°/a NH NH H T H 2% NH2NH2 HNO HNs SO2 DMF DMF S02 1-5 NHPh 1-6 Ph 0 2% NH2NH2 2% NH2NH2 O in DMF DMF II HN 0 0 0 HN HNO- O H2N/v\O (' H2N0 O Ph HN. 0 HN 1-8 S02 NHPh Ph 1-9 1-10

2 (S)- (Fluorenylmethyloxvcarbonyl) arnino-3- (4, 4-dimethyl-2, 6dioxocvlohex-1- ylideneethyl) aminopropionic Acid on Wang Resin (1-2) Wang resin (Wang, S. J. Am. Chem. Soc. (Advanced ChemTech 200-400 mesh, 1% crosslinked; loading: 0.92 mmol/g; 5g, 4.6 mmol) was swollen in N, N-dimethylformamide (DMF) (20 mL). A solution of N-a-fmoc-N-b-1- (4,4-dimethyl-2, 6-dioxocyclohex-1-ylidene) ethyl-L-diaminopropionic acid 1-1 (Fmoc- Dpr (Dde)-OH) (Nova Biochem) 9.2 mmol) in DMF (30mL) was treated with N-hydroxybenzotriazole (HOBT) (1.242g; 9.2 mmol), 2- (1H-benzotriazole-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) 9.2 mmol) and N, N-diisopropylethylamine (DIEA) (3.2 mL; 18.4 mmol) and added to the resin. The mixture was shaken at room temperature for 8 h. The mixture was filtered and the resin was washed with DMF (3 x 40mL), methanol (MeOH) (3 x 40mL) and dichloromethane (DCM) (3x 40mL). The resin was dried in vacuo to give 6.956g.

Resin Loading: 0.8 mmol/g.

2-Arnino-3-(4, 4-dimethYl-2. 6-dioxocvlohex-l-ylideneethvl) aminopropionic(4, 4-dimethYl-2. 6-dioxocvlohex-l-ylideneethvl) aminopropionic Acid on Wang Resin (1-3) The resin 1-2 (6.956 g) in DMF was treated with 20% piperidine in DMF (40mL) for 10 min and filtered. Another 40mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3 x 40mL), MeOH (3 x 40mL) and DCM (3 x 40mL). The resin (1-3) was dried in vacuo.

2 (S)-(2, 2-Dimethyl-propoxvCarbonylamino)-3-(4, 4-dimethyl-26-dioxocylohex-1- vlideneethyl) amino-propionic acid on Wang Resin (1-4) The resin 1-3 (925 mg; 0.75 mmol) was swollen in dichloromethane and treated with diisopropylethylamine (969 mg; 1.3 mL; 7.5 mmol) followed by neopentyl

chloroformate (451.8 mg; 3mmol). The reaction mixture was shaken at room temperature using orbital shaker (Thermolyne RotoMix Type 50800) for 18 h. The mixture were filtered and the resin was washed with dichloromethane (4 x 4 mL), _ methanol (4 x mL) and dichloromethane (2 x 4 mL). The resins was dried under vacuum. A sample of the was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

A sample of the resin was removed and subjected to cleavage with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 mm at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 4.28 min (82% @ 220 nm); MS: 383 (M+H) +.

The above reaction conditions were applied for synthesis of urea 1-5 and sulfonamide 1-6, using phenyl isocyanate and phenyl sulfonyl chloride, respectively, in the place of neopentyl chloroformate.

A number of chloroformates, isocyanates and sulfonyl chlorides were used in the above reaction.

2 (S)-benzoylamino-3- (4, 4-dimethyl-2. 6-dioxocylohex-1-ylideneethyl) amino-propionic acid on Wang Resin (1-7) The resin 1-3 (925 mg; 0.75 mmol) was washed with DMF to swell the resin.

A solution of benzoic acid (183 mg; 1. Smmole) in DMF was mixed with diisopropylcarbodiimide (192 mg; 0.25 mmole), hydroxybenzotriazole (228 mg; 1.5 mmole) and dimethylaminopyridine (18 mg; 1.5 mmole) and the mixture was added to the resin. The reaction mixture was shaken at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol

(4 x mL) and dichloromethane (4 x 4 mL). The resulting resin 1-7 was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described_ above was repeated.

Alternately, carboxylic acids were used in the above reaction in the place of benzoic acid.

3-Amino-2 (S)- (2. 2-dimethyl-propoxycarbonylamino)-propionic acid on Wana Resin The resin 1-4 was shaken with a solution of 2% hydrazine in dimethylformamide (3mL) for 5 mm. at room temperature. The reaction mixture was filtered and an additional 3 mL of a solution of 2% hydrazine in dimethylformamide was added and the reaction mixture was shaken at room temperature for 5 mm. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test for the presence of free amine (resin turns blue).

A sample of the resin was removed and subjected to cleavage with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 mm at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 4.686 min (78% @ 220 nm); MS m/z 219 (M+H) +.

Resin bound compounds 1-5,1-6 and 1-7 were subjected to similar deprotection condition to afford the free amines 1-9,1-10 and 1-11 respectively.

Scheme 2 OH 0 OMe + cHN OH OU HO \ Aldrich Aldrich DEAD Ph3P, THF OH O OMe BocHN,. oe u 2-1 1. KOH 2. HCI OH O OH HCI. H2N Oi\ 0 DIEA, TMSCI 2-2 \ FMOC-OSu/Na2CO3 Acetone-H20 lN OU O OH 0 OH 0 H o¢OH FmocHN O) OH T-F F 0 2-6 zon F OH H2, DCC, DIEA HCI-HO F F /\. F F OH O OH O F OH H p F CL wN 2-5 2-4-

benzoate(2-1)Methyl4-[2-N-(t-butoxycarbonyl)ethoxy]-2-hydrox y Methyl 2,4-dihydroxy benzoate (14.5g, Aldrich), 2- (N-t-butoxycarbonyl) ethanol (13.9g, Aldrich) and triphenyl phosphine (22.6g, Aldrich) were combined in 350 mL of THF and cooled in ice under N2 atmosphere. Diethyl diazodicarboxylate (DEAD,

15g, Aldrich) was added, the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 15h. The solvent was removed on a rotary evaporator and the residue chromatographed on silica gel (300g, Merck silica 60), elution with CH2CI2 to give 18g of methyl 4- [2-N- (t-butoxycarbonyl) ethoxy]-2-hydroxy benzoate, as a viscous oil. NMR (300 MHz, CDC13) 5 11. 0 (s, 1 H), 9.5 (d, J = 8Hz, 1H), 6.4 (m, 2H), 5.0 (broad, 1H), 4.0 (t, J = 5Hz, 2H), 3.91 (s, 3H), 3.54 (m, 2H), 1.45 (s, 9H), MS (+ESI) m/z 334 (M+Na) +.

4- (2-Aminoethoxy)-2-hydroxybenzoic acid. hydrochloride (2-2) Ester 2-1 (7.2g) was treated with 5eq. KOH (dissolved in mmimum amount of water and equal volume of 1,4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h). The reaction mixture was acidified (pH = 6) with the addition of IN HCl solution and extracted with ethyl acetate. The extract was washed with saturated aqueous brine solution, dried over Mus04, filtered and concentrated on the rotary evaporator. The crude product (5.34g) was recrystallized from ether, then dissolved in 1,4-dioxane and treated with an excess of anhydrous HCl (4M in dioxane, Aldrich). The mixture was allowed to stand at ambient temperature for 24h. Volatile materials were removed in vacuo on the rotary evaporator to give 2-2 as a hydroscopic off-white solid. NMR (400 MHz, DMSO-d6) 8 13.6 (broad, 1H), 11.6 (broad, 1H), 8.3 (broad, 3H), 7.7 (d, J = 9 Hz, 2H), 6.53 (m, 2H), 4.23 (t, J = 5Hz, 2H), 3.2 (s, broad, 2H).

2-Hydroxy-4-r2- (pyrimidine-2ylamino) ethoxylbenzoic acid (2-3) A mixture of compound 2-2 (20g), diissopropylethylamine (DIPEA, 74 mL), trimethylsilylchloride (TMSCl, 21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5g) were combined in 350 mL 1,4-dioxane at room temperature, then brought to reflux under N2 atmosphere. After 2 days, an additional 12 mL trimethylsilyl chloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed

no stating material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give <BR> <BR> <BR> <BR> 15.3g of 2-3, as a tan powder. NMR (400 MHz, DMSO-d6) b 12 (very broad, 2H) 8.3 (d, J = 5 Hz, 2H) 7.7 (d, J = 9Hz, 1 H), 7.28 (t, J = 6Hz, 1H), 6.57 (t, J = 5Hz, 1H), 6.49 (m, 2H), 4.13 (t, J = 6Hz, 2H), 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H) + ; IR (KBr) v (cl'') 3275,3000,1660,1625.

2-Hydroxv-4-f2-(3,4. 5,6-tetrahydropyrimidin-2ylamino) ethoxyl-benzoic acid (2-4).

Compound 2-3 (2g) was combined with 10% Pd/C (0.5g), acetic acid (100 mL) and concentrated hydrochloric acid (0.7 mL). The mixture was stirred at room temperature under an atmosphere of H2 (balloon) for 2 days. Celite was added and the mixture stirred for 0.5h, then filtered through a pad of celite with the aid of isopropanol. Volatile materials were removed on the rotary evaporator and the residue warmed with heptane (-0.5h, 100°C) followed by concentration in vacuo to give 2-4 as a tan foam. NMR (400 MHz, DMSO-d6) # 12.9 (broad, 2H), 8.25 (s, <BR> <BR> <BR> <BR> broad, 2H), 7.85 (t, J = 6Hz, 1H), 7.66 (d, J = 9 Hz, 1H), 6.48-6.41 (m, 2H), 4.07 (t, J = 5Hz, 2H), 3.56-3.50 (m, 2H), 3.22 (m, 2H, overlapping with H20 peak), 1.79 (m, 2H); IR (KBr) n (crin') 3450 (broad); MS (+ESI) m/z 280 (M + H) +.

2,3,4,5.6-Pentafluorophenvl 2-hydroxy-4-f 2- (pyrimidine-2-ylamino) ethoxYl-benzoate Acid 2-3 (1.18g; 4.3 mmol) in dioxane (40 mL) was treated with DIEA (1.5 mL; 8.6 mmol) and cooled to 0°C. Pentafluorophenol (3.16g; 17.2 mmol) was added followed by dicyclohexyl carbodiimide. The reaction mixture was allowed to warm to room temperature and stirred for additional 16 h. The solid precipitated was filtered off and the mother liquor was concentrated to dryness and the residue was purified using silica

column chromatography, eluted with 50% ethyl acetate in hexane to give 1.01 g of 2- 5 as a white solid. NMR (300 MHz, CDCl3) S 10.0 (s, 1H), 8.3 (d, J = 5 Hz, 2H) 8.0 <BR> <BR> <BR> <BR> (d, J = 9Hz, 1H), 6.57 (t, J = 5Hz, 1H), 6.49 (m, 2H), 5.5 (t, J = 3Hz, 1H), 4.2 (t, J = 6Hz, 2H), 3.9 (q, 2H).

4-r(2-fluorenylmethyloxycarbonylamino) ethoxyl-2-hydroxybenzoic acid (2-6) The Amino acid 2-2 8 mmol) was dissolved in 1: 1 acetone-water (50 mL) containing sodium carbonate 16 mmol). To the solution was added Fmoc- Osu (2.696 g ; 8 mmol) in acetone (25 mL) dropwise at room temperature. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was dissolved in water and extracted with ether (2 x 50 mL). The aqueous layer was cooled in an ice bath and acidified with 6N HCl to pH 3.

The solid obtained was filtered and washed with water and dried under vacuo (3.22g).

NMR (300 MHz, DMSO-d6) 8 7.9 (d, 2H), 7.65-7. 75 (m, 2H), 7.55 (t, 2H), 7.4 (t, 2H), 7.3 (t, 2H), 6.5 (m, 2H), 4.35 (d, 2H), 4.25 (t, 1H), 4.05 (t, 2H), 3.4 (t, 2H).

Scheme 3 o H2N90 O HNO- . _ I \ OH O O OH O Phi ; /OH 18 I NYNO/O N r F NH 2-4/\% N 2-5 1 DIC, DMAP, DMF Path A Path BMF PhF _ F F OH O O OH 0 0 , No' H HN O H H0 O N\ N HN O- NH 3'1 p N O 3_3 O- TFA-CH2CI2 (1 : 1) TFA-CH2CI2 (1: 1) OH 0 0 OH 0 0 KOH HOJHN+OH H oN O . 3-2 O CN H HN (O O il C 3-2 O I 3-4

Example 1 (2S)-3- ( {2-hydroxy-4- [2- (1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino)-2-{ [(neopentyloxy) carbonyl] amino} propanoic acid (3-2) (2S)-3- (2-h droxv-4-f2- (1, 4, 5, 6-tetrahydropyrimidin-2-ylaminolethoxylbenzoyl amino)-2-f r (neopentvloxy) carbonyllaminopropanoic acid on Wang Resin (3-1) The resin 1-8 (lOOmg) was washed with DMF to swell the resin. A solution of 2-hydroxy-4- [2- (3,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy]-benzoic acid 2-4 (70 mg; 0.25mmole) in DMF was mixed with diisopropylcarbodiimide (32 mg; 0.25 mmole), hydroxybenzotriazole (38mg; 0.25 mmole) and dimethylaminopyridine (3 mg; 0.025 mmole) and the mixture was added to the resin. The reaction mixture was shaken at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resulting resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

The resin 3-1 was treated with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 3-2 was purified via preparative HPLC. NMR (400MHz, MeOH-d4) 8 7.7 (d, J = 7 Hz, 1H), 6.5 (m, 2H), 4.45 (q, 1H), 4.1 (t, 2H), 3.8-3.65 (m, 4H), 3.55 (t, 2H), 3.35 (t, 4H), 2.0 (m, 2H), 0.9 (s, 9H).

HR-MS FAB m/z for C22H33N507calcd. 480.2458 (M++1), obsd. 480.2431.

The following compounds were synthesized as described in the above Scheme 3 (Path A), using various resin bound carbamates in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 1.

Example 2 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(methoxycarbonyl) amino] propanoic[(methoxycarbonyl) amino] propanoic acid.

Example 3 <BR> <BR> (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 4 (2S)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl]- amino)-2-[(propoxycarbonyl)[(propoxycarbonyl) amino] propanoic acid.

Example 5 (2S)-3-({2-hydroxy-4-[2-(1,4,5,6-tetrahydroprimidin-2-ylamin o)ethoxy]benzoyl}- amino)-2-[(isopropoxycarbonyl) amino] propanoic[(isopropoxycarbonyl) amino] propanoic acid.

Example 6 (2S)-2-{[(allyloxy)carbonyl]amino]-3-({2-hydroxy-4-[2-(1,4,5 ,6-tetrahydropyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 7 (2S)-2- { [ (but-3-enyloxy) carbonyl] amino}-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 8 (2S)-2-{[(exyloxy)carbonyl]amino}-3-({2-hydroy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 9 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(octyloxy) carbonyl] amino} propanoic acid.

Example 10 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy]- benzoyl} amino)-2- { [ (2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid.

Example 11 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy]- benzoyl} amino)-2-[(butoxycarbonyl) amino] propanoic[(butoxycarbonyl) amino] propanoic acid.

Example 12 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(isobutoxycarbonyl)amino]propanoicacid.

Example 13 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5, 6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}propanoicacid.

Example 14 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(1, 4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Table 1 Ex. @254(M+H)+Ex.R9LC@254(M+H)+LC nm nm 2.92min4248n-Hexyl4.12min4942Methyl 3 Ethyl min 522 4 n-Propyl 3.30 min 452 1 (CH3) 3CCH2 3.77 min 480 5 i-Propyl 3.28 min 452 10 (CC13) 3CCH2 3.81 min 542 6 Allyl 3.21 min 450 11 n-Butyl 3. 60 min 466 7 Homoallyl 3.46 min 463 12 i-Butyl 3.58 min 466 13 Propargyl 3.18 min 448 14 Benzyl 3.74 min 500

The following compounds were synthesized as described in the above Scheme 3, (Path A) using various resin linked ureas 1-9 in the place of carbamate (1-8). These compounds were characterized using LC and MS as shown in Table 2.

Example 15 (2S)-2-{ [(butylamino) carbonyl] amino}-3- ( {2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 16 (2S)-3-{[(hexylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1,4 ,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid.

Example 17 (2S)-3-({2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimdin-2-ylamin o)ethoxy]benzoyl}- amino)-2-{[(octylamino)carbonyl]amino}propanoicacid.

Example 18 (2S)-2-{[(allylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1,4 ,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid.

Example 19 (2S)-2-{[(1-allylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(1 , 4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 20 (2S)-2-[(anilinocarbonyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 21 (2S)-2-{[(acyclohexylamino)carbonyl]amino}-3-({2-hydroxy-4-[ 2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 22 (2S)-2-{ [(benzylamino) carbonyl] amino}-3-(t 2-hydroxy-4-[2-(1,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 23 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (4-toluidinocarbonyl) amino] propanoic acid.

Example 24 (2S)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [(2-toluidinocarbonyl) amino] propanoic acid.

Example 25 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(2-methoxyanilino) carbonyl] amino} propanoic acid.

Example 26 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(4-methoxyanilino) carbonyl] amino} propanoic acid.

Example 27 (2S)-2-{[(2-chloroanilino) carbonyl] amino}-3- ( {2-hydroxy-4- [2- ( 1,4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 28 (2S)-2-{[(2-bromoanilino) carbonyl] amino}-3- ( {2-hydroxy-4-[2-(1, 4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 29 (2S)-2-{[(1,1'-biphenyl]-2-ylamino)cabonyl]amino)-3-({2-hydr oxy-4-[2-(1, 4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 30 (2S)-2-{[(4-chloroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(1,4,5,6- tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid.

Example 31 (2S)-3-({2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylami no)ethoxy]benzoyl- amino)-2-{[(1-naphthylamino)carbonyl]amino}propanoicacid.

Example 32 (2S)-3-({2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylami no)ethoxy]benzoyl- amino)-2-{[(2-phenylethyl)amino]carbonyl}amino)propanoic acid.

Table 2 Ex. R9 LC @ 25J llm (M+H) + T = LC iD 254 = nm 15 H3Ct 3.30 min 465 24 3. 45 min 499 CH, 16"3w 3. 77 min 493 25 iril-Ir 3.50 min 515 OH 17 H, c 4.31 min 521 26 z 3 39 min 515 ce 1802 min 449 27 21 ce 19 4. 00 min 543 28 3. 60 min 565 e 20 3. 42 min 485 29 C ; 3-95 mi n 561 3. 95 min 561 Ph 21 3. 45 min 491 30 ce 22 673. 43 min 499 31 3. min 535 . 23 499 32 rl"k 3.56 min 513 k---,

The following compounds were synthesized as described in the above Scheme 3, (Path A) using various resin linked amides 1-11 in the place of carbamate (1-8). These compounds were characterized using LC and MS as shown in Table 3.

Example 33 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- (isobutyrylamino) propanoic acid.

Example 34 (2S)-2-(hexanoylamino)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl) amino) propanoic acid.

Example 35 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-(pentanoylamino)propanoicacid.

Example 36 (2S)-2-[(3, 3-dimethylbutanoyl) amino]-3-( {2-hydroxy-4-[2-(1,4, 5, 6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 37 <BR> <BR> (2S)-2-[(cyclohexylcarbonyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 38 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- arnino)-2-[(2-phenylacetyl) amino] propanoic[(2-phenylacetyl) amino] propanoic acid.

Example 39 (2S)-3= ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (3-phenylpropanoyl) amino] propanoic acid.

Example 40 <BR> <BR> (2S)-2-[(2-cyclohexylacetyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 41 (2S)-3- ( {2-hydroxy-4- [2- ( 1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-f [ (E)-3-phenylprop-2-enoyl] amino) propanoic acid.

Example 42 <BR> <BR> (2S)-2-[(2-chlorobenzoyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 43 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino)-2- [(2-methylbenzoyl) amino] propanoic acid.

Example 44 (2S)-3-({2-hydroxy-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(2-methoxybenzoyl) amino][(2-methoxybenzoyl) amino] propanoic acid.

Example 45 (2S)-2-[(4-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 46 (2S)-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2- [ (4-methylbenzoyl) amino] propanoic acid.

Example 47 (2S)-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-[(4-methoxybenzoyl) amino][(4-methoxybenzoyl) amino] propanoic acid.

Example 48 (2S)-2-[(2,5-dimethyl-3-furoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 49 (2S)-2-[(2-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 50 (2S)-2-[(4-bromobenzoyl))amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 51 (2S)-2-[(2,3-dimethylbenzoyl)amino]-3-({2-hydroxy-4-[2-(1, 4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 52 <BR> <BR> (2S)-2-[(3-chlorobenzoyl) amino]-3-( {2-hydroxy-4-[2-(1,4,5,6-tetrahydropyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Table 3 Ex. R9 LC @ 254 nm (M+H) + Ex. R9 LC @ 254 nm (M+H) + 33"3Y 3.03 min 436 43 42 min 484 H3C/CH 34 H3C 3.46 rrn 464 44 3.48 min 500 OCH3 35 H, c- 3.24 min 450 45 3. 70 min 504 cl 36 3.37 min 464 | 46 HX H 37 3. 49 min 476 47 HCOv 3. 44 min 500 ho 38 484 48 H3CtCH3 3.59 min 488 39 3.54 min 498 49 3.39 min 548 ex 40 3.62 min 490 50 3 76 min 548 B 41 O~f/3. 66 min 496 51 CH, 3.58 min 498 CH, CH, 42 36 min50452 3. 70 min 504 ci ce Example 53 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl}- amino)-2-{[(neopentyloxy){[(neopentyloxy) carbonyl] amino} propanoic acid (3-4) (2S)-3- (2-hvdroxy-4-r2- (pvrimidin-2-vlamino) ethoxylbenzoyl ? amino)-2- f (neopentyloxy) carbonvllamino} propanoic acid on Wang Resin (3-3) The resin 1-8 (100mg) was washed with DMF to swell the resin and was treated with a solution of 2,3,4,5,6-pentafluorophenyl 2-hydroxy-4- [2- (pyrimidine-2- ylamino) ethoxy]-benzoate 2-5 (110 mg; 0.25mmole) in DMF. The reaction mixture was shaken at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resulting resin 3-3 was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

The resin 3-3 was treated with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 3-4 was purified via preparative HPLC. 3.907 min (78% @ 220 nm); MS m/z 476 (M+H) +.

The following compounds were synthesized as described in the above Scheme 3 (Path B), using various resin bound carbamates in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 4.

Example 54 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2- [(phenoxycarbonyl) amino] propanoic acid.

Example 55 (2S)-2- { [ (benzyloxy) carbonyl] amino}-3- ( {2-hydroxy-4- [2- (pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 56 (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [ (isobutoxycarbonyl) amino] propanoic acid.

Example 57 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(4- methoxyphenoxy) carbonyl] amino} propanoic acid.

Example 58 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2- { [ (octyloxy) carbonyl] amino} propanoic acid.

Example 59 (2S)-2-[(butoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 60 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(2,2,2- trichloroethoxy) carbonyl] amino} propanoic acid.

Example 61 (2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- ( { [ (4- nitrobenzyl) oxy] carbonyl}amino) propanoic acid.

Example 62 (2S)-2-{ [(hexyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid.

Example 63 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(prop-2- ynyloxy) carbonyl] amino} propanoic acid.

Example 64 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(4- methylphenoxy) carbonyl] amino} propanoic acid.

Example 65 (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [ (methoxycarbonyl) amino] propanoic acid.

Example 66 (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid.

Example 67 (2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [(propoxycarbonyl) amino] propanoic acid.

Example 68 (2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [(isopropoxycarbonyl) amino] propanoic acid.

Example 69 (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrim idin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 70 (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Table 4 Ex. @254nm(M+H)+Ex.R9LC@254nm(M+H)+LC 54 Phenyl 3. 77 min 481 62 n-Hexyl 4. 26 min 490 55 Benzyl 3.88 min 495 63 Propargyl 3. 30 min 444 56 i-Butyl 3.73 min46164p-Me-Phenyt3.94 v 496 57 p-OMe-phenyl 3.75 min 511 65 Methyl 3. 06 v 420 58 Octyl 4.79 min 517 66 Ethyl 3.26 min 434 59 n-Butyl 3. 77 min 462 67 n-Propyl 3.48 v 448 60 CCl3CH2 3. 94 min 538 68 i-Propyl 3.46 v 448 53 neopentyl 3.90 min 476 69 Ailyl 3.40 min 446 61 p-N02-Benzyl 3.80 min 541 70 Homoallyl 3.58 min 460 The following compounds were synthesized as described in the above Scheme 3 (Path B), using various resin bound ureas 1-9 in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 5.

Example 71 <BR> <BR> (2S)-2-[(anilinocarbonyl) amino]-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy]- benzoyl} amino) propanoic acid Example 72 (2S)-2-{[(tert-butylamino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl amino) propanoic acid.

Example 73 (2S)-2-{[(butylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyr imidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 74 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(4- methoxyanilino) carbonyl] amino} propanoic acid Example 75 (2S)-2-{[(2-ethylanilino)carbonyl]amino}-3-({2-hydroxy-4-[2- (pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 76 (2S)-2-{[(allylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyr imidin-2-ylamino)- ethoxy] benzoyl} amino) propanoic acid Example 77 (2S)-2-{[(2,4-dichloroanilino)carbonyl]amino}-3-({2-hydroxy- 4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 78 (2S)-3-( {2-hydroxy-4- [2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2-[(2- toluidinocarbonyl) amino] propanoic acid.

Example 79 (2S)-3-( {2-hydroxy-4-[2-(pyrirnidin-2-ylamino) ethoxy] benzoyl} amino)-2- { [(2- methoxyanilino) carbonyl] amino} propanoic acid.

Example 80 (2S)-2-{[(2-chloroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 81 (2S)-2-{[(2-bromoanilino)carbonyl]amino}-3-({2-hydroxy-4-[2- (pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 82 (2S)-2-{[([1,1'-biphenyl]-2-ylamino)carbonyl]amino}-3-({2-hy droxy-4-[2-(pyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 83 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- [ (4- toluidinocarbonyl) amino) propanoic acid.

Example 84 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-({[4- (trifluoromethyl) anilino] carbonyl} amino) propanoic acid.

Example 85 (2S)-3- ( {2-hydroxy-4- [2- (pyrimidin-2-ylamino) ethoxy] benzoyl} amino)-2- ( { [4- (trifluoromethoxy) anilino] carbonyl} amino) propanoic acid.

Example 86 (2S)-2-{[(4-chloroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 87 (2S)-2-{[(4-fluoroanilino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 88 (2S)-2-t [(4-acetylanilino) carbonyl] amino}-3-( {2-hydroxy-4-[2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 89 (2S)-2-({[4-(ethoxycarbonyl)anilino]carbonyl)amino)-3-({2-hy droxy-4-[2-(pyrimidin- 2-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 90 (2S)-2-{[(cyclohexylamino)carbonyl]amino}-3-({2-hydroxy-4-[2 -(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 91 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-{[(1- naphthylamino) carbonyl] amino} propanoic acid.

Example 92 (2S)-2- { [(benzylamino) carbonyl] amino}-3-( {2-hydroxy-4- [2-(pyrimidin-2- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 93 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2-({[(2- phenylethyl)amino]Carbonyl}amino)propanoicacid Example 94 (2S)-3- ( {2-hydroxy-4- [2- (pyrimidm-2-yIamino) ethoxy] benzoyl} ammo)-2- {[(octylamino) carbonyl] amino} propanoic acid Table 5 Ex. R9 LC @ 254 nm (M+H)'G LC @ 254 nm = l 71 C 3. 70 min 480 83 3 79 min 495 72! 3. 45 min 460 84 FjCv 4.22 min 549 6T8 5 73 3. 50 min 460 85 4.27 min 565 74 3. 56 min 510 86 crO'3. 96 min 515 3. 56 min 510 86 3. 96 min 51 o i 75 3.81 min 508 87 3. 68 min 499 i 7613 min 444 88 88 3. 50 min 523 0 o 77 cra 4. 19 min 549 89 3. 92 min 553 cl o 0 78 3. 63 min 495 90 3.66 min 487 79 3. 68 min 511 1 3.86 min 487 00 80 j 3.78 min 515 92 ( : r 3.55 min 495 ce 81 j 3.80 min 559 93 3. 70 min 509 s 82 4. 13 min 557 94 ^ 4. 56 min 517 '-ph Scheme 4 0 H2N'\Ow HN\/O\- o 0 1-8 OHM -'-OH FmocHN OC u 2-6 DIC, DMAP, DMF OH O O I \ HO FmocHN O<J HNO 4-1 O 20% Piperidine DMF OH O O HHX < 2 4*2 O 4.2 0

(2S)-(2,2-dimethyl-propoxycarbonylamino)-3-({2-Hydroxy-4-(2- fluorenylmethyloxy- carbonvlamino) ethoxylbenzovlamino}-propionic acid on Wang Resin (4-1) The resin 1-8 was washed with DMF to swell the resin. A solution of 4- [ (2- fluorenylmethyloxycarbonylamino) ethoxy]-2-hydroxybenzoic acid (2-6) (628.5 mg; 1.5 mmole) in DMF was mixed with diisopropylcarbodiimide (189 mg; 1.5 mmole), hydroxybenzotriazole (202.5 mg; 1.5 mmole) and dimethylaminopyridine (18.33 mg; 0.15 mmole) and the mixture was added to the resin. The reaction mixture was shaken

at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL).

The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

2(S)-(2,2-dimethyl-propoxycarbonylamino)-3-({2-Hydroxy-4- (2-aminoethoxy)benzoyl- aminol-propionic acid on Wang Resin (4-2) The resin 4-1 was shaken with a solution of 20% piperidine in DMF (5mL) for 10 min and filtered. Another 5mL portion of 20% piperidine in DMF was added and shaken at room temperature for 20 mm. The resin was filtered and washed with DMF (3 x 40mL), MeOH (3 x 40mL) and DCM (3 x 40mL). The resin were dried under vacuum.

A sample of the resin was removed and subjected to cleavage with dichIoromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 mm at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 3.35 min (70% @ 220 nm); MS m/z 398 (M+H) +.

Scheme 5 OH O O OH 0 0 eN'-") rjO"-'o 4-2 0 4_2 O / DIEA, DMF, N/\ N, Dioxane N/PathA \- Path A Path A OH O O OH O O H H H H H N i HNO'N O -N 0 IN 5-3 0 |TFA (1 : 1) TFA-CH2CI2 (1: 1) OH O O OH O O H H N"RAOH OH 5-2 CX ~°< HN"O O O I N 5_2 O 5_4 O

Example 95 (2S)-3-({4-[2-(4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2- hydroxybenzoyl} amino)-2-{ [(neopentyloxy) carbonyl] amino} propanoic acid (5-2) (2S)-3-(4-F2-(4. 5-dihydro-1 H-imidazol-2-vlamino) ethoxvl-2-hydroxvbenzovl}- onWangResin(5-1)amino)-2-{[(neopentyloxy)carbonyl]amino}prop anoicacid The resin 4.2 (lOOmg; 0.1mmole) was swollen in DMF. To the resin was added a solution of 2- (3, 5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide (123 mg; 0.5 mmole) in DMF (1.5 mL) followed by diisopropylamine (0.15 mL; 1 mmole). The reaction vessel was shaken at 60 °C for 18h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

The resin 5-1 was cleaved by treatment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated@ and dried in vacuo on a Savant Speed Vac Plus. This crude product 5-2 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) 5 7.7 (d, J = 7 Hz, 1H), 6.5 (m, 2H), 4.5 (q, 1H), 4.2 (t, 2H), 3.85 (m, 1H), 3.75-3.8 (m, 7H), 3.5 (t, 2H), 0.9 (s, 9H).

HR-MS FAB m/z for C21H31N5O7 calcd. 466.2302 (M++1), obsd. 466.2289.

The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 6.

Example 96 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-(4,5-dihydro-1H -imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 97 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazo-2-ylamino)ethoxy]-2-hy droxybenzoyl}- amino)-2- [ (methoxycarbonyl) amino] propanoic acid.

Example 98 (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (ethoxycarbonyl) amino] propanoic acid.

Example 99 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazo-2-ylamino)ethoxy]-2-hy droxybenzoyl}- amino)-2-[(propoxycarbonyl) aminoapropanoic[(propoxycarbonyl) aminoapropanoic acid.

Example 100 (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (isopropoxycarbonyl) amino] propanoic acid.

Example 101 (2S)-2- { [ (aMyloxy) carbonyl] ammo}-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 102 (2S)-2- { [ (but-3-enyIoxy) carbonyl] amino}-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 103 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}propanoicacid.

Example 104 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(hexyloxy){[(hexyloxy) carbonyl] amino} propanoic acid.

Example 105 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(octyloxy)carbonyl]amino}propanoicacid.

Example 106 (2S)-2-[(butoxycarbonyl) arnino]-3-( {4-[2-(4, 5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 107 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-[(isobutoxycarbonyl)[(isobutoxycarbonyl) amino] propanoic acid.

Table 6 Ex. @254nm(M+H)+Ex.R9LC@254nmLC 97 Methyl 2.82 min 410 104 n-Hexyl 3.97 min 480 98 Ethyl 2.99 min 424 105 n-Octyl 4.49 min 508 99 n-Propyl 3.21 min 438 95 (CH3) 3CCH2 3.63 min 466 100 i-Propyl 3.17 min 438 106 n-Butyl 3. 46 min 452 101 Allyl 3.13 min 436 107 i-Butyl 3.44 min 452 102 Homoallyl 3.31 min 450 96 Benzyl 3.60 min 486 103 Propargyl 3.01 min 434 The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound ureas in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 7.

Example 108 (2S)-2-{[(butylamino)carbonyl]amino}-3-({4-[2-(4,5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 109 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(hexylamino) carbonyl] amino} propanoic acid.

Example 110 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(octylamino) carbonyl] amino} propanoic acid.

Example 111 (2S)-2-{[(allylamino)carbonyl]amino}-3-({4-[2-(4,5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 112 (2S)-2-{[(cyclohexylamino)carbonyl]amino}-3-({4-[2-(4,5-dihy dro-1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 113 (2S)-2- { [ (benzyIamino) carbonyl] ammo}-3- ( {4- [2- (4, 5-dihydro-lH-imidazoI-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 114 3- ( {4- [2- (2, 5-dihydro-1 H-imidazol-4-ylamino) ethoxy]-2-hydroxybenzoyl) amino-N- ({{(1S,2R)-phenylcyclopropyl]amino)carbonylalanine.

Example 115 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- { [(2-methoxyanilino) carbonyl] amino} propanoic acid.

Example 116 (2S)-2-{[(1,1'-biphenyl]-2-ylamino)carbonyl]amino}-3-({4-[2- (4,5-dihydro-1H- imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 117 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-({[(2-phenylethyl)amino]carbonyl} amino) propanoic acid.

Table 7 Ex. R9 LC @ 254 nm (M+H) + Ex. R9 LC @ 254 (M+H) + nm 108 H3c 3. 20 min 451 113 3. 26 min 48 109 3.69 min 479 I 14 3.57 min 511 110 H, c 4.24 min 507 115 3.42 min 501 HF3C 111 84 min 435 116 3.89 min 547 Pu 112 3. 37 min 477-T47 m-in 499

The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound amides in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 8.

Example 118 <BR> <BR> (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}-<BR> <BR> <BR> amino)-2-(isobutyrylamino)propanoicacid.

Example 119 <BR> <BR> (2S)-2-(butyrylamino)-3-( {4-[2-(4, 5-dihydro-lH-imidazol-2-ylamino) ethoxy]-2-<BR> <BR> <BR> hydroxybenzoyl} amino) propanoic acid.

Example 120 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-(hexanoylamino)propanoic acid.

Example 121 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-(hexanoylamino)propanoic acid.

Example 122 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2- [ (3,3-dimethylbutanoyl) amino] propanoic acid.

Example 123 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{[(2, 2,3,3-tetramethylcyclopropyl) carbonyl] amino} propanoic acid.

Example 124 (2S)-2-{[2-(1-adamantyl)acetyl]amino}-3-({4-[2-(4,5-dihydro- 1H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 125 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2-(hexanoylamino)propanoicacid.

Example 126 (2S)-2- [ (cyclohexylcarbonyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 127 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2- [ (2-phenylacetyl) amino] propanoic acid.

Example 128 <BR> <BR> (2S)-3-( {4- [2-(4, 5-dihydro-l H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (3-phenylpropanoyl) amino] propanoic acid.

Example 129 (2S)-2-[(2-cyclohexylacetyl) amino]-3-( {4-[2-(4, 5-dihydro-l H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 130 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-{ [(E)-3-phenylprop-2-enoyl] amino}{ [(E)-3-phenylprop-2-enoyl] amino} propanoic acid.

Example 131 (2S)-2-[(2-chlorobenzoyl)amino]-3-({4-[2-(4,5-dihydro-1H-imi dazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 132 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(2-methylbenzoyl)amino]propanoicaci d.

Example 133 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-[(2-methoxybenzoyl) amino][(2-methoxybenzoyl) amino] propanoic acid.

Example 134 (2S)-2-[(4-chlorobenzoyl)amino]-3-({4-[2-(4,5-dihydro-1H-imi dazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 135 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2- [ (4-methylbenzoyl) amino] propanoic acid.

Example 136 (2S)-3-({4-[2-(4,5-dihydro-1H-imidazol-2-ylamino)ethoxy]-2-h ydroxybenzoyl}- amino)-2- [ (4-methoxybenzoyl) amino] propanoic acid.

Example 137 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2-[(2, 5-dimethyl-3-furoyl) amino][(2, 5-dimethyl-3-furoyl) amino] propanoic acid.

Example 138 (2S)-2-[(2-bromobenzoyl)amino]-3-({4-[2-(4,5-dihydro-1H-imid azol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 139 (2S)-2- [ (4-bromobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2- ylamino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Example 140 <BR> <BR> (2S)-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino) ethoxy]-2-hydroxybenzoyl}- amino)-2- [ (2,3-dimethylbenzoyl) amino] propanoic acid.

Example 141 <BR> <BR> (2S)-2- [ (3-chlorobenzoyl) amino]-3- ( {4- [2- (4, 5-dihydro-1 H-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino) propanoic acid.

Table 8 Ex. R9 LC @ 254 nm (M+H) + Ex. R9 LC @ 254 nm (I\iI+H) + 118 H, C 2. 90 min 422 130 3. 57 min 482 H3C (M+H) (M+H) 119 H3C 2.90 min 422 131 3.24 min 490 (M+H) (NI+H) 120 H, C min 470 (M+H) cH, (M+H) 121 H3C> 3.10 min 436 1 133 3. (M+H) ocH, (M+H) 122 3.26 min 450 134 3.59 min 490 (M+I (Vi+I 123 H39 3.71 min 476 135 3. 46 min 470 3 (M+I- H3 (Vf+H) H3C 124 3. 90 min 528 136 3. 34 min 486 (M+H) H, co 125 2. 86 min 432 137 H, CH, 3. 45 min 474 (M+H) (VI+I 126 36 rnin 462 138 3. 16 min 534 -9 (M+H) | WBr (M+H) 127 3.22 min 470 1 139'3. 28 min 534 (M+H) (M+H) 128 3. 42 min 484 140 3. 65 n-iin 484 (M+H) CH, (M+H) 161, CH3 129 3. 50 min 476 141 3. 56 min 490 k' (M+H) d (M+H) c

Example 142 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7- ylamino) ethoxy] benzoyl} amino)-2-{ [(neopentyloxy){ [(neopentyloxy) carbonyl] amino} propanoic acid (5-4) <BR> <BR> <BR> <BR> <BR> (2S)-3- (f 2-hydroxy-4-r2- (3.4.5,6-tetrahydro-2H-azepin-7-vlamino) ethoxylbenzovl l- amino)-2-f f (neopentvloxy) carbonvllaminolpropanoic acid on Wang Resin (5-3) The resin 4-2 (100 mg: O. lmmole) was swollen in dioxane and treated with a solution of l-aza-2-methoxy-1-cycloheptene (127 mg; 1 mmole) in dioxane (1.5 mL).

The reaction mixture was shaken at room temperature for 18h. The mixture was filtered and the resin was washed with dioxane (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

The resin 5-3 was cleaved by tratment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 5-4 was purified via preparative HPLC. NMR (300MHz, DMSO-d6) 5 12.8 (s, 1H), 9.55 (t, 1H), 9.25 (t, 1H), 8.8 (t, 1H), 7.8 (d, J = 9 Hz, 1H), 7.7 (d, J = 8 Hz, 1H), 7.3 (m, 5H), 6.5 (m, 2H), 5.0 (s, 2H), 4.3 (q, 1H), 4.2 (t, 2H), 3.8 (m, 3H), 3.6 (m, 1H), 3.5 (m, 2H), 2.7 (m, 2H), 1.7 (m, 2H), 1.6 (m, 4H).

The following compounds were synthesized as described in the above Scheme 5 (Path B), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 9.

Example 143 (2S)-2-{ [(benzyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 144 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-[(methoxycarbonyl) amino] propanoic[(methoxycarbonyl) amino] propanoic acid.

Example 145 <BR> <BR> (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 146 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2- [ (propoxycarbonyl) amino] propanoic acid.

Example 147 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-[(isopropoxycarbonyl) amino] propanoic[(isopropoxycarbonyl) amino] propanoic acid.

Example 148 (2S)-2-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3, 4,5,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 149 (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( 3, 4,5,6-tetrahydro- 2H-azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 150 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-{[(prop-2-ynyloxy) carbonyl] amino} propanoic acid.

Example 151 (2S)-2-{[(hexyloxy) carbonyl] amino}-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H- azepin-7-ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 152 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-{[(octyloxy) carbonyl] amino} propanoic acid.

Example 153 (2S)-3- ( {2-hydroxy-4- [2- (3,4,5,6-tetrahydro-2H-azepin-7-ylamino) ethoxy] benzoyl}- amino)-2-{[(2, 2,2-trichloroethoxy) carbonyl] amino} propanoic acid.

Example 154 (2S)-2-[(butoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino) ethoxy] benzoyl} amino) propanoic acid.

Example 155 (2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylam ino)ethoxy]- benzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoicacid.

Table 9 Ex. @254nm(M+H)+Ex.R9LC@254nm(M+H)+LC 144 Methyl 3.08 min 437 151 n-Hexyl 3. 19 min 507 145 Ethyl 3.25 min 451 152 n-Octyl 4. 67 min 535 146 n-Propyl 3.46 min 465 142 (CH3) 3CCH2 3. 85 min 493 3.38147i-Propyl 153(CCl3)3CCH23.89min553465 148 Allyl 3.70 min 479 149 Homoallyl 3.55 min 477 155 i-Butyl 3.67 min 479 150 Propargyl 3.27 min 461 143 Benzyl 3.83 min 513 Scheme 6 OH O O Fi N I/H HN 0 O 4-2 O BocN S 1. p-NO2PhOCOCI Y DIEA, THF, CH2C12 NHBoc/\ 2. PhCH2NH2 DIEA, DMF Path A Path Et3N, DMF fTNYoQ H H fftoQ OH O O OH O O BocHNN OW HNOs Ph NN oJ<H HN°sF O IIO O 6-3 O Box TFA-CH2CI2 (1: 1) TFA-CH2CI2 (1: 1) H AroH,, H H rTHi OH O O OH O O N OH H H H N N I i H HN OH PhN N I/H HN O NH 6-2 0 0 6-4 6-4 6-2

Example 156 (2S)-3-{ [4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxy- benzoyl] amino}-2-{ [(neopentyloxy) carbonyl] amino} propanoic acid{ [(neopentyloxy) carbonyl] amino} propanoic acid (6-2) (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- {[(neopentyloxy)carbonyl]amino}propanoic acid on Wana Resin (6-1) The resin 4-2 (100 mg; 0.1 mmole) was swollen in DMF and treated with a solution of 1,3-bis (tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (145 mg; (0.5 mmole) in DMF (1.5 mL) followed by diisopropylamine (0.15 mL; 1 mmole). The reaction mixture was shaken at room temperature for 18h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.

The resin 6-1 was cleaved by tratment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 6-2 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) 8 7.7 (d, J = 7 Hz, 1H), 6.5 (m, 2H), 4.5 (q, 1H), 4.2 (m, 2H), 3.85 (m, 1H), 3.8 (m, 2H), 3.75 (m, 1H), 3.7 (m, 2H), 0.9 (s, 9H).

HR-MS FAB m/z for C, 9H29N507calcd. 440.2145 (M++1), obsd. 440.2154.

The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 10.

Example 157 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- { [(benzyloxy) carbonyl] amino} propanoic acid.

Example 158 (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (methoxycarbonyl) amino] propanoic acid.

Example 159 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- [(ethoxycarbonyl) amino] propanoic acid.

Example 160 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- [ (propoxycarbonyl) amino] propanoic acid.

Example 161 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(isopropoxycarbonyl)amino]propanoicacid.

Example 162 (2S)-2- { [ (allyloxy) carbonyl] amino 1-3-1 [4- (2-1 [amino (imino) methyl] amino} ethoxy)-2- hydroxybenzoyl] amino} propanoic acid.

Example 163 (2S)-3- { [4- (2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(but-3-enyloxy) carbonyl] amino} propanoic acid. Example 164 (2S)-3- { [4- (2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(butoxycarbonyl) amino] propanoic acid. Example 165 (2S)-3- { [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid. Example 166 (2S)-3- { [4-(2- { [amino (imino) methyl] arnino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(hexyloxy) carbonyl] amino} propanoic acid. Example 167 (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(prop-2-ynyloxy) carbonyl] amino} propanoic acid. Example 168 (2S)-3- { [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [([1, 1'-biphenyl]-2-ylmethoxy) carbonyl] amino} propanoic acid. Example 169 (2S)-3- { [4- (2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [ (4-bromobenzyl) oxy] carbonyl} amino) propanoic acid. Example 170 (2S)-3-{ [4-(2- { [amino (imino) methyl] amino ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [ (4-fluorobenzyl) oxy] carbonyl} amino) propanoic acid. Example 171 (2S)-3- { [4-(2- { [amino (imino) methyl] amino ethoxy)-2-hydroxybenzoyl] amino}-2- ( { [ (2-bromobenzyl) oxy] carbonyl} amino) propanoic acid. Example 172 (2S)-3- { [4- (2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [( { [4-(trifluoromethyl) benzyl] oxy} carbonyl) amino] propanoic acid.

Table 10 Ex. R9 LC @ 254 mn (M+H) + Ex. R9 LC @ 254 nm (M+H) + 158 Methyl 2.75 min 384 165 (CC13) 3CCH2 3. 159 Ethyl 2.93 min 397 164 n-Butyl 3.39 min 426 160 n-Propyl 3.15 min 412 157 Benzyl 3.53 min 460 161 i-Propyl 3.11 min 412 1 168 aPh 4.20 min 536 Ph 162 Allyl 3.05 min 410 169 3.85 min 539 B r 163 Homoallyl 3.25 min 414 1 170 3.60 min 478 F 167 Propargyl 2.95 min 401 1 171 3.81 min 539 er 166 n-Hexyl 3.91 min4454 172fF"3. 97 min528 foc FC 156 (CH3) 3CCH2 3. 57 min 440

The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound ureas in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 11.

Example 173 <BR> <BR> (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- toluidinocarbonyl) amino] propanoic acid.

Example 174 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- {[(2-methoxyanilino)carbonyl]amino}propanoic acid.

Example 175 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(2-chloroanilino)carbonyl]amino}propanoic acid.

Example 176 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(2-bromoanilino)carbonyl]amino}propanoic acid.

Example 177 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(1,1'-biphenyl]-2-ylamino)carbonyl]amino}propanoic acid.

Example 178 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-[(4-<BR> <BR> <BR> <BR> toluidinocarbonyl)amino]propanoic acid.

Example 179 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> <BR> {[(4-(trifluoromethoxy)amino]carbonyl]amino}propanoic acid.

Example 180 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)metyl]amino}ethoxy)-2-hydroxyben zoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(4-chloroanilino)carbonyl]amino}propanoic acid.

Example 181 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)metyl]amino}ethoxy)-2-hydroxyben zoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(4-fluoroanilino)carbonyl]amino}propanoic acid.

Example 182 <BR> <BR> (2S)-3-{[4-(acetylanilino)carbonyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> <BR> amino)ethoxy)-2-hydroxybenzoyl]amino}proopanoicacid.

Example 183 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(cyclohexylamino)carbonyl]amino}propanoicacid.

Example 184 <BR> <BR> (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> <BR> <BR> <BR> {[(1-naphthylamino)carbonyl]amino}propanoic acid.

Example 185 <BR> <BR> (2S)-3- { [4- (2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-<BR> <BR> <BR> <BR> <BR> { [(benzylamino) carbonyl] amino} propanoic acid.

Example 186 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- ({[(2-phenylethyl)amino]carbonyl}amino}propanoicacid.

Example 187 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- {[(octylamino)carbonyl]amino}propanoic acid.

Example 188 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- {[(4-methoxyanilino)carbonyl]amino}propanoic acid.

Example 189 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- [(anilinocarbonyl)amino]propanoicacid.

Table 11 Ex. RI LC @ 254 nm (M+H) + Ex. Rl LC @ 254 nm (M+H) + l 187, cB 4.18 min 481 182 p~ 3.26 min 487 HaC/ 0 189 3. 29 min 445 175 3.46 min 481 i i ci 183 3. 32 min 451 176 3.48 min ex 185 3. 20 min 459 177 fl---y 3.81 min 521 Ph 173 aCH3 3. 32 min 459 181 FJa 3 39 min 463 C3 F 178 H3CJW 3.50 min 459 180 3.68 min 481 Hic ci 188 3. 27 min 475 184 3. 57 min 495 Hz I w 3. 36 min 475 186 \ 3.37 min 473 OCH3 179 3. 92 min 529 CF30'- CFsCr" The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound amides in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 12.

Example 190 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-<BR> <BR> (isobutyrylamino)propanoic acid.

Example 191 (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (butyrylamino) propanoic acid.

Example 192 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (hexanoylamino) propanoic acid.

Example 193 (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (pentanoylamino) propanoic acid.

Example 194 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (3,3-dimethylbutanoyl) amino] propanoic acid.

Example 195 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- { [ (2,2,3,3-tetramethylcyclopropyl) carbonyl] amino} propanoic acid.

Example 196 (2S)-2-{[2-(1-adamantyl)acetyl]amino}-3-{[4-(2-{[amino(imino )methyl]amino}- ethoxy)-2-hydroxybenzoyl] amino} propanoic acid.

Example 197 (2S)-3- { [4-(2-{[amino(imino)methyl]amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (pent-4-ynoylamino) propanoic acid.

Example 198 (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (cyclohexylcarbonyl) amino] propanoic acid.

Example 199 (2S)-3-{[4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- phenylacetyl) amino] propanoic acid.

Example 200 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (3- phenylpropanoyl) amino) propanoic acid.

Example 201 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- cyclohexylacetyl) amino] propanoic acid.

Example 202 (2S)-3- ( [4-(2-{[amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- { [(E)-3-phenylprop-2-enoyl] amino} propanoic acid.

Example 203 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(2- chlorobenzoyl) amino] propanoic acid.

Example 204 (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- methylbenzoyl) amino] propanoic acid.

Example 205 (2S)-3-{[4-(2-{[amino (imino) methyl) arnino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(2- methoxybenzoyl) amino] propanoic acid.

Example 206 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-[(4- chlorobenzoyl) amino] propanoic acid.

Example 207 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (4- methylbenzoyl) amino] propanoic acid.

Example 208 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-[(4- methoxybenzoyl) amino] propanoic acid.

Example 209 (2S)-3- { [4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(pyridin-3-ylcarbonyl) amino] propanoic acid.

Example 210 (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- (isonicotinoylamino) propanoic acid.

Example 211 (2S)-3-{[4-(2-{[amino(imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (2,5-dimethyl-3-furoyl) amino] propanoic acid.

Example 212 (2S)-3-{[4-(2-{ [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(2- bromobenzoyl) amino] propanoic acid.

Example 213 (2S)-3- { [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (4- bromobenzoyl) amino] propanoic acid.

Example 214 (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (2,3-dimethylbenzoyl) amino] propanoic acid.

Example 215 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-[(3- chlorobenzoyl)amino]propanoic acid.

Example 216 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2- (benzoylamino)amino]propanoicacid.

Example 217 (2S)-3-{[4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybe nzoyl]amino}-2-[(4- ethylbenzoyl)amino]propanoic acid.

Example 218 (2S)-3-{ [4-(2- { [amino (imino) methyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2-[(4- butoxybenzoyl) amino] propanoic acid.

Table 12 Ex. R9 LC @ 2S4 mn (M+H) + Ex. R9 LC @ 254 nm (M+H) + 190"y-2.88 min 396 (M+H) 205 3. 38 min 460 (M+H) H, C OCH3 191 H3C > 2.88 min 396 (M+H) 206 3. 58 min 464 (M+H) cru 192 3.34 min 424 (M+H) 207 45 min 444 (M+H) H C-" 3 193 H, c^ 3.09 min 410 (M+H) 208r" 3.33 min 460 (M+H) H, CO 194 3. 24 min 424 (M+H) 209 2. 61 min 431 (M+H) 195''3. 70mm 450 (M+H) 210 58mm 431 (M+H) nez 3 H3C 196 3. 85 min 502 (M+H) 211 H3<CH3 3.45 min 448 (M+H) 197 2. 84 min 406 (M+H) 212 27 min 509 (M+H) Br 198 3. 35 min 436 (M+H) 213 65 min 509 (M+H) LJ gk 199 3. 21 min 444 (M+H) 214)"3.65 min 458 (M+H) 6i"CH3 CH, 200 3.42 min 458 (M+H) 215 46 min 464 (M+H) Ccl 201 50 min 450 (M+H) 216 ¢ 3. 19 min 430 (M+H) 202 3.55 min 456 (M+H) 217 3.66 min 458 (M+H) 203 3. 25 min 464 (M+H) 218 4. 08 min 502 (M+H) n-Bu0 204 3. 29 min 444 (M+H) CH-

Example 219 (2S)-3-{[4-(2-{ [(benzylamino) carbonyl] amino} ethoxy)-2-hydroxy- benzoyl] amino}-2-{[(neopentyloxy) carbonyl] amino}{[(neopentyloxy) carbonyl] amino} propanoic acid (6-4) <BR> <BR> <BR> <BR> <BR> (2S)-3- { (2- ( f (benzvlamino) carbonvllamino ethoxy)-2-hydroxybenzo TLl amino}-2-<BR> <BR> <BR> <BR> neopentvloxy carbonyllamino} propanoic acid on WangResin (6-3) The resin 4-2 (100 mg; 0.1 mmole) was swollen in 1: 1 tetrahydrofuran and dichloromethane. To it was added a solution of 4-nitrophenylchloroformate (50 mg; 0.25 mmole) in 1: 1 THF: DCM (1.5 mL) followed by diisopropylamine (0.075 mL; 0.5 mmole). The reaction mixture was shaken at room temperature for 30 mm. The mixture was filtered and the resin was washed with THF (4 x 4 mL) and dichloromethane (4 x 4 mL) and dried. The resin was suspended in DMF (1.5 mL) and benzyl amine (54 mg; 0.5 mmole) was added followed by triethylamine (101 mg; 1 mmole). The reaction mixture was shaken at room temperature for 2 h. The mixture were filtered and the resin in each vessel was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum.

The resin 6-3 was cleaved by treatment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 6-4 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) 8 7.65 (d, J = 7 Hz, 1H), 7.25 (m, 5H), 6.5 (m, 2H), 4.4 (q, 1H), 4.3 (s, 2H), 4.15 (t, 2H), 3.85 (m, 1H), 3.75 (m, 3H), 3.5 (t, 2H). 0.9 (s, 9H).

HR-MS FAB m/z for C26H34N408calcd. 531.2455 (M++1), obsd. 531.2459.

The following compounds were synthesized as described in the above Scheme 6 (Path B), using various amines in the place of benzyl amine. These compounds were characterized using LC and MS as shown in Table 13.

Example 220 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- {[(benzyloxy) carbonyl] amino} propanoic acid.

Example 221 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- [ (methoxycarbonyl) amino] propanoic acid.

Example 222 (2S)-3-{[4-(2-{[(benzylamino) carbonyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [ (ethoxycarbonyl) amino] propanoic acid.

Example 223 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- [ (propoxycarbonyl) amino] propanoic acid.

Example 224 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- [ (isopropoxycarbonyl) amino] propanoic acid.

Example 225 (2S)-2- { [(allyloxy) carbonyl] amino}-3-{[4-(2-{[(benzylamino) carbonyl] amino}- ethoxy)-2-hydroxybenzoyl] amino} propanoic acid.

Example 226 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- { [ (but-3-enyloxy) carbonyl] amino} propanoic acid.

Example 227 (2S)-3-{[4-(2-{[(benzylamino) carbonyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- {[(prop-2-ynyloxy) carbonyl] amino} propanoic acid.

Example 228 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- {[(hexyloxy) carbonyl] amino} propanoic acid.

Example 229 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- { [(octyloxy) carbonyl] amino} propanoic acid.

Example 230 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- { [ (2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid.

Example 231 (2S)-3-{[4-(2-{[(benzylamino) carbonyl] amino} ethoxy)-2-hydroxybenzoyl] amino}-2- [(butoxycarbonyl) amino] propanoic acid.

Example 232 (2S)-3-{[4-(2-{[(benzylamino)carbonyl]amino}ethoxy)-2-hydrox ybenzoyl]amino}-2- [(isobutoxycarbonyl) amino] propanoic acid.

Example 233 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydory-4-[2-({[(py ridin-3-ylmethyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 234 (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl) amino] carbonyl}-amino) ethoxy]- benzoyl} amino)-2- [ (methoxycarbonyl) amino] propanoic acid.

Example 235 (2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydory-4-[2-({[(pyridin -3-ylmethyl)-amino]- carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 236 (2S)-3-({2-hydroxy-4-[1-({pyridin-3-ylmethyl)amino]carbonyl} amino)ethoxyl]- benzoyl} amino)-2- [(propoxycarbonyl) amino] propanoic acid.

Example 237 (2S)-3-({2-hydroxy-4-[2-({pyridin-3-ylmethyl)amino]carbonyl} amino)ethoxyl]- benzoyl} amino)-2- [(isopropoxycarbonyl)amino] propanoic acid.

Example 238 (2S)-3-{[(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(py ridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 239 (2S)-2-{[(but=3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( {[(pyridin-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid Example 240 (2S)-3-( {2-hydroxy-4- [2-( { [(pyridin-3-ylmethyl) amino] carbonyl}-amino) ethoxy]- benzoyl} amino)-2- { [(prop-2-ynyloxy) carbonyl] amino} propanoic acid.

Example 241 (2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(py ridin-3-ylmethyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 242 <BR> <BR> (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl) amino] carbonyl}-arnino) ethoxy]- benzoyl} amino)-2-{ [(octyloxy){ [(octyloxy) carbonyl] amino} propanoic acid.

Example 243 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}-amino)ethoxyl- benzoyl} amino)-2-{[(neopentyloxy) carbonyl] amino} propanoic acid.

Example 244 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}-amino)- ethoxy] benzoyl}amino)-2-{[(2, 2,2-trichloroethoxy) carbonyl] amino} propanoic acid.

Example 245 (2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({[(pyridi n-3- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 246 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}-amino)ethoxyl- benzoyl} amino)-2-[(isobutoxycarbonyl)[(isobutoxycarbonyl) amino] propanoic acid.

Example 247 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydrox-4-[2-({[(py ridin-4- ylmethyl) amino] carbonyl} amino) ethoxy) benzoyl} amino) propanoic acid.

Example 248 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-4-ylmethyl)amino]carbony l}-amino)- ethoxy] benzoyl} amino)-2-[(methoxycarbonyl) amino] propanoic acid.

Example 249 (2S)-2-[(ethoxycarbonyl) amino]-3-( {2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 250 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-3-ylmethyl)amino]carbony l}- amino) ethoxy]benzoyl}amino)-2-[(propoxycarbonyl) amino] propanoic acid.

Example 251 (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl) amino] carbonyl}- amino) ethoxy] benzoyl} amino)-2- [(isopropoxycarbonyl) amino] propanoic acid.

Example 252 (2S)-2-t [ (allyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 253 (2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( {[(pyridin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl}amino) propanoic acid.

Example 254 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-4-ylmethyl)amino]carbony l]-amino)ethoxy]- benzoyl}amino)-2-{[(prop-2-ynyloxy)carbonyl]amino}propanoica cid.

Example 255 (2S)-2-{[hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(pyr idin-4- ylmethyl) amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid.

Example 256 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-4-ylmethyl) amino] carbonyl}-amino) ethoxy]- benzoyl}amino)-2-{[(octyloxy)carbonyl]amino}propanoicacid.

Example 257 (2S)-3-( {2-hydroxy-4- [2-( { [(pyridin-4-ylmethyl) amino] carbonyl}-amino) ethoxy]- benzoyl)amino)-2-{[(neopentyloxy) carbonyl] amino} propanoic acid.

Example 258 (2S)-3-({2-hydroxy-4-[2-({[(pyridin-4-ylmethyl)amino]carbony l]-amino)ethoxy]- benzoyl} amino)-2-{[(2,2,2-trichloroethoxy) carbonyl] amino} propanoic acid.

Example 259 (2 S)-2- [ (butoxycarbonyl) amino]-3- ( {2-hydroxy-4- [2- ( { [ (pyridin-4-ylmethyl) amino}- carbonyl} amino) ethoxy] benzoyl}amino) propanoic acid.

Example 260 (2S)-3-( {2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl) amino] carbonyl}-amino) ethoxy]- benozyl}amino}-2-[(isobutoxycarbonyl)amino]propanoicacid.

Example 261 (2S)-2-{ [(benzyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-( { [(4-methylbenzyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid. LC 4.75 min., M+H 565.

Example 262 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[4- methoxybenzyl)- amino) carbonyl}amino) ethoxy] benzoyl} amino) propanoic acid. LC 3.75 min., M+H 581.

Example 263 (2S)-2- { [(benzyloxy) carbonyl] amino}-3- ( {4- [2- ( { [ (4-chlorobenzyl) amino]-carbonyl}- amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid. LC 4.83 min., M+H 5.86.

Example 264 (2S)-2-{[(benzyloxy) carbonyl] amino}-3- [ (4- {2- [ ( { [4- (dimethyIamino) benzyl]- amino} carbonyl) amino] ethoxy}-2-hydroxybenzoyl) amino] propanoic acid. LC 3.7 min., M+H 594.

Example 265 (2S)-3-[(4-{2-[({[4-(aminosulfonyl)benzyl]amino]carbonyl]ami no]ethoxy}-2- hydroxybenzoyl) amino]-2-{[(benzyloxy)carbonyl]amino}propanoic acid. LC 4.08 min., M+H 630.

Example 266 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2-hydroxy-4-{2-[({[4 -(trifluoromethoxy)- benzyl] amino} carbonyl) amino) ethoxy} benzoyl) amino] propanoic acid. LC 5. 06 min., M+H 635.

Example 267 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2-chloroben zyl)amino]carbonyl}- amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid. LC 4.8 min., M+H 586.

Example 268 (2S)-2- { [(benzyloxy) carbonyl] amino}-3-( {2-hydroxy-4-[2-( { [(2-methylbenzyl) amino]- carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid. LC 4.74 min., M+H 565.

Example 269 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2-chloroben zyl)amino]carbonyl}- amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid. LC 4.85 min., M+H 630.

Example 270 (2S)-2- { [ (benzyloxy) carbonyl] amino}-3-({4-[2-({[(2,4-dichlorobenzyl) amino]- carbonyl} amino) ethoxy]-2-hydroxybenzoyl} amino) propanoic acid. LC 5.08 min., M+H 620.

Example 271 (2S)-3-({4-[2-({[(2-aminobenzyl)amino]carbonyl}amino)ethoxy] -2-hydroxybenzoyl}- amino)-2-{[(benzyloxy){[(benzyloxy) carbonyl] amino} propanoic acid. LC 3.81 min., M+H 566.

Example 272 (2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(p yridin-2-ylmethyl)- amino] carbonyl} amino) ethoxy] benzoyl} amino) propanoic acid. LC 3.58 min., M+H 552.

Table 13 Ex. 221-227 248-254 234-240 219-220 247 & 233 & 228-232 255-260 241-246 I R9 N N R9 N N r r 228-232 22S-232 methyl 475 M+H 476 M+H 476 M+H hexyl 545 M+H 546 M+H 546 M+H 3.84min 2. 84min 2. 84min 4. 90min 3. 90min 3. 90min 221248234"''-'" ethyl 489 M+H 490 M+H 490 M+H octyl 573 M+H 574 M+H 574 M+H 4.00min3. 01min2. 99min5. 37min4. 38min4.37min 222 249 235 229 256 242 n-propyl 503 M+H 504 M+H 504 M+H (CH3) 3CCH2- 531 M+H 532 M+H 532 M+H 4.21min 3. 20min 3. 19min 4. 58min 3. 57min 3. 58min 223 250 236 219 257 243 i-propyl 503 M+H 504 M+H 504 M+H (C03) 3CCH2- 593 M+H594 M+H594 M+H 4.19min 3. 17min 3. 17min 4. 62min 3. 62min 3.62min 224 251 237 230 258 244 allyl 501 M+H 502 M+H 502 M+H n-butyl 517 M+H 518 M+H 518 M+H 4.14min 3. 12min 3. 12min 4. 43min 3. 43min 3. 43min 225 252 238 231 259 24 homo-515 M+H 516 M+H 516 M+H i-butyl 517 M+H 518 M+H 518 M+H allyl 4.31min 3. 28min 3. 29min 4. 41min 3. 40min 3. 40min 226 253 239 232 260 246 propargyl 499 M+H 500 M+H 500 M+H benzyl 551 M+H 552 M+H 552 M+H 4.06min 3. Olmin 3. 02rriin 4. 59min 3. 52min 3. 55min 227 254 240 220 247 233

Alternatively, Schemes 7-12 demonstrate the solution phase synthesis practice of this invention with detailed synthetic procedures for representative compounds.

Scheme 7. QU 0 U OMe +, O H DEAD, (PhP/THF H " H ffY"OMe Ns X O Me i o 0 7-1 1.KOH 2. HCI y H O H O eO HHCI. H2N/ 7-2 rN TMSCI DIPEA/1,4-dioxane N Br I ZON N \/ OH 7-3

Example 273 2 (S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylami no)- ethoxy] benzoylamino] propionic acid ethyl ester (8-1) Methyl 4-r2-N- (t-butoxycarbonyI)ethoxvt-2-hvdroxy benzoate (7-1) Methyl 2,4-dihydroxy benzoate (14.5g, Aldrich), 2-(N-t-butoxycarbonyl) ethanol (13.9g, Aldrich) and triphenyl phosphine (22.6g, Aldrich) were combined in 350 mL of THF and cooled in ice under N2 atmosphere. Diethyl diazodicarboxylate (DEAD, 15g, Aldrich) was added, the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 15h. The solvent was removed on a rotary evaporator and the residue chromatographed on silica gel (300g, Merck silica 60), elution with CH2CI2 to give 18g of methyl 4- [2-N- (t-butoxycarbonyl) ethoxy]-2-hydroxy benzoate, as a viscous oil. NMR (300 MHz, CDCl3) 5 11.0 (s, 1 H), 9.5 (d, J = 8Hz, 1H), 6.4 (m, 2H), 5.0 (broad, 1H), 4.0 (t, J = 5Hz, 2H), 3.91 (s, 3H), 3.54 (m, 2H), 1.45 (s, 9H), MS (+ESI) m/z 334 (M+Na) +.

4- (2-Aminoethoxy)-2-hvdroxybenzoic acid, hydrochloride (7-2) Ester 7-1 (7.2g) was treated with 5eq. KOH (dissolved in minimum amount of water and equal volume of 1,4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h). The reaction mixture was acidified (pH = 6) with the addition of IN HCI solution and extracted with ethyl acetate. The extract was washed with saturated aqueous brine solution, dried over MgS04, filtered and concentrated on the rotary evaporator. The crude product (5.34g) was recrystallized from ether, then dissolved in 1,4-dioxane and treated with an excess of anhydrous HCl (4M in dioxane, Aldrich). The mixture was allowed to stand at ambient temperature for 24h. Volatile materials were removed in vacuo on the rotary evaporator to give 7-2 as a hydroscopic off-white solid. NMR (400 MHz, DMSO-d6) 8 13.6 (broad, 1H), 11.6 (broad, 1H), 8.3 (broad, 3H), 7.7 (d, J = 9 Hz, 2H), 6.53 (m, 2H), 4.23 (t, J = 5Hz, 2H), 3.2 (s, broad, 2H).

2-Hvdroxy-4-f2- (pyrimidine-2ylamino) ethoxylbenzoic acid (7-3) A mixture of compound 7-2 (20g), diissopropylethylamine (DIPEA, 74 mL),- trimethylsilylchloride (TMSCI, 21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5g) were combined in 350 mL 1,4-dioxane at room temperature, then brought to reflux under N2 atmosphere. After 2 days, an additional 12 mL trimethylsilyl chloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed no stating material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give 15.3g of 7-3, as a tan powder. NMR (400 MHz, DMSO-d6) 8 12 (very broad, 2H) 8.3 (d, J = 5 Hz, 2H) 7.7 (d, J = 9Hz, 1H), 7.28 (t, J = 6Hz, 1H), 6.57 (t, J = 5Hz, 1H), 6.49 (m, 2H). 4.13 (t, J = 6Hz, 2H), 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H) +; IR (KBr) v (cmi') 3275,3000,1660,1625.

A mixture of compound 7-3 (5.51g), N-hydroxybenzotriazole hydrate (HOBt-H20, 4.6g, Aldrich), N-methyl morpholine (NMM, 8.8 mL) and 1- [3- (dimethylamino)- propyl]-3-ethyl carbodimide hydrochloride (DEC, 7.6g, Aldrich) were stirred at room temperature in 60 mL DMF for-0.3 h, followed by the addition of 2 (S)- benzenelsulfonylamino-p-alanine ethyl ester (W09532710, Scheme 2). The mixture was allowed to stir at room temperature for 2 days under N2 atmosphere. Volatile materials were removed in vacuo on a rotary evaporator, and the residue dissolved in ethanol. Twenty grams of silica gel (silica 60, Merck) were added and the solvent removed. Chromatography on 300g of silica gel (ethyl acetate elution, gave 8.1g of the title compound as a pale yellow glass, which upon hardening and pulverizing produced an off-white powder. NMR (400 MHz, DMSO-d6) 8 12.5 (s, 1H), 8.68 (t, J = 6Hz, 1H), 8.48 (d, J = 9Hz, 1H), 8.27 (d, J = 5Hz, 1H), 7.73 (m, 2H), 7.64 (d, J = 9Hz, 1H), 7.55-7.5 (m, 1H), 7.48-7.44 (m, 2H), 7.27 (t, J = 6Hz, 1H), 6.58 (t, J =

5Hz, 1H), 6.47 (dd, J = 6Hz, 3Hz, 1H), 6.42 (d, J = 2Hz, 1H), 4.1 (t, J = 6Hz, 2H), 4.05 (q, J = 7Hz, 1H), 3.79 (q, J = 7Hz), 3.62 (q, 2H), 3.54 (m, 1H), 3.34 (m, 1H overlapping with H20 peak), 0.94 (t, J = 7Hz); MS (+ESI) m/z 530 (M + H) +; IR (KBr) v (ci') 3400,1740,1650,1580.

Scheme 8

Example 274 2 (S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylarn ino)- ethoxy] benzoylamino] propionic acid (8-2).

To a solution of compound 8-1 (8.1g), dissolved in 75 mL 1,4-dioxane, was added a solution of NaOH (4g) in 75 mL H20 and the reaction mixture was stirred at room temperature for 15h. The mixture was concentrated in vacuo and the residue partitioned between water and dichloromethane. The aqueous phase was acidified with IN aqueous HCl solution to pH 7, which produced a gum precipitate. This material (7g) was absorbed onto 15g of silica gel as in example 1, followed by chromatography on 200g silica gel. Elution with chloroform (90)-methanol (10)-acetic acid (0.1 gave the title compounds as an amber syrup. MS (-ESI) m/z 500 (M-H)-; [α]D25=6.84 (c. 9.497, methanol).

Analysis for C22H23N507S : Calculated: C, 52.69; H, 4.62 ; N, 13.96.

Found: C, 52.65; H, 4.43 ; N, 13.6.

Example 275 2 (S)-Benzenesulfonylamino-3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoylamino] propionic acid hydrochloride (8-3).

A mixture of compound 8-2 (8g) and 10% Pd/C (Ig) was stirred at room temperature in 1,4-dioxane (125 mL), acetic acid (125 mL), water (50 mL) and concentrated HCl (2-mL) under H2 atmosphere (balloon) for 2 days. Celite was added to the mixture with stirring for 0.25h, and the mixture was filtered through a pad of celite with the aid of isopropanol. The filtrate was concentrated on the rotary evaporator and the residue treated sequentially with (1) warm heptane, then concentrated; (2) 1: 1 water-1,4- dioxane, then filtered and concentrated, followed by vacuum drying in an abderhalden apparatus (isopropanol, reflux) to give the title compound 8-3 (4.7g) as a hygroscopic <BR> <BR> <BR> <BR> white powder. NMR (400 MHz, DMSO-d6) 5 12.6 (broad, 2H) 8.77 (broad, 1H), 8.2 (broad, 1H), 8.1 (broad, 2H), 7.72 (m, 3H), 7.47-7.37 (m, 3H), 6.46 (m, 1H), 6.44 (s, broad, 1H), 4.07 (t, J = 5Hz, 2H), 3.93 (broad, 1H), 3.63-3.43 (m, 1H), 3.4-3.25

(m, 2H), 1.9-1.77 (m, 2H); IR (KBr) v (cm-1), 3360,1720,1580; MS (+ESI) m/z 506 (M+H) +.

Example 276 2 (S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylami no)- ethoxy] benzoylamino] propionic acid ethyl ester hydrochloride (8-4) The above acid (8-3) was dissolved in ethanol (25 mL) and concentrated HCl (1 mL).

The mixture was heated to reflux for 15h, concentrated on a rotary evaporator and filtered through a short plug of silica gel with the aid of ethanol to give the title compound as a hygroscopic tan powder. IR (KBr) v (cm-1) 1745,1690; MS (+ESI) m/z 534 (M+H) +.

Analysis for C24H3, N507S-HCl.

Calculated: C, 50.57; H, 5.66; N, 12.29.

Found: C, H, 5.66; N, 12.53 Scheme 9

Example 277 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (3,4,5,6-tetra- hydropyrimidin-2-ylamino) ethoxy] benzoylamino] propionic acid ethyl ester hydrochloride (9-2).

2-Hydroxv-4-f2-(3. 45. 6-tetrahydropyrirnidin-2vlamino ! ethoxy]-benzoic(3. 45. 6-tetrahydropyrirnidin-2vlamino ! ethoxy]-benzoic acid (9-1).

Compound 7-3 (2g) was combined with 10% Pd/C (0.5g), acetic acid (100 mL) and concentrated hydrochloric acid (0.7 mL). The mixture was stirred at room temperature under an atmosphere of H2 (balloon) for 2 days. Celite was added and the mixture stirred for 0.5h, then filtered through a pad of celite with the aid of isopropanol. Volatile materials were removed on the rotary evaporator and the residue warmed with heptane (-0.5h, 100°C) followed by concentration in vacuo to give 9-1 as a tan foam. NMR (400 MHz, DMSO-d6) 8 12.9 (broad, 2H), 8.25 (s, broad, 2H), 7.85 (t, J = 6Hz, 1H), 7.66 (d, J = 9 Hz, 1H), 6.48-6.41 (m, 2H), 4.07 (t, J = 5Hz, 2H), 3.56-3.50 (m, 2H), 3.22 (m, 2H, overlapping with HO peak), 1.79 (m , 2H); IR (KBr) v (cm') 3450 (broad); MS (+ESI) m/z 280 (M + H) +.

Compound 9-1 (1.58g), 3-amino-2 (S)-benzyloxycarbonylaminopropionic acid, ethyl ester hydrochloride (1.51g; from the amino acid (Fluka) esterified with HCl in ethanol), N-methyl morpholine (NMM, 1.52g) and benzotriazol-1- yloxytris (dimethylamino) phosphoniumhexafluorophosphate (BOP, 2.21g) were combined in 40 mL anhydrous DMF. The mixture was stirred for 48h at room temperature, additional BOP reagent (Ig) was added and the reaction stirred for 15h.

Volatile materials were removed on the rotary evaporator, the residue dissolved in ethanol and absorbed onto 20g silica gel, and this added to the top of a 200g silica gel column. Flash chromatography, elution with chloroform-methanol-acetic acid (90: 10: 1) followed by treatment with an equivalent concentrated aqueous HCl in ethanol and concentration provided the title compound as a hygroscopic tan powder.

NMR (400 MHz, DMSO-d6) 8 12.7 (s, 1H), 8.85 (t, J = 6 Hz, 1H), 8.00 (s, broad,

2H), 7.84 (d, J = 7.5Hz, 1H), 7.80 (d, J = 9 Hz, 1H), 7.60 (t, J = 6 Hz, 1H), 7.32 (m, 5H), 6.49-6.45 (m, 2H). 5.02 (s, 2H), 4.27 (q, 1H), 4.06 (m, 4H), 3.66-3.55 (m, 2H), 3.49 (m, 2H), 3.23 (m, 4H), 1.79 (m, 2H), 1.10 (t, J = 7 Hz, 3H); IR (KBr) v (cl'') 3300,1730,1650; MS (+ESI) m/z 528 (M+H) +.

Example 278 2 (S)-Benzyloxycarbonylamino-3- [2-hydroxy-4- [2- (3,4,5,6-tetrahydro- pyrimidin-2-ylamino) ethoxy] benzoylamino] propionic acid hydrochloride (9-3).

The above ester 9-2 was hydrolyzed to the title compound 9-3 by refluxing (15-24h) 1N aqueous HCl solution. When TLC indicated no starting ester remained, the solution was concentrated on the rotary evaporator and the residue treated with warm isopropanol, filtered and concentrated to give 9-3 as a hygroscopic tan powder. MS (+FAB) m/z 500 (M+H) +; [α] D25 =-7.83 (c. 5.36, MeOH).

Analysis for C24H29N5O7#HCl#H2O; Calculated: C, 52.03; H, 5.82; N, 12.64.

Found: C, 52.02, H, 5.53; N, 12.00.

Scheme10 OHO OH o 0 10-1 10-1 eHil O~1.~°) 9 3. EDH HR H 1'H. N p^ Y HO \ OHHCI OH 0 0 H H N OH Y-, ^II/J H ( H OH O'v 3. IH O O 12 10-3 nu 4. HNO.-HNS/N : iJHm/Pl, 4<ibxane N- 5. HaFiOH OH ouzo N 0 et HYH H N,,-, H20 un NHJ NU OH 0 0 HCI-H 20 H KOH H I \ H OH / N H lO-S

Example 279 3- [4- (2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3- phenylpropanoic acid ethyl ester hydrochloride. (10-4) Compound 10-1 (1.33g, scheme 7) and p-phenylalanine ethyl ester hydrochloride from ethanol-HCl treatment of p-phenylalanine (Aldrich)) were combined in dichloromethane (20 mL) with DEC coupling agent (0.94g), HOBt (0.75g) and NMM (0.99g). The mixture was stirred at room temperature for 15h. Volatile materials were removed in vacuo on a rotary evaporator and the residue partitioned between ethyl ether and IN aqueous HCl solution. The organic phase was washed with saturated aqueous brine solution, dried over MgSO4, filtered and concentrated to give 2.8g of crude coupling product 10-2 (Scheme 10). The N-terminal Boc group was removed by dissolving the product in a minimum amount of absolute ethanol and adding an equal volume of anhydrous HCl in 1,4-dioxane (4M, Aldrich). This mixture was allowed to stand at room temperature for 15h, concentrated in vacuo on a rotary evaporator, and treated with an excess of 5 eq. of the theoretical amount of KOH (-1.7g,-85%, Baker) in water (20 mL) at reflux for 24h. The mixture was cooled to room temperature and acidified with IN HCl solution to pH 6.3,5-Dimethylpyrazol- 1-carboxamidine nitrate (lg, Aldrich) and 0.75g of NaHC03 were added and the mixture refluxed for 15h. An additional 0.2g carboxamidine were added, and reflux continued for 3h, when TLC (MeOH: CHCl3: NH40H (2: 8: 0.1) indicated complete conversion of 10-3 (lower spot) to product 10-4 (upper spot). The reaction mixture was concentrated on the rotary evaporator, and the residue slurried in a mixture of MeOH-CHCl3-NH40H (3: 7: 0.1). Anhydrous Na2SO4 was added and the mixture was stirred at room temperature for 12h, filtered and concentrated to give 3.4g of crude guanidino acid 10-5. This material was chromatographed on silica gel (50g), elution with MeOH-CHC13-NH4OH (2: 8: 0.1) to give 0.65g of 10-5, contaminated with inorganic matter (inferred from C, H, N analysis). This material was treated with concentrated HCl (0.5 mL) in absolute ethanol (10 mL) at reflux for 15h, cooled to room temperature, concentrated, dissolved in EtOH (95: 5), dried (MgS04), filtered and concentrated to give 0.34g of the title compound as a hygroscopic tan powder.

NMR (400 MHz, DMSO-d6) 8 12.78 (s, 1H), 9.15 (d, J = 8Hz, 1H), 7.93 (d, J = 9 Hz, 1H), 7.84 (t, J = 6 Hz, 1H), 7.37 (d, J = 7 Hz, 2H), 7.32 (t, J = 7Hz, 2H), 7.25 (m, 1H), 7.1-7.6 (broad, 3H), 7.11 (s, broad 1H), 6.5 (dd, J = 6 Hz, 2.6 Hz, 1H), <BR> <BR> 6.44 (d, J = 2.6 Hz, 1H), 5.48 (q, A portion of an AMX, JAM = 4Hz, 1H), 4.07 (t, J = 5Hz, 2H), 4.0 (m, 2H), 3.53 (m, 2H), 3.03 (q, M portion of an AMX, JMX = 16 Hz, <BR> <BR> 2H), 2.89 (q, X portion of an AMX, JAx = 6 Hz, 2H), 1.08 (t, J = 7 Hz, 3H); (KBr) v<BR> <BR> (cm'') 3350,3180,1745,1690; MS (+FAB) m/z 415 (M+H) +.

Analysis for C2, H26N405HCl. 0@5H20 Calculated: C, 54.85; H, 6.14; N, 12.18.

Found: C, 54.54; H, 6.04; N, 12.58.

Example 280 3- [4-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoi c acid, hydrochloride (10-5) Ester 10-4 was refluxed in IN HCl for 15h. The reaction was cooled and concentrated in vacuo to provide the title compound as a hygroscopic tan powder.

MS (-FAB) m/z 385 (M-H)- ; IR (KBr) v (cl'') 3350,3180,1720,1590.

Analysis for C18H22N4O5#HCl#H2O Calculated: C, 51.76; H, 5.72; N, 12.71 Found: C, 51.76; H, 5.74; N, 12.77.

Scheme 11 fi 10-1--o. 2 HCI H2N O (J. Org. Chem. 1993, 58,7948) 1. DEC, HOBt, NMM/DMF 2. HCL/dioxane nu OH 0 0 0 H HCI \ H2N (/ 11-1 N TMSCI, EtN (i-Pr) 2/dioxane N r IN OH 0'0 I N O H H N 11-2 1. HCI/H20 2. Hz/Pd/C OH O kd O N OH H H NH 11-3 ION HCI-EtOH OH O O o 2 HCI N H) ! ! H N N cri 11-4

Example 281 3-[2-Hydroxy-4-[2-(pyrimidin-2ylamino) ethoxy]-benzoylamino]-3- pyridine-3-ylpropionic acid ethyl ester (11-2).

3-f4- (2-aminoethoxy)-2-hydroxy-benzoylaminol-3-pyridine-3-yl-prop ionic acid ethyl ester dihydrochloride (11-1).

Compound 10-1 see Scheme 1), 3-amino-3- (pyridine-3yl, propionic acid ethyl ester dihydrocloride (1.84g; see J. Org. Chem. 1993,58,7948), NMM (2.58g). HOBt (1.16g), and DEC (1.45g) were combined in dichloromethane (50 mL) and stirred at room temperature for 60 h. Volatile materials were removed on the rotary evaporator, the residue partitioned between ether and H20, the organic phase washed with saturated aqueous brine solution, dried over MgS04, filtered and concentrated to give 3.52g of crude coupled product, which was dissolved in a minimum amount of ethanol and treated with an excess of 4M HCl in anhydrous dioxane (Aldrich). After standing overnight (-15 h), volatile materials were removed on the rotary evaporator to give 3.31g of 11-1. NMR (400 MHz, DMSO-d6) was consistent with the structure of 11- 1; MS (+ FAB) m/z 374 (M + H) +.

Compound 11-1 (3.31g), 2-bromopyrimidine (1.11 g, Lancaster) and DIPEA (7.5 mL) were combined in dioxane (50 mL) at room temperature under N2. Chlorotri- methylsilane (1.89 mL) was added and the mixture was brought to reflux. Stirring continued at this temperature for 4 days. The mixture was concentrated on the rotary evaporator, and the residue partitioned between aqueous HCl solution and chloroform.

The aqueous phase was concentrated to a dark oil and the pH adjusted to 7 with aqueous ammonia. Volatile materials were removed in vacuo and the residue chromatographed on 200g of silica gel, elution with ethyl acetate to give 1.37g of the title compound, as an off-white powder. NMR (400 MHz, DMSO-d6) was consistent with the structure of 11-2; (KBr) v (cl'') 1720; MS (+FAB) m/z 452 (M+H) +.

Analysis for C23H25N505-0-5H20 Calculated: C, 59.99; H, 5.69; N, 15.21 Found: C, 60.45; H, N, 14.79.

Example 282 3- [2-Hydroxy-4- [2- (3,4,5,6-tetrahydropyrimidine-2ylamino)- ethoxy] benzoylamino]-3-pyridin-3-ylpropionic acid (5-3).

A mixture of compound 11-2 (0.9g) and KOH (0.34g) were stirred in water-dioxane mixture (1: 1) at room temperature. When TLC (EtOAc) showed complete absence of starting ester, solvents were removed on the rotary evaporator, 10% Pd/C (0.2g, Aldrich) was added and the mixture suspended in acetic acid (20 mL), dioxane (10 ml), water (5 ml) and concentrated HCl (0.6 mL). The mixture was stirred at ambient temperature under H2 atmosphere (balloon) for 2 days. Celite was added, and the mixture stirred 0.25h, filtered through a pad of celite with the aid of dioxane-water (1: 1), and concentrated. The residue was chromotographed on silica gel (25g), elution with chloroform-methanol-ammonium hydroxide (7: 3: 0.1) to give the title compound 11-3 as an off-white hygroscopic powder. NMR (400 MHz, DMSO-d6 + DO) was consistent with the structure 11-3; IR (KBr) v (cl'') 3400,1650 (broad), 1580; MS (+FAB) m/z 428 (M+H) +.

Example 283 3- [2-Hydroxy-4- [2- (3,4,5,6-tetrahydropyrimidin-2-ylamino) ethoxy] benzoylamino]-3-pyridin-3-ylpropionic acid ethyl ester dihydrochloride (11-4).

A sample of the above zwitterion 11-3 (0.285g) was esterified with absolute ethanol- HCl mixture at reflux. Concentration on the rotary evaporator gave the title compound 11-4. NMR (400 MHz, DMSO-d6) 8 12.55 (s, broad, 1H), 9.5 (d, J = 8Hz, 1H), 8.94 (d, J = 2Hz, 1H), 8.73 (m, 1H), 8.48 (d, J = 2 Hz, 1H), 8.73 (m, 1H), 8.48 (d, J = 8 Hz, 1H), 8.1 (s, broad, 2H), 7.99 (d, J = 9 Hz, 1H), 7.86 (m, 1H), 7.68 (t, J = 6Hz, 1H), 6.5 (d, J = 2 Hz, 1H), 6.47 (m, 1H), 5.58 (q, A portion of an AMX, JAM = 14 Hz, 1H), 4.08-4.0 (overlapping m, 4H), 3.5 (m, 2H), 3.25-3.19 (overlapping m, 3H), 3.09 (q, X portion of an AMX, JMX = 16 Hz, JAx = 6 Hz, 1H), 1.79 (m, 2H), 1.08 (t, J = 7 Hz, 3H).

Analysis for C23H29N5052HCI. 0*7 H20.

Calculated: C, 51.39; H, 6.00; N, 13.03.

Found: C, 51.40; H, 6.01; N, 12.56. a) KOH, 2O, then 20; 0H15(CH2nO(CO)O6H4NO2, 3CN, then HR-MS FAB m/z for C26H34N4O8 calcd. 531.2455 (M++1), obsd. 531.2459.

Scheme 12

Example 284 2 (S)-2-tert-Butoxycarbonylamino-3- {2-hydroxy-4-[2-(1,4,5,6- tetrahydropyrimidin-2-ylamino) ethoxy]-benzoylamino} propionic acid, (12-4) acetic acid salt.

Compound 12-1 (2.43g, scheme 12; obtained as for compound 8-1, Scheme 8, by substituting 2 (S)-2-benzyloxycarbonylamino-3-amino propionic acid ethyl ester (from esterification of the acid (Fluka) using EtOH-HCl) for 2 (S)-2-phenylsulfonylamino-3- amino propionic acid) and NaOH (4g) in 1,4-dioxane-water (-1: 1) were refluxed for 1.5h. The mixture was cooled and volatile materials removed on the rotary evaporator. The residue was neutralized with aqueous 1N HCl and stirred overnight at room temperature. The precipitate was collected by vacuum filtration, re-esterified (EtOH-HCl, reflux), and chromatographed on silica gel, elution with CHCl3,/MeOH/HOAc (90: 10: 1---): 20: 2) to give 850 mg of 12-2, as a tan powder.

The ester 12-2 (0.5g) was hydrolyzed with excess KOH in dioxane-H20 at room temperature. When TLC analysis indicated an absence of starting material, an excess of di-tert-butyl dicarbonate was added and the mixture stirred at room temperature until complete by TLC. The mixture was concentrated on the rotary evaporator and the residue chromatographed on silica gel, elution with CHCl/MeOH/NIOH (90: 1: 1->80 : 20: 2) to give 200 mg of 12-3. This material was dissolved in a minimum amount of acetic acid, then diluted with an-volume of dioxane-H20 (2: 1).

Hydrogenation (5% Pd/C (catalytic), H2, balloon, rt,) was complete within 2 days.

The catalyst was filtered, and the filtrate concentrated on the rotary evaporator. The residue was stirred/concentrated sequentially with heptane and isopropanol, dissolved in CHC13 and treated with a mixture of activated charcoal and celite, filtered and concentrated to give the title compound 12-4 (0.18g) as a fine buff powder. NMR (400 MHz, DMSO-d6) 8 8.85 (broad, 1H), 8.6 (broad, 1H), 8.4 (broad, 1H), 7.68 (d, J = 8.8 Hz, 1H), 6.47 (overlapping peaks, 2H), 6.4 (d, J = 8.8Hz, 1H) 4.02 (t, broad, 2H), 3.88 (m, 1H), 3.45 (m, overlapping, 4H), 3.23 (m, broad, 4H), 1.9 (s, 3H), 1.8

(m, broad, 2H), 1.35 (s, 9H); IR (KBr) v (crin~') 3400 (broad), 1710,1640; MS (ESI-) m/z 464 (M-1) +. Analysis for C21H31N5O7#HOAc#H2O Calculated: C, 50.82; H, 6.86; N, 12.88 Found: C, 50.96; H, 6.56; N, 12.11 HPLC analysis of purity: 96.8 % In like manner, examples 284-315 (Table 14) were prepared, using the synthetic methods outlined above, as indicated by scheme numbers in the table. All final products were characterized as in Examples 1-283, and had spectra consistent with the assigned structures.

Am = Aminidino<BR> Pyr = pyrimidin-2-yl<BR> Thp = tetrahydropyrimidine<BR> Ph = phenyl<BR> Py = 3-pyridin-3-yl<BR> Cbz = benzyloxycarbonyl Table 14. Examples 284-315 Example Synth.<BR> <P>No. &num G n R1 R2 R3 R4 R5 Method<BR> 284 4 Am 1 H H Py H Et 10 b<BR> 285 4 Am 1 H H Py H H 10 b<BR> 286 4 Pyr 1 H H Py H H 11 y<BR> 287 4 Pyr 1 H H Ph H H 8 y<BR> 288 4 Pyr 1 H H Ph H Et 8 v<BR> 289 5 Pyr 1 H H Ph H H 8 t<BR> 290 5 Pyr 1 H H Ph H Et 8 g<BR> 291 4 Thp 1 H H Ph H H 8 b<BR> 292 4 Thp 1 H H Ph H Et 8 b<BR> 293 5 Thp 1 H H Ph H H 8 b<BR> 293 5 Thp 1 H H Ph H Et 8 t<BR> 295 4 Thp 1 H H H NH2 H 8 o<BR> 296 4 Pyr 1 H H H NHCbz Me 8 v<BR> 297 4 Pyr 1 H H H NHCbz H 8 c<BR> 298 4 Pyr 1 Me H H NHSO2 H 8 y<BR> 299 4 Pyr 1 H H H NHCbz ET 8 w Table 14 (Continued)<BR> 300 5 Thp 3 H H Ph H H 12 buffl<BR> 301 5 Pyr 3 H H Ph H Et 8 fused<BR> 302 5 Pyr 3 H H Ph H H 8 fine t<BR> 303 5 Pyr 4 H H H NHSO2Ph H 8 fine c<BR> 304 5 Thp 4 H H H NHSO2Ph Et 8 fused<BR> 305 5 Thp 4 H H H NHSO2Ph H 8 fine b<BR> 306 4 Pyr 3 H H H NHSO2Ph H 8 fine v<BR> 307 4 Thp 3 H H H NHSO2Ph Et 8 fused<BR> 308 4 Thp 3 H H H NHSO2Ph H 8 white<BR> 309 5 Thp 3 H H H Ph Et 8 off-w<BR> 310 4 Thp 2 H H H NHSO2Ph i-Pr 8a fine @<BR> 311 4 Thp 2 H H H NHSO2Ph t-Bu 8b fine @<BR> 312 4 Thp 2 H H H NHSO2Ph (CH2)2O 8c tan w<BR> (CH2)2NH-<BR> BOC<BR> 313 4 Thp 2 H H H NHCO2- H 12 fine t<BR> CH2CH2C10H15<BR> 314 4 Thp 2 H H H NHCO2C10H15 H 12 fin ta<BR> 315 4 Thp 2 H H H NHSO2Ph H2N-C 8d tan p<BR> (CH2OH)3

Vitronectin Receptor Ctvß3 Binding Assay The purpose of this assay is to measure the effect of various <BR> <BR> <BR> compounds on the aVß3-ligand interaction.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Reagents Plasma Membrane Isolation: 15 confluent T 150 flasks of 512P5 cells (aVß3-overexpressing cell line) are washed 2X with Dulbecco's phosphate buffered saline (D-PBS) without calcium or magnesium, pH 7.1. Cells are harvested with 10 mL of trypsin/EDTA and collected by centrifugation. The cell pellet is washed 2X with 0.5 mg/mL of soybean trypsin inhibitor, and resuspended at 10% weight/volume in homogenization buffer (25 mM Tris-HCI, pH=7.4; 250 mM sucrose). The cell suspension is homogenized with 2x30 seconds bursts of a Polytron homogenizer. The homogenate is centrifuged at 3000g for 10 minutes at 4 C. The supernatant is collected, measured, and made 100 mM in NaCl and 0.2 mM in MgSO4. The supernatant is centrifuged at 22,000g for 20 minutes at 4 C, the pellet is resuspended in 7 mL of membrane buffer (25 mM Tris- HCI, pH=7.4; 100 mM NaCl ; 2 mM MgCl2) by 5 strokes of a Dounce homogenizer (tight pestle) and recentrifuged at 22,000g for 20 minutes at 4 C. The pellet is resuspended in 0.5 mL/flask of membrane buffer (stock membranes) and frozen at-80C. Prior to use, stock membranes are Dounce homogenized and diluted 2 uL to 1000 pL in membrane buffer.

Compound Dilution: The stock compounds are dissolved in an appropriate vehicle (typically DMSO) and subsequently diluted in assay buffer composed as follows: 25 mM Tris-HCl (pH=7.4), 100 mM NaCl, 2 mM MgCl2,0.1% BSA.

Plate Preparation Wells of Multiscreen-FB assay plates (Millipore MAFB NOB 50) are blocked with 150 mL of 0.1% polyethylenimine for 2 hours at

4° C. Following incubation the wells are aspirated and washed with isotonic saline solution.

Binding Assay _ 125 IIL of assay buffer is added to each well. Next, 25 pL of labeled ligand is added to each well. 25 pL of unlabeled ligand is added to non-specific binding wells (NSB). 25 pL of assay buffer is added to all other wells. 2 pL of compound is added to appropriate sample wells, and 2 pL of DMSO is added to NSB and total binding (TB) wells. Finally, 25 pL of membrane is added to each well.

The plates are covered and incubated at 37° C for 2 hours in a humidified incubator. Wells are aspirated on a Millipore vacuum manifold, and the wells are washed with 150 pL isotonic saline solution. Wells are again aspirated. The plates are then dried for 1 hour in an 80° C vacuum drying oven. Plates are placed on a Millipore filter punch apparatus, and filters are placed in 12 x 75 mm polypropylene culture tubes. The samples are counted on a Packard gamma counter.

Example Using'25I-Echistatin (specific activity = 2000 Ci/mmol) supplied by Amersham at a final concentration of 50pM, the following parameters are routinely observed: Input 80000 cpm Total Counts 8000 cpm Non-specific binding 200 cpm Analysis of Results: The individual well activity is expressed as a percentage of the specific binding; % Max, and reported as the mean standard deviation. Dose-inhibition relationships are generated for dose (X-axis) vs. % Max (Y-axis) for active compounds using a non-linear regression

computer program (PS-NONLIN), and IC50 values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment.

Results are shown in Table 15 (VnR).

Reference Compounds: Various Arginine-Glycine-Aspartic Acid (RGD)-containing peptides were assessed for the ability to inhibit avb3 binding and the corresponding IC50 values with 95% confidence intervals were generated; peptide structures are given by the standard single letter designation for amino acids. Values obtained compared favorably with adhesion assay results.

Peptid IC50 (pM) 95% Confidence Interval GPenGRGDSPCA 0.064 0.038 to 0.102 GRGDSP 1.493 1.058 to 2.025 GRGDTP 0.490 0.432 to 0.556 GRGDS 0.751 0.690 to 0.817 RGDS 1.840 1.465 to 2.262 GRGDNP 0.237 0.144 to 0.353 GdRGDSP 0.692 0.507 to 0.942 GRGESP inactive at 100 pM References 1. Nesbitt, S. A. And M. A. Horton, (1992), A nonradioactive biochemical characterization of membrane proteins using enhanced chemiluminescence, Anal. Biochem., 206 (2), 267-72.

Osteopontin-avß3 Cell Attachment Assay The purpose of this assay is to measure the effect of various compounds on the RGD-dependent attachment of cells to osteopontin mediated by the av ? 3 integrin.

Reagents Cell Suspension Media: The cells are suspended for assay in the tissue culture media used for normal culture maintenance bufferedwith25mMHEPES(pH7.4)withoutserumsupplementation. with 25 mM HEPES (pH 7.4) without serum supplementation.

Compound Dilution Media: The stock compounds are dissolved in an appropriate vehicle (typically DMSO) and subsequently diluted in the tissue culture media used for normal culture maintenance buffered with 25 mM HEPES (pH 7.4) supplemented with 0.2% BSA (no serum); final vehicle concentration is < 0.5%.

Plate Preparation Human recombinant osteopontin (prepared such as described in Stubbs, J. III, Connective Tissue Research. 1996,35 (1-4), 393-399 is diluted to an appropriate concentration in Dulbecco's phosphate buffered saline (D-PBS) without calcium or magnesium, pH 7.1.100 mL of this solution is incubated in the wells of PRO-BIND assay plates (Falcon 3915) for 2 hours at 37 C. Following incubation the wells are aspirated and washed once with D-PBS; plates can either be used immediately or stored for up to 1 week at 4° C. Prior to assay, the wells are blocked with 1 % bovine serum albumin (BSA) in cell suspension media for 1 hour at 37° C. Following the blocking period, wells are aspirated and washed once with D-PBS.

CellSuspension ocvß3-expressing cell lines are maintained by standard tissue culture techniques. For assay, the cell monolayer is washed three times with D-PBS, and the cells are harvested with 0.05% trypsin/0.53 mM EDTA (GIBCO). The cells are pelleted by low-speed centrifugation and washed three times with 0.5 mg/mL trypsin inhibitor in D-PBS (Sigma). The final cell pellet is resuspended in cell suspension media at a concentration of 106 cells/mL.

Attachment Assay Incubation: 100 mL of diluted test compound is added to osteopontin-coated wells (in triplicate) followed by 100 mL of cell- suspension; background cell attachment is determined in uncoated wells. The plate is incubated at 25° C in a humidified air atmosphere for 1.5 hours. Following the incubation period, the wells are gently aspirated and washed once with D-PBS.

Cell Number Detection: The number of cells attached is determined by an MTT dye conversion assay (Promega) according to the manufacturer's instructions. Briefly, MTT dye is diluted in cell suspension media (15: 85) and 100 mL is added to each well. The assay plates are incubated for 4 hours at 37° C in a humidified 5% C02/95% air atmosphere, followed by the addition of 100 mL stopping/solubilization solution. The assay plates are covered and incubated at 37° C in a humidified air atmosphere overnight. After the solubilization period, the optical density of the wells is measured at a test wavelength of 570 nM with a reference measurement taken simultaneously at 630 nM.

Analysis of Results: The individual well optical density is expressed as a percentage of the maximal attachment (% Max) wells minus background attachment, and reported as the mean standard deviation. Dose- inhibition relationships are generated for dose (X-axis) vs. % Max (Y- axis) for active compounds using a non-linear regression computer program (PS-NONLIN), and ICst values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment.

Results are shown in Table 16 ("cell").

Reference Compounds: Various Arginine-Glycine-Aspartic Acid (RGD)-containing peptides, and monoclonal antibodies (Chemicon, Temecula, CA) were assessed for the ability to inhibit osteopontin-avb3 attachment and the corresponding IC50 values with 95% confidence intervals were generated in the SK-MEL-24 human alignant melanoma cell line;

peptide structures are given by the standard single letter designation for amino acids: Peptide IC50 (95% Confidence Interval) GPenGRGDSPCA 0.58 mM (0.51 TO 0.67) n-Me-GRGDSP 4.0 mM (3.4 TO 4.7) GRGDSP 4.1 mM (3.4 TO 4.9) GRGDTP 5.2 mM (3.4 TO 4.9) Antibody Dilution % Maximal Attachment (mean SD) 1:1000111#3.3αvß5(P1F6) 1: 100 112+2.6 1: 10 111 # 3.3 UIVP3 (LM609) 1: 1000 0 1: 100 5.1 + 1.7 Literature References: Ruoslahti, R. Fibronectin and its receptors. Ann. Rev. Biochem.

57: 375-413,1988.

Hynes, R. O. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell. 69: 11-25,1992.

Osteoclast Pitting Assay The assay is conducted as described in Murrills and Dempster (1990). Briefly, 4 x 4 x 0.2mm slices of devitalized bovine cortical bone are numbered, placed in the wells of 96-well culture plates and wetted with 100ul of Medium 199 containing Hanks salts, IOmM HEPES, pH 7.0 (Medium 199/Hanks). Bone cell suspensions containing osteoclasts are prepared by mincing the long bones of neonatal rats (Sprague-Dawley, 4-6 days old) in Medium 199/Hanks. 100uL of the suspension is then plated onto each slice and incubated 30 minutes to allow osteoclasts to adhere.

The slices are rinsed to remove non-adherent cells and incubated 24h in Medium 199 containing Earle's salts, IOmM HEPES and 0.7g/L NaHCO3, which equilibrates at pH 6.9 in a 5% CO2 atmosphere. At this pH the adherent osteoclasts excavate an adequate number of resorption pits for assay purposes. Slices are fixed in 2.5% glutaraldehyde and osteoclasts counted following tartrate-resistant acid phosphatase staining. In experiments in which osteoclast numbers are significantly reduced in a particular treatment, a check is made for non-specific cytotoxicity by counting the number of contaminant fibroblast-like cells following toluidine staining. All cells are stripped from the slice by sonication on 0.25M NH40H and the resorption pits formed by the osteoclasts during the experiment stained with toluidine blue. Resorption pits are quantified by manually counting.

Statistics The experiments are conducted according to a block design with osteoclasts from each animal exposed to each treatment. Three replicate slices are used per treatment per animal, such that a total of 96 slices are examined for an experiment involving four animals and eight treatments (including control). Several parameters are recorded on a"per slice"basis: number of pits, number of osteoclasts, number of pits per osteoclast, number of fibroblast-like bone cells. SAS or JMP statistical software is used for statistical analysis. If analysis of variance reveals significant effects in the

experiment, those treatments differing significantly from control are identified using Dunnett's test. IC50s are calculated for active compounds using dose-response curves. <BR> <BR> <BR> <BR> <P>Results are shown in Table 16 ("Bone Pitting"). _ Reference Compound: Rat calcitonin.

Clinical Relevance: Osteoclasts are responsible for the bone loss that occurs in the onset of osteoporosis and anti-resorptive drugs directed against the osteoclast are a requirement for patients losing bone. Calcitonin and bisphosphonates, both used as anti-resorptives in the clinic, show significant osteoclast inhibitory activity in this assay. Hence it is a reasonable assay in which to identify novel anti-resorptives.

Reference: Murrills and Dempster (1990) Bone 11: 333-344.

Effects of test compounds on PTH-induced hypercalcemia of thyro- parathyroidectomized male rats.

Male thyro-parathyroidectomized (TPTX) rats (Charles River) were randomly assigned to groups of 7 rats/group. Following a baseline serum calcium determination an Alzet 1003D minipump (Alza Corporation, Palo Alto, CA) loaded with 0.3 mg/ml PTH (Bachem, Philadelphia, PA) was implanted subcutaneously in each rat. For evaluation of prophylactic effects of a test drug, another minipump with appropriate concentration of the test drug solution was implante subcutaneously at a site away from PTH minipump. Alternatively, test drugs were administered by oral gavage as a solution or uniform suspension in an appropriate medium depending on the physical properties of the test compound. A group of 7 unimplanted TPTX rats was set aside as a normal control group. Twenty hours after minipump implantation blood was collected from each rat to confirm the presence of hypercalcemia (judged by elevation of serum calcium levels, 2 SD > normal non-implanted level). At various intervals between 0.5 and 24 hours after dosing (usually one to three time points), blood was collected from each rat and the serum evaluated for total calcium. Serum calcium levels were measured using the Nova 7 + 7 calcium auto analyzer spectrophotometrically using the Sigma test kit (#587A). Test results were

determined by the difference in serum calcium between vehicle and treatment group following PTH administration, using a one-way analysis of variance with Dunnett's test or other multiple comparison methods. Results are shown in Table 17.

References: 1. Takeuchi M, Sakamoto S, Kawamuki K, Kudo M, Abe T, Fujita S, Murase K, and Isomura Y, (1990). Synthesis and structure activity relationship of new bisphosphonate derivative. Abstract #53, 199th American Chemical Society Meeting, Boston, MA.

2. Fisher J, Caulfield M, Sato M, Quartuccio H, Gould R, Garsky V, Rodan G.

Rosenblatt M, (1993). Inhibition of osteoclastic bone resorption in vivo by echistatin, an"arginyl-glycyl-aspartyl" (RGD)-containing protein.

Endocrinology, Vol. 132 (3) 1411-1413.

Table 15 Representative Biological Data Example VnR (IC50µM) Example VnR (ICjORM) 10. 0241137>luM 2 0. 187 138 0. 361 30. 123n9>IuM 4 0. 095 140 0.0978 141>1uM50.061 6 0. 108 142 1. 6 1434.7970.092 8 >luM 144 9 0. 11 145 10 0. 061 149 11 0. 0696 150 151120.0661 13 0. 1828 152 14 0. 0445 153 2. 4 (IC50µM)ExampleVnR(IC50µM)ExampleVnR 15154 16-1-25 156 17 156 0. 25 18157 4.619158 201. 4371592 21 1. 516 160 0. 97 22 161 0. 9 23 1.0216 162 1.1 24 1. 48 163 1. 1 25 0. 6743 164 0 61 0.3926165 1660.8270.3308 28 0. 159 167 2. 6 29 0. 405 168 30 1. 27 169 31 0. 261 170 32 171 33 172 4.2834173 3.8935174 3. 89 36 175 3. 8 37176 2. 14 38 177 4. 87 4. 87 39 178 3. 13 3. 13 >1uM40179 41 180 19. 46 42 19.72 43 182 40. 88 44 183 4.98 17.8845184 17. 88 46 185 4.57 47186 6. 99 Example VnR(IC50µM)Example 48 187 19. 46 12.1449188 50 189 6.87 51 190 >1uM >1uM52191 53 34 192 >Ium 54 34 193 > I uM 194>1uM55100.6 195>1uM5685.8 5.712757196 197>1uM58100 198>1uM59100 14.69460199 61200>IuM 20113.21562100 >1uM63202 14.13664203 651002047.4788 66100205>luM 206>1uM67100 207>1uM68100 69100208>luM >1uM100209 71>luM210>IuM >1uM>1uM211 13.066>1uM212 >1uM>1uM213 2142.3125 215>1uM 77 216 21778>1uM 21879>1uM 2191.880>1uM Example VnR(IC50µM)Example 2208.881>1uM 22122.882>1uM 83>IuM222208- 5.584223 2244.185>1uM 86 > luM 225 5 2265.287>1uM 2275.188>1uM 10.289228 22917.190>1uM 230491>1uM 2316.792>1uM 2323.793>1uM 2333.394>1uM 95 0. 105 234 8. 7 2353960.119 97 0.77 236 1. 9 2362.7980.15 99 0. 088 238 100 0. 079 239 2. 1 101 0. 094 240 102 0. 069 241 4. 1 103 0. 21 242 7. 9 104 0. 086 243 0. 69 105 0. 135 244 1. 6 106 0. 114 245 2461.61070.13 2475.51081.105 109 0. 251 248 110 0. 544 249 111 0. 856 250 112 1. 092 251 113 3. 026 252 Example VnR(IC50µM)Example 114 3. 139 253 115 0. 258 254 116 2. 761 255 5. 31 117 1. 518 256 9. 08 2571.26118>1uM 2584.31119>1uM 259120>1uM 260121>1uM 26120.18122>1uM 123>luM 26212. 64 124 0. 734 263 29.03 26459.27125>1uM 26512.88126>1uM 127 0. 9546 266 29.57 26710.16128>1uM 129 0. 6349 268 33. 44 26921.23130>1uM 131 0. 4055 270 21.66 132 0. 9625 271 13. 7 27210.63133>1uM 273134>1uM 274135>1uM 136 >luM 275 276 277 278 279 0. 013 280 12. 3 281 inactive 282 -42%100 283 123 284 inactive 285 5 Example VnR(IC50µM)Example 286 2. 8 287 0.26 288 0.03 bone pitting µM 289 inactive 290 0.334 291 0. 44 292 0.115 293 0.006 294 0. 0035 2950.0018 Table 16. In Vitro Biological Data

(µM)ExampleIC50 No. BonePittingBA 280 78 inactive @200 297 50 25 277 0. 05 0. 4 278 0. 02 0. 5 274 18 0. 9 293 48 276 0. 12 0.15 291 28 275 0. 002 0.43 299 inactive @ 100 1. 9 298 285 56 286 86 282 33 289 34 A Osteopontin - αvß3 Cell Attachment Assay B Osteoclast Pitting Assay Table 17. In Vivo Biological Data

Example dose(mg/kg, No. (% inhibition) route) 292 s.c.100. 279 59 100, s. c.. 27357100. s. c. 100.s.c.27786* 79* lOt. p. o. 276 170* 100 sc 100.s.c.27454* 275 112* 100, S. C. (64) 30, s. c. * 75. s. c. 39100. p. p. 291 l00. s. c. 100.p.o.299102* * p< 0.05 when compared to vehicle control The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and salts with organic acids such as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium. The compounds of the present invention can also be used in the form of esters at the C-terminus; carbamates, amides and the like at the N-terminus or other conventional"pro-drug"forms which, when administered, convert to the active moiety in vivo.

Compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene

glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils.

Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. These compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. When administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions, formulations may contain, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, or elixirs containing, for example, from about 20 to 50% ethanol, and the like. When administration is parenterally, formulation may be, for example, sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% by weight of active ingredient in <BR> <BR> <BR> <BR> combination with a carrier, and more preferably between about 5% and 60% by weight of active ingredient.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release release form. Preferably, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response as would be appreciated by one skilled in the art. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigences of the therapeutic situation.