Title of Invention

VLA-4 INHIBITOR COMPOUND OF FORMULA I

Abstract

ABSTRACT OF THE INVENTION Compounds that sdectively inhibit the binding of ligands to α&β1 integrin (VLA-4) and methods for their preparation are disclosed. In one embodiment, compounds of the invention are represented by Formula 1: As selective inhibitors of VLA-4 mediated cell adhesion, compounds of the present invention are useful in the treatment of conditions associated with such adhesion, including, but not limilcd to, such conditions as inflammatory and autoimmune responses, diabetes, asthma, psoriasis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. Also disclosed are methods of inhibiting VLA-4 mediated cell adhesion and methods of treating conditions associated with LA-4 mediated cell adhesion.

Full Text

FIELD OF THE INVENTION The present invention relates to compounds that selectively inhibit the binding of ligands to the adhesion receptor, a,P] inlegrin, also known as VLA-4. Compounds of the present invention are useful in the treatment and prevention of pathologies associated with VLA-4 mediated cell adhesion, such as inflammatory and autoimmune diseases, and tumor metastasis. BACKGROUND OF THE INVENTION A primary feature of such pathologies as inflammation and autoimmune diseases is the accumulation of activated leukocytes in affected tissues. The process by which leukocytes transmigrate from the circulation at a site of inflammation involves a cascade of interactions that can be divided into four major steps: tethering and rolling, activation, firm adhesion, and transmigration (Springer, T., Ann. Rev. Physiol. 57:827 (1995)). Initially, leukocytes are lightly tethered to the endothelium and roll along its surface. This is followed by cell activation, mediated by soluble chemotactic stimuli, which initiates the development of a firmer bond between individual leukocytes and endothelial cells. The firm bond then results in the successful adhesion and transmigration of the leukocytes through endothelial cell junctions. The steps occur in series and each is essential for transmigration to occur. This also means that transmigration can be modulated at each step, thus providing a number of potential targets for pharmacological inhibition. The receptors involved in leukocyte migration have, to a large extent, been characterized as belonging to particular cell adhesion molecule families (Carlos and Harlan, Blood, 84:2068 (1994)). The initial attachment and rolling step is mediated by a family of adhesion receptors referred to as selectins. Firm adhesion is mediated by interaction of leukocyte surface integrins with molecules of the immunoglobulin superfamily expressed on the surface of the endothelium. Both integrins and the immunoglobulin-type adhesion molecules are also primarily involved in leukocyte transmigration. After transmigration, the leukocytes rely on integrins to traverse through the extracellular matrix and remain at the site of inflammation, Integrins are a large family of heterodimeric glycoproteins composed of two noncovalently associated subunits, a and p (Hynes, R.. Cell. 69:11 (1992)), There are at least 16 different a subunits (arct9, ctL, aM, aD, ctx aE, a^, a.) and at least 9 different p (P,-Ps) subunits. Integrins are divided inlo sub-families, based upon the p subuiiit. Leukocytes express a number of different integrins, including a4P,, (XJP,, a6p,, a,p7, aLP 2, ax^h and ctvp3. a4p, integrin, also known as very late antigen-4 (VLA-4) or CD49d/CD29, is expressed on monocytes, lymphocytes, eosinophils, and basophils, all of which are key effector cells in various inflammatory disorders (Helmer, M., Ann. Rev. Immunol.. 8:365 (1990)). a4p, integrin serves as a receptor for vascular cell adhesion molecule-1 (VCAM-1), as well as to the extracellular protein fibronectin (FN) (Elices eta!.. Cell. 60:577 (1990)). Anii-inflammatory effects and delayed disease progression have been demonstrated after in vivo monoclonal antibody blockade of the tx4p/VCAM-1 pathway (Lobb ef a/.. J. Clin. Invest.. 94:1722-28 (1994)). In a-guinea pig mode] of pulmonary inflammation, anti-a4 inhibited both antigen-induced bronchial hyperreactivity and leukocyte recruitment in bronchoalveolar lavage fluid (Pretolani et al., J. Exp. Med.. 180:795 (1994)). Antibodies to aA or VCAM-1, prevented antigen-induced eosinophil infiltration of the mouse trachea fNakajima et al.. J. Exp. Med., 179:1145 (1994)). a4or VCAM-1 monoclonal antibody treatment also delayed or prevented cutaneous delayed hypersensitivity response in mice and monkeys (Chisholmef a!., Eur. J. Immunol.. 23:682 (1993); Silberef al., J, Clin. Invest.. 93:1554 (1993); cardiac allograft rejection in mice, accompanied by specific immunosuppression (Isobeer al.. J. Immunol.. 153:5810 (1994); grafi-versus-host disease in mice after bone marrow transfer (Yanee/a/. .Proc. Natl. Acad. Sci. USA, 90:10494. (1993); and experimental autoimmune encephalomyelitis in rats and mice (Yednock ef at., Nature, 356:63 (1992); Baron et al.. J. Exp. Med.. 177:57 (1993)). Rational drug design studies have produced soluble VCAM-Ig fusion protein containing the two N-tenninal domains of human VCAM-1 fused to a human IgGl constant region. In vivo administration of the fusion protein significantly delays the onset of adoptively transferred autoimmune diabetes in n on obese diabetic mice (Jakubowski et a I.. J. Immunol.. 155:938 (1995)), Another approach has used three-dimensional crystallographic structures of VCAM-1 fragments lo synthesize cyclic peptide antagonists that closely mimicked the a4 integrin binding loop in domain 1 of VCAM-I. Synthetic VCAM-1 peptide CQIDSPC, was able to inhibit the adhesion of VLA-4-expressing cells to purified VCAM-1 (Wang et a!., Proc. Natl. Acad. Sci. USA. 92:5714 (1995)). An additional strategy is to block the binding of a4pi lo its other counter receptor, that is, an alternatively spliced region of fibronectin containing the connecting segment-1 (CS-1) motif (E.A. Wayner, J. Cell. Biol., 116:489 (1992)). A synthetic CS-1 tetrapeptide (phenylacetic acid-Leu-Asp-Phe-d-Pro-amide) inhibited VLA-4-mediated lymphocyte adherence in vitro and reduced accelerated coronary arteriopathy in rabbit cardiac allografts (Molossi et a!., J. Clin. Invest-, 95:2601 (1995)). Each of these studies provide evidence that selective inhibition of a4p,/VCAM-1 mediated adhesion is a proven strategy in the treatment of autoimmune and allergic inflammatory diseases. Moreover, while United States Patent 5,821,231 and PCT Applications WO 96/22966, WO 97/03094, WO 98/04247 and WO 98/04913 describe compounds exhibiting VLA-4 inhibitory activity in in vitro binding assays, none of the described compounds have exhibited efficacy in oral administration. Accordingly, despite these advances, there remains a need for small, non-peptidic, specific inhibitors of VLA-4 dependent cell adhesion that are orally bioavailable and that are suitable for the long-term treatment of chronic inflammatory diseases and other pathologies associated with leukocyte migration and adhesion. SUMMARY OF THE INVENTION The compounds of the present invention selectively inhibit the binding of ligands toa,p, and therefore, are useful for inhibition, prevention and suppression of VLA-4-mediated cell adhesion and the pathologies associated with that adhesion, such as, for example, inflammation, asthma, arthritis, diabetes, autoimmune responses, multiple sclerosis, psoriasis, transplantation rejection, and tumor metastasis. In one embodiment, the present invention provides a compound represented by Formula I, or a sail thereof, wherein W is chosen from aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group; ■ W1 is chosen from arylene group, substituted arylene group, heteroarylene group and substituted heteroarylene group; A is chosen from =0, =S and =NH; R , R and R are independently chosen from -H, -OH,-NH2, halogen atom, alkyl group, substituted alkyl group, aryl group, substituted aryl group, alkoxy group, substituted alkoxy group, monoalkylamino group, substituted monoalkylamino group, dialkylamino group, substituted dialkylamino group, cycloalkylamino group, substituted cycloalkylamino group, alkylsulfonylarnino group, substituted alkylsulfonylamino group, aryl sulfonyl amino group, substituted arylsulfonylamino group, aryloxy group, substituted aryloxy group, heleroaryloxy group, substituted heteroaryloxy group, benzyloxy group and substituted benzyloxy group, or two ofR1, R1 and R3 taken together may form a 3-, 4-, 5-, 6-, or 7-membered earbocyclic or heterocyclic residues optionally substituted with from 1 to 3 substituents chosen independently from -OH, halogen atom, -NH2> alkyl group, alkoxy group, aryl group, aryloxy group, alkylamino group, benzyloxy group and heteroaryl group; R4 is chosen from -H and lower alkyl group; Y is a direct bond or a divalent radical chosen from -C(0)-, -C(0)NH-, alkenylene group, alkynylene group and -(CH3)kY , wherein k is chosen from 1, 2 and 3; and Y2 is a direct bond or a divalent radical chosen from -O-, -S-, -S(O), -5(0)r and -NY3-, wherein Y is chosen from -H and lower alfcyl group; Z is chosen from arylene group, substituted aryfene group, heterocydylene group, substituted heterocyclylene group, cycloalkylene group afld substituted cydoaUcylene group; A1 is a direct bond or a divalent radical chosen from aUcenylene group, alkynylene group, -(CH2)f and -0(CH!)v, wherein embodiment, more preferred compounds are those wherein A is =0, R is -(CH2)„- and X is -C(0)-. Y is preferably chosen from alkenylene group, alltynylene group, -{CHj^Y2, -CH2S(0> and -CH20-, arid more preferably, Y is -CH20-. Preferred compounds of this embodiment are those wherein W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alicyl group and halogen atom at the ortho positions thereof. W1 is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-. In preferred compounds of this embodiment, A is preferably =0 and A1 is a direct bond or -(CH2)[- More preferred compounds are those wherein A is a direct bond and R5 is -OH, this embodiment, more preferred compounds are those wherein A is =0, R is -(CHj),,- and X is -C(0>. Y is preferably chosen from -0-.-S-, -S(0)-, -S(0)j- and -NY'.and more preferably, is -0-. Preferred compounds of this embodiment are those wherein W is unsubstituted phenyl gTOup or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof. W is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-. In this embodiment of Formula I, A is preferably =0 and A2 is a direct bond or -(CH3)e-. More preferred compounds are those wherein A2 is a direct bond and R1 is -OH. is -CH2-andXis =0, are represented in Table 3. With respect to the representation of-W1, the lower bond is the point of attachment to -NH- and the upper bond is the point of attachment to -R-. The principles of the present invention also encompass prodnigs in the scope of Fonnula 1, and compounds lepresemalive iheieof include Ihose wheiein R oi R* is a lowci alkoxy group, and those wherein R'" or R" is a lower alkoxycarbony! group. The principles of the present invention also provide a method for inhibiting cell adhesion, and in particular, VLA-4 mediated cell adhesion at o:4pl receptor sites in a manunal, wherein the method comprises administering an effective amount of a compoimd represented by Formula I. As used herein, inhibiting ceil adhesion is intended to include inhibiting, suppressing and preventing VLA-4 mediated cell adhesion-associated conditions, including but not limited to, inflammation and cell adhesion-associated immune or autoimmune responses. The principles of the present invention therefore also provide a method of treating a condition associated with VLA-4 mediated eel! adhesion, wherein the method comprises adminisiering to a mammal in need of such treatment, an effective amoimt of a compoimd TepicsenWd by Formula I. Such conditions include for example, but are not limited to, inflammatory and autoimmune responses, diabetes, asthma, artluitis, psoriasis, multiple sclerosis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. As used herein, "treatment" of a mammal is intended to include prophylaxis as well. The compounds of the present invention may be administered as a monotherapy, or in combination with antiinflanunalory or immunosuppressive agents. Such combination therapies can involve the administration of the various phannaceuticaJs as a single dosage form or as mtiltiple dosage forms administered at the same time or at different times. Any suitable route of administration may be crapioyed for providing a patient with an effective amount of a compound of the present invention. Suitable routes of administration may include, for example, oral, rectal, nasal, buccal, parenteral (such as, intravenous, intrathecal, subcutaneous, intramuscular, intrastemal, intrahepatic, inlralesional, intracranial, intra-aiticular, and intra-synovial), transdermal (such as, for example, patches), and the like. Due to their case of administration, oral dosage forms, such as, for example, tablets, troches, dispersions, suspensions, solutions, capsules, soft gelatin capsules, and the like, may be preferred. Administration may also be by controlled or sustained release means and delivery devices. Methods for the preparation of such dosage forms are well known in the art Pharmaceutical compositions incorporating compounds of the present invention may include excipients, a pharmaceutically acceptable carrier, in addition to other therapeutic ingiedicnts. Exdpients such as starches, sugars, microcrystalline cellulose, diluents, lubricants, binders, coloring agents, flavoring agents, granulating agents, disintegrating agents, and the like may be appropriate depending upon the route of administration. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, ammonium salts, alkali metal salts, metallic salts made irom aluminum, calcium, lithium, magnesium, potassiimi, sodium and zinc, organic salts made fiom ciiloroprocaine, choline, ^.y-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, cthylenediamine, lysine, meglumine (A'-methylglucamine) and procaine, as well as salts with amino acids, such as arginine, lysine, and so forth. Where the compounds of the invention have a basic moiety, such as an amino group, the compounds may be used in the form of pharmaceutically acceptable non-toxic organic or inorganic acids. Such acids include acetic, benzenesuifonic, benzoic, camphorsuifonic, citric, cthanesulfonic, mcthanesulibnic, fiimaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-loluenesulfonic acids, and the like. Particularly preferred are citric, hydrochloric, maleic, fiimaric, phosphoric, sulfuric, tartaric and/i-tolucnesulfonic acids. Compounds of the invention may also be in the form of hydrates. immuloglobulin domains) VCAM-IgG fusion protein = a VCAM IgG ftision prolcin containing the one to seven immunoglobulin domains of human VCAM-l (D1D7) attached above the hinge region of an IgGl molecule "Alkyl group" is intended to include linear or branched hydrocarbon radicals and combinations thereof of I to 20 carbons. "Lower alkyl group" means alkyl groups of from 1 to about 10, preferably from 1 to about 8, and more preferably, from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, /i-propyl, isopropyl, n-butyl, isobutyl, jec-butyl, /erf-butyl, pentyl, /jo-amyl, hexyl, octyl groups and the like. "Alkylene group" means a divalent radical formed by removing a hydrogen atom from an "alkyl group." "Aiyl group" means a radical formed from an aromatic hydrocarbon ring of 4 to about 16 carbon atoms, preferably of 6 to about 12 carbon atoms, and more preferably of 6 to about 10 carbon atoms. The rings may optionally be substituted with 1-3 substitucnts selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, phenyl and heteroaryl. Examples of aryl groups are phenyl, biphenyl, 3,4-dJchlorophenyl and naphthyl. "Arylene group" means a divalent radical formed by removing a hydrogen atom from an "aryl group." "Aiylalkyl group" denotes a structure comprising an alkyl attached to an aiyl ring. Examples include benzyl, phenethyl, 4-chlorobenzyl, and the like. "Cycloalkyl group" refers to a saturated hydrocarbon ring radical of from 3 to 12 carbon atoms, and preferably from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, adamantyl, myrtanyl groups and the like. "Lower cycloalkyl group" refers to cycloalkyl of 3 to 6 carbons. "Cycloalkylene group" means a divalent radical formed by removing a hydrogen atom from a "cycloalkyl group." "Divalent C, to C20 aliphatic hydrocarbon moiety" includes alkylene, cycioallcyJcne, alkenylene, alkynylcne groups and combinations thereof. Examples include ethylene, propylene, propynylcne, 2,4-hepIadieny!ene groups and the like, "Heterocyclyl group" refers to a cyclic radical having from 1 to 6 carbon atoms, preferably 3 to 6 carbon atoms, and from 1 to 4 hclcroaloms chosen from 0, N and S. Examples include: pyiTOlyl. pyridinyl, pyiazolyl, uiazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thienyl, furyl, azelidiyl, letrazolyl, 2-pyrTolinyl, 3-pyiTolinyl, pyirolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazoIyl, l,2,3-tria2olyl, I,3,4-thiadia2olyl, 2H-pyranyl, 4H-pyranyI, piperidinyl, 1.4-dithianyl, morpholinyl, thiomoipholinyl, pyrazinyl, pipcrazinyl, l,3,5-tria2inyl, 1,2,5-trithiaiiyl, ben2o(b)thiophenyl, bcnzimidazolyl, quinolinyl groups and the like. "Heterocyclyl ene group" means a radical fonned by removing a hydrogen atom from a "heterocyclyl group." "Heteroaryl group" refers to an aromatic cyclic radical having from I to 12 carbon atoms, preferably 1 to 6 carbon atoms, and from 1 to 4 heteroatoms chosen from 0, N and S; or a bicyclic 9- or 10-mcmbcred heteioaromatic ring system containing 1-4 heteroatoms selected from O, N and S, The methine H atoms of a heterocyclyl or heleroaiyl structure may be optionally substituted with alkyl, alkoxy or halogen. Examples include: imidazolyl. pyiidyi, indolyl, thienyl, benzopyranyl, thiazolyl, furyl, bcnzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, tetrazolyl, pyrazolyl groups and the like. "Hcteroarylene group" means a divalent radical fonned by removing a hydrogen atom from a "heteroaryl group," "Alkoxy group" means a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 4 carbon atoms, and an oxygen atom at the point of attachment. Suitable alkoxy groups include methoxy, elhoxy, n-propoxy, isopropoxy. «-bu(oxy, wo-buloxy. sec-butoxy, /erf-butoxy, cyclopropoxy, cyclohexyloxy groups and the like. "Lower alkoxy group" refers to alkoxy groups having from 1 to 4 carbon atoms. "Alkcnyl group" refers lo an ursaturaled ac>-c!ic hydrocarbon radical in so much as it contains at leasl one double bond. "Lower allcenyl group" refers to such radicals containing from 2 to JO cartwn atoms, preferably from 2 to 8 carbon atoms and more preferably fr-om 2 Jo6 caibon atoms. Examples of suitable aJkcnyl radicals include propenyl, buten-I-yl, isobulcnyl, pcnien-1-yI, 2-metbylbuten-l-yl, 3-mctbyibuten-l-yi, hcxen-1-yl, heplen-!-yl, and octen-l-yl groups and the like. "Alkenylene group" means a divalent radical formed by removing a hydrogen atom from an "alkenyl group," "Alkynyl group" refers lo an unsaturated acyclic hydrocarbon radical containing at least one triple bond. Examples include ethynyl, propynyl groups, and the Jiltc. "Alkynylcne group" means a divalent radical formed by removing a hydrogen atom from an alkynyl group." "Substituted alkyl group" means a linear or branched allg-l group wherein at least one hydrogen atom attached to an aliphatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carlwxy, alkoxycarbonyl, monoalkylamino, alkyJoxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsolfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalky], haloalkyl, acylamino. dialkj'lamino, cyclicamino groups, halogen atom and nitro. Examples of such substituent groups include methyl, isopropyl, methoxy, ethoxy, propoxy, amino, methylamino, phenyl, naphthyl groups, chlorine, fluorine and the like. "Substituted alkylene group" means a linear or branched alkylene group wherein al least one hydrogen atom attached to an aliphatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl. alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonyialkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro. "Substituted cycloalkyl group" means a cycloalkyl group wherein al least one hydrogen alom attached to a ring carbon atom is replaced with a substiment such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl. aikylthio, alkylsulfinyl, alkylsuifonyl, arylthio, cartraxyalkyl, alkoxycarbonyJalkyl, haloalkyl. acylamino, diaikylamino, cyclicamino groups, halogen atom and nilro. "Substituted cycloalkyene group" means a cycloalkylene group wherein at least one hydrogen atom attached lo a ring carton is replaced with a substituetit such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycaibonyl, monoalkylamino, alkyloxy. cyanoalkyl, cycloalkyl, aikylthio, alkylsulfinyl, alkylsuifonyl. aiylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalky!, acylamino, diaikylamino, cyclicamino groups, halogen atom and nitro. "Substituted aiyl group" means an aiyl group wherein at least one metfiinc hydrogen atom attached lo an aromatic carbon is replaced with a substitucnt such as alkyl, amino, alkoxy, ■ hydroxy, aryl, cyano, carboxy, alkoxycaibonyl. monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, aikylthio, alkylsulfinyl, alkylsuifonyl, arylthio, carboxyalkyl, alkoxycaibonylalkyl, haloalky], acylamino, diaikylamino, cyclicamino groups, halogen atom and nitro. Substituted arylene group" means an arylene group wherein at least one hydrogen atom attached to an aromatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, cartoxy, alkoxycaibonyl, monoalkylamino, alkyloxy, cyanoalkyl. cycloalkyl, . aikylthio, alkylsulfinyl, alkylsuifonyl, arylthio. carboxyalkyl, alkoxycartjoi^lalkyl, haloalky!. acylamino, diaikylamino, cyclicamino groups, halogen atom and nitro. "Substituted heteroaryl group" or "substituted heterocyclyl group" means a hcteroaryl or heterocyclyl group wherein at least one hydrogen atom attached to a ring thereof is replaced with a substituent such as alkyl, amino, alkoxy. hydroxy, aryl, cyano, carboxy, alkoxycaibonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, aikylthio, alkylsulfinyl, alkylsuifonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, diaikylamino. cyclicamino groups, halogen atom and nitro. "Substituted heteroaiylene group" or "substituted heterocyclylene group" means a heteroaiylene or heterocyclylene group wherein at least one hydrogen atom attached to a ring thereof is replaced with a substituent such as alkyl, anuno, alkoxy. hydroxy, aiyl, cyano, carboxy, alkoxycaibonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl. aikylthio, alkylsulfinyl, alkylsuifonyl, aiylthio, carEioxyaikyJ, alkcxycarbonyJalkyl, haloalkyl, acylamino. diaikylamino, cyclicamino groups, halogen atom and nitro. "Substituted aiylalkyl group" means an aiylalkyl having one or more subsdtuents such as alkyl, amino, alkoxy, hydroxy, aiyi, cyano, carboxy, alkoxycarbonyl, monoalkylamino, aUcyloxy, cyanoalkyl, cycloalkyl, alkyiihio, alkylsulfinyl, alkylsulfonyl, aiyllhio, caitoxyalkyl, haJoalkyl, alkoxycarbonylalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro, "Halogen" is intended to include for example, F, CI, Br and I. The term "prodrug" refers to a chemical compound that is converted to an active agent by metabolic processes in vivo. [See, e.g., N. Boder and J.J. Kaminski, .^nn. Rep. Med. Chem. 22:303 (T987) and H. Bundgarrd, ^(A', Drug Delivery Rev., 3:39 (1989)]. The use of prodrug precursors of compounds of the present invention in any of the methods described herein is contemplaled and is intended to be within the scope of the invention. Terminology related to "protected," "protecting" and/or "deprotecting" functionalities is used throughout this application. Such tenninology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In this context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirabJe. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in wliich the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups" for the fimctionalities involved. In the case of the present invention, the functionalities that must be protected are amines. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistiy, such as Protective Groups in Organic Svnthesis by T.W.Greene fJohn Wilev & Sons. New York. 1991], which is incorporated herein by reference. Particular attention is drawn to the chapter entitled "Proiecrion for the Amino Group" (pages 309-405). Preferred protecting groups include BOC and Fmoc. E^templary mediods for protecting and deprotecting with these groups are found in Greene and Wuts on pages 318 and 327. The materials upon which the syntheses described herein are performed are referred to as solid supports, beads, and resins. These terms are intended to include: (a) beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzenc and optionally grafted with polyethylene glycol, poly- acrylamide beads, latex beads, dimethylacryjamide beads optionally cross-linked with NJ TcntageFM NH, (Rapp Polymere, Tubingen, Germany) is a preferred amine fbnctionalizcd polyethylene glycol- grafted polystyrene resin. Tentagei'"-S-PHB resin has a para-hydroxy benzyl linker which can be cleaved by the use of 90% trifluoroacetic acid in dichloromcthane. Techniques for fimctionalizing the surface of solid phases arc well known in the ait. Attachment of lysine to the amino groups on a bead (lo increase the number of available sites) and subsequent attachment of linkers as well as fiirther steps in a typical combinatorial synthesis are described, for example, in PCT application WO95/30642, the disclosure of which is incorporated herein by reference. In Hie synthesis described in W095/3Q642, the linker is a photolyticaliy cleavable linker, but the general principles of the use of a linker are well illustrated Optical Isomers - Diaslereomers - Geometric Isomers Some of the compounds described herein contain one or more asymmetric centers and may thus give rise lo enaniiomers, diaslereomers, and other stcreoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (5)-, or as (D)- or (i)- for amino acids. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (i)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using convendonal techniques. When the compounds described herein contain olcfinic double bonds or other centers of geometric asymmetry, and unless specified olhenvisc, it is intended lo include both (£)- and (Z)- geometric isomers. Likewise, all tautomeric forms are intended to be included. The configuration of any carbon-Carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-caibon double bond depicted arbitrarily herein as trans may be cis. Irons, or a mixture of the two in any proportion. In view of the above definitions, other chemical terms used throughout this application ■ can be easily understood by those of skill in the ait. Terms may be used alone or in any combinaijoij thereof The preferred and more preferred chain lengths of the radicals apply to all such combinations. Utility The compounds of the present invention have demonstrated utility as selective inhibitors at VLA-4 receptors. The inhibiloiy concentration (ICjo) and the VLA-4 selectivity of test compounds for an ct4pi receptor using in vitro assays arc determined in direct binding assays and competitive assays with other integiin receptors such as P2 (LFA-1 and Mac-1), P3 (GPIIb/IIIa and avp3) and pi (a4p7). Compounds of the present invention have K, values Examples of preferred compounds having a Kj value In vitro Assays A direct binding assay was used to quaniify the inhibitory activity of the compounds. In this assay, VLA-4-expressing cells were seeded in a 96-weJl microliter plate. The cells were allowed to grow for 2 days until confluent. Various concentrations of the lest comfwund were added together with 2 nM of the europium-labeled, VCAM-IgG fusion protein. The cells were allowed to inoAate at room temperature in the microwells for at least 30 minutes. Following incubation, the microwells were emptied and washed. The amount of europium-labeled VCAM-IgG fijsion protein bound was determined by time-resolved fluorescence measurement. Inhibition of binding was determined by quantifying the fluorescence bound to Ihe plate for each of the various concentrations of test compound, as well as for controls containing no test compound. The VLA-4-expressing cells used in this assay was a CHO cell line stably transfecled with the cDNA of the human a4 and pi subunits. Construction and maintenance of the cell line are described in the assay procedures. A VCAM IgG fusion protein containing the one to seven immunoglobulin domains of human VCAM-1 (DID?) attached above the hinge region of an IgGl molec\ilc was labeled with euiopium chelates. The preparation and labeling of the fusion protein are described in the assay procedures. The cell adhesion inhibitory activity of the test compound was detennined by blocking the Jurkat cell attachmcnl to the DID7-VCAM IgG fusion protein, Jurkal cell is a human lymphocytic cell line expressing VLA-4 on cell surface. In this assay, each of the 96-well inicrotiter wells was coated with 75 ng of the VCAM IgG fusion protein. The wells were then blocked by the addition of 1% bovine senmi albumin to remove nonspecific adhesive sites. Varying concentrations of the test compound were added together with the calcein-labcled Jurkat cells. The cells were allowed to adhere to the VCAM coated wells at room temperature for 1 hour in the dark. Following incubation, the piate was washed by immersing face down into a container filled with phosphate buffered saline. The wells were blotted dry on paper towel. Quantitation of the adhered cell was detennined by fluorescence measurement. Decreased fluorescence indicated inhibition of cell adhesion by the test compound. Specificity for a4 pi of each test compound among other integrin receptors, namely, P2 (LFA-1 and Mac-1). p3 (GPIIb/IIla and ctvpS), pi Ca5pi) and p? (a4p7) was examined. LFA-1 binds to ICAM-1 and mediates the emigration of leukocytes into inflammatory sites. Mac-1 binds to a number of ligands, including lCAM-1 and fibrinogen, and plays an important role in neutrophil phagocytosis and oxygen free radical generation. GPilb/IIIa on platelet smfacc binds to fibrinogen in plasma and induces plaJeJel aggiegalion. avp binds lo a number of exlracciluJar matrix proteins, including vitronectin and mediates cell migration and prevents cell apoptosis. n4p7 shares the same ligands as VLA-4 (VCAM-l, MAdCAM-l,and libronectin), but with different preference, This receptor is expressed on lymphoid cells and is involved in lymphocyte migration to mucosal tissues. Assays of LFA-1, Mac-1, GPIIb/IIIa and avp3 involved coating the purified receptor on a 96-well microliter plate. The specific ligands for these receptors were labeled with europium chelates. In the assays of LFA-1 and Mac-1, an ICAW-1 IgGfijsion protein containing the one to five immunoglobulin domains of human ICAM-1 (DIDS) attached above the hinge region of an IgGl molecule, was used. In the assays of GPIIb/nia and avP3, europium-labeled fibrinogen and vitronectin, respcc^veJy, was used. The purified receptors were allowed to incubate in the wells with various concentrations of test compound, in the presence of europium-labeled ligands. Following incubation, the wells are emptied and washed. The amount of europium-labeled ligand bound was determined by time-resolved fluorescence measurement. Assay of o4P7 is similar to the adhesion inhibition assay of VLA-4 described above, and uses the c4P7-expressing cell, RPMI-8886. A MAdCAM-1 IgG fusion protein containing the one and two immunoglobulin domains of human MAdCAM-1 and mucin-like repeat domain, is used as the corresponding ligand for o;4p7. Eu**-VCAM-l IgG binding to CHOA'LA-4 cells may be determined as follows, 4B4 cells (CHO/VLA-4 cells) are distributed into each well of a 96-well microtitcr plate ai 3 x lO'/well. The plate is incubated at 37°C, 5% CO, for 48 hours and then washed twice with washing buffer, then blot dried. 50 ^1 of the inhibitor solution diluted with assay buffer (2% DMSO final) is added to each well, followed by 50 ^! of Eu^-VCAM-l IgG diluted with assay buffer at 2 nM. The plate is incubated at room temperature for at least 30 min. Each well is then washed four times with washing buffer and blot dried. 100 ^1 of DELFIA Enhancement solution is added to each well, followed by agitation ofthe plate at room temperature for 5 min. Fluorescence of each sample is then measured (e.g., DELFIA Fluoromcter 1234, Wallace, Inc., USA). In this assay, the washing buffer comprises 25 mM HEPES (pH 7,5), 150 mM NaCl, 1 mM CaCij, 1 mM MgCli,and 4 mM MnClj; the assay buffer comprises 25 mMHEPES(pH 7.5), 150 mM NaCl, 1 mM CaClj, I mM MgClj, 4 mM MnCl,, 1% BSA, and 20 tM DTPA. The ■VLA-4 inhibitors may be ftirther characterized in in vivo assays. One such assay examines the inJiibition o/eosinophil infiJiralion into Ihe bronchoalveolai lavage Add in the mouse (murine) model. In this assay, the animals are treated with cyclophosphamide on day 0, On days 2 and 14, the aniniaJs are immunized intraperitoneally with Ascans suum extract. Seven days later, the animals are treated with various doses of the ■VLA-4 inhibitor. Shortly after drug administration, the animaJs are chaJIenged vnthAscaris suum extract by instillation into the trachea, Bronchoalveolar lavage of the animal is performed by instilling saline into the lung, 48 hours later. Total ceil and eosinophil counts in the lavage are determined. In the murine model of-^Jcon>induced bronchial inflanimation, one of the representative compounds (example number 32) inhibited eosinophil infiltration by 49% at an oral dosage of 30 mg/kg. By contrast, a representative prior art compound, 4-(A^-2-methylphenyIurea)phenylacctyI-LDVP-OH, described in WO 97/03094, did not inhibit eosinophil infiltration (% inhibition = -2%) at an oral dosage of 50 mg/kg. Other representative compounds were also tested in mice. The dosage, route of administration and inhibitory effect of representative compounds (hcreinaiter, all tested compounds are referenced by compound number provided in the Synthetic Examples) are shown in The compounds of the present invention may also be further characterized in other in vivo assays, such as the cosioophil accumulation model tested in the rat. Fifty//g of Compound 48/30 BindinE assay of VCAM-1 to VLA-4 expressing cells Preparation of VCAM leG fiision protein A VCAM IgG fusion protein containing the one to seven immimoglobulin domains of VCAM-1 (DlD7)ligatedtothehinge(H), cm and CH3 regions of human IgGl was used in the binding assay. Construction of a stable cell line expressing D1D7-VCAM IgG fiision protein An Epstcin-Barr vims based, episomal plasmid containing a D1D7-VCAM IgG fiision gene under transcriptional control of the CMV promoter, was transfecled into 293E human embryonic kidney cells. Stably transfected cells were selected using 250 Mg/mL hygromycin in DMEMwith 10% feial calf serum. The cells secreted D1D7 VCAM IgG fiision protein into the medium cumulatively for up to 9 days. Purification of D1D7 VCAM IgG fusion protein The cells were cultured in DMEM with 10% feial calf serum for 2 days, then changed to CCM5 medium and cultured for a ftirther 10 days. The medium was centriiiiged, filtered and then jncubaled ovemighl with Prolein A Sepharose 4. The Protein A Sepharose was washed extensively and the D1D7 VCAM IgG fusion protein bound was cluled using 100 inM citric acid, pH 3. Preparation of europium Iabeled-D1D7 VCAM leG fasion protein The D1D7-VCAM IgG fusion prolein, ai 1 ing/mL, wasdia]yzed against 50 mM NaHCOj, 0,9% NaCl, pH 8.5. The fusion protein was added to one viaJ of europium-labeling reagent {DELFIA labeling Idt from Wallac. Gailhersberg. MD; catalog no. 1244-302) and incubated at room temperature in the dark ovemighl. The labeled protein was purified using a Sepharose GIO coluxnn and assayed for the europium content and prolein concentration. The prolein was stored at minus 80°C until used. Constraction of cell Jine expiessine VLA-4 fCHO/VLA-4A CHO cell line stably Iransfecled with the cDNA of a4 and p 1 was used in the binding assay. The gene for human a4 was (Plained from the American Type Culture Collection and recloned between the jOio/and .ASfl sites of the mammalian expression vector pCI-neo (Promega, Madison, WI). The ^ I gene was amplified by PCR from human peripheral leukocyte cDN A and engineered such that the sian codon was placed in the context of a consensus Kozak sequence. The gene was recloned into pCl-neo downstream of the CMV promoter and chimeric intron. CHO-Kl cells were stably co-transfecled with plasmids encoding the ct4 and pi genes, and single cells expressing high levels of VLA-4 were selected by fluorescence cell sorting (FACS), The antibodies used in FACS analysis were: anti-a4-PE conjugated (PharMingen, San Diego, CA) and anti-pi-FITC conjugated (Biosourcc, Camarillo, CA). A cell line 4B4, which expresses 400,000 and 300,000 sites/cell of the a4 and pi subunit, respectively, was used in the binding assay. The subunit numbers were determined by FACS analysis, using Quantum Simply Cellular microbeads (Flow Cytometry Standards Corporation, Puerto Rico) as standards. The cells were maintained in F12 medium, containing 10% fetal bovine serum. 10 mM HEPES, pH 7.5, 0,5 mg/mL G41S, using a 1:48 passage/week. Binding Assay The CHOA'LA-4 cells were seeded in a 96-well microliter plate at 30,000 cells/well and incubated at 37'C, 5% CO, for 48 hours until confluent. On the day of assay, the weils were emptied and washed twice with 350 /^\ of a washing buffer containing 25 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM MgCl^, ] mM CaClj, 2 mM MnClj, The plate was then drained and blotted dry on paper towels to remove buffer. The test compound was serially diluted in assay buffer (washing buffer together with 0.1% bovine serum albumin, 20^MDTPAand l%dimcthysuIfoxide), in the presence of 2 nMof europium-labeled DJD7-VCAM IgG fusion protein. Final concentrations used ranged from 0.1 nM-10 /.iM. 50 ui aliquot of tile lest compound mixture was added to duplicate wells in the plate. Control wells for total binding received no test compound. Non-specific binding wells contained an anti-Ki4 monoclonal antibody (L25.3, Beclon Dickinson, Bedford. MA). The celts were allowed to incubate with the Wsl compound mixture, in the presence of europium-labeled D]D7-VCAM IgG fiision protein at room temperature for ai least 30 minutes. The cells were then washed three times with 350 ul of washing buffer, using a Skatron plale washer and blot diy. An 100 >A aliquot of DELFIA Enhancement solution was added to each well, followed by gentle agitation at room temperature for 10 minutes. The amount of europium-labeled VCAM-IgG fusion protein bound was dcttimincd by \ime-TCSol\cd fluorescence measurement (Model: Victor™, Wallac Inc., Gaithersberg, MD). Percent binding was calculated as: [(F-i-F^s) - (Fj-F^j)] / (FT-F(JS) X 100 wherein FT and FNS is the fluorescence signal oflhe europium labeled D1D7-VCAM IgG fusion protein bound to cells, in the absence of lest compound and containing an anli-«4 monoclonal antibody, respectively. F,. is the fluorescence in wells conlaining a test compound. The ICJQ (concentration of the inhibitor to inhibit 50% binding of VACM to CHOA'LA-4 cell) was determined by a curve irlting routine, PRIZM (GraphPad Software, Inc., San Diego, CA). Adhesion of VLA-4 expressing cell lo VCATU-l This secondary fimctional assay was used lo delennine the potency of a test compound in inhibiting VLA-4 mediated cell adhesion. Preparation of VCAM coated plate A 50 iA aliquot of theDlD7-VCAM IgG fusion protein (1.5 /ig/mL in phosphate buffered saline, PBS) was added lo each well of a 96-well Coslar flat bottom plate (Costar, Franklin Lakes, NJ, catalog no. 2580). The plate was then incubated overnight ai 4'C. On the day of assay, the wells were emptied and washed twice with 350 ^1 of PBS. The plate was then blocked with lOO ^.^1 of 1% bovine serum albumin (BSA. Sigma, cat# A9418) in PBS at room temperature for at least a hour. Cell preparation Jurkat cell (clone E6-1) was obtained from American Type Cultured Collection and was maintained in RPMI medium, 10 mM HEPES. pH 7.5.1 mM sodium pyruvate, 10% PCS, using a 1:64 passagaJweek. Just prioi to nmning the assay, Jurkat cells were labeled with 5 ^M of calcein-AM (Molecular Probe, Eugene, OR, catalog no, C1430) in RPMI medium, at room temperature for 30 min in the dark. Pollowing labeling. ccISs were washed twice with RPMI medium and resupended at 1 x ID' cells/mL. Cell adhesion assay Immediately before the assay, the BSA solution was emptied from the VCAM-coated plate. The plate was then washed twice with RPMI medium. A 100 ;JI aliquot of the labeled Jurkat cells was added to each well, followed by the addition of 50 ;J1 of the inhibitor solutions. Final inhibitor concentrations range from I nM to 10 IJM and each concentration was tested in triplicates. The inhibitor and cells were allowed to incubate at room temp for I hi in the dark. Following the incubation, the plate was immersed gently into a container filled with PBS. then inverted face down under PBS. The wells were drained and blotted dry on a layer of paper towel, A 50 ^1 aliquot of 0,1% Triton X-100 was added to each well. The plate was incubated in the dark for 10 min, Adhesionof Jurkalcell wasquantitatedinaMilliporeCytofluor2300 System plate reader set at 485 nM excitation and 530 nM emission. The ICjo (concentration of the inhibitor to irdiibit 50% Jurkat cell adhesion) was determined by a curve fitting routine, PRIZM (GraphPad Software, Inc, San Diego, CA), Methods pf Synthesis Compounds of the present invention may be prepared by standard chemical synthesis methods, as well as by methods of combinatorial chemistry, such as that described in Published PCT application, WO 95/30642, Synthetic Examples General methods of synthesis are illustrated by the following examples. The specific embodiments are presented by way of illustration only, and are not intended to limit the invention. Modifications and variations in any given material or process step will be readily apparent to one of skill in the an. Unless otherwise indicated, the solid-phase support used in certain examples is Tenlage]'"-S-PHB resin. This resin has a para-hydroxy benzyl linker which can be cleaved by the use of 90% trifluoroacetic add in dichloromethanc. The loading for this resin varies between 0.27 acid in 100 mL of methanol for 10 min. The resulting solution was partitioned between lOOmL water and lOOmL CHjCI. The organic layer was dried over MgSoj and the solvent was removed under reduced pressure to give 16,8 g (73.5 mmol) of methyl-2-brompophenyl acetate which was combined with 9.0 g(80,8 mmol) of l-vinyl-2-pyrroIidinone, and 100 mL of diy THF under argon in a 250 mL round-bottomed flask. To this flask was added 3.5 g (147 (mmol) sodium hydride (95%) and the solution was stirred for 10 min at room temp. A reflux condenser was added and the mixture was heated to reflux for 1 hr. The solution was cooled lo room temp and the soivcnt was removed under reduced pressure. Asolutionof 30 mL aqueous hydrochloric acid and 50 mL water was added to the resultant mixture and was heated to reflux with no condenser until the solution temperature ■ reached 96°C at which time a condenser was added and the solution was allowed to reflux for 16 hr. The solution was cooled to room temp, made basic with 150 mL ofan aqueous solution of 40% sodium hydroxide, extracted with 3 x 125 mL CH,Cli, and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the soWcnt was removed under educed piesswre to give 15.0 g (63.0 mmol, 86%) of 2-(l-bromobenzyi) -1 -pyroi line. To a solution of 15 g(63 mmol)of 2-(2-bromobenzyi)-l-pyrolIineina solution of 80;20 methanol:aqueous acetic acid cooled to minus 78°C was added, in portions over a 15 min period, 5.3 g (140.0 mmol) sodium borohydride. The mixture was allowed to stir for 1 hr warming to room temp at which time the solvent was removed under reduced pressure, 150 mL of water was added and the solution was made basic with an aqueous solution of sodium hydroxide which was extracted 10 x 100 mL CHiCJ, which resulted in emulsions. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and the soivcnt was removed in vacuo to give 14.6 g (60.8 mmol, 97%) of the benzyl proline. To a solution of 14.6 g( 60.8 mmol) of the benzyl proline in a solution of 70 mL of saturated aqueous sodium bicarbonate and 70 mL dioxane was added 15.1 g (67.0 mmol) of di-/-butyi-dicarbonale and the mixture was stirred for 16 hr at room temp. The solution was then partitioned between a 200 mL aqueous solution of hydrochloric acid and 200 mL ethyl acetate. The ethyl acetate layer was washed with 200 mL of a saturated aqueous solution of sodium chloride, dried over MgSOj and the solvent was removed under reduced pressure to give a residue which was purified by flash column chromatography {20%-100% ethyl acetale/hexane) to give ! 1.5 g (33.8 mol, 56%) pure A'. DMF (50 mL). To this solution was added Pd(OAc)i (23 mg, 0.3 mmol), P(o-Toi)j (12 mg, 0.3 muiol), methyl acrylaic (0.47 g, 5.5 mmol), and NaOAc (0.5 g, 5.5 iiunol). This mixture was then heated to 80 °C for 14 hi. The reaction mixture was then cooled to room temp and 1 N HCl (100 mL) was added. The solution was then extracted 3x with ElOAc, dried over MgSOj, and then concentrated in vacuo to afford a brown oil. This oil was chromatographed with 25% EtOAc:hexaiies to afford 1.32 g of the alkenc ester as a colorless viscous oil. The alkene ester (1,32 g, 4.1 mmol) was then subjected to hydrogcnation. Thealkene was placed in a Parr hydrogcnation bottle, EtOAc (10 mL) and 10% Pd/C (100 mg) was added under inert atmosphere. The bottle was then pressurized with hydrogen at 45 psi and shaken for 4 hi at loom temp. The solution was then filtered through celitc and conccnUaled in vacvo to afford 1.29 g of the allcane ester. The alkane ester (1.29 g, 4.0 mmol) was dissolved in THF (30 inL), MeOH {20mL), and water (10 mL) and saponified with LiOH (200 mg, 8,0 mmol). The reaction was stirred at room temp for 3 hr and then poured into I N HCl (50 mL). This solution was then extracted 3x with EtOAc, dried over MgSOj, and then concentrated in vacuo lo afford 1.02 gofthe alkane acid as a yellow solid. The alkane acid (1.02 g, 3.3 mmol) was then deprotected by the addition of a 25% TFA/CHjCl, solution and stirred for 2 hi at room temp. The resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding KjCOj (1.2 g), andFmoc-Cl (1.08 g, 4.0 mmol). This mixture was stirred at room temp for 14 hr and then poured in 1 NHCl (100 mL). The solution was then extracted 3x with EtOAc, dried over MgSOj, and (hen concentrated in vacuo to afford 495 mg 1 as a white co'stalhne solid. A solution of dicyclohexylborane was generated by the addition of borane-THF (12.0 mL, 12 mmc!), at 0°C to a solution of cyclohexenc (2,3 mL) in 6 mL of anhydrous THF. This solution was stirred for an additional I hi at 0°C, The acetylene (2) (2.0 g, 5.84 mmol) was then added dropwise over 15 min at 0°C and then allowed to wann to room temp over 1 hr. The reaction mixture was then diluted withMeOH(20 mL) and thenrecooied toO°C. A solution of 2 NNaOH (6 mL) and 30% HjOj (3.5 mL) was then added dropwise. The reaction mixture was then stirred atCCfor 1 hr and then wanned to 40 °C for 2.5 hr. The mixture was then cooled to room temp and an additional 6 mL of 2 N NaOH was added. The organics were removed in vacuo and the remaining aqueous solution was extracted 3x EtjO and the organics were discarded. The aqueous extracts were then acidified with I N HCl and extracted with EtOAc dried over MgSO,, and then concentrated in vacuo to afford 1.7 g of the phenylacetic acid as a tan crystalline solid. The dried resin (500 mg. 0.14 mmol) was placed inlo a small shaker vessel. The vessel wasthenchargedwith9mLofDMF,4{184mg, 0.42 mmol). Die (102 mg, 0.84 mmol). and DMAP{17 mg, 0.14 mmol). Thevessel was subsequently shaken for 16 hrai room lemp. The contents were drained and Uic resin was washed 3x with DMF, MeOH, and CHiClj. The Fmoc group was then removed by the addition of 10 mL of 50% piperidine/DMF to the shaker vessel and shaking for 2 hr at room temp. The resulting amine resin was washed 3x with DMF, MeOH, and CH,Clj. To the above resin was added 9 mL of DMF, 4-[N'-(o-TolyIurca)]-phenylacetic acid (132 mg, 0.42 mmol), PyBnaP (196 mg. 0.42 mmol), and DEA (107mg, 0.82 mmol). The contents were shaken for 14 hr at room temp and then drained and washed 3x with DMF, MeOH, and CHjClj. The compound was then cleaved from the resin and the filtrate was collened and then concentrated in vacuo. The resulting oil was triturated by taking up the oil in MeOH and slowly adding in EtjO until a precipitate formed. This precipitate was collected and dried in vacuo to afford 27 mg 4' as a white crystalline material. 78'C. Butyliilhium (2.21 tnL, 1.6M soln) was added dropwise and then the cooling bath was removed and gaseous CO, was bubbled through for 10 min. The reaction mixture was poured onto dry ice and then 1 M HCl (100 mL) was added. The mixture was extracted 3x EtOAc, the combined organics were dried over MgSO^, and then concentrated in vacuo to afford 0.32 g of the benzoic acid as a white crystalline solid. The benzoic acid (0.32 g, 1.68 mmol) was then deprotectedby theadditionofa25% TFA/CH2CI3 solution and stirred for 2 hr at room temp. The resulting mixture was then concentrated in vacuo and immediately proteaed by dissolving the deprotected acid in 50% dioxane/water, adding KjCOj (15 g), and Fmoc-Cl {0.44 g, 1.67 mmol). This mixture was stirred at room temp for 14 hr and then poured in 1 N HCl (100 mL). The solution was then extracted 3x with EtOAc, dried over MgSOj, and then concentrated in vacuo to afford 0.38 g 5 as a white crystalline solid. extract was washed with brine (200 mL), dried over MgSO., and evaporated. The residue was chromatographed on silica-gel with «-hexane-EiOAc (8:i,v/v) aseluentto give 713 mg (82%) ethyl (£)-4-[2-[l-(/er(-butoxycaibonyl)-2-pyiTolidinyl]ethcnyl]bcnzoale as a colorless crystalline To a stined solution of ethyl (£)-4-[2-[l-C/er/-bulo)cycari)Onyl)-2-pyTrolidiityl]c:hcnyl) benzoate (700 rag, 2.03 minol) in CHiCI, (3 mL) was added TFA (3 mL) and the resulting mixture was stirred for 3 hr. The mixture was concentrated and ihe residue was made basic by the addition of sat. NaHCOs. The mixture was extracted with CHClj (2x 100 mL). The combined cxUacls were dried over NajCOi and concentrated in vacuo to give 434 mg (87%) ethyl (£)-4-12-(2-pyrrolidinyl) ethenyl]benzoate as a brown oil. 'H-NMR (CDCIJ 5 1.39 (3 H, t, y = 7,3 Hz), 1.52-2.06 (4 H, series of m), 2.93-2.99 (1 H, m), 3.07-3.13 (1 H, m), 3.74 (1 H, q,y= 7.3 Hz), 4.37 (2 H, q, y = 7.3 Hz), 6,34 (1 H, dd, J = J5.6, 7.3 Hz), 6.54 (1 H, d, -7« 15.6 Hz), 7.41 (2 H, d, >= 8,3 Hz),7.97(2H,d,J=8.3HE). A mixture of ethyl (£)-4-[2-(2-pyrroIidinyl)ethcnyl]benzoaIe (434 mg, 1.77 mraol), pentafiuorophenyi 4-[A^-(2-methylphenyJ)ureido]phenylacetate (797 mg, 1,77 irnnol), EtjN (0,37 mL. 2.66 mmol) in DMF (15 mL) was stirred for 15 hr. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2 x 200 mL), dried over MgSO^, and evaporated off in vacuo. The residue was chromalographed on silica-gel with CHCIj-EtOAc (4:1) as eluent to give 906 mg (q.y.) ethyl {£)-4-(2-[l-[4-[A'-(2-methyiphenyl)ureido]pheny]acetyl]-2-pyrrolidinyl] cthenyl]benzoate as a brown oil. 'H-NMR (CDCIj) 5 1.39 (3 H, t. J= 7.3 Hz). l.?3-2.20 (4 H. scries of m), 2.24 (3 H, 6, J =4.9 Hz), 3.63 (4 B, m), 4.36 (2 H, q. J= 7.3 Hz), 4.62 and 4.84 (total I H. m), 6.18-6.47 (2 H, m), 7.03-8.02 (14 H. scries of m). A stincd mixture of ethyl (£)-4-[2-[l-[4-[i^-(2-i!Whylphe!iyl)ureido3 phenylacctyll-2-pyrTolidinyl]ethcnyl]ben2Qaie (906 mg, 1.77 mmol) in 0.25 NNaOH (14 mL) and THF (14 mL) was healed under reflux for 3 days. The mixture was poured into icc-lN HCl (200 mL) and the precipitate was collected with suction. The solid was recrysiallized from CHClj-MeOH-n-hexane to give 453 mg (53%) 6 as a light yellow crystalline powder, mp 165-168 "C; IR (KBr) 3282.2974, 2663. 2537, 1700, 1685 cm*'; 'H-NMR PMSO-d.) 5 1.74-2.12 (4 H, m), 2.24 (3 H. d,J=A,9 Hz), 3.35-3.66 (4 H, m). 4.67-4,74 (1 H, m), 6.25-6,41 (I H, m). 6.53 (1 H, s). 6.93 (1 H, t, J= 7.3 Hz), 7.08-7.92 (12 H, series of m), 9.00 (1 H, m), 12,87 (1 H, br s); MS (FAB) m/z 484 (M*+l); Anal. CaJcd for CiiJI^NAO.SHiO: C, 70.71; H, 6.14; N. 8.39. Found: C, 70,46; H. 6,07; H. 8,39, Example 6 The residue was purified by colunui chromalography on silica gel with EtOAc-n- hexane (1:4. v/v) as eluent lo give 4.88 g (93 %) eiliyl (5}-4-(l-/er/-buloxycarbonyl-2-pyiTolldinyl)methoxybenzoale as an oil. To the above ethyl (5)-4-(l-/erf-buloxycarbonyl-2-pynolidiny!)niethoxybenzoate ^*'as added MeOH (100 mL) and 1 N NaOH (50 mL). The mixture was stirred for 15 hr at room temp. After removal of MeOH under a reduced pressure, water (50 mL) was added to the residual solution. The aqueous solution was washed with EljO (x2) and then acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSOj and evaporated in vacuo to afford 4.26 g (95 %} (5)-4-(l-(er(-butoxycarbonyl-2-pynolidinyl) methoxybenzoic acid as a crystalline solid. To the above (5)-4-(l-/ert-butoxycarboiiyl-2-pyrTOlidinyl)methoxyben2oic acid was added CHjCli (10 mL)and TFA (10 mL), The mixture was stirred at room temp for 1 hr EtjO was added to the mixture and resulting solid was coileaed. The solid was dissolved in water (100 mL), dioxanc (50 mL) and NaHCO, (4.4 g). Fmoc-Cl (3.34 g. 12.9 mmol) was added to the solution, and the resulting mixture was stirred for 20 hr at room temp. The mixture was washed with El,© (x2) and aqueous layer was separated. The layer was acidified by the addition of 1 N HCI. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSOj and evaporated in vacuo to afford 5,36 g (91%) (S)-4-(I-Fmoc-2-pyjTolidinyl)methoxybenzOic acid as a viscous oil, which was crystallized on standing, Wang resin (0,71 mmoiyg, 400 mg) was suspended in a solution of (5)-4-Cl-Fmoc-2-pyrrolidinyl) mcthoxybenzoic add (500 mg, 1.13 mol), DMAP (35 mg, 0.29 mmol), HOBt'('10 nig, 0,30 mmol) and DIG (0.45 mL, 2.9 mmol) in a mixture of DMF (3 mL) and CH,CIj (7 mL), The mixture was shaken for 20 hr and drained. The resin was washed with DMF (x3), MeOH (3(3), CHjClj (x3) anddriedunder a reduced pressure to give 522 mg of resin, which was used to prepare 8, 9 and 10, 8 To the above resin (115 rag) was added a solution of piperidine-DMF (50 % vA", 4 mL) and the mixture was shaken for 1 hr. The resin was washed with DMF (x3), MeOH (x3), CH,C1, (x3). To the resin was added DMF (4 mL), CHjCi, (2 mL), 4-[A^-(2-mcthylphcnyl)ureido] phenylaceticacid (70 mg, 0,25 mmol), PyBrop (il5 mg, 0,25 mmol) and DIEA (0,13 mL, 0,75 mmol). The mixture was shaken for 21 hr and drained. The resin was washed with DMF (x3), MeOH (x3), CH,C1, (x3). To the resin was added a solution of TFA in CHjClj (50 % v/v, 4 mL) and the mixture was shaken for 2 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by Sep-Pak column. After remcJva] of the solvent, Et,0 was added to the residue and resulting solid was collected to afford 23 rag 8 as a pale yellow crystalline material, MS (FAB) m/2 488 (M*+l) 9 To the above resin (60 mg) was added a solution of piperidine in DMF (50 % v/v, 3 mL) and the mixture was shaken for 2 hr. The resin was washed with DMF (x3), MeOH (x3), CHjClj (x3). To the resin was added DMF (2 mL), CH,Clj (1 mL) 3-methoxy-4-(A^-phenylureido)phcnylaceticacid(40mg, 0.13 mmol), PyBrop (60 mg, 0.13 mmo!)andDIEA (0.060 mL, 0.34 mmol). The mixture was shaken for 40 hr and drained. The resin was washed with DMF (x3), MeOH (x3), CH,Clj (x3). To the resin was added a solution of TFA in CHjCIj (30 % v/v, 3 mL) and the mixture was shaken for 5 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by Sep-Pak column. After removal of the soivenl, Et^O was added to the residue and the solid was collected to afford 8 mg 9 as a crystalhne solid. MS (FAB) jn/z 504 (M*+l) 10 To the above resin (637 mg) was added a solution of piperidine in DMF (50 % v/v, 20 mL) and the mixture was shaken for 4 hr. The resin was washed with DMF (x3), MeOH {x3), CH^Clj (x3). To the resin was added DMF (12 mL). CHiCli (8 mL). 4-(Fmoc-amino)phenylacetic acid (530 mg, 1.42 mmol), PyBrop (660 mg. 1.43 mmol) and DIEA (0.62 mL, 3.56 nunol). The mixture was shaken for 60 hr and drained. The lesin was washed with DMF (x3), MeOH(x3), CHjCli(x3) and dried under a reduced pressure to afford 617 mg of the resin. 57 mg ofthis resin was added Piperidine in DMF (40% v/v, 2 mL), The mixture was shaken for 1 hr. The resin was washed with DMF (x3), MeOH (x3), CH,C1, (x3). 2-chlorophenyl isocyanaie (0,050 mL, 0.41 mmol) was added to a suspension of resin in THF(1 mL) and CHjCIj (1 mL). The mixture was shaken for 20 hr and drained. The resin was washed with DMF (x3), MeOH (x3), CHjCli (x3). To the resin was added a solution of TFA in CHjCl, (25 % vA', 2 mL) and the mixture was shaken for 1.5 hr. The mixture was fillered and the filtrate was concentrated in vacuo. The residue was purified by Sep-Pak column. After removal of the solvent, EtjO was added to the residue and the solid was coliecied lo afford 2 mg 10 as a crystalline solid. MS (FAB) m/i 508 (M*+]) Example 8 (S)-3-[2-[l-I3-methoxy-4-(A'-phenylureido)phcnylacctyl]pyrrolidiiiyl]methoxy] phenylacclic acid (x2), and the aqueous layer was acidified by the addition of i N HCl. The mixture was extracted with ElOAc. The extract was washed with water, brine, dried over MgSOj and concentrated in vacuo to afford 5.08 g (81 %) (S)-3-(l-Fmoc-2-pyiToUdinyl)methoxyphenylacetic acid as a viscous oil. Wang resin (0.71 mmol/g, 400 mg) was suspended in a solution of (5)-3-(l-Fmoc-2-pyrrolidinyj) methoxyphcnylacetic acid (520 mg, 1.14 mol), DMAP (35 mg, 0.29 nunol), HOBt (40 mg. 0.30 mmol) and DIG (0.45 mL, 2.9 mmol) in a mixture of DMF (3 mL) and CHjCli (7 mL). The mixture was shaken for 20 hr and drained. The resin was washed with DMF (x3), MeOH (x3), CHjCI, (x3) and dried under a reduced pressure to give 593 mgof resin, which was used for the preparation of 11 and 12. To a stirred cold (minus 50 °C) solution of A'-boc-prolinal (5.98 g. 30 mmol) and PPhj (62.95 g, 240 mmol) in CHjClj (200 mL) was slowly added a solution of CBrj (39.80 g, 120 mmol) in CH5CI, (50 mL), and tlic stirring was continued for I hr at 0 °C. To this mixture was added sat. NaHCOj and the mixture was extracled with CHCly The sjctract was washed with HjO. dried over MgSO^, and evaporated. The residue was chromatographed on silica-gel with CHCl, and n-hexane-AcOEt (4:1, vA-) as eluenl to give 7.84 g (74%) l-(/er^butoxycaIbonyl)-2-{2,2-dibromoethenyl) pynolidinc as colorless plales. mp 61-63; IR (KBr) 1693 cm'; 'H-NMR (CDCI3) 5 1.46 (9 H, s), 1.72-2.19 (4H, m), 3.35-3,45 (2H, m),4.35 (IH, br s), 6.36 (IH. br s); MS (FAB) m/2 352, 354. 356, 358; Anal. Calcd for CuHijNOiBrj: C, 37.21; H, 4.83; N. 3.94. Found: C. 37.14;H, 4.83; N, 4,00, To a stirred cold (minus 78 "C) solution of I - A suspension of etifyl 4-iodobcTvzoalc (1.7 mL, 10 mmol), Pd(PPh,)j (578 mg, 0.5 mmol), and Oil (190 mmol, 1 mmol) in i-Pr,NH (20 mL) was stirred for 0,5 hr under Nj. To this mixture was added a solution of l-(/e;-Nbutoxycarbonyl)-2-ethynylpyrrolidine (1.95 g, 10 mmol) in j-pTiNH (20 mL) for over 10 min. After stirring for 3 hi at room temp, the mixture was poured into HjO and extracted with EtOAc. The extraci was washed with brine, dried over MgSOj, and evaporated. The residue was chromatographed on silica-gel with n-hexane-AcOEt (10:1, vA-) as eluent to give 2.77 g (81%) l-(/er/-bulyloxj'carbonyI)-2-(2-(4-ethoxycarhonyIphenyI)cthynyl) pyrrolidine as a colorless oil, 'H-NMR (CDCI3) 5 1,37 (3 H. t, J=6,8 Hz), 1,49 (9 H. s), 1.85-2.12 (4 H. m), 3.37-3.51 (2 H, m). 4,37 (2 H, q, ^=6,8 Hz). 4.54-4.77 (1 H, m). 7.44 (2 H, d, J=l.% Hz), 7.96 (2 H. d, y=7,8 Hz) To a stirred solution of l-(/e?-r-buloxycarbony!)-2-[2-(4-ethoxycarbonylphenyl) ethynyl] pyrrolidine (2,75 g, 8 mmol) in CHiCl, (5 mL) was added TFA (5 mL). and the resulting mixture was stirred ovemighl. The mixture was concentrated in vacuo and made basic with sat. NaHCO, and extracted with CHClj. The extract was washed with brine, dried over MgSO,, evaporated lo mmoi). DMA? (562 mg, 4,6 mmol) in DMF (20 mL) was stirred overnight. The mixture was poured into 1 N HCJ and the solid was collected with suction. The solid was dissolved in CHCl, and dried over MgSO,. Aficr removal of the solvent, the residue was chromatographed on silica-gel with CHClj-MeOH (100:1, v/v) as eluent lo give 2.20 g (89%) ethyl 4-[2-[l-[3-methoxy-4-(A^-(2-methylphen)'l)ureido] phcnyiacetyl]-2-pyrrolidinyl]ethynyl]ben2oaie as a white amorphous To a stirred solution of the 4-[2-[2-CA'-ter(-butojtycarbon>'l)p>Trolydiny]etlienyl] benzonitriie (2.26g, 7.57mmol) in CHjClj (23 niL) was added dropwise a I.5M solution of diisopropylaluminum hydride (toluene solution) C6,06mL. 9,09niraoI)atO°Cforover 15inin. The resulting solution was stirred for3 hr at CC. The solution was quenched by the addition of sat.NH.Cl. The resulting mixture was filtered through Celilc, and the filtrate was extracted with ElOAc. The filtrate was washed with brine, dried over NaiSOj and evaporated in vacuo to afford 1.89 g (83%) 4-[2-[2-(A'-/ert-buloxy carbonyl)pyrrolidinyl]ethenyl] bcnzaldehyde as a yellow syrap. To a stined solution of NaOH (J.00 g, 25.1 mmol) in water(10 mL) was added a solution of AgNO,(2.13g, 12.5inmol)iiiCH3CN(10inL)atO'Cforov«O.Shi. To the stined above mixture was added dropwise a solution of 4-[2-[2-(N-tert- butoxycarbonyl) pynolydinyl]ethcnyI] bemaldehydc (1.89g, 6.27mmol) in CHjCN (lOrdL) at 0°C for over 20 inirv. After the resulting mixture was stirred for a further 3 hr at room temp. The mixture was filtered with suction, and then washed with hot water. After the filtrate was washed with E\OAc, the aqueous layer was acidified by carefully adding 1 H HCl, and then cxtraaed with CHClj. The extract was dried over NajSOj and evaporated in vacuo to afford 0.7QOg (35% lot 2 steps) 4-[2-[2-(N'-(ert-butoxycaiboi\y!) pyiTolidinylJethenyl] benzoic acid as a pale yellow crystalline material. To a stirred solution of 4-[2-(2-(A^-i'eri-butoxycaibonyl)pyrrolidinyl) ethenyI]benzoic acid (0,?00g, 2.21mmol) in MeOH-benzene(l:4. v/v, 30mL) was added dropwise a 2 M-n-hexane solution of TMSCHNi (1.32mL, 2.65mmol) at room temp. After the solution was stirred for 0.5 hr at room temp, the solution was evaporated in vacuo. The resulting oily residue was chromatographedonsilica-gel withEtOAc-rt-hexane(l:6, v/v)aselucnttoafford0.64g(88%) methyl 4-12-[2-(A'-fe/-Nbuloxycaibony!) pyrrolidinyl] ethenyllbenzoate as a paie yeilow crystalline material. To a stirred solution of methyl 4-[2-[2-(A'-(er/-butoxycarbonyl)pyTTOlidinyl] ethenyl] benzoate (0,64§,1.93 mmol) in CHjCl, (SmL) was added TFA (5mL) at room temp. After the mixture was stirred for 1 hr at room temp, the mixture was evaporated in vacuo. The residue was treated with sat. NaHCOjand exuacted with CHClj. The extract was dried over NalSO^ and evaporated in vacuo to afford 0.45g (100%) methyl 4-[2-(2-pyTTolidinyl)ethenyl]ben20ate as a yellow crystalline material. To a stirred mixiurc of 3-meihoxy-4-[A'-C2-mc[hylpheii)'l)urcicJo]phcny)acetic acid C285mg, 0.906nimol), methy! 4-[2-(2-pyrTolydinyl)elhenyl]benzoaic (2I0ing, 0.906mino!) in DMF C4mL) was added ]-ethyI-3-(3-dimcChy]aniinoprDpyl)cajtodiimide(EDC){209nig, I.OSmmoI), 1-hydroxybcnzotriazole (HOBl) (I47mg, 1.09miiiol) and4-diinelhylaimnopyridiiic (DMAP) (llmg, Q.0906mmol) at room temp. After the lesulting mixturt was stirred for *B hr ai room ttmp, the mixture ^vas poured into ice-1 N HCI and extracied with EtOAc. The extract was dried over Na,SO, and evaporated in vacuo. The residue was chromatographcd on siJica-gel with acetone-toluene (1:4 to 1:1, v/v) as eluent to afford 0.47g (98%) methyl 4-[2-[l.{3-mcthoxy-4-[A'-(2-melhy]phenyl)ureido] phenylacety 11-2-pyrrolidinyljcthenyI]benzoate as a white crystalline material. To a stirred solution of methyl 4-[2-[!-[3-methoxy-4-(A'-phcnyluiddo) phcnyIacetyl]-2-pyrrolidinyljethcnyijbenzoate (0.43g, 0,837ininol) in THF (5niL) was added a solution of 0.25 N NaOH (5.04mL) at room temp. After the rcsuJting mixture was stirred for 20 hr, the mixture was acidified by the carefully addition of 1 N HCl. The mixture was cxUacted with EtOAc. The extract was washed with brine, dried over Na,SO, and evaporated in vacuo to afford 397mg (95%) 18 as a while crysUlline malerial. 'K-NMR (400MHz, DMSO-dJ 5 1.78-2.13 C4H, m), 3.17-3.68 (4H. m), 3.74, 3.82 (3H, s), 4.71 (IH, m), 6.27-9.28 (16H, m). A solution of 0-m-iodophenyl dimethylthiocarbamale (10.0 g, 32.6 mmo!) in PhjO (25mL) was heated at 230'C for 10 hr. After cooling, Uie reaction mixture was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v)as eluent to give 9.31 g (93%) S-m-iodophenyl dimethylthio carbamate as a pale yellow oil. 'H-NMR(400MHz, CDCySS.OS (brs, 6H), 7,11 (t, y= 7.8 Hz, IH). 7,46 (d,y= 7.3 Hz. IH), 7.71 (d, J= 7.3 Hz. IH), 7.85 (s. IH); MS (FAB) m/z 307 (M*+l). To a sDlution of S'-ra-iodophcnyl dimethylthiocarbajnaie (5.01 g, 16.3] mmoY} m MeOH (20 mL) was added 28%-MeONa in MeOH (3.46 mL, I7.94inmol). The resulting mixture was stiired at room temp for 3.5 hr and then heated at 70'C overnight. After cooling, IN HCl was added. The solvent was removed under a reduced pressure and the residue was diluted with EtOAc. The solution was washed with H,0, brine, and dried over NajSOj, The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexanc-AcOEt (10:1, yh') as eluent to afford 3.42 g (89%) m-iodothiophenol as an oil. 'H-NMR (400 MHz, CDCy 6 3.45 (s. IH), 6.95 (I, / = 7,g Hz,H),7,Z3 (d/= 7,8 ffe IH), 7,48 (d, /= 7,3 Hz,lH), 7,64 (1. J= 1.5 Hz,lH); MS(EI)m/z 236(M*), To a stirred solution of A'-(/erf-butoxycarbonyl)-2-pyTToiidinyimethanol (4.30 g, 20,0 mmol) in pyridine (40 mL) was added/i-TsCI (5,72 g, 30.0 mmol). The resulting mixture was stirred at room temp for 3 hr. The reaction mixture was quenched with H,0, and evaporated off. The residue was diluted with EtOAc and washed with IN HCl, brine, and dried over Na,SOj, The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with /j-hexane-ElOAc (2:1, vA') as eluent to afford 5,76 g (81 %) W'-(i'erf-butoxycaibonyl)-2- Toa stirred mixture of m-iodothiophenol (2.67 g, 11.31 mmol) and//-(/erf-buloxy carbonyl)-2- pyrrol idiny I methyl p-toluencsulfonate (3.34 g, 9.43 mmol) in pyridine (9.4 mL) was added 8N KOH (1,77 mL). The resulting mixture was stined at room temp overnight. The reaction The mixture of S-methoxy^-IZ/XZ-methylphenyOureidolphenylaceticacid (1.18 g, 3.77 mmol), EDC (1.08 g, 5.65 iiuiiol), DMAP (23 mg, 0.19 mmol) andHOBt (25 mg, 0-19 mmol) in DMF (5 mL) was stirred al room temp for Ihr methyl 3-(2-pyrTolidinyl)melhylthio bcnzoate (947 mg, 3.77 mniol) was added lo the mixture and the resulting mixture was stirred overnight. After DMA? (■160 mg, 3.77 mmol) and HOBt (835 mg. 6.18 mmol) was added and stirred for a ftmher 5 hr. The reaction mixture was diluted with ElOAc. The solution was washed with brine and dried over NajSO*. The solvent was removed under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EtOAc {2:3, vA') a eluent lo afford 294.3 mg (14%) methyl 3-[l-[3-methoxy-4-[A'-(2-methylphenyl)urcido]phenylacetyl]-2-pym)!idinyl]meEhyIthio layer was separated, washed wilh sal. NaHCOj solution, brine, and dried over NajSO,. The splvent was removed under a reduced pressure to afford methyl 3-[[l-[3-methoxy-4-[A'-{2-metliyipheny]) mL) was added MeOHa (495 mg. 9. lAmmol), and the resulting mixture was stirred at 70°C overnight. After cooling, JN HCl was added and the mixtuie was concentrated under a reduced pressure. The residue was diluted with ElOAc and washed with HjO, brine, and dried over NaiSO,, The organic layer was concentrated under a reduced pressure and the residue was chromatographed on silica-gel ivilh n-hexane ElOAc (5:1, v/v) as eluent to afford 1.75 g {89%)/>-iodolhiophcnol as a pale yellow crystalline solid, JR (KBr) 2539, 1097,1002, 806cin"'; 'H-NMR (400MHz, CDClj) 5 3,43 (s, IH), 7.10 (d, J = 8.3 Hz, 2H}, 7.53 (d, J= 8.3 Hz. 2H); MS (FAB) m/z 236 (IvT+l); Anal. Calcd for QHjIS: C, 30.53; H, 2.13, Found: C, 30.57; H, 2.15. To a stirred mixture of ;!-iodothiopheiiol (1.75 g, 7.43 mmol) and//-(/erf-butox>'caJtiony])-2- pyrTolidinylmelhyl p-toluenesu]fomle (2.39 g, 6,75 mmo]) in pyridine (12.7 mL) was added 8NKOH(I.27mL) at room temp, and the resulting mixture was stirred for 4 hrat the same temp. The reaction mixture was diluted with ElOAc. The solution was washed with HjO. sat, NH4CI, brine, and dried over NajSOj. The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EiOAc (5;], vA-) aseluent to afford 1.49 g (53%) [A/-Cfer/-butoxycaTbonyl)-2-pyTTolidinyl]methyl 4-iodophenyl sulfide as a pale yellowish oil, 'H-NNfll (400 MHz, CDCI3) 5 (s, 9H), 1.78-2.01(brm,4H), 2.71 (dl, IH). 3.32 - 3.49 (br m, 3H), 3.90 - 4.02 (br m, IH), 7.12 (d, J = 7.8 Hz.lH), 7.18 (d^ = 7.8Hz, l),7.57(dd^= 2.0,8.3Hz,2H);MS(FAB)ffi^ 420(M*+1). To a stirred solution of [l-(/er/-butoxycarbonyl)-2-pyTrolidinyl] methyl 4-iodophenyl sulfide (1.49 g, 3.56 mmoi) in DMSO (16 mL) and MeOH (13mL) was added EtjN (1.09 mL, 7.84 mmol), Pd(0Ac)3 (40 mg, 0.178 mmo!). and 1.3-bis(diphenylphosphino)pn)pane (73.4 mg, 0.178 mmol). To the stirred resulting mixture was induced CO gas for 5 min, and the mixture was stirred at 70°C ovemighi. After cooling, the mixture was concentrated to a small volume. The residue was diluted with EtOAc, washed with brine, and dried over NajSOj. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with «-hcxane-EtOAc (5:1, v/v) as eluent to afford 1.16 g (93%) methyl 4-[l-(ler/-butoxycarbonyl)-2- To a stirred solution of methyl 4-[I-(/ert-butoxycarbonyl)-2-pyTTolidinyl]methyltluo benzoate (1.16 g, 3.32 mmol) in CH5CI, (20 mL) was added TFA (4 mL), and the mixture was stirred at room temp for 1.5 hr. The solvent was removed under a reduced pressure and the residue was treated with IN NaOH, The mixture was extracted with CHCl,. The extract was washed with brine, dried over KOH, and concentrated under a reduced pressure lo afford 767 mg (92%) methyl To a stirred solution of methyl 4-[[l-[3-melhQxy-4-[//'-(2-methylphcnyl)ureido) phenylacetyl]-2-pyrTolidinyl]nieIhyllJuo]benzoale (300 mg, 0.548 nunol) in THF (5.5 inL) and H5O (].] mL) was added LiOH (39.4mg, 1,643 mmol). and liiereaction mixture was stirred at room lemp overnight and at 50°C for 9 hr. The mixture was diluted with CHCI3. The solution was concenlraled in vacuo and made basic with sat. NaHCOj. The mixture was extracted with CHjCli, washed with brine, and dried over MgSOj. The solvent was evaporated and the residue was purified by column chromatography on silica-ge! with CHC!j-McOH (20; 1, vA') as eiuenl lo give 3.27 g (77% for 2 steps) ethyl (5)-3-melhoxy-4-(2-pyTT0lidinylmelhoxy) benzoaie as a yellow oil. 'H-NMR(CDCl3)5 1.39(t, 3H,J=7,lHz), 1,52-1,59 (m. 1 H), 1.76-1.88 (m, 2 H), 1.92-2,01 (m. IH), 2.92-3.06 Cm, 2 H). 3.56-3.63 (m, 1 H), 3.90 (s, 3 H), 3,91-4,02 (m, 2 H). 4,35 (q, 2 H, >7.1 Hz). 6.89 (d, 1 H, J=8-3 Hz), 7.54 (d, 1 H, J=2.0 Hz), 7.65 (dd, 1 H. J=2.0. 8.3 Hz). To a stirred solution of ethyl (S)-3-mclhoxy-4-(2-pyTTolidinylmeIhoxy)ben2oate (424 mg, 1,52 nunol) inDMF(8 mL) was added pentafluorphenyl ester of 3-mctlioxy-4-[7v'-(2-melhylphcnyl) ureido]phenylacetic acid (728 mg, 1.52 mmol) and EtjN (0.26 mL, 1.87 mmol). And the resulting mixture was stirred at room temp overnight. The mixture was diluted with ElOAc, washed with 1N HCl, sat. NaHCOj, brine, and dried over MgSO,. The solvent was evaporated off ;'n vacuo and the residue was purified by column chromatography on silica-gel with CHCIj-MeOH (50:1, vh) as eluent to give 830 mg (95%) ethyl (S)-3-methoxy-4-[l-t3-methoxy-4-{A^'-(2-methylphcnyl)ureido]phenyl acetyl]-2-pynolidiny! methoxyjbenzoate as an amorphous solid. 'H-NMR (CDCy 5 1,38 (t, 3 H, 7=7-3 Hz). 1.88-2.20 (m, 4 H, m), 2.24 (m. 3 H), 3.44-3.50 (m, 1 H), 3.53-3.58 (m. 7 H), 3.82 (s, 3 H), 4,09^,17 {m, 1 H), 4.22-4.25 (m, 1 H), 4.35 (q. 2 H, J=1.2 Hz), 4.38-4.49 (m, 1 H). 6.71-6.78 (m, 1 H). 6.99 (d. 1 U, J=8.3 Hz), 7.04-7.07 (m, IH). 7.16-7.19 (m, 2 H), 7.49-7.66 (m, 3 H), 8.06 {d, 1 H, 7=8.3 Hz). To a stirred solution of ethyl (5)-3-methoxy-4-[[l-[3-methoxy-4-[//'-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]methoxyjbenzoate (760 mg, 1,32 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL), and the resulting mixture was heated under reflux overnight. After cooling lo room temp, the mixture was poured into 1 N HC! (100 mL) and the solid was collected. The crude solid was washed with EijO lo give 429 mg (59%) 27 as a yellow amorphous solid, mp 132-135; IR (KBr) 1707 cm'; 'H-NMR (DMSO-d^) 5 1.84-2.18 (m, 4 H). 2.25 (s, 3 H), 2.49-2.51 (m, 2 H), 3.29-3.59 (m, 4 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 4.00^.05 (m, 1 H), 6.53-8,01 (m, 10 H), 8.45 (s, 1 H), 8.54 (s, 1 H), 12.63 (bs, 1 H); MS (FAB) m/i 548 (IvT+l). Example 24 (5)-4-[l-[3-meihoxy-4-[A'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]phthalic acid A'-reW-buloxycarbonylproiinol (354.6 mg. 1.762 mmol), and Ph^ (354.6 mg. 2.114 mmol) in THF (10 mL) was slowly added DIAD (0.42 mL, 2.1J4 mmol) ai room lemp, and the resulUng mixture was stirred for 6 hr at 70°C, The reaction mixture was concentrated and the residue was chiomatographed on silica-gel with n-hexane:EtOAc (5:1, v/v) as elucnt to give 262.5 mg (44%) methyl 2-[[l-((erf-butoxycarbonyl)-2-pyrTDlidii^l]methoxy]pyTidine-5-carboxylate as an oil. 'H-NMR (400 MHz, CDCl,) 6 1.47 (s, 9H), 1.85 - 1.98 (m, 4H), 3.37 (br s. 2H), 3.92 (s, 3H), 4.12 -4,33 (hr m. 2H),4.4 (brs, lH),6,75(m, 1H),8.15 (m, IH). 8.79 (m, IH); MS (FAB) m/z 337 (M*+l). To a stirred solution of methy! 2-[[l-(?erf-butoxycarbony!)-2-pyTTolidinyl]methoxy] pyridine-5-carboxylatc (262.5mg. 0.870 mmol) in CHjCl, (5,3 mL) was added TFA (1.1 mL) at 0 ° C, and the resulting mixture was stirred at room temp for l hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of the IN NaOH, and extracted with CHClj. The extract was washed with brine, dried over NajSO,, and concentrated under a reduced pressure to afford 173.1 mg (94%) methyl 2-[(2-pytToIidiiiyl)methoxy]pyTidine-5-carboxylate as a pale yellowish oil. 'H-NMR(400MHz, CDcy 5 1.49- L58 (ddt,7=6.8. 8,8 Hz, IH), 1.72 - 1,87 (m, 2H), 1.90 - 1.99 (m. IH), 2.92 - 3.05 (in, 2H). 3.50 -3.57 (ddd,^ =4.4,7.3, 15.1 Hz, IH), 3.91 (s,3H), 4,23 (dd,y= 7,8,10,7Hz. IH), 4.38 (dd,y= 4.4, 10.7 Hz, IH), 6.78 Cd,J' = 8.8 Hz, IH), 8,15 (dd, J = lA, 8,8 Hz, IH), 8.80 (d, J= 2,4 Hz, IH); MS (FAB) m/z 131 (M'+l), A mixture of pentafluoropheny! 3-methoxy-4-[^-(2-methylphenyl)ureido]phenylacetate (351,7 mg, 0,732 mmol), methyl 2-[(2-pyrTolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), EtjN (122.4 ^il, 0,878 mmol) in DMF (5.2 ml.) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over NajSOj. The solveni was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane;EtOAc (1:5, vA') as eluent to afford methyl 2-I[l-[3-methoxy-4-[//'-(2-methylphenyl) uTeido]phenylacetyl]-2-pyirolidinyl]metiioxy] pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred soludon of this compound in THF (5,6 mL) and H^O (1,4 mL) was added LiOH (45,7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCI3, and treated with sat, NHjCl, washed with brine, dried over NajSO., The solvent was removed imder a reduced pressure, and the obtained crude solid was recrystailized from fj-hexane-EtjO-CHOrMcOH to afford 193,8 mg (59%) 40 as a white crystalline powder, mp 125- 128;m(KBr) 1716, 1600, 1533, 1255cm-'; 'H-NMR (40O MHz. DMSO-d*) 5 1,67-2,03 (m, 4H), 2,50 (s,3H), 3,33-3,42 (m, IH). 3,52 (m. 2H), 3,58 ((l,J= 4,4 Hz, IH), 3,83 (s, 3H), 4,27-4.31(m,2H), 4,42-4,47 (m, IH), 6,73 (d, 7= 7,8 Hz, IH), 6,87 - 6,95 (m, 3H), 7,11 - 7.17 (m, mixture was stirred for 24 hr, the mixture was diluted with water and washed with ElOAc, The separated aqueous iayer was acidified by the addition of IN HCJ, and extracled with ElOAc. The To a stirred solution of methyl (25, 4/()-4-[4-bcnzyloxy-l-(rer/-butoxycarbonyl)-2-pyiTOlidinyl] inetlioxy-3-nitrobenzoaIe {681 mg, 1.4 mmol) in CHjClj (2 iiiL) was added TFA (2 mL), and the resulting mixture was stirred for 2 hr. After the reaction mixture was concentrated, the residue was made basic by the addition of sat. NaHCOj and extracted with CHCIs. The extract was washed with HjO, dried over MgSO^, and evaporated to give 311 mg (95%) inethyl (2S',4.R)-4-[4-bcnzyloxy-2-pyrrolidinyl]mcthoxy-3-nitroben2oate as aycllow oil. A mixture of3-methoxy-4-[A'"-(2-meihylpheny])ureldo]phenylacetic add (409 mg, 1.3 nunol), methyl (25,4fl)-4- (benzyioxy-2-pyTTolidinyI)methoxy-3-nitrobeii2oatc (502 mg, 1.3 mmol), EDC(383mg. 2mmol}, andDMAP(159mg, 1.3 mmol) in DMF (20 mL) was stirred for 3 days. The mixture was poured into 1 N HCl and the resulting precipitate was collected with Suction. Theresidtic was dissolved in CHCJ, and dried over MgSO,- After removal of solvent, the residucwaschromatographedonsihca-gel with CHCljiMeOH (200; 1, vA') as eluent to give 680 mg (91%) methyl (25,4ii)4-[4-benzj'loxy-l-[3-mcthoxy-4-[JV'-(2-methylphenyl)uTcido] phenylacetyl]-2-pyrrDlidinyl]melhoxy-3-nitroben2Qale as a white amorphous solid. A solution of methyl (2S,4R)-4- [4-benzyioxy-l-[3-mclhoxy-4-[Af'-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]mcthoxy-3-nitrobenzoate (676 mg, 0.99 mmol) and 5% Pd-C To a stirred solution of ethyl 4-[l-((ert-butoxycartionyl)-4-fluoro-2-pyiTolidinyl]n]cthoxy-3-metl!D.\yben2oa;e (482.2 wg, 1.213 miuol) m CH^C], (10.0 mL) was added TFA (1.9 jnL) al O'C, and the mixture was stirred at room temp for 2 hr. The solvent v/zs removed under a reduced pressure and the residue was made basic by the addition of IN NaOH and extracted with CHCly The extract was washed with brine, dried over NajSOi, and concentrated under a reduced pressure to afford 348.7 mg (97%) ethyl 4-C4-fluoro-2-pyiTolidinyi)meihoxy-3-methoxybenz[3ate as a brownish oil. 'H-NMR (400 MHz, CDCy 5 1.39 (t, J= 6,8 Hz, 3H), 1.97 (ddt, J= 1,5, 5.4, 14.7 Hz.lH), 2,27 (dddd, J= 5.9, 8.8,14,7, 32,7Hz,IH), 3,02 (ddd, J= 3.9, 13.1, 35,2Hz,lH). 3,36 {dd,^= 12.7, 21,5 Hz,lH), 3,65 (m. IH). 3,90 (s, 3H). 4,09 (m, IH), 4.35 (q, J= 6.8 Hz, 2H). 5,17, 5,31 (brm each, !H), 6.90(d, J'=8,3 Hz, IH), 7.75 (d, J= 2,0H2, IH), 7,65 {dd,y= 2,0, 8,3 Hz, IH); MS (FAB) m/z 298 (M'+l). A mixture of pcntafluorophcnyl 3-incthoxy-4-IA'-(2-methylphenyl)ureido Jphenylacetate (404.0 mg, 0.840 mmol), elhyl 4-C4-fliioro-2-pyTTOlidinyI)methoxy-3-inct]ioxybenzt}ate (250.0 mg, 0.840 mmol), EljN (141^^1, 1.009 mmol) in DMF (4.0 mL) was stirred for 1 hi at room temp. The mixture was diluted with EtOAc, washed with water, briue, and dried over NajSO^, The solvent was removed under a reduced pressure and the residue was chromatogiaphed on silica-gel with n-hexaneiEtOAc (1:3, v/v) to afford 502 mg (q.y.) of ethyl 4-[[4-fluoro-l-[3-methojcy-4-[Ar'-(2-methylphcnyOureido] phenylacetyl]-2-pyiTolidiny]]mcthoxy]-3-methoxybenzoatc as a yellow oil. To a stirred solution of this compound in THF (8.0 mL) and H,0 (2.0 mL) was added LiOH (60.4mg, 2,520 mmol), and the mixture was stirred at room temp, overnight, and 50°C for 1 day. The mixture was diluted with CHClj, and extracted with IN NaOH. The aqueous layer w^s acidified by the addition of IN HCI and ejrtracled with CHCij. The extract was wasiied with brine and dried over Na2S0j. The solvent was removed under a reduced pressure and the obtained crude solid was reciystallized from EtOAc-CHClj-EtOH-n-hexanc to afford 294.8 mg (62%) 45 as a white crystalline powder. IR (KBr) 2958, 2937, 1687, 1601, 1531. 1454. 1419, 1267, 1214, 1029cm-'; 'H-NMR (400 MHz, DMSO-dJ 5 1.86 - 2.09 (m, 5H), 2.06 (s, 3H), 2.25 (s, 3H), 3.47 -3.67 (ra, 6H), 3,76 (s. 3H), 4.05 ■ 4.12 (m, 2H), 4.30 - 4.31 (ra. IH), 6,51 (s, IH), 6.55 (s, IH), 6.73 -6.95(m, 2H). 7.11-7.17 (m,2H), 7.64 (S, IH), 7.79 (d. 7= 7.8 Hz, IH), 7,99 (d, y= 7,8 Hz, IH). 8,47 (s, IH), 8,55 (s. IH); MS (FAB) m/2 566 (M'+l); Anal. Caicd for CjoH3iFN,0,-3/2H50; C. 62,71; H, 5.79; F. 3.31; N, 7.31. Found: C. 63.13; H, 6,17; F, 3.12; N, 7.04. Examnlc 42 3-acetylamino-4-[l-[3-mcthoxy-4-[A'-(2-methylphenyl)uieido]phenylaceCyll-2-pyTTolidinyl methoxy]benzoic acid To a stirred solution of methyl 3-cli]oro-2-hydroxypyridine-5-carboxylate (300 mg, 1.599 minol), ^■-re7■r-butoxyca^bonyJproIiIloi (321.9 mg, 1.599 mmol}, and PhjP(503 mg, 1-919 mmol) in THF (3 mL) was slowly added DIAD (378 f^l, 1.919 mmol) at room Icmp, and the mixture was stincd for 13 hr at 70°C. The mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane - EtOAc (3:!, vA') as eluent lo give 235.6 mg (40%) methyl 3-chloro-2-[ll-C(ert-butoxycarbonyl)-3-pynolidinyl]methoxy]pyTidine-5-carboxylatc as a pale yellowish oil, 'H-NMR (400 MHz, CDCl,) 5 1.46 (s, 9H), 1,87 (ra, IH), 2.05 (br s, 3H), 3.43 (br s, 2H), 3,92 (s, 3H), 4.17,4.26 (brs each, IH). 4.45-4.51 (in, !H), 4.50 (s, IH), 8.21(s, IH), 8.67 (d, J = 2.0 Hz, IH); MS (FAB) m/z 371 (M*+l). To a stirred solution of methyl 3-chloro-2-[[]-{/ert-butoxycaibonyl)-2-pyrralidinyljmctjioxy] pyridine-5- The mixture of pentafluOTOphenyl 3-methoxy-4-IA'-(2-mcthylphenyl)ureido] phenylacetate (317.0 mg, 0,660 mmol), methyl 3-chloro-2-[(2-pyrTolidinyl)methoxy] pyiidine-5-carboxylate (172,0 mg, 0.635 mmol), EtjN (105 ul, 0.756 mmol) in DMF (2.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over NajSOj. The solvent was removed under a reduced pressure to afford methyl 3-chloro-2-[[I-[3-methoxy-4-[yV-(2-methylphcnyi)ureidoIphenylacetyr]-2-pyrToJidinyJImeihoxy]pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0 mL) and H,0 (2,0.mL) was added LiOH (45.3 mg, 1.89 mmoJ), and the reaction imxlure was stirred for 5 hr at room temp. The mixture was diluted with n-hexane and extraacd with IN-NaOH. The aqueous layer was acidified by the addition of IN HCl and extracted with CHClj. The extract was washed with brine, dried over NajSO,, The solvent was removed under a reduced pressure and the obtained crude solid was reciystallized from n-hexane-EtOAc-EiOH to afford 242.2 mg (70%) 47 as an orange crystalline powder, mp 122 -125; IR (KBr) 3354,1709, 1593,1535, 1454, 1257cm-'; 'H-NMR (400 MHz. DMSO-d^) 5 1.67 - 2.03 (m, 4H). 2.50 (s, 3H), 3.33 - 3.42 (m, IH), 3.52 (m, 2H), 3,58 (d, J = 4.4 Hz, IH), 3.83 (s, 3H), 4.27 - 4.31 (m, 2H), 4,42 - 4,47 (m, !H). 6.73 (d. / = To a stirred solution of meUiyl 2-[Il-{(erI-butoxycait)onyl)-2-pyiTolidinylJmethyloxyjpyridine -5-carboxylate (232.3mg, 0.691 mmol) in CHiClj (4.6 mL) was added TFA (0.9 mL) at 0°C, and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of IN NaOH. The aqueous solution was extracted vnth CHC!,, washed with brine, and the dried minol) in DMF (30 mL) was added ethyl bromoacelale (4.74 g, 28.4 mmol) at room temp. The resulting mixture was stirred for a further 3 hr. The mixture was diluted with EtOAc (300 mL), washed with brine (2 x 100 mL), dried over MgSOi and evaporated. The residue was chromaiographed on silica-gel with CHCljiElOH (10:1, v/v) as eluenl lo give 7.45 g (q.y.) ethyl 4-bcnzyl-l-piperazinylacetate as a yellow oil. 'H-NMR (CDClj) 5 1.27 (3 H, t, J= 7.3 Hz), 2,88-2.96 (8 H, m). 3.20 (2 H, s). 3,52 (2 H, s), 4.18 {2 H,q,J= 7.3 Hz), 7.22-7.32 {5 H, m). A stirred solution of ethyl 4-bcnzyM -pipeTazinyhcstste (2.00 g, 7.62 nunol) SJid 5% Pd/C(2g)iiiAcOH:EtOH(l:!,40!nL)washydrDgenatedat latmforShr, The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made basic by the addition of saturated KaHCOj and extracted with CHCI3 (2 x 200 mL). The combined extracts were dried over KjCOjand evaporated to give 1.16g(88%) ethy! l-piperazinylacetate as a yellow oil. 'H-NMR (CDCI3) 5 L26-1.30 (3 H. m), 1.67(1 H. br s), 2.55{4 H, m). 2.92-2,96(4 H, m), 3.19-3.20(2 H, m), 4.16-4.22(2 H,m). To a stirred solution of//-Boc-L-prohnol(i,00 g, 5.02nimol) and ethyl 1-piperazinyl acetate (864 mg, 5.02 mmol) in MeOH:AcOH {10:1, v/v. II mL) was added NaBH^CN (664 mg. 10.0 mmol) at room temp. After being stirred overnight, the mixture was poured into ice water (100 mL) and made basic by the addition of NaHCOj. The mixture was extracted with CHCI3 (2 x 200 mL). The combined extract were dried over NajCO, and evaporated. The residue was chromatographed on silica-gel with CHCljiEtOH (10:1, vA*} as eluent to give 1.20 g (67%) ethyl 4-[!-(/er(-butoxy caTbonyI)-2-pyiTolidinylmcthyl]-l-piperazinylacetate as a colorless oil. 'H-NMR (CDClj) 5 1.27 (3 H. t, J^ 7.3 Hz), 1,46-1.47 (9 H, m), 1.79-3.96 (total 19 H, series of m), 4.19 (2 H, q./=7,3Hz)- A mixture of ethyl 4-ll-(/erf-butoxycarbonyl)-2-pyrrolidinylniethyl]-l-piperazinylacetate (1.20g. 3,38 mmol) in TFA (5 mL) and CHjClj (5 mL) was stirred overnight After removal of the solvent, the residue was made basic by the addition of sat. NaHCO^. The mixture was extracted with CHCl, (2 x 200 mL). The combined extracts were dried over Na^COj and evaporated to give 386 mg(45%) ethyl 4-(2-pyrTolidinylmethyl)-l-pipcrazinyiacctate as a yellow oiJ. MS (FAB) 25(5 (M*+J). To a stirred solution of ethyl 4-(2-pyrrolidinylraethyi)-l-piperazinylacetate (380 mg, 1.49 iimiol) and 3-methoxy-4-[?i/'-(2-meihylphenyl)ureido]phenylacetic acid (468 mg, 1.49 mmol) in DMF (10 mL) was added EDCHCI (428 mg, 2,24 mmol), HOBt, and DMAP (cat,). After being stirred ovcmigh!, the mixture was dilated with ElOAc (300 mL), washed with brine (2 x 20O mL), and dried over MgSO,, After removaJ of the solvent, the residue was chramatographed on silica-gel with CHOyElOH (9:1. v/v) as eluent to give 257 mg (31%) elhyl 4-[l■[3-mclho^7-4-[A'-(2- The mixture of the above methyl 4-(2-pyrro!idinylmethylainino}beii2oatc (397.8 mg, 1.69 minol), 3-methoxy-4-[A'-(2-m«hylphcnyl)iireido]phenylacelic acid (587,1 mg, 1.87iniiiol), EDC (HCI) (486 mg. 2.54 mmol), HOBl (23 mg. 0.17 mmol), andDMAP (21 mg, 0,17 mmol) inDMF (4 mL) was stirred overnight at room temp. The mixture was diiuted with EtOAc, washed with brine, and dried over Na,SOj, The solvent was removed under a reduced pressure. The residue was chromatographed on siiica-gel with CHClj - JvfeOH (50; 1, vA') as eluent to afford 882mg (98%)nicthyl4-[l-I3-methoxy-4-[//'-(2-methylpheny!)ureido]phenyIacetyl]-2-pyrTolidiiiy! methyl amino] benzoate as a brown amorphous solid, which is used to the subsequent reaction without further purification. To a stirred solution of methyl 4-IA'-[l-(terf-butoxycarbonj'0-2-j)>TrolidinylmctJiylJ-;\f-methylaminojbenzoate (645 mg, 1.794 mmol) in CHjCli (6.5 mL) was added TFA (1.3 itiL) at 0°C, and the mixture was stirred oveniight at room temp. The solvent was removed under a reduced To a stirred solution of the above methyl 4-[A'-[l-[3-methoxy-4-[A'-{2-fluorophenyl) ureido]pherylaceiyl]-2-pjTTolidinylmeihyl]-A'-methylainino]-3-mtroben2oate (2.50 mg, 0.421 dich]orophenyi)ureido]-3-ineIhoxyphcryIacetatc (2.27 g, 59%) as a colorless powder, mp 177-lS] °C (dec); 'H-NMR (CDCl,) 5 1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s. IH). 6.81 (s. IH), 6.84 (d. J= 8.3 Hz. IH), 7.06 (br. IH), 7.27 (t,y=8.1 Hz, !H), 7.39 (c!,y= 8.1 Hz. 2H). 8.O4 (d. J = 8.3H2, IH). To a stirred solution of/e/-(-butyl 4-[W-(2,6-diclilorophenyl)ureido]-3-inethoxyphenylaceta[e (2.27 g, 5.34 nunol) in CHiClj (50 ml) was added TFA (20 ml) at room temperature. After 2 h stimng, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[iV'-(2,6-dichlorophenyl)ureidoJ-3-methoxyphcnylacetic acid (1.50 g, 76%) as a colorless powder, mp 246-249 "C (dec); 'H-NMR CDMSO-d A mixture of 4-[W-(2,6-dichIorophenyl)ureido]-3-melhoxyphenylacctic add (288 mg, 0.78 mmol), methyl 4-[(25,45)-4-fIuoro-2-pyiTolidinyl]methoxybenzoale (200 rag. 0.79 mmol), EDC-HCl (227 mg, 1.19 ramol),HOBT (161 mg, l-19imnol)andEt3N(0.55 ml, 3.95mmoI)inDMF(4 ml) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with ElOAc. The combined extracts were washed with ice water and brine. After dried over Na]SO^. the extracts were cont^ntrated in vacuo. The residue was chroraatographcd on silica ge! [50 g, CHC]j/MeOH(40/l)] to give methyl 4-[l-[4-[A'-{2,6-dichlorophenyI)ureido]-3-methoxyphenyl acetyl]-(4S)-fluoro-{2S)-pyrrolidinyl]methoxybenzoate (530 mg, 100%) as a colorless amorphous solid. !H-NMR (CDCl^ 5 2.03-2.62 (m. 2H), 3.61 (d, 2H, J= 4.7 Hz), 3.62-3.66 (m, 2H), 3.73 and 3.77 (each s. 3H, amide isomers), 3.78-3.85 (m, IH), 3.87 and 3.88 (each s, 3H, amide isomers), 3.95^1.63 (m. 4H), 5.22-5.36 (m, IH), 6.82 (s, IH). 6.88 (d, J= 8.8 Hz, IH), 6.95 (d. J = 8.8 Hz, 2H), 7.14-7.25 (m, IH), 7.38 (d, J= 8.1 Hz. 2H), 7.94-8.10 (m, 3H); MS (ESD m/z 6O4 (M*+l). 606 (M*+3), 608 CM'+5). To a solution of methyl 4-[l-[4-[A'-(2,6-dichlorophcnyI)ureido]-3-methoxyphenyIacctyl]-(4S). f]uoro-(2S)-pyrrolidinyl]raelhoxyben2oate (530 mg, 0.78 mmol) in THF (40 ml), 0.25 N NaOji (40 ml) was added. After stirring at room temperature for 11 h, the mixture was acidified with 1 N HCl and extracted with CHClj-MeOH (10/1), The combined extracts were dried over NajSO, and concentrated in vacuo. The residue was purified on TLC [CHClj/MeOH (10/1)] to give 88 (120 mg, 75%) as a colorless amorphous solid. MW 590,43 mp 162-168 °C (dec); IR (KBr) 3346, 2974, 1709, 1604, 1533, 1254 cm'; 'H-NMR (DMSO-d^) 5 1.98-2.36 (m, 2H), 3.58 (s, 2H), 3.78- The combined extracts were washed with aq. NaHCO, and brine. After dried over NajSO,, the extracts were concentrated in vacuo. The residue was chromalographcd on silica gel [1 kg, n-hexane/ElOAc (40/1)] to give methyl 3-chloro-4-nitropheiiylacetatc (11.4 g. 36%) as a yellow oil. 'H-NMR(CDCli)5 3.69 (s, 2H), 3.74 (s. 3H), 7.33 (dd,/= 8.3.1.5 Hz, IH), 7.49 (d.J^ 1.5 Hz, lH),7.87Cd.-/=8.3Hz,lH). A mixture of methyl 3-chloro-4-mtiophenylacetaie (10.9 g, 47.5 mmol), reduced iron powder (8.58 g, 153.6 mmol), AcONa-3H:0 (6,05 g. 44,5 mmol) and AcOH (17.6 ml) in MeOH/H,0 (100/400 ml) was heated at 110°Cfor Ih. After cooled to room leraperatuie, the reaction mixture was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The combined extracts were washed with brine, dried over Na^SO, and concentrated in vacuo. The residue was chromalographed on silica gel [150 g, CHClj/EiOAc (10/1)] to give methyl 4-aimno-3-chlorophenylacetate (4.58 g, 48%) as a red oil. 'H-NMR (CDCI3) S 3.49 (s, 2H), 3.68 (s, 3H). 4.01 (br, 2H), 6.70 (d. J = 7.4 Hz, IH), 6.96 (dd, y = 8.1,2.0Hz, lH).7.17(d,J=2.0H2, IH). To a mixture of methyl 4-aniino-3-clilorophenyIacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5.01 mmol) in THF (20 ml) was added EljN (0.14 ml, 1.00 mmol) at room temperature. After 1 day Stirring, 2-methyIphenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixtm* was concentrated in vacuo. The residue was triturated by the addition of n-hexanc to give methyl 3-chlovo-4-[W '-(2-mcthylpncnyl) ureidojphenylacetate (1.23 g. 74%) as a colorless powder. 'H-NMR (CDClj) 5 2.34 (s, 3H)', 3.54 {S, 2H), 3.68 (s, 3H). 6.24 (br. IH), 6.99 (br, IH), 7.15 (dd, J= 8.3, 2.0 Hz, IH), 7.21-7.31 (m. 5H), 7.44 (d, J= 7.6 Hz, IH), 8.20 (d,J=B.5 Hz, IH); MS (ESI) m^ 333 (IvT+l), 335 {M*+3). To a stirred solution of methyl 3-chloro-4-[A'-(2-methylphenyl)ureido]phenylacetate (1.23 g, 3.70 nunoi) in THF (30 m]) was added 0.25 N NaOH {30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried over 60 "C for 2 days under a reduced pressure to give 3-chloro-4-[A'-(2-methylpbcnyl) ureido]phenylacetic acid (1.22 g, 100%) as colorless powder. 'H-NMR (DMSO-d«) 6.26 (s, 3H), 3,40 (s, 2H), 6.95 (t, J= 7.3 Hz, IH), 7,11 (d, J= 7,6 Hz. 2H), 7.16 (d, 7= 7.3 Hz, IH), 7.32 (s. IH), 7.76 (d, 7= 8.0 Hz. IH), 7.94 (dd, 7= 9.3, 1,0 Hz, IH), 8.72 (s, 2H); MS (ESI) m/z 319 (M'-i-l), 321 (M-+3). 341 (M*+Na). A mixture of 3-chloro-4-[A'-(2-methyiphenyl)uTeido]phenylacctic add (319 mg, l.OOimnol). methyl 4-[(4S)-fluoro-{25)-pyrrolidinyl]mcthoxyben2oate (253 mg. I.OO mmol). EDC'HCl (288 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol) and EljN (0,70 ml, 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 15 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over NajSOj, the extracts were concentrated in vacuo. The residue was purified on TLC [CHClj/acetone (5/1)] to give methyl 4-[l-[3-chloro-4-[A'-(2-mcthylphenyl)ureido]phcnylacetyl]-{45)-fluoro-(25)-pyTToiidinyl]methoxybcnzoale (480 mg, 87%) as a colorless amorphous solid. 'H-NMR (CDCl,) 5 2.10-2.60 (m, 2H), 2.29 (s, 3H), 3.56 (d, J= 6.8 Hz. IH). 3.71-3.84 (m, IH), 3,87 and 3.89 (each s, 3H, amide isomers). 3,91-4.20 (m, 3H), 4.49-4.60 (m, 2H), 5.32 (dt, 7= 53.0, 4.2 Hz, IH), 6.80 (br, IH), 6.89 and 6.95 (each d,J= 8.8 Hz, 2H, amide isomers), 7.09-7.26 (m,6H), 7.50 {d,-/ = 7.3 Hz, IH), 7.94 and 8.00 (each d. J-= 8.8 Hz, 2H, amide isomers), 8.10 and 8,15 (each d, 7 = 8.3 Hz, IH, amide isomers); MS (FAB) m/z 554 (M*+l). 556 (M*+3). To a solution of methyl 4-[l-[3-chloro-4-[A'-(2-raelhylphenyl)ureido]phcnylacetyl]-(4S)-fluoro-(25)-pyTTolidinyI]mcthoxybenzoaie (480 mg, 0.866 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 2 days, the mixture was concentrated under a reduced pressure and acidified with 1 N HCl. The precipitates were collected, washed with water and dried under a reduced pressure to give 90 (374 mg, 80%) as a colorless powder. MW 539.98 ffi. (KBr) 3354, 3060, 2976, 1709, 1604, 1244 cm'; 'H-NMR (DMSO-d.) 5 2.27 (s, 3H), 2.31 (s, 2H>, 3.66 (d, J= 7.1 Hz, 2H), 3.71-4.67 (m, 5H), 5.32-5.53 (m, IH), 6.97 (t, J= 7.3 Hz, IH). 7.04-7,22 (m. 5H). 7,32 and 7.35 (each d. J == 1.7 Hz, IH, amide isomers). 7.77 (d, J= 7.6 Hz, IH), 7.87 and 7.90 (each d, 7= 9.0 Hz. 2H, amide isomers), 8.01 and 8.03 (each d.J= 8.5 Hz, IH, amide isomers), 8.57 and 8.59 (each s, IH, amide isomers), 8,63 and 8,65 (each s, IH, amide isomers), 12,63 (s, IH); MS (ESI) m/z 540 (M*+!), 542 (W*+3). Example 85 4-[l-[3-chloro-4-[JV'-(2-chlorophenyl)ureido]phenylacetyl]-(4S)-fluoro-(25)-pyrrolidinyl]mclhoxy benzoic acid temperature. After 1 day stirring, 2-chIorophcryl isocyanate (0.60 mJ, 5.01 mmol) was added to the reaction mixture and stirred 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated hy the addition of n-hexane to give methyl 3-chloro-4-[//'-(2-chlorophenyl) ureido]phenylacctate {1.35 g, 76%} as a colorless powder. 'H-NMR {CDClj) 5 3.58 (s, 3H), 3.71 F (s, 2H), 7,04 (m, 3H), 7.18 (dd, J= 8.5, 2.0Hz, IH), 7.27-7.39 (m, 3H), 8.07 (m, 2H); MS (ESI) m/z 353 (M*+I), 355 (M-+3), 357 (M*+5). To a stilled solution of methyl 3-chloro-4-[^'-{2-chloropheny!)ureido]phcnyiacetate (1.35 g, 3.82 mmol) in THF (30 ml) was added 0.25 NNaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60 "C for 2 days under a reduced pressure to give 3-ch]oro-4-[A'-(2-chlorophenyl) ureido]phenylacetic add (1.12 g, 86%) as colorless powder. 'H-NMR (DMSO-d^) 5 3.52 (s. 2H), 7.05 (ro, IH), 7.17 (d. J = 8.5 Hz, IH). 7.30 (d, J- 7.6 Hz, IH), 7.37 (s, IH), 7.46 (dd, J= 8.0, 1.5 Hz, IH). 7.95 (dd, J = 8.3.1.2 Hz, IH), 8.07 (d, J = 8.3 Hz, IH), 9.00 (d. J = 8,0 Hz, 2H); MS (FAB) mA 339 (M*+l), 341 (IvT+S). 343 (M*+5). A mixture of 3-chloro-4-[A'-(2-chlorophenyl)ureido]phenyiacetic add (339 mg, 1.00 mmol), methyl 4-[(25,45)-4-fluoro-2-pyrTOlidinyl]methoxybcn2oale (253 mg. 1.00 mmol), EDC'HCl (288 mg, 1.50 mmoO.HOBT (203 mg. 1.50 mmol) and EtjN (0.70 ml. 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 15 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2S04, the extracts were concentrated in vacuo. The residue was chromatographcd on silica gel [50 g, CHClj/acetone(10/l)] to give methyl 4-[l-[3-chloro-4-[A''-(2-chlorophenyl)ureido]phenyiacetyl]-(4i)-fluoro-(25)-pyrTolidinyl]metiioxybcnzoate (550 mg, 96%) as a colorless amorphous solid. 'H-!^MR(l2DClj) 5 2.14-2.64 (m, 2H), 3.59 (d.J= 11.2 Hz, 2H), 3.78-3.82 (m, IH), 3.86 and 3.89 (each s. 3H. amide isomers), 3.91-4.28 (m, 2H), 4,50-4.79 (m. 2H), 5.34 and 5.39 (each dt, ^ = 52,5, 4.4 Hz, IH, amide isomers), 6.89-6.98 {m.3H). 7.09-7,13 (m. 2H). 7,22 (dt J = 7.3, 2.2 Hz, IH). 7.29 (dd, J= 8.1.2.0Hz, IH), 7.79 and7.86 (eachs, IH. aniideisomets). 7.86-8.03 (m.4H), 8.11 (dd, J= 8,3, 1.0 Hz. IH); MS (FAB)m/r 574 (M*+l). 576 (M^+3), 578 CM*+5). To a solution of methyl 4-[l-[3-ch]oro-4-[A'-(2-chlorophenyl)urcido]phenylacetyl]-(45)-fluoro-(25)-pyrrolidinyi]methoxybenzoate (550 mg, 0,957 mmol) in THF (30 ml) was added 0,25 N NaOH (30 m!). After stirring at room temperature for 2 days, the mixture was concentrated under a reduced pressure and acidified with 1 N HCl. The precipitates were collected, washed with water isocyanaie (0,62 ml, 5,01 mmo!) inTHF [20 ml) was added EtjN (O.U m), 1.00 mmol) at room temperature. After 1 day stirring, 3-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[iV'-(2-bromophenyl)ureido]-3-chlorophenylacelate (1,34 g, 67%) as a colorless powder. 'H-NMR (CDCI3) 5 3.58 (s, 3H). 3.70 (s, 2H).6.98(m, 3H), 7.l9(dd,7=8.3. 1.9 Hz. IH), 7.32 (m. IH), 7.5] (m, 2H), 8.05 (m, IH); MS (ESI) m/z 398 (M'+l), 400 (M*+3), 402 (IvT+S). To a stirred solution ofmethyl4-[W-(2-bromoplienyi)ureido]-3-chlorophenylacetate (1.34 g, 3.37 mmoi) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperamre for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60 °C for 2 days under a reduced pressure lo give 4-[A'-(2-bromophenyI)ureido]-3-chlorophenylacetic acid (1.03 g, 80%) as coloriess powder, 'H-NMR (DMSO-d^) 5 3,56 {s, 2H). 7.00 (m. IH), 7.17 (dd,y= 9.0, 1.7 Hz. IH), 7.32-7,40 (m, 2H), 7.62 (dd,y= 8.0, 1.2 Hz, IH), 7.95 (m. 2H), 8.83 (s, 1), 9.01 (s, H). 12.41 (br, IH); MS{FAB) m/z 385 CM'+2).386(M*+4).388 (W-f^). AmistuTeof 4-[jV'-(2-b[oinopheny!)uieidol-3-chlciiophcnylaccticacid(384 mg, 1,00 mmol), methyl 4-[(45)-fluoro-(2S)-pyTToIidiny!]mcthoxyben2oaIe (253 mg, I.OO mmol), EDC'HCl (288 mg, 1.50 mmol), HOBT (203 mg, 1,50 mmol) and EljN (0.70 ml, 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 15 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over NajSOj, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCVacclone(10/l)] to give methyl 4-[l-[4-[//' -{2-bromophenyl)urcido]-3-chlorophenylacetyl]-(45)-fluoro-{2S)-pyrTO]idinyl]methoxyben2oate (530 mg, 86%) as a colorless amorphous solid. 'H-NMRCCDCWS 2.14-2.63 (m, 2H), 3,58 (d, J= 10.0Hz, IH), 3,73-3,83 (m, IH). 3,86 and 3,89 (each s, 3H. amide isomers), 3,90-4.29 (m, 3H), 4,50-4,69 (m, 2H). 5.33 and 5.37 (each m, IH, amide isomers), 6,88-6.93 (m, 3H), 7.II-7.14 (mZH), 7.26 (m. IH). 7,46 (d, J = 8,1 Hz, IH), 7,62-7,78 (m, 2H), 7,89 and 7,93 (each m, 2H, amide isomcre), S.Ol (dd, J = 8.8, 1,7 Hz, 2H); MS (FAB) m/z 6lS (M'). 620 (M*+2), 622 (M*+4). To a solution of methyl 4-[l-[4-[A^'-(2-bromophenyl)iireido]-3-chIoropheiiylacetyl]-(45)-fluoru-(25)-pyrrolidinylJmcthoxyben2oate (530 mg. 0.856 mmol) in THF (30 ml) was added 0,25 N NaOH (30 ml). After stining at room temperature for 2 days, the mixture was concentrated under a reduced pressure and acidified with 1 N HCl. The mixture was extracted with CHCIj/MeOH (10/1). The combined extracts were washed with ice water and brine. Alter dried over Na^SOj, the extracts were concentrated in vacua. The residue was chromatographed on silica gel [20 g. CHCyaci:tone(I0/])-CHClj/MeOH(10/l)] to give 92 (59 mg, 11%) as a colorless amorphous solid, MW 604-85 ffi. (KBr) 3329, 3060,2976, 1712, 1526,1435 cm"'; 'H-NMR pMSO-d^ 5 2,3] (m, H), 3,48-4,68 (m, 7H), 5,32-5.53 (m, IH), 6.99-7,19 (m, 4H), 7.36 (s, IH), 7,63 (dd, ^ = 6,7, 1.2 Hz, IH), 7,86-8.18 (m.4H), 8,83 (s, IH), 9,02 (s, IH), 12,67 (br, IH); MS (ESD m/z 604 (M*-H), 606 (M-'+3). 608 (M*+5); Anal. Calcd for C„H„BrClFN3O3-0,5HiO: C, 52.83; H, 4.10; N, 6,85; CI, 5.78; F, 3.09. Found; C. 53.24; H. 4.32; N, 6.43; CI, 6,01; F, 3.07. Example 87 4-[]-[3-chloro-4-(W-phenylureido)phenylacetyI]-(45)-fluoro-(25)-pyTTolidinyl]methoxybcnzoic acid the addition of/i-hexane to give methyl 3- To a stirred solution of methyl 3 •chloro-4-(^'-phenyl urcido)phenylaccUIe (1.79 g, 5,62 minol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 20 h. the solvent was concentrated in vacuo. The residue was triturated by the addidon of I N HCl and dried at 60 "C for 2 days under a reduced pressure to give 3-chloro-4-(iV'-phenylurcido) pheny!aceticacid{1.58g, 92%) as pale brown solid 'H-NMR(DMS0-dJ5 3.55 (s, 2H), 6,99{t, J = 7,3 Hz, IH). 7.17 (d, J= 8,3 Hz, IH), 7,29 (t, ^ = 7.6 Hz, 2H), 7.36 (s, IH), 7.46 (d, y = 8:0 Hz. 2H), 8,01 (d, J= 8,3 Hz, IH), 8.28 (s, IH), 5,37 (s, IH), 12.37 (br, IH). A mixture of 3-chloro-4-(W-ph«iylureldo)plienyIacetic acid (305 mg, 1.00 mmal), methyl 4-[(25.45)-4-fluoro-2-pyiTOlidinyl]mcthoxybenzoale (253 mg, 1.00 mmol), EDC-HQ (288 mg, 1.50 mmol), HOST (203 mg, 1.50mmDl)aiidEt3N(0.70ml, 5.00 mmol}inDMF(4 ml) wassdrrcdat room temperature for 17 h. The mixture was poured into ice water and extracted withElOAc. The combined extracts were washed with ice water and brine. After dried over NaJSO^, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel {30 g, CHCVacetone(20/l)J to give methyl 4-[l-[3-chloro-4-(A"-phenyliiTeido)phcnyIaceiyl]-(4S)-fluoro-(2S)-pyrro\idiiiyl]melhoxybenzoale (720 mg, 100%) as a colorless amorphous scplid. MS (FAB) m/i 540 (M*-*-l)^ 542 (M*+3). To a solution of methyl 4-[l-[3-chloro-4-(A'-phenylureido)phenylacetyI]-(4S)-fluoro-(ZS)-pyiTolidinyl]tnethoxybenzoate (720 mg, 1.00 mmol) in THF/MeOH (30/30 ml) was added 0,25 N NaOH (30 ml). After stirring at room temperature for 2 h, the reaction mixture was heated at 50 'C for 22 h. After removed the solvent, the resulting residue was acidified with 1 N HCl. The precipitates were collected, washed vwth water and dried under a leiiuced pressure to give 93 [412 ng, 78% (2 Steps)] as a colorless powder. MW 525.96 IR (KBr) 3346, 3302, 2976, 1712, 1604, 1240 cm'; 'H-NMR (DMSOA) 5 2.25-2.31 (m, 2H), 3.66 (d, J = 7.8 Hz, 2H), 3.7M.67 (m, SH), i,31-5.52 (m, IH), 6,99 (t, J= 7,3 Hz, IH), 7.04 and 7.07 (each d.J = 8,7 Hz. 2H, amide isomers), M4-7.1B(m, IH), 7,29 (t.y= 7.3 Hz, 2H), 7.35 {d,J= 1,7 Hz. IH), 7,46 (d, 7= 7,8 Hz, 2H). 7,87 md7,90 (eachd,y= 9.0 Hz, 2H, amide isomers), 8,04 and 8.06 (each d. J = 8,5 Hz, IH, amide somers), 8,26 and 8,28 (each s, IH, amide isomers), 9,36 (s, IH), 12.63 (S, IH); MS (ESI) m/i 526 To a stirred mixture of methyl 3-<:hlorapheiiyiacelale g iiimol ml was added hnoj mmol at the reaction mixture gradually raised to room temperature for h. poured into ice water and extracted with chclj. combined extracts were washed aq. nahco brine. after dried ovsr na concentrated in vacuo. residue chromatographed on silica gel n-hexane give methyl as a yellow oil. hz ih> A mixture of methyl 3-bromo-4-mtrophenylacetate (14.8 g, 53,8 mmol), reduced iron powder (9,62 g, 172 mmol), AcONa-SHjO (7.32 g, 53.8 mmol) and AcOH (20.0 ml) in MeOH/H,0 (150/600 ml) was healed at 90 'C for Ih. Afler cooled lo room temperature, Ihe reaction mixiurc was filtered through Celite and the filtered cake was washed with MeOH. The combined filtrate were evaporated and extracted with EtOAc. The extracts were washed with brine, dried over NajSO^ and concentrated in vacuo. The residue was chromatographed on silica gel [400 g, CHQj/EtOAc . (20/1)] to give metJiyl 4-anuno-3-bromophenylacetate{9.0! g, 69%) as a brown oil, 'H-NMR (CDCI3) 5 3,48 (s, 2H). 3,68 (s, 3H). 4.05 (br, 2H), 6,69 (d, y = 8.3 Hz, IH), 7,00 (dd, J = 8.1, 2.0 Hz, lH),7,32(d.y-2.0Hz, IH), To a mixture of methyl 4-amino-3-broinopheny!acetate (587 mg, 2.40 mmol) and 2-meUiylphenyl isocyanale (0.287 mJ, 2.40 ininol) in THF (2 mJ) was added EtjN (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixtuje was concentrated in vacua. The residue was triturated by the addition of n-hexane to give methyj 3-bromo-4-[A'-(2-methylpheny])urEido] phenylacelate (650 mg, 72%) as a pale brown powder. 'H-NMR (CDClj) 52.34 (s, 3H), 3.53 (s, 2H), 3.68 (s. 3H), 6.18 (br, IH), 6.96 (br, IH). 7.18-7.33 (m, 4H). 7.29 (d, J= 4.4 Hz. IH), 7.30 (d,y= 7.3 Hz. IH), 8.19 (d, J= 8.3 Hz, IH); MS (ESI) m/^ 377 (M*), 379 (M*+2), To a stirred solution of methyl 3-bromo-4-[A'-(2-methy]phcnyI)urcido]phcnylacetate (650 mg, 1.72 mmo!) in THF (10 ml) was added 0.25 N NaOH {10 mJ). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60 °C for 2 days under a reduced pressure to give 3-brorao-4-[A'-(2-methylphenyl)ureido] phenylacetic acid (1.22 g, 100%) as colorless powder. 'H-NMR (DMSO-dJ 5 2.26 (s. 3H), 3.32 (s, 2H), 6,93 (m, 2H), 7,10-7.17 (m, 4H). 7.76 (d,J= 8.1 Hz, 2H). 8.52 (s, IH); MS (ESI) m/2 385 (M*+Na), 387 {M*+2+Na). A mixture of 3-brorao-4-[//'-(2-methylphenyl)ureido] phenyl acetic acid (80 mg, 0.22 mmol), methyl 4-I(4S)-fluoro-(25)-pyrToiidinyl]methoxyben2Date {56 mg, 0.22 mmol), EDC-HCl (63 mg. 0.33 mmol), HOBT (45 mg, 0.33 mmol) and EtjN (0.15 ml, 1.10 mmol) in DMF (1 ml) was stirred at room temperature for 18 h. The nii?cture was poured into ice water and extracted with ElOAc. The combined extracts were washed with ice water and brine. After dried over Na]SO.,lhe extracts were concentrated in vacuo. The residue was purified on TLC [CHCyacetone (5/1)] to give methyl 4-(l-[3-bromo-4-[//'-(2-methylphenyl)urcido]phenylacctyl]-(45)-fluoro-(2S)-pyiTolidinyl ]methoxybenzoalc (140 mg, 100%) as a yellow oil. 'H-NMR (CDCI3) 5 2.30 (s, 3H), 2.55 (m. IH), 3.56 (d,J= 6.4 Hz, 2H), 3.70-3.84 (m, 3H), 3.87 (s, 3H), 3.99-4.59 (m, 3H), 5.23-5,38 (m, IH), 6.83-6.94 (m, 2H). 6.95 (d, J^ 8.8 Hz, IH), 7.07-7.26 (m, 5H), 7.36-7.63 (m, 2H), 7.94-8.15 (m, 3H); MS (ESI) m/z 598 (M*-H), 600 (M*+3). To a solution of methyl 4-[l-[3-bromo-4-[W-(2-methylphenyl)ureido]phenylacetyi]-(45)-fluoro-(23)-pyrTolidinyl]mcthoxybenzoate (140 mg, 0.22 mmol) in THF (10 ml) was added 0.25 NNaOH (10 ml). After stirring al room temperature for 14 h, the mixture was concentrated under a reduced pressure and acidified with 1 N HCI. The precipitates were collected, washed with water and dried under a reduced pressure to give 94 (109 mg, 85%) as a colorless powder. MW 584.43 IR (KBc) 3313. 3060, 2976. 1687. 1604, 1525, 1244 cm'; 'H-NMR (DMSO-ds) 5 2.27 (s. 3H), To a stirred solution of methyl 3-broiiio-4-[jV'-(2-chJoiophenyl)uTeido]phGnylacetate (710 mg, 1.79 mmol) in THF (10 mJ) was added 0.25 N NaOH (10 ml). After Stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCI and dried at 60 "C for 2 days under a reduced pressure to give 3-bromo-4-[//'-(2-chlorophcnyl) ureido]phenylacctic acid (643 mg, 94%) as colorless powder, 'H-NMR {DMSO-d«) 5 3,56 (s, 2H), 7.05 (m, IH), 7.21 (dd,J'= 8,6. l,7Hz, IH), 7.29 (1, J= 7,8 Hz, IH), 7.46 (d, 7= 8.1 Hz, IH), 7.46Cd,J=8.1Hz, IH), 7,53 (d,y= 1.7 Hz, IH). 7.83 (d,J-= 8.3 Hz, IH), 8.06 (d. J= 7.6Hz. IH). 8.86(5. iH),S,89(s, IH). 12.40 (s, !H); MS (ESI) m^ 382 (M*+I), 384(M*+3}. A mixture of 3-bromo-4-[A'-(2-chloropheny!)uTeido]phenylacetic acid (384 mg. 1.00 mmol), methyl 4.[(45^-fluoro-{25)-pyTTolidinynmethoxyb?r-zoate (253 mg, 1.00 mmoi), EDC-HCl (288 mg, 1,50 mmol), HOBT (203 mg, 1.50 mmol) and EtjN (0.70 ml. 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 18 h. The mixture was pouted into ice water and extracted with EtOAc. The combined exu^cts were washed with ice water and brine. After dried over NajSO,, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [30 g. CHCl>/acetone(10/l)] to give methyl 4-[l-[3-bromo-4-(A'-(2-ch]orophciiyl)ureido]ptienylacetyll-('iS)-£ui>To-C2S}-pynDlidii}yl]inetiioxybemoate (640 mg, 100%) as a colorless amorphous solid. 'H-NMR(CDCy 52,07-2,46 (m, 2H). 2,59 (\,J= 18.4 Hz, IH), 3,57 (i.J= 10,5 Hz,2H). 3,63-4.67 (m, 7H), 5.26-5.44 (m, IH), 6,89-6,96 (m, 3H), 7.13 (d, J= 7.6 Hz, IH), 7,1 (t. J= 7,3 Hz, IH), 7.26-7,29 (m, 2H). 7.52-7,94 (m. 4H), 8,01(d, J = 8.5 Hz, IH), 8.09 (d, J= 8,5 Hz. IH); MS (FAB) m/z 618 (M"). 620 (M*+3), 622 (M*+5). To a stirred soJution of methyl 3-bromo-4-[A'-(2-bromophenyl)iircido]phenylac«aic (770 mg, 1.74 niniol)iiiTHF(10nil)wasadded0.25NNaOH(10ml). Afterstimngat roomtemperatuitfor 14 h, the solvent was concentrated in vacua. The residue was triturated by the addition of 1 N HCl and dried at 60 °C for 2 days under a reduced pressure to give 3-brDmo-4-[y-(2-bromophcryl) ureidojphenylacetic acid (702 mg, 94%) as colorless poivder. 'H-NMR (DMSO-d,) 5 3.56 (s, 2H), 6.99 (dt,7= 7.8, 1.5 Hz, IH), 7.21 (dd, J= 8.3, 1.7 Hz, IH), 7.33 (dt,/= 7.1, 1,5 Hz. IH), 7.53 (.d.J= 1.7Hz, IH), 7.62 (dd,J= 8.1,1.5 Hz, IH), 7.82 (d.y= 8.3 Hz, IH), 7.93 (dd,y= 8.1, 1.5 Hz, IH). 8.82 (s, IH), 8,86 (s, IH), 12.39 (s, IH); MS (ESI) m/2 428 (M*+l), 430(M*+3). A mixture of 3-bromo-4-[Af'-(2-ch]orophenyl)urcido]phenylacclic acid (428 mg, 1.00 ramol). methyl 4-[{25,4S)-4-fluoro-2-pyTToIidinyl]methoxybenzoate (253 mg. I.OO mmol), EDC'HCl (288 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol) and EtjN (0,70 ml, 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with ElOAc. The combined extracts were washed with ice water and brine. Afler dried over NajSO* the extracts were concentrated in vacuo. The residue was chroraatogiaphed on silica gel [30 g, CHCyacetone(!0/l)] to give methyl 4-|l-13-bromo-4-[A'-(2-bromophenyl)urci(io]phenyIacetyl]-(45)-fIuoro-(2S)-pyiTolidinyl]methoxybenzoate (720 mg, 100%) as a colorless amorphous solid. 'H-NMR (CDCl,) 5 2.07-2,45 (m, 2H). 2.58 (m, IH), 3.58 (d. J= 9.0 Hz, 2H), 3,63-4,69 (m, 9H), 5,26-5,43 (m. IH). 6,88-^,99 (m, 3H), 7,16 (d, J = 8.3 Hz, IH), 7,23-7,32 (m, 2H), 7.46 (dd, J -8.1, 1,5 Hz, IH), 7,51-8.20 (m. 5H); MS (FAB)m^66A (M*), 666 (M*+3), 668 (M'+S). To a solution of methy!4-[l-I3-bromo-4-[A'-(2-bromophenyI)urcido]phcnylacetyl]-(45)-flubro-{2S)-pyiTolidinyI]mcthoxybenzoate (720 mg, 1.00 mmol) in THE (40 ml) was added 0.25 N NaOH (40 ml). After stirring at room temperature for 14 h. the mixture was concentrated in vacuo and acidified with 1 N HCl, The mixture was extracted with CHClj/McOH (10/1), Thecombined extracts were washed with ice water and brine, Afier dried over NajSOj, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [20 g. CHCIj/acclone (10/l)-CHClj/MeOH(20/l)] and triturated by the addition of ether to give 96 (489 mg. 75%) as a colorless amorphous solid, MW 649.30 IR(KBr) 3450, 3313, 3070, 1709, 1684,1525, 1435 cm-'; 'H-NMR (DMSO-d() 5 2,25-2.50 (m, 2H), 3,67 (d, /= 8,3 Hz, 2H), 3,73-4,68 (m, 5H), 5,31-5.53 (m, IH), 6.98-7,08 (m, 3H). 7.21 (d,-'= 8,2 Hz, IH), 7,34 {t,^= 8,8 Hz, IH), 7,50 and 7.53 (each s, IH, amide isomers), 7,62 (d. y= 8,0 Hz, IH), 7,80-7.96 (m, 4H), 8,82 (s, IH). 8,85 and 8,86 (each s, IH, amide isomers), 12,63 (br, IH); MS (FAB) m/z 650 (M'+l), 652 {M•^■3), 654 (M*-^3), 672 (M*+Na),^/)a/, Calcd for C,,H„BrjFN,Oj-0,9H,O; C, 48,73; H, 3,91; N. 6,31; F, To a stirred solution of ethyl 4-amino-2,3-difluorophenylacelaie (323 mg. 1.5 mmol) in DMF (8 mL), were added tricthylamine (0,209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0,372 ml, 3.0 mmol) al n. The stirring was continued for 48 hour at 80 " C. The reaction mixture was evaporated in vacuo, and the solid ^vas suspended to n-hexane. The solid was collected throu|h filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 niL) at rt. The stirring was continued for 18 hours at n. The reaction was poured into IM HCl, and the resulting precipitate was collected through filtration. The solid was recrysiallized with CHClj-n-hexane to give 4-[(2-inethylphenyl)uTeido]-2,3-difluorophcnyiacelic acid (200 mg, 42%) as a white solid. 'H-NMR (CDCl,) 5 2.30 (s, 3 H), 3.35 (s, 2 H), 6.98 (m, 1 H), 7.04 (m, 1 H), 7.18 (d, J = 7.3 Hz, 2 H), 7.69 (d, J= 8,] Hz, 1 H), 7.90 (m. 1 H); MS (FAB)m/z 321 (M'41). (100 mL). The mixture was extracicd with EtOAc and the combined organic layer was washed with IM HCl and brine, dried over MgSOj, filtered and concentrated. The residue was dissolved to dichloTomethane (20 mL), and added TFA (20 mL) al rt. The mixture was refluxed for 18 h. The mixture was evaporated in vacuo, coevaporated with toluene (20 mL x 2). The residue was dissolved in MeOH (150 mL), and added cone. H,SOj (5 mL), The mixture was refluxed for 18 h. The mixmre was diluted with ElOAc (300 mL), washed with water, IM HCl. and brine, dried over anhydrous MgSO,, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1: 1, i|) 50mmx300 mm, 15 mL/min) to give ethyl 2,5-difluoro-4-nitrophenylacetic acid (6.53 g, 90%) as a yellow oil. 'H-NMR (COaj) 5 3.75 (s, 2 H), 3.76 (s, 3 H), 7.29(dd,J=5.8H2, 10.3 Hz, 1 H). 7.81 (dd, J= 6.0 Hz, 8.4 Hz, 1 H);MS (ESI) m/i 232 (M*+l). To a stirred solution ofethyl2,5-difluoro-4-iiitrophenylacelale (5.88 g, 25.4 mol) in EtOH (100 mL), was added SnClj (17.2 g, 76.3 mmo!) at rt. The stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCls (100 mL) and poured into ice waier-4M NaOH (40 mL of 4M NaOH in 300 mL of ice-water), extracted with CHCl, (100 mL X 2). dried over anhydrous MgSOi, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexanc-EtOAc from 9:1 to 7:3, ^ 50 ram x 500 mm, 15 ihl/min) to give ethyl 4-amino-2,5-difluorophenylacetic acid (2.85 g, 52%) as a colorless oil. ' H-NMR (CDCIj) 5 1.28 (t, J-= 7.3 Hz, 3 H), 3.51 (s, 2 H), 3.78 (brs, 2 H), 4.15 (dd,y= 7.2 Hz, 14.2 Hz, 2 H), 6,47 (dd.J= 7.5, 10.4 Hz, IH), 6.88 (dd,J= 6.7, 11.0 Hz, 1 H); MS (FAB) m/z 216 (M*+I). To a stirred solution of ethyl 4-amino-2,5-difluorophenylacetate (323 mg, 1.5 mmo!) inDMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80 "C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF-MeOH (1:1. v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into IM HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHClj-n-hexane to give 4-K2-methylphenyI)ureido]-2,5-di[luorophenylacctic acid (214 mg, 46%) as a white solid, 'H-NMR (CDCIj) 5 2,30 (s, 3 H), 3,35 (m, 2 H). 7.02 (m, 2 H), 7.18 {d,J = neutralized with JN HCl. The mixture was extracted with EiOAc. The extract was washed with water, then dried over Na,SOj, and concentrated in vacuo to give l-/er/-butoxycarhonyl-4- fluoropyrrolidine-a-carboxylic acid (l.I g, quanl) as a colorless oil, 'H-NMR (CDClj) 5 1,47 (br s, 9H). 2.78-2,83 (br s. 3H), 4.37 (s, 2H), 6.73-6.76 (m, 3H), 7.17 (m. IH). To a stirred solution of l-/e/'/-butoxycarbonyI4-fluoropyrrolidine-2-caTt)oxylic acid (1.1 g. 4.7 minol) in THF (iO.O nU) was added BH3-THF(I,0 M solution in THF, 10.0 nil. 10.0 nrniol) at O^C. After stined at room temperature for 1.0 h. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0°C, and extracted with EtOAc. The extract was washed with water, then dried over Na,S04, and concentrated in vacuo to give l-ferf-buloxycarbonyM-fluoro-2-pyiTolidinyImcthanol (1.0 g, quant) as a a colorless oil. 'H-NMR (CDClj) S 1.48 (s. 9H), 2.29-2.39 (m, IH), 3.38-3.59 (m, 2H), 3.74-3.88 (m, 2H). 4.09-4.14 (m, 2H), 4,85 (m, IH). 5.03 (brs, IH), 5.16Cbrs, IH), To a stirred solution of oxalyl chloride (0.28 ml, 2.3 irnnol) in CHjClj (20,0 ml) was added DMSO (0.39 ml) at -78 "C. After 5 minutes, to the mixture was added l-/erf-butoxycaibonyI-4-fIuoro-2-pyiroiidinyimethaiiol (500 mg, 2.28 mmol) in CH,CI, (5.0 ml). The mixture was stirred for 30 minutes at -78 "C, and tricthylamine (1,6 ml) was added. The mixture was stirred for 30 minutes at-78 °C, and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CHjClj. The organic layer was dried over NajSOj, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, methyl 4-aminoben2oate(302 mg, 2,0 mmol), and AcOH (0.13 ml) in DCE (10 ml) was added NaBH(OAc)i (656 rag, 3,09 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CH,Clj, The extract was washed with brine, dried over NajSOj, and concentrated in vacuo. The residue was puiifiedby column chromatography on silica gel with EtOAc-n-hexane (1:3, vA') as elucnt to give methyl 4-(l-fert-butoxycaibonyl-4-fluoro-2-pyrrolidinyl)methylainJnobenzoatc (541 mg, 77%) as a pale yellow oil, 'H-NMR (CDClj) 5 1.55-1.59 (m, IH), 2.16-2.27 (m, IH), 2.89-3.03 (m, 2H), 3.19-3.28 (m, 2H), 3.69-3.73 (m, IH), 3.84 (s, 3H}, 5,15 and 5.29 (each s, total IH), 6.55-6.58 (m, 2H), 7.84-7.86 (m, 2H). To a stirred solution of methyl 4-(l-rer/-butoxycaibonyl-4-fluoro-2-pyrTOlidinyl)methylamino benzoate{541 mg, 1.53 mmol) in CH,Clj(8,0 ml) wasaddcdTFA(4.0 ml) atO°C, ThereacUon mixture was stirred at room temperature for 0,5 hr. The mixture was concentrated in vacuo. Sat, NaHCOj was added to the residue, and extracted with CHjCli, The extract was washed with brine .dried over NajSO,, and concentrated in vacuo. The crude product was used to the subsequent reaction wilhoui /uither purification. To a stiired solution of [he crude productOiJ mg, 0.6 mmoi), 4-[A'-{2-chlorophenyl)urcdio]-3-niethoxyphenyiacetic acid (201 mg. 0,6 mmol), HOBt (94 mg, 0.7 mmol), and triethyJamine (167 ji], i. 1.2 mmol) in THF (lO.O zn}) and McCN (10.0 mJ) was added EDC'HCl (173 mg, 0.9 mmol) at 0 "C. The reaction mixture was stirred at room lemperahire for 16 hr. and concenlrated Jn vacuo. Waierwasadded to the residue, and extracted with EtOAc, The extract was washed with sat. NaHCOi, 2-M ritiic acid, and sat. NaHCOj, then dried over NajSO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(l:2 .v/v) as eluent to give methyl 4-ll-[4-{A'-(2-ch]orophenyl)ureido]-3-methoxyphenylacetyl]-4-f]uoro-2-pyrrolidinyl]melhyIaminoben2oale (320 mg. 94%) as an amorphous solid. 'H-NMR (CDCl^ 5 1.80-1.95 (m, IH), 2.42-2.58 (m, IH). 3.20-3.51 {m. 3H), 3,51-3.76 (m, 3H), 3,84 (s. 3H). 3,85-3.98 (m, IH), 4,67-4.70 (m, IH), 5.10 and 5,23 (s, each, total IH), 5,50 (br s. IH). 6.49-6.52 (m, 2H), 6,78-6,81 (m, 2H). 6,97-7,01 (m, IH). 7.14-7,18 (m. 2H), 7.24-7.36 {m, 2H), 7.80-7.82 (m, 2H). 7.99-8.01 (m, IH). 8.15-8.18 (m, IH), To a stirred solution of methyl 4-[l-[4-[jV'-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-4-fluoro-2-pyrTolidiny5]niethylaminQbenzoate (320 mg, 0.56 mmol) in THF (5.0 ml) and MeOH (3,0 ml) was added IN NaOH (0,8 ml. 0.8 mmol). The mixture was stirred at 70 "C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HCI, The resulting solid was colleaed. washed with water, and dried in vacuo to give 99 (280 mg. 90%) as a white crystalline solid. MW 555,00 mp 132-136 "C; IR (KBr) 3332, 2937, 1602. 1531, 1174. 752 cm'; 'H-NMR (DMSO-d^} 5 2.00-2,40 (m, 2H). 3.50-3.90 (m. 4H). 3.75-3,85 (m, 5H). 4.27 (m. IH). 5.23 and 5.37 (each s, total IH). 6.51-7,03 (m, 5H). 7.25-7.29 (m, IH), 7.41-7,44 (m, IH), 7,64-7,68 (m. 2H). 7,92-S, JO (m, 2H), 8.87-6,94 (m, 2H);^no/, caJcdfor C„H„N^OsFa'0,6HiO; C, 59.44; H, 5,20; N, 9,90, Found: C, 59.41; H, 5.19; N. 9.72. To a stirred soludon of methyl 4-(l-fert-butoxycaibonyl-4-fluoro-2-pyrrolidinyl)melhylamino bcnzoate(54I mg, 1.53 mmol) inCH,Cl, (8.0 mI)wasaddedTFA(4.0mI) atO^C. Thereaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to OK residue, and extracted with CHjCl,. The extract was washed with brine, dried over NajSO,, and concentrated in vacuo. The crude product was used to the subsequent reaction without fiinhcr puriScation. To a stirred soJation of the cnjde product (151 mg. 0.6 mmoi), 4-[A'-(2-bromophenyl)uredio]-3-methoxyphenylacetic acid (227 mg, 0,6 mmol). HOBt (94 mg, 0,7 irnnol), and triethylainine (167^1, 1.2imnol)inTHF(!0.0 m])andMeCN (10,0 ml) was added EDC'HCI (173 mg, 0.9 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the iBsidue, and exiracled with EtOAc. The extract was washed with sal. NaHCO,, 2-M citric acid, and sat. NaHCOj, then dried over NajSOj. and concentrated in vacuo. The residue was purified by column chromatography on silica gel widi /i-hexane-EtOAc (2:3, vA-) as elucnl to give methyl 4-[l-[4-[A'-(2-broinophenyl)oreido]-3-methoxyphenylacctyl]-4-fluoro-2-pyirolidinyl]methylaminoben2oaIe (280 mg, 76%) as a colorless oil, 'H-NMR(CDClj) 5 1.80-1.98 (m. 3H), 1.42-1.58 (m, IH), 3.20-3,52 (m, 3H), 3.67-3.79 (m, 5H), 3,84 (s, 3H). 3.94-3.97 (m, IH), 4.68-4.71 (m, IH), 5.10 and 5.23 (each s, total IH), 5.51 (br s, IH), 6.50-6,52 (m. 2H), 6.79-7.07 (m. 5H), 7.25-7.33 {m,. IH), 7.51-7.53 (m, IH), 7.80-7.83 (m, 2H), 7.98-8.00 (m. IH), 8.11-8.14 (m. IH). EtOAc (4:1) as ducni lo give methyl 4-[l-[3-methoxy-4-[A'-(2-melhylphenyl)ureido] phenylacetyl]-(4if)-fluoro-(2^-pyiTolidirylnicthoxy]benzoate (1.37 g, quarl) as a pale yellow viscous solid. 'H-NMR (CDClj) 5 2.24 (s, 3 H), 2,26-2.47 (m, 2 H), 3.46 (s, 3 H), 3.49-3,64 (m, 4 H), 3.87 (s, 3 H), 4,06 (dd, J = 9.5, 2,0 Hz, 1 H), 4.5M.62 (m , 2 H), 5.20 and 5.33 (br s, each, total IH), 6.63 (s, 1 H), 6,72 (d,/= 8.3 Hz, 1 H), 6,77 (d, J = 9.0 Hz, 2 H), 7.05 (1, J = 7,6Hz, I H), 7,16-7,20 (m, 3 H), 7.53 (s, 1 H), 7.63 (d,/=7,8Hz, 1 H), 7.91 (d, y= 9,0 Hz, 2H), 8.07 (d, y=8,lHz, IH). methoxybenzoale (369mg, 1,0 mmol) in CH,C1, (3.0 m]) was added TFA (3.0 ml) at 0 "C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CHjClj. The extract was washed with brine, dried over NajSOj, and concentrated in vacuo. The crude product was used to Ihesubsequcnt reaction without fiirther purification. To a stirred solution ofthe crude product (185 mg. 0.5 mmol), 4-[A'-(2-ch]orophenyl)uredio]-3-methoxyphenylacetic acid (167 mg, 0.5 mmof), HOBI (68 mg, 0,5 mmol), and Iriethylamine C208ml, 1.5 mmol) in THF (8.0 ml) and MeCN (8.0 ml) was added EDOHCl (344 mg, 0.75 mmol) at 0 "C. The reaction mixnire was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat, NaHCOs. 2-M citric acid, and sat. NaHCO), then dried over NajSOj, and concentrated in vacuo. The residue was purified by ' column chromatography on silica gel with n-hexane-EtOAc (1:2, vA") as eluent to give methyl 4-[(45)-chloro-l-[3-methoxy-4-[Af-(2-chloropheny[)ureido]phcnylacctyl]-(2S)-pym)lidinyl]methoxy benzoate (210 mg, 72%) as a colorless oil. 'H-NMR (CDClj) 5 3.35-3.50 (m, IH), 3.55-3.65 (m, IH), 3.61-3.66 (m, 3H), 3.75 (s, 3H), 3.88 (s, 3H), 3.99-4,04 (m. IH), 4.35-4.40 (m, 3H), 4.48-4.53 (m, IH), 6.77-7.10 (m, 7H), 7.25-7.36 (m, 2H). 7.93-8.00 (m, 2H), 8.18 (d, /= 8.0 Hz, IH). methoxybenzoate (369nig, 1.0 mmol) in CHjClj (3.0 ml) was added TFA (3.0 ml) at 0 "C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentraled in vacuo. Sat. NaHCOj was added to the residue, and extracted with CHjClj. The extract was washed with brine, dried over NajSOj, and concentrated in vacuo. The crude product was used lo the subsequent reaction without further purification. To a stirred solution of the crude product (185 mg, 0.5 mmol), 4-[A'-(2-bromophenyl)uredio]-3-methoxyphenyIacetic acid (190 mg. 0.5 mmol), HOBt (68 mg. 0.5 mmo!), and trielhylamine (208ml, 1.5 mmol) in THF (8.0 ml) and MeCN (8.0 ml) was added EDC-HCI (144 mg, 0.75 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added lo the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over NajSOj, and concentrated in vacuo. The residue was purified by' column chromatography on silica gel with n-hexanc-EtOAc (1:2 ,v/v) as elucnt to give methyl 4-[ 1 - [4- [N'-{2 -brom opheny Ourcido] -3 -methoxyp henylacety 1] -(4S)-ch] oro-(25)-pyrTolidiny 1] methoxybenzoate (260 mg, 83%) as a colorless oil. 'H-NMR (CDClj) 5 2.32-2.50 (m, IH), 2.53-2.65 (m, IH), 3.61-3-67 (m, 3H), 3.75 (s, 3H), 3.88 (s, 3H), 3.99^.03 (m, IH), 4.35-4.40 (m, 3H), 4.45-4.55 (m. IH), 6,78-7.10 (m. 7H). 7,28-7.33 (m, IH), 7.52 (d, J= 8,0 Hz, IH), 7.94-7.99 (m, 3H), 8.14{d,y=8.3Hz, IH), To a stirred solution of meihy] l-{/er(-buIoxycarbonyl)-(4;?)-chloro-{2S)-pyrToIidinyl caiboxylate (1.35 g. 5.12 mmol) in THF (10 ml) was added 0.5 N NaOH (10 ml)'and the reaction mixture was heated under reflux for 1.5 hr. After cooled to room temperature, the mixture was poured into ice-1 N HCl and the mixture was extracted with CHClj-MeOH (9:1, v/v). The extract was was washed with brine, dried over NajSOj and evaporated to give ]-{'e''-butoxycart)onyl)-(4.R)^hloro-(25)-pyTTolidinylcaiboxylic acid (1.28 g, quant.) as a colorless oil. 'H-NMR (CDCIJ) 5 1.44 (S, 9 H), 2.37-2.54 (m, 2 H), 3,68-3.88 (m, 2 H), 4,42-4.45 (m, 2 H). To a stirred solution of l-(rcrt-butoxycarbonyl)-(4fl)-chloro-(25)-pyTToUdinylcart)Oxylic acid (1.28 g, 5.13 mmol) in THF (20 ml) vras added dropwise BH,DMS (0.60 ml, 6,33 mmol) via a syringe and the reaction mixture was stirred at room temperature for 1 hr. After removal of the solvent, the residue was dissolved in CHiClj. The solution was washed with HjO, brine, dried over NajSOj, and evaporated. The residue was purified by column chromatography on silica-gel with CHClj-MeOH (50:1, v/v) as eluent to give l-(i'ew-butoxycarbonyl)-(4fi)-chloroprolinol (0.88 g, 73%) as a coloriess oil. 'H-NMR (CDClj) 5 1,48 (s, 9 H), 1.98 (m, 1 H), 2.26-2.32 (m, 1 H), 3.56- 3,65 (m, 2 H), 3.77 (m, 2 H). 4.24 (m, 1 H), 4.41-4.46 (m. 2 H); MS(FAB) mi236 (W+I). To a cooled (O'C), stirred solution of methyl 4-hytiroxybeiizoate (560 mg, 3.68 ininol), 1-(/e/-/-butoxycaibonyl)-(4^)-cliloroproiinol (870 mg, 3,69 mmol), PhjP (1,16 g, 4.42 mmol) in THF (15 ml) was added DIAD (870 ml, 4,42 mmol) and the reaction mixture was heated under reflux for 10 hr. After cooled to room tennperature, the mixture was evaporated. The residue was purified by column chromatography on silica-gel with n-hexanc-EtOAc (5:1, v/v) as eltient to give methyl 4-[l-{fer(-butoxycaTbonyl)-(4fi)-chloro-(25)-pynolidinylmethoxy]ben2oate (890 mg, 65%) as a white solid, mp 1I6-!20°C; 'H-NMR (CDClj) 8 1.47 (s. 9 H). 2,39-2,53 (m, 2 H). 3.69-3,70 and 4,13-4,17 (m, total 3 H), 3,88 (s, 3 H), 4,30-1,41 (m, 2 H), 4.50-4.55 (m, 1 H), 6.90-6.92 (m, 2 H), 7.96-7,98 (m, 2 H); MS(FAB) m/i 370 (M*+l);.4na/. Calcd for C,^j,C]NOj: C, 58.46; H, 6.54; CI; 9.59; N, 3.79, Found: C, 58,35; H. 6,56; CI, 9,75; N, 3.77, To 3 stirred solutJoj! of methyl A-\\-(le>-t-hatBsyczibony\)-iAK)-c\iloio-QS)-pyrrolidinylmethoxyjbcnzoale (840 mg, 2.27 mmol) in CHiClj (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and made basic by sat, NaHCOj. Tiie mixture was extracted with CHCJj, washed with brine, dried over NajSOj, and evaporated to give methyl 4-[(4/!)-chloro-(2S)-pyiTolidinylmethoxy] benzoate (580 mg, 95%) as a white solid, mp 61-64'C; 'H-NMR (CDClj) 5 1,85 (brs, IH), 2,03-2,10 (m, 1 H), 2.29-2,35 (m, i H), 3.19-3.31 (m, 2 H), 3.88 (s, 3 H), 3.92-4,06 (m, 3 H), 4.53-4.56 (m, 1 H), 6.91 (d, J = 8.8 Hz, 2 H), 7.98 (d, J - 8,8 Hz, 2 H); MS (FAB) m/z270(M*+l), A mixture of 3-methoxy-4-[A'-{2-mcthylphenyI)ureido]phenylacetic acid (385 mg, 1.22 mmol), methyl 4-[(4/;)-chloro-(25)-pyiTolidinylmethoxy]ben2oate (330 mg, 1,22 mmol), EDCHCl (281 mg, 1,47 mmol), HOBt (200 mg, 1,48 mmol) and EtjN (205 ml, 1.47 mmol) in THF (10 ml) was stirred at room temperature overnight. The mixture was diluted with HjO and extracted with EtOAc. The extract was washed with brine, dried over NajSOj and evaporated. The residue was purified by coiumn chromatography on silica-gel with CHClj-McOH (100:1 to 50:1, v/v) aseluent to give methyl 4-[(4/?)-chloro-l-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phcnylacetyl]-(2S)-pyrrolidinyjmethoxyjbcnzoale (670 mg, 97%) as a while foam. 'H-NMR (COaj) 5 2.38 (s, 3 H), 2.33-2.57 (m, 2 H), 3,50 (s, 3 H), 3.59-3.60 (m, 2 H), 3,75-3.82 (m, 2 H), 3.88 (s, 3 H), 4.06-4.09 (m, 1 H), 4.51-4.63 (m, 3 H), 6.65-6,80 (m, 5 H), 7,09-7,13 (m, 1 H), 7,20-7,27 {m, 3 H), 7,56-7,58 (m, 1 H), 7,91-7,93 (m, 2 H), 8,05-8,07 (m, I H); MS(FAB) m/z 566 (M*+l), To a stirred solution of methyl 4-[(4;!}-ch]oro-l-[3-methoxy-4-[A"-(2-mediylphenyl) ureido]phenylacetylI-C2S)-pyTTOlidinylinethoxy]beiizoale (480 mg, 0.85 mmol) in THF (5 ml} was added 0.5 N NaOH (5 ml) and the reaction mixture was healed under reflux for 2 hr. After cooled to room lemperature, the mixture was poured into ice-1 N HCI and the resulting precipitate was collected under a reduced pressure. The crude solid was dissolved in CHClj-MeOH and evaporated. The residue was washed with El,0 to give 104 (355 mg, 76%) as a white amoiphous solid, MW 552.02 mp ]28-132'C; 'H-NMR (DMSO-d^ 5 2.25 (s, 3 H), 2.29-2.46 (m, 2 H), 3.57-3.73 (m, 2 H), 3,78 (s, 3 H), 3,81-3.99 (m, 2 H). 4.1H.31 (m, 2 H), 4.43-4.45 and 4,64-4,67 (each m, lotai i H), 4.83-4,55 (m, 1 H), 6,71-7,17 (m, 7 H), 7.78-7.S0 (m, I H), 7,S7-7,9J (m, 2 H), 7,99-8.01 (m, 1 H), 8,47 (s, 1 H), 8.56 {s, 1 H), 12.66 (brs, I K);MS(PAB) m/z 552 QA'+\): Anal. Calcd for C„H3oClNjO(-3/4H,0: C, 61.59; H, 5,61; CI, 6,27; N. 7,43. Found: C, 61.56; H, 5,51; CI, 6,68; N, 7.26. A mixture of 4-[/v"-(2-chloropheny])urcido]-3-methoxyphcnylacetic acid (400 mg, 1.19 minol), methyl 4-[(4fl)-chloro-(2S)-pyrTolidinyImethoxy]benzoale (320 mg, 1,19 mmol), EDCHCl (275 mg, 1.43 mmol), HOBt (195 mg, 1,44 nunol) andEtjN (200 ml, 1.43 mmol) in THF (10 ml) was stirred at room temperature overnight. The mixture was diluted with HjO and extracted with EtOAc. The extract was washed with brine, dried over NajSOj, and evaporated. The residue was purified by column chromatography on silica-ge! with CHClj-MeOH (100:1, vA') as elucnt to give methyl 4-[(4;?)-chloro-l-[4-[A'-(2-chlorophenyl)ureido]-3-methoxyphcnylacetyl]-(2S)-pyrrolidinylmethoxylbenzoale (690 mg, 98%) as a pale yellow foam. 'H-NMR (CDClj) 5 2.35-2.41 (m, 1 H), 2.49-2.39 (m, 1 H), 3.55 (s, 3 H), 3.57-3.70 (ra, 2 H), 3.73-3.86 (m. 2 H), 3.88 (s, 3 H). 4.06-4.09 (m. 1 H), 4.54-4,66 (m, 3 H), 6.67-6.81 (ra, 4H), 6.95-6.99 (m, 1 H), 7.23-7,25 (m, 1 H), 7.29-7.33 (m, 1 H), 7,47-7,49 (m, 2 H), 7.90-7.99 (ra, 3 H), 8.18-8.21 (m, 1 H); MS(FAB) m/2 586 (M-+1). To a stirred solution of methyl 4-[(4J?)-chloTO-l-[4-[A'-(2-chlorophenyl)ureido]-3-methoxyphenyIaCBlyI]-(25)-pyrToiidinyInicthoxy]bcnzoale (410 mg, 0.70 mmol) in THF (5 mJ) was added 0,5 N NaOH (5 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperature, the mixture was poured into ice-1 N HCI and the resulting precipitate was collected under a reduced pressure. The crude solid was dissolved in CHCIj-MeOH and evaporated. The residue was washed with Et,0 to give 105 (282 mg, 70%) as an amorphous solid. MW 572.44 mp 131-136°C; 'H-NMR (DMSO-dJ 5 2.29-2,35 (m, 1 H), 2,44-2.47 (m. 1 H), 3.58-3,74 (m, 2 H). 3.78 (s, 3 H), 3.81-3.99 (m, 2 H), 4.10-1.32 (m, 2 H), 4,44-4.46 and 4.66 (each m. A mixture of 3-methoxy-4-[?/'-{2-meihylphenyl)ureido]phenylacctic acid (343 mg, 1,09 mmol), methyl 4-[(45)-acetoxy-(2S)-pyrTolidiiiyl]mcthoxyben2oate {320 mg. 1.09 mmol), EDC-HCl (313 mg, 1.64 mmoi), HOST (222 mg, 1,64 mmol) and Et,N (0.76 ml, 5.45 mmol) in DMF (7 ml) was stirred at room temperature foi 16 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over NajSOj, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHClj/Aectone (5/1)]. to give methyl 4-[(4S)-acetoxy-!-[3-methoxy-4-[A'-(2-meihylphenyl) ureido]phcnylacetyll-(25)-pyrrDlidinyl]methoxybenzoate (520 mg, 81%) as a brown amorphous solid. 'H-NMR (CDCy 5 2,00 (s, 3H, one of isomers), 2.03 {s, 3H. one of isomers). 2.28 (m, 5H), 3.54 (s, IH), 3.58 (s, 2H), 3.64 (s. IH). 3.67 and 3.69 (each s. 3H, amide isomers), 3.85 (d. J = 5.4 Hz, IH), 3,88 (s,3H), 4.04 (t.J= 9.3 Hz, IH), 5.27-5.34 (m, IH), 6,51 (m, IH), 6.76-6.89 (m, IH), 6.94 (d.y= 8,1 Hz. IH), 7,14 (m, IH). 7.25 (m, 4H). 7.53 (d.J= 8.3 Hz, IH), 7.96 (d.-/ = g.O Hz, IH), 8.00-S.lO (m. 2H); MS (ESI) m/z 590 (M*+J). To a solution of methyl 4-[(4^-acetoxy-I-I4-[W-(2-meaiylphenyI)ureido]phen>'lacetyI]-(2S)-pyiTolidinyl]methoxybenzoale (520 mg, 0.882 imnol) in THF (30 ml), 0,25 N NaOH (30 ml) was added. After stirring ai room temperature for 2 days, the rnixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCI and cxtiacled with CHClj-MeOH (10/1). The combined extracts were washed with brine. After dried over NajSO,, the extracts were concentrated in vacuo. The residue was crystaJlized by the addition of CHCl,, ElOH and ether to give 106 (68 rag, 14%) as a coloriess powder. MW 533.57 mp 148-152 "C (dec); IR (KBr) 3356, 2939, 1687, 1604. 1533, 1454, 1255 cm"'; 'H-NMR (DMSOA) 5 1.95-2.09 {m, 2H), 2.25 (s, 3H). 3.59 (d, J = 5.9 Hz, 2H), 3.71 (m. IH), 3.8! and 3,85 (each s, 3H, amide isomers), 4.13-4.47 (m. 4H), 5.19 (br. IH), 6.70-7.21 (m, 7H). 7.79 (d, J- 7.9 Hz, IH), 7.86 (d, J= 8.8 Hz, 2H), 8.01 (d, J= 8.3 Hz,. IH). 8.47 (s, IH), 8.57 (s, IH); MS (ESI) nt/z 533 was added. After stirring at room temperature for 2 days, tiie mixture was extracted with ElOAc. To a solution of methyl 4-[(45)-acetoxy-l-[4-[//'-{2-broiiiopheriyl)urcido]phenyiacet>'l]-(2S)-pyrTolidinyl]mcthoxyberRoate (510 mg. 0.779 mmol) in THF (30 ml). 0.25 N NaOH (30 ml) was added. After stirring at room temperature for 2 days, the mixture was extracted with ElOAc. The remaining aqueous layer was acidified with 1 NHCiandextracled witliCHCIj-McOH(I0/I). The To a stirred solution of methyl 4-[l-[4-[W-(2-chlorophenyl)uriedo]-3-methoxyphenylacetyl]-(4S)-(4-methoxycarbouylphenaxy)-(2S)-pyrroli 4-[\ -[4-[N '-(2 -bnjji)Opheny])uried0]-3 -m ethoxyphenyj acetyl )-(4S> (4 -carboxyphenoxyM 2$) -Dvrrolidinylmethoxylbenzoic acid To a stirred solution of methyl 4-[l-[4-[A'-(2-bromophenyl)uriedo]-3-methoxypheirylacetyI]-(4£)-(4-methoxycaibonylphenoxyJ-(2S)-pyirolidinylmethoxy]benzoale (379 mg, 0.51 mmol) in THF (5 ml) was added 0.5 N NaOH (5 ml) and the reaction mixture was heated under reflux for 5 hi. After cooled to room temperature, the mixture was poured into ice-I N HC1 and the resulting precipitate was collected. The crude solid was purified by preparative TLC to give 118 (51 mg, 14%) as a pale yellow amorphous solid. MW 718.55 'H-NMR (DMSO-d*) S 2.20-2.40 (m; 2 H), 3.65-3.89 (series of m, total 6 H), 4.02-4.63 (series of m, total 4 H), 5.19-5.26 (m, 1 H), 6.74-7.06 (m, 7 H), 7.30-7.34 (m, 1 H), 7.59-7.61 (m, 1 H), 7.83-7.96 (m, 6 H), 8.74 (s, 1 H), 8.93 (s, 1 H); Anal. Calcdfor CjAiBrNjO,2H,0: C, 55.71; H, 4.81; N, 5.57. Found: C, 55.92; H, 4.80; N, 5.30. EDCHCl (265 mg, 1.38 raraol), HOBt (187 mg, 1.38 mmol), and Et,N (195 ul, 1,40 mmol) in THF (10 ml) was stirred at room temperature overnight. The mixture was diluted with HjO, and extracted with EtOAc. The extract was washed with brine, dried over NajSO,, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl,-McOH (60:1 to 50:1, v/v) as elucnt to give methyl 4-[(4SM4-methoxycarbonylphenoxy)-l-[4-[Ar-(2-methyl phenyl)uriedo]phenylacetylH2S)-pynolidinylmethoxy]benzoate (332 mg, 44%) as a white foam. 'H-NMR (CDC]3) 5 2.13 (s, 3 H), 2.24-2.48 (m, 2 H), 3.52-3.90 (series of s and m, total 10 H), 4.05-4.58 (series of m, total 3 H), 5.01 (m, 1 H), 6.78-6.90 (m, 4 H), 6.98-7.20 (m, 8 H), 7.51-7.56 (m, 2 H), 7.90-8.00 (m, 4 H); MS (ESI) m/z 652 (M*+I). 0 a stirred solution of methyl I-(i,en,-butoxycartwnyIH-(2,4-difluorophcnoxy)pjTroIi04nc-2-arboxylate (5.82 g, 16.3 mmol) in THF {130 m!) was added 0.25 N NaOH (130 ml, 32.6 mmol). "he resulting mixture was stirred overnight. The mixture was poured into 1 N HC1 (100 mi) and xtracted with CHC13 (2 x 200 ml). The extracts were dried over MgSO, and evaporated. The esidue was chromatographed on silica geJ with CHClj-EtOAc (4:3) as eluenl to give l-(isrt-jutoxycarbony])-4-(2,4-dif]uorophejioxy)pyrro!Jdiiie-2-carf)oxylic acid (2.55 g, 46%) as a colorless bam, 'H-NMR (CDCl3) 5 1.42-1.47 (m, 9 H), 2.29-2.74 (series of m, 2 H), 3.66-3.71 (m, 2 H), 1.46-4.5] (m, 1 H), 4.83 (m, 1 H), 6.73-6.95 (m, 3H). To a stirred solution of l-(ferr-buto)rycarbonyl)-4-(2,4-difluorophenoxy)pyrTOlidine-2-carboxylic acid (2.55 g, 7.43 mmo!) in THF (50 ml) was added BHj-DMS (452 ul, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concntrated in vacuo and quenced by the addition of H,0 (100 ml). The mixture was extracted with CHC13 (2 x 200 ml), dried over MgSO,, and evaporated. The residue was chromatographed on silica gel with CHClj-EtOAc (4:1) as eluent to give l-(/ert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrohdinylmethanol (1.76 g, 72%) as a colorless oil. 'H-NMR (CDClj) 5 1.45 (s, 9 H), 2,28-2.36 (m, 2 H), 3.58-4.99 (series of m, 8 H), 6.74-6,90 (m, 3 H). To a stirred solution of l-(/ert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (500 mg, 1.52 mmol), methyl 4-hydroxyben2oate (277 mg, 1.82 nunol), and Ph,P (477 mg, 1.82 mmol) in THF (10 ml) was added DIAD (358 ul, 1.82 mmol), and the mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo and theresidue was chromatographed on silica gel with CHCI3-EtOAc (20:1) as eiuent to give methyl 4-[l-(ter(-butoxycarbonyI)-4-(2,4-difluorophenoxy)-2-pyrrQlidinyImethoxy]benzoate (529 mg, 75%) as a coloriess oil, 'H-NMR (CDC13) 5 1.46 (s, 9 H), 2.20-2.47 (m, 2 H), 3.64(m, 2 H), 3.86 (s, 3 H), 4.07-4.43 (m, 3 H), 4.86 (m, 1 H), 6.74-6.87 (m, 3 H), 6.94 To a stirred solution of methyl 4-[l-(/ew-butcofycarbony])-4-(2,4-difluorophenoxy)-2-pyrrolidinyl melhoxyjbenzoate (529 mg, 1.15 mmol) in CH,C13 (5 ml) was added TFA (5 ml). The mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCOj, The mixture was extracted with CHC13 (2 x 100 ml), Theextracts were dried over K,CO, and evaporated to give methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinyl methoxy]benzoate (385 mg, 92%) as a yellow oil, 'H-NMR (CDClj) 8 1.89-1.95 (m, 1 H), 2,28- 2.35 (m, 1H), 3.09 (dd, J- 12,5, 4.9 Hz, 1 H). 3.33 «,./» 12,5 Hz, 1 H), 3.60 (m, 1 H), 3,86 (s, 3 H), 4.10 (d, ./ = 5.6 Hz, 2 H), 4.84 {m, 1 H), 6.73-6.89 (m, 3 H), 6.91 (d,7= 8.5 Hz. 2 H), 7,96 (d. .7=8.5 Hz, 2 H). A mixture of methyl 4-[4-(2,4-difluorophenoxy)-2-pyTTolidinylmethoxy]berizoate (380 mg, 1.05 mmol), 3-methoxy-4-[W'-(2-methylphenyl)ureido]phenylacetic acid (329 mg, 1.05 mmol), EDC-HC1 (302 mg, 1,58 mmol), and catalytic amount of HOBi and DMAP in DMF (10 ml) was stirred for 3 days. The mixture was diluted with EtOAc (200 ml) and washed with brine (2 x 200 ml). After removal of the solvent, residue was chromatographed on silica gel with CHCl}-EtOAc (4:1) to CHOi-MeOH (10:1) as eluent to give methyl 4-[4-(2,4-difluorophenoxy)-l-t3-methoxy-4-^'-{Z-rnethylphenyiiureidolphenylacetyll-J-pyiTolidinylmethoxybenzoate (693 mg, quant). 'H-NMR (CDCy 52.16-2.53 (m. 5 H), 3.61-4.93 (series of m, 14 H), 6.48-8,12 (series of m, 16 H). To a stirred solution of methyl 4-[4-(2,4-difiuorophenoxy)-l-[3-mcfhoxy-4-[^/'-(2-methylphenyl) ureido]phenylacetyl]-2-pyrToUdinylmethoxybenzoate (693 mg, 1.05 mmol) in THF (8 ml) was added 0.25NNaOH(8,4 ml, 2,10 mmol). The mixture was stirred overnight. The mixture was poured into ] N HC1 (200 ml) and the resulting precipitate was collected with suction. The solid was chromatographed on silica gel with CHCl3-MeOH (50:1 to 10:1) as eluent to give 120 (323 mg, 48%) as a colorless amorphous soid. MW 645.65 'H-NMR (DMSO-dJ 5 2.25 (s, 3 H), 2.35 (m, 2 H), 3,33-5.18 (series of m, 11 H), 6.75 (dd, 1 H,/= 8.3, 1.7 Hz), 6.87-7.30 (series of m, 8 H), 7.79 (d, 1H, J = 8.3 Hz), 7.85-7.90 (m, 3 H), 8.01 (d, 1 H,/*= 8.3 Hz), 8.49 (s. 1 H), 8.57 (s, 1 H); MS (FAB) mfz, 646 (NT+1). stirred solution ofthc product in CHJCIJ (6.0 ml) was added TFA (6.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CH,Ci2. The extract was washed with brine ,dried over NasSO(, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CHiO:(]% to 10%,v/v) as.eluent to give methyl 4-[(4S)-[(6-quinolyloxy-(2S)-pyirolidinyl)]methoxybenzoate (900 mg, 82%) as a pale yellow oil. 'H-NMR (CDC13) 5 1.92-2.10 (m, IH), 2.45-2.55 (m, 1H), 3.20-3.30 (m, 1H), 3.38-3.50 (m, 1H), 3.60-3.70 (m, IH), 3.88 (s, 3H), 4,05-4.18 (m, 2H), 5.03 (m, IH), 6.91 (d,J= 8.5 Hz, IH), 7.02 (d,/= 2.7 Hz, IH), 7.35-7.38 (m, 2H), 7.96 (d,y = 8.5 Hz, IH), 8.00-8.05 (m, 2H), 8.76 (d, J= 3.2 Hz, IH). To a stirred solution of methyl 4-(4S-(6-quinoly]oxy-2S-pyrroIidinyl)methoxybenzoate (300 mg, 0.79mmol), 4-[W-(2-chIorophenyI)urecao]-3-metrLaxyphenylacetic acid (264 mg, 0.79 mmol), HOBt (107 mg, 0.79 mmol), and triethylamine (330 ml, 2.37 mmol) in THF (10.0 ml) and MeCN (10.0 ml) was added EDC-HC1 (228 mg, 1.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHC03 then dried over Na,SO«, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc to EtOH-EtOAc (10%, v/V) as eluent to give methyl 4-[l-[4-[A"-(2-chiorophenyi)ureido]-3-methoxyphenylacetyl]-4-(6-quinolyloxy-(2S)-pyrrolidinyl]methoxyben2oate (520 mg, 95%) as a colorless Oil. 'H-NMR (CDClj) 5 2.30-2.60 (m, 3H), 3.64 (s, 2H), 3.73 (s, 3H), 3,80-3.95 (m, IH), 3.87 (s, 3H), 4.15-4.30 (m, IH), 4.50-4.70 (m, 2H), 5.11 (br S, IH), 6.81-7.01 (m, 6H), 7.26 -7.39 (m, 6H), 7.93-8-.03 (m, 5H), 8.19 (d, J= 8.3 Hz, IH), 8,80 (s, IH). To a stirred solution of methyl 4-[l-[4-[A'-(2-chlorophcnyl)ureido]-3-methoxyphenyl acetyl]-4-(6-quinolyloxy-25'-pyrrolidinyI]melhoxybenzoate (520 mg, 0.75 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added IN NaOH (1.5 ml, 1.5 mmol). The mixture was stirred at 60 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with i K HCI. The resulting solid was collected, washed with water, and dried in vacuo to give 121 (450 mg, 88%) as a white crystalline solid. 681.13 mp 129-133 °C; IR (KBr) 3332,1704,1604, 1531, 1419, 1222,1166 cm'1; 'H-NMR pMSO-d«) 5 2.25-2.55 (m, 2H), 3.67 (s, 2H), 3.82 (s, 3H), 3.81-3.92 (m, IH), 4,02-4.15 (m, 2H), 4.40-4.50 (m, 2H), 5,25-5,40 (m, IH), 5,33-7.07 (m, 5H), . 7.26-7.49 (m, 5H), 7.83-8.23 (m, 6H), 8.73-8.74 (m, IH), 8.90 (s, IH), 8.94 (s, IH); MS (FAB) m/z 681 (M*+I); Anai. cafed for C^HnN40-,Cl-Q.5E.-lO: C, 64.39; H, 4.97; N, 8.12. Found: C, 64.22; H, 4.90; N, 7.96. To a stirred solution of methyl 4-[l-[4-[W-(2-bromophenyl)uicido]-3-methoxypheriyl acetyl]-4-(6-quinolyloxy-25-pyrrolidinyl]nicthoxybenzoate(530 mg, 0.72 nunol) in THF (10,0 ml) and MeOH {5.0 ml) was added IN NaOH (1.4 ml, 1.4 mmol). The mixture was stirred at 70 °C for 24 hi. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 122 (460 mg, 88%) as a white crystalline solid. MW 725.59 mp 149-153 °C; IR (KBr) 3332, 1704, 1604, 1527. 1222, 1164 cm"1; 'H-NMR (DMSO-dJ 5 2.28-2.58 (m, 2H), 3.67 (s, 2H), 3.82 (s, 3H), 3.85-3.90 (m, 1H), 4.05-4.15 (m, 2H), 4.40-4.50 (m, 2H), 5.20-5.32 (m, 1H), 6.77-7.07 (m, 5H), 7.31-7.61 (m,5H), 7,83-7.97 (m,5H), 8.21-8.22 (m, 1H), 8.73-8.74 (m, 2H), 8.92 (s, 1H);MS (FAB) m/z 725 (M*), 727 (M'+2); Anal, calcd for C37H33N,,O«Br0.5HJO: C, 60.50, H, 4,67; N, 7.63; Br, 10.88. Found: C, 60.51; H, 4.60; N, 7.52; Br, 11.06. Example 115 4-[(25,4S)-l-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2- To a stirred solution of methyl (2£,4S)-l-te^butoxycarbonyl-4-(2-napthhyloxy)-2-pyrTolidinyl carboxylate (5.37 g) in THF (116 ml) was added 0.25 N NaOH (116 ml, 29.0 mmol) at room temperature. The resulting mixture was stirred over night. After removal of the solvent, the mixture was acidified by the addition of 1 N HC1 and extracted with CHC13. The combined extracts were washed with brine, dried over Na,SO, and evaporated. The residue was recrystallized from n-hexane-CHCl3, to give (2S,4S)-l-(er/-butoxycarbonyI-4-(2-naphihyloxy)-2-pyrrolidinylcarboxylic acid [4.44 g, 85%(2 steps)] as a white powder. 'H-NMR (DMSO-dj) 5 1.37 and 1,41 (s, 9H, amide isomers), 2.26 (d,J= 13.9 Hz, 1H), 2.65 (m, 1H), 3.47 (d, J= 11.5 Hz, 1H), 3.81 (m, 1H), 4.30 (m, 1H), 5.14 (m, 1H), 7.02-7.86 (m, 7H). To a stirred solution of (2S,4S)-l-terr-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) was added BHj-DMS (0.63 ml, 6.3 mmol) at 0 °C. The mixture was raised to room temperature immediately and then heated at 50 °C for 1.5 h. After cooling to room temperature, the mixture was quenched by the addition of water at 0 "C and extracted with EtOAc. The combined extracts were washed with brine, dried over Na,S04 and evaporated. The residue was chromatographed on silica gel [50 g, CHClj/MeOH (50/1)], to give (25,45)-l-ter/-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrTolidinylmethanol (1.10 g, 100%) as a pale yellow oil. 'H-NMR (CDC13) S 1.48 To a stirred mixture of (2S,45)-l-ier/-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl methanol (640 mg, 1.86 mmol), methyl 4-hydroxybenzoate (283 mg, 1.86 mmol) and PPh3 (488 mg, 1.86mmol)inTHF(18ml)wasaddedDIAD(0.37nii, 1.86 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(2/\)], to give methyl 4-[(2S,,46)-l-i'er/-butoxycarbonyl-4-(2-naphthyloX)')-2-pyTTolidinyl]methoxybenzoate (830 mg, 93%) as a colorless oil. 'H-NMR (CDC13) 6 1.50 (d, J= 8.3 Hz, 9H), 2.34 {m, 1H), 2,53 (d,y= 14.2 Hz, 1H), 3.72-3.85 (m, 1H), 3.86 and3.87 (s, 3H, amide isomers), 4.17 (m, 1H), 4.26-4.52 (m, 2H), 5.06 (br, 1H), 6.87 (d, J= 8.8 Hz, 1H), 6.94 (d,-/=8.8 Hz, 2H), 7.04 (br, 2H), 7.33 (t, J= 7.3 Hz, IH). 7.42 (t, J= 7.3 Hz, 1H), 7.64-8,02 (m, 5H). To a stirred solution of methyl 4-[(25',45)-l-/ert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyljmethoxybenzoate (870 mg, 1.74 mmol) in CH,CI, (24 ml) was added TFA (6 ml) at room temperature. The mixture was stirred over night, which was concentrated in vacuo. The residue was diluted with CHjCl3 and made basic by the addition of 1 N NaOH, which was extracted with CH,C1,. The organic layer was washed with brine, dried over NaSOj and concentrated. The residue was chromatographed on silica gel [100 g, /i-Aeiane/EtOAc{2/l)], to give methyl 4-[(2S',45)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (750 mg, 100%) as a black oil 'H-NMR (CDClj) 8 1.99 (dd,J= 14.2, 5.6 Hz, IH), 2.48 (m, IH), 3.22 (dd,y= 12.2, 4.6 Hz, IH), 3.43 (d,y= 12.5 Hz, IH), 3.67 (m, IH), 3.86 and 3.87 (s, 3H, amide isomers), 4.11 (m, 2H), 5.04 (m, IH), 6.83 (d, J = 8.5 Hz, IH), 6.89 (d, J= 8.8 Hz, 2H), 7.07 (d, J= 2.0 Hz, IH), 7.12(d,/=9.0Hz, IH), 7.33 (dt, .7=8.1, 1.2 Hz, IH), 7.44 (dt,^= 6.8, 1.2 Hz, IH), 7.70 (d, 7= 8.1 Hz, IH), 7.75 (dd, /= 9.0, 5.1 Hz, 2H), 7.90 (d, J= 8.5 Hz, IH), 7.96 (dd^= 6.8, 2.0 Hz, 2H). A mixture of 3-methoxy-4-[W'-(2-methylphenyl)ureido]phenylacetic acid (333 mg, 0.106 mmol), methyl 4-[(ZS,,45)-4-(2-naphthyloxy)-2-pyrrolidinyl)methoxybenzoate (400 mg, 1.06 mmol), EDCHC1 (305 mg, 1.59 mmol) and DMAP (194 mg, 1.59 mmol) in DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na:SO 8.09 (m, 8H); MS (ESI) mh 674 (M'+l). To a solution of methyl 4-[(25,45)-l-[3-inethoxy-4-[A',-C2-methyIphcnyl)uicido] phenytacctylJ^^-nflphthyJo^^-pyrTolidinylJnrethoKybenzoate (415 mg, 0.61 mmol), methyl 4-[(2S,4S)-4-(2-naphthyloxy)-2-pyrroMnyl]methoxybenzoate (350 mg, 0.93 mmol), EDC-HC1 (267 mg, 1,40 mmol) and DMAP (171 mg, 1.40 mmol) in DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na3SO,, the extracts were concentrated in vacuo. The residue was chiomatographed on silica gel [100 g, n-/iexa/7e/EtOAc(l/l)CHCl,/MeOH(50/l)], l0 give methyl 4-[(25,45)-l-[4-[W-(2- To a solution of methyl 4-[(25,45)-l-[4-[JV'-(2-chlorophenyl)ureido]-3-methoxyphenyl acetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (381 mg, 0.535 mmol) in THF (4.3 ml), To a stirred solution of methyl (25,45)- l-/er/-butoxycarbonyl-4-(2-naphthyloxy)-2-pyiTolidinyl carboxylate (5.37 g) in THF (116 ml) was added 0.25 N NaOH (116 ml, 29.0 mmol) al room tempera Hire. The resulting mixture was stiiied over night. After removal of the solvent, the mixture was acidified by the addition of 1 N HC1 and extracted with CHClj. The combined extracts were washed with brine, dried over NaiSO* and evaporated. The residue was recrystallized with n-hexane-CRCl), to give (2S,4S)-l-fer/-butOxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid {4.44 g, S5%(2 steps)] as a white powder. 'H-NMR (DMSO-dJ 5 1.37 and 1.41 (s, 9H, amide isomers), 2.26 (d, J = 13.9 Hz, 1H), 2.65 (m, 1H), 3.47 (d,y= 11.5 Hz, 1H), 3.81 (m, 1H), 4.30 (m, 1H), 5.14 (m, 1H), 7.02-7.86 (m, 7H). To a stiiTed solution of (25,45)-l-/erf-buloxycarbonyI-4-(2-iiaphthyloxy)-2-pyrTolidmylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) was added BHS-DMS (0.63 ml, 6.3 nunol) at 0 °C. The mixture was raised to room temperature immediately and then heated at 50 "C for 1.5 h. After cooling to room temperature, the mixture was quenched by the addition of water at i 0 °C and extracted with EtOAc. The combined extracts were washed with brine, dried over Na5SO, and evaporated. The residue was chiomatographed on silica gel [50 g, CHCVMeOH (50/1)], to give (25,4S)-l-fer(-butoxycarbonyM-(2-naphthyloxy)-2-pynolidinylmetlianol (1.10 g. 100%) as a pale yellow oil. 'H-NMR (CDClj) 8 1.48 (s, 9H), 2.45 (m, 1H), 3.58-4.80 (m, 4H), 5.01 (br, 1H), 7.04-7.99 (m, 7H). To a stirred mixture of {2J,4S)-l-terf-butO!tycarbonyl-4-(2-naphthyloxy)-2-' pyrrolidinylmethanol (484 mg, 1.41 mmol), methyl 2-hydroxy-5-pyridinecarboxylate (216 mg, 1.41 mmol) and PPh3 (370 mg, 1.41 mmoi) in THF (15 ml) was added DIAD (0.28 ml, 1.41 mmol) at room temperature under an atmosphere of nitrogen . The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [50 g, n-Aearo/7e/EtOAc(2/l)l, to give methyl-2-[(25,45)-1 -fer(-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyljmethoxypyridine-5-carboxylate (170 mg, 25%) as a colorless oil. 'H-NMR (CDC13) 8 1.47 (s,9H), 2.37 (m, 1H), 2.46 (d, J= 14.2 Hz, IH), 3.71-4.00 (m. 2H), 3.89 (s, 3H), 4.30-4.56 (m, 2H), 4.74 (dd, J= 9.8, 4.6 Hz, 1H), 5.06 (br, 1H), 6.70 (d, J= 8.8 Hz, 2H), 7.05-7.09 (m, 2H), 7.33 (t, J = 6.9 Hz, 1H), 7.42 (t, J= 6.9 Hz, 1H), 7.67-7.75 (m, 3H), 8.09 (d, J = 8.8 Hz, 1H), 8.77 (d, J =2,2 Hz, 1H). To a stirred solution of 5-carboxymethyl-2-[(25,45>l-i'er/-butoxycarbonyl-4-(2-napthyloxy)-2-pyrTolidinyl]methoxypyridine (170 mg, 0.36 mmol) in CH,C15 (5 ml) was added TFA (2 ml) at room temperature. After 2 h stirring, the mixture was concentrated in vacuo, which was diluted with CH,C1] and basified by the addition of 1 N NaOH. The combined reaction mixture was extracted with CH5C1,. The organic layer was washed with brine, which were dried over NaSO,, and concentrated. The residue was purified on TLC [CHCl^MeOH (10/1)], to give methyl 2-[(25,45)-4-(2-naphthyloxy)2-pyrralidinyI]meUioxypyridine-5-carboxylate (107 mg, 80%) as a colorless oil 'H-NMR (CDClj) 5 1.95 (m, 1H), 2.27 (br, 1H), 2.46 (m, 1H), 3.19 (dd, J = 12.2, 4.9 Hz, 1H), 3.41 (d,J= 12.2 Hz, 1H), 3.65 (m, 1H), 3.89 (s, 3H), 4.58 (m, 2H), 5.00 (br, 1H), 6.77(d,/=8.8Hz, 1H), 7.06 (br, 1H), 7.11 (dd,-/= 8.8, 2.7 Hz, 1H), 7.31-7.45 (m, 2H), 7,69-7.76 (m, 3H), 8.13 (dd, J = 8.8, 2,4 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H). A mixture of 3-methoxy-4-[Ar'-(2-methylphenyI)ureido]pbenylacetic acid (89 mg, 0.283 ramol), methyl-2-I(25,45)4TTolidiny]]methoxypyridiric-5-carboxylate(107 mg, 0.78 mmol), EDGHC1 (81 mg, 0.425 mmol) and DMAP (52 mg. 0.425 mmol) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted •withEtOAc. The combined extracts were washed with ice water and brine. After dried over NajSOfc the extracts were concentrated in vacuo. The residue was purified on TLC [CHClj/MeOH (10/1)], to give 2-[(25,45)-l-[3-methoxy-4-[A',-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyTTOlidinyl]methoxy-5-pyridinecarboxylic acid methyl ester (193 mg, 100%) as a colorless amorphous. 'H-NMR (CIDClj) 5 2.27 (d, J = 3.2 Hz, 3H), 2.30 (m, 1H), 2.49 (dd, J = 14.2,2.0 Hz, 1H), 3.60 (d, J= 3.9 Hz, IH), 3.67 (d, J= 5.9 Hz, 3H), 3.81 (s, 1H), 3.85 (s, 1H),. 3.88 and 3.91 (s, 3H, amide isomers), 3.95 (m, IH), 4.02-5.09 (m, 4H), 6.67 (d, J = 8.8 Hz, IH), 6.73-7.13 (m, 3H), 7.20-7.45 (m, 7H), 7.53 (t, J = 7.8 Hz, IH), 7.67-7.77 (m, 3H), 8.02-8.84 (m, 3H). For HC1 salt: a pale brown amorphous. IR(KBr) 3346, 2951,1720,1601, 1533,1281 cm'1; MS (FAB)m/z675(M++l). mixture was gradually wanned up to rt with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHClj. The organic layer was dried over anhydrous Na2SOj and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc {5 : 1) as eluenl lo give 1 -benzyJoxy-2-(7?)-hydnMy-5.hexene (2.18 g, 35%) as a colorless oil: lH-NMR(CDCl3)5I.52-l,60{m, 2 H), 2.11-2.25 (m, 2 H), 2.34 (d,y= 3.2Hz, 1 H), 3.35 (dd, J = 9.6, 8.0 Hz, 1 H), 3.52 (dd, J= 9.6, 3.2 Hz, 1 H), 3.84-3.86 (m, 1 H), 4.57 (s, 2 H), 4.96-5.07 (series of m, 1 H), 5.78-5.88 (m. 1 H), 7.29-7.38 (m, 5 H); MS (ESI) m/z, 224 (M*+NH/). To a stirred solution of l-benzyIoxy-2-{./?)-hydroxy-5-hexene (2.18 g, 10.5 mmol), triphenylphosphine (3.32 g, 12.7 mmol) and phthalimide (1.86 g, 12.7 mmol) was added diisopropyl azodicarboxylate (2.62 ml, 12.7 mmol) at rt, and the resulting mixture was stirred for overnight at rt The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, drying over anhydrous Na2S04, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5 : 1) as eluent to give 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 83%) as a colorless oil: 'H-NMR (CDC1,) 6 1.76-1.84(m,2H), 2.06 (dd,y= 14.4, 6.8 Hz), 2 H, 2.12-2.22 (m.lH), 3.69 (dd,J= 10.0, 5.6 Hz, 1 H), 4.00 (t, J= 9.6 Hz, 1 H), 4.46 (d, .7=12.0 Hz, 1 H), 4,53 (d,J= 12.0 Hz, 1 H), 4.51-4.58 (m, 1 H), 4.9M.99 (series of m, 2 H), 5,72-5.79 (m, 1 H)7.21-7.26 (m, 5 H), 7.71-7.83 (series of m, 2 H); MS (ESI) m/z, 336 (M*+H). To a stirred solution of l-benzyloxy-2-(.S)-phthalinudo-5-hcxene (2.95 g, 8.80 mmol) in EtOH (30 ml) was added hydrazine hydrate (80% in water, 460 ml, 11.4 mmol) at rt, and the resulting mixture was heated under reflux for 7.5 h with stirring. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was poured into aq.NaHC03 and extracted witfi CHClj. The organic layer was dried over anhydrous Na]S04, then concentrated in vacuo to give 2-(5)-amino-l-benzyloxy-5-hexene (1.90 mg, quant.) as a colorless oil. 'H-NMR (CDClj) 5 1.37-1.55 (series of m, 4 H), 2.08-2.19 (m, 2 H), 2.99-3.03 (m, 1 H), 3.25 (dd, J= 9.2, 7.6 Hz, 1 H), 3.45 (dd, J= 9.2, 4.0 Hz, 1 H), 4.53 (s, 2 H), 4.94-5.06 (series otm, 2 H), 5.76-5.85 (m, J H), 7.27-7.37 (m, 5 H); MS (ESI) m/z, 206 (M*+H), 247 (M*+H+CH,CN). To a stirred solution of 2-(S)-amino-l-benzyloxy-5-hexene (1.89 g, 9.21 mmol) and triefhylamine (1.28 ml, 9.21 mmol) in CH,C1, (20 ml) was added benzoyl chloride (1.07 ml, 9.21 mmol) at rt, and the resulting mixture was stirred for 23 h. The mixture was poured into water and extracted with CH,C1,. The organic layer was washed with water, drying over anhydrous Na3SO«, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-ElOAc (5 : 1) as eluent to give W-[2-{S)-(l-benzYloxy)-5-hexenyl]benzamide (2.67 g, 94%) as a colorless needles, mp 78-79 "C; 'H-NMR (CDCI,) 8 1.76-1.82 (m, 2 H), 2.11-2,17 (m, 2 H), 3.59 (brs, 2 H), 4.29-4.35 (m, 1 H), 4.54 (dd, J = 19.2,12.0 Hz, 2 H), 4.96-5.05 (series of m, 2 H), 5.78-5.89 (m, 1H). 6.39 (d,J= 8.0Hz, 1 H), 7.27-7.51 (m, 8 H), 7.74 (d,J = 7.2 Hz, 2 H); MS (ESI) m/z, 310 (M*+H). ToastiuedsolutionofN-[2-(S)-(]~ben2yloxy)-5-htxeny]]ben2ainidc(2.41 g, 7.79mmol) in CHJCN-HJO (3 : 1, 40 ml) was added iodine {2.97 g, 23.4 mmol) in one portion, and the resulting mixture was stirred for 20 h. The mixture was poured into aq.NaiS]03 and concentrated in vacuo, then extracted with CHCla. The organic layer was washed with brine, drying over anhydrous Na,Sb4, then concentrated in vacuo. The residue was dissolved in CH,C13 (30 ml) and was added di-/«7-buryl dicarbonate (2.55 g, 11.7 mmol), EljN (1.63 ml, ] 1.7 mmol) and N, N-dimethyl aminopyridine (180 mg, 1.47 mmol), and the resulting mixture was stirred overnight at rt. The mixture was poured into water and extracted with CH3C12. The organic layer was washed with water, drying over Na3SOi, and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5 : 1) to give A'-Boc-2-(S)-benzoyloxymethyl-5-(S)-benzyloxy methylpyrrolidine(1.27g, 38%) as a colorless oil, 'H-NMR (CDC1J 5 1.41 and 1.49 (s, total 9H), ' 1.85-2.00 (series of m, 4 H), 3.33-4.59 (series of m, 8 H), 7.26-7.32 (m, 5 H), 7.41-7.46 (m. 2 H), 7.54-7.57 (m, 1 H), 8.02 (d, J= 7.6 Hz, 2 H); MS (ESI) m/z, 426 (M*+H), 448 (M*+Na*). To a stirred solution of W-Boc-2-(5)-ben2oyloxymethyI-5-(S)-benzyloxymethylpyrrolidine (1.23 g, 2.89 mmol) in MeOH (30 ml) was added NaOH (1.0 Win water, 3.47 ml, 3.47 mmol) at rt, and the resulting mixture was stirred for 4 h. The mixture was neutralized with aq.lW-HCl and concentrated in vacuo, then extracted with CHCl,. The organic layer was washed with brine, drying over anhydrous Na3SO then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (3 :1) as eluent to give A'-Boc-5-(S)-hydroxymethyl-2-(5)-benzyloxymethvl pyrroUdine (847 mg, 91%) as a colorless oil. 'H-NMR (CDCIJ 5 1.41 (s, 9H), 1.57 (brs, 1H), 1.95-1.97 (m, 2 H), 2.05-2.18 (m, 1 H), 3.36 (t,J= 8.4 Hz, 1 H), 3.56-3.62 (m, 2 H), 3.67-3.72 (m, 2 H), 3.95 (brs, 1 H), 4.03 (brs, 1 H), 4,51 (s, 1 H), 7.28-7.37 (rn, 5H); MS (FAB) m/z, 322 (M-+H). To a stirred solution of Ar-Boc-2-(5)-hydroxymethyl-5-(S)-benzyloxymethylpyTTolidine (388 mg, 1.21 mmol), triphenylphosphine (380 mg, 1.45 mmol) and methyl 4-hydroxybenzoate {220 mg, 1.45 mmol) was added diisopropyl azodicartwxylate (200 ml, 1.45 mmol) at rt, and the resulting mixture was stirred overnight. The rajxtore was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, drying over anhydrous Na,SO,, then concentrated in vacuo. The residue was chrornatographed on silica gel with hexane-EtOAc (3 ; 1) as eluent to give methyl 4-[2-(S)-(A,-Boc-5-{^-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (462 mg, 84%) as a colorless oil: 'H-NMR (CDC13) 5 1.40 and 1.48 (s, total 9 H), 1.98-2.13 (m, 4 H), 3.83 and 3.85 (s, 3 H), 3.33-4.25 (series of m, 4 H), 4.47-4.59 (m, 2 H), 6.91-6.96 (m, 2 H), 7.26-7.34 (m, 5 H), 7.95-7.98 (m, 2 H); MS (FAB) m/z, 456 (M*+H), 478 (M*+Na*). To a stirred solution, of methyl 4-[2-(S>(r/-Boc-5-(S)-benzyloxymethyl)pyn-olidinyl methoxy] benzoate (446 mg, 0.98 mmol) in CH^Cl, (10 ml) was added trifluoroaceticacid (10 ml) at rt, and the resulting mixture was stirred for 1 h. The mixture was concentrated in vacuo and poured info aq.NaHCOj, then extracted with CHCJj. The.organic layer was washed with water, drying over anhydrous Na,S04, then concentrated in vacuo to give methyl 4-[2-(i>(5-(.S> ben2yloxymethyl) pyrTOlidinylmethoxyJbenzoate (363 mg, quant.) as yellowish oil. The product was used for next reactions without further purification. 'H-NMR (CDClj) 5 1.43-1.65 (m, 2 H), 1.93-2.07 (m, 3 H), 3.36-3.68 (series of m, 4 H), 3.89 (s, 3 H), 3.86-3.93 (over lap, 2 H), 4,55 (s, 2 H), 6.90 (d, J= 8.4 Hz, 2 H), 7.26-7.37 (m, 5 H), 7.97 (d, J= 8.4 Hz, 2 H); MS (FAB) m/z, 356 (M'+H). To a stirred solution of methyl 4-[2-(S)-(5-(£)-benzyloxymethyl)pyrrolidinylmethoxy] benzoate (] 15 rag, 0.32 mmol), 4-[//'-(2-methylphenyI)ureido]phenylacetic acid (92.0 mg, 0.32 mmol) and W.A'-dimethylaminopyridine (52.0 mg, 0.42 mmol) in DMF (10 ml) was added EDCHC1 (81.0mg,0.42mmol)ai rt, and Che resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHC13. The organic layer was washed with brine, drying over anhydrous NajSO,, then concentrated in vacuo. The residue was chrornatographed on silica gel with CHClj-MeOH (20 : 1) as eluent to give methyl 4-[5- benzoate (169 mg, 84%) as a colorless amorphous solid. 'H-NMR (CDClj), mixture of rotamars 5 1.92-2.18 (m, 3H), 2.24 and 2.25 (s, total 3 H), 2.20-2.31 (overlap, 1 H), 3.39-3,70 (series of m, 4 H), 3.87 and 3.89 (s, total 3 H), 4.17 and 4.18 (s, total 2 H), 4.30-4.45 (series of m, 2 H), 4.53 (s, 2 H), 6.43-7.13 (series of m, 9 H), 7.20-7.36 (series of m, 7 H), 7.58-7.99 (series of m, 3 H); MS IT4HUA fiTJ fM*+HY To a stirred solution of methyl 4-[5-(7?)-ben2yioxymethyl-l-[4-[W'-(2-cWorophenyl) ureido]-3-methoxyphenylacetyl]-2-(5)-pyTTOlidinylmethoxy]ben2oate (169 mg, 0.25 mmol) in MeOH-THF{2 : 5, 7 ml) was added 1.0A/-NaOH (750 ml, 0.75 mmol) at rt, and the resulting miaure was heated at 80°C with stirring for 2 h. The mixture was poured into W-HCI, then extracted with CHC13. The organic layer was washed with brine, drying over anhydrous NajSO,,, To a stirred solution of methyl 4-[5-(£)-benzyloxyrnethyl-l-[4-[A'-{2-brornophenyl) ureido]-3-methoxyphenylacetyl]-2-(S)-pyiTolidinylmethoxy]benzoate (178 mg, 0.25 mmol) in MeOH-THF (2:5,7 ml) was added 1 .(W-NaOH (750 ml, 0.75 mmol) at rt, and the resulting mixture was heated at 80°C with stirring for 1.5 h. The reaction mixture was poured into ltf-HCl, then extracted with CHClj. The organic layer was washed with brine, drying over anhydrous Na2SOj, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCI3-MeOH (15 : 1) as eluent to give 128 (159 mg, 91%) as a colorless amorphous solid. MW 702.59 'H-NMR (CD3OD), mixture of rolamars 8 1.88-2.35 (series of m, 4 H), 3.51-4.49 (series of m, 8 To a stirred solution of meihyl 3-[2-(S)-(A'-Boc-5-(5)-ben^']oxyniethyl)pyrralidinyl-methoxy]ben2oate(501 mg, 1.10 mmol) in CHjCl] (10 ml) was added trifluoroacelic acid (10 ml) at it, and the resulting mixture was stirred for 1 h. The mixture was concentrated in vacuo and poured into aq.NaHCOj, the extracted with CHCI3. The organic layer was washed with water, drying over anhydrous Na,S01, and concentrated in vacuo to give methyl 3-[2-(S)-(5-(5)-benzyloxymethyJ) pyrrolidinyl-methoxyjbenzoate (387 mg, quant.) as yellowish oil. The product was used for next reactions without further purification. 'H-NMR (CDC13) 5 1.26-1.65 (m, 2 H), 1.94-2.04 (m, 3 H), 3.37-3.52 (m, 2 H), 3.63-3.66 (m, 1 H), 3.85-3.93 (m, 1 H), 3.91 (s, 3 H). 4.55 (s, 2 H), 7.09-7.11 (m, 1 H), 7,27-7.54 (m, 6 H), 7.54-7.55 (m, 1H), 7.61-7.63 (m, 2 H); MS (ESI) m/z, 35 (M++H). To a stirred solution of methyl 3-[2-(5)-(5-(S)-benzyloxymethyl)pyTTolidinylmethoxy] benzoate (140 mg, 0.39 mmol), 4-[A,^(2-methylphenyl)ureidoJ-3-methoxyphenylacetic acid (125 mg, 0.39 mmol) and W.^-dimeihylaminopyridine (58,0 mg, 0.47 mmol) in THF (15 ml) was added EDCHC1 (90.0 mg, 0.47 mmol) al rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCI,. The organic layer was washed with brine, drying over anhydrous Na,SOj, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10 : 1) as eluent to give methyl 3-[5-(R)-benzyloxymethyl-! -[4-[//'-(2-methyIphenyI)ijreido]-3 -methoxyphenylacetyl] -2-{S)-pyrrolidiny 1 methoxy]benzoate (256 mg, quant.) as a colorless amorphous solid. 'H-NMR (CDCI3), mixture of rotamars 5 1.67 (s, 3 H), 1.97-2.40 (series of m, 4 H), 3.42-3.85 (series of m, 5 H), 3.60 (s, 3 H), 3.95 and 3.97 (s, total 3 H), 4.15-4.26 (m, 2 H), 4.36-4.49 (m, 1 H), 4.59 (s, 2 H), 6.32 and 6.36 (s, total 1 H), 6.75-6.87 (series of m, 2 H), 7.20 (brs, 2 H), 7.16-7.72 (series of m, 10 H), 8.03-8.09 (m, 1 H); MS (ESI) m/z, 652 (M*+H). with brine, drying over anhydrous NajSC^, then concentrated in vacuo. The residue was chromatographed on silica get with CHCk-McOH (10 : I) as eluent to give methyl 3-[5-{R)-benzyloxymeihyl-1 -[4-[//' -(2-chlorophenyl)uieido]-3-methoxyphenylacetaraido] -2-(S)-pvrrolidinylmethoxyjbenzoate (226 mg, quanl.) as a colorless amorphous solid. 'H-NMR (CDCIj), mixture of rotamars 5 1.99-2.40 (series of m, 4 H), 3.43-3.92 (series of m, 5 H), 3.67 (s, 3 H), 3.98 and 4.02 (s, lota! 3 H>, 4.18-4.29 (m, 2 H), 4.36-4.51 (m, 1 H), 4.60 (s, 2 H), 6". 75-6.92 (series of m, 2 H). 7.01-7.22 (series of m, 4 H), 7.29-7.53 (series of m, 9 H), 7.62-8.26 (series of m, 3 H); MS (ESI) m/z, 672 (M*+H). benzyloxymethyl-1 -[4-[//' -(2-bromophenyl)ureido]-3-methoxyphenylacety]] -2-(S)-pyrTo) idinyl methoxy]benzoate (209 mg, 89%) as a colorless amorphous solid. 'H-NMR (CDClj), mixture of rotamars 6 1.99-2.37 (scries of m, 4 H), 3.43-3.91 (series of ra, 5 H), 3.70 (s, 3 H), 3.93 and3.96 (s, total 3 H), 4.19-4.28 (m, 2 H), 4.37-4.51 (m, 1 H), 4.60 (s, 2 H). 6.77-7.11 (series of m. 6 H), 7.28-7.74 (series of m, 10 H), 7.91-7.95 (series of m, 1 H), 8.20-8,23 (series of m, 1 H); MS (ESI) OT/r716(M*),718(M++2). 7.71 (m,4H). To a stirred mixture of (25,4S)-4-acetoxy-l-/er/-butoxycarbonyl-2-fer(-butyldiplienyl silyloxy methypynolidine (23.3 g, 46.9 mmol) and acetic acid (6.0 ml, 104.8 nunol) in THF (470 ml) was added TBAF (93.8 ml, 93.8 mmol) at 0 *C. After 24 h stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aq. NH,CI and extracted with EtOAc. The combined extracts were washed with brine, which were dried over Na,SO, and concntrated in vacuo. The residue was chromatographed on silica gel [700 g, CHCy EtOAc (4/1)], to give (25,,4S)-4-acetoxy-I-/er/-butoxycarbonjrl-2-pyrrolidincmethanol (9.70 g, 8%) as a colorless oil. 'H-NMR (CDO,) 8 1.47 (s, 9H), 1.63 (m, IH), 1.81 (m, 1H), 2.07 (s, 3H), 2.34 (m, 1H), 3.42 (dd,-> = 12.7, 0.9 Hz, IH), 3.62-3.85 (m, 3H), 4.48 (br, IH), 5.20 (br, IH). To a stirred mixture of (2S,4S)-4-acetoxy-l-ferNbutoxycarbonyl-2-pynolidinemethanol (9.70 g, 37.4 mmol), p-hydroxybenzoic acid methyl ester (5.69 g, 37.4 mmol) and PPh3 (10.8 g, 41.1 mmol) in THF (200 ml) was added DIAD (8.10 ml, 41.1 mmol) at room temperature. After 1.5 h stirring, the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [700 g, CHCl,/EtOAc (10/1)], to give methyl 4-[(2£,4S)-4-acetoxy-l-fer(-butoxycarbonyl-2-pyrrolidinyi]methoxybenzoate (11.8 g, 81%) as a pale yellow oil. 'H-NMR (CDC13) 5 1.48 (s, 9H), 2.03 (s, 3H), 2.27 (m, 2H), 3.46 (m, IH), 3.72 (m, IH), 3.88 (s, 3H), 3.98 (t, J= 9.0 Hz, IH), 4.21-4.47 (m, 2H), 5.31 (br, IH), 6.96 (br, 2H), 7.98 (d, J = 8.8 Hz, 2H). To a stirred solution of methyi 4-[(2£4,^-4-ace(oxy-l-rert-butoxycarbonyI-4-hydroxy-2-pyrrolidinyl]methoxybenzoate (7.43 g, 18.9 mmol) in MeOH (150 ml) was added cat. K2CO, at room temperature. After I day stirring, (he mixture was concentrated in vacuo. The resulting residue was recrystallized by the addition of CHOyn-hexane, to give methyl 4-[(2S,4.S>l-/er7-butoxycarbonyJ-4-hydroxy-2-pj7Tolidinyl3methoxj'benzoa!e (5.76 g, 87%) as a colorless solid. 'H-NMR (CDC1,) 5 1.46 (s, 9H), 2.11 (m, IH), 2.35 (br, IH), 3.27-3.65 (m, 2H), 3.89 (s, 3H), 4.07-4.54 (m, 4H), 6.96 (d, J= 6.9 Hz, 2H), 7.99 (d,J=6.9 Hz, 2H). To a stirred solution of methyl 4-((2S 4S)-i -/erZ-butoxycarbony!-4-hydroxy-2-pyrrolidinyl] methoxybenzoate (2.10 g, 5.98 mmol) in THF (60 ml) was added 60% oil NaH (359 mg, 8.97 mmol) at 0 °C. After 15 minutes stirring, Mel (1,20 ml, 8.97 mmol) was added to the mixture was added at same temperature, and the resulting mixture was allowed to raise to room temperature for over 1 h. Then 60% oil NaH (359 mg, 8.97 mmol) and Mel (1.20 ml, 8.97 mmol) was added to le reaction mixture at room temperature and stirred for 14 h. The reaction mixture was poured lto ice water and extracted with CHC13. The combined extracts were washed with aq. NaHCO, nd brine. After dried over Na3SOj, the extracts were concentrated in vacuo. The residue was hromatographed on silica gel [50 g, n-Aejwww/EtOAcf.4/1)], to give methyl 4-[(2S,4S)-l-te«-utoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxyben2oate (1.32 g, 60%) as a colorless oil. 'H-rMR(CDCl3) 5 1.48 (s, 9H), 2.05 (m, 1H), 2.29 (d, J= 14.2 Hz, 1H), 3.30 (s, 3H), 3.36-4.38 (m, H), 6.76 (br, 2H), 7.97 (d,J= 8.8 Hz, 2H). To a stirred solution of methyl 4-[(25,4S)-l-/erf-butoxycarbonyl-4-methoxy-2-yrrolidinyl] methoxybenzoate (2.38 g, 3.61 mmol) in CH3C1, (46 ml) was added TFA (23 ml) at som temperature. After 14 h stirring, the mixture was concentrated in vacuo. The residue was iluted by the addition of CH,C1, and 1 N NaOH, and extracted with CH,C!L The combined xtracts were washed with brine, dried over Na,SO(, which was concentrated in vacuo. The ssidue was chromatographed on silica gel [50 g, CHClj/MeOH (20/1)], to give methyl 4-[(2S',4S)--methoxy-2-pyiTolidinyl]methoxybenzoale (950 mg, 99%) as a yellow oil. 'H-MMR (CDCy 6 .16(t,J=5.3Hz, 1H), 2.72 (s, 1H), 2.95 (d,J= 6.8 Hz, 1H), 3.11 (d,J= 11.0 Hz, 1H), 3.26 (t, J 1.9 Hz, 3H), 3.52 (br, 1H), 3,84 (d, 7= 1.7 Hz, 3H), 3.92 (s, 1H), 4.00 (d, J= 4.1 Hz, 2H), 6.88 m,2H),7.94(m, 2H). A mixture of 3-mcthoxy-4-[W-(2-methylphenyl)ureido]phenylacetic acid (375 mg, 1.19 unol), methyl 4- ((2S,4S)-4-methoxy-2-pyrrolidinyl] methoxybenzoate (317 mg, 1.19 mmol), DC-HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) andEt3N (0.83 ml, 5.95 mmol) in IMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and xtracted with EtOAc. The combined extracts were washed with ice water and brine. After dried ver NajSO,, the extracts were concentrated in vacuo. The residue was chromatographed on silica el [50 g, CHClj/Aectone (10/l)CHClj/MeOH (20/1)), to give methyl 4-[(25,4i)-4-methoxy-l-[3-iethoxy-4-[A'-(2-methylphenyI)ureido}phenylacetyl]-2-pyrrolidinyI]methoxyberizoate (650 mg, 8%) as a pale brown amorphous solid 'H-NMR (CDC13) 52.03 (m, JH), 2.31 (s, 3H), 2.32 (m, H), 3.29 (d, J= 1.0 Hz, 3H), 3.57-3.68 To a solution of methyl 4-[(25,4S)-4-methoxy-l-[3-methoxy-4-[W-(2-methylphenyl) reido] phenylacetyl]-2-pyrrolidinyl] methoxybenzoate {650 mg, 1.16 mmol) in THF (18.5 ml), 0.25 N NaOH (18.5 ml) was added. After stirring at room temperature for 12 h, the mixture was acidified with 1 N HCI and extracted with CHCIj-MeOH (10/1). The combined extracts were dried over Na:S04 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g, CHCJ^MeOH (20/1)] to give 132 (540 rog, 85%) as a colorless amorphous solid. MW 547.60 IR (KBr) 3354, 2937,1709,1685,1604, 1533, 1454 cm'1; 'H-NMR PMSO-ds) 8 2.11 (m, 2H), 2.25 (s, 3H), 3.22 (s, 3H), 3.49-3.78 (m, 4H), 3.82 and 3.86 (s, 3H, amide isomers), 3.87-4.52 (m, 4H), 6.71-7.17 (m, 7H), 7.79 (d>L7= 8.1 Hz, 1H), 7,86-8.03 (m, 3H), 8.45-8.57 {m, 2H), 12.64 (br, 1H); MS (ESI) m/z 548 QAT+l);A»al. Calcd for C„H33N30,TNa-1.5H,0: C, 60.29; H, 6.07; N, 7.03. To a solution of methyl 4-[(2S,4S)-l-i4-fAr'-(2-cWoraphenyl)ureido]-3-methoxyphenyl acetyl]-4-methoxy-2-pyn-olidinyl]niethoxybenzoate (600 mg, 1.03 mmol) in THF (16 ml), 0.25 N NaOH (16 ml) was added. After stirring at room temperature for 12 h, the mixture was acidified with 1 N HCI and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na,S04 and concentrated in vacuo, The residue was purified on TLC [CHClj/MeOH (10/1)] to To a solution of methyl 4-{(25,45)-l-[4-IW-(2-bromophenyl)ureido]phcnylacctyl]-4-mcihoxy-2-pyn-olidinyl]iiieihoxybcnzoatc (760 mg, 1.19 mmoI)inTHF(19 ml). 0.25 NNaOH(19 ml) was added. After stirring at room temperature for 12 h, the mixture was acidified with 1N HC1 and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na^SO, and concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCI,/MeOH (20/1)] to give 134 (580 rug, 78%) as a colorless amorphous solid. MW 612.47 IR (KBr) 3330, 2935,1709, 1685, 1604, J529, 1434 cm"1; 'H-NMR (DMSO-dJ 8 2.11 {m, 2H), 3.22 (s, 3H), 3.58-3,78 (m,4H), 3.81 and 3.86 (s, 3H, amide isomers), 3.92-4.52 (m, 4H), 6.72 (d, J= 8.6 Hz, 1H), 6.77 (d,J= 8.3 Hz, 1H), 6.85 and 6.91 (s, 1H, amide isomers), 6.97 (t,J= 7.1 Hz, 1H), 7.02 and To a stirred solution of methyl 4-hydroxybenzoate (1,18 g, 7.76 nunol),'l-('er/-butoxy carbonyl)-(4fl)-methoxy-(25)-prolinoI (1,79 g, 7.74 mmol) andPhjP (2.44 g, 9.30 mmol) in THF (30 ml) was added D1AD (1.83 ml, 9,29 mmol) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperature, the mixture was evaporated. The residue was filtered on silica-gel with toluene-acetone (5:1, v/v) as eluent to give the crude product. The crude product was dissolved in CHjCl2 (20 ml). The solution n-as added TFA (20 ml) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and made basic by sat. NaHC03. The mixture was extracted with CHClj, washed with brine, dried over KJCOJ, and evaporated. The residue was purified by column chromatography on silica-gel with CHClj-McOH (30:1 to 30:2, v/v) as eluent to give methyl 4-[(4^)-methoxy-(2,S)-pyrrolidiriyI methoxyjbenzoate (1.67 g, 81% for 2 steps) as a reddish brown oil. 'H-NMR (CDC13) 5 1,65-1.72 (m, 1 H), 1.89 (bs, 1 H), 2.05-2.22 (m, 1 H), 2.95-3.15 (m, 2 H), 3.31 (s, 3 H), 3.69-3,76 (m, 1 H), 3.88 (s, 3 H), 3,91-4.06 (m, 3 H), 6.89-6,92 (m, 2 H), 7.96-7,98 (m, 2 H); MS (FAB) m/z 266 (M++l). A mixture of 3-methoxy-4-[//'-(2-methylpheny!)iireido]phenyIacetic acid (470 mg, 1.50 mmol), methyl 4-[(4.K)-methoxy-(2pyrTo!idiny!methoxy]benzoate (396 mg, 1.49 mmol), EDCHC] (343 mg, 1.79 mmol), HOBt (242 mg, 1.79 mmol) and Et3N (250 ml, 1.79 mmol) in THF (10 ml) was stirred at room temperature overnight. The mixture was diluted with H,0 and extracted with EtOAc. The extract was washed with brine, dried over Na,S04, and evaporated. The residue was purified by column chromatography on silica-gel with CHCI3-MeOH (100:1, v/v) as eluent to give methyl 4-[(4^?)-methoxy-l-[3-methoxy-4-[Ar'-(2-methylphenyl)ureido]prienyl acerylK23>pyn-olidinylmethoxy]benzoate (822 mg, 98%) as a white foam. 'H-NMR (CDClj) 5 2.14-2.24 (m, 2 H). 2.27 (s, 3 H), 3.25 (s, 3 H), 3.51 (s, 3 H), 3.58-3.73 (m, 4 H), 3.88 (s, 3 H), 3.98-4.09 {m, 2 H), 4.40-4.53 (m, 2 H), 6.67-7.29 (series of m, total 9 H), 7.57-7.59 (m, I H), 7.91-7.93 (m, 2 H), 8.04-8.06 (m, 1 H); MS (FAB) mh 562 (IvT+l). The residue was purified by column chromatography on silica-gel with CHClj-MeOH (100:1, v/v) as eluent to give methyl 4-[l-[4-[/>/'-{2-fluorophenyl)ureido]-3-methoxvphenylacetyl]-(4/;)-methoxy-(2i)-pyrrolidinylmethoxy]benzoate (806 mg, 95%) as a pale yellow foam. 'H-NMR (CDC13) 5 2.14-2.37 (m, 2 H), 3.28 (s, 3 H), 3.44 (s, 3 H), 3.48-3.74 (m,4H), 3.88 (s, 3 H), 4.02-4.15 (m, 2 H), 4.43-4.58 (m, 2 H), 6.63-7.10 (series of m, total 7 H), 7,68-7.73 (m, 1 H), 7.89-8.02 (m, 4 H), 8.16-8.20 (m, 1 H); MS (FAB) m/z 566 (M*+l). To a stirred solution of methyl 4-[l-[4-[A,'-(2-bromophenyl)ureido]-3-methoxyphenyl acetyl]-(4/0-methoxy-(2i>p>TToliainylmethoxy]benzoate (697 mg, 1.11 mmol) in THF (8 ml) was added 0,5 N NaOH (8 mJ) and the reaction mixture was heated under reflux for 2 hi. After cooled to room temperature, the mixture was poured into ice-1 N HC1 and the resulting precipitate was collected under a reduced pressure. The crude solid was purified by recrysuliization from MeOH- To a cold (-78°C), stirred solution of methyl l-(tert-butoxycarbony])-4-oxopyTTolidine-2- ' carboxylate (1.13 g, 4,65 mmol) in CH,Clj (20 ml) was added methylDAST (1.1 ml, 11.6 mmol). The mixture was allowed to warm to room temperature. After 15 h stirring, the mixture was poured into H]0 (50 ml) and extracted with EtOAc (200 ml). The extract was washed with brine (2 x 200 ml), dried over MgS04, and evaporated. The residue was chiomatographed on silica gel with CHClj-EtOAc (20:1) as eluent to give methyl l-(/er(-butoxycarbonyl)-4,4-difiuoropynolidine -2-carboxylate (885 mg, 72%) as a yellow oil. 'H-NMR (CDC13) 5 1.42 and 1.47 (s, each, total 9 H), 2.46 (ddd, d= 26.9 13.7, 5.1 Hz,lH), 2.62-2.78 To a stirred solution of methyl l-(/er(-butoxycarbonyl)-4,4-difluoropyrTolidine-2-carboxylate (885 mg, 3.34 mmol) in THF (25 ml) was added 0.25 N NaOH (26.7 ml, 6.67 mmol) and the stirring was continued for I h. The mixture was poured into 1 N HC1 (100 ml) and extracted with CHC13 (2 x 200 ml). The combined extracts were washed with brine (100 ml), dried over MgS04, and evaporated to give l-(/er(-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (775 mg, 92%) as a yellow crystalline solid, mp 113-117 °C; 'H-NMR (CDCI3) 5 1.44 and 1.49 (s, each, total 9 H), 2.53-2.80 (m, 2 H), 3.71-3.90 (m, 2 H), 4.20-4.61 (m, 1 H); MS (FAB) m/i, 252 (M'+lJ^na/. Calcd for 0,^,0,: C, 47.81; H, 6.02; N, 5.58. Found: C, 48.06; H, 6.05; N, 5.45. To a stirred solution of //-(/erf-butoxycarbonyl) 4,4-difluoroproiine (3.00 g, 11.9 mmol) in THF (20 ml) was added BH,-DMS (1.1 ml, 11.9 mmol) at room temperature. The mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was concntrated »i vacuo. The residue was quenched by the addition of HjO (100 ml) and extracted with CHCl, (2 x 200 ml). The combined extracts were dried over MgSOj and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give l-(/er/-butoxycarbonyl)-4,4-difIuoro-2-pyTTolidinylmetHanol (2.11 g, 75%) as a colorless oil. 'H-NMR (CDCIj) 5 1.48 (s, 9 H), 2.04-2.55 (m,2H},3.59-4.]7(m,5H). To a stirred mixture of 3-(/er/-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanoI (600 mg, 2.53 mmol), methyl 4-hydroxybenzoate (462 mg, 3,03 mmol), Ph,P (795 rag, 3.03 mmol) in THF (10 ml) was added DIAD (597 ul, 3.03 mmol) at room temperature. The mixture was heated at reflux for 3 h with stirring. After cooling to room temperature, the mixture was concntrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give methyl 4-[l-((er(-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmetlioxy]benzoate (831 mg, 88%) as a colorless oil. 'H-NMR (CDC13) 5 1.48 (s, 9 H), 2.53-2.61 (m, 2 H), 3.63-4.41 (series of m, total 8 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.99 (d, J = 8.8 Hz, 2 H). A mixture of methyl 4-[l-(/er;-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy] benzoate (830 mg, 2.23 mmol) and TFA (5 ml) in CH2Clj (5 ml) was stirred for 3 h and concntrated in vacuo. The residue was made basic with sat. NaHCOj and extracted with CHC13 (2 x 200 ml). The combined extracts were dried over K3C0j and concntrated in vacuo to give methyl 4-(4,4-difluoro-2-pyrTolidinylmelhoxy)ben2oate (550 mg, 91%) as a pale yellow solid. 'H-NMR (CDC1,) 52.19 (m, 1 H), 2.43 (m, 1 H), 3.19-3.41 (m, 2 H), 3.77 (m, 1 H), 3.89 (s, 3 H), 4.00-4.09 (m, 2 H), 6.92 (d, J= 9.0 Hz, 2 H). 7.99 (d, J = 9.0 Hz, 2 H); MS (FAB) m/z 111 (M*+l); Anal. Calcd for CJH.JF^NOJ: C, 57.56; H, 5.57; N, 5.16. Found: C, 57.65; H, 5.67; N, 5.16. A mixture of methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (540 mg, 1.99 mmol), 3-methoxy-4-{//'-(2-methy]phenyl)ureido]pheny!acetic acid (626 mg, 1.99 mmol), EDC'HCl (572 mg. 2.99 mmol), HOBl (cat.), and DMAP (cat.) in DMF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (300 ml), washed with brine {2 x 100 ml), dried over MgSO*, and concntrated in vacuo. The residue was chromatographed on silica gel with CHClrMeOH (20:1) as eluent to give methyl 4-[4,4-difluoro-l-E3-methoxy-4-[JV'-(2-methy]phenyJ)ureido] phenyIacetyl]-2-pyrroIidinylmethoxy]benzoate (1.00 g, 89%) as a colorless foam. 'H-NMR (CDC13) 8 2.31 (s, 3 H), 2.47-2.63 (m, 2 H), 3.52-3.97 (series of s and m. total 10 H), 4.07-4.30 (m, 2 H), 4.67-4.69 (m, 1 H), 6.45 (s, 1 H), 6.65 (d, 7= 1.7 Hz, 1 H), 6.74-6.76 (m, 1 H), 6.84 (d, J= 8.8 Hz, 2 H), 7.14 (m, 2 H), 7.24 (m. 2 H), 7.52-7.54 (m, 1 H), 7.94 (d,/ = 8.8 Hz, 2H), 8.09 (d,.7=8.1 Hz, 1 H). phenylacetyl]-4,4-difluoro-2-pyiTOlidinylinclhoxy]b«izoate (482 mg, 97%) as a colorless viscous solid. 'H-NMR (CDC1,) S2.50-2.67 (m, 2 H), 3.54-4.7! (series of m, 13 H), 6.69 (d, J= 1.5 Hz, J H), 6.76 (d, J - 8.3 Hz, I H), 6.84 (d, ./ = 8.8 Hz, 2 H), 6.98 (dt, J= 7.S, 1.5 Hz, 1 H), 7.23-7.27 To a sliced solution of (25,3fl,45)-l-ben2yloxycartx)nyl-3,'(-isDpropylidenedioxy-2-pyrTolidinyl carboxylic acid (9.87 g, 30.7 mmol) in THF {200 ml) was added BH3-DMS (6.14 m], 61.4 mmol) at 0 °C. The mixture was allowed to room temperature and then heated under reflux for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by the addition of water at 0"C. The mixture was extracted with EtOAc. The combined extracts were washed with water and brine, which were dried over Na5SO, and concentrated in vacuo. The residue was chromatographed on silica gel [200 g, CHClj/MeOH (20/1)], to give (2K,3.fl,4£)-l-benzyloxy caibonyl-3,4-isopropylidenediQxy-2-pyTTOlidinylmethanol (10.1 g, 100%) as a colorless oil. 'H-NMR(CDClj) 5 1.31 (s, 3H), 1.45 (s, 3H), 3.56-4.74 (m. 7H), 5.14 (s, 2H), 7.34 (m, 5H). To a stirred mixture of (2Jt,3^,4S)-l-benzyloxycarbonyl-3,4-isoprorvlidenedioxy-2-pvrrolidinyI methanol (312 rrig, 0.64 mrool), methyl /J-hydroxybenzoate (67 ml, 0.70 mmol), PPh3 (184 rng, 0.70 mmol) in THF (7 ml) was added DIAD (138 ml, 0.70 mmol) at 0 8C under an atmosphere of nitrogen. The mixture was allowed to reach room temperature and stirred for 3 h. After removal of the solvent, the resulting residue was chromatographed on silica gel [10 g, n-hexane/ElOAc (4/1)], to give methyl 4-[(2ft,3/!,45)-benzyloxycarbonyl-3,4-isopropyIidenedioxy-2-pyrrolidinyl] methoxybenzoate (321 mg, 83%) as a colorless oil. 'H-NMR (CDCI3) 8 1.01 (s, 6H), 1.03 (s, 3H), 2.23 (m, 1H), 2.63 (m, 1H), 3.61 (&,J= 12.5 Hz, 1H), 3.80-4.27 (m, 4H), 4.84 (JOT, IH), 5.01 and 5.08 (ABq, J= 12.2 Hz, IH, amide isomers), 6.75-6.87 (m, 3H), 7.19-7.63 (m, 15H). A suspension of methyl 4-I(2#J3fl,4S)-l-benzyloxycarbonyl-3,4-isoprqpyIidenedioxy-2-pyrrolidiny]]methoxybenzoate (2.37 g, 5.76 mmol) and 10% PdVC (240 mg ) in EtOH (170 ml) was stirred at room temperature under an atmosphere of hydrogen. After 1 day stirring, the catalyst and solvent were changed for 10% Pd/C (500 mg) and THF (50 ml). The suspension was stirred at room temperature under an atmosphere of hydrogen for 5 days. After removed the catalyst by filtration, the filtrates were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCIj/acetone (20/1)], to give methyl 4-[(27J,3fl,4S)-3,4-isopropylidenedioxy-2-pyTTolidinylJmethoxybenzoate (930 mg, 53%) as a brown oil. 'H-NMR (CDC13) 5 1.35 (s, 3H), 1,50 (s, 3H),3.02 (dd,y= 13.7.4.1 Hz, IH), 3.13(d, J= 13.7Hz, IH), 3.58 (t, J =6.3 Hz, IH), 3.88 (s, 3H), 3.90 (dd, J = 9.3, 6.6 Hz, IH), 4.02 (dd, J= 9.5, 3.9 Hz, IH), 4.74 (d, J= 5,6 Hz, IH), 4.79 (m, IH), 6.90 (d, J= 9.0 Hz, 2H), 7.98 (d, J= 9.0 Hz, 2H). A mixture of 3-methoxy-4-[A'-(2-inethylphenyl)uTeidojphenylaceuc acid (437 mg, 1.39 mmol), methyl 4-[(2i?,3R,45)-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (428 mg, 1.39 nunol), EDOHC1 (400 mg, 2.09 mmol) and DMAP (170 mg, 1.39 mmol) in DMF (12 ml) was stirred at room temperature for 20 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over NajSO,, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [70 g, CHCtyacetone (10/1)], to give methyl 4-[{2R,3R,45)-3,4-isopropylidenedioxy-I-[4-[A'-(2-methylphenyl)ureido]-3-meu^oxyphcny]a«tyl]-2-pvrrolidinyl]rnethoxyben20ate (840 mg, 100%) as a colorless amorphous solid IR (KBr) 3354,2985, 2939, 1716,1533, 1254 cm'1; 'H-NMR (CDCy 6 1.31 (s, 3H), 1.42 (s, 3H), 2.05 (s, 3H), 3.50 (s, 3H), 3.55-3.88 (m, 4H), 3.89 (s, 3H), 4.13 (m, lH),4.67(br, 1H), 4.78 (d, J" 6.1 Hz, 1H), 4.88 (1,./= 5.6 Hz, 1H), 6.46 (s, 1H), 6.62 (d,J= 1.5 Hz, IH), 6.74 (m, 3H), 7.05 (s, 1H), 7.14-(d,y= 7.3 Hz, 1H), 7.23 (m, 2H), 7.57 (d, J = 7.8 Hz, IH), 7.91-8.08 (m, 3H); MS (ESI) m/z 604 (M'+l);Anal. Calcd for C„H37NjCy0.6HjO: C, 64.50; H, 6.27; N, 6.84. Found: C, 64.38; H, 6.18; N, 6.66. A mixture of methyl 4-[(2fi,3J(,45)-3,4-isopropylidenedioxy-l-[4-[Ar'-(2-m«hylphenyI)ureidoJ-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoate (183 mg, 0.303 mmol) and g.HCl-MeOH (6 ml) was stirred at room temperature for 17 h. The mixture was concentrated in vacuo. The residue was purified on TLC [CHClj/MeOH (10/1)], to give methyl 4-[(M,3^,45)-3,4-dihydroxy-l-[4-[//'-(2-methylphenyl)ureido]-3-methoxyphenyJacety!]-2-pyrrolidinyl]methoxybenzoate (162 mg, 95%) as a colorless amorphous solid IR (KBr) 3342,1716, 1604,1535.1255 cm"1; 'H-NMR (CDClj) 5 2.25 (or, 3H). 3.33-3.75 (m, 7H), 3.87 (s, 3H), 4.10 (d, J= 8.3 Hz, IH), 4.24 (s, 2H), 4.37 (m, 2H), 6.62-7.94 (m, 13H); MS (ESI) mh 564 (M*+l). To a solution of methyl 4-[(2fi,3fl,4S)-3,4-isopropy]idenedioxy-l-[4-[Ar'-(2-methylphenyl)ureido]-3-methoxyphenylacety]]-2-pyrTolidinyl]methoxybcnzoate (490 mg, 0.812 mmol) in THF (9.8 ml), 0.25 N NaOH (9.8 ml) was added. After stirring at room temperature for 4 days, the mixture was acidified with 1 N HC1 and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na,SO, and concentrated in vacuo to give 141 (445 mg, 93%) as a colorless amorphous solid. MW 689.64 IR (KBr) 3354, 2983, 2937, 1707, 1604, 1533 cm'; 'H-NMR (DMSO-d,s) 6 .24 and 1.26 (s, 3H, amide isomers), 1.26 and 1.32 (s, 3H, amide isomers), 2.24 (s, 3H), 3.40 (dd, J = 14.0, 5,1 Hz, IH), 3.60 (m, 2H), 3.71 (m, IH), 3.76 (s, 3H), 3.82 (s, 3H), 3.92^1.96 (m, 5H), 6.74 and 6.78 (m, IH, amide isomers), 6.83-7.16 (m, 6H), 7.79 (d, J = 8.3 Hz, IH), 7.87 (t, J = 9.1 Hz, 2H), 8.01 (m, IH), 8.49 (d,/= 3.4 Hz, IH), 8.57 (s, IH); MS (FAB) m/z 590(M-i-iy, Anal. Calcd for CnH„N30,-2.3H10: C, 60.90; H, 6.32; N, 6.66. Found: C, 61.00; H, 6.00; N, 6.27. methyl 4-[(2R,3fi,45)-3,4-isopropylidenedioxy-2-pyiro]idinyl]mclhoxybenzoate (447 mg, 1.45 mmol), EDC-HC1 (418 mg, 2,18 mmol) and DMAP (177 mg, 1.45 mmol) in DMF (12 ml) was stirred at room temperature for 19 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over NajSOj, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [70 g, CHCyacetone (10/1)], to give methyl 4-[(2ff,3fl,4S)-l-[4-[A'-(2-chlorophenyI)ureido]-3-methoxyphenylacetyl]-3,4-isopropylidenedioxy-2-pyTTOlidinyl]methoxybenzoate (850 mg, 94%) as a colorless amorphous solid IR(KBr) 3329, 2939, 1716, 1627, 1531, 1254 cm'1; 'H-NMR (CDC13) Ri«'ciin i di Cc I'm T sf.(s 1R1 3.61 fs. 1HY 3.64 fs. 1H1 3.70 fm. 1H1. 3.79 (d.J= 10.4 Hz, 1H), 3.88 (s. 3H>, 4.14 (dd,J = 9.8, 2.2 Hz, IH), 4.40 (dd, ./= 9.8, 3.4 Hz, 2H), 4.67 (s, IH), 4.80 (d, J = 6.1 Hz, 1H), 4.90 (t,/= 4.6 Hz, 1H), 6.65 (d, J= 1,7 Hz, 1H), 6.71-6.84 (m, 3H), 6.98 (eft, y= 7.6, 1.5 Hz, IH), 7.27 (m, 2K), 7.33 (dd, /= S.O, 1.2 Hz, 2H), 7.90-8.01 (m, 3H), 8.20 (dd. /= 8.3, 1.5 Hz, IH); MS (ESI)m/2 624 (M*+l), 626 (M*+3); ^MO/. Calcd for C„HMN30„-1.4H,0; C, 59.19; H, 5.71; N, 6.47. Found: C, 58.85; H, 5.35; N, 6,21. AnuxtmeofmcthyH-K^.S^^-l-H-l^^-chlorophenylJuTeidolO-mdhoxyphcnylacetyll-S.A-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (177 mg, 0.284 mmol) and g.HCl-MeOH (4 ml) was stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was purified on TLC [CHClj/MeOH (15/1)], lo give methyl 4-[(2J?,3^,45>l-[4-[A',-(2-c hi oropheny l)urei do]-3-m ethoxyphenylacety 1]-3,4-isopropy lidenedioxy-2-pyrroli di ny 1] methoxybenzoate (140 mg, 85%) as a colorless amorphous solid IR (KBr) 3338,2949,1712, 1623,1604, 1533 cur'; 'H-NMR (CDOj) 5 2.27 (m, IH), 2.79 (m, IH), 3.53 (dd. J= 10,5,5.9 Hz, IH), 3.63 (s, 3H), 3.88 (s, 3H), 4.21 (d, J = 7.8 Hz, IH), 4.31 (m, 2H), 4.43 (dd, J= 9.8, 4.4 Hz, IH), 4.52 (t, J= 4.6 Hz, IH), 6.71 (s, IH), 6.80 (m, 3H), 6.99 (t,./= 7.3 Hz, IH), 7.16 (s, IH), 7.21 (s, IH), 7.39 (d, J = 8.1 Hz, IH), 7.91 (d, J= 8.6 Hz, 2H), 8.16 (d, J= 8.3 Hz, IH); MS (ESI) m/z 584 (M*+l), 586 (M*+3). To a solution of methyl 4-[(2fl,3fl,4S)-l-[4-[W-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-3,4-;sopropyJideiiedioxy-2-pj,rro]idJiiyJ]metho)rybenzoate (511 mg, 0.819 mmol) in THF (9.8 ml), 0.25 N NaOH (9.8 ml) was added. After stirring at room temperature for 20 h, the mixture was acidified with 1 NHC1 and extracted with CHQj-MeOH (.10/1). The combined extracts were dried over Na^O* and concentrated in vacuo to give 143 (504 mg, 100%) as a colorless amorphous solid. MW610.05 IR (KBr) 3330, 2983, 2937, 1711,1689,1604, 1533, 1252 cm"1; 'H-NMR (DMSCKj) 5 1.26 (s, 3H), 1.32 (s, 3H), 3.40 (m, IH), 3.60 and3.61 (d, J= 2.5 Hz, 3H, amide isomers), 3.62 (m, iH), 3.78 and 3.83 (s, 3H, amideisomers), 4.16 (m, 2H), 4.42-4.98 (m, 3H), 6.74-7.15 (m, 6H), 7.28 (t, J= 7.3 Hz, IH), 7.43 (d, J= 8.1 Hz, IH), 7.78-7.97 (m, 4H), 8.08 (d, J = 8.3 Hz, IH), 8.89 (s, IH), 8.92 (s, IH), 12.68 (or, IH); MS (ESI) m£ 610 (M'+l), 612 (M"+3). To a solution of methyl 4-[l-[4-[A^-(2-chloropheny0ureido]-3-inethoxyphenyIacetyI]-3,4-dihydroxy-2-pyrrolidinylinethoxyJbenzoate (63 mg, 0.108 mmol) in THF (0.80 ml), 0.25 N NaOH (0.80 ml) was added. After stirring at room temperature for 3 days, the mixture was acidified with 1 N HC1 and extracted with CHC!3-MeOH (10/1). The combined extracts were dried over Na3SO, and concentrated in vacuo to give 144 (61 mg, 100%) as a colorless amorphous solid. MW 569.99 IR (KBr) 3338, 1687, 1604,1533,1255, 1169,1036 cm"1; 'H-NMR pMSO-^ 5 3.59 (d, J" 5.5 Hz, 2H), 3.61 (m, 1H), 3.66 (dd, J= 10.0, 7.1 Hz, 1H), 3.80 (s, 3H), 4.00-4.33 (m, 5H), 5.10 (br, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.87 (s, 1H), 7.03 (m, 3H), 7.28 (t, J= 8.3 Hz, 1H), 7.43 (d, J" 6.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.32 (s, 1H), 8.89 (s, 1H), 8.93 (s, 1H); MS (ESI) m/z 570 (M*+l), 572 (M++3); ^na/. Calcd for C„H,,ClNjOt-1.4H,0: C, 57.19;H, 5.14;N, 7.15. Found: C, 57.52;H, 5.22; N. 6.76. Example 137 was added phenyllithium (1.0Min Et,0-cyclohexane, 33.5 ml, 33.5 mmol) at -78°C, and the resulting mixture was gradually wanned up to -40°C, then stirred overnight aq.NH,Cl was added to the reaction mixture, THF was removed in vacuo, then extracted with EtOAc. The organic layer was washed with water and, drying over anhydrous Na3SOJp then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4 :1) as eluent, then recrystallized from hexane-EtOAc to give benzyl [2-{.S)-{A'-Boc-amino)-5-oxo-6-phenyl]pentanoate (5.02 g, 45%) as a colorless needles, mp 85-87 °C; 'H-NMR (CDC13) 5 1.43 (s, 9 H), 2.07-2.19 (m, 1 H), 2.27-2.36 (m, 1 H), 2.97-3.13 (m, 2H), 4.44 (brs, 1 H). 5.19 (dd, J= 25.2, 12.0 Hz, 2 H), 5.19 (overlap, 1 H), 7.28-7.98 (series of m, 10 H); MS (EST) m/i, 322 (M*+H). To a stirred solution of benzyl [a-CSHAf-Boc-aminoJ-S-oxc-e-phenylJpentanoate (2.20 g, 5.54 mmol) in CHjCl3 (50 ml) was added trifluoroacetic acid (15 ml) at rt, and the resulting mixture was stirred for 2 h. The mixture was concentrated in vacuo and poured into aq.NaHCOj, then extracted with EtOAc. The organic layer was dried over anhydrous Na5SOi, then concentrated in vacuo to give benzyl 5-phenyl-5-pyrroline-2-(5)-carboxy!aie (1.60 g, quant.) as yellowish solid- The product was used for next reaction without further purification: 'H-NMR (CDC13) S 2.20-2.29 (m, 1 H), 2.32-2.42 (m, 1 H), 2.96-3.05 (m, 1H), 3.12-3.21 (m, 1H), 4.96-5.00 (m, 1H), 5,24 (s, 2 H), 7.31-7.49 (m, 8 H), 7.88-7.91 (m, 2 H); MS (ESI) m£, 280 (M*+H). A mixture of benzyl 5-phenyI-5-pyrrol ine-2-(S)-carboxy late (1.59 g, 5.69 mrnol) and Pd/C (10%, 128 mg) in MeOH (30 ml) was stirred under H, al rt for 28 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH3CN-HjO (3 : 2, 25 ml), then was added di-(er/-butyl dicarbonate (1.86 g, 8.54 nunol) and 1.0 W-NaOH (8.54 ml, 8.54 mmol), and the resulting mixture was stirred for 30 min. The mixture was concentrated in vacuo and poured into aq.NaHCO,, then extracted with EtOAc. The organic layer was washed with water, saturated brine, drying over anhydrous NajSOj, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (9 : 1) and reciystaJlized from hexane-EtOAc to give A'-Boc-5-{i?)-phenyl-(i)-proHne (810 mg, 49%) as a colorless solid. Mp 113-117 °C; 'H-NMR(CDCl,)SU3(s, 9H), 1.43 (brs, 1 H). 1.96 (brs, 1 H), 2.09 (brs, 1 H), 2.31-2.34 (m, 1 H), 2.46 (brs, 1 H), 4.52 (brs, 1 H), 4.69 (brs, 1 H), 7.22-7.37 (m, 5 H). To a stirred solution of #-Boc-5-(tf)-phenyl-2-(.S>proHne (1.14 g, 3.91 mmol) in THF (20 ml) was added IOW-BHJM^S (780 ml, 7.82 mmol) at rt, and the resulting mixture was heated under reflux for 30 min. The mixture was poured into aq.lA'-HCl and extracted with EtOAc. The organic layer was dried over anhydrous NajSO,, then concentrated in vacuo. The residue was chromatographed on silica ge! with CHCIrMeOH (10 :1) as eluent to give A'-Boc-2-(.S)-hydoxymethyI-5-(K> phenylpyrrolidine(l.llg, quant.) as a colorless oil: 'H-NMR (CDClj) 5 1.19 (brs, 9 H), 1.65 (brs, 1 H), 1.83-1.90 (m, 1 H), 1.98-2.06 (m, 1 H), 2.22-2.31 (m, 1 H), 3.75-3.86 (m, 2 H), 4.16-4.19 (m, 1 H), 4.83 (t, J= 6,8 Hz, 1 H), 4.89 (brs, 1 H), 7.19-7.31 (m, 5 H); MS (ESI) m/z, 278 (M*+H). To a stirred solution of Ar-Boc-2-(S)-hydoxymethyl-5-(^)-phenylpyn-olidine (1.10 g, 3.97 mmol), triphenylphosphine (1.25 g, 4.76 mmol) and methyl 4-hydroxybenzoate (724 mg, 4.76 mmol) was added diisopropyl azodicarboxylate (955 ml, 4.76 mmol) at it, and the resulting mixture was stirred at 60°C for 45 min. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (4 : 1) as eluent to give methyl 4-[A'-Boc-5-(fl)-phenyl-2-(S)-pyrrolidinylmethoxyJbenzoate (1.31 g, 80%) as a colorless oil. 'H-NMR (CDClj) 5 1.19 and 1.47 (brs, total 9 H), 2.09-2.15 (m, 3 H), 2.33-2.37 (m, 1 H), 3.94 (s, 3 H), 4.30 (brs, 1 H), 4.41 (brs, 2 H), 4.77 (brs, 1 H), 7.03 (d, J = 8.8 Hz, 2 H), 7.24-7.36 (m, 5 H), 8.03-8.06 (m, 2 H); MS (ESI) m/z, 412 (M++H). To a stirred solution of methyl Mtt-Boc-5-(fl)-phenyl-2- The organic layer was washed with water, drying over anhydrous NajSO*, and concentrated in vacuo to give methyl 4-[5-{tf)-phenyl-2-(.S)-pirrolidinyl methoxyjbenzate (363 mg, quant.) as yellowish oil. The product was used for next reactions without further purification. 'H-NMR (CDClj) 8 1.71-1.83 (m, 2 H), 2.03-2.10 (m, 1 H), 2.15-2.24 (m, 1 H), 3.68-3.74 (m, 1 H), 3.89 (s, 3 H), 4.01-4.09 (m, 2 H), 4.28 (t, J= 7.2 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.22-7.27 (m, 1 H), 7.33 (t, J = 8.0 Hz, 2 H), 7.42 (d, J = 7.6 Hz, 2 H), 8.00 (d, J = 8,8 Hz, 2 H); MS (ESI) m/z, 312 (M*+H) 353 (M*+CH3CN). To a stirred solution of methyl 4-[5-(fl)-phenyl-2-(S)-pirro]idinylrnethoxy]benzoate (135 mg, 0.43 mmol), 4-[A'-(2-methy]phenyl)ureido]-3-meuioxyphenyIacetic acid (136 mg, 0.43 mmol) and Nfl-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 ml) was added EDCHC1 (90.8 mg, 0.48 mmol) at rt, and the resulting mixture was stirred overnight The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO,, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1 : 5) as eluent to give methyl 4-tl-[4-[W'-(2-methylpherryJ)ureido]-3-methoxyphenyl acetyl]-5- To a stirred solution of methyl 4-[l-[4-[A,'-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-5-(J?)-pheny]-2-(.S>pynulidinylmethoxy]benzoate (243 mg, 0,40 ramol) in MeOH-THF (1 : 1,10 ml) was added 1.0AY-NaOH(2.4 ml, 2.40 mmol) at rt, and the resulting mixture was heated at 60"C with stirring for 1.5 h. The reaction mixture was poured into 1W-HC1, then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na^SOt, then concentrated in vacuo. The residue was chromatographed on silica gel wilh CHClj-MeOH (10 : 1) to give 145 (224 mg, 94%) as a colorless amorphous solid. MW 593,67 'H-NMR (CD3OD), mixture of rotamars, 6 2.00-2.19 (m, 3 H), 2.28 and 2.30 (s, total 3 H), 2.45-2.49 (m, 1 H), 3.37 (dd, J = 39, 16 Hz, 2 H), 3,77 and 3.80 (s, total 3 H), 3.92-5.18 (series of m, 4 H), 6.48-8.03 (series of m, 16 H); MS (FAB) m/z, 594 flvT+H). To a stirred solution of methyl 4-[l-[4-[A'- 4-[l-[4-[A'-{2-bromopheny])ureido]-3-methoxyphenylacetyl]-5-(ff)-phenyl-2-(5)-pyrrolidiriyl elhoxyjbenzoic acid mmol), 4-[//'-(2-bromophciiyl}ureido]-3-mcthoxyphenylacetic acid (178 mg, 0.47 nunol) and N,N-dimethylaminopyridine {57.4 mg, 0.47 mmol) in DMF (10 ml) was added EDCHCI (99.0 mg, 0.52 nunol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO„ then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1 : 5) as eluent to give methyl 4-[l-[4-[//,-(2-bromophenyI)ureido]-3-meUioxyphenyl acetyl]-5-(i?)-phenyl-2-(S)-pyirolidinylmethoxy]ben2oate (288 mg, 91%) as a colorless amorphous solid. 'H-NMR (CDCl,) 5 2.00-2.20 (m, 3 H), 2.34-2.43 (m, 1 H), 3.35 (s, 2 H), 3.72 (s, 3 H), 3.89 (s, 3 H), 4.38-4.49 (m, 2 H), 4.62 (brs, 1 H), 4.94 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H). 6.67 (s, 1 H), 6.91-7.05 (m, 4 H), 7,28-7.42 (series of m, 7 H), 7.51 (d,./= 8.0 Hz, 2H), 7,87 (d, J= 8.4 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 2 H), 8.14 (d, J = 8.4 Hz, 2H); MS (ESI) m/z, 672 (M*), 674 (M*+2). To a stirred solution of methyl 4-[ 1-[4-1^(2-bromopheiryl )ureido]-3-methoxypheny lacetyl]-5-(/J> phenyl-2-(5)-pyrrolidinylmethoxy]benzoate (270 mg, 0.40 nunol) in MeOH-THF (1:1, 10 ml) was added l.QM-NaOH (2.0 ml, 2.0 mmol) at rt, and the resulting mixture was heated at 60°C with stirring for 1 h. The reaction mixture was poured into 1W-HC1, then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous NajSO* then concentrated in vacuo. The residue was chromatographed On silica gel with CHClj-MeOH (10 : 1) togivel47(2I2 mg, 80%) as a colorless amorphous solid. MW 658.54 'H-NMR (CD3OD), mixture of rotamars, 8 1.99-2,19 (m, 3 H), 2.42-2.53 (m, 1 H), 3.38 (dd,7= 39, 16 Hz, 2H), 3.79 and 3.80 (s, total 3 H), 3.94-5.19 (series of m, 4 H), 6.49-8.00 {series of m, 16 H); MS (FAB) m/z, 658 (M*), 660 (M*+2). mmol), 4-[//>-(2,4-d!ch]orophenyl)Lreido]-3-melhoxypheny]acetic acid (129 mg, 0.35 mmol) and Ay/-dimethylaminopyridine (42.8 mg, 0.35 mmol) in DMF (10 ml) was added EDCHC1 (73.4 mg, 0.39 nunol) at rt, and the resulting mixture was stirred for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na3SO(, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-ElOAc (1 :4) as cluent to give methyl 4-[l-[4-[N"-(2,6-dichtorophenyl)ureidQ]-3-methoxyphenyJacety]]-5-(^)-phenyl-2-(5)-pyrrolidinylmethoxy]benzoaie (208 mg, 90%) as a colorless amorphous solid. 'S-NMR (CDC13) 8 2.00-2.21 (m, 3 H), 2.33-2.39 (m, 1H), 3.31 (s, 2 H). 3.69 (s, 3 H). 3.88 (s, 3 H), 4.34-4.45 (m, 2 H), 4.59 (brs, 1 H), 4.93 (I, J= 6.8 Hz, I H), 6-47 (d, J = 8.0 Hz, 1 H), 6.63 (s, 1 H), 6.68 (s, 1 H), 6.92-6.95 (m, 2 H), 7.12-7.41 (series of m, 9 H), 7.96-8.01 (m, 4 H); MS (FAB) m/z, 662 (M*+H). Na3S04, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[l-[4-[A,'-(2-bromophenyI)ureido]-3-methy!phenylacetyJ]-5-{K)-phenyl-2-(S)-pyiTOlidinylmeihoxy]benzoate (238 mg, 90%) as a colorless amorphous solid. 'H-NMR (CDC1,) 8 1.92 (s, 3 H), 2.09-2.27 (m, 3 H), 2.42-2.50 (m, 1 H), 3.22-3.41 (m, 2 H), 3.88 (S, 3 H), 4.39 (d, J = 4.4 Hz, 1 H). 4.64 (brs, 1 H), 5.00 (t, ./ = 6,8 Hz, 1 H), 6.72 (s, I H), 6.81-6.93 (series of m, 8 H), 7.22-7.42 (series of m, 6 H), 8.01 (d, J =8.4 Hz, 2 H), 8.13 (d, 7= 8.0 Hz, 1H); MS (FAB) m/z, 656 (M*), 658 (M*+2). To a stincd solution of benzyl [2-(S)-(A'-Boc-arnino)-5-oxo-6-methyl ]pentanoate (4.46 g, 13.3 mmol) in CHjClj (50 ml) was added Irifluoroacetic acid (20 m!) at rt, and the resulting mixture was stirred for 1.5 h. The mixture was concentrated in vacuo, and dissolved in toluene, then evaporated to give benzyl 5-methyl-5-pyrroIine-2-(.S)-carboxylale trifluoroacetic acid salt (5.74 g, quant) as a crude brown oil. This compound (1.97 g, 5.94 mmol) in MeOH (30 ml) was added Pd/C (10%, 153 mg), and the resulting mixture was stirred for 3 days under H3 atomosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give 5-methyl-5-pyrrolidine-2-(S)-carboxylic acid trifluoroacetic acid salt (956 mg, 66%) as a crude white solid. To a solution of this compound (939 mg, 3.86 mmol) and di-rerf-buyl dicarbonate in MeCN-water (15 : 1, 16 ml) was added 1.0M-NaOH(8.49 mmol, 8.49 ml) at rt, and the resulting mixture was stirred for lh. The resultiong mixture was evaporated and poured into aq.-W-HCI, then extracted with CHClj/MeOH (5': 1). The organic layer was dried over anhydrous NajSOt, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (7 :1) to give A'-Boc-S-(fl)-methyl-(55-pro!ine (711 mg, 80%) as a colorless oil. 'H-NMR (CD3OD) 5 1.27 (d, J = 6,0 Hz, 3H), 1.41-1.46 (m,9H), 1.62-1.64 (m, 1H), 1.96-2.01 (m, 2H), 2.22 (brs, 1H), 3.94 (brs, 1H), 4.17 (brs, 1H).; MS (ESI) m/z, 230 (M*+H). To a stirred solution of A'-Bac-5-y?)-methyI-2-(.S)-proiine (1.03 g, 4.49 mmol) in THF (20 ml) was added 10A/-BH3MejS (1.57 ml, 15.7 mmol) at rt, and the resulting mixture was heated under reflux for 5 h. The mixture was poured into aq.lA'-HCl and extracted with EtOAc. The organic layer was dried over anhydrous NajSQ,, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-AcOEt (1 : 3) as eluent to give A'-Boc-2-(S)-hydoxymethyl-5-(ff)-methylpyrrolidine (838 mg, 87%) as a colorless oil: 'H-NMR (CDC13) S 1.17 (d,J=6.0Hz, 3H), 1.48 (s,9H), 1.48-1.64 (m, 2H), 1.90-2.11 (m, 2H), 3.52-3.57 (m, 1H), 3.68-3.70 (m, 1H), 3.94-4.13 (m, 1H). To a stirred solution of A'-Boc-2-(5)-hydoxymethyl-5-(/!)-methylpyrrolidine (820 mg, 3.81 mmol), triphenylphosphine (1.10 g, 4.19 mmol) and methyl 4-hydroxybenzoate (580 mg, 3.81 mmol) was added diisopropyl azodicarboxylate (841 ml, 4,19 mmol) at rt, and the resulting mixture was stirred at 60°C for 1 h. The mixture was concentrated in vacuo, and the residue was chromatographed on silica gel with hexane-EtOAc (5 : 1) as eluent to give methyl 4-[A'-Boc-5-(fl)-methyl-2-(S>pyrro!idinylmethcxy]ben2oate (1.32 g, 80%) as a colorless oil. 'H-NMR (CDCl3) 5 1.24 (brs, 3 H), 1.49 (s, 9 H), 1.55-1.70 (m, 2 H), 1.94-2.11 (m, 2 H), 3.88 (s, 3 H), 3.88 (overlap, 1H), 4.06-4.20 (m, 2H), 6.93-6.96 (m. 2H), 7.97 (d, J= 8.8 Hz, 2 H); MS (ESI) m/z, 350 (M*+H). To a stirred solution of methyl 4-IA,-Boc-5-(K)-methy]-2-(S)-pyrro]idinylmethoxy] benzoate (1.29 g, 3.70 mmol) in CH3C1] (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aq.NaHCOj, then extracted with CHClj. The organic layer was washed with water, drying over anhydrous NajSOj, and concentrated in vacuo to give methyl 4-[5-(J?)-methyl-2-(5)-piiTolidiny[ methoxy]benzate (871 mg, 95%) as a colorless oil. The product was used for next reactions without further purification. 'H-NMR (CDClj) 5 1.18 (d, J = 6.4 Hz, 3 H), 1.30-1.40 (m, lH), 1.59-1.67 (m, 1 H), 1.87-1.97 (m, 2 H), 3.19-3.27 (m, 1 H), 3.49-3.55 (m, 1 H), 3.87 (s, 3 H), 3.89-4.05 (m, 2 H), 6.89 (d, J= 8,8 Hz, 2 H), 7.96 (d, J= 8.8 Hz, 2 H); MS (ESI) m/z, 250 (M*+H) To a stirred solution of methyl 4-[5-(J!)-methyl-2-(5)-pirrolidinylmethoxy]benzoate (141 mg, 0.57 mmol), To a stirred solution of methyl 4-[l-[4-[A'-(2-methylphenyl)ureido]-3-methoxyphenyIacefyl]-5-(R)-methyl-2-(5)-pyrrolidinylmethoxylbenzoate (279 mg, 0.51 mmol) in.MeOH-THF (1: 1,10 ml) was added 1.0A/-NaOH (2.56 ml, 2.56 mmol) at rt, and the resulting mixture was heated at 60°C with stirring for 2 h. The reaction mixture was poured into lA'-HCl, then extracted with CHClj. The organic layer was washed with brine and dried over anhydrous NajSO., then concentrated in vacuo. The residue was chromatographed on silica gel with CHClj-MeOH (15 :1) lo give 150 (269 mg, 99%) as a colorless amorphous solid. MW 531.60 'H-NMR (CD3OD), mixture of rotamars. 5 1.28-1.35 (m, 3 H), 1.74-2.21 (series of m, 4 H), 2.28 (s, 3 H), 3.71-4.37 (series of m, 6 H), 6.76-7.99 (series of m, 11 H); MS (ESI) m/z, 532 (M*+H). . Example 143 4-[(ran5-4-amino-l-[3-methoxy-4-[jV'-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl) methoxybenzoic acid To a stirred solution of methyl 4-(frani-.l-(er(-butoxycarboriy]-4-trif)aoroacetamido-(25)-pyTTolidinyl)methoxybenzoate (470 mg, 1.05 mmol) in CHjClj (10.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CHjCl3. The extract was washed with brine, dried over Na]SO 4-trifluoroacetanudo-(2S>pynohdTryl]methoxybenzoate (200 mg, 0.31 mmol) in MeOH (4.0 mm!) was added water (2.0 ml) and KjCO, (138 mg, 1,0 mml) at room temperature. After stirred for 18hr at room temperature, water was added to the mixture and extracted with CHjCl}. The extract was washed with water, then dried over NajSO«, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CHiCI, (5:95 to 15:85, v/v) as eluent. The product was dissolved in EtOH (5.0 ml), and IN HC1 (in EtOH) (1.0 ml, 1.0 mmol) was added thereto. The mixture was concentrated in vacuo to give 152 (120 mg, 63%) as an amorphous solid. MW 546.61 IR (KBr) 3382, 2948, 2879, 1604, 1533, 1286, 1255, 771 cm'1; 'H-NMR (DMSO-d«) 5 2.25 (s, 3H), 2.10-2.30 (m, 2H), 3.59-3.70 (m, 3H), 3.77-3.80 (m, 8H), 4.00^1.24 (m, 2H), 4.47-4.67 (m, 1H), 6.70-7.16 (m, 7H), 7.77-8.00 (m, 4H), 8.49 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 547 (M*+l); Anal calcd for C30HMN,0,-HCl-1.4H,0: C, 59.24; H, 6.26; N, 9.21; CI, 5,83 Found: C, 59.42; H, 6,42; N, 9.04; CI, 6.11. Example 145 4-[(ranj-l-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phenylacetyl]-4-methylamino-(25)-pyrrolidinyl]methoxybenzoic acid To a stirred solution of methyl 4-[frnn.s-]-/er/-butoxycarbonyI-4-(A'-inethyl-trifluoro acetoamido)-(25>pym)]idiny]]methoxybenzoate (390 mg, 0.85 mmol) in CH,C1, (8.0 m!) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat NaHCOj was added to the residue, and extracted with CHjCI,. The extract was washed with brine, dried over Na,SOj, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[A'-(2-methylphenyI)uredio]phenyIacetic acid (279 rag, 0.89 mmol), HOBt (143 mg, 1.1 mmol), and triethylamine (246 ml, 1.77 mmol) in THF (8.0 ml) and MeCN (8.0 ml) was added EDOHC1 (255 mg, 1.3 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHC03, 2-M citric acid, and sat. NaHCOj, then dried over NajSO*, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (4:1 ,v/v) as eluent to give methyl 4-[/ronj--l-[3-methoxy^-[//'-(2-methylpheiiyl)ure!do]phenylacetyl]^-(A'-methyl-trifluoroacetoamido)-(25)-pyrrolidinyl]methoxybenzoate (480 mg, 82%) as a colorless oil. 'H-NMR (CDC13) 6 2.18-2.35 (m, 2H), 2.31 (s, 3H), 2.87 and 2.97 (each s, total 3H). 3.45-3.46 (m, 3H), 3.47 (s, 3H), 3.49 (s, . 2H), 3.88 (s, 3H), 4.30-4.70 (m, 2H), 5.20-5.40 (m, 1H), 6.38-6.43 (m, 1H), 6.67-6.86 (m, 4H), 7.09-7.24 (m, 4H), 7.51-7.54 (m, 1H). 7.93-8.08 (m, 3H). To a stirred solution of methyl 4-[f7-onj-l-[3-raethoxy-4-[yV,-(2-methyIphcnyl)ureido]phcny]accQ'I]-4-(//-methyl-A'-tjif]uoroacctylaniino)-{25)-pym)Iidinyl]methoxybenzoate (240 rag, 0.37 mmol) in THF (5.0 ml) and MeOH (3.0 ml) was added IN NaOH (1.27 ml, 1.27 mmol). The mixture was stirred at 60 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 153 (140 mg, 70%) as a white crystalline solid. MW546.61 mp 162-164 °C; IR (KBr) 3338, 1604, 1535,1255, 1033, 755 cm'1; 'H-NMR (DMSO-dJ 6 1.85-1.95 (m, 1H), 2.10-2.20 (m, 1H), 2.24 (s, 3H), 2.34 and 2.39 {each s, total 3H), 3.41-3.71 (m, 3H), 3.58 (s, 2H), 3.80 (s, 3H), 4.05-4.20 (m, 2H), 4.36-4.60 (m, 1H), 6.73-7.16 (m, 7H), 7.77-8.01 (m, 4H), 8.45 (s, 1H), 8.53 (s, 1H); MS (FAB) m/z 547 (M*+1); Anal, calcd for CHJ.NA^.SHJO: C, 60.90; H, 6.64; N, 9.47. Found: C. 61.01; H, 6.50; N, 9.31. Example 146 methyl 4-[^ans-I-[3-methoxy-4-[?/H2-meihylphcnyl)uieido]phenyIacetyl]-4-mcthylarnino-(25)- 4-(Af-methyItrifluoroacetamido)-(2S)-pyTTolidinyl]methoxybenzoate (240 mg, 0.36 mmol) in THF (5.0 mml) and MeOH (5.0 ml) was added water (2.0 ml) and K^COj (138 mg, 1.0 mml) at room temperature. After stirred for 18hr at room temperature, water was added to the mixture and extracted with CH3C1,. The extract was washed with water, then dried over Na,S04, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl, (5/95 to 20/80, v/v) as eluent. The product was dissolved in EtOH (5.0 ml), and IN HC1 (in EtOH) (0.71 ml, 0.71 mmol) was added thereto. The mixture was concentrated in vacuo to give 154 (180 mg, 85%) as an amorphous solid. MW 560.64 IR (KBr) 3311, 2692, 2453,1712, 1604, 1533 cm-'; 'H-NMR (DMSO-ds) 5 2.24 (s, 3H), 2.15-2.30 (m, 2H), 2.60 (brs, 3H), 3.60-4.20 (m, 5H), 3.78-3.81 (m, 8H), 4.47-1.70 (m, 1H), 6.71-7.16 (rn, 7H), 7.77-8.00 (m, 4H), 8.48 (s, 1H), 8.55 (s. 1H), 9.21 (br S, 2H); MS (FAB) m/z 561 (M'+l); Anal, calcd for C),HMN,06HC1-1.4H,0: C, 59.83; H, 6.45; N, 9,00; CI, 5.70. Found: C, 60.08; H, 6.51; N, 8.68; CI, 5.99. Example 147 4 - [Iran j-4-dimethy lamino-1 - [ 3 -methoxy-4- [W-(2 -methyl phenyl)ureido ] pheny [acetyl ] -{25) -pyrrolidinyl]methoxybenzoic acid To a stirred solution oi frffrtJ-l-'er^Dutoxycartx)^y]-(2i>hydroxymeIhyI-4-hyd^oxypyTTolidi^e (2-17 g. 10.0 mmol) and imidazole [2.04 g, 30.0 mmol) inDMF (50 ml) was added TBDPS-C1 (3.03 g, 11.0 mmol) atO "C. The reaction mixture was stirred at room temperature for 18 hr. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over Na3SO To a stirred solution of ff-oni-l-/crr-butoxycarbonyl-(2S)-((er(-butyIdiphenyIsilyloxy) methyl-4-hydroxypynolidine (910 mg, 2.0 nunol) and Ph,P (628 mg, 2.4 mmol) in THF (20 ml) was added CBr. (993mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hr. n-Hexane (40ml) was added thereto. The resulting solid was filtered off, and dried in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (3:2, wv) as eluent to give ci's4-bromo-l-ter To a stirred solution of cw-4-broino-l-/?ri-butoxycarbonyi-(25)-(/ert-butyldiphcnylsilyloxy) methylpyrrolidine (480 mg, 0.93 mmol) in DMF (5 ml) was added NaN3 (241 mg, 3.70 mmol) at room temperature. The reaction mixture was stirred at 70 for 3 days. Water was added thereto, and extracted with EtOAc. The extract was washed with water, then dried over NajSO* and concentrated in vacua. The crude product was used to the subsequent reaction without further purification. The solution of the crude residue in EtOH (10 ml) was hydiogenated over 10% Pd-C . under an atmospheric pressure at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give iro«i-4-amino-l-(e«-butoxycaibonyl-(2S)-(/err-butyldiphenylsilyloxy)methj,lpyrroltdine (400 mg, 95%) as a colorless oil. 'H-NMR (CDC13) 5 1.06 (s, 9H), 1.32 and 1.45 (each s, total 9H), 2.20-2.35 (m. 1H), 3.05-3.18 (m, 1H), 3.55-4.05 (m, 6H), 7.35-7.41 (m, 6H), 7.61-7.69 (m. 4H). To a stirred solution of fronj-4-amino-l-ier/-butoxycarbonyl-(25)-((erf-butyldiphcn>,lsilyloxy) methylpyrroiidine (400 mg, 0.88 mmol), AcOH (120 m!, 2.0 mmol), and 37% HCHO aq (500 ml) inMeOH(10 ml) was added NaBHjCN(lllmg, 1.76 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH]C1,. The extract was dried over NajSO^ and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH3Cli (3:97, v/v) as eluent to give trans-1 -terl -butoxycarbonyl-(2S)-(/erf-buty Idip henyl si lyloxy)roethy 1-4-dimethylaminopyrrol idin e (330 mg, 78%) as a pale yellow oil. 'H-NMR (CDC13) 5 1.06 (s, 9H), 1.33 and 1.45 (each s, total 9H), 1.80-2.25 (ra, 2H), 2.23 (br s, 6H), 2.95^.05 (m, 6H), 7.36-7.39 (m, 6H), 7.63-7.65 (m, 4H). To a stirred solution of frflrtj-l-(e«-butoxycarbonyl-(2S)-(/e/-r-buryldiphenylsilyloxy)methyl-4-dimethylaminopyTTolidine (330 mg, 0.68 mmol) inTHF (5 ml) was added TBAF (1.0 M solution in THF, 1.0 ml, 1.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CHjCljp^ to 20:80, v/v) as eluent to give rronj-l-/ert-butoxycarbonyI-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (180 mg, quant) as a pale yellow oil. 'H-NMR (CDC13) 5 1.47 (s, 9H), 2.23 (s, 6H), 1.65-1.75 (m,2H),2.75-4.10 (m, 4H), 3.61 (d, J= 5.6 Hz, 2H). To a stirred solution of rro/iJ-l-fc^butoxycarbom/l-4-dimethyIamino-(25)-hydroxymethyl pyrrolidine (180 mg, 0.73 mmol), methyl 4-hydroxybenzoaie (114 mg, 0.75 mmol), and PhjP (296 mg, 1.13 mmol)inTHF(10ml)wasaddedDlAD(227mg, 1.13 mmol) at 0°C. The reaction mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) to MeOH-CHiCl}(5:95, v/v) as eluent to give methyl 4-[fran.M-rerNbuta>Q'carb«rryl-4-dimemylamino-(2S)-pyrrolidinyl]methoxybenzoate (180 mg, 68%) as a pale yellow oil. 'H-NMR (CDCIJ 5 1.46 (s, 9H), 1.80-1.95 (m, 1H), 2.20-2.23 (m, 1H), 2.24 (s, 6H), 2.90-2.95 (m, 1H), 3.10-3.30 (m, 1H), 3.50-3.65 (m, 1H), 3.88 (s, 3H), 3.95-4.35 (m, 3H), 6.93-6.95 (m, 2H), 7.96-7.98 (m, 2H). To a stirred solution of methyl 4-(frani--l-/ert-butoxycarbonyl-4-dimethylamino-(25)-pyrTolidinyl)methoxybenzoate (200 mg, 0.53 mmol) in CHjClj (6 ml) was added TFA (3ml) at 0°C. The reaction mixture was stirred ai room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the lesidue, and extracted with CH,Cli. The extract was washed with brine .dried over Na,SO,, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[A'-(2-methylpheny])uredio]pheny]acetic acid (166 mg, 0.53 mmol), HOBt (71 mg, 0.53 mmol). and triethylamine (140 ml, 1.10 mmol) in THF (5 ml) and MeCN (5 ml) was added EDC-HCI To a stirred solution of methyl 4-[/raraj-4-dimethylamino-I-[3-methoxy-4-[A"-(2-nethylphenyl) ureido] phenylaceryl]-2-pyrrolidinyl]methoxybenzoate (260 mg, 0.45 mmol) in THF 4.0 ml) and MeOH (2.0 ml) was added IN NaOH (0.90 ml, 0.90 mmol). The mixture was stirred it 70 °C for 24 hr. The mixture was concentrate in vacuo, water was added thereto, and leutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo o give 155 (200 mg, 79%) as a white crystalline solid. MW 560.64 mp 145-150 °C; m (KBr). 355, 2948, 1698, 1604, 1533, 1454, 1417, 1255, 1226, 1166, 1035, 755 cm"1; 'H-NMR (DMSO-6) 8 1.82-1.98 (m, lH), 2.08-2.11 (m, 1H), 2.20 (S, 6H), 2.25 (s, 3H), 3,40-3.60 (m, 3H), 3.64 (s, H), 3.82 (S, 3H), 4.01-4.16 (m, 2H), 4.36 (m, IH), 6.74-7.15 (m, 7H), 7.77-8.02 (m, 4H), 8.44 (s, H), 8.54 (s, 1H); MS (FAB) m/i 561 W+\); Anal calcd for Cj^K^O^l^Hp-. C, 63.95; H, .65; N, 9.62. Found: C, 63.82; H, 6.72; N, 9.44. Example 148 iethyl4-[fro«J-4-dimethyIamino-l-[3-methoxy-4-[A/'-(2-methylphenyl)ureido]phenylacetyl]-(25)- pyrroli dinyl)methoxybenzoate HC1 salt ureido] phenylacetyl-(2.S)-pyTTolidinyi]rnethoxybenzoic acid (80 mg, 0.14 mmol) in toluene (4,0 ml) and MeOH (1.0 ml) was added TMSCHNj (2.0 M in hexanc, 100 ml, 0.20 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hr. The mixture was concentrated, in vacua. The residue was purified by column chromatography on silica gel with MeOH-CH,C12(5;95, v/v) as eluent. The product was dissolved in EtOH (5.0 ml), and IN HC1 (in EtOH) (244u 1,, 0.244mmol) was added thereto. The mixture was concentrated in vacuo to give 156 (72 mg, 88%) as an amorphous solid. MW 574.67 IR(KBr) 3345, 2950, 2586,1712, 1604, 1511, 1454, 1284, 1255, 1170, 1114, 1029, 850, 771 cm"1; 'H-NMR (DMSO-d,) 5 2.25 (s, 3H), 2.35-2.37 (m, 2H), 2,77-2.81 (m, 6H), 3.62-3.71 (m, 2H), 3.79-3.81 (m, 8H), 3.99-4.16 (m, 3H), 4.50-4.70 (m, 1H), 6.74-7.16 (m, 7H), 7.77-8,01 (m, 4H), 8,48 (s, IH), 8.55 (s, YHy.AnaL calcdfor C32HMNA-I.0HC1 1.2 HjO: C, 60.74; H, 6.59; N, 8.85. Found; C, 61.03; H, 6.78; N, 8.33. 4-hydroxypyrrolidine (1.82 mg, 4.0 mmol), phthalimide (647 rag, 4.4 mmol), and Ph.jP (1.26 g, 4,8 mmol) in THF (20 ml) was added DIAD (889 mg, 4.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5/1, v/v) as eluent to give A'- [ci's-1 - To a stirred solution of Af-[cij-l-(erf-butoxycarbonyl-(2S)-(/c/-f-butyldiphenylsi]yloxy) methyl-4-pyrrolidinyI]phthalimide (1.60 g, 2.74 mmol) in EtOH (8 ml) was added NH,NHJ«HJO(206 mg, 4.11 mmol) at room temperature. The reaction mixture was stirred at 70 for 1 hr. The mixture was concentrated in vacuo. The resulting solid was filtered off, and washed with CHC13. The filtrate was concentrated in vacuo. The resulting solid was filtered off, and washed with CHClj. The filtrate was concentrated in vacuo to give eiJ-4-amino-l-/erf-butoxycarbonyl-(2.S)-( To a stirred solution of c«-4-amino-l-i'er/-butoxycarbonyl-(2S)-(rert-butyldiphenyl ilyloxy) methylpyrrolidine (1.24 g, 2.74 mmol). AcOH (374uJ, 5.48 mmol), and 37% HCHO aq (1.0 ml) in MeOH (20 ml) was added NaBH3CN (345 mg, 5.48 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH2C12. The extract was dried over NajS04. and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH,Cl, (3/97, v/v) as eluent to give ci^-l-(er^butoxycarbonyl-{2^-(rc^butyldphcny]silyloxy)memyl-4-dimethylamino pyrrolidine (l.lg, 83%) as a pale yellow oil. 'H-NMR (CDClj) 5 1.05 (s, 9H), 1.29 and 1.45 (each s, total 9H), 1.95-2.04 (m, 1H), 2.20-2.26 (m, 1H), 2.27 (s, 6H), 2.54 (m, 1H), 3.00-3.02 (m, lH), 3.62-4,03 (m, 4H), 7.34-7,41 (m, 6H), 7.63-7.65 (m, 4H). To a stirred solution of c/j-l-(erNbutoxycarbony 1-2-(/erf-butyldiphenylsilyloxy)methyl-4-diinethyl amino pyrrolidine (1,1 g, 2.27 mmol) in THF (10 mi) was added TBAF (1.0 M solution in THF) (4.5 ml, 4.5 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH3Cli (3/97 to 20/80, v/v) as eluent to give c/j-l-fcrZ-butoxycarbonyM-dimethylairuno-(2S)-hydroxymemylpyrrolidine (580 mg, quant.) as a pale yellow oil. 'H-NMR (CDC13) 8 1.47 (s, 9H), 1.25-1.96 (m, 2H), 2.25 {s, 6H), 2.53-2.58 (m, 1H), 3.17-4,02 (m, 5H). To a stirred solution of m-l-fe^butoxycarbonyI-4-dimethylamino-(25)-hydroxymethylpyrrolidine 1555 mg, 2,27 mmol), methyl 4'hydroxybenzoate (380 mg, 2.5 mmol), and Ph3P (1.07 g, 4.09 mmol) in THF (10 ml) was added DIAD (826 mg, 4,09 mmol) at 0 °C. The reaction mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica ge! with n-hexane-EtOAc (1/2, v/v)MeOH-CH,Clj(5/95, v/v) as eluent to give methyl 4-(ci.M-fe^buto>^carbonyL-4-dimethylanuw-(2SypyTTolidi:\yt)methoxy benzoate(260mg, 30%) as a pale yellow oil. 'H-NMR (CDCI3) 5 1.45 (s, 9H), 3.70-1.90 (m, 1H), 2.26 (s, 6H), 2.33 (m, IH), 2.57 (m, IH), 3.06 (m. 1H), 3.85-4.23 (m, 4H), 3.88 (s, 3H), 6.93 (m, 2H), 7.95 (m, 2H). To a stirred solution of methyl 4-(ci'j-I-i'ert-hutoxycarbonyl-4-climethylamino-(2^)-pyrrolidinyl) methoxybenzoate (208 mg, 0.55 mmol) in CH3C1, (6 ml) was added TFA (3ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHC03 was added to the residue, and extracted with CHjCl,. The extract was washed with brine .dried over Na3SO^, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[A"-(2-rnethyIphenyJ)uredio]phenylacetic acid (173 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), and triethylamine (153ul, 1.1 mmol) in THF (6 ml) and MeCN (6 ml) was added EDC-HC1 (160 mg, 0.83 mmol) at 0°C. The reaction mixture was .stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHC03, then dried over NajSOj, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-CHjClj-MeOH (5/95, v/v) as eluent to give methyl 4-[cw-4-dimethyIamino-]-[3-methoxyi4-[A'-{2-methylphenyl) ureido]phenyIacetyl]-(25)-pyiTolidinyI]methoxybenzoate (270 mg, 47%) as a colorless oil. 'H-NMR (CDCI,) 5 1.95-2.04 (m, 1H), 2.25 (s, 6H), 2.32 (s, 3H), 2.61 (m, 1H), 3.21 (m, IH), 3.56-3.58 (m, 5H), 3.80-3.83 (m, 1H), 3.88 (s, 3H), 4.18-4.20 (m, 1H), 4.41-4.45 (m, 2H), 6.36 (s, IH), 6.68-6.85 (m, 4H), 7.08-7.25 (m, 4H), 7.52-7.55 (m, IH), 7.91-8.07 (m, 3H). To a stirred solution of methyl 4-[c!s-4-dimethylamino-l-[3-methoxy-4-[iV'-(2-methy[phenyl) ureido] phenylacetyl]-(2S)-pyTTolidinyl]methoxybenzoate (270 mg, 0.47 mmol) in THF (4.0 ml) and MeOH (2.0 ml) was added IN NaOH (1.0 ml, 1.0 mmol). The mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 157 (170 mg, 65%) as a white crystalline solid. MW 560.64 mp 147-150 °C; IR (KBr) 3353,2952, 1700, 1604, 1533, 1454, 1415, 1255, 1166, 1035,755 cm'1', 'H-NMR (DMSO-d^) S :1.83-1.84 (m, IH), 2.08-2.10 (in, IK), 2.21 (or s, 6H), 2.24 (s, 3H), 3.00 (m, 2H), 3.60 (s, 2H), 3.78 (S, 3H), 3.85-4.29 (m, 4H), 6.71-7.16 (m, 7H), 7.77-8.01 (m, 4Hm), 8,46 (s, IH), 8.54 (s, lH)', MS (FAB) m/z 56] (M+H)'; Anal, calcdfor C3IHMNA"2 H,0: C, 62.40; H, 6.76; N, 9.39. Found: C, 62.51; H, 6.60; N, 9.36. Example 150 methyl 4-tc/j-4-dimethylamino-!-[3-mcthoxy-4-[iV'-(2-niethylpheiiyOiireido]phenylacctyl]-(25)- ureidojphcnylacetyl)-(2S)-pjTTolidinyl]methoxybenzoic acid (80 mg, 0.14 mmol) in toluene {4.0 ml) and MeOH (1.0 ml) was added TMSCHNj (2.0 M in hexane) (lOOuJ, 0.20 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CHjOi^W, v/v) as eluent. The product was dissolved in EtOH (5.0 ml), and IN HC1 (in EtOH) (244^1, 0.244mmol) was added thereto. The mixture was concentrated in vacuo to give 158 (75 mg, 79%) as an amorphous solid. MW 574.67 IR (KBr) 3345, 2950, 2456, 1712, 1646, 1604, 1511, 1454, 1434, 1415, 1284, 1257, 1168, 1114, 1031, 77] cm"'; 'H-NMR (DMSO-dj) 6 2.10-2.20 (m, 2H), 2.25 (s, 3H), 2.83 (m, 6H), 3.60-3.62 (m, 2H), 3.76-3.81 (m, 8H), 4.20-4.33 (m, 4H), 6.71-7.17 (m, 6H), 7.77-7.98 (m, 5H), 8.47 (s, 1H), 8.55 (s, 1); MS (FAB) m/z 574 (M+H)*; Anal, calcd for CJIHMNA' i-O-HCl 1.3 H,0: C, 60.57; H, 6.61; N, 8.83. Found: C, 60.80; H, 6.82; N, 8.44. Example 151 4 - [Irans- I - [4-[JV'-(2-chlorophenyl)ure i do] -3 -methoxylphenylacetyl ] -4 -dimethylamino-(2S) - pyrrohdinyl) methoxybenzoaie (430 mg, 1.1 mmol) in CHjCli (10.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CH2C1,. The extract was washed with brine, dried over Na3SO„ and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[y-(2-chlorapheny))uredio]-J-[nethoxyphenylacetic acid (368 mg, 1.1 mmol), HOBt (162 mg, 1.2 mmol), and tri«hyiamine(417ml, 3.0 mmol) inTHF(10.0 ml)andMeCN (10.0 ml) was added EDOHC1 (288 mg, 1.1 mmol) at 0 DC. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOJp 2-M citric acid, and sat. NaHCOj, then dried over NajSO^, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:1, v/v) as eluent to give 4-[(/-onj--l-[4-[Af'-{2K:hlorophenyl)ureido]-3-methoxylphenylaceryl]^^methylarnino-(25)-pyrrolidinyl]methoxy benzoate (530 mg, 78%) as a colorless oil. 'H-NMR (CDClj) 5 1.94-1.99 (m, 1H), 2.48 To a stirred solution of methyl 4-[trans-l-[4-[A'-(2-chlorophenyl)ureido]-3-methoxyl phenyl acetyl]-4-dimethy]anuno-(2S)-pyrrolidinyl]methoxyben2oate (190 mg, 0.32 mmol) in THF (3.0 mi) and McOH (2.0 mi) was added IN NaOH (0.64 mi, 0.64 mmol). The mixture was stirred at 70 °C for 24 hr. The mixture was concentrate in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 159 (150 mg, 83%) as a white crystalline solid. MW 581.06 mp 159-161°C; IR (KBr) 3318,2938, 1604,1531, 1438,1340 cm"1; 'H-NMR (DMSO-d*) 8 2.10-2.40 (m, 8H), 2.50-2,70 (m, 2H), 3.85-3.90 (m, 5H), 4.02-4.18 (m, 3H), 4.30-4,60 (m, 1H), 6.75-7.43 (m, 7H), 7.86-8.09 (m, 4H), 8.86 (s, 1H), 8.91 (s, 1H); MS (FAB) m/i 581 QA+U)';Anai. calcd for (V^NACH^HjO: C, 59,79; H, 5.92; N, 9.30, Found: C, 59.69; H, 5.93; N, 9.09. Example 152 4-[ci's-l-[4-[A'-(2-chlorophenyl)ureido)-3-methcxylphenylacetyl]-4-di methy lamino -(2S) - pyrrol idiny1]methoxybenzoic acid To a stirred solution of methyl 4-(ci$-l-[4-[W-{2-chlorophenyl)urcido]-3-meth.oxyl phenylacctyl]^-diniethylaiiiino-(25)-pyrroIidinyl]metho5cybcn2oate (250 mg, 0.42 mmol) in THF (5.0ml)andMeOH(3.0rnl)wasadded IN NaOH (1.0 ml, 1.0 mmol). The mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 160 (170 mg, 70%) as a white crystalline solid. MW 581.06 mp 165-167 °C;IR(KBr) 3328, 1604, 1531, 1164, 1033cm-';lH-HMR(DMSO-ds)6 1.80-1.90 (m, 1H). 2.20-2.50 (m, 7H), 3.60-3.70 (m, 2H), 3.77-3.81 (m, 5H), 4.00-4.30 (m, 4H), 6.72-7.44 (m,7H), 7.86-8,10 (m, 4H), 8.88-8.92 (m,2H).; MS (FAB) m/z 581 (M*+l), Anal, calcd for CJOHJJNACM.IHJO: C, 59.87; H, 6.06; N, 9.31. Found: C, 59.65; H, .5.76; N, 9.09. To a stirred solution of methyl 4-(c;'j-l-ferf-butoxycaibonyl-4-(2-naphthylsuJfonainido)-(2S)-pyrrolidinyl) methoxybenzoate (240 mg, 0.44 mmol) in CH,CI2 (5.0 ml) was added TFA, (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCO, was added to the residue, and extracted with CHjClj. 'The extract was washed with brine, dried over Na3SO^, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the Crude product, 4-[W-(2-chlorophenyl)uredio]-3-methoxyphenylacetic acid (147 mg, 0.44 mmol), HOBt (59 mg, 0.44 mmol), and triethylamine (275 ml, 1.9 mmol) in THF (6.0 ml) and MeCN (6.0 ml) was added EDC-HC1 (127 mg, 0.66 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over NajSO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:3, v/v) as eluent to give methyl 4-[CJ>1-[4-(A"- (2 -chiorophenyOureido]- 3 -me thoxyphertylacetyl ]-4- (2 - naph thai enesulfonamido)-(2i)-pyrrolidinyljmethoxybenzoate (200 mg, 65%) as a colorless oil. 'H-NMR (CDClj) 5 1.75-1.80 (m, 1H), 2.25-2.40 (m, 1H), 3.43 (s, 2H), 3.40-3.50 (m, 1H), 3,60 (s, 3H), 3.65-3.75 (m, 1H), 3.90 (s, 3H), 3.85-3.92 (m, IH), 3.95-4.00 , 7.23-7.36 (m,3H), 7.61-7.96 (m, 9H), 8.20 (d,J= 8.1 Hz, IH), 8.43 (s, IH). To a stirred solution of methyl (rij-l-(ert-butoxycarbonyl-4-(2-mesitylenesulfonamido)-(2S)- pvrrolidjnyl)meihoxybenzoate (170 mg, 0.32 mmol) in CH,C1, (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. KaHCOj was added to the residue, and extracted with CH3Clj. The extract was washed with brine .dried over NasSOH, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 4-rW-{2-bromophenyl)uredio]-3-methoxvphenylacetic acid (121 mg, 0.32 mmol), HOBt (43 mg, 0.32 mmol), and triethylamine (139 ml, 1.0 mmol) in THF (5.0 ml) and MeCN (5.0 ml) was added EDOHC1 (91 mg, 0.48 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over Na2SOA, and concentrated in vacuo. The residue was purified by column chromatography'on silica gel with n-hexane-EtOAc(l:4 ,v/v) as eluent to give methyl 4-[l-[4-[A'-(2 -bromophenyl)ureido] -3 -methoxyphenyl acetyl] -4 -(2-mesity lenesuIfonamido)-(2S)-pyTTOl idi nyl] methoxybenzoate (210 mg, 83%) as a colorless oil. 'H-NMR (CDClj) 5 1.85-1.90 (m, 1H), 1.95-2.05 (m, 1H), 2.32 (s, 3H), 2.60 (s, 6H), 3.40-3.50 (m, 3H), 3.60-3.70 (m, 2H), 3.6S (s, 3H), 3.89 (s, 3H), 3.96-3.99 (m, 1H), 3.35-3.45 (m, 1H), 3,70-3.75 (m. 1H), 6.00 {d, J= 9.5 H2, 1H), 6.57-7.08 (m, 9H), 7.29-7.34 (m, 1H), 7.51-7.53 (m, 1H), 7.92-7.96 (m, 3H), 8.15 (d,./= 6.8 Hz, 1H). To a stirred solution of methyl 4-[I-[3-methoxy-4-[^'-(2-bromophenyl)ureidoJpheny/acetyI]-4-(2-mesitylenesulfonamido-(25)-pyrrolidiryl]methoxyben2oate (210 mg, 0.26 mmol) jn THF (5.0 ml) and MeOH (3.0 ml) was added IN NaOH (0.47 ml, 0.47 mmol). The mixture was stirred at 70 DC for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with 1NHC1. The resulting solid was collected, washed with water, and dried in vacuo to give 162 (180 mg, 87%) as a white crystalline solid. MW 779.70 mp 130-132 °C; IR (KBr) 3332, 1689, 1604,1529, 1155 cm'1; 'H-NMR (DMSO-d*) 8 1.70-1.85 (m, 1H). 2.02-2.12 (m, 1H), 2.25 (s, 3H), 2.52 (s, 6H), 3.05-3.12 (m, 1H), 3.48 (s, 2H), 3.60-3.70 (m, 2H), 3.77 (s, 3H). 3.90^.20 (m, 3H), 6.59 (d, J= 8.3 Hz, 1H), 6.77-6.80 (m, 1H), 6.95-7.01 (m, 4H), 7.31-7.35 (m, 1H), 7.60 (d, J= S.I Hz, 1H), 7.86-7.97 4-[l-[4-[An-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-4-dansylamino-(25)-pyrTolidinyl] methoxybenzoic acid To a stirred solution of methyl 4-{cM-l-/er(-butoxycaibonyl-4-dansylamino-(25)-pyiTOlidinyI) uethoxybenzoate (200 mg, 0.34 mmol) in CH3CI, (5.0 ml) was added TFA (5.0 ml) at 0 °C The reaction mixture was stirred at room temperature for 0,5 hr. The mixture was concentrated in >acuo. Sat. NaHCOj was added to the residue, and extracted with CrijCIj. The extract was washed with brine .dried over NajS04, and concentrated in vacuo. The crude product was used to Jie subsequent reaction without further purification. To a stirred solution of the crude product, 4-[A^-(2-bromophtnyl)uredio]-3-methoxyphenylacetic acid (129 mg, 0.34 mmol), HOBt (46 mg, 0.34 mmol), and triethylamine (142 ml, 1.0 mmol) in THF (5.0 ml) and MeCN (5.0 ml) was added EDC'HCl (98 mg, 0.51 mmol) at 0 °C. The reaction mixture was stirred at room temperature for ) 6 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtQAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over NaiSO*, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(l:4 ,v/v) as eluent to give methyl 4-[l-[4-[A'-(2-bromophenyl) ureido]-3-methoxyphenylacetyi]4-d^sylarmno-(2^-pyrroIidinyl]methoxyben2oate (250 mg, 88%) as a colorless oil. 'H-NMR (CDClj) 5 1.55-1.65 (m, 1H), 2.15-2.25 (m, 1H), 2.87 (s, 6H), 3.20-3.35 (m, 3H), 3.50-3.55 (m, 1H), 3.67 (s, 3H), 3.78-3.81 (m, 1H), 3.S8-3.93 (m, ]H), 3.91 (s, 3H), 4,28-4.31 (m, 1H), 4.65-4.70 (m, 1H), 6,35 (d, 7= 9.5 Hz, 1H), 6.54 (d,J= 8.5 Hz, 1H), 6.63 (s, 1H), 6,90-7J3{m,6H), 7,22-7.31 (m, 2H), 7.50-7.56 (m, 2H), 7,88 {d, J= 8.0 Hz, 1H), 7.99 ( d, J = To a stirred solution of methyl 4^n'M-terNbutoxycaibonyl-4-methanesulfonamido-(2S)-pyrrolidinyl) methoxybenzoate (150 mg, 0.43 mmol) in CHjCl^ (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. SaL NaHCOj was added to the residue, and extracted with CH,Clj. The extract was washed with brine .dried over Na,SO(, and concentrated in vacua. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[#,-(2-bromophenyl)uredio]-3-methoxyphenylacetic acid (163 mg, 0,42 mmol), HOBt (58 mg, 0.43 mmol), and triethylamine (179 ml, 1.3 mmol) in THF (5.0 ml) and MeCN (5.0 mi) was added EDC-HC1 (144 mg, 0.75 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO* 2-M citric acid, and sat. NaHCO* then dried over Na2SO«, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4, vA-) to EtOH-EtOAc (10%, v/v) as eluent to give methyl 4-[4-memanesulfonamido-l-[4-[Ar'-(2-bromophenyl)ureido]-3-methoxypheiiyl acety!]-(2^-pynt)lidinyI]methoxybenzoate (210 mg, 73%) as a colorless oil. 'H-NMR (CDCI3) 5 1.95-2.00 (m, 1H), 2.55-2.65 (m, 1H), 2.17 (s, 3H), 3.55-3.70 (m, 1H), 3.60 (s, 2H), 3.67 (s, 3H), 3.85-3.90 (m, 1H), 3.89 (s, 3H), 3.95-4.18 (m, 2H), 4.45-4.55 (m, 1H), 4.70-4.80 (m, IH), 5.87 (d, J = 9.3 Hz, IH), 6.73-6.95 (m, 5H), 7.09 (s, 2H), 7.28-7.33 (m, 1H), 7.51 (d, J = 8.0 Hz, IH), 7.93-7.97 (m, 3H), 8.13 (d, J= 8.3 Hz, 1H). To a stirred solution of methyl 4-[4-methanesulfonamido-I-[4-[//'-(2-bromophenyl) ureido]-3-methoxyphenylacetyl]-(2S)-pyrroIidinyI]methoxybenzoate (210 mg, 0.3 mmol) in THF (5.0 ml) and MeOH (3.0 ml) was added IN NaOH (0.8 ml, 0.8 mmol). The mixture was stirred at 70 °C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC3. The resulting solid was collected, washed with water, and dried in vacuo to give 164 a?0mg,83%)asawhitecrysta]]inesDlid MW675.55 mp 125-128°C;TR(KBi)$353, 1689, 1604.1529, 1419, 1155 cm'1;'H-NMR (DMSO-dJS 1.88-2.00 (m. 1H), 2.35-2.45 (m, 1H), 2.96 (m, 3H), 3.15-3.23 (m, 1H), 3.60 (s, 2H), 3.SO-3.70 (m, IH), 3.7S (s, 3H). 3.80-3.90 (m, 1H), 3.95-4.05 (m, IH), 4.10-4.30 (m, 2H), 6.71-7.03 (m, 4H), 7.32 (m, IH), 7.45 (d, J= 6.8 Hz, IH), 7.60 (d, J = 7.8 Hz, IH), 7.87-7.95 (m, 4H), 8.74 (s, IH), 8.92 (s, IH); MS (FAB) m/z 675 (M*), 677 (M*+2); \Anat. calcdforCsH^NABrS-O.eHjO: C, 50.75; H, 4.73; N, 8.16. Found: C, 51.04; H, 4.62; N, 7.79. Eiamole 157 4-[l-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenylacetyl]-(2S)-octahydroindolylmethoxy] benzoic acid To a cooled (0°C), stirred solution of methyl 4-hydioxybenzoate (560 mg, 3.68 mmol), 1-(fcr/-butoxycaibonyl)octahydroJndolc-(25)-methajiol (940 mg, 3.68 mmol) and PhjP (1.16 g, 4.42 mmol) in THF (20 ml) was added DIAD (870 ml, 4.42 mmol) and the reaction mixture was heated under reflux for 8 hi. After cooled to room temperature, the mixture was evaporated. The residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl 4-[l-(/erf-butoxycaibonyl)-(2S)-ociahydroindolylmethoxy]benzoate (1.16 g, 81%) as a colorless oil. 'H-NMR (CDC13) 8 1.14-1.47 (series of s and m, total 13 H), 1.60-2.13 (series Of m, total 6 H), 2.22-2.28 (m, 1 H), 3.75-3.91 (series of s and m, total 4 H), 4.06-4.18 (m, 2 H), 4.37 (m, 1 H), 6.94-6.96 (m, 2 H), 7.96-7.98 (m, 2 H); MS (FAB) m/z 390 (M'+l). To a stirred solution of methyl 4-[l-(/er/-butoxycarbonyl}-(2£)-octahydroindolylmethoxy] enzaats (1.16 g, 2.98 mmoJ) in CHJCJJ (JO ml) was added TFA (JO ml) and the reaction mixture ras stirred at room temperature for 2 hr. The mixture was concentrated in vacuo, made basic by at. NaHCOj, and extracted with CHCl3. The extract was washed with brine, dned over K2CO3, nd evaporated to give methyl 4-[(2S)-octahydroindolylmethoxy]benzoate (860 mg, q.y.) as a rownoil. 'H-NMR (CDC13) 5 1.23-1.78 (series of m, total 10 H), 2.00-2.09 (m, 2 H), 3.14-3.18 m, I H), 3.55-3.62 (m, I H), 3.88 (s, 3 H), 3.96-4,06 (m, 2 H), 6.92 (d, J= 9.1 Hz, 2 H), 7.97 (d, / = 9.1 Hz, 2 H); MS (FAB) m/z 290 (M'+i). A mixture of 3-methoxy-4-[Af'-(2-methylphenyl)ureido]phenylacetic acid (298 mg, 0.95 ftmol), methyl 4-[(2S)-octahydroindo!ylmethoxy]benzoate (274 mg, 0.95 mmol), EDCHC1 (218 ng, 1.14 mmol), HOBt (154 mg, 1.14 mmol), Et3N (160 ml, 1.15 mmol) in THF (7 ml) was'stirred t room temperature overnight. The mixture was diluted with H30 and extracted with EtOAc. "he extract was washed with brine, dried over Na:SOj, and evaporated. The residue was purified y column chromatography on silica-gel with CHCl3-MeOH (100:1 to 50:1, v/v) as etuent to give nethy!4-[I-I3-methoxy-4-[A',-(2-methylphenyl)ureido]phenylacetyl]-(2S)-octahydroindolyl nethoxyjbenzoate (532 mg, 96%) as a white foam. 'H-NMR (CDCI3) 6 1.13-2.05 (scries of m, atal 9 H), 2.14-2.24 (m, 2 H), 2.26 (s, 3 H), 3.60 (s, 2 H), 3.62 (s, 3 H), 3.80-3.85 (m, 1 H). 3.88 S, 3 H), 4.27-4.37 (m, 3 H), 6.62 (s, 1 H), 6.74-6.76 (m, 2 H), 6.91 (d. J~ 8.8 Hz, 2 H), 7.09-7.13 m, 1 H), 7.20-7.24 (m, 3 H), 7.55 (d, J= 7.8 Hz, 1 H), 7.94 (d, J= 8.8 Hz, 2 H), 8.04 (d, J= 7.8 Iz, 1 H); MS (FAB) wi 586 (M*+l). To a stirred solution of methyl 4-[l-[3-methoxy4-[Ar'-(2-methylphenyl)ureido)phenyl icety]]-(2S)-octahydroindolylmethoxy]benzoate (532 mg, 0.91 mmol) in THF (5 m]) was added 0.5 J NaOH (5 ml) and the reaction mixture was heated under reflux for 3 hr. After cooled to room emperature, the mixture was poured into ice-1 N HC1, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHClj-EPE to give 165 (278 mg, 54%) as a while ;rystalline powder. MW 571.66 mp 130-134°C; 'H-NMR (DMSO-dJ S 1.16-2.10 (series of m, otal 9 H), 2.15-2.30 (series of S and m, total 4 H), 3.55-3.79 (m, 3 H), 3.81 (s, 3 H), 3.90-3.95 (m, . H), 4.17-4.23 (m, 2 H), 4.34-4.36 (m, 1 H), 6,72-6.74 (m, 1 H), 6.87-6.88 (m, 1 H), 6.91-6.95 m, 1 H), 7.03 (d, J= 8.8 Hz, 2 H), 7.10-7.16 {m, 2 H), 7.78-7,80 (m, I H). 7.87 (d, /= 8.8 Hz, 2 1), 7.98-8.00 (m, 1 H), S.45 (s, I H), 8.54 (s, 1 H), 12.61 (br s, 1 H); MS (FAB) m/z 572 (MVl); Ina/. Calcd for C^NAIMHA c, 68,79; H, 6.56; N, 7.29. Found: C, 68.70; H, 6.82; N, 6.97. Example 158 l-[l-[4-[A,'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(25)-octahydroindolylmethoxy] To a stirred solution of methyl 4-[l-[4-[A,'-(2-chJorophcnyl)urcido]-3-methoxyphenylaccty!]-(25)-octahydroindolylmetlioxyjbenzoate (550 mg, 0.91 mmol) inTHF(5 ml) was added 0.5 NNaOH (5 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperature, the mixture was poured into ice-1 NRC1, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCIj-IPE to give 166 (286 mg, 53%) as a white crystalline powder. MW 388.29 mp 133-136°C; 'H-NMR (DMSO-dJ S 1-16-2.10 {series of m, total 10 H), 2.24-2.27 (m, 1 H), 3.55-3.75 (m, 2H), 3.80 (s, 3 H), 3.90-3.96 (m, I H), 4.17-4.23 (m, 2 H), 4.34-4.36 (m, 1 H), 6.73-6.75 (m, 1 H), 6.88 (d, J = 1.5 Hz, 1 H), 6.99-7.05 (m, 3 H), 7.25-7.30 (m, 1 H), 7.43 (dd,J = 1.5, 8.1 Hz, 1 H), 7.87-7.89(m, 2H), 7.95(d,J=S.l Hz, 1 H), S.08(dd,J= 1.5, 8.3 Hz, 1H), 8.88 (s, 1 H), 8.92 (s, 1 H), 12.61 (brs, 1 H); MS (FAB) m/z 592 (M*+l);/W. Calcdfor C,IH3,C1NJO(1/4H20: C,64.42; H, 5.83; N, 7.04; CI, 5.94. Found: Q64.55; H.6.09; N.6.64; Cl,5.93. Example 159 4-[l-l4-[N'^2^Tomopheny])meido]-3'niel}ioxyphei]y}acety]]^2S} mg, 1.44 mmol), HOBt (196 mg, 1.45 mmol), and Et^N (200 ml, 1.43 mmol) in THF (7 ml) was stirred at room temperature overnight. The mixture was diluted with H,0 and extracted with EtOAc. The extract was washed with brine, dried over Na^., and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (100:1, v/v) as eluent to give methyl 4-[l-[4-[//'-{2-bromophenyl)ureido]-3-methoxyphenylacety] ]-(25)-octahydroijido]yl' methoxyjbenzoate (423 mg, 54%) as a white foam. 'H-NMR (CDCy 5 1.15-1.89 (series of m, total 8 H), 1.96-2.02 (m, 1 H), 2.16-2.32 (m, 2 H), 3.63 (s, 2 H), 3.65 (s, 3 H), 3.82-3.86 (m, 1 H), 3.88 (s, 3 H), 4.30-4.39 (m, 3 H), 6.75-6.77 (m, 2 H), 6.88-6.93 (m. 3 H), 7.24-7.31 (m, 1 H), 7.37-7.50 (m, 3 H), 7.91-7.99 (m, 3 H), 8.12-8.15 (m, 1 H); MS (FAB) mft 650 (M*+l). To a stirred solution of methyl 4-[l-[4-[A'-(2-bromophenyl)ureido]-3-methoxyphenyl iceryl]-(2S)-octahydroindolylmelhoxy]benzoate (420 mg, 0,65 mmol) in THF (5 ml) was added 0.5 J NaOH {5 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room emperature, the mixture was poured into ice-1N HCl, and the resulting precipitate was collected, 'he crude solid was recrystahized from MeOH-CHCIj-JPE to give 167 (197 mg, 48%) as a white rystalline powder. MW 636.53 mp H8-123°C; 'H-NMR (DMSO-d«) 5 1.16-2.27 (series of m, Dial 10 H), 3.56-3.75 (m, 3 H), 3.81 (s. 3 H), 3.90-3.96 (m. 1 H), 4.17-4.23 (m, 2 H), 4.34-4.36 m, 1 H), 6.73-6.75 (m, I H), 6.88-7.05 (m, 4 H), 7.30-7.34 (m, 1 H), 7.59-7.61, (m, 1 H), 7.87-,96 (m, 4H), 8.73 (S, 1 H), 8.91 (s, 1 H), 12.64 (br s, 1 H);MS (FAB) mh 636 W+\)\Anal :alcd for C3,H3,BrN,O6'l/4Hj0: C,59.96;H,5.42;N,6.55; Br,12.46. Found: C,60.12; H.5.86; 1,6.09; Br,12.47. temperature for 18 hr. Water was added to the mixture and extracted with EtOAc. The organic layer was washed with water, then dried over Na,SO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3 ,v/v) as eluent to give 3-fert-butoxYcarbonylUiiazolidine-4-carboxyIic acid (6,5 g, 74%) as a white crystalline solid. 'H-NMR (CDClj) 8 1.49 (br s, 9H), 3.20-3.30 (m, 2H), 4.09-4.87 (m, 3H). To a stirred solution of 3-/er/-butoxycarbonylthia2olidine-4-carboxylic acid (2.3 g, 10.0 mmol) in THF (30 ml) was added BH3-THF(1.0 M solution in THF, 20.0 ml, 20.0 mmol) at 0°C. After stirred at room temperature for 1.0 h, the reaction mixture was heated under reflux for 1.0 hr. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0°C, and extracted with EtOAc. The extract was washed with water, then dried over NajSO,, and concentrated in vacuo to give 3-ferNbutQxycarbonyl-5-hydroxymethylthiazolidine (2.0 g, quant) as a a colorless oil. 'H-NMR (CDC13) 6 1.48 (s, 9H), 2.80-2.85 (m, 1H), 3.13-3.17 (m, 1H), 3.20-3.30 (m, 1H), 3.64-3.70 (m, 2H), 4.34 (br s, 1H), 4.60 (br S, 1H). To a stirred solution of 3-«rt-butoxycarbonyl-5-hydroxymethylthiazolidine (1.9 g, 8.7 mmol), methyl 4-hydroxybenzoate (1.3 g, 8.7 mmol), and Ph3P (3.2 g, 12.2 mmol) in THF (10 ml) was added D1AD (2.2 g, 10.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc- n-hexane (1:9, v/v) as eluent to give methyl 4-(3-/err-butoxycarbonyl-4-ihiazolidinyl)methoxybenzoate(1.6g, 52% ) as a pale yellow oil. 'H-NMR (CDC13) 8 1.49 .(s, 9H), 3.11-3.19 (m, 2H), 3.88 (s, 3H), 4.04-4.31 (m. 3H), 4.61 (m, 2H), 6.'96 (d, J= 8,8 Hz, 2H), 7.98 (d, J= 8.8 Hz, 2H). To a stirred solution of methyl 4-(3-/er(-butoxycarbonyl-4-thiazolidinyl)methoxyben2oate (440 mg, 1.25 mmol) in CHiCl2 (6 ml) was added TFA (3ml) at 0 °C. The reaction mixture was stirred at room temperature far 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CHjClj. The extract was washed with brine .dried over Na,SOj, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (0.6 mmol), 3-methoxy-4-[fV-(2-methyl phenyI)uredio]phenylacetic acid (188 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), and triethylamine (280 ml, 2.0 mmol) in THF (5 ml) and MeCN (5 ml) was added EDC-HC1 (173 mg, 0.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over Na,S04. and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:3, v/v) as eluent to give methyl 4-[3-13-rnethoxy-4-[N'-(2-methylphenyI)ureido] phenyl]acetyI-4-thiazolidinyt] methoxybenzoaw (340 ing, quant) as an amorphous solid. 'H-NMR (CDC13) 5 2.31 (s, 3H), 3.15-3.16 (m, 2H), 3.67-3.69 (m, 5H), 3.88 (s, 3H), 4.09-4.14 (m, 2H), 4.22-4.90 (m, 3H), 6.30 (m, 1H), 6.74-6.96 (m, 4H), 7.11-7.25 (m, 4H), 7.49-7.51 (m, 1H), 7.95-8.12 (m, 3H). To a stirred solution of methyl 4-[3-[3-methoxy-4-[Ar'- 1.7 mmol) in CH,C]3 (6,0 ml) was added TFA (6.0 ml) at 0 °C. The reaction mixture was stirred al room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHC03 was added to the residue, and extracted with CH,Clj. The extract was washed with brine .dried over NajSOj, and concentrated in vacuo. The crude product was used to the subsequent reaction widiout further purification. To a stirred solution of the crude product, 4-[Af-(2-chlorophenyl)uredio]-3-methoxyphenylacetic acid (570 mg, 1.7 mmol), HOBt (230 mg, 1.7 mmol), and triethylamine (709 ml, 5.1 mmol) in THF (10.0 ml) andMeCN (10,0 ml) was addedEDCHC1 (490 mg, 2.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over Na,SO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:1, v/v) as eluent to give methyl 4-[3-[4-[ArH2-ch]orophenyl)iireido]-3-methoxyphenylacety]]-4-thiazolidinyl]methoxybenzoaie (900 mg, 93%) as a colorless oil. 'H-NMR (CDC13) 5 3.15-3.18 (m, 2H), 3.70 (s, 2H), 3.78 (s, 3H), 3.86 (s, 3H),4.09-4.93 (m, 5K),6.RO-7.01 (m, 5H), 7.19-7.35 (m,4H), 7.94-8.18 (m, 4H). To a stirred solution of methyl 4-[3-[4-[jV'-(2-chlDrophenyl)ureido]-3-methoxyphenylacety]]-4-thiazolidinyljmethoxybenzoate (900 mg, 1.6 mmol)inTHF(8.0ml)aiidMeOH(4.0ml) was added IN NaOH (3.1 ml, 3.1 mmol). The mixture was stirred at 70 °C for 24 hi. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 169 (780 mg, 89%) as a while crystalline solid. MW 556.03 mp 126-129 °C; IR (KBr) 3343, 2937,1604.1531,1421,1245, 1166, 1035, 752 cm'1; 'H-NMR (DMSO-d,) fi 3.06-3.24 (m, 2H), 3.72-3.85 (m, 5H), 4.02-4.27 (m, 3H), 4.53-4.76 (m, 2H), 6.74-7,44 (m, 7H), 7.87-8.30 (m, 4H), 8.89-8.95 (m, 2H); MS (FAB) m/z 556 (M*+l);Anal. calcd for ^H^NAClS-OJHjO: C, 56.93; H, 5.03; N, 7.38; CI, 6.22. Found: C, 56.89; H, 4.84; N, 7.42; CI, 6.35. 1.6 mmo!) in CHjClj (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHC03 was added to the residue, and extracted with CH2Clj. The extract was washed with brine ,dried over Na,S04, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[//'-(2-bromophenyl)uredio]-3-inethoxy phenylacetic acid (599 rng, 1.6 mmol), HOBt (213 mg, 1.6 mrool), and triethylamine (659 ml, 4.7 mmol) in Tiff (10.0 ml) and MeCN (10.0 ml) was added EDC-HC1 (455 mg, 2.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc, The extract was washed with sat. NaHCO,, 2-M citric acid, and sat, NaHCO,, then dried over Na2SO„, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (2:3, v/v) as eluent to give methyl 4-[3-[4-[W-(2-bromophenyl)ureido)-3-methoxyphenylacetyl]-4-thia2olidinyl] methoxybenzoate (870 mg, 89%) as a colorless oil. 'H-NMR (CDCIj) 5 3.00-3.20 (m, 3H), 3,70 (s, 2H), 3.81 (s, 3H), 3.88 (s, 3H), 4.09-4.23 (m, 1H), 4.42 (d, J= 8.5 Hz, 1H), 4.59 (d,y=» 8.5 Hz, 1H), 4.70-4.92 (m, 1H), 6.81-7.53 (m, 9H), 7,95-8.15 (m, 4H). To a stirred solution of methyl 4-[3-[4-{W-(2-bromophenvl)uieido]-3-methoKyphenylacctyI]-4-thiazolidinyl]methoxybenzoate (870 mg, 3.4 mmol) in THF (8.0 ml) and MeOH {8.0 m!) was added IN NaOH (2.8 ml, 2.8 mmol). The mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 170 (740 mg, 87%) as a while crystalline solid. MW 600.48 mp 125-133 °C; IR (KBr) 3332,2935,1604,1527, 1421,1245, 1166, 1027, 750 cnT1; 'H-NMR PMSO-d^) 5 3.01-3.25 (m, 2H), 3.72-3.85 (m, 5H), 4.02-4.30 (m, 2H), 4.54 (d, J = 8.8 Hz, 1H), 4.74-4.87 (m, 2H), 6.76-7.07 (m, 5H), 7.30-7.34 (m, 1H), 7.59 (d, J = S.l Hz, 1H), 7.86-7.98 (m, 4H), 8.74 (s, 1H), 8.92-8.94 (s, 1H); MS (FAB) m/z 600 (M'+l); yino/.calcd for C,,HMN3O,BrS-0.3H2O: C, 53.52; H.4.43 N 6.94 Found: C, 53.54; H, 4.45; N, 6.80, phenyI)uredio]pheny!acetic acid (6.28 g, 20.0 mmol), HOBt (71 mg, 0.53 mmol),'and triethylamine (5.5 ml, 40.0 mmol) in THF (50.0 ml) and MeCN (40.0 ml) was added EDC'HCl (5.7 g, 30.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The organic layer was washed with sat. NaHC03,2-M citric acid, and sat. NaHCOj, then dried over Na^SO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc to MeOH- CH,C1S (1:9, v/v) as eluent to give I-[3-methoxy-4-[tf'-(2-methy[phenyl) ureido]phenylacetyl]-2S'-pynolidinemcthanol (7.0 g, 89%) as a white crystalline solid, 'H-NMR (CDC13) 5 1.54-1.58 (m, 1H), 1.80-2,04 (m, 3H), 2.27 (s, 3H), 3.42-3.46 (m, 1H), 3.54-3.65 (m, 2H), 3,62 (s, 2H), 3.69 (s, 3H), 4.21-4.23 (m, 1H), 5.04 (m, 1H), 6.68-6.79 (m, 3H), 7.09-7.31 (m, 4H), 7.52 (d, J = 7.8 Hz, IH), 8.07 (d, J= 8.0 Hz, 1H). To a stirred solution of oxalyl chloride (0.3 ml, 3.3 mmol) in CHJCIJ (30.0 ml) was added DMSO (6.6 ml, 0.51 mmol) at -78 °C. After 5 minutes, to the mixture was added l-[3-melhoxy-4-[A'-(2- memylphenyl)uieido]pheny)acetyl]-2-pynolidinemethanoI {1.2 g, 3.0 mmol) in CH,Clj (5.0 ml). The mixture was stirred for 30 minutes at -78 °C, and triethylamine (2.1 ml, 15.0 mmol) was added. The mixture was stirred for 30 minutes at -78 °C, and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CH3C1,. The extract was washed with water, then dried over NajSO* and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, benzyl cis-4-aminocyciohexanccaiboxylatc (769 mg, 3.3 mmol), and AcOH (0.32 ml) in DCE (10 ml) was added NaBH(OAc)3 (1.1 g, 5.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCO, was added to the residue, and extracted with CH)CIj. The extract was washed with brine, dried over Na5SO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl, (1:9, v/v) as eluent to give ben2ylc/j-4-I[l-[3-methoxy-4-[JV'- To a stirred solution of benzylcis-4-[[l-J3-methoxy-4-[Af'-(2-methylphenyl)ureido]phenyI acetyl]-2-pyrTolidinyl]meuiylaiiu'no]cyclohexanecarboxylate (1.5 g, 2.45 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added IN NaOH(3.68 ml, 3.68 mmol). The mixture was stirred at 70 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH^Clj (1;5, v/v) as eluent to give c/j-4-[[l-[3-methoxy-4-[A^'-(2-methy!phenyl)ureido]phenylacetyl]-2-pyrrolidinyl]memy]ajnino]cyclohexanecarboxylic acid 171 (940 mg, 73% ) as an amorphous solid MW 522.64 IR (KBr) 3283, 2945, 2860, 1534, 1453, 1415 cm'1; 'H-NMR (DMSO-dJ 5 1.38-2.00 (m, 12H), 2.45 (s, 3H), 2.30-3.95 (m, AH), 3.22-3.75 (m, 2H), 3.58 (s, 2H), 3.86 (s, 3H), 4.12 (m, 1H), 6.73-7.16 (m, 5H), 7.77-7.79 (m, lH), 7.98-E.02 (m, 1H), 8.51-8.52 (m, 1H), 8,57-8.59 (m, 1H); MS (FAB) m/z 523 (M*+l); Anal calcd for C^NA-O-SNaCl^J^O; C, 58.89; H, 7.23; N, 9.47, Found: C, 59.21; H, 7.11; N, 9.11. Example 164 methyl dj4-Ul-[3-methoxy-4-tN,-(2-methylphenyl)urei do] phenyl acetyl]-2-pyrrolidinyl] methyl aminojeydohexanecarboxyiate HCI salt m«hylphenyl)urcido)phenylacetyl]-2-pyTTolidJny]]meIhylainino]cyclohexanecarboxylic acid (200 mg, 0.38 mmol) was added. The mixture was stirred at room temperature for 5 hr. The mixture was concentrated in vacuo, Aq. NaHC03 was added to the residue, and extracted with CHjOj. The extract was washed with brine, dried over NajSO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CHiCI3 (5:95 to 18:92, v/v) as eluent. The product was dissolved in EtOH (5.0 ml), and IN HC1 (in EtOH) (1.0 ml, 1.0 mmol) was added thereto. The mixture was concentrated in vacuo to give 172 (160 mg, 74%) as art-amorphous solid MW 536.66 IR (KBr) 3247, 2950, 2875, 1731, 1671, 1612, 1533, 1454, 1205 cm"1; 'H-NMR (DMSO-4s) 5 1.45-2.10 (m, 12H), 2.25 (s, 3H), 2.60-2.70 (m, 1H), 2.90-3.20 2-pyTTolidinyl]methylamino]cyclohexanecarboxylate (300 mg, 0.55 mmol), HCHO (300 ml), and AcOH (66 mg, 1.1 mmol) in MeOH (10.0 ml) was added NaBH3CN (70 jug, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH]C13. The extract was washed with water, then dried over Na2SO,, and concentrated in vacuo. The residue was purified by TLC with MeOH-CH3Cl3 (3:97, v/v) as eluent to give methyl 4-[W-[l-[3-methoxy-4-[W-(2-methy5pherJyl)uicido]phenylacetyI]-2-pytrolidinylmethyl]-W-methylamino] cyclohexanecarboxylate (160 mg, 52%) as an amorphous solid. 'H-NMR (CDClj) 5 1.30-2.20 (m, 12H), 2.27-2.37 (m, 6H), 2.50-2.60 (m, 1H), 3.30-3.80 (m, 5H), 3.55 (s, 2H), 3.66-3.73 (m, 6H), 4.10-4,20 (m, 1H), 6.60-7.55 (m, 7H), 8.03 (m, 1H), 8.15 (m, 1H). To a stirred solution of methyl 4-[A'-[l-[3-methoxy-4-[A',-(2-methy]phcnyl)ureido]phenyIacetyl]-2-pyrrolidinylmethy]l-A'-melhylamino]cyclohexanecarboxylale (100 mg, 0.18 mmol) in THF (5.0 ml) and MeOH (2.5 ml) was added IN NaOH (0.36 ml, 0.36 mmol). The mixture was stirred at 60 °C for 18 hr. The mixture was concentrated in vacuo, waier was added thereto, and neutralized with 1NHC1. The mixture was concentialed in vacuo. The residue was purified by TLC with MeOH-CHjClj (1/4, v/v) as eluent to give 173 (10 mg, 10%) as an amorphous solid. MW 536.66 TR (KBr) 3440, 2954, 1697, 1533, 1454 on"1; 'H-NMR (DMSO-d«) 5 1,20-2.30 (m, 13H), 2.24 (s, 3H), 2.35-4,00 (m, 13H), 6.50-8.10 (m, 8H), 8.50 (m, 1H); MS (FAB) m/z 537 (M*+l); Anal, calcd for CjoH^O^.ONaCl-O.SI^O: C, 53.94; H, 6.28; N, 8.39. Found: C, 54.08; H, 6.52; N, 8.04. mmol) and 5%Rh on alumina (500 mg) inEtOH(10.0ml)and AcOH(I.O ml) was hydrogenated at room temperature at 5 atm for 36 hi. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtO Ac (6:1, v/v) as eluent to give methyl cij--4-[( l-lerl-butoxycarbonyl-(2S)-pyrrDlidinyl) methoxy]cyc!ohexanecarboxylate (900 mg, 89%) as a pale yellow oil. 'H-NMR (CDC13) 5 1.46 (s, 9H), 1.46-2.00 (m, 12H), 2.34 (m, 1H), 3,20-3.55 (m, 5H), 3.67 (s, 3H), 3.84-3.92 (m, lH).- To a stirred solution of methyl c;j-4-[(I-(er/-butoxycarbonyl-(2S)-pyrroIidinyl)methoxy] cyclohexanecarboxylate (900 mg, 2.6 mmol) in CH,C12 (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred a! room temperature for 0.5 hr. The mixture was concentrated in vacua. Sat. NaHCO, was added to the residue, and extracted with CHjClj, The extract was washed with brine, dried over NajSO,, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 3-methoxy-4-[W-( 2-mewylpheny])uredio] phenyl acetic acid (260 mg, 0.83 mmol), HOBt (135 mg, 1.0 mmol), and triethylamine To a stirred solution of methyl 4-[[l-[3-methoxy-4-[A',-(2-methyIprienyl)ureido] phci\yla«tyl}H2S)-pyrToUiiinyl]nicthoxy]cydohexaiiecaiboxylate (460 mg, 0.86 mmol) in THF (10.0 ml) and EtOH {5.0 ml) was added IN NaOH (1.4 ml, 1.4 mmol). The mixture was stirred at 60 °C for 18 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HCI. The resulting solid was collected, washed with water, and dried in vacuo to give 174 (370 mg, 83%) as a white crystalline solid. MW 523.63 mp 110-113 "C;IR (KBr) 3345, 2937, 1612,1533, 1454 cm"1; 'H-NMR (DMSO- carboxylate (900 mg, 2.6 mmol) in CH,CIi (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHC03 was added to the residue, and extracted with CHjCl3. The extract was washed with brine .dried over Na2SO(, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 4-[y-(2-chlorophenyl)uredio]-3-methoxyphenylacetic acid (277 mg, 0.83 mmol), HOBt (135 mg, 1.0 mmol), and triethylamine (344 ml, 2.48 mmol) in THF (10.0 ml) and MeCN (10.0 ml) was added EDOHC1 (238 mg, 1.24 mmot) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO,. 2-M citric acid, and sat. NaHCO,, then dried over NajSO,, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1-.6, v/v) as eluent to give methyl 4-[[l-[4-[f/'-(2 -chloropheny l)u reido] -3 -methoxylph eny lacety 1} -(2S)-pyrrol idiny 1] methoxy] cyclohexane carboxylate (450 mg, 97%) as a colorless oil. 'H-NMR (CDClj) 6 1.35-2.15 (m, 12H), 2.25-2.40 (m, 1H), 3.40-3.70 (m, 5H), 3.61 To a stirred solution of methyl 4-[[l-[4-[Af'-(2-chlorophenyI)ureido]-3-mcihoxylphcnylacetyll-(2i)-pyrrolidinyljrnethoxyjcyclohexariecarboxylate (450 mg, 0,86 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added IN NaOH (1,4 ml, 1.4 mmol). The mixture was stirred at 70 °C for 24 hi. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HCI. The resulting solid was collected, washed with water, and dried in vacuo to give 175 (370 mg, 84%) as a white crystalline solid. MW 544.04 mp 111-115 °C;IR(KBr) 3330,2938, 1704,1594, 1533,1438, 1199 cm-1; 'H-NMR (DMSO-dJ 6 1.00-2.00 (m, 12H), 2.20-2.30 (m, IH). 3.20-3.80 (m, 5H), 3.55 (s, 2H), 3.85 (s, 3H), 4.00-4.20 (m, IH), 6.73-6.75 (m, IH), 6.87 (s, IH), 6.99-7.03 (m, IH), 7.25-7.29 (m, IH), 7.42 (d, J= 7.1 Hz, IH), 7.95 (d, J= 8.3 Hz, IH), 8.08 (d, J= 8.0, IH), 8.78 (s, IH), 8.92 (s, IH); MS (FAB) mh 544 QA^\)\Anal. calcd for Cj,HMN3O6CI-0.2H,O: C, 61,41; H, 6.33; N, 7.67; CI, 6,47. Found: C, 61.37; H, 6.32; N, 7.56; CI, 6.55, carboxylate (900 mg, 2.6 mmol) in CHjC^ (5,0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CH,CIj. The extract was washed with brine, dried over NajSO«, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 4-[A'-(2-bromophenyl)uredio]-3-methoxyphenylacetic acid (314 mg, 0.83 mmol), HOBt (135 mg, 1.0 mmol), and triethylamine (344 ml, 2.48 mmol) in THF (10.0 ml) and MeCN (10,0 ml) was added EDC-HC1 (238 mg, 1.24 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over NajSO To a stirred solution of methyl 4-[l-[4-[N'-(2-bromophenyl)uieido]-3-mcthoxylphenylacetyl]-(25>-pynolidinyljmethoxyc^clohexanecarboxylate (450 mg, 0.74 mmol) in THF (10.0 m!) and MeOH (5.0 mJ) was added INNaOH(1.2ml, 1.2 mmol). The mixture was stirred at 70 °C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized witii IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 176 (340 mg, 77%) as a white crystalline solid. MW 588.49 mp 108-111 °C; IR(KBr) 3328,2938,1702, 1594, 1529, 1434 cm'1; 'H-NMR (DMSO-dj) 8 1.00-2.00 (m, 12H), 2.15-2.25 (m, 1H), 3.40-3.75 (m, 5H), 3.48 (s, 2H), 3.85 (s, 3H), 4.04-4.15 (m, 1H), 6.70-6.72 (m, 1H), 6.87 (s, 1H), 6.94-6,98 (m, 1H), 7.29-7.33 (m, 1H), 7.59 (d, J= 8.1 Hz, 1H), 7.93-7.95 (m, 2H), 8.73-8.74 (m, 1H), 8.91-8.92 (m, 1H); MS (FAB) wi 589 (M*+l); ^na/. calcd for CjsHnNjO^rO^O: C, 56.80; H, 5.86; N, 7.10; Br, 13.49. Found: C, 56.66; H, 5.83; N, 6.97; Br, 13.66. carboxylate (450 mg, 1.3 mmol) in CH,C13 (5.0 ml) was added TFA (5.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CH2Cl2. The extract was washed with brine, dried oyer Na;SOi, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[A',-(2-methylphenyl)uredio]phenylacetic acid (375 mg, 1.3 mmol), HOBt (178 mg, 1.3 mmol), and triethylamine (550 ml, 3.9 mmol) in THF (6.0 ml) and MeCN {6.0 ml) was added EDC-HC1 (380 mg, 1.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat NaHCOj, then dried over Na,SO«, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:6, v/v) as eluent to give methyl 4-[[l-[4-[A'-(2-methylphenyl)urcido] phenylacetyl]-(2S)-pyiTolidinyl]methoxy]cycIohexanecarboxylate (520 mg, 78%) as a colorless oil. 'H-NMR (CDClj) 5 1.30-2.40 (m, 13H), 2.21 (s, 3H), 3.30-3.80 (m, 7H), 3.65 (s, 3H), 4.10-4.30 (m, 1H), 6,90-7.20 (m, 8H), 7.40-7.70 (m, 2H). To a stirred solution of methyl 4-[[3-[4-[M-(2-methylphenyl)ureido]phenylacetyI]-(2S)-pyi7olidinyl]methoxy]cydohexanecarboxylate (520 mg, 1.0 mmol) in THF (10.0 ml) and McOH (5.0 ml) was added IN NaOH (1.5 ml, 1.5 mmol). The mixture was stirred at 70 °C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 177 (450 mg, 91%) as a white crystalline solid. MW 493.60 mp 107-111 °C; IR(KBr) 3353, 2938, 1704, 1540, 1454, 1240 cm"1;'H-NMR (DMSO-4) 8 1.20-2.00 (m, 12H), 2.23 (s,3H), 2.22-2.24 (m, 1H), 3.20-3.80 (m, 7H), 4.00-4.18 (m, 1H), 6.90-6.94 (m, 1H), 7.10-7.16 (m, 5H), 7.36-7.38 (m, 2H), 7.82-7.87 (m, 2H), 8.89 (s, 1H), 12.0 (br s, 1H); MS (FAB) mh 494 (M*+l); ^na/. calcd for CJIHJJNJOJ-OJHJO: C, 67.64; H, 7.18; N, 8.45. Found: C, 67.66; H. 7.19; N, 8.24. mmol) in THF (10.0 ml) was addedBH3-THF(I,0M in THF, 8.0ml)at0°C. After stirred at room temperature for 1.0 h, the reaction mixture was heated under reflux for 1.5 hr. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0°C, and extracted with EtOAc. The extract was washed with water, then dried over Na3SO«, and concentrated in vacuo to give [1-/er/-butoxycarboyl-(23)-octahydroindolyl]methanol (947 mg, quant) as a a colorless oil. To a stirred solution of [l-fer/-butoxycarboyl-(2S)-octahydroindolyl]methanol (947 mg, 3.7 mmol), methyl 4-hydroxybenzoaie (565 mg, 3.7 mmol), and Ph,P (1.2 g, 4.5 mmol) in THF (10 ml) was added DIAD (984 mg, 4.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (9/1, v/v) as eluent to give methyl 4-[l-/er/-butoxycarbonyI-(2^)-octahydroindolylmethoxy]benzoate (700 mg, 50%) as a pale yellow oil. 'H-NMR (CDC13) 5 1.10-2.25 (m, 11H), 1.45 (s, 9H), 3.88 (s, 3H), 3.70-4.20 (m, 3H), 4.36 (br s, 1H), 6.94 (d, J= 8.8 H z, 2H), 7,96 (d, J= 8.5 H z, 2H). A mixture of methyl 4-[l-(ert-bu!oxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 1.8 mmol) and 5%Rh on aJumina (400 mg) in ElOH (10.0 ml) and AcOH (1.0 ml) was hydrogcnatcd at room temperature at 5 atm for 48 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give methyl cJS-4-n-ler(-buloxycarbonyl-(2S)-ociahydro indolylniethoxy]cyclohexanecarboxylate (600 mg, 85%) as a pale yellow oil, 'H-NMR (CDCl3) 8 1.10-2.35 (m, 20H), 1.44 (s, 9H), 3.45-3.90 (m, 5H), 3.80 (s, 3H). To a stirred solution of methyl c;j-4-[l-i,crf-butoxycarbonyl-(2S)-octahydroindolylmcthoxy] cyclahexanecaiboxylate (600 mg, 1,5 mmol) in CBjCl^ (6.0 ml) was added TFA (6.0 ml)atQ°C. The reaction mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. Sat. NaHC03 was added to the residue, and extracted with CHjClj. The extract was ■ washed with brine, dried over Na,S04, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (221 mg, 0.75 mmol), 4-[W'-(2-chlorophenyJ)uredio]-3-methoxyphenylacetic acid (250 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), and triethylamine (312 ml, 2.3 mmol) in THF (10.0 ml) and MeCN (10.0 ml) was added EDCHC1 (216mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hi, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO,, 2-M citric acid, and sat. NaHCOj, then dried over NajS0lp and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(l:3, v/v) as eluent lo give methyl CJ'S-4-[1-[4-[A'-(2-chloropheny 1 Jureido] -3 -methoxy lpheny iacety 1] -(25) -octahydroi ndoly lmethoxy] cyclohexane carboxylate (430 mg, 94%) as a colorless oil. 'H-NMR (CDClj) 5 1.10-2.40 (m, 20H), 3.45- (br s, 1H), 3.62 (S, 2H), 3.66 (s, 3H), 3.73 (s, 3H), 3.60-3.85 (m, 2H), 4.09-4.14 (m, 2H), 6.75-6.98 (m, 3H), 7.22-2.46 (m, 4H), 7.92 (d, J = 8.0 Hz, 1H), 8.18 (d, J= 8.3 Hz, 1H). To a stirred solution of methyl c/j-4-[l-[4-[Af'-(2-chlorophenyl)ureido]-3-methoxylphenylacetyl]-(2iS)-octahydroindolylmethoxy]cyclohexanecaiboxyIate (430 mg, 0.7 mmol) in THF (10.0 ml) and MeOH(5.0ml)was3ddedlNNaOH(l,4ml, 1.4 mmol). The mixture was stirred at 70 °C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to givel78 (360 mg, 86%) as a white crystalline solid. MW 598.13 mp 120-121°C; IR (KBr) 3338, 2933, 2859, 1614,1533, 1438 cm"'; 'H-NMR (CDClj) 6 1.05-2.40 (m, 20H), 3,38-3.50 (m, 2H), 3.63 and 3.65 (each s, tola! 2H), 3,71 and 3.75 (each s, total 3H), 3.70-3.80 (m, 1H), 3.93-3.97 (m, 1H), 4.15 (br s, IH), 6.75-6.77 (m, 2H), 6.93-6.97 8.3 Hz, 1H), 8.16 (d, J= 8.3 Hz, 1H); MS (FAB)m/z 598 flvf+l);^/. calcdfor CHH^O.CI-0.5H,O: C, 63.30; H, 6.81; N, 6.92; CI, 5.84. Found: C, 63.68; H, 6.81; N, 6.81; CI, 5.98. cyclohexanecarboxylate (600 mg, 1.5 mmol) in CHjCl2 (6.0 ml) was added TFA (6.0 ml) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hi. The mixture was concentrated in vacuo. Sat. NaHCOj was added to the residue, and extracted with CHjClj. The extract was washed with brine .dried over NajSOi, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (221 mg, 0.75 mmol), 4-[W-(2-bromophenyl)uredio]-3-methoxyphenylacetic acid (284 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), and triethylamine (312 ml, 2.3 mmol) in THF {10.0 ml) and MeCN (10.0 ml) was added EDC-HCl(216mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat NaHC03, 2 M citric acid, and sat. NaHCOj, then dried over NaiSOj, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc(l:3 ,v/v) as eiuent to give methyl c/s-4-(l-[4-[JV'-(2-bromophenyl)ureido]-3-methoxylphenyiacetyI]-(2S)-octahydroindolylmcthoxy] cyclohexane carboxylate (480 mg, 96%) as a colorless oil. 'H-NMR (CDC1S) 5 1.10-2.40 (m, 20H), 3.45 (brs, 1H), 3.61 (s, 2H), 3.66 (s, 3H), 3.76 (s, 3H), 3.60-3.80 (m, 2H), 4.11-4.14 (m, 2H), 6.76-6.92 (m, 3H), 7.25-7.32 (m, 3H), 7.49 (d, J= 7.1 Hz, 1H), 7.90 (d, J= 8.0 Hz, 1), 8.13 (d, J= 8.0 Hz, 1H). To a stirred solution of methyl cis-4-[l-[4-[A',-(2-bromophenyl)ureido]-3-methoxylphenylacetyl]-(2S)-octahydroindolylmethoxy]cycIohexanecarboxylate (480 mg, 0.73 mmol) in THF (10.0 ml) and MeOH (5.0 ml) was added IN NaOH (1.5 ml, 1.5 mmol). The mixture was stirred at 70 "C for 24 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 179 (400 mg, 85%) as a white crystalline solid. MW 642.58 mp 115-120 °C; IR (KBr) 3332,2933, 2859, 1704, 1592, 1529, 1434 cm'1; 'H-NMR (CDC13) 5 1.10-2.40 (m, 20H), 3.40-3.50 (m, 2H), 3.61 and (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol), and triethylamine (1.6 ml, 11.6 mmol) in CH,Clj (30,0 ml) was added EDC-HC1 (I.Ig, 5.8 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over Na,SOt, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give benzylm-4-[(I-(er(-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxyIate (600 mg , 36%) as an amorphous solid. 'H-NMR (CPCI3) 5 1.44 (s, 9H), 1.50-1.90 (m, 12H), 2.20-2.26 (m, 1H), 3.25-3.50 (m, 2H), 3.80-3.90 (m, lH), 4,10-4.25 (m, 1H), 5.12 (s, 2H), 7.35-7.36 (m, 5H). To a stirred solution of bei^lci'j-4-[(l-/er(-butoxycarbonyl-2-pyrTolidinyI)cairx)nylamino] ■ cyclohexanecarboxylatc (600 mg, 1.4 mmol) in CH^Clj (6.0 ml) was added TFA (3.0 ml) at 0 "C. The reaction mixture was stirred at room temperature for 0,5 hi. The mixture was concentrated in vacuo. Sat. NaHCOj was added to die residue, and extracted with CHjCl3. The extract was washed with brine, dried over NajSOj, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (300 mg, 0.7 mmol), 3 -methoxy -4- [W-(2-methylphenyl)uredio] phenyl acetic acid (220 mg, 0.7 mmol), HOBt (94 mg, 0.7 mmol), and triethylamine (291 ml, 2.1 mmol) in THF (10.0 ml) and MeCN (10.0 ml) was added EDCHC1 (201 mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCOj, 2-M citric acid, and sat. NaHCOj, then dried over NaiSO,, and concentrated in vacuo. The resulting solid was collected and washed with EtOAc to give benzyl 4-[ [H3-methoxy-4-[iV'-(2-methyl phenyl )ureido] phenyl a cetyl]-2-pyTTolidinyl]carbonylamino]cyclohexanecarboxy late (380 mg, 87%) as a white crystalline solid. 'H-NMR (CDC1,) 5 1.40-2,15 (m, 12H), 2.23 (m. 3H), 2.30-2.50 (in, 2H), 3.40-3.55 (m, 2H), 3.61 (s, 2H), 3.71 (s. 3H), 3.82 (m. 1H), 4.53 (d,./ = 6.3 Hz, 1H), 5.10 (s, 2H). 6.42 {s, 1H), 6.77-6.79 (m, 2H), 7.04-7.34 (m, 9H), 7.50-7.52 (m, 1H), 8.05-8.07 (m, 1H). To a stined solution of benzyl 4-[[l-[3-methoxy-4-[//'-(2-methylphenyI)ureido]phenylacetyl]-2-pyrrolidiiryl]carbonylaminojcyclohexanecarboxylate (380 rag, 0.6 mmol) in THF (10.0 ml) and EtOH (5.0 ml) was added IN NaOH (0.9 ml, 0.9 mmol). The mixture was stirred at 50 °C for 18 hi. The mixture was concentrated in vacuo, water was added thereto, and neutralized with IN HC1. The resulting solid was collected, washed with water, and dried in vacuo to give 180 (230 mg, 71%) as a white crystalline solid. MW 636.62 mp 136-142 °C; IR(KBr) 3345, 2940, 1650, 1625, 1535,1454 cm"'; 'H-NMR (DMSO-d.) 8 1.40-2.00 (m, 12H), 2.24 (s, 3H), 2.30-2.40 (m, 1H), 3.45-3.80 (m, 5H), 3.86-3.87 (m, 3H), 4.30-4.43 (m, 1H), 6.65-7.30 (m, 5H), 7.70-7.80 (m, 1H), 7.98-8.09 (m, 1H), 8.46-8.57 (m, 1H); MS (FAB) mh 537 (MN-l)Mna/. calcd for CMHJ^NA-0-5 H,0: C, 63.84; H, 6.83; N, 10.27. Found: C, 64.18; H, 6.91; N, 9.85. vacuo. Sat. NaHCOj was added to the residue, and extracted with CH,C13. The extract was washed with brine, dried over Na3S04, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product (300 mg, 0.7 mmol), 4-[W-(2-ch]orophenyl)uredia]-3-melhoxyphenylacetic acid (237 mg, 0.7 mmol), HOBt (94 mg, 0.7 mmol), and triethylamine (291 ml, 2.1 mmol) in THF (10.0 ml) and MeCN(10.0 ml) was added EDC-HC1 (201 mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO], 2-M citric acid, and sat. NaHCO,, then dried over NajSOj, and concentrated in vacuo. The resulting solid was collected and washed with EtOAc to give benzyl 4-[[l-[4-[Ar'-(2-chlorophenyl)ureido]-3-methoxyl phenylacetyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylate (310 mg , 68%) as a white crystalline solid. 'H-NMR (CDC13) 5 1.40-2.15 (m, 12H), 2.30-2.60 (m, 2H), 3.42-3.55 (m, 2H), 3.64 (s, 2H), 3.84 (s,3H),4.55 (d, J=6.1Hz, 1H),5.12 (s,2H), 6.81-7.35(m,]2H),7.96-7.98 (m, IH), 8.17-8,19 (m, IH). To a stirred solution of methyl benzyl 4-[[l-[4-[W-(2 After cooled to room temperature, the mixture was evaporated. The residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give methyl 4-[ i-benzyl-(3S)-pyrrolidinyloxy]benzoate (3.66 g, 97%) as a pale yellow oil. 'H-NMR (CDCIJ 6 1.95-2.02 (m, 1 H), 2.28-2.37 (m. 1 H), 2.57-2.63 (m, 1 H), 2.72-2.81 (m, 2 H), 2.96-3.01 (m, 1 H), 3.63-3.71 (m, 2 H), 3.87 (s, 3 H), 4.84-4.89 (m, I H), 6.84 (d, J - 8.8 Hz, 2 H), 7.23-7.34 (m, 5 H), 7.95 (d, .7=8.8 Hz, 2 H). A solution of methyl 4-[]-benzyl-(3i)-pyrrolJdiny)c«y]benzoate (3.66 g, 11.8 mmol) in MeOH {25 ml) was hydrogenated over Pd(OHyC (0.73 g, 20 wt%) overnight. The reaction mixture was filtered to remove the calaJyst and the solution was evaporated to give methyl 4-[(35)-pyrrolidinyloxy]benzoate (2.60 g, q.y.) as a pale yellow oil. 'H-NMR (CDCij) 5 1.94-2.01 (m, 2 H), 2.09-2.18 (m, I H), 2.91-2.97 (m. 1 H), 3.04-3.09 (m, 1 H), 3.16-3.23 (m, 2 H), 3.88 (s, 3 H), 4.884.91 (m, I H), 6.86 (m, 2 H), 7.96-7.98 (m, 2 H); MS (ESI) m/z 222 (M*+l). A mixture of 3 - me thoxy-4-[// '-(2 -methyl phenyl) ureido]phenylacctic acid (449 mg, 1.43 mmol). methyl 4-[(3S)-pyTTolidinyloxy]benzoate (316 mg, 1.43 mmol), EDCHC1 (330 mg, 1.72 mmol), HOBt (193 mg, 1.43 mmol), and EtjN (240 ml, 1.72 mmol) in THF (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with HjO, and extracted with EtOAc. The extract was washed with brine, dried over NajSOi, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (100:1 to 50:1, v/v) as eluent to give methyl 4-[l-[3-methoxy-4-[Ar'-(2-methy!phenyl)ureido]phenylacetyl]-(35)-pyrrolidinyloxy] benzoate (735 mg, 99%) as a pale yellow oil. 'H-NMR (CDClj) 5 2.03-2.31 (series of s and m, total 5 H), 3.57-3.78 (series of m, total 9 H), 3.88 (s, 3 H), 4.954.99 (m, I H), 6.73-7.00 (m, 5 H), 7.06-7.10 (m. 1 H), 7.18-7.22 (m, 2 H), 7.42-7.46 (m, 1 H), 7.57-7.62 (m, 1 H), 7.95-8.08 (m, 3 H); MS (ESI) m/z 518 (M*+l). temperature overnight. The reaction mixture was diluled with H,0, and extracted with EtOAc. The extract was washed with brine, dried over NajSOj, and evaporated. The residue was purified by column chromatography on silica-gel with CHCIj-MeOH (100:1 to 60:1, v/v) as eluent to give methyl 4-[l-[4-[A'-(2-chlorophenylJureidol-S-melhoxyphenylacerylXS^-pyrrolidinyloxy] benzoate (652 mg, 99%) as a white solid, mp 200-203 °C; 'H-NMR (CDC1,) 6 2.06-2.32 (m, % H), 3.60-3.82 (series of m, total 9 H), 3.88 (s, 3 H), 4.97-5.01 (m, 1 H), 6.76-6.86 (m, 4 H), 6.95-6.99 (m, I H), 7.23-7.47 (m, 4 H), 7.91-7.99 (m, 3 H), 8.19-8.21 (m, 1 H); MS (ESI) m/z537 (M*). To a stirred solution of methyl 4-[l-[4-[A"-(2-chJorophenyl)ureidol-3-methoxyphenylacetyl]-(355-pynolidinyloxy]benzoate (650 mg, 1.21 mmol) in THF (5 mi) was added 0.5 N NaOH (5 ml) {uid the reaction mixture was heated under reflux for 5 hi. After cooled to room temperature, the mixture was poured into ice-1 N HC1 and the resulting precipitate was collected under a reduced pressure. The crude solid was recrystallized from MeOH-CHClj-IPE to give 183 (443 mg, 70%) as a pale yellow crystalline powder. MW 523.97 mp I90-193°C; 'H-NMR (DMSO-dJ 8 2.06-2.27 (m, 2 H), 3.56-3.62 (m, 4 H), 3.71-3.88 (series of s and m, total 5 H), 5.11 and 5.20 (each m, total 1 H), 6.74-6.78 (m, 1 H), 6.89-6.91 (m, I H), 7.00-7.05 (m, 3 H), 7.26-7.30 (m, 1 H), 7.43-7.45 (m, 1 H). 7.88-7.98 (m, 3 H), 8.08-8.10 (m, 1 H), 8.89-8.95 (m, 2 H), 12.67 (br s, 1 H); MS (ESI) m/z 524 (M*+l); Anal. Calcd for Ci,H3)SClNA'l/' A solution of methyl 4-[l-benzyl-(3K)-pyTTo!idinylo)cy]benzoate (3.56 g, 11.4 nunol) in McOH (25 ml) was hydrogenaled over Pd(OH),/C (0-^2 g, 20 wt%) overnight. The reaction mixture was filtered to remove the catalyst and the solution was evaporated to give methyl 4-[(3fl)-pyrralidinyloxy]benzoate {2.53 g, q.y.) as a pale yellow oil. 'H-NMR (CDC1J 8 1.94-2.18 (m, 3 H), 2.91-2.97 (m, 1 H), 3.04-3.09 {m, 1 H), 3.16-3.22 (m, 2 H), 3.88 (s, 3 H), 4.88-4.91 (m, 1H), 6.86-6.89 (m, 2 H). 7.97-7.99 (m, 2 H); MS (ESI) m/z 263 [MN-1+41, (+MeCN)]- A mixture of 3-methoxy-4-[W'-(2-methylphenyl)ureido]pheny]aceticacid (460 mg, 1.46 nunol), methyl 4-[(3^)-pyrro]idiiiyloxyjben2oate (324 mg, 1.46 mmol), EDCHC1 (337 mg, 1.76 mmol), HOBt(237mg, 1.75 mmol), and Et3N (245 ml, 1.76 mmol) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with HjO, and extracted with ElOAc. The extract was washed with brine, dried over Na2SO ]benzoale (561 mg, 70%) as a white form. 'H-NMR (CDClj) 5 2.05-2.34 (m, 2 H), 3.59-4.07 (series of s and m, tola! 12 H), 4.97-5.02 (m, I H), 675-6.86 (m, 4 H), 6.94-7.00 (m, I H), 7.22-7.33 (m, 2H), 7.59-7.66 (m, 2H), 7.92-7.99 (m. 3H), 8.19-8,22 (m, 1H); MS (ESI) m/z 538 (M*+i). To a stirred solution of methyl 4-[l-[4-[W-(2-bromophenyi)ureido]-3-methoxyphenylacetyl]-(3/i)-pyrrclidinyloxyjbenzoate (555 mg, 0,95 mmal) in THF (5 m)) was added 0,5 N NaOH (5 mJ) and the reaction mixture was healed under reflux for 5 hr. After cooled to room temperature, the mixture was poured into ice-1 N HC1 and the resulting precipitate was collected under a reduced pressure. The crude solid was recrystailized from MeOH-CHCl,-EtiO to give 187 (330 mg, 61%) as a white crystalline powder, MW 568.42 mp 175-177°C; 'H-NMR (DMSO-dJ 8 1.99-2.27 (m, 2 H), 3.56-3.63 The resin was drained and washed with DMF (3x), CH,OH (3x) and CH,C1: (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CHjOH (3x) and CH,C13 (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and Fmoc-L- morpholine-2-carboxylic acid (307 mg, 0.87 mmol) was added. The resin was shaken for 5 min then PyBroP (406 mg, 0.87 nunol) and DEA (123 mg, 0.15 mL, 0.87 mmol) were added and the resin was shaken for 24 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CHjOH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and 4-o-totylureidophenylacelic acid (247 nig, 0.87 mmol) was added and the resin was shaken for 5 min. PyBroP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) was added and the resin was shaken for 24 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was then taken up in 90% TFA in CH,C1, and shaken for 4 hr. The resin was drained and the eluate collected. The resin was taken up in fresh CHjClj and shaken for 30 min. The resin was drained and the eluate collected and combined with the first fraction. The solvent was removed under vacuum arid the residue was recrystallized from ethyl acetate-hexane, yielding 85 mg 188. Fmoc- The resin was drained and washed with DMF (3x), CH3OH (3x) and CH,Clj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and Fmoc-L- 4-phenylproline (307 mg, 0.87 mmol) was added. The resin was shaken for 5 min then PyBroP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) were added and the resin was shaken for 24 hi. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjCli (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25mL of DMF and 4-o-tolyhireidophenylacetic acid (247 mg, 0.87 mmol) was added and (he resin was shaken for 5 min. PyBroP (406 mg, 0,87 mmol) and DEA (123 mg, 0.15 mL, 0.87 mmol} was added and the resin shaken for 24 hi. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CHjOH (3X) and CH;C1: (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and 4-o-tolylureidophenyl acetic acid (247 mg, 0.87 ramol) was added and the resin was shaken for 5 min. PyBroP (406 mg, 0.87 mmol)andDIEA(123 mg. 0.15 mL, 0.87 mrnol)was added and the resin was shaken for 24 hi. The resin was drained and washed with DMF (3x), CHjOH (3x) and CHjCli (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CHjOH (3x) and CH,C1, (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and 4-o-tolylureidopheny! acetic acid (247 mg, 0.87 mmol) was added and the resin was shaken for 5 min. PyBroP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) was added and the resin was shaken for 24 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHJCIJ (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH,CIS (3x) then dried under vacuum. The resin gave a positive bromophenylblue [est. The resin was taken up in 25 inL of DMF and Fmoc-3-amino-2-oxo-l-pyrroUdineacclate (331 mg, 0.87 mmol) was added and the resin was shaken for 5 min. PyBroP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) was added and the resin was shaken for 24 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CHjOH (3x) and CHjCI, (3x) Ihen dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in CH]Cli ando-tolyl isocyanate{193 mg, 1.45 mmol, 0.18 mL) was added. The resin was shaken for 24 hr. The o-tolylthiourea (10.12 g, 61 mmol) was then methylated by addition of methyl iodide (9.1 g, 62 mmol) in anhydrous methanol (100 mL). The reaction was stirred at room temp for 6 hr and then concentrated in vacuo. The residue was poured into aqueous ammonium chloride and extracted 3x with EtOAc. The combined organics were dried and concentrated in vacuo to give 8.7 g(84%yield)of2-methyl-2-thio-o-lolylpseudourea. The pseudourea (8.7 g, 51 mmol) was dissolved in methanol (100 mL) and piperidine (8.7 g, 102 mmol) at room temp. The mixture was To a solution of ethyl 4-[]-[3-methDxy-4-[//*-(2-meIhj'Iphcnyl)ureido]phenylacet>'l]-{25, 1R, 4/?)-3,4-dihydroxy-2-pyrTolidinylcarbonyl]-l-pipera2inylacetaie(870 mg, 1.46 mmol) inTHF (15 ml) was added 0.25N NaOH (7.00 mL, 1.75 mmol)- After being stirred at room temp, for 3.5 hr, the reaction mixture was concentrated. The residue was diluted with water and neutralized ■with IN HC1 at 0 °C. The mixture was concentrated and purified by ion-exchanged resin (HP-20, Mitsubishi Chemical) to give 195 (645 mg, 78 %) as a colorless amorphous solid. IR (KBr) 3330, 2937, 1627, 1535, 1454 cm'1; 'HNMR pMSO-rft) d 2.25 (s. 3H), 2.38 (m, 1H), 2,42 - 2.58 (m, 2H), 2.64 {m, 1H), 3.01 (s, 2H), 3.13 -3.71 (m, 8H), 3.88 (s, 3H), 3.89 (m, JH), 4.05 (m, ]}J), 4. 58 (d, J= 3.2 Hz, 1H), 6.76 (dd, J= 8.3, 1.5 Hz, IH), 6.91 - 6.95 (m. 2H), 7.10 - 7.16 (m, 2H), 7.79 (d, J = 8.3 Hz, IH), 8.00 (d, J = 8.3 Hz, IH), 8.49 (s, IH), 8.57 (s, IH); MS (FAB) m/z 570 (M*+l);v4na/. Calcd for C,sH3jNjO,-2.75^0: C, 54.32; H, 6.59; N, 11.31. Found: C, 54,07; H, 6.11; N, 11.00. argon. The reaction was cooled to minus 78° C. Lithium bis(lrimeihylsily!)amide (13.98 mL, 13.98mmole) was added over 10 min. The reaction was stirred for one hr at minus 78" Cthen icdomethane (1.98g, 33.98mmo!e, 0.87 mL) was added rapidly. The reaction was allowed \o slowly warm to room temp and stir overnight. The reaction was poured into IN HCI and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (7:1 hexane- dissolved in ethyl acetate. Pd/C was added and the vessel was pressured to 50 psi with H3. The vessel was agitated for 12 hr. The Paar vessel was flushed with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure. Yield 996.41mg202. The Boc ester (304mg, ].04mrnole) was taken up in CHjC!, and excess trifluoroacetic acid was added. The reaction was then stirred for 2 hr. The solvent was removed and the residue was taken up in ethyl acetate and washed with sat. NaHCO, solution. The organic layer was * washed with water, brine then dried over Na}SOj. The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CHjCls-DMF and HOBt (I54.30mg, 1.14mmole), 4-[N'-(o-tolylurca}-phenylacelic add (324.11mg, 1.14mmole) and EDCI (218.53mg, I.Hmmole) were added. The reaction was stirred for 24 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, {ethyl acetate) Yield 380.32mg 203. The ester (380,32mg, O.SOmmole) was taken up in ethanol-water (4:1) and NaOH was added. The reaction was then heated to 50° C for 2 hr. The TLC (ethyl acetate) showed no starting material present. The reaction was cooled to room temp. The solution was poured into IN HC1 and the aqueous layer was extracted 3x ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallizied from ethyl acetate-hexane. Yield 319.40mg 204, The Boc ester (209.60,0.65mmole) was taken up in CH]C1S and excess trifluoroacetk acid was added. The reaction was then stirred for 2 hr. The solvent was removed and the residue was taken up in ethyl acetate and washed with sat. NaHCOj solution. The organic layer was washed with water, brine then dried over NajSCv The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CHjClj-DMF and HOBt (97.45mg, 0.72mmole), 4-fN'-(o-toIylurea)-phenylacetic acid {204.70mg, 0.72mrnole) and EDCI (138.03mg. 0.72mmole) were added. The reaction was stirred for 24 hr. The solution was poured into IN HCI and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, (ethyl The ester (237.8mg, 0.49mmole) was taken up in ethanol-water (4:1) and NaOH added. The reaction was heated to 50° C for 2 hr. The TLC (ethyl acetate) showed no starting material present. The reaction was cooled to room temp. The solution was poured into IN HCI and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO*. The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystalized from ethyl acetate-hexane. Yield 207.8mg 206. Eiample 191 Thel,2,3,4- tetrahydroisoquinoline (12.20g, 91.60mmole) was taken up in HjSO^OmL) and cooled to minus 10° C. Concentrated HNOj (9.0rnL) was slowly added to the solution while maintaining the internal temp at minus 10° C. On completion of the addition the reaction was allowed to stand and slowly warm to room lemp over 12 hr. The reaction mixture was slowly added to ice and the aqueous solution was basified with NH4OH. The aqueous layer was extracted 4 times with CHC15. The combined organic layers were washed with water then dried over NajSO,. The solution was filtered and the solvent was removed under reduced pressure. The resulting brown oil was taken up in elhanol and concentrated HCI was added. The resulting white solid was collected by filtration and dried under vacuum. Yield 8,0g 207. The 6- nitro-l,2,3,4-tetrahydroisoquinoline (l.OOg, 5.6!mraoIc) was taken up in ethanol. Methyl bromoacetatc (0.86g, 5.Slmmole, 0.53 mL)and triethylamine{1.17g, 11.59mmole, 1.62 mL) were then added and the mixture was heated to reflux for 5 hr. The solution was cooled to room temp and the solution was concentrated under vacuum. The solution was added to water and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were dried over NajSOa, filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (3:1 hexane-ethyl acetate). Yield 702mg 208. The above ester (702mg, 2.81mmole)was placed in a Paar vessel and dissolved in cthanol. Pd/C (lOOmg) was added and the vessel was pressured to 50 psi with H,. The vessel was agitated for 24 hr. The Paar vessel was flushed with argon and the catalyst was removed by filtration through celite. The solvent was removed under reduced pressure. 1H-NMR showed only The reaction was cooled to 0"C. A CHjCli solution of 3-methoxy-4-(N'phenylureido) phenylacetyl chloride (837.70mg, 2.66mmole) was added over 5 min. The reaction was then allowed to warm lo room temp and stir overnight. The reaction mixture was then poured into IK HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with sat. NaHCOj, water, brine then dried over MgSO(. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl (558,07mg, 13.30mmole) was added. The reaction mixture was stirred at room temp for 24 hr. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was purified by recrystallizauon. (hexane-ethyl acetate). Yield 600mg 211. argon. The reaction was cooled 10 0° C and BHj-THF (I.OM, 15.37mmole, 15.37 mL) was added over 10 min. The reaction was stirred at 0° C for 1 hr then slowly quenched with water. The solution was slowly wanned to room temp then poured into IN HC1. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with sat. NaHCO,, water, brine then dried over MgSO«. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (1:1 hexane-ethyl acetate) Yield 909.0rog 212. The 3-nitro-phenyl propanol (909.0mg, 5.02mmole) was taken up in dry CHjClj. In a second round bottom flask (COCl)3 (700.65mg, 5.52mmole, 0.48 mL) was added to dry CH,C1, under argon. The (COC!),-CHiCl5 solution was then cooled to minus 60" C and DMSO (862.56mg, 1 Mmmole, 0.78 mL) was slowly added. The reaction was stirred at minus 60" C for 5 min then the alcohol solution was added via a cannula over 5 min. The reaction mixture was stirred at minus 60° C for 1 hr then Et3N (2.54g, 25.10mmole, 3.50 mL) was added and the reaction was allowed to slowly warm to room temp. The reaction was poured into IN HCI and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with sat. NaHC03, water, brine then dried over MgS04. The solution was filtered and the solvent was removed under reduced pressure, Hl-NMR showed no starting material present. The aldehyde argon. Triethyl 2-phosphonopropionaie (1.3 Ig, 5.52mmo]e, J. 18 mL) dissolve in dry THF was added slowly via a syringe. The reaction mixture was stirred for 30 min at room temp. The above aldehyde, dissolved in dry THF under argon, was added to the phosphonate solution via syringe over 10 min. The reaction mixture was stirred for 12 hr. The reaction was poured into IN HCI and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with sat. NaHCOj, water, brine then dried over MgSO<. the solution was filtered and solvent removed under reduced pressure. product isolated by flash chromatography. ethyl acetate-hexane yield> issolved in ethanol. The vessel was flushed with argon and Pd/C (200.0mg) was added. The rgon atmosphere was replaced with Hj at 50 psi. The Paar vessel was then shaken for 12 hr. The pdrogen was flushed from the vessel with argon and the catalyst was removed by filtration irough celite. The solvent was removed under reduced pressure. 1H-NMR showed only the gon. The reaction was cooled to 0" C. A CHjClj solution of 3-methoxy-4-(N'phenyIureido) lenylacetyl chloride (1.14g, 3.61mmolc) was added over 5 min. The reaction was then allowed warm to room temp and stir overnight. The reaction mixture was then poured into IN HC1 and E aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then ished with sat. NaHCOj, water, brine then dried over MgSO,. The solution was filtered and the Ivent was removed under reduced pressure. The product was isolated by flash chromatography ded. The reaction mixture was healed to 50" C for 2 hi. The reaction was cooled to room temp d then poured into IN HCI. The aqueous layer was extracted 3x limes with ethyl acetate. The nbined organic layers were then washed with water, brine then dried over MgS04. The solution s filtered and the solvent was removed under reduced pressure. The product was purified by p-Pak column. Yield 534mg 217. of 3-(Fmoc-amino)phenyIpropionk acid (36I.31mg, 0.90mmole), DMAP (109.95mg, 0.90mniole), HOBt 243.63mg, 0.90mmo]e), and DIC (227.16mg, l.SOmmole, 0.28 mL) in a mixture of DMF and CHJCIJ. The mixture was shaken for 20 hi and drained. The resin 218 was washed with v/v, 4 mL) and the mixture was shaken for 4 hr. The resin was washed with DMF, MeOH,' 'CHjClj. To the resin was added TMOF and isobutrylaJdehyde (108.17mg, 1.50mmole, 0.14 mL). The mixture was shaken for 4 hr. The resin was drained and fresh TMOF and isobutrylaldehyde was added. The mixture was then shaken for 12 hr. The resin was drained and taken up in MeOH-1% AcOH and NaCNBH3(150.Omg, 2.39mmole) was added. The resin was shaken for 6 hr. The resin was drained and washed with MeOH, MeOH-EtjN, MeOH, DMF, CH,Clj. The resin was taken up in DMF and S-methoxy^^N'-phenylureido^henylacetic acid (141.45mg,0.45mmole), PyBrop (209.78mg, 0.45mmolc),and DIEA (58.16mg, 0.45mmole, 0.08 mL) were added. The resin was then shaken for 24 hr then drained. The resin was washed with DMF, MeOH, CHjCI,. To the resin was added a solution of TFA in CHjClj (30% v/v 3 mL) and the mixture was shaken for 5 hr. The mixture was filtered and the filtrate was concentrated in vacuo.. The residue was purified by Sep-Pak column. After removal of the solvent, EtjO was added to the residue and the solid was collected to afford 15mg 219 as a crystalline solid 6-bromohexanoic acid (169mg, 0.87mmol) was added. The resin was shaken for 5 min then DIC (220mg, 0.27 mL, 1.74mmo!es) and DMAP (35mg, 0.29mmole) were added and the resin was shaken for 14 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH,Clj (3x) then dried under vacuum. To this resin was added 2,2-dimetliyl-l,3-dioxo!ane-4-inethanamine (227mg, 1.74 mmoI)and lithium iodide (232mg, 1.74mmol)in 15 mLofDMF. The resin was shaken for 14 hr at room temp. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH,C1, (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and 4-o-tolyIureido-3-methoxyphenyIacetic acid (247mg, 0.87mmole) was added and the resin was shaken for 5 min. PyBrOP (406mg, 0.87mmole) andDIEA(123mg, 0.15 mL, 0.87mrnole) was added and the resin was shaken for 14 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test. The resin was then taken up in 90% TFA in CH2C1, and shaken for 4 hr. The resin was drained and the elutant collected. The resin was taken up in fresh CHjCl2 and shaken for 30 min. The resin was drained and the elutant collected and combined with the first fraction. The solvent was removed under vacuum and the residue was recrystallized from ethyl acetate-hexane, yield 56mg 220. Fmoc- 7-aminoheplanoic acid (3I9mg, 0.87mmole) was added. The resin was shaken for 5 min then D1C (220mg, 0.27 mL, 1.74 mmo!) and DMAP (106mg, 0.87mmole) were added and the resin was shaken for 24 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjClj (3x) then dried under vacuum. The resin gave a negative bromophenylblue test The resin was taken up in 20% piperidJne in DMF and shaken for 4 hr. The resin was drained and washed with DMF (3x), CH3OH (3x) and CHjCli (3x) then dried under vacuum. The resin gave a positive bromophenylblue test. The resin was taken up in 25 mL of DMF and 4-c-tolyIureido-3-methoxypheny] acetic acid (247mg, 0.87mmole) was added and the resin was shaken for 5 min. PyBrOP (406mg, 0.87mmole) andDIEA (123mg, 0.15 mL, 0.87mmole) was added and the resin was shaken for 14 hr. The resin was drained and washed with DMF (3x), CHjOH (3x) and CHjCl] (3x) then dried under vacuum. The resin gave a negative bramophenyiblue test The resin was then taken up in 90% TFA in CHjCl, and shaken for 4 hr. The resin was drained and the elutant collected. The resin was taken up in fresh CH,CJ, and shaken for 30 min. The resin was drained and the elutant collected and combined with the first fraction. The solvent was removed under vacuum and the residue was recrystallized from ethyl acetate-hexane, yield 66mg 221. (2.4 g, 31 mmol) dropwise over 30 min at minus 78° C. To this solution was added N-Boc-prolinol (5.0g, 25mmol) dropwise over 15 min. The reaction was stirred at minus 78" C for 3 hr and then quenched by the cold addition of IN HC1, extracted 3x with EtOAc, dried, and concentrated in vacuo to afford the crude prolinal which was chromatogiapned (25% EtOAc/hexanes) to yield 3.8 g of the desired product A solution of Methyl (triphenylphosphoranylidene)butanoate (6.9 g, 19 mmol) in THF (100 mL) was generated. LiHMDS (10 mL of a 2.0M soln, 20 mmol) was added at minus 78° C and then stirred for 1 hr. The above prolinal (3.8 g, 19 mmol) was then added in one portion and the mixture was allowed to warm to room temp over 4 hr. The reaction was quenched by the addition of IN HC1, extracted 3x with EtOAc, dried, and concentrated in vacuo to afford the crude alkene which was chromatographed (25% EtOAc/hexanes) to yield 2.9 g of he desired product Hydrogenation of the alkene was performed by placing the alkene (2.9 g, 10 mmol) in ethanol (20 mL) and adding a catalytic amount of 10% Pd/C followed by Parr hydrogenation at 40 psi for 4 hr, the resulting alkane was used without purification. The Boc group was removed by the addition of 1:1 TFA/CH3Cli at room temp. The reaction was stirred for 2 hr and the solvent was removed in vacuo. The crude amine 1.9 g was used without further purification. A solution of the above free amine (1.9 g, 10 mmol) in CHjCl, (100 mL) was generated. To this solution was added EDCI (2.95 g, 10 mmol), DMAP (1.2 g, 10 mmol), and 4-o-tolylureido-3-methoxyphenytacetic acid (3.15g, 10 mmol) at room lemp. The reaction mixture was stirred for 4 hr and then quenched by the addition of 1 N HCI, extracted 3x with EtOAc, dried, and concentrated in vacuo. The crude amide was chromatographed (5% MeOH/ CH2Cli) to yield 1.95 g of the desired product. The ester (1.95 g, 4.2 mmol) was taken up in 1:1 THF-H,0 and LiOH was added at room temp. The reaction mixture was then stirred for 3 hr. The solution was poured into IN HCI and the aqueous layer was extracted 3x with EtOAc. The combine organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the . solvent removed under reduced pressure. The solid was then triturated with cold ether to give 1.65 g of the desired carboxylic acid 222. mL) was added Boc anhydride (2.8 g, 13 mmoOandK^COjOO g). This solution'was allowed to stir at room temp for 14 hr. The reaction was then poured onto 1 N HCI, extracted 3x with EtOAc, dried, and concentrated in vacuo. The crude carbamate was chromatographed (50% EtOAc/hexanes) to yield 2,7 g of the desired product. The Boc-protected amine was methylated by placing it in THF (75 mL), followed by the addition of LiHMDS (25 mL of a 2.0M sola, 50 mmol) at minus 78° C, this solution was then stirred for 30 min and methyl iodide (7.2 g, 50 mmol) was added in one portion the reaction mixture was allowed to warm to room temp overnight. The reaction was quenched by the addition of 1 N HCI, extracted 3x with EtOAc, dried, and concentrated in vacuo. The crude methylated carbamate was chromatographed (50% EtOAc/hexanes) to yield 1.9 g of the desired dimethyl product. The Boc group was removed by the addition of 1:1 TFA/CH,C1, at room temp. The reaction was stirred for 2 hr and the solvent was removed in vacuo. The crude amine 900 mg was used without iiirther purification. A solution of the above free amine (900 mg, 4.5 mmol) inCH,Cl, (100 mL) was generated. To this solution was added EDCI (J.33 g, 4.5 mmol), DMAP (567 mg, 4,5 mmol), and 4-o-toly!ureido-3-methoxyphenylacetie acid (1.45 g, 4.6 mmol) at room temp. The reaction | mixture was stirred for 4 hr and then quenched by the addition of 1 N HCI, extracted 3x with EtOAc, dried, and concentrated in vacuo. The crude amide was chromatographed (5% MeOH/ CHjCIJ to yield 1.2 g of the desired product. The ester (1.2 g, 2.4 mmol) was taken up in 1:1 THF-HjO and LiOH was added at room temp. The reaction mixture was then stirred for 3 hr. The solution was poured into IN HCI and the aqueous layer was extracted 3x with EtOAc. The combine organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The solid was then triturated with cold ether to give 1.01 g of the desired carboxylic acid 223. mL) was added o-tolyisocyanate (8.8 g, 66 mmol). The mixture was heated to reflux for 4 hr at which time a white precipitate had formed. The precipitate was filtered and the solid washed generously with 1:1 CH,Cl2:acetone. The solid was recrystalli2ed with hot methanol and dried under vacuum to yield 14.1 g (75% yield) of the desired 4-(o-tolylureido)phenyIacetic acid 224.- (100 mL) was added o-tolylisocyanate (3.5 g, 26 mmol). The mixture was heated to reflux for 8 hr at which time a yellow precipitate had formed, the precipitate was filtered and the solid washed generously with 1:1 CH:C!]:acetone. The solid was recrystallized with hot methanol and dried under vacuum to yield 4.8 g (66% yield) of the desired 2-(o-toIylureido)-4-ihiazoleacetic acid 225. Example 200 3-Bromo-4-hydroxybenzonitrile (5,OOg, 25.25mmol) was lakcn up in DMF. Benzyl bromide (4.75g, 27.78mmoI, 3.30mL) and CSjCOj(16.45g, 50.50mmol) were added and the reaction was heated to 50° C for 2 hr. The solution was cooled to room temperature and poured into 1NHC1. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, (hexane to 8:1 hexane-ethyl aceiale) Yield 8.90g 226. 3-Bromo-4-benzyloxybenzonitrile (1.50g, 5.21mmol) was taken up in dry THF under argon and the solution was cooled to 0° C. BH3-THF(10.41mL, 10.41mmol) was added via syringe over 5 min. The reaction mixture was then warmed to room temp then heated to reflux for 12 hr. The solution was cooled to 0° C and methanol was slowly added. When no more gas evolution was observed the solution was wanned to room temp and excess IN NaOH solution was added. BocjO(1.25g, 5.73mmoI) was added and the reaction mixture was stirred at room temp for 12 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO(. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (7:1 ethyl acetate-hexane) Yield ].80g227 The Boc-protecied benzyl amine (1.80g, 4.59mmoI) was dissolved in dry THF under argon. The reaction was cooled to minus 78° C. Lithium bis(trimeihyisilyl)amide (13.77mL, 13.77mmoI) was added over 10 min. The reaction was stirred for 1 hr at minus 78s C, then iodomethane (1.95mL, 13.77mmol, 0.86mL) was added rapidly. The reaction was allowed to slowly warm lo room temp and slir overnight. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (7; 1 hexane-ethyl acetate) Yield 1.70g 228. In a pressure tube was placed the 4-(N-methyl-Bcc-aminomethyl)-2-bromoben2yloxy phenol (1.70g, 4.I8mmol). The tube was then charged with DMF, sodium acetate (0.38g, 4.60mmol), dppp (0.35g, D.84mmol), and Pd{OAc)j (0.19g, 0.84mmol) The tube was flushed with argon for 10 min and then methyl acrylate (0.40g, 4.60mmol, 0.41mL) was added. The tube was sealed and heated to 135°C for 24 hr. The reaction was cooled to 0" C and the tube was slowly opened. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (6:1 hexane-ethyl acetate) Yield 1.12g 229 The unsaturated ester (307.40mg, 0.75 mmol) was taken up in CH,Clj and excess TFA was added. The reaction was stirred for 4 hi at room temp. The solvent was removed under reduced pressure and the residue was dried under high vacuum. The solvent was removed and the residue was taken up in ethyl acetate and washed with sat. NaHC03 solution. The organic layer was washed with water, brine then dried over NajS04. The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CHjCl3-DMF and HOBt ( 110.99 mg, 0.82 mmol), 3-methoxy-4-(N'-phenyhireido) phenylacetic acid (258.3Img, 0.82 mmol) and EDCI (157.20mg, 0.82 mmol) were added. The reaction was stirred for 24 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine thtn dried over MgSO* The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, {ethyl acetate) Yield 296.30mg 230 The unsaturated ester (296.30mg, 0.49 mmol) was taken up in EtOAc and Pd/C (75mg) was added under argon. The argon atmosphere was replaced with hydrogen at 1 atmosphere and stirred for 24 hr. The hydrogen atmosphere was removed and replaced with argon. The catalyst was removed by filtration through celite and the ceiite pad was washed with ethyl acetate 3x. The solvent was removed under reduced pressure. H'-NMR showed only the desired product. No ■ further purification was needed. Yield 233.00mg 231 The esler (233-OOmg, 0.45mmol) was taken up inTHF-H,0 (4:1) and LiOH (94.4Img, !,25mmoI) was added. The reaction mixture was stirred at room temp for 24 hr. The solution was loured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined irganic layers were washed with water, brine then dried over MgSO,. The solution was filtered md the solvent was removed under reduced pressure. The product was washed with ether-hexane 1:1) and dried under high vacuum. Yield211.58mg 232 Example 201 The carboxylic acid {65.00mg, 0.13 mmol) was taken up in benzene and para-3luenesulfonicacid(10.00mg, 0.06 mmol) was added. A Dean-Stark trap was added and the olution was heated to reflux for 24 hr. The reaction was cooled to room temp and poured into sat. faHCOj. The organic layer was seperated and the aqueous layer was extracted 3x with ethyl cetate. The combined organic layers were washed with water, brine and dried over MgSO«. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (4:1 hexane-ethy! acetate to ethyl acetate) Yield 29.00mg 233 Example 202 5-Bromonicotinicacid(5.15g, 25.49 mmol) was taken up in EtOH and HjSO i The ethyl 5-Bromonicotinate (5.40g, 23.47 mmol) was taken up in 95% EtOH and NaBH, (8.3 lg, 225.69 mmol) was added slowly at room temp. After addition the solution was stirred for 24 hr at room temp. Water was slowly added to the solution, then the mixture was stirred for 4 hr. The EtOH was removed under reduced pressure and the aqueous layer was extracted 3x with CHjClj. The combined organic layers were dried over NajSO,, filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (2:1 ethyl acetate-hexane) Yield 2.12g 235 The benzyl alcohol (2.12g, 11.28 mmol) was taken up Et,0 and HCl^ was bubbled, through the solution for 10 min. The solution was stirred at room temp for 1 hr and then the solid was collected by filtration. The solid was washed with EtjO and the then dried. The HC1 salt was added to SOClj and the mixture was heated to reflux for 1.5 hr. The solution was cooled to room temp and Et,0 was added to precipitate the product. The Solid was collected by filtration, washed with Et,0 and dried under vacuum. Yield 2.42g 236 The benzyl chloride (2.42g, 9.96 mmol) was added over 1 hr to CH3NHi (75.9mL, 2.5M in EtOH) at room temp. The reaction was stirred at room temp for 48 hr. The solution was concentrated and added to sat. NaHC03. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were dried over Na,SOj, filtered and the solvent was removed under reduced pressure. Yield 1.19% 237 The 3-bromo-5-(N-methyl -aminomethyl)-pyridine(1.19g, 5.01 mmol) was taken up in DM? and triethylamine {0.90g, \.24mL, 8.S9 mmol) was added. BocjO (1.55g, 7.10 mmol) was added and the reaction mixture was stirred at room temp for 48 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3 x with ethyl acetate. The combined organic layers tvere washed with water, brine then dried over MgS04. The solution was filtered and the solvent tvas removed under reduced pressure. The product was isolated by flash chromatography (2% -nethanol-CH2Cy Yield 1.6g 238 The sodium salt of a-methyl acrylic acid (5.00g, 46.27 mmol) was dissolved in DMF and lenzy] bromide (8.70g, 50.89 mmol) was added at room temp. Potassium carbonate (7.03g, 50,89 runol) was then added and the solution was healed lo 50° C for 24 hr. The solution was poured nto IN HC1 and the aqueous layer was extracted 3x with diethyl ether. The combined organic syers were washed with water, brine then dried over MgSO*. The solution was filtered and the alvent was removed carefully under reduced pressure. The product was isolated by flash hiomatt>graphy{2%eth«-pcntane) Yield 6.93g 239 In a pressure tube was placed the 3-bromo-5-(N-methyl-Boc-aminometliyl)-pyridine OO.OOmg, 2.33 mmol). The tube was then charged with DMF, triethylamine (260.05mg, 57rnmoI, 0.36mL), dppp (193.85mg, 0.47 mmol), and Pd(OAc),(105.52mg, 0.47 mmol) The be was flushed with argon lot 10 min then benzyl melhacrylate (452.86mg, 2.57 mmol) was !ded. The tube was sealed and heated lo 135° C for 24 hr. The reaction was cooled to 0° C and e tube was slowly opened. The solution was poured into IN HCl and the aqueous layer was traded 3x with ethyl acetate. The combined organic layers were washed with water, brine then ied over MgS04. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (6:1 hexane-ethyl acetate) Yield 785.23mg 240 The unsaturated ester (392.61mg, 0.99 mmol) was taken up in CH,C13 and excess TFA was added. The reaction was stirred for 4 hr at room temp. The solvent was removed under . reduced pressure and the residue was dried under high vacuum. The solvent was removed and the residue was taken up in ethyl acetate and washed with sat. NaHC03 solution. The organic layer was washed with water, brine then dried over NajSO* The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CHJCIJ-DMF and HOBt ( 147.53mg, 1.09 mmol), 3 -methoxy-4-(N'-phenylureido)phenylacetic acid (342.64mg, 1.09 mmol) and EDC1 ( 208.96mg, 1.09 mmol) were added. The reaction was stirred for 24 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO«. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, (ethyl acetate) 363.79mg 241 The unsaturated ester (363.00mg, 0.61 mmol) was taken up in CHjOH and Pd/C (lOO.OOmg) was added under argon. The argon atmosphere was replaced with hydrogen at 1 atmosphere and stirred for 24 hr. The hydrogen atmosphere was removed and replaced with argon. The catalyst was removed by filtration through celite and the celile pad was washed with ethyl acetate 3x. The solvent was removed under reduced pressure. H'-NMR showed only the desired product. The solid was washed with ether and then dried under high vacuum. Yield 254,79mg242 Example 203 3-Cyanobenzaldehyde (9.41g, 71.76 mmol) was taken up in ethanol and cooled lo 0" C. The NaBH, (2.71 g, 71.76 mmol) was added in small portions. The solutions was stirred for 30 ' min at 0 ° C then allowed to warm to room temp and stirred for 1 hr. The reaction was slowly poured into INHC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO<. the solution was filtered and solvent removed under reduced pressure. residue taken up in dmf imidazole mmol added. tbdpsc1 then _ added reaction stirred at room temp for hr. poured into hc1 aqueous layer extracted with ethyl acetate. combined organic layers were washed water brine dried over mgso.. product isolated by flash chromatography. hexane-ethyl acetate to yield> The silyl protected 3-cyanobenzyI alcohol (8.50g, 34.36 mmol) was taken up in ethyl acetate and BocjO (8.25g, 37.79 mmol) was added. Pd/C (l.Og) was added and the Parr vessel was pressurized with hydrogen at 50 psi. The vessel was shaken for 24 hr then the hydrogen was flushed with argon and the catalyst was removed by filtration through a celite pad. The celite was washed 3x with ethyl acetate. The solvent was removed under reduced pressure and the product was isolated by flash chromatography (10:1 hexane-ethyl aceiate) Yield 11.10g 244 The 0-sily!-N-Boc-protected benzyl alcohol (5.00g, 14.22 mmol) was dissolved in dry THF under argon. The reaction was cooled to minus 78° C. Lithium bis(tri methyl si lyl)amide (42.67mL, 42.67 mmol) was added over 10 min. The reaction was stirred for 1 hr at minus 78° C then iodomethane (6.06g, 42.67 mmol, 2.66mL) was added rapidly. The reaction was allowed to slowly warm to room temp and stir overnight. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (2% ethyl acetate-hexane) Yield 4.7g 245 The O-silyl-Boc-N-methy! protected benzyl alcohol (4.7g, 9.60 mmol) was taken up in THF and TBAF (14.39mL, 1.0M in THF) at room temp. The solution was stirred for 4 hr. TLC showed no starting material present. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane-ethyl acetate to 1:1 hexane-ethyl acetate) Yield 2.39g 246 The N-methyl Boc protected benzyl alcohol (l.OOg, 3.98 mmol) was taken up in dry CH:Cli under argon. Triphenylphosphine (1.46g, 5.57 mmol) was added and the solution was cooled to 0" C. Carbon tetrabromide (1.85g, 5.57 mmol) dissolved in dry CH,C1, was added over 10 min. The solution was stirred for 1 h at 0" C then the solvent was removed under reduced pressure. The residue was taken up in EtsO and the resulting solid was removed by filtration and the filtrate was collected and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (2%ether-pentane) Yield 1.15g 247 LHMDS (3.23mL, 3.23 mmol) was added to dry DME under argon at minus 78° C. Methyl butyrate (300mg, 2.94 mmol, 0.33mL) dissolved in dry DME was added to the LHMDS over 15 min and the solution was stirred for lhr at minus 78s C. 3-N-methyl-N-Boc protected benzyl bromide (1.02g, 3.23 mmol) dissolved in dry DME was added to the cnolate solution over 15 min then the solution was allowed to slowly warm to minus 20° C and stirred for 4 hr. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. The Boc ester (12I.60mg, 0.36 mmol) was taken up in CH;CI, and excess trifluoictfcetic acid was added. The reaction was then stirred for 2 hi. The solvent was removed and the residue was taken up in ethyl acetate and washed with sat. NaHCOj solution. The organic layer was washed with water, brine then dried over NajSO* The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH^Clj-DMF and HOBt (54. lOmg, 0.40 mmol) 3-methoxy-4-(N*-phenylureido)phenylacetic acid (125.74mg, 0.40 mmol) and EDO (77.0mg, 0.40 mmol) were added. The reaction was stirred for 24 hr. The solution was poured into INHCland the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, (ethyl acetate) Yield 165.20mg 249 The ester (165.20, 0.31 mmol) was taken up in ethanol-water (4:1) and NaOH was added. The reaction was then heated to 50° C for 2 hr. The TLC (ethyl acetate) showed no starting material present. The reaction was cooled to room temp. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgSO,,. The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane. Yield no.OOmg 250 Example 204 Bmyrolactone (250mg, 2.90 mmol, 223.20mL) was added to LHMDS (2.90mL, 1.0M in hexane) in THF at minus 78° C under argon over lOmin. The solution was stirred at minus 78°C for lhr. 3-N-methyl-N-Boc protected benzyl bromide (991.24mg, 2.90 mmol) dissolved in dry DME was added to the enolate solution over 15 min then the solution was allowed to slowly warm to room temp and stirred for 12 hr. The reaction was poured into IN HC1 and the aqueous layer was extracted 3x with ethy! acelate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexant-ethyl acetate to 1:1 ethyl acetate-hcxane) Yield 501.18mg 251 The Boc ester (250.00mg, 0.78 mmol) was taken up in CH,Clj and excess trifiuoroacetic acid was added. The reaction was then stirred for 2 hr. The solvent was removed andthe residue was taken up in ethyl acetate and washed with sat. NaHCOj solution. The organic layer was washed with water, brine then dried over Na5SOj. The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH]Clj-DMF and HOBt (116.40mg, 0.86 mmol) 3-methoxy-4-(N'-pheny]uTeido) phenylacetic acid (270.33mg, 0.86 mmol) and EDCI (165,06mg, 0.86 mmol) were added. The reaction was stirred for 24 hr. The solution was poured into IN HC1 and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine then dried over MgS04. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography, (ethyl acetate) Yield I19.00mg 252 Example 205 . 3 -methoxy-4 - [ 2 - [3 -methoxy-4 - [A'1 -(2 -methy lphenyl) ureido]pheny lacetyl] -tf-methy lami noethoxy] benzoic acid To a stirred and cooled (0° C) solution of//-methyl ethanolamine (3.10 g, 41.27 mmol), EijN (ll.SO mh, 84.66 mmol) in DMF-H20 (3:1, vA-, 40 jnL) was added dropwise 30% toluene solution of benzyl chloroformate (25.40 g, 49.13 mmol) for over 15 min. The resulting mixture was stirred for 1 day at room temp. The mixrure was extracted with EtOAc. The extract was washed with sat. NaHCOj, brine, dried over NajSO,, and evaporated. The residue was purified by column chromatography on silica-gel with n-hexane:EtOAc (3:1, v/v) then CHCljas eluent to give 4,67 g (54%) W-methyl-A'-(benzyloxy carbonyl)ethanolamine as a colorless oil. 'H-NMR (CDC13) d 1.82 (bs, 1 H), 3.00 To a stirred solution of ethyl 4-hydoxy-3-methoxybenzoate (2,01 g, 10.25 mmol), tf-methyl-/v'-(benzyloxycarbonyl)ethanolamine (2.11 g, 10.08 mmol), PPh3 (3.26 g, 12.43 mmol) in THF was added DIAD (2.65 jnL, 13.46 mmol) and the reaction mixture was heated under reflux overnight. The mixture was evaporated, and the residue was subjected to short column chromatography on silica-gel with n-hexane/EtOAc (5:1, v/v) as eluenl to give ethyl 3-methoxy-4-[2-methyl-2-(benzy]oxycarbonyI) aminoethoxy]benzoate as a crude product. To a solution of the crude product (5.20 g, 13.42 mmol) in EtOH (50 mL) was added AcOH (5 mL) and the solution was hydrogenated over 5% Pd/C for 4 hr. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was diluted with CHClj and washed with sat. NaHCO,, brine, dried over Na,SO(, and evaporated. The residue was chromatographed on silica-gel with CHCljiMeOH (10:1, v/v) as eluent to give 510 mg (2 steps 20%) ethyl 3-methoxy-4-(2-methylamino ethoxy) benzoate as a yellow oil. 'H-NMR (CDC13) d 1.39 (t, 3 H, .7=7.3 Hz), 1.82 (bs, 1 H), 2.52 (s, 3 H), 3.04 (t, 2 H, 7=5.3 Hz), 3.91 (s, 3 H), 4.18 (t, 2 H, .7=5.3 Hz), 4.36 (q, 2 H, 7=7.3 Hz), 6.90 (d, 1 H, 7=8.3 Hz), 7.55 (d, 1 H, 7=2.0 Hz). 7.65 (dd, 1H, 7=2.0, 8.3 Hz). To a stirred solution of ethyl 3-melhoxy-4-(2-methylaminoethoxy) benzoate (510 mg, 2.01 mmol) in DMF (13 mL) was added pentafluorophenyl ester of 3-methoxy-4-[N'-{2-methylphenyl) ureido] phenylacetic acid (900 mg, 1.87 mmol) and Et3N (0.420 mL, 3.01 mmol), and the resulting mixture was stirred for 2 days. The mixture was diluted with EtOAc, washed with 1 N HC1, sat. NaHCO,, brine, and dried over Na2SO«. After being evaporated, the residue was purified by column chromatography on silica-gel with CHCljiMeOH {50:1, v/v) to give 880 mg (85%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[A',-(2-methylphenyl)ureido]phenylacetyl]-A'-methylaminoethoxy] benzoate as a colorless amorphous solid. 'H-NMR (CDClj) d 1.37-1.41 (m, 3 H), 2.28 (s, 3 H), 3.03 and 3.18 (s, 3 H), 3.56 (s, 2 H), 3.65 (s, 2 H), 3.75-3.87 (m, 6 H), 4.06-4.24 (2 H, m), 4.33-4.39 (m, 2 H), 6.68-8.08 (series of m, 12 H). To a solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[iV-{2-methylphenyl)ureido] phenylacetyl]-//-methIaminoethoxy]benzoate (880 mg, 1.601 mmol) in THF (15 mL) was added 0.25 NNaOH(15 mL). Then the reaction mixture was heated under reflux overnight. The mixture was poured into 1 N HC1 (100 mL), and the solid was collected. The crude solid was recrystallized from MeOH-CHCl3 io give 253 as a white powder, ffi. (KBr) 1700 cm"1; 'H-NMR (DMSO-(L) d 2.25 (s,3 H), 2.50 (s, 2 H), 2.91 and 3.12 (s, 3 H) 3.53-3-76 (m. 2 H), 3.80 (s, 3 H), 3.84 (s, 3 H), 4.16-4.21 (m, 2 H), 6.72-8.56 (scries of m, 12 H), 12,68 (bs, 1 H); MS (FAB) m/; 522 (M*+l);^^/. Cakd. for CH^O,'1H,0: C, 62.33; H, 6.16; N, 6.63. Found: C, 62.17; H, 6.05; N, 7.57. Example 206 4-[[2-[3-methoxy-4-[A^-(2-mEthylphenyl)ureido]phenylacctyl]mcili)'lamino]e[hoxy]isophtri3lic acid To a stirred solution of A'-memyl-A'-benzyloxycarbonylethanolamine (1,05 g, 5.02 mmol), dimethyl 4-hydroxy isophthalate (1.05 g, 5.00 mmol), PhjP (1.59 g, 6.06 mmol) in THF (20 mL) was added DIAD (1.28 mL, 6.50 mmol) at room temp. The resulting mixture was then heated under reflux overnight. After cooling to room temp, the mixture was evaporated. The residue was dissolved in EtOH and added 5% Pd/C(200mg). The stirred resulting mixture was hydrogenated for 2 hr at latm. The mixture was filtered to remove the catalyst, and the filtrate was evaporated. The residue was purified by column chromatography on silica-gel with CHClj-MeOH (30:1, v/v) as eluent to give 480 mg (36% for 2 steps) dimethyl 4-(2-methylaminoethoxy) isophthalate as an Oil. 'H-NMR (CDCtj) d 1.68 (s, 1 H), 2.53 (s, 3 H), 3.01-3.04 (m. 2 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 4.21-4.23 (m, 2 H), 7.00 (d. 1 H, .7=8.8 Hz), 8.14 (dd, 1 H, J=2A, 8.8 Hz), 8.50 (d, 1 H, >2.4 Hz), MS (FAB), m/z 268 (M*+l). To a stirred solution of dimethyl 4-(2-methylaminoedioxy)isophlhalate(410 mg, 1.53 mmol) inDMF (13 mL) was added pentafluorophenyl ester of 3-methoxy-4-[^T-(2-methylphenyl)ureido] phenylaceic acid (700 mg, 1.46 mmol) and Et3N (340 /A, 2.44 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 1 N HC1, sat. NaHC03, and brine. The solution was dried over NajSO* and evaporated to give 780 mg (95%) dimethyl 4- [2-[3-methoxy-4-[A'*-(2-methylphenyl)ureido]phenylacetylJmethylamino ethoxy)isophthalate as a crystalline powder. 'H-NMR (CDClj) d 2.29 (s, 3 H), 3,24 {s, 3 H), 3.59 (S, 3 H), 3.67-3.68 (m, 2 H), 3.84 (s, 3 H), 3.91 (s, 3 H), 3,81-3.86 (m, 2 H), 4.25-4.28 (m, 2 H), 6,51-8.48 (series of m, 12 H); MS (FAB) m/z 564 (M'+l). To a solution of dimethyl 4- [2-[3-metooxy-4-[Ar-(2-methyIpheny!)ureido]phenyIacetyl] methylanunoethQxy]isophthalatc (780 mg, 1.384 mmol) in THF (30 mL) was added 0.25 N NaOH (30 mL). The resulting mixture was then heated under reflux overnight. The mixture was poured into ice-1 N HC1 (200 mL) and the solid was collected. The crude solid was recrystallized from MeOH-CHClj lo give 420 mg (57%) 4-[[2-[3-methoxy-4-[//,-(2-roethylphenyI)ureido]phenyl acetyl]methylamino]ethoxy] isophthaJic acid 254 as a white crystailine powder, mp 139-141 "CIR (KBr) 1700 cm'; 'H-NMR (DMSO-dJ d 2.94 (s, 3 H), 3.18 (s, 3 H) 3.62-3.86 (m, total 8 H), 4.24-4,28 {m, 2 H), 6.74-8.58 (series of m, total 12 H), 12.91 (bs, 1 H); MS (FAB) m/z 536 (M'+l); Anal. Calcd. for CliHJ'»iO,-2.5Ha: C, 53.66; H, 5.07; N, 6.70, Found: C, 53.80; H, 4.64; N, 6.70. Example 207 3-methoxy-4-[2-[3-methoxy-4-[A',-(2-methylphenyl)ureido]phenylaceryl]aiiunoethoxy]benzoicacid To a solution of 2-ethanolamine (5.16 g, 84.48 mmol), EtjN (23.50 mL, 168.60 mL) in dioxane-HjOfl/l, 160 mL) was added dropwise (Boc);0 (23,40 mL, 101.86 mmol) at room temp. The reaction mixture was stirred for 2 days at room temp. The resulting mixture was diluted with CHClj, washed with 0.5 N HCI, sat. NaHC03, and brine. The separated organic layer was dried over NajSO, and evaporated to give 11.86 g (87%) jV-Boc-2-ethanolamine as an oil. 'H-NMR (CDC13) d 1.45 (s, 9 H), 3.29-3.31 (m, 2H), 3.71-3.72 (m, 2 H). To a stirred solution of eihyl4-hydroxy-3-methoxybenzoate (1.46 g, 7.44 mmol), W-Boc ethanolamine (1.19 g. 7.38 mmol), PPfij (2.53 g, 9.65 mmol) in THF (30 mL) was added DIAD (1.90 mL, 9.65 mmol), and the resulting mixture was then heated under reflux overnight. The mixture was evaporated to give a crude gum. The crude product was dissolved in CH,C1] (20 mL) and TFA (20 mL). The resulting mixture was stirred for 2.5 hr at room temp. The mixture was concentrated in vacuo and the residue was made basic with sat. NaHCOj and extracted with CHCij. The extract was washed with brine, dried over Na,SO,, and evaporated (o give the 1.61 g (90% for 2 steps) ethyl 3-methoxy-4-(2-aminoethoxy) benzoate as a yellow oil. 'H-NMR (CDClj) d 1.39 (t, 3 H«>7.3 Hz), 3.14-3.17 (m, 2 H), 3.92 (s, 3 H), 4.09-4.11 (m, 2 H), 4.36 (q, 2 H. J=1.3 Hz), 6.89 (d, 1 H, >S.3 Hz), 7.56 (d. 1 H, /-2.0 Hz), 7.66 (dd, 1 H, J=2.0, 8.3 Hz). To a stirred solution of ethyl 3-methoxy-4-(2-aminoethoxy)ben2oate (250mg, 1.04 mmol) and pentafiuoropheny] ester of 3-meihoxy-4-[//'-(2-methylphenyl)ureidoJpheiiy)acetic acid {500 mg, 1.04 mmol) was added Et3N (210^1,3.01 mmol), and the resulting mixture was stirred for 2 days. 0.25 N NaOH {20 mL) and THF (20 mL) was added to the mixture and the resulting mixture was heated under reflux overnight. After cooling, the mixture was evaporated and the residue was acidified by the addition of 1 N HC1. The mixture was extracted with CHC1> and the extract was washed with brine, dried over Na,SOi, and evaporated. The obtained crude solid was recrystallized from CHClj to give 110 mg (20% for 2 steps) 3-methoxy-4-[2-[3-methoxy-4-[Ar'- mmol) and EtjN (2.00 mL, 14.35 mmol) was added TFAA (1.35 mL, 9.56 mmol) and the resulting mixture was stirred overnight at room temp. The resulting mixture was diluted with Et,0 and washed successively with sat. NaHC03, 1 N HC1, H,0, and brine. The extract was dried over NajSC^ and evaporated to give 1.22 g (45%) ethyl 3-methoxy-4-(2-//-trifluoroacetamidoethoxy) benzoate as an oil. 'H-NMR (CDCl3) d 1.39 (t, 3 H, 7=7.3 Hz), 3.77-3.81 (m, 2 H), 3.92 (s, 3 H), 4.13-4.20 (m, 2 H), 4.37 (q, 2 H, .7=7.3 Hz), 6.92 (d, 1 H, .7=8.7 Hz), 7.59 (d, 1 H, J=2.0 Hz), 7.67 (dd, 1 H, 7=2.0, 8.7 Hz); MS (FAB) m/z 335 (M*), 290 (M"-OEt). To a stirred solution of ethyl 3-methoxy-4-(2-Af-trifluoroacelamidoethoxy)benzoate (1.20 g, 3.58 mmol) in DMF (15 mL) was added K,COj (0.98 g, 7.09 mmol) and EtI (0.43 mL, 5.38 mmol) at room temp. The resulting mixture was stirred for 2 days at 60' C. The mixture was diluted with EtOAc, washed successively with 1 N HC1, brine, and dried over NajSO,. The solvent was evaporated and the residue was purified by column chromatography on silica-gel with n- hexane-EtOAc (2:1, v/v) as eluent to give 990 mg (76%) ethyl 3-methoxy-4-[2-(#-ethyl-//-trifluoroacetamido)emoxybeiizoate as a yellow crystalline solid. 'H-NMR (CDCIj) d 1.28-1.31 (m, 3 H), 1.37-1.40 To a stirred solution of ethyl 3-methoxy4-[2-(A,-ethyl-A'-trifluoroacetamido) ethoxybenzoale (990 mg, 2.73 mmol) in THF-MeOH-HjO (2:1:1, v/v, 20 mL) was added KsCOj (560 mg, 4.05 mmol), and the resulting mixture was stirred overnight. The resulting mixture was diluted with H30 and extracted with ElOAc. The extract was washed successively with sat. NaHC03, brine, dried over NajSO To a stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-IA,"-(2-meihylphenyl)uTeido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added EtjN (250 iA, 1.79 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCI, brine, and dried over NaiSO* The solvent was evaporated and the residue was purified by.column chromatography on silica-gel with CHClj-MeOH (40:1, v/v) as an eluent to give 550 mg (93%) ethyl 3-methoxy-4-[2-[3-methoxy-4-[tf'-{2-methylphenyI)ureido] phenylacety]]ethylaminoethoxy] benzoate as an amorphous solid. 'H-NMR (CDC10 d 1.11-1-18 (m, 3 H), 1.37-1.41 (m, 3 H), 2.30 (s, 3 H), 3.47-3.53 (m, 2 H), 3.61-3.75 (m, 7 H), 3.84 (s, 3 H), 4.034.27 (m, 2 H), 4.334.39 (m, 2 H), 6.34-8.07 (series of m, total 12 H). To a solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[?7*-{2-methylpbenyl)ureido]phenyl acetyl]ethylaminoethoxyjbenzoate (550 mg, 0.98 mmol) in THF (15 mL) was added 0.25 N NaOH (15 mL). The resulting mixture was then heated under reflux for 2 days. The mixture was poured into 1 N HCI and the solid was collected. The crude solid was recrystallized from EtOH-CHClj to give 182 mg (35%) 3-methoxy-4-[2-[3-methoxy-4-[Ar'-(2-methylphenyl)ureido]pheny!acetyl] ethylaminoethoxy]benzoic acid 256 as a white crystalline powder, mp 115-118 "C; IR(KBr) 1707 cm"1; 'H-NMR (DMSO-dJ d 1.02-1.12 (m, 3 H), 2.25 (s, 3 H), 2-50 (s, 2 H), 3.35-3.89 (m, 10 H), 4.11-4.16 (m, 2H), 6.71-8.56 (series of m, total 12H), 12.65 (br s, 1H); MS (FAB) m^ 536 (M*+l); Anal. Calcd for Cj9H33N3O,-3/4H,0: C, 63.43; H,6.33; N, 7.65. Found: 63.34; H, 6.28; N, 7.2S. MeOH (4:1, v/v, 140 mL) was added TMSCHNj (14.10 mL, 28.20 mmol, 2 M solution in hexane) at room temp, and the resulting mixture was stirred overnight. The mixture was evaporated and the residue was purified by column chromatography on silica-gel with CHC1} as eluent to give 4.18 g (75%) methyl 3-nitro-4-hydroxybenzoate as a yellow crystalline solid. 'H-NMR (CDC13) d 3.95 (S, 3H), 7.22 (d, 1H, .7=8.8 Hz), 8.24 (dd, 1 , >2.0, 8.8 Hz), 8.83 (d, 1H, 7=2.0 Hz), 10.89 (s, 1H). To a stirred solution of methyl 3-nitro-4-hydroxyben2oate (1.9a g, 10.04 mmol), M-Boc ethanoIamine(1.63g, 10.11 mmol) and PPhj (3.43 g, 13.08 mmol) in THF (40 mL) was added DIAD (2.57 mL, 13.05 mmol), and the reaction mixture was then heated under reflux overnight. The resulting mixture was evaporated to give a gum. The residual crude gum was dissolved in CH2CI, (30 mL) and TFA (30 mL), and the mixture was stirred for 1 hr at room temp. The mixture was concentrated In vacuo and made basic with sat. NaHCOi- The mixture was extracted with CHClj, washed with brine, and dried over Na3SO,. The solvent was evaporated in vacuo to give the oily residue, which was purified by column chromatography on silica -gel with CHC13 then CHClj-MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps) methyl 3-nitro-4-(2-aminoethoxy) benzoate as gum. 'H-NMR (CDCI3)d 3.16-3.19 (m, 1 H), 3.53-3.57 (m, 1 H), 3.90 and 3.94 (s, 3 H), 3.95-3.98 (m, 1 H), 4.21-4.24 (m, 1 H), 6.89-6.91 and 7.11-7.13 (m. 1 H), 8.03-8.19 and 8.21 (m, 1 H), 8.52 and 8.86 (m, I H). To a stirred solution of peniafluoropheny! ester of 3-methoxy-4-[Ar'-(2-methyl phenyl) ureido] phenylacetic acid (1.86 g, 3,87 mmol) and melhyl3-iulro-4-(2-aminoethoxy)benzoicacid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0,5 N HC1 and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with ElOAc, washed with brine, dried over Na,SO ureido] phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaiiunoethoxy) beraoate (78 mg, 0.29 mmol) was added Et3N (0. lmL, 0.72 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed successively with 0.5N HC1, brine, dried over NasSO., and evaporated. The residue was purified by column chromatography on silica-gel with CHClj-MeOH (50:1, v/v) as eluent to give 160 mg(q.y.) ethyl 3-methoxy.-4-[2-I3-methoxy -4-[A'-(2-fluorophenyt) ureido]phenylacetyl]ethylaminoethoxy]ben2oate as an oil. 'H-NMR (CDClj) d 1.13-.1.23 (m, 3 H), 1.37-1.40 (m, 3 H), 2.90-3.89 (m, 12 H), 4.09-4.28 (m, 2 H)| 4.33-4.39 (m, 2 H), 6.70-8.21 (series of m, total 12 H). To a stirred solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[//,-(2-fiuorophenyl)urcido] phenylacetylJethylamiriQethoxyJbenzoate (160 mg, 0.28 mmol) in THF (5 mL) was added 0.25 N NaOH (5 mL) and the resulting mixture was the heated under reflux overnight. The mixture was poured into 1 N HCl and the solid was collected. The crude solid was recrystalliaed from ElOH-CHClrrt-hexane lo give 70 mg (46%) 3-methoxy-4-[2-[3-methoxy-4-[Ar-(2-nuorophenyl)ureido] phenyJacetyl]ethylaminoethoxy] benzoic acid 258 as a yellow crystalline powder, mp 105-110 °C; IR (KBr) 1687 cm'; 'H-NMR (DMSO-d,) d 1.00-1.10 (m, 3 H), 2.48 (s, 2 H), 3.35-3.81 (m, 10 H), 4.13-4.14 (m, 2 H), 6.70-9.15 (series of m, 12 H); MS (FAB) m/z 540 (M*+!);,4na/. Caicd for r..H..PN.O,l/2H,0: C. 61.31; H, 5,82; N, 7.47. Found: C, 61,05; H, 5.82; N, 7.47. fluoroben2oate (903 mg, 5.37 mmol), andKsCOj(I.Il g, 8.06 mmol) in DMF (10 mL) was heated at 120°C overnight. After cooling, the mixture was diluted with EtOAc (300 mL), followed by washing withbrine (2 x 200 mL), drying over MgSO,, and evaporation. The residue was . chromatographcd on silica-gel with CHCIrEtOAc (20:1 to 4:1, v/v) as eluent to give 257 mg (14%) ethyl 4-[4K'e«-butyloxycarbonyl)-l-piperazinyl]benzoate as a pale yellow amorphous solid. IP. (KBr) 1701,1612 cnv!; 'H-NMR (CDCy d 1.37 (3 H, \, J= 73 Hz), 1.49 (9 H, s), 3.30 (4 H, t, J = 5.4 Hz), 3.58 (4 H, t, J= 5.4 Hz), 4.33 (2 H, q, J= 7.3 Hz), 6.87 (2 H, d, J = 8.8 Hz), 7.94 (2 H, dt, J = 8.8, 2.4 Hz); MS (FAB) m/z 335 (MM); Anal. Calcd for C^j^O,: C, 64.54; H, 7.84; N, 8,38. Found: C, 64.39; H, 7.89; N, 8.38. To a stirred solution of eihyl 4-[4-(rew-butyloxycarbony])-l-piperazinyl]benzoate (240 mg, 0.718 mmol) in CHjCl, (5 mL) was added TFA (5 mL), and the resulting mixture was stirred for 3 hr. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO,, followed by extraction with CHC13 (2 x 100 mL). The combined' extracts were dried over Na3CO} and evaporated to give 168 mg ethyl 4-(l-piperazinyl)benzoate (100%) as a yellow oil. 'H-NMR (CDClj) d 1.37 (3 U.X.J " 7.3 Hz), 3.03 (4 H, t, J= 4.9 Hz), 3.29 (4H,t,7 = 4.9 Hz), 4.33 (2 H, q, /= 7.3 Hz), 6.87 (2 H, dt, J= 8.8, 2.4 Hz),. 7.91-7.94 (2 H, m). To a stirred solution of ethyl 4-(l-piperazinyl)benzoate (170 mg, 0.730 mmol) and 3-methoxy-4-[//,-(2-methylphenyl)ureido]phenyIacetic acid (229 mg, 0.730 mmol) in DMF (10 mL) was added EDC-HC1 (210 mg, 1.10 mmol), DMAP (catalytic amount), andHOBt (catalytic amount), and the mixture was stirred overnight. The mixture was poured into H,0 (100 mL) and the solid was collected with suction. The residue was recrystallized from CHCl3-n-hexane to give 290 mg (75%) ethyl 4-[4-[3-methoxy-4-[An-(2-methylphenyl)ureido]phenyl]acetyI-l-piperazinyl benzoate as a colorless crystalline powder, mp 208-210 °C; IR(KBr) 1711, 1695 cnv'; 'H-NMR (CDC13) d 1.37 (3 H, t, J = 7.3 Hz), 2.29 (3 H, s), 3,14 (2 H, t, /= 4.9 Hz), 3.28 (2 H, t, J = 4.9 Hz), 3.62 (2 H, l, J= 4.9 Hz). 3.71 (3 H, s), 3.72 (2 H, s), 3.79 (2 H, t, J = 4.9Hz), 4.33 (2 H, q, J = 7.3 Hz), 6.38 (1 H, s), 6.78-6.99 (4 H, m), 7.13-7.24 (4 H, m), 7.50 (1 H, d, J = 7.8 Hz), 7.92 (2 H, d. J = 8.8 Hz), 8.12 (1 H, d, J = 7,8 Hz); MS (FAB) m/z 531 (M'+l); Anal. Calcd for C3(HWNAO-5H,0: C,66.77; H, 6.54;N, 10.38. Found; C, 66.89; H, 6.39; N, 10.45. To a stirred solution of ethyl 4-[4-[3-methoxy-4^-(2-methyIphenyl)ureido]phenyl]-acetyl-1-piperazinylbenzoate (290 mg, 0.547 mmol) in MeOH-THF (2:1, v/v, 15 mL) was added 0.25 N NaOH {5 mL, 1.25 mmol) and the mixture was heated under reflux for 3 hi. The mixture was poured into ice-lN HC1 (100 mL) and the solid was collected with suction. The residue was recrystallized from CHCIj-MeOH to give 190 mg (69%) 4-[4-[3-methaxy-4-[Ar.{2-methyipheny]) ureido]phenyl]acetyI-l -piperazinylbenzoic acid 259 as a yellow crystalline powder, mp 240-245 °C; 'H-NMR (DMSO) d 2.24 (3 H, s), 3.17-3.50 (8 H, m), 3.72 (2 H. s), 3.86 (3 H, s), 6.77 (1 H, d, J= 8.3 Hz), 6.90 (1 H, s), 6.91-6.96 (3 H, m), 7.11-7.17 (2 H, m). 7.76-7.80 (3 H, m), 8.03 (1 H, d, J = 8.3 Hz), 8.47 (1 H, s), 8.58 (1 H, s), 12.30 (1 H, s); Anal.Caicd for Q.HJONAHJO: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.64; H, 5.85; N, 10.51. (6.70 mL, 0.05 mmol) in DMF~H,0 (1:1, v/v)(40 mL) was added (Boc),0 (10.0 mL, 0.04 mmol), and the resulting mixture was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with H,0, brine, dried over Na,SO, and evaporated to give 6.91 g (98%) (R)-2-N-rerj-butoxycarbonylamino-l-propanol as a colorless oil. 'H-NMR (CDCIj) 51.15 (d, 3 H, J=6.8 Hz), 1.45 (s, 9 H), 3.48-3.53 (m, 1 H), 3.62-3.66 (m, 1 H), 3.76-3.77 (m, 1 H); MS (FAB)m/z 176 (M'+l), 120 (M*-"Bu). To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (7.74 g, 0.04 mmol), (R)-2-N-/eM-butoxycarbonylamino-l-propanol (6.91 g, 0.04 mmol) and Ph3P (13.44 g, 0.05 mmol) in THF (70 mL) was added diisopropyl azodicarboxylale(DIAD)(10.0 mL, 0.05 mmol), and the resulting mixture was heated under reflux overnight. After cooling to room temp, the solvent was evaporated. The mixture was dissolved in CHJCIJ (50 mL) and TFA (30 mL) and the solution was stirred at room temp for 1 hr. After concentration in vacuo, the residue was poured into sat. NaHC03 and extracted with CHCI,. The extract was washed with brine, dried over Na3SO« 3nd evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHClj as eluent to give 7.93g (2 steps 79%) ethyl (tf)-3-methoxy-4-(2-amino-l-propoxy)ben2oate as a yellow oil. 'H-NMR (CDC13) 6 1.90 (d, 3H, >6.8Hz), 1.39 {t, 3 H, .7=7.3 H2), 1.72 (bs, 2 H), 3.42-3.47 (m, 1 H), 3.74-3.89 (m, 1 H), 3.91 (s, 3 H), 3.96-4.00 (m, 1 H), 4.35 (q, 2 H, 7=7.3 Hz), 6.88 (d, 1 H, >8,3 Hz), 7.55 (d, 1 H, J=2.0 Hz), 7.65 (dd, 1 H, .7=2.0, 8.3 Hz); MS (FAB) m/z 254 (M++l). To a stirred solution of pentafluorophenyl 3-methoxy-4-IW-(2-methylphenyl)ureido] phenylacetate (459 mg, 0.96 mmol) and ethyl (fi)-3-methoxy-4-(2-aminopropoxy)bcnzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3N (200 tA, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCI, brine, dried over Na,SO, and evaporated. The residue was purified by column chromatography on silica-gel with CHCVMeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (7?)-3-mcthoxy-4-[2-[3-methoxy-4-[iV'-(2-methylphenyl)ureido]phenylacetylamino]-l-propoxy]benzoate as a colorless crystalline solid. 'H-NMR. (CDC13) 5 1.23-1.28 (m, 3 H), 1.38-1.41 (t, 3 H, .7=7.3 Hz), 2.32 (S, 3 H), 3.50-4.13 (m, total 11 H), 4.36 (q, 2 H,.7=7.3 Hz), 6.65-8.13 (series of m, total 12 H). To a stirred solution of ethyl (£)-3-methoxy-4-[2-[3-rnethoxy-4-(Ar'-(2-methylphenyl) ureido] phenyiacetylamino]-l-propoxy]benzoate(360 mg, 0.66 mmol) in THF-MeOH (20 mL, 9:1, v/v) was added 0.25 N NaOH (10 mL), and the resulting mixture was heated under reflux overnight. The.mixture was poured into ice-1 N HCI, and precipitate was collected. The crude solid was recrystallized from CHClj-n-hexane to give 172 mg(50%) 260 as a white crystalline powder, mp 168-169 "C; IR{KBr) 1687 cm"1; 'H-NMR (DMSO-d«) 5 1.18 (d, 3 H, .7=6.8 Hz), 2.24 (s, 3 H), 2.50-2.51 (m, 2 H), 3.80 (s, 3 H), 3.84 (s, 3 H), 3.87-4.06 (m, 2 H), 4.07-4.14 (m, 1 H), 6.76-8.57 (series of m, total 12 H), 12.66 (bs, 1 H); MS (FAB) m/z 522 (M'+l); Anal. Calcd for CKH^30fy4 H20: C, 62.85; H, 6.12; N, 7.85. Found: C, 62.77; H, 5.95 N, 7.79. To a stirred mixture of ethyl 4-(2-JV-trifluoroacety]aminoethoxy)-3-methoxy benzoate (3.5g, 10.4mmoi)and KiCOi(2.3g, 36.4mmol) in DMF (20mL) was added allyl bromide (14.2mL, 16".5mmol), and the resulting mixture was stirred for 45 min at 65° C. After cooling, water was added to the mixture and extracted with EtOAc. The extract was washed with brine, dried over NasS04, and evaporated in vacuo. The residue was dissolved in THF-MeOH-HjO (l:l:l,v/v/v) (30 mL) and added K,COj(2.3 g, 16.4 mmol). The resulting mixture was stirred for 16 hr at room temp. The mixture was diluted with EtOAc, washed with brine, dried over Na,SO,, and evaporated. The residue was chromatogTaphed on silica-gel with CHCl3:MeOH (95:5 to 95:5, v/v) as eluent to give 2.9 g (100%) ethyl 4-(2-allyIaminoethoxy)-3-methoxybenzoate as a pale-yellow oil. 'H-NMR(CDC13,400MHz) 8 1.39 (t, 3H, /=7.3Hz), 3.07 ft 2H, J=S.3tiz), 3.34 (d, 2H, y=5.9Hz), 3.91 (s. 3H), 4.18 (t, 2H,>5.4Hz), 4.35 (dd, 2H,/=7.3Hz, 14.1Hz), 5.12 (d, IH,' y=10.3Hz), 5.22(dd, 1H, J=1.5Hz, 17.1Hz), 5.92 (m, 2H), 6.90 (d, 1H, J=$.3H2), 7.55 (d, 1H, J=1.5Hz), 7.65 (dd, lH,>2.GHz, 8.3Hz); MS(FAB) m/z 278,280(M+H)*. To a stirred mixture of ethyl 4-(2-aitylaminoelhoxy)-3-methoxy benzoate (578mg, 2.Irnmol), 3-methoxy-4-[AM2-methylphenyI)ureido]phenylaceticacid (650mg,2.1mmol), HOBt (420mg, 3.! Immol). and DMAP (catalytic amount) in DMF (4 mL) was added EDC (596mg,3.1Immol) at room temp. The resulting mixture was stirred for a further 18 hr at room temp. The mixture was poured into IN HC1 and extracted with EtOAc. The extract was washed with brine, dried over Na,SO,, and evaporated in vacuo. The residue was chromatographed on silica-gel with CHCl3:EtOAC (95:5 to 1:1, v/v) as ehient to give Ig(84%) 3-methoxy-4-[[2-[3-methoxy-4-[A'-(2-methyIphenyI)ureido] phenylacetyl]allylamino]ethoxy] benzoic acid as a pale-yellow gum. 'H-NMR(CDC13, 400MHz) 5 1.39 (t, 3H, >7.3Hz), 2.29 (s, 3H), 3.58 and 3.63 (s, total 3H), 3.70-3.77 (m, 2H), 3.83 and 3.87 (s, 3H), 4.05-4.13 (m, 2H), 4.25 (m, 1H), 4.36 (q, IH, >7.0Hz), 5.04-5.22 (m, 2H), 5.73 (m, IH), 6.32 and 6.47 (s, IH), 6.69-6,85 (m, 2H), 7.12 (m, 2H), 7.23 (m, 2K), 7.50-7.65 (m, 2H). 8.05 (d, lH,J=7.8Hz)-, MS (FAB) m/z 576(M+H)*. A mixture of 3-meliioxy-4-[[2-I3-methoxy-4-[N'-(2-inethylphenyl)weido]pheny\aceyl] allylamino]ethoxy]ben20!C acid (50mg, 0.09mmo!) in THF-MeOH (1:1, v/v) (2mL) and IN NaOH (O.I35mL, 0,135mmol was stirred for 15 hrat room temp and 3 hratSO^C. The mixture was poured into ice-lN HCI. Solid was collected, washed with water, and air-dried. The crude solid was recrvstallized from CHClj-n-hexane to give 38mg (77%) 261 as a white crystalline material, mp 125-130 °C; IR(KBr), 3319, 2939, 1687, 1647, 1601, 1535, 1456, 1417, 1269, 1223, 1034, 760cm-'; 'H-NMRQMSO-d* 400MHz) 5 2.29 (s, 3H), 3.68 (s, 2H), 3.75-3.85 (m, 8H), 4.05 {br, 1H), 4.19 (m, 3H), 5.10-5,25 (m, 2H), 5.65-5.90 (m, 1H), 6.75 (m, 1H), 6.85 (s, 1H), 6.92 (m. 1H), 7.02-7.20 (m, 3H), 7.48 (d, 1H, J=10.2Hz), 7.56 (m, 1H), 7.79 (d, 1H, >6.BHz). 8.01 (m, 1H), 8.46 (s, )H), 8.56 (d, 1H, /=4.4Hz), 12.7 (br, 1H); MS (FAB) m£ 548(M+Hr;-4/ifl/. calcd. for C3oH33NjO,'0.5H,O, C, 64,74; H, 6.16; N, 7,55. Found, C, 64.72; H, 6.07; N, 7.55, phenylacetylJa!lylamino]ethaxy]benzcic acid (950mg, I.65mmo!) in THF:H,0 (7mL) was added A'-methylmorpholine-A'-oxide (579mg,4.95mmol) and osmium tetroxide (0.2M solution in water) (0.413mL, O.OSmmoI). The resulting mixture was stirred for 3 hr at room temp. SatNaHSOjwas added to the mixture, and the mixture was filtered through Celite. The filtrate was extracted with EtOAc. The extract was washed with brine, dried over MgSO,, and evaporated in vacuo. The residue was dissolved in MeOH-THF-HjO (1:1:1, v/v)(12mL) and added sodium periodate (318mg,1.5mmol). The resulting mixture was stirred at an ambient temp for 1 hi. Themixture was diluted with EtOAc, washed with brine, and dried over MgS04. Solvent was evaporated in vacuo to afford'862rng (90%) ethyl 3-methoxy-4-[[2-[3-methoxy-4-[W-(2-methylphenyI)uieido] phenylacetyl]-Af-forrnylmethylamino]ethoxy] benzoate as a pale-yellow gum. 'H-NMR (CDC13, 400MHz) 8 1.39 (t, 3H, >7.3Hz), 2.29 (s. 3H), 3.31-3.95 (m, 11H), 4.10-4.42 (m, 5H), 6.51-6.82 (m, 3H), 7.10-7.25 (m, 3H), 7.50 (m, 2H), 7.60 (m, 1H), 8.10 (m, 1H), 9.50 (m, IH); MS (FAB) m/z 578 (M+H)*. To a stirred mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[A'-(2-methylphenyl)ureido] pheny!acetyl]-Ar-fonnyImethylamino]ethoxy]benzoate (265mg, 0.46mmol), morpholine (0.40mL, 4.59mmol), and AcOH (0.263mL, 4.6mmol) in EtOH (3mL) was added NaBHjCN (288mg, 4.6mmol)at room temp. The resulting mixture was stirred for 15 hr at room temp and the mixture was diluted with EtOAc and added sat. NaHCOj al 0" c. The resulting mixture was stirred for 0,5 hr at 0° C. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO,, and evaporated in vacuo. The residue was chromatographed on silica- gel with CHCl3:MeOH (95:5, v/v) as eluenl to give 213mg (71%) ethyl 3-mcthoxy-4-[[2-I3- mcthoxy-4-[//,-(2-meUiy]pheny])urcido]phenylacetyl]-(2-morpholino)ethy]amino]eihoxy]bcn2oate as an oil. JH-NMR (CDClj, 400MHz) 6 1.28 (t, 3H, ^7.0Hz), 2.31(s, 3H), 2.48 (brs, 4H), 2.52 (m,2H), 3.60-3.91 (m, 16H), 4.11 and 4.28 (m , total 2H), 4.39 (q. 2H,y=7.0Hz), 6.70-6.85 (m, 4H), 7.15 (m, 2H), 7.50-7.63 (m, 3H), 8.08 (d, 1H, y=8.0Hz); MS (FAB) m/i 649(M+H)'. A mixture of ethyl 3-mcthoxy-4-[[2-[3-methoxy-4-(^-{2-incthylphenyl)ureido]phenyl acetyl]-(2-inorpholino)ethytamino]etrioxy]benzoate (265mg, 0.46mmol) in THF (4mL) and IN NaOH (0.984roL) was stirred at 50° C for 15 hi. The pH of the mixture was adjusted to 7.4 by the addition of IN HC1, and extracted with CHCl3:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO., and evaporated in vacuo. The residue was crystallized with Et,0 to give 160 mg(78%) 262 as a white crystalline material, mp 125-130 "C; IR. (KBr), 3346, 2956, 2937, 1705,1622, 1599, 1537, 1456, 1417,1299,1114, 1032, 752cm-1; 'H-NMR (CDjOD, 400MHz) 5 2.29 (s, 3H), 2.49-2.64 (m, 6H), 3.65-3.S5 (m, 16H), 4.13 (m, 1H), 4.26 (m, JH), 6.78-7.04 (m, 4H), 7.18 (m, 2H), 7.55-7.64 (m, 3H), 7.99 (m, 2H); MS (FAB) m/i 621(M+H)*M/io/. Calcd. for CJJH^NA^^HA C, 59.54; H, 6.81; N, 8.42. Found, C, 59.71; H, 6.35; N, 7.98. pheny I acetyl]-A'-formylmethy lamina Jethoxy]benzoate (242mg, 0.42mmol), //-methyl piperazine (0.465mL, 4.2mmol), and AcOH (0.240mL, 4,2mmol) in ElOH (3mL) was added NaBH3CN (263mg, 4.2mmol) at room temp. The resulting mixture was stirred for 15 hr at room temp. The mixture was diluted with EtOAc and added sal. NaHCOj at 0° C. The resulting mixture was stirred for 0,5 hr at 0° C. The mixture was extracted with ElOAc. The extract was washed with brine, dried over MgSO,, and evaporated in vacuo. The residue was chromatographed on silica-gel with CHCl,:MeOH (95:5, v/v) as eluent to give 195mg (70%) ethyl 3-meUioxy-4-[[2-[3-methoxy-4-[Af,-(2-methylphenyl)ureido] pheny!ac«yl]-[2-(4-methyl-l-piperazinyl]ethylamino] ethoxyjbenzoate as an oil. 'H-NMR (CDCIj, 400MHz) 5 1.23 (t, 3H, >7.0Hz), 2.25 (s, 3H), 2.29 (s, 3H). 2.50 {br m, 12H), 3.44-3.85 (m, 12H), 4.10 (br, 1H), 4.22 (br, 1H), 4.35 (m, 2H), 6.70-6.85 (m, 3H), 6,98 (s, 1H), 7.10 (m, 1H), 7.20 (m. 2H), 7.40 (m, 1H), 7.60-7.70 (m, 3H), 8.05( d, 1H, J=7,8Hz); MS (FAB) mh 662(M+H)*. A mixture of ethyl 3-melhoxy-4-[[2-[3-methoxy-4-[/V-{2-mcthylphenyl)ureido] pheny]acery]]-[2-(4-methyl-l-piperazinyl]ethylarnino]ethoxy]beiizoate (I95mg, 0.30mmol) in THF:MeOH(4:l, v/v) (5mL) and IN NaOH(0.885mL) was stirred at 50° C for 15 hr. The pH of the mixture was adjusted to 7.4 by the addition of IN HC1, and extracted with CHClj:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO«, and evaporated in vacuo. The residue was crystallized with Et,0 to give 141 mg(75%) 2S3 as a white crystalline material, mp 155-160 °C; 1R (KBr), 2937, 1537, 783cm-'; 'H-NMR (CD3OD, 400MHz) 6 2.29 (s, 3H), 2.49-2.80 (m, 15H), 3.60-3.85 (m, 9H), 3.92 (s, 1H), 4.12 (m, 1H), 4.25 (m, 1H), 6.78-7.20 phenylacetyl]-W-formylmethylamino)ethoxy]benzoate (267mg, 0.46mmol), cyclopropylamine (0.32mL, 4.6mmol), and AcOH (0.264tnL, 4.6mmol) in EtOH (3mL) was added NaBHjCN (290mg, 4.6mmol) at room temp. The resulting mixture was stirred for 15 hr at room temp. The mixture was diluted with EtOAc and added sat. NaHCO, at 0° C. The resulting mixture was stirred for 0.5 hr at 0°C. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO., and evaporated in vacuo. The residue was chromatographed on silica-gel with CHC!3:MeOH {95:5, v/v) as eluent to give 156mg (55%) ethyl 3-methoxy-4-[[2-[3-methoxy-4-[A'-(2-meihylpheny!)ureido]phenylacetyl]-[2-cyclopropylamino]ethylamino] ethoxyjbenzoate as an oil. 'H-NMR (CDCIj, 400MHz) 5 0.35 (m, 4H), 1.22 (brs, 3H), 2,10 (m, 1H), 2,20 (s, 3H), 2.42 (br, 2H), 2.90 (br s, 2H), 3.60-3.80 (m, 10H), 4.10 (br, 1H), 4.22 (br, 1H), 4.33 (br, 2H), 6.72 (m, 3H), 7.05-7.30 (m, 4K), 7.55 (m, 4H), 8.06 (br s. 1H); MS (FAB) /n/i 619(M+H)'. A mixture of ethyl 3-melhoxy-4-[f2-[3-methoxy-4-[A'-(2-m«}3y!phenyJ)ureido] phenylacetyl]-W-[2-cyclopropylanuno]cthylamino]elhoxy]bcn2oate (195mg, 0.30mmol)) in THF:MeOH(4:l, v/v) (5mL) and IN NaOH(0.756mL) was stirred at 50° C for 15 hr. ThepHof the mixture was adjusted to 7.4 by the addition of IN HC1, and extracted with CHCVMeOH(9;J, v/v). The extract was washed with brine, dried over MgSO., and evaporated in vacuo. The residue was crystallized with El20 to give 57 mg (38%) 3-methoxy-4-[[2-[3-methoxy-4-[#,-(2-methyl phenyl)ureido]phenylacetyl]-[2-cyclopropylamino) ethylamino]ethoxy]benzoic acid 264' as a white crystalline material, mp 135-140 °C; IR (KBr), 3324, 2937, 1535,1032, 754cm-'; 'H-NMR (CD,OD, 400MHz) 6 0.50-0.73 (m, 4H), 2,29 (s, 3H), 2.53 (m, 1H), 2.98 (m, 1H), 3.21 (m, 1H), 3.58-3.88 (m, 11H), 3,91 (s, 1H), 4.09 (m, 1H), 4.25 (m, 1H), 6.76-6.92 (m, 3H), 7.01 (m, 1H), 7.18 (m, 2H), 7.60 (m, 3H), 8.00 (d, J=8.3Hz, 1H); MS (FAB) m/z 591(M-l-H)*;,W. Calcd. for C^H^O,-3.0H2O, C, 59.62; H, 6.88; N, 8.69. Found, C, 59.25; H, 6.29; N, 3.29. g, 14.4 mmol), methyl 3-chloro-4-hydr0)Cybenzoate (2.68 g, 14.4 mmol), PhjP (5.65 g, 21.5 mmol) in THF (30 mL) was added diisopropyl azodicarboxylate (DIAD) (4.25 mL, 21.6 mmol), and the resulting mixture was heated under reflux overnight. The solution was evaporated off and the residue was purified by column chromatography on silica-gel with CHC13 as eluent to give 3.90g . (72%) methyl 3-chloro-4-[2-(A'-benzyloxycarbonyl-Af-methylamino)ethoxy]ben2oate as a pale yellow solid. 'H-NMR (CDO,) o 3.15 (s, 3 H), 3.74-3.76 (m, 2 H), 3.89 (s, 3 H), 4.17-4.27 (m, 2 H), 5,14 A solution of methyl 3-chloro4-[2-(AM«nzyJoxycarbonyl-A'-memylajruno)ethoxy] benzoate (3.90 g, 10.3 mmol) in EtOAc-AcOH (40 mL, 1:1, v/v) was hydrogenaled over 5% Pd-C (1.95 g, 50 wt%) at 3 atm for 2 hr. The mixture was filtered and the filtrate was washed with sat. NaHC03 and the basic aqueous layer was extracted with CHC13, washed with brine and evaporate to give inseparable mixture of methyl 3-chloro-4-{A'-meUiylaininoethoxy)benzoate and methyl 4-E2-{M-methylamino) ethoxy]benzoate the title compound (1.61 g) as a pale yellow oil. 'H-NMR (CDC13) S 2.52-2.52 and 2.53-2.54 (each m, 3 H), 2.98-3.00 and 3.03-3.05 (each m, each 2 H), 3.88 and 3.99 (each s, each 3 H), 4.11-4.14 and 4.18-4.20 (each m, each 2 H), 6.91-6.96 and 7.90-8.05 (series of m, total 7 H). A mixture of 3-methoxy-4-[A'-(2-fluorophenyl)ureido]phenylacetic acid (392 mg), a mixture of methyl 3-chloro-4-[2-{A,-methylamino)ethoxy]benzoate and methyl 4-[2-(rV-methylamino)ethoxy] benzoate {305 mg), EDC(hydrochloride) (354 mg), HOBt (250 mg), and DMAP (250 mg) in DMF (8 mL) was stirred at room temp for 6 hr. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over NajSO, and evaporated. The residue was purified by column chromatography on silica-gel with 1% MeOH in CHClj as eluent to give a mixture of methyl 3-chloro-4-[[2-{3-rnethoxy-4-[A'-(2-fluorophenyl) ureido]phenylacetyl]-#-methylaminoethoxy]benzoate and methyl 4-[[2-[3-methoxy-4-[W-(2-fluorophenyl)ureido] phenylacetyl]-W-methylaminoethoxy]benzoate (550 mg) as a brown amorphous solid. To a stirred solution of this mixture (550 mg) of methyl 3-chloro-4-[[2-[3-methoxy-4-[//'-(2-fluorophenyl)ureido}phenylacetyl]-A'-methylaminoethoxy]benzoate and methyl 4-[[2-[3-metho>^-4-[A'-(2-fluorophenyl)uieido]phenylacetyl]-Ar-methylaminoethoxy]ben2oate inTHF-MeOH(20 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux for 6 hr. The mixture was poured into ice-1 N HC1, and the solid was collected. The crude solid was purified by preparative TLC with 10% MeOH in CHC13 as eluent to give 265 {56 mg, as a white amorphous solid) and 266 (88 mg, as a brown amorphous solid). 1.2mmoI), 3-methoxy-4-[An-(2-niethylpheny])urcido]phenylaceticacid (377mg,1.2mmol), EDC (345mg,1.8mmol), HOBt(243mg,].8mmoI), and DMAP(29mg, 0.24mmol) in DMF(2.7mL) was stirred for 6 hr at room temp. The mixture was poured into ice-lN HC1 and extracted with ElOAc. The extract was washed with brine, dried over MgSO,, and evaporated in vacuo. The residue was chiomatographed on silica-gel with CHCl,:ElOAc (95:5 to 0:100, v/v) as eluent to give unseparable mixture (489nig) of methyl 3-cbJoro-4-[[2-[3-methoxy-4-[A',-(2-irKthylphenyl)ureido]phenylacetvI) methylaminojethoxyjbenzoate and methyl 4-[{2-[3-methoxy-4-ryV-(2-methy]phenyl)ureidD]pheny] acetyl] methyl amino] ethoxy]benzoate as pale-yellow oil, A mixture (480mg as mixture) of methyl 3-chloro-4-[[2-[3-methoxy-4-[A'-(2-methy! phenyl)ureido] phenyl acetyl] methyl amino] ethoxy]benzoate and methyl 4-[[2-[3-methoxy-4-[A^-(2-methylphenyl)ureido]pheiiyl3cetyl]methylaniino]et]ioxy]ben2oateinTHF-MeOH(4mL, 1:1, v/v) was stirred at 50° C for 15 hr. The mixture was poured into ice-lN HC1. The solid was collected, washed with water, and air-dried. The crude solid was purified by preparative TLC CHCl^MeOH (93:7, v/v) as eluent to afford 267 (ISOmg, 2steps3J% as a crystaJline material) and 268 {280mg, 2steps 44% as a crystalline material).' 267 : mp 145-150 "C; 'H-NMR (DMSO-dj, 400MHz) 8 2.31 (s, 3H), 3.05 and 3.19 (s, 3H), 3.35 and 3.38 (s, 3H), 3,72-3.85 (m, 7H), 4.09 and 4.23 (m, total 2H), 6,79-7.20 (m, 7B), 7.60 (m, 1H), 7.86-8.09(m, 3H); MS (FAB) m/z 493(M+H)+; Anal, calcd. for CHDNA'I-^HJO, C, 62.00; H, 6.26; N, 8.03. Found, C, 62.16; H, 5.88; N, 7.82. 268: mp 145-150 °C; 'H-NMR (DMSO-fL,, 400MHz) 5 2,29 (s, 3H), 3.06 and 3.26 (s, 3H), 3.31 and 3.35 (s, 3H), 3.85-3.94 (m, 4H), 4,18 and 4.32 (m, total 2H), 6,75-6.85 (m, 2H), 6.99-7.20 (m, 4H), 7.59 (m, IH), 7.90-8.02 (m, 3H); MS (FAB) m/z 526(M+H)*; Anal, calcd. for C„HJSClN3O«-2.0HA C, 57.70; H, 5.74; N, 7.48. Found, C, 57,99; H, 5.53; N, 7.07. Example 219 4-[3-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phenylacetyl] -W-methy lamino] -1 -propy 1 ] be nzo i c acid 4.05 mmol) in THF (10 mL) was added NaHMDS (1.0 M in THF) (4.0 mL, 4.0 mmol), and the resulting mixture was stirred for 1 Jir at the same temp, A solution of 2-{A,-ben2yloxycarbony]-Af-methylamino) acetaldehyde (700 mg, 3.38 mmol) in THF (5 mL) was slowly added to this solution at that temp, and the mixture was allowed to warm to room temp for over 2 hr with stirring. The solution was quenched by the addition of sat. NH(C1 (100 mL), and extracted with EtOAc. The extract was washed with brine (200 mL), dried over MgSO,, and evaporated. The residue was chromatographed on silica gel with CHClj-EtOAc (20:1, v/v) as eluent to give 810 mg (68%) ethyl (£)-4-[3-(//-benzyIoxycarbonyI-A'-methyIamino)-l-propenylben2oate as a yellow oil. 'H-NMR (CDClj) 5 1.40 (t, ./= 7.3 Hz, 3 H), 2.95 (m, 2 H). 4.09 (m, 2 H), 4.35^.40 (m, 2 H), 5,17 (s, 2 H), 6.26-6.64 (series of m, 2 H), 7.36 (m, 7 H), 7.99 (d,J = 8.3 Hz, 2 H). A stirred solution of ethyl (£)-4-[3-(A,-benzyloKycarbonyl-A'-methylamino)-l-propcnyl benzoate (810 mg, 2.29 mmol) in EtOH-AcOH (10:1, v/v, 22 mL) was hydrogenated over 5%pd-C (1 g) for 3 days. The mixture was filtered and the filtrate was evaporated. The residue was made basic with sat. NaHC03 and extracted with CHClj. The extract was dried over NajCO, and evaporated to give 438 mg (86%) ethyl 4-(3-methylamino-l-propyl)ben2oate as a.yellow oil. lH-NMR (CDC1,) 6 1.39 (t, J =7.3 Hz, 3 H), 1.82 (m, 2 H), 2.43 (s, 3 H), 2.61 (t, J= 7.3 Hz, 2 H), 2.72 (t, J= 7.3 Hz, 2 H), 3.33 (br s, 1 H), 4.36 (q, J= 7.3 Hz, 2 H), 7.25 (d, J= 8.3 Hz, 2 H), 7.96 (d,/=8.3Hz,2H). To a stirred solution of 3-methoxy-4-lJV'-(2-rnethylphenyl)ureido]prienylacetic acid (456 mg, 1.45 mmol) and ethyl 4-(3-melhylamino-l-propyl)benzoate (220 mg, 1.45 mmol) were added EDC-HC1 (417 mg, 2.16 mmol), HOBt (cat.), and DMAP (catalytic amount) in DMF (10 mL), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc (300 mL), washed with brine, dried over MgS04, and evaporated. The residue was chromatographed on silica-gel with CHClrEtOH (10:1) to give 503 mg (71%) ethyl 4-l3-[3-methoxy^-[A'-(2-methylphenyl) ureid □]phenylaceryl-A'- methyl ami no] -1 -propyl] benzoate as a yellow oil. MS (FAB) m/z 518(M+H)*. To a stirred solution of ethyl 4-[3-[3-methoxy-4-]A'-(2-methylphenyl)ureido]phenyl acetyl-A'-methylamino3-l-propyl]benzoate (500 mg, 0.966 mmol) in THF (8 mL) was added 0.25 N NaOH (8 mL), and the mixture was heated under reflux overnight. The resulting solution was poured into ice-1 N HC1 (100 mL) and the solid was collected with suction. The solid was dissolved in CHClj (100 mL) and dried over MgSO,. After removal of the solvent, the residue was chromatographed on silica ge! with CHCl3-MeOH (10:1 to 5:1, v/v) to give 131 mg (28%)4-[3-[3-methoxy-4-[.W'-(2-methylphenyI)ureido] phenylacetyl-A'-methyl ami no] -1 -propyl] benzoic acid 269 as a pale yellow amorphous solid. 'H-NMR (DMSO-dJ 6 1.68-1.80 (m, 2 H), 2.24 (s, 3 H), 2.57 (m, 2 H), 2.81 and 2.97 (s, each, total 3 H). 3.33 (in, 2 H), 3.57-3.61 (m, 2 H), 3.84 (s, 3 H), 6.71 (d 1.29mmol), a mixture (304 mg) of methyl 3-chIoro4-[2-(Af-methylamino)ethoxy]benzoate and methyl 4-[2-(A'-methyl amino)ethoxy]benzoate and Et3N (260 mL) in DMF (8 mL) was stirred at room temp for 4 hr. The mixture was diluted with EtOAc, washed with 0.5 N BO, brine, dried over NajSO, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl,-MeOH (50:1, v/v) as eluent to give a mixture (670 mg) of methyl 3-chloro-4-[[2-[4-[W-(2-methylpherryl)ureido) phenylacetyl]-A'-tnethylamino) ethoxy]benzoate and methyl 4-J[2-[4-[JV '-(2-methylphenyl)ureido] phenylacetyl3-A'-melhylamino)ethoxy] benzoate as an oil. To a stirred suspension of this mixture (670 mg) in THF-MeOH (20 mL, 1:1, v/v) was added 0.5 N MaOH (10 mL) and the resulting mixture was heated under reflux for 6 hr. The solution was poured into ice-1 N HC1 and the solid was collected. The crude solid was purified by preparative thin layer chromatography (TLC) with 10% MeOH in CHClj as eluent to give 73 mg 270 as an amorphous solid and 110 mg 271 as a white amorphous solid. 270 MS (FAB) mfr 462 (M*+l). 271MS(FAB)m/z496(M'+l). (4.63 mL, 33.2 mmol) in DMF-HjO (40 mL, 1:1, v/v) was added (Boc),0 (6.36 mL, 27.7 mmol). and the resulting solution was stirred at room lemp for 2 days. HjO was added to the mixture and extracted with EtOAc. The extract was washed with brine and dried over NajSO,,. The solvent was evaporated to give 4.24 g (87%) (5)-2- (JV-ferf-butoxycarbonylaminoH-propanol as a colorless oil. 'H-NMR (CDC1J 5 1.14 (d, 3H, J=6.8Hz), 1.45 (s, 9 H), 3.51-3.52 (m, 1 H). 3.63-3.66 (m, 1 H), 3.77 (m, 1 H), 4.62 (m, I H). To a cooled (0° C) solution of (Sy2-(//-(erf-butoxycarbonylamino)-l-propanol (1.02 g, 5.82 mmol), methyl 4-hydroxybenzoate (0.89 g, 5.85 mmol), and PhjP (1.98 g, 7.55 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (1.49 mL, 7.57 mmol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH,Cli (20 mL) andTFA (10 mL). The mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo and the residue was treated with sat. NaHCO,. The mixture was extracted with CHClj, washed with brine, dried over Na^O* and evaporated. The residue was purified by column chromatography on silica-gel with CHC3:MeOH (50:1, v/v) to give 480 mg (2 steps 39%) methyl (i)-4-(2-amino-l-propoxy) benzoate as a pale yellow oil. 'H-NMR (CDClj)5 1.19 (d, 3 H, .7=6.4 Hz), 3.35-3,39 (m, 1 H), 3.72-3.76 (m, 1 H), 3.89 (s, 3 H), 3.90-3.94 (m, 1 H), 6.92 (d, 2 H, 7=8.8 Hz), 7.99 (d, 2 H, J=8.8 Hz). A mixture of pentafluorophenyi 3-methoxy-4-[Af'-(2-methylphenyl)oreido]phenylacetate (505 mg, 1.05 mmol), methyl (S)-4-(2-amino-l-propoxy)benzoate (220 mg, 1.05 mmol), andEt3N (0.220mL, 1.58 mmol) in DMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc, washed with 0.5 NHC!, brine, and dried over NajS04. After removal of the solvent, the residue was recrystallized from MeOH-CHCIj-n-hexane to give 290 mg (55%) methyl (S)-4-[2-[3-methoxy-4-[A'-(2-meUvylphenyi) ureido]phenylacetylarnino]-l-propoxy]benzQate as a white crystalline powder. 'H-NMR (DMSO-d^) 8 1.18 (d, 3 H, >6.8 Hz), 2,24 (s, 3 H), 3.36 (s, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 3.934.03 (m, 2H), 4,09-4.14 (m, 1H), 6.75-8.57 (series of m, tola! 13 H). To a stirred solution of methyl (S)-4-[2-[3-meihoxy-4-[Ar-(2-methylphenyi)ureido]phenyl acelyiaminoj-l-propoxyjoenzoaie (290 mg, 0.57 mmolj in THF-MeOH (20 mL, 1:1, v/V) was added 0.5 N NaOH (20 inL) and the solution was heated under reflux for 2 hr. The mixture was poured into ice-1 N UO and extracted with CHClj-MeOH (10 :\,vN), The extract was washed with brine, dried over NajSO( and evaporated. The residue was recrystallized from MeOH-CHCl,-n-hexane to give I5S mg (56%) 272 as a white crystalline powder, mp 198-201 "C; 'H-NMR (DMSO-cW 5 1.18 (d, 3 H,>6.3 Hz), 2.24 (s, 3 H), 3.36 (s, 2 H), 3.82 (s, 3 H), 3.87-4.10 (m, 2 H), 4.10-4.16 (m, I H), 6.75-6.78 (m, I H), 6.92-7.02 (m, 4 H), 7.11-7.18 (m, 2 H), 7.78-7.80 (m, 1 H), 7.86-7.89 (m, 2 H), 7.98-8.00 (ra, 1 H), 8.12-8.14 (m, 1 H), 8.46 (s, 1 H), 8.55 (s, 1 H), 12.62 (bs, I H); MS (FAB) m/z 492 (M*+l); ,4no/. Calcd for C^H^OJ-IQHJO: C, 64.79; H, 6.04; N, 8.21. Found: C, 64.36; H, 5.85; N, 8.21. 1.24 mmol), methyl (5>4-(2-amino-l-propoxy)beraoate (260 mg, 1.24 mmol), Et,N (0.260mL, 1.87 mmol) inDMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, brine, and dried over Na,SCV After removal of the solvent, the residue was purified by recrystallization from MeOH-CHCl,-n-hexane to give 210 mg (36%) (S)-4-[2-[3-methoxy4-[W'-(2-methyiphenyl)«reidoiphenylacetylamino]-l-propoxy]benzoic acid as a white crystalline powder. 'H-NMR (DMSO-dJ 8 1,17 (d, 3 H, ,7=6.8 Hz), 2.24 (s, 3 H), 3.32 (s, 2 H), 3.81 (s, 3 H), 3.92-4.03 (m, 2 H), 4.08-4.15 (m, 1 H), 6.92-6.95 (m, 1 H), 7.04-7.06 (m, 2 H), 7,12-7.18 To a stirred solution of methyl (S>4-[2-I4-[A'-(2-methylphenyl)ureido]phenylacetyl 5rnino]-l-propoxy]benzoale(200mg, 0.42 mmol) inTHF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the mixture was heated under reflux for 2 hr. The mixture was poured into ice-1 N HC1, and the solid was collected. The crude solid was recrystallized from MeOH-CHClj-n-tiexane to give 68 mg (34%) 273 as a white crystalline powder, mp 262-265 °C; 'H-NMR [DMSO-d,) 5 1.17 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.32 (s, 2 H), 3.91-4.02 (m, 2 H), 4.09-4.15 (m, 1 H), 6.92-6.96 {m, 1 H), 7.01-7.03 (m, 2 H), 7.12-7.20 (m, 4 H), 7.36-7.40 (m, 2 H), 7.83-7.95 (m, 4 H), 8.12-8.14 (m, 1 H), 8,99 (s, 1 H), 12.63 (bs, 1 H); MS (FAB) m/z 462 QJ?+\)\Anal, CaJcdfor CWH,rN3Oj-l/4HzO: C, 67.0J; H, 5.95; N, 9.02. Found: C, 67.13; H, 5,90; N, 9.02. 5.99 mmol), methyl 3-chJoro-4-hydroxybenzoate (1.12 g, 6.00 mmol), and PhjP (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylale (DIAD) (1.77 mL, 8.99 mmol), and the resulting mixture was heated under reflux for 2 days. The solution was evaporated off and . the residue was dissolved in CH,C1, (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temp for 1.5 hr. The solution was concentrated in vacuo, and the residue was dissolved in CHCIj. The mixture was extracted with H30, and the aqueous layer was made basic by the addition of sat. NaHC03. This basic aqueous layer was extracted with CHCI3. The extract was washed with brine, dried over Na2SOi and evaporated to give 660 mg (2 steps, 32%) methyl (S)-3-chloro-4-(2-aminc-l-propoxy)benzoate as a colorless oil. 'H-NMR (CDC13) 6 1.21 (d, 3 H, -/=6.4 Hz), 3.41-3.48 (m, 1 H), 3.77-3.81 (m, 1 H), 3.89 (s, 3 H), 3.98-4.01 (m, 1 H), 6.91-6.94 (m, 1 H), 7,90-7.93 (m, 1 H), 8.05-8.06 (m, 1 H). A mixture of pentafluorophenyl 4-[W-(2-methylphenyl)ureido]phenylacetate (508 mg, 1.13 mmol), methyl (pS)-3-chloro-4-(2-amino-l-propoxy)benzoate (275 mg, 1.13 mmol) and EtjN (0.240 mL, 1.72 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc, and the solution was washed with 0.5 N HC1, sat. NaHCOj, brine,, dried over Na,S04, and evaporated. The residue was recrystallized from MeOH-CHCl3-n-hexane to give 240 mg (42%) methyl (5)-3-chloro-4-[2-[4-[Af'-(2-methyIphenyl)i]reido]phenylacetylamino]-l-propoxy]benzoate as a white crystalline powder. 'H-NMR (DMSOA) 5 1.21 (d, 3 H, J=6.4 Hz), 2.25 (s, 3 H), 3.33 (s, 2 H), 3.82 (s, 3H), 4.04-4.14 (m, 3H), 6.90-6.94 (m, IH), 7.11-7.16 (m, 4H), 7,29-7.38 (m, 3H), 7.83-7.94 (m, 3H), 8.13-8.17 (m, 2H), 9.34 (s, 1 H); MS(FAB) m/z 510 (WT). To a stirred solution of methyl ©-3-chJoro-4-p-[4-[A'-(2-meth>'Jphcnyi)ureido] phenyIacetylamino]-S-propoxy]benzoate (240 mg, 0.47 mmol) in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux ovcnught. The mixture was poured into ice-1 N HC1 and the solid was collected. The crude solid was recrystallized from MeOH-CHClj-n-hexane to give 98 mg (42%) 274 as a white crystalline powder, mp 228-231 °C; 'H-NMR (DMSO-d,) 5 3.20 (d, 3 H, .7=6.3 Hz), 2.24 (s, 3 H), 3.34 (s, 2 H), 4.02-4.18 (m, 3 H), 6.92-6.95 {m, 1 H), 7.12-7.42 (series of m, total 7 H), 7.82-8.18 {series of ra, total 5 H), 9,12 (s, 1 H); MS (FAB) m/z 496 (M*), 497 (M*+l);^nfl/. CaJcdfor CHMCINA' 1/2H30: C, 61.84; H, 5.39; Cl.7.02; N,8.32. Found: C,61.76;H,5.25; Cl.7.09; N.8.25. (513 mg, 1.07 mmol), methyl (5)-3-chloro-4-(2-amino-l-propoxy)oen2oate (260 mg, 1.07 mmol) and Et3N (220 /A, 1.58 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc and the solution was washed with sat. NaHC03, dried over Na2S04, and evaporated. The residue was recrystallized from MeOH-CHCI3-EtOAc-fl-hexane to give 400 mg (69%) methyl (5)-3-chloro-4-I2-[3-methoxy-4-[/V'-(2-methylphenyl)ureido]phenylacetylamino]-]-propoxy]benzoate as pale brown crystalline powder. 'H-NMR (DMSO-cL,) 6 1.21 (d, 3 H, J=6A Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 4.04-4.12 (m, 3 H), 6.75-6.77 (m, 1 H), 6.91-6.95 (m, 2 H), 7,11-7. IT (m, 2 H), 7.29-7.31 (m, I H), 7,78-7.99 (m, 4 H), 8,12-8.13 (m, 1H), 8.46 (s, 1H), 8,55 (s, 1 H), To a stirred solution of methyl (5)-3-chloro-4-[2-[3-methoxy-4-[/V'-(2-methylpheny!) ureido]phenylacetylamino]-l-propoxy]ben2oate(400 mg, 0.74 mmol) in THF-MeOH (20 mL, 1:1, v/v) was added 0.5 N NaOH (20 mL), and the resulting mixture was heated under reflux overnight. The mixture was poured into ice-1 N HC1 and the solid was collected. The crude solid was recrystallized from MeOH-CHClj-EtjO to give 200 mg (51%) 275 as a pale brown crystalline powder, mp 198-201 °C; 'H-NMR (DMSO-d.) 6 1.21 (d, 3 H, .7=6.8 Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3.84 (s, 3 H), 4.00-4.15 (m, 3 H), 6.76-7.28 (series of m, total 6 H), 7.77-8.14 (series of m, total 5 H), 8.46 (s, 1 H), 8.56 (s, 1 H); MS (FAB) TTL£ 526 (M*), 528 (M*+2); Anal. Calcd for C^HjjClNA'l/^O: C,61.13,H,5,42;C!,6.68;N, 7.92. Found: C. 60.97; H.5.48; Cl.6.86; N, 7.89. Example 225 3 -diraethylamino-4-[ [2-[3-methoxy-4-[JV-(2-methyIphenyl)ureido] phcnylacetyl] 17mmol), methyl 4-hydroxy-3-nitro benzoate (3.38g, 17mmoI), and PhjP (5.4g, 21mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD) (4mL, 21mmol), and the resulting ■ mixture was heated under reflux for 15 hr. The solution was evaporated off. The residue was chromatographed on silica-gel with CHCl^MeOH (100:0 to 4:1, v/v) as eluent to give 2.5g (39%) methyl 4-[2-(W-methyl-2-amino)ethoxy]-3-nitro benzoate as a pale yellow oil. 'H-NMR (CDCi3, 400MHz) 5 2.82 (s, 3H), 3.50 (t, 2H, J=4.5Hz), 3.95 (s, 3H), 4.54 (t, 2H, J=4.5Hz), 7.26 (d, 1H, y=8.8Hz), 8.25 (d, 1H, y=8.8Hz), 8.56 (s, 1H); MS (FAB) m/z 255 (M*+l). A mixture of 3-methoxy-4-[A'-(2-metfiylphenyl)ureido]phenylacetic acid (992mg, S.llmmol), methyl 4-{//-methyl-2-aminoethoxy)-3-nitrohetizoate (800mg, 3.11mmol) and 4-DMAP (77mg, 0.63mmol), HOBt (640mg,4.7mmol), and EDC (904mg,4.7mmol) in DMF (20 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc, and the solution was washed with 0.5 N HC1, sat. NaHC03. brine,, dried over Na,SO„ and evaporated. The residue was chromatographed on silica-gel with CHCl3:EtOAc(95:5 to 0:100, v/v) as eluent to give 587mg (34%) methyl 3-nitro-4-[[2-[3-methoxy-4-[Ap-(2-methylphenyl)ureido]phenylacetyl] methylamino)ethoxy]benzoate as a pale yellow oil. 'H-NMR (CDCI3, 400MH2) 5 2.31 (s, 3H), 3.05 (s, 1H), 3.23 (S,2H), 3.71 (s,2H), 3.83 (s,3H), 3.85 (m,3H), 3.94 (s,3H), 4.19 and 4.39 (m, total 2H), 6.80 (m, 2H), 7,05 (m, 1H), 7.22 (m, 3H), 7,62 (d, 1H, J=8.2Hz), 8.02 (d, 1H, J=8.2Hz), 8.21 (dd, 1H,/=2.1Hz, 8.8Hz, 8.55 (d, 1H, >2.1Hz); MS (FAB) m/z 551(M*+1). A mixture of methyl 3-niUo-4-[[2-[3-methoxy-4-[A".(2-methylphenyl)ureido]phenyl acetyl]methylamino}ethoxy)benzoate (587mg, l.lmmol) and 5%-Pd-C (600mg) inTHF-MeOH-AcOH (1:1:1, v/v, 150mL) was hydrogenated at 45psifor 18.hr. Insoluble catalyst was removed with suction, and the filtrate was evaporated in vacuo to afford 555mg (100%) methyl 3-amino-4-[[2-[3-methoxy-4-[A^-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoateasa pale yellow gum. 'H-NMR (CDC13, 400MHz) 5 2.29 (s, 3R), 3.08 (m, 1H), 3,19 (s, 2H), 3.65 (s, 1H), 3.73-3.80 (m, 3H), 3.84 (s, 3H), 3.87(s, 3H), 4.19 and4.40 (m, lolal 2H), 6.70-6.82 (m, 2H), 7.02-7.29 (m, 6H), 7.60 (d, lH,y=7.8Hz), 7.92-7.99 (m, 3H); MS (FAB) W? 521 (M* + l). To a stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-(A'-(2-methylpheny])ureido] phenylacetyl]rnethylamino]ethoxy]benzoate(555mg, l.limnol), formaldehyde (lOmL). and AcOH (0.58mL, lOmmol) in MeCN (lOmL) was added NaBHjCN (0.67g, lOmmol) at room temp, and the resulting mixture was stirred for 15 hr at the same temp. Sat. NaHCOj was added to the mixture and extracted with CHC13. The extract was washed with brine, dried over MgSO(, and evaporated in vacuo. The residue was chromatographed on silica-gel with toluene:ace!one (7:3 to 1:1, v/v) as ehient to give 123mg (21%) methyl 3-dimethylamino-4-([2-[3-methoxy-4-[A^-(2-methylphenyl) ureidojphenylacetyl] rnethylanuno]ethoxy]benzoate as an oil. 'H-NMR (CDC13, 400MHz) 6 2.30'(s, 3H), 2.70 (s, 3H), 2.75 (s, 3H), 3.05 (s, 1H), 3.18 (s, 2H), 3,61 (s, 3H), 3.70 (s, 1H), 3.80 (m, 3H), 3.86 (s, 3H), 4.07 and 4.22 (m, total 2H), 6.28 (m. 1H), 6.70-6.80 (m, 3H), 7.03 (m, 1H), 7.15-7.25 (m, 4H), 7.46-7.65 (m, 2H), 8.02 (m, 1H)-, MS (FAB) m/z 548 (M* + 1). A stirred mixture of methyl 3-dimethylarruno-4-[[2-[3-methoxy-4-[/V-(2-methy3phenyl) ureido] phenylacetyl]methylamino]ethoxy]benzoate (I23mg, 0.22mmol) in THF (I5mL) and IN NaOH (0.885mL, 0.885mmol) was heated under reflux for 15 hr. The pH of the mixture was adjusted to 5.0 by the addition of IN HC1, and extracted with CHCI5-MeOH(9:l, v/v). The extract was washed with brine, dried over MgS04, and evaporated in vacuo. The residue was crystallized with Et;0-n:hexane to give 118 mg(100%) 276 as a white crystalline material, mp 125-130 °C; IR (KBr) '3346, 29^0, 1620, 1597, 1535, 1456, 1417, 1227, 1039, 754cm"1; 'H-NMR (CD3OD, 400MHz) 5 2.29 (s, 3H), 2.70 (s, 3H), 2.79 (s, 2H), 3.05 (s, 1H), 3.22 (s, 2H), 3.75 (s, 3H), 3.85 (m, 4H), 4.15 and 4.28 (m, 2H), 6,78-7,05 (m, 4H), 7.18 (m, 2H), 7.55-7.70 (m, 3H), 7,98 (m, 1H); MS (FAB) mh 535(M* + 1); Anal, calcd. for C^NA^.OHiO: C, 61,04; H, 6.71; N, 9,82. Found: C, 61.15; H, 6,43; N, 8.94, methyl 4-[2-(A'-methyl-2-amino)ethoxy]-3-nitrobenzoaie (800mg, 3.1 Immol) and 4-DMAP (77mg, 0.63mmo]), HOBt(640mg,4.7mmo]), and EDC (904mg,4.7mmol) in DMF (20 mL) was stirred al room temp overnight. The mixture was diluted with EtOAc, and the solution was washed with 0.5 N HC1, sat. NaHC03, brine,, dried over Na2SO«, and evaporated. The residue was chromaiographed on silica-gel with CHCl3-EtOAc (95:5 to 0:100, v/v) as eluent to give 420mg (19%) methyl 3-nitro-4-[[2-[3-fluoro-4-[W-(2-fluorophenyl)ureido]phenylacetyl] methylamino] ethoxy]benzoate as a pale yellow oil. 'H-NMR (CDCI}, 400MHz) 5 3.04 (s, 1H), 3.24 (S, 2H), 3.72 (s, 1H), 3.85 (s, 3H), 3.90 (m, 3H), 3.93 (s, 3H), 4.16 and 4.39 (2m, 3H), 6.80 (m, 2H), 6.99 (m, 1H), 7.05 (m, 2H), 7,22 (d, lH,./=8.BHz), 7.51 (s, 2H), 8.00 (m, 1H), 8.08 (m, 1H), 8,21 (d, lH,J=8.6Hz), 8.51 {s, 1H); MS (FAB) m/z 555 (M* + 1). A mixture of methyl 3-nitro-4-[[2-[3-methoxy-4-[JV-(2-fluorophenyl)ureido]phenylacetyl] methylamino]ethoxy]benzoate (420mg, 0.76mmol) and 5%-Pd-C (lg) in THF-MeOH-AcOH (1:1:1, v/v, 150mL) was hydrogenated at 45psi for 18 hr. Insoluble catalyst was removed with suction, and the filtrate was evaporated in vacuo to afford 397mg (100%) methyl 3-amino-4-[[2-[3-methoxy-4-[A'-(2-fluoropheny])ureido]pherry]aceryl]methylamino]ethoxy]ben2oate as a pale yellow gum. 'H-NMRv (CDC13, 400MHz) 6 3.05 and 3.13 (s, total 3H), 3.66 (s, 3H), 3.70 (s, 2H), 3.65-3.90 (m, 4H), 3.86 (s, 3H), 4.10 and 4.23 (m, 2H), 6.70-6.83 (m, 3H). 6.98-7.15 (m, 6H), 7.25-7,43 (m, 2H), 7.99 (m, 1H), 8.13 (m, 1H); MS (FAB)m^r 525 (M*+l). To a stirred solution of methyl 3-armno-4-[[2-[3-meihoxy-4-[W-(2-fluorophenyl)ureido] phenylacetyl]methylamino]ethoxy]benzoate (397mg, 0,76minol), formaldehyde (lOmL), and AcOH (0.43mL, 7.6mmol) in MeCN (lOmL) was added NaBH3CN (0.48g, 7,6mmol) at room temp, and the resulting mixture was stirred for 15 hr at the same temp. Sat. NaHC03 was added to the mixture and extracted with CHClj. The extract was washed with brine, dried over MgSO,, and evaporated in vacuo. The residue was chromaiographed on silica-gel with toluene:acetone (7:3 to 1:1, v/v) as eluent to give 123mg (21%) methyl 3-dimethylamino-4-[[2-[3-methoxy-4-[A',-(2-methylphenyl)ureido]phenylacetyl] methylamino] ethoxyjbenzoate as an oil. 'H-NMR (CDC15, 400MHz) 5 2.74 (s, 3H), 2.77 (s, 3H), 3.08 (s, 1H), 3.22 (s, 2H), 3.52 (s, 3H), 3.61 (s, 1H), 3.83 (m, 3H), 3.88 (s, 3H), 4.12 and 4.23 (m, total 2H), 6,68 (s, 1H), 6.78 (m, 2H), 6.98 (m, 2H), 7.10 (m, 1H), 7.55-7.68 (m, 4H), 7.99 (m, 1H), 8,16 (t, 1H, -7=8.3Hz); MS (FAB) m/z 553 (M*+l). A stirred mixture of methyl 3-dimethylamino-4-[[2-[3-methoxy4-[A',-(2-fluorophenyl) ureido] phenylacetyl]methylamino]ethoxy]benzoate{61mg, O.llmmol) inTHF (I5mL) and IN NaOH (0.22mL, 0.22mmol) was heated under reflux for 15 hr. The pH of the mixture was sHincieH m S nfcufh** addition nf IN Hfl and extracted with CHni.'MeOHf"!. v/vV The extract was washed with brine, MeOH:acetone (93:7, v/v) as eluent to give 37 mg (63%) 277 as a white crystalline material, mp 120-125 °C; 'H-NMR (CD30D, 400MHz) 8 2.60 (s, 4H), 2.78 (s, 2HJ, 3.06 (s, IH), 3.22 (s, 2H), 3.75 (s, 3H), 3.85-3.92 (m, 4H), 4.17 and 4.29 (m, total 2H), 6.80-7.12 (m, 6H), 7.63-7.70 (m, 2H). 8.00 (m, 1H), 8.08 (m, 1H); MS (FAB) 539 (M* + l); ,*«,/. calcd. for CJJn-FN,Os2J5HjO: C, 57.18; H, 6.26; N, 9.53. Found, C, 57.20; H, 5.62; N, 9.06. Example 227 3-dime%lam!no-4-[[2-[4-[A^-(2-me%lphenyl)ureido]pherrylacetyl]rnethylamino]ethoxy] 3.15mmol), methyl 4-[2-{A'-methyl-2-amino)ethoxy]-3-nitro benzoate (SOOmg, 3.15mmol) and triethylamine (0.66mL,4.73mmol) in DMF (8 mL) was stirred at 50° C for 15 hr. The mixture was poured into ice-lN HCI and extracted with CHC13. The extract was brine, dried over Na3SO,, and evaporated. The residue was chiomalagraphed on silica-gel with CHCl3'.EtOAc (95:5 to 0:100, v/v) as eluent to give 1.04g (63%) methyl 3-nJUo-4-[[2-[4-[A^-(2-methylphenyl)ureido] phenylacetyl]mewylarnino]ethoxy]benzoate as a pale yellow oil. 'H-NMR (CDC13,400MHz) 5 2.30 (s, 3H), 2.90, 3.02 and 3.05 (s, total 1H), 3.22 (s, 2H), 3.71 (s, 1H), 3.85 ( 3H), 3.93 (s,3H), 4.19 and 4.39 (m, 2H), 7.02 (m, IH), 7.19 (m, 4H), 7.35 (d, 1H, J=8.3Hz), 7.40 (&, 1H, J=8.0Hz), 7.55 (s, 2H), 7.70 (m, IH), 8.22 (d, IH, J=6.7Hz), 8.51 (s, IH); MS (FAB) m/z 521(M*+1).. A mixture of methyl 3-nitro-4-[[2-[4-[W-(2-methylphenyl)ureido]phenylacetyl] methylamino]ethoxy]benzoate (1.04g, 2mmol) and 5%-Pd-C (1.2g) in THF-MeOH-AcOH (1:1:1, v/v, 150mL) was hydrogenated at 45 psi for 18 hr. Insoluble catalyst was removed with suction, and the filtrate was evaporated in vacuo to afford methyl 3-amino-4-[[2-[4-[JV,-(2-rnethylphenyl) urei do] phenyl a cetyi]methylami no] ethoxy ] benzoate as a pale yellow gum, To a stirred solution of 3-arnino-4-[[2-[4-[W-(2-methyIphenyl)ureido]phcnylacetyl] methylamino]ethoxy]benzoaie, formaldehyde (5mL), and AcOH (1.14mL, 20mmol) in MeCN (5mL) was added NaBHjCN(1.26g, 20mmol)at room temp, and the resulting mixture was stirred for 15 hr at the same temp. Sat. NaHCOj was added to the mixture and extracted with CHC13. The extract was washed with brine, dried over MgSOj, and evaporated in vacuo. The residue was chromatographed on silica-gel with toluene:acetone£7;3 to 1:1, v/v) as eluent to give 85mg (2 steps, 8%) methyl 3-dimcthylamino-4-[I2-[4-[//,-(2-methyIpheny])ureido]phenylaccty]]methy[ aminojethoxyjbeiizoate as an oil. 'H-NMR (CDCi,, 40OMHz) 6 2.12 (s, 3H), 2.73 (s, 3H), 2.75 (s, 3H), 3.05 (s, 1H), 3.20 (s, 2H), 3.60 (s, 1H), 3.80 (m, 3H), 3.88 (s, 3H), 4.17 (m, 2H), 6.95-7.28 (m, 8H), 7.55-7.75 (m, 3H); MS (FAB) m/z 518 (M*+l). A stirred mixture of methyl 3-dimethylainino^-[[2-[4-[A^-(2-melhylphenyl)ureido] phenylacetyl] methylamino]ethoxy]benzoate(ap315201)(85mg, 0.16mmol) in THF (15mL) and IN NaOH (0.32mL, 0.32mmol) was heated under reflux for 15 hi. ThepHof the mixture was adjusted to 5.0 by the addition of IN HC1, and extracted with CHCl3:MeOH(9:1, v/v). The extract was washed with brine, dried over MgSO phenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate (lOOmg, 0.19nunol) in acetone / AcORTJMF (13 mL, 6:6:1, v/v/v) was added NaBHjCN (300 mg), and the resulting mixture was stirred for 60 hr at room temp. The mixture was pored into sat. NaHC03 and the solid was collected with suction. The precipitate was dissolved in CHC1, (20tnL), and the solution was washed with brine, dried over MgS04, and evaporated under a reduced pressure. The residue was chiomatographed on silica-gel piate with toluene:acetone (2:1, v/v)aseluent to give 108 mg (100%) methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[A'-(2-fluorophenyl)uieido]phenylacetyl] methylamino]ethoxy]benzoate as a colorless oil. 'H-NMR (CDC13,400MHz) 6 1.20 (m, 1H), 2.88 (s, 6H), 3.02 and 3.12 (s, total 3H), 3.53 (s, 2H), 3.60-3.80 (m, 7H), 3.85 (s, 3H), 4.10 and 4.20 (m, 2H), 6,65-675 (m, 2H), 6.90-7.08 (m, 2H), 7.22-7.35 (m, 2H), 8.02 (s, 2H), 8.10 (m, 2H), 8.21 (br, 1H), 8.33 (br, 1H); MS(FAB)m/z566(M*+l). A stirred mixture of methyl 3-isopropylamino-4-[[2-i3-methoxy-4-[A',-(2-f]uorDphenyl) UTeido}phenylacetyl]methylammo]elhoxY]benzoate (116mg, 0.2mmoi), 0.25 N NaOH (6 mL), and THF (6 mL) was heated under reflux for 8 hi. The mixture was poured into water (200 irtL), acidified by IN HC1 and the solid was collected with suction. The solid was recrystallized from CHCb-n-hexane-diisopropylether to give 56mg (50%) 279 as a colorless crystalline powder, mp 195-200 "C; 'H-NMR (CD,OD, 400MHz) 5 3.15-1.20 (m, 6H), 3.01 {s, 1H), 3.12 (s. 2H), 3.48-3.60 (m, 1H), 3.68 (s, 3H), 3.75 (s, 2H), 3.82 (s, 1H), 3.86 (m, 3H), 4.15-1.23 (m, 2H), 6.80 (m, 3H), 4.15-4.23 (m, 2H), 6.80 (m, 3H),6.98 (m, 1H), 7.10 (m, 2H), 7.20 and7.25 (s, total 1H), 7.32 (m, 1H), 7.98 (m, 1H), 8.05 (m, 1H); MS (FAB) m/z 552 (M+H)*; ,4na/. calcd. for CMHMFNA-I.OHJO: C, 61.04; H, 6.18; N, 9.82. Found, C, 61.36; H, 6.25; N, 9.45. ETamPle 229 4-[[l-[4-[A'-(2-fIuorophenyI)ureido)-3-methoxyphenyJacetyI]-2-methylamino]-2-meliiyl-2- triethylamine (I1.4g, 0.1I3mol) inDMF-water(l:I, v/v, lOOmL) was added di-terr-butyl dicarbonate (25g, O.115mol)at5 to 10° C. The resulting solution was stirred for 2 hi at room temp. The mixture was diluted with water(lOOmL) and extracted with EtOAc. The extract was washed with brine, dried over Na,SO(, and evaporated. The residue was chromatographed on silica-gel with CH,C1, as eluent to give 12g (68%) 2-/er/-butoxycarbonylamino-2-methyl-1-propanol as a syrup. 'H-NMR (CDC1,) 6 1.25 (s, 6H), 1.43 (s, 9H), 3.59 (d, y=8.3H2, 2H). 4,68 (br, 1H). To a stirred suspension of 2-reW-butoxycarbonylamino-2-methyl-l-propanol (5.7g, 30.11mmol) and powdered NaOH(6,7g, 0.151mol) inEt2O(200mL) was added/Moluenesulfonyl chloride (6.9g, 36,14mmol) at room temp. The stirred resulting mixture was heated under reflux for 8 hi. After cooling, ice-waler(lOOmL) was added to the solution. Separated Et20 layer was washed with brine, dried over Na,SO,, and evaporated. To the residue was added n-hexane and triturated. The solid was collected to afford 8.5g (82.2%) 2-/er/-butoxycarbonylamino-2-methyl-l-propylp-toluenesulfonate as a crystalline material. 'H-NMR (CDClj) 5 1.26 (s, 6H), 1.38 (s, 9H), 2.37 (S, 3H), 4.05 (s, 2H), 4.49 (br, 1H), 7.34 (d, J=7.8Hz, 2H), 7.78 (d, J=7.8Hz, 2H). A stirred mixture of 2-/ert-butoxycarbonylamino-2-methyl-l-propyl/i-toluenesufibnate (8.2g, 23.88mmol) and powdered NaOH (6\7g, 0.151mo]) in Et,0 (200mL) was heated under reflux for 10 hr. After cooling, the mixture was filtered. And the filtrate was washed with water, brine, dried over Na,SOj, and evaporated. The residue was chromatographed on silica-gel with n-hexane:EtOAc (6:1, v/v) as eluent lo give 2.7g (66.2%) l-ter/-butoxycarbonyl-2-methy!propylene imine as an oil. 'H-NMR (CDC13) 5 1.29 (s, 6H), 1.47 (s, 9H), 2,05(s, 2H). To a stirred solution of l-/er?-butoxycarbony-2-methylpropy!eneimine (1.03g, 6.01mmol) and methyl 4-hydroxyben2oate (800mg, 6.26mmol) in CHjClj (lOmL) was added boron trifluoride diethyl ether (0.127mL, Inunol) at ambient lemp. The resulting solution was stirred for a further 3 hr at the same temp. The mixture was washed with water, brine, dried over NaiSOj, and evaporated. The residue was chromatographed on silica-gel with n-hexane:EtOAc (6:1, v/v) as eluent to give 550mg (33%) methyl 4-(l-ierf-butoxycarbonylamino-2-methyl-2-propoxy)ben2oate as a gum. 'H-NMR (CDClj) 5 1.33 (s, 6H), 1.47 (s, 9H), 3.36 (d, J=6.3Hz, 2H), 3.90 (s, 3H), 5.05 (br, 1H), 6.99 (d, 7=8.8Hz, 2H), 7.97 (d, 7=8.8Hz, 2H). A mixture of methyl 4-{l -i,er/-butoxycarbonylamino-2-melliyl-2-propoxy)benzoate (460mg, ].42mmol) and anisole (0.155mL, 1.42mmol) in CH,Cl,(15mL) andTFA (3mL) was stirred for 3 hr at room lemp. The mixture was evaporated off. The residue was dissolved in CH,C13 (30mL) and made basic by the addition of 0.5N NaOH. The CH}C1, layer was separated, dried over NajSOj, and evaporated. The residue was chromatographed on silica-gel with CH3C12 as eluent to give 370mg (100%) methyl 4-(l-amino-2-methyl-2-propoxy)benzoate as a gum. 'H-NMR (CDCy § 1.34 (s, 6H), 2.87(s,2H),3.90 (s,3H),7.10 (d, J-8.8Hz,2H), 7.97 (d, J-8.8H2, 2H). To a stirred solution of methyl 4-(l-ajruno-2-niethyl-2-propoxY)benzoate (370mg, 1.66mmol) and triethylamine (0.35mL, 2.49mmol) in CH,C1, (15mL) was added trifluoroacetic anhydride (0.316mL, 2.24mmol) at 0° C. After stintd for 1 hi at the same temp, water was added to the solution. CH,C1, layer was separated, washed with water, dried over NaiSOj, and evaporated. The residue was chromatographed on silica-gel(20mL) with CHjClj as eluent to give 530mg (100%) methyl 4-(l-trifluoroacetamido-2-methyl-2-propoxy)benzoate as a gum. This compound was used to the subsequent reaction without further purification. To a stirred mixture of methyl 4-(l-trifluoroacetamido-2-methyl-2-pTopoxy)benzoate (530mg, 1.66mmol) andK,C03(345mg, 2,49mmol) in DMF (lOmL) was added Mel (0.14mL, 2,37mmoI) at room temp. The resulting mixture was stirred for 18 hr at room temp. The mixture was poured into water, and extracted with EtOAc. The extract was washed with washed with brine, dried over NajSO, and evaporated. The residual gum was used to the subsequent reaction without further purification. The above crude residue was dissolved in MeOH(IOmL). To the stirred solution was added water (5mL) and NajCO, (352mg, 3.32mmol), and the resulting mixture was stirred for 5 hr at room temp. The mixture was poured into water and extracted with CHClj. The extract was washed with water, dried overNa,S04, and evaporated. The residue was chiomalographed on silica-gel with CHClj as eiuent to give 390mg (100%) methyl 4-(l-melhylamino-2-methyl-2- propoxy)ben2oate as a gum. 'H-NMR (CDCI3) 6 1.37 (s,6H), 2.51 (s, 3H), 3.89 (s, 3H), 6,92 (d, y=8.8Hz, 2H), 7.97 (d,-/=8.8Hz, 2H). To a stirred mixture of methyl 4-(l-methylamino-2-methyl-2-propoxy)benzoate (200mg, 0.84mmol), 4-[Ar-(2-fluorophenyl)ureido]-3-methoxypherrylacetic acid (268mg, 0.84mmol), 4-DMAP(I25mg, l.Ommol) in DMF(5mL) was added EDC{220mg, 1.14mmol) at ambient temp. The resulting mixture was stirred for a further 10 hr at ambient temp. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over NajSO,, and evaporated. The residual gum was triturated with CH,C1: and EtsO to give 200mg (44.1%) methyl 4-[[l-[4-[A"-(2-fliiorophenyl)ureido]-3-methoxyphenylacetyl]methylamino]-2-methyI-2-propoxy]benzoate as a crystalline material. 'H-NMR (CDClj) 5 1.36 and 1.31 (each s, 6H), 3.24-3.88 (series of s, 13 H), 6,65-8.20 (seris of m, 14H). A mixture of methyl 4-[[l-[4-[W-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-methylarnino]-2-mediyl-2-propoxy]benzoatc(180mg, 0.335mmol) in THF(3mL) and 0.25N NaOH(4mL) was stirred for 5 hr at room temp. The mixture was poured into ice-lN HCl(5mL). The solid was collected, washed with water, and air-dried. The crude solid was recrystalhzed from EtOH-CHCl3-n-hexane to give 70 mg (40%)280 as fine needles, mp 200-207 (C; 'H-NMR (DMSO-ds) 5 1.26 and 1.33 (each s, 6H), 3,70-3,81 (series of s, 7H), 3.83 (s, 3H), 6.75-8.20 (series Ofm, 10H),8.71(s, 1H), 9.17 (brs,lH), 12.72 (s,lH). Example 230 (-S-chloro-p-p-memo-tA'KS-fluorophenyDureidolphenylacetylarninoJ-l-propoxy] mmol), methyl {S)-3-chloro-4-(2-arnino-l-propoxy)benzoate (250 mg, 1.03 mmol), EDC(hydrochloride) (295 mg, 1.54 mmol), HOBt (208 mg, 1.54 mmol), and DMAP (25 mg, 0.20 mmol) in DMF (8 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc washed with 0.5 N HC1, brine, dried over Na,SO, and evaporated. The residue was recrystalHzed from CHCirEtOAc to give 308 mg (55%) as a white crystalline powder. 'H-NMR (CDC13) 8 1.29 (d, 3 H, .7=6.8 Hz), 3.51 (s, 2 H), 3.84 (s, 3 H), 3.88 (s, 3 H). 4.01-4.08 (m, 2 H), 4.38-4.39 (m, 1 H), 6.25 (d, 1 H, .7=8.3 Hz), 6.78-6.83 (m, 2 H), 6.90-6.95 (m, 2 H), 7.02-7.11 (m, 2 H), 7.89 (dd, I H, .7=2.0, 8.8 H2), 8.02 (d, 1 H, .7=2.4 Hz), 8.20 (d, 1 H, .7=8.3 Hz), 8.27-8.31 (m, 1 H), 8.53 (s, 1 H), 8.84 (s. 1 H). To a stirred solution of methyl (,S)-3-chIoro-4-[2-[3-methoxy-4-[A'-(2-fluoropheny!) uretdo]phenylacetylamino]-I-propoxy]benzoate (308 mg, 0.57 mmol) inTHF-MeOH(10mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), ajid the reaction mixture was heated under reflux for 1 hr. The mixture was poured into ice-1 N HC1 and the solid was collected. The crude solid was purified by recrystallization from MeOH-CHCl3-n-hexane to give 196 mg(65%)281 as a white crystalline powder, mp 188-191 °C; 'H-NMR(DMSO-d«) 5 1.21 (d, 3 H.,7=6.4 Hz), 3.38 (s, 2 H), 3.83 (s, 3 H), 4.02-4.18 (m, 3 H), 6.78-7.29 (series of m, total 6 H), 7.85-8.00 (m, 3 H). 8.12-8.19 (m, 2 H), 8.70 (s, 1 H), 9.17 (s, 1 H), 12.98 (bs, 1 H); MS (FAB) m/z 530 (M*), 531 (M"+l), 532 (M*+2); Anal. Calcd for djHClFNA-lHjO: C, 58.43; H, 4.81; CI, 6.63; F, 3.55; N, 7.86. Found; C, 58.45; H, 4.83; CI, 6.68; F, 3.38; N, 7.79. Example 231 4- [ [2 - [3 -methoxy-4 - [iV-(2-methy 1 pheny l)ureido]pheny lacetyl ] methy lami no]ethylami nojbenzoic in toluene (3mL) was added methy 1-4-aminobenzoate (1.29g, 8.5mmol), and the mixture was stirred for 1 hr at room temp. The reaction mixture was evaporated under a reduced pressure and the residue was dissolved into MeCNQ 5 mL). To the solution was added AcOH (2,44mL, 43mmol) and NaBH3CN (2.67g, 43mmol), and the resulting mixture was stirred for 15 hr at room temp. The reaction was quenched by the addition of sat. NaHCO,. The mixture was extracted with EtOAc, washed with brine, dried over MgSO,, and evaporated. The residue was chromatographed on silica-gel with n-hexane: EtOAc (7:3, v/v) as eluent to give 1.26g (43%) methyl 4-[2-(jV-benzyloxy carbonyl-tf-methylainino)my]amino] benzoate as a colorless oil. 'H-NMR (CDClj, 400MHz) 8 2.96 (s, 3H), 3.32 (br m, 2H), 3.50-3.60 (m, 2H), 3,82 {s, 3H), 5.15 (each d, 2H, J=14.6Hz), 6.35 and 6.58 (m, total 2H), 7.36 (s, 5H), 7.76 and 7.84 (m, total 2H); MS(FAB)m/z342(M*+l). To a stirred solution of methyl 4-[2-(#-benzyIoxycarrxmyl-jV-memy]ajmo)ethylamino] benzoate (1.26g, 3.68mmoI) in MeOH(20mL) was added 5 wt. Pd-C (700mg), and the mixture was hydrogenated (3 aim) for 4 hr at room temp. The mixture was filtered, and the filtrate was evaporated under a reduced pressure to give 600mg (78%) methyl 4-[2-(Ar-methyIamino) ethylamino]benzoate as a colorless oil. 'H-NMR (CDClj, 400MHz) 5 2.46 (s, 3H), 2.88 (t, 2H, >5.5Hz), 3.27 (br S, 2H), 3.85 (s, 3H), 6.57 (d, 2H, J=8.8Hz), 7.85 (d, 2H, J=8.8Hz); MS (FAB) m/x 209 (M++I). To a stirred solution of methyl 4-[2-(Ar-methylamino)ethylamino]benzoate (590mg, 2.83mmol)3-methoxy-4-[A',-(2-raethylphenyl)ureido]phenylacetic acid (891mg,2.83mmoI) in DMF(I4mL) was added EDC (815mg,4.25mmol), HOBt (574mg,4.25mmol),and 4-DMAP (519mg, 4.25mmol), and the resulting mixture was stirred overnight at room temp. The mixture was poured into IN HC! and the solid was collected with suction. The crude solid was purified by chromatography on silica-gel (middle pressure) with CHClj-EtOAc (10:0 to 7:3, v/v) as eluent to give 1.25g (87%) methyl 4-[[2-[3-methoxy-4-[A"-(2-methylpheny])ureido]phenylacetyl] methylamino]ethylamino]benzoate as a light yellow oil. 'H-NMR (CDCl* 400MHz) 5 3.18 (s, 2H), 3.05 and 3.32 (s, total 2H), 3.72-3.85 (m, 9H), 4.12 and 4.23 (m, total 2H), 6.78 (m, 3H). 7,05 (t, 1H, J=7.5Hz), 7.20 (m, 2H), 7.43-7,50 (m, 3H), 7.62 (d, 1H, >8.8Hz), 8.05 (d, 1H, >=8.8Hz); MS (FAB) mh 505 (M*+I ). A stirred mixture of methyl 4-[[2-[3-methoxy-4-[y-(2-methylphenyl)ureido]phenylacetyl] methylamino]ethylamino]benzoate (300mg, 0,6mmol) in 0.25 N NaOH (6 mL) and THF (6 mL) was heated under reflux for 8 hr. The mixture was poured into water, and acidified with IN HCI. The solid was collected with suction. The crude solid was recrystallized from n-hexane-diisopropylether to give 202mg (69%) 282 as a pale yellow crystalline powder, mp 115-120 °C; IR(KBr) 3346, 2935, 1603, 1531, 1454, 1417, 1257, 1174, 1036, 754cm'1; 'H-NMR (CD,OD, 400MHz) 5 2.28 (s, 3H), 2.98 (s, 1H), 3,10 (s, 2H), 3.35-3.42 (m, 2H), 3,53-3.65 (m, 3H), 3.70 (s, 1H), 3.80 and 3.82 (s, 3H), 6.60-6.85 (m, 4H), 7.02 (m, 1H), 7.18 (m, 2H), 7.58 (m, 1H), 7.82 (m, 2H), 7,96 (m, 1H), MS (FAB) m/z 491 (M++l). Example 232 (6)-3-chbro-4-[2-[A'-methyI-W-[3-mclhoxy-4-[//--(2-fluoropheny])ureido]pheny]acety]] g, 7.14 mmol) in CHjCl] (20 mL) was added ElaN (1.19 mL, 8.54 mmol) and trifluoroacetic anhydride (TFAA) (1.11 mL, 7.86 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHC13, washed with 0,5 N HC1, brine, dried over Na,SO, and evaporated. The residue was recrystallized from CHCl3-«-hexane to give 1.59 g (66%) (S)-3-chJoro-4-(2-trifluoroacetamido-l-propoxy)benzoate as a white crystalline material, mp 122-125 DC; 'H-NMR (CDC1,) 6 1.48 (d, 3 H, .7=6.8 Hz), 3.91 (s, 3 H), 4.10-4.19 (m, 2 H), 4.47-4.52 (m, I H), 6.68 (bs, 1 H), 6.92-6.94 (m, 1 H), 7.93-7.95 (m, 1 H), 8.07-8.08 (m, 1 H); MS (FAB) m/z 340 (M*+I);no(. Calcd for C„H,jClF3NCv C, 45.96; H, 3.86; CI, 10.44; F, 16.78; N, 4.12. Found; C, 45,88; H, 3.97; CI, 10.24, F, 16.72; N, 4.18. To a stirred solution of methyl (5)-3-chloro-4-(2-trifiuoroacetamido-l-propoxy)benzoate (800 mg, 2.36 mmol) in DMF (5 mL) was added K,C03 (651 mmol, 4.71 mmol) and Mel (0.22 mL, 3.53 mmol), and the reaction mixture was stirred at 60° C overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCI, brine, dried over NaTSO, and evaporated. The residue was purified by column chromatography on silica-gel with 5% EtOAc in CHCl, as eluent to give 850 mg (100%) methyl (5>3-cWoro-4-[2-(W-methyl-A'-trifluoroacetaimdo)-l-propoxy] benzoate as a colorless oil. 'H-NMR (CDCy 8 1.43-1.46 (m, 3 H), 3.03 and 3.21 (s, 3 H), 3.90 (s, 3H), 4.04-4.22 (m, 2 H), 4.S1-4.87 (m, 1 H), 6.91 (d, 1 H,J=8.3 Hz), 7.93 (dd, 1 H, >2.0, 8.3 H), 8.06 (d, 1H, .7=2.0 Hz). To a Stirred solution of methyl (5)-3-chJoro-4-[2-(A'-methyl-//-trifluoroacetamido)-l-pTopoxy] benzoate (880 mg, 2.49 mmol) in MeOH-HjO (10 mL, 1:1, v/v) was added K,C03 (516 mg, 3.73 mmol), and the resulting mixture was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with HjO, brine, dried over NasSO and evaporated to give 460 mg (72%) (5)-3-chloro-4-(2-methylamino-l-propoxy)benzoate as a colorless oil. 'H-NMR (CDC13) 5 1.20(d, 3 H,/=6.4 Hz), 2.51 (s, 3 H), 3.07-3.12 (m, 1 H), 3,89 (s, 3 H), 3.92-4,04 (m, 2 H), 6.93-6.95 (m, 1 H), 7.90-7.93 (m, 1 H), 8.05-8.06 (m, 1 H). A mixture of 3-methoxy-4-[A'-(2-f]uoropheny])ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (,S)-3-chloro-4-(2-methylanimo-l-propoxy)benzoate (240 mg, 0.93 mraol), EDC(hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over Na2SO and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHC13 as eluent to give 520 mg (100%) methyl (5)-3-chloro-4-[2-[A'-methyl-//-[3-methoxy-4-[A'-(2-fluoropheriyI)ureido]phenyIacetyI] amino] -l-propoxy]benzoate as a red-brown amorphous solid. To a stirred solution of this product (520 mg, 0.93 mmol) in THF (10 mL) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux for 3 hr. The mixture was poured into ice-1 N HC1 and the solid was collected. The crude solid was recrystallized from CHC]j-Et20 to give 170 mg (2 steps, 37%) 283 as a white crystalline powder, mp 142-147 °C; 'H-NMR (DMSO-d,) 5 1.13-1.20 (m, 3 H), 2.74 and 2.94 (s, 3 H), 3.65 (s, 2 H), 3.82 and 3.84 (s, 3 H), 4.13-4.22 (m, 2 H), 4.53 and 4.91-4.92 (m, 1 H), 6.71-7.29 (series of m, total 6 H), 7.86-8.02 (m, 3 H), 8.15-8.19 (m, I H), 8.71 (s, 1 H), 9.17 (s, 1 H), 13.00 (bs, 1 H); MS (FAB) m/z 544 (\T), 545 (lvr+1); Anal. Calcd for CJJHCIFNJCVI/4HjO: C, 59.13; H, 5.05; CI, 6.46; F, 3.46; N, 7,66, Found: C, 59.19; H, 4.99; CI, 6.64; F, 3.23; N, 7.55. Example 233 (£)-3-chloro-4-[2-[A'-methyl-W-[3-methoxy-4-[Ar'-{2-methylphenyl)ureido]phenyl,acetyl] A mixture of3-metlioxy-4-[A'-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), methyl (5)-3-chloro-4-(2-methylamino-l-propoxy)ben2oate (214 mg, 0.83 mmol), EDC(hydrochloride) (239 mg, 1.25 mmol), HOBt (168 mg, 1.24 mmol), and DMAP (20 mg, 0.16 mmol) in DMF (8 mL) was stirred at room temp for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over NajSOj and evaporated. The residue was purified by column chromatography on silica-gel with CHCIj-MeOH (50:1, v/v) as eluent to give 470 mg (100%) methyl (5)-3-chloro-4-[2-[/i/-methyl-A'-[3-methoxy-4-[A'-(2-methylpheny:)ureido] phenylacety3]arnino]-l-propoxy]benzoate as a pale yellow amorphous solid. To a stirred solution of the above product (470 mg, 0.95 mmol) in THF (10 mL) was added 0.5 N NaOH (10 mL) and the reaction mixture was healed under reflux for 3 hi. The mixture was poured into ice-1 N HCL and the solid was collected. The crude solid was recrystallized from CHCI3-El,0 to give 168 mg (2 steps, 33%) 284 as a pale yellow crystalline powder, mp 125-130 "C; 'H-NMR (DMSO-dJ 6 1.13-1.19 (m, 3 H), 2.24 (s, 3 H), 2.74 and 2.94 (S, 3 H), 3.65 (s, 2 H), 3.83 and 3.85 (s, 3 H), 4.14-4.22 (m, 2 H), 4.9M.93 (m, 1 H), 6.70-6,74 (m. 1 H), 6.84 (m, 1 H), 6.92-6.95 (m, 1 H), 7.11-7.17 (m, 2 H), 7.25-7.29 (m, 1 H), 7.78-7,80 (m, 1 H). 7.85-7.93 (m, 2 H), 7.99-8.02 (m ,1 H), 8.46 (s, 1 H), 8.56 (s, 1 H), 12.99 (bs, 1 H); MS (FAB) m/z 540 (M*), 541 (M*+l); -4na/. Calcd for CMHCINA' 1/20: C, 61.26; H, 5.69; N, 7,65. Found: C, 61.15; H, 5.58; N, 7.51. Example 234 3-isopropylamino-4-[[2-[3-methoxy-4-[An-(2-methylphenyl)ureido]phenylacety!]methylarnino] To a cold (0° C), stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[W-(2-methyl phenyl) ureidojphenylacetyl] methyl amino] ethoxy]benzoate (300mg, 0.58mmol) in acetone-AcOH-DMF (13 mL, 6:6:1, v/v/v) was added NaBH3CN (300 mg) and the resulting mixture was stirred for 60 hr at room temp. The mixture was poured into sat. NaHCOj and extracted with CHClj. The extract was washed with brine, dried over MgS04, and evaporated to give 280 mg (86%) methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phenylacetyl] methylamino]ethoxy]benzoate as a colorless oil. 'H-NMR (CDC1}, 400MHz) 5 1.21 (m, 6H), 2.30 (s, 3H), 3.05 and 3,10 (s, total 2H), 3.59 (s, 3H), 3,62-3.81 (m, 6H), 3.89 (s, 3H), 4.10 arid 4.21 (m, 2H), 6.65-6.80 (m, 4H), 7,10 (m, 1H), 7.20 (s, 3H), 7.32 (m, 2H), 7.54 (d, 1H, J=8.3Hz), 8.00 (s, 1H), 8.07 (d, 1H, J=8.3Hz); MS (FAB) m/z 563 (M+l), A stirred mixture of methyl 3-isopropylajnino-4-[[2-[3-methoxy-4-[A'-(2-methylphenyl) ureido]phenylaceryl]methylamino]ethoxy]benzoate (280mg, 0,5mmo!), 0.25 N NaOH {6 mL), and THF (6 mL) was heated under reflux for 8 hr. The mixture was poured into water (200 mL), acidified with IN HC1 and the solid was collected with suction. The solid was recrystallized from CHClj-n-hexane-diisopropylether to give 202mg (74%) 285 as a light yellow crystalline powder, mp 130-135 °C; 'H-NMR (CD,OD, 400MHz) 5 1.18 and 1.22 (d, total 6H, J=6.3Hz), 2.29 and 2.32 (s, total 3H), 3.04 and 3.14 (s, total 2H), 3.60-3.90 (m, 9H), 4.16 and 4,25 (m, total 2H), 6,80 (m, 3H), 7.02 (m, 1H), 7,12-7,24 (m, 3H), 7.29-7.38 (m, 1H), 7.59 (m, 1H), 8.02 (m, 1H); MS (FAB) m/z 548 (M+H)*; /Inn/, calcd. for CNA: C, 65.68; H, 6.61. Found: C, 65.80; H, 6.83. Example 235 4-[[2-[3-methoxy4-[y-(2-methy]phenyI) ureido]phenylaceryl]metliylamino]ethyl]aminobenzoate (300mg, 0.6mmol) in MeCN-formaldehyde-AcOH (11 mL, 8:2:1, v/v/v) was added NaBH3CN (187 mg, 2.40 mmol), and.the resulting mixture was stirred for 18 hr at room temp. The mixture was poured into sat. NaHC03 and extracted with CHC1,. The extract was washed with brine, dried over MgS04, and evaporated to give 309 mg (100%) methyl 4-[I2-[3-methoxy-4-[A'-(2-methylphenyI)ureido]phenylacetyl]-2-iV-methy]amino]ethyl]W-methylaminobenzoate as a colorless oil. 'H-NMR (CDC1,, 400MHz) S 2.30 (m, 3H), 2.98 (m, 7H), 3.46-3.72 (m, 9H), 3.82 (m, 3H), 6.32 (m, 1H), 6.55-6.75 (m, 4H), 7.05-7.50 (m, 2H), 7.82-8.02 (m, 4H); MS (FAB) m/z 518 (M*+l). A stirred mixture of methyl 4-[[2-[3-methoxy-4-rW-(2-methyIphenyl)ureido]phenyIacetyI] -2-Amethylamino]ethy!]methylaminobenzoate (309mg, 0.6mmol) in 1 N NaOH (2.4 mL), and THF (10 mL) was heated under reflux for 8 hr. The mixture was poured into water (200 mL), acidified by the addition of IN HC1. The solid was collected with suction. The crude solid was recrystallizedfromCHCl1-n-hexane-diisopropylethertogive211mg (70%) 286 as a light yeJlow crystalline powder, mp 125-130 °C; IR(KBr) 3338, 2933, 160], 1529, 1182, 1036, 752cm"1; 'H-NMR (CD3OD, 400MHz) 8 2.28 and 2.29 (s, 3H), 2.95-3.02 (m, 6H), 3.60 (br, 6H), 3.80 (s, 1H), 3.86 (s, 2H), 6.60-6.82 (m, 4H), 7.01-7.18 (m, 3H), 7.58 (m, 1H), 7.82-7.99 (m, 3H); MS (FAB) m/z 504(M*+1). Example 236 (S)-3-ch!oro-4-[2-[W-ben2yl-/vr-[3-methoxy-4-[//'-(2-fluorophenyl)ureido)phenylacetyJ]amino]-l- propoxy]benzoic acid r- .COOH F H H icH3 287 To a stirred solution of NaBH3CN (985 mg, 15.68 mmol) in MeOH (5 mL) was added a solution of methyl (S>3-chloro-4-(2-amino-l-propoxy)benzoate (352 mgi 1.57 mmol) and benzaldehyde (0.19 mL) in MeOH (5 mL), and the resulting mixture was stirred at room temp overnight. The mixture was quenched by H,0 and extracted with CHClj. The extract was washed with brine, dried over Na,S04 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3:MeOH (30:1, v/vj as eluent to give 336 mg (64 %) (5)-3-chloro-4-(2-//-benzylamino-l-propoxy)benzoate as a colorless oil. 'H-NMR (CDC13) 5 1.22 (d, 3 H, J=6A Hz), 3.21-3.25 (m, i H), 3.84-4.03 (m, total 7H), 6.89-6.91 (m. I H), 7.23-7.37 (m, 5 H), 7.89-7.91 (m, 1 H), 8.05 (m, 1 H). A mixture of 3-methoxy-4-I?/'-(2-iluorophenyl)ureido]phenylaceticacid (320 mg, 1,01 mmol), methyl (S)-3-chloral-(2-N-beiizyl ami no-l-propoxy)benzoate (336 mg, 1.01 mmol),EDC (hydrochloride) (289 mg, 1.51 mmol), HOBt (204 mg, 1.51 mmol) andDMAP (25 mg, 0.20 mmol) in DMF (7 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over Na,S04 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3:MeOH(50:l, v/v) as eluent to give 607 mg (95%) methyl (S)-3-chloro-4-[2-[A'-benzyl-A'-[3-methoxy-4-[Af'-(2-fluorophenyl)ureido]phenyl acetyl] amino]-l-propoxy]benzoaie as a pale yellow amorphous solid. 'H-NMR (CD CI J 5 1.20-1.27 (m, 3 H), 3.62 (s, 2 H), 3.73-4.16 (series of m, total 9 H), 4.71 (bs, 2 H), 6.67-7.38 (series of m, total 12 H), 7.77-8.17 (series of m, total 5 H). To a stirred solution of methyl (5)-3-cWoro-4-[2-[W-benzyI-//-{3-methoxy-4-[JV'-(2-fiuoropherryl) ureido]phenylacetyl]amino]-l-propoxy]benzoate (607 mg, 0.96 mmol) in THF (6 mL) was added 0.5 N NaOH (6 mL), and the resulting mixture was heated under reflux overnight. The mixture was poured into ice-1 N HC1 and the solid was collected. The crude solid was recrystallized to give 192 mg (32%) 287 as a white crystalline powder, mp 125-130 °C; 'H-NMR (DMSO-cW 5 1.07-1.23 (m, 3 H), 3.76 (s, 2 H), 3.85 (s, 3 H), 3.90-4.26 (m, 3 H), 4.56 (s, 2 H), 6.66-7.38 (series of m, total 10 H), 7,82-8.20 (series of m, total 5 H), 8.70-8,74 (m, 1 H), 9.18-9.20 (m, 1H), 13.02 (bs, 1 H); MS (FAB)m/z62I (M*+l); Anal. Calcdfor CJJHJ.CIFNA'IHJO: C, 63.46; H, 5.08; CI, 5,68; F, 3.04; N, 6.73. Found: C, 63.67; H, 5.16; CI, 5.75; F, 2.95; N, 6.55. Example 237 3 -(AMsopropyl-A'-methy!amino)-4- [[2- [3 -methoxy-4-[A',-(2-methylphenyl)ureido]phenylaceryl] methylamino]ethoxy]ben2oic acid mettyJphenyl)ureido]phenylaceryl]methyIairuno]emoxy]ben2oate (324mg, 0.58mmol) in CH,CN-formaldehyde-AcOH (11 mL, 8:2:1, v/v/v) was added NaBHjCN (145 mg, 2.30 mraol), and the resulting mixture was stirred for 18 hi at room temp. The mixture was poured sat. NaHCOj and the solid was collected with suction. The crude solid was dissolved in CHClj (20mL), and the solution was washed with brine, dried over MgSO,, and evaporated to give 317 mg (95%) methyl 3-(Af-isopropy\--melhylarmrio)4-[[243-melhoxy-[N'-(2-methylpheriy0ureido]phenylacel]' methylamino]ethoxy] benzoate as a colorless oil. 'H-NMR (CDC13) 8 1.02 (m, 6H), 2.29 (s, 3H), 2,63 (m, 3H), 3.02-3.20 (m, 3H), 3.49-3.80 (m, 8H), 3.88 (s, 3H), 4.06 and 4.21 (m, total 2H), 6.59 {m, 1H), 6.76 (m, 2H), 7.11-7.23 (m. 3H), 7.50-7.62 (m, 3H), 8.05 (d, 1H, J=8.3Hz); MS (FAB) m/2 576 (M*+l). A stirred mixture of methyl 3-(A,-isopropyI-A,-methyIamino)-4-[[2-[3-methoxy-4-[An-(2-methylphenyl)ureidolpheny]acety!]methylamino]ethoxylbenzoate(317mg, 0.55mmol) in 0,25 N NaOH (8.2 mL) and THF (8 mL) was heated under reflux for 8 hr. The mixture was poured into water (200 mL), acidified by the addition of IN HC1 and the solid was collected with suction. The crude solid was recrystallized from CHCl3-n-hexane-diisopropyIether to give 288'as a light yellow crystalline powder, mp 130-135 °C; IB. (KBr) 2970, 1537, 1038, 754 cm"'; 'H-NMR (CD3QD) 6 1.12(m, 6H), 2.29 (s, 3H), 2.76 (m, 1H), 2.89 (s, 2H), 3.02 (s, 1H), 3.21 (s, 2H), 3.72 (s, 2H), 3.80 (s, 3H), 3.84 (m, 3H), 4.13 and 4,40 (m, total 2H), 6.76 (d, 1H, .A=7.8Hz), 6.86 (s, 1H), 7.00 (m, 2H), 7.18 (m, 3H), 7.57 (d, 1H, J=7.8Hz), 7.95 (m, 2H); MS (FAB) m/z 562 (M*+l); Anal. Calcd for Cj.HaNAOHO: C, 62.19; H, 7.07; N, 9.36. Found: C, 62.54; H, 6.85; N, 8.90. Example 23S 3-(l-piperidi]iyl)-4-[[2-[3-methoxy-4-[A',-(2-fluorophenyl)ureido]phenylacetyl]meihylamino] phenylacetyl]methylamino]ethoxy]benzoate (300mg, 0,57mmol) in THF (2 mL) was added a solution of glutaraldehyde (50% aqueous solution) (0,13mL, 0.69mmol) in MeOH (1.4 mL), THF (0.993tnL), and 3N H3SO, (0.952 mL) at 0° C. To the solution was added NaBH3CN (150 mg), DMF (5 mL), and MeOH (2 mL) at room temp, and the resulting mixture was stirred for 15 hi. The mixture was poured into sat. NaHC03 and extracted with CHClj. The extract was washed with brine, dried over MgSO,, and evaporated under a reduced pressure. The residue was chromatographed on silica gel with toluene: ace tone (7:3, v/v) as eluent to give 145 mg (43%) methyl 3-(l-piperidinyl)-4-[[2-[3-methoxy-4-iy-(2-fluorophenyl)ureido]phenyIacetyl]methyl airuno]ethoxy]benzoate as a colorless oil. 'H-NMR (CDC13, 400MHz) 8 1.58-1.72 (m, 6H), 2.80-2.92 (m, 4H), 3.26 (s, 2H), 3.58 (s, 2H), 3.69 (s, 2H), 3.80-3.89 (m, 7H), 4.22 (m, 2H), 6.72 (s, 1H), 6.78 (m, 2H), 6.95-7.18 (m, 2H), 7.32 (s, 1H), 7.60 (s, 1H), 7.63 (d, 1H, J=7.8Hz), 7.98 (d, 1H, >7.8Hz), 8.18 (m, 1H); MS (FAB)m/z 593 (M*+l). A stirred mixture of methyl 3-(l-piperidinyI)-4-[[2-[3-methoxy-4-[Ap-(2-fluorophenyl) ureido]phenylacetyl]methylamino]ethoxy]benzoate (290mg, 0.49mmol), IN NaOH (1.95 mL) in MeOH(5mL) and THF (10 mL) was heated under reflux for 4 hr. The mixture was poured into water (200 mL), acidified with IN HCI (pH=4,0), and extracted with CHCl3-MeOH(9:l, v/v). The combined extract was dried over MgSO* and evaporated. The residue was crystallized from diisopropyiether-hexane to give 201mg (71%)289 as a light yellow crystalline powder, mp 125-I30°C; 1R (KBr) 3338, 2935, 1599, 1537, 1041, 752 cm-'; 'H-NMR (CD3OD) 5 1.52-1.73 (m, 6H), 2.88 (s, 3H), 2.98 (br, 1H), 3.09 (s, 1H), 3.23 (s, 2H), 3.66 (s, 2H), 3.75 (s, 1H), 3.82 (s, 4H), 4.13 and 4.29 (m, total 2H), 6.78 (m, 2H), 6.99 (m, 2H), 7.10 (m, 2H), 7.60-7.70 (m, 2H), 7..96-8.07 (m, 2H); MS (FAB) m/z 578 (M*+l); Anal Calcd for C3,H3JFN,O6-0.5H5O: C, 63.36; H, 6.17; N, 9.53. Found: C, 63.22;H, 6.15; N, 9.16. Example 239 3 -amino-4 -[[2-[3-methoxy-4-[A',-(2-methylphenyl)ureido] phenyl acetyl] methy lamino] elhoxy} phenylacetyI]methylamino]ethoxy]benzoate (300 mg, 0,58 mmol) in MeOH-THF (2:1, v/v, 12 mL) was added 0.25 N NaOH (9 mL), and the resuldng mixture was heated under reflux for 16 tir. The mixture was poured into wa(er( 100 mL) and acidified by the addition of IN HCI. The solid was collected with suction. The residue was recrystaliized from diisopropylether to give 243 mg (83%) 290 as a yellow crystalline powder, mp 125-130 °C; IR (KBr) 3346, 2935, 1533, 1211, 1034,756, 637cm-1; 'H-NMR (DMSO-d6) § 2.29 (s, 3H), 3.05 (s, 1H), 3.72-3.85 (m, 7H), 4.12 and 4.25 (m, tola! 2H), 6.76-6,89 (m, 3H), 7.00 (m, 1H), 7.18 (m, 2H), 7.39 (m, 2H), 7.60 (d, lH,./=7.8Hz), 7.96 (m, Hno/.CalcdforCHjjNA-O.HjO: C,62.90;H, 6.06; N, 10.87. Found: C, 63.03; H, 6.14; N, 10.56. Example 240 3-(l-piperidinyl)-4-[[2-[3-methDxy-4-[//-(2-methylphenyl)ureido]phenylacetyl]methylamino] methylphenyl) ureido]phenylacetyl]memyl amino] ethoxy]benzoate (573mg, l.lmmol) in THF-MeOH (2:1, v/v, 6mL) was added glutaraldehyde (0.423mL, 2.2mmol), 3N HiSO,(1.83mL, 5.5mmol), and NaBHjCN (276mg, 4.4mmol). The resulting mixture was stirred for 18 hr at room temp. The mixture was poured into sal. NaHCO3(100mL)and the solid was collected with suction. The crude solid was purified by column chromatography on silica-gel with toluene-acetone (10:0 to 4:1, v/v) to give 240mg (37%) methyl 3-(l-piperidinyl)-4-[[2-[3-methoxy-4-IA',-(2-metriyI phenyl)ureido]phenylacetyl]methylamino]ethoxy] benzoate as a gum. 'H-NMR (CD3OD) 8 1.52-1.72 (m, 6H), 2.30 (s, 3H), 2.36 (s, 2H), 2.89 (br s, 3H), 2.98 (m, 1H), 3.05 (s, 1H), 3.20 (s, 2H), 3.68 (s, 2H), 3.69 (m, 2H), 3.79 (m, 2H), 3.88 (s, 2H), 4.08 and 4.21 (m, 2H), 6.35 and 6.42 (s, total 1H), 6.70 (s, 1H), 6.70 (s, 1H), 6,79 (m, 2H), 7.09-7.24 (m, 4H), 7.50-7.65 (m, 3H), 8.05 (d, 1H, J=8.3Hz); MS (FAB) m/z 588 (NT+1), A stirred mixture of methyl 3-(l-piperidinyI)-4-[[2-[3-methoxy-4-[-(2-methylphenyl) ureidojpheny la cetyl]methy lamino J ethoxy Jben2oate (240 mg, 0.41 mmol), 1 N NaOH (1.63 mL) in MeOH (6.5 mL), H,0 (5 mL), and THF (6.5 mL) was heated under reflux for 11 hr. The mixture was poured into water (200 mL), acidified by the addition of IN HC1 until pH=4.0, and the solid was collected with suction. The aqueous layer was extracted with CHCl3-MeOH (9:1, v/v, 30mL x 3). The precipitate was dissolved in the combined organic extract. The organic layer was dried overMgSOj and evaporated. The residue was crystallized from diisopropylether to give 151 mg (65 %) 291 as a light yellow crystalline powder, mp I20-i25°C; ffi (KBr) 3354, 2935, 1535, 1252, 1217,1034,754,638 cm1; 'H-NMR (CD3OD) 5 1.55-1.72 (m, 6H), 2.30 (s, 3H), 2.89 (br, 2H), 2.98 (br, 1H), 3,09 (s, 1H), 3.22 (s, 2H), 3.69 (s, 3H), 3.74 (s, 1H), 3.83 (m, 4H), 4.12 and 4.28 (m, total 2H), 6.75 (m, 2H), 6.88-7.02 (m, 1H), 7.17 (m, 2H). 7.58-7.73 (m, 4H), 7.99 (d, 1H, J=8.3Hz); MS (FAB) m/z 574 (M*+I); 4/ia/. Calcd for C3sHMNA-0.5H,O: C, 65.85; H, 6.73; N. 9.60. Found: C, 65.94; H, 6.88; N, 9.03. phenylacetyl]methylamino}ethoxY]beiizoate (250 rag, 0.48 nunol) in IN NaOH (1.91 mL), MeOH (8 mL), Kip (6 mL), and THF (8 mL) was healed under reflux for 10 hr. The mixture was poured into water {200 mL), acidified by the addition of IN HC1 (pH=4.8), and the solid was collected with suction. The crude solid was recrystallized from diisopropy]ether to give 209 mg (86 %) 292 as a pale yellow crystalline powder, mp 125-130°C; 1R (KBr) 3325, 2935, 1537, 1209, 1032, 752, 449 cm-'; 'H-NMR (CD3OD) 5 3.05 (s, 1H), 3.31 (s, 2H), 3.77 (m, 3H), 3.80 (s, 1H), 3.84 (m. 3H), 4.144.26 (in, 2H), 6.80-6.87 (m, 3H), 7.01 (m, 1H), 7.10 (m, 2H), 7.39 (m, 2H), 7.80 (m, 1H), 8.07 (m, 1H);MS (FAB)wv'z 510 (M'+l); Anal. Calcd for CFNA'O.SHO: C, 60.11; H, 5.43; F, 3.66; N, 10,78. Found: C, 60.29; H, 5.40; F, 3.60; N, 10.59. mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol), and PI13P (1.75 g, 6.67 mmol) in THF (15 mL) was added diisopropy 1 azodicarboxyiale (DIAD) (1.31 mL, 6.65 mmol) at room temp, and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CHCl, (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 3 hr. The mixture was concentrated in vacua. The residue was dissolved in CHG3, washed with sat. NaHC03, brine, dried over Na;SO, and evaporated. The residue was purified by column chromatography on silica-ge! with 5% MeOH in CHClj as eluent to give 313 mg (24%) methyl(5)-3-nitio-4-(2-amino-l-propoxy)benzoateasa pale yellow oil. 'H-NfvTft (CDCJJ 5 1.22 (d, 3 H, J=6.S Hz), 3.43-3.48 (m, I H), 3.69-3.87 (m, 2 H), 3.89 (s, 3 H), 6.93-6.95 (m, 1 H), 7,99-8,02 (m, 1 H), 8,18-8.21 (m, 1 H). A mixture of pentafluorophenyl 3-methoxy-4-[A'-(2-methylphenyl)ureido]pheriylacetate (591 mg, 1.23 mmol), methyl (5)-3-nilTo-4-(2-amino-l-propoxy)ben2oate (313 mg, 1.23 mmol), and EtjN (257 mL, 1.84 mrao)) in DMF (5 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over NajSO* and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCJ, as eluent to give 310 mg (46%) methyl (5)-3-nitro-4-[2-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenyl acetylamino]-]-propoxy]benzoateasagum, 'H-NMR (CDC13) 6 1.28 (d, 3 H, 7=6.8 Hz), 2.31 (s, 3 H), 3.49 (S, 2 H), 3.71 (s, 3 H), 3.92 (s, 3 H), 4.144.16 (m, 2 H), 4.384.41 (m, 1 H), 5.88-5.90 (m, 1 H), 6.49 (s, 1 H), 6.70-6.71 (m, 1 H), 6.77-6.79 (m, I H), 7.05-7.30 (m, 4 H), 7.55-7.57 (m, I H), 8.02-8.06 (m, 2 H), 8.16-8.19 (m, J H), 8.51-8.52 (m, 1 H); MS (FAB) m/z 551 (M'+l). A stirred solution of methyl (5)-3-nitro-4-I2-[3-methoxy-4-[A'-(2-methyIphenyl)ureido] phenylacetylamino]-l-propoxy]benzoate (310 mg, 0.56 mmol) in MeOH-THF (10 mL, 1:1, v/v) was hydrogenated over 5% Pd-C (50 mg, 16 wt%) ovemighL The mixture was filtered to remove the catalyst and the filtrate was evaporated to give methyl (S)-3-amino-4-[2-[3-methoxy-4-[W-(2-methylphenyl) ureido]phenylacetylamino]-l-propoxy]benzoate (240 mg) as a gum. To a stirred solution of the above crude product (220 mg) in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux for 2 hr. The mixture was poured into ice-HjO, and the aqueous layer was made acidic (pH 4.8) by the addition of 1 N HC1. The solid was collected and the crude solid was recrystallized from MeOH-CHCi3-n-riexane to give 116 mg (2 steps, 44%) 293 as a pale yellow crystalline powder, mp 200-204 °C; 'H-NMR (DMSOA) 6 1.21 (d, 3 H, .7=6.8 Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3,80 (s, 3 H), 3,83-3.99 (m, 2 H), 4,10-4.19 (m, 1 H), 4,99 (bs, 2 H), 6.75-7.23 (series of m, total 8 H), 7.79 (d, 1 H, 7=7.8 Hz), 7,98 (d, 1 H, 7=7.8 Hz), 8.17 (d, 1 H, 7=8.3 Hz), 8.46 (s, 1 H), 8,55 (s, 1 H); MS (FAB) m/z 507 (M*+l)Mwa/. Calcdfor CHCV 1/2H,0; C, 62.90; H, 6,06; N, 10,87. Found: C, 62.85; H, 6.10; N, 10.51, (6,74 g, 0.04 mol), benzyl 4-hydroxybenzoale (8.78 g, 0.04 mol), and Ph3P (15.13 g, 0.06 mol) in THF (100 mL) was added diisopropyl azodicarboxylate (DIAD) (11.4 mL, 0.06 mol), and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH,C13 (30 mL) and TFA (30 mL). The resulting solution was stirred at room temp for 30 min., and the solution was evaporated in vacuo. The residue was dissolved in CHC13, washed with sat. NaHCOj, dried over Na,SO and evaporated. The residue was purified by column chromatography on silica-gel with CHClj to CHCljiMeOH (9:1, v/v) as eluent to give 6.63 g (2 steps, 60%) benzy! (5)-4-(2-amino-l-pjopoxy) benzoate as a yellow oil. 'H-NMR (CDC13) 5 1.18 (d, 7= 6.3 Hz, 3 H), 3.35-3.39 (m, 1 H), 3.71-3,75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2 H), 7.32-7.46 (m, 5 H), 8.01-8,04 (m, 2 H). A mixture of 3-methoxy-4-[A'-(2-bromophenyl)ureido]phenylaceticacid (480 mg, 1.27 rnmol), benzyl (S)-4-(2-amino-l-propoxy)benzoate (361 mg, 1.27 mmol), EDC(hydrochloride) (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol), and 4-DMAP (31 mg, 0.25 mmol) in DMF (8 mL) was stirred ai room temp, overnight. The mixture was diluted with ElOAc, washed with 0.5 N HC1, brine, dried over NaiSO, and evaporated. The residue was purified by column chromatography on silica-gel with CHC13 to 5% MeOH in CHC13 as eluent to give 476 mg (58%) benzyl (5)-4-[2-[3-methoxy-4-[A'-(2-bromophenyI)ureido]phenylacetylamino]-]-propoxy]benzoate as a brown solid. 'H-NMR (CDClj) 5 1.25-1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95-3.97 (m, 2 H), 4.36-4.39 (m, 1 H), 5.33 (s, 2 H), 6.75-6.94 (m, 5 H), 7.26-7.70 (m, 8 H), 7.99-8.26 (m, 5H). To a stirred solution of benzyl (i)-4-[2-[3-methoxy-4-[A'-(2-bromophenyl)ureido] ' pheny]acetylamino]-l-propoxy]benzoate (476 mg, 1.39 mmol) in THF (10 mL) was added 0.5 N NaOH (10 mL), and the resulting mixture was healed under reflux for 2 hr. The mixture was poured into ice-1 N HC1, and the solid was collected. The crude solid was recrystallized from MeOH-CHClj-n-hexane to give 240 mg (59%) 294 as a white crystalline powder, mp 202-205 °C; 'H-NMR CDMSO-dJ 6 1.18 (d, J = 6.8 Hz, 3 H), 3.37 (s, 2 H), 3.82 (s, 3 H), 3.92.00 (m, 2 H), 4.03-4.15 (m, 1 H), 6.77-6.79 (m, 1 H), 6.93-7.03 (m, 4 H). 7.30-7.34 (m, 1 H), 7.59-7.61 (m, 1 H), 7.87-7.97 (m, 4 H), 8.13-8.15 (m, 1 H), 8.73 (s, 1 H), 8,91 (s, 1 H), 12.63 (bs, 1 H); MS (FAB) m/z 557 (M*+l); Anal. Calcdfor CjHaBrNA: C, 56,12; H, 4.71; Br, 14.36; N, 7.55. Found: C, 56.11;H,4,74;Br, 14,56; N, 7.49. Example 244 (-[[2-[3-methoxy-4-[W'-(2-methylphenyl)ureido]phenylacetyl]-(2-aminobenzyl)amino]-l- propoxy] benzoic acid 5.26 mmol) and 2-nitrobenzaidehyde (0.87 g, 5.76 mmol) in MeOH-AcOH (16 mL, 15:1, v/v) was added NaBHjCN (1.65 g, 26.3 mmol), and the resulting mixture was stiired at room temp overnight. The mixture was quenched by sat. NaHC03 and extracted with EtOAc. The extract was washed with brine, dried over NaiSO«, and evaporated. The residue was purified by column chromatography on silica-gel with CHC13 to 5% MeOH in CHClj as eluent to give 931 mg (42%) benzyl 0S)-4-[2-{2-nitrobenzylamino) -l-propoxy]benzoate as a yellow oil. 'H-NMR (CDC13) 5 L21 (d, J= 6.4 Hz, 3 H), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2 H), 5.34 (s, 2 H), 6.89-6.94 (m, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); MS (FAB) m/z 421 (M*+l). A mixture of pentafluorophenyl 3-methoxy-4-[A'-{2-methylphenyl)ureido]phenylacetate (460 mg, 0.96 mmoi), benzyl (5)-4-[2-{2-nitroben2ylamino)-l-propoxy]benzoate (403 mg, 0.96 mmol), and Et3N (200 mL, 1.43 mmol) in DMF (8 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over Na2S04, and evaporated. The residue was purified by column chromatography on silica-gel with 1% MeOH in CHCij as eluent to give 504 mg (73%) benzyl (S)-4-[[2-[3-methoxy-4-[A"-(2-methyIphenyl)ureido] phenyl acetyl]-(2-nitrobenzyl)ami no]-l-propoxy]benzoate as a brown amorphous solid. MS (FAB) m/z 717 flvT+J), A stirred solution of benzyl (S)-4-[[2-[3-melhoxy-4-[Af'-(2-metlryiphenyl)ureido]phenyl acetyl]-(2-nitrobenzyl)amino]-l-propoxy]benzoate (504 mg, 0.70 mmol) in MeOH-THF (11 mL, 10:1, v/v) was hydrogenated over 5%Pd-C (100 mg, 20 wt%) at 3 aim overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was purified by preparative TLC with 5% MeOH in CHCL, as eluent to give 115 mg (27%) 295 as a white powder. MS (FAB) m-i 597 (M'-H), Example 245 (5)-4-[[2-[3-memoxy-4-[W-(2-bromophenyl)ureido]phenylacetylJ-{2-nitrobenzyl)amino]-l- propoxy]benzoic acid (1.50 g, 5.26 mmol) and 2-nitrobcnzaldehyde (0.87 g, 5.76 mmol) in MeOH-AcOH (16 ml,, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol), and the resulting mixture was stirred at room temp overnight The mixture was quenched by sat. NaHCOj and extracted with EtOAc. The extract was washed with brine, dried over Na,SO* and evaporated. The residue was purified by column chromatography on silica-gel with CHClj to 5% MeOH in CHClj as eluent to give 931 mg (42%) benzyl (5)-4-[2-(2-nitrobenzylamino) -l-propoxy]benzoate as a yellow oil. 'H-NMR (CDC15) 5 1.21 (d, 3 H,J=6.4 Hz), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2 H), 5.34 (s, 2 H), 6.89-6.94 (m, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); MS (FAB) tnfr 421 (M*+l). A mixture of3-methoxy-4-[A'-(2-Drornopheiiyl)ureido]phenylacetic acid (476 mg, 1.26 mmol), benzyl (5)-4.[2-(2-nitrobenzylamino)-l-propoxy]benzoate (528 mg, 1.26 mmol), EDC(hydrochloride) (361 mg, 1.88 mmol), HOBt (255 mg, 1.89 mmol), and DMAP (30 mg, 0.25 mmol) in DMF (10 mL) was stirred at room temp, overnight and at 60° C for 1 day . The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over NaC and evaporated. The residue was purified by column chromatography; on silica-gel with CHClj to 2% MeOH in CHClj as eluent to give benzyl (S)-4-[[2-[3-methoxy-4-IA''-(2-bromophenyi)ureido]phenylacetyl]-(2-nitrobenzyl)amino]-l-propoxy]benzoic acid as an oil, which is used to the subsequent reaction without further purification. To a stirred solution of the above crude in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux for 3 hi. The mixture was poured into ice-H,0, and the basic aqueous layer was made acidic (pH 4.3) with 1 N HC1. The solid was collected, and the crude solid was purified by preparative TLC with 5% MeOH in CHC13 as eluent to give 162 mg (2 steps, 19%) 296 as a white amorphous solid. MS (FAB) m/z 692 (M*+l)Mnn/. Calcd for C33H3,BrNA-7/4H,0: C, 54.82; H, 4.81; N, 7.75. Found: C, 54,80; H, 4.61; N, 7.24, Example 246 4-[2-A'-[3-meihoxy-4-[//,-{2-methylphenyl)iiTeido]pheiiylacetamido]ethoxy]benzcjicacid nclhyl 4-hydroxybenzoate (3.02 g, 19.9 mmol) and PhjP (6.25 g, 23.8 mmol) in THF (50 ml) was idded dropwise DIAD (4.69 ml, 23.8 mmol) over for 5 min. The reaction mixture was heated tnder reflux for 3 hr. The mixture was evaporated and the residue was dissolved in CH7Clj (30 nl) andTFA (30 ml). The reaction mixture was stirred at room temperature overnight. The ru'xture was concentrated in vacuo and the residue was dissolved in CHCI, and H20. The solution vas made basic by sat. NaHCOj and extracted with CHClj. The extract was washed with brine, Iried over NasSQ( and evaporated. The residue was purified by column chromatography on silica-;el with CHCl3-MeOH (30:1, v/v) as eluent to give methyl 4-(2-aminoethoxy)benzoate (1.03 g, ■4% for 2 Steps) as a colorless oil. 'H-NMR (CDClj) 5 3.10-3.13 (m, 2 H), 3.89 (s, 3 H), 4.03-1.06 (m, 2 H), 6.92-6.94 (m, 2 H), 7.98-8.00 (m, 2 H). A mixture of 3-methoxy-4-[W-(2-methylphenyl)ureido]pheny]acetic acid (557 mg, 1.77 nmol), methyl 4-(2-ammoethoxy)ben2oate (346 mg, 1.77 mmol), EDCHC1 (408 mg, 2.13 mmol), lOBt (287 mg, 2.12 mmol) and DMAP (52 mg, 0.43 mmol) in DMF (10 ml) was stirred at room emperature for 2 days. The mixture was diluted with EtOAc and H30. The resulting precipitate vas collected to give methyl 4-[2-A'-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phenylacetainido] :thoxy]benzoate (598 mg, 69%) as a white crystalline powder. 'H-NMR (DMSO-d*) 5 2.23 (s, 3 Tj, 3.36 (s, 2 H), 3.42-3.45 (m, 2 H), 3.79 (s, 3 H), 3.81 (s, 3 H), 4.02-4.09 (m, 2 H), 6.73-6.75 m, 1 H), 6.90-6.94 (n% 2 H), 7.02-7.04 (m, 2 H), 7.09-7.15 (m, 2 H), 7.77-7.79 (m, 1 H), 7.88-'.90 (m, 2 H), 7.95-7.98 (m, 1 H), 8.23-8.24 (m, 1 H), 8.44 (s, 1 H), 8.53 (s, 1 H); MS (FAB), m/z 192 (M'+l); Anal Calcd for C3JH,9N30« 1/4H,0: C, 65.38; H, 5.99; N, 8.47. Found: C, 65.26; H, i.99;N, 8.49. To a stirred solution of methy] 4-[2-A'-(3-methoxy-4-[Af '-(2-methy}phcnyl)urcido] >henyiacetamido]ethoxy]benzoate (280 mg, 0.57 mmol) inTHF-MeOH(10 ml, 1:1, v/v) was idded 0,5 N NaOH (10 ml) and the reaction mixture was heated under reflux for 5 hi. The Tuxture was cooled to room temperature and poured into ice-1 N HC!. The resulting precipitate *as collected and recrysta!li2ed from Et20-CHCl3-MeOH to give 297 (135 mg, 50%) as a white :rysialline powder. MW 477.51 'H-NMR (DMSO-d*) 5 2,24 (s, 3 H), 3.38 (s, 2 H), 3.43-3.47 (m, 1 H), 3,82 (s, 3 H), 4.06-4.09 (m, 2 H), 6.76-6.78 (m, 1 H), 6,92-7,17 (m, 6 H), 7.79 (d, J = 8.1 4z, 1 H), 7.88-7.89 (m, 2 H), 7.98 (d, J = 8.1 Hz, 1 H), 8.24-8.27 (m, 1 H), 8.45 (s, 1 H), 8.55 (s, 1 H); MS (FAB)m/z478 (M*+l);Anal. Calcdfor CiAiNAlrtHjO: C,64.79; H, 5.75; N, 8.72. Found: C, 64.67; H, 5.63; N, 8.60. (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol), and PhjP (15.13 g, 0.06 mol) in THF (100 ml) was added D1AD (11.4 ml, 0.06 mol), and ihe reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CHjClj (30 ml) and TFA (30 ml). The solution was stined at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHC13, washed with sat. NaHCOj, dried over NajSOj and evaporated. The residue was purified by column chromatography on silica-gel with CHC13 to CHClj-MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-l-propoxy)benzoate (6.63 g, 2 steps, 60%) as a yellow oil. 'H-NMR (CDCh.) 5 J.IS (d, J=63Hz, 3H), 3.35-3.39(m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (m, 1 H), 5.34 (s, 2 H), 6.90-6.93 (m, 2H), 7.32-7.46 (m, 5H), 8.01-8.04 (m,2H). A mixture of 4-[//'-(2-bromophenyl)ureido]-3-meihoxyphenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-l-propoxy)benzoate (361 mg, 1.27 mmol), EDCHC1 (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol) and DMAP (31 mg, 0.25 mmol) in DMF (8 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 0.5 N HC1, brine, dried over Na]SOj and evaporated. The residue was purified by column chromatography on silica-gel with CHClj to 5% MeOH in CHC13 as eluent to give benzyl (5)-4-[2-[4-[A''-{2-bromophenyl) ureido]-3-methoxyphenylacetamido] -l-propoxy]benzoate (476 mg, 58%) as a brown solid. 'H-NMR (CDCI3) 5 1.25-1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95-3.97 (m, 2 H), 4.36-1.39 (m, 1 H), 5.33 (s, 2 H), 6.75-6.94 (m, 5 H), 7.26-7.70 (m, 8 H), 7.99-8.26 (m, 5 H). The a stirred solution of benzyl (S)-4-[2-[4-[W'-(2-bromophenyl)ureido]-3-methoxyphenyl acetamido]-l-propoxy]benzoate (476 mg, 1.39 mmol) in THF (10 ml) was added 0.5 N NaOH (10 ml), and the reaction mixture was heated under reflux for 2 hr. The mixture was poured into ice-I N HC1, and the resulting precipitate was collected. The crude solid was purified by recrystailization from MeOH-CHClj-n-hexane to give 298 (240 rag, 59%) as a white crystalline powder. MW 556.41 'H-NMR pMSO-d*) 5 1.18 {d,J= 6.8 Hz, 3 H), 3.37 (s, 2 H), 3.82 (s, 3 H), 3.92-4.00 (m, 2 H), 4.03-4.15 (m, 1 H), 6.77-6.79 (m, 1 H), 6.93-7.03 (m, 4 H), 7.30-7.34 (m, 1 H), 7.59-7.61 Cm, 1 H), 7.87-7.97 (m, 4 H), 8.13-8,15 (in, 1 H), 8.73 (s, 1 H), 8.91 (s, 1 H), 12.63 (bs, 1 H); MS (FAB) m/z 557 (M*+1)M™/. Calcd for QAaBrNA: C, 56.12; H, 4.71; Br, 14,36; N, 7.55. Found: C, 56.11; H, 4.74; Br, 14.56; N, 7.49. 17.6 mmol), methyl 4-hydroxybenzoate (2.67 g, 17.6 mmol) and PhjP (5.53 g, 21.1 mmol) in THF (35ml)wasaddeddropwiseDIAD(4.15inl,21.1 mmol). The reaction mixture was heated under reflux oveniight. The mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl (S)-4-[2-[(A'-(er(-butoxycarbonyI)airono]-l-propoxy]beiizoate (1.24 g, 23%) as a white solid. 'H-NMR (CDClj) 5 1.30 (d, J = 6.8 Hz, 3 H), 1.45 (s, 9 H), 3.89 (s, 3 H), 3.98-3.99 (m, 2 H), 4.07 (m, 1 H), 4.76 (m, 1 H). 6.91-6.93 (m, 2 H), 7.98-8.00 (m, 2 H); MS (FAB) m/z 310 (M*+l). To a stirred solution of methyl {5)-4-[2-[{A'-/er(-butoxycarbonyl)amino]-l-propoxy] benzoate (1.24 g, 4.01 mmol) in CH,C1, (10 ml) was added TFA (10 ml) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, and made basic by sat. NaHCOj. The mixture was extracted with CHClj, washed with brine, dried over KjC03 and evaporated to give methyl (S)-4-(2-amino-l-propoxy) benzoate (790 mg, 94%) as a yellow oil. 'H-NMR (CDC13) 5 1,19 (d, J = 6.7 Hz, 3 H), 3.34-3.42 (m, 1 H), 3.70-3.77 (m, 1 H), 3.86-3.94 (series of s and m, total 4 H), 6,92 (d, J = 9,0 Hz, 2 H), 7.98 (d, J = 9.0 Hz, 2 H). To a cooled (0°C) solution of methyl (S)-4-(2-amino-l-propoxy)benzoate (790 mg, 3.78 mmol) and Et3N (630 ml, 4.52 mmol) in THF (10 ml) was added TFAA (640 ml, 4.53 mmol) and the reaction mixture was stirred at room temperature for 4 days. The mixture was diluted with 0.5 N HCI and extracted with CHC1,. The extract was washed with brine, dried over K]C03, and evaporated. The residue was purified by recrystallization from n-hexane-CHCl3 to give methyl (S)-4-[2-(trifluoroacetamido)-l-propoxy]benzoate (790 mg, 69%) as a white crystalline material. 'H-NMR(CDCl3)5 1.42(d,y=6,8Hz, 3 H), 3.89 (s, 3 H), 4.01-4.13 (m, 2 H), 4.44-4.50 (m, 1H), 6.57-6.61 (m, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 8,00 (d, J = 9.0 Hz, 2 H); MS (FAB) m/z 306 (M*+I); Anal. Calcd for CNO,: C, 31.15; H, 4.62; F, 18.67; N, 4.59. Found: C, 5M4; H, 4.60; F, 18.50; N, 4.54. To a stined solution of methyl (S)-4-[2-(lrifl\ioroacetainido)-l-propoxyJbcnzoalc (695 mg, 2.28 mmol) and K2COj {630 mg, 4.56 mmol) in DMF (10 ml) was added Mel (210 ml, 3.37 irnnol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with H20 and extracted with EtOAc. The extract was washed with brine, dried over Na2SO„ and evaporated. The residue was purified by column chromatography on silica-gel with EtOAc-CHClj (1:19, v/v) as eluent to give methyl (S)-4-[2-[(A'-methyl)trifluoroacetamido]-l-propoxy]benzoate (720 mg, 99%) as a white solid, mp 73-75°C; 'H-NMR (CDClj)5 1.36-1.39 (m, 3 H), 2.96 and 3. JO (each s, total 3 H), 3.89 (s, 3 H), 3.99-4.14 (m, 2 H), 4.84-4.92 (m, i H), 6.88-6.92 (m, 2 H), 7.98-8.00 (m, 2 H); MS (FAB) m/z 320 (M*+l); Anal. Calcd for CMHFNO,: C, 52,67; H, 5.05; F, 17.85; N, 4.39. Found: C, 52.76; H, 5.09; F, 17.53; N, 4.32. To a stirred solution of methyl (5)-4-[2-[(A'-methyl)trifiuoroacetamido]-l-propoxy] benzoate (710 mg, 2.22 mmol) in MeOH-H30 (10 ml, 1:1, v/v) was added KjCO, (460 mg, 3.33 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with H,0 and extracted with EtOAc. The extract was washed with brine, dried over NajSOj, and evaporated lo give methyl (.S)-4-[2-(Af-methylanuno)-l-propoxy]benzoate (430 mg, 87%) as a colorless oil. 'H-NMR (CDC1,) 8 1,17 (d,-7 = 6.6 Hz, 3 H), 2,48 (s, 3 H), 2.98-3.06 (m, 1 H), 3.86-3.96 (series ofs andm, total 5 H), 6.92 (d, J-9.0Hz, 2H), 7.98 (d,J = 9.0Hz, 2H). A mixture ofS-methoxy-J-'--methylphenylJureidolphenylacetic acid (605 mg, 1.93 mmol), methyl (S)-4-[2-(jV-methyiamino)-l-propoxy]beri2oate (430 mg, 1.93 mmol), EDCHC1 (444 mg, 2.32 mmol), HOBt (313 mg, 2.32 mmol), Et3N (320 ml, 2.30 mmol) in THF (13 ml) was stirred at room temperature overnight. The mixture was diluted with H,0 and extracted with ElOAc. The extract was washed with brine, dried over Na,SO,, and evaporated. The residue was purified by column chromatography on silica-gel with CHCIrMeOH (100:1 (o 75:1, v/v) as eluent to give methyl (S)-4-[2-A'-[[3-methoxy-4-[W-(2-metliylphenyl)ureido]phenyl]-A'-methylacetamido3 -l-propoxy]ben2oate (953 mg, 95%) as a white foam. 'H-NMR (CDC13) 5 1.12-1.13 and 1.25-1,27 (each m, total 3 H), 2.27 (s, 3 H), 2.84 and 2.92 (each s, total 3 H), 3,63 (s, 3 H), 3.67 (s, 1H), 3.71-4,05 (series ofs and m, total 5 H), 4.39-4,44 and 4.96-5.01 (each m, total 1 H), 6,66-6.85 (m, 5 H), 7.09-7.27 (m, 4 H), 7.53-7,55 (m, 1 H), 7.92-7.98 (m, 2 H), 8.04-8.08 (m, 1 H); MS (FAB) m/z 520 W+\);Anal. Calcd for CHNA 11/4H;0: C, 61,20; H, 6.82; N, 7.38. Found: C, 61.14; H, 5.86; N, 7,16. To a stirred solution of methyl (■S)-4-[2-A4[3-methoxy-4-[A'H2-rnethylpheny])uxeido] phenyl]-//-methylacetamido]-l-propoxy]benzoate (663 mg, 1.28 mmol) in THF (5 ml) was added 0.5NNaOH(5 ml) and the reaction mixture was heated under reflux for 5 hr. After cooled to room temperaiure, the mixture was poured into ice-1 N HC1 and the resulting precipitate was collected under a reduced pressure. The crude solid was dissolved in CHC13 and evaporated. The residue was washed with Et:0 to give 299 (465 mg, 72%) as a white amorphous solid. MW 505.56 'H-NMR {DMSO-d*) 5 1.11-1.15 (m, 3 H), 2.25 (s, 3 H), 2.73 and 2.88 (each s, total 3 H), 3.60-3.76 (m, 2 H), 3.83 (s, 3 H), 4.03-4.12 (m, 2 H), 4.4M.50 and 4.48-4.94 (each m, total I H), 6.71-6.76 (m, 1 H), 6.84-6.86 (m, 1 H), 6.91-7.01 (m, 3 H), 7.11-7.12 (m, 2 H), 7.78-7.80 (m, 1 H), 7.86-7.90 (m, 2 H), 8.01-8.03 (m, 1 H), 8.45 (s, 1 H), 8.54 (s, 1H); MS (FAB) m/z 520 (M*+l); Anal. Calcd for CINJO.HJO: C, 63,15; H, 6.43; N, 7.89. Found: C, 63.09; H, 5.99; ti, 7.64. Example 249 mmol), 3-chloropivalic acid (2.9 g, 21.69 mmol) and catalytic amount of KI (200 mg) inUMF (70 ml) was heated at 100 °C for 14days under a current of nitrogen. The mixture was poured into ice-water, and extracted with EtOAc. The extracts were washed with brine, dried over Na3SO,, and evaporated. The residue was chromatographed on silica gel (50ml) with CHCl3-EtOH (10:1, v/v) as eluent to give the tide compound (1 g, 23%) as an amorphous solid. 'H-NMR (CDC1,) 5 1.37 (s, 6 H), 3.89 (s, 3 H), 4.03 (s, 2 H), 6,92 (d, J=9 Hz, 2 H), 7.98 (d, J = 9Hz, 2 H). To a stirred mixture of 2,2-dimethyl~3-{4-methoxycarbonyl)phenoxypropionJc acid (720 mg, 2.85 mmol) and triethylamine (0.46 ml, 3.28 mmol) in fert-BuOH (10 ml) and benzene (10 ml) was added a solution of diphenyl phosphoryl azide (870 mg, 3.14 mmol) in benzene (3 ml) at room temperature. The resulting mixture was heated at reflux for 20 hr. After cooling, ice and IN HC1 (5ml) was added to the mixture and extracted with toluene. The extracts were washed with brine, dried over Na,SO(, and evaporated. The residue was chromatographed on silica gel (50ml) with toluene-EtOAc (10:1, v/v) as eluent to give methyl 4-[l-(2-amino-2-methyl)prpoxy]benzoate as a gum (520 mg), which was used to the subsequent reaction without further purification, 'H-NMR(CDC13)6 1.41 (s, 9 H), 3.89 (s, 3 H), 4.04 (s, 2 H), 4,69 (br s, 1H), 6.94 (dd, J =2 and 7 Hz, 2 H), 7,98 dd, .7=2 and 7 Hz). A solution of methyl 4-[l-{2-methyl-2-ferNbutoxycarbonyIamino-)prpoxy]benzoate (520 mg) and anisole (0.175 ml, 1.61 mmol) in CHjCl, (5 ml) and TFA (3 ml) was stirred at room temperature for 18 hr. The mixture was evaporated off. The residue was dissolved in CH,C1,, and the mixture was made basic by the addition of sat. NaHC03. Separated CH3C1, layer was dried over NajSOj and NajCOj, and evaporated. The residue was chromatographed on silica gel with CHClj-EtOH (10:1, v/v) as eluent to give methyl 4-[l-(2-amino-2-methyl)prpoxy]benzoate (250 mg, 39% in two steps) as a gum. 'H-NMR (CDC1,) 5 3.75 (s. 2 H), 3.89 (s, 3 H), 6.93 (d, J =8.8 Hz, 2 H), 7.98 (d, J =8.8 Hz, 2 H). To a stirred mixture of methyl 4-[l-(2-amino-2-rnethyI)prpoxy]benzoate (250 mg, 1.12 mmol), 3-methoxy-4-[//,-(2-methylpheny!)ureido]phenylacctic acid (352 mg, 1.12 mmol), 4-DMAP (165 mg; 1.34 mmol) in DMF (10 ml) was added EDC-HC1 (290 mg, 1.51 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica gel column chromatography with CHCl3-EtOH (4:1, v/v) as eluent to give methyl4-[2-Ar-[3-methoxy-4-[y-(2-methylphenyl)ureido]phenylacetamido]-2-methyl-l-propoxy]benzoate (580mg, q.y.) as a crystalline material. IR (KBr) 3350, 3286,1712, 1687, 1637, 1606cm-1; 'H-NMR (CDC1}) 5 1.39 (s, 6 H), 2.33 (s, 3 H), 3.41 (s, 2 H), 3.63 (s, 3 H), 3.88 (s, 3H), 4,05 (s, 2 H), 5.44 (br s, 1 H), 6.33 (br s, 1 H), 6.79 (d,./= 8.3 Hz, 2 H), 7.12 (s, 1 H), 7.18 (t, J = 7.5 Hz, 1H), 7.53 (d, 7=7.8 Hz, 1 H), 7.94 (d, J= 7.8 Hz, 2 H), 8.14 (d, 7= 8.3 Hz, 1 H); MS (FAB) ni/z 520 (M* +1); Anal. Calcd for C„H3JN3CV C. 67.04; H, 6.40; N, 8,09. Found: C, 66.86; H, 6.36; N, 8.22. To a stirred solution of methyl 4-[2-[3-methoxy-4-[W-(2-methyiphenyl)ureido]phenyl acetamido]-2-methyl-2-propoxy]benzoate (510 mg, 0.98 mmol) was added 0.25N NaOH (8 ml, 2 mmol) at room temperature. The resulting mixture was stirred at an ambient temperature for 18 hr. The mixture was pored into ice-lN HC1 (5 ml), the solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHCla-EtOH-Et,0 to give 300 (480 mg, 97%) as fine needles. MW 505.56 IR(KBr)n 3346, 3294, 1687,1637, 1604 cm';'H-NMR PMSO-d*) 5 1.35 (S, 6 H), 2.24 (s, 3 H). 3.33 (s, 2 H), 3,80 (s, 3 H), 4.15 (s, 2 H), 6.75 (d, J = 8,3 Hz, 1H), 6.88 (s, 1 H), 6.95-6.99 (m, 3 H), 7.11-7.17 (m, 3 H), 7.80 (d,J= 8,3 Hz, 1H),7.82 (S, 1 H), 7,87 (d,J= 8.8 Hz. 2 H), 7.98 (d,./ =7.8 Hz, 1 H), 8.45 (s, 1 H), 8.54 (s, 1 H), 12.62 (br s, 1H); MS(FAB)m/z506(M'+l); Anal. Calcd for C„H3,N3Os: C, 66.52; H, 6.18; N, 8.31. Found: C, 66.22; H, 6.28; N, 8.11. DMSO (20 ml) was added c. H,SO, at 0-5 °C. To a stirred this solution was added dropwise a solution of NaNO, (5.4 g, 77.9 mmol) in water (5 ml) below 20 "C for over 10 min. The resulting mixture was further stirred for 0.5 hr at 5 °C. This mixture was poured into a stirred solution of KI (30 g, 0.182 mol) and catalytic amount of Cu powder (200 mg) in ice-water (200 ml) for over 10 min. The resulting mixture was for a further I hr at an ambient temperature. The mixture was extracted with CH3C13. The extracts were washed successively with sat. Na3SiO, and brine. The organic layer was dried over NasSO, and evaporated. The residue was chromatographed on silica-gel (50ml) with CHClj-EtOAc (3:1, v/v) as eluent to give 4-iodo-2-nitrophenol (2.5 g, 15%) as a yellow crystalline material. 'H-NMR (CDC13) 6 6.94 (d, J = 8.8 Hz, 1 H), 7.82 (dd, J = 2 and 8.8Hz, 1H), 8,42 (d, J =2 Hz, 1H), 10.49 (s, 1 H). To a stirred solution of 4-iodo-2-nitrophenol (2 g, 7.75 mmol), hydroxypivalic acid methyl ester (1.05 g, 7.92 mmol) and PPh3 (2.3 g, 8.68 mmol) in THF (10 ml) was added dropwise a solution of DIAD (1.77 g, 8.30 mmol) in THF (2 ml) under ice-water bath cooling. The resulting mixture was then heated under reflux for 18hr. After cooling, the mixture was evaporated off. The residue was chromatographed on silica gel (100 ml) with with toluene-ElOAc (4:1, v/v) as eluent to give methyl 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionate (2.9 g, q.y.) as a crystalline material. 'H-NMR (CDC15) 5 1.34 (s, 6 H), 3.71 (s, 3 H), 4.08 (s, 2 H), 6.86 (d, / = 8.8 Hz, 1 H), 7.78 (dd, J= 2 and 8.8Hz, 1 H), 8.12 (d, J = 2 Hz, 1H). A mixture of methyl 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionate (2.8 g, 7.38 mmol) in THF (15 ml) and 0,25 N NaOH (60 ml, 15 mol) at an ambient temperature for 18 hr. The mixture was poured into ice-lN HC1 (20 ml). The solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHClrEtOH-IPE to afford 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionic acid (2,0 g, 74%) as a crystalline material. Mp 165-182°C; IR (KBr) n 1716, 1525, 1344 cm"'; 'H-NMR (CDC15) 5 1.38 (s, 6 H), 4.10 (s, 2 H), 6.86 (d, J= 8,8 Hz, 1 H), 7.79 (dd, J= 12 and 8.8Hz, 1 H), 8,12 (d, J= 2 Hz, 1H); MS (FAB) m/z 366 (M* +1); Anal. Calcd for CI9H3JN,CV C, 36,18; H.3.18; N, 3.84. Found: C, 36.85; H, 3,35; N, 3.79. To a stirred mixture of 3-Ct-iodo-2-nitro)phenoxy-2,2-dimethy]propionic acid (l.?3 g, 5.29 mmol) and triethylamine (590 mg, 5.S1 mmol) in fert-BuOH (15 ml) and toluene (15 ml) was added a solution of diphenyl phosphoryl azide (1.53 g, 5.55 mmol) in toluene (3 ml) at room temperature. The resulting mixture was then heated at reflux for 20 hr. After cooling, ice and IN HC1 (5ml) was added to the mixture and extracted with toluene. The extracts were washed with brine, dried over NajSOj, and evaporated. The residue was chromatographed on silica ge! (50ml) with toluene-EtOAc (10:1, v/v) as eluent to give 3-nitro-4-(2-fer/-butoxycarbonylamino-2-methyl-l-propoxy)iodobenzene(1.91 g, 83%) as a gum. 'H-NMR (CDClj) 5 1.38 (s, 9 H), 1.39 (s, 6 H), 4.19 (s, 2 H), 4.67 (or s, 1 H), 6.88 (d, J~ 8.8 Hz, 1 H), 7.77 (dd, J= 2.0 and 8.8Hz, I H), 8.12 (d, 7= 2.0 Hz, 1H). A mixture of 3-nitro-4-(2-(err-butoxycarbonylamino-2-methyl-l-propoxy)iodobenzene (1.9 g, 4.36 mmol), Pd(OAc)j and ],3-bJs(diphenylphosphino)propane (dppp) (90 mg, 0.22 mmol) in triethylamine-MeOH-DMSO (1:2:5, v/v, 48 ml) was stirred under a current of CO (gas) at 70 °C for 6 hr. After cooling, the mixture was poured into water and extracted with EtOAc. The extracts were washed with brine, dried over NajSOj, and evaporated. The residue was chromatographed on silica gel (50ml) with toluene-EtOAc (6:1, v/v) as eluent to give methyl 4-(2-/erf-butoxycarbonyl amino-2-methyl-l-propoxy)-3-nitrobenzoate (820 mg, 51%) as a gum. 'H-NMR (CDC13) 6 1.38 (s, 9 H), 1.42 (s, 6 H), 3.93 (s, 3 H), 4.29 (s, 2 H), 4.67 (br s, 1 H), 7. J5 (d, J = 8.8 Hz, 1H), 8.18(dd,J= 1.7 and 8.8Hz, 1 H), 8.52 (d, J= 1.7 Hz, 1H). ' A stirted mixture of methyl 4-{2-/erf-butoxycarbonylamino-2-methyl-l-propoxy)-3-nitrobenzoate (350 mg, 0.95 mmol) and 5% Pd-C (70 mg) in EtOH (30 ml) was hydrogenated in an atmospheric hydrogen pressure at room temperature for 20 hr. Insoluble Pd-catalysl was removed with suction and washed with EtOH, The filtrate was evaporated off to afford methyl 4-(2-(er/-butoxycarbonyl arnino-2-methyl)-l-propoxy-3-aminobenzoate as a gum, which was used to the subsequent reaction without further purification. 'H-NMR. (CDC13) S 1.41 (s, 9H), 1.43 (s, 6 H), 3.86 (s, 3 H), 4.07 (s, 2 H), 4.67 (br s, 1 H), 6.80 (d, J= 8.5 Hz, 1 H). 7.39 (d, /= 2.2 Hz, 1H), 7.44 (dd,/= 2.2 and 8.5Hz, 1 H). To a stirred mixture of the above methyl 4-(2-(er(-butoxycarbonylamino-2-methyl)-l-propoxy-3-aminobenzoate and triethylamine (0.20 ml, 1.43 mmol) in CH5Cli (10 ml) was added a solution of triiluoroacetic anhydride (0.182 ml, 1.28 mmol) in CHjCl, (3 ml) at 0-5 °C. The resulting mixture was stirred at room temperature for 1 hr. Ice-sat. NaHCO, was added to the mixture, and extracted with CHjCl,. The extracts were washed with brine, dried over Na2S04, and evaporated. The residue was dissolved in CHiCl;(5 ml) and added anisoie {0.105 ml, 0.95 mmol) and TFA (2 ml). The resulting mixture was stirred at room temperature for 18 hr. The mixture was evaporated in vacuo, and the residue was diluted with CHjClj and made basic by the addition of sat. NaHCO,. The separated CH3CI5 layer was dried over Na3SO, and evaporated. The residue was chromatographed on silica gel (50ml) with CHCl3-EtOH(99:l,v/v)as eluentto give methyl 4-(2-amino-2-methyl-l-propoxy)-3-trfluoroacetamidobenzoate (631 mg, 63% in 3-steps) as a gum. 'H-NMR (CDClj) 6 1.29 (s, 9 H, ferf-Bu), 3.86 (s, 2 H, CH3), 3.91 (s, 3 H,), 6.99 (d, J = B.5 Hz. 1 H), 7.91 (dd,/= 2.0 and 8.5 Hz, 1H),8,83 (d,/=8.5Hz, 1 H). To a stirred mixture of methyl 4-(2-ainino-2-methyl)-l-propoxy-3-trfluoroacetamido benzoate (200 mg, 0.598 mmol), 4-[A"-(2-chlorophenyl)ureido]-3-methoxypheny!acetic acid (210 mg, 0.598 mmol), 4-DMAP (90 mg, 0.72 mmol) in DMF (7 ml) was added EDC-HC1 (160 mg, 0.81 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hr. The mixture was pored into ice-water. The solid was collected, washed with water and air-dried. The crude solid was purified by silica gel column chromatography with CHC13- EtOH (98:2, v/v) as eluent to give methyl 4-[2-A-[4-[A'-(2-chloroplienyl)ureido]-3-methoxyphenylacetamido]-2-methyl-l-propoxy]-3-trfluoroacetamidobenzoate (580mg, q.y.) as a crystalline material. 'H-NMR (CDCl3)6 1.42(s, 6H), 3.42 (s, 2 H), 3.69 (s, 3H),3.89(s, 3 H), 4.23 (s, 2 H), 5.33 (brs, I H), 6.66 (s, 1 H), 6.71 (m, 1 H), 6.92 (d, J= 8.5 Hz, 1 H), 7.02 (m, 1 H). 7.09 (m, 2 H), 7.29 (m, 1 H), 7.37 (d, J= 8.0 Hz, 1H), 7.87 (dd, J= 2 and 8.5Hz, 1 H), 7.97 (d, J= 8.0 Hz, 1 H), 8.19 (d,J = 8.2 Hz, 1 H), 8.59 (or s, 1 H). 8.74 (d, J= 2.0 Hz, 1 H). To a stirred solution of methyl 4-[2-A'-[4-[A',-(2-chlorophenyl)ureido]-3-methoxyphenyl acetamido]-2-methyl-l-propoxy]-3-trfluoroacetamidobenzoate (320 mg, 0.492 mmol) in THF (2 ml) was added 0.25N NaOH (6 ml, 1.5 mmol) at an ambient temperature. And the resulting mixture was stirred for 20 hr. The mixture was poured into ice-lN HC1 (2 ml). The solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHClj- EtOH-EljO to give 301 (240rag, 89%) as fine needles. MW 541.00 IR (KBr) n 3338, 3296, 1691, J641 cm'1; 'H-NMR (CDC13) 5 'H-NMR (DMSO d«) 5 1.37 (s, 6 H), 3.35 (s, 2 H), 3.77 (s, 3 H), 4.05 (s. 2 H),4.96 (brs, 1 H),6.75 (br d, J= 8.3 Hz, 1 H), 6.78 (d, J= 8.3 Hz, 1 H),6.87 (d. J= 1.7Hz, 1 H), 7,01 (m, 1H), 7.15(dd,y=2and8.5Hz, 1H), 7.24 (d,./= 2 Hz, 1 H), 7.27 (dt, J = 2.0 and 8.5 Hz, lH),7,43(dd,J'=2and8.0Hz, 1 H), 7,78 (brs, 1 H), 7.90 (d, 7= 8.0 Hz, 1 H), 8.08 (dd, /= 2 and 8.3 Hz, 1 H), S,85 (s, 1 H), 8,89 (s, 1 H), 12.23 (brs, 1 H); MS (FAB) m/z 541 (M* +1); Anal. Calcd for C2,H„CIN,06: C, 58.00; H, 5.59; N, 10.02. Found: C, 57.97; H, 5.39; N, 10.01. Eiample 251 2-acetylainino-4-[2-Ar-[3-methoxy-4-[JV'-(2-methylphenyl)iireido]phenyl]-//'-nicihy]acetamido] bcnzcnc-MeOH (4:1, v/v, 25 mL), was added trimethylsiryldiazomethane (2.0 M solution in n-hexane, 4.28 ml, 8.56 mmol) al 0 "C. The stirring was continued for 18 hours at it. The reaction was poured into hexane, and the resulting precipitate was collected by filtration to give methyl 2-acetylamino-4-nitrobenzoate (1.32 g, 97%) as a white solid; mp no data; 'H-NMR (400 MHz, CDCy 8 2.30 (s, 3 H), 4.00 (s, 3 H), 7.88 (m, 1 H), 8.18 (dd, J= 2.0 Hz, 8.8 Hz, 1 H), 9.60 (t,y= 2.2 Hz, 1 H), 11.10 (s, 1 H); MS (ESI) m/z 238 (M+). To a solution of methyl 2-acetylamino-4-nitrobenzoate (1.31 g, 5.50 mmol) in MeOH (30 mL) was added 5%Pd on carbon (195 mg), and the stirring under H, gas (3 atm) was continued for 18 hours at rt. The catalyst was filtered off and the mixture was evaporated. The resulting crude solid was recrystallized with CHCl3-MeOH-hexane to give methyl 2-acetylamino-4-aminobenzoate (1.03 g, 90%) as a white solid. 'H-NMR (400 MHz, CDCIj) S 2.23 (s, 3 H), 3.82 (s, 3 H), 4.20 (s, 2 H), 6.30 (dd, J = 2.5 Hz, 8.8 Hz, 1 H), 7.80 (d, J = 8.8 Hz, 1 H), 8.06 (s, 1 H), 11.26 (S, 1 H); MS (FAB), m/z 208 (M*). To a cooled solution of methyl 2-acetylamino-4-aminobenzoate (300 mg, 1.44 mmol) and A'-terf-butoxycarbonyl-A'-niethylglycinal (499 mg, 2.88 mmol) in 1,2-dichloroethane (30 ml), was added NaBH(OAc), (964 mg, 4.32 mmol) and the stirring was continued for 64 h at 0 °C. The mixture was poured into sat. NaHC03 and was extracted with CHClj (50 ml x 3), washed with brine, and dried over MgSO. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: VAMAZEN YFLC-5404-FC, linear gradient of hexane-EtOAc from 9:1 to 2:1) to give methyl 2-acetylamino-4-[2-(A'-/er/-butoxycarbonyl-A'-methylamino)ethylamino]benzoate (451 mg, 86%) as a colorless oil. 'H-NMR (CDC13, 400 MHz) 5 1.48 (s, 9 H), 2.22 (s, 3 H), 2.90 (s, 3 H), 3.32 (m, 2 H), 3.50 (m, 2 H), 3.80 (s, 3H), 6.20 (dd, .7 = 2.2 Hz, 8.8 Hz, 1 H), 7.80 (m, 1 H), 7.95 (m, 1 H), 11.30 (brs, 1 H); MS (FAB) m/z 366 (M*+I). To a stirred solution of methyl methyl 2-acetylamino-4-[2-(A'-rerr-butoxycarborryl-Af- methylajnino)ethylarnino]benzoate (450 mg, 1.23 nunol) in dichloromcthanc (5 mL), was added TFA (5 mL) and the stirring was continued for 18 h atrt. After removal of the solvent in vacuo, the residue was dissolved in CHClj (200 mL), washed with brine, sat. NaHC03, and dried over MgSO*. The solvent was removed to give methyl 2-acetylamino-4-[2-(//-methylamino) ethylamino] benzoate (298 mg, 88%) as a colorless oil. 'H-NMR (CDC13,400 MHz) 5 2.21 (s, 3 H), 2.46 (s, 3 H), 2,88 (m, 2 H), 3.31 (m, 2 H), 3.83 (s, 3 H), 4.85 (br, 1 H), 6.24 (dd, J = 2.5 Hz, 8.8 Hz, 1 H), 7,80 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 2.5 Hz, 1 H); MS (FAB), mh 266 OT+1). A mixture of methyl 2-acetylarruno-4-[2-(Af-methylanuno)ethyIamino]benzoate (145 mg, 0.55 mmol), S-memoxy--(2-methylphenyl)ureido]phenyl acetic acid (172 mg, 0.55 mmol), EDOHC1 (158 mg, 0.83 mmol), HOBt (141 mg, 1.05 mmol), andDMAP (13 mg. 0.11 mmol) in DMF (10 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (300 ml), washed with brine, and dried over MgSO,. After removal of the solvent, residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of CHClj-MeOH from 100:0 to 70:30) to give methyl 2-acetylarnino-4-[2-A'-[3-methoxy-4-[A'-(2-methylphenyl)ureido]phenyl]-A'-methyIacetamido]ethylaminoben2oate (309 mg, 100%) as an amorphous foam. 'H-NMR (CDC13)5 2.22 (s, 3 H), 2.30 (s, 3 H), 3.02 (s, 3 H), 3.35 (m, 2 H), 3.58 (s, 3 H), 3.50-3.74 (m, 4 H), 3.85 (s, 3 H), 6.20 (m, 1 H), 6.58 (s, 1 H), 6.65-6.75 (m, 3 H), 7.13 (m, 2 H), 7.40-7.50 (m, 2 H), 7.75 (m, 2 H), 7.90 (m, 1 H), 8.00 (m, 1 H), 11.32 (s, 1 H); MS (FAB)m/z562(M*+I). - To a solution of methyl 2-acetylamino-4-(2-A'-[3-methoxy-4-[A'-(2-methylphcny])Ureido] phenyl]-Ar-methylacetamido]eihylaminobenzoate (309 mg, 0.55 mmol) inTHF-MeOH(l: 1, v/v, 9 ml), was added 0.25 NNaOH (4.4 ml, 1.1 mmol) at rt, and heated to reflux. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, and acidified to pH 5.0 with 1.0NHC1. The resulting precipitate was recrystallized with hexane-diethylether to give 302 (175 mg, 58%) as a pale red powder. MW 547.60 'H-NMR (CDjOD) 5 2.16 (d, J = 4.8 Hz, 3 H), 2.28 (d, J = 4.2 Hz, 3 H), 2.98 and 3.10 (2 s, total 3 H), 3.35 (m, 2 H), 3.68 (m, 4 H), 3.81 and 3.84 (2 s, total 3 H), 6.30 (m, 1 H), 6.60-6,82 (m, 2 H), 7.00 (m, 1H), 7.15 (m, 2 H), 7.53 (m, 1 H), 7.77-7.96 (m, 3 H); MS (FAB) m/z 548 (M*+I); Anal. Calcd for C»HMN,CV0-5 H30: C, 62.58; H, 6.16; N, 12.58. Found: C, 62.55; H, 6.31; N, 12.15. Example 252 2-acetylamino-4-[2-/-[4-[Ar'-(2-bromophenyl)ureido)-3-mcthoxyphenyl]-Af-methylacetamido] ethylaminobenzoic acid 0.55 mmol), 3-methoxy-4-[//'-(2-bromophenyl)ureido]phenylacetic acid (209 mg, 0.55 mmol), EDC-HCI (158 mg, 0.83 mmol), HOBl (141 mg, 1.05 mmol), and DMAP (13 mg, 0.11 mmol) in DMF (10 ml) was stirred for 18 hours. The mixture was diluted with ElOAc (300 ml), washed with brine, and dried over MgS04. After removal of the solvent, residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of CHClj-MeOH from 100:0 to 70:30) to give methyl 2-acetylamino-4-[2-JV-[4-[tf,-(2-bromo phenyl)ureido]-3-methoxyphenyl]-A'-methylacetamido]ethylaminobenzoate (294 mg, 85%) as an amorphous foam. 'H-NMR (CDC1,) 5 2.21 (s, 3 H), 3.05 (s, 3 H), 3.40 (m, 2 H), 3.65-3.70 (m, 4 H), 3.78 (s, 3H), 3.86 (s, 3H),6.2i(m, 1 H), 6.79 (m, 2 H), 6.93 (m, IH), 7.10 (d,J = 10.3 Hz, 1 H), 7.30 (m, 1 h), 7.42 (m, 1 H), 7.61 (m, 1 H), 7.78-7.85 (m, 2 H), 7.93 (m, 2 H), 8.13 (m, 1 H); MS (FAB), m/z 627 (M*). To a solution of methyl 2-acety!amino-4-[3-methoxy-4-[A'-(2-bromophenyl)ureido] phenylacetanudo]-2-Mmethylamino-l-cthylaminobenzoate (294 mg, 0.47 mmol) in THF-MeOH (1: l,v/v, 8ml), was added 0.25 NNaOH (3.8 ml, 0.94 mmol) at n, and heated to reflux. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, and acidified to pH 5.0 with 1.0 N HC1. The resulting precipitate was recrystallized with hexane-diethylether to give 303 as a white powder (210 mg, 73%). MW 612.47 mp 155-160 ° C;"'H-NMR (CD3OD) 8 22.18 (d, J= 5.5 Hz, 3 H), 3.00 and 3.12 (2 s, total 3 H), 3.39 (m, 1 H), 3.60 (m,4H), 3.70 (s, IH), 3.85 and 3.86 (2 5, total 3 H), 6.3] (m, 1 H), 6.68 (m, 1 H), 6.78 (m, 1 H), 6.78 and 6.85 (2 m, total 1H), 6.97 (m, 1 H), 7.30 (m, 1 H), 7.56 (m, 1 H), 7.80-7.95 (m, 4 H); MS (ESI) m/z 613 (M*);Anal. Calcd for Cj.HBr.NA-OS H,0: C, 53,64; H, 5.22; N, 11.17. Found: C, 53.89; H, 5.23; N, 10.69. MeCN(50 ml), was added aniline (9.1 ml, 100 mmol) am. The reaction was stirred for 64 hours at reflux. The mixture was poured into H50 (200 rnL), extracted with EtOAc (100 mL x 2), dried over MgSOj. After removal of the solvent in vacuo, the unreacted aniline was removed in vacuo by co-evaporation with toluene (10 mL x 3) at 80 °C. The residue was chromalographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm x 150 mm, CHClj) to give methyl 4-[2-(W-phenylamino)ethoxy]benzoate (2.23 g, 82%) as a colorless oil. 'H-NMR(CDClj) 5 3.56(1,,/= 5.1 Hz, 2H), 3.90 (s, 3 H), 4.21 (l,J= 5,1 Hz, 2 H), 6.68 (dd,J = 1.0 Hz, 8.6 Hz, 2 H), 6.75 (t. J = 7.3 Hz, 1 H), 7.20 (AB type d, J = 7.3 Hz, 2 H), 8.00 (d, J = 9.1 Hz, 2 H); MS (ESI) m/z 272 (M++l). A mixture of methyl 4-I2-(W-phenyIamino)ethoxy]benzoate (136 mg, 0.5 mmol), 3-methoxy-4-[W,-(2-ch!orophenyl)ureido]phenylacetic acid (167 mg, 0.5 mmol) and PyBOP (781 mg, 0.75 mmol), /-PrNEt, (261 ml, 0.96 mmol) in DMF (10 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (100 mL), washed with 1 N HC1, brine and dried over MgSO. The residue was co-evaporated with toluene (10 ml x 3) to remove DMF. The residue was chromatographed on TLC (MERCK, silicagel 60, 2 mm, 2 plates, CRClj-MeOH, 20:1) to give methyM-[2-A/-[f4-[A'-(2:h]orophenyl)ureido]-3-rnethoxyphery3]-A'-pherryiaOTtamidoJethoxy] benzoate (129 mg, 44%) as a white amorphous foam. 'H-NMR (CDCIJ 5 3.42 (s, 1 H), 3.69 (d, J = 8,3 Hz, 1 H), 3.74 (s, 3 H), 3.87 (s, 3 H), 4.10 (m, 2H), 4.23 (m, 2 H), 6.48-7.44 (m, 13 H), 7.93 (d, J= 9.3 Hz, 2 H), 8.18 (dd, J= 1.5 Hz, 8.3 Hz, 1 H); MS (ESI) m/z 588 (M*). To a solution of methyl 4-[2-/-[[4-[W-(2-chlorophenyI)ureido]-3-methoxyphenyl]-Ar-phenyi acetamido]ethoxy]benzoate (124 mg, 0.19 mmol) in THF-MeOH (6:1, v/ v, 3 ml), was added 0.5 N NaOH (2 ml, 1 mmol) at rt, and heated to reflux in a sealed bottle. The stirring was continued for 15 hours at reflux. The reaction mixture was poured into water, acidified with 1.0 N HC1, extracted with CHCl3-MeOH (2:1, 20 mL x 3), and dried over MgSO,. After removal of the solvent, the residue was crystallized with CHCl,-hexane-diethylether to give 304 (77 mg, 64%) as a white powder. MW 574.02 'H-NMR (CDjOD) 5 3.45 (s, 2 H), 3.79 (s. 3 H), 4.12 (m, 2 H), 4.22 (m, 2H), 6.48 (dd, ./= 2.0 Hz, 8.3 Hz, 1 H), 6.61 (d,y= 2.0 Hz, 1 H),6.87{d,y= 8.8 Hz, 2 H), 7.00 (m, 1 H), 7.22 (m, 3 H), 7.36 (m, 1 H), 7.43 (m, 3 H), 7.90 (d, J= 8.3 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 8.02 (dd, J = 1,5 Hz, 8.3 Hz, 1 H); MS (ESI) m/z 574 W);Anal. Calcd for C3lH„ClNA-0.5 H30: C, 63.86; H, 5.01; N, 7.21. Found: C, 63.67; H, 4.91; N, 6.99. Example 254 (S)-4-[2-y-[[3-methoxy-4-[W'-(2-methylphenyl)ureido]phenyl]-W-(2-aimnobenzyl)acetamido]-l- propoxy]benzoic acid mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in McOH-AcOH (16 ml, 15:1, v/v) was added NaBHjCN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by sat. NaHCO, and extracted with EtOAc. The extract was washed with brine, dried over Na3SOj and evaporated. The residue was purified by column chromatography on silica gel with CHCI, to 5% MeOH in CHC13 as eluent to give benzyl ($)-4-[2-{2-nitrobenzyiamino) -l-propoxy]benzoate (931 mg, 42%) as a yellow oil. 'H-NMR (CDCQ 5 1.21 (d, J= 6.4 Hz, 3 H), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2 H), 5.34 (s, 2 H), 6.89-6.94 (m, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); MS (FAB) m/z 421 (M*+l). A mixture of pentafluorophenyl 3-memoxy-4-[tf'-(2-methylphcnyl)ureido]phenylacetate (460 mg, 0.96 mmol), benzyl (5)-4-[2-(2-nitrobenzylamino)-l-propoxy]benzoate (403 mg, 0.96 mmol) and Et3N (200 ml, 1.43 mmol) in DMF (8 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 0.5 NHC1, brine, dried over NajSO,, and evaporated. The residue was purified by column chromatography on silica-gel with 1% MeOH in CHClj as eluent to give benzyl (-4-[2-A'-[[3-methoxy-4-[A'-(2-methylphenyl)ureidoJphenyl]-A'-{2-nitrobenzyl) acetamido]-l-propoxy]benzoate (504 mg, 73%) as a brown amorphous solid. MS (FAB),m/z717(M*+l). A stirred solution of benzyl (S)-4-[2-A'-[[3-methoxy-4-['-(2-methylphenyl)ureido] phenyl]-A'-(2-nitrobenzyl)aceiamido]-l-propoxy]benzoate (504 mg, 0.70 mmol) in MeOH-THF (11 ml, 10:1, v/v) was hydrogenated over 5% Pd-C (100 mg, 20 wt%) at 3 atm overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was purified by preparative thin layer chromatography with 5% MeOH in CHCI3 as eluent to give 305 (115 mg, 27%) as a white powder. MW 596.67 MS (FAB), m/z 591 (M*+l). Eiamplc 255 (S)-4-[2-W-[[4-[AfH2-bromophenyl)ureido]-3-memoxyphcnyI]-W-(2-niu-obenzyl)acetarnido]-l- propoxyjbenzoic acid mmol) and 2-niirobenzaJdehyde (0.87 g, 5.16 mmol) in MeOH-AcOH (16 ml, 15:1, v/v) was added NaBH3CN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by sat. NaHCOj and extracted with EtOAc. The extract was washed with brine, dried over Na]SQ4 and evaporated. The residue was purified by column chromatography on silica gel with CHCI, to 5% MeOH in CHCI3 as eluent to give ben2yl (S)-4-[2-(2-nitrobenzylainino) -l-propoxy]benzoate (931 mg, 42%) as a yellow oil. 'H-NMR (CDClj) 5 1.21 (d, J«= 6.4 Hz, 3 H), 3.13-3.18 (m, 1 H), 3.88-3.97 (m, 2 H), 4.06-4.20 (m, 2H), 5.34 (s, 2 H), 6.89-6.94 (in, 2 H), 7.29-7.65 (m, 8 H), 7.94-8.03 (m, 3 H); FAB-MAS, m/z 421 (M*+l). A mixture of 4-[A'-(2-bromophenyl)ureido]-3-mMhoxyphenylacetic acid (476 mg, 1.26 mmol), benzyl (S)-4-[2-(2-nitrobenzylamino)-l-propoxy]benzoate (528 mg, 1.26 mmol), EDCHC1 (361 rag, 1.88 mmol), HOBt (255 mg, 1.89 mmol) and DMAP (30 mg, 0.25 mmol) in DMF (10 ml) was stirred at room temperature overnight. And the reaction could not be completed, so the reaction mixture was stirred at 60°C for 1 day. The mixture was diluted with EtOAc, washed with 0.5 NHC1, brine, dried over NajSO, and evaporated. The residue was purified by column chromatography on silica-gel with CHCI3 to 2% MeOH in CHC13 as eluent to give the title compound as a crude oil. To a stirred solution oftheemde product inTHF-MeOH(10ml, 1:1, v/v) was added 0.5 N NaOH (10 ml) and the reaction mixture was heated under reflux for 3 hr. The mixture was poured into ice-H,0 and the basic aqueous layer was acidified (pH 4.3) with 1 N HC1. The resulting precipitate was collected and the crude solid was purified by preparative thin layer chromatography with 5% MeOH in CHC13 as eluent to give 306 (162 mg, 2 steps, 19%) as a white amorphous solid. MW691.53 MS (FAB), m/z 692 (M'+\);Anal. Calcdfor C31H3lBrN10B7/4H10: C, 54.82; H, 4.81; N, 7.75. Found: C, 54.80; H, 4.61; N, 7.24. chI6rophenyl)ureidoJ-3-methoxyphenylacetic acjd (412 mgi 1.23 mmol), EDC-HC1 (354 mg, 1.85 nunol), HOBt (cat.), and DMAP (cat.) in DMF (10 ml) was stirred overnight. The mixture was partitioned between EtOAc (300 ml) and H:0 (100 m3). The organic phase was separated, washed with brine (2 x 100 ml), dried over MgSO,, and evaporated. The residue was chromatographed on ft i silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[2-A'-cyclopropyl-A'-[4-[iV,-(2-chlorophenyI)ureido]-3-mewoxyphenyl]acetamido]ethoxyberizoate (506 mg, 75%) as a yellow viscous oil. 'H-NMR(CDCIj) 5 0.90-0.97 (m, 4H), 2.75 (m, 1 H), 3.61 (s, 3 H), 3.79 (1,7= 5.4 Hz, 2 H), 3.87 (s, 3 H), 3.88 (s, 2 H), 4,16 (t, J = 5.4 Hz, 2 H), 6.76-6.80 (m, 4 H), 6.95 (dt, J = 7.8, I.5Hz, IH), 7.21-7.31 (m, 2 H), 7.53 (s, 1 H), 7.56 (s, 1 H), 7.93 (d, J= 8.3 Hz, 3 H), 8.19 i (dd,J=8.3, 1.5Hz, IH). To a stirred solution of methyl 4-[2-Af-cyclopropyl-A-[4-[W-(2-chiorophenyl)ureido]-3-methoxyphenyl]acetamido]ethoxybenzoate (506 mg, 0.917 mmol) in THF (7 ml) was added 0.25 N NaOH (7.3 ml, 1.83 mmol). After stirring overnight, the mixture was poured into 1 N HC1 (50 ml) and extracted with CHClj-MeOH (4:1, 2 x 200 ml). The combined extracts were dried over i MgSOj and evaporated. The residue was chromatographed on silica gel with CHClj-MeOH (20; 1 to 10:l)aseluenttogive307 (403 mg, 82%) as a colorless amorphous solid. MW 537.99 'H-NMRPMSO) 6 0.86-0.91 (m, 4 H), 2.75 (m, 1 H), 3.69 (t,/= 5.5 Hz, 2 H), 3.81 (s, 3 H), 3.84 (s, 2 H), 4.16 (t, J= 5.5 Hz, 2 H), 6.76 (d, J= 8,3 Hz, 1 H), 6.88 (s, 1 H). 6.97-7.04 (m, 3 H), 7.28 (t, J=7,8Hz, IH), 7.44 (d, .7=7,8 Hz, 1 H), 7.88 (d, 7= 8.8 Hz, 2 H), 7.96 (d,/= 8.1 Hz, 1 H), 8.10 (d, .7=8.3 Hz, 1 H), 8.89 (s, 1 H), 8.93 (s, 1 H), 12.65 (s, or s); MS (FAB), m/z 538 (M*+I); Anal. Calcd for C,BH,BC1NA: C, 62.51; H, 5.25; N, 7.81. Found: C, 61.85; H, 5.42; N, 7.41. Example 257 4- [2 -A-cycl ohexy 1 -N- [3 -melhoxy-4 - [N1- (2 -methyIphenyl)ureido] phenyl] acctamido] ethoxybenzoic in MeCN (50 ml), was added cyclohexy 1 amine (5.72 ml, 50 mmol) at rt. The reaction was stirred for 18 hours at reflux. The mixture was poured into HjO (200 raL), extracted with EtOAc (100 mLx 2), dried over MgS04. After removal of the solvent, residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm x 150 mm, linear gradient of CHCI3-EtOAc from 10:0 to 1:1) to give methyl 4-(2-Af-cyclohexyIamino)ethoxy benzoate (2.43 g, 88%) as a colorless oil. 'H-NMR (CDCIJ 8 1.10 (m, 2 H), 1.25 (m, 2 H), 1.60 (br, 2 H), 1.73 (m, 2 H), 1.90 (br, 2 H), 2.49 (m, 1 H), 3.02 (t, J= 5.2 Hz. 2 H), 3.88 (s, 3 H), 4.12 (t, J = 5.2 Hz, 2 H), 6.90 (d, J = 6.90 Hz, 2 H), 7.99 (d, ./ = 7.99 Hz, 2 H); MS (ESI) m/z 278 (M*+l). A mixture of methyl 4-(2-//-cyclohexylamino)ethoxybenzoate (139 mg, 0.5 mmol), 3-methoxy-4-[iV'-(2-methylphenyl)ureido)phenylacetic acid (157 mg, 0.5 mmol), EDC'HCl (144 mg, 0.75 mmoi). HOBt (128 mg, 0.95 mmol), and DMAP (12 mg, 0.1 mmol) in DMF (2.5 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (200 ml), washed with IN HC1 and brine, and dried over MgSOj. After removal of the solvent, residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHC13-EtOAc 10:0 to 1:4) to give methyl 4-[2-A'-cyclohexyl-A'-[3-methoxy-4-[A"-{2-mcthylphenyl) ureido]phenyl] acetamido] ethoxybenzoate (247 mg, 86%) as an amorphous foam. 'H-NMR (CDCI3) 5 1.08-1.80 (m, 10 H), 2.30 (s, 3 H), 3.60-3.79 (m, 8H), 3.88 (s, 3 H), 4.16 (m, 2 H), 6.30 (s, I H), 6.70-6.83 (m, 2 H), 6.88 (d, 2H,J= 9.0 Hz), 7.12 (m. 2 H), 7.23 (m, 1 H), 7.60 (d, 1 H, J = 8.3 Hz), 7.92 (d, 2 H, J = 9.0 Hz), 8.10 (d, 1 H, J = 8.0 Hz); MS (ESI) m/z 51A (M*+l). To a solution of methyl 4-[2-W-cyclohexyl-Ar-[3-methoxy-4-[//'-(2-methylphenyl)ureido) phenyl] acetamido]ethoxybenzoate (247 mg, 0.43 mmol) in THF-MeOH (6: 1, v/ v, 7 ml), was added 0.5 N NaOH (3.4 ml, 0.84 mmol) at rt, and heated to reflux in a sealed bottle. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, acidified with 1.0 N HC1, extracted with CHClj-MeOH (2:1, 20 mL x 3), and dried over MgSO,. After removal of the solvent, the residue was crystallized with CHCl3-hexane-diethylether to give 308 (196 mg, 81%) as a white powder. MW 559.62 'H-NMR (CD,OD) 5 0.90-1.82 (m, 10 H), 2.29 (s, 3 H), 3.62 (m, 2 H), 3.78 (s. 3 H), 3.80 (m, 3 H), 4.12 (m, 2 H), 6.82 (m, 2H), 6.96 (m, 3 H), 7.16 (m, 2 H), 7.58 (d, J= 7.7 Hz, 1 H), 7.92 (m, 3 H); MS (ESI) m/z 560 Q+}),Anal. Calcd for C3,Hj,N,04-°-5 H!°: c> 67-59; H. 6-74; N, 7.39. Found: C, 67.83; H, 6.80; N, 7.13. Example 258 4-[2-Af-[4-[A'-{2-ctilorophenyl)uTeido]-3-methoxyphenyl]-A'-propaTgylacctaniido] ethoxybenzoic in MeCN (50 ml), was added propargylamine (3.43 ml, 50 nunol) at it The reaction was stirred for 18 hours at reflux. The mixture was poured into H,0 (200 mL), extracted with EtOAc (100 mL x 2), dried over MgSCy After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, SO mm x 150 mm, linear gradient of CHCl,-EtOAc from 10:0 to 9:1) to give methyl 4-(2-JV-propargylamino) ethoxybenzoate (2.33 g, 100%) as a colorless oil. 'H-NMR (CDC13) 5 2.28 (d, J= 2.4 Hz, 1 H), 3.11 (t,y= 5.1 Hz, 2 H), 3.52 (d, 7 = 2.4 Hz, 2 H), 3.88 (s, 3 H), 4.15 (t, J = 5.1 Hz, 2 H), 6.90 (d, J= 8.8 Hz, 2 H), 7.98 (d, J= 8,8 H2, 2 H); MS (ESI) mh 234 (M*+l). A mixture of methyl 4-(2-A'-propargylarnino)elhoxyben2oate (117 mg, 0.5 mmol), 3-. methoxy-4-[(vn-(2-chlorophenyl)ureido]phenylacetic acid (167 mg, 0.5 nunol), EDC-HC1 (144 mg, 0.75 mmol), HOBt (128 mg, 0.96 mmol), and DMAP (12 mg, 0.1 mmol) in DMF (10 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (100 mL), washed with 1 N HCI, brine and dried over MgSO*. The residue was co-evaporated with toluene (10 ml x 3) to remove DMF. The residue was chromatographed on TLC (MERCK, silicagel 60,2 mm, 2 plates, CHCIj-MeOH, 20:1) to give methyl 4-[2-A'-[4-[(V'-(2-chlorophcnyl)ureido]-3-methoxyphenyl)-/V-propargyl acetamido] ethoxybenzoate (244 mg, 89%) as a white amorphous foam. 'H-NMR (CDC13) 5 2.20 and 2.32 (2 m, total 1 H), 3.72 (s, 2 H), 3.83 (m, 5 H), 3.88 (s, 3 H), 4.09-4.35 (m, 4 H), 6.77-6.86 (m, 4H), 6.99 (m, 1 H), 7.1] (m, 2 H), 7.24 (m, 1 H), 7.34 (d,./= 7.9Hz, I H), 7.96 (m, 3 H), 8.18 (dd, J = 1.5 Hz, 8.3 Hz, 1 H); MS (ESI) m/2 550 (M*). To a solution of methyl 4-[2-/V-[4-[A"-(2-cliIorophenyl)ureido]-3-methoxvphenyl]-rV-propargy] acetamido]clhoxybenzoate (240 mg, 0.44 mmol) in THF-MeOH-O (2:2:1, v/v, 10 ml), was added NaOH (500 mg, 12.5 mmol) at it. The stirring was continued for 2 hours at rt. The reaction mixture was poured into water, acidified with 1.0 N HCI, extracted with CHCIj-MeOH (2:1, 20 mLx3), and dried over MgSCV The residue was chromatographed on TLC (Whatman, 1 mm, 3 plates, CHCIj-MeOH, 92:8) to give 309 (202 mg, 86%) as a white solid. MW 535,98 'H-NMR. (CD3OD) 8 2.60 and 2.81 (2d, J = 2.5 Hz, total 1 H), 3.79-3.94 (m, 4 H), 3.85 (s, 3 H), 4.15 (m, 1 H), 4.24 (m, 1 H), 4.32 (m, 2 H), 6.80 (d, J= 8.3 Hz, 1 H), 6.85 (d, J = 4.3 Hz, 1 H). 6.94 (m, 2 H), 7.02 (m, 1 H), 7.25 (m, 1 H), 7.38 (m, 1 H), 7,87-8.02 (m, 4 H); MS (ESI) m/z 536 (M++l); Anal Calcd for C,, HMClNA-2-25 H,0: C.58.33; H.5.33; N.7.29. Found: C.58.23; H,4,77;N,6.91. Examples 259 and 260 4-[2-A'-allyl-A'-[4-[Ar-(2-crJorophenyl)ureido]-3-meihoxyphenyl]acetamido]ethoxybenzoicacid 4-[A-(2-chJorophenyl)ureidolphenyIacetic acid (167 mg, 0.5 ramol), EDC-HCI (144 g, 0.75 mmol), HOBt (128 mg, 0.95 mmol), and DMAP (12 mg, 0.] mmol) in DMF (2.5 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (300 ml), washed with IN HC1 and brine, and dried over MgSO,. After removal of the solvent, residue was chromatographcd on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHClj-EtOAc 100:0 to 85; 15) to giw methyl 4-[2-A'-aJlyl-M[4-[Ap-{2-chJorophcnyl)ureido]-3- ■ mefhoxyphenyl]acetaniido] ethoxybenzoate (253 mg, 92%) as an amorphous foam. 'H-NMR (CDCIJ 5 3.65-3.85 (m, 4 H), 3.73 (s, 3 H), 3.88 (s, 3 H), 5.08 (m, 2 H), 4.22 (m, 2 H), 5.10-5.24 (m, 2 H), 5.76 (m, 1H), 6.77 (m, 2 H), 6.85 (m, 2 H), 6.99 (m, 1 H), 7.06 (m, 2 H), 7.26 (m, 1 H), 7.34 (d, 1 H, J = 8.) Hz), 7.94 (d, 2 H, J = 8.8 Hz). 7.98 (m, 1 H), 8.18 (d, 1 H, J * 6.9 Hz); MS (FAB) m/j 552 (M*). To a solution of methyl 4-[2-A,-allyl-AH4-[-(2-chlorophenyI)ureido]-3-methoxyphenyl] acetamido]ethoxybenzoate (250 mg, 0.45 mmol) in THF-MeOH (I: 1, v/ v, 8 ml), was added 0.25 N NaOH (3.6 ml, 0.91 mmol) at rt, and heated to reflux. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, and acidified with 1.0 N HC1. The resulting precipitate was collected by filtration. The precipitate was recrystallized with hexane-diethylether to give 310 as a white powder (195 mg, 80%). MW 537.99 'H-NMR (CD3OD)8 3.61 (s, 1 H), 3.76 (s, 3 H), 3.82 (m, 1 H), 3.85 (s, 1 H), 3.88 (m, 1 H), 4.11-4.25 (m, 4 H), 5.12-5.25 (m, 2 H). 5.81 (m, 1 H), 6.78 (d, 1 H, J = 8.3 Hz), 6.82 (m, 1 H), 6.92 (m, 2 H), 7.01 (m, 1 H), 7.26 (m, 1 H), 7.37 (m, 1 H), 7.96 (m, 3 H), 8.02 (m, 1 H); MS (FAB) m/z 537 (M*); Anal. Calcd for C,SHISC1NA 1/4 H,0: C, 61.99; H, 5.30; N, 7.75. Found: C, 62.00; H, 5.56; N, 7.76. Eiamole 261 4-[2-A'-allyl-A'-[4-[/i/'-(2-bromophenyl)ureido]-3-methoxyphenyl]aceiamido]ethoxybenzoicacid bromophenyl)ureido]-3-melhoxyphenylacetie acid (190 mg, 0.5 mmol), EDOHC1 (144 mg, 0.75 mmol), HOBt (128 mg, 0.95 mmol), and DMAP (12 mg, 0.1 mmol) in DMF (2.5 ml) was stirred for 18 hours. The mixture was diluted with ElOAc (300 ml), washed with IN HCJ and brine, and dried over MgSO,. After removal of the solvent, residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCIj-EtOAc 100:0 to 70:30) to give methyl 4-[2-A'-aliyl-//-[4-[A'-(2-bromophenyI)ureido]-3-methoxyphenyl] acetamidojethoxybenzoate (251 m& 84%) as an amorphous foam. 'H-NMR (CDClj)5 3.65-3.85 (m, 4 H), 3.73 (s, 3 H), 3.83 (s, 3 H), 4.08 (m, 2 H), 4.22 (m, 2 H), 5.10-5.25 (m, 2 H), 5.78 (m, 1 H), 6.79 (m, 1 H), 6.85 (m, 3 H), 6.93 (m, 1 H), 7.02 (m, 2 H), 7.30 (m, 1 H), 7.51 (m, 1 H), 7.94 (d, 2 H, J = 8.3 Hz), 7.97 (m, 1 H), S.14 (m, 1 H); MS (FAB) m/z 596 (W*)- To a solution of methyl 4-[2-//-allyl-A'-[4-[Af'-(2-bromophenyl)ureido)-3-mcthoxypheny]] acetamidojethoxybenzoate (251 mg, 0.42 mmol) in THF-MeOH(l: l.vfv, 8 ml), was added 0.25 N NaOH (3.4 ml, 0.84 mmol) at it, and heated to reflux. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, and acidified with 1.0 NHC1. The resulting precipitate was collected by filtration. The precipitate was recrystallized with Hexane-diethylether to give 311 (192 mg, 78%) as a white powder. MW 582.44 'H-NMR CDsOD) S 3.61 (s, 3 H), 3.77 (s, 3 H), 3.80 (m, 1 H), 3.85 (s, 1 H), 3.88 {s, 1 H), 4.12-4.25 (m, 4 H), 5.12-5.23 (m, 2 H), 5.81 (m, 1 H). 6.76 (m, 1 H), 6.82 (m, 1 H), 6.93 (m, 3 H), 7.29 (m, I H), 7.56 (m, 1 H), 7.94 (m, 4 H); MS (FAB), m/z 582 ($tfy,Anal, Calcd for Cj.HBrNA: C, 57.74; H, 4.85; N, 7.21. Found: C, 57,40; H, 5.07; N, 7.04. For HC1 salt of 311 : Anal. Calcd for CHnBrNjCVO.25 H,0: C, 55.23; H, 4.55; N, 6.90. Found: C, 54.98; H, 4.71; N, 6.53. methyl-4-[Ar-(2-methylphenyl)uieido]pheny!acetic acid (100 mg, 0.37 mmol), EDC-HC1 (105 mg. 0.56 mmol), HOBt (95 mg, 0.70 mmol), and DMAP (9 mg, 0.07 mmol) in DMF (7.4 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (100 ml), washed with IN HCI and brine, and dried over MgSCv The residue was co-evaporated with toluene (10 ml x 3) to remove DMF. The residue was chromatographed on TLC (Whatman, PLK-5F, 2 plates, CHCl3-MeOH, 97:3) to give methyl 4-[2-W-allyl-W-[3-methyl-4-[//'-(2-methylphenyI)urcido]phenyl]acetamido] ethoxybenzoate(190mg, 100%) as a white amorphous foam. 'H-NMR (CDClj)8 2.05 and 2.09 (2s, total 3 H). 2.20 and 2.21 (s, total 3 H), 3.62 (s, 2 H), 3.76 (m, 2 H), 3.90 (s, 3 H), 3.88 (m, 1 H), 4.0S (m, 2 H), 4.11 (m, 1 H), 6.28 (m, 2 H). 5.78 (m, 1 H), 6.88 (d, J = 8.8 Hz, 2 H), 7.05 (m, 1 H), 7.12 (m, 1 H), 7.21 (m, 1 H), 7,58 (m, 2 H), 7.95 (d, J = 8.8 Hz, 2 H), 8.02 (m, 1 H); MS (FAB), m/z 516 (M*+l). To a solution of methyl 4-[2-W-a]lyl-JV-[3-methyM-[A-(2-methylphenyl)ureido]phenyl] acetamidojethoxybenzoate (217 mg, 0.43 mmol) in THF-MeOH (6: 1, v/ v, 7 ml), was added 0.5 N NaOH(1.9 ml, 0.86 mmol) at rt, and heated to reflux. The stirring was continued for 2 hours at reflux in a sealed bottle. The reaction mixture was poured into water, acidified with 1.0 N HC1, extracted with CHCtj-MeOH (2:1, 20 mL x 3), and dried overMgSO,. After removal of the solvent, the residue was crystallized with CHC]3-hexane-diethylcther to give 312 (84 mg, 38%) as a white powder. MW 501.57 'H-NMR (CD3OD)5 2.18 arid 2.24 (s, total 3 H), 2.30 (d, J= 4.9 Hz, 3 H), 3.70 (s, 1 H), 3.78 (m, 2H), 3.88 (s, 1 H), 4.12 (m, 4 H), 5.20 (m, 2 H), 5.81 (m, 1 H), 6.92-7.20 (m, 7 H), 7.58 (m, 2 H), 7.96 (m, 2 H); MS (ESI) m/i 502 Q)\Anal. Calcd for CHJINA: C, 69.44; H, 6.23; N, 8.38. Found: C, 68.99; H, 6.39; N. 8.03. and 3-chloro-4-[A'-(2-methylphenyl)ureido]pheriyIacetic acid (191 mg, 0.60 mmol) in DMF (5 mL) were added EDC-HC! (172.5 mg, 0.90 mmol), HOBt (154 mg, 1.14 mmol), and DMAP (15 mg, 0.12 mmol), and the stirring was continued overnight at rt. The mixture was diluted with EtOAc {50 mL) and washed with 1M HC1 (x 3), 1M NaOH (x 1), and brine. The mixture was dried over anhydrous MgSO and concentrated under a reduced pressure to give methyl 4-[2-M-allyl-Ar-[3-chloro-4-[W-(2-methylphenyl)ureido] phenyl]acetamido]eihoxybenzoate (350 mg, 109%) as a white powder. 'H-NMR (CDC13) 8 2.35 (s, 3 H), 3.60 (s, 1 H), 3.75 (m, 2 H), 3.90 (s, 3 H), 4.10 (m, 4 H), 4.21 (m, 1 H), 5.20 (m, 2 H), 5.80 (m, 1 H), 6.50 (s, 1 H) , 6.85 (m, 2 H), 7.08 (m, 2 H). 7.20 (m, 4 H), 7.50 (d. J =8.1 Hz, 1 H), 7.95 (d, J= 8.1 Hz, 2 H), 8.12 (d. J= 8.1 Hz, 1 H); MS (ESI) m/r. 536 (M*+H). To a stirred solution of methyl 4-[2-Af-aIlyl-W-[3-cWoro-4-[Af'-{2-methylphenyl)ureido] phenyl]acetamido]ethoxybenzoate(321 mg, 0,6 mmol) in THF-MeOH-HjO (2:2:1, v/v, 30 ml), was added NaOH (500 mg, 12.5 mmol) at rt. The stirring was continued for 18 hours at rt The reaction mixture was poured into water, washed with diethyl ether, acidified with 1M HCJ, extracted with CHClj-MeOH (2:1,20 mL x 3), dried over anhydrous MgSO,, and concentrated under a reduced pressure. The residue was solidified with CHCV/i-hexane to give 313 (283 rag, 83%) as a white solid. IR (KBr): 3345,1581, 1529, 1243, 1167 cm"1; 'H-NMR (CD,OD)S 2.30 (s, 3 H), 3.71 (s, 1 H), 3.78 (m, 1H), 3.82 (m, 1 H), 3.89 (s, 1 H), 4.10 (m, 1 H), 4.19 (m, 2 H), 4.21 (t, J = 5.4 Hz, 1 H), 5.20 (m, 2 H). 5.82 (m, 1 H), 6.95 (m, 2 H), 7.03 (m, 1 H), 7.18 (m, 3 H), 7.28 {s, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.99 (m, 3 H); MS (ESI) m/z 522 (M*+l); no/. Calcd for CHHCINJCVI H,0: C, 60.76; H, 5.74; N, 7.59. Found: C, 60.43; H, 5.34; N, 7.17. Example 264 methylphenyl) ureido]phenylacetamido]cthoxy]benzoate (1.83 g, 3.24 mmol) in THF-MeOH-HjO (1: 1: l,v/v/v, 15 mL) was added sodium periodate (2.08 g, 9.71 mmol), and stirred for 18 hours at rt. A saturated Na,Sj03 (50 ml) was added to the reaction mixture and the mixture was stirred for 1 hour. The mixture was extracted with EtOAc (100 ml x 3), washed with brine, dried over MgSO,. The solvent was removed to give the title compound (1.73 g, 100%) as an amorphous foam. 'H-NMR (CDC13) 5 2.32 (t, 3 H, J= 2.8 Hz), 3.33-4.30 (m, 8 H), 3.72 {s; 3 H), 3.86 (s, 3 H), 6.20 (m, 1 H), 6.70 (m, 1 H), 6.80 (ra, 4 H), 7.06 (m, 1 H), 7.18 (m, 1 H), 7.26 (m, 1 H), 7.49 (d, 1 H, J= 7.4 Hz), 7.96 (ra, 2 H), 8.10 (m, 1 H). 9.57 and 9.63 (2 s, total 1 H); MS (FAB),m/z534(M*+l). To a stirred solution of methyl 4-I2-/V-formylmethyl-A'-[3-methoxy-4-[Jv',-(2-methyl pheny])ureido]phenylacetamido]ethoxy]benzoate (400 mg, 0.75 mmol) in EtOH (7.5 ml), were added morpholine (654 ml, 7.5 mmol) and acetic acid (429 ml, 7.5 mmol) at rt. The reaction was stirred for 5 min. at rt, then cooled to 0 "C. To the cooled solutionl, was added NaBH3CN (471 mg, 7.5 mmol) and the stirring was continued for 1 h at rt. The mixture was poured into sat. NaHC03 and was extracted with EtOAc (50 ml x 3), washed with brine, and dried over MgSO,. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient toluene-acetone 100:0to 1: 1) to give 314 (346 mg, 76%) as a white amorphous foam. 'H-NMR (CDCI,, 400 MHz) 5 2.31 (s, 3H), 2.46 (m, 4 H), 3.52-3.79 (m, 12 H), 3.70 (d, 3 H, J = 2.7 Hz), 4.05 and 4.22 (m, tola! 2 H), 6.24 and 6.29 (5, total 1 H), 6.73 (m. 2 H), 6.85 (m, 2 H), 7.07 (s, 1 H), 7.17 (m, 1 H), 7.25 (m, 2 H), 7.50 (t, 1 H, 7= 7.3 Hz), 7.96 (m, 2 H), 8.08 (m, 1 H); MS (FAB), m/z605 (M*+ l)Mna/. Caicd for CjN.0,1/2 H,0: C. 64.58; H, 6.73; N, 9.13. Found: C, 64.95; H, 6,88; N, 8.82. HC1 salt of 314 : Anal. CaJcd for CJJHCIN.OJJ H,0: C, 57.76; H, 6.76; N, 8.16; CI, 5.17; Found: C, 58.29; H, 6.81; N, 7.42; CI, 5.05. ureido]phenyl]acetamido]ethoxybenzoate(146 mg, 0.24 mmol) inTHF-MeOH (1:1, v/v, 6 ml), was added 0.25 N NaOH (1.9 ml, 0.48 mmol) at rt, and heated to reflux. The stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, and acidified with 1.0NHC1. The mixture was extracted with CHClj-MeOH (3: 1, v/v, 30 ml x 5). The combined organic solvent was dried over MgSCv After removal of solvent, the residue was crystallized with diethylether to give 315 (102 mg, 71%) as a white powder, 'H-NMR (CD3OD) 6 2.28 (d,J= 3.0 Hz, 3 H), 2.46 (m, 1 H), 2.40 (m, 1 H), 2.56 (m, 1 H), 2.63 (m, 1 H), 3.62-3.80 (m, 12 H), 3.85 (s, 3H),4.12(m, 1H), 4.26 (m, 1 H), 6.82 (m, 2 H), 6.96 (m, 2 H), 7.01 (m, 1 H), 7.17 (m, 2 H), 7.58 (d, J= 7,8 Hz, 1 H), 7.93 (m, 3 H); MS (FAB) m/z 591 QA*);Anal. Calcd for C3IHMN,1OJ1.0 H,0: C, 63.14; H, 6.62; N, 9.20. Found: C, 63.48; H, 6.66; N, 8.79. DMSO (18.1 ml, 255 mmol), EtjN (17.7 ml, 127.5 mmol) in CHjCl, (200 ml) was added SCyPy (12.2 g, 76.5 mmol). After Stirring for 5 h, the mixture was concentrated in vacuo and the residue was diluted with H;0 (100 ml). The mixture was extracted with EtOAc (2 x 200 ml). The combined extracts were washed with brine (100 ml), dried over (MgSOJ, and evaporated. The residue was chromatographed on silica gel with hexane-EtOAc {4:1) to give 4:1 mixture of methyl 4-formyl methyloxybenzoate and methyl 4-hydroxybenzoate (2.00 g) as a white solid. 'H-NMR (CDC13)5 3.90 (S, 3 H), 4.64 {d,J = 1,0 Hz, 2 H), 6,92 (d, J- 9.0 Hz, 2 H), 8.02 (d, J- 9.0 Hz, 2 H), 9.86 (d, 7 = 1.0 Hz, 1 H). To a stirred solution of 4:1 mixture of methyl 4-formylmethyloxybenzoate and methyl 4-hydroxybenzoate (1.00 g) and cyclopropylamine (425 ml, 6,18 mmol) in MeOH-AcOH (10:1,11 ml) was added NaBH3CN (681 mg, 10.3 mmol). After stirring overnight, the mixture was quenched by addition of sat. NaHCOj (50 ml) and extracted with CHClj (2 x 200 ml). The combined extracts were dried over MgSOj and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH(20:l) to give methyl 4-(2-cyclopropyl aminoethoxy)benzoate (595 mg, 49%) as a colorless oil. 'H-NMR (CDCI3)S 0.37-0.49 (m, 4 H), 1.91 (m, 1 H), 2.18-2.23 (m, 1 H), 3.11 (t, J= 5.2 Hz, 2 H), 3,88 (s, 3 H), 4.12 (t,/ = 5.2 Hz, 2 H), 6.92 (6,J= 8.8 Hz, 2 H), 7.98 (d, .7=8.8 Hz, 2H). A mixture of methyl 4-(2-cydoprDpylaminoethoxy)benzoate (290 mg, 1.23 mmol), 3-memoxy-44/TK2-methylphenyl)ureido]phenylacetic acid (387 mg, 1.23 mmol), EDC-HC1 (354 mg, 1.85 mmol), HOBt (cat.), and DMAP (cat.) in DMF (10 ml) was stirred overnight. The mixture was partitioned between EtOAc (300 ml) and H30 (100 ml). The organic phase was separated, washed with brine (2 x 100 ml), dried over MgS04, and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (50:1) to give the title compound (426 mg, 65%) as a yellow viscous oil. 'H-NMR (CDC13)5 0,90-0.97 (m, 4 H), 2.28 (s, 3 H), 3.60 (s,' 3 H), 3.77 (t, J= 5.4 Hz, 2 H), 3.85 (s, 2 H), 3.87 (s, 3 H), 4.15 (t,J~ 5.4 Hz, 2 H), 6.60-6.81 (m, 5 H), 7.09-7.23 (m, 4 H), 7.57 (d,/ = 8.3 Hz, 1 H), 7.92-7.95 (m, 2 H), 8.04 (d,J = 8.3 Hz, 1 H). To a stirred solution of methyl 4-[2-[Af-cyclopropyl-[3-methoxy-4-[Ar'-(2-methylphenyl) ureido]phenyl]acetamido]ethoxy]benzoate (426 mg, 0,801 mmol) in THF (7 ml) was added 0.25 N NaOH (6,4 ml, 1.60 mmol). After stirring overnight, the mixture was poured into 1 N HC1 (50 ml) and extracted with CHClj-MeOH (4:1, 2 x 200 ml). The combined extracts were dried over MgS04 and evaporated. The residue was chromatographed on silica gel with CHCl,-MeOH(20:l to 10:l)aseluenttogive316 (333 mg, 80%) as a colorless amorphous solid 'H-NMR (DMSO) 5 0.86-0.91 (m, 4 H), 2,25 (s, 3 H), 2.74 (m, 1 H), 3.69 {t, J = 5.5 Hz, 2 H), 3.81 (s, 3 H), 3.83 (s, 2 H), 4.15 (t, J= 5.5 Hz, 2 H), 6.75 (d, J= 8.3 Hz, 1 H), 6.87 (s, 1 H), 6.92-6.99 (m, 3 H), 7.11-7.17 (m, 2H), 7.81 (d, 7=8.1 Hz, 1 H), 7,88 (d, J= 8,5 Hz, 2 H), 8.01 (d, 7=8.1 Hz, I H), 8.47 (s, 1 H), 8.55 (s, 1 H), 12.96 (s, br s); MS (FAB), m/z 518 (W*+l); ylno/. Cakd for C,„Nj04: C, 67.30; H, 6.04; N, 8.12. Found: C, 66.71; H, 6.26; N, 7.82. Example 267 A-[2-N-[2-{N>, Ar-dimethylainino)-l-eihy])-A'-[-4-[W"-(2-chlorophcnyl)ureido]-3-nicthoxpheny!] chlorophenyl) ureido]-3-methoxphenyl]acetamido]ethoxybenzoate (100 mg, 0.17 mmol) in THF-MeOH (1:1, v/v, 3 ml), was added 0.25 NNaOH (2.0 ml, 0.3 mmol) at rt, and heated to reflux. The stirring was continued for 3 hours at reflux. The reaction mixture was poured into water, and acidified to pH 5.0 with 1.0NHC1. After removal of the organic solvent in vacuo, the resulting mixture was chromatographed with HP-20 (IO-MeOH 100:0 to 0:100) to give 317 (63 mg, 64%) as a white powder. 'H-NMR (CD3OD) 5 2.41 (s, 2 H), 2.65 (s, 3 H), 2.69 (s, 3 H), 3.02 (m, 2 H), 3.62-3.85 (m, 4 H), 3.84 (s, 3 H), 4.05 and 4.22 (m, total 2 H), 6.82-6.88 (m, 4 H), 7.02 (m, 1 H), 7.25 (m, 1 H), 7.38 (m, 1 H), 7.92 (m. 2 H), 8.01 (m, 2H); MS (FAB), m/z 569 (M*); Anal. Calcd for CaftjClNAS.OHjO: £ 55.90; H, 6.31; N, 8.99. Found: C, 56.40; H, 6.50; N, 8.08. Eiample 268 isopropyl4-[2-A'-[2-(4-morpJiolinyl)ethyl]-A'-[3-methoxy-4-[//'-(2-methyIphenyl)ureido]phenyl] methylphenyl) ureido]phenyl]acetamido]ethoxybenzoic acid (250 mg, 0.42 mmol) in DMF (2 mL), were added isopropyl iodide (264 ml, 2.53 mmol) and K,C03 (88 mg, 0,64 mmol) at rt. The reaction was stirred for 2 hours at 50 °C. The mixture was poured into brine and was extracted with CHCl, (50 ml x 3), washed with brine, and dried over MgSO,. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient toluene-acetone 100:0 to 40: 60) to give 318 (261 mg, 97%) as a white amorphous foam. 'H-NMR (CDC13, 400 MHz) 5 1.35 (s, 3 H), 1.36 (s, 3 H), 2.31 (s, 3 H), 2.45 (m, 4 H), 2.50 (m, 2 H), 3.55-3,78 (m, 10 H), 3.70 (s, 3 H), 4.05 and 4.20 (t, J = 5.2 Hz, total 2 H), 5.22 (m, 1 H), 6.24 and 6.33 (2 S, total 1 H), 6.70-6.83 (m, 4 H), 7.08 (s, 1 H), 7.15 (m, 1 H), 7.22 (m, 1 H), 7.40 (t, J= 9.0 Hz, 1 H), 7.93 (d, J= 8.8 Hz, 1 H), 7.97 (d, J= 8.8 Hz, 1 H), 8.07 (t, J = 7.8 Hz, I H); MS (FAB), m/i 633 (M*+ \);Anai. Calcd for C:sHMN4O7-0.75 H,0: C, 65.05; H, 7.10; N, 8.67. Found: C. 65.19; H, 7.09; N, 8.50. Example 269 4-[2-M[2-(3,3-difluoro-l-pyn'oIidnyl)e[hyl]-A'-[4-[Af'-{2-bromoplienyl)ureicio]-3-inelhoxyphenyl] bromaphenyl)uieido] phenyl]awtamida]ethQxybenzcate (300 mg, 0.5 mmol) in 1,2-dichloroethane (3,6 ml), was added 3,3-difluoropyrrolidine AcOH salt (420 mg, 2.5 mmol) at rt The reaction was stirred for 5 min. at rt, then cooled lo 0 "C. To the cooled solution, was added NaBH(OAc)3 (530 mg, 2.5 mmol), and the stirring was continued for 4 h at rt. The mixture was poured into sat. NaHC03, was extracted with CHClj (50 mL x 3), washed with brine, and dried over MgSCv After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCIrMeOH 10:0 to 97:3) to give methyl 4-[2-A'-[2-(3,3-difluoro-I-pyrrolidinyI)ethy]]-A'-[4-[A',-(2-bromophenyl) ureido]-3-methoxyphenylJ acetamido]ethoxybenzoate (345 mg, 100%) as a white amorphous foam. 'H-NMR (CDC1,, 400 MHz) 5 2.20-2.80 (m, 6 H), 3.48 (m, 2 H), 3.70-3.80 (m, 9 H), 3.89 (s, 3 H), 4.09 (m, 1 H), 4.21 (m, 1 H), 6.79-6.85 (m, 4 H), 6.93 (m, 1 H), 7.08 (m, 2 H), 7.30 (m, 1 H), 7.50 (m, 1H), 7.96 (m, 3 H), 8.13 (dd, J =1.5 Hz, 8.3 Hz, 1 H); MS (ESI) m/z 689 (M*). To a solution of methyl 4-[2-M-[2-(3,3-difluoro-l-pYirolidinyl)ethyl]-A'-[4-[Af'-(2-bromophenyl) ureido]-3-methoxyphenyl]acetamido]ethoxybenzoate (345 mg, 0,5 mmol) in THF-MeOH (1: 1, v/ v, 8 ml), was added 0.25 N NaOH (4 ml, 1.0 mmol) at rt, and heated to reflux. The stirring was continued for 6 hours at reflux. The solvent was removed, and the residue was chromatographed on HP-20 (HjO-MeOH, 0: 100 to 100: 0) to give 319 (306 mg, 91%) as a pale red powder. 'H-NMR CD3OD, 400 MHz) 8 2.20-2,90 (m, 6 H), 3.60 (m, 2 H), 3.70-3.92 (m, 9 H), 4,10 (m, 1 H), 4.22 (m, 1 H), 6.84 (m, 4 H), 6.96 (m, 1 H), 7.30 (m, 1H), 7.55 (m, 1H), 7.93 (m, 3H), 7.97 (m, 1 H); MS (ESI) m/z 676 Qtf+\);Anal. Calcd for C3lH3,BrFiN„Cv2.5 H30: C, 52,85; H, 5,29; N, 7.95. Found: C, 52.67; H, 5.20; N, 8.11. Example 270 4-[2-A,-(AT-metJioxy-A"-methylamino)ethyl-A'-[3-methoxy-4-[/Vn'-(2-methylpherryl)ureido] ureido] phenylacetamido]ethoxy]benzoate (350 mg, 0.66 mmol) inEtOH(13 ml), was added N-methoxy-A'-methylamine hydrochloride (637 mg, 6.6 mmol) at rt The reaction was sonicated for 5 min. at rt, then cooled to 0 "C. To the cooled solution, was added NaBHaCN (105 mg, 1.65 mmol) and the stirring was continued for 18 h at it. The mixture was povired into sat NaHCOj and was extracted with CHC1] (50 ml x 3), washed with brine, and dried over MgS04. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient toluene-acetone 9: 1 to 2: 3) to give the title compound (344 mg, 91%) as a white amorphous foam. 'H-NMR (CDC13,400 MHz) 5 2.29 (s, 3 H), 2.52 and 2.58 (s, total 3 H), 2.79 (m, 2 H), 3.49-3.76 (m, 9 H), 3.88 (s, 3 H), 4.05 and 4.20 (m, total 2 H), 6.69-6.86 (m, 5 H), 7.10 (m, 1 H), 7.20 (m, 2 h), 7.29 (m, 1 H), 7.44 (m, 1 H), 7.94 and 7.99 (d, J* 8.6 Hz, total 2 H), 8.06 (m, 1 H); MS (FAB), m/z 579 (M*+ 1); Anal. Calcd for C3iH3!N,07-2.5H,0:C, 59.70; H, 6.95; N, 8.98. Found: C, 59.58; H.6.65; N, 8.90. To a solution of methyl 4-[2-A'-(A'-inethoxy-j\'-metliylamino)ethyl-A'-[3-metho?[y-4-rA'"-(2-inethylpheriyl)ureido]phenyI]acetarnido]ethQxybenzoate (138 mg, 0.24 mmol) in THF-MeOH (1: 1, v/v, 4 ml), was added 0.25 N NaOH (1.9 ml, 0.48 mmol) at rt, and heated to reflux.' The stirring was continued for 18 hours at reflux. The solvent was removed, and the residue was chromatographed onHP-20 (O-MeOH, 100: OtoO: 100) to give 320 (140 mg, 100%) as a white powder. 'H-NMR (CD3OD) 5 2.29 (s, 3 H), 2.54 and 2.56 (2 s, total 3 H), 2.82 (m, 2 H), 3.48 (m, 2 H), 3.65-5,80 (m, 9 H), 4.09 and 4.21 (2 m, total 2 H), 6.80 (m, 4 H), 7,00 (t, J= 7.5 Hz, 1 H), 7.18 (m, 2 H), 7.57 (d,J= 7,8 Hz, 1 H), 7.88 (m, 2H), 7.99 (m, 1 H); MS (FAB), m/z 565 (MM); Anal Caicdfor C,oH3)N,07Nal.O H|0: C, 59.59; H, 6.17; N, 9.27. Found: C, 59.10; H, 6.28; N, 8.86. Example 271 4-[2W-(/-meuioxy-A-methylamino)ethyl--[4-[//,-(Z-bromophenyl)ureido]-3-methoxyphenyI acetamiiio)ethoxy]ben2oic acid bromophenyl)ureido] phenyl]acetamido]ethoxyberaoate (209 mg, 0.35 mmol) in ElOH (7 ml), was added A'-methoxy-//-methylamine HC1 sail (341 mg, 3.5 mmol) at rt. The reaction was sonicated I for 5 min. at rt, then cooled to 0 * C. To the cooled solution, was added NaBH(OAc)3 (370 mg, 1.75 mmol) and the stirring was continued for 18 hatrt. The mixture was poured into sat. NaHCOj, extracted with CHC13 (50 ml x 3), and dried over MgSO,. After removal of the solvent, the residue was chromatographed on TLC (Whatman, PLK-5F, 2 plates, CHClj-MeOH, 98:2) to gememyl4-[2-A'-memo>-A-methylaniino)ethyl-A'-[4-[A'-(2-bromophenyl)ureido]-3-methoxyphenyl acetamido]ethoxy]benzoate (89 mg, 40%) as a white amorphous foam. 'H-NMR (CDClj, 400 MHz) 8 2.52 and 2.60 (2 s, 3 H), 2.80 (m, 2 H), 3.48 and 3.50 (2 s, total 3 H), 3.65 (m, 2 H), 3.72 (s, 3 H), 3.77 {m, 4 H), 3.90 (s, 3 H), 4.08 (m, 1 H), 4.22 (m, 1 H), 6.82 (m, 5 H), 7.12 (s, 2H), 7.30 (m, 1 H), 7.52 (d, J= 8.1 Hz, 1 H), 7.94 (m, 3 H), 8.15 (6,J= 8.3 Hz, 1 H); MS (ESI) m/z 643 (M*). To a solution of methyl 4-[2-/V-(A'-metho)cy-//,-methylamino)ethyl-Ar-[4-[/v',-(2-bromophenyl)ureido]-3-methoxyphenylacetarnido]ethoxy]benzoate (89 mg, 0.14 mmol) in THF-MeOH (5: 1, v/v, 6 ml), was added 0.5 N NaOH (1.4 ml, 0.7 mmol) at rt, and heated to reflux in a glass sealed bottle. The stirring was continued for 3 hours at reflux. The reaction was poured into water, and was acidified with 1 N HC1 to pH 5, extracted with CHCl3-MeOH (2:1, v/ v, 30 mL x 3), dried over MgSO.. The solvent was removed in vacuo to give 321 (53 mg, 60%) as a white powder. 'H-NMR (CD3OD, 400 MHz)S 2.62 and 2.64 (2 s, total 3 H), 2.80 (m, 2 H), 3.50 (d, J = 7.3 Hz, 3 H), 3.63-3.88 (m, 6 H), 4.12 (m, 1 H), 4.25 (m, I H), 6.82-7.00 (m, 5 H), 7.30 (m, 1 H), 7.58 (m, 1H), 7.95 (m, 4 H); MS (FAB), m/z 629 QA*);Anal. Calcd for Ci,H„BrN4OT-0.25 H,0: C, 54.94; H, 5,33; N, 8.84. Found: C, 55.39; H, 5.53; N, 8.23. Example 272 4-[2-A'-(Af', //'-diallyl)ethyl-JV-[3-methoxy-4-[,-(2-methylpheny!)uTeido]phenyl]acetamido) To a stirred solution of methyl 4-[2-A,-fontiy]methyl-A'-l3-methoxy-4-[A',-(2-methylphenyl)ureido] phenyl]acetamido]ethoxybenzoate (400 mg, 0.75 mmol) in EtOH (15 ml), were added diallylamine (926 ml, 7.5 mmol) and acetic acid (429 ml, 7.5 mmol) at rt. The reaction was stirred for 5 min. at rt, then cooled !o 0 *C. To the cooled solution, was added NaBH,CN (118 mg, 1.9 mmol) and the stirring was continued for 1 h at rt. The mixture was poured into sat. NaHCOj and was extracted with EtOAc (50 ml x 3), washed with brine, and dried over MgSOj. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradieni toluene-acetone 9: 1 to 1: 1) to give methyl 4-[2-//-(JV\ W-diaI!yl)ethyl-A'-I3-methoxy-4-lA'"-(2-methylphenyl)ureido] phenyl] acetami do] ethoxybenzoate (385 mg, 84%) as a white amorphous foam. 'H-NMR(CDC13, 400MHz)5 2.30 (s, 3 H), 2.60 {m, 2 H), 3.09 (m, 4 H), 3.49 (m, 2H), 3.60 (s, 2 H), 3.70 (m, 5 H), 3.89 (s, 3 H), 4.02 and 4.19 (2 m, total 2 H), 5.01-5.20 (m, 4 H), 4.79 (m, 2 H), 6.30 and 6.32 (2 S, total 1 H), 6.70-6.84 (m, 5 H), 7.08 (m, 1 H), 7.14 (m, 1 H), 7.25 (m, 1H), 7.60 (m, lH),7.93and7.98(2d,J=8.8Hz, 2.H), 8.03 and 8.06 (2 d, J = 8.3 Hz, 1 H); MS (FAB),/n/z615(M*+l). To a stirred solution of methyl 4-[2-M{A', JY-mallylJethyl-jV-p-methoxy-t//' '-{2-methylphenyl) ureido] phenyl] acetami do] ethoxybenzoate (385 mg, 0.63 mmol) in MeOH (3 ml), was added IN HC1 (756 ml, 0.76 mmol) at rt. The reaction was stirred for 5 min. at rt, then evaporated to give methyl 4-{2-W-(Ap, Ar-diallyl)ethyl-A,-[3-metlioxy-4-[Af"-{2-miethyIphenyl) ureido]phenyl] acetamido]ethoxybenzoate HC1 salt (385 mg, 99%) as an amorphous foam. Anal. Calcd for QjHClNA-O-S H,0: C, 63.67; H, 6.72; N, 8.49. Found: C, 63.67; H, 6.69; K 8.43. To a solution of 4-[2-A'-(A'\ W-diallyl)ethyl-A'-[3-methoxy-4-[Af"-(2-methylphenyl) ureido]phenyl]acetamido]ethoxybenzoate(175 mg, 0.29mmol)inTHF-MeOH(I: 1, v/v, 20 ml), was added 0.25 W, NaOH (2.5 ml, 0.63 mmol) at rt, and heated to reflux. The stirring was continued for 1 hours al reflux. The solvent was removed, and the residue was chromatographed on HP-20 (H20-McOH, 100: 0 to 0: 100) to give 322 (160 mg, 94%) as a white powder. 'H-NMR (CD3OD) 5 2.29 (s, 3 H), 2.60 (t, J = 6.9 Hz, 1 H), 2.67 (t, J = 7.0 Hz, 1 H), 3.10 (d, J = 6.6 Hz, 2 H), 3.14 (d, J = 6.6 Hz, 2 H), 3.59 (m, 2 H), 3.69-3.80 (m, 4 H), 3.80 (s, 3 H), 4.06 (t, J= 5.2 Hz, 4,21 (t,J=5.1Hz, 1H), 5.15 (m, 4 H), 5.80 (m, 2 H), 6.79 (m, 2 H), 6.84 (d,./ = 8.8 Hz, 2 H), 7.00 (t,-7=7.5Hz, 1H), 7.14 (m, 2 h), 7,48 (m, 1H),7.91 (dd,y=6.1 Hz, 8.8 Hz, 2 H), 8.00 (m, 1 H); MS (FAB), m/z 601 (M*); Anal Calcd for C3JH3,NANa -0.5 H,0: C, 64.65; H, 6.38; N, B.87. Found: C, 64.53; H, 6,58; N, 8,78. Example 273 4-[2-//-(A', //'-dia]iyl)cthyI-iV-[4-[A',-(2-chloropheiiyl)iireido]-3-inetlioxypheny]acetaiiiido]ethoxy] racthoxy phenyl acetami do] ethoxy]benzoate (100 mg, 0.18 mmol) in ElOH (3.6 ml), was added diallylamine (223 ml, 1.81 mmol) at rt. The reaction was stirred for 5 min. atrt, then cooled Jo 0 'C. To the cooled solution, were added AcOH (104 ml, 1.81 mmol) and NaBH3CN (28 mg, 0.45 mmol), and the stirring was continued for 18 h at it. The mixture was poured into sat. NaHCOj, was extracted with CHCli(30mLx3), washed with brine, and dried over MgSO«. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHClrMeOH 10:0 to 20: 1) to give methyl 4-[2-A'-(An, yV-diallyl)ethyl-A'-[4-[A'-(2-chJorophenyl)ureido]-3-methoxYphenyl acetamido]ethoxy] benzoate {96 mg, 83%) as a white amorphous foam. 'H-NMR (CDClj, 400 MHz) 5 2.60 (m, 2 H), 3.09 (d, J = 6.4 Hz, 1 H), 3.11 {d, J = 6.4 Hz, 3 H), 3.52 (m, 2 H), 3.61 (s, 2 H), 3.70-3.80 (m, 5 H), 3.86 (s, 3 H), 4.05 and 4.20 (2 m, total 2 H), 5.06-5.21 (m, 4 H), 5.80 (m, 2H), 6.71-6.85 (m, 4 H), 6.98 (m, 1 H), 7.22 (m, I H), 7.32 (m, 3 H), 7.93 (d, Jf 7.8 Hz, 2H), 7.98 (m, 1 H), 8.18 (dd, J= 1.5 Hz, 8.2 Hz, 1 H); MS (ESI) m/z635 (M*). To a solution of methyl 4-[2-#-(W, Ar-diallyl)ethyl-A'-[4-[A'-{2-chlorophenyl)uieido]-3-methoxy phenylacetamidojethoxy] benzoate (96 mg, 0.15 mmol) in THF-MeOH (1: 1, v/v, 8 ml), was added 0.25 N NaOH (3.91 ml, 0.98 mmol) at rt, and heated to 50 "C. The stirring was continued for 6 hours at reflux. The solvent was removed, and the residue was chromatographed on HP-20 (HiO-MeOH, 0: 100 to 100: 0) to give 323 (88 mg, 94%) as a white powder. 'H-NMR (CDjOD, 400 MHz) 52.61 (m, 2 H), 3.10 (s, 2 H), 3.12 (s, 2 H), 3.59 (m, 2 H), 3.70 (s, 2 H), 3.78 (m, 2 H), 3.82 (s, 3 H), 4.10 (m, 1 H), 4.21 (m, 1 H), 5.18 (m, 4 H), 5.81 (m, 2 H), 6.82 (m, 4 H), 7.01 (t, J = 7.8 Hz, 1 H), 7.25 (m, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.90 (m, 2 H), 8.02 (m, 2 H); MS (ESI) m/z 621 (M*)Mna/. Calcd for C„HMClN,06Na'1.25 H,0: C, 59.55; H, 5.83; N, 8.42. Found: C, 59.90, H, 5.74; N, 7,96. Example 274 4-[2-iv'-[3-methoxy-4-[Ar,-(2-methy]phenyl)ureido]pheny]] --methy lacetoami d o] ethyl-1 - piperazinylacetic acid (8.76g, 63.4mmoJ) in CHjCN (100ml) was added ethyl bromoacetate (5.60ml, 50.5mmol) at 0°C. The reaction mixture was healed under icilux foT 5h, diluted with EtOAc, and washed with water and brine. The extract dried over Na3S04, concentrated to dryness and afforded ethyl 4-(2-hydraxyethyl)-l-piperazinylacetate (9.65g. 100%) as a yellow oil. 'H-NMR (CDC13) 5 1.23 (t, 3H, -/=7.3Hz). 2.51-2.61(m, 11H), 3.22{s, 2H), 3.61(t, 2H, J=5.4Hz), 4.19(q, 2H, 7=7.3Hz). To a solution of 2,4-dinitrobenzenesulfonyl chloride (l.Og, 3.75mmoI) and pyridine (0.34ml, 4.20rnmol) in THF (I9ml) was added dropwise methylamine (2.0M THF solution, 2.3ml, 4.60mmol) at 0°C. The reaction mixture was stirred for Ihr, quenched by the addition of IN HC1 solution, and extracted with EtOAc. The extract was washed with sat. NaHC03 solution and brine, dried over NajS04, and concentrated to dryness. The residue was recrystallized from EtOAc-EljO to give methyl 2,4-dinilrobenzenesulfonamide (546mg, 56%) as a colorless solid. 'H-NMR (DMSO) 6 2.60 (d, 3H, J=4.9Hz), 8.22 (d, 1H, J=8,8Hz), 8.31 (q, 1H, ,/=4.9Hz), 8.66 (dd, 1H, J=8.8, 2.0Hz), 8.90 (d, lH,./=2.0Hz). To a solution of ethyl 4-(2-hydroxyethyl)-l-piperazinyIacelate (452mg, 2.09mmol), methyl 2,4-dinitrobenzenesulfon-amide (546mg, 2.09mmol) and PPh, (658mg, 2.51 mmol) in THF was added DIAD (0.50ml, 251mmol) at 0°C. After stirring 17h at room temperature, the reaction mixture was concentrated to dryness. Chromatography of the residue with EtOAc-MeOH (10:1) to afford emyl4-[2-[A'-(2,4-dirdtrobenzensuonyl)-Af-methylamino]ethyl]-l-piperazinylacetate (864mg, 90%) as a reddish oil. 'H-NMR (CDClj) 6 1.27 (t, 3H, J=6.RHz), 2.35-2.63 (m, IQH), 2.98 s, 3H), 3.20 (s, 2H), 3.41 (t, 2H, J=6.8Hz), 4.17 (q, 2H, J=6.SBz), 8.33 (d, 1H, J=8.3Hz), 8.46 (d, 1H, y=2.0Hz), 8.50 (dd, 1H, J=8.3, 2.0Hz). A solution of ethyl 4-(2-(W2,4-dimliobeii2ensulfonyl)-W-methylairuno]ethyl]-l-piperazinylacetate (864mg, 1.88 nunol) .mercaptoacetic acid (0.17ml, 2.44mmol) and Et3N (0.53ml, 3.76mmol) in CH,Cli (25ml) was stirred at rt for 3hr. The reaction mixture ethyl 4-(2-methy]aminoethyl)-l-piperazinylacetate (388mg, 90%) as reddish oil. 'H-NMR (CDClj) 5 1.27 (t, 3H, J=6.8Hz), 2.50 (s, 3H), 2.53-2.60 (m, 8H), 2.75 (t. 2H, .7=5.9Hz), 3.20 (s, 2H), 4.18 (q, 2H, y=6,8Hz). To a solution of ethyl 4-(2-methylaminoethyI)-l-piperazinylacetate (388mg, 1.69mmoT), EljN (0.32ml, 2.25mmol) and DMAP (46mg, 0.38mmol) in DMF (15ml) was stirred for 15min at room temperature, then (532mg, 1.69mmol), HOBt (103mg, 0.76mmol) andEDC-HCl (486mg, 2.53mmol) was added to the reaction mixture which was stirred for 15hat rom temperature The reaction mixture was diluted with EtOAc, which was washed with brine, dried over NasSOj, and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (10:1, v/v) to afford ethyl 4-(2-A'-[3-methoxy-4-[Ar-(2-rnethylphenyI)ureido]phenylJ-A'-methylacetoairiido]ethyl-l-piperazirrylacetate (889mg, mixture of DMF) as a reddish oil. 'H-NMR (CDClj) 5 1.25-1.29 (m, 3H), 2.29 (s, 3H), 2.42-2.63 (m, 10H), 3.20, 3.18 (each s, total 3H), 3.55, 3.40 (each t, total 2H, /=6.8H2), 3.65, 3.69 (each S, total 2H), 3.72 (s. 3H), 4.15-4.21 (m, 2H), 6.50 (m, IH), 6.77-6.81 (m, 8H), 7.11-7.24 (m,3H), 7.53 (d, IH, >8.3Hz), 8,02 (s, IH), 8.06 (d, lH,y=7.8Hz). To a stirred solution of ethyl 44-[2-W-[3-methoxy-4-[A',-(2-methylphcnyl)ureido]phenyI]-A/-methylacetoamido]ethyl-l-piperazinyIacetate (889mg, 1.69mmol) in THF-EtOH (5:1, v/v, 18 ml) was added 4N NaOH (0.84ml, 3.38mmol). The reaction mixture was stirred at rt for 4h, adjusted to pH 7.5 with IN HC1 and extracted with CHCl3-MeOH (4:1, v/v). The combined extracts were dried over MgSO, and concentrated to afforded 324 (218mg, 26% 2steps) as a brown amorphous foam, IR(KBr) n 3299,3004, 1700, 1627, 1598. 1536cm-'; 'H-NMR (DMSO) 5 2.25 (S, 3H), 2.36-2.62 (m, 10H), 2.84, 2.99 (each s, total 3H), 3.13. 3.14 (each s, total 2H), 3.38-3.45 (m, 2H), 3.61, 3,65 (each s, total 2H), 3.86 (s, 3H), 6.74 (t, IH, y=7.8Hz), 6.87 (s, IH), 6.93 (t, IH, J=7.8Hz), 7.11-7.17 (m, 2H), 7.79 (d, IH, ,/=7.BHz), 8,01 (d, IH, ./=7.8Hz), 8.47 (s, IH), 8.57 (s, IH); MS (FAB) m/z 498 (M*+l); Anal. Calcd for CJSHJJNJOJHCI-O: C, 53.06; H, 6.67; N, 11.89, Found: C, 53.04; H, 6.15*, N, 11.09. Example 275 l-[2-[A'-methyl-A'-[3-metho-4-[A-(2-methylphenyl)iireido]phenyl]acetamido]ethyl]-4- 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH-AcOH (10:1, v/v, 22 ml) was added NaBHjCN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addtion of sat. NaHC03 (200 ml) and extracted with CHCl, (3 x 150 ml). The combined extracts were dried over MgSC\ and evaporated. The residue was crhomatographed on silica-gel with CHCl3-EtOH (40:1, v/v) to give ethyl l-[2-(A'-benzy]oxycarbonyl-Af- methylamino) ethyl]-4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 'H-NMR (CDC1}) 5 1.25 (l, J= 7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 {m, 4 H), 2.95 (m, 7 H), 3.44 (m,2 H), 4.13 (q,J = 7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49-5.53 (m, 1 H), 7.35 (m, 5 H). A solution of ethyl l-I2-(A,-benzyloxycarbony3-Ar-metlrylarmo)ethyl]-4-pipcridinylidene acetate (1.70 g, 4.72 mmol) in EtOH-AcOH (20:1, v/v, 21 ml) was hydrogcnated over 5% Pd/C (2 g) for 3 days with stirring. The mixture was filtered arid the filtrate was concentrated in vacuo. The residue was made basic with sat. NaHCOj and extracted with CHCl, (300 ml). The extract was dried over Na3COj and evaporated to give ethyl l-(2-memylaminoethy])-4-piperidinylacetate (813 mg, 75%) as a yellow oil. 'H-NMR (CDClj) 6 1.25 (t, J= 7.3 Hz, 3 H). 1.68-1.81 (m, 5 H), 1.97 ft J = 11.2 Hz, 2 H), 2.22 (d, J = 7.3 Hz, 2 H), 2.43-2.47 (m, 5 H), 2.66 ft J = 6.4 Hz,'2 H), 2.85-2.90 (m, 2 H), 4.13 (q, J= 7.3 Hz, 2 H). To a stirred solution of 3-methoxy-4-lAr'-(2-methylphenyl)ureido]phenylacetic acid (550 mg, 1.75 mmol) arid ethyl l-(2-methy!aminoethyI)-4-piperidinylacetate (400 mg, 1.75 mmol) in DMF (10 ml) were added EDCHC1 (503 mg, 2.63 mmol), HOBt (cat.), andDMAP (cat.) and the stirring was continued overnight. The mixture was diluted with EtOAc (300 ml), washed with brine (200 ml), dried over MgSO„ and evaporated. The residue was crhomatographed on silica gel with CHCl3-EtOH (10:1, v/v) to give ethyl l-[2-[A'-methyl-A'-[3-methoxy-4-[Ar'-(2-methylphenyl) ureido]phenyl]acetamido]ethyl]-4-piperidinylacetate (697 mg, 76%) as a yellow gum. 'H-NMR (CDClj) 8 1.19-2.06 (series of m, 12 H), 2.21 (t, J= 7.8 Hz, 2 H), 2.28 (s, 3 H), 2.41 (t,J= 7.3 .Hz, IH), 2.46 (t, .7=7.3 Hz, 1 H), 2,80-2.89 (m, 2 H), 2.95 and 3.01 (s, each, total 3 H), 3.40 and 3.50 (t, J= 6.8 Hz, each, total 2 H), 3.64-3.75 (m, 5 H), 4.09-4.16 (m, 2 H), 6.59 (s, IH), 6.77-6,79 (m, 2 H), 7.12 (t,y= 7.3 Hz, 1 H), 7.21-7.27 (m, 3 H), 7.54 (d, J = 8.3 Hz, 1 H), 8.06 (dd,-7=8.3,2.4Hz, 1 H), To a stirred solution of etfiyl l-[2-[//-methyl-A'-[3-methoxy-4-[A'*-(2-methylphenyl) ureido]phenyl]acetamido]ethyI]-4-piperidinyiacetate(690mg, 1.32 mmol)inTHF(ll ml) was added 0.25 Naq. NaOH (11 ml, 2.75 mmol) and the stirring was continued overnight. The mixture was diluted with H,0 (50 ml), neutralized with 1 N HC1, and extracted with CHCl3-MeOH {2:1, v/v, 3 x 100 ml). The combined extracts were dried over MgSOj and evaporated. The residue was dissolved in MeOH (50 ml) and activated carbon (2 g) was added to this solution. The suspension was refluxed for 30 min with stirring and filtered through Celite. The filtrate was evaporated and the residue was triturated by taking up CHC13 and adding hexane until a precipitate fomed. This precipitate was collected and dried in vacuo to give 325 (75 mg, 11%) as a white amorphous solid. 'H-NMR (DMSO) 5 1.19-2.99 (series of ra, total 17 H), 3.32-3.43 (m, 4 H), 3.62-3.65 (m, 2H). 3.86 (s, 3 H), 6.73 (t,y= 8.3 Hz, 1 H), 6.87 (s, 1 H), 6.93 (t, / = 7.8 Hz, I H), 7.11-7.17 (m, 2 H), 7.79 (d, 7= 8.3 Hz, 1 H), 8.01 (d, ./ = 8.3 Hz, 1 H), 8.47 (s, 1 H), 8,57 (s, 1 H); MS-FAB /n/r 497 (M*+l);io/. Calcd for C,,H«N,0,-HC1; C, 60.84; H, 7.00; N, 10.51. Found: C, 60.97;H,7.14;N, 10.17. mmol) and Et3N (366 ul, 2.63 mmol) in DMF (10 ml) was added peniafluorophenyl 4-(A"-{2-rnethylphenyI)ureido)phenylacetate (788 mg, 1.75 muiol) and the stirring was continued overnight. The mixture was diluted with EtOAc (300 ml), washed with brine (200 ml), dried over MgSO,, and evaporated. The residue was crhomatographed on silica-gel with CHClj-EtOH (10:1, v/v) to give ethyl l-[2-[A'-methyl-Af-[4-[iV-(2-niethylpheryl)ureido]phenyl]acetainido]ethyI]-4-piperidinyl acetate (630 mg, 73%) as a colorless oil. To a stirred solution of ethyl l-[2-[//-methy!-A'-[4-[//,-(2-methy]phenyl)uieido]phenyl] acetamido]ethyl]-4-piperidinylacetate (630 mg, 1.27 mmol) in THF (10 ml) was added 0.25 N aq. NaOH (10 ml) and the stirring was continued overnight. The reaction mixture was diluted with H20 (100 ml), neutralized with 1 N HC1, and extracted with CHCl3-MeOH (2:1, v/v, 3 x 100 ml). The combined extracts were dried over MgSO, and evaporated. The residue was triturated by taking up CHCl, and adding hexane until precipitate formed. This precipitate was collected and dried in vacuo to give 326 (20 mg, 3%) as a white amorphous solid. 'H-NMR (DMSO)5 1.69 (m, 5 H), 2.15 (m, 4 H), 2.24 (s, 2 H), 2.50 (m, 2 H), 2.83 and 2.99 (s, each, total 3 H), 3.32-3.49 (m, 4 H). 3,63 (d, J= 6.8 Hz, 2 H), 6.91-6,95 (m, 1 H), 7.13 (m, 4 H), 7.39 (d, J = 8.3 Hz, 2 H), 7.83 (d, J =7.3 Hz, 1H), 7.97 (m, 1 H), 9.12 (m, 1 H); MS (FAB): mi 467 (M*+l). Et3N (0.64ml, 4.58mmol) and DMAP (75mg, 0.61mmol) in THF (15ml) was stirred for 30min at rt, then 4-[A'-(2-methyIphenyI)ureido]pheny]acetic acid (917mg, 3.05mmol), HOBt (82mg, 0.61mmol) and EDOHC1 (879mg, 4.58mmo!) was added to the reaction mixture which was stirred for 12h at rt. The reaction mixture was diluted with EtOAc, which was washed with brine, dried over NajSOj, and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (10:1, v/v) afforded ethyl 4-[2-A'-[4-[A-(2-niethylphenyI)ureido]phenyl]-A'-rnethylacelamido]ethyl-1-piperazinyiacetate (996mg, 66%) as a yellow amorphous foam. 'H-NMR (CDClj) 5 1.25-1.29 (m, 3H), 2.20 (s, 3H), 2.47-2.58 (m, 10H), 2.97, 3.05 (each S, total 3H), 3.17, 3.20 (each s, total 2H), 3.45, 3.52 (each d, total 2H, J=6.8Hz), 3.64, 3.68 (each s, 2H), 4.15-4.21 (m, 2H), 7.01-7.19 (m, 8H), 7.48 (m, 1H), 7.64 (m, 1H); MS (FAB) m/z 496 (M*+l). To a stirred solution of ethyl 4-[2-A44-[A-(2-meWy]phenyl)mw do] phenyl ]-tf-methyl acetamidojethyl-l-piperazinylacetate (996mg, 2.01mmol) in THF-EtOH (5:1,12 ml) was added 4N NaOH (1.0ml, 4.00mmol). The reaction mixture was stirred at rt for 4h, adjusted to pH 7.5 with IN HC1 and extracted with CHClj-MeOH (4:1, v/v). The combined extracts were dried over MgSO« and concentrated to afforded 327 (73mg, 8%) as a yellow amorphous foam. IR(KBr)n 3338, 2925, 2850, 2821, 1704, 1627, 1540cm'; 'H-NMR (DMSO) 5 2.24 (s, 3H), 2.33-2.61 (m, 10H), 2.82, 2.95 (each S, total 3H), 3.00, 3,02 (each s, total 2H), 3.39 (1, 2H, ,/=6.8Hz), 3.60, 3.62 (each s, total 2H), 6.92 (t, lH,/=7.8Hz), 7.09-7.16 (m, 4H), 7.41-7.44 (m, 2H). 7.76, 7.77 (each d, 2H, J=l.ZHz), 8.46, 8.53 (each s, 1H), 9.54, 9.59 (each s, 1H); MS (FAB) m/z 468 (M*+l);-4no/. Calcd for CNA'SHCl: C, 55.56; H, 6.53; N, 12.96. Found: C, 54.99; H, 6.45; N, 11.58. Example 278 4 - [2 -N- [4 - [N '-(2 -iluoropheny l)ureido] -3 -methoxypheny 1] -W-methy lacetamidojethy 1-1 - Et3N (0.64ml, 4,58mmol) and DMAP (75mg, 0.61mmol) in DMF (15ml) was stirred for 15min at rt, then 4-[//'-(2-fluorophenyl)urei do]-3-methoxypheny lacetic acid (965mg, 3.03mmol), HOBt (82mg, 0.61mmol) and EDC-HC1 (872mg, 4.54mmoi) was added to the reaction mixture which was stirred for 12h at rt. The reaction mixture was diluted with EtOAc, which was washed with brine, dried over Na2SO„ and concentrated to dryness. Chromatography of the residue with CHC13-MeOH (10:1, v/v) afforded ethyl 4-[2-A'-[4-[A'-(2-fluorophenyl)ureido]-3-methoxyphenyl]-A'-methyl acelarnido]ethy!-l-piperazinylacetate(1.21g, mixture of DMF) as a black oil. 'H-NMR (CDClj) 5 1,24-1.29 (m, 3H), 2.45-2.59 (m, 10H), 2.98, 3.05 (each s, total 3H), 3.17, 3.20 (each s. total 2H), 3.44, 3.52 (each t, total 2H,y=6.8Hz), 3.66 (s,2H), 4.15-4.21 (m, 2H), 6.77-6.78 (m, 2H), 6.79-7.11 (m, 3H), 7.68-7.95 (m, 2H), 7.64 (broad s, 1H), 8.20 (t, 1H, J=7.8Hz); MS (FAB) m/z530(M*+l). To a stirred solution of ethyl 4-[2-A'-[4-[A'-(2-:fluorophenyI)ureido]-3-methoxyphenyi]-A'-methyl acetamido]ethyl-1 -piperazinylacetate (1.2]g, mixture of DMF) in THF-EtOH (5:1, v/v, 12 ml) was added 4N NaOH (1.0ml, 4,00mmol). The reaction mixture was stirred at rt for 4h, adjusted to pH 7.5 with IN HC1 and extracted with CHCIj-MeOH (4:1, v/v). The combined extracts were dried over MgSO, and concentrated to afforded 328 (78mg, 5% 2steps) as a brown amorphous foam. lR(KBr) n 3299, 2940, 2830, 1704, 1627, 1598, 1536cm"1; 'H-NMR (DMSO) 5 2.36-2.61 (m, 10H), 2.83, 2.98 (each s, total 3H), 3.11 (s, 2H), 3.37-3.43 (m, 2H), 3.62, 3.65 (each s, total 2H), 3.85 (s, 3H), 6.75 (m, 1H), 6.87 (s, 1H), 6.98 (s, 1H), 7.12 (t, 1H,J=7.8H2). 7.20, 7.23 (each d, 2H,y=7.8Hz), 8.01 (d, IH, ./=7.8Hz), 8.17 (t, IH, >7.8H2), 8.72 (s, 1H), 9.19 (s, 1H); MS (FAB) m/i 502 (M*+l); Ami. Calcd for CyiFNjOjHCl-0.50; C, 51.46; H, 6.05; K 12.00. Found: C, 51.08; H, 5.69; N, 11.27. Example 279 3 -fluoro-l-[2-W-methyl-A'-[3 -methoxy-4-[W -(2 -mcthylphenyl)ureido]phenyl) acetamido] ethy 1-4- (35 mL) was added TMSC1 (11.4 mL, 89.7 mmol) and then Et3N (25.0 mL, 179 mmol) dropwise at room temperature, and the reaction mixture was heated at 80 DC for 18 hi. Hexane was added to the reaction mixture, and the resulting mixture was washed with sat. NaHC03 and brine, dried overNa:S04, and concentrated to dryness. Chromatography of the residue with hexane -EtO Ac (5 : 1, v/v) as eluent gave l-rer/-butoxycarbonyl-l,2,3,6-letrahydro-4-(trimethylsilyloxy)pyridine (20.4 g, 99 %) as a yellow oil. 'H-NMR (CDC13) 5 0.19 (s, 9H), 1.46 (s, 9H). 2.05 - 2.15 (m, 2H), 3,48 - 3.56 (m, 2H), 3.83-3.91 (m, 2H), 4.79 (broad s, 1H). To a solution of l-i,er/-butoxycarbonyl-l,2,3,6-tetrariydro-4-(trimethylsily[oxy)pyridirie (20. 4 g, 75.0 mmol) in CH3CN (500 mL) was added Selectfluor™ (29.2 g, 82.5 mmol) at room temperature, and the reaction mixture was stirred for 2 hr, EtOAc was added to the reaction mixture, and the mixture was washed with brine, dried over NajSO«, and concentrated to dryness. Chromatography of the residue with CHCIj-MeOH (6 : 1, v/v) as eluent gave 1-terl- buto)cycarbonyl-3-fluoro-4-pLpi:ridone (14.5 g, 89 %) as a colorless oil. 'H-NMR. (CDC13) S 1.50 (s, 9H), 2.44 (t, J = 6.9 Hz, IH), 2,48 -2,63 (m, 2H), 3.26 (ddd, /= 13.5, 10.5, 3.9 Hz, IH), 3.72 (t, J = 6.9 Hz, 1H), 4,16 (m, 1H), 4,42 (m, 1H), 4.83 (dt, 49.2, 6.9 Hz, IH). To a solution of trielhyi phosphonoacetate (3.72 g, 16.6 mmol) in THF (70 mL) was added lithium bis(Irimeihylsilyl)amide(1.0MTHF solution, 15.5 mL, 15.5 mmol) at -78 °C. After being stirred at the same temperature for 1 hr, l-er/-butoxycarbonyl-3-fluoro-4-piperidone (3.02 g, 13.9 mmol) was added to the reaction mixture. The mixture was stirred for 30 min at the same temperature, quenched by the addition of sat. NH,C1 solution and extracted with EtOAc. The extracts were washed with brine, dried over Na3SOj, and concentrated to dryness. Chromatography of the residue with hexane - EtOAc (8 : 1, v/v) as eluent gave ethyl (1-butoxycarbonyl-3-fluoropiperidin-4-yliden)acetate (3.23 g, 81 %) as a colorless solid. 'H-NMR 6 1.30(t,J=7.1Hz,3H), I.4B(s,9H), 2.10 (m.lH), 2.56 (m, 1H), 2.77 (m, 1H), 3.13 - 3.54 (m, 2H), 3.70 (m, IH), 4.17 4.18 (each q, /= 7.1 Hz, total 2H), 5.82 5.98 (each s, total 1H), 6.41 (each i,J= 46.9 Hz, total IH); MS (FAB) m/z 288 (M*+l). A solution of ethyl (l-butoxycarbonyl-3-fluoropiperidin-4-yliden)acetate (1.32 g, 4.59 nmol) in THF (30 mL) was hydrogenated over Pd-C (TMEDA complex, 66.0 mg) at room emperature for 2 hr under hydrogen atmosphere. The catalyst was filtered off and the filtrate was ;oncentrated to dryness. Chromatography of the residue with hexane-EtOAc (9 :1, v/v) as eluent >ave ethyl l-febutoxycarbonyl-3-fluortM-piperidinylacetate (653 mg, 73 %) as a colorless oil. H-NMR(CDC1,)S 1.26 (1,7 = 7.1 Hz, 3H), 1.45 (s, 9H), 1.53 - 1.79 (m, 2H), 1.92-2.09 (m, !H), 2.31 (dd, J= 16.4, 6.9 Hz, IH), 2.52 (dd,7= 16,4, 7.3 Hz, IH), 2.61 - 3.06 (m, 2H) , 4.14 {q, f = 7,1 Hz, 2H), 4.2* - 4.17 (m, 2H); UC NMR (CDClj) 14.29, 25,80, 28.42, 35.99, 36.20, 60.55, '9.78, 86.72. 88.48, 154.94, 171.93; FAB-MS m/z 290 (M++l). To a solution of ethyl l-/e/T-butoxycarbonyl-3-f]uoro-4-piperidinylacetate (653 mg, 2.26 nmol) in CHiClj (10 mL) was added TFA (5 mL) at 0 °C. After being stirred at room temperature or 4 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCOj ohition and extracted with THF -EtOAc (1 : l,v/v). The extracts were dried over MgSO, and oncentiated to afford ethyl 3-fluoro-4-piperidinylacetate (420 mg, 98 %) as a yellow oil. 'H-NMR CDCL,)S 1.26 (t, J =7.4 Hz, 3H), 1.68- 1.80 (m. 2H), 2.18 (m, IH), 2.32 (dd, J= 16.6, 6.8 Hz, H), 2.54 (dd, J= 16,6, 7.5 Hz, IH), 2.82 (m, IH), 2.90, 3.00 (eachd,./= 14.4 Hz, total IH), 3.31 m, IH), 3.51 (m, IH), 4.15 (q,J= 7.4 Hz, 2H), 4,82, 4.71 (each broad s, total IH). To a solution of ethyl 3-fluoro-4-piperidinylacetate (230 mg, 1.22 mmol) and 2-{N-lerl-butoxy carbonyl-N-methySaminoyacetaldehyde (212 mg, 1.22 mmol) in THF (5 mL) was added NaBH(OAc)j (386 mg, 1.82 mmol) and acetic acid (70.0 mL, 1.22 mmol) at room temperature After being stirred for 24 hr, the reaction mixture was quenched by the addition of sat. NaHC03 solution and extracted with EtOAc. The extracts were washed with brine, dried over Na,C03, and concentrated to dryness. Chromatography of the residue with CHC13 - MeOH (6 : 1, v/v) as eluent gave ethyl 3-fluoro-l-[2-(A'-ferr-biitoxycarbonyl-A'-methylaniino)ethyl]-4-piperidinylacetate (236 mg, 56 %) as a reddish oil. 'H-NMR (CDC13) 6 1.25 (t, J= 7.1 Hz, 3H), 1.45 (s, 9H), 1.53 1.79 (m, 2H), 1.90 - 2.09 (m, 2H), 2.15 (dd, J= 16.4, 7,1 Hz, 1H), 2.45 - 2.58 (m, 2H). 2.87 (s, 3H), 2.90 - 2.99 (m, 2H), 3.20 (m,lH), 3.24 - 3.45 (m, 2H), 4.14 (%J = 7.1 Hz, 2H), 4.61, 4.73 (each broad s, 1H); ESI-MS m/i 347. To a solution of ethyl 3-fluoro-l-[2-(A'-ferr-butoxycarbonyI-Ar-mtthylamino)ethyl]-4-piperidinylaceiate (236 mg, 0.68 mmol) in CH,C13 (10 mL) was added TFA (5 mL) at 0 °C. After being stirred at room temperature for 4 hi, the reaction mixture was concentrated. The residue was taken up with sat. NaHCOj solution and extracted with CHC13. The extracts were dried over MgSOj and concentrated to afford ethyl 3-fluoro-l-[2-(W-methylamino)ethyl]-4-piperidinylacetate (117 mg, 70%) as a reddish oil. 'H-NMR (CDCIJS 1.26 (t,J = 7.1 Hz, 3H), 1.58 (m ,1H), 1.70 (m, 1H), 1.99 (m, 1H), 2.14 (m,lH), 2.27 - 2.33 (m, 1H), 2.47 (s, 3H), 2.48 - 2.56 (m, 4H), 2.72 (t, J= 6.3 Hz, 2H), 2.90 (m, 1H), 3.16 (m, 1H), 4.14 (q, J= 7.1 Hz, 2H), 4.67 (d,/= 48.3 Hz, 1H); ESI-MS mJz 247 (M'+J). To a solution of 3-methoxy-4-IA-(2-methylphenyI)ureido]phenylacetic acid (164 mg, 0.52 mmol), ethyl 3-fluoro-l-[2-(JV-meU)ylamino)ethy]]-4-piperidinylacetate (117 mg, 0.47 mmol), Et3N (0.10 mL, 0.71 mmoO, and HOBl 030 mg, O.09 mmol) in THF (5 mL) was added EDC-HCI (137 mg, 0.71 mmol). After being stirred at room temperature for 8 hr, the reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na,SOj, and concentrated to dryness. Chromatography of the residue with toluene - acetone (1 : 2, v/v) as eluent gave ethyl 3-fIuoro-I-[2-A'-methyI-Ai'-[3-methoxy-4-[//T-(2-mcthylphenyI)ureido] pheny]]acetamido]ethy!-4-piperidmylacetate (160 mg, 62 %) as a yellow amorphous solid. 'H-NMR (CDClj) 6 1.24 - 1.28 (m, 3H), 1.51 - 2.23 (m7H), 2.26 (s, 3H), 2,35 (s, 2H), 2.39 - 2.56 (m, 3H), 2.88 (m, 1H), 2.95,3.03 (each s, total 3H), 3.11 (m, 1H), 3.44 (m, 1H), 3.56 (m, 1H), 3.64 (s,2H), 3.68 (s, 3H), 4.11 -4.17 (m, 2H), 4.57, 4.69 (each s, total 1H), 6.72-6.82 (m, 2H), 7.10-7.33 (m, 5H), 7.54 (d, ./= 8.1 H2, 1H), 8.06 (d, J= 8.1 Hz, 1H); ESI-MS m/z 543 (M*+l). To a solution of ethyl 3-fluoro-l-[2-Ar-methyl-/V-[3-methoxy-4-[Af,-(2-mcthy]phenyI) ureidoJphenyJ]aeetamidD]etbyJ-4-pjperidinvJacet2le (J60 mg, 0.29 nunoi) in THF (3 mL) was added 0.25NNaOH (1.30 mL, 0.32 mmol). After being stirred at room temperature for 1 hi, the reaction mixture was concentrated. The residue was diluted with water and neutralized with IN HC1 at 0 °C. The mixture was concentrated and purified by ion-exchanged resin (HP-20, Mitsubishi Chemical) to give 329 (110 mg, 74%) as a yellow amorphous solid. IR (KBr) 3343, 2937, 1700, 1617, 1589, 1535, I486, 1455, 1417 cm'1; 'H-NMR (CD3OD) 5 1.57 - 1.72 (m ,2H), 1.98 (m, 1H), 2.26 (m, 1H), 2.28 (s, 3H), 2.37 - 2.59 {m, 3H), 2.66 - 2.89 (m, 2H), 2.95, 3.09 (each s, total 3H), 3.14 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 3.59 (m, 1H), 3.71 (s, 2H), 3.78 (m, 1H), 3.89 (s, 3H), 4.69, 4.81 (each s, total 1H), 6.79 (dd, J= 8.1. 1.5 Hz, 1H), 6.90 (broad s, 1H), 7.01(t,y=7.8Hz,lH), 7.13-7.19 (m,2H),7.58(d,J'= 7.8Hz, lH),8.00(d/= 8.1 Hz, 1H)'; ESI-MS m/z 515 (M*+I);-4wo/. Calcd for CHJSFNA-HJO: C. 60.89; H. 7.00; N, 10.52. Found: C, 61.09; H, 6.80; N, 9.87. Example 280 4-[2-A'-(2-(4-fluorophenoxy)ethyl]-A'-[3-methoxy-4-[A'-(2-methylphenyl)ureido]pheny]] fluorophenol (3,07 g, 27.3 mmol) and PPhj (7.83 g, 30.0 mmol) in THF (100 mL) was added DIAD (6.00 mL, 30.0 mmol) at room temperature After being stirred for 3 hr, the reaction mixture was concentrated. Chromatography of the residue with hexane-EtOAc (8 : l,v/v)as eluent gave l-[2-(A'-benzyl-A'-(ert-butoxycarbonylaniiiio)etJioxy]-4-fluoroben2ene (8.19 g, 64 %) as a yellow oil. 'H-NMR (CDCLJS 1.42 - 1.50 (m, 9H), 3.41 - 3.67 (m, 2H), 3.92 - 4.11 (m, 2H), 4.51 - 4.63 (m, 2H), 6.73 - 6.85 (m, 2H), 6.89 - 6,98 (m, 2H), 7.24 (m 5H); FAB-MS m/z 346 (M*+l). To a solution of l-[2-(-benzyl-A'-rert-butoxycarbonylamino)ethoxy]-4-fluorobenzene (8.19 g, 23.7 mmol) in CHjCl, (50 mL) was added TFA (40 mL) at 0 °C. After being stirred at room temperature for 1 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCOj solution and extracted with CHC13. The extracts were washed with brine, dried over NajSOj, and concentrated to give l-(2-JV-berizylaminoetrjoxy)-4-fliiorobenzene (4.38 g, 75 %) as a reddish oil. 'H-NMR (CDCyS 3.00 (t, J = 5.2 Hz, 2H), 3,87 (s, 2H), 4.04 (I, J = 5.2 Hz. 2H), 6.80 - 6.85 m, 2H), 6.92 - 6.98 (m, 2H), 7.23 - 7.36 (m, 5H); FAB-MS m/z 246 (M++l). A mixture of l-(2-Af-benzylaminoethoxy)-4-fiuorobenzerie (1.08 g, 4.40 nunol), ethyl 4-(2-bromoelhyl)piperazinyl-l-acetate (1.23 g, 4.40 mmol), and KjCO, (0.61 g, 17.9 mmol) in CHjCN (50 mL) was heated under reflux for 8 hr. The resulting mixture was filtered and the filtrate was concentrated to dryness. Chromatography of the residue with loluene- acetone (3 : 1, v/v) as eluent gave ethyl 4-[2-W-benzyl-A'-[2-(4-fluorophenoxy)ethyl]ainino]ethylpiperazinyl-l-acetate(1.51 g, 77 %) as a reddish oil. 'H-NMR (CDC13)5 1.27 (t, .7=7.1 Hz, 3H), 2.31 -2.66 (m, 10H), 2.75 (t,y = 6.6 Hz, 2H), 2.90 (i,J= 6.1 Hz, 2H). 3.18 (s, 2H), 3.72 (s, 2H), 3.97 (t, J = 6.1 Hz, 2H), 4.17 (q, 7 = 7.] Hz, 2H), 6.75 - 6.79 (m, 2H), 6.91 - 6.96 (m, 2H), 7.21 - 7.35 (m, 5H); FAB-MS m/z 444 (M*+l). A solution of ethyl 4-[2-A'-beii2yl-A'-[2-(4-fluorophenoxy)ethyl]anu"no]cthy]piperazinyI-I-acetate (1.50 g, 3.38 mmol) in EtOH (30 mL) was hydrogenated over 5 %Pd-C (53.1 % wet, 0.73 g) under hydrogen atmosphere for 4 hx. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up with sat. NaHCOj solution and extracted with CHC1}. The extracts were washed with brine, dried over Na,S04, and concentrated to afford ethyl 4-[2-//-[2-(4-fluoTOphenoxy)cthyl]amino]ethylpiperazinyI-l-acetate (1.12 g, 94%) as a reddish oil, 'H-NMR (CDCy 5 1.27 (t, J= 7.1 Hz, 3H), 1.81 (broad s, 1H), 2.47-2.66 (m, 12H), 3.00 (t, J" 5.4 Hz, 2H), 3.20 (s, 2H), 4.03 (t, J= 5.4 Hz, 2H), 4.18 (q. J= 7.1 Hz, 2H), 6.81 - 6.85 (m, 2H), 6.90 - 6.99 (m, 2H); FAB-MS m/z 354 pvT+l). To a solution of 3-methoxy-4-[An-(2-methylphenyl)ureido]phcnylacetic acid (485 mg, 1.54 mmol), ethyl 4-[2-A,-[2-(4-fluorophenoxy)ethyl]amino]ethylpiperaziiryl-l-acetate (545 mg, 1.54 mmol), EtjN (0.32 mL, 2.32 mmol), and HOBt (41.5 mg, 0.31 mmol) inTHF (15 mL) was added EDOHC1 (883 mg, 2.32 mmol) at room temperature After stirring for 24 hr, the reaction mixture was diluted with waterand extracted with CHClj-MeOH (10 : l,v/v). The extracts were washed with brine, dried over Na;S04, and concentrated to dryness. Chromatography of the residue with CHC13 - MeOH (4 : 1, v/v) as eluent to give ethyl 4-[2->/.[2-(4-fluorophenoxy)ethyl]-W-[3-methoxy-4-[W'-(2-methylphenyl)ureido]phenyl]acetamido]ethylpipera2inyl-l-acetate(532 mg, 53 %) as a yellow amorphous solid. 'H-NMR (CDClj)5 1.26, 1.27 (each t,J= 7.1 Hz, total 3H), 2.27 (s, 3H), 2.51-2.63 (m, 10H), 3.16, 3.19 (each s, total 2H), 3.51 -3.56 (m, 2H), 3.63, 3.67 (each s, total 2H), 3.69 - 3.81 (m, 5H), 3.95, 4.10 (each t, J= 5.2 Hz, total 2H), 4.16, 4.18 (each q, J = 7.1 Hz, total 2H), 6.56 (d, J = 8.1 Hz, 1H), 6.72 - 6.78 (m, 4H), 6.89 - 6.98 (m, 2H), 7.12 (t, J=7.6Hz, ]H), 7,20-7.23 (m,3H), 7.51 (d,J=7.6Hz, 1H), 8.04 (d, ./= 8.1 Hz, 1H); FAB-MS m/2 650 (W+l). To a solution of elhyU-[2-A'-[2-(4-fluorophenoxy)ethy]]-W-[3-methoxy-4-[//'-(2-methylphenyl) ureido]pheriyl]acetainido]ethylpiperazinyl-l-acetate (532 rag, 0.82 mmol) in dioxane (8 mL) was added dropwise 0.25N NaOH (5.00 mL, 1.25 mmol) at room temperature, and the reaction mixture was stirred for 1 hr. The resulting mixture was concentrated, diluted with water, and neutralized with IN HC1 at 0 DC. The mixture was extracted with CHClj - MeOH (4 : 1, v/v). The extracts were washed with brine, dried over NaiSO,, and concentrated to dryness. Chromatography of the residue with CHC13- MeOH (3 : 1, v/v) aseluentgave 330 (16Smg, 33 %) as a pale yellow amorphous solid. K(KBr) 3338, 2938, 2829,1635, 1533, 1506, 1454,14\ 5 cm'1; 'H-NMR (DMSO-4J}5 2.25 (s, 3H), 2.37 - 2.48 (m, 6H), 2.53 - 2.67 (m, 6H), 3.09 (m, 2H), 3.44 - 3.49 (m, 2H), 3.64 - 3.69 (m, 2H), 3.72 (s, 2H), 3.80, 3.84 (each s, totat 3H), 4.06 - 4.09 (m, 2H), 6.73 (m, IH), 6.85 (s, IH), 6.91 - 6.97 (m ,3H), 7.07 - 7.18 (m, 4H), 7.78 (d,J= 8.1 Hz, IH), 8.00 (dd,y= 8.1, 2.7 Hz, IH), 8.53 (m, IH), 8.59 (m, 1H); FAB-MS mti 622 (M*+l); «a/. Calcd for CJJHFNJOHCI: C, 57.06; H, 6.09; N, 10.08. Found: C, 56.83; H, 6.05; N, 9.90. Eiample 281 4-[2-/V-[2-(4-acetyiphenoxy)ethyl]-/i/-[3-methoxy-4-[Ar.(2.niethylphenyl)ureido]phenyl] hydroxyacetophenone (3.18 g, 23.5 mmol) and PPh, (6.74 g, 25.8 mmol) in THF (100 mL) was added DIAD (5.20 mL, 25.8 mmol) at room temperature The reaction mixture was heated under reflux for 4 hr and concentrated. Chromatography of the residue with hexane - EtOAc (5:1, v/v) as eluent gave 4-[2-(/-berr2yl-//-(er/-butoxycaibonylarnino)ethoxy]acetophcnone (3.64 g, 42 %) as a yellow oil. 'H-NMR (CDC1,) 5 1.43 -1.65 (m, 9H), 2.55 (s, 3H), 3.41 - 3.69 (m, 2H), 4.02 - 4.24 (m, 2H), 4.49 - 4.66 (m, 2H), 6.81 - 6.93 (m, 2H), 7.19 - 7.37 (m, 5H), 7.91 (d, J" 8.8 Hz, 2H); FAB-MS m/z 370 (M*+l). To a solution of 4-[2-(W-benzyl-A'-/er(-butoxycarbonylamino)ethoxy]acetophenone (3.05 g, 8.26 mmol) in CHjClj (30 mL) was added TFA (20 mL) at 0 °C. After being stirred at room temperature for 2 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCO, solution and extracted with CHC13. The extracts were washed with brine, dried over Na:SC\, and concentrated to give 4-(2-tf-benzy!ammoethoxy)acetophenone (2.21 g, 99 %) as a reddish oil. 'H-NMR (CDCh) 5 2.04 (broad s, 1H), 2.55 (s, 3H), 3.05 (t, J- 5.4 Hz, 2H), 3.88 (s, 2H), 4.15 (t, J= 5.4 Hz, 2H), 6.92 (d, J= 8.9 Hz, 2H), 7.24 - 7.36 (in, 5H), 7.91 (d, / = 8.9Hz, 2H); FAB-MS m* 270 (M*+l). To a solution of eihyl 4-(2-hydroxyeth>'i)piperazinyl-l-2cetate (11.3 g, 52.] mmol) and CBu (20.7 g, 62.5 mrnol) in CH,C1, (200 mL) was added PPh3 (19.2 g, 73.0 mraol) portionwise at 0 BC and the reaction mixture was stirred for 30 min. Hexane was added to the mixture, the precipitates were filtered off, and the filtrate was concentrated lo afford ethyl 4-(2-bromocthyl) piperazinyl-1-acetate (13.7 g, 94 %) as a yellow oil. 'H-NMR (CDClj)5 1.27 (t, J = 7.1 Hz, 3H), 2.61 - 2.78 (m, SH), 2.81 (t, J= 7.6 Hz, 2H), 3.20 (s, 2H), 3.42 (t, J= 7.6Hz, 3H). 4.18 (q, J = 7.1 Hz, 2H). A mixture of 4-{2-A'-benzylaminocthoxy)acetophenone (681 nig, 2.52 mmol), ethyl 4-(2-bromoethyl)piperazinyl-l-acetate (705 mg, 2.52 mmol), andKiCOj (349 g, 2.52 mmol) in CH3CN (10 mL) was heated under reflux for 22 hr. The resulting mixture was filtered and the filtrate was concentrated to dryness. Chromatography of the residue with toluene -acetone (I : l,v/v)as eluent gave ethyl 4- [2 -[M-benzyl -Af-[2-(4-acetylphenoxy)ethyl] amino] ethylpiperaziny 1-1 -acetate (920 mg, 78 %) as a reddish oil. 'H-NMR (CDCI,) 8 \.n (t, J= 7.1 Hz, 3H), 2.45 - 2.53 (m, 10H), 2.55 (S, 3H), 2.76 (t, J= 6.8 Hz, 2H), 2.94 (t,7= 6.1 Hz, 2H), 3.18 (s, 2H), 3.73 (s, 2H), 4.06 (£, J= 6.1 Hz, 2H), 4.17 (q,J=7.1 Hz, 2H), 6.85 (d,J= 7.1 Hz, 2H), 7.22-7.35 (m, 5H), 7.90 (d, J = 7.l.Hz, 2H); FAB-MS m/z 468 (M'+l). A solution of ethyl 4-[2-[W-benzyl-A'-[2-(4-acetylphenoxy)ethyl]amino]eihylpiperazinyl-l-acetate (920 mg, 1.97 mmol) in EtOH (30 mL) was hydrogenated over 5 % Pd-C (53.1 % wet, 510 mg) under hydrogen atmosphere for 4 hr. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up with sat. NaHCOj solution and extracted with CHClj. The extracts were washed with brine, dried over NajSOj, and concentrated to afford ethyl 4-(2-JV-[2-(4-acetyl phenoxyjethyl]amino]ethylpiperazinyl-1 -acetate (690 mg, 93%) as a reddish oil. 'H-NMR (CDClj) 5 1.27 (t, /= 7.1 Hz, 3H), 2.55 (s, 3H), 2.46-2.54 (m, 10H), 2.78 (t, J= 6.2 Hz, 2H), 3.04 (t, J = 5.2 Hz, 2H), 3.20 (s, 2H), 4.13 (I, J* 5.2 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 6.92 (d, J = 8.8 Hz. 2H), 7.92 (d, J = 8,8 Hz, 2H); FAB-MS m/z 378 (M-+l). To a solution of 3-methoxy-4-{A-(2-methylphenyI)ureido]phenyIacetic acid (558 mg, 1.77 mmol), ethyl 4-[2-rV-[2-(4-acetylphenoxy)ethyl]amino]ethylpiperazinyl-l-acetate (67Q mg, 1.77 mmol), Et3N (0.38 mL, 2.66 mmol), andHOBt (50.0 rag, 0.35 mmol) inTHF (10 mL) was added EDC'HC! (883 mg, 2.32 mmol) at room temperature After stirring for 15 hr, the reaction mixture was diluted with water and extracted with CHClj-MeOH (10 :1, v/v). The extracts were washed with brine, dried over NajSO* and concentrated to dryness. Chromatography of the residue with CHClj - MeOH (4 : ], v/v) as eluent to give ethyl 4-[2-A'-[2-(4-acetylphenoxy)ethyl]-//-[3-rnethoxy-4-[//,-(2-methylphenyl}ureido]phenyl]acetamido]ethylpiperaziriyl-l-acetate(724 mg, 61 %) as a yellow amorphous solid. 'H-NMR (CDC13) 5 1.25, 1.27 (each t, J= 7.1 Hz, total 3H), 2.29 (s, 3H), 2.45 - 2.5J (m, 8H), 2.54 (s, 3H), 2.55 - 2.63 (m, 2H). 3.17, 3.19 (each s, total 2H), 3.51 - 3.55 (m, 2H), 3.60 (s, 2H), 3.69 (s, 3H), 3.71 - 3.78 (m, 2H), 4.04 - 4.23 (m, 4H), 6.47 (m, 1H, .7=8.1 Hz), 6.72-6.76 (m. 2H), 6.85 (d, J= 8.8Hz,2H), 7.12-7.19 (m, 2H), 7,20 - 7.24 (m, 2H), 7.51 (d, 8-1 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 8,04 (d, J = 8.1 Hz, 1H); FAB-MS m/z674(M*+l). To a solution of ethyl 4-[2-tf-[2-(4-acetylphenoxy)cthyl]-M[3-rnethoxy-4-[jV'-(2-methylphenyl) ureido] phenyl] acetamido] ethyl piperasinyl-1 -acetate (724 mg, 1.07 mmol) in THF (10 mL) was added dropwise 0.25N NaOH (6.50 mL, 1.61 mmol) at room temperature, and the reaction mixture was stirred for 1 hr. The resulting mixture was concentrated, diluted with water, and neutralized with lNHClat0°C. The mixture was extracted with CHC13-MeOH (4 : l,v/v). The extracts were washed with brine, dried over NajSO,, and concentrated to dryness. Chromatography of the residue with CHClj - MeOH (3 : 1, v/v) as eluent gave 331 (450 mg, 65 %) as a pale yellow amorphous solid. IR(KBr) 3345,2938, 2821,1673,1631, 1598,1533, 1455, 1417 cm'1; 'H-Jflvffi. (DMSO-rf*) 5 2.25 (s, 3H), 2.35 - 2.47 (m, 8H), 2.51 (s, 3H), 2.53 - 2.58 (m, 2H), 2.96 (s, 2H), 3.46 - 3.50 (m, 2H), 3.69 (s, 2H), 3.73 - 3.77 (m, 2H), 3.80, 3.83 (each s, total 3H), 4.19 - 4.22 (m, 2H), 6.73 (m, 1H), 6.85 (s, 1H), 6.92 (t, J= 7.3 Hz, 1H), 7.30 (d, J = 7.3 Hz, 2H), 7.10-7.16 (m,2H), 7.79 (d,y= 8.3 Hz, 1H), 7.90 - 7.95 (m, 2H), 8.00 (l,J= 8.3 Hz, 1H), 8.55 (m, 1H). 8.61 (m, 1H); FAB-MS m/z 646 (NT+1); Anal. Calcd for C„H„NjO,'2HCHH20: C, 57,06; H, 6,43; N, 9.51. Found: C, 59,17; H, 6.32; N, 9.61. Example 282 4-[2-Ar-[4-[Ar-(2-bromophenyl)ureido]3-methoxyphenyl]-A,-benzylacetamido]ethyl-l- 77.6 mmol) and K1CO3 (25.4 g, 155 mmol) in CH3CN (200 ml) was healed under reflux with stirring for 2 h. The insoluble solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was poured into ice cooled 1W-HC1 and extracted with CHClj. The organic layer was washed with water, drying over anhydrous NajSO*, and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give benzyl 4-(2-hydroxyethyl)-l-piperidinylacetate (16.3 g, 76%) as a colorless oil. 'H-NMR (CDC13)5 1.31-1.40 (m, 3 H), 1.52 (dd, J" 12.8, 6,3 Hz, 2H), 1.68 (brd, J= 10.0 Hz, 3 H), 2.16 (t, J= 11.6 Hz, 2 H), 2.92 (brd, J = 11.6 Hz, 2 H), 3.24 (s, 2 H), 3.69 (t, J= 6.8 Hz, 2 H), 5.16 (s, 2 H), 7.35 (m, 5 H). To a stirred solution of benzyl 4-(2-hydroxyethyl)-l-piperidinylacetate (14.9 g, 53.8 mmol) in CH;C12 (150 ml) was added EtjN (37,5 ml, 269 mmol) andDMSO (41.6 ml, 538 mmol). The reaction mixture was cooled to 0 °C and SOjPy (25.7 g, 161 mmol) was added portion wise, and the resulting mixture was stirred at rt overnight. The mixture was concentrated in vacuo, and the residue was diluted with water, followed by extracted with EO. The organic layer was washed with water, dried over anhydrous Na,C03 and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc-hexane (2 : 1) as eluent to give (4-rV-carbobenzyloxy metbyjpiperidinyl)acetaldehyde (4.63 g, 31%) as a colorless oil. 'H-NMR (CDClj) 5 1.36-1,46 (m, 2H), 1,69 (brs, 2 H), 1.72 (brs, 1H), 1.90 (m, 1 H),2.21 (dt, J" 11,6,2.4 Hz, 2 H), 2.37 (dd, J = 6.8, 1.6 Hz, 2 H), 2.92 (d, J= 11.6 Hz, 2 H), 3.25 (s, 2 H), 5.16 (s, 2 H), 7.35 (ro, 5 H), 9.77 {t, J = 2.0 Hz, 1H). To a stirred solution of A'-benzylamine (1.06 ml, 9.75 mmol) in MeOH (20 ml) was added AcOH (560 ml, 9.75 mmol) and (4-Af-carbobenzyloxymethylpiperidiny])acetafdehyde (1.79 g, 6.50 mmol) in MeOH (5 ml) and cooled to 0 °C. NaBHCN (645 mg, 9.75 mmol) was added in one portion, and Ihe resulting mixture was stirred overnight at rt. The mixture was concentrated in vacuo, and the residue was poured into aq.NaHCOj, then extracted with CHClj, The organic layer was washed with water, dried over anhydrous NaiSOj and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH-EtOAc (10:1:1) as eluent to give N-bertzyl-2-[4-(A,-carbobenzyloj(TmethyJpiperidJnyl)]etJiy]amine (872 mg, 37%) as a colorless oil. 'H-NMR (CDCy 6 1.36-1.46 (m, 2 H), 1.69 (brs, 2 H), 1.72 [brs, 1 H), 1.90 (m, 1 H), 2.21 (it, J = 11.6, 2.4 Hz, 2 H), 2.37 (dd, ./= 6.8, 3.6 Hz, 2 H), 2.92 (d, J= 11.6 Hz, 2 H), 3.25 (s, 2 H), 5.16 (s, 2 H), 7.35 (m, 5 H), 9.77 (t, 7 = 2.0 Hz, 1 H). To a stirred solution of A,-beuzyl-2-[4-{//-carbobenzylox3TnethylpiperidinyI)]ethylamine (356 mg, 0.972 mmol), 4-[Ar'-(2-brornophenyl)ureidoJ-3-inethoxyphenyJacetJc acid (369 mg, 0.972 mmol) andiV-dimcthylaminopyridine (119 mg, 0.972 mmol) in DMF (15 ml) was added EDCHCI (372 mg, 1.94 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous NajSOj, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCIj-MeOH (10 : 1) as eluent to give benzyl H2-W-[4-[W-(2-bromophenyl )ureido]3-methoxyphcnyl3-Ar-benzylacetamido]eihyI-l-piperidinylacetate (611 mg, 86%) as a colorless oil. 'H-NMR (CDClj) mixture of rotamars 5 1.15-2.09 (series of m, 7 H), 2.06-2.14 (m, 2 H), 2.84-2.96 (m, 2 H), 3.17-3.23 (s, total 2 H), 3.21 and 3.23(s, total 2 H), 3.38-3.42 (m, 1 H), 3.65 and 3.73 {s, total 2 H), 3.83 and 3.84 (s, total 3 H),4,49 (s, 1 H), 4.60 (s, 1 H), 5.15 d, J= 2.8 Hz, 2 H), 6.74-7.83 (series of m, 16 H), 7.51-7.53 (m, 1 H), 7.94-8.02 (m, 1 H), 8.18 (d, J= 8.4 Hz, 2 H); MS (FAB) m/z 727 (M*), 729 0+2). To a stirred solution of benzyl 4-[2-#-[4-[?vn-(2-bromophenyl)uieido]3-methoxyphenyl]-W-benzylacetamido] ethyl-1-piperidinylacetate (347 mg, 0.477 mmol) in MeOH-H}0 (5:1,6 ml) was added LiOH (13.6 mg, 0.57 mmol) at rt, and the resulting mixture was stirred for overnight. The reaction mixture was poured into water and the solution was neutralized with aq.ltf-HCl, then extracted with CHCla. The organic layer was washed with brine and dried over anhydrous Na3SOip then concentrated in vacuo. The residue was chromatographed on silica gel with CHClj-MeOH (10 : 1) as eluent to give 332 (97.3 mg, 32%) as a colorless amorphous solid, and 333 (168 mg, 54%) as a colorless amorphous solid, respectively. 332 'H-NMR (CDOD), mixture of rotamars 6 1.29-1.90 (series of m, 7 H), 2.75-2.86 (m, 2H), 3.28-3.51 (series of m, 6 H), 3.74 and 3.78 (s, total 2 H). 3.87 and 3.89 (s, total 3 H), 4.66 (s, 1H), 4.85 (s, 1 H). 6.79-7.00 (series of m, 3 H), 7.16 (d, J= 7.2 Hz, 1 H), 7.23-7.37 {m, 5 H), 7.57 (dd, J= 8.4, 1.2 Hz, 1 H), 7.88-8.00 (series of m, 2 H); MS (FAB) m/z 637 (M*), 639 (M*+2). 333 'H-NMR (CDC13), mixture of rotamars S 1.15-2.11 (series of m, 7 H), 2.89-2.97 (m, 2 H), 3.17-3,49 (series of m, 6 H), 3.17 and 3.18 (s, total 3 H), 3.70 and 3.71 (s, total 3 H), 3.83 and 3.84 (s, total 2 H), 4.49,4.60 and4.71 (s. total 2 H), 6.75-8.16 (series of m, 14 H); MS (FAB) mh 651 (M*), 653 (M*+2). Example 283 4-[2-N-[4-[//'-(2-chlorophenyl)-3 -methoxyiireido] phenyl ]-M-benzylacetamido] ethyl-1 -piperidinyl (372 mg, 1.11 mmol), 4-N-(2-chlorophenyl)urcido]-3-methoxypheiiyl]acctic acid (758 mg, 1.11 rnmol) and ///-dimethylaminopyiidine (136 mg, 1.11 nunol) in DMF (15ml) was added EDCHC1 (426 mg, 2.22 rnmol) at rt, and the resulting mixture was stirred for 12 h. The reaction mixture was poured into water and extracted with EtO Ac. The organic layer was washed with brine and dried over anhydrous NaiSO(, then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10 :1) as eluent to give benzyl 4-I2-//-[4-|W'-(2-chlorophenyl)-3-methoxyureido]phenyl]-W-benzylacetamido]ethyl-l-piperidinylacetate (668 mg, 88%) as a pale yellowish oil. 'H-NMR (CDCtj) mixture of nrtamars5 1.15-183 (series of m, 7 H), 2.04-2.13 (m, 2 H), 2.83-2.95 (m, 2 H), 2.88 and 2.99 (s, total 2 H), 3.20 and 3.23 (s, total 2 H), 3.20-3.23 (overlap, 1 H), 3.38-3.42 (m, 1 H), 3.65-3.74 (m, 3 H), 4.50 (s, 1H), 4.61 (s, 1 H), 5.14 (d, J= 4.4 Hz, 2 H). 6.72-6.82 (series otm, 2 H), 6,94-6.99 (m, 1 H), 7.13-7.50 (series of m, 14 H), 7.94-8.02 (m, 1H), 8.18(d,/=8.0Hz,2H);MS(FAB)mi683(MN-H). To a stirred solution of benzyl 4-[2-Mf4-[A"-(2-chiorophenyI)-3-methoxyureido]phenyI]-A,-benzylacetanudo]ethyl-l-piperidinylacetate (633 mg, 0.93 rnmol) in MeOH-H30 (10 : 1,10 ml) was added LiOH (24.4 mg, 1-02 rnmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and the solution was neutrallized with aq. 1M-HC1, then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na3SO,, then concentrated in vacuo. The residue was chromato graphed on silica gel with CHCl3-MeOH (20 : 1) as eluent to give methyl 4-[2-W-[4-[A-(2-chlorophenyl)-3-methoxyureido]phenyl]-A'-benzylacetamido]ethyM-piperidmy]acetate (504 mg, 89%) as a colorless amorphous solid. 'H-NMR(CDC13), mixture of rotamars 6 1.26-1.64 (series of m, 7 H), 2.02-2.10 (m, 2H), 2.86 (t, J = 10.4 Hz, 2 H), 3.17 (d,y= 8.0Hz, 2 H), 3.16-3.22 (m, overlap, 1 H), 3.40 (:,-/■= 7.6 Hz, 1 H), 3.48 (s, 1 H), 3.65 and 3.73 (s, total 2 H), 3.70 and 3.71 (s, total 3 H), 3.79 and 3.80 (s, total 3 H), 4.50, 4.60 and 4,70 (s, total 2 H), 6,73-6.85 (series of m, 2 H), 6.98 (t, J= 7.6 Hz, 1 H), 7.13-7.37 (series of m, 9H), 7.96 (m, 1 H), 8.18 (d, J=* 8.0 Hz,2H); MS (FAB) m/z 607 (M*+H). To a stirred solution of methyl 4-]2-A'-[4-I//*-(2-chlorophenyl)-3-methoxvureido]phenyl]-W-benzylacetamidoJethyl-l-piperidinylacetate (177 mg, 0.292 rnmol) in MeOH-HjO (5:1,6 ml) was added LiOH (21.6 mg, 0.90 mmol), and the resulting mixture was stirred for 4 hatrt The mixture was poured into water, and the solution was neutralized with aq. 1W-HC1, then extracted with CHClj. The organic layer was washed with brine and dried over anhydrous Na,SO* then concentrated to yield 334 (155 mg, 92%) as a colorless amorphous solid. 'H-NMR (CDjOD) mixture ofrotamars 5 1.28-1.90 (series of ro, 7 H), 2.84 (brs, 2 H), 3.30-3.52 (series of m, 6 H), 3.74 and 3.82 s, total 2 H), 3.87 and 3.88 (s, total 3 H), 4.63 (s, 1 H), 4.66 (s, 1 H), 6.79-7.05 (series of m, 3 H), 7.16 (d, J= 7.2 Hz, 1 H), 7.24-7.40 (m, 5 H), 7.88 (s, 1 H), 7.98-8.04 (series of m, 2 H); MS (ESI) m/i 593 (M*), 615 (M*4-Na*). It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of general principles, and the invention is not necessarily limited thereto. Modifications and variations in any given material or process step will be readily apparent to those skilled in the an without departing from the true spirit and scope of the following claims, and all such modifications are included within the scope of the present invention. We claim: 1. A compound represented by Formula (I), or a salt thereof, wherein W is an unsubstituted phenyl group or a substituted phenyl group having one to five substituents selected independently from the group comprising C1-Cs-alkyl, halogen atom, C1-C4-aIkoxy, -OH and -CF3; W' is an unsubstituted phenylene group or a substituted phenylene group having one to four substituents selected independently ftom the group comprising C1-C6-alkyl, C|-C4-alkoxy and halogen atom; A is =0; R is -(CH2V, wherein n is 1 or 2; X is -C(0)-; M is is a divalent pyrrolidine, thiazolidine or morpholine moiety, wherein the nitrogen atom is the point of attachment to X; R', R^ and R^ are independently -H, -OH, -NH2, halogen atom, an unsubstituted C1-Cs-alkyl group, phenyl-C|-C4-alkoxy-substituted C1-C6-alkyl group, a phenyl group, a C1-C4alkoxy group, a niono-C|-C6-alkyiamino group, a di-C1-Cfi-alkylamino group, a CrCe-alkylsulfonylamino group, an unsubstituted phenyisulfonylamino group, a C1-Cs-alkyl- substituted phenylsulfonylamino group, an unsubstituted naphthylsujfonylamino group, a di-C1-Cft-alkylamino-substituled naphthylsulfonylamino group, an unsubstituted phenoxy group, a substituted phenoxy group having a substituent selected Irom the group comprising carboxy and halogen, a naphthyloxy group, a quinolinyloxy group, or two of R', R^ and R^ taken together form an unsubstituted C1-Cs-alkylenedio)^ group, a substituted C1-Cj-alkylenedioxy group having from 1 to 3 substituents selected independently from C1-Ct-alkyl, an unsubstituted 3-, 4-, 5-, 6-, or 7-menibered carbocyclic residue or a substituted 3-, 4-, 5-, 6-, or 7-membcred carbocyclic residue having from 1 to 3 substituents selected independently from 1 to 3 substituents selected independently from C1-Cfi-alkyl; R* is -H or a C1-Ce-alkyt group; Y is a direct bond or a divalent radical selected from the group comprising -C(0)-, -C(0)NH-, a C2-C6-alkenylene group, a C2-C6-alkynylene group and -(CH2)kY^-, wherein k is 0, 1,2 or 3; and Y^ is a direct bond or a divalent radical selected from the group comprising -0-, -S-, -S(0)-, -S(0)2- and -NY^-, wherein Y' is -H or a C1-Cjo-alkyI group; Z is an unsubstituted phenylene group, a substituted phenylene group having a substituent selected the group comprising carboxy, C|-C4-alkoxy, halogen, -NOj, -NH2, C|-C6-aIkyl, di-C1-Cfi-alkytamino and CrCc-alkanoytamino, a n^hthylene group, an unsubstituted heterocyclylene group, a heterocyclylene group substituted witii caiboxy or halogen, wherein a heterocyclylene group is selected from piperidinylene, pyridinylene or piperazinylene, or a C3-C7-cycloalkylene group; A' is a direct bond or -(CHj),-, wherein t is 1, 2 or 3; and R' is -OH or C1-C,-alkoxy group, ; or 2. The compound as claimed in claim I, or salt thereof, wherein W is an unsubstituted phenyl group or a substituted phenyl group having one to five substituents selected independently from the group comprising C1-C^-alkyl group and halogen stem at the ortho positions thereof 3. The compound as claimed in claim 2, or a salt thereof, wherein W' is an unsubstituted phenyl group or a substituted phenylene group having a substhuent selected from Xhe group comprising methoxy, C1-Cfi-alkyl group and halogen stom at the ortho position to the -NH thereof 4. The compound as claimed in claim 3, or a salt thereof, wherein W' is substituted phenylene group having a substituent selected from group comprising methoxy, C1-Cs-alkyl group and halogen atom at the ortho position to the -NH thereof 8. The compound as claimed in claim 6, or a salt thereof, wherein at least one of R', R^ and R^ is -OH or halogen. 9. The compound as claimed in cJaim 6, or a salt thereof, wherein Y is a Cj-Ce-alkenylene group, a Cj-Cs-allQTiylene group or -(CHjJiiY^-, wherein Y^ is a direct bond, -0-, -S(0)-, or -NV'- and Y^ is -H. 10. The compound as claimed in claim 9, or a salt thereof, wherein Y^ is -O- or -NH-. 11. The compound as claimed in claim 6, or a salt thereof, wherein R* is -H. 12. The compound aS claimed in claim 6, or a salt thereof, wherein A' is a direct bond. 13. The compound aS claimed in claim 12, or a salt thereof, wherein R^ is OH. 14. The compound as claimed in claim 12, or a salt thereof, wherein Y is -CHjO-; and Z is an unsubstituted phenylene group, a substituted phenylene group having a substituent selected firom the group comprising carboxy, C|-C4-alkoxy, halogen, -N02, -NHj, CpCfi-alkyl, di-C1-Cj-alkylamino and C1-Ce-alkanoylamino, an unsubstituted heterocyclylene group, a substituted heterocyclylene group having a substituent selected from the group comprising carboxy and halogen, wherein a heterocyclylene group is selected from piperidinylene, pyridinylene or piperazinylene, or a Ca-CT-cycloalkylene group. 15. The compound as claimed in claim 6, or a salt thereof, wherein R' is C1-C4-alkoxy group.

Documents:

in-pct-1784.rtf

in-pct-2001-1784-che abstract.pdf

in-pct-2001-1784-che assignment.pdf

in-pct-2001-1784-che claims.pdf

in-pct-2001-1784-che correspondence others.pdf

in-pct-2001-1784-che correspondence po.pdf

in-pct-2001-1784-che description (complete)-1.pdf

in-pct-2001-1784-che description (complete)-2.pdf

in-pct-2001-1784-che description (complete)-3.pdf

in-pct-2001-1784-che description (complete)-4.pdf

in-pct-2001-1784-che description (complete)-5.pdf

in-pct-2001-1784-che description (complete)-6.pdf

in-pct-2001-1784-che description (complete)-7.pdf

in-pct-2001-1784-che description (complete)-8.pdf

in-pct-2001-1784-che description (complete).pdf

in-pct-2001-1784-che form-1.pdf

in-pct-2001-1784-che form-13.pdf

in-pct-2001-1784-che form-18.pdf

in-pct-2001-1784-che form-26.pdf

in-pct-2001-1784-che form-3.pdf

in-pct-2001-1784-che form-5.pdf

in-pct-2001-1784-che form-6.pdf

in-pct-2001-1784-che pct search report.pdf

in-pct-2001-1784-che pct.pdf

in-pct-2001-1784-che petition.pdf