NO324892B1 - VLA-4 inhibitor compounds, their use as well as pharmaceutical preparation - Google Patents

Description

The present invention relates to compounds that selectively inhibit the binding of ligands to the adhesion receptor, α4Px integrin, also known as VLA 4. The compounds according to the 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 metastases.

The invention also relates to the use of a compound according to the invention as well as a pharmaceutical preparation comprising a compound according to 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 trans-migrate from the circulation to a site of inflammation involves a cascade of interactions that can be divided into four main steps: anchoring and rolling, activation, solid/stable adhesion, and transmigration (Springer, T., Ann.Rev.Physiol., 57 :827 (1995)). Initially, leukocytes are loosely anchored 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 more solid bond between individual leukocytes and endothelial cells.

The solid bond then results in the successful one

adhesion and transmigration of the leukocytes through endothelial-cell junctions. The steps occur in series and each step is essential for the 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 largely 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. Stable 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 immunoglobulin-type adhesion molecules are also primarily involved in leukocyte transmigration. After transmigration, leukocytes depend on integrins to cross through the extracellular matrix and remain at the site of inflammation.

Integrins are a large family of heterodimeric glycoproteins comprising two non-covalently associated subunits, α and β (Hynes, R., Cell, 69:11 (1992)). There are at least 16 different a subunits (a1-"a9, aL, aM, aD, ax, aE, aIIb, av) and at least 9 different p (P1-p9) subunits. Integrins are divided into subfamilies based on the p subunit. Leukocytes express a number of different integrins that include α4P1,α5β1,α6β1,α4β7, αLβ2,axβ2 and <<x>v<p>3.

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)). α4Pi integrin serves as a receptor for vascular cell adhesion molecule-1 (VCAM-1), as well as the extracellular protein fibronectin (FN) (Elices et al., Cell, 60:577 (19'90)). Anti-inflammatory effects and delayed disease progression have been demonstrated following in vivo monoclonal antibody blockade of the o^Pi/VCAM-1 pathway (Lobb et al., J.Clin.Invest., 94:1722-28 (1994)). In a guinea pig model of pulmonary inflammation, anti-α4 inhibited both antigen-induced bronchial hyperreactivity and leukocyte influx into bronchoalveolar lavage fluid (Pretolani et al., J.Exp.Med., 180:795 (1994)). Antibodies against α4 or VCAM-1 prevented antigen-induced eosinophilic infiltration of mouse trachea (Nakajima et al., J.Exp.Med., 179:1145 (1994)). cc4 or VCAM 1 monoclonal antibody treatment also delayed or prevented cutaneous-induced hypersensitivity responses in mice and monkeys (Chrisholm et al., Eur.J.Immuol., 23:682 (1993); Silber et al., J.Clin.Invest., 93 :1554 (1993); cardiac allograft rejection in mice, accompanied by specific immunosuppression (Isobe et al., J.Immunol., 153:5810 (1994); graft-versus-host disease in mice following bone marrow transplantation (Yang et al. ,

Proe.Nati.Acad.Sei.USA, 90:10494, (1993); and experimental autoimmune encephalomyelitis in rats and mice (Yednock et al., 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-terminal domains of human VCAM-1 fused to a human IgG1 constant region. In vivo administration of the fusion protein significantly delays the onset of adoptively transferred autoimmune diseases in non-obese diabetic mice (Jakubowski et al., J. Immunol., 155:938 (1995)). Another approach has used three-dimensional crystallographic structures of VCAM-1 fragments to synthesize cyclic peptide antagonists that closely mimic the α4 integrin binding loop in domain 1 of VCAM-1. Synthetic VCAM-1 peptide CQIDSPC, was able to inhibit adhesion of VLA-4 expressing cells to purified VCAM-1 (Wang et al., Proe.Nati.Acad.Sei. USA, 92:5714

(1995)).

A further strategy is to block the binding of to its second counter-receptor, i.e. an alternatively spliced region of fibronectin containing the connection 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 al., J. Clin.Invest., 95:2601 (1995)). Each of these studies provides evidence that selective inhibition of α4P1/VCAM-1 mediated adhesion is a proven strategy for the treatment of autoimmune and allergic inflammatory diseases.

Moreover, while US patent 5,821,231 and PCT applications WO 96/22966, WO 97/03094, WO 98/04247 and WO 98/04913 describe compounds that exhibit VLA-4 inhibitory activity in in vitro binding assays, none of the described compounds have demonstrated effectiveness when administered orally.

Consequently, despite these advances, there remains a need for small, non-peptide, specific inhibitors of VLA-4 dependent cell adhesion that are orally bioavailable and suitable for a long-term treatment of chronic inflammatory diseases and other pathologies associated with leukocyte migration and adhesion.

The compounds according to the invention selectively inhibit the binding of ligands to a4Px and are therefore useful for the inhibition, prevention and suppression of VLA-4 mediated cell adhesion and the pathologies associated with adhesion, such as for example inflammation, asthma, arthritis, diabetes, autoimmune responses, multiple sclerosis, psoriasis , transplant rejection and tumor metastasis.

The present invention provides a compound represented by formula I, or a salt thereof,

in which

W is a phenyl group which is optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy, -OH, CF 3 or halogen;

W<1> is a phenylene group which is optionally substituted with C1-C6 alkyl, C1-C8 alkoxy or halogen;

A is =0;

R is -(CH2)n-,

wherein n is 1 or 2;

X is -C(O)-;

M is

in which

is a divalent 5-. or 6-membered heterocyclic unit, and the nitrogen atom is the point of attachment to X;

wherein Q is -CH 2 -, -S- or -O-;

R<1>, R<2> and R<3> are independently -H, -OH, -NH2, halogen, an O-,C6-alkyl group which is optionally substituted with phenyl-C6-C6-alkyloxy, a phenyl group, a Cx-Cg-

alkoxy group, a mono-C1-C8-alkylamino group, a di-Cx-C8-alkylamino, a C1-C8-alkylsulfonylamino group, a phenylsulfonylamino group which is optionally substituted with C1-C8-alkyl, a naphthylsulfonylamino group which is optionally substituted with di-C-L-Cg-alkylamino, a phenoxy group optionally substituted by carboxy or halogen, a naphthyloxy group, a

quinolinyloxy group, or two of R<1>, R2 and R<3> together form a C1-C3 alkylenedioxy group or a 3-, 4-, 5-,

6- or 7-membered carboxylic acid residue optionally substituted with 1 to 3 substituents independently selected from C 1 -C 8 alkyl;

R<4 > is -H or a C 1 -C 8 alkyl group;

Y is a direct bond or a divalent radical selected from the group consisting of -C(0)-, -C(0)NH-, a C2-C6 alkenylene group, a C2-C6 alkynylene group and -(CH2)kY<2 ->,

wherein k is 0, 1, 2 or 3; and

Y<2> is a direct bond or a divalent radical selected from the group consisting of -0-, -S-, -S(0)-, -S(0)2- and -NY3-, wherein Y<3> is -H or a C 1 -C 10 alkyl group;

Z is a phenylene group which is optionally substituted with carboxy, C₁-C₆ alkoxy, halogen, -NQ₂, -NH₂, C₁-C₆-alkyl, di-C₁-C₆-alkylamino or C₁-C₆-alkanoylamino, a heterocyclylene group selected from piperidinylene, pyridinylene or piperazinylene optionally substituted with carboxy or halogen, or a C3-C7 cycloalkylene group;

A<1> is a direct bond or -(CH2)t-,

wherein t is 1, 2 or 3; and

R<5 > is -OH, C 1 -C 8 alkoxy group, or

M is

in which

R<11> is

in which

R<12> is -H, a C1-<C>10 alkyl group which is optionally

substituted with C3-C7-cycloalkylamino,

C₁Cg-Alkoxy-C₁-Cg-alkylamino, di-C2-C10-alkenylamino, phenoxy (optionally substituted with halogen or C1-C6-alkanoyl),

-OH, morpholinyl, piperazinyl (optionally substituted with C1-C6-alkyl), di-C-L-C8-alkylamino, pyrrolidinyl

(optionally substituted with halogen), a C3-C7 cycloalkyl group, a phenyl group, a benzyl group substituted with -NO2 or -NH2, a C2-C10-

alkenyl group, or a C2-<C>10 alkynyl group, and the left bond is the attachment point of X and the right bond is the attachment point of Z<3>;

Z<3> is a direct bond, a divalent aliphatic hydrocarbon unit of 1 to 12 carbon atoms in which one or more carbon atoms may be replaced by -0- or -NR<13->,

in which

R<13> is -H or a C1 -C8 alkyl group, and

in which one or more hydrogen atoms attached to an aliphatic carbon atom can be replaced by a C^-Cg-

alkyl group; or

Z<3> is

9

in which

x is 0 or 1;

y is 1, 2, or 3; and

R<14> is -H, -OH or halogen, or

The Z3 is

or, when R<11> is -NR<12>, then is wherein Z<4> is

in which

Ri 4<a> is _Hf _OH/ a C-L-C^o-alkyl group or halogen, or Z<4> is

wherein the left bond is the attachment point of R<11> and the right bond is the attachment point of Q<2>;

Q<2> is a divalent radical selected from the group consisting of a phenylene group which is optionally substituted with -OH, C 1 -C 8 -alkyloxy, carboxy, -NO 2 -, NH 2 , halogen, mono-C 1 -C 6 -alkylamino, di- C 1 -C 6 -alkylamino, piperidinyl or C 1 -C 8 -alkylcarbonylamino, and a pyridinylene group,

in which

R<17> and R<18> independently are selected from the group consisting of

-H and a C 2 -C 8 alkyl group; and

L<1> is -CO2H and -CO2R<19>

in which

R<19> is a C1-C6 alkyl group.

The present invention also relates to the use of a compound according to the invention for the production of a drug to inhibit a cell adhesion in a mammal.

The invention also relates to a pharmaceutical preparation which comprises, as a therapeutic agent, a compound according to the invention and a pharmaceutically acceptable carrier or excipient.

In a preferred embodiment of formula I, M is

In this embodiment, more preferred compounds are those wherein Y is preferably selected from a C2-C6 alkenylene group, a C2-C6 alkynylene group, -(CH2)kY<2>, -CH2S(0)- and -CH2O-, and more preferably Y is -CH 2 O.

Preferred compounds in this embodiment are those where W is an unsubstituted phenyl group or phenyl group with one or two substituents selected from a C-L-C8 alkyl group and a halogen atom in the ortho groups thereof. W<1> is preferably an unsubstituted phenylene group or a phenylene group with a substituent selected from a methoxy group, a C 1 -C 8 alkyl group and a halogen atom in the ortho position of -NH-.

Preferred compounds are those where A<1> is a direct bond and R<5> is -0H.

Preferred compounds of formula I wherein

and A is =0 are represented in table 1, as this table will also be able to include further compounds that appear as reference compounds. With respect to the representation of -W<1>, the lower bond is the attachment point of -NH- and the upper bond is the attachment point of -R-. The heading denoted --R R5 indicates the portion of the particular compound represented by

Another preferred embodiment of formula I includes compounds where M is }—r<11>—z^-Q<2>—L<1> r is preferably -CH2-.

W is preferably an unsubstituted phenyl group or a phenyl group with one or two substituents selected from a C 1 -C 3 alkyl group and a halogen atom in the ortho position thereof. W<1> is preferably an unsubstituted phenylene group or a phenylene group. with a substituent selected from a methoxy group, a C-L-C8 alkyl group and a halogen atom in the ortho position of -NH-.

In compounds where Q<2> is

and Z<3> is a divalent

aliphatic hydrocarbon unit, preferred compounds are those where R<11> is

A

or -NR<12>, more preferably NR<12>, where R12 is

selected from -H, a C 1 -C 4 alkyl group and a substituted C 1 -C 10 alkyl group, most preferably a dihydroxy C 1 -C 10 alkyl group. Preferred choices for Z<3> are a divalent aliphatic hydrocarbon moiety of 4, 5 or 6 carbon atoms. A preferred choice for W<1> is phenylene group with a substituent selected from a methoxy group, a C-L-C8 alkyl group and a halogen atom in the ortho position of -NH-.

In compounds where Q<2> is

and Z<3> is R1<1> preferably -NR1<2>. In these compounds x and y are preferably 1. Preferred choices for R<14> include -H, -OH and -F. A preferred choice for W<1> is phenylene group with a substituent selected from a methoxy group, a C 1 -C 8 alkyl group and a halogen atom in the ortho position of -NH-. In compounds where Q<2> is and Z<3> is R<11> is preferably -NR<12>, where R<12> is preferably a Cx-C1Q alkyl group. Preferred compounds in this embodiment • also include those where at least one of R<17> and R18 is a C1-C8 alkyl group. In compounds where Q<2> is and Z<3> is

R1<1> is preferably -NH- and R<17><p>g R<18> is each preferably -H. A preferred choice for W<1> is a phenylene group with a substituent selected from a methoxy group, a C 1 -C 8 alkyl group and a halogen atom in the ortho position of -NH-.

In compounds where Q<2> is selected from a phenylene group and a phenylene group substituted at the point of attachment of Z<3>, Z<3> is preferably a divalent aliphatic hydrocarbon unit'.

Preferred compounds of formula I, where M is }—R<11>—Z^—Q2—11 and R is -CH2- are represented in table 4, as this table may also include further compounds that appear as reference compounds. With respect to representation of

-W<1>, the lower bond is the attachment point of -NH- and the upper bond is the attachment point of -R-. The heading entitled --R11 L1 indicates the portion of the particular compound represented by H*1"1-21"0-<2>-<1-1>.

Compounds representative of prodrugs include those in which R<5> is a lower alkoxy group and those in which R<19> is a lower alkoxycarbonyl group.

A method for inhibiting cell adhesion, and in particular VLA-4 mediated cell adhesion in cc4pl receptor sites in a mammal, is also described. The method comprises administering an effective amount of a compound represented by formula I. As used herein, inhibition of cell adhesion shall include inhibition, suppression and prevention of VLA-4 mediated cell adhesion associated conditions, including but not limited to inflammation and cell adhesion associated immune or autoimmune responses .

A method of treating a condition associated with VLA-4 mediated cell adhesion is also described. The method comprises administering to a mammal in need of such treatment an effective amount of a compound represented by formula I. Such conditions include, for example, but are not limited to, inflammatory and autoimmune responses, diabetes, asthma, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, transplant rejection and tumor metastases. As used herein, "treatment" of a mammal shall likewise include prophylaxis. The compounds according to the invention can be administered as a monotherapy or in combination with anti-inflammatory or immunosuppressive agents. Such combination therapies may involve the administration of different pharmaceuticals as a single dosage form or as multiple dosage forms administered simultaneously or at different times.

Any suitable route of administration may be used to provide an effective amount of a compound of the invention to a patient. Appropriate administration routes can e.g. include oral, rectal, nasal, buccal, parenteral (such as intravenous, intrathecal, subcutaneous, intramuscular, intra-sternal, intrahepatic, intralesional, intracranial, intra-articular and intra-synovial), transdermal (such as plasters) and such. Due to their ease of administration, oral dosage forms such as tablets, dragées, dispersions, suspensions, solutions, capsules, soft gelatin capsules and the like are preferred. Administration may also be by means of controlled or delayed release and by delivery devices. Methods for producing such dosage forms are well known in the art.

Pharmaceutical preparations incorporating compounds according to the invention may include excipients, a pharmaceutically acceptable carrier, in addition to other therapeutic ingredients. Excipients such as starches, sugars, microcrystalline cellulose, diluents, lubricants, binders, coloring agents, flavoring agents, granulating agents, disintegrating agents and the like may be suitable depending on the route of administration. Because of the ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

The compounds according to the invention can 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, metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, organic salts formed from chloroprocaine, choline, N,W-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, lysine, meglumine (N-methylglucamine) and procaine, - as well as salts with amino acids, such as arginine, lysine, etc.

Where the compounds according to the invention have a basic unit, such as an amino group, the compounds can be used in the form of pharmaceutically acceptable non-toxic organic or inorganic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, methanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid , p-toluenesulfonic acid and the like. Particularly preferred are citric acid, hydrochloric acid, maleic acid, fumaric acid, phosphoric acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. Compounds according to the invention can also be in the form of hydrates.

Abbreviations and definitions

The subsequent designations and abbreviations have the indicated meaning throughout the description.

293E HEK cells = 293E human embryonic kidney cells Ac = acetyl

anti-a4-PE-

conjugated = monoclonal antibody against integrin oc4

subunit, phycoerythrin-conjugated anti-pi-FITC-

conjugated = monoclonal antibody against integrin pi

subunit, fluorescein conjugated

oc5pi = integrin <x5pl, fibronectin receptor, VLA-5

ocvP3 = integrin ccvP3, vitronectin receptor oc4p7 integrin cc4P7

Bn = benzyl

Boe = t-butoxycarbonyl

BSA = bovine serum albumin

c- = cyclo-

cDNA = complementary DNA

CHO cells = Chinese Hamster ovary cells p-ClPh = para-chlorophenyl

CMV promoter = cytomegalovirus promoter

772-CPBA = 3-chloroperoxybenzoic acid

DAST = diethylaminosulfur trifluoride.

DCM = dichloromethane = methylene chloride = CH2C12 DELFIA = dissociation-enhanced lanthanide fluoride immunoassay

DIAD = diisopropylazodicarboxylate

DIC = diisopropylcarbodiimide

DIEA = N,N-diisopropylethylamine

DMAP = 4-N,N-dimethylaminopyridine

DMEM = Dulbecco's modified Eagle's medium DMF = N,Itf-dimethylformamide

DTPA = diethyltriaminopentaacetic acid

EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et20 = ethyl ether

FACS = fluorescence cell sorting

Fmoc = 9-fluorenylmethoxycarbonyl

GPIIb/IIIa = integrin allbp3, fibrinogen receptor HEPES = N-(2-hydroxyethyl)piperazine-W-(2-ethanesulfonic acid)

HMDS = 1,1,1,3,3,3-hexamethyldisilazane

HOAc = acetic acid

HOBt = 1-hydroxybenzotriazole

human IgGl = human immunoglobulin Gl ICAM = intracellular adhesion molecule

LDV = Leu-Asp-Val

LFA-1 and Mac-1 = lymphocyte function-related antigen LiHMDS = lithium l,1,1,3,3,3-hexamethyldisilazane Me = methyl

p-MeOPh = para-methoxyphenyl

nM = nanomolar

PBS = phosphate buffered saline

PEG = polyethylene glycol

Ph = phenyl

PhOH = phenol

PyBroP = bromo-tris-pyrrolidinephosphonium hexafluoro-phosphate

RPMI medium = Russel Park Memorial Institute medium TFA = trifluoroacetic acid

TFAA = trifluoroacetic anhydride

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS trimethylsilyl

Ts = toluenesulfonyl

VCAM-1 (D1D7) = vascular cell adhesion molecule (containing one to seven immunoglobulin domains)

VCAM-IgG fusion

protein = a VCAM IgG fusion protein containing one to seven immunoglobulin domains of human VCAM-1 (D1D7) attached over the hinge region of an IgG1 molecule

"Alkyl group" shall include straight-chain or branched hydrocarbon radicals and combinations thereof having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,

iso-amyl, hexyl, octyl and the like.

"Alkylene group" means a divalent radical formed by removing a hydrogen atom from an "alkyl group".

"Cycloalkyl group" refers to a saturated hydrocarbon ring radical having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,

myrtanyl and the like.

in

"Cycloalkylene group" means a divalent radical formed by removing a hydrogen atom from a "cycloalkyl group".

"Divalent C± to C12 aliphatic hydrocarbon moiety" includes alkylene, cycloalkylene, alkenylene, alkynylene and combinations thereof. Examples include ethylene, propylene, propynylene, 2,4-heptadienylene and similar groups.

"Heterocyclylene group" means a radical formed by removing a hydrogen atom from a "heterocyclyl group".

"Alkoxy group" means a straight-chain, branched or cyclic hydrocarbon configuration and combinations thereof including from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and an oxygen atom at the point of attachment. Suitable alkoxy groups include methoxy, ethoxy, 77-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclopropoxy, cyclohexyloxy and similar groups.

"Alkenyl group" refers to an unsaturated acyclic hydrocarbon radical to the extent that it contains at least one double bond and from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and more preferably from 2 to 6 carbon atoms. Examples of suitable alkenyl radicals include propenyl, 'buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl and octen-1-yl and similar groups.

"Alkenylene group" means a divalent radical formed by removing a hydrogen atom from an "alkenyl group".

"Alkynyl group" refers to an unsaturated acyclic hydrocarbon radical containing at least one triple bond. Examples include ethynyl, propynyl and similar groups.

"Alkynylene group" means a divalent radical formed by removing a hydrogen atom from an "alkynyl group".

"Halogen" shall include e.g. F, Cl, 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, Ann. Rep. With. Chem. 22:303 (1987) and H. Bungaard, Adv. Drug Dilvery Rev., 3:39 (1989)].

Terminology related to "protected", "protection" and/or "deprotection" of functionalities is used in this application. Such terminology is understood by those skilled in the art and is used in connection with processes involving sequential treatment with a number of reagents. In this context, a protecting group refers to a group used to mask a functionality during a process step in which it would otherwise react, but where reaction is undesirable. The protecting group prevents reaction in this step, but can then be removed to expose the nascent functionality. Removal or "deprotection" takes place after the reaction or reactions where the functionality could interfere is finished. Thus, when a sequence of reagents is specified, as in connection with the method for preparing the compounds according to the invention, a person skilled in the art can easily form an image of the groups that will be suitable as "protecting groups" for the functionalities involved.

In the context of the invention, the functionalities that must be protected are amines. Appropriate groups for this purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene [John Wiley & Sons, New York, 1991] ..Special attention should be paid to the chapter entitled "Protection for the Amino Group" (pages 309-405).j Exemplary methods for protection and deprotection with these groups can be found in Greene and Wuts on pages 318 and 327.

The materials on which the synthesis described herein is carried out are referred to as solid supports, spheres and resins. These denote-. should include: (a) spheres, pellets, disks, fibres, gels or particles such as cellulose spheres, porous glass spheres, silica gels, polystyrene spheres which are optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, polyacrylamide spheres, latex spheres, dimethylacrylamide beads optionally crosslinked with N,Wbis-acryloylethylenediamine, glass particles coated with hydrophobic polymer, etc., i.e. material with a rigid or semi-rigid surface, and (b) soluble carriers such as polyethylene glycol or non-crosslinked low molecular weight polystyrene. The solid supports can have, and usually have, functional groups such as amino, hydroxy, carboxy or halo groups, with amino groups being the most common.

Tentagel NH2 (Rapp Polymere, Tubingen, Germany) is a preferred amine-functionalized polyethylene glycol-grafted polystyrene resin. Tentagel-S-PHB resin has a parahydroxy-benzyl linker that can be cleaved using 90% trifluoroacetic acid in dichloromethane. Techniques for functionalizing the surface of solid phases are well known in the art. Attaching lysine to the amino groups on a sphere (to increase the number of available sites) and then attaching linkers as well as further steps in a typical combinatorial synthesis are e.g. described in PCT application WO95/30642. In the synthesis described in WO95/3 0642, the linker is a photolytically cleavable linker, but the general principles of using a linker are well illustrated.

Some of the compounds described herein contain one or more asymmetric centers and can thus lead to enantiomers, diastereomers and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S), or as (D)- or ( L) -■ for amino acids. The present invention shall include all such possible diastereomers as well as their racemic and optically pure forms. Optically active (R) and (S), or (D) or (L) isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specifically stated, this shall include both (E)- and (Z)-geometric isomers. Likewise, all tautomeric forms shall be included^ The configuration of any carbon-carbon double bond appearing herein is chosen for convenience only and shall not indicate a particular configuration, and a carbon-carbon double bond arbitrarily designated herein as trans may thus be cis, trans or a mixture of the two in any ratio.

Seen against the background of the above definitions, other chemical expressions used in this application can be easily understood by experts in the field. Expressions may be used alone or in any combination thereof. The preferred and more preferred chain lengths for the radicals apply to all such combinations.

The compounds according to the invention have shown their utility as selective inhibitors of VLA-4 receptors. The inhibitory concentration (IC50) and VLA-4 selectivity of test compounds for a 1x401 receptor using in vitro assays is determined by direct binding experiments and competitive experiments with other integrin receptors such as O2 (LFA-1 and Mac-1), p3 (GPIIb /lIIa and ocvP3) and 01 (<x4p7) . The compounds according to the invention have iq values <1 /*M. Preferred compounds according to the invention are those with I^ values <300 nM, more preferably <100 nM, even more preferably <50 nM and most preferably <12 nM.

Examples of preferred compounds according to the invention with a Ki value <50 nM are shown below.

In vitro experiments

A direct binding assay was used to quantify the inhibitory activity of the compounds. In this experiment, VLA-4-expressing cells were seeded in a 96-well microtiter plate. The cells were cultured for 2 days until confluence. Various concentrations of the test compound were added together with 2 nM of the europium-labeled VCAM IgG fusion protein. The cells were incubated at room temperature in the micro-wells for at least 30 minutes. After incubation, the micro-wells were emptied and washed. The amount of europium-labeled VCAM IgG fusion protein bound was determined by time-resolved fluorescence measurement. Inhibition of binding was determined by quantifying the fluorescence bound to the plate for each of the different concentrations of test compound, as well as for controls containing no test compound.

The VLA-4-expressing cells used in this experiment were a CHO cell line stably transfected with cDNA from the human α4 and β1 subunits. Construction and maintenance of the cell line are described in the experimental procedures. A VCAM IgG fusion protein containing the one to seven immunoglobulin domains of human VCAM-1 (D1D7) attached over the hinge region of an IgG1 molecule were labeled with europium chelates.Preparation and labeling of the fusion protein is described in the experimental procedures.

The cell adhesion inhibitory activity of the test compound was determined by blocking Jurkat cell attachment to the D1D7-VCAM IgG fusion protein. Jurkat cell is a human lymphocyte cell line that expresses VLA-4 on the cell surface. In this experiment, each of the 96-well microtiter wells was coated with 75 ng of the VCAM IgG fusion protein. The wells were then blocked by the addition of 1% bovine serum albumin to remove non-specific adhesive sites. Varying concentrations of the test compound were added together with the calcein-labeled Jurkat cells. The cells were allowed to adhere to the VCAM-coated wells at room temperature for 1 hour in the dark. After incubation, the plate was washed by dipping it upside down in a container filled with phosphate-buffered saline. The wells were dried with paper towel. Quantification of adhered cells was determined by fluorescence measurement. Decreased fluorescence indicated inhibition of cell adhesion by the test compound.

Specificity for a4 01 of each test compound among other integrin receptors, namely 02 (LFA-1 and Mac-1), 03 (GPIIb/Illa and ccvp3), 01 (cc501) and P7 (a407) was investigated. LFA-1 binds to ICAM-1 and mediates the emigration of leukocytes into the sites of inflammation. Mac-1 binds to a variety of ligands, including ICAM-1 and fibrinogen, and plays an important role in neutrophil phagocytosis and oxygen-free radical generation. GPIIb/IIIa on the platelet surface binds to fibrinogen in plasma and induces platelet aggregation. av03 binds to a number of extracellular matrix proteins, including vitronectin and mediates cell migration and prevents cell apoptosis. a4 07 share the same ligands as VLA-4 (VCAM-1, MAdCAM-1 qg fibronectin), but with different preferences. This receptor is expressed on the lymphoid cells and is involved in lymphocyte migration to mucosal tissue.

Assays of LFA-1, Mac-1, GPIIb/IIIa and <x403 involved plating the purified receptor on a 96-well microtiter plate. The specific ligands for these receptors were labeled with europium chelates. In the analyzes of LFA-1 and Mac-1, an ICAM-1 IgG fusion protein containing the one to five immunoglobulin domains of human ICAM-1 (D1D5) attached over the hinge region of an IgG1 molecule was used. In the analyzes of GPIIb/IIIa and av03, europium-labeled fibrinogen and vitronectin were used, respectively. The purified receptors were allowed to incubate in the wells at different concentrations of test compound, in the presence of europium-labeled ligands. After incubation, the wells were emptied and washed. The amount of europium-labeled ligand bound was determined by time-resolved fluorescence measurement. Assay of a407 is similar to the adhesion inhibition assay of VLA-4 as described above, and uses the <x407-expressing cell RPMI-888 6. A MAdCAM-1 IgG fusion protein containing one or both immunoglobulin domains of human MAdCAM- 1 and muein-like repeat domain, is used as the corresponding ligand for a4p7.

Eu<3+->VCAM-1 IgG binding to CHO/VLA-4 cells can be determined as follows. 4B4 cells (CHO/VLA-4 cells) are distributed in each well of a 96-well microtiter plate with 3 x 10<4>/well. The plate is incubated at 37°C, 5% CO 2 for 48 hours and then washed twice with wash buffer, and then pressure-dried. 50 µl of the inhibitor solution diluted with assay buffer (2% DMSO final) is added to each well followed by 50 µl of Eu<3+->VCAM-1 IgG diluted with assay buffer to 2 nM. The disc in-. incubate at room temperature for at least 30 minutes. Each well is then washed four times with wash buffer and pressure-dried. 100 (µl DELFIA Enhancement solution is added to each well followed by shaking the plate at room temperature for 5 minutes. Fluorescence for each sample is then measured (e.g. DELFIA Fluorometer 1234, Wallace, Inc., USA). In this assay, the wash buffer comprises 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM CaCl2, 1 mM MgCl2 and 4 mM MnCl2, the analysis buffer comprising 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM CaCl2, 1 mM MgCl 2 , 4 mM MnCl 2 , 1% BSA and 20 µM DTPA.

In vivo experiments

The VLA-4 inhibitors can be further characterized in in vivo trials. One such experiment investigates the inhibition of eosinophilic infiltration into the bronchoalveolar lavage fluid in the mouse (murine) model; In this experiment, the animals are treated with cyclophosphamide on day 0. On days 2 and 14, the animals are immunized intraperitoneally with Ascaris suum extract. Seven days later, the animals are treated with different doses of the VLA-4 inhibitor. Shortly after drug administration, the animals are challenged with Ascaris suum extract by instillation into the trachea. Broncho-alveolar lavage of the animal is performed by instilling saline into the lungs, 48 hours later. Total cell count and eosinophil count in the lavage are determined.

In the murine model of Ascaris-induced bronchial inflammation, one of the representative compounds inhibited

(example number 32) eosinophilic infiltration by 49% at an oral dosage of 30 mg/kg. In contrast, a representative previously known compound, 4-(W-2-methyl-phenylurea)phenylacetyl-LDVP-OH, described in WO 97/03094, did not inhibit eosinophilic infiltration (% inhibition = -2%) at an oral dose of 50 mg/kg.

Furthermore, a representative known compound, (R)-3-(4-carboxybutanoylamino)-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)propanoic acid, described in WO 99/23063, no eosinophilic infiltration (% inhibition = -13%) at a subcutaneous dosage (b.i.d x 2 days) of 40 mg/kg.

Other representative compounds were also tested in mice. The dosage, the route of administration and the inhibitory effect for representative compounds (hereafter all tested compounds are referred to by compound number provided in the synthesis examples) are shown in Table 5.

The compounds according to the invention can furthermore also be characterized in other in vivo tests, such as the eosinophil accumulation model tested in the rat. Fifty µg of compound 48/80 was injected into the pleural cavities of male Sprague Dawley rats. After 24 hours, each cavity was washed twice with Hank's balanced salt solution containing 0.2% EDTA. The total cell count and eosinophil count were determined. Test compounds were administered intravenously, orally or subcutaneously, b. i.d. at 0 and 8 hours. Dosage, route of administration and inhibitory effect for the test compounds are shown in Table 6.

Bio-assay method for mice

A compound was dissolved or suspended with an appropriate solvent to 1 mg/ml. Balb/c female mice (7-9 weeks old) were given the compound orally. Blood samples were collected from the postcaval vein of the anesthetized animals after fifteen minutes. Serum was prepared and stored at -20°C. Serum concentration of the compound was determined from inhibitory activities of the diluted serum in a direct binding assay using VLA-4 expressing cells and VCAM-IgG fusion protein. Serum concentration determined by this method correlated well with the concentration determined by LC/MS/MS methodologies. Dosage, administration route and achieved inhibitory effect for the test compounds are shown in Table 7.

Pharmacokinetic evaluations

Pharmacokinetic parameters for example compounds in mouse, rat and monkey models are shown in Tables 8, 9 and 10. Binding test for VCAM-1 to. VLA-4 expressing cells Preparation of VCAM IgG fusion protein A VCAM IgG fusion protein containing the one to seven immunoglobulin domains of VCAM-1 (D1D7) ligated to the hinge (H), CH2 and CH3 regions of human IgG1 was used in the binding experiment.

Construction of a stable cell line expressing D1D7-VCAM IgG fusion protein

An Epstein-Barr virus-based episomal plasmid containing a D1D7-VCAM IgG fusion gene under transcriptional control of the CMV promoter was transfected into 2 93E human embryonic kidney cells. Stably transfected cells were selected using 250 µg/ml hygromycin in DMEM with 10% fetal

■ calf serum. The cells secreted D1D7 VCAM IgG fusion protein cumulatively into the medium for up to 9 days.

Purification of D1D7 VCAM IgG fusion protein

The cells were cultured in DMEM with 10% fetal calf serum for 2 days, then changed to CCM5 medium and cultured for a further 10 days. The medium was centrifuged, filtered and then incubated overnight with Protein A Sepharose 4. Protein A Sepharose was washed extensively and D1D7 VCAM IgG fusion protein that was bound was eluted using 100 mM citric acid, pH 3.

Preparation of europium-labeled D1D7 VCAM IgG fusion protein The D1D7 VCAM IgG fusion protein, at 1 mg/ml, was dialyzed against 50 mM NaHCO 3 , 0.9% NaCl, pH 8.5. The fusion protein was added to a tube of europium-labeled reagent (DELFIA labeling kit from Wallac, Gaithersberg, MD, catalog no. 1244-302) and incubated at room temperature in the dark overnight. The labeled protein was purified using a Sepharose G10 column and analyzed for europium content and protein concentration. The protein was stored at -80°C until use.

Construction of cell line expressing VLA-4 (CHO/VLA-4)

A CHO cell line which was stably transfected with cDNA of cc4 and Ø1 was used in the binding experiment. The gene for human oc4 was obtained from the American Type Culture Collection and recloned between the Xhol and Xba sites of the mammalian expression vector pCI-neo (Promega, Madison, WI). The pi gene was amplified by PCR from human peripheral leukocyte cDNA and manipulated so that the start codon was placed in conjunction with a consensus Kozak sequence. The gene was recloned into pCI-neo downstream of the CMV promoter and chimeric intron.

CH0-K1 cells were stably co-transfected with plasmids encoding the cc4 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-α4-PE conjugate (PharMingen, San Diego, CA) and anti-β-FITC conjugate (Biosource, Camarillo, CA). A cell line 4B4, which expresses respectively 400,000 and 300,000 sites/cell of the a4 and P1 subunit, was used in the binding experiment. The subunit numbers were determined by FACS analysis using

Quantum Simply Cellular microbeads (Flow Cytometry Standards Corporation, Puerto Rico) as standards. The cells were kept

in F12 medium containing 10% fetal bovine serum, 10 mM HEPES, pH 7.5, 05 mg/ml G418, using a 1:48 passage/week.

Binding attempt

The CHO/VLA-4 cells were seeded in a 96-well microtiter plate at 30,000 cells/well and incubated at 37°C, 5% CO 2 for 48 hours until confluence. On the day of analysis, the wells were emptied and washed twice with 350 µl of a wash buffer containing 25 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM MgCl 2 , 1 mM CaCl 2 , 2 mM MnCl 2 . The plate was then emptied of liquid and pressed dry on paper towel to remove buffer.

The test compound was serially diluted in assay buffer (wash buffer together with 0.1% bovine serum albumin, 20 µM DTPA and 1% dimethyl sulfoxide), in the presence of 2 nM europium-labeled D1D7-VCAM IgG fusion protein. Final concentrations used were from 0.1 nM-10 /µM. 50 µl aliquots of the test compound mixture were added to duplicate wells of the plate. Control wells for total binding received no test compound. Nonspecific binding wells contained an anti-oc4 monoclonal antibody (L25.3, Becton Dickinson, Bedford, MA).

The cells were allowed to incubate with the test compound mixture in the presence of europium-labeled D1D7-VCAM IgG fusion protein at room temperature for at least 30 minutes. The cells were then washed three times with 350 µl wash buffer using a Skatron plate washer and dried with paper towels. A 100 µl aliquot of DELFIA Enhancement solution was added to each well, followed by gentle shaking at room temperature for 10 minutes. The amount of europium-labeled VCAM IgG fusion protein bound was determined by time-resolved fluorescence measurement

(Model: Victor, Wallac Inc., Gaithersberg, MD).

Percent binding was calculated as [ (FT-FNS) - (F-j-F^) ] / (FT-FNS) x 10 0 where FT and FNS are the fluorescence signal of europium-labeled D1D7-VACM IgG fusion protein bound to cells, in the absence of test compounds and containing an anti-a4 monoclonal antibody. For example, the fluorescence in wells that contained a test compound. IC50 (concentration of inhibitor to inhibit 50% binding of VACM to CHO/VLA-4 cell) was determined using a curve fitting routine, PRIZM (GraphPad Software, Inc., San Diego, CA).

Adhesion of VLA-4 expressing cell to VCAM-1

This secondary functional assay was used to determine the potency of the test compound to inhibit VLA-4 mediated cell adhesion.

Production of VCAM-coated plate

A 50 µl aliquot of the D1D7-VCAM IgG fusion protein (1.5 µg/ml in phosphate-buffered saline, PBS) was added to each well of a 96-well Costar flat-bottom plate (Costar, Franklin Lakes, NJ, catalog no. 2580). The plate was then incubated overnight at 4°C. On the day of analysis, the wells were emptied and washed twice with 350 µl PBS. The plate was then blocked with 100 µl of 1% bovine serum albumin (BSA, Sigma catalog no. A9418) in PBS at room temperature for at least one hour.

Cell production

Jurkat cells (clone E6-1) were obtained from the American Type Cultured Collection and were maintained in RPMI medium, 10 mM HEPES, pH 7.5, 1 mM sodium pyruvate, 10% FCS, using 1:64 passage/week. Just before running the experiment, Jurkat cells were labeled with 5 µM calcein-AM (Molecular Probe, Eugene, OR, catalog no. C1430) in RPMI medium at room temperature for 30 minutes in the dark. After labeling, cells were washed twice with RPMI medium and resuspended with 1 x 10<6> cells/ml.

Cell adhesion experiments

Immediately before the experiment, the BSA solution was emptied from the VCAM-coated plate. The plate was then washed twice with RPMI medium. A 100 µl aliquot of the labeled Jurkat cells was added to each well followed by the addition of 50 µl of the inhibitor solutions. Final inhibitor concentrations range from 1 nM to 10 µM and each concentration was tested in triplicate. The inhibitor and cells were incubated at room temperature in the dark. After incubation, the plate was carefully immersed in a container filled with PBS and then turned face down into the PBS. The wells were drained and dried on a layer of paper towel. A 50 µl aliquot of 0.1% Triton X-100 was added to each well. The plate was incubated in the dark for 10 minutes. Jurkat cell adhesion was quantified in a Millipore Cytofluor 2300 system plate reader set at 485 nM excitation and 530 nM emission. The IC50 (concentration of the inhibitor to inhibit 50% Jurkat cell adhesion) was determined using a curve fitting routine, PRIZM (GraphPad Software, Inc., San Diego, CA).

Methods of synthesis

The compounds according to the invention can be prepared using standard chemical synthesis methods as well as using methods for combination chemistry, as described in published PCT application, WO/95/30642.

Synthesis examples

General methods of synthesis are illustrated in the following examples. Modifications and variations in any material or process step will be readily apparent to a person skilled in the art. Unless otherwise indicated, the solid phase carrier as used in certain examples is Tentagel-S-PHB resin. This resin has a parahydroxybenzyl linker which can be cleaved using 90% trifluoroacetic acid in dichloromethane. The loading for this resin varies between 0.27 and 0.30 mmol/g and is not double-loaded.

EXAMPLE 1

Into a three-necked 500 ml round bottom flask was introduced 200 ml of THF and NaH (1.5 g, 62.9 mmol). A solution of 1-vinyl-2-pyrrolidinone (6.9 g, 62.9 mmol) and methyl 3-iodobenzoate (15.0 g, 57.3 mmol) in THF (100 mL) was added dropwise to the flask in within 15 min. After the addition was complete, the reaction mixture was heated to oxygen reflux. The reaction vessel was cooled to room temperature and then 6 N HCl (100 mL) was carefully added. The reaction mixture was concentrated in vacuo to remove THF and then a further aliquot of 6 N HCl (100 mL) was added and the reaction mixture was heated under reflux for 14 hours. The reaction was quenched by addition of NaHCO 3 until pH 9 and then the mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO 4 and concentrated in vacuo to give a yellow oil.

This oil was then taken up in MeOH (100 mL) and cooled to -78°C. NaBH 4 (3.5 g, 96.5) was then added portionwise and the reaction mixture was warmed to room temperature over 2 hours. The reaction was stopped by the addition of 6 N HCl until acidity and then made basic by the addition of 40% aqueous NaOH. The solution was extracted three times with CH 2 Cl 2 , the combined organic phases were dried over MgSO 4 and then concentrated in vacuo to give 11.4 g as a yellow oil.

The above amine was then Boe-protected by placing the amine in 50% dioxane-H 2 O (100 mL) and adding K 2 CO 3 until basic. Boc anhydride was added to this solution

(9.1 g, 41 mmol) and the mixture was then stirred for 14 h at room temperature. The reaction was stopped by the addition of 1 N HCl until acidity. The solution was extracted three times with EtOAc, dried over MgSO 4 and concentrated in vacuo to give a yellow viscous oil. The oil was chromatographed (25% EtOAc:hexanes) to give 7.0 g of A.

Hydrochloric acid (gas) was bubbled through 15.8 g (73.5 mmol) of 2-bromophenylacetic acid in 100 ml. methanol for 10 min. The solution obtained was partitioned between 100 ml of water and 100 ml of CH 2 Cl. The organic layer was dried over MgSO 4 and the solvent was removed under reduced pressure to give 16.8 g (73.5 mol) of methyl 2-bromophenyl acetate which was combined with 9.0 g (80.8 mmol) of l-vinyl- 2-pyrrolidinone, and 100 ml of dry THF under argon in a 250 ml round bottom flask.

To this flask was added 3.5 g (147 mmol) of sodium hydride (95%) and the solution was stirred for 10 min. at room temperature. A reflux condenser was added and the mixture was heated to reflux for 1 hour. The solution was cooled at room temperature and the solvent was removed under reduced pressure. A solution of 30 ml of aqueous hydrochloric acid and 50 ml of water was added to the resulting mixture and this was heated to reflux without a condenser until the solution temperature reached 96°C, at which point a condenser was added and the solution was heated to reflux for 16 hours. The solution was cooled to room temperature, basified with 150 ml of an aqueous solution of 40% sodium hydroxide, extracted with 3 x 125 ml of CH 2 Cl 2 and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and dissolved the solvent was removed under reduced pressure to give 15.0 g (63.0 mmol, 86%) of 2-(2-bromobenzyl)-1-pyrroline.

To a solution of 15 g (63 mmol) of 2-(2-bromobenzyl)-1-pyrroline in a solution of 80:20 methanol:aqueous acetic acid and cooled to -78°C was added, in portions over a 15 minute period , 5.3 g (140.0 mmol) of sodium borohydride. The mixture was stirred for 1 hour by warming to room temperature and then the solvent was removed under reduced pressure, 150 ml of water was added and the solution was basified with an aqueous solution of sodium hydroxide which was extracted with 10 x 100 ml of CH 2 Cl 2 resulting in emulsions. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and the solvent was removed in vacuo to give 14.6 g (60.8 mmol, 97%) of benzylproline.

To a solution of 14.6 g (60.8 mmol) of the benzylproline in a solution of 70 ml of saturated aqueous sodium bicarbonate and 70 ml of dioxane was added 15.1 g (67.0 mmol) of di-t-butyl dicarbonate and the mixture was stirred for 16 hours at room temperature. 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 MgSO 4 and the solvent was removed under reduced pressure to give a residue which was purified by flash column chromatography (20%-100% ethyl acetate/ hexane) to give 11.5 g (33.8 mol, 56%) of pure A<1>.

A (1.88 g, 5.0 mmol) was placed in a 100 mL round bottom flask and dissolved in DMF (50 mL). To this solution was added Pd(OAc)2 (23 mg, 0.3 mmol), P(o-Tol)3 (12 mg, 0.3 mmol), methyl acrylate (0.47 g, 5.5 mmol) and NaOAc (0.5 g, 5.5 mmol). This mixture was then heated to 80°C for 14 hours. The reaction mixture was then cooled to room temperature and 1 N HCl (100 mL) was added. The solution was then extracted 3 times with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give a brown oil. This oil was chromatographed with 25% EtOAc:hexanes to give

1.32 g of the alkene ester as a colorless viscous oil.

The alkene ester (1.32 g, 4.1 mmol) was then subjected to hydrogenation. The alkene was placed in a Parr hydrogenation flask, EtOAc (10 mL) and 10% Pd/C (10 mg) were added under an inert atmosphere. The bottle was then pressurized with hydrogen at 45 psi and shaken for 4 hours at room temperature. The solution was then filtered through diatomaceous earth and concentrated in vacuo to give 1.29 g of the alkane ester.

The alkane ester (1.29 g, 4.0 mmol) was dissolved in THF (30 mL), MeOH (20 mL), and water (10 mL) and saponified with LiOH (200 mg, 8.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and then poured into 1 N HCl (50 mL). This solution was then extracted three times with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give 1.02 g of the alkanoic acid as a yellow solid.

The alkanoic acid (1.02 g, 3.3 mmol) was then deprotected by addition of a 25% TFA/CH 2 Cl 2 solution and stirred for 2 hours at room temperature. The resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 CO 3

(1.2 g), and Fmoc-Cl (1.08 g, 4.0 mmol). This mixture was stirred at room temperature for 14 hours and then poured into 1 N HCl (100 mL). The solution was then extracted 3 times with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give 495 mg of 1 as a white crystalline solid.

The dried resin (500 mg, 0.14 mmol) was placed in a

small shaking container. 9 ml of DMF (2 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol) and DMAP (17 mg, 0.14 mmol) were then introduced into the vessel. The container was then shaken for 16 hours at room temperature. The contents were drained and the resin was washed 3 times with DMF, MeOH and CH 2 Cl 2 . The Fmoc group was then removed by adding 10 ml of 50% piperidine/DMF to the shaking container and shaking was carried out for 2 hours at room temperature. The amine residue obtained was washed 3 times with DMF, MeOH and CH 2 Cl 2 .

To the above resin was added 9 mL of DMF, 4-[N'-(o-tolylurea)]-phenylacetic acid (132 mg, 0.42 mmol), PyBroP (196 mg, 0.42 mmol) and DIEA (107 mg , 0.84 mmol). The contents were shaken for 14 h at room temperature and then drained and washed 3 times with DMF, MeOH and CH 2 Cl 2 . The compound was then cleaved from the resin and the filtrate was collected and

then concentrated in vacuo. The oil obtained was triturated by taking up the oil in MeOH and slowly adding Et 2 O until a precipitate formed. This precipitate was co-

and dried in vacuo to give 67 mg l' as a white crystalline solid.

EXAMPLE 2

A (4.2 g, 11.3 mmol) was placed in a 100 ml round bottom flask and dissolved in NEt3 (50 ml). To this solution was added Pd(PPh 3 ) 2 Cl 2 (0.16 g, 0.23 mmol), Cu (21 mg, 0.12 mmol) and trimethylsilylacetylene (1.38 g, 13.5 mmol). This mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched by the addition of 1 N HCl (100 mL). The solution was then extracted 3 times with EtOAc, dried over MgSO 4 , and then concentrated in vacuo to give a yellow oil. This oil was chromatographed with 15% EtOAc:hexanes to give 3.8 g.2 as a colorless viscous oil.

A solution of dicyclohexylborane was formed by adding borane-THF (12.0 mL, 12 mmol), at 0°C to a solution of cyclohexene (2.3 mL) in 6 mL of anhydrous THF. This solution was stirred for an additional 1 hour at 0°C. The acetylene (2) (2.0 g, 5.84 mmol) was then added dropwise over 15 min. at 0°C and was then heated at room temperature during 1 hour. The reaction mixture was then diluted with MeOH (20 mL) and then cooled to 0 °C. A solution of 2 N NaOH (6 mL) and 30% H 2 O 2 (3.5 mL) was then added dropwise. The reaction mixture was then stirred at 0°C for 1 hour and then heated to 40°C for 2.5 hours. The mixture was then cooled to room temperature and an additional 6 mL of 2 N NaOH was added. The organic layers were removed in vacuo and the remaining aqueous solution was extracted 3 times with Et 2 O and the organic layers were removed. The aqueous extracts were then acidified with 1 N HCl and extracted with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give 1.7 g of the phenylacetic acid as a light brown crystalline solid.

The acid (1.7 g, 5.6 mmol) was then deprotected by addition of a 25% TFA/CH 2 Cl 2 solution and stirred for 2 hours at room temperature. The resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 CO 3 (15 g) and Fmoc-Cl (1.4 g, 5.5 mmol). This mixture was stirred at room temperature for 14 hours and then poured into 1 N HCl (100 mL). The solution was then extracted three times with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give 1.7 g of 3 as a white crystalline solid.

The dried resin (500 mg, 0.14 mmol) was placed in a small shaking vessel. 9 ml of DMF, 3 (180 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol) and DMAP (17 mg, 0.14 mmol) were then introduced into the vessel. The vessel was then shaken for 16 hours at room temperature. The contents were drained and the resin was washed 3 times with DMF, MeOH and CH 2 Cl 2 . The Fmoc group was then removed by adding 10 ml of 50% piperidine/DMF to the shaking vessel and shaking for 2 hours at room temperature. The obtained amine resin was washed 3 times with DMF, MeOH and CH 2 Cl 2 .

To the above resin was added 9 ml of DMF, 4-[N'-(o-tplylurea)]phenylacetic acid (132 mg, 0.42 mmol), PyBroP (196 mg, 0.42 mmol) and DIEA (107 mg, 0.84 mmol). The contents were shaken for 14 h at room temperature and then drained and washed 3 times with DMF, MeOH and CH 2 Cl 2 . The compound was then cleaved from the resin and the filtrate was collected and then concentrated in vacuo. The oil obtained was triturated by taking up the oil in MeOH and slowly adding Et 2 O until a precipitate formed. This precipitate was collected and dried in vacuo to give 52 mg of 3' as a white crystalline material.

EXAMPLE 3

The iodide (A) (0.5 g, 1.3 mmol) was placed in THF (20 mL) and cooled to -78 °C. Butyl lithium (2.21 mL, 1.6 M solution) was added dropwise and then the cooling bath was removed and gaseous CO 2 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 3 times with EtOAc, the combined organic layers were dried over MgSO 4 and then concentrated in vacuo to give 0.32 g of the benzoic acid as a white crystalline solid.

The benzoic acid (0.32 g, 1.68 mmol) was then deprotected by addition of a 25% TFA/CH 2 Cl 2 solution and stirred for 2 hours at room temperature. The resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 CO 3

(15 g), and Fmoc-Cl (0.44 g, 1.67 mmol). This mixture was stirred at room temperature for 14 hours and then poured into 1 N HCl (100 mL). The solution was then extracted 3

times with EtOAc, dried over MgSO 4 and then concentrated in vacuo to give 0.38 g of 5 as a white crystalline solid.

The dried resin (500 mg, 0.14 mmol) was placed in a small shaking vessel. 9 ml of DMF, 5 (173 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol) and DMAP (17 mg, 0.14 mmol) were then introduced into the vessel. The vessel was then shaken for 16 hours at room temperature. The contents were drained and the resin was washed 3 times with DMF, MeOH and CH 2 Cl 2 . The Fmoc group was then removed by adding 10 ml of 50% piperidine/DMF to the shaking vessel and shaking for 2 hours at room temperature. The resulting amine resin was washed 3 times with DMF, MeOH and CH 2 Cl 2 .

To the above resin was added 9 mL of DMF, 4-[N'-(o-tolylurea)]phenylacetic acid (132 mg, 0.42 mmol), PyBroP (196 mg, 0.42 mmol) and DIEA (107 mg, 0.84 mmol). The contents were shaken for 14 hours at room temperature and then drained and washed 3 times with DMF, MeOH and CH 2 Cl 2 . The compound was then cleaved from the resin and the filtrate was collected and then concentrated in vacuo. The oil obtained was triturated by taking up the oil in MeOH and slowly adding Et 2 O until a precipitate formed. This precipitate was collected and dried in vacuo to give 51 mg of 5' as a white crystalline material.

EXAMPLE 4

( E )-4-[2- [1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoic acid

To a cold (-78°C), stirred solution of triethyl-4-phosphonomethylbenzoate (904 mg, 3.01 mmol) in THF (20 mL) was added LiHMDS (1.0 M in THF, 3 mL, 3.00 mmol) and stirring was continued for 1 hour at the same temperature. N-Boc. prolinal (500 mg, 2.51 mmol) in THF (10 mL) was added to this mixture and the mixture was warmed to room temperature for 1 h. After stirring for 2 h, the mixture was quenched by adding water and extracted with EtOAc. The extract was washed with brine (200 ml), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane-EtOAc (8:1, v/v) as eluent to give 713 mg (82%) of ethyl (£)-4-[2-[1-(tert-butoxycarbonyl)- 2-pyrrolidinyl]ethenyl]benzoate as a colorless crystalline solid. Temp. : 68-70.<6>C;-

IR (KBr) 1710, 1697, 1681 cm'<1>; 1 H-NMR (CDCl 3 ) 51.39 (12 H, sscie-: of nt),

1 77-1.93 (3 H, m), 2.11 (1 H. m), 3.47 (2 H, m), 4.34-4.54 (total 3 H, rn), 6.22 (1H, m), 6.43 (1 H. "d, J = 14.2 Hz), 7.39 (2 H, J = 8.3 Hz), 7.97 (2 H, d, J = -8.3 Hz); MS (FAB) m/ z 346 (M<*>+l) ; ^na/.Calculated for C^NO,: C, 69.54; H, 7.88; N, 4.05. Found: C, 69.52; H, 8.08; N, 4.07.

To a stirred solution of ethyl (E)-4-[2-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]ethenyl]benzoate (700 mg, 2.03 mmol) in CH 2 Cl 2 (3 mL) was added FTA (3 ml) and the resulting mixture was stirred for 3 hours. The mixture was concentrated and the residue was made basic by the addition of saturated NaHCO 3 . The mixture was extracted with CHCl 3 (2 x 100 mL). The combined extracts were dried over Na 2 CO 3 and concentrated in vacuo to give 434 mg (87%) of ethyl {E)-4-[2-(2-pyrrolidinyl)ethenyl]benzoate as a brown oil.

'H-NMR (CDClj) 6 1.39 (3 H, t, J= 7.3 Hz), 1.52-2.06 (4 H, series a^m), 2.93-2.99 (1H, m), 3.07-3.13 (1H, m ), 3.74 (1H, q, J= 7.3 Hz), 4.37 (2

H, q, J= 7.3 Hz), 6.34 (1 H, dd, /= 15.6, 7.3 Hz), 6.54 (1 H, d, J= 15.6 Hz), 7.41 (2 H, d, >= 8.3 Hz) ,7.97(2H,d,J-=8.3Hz).

A mixture of ethyl ( E )-4-[2-(2-pyrrolidinyl)ethenyl]benzoate (434 mg, 1.77 mmol), pentafluorophenyl 4-[ N'~ (2-methylphenyl)-ureido]phenyl acetate (797 mg , 177 mmol), Et 3 N (0.37 mL, 2.66 mmol) in DMF (15 mL) was stirred for 15 h. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2 x 200 mL), dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1) as eluent to give 906 mg (quantified yield) ethyl ( E )-4-[2-[1-[4-[ N'-(2-methylphenyl) ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a brown oil.

1H-NMR (CDCl 3 ) δ 1.39 (3 H, t, J = 7.3 Hz), 1.83-2.20 (4 H, series avm), 2.24 (3 H, d,7=4.9 Hz), 3.63 (4 H, m) , 4.36 (2 H, q,J= 7.3 Hz), 4.62 and; 4.84 (total-1H ia), 6.18-6.47 (2 H, m), 7.03-8.02 (14 H, series avm),

A stirred mixture of ethyl ( E )-4-[2-[1-[4-[ N'-(2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate (906 mg, I, 77 mmol ) in 0.25 N NaOH (14 mL) and THF (14 mL) was heated under reflux for 3 days. The mixture was poured into ice-IN HCl (200 mL) and the precipitate was collected by suction. The solid was recrystallized from CHCl 3 -MeOH-n-hexane to give 4.53 mg-(53%) 6 as a pale yellow crystalline powder. Temp. : ij65-168°C;

IR (KBr) 3282, 2974, 2663, 2537, 1700, 1685 cm<4>; 1H-NMR (DMSO-o^) 8 1.74-2.12 (4 H, m), 2.24 (3 H, d, J= 4.9 Hz), 3.35-3.66 (4 H, m), 4.67-4.74 (1 H , m); 6.25-6.41 (1 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<*>+1); Anal Calcd for C 2 AsN 2 O/OJH 2 O: C, 70.71; H, 6.14; N, 8.39. Found: C, 70.46; H, 6.'07; N, 8.39.

EXAMPLE 5

4-[2-[1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoic acid

A mixture of [ E )-4- [2-[1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate (200 mg, 0.414 mmol) and 5% pd /C (200 mg) in MeOH (20 mL) hydrogenated at 1 atm for 1 h with vigorous stirring. The mixture was filtered and the filtrate concentrated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (4:1) as eluent to give 201 mg (quantified yield) of 7 as a colorless crystalline powder. Temp. : 180-190 °Ci JR (KBr) 3345, 3124, 3060, 3027, 2960, 2927, 2875, 1706, 1672 cm"!; 'H-NMR (DMSO-d«) 5 1.04-3.96 (total 16 H, series of m), 6.91-7.41 (9 H, m),'7.79-7.90 (3 H, m), 8.23 (1 H, br s), 9.31 (1H, br s); MS ( FAB) m/ z 486. 2- [1- [4- [W - (2-methylphenyl) ureido] phenylacetyl] pyrrolidinyl] methoxy] benzoic acid (S) -4- [2- [1- [3-methoxy-4- (W-phenylureido) f phenylacetyl] pyrrolidinyl] methoxy] benzoic acid i (S)-4-[2-[l-[4-[ N'~ (2-chlorophenyl)ureido]phenylacetyl]pyrro lidinyl] methoxy] benzoic acid

8, 9, and 10 To a stirred mixture of Boc-prolinol (3.00 g, 14.9 mmol), ethyl p-hydroxybenzoate (2.40 g, 14.5 mmol), and triphenylphosphine (3.91 g, 14.9 mmol) in THF (80 ml) was added dropwise diethyl azodicarboxylate (2.86 g, 16.4 mmol) at room temperature. After the addition was complete, the resulting mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed subsequently with 1 N NaOH, water and brine. The EtOAc layer was dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:4, v/v) as eluent to give 4.88 g (93%) of ethyl (S)-4-(1-tert-butoxycarbonyl-2 -pyrrolidinyl)methoxybenzoate as an oil.

To the above ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoate was added MeOH (100 mL) and

1 N NaOH (50 mL). The mixture was stirred for 15 hours at room temperature. After removal of MeOH under a reduced pressure

water (50 ml) was added to the residual solution. The watery one

solution was washed with Et 2 O (x2) and then acidified by addition of 1 N HCl. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSO 4 and evaporated in vacuo to give 4.26 g (95%) of (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid as a crystalline solid.

To the above ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid was added CH 2 Cl 2 (10 ml) and TFA (10 ml). The mixture was stirred at room temperature for 1 hour, Et 2 O was added to the mixture and the resulting solid was collected. The solid was dissolved in water (100 mL), dioxane (50 mL) and NaHCO 3 (4.4 g). Fmoc-Cl (3.34 g,

12.9 mmol) was added to the solution and the resulting mixture was stirred for 20 hours at room temperature. The mixture was washed with Et 2 O (x2) and the aqueous layer was separated. The layer was acidified by addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO 4 and evaporated in vacuo to give 5.36 g (91%) of ( S )-4-(1-Fmoc-2-pyrrolidinyl)methoxybenzoic acid as a viscous oil, which crystallized on standing.

Wang resin (0.71 mmol/g, 400 mg) was suspended in a solution of (S)-4-(1-Fmoc-2-pyrrolidinyl)methoxybenzoic acid (500 mg, 1.13 mmol) DMAP (35 mg, 0.29 mmol), HOBt (40 mg, 0.30 mmol) and DIC (0.45 mL, 2.9 mmol) in a mixture of DMF (3 mL) and CH 2 Cl 2 (7 mL). The mixture was shaken for 20 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3) and dried under reduced pressure to give 522 mg of resin which was used to prepare 8, 9 and 10.

8 To the above resin (115 mg) was added a solution of piperidine-DMF (50% v/v, 4 ml) and the mixture was shaken for 1 hour. The resin was washed with DMF

(x3), MeOH (x3), CH 2 Cl.2 (x3). To the resin was added DMF (4 mL), CH 2 Cl 2 (2 mL), 4-[N'-(2-methylphenyl)'ufeido]phenylacetic acid (70 mg, 0.25 mmol); PyBroP (115 mg , 0.25 mmol) and DIEA (0.13 mL, 0.75 mmol). The mixture was shaken for 21 h and drained. The resin was washed in DMF (x3), MeOH (x3), CH 2 Cl 2 (x3). To the resin a solution of TFA in CH 2 Cl 2 (50% v/v, 4 mL) was added and the mixture was shaken for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by Sep-Pak column. After removal of the solvent Et 2 O was added to the residue and the resulting solid was collected to give 25 mg 8

as a pale yellow crystalline material. MS (FAB) m/z 488 (M<+>+1). 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 h. The resin was washed with DMF (x3), MeOH (x3), CH2Cl2 (x3). To the resin was added DMF (2 mL), CH 2 Cl 2 (1 mL), 3-methoxy-4-(N'-phenyl)-ureido)phenylacetic acid (40 mg, 0.13 mmol), PyBroP (60 mg, 0, 13 mmol) and DIEA (0.060 ml, 0.34 mmol). The mixture was shaken for 40 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3). To the resin was added a solution of TFA in CH 2 Cl 2 (30% v/v) and the mixture was shaken for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified with a Sep-Pak column. After removal of the solvent, Et 2 O was added to the residue and the solid was collected to give 8 mg of 9 as a crystalline solid. MS (FAB) m/z'504 (M++1). 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 hours. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3). To the resin was added DMF (12 mL), CH 2 Cl 2 (8 mL), 4-(Fmoc-amino)phenylacetic acid (530 mg, 1.42 mmol), PyBroP (60 mg, 1.43 mmol) and DIEA (0, 62 ml, 3.56 mmol). The mixture was shaken for 60 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3) and dried under reduced pressure to give 617 mg of the resin. 57 mg of this resin was added to piperidine in DMF (40% v/v, 2 ml). The mixture was shaken for 1 hour. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3). 2-Chlorophenyl isocyanate (0.050 mL, 041 mmol) was added to a suspension of resin in THF (1 mL) and CH 2 Cl 2 (1 mL). The mixture was shaken for 20 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2Cl2 (x3). To the resin was added a solution of TFA in CH 2 Cl 2 (25% v/v, 2 mL) and the mixture was shaken for 1.5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified with a Sep-Pak column. After removal of the solvent, Et 2 O was added to the residue and the solid was collected to give 2 mg of 10 as a crystalline solid. MS (FAB) m/z 508 (M<+>+1). EXAMPLE 7 (S)-3-[2-[1-[3-methoxy-4-[ N'-phenylureido)phenylacetyl]pyrrolidinyl] methoxy]phenylacetic acid (S)-3-[2-[1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]pyrrolidinyl]methoxy]phenylacetic acid 11 and 12 To a stirred mixture of Boc-prolinol (3.51 g, 17.5 mmol), methyl m-hydroxyphenylacetate (2.90 g , 17.5 mmol), triphenylphosphine (4.60 g, 17.6 mmol) in THF (50 mL) was added dropwise diethyl azodicarboxylate (3.95 g, 17.5 mmol) at room temperature. After the addition was complete, the mixture was heated at reflux for 3 hours. After cooling, the mixture was concentrated in vacuo, the residue was dissolved in EtOAc, washed subsequently with 1 N NaOH, water, brine and dried over MgSO 4 . After removal of the solvent, the residue was purified by column chromatography on silica gel with EtOAc-hexane (1:4 v/v) as eluent to give 5.49 g (90%) of methyl-(S)-3-(1-tert -butoxycarbonyl-2-pyrrolidinyl)methoxyphenylacetate as an oil.

A mixture of the above methyl (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxyphenylacetate in MeOH (60 mL) and 1 N NaOH (20 mL) was stirred for 8 hours at room temperature. After removal of the solvent under reduced pressure, water (50 ml) was added to the residue. The mixture was extracted with Et 2 O (x2), and the aqueous layer was acidified with. addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, saline,

dried over MgSO 4 and then concentrated in vacuo to give 4.43 g (88%) of (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl)-methoxyphenylacetic acid as a viscous oil.

A mixture of the above (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy enylacetic acid in CH 2 Cl 2 (10 mL) and TFA (10 mL) was stirred for 1 hour at room temperature. Et20 was added to the mixture and this was allowed to stand. The upper layer was removed by decantation to give an oil. To a mixture of this oil in water (100 mL), dioxane (30 mL) and NaHCO 3 (6.0 g) was added Fmoc-Cl (2.86 g, 11.1 mmol) and the mixture was stirred for 20 hours at room temperature. The mixture was extracted with Et 2 O (x2), and the aqueous layer was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO 4 and concentrated in vacuo to give 5.08 g (81%) of (S)-3-(1-Fmoc-2-pyrrolidinyl)methoxyphenylacetic acid as a viscous oil.

Wang resin (0.71 mmol/g, 400 mg) was suspended in a solution of (S)-3-(1-Fmoc-2-pyrrolidinyl)methoxyphenylacetic acid (520 mg, 1.14 mmol), DMAP ( 35 mg, 0.29 mmol), HOBt (40 mg, 0.30 mmol) and DIC (0.45 mL, 2.9 mmol) in a mixture of DMF (3 mL) and CH 2 Cl 2 (7 mL). The mixture was shaken for 20 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH 2 Cl 2 (x3) and dried under reduced pressure to give 593 mg of resin which was used for the preparation of 11 and 12.

11 A mixture of the above resin (70 mg) in piperidine in DMF (40% v/v, 3 mL) was shaken for 1 h. The resin was washed with DMF (x3), MeOH (x3), CH2Cl2 (x3). To the resin was added DMF (1.5 mL), CH 2 Cl 2 (1.5 mL), 3-methoxy-4-(N\-phenylureido)phenylacetic acid (42 mg, 0.14 mmol), PyBrop (70 mg, 0 .15 mmol) and DIEA (0.065 ml, 0.37 mmol). The mixture was shaken for 15 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2Cl2 (x3). To the resin was added a solution of TFA in CH 2 Cl 2 (25% v/v, 2 mL) and the mixture was shaken for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified with a Sep-Pak column. After removal of the solvent, Et 2 O was added to the residue and the solid was collected to give 8. mg of 11 as a crystalline solid. MS (FAB) m/z 518 (M<+>+1).

12 A mixture of the above resin (70 mg) in piperidine in DMF (40% v/v, 3 mL) was shaken for 1 h. The resin was washed with DMF (x3), MeOH (x3), .CH 2 Cl 2 (x3). To the resin was added DMF (1.5 mL), CH 2 Cl 2 (1.5 mL), 4-[W-(2-methylphenyl)ureido]phenylacetic acid (40 mg, 0.14 mmol), PyBroP (70 mg, 0 .15 mmol) and DIEA (0.065 ml, 0.37 mmol). The mixture was shaken for 15 hours and drained. The resin became

washed with DMF (x3), MeOH (x3), CH2Cl2 (x3). A mixture of the resin in TFA-CH 2 Cl 2 (25% v/v, 2 mL) was shaken for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified with a Sep-Pak column. After removal of the solvent, Et 2 O was added to the residue and the solid was collected to give 11 mg of 12 as a crystalline solid. MS (FAB) m/z 50.2 (M++1).

EXAMPLE 8

4-[2-[1-[3-Methoxy-4-(W<r->phenylureido)phenylacetyl]-2-pyrrolidinyl] ethynyl] benzoic acid

To a stirred cold (-50?C) solution of N-Jb>oc-prolinal (5.98 g, 30 mmol) and PPh 3 (62.95 g, 240 mmol) in CH 2 Cl 2 (200 mL) was slowly added a solution of CBr 4 (39.80 g, 120 mmol) in CH 2 Cl 2 (50 mL), and stirring was continued for 1 h at 0 °C. To this mixture was added saturated NaHCO 3 and the mixture was extracted with CHCl 3 . The extract was washed with H 2 O, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) of 1-(tert-butoxycarbonyl)-2-(2,2- dibromothenyl)pyrrolidine as colorless plates. Temp. 61-63°C, IR (KBr) 1693 cm"1; 1H-NMR (CDCl 3 ) δ 1.46 (9H, s), 1.72-2.19 (4H, m), 3.35-3.45 (2H, m), 4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/ z 352, 354, 356, 358; Anal. Calcd for C11HI7NOJBr2: C, 37.21; H, 4.83; N, 3.94. Found: C ,

37.14; H, 4.83; N, 4.00.

To a stirred cold (-78°C) solution of 1-(tert-butoxycarbonyl)-2-(2,2-dibromothenyl)pyrrolidine (7.81 g, 22 mmol) in THF" (200 ml) was added n -BuLi (1.59 M in hexane, 28 mL, 44 mmol) over 10 min and stirring continued for 2 h at the same temperature. The reaction was quenched by addition of saturated NH 4 Cl and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated.The residue was chromatographed on silica gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 4.15 g (97%) of 1-(tert-butoxycarbonyl)-2 -ethynylpyrrolidine as a pale yellow oil.1 H-NMR (CDCl 3 ) 5 1.48 (9 H, s), 1.82-2.21 (4 H, m), 3.30-3.45 (2 H, m), 4.41-4.52 (1 H, m).

A suspension of ethyl 4-iodobenzoate (1.7 mL, 10 mmol) Pd(PPH3)4 (578 mg, 0.5 mmol) and CuI (190 mmol, 1 mmol) in i-Pr2NH (20 mL) was stirred for 0.5 hours under N2. To this mixture was added a solution of 1-(tert-butoxycarbonyl)-2-ethynylpyrroidine (1.95 g, 10 mmol) in i-Pr 2 NH (20 mL) over 10 min. After stirring for 3 h at room temperature, the mixture was poured into H 2 O and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane-AcOEt (10:1.v/v) as eluent to give 2.77 g (81%) of 1-(tert-butyloxycarbonyl)-2-(2-(4- ethoxycarbonylphenyl)ethynyl)pyrrolidine as a colorless oil.

1H-NMR (CDCl 3 ) δ 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, J=6.8 Hz), 4.54-4.77 (1H, m), 7.44 (2 H, d, .7=7.8 Hz), 7.96 (2 H, d, J=7.8 Hz)

To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (2.75 g, 8 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL), and the resulting mixture was stirred overnight. The mixture was concentrated

in vacuo and basified with saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 , and evaporated to give 1.95 g (quantitative yield) of 2-[2-(4-ethoxycarbonyl)ethynyl]pyrrolidone as a pale yellow oil. 1H-NMR (CDCl 3 ) δ 1.38 (3 H, t, .7=6.8 Hz), 1.82-2.16 (4 H, m), 3.01-3.48 (2 H, m), 4.00-4.11 (1 H, m ), 4.37

(2H, q, .7=6.8 Hz), 4.54-4.77 (1H, m), 7.44-7.46 (2H, m), 7.95-7.97 (2H, m).

A mixture of 3-methoxy-4-(N-phenylureido)phenylacetic acid

(180 mg, 0.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)-pyrrolidine (146 mg, 0.6 mmol), EDC (173 mg, 0.9 mmol), DMAP

(73 mg, 0.6 mmol) and cat. HOBt in DMF (10 mL) was stirred overnight. The mixture was poured into 1-N HCl and the solid was collected by suction. The residue was dissolved in CHCl 3 and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel with CHCl3-MeOH (10:1,

v/v) as eluent to give 192 mg (61%) of ethyl 4- [2- [1- [3-methoxy-4-(N-phenylureido) phenylacetyl]-2-pyrrolidinyl'3 ethynyl] benzoate as a " pale yellow amorphous solid.

1H-NMR (CDCl 3 ) 6 1.38 (3 H, t, >6.8 Hz), 1.98-2.24 (4 H, m), 3.48-3.89.(2 H, m), 3.53 (2 H, s), 3.62 (3 H, s), 4.33-4.40 (2 H, m), 4.78-5.04 (1 H, rn), 6.77-8.00/14 H, m).

To a stirred solution of ethyl 4-[2-[l-[3-methoxy-4-(N-phenylureido)phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate (184

mg, 0.35 mmol) in THF (5 mL) was added 0.25 N NaOH (4

ml). The resulting mixture was stirred overnight.

The mixture was poured into H20 and acidified by adding 1

N HCl (1 mL). The solid was collected with suction and dissolved in CHCl 3 . The solution was dried over MgSO 4 and evaporated.

The residue was recrystallized from CHCl3-n-hexane to give 65 mg (37%) of 13 as a white crystalline powder. Temp. 154-157°C,

3346, 2952, 2615, 1712, 1693cm;'; 1H-NMR (CDCl 3 ) δ 1.92-2.29 (4H, m), 3.32-3.82 (2H, m), . 3.78 (2 H, s), 3.80 (3 H, s), 4.87-5.11 (1 H, m), 6.77-9.26 (14 H, m), 13.10 (1 H, br s); MS (FAB) m/z 498 (M<*>+1).

EXAMPLE.9 '

4- [2- [1- [3-methoxy-4-.( [ N* - (2-methylphenyl)ureido] phenylacetyl] - 2-pyrrolidinyl]ethynyl]benzoic acid

A mixture of .3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (1.45 g, 4.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)-ethynyl)pyrrolidine (1.12 g, 4.6 mmol), EDC 1.32 g (6.9 mmol), DMAP (562 mg, 4.6 mmol) in DMF (20 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected

with suction. The solid was dissolved in CHCl 3 and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel with CHCl3-MeOH (100:1,

v/v) as eluent to give 2.20 g (89%) ethyl 4-[2-[1-[3-methoxy-4- ^[ N1 -(2-methylphenyl)ureido]phenylacetyl]-2- pyrrolidinyl] ethynyl] benzoate as a white amorphous solid..

1H-NMR (CDCl1) δ 1.37-1.41 (3H, m), 1.94-2.22 (4H, m), 2.29 (3H, s), 3.41-3.89 (2H, m), 3.62

(3 H, s), 3.69 (2 H, s), 4.34-4.40 (2 H, m), 4.72-5.01(1 H, iri), 6.33 (1 H, br s), 6.80-8.06 (12 H ,

m).

To a stirred solution of ethyl 4-[2-[1-[3-methoxy-4-([W' -

(2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]tetynyl]benzoate (2.16 g, 4 mmol) in THF (30 mL) was added 0.25 N NaOH (32 mL) and stirring was continued over the night. The mixture;

was poured into H20 and acidified by adding 1 N HCl (8

ml). The precipitate obtained was collected with suction and dissolved in CHCl3. - The solution was dried over MgSO 4 and evaporated.

The residue was recrystallized from CHCl 3 -n-hexane to give 555 mg (27%) of 14 as a white crystalline powder. Temp. 161-164°C,

IR (KBr) 3338, 2954, 2875, 1707, 1691 cm -1 ; 'H-NMR (CDCl 3 ) δ 1.96-2.10 (4 H, m), '

2.24 (3 H, s), 3.32-3.81 (2 H, xn), 3.62 (2 H, s), 3.81 (3 H, s), 4.87-5.10 (1 H, m), 6.76-8.58 (13 H , '

m); MS (FAB) m/z512(M<*>+1)

EXAMPLE 10

4- [2- [1- [3-methoxy-4- [iM' - (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinyl] ethynyl] phenylacetic acid

A mixture of 3-methoxy-4-[ N -(2-methylphenyl)ureido]phenylacetic acid (141 mg, 0.45 mmol), 2-[2-(3-ethoxycarbonylmethyl-phenyl)ethynyl]pyrrolidine (116 mg, 0.45 mmol), EDC (130 mg, 0.68 mmol), DMAP (55 mg, 0.45 mmol), cat. HOBt in DMF (10 mL) was stirred overnight. The mixture was poured into 1N HCl and the solid was collected by filtration. The solid was dissolved in CHCl 3 , dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (100:1, v/v) as eluent to give an oil which was dissolved in THF (5 mL). 0.25 N NaOH (4 mL) was added to this solution with stirring. After stirring overnight, the mixture was poured into 1 N HCl (20 mL). The precipitate obtained was collected with suction and dissolved in CHCl3. The solution was dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (5:1, v/v) as eluent to give 92 mg (39%) of 15 as a white amorphous solid. 1H-NMR (CDCl 3 ) δ 1.96-2.18 (7H, m), 3.50-3.88 (9H, nr), 4.78-4.98 (2

H,' m), 6.72-7.99 (14 H, m); MS (FAB) m/z 526 (MN-1).

EXAMPLE 11

4-[1-[4-[W -(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalic acid

To a stirred solution of pentafluorophenyl ester of 4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (2.32 g, 5.15 mmol), dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (1, 51 g, 5.15 mmol in DMF (20 mL) was added Et 3 N (1.0 mL, 6.65 mmol) and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc. The solution was washed with brine , dried over MgSO 4 and evaporated in vacuo The residue was purified by column chromatography on silica gel eluting with CHCl 3 -MeOH (10:1, v/v) to give 1.58 g

(55%)dimethyl '4- [1- [4- [ N'~ (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinylmethoxy]isophthalate as a yellow crystalline solid ... 'H-NMR (CDO,) 5 1.87-2.25 (m, total 7 H), 3.50-3.65 (m, 4 H), 3.85

(s, 3 H), 3.89 (s, 3 H), 4.18-4.31 (m, 2 H), 4.44 (m, 1 H), 6.95-8.45 (m, total 13 H).

To a stirred solution of dimethyl 4-[1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate (1.56 g, 2.79 mmol) in THF (30 mL ) 0.25 N NaOH (20 mL) was added and the reaction mixture was heated at reflux overnight. The resulting mixture was poured into 1 N HCl and the solid was collected. The impure solid became. washed with Et 2 O to give 574 mg (39%). 16 as a yellow amorphous solid. TR (KBf) 1710 cm"1; 1H-NMR (DMSO-ds) δ 1.83-2.18 (m, 4H), 2.24 (s, 3H), 3.36-4.28 (m, 8H) 6:91- 9.02 (series a* m, total 13 H), 12.89 (br s, 1 H);

MS (FAB) m/z 532 (M<*>+1).

EXAMPLE 12

4-[2-[1- [3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl] -2-pyrrolidinyl]ethenyl]benzoic acid

■To a stirred solution of 4-[2-[2-(N-tert-butoxycarbonyl)-pyrrolidinyl]ethenyl]benzonitrile (2.26 g, 7.57 mmol) in CH 2 Cl 2

(23 ml) was added dropwise a 1.5M solution of diisopropylaluminum anhydride (toluene solution) (6.06 ml, 9.09 mmol) at 0°C over 15 min. The obtained solution was stirred for 3 hours at 0°C. The solution was quenched with

•addition of saturated NH4C1. The resulting mixture was filtered through diatomaceous earth and the filtrate was extracted with EtOAc. The filtrate was washed with saline, dried over

Na 2 SO 4 and evaporated in vacuo to give 1.89 g (83%) of 4-[2-[2-(N-tert-butoxycarbonyl)pyrrolidinyl]ethenyl]benzaldehyde as a yellow syrup.

To a stirred solution of NaOH (1.00 g, 25.1 mmol) in water (10 mL) was added a solution of AgNO 3 (2.13 g, 12.5 mmol) in CH 3 CN (10 mL) at 0° C within 0.5 hours. To the stirred above mixture was added dropwise a solution of 4-[2-[2-(N-tert-butoxycarbonyl)pyrrolidinyl]-ethenyl]benzaldehyde (1.89 g, 6.27 mmol) in CH 3 CN (10 mL) at 0°C within 20 min. After the resulting mixture was stirred for an additional 3 hours at room temperature, the mixture was filtered with suction and then washed with hot water. After the filtrate was washed with EtOAc, the aqueous layer was carefully acidified by the addition of 1 N HCl and then extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 0.700 g (35% for 2 steps) of 4-[2-[2-(N-tert-butoxycarbonyl)pyrrolidinyl]ethenyl]benzoic acid as a pale yellow crystalline material.

To a stirred solution of 4-[2-[2-(N-tert-butoxycarbonyl)-pyrrolidinyl]ethenyl]benzoic acid (0.700 g, 2.21 mmol) in MeOH-benzene (1:4, v/v, 3 0 ml) a 2 M n-hexane solution of TMSCHN2 (1.32 ml, 2.65 mmol) was added dropwise at room temperature. After the solution had been stirred for 0.5 hours at room temperature, the solution was evaporated in vacuo. The oily residue obtained was chromatographed on silica gel with

in EtOAc-n-hexane (1:6, v/v) as eluent to give 0.64 g (88%) methyl 4-[2-[2-(N-tert-butoxycarbonyl)-pyrrolidinyl]ethenyl]benzoate as a pale yellow crystalline material.

To a stirred solution of methyl 4-[2-[2-(N-tert-butoxycarbonyl)pyrrolidinyl]ethenyl]benzoate (0.64 g, 1.93 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL ) at room temperature. After the mixture had been stirred for 1 hour at room temperature, the mixture was evaporated in vacuo. The residue was treated with saturated NaHCO 3 and extracted with CHCl 3 . The extract was dried over Na2SO4 and evaporated in vacuo to give 0.45 g (100%) of methyl 4-

[2-(2-pyrrolidinyl)ethenyl]benzoate as a yellow crystalline material.

To a stirred mixture.-of' 3-methoxy-4-[AT-(2-methylphenyl)-ureido]phenylacetic acid (285 mg, 0.906 mmol), methyl 4-[2-(2- ■ pyrrolidinyl)ethenyl]benzoate ( 210 mg, 0.906 mmol) in DMF (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (209 mg, 109 mmol), a hydroxybenzotriazole (HOBt) (147 mg, 1.09 mmol) and 4-dimethylaminopyridine (DMAP) (11 mg, 0.0906 mmol) at room temperature. After the resulting mixture was stirred for 48 hours at room temperature, the mixture was poured into ice-1N HCl and extracted with EtOAc. The extract was dried over Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with acetotoluene (1:4 to 1:1 v/v as eluent) to give 0.47 g (98%) of methyl 4-[2-[l-[3-methoxy-4- [ N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a white crystalline material.

To a stirred solution of methyl 4-[2-[1-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]-benzdate (0.47 g, 0.891 mmol ) in THF (5 mL) was added 0.25 N NaOH (5.36 mL). The resulting mixture was stirred at room temperature for 20 hours. The mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 430 mg (94%) of 17 as a white crystalline material. 1H-NMR (400MHz, DMSO-ds) δ 1.78-2.13 (4H, m), 2.50 (3H, s), 3..44 -3.68 (4H, m),

3.75 and 3.82 (3H, s), 4.71 (1H, m), 6.26-8.59 (15H, m).

EXAMPLE 13

4-[2-[l-[-3-methoxy-4-(N'-phenylureido)phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoic acid

To a stirred solution of 3-methoxy-4-(N'-phenylureido)-phenylacetic acid (305 mg, 1.01 mmol), methyl 4-[2-(2-pyrrolidinyl)ethenyl]benzoate (235 mg, 1, 01 mmol) in DMF (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (232 mg, 1.21 mmol), 1-hydroxybenzotriazole (HOBt) (164 mg, 1.21 mmol) and 4-dimethylaminopyridine (DMAP) (12 mg, 0.101 mmol) at room temperature. After the mixture was stirred for 48 hours, the mixture was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to an oily residue. The residue was chromatographed on silica gel with acetone:toluene (1:4 to 1:1, v/v) as eluent to give 0.43 g (83%) of methyl 4-[2-[l-[3-methoxy-4 - [ N' -(phenylureido)phenylacetyl]-2-pyrrolidinyl]-ethenyl]benzoate as a white crystalline material.

To a stirred solution of methyl 4-[2-[1-[3-methoxy-4- [ N'~

(phenylureido)phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate (0.43 g, 0.837 mmol) in THF (5 mL) was added a solution of 0.25 N NaOH (5.04 mL) at room temperature. After the resulting mixture was stirred for 20 hours, the mixture was acidified by careful addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 397 mg (95%) of 18 as a white crystalline material.

1H-NMR (400MHz, DMSO-dj) δ 1.78-2.13 (4H, m), 3.17-3.68 (4H, m),

3.74, 3.82 (3H, s), 4.71 (1H, m), 6.27-9.28 (16H, m)..

EXAMPLE 14

4-[2-[1-[3-Methoxy-4-(N-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoic acid

A mixture of 4-[2-[1- [3-methoxy-4-[ N'~ (2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoic acid (184 mg, 0.358 mmol) and 5% Pd-C (368 mg) in MeOH was hydrogenated at atmospheric pressure at room temperature. After the mixture was stirred for 21 hours at room temperature, insoluble catalyst was filtered off and the filtrate was evaporated in vacuo, the residue was chromatographed on silica gel with MeOH-CHCl3 (1:4 to 1:3, v/v) as eluent to give 123 mg (66%) 19 as 'a' white crystalline material. (H-NMR pMSO-d«) 8 1.55-2.03 (m, 6H), 2.24 (s, 3H),

2.60 (m, 2H), 3.17-3.59 (m, 4H), 3.83 (s, 3H), 3.97 (m, 1H), 6.61-8.57 (m, 13H); MS (FAB) m/z 516 (IVT+I).

, EXAMPLE 15

.3- [1- [3-methoxy-4- [ N'~ (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinyl,] methyl thiobenzoic acid

To a solution of m-iodophenol (20.0 g, 90.9 mmol) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane (20.4 g, 181.8 mmol) and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol). The cloudy solution obtained was stirred for 0.5 hours at 35°C and then heated at 75°C for 0.5 hours. After cooling, 300 ml of water was added to the mixture. The solid was collected, washed with water and dried under reduced pressure to give 27.63 g (99%) of O-m-iodophenyldimethylthiocarbamate as a pale yellow crystalline powder.

IR (KBr) 1540, 1463, 1278, 1193, 1166, 1124 cm-';

1 H-NMR (400 MHz, CDCl 3 ) 6 3.33 (s, 3H), 3.45 (s, 3H), 7.05 - 7.14.(m, 2H), 7.43 (d, 7= 1.9 Hz, 1H), 7.58 (dd , J = 1.0, 7.8 Hz, IH); MS (FAB) mh 307 (M<+>+1); Anal Calculated for C,H10INOS: C, 35.19; H, 3.28; N, 4.56. Found: C, 35.23; H.3.40; N, 4.41.

A solution of O-m-pdphenyldimethylthiocarbamate (10.0 g, 32.6 mmol) in (10.0 g, 32.6 mmol) in Ph 2 O (25 mL) was heated at 230°C for 10 h. After cooling, the reaction mixture was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 9.31 g (93%) of S-m-iodophenyldimethylthiocarbamate as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) 8 3.08 (br s, 6H), 7.11 (t, J= 7.8 Hz, 1H), 7.46 (d, /= 7.3 Hz, 1H), 7.71 (d, /= 7.3 Hz, 1H), 7.85 (s, 1H); MS (FAB) m/z 307(^+1).

(

To a solution of S-m-iodophenyldimethylthiocarbamate (5.01 g, 16.31 mmol) in MeOH (20 mL) was added 28% MeONa in MeOH (3.46 mL, 17.94 mmol).;: It gave mixture was stirred at room temperature for 3.5 hours and then heated at 70°C overnight. After cooling, 1 N HCl was added. The solvent was removed under reduced pressure and. the residue was diluted with EtOAc. The solution was washed with H 2 O, brine and dried over Na 2 SO 4 . The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 3.42 g (89%) of m-iodothiophenol as an oil. 1H-NMR (400 MHz, CDClj) δ 3.45 (s, 1H), 6.95 (t, J = 7.8 Hz,H),7.23 (d/= 7.8 Hz 1H), 7.48 (d, J = 7.3 Hz,lH ), 7.64 (t, J= 1.5 Hz, 1H); MS(EI) m/z 236(M<*>).

To a stirred solution of N-(tert-butoxycarbonyl)-2-pyrrolidinyl methanol (4!, 30 g, 20.0 mmol) in pyridine (40 mL) was added p-TsCl (5.72 g, 30.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched. with H 2 O and evapd. The residue was diluted with EtOAc and washed with 1 N HCl, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (2:1, v/v) as eluent to give 5.76 g (81%) of N-(tert-butoxycarbonyl)-2- pyrrolidinylmethyl p-toluenesulfonate as eh colorless oil.

'H-NMR (400 MHz, CDClj) 6 1.36 and 1.41 (each total^H), 1.82 (br m, 2H), 1.96 (br m, 2H), 2.44 (s, 3H), 3.30 (br m, 2H ),.3.89 (br s, 1H), 3.96 (br.s, 1H), 4.09 (br m, 1H), 7.34 (br s, 2H), 7.<y>7 (d, J= 8.3 Hz, 2H); MS (FAB) m/z 35.6 (M<*>+1).

To a stirred mixture of n-iodothiophenol (2.67 g, 11.31 mmol) and N-tert-butoxycarbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (3.34 g, 9.43 mmol) in pyridine ( 9.4 ml) 8 N KOH (1.77 ml) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc. The solution was washed with H 2 O, saturated NH 4 Cl solution; brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 1.79 g (45%)

[ N -(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl-3-iodophenyl sulfide as an oil. , r,^ m (400 MHz, CDC13) 5 1.45 (s, 9H), 1.78 - 2.01 (br m, 4H), 2.71 (dt, 1H), 3.32 - 3.49 (br m, 3H), 3.90 - 4.02 ( br m, 1H), 7.12 (d, J= 7.8 Hz, 1H), 7;18 (d, J= 7.8 Hz, 1H), 7.57 (dd, 7= 2.0, 8.3 Hz, 2H); MS (FAB) m/z 420 (M<*>+1).

To a stirred solution of [1-(tert-butoxycarbonyl)-2-pyrrolidinyl] methyl-3-iodophenyl sulfide (1.76 g, 4.20 mmol)' in DMSO (20 mL) and MeOH (16 ml) were added Et 3 N (1.28 ml,' 9.24 mmol), Pd(0Ac) 2 (47.1 mg; 0.21 mmol) and 1,3-bis-(diphenylphosphino)propane' (86, 6 mg, 0.21 mmol), and then CO gas was bubbled through for 5 min. The resulting mixture was stirred at 70°C overnight. After cooling, the mixture was concentrated. The residue was diluted with EtOAc and washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 1.28 g (87%) of methyl 3-[1-(tert- butoxycarbonyl)-2-pyrrolidinyl] methylthiobenzoate as an oil.

NMR (400 MHz, CDCl 3 ) 6 1.42.0g:^ 1.45 .fcver^B^ 1.79 r 2.05 (br m, 4H) 2.83 (dt, J= 10.8, 30.3 Hz, 1H), 3.34 - 3.54 (br m, 3H ), 3.92 (s, 3H), 3.92 and ] A. 6' 5 (d, J= 7.8 Hz, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.63 (br d, J= 14.7 Hz, 1H), 7.83 (br d, J =' 12.7- Hz, 1H), 8.04 (s, 1H); MS (FAB) r/z 352 (MM-1).

To a stirred solution of methyl 3-[1-tert-butoxycarbonyl)-2-pyrrolidinyl]methylthiobenzoate (1.46 g, 4.16 mmol) in CH 2 Cl 2 (30 mL) was added TFA (15 mL) at 0 °C . The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was treated with 1 N >NaOH and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 947 mg (91%) of methyl 3-(2-pyrrolidinyl)methylthiobenzoate as a brown oil.

'H-NMR (400 MHz, CD Cl3) 8 1.45 - 1.54 (m, 1H), 1.72 - 2.00 (m, 4H) 2.88 - 3.10 (m, 4H), 3.30 (m, 1H), 3.92 (s, 3H ), 7.34 (t, J= 7.8 Hz, 1H), 7.52 (m, 1H), 7.84 (m, 1H), 8.01 (t, J= 2.0 Hz, 1H); MS (FAB) m/z 252 (M<*>+1).

The mixture of 3-nitrophletoxy-4-[N-(2-methylphenyl)ureido]phenylacetic acid (1.18 g, 3.77 mmol), EDC.(1.08 g, 5.65 mmol), DMAP

(23 mg, 0.19 mmol) and HOBt (25 mg, 0.19 mmol) in DMF (5 mL)

/—

was stirred at room temperature for 1 hour.' Methyl 3-(2-pyrrolidinyl)methylthiobenzoate (947 mg, 3.77 mmol) was added to the mixture and the resulting mixture was stirred overnight. After DMAP (460 mg, 3.77 mmol) and .HOBt (835 mg, 6.18 mmol) were added, the mixture was stirred for an additional 5 hours. The reaction mixture was diluted with EtOAc. The solution was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was chromatographed on silica gel with n-hexane-EtOAc (2:3, v/v) as eluent to give 294.3 mg (14%) of methyl 3-[1-[3-methoxy-4-[AM- 2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthiobenzoate as a pale yellow amorphous solid IR (KBr) 2875, 1724, 1620, 1284, 1182 cm-'; 1H-NMR (400 MHz, CDCl 3 ) δ 1.86 - 2.05 (m, 4H), 2.3 l(s, 3H), 2.84 (dd, J= 9.3, 13.7 Hz, 1H), 3.43 - 3.59 (m, 5H) , 3.73 (s, 3H), 3.92 (s, 3H), 4.33 (m, 1H), 6.16 (s, 1H), 6.77 - 6.80 (m, 2H), 7.04 (s, 1H), 7.16 (t, J = 8.3 Hz, 1H), 7.38 (t, J= 7.8 Hz, 1H), 7.49 ( t, J= 7.8 Hz, 1H), 7.73 (dt, 7= 1.0, 7.8 Hz, 1H), 7.79 (dd, . 7 = 2.0, 6.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8.05 (dd, J= 2.4, 7.8Hz, 1H); MS (FAB) m/z 548 (M<*>+1).

To a stirred solution of methyl 3-[l-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthiobenzoate

(148.2 mg, 0.271 mmol) in TFH (7.4 mL) and H 2 O' (1.8 mL) was added LiOH (19.4 mL, 0.812 mmol) and the resulting mixture was stirred for 9 h at room temperature . The mixture was treated with 1N HCl and extracted with CHCl 3 . The extract was washed with brine and dried over Na 2 SO 4 . Solvent was removed under reduced pressure and the residue was purified by preparative TLC eluting with CHCl 3 -MeOH

(10:1, v/v) and crystallized from n-hexane-EtOAc to give 98.7 mg (62%) of 20 as a white powder.

JR (KBr) 2960, 1708cm-'; 1H-NMR (400 MHz, DMSO-d<) 8 1.82 - 2.01 (m, 4Hj, 2.24 (s, 3H), 2.93 (dd, J= 9.3,

in

12.7 Hz, 1H), 3.40 - 3.54 (m, 5H), 3.86 (s, 3H), 4.13 (br m, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.87 (d, J= 1.5Hz , lH),6.94(t,./= 7.8 Hz, lH), 7.10-7.17 (m, 2H), 7.42 (t, J= 7.8 Hz, 1H), 7.70 (d, J= . 7.8 Hz, 1H) , 7.74 (d, J= 8.3 Hz, 1H), 7.79 (d, J= 7.8 Hz, 1H), 7.84 (s, 1H), 8.00 (d, J= 8.3 Hz, 1H), 8.48 (s, 1H) , 8.57 (p, 1H); MS (FAB) m/z 534 (M<+>+1).

EXAMPLE 16

3-t[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-' pyrrolidinyl]methylsulfonyl]benzoic acid

To a stirred solution of methyl 3-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl) ureido] phenylacetyl] .-2-pyrrolidinyl] methylthio] - benzoate (131.8 mg, 0.241 mmol ) in CH 2 Cl 2 (3 mL) was added jn-CPBA (13 0.5 mg, 0.52 9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with CHCl 3 and quenched with saturated Na 2 S 2 O 3 solution. The organic layer was separated, washed with saturated NaHCO 3 solution, brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give methyl 3-[[1-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylsulfonyl]benzoate as an amorphous solid. To a stirred solution of this crude compound in THF (7.4 mL) and H 2 O (1.8 mL) was added LiOH (17.3 mg, 0.723 mmol)- and stirring was continued overnight at room temperature. The reaction mixture was diluted with CHCl 3 and washed with 1 N HCl, then brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was purified by preparative TLC with CHCl3-MeOH (10:1, v/v) as eluent, and the crude solid was recrystallized from n-hexane-EtOAc to give 69.9 mg (51%) 21 as a white crystalline powder. Temp. 243 - 245°C; IR (KBr) 3354.2974, 1533cm"'; .'H-NMR(400 MHz, DMSO-dJ 8 1.80 - 2.00 (m, 4H), 2.24 (s, 3H), 3.19 - 3.62 (m, 6H), 3.82 (s, 3H), 4.18 (m, 1H), 6.67 (d, J= 8.8 Hz, 1H), 6.80 (d, J= 1.0 Hz, 1H), 6.93 (t, J= 7.3 Hz, 1H), 7.10 - 7.17 (m, 2H), 7.66 (t, J= 7.8 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 7.91 - 7.99 (m, 2H), 8.20 (d, J = 7.3 Hz , 1H), 8.34 (s, 1H), 8.48 (s, 1H), 8.56 (s, 1H); MS (FAB) m/ z 566 ( M*+ l) ; Anal. Calculated for C»Hj,N3O7S- 1HCMH 2 O: C, 56.17; H, 5.5.3; N, 6.78. Found: C, 55.92; H. 5.58; N, 6.71. EXAMPLE 17 4- [ [1- [3-methoxy-4- [AT - (2 -methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylsulfonyl]benzoic acid

To a stirred solution of methyl 4- [.[1.- [3-methoxy-4- [ N'~ (2-methyl phenyl) ureido] phenylacetyl] -2-pyrrolidinyl] methylthio] - benzoate (300 mg, 0.548 mmol) in CH 2 Cl 2 (6 mL) was added J71-CPBA■ (297 mg, 1.206 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with CHCl 3 and quenched with saturated Na 2 S 2 O 3 solution. The separated organic layer was washed with saturated NaHCO 3 solution, brine, and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give methyl 4- [ [1- [3-methoxy-4- [ N'~ (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinyl]methylsulfonyl] benzoate as a impure yellow oil. To a stirred solution of this crude compound in THF (4.4 mL) and H 2 O (1.1 mL) was added LiOH (39.4 mg, 1.643 mmol) and stirring was continued overnight at room temperature.

■ The reaction mixture was diluted with CHCl 3 and washed with 1 N HCl, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was purified by preparative TLC eluting with CHCl 3 -MeOH (10:1, v/v) and crystallized from n-hexane-EtOAc to give 128.0 mg (41 %) 22 as a white powder.

IR (KBr) 3388, 2974, 1537, 1298, 1155 nm'; 1H-NMR (400 MHz, DMSO-d,) δ 1.80 -.,1.98 (m, 4H), 2.24 (s, 3H), 2.54 (s, 1H), 3.20 - 3.70 (m, 5H), 3.82 ( p, 3H), 4.16,

(brm, 1H), 6.67 (dd, J= 1.5, 8.3 Hz, 1H), 6.80 (d, J= 1.5Hz, 1H), 6.93 (d,-7= 7.3 Hz, 1H), 7.10 - 7.16 (m , 2H), 7.78 (d, J= 7.3 Hz, 1H), 7.95 (d, J= 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 1H), 8.14 (d, /= 8.3 Hz, 2H ), 8.49'(s, 1H), 8.57 (s, 1H); MS (FAB) ni/ z 566 (M*+ 1); Anal. Calculated for C^Hj.NAS-SHjO: C.56.21; H, 6.02; N, 6.78.Found:.C, 56.76; H, 5.37; N, 6.70.

EXAMPLE 18

4-[[1- [3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]benzoic acid

To a stirred solution of p-iodophenol (20.0 mg, 90.9 mmol) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane

(20.4 g, 181.8 mmol)" and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol) the resulting solution was stirred for 3.5 hours at 75°C. After cooling, 300 ml of water was added. The solid was collected with suction and dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na 2 SO 4 and evaporated under reduced pressure. The crude solid was recrystallized from H 2 O to give 2 6.75 g (96%) of 0-p-iodophenyldimethylthiocarbamate as a pale yellow crystalline powder.

IR (KBr) 1479, 1207, 827 cm-'; 1H-NMR (400 MHz, CDCl 3 ) δ 3.37 (s, 3H), 3.45 (s, 3H), 6.83 (d, J= 8.8 Hz, 2H), 7.69 (d, J= 8.3 Hz, 2H); MS (FAB) m/z 307 (M<*>+1); Anal. Calculated for QHIOINOS: C, 35.19; H, 3.28; N, 4.56. Found:;

C, 35.17; H, 3.35; N, 4.44.

A stirred solution of O-p-iodophenyldimethylthiocarbamate (10.0 g, 32.6 mmol) in Ph 2 O (25 mL) was heated at 230 °C for 5.5 h. After cooling, the reaction mixture was chromatographed on silica gel n-hexane-EtOAc (3:1, v/v) as eluent to give 2.55 g (26%) of S-p-iodophenyldimethylthiocarbamate as a white crystalline powder.

IR (KBr) 3299, 1651, 1469, 1371cm-';'H-NMR (400 MHz, CDCl3) 8 3.03 (br s, 3H), 3.08 (br s, 3H), 7.21 (d, J= 8.3 Hz, 2H), 7.70 (d, J =

8.3 Hz, 2H); MS (FAB) m/z 308 (M*+1);

Found: C.35.49; H.3.28; N, 4.43.

To a solution of S-p-iodophenyldimethylthiocarbamate (2.55 g, 8.31 mmol) in MeOH (10 mL) was added MeONa (495 mg, 9.14 mmol) and the resulting mixture was stirred at 70°C overnight . After cooling, 1N HCl was added and the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with H 2 O, brine and dried over Na 2 SO 4 . The organic layer was concentrated under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 1.75 g (89%) of p-iodothiophenol as a pale yellow crystalline solid IR (KBr) 2559, 1097, 1002, 806cni-'; 'H-NMR (400 MHz, CDClj) 5' 3.43 (s, 1H), -7.10 (d, J= 8.3 Hz, 2H), 7.53 (d, J= 8.3 Hz, 2H); MS !(FAB) m/ z 236 (^r+^Mno/.Calculated for C^jIS: C, 30.53; H, 2.13. Found: C, 30.57; H, 2.15.

To a stirred mixture of p-iodothiophenol (1.75 g, 7.43 mmol)

and A7-( tert -butox<y>carbon<y>l )-2- p<y>rrolidin<y>methyl p -toluenesulfonate (2.39 g, 6.75 mmol) in pyridine (12.7 mL) 8 N KOH (1.27 ml) was added at room temperature and the resulting mixture was stirred for 4 hours at the same temperature. The reaction mixture was diluted with EtOAc. The solution was washed with H 2 O, saturated MH 4 Cl, brine and dried over Na 2 SO 4 . The organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 1.49 g (53%) [ N -(tert-butoxycarbonyl)-2-pyrrolidinyl]-methyl 4- iodophenyl sulfide as a pale yellow oil.

1H-NMR (400 MHz, CDCl 3 ) δ (s, 9H), 1.78 - 2.01 (br m, 4H), 2.71 (dt, 1H), 3.32 - 3.49 (br m, 3H), 3.90 - 4.02 (br m . ^+1).

To a stirred solution of [1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl-4-iodophenyl sulfide (1.49 g, 3.56 mmol) in DMSO (16 mL) and MeOH (13 mL) was added Et3N (1.09 mL, 7.84 mmol), Pd(OAc) 2 (40 mg, 0.178 mmol) and 1,3-bis(diphenyl-phosphino)propane (73.4 mg, 0.178 mmol). CO gas was introduced into the resulting stirred mixture for 5 min. and the mixture was stirred at 70°C overnight. After cooling, the mixture was concentrated to a small volume. The residue was diluted with EtOAc and washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 1.16 g (93%) of methyl 4-[1-(tert- butoxycarbonyl)-2-pyrrolidinyl]methylthiobenzoate as an oil. 'H-NMR(400MHz, CDClj) δ 1.51 and 1;47 (hyers, 9H), 1.78 - 2.05 (br m, 4H) 2.77 (dt, J=10.8, 37.1 Hz, 1H), 3.34 - 3.58 (m, 3H), 3.89 (p, 3H), 4.03

(br d, J= 27.3 Hz, 1H), 7.38 (d, 7= 7.3 Hz, 1H), 7.47 (d, /= 7.3 Hz, 1H), 7.92 (br s, 2H); MS

(FAB) m/z 352 (M<*>+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl] methylthiobenzoate (1.16 g, 3.32 mmol)

in CH 2 Cl 2 (20 mL) was added FTA (4 mL) and the mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue was treated with 1 N NaOH. The mixture was extracted with CHCl 3 . The extract was washed, brine, dried over KOH and concentrated under reduced pressure to give 767 mg (92%) of methyl 4-(2-pyrrolidinyl)methylthiobenzoate as a yellow oil. . 1H-NMR (400 MHz, CDClj) δ (dt, J= 3.9, 12.7 Hz, 1H), 1.85 - 2.09 (m, 2H) 2.13 (m, 1H), 3.11 - 3.27 (m, 3H), 3.40 ( dd, J= 6.8, 13.2 Hz, 1H), 3.54 (dd, J = 7.3, 15.1 Hz, 1H), 3.89 (s, 3H), 5.07 (br, 1H), 7.38 (d, J= 8.3 Hz, 2H ), 7.91 (d, J = 8.3 Hz, 2H); MS (FAB) m/z 252 flvf+1).

To a stirred mixture of 3-methoxy-4-[ N -(2-methylphenyl)-ureido]phenylacetic acid (1.30 g, 4.136 mmol) and Et 3 N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added the added pentafluorophenyl-trifluoroacetate at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into water (60 ml) and the precipitate was collected by suction. The crude solid was washed with 0.1 N HCl, H 2 O, n-hexane and dried at 40°C to give 1.91 g (96%) of pentafluorophenyl 3-methoxy-4-[ N'~ (2-.methylphenyl )ureido]phenylacetate as a light brownish crystalline powder. JR<KBr) 1785,1224,1216cm-'; 1H-NMR (400 MHz, CDCl 3 ) δ 2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), .

6.49 (s, 1H), 6.81 (d, J= 1.5 Hz, 1H), 6.91 (dd, J= 1.5, 8.3 Hz, 1H), 7.15 (t, J= 7.3 Hz, 3H), 7.24 (m, 1H ), 7.50 (d, J= 7.8 Hz, 1H), 8.17 (d, J= 7.8 Hz, 1H); MS, (FAB) m/z 481 (M*+1); Anal Calcd for CjoHjjNjOjS-1/4H,0: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H.3.75; N, 5.68.

A mixture of pentafluorophenyl 3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenylacetate (1.47 g, 3.05 mmol), methyl 4-(2-pyrrolidinyl)methylthiobenzoate (767 mg, 3, 05 mmol) and Et3N

(0.51 mL, 3.66 mmol) in DMF (15 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (1:2, • v/v) as eluent to give 1.366 g (82%) of methyl 4-[[1-[3-methoxy -4-[ N' -(2-methylphenyl)ureido]phenylacetyl]-2-

pyrrolidinyl]methylthio]benzoate as a white crystalline powder. IR (KBr) 1785, 1224, 1216 cm-'; 1H-NMR (400 MHz, CDCl 3 ) 8 1.88 - 1.99 (m, 4H), 2.30

(s, 3H), 2.75 (dd, J= 9.8, 13.2 Hz, 1H), 3.43 - 3.55 (m, 3H), 3.56 (s, 2K), 3.64 (dd, J= 1.1, 14.2 Hz, 1H), 3.73 (s, 3H), 3.88 (s, 3H), 4.33 (m; 1H), 6.29 (s, 1H), 6.78 - 6.81 (m, 2H), 7.11 - 7.26. (m, 5H), 7.50 (d, J= 8.3 Hz, 3H), 7.93 (d, J= 8.8 Hz, 2H), 8.07 (d, J= 7.8 Hz, 1H); MS (FAB) m/z 548 (M + 1); Anal. Calcd for C30H33N3O3S-1/4H,O: C, 65.26; H, 6.12; N, 7.61. Found: C, 65.48;

H.6.20; N, 7.47.

To. a stirred solution of methyl 4-[[1-[3-methoxy-4-.[N'-(-2-..methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]-benzoate (300 mg, 0.548 mmol ) in TFH (5.5 mL) and H2O (1.1 mL) was added LiOH (3.9.4 mg, 1.643 mmol) and the reaction mixture was stirred at room temperature overnight at 50°C

for 9 hours. The mixture was diluted with CHCl 3 . The solution was washed with 1 N HCl, brine and dried over Na 2 SO 4 . ■ The solvent was removed under reduced pressure and the resulting crude solid was crystallized from n-hexane-EtOAc-MeOH to give 218.6 mg (75%) of 23 as a white crystalline powder. IR (KBr) 3318, 2952, 1596, 1536, 1299, 1155 cm-'; 1H-NMR (400 MHz, DMSO-d,) δ 1.82 - 2.05 (m, 4H), 2.25 (s, 3H), 2.91 (dd, 7= 9.8, 13.2 Hz, 1H), 3.47 - 3.52 (m, 3H), 3.57 (s, 2H), 3.87 (s, 3H), 4.14 (br m, 1H), 6.76 (d, J= 1.5, 8.3 Hzd, 1H), 6.89 (d, J= 1.5 Hz, 1H) , 6.94 (t, J= 7.3 Hz, 1H), 7.11 - 7.19 (m, 2H), 7.57 (d, J= 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 1H), 7.83 (d, J= 8.3 Hz, 2H), 8.02 (d, J= 8.3 Hz, 1H), 8.49 (s, 1H), 8.58 (s, 1H); MS (FAB) m/z 534 (M*+1); y4/7a/.Calcd for C^NAS-SMHjO: C, 62.63; H, 6.07; N, 7.36; S, 5.77. Found: C, 62.62; H.5.74; N, 7.36; S, 5.67.

ts EXAMPLE 19

4-[[1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylsulfinyl]benzoic acid

To a stirred solution of methyl 4-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylthio]-benzoate (264 mg, 0.482 mmol) in CH 2 Cl 2 (5.2 mL) was added m-CPBA (118.8 mg, 0.482 mmol) at 0°C and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CHCl 3 and quenched with saturated Na 2 S 2 O 3 . The separated organic layer was washed with saturated NaHCO 3 , brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give methyl 4-[[1-[3-methoxy-4-[Δ7r-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl] methylsulfinyl]-benzoate as an impure amorphous solid . To a stirred solution of this crude compound in THF (4 mL) and H 2 O (1 mL) was added LiOH (34.6 mg, 1.45 mmol) and stirring was continued overnight at room temperature. The mixture was diluted with CHCl 3 and washed with 1 N HCl, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting impure solid was recrystallized from n-hexane-CHCl3-MeOH to give 193.2 mg (73%) of 24 as a white crystalline powder. IR (KBr) 3338, 2956, 1708, 1529, 1299, 1207, 11SScm-<1>; 1H-NMR (400 MHz, DMSO-dJ 5 1.70 - 2.06 (m, 4H), 2.24 (s, 3H), 2.90 (dd, J= 8.3, 13.2 Hz, 1H), 3.02 - 3.08 (m, 1H) . 3.16 - 3.25 (m, 1H), 3.41 - 3.60 (m, 3H), 3.84 (s, 3H), 4.40 (brs, 1H), 6.74 (d, .7=7.8 Hz, 1H), 6.87 (s, 1H), 6.94 (d,J= 7.3 Hz, 1H), 7.11 - 7.17 (m, 2H), 7.75 - 7.81 (m, 3H), 7.98 - 8.05 (m, 1H), 8.10 (d, /'= 8 :3 Hz, 2H), 8.46 (s, 1H), .8.56 (s, 1H); MS (FAB) m/z 550 (M++1), 572 QvT+Na); Anal Calculated for Cj^NjO^^ÆHjO: C, 60:40; H, 5.94; N, 7.29. Found: (j, 60.15; H.5.82; N, 6.90.

EXAMPLE 20

(S)-4-[l-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 4-hydroxybenzoate (1.96 g, 12.88 mmol), W-Boc-prolinol (2.59 g, 12.87 mmol) and PPh3 (4.06 g, 15.48 mmol ) in THF (40 mL) was added DIAD (3.10 mL, 15.74 mmol_l). The resulting mixture was heated under reflux for 14 hours. The mixture was evaporated in vacuo and the residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give 3.34 g (77%) of methyl (S)-4-[ 1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy] benzoate as an oil.

1H-NMR (CDCl1) δ 1.48 (s, 9 H), 1.67 (d, J=9.3 Hz, 1 H), 1.87-2.03 (m, 3 H), 3.36-3.43 (m, 2 H), 3.87- 4.09 (m,1H), 4.13-4.20 (m,2 H, 6.94 <d, J=8.3 Hz, 2H), 7.98 (d, .7=8.3 Hz, 2H).

■A mixture of methyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate (3.34 g, 9.96 mmol) in TFA (20 mL) and CH 2 Cl 2 (35 mL) was stirred at room temperature for 15 hours. The mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine and dried over Na 2 CO 3 . The organic layer was evaporated to give 1.70 g (73%) of methyl (S)-4-(2-pyrrolidinylmethoxy)benzoate as a yellow oil. 1H-NMR (CDCl 3 ) δ 1.54-1.61 (m, 1H), 1.77-1.86 (m, 2H), 1.87-1.97 (m, 1H), 2.00 (bs, 1H), 2.93-3.06 (m , 2H), 3.52-3.57 (m, 1H), 3.88 (s.3 H), 3.90-3.99 (m, 2 H), 6.92 (d, .7=9.0 Hz, 2 H), 7.98 (d, . 7=9.0 Hz, 2

H)

A mixture of 3-methoxy-4-[ N -(2-methylphenyl)ureido]phenylacetic acid (428 mg, 1.36 mmol), methyl ( S )-4-(2-pyrrolidinylmethoxy)benzoate (330 mg, 1, 40 mmol), EDC (312 mg, 1.63 mmol), HOBt (220 mg, 1.63 mmol) and a catalytic amount of DMAP in DMF (15 mL) were stirred for 6 h. The resulting mixture was diluted with EtOAc, washed with 0.5 N HCl, saturated NaHCO 3 , brine and dried over MgSO 4 . The solvent was evaporated in vacuo to give an oily residue which was purified by column chromatography on silica gel with CHCl 3 -MeOH (50:1, v/v) as eluent to give 540 mg (75%) of methyl

(S)-4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate as an oil. 1H-NMR (CDCl 3 ) S 1.81-2.12 (m, 4 H) 2.88 (bs, 3 H), 3.48-3.61 (m, total 7 H), 3.88 (s, 3 H), 4.10-4.21 (m, 2 H), 4.42-4.46 (m, 1 H), 6.75-8.08 (series of m, total 13 H).

To a stirred solution of methyl (S)-4-[1-[3-methoxy-4-[ N'~

To (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate (540 mg, 1.02 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL). The resulting mixture was heated under reflux for 16 hours. The mixture was poured into 1 N HCl and the solid was collected. The crude solid was washed with Et 2 O to give 278 mg (53%) of 25 as a white amorphous solid.

IR (KBr)-1708 cm-<1>; 1H-NMR (DMSO-d<) 5 1.83-2.14-(m, 4H), 2.21 (s, 3H), 2.46 (s,'-2H), 3.78 (s, 3H), 3.95- 4.02 (m, 1H), 4.13-4.16 (m, 1 H), ■ 4.24 (bs, 1 H), 6.51-7.98 ( series of m, 12 H), 8.43 (s, 1 H), 8.53 (s, 1H), 12.57 (bs, 1H); MS (FAB) m/z 517 (M*).

EXAMPLE 21

(S) -3-Methoxy-4- [1- [3-methoxy-4- [W-(2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinyl]methoxy]benzoic acid

To a stirred; solution of ethyl 4-hydroxy-3-methoxybenzoate (3.00 g, 15.29 mmol), ( S )-N-Boc-prolinol (3.08 g, 15.30 mmol), Ph3P (4.81 g, 18.34 mmol) in THF (50 mL) was added DIAD (3.61 mL, 18.33 mmol) at 0 °C. The resulting mixture was heated at reflux for 6.5 hours. After cooling to room temperature, the mixture was evaporated and purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give ethyl (S)-3-methoxy-4-[1-(tert-butoxycarbonyl) -2-pyrrolidinylmethoxy]benzoate as a gum. The above ethyl (5)-3-methoxy-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]benzoate was dissolved in CH 2 Cl 2 (50 mL) and TFA (45 mL). The mixture was stirred for 2 days at room temperature. The resulting mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CH 2 Cl 2 , washed with brine and dried over MgSO 4 . The solvent was evaporated and the residue was purified by column chromatography on silica gel with CHCl3-MeOH

(20:1, v/v) as eluent to give 3.27 g (77% for 2 steps) ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)-benzoate as a yellow oil.

1H-NMR (CDCl1) 5 1.39 (t, 3 H, «7=7.1 Hz), 1.52-1.59 (m, 1 H), 1.76-1.88 (m, 2 H), 1.92-2.01 (m, 1H) , 2.92-3.06 (m, 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, J=7.1 Hz ), 6.89 (d, 1 H, 7=8.3 Hz), 7.54 (d, 1 H, .7=2.0 Hz), 7.65 (dd, 1 H, 7=2.0, 8.3 Hz).

To a stirred solution of ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)benzoate (424 mg, 1.52 mmol) in DMF (8 mL) was added pentafluorophenyl ester of 3-methoxy-4 - [N1 - (2-methylphenyl)ureido]phenylacetic acid (728 mg, 1.52 mmol), and Et 3 N (0.26 mL, 1.87 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO 3 , brine and dried over MgSO 4 . The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 830 mg (95%) of ethyl (5)-3-methoxy-4-[ 1-[3-Methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate as an amorphous solid.

'H-NMR (CDClj)-6 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), 4.09-4.17 (m, 1 H), 4.22-4.25 (m, 1 H), 4.35 (q, 2 H, /= 7.3 Hz), 4.38-4.49 (m, 1H), 6.71-6.78 (m, 1 H), 6.99 (d, 1 H, .7=8.3 Hz), 7.04-7.07 (m, 1H), 7.16- 7.19 (m, 2 H), 7.49-7.66 (m, 3 H), 8.06 (d, 1 H, J=8.3 Hz).

To a stirred solution of ethyl (S)-3-methoxy-4-[ [1- [3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (760 mg, 1.32 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL), and the resulting mixture was refluxed overnight. After cooling to room temperature, the mixture was poured into 1 N HCl (100 mL) and the solid was collected. The crude solid was washed with Et 2 O to give 429 mg (59%) of 27 as a yellow amorphous solid. Temp. 132-135°C.

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), 4.00-4.05 (m, 1 H), 6.53-8.01 (m, 10 H), 8.45 (s, 1 H ), 8.54 (s, 1H), 12.63 (bs, 1H); MS (FAB) m/z 548 (M<*>+1).

EXAMPLE 22

(S)-4-[1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy] phthalic acid

To a stirred solution of dimethyl 4-hydroxyphthalate (3.00 g, 14.27 mmol), A7-Boc-prolinol (2.87 g, 14.26 mmol), Ph3P (4.49 g, 17.12 mmol) in THF (50 mL) was added DIAD (3.40 mL, 17.27 mmol) at 0 °C. The resulting mixture was heated under reflux overnight. The resulting mixture was evaporated and the residue was purified by column chromatography on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 5.75 g (quantitative yield) of dimethyl (S)-4-[1 -(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]phthalate as an oil. 1H-NMR (CDCl1) δ 1.47 (s, 9 H), 1.86-2.05 (m, 4 H), 3.36-3.40 (m, 2 H), 3.87 (m, 3 H), 3.91 (s, 3 H ), 3.96-4.19 (m, 3H), 7.03-7.24 (m, 2H), 7.80 (m, 1H). To a solution of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]phthalate (5.75 g, 14.62 mmol) in CH 2 Cl 2 (25 mL) was added TFA (20 mL) and the resulting mixture was stirred for 50 min. at room temperature. The resulting mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CH 2 Cl 2 , washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (50:1, v/v) as eluent to give 790 mg (18%) of dimethyl (S)-4-(2^pyrrolidinylmethoxy)phthalate as a brown oil. 1H-NMR (CDCl1) δ 1.48-1.57 (m, 1 H), 1.72-1.84 .(m, 2 H), 1.89-1.98 (m, 2 H), 2.91-3.03 (m, 2 H), 3.48 -3.54 (m, 1 H), 3.82-3.97 (rn, total 8 H),

6.98 (dd, 1 H, .7=2.4, 8.8 Hz), 7.06 (d, 1 H, .7=2:4 Hz), 7.78 (d, 1 H, .7=8.8 Hz).

To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy) phthalate (212 mg, 072 mmol) in DMF (8 mL) was added pentafluorophenyl ester of 3-methoxy-4-[ W -(2-methylphenyl ) ureido] f phenylacetic acid (346 mg, -.0.72 mmol) and Et3N

(120 mL, 0.86 mmol) and the mixture was stirred at overnight. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO 3 , brine and dried over MgSO 4 . The solvent was evaporated in vacuo to give 413 mg (97%) of dimethyl (S)-4-[1-[3-methoxy-4-[Δ7r-(2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethoxy] phthalate as an oil.

1H-NMR (CDCl1) 5 1.92-2.12 (m, 4 H), 2.29 (br s, 3 H), 3.51-3.64 .(m, 7 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.10-4.19.(rri, 2 H), 4.44 (m, 1 H), 6.73-8.02

(series of 'rn, total 12 H).

To a stirred solution of dimethyl (S)-4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido] phenylacetyl]-2-pyrrolidinylmethoxy] phthalate (413 mg, 0.70 mmol ) in THF (10 mL) was added 25 N NaOH (10 mL) at room temperature and the resulting mixture was refluxed overnight. After

cooling to room temperature, the reaction mixture was poured into 1 N HCl (100 mL). The solid was collected, washed with water and air dried. The crude solid was washed with Et 2 O to give 310 mg (79%) of 28 as a yellow amorphous solid.

IR (KBr) 1701 cm"'; 'H-NMR (DMSO-c^) 5 Tr8'7^2:i8 (mi 4 H), 2.25 (s, 3 H), 2.50 (s, 2 H), 3.38 -3.60 (m, 4 H), 3.83 (s, 3 H), 4.00-4.14 (m, 1 H), 6.74-8.02 (series of .m, 10 H), 8.46 (s, 1 H), 8.54 ( s, 1H); MS (FAB) m/z 562 (M<*>+1).

EXAMPLE 23

3-Chloro-4-[[1-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoic acid

i To a stirred solution of methyl 3-chloro-4-hydroxybenzoate (600 mg, 3.215 mmol), N-tert-butoxycarbonylprolinol (647.1 mg, 3.215 mmol) and Ph3P (1.01 g, 3.858 mmol) in THF ( 10 ml) diisopropylazodicarboxylate (DIAD) was added dropwise

(0.8 mL, 3.890 mmol) at room temperature and the mixture became

stirred for 3 days at room temperature and for 18 hours at 70°C. The reaction mixture was evaporated in vacuo and the residue was chromatographed on silica gel with n-hexane:EtOAc (5:1, v/v) as eluent to give 1.147 g (97%) methyl 3-chloro-[1-tert-butoxycarbonyl)-2-pyrrolidinyl]methoxybenzoate as an oil.

1 H-NMR (400 MHz, CDCl 3 ) δ 1.46, 1.48 (s each,, 9H),

1.59 - 1.63 (br, 1H), 1.88 (br s, 1H), 2.05 (s, 1H), 2.05 - 2.21 (m, 2H), 3.34 - 3.45 (br m, 1.5H),

3.89 (s, 3H), 3.97(br m, 0.5H), 4.21 (br s, 2H), 7.05 (d, J= 8.8 Hz, 1H), 7.90 (dd, J= 2.0, 8.8 Hz,

1H), 8.04 (d, J= 2.0 Hz, 1H); MS (FAB) m/z 370 (M<+>+1).

To a stirred solution of methyl 3-chloro-[1-tert-butoxycarbonyl)-2-pyrrolidinyl]methoxybenzoate (1.14 g, 3.10 mmol) in CH 2 Cl 2 (20 mL) was added TFA (5 mL) at 0°C and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and

the residue was treated with 1 N NaOH. The mixture was extracted with CHCl 3 . The extract was washed with brine, dried over KOH and concentrated under reduced pressure to give 741 mg (89%) of methyl 3-chloro-4-(2-pyrrolidinylmethoxy)benzoate as a yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1.60 - 1.67 (m, 1H), 1.78 - 2.02 (m, 3H), 2.93 - 2.98 (m, 1H), 3.03 - 3.09 (rn, 1H), 3.59

(dt, J=2.0, 9.3 Hz, 1H), 3.89(s, 3H), 3.98(dd, J= 6.3, 8.8 Hz, 1H), 4.05 (dd, J= 4.9, 9.3 Hz, 1H), 6.93 ( d, J= 8.8 Hz, 1H), 7.90 (dd, J= 2.0, 8.8 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H); MS (FAB) m/z

270 (M<+>+l).

The mixture of pentafluorophenyl 3-methoxy-4-[A71-(2-methylphenyl)--ureido]phenylacetate (5.00 mg, 1.04 mmol), methyl 3-chloro-4-(2-pyrrolidinyl)methoxybenzoate ( 281 mg, 1.04 mmol), Et3N (0.17

mL, 1.25 mmol) in DMF (5 mL) was stirred for 1 h at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (1:3, v/v) as eluent to give methyl 3-chloro-4-[[1-[3-methoxy-4 -[ N'~ (2-

methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (620 mg, 1.04 mmol) as a white crystalline material.

TR. (KBr) 1676, 1599, 1487, 1267, 758, 754 cm-'; 1H-NMR (400 MHz, DMSO-dJ 5 1.82 - 2.24 (m, 4H), 2.25 (s, 3H), 3.48 - 3.60 (m, 4H), 3.78 (s, 3H), 4.18 (m, 2H) , 4.31 (m, 1H), 6.74 (dd, J= 1.5, 8.3 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.91 - 6.95 (m, 1H), 7.11-7.17 (m, 3H ), 7.79 (dd, J= 2.0, 8.3 Hz, 2H), 7.85 (d, J= 2.0.Hz, 1H), 7.98 (d, J= 8.3 Hz, 1H), 8.53(s, 1H), 8.58 ( s, 1H); MS (FAB) m/r 552 (M++1).

EXAMPLE 24

3, 5-dichloro-4-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoic acid

To a stirred solution of methyl 3,5-dichloro-4-hydroxybenzoate (600 mg, 2.714 mmol) N-tert-butoxycarbonylprolinol (546 mg, 2.714 mmol) and Ph3P (854 mg, 3.257 mmol) in THF (10 mL) was added DIAD (0.68 mL, 3.283 mmol) was added dropwise at room temperature and the mixture was stirred for 3 days at room temperature and for 18 hours at 70°C. The reaction mixture was concentrated and the residue was chromatographed on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give 988.8 mg (90%) of methyl 4-[1-(tert-butoxycarbonyl)-2 -pyrrolidinyl]methoxy-3,5-dichlorobenzoate as a pale yellow oil.

1H-NMR (400 MHz, CDCl 3 ) 6 1.44 (s, 9H), 1.88 - 2.15 (br m, 3H), 2.34 (br s, 1H), 3.40 - 3.44 (m, 2H), 3.92 (s, 3H ), 3.92, 4.14 (rn, 1H), 4.18 (br s, 2H), 7.98 (s, 2H); MS (FAB) m/z 404 0VT+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl] methoxy-3,5-dichlorobenzoate (988 mg, 3.248 mmol) in CH 2 Cl 2 (20 mL) was added TFA (5 mL) at 0°C and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was treated with 1 N NaOH. The solution was extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 672 mg (68%) of methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate as a pale yellow oil.

'H-NMR (400 MHz, CDClj) 8 1.62 - 1.69 (m, 1H), 1.78 - 1.86 (m, 2H), 1.89 - 1.99 (m, 1H), 2.92 - 2.98 (m, 1H), 3.04 - 3.09 (m, 1H), 3.55 - 3.60 (m, 1H), 3.91 (s, 3H), 4.01 (dd, J= 6.8, 8.8 Hz, 1H), 4.08 (dd, J= 4.9, 8.8 Hz, 1H), 7.97 (p, 2H); MS (FAB) m/z 304 (M<+>+1).

A mixture of pentafluorophenyl 3-methoxy-4-[AJ'- (2-methylphenyl)ureido]phenylacetate (385.8 mg, 803 mmol), methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate ( 244.3 mg, 0.803 mmol) and Et 3 N (0.13 mL, 0.964 mmol) in DMF (4 mL) were stirred for 1 h at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane:EtOAc

(1:2, v/v) as eluent to give methyl 3,5-dichloro-4- [ [1- [3-methoxy-4- [A7f-(2-methylphenyl)ureido] phenylr acetyl]-2- pyrrolidinyl]methoxy]benzoate as an oil. To a stirred solution of this compound in THF (8 mL) and H 2 O (2 mL) was added LiOH (57.7 mg, 2.409 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was diluted with CHCl 3 . The solution was washed with 1 N HCl, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting impure solid was recrystallized from /3-hexane-MeOH-CHCl 3 to give 428.2 mg (91%) of 30 as a white crystalline powder.

IR (KBr) 1618, 1535, 1454, 1257, 754 cm-'; 1H-NMR (400 MHz, DMSO-ds) δ 1.83 - 2.24 (m, 4H), 2.24 (s, 3H), 3.50 - 3.58 (m, 4H), 3.84 (s, 3H), 3.98 - 4.05 (m , 1H), 4.15 (dd, J = 2.9, 8.7 Hz, 1H), 4.29 (br m, 1H), 6.74 (d, J= 8.3 Hz, 1H), 6.87 (s, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.11 (d, J= 7.8 Hz, 1H), 7.16 (d, J= 8.3 Hz, "1H), 7.79 (d, /= 8.3 Hz,lH), 7.86 (s, 1H) , 7.87 (d, J = 9.8 Hz, 1H), 7.99 (d, /= 8.3 Hz, 1H), 8.49 (s, 1H), 8.58 (s, 1H); MS (FAB) m/ z 586 (M+ +l)

EXAMPLE 25

4-[1- [3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-nitrobenzoic acid

To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (3.00 g, 0.0164 mmol) in MeOH-benzene (1:4, v/v) was added dropwise a 2.0 M n-hexane solution of TMSCHN2' ( 8.2 mL, 0.0164 mol) at room temperature. After the resulting solution had been stirred for 4 hours at room temperature, the mixture was evaporated in vacuo. The oily residue was chromatographed on silica gel with CHCl 3 as eluent to give 4.23 g (79%) of methyl 4-hydroxy-3-nitrobenzoate as a pale yellow crystalline material.

To a stirred mixture of N-tert-butoxycarbonylprolinol (1.02 g, 5.07 mmol) methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol) and Ph3P (1.46 g, 5 .58 mmol) in THF (10 mL) was added dropwise isopropyl azodicarboxylate DIAD (95%) (1.16 mL, 5.58 mmol) at 0°C. The resulting mixture was heated under reflux for 46 hours. After cooling, the mixture was evaporated in vacuo. The residue was dissolved in CH 2 Cl 2 (10 mL) and TFA (10 mL) was added. After the solution had been stirred for 0.5 hours at room temperature, the solution was evaporated in vacuo. Water was added to the residue and washed with EtOAc. The aqueous layer was neutralized by addition of saturated NaHCO 3 and extracted with EtOAc. The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 0.698 g (49%) of methyl 3-nitro-4-(2-pyrrolidinylmethoxy)benzoate as a gum.

A mixture of methyl 3-nitro-4-(2-pyrrolidinylmethoxy)benzoate (0.668 g, 2.38 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetic acid (1.12 g , 3.57 mmol), 1-hydroxybenzotriazole (HOBt) (0.482 g, 3.57 mmol), 4-dimethylaminopyridine (DMAP)

(43.6 mg, 0.357 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) (0.684 g, 3.57 mmol) in DMF (10 mL) were stirred for 15 h at room temperature. EtOAc was added to the mixture and it was washed successively with 1 N HCl, saturated NaHCO 3 and brine. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on

silica gel with EtOH-CHCl3 (1:20, v/v) as eluent to give 0.927 g (68%) of methyl 4-[1-[3-methoxy-4- [ N'~ (2-methylphenyl)ureido]phenylacetyl ]-2-pyrrolidiylmethoxy]-3-nitrobenzoate as a yellow crystalline material.

A mixture of methyl 4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-nitrobenzoate (0.917 g, 1.59 mmol) in THF (10 mL) and 1 N NaOH (2.38 mL, 2.38 mmol) were heated under reflux for 2 h. After cooling, the mixture was poured into ice water and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo to give 0.826 g (92%) of 31 as a yellow crystalline solid. 'H-NMR (400MHz,

CDC13) 5 1.91, 2.09 (1H, 3H, each, m), 2.28 (3H, s), 3.54-3.62 (4H, m), 3.64 (3H, s), 4.15, 4.59

(each 1H, each. d, J=7.8Hz), 4.46 (1H, m), 6.66, 7.22 (each. 1H, each s);6.72 (1H, d, /=8.3Hz), 7.11-7^28 (4H, rfO; 7.46 (1H, d,>7.8Hz), 7.74 (1H, d,>7.8Hz), 7.85 (1H, s), 8.17 (1H, dd, J=2.0, 8.8Hz), 8.48 ( 1H, d, J=2.4Hz); MS (FAB) m/z 563 (M<+>+1).

EXAMPLE 26

3-amino-4-[1-[3-methoxy-4-[ N' -(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid

A stirred mixture of 4-[1-[3-methoxy<y>-4-[ N'~(2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-nitrobenzoic acid (101 mg, 0.190 mmol) and 5% Pd-C (0.247 g) in methanol was hydrogenated at 1 atmosphere for 48 hours. Insoluble catalyst was removed and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel with EtOH-CHCl3 (1:1, v/v) as eluent to give 61.0 mg (60%) of 32 as a crystalline material.

1H-NMR (400MHz, DMSO-tLJ 5 1.95 (4H, m), 2.23 (3H, s), 3.60, 3.91, 4.10, 4.34 (5H, each.m), 3.81 (3H, s), 4.88 (2H , m); 6.74

(1H, d, J=8.3Hz), 6.86-7.28 (5H, m), 7.78 (1H, d, >7.8Hz), 7.99 (1H, d, J=8.3Hz), 8.30 (1H, s), 8.45, 8.55 (each 1H, h<y>er s); MS (FAB) m/z 533 (M*+1).

EXAMPLE 27

4- [2- [1- [4- [W-(2-fluorophenyl)ureido] 3-methoxyphenylacetyl] -2-pyrrolidinyl]ethynyl]benzoic acid

To a stirred solution of benzyl 4-amino-3-methoxyphenyl acetate (1.36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 µl, 5 mmol) and a catalytic amount of Et 3 N . The resulting mixture was stirred for 3 hours. The mixture was quenched by the addition of H 2 O (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 as eluent to give 2.06 g (quantitative yield) of benzyl 4-[N'~ ('^'-fluoro-phenyl)ureido]-3-methoxyphenylacetate as a green oil. 'HrNMR (CDC1)3 5 3.63 (2H, s), 3.82 (3H, s), 5.14 (2H, s), 6.79-7.37 (12H, m), 8.01 (1H, d,.7=7.8 Hz), . 8.09-8.14 (1H, m).

To a stirred solution of benzyl 4-[ N'~ (2-fluoro-phenyl)ureido]-3-methoxyphenylacetate (2.04 g, 5 mmol) in THF (40 mL) was added 0.25 N NaOH ( 40 ml). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (10 mL) and the resulting precipitate was collected by suction. The residue was recrystallized from CHCl 3 -EtOH to give 1.04 g (66%) of 4-[ N'~ (2-fluorophenyl)ureido]-3-methoxyphenylacetic acid as a white crystalline powder. Temp. 185-188°C (decomposition).

1H-NMR (DMSO-d*) δ 3.50 (2H, s), 3.82 (3H, s), 6.78 (1H, dd, J=1A and 8.3 Hz), 6.92

(1H, d, .7=1.4 Hz), 6.95-7.01 (1H, m), 7.10-7.14 (1H, m), 7.19-7.24 (1H, m), 8.01 (1H, d, .7=8.3 Hz ), 8.14-8.18 (1H, m), 8.72 (1H, s), 9.17 (1H, s);.MS (FAB) m/z 319 (M*+1); Anal. Calculated for C^ FjOF: C, 60.37; H, 4.75; N, 8.80. Found: C, 60.20; H, 4.82; N, 8.67.

A mixture of 4-[N-(2-fluorophenyl)ureido]-3-methoxy enylacetic acid (255 mg, 0.8 mmol) 2-[2-(4-ethoxycarbonylphenyl)-ethynyl]pyrrolidine (195 mg, 0 .8 mmol), EDC (230 mg, 1.2 mmol), DMAP (98 mg, 0.8 mmol) in DMF (20 mL) was stirred overnight. The reaction mixture was poured into 1 N HCl and the precipitate obtained was collected with suction and dissolved in CHCl 3 . The solution was dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (100:1, v/v) as eluent to give the desired compound which was dissolved in THF (8 mL). 0.25 N NaOH (8 mL) was added to this solution and the resulting mixture was stirred overnight. The mixture was poured into 1 N HCl and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was recrystallized from CHCl 3 -n-hexane to give 144 mg (37%) 33 as a pale yellow crystalline powder, mp 152-155°C (dec).

'H-NMR (DMSO-d^ 8 1.92-2.27 (4 H, ro); 2.50 (2 H, s), 3.33-3.78 (2H, m), 3.80". and" 3.82 (total 3 H, s, respectively), 4.88-5.12 (1 H, m), 6.77-7.24 and 7.99-8.20 (total 7 H, m), 7.48 and • 7.52 (2 H, d, .7=8.3 Hz,'hverD, 7.91 (2H , d, J=8.3 Hz), 8.72 (1H, s), 9.18 (1H, s), 13.11 (1H, br-s); MS (FAB) m/ z 516 (M*+l); Anal. Calcd forC^jNjOjF^HjO: C, 63.15; H, 5.48; N, 7.62. Found:

C, 63.58; H, 5.15; N, 7.22. EXAMPLE 28 '4-[[1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]-3-methylbenzoic acid

To a stirred solution of 4-iodo-2-methylphenyl (465 mg, 1.987 mmol), N-tert-butoxycarbonylprolinol (400 mg, 1.987 mmol) and Ph3P (625 mg, 2.384 mmol) in THF (7 ml) was added dropwise DIAD (0.5 ml, 2.404 mmol) at room temperature and the mixture was stirred for 13 hours at 70°C. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel with n-hexane-EtOAc (9:1, v/v) as eluent to give 645.3 mg (78%) of 4-[1-(tert-butoxycarbonyl) -2-pyrrolidinyl]methoxy-1-iodo-3-methylbenzene as a pale yellow oil.

'H-NMR,

(400 MHz, CDClj) 5 1.47 (s, 9H), 1.83 r 1.89 (m, 1H), 1.96- 2.04 (m, 3H), 2.16 (s, 3H), 3.37 - 3.43 (br m, 2H), 3.81 , 3.94 (br m each, 1H), 4.08 - 4.18 (m, 2H), 6.62 (br s,. 1H), 7.42 (s, 2H); MS (FAB)/n/z 418 (M++1).

To a stirred solution of 4-[1-(tert-butoxycarbonyl)-2-. pyrrolidinyl]methoxy-1-iodo-3-methylbenzene (45.3 mg, 1.546 mmol) in DMSO (7 mL) and MeOH (6 mL) was added Et3N (0.47 mL, 3.401 mmol), Pd(OAc) 2 (17.4 mg, 0.077 mmol) and 1,3-bis(diphenyl osphino)propane (31.46 mg, 0.077 mmol). CO gas was introduced into the stirred solution for 10 min. The mixture was stirred at 70°C for 2 days and concentrated. The residue was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 301.6 mg (56%) of methyl 4-[l-(tert- butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-methylbenzoate as an oil.

1H-NMR (400 MHz, CDCl 3 ) 8 1.47 (s, 9H), 1.86 - 2.10 (br m, 4H), 2.33 (s, 3H), 3.32 - 3.50 (br m, 2H), 3.88 (s, 3H ), 3.88, 4.04 (br m Each, 1H), 4.13- 4.20 (m, 2H), 6.89 (br rft, 1H), 7.82 (s, 1H), 7.85 (dd, J= 2.0, 8.8 Hz, 1H) ; MS (FAB) m/z 350 (M<+>+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyloxy-3-methylbenzoate (301.6 mg, 0.863 mmol) in CH 2 Cl 2 (6 mL) was added TFA (r.2 mL ) at 0°C and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and

the residue was made basic by the addition of 1 N NaOH.

The mixture was extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 192.5 mg (90%) of methyl 3-methyl-4-(2-pyrrolidinyl)methoxybenzoate as an oil.

1H-NMR (400 MHz, CDCl 3 ) δ 1.58 - 1.65 (m, 1H), 1.78 - 2.00 (m, 3H), 2.24 (s, 3H), 2.97 (dt, / =

6.8, 10.2 Hz, lH),3.05(dt,J=5.9,6.8Hz, 1H), 3.54 - 3.58 (m, 1H), 3.87 (s, 3H), 3.92 (dd,J = 6:3, 9.3 Hz , 1H), 3.99 (dd, J= 4.9, 9.3 Hz, 1H), 6.81(d, 7= 8.3 Hz, 1H),'7.83 (s, 1H), 7.85 (dd, J = 2.0, 8.3 Hz, 1H ); MS (FAB) m/z 250 (M<*>+1).

A mixture of pentafluorophenyl 3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetate (211.3 mg, 0.44 mmol), methyl 3-methyl-4-(2-pyrrolidinyl)methoxybenzoate (109, 7 mg, 0.44 mmol), Et 3 N (73.6 µl, 0.528 mmol) in DMF (2 mL) was stirred for 1.5

hours at room temperature. The reaction mixture was diluted with EtOAc. The solution was washed with brine,

dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (1:3, v/v) as eluent to give methyl 4-[ [1-[3-methoxy-4-[W- (2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]-3-methylbenzoate (241.6 mg, quantitative yield) as an oil. To a stirred solution of this compound in THF (4.4 mL) and H 2 O (1.1 mL) was added LiOH (32 mg, 1.32 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with CHCl 3 and acidified by the addition of 1 N HCl. The solution was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting crude solid was recrystallized from n-hexane-EtOAc-CHCl3-MeOH to give 126.3 mg (54%) of 34 as a white crystalline powder.. IR (KBr) 1685.1606 , 1454, 1257, 752cm-'; 'H-NMR (400

MHz, DMSO-dJ 5 1.87.-2.10 (m, 4H), 2.12 (s, 3H), 2.25 (s, 3H), 3.51 - 3.71 (m, 4H), 3.76 (s, 3H), 4.08 - 4.18 ( m, 2H), 4.34 (m, 1H), 6.74 (dd, 7= 1.5, 9.8 Hz, 1H), 6.84 (d, J= 1.5 Hz, 1H), . 6.94 (t, J=6.8Hz, 1H), 7.06 (d,J=8.8Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.16 (d, J= 7.8 Hz, 1H), 7.72 ( s,lH), 7.76 (dd, 7 = 2.0, 8.3 Hz, 1H), 7.79 (d, 7= 7.8 Hz, IH), 7.99 (d, 7= 8.3 Hz, 1H), 8.46 (s, 1H), 8.54 (p, 1H); MS (FAB) m/z 532 (M<*>+1); <y>lna/. Calculated for C^<N>jO^l^HjO: C, 66.65; H, 6.34; N, 7.77. Found: C, 66.16; H, 6.37; N, 7.50.

EXAMPLE 29

(S)-4-[1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalic acid

To a solution of dimethyl 4-acetoxyisophthalate (.1.52 g,

6.03 mmol) in MeOH (70 mL) was added saturated NaHCO 3 and the resulting mixture was stirred for 3 h at room temperature. The resulting mixture was completely dissolved in 1 N HCl and extracted

with EtOAc. The extract was washed with saturated NaHCO 3 , brine and dried over MgSO 4 . The solvent was evaporated to give 1.27 g (quantitative, yield) of dimethyl 4-hydroxyisophthalate as a white crystalline powder.

1 H-NMR (CDCl 1 ) δ 3.91 (s, 3 H),

3.99 (s, 3 H), 7.01 (d, 1 H, 7=8.8 Hz), 8.11 (dd, 1H, 7=2.4, 8.8 Hz), 8.55 (d, 1 H, 7=2.4 Hz)

To a stirred solution of dimethyl 4-hydroxyisophthalate (1.27'' g, 6.04 mmol), ( S )-AZ-jBpc-prolinol (1.22 g, 6.06 mmol), PPhf

(1.90 g, 7.24 mmol) in THF (30 mL) was added DIAD (1.43 mL, 7.26 mmol) at room temperature. The resulting stirred mixture was then heated under reflux for 15 hours. After cooling to room temperature, the resulting mixture was evaporated and the residue was purified by column chromatography on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 2.10 g (88%) of dimethyl (S)- 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy] isophthalate as a yellow oil e.

1H-NMR (CDCl 3 ) δ 1.26 (s, 9 H), 1.85-2.16 (m, 3 H), 3.36-3.46 (m, 2 H), 3.90 (s, 6 H), 4.11-4.31

(m, 2 H), 4.95-5.02 (m, 2 H), 7.09 (dd, 1 H, 7=9.3, 24.9 Hz), 8.11-8.14 (m, 1 H), 8.46 (d, 1 H,

7=9.3 Hz)

A mixture of dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethoxy]isophthalate (2.01 g, 5.11 mmol), TFA

(20 mL) and CH 2 Cl 2 (25 mL) were stirred for 1.5 h at room temperature. The resulting mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CH 2 Cl 2 , washed with brine, dried over Na 2 CO 3 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (9:1, v/v) as eluent to give 0.80 g (53%) of -dimethyl ( S )-4-(2-pyrrolidinylmethoxy) isophthalate as a yellow oil. 1 H-NMR (CDCl 3 ) δ 1.71 (m, 1 H), 1.89 (m, 2 H), 2.00 (m, 1 H), 3.05-3.13 (m, 2 H), 3.67 (m, 1 H), 3.90 (s/ 3 H), 3.91 (s, 3 H), 4.05-4.18 (m, 2 H), 7.00 (d, 1 H, 7=8.8 Hz), 8.14 (dd, 1 H, 7=2.4, 8.8 Hz), 8.50 (d, 1 H, 7=2.4 Hz).

To a stirred solution of dimethyl ( S )-4-(2-pyrrolidinylmethoxy) isophthalate (616 mg, 210 mmol) in DMF (13 mL) was added the pentafluoroester of 3-methoxy-4-[ N'~ (2-methylphenyl )ureido]phenylacetic acid (1.00 mg, 2.08 mmol) and Et 3 N (4.25 µl, 3.12 mmol), and the resulting mixture was stirred for 3.5 h at room temperature. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, saturated NaHCO 3 , brine and dried over Na 2 SO 4 . After removal of the solvent, the residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 1.41 g (quantitative yield) of dimethyl (S)-4-[1-[3- methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow oil.

1 H-NMR (CDCl 3 ) δ 1.86-2.29 (m, 4 H), 2.30 (s, 3 H), 3.47-3.57 (m, 2 H), 3.58 (s, 3 H), 3.59 (s, 2 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.22-4.37 (m, 2 H), 4.42-4.47 (m, 1 H), 6.44-8.46 (series of m, 12 H ).

To a stirred solution of dimethyl (S)-4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy] isophthalate (1.41 g, 2, 39 mmol) in THF (20 mL) was added 0.25 N NaOH (20 mL) and the resulting mixture was then refluxed overnight. After cooling to room temperature, the mixture was poured into 1 N HCl (150 ml) and the solid was collected. The crude solid was recrystallized from CHCl 3 -MeOH to give 140 mg (10%) of 35 as a white crystalline powder. 1H-NMR (CDCl 3 ) 6 1.83-2.18 (xn, 4H), 2.24 (s, 3H),

3.44-3.55 (m, 4H), 3.59 (s, 2 H), 3.80 (s, 3 H), 4.05^.24 (m, 2 H), 4.28-4.32 (rn, 1H), 6.73-8.55 (series of m, total 12 H); MS (FAB) m/z 562 (M++1); >W. Calculated for C 3 t H 3 ) N 3 CY 4 H 2 O: C, 56.87;

H, 6.20; N, 6.63. Found: C, 56.73; H, 5.56: N, 6.52.

EXAMPLE 30

3-Methoxy-4- [2- [l- [3-methoxy-4- [W-(2-methylphenyl) ureido] - phenylacetyl] -2-pyrrolidinyl] ethynyl] benzoic acid

A stirred mixture of methyl 3-methoxy-4-nitrobenzoate (1.20 g, 5.7 mmol) and 5% Pd-C (1.0 g) in EtOH (30 mL) and THF (20 mL) was hydrogenated over the night at 1 atmosphere. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3 as eluent and the solid obtained was further purified by recrystallization from CHCl3-n-hexane to give 805 mg (78%) of methyl-4-amino-3-methoxybenzoate as white plates. Temp. 126-128°C. IR(KBr) 3475, 1700 cm -1 ; 1H-NMR (CDCl 3 ) 6 3.86 (3H, s), 3.89 (3H, s), 4.21 (2H, br s), 6.66 (1H, d, 7=8.3 Hz), 7.45 (1H, d, 7=1.9 Hz), 7.54 (1H, dd, 7=1.9 °9 8.3 Hz); MS (FAB) m/ z 182 Øvf+1); Anal.

■Calculated for CjH„N03: C, 59.66; H, 6.12; N, 7.73. Found^,. 59.65; H, 6.15; N, 7.65.

A stirred solution of methyl 4-amino-3-methoxybenzoate (725 mg, 4 mmol) in EtOH (10 mL) was added to dilute H 2 SO 4 (prepared from H 2 SO 4 0.5 mL and H 2 O 10 mL) at 0 °C. A solution of NaNO 2 (331 mg, 4.8 mmol) in H 2 O (10 mL) was added to the mixture. After stirring for 0.5 h at the same temperature, the mixture was poured into a cooled (0°C), stirred suspended solution of Kl (1.83 g, 11 mmol) and cat. Cu in H 2 O (100 mL). The mixture was stirred vigorously for 1 hour at room temperature and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane-EtOAc (10:1, v/v) as eluent to give a mixture of methyl-4-iodo-3-methoxybenzoate and methyl-3-methoxybenzoate (748 mg) as a colorless oil.

To this oil was added Pd(PPh3)4 (150 mg, 0.13 mmol), Cul

(57 mg, 0.3 mmol and i-Pr2NH (10 mL).. The mixture was stirred for 1 h under N2 and a solution of 1-(tert-butoxycarbonyl)-2-ethynylpyrrolidine (488 mg, 2.5 mmol) in i-Pr2NH (10 mL) was

added to the mixture.- After stirring for 2 hours, the mixture was poured into H 2 O and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 431 mg (48%) of 1-(tert-butoxycarbonyl)-2-[2-methoxy-4-methoxycarbonylphenyl) ethynyl] pyrrolidine as a yellow oil.

1 H-NMR (CDCl 3 ) δ 1.49 (9 H, s), 1.77-2.14 (4 H, m), 3.36-3.51 (2 H, m), 3.90 (3 H, s), 3.91

(3 H, s), 4.60-4.81 (1 H, m), 7.36-7.39 (1 H, m), 7.51 ( 1 H, s), 7.55-7.57 (1 H, m).

■To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-methoxy-4-methoxycarbonylphenyl)ethynyl]pyrrolidine (395 mg, 1.1 mmol) in CH 2 Cl 2 (3 mL) was added TFA (3 mL ). The resulting mixture was stirred for 1 hour. The mixture was concentrated in vacuo and basified by the addition of sat. -methoxycarbonylphenyl)ethynyl]pyrrolidine as a ^yellow oil e . 1 H-NMR (CDCl 3 ) δ 1.81-2.16 (4 H, m), 2.97-3.17 (2 H, m), 3.91 (6 H, s), 4.13-4.15 (1 H, m), 7.41 (1 H , d, 7=8.3 Hz), 7.51 (1 H, s), 7.56 (1 H, d, 7=8.3 Hz).

A mixture of 2-[2-(2-methoxy-4-methoxycarbonylphenyl)-ethynyl]pyrrolidine (233 mg, 0.9 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid ( 314 mg, 1 mmol), EDC

(268 mg, 1.4 mmol), DMAP (110 mg, 0.9 mmol) in DMF (10 mL) was stirred overnight. The mixture was poured into 1 N HCl and the resulting solid was collected with suction. The resulting solid was dissolved in CHCl 3 and the solution was dried over MgSO 4 and evaporated. The residue was subjected to flash column chromatography on silica gel with EtOAc as eluent to give an oil. The oil was dissolved in THF (5 mL) and 0.25 N NaOH

was added to this solution with stirring. The solution was poured into ice-1N HCl to give a solid. The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl 3 -n-hexane to give 215 mg (44%) of 36 as a white crystalline powder, mp 141-145°C.

IR (KBr) 3338, 2956, 2935, 2875, 2593,1711 cm"'; 'H-NMR (DMSO-d*) δ 1.91-2.14 (4 H, m), 2.24 (3 H, s), 3.38- 3.68 (4 H, m), 4.88-5.08 (1 H, m), 6.76-8.56 (12 H, m); MS (FAB) m/z 542 (M<*>+1).

EXAMPLE 31

3-W,]v"-dimethylamino-4-[1-[3-methoxy-4-[N'~ (2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid

A stirred mixture of methyl 4-hydroxy-3-nitrobenzoate

(3.22 g, 0.0163 mol) and 5% Pd-C (12.9 g) in MeOH (30 mL) were hydrogenated under atmospheric pressure for 70 h at room temperature. Insoluble catalyst was removed and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel with EtOH-CHCl 3 (1:20, v/v) as eluent to give 1.89 g (69%) of methyl 3-amino-4-hydroxybenzoate as a pale brown syrup.

A stirred mixture of methyl 3-amino-4-hydroxybenzoate

(1.07 g, 6.40 mmol) and 5% Pd-C (2.14 g) in MeOH (20 mL) and 37% aqueous formaldehyde (1.08 mL, 0.0122 mol) and 1 N HCl ( 6.1 ml) was hydrogenated under atmospheric pressure for 26 hours at

room temperature. Insoluble catalyst was removed and the filtrate was evaporated in vacuo. The residue was chromatographed

on silica gel with EtOAc-n-hexane (1:10, v/v) as

eluent to give 0.817 g (70%) of methyl 3-(N,N-dimethylamino)-4-hydroxybenzoate as a syrup.

To a stirred mixture of methyl 3-(N,N-dimethylamino)-4-hydroxybenzoate (0.817 g, 4.18 mmol), N-tert-butoxycarbonylprolinol (0.926 g, 4.60 mmol), Ph3P (1.21 g, 4.60 mmol) in THF (20 mL) was added dropwise DIAD (95%) (0.953 mL, 4.60 mmol) at 0 °C. The resulting mixture was heated under reflux for 41 hours. After cooling, the mixture was evaporated in vacuo. The residue was chromatographed on silica gel with EtOAc-n-hexane (1:6, v/v) as eluent to give a syrup which was used for the subsequent reaction without subsequent purification. This syrup was dissolved in CH2C12

(10 ml) and added TFA (10 ml). After the solution was stirred for 5 hours at room temperature, the solution was evaporated in vacuo. Water was added to the residue which was washed with CHCl 3 . The aqueous layer was neutralized by addition of saturated NaHCO 3 and extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 1.03 g (89%) of methyl 3-(A7,A7-dimethylamino)-4-(2-pyrrolidinylmethoxy)benzoate as a gum.

A mixture of methyl 3-(N, N-dimethylamino)-4-(2-pyrrolidinylmethoxy)benzoate (0.529 g, 1.90 mmol), 3-methoxy-4-[N'-(2-methylphenyl)ureido ]phenylacetic acid (0.597 g, 1.90 mmol), HOBt (0.308 g, 2.28 mmol), 4-dimethylaminopyridine (DMAP) (23.2 mg, 0.190 mmol) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (0.437 g, 2.28 mmol) in DMF (10 mL) was stirred for 15 h at room temperature. Mixture was neutralized by careful addition of 1N HCl and extracted with EtOAc. The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 0.607 g (56%) of methyl-3-(W/W-dimethylamino)-4-[1-[3-methoxy-4-'[N'- (2 -methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate as a white crystalline material.

A mixture of methyl 3-(A7,A7-dimethyl amino)-4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-benzoate (0.600 g, 1.04 mmol) in THF (10 mL) and 0.25 N NaOH (5 mL, 1.25 mmol) was stirred for 21 h at room temperature. CHCl 3 was added to the mixture and it was extracted with a mixture of water (100 mL)-1 N NaOH (4 mL). The extract was neutralized with saturated NH 4 Cl and extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 428 mg (70%) of 37 as a white crystalline solid.

1H-NMR (400MHz, DMSO-d*) δ 1.88, 1.99 and. 2.11 (4H, each. rn), 2.24 (3H, s), 2.67 (6H, s), 3.33 (2H, m), 3.58 (2H, xn), 4.05-4.32 (3H, m),'6.75 (1H , d, J=7.3Hz), 6.92-6.95 (1H, m), 7.05 (1H, d, J=8.3Hz), 7.11-7.17 (2H, m), 7.42 (IH, s), 7.52 (1H, d, >7.8Hz), 7.79 (1H, d, >7.8Hz), 8.00 (1H, d, /=7.8Hz), 8.31 (1H, s), 8.46, 8.55 (each 1H, each s); MS (FAB) m/z 533 (M<*>+1).

EXAMPLE 32

3-fluoro-4- [ [1- [3-methoxy-4- [W-(2-methylphenyl) ureido] phenylacetyl] -2-pyrrolidinyl] methoxy] benzoic acid

To a stirred solution of 4-bromo-2-fluorophenol (217 µl, 2.002 mmol), N-tert-butoxycarbonylprolinol (403 mg, 2.002 mmol) and Ph 3 P (630 mg, 2.403 mmol) in THF (7 mL) DIAD (477 µl, 2.423 mmol) was added at room temperature. The resulting mixture was stirred for 6 hours at room temperature and then overnight at 70°C. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give 549.4 mg (73%) of 1-bromo-4-[1-(tert -butoxycarbonyl)-2-pyrrolidinyl] methoxy-3-fluorobenzene as an oil.. NMR (400 MHz, CDCl 3 ) δ 1.46 (s, 9H), 1.85 (br m, 1H), 1.90 - 2.10 (br s, 3H) , 3.30 - 3.47 (m, 2H), 3.85, 4.04 (brs hven, 1H), 4.11 - 4.20 (m, 2H), 6.82 - 6.98 (m, 1H), 7.13 - 7.26 (m, 2H); MS (FAB)/72/z374(M++1).

To a stirred solution of l-bromo-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzene (549.4 mg, 1.468 mmol) in DMSO (6 mL) and MeOH (5 mL ) was added Et 3 N (448 µl, 3.229 mmol), Pd(OAc) 2 (36.2 mg, 0.161 mmol) and 1,3-bis(diphenylphosphino)propane (66.4 mg, 0.161 mmol). CO gas was introduced into the mixture for 10 minutes. The resulting mixture was stirred at 70°C for 2 days under a stream of CO. After the mixture was concentrated, the residue was

. diluted with. EtOAc. The solution was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with n-hexane:EtOAc (5:1, v/v) as eluent to give 323.0 mg (62%) of methyl 4-[1- (tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzoate as a pale yellow oil.. 'H-NMR(400

MHz, CDClj) 5 1.47 (s, 9H), 1.87 (br s, 1H), 1.95 - 2.10 (m, 3H), 3.34 - 3.44 (br m, 2H), 3.89 (s, 3H). 3.94 and 4.11 - 4.26 (br m each, 3H), 7.03 - 7.11 (m, 1H), 7.75 - 7.80 (m, 2H); MS (FAB) m/z 354 (MT+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzoate (323.0 mg, 0.914 mmol) in CH 2 Cl 2 (6.5 mL) was added TFA (1 .3 ml) at 0°C and the mixture was stirred for 1.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was made basic by addition of 1 N NaOH. The mixture was extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to give 174.8 mg (76%) of methyl 3-fluoro-4-(2-pyrrolidihyl)methoxybenzoate as a brownish oil.

1H-NMR (400 MHz, CDCl3) δ 1.54 - 1.63 (m, 1H), 1.76 - 2.02 (m, 3H), 2.93 - 3.07 (m, 2H), 3.57 (ddd, J= 4.9, 6.9, 14.3 Hz , 1H), 3.89 (s, 3H), 3.97 (dd, J= 6.8, 9.3 Hz, 1H), 4.04

(dd, J= 5.0, 8.8 Hz, 1H), 6.98 (t, /= 17.6 Hz,lH), 7.73 (dd, 7= 2.0, 11.7 Hz, 1H), 7.78 (dt, J = 2.0, 8.8 Hz, 1H); MS (FAB) m/z 253 QvF+1).

A mixture of pentafluorophenyl-3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetate (324.5 mg, 0.676 mmol), methyl 3-fluoro-4-(2-pyrrolidinyl)methoxybenzoate (171, 1 mg, 0.676 mmol), Et 3 N (113 µl, 0.811 mmol) in DMF (5 mL) was stirred for 2 h at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane:EtOAc (1:2, v/v) as eluent to give methyl-3-fluoro-[ [1-[3-methoxy- 4-[ N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (365.1 mg, 0.664 mmol) as an oil.

To a stirred solution of this compound in THF (4.4 mL) and H 2 O (1.1 mL) was added LiOH (46.3 mg, 1.932 mmol) and the reaction mixture was stirred at room temperature overnight. - The mixture was diluted with CHCl 3 and acidified by the addition of 1N HCl. The separated organic layer was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting impure solid was recrystallized from n-hexane-EtOAc-CHCl 3 to give 102 mg (30%) of 38 as a white crystalline powder. Temp. 123 -12 6°C. IS. (KBr) 1616, 1537, 1282, 756 cm-'; 1H-NMR (400 MHz, DMSO-dJ 5 1.87 - 2.09 (xn, 4H), 2.25 (s, 3H), 3.48 - 3.57 (m, 2H), 3.60 (s, 2H), 3.83 (s, 3H) , 4.11 -4.16 (m, 1H), 4.24 (dd,7= 2.9, 9.8 Hz, 1H), 4.28-4.34 (br s, 1H), 6.74 (dd, J= 1.5, 8.3 Hz, 1H), 6.87 (s, 1H), 6.94 (i, J = 7.3 Hz, 1H), 7.12 (d, J= 7.8 Hz, 1H), 7.15 (t, J= 8.3 Hz, 1H), 7.34 (t, J= 8.8 Hz, 1H), 7.66 (dd, J= 2^0,12.2 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.79 (d, J= 8.3 Hz, 1H), 7.99 ( d, J= 7.8 Hz, 1H), 8.46 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 536 (M++1); yl/ia/. Calcd for C20FNjCVO.SHjO: C, 63.96; H, 5.74; N, 7.72; F; 3.49. Found: C, 64.U; H, 5.80; N, 7.39; F, 3.54. EXAMPLE 33 4-[1-[4-[ N'~ (2-fluorophenyl)ureido]3-methoxyphenylacetyl]-2- pyrrolidinyl]methoxy-3-methoxybenzoic acid

A mixture of 4-[N-(2-fluorophenyl)ureido]3-methoxyphenylacetic acid (318 mg, 1 mmol), 2-(2-methoxy-4-ethoxycarbonyl)-phenoxymethylpyrrolidine. (279 mg, 1 mmol), EDC (288 mg, 1.5 mmol) and DMAP (122 mg, 1 mmol) in DMF (20 mL) were stirred overnight. The mixture was poured into 1 N HCl and the resulting

in

solids were collected with suction. The solid was dissolved in CHCl 3 and dried over MgSO 4 and evaporated. After removal of the solvent, the residue was chromatographed on silica gel with CHCl 3 :MeOH (100:1, v/v) as eluent to give an oil which was dissolved in THF:MeOH (4:1, v/v, 10 mL).

0.25 N NaOH (8 mL) was added to the solution and the resulting stirred mixture was heated under reflux for 3 hours. The mixture was poured into 1 N HCl. The solid obtained was collected with suction, dissolved in CHCl 3 , dried over MgSO 4 and evaporated. The residue was recrystallized from CHCl3-n-hexane-ether to give 329 mg (60%) of 39 as a white crystalline powder. Temp. 140-144°C.

TR. (KBr) 3338, 2956, 2875,2607,1709 cm"1; 1H-NMR (CDCl 3 ) δ 1.95-2.25 (4 H, m), 3.454.50 (12 H, m), 6.66-8.15 (12 H , mj; MS (FA<B>) m/z 552 (M<*>+1).

EXAMPLE 34

2-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylic acid

To a stirred solution of 6-hydroxynicotinic acid (500 mg, 3.594 mmol) in benzene (8 mL) and MeOH (2 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0 °C and the mixture was stirred .overnight at room temperature. The reaction mixture was quenched by addition of AcOH and the resulting mixture was concentrated in vacuo. The residue was chromatographed on silica gel with n-hexane-EtOAc (1:3, v/v) as eluent to give 269.8 mg (49%) of methyl 2-hydroxypyridine-5-carboxylate as a white crystalline powder.

IR. (KBr') 3062. 1657, 1654, 1612,

1435, 1300, 1113,775, 642cn<v>'; 1 H-NMR (400 MHz, CDCl 3 ) δ 3.87 (s, 3H), 6.58 (d, J = 9.8 Hz, 1H), 7.99 (dd, J = IA, 9.8 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H); MS (FAB) m/z 154 (MN-1); Anal.

Calculated for C7H7N03-1/4H2O: C, 53.33; H, 4.80; N, 8.89.-Found:- G, 53.58; H, 4.65; N, 8.87.

To a stirred solution of methyl 1-2-hydroxypyridine-5-carboxylate (269.8 mg, 1.762 mmol), N-tert-butoxycarbonylprolinol (354.6 mg, 1.762 mmol) and Ph3P (554.6 mg, 2.114 mmol) ) in THF (10 mL) was slowly added DIAD (0.42 mL, 2.114 mmol) at room temperature and the resulting mixture was stirred for 6 h at 70 °C. The reaction mixture was concentrated and the residue was chromatographed on silica gel with n-hexane:EtOAc (5:1, v/v) as eluent to give 262.5 mg (44%) of methyl-2-[[1-(tert-butoxycarbonyl) -2-pyrrolidinyl] methoxy] pyridine-5-carboxylate as an oil. 'H-. NMR (400 MHz, CDClj) δ 1.47 (s, 9H), 1.85 - 1.98 (xn, 4H), 3.3.7 (br s, 2H), 3.92 (s, 3H), 4.12 - 4.33 (br m, 2H) ,4.4 (brs, 1H), 6.75 (m, 1H), 8.15 (m, 1H), 8.79 (xn, 1H); MS (FAB) m/z 337 (W+1)."

To a stirred solution of methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate

(262.5 mg, 0.870 mmol) in CH 2 Cl 2 (5.3 mL) was added TFA (1.1 mL) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was made basic by addition of 1 N NaOH and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 173.1 mg (94%) of methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate as a pale yellow oil. .- -

1H-NMR (400 MHz, CDCl 3 ) δ 1.49 - 1.58 (ddt, J= 6.8, 8.8Hz,.

1H), 1.72 - 1.87 (m, 2H), 1.90 - 1.99 (m, lH), 2.92 - 3.05 (m, 2K), 3.50 -3.57 (ddd/=4.4,7.3,. 15.1 Hz, 1H), 3.91 ( s, 3H), 4.23 (dd, J= 7.8, 10.7 Hz, 1H), 4.38 (dd, J= 4.4, 10.7 Hz, 1H), 6.78 (d, J= 8.8 Hz, 1H), 8.15 (dd, J = 2.4, 8.8 Hz, 1H), 8.80 (d, J= 2.4 Hz, 1H); MS (FAB) m/z 237 (M<+>+1).

A mixture of pentafluorophenyl-3-methoxy-4-[ N' - (2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5- carboxylate (173.0 mg, 0.732 mmol), Et 3 N (122.4 µl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 h at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane:EtOAc (1:5, v/v) as eluent to give methyl-2-[ [1-[3-methoxy-4-[ N (2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H 2 O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with CHCl 3 and treated with saturated NH 4 Cl , and washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting crude solid was recrystallized from n-hexane-Et 2 O-CHCl 3 -MeOH to give 193.8 mg (59%) of 40 as a white crystalline powder. Temp. 125-12 8°C.

IR (KBr) 1716, 1600, 1533, 1255 cm-'; 1H-NMR (400 MHz, DMS0-d<) 5 1.67 - 2.03 (m, 4H), 2.50 (s, 3H), 3.33 - 3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J= 4.4 Hz, 1H), 3.83 (s, 3H), 4.27 - 4.31 (m, 2H), 4.42 -.4.47 (m, 1H), 6.73 (d,J= 7.8 Hz, 1H), 6.87 -6.95 ( m, 3H), 7.11 -7.17 (m, 2H), 7.79 (d, J~ 8.3 Hz, 1H), 7.99. (d, J= 8.3 Hz, 1H), 8.14 (dd, J= 2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H) , 13.06 (br s, 1H); MS (FAB) m/z 519 (MM); ,W Calculated

in i

for CmH2ONA-I^H-O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.

EXAMPLE 35

4 - [ [1- [3-Methoxy-4-[A7r-(2-methyl phenyl) ureido] phenylacetyl] -2-methyl-2-pyrrolidinyl] methoxy] 3-nitrobenzoic acid

To a stirred solution of W-tert-butoxycarbonylproline (6.00 g, 0.0279 mmol) in MeOH:benzene (1:4, v/v) was added dropwise a 2.0 M n-heJesane solution of TMSCHN2 (16 .7 ml, 0.0334 mol) at room temperature. After the resulting solution was stirred for 1 hour at room temperature, the mixture was evaporated in vacuo to give 6.39 g (100%) of N-tert-butoxycarbonylproline methyl ester as a yellow syrup.

1 H-NMR (CDCl 3 ) δ -1.41. ($.9H), 1.85-1.9^ (m^H), ; 2.21-2.28 (m, 2H),

3.72 (s, 3H), 4.29 (m, 1H).

To a stirred solution of diisopropylamine (2.02 mL, 0.0144 in mol) in THF (30 mL) was added dropwise a 1.59 M n -hexane solution of n -BuLi (9.06 mL, 0.0144 mol) at -78°C within 5 minutes. The obtained solution was stirred for 10

minutes at -78°C. A7-tert-butoxycarbonylproline methyl ester (3.00 g, 0.0131

mmol) in THF (30 mL) at -78°C over 5 min. The obtained solution was stirred for 10 minutes at -78°C. To the solution was added dropwise Mel (0.900 ml, 0.0144 mol) at -78°C. The obtained solution was stirred for 30 minutes at -78°C. The solution was quenched by addition of saturated NH4Cl. The resulting mixture was extracted with CHCl 3 . The extract was washed with water, dried over Na 2 SO 4 and evaporated in vacuo to give 3.20 g (quantitative yield) of N-tert-butoxycarbonyl-2-methylproline methyl ester as a yellow syrup. "H-NMR (CDCl 3 ) δ 1.33 (s, 9H), 1.38 (s, 3H), 1.72-2.20 (m, 4H) 3.27-3.59 (m, 2H) 3.63 (d, J=6.3Hz, 3H).

To a stirred solution of N-tert-butoxycarbonyl-2-methyl-proline methyl ester (3.20 g, 0.0131 mol) in THF (20 mL) was added 1 N NaOH (15.7 mL) at room temperature. After the resulting mixture was stirred for 24 hours, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified by addition of 1N HCl and extracted with EtOAc. The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 1.71 g (57%) of N-tert-butoxycarbonyl-2-methylproline as a yellow syrup. 1H-NMR(CDCl 3 ) δ 1.42 (s, 9H), 1.48 (s, 3H), 1.88-2.31 (m, 4H), 3.34-3.57 (m, 2H), 9.35 (brs, 1H)

To a stirred solution of A7-tert-butoxycarbonyl-2-methyl-proline (1.10 g, 4.80 mmol) in THF (20 mL) was added dropwise BH3-SMe2 (0.546 mL, 5.76 mmol) at room temperature. After the resulting mixture had been stirred for 6 hours at 80°C, the mixture was evaporated in vacuo. The residue was diluted with MeOH, washed with n-hexane (3x) and evaporated in vacuo to give 0.648 g (60%) of N-tert-butoxycarbonyl-2-hydroxymethyl-2-methylpyrrolidine as a yellow syrup.

1H NMR (CDCl3)

5 1.47 (s, 9H), 1.76-2.05 (m, 4H), 3.28-3.48 (m, 2H), 3.66 (m, 2H, d).

To a stirred solution of N-tert-butoxycarbonyl-2-hydroxy-methyl-2-methylpyrrolidine (0.648 g, 3.01 mmol), methyl 4-hydroxy-3-nitrobenzoate (0.593 g, 3.01 mmol) and Ph3P

(0.868 g, 3.31 mmol) in THF (10 mL) was added dropwise DIAD (95%) (0.686 mL, 3.31 mmol) at 0 °C. After the resulting mixture was stirred for 24 hours at 80°C, the mixture was evaporated in vacuo. The residue was diluted with CH 2 Cl 2 (5 mL) and TFA (5 mL) was added. After the resulting mixture had been stirred for 2 hours at room temperature, the mixture was evaporated in vacuo. The residue was diluted with 0.5 N HCl and extracted with CHCl 3 . The aqueous layer was neutralized with saturated NaHCO 3 and extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 0.188 g (21%) of methyl 3-nitro-4-(2-methyl-2-pyrrolidinylmethoxy)benzoate as a yellow syrup.

A mixture of methyl 3-nito-4-(2-methyl-2-pyrrolidinylmethoxy)benzoate (0.188 g, 0.920 mmol), 3-methoxy-4-[Nr<->

(2-methylphenyl)ureido]phenylacetic acid (0.289 g, 0.920 mmol), HOBt (0.0.149, 1.10 mmol), DMAP (11.2 mg, 0.0920 mmol) and EDC (0.211 g, 1.10 mmol ) in DMF (5 mL) was stirred for 14 h at room temperature. EtOAC was added to the mixture and the solution was washed successively with 0.5 HCl, saturated NaHCO 3 and brine. The organic layer was dried over Na 2 SO 4 and evaporated in vacuo to give 0.489 g (quantitative yield) methyl-4-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2 -methyl-2-pyrrolidinyl] methoxy] -3-nitrobenzoate as a yellow crystalline material.

1H-NMR (CDCl 3 ) δ 1.26 (d, J=5.9Hz), 1.85-4.50 (m, 10H), 2.30 (s, 3H), 3.67 fe 2H), 3.92 (s, 3H>), 6.36 (s, 2H), 6.75-7.52 (m, 7H), 8.02 (d, J=7.8Hz, 1H), 8.15 (d>8.8Hz,

1H), 8.47 (p, 1H).

A stirred mixture of 4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)-ureido]phenylacetyl]-2-methyl-2-pyrrolidinyl]methoxy]-3-nitrobenzoate (0.489 g, 0.828 mmol) in MeOH-(5 mL) and 1 N NaOH (1.24 mL) was heated at reflux for 2 h. After cooling, the mixture was diluted with water and extracted with CHCl 3 . The aqueous layer was acidified with 1 N HCl and extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and evaporated in vacuo to give 0.366 g (99%) of 42 as a yellow crystalline material.

EXAMPLE 36

4-[4-hydroxy-1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoic acid

A stirred mixture of 4-[4-benzyloxy-1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate (440 mg, 0.645 mmol) and 5% Pd/C (400 mg) in AcOH:EtOH (1:1, v/v, 100 mL) was hydrogenated at 1 atmosphere for 5 h. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3:EtOH (10:1, v/v) as eluent to give 90 mg (24%) of 4-[4-hydroxy-1- [3-methoxy-4- [ N'.~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate as a pale yellow oil. 1 H-NMR (CDCl 3 ) δ 1.39 (3 H, t,J = 7.3 Hz), 2.04-2.37

(total 5 H, m), 3.44-4.70 (16 H, series of L m), 6.63 (1 H, s), 6.70-6.80 (2 H, m), 6.84 (1 H, d, J= 8.3 Hz ), 7.11 (1 H, l, J= 7.8 Hz), 7.20-7.24 (3 H, m), 7.45 (1 H, d, /= 2.0 Hz), 7.59 (2 H, dd, J= 8.3, 2.0 Hz), 8.01 (1 H, d, .7=7.8 Hz).

A stirred mixture of ethyl 4-[4-hydroxy-1-[3-methoxy-4-[ N'~

(2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate (90 mg, 0.152 mmol) in 0.25 N NaOH (5 mL, 1.25 mmol) and THF (5 mL) was heated with refluxed overnight. The mixture was poured into ice-1 N HCl (200 mL). The precipitate was collected with suction and recrystallized from CHCl 3 -MeOH-n-hexane to give 40 mg (47%) of 43 as a colorless amorphous solid.

'H-NMR (DMSO- ,

dj 5 1.92-2.11 (2 H, m), 2.24 (3 H, s), 3.31-5.07 (14 H, series of ' m),"6.73 (1 H, d, 7= 8.3 Hz), 6.84 (1 H, s), 6.93 (1 H, t, J= 7.8 Hz), 7.01-7.17 (3 H, m), 7.44 (1H, s), 7.52 (1 H, d, J = 8.8.Hz^ 7.79 ( 1 H, d, J= 8.3 Hz), 7.99 (1 H, d. J = 7.8 Hz), 8.46 (1 H, s), 8.55 (1 H, s), 12.67 (1 H, br s); MS (FAB) m/z 564 (M<+>+1).

EXAMPLE 37

(2S,4R)-3-amino-4-[4-hydroxy-1-[3-methoxy-4-IN'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of (2S,4R)-4-benzyloxy-1-(tert-butoxycarbonyl)-2-prolinol (891 mg, 2.9 mmol), methyl 4-hydroxy-3-nitrobenzoate (572 mg, 2.9 mmol) and PPh3 (839 mg, 3.2 mmol) in THF (6 mL) was added DIAD (630 mL, 3.2 mmol) and the mixture was heated under reflux overnight. After removal of the solvent, the residue was chromatographed on silica gel with n-hexane:EtOAc (1:1) and toluene:EtOAc (10:1, v/v) as eluent to give 700 mg (50%) of methyl-(2S,4R )-4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a pale yellow oil.

To a stirred solution of methyl-(2S,4R)-4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate (681 mg, 1.4 mmol) in CH 2 Cl 2 (2 ml) was added TFA (2 ml) and the resulting mixture was stirred for 2 hours. After the reaction mixture was concentrated, the residue was basified by the addition of saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with H 2 O, dried over MgSO 4 and evaporated to give 511 mg (95%) of methyl-(2S,4R)-4-[4-benzyloxy-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a yellow oil.

A mixture of 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (409 mg, 1.3 mmol), methyl-(2S,4R)-4-(benzyloxy-2-pyrrolidinyl)methoxy- 3-nitrobenzoate (502 mg, 1.3 mmol), EDC

(383 mg, 2 mmol) and DMAP (159 mg, 1.3 mmol) in DMF (20 mL) were stirred for 3 days. The mixture was poured into 1 N HCl and the precipitate obtained was collected by suction. The residue was dissolved in CHCl 3 and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel with CHCl3:MeOH (200:1, v/v) as eluent to give 680 mg (91%) of methyl-(2S,4R)-4-[4-benzyloxy- 1-[3-Methoxy-4-[N- (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a white amorphous solid.

A solution of methyl-(2S,4R)-4-[4-benzyloxy-1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]-methoxy-3- Nitrobenzoate (676 mg, 0.99 mmol) and 5% Pd/C (1 g) in EtOH:AcOH (1:1, v/v, 30 mL) was hydrogenated at 1 atmosphere for 6 h. The mixture was filtered and the filtrate was evaporated to give an oil which was made basic by the addition of saturated NaHCO 3 . The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was recrystallized from CHCl 3 -EtOH-n-hexane as eluent to give 120 mg (22%) of 44 as a pale yellow crystalline powder. MS (FAB) m/z 549 (M<+>+1)

EXAMPLE 38

41 [ [4-fluoro-1- [3-methoxy-4- [N-(2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinyl] methoxy]-3-methoxybenzoic acid

A stirred mixture of ethyl 4-[4-benzyloxy-1-[tert-butoxycarbonyl)-2-^pyrrolidinyl]methoxy-3-methoxybenzoate (1.189 g, 2.449 mmol) and 5% Pd-C (240 mg) in EtOH (10 mL) was hydrogenated overnight at room temperature. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo to give ethyl 4-[1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinyl]methoxy-3-methoxybenzoate (735.3 mg, 76% ) as a pale yellow oil. To a stirred cold (-78°C) solution of DAST (0.491 mL, 3.718 mmol) in CH 2 Cl 2 (7.4 mL) was added dropwise a solution of this compound in CH 2 Cl 2 (2 mL) and the resulting mixture was stirred over the night. The mixture was quenched with water and extracted with CHCl 3 . The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed

silica gel with n-hexane:EtOAc (3:1, v/v) as eluent to give 418.7 mg (57%) ethyl-4-[1-(tert-butoxy-

carbonyl)-4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate as an oil.-

1H-NMR (400 MHz, CDCl 3 ) δ 1.39 (t, J- 7.3 Hz, 3H), 1.49 (s, 9H), 2.16 (brm, 1H), 2.58 (dd, J= 15.6, 19.0 Hz, 1H) , 3.60 - 3.75 (m, 2H), 3.91 (s, 3H), 3.97 (t, J= 9.3 Hz, 1H), 4.35 (q, J= 7.3 . Hz, 2H), 4.33 - 4.53 (m, 2H) , 5.25 ( d, J = 52.7 Hz, 1H), 7.04 (dd, 7= 7.8, 56.2 Hz, 1H), 7.55 (s, 1H), 7.65 (br s, 1H); MS (FAB) m/z 398 (M++1).

To a stirred solution of ethyl 4-[1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate (482.2 mg, 1.213 mmol) in CH 2 Cl 2 (10.0 mL) was added added TFA (1.9 mL) at 0°C and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was basified by addition of 1 N NaOH and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 348.7 mg (97%) of ethyl 4-(4-fluoro-2-pyrrolidinyl) methoxy-3-methoxybenzoate as a brownish oil .

1H-NMR (400 MHz, CDCl 3 ) δ 1.39 (t, J= 6.8 Hz, 3H), 1.97 (ddt, J= 1.5, 5.4, 14.7 Hz, 1H), 2.27 (dddd,/= 5.9, 8.8, 14.7 , 32.7Hz,lH), 3.02 (ddd.J = 3.9, 13.1, 35.2Hz,lH), 3.36 (dd, J= 12.7, 21.5 Hz,lH), 3.65 (m, 1H), 3.90 (s, 3H) , 4.09 (m, 1H), 4.35 (q, J= 6.8 Hz, 2H), 5.17, 5.31 (br m each» 1H), 6.90 ( d, J= 8.3 Hz, 1H), 7.75 (d, J= 2.0 Hz, 1H), 7.65 (dd, J= 2.0, 8.3 Hz, 1H); MS (FAB) m/z 298 (M<*>+1).

A mixture of pentafluorophenyl 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetate, (404.0 mg, 0.840 mmol), ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate (250.0 mg, 0.840 mmol), Et 3 N (141 µl, 1.009 mmol) in DMF (4.0 mL) was stirred for 1 h at room temperature. The mixture was diluted with EtOAc, washed with water, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane:EtOAc (1:3, v/v) to give 502 mg (quantitative yield) of ethyl 4-[[4-fluoro-l-[3 -methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinyl]methoxy]-3-methoxybenzoate as a yellow oil. To the stirred solution of this compound in THF (8.0 mL) and H 2 O (1.0 mL) was added LiOH (60.4 mg, 2.520 mmol) and the mixture was stirred at room temperature overnight and at 50 °C for 1 day. The mixture was diluted with CHCl 3 and extracted with 1 N NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl 3 . The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting crude solid was recrystallized from EtOAc-CHCl3-EtOH-n-hexane to give 294.8 mg (62%) of 45 as a white crystalline powder.

IR (KBr) 2958, 2937, 1687, 1601, 1531, 1454, 14J9, 1267,1214,

1029CIT1-<1>; 1H-NMR (400 MHz, DMSO-ds) 8 1.86 - 2.09 (m, 5H), 2.06 (s, 3H), 2.25 (s, 3H), 3.47 - 3.67 (m, 6H), 3.76 (s, 3H ), 4.05 - 4.12 (m, 2H), 4.30 - 4.31 (m, 1H), 6.51 (s, 1H), 6.55 (s, 1H), 6.73 - 6.95 (m, 2H), 7.11-7.17 (m, 2H ), 7.64 (s; 1H), 7.79 (d, J= 7.8 Hz, 1H), 7.99 (d, J= 7.8 Hz, 1H), 8.47 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 566 (M<+>+1); Anal. Calculated for C30H31FN3O7-1/2H2O: 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.

EXAMPLE 39

3-acetylamino-4-[1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethoxy]-benzoic acid

A solution of 3-amino-4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid (130 mg, 0.244 mmol) and DMAP (2.9 mg, 0.0244 mmol) in pyridine (5 mL) and acetic anhydride (5 mL) was stirred for 2 h at room temperature. The mixture was evaporated in vacuo (excess acetic anhydride was removed azeotropically with toluene). Water was added to the residue and extracted with CHCl 3 . The extract was washed over Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with MeOH:CHCl3 (1:15 to 1:1, v/v) as eluent to give 29 mg (21%) of 46 as a white crystalline material. 1H-NMR(DMSO-dg)8 1.80-2.30 (m, 4H), 2.04 (s, 3H), 2.26 (s, 3H), 3.33(s, 3H), 3.40-4.80 (m, 7H), 6.59 (s, 1H), 6.74(d, J=8.3Hz, 1H), 6.79 (d, J=8.8Hz, 1H), 7.07-7.57 (m, 6H), 7.75 (d, J=8.8Hz, 1H) , 8.07 (d, <y>=8.3Hz,

c

1H), 8.41 and 8.96 (each s, each 1H); MS' (FAB) m/z 575 (MN-1).

EXAMPLE 40

3-chloro-2-t[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl] -2-pyrrolidinyl]methoxy]pyridine-5-carboxylic acid

To a stirred solution of 3-chloro-2-hydroxypyridine-5-carboxylic acid (1 g, 5.762 mmol) in benzene (16 mL) and MeOH (4 mL) was added dropwise TMSCHN2 (3.17 mL, 6.338 mmol) at 0°C and the resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched by addition of AcOH and the mixture was cooled. The residue was suspended in water and the precipitate was collected. The crude solid was washed with Et 2 O and dried under reduced pressure again. to give. 728.1 mg (-67-3?.) metvl.. 3.-chloro-2-hydroxypyridine-5-carboxylate.. as. a white one. Jcrystalline powder.

IR (KBr) 1.655, 1282, 1245, 769cm-';.'H-NMR (400"

MHz, DMSO-d*) 6.3.79'(s, 3H), 8.01<J>(s, 1H), 8.06 (s, 1H); MS (FAB) Wz 188 QA*+ 1) ; Anal. Calculated for C^ClNOj: C, 44.82; H, 3.22; Cl, 18.90; N, 7.47. FoundC, 44.74; H, 3.22; Cl, 7 p.m.;

N, 7.34. '

To a stirred solution of methyl 3-chloro-2-hydroxypyridine-5-carboxylate (300 mg, 1.599 mmol), AT-tert-butoxycarbonylprolinol (321.9 mg, 1.5~99 mmol) and 'Pn3P (503 mg, 1.919 mmol) in THF (3 mL) was slowly added DIAD (378 µl, 1.919 mmol) at room temperature and the mixture was stirred for 13 h at 70°C. The mixture was concentrated and the residue was chromatographed on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 235.6 mg (40%) of methyl 3-chloro-2-[[I-( tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellow oil.

1H-NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.87 (m, 1H), 2.05 (br s, 3H), 3.43 (br s, 2H), 3.92 (s, 3H), 4.17, 4.26 (br s each, 1H), 4.45 - 4.51 (m, 1H), 4.50 (s, 1H), 8.21 (s, 1H), 8.67 (d, /= 2.0 Hz, 1H); MS (FAB) m/z 371 (M₂+1).

To a stirred solution of methyl 3-chloro-2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (235.5 mg, 0.G35 mmol). in CH 2 Cl 2 (5.0 mL) was added TFA (1.0 mL) at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was made basic by the addition of 1 N NaOH and extracted with CHCl 3 . The extract was dried over Na 2 SO 4 and concentrated under reduced pressure to give 172.3 mg (quantitative yield) methyl 3-chloro-2-[(2-pyrrolidinyl)-mf

methoxy]pyridine-5-carboxylate as a pale yellow oil.

4H-NMR (400-MHz, CDClj) 8 1.55 - 1.63 (m, 1H), 1.76 - 1.99 .,(m, 3H), 2.93 - 2.99 (m, 1H), 3..02 - 3.08 (m, 1H ); 3.57 -3.62 (m, 1H), 3.92 (s, 3H), 4.33 (dd, J = 7.3, 10.7 Hz, 1H), 4.44 (dd, J= 4.4, 10.7Hz, IH), 8.21 (d, J= 2.0 Hz, 1H), 8.67 (d, J= 2.0 Hz, 1H); MS (FAB) m/z 271 (M<*>+1).

The mixture of pentafluorophenyl 3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenylacetate, (317.0 mg, 0.660 mmol) methyl 3-chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5rcarboxylate ( 172.0

in

mg, 0.635 mmol), Et 3 N (105 to , 0.756 mmol) in DMF (2.0 mL) was stirred for 1 h at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give methyl 3-chloro-2-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinyl]methoxy] pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0/mL) and H 2 O (2.0 mL) was added LiOH (45.3 mg, 1.89 mmol) and the reaction mixture was stirred for 5 h at room temperature overnight . The mixture was

diluted with n-hexane and extracted with 1 N NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl 3 . The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the resulting crude solid was recrystallized from n-hexane-EtOAc-EtOH to give 242.2 mg (70%) of 47 as an orange crystalline powder.. M.p. 122-125°C. IR (KBr) 3354, 1709, 1593, 1535. 1454. 1257cnr<l>;

1 H-NMR (400 MHz. DMSO-d< ) δ 1.67 - 2.03 (m, 4H). 2.50 (s, 3H), 3.33- 3.42 (m. 1H). 3.52 (m.

2H), 3.58-(d,/= 4.4 Hz, 1H). 3.83 (s, 3H), 4.27 - 4.31 (m. 2H), 4.42 - 4.47 (m, 1H), 6.73 (d, J <=>

7.8 Hz, 1H), 6.87 - 6.95 (m, 3H), 7.11 - 7.17 (m. 2H), 7.79 (d. J= 8:3 Hz, 1H), 7.99 (d. J= 8.3 Hz,

1H), 8.14 (dd. J= 2.0, 8.8 Hz, 1H). 8.46 (s. 1H), 8.56 (s, 1H), 8.69'(d, .7=2.0 Hz, 1H), 13.06 (brs.

1H); MS (FAB) m/z 553 (M<*>+1); Anal. Calculated for CHaClN.O,: C, 60.81; H, 5.29; N, 10 31

Found: C, 60.98; H, 5.50; N, 9.46.

EXAMPLE 41

2- [ [1- [4- [A7r-(2-fluorophenyl) ureido] -3-methoxy enylacetyl] -2-pyrrolidinyl] methoxy] pyridine-5-carboxylic acid

To a stirred solution of 6-hydroxynicotinic acid (2 g, 14.38 mmol) in benzene (32 mL) and MeOH (8 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0 °C and the obtained mixture was stirred for 2 hours at room temperature. The mixture was quenched by addition of AcOH and concentrated in vacuo. The residue was suspended in water and the solid was collected. The crude solid was washed with Et 2 O and dried in vacuo to give 1.566 mg (71%) of methyl 2-hydroxypyridine-5-carboxylate as a pale brown crystalline powder. IR (KBr) 1655, 1645, 1610, 1433, 1300, 1113, 777, 642 irfI; 1H-NMR (400 MHz, DMSO-d<) δ 3.77 (s, 3H), 6.37 (d, J= 9.8 Hz, 1H), 7.99 (dd, J = 2.4, 9.8 Hz, 1H), 8.03 (d , J= 2.4 Hz, 1H); MS (FAB) m/z 154 (M*+1); Anal. Calculated Tor C^NC-j: C, 54.90; H, 4.61; N, 9.15. FoundC, 54.89; H, 4.60; N, 9.13.

To a stirred solution of methyl 2-hydroxypyridine-5-carboxylate (1.00 g, 6.529 mmol), N-tert-butoxycarbonylprolinol (1.31 g, 6.529 mmol) and Ph3P (2.06 g, 7.836 mmol) in THF (10 ml) was added DIAD (1.54 ml, 7.836 mmol) at room temperature and the resulting mixture was stirred for 13 hours at 70°C. The mixture was concentrated and the residue was crotographed on silica gel with n-hexane: EtOAc (3:1, v/v) as eluent to give 712.3 mg (32%) of methyl 2-[[l-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellow oil'. 'H-NMR (400 MHz, CDC13) 6 1.47 (s, 9H), 1.85 - 1.98 (m, 4H), 3.37 (br s, 2H), 3.92 (s, 3H), 4.12 - 4.33 (br rn, 2H), 4.48 (brs, 1H), 6.75 (m, 1H), 8.15 (m, 1H), 8.79 (m, 1H); MS (FAB) m/z 337 (M<*>+1).

To a stirred solution of methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]"methyloxy]pyridine-5-carboxylate

(232.3 mg. 0.691 mmol) in CH 2 Cl 2 (4.6 mL) was added TFA (0.9 mL) at 0°C and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under ■

a reduced pressure and the residue was made basic by the addition of 1 N NaOH. The aqueous solution was extracted with CHCl 3 , washed with brine and then dried over Na 2 SO 4 . The solvent was evaporated under reduced pressure to give 146.2 mg (90%) of methyl 2-[(2-pyrrolidinyl)methoxy]-pyridine-5-carboxylate as an oil. 1H-NMR(400MHz, CDCl 3 ) δ 1.49 - 1.58 (xn, 1H), 1.72 - 2.18 (m, 3H), 2.92 - 3.05 (xn, 2H), 3.50 -3157 (xn, 1H), 3.91 (s, 3H), 4.23 (dd, J= 8.0, 10.7 Hz, 1H), 4.38 (dd, J= 4.4, 10.3 Hz, 1H), 6.78 (d, J= 8.8 Hz, 1H), 8.15 (dd, J= IA , 8.8 Hz, 1H), 8.80 (d, J= 2.4 Hz, 1H); MS (FAB) m/z 237 (M<+>+1).

The mixture of pentafluoromethyl 4-[N-(2-fluorophenyl)ureido]-3-methoxyphenylacetate (314.8 mg, 0.650 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (146.2 mg , 0.619 mmol), Et 3 N (103 µl, 0.743 mmol) in DMF (1.5 mL) was stirred for 1 h at room temperature. The mixture was diluted with Et 2 O, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give methyl 2-[[l-[4-[iV'-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyi].methoxy]pyridine-5 -carboxylate as an impure pale yellow oil e.

To a stirred solution of this compound in THF (6.0 mL) and H 2 O (2.0 mL) was added LiOH (44.5 mg, 1.857 mmol) and the reaction mixture was stirred for 17 h at room temperature. The mixture was diluted with n -hexane and made basic by addition of 1 N NaOH'. The aqueous layer was acidified with 1 N HCl and extracted with CHCl 3 . The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the crude solid obtained was recrystallized from n-hexane-EtOAc-EtOH to give 202.5 mg (63%) of 48 as a white crystalline powder.

IR (KBr) 1602, 1537, 1456, 1265, 752 cm-.'; H-NMR (400 MHz, DMSO-dJ 5 1.67 - 2.03 (m, 4H), 2.50 (s, 3H), 3.33 - 3.42 (xn, 1H), 3.52 (xn, 2H), 3.58 (d, -/ = 4.4 Hz, 1H), 3.83 (s, 3H), 4.27 - 4.31 (m, 2H), 4.42 - A Al (m, 1H), 6.73 (d, J= 7.8 Hz, 1H), 6.87 - 6.95 (m, 3H), 7.11 - 7.17 (xn, 2H), 7.79 (d, J= 8.3 Hz, 1H), 7.99 (d, J= 8.3 Hz, 1H), 8.14 (dd, J= 2.0, 8.8 Hz,

• 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J= 2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 523

(M*+l)Mna/.Calculated for Cj7H„FNA-1/2HiO: C, 61.01; H, 5.31; N, 10.54. FoundC, 61.52; H, 5.39; N, 10.01.

(

EXAMPLE 42

To a suspension of 4-aminophenylacetic acid (10 g, 66 mmol) in 1:1 CH 2 Cl 2 :acetone (10 mL) was added o-tolyl isocyanate (8.8 g, 66 mmol). The mixture was heated at reflux for 4 hours during which time a white precipitate formed. The precipitate was filtered and the solid washed copiously with 1:1 CH 2 Cl 2 :acetone. The solid was recrystallized with hot methanol and dried under vacuum to give 14.1 g (75% yield) of the desired 4-(o-tolylureido)phenylacetic acid 50.

EXAMPLE 43

4-[[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl] -2-pyrrolidinylmethylamino]benzoic acid e

A stirred mixture of methyl 4-aminobenzoate (1.52 g, 10.04 mmol) and 1-tert-butoxycarbonylprolinal (3.00 g, 15.06 mmol) in toluene (30 mL) was heated under reflux for 3 h . After cooling to room temperature, the solvent was evaporated in vacuo. The solid was dissolved in MeOH (27 mL) and AcOH (3 mL), and then NaBH 3 CN (1.33 g, 20.08 mmol) was added to the mixture and the resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and the solvent was removed under reduced pressure. Water was added to the residue and extracted with EtOAc. The extract was washed with H 2 O, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 2.17 g (65%) of 4-[1-(tert-butoxycarbonyl )-2-pyrrolidinylmethylamino]benzoate as a pale yellow oil.

1 H-NMR (400 MHz, CDCl3) δ 1.48 (s,

9H), 1.51 - 2.09 (rn, 4H), 3.05 - 3.07 and: 3.43 - 3.48 (br.m, 1H), 3.18 (br s, 1H), 3.36 (br s, 2H), 3.84 (s, 1H) ,4.06 - 4.08,4.20 - 4.24 (br m each, 1H), 6.49 - 6.65 (m, 2H), 7.84 (d, J= 8.3 Hz, 2H); MS (FAB) m/z 335 (M<+>+1).

To a stirred solution of 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethylamino]benzoate (2.17 g, 6.490 mmol) in CH 2 Cl 2 (44 mL) was added TFA (8.7 mL) at 0 °C and the resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was treated with 1 N NaOH. The mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and the solvent was concentrated under reduced pressure to give 1.34 mg (88%) of methyl 4-(2-pyrrolidinylmethylamino)benzoate as a brown oil. which is used in the subsequent reaction without further purification.

The mixture of the above methyl 4-(2-pyrrolidinylmethyl-amino)benzoate (397.8 mg, 1.69 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (587.1 mg, 1.87 mmol), EDC (HCl) (486 mg, 2.54 mmol), HOBt (23 mg, 0.17 mmol) and DMAP (21 mg, 0.17 mmol) in DMF (4 mL) were stirred over overnight at room temperature. The mixture was diluted with EtOAc, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure. The residue was chromatographed on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 882 mg (98%) of methyl 4-[[1-[3-methoxy-4-[ N'~(2- methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]benzoate as a brown amorphous solid which is used in the subsequent reaction without further purification.

To a stirred solution of the above methyl 4-[1-[3-methoxy-4-[Δ7r-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl- N amino]benzoate (882 mg, 1.662 mmol) in TFA ( 18 mL) and MeOH (5.0 mL) was added 1 N NaOH (5.0 mL, 5.000 mmol) and

the mixture was heated under reflux for 3 days. The mixture was concentrated. The residue was treated with 1 N HCl

and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo. The solid was recrystallized from n-hexane-diisopropyl ether-CHCl3-MeOH to give 180.5 mg (21%) of 52 as a pale yellow amorphous solid. IR (KBr) 1604, 1535, 1511, 1454,1255',

1224, 1174cm-';-'H-NMR (400 MHz, DMSO-dJ 5 1.79 - 1.99 (br m, 4H), 2.25 (s, 3H), 2.90 - 2.94

(m, 1H), 3.35 - 3.62 (m, 6H), 3.87 ( s, 3H), 4.12 - 4.15 (br s, 1H), 6.63 - 6.78 (m, 4H), 6.89 - 6.95 and 7.11 - 7.17 (m each, 3H), 7.65 (d, J= 8.3 Hz, 2H), 7.80 (d, J= 8.3 Hz, 1H), 8.02 (d, J= 8.3 Hz> 1H), 8.47 (s, 1H)j 8.57 ( s, 1H), 12.0 (brs, 1H)fteoE (FAB) m/z 517 (M<N>-1); Meant for

C 2 H 2 -NA-1 2 O: C, 65.15; H, 6.41; N, 10.48. Found: €, 65.45; H, 6.33; N, 10.02.

EXAMPLE 44

4- [ N- [1- [3-methoxy-4- [ W - (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinylmethyl] -N-methylamino] benzoic acid

To a mixture of 4[ N-(2-pyrrolidinyl)methylamino]benzoate (600 mg, 1.794 mmol), 37% formaldehyde (1.79 mL, 23.32 mmol) and NaBH3CN (368 mg, 5.561 mmol) in CH 3 CN (6.0 mL) was added dropwise AcOH (0.205 mL, 3.588 mmol) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was quenched by the addition of saturated NaHCO 3 and extracted with EtOAc. The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 645 mg (100%) of methyl 4-[A7- [1-(tert -butoxycarbonyl)-2-pyrrolidinylmethylamino]benzoate as a colorless oil. i^nmr .'

(400 MHz, CDClj) 51.50 (s, 9H), 1.76 - 1.91 (m, 4H), 3.07 (s, 3H), 3.15 - 3.43 (m, 3H), 3.67 - _ 3.71 (m, 1H), 3.85 ( s, 3H), 4.11-4.17 (m, 1H), 4.37 (s, 1H), 6.75 (d, J = 8.3 Hz, 2H), 7.89 (d, / = 8.8 Hz, 2H); MS (FAB) m/z 349 (M<+>+1).

To a stirred solution of methyl 4-[N-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethyl]-Δ7-methyl amino]benzoate (6.45 mg, 1.794 mmol) in CH 2 Cl 2 (6.5 mL) was added added TFA (1.3 mL) at -0°C and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was treated with 1 N NaOH solution. The mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and the solvent was concentrated under reduced pressure to give 363.2 mg (82%) of methyl 4-[ N -(2-pyrrolidinyl)methyl- N -methyl]aminobenzoate as a yellowish oil which is used in the subsequent reaction without further purification.

The mixture of methyl 4-[ N -(2-pyrrolidinyl)methyl- N -methyl]-aminobenzoate (191.8 mg, 0.772 mmol), 3-methoxy-4-(Δ7'-2-methylphenylureido)phenylacetic acid (258.1 mg, 0.811 mmol), EDC

(hydrochloride) (221.9 mg, 1.158 mmol), HOBt (10.0 mg, 0.077 mmol) and DMAP (9.4 mg, 0.077 mmol) in DMF (2.0 mL) were stirred for 3 h at room temperature. The reaction mixture was diluted with Et 2 O, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure to give 482.5 mg of methyl 4-[A7-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl]-N -methylamino]-benzoate as a white amorphous powder which is used in the subsequent reaction without further purification.

To a stirred solution of methyl 4-[W-[1-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]benzoate in THF (5.0 ml) 1 N NaOH was added

(6.2 mL, 6.2 mmol) and the mixture was heated at reflux for 3 days. The reaction mixture was concentrated in vacuo. The residue was neutralized with 1 N HCl and extracted with CH 2 Cl 2 . The extract was washed with saturated NH 4 Cl, brine, dried over Na 2 SO 4 and evaporated in vacuo. The crude solid was recrystallized from n-hexane-CHCl 3 -MeOH-isopropyl ether to give 102.8 mg (25%, 2 steps) 53 as a pale yellow amorphous solid. Temp. 144-146°C.

IR (KBr) 3325, 1600, .1529, 1454, 1284, 1257, 1184 cm-'; 1H-NMR (400 MHz, DMSO-d*) δ 1.73 - 1.91 (m, 3H), 2.03 - 2.11 (m, 1H), 3.03 (s, 3H), 3.16 (dd, 7= 9.3,14.2 Hz, UT), 3.37 - 3.60 (m, 4H); 3.76 - 3.80 (m, 1H), 3.86 (s, 3H), 4.25 (br s, 1H), 6.75 (dd, J= 1.5, 8.3 Hz, 1H), 6.86 (d, /= 1.5 Hz, 1H), 6.90 (d, J= 8.8 Hz, 2H), 6.95-7.01 (m, 1H), 7.12 (t, .7=7.8 Hz, 1H), 7.20-7.25 (m, 1H), 7.73 (d, J=8.8 Hz, 2H), 8.01 (d, .7= 7.8 Hz, 1H), 8.16-8.20 (m, lH)i 8.73 (s, 1H), 9.19 (d, .7= 2.0 Hz, 1H), 12.0 (br s, 1H); MS (FAB) 535 (M<+>+1);,W. Calculated fwC^H3iFNA,l/2HsO: C, 64.08; H, 5.93; N,' 10.31; F, 3.49. Found: C, 64.17; H, 5.84; N, 10.06; F, 3.26.

EXAMPLE 45

4-[ N-[1-[-4-[ N'-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]-3-nitrobenzoic acid

To a mixture of methyl 4-fluoro-3-nitrobenzoate (1.58 g, 4.666 mmol) and [1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-methylamine (500 mg, 2.333 mmol) in DMF (8.0 ml) was added K 2 CO 3 (967 mg, 6.999 mmol) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with EtOAc, washed with water and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 834.9 mg (91%) of methyl 4-[A7- [1- (tert-butoxycarbonyl)-2-pyrrolidinyl-methyl]-N-methyl]amino-3-nitrobenzoate as a pale yellow oil which is used in the subsequent reaction without further purification'.

To an ice-cooled solution of the above oil in CH 2 Cl 2 (8.3 mL) was added TFA (1.7 mL) and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was treated with 1 N NaOH and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to give 553.6 mg (90%) of methyl. 4-[ N -(2-pyrrolidinylmethyl)-α7-methyl] amino-3-nitrobenzoate as a pale yellow Oil. "H-NMR (400 MHz, CDCl3) 5 1.31 - 1.40 (rn, 1H), 1.74 - 2.05 (m, 4H), 2.73 - 2.79 (m, 1H), 2.81 - 2.99 (m, 1H), 2.94 (s , 3H), 3.29 -3.55 (m, 2H), 3.89 (s, 3H), 7.14 (d, J= 9.3 Hz, 1H), 7.98 (dd; J = 2.0, 8.8 Hz, 1H), 8.42 (d, J= 2.0 Hz, 1H); MS (FAB) m/z 294 (M<*>+1).

A mixture of 3-methoxy-4-[N'~(2-fluorophenyl)ureido]phenyl--acetic acid (630.0 mg, 1.979 mmol), methyl 3-nitro-4-[A7-(2-pyrrolidinyl)methyl -N-methylamino]benzoate (553.0 mg, 1.885 mmol), EDC (hydrochloride) (542.0 mg, 2.827 mmol), HOBt (25.5 mg, 0.189 mmol) and DMAP (23.1 mg, 0.189 mmol ) in DMF (5.0 mL) was stirred at room temperature for 2 h. The mixture was diluted with Et 2 O, washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with CHCl3-MeOH (30:1, v/v) as eluent to give 1.18 g (100%) of methyl 4-[ N- [1-[ 3-Methoxy-4-[N-(2-fluorophenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]-3-nitrobenzoate as a yellow foam used in the subsequent reaction without further purification.

To a stirred solution of the above methyl 4-[A7- [1- [3-methoxy-4- [A7'-(2-fluorophenyl)ureido] phenylacetyl] -2-pyrrolidinylmethyl]-AT-methylamino]-3- nitrobenzoate (2.50 mg, 0.421 mmol) in THF (3.0 mL) was added 1 N NaOH (1.5 mL, 1.500 mmol) and the mixture was heated at reflux overnight. After cooling, the mixture was concentrated to a small volume. The residue was treated with 1 N HCl and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo. The crude solid was recrystallized from n-hexane-diethyl ether-CHCl 3 -MeOH to give 194.4 mg (80%) of 54 as a yellow amorphous solid. IR

(KBr) 1685, 1610, 1529,1454, 1284, 1259, 1228 cm"<1>; 'H-NMR (400 MHz, DMSO-dJ 6 1.63 - 1.91 (m, 3H), 2.04 - 2.07 (br s, 1H), 2.60 (br s, 1H), 2.80 (s, 1H), 2.99 (s, 2H), 3.05 - 3.10 (m, 1H), 3.32 - 3.58 (m, 3H), 3.76 - 3.81 (m, 1H ), 3.81 (s, 3H), 4.25 (br s, 1H), 6.68 (t, J= 3.9 Hz, 1H), 6.71 (d, J= 8.8 Hz, 1H), 6.81 - 6.96 (m, 1H), 7.07 (t, J= 7.3 Hz, 1H), 7:17 (dd, J= 7.8, 9.8 Hz, 1H), 7.48 (t, J= 7.8 Hz, 1H), 7.85 (d, J= 8.8 Hz, iH ), 7.97 (t, J= 8.8 Hz, 1H), 8.11 - 8.20 (m, 2H), 8.68 (s, 1H), 9.14 (s, 1H), 12.8 (br s, 1H); MS (FAB) m / z 580 (M*+l); Anal Calc. for C^joFNjO/lAlHjO: c, 59.63; H, 5.26; N, 11.99; F, 3.25. Found: C, 59.68; HI 5.34; N, 11.80; F, 3.21.

EXAMPLE 46

3-amino-4- [A7-methyl- [1- [4- [ N'~ (2-fluorophenyl) ureido] -3-methoxyphenylacetyl]-2-pyrrolide<i>n<y>lmet<y> l]-Jv"-meth<y>lamino]benzoic acid

A stirred solution of methyl 4-[ N- [1-[4-[ N'~(2-fluoro-phenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethyl]- N -methylamino]-3-nitrobenzoate (901 .0 mg, 1.518 mmol) in MeOH (18.0 mL) was hydrogenated over 5% Pd-C (1.35 g) at 45 psi overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made basic with 1 N NaOH solution and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel with CHCl3-MeOH (24:1, v/v) as eluent to give 283.7 mg (48%) of methyl 3-amino-4-[ N-[1-[4-[ N' ~(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]benzoate as a brownish amorphous solid which was used in the subsequent reaction without further purification.

To a stirred. solution of the above compound in THF

(3.0 mL) was added 1 N NaOH solution (1.5 mL, 1.500 mmol) and the mixture was heated at reflux overnight. The mixture was concentrated, treated with 1 N HCl and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo. The solid was recrystallized from n-hexane-diethyl ether-CHCl 3 -MeOH to give 179.8 mg (65%) of 55 as a white amorphous solid. IR (KBr) 1614,

1601, 1537, 1454, 1228, 1219, 1184 cnV<1>; 1H-NMR (400 MHz, DMSO-dJ 8 1.60 - 2.20 (m, 4H), 2.61 - 2.68 (m, 1H), 2.89 (s, 3H), 3.13 - 3.18 (m, 1H), 3.40 - 3.61 ( m, 4H), 3.85 (s, 3H), 4.01 (br m, 1H), 4.93 (br s, 2H), 6.50 - 7.31 (m, 8H), 8.01 (dd, J= 2.9, 8.3 Hz, 1H) , 8.18 (t, J= 8.3 Hz, 1H), 8.71 (s, 1H), 9.17(d, J= 1.5 Hz, 1H), 12.3 (br s, 1H); MS (FAB) m/ z 550 (M *+l); Anal. Calculated for C^FNjCylMHA C, 62.86; H, 5.91; N, 12.64; F, 3.43. Found: C, 62.71; H, 6.00; N, 12.39; F, 3.16.

EXAMPLE 47

4- [1-[4- [ N' - (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinyl-methyl] methylamino] benzoic acid

To a stirred mixture of methyl 4-[(2-pyrrolidinyl)methylamino] benzoate (220 mg, 0.94 mmol), 4-[ N'~ (2-methylphenyl)-ureido]phenylacetic acid (285 mg, 0.94 mmol ), 4-DMAP (140 mg, 1.13 mmol) and a catalytic amount of HOBT in DMF (7 mL) was added EDC-HCl (220 mg, 1.13 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (20 mL) column chromatography with CHCl 3 -EtOAc (3:1, v/v) to CHCl 3 -EtOH (9:1, v/v) as eluent to afford methyl 4-[1- [4-[ N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]benzoate (400 mg, 85%) as a gum. 1H-NMR(CDC13)51.75-

2.05 (series avi-m, 4 H), 2.24 (s, 3 H), 3.18 and 3.27 (each iri, each 1 H), 3.51 (rn, 2 H), 3.60 (s, 2 H), 3.83 (s , 3H), 4.52 (m, 1H), 6.52 (m, 3H), 6.81 (s, 1H), 7.11-7.25. (:series_ay_jn, 7 H), 7.53 (m, 1H), 7.81 (d,/= 8.8Hz, 2H).

A mixture of methyl 4-[1-[4-[N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]benzoate (280 mg, 0.56 mmol) in THF (3 mL) and 0 .25 N NaOH (6.8 mL, 1.75 mmol) was stirred for 3 h at 60-70°C. After cooling, the mixture was poured into ice-1 N HCl (3 mL). The solid was collected, washed with water and air dried. The crude crystalline material was recrystallized from CHCl 3 -EtOH-IPE to give 56 (180 mg, 66%) as fine needles. Molecular weight 486.56 IR

(KBr) n 3367, 3294, 1712, 1606, 1539 cm-'; 'H-NMR (CDClj-DMSCK) 6 1.80-2.05 (series of m,

4 H), 2.26 (s, 3 H), 2.94(m, 1 H), 3.38 and; 3.56 (series of ' m, 3 H), 3.57 (s, 2 H), 4.23 (iri,2 H),

6.48 (br s, 1 H), 6.69 (d, /= 8.8 Hz,' 2H), 6.91 (t, /= 7 Hz, 1 H), 6.91 (m, 4 H), 7.39 (d, J= 8.3 Hz, 2H), 7.66 (d, J= 8.8.Hz, 2H)„ 7.80 (m, 2H), 8.88 (s, 1H), 11.76 (s, 1H); MS(FAB). m/z 487

(M<*> +l);^a/.BeregWr6r €J8H30N,Ov0.75xHJO: C, 67.24; H, 6.45; N, 11.20. Found: C, 67.13; H,

6.32; N,. 11.6 U...

EXAMPLE 48

Methyl 4- [1- [4-[ N'-(2-chlorophenyl)ureido] -3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate

4- [1- [4- [A7r-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of 2S-pyrrolidine methanol (15., 1 g, 149.5 mmol) in dioxane (100 mL) was added a solution of (Boc)20 (32.6 g, 164.4 mmol) in dioxane ( 100 ml). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The rest was cleaned with wood

column chromatography on silica gel with EtOAc-hexane (1:5, v/v) as eluent to give (1-tert-butoxycarbonyl)-(2S)-pyrrolidinyl)methanol (31.6 g, quantitative) as a colorless oil. 1 H-NMR(CDCl 3 ) 8

1.47 (s, 9H), 1.60-2.00 (m, 3H), 3.25-3.70 (4H, m), 3.92-4.00 (m, 1H).

To a stirred solution of (1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methanol (4.02 g, 20.0 mmol), methyl 4-hydroxybenzoate (3.04 g, 20.0 mmol) and Ph3P (6 .28 g, 24.0 mmol) in THF

(50 mL) was added DIAD (4.85 g, 24.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. 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 methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (5.4 g, 81%) as a pale yellow oil. "H<->

NMR (CDCl1) δ 1.47 (s, 9H), 1.88-2.04 (m, 4H), 3.41 (m, 2H), 3.91 (s, 3H), 3.90-3.92 (rn, 1H), 4.11-4.16 (xn, 2H), 6.94 (d, J= 8.6 Hz, 2H), 7.94 (d, J= 8.3 Hz, 2H).

To a stirred solution of methyl 4-(1-tert-butoxycarbonyl-.

To (2 S )-pyrrolidinyl)methoxybenzoate (2.1 g, 6.27 mmol) in CH 2 Cl 2 (9.0 mL) was added TFA (6.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (470 mg, 2.0 mmol), 4-[N'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetic acid (669 mg, 2.0 mmol), HOBt (405 mg , 3.0 mmol) and triethylamine (554 mL, 4.0 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (576 mg, 3.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4, v/v) as eluent to give 57 (900 mg, 82%) as a colorless

oil. Molecular weight 552.02. 1H-NMR (CDCl 3 ) δ 2.04-2.10 (m, in 4H), 3.51-3.70 (xn, 6H), 3.87 (s, 3H), 4.11-4.18 (m, 2H), 6.77-6.88 (xn, 4H ), 7.23-7.34 (m, 4H),

7.91-7.96 (m, 2H), 8.17-8.19 (m, 1H).

The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and it was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to 58 (640 mg, 94%) as a white crystalline solid. Molecular weight 537.99. M.p.: 126-130°C.

IR (KBr) 3324, 2938, 2877, 1604, 1533, 1249, 1166, 750 cm -1 ; 1H-NMR pMSO-ds) 6 1.93-

2.05 (m, 4H), 3.52-3.61 (m, 5H), 3.82 (s, 3H), 3.99-4.01 (m, 2H), 4.18-4.20 (m, 1H), 4.29 (m, 1H), 6.74- 6.76 (d, 1H, J= 8.3 Hz), 6.87 (s, 1H), 6.99-7.04 (m, 3H), 7.25-7.29 (m, 1H), 7.41-7.43 (d, 1H, J= 8.1 Hz) , 7.86-7.91 (m, 2H), 7.95-7.97 (m, 1H), 8.09-8.11 (d, 1H, J= 8.3 Hz), 8.87-8.92 (m, 1H); MS (FAB) m/z 538 (K+1); Anal. Calcd for CMH3.,N3Cv0.5HJO: C, 61.48; H, 5.34; N, 7.68; Cl, 6.48. Found: Q 61.46; H, 5.36; N, 7.62; CI, 6.50. For Na saltav58 : Ana^ Berégrief for CjjHnNjOj-Na- 1.5HjO: C, 57.29; H, 5.15; N, 7.16. Found: C, 57.48; H, 5.04; N, 6.99.

EXAMPLE 49

■ 4- [1- [4- [ N' - (2-bromophenyl) ureido] -3-methoxy enylacetyl] - (2S) - pyrrolidinyl] methoxybenzoic acid

To a stirred solution of methyl 4-(2S)-pyrrolidinyl)-methoxybenzoate (470 mg, 2.0 mmol), 4-[ N'~ (2-bromophenyl)-ureido]-3-methoxyphenylacetic acid (758 mg, 2, 0 mmol), HOBt

(405 mg, 3.0 mmol) and triethylamine (554 mL, 3.0 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (576 mg, 3.0 mmol ) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 and then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4, v/v) as eluent to give methyl 4-[1-[4-[ N'~

(2-Bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (1.0 g, 84%) as a colorless oil.

1 H-NMR (CDCl 3 ) δ 2.04-2.10 (m, 4H), 3.52-3.54

(m, 1H), 3.62 (s, 2H), 3.70 (s, 3H), 3.88 (s, 3H), 4.13-4.19 (m, 2H), 6.79-6.94 (m, 4H), 7.20-7.31 (m , 1H), 7.91-8.12 (rn, 2H), 8.13-8.15 (ni, 1H).

To a stirred solution of methyl 4-[1- [4-[AT'-(2-bromophenyl)ureido]-3-methoxy enylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (.780 mg, 1.31 mmol) in THF (10.0 mL) and MeOH (5.0 mL) was added 1 N NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and it was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 59 (730 mg, 96%) as a white crystalline solid. Molecular weight 582.44.'

Smp. : 120-125 °C; IR (KBr) 3318, 2938, 1604, 1529, 1166, 1025 cm'

'; 1H-NMR (DMSC-ctøo 1.92-1.96 (m, 4H), 3.52-3.60 (m, 5H), 3.82 (s, 3H), 3.98-4.02 (m, 1H), 4.16-4.19 (m, 1H) , 4.29 (m, 1H), 6.75 (d, J= 8.3 Hz, 1H), 6.87 (m,lH), 6.94-7.04 (m, 3H), 7.29-7.33 (m, 1H), 7.57-7.59 (rri , 1H), 7.85-7.96 (m, 4H), 8.72 (s, 1H), 8.91 (s, 1H); MS (FAB) m/ z 582 (M<++>I);^na/.Calculated for CJ1jH2lN3OtBrl. 0HIO: C, 56.01; H, 5.04; N, 7.00; Br, 13.3 in. Found: C, 56.12; H, 4.98f N, 6.96; Br, 13.57..

EXAMPLE 50

3-amino-4- [1- [4- [AT'-(2-hydroxyphenyl)ureido]-3-methoxy enylacetamido]-2-pyrrolidinylmethoxy]benzoic acid '■

To a stirred solution of 2-nitrophenol (10.0 g, 72.0 mmol) and K 2 CO 3 (9.96 g, 72.0 mmol) in DMF (150 mL) was added dropwise benzyl bromide (9.40 mL, 79 .2 mmol) at 0°C. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water, which was extracted with Et 2 O. The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness. Chromatography of the residue with hexane-EtOAc

(2:1, v/v) as eluent gave 2-benzyloxynitrobenzene (14.7 g, 89%) as a yellow oil.

1 H-NMR (CDCl 3 ) δ 5.24 (s, 2H), 7.04 (t, J= 7.8 Hz,

1H), 7.12 (d, J= 7.8 Hz, lH), 7.31 - 7.50 (m, 5H), 7.51 (d, J= 1.5 Hz, 1H), 7.86 (dd, / = 7.8, 1.5

Hz, 1H).

To a stirred solution of 2-benzyloxynitrobenzene (9.92 g, 43.3 mmol) and NiCl2 (2 0.3 g, 157 mmol) in MeOH (350 mL) was added portionwise NaBH4 (8.09 g, 214 mmol) ) at 0°C. After disappearance of the starting material (measured by TLC), the mixture was evaporated. The black precipitate was dissolved in 1N HCl and then the acidic solution was made alkaline by addition of 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness. Chromatography of the residue with CHCl3

as eluent gave 2-benzyloxyaniline (8.60 g, 100%) as a reddish oil e. 1 H-NMR (CDCl 3 ) δ 3.71 (. broad s ,2H), 5.06 (s, 2H), 6.68 - 6.86 (m , 4H),

7.32 - 7.44 (m, 5H); FAB-MS m/z 200 (M<*>+1).

To a solution of 2-benzyloxyaniline (1.15 g, 5.77 mmol) in benzene (60 mL) was added triphosgene (1.27 g, 6.35 mmol)

and Et 3 N (2.60 mL, 17.3 mmol) at 0 °C. The reaction mixture was heated at reflux for 20 hours. The resulting mixture was filtered and washed with hexane and the filtrate was concentrated to give a residual oil which was chromatographed with hexane-EtOAc (4:1, v/v) as eluent to give tert-butyl 4-[A7'- (2 -benzyloxyphenyl)ureido]-3-methoxyphenylacetate (2.38 g, 89%) as a yellow oil. 1H-NMR (CDCl 3 ) δ 1.44 (s, 9H), 3.44 (s, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 6.73 (dd, J= 8.0, 1.7 Hz, 1H), 6.78 (d, J= 1.7 Hz, 1H), 6.90 - 6.98 (m; 3H),

7.07 (s, 1H), 7.29 (s, 1H), 7.33- 7.38 (m, 5H), 7.91 (d, J= 8.0 Hz, 1H), 8.14 (m, 1H).

To a solution of tert-butyl 4-[iVr-(2-benzyloxy-phenyl)ureido]-3-methoxyphenylacetate (2.35 g, 5.08 mmol) in CH 2 Cl 2 (25 mL) was added TFA. (25 mL ) at 0°C. After stirring at room temperature for 3 hours, the mixture was concentrated. The residue was dissolved in 1 N NaOH and washed with Et 2 O. The basic aqueous layer was poured into ice-1 N HCl and the resulting mixture was extracted with CHCl 3 -MeOH (4:1, v/v). The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness. The residue was dissolved in isopropyl ether and hexane was added to this solution until crystallization was complete. The solid was collected to give 4-[AT<->(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetic acid (1.59 g, 77%) as a brownish solid.

'H-NMR PMS.CK) 5 3.50 (s, 2H), 3.85 (s, 3H), 5.26 (s, 2H), 6.76 ( å, J= 8.3 Hz, 1H), 6.83 - 6.89 (m, 2H) , 6.91 (s, 1H), 7.01 (dd, J= 8.3, 2.3 Hz, 1H), 7.31 (t, /•= 7.3 Hz, 1H), .7.39 (t, J= 7.3 Hz, 2H), 7.49 ( d, J= 7.3 Hz, 2H), 7.97 (d, J= 8.3 Hz, 1H), 8.04 (d, J= 8.3 Hz, 1H), 8.80 (s> 1H), 8.86 (s, 1H), 12.24 ( Wed's, 1H); FAB-MS m/z 407 (M<+>+1).

To a solution of 4-[α7r-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetic acid (1.12 g, 2.76 mmol), methyl 4-(2-pyrrolidinylmethoxy)-3-nitrobenzoate (890 mg, 2, 76 mmol), HOBt (74.0 mg, 0.55 mmol), DMAP (67.0 mg, 0.55 mmol) and Et3N (0.58 mL, 4.13 mmol) in THF (15 mL) gave added EDCHC1 (792 mg, 4.13 mmol). After stirring at room temperature for 12 h, the reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness. Chromatography of the residue with EtOAc as eluent gave methyl 4- [1- [4- [ N'~

(2-Benzyloxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]-3-nitrobenzoate (1^5.2 g, 82%) as a yellow amorphous solid. 'H-NMR

(CDClj) 5 1.91 (m, 1H), 1.95 - 2.17 (m, 3H), 3.47 - 3.53 (m, 2H), 3.56 (s, 2H), 3.60 (m, 1H), 3.68 (s, 3H), 3.90 (s, 3H), 4.11 (d, 7= 7.3 Hz, 1H), 4.45 (m, 1H), 5.08 (s, 2H), 6.70 (dd, .7 = 8.3, 1.9 Hz, 1H), 6.75 ( d, J= 1.9 Hz, 1H), 6.91 - 6.99 (m, 3H), 7.16 (s, 1H), 7.18 (d, J= 8.3 Hz, 1H), 7.33 - 7.40 (m, 6H), 7.91 (d , 7= 8.3 Hz, 1H), 8.11 - 8.16 (m, 2H), 8.46 (s, 1H).

A solution of methyl 4-[1-[4-[ N'~ (2-benzyloxyphenyl)-ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]-3-nitrobenzoate (1., 52 g, 2.27 mmol) in MeOH (20 mL) and THF (5 mL) was hydrogenated over 5% Pd-C (wet, 52.2%, 1.21 g) under a hydrogen atmosphere (4 kg/cm<2>) at room temp. After stirring for 17 hours, the catalyst was filtered off and the filtrate was concentrated to dryness. Chromatography of the residue eluting with EtOAc gave methyl 3-amino-4-[1-[4-[A7r-(2-hydroxyphenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy]benzoate (1.12 g, 90% ) as a brownish amorphous solid.

1H-NMR (CDCl 1 ) 6 1.97 = 2.10 (m, 4H),

3.44 (s, 3H), 3.52 - 3.63 (m, 2H), 3.85 (s, 3H), 4.10 - 4.18 (m, 2H), 4.53 (m, 1H), 6.65 - 6.67 (m, 4H), 6.93 - 7.02 (m, 3H), 7.33 (d, 7 = 2.2 Hz, 1H), 7.36 (dd, 7 = 8.3, 2.2 Hz, 1H), 7.60 (s, 1H),

7.69 (d, 7 = 8.3 Hz, 1H), 8.08 (s, 1H), 9.47 0 wide! s, 1H); FAB-MS m/z 549 (M<+>+1).

To a solution of methyl 3-amino-4-[1-[4-[ N'~ (2-hydroxy-phenyl)ureido]-3-methoxyphenylacetamido]-2-pyrrolidinylmethoxy] benzoate (1.12 g, 2.04 mmol) in THF-MeOH (4:1, v/v, 20 mL) was added 1 N NaOH (4.20 mL,

4.20 mmol). After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was diluted with water and neutralized with 1N HCl at 0°C. The mixture was extracted with CHCl 3 -MeOH (4:1, v/v), washed with brine, dried over Na 2 SO 4 and concentrated to dryness. Chromatography of the residue with CHCl3:MeOH (5:1, v/v) as eluent gave 60 (352 mg, 32%) as a pale yellow amorphous solid. Molecular weight 534.56.'

(KBr) 3282, 3062, 3025, 2952, 2865, 1629, 1546, 1509, 1454,

. 1419 cm-'; 1H-NMR (DMSO-rf6) δ 1.87 - 2.04 (m, 4H), 3.48 - 3.57 (m, 2H), 3.60 (s, 2H), 3.79 (s, 3H), 3.94 (dd, 7= 9.5, 7.6 Hz, 1H), 4.12 (dd,7= 9.5, 3.9 Hz), 4.35 (m, 1H), 4.87 C broadl.s, 1H), 6.70 - 6.91 (m, 6H), 7.16 (dd, 1H,7 = 8.3, 2.0 Hz, 1H), 7.26 (d, 7= 2.0Hz, 1H), 7.96 (d,7= 8.3 Hz, 1H), 7.97 (d, 7= 8.3 Hz, UT), 8.80 (s, UT ), 8.82 (s, 1H); FAB-MS m/z 535 (thoT+1); Anal. Calculated for C 1 H 3 oNA-4.5 H 2 O: C, 55.63; H, 6.39; N, 9.10. FoundfcC, 55.08; H, 5.06<;> N, 8.69. EXAMPLE 51 5- [ [1- [4- [A7r-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl] -2- pyrrolidinyl]methylamino]pyridine-2-carboxylic acid 5-[[1-[3-methoxy-4- [ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino] pyridine-2-carboxylic acid

To a stirred solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (2.5 g, 13.8 mmol) and 4-DMAP (340 mg, 2.8 mmol) in tert-BuOH (15 mL) was added Boc 2 O (6 g, 27.6 mmol) at room temp. After stirring for 2 h at room temperature, ice and 0.2 N HCl (20 mL) were added to the mixture and extracted with CH 2 Cl 2 . The extracts were washed with saturated NaHCO 3 , dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with CH 2 Cl 2 as eluent to give methyl 6-tert-butoxycarbonylnicotinate (2.92 g, 89%) as needles. IR (KBr) 2729,

1736, 1720,, 1590, 1570 cm'<1>; MS (FAB) m/z 238 (M* +1); ylna/.Calculated for CnH15NO,: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.72; H, 6.46; N, 5.78.

A mixture of methyl 6-tert-butoxycarbonylnicotinate (1.2 g, 5.06 mmol) in THF (15 mL) and 0.25 N NaOH (40 mL, 10 mmol) was stirred at ambient temperature for 0.5 h. The mixture was poured into ice-1 N HCl (10 mL). The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl3-EtOH-IPE to give 6-tert-butoxycarbonylnicotinic acid (850 mg, 76%) as needles.

IR (KBr)n 3095, 1728, 1705 cm"1; 1H-NMR (DMAO-d<) δ 1.63 (s, 9.H), 8.09 (m, 1H), 8.17 (m, 1H), 8.42 ( dt, J= 2.4 and?8.3 Hz, 1H), 9.21 (t, J= 2.4.qg -8.8Hz, 1H);

MS (FAB) m/ z 224 (M++1); H.3.18; N, 3.84. Found: C, 36.85; H, 3.35; N, 3.79.

To a stirred mixture of 6-tert-butoxycarbonylnicotinic acid (1.9 g, 8.51 mmol) and triethylamine (1.17 g, 11.49 mmol) in tert-BuOH (30 mL) and toluene (30 mL) was added a solution of diphenylphosphoryl azide (2.93 g, 10.64 mmol) in toluene (3 mL) at room temperature. The resulting mixture was then heated at reflux for 5 hours. After cooling, ice and 1 N HCl (5 mL) were added to the mixture and extracted

with toluene. The extracts were washed with saline,

in dried over Na 2 SO 4 and evaporated. The residue was chromatographed on

silica gel (50 mL) with toluene-EtOAc (5:1, v/v) as eluent to give tert-butyl 5-tert-butoxycarbonyl-amino-2-pyridinecarboxylate (1.9 g, 76%) as a gum.

1H-NMR (CDCl 3 ) δ 1.53 (s, 9 H), 1.63 (s, 9 H), 6.82 (br s, 1 H), 8.01 (d, J =

8.8 Hz, 1H), 8.17 (m, 1 H)/8.46 (d, 7 = 2.4 Hz, 1 H).

To a stirred mixture of tert-butyl 5-tert-butoxycarbonyl-amino-2-pyridinecarboxylate (1.9 g, 6.45 mmol) in CH 2 Cl 2 (20 mL) was added TFA (5 mL). ■ The mixture was evaporated and the residue was dissolved in EtOH (30 mL). HCl gas was introduced into the solution with stirring at 0-10°C for 10 min. The resulting mixed mixture was then heated under reflux for 10 hours. After cooling, N2 gas was introduced to remove the large excess of HCl gas for 15 min. The mixture was evaporated. The residue was made alkaline by addition of saturated NaHCO 3 and extracted with CH 2 Cl 2 . The extracts were washed with saline, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (30 mL) with CHCl 3 -EtOH (98:2, v/v) as eluent to give ethyl 5-amino-2-pyridinecarboxylate (700 mg, 65%) as a crystalline material. IR (KBr) n 3423, 3190,

1708, 1657, 15873338, 3296, 1691, 1641 cm"1; 'H-NMR (CDC1,)5 1.42 (t, 7 = 7.0 Hz, 3 H), 4.11 (br s, 1 H), 4.43(q, 7 = 7.0 Hz, 2 H), 6.99 (dd, 7= 2.7 og. 8.5 Hz, 1 H), 7.95 (d, 7 = 8.5 Hz, 1 H), 8.16 (d, 7= 2.7 Hz, 1 H) ; MS (FAB) m/ z 167 (M<*>); Andi. Calculated for C^aNA: C, 57.47; H, 6.63; N, 16.76. Found: C, 57.27; H, 5.99; N, 16.72.

A stirred mixture of ethyl 5-amine 6-2-pyridine carboxylate

(660 mg, 3.95 mmol) and 1-tert-butoxycarbonylprolinal (1.1 g, 5.33 mmol) in toluene (10 mL) were heated at reflux for 1 h during which time water was removed azeotropically with a Dean -Strong water trap. After cooling, the mixture was evaporated in vacuo. The residue was dissolved in MeOH-AcOH (9:1, v/v, 30 mL). To the stirred solution was added NaBH 3 CN (500 mg, 7.90 mmol) at 0-5°C. The resulting mixture was stirred for a further 12 hours at room temperature. The mixture was poured into ice-saturated NaHCO 3 (50 mL) and extracted with CH 2 Cl 2 . The extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with CHCl 3 -EtOAc (98:2, v/v) as eluent to give ethyl 5-[N-[2-(l-tert-butoxycarbonyl)pyrrolidinyl]methylamino]pyridine- 2-carboxylate (1.1 g, 70%) as a gum.

1 H-NMR (CDCl 3 ) δ 1.38 (s, 9 H); 1.42 (s, 6 H),

3.93 (s, 3 H), 4.29 (s, 2H), 4.67 (br s, 1 H), 7.15 (d, 7= 8.8 Hz, 1 H), 8.18 (dd, 7= 1.7 and 8.8Hz,

1H), 8.52(d,7= 1.7 Hz, 1H).

A mixture of ethyl 5-[[2-(1-tert-butoxycarbonyl)pyrrolidinyl] methylamino] pyridine-2-carboxylate (800 mg, 2.29 mmol) in CH 2 Cl 2 (17 mL) and TFA (3 mL) was stirred at room temperature for 3 hours. The mixture was evaporated and the residue basified with saturated NaHCO 3 . The mixture was extracted with CH 2 Cl 2 . The extracts were washed with brine, dried, over Na 2 SO 4 -Na 2 CO 3 and evaporated. to give ethyl 5-[(2-pyrrolidinyl)methylamino]pyridine-2-carboxylate (460 mg, 81%) as a gum.

1 H-NMR (CDCl 1 ) δ 1.32 (t, 7 = 7 Hz, 3 H), 1.58-2.10

(series of m, 4 H), 3.12-3.28 (series of m, 3 H), 3.65 (m, 1 H), 4.30 (be q, 7 = 7 Hz, 2 H), 6.27 (br, 1 H) , 6.59 (dd, 7 = 2.4 and 8.5 Hz, 1 H), 7.65 (d, 7= 8.5 Hz, 1 H), 7.94 (d, 7= 2.4 Hz, 1 H).

To a stirred mixture of ethyl 5-[(2-pyrrolidinyl)methylamino]pyridine-2-carboxylate (220 mg, 0.88 mmol), 4-[α7r-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (300 mg, 0.88 mmol), 4-DMAP (135 mg, 1.10 mmol) in DMF (7 mL) was added EDC-HCl (215 mg, 1.10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (30 mL) column chromatography with CHCl 3 -EtOH (98:2, v/v) as eluent and crystallized with Et 2 O to give 5-.[l- [4-[ N'- (2 -chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methylamino]pyridine-2-carboxylate (420 mg, 84%) as fine needles. IR (KBr) 3319,

1703, 1628, 1585, 1529 cm"'; 'H-NMR (CDC13)5 1.38 (t,7= 7 Hz, 3 H), 1.73-2.17 (series of m, 4 H), 3.19 and 3.54 (each lm, each 1 H), 3.63 (s, 2 H), 3.70 (s, 3 H), 4.39 (bé q, 7= 7 Hz, 2 H), 4.55 (xn, l.H), 6.02 (br s, 1 H) , 6.78-6.84 (series.of s and fn, 3 H), 6.98 (dt, 7= 2.4 and 8.0 Hz, 1 H), 7.16 (s,lH), 7.21-7.26 (series of iri; 3 H), 7.34 (dd, 7 = 2.4 and 8.0 Hz, 1 H), 7.90 (d, 7 = 8.3 Hz, 1H), 7.98 (m, 2H), 8.16 (dd, 7= 1.2 and" 8.8 Hz, 1H); MS (FAB) m/z 566 (M + +1); Anal. Meant for. CClN 3 -H 2 O: c, 59.63; H- 5^87; N, 12.37 Found: C, 60.06; H, 5.76; N, 11.95.

A mixture of ethyl 5-[[1-[4-[AT'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methylamino]pyridine-2-carboxylate (300 mg, 0.53 mmol ) in THF:MeOH (1:1, v/v, 16 mL) and 0.25 N NaOH (11 mL, 2.75 mmol) was stirred for 3 h

at room temperature. The mixture was poured into ice-1 N HCl

(3 ml). The solid was collected, washed with water and air dried. The crude crystalline material was collected with CH 2 Cl 2 i-Et 2 O to give 61 (180 mg, 6.3%) as an amorphous solid. • Molecular weight 537.99. IR (KBr) 3319, 1701, 1620, 1585, 1533 cm"1; 'H-NMR (CDCl 3 ) 6 'H-NMR (DMSO-cU 8 1.80-2:05 { series of m, 4 H), 2.99 ( m, 1 H), 3.50- 3.59 (series of m, 3 H), 3.60 (s, 2 H), 3.86 (s, 3 H), 4.11 (m, 1 H), 6.78 (d, J= 8.5 Hz, 1 H), 6.91 (s, 1 H), 6.94 (iri, 1 H), 7.02 (m, 1 H), 7.14 (dd,J=2.5 and .8.5 Hz, 1 H), 7.28 (t, J= 7.6 Hz, 1 H), 7.45 (d,J= 8.0 Hz, 1 H), 7.78 (d, J= 8.8 Hz, 1 H), 7.97 ( d, J= 8.3 Hz, 1 H), 8.08 ( brs, 1 H), 8.11 (m, 1 H), 8.89 (s, 1 H), 8.94 (s, 1 H); MS (FAB) m/ z 538 (M<+> +1); Anal.Calc. For.

To a stirred mixture of ethyl 5-[(2-pyrrolidinyl)methylamino]pyridine-2-carboxylate (230 mg, 0.923 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (290 mg ,

0.923 mmol), 4-DMAP (145 mg, 1.15 mmol) in DMF (7 mL) was added EDC-HCl (225 mg, 1.15 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (30 mL) column chromatography with CHCl 3 -EtOH (98:2, v/v) as eluent to give ethyl 5-[[1-[3-methoxy-4-[ N'~ ( 2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]pyridine-2-carboxylate (400 mg, 80%) as fine needles. IR (KBr) n 3325, 1709,

1618, 1585, 1531 cm"'; 'H-NMR (CDClj),6 1:39 (t, J= 7 Hz, 3 H), 1.73-2.07 (series of m, 4 H), 2.28 (s, 3 H), 3.12 and 3.49 (every m, every 1 H), 3.60 (s, 2 H), 4.39 (br q, J = 7 Hz, 2 H), 4.53 (m,

1 H), 6.07 (br s, 1 H), 6.23 (br S, 1 H), 6.75-6.77 (series of s and m,' : 2 H), 6.82 (dd, J r 3.0 and 8.5

Hz, 1 H), 7.09-7.22 (series of m, 3 H), 7.49 (d,'j = 8.0 Ez, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.98 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS (FAB) m/z 546 (M* +1); Anal. Calcd for C 10 H jj N j Cyl-5 x H 2 O: C, 52.92; H, 6.69; N, 12.23. FoundC, 63.11; H, 6.48; N, 11.96.

A mixture of ethyl 5-[[1-[3-methoxy-4-[ N'~(2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinyl] methylamino]pyridine-2-carboxylate (D91-4596) (290 mg, 0.53 mmol) in THF:MeOH (1:1, v/v, 16 mL) and 0.25 N NaOH (11 mL, 2.75 mmol) was stirred for 3 h at room temperature. The mixture was poured into ice-1 N HCl (3 mL). The solid was collected, washed with water and air dried. The crude crystalline material was collected with CH 2 Cl 2 -Et 2 O to give 62 (170 mg, 62%) as an amorphous solid. Molecular weight 517.58.

IR (KBr) 3283, 1701, 1618, 1529 cm-<1>; 'H-NMR

(CDCl 3 ) 6 'H-NMR (DMSO-d*) 8, 1.78-2.04 (series of" iri, 4 H), 2.25 (s, 3 H), 2.95-3.55 (series of m, 4 H), 3.59 (s, 2 H), 3.87 (s, 3 H), 4.11 (m, I H), 6.75-7.24 ( series of m, 7 H), 7.83-7.97 ( series of sc, 3 H), 8.01 (d, J = 8.3 Hz/l H), 8.13 (d, J= 2.6Hz, 1 H), 8.11 (m, 1 H), 8.47 (s, 1 H), 8.57 (s, 1 H); MS (FAB) m /z 518 (M<*> +l);>4na/. Calculated for C^H31N5Cy2.5xH20: C, 60.50; H, 6.39; N, 12.60. Found: C, 60.31; H, 6.28; N, 12.10.

EXAMPLE 52

2-[1-[[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylic acid

To a stirred solution of methyl 2-hydroxy-5-pyridine carboxylate (2.0 g, 13.06 mmol), PPh3 (4.2 g, 15.93 mmol) and 1-tert-butoxycarbonyl-(i) -prolinol (2.63 g, 13.06 mmol) in THF (25 mL) was added a solution of DIAD (3.3 g, 15.67 mmol) in THF (5 mL) at 0-10°C. The resulting stirred mixture was then heated under reflux for 3 hours. After cooling, the mixture was evaporated in vacuo. The residue was chromatographed on silica gel (120 mL) with n-hexane-EtOAc (4:1, v/v) as eluent to give methyl 2-[2-(1-tert-butoxycarbonyl)pyrrolidinyl]methoxypyridine-5-carboxylate

(3.0 g, 68%) as a gum.

1H-NMR (CDCl1) δ 1.46 (s, 9 H), 1.82-2.04 (series of m, 4 H), 3.45 (m, 2 H), 3.91 (s, 3 H), 4.10-4.32 (series of m, 2H), 4.48 (m, 1 H), 6.32 (br, 1 H), 6.75 (d,J = 8.8Hz, 1 H), 8.15 (dd, J = 2 and' 8.8Hz, 1 H), 8.79 (d, J = 2 Hz, 1H).

i A mixture of methyl 2-[2-(1-tert-butoxycarbonyl)pyrrolidinyl] methoxypyridine-5-carboxylate (2.9 g 8.62 mmol) in CH 2 Cl 2 (80 mL) and TFA (20 mL) was stirred at room temperature for 3 hours. The mixture was evaporated and the residue made alkaline with saturated NaHCO 3 . The mixture was extracted with CH 2 Cl 2 .

The extracts were washed with brine, dried over Na 2 SO 4 -Na 2 CO 3 and evaporated to give methyl 2-(2-pyrrolidinyl)methoxy-pyridine-5-carboxylate (1.2 g, 59%) as a gum.

1 H NMR (CDC 13 ) 5 1.58-2.050 (series of m, 4 H), 2:90-3.02

(series of^rn, 2 H), 3.87 and 3.90 (every s, 3 H), 4.23 (m, 1 H), 4.37 (m; 1 H), 6.33 (br, 1 H),"6.78 (d, J= 8.5 Hz, 1H), 8.15 (dd, J= 2.2 and 8.8 Hz, 1 H), 8.79 (d, J= 2.2 Hz, 1H).

To a stirred mixture of methyl 2-(2-pyrrolidinyl)methoxy-pyridine-5-carboxylate (370 mg, 1.57 mmol), 4-[N-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (525 mg , 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 mL) was added

EDC-HCl (3 60 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (30 mL) column chromatography with CHCl 3 -EtOH (98:2, v/v) as eluent and crystallized with Et 2 O

to give methyl 2-[1-[4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethoxy]pyridine-5-carboxylate (600 mg, 69%) as an amorphous solid. <1>H-NMR (CDC13)5 0.21 and 2.01 (each m, 4H), 3.45-4.50 (series of s and m, 13 H containing amide isomers), 6.58-8.83 (series of s and m, 12 H as contains amide isomers) ..

A mixture of methyl 2-[1-[4-[N-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethoxy]pyridine-5-carboxylate (230 mg, 0.415 mmol) in THF (1 mL) and 0.25 N NaOH

(4 mL, 1 mmol) was stirred for 14 hours at room temperature and for 3 hours at 60°C. After cooling, the mixture was poured into ice-1 N HCl (2 mL). The solid was collected, washed with water and air dried. The impure crystalline material was purified by preparative TLC plate with CHCl3-EtOH (9:1, v/v)

as eluent and crystallized with Et2O to give 63

(150 mg, 67%) as an amorphous solid. Molecular weight 538.98

:'IR (KBr) 3329'i:i709, 1601, 1533 tan* 'H-NMR (CDClj) 6 1.85-.2.05 (series of m, 4 H), 3.50-3.60 (series of ^m, 2 H) , 3.82 (s, 3 H), 3.86 (s, 2 H), 4.29 (m, 1 H), 4.42 (m, 1 H), 6.72-7.05 (series of ™, 4 H), 7.28 (m, 1 H), 7.43 (d, J= 8 Hz, 2 H), 7.95 (d, J= 8.3 Hz, 1 H), 8.09 (d, J= 8V3 Hz, 2 H), 8.64 (rn, 1 H), ' 8.89 fe in Hl 8.93 fe 1 H); MS (FAB) m/z 539 (M<*>); Anal. Calculated for C17HmC1NA' 1.3xH2O: C, 57.55; H, 5.47; N, 9.94 Funriet: C, 57.94; H,

5.00; N, 9.45.

EXAMPLE 53

5- [1- [4- [W-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinylmethoxy]pyridine-2-carboxylic acid

To a stirred mixture of methyl 5-(2-pyrrolidinyl) methoxy-pyridine-2-carboxylate (370 mg, 1.57 mmol), 4-[ W -(2-bromo)-phenyl)ureido]-3-methoxyphenylacetic acid ( 595 mg, 1.57 mmol), 4-DMAP (230 mg, 1.88 mmol) in DMF (10 mL) was added EDC-HCl (360 mg, 1.88 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel (30 mL) column chromatography with CHCl3^EtOH (98:2, v/v) as eluent and crystallized from Et2 O to give methyl 5- [1- [4-[ N'~ (2 -bromophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidiriylmethoxy]pyridine-2-carboxylate (650 mg, 69%) as an amorphous solid. Dl (KBr) n 3323, 1720, 11S24, 1601, 1527 cm"<1>; 'H-NMR (CDC13) 6 1.22 and 2.0© (ihverm, 4 H), 3'.48-4.55 .<series of s ; and m, 13'H containing amide isomers ), 6.93-8.82 (series of s and m, 12 . H . ,containing amide isomers •:); MS (FAB) m/ z 597 (MT -1 ) and 599 (M* +1); Anal. Calcd for QBHjoBrNA-l-OxHjO: C, 54.55; H, 5.23; N, 9.09. Found: C, 54.13; H, 5.03; N, 9.33.

A mixture of methyl 5- [1- [4- [A7f - (2-bromphenyl) ureido]-3 - methoxy enylacetyl] -2-pyrrolidinylmethoxy] pyridine-2-carboxylate (300 mg, 0.5 mmol)1 in THF:MeOH (1:1, v/v,

■2 ml) and 0.25 N NaOH (4 ml, 1 mmol) were stirred for 3 hours at room temperature and 5 hours at 60°C. After cooling, the mixture was poured into ice-1 N HCl (2 mL). The solid was collected, washed with water and air dried. The crude crystalline material was purified by preparative TLC plate with CHCl 3 -EtOH (9:1, v/v) as eluent and crystallized with Et 2 O to give 64 (180 mg, 62%) as an amorphous solid. Molecular weight 583.43

IR (KBr) ri 3319, 1705, 1685, 1601, 1529 cm"<1>; 'H-NMR (DMSO-d") 6 l;82-2.05-(in series of m, 4 H), 3.48-3.58 (series of m, 2 H), 3.82 (s, 3 H), 3.86 (s, 2 H), 4:42-4.55 (. series of; m, 3 H), 6.72-6.98 ( series of. m, 4 H),7.32 (t, J= 8 Hz, l.H), 7.60 (d, J= 8 Hz, 1 H), 7.95 (m, 2 H), 8.08 (m, 1 H), 8.63 (m, 1 H ), 8.64 (m, 1 H), 8.89 (s, 1 H), 8.93 (s, 1 H); MS (FAB) m/z 583 (M* ) ; Anal. Calculated forC^HjjBrNA^.OxHjO: C , 52.26; H, 5.20;' N, 9.03 Found: C, 52.72; H, 4.63; N, 8.50.

EXAMPLE 54

4-[1- [3-[ N'~ (2-bromophenyl)ureido]-2-methoxy-6-pyridylacetyl]-(4S)-fluoro-(2.S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of ethyl 3-amino-2-ethoxy-6-pyridyl acetate (1.61 g, 7.66 mmol) in THF (10 mL) was added 2-bromophenyl isocyanate (948 mL, 7.66 mmol ) and Et 3 N (107 mL, 0.776 mmol). After stirring overnight, the mixture was poured into H 2 O (100 mL) and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was recrystallized from CHCl3-MeOH-hexane to give ethyl 3-[N'~ (2-bromophenyl)ureido]-2-methoxy-6-pyridyl acetate. (2.91 g, 93%) as a colorless crystalline powder. M.p.: 160-163 °C; 'H- -

NMR (DMSO-dj) 6 1.19 (dt,/- 7.1, 0.7Hz, 3 H), 3.69 (s, 2H), 3.95 (s, 3 H), 4.07-4.13 (m, 2 H), 6.90 (d , J= 7.8 Hz, 1 H), 6.99 (t, J= 7.8 Hz, 1H), 7.33 (t, J= 7.8 Hz, 1 H), 7.61 (d, J= 7.8 Hz, 1 H), 7.96 ( dd, 7=7.8, 1.5 Hz, 1 H), 8.31 (d, J= 7.8 Hz, 1 H), 8.82 (^ 1 H), 9.12 (s, 1 H); MS (FAB) m/z 408 (rvT), 410 (M++2); Anal. Calculated for C.17H„BrN3O4-0.25 H70: C, 49.47; H, 4.52; 9.96.

Found: C, 49.34; H; 4.48; N, 9.96.

A mixture of ethyl 3-[ N'~(2-bromophenyl)ureido]-2-methoxy-6-pyridyl acetate (2.90 g, 7.10 mmol), 0.25 N NaOH (56.8 mL, 14, 2 mmol) of THF (50 mL) was stirred for 5 h. The mixture was neutralized with 1 N HCl and the precipitate obtained was collected by filtration. The residue was recrystallized from CHCl 3 -MeOH-hexane to give 3-[N'~ (2-bromophenyl)ureido]-2-methoxy-6-pyridylacetic acid (2.40 g, 89%) as a colorless crystalline powder. M.p.: 195-197 °C; ,H-

NMR (DMSO-d<) δ 3.59 (s, 2H), 3.95 (s, 3H), 6.88 (d, J= 8.1 Hz, 1H), 6.97-7.01 (m, 1H), 7.33 (t, / - 7.3 Hz, 1 H), 7.61 (d, 7= 8.1 Hz, 1 H)", 7.95-7.97 (m, 1 H), 8.29 (d, J= 8.1 Hz, 1 H), 8.81 (s, 1 H), 9.10 (s, 1 H), 12.35 (br s, 1 H);

11.05. Found: C, 47.27; H, 3.59; N, 10.86.

To a stirred solution of 3-[N-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetic acid (751 mg, 1.97 mmol) and methyl (4S)-fluoro-(2S)-pyrrolidinylmethoxybenzoate (500 mg , 1.97 mmol) in DMF (10 mL) was added EDC-HCl (566 mg, 2.96 mmol) DMAP (cat.) and HOBt (cat.). After stirring overnight, the mixture was partitioned between EtOAc (200 mL) and brine (200 mL). The phases were separated. The organic phase was washed with brine (100 ml), dried over MgSO 4 and evaporated. The obtained residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[1-[3-[A7'-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetyl ] -

(4S)-Fluoro-(2S)-pyrrolidinyImethoxy]benzoate (1.16 g, 96%) as a yellow viscous solid.

A mixture of methyl 4-[1-[3-[ N'~ (2-bromophenyl)ureido]-2-methoxy-6-pyridylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (1,16 g, 1.88 mmol), 0.25 N NaOH (15 mL, 3.75 mmol) and THF (15 mL) were stirred overnight. The mixture was neutralized with 1 N HCl and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue obtained was chromatographed on silica gel with CHCl 3 -MeOH (40:1 to 10:1) as eluent to give 65 as a pale yellow amorphous solid. Molecular weight 601.42

'H-NMR

(DMSO-di) 5 2.27-2.39 (m, 2 H), 3.33-4.84 (series of, m, 10 H), 5.33-5.53 (m, 1 H), 6.87-6.90 (m, 1 H), 6.99 (t, 1 H, J= 7.6 Hz), 7.08 (d, 2 H, J= 9.0 Hz)|.7.34 (t, 1 H, J= 7.6 Hz), 7.61 (d, 1 H, J = 7.8 Hz ), 7.88 (d, 2 H, J= 9.0 Hz), 7.97 (d, 1 H, /= 8.3 Hz), 8.28-8.32 (m, 1 H), 8.81-8.82 (m, 1 H), 9.10- 9.12 (m, 1 H), 12.66 (br s, 1 H); MS (FAB) m/z 601 (M<+>), 603 (M*+2); Anal Calculated for QTH^BrFN.Cv C, 53.92; H, 4.36; N, 9.32. Found: C, 52.37; H, 4.62; N, 8.38.

EXAMPLE 55

4-[(AS)-fluoro-1-[4-'[N-(2-methylphenyl)ureido] phenylacetyl] -

(2S)-pyrrolidinevlmethoxy]benzoic acid

To a stirred solution of 4-[N'~ (2-methylphenyl)ureido]phenylacetic acid (337 mg, 1.18 mmol) and methyl 4-[(AS)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (300 mg , 1.18 mmol) in DMF (10 mL) was added EDC-HCl (339 mg, 1.77 mmol), HOBt (cat.) and DMAP (cat.). The reaction mixture was stirred overnight. The mixture was partitioned between EtOAc (200 mL) and H 2 O (200 mL) and the organic phase was separated. The organic phase was washed with brine (200 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (50:1) to give methyl 4-[{AS)-fluoro-1-[4-[N-(2-methylphenyl)ureido]phenylacetyl]-(2si -pyrrolidinylmethoxy]-benzoate (613 mg, quantitative) as a yellow viscous oil. 'H-NMR (CDC13)5 2.03-7 ^ S r series of > ..ra, total 5 H), 3.47-4.21 ( series of m , total 7 H), 4.44-4.60 (iri, 3 H), 5.21 and" 5.34 (m.each, total 1 H), 6.87-7.16 (m, 8 H), 7.52-7.55 (m, 3 H), 7.93 (d, J = 8.8 Hz, 2 H), 7.99 (d, ^7 = 8.8 Hz, 1 H).

To a stirred solution of. methyl 4-[( AS )-fluoro-1-[4-[ N'-(2-methylphenyl)ureido]phenylacetyl]-( 2S )-pyrrolidinylmethoxy]-benzoate (613 mg, 1.18 mmol) in THF (10 ml) 0.25 N NaOH (9.4 ml, 2.36 mmol) was added. The mixture was heated at reflux for 1 day. After cooling to room temperature, the mixture was poured into 1 N HCl (50 mL) and extracted with CHCl 3 -MéOH (5:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 66 (378 mg, 63%) as a colorless amorphous solid. Molecular weight 505.54

'H-NMR (DMSO-dje .08-2.30 (m, total 5 H), 3.47-4.63 (series of m, 7 H), 5.30-5.50 (m,

1 H), 6.94 (t, J= 7.3 Hz, 1 H), 7.02-7.17 (m, 6 H), 7.37-7.41 (m, 2 H), 7.82-7.96 (m, 4 H), 9.05 (s ,

1H); MS' (FAB) m/z 506 (K+1); Anal Calcd for C<j>,H 2 ,FNA-1.75 H 2 O: C, 62.62; H, 5.91;-N,

7.82. Found C, 62.23; H, 5.63; N, 7.18.

EXAMPLE 56

4-[(4S)-fluoro-1-[3-methoxy-4-[AT'-(2-methylferriyl)ureido]phenylacetyl]-'(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of 1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-proline (1.85 g, 7.93 mmol) in THF (15 mL), was added BH3 -DMS (0 .75 ml, 7.93 mmol) at room temperature. After heating at reflux for 5 hours with stirring, the mixture was cooled to room temperature and concentrated in vacuo. The residue obtained was quenched by the addition of H 2 O (100 ml) and extracted with CHCl 3 (2 x 200 ml). The combined extracts were washed with brine (100 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-pyrrolidinyl methanol (1.76 g, quantitative) as a colorless oil .

1H-NMR (CDCl 3 ) δ 1.48 (s, 9H), IM^ m, LH), 1.97-2.28 (m, 2H), 3.53-3.87 (series of m, 4H), 4.09-4.25 (m, 1H ), 5.09 .and 5.22 (ril, hyer, total 1 H)7

To a stirred mixture of 1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-pyrrolidinyl methanol (500 mg, 2.28 mmol), methyl 4-hydroxybenzoate (416 mg, 2.74 mmol), To Ph 3 P (719 mg, 2.74 mmol) in THF (10 mL) was added DIAD (0.54 mL, 2.74 mmol) at room temperature. The mixture was heated at reflux for 5 hours with stirring. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-EtOAc as eluent (10:1 to 4:1) to give methyl 4-[1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate ( 597 mg, 74%) as a colorless oil. 1H-NMR(CDCl 3 ) δ 1.49-1.59 (rn, 9H), 2.05-

2.21 (m, 1H), 3.56-4<->43 (series of m, 8 H), 5.19 and 5.32 (m, each, total 1 H), 6.97 (m, 2 H), 7.98 (d, J = 8.5 Hz, 2H).

A mixture of methyl 4-[1-(tert-butoxycarbonyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (5.90 mg, 1.67 mmol) and TFA

(5 mL) in CH 2 Cl 2 (5 mL) was stirred for 3 h. After the mixture was concentrated in vacuo, the residue was basified with saturated NaHCO 3 and extracted with CHCl 3 (2 x 200 mL). The combined extracts were dried over K2CO3 and evaporated to give methyl 4-[(45)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (414 mg, 98%) as a yellow solid. <l>H-.

NMR(CDCl 3 ) δ 1.89-2.02 (m, 1H)', 2.16-2.31 (m, 1H), 2.98 (m, 1H), 3.35 (m, 1H), 3.46-3.68 (m, 1H ), 3.86 (s, 3 H), 4.00-4.08 (m, 2 H), 5.16 and 5.29 (t,each,./ = 4.7 Hz, total 1 H), 6.91 (d, J = 8.8 Hz, 2 H ), 7.96 (d, J ~ 8.8 Hz, 2 H).

A mixture of methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (205 mg, 0.810 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid ( 254 mg, 0.810 mmol), ED C-HCl (233 mg, 1.22 mmol), HOBt (cat.) and DMAP (cat.) in DMF (10 mL)

was stirred overnight. The mixture was diluted with EtOAc

(200 mL) washed with brine (2 x 100 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[(4S)-fluoro-1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl ] - (2 S )-pyrrolidinylmethoxy] benzoate (445 mg., quantitative) as a light brown viscous substance. <>>h-NMR (CDC13)5 2.05-2.55 (m, total 6 H), 3.55-4.13 (m, 11H), 4.48-4.60 (rn, 2 H), 5.20 pgr. 5.33

Chver m, total 1 H), 6.29 (s, 1 H), 6.79 (m, 2 H), 6.96 (d, J= 8.8 Hz, 2 H), 7.11-7.25 (m, 3 Jl), 7.48 (d , J'='7.6 Hz, 1H), 7.93-8.09 (m, 4H).

A mixture of methyl 4-[(4S)-fluoro-[3-methoxy-4-,tNr-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]-benzoate (445 mg, 1.62 mmol ) and 0.25 N NaOH (15 mL, 3.75 mmol) 1 THF (15 mL) was stirred overnight at room temperature and then heated at reflux for 2 h. The mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) as eluent to give 67 (260 mg, 30%) as a pale yellow amorphous solid. Molecular weight 535.56.

1H-NMR (DMSO-dJ 5 2.25-2.51 (m, 5 H), 3.33-4.41 (series of/m, 10 H); 5.30-5.50 (mt 1H), 6.75-7.17 (m, 7 H), 7.79 (d, /= 8.1 Hz, 1 H), 7.87-8.04 (m, 3 H), 8.48

(m, 1H), 8.58 (m, 1H); MS (FAB) m/z 536 (M++1); Calcd for C2FNA-H2O: C, 62.92;

H, 5.83; N, 7.59. Found: C, 62.40; H, 5.82; N, 6.93.

EXAMPLE 57

4- [1- [4- [W-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of methyl 4-[ (4S)-fluoro-(2S)'-pyrrolidinylmethoxy]-benzoate (501 mg, 1.98 mmol), 4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetic acid ( 750 mg, 1.98 mmol), EDC-HCl (569 mg, 2.97 mmol), HOBt (cat.) and DMAP (cat.) in DMF (10 mL) were stirred overnight. The mixture was diluted with EtOAc (300 mL), washed with brine (100 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1). to CHCl3-MeOH (10:1) as eluent to give methyl 4- [1- [4 - [ N' -(2-bromophenyl)ureido]-3-methoxyphenylacetyl] -(4 S )-fluoro-(2 S )-pyrrolidinylmethoxy] benzoate (1.29 g, quantitative) as a brown viscous oil. "H-

NMR (CDCl3) 5. 2.05-2.58 (m, 2 H), 3.49-4.17 (series of'm, 12 H), T52-4.65 (m, 2 H), 6.82-7.33 (isenes of m, 8H ), 7.53 (dd, .7 =8.1, i. 5 Hz, 1H), 7.95-8.02 (m, 4H), 8.14 (dd, J= 8.3, 1.7 Hz, 1H).

A mixture of methyl 4-thi-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]-benzoate (1.29 g, 2, 10 mmol) and 0.25 N NaOH (17 mL, 4.20 mmol) in THF (20 mL) were heated at reflux for 5 h with stirring. The mixture was poured into ice-cooled 1 N HCl (100 mL) and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl-,-MeOH (10:1) as eluent to give 68 (860 mg, 68%) as a colorless amorphous solid. Molecular weight 60 0.43. 'H-NMR (DMSO-d<) 6 2.24-2.31 (m, 2 H), 3.21-4.63 (series of-m, 10 H), 5.31-5.51 '(m, 1 H), 6.74-7.10 (m , 5 H), 7.32 (t, J= 7.8 Hz, 1 H), 7.60 (d, J= 7.8 Hz, 2 H), 7.87-7.99 (m, 4 H), 8.74-8.75 (m, 1 H ), 8.92-8.94 (m, 1H); MS (FAB) m/z 601 (M 1 ); Anal.Calcd for <;>d,H27BrFN3CV2 H20: C, 52.84; H, 4.91; N, 6.60. Found: C, 52.38; H, 4.62; N, 5.99. For Na saltav68: mp 180-182 ^j^.na/. Calculated for CaH^BrFNjNaO^OJS H2O: C, 52.88; H, 4.36; N, 6:61 Found: C, 52.97; H, 4.36; N, 6.61. ... EXAMPLE 58 4-[1-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]-benzoate (205 mg, 0.810 mmol) 3-methoxy-4-[AP<->(2-methylphenyl)-ureido]phenylacetic acid (254 mg, 0.810 mmol), EDC-HCl (233 mg/ 1.22 mmol), HOBt (cat.) and DMAP (cat.) in DMF (10 mL) were stirred overnight. The mixture was diluted with EtOAc (200 mL), washed with brine (2 x 100 mL), dried over MgSO 4

and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give 4- [1- [4- [A7'~

(2-chlorophenyl)ureido]-3-methoxy enylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (376 mg, 81%) as a yellow foam.

1 H-NMR (CDCl 1 ) δ 2.07-2.56 (m,

2 H), 3.57-4.14 ( tendons of m, 11 H), 4.50-4.61 (m, 2 H), 5.22 and 5.35 ( series aV.m, total 1 H),

6.80-7.33 (.series ayjm, 9 H), 7.93-8.00 (m, 3 H), 8.16 (d, J= 8.1 Hz, 1H).

A mixture of methyl 4-[1-[4-[A7r-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]-benzoate (376 mg, 0.660 mmol) and 0.25 N NaOH (15 mL, 3.75

mmol) in THF (15 mL) was stirred overnight at room temperature

and then heated at reflux for 2 hours. The mixture was acidified with 1 N HCl and extracted with CHCl3-MeOH (4:1,

2 x 200 mlj. The combined extracts were dried over MgSO 4

and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give 69 (26_0 mg,

30%) as a pale yellow amorphous solid. Molecular weight 555.98.

1H-NMR pMSO-ds)5 2.24-2.501 (m, 2 H), 3.48-4.65 (series of m, 10 H), 5.30-5.50 (m, 1H), 6.75-7.08 (m, 5 H), 7.29 (t, 7.3 Hz, 1 H), 7.43-7.45 (rn, 1H), 7.89-

7.98 (m, 2 H), 7.99. (d,/= 8.3 Hz, 1 H), 8.09 (d, /= 7.1 Hz, 1 H), 8.90-8.96 (m, 2 H); MS (FAB)

w/ x 556 (MN-1); ^na/.Calculated for^HtfClFNaCy 1/4H2O: C, 60.00; H, 4.95; N, 7.50. Found: C,

59.67; H, 5.08; N, 7.10.

EXAMPLE 59

4- [1- [4- [ N'~ (2-bromophenyl) ureido] phenylacetyl] - (4S) - fluoro-(2S) - pyrrolidinylmethoxybenzoic acid

Methyl 4-[1-(4-benzyloxycarbonylaminophenylacetyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (300 mg, 0.576 mmol) was added to EtOH-THF (5:1, 30 mL) and the solution was hydrogenated over 5% Pd/C (300 ml) for 12 hours with stirring. The mixture was filtered to remove the catalyst.

The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel with CH3Cl3-MeOH (20:1) as eluent to give methyl 4-[1-(4-aminophenylacetyl)-(45)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (200 mg, 90% ) as a yellow oil.

H-NMR (CDCy 5 2.01-2.56 (series of m, 2 H), 3.50-4.14 (series of: m, 5 H), 4.45-4.62 (m, 2 H), 5.21 and ; 5.34 ^r!m , total 1 H), 6.60-6.65 (m, 2 H), 6.88 (d, j = 8:8 Hz, 0.5 H), .6.99-7.05 (m,

3.5H),'7.95r8.0.0 (m, 2H).

Methyl 4-[1-(4-aminophenylacetyl)-(4S)-fluoro^(2S)-pyrrolidinylmethoxy]benzoate (200 mg, 0.518 mmol) was dissolved in THF (10 mL), Et 3 N (10 µl, 0.776 mmol ) and 2-bromophenyl isocyanate (96

/xl, 0.776 mmol) was added to the solution. The mixture was stirred overnight and diluted with EtOAc (200 mL). The solution was washed with brine (100 ml), dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) to CHCl3'-MeOH (10:1) as eluent to give methyl 4-[1- [4- [ Nr-(2-bromophenyl) ureido] f enylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (303 g, quantitative) as a yellow oil.

1 H-NMR (CDCl 3 ) δ 2.08-2.60 (series of .m, 2 H), 3.56-4.69 (series of .'m, 10 H), 5.28 and . 5.40 (m,. each, total 1 H), 6.84-6.92 (m, 3 H), 7.03-7.10 (m, 3 H),7.14(d, J=8.1<Hz,l H), 7.23 (t, J= 8.1 Hz, 1 H), 7.39-7.44 (m, 2 H), 7.89 (d, J= 8.1 Hz, 1 H), 7.98-8.03 (m, 2H), 8.09(d, J= 8.1 Hz, 1H).

Methyl 4- [1- [4- [ N'~ (2-bromophenyl)ureido] phenylacetyl] - (4S) - fluoro-(25)-pyrrolidinylmethoxy] benzoate (300 mg, 0.513 mmol) was dissolved, in THF (5 mL), and 0.25 N NaOH (4.0 mL, 1.00 mmol) was added to this solution. After stirring for 3 days, the mixture was poured into 1 N HCl (100 mL) and extracted with CHCl 3 -MeOH (5:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 70 (209 mg, 71%) as a colorless amorphous solid. Molecular weight 57 0.41.

1H-NMR (DMSO-d6)S 2.24-2.51 (m, 2 H), 3.36-4.64 (series avi m, 7 ■ H), 5.31-5.50 (m, 1 H), 6.97 (t, J= 7.8 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 7.09 (d, J= 8.8Hz, 1 H), 7.14-7.20 (m, 2 H), 7.34 (t, J= 7.8 Hz , 1 H), 7.38-7.43 (m, 2 H), 7.61 (d, J= 8.1 Hz, 1 H), 7.87-7.92 (m, 2 H), 8.08 (d, J= 8.1 Hz, 1 H) , 8.15 (s, 1 H), 9.45-9.47 (fn, 1H), 12.66 (br s, 1 H);

MS (FAB) m/z 572 (M<*>+2), 570 (M*)M/;a/. Calcd for C^HuBrFNA* 1-5 H,0: C, 54.28; H, 4.72;

N, 7.03.Found: C, 54.67; H, 4.51; N, 6.61.

EXAMPLE 60

4- [1- [4- [ N' - (2-iodophenyl) ureido] -3-methoxy enylacetyl] - (4S) - fluoro-(25)-pyrrolidinylmethoxy] benzoic acid

To a stirred solution of tert-butyl 4-amino-3-methoxy-phenylacetate (1.94 g, 8.16 mmol) in THF (20 mL) was added 2-iodophenyl isocyanate (2.0 g, 8.16 mmol ) and Et 3 N (114 µl, 0.816 mmol). After stirring overnight, the mixture was poured into

1 N HCl (200 mL). The precipitate obtained was collected by

filtration and dissolved in CHCl 3 (200 mL) The solution was dried over MgSO 4 and evaporated to give tert-butyl! 4-[N-(2-iodo-phenyl)ureido]-3-methoxyphenylacetate (3.93 g, quantitative) as a pale yellow amorphous solid.

1H-NMR (CDCl 3 ) 6 1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78-6.88 (m, 4 H), 7.07 (s, 1 H), 7.31-7.35 (m, 1 H), 7.76 (dd, J= 7.8,1.5 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.99 (dd, /= 8.3, 1.5 Hz, 1 H)'. MS (ESI), m/z 483 (M<*>+1).

A stirred mixture of tert-butyl 4-[N-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, 8.16 mmol) and THA (5 mL) in CH 2 .Cl 2 (5 mL) was heated at reflux for -3 hours. After cooling to room temperature, the mixture was concentrated in vacuo and H 2 O (50 mL) was added to this residue. The precipitate obtained was collected by filtration and purified by column chromatography on silica gel with CHCl 3 -MeOH (9:1) as eluent to give 4-[ N'~ (2-iodophenyl)ureido]-3-methoxyphenylacetic acid (2.89 g, 83%) as a pale yellow crystalline powder. 1H-NMR (DMSO-d<)5 3.62 (s, 2 H), 3.88 (s, 3 H), 6.78 (d, J = 8.3 Hz, 1H), 6.83-6.87 (m, 1 H), 6.94 (s, 1 H), 7.32-7.36 (m, 1 H), 7.69 (dd, J = 8.3, 1.5 Hz, 1 H), 7.84 (dd, J= 8.3, 1.5 Hz, 1 H), 7.97-8.00 (m, 1H), 8.55 (m, 1H), 8.82 (m, 1H), 12.26 (br s, 1H). A mixture of 4-[N'~(2-iodophenyl)ureido]-3-methoxyphenyl-acetic acid (505 mg, 1.18 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate ( 300 mg, 1.18 mmol) EDC-HCl (339 mg, 1.77 mmol), DMAP (catalytic amount) and HOBt (catalytic amount) in DMF (10 mL) were stirred overnight. The mixture was diluted with EtOAc (300 mL) and washed with brine (2 x 200 mL). The solution was dried over MgSO 4 and evaporated. The obtained residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1) as eluent to give methyl 4-[1-[4-[W- ■ (2-iodophenyl) ureido] -3-methoxy enylacetyl] - ( 4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (500 mg, 64%) as a colorless viscous oil. <J>H-NMR(CDCl1) 6 07-2.58 (m, 2H), 3.59-4.20 (m, 1H), 4.5M.64 (m, 2H), 5.24 °9" 5.37 (m,when, total 1H), 6.80-6.91 (m, 5 H), 6.98 (d, J= 8.8 Hz, 2 H), 7.34 (t, J' = 7.8 Hz, 1 H), 7.78 (dd, J'= 7.8, 1.2 Hz, 1 H), 7.95-8.02 (m, 4 H).

To a stirred solution of methyl 4-[1- [4-[A7r-(2-iodophenyl)-" ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy] benzoate (500 mg, 0.756 mmol) in THF (6 mL) was added 0.25 N NaOH (6 mL). Stirring was continued overnight at room temperature and the mixture was then heated to reflux for 5 hours. After cooling to room temperature, the solution was poured into 1 N HCl .(100 ml) and extracted with CHCl 3 -MeOH (4:1, 2 x 200 ml). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) as eluent. to give 71 (295 mg, 60%) as a colorless amorphous solid, molecular weight 647.43.

'H-NMR (DMSO-djS 2. 2.09-2.31

(m, 2 H), 3.33-4.41 (series of m, 10 H), 5.30-5.50 (m, 1 H), 6.77-6.92 (m, 3 H), 7.03-7.09 (m, 2 'h), 7.34 (t, 7= 8.1 Hz, 1 H), 7.69 (dd, J= 8.3, 1.5 Hz, 1 H), 7.83-7.99 (m, 4 H), 8!54 (m, 1 H), 8.82 ( irt, 1 H); MS (FAB) m/r 648 (M<*>+1); ^na/.Calculated for Cj,H„FIN30,: C, 51.94; H, 4.20; N, 6.49. Found: C, 51.17; H, 4.53; N, 5.76.

EXAMPLE 61 j

4-[(4S)-fluoro-1-[4-(N-phenylureido)phenylacetyl](2S)-

pyrrolidinylmethoxy]benzoic acid

To a stirred solution of ethyl 4-aminophenyl acetate (6.43 g, 3 5.9 mmol) and Et3N (5.50 mL, 3 9.5 mmol) in THF (70 mL) was added

added phenyl isocyanate (3.90 ml, 35.9 mmol) and the reaction mixture was stirred at room temperature for 4 days. The resulting precipitate was collected under reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-(Å7'-phenylureido)phenylacetate (9.64 g, 90%) as a white crystalline powder. Temp. : 153-155°C; 1H-NMR(CDC13)5 1.26 (t, J = 7.1 Hz, 3 H), 3.52 (s, 2 H), 4.15 (q, J - 7.1 Hz, 2 H), 6.98-7.04 (m, 1 H), 7.07-7:11 (m, 4 H), 7.18-7.25 (ni, 5 H), 7.42 (s, J H); MS (FAB) m/ z 299 QJt+ i)\ AnaL Calcd for Cl7H,gNjO3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.22; H, 6.10; N, 9.36.

To a stirred solution of ethyl 4-(N'-phenylureido)phenylacetate (9.64 g, 32.3 mmol) in THF (80 mL) was added 0.5 M NaOH (80 mL) and the reaction mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into .is-1 N HCl.- The resulting precipitate was collected under reduced pressure and the crude solid was recrystallized from MeOH-CHCl 3 to give .4-( N'-phenylureido)-f enylacetic acid (8.14 g, 93%) as a white crystalline powder. MS (FAB) m/z 271 (M*+1); Anal. Calculated for CjH^NjCv C, 66.66; H, 5.22; N, 10.36.

Found: G, 66.45; H, 5.22; N, 10.30;

A mixture of 4-[N'~phenylureido)phenylacetic acid (310 mg,

1.15 mmol), methyl 4-[(4 S )-fluoro-(2 S )-pyrrolidinylmethoxy] benzoate (2 87 mg, 1.13 mmol):, EDC-HC1 (2 60 mg,

1.36 mmol), HOBt (185 mg, 1.37 mmol) and Et3N (190 mL,

1.3 6 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 50:1, v/v) as eluent to give methyl 4-[(4S)-fluoro-1-[4-(N'-phenyl- ureido)phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (570 mg, 99%) as a pale yellow foam.

1 H-NMR (CDCl 3 ) δ 2.07-2.58 (rn, 2 H), 3.55-3.56 (m, 1 H), 3.69-

3.98 ( series of s 03 m, total 6 H), 4.01-4.08 and 4.21-4.25 (each m, 1 H), 4.46-4.65 (m, 2 H), 5.23-5.25 and 5.38 (each m, in H ), 6.88-7.07 (rn, 7 H), 7.15-.7.20 (m, 2 H), 7.28-7.30 (xn, 2 H), 7.34 and 7.40 (river, s, 1 H), 7.71 and 7.81 (each .s, 1 H), 7.91-7.95 6g 7.99-8.01 (each m, 2 H); MS

(ESI) m/z 506 (M/+1).

To a stirred solution of methyl 4-[(4S)-fluoro-1-[4-{ N'~ phenylureido)phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (570 mg, 1.13 mmol) in THF (5 mL ) 0.5 N NaOH was added

(5 mL), and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-IPE to give 72 (348 mg, 63%) as a. white crystalline powder. Molecular weight 491.51. M.p.: 169-i71"C;;

1 H-NMR (DMSC-d*) 5 2.24-2.36 (m, 2

H), 3.47-4.08 (m, 5 H), 4.20-4.64 (m, 2H), 5.31-5.50 (m, 1 H), 6.94-7.46 (series of. m, total 11 H), 7.87-7.92 ( m, 2 H), 8.64-8.67 (m, 2 H), 12.63 (br s, 1 H); MS (FAB) m/z492 (b^+1); Anal. Calculated for CÆFNjOjlMHjO: C, 65.38; H, 5.38; N.8.47; F.3.83. Found:C.65.13; H.5.38; N.8.25; F.3.78 EXAMPLE 62 4-[(4S)-fluoro-1-[3-methyl-4-(Δ7r-phenylureido)phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of tert-butyl 4-amino-3-methyl-phenylacetate (1.20 g, 5.42 mmol) and Et3N (830 mL, 5.95 mmol) in THP (10 mL) was added phenyl isocyanate ( 650 ml,

.5.98 mmol) and the reaction mixture was stirred at room temperature. raw ride overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The resulting precipitate was collected under reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-(ATr-phenylureido)phenylacetate' (1.12 g, 61%) as a white crystalline powder. M.p.: 143-145°C; 'H-

NMR (CDCl1) δ 1.47 (s, 9 H), 2.09 (s, 3 H), 3.47 (s, 2 H), 6.44 (s, 1 H), 7.01-7.07 (m, 4 H), 7.16-7.27 (m, 2 H), 7.30-7.33 (m, 2 H), 7.45-7.47 (m, 1 H).

, To a stirred solution of tert-butyl 3-methyl-[4-(N-phenylureido)phenylacetate (1.12 g, 3.29 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to a small volume and poured into ice-H 2 O. The resulting precipitate was collected under reduced pressure and the crude solid was recrystallized from MeOH-CHCl 3 to give 3-methyl-4-(N-phenylureido)phenylacetic acid (680 mg, 73%) as white needles. 1H-NMR (DMSO-dJ 5 2.22 (s, 3 H), 3.46 (s, 2 H), 6.93-7.05 (m, 3 H), 7.25-7.29 (m, 2 H), 7.43-7.46 (m , 2H), 7.72-7.74 (m, 1H), 7.90 (s, 1H), 8.98 (s, 1H), 12.26 (br s, iH); y4/Jo/.Bire"gnetrfor CHwNA: C, 67.59 ; H, 5.67; N, 9.85. Found: C, 67.47; H, 5.68; N, 9.73.

A mixture of 3-methyl-4-[N'-phenylureido)phenylacetic acid

(301 mg, 1.06 mmol), methyl 4-[(4S)-fluoro-(25)-pyrrolidinylmethoxy] benzoate (268 mg, 1.06 mmol), EDC-HC1 (243 mg,

1.27 mmol), HOBt (172 mg, 1.27 mmol) and Et3N (180 mL,

1.29 mmol) in DMF (5 mL) was stirred. at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 60:1, v/v) as eluent to give methyl 4-[(4S)-fluoro-1-[3-methyl-4-

(N'-phenylureido)phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (550 mg, quantitative yield)- as a white foam.

1 H-NMR (CDCl 1 ) δ 1.79 and . 1.87 (each s, 3 H), 2.04-2.61 (m, 2 H), 3.52-3.54 (m, 1H), 3:73-4.27 ( series of s and m, total 7 H), 4.47-4.67 ( m, 2 H), 5.26-5.27 and 5.40 (each m, 1H), 6.79-6.99 (m, 6 H>, 7.14-7.18 (m, 2 H), 7.27-7.31 (m, 2 H), 7.40- 7.44 (rn, 1H), 7.89-8.01 (m, 3H);MS (ESI) m/z 520 (M<*>+1).

To a stirred solution of methyl 4-[(4S)-fluoro-1-[3-methyl-4-'( N'-phenylureido)phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (550 mg, 1.06 mmol) in THF (5 ml) was added 0.5 N NaOH.

(5 mL), and the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl 3 -IPE to give 73 (226 mg, 42%) as a white crystalline powder. Molecular weight 505.54. M.p.: 130-135°C; 'H-NMR

(DMSO-dfi) 8 2.18-2.30 (series of s and m, total 5 H), 3.47-3.92 (series of m, total 5 H), 4.03-4.63 (m, 2 H), 5.31-5.50 (m, 1 H),-6.94-7.10 (m, 5 H), 7.26-7.30 (rn, 2 H), 7.45-7.47 (m, 2 H), 7.70-7.75 (m, 1 H), 7.87- 7.92 (m, 3 H), 8.96-8.98 (m, 1 H), "12.63 (br s,. 1 H); MS (ESI) m/ z 506 (M<+>+1); Anal Calcd Tor CjgHaFNA- 1/2H 2 O: C, 65.36; H, 5.68; N, 8.17; F, 3.69. Found C, 65.61; H, 5.71; N, 7.84; F, 3.60.

EXAMPLE 63 <

A-[{AS)-fluoro-1-[4-[ N'~ (2-fluorophenyl)ureido]-3-methylphenyl-acetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred. To a solution of tert-butyl 4-amino-3-methyl-phenylacetate (1.09 g, 4.93 mmol) and Et3N (755 mL, 5.42 mmol) in THF (10 mL) was added 2-fluorophenyl isocyanate (610 µl, 5.44 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The resulting precipitate was collected under reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 4-(N-(2-fluoro-phenyl)ureido]-3-methylphenylacetate (1.31 g, 74%) as a white crystalline powder, m.p.: 89-91°C;

1H-NMR (CDCl1) δ 1.47 (s, 9 H), 2.06 (s, 3 H), 3.49 (s, 2 H), 6.62 (s, 1 H), 6.92-7.09 (m, 5 H), 7.21 (br s, 1 H), 7.49-7.51 (m, 1 Hj, 8.10-8.15 (m, 1 H); Anal. Calculated for CjoHaFNiOj: C,

67.02; H, 6.47; N, 7.82; F, 5.30. Found: C, 66.74; H, 6.35; N, 7.85; F, 5.69.

To a stirred solution of tert-butyl 4-[N-(2-fluorophenyl)-ureido]-3-methylphenylacetate (1.25 g, 3.49 mmol) in CH 2 Cl 2

(10 mL) was added TFA (10 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and poured into ice-H 2 O. The precipitate obtained was collected under reduced pressure and the impure solid was recrystallized. from MeOH-CHCl3-IPE to give 4-[A7'~ (2-fluorophenyl)ureido]-3-methylphenylacetic acid (830 mg, 79%) as white needles. 1 H-NMR (DMSO-dj) δ 2.23 (s, 3 H),

3.47 (s, 2 H), 6.96-7.30 (m, 5 H), 7.74-7.76 (m, 1 H), 8.17-8.20 (m, 1 H), 8.33 (s, 1 H)4 8.94 <s, 1 H), 12.27 (br s, 1H); ylna/.Calcd for C16H15FNA: C, 63.57; H, 5.00; N, 9.27; F, 6.28. Found: C, 63.28; H, 5.00; N, 9.14;/F, 6.43..

A mixture of 4-[ N'~ (2-fluorophenyl)ureido]-3-methylphenyl-acetic acid (321 mg, 1.06 mmol), methyl 4-[ (4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (269 mg, 1.06 mmol), EDC-HCl

(244 mg, 1.27 mmol), HOBt (172 mg, 1.27 mmol) and Et 3 N (177 mL, 1.27 mmol) in DMF (5 mL) were stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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-[(4S)-fluoro-1-[4-[ N'~ (2-fluorophenyl)ureido ]-3-methylphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (560 mg, 98%)- as a white foam.

'H-NMR (CDC13)5 1.78 and 1.86 (each, 3 H), 2.16-2.65 (m, 2 H), 3.58-3.61 (m, 1 H), 3.74-4.15 (. series avs and m/lotal 7 H), 4.29-4.34 and 4.46-4.49 (each m<*> 1 H), 4.64-4.73 (m, 1 H), 5.29-5.34 and 5.43-5.47 (each m, 1 H), 6.84-6.97 (m ,

6 H), 7.04-7.-07 (m, 1 H), 7.21 (br s, 1 H), 7.55-7.59 (m, 1H), 7.85-8.02 (rri, 3 H), 8.18-8.22 (m , 1

H); MS (ESI) m/z 538 (ivT+1). - To a stirred solution of methyl 4-[(4S)-flupr-1-[4-[ N'~ (2-fluorophenyl)ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinylmethoxy] benzoate (560 mg, 1 .04 mmol) in THF (5 mL), 0.5 N NaOH (5 mL) was added, and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-IPE to

yield 74 (2 97 mg, 42%) as a white crystalline powder. Molecular weight 523.53. M.p.:- 137-143°C; 'H-NMR j

(DMSO-d4)5 2.20-2.31 (series of s and ra,, total 5 H), 3.56-3.92 (series of: m, total 5 H), 4.03-4.63

(m, 2 H), 5.31-5:50 (m, 1H), 6.96-7.26 (series of ' m, total 7 H), 7.72-7.77 (m; 1 H), 7.87-7.92 (m,

2 H), 8.17-8.22 (m, 1 H), 8.32-8.36 (m, 1 H), 8.94-8.95 (m, 1 H), 12.66 (br s, 1 H); MS (ESI) m/z

524 Ovf+1); Anal. Calculated for CAFjNA: C, 64.24; H, 5.20; N, 8.03; F, 7.26. FoundC, 64.44;

H, 5.75; N, 7.40; F, 6.73;

EXAMPLE 64

4- [ (4S) -fluoro-1- [4- [ N' - (2-trifluoromethylphenyl) ureido] phenylacetyl] - (2S) -■pyrrolidinylmethoxy]benzoic acid

To a stirred solution of ethyl 4-aminophenyl acetate (1.13 g, 6.31 mmol) and Et3N (965 mL, 6.92 mmol) in THF (10 mL) was added 2-trifluoromethylphenyl isocyanate (953 mL, 6.31 mmol), and the reaction mixture was stirred at room temperature for 2 days. The precipitate obtained was collected under a reduced pressure and

the filtrate was washed with n-hexane to give ethyl 4- [ N'~ (2-

! trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%). as white ■

needles. M.p.: 137-139"C; 'H-

NMR (CDCl 3 ) 6 1.25-1.29 (m, 3 H), 3.59 (s, 2 H), 4.15-4.20 (m, 2 H), 7.05 (br s,'1 H), 7.13-7.23 (m, 6 H), 7.47-7.51 (m, 1 H), 7.54-7.56 (m, 1 H), 8.01-8.03 (m, 1 H).

To a stirred solution of ethyl 4-[AT-(2-trifluoromethyl-phenyl)ureido]phenylacetate (1.93 g, 5.27 mmol) in THF (10 mL) was added 1 N NaOH (10 mL), and the reaction mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice-1 N HCl. The resulting precipitate was collected under reduced pressure and the crude solid was recrystallized from MeOH-CHCl3-IPE to give 4-[A7'-(2-trifluoromethylphenyl)ureido]phenylacetic acid '910 mg, 51%) as a white crystalline powder . Temp. : 224-225°C;

.'H-NMR (DMSQ&) 5 3.50 (s,

2 H), 7.18 (d, J - 8.3 Hz, 2 H), 7.25-7.29 (rn, 1 H), 7.40 (d, J = 8.3 Hz, 2 H), 7.62-7.69 (m, 2 H), 7.95-7.97 (m, 1 H), 8.06 (s, 1 H), 9.37 (s, 1 H), 12.27 (br s, 1 ^^na/.BeregneforCAaFsNA: C, 56.81; H, 3.87; N, 8.28 ; F, 16.85. Found: C, 56.68; H, 3.87; N, 8.16; F, 16.89. A mixture of 4-[AT'-(2-trifluoromethylphenyl) ureido] phenylacetic acid (302 mg, 0.89 mmol ), methyl 4-[ (4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (226 mg, 0.89 mmol), EDC-HCl (205 mg, 1.07 mmol), HOBt (145 mg, 1, 07 mmol) and Et 3 N (150 mL, 1.08 mmol). in DMF (5 mL) was stirred at room temperature for 3 days. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated The residue was purified by column chromatography on silica gel with CHCl3-MeOH (100:1 to 60:1, v/v) as eluent to give methyl 4-[(4S)-fluoro-1-[4-[A7'- (2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (463 mg, 90%) as a pale yellow foam.. 'H- NMR (CDCl 1 ) 82.09-

2.60 (m, 2 H), 3.56-4.12 (series of s and m, total 8 H), 4.26-4.65 (m, 2 H), 5.26-5.29 and 5.39-5.42 (each m, total 1 H); 6.87-6.93 (m, 2 H), 6.99-7.13 (m, 5 H), 7.30-7.33 (m, 1 H), 7.44-7.53 (m, 2 H), 7.88-7.92 (m, 1 H), 7.99-8.04 (m, 2 H), 8.09-8.15 (m, 1 H); MS (ESI) w/ i 574 (M<*>+i).

To a stirred solution of methyl 4-[(4S)-fluoro-1-[3-methoxy-4.- [ N'~ (2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (460 mg, 0.80 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL), and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-IPE-to

yield 75 (16 9 mg, 3 8%) as a white crystalline powder.

Molecular weight 559.51. M.p.: 130-1359C; 'H-NMR

PMSO-d^.S 2.24-2.30 (m, 2 H), 3.51-4.24 (series amber, m, total 5 H), 4.38-4.40 and 4.61 (each,

total 2 H), 5.31-5.50 (m, 1 H), 7.03-7.42 (series of an, total 7 H), 7.62-7.69 (nine, 2 H), 7.87-8.07 (m,

4 H), 9.36-9.37 (m, 1 H), 12.64 (br s, 1 H); MS (ESI) m/z 560 (M*+1); ^na/. Calculated for CmHjjF^Oj: C, 60.11; H, 4.50; N, 7.51; F, 13.58. FunnebC, 60.10; H, 4.85; H 7:01-; F, 12.90. EXAMPLE 65 4-[(4S)-fluoro-1-[3-methoxy-4-[N'-(2-trifluoromethylphenyl)-ureido] phenylacetyl]-(2S)-pyrrolidinylmethoxy] benzoic acid

To a stirred solution of. tert-butyl 4-amino-3-methoxy-phenylacetate (1.11 g, 4.68 mmol) in Et3N (720 mL, 5.17 mmol) in THF (10 mL) was added 2-trifluoromethylphenyl isocyanate

(707 ml, - 4.68 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The precipitate obtained was collected under reduced pressure and washed with n-hexane to give tert-butyl 3-methoxy-4-[N'~ (2-trifluoro-methylphenyl)ureido]phenylacetate' (lvli g, 56% ) as a white crystalline powder.' M.p.: ,131- 133°0'

1H-NMR (CDCl1) δ 1.44 (s, 9 H), 3.49(3, 2 H), 3.85 (s, 3 H), 6.83.6.88 (m, 3 H), 6.98 (bf s, 1 H), 7.17-7.21 (m, 1 H), 7.52-7.59 (m, 2 H), 7.89-7.91 (m, 1 H), 8.04-8.06 (m, 1 H).

To a stirred solution of tert-butyl 3-methoxy-4-[ N'~(2-

> trifluoromethylphenyl)ureido]phenylacetate. (1.11 g, 2.62 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to a small volume and poured into ice-H 2 O. The precipitate obtained was collected under a

reduced pressure and the crude solid was recrystallized from MeOH-CHCl3-IPE to give 3-methoxy-4-[N'~ (2-trifluoromethyl-phenyl)ureido]phenylacetic acid (83.9 mg, 87%) as a white crystalline powder. Temp. : 2i8-220°C;

1H-NMR (DMSO-d,) 6 3.5L(s, 2 H), 3.87 (s, 3 H), 6.76-6.79 (m, 1 H), 6.93-6.94 (m, 1H), 7.27-7.30 (m, 1 H), 7.61-7.69 (irt, 2^.7.82-7.84 (m, 1 H), 7.97-7.99 (m, 1 H), 8.71 (s,, 1 H), 8.89 (s, 1 H ), 12.30 (br s, 1 H); Anal. Calculated forC17H1JF3NJ04: C, 55.44; H, 4.11; N, 7.61; F, 15.47. Found: C, 55.30; H, 4.08; N, 7.63;"F, 15.13 .

A mixture of 3-methoxy-4-[ N'~ (2-trifluoromethylphenyl)-ureido]phenylacetic acid (353 mg, 0.96 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (243 mg, 0.96 mmol), EDC-HCl (221 mg, 1.15 mmol), HOBt (156 mg, 1.15 mmol) and Et3N

(160 mL, 1.15 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 60:1, v/v) as eluent to give methyl 4-[(4S)-fluoro-1-[3-methoxy-4-[ N'~ (2-trifluoromethylphenyl)ureido]phenylacetyl]-(;2S)-pyrrolidinylmethoxy]benzoate (570 mg, 98%) as a white foam. 1H-NMR (CDCl 3 ) δ 2.05-2.58

(m, 2H), 3.56-4.21 (series rav . m, total 11 H), 4.05-4.64 (m, 2 H), 5.23-5.25 and 5.36-5.37 (each rn, total 1 H), 6.79-6.82 (m, 2-8), 6.89-7.00 (m, 2 H), 7.16-7.20 (m, 2 H), 7.39-7.43 (m, 1 H), 7.51-7.59 (m, 2 H), 7.93- 8.02 (m, 4H); MS (ESI) m/z 604 (MT+1).

To a stirred solution of methyl 4-[(4S)-fluoro-1-[3-methoxy-4-[W-(2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (570 mg , 0.94 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL), and the reaction mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl 3 -IPE to give 76 (234 mg, 42%) as a white crystalline powder. Molecular weight 589.54. M.p.: 129-132°C;

'H-NMR (DMSO-d^S 2.23-2.29 (m, 2 H), 3.54-4.38 f series of s and m, . total 8 H), 4.40-4.61 (m, 2 H), 5.30-5.36 and 5.43-5!49 (each rn, total 1 H), 6.72-6.91 (m, 2 H), 7.02-7.08 (m, 2 H),

7.25-7.29 (rn, 1H), 7.59-7.67 (m, 2 H), 7.81-7.99 (rn, 4 H), 8.69-8.70 (m, 1H), 8.87-8.90 (m, 1 H), 12, 67 <br&J.H); MS (ESI) m/z 589 flvT+1); ^na/. Calculated for C^H^NA-' C, 59.08; H, 4.62; N, 7.13. FoundC, 59.22; H, 5.10; N, 6.58.

EXAMPLE 66

4-[(4S)-fluoro-1-[3-methyl-4-.[xVr-(2-trifluoromethylphenyl)-ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of tert-butyl 4-amino-3-methylphenyl acetate (927 mg, 4.19 mmol) and Et 3 N (645 mol, 4.63 mmol) in THF (10 mL) was added 2-trifluoromethylphenyl isocyanate

(633 µl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The precipitate obtained was collected under reduced pressure and the filtrate was washed with n-hexane to give tertylbutyl-3-methyl-4-[N'~ (2-trifluoromethylphenyl)ureido]phenylacetate- ^ 1.06 g, 62%) as a white crystalline powder. Temp. :■ 178-180°Cj

'H-NMR (CDCl1) 8 1.44 ~(s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12-7.18 (m, 3 H ), 7.36-7.37 (m, 1H), 7.49-7.53 (m, 2H), 8.13-8.16 (m, 1H).

To a stirred solution of tert-butyl 3-methyl-4-[ N'~ (2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 2.60 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL ) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to a small volume and poured into ice-H 2 O. The precipitate obtained was collected under a

reduced pressure and the crude solid was recrystallized from MeOH-CHCl3-rPE to give 3-methyl-4-[N'-(2-trifluoromethylphenyl)-

ureido] f phenylacetic acid (702 mg, 77%) as a white crystalline powder. Temp. : 262-263°C</>

1H-NMR (DMSO-cy 8 2.24 (s, 3 H), 3.48 (s, 2 H), 7.03 (d, J = 8.3 Hz, 1 H), 7.08 (s, 1 H), 7.26-7.30 ( m, 1 H), 7.61-7.69 (m, 3 H), 7.88 (d, J= 8.3 Hz, 1 H), 8.39 (s,"l H), 8.55"(s, 1 É),

12.28 (brs, 1H)Mna/.Calcd for C17H13F3NA: C, 57.96; H, 4.29; N, 7.95; F, 16.18. Found: C, 57.73; H, 4.23; N, 7.92; F, 4:05 p.m.

A mixture of 3-methyl-4-[ N'~ (2-trifluoromethylphenyl)-ureido]phenylacetic acid (359 mg, 1.02 mmol), methyl 4-[(4S)-fluoro-(2S)- pyrrolidinylmethoxy] benzoate (258 mg, 1.02 mmol), EDC-HCl (234 mg, 1.22 mmol), HOBt (165 mg, 1.22 mmol) and Et3N (170 mg, 1.22 mmol) in DMF ( 5 ml) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 60:1, v/v) as eluent to give methyl 4-[(4S)-fluoro-1-[3-methyl-4- [ N'~ (2-trifluoromethylphenylD.ureido]phenyl-acetyl]-(2S)-pyrrolidinylmethoxy]benzoate (612 mg, quantitative yield) as a white foam. 1H-NMR(CDC13)5 1.92 and 2.00 Ohvers, total 3 H), 2.09-2.61 (m, 2 H), 3.56-4.29 (series of, m, total 8 H), 4.45-4.48 and 4.59-4.64 (each m, total 2 H), 5.24-5.30 and. 5.38-5.44 (each rhyme, total 1 H), 6.90-7.14 (m, 5 H), 7.22-7.53 (m, 5 H), 7.90-7.92 (m, 1 H), 8.00-8.06 (m, 2 H);MS (ESI) m/z 588 (M<*>+1).

To a stirred solution of methyl 4-[(4S)-fluoro-1-[3-methyl-4-[ N' -(2-trifluoromethylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (610 mg, 1.04 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-IPE to give 77 (186 mg, 31%) as a white crystalline powder. Molecular weight 573.54. M.p.: T23-126°C; 'H-NMR (DMSO-ds) 5 2. i9-2.29 (' series of s and rn, total 5 H), 3.64-4.21 ( series of 'm, total 5 H), 4.36-4.60 (m, 2 H ), 5.30-5.36 and 5.43-5.49 (each m, total 1 H), 6.97-7.08 (m, 4 H), 7.24-7.28 (m, 1 H), 7.59-7.68 (m, 3 H), 7.85- 7:90 (m, 3H), 8.37-8.39 (m, 1H), 8.54-8.55 (m, 1H), 12.67 (br s, 1-H);

MS (ESI) m/z 573 (M<4>).

EXAMPLE 67

4-[ ,(4S)-fluoro-1-[3-methyl-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

A mixture of 3-methyl-4-[N-(2-methylphenyl)ureido]phenylacetic acid (250 mg, 0.84 mmol), methyl 4-.[(4S)-fluoro-(2S)-pyrrolidinyl] Methoxybenzoate (400 mg, 1.06 mmol), EDC-HCl

(242 mg, 1.26 mmol) and DMAP (154 mg, 1.26 mmol) in DMF (5 mL) were stirred at room temperature for 21 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /MeOH

(50/1)] and then purified on TLC [CHCl3/acetone (10/1)] to give methyl'4-[(4S)-fludr-1-[3-methyl-4-[A/'- ( 2-Methylphenyl)-ureido]phenylacetyl]-(2 S )-pyrrolidinyl]methoxybenzoate (342 mg, 76%) as a colorless amorphous solid.

IR (KBr) 3356, 2951, 1716, 1651, 1604, 1537, 1252 cm'<1>;

1H-NMR (CDCl 1 ) 8 2.07 (d, J = 6.6 Hz, 2H), 2.12 (s, 3H), 2.27 (m, 1H), 2.24 (s, 2.30-2.59 (m, 1H), 3.60 (d , J= 5.3 Hz, 1H), 3.65-4.23 (m,3H), 3.87 (s, 3H), 4.50r4.62 (m, 1H), 5.31 (d,J =

52.4 Hz, 1H), 6.23 (d, J = 11.2 Hz, 1H), 6.26 (d, J= 11.9 Hz, 1H)„ 6.87^7.27 (ra, 8H), 7.54-7.65 (m, 3H), 7.94^ 8.01 (m, 2H); MS (FAB) m/z 534 (M<+>+1); J4na/.Béreanetfor.C30H33FNA,0-7HIO: C,

65.97; H, 6.16; F, 3.48; N, 7.69. Found.; C, 66.04; H, 6.07; F, 3.55; N, 7.64.

To a stirred solution of methyl 4-[( AS )-fluoro-1-[3-methyl-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (227 mg, .0.425 mmol) in THF (3.4 mL) was added 0.25 N NaOH (3.4 mL). After stirring at room temperature for 4 days, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on preparative TLC [CHCl 3 /MeOH (10/1)] to give 78 (190 mg, 86%) as a colorless amorphous solid. Molecular weight 519.56. IS.

(KBr) 3356, 2974, 1604, 1537, 1454, 1252 cm -1 ; 1H-NMR (DMSO-cU 8 2.24 (s, 3H), 2.26 (s, 3H), 3.60 (d, J= 3.7 Hz, 2H), 3.65-4.65 (m, 8H), 5.31-5.50 (m, 1H), 6.92-7.18 (m, 7H), 7.67-7.92 (rn, 4H), 8.22-8.32 (rn, 2H); MS (FAB) m/ z 520 (M*+1); Anal. Calcd for C ^JFNA-1-lHaO: C, 64.58; H, 6.02; F, 3.52; N, 7.79. Found: C, 64.71; H, 5.90; F, 3.24; N, 7.51.

EXAMPLE 68

4- thi-[4- [W-(2-chlorophenyl)ureido]-3-methylphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred mixture of tert-butyl 4-amino-3-methyl-phenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 mL, 4.52 mmol) in THF (10 mL) was added Et 3 N (0.13 mL, 0.90 mmol) was added at room temperature. After stirring for 6 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give tert-butyl 4-[ N'~ (2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. Melting point: 104-106°C (decomposition). :IH-

NMR (CDCl 3 ) δ 45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H) 4 6.96 (t, J= 1, 6 Hz, 1H), . 7.08 (br, 1H), 7.16-7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J = 8.1 Hz, 1H).

To a stirred solution of tert-butyl 4-[N'-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 4.19 mmol) in CH 2 Cl 2 (10 mL) was added TFA (6 mL) at room temperature. After stirring for 4 hours, the mixture was concentrated in vacuo. The residue was triturated by addition of water to give 4-[N'-(2-chlorophenyl)ureido]-3-methylphenylacetic acid (1.33 g, 100%) as a yellow powder. Melting point: 243-245°C (decomposition).

1H-NMR (CDCl 3 ) δ 2.24 (s, 3H), 3.47 (s, 2H), 6.99-7.08 (m, 3H), 7.28 (t, J = 7.6 Hz, 1H), 7.44 (dt, J = 8.0 , 2.4 Hz, 1H), 7.66 (dd, J= 8.3, 1.9 Hz, 1H), 8.13 (dd, J= 6.1, 1.7 Hz, 1H), 8.61 (d, J= 6.3 Hz, 2H); MS (ESI); m/ z 319 (M*+1), 321 (M*+ 3) ;Anal. Calcd for ClH 13 ClNA-0.7TFA: C, 59.33; H, 4.65; Cl, 10.85; N, 8.57. Found: C, 59.23; H, 4.64; Cl,

10.90; N, 8.40.

A mixture of 4-[N'~ (2-chlorophenyl)ureido]-3-methylphenyl-acetic acid (252 mg, 0.79 mmol), methyl 4-[(4S)-fluoro-(2S) -pyrrolidinyl]methoxybenzoate (200 mg, 0.79 mmol), EDC-HCT

(227 mg, 1.20 mmol) and DMAP (147 mg, 1.20 mmol) in DMF (5 mL) were stirred at room temperature for 17 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl 3 /acetone (10/1)] to give methyl 4- [1- [4- [ N' - (2-chlorophenyl) ureido] -3-methylphenylacetyl] - (4S) - fluoro-(2S)-pyrrolidinyl]methoxybenzoate (390 mg, 89%) as a colorless amorphous solid. IR (KBr) 3340, 2951, 1712, 1624, 1604, 1533, 1438 cmJ; 1H-NMR (CDCl1) δ 1.92-2.05 (m, 3H), 2.07-2.63 (m, 2H), 3.61 (d, 2H, J= 8.8 Hz), 3.70-4.15 (m, 5H), 4.25-4.67 (m, 2H), 5.26-5.44 (m, 1H), 6.84-8.19 (m, 13H); MS (FAB) m/z 554 (M<+>+1), 556 (MN-3).

To a stirred solution of methyl 4-[1-[4-[ N')-(2-chlorophenyl)ureido]-3-methylphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (268 mg , 0.484 mmol) in THF (3.8 mL) was added 0.25 N NaOH (3.8 mL). After stirring at room temperature for 1 day, the mixture was acidified with 1 N HCl and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (10/1)] to give 79 (124 mg, 47%) as a colorless amorphous solid. Molecular weight 539.98.

m (KBr) 334"6, 2976, 1709, 1685,. 1604, 1533, 1439 cm"'; 'H-NMR (DMSO-dJ 8 2.20 (s, 3H£- one of isomers 2.24 (s, 3H, one.-.' of isomers ), 2.30 (m, 1H), 3.60 (s, 2H), 3.71 -4.62 (m, 6H), 5.30-SM(nir 1H5U7J01-7.O9 (m, 5H), 7.28 (t, J= 7.8 Hz, 1H), 7.44 (d( J = 8.1 Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.87 (d, J = 7.1 Hz, 2H), 8.13 (d, J = 7.9 Hz, 1H), .8.62 (d, J = 6.1 Hz, 2H); MS (FAB) m/ z 540 (MT+1), 542 (M^+3). For Na salt: Anal. Calculated for ^Cj^ClFNjOi-Na-O.SÉtOH- 1.5H30: C, 56.91; H, 5.27 ; Cl, 5.79; F, 3.10; N, 6.87. Found: C, 56.60; H, 4.98; Cl, 5.88; F, 3.08; N, 6.52.

EXAMPLE 69

4- [I- [4- [Ar-(2-bromophenyl)ureido]-3-methylphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred mixture of tert-butyl 4-amino-3-methyl-phenylacetate (780 mg, 3.30 mmol), 2-bromophenyl isocyanate (0.41 mL, 3.30 mmol) in THF (7 mL) was added Et3N

(0.092 mL, 0.66 mmol) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give tert-butyl 4-[ N'~ (2-bromophenyl)ureido]-3-methylphenylacetate (1.5<7>' g, 93%) as a pale yellow powder. Melting point: 138-145°C (decomposition). 1H-NMR (CDCl 3 ) δ 1.44 (s, 9H), 2.33 (s, 3H), 3.51 (s, 2H), 6.90 (dt, J= 9.0, 1.4 Hz, 1H), 6.98 (br, 1H), 7.18-7.31 (m, 4H), 7.39 (dd, J= 8.1, 2.9 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 8.22:(d, J= 8.3 Hz, 2H); Calcd for C2J17&TX1Oi-0.2H7O: C.56.80; H.5.58; N.6.62. Found: C.56.85; H.5.42; N, 6.62. -

To a stirred solution of tert-butyl 4-[N-(2-bromophenyl)ureido]-3-methylphenylacetate (1.27 g, 3.03 mmol) in CH 2 Cl 2 (10 mL) was added TFA (5 mL) at room temperature. After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was triturated by addition of water to give 4-[ N'~ (2-bromophenyl)ureido]-3-methylphenylacetic acid (1.05 g, 95%) as a

pale yellow powder. Melting point: 245-248°C (decomposition).

1H-NMR (CDCl 3 ) δ 2.24 (s, 3H), 3.48 (s, 2H), 6.96 (dt, J= 7.3,1.5 Hz, 1H), 7.02 (d, J= 8.3 Hz, 1H), 7.07 ( s, 1H), 7.32 (t, /= 8.1 Hz, 1H), 7.59-7.66 (m, 2H), 8.44 (s, 1H), 8.62 (s, 1H); MS (ESI), m/z 363 (M++1), 365 (M*+3); Anal. Calculated for C^uBrNA-O.VHjO: C, 51.13; H, 4.40; Br, 21.26; N, 7.45.Furinet: C, 50.84; H, 4.62; Br, 21.72; N, 7.18.

A mixture of 4-[α7r-(2-bromophenyl)ureido]-3-methylphenylacetic acid (287 mg, 0.79 mmol), methyl'4-[(4S)-fluoro-(2S)-' pyrrolidinyl]methoxybenzoate (200 mg, 0.79 mmol), EDC-HCl (228 mg, 1.20 mmol), HOBt (160 mg, 1.19 mmol) and Et3N

(0.55 mL, 3.95 mmol) in DMF (5 mL) was stirred at room temperature for 4 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC

[CHCl3/acetone (10/1)] to give methyl 4-[(2S,4S)-1-[4-[W-(2-chlorophenyl)ureido]-3-methylphenylacetyl]-4-fluoro-2 -pyrrolidinyl]methoxybenzoate (440 mg, 93%) as a colorless amorphous solid. 1H-NMR (CDC13) 5

1.90 and <:>i.97 (each, 3H,amide isomers^ 2.05-2.62 (m, 2H), 3.58 (d, J= 8.1 Hz, 1H), 3.77 (m, 1H), 3.86 and 3.89 (each, 3H, amide isorhere), 3.92-4.64 (m, 5H), 5.24-5.42 (m, 1H), 6.83-7.23 (m, 6H), 7.41-7.62 (rn, 4H), 7.86- 8.09 (m-, 3H); MS (ESI), m/z 598 (M<+>+1), 600 flVT+3).

To a stirred solution of methyl 4-[1-[4-[ N')-(2-bromophenyl)ureido]-3-methylphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (440 mg, 0 .74 mmol) in THF (6.0 mL) was added 0.25 N NaOH (6.0 mL). After stirring at room temperature for 1 day, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/l). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (10/1)] to give 80 (229 mg, 53%) as a colorless amorphous solid. Molecular weight 584.44.

IR (KBr) 3325. 2972,1709, j

1604, 1529.1252 cm'<1>; 1H-NMR pMSO-d6) 6 2.25 (5, 3H), 2.31 (m, 1H), 3.17 (s, 1H), 3.60 (d, J = 4.7 Hz, 2H), 3.83-4.67 (m, 5H) , 5.31-5.51 (m, 1H), 6.97 (t, J= 7.3 Hz, 1H), 7.02-7.09 (m, 5H), 7.33 (t, J=8.0Hz, 1H), 7.61 (d, .7= 7.8 Hz, 1H), 7.64 (d,J= 8.3 Hz, 1H), 7.87 (d,/=8.3Hz, 2HX 7.90 (d, J= 8.8 Hz, 1H), 8.44-8.65 (m, 2H); MS (ESI), m/z 584 (M<*>+1), 586 (M<+>+3);'^na/.Calculated for'Cj?HI7BrFN3O7-0.4HIO: C, 56.84; H, 4.74; Br, 13.51; F, 3.21; N, 7.10. Found: C, 56.91; H, 4:93; Br, 13.23; F, 3.15; N, 6.88. For Na saltavSO :Ånal: Calculated for-CjsH^rFNA-Na- LSHjO: C, 52.64; H, 4.67; Br, 12.51; E, 2.97; N, 6.58. Found: C, 53.04; H, 4.67; Br, 12.95; F, 3.28; N, 6.11.

EXAMPLE 70

4- [1- [4- [W-(2-chlorophenyl)ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinyl] methoxybenzoic acid

To a stirred solution of methyl 4-(1- tert -butoxycarbonyl-(2 S )- p<y>rrolidin<y>l ) methoxybenzoate (2.0 g, 5.9 mmol) in EtOH

(10.0 mL) was added concentrated HCl (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 4.0 hours. The mixture was concentrated in vacuo. The resulting solid was collected and washed with EtOH-Et 2 O to give methyl 4-(2S)-pyrrolidinyl)methoxybenzoate HCl salt (1.4 g, 87%) as a white crystalline solid. 1 H-NMR (CDCl 1 ) 5 1.90-2.25 (m, 4H), 3.25^3.45

(rn, 2H), 3.88 (s, 3H), 3.90-4.00 (m, 1H), 4.25-4.45 (m, 2H), 6.96 (d, J= 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H).

To a stirred solution of methyl 4-[ (2 S )-pyrrolidinyl]-methoxybenzoate HCl salt (135 mg, 0.5 mmol), 4-[AJ'-(2-chlorophenyl)ureido]-3-meth.ylf enylacetic acid (159 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol) and triethylamine' (278 mL, 2.0 mmol) in THF (5.0 mL) and MeCN (5.0 mL) were the added EDC-HC1

(144 mg, 0.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) as eluent to give methyl 4-[1-[4-[A7f-(2-chlorophenyl)-ureido]-3 -methylphenylacetyl]-2-pyrrolidinyl]methoxybenzoate (220 mg, 82%) as one colorless oil. 1H-NMR (CDC13) 8" 1.91 pg 1.97 (each .s, total 3H), 2.00-2.20 (m, 4H), 3.55-3.65 (m, 4H), 3f8_7 and 3.89(each s, total 3H), 4.10-4.20 (m,2H), 4.51 (m, 1H), 6.86-7.04 (m, 6H), 7.20-7.53 (m, 4H), 7.89-8.01 (m, 2H), 8.22 (d, J= & .3 Hz, 1H).

To a stirred solution of methyl 4-[1-[4-[N-(2-chlorophenyl)ureido]-3-methylphenylacetyl]-•2S-pyrrolidinyl]-methoxybenzoate (220 mg, 0.41 mmol) in THF (8.0 mL) and MeOH (4.0 mL) was added 1 N NaOH (0.8 mL, 0.8 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1 N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 81 (220 mg, quantitative) as a white crystalline solid. Molecular weight 521.99.-Smp . : 122-124 °C; IR (KBr) 3340,1710, 1685, 1604, 1533. 1511,

1438cm"'; 'H-NMR (DMSO-dj) 8 1.81-2.11 (m, 4H), 2.18 and. 2.20 (each, total 3H), 3.45-3.80

(m, 4H), 3.95-4.05 (m, 1H), 4.12.4.20 (m, 1H), 4.21-4.31 (m; 1H), 6.99-7.06 (m, 5H), 7.26-7.30 (m, 1H) , 7.44 (di 7.8 Hz, 1H), 7.62-7.64 (m, 1H), 7.85-7.90 (m, 2H), 8.13 (d,J= 6.8 Hz, 1H), 8.60-8.62 (xn, 2H); MS (FAB) m</>2,522 (hT+1); y4na/.Calculated for CjsHjgNjOjCl-O^HjO: C, 63.99; H, 5.45; N, 7.99. Found C, 63.90; H, 5.40; N, 7.72. •

EXAMPLE 71

4- [1- [4- [ N'~ (2-bromophenyl)ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl [(2 S )-pyrrolidinyl]-methoxybenzoate HCl salt (135 mg, 0.5 mmol), 4-[A7'-(2-bromophenyl)ureido]-3-methylphenylacetic acid (181 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol) and triethylamine (278 mL, 2.0 mmol) in THF

(5.0 mL) and MeCN (5.0 mL)- was added EDC-HCl (144 mg, 0.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1/2, v/v)

as eluent to give methyl 4-[1-[4-[ N'~ (2-bromophenyl)-ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (290 mg, quantitative) as a colorless oil. 1H-NMR (CDC13) 6 1.95 and 2.01 (each s, total 3H), 2.00-2.20 (m, 4H), 3.50-3.65 (m, 4H), 3.87 and 3.89.(each, s, total 3H), 4.10-4.2©-(Tn, -2H), 4.50 (m, 1H), 6.85-7.06 (m, 6H), 7.24-7.28 (m, 1H), 7.40-7.44 (m, 3H), 7.89-8.16 ( m, 2H), 8.17-8.18 (m, 1H).

To a stirred solution of methyl 4-[1-[4-[A7r-(2-bromophenyl)ureido]-3-methylphenylacetyl]-2S-pyrrolidinyl]methoxybenzoate (290 mg, 0.5 mmol) in THF (8.0 ml) and MeOH.(4.0 ml) was added 1 N NaOH (1.0 ml, 1.0 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 82 (240 mg, 85%) as a white crystalline solid. Molekylyék>, $566.44.. M.p.: 125-130 °C;!

IR (KBr) 3340, 1604, 1529, 1434 cm"1; 'H-NMR

(DMSb-dj) 5 1.80-2.10 (m, 4H), 2.18 and 2.20 (nyers, total 3H), 3.45-3.80 (m, 4H), 3.95-4.05 (m, 1H), 4.15-4.20 (m, 1H ), 4.25-4.30 (m, 1H), 6.94-7.-06 (m, 5H), 7.30-7.34 (m, 1H), 7.59-7.62 (m, 2H), 7.85-7.90 (m, 2H) , 8.01 (d, J= 8.1 Hz, 1H), 8.44 (s, 1H), 8.62 (s, 1H); MS (FAB) m/z 566 (M*); ^no/Calculated for^HaNjOjBrO.SHjO: C, 58.44; H, 5.08; N, 7.30. Found: C, .58.57; H, 4.99; N, 7.18.

EXAMPLE 72

4-[1-[3-methyl-4-[W-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

A mixture of 3-methyl-4-[AJ'-(2-methylphenyl)ureido]phenylacetic acid (438 mg, 1.47 mmol), methyl 4-[(2 S )-pyrrolidinyl]-methoxybenzoate (420 mg, 1.79 mmol), EDC-HCl (410 mg,

2.14 mmol), HOBt (228 mg, 1.69 mmol) and Et 3 N (240 mL, 1.72 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1 to 25:1, v/v) as eluent to give methyl 4-[1-[3-methyl-4-[AT<->(2 -methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (760 mg, quantitative) as a white foam.

1H-NMR (CDCl 3 ) δ 1.89 (s, 3 H), 1.94-2.14 (m, 4 H),

2.16 (s, 3 H), 3.50-3.69 (m, 4 H), 3.87 (s, 3 H), 4.09-4.17 (m, 2 H), 4.42-4.45 (m, 1 H), 6.85-7.02 ( m, 6H), 7.10-7.16 (m, 3H), 7.51-7.53 (m, 1H), 7.62-7.64 (m, 1H), 7.91-7.94 (m, 2H); MS (FAB) m/z 516 (tvT+1).

To a stirred solution α<y> methyl 4-[1-[3-methyl-4-[α7'-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]-benzoate (420 mg, 0.71 mmol) in THF (7 mL) was added 0.5 N NaOH (7 mL) and the reaction mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was xerized by recrystallization in sering from CHCl3-IPE to give 83.

(526 mg, 69%) as a white crystalline powder. Molecular weight 501.57. M.p.: 191-193°C;

NMR (DMSO-d^ 6 1.87-2.10 (m, 4 H), 2.20 (s, 3 H), 2.26 (s, 3 H), 3.44-3.79 ( series of m, total 4 H), 3.99-4.45 ( «rierav ,'m, total 3 H), 6.91-7.17 (serieray;m, total 7 H), 7.66-7.68 (m, 1H), 7.80-7.90 (m, 3 H), 8.1.9-8.21 (m , 2 H), 12.62 (br s, 1 H); MS (FAB) m/ z 502 (M<*>+1); Anal Calcd for' C^Hj^A-IMHjO: C, 68.83; H, 6.27 ; N, 8.30.Found: C, 68.81; H, 6.17; N, 8.23.

EXAMPLE 73

4-[(45)-fluoro-1-[4-[A7'-(2-methoxyphenyl)ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of tert-butyl 4-amino-3-methyl-. phenylacetate (1.36 g, 6.15 mmol) and triethylamine (170 ml, 1.23 mmol) in THF (30 ml) was added 2-methoxyphenyl isocyanate (820 ml, 6.15 mmol) and the resulting mixture was stirred for 2 7 hours. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give a precipitate which was collected by filtration to give tert-butyl 4-[α7r-(2-methoxyphenyl)ureido]-3-methylphenylacetate, .(1.74 g, 76%)- as -a white crystalline material. M.p.: 157-158°C;, 1H-NMR(CDCl3)8 1..46(sI9H), ■ -

2.30 (s, 3 H), 3.50 (s, 2 H), 3.76 (s, 3 H), 6.43 (s, 1H), 6.83 (br d, J= 8.4 Hz, 1H), 6.95 (br d, J = 8.0 Hz, 1 H), 6.98-6.99 (m, 2 H), 7.13 (brs, 1 H), 7.23 (br s, 1 H), 7.48 (d, J = 8.8 Hz, 1H), 8.14 (d , J= 8.4 Hz, 1 H); MS (ESI) m/z 371 (M<*>+H).

To a stirred solution of tert-butyl 4-[ N'~ (2-methoxyphenyl)ureido]-3-methylphenylacetate (1.32 g, 3.56 mmol) in CH 2 Cl 2 (15 mL) was added trifluoroacetic acid (10 mL ) and the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo and water was added to give a precipitate which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid (932 mg, 83%) as a white powder. M.p.: 260-264°C;

'H-NMR (CD30D) 6 2.30 (s, 3 H), '3.55 (s, 2 H), 4.87 (s, 3 H), 6.87-6.92 (m, 2 H)~ 6.97-6.99 (ra, 2 H), 7.10-7.24 (m, 2H), 7.53-7.58 (m, 1H), 8.04 (d, J = 7.2 Hz, 1H); MS (ESI) m/z 314 (M<*>).

To a stirred solution of 4-[A7'-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid (336 mg, 1.07 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoate (271 mg, 1.07 mmol) and N,N-dimethylaminopyridine (130 mg, 1.07 mmol) in DMF (10 mL) was added EDC-HCl (226 mg, 1.18 mmol) at room temperature, and the the resulting mixture was stirred for 20 hours. The mixture was poured into 1A7 aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give methyl 4-[(4S)-fluoro-1-[4-[ N'~ (2-methoxyphenyl)ureido]-3-methylphenylacetyl] -(2S)-pyrrolidinylmethoxy]-benzoate (583 mg, 99%) as a colorless amorphous solid.

1

'H-NMR (GDCI3): mixture of rotamers, . 8 2.05 °g 2.12 (s, total 3 H), 2.05r2.61 (m; 2 H), 3.55-4.73 (sérienav^m, 13 H), 4.51-4.66 (m, 2 H), 5.26-5.40 ( m, 1 H), 6.72-7.01 (sefienåv; m, 8 H), 7.38-8.13i^rrierav<:>fm, 3 H); MS (ESI) m/z 550 (M<+>+H).'

To a stirred solution of methyl 4-[(4S)-fluoro-1-[4-[ N'~ (2-methoxyphenyl)ureido]-3-methylphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (557 mg, 1, 01 mmol) in MeOH-THF (1:1, 10 mL) was added 1.0 N aqueous NaOH (4.05 mL, 4.05 mmol) at room temperature and the resulting mixture was heated at 60°C for 2 hours. The mixture was poured into 1N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give 84

(492 mg, 91%) as a colorless amorphous solid. Molecular weight 535.56.

'H-NMR (CD3OD), mixture of ■

rotamars, 5 2.96 (s, 3 H), 2.11-2.45 (m, 2 H), 3.64-4.15 ( series of in, 5 H), 3.91 (s, 3 H), 4..41-4.45 (m, 1- H), 4.52-4.61 (m, 1 H), 5.25-5.38 (m, 1 H), 6.84-7.10 (series of m, 7 H), 7.54-7.58 (m, 1H), 7.93 (d, J= 8.8 Hz, 2 H), 8.02 (d, / = 8.8 Hz, 2 H); MS (ESI) m/z 536 tfvT+H), 538 (M*+Na+). EXAMPLE 74

4- [ (4S) -fluoro-1- [4- [AJ'-(2-methoxyphenyl)ureido] phenylacetyl] -

(2 S )-Pyrrolidinylmethoxy]benzoic acid

To a stirred solution of ethyl 4-amino-3-methylphenylacetate (1.32 g, 7.37 mmol) and triethylamine (205 mL, 1.47 mmol) in THF (20 mL) was added 2-methoxyphenyl isocyanate (98 0 ml, 7.37 mmol) and the resulting mixture was stirred for 23 hours. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give a precipitate which was collected to give ethyl 4-[A7'-(2-methoxyphenyl)ureido]phenylacetate (2.44g, quantitative } !■ as- et'; white' crystalline material. Mp . 107-109 °C; 'H-NMR (CDCl 3 ) 5 1.26 (t, J= 7.1 Hz, 3 H), 3.56 (s, 3 H),

3.79 (s, 3 H), 4.15 (q, J= 7.1 Hz, 2 H), 6.82-6.85 (m, 1 H), 6.91-7.00 (m, 2 H), 7.08 (s, 1 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H), 7.33 (s, 1 H), 8.07-8.10 (m, 1 H); MS (ESI) m/z 329

(M<+>+H)-.

To a stirred solution of ethyl. 4-[A7'-(2-Methoxyphenyl)-ureido]phenylacetate (2.22 g, 6.78 mmol) in MeOH (30 mL) was added 1.0 M aqueous NaOH (10.2 mL, 10 .2 mmol) and the resulting mixture was stirred overnight. 1 A7 (aq) HCl was added and the mixture was concentrated in vacuo. Water was added to the residue to give a precipitate which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[A7'-(2-methoxyphenyl)ureido]phenylacetic acid as a white powder (1.87 g, 92%). M.p.: 165-168 °C;

'H-NMR (CD3OD) 5 2.3 0 (s,

3 H), 3.55 (s, 2 H), 4.87 (s, 3 H), 6.87-6.92 (m, 2 H), 6.97-6.99 (m, 2 H), 7.10-7.24 (m, 2 H), 7.53-

7.58 (m, 1 H 1, 8.04 (d, J= 1.2 Hz, 1 H); MS (ESI) m/z 300 (M<*>).

To a stirred solution of 4-[ N' -(2'methoxyphenyl)ureido]-phenylacetic acid (353 mg, 1.18 mmol), methyl 4-[.(4S)-fluoro-(2S)--pyrrolidinylmethoxy] benzoate (298 mg, 1.18 mmol) and N,N-dimethylaminopyridine (144 mg, 1.18 mmol) in DMF (10 mL) was added EDCHC1 (226 mg., 1.18 mmol) at room temperature and the obtained mixture was stirred for 22 hours. The mixture was poured into 1N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous

Na2S04 and then concentrated in vaJcuuzn. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give methyl

.4- t (45) -fluoro-1-' [4- [ N'~ (2-methoxy f phenyl) ureido] phenylacetyl] - .

(2 S )-pyrrolidinylmethoxy] benzoate • (594- mg, 54%) as -efe ■ colorless amorphous solid. 'H-MvlR^CDCy

:blaoding of rotamars- •-, 5 2.05-2.58 (series of in, 2 H), 3.55-4.25 £'series of! m, 5H), 3.77 (s, 3H), 3.87-3.90 (m, 3H), 4.50-4.63 jm, 2H), 5.23-5^7;>(m, 1H), "6.81r6. 84 (in, 1H), 6.91-6.99 (m, 4 H), 7.09-7.12 (m, 2 H), 7.18-7.26 (m, 2 H), 7.45-7.53 (m, 2 H), 7.91-8.03 (m, 2 H), 8.10-8.12 (m,

1H); MS (ESI) m/z 536 (M<*>+H).

To"..a stirred solution<i>g of methyl 4-[-(4S)-fluoro-1-[4-[A7<r->(2-methoxyphenyl) ureido] phenylacetyl] - (2S) -pyrrolidinylmethoxy]-benzoate (568 mg, 1.06 mmol) in MeOH-THF (1:1, 10 mL) was added 1.0 N aqueous NaOH (4.24 mL, 4.24 mmol) at room temperature and the resulting mixture was heated at 60°C for 1

hour. The mixture was poured into 1N aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) as eluent to give 85 (516 mg, 93%) as a colorless amorphous solid. 'Molecular weight 521_,54.-<1>H-NMR."(CD,OD), mixture of rotamars;,

..li42-2.:46 (m, 2 H), 3.65-4.19 (series of m, 5 H), 3.88 (s, 3 H), 4.42-4.45 (m; 1 H), 4.52-4.- é2:(rn, 1 H),'5.24-5.39 (m, 1 H), 6.85-6.91 (m, 1 H), 6:94-7.03 X series-of"5n; 4 H), 7.14-7.19 ( m, 2H), 7"35-7.'40 (m, 2H), 7.92-7.96 (m, 2H), 8:02-8.04 (m, 1H); MS (EST) m/z 521 (M^H), 544 (MN-Na<*>). EXAMPLE 75 4- [ (4S)-fluoro-1- [4- [ N - (2-methoxyphenyl) ureido] r3-methoxyphenylacetyl] ~{ 2S ) -pyrrolidinylmethoxy] benzoic acid To a stirred solution of tert-butyl 4-amino -3-methoxy-phenylacetate (1.41 g, 5.94 mmol) and triethylamine (165 mL, 1.19 mmol)' in THF (20 mL) was added 2-methoxyphenyl isocyanate (790 mL, 5.94 mmol ) and the resulting mixture was stirred for 4 days. The mixture was concentrated to a small volume in vacuo and hexane was added to the residue to give a precipitate which was collected to give tert-butyl 4-[N'~ (2-methoxyphenyl)ureido]-3-methoxyphenylacetate,( 2.06 g, 90%) as a white crystalline material. M.p.: 132-134°C; 1 H-NMR (CDCl 3 ) δ 1.46 (s, 9 H), 3.50 (s, 2 H), 3.87 (s, 3H); 3.88 (s, 3 H), 6.84 (s, 1 H), 6.87-6.90 (m, 2 H), 6.98-7.03 (m, 2 H), 7.12 (s, 1 H), 7.16 (s, 1 H ), 8.06 (d, J= 8.4 Hz, 1 H), 8.13 (dd, J = 7.2, 2.0 Hz, 1 H); MS (EST) m/z 387 (M<*>+H).

To a stirred solution of tert-butyl 4-[ N (-(2-methoxyphenyl)ureido]-3-methoxyphenylacetate (2.01 g, 5.20 mmol) in CH 2 Cl 2 (15 mL) was added trifluoroacetic acid (10 mL) and

the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo. Water' was added to the residue to give a precipitate which was collected by filtration.

The crude solid was recrystallized from EtOH/hexane to

to give 4-[ N'~ (2-methoxy enyl.)ureido]-3-methoxy enylacetic acid as a white powder (1.40 g, 82%). M.p.: 182-185 °C;

'H-NMR.(CDjOD) 8 3.55 (s, 2

H), 3.88 (s, 3 H), 3.89 (s, 3 H), 6.80r6.99 (m, 5 H), 7.94 (d, J= 8.4 Hz, 1 H), 8.00 (d, J= 7.2 Hz, 1"H); MS (ESI) m/z 330 (M<*>).

To a stirred solution of 4-[ N'~ (2-methoxyphenyl)ureido]-3-methoxy enylacetic acid (353 mg, 1.07 mmol), methyl-[(4S).-fluoro-(2S)-pyrrolidinylmethoxy] benzoate (271 mg, 1.07 mmol) and N,N-dimethylaminopyridine (131 mg, 1.07 mmol) in DMF (10 mL) was added EDC-HCl (224 mg, 1.18 mmol) at room temperature, and the resulting mixture was stirred for 14 hours. The mixture was poured into 1 A7 aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) as eluent to give methyl 4-[(4S)-fluoro-1-[4-[ N'-(2-methoxy-phenyl) ureido]-3- methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (372 mg, 61%) as a colorless amorphous solid. "H-NMR (CDC13), mixture of rotamers;, 6 2.04-2.57 (series of m, 2 H), 3.58-4.18 (series of fn, 5 H), 3.79 and 3.83 (s, total 3 OT), 3.86 (s, 3 H),.3.87 (s, 3 H), 4.51-4.63 (m, 2 H), 5.22-5.36 (m, 1 H), 6.80-6.89 (m, 3 H), 6.94-7.03 ( -rn,4 H), 7.15-7.25 (m, 2 H), 7.94-8.01 (m, 2 H), 8.04-8.11 (m, 2 H); MS (ESI) m/z 566 (MN-H) .

To a stirred solution of methyl 4-[(4S)-fluoro-1-[4-[Ajr-(2-methoxyphenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (356 mg, 0, 63 mmol) in MeOH-THF (1:1, 10 mL) was added 1.0 N aqueous NaOH (1.88 mL, 1.88 mmol) at room temperature and the resulting mixture was heated at 60°C for 2 hours. The mixture was poured into 1A7 aqueous HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MéOH (10:1) as eluent to give 86

(335 mg, 97%) as a colorless amorphous solid. Molecular weight 551.5<6.> 'H-NMR (CD 3 OD), mixture of rotamers 8;

2.14-2.48 (m, 2 H), 3.69-4.20 (series of m, 5 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 4.46-4.57 .(m, 2H), 5.27-5.41 (m, 1H), 6.79-7.04 (m, 7H), 7.90-8.02 (m, 4H); MS (ESI) m/z 552 (M₂H).

EXAMPLE 76

4.- [1- [4- [ N'~ (2, 6-dichloro.phenyl)ureido] phenylacetyl] - [ (4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoic acid

To a mixture of ethyl 4-aminophenylacetate (1.62 g, 9.04 mmol) and 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 mmol) in THF (40 mL) was added Et3N (0.25 ml, 1.81 mmol) at room temperature. After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give ethyl 4-[ N'-(2,6-dichlorophenyl)-

ureido]phenylacetate (3.19 g, 96%) as a colorless powder.

Melting point: 168-170°C (decomposition). 1 H-NMR (CDCl 3 ) δ 1.25 (t, /=

7.1 Hz, 3H), 3.56 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 6.50 (br, 1H), 6.67 (br, 1H), 7.12-7.52 (rn, 7H).

To a stirred solution of ethyl 4-[Af-(2,6-dichlorophenyl)-ureido]phenylacetate (3.19 g, 8.69 mmol) in THF (70 mL) was added 0.25 N NaOH (70 mL) . After stirring at room temperature for 17 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of water to give 4-[N'~ (2,6-dichloro-phenyl)ureido]phenylacetic acid (2.44 g, 82%) as a colorless powder. M.p.: 262-263°C (decomposition).

1H-NMR (DMSO-d6) 6 3.48 (s, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 8.3 Hz, 1H),

7.37 (d, J= 8.3-Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 8.18 (s, 1H), 8.90 (s, 1H), 12.22 (br, 1H); MS (ESI) m/z 339 (M<*>+1), 341 (M<*>+3), 343 (M<+>+5).

A mixture of 4-[A7r-(2,6-dichlorophenyl)ureido]phenylacetic acid

(268 mg, 0.79 mmol), methyl 4-[(2S,4S)-4-fluoro-2-pyrrolidinyl] methoxybenzoate (200 mg, 0.79 mmol), EDC-HC1 (227 mg, 1.19 mmol ),HOBt (161 mg, 1.19 mmol) and Et 3 N (0.35 mL, 3.95 mmol) in DMF (4 mL) were stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (10/1)] to give methyl 4-[1-[4-[ N'~ (2,6-dichlorophenyl)ureido]-phenylacetyl]-(4S)-fluoro- [ 2S )-pyrrolidinyl]methoxybenzoate (465 mg, 100%) as a colorless amorphous solid. • H-NMR (CDCl 1 ) δ 2.05-2.57 ;

(m, 2H), 3.60 (d, 2H,/= 3.4 Hz), 3.64-3.84 (m, 2H), 3.88 and 3:89 (each s, SH.amid.isoraerj, 3.92-4.63 (m, 3H) . ), 7.92 (d, /= 8.8 Hz, 1H), 7.79 (d, 7= 8.8 Hz, 1H);' MS (ESI) m/z 574 (M<*>+1), 576 (M<*> +3), 578 (M^+5).

To a solution of methyl 4 - [ (2S,4S) -1- [4- [W - (2,6-dichlorophenyl)ureido]phenylacetyl]-4-fluoro-2-pyrrolidinyl]-methoxybenzoate (4 65 mg, 0 .80 9 mmol) in THF (40 mL) 0.25 N NaOH (40 mL) was added. After stirring at room temperature for 11 h, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (10/1)]. to give 87 (340 mg, 75%) as a colorless powder. Molecular weight 560.40. M.p.: 168-172°C (decomposition). IR (KBr) 3340, 1711. 1685,

1604, 1240, 773 cm -1 ; 1H-NMR (DMSO-d,) 6 2.22-2.30 (m, 2H), 3.61 (d, J= 7.4 Hz, 2H), 3.70-4.75 (m, 6H), 5.30-5.49 (m, 1H), 7.02-7.18 (m, 5H), 7.28-7.41 (m, 4H), 7.52 (dd, /= 8.0, 2.9 Hz, 2H), 7.86 (m, 2H), 8.29 (br, 1H), 9.01 ( br, 1H), 12.66 (br, 1H); MS (ESI) m/z 560 (M<*>+1), 562 (M++3), 564 (MN-5); ,4/70/.Calculated for ^H^CljFNjOj-O.SHjO: C, 56.95; H, 4.43; Cl, 12.45; F, 3.34; N, 7.38: Found: C, 57.04; H, 4.34; Cl, 12.98; F, 3.27; N, 7.21.

EXAMPLE 77

4-[1-[4- [ N'~ (2,6-dichlorophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoic acid

To a mixture of tert-butyl 4-amino-3-methoxyphenyl acetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g,

9.04 mmol) in THF (40 mL) was added Et3N (0.25 mL,

9.04 mmol) at room temperature. After stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexari to give tert-butyl 4-[ N'~ (2,6-dichlorophenyl)ureido]-3-methoxyphenylacetate (2.27 g, 59%) as a colorless powder. M.p.: 177-181°C (decomposition).

1H-NMR (CDCl 3 ) δ 1.43 (s, 9H), 3.74 (s, 2H), 3.83 (s, 3H), 6.34 (s, 1H), 6.81 (s, 1H), 6.84 (d, J= 8.3 Hz, 1H), 7.06 (br, 1H), 7.27.(t,V= 8.1 Hz, 1H), 7.39 (d, /= 8.1 Hz, 2H), 8:04 (d, J = 8.3 Hz, 1H) .

To a stirred solution of tert-butyl 4-[N-(2,6-dichloro-';

phenyl)ureido]-3-methoxyphenylacetate (2.27 g; 5.34 mmol) in CH 2 Cl 2 (50 mL) was added TFA (20 mL) at room temperature. After stirring for 2 hours, the mixture was concentrated in vacuo. The residue was triturated by addition of water to give 4- [A7r-

(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (1.50 g,

76%) as a colorless powder. M.p.: 246-249°C (decomposition).

'H-NMR (DMSO-d*) 8 3.49 (s, 2H), 3.88 (s, 3H), 6.75 (d, J= 8.3 Hz, 1H), 6.93-(s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.52 (d, J= 8.0 Hz, 2H), . 7.97 (d, J= 8.0 Hz/IH), 8.40 (s, 1H), 8.86 (s, 1H), 12.23 (br, 1H); MS (ESI) m/z 369 (M<+>+1), 371 (fcT+3), 373 OvT+5).

A mixture of 4-[ N'~ (2,6-dichlorophenyl)ureido]-3-methoxyphenyl-' acetic acid (288 mg, 0.78 mmol), methyl 4-[ (2S,4S)-4-fluoro- 2-pyrrolidinyl] methoxybenzoate (200 mg, 0.79 mmol), EDC-HC1

(227 mg, 1.19 mmol), HOBt (161 mg, 1.19 mmol) and Et 3 N -(0.55 mL, 3.95 mmol) in DMF (4 mL) were stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /MeOH (40/1)] to give methyl 4- [1- [4-[ N'~(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetyl]-( 4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (530 mg, 100%) as a colorless amorphous solid.

1H-NMR (CDCl1) 5 2.03.-2.62 (m, 2H), 3.61 (d, 2H, J= 4.7 Hz), 3.62-3.66 (m, 2H), 3.73

*>g 3.77 (each s> 3H, amide isomers), 3.78-3.85 (m, 1H), 3.87 and 3.88 (each s, 3H, arhld isomers), 3.95-4.63 (m, 4H), 5.22-5.36 (m, 1H), 6.82 (s, 1H), 6.88 (d, J= 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.14-7.25 (m, 1H), 7.38 (d, J= 8.1 Hz, 2H), 7.94-8.10 (m, 3H); MS (ESI) m/z 604 (M+1), 606 (MT+3), 608 (M+3).

To a solution of methyl 4 - [1- [4- [W - (2, 6-dichlorophenyl)-ureido]-3-methoxyphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoate (530 mg, 0.78 mmol) in THF (40 mL), 0.25 N NaOH (40 mL) was added. After stirring at room temperature for 11 h, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (10/1)] to give 88 (420 mg, 75%) as a colorless amorphous solid. Molecular weight 590.43. M.p.: 162-168°C (decomposition). iR(KBr)3346,

2974, 1709, 1604, 1533, 1254 cm"'; 'H-NMR (DMSOO 5 1.98-2.36 (m, 2H), 3.58 (s, 2H), 3.78-3.95 (m, 6H), 4.02-4.68 (m , 2H), 5.31-5.50 (m, 1H), 6.71-7.09 (m, 4H), 7.31 (t, J= 7.8 Hz,' 1H), 7.53 (d, J= 8.1 Hz, 2H), 7.87 (d , J= 8.1 Hz, 2H), 7.88-8.00 (m, 1H), 8.30-8.40 (m, 1H), 8.89 (s,

1H); MS (ESI) m/ z 590'(M<*>+1), 592 (Nf+3), 594 CM<*>+5);i4/io/. Calculated CÆa^A"1-5HjO: . C.54.47; H.4.73; F.3.08; N.6.81. Found: C.54.53; H.4.49; F, 2.93; N, 6.65. EXAMPLE 78 4- [ (2S,4S) -i- [4-[#'-(2,6-dichlorophenyl)ureido]-3-methylphenyl acetyl]-4-fluoro-2-pyrrolidinyl]methoxybenzoic acid

To a mixture of tert-butyl 4-amino-3-methylphenyl acetate

(1.88 g, 8.51 mmol), 2,6-dichlorophenyl isocyanate (1.60 g,

8.51 mmol) in THF (40 mL) was added Et,N (0.24 mL, 1.70 mmol) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of h-hexane to give tert-butyl [4-[ N'~ (2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 74%) as a colorless powder. Melting point: 243-244°C (decomposition).

'H-NMR

(CDClj) 8 1.45 (s, 9H), 2.30 (s, 3H), 3.49 (s, 2H), 6.24 (s, 2H), 7.12-7.16 (m, 3H), 7.35 (d, J= 8.3 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H).

To a stirred solution of tert-butyl 4-[N-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 6.30 mmol)- in CH 2 Cl 2 (50 mL) was added TFA (20 ml) at room temperature. After stirring for 2 hours, the mixture was concentrated in vacuo. The residue was triturated by the addition of water to give 4- [ N'~

(2,6-Dichlorophenyl)ureido]-3-methylphenylacetic acid (2.12 g, 95%) as a colorless powder. M.p.: 274-283°C (decomposition).

'H-NMR pMSO-d*) 8 2.24 (s, 3H), 3.46 (s, 2H), 7.00 (d, J = 8.6 Hz, 1H), 7.06 (s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.52 (d, J= 8.3 Hz,-2H), 7.65 (d, J= 8.2 Hz, 1H), 8.12 (s, 1H), 8.50 (s, 1H), 12.22 (br, 1H) ; MS (ESI) m/z 353 (MM-1), 355 (MH3), 357 0^+5).

. A mixture of 4-[ N'~ (2,6-dichlorophenyl)ureido]-3-methylphenyl-acetic acid (181 mg, 0.51 mmol), methyl 4-[(2S,4S)-4-fluoro-2- pyrrolidinyl]methoxybenzoate (130 mg, 0.51 mmol), EDC-HCl

(147 mg, 0.77 mmol), HOBt (104 mg, 0.77 mmol) and Et3N

(0.35 mL, 2.55 mmol) in DMF (4 mL) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (20/1)] to give methyl 4-[1-[4-[ N'-(2,6-dichloro-phenyl)ureido]-3-methylphenylacetyl]-(4S )-fluoro-(2S)-pyrrolidinyl] methoxybenzoateN (283 ; mg, .94%) as a colorless amorphous solid. 'H-NMR (CDCl1) 6

1.95-2.61 (ra, 3H), 3.55 (br, 2H). 3.67-3.81 ,(m, 2H), 3.87 (s, 6H), 3.89-4.68~(rn, 2H), 5.23-5.43 (m, lHj, 6.81-7.10 (m, 6H), 7.13-7.43 (m, 3H), 7.56 (br, 1H, one of isomers), 7.73 (br, 1H, era of lampreil, 7.89-8.00 (m, 2H); MS (ESI) m/ z 588 ØvT+1), 590 (M <*>*3), 592 (M*+5).

To a solution of methyl 4-[1-[4-[AJ'-(2,6-dichlorophenyl)-ureido]-3-methylphenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]-methoxybenzoate (283 mg , 0.48 mmol) in THF (20 mL) 0.25 N NaOH (20 mL) was added. After stirring at room temperature for 11 h, the mixture was extracted with EtOAc. The remaining aqueous layers were acidified with 1 N HCl and extracted with EtOAc. The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (20/1)] to give 89 (450 mg, 67%) as a pale brown amorphous solid. Molecular weight 574.43. Melting point: 174-180°C (decomposition).

IR (KBr) 3330, 3288, 1711, 1685, 1604, 1512, 1242 crrf'; 1H-NMR (DMSO-dJ 8 2.24 (m, 3H), 3.61 (d, 2H, J= 6.1 Hz), .3.72-4.68 (m, 7H), 5.30-5.50 (m, 1H), 6.97-7 .20 (m, 4H), 7.29-7.68 (m, 5H), 7.87 (m, 2H), 8.10^8.95 (m, 1H), 12.65 (br, 1H); MS (ESI) m/ z 574 Gvf+ 1), 576 (K+3), 578 Qtf+ 5) ;Anal. Calculated'^TorClHMClIFN3Cy0.5H2O: C, 57.64; H, 4.66;

Cl, 12.15, F, 3.26; N, 7120. Found: C, 57.37; H, 4.44; Ci; 12.64; F, 3.23; N, 7.25.

EXAMPLE 79

4- [1- [3-chloro-4- [N'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of 3-chlorophenylacetic acid (21.76 g,

127.6 mmol) in dichloroethane (100 mL) was added MeOH

(15.6 mL, 383 mmol) and H 2 SO 4 (1 mL) at room temperature. After 20 min. stirring, the mixture was heated at 80°C for 2 hours. The reaction mixture was poured into ice water and extracted with CHCl 3 . The combined extracts were washed with aqueous NaHCO 3

and saline solution. After drying over Na 2 SO 4 , the extract was concentrated in vacuo to give methyl 3-chlorophenyl acetate (25.4 g, 100%) as a colorless oil. 1H-NMR(CDCl 3 ) 63.60 (s, 2H), 3.70 (s,

3H), 7.15-7.26 (m, 4H).

To a stirred mixture of methyl 3-chlorophenyl acetate (25.4 g,

128 mmol) in H2SO4 (44 mL) was added HN03 (5.5 mL,

13 8 mmol) at 0°C. The reaction mixture was gradually warmed to room temperature over 4 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with aqueous NaHCO 3 and brine. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [1 kg, n-hexane/EtOAc (40/1)] to give methyl 3-chloro-4-nitrophenyl acetate (11.4 g, 36%) as a yellow oil.

1H-NMR (CDCl1) 8 3.6.9 (s, 2H), 3.74 (s, 3H), 7.33 (dd,/= 8.3,1.5 Hz, 1H), 7.49 (d, .7= 1.5 Hz, 11$ , 7.87 (d, J=8.3Hz, 1H).

A mixture of methyl 3-chloro-4-nitrophenyl acetate (10.9 g,

47.5 mmol), reduced iron powder (8.58 g, 153.6 mmol,

AcONa-3H2O (6.05 g, 44.5 mmol) and AcOH (17.6 mL) in MeOH/HzO

(100/400 ml) was heated at 110°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filter cake was washed with MeOH. The combined filtrate was evaporated and extracted with EtOAc. The combined extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [150 g, CHCl 3 /EtOAc (10/1)] to give methyl 4-amino-3-chlorophenyl acetate (4.58 g, 48%) as a red oil. "H-NMR (CDCl 3 ) δ 3.49 (s, 2H), 3.68 (s, 3H), 4.01 (br, 2H), 6.70 (d, J= 7.4 Hz, 1H), 6.96 (dd, J =

8.1, 2.0 Hz, 1H), 7.17 (d, J= 2.0 Hz, 1H).

To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-methylphenyl isocyanate (0.60 mL, 5.01 mmol) in THF (20 mL) was added Et3N (0 .14 ml, 1.00 mmol) at room temperature. After stirring for 1 day, 2-methylphenyl isocyanate. (0.60 mL, 5.01 mmol) added to the reaction mixture and stirred for 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give methyl 3-chloro-4-[N-(2-methylphenyl)ureido]phenylacetate

(1.23 g, 74%) as a colorless powder. 'H-NMR (CDCl 3 ) 6 2.34'(s, 3H), 3.54

(s, 2H), 3.68 (s, 3H), 6.24 (br, 1H), 6.99 (br, 1H), 7.15 (dd, J= 8.3,2.0 Hz, 1H), 7.21-7.31 (r4 5H), 7.44 (d, J= 7.6 Hz, 1H), 8.20 (d, J= 8.5 Hz, 1H); MS (ESI) m/z 333 (M++1), 335 (M*+3).

To a stirred solution of methyl 3-chloro-4-[α7'-(2-methyl-phenyl)ureido]phenylacetate (1.23 g, 3.70 mmol). in THF (30 mL) was added 0.25 N NaOH (30 mL). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1N HCl and dried at 60°C for 2 days under reduced pressure to give 3-chloro-4-[N'~(2-methylphenyl)ureido]phenylacetic acid (1, 22 g, '100%) as a colorless powder. "H-NMR (DMSO-d*) 6.26 (s, 3H), 3.40 (s, 2H), 6.95 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.16 ( d, J= 7.3 Hz, 1H), 7.32 (s, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.94 (dd, J= 9.3, 1.0 Hz, 1H), 8.72 (s, 2H); MS (EST) m/z 319 (M<+>+1), 321 (MN-3), 341 (M^Na).

A mixture of. 3-Chloro-4-[A7'~ (2-methylphenyl) ureido] phenyl- . acetic acid (319 mg, 1.00 mmol), methyl 4-[ (4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (253 mg, 1.00 mmol), EDC-HCl (288 mg, 1.50 mmol ), HOBt (203 mg, 1.50 mmol) and Et 3 N

(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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/acetone (5/1)] to give methyl 4-[1-[3-chloro-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]-(4S)-fluoro -(2S)-pyrrolidine-

nyl] methoxybenzoate (4-80 mg, 87%) as a colorless amorphous solid. 'H-NlvIRCCDClj) 6 2.10-2.60 (m, 2H), 2.29 (s, 3H), 3.56 (d, J= 6.8 Hz, 1H), 3.71-3.84 (m, 1H), 3.87 and 3.89 (each s, 3H,one of isomers), 3.91-4.20 (m, 3H), 4.49-4?60 (m, 2H), .5.32 (dt, J = 53.0, 4.2 Hz, 1H), 6.80 (br, 1H) , 6.89 and 16.95 (each d, J= 8.8 Hz, 2H, amide isomers), 7.09-7.26 (m, 6H), 7.50 (d, J = 7.3 Hz, 1H), 7.94 and' 8.00 (each, J= 8.8 Hz, 2H, amide isomers];;*.. 10 and' 8.15 (each d, J= 8.3 Hz, 1H, amide isomersD.; MS (FAB) m/ z 554 .(tvT+lj, 556 ( rvf+3).

To a solution of methyl 4-[1-[3-chloro-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-( AS )-fluoro-( 2 S )-pyrrolidinyl]-methoxybenzoate (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 reduced pressure and acidified with 1 N HCl. The precipitates were collected, washed with water and dried under reduced pressure to give 90 (374 mg, 80%) as a colorless powder. Molecular weight 539.98.. ER. (KBr) 3354, 3060, 2976, 1709, 1604, 1244 cm"<1>; 'H-NMR (DMSO-d*) 6 2.27 (s, 3H), 2.31 (s, 2H), 3.66 (d, J = 7.2 Hz,' 2H),\3.71-4;67 (m, 5H), 5.32-5.53 (m, 1H), 6.97 (t, J= 7.3 Hz, 1H), 7.04-7.22 (m, 5H), 7.32 and 7.35 (each d, J= 1.7 Hz, .1H, amide isomers)., 7.77 (d, J= 7.6 Hz, 1H), 7.87 and 7.90 (each. d,'J= 9.0 Hz . -8.65 (each s, 1H, amide-' isomers^ 12.63 (s, 1H);. MS (ESI) m/ z 540 (M<+>+1), 542 (M<*>+3).

EXAMPLE 80

4-[1-[3-chloro-4-[ N'-(2-chlorophenyl)ureido] phenylacetyl]-{AS)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 mL, 5.01 mmol) in THF (20 mL) was added Et3N (0 .14 ml, 1.00 mmol) at room temperature. After stirring for 1 day, 2-chlorophenyl isocyanate (0.60 mL, 5.01 mmol) was added to the reaction mixture which was stirred for 17 h. The reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give methyl 3-chloro-4-[N'~ (2-chlorophenyl)ureido]phenylacetate

(1.35 g, 76%) as a colorless powder. 1 H-NMR (CDCl 1 ) 6 3.58 (s, 3H), 3.71

(s, 2H), .7.04 (m, 3H), 7.18 (dd, J= 8.5, 2.0 Hz, 1H), 7.27-7.39 (m, 3H), 8.07 (m, 2H); MS (ESI) m/z 353 (M<*>+1), 355 (M*+3), 357 (M<*>+5).

To a stirred solution of methyl 3-chloro-4-[AJ'-(2-chlorophenyl)ureido]phenylacetate (1.35 g, 3.82 mmol) in THF (30 mL) was added 0.25 N NaOH ( 30 ml). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1N HCl and dried at 60°C for 2 days under reduced pressure to give 3-chloro-4-[AJ'-(2-chlorophenyl)ureido]phenylacetic acid (1.12 g, 86%) as a colorless powder. 1H-NMR (DMSO-dJ 8 3.52 (s, 2H), 7.05 (m, 1H), 7.17 (d/J - 8.5 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.37 (s , 1H), 7.46 (dd, J= 8.0,1.5 Hz, 1H), 7.95 (dd, J= 8.3,1.2 Hz, 1H), 8.07 (d, J= 8.3 Hz, 1H)? 9.00 (d, J= 8.0 Hz, 2H); MS (FAB) m/z 339 (MT+1), 341 (MN-3), 343 (MN-5).

A mixture of 3-chloro-4-[AJ'-(2-chlorophenyl)ureido]phenylacetic acid (339 mg, 1.00 mmol), methyl 4-E (2S) , (4S)-4-fluoro-2- pyrrolidinyl]methoxybenzoate (253 mg, 1.00.mmol), EDC-HC1

(2 88 mg, 1.5 0 mmol), HOBt (2 03 mg, 1.50 mmol) and Et3N

(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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /acetone (10/1)] to give methyl 4-[1-[3-chloro-4-[AJ'-(2-chlorophenyl)ureido]phenylacetyl]-(4S )-fluoro-(2 S )-pyrrolidinyl]methoxybenzoate (550 mg, 96%) as a colorless amorphous solid.

'H-NMR (CDCl1)o 2.14-2.64 (m, 2H), 3.59 (d, J= 11.2 Hz, 2H), 3.78-3.82 (m, 1H), 3.86 «gf 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, J= 52.5,4.4- Hz, 1H, ■amide isomers), 6.89-6.98 ( m, 3H), 7.09-7.13 (m, 2H), 7.22 (dt J = 7.3, 2.2 Hz, 1H), 7.29 (dd, J= 8.1, 2.0 Hz, 1H), 7.79 .and 7.86 (each, 1H, amide isomers), 7.86-8.03 (m, 4H), 8.11 (dd, J= 8.3, 1.0 Hz, 1H); MS (FAB) m/z 574 (MN-1), 576 (M<*>+3)("578 GvT+5).

To a solution of methyl 4-[1-[3-chloro-4-[AJ'-(2-chlorophenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]-methoxybenzoate (550 mg, 0.957 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 reduced

pressure and acidified with 1. N HCl. The precipitate was collected, washed with water and dried under reduced pressure to give 91

(43.7 mg, 82%) as a colorless powder. Molecular weight 560.40. IS (KBr) 3348, 3072, 2954,1703, 1604,1529,1439 cnv'; 'H-NMR (DMSOd,) 8 2.25-2.42 (m, 2H), 3.67 (d, J=8.3 Hz, 2H), 3.81-4.68 (m, 5H), J.39 and 5.46 (each d, J = .54.4 Hz, 1Ht&nide-' isomers), 7.04-7.10 (m, 3H), 7.18 (d,J = 8.3 Hz, 1H), 7.31 (t, i = 8.3 Hz,,1H), 7.33 and 7.37 (each

■ X^lH,|the amide isomer), 7.47 (d, J= 8.1 Hz, 1H), 7.88 (dd] J= 9.0, 3.2 Hz, 2H); 7. 9^( yy, J= 8.5, 3.0 Hz, 1H) m, 1H), 8.09 (d, J= 8.3 Hz, 1H), 8.99 (d, J= 2.9 Hz, 1H), 9.02 (s, 1H ), 12.64 (s, 1H); MS (ESI) m/z 560 (M*+.1), 562 (M*+3), 564 (M*+5); Calculated fbrCnHj.C^FNsOj-O^^O: C,

57.50; H, 4.36; N, 7.45; Cl, 12.57; F, 3.37. Found: C, 57.72; H > 4.47; N, 7.14; Cl, 12.44; F, 3.44.

EXAMPLE 81

4- [1- [4- [AJ'-(2-bromophenyl)ureido]-3-chlorophenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 mL, 5.01 mmol) in THF (20 mL) was added Et3N (0 .14 ml, 1.00 mmol) at room temperature. After stirring for 1 day, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture which was stirred for 24 hours. The reaction mixture was concentrated in

. vacuum. The residue was triturated by adding n-hexane to

to give methyl 4-[AJ'-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1 H-NMR (CDCl 3 ) δ 3.58 (s, 3H), 3.70 (s,

2H), 6.98 (m, 3H), 7.19 (dd, J= 8.3,' 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H), 8.05 (m, 1H); MS (ESI) m/z 398 (M*+1), 400 (^+3), 402 (MT+5).

To a stirred solution of methyl 4-[AJ'-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 3.37 mmol) in THF (30 mL) was added 0.25 N NaOH (3 0 ml). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1 NHCl and dried at 60°C for 2 days under reduced pressure to give 4-[N'~(2-bromophenyl)ureido]-3-chlorophenylacetic acid (1.03 g, 80%) as a colorless powder. 1H-NMR (DMSO-d«) 8 3.56 (s, 2H), -7.00 (m, IH), 7.17 (dd, J= 9.0, 1.7 Hz, IH), 7.32-7.40 (m, 2H), 7.62 (dd, J= 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 (M<+>+2),386(M<*>+4),388 Ovf+6). A mixture of 4-[N-(2-bromophenyl)ureido]-3-chlorophenylacetic acid (384 mg, 1.00 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoate. (253 mg, 1.00 mmol), EDC-HCl (288 mg, 1.50 mmol), HOBt (203 mg, 1.50 mmol) and Et3N (0.70 mL, 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 15 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/acetone (10/1) ] to give methyl 4-[1-[4-[W-(2-bromophenyl)ureido]-3-chlorophenylacetyl]-(4S) -fluoro-(2S)-pyrrolidinyl] methoxybenzoate (530 mg, 86%) as a colorless amorphous solid. 'H-NMR (CD.C13) 8 2.14-2/63 (m, 2H), 3.58 (d, J= 10.0 Hz, IH), 3.73-3.83 (m, IH), 3.86 and 3.89 (each s . )^,.ll- l.U (m2H),'7.26 (m, IH), 7.46 (d,/- 8.1Hz, IH), 7.62-7.78 (m, 2H), 7.89 and 7.93 (each an , 2H,amide isomers}, 8.01 (dd, J= .

8.8, 1.7 Hz, 2H); MS (FAB) m/z 618.0^, 620 622 (M<*>+4).

To a solution of methyl 4-[1-[4-[N-(2-bromophenyl)ureido]-3-chlorophenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (530 mg, 0.856 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 reduced pressure and acidified with 1N HCl. The mixture was extracted with CHCl 3 /MeOH (10/1). The combined extracts were washed with ice water and saline. After drying over Na2S04. the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [20 g, CHCl 3 /acetone (10/1)-CHCl 3 /MeOH (10/1)] to give 92 (59 mg, 11%) as a colorless amorphous solid. Molecular weight 604.85..

IR (KBr) 3329, 3060, 2976, 1712, 1526, 1435 cm"<1>; 'H-NMR (DMSO-d<) 8 2.31 (m,H), 3.48-4.68 (in, 7H), 5.32- 5.53 (m, IH), 6.99-7.19 (m, 4H), 7.36 (s, IH), 7.63 (dd, J = 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 (ESI) m/z 604 (M<*>+l), 606 (rvT+3), 608 ^^ 5)\ Anal. BVegnet 'forQ7H„BrClFN3O3-0.5H3O: C, 52.83; H, 4.10; N, 6.85; Cl, 5.78; F, 3.09. Found: C, 53.24; ..H, 4.32; N, 6.43; Cl, 6.01; F, 3.07.

EXAMPLE 82

4-[1-[3-chloro-4(AT'-phenylureido)phenylacetyl-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a mixture of methyl 4-amino-3-chlorophenylacetate (1.31 g, 6.56 mmol) and phenyl isocyanate (0.71 mL, 6.56 mmol) in THF

(20 mL) was added Et 3 N (0.19 mL, 1.33 mmol) at room temperature. After stirring for 15 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give methyl 3-chloro-4-(N'-phenylureido)phenylacetate (1.79 g, 86%) as a pale brown solid. •

1 H-NMR (CDCl,) δ 3.56 (s, 2H), 3.70 (s, 3H), 6.70 (m, 1H), 7.06 (s, 1H), 7.14-7.18 (m, 2H), 7.26 (dd, J = 7.8, 1.9 Hz, 1H), 7.33-7.38 (m, 4H), 8.14 (dd, 7= 8.3, 3.0 Hz, 1H); MS (ESI) m/z 319 (M<*>+1), 321 (M<N>-3).

To a stirred solution of methyl 3-chloro-4-(Δ7'-phenylureido)phenylacetate (1.79g, 5.62mmol) in THF (30ml) was added 0.25N NaOH (30ml ). After stirring at room temperature for 20 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1 N HCl and dried at 60°C for 2 days under reduced pressure to give 3-chloro-4-(Δ7'-phenylureido)phenylacetic acid (1.58 g, 92%) as a pale brown

solid.

1H-NMR (DMSO-dJ 6 3.55 (s, 2H), 6.99 (t, J

= 7.3 Hz, IH), 7.17 (d, J- 8.3 Hz, IH), 7.29 (t, J= 7.6 Hz, 2H), 7.36 (s, IH), 7.46 (d, J= 8:0 Hz, 2H ), 8.07 (d, J- 8.3 Hz, IH), 8.28 (s, IH), 9.37 (s, IH), 12.37 (br, IH).

A mixture of 3-chloro-4-(AJ'-phenylureido)phenylacetic acid (305 mg, 1.00 mmol), methyl 4-[(2S,4S)-4-fluoro-2-pyrrolidinyl]-methoxybenzoate (253 mg, 1.00 mmol), EDC-HCl (288 mg, 1.50 mmol), HOBt (203 mg, 1.50 mmol) and Et3N (0.70 mL, 5.00 mmol)

in DMF (4 mL) was stirred at room temperature for 17 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [30 g, CHCl3/acetone (20/1)] to give methyl 4-[1-[3-chloro-4-(N'-phenylureido)phenylacetyl-(4S)'-fluoro- ( 2S )-pyrrolidinyl]-methoxybenzoate (720 mg, 100%) as a colorless amorphous solid. MS (FAB) m/z 540 (M++1), 542 (M+ + 3).

To a solution of methyl 4-[1-[3-chloro-4-((AJ'-phenylureido)phenylacetyl-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (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 removal of the solvent, the obtained residue was acidified with 1 N HCl. The precipitates were collected, washed with water and dried under reduced pressure to give 93 [412 mg, 78% (2 steps)] as a colorless powder. Molecular wt.. 525.96. IR (KBr) 3346, 3302, 2976, 1712, 1604,

1240 cm-<1>; 1H-NMR (DMSO-dj) δ 2.25-2.31 (m, 2H), 3.66 (d, 7.8 Hz, 2H), 3.71-4.67 (m, 5H), 5.31-5.52 (m, 1H), 6.99 (t , J = 7.3 Hz, IH), 7.04 and 7.07 (respectively d, J = 8.7 Hz, 2H, amide isomerb, 7.14-7.18 (m, IH), 7.29 (t, J= 7.3 Hz, 2H), 7.35 ( d, J= r-7 Hz, IH), 7.46 (d, J= 7.8 Hz, 2H), 7.87-.and 7.90 (each é, J= 9.0 Hz, 2H,amide isomers), 8.04 and 8.06 (each d, J= 8.5Hz, IH, amide-i isomers), *.26 6g 8;'28 (each, ■IH.kWisomers), 9;i36 (s, IH), 12.63 (s, IH); MS (ESI) m/ z 526 Ovf+1), 528 0^+ 3) ;, Anal ^r^BrCz^CIFNA-0.5H,O: C, 60.62; H, 4.90; N, 7.85; Cl, 6.63; F, 3.55. Found: C, 61.00; H, 5.19; N, 7.40; Cl, 6.66; F, 3.39.

EXAMPLE 83

4-[1-[3-bromo-4-[AT-(2-methylphenyl)ureido)phenylacetyl-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid'

To a stirred solution of 3-bromophenylacetic acid (10.2 g, 47.4 mmol) in dichloroethane (50 mL) was added MeOH (5.8 mL, 142 mmol) and H 2 SO 4 (0.5 mL) at room temperature. After 20 min. stirring, the mixture was heated at 80°C for 7 hours. The reaction mixture was poured into ice water and extracted with CHCl 3 . The combined extracts were washed with aqueous NaHCO 3 and brine. After drying over Na2SO4, the extracts were concentrated in vacuo to give methyl 3-bromophenylacetate

(10.8 g, 99%) as a colorless oil.

1 H-NMR (CDCl 3 ) δ 3.60 (s, 2H), 3.71 (d, J = 1.0 Hz, 3H), 7.18-7.44 (m, 4H).

To a stirred mixture of methyl 3-chlorophenylacetate (10.8 g, 47.1 mmol) in H 2 SO 4 (15.1 mL) was added HN0 3 (2.8 mL, 70.7 mmol) at 0°C. The reaction mixture was gradually warmed to room temperature over 5.5 hours. The reaction mixture was poured into ice water and extracted with CHCl 3 . The combined extracts were washed with aqueous NaHCO 3 and brine. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [500 g, n-hexane/EtOAc (10/1)] to give methyl 3-bromo-4-nitrophenyl acetate (3.69 g, 29%) as a yellow oil.

1H-NMR (CDCl 3 ) 6 3.68 (s, 2H), 3.73 (s, 3H), 7.38 (dd, J= 8.3, 1.2 Hz, 1H), 7.67 (d, J = 1.3 Hz,

1H), 7.83 (d, / - 8.3 Hz, 1H).

A mixture of methyl 3-bromo-4-nitrophenyl acetate (14.8 g, 53.8 mmol), reduced iron powder (9.62 g, 172 mmol), AcONa"3H2O (7.32 g, 53.8 mmol) and AcOH ( 20.0 mL) in MeOH/H 2 O (150/600 mL) was heated at 90°C for 1 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and the filter cake was washed with MeOH. The combined filtrate was evaporated and extracted with EtOAc The extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [400 g, CHCl 3 /EtOAc (20/l)] to give methyl 4-amino-3-bromophenyl acetate (9.01 g, 69%) as a brown oil. 1H<->NMR (CDCl 3 ) δ 3.48 (s, 2H), 3.68 (s, 3H), 4.05 (br, 2H), 6.69 (d, J= 8.3 Hz, IH), 7.00 (dd, J= 8.1, 2.0 Hz, IH), 7.32 (d, J = 2.0 Hz, IH).

To a mixture of methyl 4-amino-3-bromophenylacetate (58 7 mg, 2.40 mmol) and 2-methylphenyl isocyanate (0.287 mL, 2.40 mmol) in THF (2 mL) was added Et3N (33 mL, 0 .24 mmol) at room temperature. After stirring for 21 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by addition of n-hexane to give methyl 3-bromo-4-(Δ7r-(2-methylphenyl)ureido)phenylacetate (650 mg, 72%) as a pale brown powder. 1 H-NMR (CDCl 3 ) 82.34 (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, 1H), 7.30 (d, / = 7.3 Hz, IH), 8.19 (d, J= 8.3 Hz, IH); MS (ESI) m/z 377 (M<*>), 379 (M<*>+2).

To a stirred solution of methyl 3-bromo-4-[N1-(2-methylphenyl)ureido]phenylacetate (650 mg, 1.72 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL ). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1 N HCl and dried at 60°C for 2 days under reduced pressure to give 3-bromo-4-[ N' -(2-methylphenyl)ureido]phenylacetic acid (1.22 g , 100%) as a colorless powder. 'H-NMR(DMSO-d^) 8 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, 1H); MS (ESI) m/z 385 (MH-Na), 3 87 (M<*>+2+Na).

A mixture of 3-bromo-4-[N-(2-methylphenyl)ureido]phenylacetic acid (80 mg, 0.22 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (56 mg, 0.22 mmol), EDC-HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol) and Et3N (0.15 mL, 1.10 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. ' The residue was purified on TLC [CHCl3/acetone (5/1)] to give methyl 4-[1-[3-bromo-4-[A7'-(2-methylphenyl)-ureido]phenylacetyl]-(45) -fluoro-(2S)-pyrrolidinyl]methoxybenzoate (140 mg, 100%) as a yellow oil.

1 H-NMR (CDCl 3 ) δ 2.30 (s, 3H),

2.55 (m, 1H), 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<*>+1), 600 (M++3).

To a solution of methyl 4-[1-[3-bromo-4-[AJ'.-(2-methylphenyl)ureido]phenylacetyl]-(45)-fluoro-(25)-pyrrolidinyl]-methoxybenzoate (140 mg, 0.22 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL). After stirring at room temperature for 14 hours, the mixture was concentrated under reduced pressure and acidified with 1 N HCl. The precipitates were collected, washed with water and dried under reduced pressure to give 94 (109 mg, 85%) as a colorless powder. Molecular weight 584.43.

IR (KBr) 3313, 3060, 2976, 1687, 1604, 1525, 1244 cm-<1>; 1 H-NMR (DMSO-d^ 8 2.27 (s, 3H), 2.29 (ra, 2H), 3.66^ J= 8.1 Hz, 2H), 3.72-4.68 (iri, 5H), 5.31-5.53 (m, IH ), 6.91-6.99 (m, IH), 7.04 and 7.07 (respectively, /== 8.3 Hz, 2H, amide isomers!), 7.11-7.21 (m, 3H), 7.48 and 7.51 (s, IH, amide- ;isomers), 7.75 and 7.79 (each d, J= 8.1 Hz, IH, amide isomersj", 7.86-7.92 (m, 3H), 8.45

and 18.47 (each: s, 1H, amide isomerjj, 8.59 (s, 1H), 12.64 (s, 1H); MS (FAB) m/z 584 (MM-1), 586

(M*+3); Anal, Birégr.érfbrC„H 2 1 BrFN 3 O 3 : C, 57.54; H, 4.66; N, 7.19; Br, 13.67; F, 3.25. Found:<1 >C, 57.93; H, 4.97; N, 7.04; Bro, 1:35 p.m.; F, 2.89.

EXAMPLE 84

4- [1- [3-bromo-4- [AJ'-(2-chlorophenyl)ureido] phenylacetyl-(45)-fluoro-(2S)-pyrrolidinyl] methoxybenzoic acid

To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-chlorophenyl isocyanate (0.29 mL, 2.40 mmol) in THF

(2 mL) was added Et 3 N (33 mL, 0.24 mmol) at room temperature. After stirring for 21 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of

n-hexane to give methyl 3-bromo-4-[ N'~ (2-chlorophenyl)ureido]-phenylacetate (710 mg, 74%) as a pale brown powder.

1 H-NMR (CDCl 3 ) δ 3.57 (s, 2H), 3.70 (s,

3H), 7.02-7.28 (m, 2H), 7.36 (d, J= 6.8 Hz, 1H), 7.48 (s, 1H), 8.00-8.11 (m, 2H); MS (ÉSI) m/z 3 97 (M<*>), 3 99 (M<*>+2), 401 (M<*>+4).

To a stirred solution of methyl 3-bromo-4-[N-(2-chlorophenyl)ureido]phenylacetate (710 mg, 1.79 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL) . After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1N HCl and dried at 60°C for 2 days under reduced pressure to give 3-bromo-4-[ N'~ (2-chlorophenyl)ureido]phenylacetic acid (643 mg, 94% ) as a colorless powder. <»>H-NMR(DMSO-dj) 83.56 (s, 2H),

7.05 (m, IH), 7.21 (dd, 7= 8.6, 1.7 Hz, IH), 7.29 (t, J= 7.8 Hz, IH), 7.46 (d, J= 8.1 Hz, IH), 7.46 (d, J = 8.1 Hz, IH), 7.53 (d, J= 1.7 Hz, IH), 7.83 (d, J = 8.3 Hz, IH), 8.06 (d, J= 7.6 Hz, IH), 8.86 (s, IH), 8.89 (p, IH), 12.40 (p, IH); MS (ESI) m/z 382 (M<*>+1), 384CMT+3).

A mixture of 3-bromo-4-[N-(2-chlorophenyl)ureido]phenylacetic acid (384 mg, 1.00 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate ( 253 mg, 1.00 mmol), EDC-HCl (288 mg, 1.50 mmol), HOBt (203 mg, 1.50 mmol) and Et3N (0.70 mL, 5.00 mmol) in DMF (4 mL ) was stirred at room temperature for 18 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [30 g, CHCl 3 /acetone (10/1)] to give methyl 4-[1-[3-bromo-4-[ N'~ (2-chlorophenyl) ureido] phenylacetyl] - ( 4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoate (640 mg, 100%) as a colorless amorphous solid.

1H-NMR (CDCl 3 ) 6 2.07-2.46 (m, 2H), 2.59 (t, J= 18.4 Hz, 1H), 3.57 (d, 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, 7=^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 solution of methyl 4-[1-[3-bromo-4-[W-(2-chlorophenyl)ureido] phenylacetyl] - (4S) -fluoro-(2S) -pyrrolidinyl] - methoxybenzoate (640 mg, 1, 00 mmol) in THF (40 ml) was added 0.25 N NaOH (40 ml). After stirring at room temperature for 14 hours, the mixture was concentrated under reduced pressure and acidified with 1 N HCl. The precipitates were collected, washed with water. and dried under reduced pressure to give 95 (522 mg, 86%) as a pale yellow powder. Molecular weight 604.85.

IR (KBr) 3317, 3072, 1709, 1685, 1604, 1529, 1290 cm"1; 'H-NMR pMSO-d*) 5 2.24-2.50 (rn, 2H), 3.67 (d, J= 8.3 Hz, 2H ), 3.73-4.68 (m, 5H), 5.31-5.52 (m, IH), 7.03-7.09 (m, 3H), 7.22 (dt,J=. 8.3, 1.7 Hz, IH), 7.30 (d„j^ 7.3 Hz, -IH), 7.46 (dd, J= 8.0, 1.4Hz, IH), 7.49 and 7.52 (hvér'd,^= 2.0 Hz, IH, amide isomers)," 7.80-7.91 (m, 3H) , 8-.07 (dd, J= 8.3,1.2 Hz, IH), 8.85 • and'[8.86 (reverse, IH, amide isomers), 8.96 and''8.97 (whose, IH,amide isomer), 12.62 (s, 1H);

MStFAB) m/z 605 (MN-1), 607 (M*+3), 609 (MM-3), 626 (M^+1+Na); Anal., Calculated for Q^BrCIFNjOj-O.SHiO: C, 52.37; H, 4.17; N, 6.79; F, 3.07. Found: C, 52.63; H, 4.12; N, 6.62;

F, 2.97.

EXAMPLE 85

4-[1-[3-bromo-4-[AT-(2-bromophenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 mL, 2.40 mmol) in THF (2 mL) was added Et3N (33 mL , 0.24 mmol) at room temperature. After stirring for 4 hours, the reaction mixture was concentrated in vacuo. "The remainder was triturated by the addition of

n-hexane to give methyl 3-bromo-4-[AT'-(2-bromophenyl)ureido]-

in phenylacetate (770 mg, 73%) as a pale brown powder.

1H-NMR (CDCl 1 ) 6 3.55 (s, 2H), 3.70 (s,

3H), 6.97 (dd, /= 7.3, 1.5 Hz, IH), 7.22 (dd, J= 8.5, 2.2 Hz, IH), 7.29-7.33 (m, 2H), 7.48 (d, J = -1.0, 2.2 Hz, IH), 7.54 (dd, /= 8.0, 1.2 Hz, IH), 8.01 (m, 2H); MS (ESI) m/z 443 (M<*>+1), 445 (M++3), 447 Qv<T>+5).

To a stirred solution of methyl 3-bromo-4-[AT'-(2-bromophenyl)ureido]phenylacetate (770 mg, 1.74 mmol) in THF (10 mL) was added 0.25 N NaOH (10 mL ). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by addition of 1 N HCl and dried at 60°C ~ for 2 days under reduced pressure to give 3-bromo-4-[AT'-(2-bromophenyi ) ureido]; f enylacetic acid (702 mg, 94%) gave a colorless powder.

6.99 (dt,J = 7.8, 1.5 Hz, IH), 7.21 (dd,./ = 8.3,1.7Hz, IH), 7.33 (dt,7= 7.1,1.5Hz, IH),7.53 (d, J= 1.7 Hz, IH), 7.62 (dd, /= 8.1,1.5 Hz, IH), 7.82 (d, J= 8.3 Hz, IH), 7.93 (dd, 7 = 8.1,1.5 Hz, IH), 8.82 (s, IH ), 8.86 (s, IH), 12.39 (s, IH); MS (ESI) m/z 428 (M^+1), 430(MM-3),

A mixture of 3-bromo-4-[AT'-(2-chlorophenyl)ureido]phenylacetic acid (428 mg, 1.00 mmol), methyl 4-[(2S,.4S)-4-fluoro-2 -pyrrolidinyl] methoxybenzoate (253 mg, 1.00 mmol), EDC-HCl (288 mg, 1.50 mmol), HOBt (203 mg, 1.50 mmol) and Et3N (0.70 mL, 5.0 0 mmol ) in DMF (4 mL) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [30 g, CHCl 3 /acetone (10/1)] to give methyl 4-[1-[3-bromo-4-[AT'-(2-bromophenyl)ureido]phenylacetyl]-( 4S)-fluoro-(2S)-pyrrolidinyl] methoxybenzoate j(72.Q mg-, 10.0%) as a colorless amorphous solid.

■H-NMR (CDCl3) 5 2.07-2.45 (m, 2H), 2.58 (m, 1H), 3.58 (d, J= 9.0 Hz, 2H), 3.63-4.69 (m, 9H), 5.26-5.43 (m , IH), 6.88-6.99 (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/z 664 (M<*>), 666 (M<*>+3), 668 (JvT+5).

To a solution of methyl 4-[1-[3-bromo-4-[AT'-(2-bromophenyl)ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinyl]-methoxybenzoate (720 mg, 1 .00 mmol) in THF (40 mL) was added 0.25 N NaOH (40 mL). After stirring at room temperature for 14 hours, the mixture was concentrated in vacuo and acidified with 1 N HCl. The mixture was extracted with CHCl 3 /MeOH (10/1). The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [20. g, CHCl3/acetone (10/1)-CHCl3/MeOH (20/1) and triturated by addition of ether to give 96 (489 mg, 75%) as a colorless amorphous solid. Molecular weight 649.30.

TR (KBr) 3450, 3313, 3070, 1709, 1684, 1525, 1435 cm -1 ;

1H-NMR (DMSp-d«) δ 2.25-2.50 (m, 2H), 3.67 (d, J= 8.3 Hz, 2H), 3.73-4.68 (m, 5H), 5.31-5.53 (m; 1H), 6.98-7.08 (m, 3H), 7.21 (d, J= 8.2 Hz, IH), 7.34 (t, J= 8.8 Hz, IH), 7.50 and 7.53 (each s, IH, amide isomers), 7.62 ( , J= 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<*>+1), 652 (MM-3), 654 (M<+>+3), 672 (M**Na;M.Mff7.tereg^ C, 48.73 ; H, 3.91; N, 6.31; F, 2.85. Found: C, 48.96; H, 3798; N, 5.92; F, 2.77.

EXAMPLE 86

4- [1- [4- [ N'-(2-methylphenyl)ureido]-2, 3-difluorophenylacetyl]-

(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of tert-butyl ethyl malonate (5.35 mL, 28.2 mmol) in DMF (150 mL) was added NaH (60% in oil, 3.38 g, 84.7 mmol) at room temperature. After 20 min. 2,3-difluoronitrobenzene (5 g, 28.2 mmol) in DMF (50 mL) was added dropwise via a dropping funnel. After addition, the mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and saturated NH 4 Cl (100 mL). The mixture was extracted with EtOAc and the combined organic layer was washed with 1M HCl and brine, dried over MgSO 4 , filtered and concentrated. The residue was dissolved in dichloromethane (20 mL) and

added TFA (20 ml) at room temperature. The mixture was heated at reflux for 18 hours. The mixture was evaporated in vacuo and co-evaporated with toluene (20 mL x 2). The rest stayed

chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, d) 50 mm x 300 mm-, 15 ml/min) to give ethyl 2,3 -difluoro-4-nitrophenylacetic acid (5.85 g, 85%) as a yellow oil.

1H-NMR (CDC13) 6 1.30-

(m, 3H), 3.78 (s, 2H), 4.22 (m, 2H), 7.22 (m, 1H), 7.84 (m, 1H); MS (FAB) m/z 246 (M<*>+1).

To a stirred solution of ethyl. 2,3-difluoro-4-nitrophenyl acetate (5.85 g, 23.9 mol) in EtOH" (100 mL) was added SnCl2 (16.1 g, 71.6 mmol) at room temperature. Stirring was continued for 18 hours at reflux After removal of the solvent, the residue was dissolved in CHCl3 (100 mL) and poured into ice-water-4 M NaOH (40 mL 4 M NaOH in 300 mL ice water), extracted with CHCl3 (100 mL x 2), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (medium pressure chromatography system YAMAZEN YFLC-5404, linear, gradient of hexane-EtOAc from 9:1 to 7:3,

(J > 50 mm x 500 mm, 15 mL/min.) to give ethyl 4-amino-2,3-difluorophenylacetic acid (1.94 g, 38%) as a colorless oil.

1 H-NMR (CDCJg) 8

1.25 (t, J= 7.3 Hz, 3 H), 3.55 (d, /= 1.0 Hz, 2 H), 3.78 (brs, 2 H), 4.15 (dd, J= 7.2 Hz, 14.2 Hz, 2 H), 6.49 (dt, J= 1.8, 8.2 Hz, 1 H), 6.78 (m, 1 H); MS (FAB) m/z 216 (M*+1).

To a stirred solution of ethyl 4-amino-2,3-difluorophenyl acetate (323 mg, 1.5 mmol) in DMF (8 mL) was added triethylamine (0.209 mL, 1.5 mmol) and 2-methylphenyl isocyanate ( 0.372 mL, 3.0 mmol) at room temperature. Stirring continued for 48 hours at 80°C. The reaction mixture was evaporated in vacuo and the solid was suspended in n-hexane. The solid was collected by filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL) and 4 M NaOH was added

(10 ml) at room temperature. Stirring was continued for 18 hours at room temperature.' The reaction mixture was poured into 1 M HCl and the resulting precipitate was collected by filtration. The solid was recrystallized with CHCl 3 -n-hexane to give 4-[(2-methylphenyl)ureido]-2,3-difluoroenylacetic acid (200 mg, 42%) as a white solid.

1H-NMR (CDCl1) 6 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 Hzi 2 H ), 7.69 (d, J = 8.1 Hz, 1H), 7.90 (m, 1H); MS (FAB) m/z 321 (MM).

To a stirred solution of methyl 4-(4S-4-fluoro-2-pyrrolidinyl) methoxybenzoate (63 mg, 0.25 mmol) and 4-[ N'~ (2-methylphenyl)ureido]-2,3-difluorophenylacetic acid ( 82 mg, 0.25 mmol) i

To DMF (5 mL) was added EDC-HCl (72 mg, 0.38 mmol), HOBt

(69 mg, 0.48 mmol) and DMAP (cat.) and stirring was continued

overnight at room temperature. The mixture was diluted with EtOAc (50 mL), washed with 1 M NaOH, 1 M HCl and brine, dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was dissolved in THF-MeOH-H 2 O (21 mL, 1:1:1, v/v/v) and stirring was continued for 6 h at room temperature. The mixture was poured into 1 M HCl and extracted with CHCl 3 -MeOH (9:1, v/v). The combined organic phase was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by TLC (Whatman, PLK-5F, CH.Cl 3 /MeOH, 20:1, v/v) to give 97 (69 mg, 51%) as a white powder. Molecular weight 541.52. IR (KBr) 3340, 1604,1540,1251,1168, 754 cm"<1>; 1H-NMR (DMSO-ds) δ 2.25 (s, 3 H), 2.32 (m, 2 H), 3.68; 4.40 (m, 7 H), 5.32-5.55 (m, 1 H), 6.98 (m, 2 H), 7.05 (d, J= 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2 H), 7.82-7.92 (m, 2 H), 8.40 (s, 1 H), 9.14 (s, 1 H); MS (ESI) m/ z 564 (M^+Na); Anal. Calculated for, C1.Hj4F3N3Oj- 2.OH 2 O: C, 58.23; H, 5.24; N, 7.28. Found C, 58.07, H, 4.84; N, 7.03.

EXAMPLE 87

4-[1-[4-[ N'~ (2-methylphenyl)ureido]-2,5-difluorophenylacetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of di-tert-butyl ethyl malonate

(6.32 mL, 28.2 mmol) in DMF (150 mL) was added NaH (60% in oil, 3.38 g, 84.7 mmol) at room temperature. After 20 min. was 2,5-difluoronitrobenzene (5 g, 28.2 mmol) in DMF. (50 ml) added dropwise via a drop funnel. After addition, the mixture was stirred for 3 hours at room temperature. The mixture was poured into ice-water and saturated NH 4 Cl (100 mL). The mixture was extracted with EtOAc and the combined organic layer was washed with 1M HCl and brine, dried over MgSO 4 , filtered and concentrated. The residue was dissolved in dichloromethane (20 ml) and TFA (20 ml) was added at room temperature. The mixture was heated at reflux for 18 hours. The mixture was

evaporated in vacuo, and co-evaporated with toluene (20 mL x 2). The residue was dissolved in MeOH (150 mL) and concentrated H 2 SO 4 (5 mL) was added. The mixture was heated at reflux for 18 hours. The mixture was diluted with EtOAc (300 mL) and washed with water, 1M HCl and brine and dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-54 04-FC, linear gradient hexane-EtOAc 10:0 to 1:1, (j) 50 mm x 300 mm, 15 mL/min.) to give ethyl 2,5-difluoro- . 4-ni tro f phenylacetic acid (6.53 g," 9.0%) as a yellow oil.

•H-NMR (CDCl1) δ 3.75 (s, 219,3.76.(5.3 H), 7.29 (dd, J= 5.8 Hz, 10.5 Hz, 1 H), 7.81 (dd,' J = 6.0 Hz, 8.4 Hz, 1 H); MS (ESI) m/z 232 (M<*>+1).

To a stirred solution of ethyl 2,5-difluoro-4-nitrophenyl acetate (5.88 g, 25.4 mol) in EtOH (100 mL) was added SnCl2 (17.2 g, 76.3 mmol) at room temperature. Stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCl 3 (100 mL) and poured into ice-water-4M NaOH (40 mL 4M NaOH in 300 mL ice-water), extracted with CHCl 3 (100 mL x 2), dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel (medium pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexane-EtOAc from 9:1 to 7:3, 50 mm x 500 mm, 15 mL/min.) to give ethyl 4- amino-2,5-difluorophenylacetic acid (2.85 g, 52%) as a colorless oil.

1 H-NMR(CDCl 3 ) 5

i:28 (t, J= 7.3 Hz, 3 H), 3.51 (s, 2 H), 3.78 (brs, 2 H), 4.15 (dd, J= 7.2 Hz, 14.2 Hz, 2 H), 6.47 (dd , J= 7.5,10.4 Hz, I H), 6.88 (dd, J= 6.7, 11.0 Hz, 1 H); MS (FAB) m/z 216 (M<+>+1).

To a stirred solution of ethyl 4-amino-2,5-difluoro-phenylacetate (323 mg, 1.5 mmol) in DMF (8 mL) was added triethylamine (0.209 mL, 1.5 mmol) and 2-methylphenyl isocyanate ( 0.372 mL, 3.0 mmol) at room temperature. Stirring was continued for 48 hours at 80°C. The reaction mixture was evaporated in vacuo and the solid was suspended in n-hexane. The solid was collected by filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL) and 4M NaOH (10 mL) was added at room temperature. Stirring was continued for 18 hours at room temperature. The reaction mixture was poured into 1M HCl and the resulting precipitate was collected by filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,5-difluorophenylacetic acid (214 mg, 46%) as a white solid.

1H-NMR (CDCl1) S 2.30 (s, 3 H), 3.35 (m, 2 H), 7.02 (m, 2 H), 7.18 (d, J =

7.3 Hz, 2 H), 7.69 (d, J= 7.8 Hz, 1 H), 8.03 (m, 1 H); MS (FAB) m/z 321 (M<*>+I).

To a stirred solution of. methyl. 4-[(45)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (63 mg, 0.25 mmol) and 2,5-difluoro-4-[A7'~ (2-methylphenyl)ureido]phenylacetic acid (82 mg, 0.25 mmol) in DMF (5 mL) was added EDC-HCl (72 mg, 0.38 mmol), HOBt (69 mg, 0.48 mmol) and DMAP (cat.), and stirring was continued overnight at room temperature. The mixture was diluted with EtOAc (50 mL), washed with 1M NaOH, 1M HCl and brine, dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was dissolved in THF-MeOH-H 2 O (21 mL, 1:1, v/v/v) and stirring was continued for 6 h at room temperature. The mixture was poured into 1M HCl and extracted with CHCl 3 -MeOH (9:1, v/v). The combined organic phase was dried over anhydrous MgSO 4 and concentrated under reduced pressure. The residue was purified by TLC (Whatman, PLK-5F, CHCl3/MeOH, 20:1, v/v) to give 98 (69 mg,

51%) as a white powder. Molecular weight 541.52 IR-ATR: 3351, '16'04, .1537, 1167, 754 (cm-1) ;

1 H-NMR (DMSO) δ 2.25 (s, 3 H), 2.32 (m, 2 H), 3.68-4.70

(m, 7 H), 5.32,5.55 (m, 1 H), 6.97(t, /= 7.6 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 2 H), 7.20 (m, 3 H) , 7.87 (d,J = 8.8 Hz, 2H), 7.83-8.04 (m, 2H), 8.45 (s, 1H), 9.18 (s, 1H); MS (ESI) m/z 564 (M++Na); Anal Calculated for 0,^.^^ 0^ 1. 15 H 2 O: C, 58.69; H, 5.19; N, 7.33. Found: C, 58.54, H, 4.85; N, 6.98.

EXAMPLE 88

4- [1- [4- [W-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-fluoro-2-pyrrolidinyl]methylaminobenzoic acid

4[1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-4-fluoro-2-pyrrolidinyl]methylaminobenzoic acid

To a stirred solution of methyl 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylate (1.2 g, 4.85 mmol) in MeOH

(5 mL) 1N NaOH (5 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, water was added thereto and neutralized with

IN HCl. The mixture was extracted with EtOAc. The extract was washed with water then dried over Na 2 SO 4 and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, quantitative) as a colorless oil.

1 H-NMR (CDCl 1 ) 6 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, 1H).

To a stirred solution of 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, 4.7 mmol) in THF (10.0 mL) was added BH3■ THF (1.0 M solution in THF, 10.0 mL, 10.0 mmol) at 0 °C. The mixture was then stirred at room temperature for 1.0 hour. After cooling, the mixture was concentrated in vacuo. Water was added thereto at 0°C and the mixture was extracted with EtOAc. The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl methanol (1.0 g, quantitative) as a colorless oil.

1 H-1 H NMR (CDCl 3 ) δ 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, 1H), 5.16 (brs, IH).

To a stirred solution of oxalyl chloride (0.28 mL, 2.3 mmol) in CH 2 Cl 2 (20.0 mL) was added DMSO (0.39 mL) at -78°C. After 5 min. 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (500 mg, 2.28 mmol) in CH 2 Cl 2 (5.0 mL) was added to the mixture. The mixture was stirred for 30 min. at -78°C and triethylamine (1.6 mL) was added. The mixture was stirred for 30 min. at -7 8°C and stirred for 30 min. at room temperature. Water was added to the mixture which was extracted with CH 2 Cl 2 . The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The impure product was used in the subsequent reaction without further purification. To the stirred solution of the crude product methyl 4-aminobenzoate (302 mg, 2.0 mmol) and AcOH (0.13 mL) in DCE (10 mL) was added NaBH(0Ac)3 (656 mg, 3.09 mmol) at 0°C. The reaction mixture. was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexaryl (1:3, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate

(541 mg, 77%) as a pale yellow oil.

1H-NMR (CDCl1) 6 1.55-1.59 (m, 1F& 2.16-2.27 (m, 1H), 2.89-3.03 (m, 2H),

r

3.19-3.28 (m, 2H), 3.69-3.73 (m, IH), 3.84 (s, 3H), 5.15 and 5.29 (each, total IH), 6.55-6.58 (m, 2H), 7.84-7.86 ( m, 2H).

To a stirred solution of methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate (541 mg, 1.53 mmol) in CH 2 Cl 2 (8.0 mL) was added TFA (4.0 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was. washed with saline, - dried over Na2S04 and concentrated in vacuo. The impure product was used in the subsequent reaction without further purification. To the stirred solution of the crude product (151 mg, 0.6 mmol), 4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid' (201 mg, 0.6 mmol), HOBt (94 mg , 0.7 mmol) and triethylamine (167 µl, 1.2 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl

(173 mg, 0.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. the extract'

was washed with saturated NaHCO 3 , 2M citric acid and saturated NaHCO 3 / then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) as eluent to give methyl 4-[1-[4-[Nr-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl ]-4-fluoro-2-pyrrolidinyl]methylaminobenzoate (320 mg, 94%) as an amorphous solid. 1H-NMR (CDCl 3 ) δ 1.80-1.95 (m, 1H), 2.42-2.58 (m, 1H), 3.20-3.51 (m, 3H), 3.51-3.76 (m, 5H), 3.84 (s, 3H) , 3.85-3.98 (m, IH), 4.67-4.70 (m, IH), 5.10

and 5.23 (s, hven, total IH), 5.50 (br s, IH), 6.49-6.52 (m, 2H), 6.78-€.81 (m, 2H), 6.97-7.01 (m,

1H), 7.14-7.18 (m, 2H), 7.24-7.36 (m, 2H), 7.80-7.82 (m, 2H), 7.99-8.01 (m, 1H); 8.15-8.18 (m,

IK)..

To a stirred solution of methyl 4-[1-[4-[AT'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-4-fluoro-2-pyrrolidinyl] methylaminobenzoate (320 mg, 0.56 mmol) in THF (5.0 mL) and MeOH

(3.0 mL) was added 1 N NaOH (0.8 mL, 0.8 mmol).

The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 99 (280 mg, 90%) as a

white; crystalline solid. Molecular weight 555.00. Temp.

132-136 °C; IR (KBr) 3332, 2937, 1602,

1531, 1174, 752 cm-'; 1H-NMR pMSO-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, 1H), 7.64-7.68 (m, 2H)/7.<!>92-8i10 (m, 2H), 8.87-8.94 (m, 2K)\ Anal. Calculated for 1 CA.N.OjFCl-O.eHjO: C, 59.44; H, 5. 20; N, 9.90. Found; C, 59.41; H, 5.19; N, 9.72.

To a stirred solution of methyl 4-[1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl]methylaminobenzoate (541 mg, 1.53 mmol)

in CH 2 Cl 2 (8.0 mL) was added TFA (4.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was

added to the residue and extracted with CH2Cl2. The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The impure product was used in the subsequent reaction without further purification. To a stirred solution

of the crude product (151 mg, 0.6 mmol), 4-[α7r-(2-bromophenyl)-■ureido]-3-methoxyphenylacetic acid (227 mg, 0.6 mmol),HOBt

(94 mg, 0.7 mmol) and triethylamine (167 µl, 1.2 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC:HCl (173 mg, 0.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 S 4 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-[1-[4-[ N'~ (2-bromophenyl)ureido]-3- methoxyphenylacetyl]-4-fluoro-2-pyrrolidinyl]methylaminobenzoate' (280 mg, 76%) as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.80-1.98 (m, 1H), 1.42-1.58 (m, 1H), 3.20-3.52 (m, 3H), 3.67-3.79 (m, 5H), 3.84 (s, 3H) , 3.94-3.97 (m, 1H), 4.68-4.71 (m, 1H), 5.10 °? 5.23 (each s, total IK), 5.51 (br s, IH), 6.50-6.52 (m, 2H), 6. 19- 1. 01 (m, 5H), 7.25-7.33 (m,. IH), 7.51 -7.53 (m, IK), 7.80-7.83 (m, 2H), 7.98-8.00 (m, IH), 8.11-8.14 (m, IH).

To a stirred solution of methyl 4-[1- [4-[A7r-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-4-fluoro-2-pyrrolidinyl]methylaminobenzoate (280 mg, 0.46 mmol ) in THF (8.0 mL) and MeOH

(8.0 mL) was added 1 N NaOH (2.8 mL, 2.8 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 100 (260 mg, 95%) as a

•white crystalline solid. Molecular weight 599, 45. Mp.: 131-135 °C; IR (KBr) 3332, 2935, 1602, 1529, 1174 cm -1 ; 1H-NMR (DMSO-ds) 5 1.95-2.01 (m, 1H), 2.20-2.35 (m, IK), 3.10-3.20 (m, IK), 3.50-3.70 (m, 3H), 3.80-3.85 ( m, 5H), 4.27 (m, IH), 5.24' °9T 5.37 (each s, total IH), 6.54-6.99 (m, 5H), 7.3.0/7.33 (m, IK), 7.58-7.94 (m , 3H), 7.94-7.98 (m, 2H), 8.73 (m, IK), 8.93 (m, \K); Anal. Calculated for d8HMN4OjBrF-0.7H:O: C, 54.95; H, 4.84; N, 9.15. FoundC, 54.98; H, 4.81; N, 8.93. EXAMPLE 89 4- [1- [3-methoxy-4- [AT - (2-methylphenyl)ureido] phenylacetyl] - (4R) - fluoro-(2S) -pyrrolidinylmethoxy] benzoic acid

A mixture of methyl 4-[( AR )-flupr-(2 S )-pyrrolidinylmethoxy] benzoate (634 mg, 2.50 mmol), 3-methoxy-4-[ATr-( 2 - methylphenyl)ureido]phenylacetic acid (787 mg , 2.50 mmol), EDC:HCl (718 mg, 3.75 mmol), HOBt (cat.), DMAP (cat.) and DMF (10 mL) were stirred overnight. • The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2 x 100 mL), dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give methyl 4-[1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-( AR)- fluoro-(2S)-pyrrolidinylmethoxy]benzoate (1.37 g, quantitative) as a pale yellow viscous solid.

1H-NMR (CDCl1) δ 2.24 (s, 3 H), 2.26-2.47 (rn, 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), 4.51-4.62 (m , 2 H), 5.20" and 5.33 (br s, each, total IK), 6.63 (s, 1 K), 6.72 (d, J= 8.3 Hz, 1 H), 6.77 (d, J= 9.0 Hz, 2 H), 7.05 (t, J= 7.6 Hz, 1 H), 7.16-7.20 (m, 3 H), 7.53 ( s, 1 H), 7.63 (d, J= 7.8 Hz, 1 H), 7.91 (d, J= 9.0 Hz, 2 H), 8.07 (d, J=8.1 Hz, 1 H).

A mixture of methyl 4-[1-[3-methoxy-4-[AJ'-(2-methylphenyl)-ureido]phenylacetyl]-( AR )-fluoro-(25)-pyrrolidinylmethoxy]-benzoate (1.37 g , 2.49 mmol)., 0.25 N NaOH (20 mL, 5.00 mmol), and THF (20 mL) were stirred for 3 days. The mixture was poured into 1N HCl (100 mL) and extracted with CHCl 3 -MeOH (5:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20:1 to 4:1) to give 101 (930 mg, 70%) as a pale yellow amorphous solid. Molecular weight 535.56. 'H-NMR (DMSO-df) 8 2.24-2.41 (m, total 5 H), 3.42-4.66 (series of m, 10 H), 5.31 and 5.44 (br s, each, total 1 H), 6.71 -7.16 (series of m, 7 H), 7.79 (d, J= 8.1 Hz, 1 H), 7.85-7.89 (m, 2 H), 7.98-8.00 (m, 1 H), 8.47 (s, 1 H ), 8.55 (s, 1 H); MS (FAB) m/z 536 (M<*>+1).

EXAMPLE 90 4-[(4S)-chloro-1-[3-methoxy-4-[ N'-(2-chlorophenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-hydroxy-(2S)-pyrrolidinyl)methoxybenzoate (351 mg, 1.0 mmol) and Ph3P (393 mg, 1.5 mmol) in To CHCl 3 (5.0 mL) was added CC 14 (5.0 mL) at room temperature. The reaction mixture was stirred at 50°C for 24 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (4:1, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycarbonyl-4-chloro-(2S) -pyrrolidinyl) methoxybenzoate (340 mg, 92%) as a pale yellow oil.

1H-NMR (CDCy 5 1.48 (s, 9H), 2.38-2.65 (ra, 2H), 3.50-3.60 (ra, IK), 3.88 (s, 3H>, 3.89-4.05

(m, IK), 4.26-4.41 (m, AK), 6.95-6.97 (m, 2H), 7.98 (d, J = 8.5 Hz, 2H).

To a stirred solution of methyl 4-(1-tert-butoxycarbonyl-(4S)-chloro-(2S)-pyrrolidinyl)methoxybenzoate (369 mg, 1.0 mmol) in CH2Cl2 (3.0 ml) was added added TFA (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The impure product was used in the subsequent ■ reaction without further purification. To a stirred solution of. the crude product (185 mg, 0.5 mmol), 4-[N-(2-chlorophenyl)-ureido]-3-methoxyphenylacetic acid (167 mg, 0.5 mmol), HOBt (68 mg, 0.5 mmol ) and triethylamine (2 0 8 mL, 1.5 mmol) in THF

(8.0 mL) and MeCN (8.0 mL) was added ÉDC-HCl (144 mg, 0.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The rest

was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) as eluent to give methyl 4-[( AS )-chloro-1-[3-methoxy-4-[ N'~ ( 2-Chlorophenyl)ureido]phenylacetyl]-(-2 S )-pyrrolidinyl]methoxybenzoate (210 mg, 72%) as a colorless oil. 1H-NMR (CDCl 3 ) δ 3.35-3.50 (m, IK), 3.55-3.65 (m, IK), 3.61-3.66 (m, 3H), 3.75 (s, 3H), 3.88 (s, 3H), 3.99 -4.04 ( two, IK), 4.35-4.40 (m, 3H), 4.48-4.53 (m, IK), 6.77-7.10 (m, 7H), 7.25-7.36 (m, 2H), 7.93-8.00 (m, 2H), 8.18 (d, / = 8.0 Hz, IK)..

To a stirred solution of methyl 4-[(4S)-chloro-1-[3-methoxy-4-[ N'-(2-chlorophenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (210 mg, 0.35 mmol) in THF (6.0 mL) and MeOH

(3.0 mL) was added 1 N NaOH (0.7 mL, 0.7 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1N HCl. The solid obtained was collected, washed with water and dried in vacuo to give 102 (200 mg, 98%) as. a white •crystalline solid. Molecular weight 572.44. Sm<p.>: 126-131 °C; IS. (KBr) 3330, 1685, 1604, 1533,

1438 cm"<1>; 'H-NMR (DMSO-d<) 8 2.15-2.25 (m, IK), 2.58-2.63 (m, IK), 3.58-3.78 (m, 3H), 3.83 (s, 3H ), 4.13-4.42 (m, 4H), 4.73 (m, IH), 6.75-7.45 (m, IK), 7.86-8.10 (m, AK), 8.90 (s, IK), 8.95 (s, 1H); MS (FAB) m/z 572 (M^OMna/.Calculated for CjgHjTNjOjCl: C, 58.75; H, 4.75; N, 7.34. Found: C, 58.93; H, 4.85; N, 7.15.

EXAMPLE 91

4-[1- [4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(AS)-chloro-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-[1-tert-butoxycarbonyl-(4 S )-chloro-(2 S )-pyrrolidinyl] methoxybenzoate ) 369 mg, 1.0 mmol) in CH 2 Cl 2 (3.0 mL) was added TFA (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The impure product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (185 mg, 0.5 mmol), 4-[W-(2-bromophenyl)-ureido]-3-methoxyphenylacetic acid (190 mg, 0.5 mmol), HOBt

(68 mg, 0.5 mmol) and triethylamine (208 mL, 1.5 mmol) in THF (8.0 mL) and MeCN (8.0 mL)' was added EDC-HCl (144 mg, 0, 75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) as eluent to give methyl 4- [1- [4- [A7r-(2-bromophenyl)ureido]-3- methoxy enylacetyl]-(4S)-chloro-(2S)-pyrrolidinyl]methoxybenzoate (260 mg, 83%)' as a colorless oil. 1H-NMR (CDCl 3 ) δ 2.32-2.50 (m, 1H), 2.53-2.65 (m, IK), 3.61-3.67 (rn, 3H), 3.75 (s, 3H), 3.88 (s, 3H), 3.99 -4.03 (m, IH), 4.35-4.40 (xn, 3H), 4.45-4.55 (m, IH), 6.78-7.10 (m, 7H), 7.28-7.33 (m, IK), 7.52 (d, /= 8.0 Hz, IK), 7.94-7.99 (m, 3H), 8.14(d, J=8.3, Hz, IH).

To a stirred solution of methyl 4-[1-[4-[N-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-(45)-chloro-(2S)-pyrrolidinyl]-methoxybenzoate (260 mg,. 0.4 mmol) in THF (6.0 mL) and MeOH (3.0 mL) was added 1N NaOH (0.8 mL, 0.8 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 103 (210 mg, 83%). as a white .crystalline solid. Molecular weight. 616.89. M.p.: 127-132°C; IR (KBr) 3330, 1685, 1604, 1529, 1434 cm -1 ; 1H-NMR (DMSO-d<) 8 2.18-2.28 (m, IK), 2.60-2.70 (m, IK), 3.55-3.75 (m, 3H), 3.83 (s, 3H), 4.12-4.42 (m , 4H), 4.60-4.75 (m, IH), 6. 15- 1. 06 (m, 5H), 7.30-7.34 (m, IK), 7.60 (d, J = 7.3 Hz, IH), 7.86-7.94 (m, 5H), 8.75 (s, 1H), 8.94 (s, 1H); MS (FAB) m/z 616 (K). 6™ (M^<+>2); ^no/.BeregriefforCjBH^NjOiClBr: C, 54.52; H, 4.41; N, 6.81. Found: C, 54.98; H, 4.54; N, 6.66. EXAMPLE 92 4-[(4J?)-chloro-1-[3-methoxy-4-[AT-(2-methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid 4-[(4JR)-klbr -1- [4- [AT'-(2-chlorophenyl)ureido]methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4S)-hydroxy-(2S)-pyrrolidinylcarboxylate (1.81 g,

7.34 mmol) in CC14-CH2Cl2 (20 mL, 1:1, v/v) was added Ph3P (3.87 mmol, 14.75 mmol) and the reaction mixture was stirred at room temperature for 2 h. To the mixture was added EtOH (5 mL) and the reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel with . n-hexane-EtOAc. (3:1, v/v) as eluent to give methyl 1-(tert-butoxycarbonyl)-(4.R)-chloro-(2S)-pyrrolidinylcarboxylate (1.36 g, 70%) as a colorless oil .

1HINMR(CDCl3)5 1.42(s19H),2J2-2.39 (m, 1 H), 2.49-2.54'(m, 1 H), 3.66-3.92 (series of s <p>g m, total 5 H), 4.44- 4.55 (m, 2H);

MS(FAB) m/z 264 (lvf+1).

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4S)-chloro-(2S)-pyrrolidinylcarboxylate (1.35 g, 5.12 mmol) in THF (10 mL) was added 0, 5N NaOH (10 mL) and the reaction mixture was heated at reflux for 1.5 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the mixture was extracted with CHCl 3 -MeOH (9:1, v/v). The extract was washed with brine, dried over Na 2 SO 4 and evaporated to give 1-(tert-butoxycarbonyl)-(4R)-chloro-(2S)-pyrrolidinylcarboxylic acid (1.28 g, quantitative) as a colorless oil. 1H-NMR (CDC13) 8

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 1-(tert-butoxycarbonyl)-(4R)-chloro-(2S)-pyrrolidinylcarboxylic acid (1.28 g, 5.13 mmol) in THF (20 mL) was added dropwise BH3 "DMS (0 .60 mL, 6.33 mmol) via a syringe and the reaction mixture was stirred at room temperature for 1 h. After removal of the solvent, the residue was dissolved in CH 2 Cl 2 . The solution was washed with H 2 O, brine, dried over Na 2 SO 4 , and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 1-(tert-butoxycarbonyl)-(4JR)-chloroprolinol (0.88 g, 73%) as a colorless oil .>H-NMR (CDCl 3 ) δ 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 (rh, 1 H), 4.41-4.46 (m, 2 H); MS(FAB) m/ z 236 (M*+lj.

To a cooled (0°C), stirred solution of methyl 4-hydroxybenzoate (560 mg, 3.68 mmol), 1-(tert-butoxycarbonyl)-(4R)-chloroprolinol (87 0 mg, 3.6 9 mmol, Ph 3 P (1.16 g, 4.42 mmol) in THF (15 mL) was added DIAD (870 mL, 4.42 mmol) and the reaction was heated at reflux for 10 h After cooling 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-ttért^bu^oxykiarbonyl) ^■<4R}.:-kldr- (2S) .-pyrrolidinylmethoxy] benzoate' (8'9"0". mg,■- :65~%') as a "white _ f ast substance. M.p. : 116-120°C; 'H-NMR (CDC13) 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), 4.30-4.41 (m, 2 H), 4.50-4.55 (m, 1 H), 6.90-6.92 (m, 2 H), 7.96-7.98 (m, 2H); MS(FAB) m/z 370 (bf+ 1); Anal. Calcd for ClgHJ4ClNpj: C, 58.46; H, 6.54; Cl; 9.59; N, 3.79. Found: C, 58.35; H, 6.56; Cl, 9.75; N, 3.77.

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-(4R)-chloro-(2S)-pyrrolidinylmethoxy]benzoate (840 mg, 2.27 mmol) in CH 2 Cl 2 (10 mL) was added TFA ( 10 ml) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine, dried over Na 2 SO 4 and evaporated to give methyl 4-[( AR )-chloro-(25)-pyrrolidinylmethoxy]benzoate (580 mg, 95%) as a white solid. M.p.: 61-64°C; 'H-NMR (CDCl1) 5

1.85 (br s, 1 H), 2.03-2.10 (m, 1 H), 2.29-2.35 (m, 1 H), 3.19-3.31 (rn, 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 (FAJ3) m^r 270 (KT+1).

A mixture of 3-methoxy-4-[N-(2-methylphenyl)ureido]-phenylacetic acid (385 mg, 1.22 mmol), methyl 4-[(4.R)-chloro^(2S)-pyrrolidinylmethoxy]benzoate (330 mg, 1.22 mmol), EDC-HCl (281 mg, 1.47 mmol), HOBt (200 mg, 1.48 mmol) and Et3N

(205 mL, 1.47 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. • The extract was washed with saline, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 50:1, v/v) as eluent to give methyl 4- [ (4i?)-chloro-1- [3-methoxy-4- [ N'~ (2-Methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate' (670 mg, 97%) as a white foam. 1 H-NMR (CDCl 3 ) δ 2.28 (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, 1H), 7.91-7.93 (m, 2H), 8.05-8.07 (m, 1H); MS(FAB) m/z 566 (M<+>+1).

To a stirred solution of methyl 4-[( AR )-chloro-1-[3-methoxy-4- [ N'~ (2-methylphenyl)ureido] phenylacetyl] - (2S) -pyrrolidinylmethoxy] benzoate (480 mg, 0 .85 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was refluxed for 2 h; After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The impure solid was dissolved in CHCl3-MeOH and evaporated. The residue was washed with .Et 2 O. to give 104 (355 mg, 76%) as a white amorphous solid.

1 H-NMR (DMSO-d,) δ 2.25 (s, 3 H), 2.29-2.46 (ni, 2 H), 3.57-3.73 (m, 2 H), 3.78 (s, 3 H), 3.81-3.99 (m, 2 H), 4.11-4.31 (m, 2 H), 4.43-4.45 °9 4.64-4.67 (each m, total 1 H), 4.83-4.85 (m, 1 H), 6.71-7.17 (m, 7H), 7.78-7.80 (m, 1H), 7.87-7.91 (m, 2H),

7.99-8.01 (xn, 1 H), 8.47 (s, 1 H), 8.56 (s, 1 H), 12.66 (br s, 1 H); MS (FAB) m/ z 552 Q^<+> 1)\AnaL Calcd fonC^H 3 oClN 3 O 6 -3/4H 2 O: C, 61.59; H, 5.61; Cl, 6.27; N, 7.43. Found: C, 61.56; H, 5.51; Cl,

6.68; N, 7.26.

A mixture of 4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (400 mg, 1.19 mmol), methyl 4-[ ( AR )-chloro-( 2 S )-pyrrolidinylmethoxy]benzoate ( 320 mg, 1.19 mmol), EDC-HCl (275 mg, 1.43 mmol), HOBt (195 mg, 1.44 mmol) and Et3N (200 mL,

1.43 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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-[(4JR)-chloro-1-[4-[AJ'-(2-chlorophenyl)ureido ]-3-methoxyphenylacetyl]-( 2S )-pyrrolidinylmethoxy]benzoate (69-0 mg, 98%) as a pale yellow foam.

1 H-NMR (CDCl 3 ) 52.35-

2.41 (m, 1 H), 2.49-2.59 (m, 1 H), 3.55 (s, 3 H), 3.57-3.70 (m, 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 (m, 4 H), 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 (m, 3 H), 8.18-8.21 (m, 1 H); MS (FAB) m/z 586 (M<*>+1). ^

To a stirred solution of methyl 4-[(AR)-chloro-1-[4-[J-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (410 mg, 0.70 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was dissolved in CHCl3-MeOH and evaporated. The residue was washed with Et 2 O to give 105 (282 mg, 70%) as an amorphous solid. Molecular weight 572, 44. Temp. : 131-136°C;

1H-NMR (DMSO-dO 8 2.29-2.35 (m, 1H), 2.44-2.47 (m, 1H), 3.58r

3.74 (m, 2 H), 3.78 (s, 3 H), 3.81-3.99 (m, 2 H), 4.10-4.32 (m, 2 H), 4.44-4.46 .and 4.66 (each, -total 1 H) , 4.84 (m, 1 H), 6.74-7.04 (m, 5 H), 7.26-7.30 (m, 1 H), 7.43-7.45 (m, 1 H), 7.87-7.91 (m, 2 H), 7.96 (d, J = 8.3 Hz, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.90 (s, 1 H), 8.94 (s, 1 H); Anal.

Calculated for d.HnCliNjO^MHjO: C, 57.39; H, 4.90; Cl, 11.66; N, 7.17. Found: C, 57:57; H, 4.94;

Cl, 11.66; N, 6.89.

EXAMPLE 93

4-[(4S)-hydroxy-1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinyl] methoxybenzoic acid

To a stirred solution of 4-[(4S)-acetoxy-1-tert-butoxycarbonyl-(2S)-pyrrolidinyl]methoxybenzoate (2.31 g, 5.87 mmol) in CH 2 Cl 2 (46 mL) was added TFA (10 ml) at room temperature. After stirring for 3.5 hours, the mixture was concentrated in vacuo. The residue was diluted with the addition of CH 2 Cl 2 and 1 N NaOH and was extracted with CH 2 Cl 2 . The combined extracts were washed with brine, dried over Na 2 SO 4 which was concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl3/MeOH (20/1)] to give methyl 4-[(4S)-acetoxy-(2S)-pyrrolidinyl]methoxybenzoate (1.89 mg, 100%) as a pale purple solid.

1 H-NMR (CDCl 3 ) 5 2.10

(s, 3H), 2.14 (m,.IH), 2.65 (m, IK), 3.52-3.63 (m, H), 3.89 (s, 3H), 4.18 (m, IK), 4.28 (d, J= 5.9

Hz, 2H), 5.38 (m, IK), 6.93 (d, J= 8.8 Hz, 2H), 7.99 (d, J= 8.8 Hz, 2H).

A mixture of 3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenylacetic acid (343 mg, 1.09 mmol), methyl 4-[(4S)-acetoxy-(2S)-pyrrolidinyl]methoxybenzoate (320 mg, 1.09 mmol), EDC-HCl (313 mg, 1.64 mmol), HOBT (222 mg, 1.64 mmol) and Et3N

(0.76 mL, 5.45 mmol) in DMF (7 mL) was stirred at room temperature for 16 h. The mixture was poured into ice water and

extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/acetone (5/1)] to give methyl 4-[(4S)-acetoxy-1-[3-methoxy-4-[W-(2-methylphenyl)ureido] phenylacetyl]-(2 S )-pyrrolidinyl]methoxybenzoate (520 mg, 81%) as a brown amorphous solid.

'H-NMR (CDCl 3 ) 5 2.00 (s, 3H, - one of isomers:), 2.03 (s, 3H, - one of isomers0, 2.28 (m,

5H), 3.54 (s, IH), 3.58 (s, 2H), 3.64 (s, IH), 3.67 and 3.69 (each, 3H, amide isomers), 3.85 (d, J = 5.4 Hz, IK), 3.88 (s, 3H), 4.04 (t, J= 9.3 Hz, IH), 5.27-5.34 (m, IH), 6.51 (m, IK), 6.76-6.89 (ra, 2H), 6.94 (d, J= 8.1 Hz, IH), 7.14 (m, IH), 7.25 (m, 4H), 7.53 (d, J= 8.3 Hz, IK), 7.96 (d, J = 8.0 Hz, IH), 8.00-8.10 (m, 2H ); MS (ESI) m/z 590 (W<T>+1).

To a solution of methyl 4-[(4S)-acetoxy-1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (520 mg, 0.882 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 EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with CHCl3-MeOH (10/1). The combined extracts were washed with brine. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was crystallized by addition of CHCl 3 -EtOH and ether to give 106 (68 mg, 14%) as a colorless powder. Molecular weight 533.57. Melting point: 148-152°C (decomposition)

IR (KBr) 3356, 2939,1687,

1604, 1533, 1454,' 1255 cm'1; 1H-NMR (DMSO-dJ 8 1.95-2.09 (m, 2H), 2.25 (s, 3H), 3.59 (d, J=

5.9 Hz,.2H), 3.71 (m, IH), 3.81 and 3.85 (each s, 3H, amide isomerized), 4.13-4.47 (m, 4.H), 5.19 (br, IK), 6.70-7.21 ( m, 7H), 7.79 (d, J = 7.9 Hz, IK), 7.86 (d, J= 8.8 Hz, 2H), 8.01 (d, J = 8.3 Hz,. IK), 8.47 (s, IK), 8.57 (s, IK) ; MS (ESI) m/z 533 (lvf+1); Anal. Calculated for C^NjCy 1H26:- C, 63.15; H, 6.03; N, 7.62. Found: C, 63.29; H, 5.76; N, 7.46.

EXAMPLE 94

4-[1-[4-[ N'~(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-hydroxy-(2S)-pyrrolidinyl]methoxybenzoic acid

A mixture of 4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (342 mg, 1.02 mmol), methyl 4-[(2S,4S)-4-acetoxy-2-pyrrolidinyl ]methoxybenzoate (300 mg, 1.02 mmol), EDC-HCl (293 mg, 1.53 mmol), HOBT (207 mg, 1.53 mmol) and Et3N (0.71 mL, 5.10 mmol) in DMF (6 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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/acetone (5/1)] to give methyl 4-[(4S)-acetoxy-1-[4-[ N'~ (2-chlorophenyl)ureido]-3 -methoxyphenylacetyl] - ( 2S )~ pyrrolidinyl]methoxybenzoate (510 mg, 82%) as a pale brown amorphous solid.

1H-NMR (CDCy 5 2.01: and 2.04 (hyer s, 3H, amide isomers), 2.17 (m, 2H), 3.56-3.66(m, 3H), 3.61 (s, 3H), 3.88 (s, 3H ), 3.89(m, IH), 4.07 (t, J= 9.6 Hz, IH), 4.45 (dd, / = 9.2, 3.4 Hz, IH), 4.56 (m, IH), 5.31-5.39 (m, IH) , 6.80-7.01 (m, 4H), 7.23 (d, J= 8.1 Hz, 4H), 7.34 (d, J= 8.1Hz, 1 H), 7.95 (d, J= 8.5 Hz, IH), 8.00 (m , 1H), 8.18 (d, /= 8.3 Hz, 1H); MS (ESI) m/2 610 (M<*>+1). 612 (M<+>+3).

To a solution of methyl 4-[(4S)-acetoxy-1-[4-[ N' -(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (510 mg, 0.836 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 EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were washed with brine. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was crystallized by addition of EtOH and ether to give 107 (22 mg, 5%) as a colorless powder. Molecular weight 553.99. M.p.: 138-142°C (decomposition);

IR (KBr) 3334, 2939, 1685, 1604,1533, 1439,1248 cm"'; 'H-NMR(DMSO-ds) δ L-93-2.14 (m, 2H), 3.60 (d, J= 5.7

Hz, 2H), 3.71 (m, IH), 3.81 and 3.85 (each, 3H, amide isomers), 4.14-4.50 (m, 4H), 5.19 (br, IH), 6.72 <and,> 6.76 (each m, IH, amide isomers,), 6.85 0^,^.90 (whose, IH, amide isomers), 7.00-7.08 (m, 3H), 7.28 (t, J= 7.3 Hz, IH) , 7.43 (dd, J= 8.1, 1.2 Hz, IH), 7.86-7.95 .(m, 2H), 7.97 (d, J = 8.1 Hz, IH), 8.-10 (dd, J= 8.3, 1.5 Hz , IH), 8.90 (s, IH), 8.94 (s, IH), 12.64 (br, IH); MS (ESI) m/z 554 (M++1), 556 (M^+3); Anal. Calculated for CaHjjClNaCy. C, 60.71; H, 5.05; Cl, 6.40; N, 7.58.

Found: C, 60.47; H, 5.37; Cl, 6.31; N, 7.19.

EXAMPLE 95

4-[(4S)-hydroxy-1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

A mixture of 4-[AT'-(2-bromophenyl)ureido]-3-methoxyphenyl-acetic acid (387 mg, 1.02 mmol), methyl 4-[(4S)-acetoxy-(2S)-pyrrolidinyl]methoxybenzoate ( 300 mg, 1.02 mmol), EDC-HCl

(293 mg, 1.53 mmol), HOBT (207 mg, 1.53 mmol) and Et3N

(0.71 mL, 5.10 mmol) in DMF (6 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 drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /acetone (5/1)] to give methyl 4-[(4S)-acetoxy-1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (510 mg, 76%) as a yellow oil.'H-NMR

(CDClj) 6 2.01 and 2.04 (each s, 3H, amide isomers), 2.31 (m, 2H), 3.54-3.68 (m, 3H), 3.76 (s, 2H), 3.88 (s, 3H), 3.89- 4.58 (m, 4H), 5.31-5.36 (m, IK), 6.81-€.96 (m, 5H), 7.19-7.32 (m, 3H), 7.51 (d, J= 8.0 Hz, IH), 7.93- 8.00 (m, 3H), 8.13 (d, J= 8.3 Hz, IH); MS (ESI) m/ z 654 (M<+>+1), 656 (TvT+3)...

To a solution of methyl 4-[(4S)-acetoxy-1-[4-[ N1-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (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 EtOAc. The remaining aqueous layer was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were washed with brine. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was crystallized by addition of EtOH and ether to give 108 (87 mg, 19%) as a pale brown powder. Molecular weight 598.44. M.p.: 143-151°C (decomposition);

IR (KBr) 3 3 3 2, 2937,

1685, 1604, 1529, 1529, 1435 cm'<1>; 1H-NMR (DMSO-dfi) 5 1.92-2.14 (m, 2H), 3.60 (d,/= 5.9 Hz, 2H), 3.72 (m, IK), 3.81 and" 3.85 (hv-s, 3H, amide -isomers), 4.14-4.49 (m, 4H), 5.19 (br, IH), 6.72 and" 6.75 (each m, IH, amide isomer), 6.85 °g -6.90 (each m,.lH, amide isomers ), 6.97 (t, .7=6.1 Hz, IK), 7.06(d,J= 8.8Hz, 2H), 7.32 (t, J= 7.1 Hz, IH), 7.60 (dd,J=7.8,1.2 Hz, "IITS <*>7 fi< IA T — O O U-, TLTi T Ol 1 OT A™ 2TLTV O IA f- 1TJ\ O m r. ITTi 11 /n n 1TT\. > JTO

(ESI) m/z 559 (NT+1), 561 (M++3); H, 4.74; Br, 13.31; N, 7.00. Found: C, 55.80; H, 4.84; Br, 13.64; N, 6.66.

EXAMPLE 96

4- [1- [4- [ N'-.(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(4jR)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of 4-[( AR )-acetoxy-1-(tert-butoxycarbonyl-(2 S )-pyrrolidinylmethoxy]benzoate (835 mg, 2.12 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo <p>g basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine, dried over K 2 CO 3 and evaporated to give methyl 4- [ ( AR)-acetoxy-(2S)-pyrrolidinylmethoxy]benzoate

(580 mg, 95%) as a brown oil.

1H-NMR (CDC13) 6 1.86-1.93 (m, 1 H), 2.00-2.12 (series of;'s and- m, total 5 H), 3.03-3.29 (m, 1 H), 3.73-3.80 ( m, 1 H), 3.88 (s, 3 H), 3.93-4.01 (m, 2 H)/5.27-5.30 (m, 1 H), 6.91 (d, J *- 9.0.Hz, 2 H), 7.98 (d, J = 9.0 Hz, 2 H); MS (FAB) m/z 294 (M*+1).

A mixture of .4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (365 mg, 1.09 mmol), methyl 4-[ (4.R)-acetoxy-(2S.)- pyrrolidinylmethoxy]benzoate (320 mg, 1.09 mmol), EDC-HCl

(250 mg, 1.30 mmol), HOBt (180 mg, 1.33 mmol) and Et3N

(182 mL, 1.31 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give methyl 4-[(AR)-acetoxy-1-[4-[ N'-(2-chlorophenyl) ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (500 mg, 75%) as a white . foam. 1H-NMR(CDCl 3 ) δ 2.01 (s, 3 H), 2.03-2.05 (m, 1 H), 2.20-2.26 (m, 1 H), 2.37-2.43 (m, 1 H), 3.59 (s, 2 H), 3.62 (p, 3

H), 3.66-3.87 (rn, 2 rows), 3.89 (S, 3 rows), 4.U7-4.U9 (m, 1 row), (rn, in row), un, in row), o. /u-6.82 (m, 4 H), 6.97-7.01 (m, 1 H), 7.24-7.35 (m, 4 H), 7.92-7.98 (m, 3 H), 8.12-8.21 (m, 1 H) ; MS (FAB) m/z 610 (M*+1). To. a stirred solution of methyl 4-[(4JR)-acetoxy-1-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidine nylmethoxy] benzoate (500 mg, 0.82 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated under reflux overnight. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the precipitate obtained was. collected under a reduced pressure. The crude solid was purified by recrystallization from CHCl 3 -IPE to give 109 (223 mg, 49%) as a white crystalline powder! Molecular weight 553.99. Melting point: 137-142°C; 'H-NMR'(DMSO-dJ 8 1.95-2.09 (m, 2 H), 3.41-3.43 (m, 1 H), 3.57 (m, 3 H), 3.78 (s, 3 H), .4.07-4.40 (series of rri, total 4 H), 5.07 (m, 1 H), 6.72-6.74 (m, 1 H), 6.85 (m, 1 H), 6.99-7.03 (m, 3 H), 7.25-7: 29 (m, 1H), 7.42-7.43 (m, 1 H), 7.85-7.87 (m, 2 H), 7.93-7.95 (m, 1 H), 8.07-8.09 (m, 1 H), 8.88 (s , 1 H), 8.92 (s, 1 H), 12.65 (br s, 1 H); MS (FAB) m/ z 554 (M++1); Anal. C, 59.73; H, 5.19; Cl, 6.30; N, 7.46. Found: C, 59.58; H, 5.32; Cl, 6.99; N, 7.21. EXAMPLE 97 4-[(4R)-hydroxy-1- [3- methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (320 mg, 1.02 mmol), methyl 4-[(4R)-acetoxy-(2S)-pyrrolidinylmethoxy]benzoate ( 300 mg, 1.02 mmol), EDC-HCl (235 mg, 1.23 mmol), HOBt (166 mg, 1.23 mmol) and Et3N

(171 mL, 1.23 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The mixture was diluted with H 2 O and extracted

with. EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with GHCl3-MeOH (50:1, v/v) as

eluent to give methyl 4-[(4R)-acetoxy-1-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenylacetyl]-(25)-pyrrolidinylmethoxy]benzoate (420 mg, 70 %) as a white foam.

1 H-NMR (CDCl 1 ) δ 1.99 (s, 3 H),

2.02-2.05 (m, 1 H), 2.15-2.41 (;series of s.-and m, total 5 H), 3;55 (s, 3 H), 3.57 (s, 2 H), 3.63-3.73 (m , 2 H), 3.89 (s, 3 H), 4.07-4.10 (m, 1 HX 4.45-4.48 (m, 1 H), 4.57 (m, 1 H), 6.56 (s, 1 H), 6.66 (m , 1 H), 6.75-6.82 (m, 3 H), 7.11-7.24 (m, 4 H), 7.54-7.56 (m, 1 H), 7.92.7.94 (m, 2 H), 8.05-8.07 (m , 1H); MS (FAB) m/z 590 (M*+1).

To a stirred solution of methyl 4-[(4J?)-acetoxy-1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (420 mg, 0.71 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux overnight. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was purified by crystallization from CHCl 3 -IPE to give 110 (182 mg, 48%) as a white crystalline powder. Molecular weight 533.57. M.p.: 178-182°C;

1H-NMR (DMSO-d«) δ 1.92-2.10 (m, 2H), 2.23 (s, 3H), 3.40-3.44 (m, 1H), 3.56-3.67 (m, 3H), 3.78 (s, 3 H), 4.05-4.39 (series of in, total 4 H), 5.06 (m, 1 H), 6.71-7.01 (m, 5 H), 7.10-7.16 (m, 2 H), 7.77- 7.79 (m, 1 H), 7.85-7.89 (m, 2 H),.7.98-8.00 (m, 1 H), 8.45 (s, 1 H), 8.54 (s, 1 H), 12.59 (br s, 1H); MS (FAB) m/z 534 (M<+>+1); Anal. Calculated for C2.NaO/lÆHjO: C.'64.20; H, 5.94; N, 7.74. FoundC, 64.35; H, 5.83; N, 7.68.

j

EXAMPLE 98

4-[(4S)-(4-carboxyphenoxy)-1-[3-methoxy-4-[ N'~(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4i?)-hydroxy-(2S)-pyrrolidinylcarboxylate (10.4 g, -.0.04 mmol) and .imidazole (8.66 g, 0 .13 mol) in DMF (40 mL) was added TBS-C1 (7.03 g, 0.05 mol) and the reaction mixture was stirred at 60°C for 3 h. After cooling to room temperature, the mixture was diluted with brine and extracted with Et 2 O. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl 1-(tert-butoxycarbonyl)-(4R)-(tert-butyldimethylsilyloxy)-(2S)- pyrrolidinyl carboxylate (15.0 g, 98%) as a colorless oil.

'H-NMR

(CDCy 8 0.06 (s, 6 H), 0.87 (s, 9 H), 1.41 and 1.46 (each s, 9 H), 1.99-2.03 (m, 1 H), 2.16-2.18 (m, 1 H), 3.31-3.42 (m, 1H), 3.56-3.63 (m, 1 H), 3.73 bg;3.74 (each s, 3 H), 4.31-4.42 (m, 2 H); MS ( EST) m/ z 360 ( M^+l).

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4JR)-(tert-butyldimethylsilyloxy)-(2S)-pyrrolidinylcarboxylate (15.0 g, 0.04 mol) in THF (60 mL) was added 1 N NaOH (60 mL) and the reaction mixture was stirred at 60°C for 2 h. After cooling to room temperature, the mixture was concentrated to a small volume, acidified with 1N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated to give 1-(tert-butoxycarbonyl)-(4R)-(tert-butyldimethylsilyloxy)-(2S)-pyrrolidinylcarboxylic acid (12.8 g, 89%) as a colorless oil.

<>>H-

NMR (CDCl 3 ) δ 0.07 and 0.08 (each s, 6 H). 0.87 (s, 9 H), 1.49 (s, 9 H),- 2.06-2.11 (m, 1 H),' 2.41-2.44 (m, 1 H), 3.40-3.59 (m, 2 H)," 4.36 -4.50 (m, 2 H); MS (ESI) m/z 346 (M<*>+1).

To a cooled (0°C) stirred solution of 1-('tert-butoxycarbonyl)-(4R)-(tert-butyldimethylsilyloxy)-(2S)-pyrrolidi- . nylcarboxylic acid (12.8 g, 0.04 mol) in THF (150 mL) was added BH 3 ■ DMS (5.30 mL, 0.06 mol) dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH 4 Cl and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with toluene-acetone (5:1, v/v) as eluent to give 1-tert-butoxycarbonyl)-(AR)-(tert-butyldimethylsilyloxy)-(2S)-prolinol (10 .5 g, 85%) as a colorless oil'. 'H-NMR

(CDCl ) δ 0.06 (s, 6 H), 0.87 (s, 9 H), 1.47 (s, 9 H), 1.58-1.63 (m, 1 H), 1.93-1.98 (m, 1 H), 3.32-' 3.44 (m, -2 H), 3.51-3.57 (m, 1 H), 3.67-3.71 (m, 1 H), 4.13-4.15 (m, 1 H), 4.27 (m,~l H), 4.87- 4.89 (m,lH).

To a cooled (0°C) stirred solution of methyl 4-hydroxybenzoate (4.81 g, 0.03 mol), 1-(tert-butoxycarbonyl)-(AR)-

(tert-butyldimethylsilyloxy-(2 S )-prolinol (10.5 g, 0.03 mol) and Ph3P (9.96 g, 0.04 mol) in THF (160 mL) was added dropwise DIAD (7, 48 mL, 0.04 mol) and the reaction mixture was heated at reflux for 7 hours. After cooling to room temperature, the mixture was evaporated. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) to give give methyl 4-[1-(tert-butoxycarbonyl)-(4.R)-

(tert-butyldimethylsilyloxy-(2S)-pyrrolidinylmethoxy]benzoate

(9.58 g, 65%) as a white solid. M.p.: 86-88°C; 1H-NMR (CDC13) 8

0.08 (s, 6 H), 0.88 (s, 9 H), 1.46 (s, 9 H), 2.04-2.15 (m, 2 H), 3.29-3.48 (m, 2 H), 3.88 (s, 3 H ), 4.06-4.30 (m, 3 H), 4.46-4.51 (rn, 1 H). 6.91-6.93 (m, 2H); 7.96-7.98 (m, 2H); MS (EST) m/z 466 (M<+>+1).

To a cooled (0°C) stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-( AR )-(tert-butyldimethylsilyloxy)-( 2S )-pyrrolidinylmethoxy]benzoate (1.49 g, 3.20 mmol ) in THF (15 mL) was added TBAF (6.40 mL, 6.40 mmol, 1 M solution in THF) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with H 2 O, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with toluene-acetone (5:1, v/v) as eluent to give methyl 4-[1-

(tert-butoxycarbonyl)-(4J?)-hydroxy-(2S)-pyrrolidinylmethoxy]benzoate (1.05 g, 93%) as a white solid. M.p.: 103-105°C; 1H-NMR (CDC13) 5

1.46 (s, 9 H), 2.11-2.28 (m, 2 H), 3.49-3.60 (m, 2 H), 3.88 (s, 3 H), 4.15-4.34 (m, 3 H), 4.5<3> "-4.57

(m, H), 6.91 (d, J = 8.6 Hz, 2 H), 7.97 (d, J = 8.6 Hz, 2 H).; MS (ESI) m/z 352 (MM-1).

To a cooled (0°C) stirred solution of methyl 4-hydroxybenzoate (0.56 g, 3.68 mmol), methyl 4-[1-(tert-butoxycarbonyl)-.(4JR)-hydroxy-(2S)- pyrrolidinylmethoxy] benzoate (1.30 g, 3.70 mmol) and Ph3P (1.16 g, 4.42

mmol) in THF (20 mL) was added dropwise DIAD (0.87 mL,

4.42 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica gel with n-hexane-

EtOAc (6:1, v/v) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-(4S)-(4-methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]benzoate (1.80 g , quantitative yield) as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.49 (s, 9H), 2.31-2.38 (m, 1H), ~2.45-2.49 (m, 1H), 3.64-3.77 (m, 2H), 3.88 ( s, 6 H), 4.07-4.15 (m, 1 H),

■ 4.33-4.44 (m, 2 H), 4.95-5.01 (m, 1 H), 6.85 (d, J = 8.8 Hz, 2 H), 6.94 (br s, 2 H), 7.97 (d, J = 8.8 Hz, 4 H); MS (ESI) m/z 486 (M<*>+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-(4S)-(4-methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]benzoate (1.80 g, 3.7.1 mmol) in CH 2 Cl 2 (15 mL ) was added TFA (15 mL) and the reaction mixture. was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo, basified with saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over K 2 CO 3 and evaporated to give methyl 4-[(4S)-(4-methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]benzoate (1.50 g, quantitative yield) as a pale yellow oil.

1H-NMR (CDCl 3 ) δ 1.87-1.92 (m, 1 H), 2.41-2.48 (m, 1 H), 3.18-3.23 (m, 1 H), 3.34-3.37 (m, 1 H), 3.60- 3.66 (m, 1 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 4.04-4.13 (m, 2 H), 4.94-5.00 (m, 1 H), 6.87-.6.93 (m , 4 H), 7.96-8.00 (m, 4 H); MS (ESI) m/z 386 (M<*>+1).

A mixture of 3-methoxy-4[ N' -(2-methylphenyl)ureido]phenylacetic acid (400 mg, 1.27 mmol), methyl 4-[(4S)-(4-methoxy- ■ carbonylphenoxy)-(2S) -pyrrolidinylmethoxy]benzoate (491 mg,

1.27 mmol), EDC-HCl (293 mg, 1.53 mmol), HOBt (207 mg, 1.53 mmol) and Et3N (215 µl, 1.54 mmol) in THF (10 mL) were stirred at room temperature over the night. The mixture was diluted with H 2 Q and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (60:1 to 50:1, v/v) as eluent to give methyl 4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl )ureido]phenylacetyl]-(4S)-(4-methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]benzoate (532 mg„ 61%) as a white foam.

H-NMR (CDC13) 8 2.26-2.49 (series bvl <s and m, total 5 H), 3.56-3.93 (series of,, s -and m, total 13 H), 4.07-4.59 (series of k m , total 3 H), 5.01 (m, 1 H), 6.69-6.94 (m, 7

in

H), 7.09-7.13^,1 H), 7.20-7.31 (m, 3,H5, 7.52-7.57 (m, 1 H), 7.92-8.00 (m, 4 H), 8.06-8.09 (m, 1 H );MS (ESI) m/z 682 (M<*>+1).

To a stirred solution of methyl 4-[1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-(4S)-(4-methoxycarbonyl-phenoxy)-(2S)-pyrrolidinylmethoxy] benzoate (532 mg, 0.78 mmol)

in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-N

HCl and the precipitate obtained was collected. The crude solid was recrystallized from MeOH-CHCl 3 -Et 2 O to give 116 (125 mg, '25%). as a pale yellow crystalline powder, molecular weight

weight 653.68. M.p.: 154-159°C; 1H-NMR (DMSO-d 6 ) 2.24 (s, 3 H), 2.38-2.49 (m, 2 H), 3.63 (s, 2 H); 3.67-3.88 (series of s bg m, total 4 H);

4.01-4.06 oi 4.15-4.19 (each st, total 2 H), 4..27-4.3.1 and 4.38-4.42 (each st, total 2 H), 5.18-

5.25 (m, 1 H), 6.72-6.77 (m, 1 H), 6.85-7.16.(series rav^m, total 8 H), 7.78-7.89 (m, 5 H), 7.99-8102

' (m, 1 H)-, 8.46 (s, 1 H), 8.57 (s, 1 H), 12.65 (br s, 2 H); MS (ESI) m/ z 654 ( M*+ l)\ Anal. Meant for.

C36H35N30,1/2H30: C, 65.25; H, 5.48; N, 6.34. Found: C, 65.29; H, 5.54; N, 6.20.

EXAMPLE 99

4-[ (45)-(4-Carboxyphenoxy)-1-[4-[A7'-(2-Chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of 4-[AT<->(2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (420 mg, 1.25 mmol), methyl 4-[(4S)-(4-methoxycarbonylphenoxy)-( 2 S )-pyrrolidinylmethoxy]benzoate (483 mg, 1.25 mmol), EDC-HCl (288 mg, 1.50 mmol), HOBt (203 mg,

1.50 mmol) and Et 3 N (210 µl, 1.51 mmol) in THF (10 mL) were stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give methyl 4-[l-.[4-[W-(2-chlorophenyl)ureido]-3-methoxy enylacetyl ] -

(AS)-(4-Methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]-benzoate (488 mg, 55%) as a white foam.

1H-NMR (CDCl1) δ 2.28-2.51 (m, 2 H), 3.62-3.94 (series of s and m, total 13 H), 4.07-4.62

(series of jn, total 3 H), 4.99-5.03 (m, 1 H), 6.78-6.99 (m, 7H), 7.23-7.34 (m, 2 H), 7.42-7.52 (m, 2 H), 7.92 -8.01 (m, 5H), 8.17-8^20 (m, 1H); MS (ESI) m/z 702 (MM-1).

To a stirred solution of methyl 4-<[>1-[4-[AJ'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(AS)-(4-methoxy-carbonylphenoxy)-(2S)-pyrrolidinylmethoxy ]benzoate (488 mg, 0.70 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1N HCl and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl 3 -Et 2 O to give 117 (137 mg, 29%) as a white crystalline powder. Molecular weight 674.10. M.p.: 150-153°C; 'H-NMR (DMSO-d*) 5

and 4.17-4.21 (each st, total 2 H), 4.30-4.34 and' 4.40-4.45 (each st, total 2 H), 5.20-5.27 (rn, 1 H), 6:77-6.81 (m, 1 H ), 6.89-6.92 (m, 1 H), 7.0.1-7.08 (rn, 5 H), 7.27-7.31 (m, 1 H), 7.43-7.46 (m, 1 H), 7.86-7.92 (rn, 4 H), 7.97-8.00 (m, 1 H), 8.10-8.12 (m, 1 H), 8.91 (s, 1 H), 8.96 (s, 1 H), 12.65j (br s, 2 H); MS (ESI) m/z 674 (M*+1); Anal. Calculated for C 3 j H 3 2 ClN 3 O 9 l/4H 2 O: C, 61.95; H.4.83;

N.6.19; Cl.5.22. Found:C.61.77; H, 4.86; N.6.13; Cl, 5.49.

EXAMPLE 100

4- [1- [4- [A7'~ (2-bromophenyl) ureido] -3-methoxy enylacetyl] - (4S) -

(4-Carboxyphenoxy)-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of [4-[<N>'~(2-bromophenyl)ureido]-3-methoxyphenyl-acetic acid (464 mg, 1.22 mmol), methyl 4-[(4S)-(4-methoxycarbonylphenoxy)- (.2S)-pyrrolidinylmethoxy] benzoate (472 mg, 1.22 mmol),' EDC-HCl (282 mg, 1.47 mmol), HOBt (200 mg, 1.48 mmol) and Et3N (205 fil, 1.47 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (60:1 to 50:1, v/v) as eluent to give methyl 4- [1- [4- [W - (2-bromophenyl)ureido] - 3 -methoxyphenylacetyl] -

(4S)-(.4-methoxycarbonylphenoxy)-(2S)-pyrrolidinylmethoxy]-benzoate (379 mg, 41%) as a white solid

1H-NMR (CDC13) δ 2.28-2.51 (m, 2 H), 3.59-3.95 (series of s and m, total 13 H), 4.07-4.62 (series of m, total 3 H), 4.99 -5.03 (m, 1 H), 6.79-6.95 (m, 7"H), 7.27-7.36 (m, 3 H), 7.49-7.51 (m, l 'H), 7.93-8.01 (m, 5 H), 8.11-8.14 (m, 1 H); MS (ESI) m/z 747 (M<*>+1).

To a stirred solution of methyl 4-[1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(4S)-(4-methoxycarbonyl-phenoxy)-(2 To S)-pyrrolidinylmethoxy]benzoate (379 mg, 0.51 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was refluxed for 5 h. After

■cooling to room temperature, the mixture was poured into ice-1 N HCl 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. Molecular weight 718.55.

'H-NMR <p>MSO-dJ 5 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 7.83-7.96 (m, 6 H), 8.74 (s, 1 H), 8.93 (s, 1 H);

Anal. Calculated for C 3 SH 3 JBrN 3 Cy 2 H 2 O: C, 55.71; H, 4.81; N, 5.57. Found: C, 55.92; H, 4.80; N, 5.30.

EXAMPLE 101

4-[ (4S)-(4-Carboxyphenoxy)-1-[4-[A7r-(2-methylphenyl)ureido]-'phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of 4-[N'~ (2-methylphenyl)ureido]phenylacetic acid

(328 mg, 1.15 mmol), methyl 4-[(45)-(4-methoxycarbonyl-phenoxy)-(2S)-pyrrolidinylmethoxy]benzoate (444 mg,

1.15 mmol), EDC-HCl (265 mg, 1.38 mmol), HOBt (187 mg,

1.38 mmol) and Et 3 N (195 µl, 1.40 mmol) in THF (10 mL) were stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (60:1 to 50:1, v/v) as eluent to give methyl 4-[ (45)-(4-methoxycarbonylphenyloxy)-1-[4-[ N' -

(2-methylphenyl) ureido] phenylacetyl] - (2 5)-pyrrolidinylmethoxy] -. benzoate (332 mg, 44%) as white foam.

1 H-NMR (CDCl 3 ) δ 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 (MN-1).

To a stirred solution of methyl 4-[(4S)-(4-methoxy-carbonylphenoxy)-1-[4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (332 mg , 0.51 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1N HCl and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHGl 3 -Et 2 O to give 119 (11.8 mg, 37%) as a white crystalline powder. Molecular weight 623.65. Temp.:

157-160°C; 1H-NMR pMSO-dJS

2.20-2.25 (series of; s. and m, total 4 H), 2.39-2.47 (m, 1 H),. 3.64 (s, 2H), 3.68-3.89 (m, 1H), 4.02-4.08 and 4.16-4.20. (each st, total 2 H), 4.29-4.33 and 4.39-4.43 (each st, total 2 H), 5.20-5.26 (m, 1 H), 6.92-6.96 (m, 1 H), 7.02-7.08 (xn , 4 H), 7.12-7.18 (m, 4 H), 7.39-7.41 (m, 2 H),

7.84-7.92 (m, 6 H). 9.01 (s, 1 H), 12.65 (br s, 2 H); MS (ESI) m/z 624 (M<*>+1);Xna/. Meant for

in

CjjHjjNjOs-IHjO: C, 65.51; H, 5.50; N, 6.55. FoundlC, 65.48; H, 5.36; N, 6.52.

EXAMPLE 102

4-[4-(2,4-difluorophenoxy)-1-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4-hydroxyproline (4.0 g, 16.3 mmol), Ph3P (5.14 g,

19.6 mmol) and 2,4-difluorophenol (2.55 g, 19.6 mmol) in THF

(50 mL) was added DIAD (3.9 mL, 19.6 mmol) and the mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1) to give methyl 1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)pyrrolidine-2- carboxylate (5.82 g, quantitative) as a yellow oil.

.To a stirred solution of methyl 1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylate (5.82 g, 16.3 mmol) in THF (130 mL) was added 0.25 N NaOH

(130 mL, 32.6 mmol). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (100 mL) and extracted with CHCl 3 (2 x 200 mL). The extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 46% ) as a colorless foam.

'H-NMR (CDCl1) 5 1.42-1.47 (m, 9H), 2.29-2.74 (. series of' m > 2 H), 3.66-3.71 (m, 2H),

4.46-4.51 (m, 1H), 4.83 (m, 1H), 6.73-6.95 (m, 3H).

To a stirred solution of 1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 7.43 mmol) in THF (50 mL) was added BHyDMS (452 µl, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by the addition of H 2 O (100 mL). The mixture was extracted with CHCl 3 (2 x 200 mL ), dried over MgSO 4 and evaporated. methanol ..(1.76 g, 72%) as a colorless oil.

1 H-NMR (CDCl 3 ) δ 1.45 (s, 9 H), 2.28-2.36

(iri, 2 H), 3.58-4.99 (series of. m, 8 H), 6.74-6.90 (m, 3 H).

To a stirred solution of 1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (500 mg, 1.52 mmol), methyl 4-hydroxybenzoate (277 mg, 1.82 mmol) and Ph3P (477 mg, 1.82 mmol) in THF (10 mL) was added DIAD (358 µl,

1.82 mmol) and the mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHCl3-EtOAc (20:1) as eluent to give methyl 4-[1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy) )-2-pyrrolidinylmethoxy]benzoate (529 mg, 75%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 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 (d, 2 H, J= 8.5 Hz), 7.95 (d, 2H, J = 8.5 Hz).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-(4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (52 9 mg, 1.15 mmol) in C.H 2 Cl 2 (5 mL ) TFA was added

(5 ml). The mixture was stirred overnight. The mixture was

concentrated in vacuo and the residue made basic by addition of saturated NaHCO 3 . The mixture was extracted with CHCl 3 (2 x 100 mL). The extracts were dried over K 2 CO 3 and evaporated to give methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (385 mg, 92%) as a yellow oil.

1 H-NMR (CDCl 3 ) δ 1.89-1.95 (rn, 1 H), 2.28-

2.35 (m, 1H), 3.09 (dd, J= 12.5, 4.9 Hz, 1 H), 3.33 (d, 7= 12.5 Hz, 1 H), 3.60 (m, 1 H), 3.86 (s, 3 H) , 4.10 (d, J= 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-pyrrolidinylmethoxy]benzoate (380 mg, 1.05 mmol), 3-methoxy-4-[α7r-(2-methylphenyl)ureido]phenylacetic acid ( 329 mg, 1.05 mmol), EDC-HCl (302 mg, 1.58 mmol) and a catalytic amount of HOBt and DMAP in DMF (10 mL) bee 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, the residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) to CHCl3-MeOH (10:1) as eluent to give methyl 4-[4-(2,4-difluorophenoxy)-1- [3-Methoxy-4-[A7r-(2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethoxybenzoate (693 mg, quantitative) 'H-

NMR (CDCl 1 ) 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-difluorophenoxy)-1-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxybenzoate (693 mg, 1.05 mmol) in THF (8 mL) was added 0.25 N NaOH (8.4 mL, 2.10 mmol). The mixture was stirred overnight. The mixture was poured into 1 N HCl

(200 ml) and the resulting precipitate was collected by suction. The solid was chromatographed on silica gel with CHCl 3 -MeOH (50:1 to 10:1) as eluent to give 120' (323 mg, 48%) ■■■ as a colorless ■ amorphous solid. Molecular weight 645.65.

1 H-NMR (DMSO-dt) 6 2.25 (s, 3 H), 2.35

(m, 2 H), 3.33-5.18 (series of ni, 11 H), 6.75 (dd, 1 H, J= 8.3, 1.7 Hz), 6.87-7.30 (series of ^ 8 H), 7.79 (d, 1 H, J = 8.3 Hz), 7.85-7.90 (m, 3 H), 8.01 (d, 1 H, J= 8.3 Hz), 8.49 (s, 1 H), 8.57 (s, 1 H); MS (FAB) m/z, 646 QvT+1).

EXAMPLE 103

4-[1-[4-[ N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(6-quinolyloxy-2S-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl (trans-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl)methoxybenzoate (1.0 g, 3.0 mmol), 6-hydroxyquinoline (435 mg, 3.0 mmol) and Ph3P

(943 mg, 3.6 mmol) in THF (10 mL) was added DIAD

(727 mg, 3.6 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (i:2, v/v). To a stirred solution of the product in CH 2 Cl 2 (6.0 mL) was added TFA (6.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (1% to 10%, v/v) as eluent to give methyl 4-[(4S)-[(6-quinolyloxy-(2S)-pyrrolidinyl)] methoxybenzoate (900 mg, 82%) as a pale yellow oil. ' 'H-NMR ;

(CDC13) 5 1.92-2.10 (m, IH), 2.45-2.55 (m, IH), 3.20-3.30 (rn, IH), 3.38-3.50 (m, IH), 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, J= 2.7 Hz, IH), 7.35-7.38 ( m, 2H), 7.96 (d, J = 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-quinopropyloxy-(2S)-pyrrolidinyl) methoxybenzoate (300 mg, 0.79 mmol), 4-[N-(2-chlorophenyl)ureido]-3-methoxyphenylacetic 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-HCl (228 mg, 1.2 mmol) at 0°C. The reaction mixture was stirred at room temperature for .16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc.

The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 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-[1-[4-[A7r-(2-chlorophenyl)ureido]-3-methoxy enylacetyl ] -4- (6-

quinolyloxy-(25)-pyrrolidinyl] methoxybenzoate (520 mg, 95%)

as a colorless oil.

1 H-NMR (CDCl 3 ) δ 2.30-2.60 (m, 3H), 3.64 (s, 2H), 3.73 (s, 3H), 3.80-3.95 (m, 1H),

3.87 (s, 3H), 4.15-4.30 (m, IK), 4.50^.70 (rn, 2H), 5.11 (br s, IK), 6.81-7.01 (m, 6H), 7.26 -7.39

(m, 6H), 7.93-8-.03 (m, SK), 8.19 (d, J= 8.3 Hz, IH), 8.80 (s, IK).

To a stirred solution of methyl 4- [1- [4-.[W-(2-chlorophenyl)ureido]-3-methoxy enylacetyl]-4-(6-quinolyloxy-2S-pyrrolidinyl]methoxybenzoate (520 mg, 0, 75 mmol) in THF

(10.0 ml')-"-and MeOH (5.0 ml) was added 1 N NaOH (1.5 ml,

1.5 mmol). The mixture was stirred at 60°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto

and neutralized with 1 N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 121

(450 mg, 88%) as a white crystalline solid. Molecular weight 681.13. M.p.: 129-133 °C; IR (KBr) 3332, 1704, 1604,

1531, 1419, 1222, 1166 cm"<1>; 1H-NMR (DMSO-dJ 5 2.25-2.55 (m, 2H), 3.67 (s, 2H), 3.82 (s, 3H), 3.81-3.92 (m , IK), 4.02-4.15 (m, 2H), 4.40-4.50 (m, 2H), 5.25-5.40 (m, IK), 5.33-7.07 (m, SK),

. 7.26-7.49 (m, 5H), 7.83-8.23 (m, 6H), 8.73-8.74 (m, IK), 8.90 (s, IK), 8.94 (s, IH); MS (FAB) m/z 681 (M<+>+1); Anal Calcd for C31H33N,O7Cl-0.5H2O: C, 64.39; H, 4.97; N, 8.12. FoundC', 64.22; H, 4.90; N, 7.96,

EXAMPLE 104

4- [1- [4- [W-(2-bromophenyl)ureido]-3-methoxy enylacetyl] - (45) -

(6-quinolyloxy-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(45-(6-quinolyloxy-2S-pyrrolidinyl)methoxybenzoate (300 mg, 0.79 mmol), 4-[N-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (299 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) were added

EDC-HCl (22 8 mg, 1.2 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 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- [1-[4-[ N' -(2-bromophenyl)ureido]-3- methoxyphenylacetyl]-(4S)-(6-quino.lyloxy-(2S)-pyrrolidinyl]methoxybenzoate (530 mg, 91%) as a colorless oil.

1H-NMR (CDCl1) δ 2.30-2.62 (m, 3H), 3.65 (s, 2H), 3.75 (s, 3H), 3.80-3.95 (m, 1H), 3.93 (s, 3H), 4.10-4 .30 (m, IK), 4.50-4.70 (m, 2H), 5.11 (brs, IK), 6.82-6.98 (m, 6H), 7.15-7.39 (m, 5H), 7.52 (d, J= 8.0 Hz , IK), 7.93-8.03 (m, SK), 8.14 (d, J= 8.3 Hz, IK), 8.80 (s, IK).

To a stirred solution of methyl 4-[1-[4-[A7r-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-4-(6-quinolyloxy-2s-pyr-r-ol-i-d-i- nyl] methoxybenzoate (530' mg, 0.72 mmol) in THF (10.0 nil) and MeOH (5.0 mL) was added 1N NaOH (1.4 mL, 1.4 mmol).The mixture was stirred at 70°C for 24 h. The mixture was concentrated in vacuo, water was added thereto and neutralized with 1 N HCl. The solid obtained was collected, washed with water and dried in vacuo to give 122 (4 60 mg, 88% ) like a

.white crystalline solid. Molecular weight 725.59.. Mp.: 149-153 °C; IR (KBr) 3332, 1704, 1604, 1527, 1222, 1164 cm-1; 1H-NMR (DMSO-dJ 8 2.28-2.58 (m, 2H), 3.67 (s, IK), 3.82 (s, 3H), 3.85-3.90 (m, IK), 4.05^.15 (m, 2H) , 4.40-4.50 (m, 2H), 5.20-5.32 (m, IH), 6.77-7.07 (m, SK), 7.31-7.61 (m, 5H), 7.83-7.97 (m, SK), 8.21-8.22 ( m, IK), 8.73-8.74 (m, 2H), 8.92 (s, IK) ; MS (FAB) m/ z 725 (M<+>), 727 Q^^ 2) ; Anal Calculated for [^HjjN/ D 2 -O.SH 2 O: 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 105 4-[ (2S,4S)-1-[3-Methoxy-4-[Δ7r-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy]-2-pyrrolidinyl]benzoic acid

To a stirred mixture of methyl (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g,

17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 mL) was added DIAD (3.72 mL,

18.9 mmol) at room temperature under a nitrogen atmosphere. After stirring overnight, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl 3 /EtOAc (10/1)] to give methyl (2S,4S)-1-tert-butoxycarbonyl -4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g ), which was used without further purification.

To a stirred solution of methyl (2S,4S)^1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g) in 1 THF (116 mL) was added 0.25 N NaOH ( 116 ml,

2 9.0 mmol) at room temperature. The resulting mixture was stirred overnight. After removal of the solvent, the mixture was acidified by addition of 1 N HCl and extracted with CHCl 3 . The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from n-hexane-CHCl3 to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid [4.44 g, 85% (2 steps) as a white powder. 1 H-NMR (DMSO-ds) 51.37

and-1.41 (s, 9H,amid46fhepr1)> 2.26 (d, J= 13.9 Hz, IH), 2.65 (m, IH), 3.47 (d, J= 11.5 Hz, IH), 3.81 (m, lk£ 430 (iri, IH), 5.14 (m, IH), 7.02-7.86 (m, 7H).

To a stirred solution of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g,

3.13 mmol) in THF (30 mL) was added BH 3 • DMS (0.63 mL, 6.3 mmol) at 0°C. The mixture was immediately warmed to room temperature and then heated1" at 50°C for 1.5 hours. 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 2 SO 4 and evaporated. The residue was chromatographed on silica gel [50 g, CHCl 3 /MeOH (50/1)] to give (2S, 4S)-1-tert-

butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (1.10 g, 100%) as a pale yellow oil.

(m, IK), 3.58-4.80 (m, 4H), 5.01 (br, IH), 7.04-7.99 (m, 7H). '

To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (640 mg, 1.86 mmol),

methyl 4-hydroxybenzoate (2 83 mg, 1.8 6 mmol) and PPh3 (4 88 mg,

1.86 mmol) in THF (18 mL) was added DIAD (0.37 mL, 1.86 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred overnight. After removal of the solvent, the obtained residue was chromatographed on silica gel [100 g, n-hexane/EtOAc (2/1)] to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-(2 -naphthyloxy)-2-pyrrolidinyi-rfnetoxybenzoate (830 mg, 93%) as a colorless , IK), 2.53

(d, J= 14.2 Hz, IK), 3.72-3.85 (m, IK), 3.86 and 3.87 (s, 3H, amide isomers), 4.17 (m, IK), 4.26-

4.52 (m, 2H), 5.06 (br, IH), 6.87 (d, J= 8.8 Hz, IH), . 6.94 (d, J- 8.8 Hz, 2H), 7.04 (br, 2H), 7.33

(t, J = 7.3 Hz, IK), 7.42 (t, J = 7.3 Hz, IH), 7.64-8.02 (m, 5H).

To a stirred solution of methyl 4-[(2S, 4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolodinyl] methoxy-. benzoate (870 mg, 1.74 mmol) in CH 2 Cl 2 (24 mL) was added

TFA (6 mL) at room temperature. The mixture was stirred overnight and concentrated in vacuo. The residue was diluted with CH 2 Cl 2 and made basic by the addition of 1 N NaOH which was extracted with eH 2 Cl 2 . The organic layer was washed with brine, dried over NaSO 4 and concentrated. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc (2/1)] to give methyl 4-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolodinyl]-methoxybenzoate (750 mg, 100%) as a black oil.

1H-NMR (CDCl1) δ 1.99 (dd, J= 14.2, 5.6 Hz, IH), 2.48 (m, IK), 3.22 (dd, J= 12.2,

4.6 Hz, IH), 3.43 (d, J= 12.5 Hz, IH), 3.67 (m, IK), 3.86 and 3.87 (s, 3H, amide isomers;), 4.11

(m, 2H), 5.04 (m, IK), 6.83 (d, J= 8.5 Hz, IK), 6.89 (d, J= 8.8 Hz, 2H), 7.07 (d, J= 2.0Hz, IH), 7.12 (d, J= 9.0 Hz, IK), 7.33 (dt, J= 8.1, 1.2 Hz, IK), 7.44 (dt, J= 6.8, 1.2 Hz, IK), 7.70 (d, J=

8.1 Hz," IK), 7.75 (dd, J= 9.0, 5.1 Hz, 2H), 7.90 (d, J= 8.5 Hz, IK), 7.96 (dd^/= 6.8, 2.0 Hz, 2H).

A mixture of 3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetic acid (333 mg, 0.106 mmol), methyl 4-[(2S,'4S)-4-(2-naphthyloxy)-2 -pyrrolodinyl] methoxybenzoate (400 mg, 1.06 mmol), EDC-HCl (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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel

[100 g, n-hexane/EtOAc (1/1) CHCl3/MeOH (50/1)] to give methyl 4- [ (2S, 4S)-1- [3-methoxy-4- [jV'-( 2-methylphenyl)ureido]-phenylacetyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (520 mg, 73%)- as a pale brown amorphous substance.

1H-NMR (CDCl1) 6 2.28 (s, 3H), 2.29 (m, 1H), 2.55 (d, J

14.2 Hz, IH), 3.60 (d,J= 3.4 Hz, 2H), 3.66 (d, J= 3.7 Hz, 3H), 3.68-4.00 (m, 5H), 4.05-4.67 (m, 3H), 5.09 ( br, IH), 6.61 (s, IH), 6.77 (m, 2H), 6.87 (d, J= 8.8 Hz, IH), 6.94-7.54 (m, 8H), 3^ 8.09 (m, 8H); MS (ESI) m/z 674 (M<*>+1).

To a solution of methyl 4-[(2S,4S)-1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl] methoxybenzoate (415 mg, 0.616 mmol) in THF (4.9 mL) was added 0.25 N NaOH (4.9 mL). After stirring at room temperature for 3 days, the mixture was acidified with 1N HCl and extracted with CHCl3'-MeOH. (10/1) . The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 -MeOH (10/1)] to give 123 (180 mg, 44%) as. a colorless amorphous substance. Molecular weight 659., 73. IR (KBr) 3354, 2937, 1685, 1601, 1533, 1255 cm-<1>; 1H-NMR (DMSO-dJ 5 2.24 (s, 3H), 2.25-2.43 (m, 2H), 3.65 (s, 2H), 3.81 (s, 3H), 3.83 (rn, 1H), 4.05-4.70 ( m, 4H),'5.21-5.33 (br, IH), 6.76 (d, J = 7.3 Hz, IH), 6.86-7.35 (m, 9H), 7.44 (t, J = 7.3 Hz, IH), 7.76- 7.89 (m, 6H), 8.01 (d, J= 8.3 Hz, IH), 8.48 (s, IH), 8.56 (s, IH); MS (FAB) m/z 660(M<*>+1).

EXAMPLE 106

4- [ (2S,4S) -1- [4- [W - (2-chlorophenyl)ureido] -3-methoxyphenylacetyl] -4-(2-naphthyloxy)-2-pyrrolodinyl]methoxybenzoic acid

One mixture of 4-tW-(2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (310 mg, 0.93 mmol), methyl 4-[ (2S, 4S)-4-(2-naphthyloxy)-2- pyrrolodinyl]methoxybenzoate (350 mg, 0.93

mmol), EDC-HCl (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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, n-hexane/EtOAc .(1/1) CHCl 3 /MeOH (50/1)] to give

methyl 4-[(2S,4S)-1-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl] methoxybenzoate (450 mg, 68 %) as a pale brown amorphous substance.

1H-NMR (CDCl1) 6 2.32 (iri, 1H), 2.58 (d, J = 14.5 Hz, 1H),

3.63 (d, J" 2.7 Hz, IH), 3.70 (s, 3H), 3.86 (s, 3H), 3.84-3.95 (rn, 2H), 4.15-4.64 (m, 4H), 5.11 (br, IH) , 6.79-7.06 (m, 7H), 7.21-7.46 (m, 7H), 7.66-7.77 (m, 3H), 7.92 (d, J= 8.8 Hz, IH), 7.97 (m, IH), 8.17 (d , J= 8.4 Hz, 1H);MS (ESI) m/z 694 (M<+>+1), 696 (ivT+3).

To a solution of methyl 4-[(2S,4S)-1-[4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate ( 381 mg, 0.535 mmol) in THF

(4.3 mL) 0.25 N NaOH (4.3 mL) was added. After stirring at room temperature for 3 days, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/l). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl3-MeOH (10/1)] to give 124

(140 mg, .39%) as a colorless amorphous substance. Molecular weight 6 8 0.15. IR (KBr) 3323, 2935, 1704,

1601, .1529, 1529, 1508 cm"'; 'H-NMR (DMSO-dJ 6 2.27-2.49 (m, 2H), 3.65 (s, 2H), 3.81 (s, 3H), 3.83 (m, 1H) , 4.05-4.71 (m, 4H), 5.30 (br, IH), 6.77 (d, /= 7.8 Hz, IH), 6.87-7.16 (m, 4H), 7.14 (dd, J= 8.8, 2.2 Hz, IH ), 7.27 (t, J= 7.3 Hz, IH), 7.29-7.46 (m, 4H), 7.76-7.86 (m, 5H), 7.96 (d, J = 8.3 Hz, IH), 8.08 (dd, J= 8.3, 1.2 Hz, IH), 8.90 (s, IH), 8.93 (s, IH); MS (FAB) m/ z 680 (IV<f>+1), 682 (M++3); ^na/ .Calculated for Cjg^ClNjCyl^O: C, 65.37; H, 5.20; N, 6.02. Found: C, 65.43; H, 5.11; N, 5.93.

EXAMPLE 107

2-[(2S,4S)-1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolodinyl]methoxy-5- pyridine-carboxylic acid

To a stirred mixture of methyl (2S,4J?)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.22 g,

17.2 mmol); To 2-naphthol (2.73 g, 18.9 mmol) and PPh3 (4.96 g, 18.9 mmol) in THF (80 mL) was added DIAD (3.72 mL,

18.9 mmol) at room temperature under a nitrogen atmosphere. After stirring overnight, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl 3 /EtOAc (10/1)] to give methyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g ) which was used in the next reaction without further purification.

To a stirred solution of methyl (2S,4S)-1-tert-butoxy- • carbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylate (5.37 g)

1 THF (116 ml) was added 0.25 N NaOH (116 ml7

2 9.0 mmol) at room temperature. The resulting mixture was

stirred overnight. After removal of the solvent, the mixture was acidified by the addition of 1 N HCl and extracted with CHCl 3 . The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized with n-hexane-CHCl 3 to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid [4.44 g, 85% (2 steps)] as a white powder. 1 H-NMR (DMSO-dj) 51.37

and 1.41 (s, 9H, amide isomers), 2.26 (d, J= 13.9 Hz, IH), 2.65 (m, IH), 3.47 (d, J= 11.5 Hz, IH), 3.81 (m, IH), 4.30 (m, IH), 5.14 (m, IH), 7.02-7.86 (m, 7H).

To a stirred solution of (2S, AS)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 mL) was added BH3 ■ DMS (0.63 ml,

6.3 mmol) at 0°C. The mixture was brought to room temperature immediately and then heated at 50°C for 1.5 hours.

After cooling to room temperature, the mixture was quenched by addition of water at 0°C and extracted with EtOAc. The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel [50g, CHCl3/MeOH (50/1)] to give (2S,AS)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (1.10g, 100 %) as a pale yellow oil.

1H-NMR (CDCl 1 ) 6 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 (2S,AS)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl methanol (484 mg, 1.41 mmol), methyl 2-hydroxy-5-pyridinecarboxylate (216 mg, 1.41 mmol) and PPh 3 (370 mg, 1.41 mmol) in THF (15 mL) was added DIAD (0.28 mL, 1.41 mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred overnight. After removal of the solvent, the obtained residue was chromatographed on silica gel [50 g, n-hexane/EtOAc (2/1)] to give methyl-2-[ (2S, AS)-1-tert-butoxycarbonyl-4-(2 -naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (170 mg, 25%) as a colorless oil.. 1 H-NMR (CDCL,) 6

1.47 (s, 9H), 2.37 (m, IH), 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, IH), 5.06 (br, IH), 6.70 (d, J= 8.8 Hz, 2H), 7.05-7.09 (m, 2H), 7.33 (t, J= 6.9 Hz, IH), 7.42 (t, J= 6.9 Hz, IH), 7.67-7.75 (m, 3H), 8.09 (d, J= 8.8 Hz, IH), 8.77 (d, Jr= 2.2Hz, IH) .

To a stirred solution of 5-carboxymethyl-2-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine (170 mg, 0.36 mmol) in CH 2 Cl 2 (5 ml) was added TFA (2 ml) at room temperature. After stirring for 2 hours, the mixture was concentrated in vacuo and diluted with CH 2 Cl 2 and made basic by the addition of 1 N NaOH. The combined reaction mixture was extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified on TLC [CHCl3/MeOH (10/1)] to give methyl 2-[(2 S,AS)-4-(2-naphthyloxy)-2-pyrrolidinyl]-methoxypyridine-5-carboxylate (107- mg, 80%) as a colorless oil. 1H-NMR (CDCl1) 8 1.95 (m, IK), 2.27 (br, IK), 2.46 (m, IH), 3.19 (dd, J = 12.2, 4.9 Hz, IH), 3.41 (d, J= 12.2 Hz, IK), 3.65 (m, IK), 3.89 (s, 3H), 4.58 (m, 2H), 5.00 (br, IK), 6.77 (d, J= 8.8 Hz, IK), 7.06 (br, IH ), 7.11 (dd, 7= 8.8, 2.7 Hz, IK), 7.31-7.45 (m, 2H), 7.69-7.76 (m, 3H), 8.13 (dd, J= 8.8, 2.4 Hz, IK), 8.78 ( d, 2. 2 Bz, IK).

A mixture of 3-methoxy-4- [ N'~ (2-methylphenyl)ureido] phenylacetic acid (89 mg, 0.283 mmol), methyl 2-[(2 S , AS)- A -(2-naphthyl-oxy)- 2-pyrrolidinyl] methoxypyridine-5-carboxylate (107 mg, 0.78 mmol), EDC-HCl (81 mg, 0.425 mmol) and DMAP (52 mg, 0.425 mmol) in DMF (3 mL) were stirred at room temperature for 18 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (10/1)] to give 2-[(2S,4S)-1-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetyl]- 4-(2-naphthyloxy)-2-pyrrolidinyl]-methoxy-5-pyridinecarboxylic acid methyl ester (193 mg, 100%) as a colorless amorphous substance.

J-'H-HMR (CDClj) 8 2.27 (d, J = 3.2 Hz, 3H), 2.30 (m, IH), 2.49 (dd, J = 14.2, 2.0 Hz, IH), 3.60 (d, J= 3.9 Hz, IH), 3.67 (d, J = 5.9 Hz, 3H), 3.81 (s, 1H), 3.85 (s, IK), . 3.88 and: 3.91 (s, 3H,amide isomers^, 3.95 (m, IK), 4.02-5.09 (m, AK), 6.67 (d, J= 8.8 Hz, IK), 6.73-7.13 (m, 3H), 7.20-7.45 (m, IK), 7.53 (t, J= 7.8 Hz, IK), 7.67-7.77 (m, 3H), 8.02-8.84 (m,

3H).

For HCl salt: a pale brown amorphous substance. IR (KBr) 3346, 2951, 1720, 1601, 1533, 1281 cm"<1>; MS (FAB) m/z 675 (M<+>+1).

To a' solution of 2-[(2S,AS)-1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetyl]-4-(2-naphthyloxy)-2-pyrrolidinyl]- methoxy-5-pyridinecarboxylic acid methyl ester (158 mg, 0.23 mmol) in THF (1.8 mL), 0.25 N NaOH (1.8 mL) was added. After

stirring at room temperature for 22 hours, the mixture was neutralized with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The

combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (5/1)] to give 125 (51 mg, 34%) as a colorless amorphous solid. Molecular weight 660.72.

IR (KBr) 3354, 2956, 1601, 1533, 1255, 1022 cm'<1>; 1H-NMR (DMSO-d«) δ 2.24 (s, 3H), 3.30-5.32

(m, 13H), 6.72-8.82 (m, 19H); MS (FAB) mh 661(M*'+1); Anal. Calculated for CjjHj^O^O.SEtOH-1HjO: C, 66.75; H, 5.89; N, 7.98. Found: C, 66.39; H, 5.55; N, 7.66.

EXAMPLE 108

4- [5-(R)-benzyloxymethyl-1-[4-[N'-(2-methylphenyl)ureido]phenylacetyl] -2-(S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of benzyl-(S)-glycidyl ether (5.0 g, 3 0.5 mmol) in THF (100 mL) was added allylmagnesium chloride (1.0 Mi Et 2 O, 30.5 mL, 30 .5 mmol) at -78°C, and the resulting mixture was gradually warmed to room temperature with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHCl 3 . The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 35%) as a colorless oil: 'H -NMR (CDCl1) δ 1.52-1.60 (m, 2 H), 2.11-2.25 (m, 2 H), 2.34 (d, J= 3.2 Hz, 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 .(st 2 H), 4.96-5.07 (series, of rh, 2H), 5.78 -5.88 (m, 1H), 7.29-7.38 (m, 5H); MS (ESI) m/z, 224 (M<+>+NH,<*>).

To a stirred solution of 1-benzyloxy-2-(R)-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 diisoprolylazodicarboxylate (2.62 mL, 12.7 mmol) at room temperature and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyl-oxy-2-(S)-phthalimido-5-hexene (2.95 g, 83%) as a colorless solid 3 e : 1H-NMR (CDCl1) 8 1.76-1.84 (m, 2 H), 2.06 (dd, J= 14.4, 6.8 Hz), 2 H, 2.12-2.22 (m, 1 H), 3.69 (dd, J= 10.0, 5.6 Hz, ,1 H), 4.00 (t, /= 9.6 Hz, 1 H), 4.46 (d, J= 12.0 Hz, 1 H), 4.53 (d, /= 12.0 Hz, 1H), 4.51-4.58 (m, 1 H), 4.91-4.99 (series of m;2H), 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, 336 (Ivf+H).

To a stirred solution of 1-benzyloxy-2-(S)-phthalimido-5-hexene (2.95 g, 8.80 mmol) in EtOH (30 mL) was added hydrazine hydrate (80% in water, 460 mL, 11.4 mmol) at room temperature, and the resulting mixture was heated under reflux for 7.5 hours with stirring. The solution was filtered, and the filtrate was concentrated in vacuo. The residue was poured into aqueous N 7 AHCO 3 and extracted with CHCl 3 . The organic layer was dried over anhydrous Na 2 SO 4 , then concentrated in vacuo to give 2-(S)-amino-1-benzyloxy-5-hexene (1.90 mg, quant.) as a colorless oil. (CDCy g 1J7_

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, IH), 3.45 (dd, J= 9.2, 4.0 Hz, 1 H), 4.53 (s, 2 H), 4.94-5.06 (series of sc, 2 H), 5.76-5.85 (m, 1 H), 7.27-7.37 (m, 5 H); MS (ESI) m/z, 206 (M<+>+H), 247 (M<+>+H+CH 3 CN).

To a stirred solution of 2-(S)-amino-1-benzyloxy-5-hexene (1.89 g, 9.21 mmol) and triethylamine (1.28 mL, 9.21 mmol) in CH 2 Cl 2 (20 mL) benzoyl chloride (1.07 mL, 9.21 mmol) was added at room temperature and the resulting mixture was stirred for 23 h. The mixture was poured into water and extracted with CH 2 Cl 2 . The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give N-2-( S )-(1-benzyloxy)-5-hexenyl]benzamide (2.67 g, 94%) as colorless rial clays, mp 7'8-79 °C;

1 H-NMR (CDCl 1 ) δ 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, sc, 2.H), 5.78-

5.89 (m, ] H), 6.39 (d, J= 8.0 Hz, 1 H), 7.27-7.51 (m, 8 H), 7.74 (d, J= 7.2 Hz, 2 H); MS (ESI)

m/z, 310 (MN-H).

To a stirred solution of iN-2-(5)-(1-benzyloxy)-5-hexenyl]benzamide (2.41 g, 7.79 mmol) in CH 3 CN-H 2 O (3:1, 40 mL) was added iodine (2.97 g, 23.4 mmol) was added in one portion and the resulting mixture was stirred for 20 h. The mixture was poured into aqueous Na 2 S 2 O 3 and concentrated in vacuo, then extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (30 mL) and di-tert-butyl dicarbonate (2.55 g, 11.7 mmol), Et 3 N

(1.63 mL, 11.7 mmol) and Δ7,N-dimethylaminopyridine (180 mg, 1.47 mmol), and the resulting mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with CH 2 Cl 2 . The organic layer was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) to give iV-Boc-2-(5)benzoyloxymethyl-5-( S )-benzyloxymethylpyrrolidine (1.27 g, 38%) as a colorless oil . 'H-NMR (CDCl1) δ 1.41 and 1.49 (s, total 9 H),';

1.85-2.00 (series> sc, 4 H), 3.33-4.59 (series sc, 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 (Nf+Na<*>).

To a stirred solution of W-Boc-2-(S)-benzoyloxymethyl-S-fs; -benzyloxymethylpyrrolidine (1.23 g, 2.89 mmol) in MeOH (30 mL) was added NaOH (1.0 mL water, 3.47 mL, 3.47 mmol) at room temperature and the resulting mixture was stirred in 4 hours.- The mixture was neutralized with aqueous 1N-HCl and concentrated in vacuo, and then extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (3:1) as eluent to give iV-Boc-5-( S )-hydroxymethyl-2-( S )-benzyloxymethylpyrrolidine (847 mg, 91%) as a colorless oil ."

1H-NMR (CDCl1) δ 1.41 (s, 9 H), 1.57 (brs, 1 H), 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 (m, 5H); MS (FAB) m/z, 322 (M<+>+H).

To a stirred solution of A7-Boc-2-(S)-hydroxymethyl-5-[S)-benzyloxymethylpyrrolidine (388 mg, 1.21 mmol), triphenylphosphine (380 mg, 1.45 mmol) and methyl 4-hydroxybenzoate (220 mg, 1.45 mmol) was added diisopropylazodicarboxylate (200 mL, 1.45 mmol) at room temperature and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (3:1) as eluent to give methyl 4-[2-(S)-(A7-Boc-5-(S)-benzoyloxymethyl)pyrrolidinylmethoxy]benzoate (462 mg, 84% ) as a colorless oil: 1 H-NMR (CDC 13 ) δ 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 (xn, 2H), 7.26-7.34 (m, 5H), 7.95-7.98 (m, 2H); MS (FAB) m/z, 456 (M<*>+H), 478 (M<+>+Na<+>).

To a stirred solution of methyl 4-[2-(S)-N-Boc-5-(S)-benzoyloxymethyl)pyrrolidinylmethoxy]benzoate (446 mg, 0.98 mmol) in CH 2 Cl 2 (10 mL) was added trifluoroacetic acid ( 10 mL) at room temperature, and the resulting mixture was stirred for 1 hour. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , then extracted with CHCl 3 . The organic layer was washed with water, dried over anhydrous Na 2 SQ 4 and then concentrated in vacuo to give methyl 4-[2-(5)-5-( S )-benzoyloxymethyl)pyrrolidinylmethoxy]benzoate- (363 mg, quant.) as a yellowish oil. The product was used in subsequent reactions without further purification.

1H-NMR (CDCl1) δ 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 (, overlap., 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, 2H); MS (FAB) m/z, 356

' (M*+H).

To a stirred solution of methyl 4-[2-(S)-5-(S)-benzoyloxymethyl)pyrrolidinylmethoxy]benzoate (115 mg, 0.32 mmol) 4-[AJ1-(2-methylphenyl)ureido]phenylacetic acid (92.0 mg, 0.32 mmol) and A^Af-dimethylaminopyridine (52.0 mg, 0.42 mmol) in DMF (10 mL) was added EDC-HCl (81.0 mg, 0.42 mmol ) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was washed with saline

ning, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-

MeOH (20:1) as eluent to give methyl 4-[5-(JR)-benz<y>lox<y>meth<y>l-1-[4-[ N'~ (2-meth<y >lphen<y>l)ureido]phenylacetamido]-2-(S)-pyrrolidinylmethoxy]benzoate (169 mg, 84%) as a colorless amorphous solid. 'H-NMR (CDCl1), mixture of rotamers" 8 1.92-2.18 (m, 3 H), 2.24 and. 2.25 (s, total 3 H), 2.20-2.31 (.over<l>a<pp>/. l'H), 3.39-3.70 (series of sc, 4 H), 3.87 and* 3.89 (s„ total 3 H),4.17 and 4.18 (s, total 2H), 4.30-4.45 (series of m, 2 H), 4.53 (p, 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

(FAB) m/z, 622 (M<+>+H).

To a stirred solution of methyl 4-[5-(R)-benzyloxymethyl-1-[4-[iV-(2-methylphenyl)ureido]phenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (15 6 mg, 0.24 mmol) in MeOH-THF

(1:5, 12 mL) was added 1.0 M NaOH (1.2 mL, 1.20 mmol)

at room temperature, and the resulting mixture was heated at 80°C with stirring for 7 hours. The mixture was poured into 1AJ-HCl, and then extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (5:1) as eluent to give 12 6 (94.0 mg, 65%) as a colorless amorphous solid. MV 607. , 3 H), 3'.55-4.55 (late-of!m, 10 H), 6.85-7.95 (series:of m, 17 H); MS (TESI) m/z, 630 (MN-Na<*>).

EXAMPLE 109

4-[5-( R )-benzyloxymethyl-1-[4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-( S )-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 4-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (117 mg, 0.33

mmol), 4-[N-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid

(110 mg, 0.33 mmol) and N,N-dimethylaminopyridine (50.0 mg, 0.40 mmol) in DMF (10 mL) was added EDC-HCL (76.0 mg, 0.40

mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[5-(R)-benzyloxymethyl- 1- [4- [ N'~ (2-chlorophenyl) ureido] -3-.methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy] benzoate (189

mg, 85%) as a colorless amorphous solid. 'H-NMR (CDCl1), mixture of xotamarsj 5 1.91-2.30 (series? of m, 4H), 3.39-3.74 (series- of m, 3 H), 3.73 (s, 2 H), 4.15-4.02 (m , 2 H), 4.32-4.44 (m, 1 H), 4.54 (s, 2H), 6.71-7.02 (series-of m, 5 H), 7.06 (s, 1 H), 7.17 (s, 1 H) ,

7.24-7.'40 (series- åv.m, 7 H), 7.89-8.22 (series:of m, 4 H); MS (FAB) m/z, 672 (Ivf+H).

To a stirred solution of methyl 4-[5-(JR)-benzyloxymethyl-1-[4- [JV'- (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (169 mg, 0.25 mmol) in MeOH-THF

(2:5.7 mL) was added 1.0 M NaOH (750 mL, 0.75 mmol) at room temperature and the resulting mixture was heated at 80°C with stirring for 2 hours. The mixture was poured into a liV-HCl, and . then extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated. in vacuum. The residue was chromatographed on silica gel with CHCl 3 -MeOH (15:1) as eluent to give 127 (114 mg, 69%) as a colorless amorphous solid. MV 65 8.14. 'H-

NMR (CDjOD), mixture of rotamers' 6 1.88-2.37 (series avm, 4 H), 3.51-4.49 (series av m, 8H), 3.64 and 3.73 (s, total 3 H), 4.86 (s,'2 H ), 6.85-7.95 (serieav'm, 16 H); MS (ESI) m/z, 658

(MHH), 680 Ovr+Na-OMna/.Calculated for C36H36ClNjO7-HzO: C, 63.95; H, 5.66; N, 6.21. Found: C, 63.65; H, 5.40: N, 5.95.

EXAMPLE 110

4-[5-( R )-benzyloxymethyl-1-[4-[AT-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-( S )-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 4-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (119 mg, 0.34 mmol), 4-[AJ'-(2-bromophenyl)ureido] -3-Methoxyphenylacetic acid (12 7 mg, 0.34 mmol) and A7,A7-dimethylaminopyridine (50.0 mg, 0.40 mmol) in DMF (10 mL) was added EDC-HCl (77.0 mg, 0 .40 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[5- [ R )-benzyloxymethyl-1- [4- [AJ'- (2-bromophenyl)ureido] -3- Methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (217 mg, 90%) as a colorless amorphous solid, Hh-nmr (cddi3), mixture of rotamers 51.92-2.31 (series^of m, 4 H), 3.39- 3.73 (series,of'm,3 H), 3.65 (s, 2H), 4.15-4.02 (m,-2 H), 4.32-4.44 (m, 1 H), 4.54 (s, 2 H), 6.71- 6.99 (series;- sc, 5 H), 7.04 (s, 1 H), 7.11 (s, 1 H), 7.22-7.39.(seriesSavm, 1H), 7.51-8.17 '(series,'of:m, 4 H); MS (FAB) m/z, 716 Qst), 718 (M<+>+2).

To a stirred solution of methyl 4-[5-( R )-benzyloxymethyl-1-r

[4- [AJ'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (178 mg, 0.25 mmol) in MeOH-THF

(2:5.7 mL) was added 1.0 M NaOH (750 mL, 0.75 mmol) at room temperature, and the resulting mixture was heated at 80°C with stirring for 1.5 h. The reaction mixture was poured into 1AJ-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 . and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (15:1) as eluent to give 128 (159 mg, 91%) as a colorless amorphous solid. MV 702.59.

H-NMR (CD3OD), mixture of rotamers 5 1.88-2.35 (serial fav m, 4 H), 3.51-4.49 (serial av m, 8 H), 3.64; and'r3.72 (s, total 3 H ),. 4.87 (s, 2 H), 6.65-8.05 (series, avm, 16 H); MS (ESI) m/z, 702 (W), 704 (M*+2)Mn^Ber^nettbrCJ<H^rNjOJ-HJO: C, 60.00; H, 5.32; N, 5.83. Found: C, 59.66; H, 5.04: N, 5.65.

EXAMPLE 111

3- [5- [ R )-Benzyloxymethyl--1- [4- [JV'-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy] benzoic acid

To a stirred solution of N-Boc-2-(5)-hydroxymethyl-5-(S)-benzyloxymethylpyrrolidine (415 mg, 1.29 mmol), triphenylphosphine (410 mg, 1.55 mmol) and methyl 3-hydroxybenzoate ( 240 mg, 1.55 mmol) was added diisopropyl azodicarboxylate (320 mL, 1.55). mmol) at room temperature and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and then the residue was chromatographed on silica gel eluting with hexane-EtOAc (3:1) to give methyl 3-[2-(S)-(JV-boc-5-(S)-benzyloxymethyl) pyrrolidinylmethoxy] benzoate (513 mg, 87%) as a colorless oil: ig_

NMR (CDCl 1 ) δ 1.40 . and 1.46 (s, total 9 H), 1.95-2.20 (serieiav. m, 4 H), 3.33-3.72 (series favm, 2 H), 3.82-4.00 (m, 1 H), 3.90 and 3.91 (s, total 3 H), 4.09-4.21 (m, 3 H), 4.21-4.57 (m, 2 H), 7.11-7.15 (m, 1 H), 7.26-7.37 (m, 6 H), 7.53-7.65 (m, 2 H); MS (ESI) m/z, 456 (MHH).

To a stirred solution of methyl 3-[2-(S)-(W-Boc-5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (501 mg, 1.10 mmol) in CH 2 Cl 2 (10 mL) was added added trifluoroacetic acid (10 mL) at room temperature, and the resulting mixture was stirred for 1 hour. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , and then extracted with CHCl 3 . The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give methyl 3 [2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinyl-methoxy]benzoate (387 mg, quant.) as a yellowish oil. The product was used in subsequent reactions without further purification .

``H-NMR (CDCl1) δ 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, 2H), 7.09-7.11 (m, 1H), 7.27-7.54 (ra, 6H), 7.54-7.55 (m, 1H), 7.61-7.63 (m, 2H); MS (ESI)

m/z, 35 (M<+>+H).

To a stirred solution of methyl 3-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (140 mg, 0.39), 4-[N-(2-methylphenyl)ureido]- 3-methoxy enylacetic acid (125 mg,

0.3 9 mmol). and A^N-dimethylaminopyridine (58-.0 mg, 0.47 mmol) in THF (15 mL) was added EDC-HCl (90.0 mg, 0.47 mmol) at room temperature, and the the resulting mixture was stirred overnight.' The reaction mixture was poured into water and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na2SO4 and 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-1-[4- [n'-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinyl methoxy]benzoate (256

mg, quant.) as a colorless .amorphous solid.

1H-NMR (CDCl1), mixture of rotamers 5 1.67 (s, 3 H), 1.97-2.40 (sen&; avm, 4 H), 3.42-3.85 (series avm, 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 fr 2 H), 6.32 and'>6.36 (s, total 1 H), 6.75- 6.87 (series iav m, 2 H), 7.20 (brs, 2 H), 7.16-7.72 (seriqiav m, 10 H), 8.03-8.09.

(m, 1H); MS (ESI) m/z, 652 OvT+H).

To a stirred solution of methyl 3-[5-{R)-^benzyloxymethyl-1[4-[N-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (185 mg , 0.28 mmol) in a MeOH-THF

(2:5.7 mL) was added 1.0 M NaOH (860 mL, 0.86 mmol) at room temperature, and the resulting mixture was heated at 60°C with stirring for 1 h. The reaction mixture was poured into 1A7-HCl, and then extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeO'H (5:1) as eluent to give 129 (17.1 mg, 94%) as a colorless amorphous solid. VAT 637.72.

H-NMR (CD3OBf •. mixture of rotamers 5 1.89-2.37 (series fav m, 4 H), 2.29 (s, 3 H), 3.52-4.53 (series. ofTn, 8 H), 3.66- and3.74 (s, total 3 H), 4.85 (s, 2 H), 6.66-7.98 (tendon avm, 16 H); MS

(ESI) /n/z, 638 (M^+H), 660 (M^+Na<*>); ^na/. Calculated for C 2 H 39 N 3 O 7 -H 2 O: C, 67.77; H, 6.30; N, 6.41.'Found: C, 67.40; H, 5.95: N, 6.14.

EXAMPLE 112

3-[5-(R)-benzyloxymethyl-1-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of. methyl 3-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (118 mg, 0.33 mmol), 4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid. (112 mg,

0.3 3 mmol) and A7,A7-dimethylaminopyridine (50.0 mg, 0.40 mmol) in THF (15 mL) was added EDC-HCl (80.0 mg, 0.40 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and 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-1- [4- [ N'~ (2-chlorophenyl)ureido] -3- methoxyphenylacetamido]-2-(S)-pyrrolidinylmethoxy]benzoate (226-mg, quant.) as a colorless amorphous solid. 1H-NMR (CDC13), mixture of rotamers 6 1.99-2.40 (series; avm, 4 H), 3.43-3.92 (series/ avm, 5 H), 3.67 (s, 3 H), 3.98 and 4.02 (s , total 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 I m, 2" H), 7.01- 7.22 (series; of m, 4 H), 7.29-7.53 (series of' iri, 9 H), 7.62-8.26 (series;:of m, 3 H);

MS (ESI) m/z, 672 (M<*>+H).

i To a stirred solution of methyl 3-[5-(R)-benzyloxymethyl-1-[4-[jV' (2-chlorophenyl)ureido]-3-methoxy enylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate ( 169 mg, 0.25 mmol) in MeOH-THF

(2:5.7 mL) was added 1.0 M NaOH (760 mL, 0.76 mmol) at room temperature and the resulting mixture was heated

at 60°C with stirring for 1.5 hours. The reaction mixture was poured into 1N HCl, and then extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 So 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (5:1) as eluent to give 130 (155 mg, 94%) as a colorless amorphous solid. WC 658.14.

'H-NMR (CDjOD), mixture of rotamers .8 1.89-2.35 (series, of m, 4 H), 3.52-4.53 (series of m, 8

H), 3.68 and 3.75 (s, total 3.H), 4.85 (s, 2 H), 6.68-8.03 (senaav'-rh, 16 H); MS (ESI) m/z, 658 (M<+>+H), 680 Ov<f>+Na*); /Ina/.Calculated for CmH^CINjCvHjO: C, 63.95; H, 5.66; N, 6.21. Found: C, 64.01; H, 5.38: N, 5.96. , EXAMPLE 113 3-[5-{ R )-benzyloxymethyl-1-[4 [ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoic acid To a stirred solution of methyl 3-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidinylmethoxy]benzoate (116 mg, 0.33 mmol), 4-[ N'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (124 mg, 0.33 mmol) and N,A7-dimethylaminopyridine (48.0 mg, 0/39 mmol) in THF (15 mL) was added EDC-HCl (75.0 mg, 0.39 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel using CHCl3-MeOH (101) as eluent to give methyl 3-[5-(R)-benzyloxymethyl-1-[4-[A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl] -2-(S)-pyrrolidinylmethoxy]benzoate (209 mg, 89%) "as a colorless amorphous solid. 'H-NMR (CDCl 3 ), "mixture of rotamers 5 1.99-2.37 (series; of m, 4 H), 3.43-3.91 (series fav m, 5 H), 3.70 (s, 3 H), 3.93 and 3.96 (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;a'v m, 10H), 7.91-7.95 (seritfavm, 1 H), 8.20-8.23 ( series savm, 1 H); MS (ESI) m/ z 116 (MO, 718 (M*+2). To a stirred solution of methyl 3-[5-[ R )-benzyloxymethyl-1-[4-[ N '- 2-bromophenyl)ureido ]-3-methoxyphenylacetyl]-2-(S)-pyrrolidinylmethoxy]benzoate (176 mg, 0.25 mmol) in MeOH-THF (2:5.7 mL) was added 1.0 M NaOH (760 mL, 0 .76 mmol) at room temperature, and the resulting mixture was heated at 60°C with stirring for 1.5 hours. The reaction mixture was poured into 1 N HCl, and then extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (5:1) as . eluent to give 131 (156 mg, 88%) as a colorless amorphous solid. MV 702.59.

: 'H-NMR(CDjOD),-mixture of rotamars • 5 1.89-2.37 (series.avm, 4 H), 2.29 (s, 3 H), 3.52-4.53 (series; avm; 8 H), 3.68' and-3.75 (s, total 3 H), 4.85 (s, 2H), 6.67-7.95 (series JaVm,. 16 H); MS (ESI) m/z?702 (MM-H), 704 (Ivf+Na<+>)M/Ja/. Calculated for C^jBrNjOvHjO: C, 60.00; H, 5.32; N, 5.83. Found: C, 59.65; H, 5.02: N, 5.65.

EXAMPLE 114

'4-[(2S,4S)-4-methoxy-1-[3-methoxy-4-[N'-(2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoic acid

To a stirred mixture of (2S,4R)-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethyl-4-hydroxypyrrolidine (21.7 g, 47.6 mmol), acetic acid (3.0 mL, 52.4 mmol) and PPh3 (12.5 g,

52.4 mmol) in THF (330 mL) was added DIAD (9.4 mL, 47.6

mmol) at room temperature under an atmosphere of nitrogen.

After 2 hours of stirring at the same temperature, the mixture was heated at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting mixture was chromatographed on silica gel

[1 Kg, n-hexane/EtOAc (5/1) ] to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethyl-pyrrolidine (23.3 g, 99%) as a colorless oil.

•H-NMR (CDCl1) 5 1.06 (s, 9H), 1.35 and 1.43 (s,*9H,'.amide isomers

1.92 (br, 3H), 2.20-2.45 (m, 2H), 3.31-4.07 (m, 5H), 5.17-5.30 (m, IH), 7.36-7.44 (m, 6H), 7.65-7.71 (m, 4H ).

To a stirred mixture of (2S,4S)-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethylpyrrolidine (23.3, 46.9 mmol) and acetic acid (6.0 mL, 104.8 mmol) in THF (470 mL) was added TBAF (93.8 mL, 93.8 mmol) at 0°C. After 24 hours of stirring, the mixture was concentrated in vacuo. The resulting residue was diluted with EtOAC and aqueous NH 4 Cl and extracted with EtOAc. The combined extracts were washed with brine, which was dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [700 g, CHCl 3 /EtOAc (4/1)] to give (2S, 4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 8%) as a colorless oil.

1H-NMR (CDCl1) δ 1.47 (s, 9H), 1.63 (m, IK), 1.81 (m, IK), 2.07 (s, 3H), 2.34 (m, IH), 3.42 (dd, J = 12.7 , 0.9 Hz, IK), 3.62-3.85 (m, 3H), 4.48 (br, IK), 5.20 (br, IK).

To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxy-•carbonyl-2-pyrrolidinemethanol (9.70 g, 37.4 mmol), p-hydroxy-benzoic 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, After 5 h of stirring, the mixture was concentrated in vacuo.The resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)] to give methyl 4-[2S,4S)-4-acetoxy-1-tert -butoxycarbonyl-2-pyrrolidinyl]methoxybenzoate (11.8 g, 81%) as a pale yellow oil e. 1 H-NMR (CDCl 3 ) δ 1.48 (s, 9H), 2.03 (s, 3H), 2.27 (m, IK ), 3.46 (rn, IK), 3.72 (m, IK), 3.88 (s, 3H), 3.98

(t, J= 9.0 Hz, IK), 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 methyl 4-[(2S, 4S)-4-acetoxy-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl] methoxybenzoate (7.43 g, 18.9 mmol) in MeOH (150 mL) was added the added cat. K2C03 at room temperature. After 1 day of stirring, the mixture was concentrated in vacuo. The resulting residue was recrystallized by addition of CHCl3-n-hexane to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]-methoxybenzoate (5.76 g, 87 %) as a colorless solid.. 'H-NMR (CDCl1) 5 1.46 (s, 9H), 2.11 (m, IK), 2.35 (br, IK), 3.27-3.65 (m, 2H), 3.89 (s, 3H), 4.07-

4.54 (m, 4H), 6.96 (d, /= 6.9 Hz, 2H), 7.99 (d, / = 6.9 Hz, 2H).

To a stirred solution of methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-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 of stirring, Mel (1.20 m, 8.97 mmol) was added to the mixture at the same temperature, and the resulting mixture was allowed to stand at room temperature for 1 hour. Then 60% oil NaH (359 mg, 8.97 mmol) and Mel (1.20 mL, 8.87 mmol) were added to the reaction mixture at room temperature and stirred for 14 hours. The reaction mixture was poured into ice water and extracted with CHCl 3 . The combined extracts were washed with aqueous NaHCO 3 and brine; After drying over Na2SO4, the extracts were concentrated in vacuo.- The residue was chromatographed on silica gel [50 g, n-hexane/EtOAc (4/1)] to give methyl 4-[(2S, 4S)-1-tert-butoxycarbonyl- 4-Methoxy-2-pyrrolidinyl]-methoxybenzoate (1.32 g, 60%) as a colorless oil: "<H>" NMR (CDCl1) δ 1.48 (s, 9H), 2.05 (m, IK), 2.29 (d, J= 14.2 Hz, IK), 3.30 (s, 3H), 3.36-4.38 (m, 4H), 6.76 (br, 2H), 7.97 (d, J= 8.8 Hz, 2H).

To a stirred solution of methyl 4-[(2S, 4S)-tert-butoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (2.38 g, 3.61 mmol) in CH2Cl2 (46 mL) was added TFA (23 mL) under room temp. After 14 hours of stirring, the mixture was concentrated in vacuo. The residue was diluted by addition of CH 2 Cl 2 and 1 N NaOH, and extracted with CH 2 Cl 2 . The combined extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (20/1)] to give methyl 4-[25,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (950 mg, 99%) as a yellow oil.. 'H-NMR (CDC13) 5

2.16 ( X, J= 5.3 Hz, IH), 2.72 (s, IH), 2.95 (d, J= 6.8 Hz, IH), 3.11 (d, J« 11.0 Hz, IH), 3.26 ( t, J

= 1.9 Hz, 3H), 3.52 (br, IH), 3.84 (d, J= 1.7 Hz, 3H), 3.92 (s, IH), 4.00 (d, J= 4.1 Hz, 2H), 6.88

(m, 2H), 7.94 (m, 2H).

A mixture^ of 3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenylacetic acid (375 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2- pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC-HCl (342 mg, 1.79 mmol), HOBT (242 mg, 179 mmol) and Et3N (0.83 mL,

5.95 mmol) in DMF (5 mL) was stirred at room temperature for 13

hours. The mixture was poured into ice water and extracted with Et1Ac.

The combined extracts were washed ice water and

saline solution. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g,. CHCl3/Acetone (10/1)CHCl3/MeOH (20/1)] to give methyl 4-[(2S,4S)-4-methoxy-1-[3-methoxy-4-[-A7-'- (2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinyl]methoxybenzoate (650 mg, 98%) as a pale brown amorphous solid. 1'H-NMR (CDCl 3 ) 6 2.03 (m, 1H), 2.31 (s, 3H), 2.32 (m, 1H), 3.29 (d, J= 1.0 Hz, 3H), 3.57-3.68 (m, 5H) , 3.88 (d, J= 1.0 Hz, 3H), 3.99-4.06 (m, 2H), 4.46

(m, IH), 6.19 (m, IH), 6.80 (s, IH), 6.81 (d, J= 9.0 Hz, IH), 6.96-7.19 (m, 4H), 7.29 (m, 2H),

7.50 (d, J= 6.7 Hz, 1H), 7.95-8.10 (m, 3H); MS (ESI) m/z 562 (M<*>+1).

To a solution of methyl 4-[(2S, 4S)-4-methoxy-1-[3-methoxy-4-[ N'-(2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidine<y>l] methoxybenzoate (650 mg, 1.16 mmol) in THF (18.5 mL)

0.24 N NaOH (18.5 mL) was added. After stirring at room temperature for 12 h, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /MeOH (20/1)] to give 132 (540 mg, 85%) as a colorless amorphous solid. VAT 547.60.

(KBr) 3354, 2937, 1709, 1685, 1604, 1533, 1454 cm-<V>,H-NMR.(pjVBO-d<) 8 2.11 (m, 2H), 2.25

Cs, 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, J = 8.1 Hz. IH), 7.86-8.03 (m, 3H), 8.45-8.57 (m, 2H), 12.64 (br, IH); MS (ESI') mV* 548 (MN-1); i4na/.BeergnetfDrCsP33NjO7-1Na-1.5H10: C, 60.29; H, 6.07; N, 7.03. Found: C, 59.90; H, 5.59; N, 6.69.

EXAMPLE 115

4- [ (2S, 4S) -1- [4- [AT-(2-Chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoic acid

A mixture of 4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenyl- . acetic acid (398 mg, 1.19 mmol), methyl 4-[(2S, 4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC-HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et 3 N (0.83 mL, 5.95 mmol) in DMF (5 mL) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel

[50 g, CHCl3/Acetone (10/1))CHCl3/MeOH (20/1)] to give methyl 4-[(2S,4S)-1-[4-[A7'-(2-chlorophenyl)ureido ] -3-methoxyphenylacetyl] -4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid.

1H-NMR (CDCl1) δ 1.99-2.06 (m, IH), 2.34 (d, J = 13.9 Hz, IK), 3.30 (s, 3H), 3.59 (d, J = 7.4 Hz, IK), 3.62 ( d,/^. 3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00-4.18 (m, 3H), 4.42-4.51 (m, IK), 6.82-7.07 (m, IK ), 7.28 (d, J= 8.3 Hz, IK), 7.35 (dd, J = 7.9, 1.5 Hz, IK), 7.94-8.00 (m, 3H), 8.18(d, J= 8.3Hz, IK) ; MS (ESI) m/z 582,584 (M<*>+3).

To a solution of methyl 4-[(2S,4S)-1-[4-[AT-(2-chlorophenyl)-ureido]-3-methoxyphenyl acetyl]-4-methoxy-2-pyrrolidinyl]-methoxybenzoate (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 HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over

Na2S04 and concentrated in vacuo. The residue was purified on TLC [CHCl 3 /MeOH (10/1)] to give 133 (495 mg, 75%) as a colorless amorphous solid. Mv 568, 02. IR (KBr) 3330, 3070, 2937, 1709, 1685, 1604, 1533 cm"<1>; 'H-NMR (DMSC-dJ 5 2.11 (m, 2H), 3.22 (s, 3H) . , 6.85 ; and -6.91 (s, IH,amide isomers), 7-01-7.07 (m, 3H), 7.28 (t, J= 8.1 Hz, IH), 7.43 (d, 7= 8.1 Hz! IH) , 7.85-7.94 (m, 2H), 7.97 (d, J= 8.6 Hz, IH), 8.09 (d, J= 8.3 Hz, IH), 8.90-8.95 (m, 2H); MS (FAB) Wz 570 ( MM), 572 Ovf+3)..

EXAMPLE 116

4- [ (2S, 4S) -1- [4- [AT-(2-bromophenyl) ureido] -3-methoxy enylacetyl] -4-methoxy-2-pyrrolidinyl] methoxybenzoic acid

A mixture of 4-[ N'-(2-bromophenyl) ureido]-3-methoxyphenyl-acetic acid (451 mg, 1.19 mmol), methyl 4-[(2S, AS)-4-methoxy-2-pyrrolidinyl ]methoxybenzoate (317 mg, 1.19 mmol), EDC-HCl (342 mg, 1.79 mmol), HOBT (242 mg, 179 mmol) and Et3N (083 mL, 5.95 mmol) in DMF (5 mL) was stirred at room temperature for 13 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl 3 /Acetone (10/1,)] to give methyl 4-[(2S, 4S)-1-[4-[N'-(2-bromophenyl)ureido]-3 -methoxy phenylacetyl]-4-methoxy-2-pyrrolidinyl] methoxybenzoate (760 mg, 100%) as a yellow oil.

'H-NMR (CDCl1) 6 1.99-2.32 (m, IH), 2.34 (d, 7= 13.4 Hz, IH), 3.30 (s, 3H), 3.59 (mr 1H), 3.63 (d, J=3.2' Hz,2H), 3.68 (dd, J= 12.2, 5.1 Hz, IH), 3.81 (br, 3H), 3.88 (s, 3H), 3.91-4.16 (m, 2H), 4.49-4.51 (rn, 2H) , 6.82-7.15 (m, 7H), 7.31 (t, J= 8.1 Hz, IH), 7.52 (d, J= 8:1 Hz, IH), 7.93-8.00 (m, 3H\ 8.14 (d, J = 8.3 Hz, 1H); MS (ESI) m/z 626 (MN-1), 628 (M*+ 3).

To a solution of methyl 4-[(2S,AS)-1-[4-[A7'~ (2-bromophenyl)ureido]phenylacetyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (760 mg, 1.19 mmol) in THF (19 mL), 0.25 N NaOH (19 mL) was added. After stirring at room temperature for 12 h, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (20/1)] to give 134 (580 mg,

78%) as a colorless amorphous solid. VAT 612.47.

IR (KBr) 3330, 2935, 1709, 1685, 1604, 1529, 1434 arr'; HtNMR (DMSO-dj) δ 2.11 (ir, 2H), 3.22 (s, 3H), 3.58-3.78 (rn, 4H), 3.81 and -3.86.(s, 3H, amide isomers), 3.92-4.52 ( rr^ 4H), 6.72 (d, 7 = 8.6 Hz, IH), 6.77 (d, 7 = 8.3. Hz, IH), 6.85 and i6.91 (s, IH, amide isomerj, 6.97 (t, 7 = 7.1 Hz, IH), 7.02 and 7.06 (d, 7= 8.6 Hz, 2H,amide isomers), 7.32 (1,7=7.3Hz, IH), 7.59 (dd,7=8.1, 1.0 Hz, IH), 7.94 (dd, 7= 8.1, 1.2 Hz, 2H), 7.95-7.98 (m, 2H), 8.74 (s, 1H)i 8.94 (s, IH), 12.63 (br, IH); MS (FAB) w/ z 612 (MT+1), 614 (M<;>+3).

EXAMPLE 117

4-[(4iR)-methoxy-1-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinyl-methoxy]benzoic acid

To a stirred solution of 1-(tert-betoxycarbonyl)-(4R)-methoxy-(2S)-pyrrolidinylcarboxylic acid (2.87 g, 11.7 mmol) in THF (25 mL) was added BH3DMS (1.66 mL , 17.5 mmol) at room temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was dissolved in CH 2 Cl 2 . The solution was washed with H 2 O, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH

(50:1, v/v) as eluent to give 1-(tert-butoxycarbonyl)-(4R)-methoxy-(2S)-prolinol (1.79 g, 66%) as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.47 (s, 9 H), 1.69-1.73 (m, 1 H), 2.12-2.17 (m, 1 H), 3.31 (s, 3 H), 3.37-3.40 (m, 1 H), 3.53-3.62 (m, 2 H), 3.68-3.73 (m, 1 H), 3.83-3.87 (m, 1 H), 4.04-4.07 (m, 1 H), 4.90-4.92 (m, 1H); MS (FAB) m/z 232 (M<+>+1).

To a stirred solution of methyl 4-hydroxybenzoate (1.18 g, 776 mmol), 1-(tert-butoxycarbonyl)-[ AR )-methoxy-(2S)-prolinol (1.79 g, 7.74 mmol) and To Ph 2 P (2.44 g, 930 mmol) in THF (30 mL) was added DIAD (1.83 mL, 9.29 mmol) and the reaction mixture was heated under reflux for 5 h. After cooling 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 a crude product. The crude product was dissolved in CH 2 Cl 2 (20 mL). To the solution was added TFA (20 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine, dried over K 2 CO 3 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (30:1 to 30:2 v/v) as eluent to give methyl 4-[[ AR )-methoxy-(2 S )-pyrrolidinylmethoxy] benzoate (1.67 g, 81% for 2 steps) as a red-brown oil. 1H-NMR (CDCl 3 ) δ 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), 3.9M.06 (m, 3 H), 6.89-6.92 (m, 2 H), 7.96-7.98 (rn, 2 H); MS (FAS) m/z 266 (M<+>+1).

A mixture of 3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetic acid (470 mg, 1.50 mmol), methyl 4-[(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (396 mg, 1.49 mmol), EDC-HCl (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 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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-[(AR)-methoxy-1-[3-methoxy-4-[W-(2 -methylphenyl)ureido]phenylacetyl-(2S)-pyrrolidinylmethoxy]benzoate (822 mg, 98%) as a white foam.

1 H-NMR (CDCl1) δ 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'ra; total 9 H), 7.57-7.59 (m, 1H), 7.91-7.93 (m, 2H), 8.04-8.06 (m, 1H); MS (FAB) m/z 562 (M<*>+1).

To a stirred solution of methyl 4-[(4f?)-methoxy-1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinylmethoxy]benzoate (517 mg, 0.92 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was purified by recrystallization from MeOH-CHCl 3 -IPE to give 135 (144 mg, 29%) as a white crystalline powder. VAT 547.60. M.p.: 112-115°C.

1 H-NMR (DMSO-dj) δ 2.04-2.17 (m, 2 H). 2.25 (s, 3 H), 3.21 (s, 3 H), 3.56-3.75 (m, 4 H), 3.79 (s, 3 H), 4:04-4.35 (m, 4 H), 6.73-7.17 ( series of sc, total 7 H), 7.79-7.81 (m, 1 H), 7.87-7.89 (m, 2 H), 7.99-8.01 (m, 1 H), 8.47 (s, 1 H), 8.55 (s, 1H), 12.63 (bs, 1H): MS (FAB) m/z 548 (MT+1); /Ina/. Calculated for -C30H33N3O7i/4HjO: C, 65.26; H, 6.12; N, 7.61. Found C, 65.36; Hj 6.45; N, 7.24.

EXAMPLE 118

4- Tl - [4- [A7'-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoic acid

A mixture of 4-[A7'-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (476 mg, 1.50 mmol), methyl 4-[(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (397 mg, 1.50 mmol), EDC-HCl (344 mg, 1.79 mmol), HOBt (243 mg, 1.80 mmol) and Et3N (250 mL, 1.79 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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-[1- [4-[ N'~ (2-fluorophenyl)ureido]-3 -methoxy enylacetyl]-(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (806 mg, 95%) as a pale yellow foam.

'H-NMR'

(CDCl 3 ) 6 2.14-2.37 (m, 2 H), 3.28 (s, 3 H), 3.44 (s, 3 H), 3.48-3.74 (iri, 4 H), 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 rn, 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<*>+1).

To a stirred solution of methyl 4-[1-[4-[AJ'-(2-fluorophenyl)-ureido]-3-methoxyphenyl acetyl]-(423)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (491 mg, 0.87 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was purified by recrystallization from MeOH-CHCl3-IPE to give 136 (173 mg, 36%) as a white crystalline powder. VAT 551.56. M.p.: 111-116°C. •H-NMR (DMSO-d,) δ 2.08-2.17 f^ ;2 H), 3.21 (s, 3 H), 3.56-3.73 (m, 4 H), 3.78 (s, 3 H), 4.04-4.33 (m, 4 H), 6.74-7.22 (sériq avm, total 7 H), 7.87-7.89 (m, 2 H), 7.99-8.01 (m, 1 H), 8.16-8.20 (m, 1H), 8.70 ( s, 1 H), 9.18 (s, 1 H), 12.64 (br s, .1 H); MS (FAB) m/z 552 Anal. Calcd for CsH20FNAO-1SH2O: C, 62.84; H.5.51; F, 3.43; N, 7.58, Found: C, 63.08; H, 5.83; F, 3.30; N, 7.15. EXAMPLE 119 4- [1- [4- [AJ'- (2-chlorophenyl)ureido] -3-methoxyphenylacetyl] - (4R) - methoxy-(2 S )-pyrrolidinyl methoxy]benzoic acid

A mixture of 4-[AJ'-(2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (460 mg, 1.37 mmol), methyl 4-[(42R)-methoxy-(2 5 )-pyrrolidinylmethoxy] benzoate (365 mg, 1.38 mmol), EDC-HCl (316 mg, 1.65 mmol), HOBt (223 mg, 1.65 mmol) and Et3N (230 mL, 1.65 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1, v/v) as eluent to give methyl 4-[1-[4-[AJ'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl ]-( AR )-methoxy-( 2 S )-pyrrolidinylmethoxy] benzoate (801 mg, quant, yield) as a white foam.

1H-NMR (CDCl1) δ 2.13-2.36 (m, 2H), 3.27 (s, 3H), 3.58 (s, 3H), 3.61-3.73 (m, 4H), 3.88 (s, 3H ), 4.06-4.14 (m, 2^ H), 4.43-4.56 (m, 2 H), 6.70-6.99 (series- of m, total 5 H), 7.23-7.42 (m, 4 H), 7.90-8.00 (m, 3 H), 8.17-8.20 (m, 1 H); MS (FAJ3) m/z 582 (M<+>+1).

To a stirred solution of methyl 4-[1-[4-A7'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-(4J?)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (541 mg, 0 .93 mmol) in THF (5 mL), 0.5 N NaOH (5 mL) was added, and the reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was purified by recrystallization from MeOH-CHCl 3 -IPE to give 137 (282 mg, 53%) as a white crystalline powder. VAT 568.02. M.p.: 116-119°C.

1 H-NMR (DMSO-d 6 ) δ 2.08-2.17 (m, 2 H), 3.21 (s, 3 H), 3.56-3.73 (ra, 4 H), 3.79 (s, 3 H), 4.04-4.33 ( m, 4 H), 6.75 (d, J = 8.3 Hz, 1.H), 6.87 (s, 1 H), 7.02 (d, J = 8.3 Hz, 3 H), 7.28 (t, J =7.8Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.87-7.89 (m, 2 H), 7.96 (d, J = 8.3 Hz, 1 H), 8.10 (d. J = 8.3 Hz,

1 H), 8.89 (s, 1 H), 8.93 (s, 1 H), 12.63 (br s, 1 H); MS (FAB) m/z 568 (MN-1);/1/ia/. Calculated for CjjHjoClNjOylMHjO: C, 60.84; H, 5.37; C1, 6.19; N, 7.34. Found: C, 61.03; H, 5.56; Cl, 6.27; N, 7.03. EXAMPLE 120 4- [1- [4- [AT-(2-bromophenyl)ureido] -3-methoxyphenylacetyl] - (4R) - methoxy-(2S)-pyrrolidinylmethoxy] benzoic acid

A mixture of 4-[A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (600 mg, 1.58 mmol), methyl 4-[(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate ( 420 mg, 1.58 mmol), EDC-HCl (364 mg, 1.90 mmol), HOBt (214 mg, 1.58 mmol) and Et3N (265 mL, 1.90 mmol) in THF (15 mL) were stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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- [1- [4- [A7'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl ] -(4E)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (1.01 g, quant., yield) as a pale yellow foam.

'H-NMR

(CDC13) 8 2.13-2.33 (m, 2H), 3.27 (s, 3H), 3.57 (s, 3H), 3.61-3.72 (m, 4H), 3.88 (s, 3H), 4.05- 4.14 (m, 2 H), 4.43-4.57 (m, 2 H), 6.70-7.00 (series: of m, total 5 H), 7.29-7.52 (m, 4 H), 7.92-8.01 (m, 3 H ), 8.12-8.15 (m, 1 H); MS (FAB) ra/z 626 (MM).

To a stirred solution of methyl 4-[1-[4-[A7'-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-(4R)-methoxy-(2S)-pyrrolidinylmethoxy]benzoate (697 mg, 1.11 mmol) in THF (8 mL) was added 0.5 N NaOH (8 mL) and the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was purified by recrystallization from MeOH-CHCl 3 -IPE to give 138 (252 mg, 37%) as a white crystalline powder. VAT 612.47. Melting point: 125-130°C.

'H-NMR PMSO-dj) 8 2.08-2.17 (m, 2 H), 3.21 (s, 3 H), 3.60-3.72 (m, 4 H), 3.79 (s, 3 H), 3.95-4.33 (m , 4 H), 6.75-7.08 (series, of m, total 5 H), 7.31-7.34 (m, 1 H), 7.59-7.61 (m, 1 H), 7.87-7.89 (m, 2 H), 7.93 -7.96 (rn. 2 H), 8.73 (s, 1 H), 8.91 (s, 1 H), 12.63 (br s, 1 H); MS (FAB) m/ z 612 Qtf+ l) ; Anat. Calculated for C^HjoBrNjCv C, 56.87; H, 4.94; Br, 13.05; N, 6.86. Found: C, 56.67; H, 4.97; Br, 13.07; N, 6.68.

EXAMPLE 121

4-[4,4-difluoro-1-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]-phenylacetyl]-2-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of N-Boc-proline methyl ester (2.0 g, 8.15 mmol) in CH 2 Cl 2 was added 3 A molecular sieves (2 G) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celite pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57% as a colorless oil. 'H -NMR(CDCl1) δ 1.46-1.48 (m, 9 H), 2.56-2.61 (m, 1 H), 2.88-3.00 (m, 1 H), 3.77 (s, 3 H), 3.82-3.88 (m, 2H), 4.71-4.83 (m, 1H).

To a cold (-78°C), stirred solution of methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 4.65 mmol) in CH 2 Cl 2 (20 mL) was added methyl -DAST (1.1 ml, 11.6 mmol). The mixture was allowed to warm to room temperature. After 15 h of stirring, the mixture was poured into H 2 O (50 mL) and extracted with EtOAc (200 mL). The extract was washed with brine (2 x 200 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (20:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4,4-difluorodipyrrolidine-2-carboxylate (885 mg, 72%) as a yellow oil. 1'H-NMR (CDCl 3 ) δ 1.42 and 1.47 (s, each, total 9 H), 2.46 (ddd, d= 26.9 13.7, 5.1 Hz, 1H), 2.62-2.78 (m, 1H), 3.75-3.95 ( m, 5H), 4.43-4.57 (m,lH)..

To a stirred solution of methyl 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylate (885 mg, 3.34 mmol) in THF (25 mL) was added 0.25 N NaOH (26.7 ml, 6.67 mmol) and stirring was continued for 1 hour. The mixture was poured into 1 N HCl (100 mL) and extracted with CHCl 3 (2 x 200 mL). The combined extracts were washed in brine (100 mL), dried over MgSO 4 and evaporated to give 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (775 mg, 92%) as a yellow crystalline solid. M.p.: 113-117°C.

'H-NMR (CDCl1) 6 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 (ni. 1H);'MS-(FAB) m/z, 252 (M++1); Anal.- Calculated forC.oH.jFjCy- C, 47.81; H, 6.02; N, 5.58. Found: C, 48.06; H, 6.05; N, 5.45.

To a stirred solution of N-(tert-butoxycarbonyl)-4,4-difluoroproline (3.00 g, 11.9 mmol) in THF (20 mL) was added BH3-DMS (1.1 mL, 11.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was quenched by addition of H 2 O (100 mL) and extracted with CHCl 3 (2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. ■ The residue was chromatographed on silica gel with CHCl 3 -EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinyl methanol (2.11 g, 75%) as. a ■ f. arge loose oil.

1 H-NMR (CDCl 1 ) δ 1.48 (s, 9 H), 2.04-2.55 (m, 2 H), 3.59-4.17 (m, 5 H).

To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (600 mg, 2.53 mmol), methyl 4-hydroxybenzoate (462 mg, 3.03 mmol), Ph3P (795 mg , 3.03 mmol) in THF (10 mL) was added DIAD (597 µl, 3.03 mmol) at room temperature. The mixture was heated at reflux for 3 hours with stirring. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane-EtOAc (4:1) to give methyl 4-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy[benzoate (831 mg, 88%) as a colorless oil.

'H-NMR (CDClj) 8 1.48 (p. 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-[1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (830 mg, 2.23 mmol) and TFA (5 mL) in CH 2 Cl 2 (5 mL) was stirred for 3 hours and concentrated in vacuo. The residue was basified with saturated NaHCO 3 and extracted with CHCl 3 (2 x 200 mL). The combined extracts were dried over K 2 CO 3 and concentrated in vacuo to give methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (550 mg, 91%) as a pale yellow solid. 2.19 (m, 1 K), 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 272 QA*+ l) ;Anal. Calculated fprf^H^NOj: C, 57.56; H, 5.57; N, 5.16. Found: Ci 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-[ N'~ (2-methylphenyl)-ureido] phenylacetic acid (626 mg, 1.99 mmol) EDC-HCl (572 mg, 2.99 mmol), HOBt (cat.) and DMAP (cat.) in DMF (10 mL) were stirred overnight. The mixture was diluted with EtOAc (300 mL), washed with brine (2 x 100 mL), dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[4,4 difluoro-1-[3-methoxy-4-[W-(-methylphenyl)ureido]-phenylacetyl] -2-pyrrolidinylmethoxy]benzoate (1.00 g, 89%) as a colorless foam.

1H-NMR (CDCl1) δ 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, J= 1.7 Hz, 1H), -6.74,6.76 (rn, 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, J= 8.8 Hz, 2H), 8.09(d, J=8.1 Hz, IH).

A mixture of methyl 4-[4,'4-difluoro-1-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate (li 00 g, 1.76 mmol) and 0.25 N NaOH (14 mL, 3.50 mmol) in THF (14 mL) was stirred overnight. The mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20:1 to 10:1) as eluent to give 139 (658 mg, 68%) as a colorless crystalline powder. VAT 553.55. Melting point: 135-140°C. 'H-NMR (DMSO-d*) δ 2.23 (s, 3 H), 2.49-2.73 (rn, 2 H), 3.36-4.55 (series of rn, 10 H), 6.73 (d, J= 8.3 Hz,

1 H), 6.84 (s, 1 H), 6.93 (t, J= 7.3 Hz, 1 H), 7.00 (d, J= 8.3 Hz, 2 K), 7.10-7.16 (m, 2 H), 7.78 ( d, J = 8.3 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 2 H). 8.00 (d, /= 8.3 Hz, IK)] &47 (s, 1H), 8.56 (s, 1 H); MS (FAB) m/z, 554 (M++1); Anal. Calculated ^^^^0^3/4^0: C, 61.42; H, 5.44; N, 7.06. Found: C, 61.30; H, 5.44; N, 7.06. EXAMPLE 122 4- [1- [4- [W-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoic acid

A mixture of methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)-benzoate (229 mg, 0.845 mmol), 4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (283 mg, 0 , 845 mmol), EDC-HCl (243 mg, 1.27 mmol), HOBt (cat.), DMAP (cat.) and DMF (10 mL) were stirred overnight. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2 x 100 mL), dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (20:1 to 4:1) as eluent to give methyl 4- [1- [4- [W-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-4 ,4-difluoro-2-pyrrolidinylmethoxy] benzoate (483 mg, 97%) as a colorless viscous solid.

'H-NMR (CDCl1) δ 2.50-2.67 (m, 2 H), 3.54-4.71 (series of'! m, 13 H), 6.69 (d, J= 1.5 Hz, 1 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.98 (dt, J = 7.8, 1.5 Hz, 1 H), 7.23-7.27 (m, 1 H), 7.33 (d, J= 8.3 Hz, 1 H), 7.39 (m, 2 H), 7.94 (d,J= 8.8 Hz, 2H), 8.00 (d, J=8.3 Hz, 1 H), 8.19 (dd, J = 8.3, 1.5 Hz, 1 H).

A mixture of methyl 4-[1- [4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4,4-difluoro-2-pyrrolidinylmethoxy]benzoate (480 mg, 0.816 mmol), 0.25 N NaOH (6.5 mL, 1.65 mmol) and THF (20 mL) were stirred for 3 days. The mixture was poured into 1 N HCl (100 mL) and extracted with CHCl 3 -MeOH (5:1, 2 x 200 mL). The combined extracts were dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20:1 to 5:1) to give 140 (270 mg, 58%) as a pale yellow amorphous solid. VAT 573.97.

'H-NMR (DMSO-ds) 6 2.45-2.74 (m, 2 H), 3.63-4.83 (series of m, 10 H), 6.76 (d, J= 8.3 Hz, 1 H), 6.87 (s, 1 H), 7.00-7.05 (m, 3 H), 7.26-7.30 (m, 1 H), 7.44 (dd, .7=8.3, 1.2 Hz, 1H), 7.88-7.93 (m,

2 H), 7.98 (d, J= 8.3 Hz, 1 H), 8.10 (d, J= 8.3 Hz, 1 H), 8.92 (s, 1 H), 8.96 (s, 1H); MS (FAB) m/ z 51A 0vr+l)Mnaf. Calcd for CjgHwClFjNjOc-HjO: C, 56.81; H, 4.77; N, 7.10. Found: C, 56.75; H, 4.69; N, 6.79.

EXAMPLE 123 4-[ (2R,3R,4S)-3,4-isopropylidenedioxy-1-[4-[ N'-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoic acid

To a solution of methyl (2S,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinylcarboxylate (10.7 g, 31.9 mmol) in THF (250 mL) was added 0.25 N NaOH ( 225 ml) added. After stirring at room temperature for 24 h, the mixture was acidified with 1 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give (2S,3i?,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinylcarboxylic acid (9.87 g, 96 %) as a colorless oil. 1H-NMR(CDC13)8 1.3.2 (s, 3H), 1.46

(d, J= 2.7 Hz, 3H), 3.61(m, lH), 3.82 and 3.92 (d, J=J12.7Hz, IH, amicWsomereO; 4.58 and M.64 (s, lH, amide isomerii, 4.77 ( t, J= 5.1 Hz, IH), 4.83 and 4.89 (d, J- 5.9 Hz, IH, amide isomers,7 5.15 and gl 5.19 (m, 2Hamid isomers<p>j, 7.31-7.37 (m, 5H) .

To a stirred solution of (2S,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinylcarboxylic acid (9.87 g, 30.7 mmol) in THF (200 mL) was added BH3-DMS ( 6.14 mL, 61.4 mmol) at 0°C. The mixture was allowed to warm to room temperature and then heated under reflux for 2 hours. 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, dried over Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel [200 g, CHCl3/MeOH (20/1)] to give (2i?,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinyl]methanol (10, 1 g, 100%) as a colorless oil.

NMR (CDCl 1 ) δ 1.31 (s, 3.H), 1.45 (s, 3H), 3.56-4.74 (xn, IK), 5.14 (s, 2H), 7.34 (m, 5H).

To a stirred mixture of (2R,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinylmethanol (312 mg, 0.64 mmol), methyl p-hydroxybenzoate (67 mL, 0.70 mmol), To PPh 3 (184 mg, 0.70 mmol) in THF (7 mL) was added DIAD (138 mL, 0.70 mmol) at 0 °C under an atmosphere of nitrogen. The mixture was now brought to room temperature and stirred for 3 hours. After removal of the solvent, the resulting residue was chromatographed on silica gel [10 g, n-hexane/EtOAc (4/1)], to give methyl 4-[(2R,3R,4S)-benzyloxycarbonyl-3,4-isopropylidenedioxy- 2-pyrrolidinyl] methoxybenzoate (321 mg, 83%) as a colorless oil. 1 H-NMR (CDCl 1 ) δ 1.01 (s, 6H), 1.03 (s, 3H), . 2.23 (m, IK), 2.63 (m, IK), 3.61 (d, J= 12.5 Hz, IH), 3.80-4.27 (m, 4H), 4.84 (br, IK), 5.01 and". 5.08 (ABq, J = 12.2 Hz, 1H, amide isomer, 6.75-6.87 (m, 3H), 7.19-7.63 (m, 15H).

A suspension of methyl 4-[(2R,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (2.37 g, 5.76 mmol) and 10% Pd/C (240 mg ) in EtOH (170 mL) was stirred at room temperature under an atmosphere of hydrogen. After 1 day of stirring, the catalyst and solvent were exchanged with 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 removal of the catalyst by filtration, the filtrates were concentrated in vacuo. The residue was chromatographed on silica gel [100 g, CHCl 3 /acetone (20/1)] to give methyl 4-[( 2R , 3R , 4S )- 3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (930 mg, 53% ) as a brown oil. 1H-NMR(CDCl3) δ 1.35 (s,3H),

1.50 (s, 3H), 3.02 (dd, J= 13.7, 4.1Hz, IK), 3.13(d, J= 13.7 Hz, IH), 3.58 (C/= 6.3 Hz, IK), 3.88 (s, 3H) , 3.90 (dd, J= 9.3, 6.6 Hz, IH), 4.02 (dd, J= 9.5, 3.9 Hz, IK), 4.74 (d, J= 5.6 Hz,

IK), 4.19 (m, iH), 6.90 (d, J= 9.0 Hz, 2H), 7.98 (d, J= 9.0 Hz, 2H).

A mixture of 3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetic acid (437 mg, 1.39 mmol), methyl 4-[(2R,3R,4S)-3,4-

isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (428 mg,

1.39 mmol), EDC-HCl (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 saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel

[70 g, CHCl3/acetone (10/1) ] to give methyl 4-[(2R,3R,45)-3,4-isopropylidenedioxy-1-[4-[N'~ (2-methylphenyl)ureido] -3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoate (840 mg,

100%) as a colorless amorphous solid.

IR (KBr) 3354, 2985, 2939, 1716, 1533, 1254 cm"1;' 'H-NMR

(CDCl 3 ) δ 1.31 (s, 3H), 1.42 (s, 3H), 2.05 (s, 3H), 3.50 (s, 3H), 3.55-3.88 (iri, 4H), 3.89 (s, 3H),

4.13 (m, IH), 4.67 (br, IH), 4.78 (d, J = 6.1 Hz, IH), 4.88 (t, J = 5.6 Hz, IK), 6.46 (s, IK), 6.62

(d,J = 1.5 Hz, IK), 6.74 (m, 3H), 7.05 (s, IK), 7.14-(d, J= 7.3 Hz, IK), 7.23 (m,°2H), 7.57 (d, J= 7.8 Hz, IK), 7.91-8.08 (m, 3H); MS (ESI) m/z 604 flvf+1); ,4™/. Calculated for C33H37N3O.-O.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-[[ 2R,3R,45 )-3,4-isopropylidenedioxy-1-[4-[ N'-(2-methylphenyl)ureido]-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

[CHCl3/MeOH (10/1)] to give methyl 4-[(2R,3R,4S)-3,4-dihydroxy-1-[4-[A7' (2-methylphenyl)ureido]-3Tmethoxyphenylacetyl ] -2-pyrrolidinyl]methoxybenzoate (162 mg, 95%) as a colorless amorphous solid. IR (KBr) 3342, 1716, 1604, 1535, 1255 cnT1; 1H-NMR (CDCl,) δ 2.25 (br, 3H), 3.33-3.75 (m, IK), 3.87 (s, 3H), 4.10 (d, /= 8.3 Hz, IK), 4.24 (s, 2H) ,

4.37 (m, 2H), 6.62-7.94 (m, 13H); MS (ESI) m/z 564 (M₂+1).

To a solution of methyl 4-[[ 2R,3R,4S)-3,4-isopropylidenedioxy-1-[4-[ N'-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoate ( 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 HCl and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 141 (445 mg, 93%) as a colorless amorphous solid. VAT 689.64.

IR (KBr) 3354, 2983,'2937, 1707,1604, 1533 cm"<1>; •H-NMR pMSO-d") δ .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), 3.92-4.96 (m, SK), 6.74 and 6.78 (m, IH, amide isomers i), 6.83-7.16 (m, 6H), 7.79 (d, J= 8.3 Hz, IK), 7.87 (t, J= 9.1 Hz, 2H), 8.01 (m, IH), 8.49 (d, J= 3.4 Hz, IK), 8.57 (s, IK) ; MS (FAB) m/ z 590( ^+1); Anal. Calculated; for C35H35N3O.-2.3HjO: C, 60.90; H, 6.32; N, 6.66. Found: C, 61.00; H, 6.00; N, 6.27.

EXAMPLE 124

4-[ (2R,3R,4S)-3,4-dihydroxy-1-[4-[BT-(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoic acid

To a solution of methyl 4-[{2R,3R,4S)-3,4-dihydroxy-1-[4-[ N'~ (2-methylphenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxybenzoate ( 63 mg, 0.112 mmol) in THF (0.89 mL) 0.25 N NaOH (0.89 mL) was added. After stirring at room temperature for 3 days, the mixture was acidified with 1 N HCl and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 142 (54 mg, 88%) as a colorless amorphous solid. VAT 549.57.

IR (KBr) 3356, 2958, 2927, 1685, 1604, 1535, 1255 cm-1; 1 H-NMR (DMSO-^) 8

2.24 (s, 3H), 3.40 (m, IK), 3.58 (s, 2H), 3.66 (dd, J= 9.8, 6.6 Hz, IK), 3.80 (s, 3H), 3.99-4.30 (rn, SK) , 5.10 (br, IK), 6.72 (d, J= 8.1 Hz, IK), 6.85 (s, IK), 6.93 (t, J= 7.3 Hz, IH), 7.03 (d, J= 8.8 Hz, 2H) , 7.14 (t, J= 8.8 Hz, 2H), 7.79 (d, J= 8.1 Hz, 2H), 7.86 (d, J= 8.8 Hz, 2H), 7.99 (d, J=

8.3 Hz, IK), 8.46 (s, IK), 8.56 (s, IH); MS (ESI) m/z 5500^+1); Anal. Calculated for CJ9H31N3O,-0.85HjO: C, 61.66; H, 5.83; N, 7.44'. Found: G, 62.09; H, 5.93; N, 6.95.

EXAMPLE 125

4-[{2R,3R,AS)-1-[4-[AJ'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoic acid

A mixture of 4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (487 mg, 1.45 mmol), methyl 4-[( 2R,3R,AS)-3,4-isopropylidenedioxy-2 -pyrrolidinyl] methoxybenzoate (447 mg, 1.45 mmol), EDC-HCl (418 mg, 2.18 mmol) and DMAP (177 mg, 1.45 mmol) in DMF (12 mL) were stirred at room temperature for 19 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and saline. After drying over Na 2 SO 4 , the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [70 g, CHCl3/acetone (10/1)] to give methyl 4-[( 2R, 3R, AS)-1-[4- [AT-(2-chlorophenyl)ureido]-3 -methoxyphenylacetyl]-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (850 mg, 94%) as a colorless amorphous solid.

IR (KBr) 3329, 2939, 1716,1627, 1531, 1254 cm"<1>; 'H-NMR'(CD Cl3) 51.33 Cs, 3H), 1.43 (s^ 3H), 3.56 (s, 3H), 3.61 (s, IH), 3.64 (s. IH), 3.70 (m, IH), 3.79 (d, J= 10.4 Hz, IH), 3.88 (s, 3H), 4.14 (dd, J = 9.8, 2.2 Hz , IH), 4.40 (dd, 7=9.8, 3.4 Hz, IH), 4.67 (s, IH), <1 >4.80 (d,J = 6.1 Hz, IH), 4.90 (t, J= 4.6 Hz, IH ), 6.65 (d,7= 1.7 Hz, IH), 6.71-6.84 (m, 3H), 6.98 (dt, J= 7.6, 1.5 Hz, IH), 7.27 (m, 2H), 7.33 (dd, 7= 8.0, 1.2 Hz, 2H), 7.90-8.01 (m, 3H), 8.20 (dd, /=8.3, 1.5Hz, 1H); MS (ESI) m/ z 624 (MN-1), 626 (M ++3);,W Calculated for C^H^NA-1.4H:0: C, 59.19; H, 5.71; N, 6.47. Found: C, 58.85; H, 5.35; N, 6.21..

A mixture of methyl 4-[[2R,3R,AS)-1-[4-[AJ'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-3,4-isopropylidenedioxy-2-,pyrrolidinyl] Methoxybenzoate (177 mg, 0.284 mmol) and g.HCl-MeOH (4 ml) were stirred at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was purified on TLC [CHCl3/MeOH (15/1U to give methyl'4-[(2R,3R,4S)-1-[4-[N-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl ]-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (140 mg, 85%) as a colorless amorphous solid.

IR (KBr) 3338, 2949, 1712, 1623, 1604, 1533 crrf'; 1H-NMR(CDCl 3 ) δ 2.27 (m, 1H), 2:79 (m, 1H), 3.53 (dd,/ = 10.5, 5.9 Hz, 1H), 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, J= 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-+1), 586 (M++3).

To a solution of methyl 4-[(2Æ,3jR,4S)-1r[4-[A7'(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-3,4-isopropylidenedioxy-2-pyrrolidinyl]methoxybenzoate (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 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 143 (504 mg, 100%) as a colorless amorphous solid. MV 610.05. TR (KBr) 3330, 2983, 2937, 1711, 1,689, 1604, 1533, 1252 crrf1; 'H-NMR (DMSO-d«) 8 1.26 (s, 3H), 1.32 (s, 3H), 3.40 (m, 1H), 3.60 and 3.61 (d, J= 2.5 Hz, 3H, arnide-^ isomerism ), 3.62 (m, IH), 3.78 and! 3.83 (s, 3H, the amide isomer), 4.16 (m, 2H), 4.4'2-4.98 (m, 3H), 6.74-7.15 (m, 6H), 7.28 (t, / = 7.3 Hz, IH), 7.43 (d, J= 87i 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 (br, IH); MS (ESI) m/z 610 flvT+1), 612 (M<*>+3).

EXAMPLE 126

4- [ (2R,3R,4S)-1- [4- [AT-(2-chlorophenyl)ureido]-3-methoxy enylacetyl] -3,4-dihydroxy-2-pyrrolidinyl]methoxybenzoic acid

To a solution of methyl 4-[1-[4-[N'(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-3,4-dihydroxy-2-pyrrolidinylmethoxy]-benzoate (63 mg, 0.108 mmol) in THF (0.80 mL), became 0.25 N NaOH

(0.80 ml) added. After stirring at room temperature for 3 days, the mixture was acidified with 1 N HCl and extracted with CHCl 3 -MeOH (10/1). The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 144 (61 mg, 100%) as a colorless amorphous solid. VAT 569.99.

IR (KBr) 3338, 1687, 1604, 1533, 1255, 1169, 1036 cm -1 ; 1H-NMR (DMSO-dJ 6 3.59 (d, J = 5.5 Hz, 2H), 3.61 (m, IH), 3.66 (dd, J = 10.0,7.1 Hz, IH), 3.80 (s, 3H), 4.00 -4.33 (m, 5H), 5.10 (br, IH), 6.74 (d, J = 8.3 Hz, IH), 6.87 (s, IH), 7.03 (m, 3H), 7.28 (t, J= 8.3 Hz, IH), 7.43 (d, J= 6.6 Hz, IH), 7.87 (d, J= 8.5 Hz, 2H), 7.95 (d, J = 8.3 Hz, IH), 8.09 (d, J= 8.3 Hz, IH) , 8.32 (s, 1H), 8.89 (s, 1H), 8.93 (s, 1H); MS (ESI) m/z 570 (M<*>+1), 572 (M++3); Calculated for: CjgHaClNjOj-l^HjO-. C, 57.19; H, 5.14; N, 7.15. Found: C, 57.52; H, 5.22; N, 6.76. EXAMPLE 127 4- [1- [4- [AJ'- (2-methylphenyl)ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoic acid.

To a stirred solution of benzyl A7-Boc-pyrroglutarate (8.93 g, 28.0 mmol) in THF (100 mL) was added phenyllithium (1.0 M in Et2O-cyclohexane, 33.5 mL, 33.5 mmol) at -78°C, and the resulting mixture was gradually warmed to -40°C and then stirred overnight. Aqueous NH 4 Cl was added to the reaction mixture, THF was removed in vacuo, and extraction was then carried out with EtOAc. The organic layer was washed with water, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent, and then recrystallized from hexane-EtOAc to give benzyl [2-(S)■-(AJ-Boe-amino)-5-oxo-6- phenyl]pentanoate (5.02 g,' 45%')- as colorless needles. Melting point: 85-87°C. 1H-NMR (CDCl 3 ) δ 1.43 (s, 9 H), 2.07-2.19.(m, 1 H), 2.27-2.36 (m, 1 H), 2.97-3.13 (m, 2 H), 4.44 (brs , 1H), 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 (ESI) m/z, 322 Øvf+H).

To a stirred solution of benzyl [2-(S)-(AJ-Boe-amino)-5-oxo-6-phenyl]pentanoate (2.20 g, 5.54 mmol) in CH 2 Cl 2 (50 mL) was added added trifluoroacetic acid (15 ml) at room temperature and the resulting mixture was stirred for 2 hours. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , then extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , then concentrated in vacuo to give benzyl 5-phenyl-5-pyrroline-2-(S)-carboxylate (1.60 g, quant.) as a yellowish solid. The product was used in the subsequent reaction without further purification.

1H-NMR (CDCl1) δ 2.20-2.29 (m, 1 H), 2.32-2.42 (m, 1 H), 2.96-3.05 (xn, 1 H), 3.12-3.21 (m, 1 H), 4.96- 5.00 (m, 1 H), 5.24 (s,

2H), 7.31-7.49 (m, 8H), 7.88-7.91 (m, 2H); MS (ESI) m/z, 280 (M<*>+H). A mixture of benzyl 5-phenyl-5-pyrroline-2-(S)-carboxylate (1.59 g, 5.69 mmol) and Pd/C (10%, 128 mg) in MeOH (30 mL) was stirred under H2 at room temperature for 28 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH 3 CN-H 2 O (3:2.25 mL), then di-tert-butyl dicarbonate (1.86 g, 8.54 mmol) and 1.0 M NaOH (854 mL, 8.54 mmol), and the resulting mixture was stirred for 30 minutes. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , then extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeoH (9:1) and recrystallized from hexane-EtOAc to give A7-Boc-5-{R)-phenyl-(S)-proline (810 mg, 49%) as a colorless solid. Temp. : 113-117°C. <l>R-NMR (CDC13) δ 1.13 (s, 9 H), 1.43 (brs, 1H), 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, 5H). To a stirred solution of N-Boc-5-[R)-phenyl-2-(S)-proline (1.14 g, 3.91 mmol) in THF (20 mL) was added 10 M-BH3 -Me2S (780 mL, 7.82 mmol) at room temperature, and the resulting mixture was heated under reflux for 30 min. The mixture was poured into aqueous 1 N HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give IV-Boc-2-(S)-hydroxymethyl-5-(i?)-phenylpyrrolidinium (1.11 g quant.) as a colorless oil: 1H-NMR (CDCl 3 ) 6 1.19 (brs, 9 H), 1.65 (brs, 1H), 1.83-1.90 (m, 1H), 1.98-2.06 (m, 1H), 2.22-2.31 (m, 1 H), 3.75-3.86 (m, 2 H), 4.16-4.19 (m, 1H), 4.83 (t, J= 6.8 Hz, 1 H), 4.89 (brs, 1 H), 7.19-7.31 (m, 5H); MS (ESI) m/z, 278 (M<*>+H). To a stirred solution of iV-Boc-2-(S)-hydroxymethyl-5-(R)-phenylpyrrolidine (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 room temperature and the resulting mixture was stirred at 60°C for 45 minutes. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with hexane-EtOAc (4:1) to give methyl 4-[W-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxybenzoate ( 1.31 g, 80%) as a colorless oil. 'H-NMR(CDCl,) δ 1.1'9 dg 1.47 (brs, total 9 H), 2.09-2.15 (xn, 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, 2H); MS (ESI) m/z, 412 (M₂H).

To a stirred solution of methyl 4-[A7-Boc-3-[R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.28 g, 3.11 mmol) in CH 2 Cl 2 (30 mL) was added trifluoroacetic acid (10 mL) at room temperature, and the resulting mixture was stirred for 45 minutes. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , then extracted with CHCl 3 . The organic layer was washed with water, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give methyl 4-[5-{ R )-phenyl-2-( S )-pyrrolidinylmethoxy]benzoate (363 mg, quant.) as a yellowish oil. The product was used in subsequent reactions without further purification.

1H-NMR (CDCl1) δ 1.71-1.83 (m, 2H), 2.03-2.10 (m, 1H), 2.15-2.24 (m, 1H), 3.68-3.74 (m, 1H), 3.89 ( s, 3 H), 4.01-4.09 (m, 2 H), 4.28 (t, J= 7.2 Hz, 1 H), 6.95 (d,7 = 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 Ovf+CH3CN).

To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (135 mg, 0.43 mmol), 4-[2v"-(2-methylphenyl)ureido]- To 3-methoxyphenylacetic acid (136 mg, 0.43 mmol) and N-dimethylaminopyridine (52.9 mg, 0.43 mmol) in DMF (10 mL) was added EDC-HCl (90.8 mg, 0.48 mmol) at room temperature, 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, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[ N'~ (2-methylphenyl)ureido]-3-methoxyphenyl acetyl] -5-[ R )-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (271 mg, quant.) as a colorless amorphous solid.

1H-NMR (CDCl1) 6 2.00-2.18 (m, 3H), 2.31-2.41 (m, 1H), 2.27 (s, 3H), 3.31

«,

(s, 2 H), 3.67 (s, 3 H), 3.89 (s, 3 H), 4.35-4.48 (m, 2 H), 4.60 (brs, 1 H), 4.92 (t, /= 6.8 Hz, 1H), 6.51 (d, J= 8.4-Hz, 1 H), 6.62 (s, 1 H), 6.96 (d, J= 8.8 Hz, 1 H), 7.11-7.40 (series of m, 8 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.97-8.00 (m, 2 H); MS (ESI) m/z, 608 (M<*>+H).

To a stirred solution of methyl 4-[1- [4-[jV'-(2-methylphenyl)-ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy] benzoate ( 243 mg, 0.40 mmol) in MeOH-THF (1:1.10 mL) was added 1.0 M NaOH (2.4 mL, 2.40 mmol) at room temperature and the resulting mixture was stirred at 6 0°C with stirring for 1.5 hours. The reaction mixture was poured into 1AMHCl, and then extracted with CHCl3. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 145 (224 mg, 94%) as a colorless amorphous solid.. MW 593.67. 'H-NMR (CDjOD), mixture of rotamars 5

2.00-2.19 (xn, 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, 4H), 6.48-8.03 (series of m, 16 H); MS (FAB) m/z, 594 (M₂+H).

EXAMPLE 128

4-[1-[4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-5-{R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 4-[5-{ R )-phenyl-2-( S )-pyrrolidinylmethoxy]benzoate (142 mg, 0.46 mmol), 4-[AJ'-(2-chlorophenyl)ureido]- 3-Methoxyphenylacetic acid (153 mg, 0.46 mmol) and A7,A7-dimethylaminopyridine (55.7 mg, 0.46 mmol) in DMF (10 mL) was added EDC-HCl (95.7 mg, 0.5 mmol) at room temperature 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, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1- [4- [A7'- (chlorophenyl)ureido]-3-methoxyphenylacetyl]-5- {R)-phenyl -2-(S)-pyrrolidinylmethoxy]benzoate (260 mg, 90%) as a colorless amorphous solid.

1 H-NMR (CDCl 3 ) δ 2.00-2.19 (m, 3 H). 2.35-2.44 (m, 1 H), 3.35 (s, 2 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.38-4.48 (m, 2 H), 4.63 (brs, 1 H) , 4.94 (t, / = 7.2 Hz, 1 H), 6.53 (d, .7 =-8.4 Hz, 1 H), 6.66 (s, 1 H), 6.96-7.01 (m, 3 H), 7.12-7.42 (tendons of, m, 8 H), 7.87 (d, J= 8.0 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 2 H), 8.17-8.19 (m, 1 H); MS (ESI) m/z, 627(M), 628 ExT+H).

To a stirred solution of methyl 4-[1-[4-[A7'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-5-( R )-phenyl-2-(S)-pyrrolidinylmethoxy] benzoate ( 2 51 mg, 0.40 mmol) in MeOH-THF (1:1.10 mL) was added 1.0AT-NaOH (2.4 mL, 2.40 mmol) at room temperature and the resulting mixture was heated at 60°C with stirring for 1.5 hours. The reaction mixture was poured into 1A7-HCl, and. then extracted with CHCl3. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 146 (181 mg, 74%) as a colorless amorphous solid. etc

614 ' 0 9 • 'H-NMR (CDjOD), mixture of: rotamars'! 5 1.99-2.19 (m, 3fl), 2.42-2.53 (m, 1 H), 3.38 (dd, J= 39, 15 Hz, 2 H), 3.79 and 3.80 (s, total 3 H)f 3- 94-5.19 (series of iri, 4 H), 6.49-8.05 (series of m, 16 H); MS (FAB) m/ z, 614 QÆ+ K)] Anal Calculated for Cj^ClNAHA C, 65.06; H, 5.62; N, 6.50. Found: C, 65.03; H, 5.75; N, 6.45.

EXAMPLE 129

4-[1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-5-( R )-phenyl-2-(S)-pyrrolidinylethoxy]benzoic acid

To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (146 mg, 0.47 mmol), 4-[A7'-(2-bromophenyl)ureido]- 3-Methoxy enylacetic acid (178 mg, 0.47 mmol) and 2N,A7-dimethylaminopyridine (57.4 mg, 0.47 mmol) in DMF (10 mL)

EDC-HCl (99.0 mg, 0.52 mmol) was added at room temperature 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, dried

over anhydrous Na 2 SO 4 and then concentrated in vacuo.

The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[AT<->(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-5-{ R)-phenyl-2-(S)-pyrrolidinylmethoxy] benzoate (288 mg, 91%) as a colorless amorphous solid.

1H-NMR (CDCl1) 8 2.00-2.20 (m, 3H), 2.34-2.43 (m, 1H), 3.35 (s, 2H), 3.72 (s, 3H), 3.89 (s, 3H ), 4.38-4.49 (m, 2 H), 4.62 (brs, 1H), 4.94 (t, J= 7.2 Hz, IK), 6.54 (d, J= 8.4 Hz, IH), 6.67 (s, 1 H) , 6.91-7.05 (m, 4 H), 7.28-7.42 (series of m, 7 H), 7.51 (d, J= 8.0 Hz, 2 H), 7.87 (d, J= 8.4 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 2H), 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-[A7'-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy] benzoate (270 mg, 0.40 mmol) in MeOH-THF (1:1.10 mL) was added 1.0Af-NaOH (2.0 mL, 2.0 mmol) at room temperature, and the ■resulting mixture was heated at 60°C with stirring for 1 hour. The reaction mixture was poured into 1N-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 147 (212 mg, 80%) as a colorless solid. amorphous t solid. etc

658>54^ 'H-NMR (CDjiOTD.), mixture of rotamars' - 6 1.99-2.19 (m, 3 H), 2.42-2.53 (m, 1H), 3.38 (dd, J= 39, 16 Hz, 2H ), 3.79 o§',3.80 (s, total 3 H), 3.94-5.19 (series of rn, 4 H), 6.49-8.00 (series of: m, 16 H); MS (FAB) m/z, 658 (M<*>), 660 (M++2).

EXAMPLE 130

4- [1- [ 4-'[ N'~ (2, 6-dichlorophenyl)ureido] -3-methoxyphenylacetyl] -5-( R )-phenyl-2-(S)-pyrrolidinylmethoxy] benzoic acid

To a stirred solution of methyl 4-[5-{R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (109 mg, 0.35 mmol), 4-[N'-(2,4-dichlorophenyl)ureido ]-3-methoxyphenylacetic acid (129 mg, 0.35 mmol) and A7,A7-dimethylaminopyridine (42.8 mg, 0.35 mmol) in DMF

(10 mL) was added EDC-HCL (73.4 mg, 0.39 mmol) at

room temperature, and the resulting mixture was stirred for 6 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4- [1- [4- [A7'-(2, 6-dichlorophenyl)ureido]-3-methoxyphenylacetyl] -5-( R)-phenyl-2-(S)-

pyrrolidinylmethoxy] benzoate (208 mg, 90%) as a colorless amorphous solid.

1H-NMR (CDCl1) δ 2.00-2.21 (m, 3H), 2.33-2.39 (m, 1H), 3.31 (s, 2H), 3.69 (s, 3H), 3.88 (s, 3H ), 4.34-4.45 (m, 2 H), 4.59 (brs, I H), 4.93 (t,/= 6.8 Hz; 1 H), 6.47 (d, J= 8.0 Hz, 1 H), 6.63 (s, 1 H), 6.68 (s, 1H), 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 (NT+H)..

To a stirred solution of methyl 4-[1-[4-[ N'~ (2,6-dichloro-phenyl)ureido]-3-methoxyphenylacetyl]-5-( R )-phenyl-2-(S)-pyrrolidinylmethoxy ] benzoate (18 6 mg, 0.28 mmol) in MeOH-THF

(1:1.10 mL) was added 1.0 M NaOH (1.4 mL, 1.4 mmol) at room temperature and the resulting mixture was heated at 60°C with stirring for 2.5 h. The reaction mixture was poured into IN-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 148 (166 mg, 91%) as a colorless amorphous solid. etc

64 8 ' 5 3 • 'H-NMR (CDCl1) 5 2.00-2.18 (m, 3 H), 2.34-2.40 (m, 1 H), 3.33 (s, 2 H), 3.68 (s, 3 H), 4.37^.47 (m, 2 H), 4.61 (brs,<1>1 H), 4.94 (t, J = 6.8 Hz, 1 H), 6.48 (d, J= 8.0 Hz, 1 H), 6.63 ( s, 1 H), 6.96 (d, J= 8.4 Hz, 3 H), 7.12-7.38 (series rav m, 9 H), 7.95 (d, J= 8.0 Hz, 1 H), 8.01 (d, J= 8.8 Hz, 2H); MS (FAB) m/z, 648 (MN-H). EXAMPLE 131 4- [1- [4- [2\T-(2-bromophenyl)ureido]-3-methylphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of methyl 4-[5-[ R )-phenyl-2-( S )-pyrrolidinylmethoxy] benzoate (125 mg, 0.40 mmol), 4-[ N'-(2-bromophenyl)ureido]- To 3-methylphenylacetic acid (146 mg, 0.40 mmol) and N,A7-dimethylaminopyridine (49.0 mg, 0.40 mmol) in DMF (10 mL) was added EDC-HCl (84.1 mg, 0.44 mmol) at room temperature, and the resulting mixture was stirred for 6 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[1-[4-[A7 '-(2-Bromophenyl)ureido]-3-methylphenylacetyl]-5-[ R )-phenyl-2-( S )-pyrrolidinylmethoxy] benzoate (238 mg, 90%) as a colorless amorphous solid.

1H-NMR (CDCl1) δ 1.92 (s, 3 H), 2.09-2.27 (ni, 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, i H), 5.00 (t, J= 6.8 Hz, 1 H), 6.72 (s, 1 H), 6.81- . 6.93 ( tendons of; m, 8 H), 7.22-7.42 (series of-nine, 6 H), 8.01 (d, /= 8.4 Hz, 2 H), 8.13 (d, J= 8.0 Hz, IH ); MS (FAB) m/z, 656 (M<*>), 658 (MT+2).

To a stirred solution of methyl 4-[1- [4-[AT'-(2-bromophenyl)-ureido]-3-methylphenylacetyl]-5-(R)-phenyl-2-(.S)-pyrrolidinylmethoxy] benzoate (216 mg, 0.33 mmol) in MeOH-THF (1:1.10 mL) was added 1.0Af-NaOH (1.7 mL, 1.7 mmol) at room temperature, and the resulting mixture was heated at 60°C with stirring for 2.5 hours. The reaction mixture was poured into 1N-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1) to give 149 (166 mg, 91%) as a colorless amorphous solid. MV ■

642.54. 1H-NMR(CDCl1) 52.01 (s, 3 H), 2.05-2.25 (m, 3 H), 2.43-2.48 (m, 1 H), 3.34 (dd, J= 45, 16 Hz, 2 H), 4.38-4.45 (m, 2 H), 4.66 (brs, 1 H), 4.99 (t, J= 6.8 Hz, 1 H), 6.77 (s, 1 H), 6.82-6.88 (m, 2 H), 6.94 (d, J= 8.8 Hz, 2 H), 7.15-7.55 (.series of m, 10 H), 8.00 (d, J= 8.8 Hz, 2 H), 8.14 (d, J = 7.2 Hz, 1 H) ; MS (FAB) m/z 642 (b/T), 644 (M<*>+2).

EXAMPLE 132

4- [1- [4- [A7'(2-methylphenyl)ureido]-3-methoxyphenylacetyl]-5-[R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoic acid

To a stirred solution of benzyl N-Boc-pyrroglutarate (7.55 g, 23.6 mmol) in THF (100 mL) was added MeLi (1.1 Mi Et 2 O, 28.4 mL, 32.4 mmol) at -78°C, and the resulting mixture was gradually warmed to room temperature and then stirred overnight. Aqueous NH 4 Cl was added to the reaction mixture, THF was removed in vacuo, <p>g extraction was then performed with EtOAc. The organic layer was washed with water and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (3:1) as eluent to give benzyl-[2-(S)-(A7-Boe-amino)-5-oxo-6-methyl] pentanoate (5.02 g , 45%) as colorless needles. Temp. : 85-87°C. 'H-NMR (CDCl1) 8 1.43 (s, 9 H), 1.61-2.15 (series of m, 3 H), 2.09 (s, 3H), 2.41-2.55 (m, 2 H), 4.30 (brs, 1 .H), 4.70 (d, J= 5.6 Hz, 1 H), 5.12-5.21 (m, 2H), 7.29-7.37 (m, 5 H); MS (ESI) m/z, 336 (M<*>+H).

To a stirred solution of benzyl [2-(S)-(iV-Boe-amino)-5-oxo-6-methyl]pentanoate (4.46 g, 13.3 mmol) in CH 2 Cl 2 (50 mL) was added , trifluoroacetic acid (20 mL) at room temperature, and the resulting mixture was stirred for 1.5 hours. The mixture was concentrated in vacuo and dissolved in toluene, then evaporated to give benzyl 5-methyl-5-pyrroline-2-(S)-carboxylate trifluoroacetic acid salt (5.74 g, quant.) as a crude brown oil. To 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 H 2 atmosphere. 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-tert-butyl dicarbonate in MeCN-water (15:1.16 mL) was added 1.0Af-NaOH (8.49 mmol, 8.49 ml) at room temperature, and the resulting mixture was stirred for 1 hour. The resulting mixture was evaporated and poured into aqueous 1A7-HCl, then extracted with CHCl3/MeOH (5:1). The organic layer was dried over anhydrous Na 2 SO 4 , and then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (7:1) to give N-Boc-5-(R)-methyl-(5)-proline (711 mg, 80%) as a colorless oil.

'H-NMR (CD3OD) 8 1.27 (d,' J= 6.0 Hz, 3H), 1.41-1.46 (m, 9H), 1.62-1.64 (m, IH), 1.96-2.01 (m, IK), 2.22 ( brs, IK), 3.94 (brs, IK), 4.17 (brs, IH).; MS (ESI) m/z, 230 (M<*.>+H).

To a stirred solution of A7-Boc-5-[R)-methyl-2-(S)-proline (1.03 g, 4.49 mmol) in THF (20 mL) was added 10M-BH3-Me2S ( 1.57 mL, 15.7 mmol) at room temperature, and the resulting mixture was heated under reflux for 5 hours. The mixture was poured into aqueous IN-HCl and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , and

then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-AcOEt (1:3) as eluent to give A7-Boc-2-(S)-hydroxymethyl-5-[R)-methylpyrrolidine (838 mg, 87%) as a colorless oil: 1H-NMR(CDCl3)8 1.17 (d, J= 6.0 Hz, 3H), 1.48 (s, 9H), 1.48-1.64 (m, 2H), 1.90-2.11 (m, 2H), 3.52-3.57 (m , IK), 3.68-3.70 (m, IK), 3.94-4.13 (m, IK).

To a stirred solution of N-Boc-2-(S)-hydroxymethyl-5-{R)-methylpyrrolidine (820 mg, 3.81 mmol), triphenylphosphine (1.10 g, 4.19 mmol) and methyl 4 -hydroxybenzoate (480 mg, 381 mmol) was added diisopropylazodicarboxylate (841 mL, 4.19 mmol) at room temperature, and the resulting mixture was stirred at 60°C for 1 hour. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with hexane-EtOAc (5:1) to give methyl 4-[AJ-Boe-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy] benzoate (1.32 g, 80%) as a colorless solid. -2.11 (m, 2 H), 3.88 (s, 3 H), 3.88 (overlap<* >IH), 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 Cvf+H). To a stirred solution of methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy] benzoate (1.29 g, 3.70 mmol) in CH 2 Cl 2 (30 mL) was added trifluoroacetic acid (10 mL) at room temperature and the resulting mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aqueous NaHCO 3 , and then extracted with CHCl 3 .The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give methyl 4-[5{ R )-methyl-2-( S )-pyrrolidinylmethoxy]benzoate (871 mg, 95%) as one colorless oil.The product was an reversed in. subsequent reactions without further purification.

1H-NMR (CDCl 3 ) 5 1.18 (d, J= 6.4 Hz, 3 H), 1.30-1.40 (m, 1 H),"" 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 Qvf+H)

To a stirred solution of methyl 4-[5-[ R )-methyl-2-( S )-pyrrolidinylmethoxy] benzoate (141 mg, 0.57 mmol), 4-[ N -(2-methylphenyl)ureido]-3 -methoxyphenylacetic acid (178 mg, 0.57 mmol) and N-dimethylaminopyridine (69.0 mg, 0.57 mmol) in DMF (10 mL) was added EDC-HCL (120 mg, 0.62 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with saline solution, dried over anhydrous Na 2 SO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give methyl 4-[1- [4-[ N'~ (2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-methyl-2-( S)-pyrrolidinylmethoxy] benzoate. (2 97 mg, 96%) as a colorless amorphous solid. 1 H-NMR (CDCl 3 ) δ 1.24-1.3.4 (m, 3 H), 1.93-2.18 (series of m, 4 H), 2.28 (s, 3 H). 3.65 (s, 3 H), 3.88 (s, 3 H), 3.62-3.87 (m, 3 H), 4.1M.38 ( series of; m, 3 H), 6.42-8.06 (seriVav<*> m, 13H)'; MS (ESI) m/z, 546 (M₂+H).

To a stirred solution of methyl 4-[1- [4-[W-(2-methylphenyl)-ureido]-3-methoxyphenylacetyl]-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy] benzoate ( 279 mg, .0.51 mmol) in MeOH-THF (1:1.10 mL) was added 1.0 M NaOH (2.56 mL, 2.56 mmol) at room temperature, and the resulting mixture was heated at 60°C with stirring for 2 hours. The reaction mixture was poured into 12V-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl 3 -MeOH (15:1) to give 150 (269 mg, 99%) as a colorless amorphous solid. VAT 531.60. 'H-NMR (CD3OD), mixture of rotamers, S 1.28-1.35 (xn, 3 H), 1.74-2.21 (series of rn, 4 H), 2.28 (s, 3 H), 3.71-4.37 (series of, m, 6 H), 6.76-7.99 (series of X 11 H); MS (ESI) m/z, 532 (M*+H).

EXAMPLE 133

4-[trans-4-amino-1-[3-methoxy-4-[AT-(2-methylphenyl)ureido]-phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a solution of methyl 4-(trans-4-amino-1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (1.0 g, 2.86 mmol) and TEA (1.2 mL, 8.6 mmol in CH 2 Cl 2 (20.0 mL) was added trifluoroacetic anhydride (720 mg, 3.43 mmol) at 0° C. After stirring for 2.5 h at room temperature, water was added to the solution and the solution was extracted with CH 2 Cl 2 . The extract was washed with water, then dried over Na 2 SO 4 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 methyl 4-( trans- 1- tert -butoxycarbonyl-4-trifluoroacetamido-(2S)-pyrrolidinyl)-methoxybenzoate (940 mg, 74%) as a colorless oil.

1H-NMR (CDCl1) 6 1.46 (s, 9H), 2.02-2.18 (m, 1H), 2.41-2.52 (m, 1H), 3.30-3.45 (m, 1H), 3.80-3.90 (m, 1H) , 3.88 (s, 3H), 4.00-4.30 (m, 3H), 4.65-4.75 (m, IH), 6.50 (br s, IH), 6.91-6.94 (m, 2H), 7.96-7.99 (m, 2H ).

To a stirred solution of methyl 4-{trans-1-tert-butoxycarbonyl-4-trifluoroacetamido-(2S)-pyrrolidinyl)methoxybenzoate (470 mg, 1.05 mmol) in CH 2 Cl 2 (10.0 mL) was added TFA ( 5.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[AT<->(2-methylphenyl)ureido]phenylacetic acid (314 mg, 1.0 mmol), HOBt (162 mg, 1.2 mmol) and triethylamine (417 mL, 3.0 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (288 mg, 1.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, and concentrated in vacuo. Water was added to the residue and extraction was carried out with EtOAc. The organic layer was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (3:1, v/v) as eluent to give methyl 4-[trans-1-[3-methoxy-4-[W-(2-methylphenyl) ureido]phenylacetyl]-4-trifluoroacetamido-(2S)-pyrrolidinyl]methoxybenzoate (350 mg, 52%) as a colorless oil.

1H-NMR (CDCl1) 6 2.01-2.10 (m, 1H), 2.31 (s, 3H), 2.42-2.48 (m, 1H), 3.45-3.50 (rn, 1H), 3.56-3.59 (m, 5H) , 3.89 (s, 3H), 4.07-4.14 (m, 2H), 4.38-4.42 (m, IH), 4.50-4.60 (m, IH), 4.72-4.80 (m, IH), 6.33 (s, IH) , 6.60-6.85 (m, 3H), 7.06-7.26 (m, 3H), 7.48-7.52 (m, 1H), 7.93-8.05 (m, 3H).

To a stirred solution of methyl 4-[trans-1-[3-methoxy-4-[A7'~ (2-methylphenyl] ureido] phenylacetyl] -4-trifluoroacetamido-(2S)-pyrrolidinyl]methoxybenzoate (150 mg, 0.23 mmol) in THF (3.0 mL) and MeOH (2.0 mL) was added 1 N NaOH (0.70 mL, 0.70 mmol). The mixture was stirred at 60 °C for 18 h. The mixture was concentrated in vacuo, water was added thereto and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 151 (100 mg, 81%) as a white crystalline solid. MV 532, 59. M.p.: 170-171° C. IR (KBr) 3264.2937,

1604, 1535, 1415, 1376, 1255, 1224, 1033 cm'<1>; 1H-NMR (DMSO-dj) 5 1.80-1.90 (m, 1H), 2.10--2.20 (m. IK), 2.24 (s, 3H), 3.55-3.80 (m, 3H), 3.57 (s, 2H ), 4.08^4.18 (m, 2H), 4.36-4.60 (m, IK), 6. 12- 1..W (m, IK), 7.77-8.01 (m, 4H), 8.46 (s, IK), 8.54 (s, IK) ; MS (FAB) m/z 532 (M*+1); .4™/. 3calculated for<^3JN<O6-2.0H2O: C, 61.26; H, 6.38; N, 9.85. Found: C, 61.07; H, 6.32; N, 9.58.

EXAMPLE 134

methyl 4-[trans-4-amino-1-[3-methoxy-4-[AT-(2-methylphenyl)-ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate HCl salt

To a stirred solution of methyl 4-[trans-1-[3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]-4-trifluoroacetamido-(2S)-pyrrolidinyl]methoxybenzoate (200 mg, 0 .31 mmol) in MeOH

(4.0 mL) was added water (2.0 mL) and K 2 CO 3 (138 mg, 1.0

ml) at room temperature. After stirring for 18 hours at room temperature, water was added to the mixture and the mixture was extracted with CH 2 Cl 2 . The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-

CH 2 Cl 2 (5:95 to 15:85 v/v) as eluent. The product was dissolved in EtOH (5.0 mL), and 1N HCl (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. MV 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, SK), 4.00-4.24 (m, 2H ), 4.47-4-.67 (m, IK), 6.70-7.16 (m, IK), 7.77-8.00 (m, 4H), 8.49 (s, IK), 8.55 (s, IK) ; MS (FAB) m/z 547 (M++1); H, 6.26; N, 9.21; Cl,

5.83 Found: C, 59.42; H, 6.42; N, 9.04; Cl, 6.11.

EXAMPLE 135

4- t trans-1-[3-methoxy-4-[IV' (2-methylphenyl)ureido]phenylacetyl]--4-methylamino-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-trifluoroacetamido-(2S)-pyrrolidinyl)methoxybenzoate (520 mg, 1.17 mmol) in DMF (10.0 mL) was added K 2 GO 3 ( 321 mg, 2.33 mmol) and Mel (330 mg, 2.33 mmol) at room temperature. The reaction mixture was stirred at 50°C for 18 hours. Water was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:2, v/v) as eluent to give methyl 4-[ trans-1-tert-butoxycarbonyl-4-(N-methyl-trifluoroacetamido)-( 2S)-pyrrolidinyl]methoxybenzoate (390 mg, 73%) as a colorless oil. 1 H-NMR (CDCl 1 ) δ 1.46 (9H,s), 2.12-2.40

(m, 2H), 2.96 and' 3.05 (each, total 3H), 3.28-3.70 (m, 2H), 3.88 (s, 3H), 3.95-4.42 (m, 3H), 5.10-5.40 (m, IH) , 6.89-6.91 (rn, 2H), 7.96-8.00 (m, 2H).

To a stirred solution of methyl 4-[trans-1-tert-butoxycarbonyl-4-(N-methyl-trifluoroacetamido)-(2S)-pyrrolidinyl]-methoxybenzoate (390 mg, 0.85 mmol) in CH 2 Cl 2 (8, 0 mL) was added TFA (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour; The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (279 mg, 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 EDC-HCl (255 mg, 1.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[trans-1-[3-methoxy-4-[W-(2- methylphenyl)ureido]phenylacetyl]-4-(Δ7-methyl-trifluoroacetamido)-(2S)-pyrrolidinyl]methoxybenzoate (480 mg, 82%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 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 (ra, IH), 6.38-6.43 (m, IH), 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-[trans-1-[3-methoxy-4-[A7'- (2-methylphenyl)ureido] phenylacetyl] -4-(A7-methyl-N-trifluoroacetylamino)-(2 S)-pyrrolidinyl] methoxybenzoate (240 mg, 0.37 mmol) in THF (5.0 mL) and MeOH (3.0 mL) was added 1N NaOH

(1.27 mL, 1.27 mmol). The mixture was stirred at 60°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 153 (140 mg, 70%) as a white crystalline solid. VAT 546.61. M.p.: 162-164°C. IR (KBr)

3338, 1604, 1535,1255, 1033, 755 cm"'; 'H-NMR (DMSO-dJ 8 1.85-1.95 (m, 1H), 2.10-2.20 (m, 1H), 2^24 (s, 3H) , 2.34 and 2.39 (whose; 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, IH ), 6.73-7.16 (m, 7H), 7.77-8.01 (m, 4H), 8.45 (s, IH), 8.53 (s, IH); MS (FAB) m/ z 547 (M*+1); Anal Calculated for CJ(>H>(N,04-2.5H2O: C, 60.90; H, 6.64; N, 9.4?. Found: C, 61.01; H, 6.50; N, 9.31.

EXAMPLE 136

methyl 4-[trans-1-[3-methoxy-4-[IV'-(2-methylphenyl)ureido]-phenylacetyl]-4-methylamino-(2S)-pyrrolidinyl] methoxybenzoate

To a stirred solution of methyl 4-[trans-1-[3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenylacetyl]-4-(N-methyltrifluoroacetamido)-(25)-pyrrolidinyl] Methoxybenzoate (240 mg, 0.36

mmol) in THF (5.0 mmol) and MeOH (5.0 mL) was added water

(2.0 mL) and K 2 CO 3 (138 mg, 1.0 mL) at room temperature. After stirring for 18 hours at room temperature, water was added to the mixture and the mixture was extracted with CH 2 Cl 2 .

The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH 2 Cl 2 (5/95 to 20/80, volume/volume) as eluent. The product was dissolved in EtOH (5.0 mL) and 12V HCl (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. VAT 560.64.

IR (KBr) 3311, 2692, 2453, 1712, 1604, 1533 cm-<1>; 1H-NMR (DMSO-d6) 6 2.24 (s, 3H), 2.15-2.30 (m, 2H), 2.60 (br s, 3H), 3.60-4.20

(m, 5H), 3.78-3.81 (m, 8H), 4.47-4.70 (m, IK), 6.71-7.16 (m, 7H),,7.77-8:00 (m, 4H), 8.48 (s, 1H ),;8.55 (s, IK), 9.21 (br s, 2H); MS (FAB) m/z 561 (M<*>+1); ^na/.Bereanét-fbrGj^MNA-HCl-

1.4H 2 O.: C, 59.83; H, 6.45; N, 9:00 a.m.; Cl, 5.70. Found: C, 60.08; H,'6.'51;, N, 8.68; Cl, 5.99.

EXAMPLE 137. 4-[trans-4-dimethylamino-1-[3-methoxy-4-[IV<->(2-methylphenyl)-ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxypyrrolidine (2.17 g, 10.0 mmol) and imidazole (2.04 g, 30.0 mmol) in DMF (50 mL) was added TBDPS-C1 (3.03 g, 11.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. Water was added thereto, and the mixture was extracted with EtOAc. The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography i. on silica gel with n-hexane-EtOAc (3:2, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4- hydroxypyrrolidine (1.5 g, 33%) as et. white crystalline solid. 1H-NMR(CDCl 3 ) δ 1.03 (s9H), 1.25 and 1.32 (each s, 9H), 1.90-2.10 (m, 1H), 2.30-2.40 (m, 1H), 3.40-3.80 (m, 3H), 3.95-4.15 (m, 2H), 4.45-4.55 (m, 1H), 7.37-7.39 (m, 6H), 7.63-7.64 (m, 4H).

To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (910 mg, 2.0 mmol) and Ph3P (628 mg, 2.4 mmol) in THF (20 mL) was added CBr 4 (993 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hour. N-hexane (40 ml) 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, v/v) as eluent to give cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert- butyldiphenyl-silyloxy) methylpyrrolidine (1.0 g, quant.) as a pale yellow oil. 1H-NMR (CDCl 3 ) δ 1.06 (s, 9H), 1.31 and 1.45 (each s, 9H), 2.63 (m, 2H), 3.49 (m, IK), 3.89.-4.14 (m, 5H), 7J5 -7.42 (m, 6H), 7.64-7.66 (, 4Hm).

To a stirred solution of cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine

(480 mg, 0.93 mmol) in DMF (5 mL) was added NaN 3 (241 mg, 3.70 mmol) at room temperature. The reaction mixture was

stirred at 70°C for 3 days. Water was added thereto, and the mixture was extracted with EtOAc. The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. The solution of the crude residue in EtOH

(10 mL) was hydrogenated over 10% Pd-C under one atmospheric pressure at room temperature for 4 hours; The catalyst was filtered off, and the filtrate was concentrated in vacuo to give trans-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenyl-silyloxy)methylpyrrolidine (400 mg, 95%) as a colorless oil. vH-miR (CDClj) 8

1.06 (s, 9H), 1.32 and 1:45 (each s, total 9H), 2.20-2.35 (m, IK), 3.05-3.18 (m, IK), 3.55-4.05 (m,

6H), 7.35-7.41. (m, 6H), 7.6-1-7.69 (rn, 4H).

To is stirred solution of trans-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (400 mg, 0.88 mmol), AcOH (120 mL, 2.0 mmol), and 37 % HCHO water. (500 mL), in MeOH (10 mL) was added NaBH 3 CN (11 mg, 1.76 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, water was added and the mixture was extracted with CH 2 Cl 2 . The extract was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on

silica gel with MeOH-CH2Cl2 (3:97, v/v) as eluent to give trans-1-tert-butoxycarbonyl-(2S)-(tert--butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (330 mg, 78% ) as a pale yellow oil. "

1H-NMR (CDC13) 8 1.06 (s, 9H), 1.33 and 1.45 (each s, total 9H), 1.80-2.25 (m, IK), 2.23 (br s, 6H), 2.95-4.05 (m, 6H ), 7.36-7.39 (m, 6H), 7.63-7.65 (m, AK).

To a stirred solution of trans-1-tert-butoxycarbonyl-(25)-(tert-butyldiphenylsilyloxy)methyl-4-dimethylamino-pyrrolidine (330 mg, 0.68 mmol) in THF (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 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (3:97 to 20:80, v/v) as eluent to give trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethyl-pyrrolidine (180 mg, quant.) as a pale yellow oil. 1H-NMR (CDCl 3 ) δ 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 trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (180 mg, 0.73 mmol), methyl 4-hydroxybenzoate (114 mg, 0.75 mmol) and Ph3P (296 mg , 1.13 mmol) in THF (10 mL) was added DIAD (227 mg, 1.13 mmol) at 0 °C. The reaction mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with h-hexane-EtOAc (1:2, v/v) to MeOH-CH2Cl2 (5:95, v/v) as eluent to give methyl 4-[trans-l-tert- butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl]-methoxybenzoate (180 mg, 68%) as a pale yellow oil.

1H-NMR (CDCl 3 ) 6 1.46 (s,

9H), 1.80-1.95 (m, IH), 2.20-2.23 (m, IK), 2.24 (s, 6H), 2.90-2.95 (m, IK), 3.10-3.30 (m, IK), 3.50-3.65 ( rn, IK), 3.88 (s, 3H), 3.95-4.35 (m, 3H), 6.93-6.95 (m, 2K), 7.96-7.98 (m, 2H).

To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl)methoxybenzoate (200 mg, 0.53 mmol) in CH 2 Cl 2 (6 mL) was added TFA (3 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with saline solution, . dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[Δ7'~ (2-methylphenyl)ureido]phenylacetic 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-CH1 (152 mg, 0.79 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc to CH2Cl2-MeOH (8:92, v/v) as eluent to give methyl 4-[trans-4-dimethylamino-1-[3-methoxy-4- [AJ'- (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (260 mg, 86%) as a colorless <o>lj e . 1H-NMR (CDCl 3 ) δ 1.95-2.15 (m, 3H), 2.23 (s, 6H), 2.31 (s, 3H), 3.30-3.34 (m, IK),

3.57 (s, 2H), 3.61 (s, 3H), 3.70-3.75 (m, IK), 4.11-4.15 (m, 2H), 4.45-4.50 (m, IK), 6.34 (s, IK), 6.72- 6.88 (m, AK), 7.08-7.24 (m, 4H), 7.51-7.53 (m, IK), 7.92-8.07 (m, 3H).

To a stirred solution of methyl 4-[trans-4-dimethylamino-1-[3-methoxy-4-[A7'~ (2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoate (2 60 mg, 0 .45 mmol) in THF (4.0 mL) and MeOH (2.0 mL) was added 1N NaOH (0.90 mL, 0.90 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 155 (200 mg, 79%) as a white crystalline solid: MW 560.64. Melting point: 145-150°C. IR (KBr), 3355, 2948, 1698, 1604, 1533, 1454, 1417, 1255, 1226, 1166, 1035, 755 cm -1 ; 'H-NMR (DMSO-

dt) 8 1.82-1.98 (m, IK), 2.08-2.11 (m, IH), 2.20 (s, 6H), 2.25 (s, 3H), 3.40-3.60 (m, 3H), 3.64 (s,

2H), 3.82 (s, 3H), 4.01-4.16 (m, 2H), 4.36 (m, IK), 6.74-7.15 (m, 7H), 7.77-8.02 (m, AK), 8.44 (s, IK) , 8.54 (p, IH); MS (FAB) m/z 561 (M<+>+1)Mna/.Calculated for C31H3<NA-1.2H20: C, 63.9.5; H,

6.65; N, 9.62. Found: C, 63.82; H, 6.72; N, 9.44.

EXAMPLE 138

methyl 4- [ trans- A-dimethylamino-1- [3-methoxy-4- [AT'- (2-methylphenyl)ureido]phenylacetyl] -(2S) -pyrrolidinyl]methoxybenzoate-

HCl salt

To a stirred solution of trans-4-[4-dimethylamino-1-[3-methoxy-4-[W(2-methylphenyl)ureido]phenylacetyl-(2S)-pyrrolidinyl]methoxybenzoic acid (80 mg, 0.14 mmol) in toluene (4.0 mL) and MeOH (1.0 mL) was added TMSCHN2 (2.0 M in hexane, 100 mL, 0.20 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (5:95, volume/volume) as eluent. The product was dissolved in EtOH (5.0 mL) and 1N HCl (in EtOH) (244 µl, 0.244 mmol) was added thereto. The mixture was concentrated in vacuo to give 156 (72 mg, 88%) as an amorphous solid. VAT 574.67.

IR (KBr) 3345, 2950, 2586, 1712, 1604, 1511, 1454, 1284, 1255, 1170, 1114, 1029, 850,771 cm-1; 1H-NMR (DMSO-d*) 6 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, IH), 6.74-7.16 (m, 7H), 7.77-8.01 (m, 4H), 8.48 (s, IH), 8.55 (s, 1H); Anal. Calculated for C33H3.NA-1.OHCl 1.2 HA C, 60.74; H, 6.59; N, 8.85. Found: C, 61.03; H, 6.78; N, 8.33.

EXAMPLE 139

4-[cis-4-dimethylamino-1-[3-methoxy-4-[A7'~ (2-methyl phenyl)-ureido]phenylacetyl]-(2S)-pyrrolidinyl] methoxybenzoic acid

To a stirred solution of cis-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy-methyl-4-hydroxypyrrolidine (1.82 mg, 4.0 mmol), phthalimide (647 mg, 4.4 mmol) and To Ph3P (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 h. 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 A7- [cis-1-tert-butoxycarbonyl-(2S)-tert-butyldiphenylsilyl-oxy)methyl -4-pyrrolidinyl]phthalimide (1.6 g, 69%) as an amorphous solid. 1H-NMR (CDCl1) 5 1.07 (s,9H), 1.30 and 1.44 (each s, total 9H), 2.27-2.37 (m, IH), 2.94-2.96 (m, IK), 3.81-4.09 (m, 5H), 4.72 (m, IK), 7.37-7.38 (m, 6H), 7.67-7.74 (m, 6H), 7.84-7.86 (m, 2H).

To a stirred solution of A7-[cis-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-pyrrolidinyl]-phthalimide (1.60 g, 2.74 mmol) in EtOH (8 mL) NH 2 NH 2 °H 2 O (206 mg, 4.11 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for 1 hour. The mixture was concentrated in vacuo. The resulting solid was filtered off and washed with CHCl 3 . The filtrate was concentrated in vacuo. The resulting solid was filtered off and washed with CHCl 3 . The filtrate was concentrated in vacuo to give cis-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyl diphenyl-silyloxy)methylpyrrolidine (1.3 g, quant.) as a pale yellow oil. The crude product was used in the subsequent reaction without further purification. 1 H-NMR (CDCl 1 ) δ 1.06 (s, 9H), 1.30 and. 1.45 (each s>tal 9H), 1.59 (m, IH), 1.85 (m, IK), 2.94 (m, IK), 3.44(m, IK), 3.78-4.07 (m, 4H), 7.36-7.41 (raw, 6H), 7.51-7.65 (m, 4H).

To a stirred solution of cis-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methylpyrrolidine (1.24 g, 2.74 mmol), AcOH (374 µl, 5.48 mmol) , and 37% HCHO water. (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 hours. After concentration in vacuo, water was added and the mixture was extracted with CH 2 Cl 2 . The extract was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (3/97, v/v) as eluent to give cis-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)-methyl-4-dimethylaminopyrrolidine (1 .1 g, 83%) as a pale yellow oil.

'H-NMR (CDCl1) 8 1.05 (s, 9H), 1.29 and 1.45 (each

s, total 9H), 1.95-2.04 (m, IK), 2.20-2.26 (m, IH), 2.27 (s, 6H), 2.54 (m, IK), 3.00-3.02 (m, IH), 3.62-4 .03 (m, AK), 7.34-7.41 (m, 6H), 7.63-7.65 (m, 4H).

To a stirred solution of cis-1-tert-butoxycarbonyl-2-(tert-butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (1.1 g, 2.27 mmol) in THF (10 mL) 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 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (3/97 to 20/80, v/v) as eluent to give cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (580 mg, quant.) as a pale yellow oil. 1H<->NMR (CDCl1) δ 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 cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (555 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 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1/2, v/v) MeOH-CH2Cl2 (5/95, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycarbonyl) -4-dimethylamino-(2S)-pyrrolidinyl)methoxybenzoate (260 mg, 30%) as a pale yellow oil. 1H-NMR(CDCl 3 ) δ 1.45 (s, 9H), 1.70-1.90 (m, IK), 2.26 (s, 6H), 2.33 (m, IK), 2.57 (m, IH); 3:06 'Cm; IH), 3.85-4.23 (m, AK), 3.88 to 3H), 6.93 (m, 2H), 7.95 (m, 2H).

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl)methoxybenzoate (280 mg, 0.55 mmol) in CH 2 Cl 2 (6 mL) was added TFA (3 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetic acid (173 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol) and triethylamine (153 µl , 1.1 mmol) in THF (6 mL) and MeCN (6 mL) was added EDC-HCl (160 mg, 0.83 mmol) at 0 °C. The reaction mixture was stirred. at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-CH2Cl2-MeOH (5/95, v/v) as eluent to give methyl 4-[cis-4-dimethylamino-1-[3-methoxy-4-[AT- (2-Methylphenyl)ureido]phenylacetyl]-(2 S )-pyrrolidinyl]methoxybenzoate (270 mg, 47%) as a colorless oil.

1H-NMR (CDCl1) δ 1.95-2.04 (m, 1H), 2.25 (s, 6H), 2.32 (s, 3H), 2.61 (m, UT), 3.21 (m, UT), 3.56-3.58 (m , 5H), 3.80-3.83 (m, UT), 3.88 (s, 3H), 4.18-4.20 (m, UT), 4.41-4.45 (ni,

2H), 6.36 (s, UT), 6.68-6.85 (m, AK), 7.08-7.25 (m, 4H), 7.52-7.55 (m, UT), 7.91-8.07 (m, 3H).

To a stirred solution of methyl 4-[cis-4-dimethylamino-1-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoate (270 mg, 0, 47 mmol) in THF (4.0 mL) and MeOH (2.0 mL) was added 1 N NaOH (1.0 mL, 1.0 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 157 (170 mg, 65%) as a white crystalline solid. MV 560, 64. Mp.: 147-150°C. DR.(KBr) 3353, 2952, 1700, 1604, 1533, 1454, 1415, 1255, 1166, 1035, 755 cm:<1>; 1H-NMR (DMSO-ds) δ :1.83-1.84 (m, UT), 2.08-2.10 (m, UT), 2.21 (br 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, UT), 8.54 (s, IK) ; MS (FAB) w/ z'561 QA+ Kf; Anal teregnf tforC31H36NA'2 HA C, 62.40; H, 6.76; N, 9.39. Found: C, 62.51; H, 6.60; N, 9.36.

EXAMPLE 140

methyl 4-[cis-4-dimethylamino-1-[3-methoxy-4-[A<T->(2-methylphenyl)ureido]phenylacetyl]-(25)-pyrrolidinyl]methoxybenzoate HCl salt

To a stirred solution of 4-[cis-4-dimethylamino-1-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid (80 mg, 0.14 mmol) in toluene

(4.0 mL) and MeOH (1.0 mL) was added TMSCHN 2 (2.0 M in hexane) (100 µl, 0.20 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (5/95, volume/volume) as eluent. The product was dissolved in EtOH (5.0 mL) and 1N HCl (in EtOH) (244 µl, 0.244 mmol) was added thereto. The mixture was concentrated in vacuo to give 158 (75 mg, 79%) as an amorphous solid. VAT 574.67.

IR (KBr) 3345, 2950h 2456, 1712, 1646, 1604, 1511, 1454, 1434, 1415, 1284, 1257, 1168, 1114, 1031, 771 cm-1; 1H-NMR (DMSO-d«) 6 2.10-2.20 (m, 2H), 2.25 (s, 3H), 2.83 (m, 6H), 3.60-3.62 (rn, 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, IK), 8.55 (s, 1); MS (FAB) m/z 574 (M+H)<+>; Anal. Calculated for C^2HMN,CV1-0-HCl 1.3 HA C, 60.57; H, 6.61; N, 8.83. FoundC, 60.80; H, 6.82; N, 8.44.

in

EXAMPLE 141

4-[trans-1-[4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenyl-acetyl]-4-dimethylamino-(2S)-pyrrolidinyl] methoxybenzoic acid

To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-dimethylamino-(25)-pyrrolidinyl)methoxybenzoate (430 mg, 1.1 mmol) in CH 2 Cl 2 (10.0 mL) was added TFA (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 2 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (368 mg, 1.1 mmol), HOBt (162 mg, 1.2 mmol), and triethylamine ( 417 mL, 3.0 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (288 mg, 1.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue, and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[ trans- 1-[4-[ N'~

(2-Chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-dimethylamino-(2 5 )-pyrrolidinyl]methoxybenzoate (530 mg, 78%) as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.94-1.99 (m, 1H), 2.48 (s, 9H), 3.06-3.12 (m, IK), 3.33-3.38 (an, IK), 3.60 (s, 2H), 3.68 (s, 3H), 3.69-3.80 (m, IK), 3.88 (s,'3H), 4.13-4.20 (m, 2H), 4.56 (m, IK), 6.76-7.00 (m, 5H), 7.22- 7.34 (m, 3H), 7.92-8.00 (m, 3H), 8.17-8.19 (m, IH). For HCl salt: IR (KBr) 3324, 2950, 2454, 1710, 1604, 1511, 1284 cm'<1>; 1H-NMR (DMSO-dJ 82.30-2.40 (m, 2H), 2.77-2.80 (m, 6H), 3.60-3.75 (m, 2H), 3.75-3.85 (m, 8H), 4.00-4.22 (m, 3H), 4.50-4.75 (m, IH), 6.75-7.43 (m, 7H), 7.89-8.09 (m, 4H), 8.87 (s, IK), 8.91 (s, IK) ; MS (FAB) w/ z 595 (M^M^a/Calculated for Ca^j^ACl-l.OHCl-l.OHiO: C, 57.23; H, 6.04; N, 8.61; Cl, 10.90. Found C, 57.43; H, 6.08; N , 8.38;Cl, 10.73^

To a stirred solution of methyl 4-[trans-1-[4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-dimeth<yl>amino-(2S)-pyrrolidinyl]methoxybenzoate ( 190 mg, 0.32 mmol) in THF

(3.0 mL) and MeOH (2.0 mL) was added 1N NaOH (0.64 mL, 0.64 mmol). ^The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto

and the mixture was neutralized with 1N HCl in the resulting

. solid was collected, washed with water and dried in vacuo to give 159 (150 mg, 83%) as a white crystalline solid...-MV 581.06. M.p.: 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^.60 (m, IH), 6.75-7.43 (m, 7H), 7.86-8.09 (m,

4H), 8.86 (p, 1H), 8.91 (p, 1H); MS ( FAB) m/ z 581 (M+H)^ ^waAcalculated for Cj^NACl-l^HjO:

C, 59.79; H, 5.92; N, 9.30. Found; C, 59.69; H, 5.93; N, 9.09. EXAMPLE 142 4-[cis-1-[4-[ N'~(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-dimethylamino-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-pyrrolidinyl)methoxybenzoate (1.2 g, 3.2 mmol) in CH 2 Cl 2 (10.0 mL) was added added TFA (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (278 mg, 1.0 mmol), 4-[ N'~

(2-Chlorophenyl)ureido]-3-methoxyphenylacetic acid (335 mg, 1.0

mmol), HoBt (135 mg, 1.0 mmol), and triethylamine (417 mL, 3.0 mmol) in THF (4.0 mL) and MeCN (4.0 mL) was added EDC-HCl (288 mg , 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for IS hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[cis-1-[4-[A7'~ (2-chlorophenyl)ureido ]-3-methoxyphenylacetyl]-4-dimethylamino-(2S)-pyrrolidinyl]methoxybenzoate (500 mg, .84%) as a colorless oil. 1 H-NMR (CDCl 1 ) δ 1.98-2.50

(m, IH), 2.26 (s, 3H), 2.25-2.40 (m, IK), 2.58-2.65 (m, IH), 3.20-3.30 (m, IK), 3.60 (s, 2H), 3.64 (s , 3H), 3.80-3.90 (m, IH), 3.88 (s, 3H), 4.18-4.20 (rn, IK), 4.42-4.46 (m, 2H), 6.72-7.00 (m, 4H), 7.20-7.35 (m, 5H), 7.91-7.94 (m, 3H), 8.18-8.21 (m, IK).

To a stirred solution of methyl 4-[cis-1-[4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-dimethylamino-(2S)-pyrrolidinyl]methoxybenzoate (250 mg, 0 .42 mmol) in THF (5.0 ml) and MeOH (3.0 ml) was added 1 N NaOH (1.0 ml, 1.0 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 160 (170 mg, 70%) as a white crystalline solid. VAT 581.06. M.p.: 165-167°C. IR (KBr) 3328, 1604, 1531, 1164, 1033 cm-<1>; 1H-NMR (DMSO-dJ 5 1.80-1.90 (m, 1H), 2.20-2.50 (m, 1K), 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++ 1) ; Anal.Calculated foréjoHjjNACM. 1 H 2 O: C, 59.87; H, 6.06; N, 9.31. Found: C, 59.65; H, .5.76; N, 9.09.

EXAMPLE 143

4-[cis-1-[4-[W-(2-chlorophenyl]ureido]-3-methoxyphenylacetyl]-4-(2-naphthalenesulfonamido)-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-amino-(2S)-pyrrolidinyl)methoxybenzoate (200 mg, 0.57 mmol) and TEA (317 mL, 2.3 mmol) in CHCl 3 -(10.0 ml) was added (2-naphthyl)sulfonyl chloride (155 mg, 0.68 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (2:1, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycarbonyl-4-(2-naphthylsulfonamido)-(2S) -pyrrolidinyl)methoxybenzoate (240 mg, 78%) as a pale yellow oil. 1 H-NMR (CDCl 3 ) 6 1.25-1.45 (br s, 9H), 1.70-1.80 (m, IK), 2.20-.2.40 ( m, IK), 3.20-3.50 (rn, 2H), 3.90 (s, 3H), 3.85-4.15 (m, 3H), 4.55-4.65 (m, IK), 6.90-7.10 (m, 2H), 7.58- 8.04 (m, 8H), 8.43(s, IK).

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-(2-naphthylsulfonamido)-(2S)-pyrrolidinyl)methoxybenzoate (240 mg, 0.44 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5.0 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[AT-(2-chlorophenyl)ureido]-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-HCl (127 mg, 0.66 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[cis-1-[4-[AT-(2-chlorophenyl)ureido]-3 -methoxyphenylacetyl]-4-(2-naphthalene-sulfonamido)-(2S)-pyrrolidinyl]methoxybenzoate (200 mg, 65%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 1.75-1.80 (m,

IH), 2.25-2.40 (m, IH), 3.43 (s, 2H), 3.40-3.50 (m, IH), 3.60 (s, 3H), 3.65-3.75 (m, IK), 3.90 (s, 3H) , 3.85-3.92 (m, IK), 3.95-4.00 (m, IK), ' 4.30-4.40 (m, IK), 4.65-4.75 (m, IK), 6.26 ( d, J= 9.3 Hz, IH), 6.50 (d, J= 8.3 Hz, IH), 6.23 (s, IK), 6.86 (d, J= 8.8 Hz, 2H); 6.75-7.01 (m, IH). 7.23-7.36 (m, 3H), 7.61-7.96 (m, 9H), 8.20 (d, J= 8.1 Hz, IK), 8.43 (s, IK).

To a stirred solution of methyl 4-[cis-1-[4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-naphthalene-sulfonamide-(2S)-pyrrolidinyl)methoxybenzoate ( 200 mg, 0.26 mmol) in THF (6.0 mL) and MeOH (3.0 mL) was added 1 N NaOH

(0.5 ml, 0.5 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 161 (210 mg, quant.) as a white crystalline solid. MV 743.22. M.p.: 135-142°C. IR (KBr) 3332, 1685, 1604, 1531, 1421, 1159 cm -1 ; 1H-NMR (DMSO-d,) 5 1.75-1.85 (m, 1H), 2.05-2J5 (nv, IK), 3.05-3.15 (m, IK), 3.47 (s, 2H), 3.60-3.80 (m ,.2H), 3.73 (s, 3H),.4.05^4.20 (m, 3H), 6.51 (d, J = 8.5 Hz, IK), 6.74-7.04 (m, 5H), 7.27-7.31 (m, IK ), 7.43-7.45 (in, 2H), 7.66-8.17 (m, 9H), 8.46 (s, IK), 8.91 (d, J= 9.5 Hz, IH); MS (FAB) m/z 743 (M*+1); y/ia/.Calcd>or.CMH33N4OgClS-OJHjO: C, 60.67; H, 4.82; N, 7.45; Cl, 4.26. Found: c, 60.77; H, 4.84; N, 7.21; Cl, 4.90.

EXAMPLE 144

4- [1- [4- [A7'~(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-4-(2-mesitylenesulfonamido-(25)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-amino-(2S)-pyrrolidinyl)methoxybenzoate (180 mg, 0.51 mmol) and TEA (283 mL, 2.0 mmol) in To CHCl 3 (10.0 mL) was added (2-mesitylene)sulfonyl chloride (122 mg, 0.56 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (3:1, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycarbonyl-4-(2-mesitylenesulfone-amido-) (2 S)-pyrrolidinyl)methoxybenzoate (170 mg, 62%) as a pale yellow oil. 1 H-NMR (CDCl 1 ) δ 1.40 (s, 9H), 1.85-1.95 (m, 1H), 2.29 (s, 3H), 2.35-2.45 (m, IH), 2.62 (s, 6H), 3.80-4.15 (m, 3H), 3.89 (s, 3H), 3.50-3.65 (m, IK), 6.94 (s, 2H), 6.94- 7.00 (m, 2H), 7.99 (d, J = 8.8 Hz, 2H).

To a stirred solution of methyl (cis-1-tert-butoxycarbonyl-4-(2-mesitylenesulfonamido)-(2S)-pyrrolidinyl)-methoxybenzoate (170 mg, 0.32 mmol) in CH 2 Cl 2 (5.0 mL) was added added TFA (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[AT-(2-bromophenyl)ureido]-3-methoxyphenylacetic 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 EDC-HCl (91 mg, 0.48 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4, v/v) as eluent to give methyl 4-[1-[4-[ N '-(2-bromophenyl)ureido]-3- methoxyphenylacetyl]-4-(2-mesitylene-sulfonamido)-(2S)-pyrrolidinyl]methoxybenzoate (210 mg, 83%) as a colorless oil. 1H-NMR(CDC13)8 1.85-1.90 (m, IK), 1.95-2.05 (m, IK), 2.32 (s, 3H), 2.60 (s, 6H), 3.40-3.50 (m, 3H), 3.60 -3.70 (m, 2H), 3.68 (s, 3H), 3.89

(s, 3H), 3.96-3.99 (m, IK), 3.35-3.45 (m, IK), 3.70-3.75 (m, IK), 6.00 { d, J= 9.5 Hz, IK), 6.57-7.08 (m , 9H), 7.29-7.34 (m, IK), 7.51-7.53 (m, IH), 7.92-7.96 (m, 3H), 8.15 (d, J= 6.8 Hz, IK).

To a stirred solution of methyl 4-[1- [3-methoxy-4-[N-(2-bromophenyl)ureido]phenylacetyl]-4-(2-mesitylenesulfonamido-(2S)-pyrrolidinyl)methoxybenzoate (210 mg, 0 .26 mmol) in THF (5.0 mL) and MeOH (3.0 mL) was added 1 N NaOH (0.47 mL, 0.47 mmol). The mixture was stirred at 70 °C for 24 h. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water, and dried in vacuo to give 162 (180 mg, 87%) as a white crystalline solid. MV 779 .70. M.p.: 130-132° C. IR (KBr) 3332, 1689, 1604, 1529, 1155 cm-'; 'H-NMR (DMSO-dJ 8 1.70-1.85 (m, IK), 2.02-2.12 (m, IH), 2.25 (s, 3H), 2.52 (s, 6H), 3.05-3.12 (ril, IH), 3.48 (s, 2H), 3.60-3.70 (m, 2H), 3.77 (s, 3H ), 3.90-4.20 (m, 3H), 6.59 (d, J= 8.3 Hz, IH), 6.77-6.80 (m, IH), 6.95-7.01 (m, 4H), 7.31-7.35 (m, IK), 7.60 (d, /= 8.1 Hz, IK), 1 M- l. 91 (m, SK), 8.72-8.76 (m, IK), 8.89-8.93 (m, IK) ; MS (FAB) m/ x 779 (M<*>), 781 (M<*>+2);J4wa/.Calculated for C37H39N4O,SBr0.5H20: C, 56.35; H, 5.11; N, 7.10; Br, 10.13. Found: C, 56.39; H, 5.07; N, 6.89; Bro, 10.25.

EXAMPLE 145

4- [1- [4- [A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-4-dansylamino-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-amino-(2S)-pyrrolidinyl)methoxybenzoate (180 mg, 0.51 mmol) and TEA (283 mL, 2.0 mmol) in CHCl 3 (10.0 mL) was added dansyl chloride (155 mg, 0.68 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The reaction mixture was purified by column chromatography on silica gel with n-hexane-EtOAc (2:1, v/v) as eluent to give methyl 4-(cis-1-tert-butoxycabonyl-4-dansylamino-(2S)-pyrrolidinyl)methoxybenzoate (200 mg, 73%) as a pale yellow oil. = 1 H-NMR (CDCl 3 ) δ L 34 (s, 9H). 1.50-1.60 (m, IH), 2.15-2.25 (m, IK), 2.87 (s, 6Hj, 3.15-3.22 (m, IK), 3.35-3.45 (m, IK), 3.48-3.52 (m, IK) , 3.80-4.10 (m, 3H), 3.91 (s, 3H), 7.01^ 7.25 (m, 4H), 7.50-7.53 (m, IK), 8.03 (d, J= 8.7 Hz, 2H), 8.16 (d , J= 8.5 Hz, IK), 8.28 (d, J=

7.1 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H).

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-dansylamino-(2S)-pyrrolidinyl)methoxybenzoate (200 mg, 0.34 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA ( 5.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[N'-(2-bromophenyl)-ureido]-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-CH1 (98 mg, 0.51 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4, v/v) as eluent to give methyl 4-[1-[4-[A7'~ (2-bromophenyl)-ureido]-3 -methoxyphenylacetyl]-4-dansylamino-(2S)-pyrrolidinyl]methoxybenzoate (250 mg, 88%) as a colorless oil.

1H-NMR (CDClO 5 1.55-1.65 (m, IK), 2.15-2.25 (m, IH), 2.87 (s, 6H), 3.20-3.35

(m, 3H), 3.50-3.55 (rn, IK), 3.67 (s, 3H), 3.78-3.81 (m, IK), 3.88-3.93 (m, IH), 3:91 (s, 3H), 4.28 -

4.31 (m, IH), 4.65-4.70 (m, IH), 6.35 (d, /= 9.5 Hz, IH), 6.54 (d, J= 8.5 Hz, IK), 6.63 (s, IH),

6^90-7.13 (m, 6H), 7.22-7.31 (m, 2H), 7.50-7.56 (m, 2H), 7.88 (d, /= 8.0 Hz, IH), 7.99 ( d, J = 9.0 Hz, IK), 8.13-8.16 (m, 2H), 8.27 (d, J= 7.6 Hz, IH), 8.56 (d, > 8.3 Hz, IK).

To a stirred solution of methyl 4-[1-[4-[T'-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-4-dansylamino-2S-pyrrolidinyl]-methoxybenzoate (250 mg; 0, 29 mmol) in THF (5.0 mL) and MeOH

(3.0 mL) was added 1 N NaOH (0.52 mL, 0.52 mmol).

The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 163 (230

mg, 94%) as a green crystalline solid. VAT 830.74.

M.p.: 138-141°C. IR (KBr) 3340, 2940, 1604,

1527, 1421, 1162, 1145 cm"'; 'H-NMR pMSO-ds) 5 1.70-1.80 (m, IK), 1.98-2.06 (m, IK), 2.81 (s, 6H), 3.00-3.10 (m, IK), 3.39-3.40 (m, 2H), 3.50-3.80 (m, 3H), 3.76 (s, 3H), 3.90-4.15 (m, 2H), .

6.52 (d, J = 9.0 Hz, IK), 6.73-7.00 (m, AK), 7.22-7.35 (m, 2H), 7.55-7.64 (m, 3H), 7.83-8.48 (m,

8H), 8.71-8.76 (m, IK), 8.88-8.92 (m, IH); MS (FAB) m/z 830 (W), 832 (MN-2); A nal. Calculated Tor C4(H,0NjO8BrS-0.7H2O: C.56.97; H..95; N,8.30;Br,9.47 Fuhnet: C,57.06; H, 4.86; N, 7.98; Br, 9.66.

EXAMPLE 146

4- [4-methanesulfonamido-1- [4- [N-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(cis-4-amino-l-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (180 mg, 0.51 mmol) and TEA (283 mL, 2.0 mmol) in CHCl 3 (10.0 ml) was. added methanesulfonyl chloride (88 mg, 0.77 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was 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-(cis-1-tert-butoxycarbonyl-4-methanesulfonamido-(2S)-pyrrolidinyl)methoxybenzoate (150 mg, 69%) as a pale yellow oil. 1 H-NMR (CDCl 3 ) δ 1.45 (s, 9H), 1.98-2.08 (m, 1H), 2.52-2.65 (m, 1H),

2.99 (s, 3H), 3.40-3.50 (m, IH), 3.55-3.80 (m, IH), 3.89 (s, IH), 4.00-4.70 (m, 4H), 6.98-7.00 (m, 2H), 8.00 (d,J=8.8HzI2H).

To a stirred solution of methyl 4-(cis-1-tert-butoxycarbonyl-4-methanesulfonamido-(2S)-pyrrolidinyl)methoxybenzoate (150 mg, 0.43 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA ( 5.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[AJ'-(2-bromophenyl)ureido]-3-methoxyphenyl-acetic 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

ml) was added EDC-HCl (144 mg, 0.75 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours

and concentrated in vacuum. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:4 v/v) to EtOH-EtOAc (10% v/v) as eluent to give methyl 4-[4-methanesulfonamido-1-[4- [A'-(2-bromophenyl)ureido]-3-methoxyphenyl acetyl]-(2S)-pyrrolidinyl]-methoxybenzoate (210 mg, 73%) as a colorless oil. 'H-NMR(CDCl3) 5

1.95-2.00 (m, IH), 2.55-2.65 (m, IH), 2.17 (s, 3H), 3.55-3.70 (m, IH), 3.60 (s, 2H), 3.67 (s, 3H), 3.85- 3.90 (m, IH), 3.89 (s, 3H), 3.95-4.18 (m, 2H), 4.45-4.55 (m, IH), 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, IH), 7.51 (d, J = 8.0 Hz, IH), 7.93-7.97 (m, 3H), 8.13 (d,J = 8.3 Hz, IH).

To a stirred solution of methyl 4-[4-methanesulfonamido-1-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxy enylacetyl]-(2S)-pyrrolidinyl] methoxybenzoate (210 mg, 0.3 mmol) in THF (5.0 mL) and MeOH (3.0 mL) was added 1N NaOH (0.8 mL, 0.8 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 164 (170 mg, 83%) as a white crystalline solid. VAT 675.55. M.p.: 125-128°C. IR (KBr) 3353, 1689, 1604, 1529, 1419, 1155 cm"'; 'H-NMR (DMSO-dJ 8 1.88-2.00 (m, 1H), 2.35-2.45 (m, 1H), 2.96 (m, 3H), 3.15-3.23 (m, IH), 3.60 (s, 2H), 3.50-3.70 (m, IH), 3.78 (s, 3H), 3.80-3.90 (m, IH), 3.95-4.05 (m, IH), 4.10-4.30 (xn, 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 (MT+2); ; J4na/.Calculated for Cl9H31NABrS-0.6HiO: C, 50.75; H, 4.73; N, 8.16. Found C, 51.04; H, 4.62; N, 7.79.

EXAMPLE 147

4-[1-[3-Methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]-(2S)-octahydroindolylmethoxy]benzoic acid

To a stirred solution of octahydroindole-(2 S )-carboxylic acid (3.00 g, 17.7 mmol) in dioxane (20 mL) was added 1 N NaOH (45 mL) and the solution was stirred at 0°C. To the mixture was added (Boc)20 (4.26 g, 19.5 mmol) in dioxane (25 ml) at 0°C and the reaction mixture was stirred at room temperature for 1 day. The mixture was acidified with 1N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated to give 1-(tert-butoxycarbonyl)octahydroindole-(2S)-carboxylic acid (4.7-8 g, quant, yield) as a colorless solid. M.p.: 130-132°C. 'H-NMR (CDClj) 8 1.10-1.46 (series of s and m, , total 14 H), 1.65-1.76 (m, 3 H), 1.90-2.18 (m, 2 H), 2.26-2.35 (ni, 1H), 3.77-3.86 (m, 1H), 4.22-4.34 (m, 1H); MS (ESI) m/z 270 (M<*>+1).

To a cooled (0°C) stirred solution of 1-(tert-butoxycarbonyl)octahydroindole-(2S)-carboxylic acid (1.00 g, 3.71 mmol) in THF (10 mL) was added BH3-DMS (530 ml, 5.59 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 MeOH (50:1, v/v) as eluent to give 1-(tert-butoxycarbonyl)octahydroindole-(2S)-methanol (940 mg, 99%) as a colorless oil.

1H-NMR (CDCl1) 8 1.05-1.30 (m, 4 H), 1.47 (s, 9 H), 1.49-1.74 (m, 4 H), 1.82-1.93 (m, 3 H), 2.19-2.26 ( m, 1H), 3.56-3.61 (m, 1H), 3.70-3.75 (m, 2H), 3.94-3.96 (m, 1H); MS (FAB) m/z 256 (M<*>+1)-

To a cooled (0°C) stirred solution of methyl 4-hydroxybenzoate (560 mg, 3.68 mmol) ,. To 1-(tert-butoxycarbonyl)octahydroindole-(2S)methanol (940 mg, 3.68 mmol) and Ph3P (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 hours. After cooling 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-[1-(tert-butoxycarbonyl)-(2S)-octahydroindolylmethoxy]benzoate (1.16 g, 81%) as eh colorless oil.

'H-NMR (CDClj) 5 1.14-1.47 (series of s and m,' total 13 H), 1.60-2.13 (tendons 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 OT+1).

To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-(2S)-octahydroindolylmethoxy]benzoate (1.16 g, 2.98 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL)' and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, basified with saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine. dried over K 2 CO 3 and evaporated to give methyl 4-[(2 S )-octahydroindolylmethoxy]benzoate (860 mg, quant, yield) as a brown oil.

1H-NMR (CDCl1) 5 1.23-1.78 (series-of m, total 10 H), 2.00-2.09 (m, 2 H), 3.14-3.18 (rn, 1 H), 3.55-3.62 (m, 1 H ). 3.88 (s, 3 K), 3.96-4.06 (m, 2 H), 6.92 (d, J= 9.1 Hz, 2 H), 7.97 (d, J-.= 9.1 Hz, 2 H); MS'.(FAB) m/z 290 (M<*>+1).

A mixture of 3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenylacetic acid (298 mg, 0.95 mmol), methyl 4-[(2S)-octahydro-indolylmethoxy]benzoate (274 mg, 0.95 mmol),' EDC-HCl (218 mg, 1.14 mmol), HOBt (154 mg, 1.14 mmol), Et 3 N (160 mL, 1.15 mmol) in THF (7 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 50:1, v/v) as eluent to give methyl 4-[1-[3-methoxy-4-[AT'-(2-methylphenyl )ureido]phenylacetyl]-(2S)-octahydroindolylmethoxy]benzoate (532 mg, 96%) as a white foam.

'H-NMR (CDCl1) 6.1.13-2.05 (series of- m, total 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 Hz, 1 H); MS (FAB) m/z 586 (X+1).

To a stirred solution of methyl 4-[1-[3-methoxy-4-[AT'-(2-'methylphenyl)ureido]phenylacetyl]-(2S)-octahydroindolylmethoxy]benzoate (532 mg, 0.91 mmol ).in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the mixture was poured into ice-1 N HCl, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl 3 -IPE to give 165 (278 mg, 54%) as a white crystalline powder. MV 571.66, Mp.: 130-134°C.. 'H-NMR (DMSO-dj) 8 1.16-2.10 (series of m, total 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,

1 H), 4.17-4.23 (m, 2 H), 4.34-4.36 (iri, 1 H), 6.72-6.74 (m, 1 H), 6.87-6.88 (rn, 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, 1 H), 7.87 (d, J= 8.8 Hz, 2 H), 7.98-8.00 (m, 1 H), -8.45 (s, 1 H), 8.54 (s, -1 H), 12.61 (br s, 1 H); MS (FAB) m/z 572 (M<+>+1); ^/Jo/.BereVetfor C^NjOj lMHjO: C, 68.79; H, 6.56; N, 7.29. Found: C, 68.70; H, 6.82; N, 6.97.

EXAMPLE 148

4- [1- [4- [W-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]benzoic acid

A mixture of 4-[A7'~ (2-chlorophenyl)ureido]-3-methoxyphenyl-acetic acid (307 mg, 0.92 mmol), methyl 4-[( 2S )-octahydro-indolylmethoxy] benzoate (265 mg, 0 .92 mmol), EDC-HCl (211 mg, 1.10 mmol), HOBt (148 mg, 1.10 mmol) and Et3N (153 mL, 1.10 mmol) in THF (7 mL) were stirred at room temperature over the night. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 50:1, v/v) as eluent to give methyl 4-[l-[4-[A7'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]-benzoate (550 mg, 99%) as a white foam .

1H-NMR (CDCl1) 8 1.15-2.02 (series of m, total 9 H), 2.17-2.33 (m, 2 H), 3.58 (s, 3 H), 3.62 (s, 2 H), 3.84-3.90 (series of sc and m, total 4 H), 4.06-4.40 (m, 3 H), 6.71-6.74 (m, 2 H), 6.88-7.00 (m, 3 H), 7.2.1-7.30 (m, 2 H), 7.62 (s, 2 H), 7.91-7.95 (m, 3 H), 8.17-8.20 (m, 1 H); MS (FAB) m/z 606

To a stirred solution of methyl 4-[l-[4-[AJ'-(2-chlorophenyl)- . ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]benzoate (550 mg, 0.91 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL) and the reaction mixture was heated under reflux in 5 hours. After cooling to room temperature, the mixture was poured into ice-1N HCl, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl 3 -IPE to give 16S (286 mg, 53%) as a white crystalline powder. VAT 388.29. M.p.: 133-136°C.

'H-NMR (DMSO-d*) 8 1.16-2.10 (series of m> total 10 H), 2.24-2.27 (m, 1 H), 3.55-3.75 (m, 2 H), 3.80 (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, 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 = 8.1 Hz, 1 H), 8.08 (dd, J= 1.5,

■8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (s, 1 H), 12.61 (br s, 1 H); MS (FAB) m/z 592 (IvT+1); Anal. Calculated for Cj^CINjCy 1/4^0: C.64.42; H, 5.83; N, 7.04; Cl, 5.94. Found:C.64.55; H.6.09; N.6.64; Cl. 5.93.

EXAMPLE 149

4- [1- [4- [A7'~ (2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]benzoic acid

A mixture of 4-[A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (457 mg, 1.21 mmol), methyl 4-[(2S)-octahydroindolylmethoxy]benzoate (320 mg, 1 .21 mmol), EDC-HCl (277 mg, 1.44 mmol), HOBt (196 mg, 1.45 mmol) and Et3N (200 mL, 1.43 mmol) in THF (7 mL) were stirred at room temperature over the night. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 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-[1- [4-[W-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]- (2S)-Octahydroindolylmethoxy]benzoate (423 mg, 54%) as a white foam.

'H-NMR (CDCl1) 6 1.15-1.89 (series of m,

total 8 H), 1.96-2.02 (m, 1H), 2.16-2.32 (m, 2H), 3.63 (s, 2 H), 3.65 (s, 3 H), 3.82-3.86 (m, 1 H),

3.88 (s, 3H), 4.30-4.39 (m, 3H), 6.75-6.77 (m, 2H), 6.88-6.93 (m, 3H), 7.24-7.31 (m, 1H), 7.37-7.50 (m, 3H), 7.91-7.99 (m, 3H), 8.12-8.15 (m, 1H); MS (FAB) m/z 650 (M<+>+1).

To a stirred solution of methyl 4-[1-[4-[N-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]-benzoate (420 mg, 0.65 mmol). in THF (5 mL) was added 0.5

N NaOH (5 mL), and the reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1N HCl, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl 3 -IPE to give 167 (197 mg, 48%) as a white crystalline powder. VAT 636.53. M.p.: 118-123°C.

'H-NMR (DMSO-d«) 5 1.16-2:27 (series of/m,

total 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, 1 H), 6.88-7.05 (m, 4 H), 7.30-7.34 (m, 1 H), 7.59-7.61. (m, 1 H), 7.87-

7.96 (m, 4 H), 8.73 (s, 1 H), 8.91 (s, 1 H), 12.64 (br s, 1 H); MS (FAB) mh 636 (M*+1); Anal. Calculated for c32H34BrN3O6 l/4Hi0: C,59.96;H,5.42;N,6.55; Br,12.46.Found:.C,6b.l2; H, 5.86;

N, 6.09; Bri 12.47.

EXAMPLE 150

4- [3- [3-methoxy-4- [N-(2-methylphenyl) ureido] phenyl] acetyl-4-thiazolidinyl] methoxybenzoic acid

To a stirred solution of thiazolidine-4-carboxylic acid (5.0 g, 37.6 mol) in DMF (50.0 mL) was added (Boc)20 (9.8 g, 45.1 mmol) and TEA ( 8.0 ml). The reaction mixture was stirred at room temperature for 18 hours. Water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was washed with water, then dried over Na 2 SO 4 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-tert-butoxy-carbonylthiazolidine-4-carboxylic acid (6.5 g, 74%) as a white crystalline solid.

1H-NMR (CDCl 1 ) δ 1.49 (br s, 9H), 3.20-3.30 (m, 2H), 4.09-4.87 (m, 3H).

To a stirred solution of 3-tert-butox<y>carbon<y>lthiazolidine-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 stirring at room temperature for 1.0 hour, the reaction mixture was heated under reflux for 1.0 hour. After cooling, the mixture was concentrated in vacuo. Water was added thereto at 0°C, and the mixture was extracted with EtOAc. The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo to give 3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine (2.0 g, quant.) as a colorless oil.

1H-NMR (CDCl1) δ 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, IH), 4.60 (br s, IK).

To a stirred solution of 3-tert-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 DIAD (2.2 g, 10.4 mmol) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. 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-tert-butoxycarbonyl-4-thiazolidinyl)methoxybenzoate (1.6 g, 52. %) as a pale yellow oil. 1H-NMR (CDCl1) 6 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-tert-butoxycarbonyl-4-thiazolidinyl)methoxybenzoate (440 mg, 1.25 mmol) in CH 2 Cl 2 (6 mL) was added TFA (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was

concentrated in vacuum. Saturated NaHCO 3 was added to the residue,

and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. ■ The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (0.6 mmol), 3-methoxy-4-[ N'~(2-methylphenyl)-ureido] 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-HCl (173 mg, 0.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[3-methoxy-4-[ N'-(2-methylphenyl)ureido ] phenyl] acetyl-4-thiazolidinyl] methoxybenzoate (340 mg, quant.) as an amorphous solid. 1 H-NMR (CDCl 1 ) 2.31

(s, 3H), 3.15-3.16 (m, 2H), 3.67-3.69 (m, 5H), 3.88 (s, 3H), 4.09^.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-[A7'~ (2-.methylphenyl)ureido]phenyl]acetyl-4-thiazolidinyl]methoxybenzoate (340 mg, 0.62 mmol) in THF (5.0 mL) and EtOH (3.0 mL) was added 1N NaOH (0.62 mL, 0.62 mmol). The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and. the mixture was neutralized with 1N HCl. The resulting solid was collected; washed with water and dried in vacuo to give 168 (290 mg, 88%) as a white crystalline solid. MV 535.62 M.p.: 125-128°C.

IR (KBf) 3357, 2937, 1604, 1533, 1419, 1253, 1166, 103.3 , 773 cm -1 ; 1H-NMR (DMSO-ds) δ 2.25 (s, 3H), 3.05-3.20'Cm, 2H), 3:71, 3.83, and 3.85 (each s, total 5H), 4.03-4.15 (m, 3H) , 4.52-4.76 (m, 2H), 6.15-6.17 (m, 7H), 7.78-8.30 (m, 4H),

8-.30 (m, IH), 8.56 (m, IH); MS (FAB) m/ z 536 (M<+>+1); H, 5.55; N, 7.72. Found: C, 61.72; H, 5.55; N, 7.49.

EXAMPLE 151

4- [3- [4- [ N'~ (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-thiazolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(3-tert-butoxycarbonyl-4-thiazolidinyl)methoxybenzoate (600 mg, 1.7 mmol) in CH 2 Cl 2 (6.0 mL) was added TFA (6.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[AT-(2-chlorophenyl)ureido]-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) and MeCN (10.0 mL) was added EDC-HCl (490 mg, 2.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid, and saturated NaHCO 3 , then dried over Na 2 SO 4 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-[W<*>(2-chlorophenyl)ureido]-3 -methoxyphenylacetyl]-4-thia-zolidinyl]methoxybenzoate (900 mg, 93%) as a colorless oil.

1H-NMR (CDCl 1 ) δ 3.15-3.18 (m, 2H), 3.70 (s, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 4.09-4.93 (m," 5H), 6.80-7.01 (m, 5H), 7.19-7.35 (ni, 4H), 7.94-8.18 (m, 4H).

To a stirred solution of methyl 4-[3-[4-[N'-(2-chlorophenyl)-ureido]-3-methoxyphenylacetyl]-4-thiazolidinyl] methoxybenzoate (900 mg, 1.6 mmol) in THF (8 .0 mL) and MeOH (4.0 mL) 1N NaOH (3.1 mL, 3.1 mmol) was added. The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water, and dried in vacuo to give 169 (780 mg, 89%) as a white crystalline solid. MV 556.03. M.p.: 126-129°C.

JR (KBr) 3343, 2937, 1604, 1531, 1421, 1245,

1166, 1035, 752'cm-1; 1H-NMR (DMSO-dJ 8 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 . ; H, 5.03; N, 7.38; Cl, 6.22. Found: -C, 56.89; H, 4.84; N, 7.42; Cl, 6.35.

EXAMPLE 152

4- [3- [4- [A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-4-thiazolidinyl]methoxybenzoic acid

To a stirred solution of methyl 4-(3-tert-butoxycarbonyl-4-thiazolidinyl)methoxybenzoate (560 mg, 1.6 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[A7'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (599 mg, 1.6 mmol), HOBt (213 mg,

1.6 mmol) and triethylamine (659 mL, 4.7 mmol) in THF (10.0 mol) and MeCN (10.0 mL) was added EDC-HCl (455 mg, 2.4 mmol) at 0° C. The reaction mixture was stirred at room temperature i

16 hours, and concentrated in vacuum. Water was added to

residue, and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The rest

was purified by column chromatography on silica gel with n-hexane-EtOAc (2:3, v/v) as eluent to give methyl 4- [3- [4- [AT'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl ] -4-thiazolidinyl]methoxybenzoate (870 mg, 89%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 3.00-3.20 (m, 3H), 3.70 (s,

2H), 3.81 (s, 3H), 3.88 (s,.3H), 4.09-4.23 (m, IK), 4.42 (d, J= 8.5 Hz, IK), 4.59 (d, J= 8.5 Hz, IK) , 4.70-4.92.(m, IK), 6.81-7:53 (m, 9H), 7.95-8.15 (m, 4H).

To a stirred solution of methyl 4- [3- [4- [W-(2-bromophenyl)-ureido]-3-methoxyphenylacetyl]-4-thiazolidinyl]methoxybenzoate

(870 mg, 1.4 mmol) in THF (8.0 mL) and MeOH (8.0 mL) was added 1N NaOH (2.8 mL, 2.8 mmol). The mixture was stirred at 70°C in 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water, and dried in vacuo to give 170 (740 mg, 87%) as a white crystalline solid.MV 600.48 M.p.: 125-133°C.

IR (KBr) 3332, 2935, 1604, 1527, 1421, 1245, 1166,' 1027, 750 cm-'; 'H-NMR (DMS0-d«) 8 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, IK), 4.74^.87 (m, IK), 6.76-7.07 (m, SK), 7.30-7.34 (m, IH), 7.59 (d, J = 8.1 Hz, IH), 7:86-7.98 (m, 4H) , 8.74 (p, IK), 8.92-8.94 (p, IK) ; MS (FAB) m/z 600 (M++1); ^na/CalculatedfonCjTHMNjO^BrS-O.SHjO: C, 53.52; H.4.43 N 6.94 Found: C, 53.54; H, 4.45; N, 6.80.

EXAMPLE 153

cis-4-[[1-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylic acid

To a stirred solution of 2S-pyrrolidinemethanol (2.0 g, 20.0 mmol), 3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetic 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 hours, and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc to MeOH-CH2Cl2 (1:9, v/v) as eluent to give 1-[3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]- 2S -pyrrolidine methanol (7.0 g, 89%) as a white crystalline solid. 1H-NMR (CDCl1) δ 1.54-1.58 (rn, 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, IK), 5.04 (m, IH), 6.68-6.79 (in, 3H), 7.09-7.31 (m, 4H) , 7.52 (d, / = 7.8 Hz, IK), 8.07 (d, J = 8.0 Hz, IH).

To a stirred solution of oxalyl chloride (0.3 mL, 3.3 mmol)

in CH 2 Cl 2 (30.0 mL) was added DMSO (6.6 mL, 0.51 mmol) at -78°C. After 5 minutes, 1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinemethanol (1.2 g, 3.0 mmol) in CH 2 Cl 2 (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 the mixture was extracted with CH 2 Cl 2 . The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, benzyl cis-4-aminocyclohexanecarboxylate (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 hours. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with saline, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (1:9, v/v) as eluent to give benzyl cis-4-[ [1-[3-methoxy-4-[AJ'-(2-

methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]-cyclohexanecarboxylate (1.5 g, 83%) as an amorphous solid.

'H-NMR (CDCl1) δ 1.40-1.65 (m, 6H), 1.80-1.98 (m,' 6H), 2.26 (s, 3H), 2.45-2.65 (m, 3H), 2.81-2.86 (m, IK ), 3.44-3.46 (m, 2H), 3.56 (s, 2K), 3.67 (s, 3H), 3.90-4.15 (m, IK), 5.09 and 5.11 (each s,'total 2H), 6.74-6.83 ( m, 3H), 7.07-7.20 (m, AK), 7.31-7.35 (m, 5H), 7.53 - 7.55 (m, IK), 8.02-8.06 (m, IK).

To a stirred solution of benzyl cis-4-[[1-[3-methoxy-4-[ N'-(2-methylphenyl) ureido] phenylacetyl] -2-pyrrolidinyl] methylamino] cyclohexanecarboxylate (1.5 g , 2.45 mmol) in THF (10.0 mL) and MeOH (5.0 mL) 1N NaOH (3.68 mL, 3.68 mmol) was added. The mixture was stirred at 70°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH-CH2Cl2 (1:5, v/v) as eluent to give cis-4-[[1-[3-methoxy-4-[ N'~ (2-methyl f enyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]-cyclohexanecarboxylic acid 171 (940 mg, 73%) as an amorphous solid. VAT 522.64. , 331(131)3283,2945,2860,1534, 1453, 1415 cm-1; 1H-NMR (DMSO-ds) δ 1.38-2.00 (m„ 12H), 2.45 (s, 3H), 2.30-3.95 (m, 4H), 3.22-3.75 (m, 2H), 3.58 (s, 2H), 3.86 (s, 3H), 4.12 (m, IK), 6.73-7.16 (m, 5H), 7.77-7.79 (m, IK), 7.98-8.02 (m, IK), 8.51-8.52 (m, IK), 8.57-8.59 (m, 1H); MS (FÅB) m/ z 523 ( M*+ l) ; Anal. Calculated for CWH3sNA-0-5NaCl-2.2H2O: C, 58.89; H, 7.23; N, 9.47. Found; C, 59.21; H, 7.11; N, 9.11...

EXAMPLE 154

methyl cis-4- [ [1- [3-methoxy-4- [A7'~ (2-methylphenyl)ureido] phenylacetyl] -2-pyrrolidinyl] methylamino] cyclohexanecarboxylate HCl salt

SOCl2 was added to MeOH at 0°^ After stirring for 5 min, cis-4-[[1-[3-methoxy-4-[A7'-(2-methylphenyl)-ureido]phenylacetyl]-2-pyrrolidinyl]methylamino ] cyclohexane-carboxylic acid (200 mg, 0.38 mmol) added. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Aqueous NaHCO 3 was added to the residue,

and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on

silica gel with MEOH-CH2Cl2 (5:95 to 18:92, v/v) as eluent. The product was dissolved in EtOH (5.0 mL), and 1N HCl (in EtOH) (1.0 mL, 1.0 mmol) was added thereto. The mixture was concentrated in vacuo to give 172 (160 mg, 74%) as an amorphous solid. VAT 536.66.

IR (KBr) 3247, 2950, 2875, 1731, 1671, 1612, 1533, 1454, 1205

<1> cW1<;>'<H>-NMR. (DMSOA) 5 1.45-2.10 (m,12H), 2.25 (s, 3H), 2.60-2.70 (m, IH), 2.90-3.20 (m, l-

3H), 2.50-2.55 (m, 2H), 3.63 (m, 5H), 3.86 (s, 3H), 4.15-4.30 (m, IH), 6.74-7.16 (m, 5H), 7.76-

7.78 (m, 1H), 8.00-8.09 (m, 1H), 8.54-8.70 (m, 2H); MS (FAB) m/z 537 (MM-1); Anal. Calculated for C30H„N4O3-1.0HCM.0H2O: C, 60.95; H, 7.33; N, 9.48; Cl, 6.00. Found: C, 60.87; H, 7.47- N,

8.97: Cl, 5.90.

EXAMPLE 155

4- [AJ- [1- [3-methoxy-4- [AT<-> (2-methyl phenyl) ureido] phenylacetyl] -2-pyrrolidinyl] methyl] -AJ-methylamino] cyclohexanecarboxylic acid

To a stirred solution of methyl cis-4-[[1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]-cyclohexanecarboxylate (3 0 0 mg, 0 .55 mol), HCHO (300 mL), and AcOH (66 mg, 1.1 mmol) in MeOH (10.0 mL) was added NaBH 3 CN (70 mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, water was added and the mixture was extracted with CH 2 Cl 2 . The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by TLC with

MeOH-CH2Cl2 (3:97, v/v) as eluent to give methyl 4- [AJ- [1- [3-methoxy'y-4- [AJ'- (2-methylphenyl)ureido] phenylacetyl] -2 -pyrrolidinylmethyl]-N-methylamino]cyclohexanecarboxylate (160 mg, 52%) as an amorphous solid.

1H-NMR (CDCl1) 6 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, IH)", 6.60-7.55 (m, 7H), 8.03 (m, IH), 8.1' 5 (m,lH).

To a stirred solution of methyl .4-[A7- [i-['3-methoxy-4- [ N'~'

(2-Methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl]-Δ7-methylamino]cyclohexanecarboxylate (100 mg, 0.18 mmol). in THF (5.0 mL) and MeOH (2.5 mL) was added 1 N NaOH (0.36 mL, 0.36 mmol). The mixture was stirred at 60°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The mixture was concentrated in vacuo. The residue was purified by TLC with MeOH-CH 2 Cl 2 (1/4, v/v) as eluent to give 173 (10 mg, 10%) as an amorphous solid. MV' 536, 66. 3R

(KBr) 3440, 2954, 1697, 1533, 1454 cm'<1>; (1H-NMR PMSO-rL) δ 1.20-2.30 (m, 13H); 2.24 (p.

3H), 2.354.00 (m, 13H), 6.50-8.10 (m, 8H), 8.50 (m, 1H); MS (FAB)' m/ z 537 Qtf+ Y) ; Anal. Calculated for C 10 H 10 NA-i.ONaCl-O.S 2 O: C, 53.94; H, 6.28; N, 8.39. Found:: C, 54.08; H, 6.52; N, 8.04.

EXAMPLE 156

4-t[1-[3-methoxy-4-\N'-(2-methylphenyl)ureido]phenylacetyl]-(2S)'-pyrrolidinyl]methoxy]cyclohexanecarboxylic acid

A mixture of methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl) methoxybenzoate (1.0 g, 2.9 mmol) and 5% Rh on alumina (500 mg) in EtOH (10.0 mL) and AcOH.(1.0 mL) was hydrogenated at room temperature at 5 atm for 36 h. 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 (6:1, v/v) as eluent to give methyl cis-4-[(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxy)cyclohexanecarboxylate ( 900 mg, 89%) as a pale yellow oil. 1H-NMR(CDC13) δ 1.46 (s,

9H), 1.46-2.00 (m, 12H), 2.34 (m, IH), 3.20-3.55 (m, SK), 3.67 (s, 3H), 3.84-3.92 (m, IK).-

To a stirred solution of methyl cis-4-[(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxy]cyclohexanecarboxylate (900 mg, 2.6 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5 .0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenylacetic acid (260 mg, 0.83 mmol), HOBt (135 mg, 1.0 mmol)

and triethylamine (344 µl, 2.5 mmol) in THF (10.0 mL) and MeCN

(10.0 mL) was added EDC-HCl (238 mg, 1.24 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue,

and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:8, v/v) as eluent to give methyl cis-4- [ [1- [3-methoxy-4- [A7'- (2- methylphenyl)ureido]phenylacetyl] -

(2 S )-pyrrolidinyl]methoxy]cyclohexanecarboxylate (460 mg, quant.) as an amorphous solid. 1H-NMR .{CQCl 2 S 1.35-2.1 Q/m. I2H12.15-2.38 (m, IH), 2.29 (m, 3H), 3.20-3.55 (rn, 5H), 3.58 (s, 2H), 3.66 (s, 3H), 3.73 (s. 3H), 4.20- 4.25 (m, IK), 6.26-6.30 (m, IK), 6.78-6.81 (m, 2H), 7.06-7.23 (m, 3H), 7.51-7.52 (m, IH), 8.01-8.03 (m, IK)..

in

To a stirred solution of methyl 4-[[1-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxy]cyclohexanecarboxylate (460 mg, 0.86 mmol) in THF (10.0 mL) and EtOH (5.0 mL) was added 1N NaOH (1.4 mL, 1.4 mmol). The mixture was stirred at 60°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 174 (370 mg, 83%) as a white crystalline solid. VAT 523.63. M.p.: 110-113°C. IR (KBr) 3345, 2937, 1612, 1533, 1454 cm:<1>; 1H-NMR (DMSO-d*) 8 1.00-2.00 (m, 12H), 2.24 (s, 3H), 2.20-2.30 (m, 1H), 3.20-3.80 (m, 5H), 3.55 (s, 2H ), 3.85 (s, 3H), 4.00-4.18 (m, IH), 6.71-7.16 (m, 5H), 7.78 (d, J = 8.0 Hz, IH), 7.90 (d, J = 8.3 Hz, IH) , 8.45 (p, 1H), 8.54 (p, 1H); MS (FAB) m/z 524 (M<*>+1); <y>l/ja/.Calculated for CjsHjTNjOt-O^HjO: C, 66.07; H, 7.15; N, 7.97. Found: C, 66.02; H, 7.14; N, 7.87. EXAMPLE 157 4- [ [1- [4-'[AJ'-(2-chlorophenyl)ureido)-3-methoxyphenylacetyl]-(25)-pyrrolidinyl]methoxy]cyclohexanecarboxylic acid

To a stirred solution of methyl 4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]cyclohexanecarboxylate (900 mg, 2.6 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5.0 mL) at 0°C. The reaction mixture with stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 4-[A7'~

(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (27.7 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-HCl (238 mg, 1.24 mmol) at 0 °C. The reaction mixture was

stirred at room temperature for 16 hours and concentrated in vacuo.

Water was added to the residue and the mixture was extracted with

EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 , and

concentrated in vacuum. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:6,

v/v) as eluent to give methyl 4-[ [1- [4-[A7'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl] -(2S)-pyrrolidinyl] methoxy] cyclohexanecarboxylate (450 mg, 97 %) as a colorless oil. '■. 1 H-NMR (CDCl 3 ) δ 1.35-2.15 (m, 12H), 2.25-2.40

(m, IH), 3.40-3.70 (m, 5H), 3.61 (s, 2H), 3.66 (s, 3H), 3.81 (s, 3H), 4.20-4.30 (m, IK), 6.81-6.99 (m, 3H), 7.17-7.34 (m, 3H), 7.92-7.94 (rn, 2H), 8.17-8.19 (m, 2H).

To a stirred solution of methyl 4-[[1-[4-[W<->(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]-methoxy]cyclohexanecarboxylate (450 mg, 0.86 mmol) in THF

(10.0 mL) and MeOH (5.0 mL) was added 1 N NaOH (1.4 mL, 1.4 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo. Water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 175 (370 mg, 84%) as a white crystalline solid. VAT 544.04. M.p.: 111-115°C. IR (KBr) 3330, 2938, 1704,1594,

1533, 1438, 1199 cm"'; 'H-NMR (DMSO-dJ 8 1.00-2.00 (m, 12H),'2.20-2.30 (m, IK), 3.20-3.80 (m, 5H), 3.55 (s, 2H), 3.85 (s, 3H), 4.00-4.20 (m, IK), 6.73-6.75 (m, IK), 6.87 (s, IH), 6.99-7.03 (m, IK), 7.25-7.29 (m, IK), 7.42 (d, .7 = 7.1 Hz, IK), 7.95 (d, J= 8.3 Hz, IK), 8.08 (d, J= 8.0, IK), 8.78 (s, IK), 8.92 (s, 1H); MS (FAB) m/z 544 (M<+>+1)M/ifl/. Calculated for CJgH3<N3O{Cl-0.2H,O:

C, 61.41; H, 6.33; N, 7.67; Cl, 6.47. Found: C, 61.37; H, 6.32; N, 7.56; Cl, 6.55. EXAMPLE 158 4-[1-[4- [AT-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxycyclohexanecarboxylic acid

To a stirred solution of methyl 4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)-methoxy]cyclohexanecarboxylate (900 mg, 2.6 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5.0 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (200 mg, 0.83 mmol), 4-[N-(2-bromophenyl)ureido]-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-HCl (238 mg, 1.24 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with sat. to give methyl [4-[1- [4-[ N'~

(2-Bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]methoxy]cyclohexanecarboxylate (450 mg, 90%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 1.30-2.10 (m, 12H), 2.35-2.40

(m, IK), 3.25-3.70 (m, 5H), 3.84 (s, 3H), 4.10-4.25 (m, IK), 6.81-7.06 (m, 4H), 7.25-7.32 (m,

2H), 7.50-7.52 (m, IK), 7.90-7.92 (m, IK), 8.13-8.15 (m, IK).

To a stirred solution of methyl 4-[1-[4-[ N'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-pyrrolidinyl]-methoxycyclohexanecarboxylate (450 mg, 0.74 mmol) in THF (10.0 mL) and MeOH (5.0 mL) was added 1 N NaOH (1.2 mL, 1.2 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 176 (340 mg, 77%) as a white crystalline solid.

VAT 588.49. Melting point: 108 - 111°C. IR (KBr) 3328, 2938, 1702, 1594,

1529, 1434 cm"<1>; 1H-NMR (DMSO-ds) 5 1.00-2.00 (m, 12H), 2.15-2.25 (m, IH), 3.40-3.75 (m, SK), 3.48 (s, 2H), 3.85 (s, 3H), 4.04-4.15 (m, IH), 6.70-6.72 (m, IH), 6.87 (s, IH), 6.94-6.98 (m, IH), 7.29-7.33 (rn, IK), 1:59 (d, J= 8.1 Hz, IH), 7.93-7.95 (m, 2H), 8.73-8.74 (m, IH), 8.91-8.92 (m, IH); MS (FAB) w/ z 589 (M<+>+l)M/ilf/.Calculated for C28H3,N306Br0.2HJ0: 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.

EXAMPLE 159

4 [ [1- [4- [ N' - (2-methylphenyl) ureido] phenylacetyl] - (2S) - pyrrolidinyl] methoxy] cyclohexanecarboxylic acid

To a stirred solution of methyl 4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]cyclohexanecarboxylate (450 mg, 1.3 mmol) in CH 2 Cl 2 (5.0 mL) was added TFA (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product, 4-[A7'-(2-methylphenyl)-ureido]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-HCl (380 mg, 1.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours, and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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- [ [1- [4- [W-(2-methylphenyl)ureido] phenylacetyl] - (2S)-pyrrolidinyl]methoxy]cyclohexanecarboxylate (520 mg, 78%) as a colorless oil.

'H-NMR (CDCl 3 ) δ 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, IH), 6.90-7.20 (m, 8H), 7.40-7.70 (m, 2H).

To a stirred solution of methyl 4-[[1-[4-[AT'-(2-methylphenyl)ureido]phenylacetyl]-(2S)-pyrrolidinyl]methoxy]-. cyclohexanecarboxylate (520 mg, 1.0 mmol) in THF (10.0 mL) and MeOH (5.0 mL) was added 1N NaOH (1.5 mL, 1.5 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N -HCl. The resulting solid was collected, washed with water and dried in vacuo to give 177 (450 mg, 91%) as a white crystalline solid. VAT 493.60. M.p.: 107-111°C. IR (KBr) 3353, 2938, 1704,1540,

1454, 1240 cm-<1>; 1H-NMR (DMSO-d«) 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^.18 ( m, IH), 6.90-6.94 (m, IK), 7.10-7.16 (m, 5H), 7.36-7.38 (m, 2H), i 7.82-7.87 (m, 2H), 8.89 (s, IK), 12.0 (br s, IH); MS (FAB) m/z 494 (M*+1); ,4*0/. Calculated for C1.H35N3O3-O.2HjO: C, 67.64; H, 7.18; N, 8.45. Found: C, 67.66; H, 7.19; N, 8.24.

EXAMPLE 160

cis^4- [1- [4- [AT'-(chlorophenyl) ureido] -3-methoxylph enylacetyl] -

(2S)-Octahydroindolylmethoxy]cyclohexanecarboxylic acid

To a stirred solution of [1-tert-butoxycarbonyl-(2 S )-octahydroindolyl]carboxylic acid (1.0 g, 3.7 mmol) in THF (10.0 mL) was added BH3• THF (1)0 Mi THF, 8.0 mL) at 0°C. After stirring at room temperature for 1.0 hour, the reaction mixture was heated under reflux for 1.5 hour. After cooling, the mixture was concentrated in vacuo. Water was added thereto at 0°C, and the mixture was extracted with EtOAc. The extract was washed with water, then dried over Na 2 SO 4 and concentrated in vacuo to give [1-tert-butoxy-" carbonyl-(2 S )-octahydroindolyl] methanol (947 mg, quant.) as a colorless oil.

To a stirred solution of [1-tert-butoxycarbonyl-(2 S )-octahydroindolyl]methanol (947 mg, 3.7 mmol), methyl 4-hydroxybenzoate (565 mg, 3.7 mmol) and Ph3P (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 hours. 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-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 50 %) as a pale yellow oil.

1H-NMR (CDCl1) δ 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,<y>= 8.8 H z , 2H), 7.96 (d, J = 8.5 H z , 2H).

One. mixture of methyl 4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]benzoate (700 mg, 1.8 mol) and 5% Rh on alumina (400 mg) in EtOH (10.0 mL) and AcOH (1 .0 ml) was hydrogenated at room temperature at 5 atmospheres for 48 hours. 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 cis-4-[1-tert-butoxycarbonyl-(2 S )-octahydroindolylmethoxy]cyclohexanecarboxylate (600 mg , 85%) as a pale yellow oil. 'H-NMR (CDCl1) 5

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 cis-4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]cyclohexanecarboxylate (600 mg, 1.5 mmol) in CH 2 Cl 2 (6.0 mL) was added TFA (6.0 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (221 mg, 0.75 mmol), 4-[A7'-(2-chlorophenyl)ureido]-3-methoxy-phenylacetic 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 EDC-CHl (216 mg, 1.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours

and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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 cis-4-[1- [4-[AT-(2-chlorophenyl)ureido]-3- methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]cyclohexanecarboxylate (430 mg, 94%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 1.10-2.40 (m, 20H), 3.45-(br s,

IK), 3.62 (s, 2H), 3.66 (s, 3H), 3.73 (s, 3H), 3.60-3.85 (ra, 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, IH), 8.18.(d, J= 8.3 Hz, IH).

To a stirred solution of methyl cis-4-.[1- [4- [AJ'- (2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-octahydro-indolylmethoxy]-cyclohexanecarboxylate (430 mg, 0, 7 mmol) in THF (10.0 mL) and MeOH (5.0 mL) was added 1N NaOH (1.4 mL, 1.4 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N CH1. The resulting solid was collected, washed with water and dried in vacuo to give 178 (360 mg, 86%) as a white crystalline solid. VAT 598.13. M.p.: 120-121°C. IR (KBr) 3338, 2933,2859,

1614, 1533, 1438 cm-'; 'H-NMR (CDC13) 6 1.05-2.40'(m, 20H), 3.38-3.50 (m, 2H), 3.63 and 3.65 (each s, total 2H), 3.71 and 3.75 (each s, total 3H), 3.70 -3.80 (m, 1H); 3.93-3.97 (m, IH), 4.15 (br s, IH), 6.75-6.77 (m, 2H), 6.93-6.97 (m, IH), 7.20-7.32 (m, 3H), 7.60-7.63 ( m, IK), 7.85 (d, J =

8.3 Hz, IH), 8.16 (d, J = 8.3 Hz, IH); MS (FAB) m/z 598 (M++1); ^/.Calculated for^H^O^Cl-0.5H3O: C, 63.30; H, 6.81; N, 6.92; Cl, 5.84. Found: C, 63.68; H, 6.81; N, 6.81; Cl, 5.98.

EXAMPLE 161

cis-4- [1- [4- [A7'- (2-bromophenyl)ureido] -3-methoxyphenylacetyl] -

(2S)-Octahydroindolylmethoxy]cyclohexanecarboxylic acid

To a stirred solution of methyl cis-4-[1-tert-butoxycarbonyl-(2S)-octahydroindolylmethoxy]cyclohexanecarboxylate (600 mg, 1.5 mmol) in CH 2 Cl 2 (6.0 mL) was added TFA (6.0 mL ) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product (221 mg, 0.75 mmol), 4-[A7'-(2-bromophenyl)ureido]-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-CH1 (216 mg, 1.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2 M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 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 cis-4-[1-[4-[A7'-(2-bromophenyl)ureido] -3-methoxyphenylacetyl]-(2S)-octahydro-indolylmethoxy]cyclohexanecarboxylate (480 mg, 96%) as a colorless oil. 1H-NMR (CDCl3) δ 1.10-2.40 (m, 20H), 3.45 (br s,

■IH), 3.61 (p, IK), 2.66 (p, 3H), 3.76 (p, 3H); 3.60-3.80 (m,2H), 4.11-4.14 (m, 2H)^76^6.92 (m, 3H), 7.25-7.32 (m, 3H), 7.49 (d, J= 7.1 Hz, IH), 7.90 ( d, J = 8.0 Hz, 1), 8.13 (d, J = 8.0 Hz, 1H).

To a stirred solution of methyl cis-4-[1-[4-[ N'-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-(2S)-octahydroindolylmethoxy]cyclohexanecarboxylate (480 mg, 0.73 mmol ) in THF (10.0 mL) and MeOH (5.0 mL) was added 1 N NaOH (1.5 mL, 1.5 mmol). The mixture was stirred at 70°C for 24 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 179 (400 mg, 85%) as a white crystalline solid. VAT 642.58. Melting point: 115-120°C. IR (KBr) 3332, 2933, 2859, 1704, 1592, 1529, 1434 cm -1 ; 1 H-NMR (CDCl 1 ) δ 1.10-2.40 (m, 20H), 3.40-3.50 (m, 2H), 3.61 and.

3.63 (every s, total 2H), 3.75 and. 3.78 (each s, total 3H), 3.70-3.80 (m, IH), 3.90-3.93 (m, IH), 4.15 (br s, m),'6.76-6.92 (m, 3H), 7.26-7.30 ( m, IH). 7^43-7.52 (m, 3H), .7.84-7.86 (m, 1H), 8.10-8.12 (m, 1H); MS (FAB) m/ z 643 (M++1); H, 6.33; N, 6.49; Br, 12.30. Found: C, 59.26; H, 6.33; N, 6.36; Bro, 12.37.

EXAMPLE 162

4-[[1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylic acid

To a stirred solution of benzyl 4-aminocyclohexane carboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol) and triethylamine (1.6 mL, 11.6 mmol) in CH 2 Cl 2 (30.0 mL) was added EDC-HCl (1.1 g, 5.8 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid, and saturated NaHCO 3 , then dried over Na 2 SO 4 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 benzyl cis-4-[(1-tert-butoxy-,carbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 36%). as an amorphous solid.

1H-NMR (CDCl 3 ) δ 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, 1H) , 4.10-4.25 (m, 1H), 5.12 (s, 2H), 7.35-7.36 (m, 5H).

To a stirred solution of benzyl cis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 1.4 mmol) in CH 2 Cl 2 (6.0 mL) was added TFA (3.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with saline, dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product

(300 mg, 0.7 mmol), 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetic acid (220 mg, 0.7 mmol), HOBt (94 mg, 0.7 mmol) and To triethylamine (291 mL, 2.1 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (201 mg, 1.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The resulting solid was collected and washed with EtOAc to give benzyl 4-[[1-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylate (3 80 mg, 87%) as a white crystalline solid.

1H-NMR (CDCl1) δ 1.40-2.15 (m, 12H), 2.28 (m, 3H), 2.30-2.50 (m, 2H), 3.40-3.55 (m, 2H), 3.61 (s, 2H), 3.71 (p. 3H), 3.82 (m, IH), 4.53 (d, J = 6.3 Hz, IH), 5.10 (s, 2H), 6.42 (s, IH), 6.77-6.79 (m, 2H), 7.04- 7.34 (m, 9H), 7.50-7.52 (m, IH), 8.05-8.07 (m, IH).

To a stirred solution of benzyl 4-[[1-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]carbonylamino]-cyclohexanecarboxylate (380 mg, 0.6 mmol) in THF (10.0 mL) and EtOH (5.0 mL) was added 1N NaOH (0.9 mL, 0.9 mmol). The mixture was stirred at 50°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water, and dried in vacuo to give 180 (230 mg, 71%) as a white crystalline solid. . VAT 636.62.

M.p.: 13 6-142°C. IR (KBr) 3345, 2940, 1650,

1625, 1535, 1454 cm-'; 1H-NMR (OMSO-d^ 1.40-2.00 (m, 12H), 2.24 (s, 3H), 2.30-2.40 (m,

IK), 3.45-3.80 (irt, 5H), 3.86-3.87 (m, 3H), 4.30-4.43 (m, IK), 6.65-7.30 (m, 5H), 7.70-7.80 (m, IK), 7.98- 8.09 (m, IK), 8.46-8.57 (m, IK); MS (FAB) m/z 537 OT+1); yi/jo/. Calcd for CH 2 A-O.S H 2 O: C, 63.84; H, 6.83; N, 10.27. Found: C, 64.18; H, 6.91; N, 9.85.

EXAMPLE 163

4- [ [l- [4- [W-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylic acid

To a stirred solution of benzyl cis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 1.4 mmol) in CH 2 Cl 2 (6.0 mL) was added TFA (3.0 ml) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo. Saturated NaHCO 3 was added to the residue and the mixture was extracted with CH 2 Cl 2 . The extract was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. To a stirred solution of the crude product

(300 mg, 0.7 mmol), 4-[ N'~ (2-chlorophenyl)ureido]-3-methoxy-phenylacetic acid (237 mg, 0.7 mmol), HOBt (94 mg, 0.7 mmol) and To triethylamine (291 mL, 2.1 mmol) in THF (10.0 mL) and MeCN (10.0 mL) was added EDC-HCl (201 mg, 1.1 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and the mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , 2-M citric acid and saturated NaHCO 3 , then dried over Na 2 SO 4 and concentrated in vacuo. The resulting solid was collected and washed with EtOAc to give benzyl 4-[[1-[4-[ N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-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, IK), 3.42-3.55 (m, IK), 3.64 (s, 2H), 3.84 (s, 3H), 4.55 (d, J=6.1Hz, 1H), 5.12 (s, 2H) T6^1-7.35(m, 12H), 7.96-7.98 (m, 1H);

8.17-8.19 (m, IH).

To a stirred solution of methyl benzyl-4-[[1-[4-[AT<->(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]-carbonylamino]-cyclohexanecarboxylate (310 mg, 0 .86 mmol) in THF (10.0 mL) and MeOH (5.0 mL) was added 1 N NaOH (0.7 mL, 0.7 mmol). The mixture was stirred at 50°C for 18 hours. The mixture was concentrated in vacuo, water was added thereto, and the mixture was neutralized with 1N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 181 (260 mg, 98%) as a white crystalline solid. MV 557.03. Mp.: 13 5 -14 0°C./ IR (KBr) 3328, 2938,

1594, 1533, 1438, 1203 cm'<1>; 'H-NMR (DMSQ-d,) 5 1.40-2.20 (m, 12H), 2.30-2.40 (m, IK), '3.40-3.80 (m, 5H), 3.65-3.85 (m, 3H), 4.30-4.43 (m, IK), 6.66-7.31 (m, 5H), 7.42-8.10 (m, IK), 8.89-8.94 (m, 2H); MS (FAB) m/z 557 (M<+>+1);>1/10/. Calcd. H, 6.02; N, 9.96; Cl, 6.30. Found: C, 59.86; H, 6.10; N, 9.60; Cl, 6.34.

EXAMPLE 164

In a round bottom flask, 3-bromobenzylamine (3.00 g, 16.13 mmol) was dissolved in dioxane-water (1:1) and solid Na 2 CO 3 was added until the pH was 8-9. Boc 2 O (3.87 g, 17.74 mmol) was added and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with water, brine and then dried over anhydrous MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography (4:1 hexane-ethyl acetate). Yield 4.39 g 197.

The Boc-protected benzylamine (2.00 g, 6.99 mmol) was dissolved in dry THF under argon. The reaction mixture was cooled to minus 78°C. Lithium bis(trimethylsilyl)amide (13.98 mL, 13.98 mmol) was added over 10 minutes. The reaction mixture was stirred for 1 hour at minus 78°C and then iodomethane (1.98 g, 13.98 mmol, 0.87 mL) was rapidly added. The reaction mixture was slowly allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed without reduced pressure. The product was isolated by flash chromatography (7:1 hexane-ethyl acetate). Yield 1.68 g 198.

Into a pressure tube was placed the Boc-protected 3-bromobenzylmethylamine (1.68 g, 5.60 mmol). The tube was then charged with DMF, sodium acetate (0.51 g, 6.16 mmol), P(o-tolyl)3 (0.51 g, 6.16 mmol) and Pd(OAc)2 (0.25 g, 1.12 mmol). The tube was flushed with argon for 10 min and then methyl acrylate (0.53 g, 0.53 mmol, 0.55 mL) was added. The tube was sealed and heated to 135°C for 24 hours. The reaction mixture was cooled to 0°C and the tube was slowly opened. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . 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 1.60 g 199.

Into a pressure tube was placed the Boc-protected 3-bromobenzylmethylamine (1.00 g, 3.33 mmol). The tube was then charged with DMF, sodium acetate (0.30 g, 336 mmol), P(o-tolyl)3 (0.20 g, 0.66 mmol) and Pd(OAc)2 (0.15 g, 0, 66 mmol). The tube was flushed with argon for 10 minutes and then methyl methacrylate (37 g, 3.66 mmol, 0.39 mL) was added. The tube was sealed and heated to 135°C for 24 hours. The reaction mixture was cooled to 0°C and the tube was slowly opened. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . 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 1.01 g 200.

The α,β-unsaturated ester (1.60 g, 5.49 mmol) was placed in a Paar flask and dissolved in ethyl acetate. Pd/C (0.3 g) was added and the vessel was pressurized to 50 psi with H 2 . The container was stirred for 12 hours. The Paar vessel was flushed with argon and the catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. Yield 1.60 g 201.

The α-methyl, β-unsaturated ester (1.01 g, 3.16 mmol) was placed in a Paar vessel and dissolved in ethyl acetate. Pd/C was added and the vessel was pressurized to 50 psi with H 2 . The container was stirred for 12 hours. The Paar vessel was flushed with argon and the catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. Yield 996.41 mg 2 02.

The Boc ester (304 mg, 1.04 mmol) was taken up in CH 2 Cl 2 and excess trifluoroacetic acid was added. The reaction mixture was then stirred for 2 hours. The solvent was removed and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was washed with water, brine and then dried over Na 2 SO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH 2 Cl 2 -DMF and HOBt (154.30 mg, 1.14 mmol), 4-[ N'~ (o^tolylurea)-phenylacetic acid (324.11 mg, 1.14 mmol) and EDCI (218 .53 mg, 1.14 mmol) was added. The reaction mixture was stirred for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 380.32 mg 203.

The ester (380.32 mg, 0.80 mmol) was taken up in ethanol-water (4:1) and NaOH was added. The reaction mixture was then heated to 50°C for 2 hours. TLC (ethyl acetate) showed that no starting material was present. The reaction mixture was cooled to room temperature. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane. Yield 319.40 mg 204.

EXAMPLE 165

The Boc ester (209.60, 0.65 mmol) was taken up in CH 2 Cl 2 and excess trifluoroacetic acid was added.

The reaction mixture was then stirred for 2 hours. The solvent was removed and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was washed with water, brine and then dried over Na 2 SO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH2Cl2-DMF and HOBt (97.45 mg, 0.72 mmol), 4-[N'-(o-tolylurea)-phenylacetic acid (204.70 mg, 0.72 mmol) and EDCI (13 8.03 mg, 0.72 mmol) was added. The reaction mixture was stirred for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 237.8 mg 205.

The ester (237.8 mg, .0.49 mmol) was taken up in ethanol-water

(4:1) and NaOH added. The reaction mixture was heated to 50°C for 2 hours. TLC (ethyl acetate) showed that no starting material was present. The reaction mixture was cooled to room temperature. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. They combined

the organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane.

Yield 207.8 mg 206.

EXAMPLE 166

The 1,2,3,4-tetrahydroisoquinoline (12.20 g, 91.60 mmol) was taken up in H 2 SO 4 (40 mL) and cooled to -10 °C. Concentrated HNO 3 (9.0 mL) was slowly added to the solution while maintaining the internal temperature at minus 10°C. On completion of the addition, the reaction mixture was allowed to stand and slowly warmed to room temperature over 12 hours. The reaction mixture was slowly added to ice and the aqueous solution was made basic with NH 4 OH. The aqueous layer was extracted 4 times with CHCl 3 . The combined organic layers were washed with water and then dried over Na 2 SO 4 . The solution was filtered and the solvent was removed under reduced pressure. The resulting brown oil was taken up in ethanol and concentrated HCl was added. The resulting white solid was collected by filtration and dried under vacuum.

Yield 8.0 g 2 07. -

The 6-nitro-1,2,3,4-tetrahydroisoquinoline (1.00 g, 5.61 mmol) was taken up in ethanol. Methyl bromoacetate (0.86 g, 5.61 mmol, 0.53 mL) and triethylamine (1.17 g, 11.59 mmol, 1.62 mL) were then added and the mixture was heated to reflux in . 5 hours. The solution was cooled to room temperature and the solution was concentrated under vacuum. The solution was added to water and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (3:1 hexane-ethyl acetate).

Yield 702 mg 2 08.

The above ester (702 mg, 2.81 mmol) was placed in a Paar container and dissolved in ethanol. Pd/C (100 mg) was added and the vessel was pressurized to 50 psi with H 2 . The container was stirred for 24 hours. The Paar vessel was flushed with argon and the catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. 1H-NMR showed only the desired product.

Yield 587 mg 209.

The aniline (587.0 mg, 2.66 mmol) was taken up dry. CH2C12 and pyridine under argon. The reaction mixture was cooled to

0°C. A CH 2 Cl 2 solution of 3-methoxy-4-(N 1 -phenylureido)-phenylacetyl chloride (837.70 mg, 2.66 mmol) was added over 5 minutes. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into IN. HCl and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were then washed with saturated NaCH0 3 , water, brine and then dried over MgSO 4 . The resolution-became

filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate).

Yield 618.36 mg 210.

The above methyl ester (618.36 mg, 1.20 mmol) was taken up in THF-H 2 O and LiOH (558.07 mg, 13.30 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were then washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was purified by recrystallization (hexane-ethyl acetate).

Yield 600 mg'211.

EXAMPLE 167

The 3-nitrophenylpropionic acid (1.00 g, 5.12 mmol) was taken up in dry THF' under argon. The reaction mixture was cooled to 0°C and BH 3 -THF (1.0 M, 15.37 mmol, 15.37 mL) was added over 10 minutes. The reaction mixture was stirred at 0°C for 1 hour and then slowly quenched with water. The solution was slowly warmed to room temperature and then poured into 1N HCl. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were then washed with saturated NaHCO 3 , water, brine and then dried over MgSO 4 . 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 9 0 9.0 mg 212.

The 3-nitrophenylpropanol (909.0 mg, 5.02 mmol) was taken up in dry CH 2 Cl 2 . In a second round bottom flask, (COCl)2 (700.65 mg, 5.52 mmol, 0.48 mL) was added to dry CH2Cl2 under argon.

The (COC1)2-CH2Cl2 solution was then cooled to -60°C and DMSO (862.56 mg, 11.4 mmol, 0.78 mL) was slowly added. The reaction solution was slowly stirred at minus 60°C for 5 minutes and then the alcohol solution was added via a cannula over 5 minutes. The reaction mixture was

stirred at minus 50°C for 1 hour and then Et 3 N (2.54 g, 25.10 mmol, 3.59 mL) was added and the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with NaHCO 3 , water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. <1>H-NMR showed that no starting material was present. The aldehyde 213 was used as is without further purification.

In a round-bottomed flask, NaH (132.48 mg, 5.52 mmol) was brought into slurry form in dry THF under argon. Triethyl 2-phosphonopropionate (1.31 g, 5.52 mmol, 1.18 mL) dissolved in dry THF was slowly added via syringe. The reaction mixture was stirred for 30 minutes at room temperature. The above aldehyde, dissolved in dry THF under argon, was added to the phosphonate solution via syringe over 10 minutes. The reaction mixture was stirred for 12 hours. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 , water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (1:1 ethyl acetate-hexane).

Yield 992.0 mg 214.

The above α,β-unsaturated ester (992.0 mg, 3.77 mmol) was placed in a Paar container and dissolved in ethanol. The vessel was purged with argon and Pd/C (200.0 mg) was added. The argon atmosphere was replaced with H2 at 50 psi. The Paar container was then shaken for 12 hours. The hydrogen was flushed from the container with argon and the catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. 1H-NMR showed only the desired product.

Yield 851.2 mg 215.

The above aniline (850.0 mg, 3.61 mmol) was taken up in dry CH 2 Cl 2 and pyridine under argon. The reaction mixture was cooled to 0°C. A CH 2 Cl 2 solution of 3-methoxy-4-(N'-phenylureido)phenylacetyl chloride (1.14 g, 3.61 mmol) was added over 5 min. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with saturated NaHCO 3 , water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate).

Yield 576.0 mg 216.

The above ethyl ester (576.0 mg) was taken up in ethanol-water and NaOH was added. The reaction mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature and then poured into 1N HCl. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was purified using a Sep-Pak column.

Yield 534 mg 217.

EXAMPLE 168

One gram of Wang resin (tentagel S-PHB 0.3 mmol loading) was suspended in a solution of 3-(Fmoc-amino)phenylpropionic acid (361.31 mg, 0.90 mmol), DMAP (109.95 mg, 0 .90 mmol), HOBt 243.63 mg, 0.90 mmol) and DIC (227.16 mg, 1.80 mmol, 0.28 mL) in a mixture of DMF and CH 2 Cl 2 . The mixture was shaken for 20 hours and dewatered. The resin 218 was washed with DMF, MeOH, CH 2 Cl 2 and dried under reduced pressure.

To the above resin (500 mg, 0.15 mmol) was added a solution of piperidine-DMF (50% v/v, 4 mL) and the mixture was shaken for 4 h. The resin was washed with DMF, MeOH, CH 2 Cl 2 . To the resin was added TMOF and isobutyraldehyde (108.17 mg, 1.50 mmol, 0.14 mL). The mixture was shaken for 4 hours. The resin was dewatered and freshly prepared TMOF and isobutyraldehyde were added. The mixture was then shaken for 12 hours. The resin was dewatered and taken up in MeOH-1% AcOH and NaCNBH 3 (150.0 mg, 2.39 mmol) was added. The resin was shaken for 6 hours. The resin was dewatered and washed with MeOH, MeOH-Et 3 N, MeOH, DMF, CH 2 Cl 2 . The resin was taken up in DMF and 3-methoxy-4-(N<1->phenylureido)phenylacetic acid (141.45 mg, 0.45 mmol), PyBrop (209.78 mg, 0.45 mmol) and DIEA (5 8.16 mg, 0.45 mmol, 0.08 ml) was added. The resin was then shaken for 24 hours, and then dewatered. The resin was washed with DMF, MeOH, CH 2 Cl 2 . It became the resin. added a solution of TFA in CH 2 Cl 2 (30% v/v, 3 mL) and the mixture was shaken for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using a Sep-Pak column. After removal of the solvent, Et 2 O was added to the residue and the solid was collected to give 15 mg of 219 as a crystalline solid. EXAMPLE 169

Tentagel PHB resin (1.0 g, loading 0.29 mmol/g) taken up in 25 mL DMF and 6-bromohexanoic acid (169 mg, 0.87 mmol) was added. The resin was shaken for 5 min and then DIC (220 mg, 0.27 mL, 1.74 mmol) and DMAP (35 mg, 0.29 mmol) were added and the resin was shaken for 14 h. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum.

To this resin was added 2,2-dimethyl-i,3-dioxolane-4-methanamine (227 mg, 1.74 mmol) and lithium iodide (232 mg, 1.74 mmol) in 15 mL of DMF. The resin was shaken for 14 hours at room temperature. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum. The resin gave a positive bromophenyl blue test.

The resin was taken up in 25 mL of DMF and 4-o-tolylureido-3-methoxyphenylacetic acid (247 mg, 0.87 mmol) was added and the resin was shaken for 5 minutes. PyBrOP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) were added and the resin was shaken for 14 h. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum. The resin gave a negative bromophenyl blue test.

The resin was then taken up in 90% TFA in CH 2 Cl 2 and shaken for 4 hours. The resin was dewatered and the eluent was collected. The resin was taken up in freshly prepared CH2C12 and shaken

30 minutes. The resin was dewatered and the eluent was collected and combined with the first fraction. The solvent was removed under vacuum and the residue was recrystallized from ethyl acetate-hexane, yielding 56 mg of 220. EXAMPLE 170 1 gram of Tentagel PHB resin (loading 0.29 mmol/g) was taken up in 25 mL of DMF and Fmoc-7-aminoheptanoic acid ( 319 mg, 0.87 mmol) was added. The resin was shaken for 5 min and then DIC (220 mg, 0.27 mL, 1.74 mmol) and DMAP (106 mg, 0.87 mmol) were added and the resin was shaken for 24 h. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum. The resin gave a negative bromophenyl blue test. The resin was taken up in 20% piperidine in DMF and shaken for 4 hours. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum. The resin gave a positive bromophenyl blue test.

The resin was taken up in 25 mL of DMF and 4-o-tolylureido-3-methoxyphenylacetic acid (247 mg, 0.87 mmol) was added and the resin was shaken for 5 minutes. PyBrOP (406 mg, 0.87 mmol) and DIEA (123 mg, 0.15 mL, 0.87 mmol) were added and the resin was shaken for 14 h. The resin was dewatered and washed with DMF (3x), CH 3 OH (3x) and CH 2 Cl 2 (3x) and then dried under vacuum. The resin gave a negative bromophenyl blue test.

The resin was then taken up in 90% TFA in CH 2 Cl 2 and shaken for 4 hours. The resin was de-sanded and the eluent was collected. The resin was taken up in freshly prepared CH 2 Cl 2 and shaken for 30 minutes. The resin was dewatered and the eluent was collected and combined with the first fraction. The solvent was removed under vacuum and the residue was recrystallized from ethyl acetate-hexane, yield 66 mg of 221.

EXAMPLE 171

To a solution of oxalyl chloride (3.8 g, 30 mmol) in CH 2 Cl 2 (100 mL) was added DMSO (2.4 g, 31 mmol) dropwise over 30 min at minus 78°C. To this solution was added N-Boc-prolinol (5.0 g, 25 mmol) dropwise over 15 minutes. The reaction mixture was stirred at minus 78°C for 3 hours and then quenched by cold addition of 1N HCl, extracted 3x with EtOAc, dried and concentrated in vacuo to give the crude prolinal which was chromatographed (25% EtOAc/hexanes ) to give 3.8 g of the desired product.

A solution of methyl (triphenylphosphoranylidene)butanoate (6.9 g, 19 mmol) in THF (100 mL) was formed. LiHMDS (10 mL of a 2.OM solution, 20 mmol) was added at -78°C and then stirred for 1 hour. The above-mentioned prolinal (3.8 g, 19 mmol) was then added in one portion and the mixture was allowed to warm to room temperature over 4 hours. The reaction was quenched by the addition of 1N HCl, extracted 3.x with EtOAc, dried and concentrated in vacuo to give the crude alkene which was chromatographed (25% EtOAc/hexanes) to give 2.9 g of the desired product.

Hydrogenation of the alkene was carried out by placing the alkene (2.9 g, 10 mmol) in ethanol (20 mL) and adding a catalytic amount of 10% Pd/C followed by Paar hydrogenation at 40 psi for 4 h, and the resulting alkane was used without purification. The Boc group was removed by addition of 1:1 TFA/CH 2 Cl 2 at room temperature. The reaction mixture was stirred for 2 hours 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 CH 2 Cl 2 (100 mL) was formed. To this solution was added EDCI (2.95 g, 10 mmol), DMAP (1.2 g, 10 mmol) and 4-o-tolylureido-3-methoxyphenylacetic acid (3.15 g, 10 mmol) at room temperature. The reaction mixture was stirred for 4 hours and then quenched by addition of 1N HCl, extracted 3x with EtOAc, dried and concentrated in vacuo. The crude amide was chromatographed (5% MeOH/CH 2 Cl 2 ) to give 1.95 g of the desired product.

The ester (1.95 g, 4.2 mmol) was taken up in 1:1 THF-H 2 O and LiOH was added at room temperature. The reaction mixture was then stirred for 3 hours. The solution was poured into 1N HCl and

the aqueous layer was extracted 3x with EtOAc. The combined 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.

EXAMPLE 172

To a solution of methyl 8-aminooctanoate (2.0 g, 12 mmol) in 1:1 dioxane:water (100 mL) was added Boc anhydride (2.8 g, 13 mmol) and K 2 CO 3 (10 g) . This solution was allowed to stir at room temperature for 14 hours. The reaction mixture was then poured onto 1N HCl, extracted 3x with EtOAc, dried and concentrated in vacuo. The crude carbamate was chromatographed

(50% EtOAc/hexanes) to give 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 solution, 50 mmol) at -78°C, and this solution was then stirred for 30 minutes and methyl iodide (7.2 g, 50 mmol) was added in one portion, and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched by addition of 1N HCl, extracted 3x with EtOAc, dried and concentrated in vacuo. The crude methylated carbamate was chromatographed (50% EtOAc/hexanes) to give 1.9 g of the desired dimethyl product.

The Boc group was removed by addition of 1:1 TFA/CH 2 Cl 2 at room temperature. The reaction mixture was stirred for 2 hours and the solvent was removed in vacuo. The crude amine 900 mg was used without further purification.

A solution of the above free amine (900 mg, 4.5 mmol) in CH 2 Cl 2 (100 mL) was formed. To this solution was added EDCI (1.33 g, 4.5 mmol), DMAP (567 mg, 4.5 mmol) and 4-o-tolylureido-3-methoxyphenylacetic acid (1.45 g, 4.6 mmol) at room temperature. The reaction mixture was stirred for 4 hours and then quenched by addition of 1N HCl, extracted 3x with EtOAc, dried and concentrated in vacuo. The crude amide was chromatographed (5% MeOH/CH 2 Cl 2 ) to give 1.2 g of the desired product.

The ester (1.2 g, 2.4 mmol) was taken up in 1:1 THF-H 2 O and LiOH was added at room temperature. The reaction mixture was then stirred for 3 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with EtOAc. The combined 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 22 3.

EXAMPLE 173

3-Bromo-4-hydroxybenzonitrile (5.00 g, 25.25 mmol) was taken up in DMF. Benzyl bromide (4.75 g, 27.78 mmol, 3.30 mL) and Cs 2 CO 3 (16.45 g, 50.50 mmol) were added and the reaction was heated to 50 °C for 2 h. The solution was cooled to room temperature and poured into 1N HCl. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed in water, brine and then dried over MgSO 4 . 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 acetate). Yield 8.90 g 226. 3-Bromo-4-benzyloxybenzdnitrile (1.50 g, 5.21 mmol) was taken up in dry THF under argon and the solution was cooled to 0 °C. BH 3 -THF (10.41 mL, 10.41 mmol) was added via syringe over 5 min. The reaction mixture was then warmed to room temperature and then heated to reflux for 12 hours. The solution was cooled to 0°C and methanol was slowly added. When no more gas evolution was observed, the solution was warmed to room temperature and 1N NaOH solution in excess was added. Boc 2 O (1.25 g, 5.73 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . 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 1.80 g 227. The Boc-protected benzylamine (1.80 g, 4.59 mmol) was dissolved in dry THF under argon. The reaction mixture was cooled to minus 78°C. Lithium bis(trimethylsilyl)amide (13.77 mL, 13.77 mmol) was added over 10 minutes. The reaction mixture was stirred for 1 hour at -78°C, and then iodomethane (1.95 mL, 13.77 mmol, 0.86 mL) was rapidly added. The reaction mixture was slowly allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 1N HCl 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 1.70 g 228 .

Into a pressure tube was placed the 4-(N-methyl-Boc-aminomethyl)-2-bromobenzyloxy phenol (1.70 g, 4.18 mmol). The tube was then charged with DMF, sodium acetate (0.38 g, 4.60 mmol), dppp (0.35 g, 0.84 mmol) and Pd(OAc) 2 (0.19 g, 0.84 mmol). The tube was flushed with argon for 10 min and then methyl acrylate (0.40 g, 4.60 mmol, 0.41 mL) was added. The tube was sealed and heated to 135°C for 24 hours. The reaction mixture was cooled to 0°C and the tube was slowly opened. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . 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 1.12 g 229.

The unsaturated ester (307.40 mg, 0.75 mmol) was taken up in CH 2 Cl 2 and excess TFA was added. The reaction mixture was stirred for 4 hours at room temperature. 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 saturated NaHCO 3 solution. The organic layer was washed with water, brine and then dried over Na 2 SO 4 . The solution was filtered and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2-DMF and HOBt (110.99 mg, 0.82 mmol), 3-methoxy-4-(N'-phenylureido)phenylacetic acid (258.31 mg, 0.82 mmol) and EDCI (157 .20 mg, 0.82 mmol) was added. The reaction mixture was stirred for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 296.30 mg 230.

The unsaturated ester (296.30 mg, 0.49 mmol) was taken up in EtOAc and PD/C (75 mg) was added under argon. The argon atmosphere was replaced with hydrogen at 1 atmosphere and the mixture was stirred for 24 hours. The hydrogen atmosphere was removed and replaced with argon. The catalyst was removed by filtration through diatomaceous earth and the diatomaceous earth pad was washed with ethyl acetate 3x. The solvent was removed under reduced pressure. 1^-NMR showed only the desired product. No further purification was required. Yield 233.00 mg 231. The ester (233.00 mg, 0.45 mmol) was taken up in THF-H 2 O (4:1) and LiOH (94.41 mg, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was washed with ether-hexane (1:1) and dried under high vacuum. Yield 211.5 8 mg 232.

EXAMPLE 174

5-Bromonicotinic acid (5.15 g, 25.49 mmol) was taken up in EtOH and H 2 SO 4 (1 mL) was added and the solution was heated to reflux for 24 h. The solution was cooled to room temperature and concentrated. The solution was then added saturated NaHCO 3 and the aqueous layer was extracted 3x with Et 2 O. The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The product was sufficiently pure for the next step. Yield 5.42 g 234.

The ethyl 5-bromonicotinate (5.40 g, 23.47 mmol) was taken up in 95% EtOH and NaBH 4 (8.31 g, 225.69 mmol) was slowly added at room temperature. After addition, the solution was stirred for 24 hours at room temperature. Water was slowly added to the solution, and then the mixture was stirred for 4 hours. EtOH was removed under reduced pressure and the aqueous layer was extracted 3x with CH 2 Cl 2 . The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (2:1 ethyl acetate-hexane). Yield 2.12 g 235.

The benzyl alcohol (2.12 g, 11.28 mmol) was taken up in Et 2 O and HCl 2 was bubbled through the solution for 10 minutes. The solution was stirred at room temperature for 1 hour and then the solid was collected by filtration. The solid was washed with Et 2 O and then dried. The HCl salt was added to SOCl 2 and the mixture was heated to reflux for 1.5 hours. The solution was cooled to room temperature and Et 2 O was added to precipitate the product. The solid was collected by filtration and washed with Et 2 O and dried under vacuum. Yield 2.42 g 23 6.

The benzyl chloride (2.42 g, 9.96 mmol) was added over 1 h to CH 3 NH 2 (75.9 mL, 2.5 M in EtOH) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The solution was concentrated and added to saturated NaHCO 3 . The aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. Yield 1.19 g 237. The 3-bromo-5-(N-methyl-aminomethyl)-pyridine (1.19 g, 5.01 mmol) was taken up in DMF and triethylamine (0.90 g, 1.24 mL , 8.89 mmol) was added. Boc 2 O (1.55 g, 7.10 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography in (2% methanol - CH2Cl2). Yield 1.6 g 238.

The sodium salt of α-methylacrylic acid (5.00 g, 46.27 mmol) was dissolved in DMF and benzyl bromide (8.70 g, 50.89 mmol) was added at room temperature. Potassium carbonate (7.03 g, 50.89 mmol) was then added and the solution was heated to 50°C for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with diethyl ether. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was carefully removed under reduced pressure. The product was isolated by flash chromatography (2% ether-pentane). Yield 6.93 g 239.

Into a pressure tube was placed the 3-bromo-5-(N-methyl-Boc-aminomethyl)-pyridine (700.00 mg, 2.33 mmol). The tube was then charged with DMF, triethylamine (260.05 mg, 2.57 mmol, 0.36 mL), dppp (193.85 mg, 0.47 mmol), and Pd(OAc)2 (105.52 mg, 0 .47 mmol). The tube was flushed with argon for 10 minutes and then benzyl methacrylate (452.86 mg, 2.57 mmol) was added. The tube was sealed and heated to 135°C for 24 hours. The reaction mixture was cooled to 0°C and the tube was slowly opened. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . 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 785.23 mg 240.

The unsaturated ester (392.61 mg, 0.99 mmol) was taken up in CH 2 Cl 2 and excess TFA was added. The reaction mixture was stirred for 4 hours at room temperature. 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 saturated NaHCO 3 solution. The organic layer was washed with water, brine and then dried over Na 2 SO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH 2 Cl 2 -DMF and HOBt (147.53 mg, 1.09 mmol), 3-methoxy-4-(N'-phenylureido)phenylacetic acid (342.64 mg, 1.09 mmol) and EDCI (208 .96 mg, 1.09 mmol) was added. The reaction mixture was stirred for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography in (ethyl acetate). Yield 363.79 mg 241.

The unsaturated ester (363.00 mg, 0.61 mmol) was taken up in CH 3 OH and Pd/C (100.00 mg) was added under argon. The argon atmosphere was replaced with hydrogen at 1 atmosphere and stirred for 24 hours. The hydrogen atmosphere was removed and replaced with argon. The catalyst was removed by filtration through diatomaceous earth and the diatomaceous earth 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 254.79 mg 242.

EXAMPLE 175

3-Cyanobenzaldehyde (9.41 g, 71.76 mmol) was taken up in ethanol and cooled to 0°C. NaBH 4 (2.71 g, 71.76 mmol) was added in small portions. The solutions were stirred for 30 minutes at 0°C and then allowed to warm to room temperature and stir for 1 hour. The reaction mixture was slowly poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in DMF and imidazole (2.08 g, 30.50 mmol) was added. TBDPSCI (4.61 g, 16.78 mmol, 4.36 mL) was then added and the reaction solution was stirred at room temperature for 12 h. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (7:1 hexane-ethyl acetate to 4:1 hexane-ethyl acetate). Yield 16.23 g 243 .

The silyl-protected 3-cyanobenzyl alcohol (8.50 g, 34.36 mmol) was taken up in ethyl acetate and Boc 2 O (8.25 g, 37.79 mmol) was added. Pd/C (1.0 g) was added and the Parr vessel was pressurized with hydrogen at 50 psi. The container was shaken for 24 hours and then hydrogen was flushed with argon and the catalyst was removed by filtration through a diatomaceous earth pad. The diatomaceous earth 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 acetate). Yield 11.10 g

244 .

The O-silyl-N-Boc-protected benzyl alcohol (5.00 g, 14.22 mmol) was dissolved in dry THF under argon. The reaction mixture was cooled to minus 78°C. Lithium bis(trimethylsilyl)amide (42.67 mL, 42.67 mmol) was added over 10 minutes. The reaction mixture was stirred for 1 hour at minus 78°C and then iodomethane (6.06 g, 42.67 mol, 2.66 mL) was rapidly added. The reaction mixture was slowly allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into 1N HCl 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 4.7 g 245. The O-silyl-Boc-N-methyl-protected benzyl alcohol (4.7 g, 9.60 mmol) was taken up in THF and TBAF (14.3 9 mL, 1.0 M in THF) at room temperature. The solution was stirred for 4 hours. TLC showed that no starting material was present. The reaction mixture was poured into 1N HCl 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 2.3 9 g 246.

The N-methyl Boc-protected benzyl alcohol (1.00 g, 3.98 mmol) was taken up in dry CH 2 Cl 2 under argon. Triphenylphosphine (1.46 g, 5.57 mmol) was added and the solution was cooled to 0°C. Carbon tetrabromide (1.85 g, 5.57 mmol) dissolved in dry CH 2 Cl 2 was added over 10 minutes. The solution was stirred for 1 hour at 0°C and then the solvent was removed under reduced pressure. The residue was taken up in Et 2 O 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-hexane). Yield 1.15 g 247.

LHMDS (3.23 mL, 3.23 mmol) was added to dry DME under argon at -78°C. Methyl butyrate (300 mg, 2.94 mmol, 0.33 mL) dissolved in dry DME was added to LHMDS over 15 minutes and the solution was stirred for 1 hour at -78°C. 3-N-Methyl-N-Boc-protected benzyl bromide (1.02 g, 3.23 mmol) dissolved in dry DME was added to the enolate solution over 15 min and then the solution was slowly warmed to minus 20°C and stirred in 4 hours. The reaction mixture was poured into 1N HCl 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 (3% ethyl acetate-hexane). Yield 414 mg 248.

The Boe ester (121.60 mg, 0.36 mmol) was taken up in CH 2 Cl 2 and excess trifluoroacetic acid was added. The reaction mixture was then stirred for 2 hours. The solvent was removed and the residue was taken up in ethyl acetate and washed with saturated NaHCO 3 solution. The organic layer was washed with water, brine and then dried over Na 2 SO 4 . Solution was filtered and the solvent was removed under reduced pressure. The residue was taken up in CH 2 Cl 2 -DMF and HOBt (54.10 mg, 0.40 mmol), 3-methoxy-4-(N'-phenylureido)phenylacetic acid (125.74 mg, 0.40 mmol) and EDCI (77 .0 mg, 0.40 mmol) was added. The reaction mixture was stirred for 24 hours. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 165.20 mg 249.

The ester (165.20 mg, 0.31 mmol) was taken up in ethanol-water (4:1) and NaOH was added. The reaction mixture was then heated to 50°C for 2 hours. TLC (ethyl acetate) showed that no starting material was present. The reaction mixture was cooled to room temperature. The solution was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and then dried over MgSO 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane. Yield 120.00 mg 250 EXAMPLE 176 3-Methoxy-4- [2- [3-methoxy-4- [A7'~ (2-methylphenyl)ureido] phenylacetyl] -N-methylaminoethoxy] benzoic acid

To a stirred and cooled (0°C) solution of A7-methylethanolamine (3.10 g, 41.27 mmol), Et3N (11.80 mL, 84.66 mmol)

in DMF-H 2 O (3:1, v/v, 40 ml) a 30% toluene solution of benzyl chloroformate (25.40 g, 49.13 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred for 1 day at room temperature. The mixture was extracted with EtOAc. The extract was washed with saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with n-hexane:EtOAC (3:1, v/v), then CHCl 3 as eluent to give 4.67 g (54%) of AT-methyl-N-(benzyloxy-carbonyl) an anolamine as a colorless oil. 1H-NMR(CDCl 3 ) d 1.82 (bs, 1 H), .3.00.(s, 3 H), 3.46 (bs, 2 H), 3.77 (bs, 2 H), 5.13 (s. 2 H ), 7.29-7.36 (m, 5 H).

To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (2.01 g, 10.25 mmol), N-methyl-N-(benzyloxycarbonyl)ethanolamine (2.11 g, 10.08 mmol), PPh3 (3 .26 g, 12.43 mmol) in THF was added DIAD (2.65 mL, 13.46 mmol) and the reaction mixture was heated under reflux overnight. The mixture was evaporated and the residue was subjected to brief column chromatography on silica gel eluting with n-hexane/EtOAc (5:1, v/v) to give ethyl 3-methoxy-4-[2-methyl-2-(benzyloxycarbonyl)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 h. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was diluted with CHCl 3 and washed with saturated NaHCO 3 , brine dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl3:MeOH (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 .

1 H-NMR (CDCl 1 ) 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, 1 H, J=2. 0, 8.3 Hz).

To a stirred solution of ethyl 3-methoxy-4-(2-methylamino-ethoxy)benzoate (510 mg, 2.01 mmol) in DMF (13 mL) was added the pentafluorophenyl ester of 3-methoxy-4- [AJ '-(2-methylphenyl)ureido]phenylacetic acid (900 mg, 1.87 mmol) and Et 3 N (0.420 mL, 3.01 mmol), and the resulting mixture was stirred for 2 days. The mixture was diluted with EtOAc, washed with 1N HCl, saturated NaHCO 3 , brine and dried over Na 2 SO 4 . After evaporation, the residue was purified by column chromatography on silica gel with CHCl3:MeOH (50:1, v/v) to give 880 mg (85%) of ethyl 3-methoxy-4-[2-[3-methoxy-4-[ N'-(2-methylphenyl) ureido] phenylacetyl] -A7-methylaminoethoxy] benzoate as a colorless amorphous solid.

1H-NMR (CDCl1) 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^.24 (2 H, m), 4.33-4.39 (m, 2 H), 6.68-8.08 (r series of m, 12 H).

To a solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[AT<->(2-methylphenyl)ureido]phenylacetyl]-N-methylaminoethoxy]benzoate (880 mg, 1.601 mmol) in THF (15 ml) was added 0.25 N NaOH (15 ml). The reaction mixture was then heated under reflux overnight. The mixture was poured into 1N HCl (100 mL), and the solid was collected. The crude solid was recrystallized from MeOH-CHCl 3 to give 253 as a white powder. IR (KBr) 1700 cm"'; 'H-NMR (DMSO-d<) 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 (series of^m, 12 H), 12.68 ( bs, 1H); MS (FAB) m/z 522 (M<*>+1); Anal. Calcd for d^NjO/ 1H2O: C, 62.33; H, 6.16; N, 6.63. Found. C, 62.17; H , 6.05; N, 7.57.

4 in.

EXAMPLE 177

4-[[2-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenylacetyl]-methylamino]ethoxy]isophthalic acid

To a stirred solution of N-methyl-N-benzyloxycarbonyl-ethanolamine (1.05 g, 5.02 mmol), dimethyl 4-hydroxyisophthalate (1.05 g, 5.00 mmol), Ph3P (1.59 g, 6 .06 mmol) in THF (20 mL)

DIAD (1.28 mL, 6.50 mmol) was added at room temperature.

The resulting mixture was then heated under reflux overnight. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in EtOH and 5% Pd/C (200 mg) was added. The stirred resulting mixture was hydrogenated for 2 hours at 1 atmosphere. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The rest was cleaned with wood

column chromatography on silica gel with CHCl3-MeOH (30:1, v/v) as eluent to give 480 mg (36% in 2

step) dimethyl 4-(2-methylaminoethoxy)isophthalate as an oil.

1H-NMR (CDCl 3 ) 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 (rn, 2 H), 7.00 (d, 1 H, 7=8.8 Hz), 8.14 (dd, 1 H, J=2.4, 8.8 Hz), 8.50 (d, 1 H, 7= 2.4

Hz); MS (FAB), m/z 268 (M<+>+1).

To a stirred solution of dimethyl 4-(2-methylaminoethoxy)-isophthalate (410 mg, 1.53 mmol) in DMF (13 mL) was added the pentafluorophenyl ester of 3-methoxy-4-[N-(2-methylphenyl)- ureido]f phenylacetic acid (700 mg, 1.46 mmol) and Et 3 N (340 µl, 2.44 mmol), and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with IN

HCl, saturated NaHCO 3 and brine. The resolution was

dried over Na2SO4 and evaporated to give 780 mg (95%) of dimethyl 4-[2-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetyl]methylaminoethoxy]isophthalate as a crystalline powder.

1 H-NMR (CDCl 1 ) 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<*>+1).

To a solution of dimethyl 4-[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]methylaminoethoxy] isophthalate (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-IN HCl (200 mL) and the solid was collected. The crude solid was recrystallized from MeOH-CHCl3 to give 420 mg (57%) of 4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy] isophthalic acid 254 as a white crystalline powder. M.p.: 139-141°C. TR (KBr) 1700 cm"<1>;

'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<*>+1); Anal. Calculated for C2,H29N30,-2.5HC1: C, 53.66; H, 5.07; N, 6.70. Found: C, 53.80; R, 4.64; N, 6.70.

EXAMPLE 178

3-Methoxy-4- [2- [3-methoxy-4- [AJ'-(2-methylphenyl)ureido]-phenylacetyl]aminoethoxy]benzoic acid

To a solution of 2-ethanolamine (5.16 g, 84.48 mmol), Et3N

(23.50 mL, 168.60 mL) in dioxane-H 2 O (1/L, 160 mL) was added dropwise (Boc) 2 O (23.40 mL, 101.86 mmol) at room temperature. The reaction mixture was stirred for 2 days at room temperature. The resulting mixture was diluted with CHCl 3 , washed with 0.5 N HCl, saturated NaHCO 3 , and brine. The separated organic layer was dried over Na 2 SO 4 and evaporated to give 11.86 g (87%) of AJ-Boc-2-ethanolamine as an oil. 1 H-NMR (CDCl 3 ) d 1.45 (s, 9 H), 3.29-3.31 (m, 2 H), 3.71-3.72 (m, 2 H).

To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate

(1.46 g, 7.44 mmol), AJ-Boc ethanolamine (1.19 g, 7.38 mmol)

To PPh3 (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 2 Cl 2 (20 mL) and TFA (20 mL). The resulting mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated in vacuo and the residue basified with saturated NaHG0 3 and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated to give 1.61 g (90% in 2 steps) ethyl 3-methoxy-4-(2-aminoethoxy)benzoate as a yellow oil. 1H-NMR (CDCl3)

d 1.39 (t, 3 H, .7=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, .7=7.3 Hz), 6.89 (d, 1 H, .7=8.3 Hz), 7.56 (d, 1 H, 7=2.0 Hz), 7.66 (dd, 1 H, 7=2.0, 8.3 Hz).

To a stirred solution of ethyl 3-methoxy-4-(2-aminoethoxy)-benzoate (250 mg, 1.04 mmol) and 3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (500 mg, 1.04 mmol) was added Et 3 N (210 µl, 3.01 mmol) and the resulting mixture was stirred for 2 days. 0.25 N NaOH (20 mL) and THF (20 mL) were 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 1N HCl. The mixture was extracted with CHCl 3 and the extract was washed with brine, dried over Na 2 SO 4 and evaporated. The crude solid obtained was recrystallized from CHCl 3 to give 110 mg (20% for 2 steps) of 3-methoxy-4-[2-[3-methoxy-4-[ N'~ (2-methylphenyl)-ureido]phenylacetyl] aminoethoxy]benzoic acid 255 as a white crystalline powder. M.p.: 180-181°C.

TR (KBr) 1687 cm'<1>; 1 H-NMR .(DMSOd<) d 2.24 (s, 3 H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.41-3.50 (m, 2 H), 3.81 (s, 3 H ), 3.83 (s, 3 H), 4.06-4.08 (m, 2 H), 6.76-8.55 (series of m, total 12 H);

MS (FAB) m/z 508 (M<+>+1); Anal. Calcd for C17H21)N3Cy 1/2H:0: C, 62.78; R, 5.85; N, 8.13. FoundC, 62.46; H, 5.69; N, 8.03.

EXAMPLE 179

3-Methoxy-4- [2- [3-methoxy-4- [AT'(2-methylphenyl)ureido] phenylacetyl] ethylaminoethoxy]benzoic acid

To a cooled (0°C) solution of ethyl 3-methoxy-4-(2-arainoethoxy)benzoate (1.93 g, 8.07 mmol) and Et3N (2.00 mL, 14.35 mol) was added TFAA (1.35 mL, 9.56 mmol) and the resulting mixture was stirred overnight at room temperature. The resulting mixture was diluted with Et 2 O and washed sequentially with saturated NaHCO 3 , 1N HCl, H 2 O and brine. The extract was dried over Na 2 SO 4 and evaporated to give 1.22 g (45%) of ethyl 3-methoxy-4-(2-N-trifluoroacetamidoethoxy)benzoate as an oil.

1H-NMR (CDCy d 1.39 (t, 3 H, .7=7.3 Hz), 3.77-3.81 (m, 2 H), 3.92 (s, 3 H), 4.18-4.20 (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, 7=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-N-trifluoro-acetamidoethoxy)benzoate (1.20 g, 3.58 mmol) in DMF (15 mL) was added K 2 CO 3 (0.98 g, 7 .09 mmol) and Et1 (0.43 mL, 5.38 mmol) at room temperature. The resulting mixture was stirred for 2 days at 60°C. The mixture was diluted with EtOAc, washed sequentially with 1N HCl, brine and dried over Na 2 SO 4 . 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%) of ethyl 3-methoxy-4-[2-(A7- ethyl-A7-trifluoroacetamido) -

ethoxybenzoate as a yellow crystalline solid.

1H-NMR (CDCl1) d 1.28-1.31 (m, 3.H), 1.37-1.40 (m, 3H), 3.64-3.69 (m, 2H), 3.81-3.84 (m, 2H), 3.92 (s, 3 H), 4.27-4.30 (m, 2 H), 4.34-4.39 (m, 2 H), 6.89 (d, 1 H, 7=8.3 Hz), 7.55 (d, 1 H, 7 =2.0 Hz), 7.66 (dd, 1 H, 7=2.0. 8.3 Hz); MS (FAB) m/z 364 (M<*>+1).

To a stirred solution of ethyl 3-methoxy-4-[2-(AT-ethyl-W-trifluoroacetamido)ethoxybenzoate (990 mg, 2.73 mmol) in THF-MeOH-H 2 O (2:1:1, v/v) volume, 20 ml) K 2 CO 3 was added

(560 mg, 4.05 mmol), and the resulting mixture was stirred overnight. The resulting mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed sequentially with saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated to give 800 mg (quant, yield) of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate as an oil.

1H-NMR (CDCl3) d 1.15 (t, 3 H, 7=7.3 Hz), 1.39 (t,3

H, 7=7.3 Hz), 1.76 (bs, 1 H), 2.74 (q, 2 H, 7=7.3 Hz), 3.08 (t, 2 H, 7=5.4 Hz), 3.91 (s, 3 H), 4.18 (t, 2 H, 7=5.4 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 ), 7.66 (dd,

1 H, 7=2.0, 8.3 Hz); MS (FAB) m/z 268 (M*+1).

To one stirred solution of ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (290 mg, 1.08 mmol) and pentafluorophenyl ester of 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (502 mg, 1.05 mmol) in DMF (7 mL) was added Et 3 N (250 µl, 1.79 mmol) and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine and dried over Na 2 SO 4 . The solvent was evaporated and the residue was purified by column chromatography on silica gel with CHCl3-MeOH (40:1, v/v) as eluent to give 550 mg (93%) of ethyl 3-methoxy-4-[2-[3-methoxy -4- [AT'-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an amorphous solid.

1 H-NMR (CDCl 1 ) d 1.11-1.18 (m, 3 H); 1.37-1.41 (m, 3 H), 2.30 (s, 3 H), 3.47-3.53 (ra, 2H), 3.61-3.75 (m, 7 H), 3.84 (s, 3 K), 4.03^.27 ( m, 2 H), 4.33-4.39 (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-[Δ7'-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate (550 mg, 0.98 mmol) in THF (15 ml) 0.25 N NaOH (15 ml) was added. The resulting mixture was then heated under reflux for 2 days. The mixture was poured into 1N HCl and the solid was collected. The crude solid was recrystallized from EtOH-CHCl3 to give 182 mg (35%) of 3-methoxy-4-[2-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoic acid 256 as a white crystalline powder. M.p.: 115-118°C. IR(KBr)1707

cm"'; 'H-NMR (DMSO-d,) 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, IH); MS (FAB)'m/r 536 Of+l); y4na/. Calculated forCJ9Hj3Nj07 -3/4H 3 O: C, 63.43; H, 6.33; N, 7.65 Found: 63.34; H, 6.28; N, 7.28.

EXAMPLE 180

3-nitro-4-[2-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]-phenylacetyl]aminoethoxy]benzoic acid

To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (5.18 g, 28.29 mmol) in benzene-MeOH (4:1, v/v, 140 mL) was added TMSCHN2 (14.10 mL, 28 .20 mmol, 2 M solution in hexane) at room temperature and the resulting mixture was stirred overnight. The mixture was evaporated and the residue was purified by column chromatography on silica gel eluting with CHCl 3 to give 4.18 g (75%) of methyl 3-nitro-4-hydroxybenzoate as a yellow crystalline solid.

1 H-NMR (CDCl 1 ) d 3.95

(s, 3H), 7.22 (d, ;1H, .7=8.8 Hz), 8.24 (dd, 1, 7=2.0, 8.8 Hz), 8.83 (d, IH, 7=2.0 Hz), 10.89 (s, .lH).

To a stirred solution of methyl 3-nitro-4-hydroxybenzoate (1.98 g, 10.04 mmol), A7-Boc-ethanolamine (1.63 g, 10.11 mmol)

and PPh 3 (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 resulting crude gum was dissolved in CH 2 Cl 2 (30 mL) and TFA (30 mL), and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine and dried over Na 2 SO 4 . The solvent was evaporated in vacuo to give an oily residue, which was purified by column chromatography on silica gel with CHCl 3 and then CHCl 3 -MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps) methyl 3-nitro-4-(2-aminoethoxy) benzoate as gum. 1H-NMR (CDCl1) 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, 1 H).

To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy )benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et 3 N (0.90 mL, 6.46 mmol) and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na 2 SO 4 and evaporated. The crude solid was recrystallized from CHCl3-EtOH to give 60 mg (3% over 2 steps) of 3-nitro-4-[2-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl] aminoethoxy] benzoic acid 257.as a yellow crystalline solid. M.p.: 112-115°C. 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37-3.66 (m, 7 H), 3.84 (s, 3 H), 4.27-4.30 (m, 1 H), 6.74-8.56 ( series of', m, total 12 H); MS (FAB) m/z 523 QA*+ 1Y, Anal. Calculated for C^NA^ÆHjO: C, 56.83; H, 5.32; N, 10.20 Found: C, 56.66; H, 4.90; N, 9.33.

EXAMPLE 181

3-Methoxy-4-[2-[3-methoxy-4-[ N'-(2-fluorophenyl)ureido] phenylacetyl] ethylaminoethoxy]benzoic acid

To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[Δ7'-(2-fluorophenyl)ureido]phenylacetic acid (135 mg, 0.28 mmol) and ethyl 3-methoxy-4-(2-ethylaminoethoxy) benzoate (78 mg, 0.29 mmol) was added Et 3 N (0.1 mL, 0.72 mmol) and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc, washed sequentially with 0.5N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 160 mg (quant, yield) of ethyl 3-methoxy-4-[2-[3-methoxy-4- [A7'-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate as an oil. 'H-NMR (CDCl1) d 1.13,1.23 (m, 3 H), 1.37-1.40 (rn, 3 H), 2.90-3.89 (m, 12 H), 4.09-4.28 (rn, 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-[W-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate (160 mg, 0.28 mmol) in To THF (5 mL) was added 0.25 N NaOH (5 mL), and the resulting mixture was heated under reflux overnight. The mixture was poured into 1N HCl and the solid was collected. The crude solid was recrystallized from EtOH-CHCl3-n-hexane to give 70 mg (46%) of 3-methoxy-4-[2-[3-methoxy-4-[A7'-(2-fluorophenyl)ureido ] phenylacetyl] ethylaminoethoxy] benzoic acid 258 as a yellow crystalline powder. M.p.: 105-110°C.

IS. (KBr) 1687 cm -1 ; 1H-NMR (DMSO-dJ 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<+>+l); Anal. Calculated for

<^8H30FN307-1/2H20: C, 61.31; H, 5:82; N, 7.47. Found: C, 61.05; H, 5.82; N, 7.47.

EXAMPLE 182

4-[4-[3-Methoxy-4-[AJ'-(2-methylphenyl)ureido]phenyl]acetyl-1-piperazinylbenzoic acid

A stirred mixture of tert-butyl 1-piperazine carboxylate

(1.00 g, 5.37 mmol), ethyl 4-fluorobenzoate (903 mg, 5.37 mmol) and K 2 CO 3 (1.11 g, 8.06 mmol) in DMF (10 mL) were heated at 12 0° C overnight. After cooling, the mixture was diluted with EtOAc (300 mL), followed by washing with brine

(2 x 200 ml), drying over MgSO 4 and evaporation. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (20:1 to 4:1, v/v) as eluent to give 257 mg (14%) of ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate as a pale yellow amorphous solid.

IR (KBr) 1701,1612 cm"';.'H-NMR (CDCl 3 ) d 1.37 (3 H, t, J= 7.3 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 (M₂+1); ^no/.Beregnefor CUHMNA: C, 64.54; H, 7.84;

N, 8.38. Found: C, 64.39; H, 7.8'9; N, 8.38.

To a stirred solution of ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate (240 mg, 0.718 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL), and the resulting the mixture was stirred for 3 hours. The mixture was concentrated in vacuo and the residue basified by addition of saturated NaHCO 3 , followed by extraction with CHCl 3 (2 x 100 mL). The combined extracts were dried over Na 2 CO 3 and evaporated to give 168 mg of ethyl, 4-(1-piperazinyl)benzoate (100%) as a yellow oil. 1H-NMR (CDCl1) d 1.37 (3 H, t, J = 7.3 Hz), 3.03 (4 H, t, J = 4.9 Hz), 3.29 (4 H, t, J = 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-(1-piperazinyl)benzoate

(170 mg, 0.730 mmol) and 3.-methoxy-4-[A7'-(2-methylphenyl)-ureido]phenylacetic acid (229 mg, 0.730 mmol) in DMF (10 mL) was added EDC-HCl (210 mg , 1.10 mmol), DMAP (catalytic amount) and -HOBt (catalytic, amount) , and the mixture was stirred overnight. The mixture was poured into H 2 O (100 mL) and the solid was collected by suction. The residue was recrystallized from CHCl 3 -n-hexane to give 290 mg (75%) of ethyl 4-[4-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenyl]acetyl-1-piperazinyl benzoate as a colourless, crystalline powder. Temp. : 2 08-210°C- ER (KBr) 1711, 1695 cm"1; 'H-NMR (CDGlj) d 1.37 (3 H, U J = 7.3 Hz), 2.29 (3 H, s), 3.14 (2 H , t, 7 = 4.9 Hz), 3.28 (2 H, t, J= 4.9

Hz), 3.62 (2 H, t, J = 4.9 Hz), 3.71 (3 H, s), 3.72 (2 H, s), 3.79 (2 H, t, J= 4.9 Hz), 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<+>+1); Anal. Calculated for C 10 H 2 , NA-0.5 H 2 O: 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-[AJ'-(2-methylphenyl)ureido]phenyl]-acetyl-1-piperazinylbenzoate (290 mg, 0.547 mmol) in MeOH-THF (2 :1, v/v, 15 mL) 0.25 N NaOH (5 mL, 1.25 mmol) was added and the mixture was heated under reflux for 3 h. The mixture was poured into ice-1N-HCl (100 mL) and the solid was collected by suction. The residue was recrystallized from CHCl3-MeOH to give 190 mg (69%) of 4-[4-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenyl]-acetyl-l-piperazinylbenzoic acid 259 as a yellow crystalline powder. Melting point: 240-245°C.

'H-NMR (DMSO) d 2.24 (3 H, sj, 3.17-3.50 (8,H, xn), 3.72 (2 Hr.s), 3.86 (3 H, s), 6.77 (1 H, d, / = 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 (l H,

d, J = 8.3 Hz), 8147 (1 H, s), 8.58 (1 H, s). 12.30 (1 H, p); ^no/Berégnéffor CgHjoNA-HjO: C, 64.60; H, 6.20; N, 10.76. Found: C, 64.64; H, 5.85; N, 10.51.

EXAMPLE 183

(R)-3-Methoxy-4-[2-[3-Methoxy-4-[N'~(2-methylphenyl)ureido]-phenylacetylamino]-1-propoxy]benzoic acid

To a cooled (0°C) solution of (R)-2-amino-1-propanol (3.01 g, 0.04 mmol) and Et 3 N (6.70 mL, 0.05 mmol) in DMF-H 2 O ( 1:1, v/v) (40 mL) was added (Boc)20 (10.0 mL, 0.04 mmol) and the resulting mixture was stirred at

room temperature for 2 days. The mixture was diluted with EtOAc, washed with H 2 O, brine, dried over Na 2 SO 4 and evaporated to give 6.91 g (98%). (R)-2-N-tert-butoxycarbonyl amino-l-propanol as a colorless oil.

1 H-NMR (CDCl 1 ) 81.15 (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<*>+1), 120 (M<*>-Bu).

To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate

(7.74 g, 0.04 mmol), ( R )-2-A7- tert -butoxycarbonylamino-1-propanol (6.91 g, 0.04 mmol) and Ph3P (13.44 g, 0.05 mmol ) in THF (70 mL) was added diisopropyl azodicarboxylate (DIAD) (10.0 mL, 0.05 mmol) and the resulting mixture was heated under reflux overnight. After cooling

to room temperature, the solvent was evaporated. The mixture was dissolved in CH 2 Cl 2 (50 mL) and -TFA (30 mL) and the solution was stirred at room temperature for 1 hour. After concentration in vacuo, the residue was poured into saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with 5% MeOH in CHCl 3 as eluent to give 7.93 g (2 steps 79%) ethyl. (R)-3-Methoxy-4-(2-amino-1-propoxy)benzoate as a yellow oil.

1H-NMR (CDCl1) δ 1.90 (d, 3 H, 7=6.8 Hz), 1.39 (t, 3 H, 7=7.3 Hz), 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, IH), 4.35 (q, 2 H, 7=7.3 Hz), 6.88 (d, 1 H, 7=8.3 Hz), 7.55 (d, 1 H, 7=2.0 Hz), 7.65 (dd, 1 H, 7=2.0, 8.3 Hz); MS (FAB)

m/z 254 (M<+>+1).

To a stirred solution of pentafluorophenyl 3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl ( R )-3-methoxy-4-(.2 -aminopropoxy) benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et 3 N (200 µl, 1.43 mmol) and the resulting mixture was stirred for 2 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 360 mg (69%) of ethyl ( R )-3-methoxy-4-[2-[3-methoxy- 4-[ N'-(2-methylphenyl)ureido]-phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid.

1H-NMR (CDCl1) δ 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 (R)-3-methoxy-4-[2-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (3 60 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 HCl and the precipitate was collected. The crude solid was recrystallized from CHCl 3 -n-hexane to give 172 mg (50%) of 260 as a white crystalline powder. M.p.:•16 8-169°C.

ER (KBr) 1687 cm"?; 'H-NMR (DMSO-d<) 8 1.18 (d, 3 H, J=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" rn, total 12 H) , 12.66 (bs, 1 H); MS (FAB) m/z 522 (M<*>+1); /Ifla/. Calculated for C1,H3IN3Cy3/4 H3O: C, 62.85; H, 6.12; N, 7.85. Found: C, 62.77; H, 5.95 N. 7.79.

EXAMPLE 184

4-[[2-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-allylamino]ethoxy]benzoic acid

To a stirred mixture of ethyl 4-(2-A7-trifluoroacetylamino-etbxy)-3-methoxybenzoate (3.5 g, 10.4 mmol) and K 2 CO 3 (2.3 g, 16.4 mmol) in DMF (20 mL ) was added allyl bromide (14.2 mL, 16.5 mmol) and the resulting mixture was stirred for 45 min at 65°C. After cooling, water was added to the mixture and the mixture was extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated in vacuo. The residue was dissolved in THF-MeOH-H 2 O (1:1:1, v/v/v) (30 mL) and K 2 CO 3 (2.3 g, 16.4 mmol) was added. The resulting mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 :MeOH (95:5 to 95:5, v/v) as eluent to give 2.9 g (.100%) of ethyl 4-(2-allylaminoethoxy)-3-methoxybenzoate as a pale yellow oil.

1H-NMR(CDC13, 400MHz) δ 1.39 (t, 3H, J=7.3Hz), 3.07 (t, 2H, J=5.3Hz), 3.34 (d, 2H,

<1> 7=5.9Hz), 3.91 (s,3H),4.18(t,2H,.7=5.4Hz), 4.35 (dd, 2H, J=7.3Hz, 14.1Hz), 5.12 (d, IH, ' J=10.3Hz), 5.22'(dd, IH, J=1.5Hz, 17.1Hz), 5.92 (m, 2H), 6.90 (d, IH, J=8.3Hz), 7.55 (d, IH, 7= 1.5Hz), 7.65 (dd, IH, J=2.0Hz, 8.3Hz); MS(FAB) m/z 278, 280(M+H)+/

To a stirred mixture of ethyl 4-(2-allylaminoethoxy)-3-methoxybenzoate (578 mg, 2.1 mmol), 3-methoxy-4- [ N'~ (2-methylphenyl)ureido]phenylacetic acid (650 mg, 2 .1 mmol), HOBt (420 mg, 3.11 mmol) and DMAP (catalytic amount) in DMF (4 mL) was added EDC (596 mg, 3.11 mmol) at room temperature. The resulting mixture was stirred for an additional 18 hours at room temperature. The mixture was poured into 1N HCl and extracted with EtOAc. The extract was washed with saline, dried over Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl3:EtOAc (95:5 to 1:1, v/v) as eluent to give 1 g (84%) of 3-methoxy-4- [ [2- [3-methoxy-4- [A7'-(2-methylphenyl)ureido] phenylacetyl] allylamino] ethoxy] benzoic acid as a pale yellow gum.

(1H-NMR tCDCl1, 400MHz) δ 1.39; (t; 3H, J=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, IK), 4.36 (q, IH, 7=7.0Hz), 5.04-5.22 (m, 2H), 5.73 (m, IK), 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 (rn, 2H), 8.05 (d, 1H, 7=7.8Hz); MS (FAB) m/z 576(M+H)<+>.

A mixture of 3-methoxy-4-[[2-[3-methoxy-4-[Δ7'(2-methylphenyl)ureido]phenylacetyl]allylamino]ethoxy]benzoic acid (50 mg, 0.09 mmol) in THF- MeOH (1:1, v/v) (2 mL) and 1N NaOH (0.135 mL, 0.135 mmol) were stirred for 15 h at room temperature and 3 h at 50 °C. The mixture was poured into ice-IN HCl. The solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHCl 3 -n-hexane to give 38 mg (77%) of 261 as a white crystalline material. Melting point: 125-130°C.

ÉR(KBr), 3319, 2939, 1687, 1647, 1601, 1535, 1456, 1417, 1269, 1223, 1034, 760cm-';, <1>H-NMR(DMSO-d«, 400MHz) 5 2.29 (s , 3H), 3.68 (s, 2H), 3.75-3.85 (m, 8H), 4.05 (br, IK), 4.19 (m, 3H), 5.10-5.25 (m, 2H), 5.65-5.90 (m, IH ), 6.75 (m, IH), 6.85 (s, IH), 6.92 (m, IH), 7.02-7.20 (m, 3H), 7.48 (d, IH, <y>=10.2Hz), 7.56 (m, IH), 7.79 (d, IH, 7=6.8Hz), 8.01 (m, IH), 8.46 (s, IH), 8.56 (d, IH, J=4.4Hz), 12.7 (br, IH); MS (FAB) m/z 548(M+H) + ; Arial. Calculated for C30H33N3O7-0.5HJO, C, 64.74; H, 6.16; N, 7.55. Found: C, 64.72; H, 6.07; N, 7.55.

EXAMPLE 185

3-Methoxy-4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]-phenylacetyl]-(2-morpholino)ethylamino]ethoxy)benzoic acid

To a stirred solution of 3-methoxy-4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]allylamino]ethoxy]benzoic acid (950 mg, 1.65 mmol) in To THF:H 2 O (7 mL) was added AJ-methyl-morpholine-AJ-oxide (579 mg, 4.95 mmol) and osmium tetroxide (0.2M solution in water) (0.413 mL, 0.08 mmol).- The the resulting mixture was stirred for 3 hours at room temperature. Saturated NaHSO 3 was added to the mixture and the mixture was filtered through Celite. The filtrate was extracted with EtOAc. The extract was washed with saline, dried over MgSO 4 and evaporated in vacuo. The residue was dissolved in MeOH-THF-H 2 O (1:1:1, v/v) (12 mL) and sodium periodate (318 mg, 1.5 mmol) was added. The resulting mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with EtOAc, washed with brine and dried over MgSO 4 . The solvent was evaporated in vacuo to give 862 mg (90%) of ethyl 3-methoxy-4-[[2-[3-methoxy-4- [AJ'-(2-methylphenyl)ureido]phenylacetyl]-A7-f ormylmethylamino]-ethoxy]benzoate as a pale yellow gum. 'H-NMR (CD Cl3 > 400MHz) 6 1.39 (t, 3H, J=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, IH), 8.10 (m, IH), 9.50 (m, IH); MS (FAB) m/z 578 (M+H)<+>.

To a stirred mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]-AJ-formylmethylamino]-ethoxy]benzoate (265 mg , 0.46 mmol), morpholine (0.40 mL, 4.59 mmol) and AcOH (0.263 mL, 4.6 mmol) in EtOH (3 mL) was added NaBH3CN (288 mg, 4.6 mmol) at room temperature. The resulting mixture was stirred for 15 hours at room temperature and the mixture was diluted with EtOAc and saturated NaHCO 3 was added at 0°C. The resulting mixture was stirred for 0.5 hours at 0°C. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl3:MeOH (95:5, v/v) as eluent to give 213 mg (71%) of ethyl 3-methoxy-4-[[2-[3-methoxy-4- [AJ' - (2-methylphenyl)ureido]phenylacetyl]-(2-morpholinep)ethylamino]ethoxy]benzoate as an oil.

. 1H-NMR (CDCl1, 400MHz) δ 1.28 (t, 3H, 7=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, J=7.0Hz), 6.70-6.85 (m, 4H), 7.15 (m, 2H), 7.50-7.63 (m, 3H), 8.08 (d, 1H, J=8.0Hz); MS (FAB) m/z 649(M+H)<+>.

A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[AJ'- (2-methylphenyl)ureido]phenylacetyl]-(2-morpholino)ethylamino]-ethoxy]benzoate (265 mg, 0.46 mmol) in THF (4 mL), and 1N NaOH (0.984 mL) was stirred at 50°C for 15 h. The pH of the mixture was adjusted to 7.4 by addition of 1N HCl, and extracted with CHCl3:MeOH (9:1, v/v). The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was crystallized with Et 2 O to give 160 mg (78%) of 262 as a white crystalline material. Melting point: 125-130°C.

IR (KBr), 3346, 2956, 2937, 1705, 1622, 1599, 1537, 1456, 1417, 1299, 1114, 1032, 752 cm-'; 1H-NMR (CDjOD, 400MHz) δ 2.29 (s, 3H), 2.49-2.64 (m, 6H), 3.65-3.85 (m, 16H), 4.13 (m, 1H), 4.26 (m, 1H), 6.78 -7.04 (m, 4H), 7.18 (m, 2H), 7.55-7.64 (m, 3H), 7.99 (m, 2H); MS (FAB) rn/ z 621 (M+H) + ; Anal. Calculated for CjjH^NAaSHA C, 59.54; H, 6.81; N, 8.42. Found: C, 59.71; H, 6.35; N, 7.98.

EXAMPLE 186

3-Methoxy-4- [ [2- [3-methoxy-4- [AJ'-(2-methylphenyl)ureido]-phenylacetyl]-[2-[4-methyl-1-piperazinyl] ethylamino]ethoxy]-benzoic acid

To a stirred mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[A7'~ (2-methylphenyl)ureido]phenylacetyl]-A7-formylmethylamino]-ethoxy]benzoate (242 mg , 0.42 mmol), N-methylpiperazine (0.465 mL, 4.2 mmol) and AcOH (0.240 mL, 4.2 mmol) in EtOH (3 mL) was added NaBH3CN (263 mg, 4.2 mmol) at room temperature.

The resulting mixture was stirred for 15 hours at room temperature. The mixture was diluted with EtOAc and saturated NaHCO 3 was added at 0°C. The resulting mixture was stirred for 0.5 h at 0°C. The mixture was extracted with EtOAc. The extract was washed with saline, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl3:MeOH (95:5, v/v) as eluent to give 195 mg (70%) of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[ N' -(2-methylphenyl)ureido]phenylacetyl]-[2-(4-methyl-1-piperazinyl]ethylamino]ethoxy]benzoate as an oil.

1H-NMR (CDCl1, 400MHz) δ 1.23 (t, 3H, 7=7.0Hz), 2.25 (s, 3H), 2.29

(s, 3H), 2.50 (br m, 12H), 3.44-3.85 (m. 12H), 4.10 (br, IK), 4.22 (br, IK), 4.35 (m, 2H), 6.70-

6.85 (m, 3H), 6.98 (s, IH), 7.10 (m, IK), 7.20 (m, 2H), 7.40 (m, IH), 7.60-7.70 (m, 3H), 8.05( d, IH, J=7.8Hz); MS (FAB) m/z 662(M+H)<+>.

A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[A7'- (2-methylphenyl)ureido]phenylacetyl]-[2-(4-methyl-1-piperazinyl]-ethylamino] ethoxy]benzoate (195 mg, 0.30 mol) in THF:MeOH (4:1, v/v) (5 mL) and 1N NaOH (0.885 mL) was stirred at 50 °C for 15 h. The pH of the mixture was adjusted to 7.4 by addition of 1N HCl, and the mixture was extracted with CHCl3:MeOH (9:1, v/v). The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized with Et2O to to give 141 mg (75%) of 263 as a white crystalline material, mp: 155-160°C.

IR (KBr), 2937, 1537, 783 cm-'; 1H-NMR (CDjOD, 400MHz) δ 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 (m, 6H), 7.61

(m, 3H), 8.00 (m, IK) ; MS (FAB) m/ z 632 (Mf; Anal. Calculated for Cj,HoNjCy2.5H2O, C, 60.16;

H, 7.13; N, 10.32. Funnetc, 59.72; H, 6.86; N, 9.97.

EXAMPLE 187 "

3-Methoxy-4- [ [2- [3-methoxy-4- [AJ'-(2-methylphenyl) ureido] - phenylacetyl] - [2-cyclopropylamino] ethylamino] ethoxy] benzoic acid

To a stirred mixture ethyl 3-methoxy-4-[[2-[3-methoxy-4-[AJ'- (2-methylphenyl) ureido] phenylacetyl] -AJ- formylmethylamino]-ethoxy]benzoate (267 mg , 0.46 mmol), cyclopropylamine (0.32 mL, 4.6 mmol) and AcOH (0.264 mL, 4.6 mmol) in EtOH (3 mL) was added NaBH3CN (2 90 mg, 4.6 mmol ) at room temperature. The resulting mixture was stirred for 15 hours at room temperature. The mixture was diluted with EtOAc and saturated NaHCO 3 was added at 0°C. The resulting mixture was stirred for 0.5 h at 0°C. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (95:5, v/v) as eluent to give 156 mg (55%) of ethyl 3-methoxy-4-[2-[3-methoxy-4- [AJ'- (2-methylphenyl)ureido]phenylacetyl]-[2-cyclopropylamino]-ethylamino]ethoxy]benzoate as an oil.

1H-NMR (CDCl1, 400MHz) δ 0.35 (rn, 4H), 1.22 (br s, 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, 4H), 7.55 (m, 4H), 8.06 (br s, IH); MS (FAB) m/z 619(M+H)<+>.

A mixture of ethyl 3-methoxy-4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl) ureido] phenylacetyl] -AJ- [2-cyclopropylamino] - . ethylamino]ethoxy]benzoate (195 mg, 0.30 mmol)) in THF:MeOH'

(4:1, v/v) (5 mL) and 1N NaOH (0.756 mL) was stirred at 50°C for 15 h. The pH of the mixture was adjusted to 7.4 by addition of 1N HCl, and extracted with CHCl 3 :MeOH (9:1 v/v). The extract was washed with saline. dried over MgSO 4 and evaporated in vacuo. The residue was crystallized with Et 2 O to give 57 mg (38%) of 3-methoxy-4-[[2-

[3-Methoxy-4- [AJ'-(2-methylphenyl)ureido]]phenylacetyl]-(2-cyclopropylamino]ethylamino]ethoxy]benzoic acid 264 as a white crystalline material. M.p.: 135-140°C.

IR (KBr), 3324, 2937, 1535, 1032, 754 cm-1; 1H-NMR (CDjOD, 400MHz) δ 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, IK), 4.09 (m, IK), 4.25 (m, IK), 6.76-6.92 (m, 3H), 7.01 (m, IH), 7.18 (m, 2H ), 7.60 (m, 3H), 8.00 (d, J=8.3Hz, IK) ; MS (FAB) m/ z 591Qti+ K)* ;Anal. Calculated for C32H3gN<Oy3-OH G, 59.62; H, 6.88; N, 8.69. Found: C, 59.25; H, 6.29; N, 8.29.

EXAMPLE 188

4-[[2-[3-methoxy-4-[AT-(2-fluorophenyl)ureido]phenylacetyl]-Δ7-methylamino)ethoxy]benzoic acid

3-chloro-4- [ [2- [3-methoxy-4- [W-(2-fluorophenyl)ureido] phenylacetyl] -A7-methylaminoethoxy] benzoic acid To a stirred cold (0°C) solution of 2-(A7 -benzyloxy-carbonyl-N-methyl) ethanolamine (3.01 g, 14.4 mmol), methyl 3-chloro-4-hydroxybenzoate (2.68 g, 14.4 mmol, Ph3P (5.65 g, 21 .5 mmol) in THF (30 mL) was added diisopropylazodicarboxylate (DIAD) (4.25 mL, 21.6 mmol) and the resulting mixture was heated at reflux overnight. The solution was evaporated and the residue was purified by column chromatography on silica gel with CHCl3 as eluent to give 3.90 (72%) of methyl 3-chloro-4-[2-(AJ-benzyloxy-carbonyl-N-methylamino)ethoxy]benzoate as a pale yellow solid.'H-NMR ( CDClj) 5 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 (s, 2 H), 6.81-6 .94 (m, 1 H), 7.33-7.36 (m, 5 H), 7.85-7.92 (m, 1 H), 8.05 (bs, 1 H).

A solution of methyl 3-chloro-4-[2-(AJ-benzyloxycarbonyl-AJ-methylamino)ethoxy]benzoate (3.90 g, 10.3 mmol) in EtOAc-AcOH

(40 mL, 1:1, v/v) was hydrogenated over 5% Pd-C (1.95 g, 50 wt%) at 3 atmospheres for 2 h. The mixture was filtered and the filtrate was washed with sat. 2-(A7-methylamino)ethoxy]benzoate (1.61 g) as a pale yellow oil.

'H-NMR

(CDClj) to 2.52-2.52 and- 2.53-2.54 (each m, 3 H), 2.98-3.0Q 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, each 2 H), 6.91-6.96 and 7.90-8.05 (series of, nine, total 7 H).

A mixture of 3-methoxy-4-[N-(2-fluorophenyl)ureido]phenylacetic acid (392 mg), a mixture of methyl 3-chloro-4-[2-(AJ-methylamino)ethoxy]benzoate and methyl 4-[2-(AJ-methylamino)-ethoxy]benzoate (305 mg), EDC (hydrochloride) (354 mg), HOBt (250 mg), and DMAP (250 mg) in DMF (8 mL) were stirred at room temperature for 6 hours. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1% MeOH in CHCl 3 to give a mixture of methyl 3-chloro-4-[[2-[3-methoxy-4-[AJ'-(2-fluoro-phenyl) ureido]phenylacetyl]-N-methylaminoethoxy]benzoate and methyl 4-[ [2- [3-methoxy-4- [ N'-(2-fluorophenyl)ureido]phenylacetyl]-N-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- [AJ'-(2-fluorophenyl)ureido]-phenylacetyl]-AJ- methylaminoethoxy] benzoate and methyl 4-[[2-[3-methoxy-4- [AJ'-(2-fluorophenyl) ureido] phenylacetyl] -AJ-methyl-aminoethoxy] benzoate in THF-MeOH (20 mL, 1 :1 v/v) was added to 0.5 N NaOH (10 mL) and the resulting mixture was heated under reflux for 6 h. The mixture was poured into ice-1 N HCl, and the solid was collected. The crude solid was purified by preparative TLC with 10% MeOH in CHCl 3 as eluent to give 2 65 (56 mg, as a white amorphous solid) and 266 (88 mg, as a brown amorphous solid).

EXAMPLE 189

4-[[2-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetyl]-methylamino]ethoxy]benzoic acid

3-chloro-4- t [ 2~. [3-Methoxy-4- [AT'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoic acid

A mixture of methyl 4-[2-(AT-methyl-2-amino)ethoxy]-3-chloro-benzoate (292 mg, 1.2 mmol), 3-methoxy-4-[AT'-(2-methylf enyl)-ureido]phenylacetic acid (377 mg, 1.2 mmol), EDC (345 mg, 1.8 mmol), HOBt (243 mg, 1.8 mmol) and DMAP (29 mg, 0.24 mmol) in DMF (2.7 ml) was stirred for 6 hours at room temperature. The mixture was poured into ice-IN HCl and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel with CHCl3:EtOAc (95:5 to 0:100, v/v) as eluent to give an inseparable mixture (489 mg) of methyl 3-chloro-4-[[2-[3-methoxy -4 - [AT'-(2-methylphenyl)ureido]-phenylacetyl]methylamino]ethoxy]benzoate and methyl 4-[[2-[3-methoxy-4- [AT'-(2-methylphenyl)ureido]phenyl acetyl ]methylamino]-ethoxy]benzoate as pale yellow oil.

A mixture (480 mg as mixture) of methyl 3-chloro-4-[[2-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetyl]methylamino]-ethoxy]benzoate and methyl 4-[[2-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate in THF-MeOH (4 mL, 1:1, v/v) was stirred at 50°C for 15 hours. The mixture was poured into ice-1N HCl. The solid was collected, washed with water and air dried. The crude solid was purified by preparative TLC, CHCl3:MeOH (93:7, v/v) as eluent to give 267 (180 mg, 2 steps 31% as a crystalline material) and 268 (280 mg, 2 steps 44% as a crystalline material) . 267 : mp .145-150 °C; 'H-NMR (DMSO-d*. 400MHz)' 6 2..31 (s, 3H), 3.05 and. 3.19 (p, 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, 7H), 7.60 (m, IH), 7.86-8.09(m, 3H ); MS (FAB) Wz"493(M+H)+;^ nal. Calcd for Cj7HMN306-1.75H20, C, 62.00; H, 6.26; N, 8.03 Found: C, 62.16; H, 5.88; N, 7.82. - 268 Smp". 145-150 °C; 1H-NMR (DMSO-d* 400MHz) δ 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), 6.75-6.8's (rn, 2H), 6.99-7.20 (m, 4HK 7.59 (m, IH ), 7.90-8.02 (m, 3H); MS (FAB) m/ z 526(M+H)<+>;^na/Calculated for CjtHmCINjO^.OHA C, 57.70; H, 5.74; N, 7.48. Found :C, 57.99; H, 5.53; N, 7.07.

EXAMPLE 190

4-[3-[3-methoxy-4-[A7'~ (2-methylphenyl)ureido]phenylacetyl]-AJ-methylamino]-1-propyl]benzoic acid

To a stirred cold (minus 78°C) solution of triethyl 4-phosphohomethylbenzoate (1.22 g, 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 hour at the same temperature. A solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (700 mg, 3.38 mmol) in THF (5 mL) was slowly added to this solution at that temperature and the mixture was allowed to warm to room temperature over 2 hours of stirring. The solution was quenched by the addition of saturated NH 4 Cl (100 mL), and extracted with EtOAc. The extract was washed with brine (200 ml), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOAc (10:1, v/v) as eluent to give 810 mg (68%) of ethyl (£)-4-[3-(A7-benzyloxycarbonyl-AJ-methylamino)-1 -prbpenyl benzoate as a yellow oil e. 1H-NMR (CDCl1) 5 1.40 (t, J= 7.3 Hz, 3 H), 2.95 (m, 2 H), 4.09 (m, 2 H), 4.35-4.40 (m , 2 H), 5.17 (s, 2 H), 6.26-6.64 (series of m, 2 H), 7.36 (m, 7 H), 7.99 ((1.7= 8.3 Hz, 2 H).

A stirred solution of ethyl [E)-4-[3-(AJ-benzyloxycarbonyl-A7-methylamino)-1-propenylbenzoate (810 mg, 2.29 mmol) in EtOH-AcOH (10:1, v/v, 22 ml) was hydrogenated over 5% Pd-C (lg) for 3 days. The mixture was filtered and the filtrate was evaporated. The residue was basified with saturated NaHCO 3 and extracted with CHCl 3 . The extract was dried over Na 2 CO 3 and evaporated to give 438 mg (86%) of ethyl 4-(3-methylamino-1-propyl)benzoate as a yellow oil. , 'H-NMR (CDClj) 5 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, J-=8.3 Hz, 2 H).

To a stirred solution of 3-methoxy-4-[A7'-(2-methylphenyl)-ureido]phenylacetic acid (456 mg, 1.45 mmol) and ethyl 4-(3-methylamino-1-propyl)benzoate (22 0 mg, 1.45 mmol) was added EDC-HCl (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 MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOH (10:1) to give 503 mg (71%) of ethyl 4-[3-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl -A7-methylamino]-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-[AJ'-(2-methylphenyl)ureido]phenylacetyl-AJ-methylamino]-1-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 HCl (100 mL) and the solid was collected by suction. The solid was dissolved in CHCl 3 (100 mL) and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel with CHCl 3 -MeOH (10:1 to 5:1, v/v) to give 131 mg (28%) of 4-[3-[3-methoxy-4-[A7' -(2-methylphenyl)ureido]-phenylacetyl-Δ7-methylamino]-1-propyl]benzoic acid 269 as a pale yellow amorphous solid.

1H-NMR (DMSO-dt) δ 1.68-1.80 (m, 2H), 2.24 (s, 3H), 2.57

(m, 2 H), 2.81 and 2.97 (s, each, total 3 H), 3.33 (m, 2 H), 3.57-3.61 (m, 2 H), 3.84 (s, 3 H), 6.71 (dd, J= 29.8, 8.3 Hz, 1H), 6.87 (d,<T>J= 11.2 Hz, 1 H), 6.93 (t, J= 7.3 Hz, 1 H), 7.15 (m, 2 H),

7.28 (m, 2 H), 7.79 (d, J = 8.3 Hz, 1 H), 7.84T7.87 (m, 2 H), 8.02 (d, J = 8.3 Hz, 1 H); 8.49 (d, 7 = 7.3 Hz, 1 H), 8.58 (d, J = 4.9 Hz, 1 H); MS (FAB) m/z 490 (M*+1); >lna/. Calculated for C,H 3 1 N 3 O 3 -1/2H 2 O: C, 67.45; H, 6.47; N, 8.43. Found C, 67.27; H, 6.51; N, 8.02.

EXAMPLE 191

4- [ [2- [4- [A7'- (2-methylphenyl)ureido] phenylacetyl] - N-methylamino] ethoxy] benzoic acid

3-Chloro-4- [ [2- [4- [AJ'-(2-methylphenyl)ureido] phenylacetyl] -A7-methylamino] ethoxy] benzoic acid

A solution of pentafluorophenyl 4-[AT<->(2-methylphenyl)ureido]-phenylacetate (562 mg, 1.29 mmol), a mixture (304 mg) of methyl 3-chloro-4-[2 -(N- methylamino)ethoxy]benzoate and methyl 4-[2-(Δ7-methylamino)ethoxy]benzoate and Et 3 N (260 mL) in DMF (8 mL) were stirred at room temperature for 4 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give a mixture (670

mg) of methyl 3-chloro-4-[[2-[4-[AJ'-(2-methylphenyl)ureido)phenyl-. acetyl]-AJ-methylamino)ethoxy]benzoate and methyl 4-[ [2-[4-[ N'~

(2-methylphenyl) ureido] phenylacetyl] -A7-methylamino) ethoxy] benzoate

as a..oil e .

To a stirred suspension of this mixture (670 mg) in THF-

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 hours. The solution was poured into ice-cold N HCl and the solid was collected. The crude solid was purified by preparative thin layer chromatography (TLC) with 10% MeOH in CHCl 3

as eluent to give 73 mg of 270 as an amorphous solid and 110 mg of 271 as a white amorphous solid. 270

MS (FAB) m/z 462 (m++1). 271 MS (FAB) m/z 496 (M++1).

EXAMPLE 192

(5) -4- [2- [3-methoxy-4- [AT-(2-methylphenyl)ureido]phenyl-acetylamino]-1-propoxy]benzoic acid

To a cooled (0°C) solution of (S)-2-amino-1-propanol (2.08 g, 27.7 mmol) and Et3N (4.63 mL, 33.2 mmol) in DMF-H2O- (40 mL, 1:1, v/v) was added (Boc)20" (6.36 mL, 27.7 mmol), and the resulting solution was stirred at room temperature for 2 days. H 2 O was added to the mixture, and the mixture was extracted with EtOAc. The extract was washed with brine and dried over Na 2 SO 4 . The solvent was evaporated to give 4.24 g (87%) of (S)-2-(AJ-tert-butoxycarbonylamino)-1-propanol as a colorless oil.

1H-NMR (CDCl1) δ 1.14 (d, 3 H, .7=6.8 Hz), 1.45 (s, 9 H), 3.51-3.52 (m, 1 H), 3.63-3.66 (m, 1 H), 3.77 (m, 1H), 4.62 (fn, IH).

To a cooled (0°C) solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (1.02 g, 5.82 mmol), methyl 4-hydroxybenzoate (0.89 g, 5.85 mmol) and Ph3P (1.98 g, 7.55 mmol) in THF (20 mL) was added diisopropylazodicarboxylate (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 2 Cl 2 (20 mL) and TFA (10 mL). The mixture was stirred at room temperature for 1.5 hours. The solution was concentrated in vacuo and the residue was treated with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3:MeOH (50:1, v/v) to give 480 mg (2 steps 39%) of methyl (S)-4-(2-amino-1-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, J=8.8 Hz), 7.99 (d, 2 H, J=8.8 Hz).

A mixture of pentafluorophenyl 3-methoxy-4-[A7' (2-methylphenyl)-ureido]phenylacetate (505 mg, 1.05 mmol), methyl (S)-4-(2-amino-1-propoxy ) benzoate (220 mg, 1.05 mmol), and Et 3 N (0.220 mL, 1.58 mmol) in DMF (8 mL) were stirred at room temperature for 3 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine and dried over Na 2 SO 4 . After removal of the solvent, the residue was recrystallized from MeOH-CHCl3-n-hexane to give 290 mg (55%) of methyl (S)-4-[2-[3-methoxy-4-[A7'-(2-methylphenyl) ureido]phenylacetylamino]-1-propoxy]benzoate as a white crystalline powder.

1H-NMR (DMSO-d 6 ) 8 1.18 (d, 3 H, .7=6.8 Hz), 2.24 (s, 3 H), 3.36 (s, .2H), 3.80 (s, 3H), 3.82 (s, 3H), 3.93-4.03 (m, 2H), 4.09-4.14 (m, IH), 6.75-8.57 (.series of, m, total 13 H).

To a stirred solution of methyl (S)-4-[2-[3-methoxy-4-[A7'~

(2-Methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (290 mg, 0.57 mmol) in THF-MeOH (20 mL, 1:1, v/v) was added 0.5 N NaOH (20 ml) and the solution was heated

under reflux for 2 hours. The mixture was poured into ice-1 N HCl and extracted with CHCl 3 -1OH (10:1, v/v). The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from MeOH-CHCl3-n-hexane to give 158 mg (56%). 272 as a white crystalline powder. M.p.: 198-201°C. °C; 1H-NMR

PMSOcU 5 1.18 (d, 3 H, J=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, 1H), 6.75-6.78 (m, 1H), 6.92-7.02 (m, 4H), 7.11-7.18 (m, 2H)', 7.78-7.80 (m, 1H), 7.86- 7.89 (m, 2 H), 7.98-8.00 (m, 1 H), 8.12-8.14 (rn, 1 H), 8.46 (s, 1 H), 8.55 (s, 1 H),

12.62 (bs, 1H); MS (FAB) m/z 492 (M^+^M/ja/.Calculated for CH^NjO^l^HjO: C, 64.79; H,

6.04; N, 8.21. Found: C, 64.36; H, 5.85; N, 8.21.

EXAMPLE 193

(S) -4- [2- [4- [W-(2-methylphenyl)ureido]phenylacetylamino)-1-propoxy]benzoic acid

A mixture of pentafluorophenyl 4-[A7(2-methylphenyl)ureido]-phenylacetate (560 mg, 1.24 mmol), methyl (S)-4-(2-amino-1-propoxy)benzoate (260 mg , 1.24 mmol), Et 3 N (0.260 mL, 1.87 mmol) in DMF (8 mL) was stirred at room temperature for 3 h. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, brine and dried over Na 2 SO 4 . After

removal of the solvent, the residue was purified by recrystallization from MeOH-CHCl3-n-hexane to give 210 mg'

(36%) (S)-4-[2-[3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenyl-acetylamino]-1-propoxy]benzoic acid as a white crystalline powder. 1H-NMR pMSO-d4)5 1.17(d,3H,J=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 (m, 4 H), 7.35-7.39 (m, 2 H), 7.83-7.85 (m, 1 H), 7.89-7.92 (m, 3 H), 8.12-8.14 (m, 1 H), 8.97 (s, 1 H)...

To a stirred solution of methyl (S)-4-[2-[4-[A7'-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (200 mg, 0.42 mmol) in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the mixture was heated under reflux for 2 h. The mixture was poured into ice-1 N HCl, and. the solid became Sami. The crude solid was recrystallized from MeOH-CHCl 3 -n-hexane to give 68 mg (34%) of 273 as a white crystalline powder. M.p.: 262-265°C. 1H-NMR (DMSO-dJ 6 1.17 (d, 3 H, .7=6.8 Hz), 2.24 (s, 3 H), 3.32 (s, H), 3.91-4.02 (m, 2 H), 4.09- 4.15

(m, 1 H), 6.92-6.96 (m, 1H), 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 (M<*>+1); v4na/.

• Calculated for CJ6H„N3Os- 1/4H,0: C, 67.01; H, 5.95; N, 9.02. Found: C, 67.13; H, 5.90; N, 9.02. EXAMPLE 194 ( S )-3-chloro-4-[2- [4- [AT"-(2-methylphenyl)ureido]phenyl-acetylamino]'-1-propoxy]benzoic acid

To a cooled (0°C) solution of (S)-2-(A7-tert-butoxycarbonylamino)-1-propanol.(1.05 g, 5.99 mmol), methyl 3-chloro-4-hydroxybenzoate (1.12 g, 6.00 mmol) and Ph3P (2.36 g, 9.00 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DI7AD) (1.77 mL, 8.99 mmol) bg the resulting mixture was heated under reflux for 2 days. The solution was evaporated and the residue was dissolved in CH 2 Cl 2 (20 mL) and TFA (10 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The solution was concentrated in vacuo and the residue was dissolved in CHCl 3 . The mixture was extracted with H 2 O and the aqueous layer was made basic by addition of saturated NaHCO 3 . The basic aq. layer was extracted with CHCl 3 , the extract was washed with brine, dried over Na 2 SO 4 , and evaporated to

to give 660 mg (2 steps, 32%) of methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate as a colorless oil.

1 H-NMR (CDCl 1 ) 8 1.21 (d, 3 H,J=6.4

Hz), 3.41-3.48 (m, 1 H), 3.77-3.8l (m,. 1 H),3.89 (s, 3 H), 3.98-4.01 (m, I H), 6.9.1-6.94 (m, 1H); 7.90-7.93 (m, 1 H), 8.05-8.06 (m, 1 H).

A mixture of pentafluorophenyl 4-[A7'-(2-methyl phenyl) ureido]-phenylacetate (508 mg, 1.13 mmol), methyl (S)-3-chloro-4-(2-amino-1 -propoxy)benzoate (275 mg, 1.13 mmol) and Et 3 N (0.240 mL, 1.72 mmol) in DMF (10 mL) were stirred at room temperature overnight. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from MeOH-CHCl3-n-hexane to give 240 mg (42%) of methyl (S)-3-klbr-4-[2- [4- [A7'-(2-methylphenyl)ureido]f enylacetylamino]-1-propoxy]benzoate as a white crystalline powder.

1H-NMR (DMSO-dJ 8 1.21 (d, 3 H, .7=6.4 Hz), 2.25 (s, 3 H), 3.33 (s, 2 H), 3.82 (s, 3H), 4.04-4.14 ( rn, 3H), 6.90-6.94 (m, 1H), 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 (MT).

To a stirred solution, of methyl CS)-3-chloro-4-[2-[4-[ N'~ (2-methylferriyl)ureido]phenylacetylamino]-1-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 overnight. The mixture was poured into ice-1N HCl and the solid was collected. The crude product was recrystallized from MeOH-CHCl3-n-hexane to give 98 mg (42%) •■ 274 as a white crystalline powder. M.p.: 228-231°C.

1H-NMR (DMSO-d<) 8 1.20 (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 m, total 5 H), 9.12 (s, 1 H); MS (FAB) m/z 496 (M<*>), 497 (M<*>+1); >Ina/<Calculated for CjfHjsClNjOj-1/2H70: 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.

EXAMPLE 1§5

( S )-3-Chloro-4- [2- [3-methoxy-4- [AT-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoic acid

A mixture of pentafluorophenyl 3-methoxy-4-[ N '-(2-methyl-

10phenyl)ureido]phenylacetate (513 mg, 1.07 mmol), methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (260 mg, 1.07 mmol) and Et3N (220 µL, 1.58 mmol) in DMF (10 mL) bee stirred at room temperature overnight. The mixture was diluted with EtOAc and the solution was washed with saturated NaHCO 3 , dried over Na2S04 and evapd. The residue was recrystallized. from MeOH-CHCl3-EtpAc-n-nexane to give 400 mg (69%) methyl (S)-3-' chloro-4- [2- [3-methoxy-4- [AJ'-(2-methylphenyl) ureido]phenyl-acetylamino]-1-propoxy]benzoate as a pale brown crystalline powder. 'H-:NMR(DMSO-djol.21 (d,3H,J=6.4 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), 7.11-7.17 (m, 2 H), 7.29-7.31 (m, 1 H), 7.7.8-7.99 (m, 4 H), 8.12-8.13 (nine ; 1 H), 8.46 (p, 1 H), 8.55 (p, 1 H).

To a stirred solution of methyl (S)-[3-chloro-4-[2-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]-benzoate (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-1N HCl and the solid was collected. The crude solid was recrystallized from MeOH-CHCl 3 -Et 2 O to give 200 mg (51%) of 275 as a pale brown crystalline powder. M.p.: 198-20<1>°C.

1H-NMR (DMSO-dfi) δ 1.21 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3.84 (s, 3 H), 4.00-4.15 (rn, 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) m/z 526 (M<+>), 528 (M<+>+2); Anal..Calcd for C„H2!ClN3Cl/4H2O: C, 61.13; H, 5.42; C1, 6.68; N, 7.92. Found: C, 60.97; H.5.48; Cl. 6.86; N, 7.89.

EXAMPLE 196

3-dimethylamino-4- [ [2- [3-methoxy-4- [AJ'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy] benzoic acid

To a stirred and cooled (0°C) solution of 2-(AZ-Boc-AJ-methylamino)ethanol (3 g, 17 mmol) methyl 4-hydroxy-3-nitro benzoate (3.38 g, 17 mmol) and To Ph 3 P (5.4 g, 21 mmol) in THF (20 mL) was added diisopropylazodicarboxylate (DIAD) (4 mL, 21 mmol) and the resulting mixture was heated under reflux for 15 h. The solution was evaporated. The residue was chromatographed on silica gel with CHCl3:MeOH (100:0 to 4:1, v/v) as eluent to give 2.5 g (39%) methyl 4-[2-(AJ-methyl-2-amino) ethoxy]-3-nitrobenzoate as a pale yellow oil..'H-NMR(CDC13 > 400MHz) δ 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, IH, J=8.8Hz), 8.25 (d, IH, J=8.8Hz), 8.56 (s, IH); MS (FAB) m/z 255 (M₂+1).

A mixture of 3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetic acid (992 mg-, 3.11 mmol), methyl 4-(AJ-methyl-2-aminoethoxy)-3-nitrobenzoate ( 800 mg, 3.11 mmol) and 4-DMAP (77 mg, 0.63 mmol), HOBt (640 mg, 4.1 mmol) and EDC (904 mg, 4.7 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 :EtOAc (95:5 to 0:100 v/v) as eluent to give 587 mg (34%) of methyl 3-nitro-4-[ [2-[3-methoxy-4- [AJ'-(2-methylphenyl) ureido] phenylacetyl] methylamino] ethoxy] benzoate as a yellow oil.

1H-NMR (CDC13, 400MHz) δ 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, IH), 7.22 (m, 3H), 7.62 (d, IH, J=8.2Hz ), 8.02 (d, IH, J=8.2Hz), 8.21 (dd, IH, J=2.1Hz, 8.8Hz, 8.55 (d, IH, J=2.1Hz); MS (FAB) m/z 551( M*+1).

A mixture of methyl 3-nitro-4-[[2-[3-methoxy-4-[AT<->(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate (587 mg, 1.1 mmol) and 5%-Pd-C (600 mg) in THF-MeOH-AcOH (1:1:1, v/v, 150 mL) was hydrogenated at 45 psi for 18 h. Insoluble catalyst was removed by suction and the filtrate was evaporated in vacuo to give 555 mg (100%) of methyl 3-amino-4- [ [2- [3-methoxy-4- [ N'~ (2-methylphenyl)ureido ] phenylacetyl] - methylamino] ethoxy] benzoate as a pale yellow gum.

'H-NMR (CDCl1, 400MHz) δ 2.29 (s, 3H), 3.08 (m, 1H), 3.19 (s, 2H), 3.65 (s,'

IH), 3.73-3.80 (m, 3H), 3.84 (s, 3H), 3.87(s, 3H), 4.19 and 4.40 (m, total 2H), 6.70-6.82 (m, 2H), 7.02-7.29 (m , 6H), 7.60 (d, 1H, J=7.8Hz), 7.92-7.99 (m, 3H); MS (FAB) m/z 521 (M<*>+1).

To a stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]-benzoate (555 mg, 1.1 mmol), formaldehyde (10 mL), and AcOH (0.58 mL, 10 mmol) in MeCN (10 mL) was added NaBH3CN (0.67 g, 10 mmol) at room temperature, and the resulting mixture was stirred in 15 hours at the same temperature. Saturated NaHCO 3 was added to the mixture and the mixture was extracted with CHCl 3 . The extract was washed with saline, dried over MgSO 4 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 123 mg (21%) of methyl 3-dimethylamino-4- [ [2- [3-methoxy- 4 - [A7'-(2-methylphenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoate as an oil.

1H-NMR (CDCl1, 400MHz) δ 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, IH), 3.80 (m, 3H), 3.86 (s, 3H), 4.07 and 4.22 (m, total 2H), 6.28 (m, IH), 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).

r

A stirred mixture of methyl 3-dimethylamino-4-[[2-[3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]-benzoate (123 mg, 0.22 mmol) in THF (15 mL) and 1N NaOH (0.885 mL, 0.885 mmol) was heated under reflux for 15 h. The pH of the mixture was adjusted to 5.0 by addition of 1N HCl, and the mixture was extracted with CHCl 3 -MeOH (9:1, v/v). The extract was washed with brine, dried over lY[gSO 4 and evaporated in vacuo. The residue was crystallized with Et 2 O-n-hexane to give 118 mg (100%) of 2.76 as a white crystalline material, m.p. : I25-130°C. IR (KBr) 3346, 2940, 1620, 1597, 1535, 1456, 1417, 1227, 1039, 754cm:'; 1H-NMR (CD3OD, 400MHz) δ 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)r7.18 (m, 2H), 7.55-7.70 (m, 3H), 7.98 (m, IH) ; MS'(FAB) m/z 5350VT+1); y4no/,Calculated'forC2!>H3<N4O6-2.0H1O-. C, 61.04; H, 6.71; N, 9.82. Found: C, 61.15; H, 6.43; N, 8.94.

EXAMPLE 197

3-dimethylamino-4-[[2-[3-methoxy-4-[A7'~ (2-fluorophenyl)ureido]-phenylacetyl]methylamino]ethoxy]benzoic acid

A mixture of 3-methoxy-4-[ N'~ (2-fluorophenyl)ureido]-phenylacetic acid (1 g, 3.11 mmol), methyl 4-[2-(Δ7-methyl-2-amino)ethoxy] -3-nitrobenzoate (800 mg, 3.11 mmol) and 4-DMAP

(77 mg, 0.63 mmol), HOBt (640 mg, 4.7 mmol), and EDC (904 mg, 4.7 mmol) in DMF (20 mL) were stirred at room temperature overnight. The mixture was diluted with EtOAc and the solution was washed with 0.5N HCl, saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 13 -EtOAc (95:5 to 0:100, v/v) as eluent to give 420 mg. (19%) methyl 3-nitro-4-"[ [2-[3-fluoro-4- [AT-(2-fluorophenyl)ureido]phenylacetyl]methylamino]-ethoxy]benzoate as a pale yellow oil.

1H-NMR (CDCl1, 400MHz) δ 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, IH), 7.05 (m, 2H), 7.22 (d, IH, J=8.8Hz), 7.51 (s, 2H) , 8.00 (m, IH), 8.08 (m, IH), 8.21 (d, IH, J=8.6Hz), 8.51 (s, IH); MS (FAB) m/z 555 (M<+> + 1).

A mixture of methyl 3-nitro-4-[[2-[3-methoxy-4-[W-(2-fluorophenyl)ureido]phenylacetyl] methylamino]ethoxy]benzoate (420 mg, 0.76 mmol) and 5% -Pd-C (1 g) in THF-MeOH-AcOH (1:1:1, v/v/v, 150 mL) was hydrogenated at 45 psi for 18 h. Insoluble catalyst was removed by suction and the filtrate was evaporated in vacuo to give 397 mg (100%) of methyl 3-amino-4-[[2-[3-methoxy-4-[A7'-(2-fluorophenyl ) ureido] phenylacetyl] methylamino] ethoxy] benzoate as a pale yellow gum.

1H-NMRv (CDCl1, 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 (rn, 2H), 6.70-6.83 (m, 3H), 6.98-7.15 (m, 6H), 7.25-7.43 (m, 2H), 7.99 (m, IH), 8.13 (m, IH) ; MS (FAB) m/z 525 (M<*>+1).

To a stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[AJ'-(2-fluorophenyl)ureido]phenylacetyl]methylamino]-ethoxy]benzoate (397 mg, 0, 76 mmol), formaldehyde (10 mL) and AcOH (0.43 mL, 7.6 mmol) in MeCN (10 mL) was added NaBH3CN (0.48 g, 7.6 mmol) at room temperature, and the resulting mixt. was stirred for 15 hours at the same temperature. Saturated NaHCO 3 was added to the mixture and the mixture was extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 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 123 mg (21%) of methyl 3-dimethylamino-4- [ [2- [3-methoxy-4 - [AJ'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate as an oil. 1H-NMR (CDCl1, 400MHz) δ 2.74 (s, 3H), 2.77 (s, 3H), 3.08 (s„ IH), 3.22 (s, 2H), 3.52 (s, 3H), 3.61 (s, IH ), 3.83 : •(m, 3H), 3.88 (s, 3H), 4.12 and 4.23 (m, total 2H), 6.68 (s, IH), 6.78 (m, 2H), 6.98 (m, 2H), 7.10

(m, IH), 7.55-7.68 (m, 4H), 7.99 (m, IH), 8.16 (t, IH, J=8.3Hz); MS (FAB) m/z 553 (M<*>+1).

A stirred mixture of methyl 3-dimethylamino-4[[2-[3-methoxy-4-[AJ'~ (2-fluorophenyl)ureido]phenylacetyl]methylamino]ethoxy]-benzoate (61 mg, 0.11 mmol) in THF (15 mL) and 1N NaOH (0.22 mL, 0.22 mmol) was heated under reflux for 15 h. The pH of the mixture was adjusted to 5.0 by addition of 1N HCl, and the mixture was extracted with CHCl 3 :NeOH (9:1, v/v). The extract was washed with saline. MeOH:acetone (93:7, v/v) was used as eluent to give 37 mg

(63%) 277 as a white crystalline material. Melting point: 120-125°C.

1H-NMR (CDjOD, 400MHz) 8 2.60 (s, 4H), 2.78 (s, 2H), 3.06 (s, IK), 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), 7.61-7.70 (m, 2H), 8.00 (m, IK), 8.08 (m, IH); MS (FAB) 539 (M<+>+1); yl/ia/. Calculated for CjjHj.FNA^SHA C, 57.18; H, 6.26; N, 9.53. Found: C, 57.20; H, 5.62; N, 9.06.

EXAMPLE 198

3-dimethylamino-4-[[2-[4- [ N'~ (2-methylphenyl)ureido]phenylacetyl] met<y>l<a>mino] ethoxy]benzoic acid

A mixture of pentafluorophenyl [4-[A7'-(2-methylphenyl)ureido]-phenyl]acetate (1.42 g, 3.15 mmol), methyl 4-[2-(A7-meth<y >1-amino)ethoxy]-3-nitrobenzoate (800 mg, 3.15 mmol) and triethylamine (0.66 mL, 4.73 mmol) in DMF (8 mL) was stirred at 50°C for 15 h . The mixture was poured into ice-IN HCl and extracted with CH 2 Cl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 :EtOAc (95:5 to 0:100, v/v) as eluent 1.04 g (63%) methyl 3-nitro-4-[[2-[4-[ N'- (2-Methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate as a pale yellow oil.

1H-NMR (CDC13, 400MHz) δ 2.30 (s, 3H), 2.90, 3.02 and 3.05 (s, total IH), 3.22 (s, 2H), 3.71 (s, IH), 3.85 ( 3H), 3.93 ( p,3H), 4.19 and 4.39. (m, 2H), 7.02 (m, IH), 7.19 (m, 4H), 7.35 (d, IH, J=8.3Hz), 7.40 (d, IH, >8.0Hz), 7.55 (s, 2H), 7.70 (m, IH), 8.22 (d, IH, J=6.7Hz), 8..5l'(s, IH); MS (FAB) m/z 521(M*+1),

A mixture of methyl 3-nitro-4-[ [2- [4- [A7'-(2-methylphenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoate (1.04 g, 2 mmol) and 5%- Pd-C (1.2.g) in THF-MeOH-AcOH (1:1:1, v/v, 150 mL) was hydrogenated at 45 psi for 18 h. Insoluble catalyst was removed by suction and the filtrate was evaporated in vacuo to give methyl 3-amino-4-[[2-[4-[AT'-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate as a pale yellow rubber.

To a stirred solution of 3-amino-4-[[2-[4-[W-(2-methylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate, formaldehyde (5 mL), and AcOH (1.14 mL, 20 mmol) in MeCN (5 mL) was added NaBH 3 CN (1.26 g, 20 mmol) at room temperature and the resulting mixture was stirred for 15 h at the same temperature. Saturated NaHCO 3 was added to the mixture and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 . 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 85 mg (2 steps, 8%) methyl 3-dimethylamino-4-[ [2-[4- [A7'-(2-methylphenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoate as an oil.

1H-NMR (CDCl1, 400MHz) 8 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<+>+1).

To a stirred mixture of methyl 3-dimethylamino-4-[[2-[4-[W (2-methylphenyl)ureido] phenylacetyl]methylamino]ethoxy]benzoate-(ap315201) (85 mg, 0.16 mmol) in THF (15 mL) and 1N NaOH (0.32 mL, 0.32 mmol) were heated under reflux for 15 h. The pH of the mixture was adjusted to 5.0 by addition of 1N HCl, and the mixture was extracted with CHCl 3 :MeOH (9:1, v/v). The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was crystallized from Et 2 O to give 53 mg (65%) of 278 as a white crystalline material. M.p.: 110-115°C. 1H-NMR (CDjOD, 400MHz) δ 2.29 (s, 3H), 2.75 (s, 3H), 2.76 (s, 3H), 3.02 (s, IH), 3.20 (s, 2H), 3.72 (s, IH ), 3.85 (m, 3H), 4.18 and 4.28 (m, total 2H), 6.95-7.03 (m, 2H), 7.18 (m, 4H), 7.34 (d, IH, J=8.3Hz), 7.38 (d , IH; >8.8Hz), 7.62 (d, IH, J=8.3Hz), 7.66 (s, IH), 7.80 (m, IH); MS (FAB)

m/ z 505 (MT+1).

EXAMPLE 199

3-isopropylamino-4-[[2-[3-methoxy-4-[AT<->(2-fluorophenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoic acid

To a stirred cold (0°C) solution of methyl 3-amino-4-[[2-[3-methoxy-4-[AT' (2-fluorophenyl) ureido] phenylacetyl] methylamino] ethoxy] benzoate (100 mg, 0.19 mmol) in acetone/AcOH/DMF (13 mL, 6:6:1, v/v/v) was added NaBH 3 CN (3 0 0 mg) and the resulting mixture was stirred for 60 h at room temperature. The mixture was poured into saturated NaHCO 3 and the solid was collected by suction. The precipitate was dissolved in CHCl 3 (20 mL), and the solution was washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The residue was chromatographed on a silica gel plate with toluene:acetone (2:1, v/v) as eluent to give 108 mg (100%) of methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[AT' - (2-fluorophenyl) ureido] phenylacetyl] methylamino] ethoxy] - benzoate as a colorless oil. 1H-NMR (CDCl1, 400MHz) 8 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 (rn,' 2H), 8.02 (s, 2H ), 8.10 (m, 2H), 8.21 (br, 1H), 8.33 (br, 1H); MS (FAB) m/z 566 (MT+1).

A stirred mixture of methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[AT'-(2-fluorophenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate (116 mg, 0.2 mmol), 0.25 N NaOH (6 mL) and THF (6 mL) were heated under reflux for 8 h. The mixture was poured into water (200 ml), acidified with 1 N HCl and the solid was collected by suction. The solid was recrystallized from CHCl 3 -n-hexane-diisopropyl ether to give 5 6 mg (50%) 2 7-9 as -et ; colorless crystalline powder. Melting point: -' 195-200 °C; 1H-NMR (CDjOD, 400MHz) δ 1.15-1.20 (m, 6H), 3.01 (s, IK), 3.12 (s, 2H), 3.48-3.60 (m, IK), 3.68 (s, 3H), 3.75 (s, 2H), 3.82 (s, IH), 3.86 (m, 3H), 4.15-4.23 (m, 2H), 6.80 (m,

3H), 4.15-4.23 (m, 2H), 6.80 (m, 3H), 6.98 (rff, IH), 7.10 (in, 2H), 7.20 and 7.25 (s, total IK), 7.32 (m, IH), 7.98 (m, IH), 8.05 (m, IK) ; MS (FAB) m/z 552 (M+H)<+>; <y>lna/.Calculated for - C2SHj3FN4O6-10H2O: C, 61.04; H, 6.18; N, 9.82. Found: C, 61.36; H, 6.25; N, 9.45.

EXAMPLE 200 4-[[1-[4-[AT'-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-methylamino]-2-methyl-2-propoxy]benzoic acid

To a stirred solution of 2-amino-2-methyl-1-propanol

(8.4 g, 93.89 mmol) and triethylamine (11.4 g, 0.113 mol) in DMF-water (1:1, v/v, 100 mL) was added di-tert-butyl dicarbonate (25 g, 0.115 mol) at 5 to 10°C. The resulting solution was stirred for 2 hours at room temperature. The mixture was diluted with water (100 mL) and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CH 2 Cl 2 as eluent to give 12 g (68%) of 2-tert-butoxycarbonylamino-2-methyl-1-propanol as a syrup.

1H-NMR (CDCl 1 ) δ 1.25 (s, 6H), 1.43 (s, 9H), 3.59 (d, J=8.3Hz, 2H), 4.68 (br, 1H).

To a stirred suspension of 2-tert-butoxycarbonylamino-2-methyl-1-propanol (5.7 g, 3 0.11 mmol) and powdered NaOH

(6.7 g, 0.151 mol) in Et 2 O (200 mL) was added p-toluenesulfonyl chloride (6.9 g, 36.14 mmol) at room temperature. The stirred resulting solution was heated under reflux for 8 hours. After cooling, ice water (100 ml) was added to the solution. Separated Et 2 O layer was washed with brine, dried over Na 2 SO 4 and evaporated. To the residue was added n-hexane and the mixture was triturated. The solid was collected to give 8.5 g (82.2%) of 2-tert-butoxy-carbonylamino-2-methyl-1-propyl-p-toluenesulfonate as a crystalline material. 1H-NMR (CDCl 3 ) δ 1.26 (s, 6H), 1.38 (s, 9H), 2.37 (s, 3H), 4.05 (s, 2H), 4.49 (br, 1H), 7.34 (d,7=7.8 Hz, 2H), 7.78 (d, J=7.8Hz, 2H).

A stirred mixture of 2-tert-butoxycarbonylamino-2-methyl-1-propyl-p-toluenesulfonate (8.2 g, 23.88 mmol) and powdered NaOH (6.7 g, 0.151 mol) in Et 2 O (2 00 mL ) was heated under reflux for 10 h. After cooling, the mixture was filtered. The filtrate was washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane:EtOAc (6:1, v/v) as eluent to give 2.7 g (66.2%) of 1-tert-butoxycarbonyl-2-methylpropylenemh as an oil.

1 H-NMR (CDCl 1 ) δ 1.29 (s, 6H), 1.47 (s, 9H), 2.05 (s, 2H).

To a stirred solution of 1-tert-butoxycarbonyl-2-methyl-propyleneimine (1.03 g, 6.01 mmol) and methyl 4-hydroxybenzoate■

(800 mg, 6.26 mmol) in CH 2 Cl 2 (10 mL) was added boron trifluoride diethyl ether (0.127 mL, 1 mmol) at ambient temperature. The resulting solution was stirred for an additional 3 h at the same temperature. The mixture was washed with

water, brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with n-hexane:EtOAc (6:1, v/v) as eluent to give 550 mg (33%) of methyl 4-(1-tert-butoxycarbonylamino-2-methyl-2-propoxy)benzoate like a rubber. 1H-NMR (CDCl1) 6 1.33 (s, 6H), 1.47 (s, 9H), 3.36 (d, J=6.3Hz, 2H), 3.90 (s, 3H), 5.05

(br, IH), 6.99 (d, J=8.8Hz, 2H), 7.97 (d, J=8.8Hz, 2H).

A mixture of methyl 4-(1-tert-butoxycarbonylamino-2-methyl-2-propoxy)benzoate (460 mg, 1.42 mmol) and anisole (0.155 mL, 1.42 mmol) in CH 2 Cl 2 (15 mL) and TFA (3 ml) became. stirred for 3 hours at room temperature. The mixture was evaporated. The residue was dissolved in CH 2 Cl 2 (30 mL) and made basic by the addition of 0.5 N NaOH. The CH 2 Cl 2 layer was separated, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CH 2 Cl 2 as eluent to give 370 mg (100%) of methyl 4-(1-amino-2-methyl-2-propoxy)benzoate as a gum. <l>H-NMR (CDClj) § 1.34 (s, 6H), 2.87 (s, 2H), 3.90 (s, 3H), 7.10 (d, y=8.8Hz, 2H), 7.97 (d, J=8.8 Hz, IK).

To a stirred solution of methyl 4-(1-amino-2-methyl-2-propoxy)benzoate (3 70 mg, 1.66 mmol) and triethylamine (0.35 mL, 2.49 mmol) in CH 2 Cl 2 (15 mL ) was added trifluoroacetic anhydride (0.316 mL, 2.24 mmol) at 0°C. - After stirring for 1 hour at the same temperature, water was added to the solution. The CH 2 Cl 2 layer was separated, washed with water, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (20 mL) with CH 2 Cl 2 as eluent to give 530 mg (100%) of methyl 4-(1-trifluoroacetamido-2-methyl-2-propoxy)benzoate as a gum. This compound was used in the subsequent reaction without further purification.

To a stirred mixture of methyl 4-(1-trifluoroacetamido-2-methyl-2-propoxy)benzoate (530 mg, 1.66 mmol) and K 2 CO 3 (34 5 mg, 2.49 mmol) in DMF (10 mL) was added Mel (0.14 ml,

2.37 mmol) at room temperature. The resulting mixture was stirred for 18 hours at room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The remaining gum was used in the subsequent reaction without further purification.

The above crude residue was dissolved in MeOH (10 mL). To the stirred solution was added water (5 mL) and Na 2 CO 3

(352 mg, 3.32 mmol) and the resulting mixture was stirred for 5 h at room temperature. The mixture was poured into water and extracted with CHCl 3 . The extract was washed with water, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 as eluent to give 390 mg (100%) of methyl 4-(1-methylamino-2-methyl-2-propoxy)benzoate as a gum. 1H-NMR (CDCl1) δ 1.37 (s, 6H), 2.51 (s, 3H), 3.89 (s, 3H), 6.92 (d, 7=8.8Hz, 2H), 7.97 (d, J=8.8Hz, 2H).

To a stirred mixture of methyl 4-(1-methylamino-2-methyl-2-propoxy)benzoate (200 mg, 0.84 mmol), 4-[ N'~ (2-fluorophenyl)-. ureido]-3-methoxyphenylacetic acid (268 mg, 0.84 mmol) and 4-DMAP (125 mg, 1.0 mmol) in DMF (5 mL) were added. EDC (220 mg, 1.14 mmol) at ambient temperature. The resulting mixture was stirred for an additional 10 hours at ambient temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The remaining gum was triturated with CH 2 Cl 2 and Et 2 O to give 200 mg (44.1%) of methyl 4-[ [1- [4-[A7r-(2-fluorophenyl) ureido]-3-methoxy enylacetyl] methylamino] -2-methyl-2-propoxy]benzoate as a crystalline material.

1H-NMR (CDCl1) δ 1.36 and 1.3i.{nver s, 6H), 3.24-3.88 (series of ;s, 13 H), 6.65-8.20 (series of m, 14H).

A mixture methyl 4-[ [1- [4-[ N'~(2-fluorophenyl) ureido]-3-methoxyphenylacetyl] methylamino] -2-methyl-2-propoxy] benzoate (180 mg, 0.335 mmol) in. THF (3 mL) and 0.25 N NaOH (4 mL) were stirred for 5 h at room temperature. The mixture was poured into ice-1N HCl (5 mL). The solid was collected, washed with water ' and air dried. The crude solid was recrystallized from EtOH-CHClj-n-hexane to give 70 mg (40%) of 280 as fine needles. Smp. : 200-207 °C; 'H-NMR

(DMSO-4;) 6 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 of m, 10H), 8.71 (s , lH).,9:i7 (br p, IH), 12.72 (p, IH).

EXAMPLE 201

(S)-3-chloro-4-[2-[3-methoxy-4-[AJ'-(2-fluorophenyl)ureido]-phenylacetylamino]-1-propoxy]benzoic acid

A mixture of 3-methoxy-4-[AJ'-(2-fluorophenyl)ureido]-phenylacetic acid (327 mg, 1.03 mmol), methyl (S)-3-chloro-4-(2-amino-1 -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 temperature overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from CHCl 3 -EtOAc to give 308 mg

(55%) as a white crystalline powder. 1 H-NMR (CDCl 3 ) 5 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, 1H, 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 , 1 H, J=2.0, 8.8 Hz), 8.02 (d, 1 H, .7=2.4 Hz), 8.20 (d, 1 H, 7=8.3 Hz), 8.27-8.31 (m, 1H), 8.53 ( p, 1H), 8.84 (p, 1H).

To a stirred solution of methyl (S)-3-chloro-4-[2-[3-methoxy-4-[AT'-(2-fluorophenyl)ureido]phenylacetylamino]-1-propoxy]-

benzoate (308 mg, 0.57 mmol) in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH-(10 mL), and

the reaction mixture was heated under reflux for 1 hour. The mixture was poured into ice-1N HCl and the solid was collected. The crude solid was purified by recrystallization from MeOH-CHCl 3 -n-hexane to give 196 mg (65%) of 2 81 as a white crystalline powder. M.p.: 188-191 °C; .'H-NMR (DMSO-d*) 8 1.21 (d, 3 H, 7=6.4 Hz), 3.38 (s, 2 H), 3.83 (s, 3 R), 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, 1H); MS (FAB) m/z 530 (M<*>), 531 (MN-1), 532 (M+2); Anal. Calculated for C^ClFNjO^1MHjO: C, 58.43; H, 4.81; Cl, 6.63; F, 3.55; N, 7.86. FoundC, 58.45; H, 4.83; Cl, 6.68; F, 3.38; N, 7.79. EXAMPLE 202 4-[[2- [3-methoxy-4- [ N'~(2-methylphenyl)ureido]phenylacetyl]- methylamino] ethylamino] benzoic acid

To a stirred solution of A7-benzyloxycarbonyl-A7-methylaminoacetaldehyde (1.77 g, 1.1 mmol) in toluene (3 mL) was added methyl 4-aminobenzoate (1.29 g, 8.5 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in MeCN

.(15 ml). To the solution was added AcOH (2.44 mL,

43 mmol) and NaBH 3 CN (2.67 g, 43 mmol), and the resulting

the mixture was stirred for 15 hours at room temperature. The reaction mixture was quenched by addition of saturated NaHCO 3 . The mixture was extracted with EtOAc, washed with

brine, dried over MgSO 4 and evaporated. The rest stayed

chromatographed on silica gel with n-hexane:EtOAc (7:3, v/v) as eluent to give 1.26 g (43%) methyl

4-[2-(A7-benzyloxycarbonyl-A7-methylamino)-ethylamino]benzoate as a colorless oil. 'H-NMR (CDClj, 400MHz) S 2.96 (s, 3H), 3.32 (br m, 2H), 3.50-3.60 (m, 2H), 3.82 (s, 3H), 5.15 (each d, 2H, 7= 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/z 342 (M<*>+1).

To a stirred solution of methyl 4-[2-(A7-benzyloxycarbonyl-N-methylamino)ethylamino]benzoate (1.26 g, 3.68 mmol) in MeOH (20 mL) was added 5 wt% Pd-C ( 700 mg), and the mixture was hydrogenated (3 atm) for 4 hours at room temperature. The mixture was filtered and the filtrate was evaporated under reduced pressure to give 600 mg (78%) of methyl 4-[2-(A7-methylamino)ethylamino]-benzoate as a colorless oil.

1H-NMR (CDCl1, 400MHz) δ 2.46 (s, 3H), 2.88 (t, 2H, J=5.5Hz), 3.27 (br s, 2H), 3.85 (s, 3H), 6.57 (d, 2H, >8.8Hz), 7.85 (d, 2H, <y>=8.8Hz); MS (FAB) m/z 209 (M<+>+1);

To a stirred solution of methyl 4-[2-(N-methylamino)ethylamino] benzoate (590 mg, 2.83 mmol) and 3-methoxy-4-[ N'~ (2-methylphenyl)ureido] phenylacetic acid (891 mg , 2.83 mmol) in DMF

(14 mL) was added EDC (815 mg, 4.25 mmol), HOBt (574 mg, 4.25 mmol) and 4-DMAP (519 mg, 4.25 mmol) and the resulting mixture was stirred overnight at room temperature. The mixture was poured into 1 N HCl and the solid was collected by suction. The crude solid was purified by chromatography on silica gel (medium pressure) with CHCl 3 -EtOAc (10:0 to 7:3, v/v) as eluent to give 1.25 g (87%) of methyl 4-[[2- [3-Methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]-methylamino]ethylamino]benzoate as a pale yellow oil.

1H-NMR (CDCl1, 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, IH, J=7.5Hz), 7.20 (m, 2H), 7.43-7.50 (m, 3H), 7:62 (d, IH, <y>=8.8Hz), 8.05 (d, IH, J=8.8Hz); MS (FAB) m/z 505 Qs/ F + l ).

A stirred mixture of methyl 4-[[2-[3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]methylamino] ethylamino] benzoate (300 mg, 0.6 mmol) in 0.25 N NaOH (6 mL) and THF (6 mL) were heated under reflux for 8 h. The mixture was poured into water and acidified with 1 N HCl. The solid was collected by suction. The crude solid was recrystallized from n-hexane-diisopropyl ether to give 202 mg (69%) of 282 as a pale yellow crystalline powder. Melting point: 115-120°C;

ER(KBr) 3346, 2935, 1603, 1531, 1454, 1417, 12S7, 1174, 1036, 754cnv'; 1H-NMR (CDjOD, 400MHz) δ 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, IH), 3.80 and 3.82 (s, 3H), 6.60-6.85 (m, 4H), 7.02 (m, IH), 7.18 (m, 2H), 7.58 (m, IH), 7.82 (m,

2H), 7.96 (m, 1H); MS (FAB) m/z 491 (M<+>+1).

EXAMPLE 203

(S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-4-[N[-(2-fluorophenyl)-ureido]phenylacetyl]amino]-1-propoxy] -benzoic acid

To a cooled (0°C) solution of methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (1.74 g, 7.14 mmol) in CH 2 Cl 2 (20 mL) was added added Et 3 N (1.19 mL, 8.54 mmol) and trifluoroacetic anhydride (TFAA) (1.11 mL, 7.86 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with CHCl 3 , washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from CHCl 3 -n-hexane to give 1.59 g (66%) of (S)-3-chloro-4-(2-trifluoroacetamido-1-propoxy)benzoate as a white crystalline material. M.p.: 122-125°C. 1H-NMR (CDCl1) δ 1.48 (d, 3 H, J=6.8 Hz), 3.91 (s, 3 H), 4.10-4.19 (m, 2 H), 4.47-4.52 (m, 1 H), 6.68 (bs, 1H), 6.92-6.94 (m, 1H), 7.93-7.95 (m, 1H), 8.07-8.08 (m, 1H); MS (FAB) m/z 340 (M^+1);^^/.Calculated for CuHuClFjNO.,: C, 45.96; H, 3.86; Cl, 10.44; F, 16.78; N, 4.12. Found: C, 45.88; H, 3.97; Cl, 10.24, F, 16.72; N, 4.18. To a stirred solution of methyl (S)-3-chloro-4-(2-trifluoro-acetamido-1-prop'oxy)benzoate (800 mg, 2.36 mmol) in DMF (5 mL) was added K 2 CO 3 (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 HCl, brine , dried over Na 2 SO 4 , and evaporated. AJ-trifluoroacetamido)-1-propoxy] benzoate as a colorless oil. 1 H-NMR (CDCl 1 ) δ 1.43-1.46 (m, 3 H), 3.03 and 3.21 (s, 3 H), 3.90 (s, 3 H); 4.04-4.22 (m, 2 H), 4.81-4.87 (m, 1 H), 6.91 (d, 1 H, .7=8.3 Hz), 7.93 (dd, 1 H, .7=2.0, 8.3 H), 8.06 (d, 1 H, .7=2.0 Hz).

To a stirred solution of methyl (S)-3-chloro-4-[2-(AJ-methyl-AJ-trifluoroacetamido)-1-propoxy]benzoate (880 mg, 2.49 mmol) in MeOH-H 2 O (10 mL , 1:1, v/v) was added K 2 CO 3 (516 mg, 3.73 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with H 2 O, brine, dried over Na 2 SO 4 and evaporated to give 460 mg (72%) of (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate as a colorless oil.

1 H-NMR (CDCl 3 ) δ 1.20 (d, 3 H, δ=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-[AJ'-(2-fluorophenyl)ureido]-phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino- 1-propoxy)benzoate (240 mg, 0.93 mmol), 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 temperature for 1.5 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5% MeOH in CHCl 3 to give 520 mg (100%) of methyl (S)-3-chloro-4-[2-[AJ-methyl-AJ-[3-methoxy -4-[AJ'-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]-benzoate as a reddish-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 h. The mixture was poured into ice-1N HCl and the solid was collected. The crude solid was recrystallized from CHCl 3 -Et 2 O to give 170 mg (2 steps, 37%) of 283 as a white crystalline powder.

M.p.: 142-147°C.

'H- NMR (DMSO-dJ 8 1.13-1.20 (m, 3H), 2.74 and' 2.94 (s, 3H), 3.65 (s, 2H), 3.82 and -3.84 (s, 3H) , 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, 1 H), 8.71 (s, 1H), 9.17 (s,i H),' 13.00 (bs, 1 H)-;MS (FAB) m/z 544 (M<*>), 545 (M++l);^nfl/.Calculated for C27H„ClFN30(i-l/4H20: C, 59.13; H, 5.05; Cl, 6.46; F, 3.46; N, 7.66. Found: C, 59.19; H, 4.99; Cl , 6.64; F, 3.23; N, 7.55.

EXAMPLE 204

(S)-3-chloro-4-[2-[AJ-methyl-AJ-[3-methoxy-4-[AT'-(2-methylphenyl)-ureido]phenylacetyl]amino-1-propoxy]benzoic acid

A mixture of 3-methoxy-4-[AT'-(2-methylphenyl)ureido]-phenylacetic acid (261 mg, 0.83 mmol), methyl (S)-3-chloro-4-(2-methylamino-1 -propoxy)benzoate (214 mg, 0.83 mmol), EDC

(hydrochloride) (23 9 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 temperature for 2 h. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3-MeOH (50:1, v/v) as eluent to give 470 mg (100%) of methyl (S)-3-chloro-4-[2-[AT-methyl- A7-[3-Methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetyl]amino]-1-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 heated under reflux for 3 h. The mixture was poured into ice-1N HCl and the solid was collected. The crude solid was recrystallized from CHCl 3 -Et 2 O

to give 168 mg (2 steps, 33%) of 284 as a pale yellow crystalline powder. Melting point: 125-130°C.

1 H-NMR.(DMSO-cy 5 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), 4.91-4.93 (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, l 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)Mna/.Calculated for C,H30ClN3O6-l/2HjO: C, 61.26; H, 5.69; N, 7.65. Found: C, 61.15; H, 5.58; N, 7.51.

EXAMPLE 205

3-isopropylamino-4- [ [2- [3-methoxy-4- [AT'-(2-methylphenyl)-ureido] phenylacetyl] methylamino] ethoxy] benzoic acid

To a cold (0°C) stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[AT' - (2-methylphenyl) ureido] phenylacetyl] methylamino] ethoxy] benzoate ( 300 mg, 0.58 mmol) in acetone-AcOH-DMF

(.13 mL, 6:6:1, v/v/v) NaBH 3 CN was added

(300 mg) and the resulting mixture was stirred for 60 hours

t - x

at room temperature. The mixture was poured into saturated NaHCO 3 and. extracted with CHCl3. The extract was washed with brine, dried over MgSO 4 and evaporated to give 280 mg (86%) methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[AT'-(2-methylphenyl) - ureido]phenylacetyl]methylamino]ethoxy]benzoate as a colorless oil. 1H-NMR (CDC13, 400MHz) 6 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 and -4.21

(m, 2H), 6.'65-6.80:Xm, 4H), 7.10 (m, IH), 7.20 (s, 3H), 7.32 (m, 2H), 7.54 (d, IH; J=8.3Hz) , 8 a.m

(s, 1H), 8.07 (d, 1H, J=8.3Hz); MS (FAB) m/z 563 (M<*>+1).

A stirred mixture of methyl 3-isopropylamino-4-[[2-[3-methoxy-4- [AT'-(2-methylphenyl)ureido]phenylacetyl]methylamino]-ethoxy]benzoate (280 mg, 0.5 mmol), 0.25 N NaOH (6 mL) and "THF

(6 mL) was heated under reflux for 8 h. The mixture was poured into water (200 ml), acidified with 1 N HCl and the solid collected by suction. The solid was recrystallized from CHCl 3 -n-hexane-diisopropyl ether to give 202 mg (74%) of 285 as a pale yellow crystalline powder. Temp.: 13 0-13 5°C.

1H-NMR (CD 3 OD, 400MHz) δ 1.18 and 1.22 (d, total 6H, J=6.3Hz), 2.29 and , 2.32 (s, total 3H), 3.04 Pg| 3.14 (s, total TS), 3.60-3.90 (m, 9H), 4.16 and<v>4.25 (m, total 2H), 6.80 (m, 3H), 7.02.(m, IH), 7.L2-7.24 (m, 3H), 7.29-7.38 (m, IK), 7.59 (jn, IK), 8.02 (m, IK) ; MS (FAB) m/z 548 (M+H)<+>;/Iha/Æcalculated for C 10 Hj XCV C» 65.68; H, 6.61. Found: C, 65.80; H, 6.83.

EXAMPLE 206

4-[[2-[3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]-methylamino] ethyl] methylaminobenzoic acid

To a stirred cold (0°C) solution of methyl 4-[[2-[3-methoxy-4- [ N'~ (2-methylphenyl)ureido]phenylacetyl]methylamino]-ethyl]aminobenzoate (300 mg, 0.6 mmol) in MeCN-formaldehyde-AcOH (11 mL, 8:2:1, v/v/v) was added NaBH 3 CN (187 mg, 2.40 mmol) and the resulting mixture was stirred for 18 h at room temperature. The mixture was poured into saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 and evaporated to give 309 mg (100%) of methyl 4-[[2-[3-methoxy-4-[AJ'-(2-methylphenyl)-ureido]phenylacetyl]- 2-AT'-methylamino]ethyl]AJ-methylaminobenzoate as a colorless oil. 1H-NMR (CDCl1, 400MHz) δ 2.30 (m, 3H), 2.98 (m, IK), 3.46-3.72 (m, 9H), 3.82 (m, 3H), 6.32 (m, IK), 6.55 -6.75 (m, AK), 7.05-7.50 (m, 2H), 7.82-8.02 (m, 4H); MS (FAB) m/z 518 (M* + 1).

A stirred mixture of methyl 4-[[2-[3-methoxy-4-[AT-(2-methylphenyl)ureido]phenylacetyl]-2-AT-methylamino]ethyl]-methylaminobenzoate (309 mg, 0.6 mmol) in 1 N NaOH (2.4 mL) and THF (10 mL) was heated under reflux for 8 h.

The mixture was poured into water (200 ml) and acidified with

addition of 1 N HCl. The solid was collected by suction.

The raw. the solid was recrystallized from CHCl3-n-hexane-diisopropyl ether to give 211 mg (70%) of 286 as a pale yellow crystalline powder. M.p.': 125-130°C.

]R(KBr) 3338, 2933, 1601, 1529, 1182, 1036, 752 cm -1 ; 'H-

NMR (CD 3 OD, 400MHz) δ 2.28 and 2.29 (s, 3H), 2.95-3.02 (ra, 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 (M₂+1).

EXAMPLE 207

( S )-3-chloro-4- [2- [AJ-benzyl-AT- [3-methoxy-4- [AT'-(2-fluorophenyl)-ureido]phenylacetyl]amino]-1-propoxy] benzoic acid

n

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-1-propoxy)benzoate ' ( 382 mg, 1.57 mmol) and benzaldehyde (0.19 mL) in MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with H 2 O and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3:MeOH (30:1, v/v) as eluent to give 336 mg (64%) of (S)-3-chloro-4-(2-AT-benzylamino-1 -propoxy) benzoate as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.22 (d, 3 H, .7=6.4 Hz), 3.21-3.25 (m, 1 H), 3.84-4.03 (m, total 7 H), 6.89-6.91 (m, 1 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-[AT'-(2-fluorophenyl)ureido]-phenylacetic acid (320 mg, 1.01 mmol), methyl (S)-3-chloro-4-(2-AT -benzylamino-1-propoxy) benzoate (336 mg, 1.01 mmol), EDC

(hydrochloride) (289 mg, 1.51 mmol) HOBt (204 mg, 1.51 mmol) and DMAP (25 mg, 0.20 mmol) in DMF (7 mL) were stirred at room temperature for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3:MeOH (50:1, v/v) as eluent to give 607 mg (95%) of methyl (5)-3-chloro-4-[2-[AT-benzyl- N-[3-methoxy-4-[ N'~ (2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a pale yellow amorphous solid.

'H-NMR (CDClj) 6 1.20-1.27 (ra, 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 rn, total 5 H).

To a stirred solution of methyl (S)-3-chloro-4-[2-[A7-benzyl-A7-[3-methoxy-4-[N'~ (2-fluorophenyl)ureido]phenylacetyl]amino ] -1-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 HCl and the solid was collected. The crude solid was recrystallized to give 192 mg (32%) of 287 as a white crystalline powder. Melting point: 125-130°C. 1H-NMR (DMSO-ds) δ 1.07-1.23 (m, 3H), 3.76 (s, 2H), 3.85 (s, 3H), 3.90-4.26 (m, 3H), 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, 1 H), 13.02 (bs, I H); MS (FAB) m/z 621 Qtf+ l)) Anal. Calculated for CjjHj^lFNjO^MHjO: C, 63.46; H, 5.08; Cl, 5.68; F, 3.04; N, 6.73 Found: C, 63.67; H, 5.16; Cl, 5.75; F, 2.95; N, 6.55.

EXAMPLE 208

3-(N-isopropyl-N-methylamino)-4- [ [2- [3-methoxy-4- [ N'~ (2-methylphenylureido].phenylacetyl] methylamino] ethoxy] benzoic acid

To a stirred cold (0°C) solution of methyl 3-isopropylamino-4-[[2-[3-methoxy-4-[A7'-(2-methylphenyl)ureido]phenylacetyl]-methylamino]ethoxy]benzoate ( 324 mg, 0.58 mmol), in CH3CN-formaldehyde-AcOH (11 mL, 8:2:1, v/v/v) was added NaBH3CN (145 mg, 2.30 mmol) and the resulting mixture was stirred for 18 hours at room temperature. The mixture was poured into saturated NaHCO 3 and the solid was collected by suction. The crude solid was dissolved in CHCl 3 (20 mL), and the solution was washed with brine, dried over MgSO 4 , and evaporated to give 317 mg (95%) of methyl 3-(A7-isopropyl-A7-methylamino)-4- [ [2- [3-Methoxy-4- [AT'-(2-methylphenyl) ureido] phenylacetyl] methylamino] ethoxy] benzoate as a colorless oil. 1H-NMR (CDCl 3 ) δ 1.02 (m, 6H), 2.29 (s, 3H), 2.63 (m, 3H), 3.02-3.20 (xn, 3HJ, 3.49-3.80 (m, 8H), 3.88 (s, 3H), 4.06 and.4.21 (m, total 2H), 6.59 (m, IH), 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/z 576 (M<*>+1).

A stirred mixture of methyl 3-(AJ-isopropyl-AT-methylamino)-4-[[2- [3-methoxy-4-[AJ' (2-methylphenyl)ureido]phenylacetyl]-methylamino]ethoxy]benzoate (317 mg, 0.55 mmol) in 0.25 N NaOH

(8.2 mL) and THF (8 mL), was heated under reflux for 8 h. The mixture was poured into water (200 mL), acidified by addition of 1N HCl, and the solid was collected by suction. The crude solid was recrystallized from CHCl 3 -n-hexane-diisopropyl ether to give 2 88 as a pale yellow crystalline powder: mp:: 13 0-135 <0>C.

IR (KBr) 2970, 1537, 1038, 754 cm"'; 'H-NMR (CD 3 OD) δ 1.12(m, 6H), 2.29 (s, 3H), 2.76 (m, 1H), 2.89 (s, 2H) , 3.02 (s, IH), 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„ IH, /=7.8Hz), 6.86 (s, IH), 7.00 (m, .2H), 7.18 (m, 3H), 7.57 (d, IH, >7.8Hz), 7.95 (m, 2H ); MS (FAB) m/ z 562 ( M*+ l) ; Anal. Calcd for C31H38N4O6-2-0HJO: C, 62.19; H, 7.07; N, 9.36. Found: C, 62.54; H, 6.85; N , 8.90.

EXAMPLE 209

t

3^(1-piperidinyl)-4-[[2-[3-methoxy-4-[AT'-(2-fluorophenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoic acid

To a stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[A7'~ (2-fluorophenyl) ureido] phenylacetyl] methylamino] ethoxy] - benzoate (300 mg, 0, 57 mmol) in THF (2 mL) was added a solution of glutaraldehyde (50% aqueous solution) (0.13 mL, 0.69 mmol) in MeOH (1.4 mL), THF (0.993 mL) and 3N H 2 SO 4 (0.952 mL) at 0°C. To the solution was added NaBH 3 CN (150 mg), DMF (5 mL), and MeOH (2 mL) at room temperature, and the resulting mixture was stirred for 15 h. The mixture was poured into saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The residue was chromatographed on silica gel with toluene:acetone (7:3, v/v) as eluent to give 145 mg (43%) of methyl 3-(1-piperidinyl)-4-[[2-[3-methoxy-4 -[ N' - (2-Fluorophenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate as a colorless oil.

1H-NMR (CDCl1, 400MHz) δ 1.58-1.72 (m, 6H), 2.80-2.92 (m, AK), 3.26 (s, 2H), 3.58 (s, 2H), 3.69 (s, 2H), 3.80 -3.89 (m, IK), 4.22 (m, 2H), 6.72 (s,

IH), 6.78 (m, 2H), 6.95-7.18 (m, 2H), 7.32 (s, IH), 7.60 (s, IH), 7.63 (d, IH, J=7.8Hz), 7.98 (d, IH , J=7.8Hz), 8.18 (m, IH); MS (FAB) m/ z 593 Gvf+1).

A stirred mixture of methyl 3-(1-piperidinyl)-4-[[2-[3-methoxy-4-[AT-(2-fluorophenyl)ureido]phenylacetyl]methylamino]-ethoxy]benzoate (290 mg, 0.49 mmol), 1 N NaOH (1.95 mL) in MeOH (5 mL) and THF (10 mL) was heated under reflux for 4 h. The mixture was poured into water (200 mL), acidified with 1N HCl (pH=4.0), and extracted with CHCl 3 -MeOH (9:1, v/v). The combined extract was dried over MgSO 4 and evaporated. The residue was recrystallized from diisopropyl ether-hexane to give 201 mg (71%) of 289 as a pale yellow crystalline powder. Melting point: 125-130°C.

ER (KBr) 3338, 2935, 1599, 1537, 1041, 752 cm"1; 1H-NMR (CD3OD) δ 1.52-1.73 (m, 6H), 2.88 (s, 3H), 2.98 (br, IK), 3.09 (s, IK), 3.23 (s, 2H), 3.66 (s, 2H), 3.75 (s, IH), 3.82 (s, AK), 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);

EXAMPLE 210

3-arrdno-4- [ [2- [3-methoxy-4- [ N'~ (2-methylphenyl) ureido] - phenylacetyl] methylamino] ethoxy] benzoic acid

To a stirred solution of methyl 3-amino-4-[[2-[3-methylpoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetyl]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 resulting mixture was heated under reflux for 16 h. The mixture was poured into water (100 mL) and acidified by addition of 1N HCl. The solid was collected by suction. The residue was recrystallized from diisopropyl ether to give 243 mg (83%) of 290 as a yellow crystalline powder. Melting point: 125-130°C. IR (KBr) 3346, 2935, 1533, 1211, 1034, 756,

637cnr'; 'H-NMR (DMSO-d6) 8 2.29 (s, 3H), 3.05 (s, IK), 3.72-3.85 (m, IK), 4.12 and 4.25 (m, total 2H), 6.76-6.89 (rn, 3H ), 700 (m, IK), 7.18 (m, 2H), 7.39 (m, 2H), 7.60 (d, IH, J=7.8Hz), 7.96 (m,.lH);^na/.Calculated for CJ7H30NA-0.5 H 2 O: C, 62.90; H, 6.06; N, 10.87. Found: C, 63.03;

H, 6.14; N, 10.56.

EXAMPLE 211

3-(1-piperidinyl)-4-[[2-[3-methoxy-4-[W-(2-methylphenyl)-ureido]phenylacetyl]methylamino]ethoxy]benzoic acid

To a cooled and stirred solution of methyl 3-amino-4-[[2-[3-methoxy-4-[ n'~ (2-methylphenyl)ureido] phenylacetyl]-methylamino]ethoxy]benzoate (573 mg, 1, 1 mmol) in THF-MeOH (2:1, v/v, 6 mL) was added glutaraldehyde (0.42 3 mL, 2.2 mmol), 3N H 2 SO 4 (1.8-3 mL, 5.5 mmol ), and NaBH 3 CN (276 mg, 4.4 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture was poured into saturated NaHCO 3 (100 mL) and the solid was collected by suction. The crude solid was purified by column chromatography on silica gel with toluene-acetone (10:0 to 4:1, v/v) to give 240 mg (37%) of methyl 3-(1-piperidinyl)-4-[ [2- [3-Methoxy-4-[N'~ter-tylphenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate as a gum. 1H-NMR(CD3OD)8 1.52-1.72 (ra, 6H), 2.30 (s, 3H), 2.36 (s, 2H), 2.89 (br s, 3H), 2.98 (ra, IK), 3.05 (s, IK), 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, tota* IK), 6.70 (s, IK), 6.70 (s, IK), 6.79 (m, 2H), 7.09-7;24 (ra, 4H), 7.50-7.65 (m, 3H)r8. 05 (d, IH, J=8.3Hz); MS (FAB) m/z 588 (NT+1).

A stirred mixture of methyl 3-(1-piperidinyl)-4-[ [2- [3-methoxy-4- [ N'~ (2-methylphenyl) ureido] phenylacetyl] methylamino] - ethoxy] benzoate (240 mg , 0.41 mmol), 1 N NaOH (1.63 mL) in MeOH (6.5 mL), H 2 O (5 mL), and THF (6.5 mL) was heated under reflux for 11 h. The mixture was poured into water (200 ml), acidified by addition of IN HCl until pH=4, and the solid was collected by suction. The aqueous layer was extracted with CHCl 3 -MeOH (9:1, v/v, 30 mL x 3). The precipitate was dissolved in the combined organic extract. The organic layer was dried over MgSO 4 and evaporated. The residue was crystallized from diisopropyl ether to give 151 mg (65%) of 291 as a pale yellow crystalline powder. Melting point: 120-125°C.

IR (KBr) 3354, 2935, 1535, 1252, 1217, 1034, 754, 638, cm -1 ; 1H-NMR (CD3OD) δ 1.55-1.72 (m, 6H), 2.30 (s, 3H), 2.89 (br, 2H), 2.98 (br, IK), 3.09 (s, IK), 3.22 (s, 2H ), 3.69 (s, 3H), 3.74 (s, IH), 3.83 (ra, 4H), 4.12 and 4.28 (m, total 2H), 6.75 (m, IK), 6.88-7.02 (m, IH), 7.17 (ra, 2H), 7.58-7.73 (ra, AK), 7.99 (d, 1H, .J=8.3Hz); MS (FAB) m/z 574 (M<*>+1); ^/.Calculated for C35H3,N4O6-0.5H2O: C, 65.85; H, 6.73; N, 9.60. Found: C, 65.94; H, 6.88; N, 9.03.

EXAMPLE 212

3-amino-4- [ [2- [3-methoxy-4- [W-(2-fluorophenyl) ureido] - phenylacetyl] methylamino] ethoxy] benzoic acid

A stirred mixture of methyl 3-amino-4-[[2-[3-methoxy-4-[ N'~

(2-fluorophenyl)ureido]phenylacetyl]methylamino]ethoxy]benzoate (250 mg, 0.48 mmol) in IN NaOH (1.91 mL), MeOH (8 mL), H 2 O (6 mL), and THF (8 mL ) was heated under reflux for 10 h. The mixture was poured into water (200 ml), acidified by the addition of IN HCl (pH=4.8) and the solid was collected by suction. The crude solid was recrystallized from diisopropyl ether to give 209 mg (86%) of 292 as a pale yellow crystalline powder. M.p.: 125-130°C.. IR (KBr) 3325, 2935, 1537, 1209, 1032, 752, 449 cm-'; 1H-NMR (CD30D) 5 3.05 (s, 1H), 3.31 (s, 2H), 3.77 (m, 3H), 3.80 (s, 1H), 3.84 (m, 3H), 4.14-4.26 (m, 2H ), 6.80-6.87 (m, 3H), 7.01 (m, IH), 7.10 (m, 2H), 7.39 (m, 2H), 7.80 (m, IH),

8.07 (m, IH); MS (FAB) m/z 510 (M^1); Anal. bereqnetfor^^^ OtO. SH1O: 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.

EXAMPLE 213

(S)-3-amino-4-[2-[3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenylacetylamino]-1-propoxy]benzoic acid

To a stirred solution of (S)-2-(Δ7-tert-butoxycarbonyl-amino)-1-propanol (0.90 g, 5.13 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol) and Ph3P (1.75 g, 6.67 mmol)

in THF (15 mL) was added diisopropyl azodicarboxylate

(DIAD) (1.31 mL, 6.65 mmol) at room temperature and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH 2 Cl 2 (20 mL) and TFA (10 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was dissolved in CHCl 3 , washed with saturated NaHCO 3 , brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with 5% MeOH in

CHCl3 as eluent to give 313 mg (24%) of methyl (S)-3-nitro-4-(2-amino-1-propoxy)benzoate as a pale yellow oil.

'H-NMR

(CDClj) 5 1.22 (d, 3 H, 7=6.8 Hz), 3.43-3.48 (m, 1 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-[AT'-(2-methylphenyl)ureido]phenylacetate (591 mg, 1.23 mmol), methyl (S)-3-nitro-4-(2-amino-1- propoxy)benzoate (313 mg, 1.23 mmol), and Et3N (257 mL, 1.84 mmol) in DMF (5 mL) were stirred at room temperature for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with 5% MeOH in ,CHCl 3 as eluent to give 310 mg (46%) of methyl (S)-3-.nitro-4-[2-[3-methoxy-4-[ AJ'-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as one gum • 'H-NMR (CDCl1) 8 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), 4.14-4.16 (m, 2 H), 4.38-4.41 (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, 1 H), 7.05-7.30 (m, 4 H), 7.55-7.57 (m , 1H), 8.02-8.06 (m, 2H), 8.16-8.19 (m, 1H), 8.51-8.52 (m, 1H); MS (FAB) m/z 551 (M<+>+1).

A stirred solution of methyl (S)-3-nitro-4-[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetylamino]-1-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%) overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to give methyl (S)-3-amino-4-[2-[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenylacetylamino] -1-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 hours. The mixture was poured into ice-H 2 O, and the aqueous layer was acidified (pH 4.8) by addition of 1N HCl. The solid was collected and the crude solid was recrystallized from MeOH-CHCl 3 -n-hexane to give 116 mg (2 steps, 44%) of 293 as a pale yellow crystalline powder. M.p.: 200-204°C.

1H-NMR (DMSO-dJ 5 1.21 (d, 3 H, J=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, 1H, 7=8.3 Hz), 8.46 (s, 1 H), 8.55 (s, 1 H); MS (FAB) m/ z 507 (M^+1);

EXAMPLE 214

(S)-4-[2-[3-methoxy-4-[A7"-(2-bromophenyl)ureido]phenylacetylamino]-1-pr<op>ox<y>]benzoic acid

To a stirred and cooled (0°C) solution of (S)-2-(AT-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (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 2 Cl 2 (30 mL) and TFA (30 mL). The resulting solution was stirred at room temperature for 30 minutes, and the solution was evaporated in vacuo. The residue was dissolved in CHCl 3 , washed with saturated NaHCO 3 , dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel eluting with CHCl 3 to CHCl 3 :MeOH (9:1, v/v) to give

6.63 g (2 steps, 60%) benzyl (S)-4-(2-amino-1-propoxy)benzoate as a yellow oil. 1H-NMR(CDCl 3 ) 6 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, 2H), 7.32-7.46 (m, 5H), 8.01-8.04 (m, 2H).

A mixture of 3-methoxy-4-[Δ7'-(2-bromophenyl)ureido]-phenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-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 at room temperature above. the night. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 476' (58%) benzyl (5)-4- [2- [3-methoxy-4- [ N'~ (2- bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a brown solid.

1H-NMR (CDCl1) δ 1.25-1.28 (m, 3H), 3.51-(s, 2H), 3.74 (s, 3H), 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 (S)-4-[2-[3-methoxy-4-[ N'~

(2-Bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (476 mg, 1.39 mmol) in THF (10 mL) was added 0.5 N NaOH (10 mL), and the resulting mixture was heated under reflux for 2 hours. The mixture was poured into ice-1 N HCl, and the solid was collected. The crude solid was recrystallized from MeOH-CHCl3-n-hexane to give 240 (5.9%) 294 as a white crystalline powder. M.p.: 202-205°C.

1H-NMR (DMSO-dj) δ 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 (rn, 1H), 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 ( yr+\) ; Anal. Calculated for^^rNjOj: C, 56.12; H, 4.71; Br, 14.36; N, 7.55. Found: C, 56.11; H, 4.74; Bro, 14.56; N, 7.49.

EXAMPLE 215

(S) -4- [ [2- [3-methoxy-4- [ N'-(2-methylphenyl) ureido] phenylacetyl] -

(2-Aminobenzyl)amino]-1-propoxy]benzoic acid

To a stirred cooled (0°C) solution of benzyl (S)-4-(2-aminob-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (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 temperature overnight. The mixture was quenched with saturated NaHCO 3 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to 5% MeOH 1 CHCl 3 as eluent to give 931 mg (42%) of benzyl (S)-4-[2-)2-hitrobenzylamino)-1-propoxy]benzoate as a yellow oil. 'H-NMR(CDC13) 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, 2H), 7.29-7.65 (m, 8H), 7.94-8.03 (m, 3H); MS (FAB) m/z 421 (M<*>+1).

A mixture of pentafluorophenyl 3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetate (460 mg, 0.96 mmol), benzyl

(S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate (403 mg,

0.96 mmol), and Et 3 N (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 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with 1% MeOH in CHCl3 as eluent to give 504 mg (73%) benzyl (S)-4-[ [2-[3-= methoxy-4- [ N' - (2- methylphenyl)ureido]phenylacetyl]-(2-nitrobenzyl)amino]-1-propoxy]benzoate as a brown amorphous solid. MS (FAB) m/z 717 (M<+>+1).

A stirred solution of benzyl (S)-4-[[2-[3-methoxy-4-[W-tertylphenyl)ureido]phenylacetyl]-(2-hydrobenzyl)amino]-1-'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 atmospheres 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 3 as eluent to give 115 mg (27%) of 295 as a white powder. MS (FAB) m/z 597 (M + + 1).

EXAMPLE 216

(S) -4- [ [2- [3-methoxy-4- [A7'~ (2-bromophenyl)ureido] phenylacetyl] -

(2-nitrobenzyl)amino]-1-propoxy]benzoic acid

To a stirred and cooled (0°C) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5.76 mmol) in MeOH-AcOH (16 mL, 15:1, v/v) was added NaBH 3 CN (1.65 g, 26.3 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHCO 3 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to 5% MeOH in CHCl 3 as eluent to give 931 mg (42%) of benzyl (S)-4-[2-(2-nitrobenzylamino)-1-propoxy]benzoate as a yellow oil.

<1> 'H-NMR (CDCl3) 5

1.21 (d, 3 H, 7=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, 2H), 7.29-7.65 (m, 8H), 7.94-8.03 (m, 3H); MS (FAB) m/z 421 (M<*>+1).

A mixture of 3-methoxy-4-[N-(2-bromophenyl)ureido]-phenylacetic acid (476 mg, 1.26 mmol), benzyl (S)-4-[2-(2-nitrobenzylamino)-1-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) were stirred at room temperature overnight and at 60 °C for 1 day. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over NA 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to 2% MeOH in CHCl 3 as eluent to give benzyl (S)-4-[[2-[3-methoxy-4-[ N'~ (2-bromophenyl)ureido]phenylacetyl ]-(2-nitrobenzyl)amino]-1-propoxy]benzoic acid as an oil, which is used in the subsequent reaction without further purification.

To a stirred solution of the above crude product 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 h. The mixture was poured into ice-H 2 O, and the basic aqueous layer was acidified (pH 4.3) with 1 N HCl. The solid was collected and the crude solid was purified by preparative TLC eluting with 5% MeOH in CHCl 3 to give 162 mg (2 steps, 19%) of 296 as a white amorphous solid.

MS (FAB) m/z 692

(M<+>+1);^na/.Calculated for C33H31BrNA-7/4HJ0: C, 54.82; H, 4.81; N, 7.75. Found: C, 54.80; H, 4.61; N, 7.24.

EXAMPLE 217

4-[2-A7-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetamido]ethoxy]benzoic acid

To a cooled (0°C) solution of 2-(N-tert-butoxycarbonyl-amino)ethanol (3.20 g, 19.9 mmol), methyl 4-hydroxybenzoate (3.02 g, 19.9 mmol) and To Ph 3 P (6.25 g, 23.8 mmol) in THF (50 mL) was added DIAD (4.69 mL, 23.8 mmol) dropwise over 5 min. The reaction mixture was heated under reflux for 3 hours. The mixture was evaporated and the residue was dissolved in CH 2 Cl 2 (30 mL) and TFA (30 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in CHCl 3 and H 2 O. The solution was basified with saturated NaHCO 3 and extracted with CHCl 3 . The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (30:1, v/v) as eluent to give methyl 4-(2-aminoethoxy)benzoate (1.03 g, 34% for 2 steps) as a colorless oil . 1 H-NMR (CDCy 5 3.10-3.13 (m, 2 H). 3.89 (s, 3 H), 4.03-4.06 (m, 2 H), 6.92-6.94 (m, 2 H), 7.98-8.00 (m , 2 H). A mixture of 3-methoxy-4-[N-(2-methylphenyl)ureido]phenyl-acetic acid (557 mg, 1.77 mmol), methyl 4-(2-aminoethoxy)benzoate 346 g, 1.77 mmol), EDC-HCL (408 mg, 2.13 mmol), HOBt (287 mg, 2.12 mmol) and DMAP (52 mg, 0.43 mmol) in DMF (10 mL) were stirred at room temperature for 2 days. The mixture was diluted with EtOAc and H 2 O. The resulting precipitate was collected to give methyl 4-[2-A7-[3-methoxy-4-[ N'-(2-methylphenyl) ureido] phenylacetamido]ethoxy]benzoate (598 mg, 69%%) as a white crystalline powder. 1H-NMR (DMSO-d*) δ 2.23 (s, 3 H), 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.(m, 2 H), .7.02-7.04 (m, 2 H), 7.09-7.15 (m, 2 H), 7.77-7.79 (m, 1 H), 7.88-7.90 (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), /t/z 492 (M<+>+1); ^/ja/.Calculated for C27HwN306 iy4HJ0: C, 6 5.38; H, 5.99; N, 8.47. Found: C, 65.26; H, 5.99; N, 8.49. To a stirred solution of methyl 4-[2-A7-[3-methoxy-4-[N'~ (2-methylphenyl)ureido]phenylacetamido]ethoxy]benzoate (280 mg, 0.57 mmol) in THF-MeOH ( 10 ml, 1:1, v/v) 0.5 N NaOH (10 ml) was added, and the reaction mixture was heated under reflux for 5 h. The mixture was cooled to room temperature and poured into ice-1N HCl. The resulting precipitate was collected and recrystallized from Et 2 O-CHCl 3 -MeOH to give 297 (135 mg, 50%) as a white crystalline powder. Molecular weight 477.51. 'H-NMR(DMSO-d*) δ 2.24 (s, 3 H), 3.38 (s, 2H), 3.43-3.47 (m, 2 H), 3.82 (s, 3 H), 4.06-4.09 (xn, -2 H), 6.76-6.78 (m, 1 H), 6.92-7.17 (m, 6 H), 7.79 (d, J = 8.1 Hz, 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/z 478 (M<*>+1);/4no/. Calcd for C 2 H 2 O 2 H 2 O : C, 64.79; H, 5.75; N, 8.72. Found: C, 64.67; H, 5.63; N, 8.60. EXAMPLE 218 (S)-4-[2-N-[4-[N'~ (2-bromophenyl)ureido]-3-methoxyphenyl-acetamido]-1-propoxy]benzoic acid

To a cooled (0°C) stirred solution of (S)-2-(A7-tert-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mol) and Ph3P (15.13 g, 0.06 mol) in THF (100 mL) was added DIAD (11.4 mL, 0.06 mol) and the reaction mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH 2 Cl 2 (30 mL) and TFA (30 mL). The solution was stirred at room temperature for 30 min. and the solution was concentrated in vacuo. The residue was dissolved in CHCl 3 , washed with saturated NaHCO 3 , dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to CHCl 3 -MeOH (9:1, v/v) as eluent to give benzyl (S)-4-(2-amino-1-propoxy)benzoate (6.63 g, 2-step, 60%) as a yellow oil. 1H-NMR (CDCl 3 ) δ 1.18 (d, J= 6.3 Hz, 3 H), 3.35-3.39 (m, 1 H), 3.71-3.75 (m, 1 H), 3.90-3.93 (rn, 1 H) , 5.34 (s, 2H), 6.90-6.93 (m, 2H), 7.32-7.46 (m, 5H),

8.01-8.04 (m, 2H).

A mixture of 4-[N-(2-bromophenyl)ureido]-3-methoxy enylacetic acid (480mg, 1.27mmol), benzyl (S)-4-(2-amino-1-propoxy) benzoate (361 mg, 1.27 mmol), EDC-HCl (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 HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give benzyl (S)-4-[2-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetamido]- 1-propoxy]benzoate (476 mg, 58%) as a brown solid.

1H-NMR (CDCl 3 ) δ 1.25-1.28 (m, 3 H), 3.51 (s, 2H), 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, 5 H).

To a stirred solution of benzyl (S)-4-[2-[4-[ N'~ (2-bromophenyl)ureido]-3-methoxyphenylacetamido]-1-propoxy]benzoate (476 mg, 1.39 mmol) in To THF (10 mL) was added 0.5 N NaOH (10 mL), and the reaction mixture was heated under reflux for 2 h. The mixture was poured into ice-1 N HCl, and the resulting precipitate was collected. The crude solid was purified by recrystallization from MeOH-CHCl 3 -n-hexane to give 298 (240 mg, 59%) as a white crystalline powder. Molecular weight 556.41. 'H-NMR (DMSO-d*) 6 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 (m, 1^7: 87-7.97 (m, 4 H), 8.13-8.15 (m, in H), 8.73 (s, 1 H), 8.91 (s, 1 H), 12.63 (bs, 1 H); MS (FAB) w/ z 557 (M++l);^na/. Assigned to CJ6HJ6BrN306: C, 56.12; H, 4.71; Br, 14.36; N, 7.55. Found:'C, 56.11; H, 4.74; Br, 14.56; N, 7749. EXAMPLE 219 (S)-4-[2-A7-[[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenyl]-A7-methylacetamido]-1-propoxy]benzoic acid

To a cooled (0°C) solution of (S)-2-[(A7-tert-butoxycarbonyl)amino]-1-propanol (3.08 g, 17.6 mmol), methyl 4-hydroxybenzoate (2.67 g, 17.6 mmol) and Ph3P (5.53 g,

21.1 mmol) in TH-F (35 ml) DIAD was added dropwise

(4.15 mL, 21.1 mmol). The reaction mixture was heated under reflux overnight. 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- [ (AJ-tert-butoxycarbonyl ) amino]-1-propoxy]benzoate (1.24 g, 23%) as a white solid. 1H-NMR (CDCl 3 ) δ 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 , 1H), 4.76 (m, 1H), 6.91-6.93 (m, 2H), 7.98-8.00 (m, 2H); MS (FAB) m/z 310 (MM).

To a stirred solution of methyl (S)-4-[2-[(N-tert-butoxycarbonyl)amino]-1-propoxy]benzoate (1.24 g, 4.01 mmol) in CH 2 Cl 2 (10 mL) was added added TFA (10 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and basified with saturated NaHCO 3 . The mixture was extracted with CHCl 3 , washed with brine, dried over K 2 CO 3 and evaporated to give methyl (S)-4-(2-amino-1-propoxy)benzoate (790 mg, 94%) as a yellow oil. 1 H-NMR (CDCl 3 ) δ 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-1-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 HCl and extracted with CHCl 3 . The extract was washed with brine, dried over K 2 CO 3 and evaporated. The residue was purified by recrystallization from n-hexane-CHCl3 to give methyl (S)-4-[2-(trifluoroacetamido)-1-propoxy]benzoate

(790 mg, 69%) as a white crystalline material. 1H NMR(CDCl 3 ) δ 1.42 (d, J = 6.8 Hz, 3 H), 3.89 (s, 3 H), 4.01-4.13 (m, 2 H) , 4.44^.50 (m, 1 H), 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^+lJ^/jalCalculated for CjjHMFjNO^: C, 51.15; H, 4.62; F, 18.67; N, 4.59. Found: C, 51.14; H, 4.60; F, 18.50; N, 4.54.

To a stirred solution of methyl (S)-4-[2-(trifluoroacetamido)-1-propoxy]benzoate (695 mg, 2.28 mmol) and K 2 CO 3

(630 mg, 4.56 mmol) in DMF (10 mL) was added Mel (210

ml, 3.37 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated,' The residue was purified by column chromatography on silica gel with EtOAc-CHCl 3 (1:19, v/v) as eluent to give methyl (S)-4-[2- [ (N-methyl) trifluoroacetamido]-1:-prbp6ks'y] benzoate (720 mg, 99%) as a white solid. Temp. : 73-75°C; 1H-NMR (CDC13)5 1.36-1.39 (m,

3 H), 2.96 and 3.10 (each s, total 3 H), 3.89 (s,.3 H), 3.99^.14 (m, 2 H), 4.84-4.92 (m, 1 H)' , 6.88- ,'

6.92 (m, 2H), 7.98-8.00 (rn, 2H); MS (FAB) m/z 320 (M<*>+1); Arial. Calculated for C14H1(!F3NO,: 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 (S)-4-[2-[(At-methyl)tri-fluoroacetamido]-1-propoxy]benzoate (710 mg, 2.22 mmol) in MeOH-H 2 O (10 mL, 1: 1, volume/volume) K2C03 was added

(460 mg, 3.33 mmol), and the reaction mixture was stirred at

room temperature overnight. The mixture was diluted with H 2 O

and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated to give methyl (S)-4-[2-[(W-methylamino)-1-propoxy]benzoate (430 mg, 87%) as a colorless oil. feNMR(000061.17(47-6.6^3^,2.48(^3^,2.98-3.06 (111, 1 H), 3.86-3.96 (.-series rav s and m, total 5 H), 6.92 (d, 7 = 9.0 Hz, 2 H), 1£S (d, 7 = 9.0 Hz, 2 H).

A mixture of 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]-phenylacetic acid (605 mg, 1.93 mmol), methyl (S)-4-[2-[(A7-methylamino)-1 -propoxy]benzoate (430 mg, 1.93 mmol), EDC-HCl (444 mg, 2.32 mmol), HOBt (313 mg, 2.32 mmol) and Et3N

(320 mL, 2.30 mmol) in THF (13 mL) was stirred at room temperature overnight. The mixture was diluted with H 2 O and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 -MeOH (100:1 to 75:1, v/v) as eluent to give methyl (S)-4-[ 2- N- [[3-methoxy-4-[ N'~ (2-Methylphenyl)ureido]-phenyl]-N-methylacetamido]-1-propoxy]benzoate (953 mg, 95%) as a white foam. 'H-NMR (CD Cl3) 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, 2 H), 3.71-4.05 (series of sog m, total 5 H), 4.39-4.44 and 4.96-5.0 L(each, 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 (M^+^Mna/.Calculated forjH^NjOs llMHA: 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-N-[[3-methoxy-4-[ N' -(2-methylphenyl)ureido]phenyl]-A7-methylacetamido]-1-propoxy]benzoate (663 mg, 1.28 mmol) in THF (5 mL) was added 0.5 N NaOH (5 mL), and the reaction was heated under reflux for 5 h. After cooling to room temperature, the mixture was poured into ice-1N HCl and the resulting precipitate was collected under reduced pressure. The crude solid was dissolved in CHCl 3 and evaporated. The residue was washed with Et 2 O to give 299 (465 mg, 72%) as a white amorphous solid. Molecular weight 505.56.

'H-NMR (DMSO-dJ 51.11-1.15 (m, 3 H), 2.25 (s, 3 Hj, 2.73 and 2.88 (river s,-total 3 H), 3.60-3.76 (m, 2 H), 3.83 ( s, 3 H), 4.03-4.12 (m, 2 H), 4.41-4.50 and 4.48-4.94 (each hi, total 1 H),

6.7.1-6.76 (m, 1 H), 6.84-6.86 (m, 1 H), 6.91-7.01 (m, 3 H), 7.11-7.12 (rn, 2 H), 7.78-7:80 (m, 1H). 7.86-7.90 (m, 2K), 8.01-8.03 (m, 1 H), 8.45 (s, 1 H), 8.54 (s, IH); MS (FAB) m/z 520 (K+1); Calculated for Cj^^A^^HjO: C, 63.15; H, 6.43; N, 7.89..Found: C, 63.09; H, 5.99; N. 7.64.

EXAMPLE 220

4-[ 2- N -[[3-methoxy-4-[ N'~(2-methylphenyl)ureido] phenylacetamido]-2-methyl-1-propoxy]benzoic acid

A stirred mixture of methyl 4-hydroxybenzoate (3 g,

19.72 mmol), K 2 CO 3 (6.8 g, 49.3 mmol), 3-chloropivalic acid (2.9 g, 21.69 mmol) and a catalytic amount of Kl (200 mg) in DMF (70 mL) were heated at 100°C for 14 days under a stream of nitrogen. The mixture was poured into ice water and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 ml) with CHCl 3 -EtOH (10:1, v/v) as eluent to give the title. compound (1 g, 23%) as an amorphous solid. 1 H-NMR (CDCl 3 ) 51.37 (s, 6 H), 3.89 (s, 3 H)| 4.03 (p, 2 H). 6.92 (d, J=9 Hz, 2 H), 7.98 (d, J= 9 Hz, 2 H).

To a stirred mixture of 2,2-dimethyl-3-(4-methoxycarbonyl)-phenoxypropionic acid (720 mg, 2.85 mmol) and triethylamine.

(0.46 mL, 3.28 mmol) in tert-BuOH (10 mL) and benzene (10 mL) was added a solution of diphenylphosphoryl azide (870 mg, 3.14 mmol) in benzene (3 mL) at room temperature. The resulting mixture was heated at reflux for 20 hours. After cooling, ice and 1 N HCl (5 mL) were added to the mixture, and the mixture was extracted with toluene.

The extracts were washed with saline, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 ml)

with toluene-EtOAc (10:1, v/v) as eluent to give methyl 4-[1-(2-amino-2-methyl)propoxy]benzoate as a gum (520 mg), which was used in the subsequent reaction without further purification.

NMR (CDCl 3 ) δ 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,

2H), 7.98 (dd, J =2 and 7 Hz).

A solution of methyl 4-[1-(2-methyl-2-tert-butoxycarbonyl-amino)propoxy]benzoate (520 mg) and anisole (0.175 ml,

1.61 mmol) in CH 2 Cl 2 (5 mL) and TFA (3 mL) was stirred at room temperature for 18 h. The mixture was evaporated. The residue was dissolved in CH 2 Cl 2 , and the mixture was made basic by the addition of saturated NaHCO 3 . Separated. CH 2 Cl 2 layer was dried over Na 2 SO 4 and Na 2 CO 3 , and evaporated. The remainder was chromato-

graphed on silica gel with CHCl3-EtOH (10:1, v/v) as eluent to give methyl 4-[1-(2-amino-2-methyl)propoxy] benzoate (250 mg, 39% over two steps) as a rubber.

1 H-NMR (CDCl 1 ) δ 3.75 (s, 2 H), 3.89 (s, 3 H), 6.93 (d, .7=8.8

Hz, 2 H), 7.98 (d, .7=8.8 Hz, 2 H).

To a stirred mixture of methyl 4-[1-(2-amino-2-methyl)-propoxy] benzoate (250 mg, 1.12 mmol), 3-methoxy-4-[A7'-(2-methylphenyl)ureido ]phenylacetic acid (352 mg, 1.12 mmol), 4-DMAP (165 mg, 1.34 mmol) in DMF (10 mL) was added EDC-HCl (290 mg, 1.51 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured 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 methyl 4-[2-A7-[3-methoxy-4-[A7r-(2-methylf enyl)ureido]phenylacetamido]-2-methyl-1-propoxy]benzoate (580 mg, quant, yield) as a crystalline material. IR (KBr) 3350, 3286, 1712, 1687, 1637, 1606 cm-'; 1H-NMR (CDCl1) 6 1.39 (s, 6 H), 2.33 (s, 3 H), 3.41 (s, 2 H), 3.63 (s, 3 H), 3.88 (s, 3 H), 4.05 (s , 2 H), 5.44 (br s, 1 H),'6.3.3 (br s, 1H), 6.79 (d, J= 8.3 Hz, 2 H), 7.12 (s, 1 H), 7.18^(t , J =

7.5 Hz, 1 H), 7.53 (d, /= 7.8 Hz, 1 H), 7.94 (d, J= 7.8 Hz, 2 H), 8.14 (d, J= 8.3 Hz, 1 H); MS

(FAB) m/z 520 (M<+> +1); ^/.Calculated for C^HjjNjCv 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-[ N'-(2-methylphenyl)ureido]phenylacetamido]-2-methyl-2-propoxy]benzoate (510 mg, 0.98 mmol) 0.25 N NaOH (8 ml,

2 mmol) at room temperature. The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was poured into ice-1 N HCl (5 mL). The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl 3 -EtOH-Et 2 O to give 300 (480 mg, 97%) as fine needles. Molecular weight 505.56.

IR (KBr) n 3346, 3294, 1687, 1637, 1604 cm"<1>; 'H-NMR (DMSO-dJ 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, 1 H), 6.88 (s, 1 H), 6.95-6.99 (m, H), 7.11-7.17 (m, 3 H), 7.80 (d, J= 8.3 Hz, 1 H), 7.82 (s , 1 H), 7.87 (d, J= 8.8 Hz, 2 H), 7.98 (d, J = 7.8 Hz, 1 H), 8.45 (s, 1 H), 8.54 (s, 1 H), 12.62 (br Si; l.H); MS (FAB) m/z 506 (M<+> +1); .4 nal.Calculated for C2gH31N3Oe: C, 66.52; H, 6.18; N, 8.31. Found: C» 66.22; H, 6.28; N, 8.11.

EXAMPLE 221

3-amino-4-[ 2- N- [4- [ N'~ (2-chlorophenyl)ureido]-3-methoxyphenyl-acetamido]-2-methyl-1-propoxy]benzoic acid

To a stirred solution of 4-amino-2-nitrophenol (10 g,

64.88 mmol) in AcOH (70 mL) and DMSO (20 mL) was added concentrated H 2 SO 4 at 0-5°C. To this solution was added dropwise a solution of NaNO 2 (5.4 g, 77.9 mmol) in water (5 ml) below 20°C over 10 min. The resulting mixture was further stirred for 0.5 h at 5°C. This mixture was poured into a stirred solution of Kl (30 g, 0.182 mol) and a catalytic amount of Cu powder (200 mg) in ice water

(2 0 0 ml) during 10 min. The resulting mixture was stirred for an additional 1 hour at ambient temperature. The mixture was extracted with CH 2 Cl 2 . The extracts were washed

sequentially with saturated Na2S203 and brine. The

the organic layer was dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with CHCl 3 -EtOAc (3:1, v/v) as eluent to give 4-iodo-2-nitrophenol (2.5 g, 15%) as a yellow crystalline material.

1H-NMR (CDCl 3 ) δ 6.94 (d, J= 8.8 Hz, 1 H), 7.82 (dd, J= 2 and 8.8 Hz, 1 H), 8.42 (d, J= 2 Hz, 1H), 10.49 ( pp, 1H).

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) while cooling with an ice water bath. The resulting mixture was then heated under reflux for 18 hours. After cooling, the mixture was evaporated. The residue was chromatographed on silica gel (100 mL) with toluene-EtOAc (4:1, v/v) as eluent to give methyl 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionate (2.9 g, quantitative yield) as a crystalline material.

1H-NMR (CDCl1) δ 1.34 (s, 6 H), 3.71 (s, 3 H), 4.08 (s, 2 H), 6.86 (d, J

= 8.8 Hz, 1 H), 7.78 (dd, J = 2 and. 8.8Hz, 1 H), 8.12 (d, J = 2 Hz, IH).

A mixture of methyl 3-(4-iodo-2-nitro)phenoxy-2,2-dimethyl-propionate (2.8 g, 7.38 mmol) in THF (15 mL) and 0.25 N NaOH (60 mL , 15 mmol) was stirred at ambient temperature for 18 hours. The mixture was poured into ice-1 N HCl (20 mL). The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl 3 -EtOH-IPE to give 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionic acid (2.0 g, 74%) as a crystalline material. M.p.: 165-182°C.

ER (KBr) n 1716, 1525, 1344 cm"1; 'H-NMR (CDCl1) δ 1.38 (s, 6 H), 4.10 (s, 2 H), 6.86 (d, Jf 8.8 Hz, 1 H), 7.79 (dd, 7 = 2.2 and 8.8Hz, l.H), 8.12 (d, J= 2 Hz, IH); MS (FAB) m/ z 366 (M<*> +1); ^nfl/.BirégnefforC^jjNjOt : 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-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropionic acid (1.93 g, 5.29 mmol) and triethylamine (590 mg, 5.81 mmol) in tert -BuOH ( 15 ml) and toluene (15 ml) was added a solution of diphenylphosphoryl azide (1.53 g, 5.55 mmol) in toluene (3 ml) at room temperature. The resulting mixture was then heated under reflux for 20 hours. After cooling, ice and 1 N HCl (5 mL) were added to the mixture, and the mixture was extracted with toluene. The extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with toluene-EtOAc (10:1, v/v) as eluent to give 3-nitro-4-(2-tert-butoxycarbonylamino-2-methyl-1-propoxy)iodobenzene ( 1.91 g, 83%) as a gum.

1 H-NMR (CDCl 3 )-δ 1.38 (s, 9 H), 1.39 (s, 6 H), 4.19 (s, 2 H). 4.67 (br s, 1H), 6.88 (d, J= 8.8 Hz, 1 H), 7.77 (dd, J = 2.0 and 8.8Hz, 1 H), 8.12 (d,

.7= 2.0Hz, IH).

A mixture of 3-nitro-4-(2-tert-butoxycarbonylamino-2-methyl-1-propoxy)iodobenzene (1.9 g, 4.36 mmol), Pd(OAc)2 and 1,3-bis(diphenylphosphino )propane (dppp) (90 mg, 0.22 mmol) in triethylamine-MeOH-DMSO (1:2:5, v/v/v, 48 mL) was stirred under a stream of CO (gas) at 70° C for 6 hours. After cooling, the mixture was poured into water and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with toluene-EtOAc (6:1, v/v) as eluent to give methyl 4-(2-tert-butoxycarbonylamino-2-methyl-1-propoxy)-3-nitrobenzoate ( 820 mg, 51%) as a gum. 1H-NMR (CDCl 3 ) δ 1.38 (s, 9 H), 1.42 (s, 6H), 3.93 (s, 3 H), 4.29 (s, 2 H), 4.67 (br s, 1H), 7.15 (d , J = 8.8 Hz, 1H), 8.18 (dd, J= 1. 1 P<g> 8.8Hz, 1 H), 8.52 (d, J= 1.7 Hz, IK).

A stirred mixture of methyl 4-(2-tert-butoxycarbonylamino-2-methyl-1-propoxy)-3-nitrobenzoate (350 mg, 0.95 mmol) and 5% Pd-C (70 mg) in EtOH (3 0 ml) was hydrogenated in hydrogen at atmospheric pressure at room temperature for 20 hours. Insoluble Pd catalyst was removed by suction and washed with EtOH. The filtrate was evaporated to give methyl 4-(2-tert-butoxycarbonylamino-2-methyl)-1-propoxy-3-aminobenzoate as a gum, which was used in the subsequent reaction without further purification.. 'H-NMR ( CDClj) 8 1.41 (s, 9 H), 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, 1H), 7.39 (d,/= 2.2 Hz, IH), 7.44 (dd, J= 2.2 and 8.5Hz, 1 H).

To a stirred mixture of the above methyl 4-(2-tert-butoxycarbonylamino-2-methyl)-1-propoxy-3-aminobenzoate and triethylamine (0.20 mL, 1.43 mmol) in CH 2 Cl 2 (10 mL) was added added a solution of trifluoroacetic anhydride (0.182 mL, 1.28 mmol) in CH 2 Cl 2 (3 mL) at 0-5°C. The resulting mixture was stirred at room temperature for 1 hour. Ice-saturated NaHCO 3 was added to the mixture and the mixture was extracted with CH 2 Cl 2 . The extracts were washed with saline, dried over Na 2 SO 4 and evaporated. The residue was dissolved in CH 2 Cl 4 (5 mL) and anisole (0.105 mL, 0.95 mmol) and TFA (2 mL) were added. The resulting mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was diluted with CH 2 Cl 2 and made basic by addition of saturated NaHCO 3 . The separated CH 2 Cl 2 layer was dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 mL) with CHCl3-EtOH (99:1, v/v) as eluent to give methyl 4-(2-amino-2-methyl-1-propoxy)-3-trifluoroacetamidobenzoate (631 mg, 63% in 3 steps) as a gum.

1H-NMR (CDCl 3 ) δ 1.29 (s, 9 H, /ert-Bu), 3.86 (s, 2 H, CH: ), 3.91 (s, 3 H,), 6.99 (d, J = 8.5 Hz, 1 H), 7.91 (dd,<y>= 2.0 and 8.5 Hz, IH), 8.83 (d,J= 8.5Hz, 1 H).

To a stirred mixture of methyl 4-(2-amino-2-methyl)-1-propoxy-3-trifluoroacetamidobenzoate (200 mg, 0.598 mmol), 4-[ N'~ (2-chlorophenyl)ureido-3-methoxyphenylacetic acid ( 210 mg, 0.598 mmol), 4-DMAP (90 mg, 0.72 mmol) in DMF (7 mL) was added EDC-HCl (160 mg, 0.81 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 hours. The mixture was poured into ice-water. The solid was collected, washed with water and air dried. The crude solid was purified by silica gel column chromatography with CHCl 3 -EtOH (98:2, v/v) as eluent to give methyl 4-[2-N- [4- [ N'~ (2-chlorophenyl)ureido] - 3-Methoxyphenylacetamido]-2-methyl-1-propoxy]-3-trifluoroacetamidobenzoate (580 mg, quantitative yield) as a crystalline material. 1H-NMR (CDCl1) 6 1.42 (s, 6 H), 3.42 (s, 2 H), 3.69 (s, 3 H), 3.89 (s, 3 H), 4.23 (s, 2 H), 5.33 ( br s, 1 H), 6.66 (s, 1 H), 6.71 (m, 1H), 6.92 (d, J= 8.5 Hz, 1 H), 7.02 (m, 1 H), 7.09 (m, 2 H) , 7.29 (m, 1H), 7.37 (d, J= 8.0 Hz, IH), 7.87 (dd, J= 2 and" 8.5Hz, 1 H), 7.97 (d, J= 8.0 Hz, 1 H), 8.19 (d,/=

8.2 Hz, 1 H), 8.59 (br s, 1 H), 8.74 (d, J= 2.0 Hz, 1H).

To a stirred solution of methyl 4-[2-N-[4-[W-(2-chlorophenyl)ureido]-3-methoxyphenylacetamido]-2-methyl-1-propoxy]-3-trifluoroacetamidobenzoate (320 mg, 0.492 mmol ) in THF (2 mL) was added 0.25 N NaOH (6 mL, 1.5 mmol) at ambient temperature. The resulting mixture was stirred for 20 hours. The mixture was poured into ice-IN HCl (2 mL). The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl 3 -EtOH-Et 2 O to give 301 (240 mg, 89%) as fine needles. VAT 541.00.

TR (KBr) n 3338, 3296, 1691, 1641 cm"<1>; 'H-NMR (CDCL,) 5 'H-NMR (DMSO d«) 6 1.37 (s, 6 H), 3.35 (s, 2 H), 3.77 (s, 3 H), 4.05 (s, 2H), 4.96 (brs, 1 H), 6.75 (br d, J= 8.3 Hz, 1 H), 6.78 (d,J = 8.3Hz, IH ), 6.87 (d, Jf 1.7Hz, 1 H), 7.01 (m, 1 H), 7.15 (dd, J= 2 and 8.5 Hz, IH), 7.24 (d, J = 2 Hz, 1 H), 7.27 (dt, J= 2.0 and 8.5 Hz, 1 H), 7.43 (dd, J= 2 and .8.0 Hz, 1 H), 7.78 (br s, 1 H), 7.90 (d, J= 8.0 Hz, 1 H ), 8.08 (dd, J= 2 and 8.3 Hz, 1 H), 8.85 (s, 1 H), 8.89 (s, 1 H), 12.23 (br s, 1 H); MS (FAB) m/z 541 (M<*> +1); ^no/. Calculated for C17HMClN406: C. 58.00; H, 5.59; N, 10.02. Found: C, 57.97; H, 5.39; N, 10.01.

EXAMPLE 222

2-acetylamino-4-[2-N- [3-methoxy-4-[ N'-(2-methylphenyl)ureido]-phenyl] -A7-methylacetamido] ethylaminobenzoacetic acid

To a stirred solution of 2-acetylamino-4-nitrobenzoic acid (1.28 g, 5.71 mmol) in benzene-MeOH (4:1, v/v, 25 mL), was added trimethylsilyldiazomethane (2.0 M solution in n-hexane, 4.28 mL, 8.56 mmol) at 0°C. Stirring was continued for 18 hours at room temperature. The reaction mixture 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. Smp.: no data.

1 H-NMR (400 MHz, CDCl3) δ 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, J= 2.2 Hz, 1 H), 11.10 (s, 1 H); MS (ESI) m/z 238 (NT).

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 H2 gas (3 atm) was continued for 18 hours at room temperature. The catalyst was filtered off and the mixture was evaporated. The resulting crude solid was recrystallized with CHCl 3 -MeOH-hexane to give methyl 2-acetylamino-4-aminobenzoate (1.03 g, 90%) as a white solid. 1H-NMR (400 MHz, CDCl3) 6 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, 1H) , 7.80 (d, J = 8.8 Hz, 1 H), 8.06 (s, 1 H),' 11.26 (s, in H); MS (FAB), m/z 208 (M<*>).

To a cooled solution of methyl 2-acetylamino-4-aminobenzoate (300 mg, 1.44 mmol) and A7-tert-butoxycarbonyl-N-methylglycinal (499 mg, 2.88 mmol) in 1,2-dichloroethane (30 mL ), NaBH(OAc) 3 (964 mg, 4.32 mmol) was added and stirring was continued for 64 h at 0 °C. The mixture was poured into saturated NaHCO 3 and extracted with CHCl 3 (50 mL x 3), washed with brine and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of hexane-EtOAc from 9:1 to 2:1) to give methyl 2-acetylamino-4 - [2 -A7- tert -butoxycarbonyl-A7-methylamino)ethylamino]benzoate (451 mg, 86%) as a colorless oil.

■H-NMR (CDC13, 400 MHz) δ 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, 3 H), 6.20 (dd, J= 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<+>+1).

To a stirred solution of methyl 2-acetylamino-4-[2-( N - tert -butoxycarbonyl- N -methylamino) ethylamino] benzoate (450 mg, 1.23 mmol) in dichloromethane (5 mL) was added TFA (5 ml) and stirring was continued for 18 hours at room temperature. After removal of the solvent in vacuo, the residue was dissolved in CHCl 3 (200 mL), washed with brine, saturated NaHCO 3 and dried over MgSO 4 . The solvent was removed to give methyl 2-acetylamino-4-[2-(N-methylamino)ethylamino]benzoate (298 mg, 88%) as a colorless oil.

1H-NMR (CDCl 3 , 400 MHz) δ 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), m/z 266 (M<*>+1).

A mixture of methyl 2-acetylamino-4-[2-(N-methylamino)-ethylamino]benzoate (145 mg, 0.55 mmol), 3-methoxy-4[ N'~ (2-methylphenyl)ureido]phenylacetic acid ( 172 mg, 0.55 mmol), EDC-HCl

(158 mg, 0.83 mmol), HOBt (141 mg, 1.05 mmol) / and DMAP (13 mg, 0.11 mmol) in DMF (10 mL) was stirred for 18 h. The mixture was diluted with EtOAc (3 0 0 ml), washed with brine and dried over MgSO 4 .After removal of the solvent, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of CHCl 3 -MeOH from 100:0 to 70:30 ) to give methyl 2-acetylamino-4- [2-Δ7- [3-methoxy-4- [Δ7'-(2-methylphenyl)ureido]-phenyl]-Δ7-methylacetamido] ethylaminobenzoate (309 mg, 100% ) as an amorphous foam.

1H-NMR (CDCl 3 )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, 4H), 3.85 (s, 3H), 6.20 (m, 1H), 6.58 (s, 1H), 6.65-6.75 (m, 3H), 7.13 (m, 2H) , 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/z 562 (M<*>+1).

To a solution of methyl 2-acetylamino-4-[2-A7- [3-methoxy-4-(N'-(2-methylphenyl)ureido] phenyl] -N-methylacetamido]ethylaminobenzoate (3 0 9 mg, 0, 55 mmol) in THF-MeOH (1:1, v/v, 9 mL) was added 0.25 N NaOH (4.4 mL, 1.1 mmol) at room temperature and the solution was heated to reflux. was continued for 18 hours with reflux • The reaction mixture was poured into water, and acidified to pH 5.0

r

with 1.0 N HCl. The resulting precipitate was recrystallized with hexane-diethyl ether to give 302 (175 mg., 58%) as a pale red powder. MV 547, 60. 'H-NMR (CD3OD) δ 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, 1H), 6.60-6.82 (m, 2 H), 7.00 (m, 1 H), 7.15 (m, 2 H), 7.53 (m, 1

H), 7.77-7.96 (m, 3H); MS (FAB) m/z 548 (Wr+\)\ Anal.Calculated for C^NA -0.5 Hj.0: C, 62.58; H, 6.16; N, 12.58. Found: C, 62.55; H, 6.31; N, 12.15. EXAMPLE 223 2-Acetylamino-4-[2-N-[4-N'-(2-bromophenyl)ureido]-3-methoxyphenyl]-α7-methylacetamido]ethylaminobenzpsy acid

A mixture of methyl 2-acetylamino-4-(2-N-methylamino-1-efcylamino)benzoate (145 mg, 0.55 mmol), 3-methoxy-4-[N'-(2-bromophenyl)ureido ] f phenylacetic acid (209 mg, 0.55 mmol), EDC-HCl (158 mg, 0.83 mmol), HOBt (141 mg, 1.05 mmol), and DMAP (13 mg, 0.11 mmol) in DMF (10 ml) was stirred for 18 h. The mixture was diluted with EtOAc (300 mL), washed with brine and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of CHCl3-MeOH from 100:0 to 70:30) to give methyl 2-acetylamino-4-[2-N - [4- [ N'~ (2-bromophenyl)ureido]-3-methoxyphenyl]-N-methylacetamido]ethylaminobenzoate (294 mg, 85%) as an amorphous foam. 1H-NMR (CDCl 3 ) δ 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, 3 H), 3.86 (s, 3 H), 6.21 (m, 1 H), 6.79 (ra, 2 H), 6f93 (m, 1H), 7.10 (d, J = 10.3 Hz, 1 H), 7.30 (m, 1 h ), 7.42 (m, 1H), 7.61 (m, 1H), 7.78-7.85 (m, 2H), 7.93 (m, 2H), 8.13 (m, 1H); MS (FAB), m/z 627 (M<*>).

To a solution of methyl 2-acetylamino-4-[3-methoxy-4- [ N'~

(2-Bromophenyl)ureido]phenylacetamido]-2-N-methylamino-1-ethylaminobenzoate (294 mg, 0.47 mmol) in THF-MeOH (1:1, v/v, 8 mL) was added 0 .25 N NaOH (3.8 mL, 0.94 mmol) at room temperature, and the solution was heated to reflux. 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 HCl. The resulting precipitate was recrystallized with hexane-diethyl ether to give 3 03 as a white powder (210 mg, 73%). Etc. 612.47. Melting point: 155-160°C,

n-NMR(CD3OD) δ 22.18 (d, J = 5.5 Hz, 3 H), 3.00 and 3.12 (2 s, total 3 H), 3.39 (m, 1H), 3.60 (m, 4 H), 3.70 (s , 1 H), 3.85 and 3.86 (2 s, total 3 H), 6.31 (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*); ^na/Calcd for C2!H3iBr1N5O6-0.75 H70: C, 53.64; H, 5.22; N, 11.17. FoundfcC, 53.89; H, 5.23; N, 10.69.

EXAMPLE 224

4- [2-N- [ [4- [N'~ (2-chlorophenyl)ureido] -3-methoxyphenyl] -N-phenylacetamido]ethoxy]benzoic acid

To a solution of methyl 4-[2-(methanesulfonyloxy)ethoxy]benzoate (2.74 g, 10 mmol) in MeCN (50 mL) was added aniline (9.1 mL, 100 mmol) at room temperature. The reaction mixture was stirred for 64 hours at reflux. The mixture was poured into H 2 O (200 mL), extracted with EtOAc (100 mL x 2) and dried over MgSO 4 . After removal of the solvent in vacuo, the unreacted aniline was removed in vacuo by coevaporation with toluene (10 mL x 3) at 80°C. The residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm x 150 mm, CHCl3) to give methyl 4-[2-(N-phenylamino)ethoxy]benzoate (2.23 g, 82% ) as a colorless oil. 1H-NMR (CDCl 3 ) δ 3.56 (t, J= 5.1 Hz, 2 H), 3.90 (s, 3.H), 4.21 (t, 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 (MN-1).

To a mixture of methyl 4-[2-(N-phenylamino)ethoxy]benzoate (136 mg, 0.5 mmol), 3-methoxy-4-[N'-(2-chlorophenyl)ureido]-phenylacetic acid (167 mg , 0.5 mmol), and PyBOP (781 mg, 0.75 mmol), i -PrNEt 2 (261 mL, 0.96 mmol) in DMF (10 mL) was stirred for 18 h. The mixture was diluted with EtOAc (100 mL), washed with 1 N HCl, brine and dried over MgSO 4 . The residue was co-evaporated with toluene (10 mL x 3) to remove DMF. The residue was chromatographed on TLC (MERCK, silica gel 60.2 mm, 2 plates, CHCl 3 -MeOH, 20:1) to give methyl 4-[2-AT-[[4-[ N'~ (2-chlorophenyl) ureido]-3-methoxy enyl]-AJ-phenylacetamido]-ethoxy]benzoate (129 mg, 44%) as a white amorphous foam.

1H-NMR (CDCl1) δ 3.42 (s, 1 H), 3.69 (d, J = 8.3 Hz, 1H), 3.74 (s, 3 H), 3.87 (s, 3 H), 4.10 (m, 2 H ), 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-AJ-[[4-[W-(2-chlorophenyl)-ureido]-3-methoxyphenyl]-AJ-phenylacetamido]ethoxy]benzoate (124 mg, 0.19 mmol ) in THF-MeOH (6:1, v/v, 3 mL), 0.5 N NaOH (2 mL, 1 mmol) was added at room temperature, and the solution was heated to reflux in a sealed flask. Stirring was continued for 15 hours at reflux. The reaction mixture was poured into water, acidified with 1.0 N HCl, extracted with CHCl 3 -MeOH (2:1, 20 mL x 3) and dried over MgSO 4 . After removal of the solvent, the residue was crystallized with CHCl 3 -hexane-diethyl ether to give 304 (77 mg, 64%) as a white powder. MV 57.4,02.

1 H-NMR (CD 3 OD) δ 3.45 (s, 2 H), 3.79 (s, 3 H), 4.12 (m, 2 H), 4.22" (m, 2 H), 6.48 (dd, J = 2.0 Hz, 8.3 Hz, 1H); 6.61 (d, J = 2.0 Hz, 1 H), 6*87. (d, J= 8.8 Hz, 2 - H), 7.00 (m, 1 H), 7.22 (m, 3 H ), 7.36 (m, 1H), 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 (M*); Anal. Meant for

< C 31 H 2 , ClN 3 O 6 -0.5 H, 0: C, 63.86; H, 5.01; N, 7.21. Found: C, 63.67; H, 4.91; N.-6.99.

EXAMPLE 225

(S)-4-[2-AJ-[[3-methoxy-4-[AJ'-(2-methylphenyl)ureido]phenyl]-AJ-(2-aminobenzyl)acetamido]-1-propoxy]benzoic acid

To a cooled (0°C) solution of benzyl (S)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde

(0.87 g, 5.76 mol) in MEOH-AcOH (16 mL, 15:1, v/v) was.

the added NaBH3CN (1.65 g, 26.3 mmol) and reaction

the mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHCd 3 and extracted with EtOAc. The extract was washed with saline, dried over Na2SO4 and evaporated. The residue was purified by column

chromatography on silica gel with CHCl 3 to 5% MeOH in CHCl 3 as eluent to give benzyl (S)-4-[2-(2-nitrobenzyl-amino)-1-propoxy] benzoate (931 mg, 41%) as a yellow oil .

'H-NMR (CDCl1) 5

1.21 (d, J= 6.4 Hz, 3 H), 3.13-3.18 (rn, 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, 2H), 7.29-7.65 (m, 8H), 7.94-8.03 (ra, 3H); MS (FAB) m/z 421 (M<*>+1).

A mixture of pentafluorophenyl 3-methoxy-4-[N '-(2-methyl-phenyl)ureido]phenylacetate (4 60 mg, 0.96 mmol), benzyl (S)-4-[2-(2-nitrobenzylamino) -1-pyropoxy] benzoate (403 mg, 0.96

mmol) and Et 3 N (200 mL, 1.43 mmol) in DMF (8 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with 0.5N HCl, brine, dried over

Na2S04 and evapd. The residue was purified by column-

- chromatography" on silica gel with 1% MeOH r CHCl 3 as eluent to give benzyl (S)-4- [2-N- [ [3-methoxy-4- [ N'-(2-methylphenyl)ureido]phenyl] -N-(2-nitrobenzyl)acetamido]-1-propoxy]benzoate (504 mg, 73%) as a brown amorphous solid MS

(FAB), m/z 717 (M++1).

A stirred solution of benzyl (S)-4-[2-N-[[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenyl]-N-(2-nitrobenzyl)acetamido]-1- ■ "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 atmospheres overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated. The residue was purified by preparative thin layer chromatography eluting with 5% MeOH in CHCl 3 to give 305 (115 mg, 27%) as a

white powder. VAT 596.67. MS (FAB), m/z 597 (M++1).

EXAMPLE1 226

(S)-4-[2-A7-[[4-[AT-(2-bromophenyl)ureido]-3-methoxyphenyl]-N-(2-nitrobenzyl)acetamido]-1-propoxy]benzoic acid

To a cooled (0°C) solution of benzyl (5)-4-(2-amino-1-propoxy)benzoate (1.50 g, 5.26 mmol) and 2-nitrobenzaldehyde (0.87 g, 5, 76 mmol) in MeOH-AcOH (16 mL, 15:1, v/v) was added NaBH 3 CN (1.65 g, 26.3 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHCO 3 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to 5% MeOH in CHCl 3 as eluent to give benzyl (S)-4-[2-(2-nitrobenzyl-amino)-1-propoxy] benzoate (931 mg, 42%) as a yellow oil.

'H-NMRCCDC^S

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, 2H), 7.29-7.65 (m, 8H), 7.94-8.03 (m, 3H); FAB-MAS, m/z 421 (tVT+1).

A mixture of 4-[N-(2-bromophenyl)ureido]-3-methoxyphenyl-acetic acid (476 mg, 1.26 mmol), benzyl (S)-4-[2-(2-nitro-benzylamino)-1 -propoxy] benzoate (528 mg, 1.26 mmol), EDC-HCl

(361 mg, 1.88 mmol), HOBt (255 mg, 1.89 mmol) and DMAP (30 mg, 0.25 mmol) in DMF (10 mL) were stirred at room temperature overnight. 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 N HCl, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on silica gel with CHCl 3 to 2% MeOH in CHCl 3 as eluent to give the title compound as a crude oil. To a stirred solution of the crude product in THF-MeOH (10 mL, 1:1, v/v) was added 0.5 N NaOH (10 mL), and the reaction mixture was heated under reflux for 3 h. The mixture was completely incorporated

ice-H 2 O and the basic aqueous layer was acidified (pH 4.3) with 1 N HCl. The resulting precipitate was collected and the crude solid was purified by preparative thin layer chromatography eluting with 5% MeOH in CHCl 3 to give 306 (162 mg, 2 steps, 19%) as a white amorphous solid. VAT 691.53.

MS (FAB), m/z 692 {M*+1); Anal. Calcd for C3jrI3IBrN<0?-7/4H10: C, 54.82; H, 4.81; N, 7.75. Found.C, 54.80; H, 4.61; N, 7.24.

EXAMPLE 227

4-[2-A7-cyclobpropyl-A7-[4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenyl]acetamido]ethoxybenzoic acid

A mixture of methyl 4-(2-cyclopropylaminoethoxy)benzoate (290 mg, 1.23 mmol), 4-[Δ7'-(2-chlorophenyl)ureido]-3-methoxyphenyl-r acetic acid (412 mg, 1, 23 mmol), EDC-HCl (354 mg, 1.85 mmol), HOBt (cat.), and DMAP (cat.) in DMF (10 mL) were stirred. over the night. The mixture was partitioned between EtOAc (300 mL) and H 2 O

(100 ml). The organic phase was separated, washed with brine (2 x 100 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[2-A7-cyclopropyl-AT-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenyl] acetamido]ethoxy-behzoate (506 mg, 75%) as a yellow viscous oil.

1H-NMR (CDCl1) δ 0.90-0.97 (m, 4 H), 2.75 (m, 1 H), 3.61 (s, 3 H), 3.79 (t, J= 5.4 Hz, 2 H), 3.87 (s , 3 H), 3.88 (s, 2H), 4.16 (t, J= 5.4 Hz, 2 H), 6.76-6.80 (m, 4 H), 6.95 (dt, J= 7.8, 1.5 Hz, 1 H), 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 (dd,.7= 8.3, 1.5Hz , IK).

To a stirred solution of methyl 4-[2-AJ-c<y>chloro<p>rop<y>l-N-[4-[A7'-(2-chlorophenyl)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 HCl (50 mL) and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL); The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20:1 to 10:1) as eluent to give 307 (403 mg, 82%) as a colorless amorphous solid.. MW 537.99. 'H-NMR PMSO) 6 0.86-0.91 (m, 4 H), 2.75 (iri, 1 H), 3.69 (t, J = 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, 7 = 7.8 Hz, 1 H), 7.44 (d, ./ = 7.8 Hz, 1 H), 7.88 (d,J= 8.8 Hz, 2 H), 7.96 (d, /= 8.1 Hz, 1 H) , 8.10 (d, J =8.3 Hz, 1 H), 8.89 (s, 1 H), 8.93 (s, 1 H), 12.65 (s, br s); MS (FAB), m/z 538 CNT+1); ^«a/Calculated for- dgHMClNA: C, 62.51; H, 5.25; N, 7.81. Found: C, 61.85; H, 5.42; N, 7.41. iEXAMPLE 228 | " 4-[2-N-cyclohexyl-A7-[3-methoxy-4-[N-(2-methylphenyl)ureido]- phenyl] acetamido] ethoxybenzoic acid

To a solution of methyl 4-[(2-methanesulfonyloxy),-1-ethoxy]benzoate (2.74 g, 10 mmol) in MeCN (50 mL), was added cyclohexylamine (5.72 mL, 50 mmol) at room temperature. The reaction mixture was stirred for 18 hours at reflux. The mixture was poured into H 2 O (200 mL), extracted with EtOAc (100 mL x 2), and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm x 150 mm, linear gradient of CHCl 3 -EtOAc from 10:0 to 1:1) to give

methyl 4-(2-A7-cyclohexylamino)ethoxybenzoate (2.43 g, 88%) as a colorless oil. 1H-NMR(CDCl1)6 1.10 (m, 2H), 1.25 (m, 2H), 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, J = 7.99 Hz, 2 H); MS (ESI), m/z 278

(M<+>+l).

A mixture of methyl 4-(2-A7-cyclohexylamino)ethoxybenzoate (139 mg, 0.5 mmol), 3-methoxy-4-[N-(2-methylphenyl)ureido]-phenylacetic acid (157 mg, 0 .5 mmol), EDC-HCl (144 mg, 0.75 mmol), HOBt (128 mg, 0.95 mmol), and DMAP (12 mg, 0.1 mmol) in DMF (2.5 mL) were stirred for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1N HCl and brine, and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCl 3 -EtOAc 10:0 to 1:4) to give methyl 4-[2-A7-cyclohexyl-N- [3-Methoxy-4-[ N'~ (2-methylphenyl) ureido] phenyl] acetamido] ethoxybenzoate (2 47 mg, 8 6%) as an amorphous foam. 1H-NMR (CDCl1) δ 1.08-1.80 (m, 10 H), 2.30 (s, 3 H), 3.60-3.79 (ra, 8 H), 3.88 (s, 3 H), 4.16 (m, 2 H ), 6.30 (s, 1 H), 6.70-6.83 (ra, 2 H), 6.88 (d, 2 H, J= 9.0 Hz), 7.12 (ra, 2 H), 7.23 (ra,' 1 H), 7.60 (d, 1H, J = 8.3 Hz), 7.92 (d, 2 H, /= 9.0 Hz), 8.10 (d, 1 H, J = 8.0 Hz); MS (ESI) m/z 574 (M<*>+1).

To a solution of methyl 4-[2-A7-cyclohexyl-A7-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate (247 mg, 0.43 mmol) in THF-MeOH (6:1, v/v, 7 mL), 0.5 N NaOH (3.4 mL, 0.84 mmol) was added at room temperature, and the solution was heated to reflux in a sealed flask. Stirring was continued for 18 hours at reflux. The reaction mixture was poured into water, acidified with 1.0 N HCl, extracted with CHCl 3 -MeOH (2:1, 20 mL x 3) and dried over MgSO 4 . After removal of the solvent, the residue was crystallized with CHCl 3 -hexane-diethyl ether to give 308 (196 mg, 81%) as a white powder.' MV 559.62..

1H-NMR (CDjOD) δ 0.90-1.82 (ra, 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, 2 H), 6.96 (m, 3 H), 7.16 (m, 2 H), 7.58 (d, J= 1. 1 Hz, 1 H), 7.92 (m , 3H); MS (ESI) m/z 560 (M*+1); Anal. Calculated for Cj2H37NjOe-0.5 HjO: C, 67.59; H, 6.74; N, 7.39. Found: C, 67.83; H, 6.80; N, 7.13.

EXAMPLE 229

4- [ 2- N- [4- [AT'-(2-Chlorophenyl)ureido]-3-methoxyphenyl]-A7-propagylacetamido]ethoxybenzoic acid

To a solution of methyl 4-[(2-methanesulfonyloxy)-1-ethoxy]benzoate (2.74 g, 10 mmol) in MeCN (50 mL), was added propargylamine (3.43 mL, 50 mmol) at room temperature . The reaction mixture was stirred for 18 hours at reflux. The mixture was poured into H 2 O (200 mL), extracted with EtOAc (100 mL x 2) and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, f50 mm x 150 mm, linear gradient of CHCl 3 -EtOAc from 10:0 to 9:1) to afford methyl 4-(2-N-propargylamino)ethoxybenzoate (2.33 g, 100%) as a colorless oil. 1H-NMR (CDCl1) δ 2.28 (d, J= 2.4 Hz, 1 H), 3.11 (t, J= 5.1 Hz, 2 H), 3.52 (d, J= 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, /= 8.8 Hz, 2 H); MS (ESI) m/z 234 (M*+1).

A mixture of methyl 4-(2-N-propargylamino)ethoxybenzoate (117 mg, 0.5 mmol), 3-methoxy-4-[ N"-(2-chlorophenyl)ureido]phenylacetic acid (167 mg, 0.5 mmol ) EDC-HCl (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 h. The mixture was diluted with EtOAc (100 mL), washed with 1 N HCl, brine and dried over MgSO 4 . The residue was co-evaporated with toluene (10 mL x 3) to remove DMF. The residue was chromatographed on TLC (MERCK, silica gel 60.2 mm , 2 plates, CHCl3-MeOH, 20:1) to give methyl 4- [2-A7- [4- [AT-(2-chlorophenyl)ureido] -3-methoxyphenyl] -A7-propargylacetamido]ethoxybenzoate (244 mg , 89%) as a white amorphous foam. 1 H-NMR (CDCl 3 ) δ 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, 4 H), 6.99 (m, 1 H), 7.11 (m, 2 H), 7.24 (m, 1 H), 7.34 ( d, /= 7.9 Hz, 1 H), 7.96 (m, 3 H), 8.18 (dd, J = 1.5 Hz, 8.3 Hz, 1 H); MS (ESI) m/ z 550 (M<*>).

To a solution of methyl 4-[2-N-[4-[N'-)2-chlorophenyl)-ureido]-3-methoxyphenyl]-A7-propargylacetamido]ethoxybenzoate (240 mg, 0.44 mmol) in To THF-MeOH-H 2 O (2:2:1, v/v, 10 mL) was added NaOH (500 mg, 12.5 mmol) at room temperature. Stirring was continued for 2 hours at room temperature. The reaction mixture was poured into water, acidified with 1.0 N HCl, extracted with CHCl 3 -MeOH (2:1, 20 mL x 3) and dried over MgSO 4 . The residue was chromatographed on TLC (Whatman, 1 mm, 3 plates, CHCl 3 -MeOH, 92:8) to give 309 (202 mg, 86%) as a white solid. MV 535.98..'H-NMR (CD3OD) δ 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 ( rn, 1 H), 4.24 (m, 1 H), 4.32 (m, 2 H), 6.80 (d, /= 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*+1); H.5.33; N, 7.29. Found C.58.23; H, 4.77; N, 6.91.

EXAMPLES 230 and 231

4-[2-A7-allyl-A7-[4-[AT-(2-chlorophenyl)ureido]-3-methoxyphenyl]-acetamido]ethoxybenzoic acid

A mixture of methyl 4-(2-N-allylamino)ethoxybenzoate (118 mg, 0.5 mmol), 3-methoxy-4- [ N'~ (2-chlorophenyl)ureido] phenylacetic acid (167 mg, 0.5 mmol ), EDC-HCl (144 g, 0.75 mmol), HOBt (128 mg, 0.95 mmol) and DMAP (12 mg, 0.1 mmol) in DMF (2.5 mL) were stirred for 18 h. The mixture was diluted with EtOAc (300 mL), washed with 1N HCl and brine, and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCl3-EtOAC 100:0 to 85:15) to give methyl 4- [2-AT-allyl-N- [ 4-[ N' -(2-chlorophenyl)ureido]-3-methoxyphenyl]acetamido]ethoxybenzoate (253 mg, 92%) as an amorphous foam.

'H-NMR

(CDCl 3 ) δ 3.65-3.85 (m, 4H), 3.73 (s, 3H), 3.88 (s, 3H), 5.08 (m, 2H), 4.22 (rn, 2H), 5.10-5.24

(m, 2H), 5.76 (m, 1H), 6.77 (m, 2H), 6.85 (xn, 2H), 6.99 (m, 1H), 7.06 (m, 2H), 7.26 (m, 1H),

7.34 (d, 1 H, J = 8.1 Hz), 7.94 (d, 2 H, J = 8.8 Hz), 7.98 (rn, 1 H), 8.18 (d, 1 H, J «= 6.9 Hz); MS

(FAB) m/z 552 (M<+>).

To a solution of methyl 4-[2-A7-allyl-N-[4-[ N'~ (2-chlorophenyl)ureido]-3-methoxyphenyl] acetamido]ethoxybenzoate

(250 mg, 0.45 mmol) in THF-MeOH (1:1, v/v, 8 mL), was

added 0.25 N NaOH (3.6 ml, 0.91 mmol) at room

temperature, and the solution was heated at reflux. Stirring was continued for 18 hours at reflux. The reaction mixture was poured into water and acidified with 1.0 N HCl. The resulting precipitate was collected by filtration. The precipitate was recrystallized with hexane-diethyl ether to give 310 as a white powder (195 mg, 80%). VAT 537.99. 1H-NMR(CD 3 OD) 5 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 (xn, 1 H), 6.92 (m, 2 H), 7.01 (m, IK) ,

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 QA*) ;Anal. Calculated)

for CHaClN 2 O, 1/4 H 2 O: C, 61.99; H, 5.30; N, 7.75. Found: C, 62.00; H, 5.56; N, 7.76.

EXAMPLE 232

4-[2-N-allyl-N-[4-[N-(2-bromophenyl)ureido]-3-methoxyphenyl]-acetamido]ethoxybenzoic acid.

A mixture of methyl 4-(2-A7-allylamino) ethoxybenzoate (118 mg, 0.5 mmol), 4-[ Nf -(2-bromophenyl)ureido]-3-methoxyphenyl-acetic acid (190 mg, 0.5 mmol ), EDC-HCl (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 h. The mixture was diluted with EtOAc (300 mL), washed with 1N HCl and brine, and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel (mid pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCl3-EtOAC

100:0 to 70:30) to give methyl 4-[2-N-allyl-N-[4-[ N -(2-bromophenyl)ureido]-3-methoxyphenyl] acetamido]ethoxybenzoate (251 mg, 84% )- as an amorphous foam..'H-NMR

(CDCyS 3.65-3.85 (m, 4H), 3.73 (s, 3H), 3.88 (s, 3H), 4.08 (m, 2H), 4.22 (m, 2H), 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, 1H),

7.51 (m, 1 H), 7.94 (d, 2 H, J = 8.8 Hz), 7.97 (m, 1 H), 8.14 (m, 1 H); MS (FAB) m/z 596 (M<+>).

To a solution of methyl 4-[2-ΔT-allyl-Δ7-[4-[N'-(2-bromophenyl)ureido]-3-methoxyphenyl] acetamido]ethoxybenzoate

(251 mg, 0.42 mmol) in THF-MeOH (1:1, v/v, 8 mL), 0.25 N NaOH (3.4 mL, 0.84 mmol) was added at room temperature, and the soln. was heated to reflux. Stirring was continued for 18 hours at reflux. The reaction mixture was poured into water and acidified with 1.0 N HCl. The resulting precipitate. was collected by filtration. The precipitate was recrystallized with hexane-diethyl ether to give 311 (192 mg, 78%) as a white powder. VAT 582.44. 1 H-NMR (CD 3 OD) 6 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, 2H), . 5.81 (m, 1 H), 6.76 (m, 1 H), 6.82 (m, 1 H). 6.93 (m, 3 H), 7.29 (m, 1 H), 7.56 (m, 1 H),

7.94 (m, 4H); MS (FAB), m/z 582 (MT); Anal. Calculated for Cj,HIBBrN306: C, 57.74; H, 4.85; N, 7.21. Found: C, 57.40; H, 5.07; N, 7.04. For HCl saltav311 : ^«a/.Bere<g>net for Ci,HI7BrN3Cv0.25 H20:

C, 55.23; H, 4.55; N, 6.90. Found: C, 54.98; H, 4.71; N, 6.53. EXAMPLE 233 4-[2-N-allyl-Δ7-[3-methyl-4-[N'-(2-methylphenyl)ureido]phenyl]- acetamido]ethoxybenzoic acid

A mixture of methyl 4-(2-N-allylamino-1-ethyl)ethoxybenzoate (87 mg, 0.37 mmol), 3-methyl-4[ N -(2-methylphenyl)ureido]phenylacetic acid (100 mg, 0, 37 mmol), EDC-HCl (105 mg, 0.56 mmol), HOBt (95 mg, 0.70 mmol), and DMAP (9 mg, 0.07 mmol) in DMF (7.4 mL) were stirred in 18 hours. The mixture was diluted with EtOAc (100 mL), washed with 1N HCl and brine, and dried over MgSO 4 . 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, CHCl 3 -MeOH, 97:3) to give methyl 4-[2-AT-allyl-N-[3-methyl-4-[ N'-( 2-Methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate (190 mg, 100%) as a white amorphous foam.

1 H-NMR (CDCl 3 ) 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), 4.08. (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<*>+1).

To a solution of methyl 4-[2-A7-allyl-A7-[3-methyl-4-[ N'-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate (217 mg, 0.43 mmol) in THF-MeOH (6:1, v/v, 7 mL), 0.5 N NaOH (1.9 mL, 0.86 mmol) was added at room temperature, and the solution was heated to reflux. Stirring was continued for 2 hours at reflux in a sealed flask. The reaction mixture was poured into water, and acidified with 1.0 N HCl, extracted with CHCl 3 -MeOH (2:1, 20 ml x 3), and dried over MgSO 4 . After removal of the solvent, the residue was crystallized with CHCl 3 -hexane-diethyl ether to give 312 (-8<*>4 ing, 3'8'%) as a white powder. MW 501.37.

'H-NMR (CD3OD)5 2.18 and 2.24 (s, total 3 H), 2.30 (d, J= 4.9 Hz,

3 H), 3.70 (s, 1 H), 3.78 (m, 2 H), 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, 7H), 7.58 (m, 2H), 7.96 (m, 2H); MS (ESI) m/z 502 (M*); Anal. Calculated ofr CÆNjOj: C, 69.44; H, 6.23; N, 8.38. Funnef.C, 68.99; H, 6.39; N, 8.03.

EXAMPLE 234

4-[2-N-allyl-N-ffc^chloro-4'-[;2v"/;--42^.methylphenyl)ureido]-phenylacetamido]ethoxybenzoic acid

To a stirred solution of methyl 4-(2-AT-allylaminoethoxy)-benzoate (141 mg, 0.60 mmol) and 3-chloro-4-[ N'~ (2-methylphenyl)-ureido] phenylacetic acid (191 mg, 0.60 mmol) in DMF (5 mL) was added EDC-HCl (172.5 mg, 0.90 mmol), HOBt (154 mg, 1.14 mmol), and DMAP (15 mg, 0.12 mmol ), and the stirring became. continued overnight at room temperature. The mixture was diluted with EtOAc (50 mL) and washed with 1M HCl (x 3), 1M NaOH (x 1), and brine. The mixture was dried over anhydrous MgSO4 and concentrated under reduced pressure to give methyl 4-{2-N-allyl-W-[3-chloro-4-[A7'-(2-methylphenyl)ureido]phenyl]acetamido ] - ethoxybenzoate .(3 50 mg, -10.9.%) as .a .white .powder.

1H-NMR (CDCl1) δ 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, 2H), 7.20 (m, 4 H), 7.50 (d, J= 8.1 Hz, 1 H), 7.95 ( å, J= 8.1 Hz, 2H), 8.12 (d, 7= 8.1 Hz, 1 H); MS (ESI) m/z: 536 (M<+>+H).

To a stirred solution of methyl 4-[2-N-allyl-AT-[3-chloro-4-[ N -(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate (321 mg, 0.6 mmol) in THF -MeOH-H 2 O (2:2:1, v/v, 30 mL), was added NaOH (500 mg, 12.5 mmol) at room temperature. Stirring was continued for 18 hours at room temperature. The reaction mixture was poured into water, washed with diethyl ether, acidified with 1M HCl, extracted with CHCl 3 -MeOH (2:1, 20 mL x 3), dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residue was solidified with CHCl 3 /n-hexane to -. to •■■give -313 ■. (28.3' ;.mg./_. 83%);; as,, a.~white • solid .

ER (KBr): 3345, 1581, 1529, 1243, 1167. cm"'; 'H-NMR (CD3OD)8 2.30 (s, 3 H), 3.71 (s, 1 H), 3.78 (m, 1 H) , 3.82 (rn, 1 H), 3.89 (s, 1 H), 4.10 (m, 1 H), 4.19 (rn, 2H), 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*+1); Anal. Calculated for Cj8HJgClN30j-1.75 HjO: C, 60.76; H, 5.74; N, 7.59. Found: C, 60.43; H, 5.34; N, 7.17.

EXAMPLE 235

Methyl 4-[2-A7-[2-(4-morpholinyl)ethyl]-A7-[3-methoxy-4-[W-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate

To a stirred solution of methyl 4-[2-A7-2,3-dihydroxy-1-propyl)-[3-methoxy-4- [ N'~ (2-methylphenyl)ureido] phenylacetamido]ethoxy]benzoate (1, 83 g, 3.24 mmol) in THF-MeOH-H 2 O (1:1:1, v/v, 15 mL) was added sodium periodate (2.08 g, 9.71 mmol) and the solution was stirred for 18 hours at room temperature. Saturated Na 2 S 2 O 3 (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, and dried over MgSO 4 . The solvent was removed to give the title compound (1.73 g, 100%) as an amorphous foam.

'H-NMR (CDC1,)'6 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 (m, 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, 1H), 9.57 and 9.63 (2 s, total 1 H); MS (FAB), m/z 534 (M<+>+ 1).

To a stirred solution of methyl 4-[2-Δ7-formylmethyl-Δ7-[3-methoxy-4-[ N -(2-methylphenyl)ureido]phenylacetamido]ethoxy]-benzoate (400 mg, 0.75 mmol) in To EtOH (7.5 mL) was added morpholine (654 mL, 7.5 mmol) and acetic acid (429 mL, 7.5 mmol) at room temperature. The reaction mixture was stirred for 5 min. at room temperature, and then cooled to 0°C. To the cooled solution was added NaBH 3 CN (471 mg, 7.5 mmol) and stirring was continued for one hour at room temperature. The mixture was poured into saturated NaHCO 3 and was extracted with EtOAc (50 mL x 3), washed with brine and dried over MgSO 4 . After removing the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient toluene-acetone 100:0 to 1:1) to give 314 (346 mg, 76%) as a white amorphous foam. 1H-NMR (CDC13,400

MHz) 5 2.31 (s, 3H), 2.46 (rri; 4 H), 3.52-3.79 (m, 12 H), 3.70 (d, 3 H, J= 2.7 Hz), 4.05 and 4.22 (m, total 2 H ), 6.24- and" 6.29 (s, total 1 H), 6.73 (m, 2 H), 6.85 (m, 2 H); 7.0? (s, .1 H), 7.17 (m, 1 H), 7.25 (m, 2 H), 7.^0 (t, 1 H, J= 7.3 Hz), 7.96 (m, 2 H), 8.08 (m, 1 H); MS.(FAB), /n/z 605

(M<+>+ 1); ^na/.-Calculated fqrC33H,0N4071/2 H30: C,-64.58; H, 6.73; N, 9.13. Found: C, 64.95; H,

6.88; N, 8.82. HCl salt of 314 : Anal Calculated for C33H<,ClN,07-2.5 H,0: C, 57.76; H, 6.76; N, 8.16; Cl, 5.17; Found: C, 58.29; H, 6.81; N, 7.42; Cl, 5.05.

EXAMPLE 236

4- [2-N- [2-(4-morpholinyl)ethyl] -A7- [3-methoxy-4- [Nf-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid

To a solution of methyl 4-[2-N-[2-(4-morpholinyl)ethyl]-N-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenyl]acetamido]-ethoxybenzoate ( 14 6 mg, 0.24 mmol) in THF-MeOH (1:1, v/v, 6 mL), 0.25 N NaOH (1.9 mL, 0.48 mmol) was added at room temperature, and the solution was heated to reflux. Stirring was continued for 18 hours at reflux. The reaction mixture was poured into water and acidified with 1.0 N HCl. The mixture was extracted with CHCl 3 -MeOH (3:1, v/v, 30 mL x 5). The combined organic solvent was dried over MgSO 4 . After removal of the solvent, the residue was crystallized with diethyl ether to give 315 (102 mg, 71%) as a white powder.

1 H-NMR (CD 3 OD) 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,

3 H), 4.12 (m, 1 H), 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, /= 7.8 Hz, 1 H), 7.93 (m, 3 H); MS (FAB) m/z 591 (M<*>); Anal Calcd for CjjHjgNA 1.0 HjO: C, 63.14; H, 6.62; N, 9.20. Found: C, 63.48; H, 6.66; N, 8.79. EXAMPLE 237 4-[2-]n"-cyclopropyl-Δ7-[3-methoxy-4-[Nf-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid

To a stirred solution of methyl 4-(2-hydroxyethyloxy)-benzoate (5.00 g, 25.5 mmol), DMSO (18.1 mL, 255 mmol), and Et3N (17.7 mL, 127.5 mmol) in CH 2 Cl 2 (200 mL) was added SO 3 -Py (12.2 g, 76.5 mmol). After stirring for 5 h, the mixture was concentrated in vacuo and the residue was diluted with H 2 O (100 mL). The mixture was extracted with EtOAc (2 x 200 mL). The combined extracts were washed with brine

(100 mL), dried over (MgSO 4 ) and evaporated. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) to give a 4:1 mixture of methyl 4-formylmethyloxybenzoate and methyl 4-hydroxybenzoate (2.00 g) as a white solid. 'H-NMR'

(CDC13)5 3.90 (s, 3 H), 4.64 (d, / = 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 ( å, J= 1.0 Hz, 1 H)<

To a stirred solution of a 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 NaBH 3 CN (681 mg, 10.3 mmol) was added. After stirring overnight, the mixture was quenched by the addition of saturated NaHCO 3 (50 mL) and extracted with CHCl 3 (2 x 200 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20:1) to give methyl 4-(2-cyclopropylaminoethoxy)benzoate (595 mg, 49%) as a colorless oil.

1H-NMR (CDCl 3 ) 6 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, J= 5.2 Hz, 2 H), 6.92 (d, J= 8.8 Hz, 2 H), 7.98 (d, J= 8.8 Hz, 2 H).

A mixture of methyl 4-(2-cyclopropylaminoethoxy)benzoate (290 mg, 1.23 mmol), 3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenylacetic acid (387 mg, 1.23 mmol), EDC-HCl (354 mg, 1.85 mmol), HOBt (cat.), and DMAP (cat.) in DMF (10 mL) were stirred overnight. The mixture was partitioned between EtOAc (300 mL) and H 2 O (100 mL). The organic phase was separated, washed with brine (2 x 100 ml), dried over MgSO 4 , and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (50:1) to give the title compound (426 mg, 65%) as a yellow viscous oil.

'H-NMR. (CDC13)8 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-[A7-cyclopropyl-[3-methoxy-4-[A7'-(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 1N HCl (50 mL) and extracted with CHCl 3 -MeOH (4:1, 2 x 200 mL). The combined extracts were dried, over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -MeOH (20-.1 to 10:1) as eluent to give 316 (333 mg, 80%) as a colorless amorphous solid. 1 H-NMR (DMSO) δ 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, J=8.1Hz, 1 H), 7.88 (d, J= 8.5 Hz, 2 H), 8.01 (d, .7=8.1 Hz , 1 H), 8.47 (p, 1

H), 8.55 (s, 1 H), 12.96 (s, br s); MS (FAB), m/ z 518 (M++l)Mno/. Calculated for C^NA<:> C,

67.30; H, 6.04; N, 8.12. Found: C, 66.71; H, 6.26; N, 7.82.

EXAMPLE 238

4- [ 2- N- [2- (AJ', A7'-dimethylamino.)-1-ethyl)-AJ- [-4- [ N' '-(2-chlorophenyl)ureido]-3-methoxyphenyl]acetamido ]ethoxybenzoic acid

To a solution of methyl 4- [2-N- [2- (N', N'-diethylamino)-1-ethyl) -N- [-4- [N"- (2-chlorophenyl)ureido] -3- methoxyphenyl]-acetamido]ethoxybenzoate (100 mg, 0.17 mmol) in THF-MeOH (1:1, v/v, 3 mL), was added 0.25 N NaOH (2.0 mL, 0.5 mmol) at room temperature, and the solution was heated to reflux. Stirring was continued for 3 hours at reflux. The reaction mixture was poured into water, and acidified to pH 5.0 with 1.0 N HCl. After removal of the organic solvent in vacuum, the resulting mixture was chromatographed with HP-20 (H 2 O-MeOH 100:0 to 0:100) to give 317 (63 mg, 64%) as a white powder.

1H-NMR (CDjOD) 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 2H), 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, 2H), 8.01 (m, 2H); MS (FAB), m/ z 569 (M*); Anal. Calcd for CbHhCINA 3.0 H,0: C, 55.90; H, 6.31; N, 8.99 .Found: C, 56.40; H, 6.50; N, 8.08.

EXAMPLE 239

Isopropyl 4-[2-N- [2-(4-morpholinyl)ethyl]-N-[3-methoxy-4-[ N' -

(2-Methylphenyl)ureido]phenyl]acetamido]ethoxybenzoate

To a stirred solution of 4-[2-N-[2-(4-morpholinyl)ethyl]-N-[3-methoxy-4-[N'~(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid (250 mg, 0.42 mmol) in DMF (2 mL), was added isopropyl iodide (264 mL, 2.53 mmol) and K 2 CO 3 (88 mg, 0.64 mmol) at room temperature. The reaction mixture was stirred for 2 hours at 50°C. The mixture was poured into brine and extracted with CHCl 3 (50 mL x 3), washed with brine, and dried MgSO 4 . After removing the solvent in vacuo, the residue was chromatographed on silica gel (medium 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. 1 H-NMR (CDC13,400 MHz) δ 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 o.g 4.20 (t, J <=>

5.2 Hz, total 2 H), 5.22 (rn, 1H), 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, IH), 7.22 (m, 1 H), 7.40 (t, J= 9.0 Hz, 1 H), 7.93 (d, J= 8.8 Hz, tH), 7.97 (d, J=8.8 Hz, 1H), 8.07 ( t, J= 7.8 Hz, 1 H); MS (FAB), m/z 633 (M<*>+ ^v^/ia/.Calculated forCjjH^NA-OJS HjO: C, 65.05; H, 7.10; N, 8.67. Found: C, 65.19; H, 7.09 ; N, 8.50.

EXAMPLE 240

4-[2-N-[2-(3,3-difluoro-1-pyrrolidinyl)ethyl]-N-[4-[N'-(2-bromophenyl)ureido]-3-methoxyphenyl]acetamido]ethoxybenzoic acid sodium salt

To a stirred solution of methyl 4-[2-N-formylmethyl-N-[3-methoxy-4-[ N -(2-bromophenyl)ureido]phenyl]acetamido]ethoxybenzoate (300 mg, 0.5 mmol) in 1 ,2-dichloroethane (3.6 mL), 3,3-difluoropyrrolidine AcOH salt (420 mg, 2.5 mmol) was added at room temperature. The reaction mixture was stirred for 5 min. at room temperature, and then cooled to 0°C. To the cooled solution was added NaBH(OAc) 3 (530 mg, 2.5 mmol) and stirring was continued for 4 h at room temperature. The mixture was poured into saturated NaHCO 3 , and was extracted with CHCl 3 (50 mL x 3), washed with brine, and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-54 04-FC, linear gradient CHCl3-MeOH 10:0 to 97:3) to give methyl 4-[2-N- [2-(3,3-difluoro-1-pyrrolidinyl)ethyl-N-[4-[ N -(2-bromophenyl)-ureido]-3-methoxyphenyl]acetamido] ethoxybenzoate (345 mg, 100%)

as a white amorphous foam.

1 H-NMR (CDCl1, 400 MHz) δ 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, 1 H), 7.96 (m, 3 H), 8.13 (dd, J = 1.5 Hz, 8.3 Hz, 1 H); MS (ESI) m/z 689 (rvf).

To a solution of methyl 4-[ 2- N- [2-(3,3-difluoro-1-pyrrolidinyl) ethyl] -A7- [4- [ Nf - (2-bromophenyl)ureido] -3-methoxyphenyl]acetamido ]ethoxybenzoate (345 mg, 0.5 mmol) in THF-MeOH (1:1, v/v, 8 mL), 0.25 N NaOH (4 mL, 1.0 mmol) was added at room temperature, and the solution was heated to reflux. Stirring was continued for 6 hours at reflux. The solvent was removed and the residue was chromatographed on HP-20 (H 2 O-MeOH, 0:100 to 100:0) to give 319 (306 mg, 91%) as a pale red powder.

1 H-NMR (CD 3 OD, 400 MHz) δ 2.20-2.90 (m, 6 H), 3.60. (m, 2 H), 3.70-3.92 (m, 9

H)i 4.10 (rn, 1 H), 4.22 (m, 1 H), 6.84 (m, 4 H), 6.96 (m, 1 H), 7.30 (m,. IH), 7.55 (m, IH), 7.93. (m, 3H), 7.97 (m, 1H); MS (ESI) m/ z 676 QA*+ l)\ Anal.^ suitable^ Cj^ BrF^ Of 2. 5 H 2 O: C, 52.85; H, 5.29; N, 7.95. Found: C, 52.67; H, 5.20; N, 8.11. EXAMPLE 241 4-[ 2- N-(A7'-methoxy-N-methylamino)ethyl-N-[3-methoxy-4-IN"-(2- methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid sodium salt

To a stirred solution.of methyl. 4-[2-N-formylmethyl-[3-methoxy-4-[N'~(2-methylphenyl)ureido]phenylacetamido]-ethoxy]benzoate (3.50 mg, 0.66 mmol) in EtOH (13 mL), was A7-methoxy-AT-methyl amine hydrochloride (637 mg, 6.6 mmol) was added at room temperature. The reaction mixture was sonicated for 5 min. at room temperature, and then cooled to 0°C. To the cooled solution was added NaBH 3 CN (105 mg, .1.65 mmol) and stirring was continued for 18 h at room temperature. The mixture was poured into saturated NaHCO 3 and extracted with CHCl 3 (50 mL x 3), washed with brine and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium 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. 1H-NMR (CDC13,400 MHz) 6 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);

*4na/. Calculated for C31H3SN407-2.5H,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-N-[N'-methoxy-A7'-methylamino)ethyl-N-[3-methoxy-4-[N"~ (2-methylphenyl)ureido]phenyl]- acetamido] ethoxybenzoate (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 room temperature , and the solution was heated to reflux. Stirring was continued for 18 hours at reflux. The solvent was removed, and the residue was chromatographed on HP-20 (H 2 O-MeOH, 100:0 to 0:100) to give 320 (140 mg, 10 0%) as a white powder.

'H-NMR (CDjOD) 6 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, 2 H), 7.99 (m, 1 H); MS (FAB), m/z 565 (M₂+1); Anal. Calculated for C^jNANa-1.0 HA C, 59.59; H, 6.17; N, 9.27. Found: C, 59.10; H, 6.28; N, 8.86..

EXAMPLE 242

4- [ 2- N - ( N' -methoxy- N -methylamino) ethyl- N - [4- [ N - (2-bromophenyl)ureido]-3-methoxyphenylacetamido]ethoxy]benzoic acid

To a stirred solution of methyl 4-[2-A7-formylmethyl-A7-[3-methoxy-4-[ N'~ (2-bromophenyl)ureido]phenyl]acetamido]-ethoxybenzoate (209 mg, 0.35 mmol ) in EtOH (7 mL) was added A7-methoxy-N-methylamine-HCl salt (341 mg, 3.5 mmol) at room temperature. The reaction mixture was sonicated for 5 min. at room temperature, and then cooled to 0°C. To the cooled solution was added NaBH(OAc) 3 (370 mg, 1.75 mmol) and stirring was continued for 18 h at room temperature. The mixture was poured into saturated NaHCO 3 , extracted with CHCl 3 (50 mL x 3), and dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on TLC (Whatman, PLK-5F, 2 plates, CHCl 3 -MeOH, 98:2) to give methyl 4-[2-N-(N'-methoxy-N'-methylamino)ethyl -N- [4- [N'-(2-bromophenyl)-ureido]-3-methoxyphenyl acetamido]ethoxy]benzoate (89 mg, 40%) as a white amorphous foam. "H-NMR (CDC13, 400 MHz) 5 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, 2 H), 7.30 (m, 1 H), 7.52 (d, J= 8.1 Hz, 1 H), 7.94 (m, 3 H), 8.15 (d, /= 8.3 Hz, 1 H); MS (ESI) m/ z 643 CM<*>).

To a solution of methyl 4-[2-N-(N'-methoxy-N'-methylamino)ethyl-N-[4-[ N -(2-bromophenyl)ureido]-3-methoxyphenyl-acetamido] ethoxy] benzoate (89 mg, 0.14 mmol) in THF-MeOH (5:1, v/v, 6 mL), 0.5 N NaOH (1.4 mL, 0.7 mmol) was added at room temperature, and the soln. was heated to reflux in a sealed glass flask. Stirring was continued for 3 hours at reflux. The reaction mixture was poured into water, acidified with 1N HCl to pH.5, extracted with CHCl 3 -MeOH (2:1, v/v, 30 mL x 3) and dried over MgSO 4 . The solvent was removed in vacuo to give 321 (53 mg, 60%) as a white powder.

'H-NMR (CD3OD, 400 MHz)5 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, 1 H), 6.82-7.00 (m, 5 H), 7.30 (free, 1 H), | 7.58 (rn, 1H), 7.95 (m, 4H); MS (FAB), m/ z.629 ( M*)\ Anal. Calculated ofrCISH33BrNA-0.25 H20:

C, 54.94; H, 5.33; N, 8.84. Found:: C, 55.39; H, 5.53; N, 8.23. EXAMPLE 243 4-[2-N-(N',N'-diallyl)ethyl-N-[3-methoxy-4-[N''-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid sodium salt

To a stirred solution of methyl 4-[2-N-formylmethyl-N-[3-methoxy-4-[ N -(2-methylphenyl)ureido]phenyl] acetamido]-ethoxybenzoate (400 mg, 0.75 mmol) in EtOH (15 mL), added diallylamine (926 mL, 7.5 mmol) and acetic acid (429 mL, 7.5 mmol) at room temperature. The reaction mixture was stirred for 5 min. at room temperature,' and then cooled to 0°C. To the cooled solution was added NaBH3CN (118 mg,

1.9 mmol) and stirring was continued for 1 hour at room temperature. The mixture was poured into saturated NaHCO 3 and extracted with EtOAc (50 mL x 3), washed with brine and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-54 04-FC, linear<1 >gradient toluene-acetone (9:1 to 1:1) to give methyl 4-L2 -A7-(Nr,N'-diallyl)ethyl-N-[3-methoxy-4-[N'(2-methylphenyl)-ureido]phenyl]acetamido]ethoxybenzoate (385 mg, 84%) as a white amorphous foam .

1H-NMR (CDCl1, 400 MHz) δ 2.30 (s, 3 H), 2.60 (m, 2 H), 3.09 (m, 4 H), 3.49 (m, 2 H), 3.60 (S..2H) , 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

(nine, 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, 1 H), 7.60 (m, 1 H), 7.93 and 7.98 (2 d, J = 8.8 Hz, 2.H), 8.03 and 8.06 (2 d, J = 8.3 Hz, 1 H); MS (FAB), m/z 615 (M<*>+ 1);

To a stirred solution of methyl 4-[2-N-(N',N'-diallyl)ethyl-. N-[3^methoxy-4-[N''-(2-methylphenyl)ureido]phenyl]acetamido]-ethoxybenzoate (385 mg, 0.63 mmol) in MeOH (3 mL), was added IN HCl (75 6 mL, 0.76 mmol) at room temperature. The reaction mixture was stirred for 5 min. at room temperature, and then evaporated to give methyl-4-[2-N-(N',N'-diallyl)ethyl-N-[3-methoxy-4-[N'-(2-methylphenyl)ureido] phenyl]acetamido]ethoxybenzoate HCl salt (385 mg, 99%) as an amorphous foam.

Anal. Calculated for CJjH<oC1NA-0.5 H,0: C,'63.67; H, 6.72; N, 8.49. Found: C, 63.67; H, 6.69; N", 8.43.

To a solution of 4-[2-N-(W,W-diallyl)ethyl-N-[3-methoxy-4-[N''-(2-ethylphenyl)ureido]phenyl]acetamido]ethoxybenzoate (175 mg, 0.29 mmol) in THF-MeOH (1:1, v/v, 20 mL), 0.25 N NaOH (2.5 mL, 0.63 mmol) was added at room temperature, and the solution was heated to return. Stirring was continued for 1 hour at reflux. The solvent was removed and the residue was chromatographed on HP-20 (H 2 O-MeOH, 100:0 to 0:100) to give 322 (160 mg, 94%) as a white solid. 'H-NMR

(CD3OD) 8 2.29 (s, 3 H), 2.60 (t, /= 6.9 Hz, 1 H), 2.67 (U= 7.0 Hz, 1 H), 3.10 (d, J= 6.6 Hz, 2 H), 3.14 ( å, 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= 5.1 Hz, 1 H), 5.15 (m, 4 H), 5.80 (in, 2 H), 6.79 (m, 2 H), 6.84 (d, J= 8.8 Hz, 2 H),

7.00 (t, J = J7.5 Hz, 1 H), 7.14 (m, 2 h), 7.48 (rn, 1 H), 7.91 (dd, J= 6.1 Hz, 8.8 Hz, 2 H), 8.00 (m ,

1H); MS (FAB), m/2 601 (M^;/^Calculated for C14H39N406Na-0.5 H,0: C, 64.65; H, 6.38; N,'

8.87. Found: C, 64.53; H, 6.58; N, 8.78.

EXAMPLE 244

4-[2-N-(N',N'-diallyl)ethyl-N-[4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenylacetamido]ethoxy]benzoic acid sodium salt

To a stirred solution of methyl 4-[2-N-formylmethyl-N-[4-[ N -(2-chlorophenyl)ureido]-3-methoxy phenylacetamido]ethoxy]-benzoate (100 mg, 0.18 mmol) in EtOH (3.6 mL), diallylamine (223 mL, 1.81 mmol) was added at room temperature. The reaction mixture was stirred for 5 min. at room temperature, and then cooled to 0°C. To the cooled solution was added AcOH (104 mL, 1.81 mmol) and NaBH 3 CN (28 mg, 0.45 mmol) and stirring was continued for 18 h at room temperature. The mixture was poured into saturated NaHCO 3 , and was extracted with CHCl 3 (30 mL x 3), washed with brine, and dried over MgSO 4 . After removal of the solvent in vacuo, the residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient CHCl3-MeOH 10:0 to 20:1) to give methyl 4-[2-A7-( N',N'-diallyl)ethyl-N-[4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenyl acetamido]ethoxy]benzoate (96 mg, 83%) as a white amorphous foam. 1H-NMR(CDCl1, 400 MHz) δ 2.60 (rri, 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, 2 H), 6.71-6.85 (m, 4 H), 6.98 (m, 1 H), 7.22 (m, 1 H), 7.32 (m, 3 H), 7.93 (d, J = 7.8 Hz, 2 H), 7.98 (m, 1 H), 8.18 (dd, J= 1.5 Hz, 8.2 Hz, 1 H); MS (ESI) m/z 635 (M<*>).

To a solution of methyl 4-[2-N-[Nr,N'-diallyl)ethyl-N-[4-[N'-(2-chlorophenyl)ureido]-3-methoxy phenylacetamido]ethoxy]-benzoate (96 mg, 0.15 mmol) in THF-MeOH (1:1, v/v, 8 mL), 0.25 N NaOH (3.91 mL, 0.98 mmol) was added at room temperature, and the solution was heated to 50°C. Stirring was continued for 6 hours at reflux. The solvent was removed and the residue was chromatographed on HP-20

(H 2 O-MeOH, 0:100 to 100:0) to give 323 (88 mg, 94%) as a white powder. 'H-NMR

(CDjOD, 400 MHz) 6 2.61 (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 Hj, 7.01 (t, J = 7.8 Hz, 1 H), 7.25 (m, 1H), 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*); /Ina/.Calculated for Cj3Hj6ClN40{Na-1.25 H,0: C, 59.55; H, 5.83; N, .8.42. Found: C; 59.90; H, 5.74 ; N, 7.96.

EXAMPLE 245

4-[2-N- [3-methoxy-4-[ N'-(2-methylphenyl)ureido]phenyl]-N-methylacetoamido]ethyl-1-piperazinylacetic acid

To a stirred suspension of 1-(2-hydroxyethyl)piperazine (5.21 g, 40.0 mmol) and K 2 CO 3 (8.76 g, 63.4 mmol) in CH 3 CN (100 mL) was added ethyl bromoacetate (5, 60 ml, 50.5 mmol) at 0°C. The reaction mixture was heated under reflux for 5 hours, diluted with EtOAc, and washed with water and brine. The extract was dried over Na 2 SO 4 , concentrated to dryness to give ethyl 4-(2-hydroxyethyl)-1-piperazinyl acetate

(9.65 g, 10<0%>) as a yellow oil. 1 H-NMR (CDCl 3 ) δ 1.23 (t, 3H,

J=7.3Hz), 2.51-2.61(m, 11H), 3.22{s, 2H), 3.61(t, 2H, 7=5.4Hz), 4.19(q, 2H, >7.3Hz).

To a solution of 2,4-dinitrobenzenesulfonyl chloride (1.0 g, 3.75 mmol) and pyridine (0.34 mL, 4.20 mmol) in THF (19 mL) was added dropwise methylamine (2.OM THF solution, 2.3 mL, 4.60 mmol) at 0°C. The reaction mixture was stirred for 1 hour, quenched by addition of 1N HCl solution, and extracted with EtOAc. The extract was washed with saturated NaHCO 3 solution and brine, dried over Na 2 SO 4 , and concentrated to dryness. The residue was recrystallized from EtOAc-Et 2 O to give methyl 2,4-dinitrobenzenesulfonamide (546 mg, 56%) as a colorless solid. 'H-NMR

(DMSO) 5 2.60 (d, 3H, J=4.9Hz), 8.22 (d, IH, J=8.8Hz), 8.31 (q, IH, /=4.9Hz), 8.66 (dd, IH, J=8.8, 2.0Hz), 8.90 (d, IH, J=2.0Hz).

To a solution of ethyl 4-(2-hydroxyethyl)-1-piperazinyl acetate (452 mg, 2.09 mmol), methyl 2,4-dinitrobenzenesulfonamide (546 mg, 2.09 mmol) and PPh3 (658 mg, 2.51 mmol) in THF was added DIAD (0.50 mL, 251 mmol) at 0°C. After stirring for 17 hours at room temperature, the reaction mixture was concentrated to dryness. Chromatography of the residue with EtOAc-MeOH (10:1) gave ethyl 4- [2- [ N - (2, 4-dinitrobenzenesulfonyl) -A7-.methylamino] ethyl] - 1-piperazinyl acetate (864 mg, 90%) as a reddish oil.

1H-NMR (CDCl1) δ 1.27 (t, 3H, J=6.8Hz), 2.35-2.63 (m, 10H),

2.98 (s, 3H), 3.20 (s, 2H), 3.41 (t, 2H, J=6.8Hz), 4.17 (q, 2H, J=6.8Hz), 8.33 (d, IH, J=8.3Hz),

8.46 (d, IH, J=2.0Hz), 8.50 (dd, IH, J=8.3, 2.0Hz).

A solution of ethyl 4-(2-[ N -(2,4-dinitrobenzenesulfonyl)- N -methylamino]ethyl]-1-piperazinyl acetate (864 mg, 1.88 mmol), mercaptoacetic acid (0.17 mL, 2.44 mmol) and Et3N (0.53 mL, 3.76 mmol) in CH2Cl2 (25 mL) was stirred at room temperature for 3 h. The reaction mixture gave ethyl 4-(2-methylaminoethyl)-1-piperazinyl acetate (388 mg, 90% ) as a reddish oil.

1H-NMR (CDCl1) δ 1.27 (t, 3H, J=6.8Hz), 2.50 (s, 3H), 2.53-2.60 (m, 8H), 2.75 (t, 2H, J=5.9Hz), 3.20 ( s, 2H), 4.18 (q, 2H, J=6.ZUz).

A solution of ethyl 4-(2-methylaminoethyl)-1-piperazinyl acetate (388 mg, 1.69 mmol), Et3N (0.32 mL, 2.25 mmol) and DMAP (46 mg, 0.38 mmol) in DMF (15 ml) was stirred for 15 min. at room temperature, and then 3-methoxy-4-[ N'~ (2-methylphenyl)ureido]phenylacetic acid (532 mg, 1.69 mmol), HOBt (103 mg, 0.76 mmol), and EDC-HCl ( 486 mg, 2.53 mmol) added to the reaction mixture which was stirred for 15 hours at room temperature. The reaction mixture was diluted with EtOAc, which was washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue with CHCl 3 -MeOH (10:1, v/v) gave ethyl 4- [2-A7- [3-methoxy-4- [ N - (2-methylphenyl)ureido]phenyl]-N-methylacetoamido]ethyl -1-piperazinyl acetate (8-89 mg, mixture of DMF) as a reddish oil. , 10H), 3.20, 3.18 (each s, total 3H), 3.55, 3.40 (each t, total 2H, 7=6.8Hz), 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, J=8.3Hz), 8.02 (s , IH), 8.06 (d, IH, J=7.8Hz).

To a stirred solution of ethyl 4-[2-N-[3-methoxy-4-[Δ7'-(2-methylphenyl)ureido]phenyl]-N-methylacetoamido]ethyl-1-piperazinyl acetate (889 mg, 1.69 mmol) in THF-EtOH (5:1, v/v, 18 mL) was added 4 N NaOH (0.84 mL, 3.38 mmol). The reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 7.5 with 1N HCl and extracted with CHCl3-1VIeOH (4:1, v/v). The combined extracts were dried over MgSO 4 and concentrated to give 324 (218 mg, 26% 2-step) as a brown amorphous foam.

ER(KBr) n 3299, 3004, 1700, 1627, 1598, 1536 cm-'; 1H-NMR (DMSO) 6 2.25 (s, 3HV2.36-2.62 (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, J=7.8Hz), 6.87 (s,.lH), 6.93 (t, IH, J= 7.8Hz), 7.11-7.17<(m, 2H), 7.79 (d, IH, J=7.8Hz), 8.01 (d, IH, J=7.8Hz), 8.47 (s, IH), 8.57 (s, IH ); MS (FAB).m/2 498 (MM); ; N, 11.09.

EXAMPLE 246

1-[2-[A7-methyl-N-[3-methoxy-4-[Nf-(2-methylphenyl)ureido]-phenyl] acetamido]ethyl]-4-piperidinyl dihydrogen

To a stirred solution of 2-(A7-benzyloxycarbonyl-AT-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylidene acetate (1.69 g, 10.0 mmol) in MeOH-AcOH (10 :1, v/v, 22 mL) was added NaBH 3 CN (1.32 g, 20 mmol) bg stirring was continued overnight. The mixture was quenched by the addition of saturated NaHCO 3 (200 mL) and extracted with CHCl 3 (3 x 150 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl 3 -EtOH (40:1, v/v) to give ethyl 1-[2-(A7-benzyloxycarbonyl-N-methylamino)ethyl]-4-piperidinylidene acetate (1.71 g, 47% ) as a colorless oil.

(CDClj)

5 1.25 (t, 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 1-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-4-piperidinylidene acetate (1.70 g, 4.72 mmol) in EtOH-AcOH (20:1, v/v, 21 mL ) was hydrogenated over 5% Pd/C (2 g) for 3 days with stirring. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was basified with saturated NaHCO 3 and extracted with CHCl 3 (300 mL). The extract was dried over Na 2 CO 3 and evaporated to give ethyl 1-(2-methyl-aminoethyl)-4-piperidinyl acetate (813 mg, 75%) as a yellow oil.

1H-NMR (CDCl1) δ 1.25 (t, J- 7.3 Hz, 3 H), 1.68-1.81 (m, 5 H),

1.97 (t, J= 11.2 Hz, 2 H), 2.22 (d, J= 7.3 Hz, 2 H), 2.43-2.47 (m, 5 H), 2.66 (t, 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-[N-(2-methylphenyl)-ureido]phenylacetic acid (550 mg, 1.75 mmol) and ethyl 1-(2-methylaminoethyl)-4-piperidinyl acetate (400 mg, 1, 75 mmol) in DMF (10 mL) was added EDC-HCl (503 mg, 2.63 mmol), HOBt (cat.), and DMAP (cat.) and stirring was continued overnight. The mixture was diluted with EtOAc (300 mL), washed with brine (200 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOH (10:1, v/v) to give ethyl 1-[2-[N-methyl-W-[3-methoxy-4-[ N'~

(2-Methylphenyl)ureido]phenyl]acetamido]ethyl]-4-piperidinyl acetate (697 mg, 76%) as a yellow gum.

1H-NMR (CDCl1) δ 1.19-2.064 (series of m, 12 H), 2.21 (t, J= 7.8 Hz, 2 H), - 2.28 (s, 3 H),

2.41 (f, J= 7.3 Hz, 1 H), 2.46 (t, J=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, 1 H), 6.77-6.79 (m, 2 H), 7.12 (t, J= 7.3 Hz, 1 H), 7.21-7.27 (m, 3 H), 7.54 (d, J= 8.3 Hz, 1 H), 8.06 (dd, J= 8.3 , 2.4 Hz, 1 H).

To a stirred solution of ethyl 1-[2-[A7-methyl-A7-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenyl]acetamido]ethyl]-4-piperidinyl acetate (690 mg , 1.32 mmol) in THF (11 mL) was added 0.25 N aqueous NaOH (11 mL, 2.75 mmol) and stirring was continued overnight. The mixture was diluted with H 2 O (50 mL), neutralized with 1N HCl, and extracted with CHCl 3 -MeOH (2:1, v/v, 3 x 100 mL). The combined extracts were dried, over MgSO 4 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 CHCl 3 and adding hexane until a precipitate was formed. This precipitate was collected and dried in vacuo to give 325 (75 mg, 11%) as a white amorphous solid.

'H-NMR PMSO) 8 1.19-2.99 (series of m, total 17 H), 3.32-3.43 (m, 4 H), 3.62-3.65 (m, 2H), 3.86 (s, 3 H), 6.73 ( i , J= 8.3 Hz, 1 H), 6.87 (s, 1 H), 6.93 (U = 7.8 Hz, 1 H), 7.11-7.17 (m, 2H), 7.79 (d, J= 8.3 Hz, 1 H) , 8.01 (d, J- 8.3 Hz, 1 H), 8.47 (s, 1 H), 8.57 (s, 1 H);

MS-FAB m/z 497 (M++1); Anal.Calcd for Cj7HMN405;HCl: C, 60.84; H.7.00; N, 10.51. Found: C, 60.97; H, 7.14; N, 10.17. EXAMPLE 247 1-[2-[N-methyl-N-[4-[Nf-(2-methylphenyl)ureido]phenyl]-acetamido]ethyl]-4-piperidinylacetic acid

To a stirred solution of ethyl 1-(2-methylaminoethyl)-4-piperidinyl acetate (400 mg, 1.75 mmol) and Et3N (366 µl, 2.63 mmol) in DMF (10 mL) was added pentafluorophenyl 4 -(AT-(2-methylphenyl)ureido)phenylacetate (788 mg, 1.75 mmol) and stirring was continued overnight; The mixture was diluted with EtOAc (300 mL), washed with brine (200 mL), dried over MgSO 4 , and evaporated. The residue was chromatographed on. silica gel with CHCl3-EtOH (10:1, v/v) to give ethyl 1-[2-[A7-methyl-A7-[4- [N'-(2-methylphenyl)ureido]phenyl]acetamido] - ethyl]-4-piperidinyl acetate (630 mg, 73%) as a colorless oil.

To a stirred solution of ethyl 1-[2-[ N-methyl- N-[4-[ N'-(2-methylphenyl)ureido]phenyl]acetamido]ethyl]-4-piperidinyl acetate (630 mg, 1.27 mmol ) in THF (10 mL) 0.25 N aqueous NaOH (10 mL) was added and stirring was continued overnight. The reaction mixture was diluted with H 2 O (100 mL), neutralized with 1N HCl, and extracted with CHCl 3 -MeOH (2:1 v/v, 3 x 10 0 mL). The combined extracts were dried over MgSO 4 and evaporated. The residue was triturated by taking up CHCl 3 and adding hexane until a precipitate formed. This precipitate was collected and dried in vacuo to give 32 6 (20 mg, 3%) as a white amorphous solid f • 'H-NMR (DMS0)5 1.69 (in,

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

j H), 3.63 (d, J= 6.8 Hz, 2H), 6.91-6.95 (nr, 1 H), 7.13<;>(m, 4 H), 7.39 (d, J= 8.3 Hz, 2H), 7.83 (d, J = 7.3 Hz, 1 H), 7.97 (m, 1 H), 9.12 (m, 1 H); MS (FAB): m/z 467 (MM).

EXAMPLE 248

4-[2-N-[4-[AT'-(2-methylphenyl)ureido]phenyl]-N-methylacetamido]-ethyl-1-piperazinylacetic acid

A solution of ethyl 4-(2-methylaminoethyl)-1-piperazinyl acetate (700 mg, 3.05 mmol), Et3N (0.64 mL, 4.58 mmol) and DMAP

(75 mg, 0.61 mmol) in THF (15 mL) was stirred for 30 min. at room temperature, and then 4-[N'-(2-methylphenyl)ureido]-phenylacetic acid (917 mg, 3.05 mmol), HOBt (82 mg, 0.61 mmol) and EDC-HCl (879 mg, 4 .58 mmol) added to the reaction mixture which was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc, and was washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (10:1, v/v) gave ethyl 4-[2-N-[4-[N'-(2-methylphenyl)ureido]-phenyl]-N-methylacetamido]ethyl -1-piperazinyl acetate (996 mg, 66%) as a yellow amorphous foam. 1 H-NMR (CDCl 3 ) δ 1.25-1.29

(m, 3H), 2.20 (s, 3H), 2.47-2.58 (m, 10H), 2.97, 3.05>(each, 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; IH), 7.64 (m, IH ); MS (FAB) m/z 496 (MM).

To a stirred solution of ethyl 4-[2-N-[4-[ N'~ (2-methylphenyl)ureido]phenyl]-N-methylacetamido]ethyl-1-piperazinyl acetate

(996 mg, 2.01 mmol) in THF-EtOH (5:1, 12 mL) was added 4N NaOH (1.0 mL, 4.00 mmol). The reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 7.5 with 1N HCl and extracted with CHCl 3 -MeOH (4:1, v/v). The combined extracts were dried over MgSO 4 and concentrated to give 327 (73 mg, 8%) as a yellow amorphous foam. IR (KBr) n 3338, 2925, 2850, 2821, ,1704, 1627, 1540cm"1; 'H-NMR (DMSO) δ 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 (t, 2H, J=6.8Hz), 3.60, 3.62 (each s, total 2H), 6.92 (t, IH, J^ i. SRz), 7.09-7.16 (m, 4H), 7.41-7.44 (m, 2H), 7.76, 7.77 (each d,"

n

2H, J=7.8Hz), 8.46, P. 53 (each s, IH), 9.54, 9.59 (each s, IH); MS (FAB) m/z 468 (M++1); Anal. Calculated for C^NA^Cl: C, 55.56; H, 6.53; N, 12.96. Found:. C, 54.99; H, 6.45; N, 11.58.

EXAMPLE 249

4- [2-N- [4- [N'~ (2-fluorophenyl)ureido]-3-methoxyphenyl]-N-methylacetamido]ethyl-1-piperazinylacetic acid

A solution of ethyl 4-(2-methylaminoethyl)-1-piperazinyl acetate (695 mg, 3.03 mmol), Et3N (0.64 mL, 4.58 mmol) and DMAP (75 mg, 0.61 mmol) in DMF (15 ml) was stirred for 15 min. at room temperature, and then 4-[N'-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (965 mg, 3.03 mmol), HOBt (82 mg, 0.61 mmol) and EDC-HCl (872 mg , 4.54 mmol) added to the reaction mixture which was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc, and was washed with brine, dried over NaSO 4 , and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (10:1, v/v) gave ethyl 4-[2-N- [4-[N'-(2-fluorophenyl)ureido]-3-methoxyphenyl]-N-methyl acetamido] ethyl 1-piperazinyl acetate (1.21 g, mixture of DMF) as a black oil. 'H-NMR

:CDC13) 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,7=6.8Hz), 3.66 (s,2H), 4.15^.21 (m, 2H), 6.77-6.78 (m,

2H), 6.79-7.11 (m, 3H), 7.68-7.95 (m, 2H), 7.64'(brd.s, IH), 8.20 (t, IH, J=7.8Hz); MS (FAB) m/z 530 (M<+>+1).

To one stirred solution of ethyl 4-[ 2- N - [4-[ N'~(2-fluoro-phenyl) ureido]-3-methoxyphenyl] -A7-methyl acetamido] ethyl-1-piperazinyl acetate (1.21 g , mixture of DMF) in THF-EtOH (5:1, v/v, 12 mL) was added 4N NaOH (1.0 mL, 4.00 mmol). The reaction mixture was stirred at room temperature for 4 hours, adjusted to pH 7.5 with 1N HCl and extracted with CHCl 3 -MeOH (4:1, v/v). The combined extracts were dried over MgSO 4 and concentrated to give 328 (78 mg, 5% 2 steps) as a brown amorphous foam.

IR (KBr) n 3299, 2940, 2830, 1704, 1627, 1598, 1536cnV'; 1H-NMR (DMSO) δ 2.36-2:61 (m, 10H), 2.83,2.98 (reverse, 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, IH), 6.87'(s, IR), 6.98 (s, IH), 7.12 (t, IH, J=7.8Hz), 7.20, 7.23 (each d, 2H, J=7.8Hz), 8.01 (d, IH, J=7.8Hz), 8.17 (t, IH, J=7.8Hz), 8.72 (s, IH), 9.19 (s, IH); MS (FAB) m/z 502 (MM); ,4«a/. Calcd for CJHjjFNA^HCl-O.SHjO: C, 51.46; H, 6.05; N, 12.00.Found: C, 51.08; H, 5.69; N, 11.27.

EXAMPLE 250

3-Fluoro-1-[2-AT-methyl-N-[3-methoxy-4-[A7/-(2-methylphenyl)-ureido]phenyl]acetamido]ethyl-4-piperidinylacetic acid

To a stirred solution of 1-tert-butoxycarbonyl-4-piperidone (14.9 g, 74.8 mmol) in DMF (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°C for 18 hours. Hexane was added to the reaction mixture, and the resulting mixture was washed with saturated NaHCO 3 and brine, dried over NaSO 4 , and concentrated to dryness. Chromatography of the residue eluting with hexane-EtOAc (5:1, v/v) gave 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethyl-silyloxy)pyridine (20.4 g, 99 %) as a yellow oil.

1H-NMR (CDCl 3 ) δ 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 C wide. pp, IH).

To a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (20.4 g, 75.0 mmol) in CH 3 CN (500 mL) was added Selectfluor ( 29.2 g, 82.5 mmol) at room temperature, and the reaction mixture was stirred for 2 h. EtOAc was added to the reaction mixture, and the mixture was washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue with CHCl 3 -MeOH (6:1, v/v) as eluent gave 1-tert-butoxycarbonyl-3-fluoro-4-piperidone (14.5 g, 89%) as a colorless oil. 1 H-NMR(CDCl 3 ) 5 1.50

(s, 9H), 2.44 (t, J= 6.9 Hz, IH), 2.48 - 2.63 (m, 2H), 3.26 (ddd, J=.13.5, 10.5, 3.9 Hz, IK), 3.72

(t, J= 6.9 Hz, IK), 4.16 (m, IK), 4.42 (m, IK), 4.83 (dt, 49.2, 6.9 Hz, IK).

To a solution of triethylphosphonoacetate (3.72 g, 16.6 mmol) in THF (70 mL) was added lithium bis(trimethylsilyl)amide (1.0 M THF solution, 15.5 mL, 15.5 mmol) at -78°C. After stirring at the same temperature for 1 hour, 1-tert-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 addition of saturated NH 4 Cl solution and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue eluting with hexane-EtOAc (8:1, v/v) gave ethyl (1-butoxycarbonyl-3-fluoropiperidin-4-ylidene)acetate (3.23 g, 81%) as a colorless solid. 'H-NMR5 1.30 (t, J= 7.1 Hz, 3H), 1.48 (s, 9H), 2.10 (m, IK), 2.56 (m, IK), 2.77 (m, IK), 3.13 - 3.54 (m, 2H), 3.70 (m, IH), 4.17 4.18 (each q, J= 7.1 Hz, total 2H), 5.82 5.98 (each s, total IK), 6.41 (each å, J- 46.9 Hz, total IH); MS (FAB) m/z 288 (MM).

A solution of ethyl (1-butoxycarbonyl-3-fluoropiperidin-4-ylidene)acetate (1.32 g, 4.59 mmol) in THF (30 mL) was hydrogenated over Pd-C .(TMEDA complex, 66, 0 mg) at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated to dryness. Chromatography of the residue with hexane-EtOAc (9:1, v/v) as eluent gave ethyl 1-tert-butoxycarbonyl-3-fluoro-4-piperidinyl acetate (653 mg, 73%) as a colorless oil.

1H-NMR (CDCl1) 8 1.26 (t, J= 7.1 Hz, 3H), 1.45 (s, 9H), 1.53 - 1.79 (m, 2H), 1.92 - 2.09 (m,

2H), 2.31 (dd, J = 16.4, 6.9 Hz, IH), 2.52 (dd, J= 16.4, 7.3 Hz, IH), 2.61 - 3.06 (m, 2H), 4.14 (q,

J = 7.1 Hz, 2H), 4.28 - 4.77 (m, 2H); <13>C NMR (CDCl 1 ) 14.29, 25.80, 28.42, 35.99, 36.20, 60.55, 79.78, 86.72. 88.48, 154.94, 171.93; FAB-MS m/z 290 (MT+1).

To a solution of ethyl 1-tert-butoxycarbonyl-3-fluoro-4-piperidinyl acetate (653 mg, 2.26 mmol) in CH 2 Cl 2 (10 mL) was added TFA (5 mL) at 0 °C. After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with THF-EtOAc (1:1, v/v). The extracts were dried over MgSO 4 and concentrated to give ethyl 3-fluoro-4-piperidinyl acetate (420 mg, 98%) as a yellow oil. 'H-NMR (CDCLj) 8 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, IH) , 2.54 (dd, J= 16.6, 7.5 Hz, IH), 2.82 (m, IH), 2.90, 3.00 (each M= 14.4 Hz, total IH), 3.31 (m, IH), 3.51 (m, IH) , 4.15 (q, 7= 7.4 Hz, 2H), 4.82, 4.71 (each wide s, total IH).

To a solution of ethyl '3-fluoro-4-piperidinyl acetate (230 mg, 1.22 mmol) and .2-(N-tert-butoxycarbonyl-N-methylamino)-acetaldehyde' (211 mg, 1.22 mmol) in To THF (5 mL) was added NaBH(OAc) 3 (386 mg, 1.82 mmol) and acetic acid (70.0 mL, 1.22 mmol) at room temperature. After stirring for 24 h, the reaction mixture was quenched by the addition of saturated NaHCO 3 solution and extracted with EtOAc. The extracts were washed with brine, dried over Na 2 CO 3 , and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (6:1, v/v) as eluent gave ethyl 3-fluoro-1-[2-(N-tert-butoxycarbonyl-AT-methylamino) ethyl]-4-piperidinyl acetate (236 mg, 56%) as a reddish oil.

1H-NMR (CDCl 3 ) 5 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, /= 16.4, 7.1 Hz, IK), 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 (q, J= 7.1 Hz, 2H), 4.61, 4.73 (each broad- s, IK) ; ESI-MS m/z 347.

To a solution of ethyl 3-fluoro-1-[2-(A7-tert-butoxycarbonyl-N-methylamino)ethyl]-4-piperidinyl acetate (236 mg, 0.68 mmol) in CH 2 Cl 2 (10 mL) was added TFA (5 mL) at 0°C. After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with CHCl 3 . The extracts were dried over MgSO 4 and concentrated to give ethyl 3-fluoro-1-[2-(N-methylamino) ethyl]-4-piperidinyl acetate (117 mg, 70%). as a reddish oil e . 1H-NMR (CDCl 3 ) 5 1.26 (t, J = 7.1 Hz, 3H), 1.58 (m, 1H), 1.70 (m, IK), 1.99 (m, 1H), 2.14 (m, 1H), 2.27 - 2.33 (m, IK), 2.47 (s, 3H), 2.48 - 2.56 (m, 4H), 2.72

(t, J = 6.3 Hz, 2H), 2.90 (m, IH), 3.16 (m, IK), 4.14 (q, J= 7.1 Hz, 2H), 4.67 (d„ J= 48.3 Hz, ;H); ESI-MS m/z 247 (MM).

To a solution of 3-methoxy-4-[ N -(2-methylphenyl)ureido]-phenylacetic acid (164 mg, 0.52 mmol),' ethyl 3-fluoro-1-[2-(N-methylamino)ethyl] -4-piperidinyl acetate (117 mg, 0.47 mmol), Et3N (0.10 mL, 6.7.1 mmol), and HOBt (13.0 mg, 0.09 mmol) in THF

.(5 ml) was added EDC-HCl (137 mg, 0.71 mmol). After stirring by. room temperature for 8 h, the reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na2CO3, and concentrated to dryness. Chromatography of the residue with toluene-acetone (1:2, v/v) as eluent gave ethyl 3-fluoro-1-[2-N-methyl- N-[3-Methoxy-4-[N'-(2-methylphenyl)ureido]phenyl]-acetamido]ethyl-4-piperidinyl acetate (160 mg, 62%) as a yellow

IT

amorphous solid. n ~ NMR (CDCl 3 ) δ 1.24 - 1.28 (m, 3H), 1.51 - 2.23 (m IK), 2.26 (s, 3H), 2.35 (s, 2H), 2.39 - 2.56 (m, 3H), 2.88 (m , IH), 2.95, 3.03 (each s, total 3H), 3.11 (m, IK), 3.44 (m, IH), 3.56 (m, IH),

3.64 (s, 2H), 3.68 (s, 3H), 4.11 - 4.17 (m, 2H), 4.57, 4.69 (each s, total IH), 6.72-6.82 (m, 2H), 7.10 - 7.33 (m, 5H ), 7.54 (d, J = 8.1 Hz, IH), 8.06 (d, J = 8.1 Hz, IH); ESI-MS m/z 543 Cvf+1).

To a solution of 3-fluoro-1-[2-AT-methyl-N-[3-methoxy-4-[N'~

(2-Methylphenyl)ureido]phenyl]acetamido]ethyl-4-piperidinyl acetate (160 mg, 0.29 mmol) ■ In THF (3 mL) was added 0.25N NaOH (1.30 mL, 0.32 mmol) . After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The residue was diluted with water and neutralized with 1N HCl at 0°C. The mixture was concentrated and purified with ion exchange resin

(HP-20, Mitsubishi Chemical) to give 329 (110 mg, 74%) as a yellow amorphous solid. ER (KBr) 3343,

2937,1700, 1617,1589, 1535, 1486, 1455, 1417 cm"<1>; 'H-NMR (CD3OD) 8 1.57 - 1.72 (m ,2H), 1.98 (m, IH), 2.26 (m, IH ), 2.28 (s^H), 2.37 - 2.59 (m, 3H), 2.66 - 2.89 (m, 2H), 2.95,. 3.09 (each s, total 3H), 3.14 ( m, IH), 3.40 (m, IH), 3.51 (m, IH), 3.59 (m, IH), 3.71 (s, 2H), 3.78 (m, IH), 3.89 (s, 3H), 4.69, 4.81 (each s, total IH), 6.79 (dd, J= 8.1, 1.5 Hz, IH), 6.90 (.-wide s, IH), 7.01 (t, J= 7.8 Hz, IH), 7.13 -7.19 (m, 2H), 7.58(d, J = 7.8Hz, 1H), 8.00 (d^7= 8.1 Hz, 1H);

ESI-MS m/z 515 (M^lJMwa/.Calculated for ^HjjFNA-HjO: C, 60.89; H, 7.00; N, 10.52. Found: C, 61.09; H, 6.80; N, 9.87. EXAMPLE 251 4- [ 2- N- [ 2-(4-fluoroenoxy) ethyl] -A7- [3-methoxy-4- [ N - (2-methylphenyl)ureido] phenyl] acetamido] ethylpiperazinyl-1-acetic acid

To a solution of 2-(A7-benzyl-N-tert-butoxycarbonyl-amino)ethanol (6.85 g, 27.3 mmol), 4-fluorophenol (3.07 g, 27.3 mmol) and PPh3 (7 .83 g, 30.0 mmol) in THF (100 mL) was added DIAD (6.00 mL, 30.0 mmol) at room temperature. After stirring for 3 hours, the reaction mixture was concentrated. Chromatography of the residue eluting with hexane-EtOAc (8:1, v/v) gave 1-[2-(N-benzyl-N-tert-butoxy-carbonylamino)ethoxy]-4-fluorobenzene (8.19 g, 64 %) as a yellow oil e. 'H-NMR (CDC13)8 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<*>+1).

TFA ( 40 ml) at 0°C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with CHCl 3 . The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to give 1-(2-N-benzylaminoethoxy)-4-fluorobenzene (4.38 g, 75%) as a reddish oil.

1H-NMR (CDCl 3 ) 5 3.00 (t, J = 5.2 Hz, 2H), 3.87 (s, 2H), 4.04 (t, 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<*>+1).. A mixture of 1-(2-Δ7-benzylaminoethoxy)-4-fluorobenzene (1.08 g, 4.40 mmol), ethyl 4-( 2-bromomethyl)piperazinyl-1-acetate (1.23 g, 4.40 mmol), and K 2 CO 3 (0.61 g, 17.9 mmol) in CH 3 CN (50 mL) were heated under reflux for 8 h. The resulting mixture was filtered and the filtrate was concentrated to dryness. Chromatography of the residue with toluene-acetone (3:1, v/v) as eluent gave ethyl 4-[2-A7-benzyl-A7-[2-(4-fluorophenoxy)ethyl]amino]ethylpiperazinyl-1-acetate (1 .51 g, ■ •77%) as a reddish oil. 1H-NMR (CDC13)5 1.27 (t, J= 7.1 Hz, 3H), 2.31 - 2.66 (m, 10H), 2.75 (t, J= 6.6 Hz, 2H), 2.90 (t, J= 6.1 Hz, 2H), 3.18 (s, 2H), 3°.72 (s, 2H), 3.97 (t, J = 6.1 Hz, 2H), 4.17 (q, J= 7.1 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 Ovf+1).

A solution of 4-[2-AT-benzyl-AT-[2-(4-fluoroenoxy)ethyl]-amino]ethylpiperazinyl-1-acetate (1.50 g, 3.38 mmol) in EtOH (30 mL ) was hydrogenated over 5% Pd-C (53.1% wet, 0.73 g) under a hydrogen atmosphere for 4 h. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with CHCl 3 . The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to give ethyl 4-(2-AT-[2-(4-fluorophenoxy)ethyl]amino]ethylpiperazinyl-1-acetate (1.12 g, 94 %) as a reddish oil.

■H-NMR (CDCl 3 ) δ 1.27 (t, J= 7.1 Hz, 3H), 1.81 C :broad. s, IK), 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 w/ zZSA (xvT+1).

To a solution of 3-methoxy-4-[N'-(2-methylphenyl)ureido]-phenylacetic acid (485 mg, 1.54 mmol), ethyl 4-[2-AT-[2-(4-fluorophenoxy) ethyl]amino]ethylpiperazinyl-1-acetate (545 mg, 1.54 mmol), Et3N (0.32 mL, 2.32 mmol), and HOBt (41.5 mg, 0.31 mmol) in THF (15 mL .) was added EDC-HCl (883 mg, 2.32 mmol) at room temperature. After stirring for 24 h, the reaction mixture was diluted with water and extracted with CHCl 3 -MeOH (10:1, v/v). The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (4:1, v/v) as eluent gave ethyl 4r [2-AT-[2-(4-fluorophenoxy)ethyl]-AT- [3-methoxy-4- [AT '-(2-Methylphenyl)ureido]-phenyl]acetamido]ethylpiperazinyl-1-acetate (532 mg, 53%) as a yellow amorphous solid. 1H-NMR (CDC13)6 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, 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, IK), 6.72 - 6.78 (m, AK), 6.89 r 6.98 (m, 2H), 7.12 (t, J = 1. 6Hz, IK), 7.20-7.23 (m, 3H), 7.51 (d, J= 1. 6Hz, IK), 8.04 (d, J= 8.1 Hz, IK) ;

FAB-MS m/z 650 (M<*>+1).

To a solution of ethyl 4-[2-AT-[2-(4-fluorophenoxy)ethyl]-AT-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenyl]acetamido] - ethylpiperazinyl-1-acetate (532 mg, 0.82 mmol) in dioxane (8 ml) 0.25N NaOH (5.00 ml, 1.25 mmol) was added dropwise at room temperature, and the reaction mixture was stirred for 1 hour . The resulting mixture was concentrated, diluted with water, and neutralized with 1N HCl at 0°C. The mixture was extracted with CHCl 3 -MeOH (4:1, v/v). The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue eluting with HCl 3 -MeOH (3:1, v/v) gave 330 (168 mg, 33%) as a pale yellow amorphous solid. . IR (KBr) 3338, 2938, 2829, 1635, 1533, 1506, 1454, 1415 cm"<1>; 1H-NMR (DMSO-rf6)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, total 3H), 4.06 - 4.09 (m, 2H), -,6.73 (m, IH), 6.85 (s, IH), 6.91 - 6.97 (m ,3H), 7.07 -718 (m, 4H), 7.78 ( d, J= 8.1 Hz, IH), 8.00 (dd, J= 8.1, 2.7 Hz, IH), 8.53 (m, IH), 8.59 (m, IH); FAB-MS m/ z 622 (M++1 ); Anal. Calculated for CjjHoFNA^HCl: C, 57.06; H, 6.09; N, 10.08. Found: C, 56.83; H, 6.05; N, 9.90. EXAMPLE 252 41 [2-AJ- [2- (4- acetylphenoxy) ethyl] - AT- [3 -methoxy-4- [AT' - (2- methylphenyl)ureido]phenyl]acetamido]ethylpyrazinyl-1-acetic acid

To a solution of 2-(AT-benzyl-AT-tert-butoxycarbonyl-.amino)ethanol (5.90 g, .23.5 mmol), 4-hydroxyacetophenone (3.18 g, 23.5 mmol) and PPh3 (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 hours and concentrated. Chromatography of the residue eluting with hexane-EtOAc (5:1, v/v) gave 4-[2-(AT-benzyl-AT-tert-butoxycarbonylamino)ethoxy] acetophenone (3.64 g, 42%) as a yellow oil e. 1H-NMR (CDCl 3 ) 6 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 (MP+1).

To a solution of 4-[2-(AT-benzyl-AT-tert-butoxycarbonyl-amino)ethoxy]acet of enone (3.05 g, 8.26 mmol) in CH 2 Cl 2 (30 mL) was added TFA ( 2 0 ml) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with .CHCl 3 . The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to give 4-(2-AT-benzylaminoethoxy)acetophenone (2.21 g, 99%) as a reddish oil. 'H-NMR (CDCl1) 6 2.04 f wide. s, IK), 2.55 (s, 3H), 3.05 (t, /= 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 (m, SK), 7.91 (d, J= 8.9 Hz, 2H); FAB-MS m/z 270 (M<+>+1).

To a solution of ethyl 4-(2-hydroxyethyl)piperazinyl-1-acetate (11.3 g, 52.1 mmol) and CBr 4 (20.7 g, 62.5 mmol) in CH 2 Cl 2 (200 mL) was added PPh 3 (19.2 g, 73.0 mmol) portionwise at 0 °C 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 to give ethyl 4-(2-bromomethyl)piperazinyl-1-acetate (13.7 g, 94%) as a yellow oil.

1H-NMR (CDCl1)5 1.27 (t, J= 7.1 Hz, 3H), 2.61 - 2.78 (m, 8H), 2.81 (t, J= 7.6 Hz, 2H), 3.20 (s, 2H), 3.42 ( t, J = 7.6 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H).

A mixture of 4-(2-AT-benzylaminoethoxy)acetophenone (681 mg, 2.52 mmol), ethyl 4-(2-bromomethyl)piperazinyl-1-acetate (705 mg, 2.52 mmol), and K 2 CO 3 ( 349 g, 2.52 mmol) in CH 3 CN (10 mL) was heated under reflux for 22 h. The resulting mixture was filtered and the filtrate was concentrated to dryness. Chromatography of the residue with toluene-acetone (1:1, v/v) as eluent gave ethyl 4-(2-AT-benzyl-AT-[2-(4-acetylphenoxy)ethyl]amino]ethylpiperazinyl-1-acetate (920 mg, 78%) as a reddish oil.

1H-NMR<1> (CDCl1) 8 1.27 (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, /= 6.1 Hz, 2H), 3.18 (s, 2H), 3.73 (s, 2H), 4.06 (t,J = 6.1 Hz, 2H), 4.17 (q,/= 7.1Hz, 2H), 6.85 (d,7=7.1 Hz, 2H), 7.22-7.35 (m, 5H), 7.90 (d, J=7.1.Hz, 2H); FAB-MS m/z 468 (M<+>+1).

A solution of ethyl 4-[2-[N-benzyl-N-[2-(4-acetylphenoxy)-ethyl]amino]ethylpiperazinyl-1-acetate (920 mg, 1.97 mmol) in EtOH (30 mL) was hydrogenated over 5% Pd-C (53.1% wet, 510 mg) under a hydrogen atmosphere for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up with saturated NaHCO 3 solution and extracted with CHCl 3 . The extracts were washed with brine, dried over Na 2 SO 4 , and concentrated to give ethyl 4-[ 2- N -[ 2-(4-acetylphenoxy)-ethyl] amino] ethyl piperazinyl-1-acetate (690 mg, 93%) as a reddish oil. 'H-NMR (CDOj) 8 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 (t, 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<+>+1).

To a solution of 3-methoxy-4-[ N -(2-methylphenyl)ureido]-phenylacetic acid (558 mg, 1.77 mmol), ethyl 4 - [2- N - [2 - (4-acetylphenoxy)ethyl] amino]ethylpiperazinyl-1-acetate (670 mg, 1.77 mmol), Et3N (0.38 mL, 2.66 mmol), and HOBt (50.0 mg, 0.35 mmol) in THF (10 mL) were EDC-HCl (883 mg, 2.32 mmol) was added at room temperature. After stirring for 15 h, the reaction mixture was diluted with water and extracted with CHCl 3 -MeOH (10:1, v/v). The extract was washed with brine, dried over Na 2 SO 4 , and concentrated to dryness. Chromatography of the residue with CHCl3-MeOH (4:1, v/v) as eluent gave ethyl 4-[2-N-[2-(4-acetylphenoxy)ethyl]-N- [3-methoxy-4-[ Nf- (2-Methylphenyl)ureido]-phenyl]acetamido]ethylpiperazinyl-1-acetate (724 mg, 61%) as a yellow amorphous solid. ; 1H-NMR (CDCl 3 ) δ 1.25, 1.27 (each, /= 7.1 Hz, total 3H), 2.29 (s, 3H), 2.45 - 2.51 (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, IH, J= 8.1 Hz), 6.72 - 6.76 (m, 2H), 6.85 (d, J= 8.8 Hz, 2H), 7.12 - 7.19 (m, 2H), 7.20

- 7.24 (m, 2H), 7.51 (d, 8.1 Hz, IH), 7.88 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.1 Hz, IH); FAB-MS m/z 674 OvT+1). To a solution of ethyl 4-[2-AT-[2-(4-acetylphenoxy)ethyl] ~ N-[3-methoxy-4-[AT'-(2-methylphenyl)ureido]phenyl]acetamido] - ethylpiperazinyl-1-acetate (724 mg, 1.07 mmol) in THF (10 ml) was added dropwise with 0.125N NaOH (6.50 ml, 1.61 mmol) at room temperature, and the reaction mixture was stirred for 1 hour. The resulting mixture was concentrated, diluted with water and neutralized with 1N HCl at 0°C. The mixture was extracted with CHCl 3 -MeOH (4:1, v/v). The extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dryness. Chromatography of the residue with CHCl 3 -MeOH (3:1, v/v) as eluent gave 331 (450 mg, 65%) as a pale yellow amorphous solid. ER (KBr) 3345, 2938, 2821, 1673, 1631, 1598, 1533, 1455, 1417 cm-<*>; 1H-NMR (DMS0-d«) 5 2.25 (s, 3H), 2.35 - 2.47 (m, 8H), 2.51 (s, 3H), 2.53 - 2-.58 (m, 1H), 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, IH), 6.85 (s, IH), 6.92 (t, J= 7.3 Hz, IH), 7.30 (d. J= 7.3 Hz, 2H), 7.10 - 7.16 (m, 2H), 7.79 ( d, J= 8.3 Hz, IH), 7.90 - 7.95 (ra, 2H), 8.00 (t, J= 8.3 Hz, IH), 8.55 (m, IH), 8.61 (ra, IH); FAB-MS m/z 646 (M<*>+1); Anal. Calculated for CjjH^NjO^HCHHjO: C, 57.06; H, 6.43; N, 9.51. Found: C, 59.17; H, 6.32; N, 9.61. ■ EXAMPLE 253 4- [2-AT- [4- [AT'-(2-bromophenyl) ureido] 3-methoxyphenyl] -AT- benzylacetamido] ethyl-1-piperidinylacetic acid

Methyl 4- [2-AT- [4- [AT' - (2-bromophenyl)ureido] -3-methoxyphenyl] -AT-benzylacetamido] ethyl 1-piperidinyl acetate

A mixture of piperidineethanol (10.0 g, 77.4 mmol), benzyl 2-bromoacetate (17.8 g, 77.6 mmol) and K 2 CO 3 (21.4 g, 155 mmol) in CH 3 CN (2 0 0 mL ) was heated under reflux with stirring i

2 hours. The insoluble solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was poured into ice-cold 1A7-HCT and extracted with CHCl3. The organic layer was washed water, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give benzyl 4-(2-hydroxyethyl)-1-piperidinyl acetate (16.3 g, 76%) as a colorless oil. 1 H-NMR (CDCl 3 ) 81.31-1.40

(m,. 3 H), 1.52 (dd, /= 12.8, 6.3 Hz, 2H), 1.68 (brd, J= 10.0 Hz, 3 H), 2.16 (t, .7 = 11.6 Hz, 2 H), 2.92 (brd, .7 = 11.6 Hz, 2H), 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)-1-piperidinyl acetate (14.9 g, 53.8 mmol). in CH 2 Cl 2 (150 mL) was added Et 3 N (37.5 mL, 269 mmol) and DMSO (41.6 mL, 538 mmol). The reaction mixture was cooled to 0°C and SO 3 Py (25.7 g, 161 mmol) was added portionwise and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was diluted with water, then extracted with Et 2 O. The organic layer was washed with water, dried over anhydrous Na 2 CO 3 and concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc-hexane (2:1) as eluent to give (4-A7-.carbobenzyloxymethylpiperidinyl)acetaldehyde (4.63 g, 31%) as a colorless oil. 1 H-NMR (CDCl 3 ) δ 1.36-1.46 (m,

2 H), 1.69 (br s, 2 H), 1.72 (br s, 1 H), 1.90 (m, 1 H), 2.21 (dt, /= 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 (m; 5 H), 9.77 (t , J = 2.0 Hz, 1 H).

To a stirred solution of N-benzylamine (1.06 mL, 9.75 mmol) in MeOH (20 mL) was added AcOH (560 mL, 9.75 mmol) and (4-A7-carbobenzyloxymethylpiperidinyl)acetaldehyde (1, 79 g, 6.50 mmol) in MeOH (5 mL) and the solution was cooled to 0 °C. NaBH 3 CN (645 mg, 9.75 mmol) was added in one portion and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was poured into aqueous NaHCO 3 , then extracted with CHCl 3 . The organic layer was washed with water, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH-EtOAc (10:1:1) as eluent to give N-benzyl-2-[4-(N-carbobenzyloxy-methylpiperidinyl)]ethylamine (872 mg, 37%) as a colorless oil.

1H-NMR (CDCl1) 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 (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 (m, 5 H), 9.77 (t, J= 2.0 Hz, 1 H).

To a stirred solution of N-benzyl-2-[4-(N-carbo-benzyloxymethylpiperidinyl)]ethylamine (356 mg, 0.972 mmol), 4-[N'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (369 mg, 0.972 mmol) and N,N-dimethylaminopyridine (119 mg, 0.972 mmol) in DMF (15 mL) was added EDC-HCl (372 mg, 1.94 mmol) at room temperature 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 Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give benzyl 4-[2-N-[4-[N'-(2-bromophenyl)ureido]3-methoxyphenyl]-N-benzylacetamido ] ethyl 1-piperidinyl acetate (611 mg, 86%) as a colorless oil.

'H-NMR (CDCl1) mixture of rotamers'" 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, 1H), 3.65 and". 3.73 (s, total 2 H), 3.83 and 3.84 (s, total 3 H), 4.49 (s, 1H), 4.60 (s, 1H), 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 (bf+ 2).

To a stirred solution of benzyl 4-[2-N-[4-[ N'~ (2-bromophenyl)ureido]3-methoxyphenyl]-N-benzylacetamido] ethyl 1-piperidinyl acetate (347 mg, 0.477 mmol) in MeOH -H 2 O (5:1, 6 mL) was added LiOH (13.6 mg, 0.57 mmol) at room temperature and the resulting mixture was stirred overnight. The reaction mixture was poured into water and the solution was neutralized with aqueous 1N-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in vacuo. The residue was chromatographed on silica gel with CHCl3-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, respectively solid.

3332 'H-NMR (CD3OD), mixture of rotamers <0 >1.29-1.90 (series of m, 7 H), 2.75-2.86 (m, 2 H), 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, 1 H), 4.85 (s, 1 H), 6.79-7.00 (tendons 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{serler.ay ■ m, 2 H); MS (FAB) m/z 637 (M<*>), 639 (M<*>+2). 333 'H-NMR (CDCl1), mixture of rotamers I 5 1.15-2.11 (series ^v., m,7H), 2.89-2.97 (m, 2 H), 3.17-3.49 (series of tm, 6 H), 3.17 °9;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 and; 4.71 (s, total 2 H), 6.75-8.16 (series of .m, 14 H); MS (FAB) m/z 651 (M<*>), 653 Qf<+> 2).

EXAMPLE 254

4- [2-N- [4- [N'-(2-chlorophenyl)-3-methoxyureido]phenyl]-N-benzylacetamido]ethyl-1-piperidinylacetic acid

To a stirred solution of N-benzyl-2-[4-(N-carbobenzyl-oxymethylpiperidinyl)]ethylamine (372 mg, 1.11 mmol), 4-[N'-(2-chlorophenyl)ureido]-3-methoxyphenyl ]acetic acid (758 mg, 1.11 mmol) and N,N-dimethylaminopyridine (136 mg, 1.11 mmol) in DMF

(15 mL) was added EDC-HCl (426 mg, 2.22 mmol) at

room temperature, and the resulting mixture was stirred for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in

vacuum. The residue was chromatographed on silica gel with CHCl3-MeOH (10:1) as eluent to give benzyl 4-[2-N-[4-[N'-(2-chlorophenyl)-3-methoxyureido] phenyl]-N-benzylacetamido ]. ethyl 1-piperidinyl acetate (668 mg, 88%) as a pale yellowish oil.

'H-NMR (CDCl1) mixture of rotamers 8 1.15-1.83 (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, 1 H), 4.61 (s, 1 H), 5.14 (d, J= 4.4 Hz, 2 H), 6.72-6.82 (series of ■ m, 2 H), 6.94-6.99 (m, 1H), 7.13-7.50 (series of . m, 14 H), 7.94-8.02 (m, 1 H), 8.18 (d, J = 8.0 Hz, 2 H); MS (FAB) m/z 683 (M^H). To a stirred solution of benzyl 4-[2-N-[4-[N'-(2-chlorophenyl)-3-methoxyureido]phenyl]-N-benzylacetamido]ethyl-1-piperidinyl acetate (633 mg, 0.93 mmol ) in MeOH-H 2 O (10:1, 10 mL) was added LiOH (24.4 mg, 1.02 mmol) at room temperature and the resulting mixture was stirred overnight. The reaction mixture was poured into water and the solution was neutralized with aqueous IN-HCl, and then extracted with CHCl 3 . The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated in water. The residue was chromatographed on silica gel with CHCl3-MeOH (20:1) as eluent to give methyl 4-[2-N-[4-[Nr-(2-chlorophenyl)-3-methoxyureido]phenyl]-N-benzylacetamido] ethyl 1-piperidinyl acetate (504 mg, 89%) as a colorless amorphous solid. 'H-' NMR (CDClj), mixture of rotamers § 1.26-1.64 (series of m, 7 H), 2.02-2.10 (m, 2 H), 2.86 (t, J= .10.4 Hz, 2 H), 3.17 (d, J= 8.0 Hz, 2 H), 3.16-3.22 (m, overlap, 1 H), 3.40 (t, /= 7.6 Hz, 1 H), i 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 ayi m, 2 H), 6.98 (t, J= 7.6 Hz, 1 H), 7.13-7.37 (series a/ m, 9 H), 7.96 (m,. 1 H), 8.18 (d, J = 8.0 Hz, 2 H); MS (FAB) m/z 607 (M++ H).

To a stirred solution of methyl 4-[2-N-[4-[N'-(2-chlorophenyl)-3-methoxyureido]phenyl]-N-benzylacetamido]ethyl-1-piperidinyl acetate (177 mg, 0.292 mmol) in To MeOH-H 2 O (5:1, 6 mL) was added LiOH (21.6 mg, 0.90 mmol) and the resulting mixture was stirred for 4 h at room temperature. The mixture was poured into water, and the solution was neutralized with aqueous 1A7-HCl, and then extracted with CHCl3. The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 , then concentrated to give 334 (155 mg, 92%) as a colorless amorphous solid. 'H-NMR (CD3OD) mixture of rotamers .5.1.28-L9Q (tendons of m, 7 H), 2.84 (brs, 2 H), 3.30-3.52 (.tendons 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 tserieravrfh, 3 H), 7.16 (d, ^= 7.2Hz, 1 H), 7.24-7.40 (m, 5 H), 7.88 (s, 1 H), 7.98-8.04 (series amber m, 2 H); MS (ESI) m/2 593 (M<*>), 615 flvr+Na4).

\

Claims (26)

1. Connection, characterized in that it is represented by formula I, or a salt thereof, ' . in which W is a phenyl group optionally substituted with C-L-Cg- alkyl, C 1 -C 8 alkoxy, -OH, CF 3 or halogen; W<1> is a phenylene group which is optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen; A is=0; R is -(CH2)n-, in which n is 1 or 2; X is -C(O)-; M is in which is a divalent 5- or 6-membered heterocyclic unit, and the nitrogen atom is the point of attachment to X; wherein Q is -CH2-,--S- or -O-; R<1>, R<2> and R<3> are independently -H, -OH, -NH2, halogen, a C^^-Cg- alkyl group which is optionally substituted with phenyl-C-L-C8- alkoxy, a phenyl group, a C1-C6- alkoxy group, a mono-C1-C8-alkylamino group, a di-C1-C8-alkylamino, a C1-C8-alkyl sulfonylamino group, a phenylsulfonylamino group which is optionally substituted with C1-C8-alkyl, a naphthylsulfonylamino group which is optionally substituted with di-C1-C8-alkylamino, a phenoxy group which is optionally substituted with carboxy or halogen, a naphthyloxy group, a quinolinyloxy group , or two of R<1>, R<2> and R<3> together form a C1-C3 alkylenedioxy group or a 3-, 4-, 5-, 6- or 7-membered carboxylic radical which is optionally substituted with 1 to 3 substituents independently selected from C 2 -C 8 alkyl; R<4 > is -H or a C 1 -C 8 alkyl group; Y is a direct bond or a divalent radical selected from the group consisting of -C(0)-, -C(0)NH-, a C2-C6 alkenylene group, a C2-C6 alkynylene group and -(CH2)kY<2->, wherein k is 0, 1, 2 or 3; and Y<2> is a direct bond or a divalent radical selected from the group consisting of -O-, -S-, -S(O)-, -S(0)2- and -NY<3->, in which Y<3> is -H or a C±-C10 alkyl group; Z is a phenylene group which is optionally substituted with carboxy, C₁-C₆-alkoxy, halogen, -NO₂, -NH₂, C₁-C₆-alkyl, di-C-L-C₆-alkylamino or C-L-C₆-alkanoylamino, a heterocyclylene group selected from piperidinylene, pyridinylene or piperazinylene which is optionally substituted with carboxy or halogen, or a C3-C7 cycloalkylene group; A<1> is a direct bond or -(CH2)t-, in which t is 1, 2 or 3; and R<5 > is -OH, C 1 -C 8 alkoxy group, or M is wherein R<11> is in which R 1 < 2 > is -H, a C 1 -C 4 -alkyl group which is optionally substituted with C3-C7-cycloalkylamino, C1-C6-alkoxy-C1-C6-alkylamino, di-C2-C10-<a>lkenylamino, phenoxy (optionally substituted with halogen or C-L-Cg-alkanoyl), -OH, morpholinyl, piperazinyl (optionally substituted with C1-C6 alkyl), di-C1-C6 alkylamino, pyrrolidinyl (optionally substituted with halogen), a C3-C7 cycloalkyl group, a phenyl group, a benzyl group substituted with -NO2 or -NH2, a C2 -C10-alkenyl group, or a C2-<C>10-alkynyl group, and the left bond is the attachment point of X and the right bond is the attachment point of Z<3>; Z<3> is a direct bond, a divalent aliphatic hydrocar bone unit with 1 to 12 carbon atoms in which one or more carbon atoms can be replaced by -0- or -NR<13->in which R<13> is -H or a C1-C8 alkyl group, and in which one or more hydrogen atoms attached to an aliphatic carbon atom may. is replaced by a C 1 -C 8 alkyl group; or Z<3> is in which x is 0 or 1; y is 1, 2, or 3; and R<14> is -H, -OH or halogen, or Z<3> is or, when R<11> is -NR<12>, then is Z<3> where Z<4> is in which Ri4<a> is _ H^ _oh, a <C>1-<C>10 alkyl group or halogen, or Z<4> is wherein the left bond is the attachment point of R<11 >and the right bond is the attachment point of Q<2>; Q<2> is a divalent radical selected from the group consisting of a phenylene group which is optionally substituted with -OH, O₁-C₆- alkoxy, carboxy, -NO₂-, NH₂, halogen, mono-C₁-C₆-alkylamino, di-C₁-C₆-alkylamino, piperidinyl or C₁-C₂ -alkylcarbonylamino, and a pyridinylene group, or in which R<17> and R<18> independently are selected from the group consisting of -H and a -C6 alkyl group; and L<1> is -CO 2 H and -CO 2 R<19 > in which R<19> is a C1-C6 alkyl group. 2. Compound as stated in claim 1, or a salt thereof, wherein W is an unsubstituted phenyl group or a phenyl group with one or two substituents selected from C1-C6 alkyl group and halogen in the ortho-positions thereof. 3. A compound as set forth in claim 1, or a salt thereof, wherein W<1> is an unsubstituted phenylene group or a substituted phenylene group having a substituent selected from methoxy, Cx-C6 alkyl group and halogen in the ortho position of -NH thereof . 4. Connection as stated in one or more of the requirements 1 to 3, or a salt thereof, wherein M is 5. Compound as stated in claim 4, or a salt thereof, wherein R is -CH2-. 6. Compound as stated in one or more of claims 4 or 5, or a salt thereof, in which at least one of R<1>, R<2> and R<3> is -OH or halogen. 7. Compound as stated in one or more of claims 4, 5 or 6, or a salt thereof, in which Y is a C2-C6 arkenylene group, a C2-C6 alkynylene group or -{CE2)^ Y2-, in which Y< 2 >is a direct bond, -0-, -S(0)- or -NY<3->, and Y<3> is -H. 8. Compound as stated in claim 7, or a salt thereof, wherein Y<2> is -0- or -NH-. 9. Compound as stated in one or more of claims 4, 5, 6, 7 or 8, or a salt thereof, wherein R<4> is -H. 10. Compound as stated in one or more of claims 4, 5, 6, 7, 8 or 9, or a salt thereof, wherein A<1> is a direct bond. 11. Compound as stated in claim 10, or a salt thereof, wherein R<5> is OH. 12. A compound as set forth in claim 10, or a salt thereof, wherein Y is -CH20-; and Z is a phenylene group which is optionally substituted with carboxy, C 1 -C 8 -alkoxy, halogen, -NO 2 , NH 2 , C 1 -C 8 -alkyl, di-C -C 8 -alkylamino or C 1 -C 8 -alkanoylamino, a heterocyclylene group selected from piperidinylene, pyridinylene or piperazinylene optionally substituted with carboxy or halogen, or a C3-C7 cycloalkylene group. 13. A compound as set forth in claim 4, or a salt thereof, wherein W is an unsubstituted phenyl group or a phenyl group with one or two substituents selected from C1-C6 alkyl and halogen in the ortho positions thereof; W<1> is an unsubstituted phenylene group or a substituted phenylene group with a substituent selected from methoxy group, C 1 -C 8 alkyl group and halogen in the ortho position of -NH thereof; and R<5> is -OH. 14. Compound as stated in claim 4, or a salt thereof, in which R<5 > is a C 1 -C 4 -alkyloxy group. 15. Compound as stated in one or more of claims 1, 2 or 3, or a salt thereof, wherein M is 16. Compound as set forth in claim 15, or a salt thereof, selected from the group consisting of 17. Compound as set forth in claim 16, or a salt thereof, selected from the group consisting of 18. Use of a compound as stated in one or more of claims 1 to 17 for the production of a drug to inhibit a cell adhesion. in a mammal. 19. Use of a compound as set forth in one or more of claims 1 to 17 for the preparation of a medicament for treating a condition associated with VLA-4 mediated cell adhesion in a mammal. 20. Use as stated in claim 19 in which the condition associated with VLA-4 mediated cell adhesion is selected from inflammatory responses, autoimmune responses and tumor metastases. 21. Use as set forth in claim 19 wherein the condition associated with VLA-4 mediated cell adhesion is selected from asthma, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and transplant rejection. 22. Pharmaceutical preparation, characterized in that it comprises as a therapeutic agent a compound as stated in one or more of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient. 23. Pharmaceutical preparation as stated in claim 22, which further comprises one or more of further therapeutic agents. 24. Pharmaceutical preparation as stated in claim 23, wherein said one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, antirheumatic agents, corticosteroid agents, immunosuppressive agents, antipsoriatic agents, bronchodilators, antiasthmatic agents and antidiabetic agents. 25. Pharmaceutical preparation as stated in claim 24, wherein one of said one or more additional therapeutic agents is an anti-inflammatory agent. 26. Pharmaceutical preparation as set forth in claim 25, wherein the anti-inflammatory agent is selected from a steroid and an NSAID.