AU782616B2

AU782616B2 - Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

Info

Publication number: AU782616B2
Application number: AU97084/01A
Authority: AU
Inventors: Ronald J. Biediger; Qi Chen; E. Radford Decker; George W. Holland; Jamal M. Kassir; Jian Li; Wen Li; Robert V. Market; Ian L Scott; Chengde Wu
Original assignee: Texas Biotechnology Corp
Current assignee: Encysive Pharmaceuticals Inc
Priority date: 1999-05-07
Filing date: 2001-12-05
Publication date: 2005-08-11
Anticipated expiration: 2020-05-05
Also published as: AU9708401A

Description

1 CARBOXYLIC ACID DERIVATIVES THAT INHIBIT THE BINDING OF INTEGRINS TO THEIR RECEPTORS Field of the Invention This invention is directed generally to the inhibition of the binding of 04 1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding; to pharmaceutically active compositions comprising such compounds; and to the use of such compounds either as above, or in formulations for the control or prevention of disease states in which a4P 1 is involved Background of the Invention When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream.

However, when a tissue is infected or becomes damaged, the white blood cells recognise that invaded or damaged tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.

There are three main types of white blood cells: granulocytes, monocytes and 20 lymphocytes. The integrin 04[ 1 (also called VLA-4 for very late antigen-4) is a .g S" heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognise and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.

[R:\LlBH]00991.doc:ljg Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the a43 1 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue as well as the initial rolling event itself.

Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to 15 VCAM-1 and fibronectin.

Some of the diseases that might be treated by the inhibition of ca43 1 binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, and type I diabetes. In addition to being found on some white blood cells, a43 1 is also found on various 20 cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving a4I3 may be involved in the metastasis of certain S* cancers. Inhibitors of a40 1 binding may, therefore, also be useful in the treatment of some forms of cancer.

The isolation and purification of a peptide which inhibits the binding of a4P 1 to a protein is disclosed in U.S. Patent No. 5,510,332. Peptides which inhibit binding are disclosed in WO 95/15973, EP 0 341 915, EP 0 422 938 Al, U.S. Patent No. 5,192,746 and WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247 and WO 98/04913.

JUN. 2005 15:53 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 48 3 It is therefore an object of the invention to provide novel compounds which are inhibitors of cz..1. binding, and pharmaceutical compositions including suach novel compounds.

Brief Summary of the Invention s According to a first embodiment the present invention provides a compound of the structure R0 0 wherein Y at each occurrence, is independently selected from the group consisting of C(O), to N, CR', C(R 2

)(R

3 NR', CH, 0 and S; q qis anineger offrom 2 T is selected from the group consisting of C(O) and (CH2), wherein b is an integer of Oto 3; L is selected from the group consisting of 0, NR' 1, S and (CH 2 wherin n is 0 or

R

6 le~, R" and R' 8 are each independently selected from the group conisisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, Maboxainide, cycloalkyl cycloalkenyl,,cycloalkynyl, cyoloalkylalkyl, aryl,.aroyl, aryloxy, arylamnino, :20 biaryl, thioaryl, diarylaznino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhet~tocyclyl, heterocyclylalkyl, carbamnate, aryloxyakl, hydrogen, and -C(O)NH(benzyl) groups; and B, R 3 k' and R' 0 l are independently selected -from the group consisting of hydrogen, halogen, alkyl4, alkenyl, allcnyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -C0 2 -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, 2$ alkoxycarbonyl, heterocycloyl, carboxy, -N(C 1

-C

3 alkyl)-C(O)-(Cj -C 3 alkcyl),

-NHC(O)N(CI-C

3 alkyl)C(O)NII(C 1 -c alkyl), -NHC(O)NE(C, -C 6 alkyl), -NHSO 2 Calkl), -NHSO 2 (aryl), alkoxyalkyl, alkylarnino, alkenylamnino, di(C 1

-C

3 alkyl)anino, -C(O)O-(Ci-Cjalkyl) -C(O)NH-(C 1 -CjalkyI), -C 3 alkyl) 2 -CH=NOH, -P0 3

H

2 -0P0 3

H

2 haloalkyl, alkox yalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloi1kylalkyl, aryl, baroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamnino, heteracyclyl, alkylaryl, aralkenyl, aralkyl, alkylbtcrocyclyl, f tAULEH1575390dlspeo.doe:aak COMS ID Na:SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 30.JUN.2005 15:54 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 49 3a heterocyclylalkyl, sulfonyl, -S0 2 -(CI-Cialkyl), -S03-(CI-Calcyl),' suonanido, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) groups; wherein B, R 2

R

3 R4, R, k, R 9

R'

0 R" and L 1 8 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; s wherein when L is NR' R 4 and R" taken together may form a ring; and wherein RY and R' 0 taken together may form a ring; and wherein when at least one Y is CR', R' and R 6 taken together may fonn a ring; with the proviso that R' 8 is not a phenyl ring substituted with a group seleed from -C(=NH)Ni 2 -CN, -C(FNH)NHOH, -C(=NOH)N1, -C(-S)NH 2 and -C(NH)SdH 3 and pharmaceutically acceptable salts thereof.

According to a second embodiment the present invention provides a compound of the structure R"0

OB

R18.N NN TLNR 0 R wherein T is selected from the group consisting of C(Q) and (CH2)b, wherein b is an Is integer of from Oto 3; L is selected fiom the group consisting of 0, NR', S and (CH 2 wherein. n is O or g is an integer of from 0 to 7; and B, 0, R, R' 0 and 0 at each occurrence are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -OH, -CO2H, -CN, -NO 2

-NH

2 alkynylanino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C -C 3 alkyl)-C(O)(C,-C 3 alkyl), -NIC(O)N(C -C~alkyl)C(Q)NH(C 1

-C

3 alkyI), -NHC(O)NH(C,-Calkl), -NHSQ 2 (Cl- C~alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkyiwnino, alkenylamino, di(C,-Calkyl)amino, -C(0)0-(C]-C3alkyl), -C(O)N-(CI-C3 kyl), -C(0)N(Cj-C3lkl), -CHWnNOH, -P0H2' -OP0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxanide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloaikylallyl, aryl, aroyl, aryloxy, arylainino, biaryl, thioaryl, diarylamio, heterocyclyl, alkylsryl, aralkenyl, arailyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S02-(CI -C~allcyl), -SO3-(CI-Calkyl), sulfdnamido, carbamate, aryloxyalkyl' and -C(Q)NH(benzyl) groups; R" and R 1 8 are each independently selected from the group consAsting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, fRAUBH157539OdIsvei.doc: ask COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:54. SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 3b heterocycloyl, Z-CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldebyde, caxtboxaniide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thicaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, allcylhetcrocyclyl, heterocyclyl alkyl, carbamnate, aryloxyalkyl, hydrogen and -C(O)NI-(benzyl) groups; wherein B, RW, RW, R7, R9, R" 0 R' RB and R 2 3 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is NR', R 4 and R" taken together may form a ring; and wherein R' and POO taken together may form a ring; with the proviso that R' 8 is not a phenyl ring substituted With a group sel~cted from i0 -C(=NH)NH 2 -CN, -C(NH)IIOH, -CQ=-NOH)NH 2

-C(=S)NH

2 and -C(NH)SCHj; and pharmaceutically acceptable salts thereof.

According to a third embodiment the present invention provides a compound of the structure 0 R OR 28 1 is wherein his an integer of 0to B, R 9

R",

0 R' and R 'are each independently selected from the group cotisisting of hydrogen, halogen, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -0F 3 -OH, -CO 2 H, -SH, -NO 2 -Nil 2 alkynylamino, alkoxycarbonyl,. heterocycloyl, curboxy, -C 3 alkyl)-C(O)(Ci rC 3 alkyl), *0 20 -N}IC(O)N(C 2

-C

3 a~kyI)C(O)NH(C, -C3 alkyl), -NHC(O)NH(Cj-C 6 alkyl), -NHSO 2 Ojalkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C,-C 3 alkyl)axnino, y-C 3 alkyl), -C~alkyl), -C 3 alkyl) 2 -CW=NOH,: -P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxynilcoxy, carboxaldehyde, carboxainide, .c~cloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamnind, biaryl, thionryl, diaryluinino, heteroryclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyi, heterocyclylalkyl, sulfonyl, -S02-(CI-Csalkyl), -S0 3 3 alkyl), sulfonarnido, carbamate, aryloxyalkyl, and C(O)NH(benzyl) groups; W7at each occurrence is independently selected from the group. consisting of halogen, hydroxyl, alkyl, alkenyl, aikynyl, alkoxy, alkenoxy, alkynoxy, thi'oalkoxy, hydroxyalcl, aliphatic acyl, -C23, -CO 2 H, -SH, -NO 2

-NH

2 alkyn :ylantino, alkoxycarbonyl, heterocycloyl, carboxy, -N(Ct-C 3 alkyl)-C(O)(CI-C3adkyl), jRALMM5l7SS90dIspaeiiov:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:54 SPRUSON AND FERGUSON 61292615486 NO. 269V7 51 -NHC(O)'N(Ct-C 3 alkyI)C(O)NH(C 1

-C

3 alkyl), -NIIC(Q)NH(Ci-C 6 alkyl), -NIISO 2

(C

1 C~alkyl), -NI{S0 2 (aryl), -N(Ci-C 3 alkyl)S0 2

(C

1

-C

3 alkyl), -N(Cz-C3alkyl)50 2 (arYl), alcoxyalkyl, alkylamino,- alkenylamino, di(C 1 I -Csalkyl) amino, -C(O)O-(Ci-C~alkyl),

C(O)NH-(C

1 -C~alkyl), -C(O)N(CI-C 3 alkYl) 2 -CHsNOH, -PO 3 H2, -OP 0 3

H

2 -haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, vyoldalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylaniino, biaryl, thioaryl, diarylamino, heterocyclyl, alkyluryl, aralkenyl, aralkyl, alkyllieterocyclyl, heterocyclylalkyl, ulfonyl, S02-(CI-C 3 alkyl), -S03-(CI-C 3 alcyI), sulfonamido, carbamate, aryloxyalkyl, and- C(O)NH(benzyl) groups;

R

6

R.

7 and R1' 8 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkox'carbonyl, heterocycloyl, -CH=NQH, haloalkyl, alkoxyalkoxy,. carboxaldehyde, carboxantide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, irylainino, biaryl, thiosryl, diarylamino, heterocyclyl, alkylairyl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, carbaniate, aryloxyalkyl, hydrogen, and -C(O)NI-(benzyl) groups;

R.

26 is selected from the group consisting of hydrogen alkyl, alkenyl, alkynyl, hyciroxyalkyl, aliphatic acyl, -CE 3 aikoxycarbonyl, heterocycloyl, carboxy, C~alky), -C(O)NH-(C,-C 3 alkyl), -C(O)N(C-C 3 alkYI) 2 -P0 3

H

2 haloalkyl, carboxarnide, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, biaryl, hetrocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

-(CI-

C

3 alkyl), sulfonamide, aryloxyalkyl, and -C(O)NH(benzyl) groups; wherein B, 1.

6

R

7 R9, R" 0

R"

2 Rtk 6 and H.

2 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein R. and K 24 taken together may form a ring; R24 and H.

25 taken together may form a ring; and wherein 9 and H.' 0 taken together may form 'a ring; and pharmaceutically acceptable salts thereof.

According to a fourth embodiment the present invention provides a compound of the structure (0 (R9k 1 OB R1 Y -N<N TLR4 0 Re rRALIB~s7539odIWci.dr:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 18:06 Date 2005-06-30 JUN. 2005 15:55 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 52 3d wherein Z at each occurrence is independently selected from the group consisting of N, CR 30

C(R")(R

2 NR", CH, 0 and S; z is an integer of from 3 to 6; k is an integer of from 0 to T is (CH 2 hb, wherein b is an integer of from 0 to 3; L is selected from the group consisting of 0, NW' S and (CH 2 whe'rei i n is 0 or R6', Rt, R 18 and R" are each independently selected from the group 'consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylarnino, alcoxycarbonyl, to heterocycloyl, -CH=NOH,. haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalicynyl, rycloalkylallcyl, aryl, aroyl, aryloxy, arylamino, biaryl, thiosryl, diarylanxino, hetercyclyl, alkylaryl, aralkenyl, aralkyl, alkylbeterocyclyl, hetercyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B3, R 9

R'

0

RW

0 W' and R"3 at each occurence are independently selected from 1s the group consisting of hydrogen, halogen, alkyl, alcenyl, alkynyl, alkoxy, 'ailenoxy, alkcynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CE 3

-CO

2 H, -SN, -OH, -CN, -NO 2 0. NH 2 alkynylainino, alcoxycarbonyl, heterocycloyl, carboxy, N(C,-C~alkyl) 2 C(O)(Cj- C~ally), -NHC(O)N(C,-C~alkyl)C(O)NH(C,-C~alkyl), -NHC(O?)NH(C-C 6 a]Icyl),- 20 NH50 2 (CI-C~alkyi4), -NHSO(aryl), alkoxyalkcyl, alkylamnino, alcenylaminio, di(C,- C~alkyl)amino, -C(O)0-(C,-C~alkyl), -C(O)NH-(C 1

-C

3 alkyl), -C(Q)N(Ci-C~alkyl), CI-INOH, -P0 3

H

2

-OPOR

2 haloalkyl, alkoxyalkoxy, earboxaldehyde, carb.oxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhetdrocyclyl, heterocyclylalkyl, sulfonyl, -S02-(C 1

-C

3 alkyl), ,-C~alkyl), sulfpnamido, 25 carbamate, aryloxyalkyl, and -C(O)NH(benzyl) groups; and

K

29 at each occurrence is independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thiosikoxy, hydroxyalkyl, aliphatic acyl, -C0 2 H, -SN, -OH, -04, -NO 2

-NH

2 alkynylumino, alkoxycarbonyl, heterocycloyl, carboxy, N(C, -C~alkyl)-C(O)(C,-C~akyl), -NHC(O)N(C 1 s0 C~alkyl)C(O)NH(C 1 -C~alkyl), -NHC(O)NH(CI-C~alkyl), -NHS02(Ce -Coalkyi), NHSO,(aryl), alkoxyalkyl, ailylamnino, alkenylarnino, di(C, -C 3 alkyl)anino, C~alkyl), -C(O)NH-(CI-C~alkyl), -C(O)N(Cr-C3alkyl)2, -CW=NOH, -PO 3 H2, -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloallcyl, cycloallwnyl, cycloalkynyl, cycloalkylalicyl, aryl, aroyl, aryloxy, arylamino, biaryl, :thicaryl, 3s diarylamino, .heterocyclyl, alkylaryl, arailcenyl, aralkyl, alkyihetejocyclyl, FRALII57S39OdI speci.dwcAk COMS ID No: SBMI-01328788 Received by IP Austraia: Time 16:08.Date 2005-06-30 JUN. 2005 15:55 SPRUSON AND FERGUSON 61292615486 NO 2697 P. 53 3e heterocyclylalkyl, sulfontyl, -S 02-(C i-C~alkyl), -S03-(Ci -C 3 alkyI), sulfonanido, carbamnate, aryloxyalkyl, and -C(O)NH(benzyl) groups; wherein B,eR, RG,R 7 R, R1%,RII,Rl& R 9 R 30 R 31

R

32 and R 33 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is NR 1 1 RW and R" taken together may form a ring; and wherein R9 and R1 0 taken together may form a ring; or a pharmaceutically acceptable salt thereof.

According to a fifth embodiment the present invention provides a compound of the structure R R1N N 00 0Q~ wherein R24 and R 25 are each independently selected from the. group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, tlioalkoxy, i:hydroxyalkyl, aliphatic acyl, -COMH, -SM, -OH, -CN, -NO 2

-NH

2 alkyhylamino, :..alkoxycarbonyl, heterocycloyl, carboxy, N(C,-C 3 alkyl)-C(O)(Ca -Csalkyl), NHC(O)N(Ci-C~alkyl)C(Q)NH(C 1 -C~alkyl), -NHC(O)NH(C 1

-C

6 alkyl), -NHSO 2

(C

1 Ojalkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(CI-.C 3 alkyl)aminio, :C(O)Q-(CI-C~alkyl), -C(O)NH-(CI-C3alky), -C(O)N(C 1 -C~alkyl~l, -CH-NOHi, -PO 3 H, 0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxainide, cyoloalcyl, cyoloalkenyl, cyoloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylaminb, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterccll O*00 heterocyclylalkyl, sulfonyl, -S0 2 -C~alkyl), -S0j-(Cl-C~alcyl), sulfonamido, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) groups; and RI:B' and. 34t~ are each independently selected from the group consisting: of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl,; -CH=NOFI, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxarnide, cycloalkyl, cyoloalkentyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylarnino,' biaiyl, thiouryl, diarylawino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhet rocyclyl, heterocyclyalkyl, carbuinate, aryloxyalkyl, hydrogen and -C(Q)NH(benzyl) groups; wherein W 24

R

2 and 14~ are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and wherein R24 and R 2 '5 taken together may form a ring; rW\LMN1575390diVidd:mn COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:55 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 54 3f with the proviso that when R 2 and R 25 taken together form a ring, the ring formed is not benzene.

According to a sixth embodiment the present invention provides a pharmaceutical composition comprising a compound according to any one of the first to fifth s embodiments together with a pharmaceutically acceptable carrier, diluent or excipient.

According to a seventh embodiment the present invention provides a method for selectively inhibiting o4pl integrin binding in a mammal comprising administering to said mammal a therapeutically effective amount of a compound according to any one of the first to fifth embodiments, or a composition according to the sixth embodiment.

According to an eighth embodiment the present invention provides a compound according to any one of the first to fifth embodiments, or a composition according to the sixth embodiment when used for selectively inhibiting aqpi integrin binding in a mammal.

According to a ninth embodiment the present invention provides use of a coinpound is according to any one of the first to fifth embodiments in the manufacture of a medicament 9 for selectively inhibiting a43 I integrin binding.

Disclosed herein are compounds of Formula I M X 99 M E T^ R 4 Formula (I) wherein Y, at each occurrence, is independently selected from the group consisting 20 of N, CR' C()(R 3 NR, CH, 0 and S; q is an integer of from 3 to A is selected from the group consisting of O, S, 7 and NR'; E is selected from the group consisting of CH2, 0, S, and NR'; J is selected from the group consisting of 0, S and NR 8 T is selected from the group consisting of C(0) and (CH 2 6 wherein b is an integer of from 0 to 3; M is selected from the group consisting of C(R)(R 1 0 and

(CH

2 wherein u is an integer of from 0 to 3; L is selected from the group consisting of 0, NR", S, and

(CH

2 wherein n is an integer of 0 or 1; rR:ALIDH1575390dl apcci.doc;aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:55 SPRUSON AND FERGUSON 61292615485 NO. 2697 P. 3g X is selected from the group consisting of CO 2 B, P0 3

H

2

SO

3 S02NH 2 SozNHCQR' 2

OPOH

2 C(O)NHC(O)R", C(O)NHSO 2

R

4 hydroxyl, tetrazolyl and hydrogen; W is selected from the group consisting of C, CR' 5 and N; and veto V..

4@4S 00 0 *000 S0.

we of** 000

I.

100.

*co 60990 S00 4 *4 4 di P 4

S

0 I RWIB11575390d I vpoAoc:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 9 10 8 12 13 14 15 16 17 B,RR',R, R R R,R,R,R, R,R, ,R R R R R and R at each occurrence are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,

-N(CI-C

3 alkyl)-C(O)(C 1

-C

3 alkyl), -NHC(O)N(C 1

-C

3 alkyl)C(O)-

NH(C

1 I -C 3 alkyl), -NHC(O)NH(C I -C 6 alkyl), -NHSO 2 (C I -C 3 alkyl), -NI-S0 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C I -C 3 )amino, I -C 3 )alkyl, -C(O)NH-(C 1

-C

3 )alkyl, -C(O)N(C I -C 3 alkyl) 2 -CH=NOH, -P0 3

H

2

-OPO

3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

I-C

3 alkyl), -S0 3

I-C

3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; wherein B, R ,R R',R R ,R 8

R

9 ,R10 0 R, RI R' 3

R'

4 R" and R' are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is R 4 and taken together may form a ring; 20 and wherein when M is C(R R' and R" taken together may form a ring; :::and wherein when A is NR 6 and at least one'Y is CR t

R

1 and R 6 taken together may form a ring; or a pharmaceutically acceptable salt thereof;, with the proviso that when A is C(R 1 7 E is not NR.

For Formula 1, presently preferred compounds may have A as NR 6 E as NR 7; J as 0; M as C(R 9 0 q as 4 or'5; T as (CH 2 )b Wherein b is 0; L as (CH 2 )n wherein n is 0; X as C0 2 13; W as C or CR1 5 R 4 as aryl, alkylaryl, aralkyl, heterocyclyl, alkyiheterocyclyl or heterocyclylalkyl; and R1 0 and R 1 5 independently as hydrogen or lower alkyl.

More specifically, the compounds of this invention may be described by Formula H.

0

R

9 Y0 Rio 08 qNN 16 17 R R Formula 11 wherein Y, at each occurrence, is independently selected from the group consisting of N, CR', C(R 2

)(R

3 NR', CH, 0 and S; ~q is an integer of from 3 to 7; T is selected from the group consisting of C(O) and (CH 2 )b wherein b is an integer of 0 to 3; L is selected from the group consisting of 0, NR''1, S, and

(CH

2 )n wherein n is an integer ofO0 or 1; W is selected from the group consisting of C, CR'5 and N; and B, R 2 R 3

W

5 RU", R 11 and R 1 5 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, :alkoxy, alkenc'v, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CE 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C 1

-C

3 alkyl)-C(O)(C, -C 3 alkyl),

-NHC(O)N(C

1

-C

3 alkyl)C(O)NH(C 1

-C

3 alkyl), -NHC(O)N1-(C 1

-C

6 alkyl),

-NHSO

2 (C I -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(Ci -C 3 )amino, -C 3 )alkyl, -C(O)NH-(CI-C 3 )alkyl, -C(O)N(C 1

-C

3 alkyl) 2 -CH=NOH, -P0 3 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalk, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

-(CI-C

3 alkyl), -S03-(CI-C-,alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; wherein B, RR, R 4 R 6 R R R" and R'aenustteo JUN. 2005 15:56 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 56 6 substituted with at least one electron donating or electron withdrawing group; wherein when L is R 4 and taken together may form a ring; and wherein R 9 and R 1 0 taken together may form a ring; and wherein when at least one Y is CR', R t and R 6 taken together may form a ring; or a pharmaceutically acceptable salt thereof.

For Formula II, presently preferred compounds may have q as 4 or 5; W as C or CR 5 T as (CH 2 )b wherein b is 0; L as (CH2), wherein n is 0; R 4 as aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; and R 6

R

7

R'

0 and R s as independently hydrogen or lower alkyl.

Also disclosed herein are compounds described by Formula III 0 0 o o0 Y0 10 R

OB

Formula L q is an integer offo 2 to 5; N N T R o T is selected from the group consisting of C(0) and (CHiX wheein b is an integer of ee L..is Formula Il S 0" wherein Y at each occurrence, is independently selected from the group consisting of N CR, alNRi CH, O and S; 2. q is an integer of from 2 to T is selected from the group consisting of C(0) and (CH2)b wherein b is an integer of Oto 3; L is selected from the group consisting of O, NR", S, and (CH2)n wherein n is an integer of 0 or 1; R R 7 R, and R 18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, carbamnate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; and B, R 2

R

4 R' and R1 0 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C,-C 3 alkyl)-C(O)(CI-C 3 alkyl), -NHC(O)N(C I-C 3 alkyl)C(O)NH(C 1

-C

3 alkyI), -NHC(O)NH(C I -C 6 alkyl),

-NHSO

2

(C,-C

3 alkyl), -NHS02(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C ,-C 3 )amino, ,-C 3 )alkyl, -C(O)NH- 1-C 3 )alkyl, -C(O)N(C I-C 3 alkyl) 2 -CH=NOH, -P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl. sulfonyl, -S0 2

-C

3 alkyl), -S0 3

-(C

1

-C

3 alkyl), sul fonamido, carbamnate, aryloxyalkyl and -C(O)NH(benzyl) groups; wherein B,R R, R 2 ,RR R R, R R, R R 1 and R1 8 are unsubstituted or 20 substituted with at least one electron donating or electron withdrawing group; wherein when L is NR", R 4 and R" taken together mnay form a 'ring; and wherein R 9 and R1 0 taken together may form a ring; and wherein when at least one Y is CR', R' and R 6 taken together may form a ring; or a pharmaceutically acceptable salt thereof.

For Formula 111, presently preferred compounds may have R1 8 as hydrogen, alkyl, aryl, aralkyl, cycloalkyl, aikyiheterocyclyl, heterocyclylalkyl or heterocyclyl; T as wherein b is 0; L as (CH 2 )n wherein n Is 0; Y as CR' and (R 2 3 and q as 2 or 3.

In Formula M, the portion of the molecule R' 8 can be (R28 and 0 5 and pharmaceutical acceptable salts thereof and pharmaceutical acceptable salts thereof :wherein R 1 9

R

20 R 1 and R 8 at each occurrence are independently selected from the group consisting of halogen, alkyl. alkenyl, alkynyl. alkoxy, alkenoxv, alkvnoxy. thioalkoxy. hydroxyalkyl. aliphatic acyl. -CF 3

-OH,

-COH, -SH, -CN, alkynviamino. alkoxycarbonyl, heterocyclovl. carboxv, -N(CI-Cs, alkvl)-C(O)(C alkyl),

-NHC(O)N(CI-C,

3 alkyl)C(O)NH(C 1 -Cialkyl), -NHC(O)NH(C 1

-C

6 alkyl),

-NHSO,(C

1 -Cs, alkvl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, 1 -Cs,)amino. -C(O)O-(C 1 -C3,)alkyl. -C(0)NH-(Cj -Csak,-CONC-C alkyl) 2 -CH=NOH, -PO 3 -0P0 3

H.

2 haloalkyl, alkoxyalkoxy, carboxaldehvde, carboxarnide. cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy. arylamino, biaryl. thioaryl, diarylamino.

heterocyc lyl. alkylaryl. aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

-C

3 alkyl), -SOA-(C -alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; RI's is selected from the group consisting of alkyl, alkenyi. alkynyl, hydroxyalkyl, aliphatic acyl. alkynylamino. alkoxvcarbonvl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, carbamiate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; R 22 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C I -C 3 alkyl)-C(O)(C I -C 3 alkyl), -NHC(O)N(C I-C 3 alkyl)C(O)NH(C 1 -Cjalkyl), -NHC(O)NH(C I-C 6 alkyl), -NHSO 2

(CI-C

3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1

-C

3 )amino, -C(O)O-(C 1

-C

3 )alkyl,

-C(O)NH-(C

1

-C

3 )alkyl, -C(O)N(C 1

-C

3 alkyl) 2 -CH=NOH, -P0 3 1- 2 -0P0 3

H-

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

-(CI-C

3 alkyl), -S0 3

-(CI-C

3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; 20 c is an integer of zero to two; d is an integer of zero to three; e is an integer of zero to four; and i is an integer of zero to two.

In one embodiment, R1 8 is aralkyl; R 4 is aryl; T is (CHA) where b is zero; L is (CH 2 where n is zero; and, B, R' and R are each independently hydrogen.

JUN. 2005 15:56 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 57 Furkier disclosed herein are conpounds descxribod by Foinmia IV 0 1,230R g%, 0- N00

R

7 T~ R Formula IV wherein T is selected from the group consisting of C(O) and (Cl4 2 wherein b is an integer of from 0 to 3; L is selected from the group consisting of 0, NR", and is (CH 2 whereinun is an integer ofO0 or 1; to g isan integer of fronm 0 to 7: B, R 4

R

9 R'1 0 and R2 3 at each occurrence are independently selecte'd from thc :group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,'alkoxy, alkenoxy, alkynoxy, rhioalkoxy, hydroxyalkyl, aliphatic acyl,

CO

2 H, -SH, .CN, -N02, -l{H 2 H, alkynylamino, alkoxycartonyl, heterocycloyl, carboxy, -N(C,-C 3 alkyl)-C(O)(C I-C 3 alkyl), -NHC(O)N(C L-C3 alkyi)C(0)NH(C -C 3 alkyl) -NHC(O)NH(C 1

-C

6 alkyl),

*NHSO

2 (C,-C3 ailkyl), -NHSO 2 (aryl), alkoxyalkyl, alcylainino, alkenylamino, di(Ci-C 3 )amino, I -C,)alkyl, -C(O)NH-(C I- C3)alkyl, -C(0)N(G.1-Cj alkyl) 2 -CHr'N0H-, -P0 3 8 2

-OPOH

2 haloalkyl, alkoxyalkoxy, rarboxaldehyde, carboxainide, cycloalkyl, cycloalkenyt, cycloalkyn~yl, cycloalkylalkyl, aryl, aroy], aryloxy, arylamino, biary], tbioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 1 i-C 3 alkyl), -SO,-C I-C 3 alkyl), sulfonamido, carbamnate, aryloxyalkyl COMS ID No: SBMI-01328788 Received by IP Australia: Time (i-tm) 16:06 Date 2005-06-30 JUN. 2005 15:56 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 58 11 and -C(0)NH(benzyl) groups; and

R

6

R

7 R" and R' are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamrnino, alkoxycarbonyl, heteracycloyl, -CH-NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; wherein B, R 4 R R, RIO?, R and R 23 are unsubstituted or substituted 10 with at least one electron donating or electron withdrawing group; wherein when L is NRI', R 4 and R" taken together may formn a ring; and wherein R' and R10 taken together may form a ring; or a pharmaceutically acceptable salt thereof- Compounds disclosed herein may also be described by Formula V.

0 00 9R S0 R 24 OR26 0 O 00 0

N

R

0 N I- (R 0 R 0 R7 Formula V wherein h is an integer of zero to five; B, R 9 R'o, R 24 and R 25 are each independently selected from the group consisting COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 -12of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2 -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,

-N(CI-C

3 alkyl)-C(O)(C 1

-C

3 alkyl), -NHC(O)N(C I-C 3 alkyl)C(O)NH(C I-C 3 alkyl), -NHC(O)NH(C I -C 6 alkyl),

-NHSO

2

(C

1

-C

3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1

-C

3 )amino, -C 3 )alkyl,

-C(O)NH-(C

1

-C

3 )alkyl, -C(O)N(C 1

-C

3 alkyl) 2 -CH=NOH, -P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylakl, sulfonyl, -S0 2 I -C 3 alkyl), -S0 3 I -C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; 27 15*~ R ,at each occurrence, is independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alky)noxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CO 2 H, -SH, -CN, -NO 2

-NH

2

-OH,

alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C,-C 3 alkyl)- C(O)(C i-C 3 alkyl), -NHC(O)N(C 1 -Cs, alkyl)C(O)NH(C 1

-C

3 alkyl), 20 -NHC(O)N}I(C I-C 6 alkyl), -NHSO 2 (C I-C 3 alkyl), -NHSO 2 (aryl),-N(C I-C 3 alkyl)S0 2 (C I -C 3 alkyI),-N(C I -C jalkyl)S0 2 (aryl),-C alkoxyalkyl,alkylamino, alkenylamino, di(C 1

-C.

3 )amino, -C(O)O-(C 1

C

3 )alkyl, -C(O)NH-(CI-Ci)alkyl, -C(O)N(C 1

-C

3 alkyl) 2

-CH=NOH,

-P0 3

-OPO

3 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

-(CI-C

3 alkyl), -S0 3

-(C

1

-C

3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; R R 7 and R1 8 are each independently selected from the group consisting of alkcyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, JUN. 2005 15-:56 SPRUSON AND FERGUSON 61292615486 NO. 260? P. 59 13 alkoxycarbonyl, heter-ocycloyl, -CH N0H, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkl, cycloalkenyl, cycloalk~nyi, cycloallcylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaiyl, diarylamino, hererocyclyl, alkylaryl, aralkenyl, aralkyl, allcylheterocyctyl, heter'ocyclylall, carbaniate, aryloxyalkl hydrogen and -C(O)NH4(beuzyl) groups; and,

R

26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalcyl, aliphatic acyl, alkoxycarbonyl, hererocycloyl; cit-boxy,

-C

3 )alkyl, -C(O)NH-(Ci-C)alcyl, -C(0)N(C 1

-C

3 alkYl) 2 P0382. haloalkyl, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloallcylalkyl, aryl, aroyl, biazyl, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhererocyclyl, hererocyclylalkyl, sulfonyl, -S02-(C, C, alkyl), sulfontarido, azyloxyalkyl and -C(O)NH(benzyl) groups; *2 25 wherein B, R 7

R

9

R

10

R'

4

R

25

R

2 and R27 are unsubstituted or substituted with at Least one electron donating or electron withdrawing group; I wherein R"1 and R 2 4 taken together may form a ring; R R 24 and R'2 5 taken together may form a ring; *M an 29tkntgthrmyfr@ ig R" hrnR and R 10 taken together may form a ring or a pharmaceutically acceptable salt thereof Presently preferred compounds of Formula V have B, R6, R 7, R9, R 10 R(2' and each .:..independently hydrogen and R's as substituted or unsubstituted aralkyl.

Yet further disclosed herein are compounds described by Formula VI.

It) 1 0 0 Rio 08

AJLL

IN N T R4 0 R R Formula VI COMS ID No: SBMI-01328788 Received by IP Australia: Time 18:06 Date 2005-06-30 wherein Z, at each occurrence, is independently selected from the group consisting of N, CR 30

C(R

3 )(R"),NR",CH,O0and S; z is an integer of from 3 to 6; k is an integer of from 0 to T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer of from 0 to 3; L is selected from the group consisting of 0, NR", S, and

(CH

2 wherein n is an integer of 0 or 1; R 6 R 7

R'

8 and R 33 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamnino, biaryl, thioaryl, diarylamino, .:669heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, 15 carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B, R R 1 0

R

30

R

3 and R 3 at each occurrence are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, ~alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,-C,

-CO

2 H, -SH,-CN, -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C 1

-C

3 alkyl)-C(O)(C 1

-C

3 alkyl), -NHC(0)N(C 1

-C

3 alkyl)C(O)NH(C 1 -C~alkyl), -NHC(O)NH(C 1

-C

6 alkyl),

-NHSO

2

(C

1

-C

3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamino, alkenylamino, di(Cj -C 3 )amino, -C(O)O-(C 1

-C

3 )alkyl, -C(O)NH-(C I -C 3 )alkyl, -C(O)N(C I-C 3 alkyl) 2 -CH=NOH, -P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thicaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2 -(Cl-

C

3 alkyl), -S0 3

I-C

3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; and, R 29at each occurrence, is Independently selected from -the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2

-OH,

alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C I-C 3 alkyl)- C(O)(C I-C 3 alkyl), -NHC(O)N(C 1 -C 3 alkyl)C(O)NH(C I -C 3 alkyl),

-NHC(O)NH(C

1

-C

6 alkyl), -NHSO 2

(CI-C

3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylamnino, alkenylamino, di(C 1

-C

3 )amino, -C(O)O-(Cl-

C

3 )alkyl, -C(O)NH-(CI-C 3 )alkyl, -C(O)N(C I-C 3 alkyl) 2

-CH=NOH,

-P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamnino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2

I-C

3 alkyl), -S0 3

I-C

3 alkyl), sulfonamido, carbamnate, aryloxyalkyl and -C(O)NH(benzyl) groups; wherein B,R,R, R, R9,R1 1, R1 8

R

2 9 ,R 3, R 31,R 32and R 33 are 15 unsubstituted or substituted with at least one electron donating or electron withdrawing group; 9:wherein when L is R 4 and taken together may form a ring; and wherein R 9and R1 taken together may form a ring; or a pharmaceutically acceptable salt thereof.

Some compounds of Formulae 1-VI can be prepared from novel intermediates of Formula VII and Formula VIII.

2 R 0 18 N R

R

Formula VII wherein R 24 and R 2 5 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -SH, -OH,

-CO

2 H, -CN, -NO 2 -Nil 2 alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C I -C 3 alkyl)-C(O)(C I -C 3 alkyl), -NHC(O)N(C I -C 3 alkyl)C(O)NH(CI -C 3 alkyl), -NHC(O)T'.H(C I-C 6 alkyl), alkylamino,

-NIISO

2 (C I-C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl, alkenylamino, di(C I-

C

3 )amino, -C(O)O-(CI-C 3 )alkyl, -C(0)NH-(C I-C 3 )alkyl, -C(O)N(C I -C 3 alkyl) 2 -CH=NOH, -P0 3

H

2 -0P0 3

H

-(CI-C

3 alkyl), -S0 3

-(C

1

-C

3 alkyl), sulfonamido, carbamnate, aryloxyalkyl and -C(O)NH(benzyl) groups; and R 1 8 and R 34 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH. haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, arovl, aryloxy, arylamino. biaryl. thioaryl, diarylamino, heterocycly], alkylaryl, aralkenyl, aralkyl, alkylheterocyc lyl, heterocyc lylalkyl, carbamate, 20 aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; wherein R1 8 R 24 R 2 5and R 3 are unsubstituted or substituted with at least one electron donating or electron withdrawing sew group;, *and wherein R 1 4 and R 25 taken together may form a ring; with the proviso that when R 24 and R 2 5 taken together form a ring, the ring formed is not benzene. Presently preferred compounds of Formula VII have R 34 as hydrogen; R1 8 as aralkyl; and R 24and R 25each indpendently as hydrogen, lower alkyl or lower alkyl wherein R 24 and R 25 are taken together to form a ring.

Formula VIE shows presently preferred novel intermnediates.

-17- Formula VII wherein R 24 and R 25 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkovy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -SH, -OH,

-CO

2 H, -CN, -NO 2

-NH

2 alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C 1

-C

3 alkyl)-C(O)(C 1

-C

3 alkyl), -NHC(O)N(C 1

-C

3 alkyl)C(O)NH(C I-G~alkyl), -NHC(O)NH(C I -C 6 alkyl), -NI-S0 2 (C I -C 3 alkcyl), -NHSO 2 -(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C 1

C

3 )amino, I-C 3 )alkyl, -C(O)NH-(C 1

-C

3 )alkyl, -C(O)N(C -C 3 alkyl) 2 -CH=NOH, -0P0 3

H

2 haloalkyl, alkoxyalkoxy, seescarboxaldehyde, carboxamide, cyc loalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarlarnnoheterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2 I -C 3 alkyl), -S0 3 I -C 3 alkyl), sulfonamido, carbamnate, aryloxyalkyl and -C(O)NH~benzyl) groups; R~is selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyi, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; and, R 35 at each occurrence, is independently selected from the group consisting of halogen, alkyl, alkenyl, alkyiiyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3

-CO

2 H, -SH, -CN, -NO 2

-NH

2

-OH,

alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C 1

-C

3 alkyl)-

C(O)(C

1

-C

3 alkyl), -NHC(O)N(C 1

-C

3 alkyl)C(O)NH(C 1

-C

3 alkyl), -NHC(O)NH(C I-C 6 alkyl), -NHSO 2 (C I -C 3 alkyl), -NHSO 2 (aryl), alkoxyalkyl,alklamino, alkenylamino, di(C 1

-C

3 )amino, -C(O)O-(C 1

C

3 )alkyl, -C(O)NI{-(CI-C 3 )alkyl, -C(O)N(C 1

-C

3 alkyl) 2

-CH=NOH,

-P0 3

H

2 -0P0 3

H

2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyc lyl, heterocyclylalkyl, sulfonyl, -S0 2

-(C

1

-C

3 alkyl), -S0 3

-(C

1

-C

3 alkyl), sulfonamido, carbamnate, *...aryloxyalkyl and -C(O)NH(benzyl) groups; 0:00* ~wherein R 2 1, R 2 1, R 34 and R 35 are unsubstituted or substituted with .000 15 at least one electron donating or electron withdrawing group; and, sooof:rn is an integer of from 0 to 5. Presently preferred compounds of Formula VIII **.*have R 3 as hydrogen; m as an integer of one to three and at each occurrence as alkyl, 0 2 halogen, alkoxy, haloalkyl, sulfonyl, -OH or -CN.

0 20 Presently preferred compounds of Formula I include: [2-methyl-4-(2-methylpropyl)-6-oxo- 1 -(phenylmethyl)- 1,6-dihydro-5o. pyrimidinyl] amino I carbonyl)amino]-3 -(4-methylphenyl)propanoic acid, (3 1,3 benzodioxol-5-yl)-3 -II(([2-oxo- 1 -(phenylmethyl )-4-propyl- 1 ,2-dihydro-3 p yn'dinyl] amino}I carbonyl)amino]propanoic acid, (3 S)-3 I -[(2-chlorophenyl)methyl] -4ethyl-2-oxo- 1 ,2-dihydro-3-pyridinyl amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid, 1 -[(2-chlorophenyl)methyl]-2-oxo-4-propyl-1I,2-dihydro-3pyridinyl }amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid, (3 1 chlo.rophenyl)methylj-4-methyl-2-oxo-1I,2-dihydro-3-pynidinyl }amino)carbonyllamino methylphenyl)propanoic acid, (3 6-methyl-2-oxo-l1-(phenylmethyl)-4- [(phenylmethyl)oxyj- 1 ,2-dihydro-3 -pyridinyl I amnino)carbonyl] amino) methylphenyl)propanoic acid, 2 -chlorophenyl)methyl]-2,4-dimethyl-6-oxo- 1, 6-Uihydro-5-pyrimidinyl amino)carbony' ]amino -3 -(4-rnethylphenyl)propanoic acid, (3 S)- 3- {4-amino-l1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid, (3 1 chlorophenyl)methyl]-4-methyl-2-oxo- 1,2-dihydro-3 -pyridinyl }amino)carbonyl]amino)}-3 (methyloxy)phenyl]propanoic acid, (3 I-[(2-chlorophenyl)methyl] 4-methyl-2-oxo- 1 ,2-dihydro-3-pyridinyl }amino)carbonyl]amino} -3 ,4-dimethylphenyl)propanoic acid, (3 S)- 3- {4-amino-l1-[(2-chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyi-idinyl}I amino)carbonyl] amino)} -3 -(4-methylphenyl)propanoic acid, (3 chlorophenyl)methyl]-4-hydroxy-2-oxo- 1 ,2-dih,,dro-3 -pyridinyl amino)carbonyl Iamino)} -3 (4-methylphenyl)propanoic acid, (3 -[(2-chlorophenyl)methyl]-4-( 1,4-oxazinan-4yI)-2-oxo- 1 ,2-dihydro-3 -pyridinyl ]amino I carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 -[(2-chlorophenyl)methyfl-2-oxo-4-(propylamino)-1I,2-dihydro-3 pyridinyl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 bromophenyl)methyl]-4-methyl-2-oxo- 1 ,2-dihydro-3 -pyridinyl amino)carbonyllamino -3 acid, (3 S)-3 I-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2to to 0:dihydro-3-pyridinyl amino)carbonyl]amino -3 -[3-methyl-4-(methyloxy)phenyl]propanoic acid, (3 {1 -[(2-chlorophenyl)methyl]-2-oxo-4-phenyl- 1 ,2-dihydro-3 pyrdinyl I amino)carbonlamino' (4-methyiphenyl )propanoic acid, (3 S)-3 1 ~chlorophenyl)methyl]-4-[(2- {[2-(methyloxy)ethyl]oxy }ethyl)oxy]-2-oxo- 1,2-dihydro-3 20 pyridinyl }amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid, (3 1 chlorophenyl)methyl]-4-hydroxy-6-methyl-2-oxo- 1,2 -dihydro-3 yridinyl }amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid, chlorophenyl)methyl]-4-[( 1,1I -dimethylethyl)amino]-2-oxo- I ,2-dihydro-3pyridinyl I amino)carbonyl] amino)} -3 -(4-methylphenyl)propanoic acid, (3 S)-3 1 chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2-dihydro-3 -pyridinyl }amino)carbonyl]amino phenyipropanoic acid, (3 {11-[(2-chlorophenyl) methyl] -4-[4-methyltetrahydro- 1(2H)pyrazinyl]-2-oxo- 1,2-dihydro-3 -pyridinyl }atnino)carbonyl]amino} -3 methylphenyl)propanoic acid, (3 S)-3 f -1(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3 -pyridinyl I am ino)carbonyll amino 3 4 -(methyloxy)phenyl ]propanoic acid, f 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2-dihydro-3pvridinyl }amino)carbonyljamino ,5-dirnethylphenyl)propanoic acid, (3S)-3 {11-+2chlorophenyl)methyl]-4-hydroxy-2-oxo- I ,2-dihydro-3-pyridinyl} amino)carbonylamnino -3- (3-methylphenyl)propanoic acid, 1 -[(2-chlorophenyl)methyl] -4-hydroxy-2-oxo- 1 ,2-dihydro-3-pyridinyl }amino)carbonyl]amino} -3 -[3-(methyloxy)phenyl]propanoic acid, (3 ,5-bis(methyloxy)phenyfl-3 1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3 -pyridinyl} amino)carbonyl] amino I propanoic acid, (3S)-3 1 chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2-dihydro-3-quinolinyl} amino)carbonyl]amino (4-methylphenyl)propanoic acid, 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1 ,2-dihydro-3-pyridinyl }amino)carbonyljamino} -3 -[3-(trifluoromethyl)phenyl]propanoic acid, (3 S)-3 1 -[(2-chlorophenyl)methyl] ethyl [(ethylamino)carbonyl] amino I carbonyl)amino] -2-oxo- 1 ,2-dihydro-3 -pyridinyl amnino)carbonyl] amino -3 methylphenyl)propanoic acid, (3 1-azetanyl)-l 1-[(2-chlorophenyl)methyl] -2-oxo- .1 ,2-dihydro-3 -yridinyl) amino)carbonyl] amino}1-3 -(4-methylphenyl)propanoic acid, (3S)-3- [1-[(2-chlorophenyl)methyl]-4-( [2-(methyloxy)ethyl]oxy} ethyl)oxy]ethyl oxy)-2-oxo- 1 ,2-dihydro-3 -pyridinyl] amino)} carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 -[(2-fluorophenyl)methyl] -4-hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl amino)carbonyfl]amino -3 -(4-methylphenyl)propanoic acid, (3 S)-3 chloro-6-fluorophenyl)methyl-4-hydroxy-2-oxo- 1,2 -dihydro-3pyridinyl }amino)carbonyl]aminol -3 -(4-methylphenyl)propanoic acid, (3 1 :chlorophenyl)m ethyl] -5 -methyl-2-oxo- 1 ,2-dihydro-3 -pyridinyl amino)carbonyl ]amino -3 methylphenyl)propanoic acid, (3 S)-3 ,3-benzodioxol-5-yl)-3-((((2-oxo-l1-((4- (trifluoromethyl)phenyl)methyl)- 1,2 dihydro-3-pyridinyl)amino)carbonyl)amino)propanoic acid, (3 S)-3 -((2-chlorophenyl)methyl)-2-oxo- I ,2-dihydro-3pyridinyl)amino)carbonyl)amino)-3 -(4-methylphenyl)propanoic acid, (3 fluorophenyl)methyl)-2-oxo- I ,2-dihydro-3-pyridinyl)amino)carbonyl)amino)- 3 -(4-methylphenyl)propanoic acid, (3 1-((2-bromophenyl)methyl)-2-oxo- 1,2-dihydro- 3 -pyridinyl)amino)carbonyl)amino)-3 -(4-methylphenyl)propanoic acid, (3 S)-3 dichlorophenyl)methyl)-2-oxo- 1,2-dihydro-3 -pyidinyl)amino)carbonyl) amino)-3 -(4-methylphenyi)propanoic acid, (3 S)-3 -chloro-6-fluorophenyl)methyl)-2oxo- 1,2-dihydro-3 -pyridinyl)amino)carbonyl)amino)-3-(4-rnethylphenyl)propanoic acid, (3 S)- 3 -((2-chlorophenyl)methyl)-4-hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl)amino)carbonyl)amino)-3-(4-trifluoromethyl)oxy)phenyl)propanoic acid, (3 S)-3 -(2-chloro-6-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yl]amino carbonyl)amino]-3 (4-rnethylphenyl)propanoic acid, [1S)-2-carboxy-l1-(4methylphenyl)ethyl] amino) carbonyl)amninoj- 1 -(2-chlorobenzyl)-2-oxo- 1 ,2-dibydropyridin-4yl]aminol}benzoic acid, 1 -(2-chlorobenzyl)-4-[(2,2-dimethylpropanoyl)amino]-2oxo- 1,2-dihydropyridin-3-yl }amino)carbonyl]aniino }-3-(4-methylphenyl)propanoic acid, (3 [(tert-butylamino)carbonyljamino -(2-chlorobenzyl)-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 S)-3 (2-cyanobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3-yIjamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino) carbonyl)amino]-3 -(2,3-dihydro- 1 ,4-benzodioxin-6-yl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1I,2-dihydropyridin-3 yl]amino }carbonyl)amino]-3-(7-methoxy- 1,3-benzodioxol-5-y)propanoic acid, (3 .(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino] -3 ethoxy-4-methoxyphenyl)propanoic acid, (3 S)-3 {[I1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino)} carbonyl)amino -3 ,4-dimethoxyphenyl)propanoic acid, (3 -(4-chlorobenzyl )-4-hydroxy-2-oxo- 1,2-dihydropyridin-3 yIl]amino carbonyl)amino]-3 -(4-methylphenyl)propanoic acid, 1 -(2-chloro-6methoxybenzyl)-4-hydroxy-2-oxo- 1,21-dihydropyridin-3 -yljamino I carbonyl)amino] -3 methylphenyl)propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2- 20 dihydropyridin-3 -yI]amino carbonyl)amino] -3 -(4-methylphenyl)propanoic acid, (3 S)-3 [I (2,6-difluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yljamino }carbonyl)amino]-3 methylphenyl)propanoic acid, 1 -(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino I carbonyl)amino I-3 5-dimethoxyphenyl)propanoic acid, {[l1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3yl ]amino)} carbonyl)amino] -3 ,4-diethoxyphenyl)propanoic acid, (3 chlorobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3 -yI]amino }carbonyl)amino]-3-(3 ethoxyphenyl)propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyidin-3 -yl]aminol carbonyl)arnino]-3 methoxy-4-methylphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3yl ]amino I carbonyl)amino] -3 5-dimethoxy-4-methylphenyl)propanoic acid, (3 S)-3 [1 (2-chlorobenzyl)-4-hydroxy-2-oxo- I ,2-dihydropyfidin-3 .yl] amino carbonyl)amino] -3 -22dimethylphenyl)propanoic acid, (3 S)-3 [1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo- 1,2dibydropyridin-3-yljamino }carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 S)-3- {1 -[2-chloro-5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl }amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid, -(2-chloro-6methoxybenzyl)-4-hydroxy-2-oxo- I ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] methylphenyl)propanoic acid, [I -(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2oxo-1I,2-dihydropyridin-3-yIjamino }carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin- 3 -yI]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 S)-3 0 dimethoxybenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3 -yI]amino }carbonyl)amino]-3-(4methylphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yljamino} carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid, (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl- 1,2-dihydropyridin-3 ]amino)} carbonyl)amino]-3 -ethoxyphenyl)propanoic acid, (3 1-(2-chlorobenzyl)- 4-hydroxy-5 ,6-dimethyl-2-oxo- 1, 2-dihydropyridin-3 -yl ]amino) carbonyl)amino] -3 methylphenyl)propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl- 1,2- .*.dihydropyridin-3 -yI ]amino carbonyl)amino] -3 ,4-diethoxyphenyl)propanoic acid, (3S)-3 (3-butoxyph,.nyI)-3-[( -(2-chlorobenzyl)-4-hydroxy-2-oxo-1I.2-dihydropyridin-3- 4: yl ]amino}I carbonyl)amino]propanoic acid, (3 S)-3 I 20 4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yH amino)carbonyl ]amnino) -3 methylphenyl)propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino I carbonyl)am ino] -3 -(2-methoxyethoxy)phenyl]propanoic acid, (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 yl] amino)} carbonyl)amino] -3 ,4-dipropoxyphenyl)propanoic acid, (3 chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl amino I carbonyl)amino]-3-[3 (difluoromethoxy)phenyl]propanoic acid, (3 S)-3 -chlorobenzyl)-4-hydroxy-5 -methyl- 2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino)} carbonyl)amino] -3 ,4-diethoxyphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3 yl ]amino I carbonyl)amino] -3 -ethoxyphenyl)propanoic acid, (3 1-(2-chloro-6methylbenzyl)-4-hydroxy-5 ,6-dimethyl-2-oxo- 1,2-dihydropyridin-3 yl ]amino I carbonyl)amino]-3 ,4-diethoxyphenyl)propanoic acid, [1-(2-chloro-6- -23cyanobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino I carbonyl)amino]-3 methylphenyl)propanoic acid, -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin- 3 -yllamino} carbonyl)amino]-3-(2-naphthyl)propanoic acid and (3 chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1I,2-dihydropyridin-3 yl] amino) carbonyl)amino]-3 ,4-diethoxyphenyl)propanoic acid, (3 {[1-(2-chloro-6- -methyl-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino) carbonyl)amino] 3-(3 ,4-diethoxyphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-5 -methyl-2-oxo- 1,2 -dihydropyridin-3yl ]amino) carbonyl)amino]-3 -(4-methoxyphenyl)propanoic acid, (3 -(2-chloro-6methylbenzyl)-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- IH-cyclopenta[b]pyridin-3yl]amino} carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3 S)-3 -(2-chloro-6ethoxybenzyl)-4-hydroxy-2-oxo- I1,2 -dihydropyridin-3 -ylj]amino) carbonyl)amino]-3 ethoxypbenyl)propanoic acid, (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2- 15 oxo-1I,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3 -(3-isopropoxyphenyl)propanoic acid, 1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- IHcyclopenta[bjpyridin-3-yflamino carbonyl)amino]-3-(3 -ethoxyphenyl)propanoic acid, I( -(2-chloro-6-ethoxybenzyl)-4-hy'droxv-5-methyl-2-oxo- 1 ,2-dihydropyridin-3amino) carbonyl)amino] 1-methyl- I H-Indol1-5-yl)propanoic acid, (3 {[l1-(2-chioro- 20 6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1 .2-dihydropyridin-3-yI]amino carbonyl)amino]- 3 -dihydro- 1 -benzoffiran-5-yl)propanoic acid, (3 S)-3 [1-(2-chloro-6-ethoxybenzyl)-4hydroxy-2-oxo-2, 5,6,7-tetrahydro- IH-cyclopenta [b]pyridin-3 -yl]amitio carbonyl)amino]-3 -diethoxyphenyl)propanoic acid, (3 {[5-chioro-lI-(2-chloro-6-ethoxybenzyl)-4hydroxy-2-oxo-1I,2-dihydropyridin-3 -yl]amino }carbonyl)amino]-3 ethoxyphenyl)propanoic acid, (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl ]amino carbonyl)amino]-3 -(3-isopropoxyphenyl)propanoic acid, (3 S)-3 [1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1Hcyclopenta[bjpyridin-3 -yI ]amino carbonyl)amino] -3 -propoxyphenyl)propanoic acid, (3S)- -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2 7-tetrahydro- 1 Hcyclopenta[b]pyridin-3 -yI] amino}I carbonyl)amino]-3-phenylpropanoic acid, (3 1 chlorobenzyl)-4-hydroxy-2-oxo-2,5 7-tetrahydro- I H-cyclopenta[b]pyridin-3 yljamino} carbonyl)amino]-3-( 1,3-diethyl-2-oxo-2,3-dihydro- 1 yl)propanoic acid, (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2dihydropyridin-3 -yl] amino) carbonyl)amino] -3 [3 -(tri fluoromethoxy)phenyl]propanoic acid, (3S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo- 1,2-dihydropyridin-3yIjarnino} carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, chlorobenzyl)-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl]amino }carbonyl)amino]-3-( 1-methyl-i H-i-idol-5 -yl)propanoic acid, (3 [1 -(2-chioro- 6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 yl ]amino)} carbonyl)amino] -3 -isopropoxyphenyl)propanoic acid, (3 -(2-chloro-6ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl]amino carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3 [1 methoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyr-idin-3 -yljamino I carbonyl)amino]- 3-(4-methylphenyl)propanoic acid, (3S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-6methyl-2-oxo- 1 ,2-dihydropyridin-3 -yll]amino carbonyl)amino] -3 isopropoxyphenyl)propanoic acid, (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3 -yI]amino carbonyl)amino]-3 -(1-methyl-i H-indol-6yl)propanoic acid, (3 -(2-chloro-6-ethoxvbenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyc lopenta[b]pyridin-3 -y ami nok carbonvl)amino -3 (cyclopropyloxy)phenyl]propanoic acid, [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- S 20 2,5,6,7-tetrahydro- 1 H-cyclopenta[bjpyri din-3 -yI] amino carbonyl)amino] -3 (cyclopropylmethoxy)phenyljpropanoic acid, (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 -yI]amino carbonyl)amino]-3 [3 -(cyclopropylmethoxy)phenyl]propanoic acid, (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-2- ,6,7-tetrahydro- 1 H-cyclopenta[bjpyridin-3 -yI]amino I carbonyl)amino]-3 dimethylphenyl)propanoic acid, (3 S)-3 f I -[(2-chlorophenyl)methyl] -4-hydroxy-2-oxo- ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3-yl am ino)carbonyl Iamino 3- [(difluoromethyl)oxylphenyl }propanoic acid, (3 S)-3 [(2-chlorophenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 -yI amino)carbonyll amino)}-3 1,1 ,2,2-tetrafluoroethyl)oxy]phenyIl}propanoic acid, (3 1 chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5 7-tetrahydro- 1 I--cyclopenta[b]pyridin-3 yl amino)carbonyl]aminol} 1-ethyl- I H-indol-5-yI)propanoic acid and 1 chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[blpyridin-3 yl }amino)carbonyl]amino -[3-(diethylamino)phenyl]propanoic acid, chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl] amino) carbonyl)amino]-3 (4-methylphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3-yl ]axnino} carbonyl)amino]-3-(4methylphenyl)propanoic acid, I1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2oxo- I ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 -(4-methylphenyl)propanoic acid, (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3 yl]amino} carbonyl)amino]-3-(3 -ethoxyphenyl)propanoic acid, (3 -(2-chlorobenzyl)- 4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3-yl]amino} carbonyl)amino]-3 (3-isopropoxyphenyl)propanoic acid, (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino]-3 -(6-methoxy-2- ~naphthyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 -y1] amino) carbonyl)amino] -methylphenyl)propanoic acid, (3 ([1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3 yl]amino }carbonyl)amino]-3 -(diethylamino)phenyllpropanoic acid, and 1-[(2-chloro-6-methylphenyl)methvl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1Hcyclopenta[bj pyridin-3 -yl Iam ino)carbonyl ]amino -3 1-methyl- I H-indol-5 -yI)propanoic acid, (3 S)-3 I-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1Hcyc lopenta[b] pyridin-3 -yl amino)carbonyll amino -3 f 3 [(methylsulfonyl)amino]phenyl }propanoic acid, (3 1-[2 -chloro-6methylphenyl)methyl]-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl I amino)carbonyl ]amino)} -3 1 3 [(rnethylsul fonyl)amino]phenyl I propanoic acid, (3 S)-3- 1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- IHcyclopenta[b]pyridin-3 -yl I amino)carbonyl )amino -3 3- [methyl(methylsulfonyl)amino]phenyl }propanoic acid, (3 -[2-chloro-6methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl amino)carbonyl] amino) -3 (3 -[methyl(methylsul fonyl)aminolphenyl Ipropanoic acid, (3 S)- 3-f 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2 ,5,6,7-tetrahydro- IHcyc Iopenta[b]pyridin-3 -yI amino)carbonyl ]amino -3 -3 [ethyl(methylsulfonylamino]phenyil propanoic acid, (3S)-3 -[(2-chloro-6- -26methylphenyl)methyl]-4-hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl }amino)carbonyl]amino} {3-[ethyl(methylsulfonyl)aminojphenyl }propanoic acid, (3 S)-3 -[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2.oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]py-idin-3-yI }amino)carbonyl]amino)}-3 -(1H-indol-5 -yl)propanoic acid and pharmaceutically acceptable salts thereof of the above compounds.

Presently preferred compounds of Formula VII include: 5-(2-chlorobenzyl)-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-6methyl-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-cjpyridine-2,4-dione, 5-(2-fluorobenzyl)-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-fluorobenzyl)-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-6-methyl-3 dihydro[ 1,3 ]oxazolo[4,5-c]py-idine-2,4-dione, 5-benzyl-3 ,5 -dihydro[ 1,3 cjpyridine-2,4-dione, 5-(2,5-dimethylbenzyl)-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2 ,4dione, 5-(2-methylbenzyl)-3,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4dichlorobenzyl)-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-methoxybenzyl)-3 dihydro[1,3]oxazolo[4,5-cjpyridine-2,4-dio'ne, 5-(2,5-difluorobenzyl)-3,5dihydro[ 1 .3]oxazolo[4,5-c]pvridine-2,4-dione, 5-[2-chloro- 5-(methylthio)benzyl]-3,5dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-fluorobenzyl)-3,5dihydro[ 1,3'oxazolo[4,5 -c ]pyridi ne-2,4-d ione, 5-(2-chloro-5-methoxybenzy)-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3 ,5-bis(trifluoromethyl)benzyl]-3,5- 20 dihydro[ 1,3]oxazolo[4,5-clpyridine-2,4-dione, 5-(4-tert-butylbenzyl)-3,5dihydro 1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-3,5dlyr[,]xzoo45cprd*e24doe 5-4clooezy)35 *dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-3(4-chloroeyl),5- diyr[,]xzl[,-*yiie24doe 5-2booeny)35 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3,-tiloromethyl)benzy-3dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5 -(2-bromolbenzyl)-3 1,3 joxazolo[4,5 -cjpyridine-2,4-dione, 5-(3 ,-chloromexbenzyl)-3 dihydro[ 1,3] oxazolo [4,5 -clpyridine-2,4-dione, 5 -(4-mthlboezyl) ,5-3,5 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chl--ebenzyl)-3 dihydro[ 1,3 Ioxazolo[4,5-c]pyridine-2,4-dione, 5-[(rifluoroymethyl)el-3 dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3 -mhlbenzyl)-3,-ehl35 -27dihyturo[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-difluorobenzyl)-3,5dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dilone, 5-[3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethoxy)benzyl]-3,5dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(trifluoromethyl)benzyl]-3,5dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methoxybenzyl)-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,3 -dichlorobenzyl)-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3 ,5 -dimethylbenzyl)-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, -(2-chlorobenzyl)-7-pentyl-3 dihydro[ 1,3 ]oxazolo[4,5-cjpyridine-2,4-dione, 5-(2,4-dichlorobenzyl)-7-methyl-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-3, dihydro[ 1,3 ]oxazolo[4,5-cjpyridine-2,4-dione, 7-butyl-5-(2-chlorobenzyl)-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5 -(trifluoromethyl)benzyl]-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichlorobenzyl)-3 dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-fluorobenzyl)-3,5dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-7-methyl-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-7-methyl-3 dihydro[ 1,3]oxazolo[4,5-cjpyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-2Hcyclopenta~b][ 1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 7-methyl-5-[4- 20 (methylsulfonyl)benzyl]-3 ,5-dihydrof 1, 3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4methoxybenzyl)-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7propyl-3,5-dihydro[ 1,3 joxazolo[4,5-cjpyridine-2,4-dione, 4-[(2,4-dioxo-2,3dihydro[ 1,3 ]oxazolo[4,5-cjpyridin-5(4H)-yI)methyl]-N,N-dimethylbenzenesul fonamide, (mesitylmethyl)-3 ,5-dihydro[ 1,3 ]oxazolo[4,5 -c]pyridine-2,4-dione, 5-(2-chlorobenzyl)- 3 ,5,6,7,8,9-hexahydro[ 1,3 joxazolo[4,5-c]quinoline-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-6methyl-3 ,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5- [2-(methylthio)benzyl]-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 2-[(2,4-dioxo-2,3 -dihydro[ 1,3 c]pyridin-5(4H)-y)nethyl]-N,N-dirnethylbenzenesul fonamiLde, 5-(2,6-di'metLhoxybenzyl)-3 dihydro[ 1,3]oxazolo[4,5-cjpyridine-2,4-dione, 5-[2-(trifluoromethoxy)benzyl]-3 dihydro[1I,3]oxazololl4,5-cjpyridine-2,4-dione, 5-(2-chlorobenzyl)-6,7-dimethyl-3,5dihydro[ 1,3]oxazololl4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(methylsulfonyl)benzyl]-3,5- -28dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chloro-2-methoxybenzyl)-3,5dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8,9, 2H-cyclohepta[b] [1 ,3]oxazolo[5,4-d]pyridine-2,4(3 H)-dione, 5-[2-(difluoromethoxy)benzyl] 3 ,5-dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-[( 1R)-l1-phenylethyl]-3 dihydro[ 1,3]oxazolo[4,5-cjpyridine-2,4-dione, 5-(4-chlorobenzyl)-7-propyl-3,5dihydro[1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(methylsulfonyl)benzyl]-3,5dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-diorne, 5-(2,6-dimethylbenzyl)-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 3-chloro-2-[(2,4-dioxo-2,3dihydro[ 1,3 ]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro-6methylbenzyl)-6,7-dimethyl-3 ,5-dihydro[ 1 '3]oxazolo[4,5-c]pyn'dine-2,4-dione, 2-[(2,4-dioxo- 2,3-dihydro[ 1,3 ]oxazolo[4,5-c]pyridin-5(4H)-yI)methyl]benzonitrile, 5-(2-chloro-6methoxybenzyl)-7-methyl-3 ,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3- (mtyti*ezl-,-iyr[,]xzl[,-~yiie24doe 5-2**ooezy)7 (myclthobenzy]-3 ,dydro[ 1,3 Ioxazolo[4,-cpyridine-2,4-dione, 5-(2-chlorobenzyl)-7-hl 3,5-dihydro[ 1,3 ]oxazooII4,5-c~Jpyridine-2,4-dione, 5-(3-chlorobenzyl)-7-methyl- 15 3 ,-dihydro[1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, el5 voooo:dihydro[ 1,3 ]oxazolo[4, 5-c]pyridine-2 ,4-dione, 7-metl5 -4methybezyl)-3 eh-, dihydro[1I,3]oxazolo[4,5-clpyridine-2A4-dione, 5-(3 ,5-dimetoxbenzyl)-7-methyl-3 diyr[,]xz*[,-~y'ie24doe *-3(ehlufnlbnyj35 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2 0 dihydro[ 1,3]oxazolo[4,5-cjpyridine-2,4-dione, 5-[3-(mhlsulf-toybenzyl]--ty-3,5dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-loro-6-ethoxybenzyl)-,-mehl35 dihydro[ 1,3 ]oxazolo[4,5 n-c]pyine24dn, 5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-floro-6-metoxbenzyl)-7-methyl-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5 -(2-chloro-mhxbenzyl)-7- propr p yl-3 dihydro[ 1,3] oxazolo[4,5-c]pyrfidine-2,4-dione, 5-(5-loro-2-fluorobenzyl)-7-methyl-3 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenz)--ipropehyl-3 dihydro[ 1,3 ]oxazolo[4, 5-c]pyr-idine-2,4-dione, 5-(5 -loro-2-methoylbenzyl-7-iethy'l- 3dihydro[ ,3]oxazolo[4,5-c]pyridine-2,4-dione, 1 S--pehoentyl-3,5 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5iopxbenzyl)-7- dihydro[ 1,3 ]oxazolo[4,5-d]pyridazine-2,4-dione, 5- [2-fluoro-6-(trifluoromethyl)benzyl] -7methyl-3 ,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5 -(2-chloro-6-methylbenzyl)- 5,6,7,8-tetrahydro-2H-cyclopenta[b] [1 ,3]oxazolo[5,4-d]pyridine-2 ,4(3H)-dione, 5-(2-chloro- 6-ethoxybenzyl)-7-ethyl-3,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2 ,4-dione, 5-(2-chloro-6propoxybenzyl)-7-methyl-3 ,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6isobutoxybenzyl)-7-methyl-3 ,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6ethoxybenzyl)-5,6,7,8-tetrabydro-2H-cyclopenta[b] [1 ,3 oxazolo[5 ,4-d]pyridine-2,4(3H)dione, 5-(2-chloro-6-isopropoxybenzyl)-7-methyl-3 ,5-dihydro[ 1,3 2,4-dione, 5-[2-chloro-6-(2,2,2-trifluoroethoxy)benzyl] -7-methyl-3 dihydro[ 1,3]oxazolo[4,5 -cjpyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3 dihydro[ 1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-[2-chloro-6-(2-methoxyethoxy)benzyl]- ,6,7,8-tetrahydro-2H-cyclopenta[b] [1,3 ]oxazolo[5,4-d]pyridine-2 ,4(3H)-dione, 5-(2-chloro- 6-ethoxybenzyl)-6,7-dimethyl-3,5-dihydro[ 1,3 joxazolo[4,5-cjpyridine-2,4-dione, 5-(2-chloro- 6-ethoxybenzyl)-7-ethyl-6-methyl-3 ,5-dihydro[ 1,3]oxazolo[4, 5-c]pyridine-2,4-dione, 5-(2chlorobenzyl)-7-ethyl-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-d]pyridazine-2,4-dione, 5-(2-chloro-6- 15.hxbny)7popl35dhdo13oa..[,-~yiie24-in,5(-hoo6 15 ethoxybenzyl)-7-cypropyl-3 ,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloroethrooxybenzyl)-7-clproyl-3 ,5-dihydro[ 1,3 oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5 mehxbny)7mty-,*lyr[,3oaoo45cpriie24doe 5-2cloo 5-proxybenzyl)--methyl-3 5-dhydro[ 1,3]oxazolo[45-cpyridine-2,4-dione, 5-(2-chloro-5- 20ethoxybenzyl)-7-methyl-3,5-dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-2-chloro-- :i :ethoxybnz1ysny)-6methyethl-3,-ihdo xazolo[, ]yri o4-jpdine-2,4-dione, 2 ehxyezy)7-ehy-d5dhydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-bnyo)6 -chlorobezl--ey- (pripeurdn-1 yluoyl)benzyl]-7-methyl-3 5-hdiyr[1,3]oxazolo[4,5-c]pyridine-2,4-dione (-2-chloro-5-(pyrolii-1-ufnlbenzyl]-7-methyl-3,5-dihydro[ 1 ,3]oxazolo[4,5-c~yiie24doe Deiaie.uhasetr,9..naeaias mieotcliomr n r-rg arlocntmltd JUN. 2005 15:56 SPRUSON AND FERGUSON 61292615486 NO. 2697' P, The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

The present invention further relates to a process of inhibiting the binding of o4Pa integrin to VCAM-I comprising exposure of a cell expressing c4 1 P integriri to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The a-ap may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses There is also disclosed herein a method for treating diseasc.states mediated by a4p, binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.

o o Detailed Description of the Invention Definitions of Terms The term "alkyl" as used herein, alone or in combination, refers to C -Ci2 straight or branched, substituted or unsubstiruted saturated chain-radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a C,-Cy designation. Representative examples of alkyl groups include methyl, ethyl, 20 n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.

The term "alkenyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited Sto, ethenyl, E- and Z-pentenyl, decenyl and the like.

The term "alkynyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term "lower" modifying "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a Ci-

C

6 unit for a particular functionality. For example lower alkyl means Ci-C alkyl.

COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 The term "aliphatic acyl" as used herein, alone or in combination, refers to radicals of formula alkyl-C(O)-, alkenyl-C(O)- and alkynyl-C(O)- derived from an alkane-, alkene- or alkyncarboxylic acid, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl, among others.

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among otners. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.

"Cycloalkyl" includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.

The term "cycloalkenyl" as used herein alone or in combination refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a 20 lower alkyl radical, including, but not limited to cyclohexylmethyl.

The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.

The term "haloalkyl" as used herein refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.

The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term "alkoxyalkyl" as used herein, refers to Ry-O-Rz, wherein R, is lower alkyl as defined above, and Rz is alkylene (-(CH 2 wherein w is an integer of from one to six.

Representative examples include methoxymethyl, methoxyethyl, and ethoxyethyl among others.

The term "alkenoxy" as used herein, alone or in combination, refers to a radical of formula alkenyl-O, provided that the radical is not an enol ether, wherein the term "alkenyl" is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z- 3-methyl-2-propenoxy and the like.

The term "alkynoxy" as used herein, alone or in combination, refers to a radical of formula alkynyl-O, provided that the radical is not an -ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.

The term "carboxy" as used herein refers to The term "thioalkoxy" refers to a thioether radical of formula alkyl-S-, wherein "alkyl" is as defined above.

The term "sulfonamido" as used herein refers to -SO 2

NH

2 *.o The term "carboxaldehyde" as used herein refers to -C(O)R wherein R is hydrogen.

The terms "carboxamide" or "amide" as used herein refer to -C(O)NRaRb wherein Ra and Rb are each independently hydrogen, alkyl or any other suitable substituent.

The term "alkoxyalkoxy" as used herein refers to RcO-RdO- wherein Re is lower alkyl as defined above and Rd is alkylene wherein alkylene is -(CH 2 wherein n' is an integer from 1 to 6. Representative examples of alkoxyalkoxy groups include methoxymethoxy, 20 ethoxymethoxy, t-butoxymethoxy among others.

The term "alkylamino" as used herein refers to ReNH- wherein Re is a lower alkyl group, for example, ethylamino, butylamino, among others.

The term "alkenylamino" as used herein, alone or in combination, refers to a radical of formula alkenyl-NH-or (alkenyl) 2 wherein the term "alkenyl" is as defined above, provided that the radical is not an enamine. An example of such alkenylamino radical is the allylamino radical.

The term "alkynylamino" as used herein, alone or incombination, refers to a radical of formula alkynyl-NH- or (alkynyl) 2 N- wherein the term "alkynyl" is as defined above, provided that the radical is not an amine. An example of such alkynylamino radicals is the propargyl amino radical.

The term "dialkylamino" as used herein refers to RfRgN- wherein Rf and Rg are -33independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.

The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.

The term "aryl" or "aromatic" as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group containing at least one endocyclic N, O or S atom such as furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, I H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, c]triazinyl and the like. "Aralkyl" and "alkylaryl" employ the term "alkyl" as defined above.

Rings may be multiply substituted.

20 The term "aralkyl" as used herein, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above.

Examples of suitable aralkyl radicals include, but are not limited to. phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl. pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.

The term "aralkenyl" as used herein, alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.

The term "arylamino" as used herein, alone or in combination, refers to a radical of formula aryl-NH-, wherein "aryl" is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, and 4pyridylamino and the like.

The term "benzyl" as used herein refers to C 6

H

5

-CH

2 The term "biaryl" as used herein, alone or in combination, refers to a radical of formula aryl-aryl, wherein the term "aryl" is as defined above.

The term "thioaryl" as used herein, alone or in combination, refers to a radical of formula aryl-S-, wherein the term "aryl" is as defined above. An example of a thioaryl radical is the thiophenyl radical.

The term "aroyl" as used herein, alone or in combination, refers to a radical of formula aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.

The term "heterocyclyl" as used herein, alone or in combination, refers to a nonaromatic 3- to 10- membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused. The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.

The term "alkylheterocyclyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group, including but not limited to 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thienyl.

The term "heterocyclylalkyl" as used herein refers to a heterocyclyl group as previously Sdefined appended to the parent molecular moiety through an alkyl group, including but not limited to 2-thienylmethyl, 2-pyridinylmethyl and 2-(l-piperidinyl) ethyl.

The term "heterocycloyl" as used herein refers to radicals of the formula heterocyclylwherein the term "hetercyclyl" is as defined above.

The term "aminal" as used herein refers to a hemi-acetal of the structure RhC(NRiRj)(NRkRI)- wherein Rh, Ri, Rj, Rk and RI are each independently hydrogen, alkyl or any other suitable substituent.

The term "ester" as used herein refers to -C(0)Rm, wherein Rm is hydrogen, alkyl or any other suitable substituent.

The term "carbamate" as used herein refers to compounds based on carbamic acid NH2C(O)OH.

The term "optical isomers" as used herein refers to compounds which differ only in the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.

Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of S' or Rings may be substituted ,multiple times.

The terms "electron-withdrawing" or "electron-donating" refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference. Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, S' 20 trifluoromethyl, sulfonyl and aryl lower alkanoyl among others. Electron donating groups S. include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.

The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, carboxy lower alkyl, arylalkoxy, alkanoylamino, alkanoyl(lower alkyl)amino, lower alkylsufonylamino, arylsulfonylamino, alkylsulfonyl(lower alkyl)amino, arylsulfonyl(lower alkyl)amino, lower alkylcarboxamide, di(lower alkyl)carboxamide, sulfonamide, lower alkylsulfonamide, di(lower alkyl)sulfonamide, lower alkylsulfonyl, arylsulfonyl and alkyldithio.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

As used herein, the term "mammals" includes humans and other animals.

The ring defined by Y in Formulae I, I and mI can be a mono-cyclic heterocycle or aromatic ring, or can be a bicyclic ring.

The dotted lines used in Formulae I, 11, h, IV and VI indicate that the bond at that location can be either single or double. The bond between the atoms Yand W for example can be a single or double bond ifY and/or W is a substitutent such as N, C or CH. Therefore, 15 the ring defined by Y in the Formulae can be either saturated or unsaturated, depending upon which W and/or Y is selected. In Formulae IV and VI, the dotted line indicates that the nitrogen -containing ring optionally contains double bonds at the indicated locations.

In the Formulae, certain R groups potentially substitute their associated rings a number of times. R 19

R

20 RR, R" 2

R

2

R

2

R

29 and R 25 may each substitute their 20 associated rings more than once. For example for R 1 9 when c is zero, the associated ring is unsubstituted, having hydrogens at the C-2 and C-4 positions; and for R 3 when g is zero, hydrogens are at the C-2 C-5 positions.

Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclyl groups or the ring defined by Y and W in the formulae described above, when present, include alcohols, amines, heteroatoms, or any combination of aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl groups either attached directly, or via suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of C, C=O, CO 2 O, N, S, S=0, SO2, as for example ethers, amides, amines, ureas, sulfamides, sulfonamides, among others.

For example, R 1

R

2

R

3

R

5

R

6

R

7 and R 8 in the above formulae may independently be, but are not limited to: hydrogen, alkyl, phenyl, thienylmethyl, isobutyl, n-butyl, 2thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1benzothiophen-2-yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenyipropylsulfanylmethyl, toluidinocarbonyl)arnino)benzyl, 2-pyridinylethyl, 1H-indol-3-yI)ethyl, 1 benzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4-(acetylamino)phenyl, 4methoxyphenyl, 4-aminophenyl, 4-chiorophenyl, (4-(benzylsulfonyl)amino)phenyl, (4- (methylsulfonyl)amino)phenyl, 2-aminophenyl, 2-methyiphenyl, isopropyl, 2-oxo- 1pyrrolidinyl, 3-(methylsulfanyl)propyl, (propylsulfanyl)metbyl, octylsulfanylmethyl, 3aminophenyl, 4-((2-toluidinocarbonyl)amino)phenyl, 2-((methylbenzyl)amino)benzyl, methylsulfanylethyl, hydroxy, chioro, fluoro, bromo, ureido, amino, methanesulfonylamino, acetylamino, ethylsulfanylmethyl, 2-chlorobenzyl, 2bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4dichlorobenzyl, 2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chioro- 5-(trifluoromethyl)benzyl, 2-chloro-6-methylbenzyl, 2,6-dimethoxybenzyl, (methylsul fonyl)benzyl, 2-chloro-6-cyanobenzyl. 2-chloro-6-ethoxybenzyl, methoxybenzyl, 2-chloro-5-fluorobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclopropyl, tert-butylamino, propylamino, 4-methyl- I -piperazinyl, 1 -azetidinyl, 4-morpholino, (4-carboxyphenyl)amino, pivaloylamino, ((tertbutylamino)carbonyl)amino, trifluoromethyl, bertzyloxy, 2-(2-methoxyethoxy)ethoxy, 2- (2-(2-methoxyethoxy)ethoxy)ethoxy and methoxyethoxy)ethoxy)ethoxy)ethoxy.

The R 4 substituent for the formulae above may be, but is not limited to 1,3- 1 -naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, I1-benzofuiran-2-yl, 2thienylmethyl, phenyl, methylsul fanyl, phenylsul fanyl, phenethylsulfanyl, 4-bromo-2thienyl, 3-methyl-2-thienyl, 4-methyiphenyl, 3,5-bis(methyloxy)phenyl, 4- (methyloxy)phenyl, 4-fluorophenyl, 3-(methyloxy)phenyl, 3 2 .3-dihydro-lI-benzofuran-5-yl, 3 -fluorophenyl, 4-(trifluoromethyl)phenyl, 4-fluoro-3 (trifluoromethyl)phenyl, 1, 1 -dimethylethyl)phenyl, 3 ,5-dimethylphenyl, 4hydroxyphenyl, 3 ,4-dimethylphenyl, 3 -methyl-4-(methyloxy)phenyl, 4-hydroxy-3 methyiphenyl, 3-methyiphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6bis(methyloxy)phenyl, 2,6-dihydroxyphenyl, 4-chiorophenyl, 3-chiorophenyl, 3,4dichiorophenyl, 4-((trifluoromethyl)oxy)phenyl, 4-ethyiphenyl, 4-(ethyloxy)phenyl, methyl, 2-propyl, 4,5-dihydro- 1,3-oxazol-2-yl, 3-(trifluoromethyl)phenyl, 4- (trifluoromethoxy)phenyl, 2,3-dihydro- 1,4-benzodioxin-6-yl, 7-methoxy- 1,3- 3-ethoxy-4-methoxyphenyl, 3 ,4-diniethoxyphenyl, 3 ,4-diethoxyphenyl, 3 -ethoxyphenyl, 3-methoxy-4-methylphenyl, 3 ,5-dimethoxy-4-methylphenyl, 3propoxyphenyl, 3 -butoxyphenyl, 3-(2-methoxyethoxy)phenyl, 3,4-dipropoxyphenyl, 3- (difluoromethoxy)phenyl, 2-naphthyl, 3-isopropoxyphenyl, 1 -methyl- I H-indol-5-yl, 2,3dihydro-l1-benzofuran-5-yl, 1,3 -diethyl-2-oxo-2,3-dihydro- 1H-benzimidazol-5-yl, 3- (tri fluoromethoxy)phenyl, 1 -methyl- I H-indol-6-yl, 3-(cyclopropoxy)phenyl, 3- (cyclopropylmethoxy)phenyl, 3-(difluoromethoxy)phenyl, 1,1,2,2tetrafluoroethoxy)phenyl, 1 -ethyl- I H-indol-5-yl, 3-(diethylamino)phenyl, 6-methoxy-2- *naphthyl, 3-[(methylsulfonyl)amino]phenyl, 3-[methyl(methylsulfonyl)amino]phenyl, 3- [ethyl(methylsulfonyl)amino]phenyl, I H-indol-5-yl, 3 -fluoro-4-methoxyphenyl and 3- (difluoromethyl)phenyl.

*Two independent R2. RS or R groups taken together may be linked to form a ring.

R

4 and R" may be linked to form a ring such as I1-pyrrolidino, I1-piperidino, 4-methyl-I 20 piperazino, 4-acetyl- I -piperazino and 4-morpholino among others.

R 9* and R1 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl among others.

Abbreviations Abbreviations which have been used in the schemes and the examples which follow are: BOG for t-butyloxycarbonyl; DMF for dimethylformamide; THF for tetrahydrofuran; DME for dimethoxyethane; DMSO for dimethylsulfoxide; NMM for N-methyl morpholine; DIPEA for diisopropylethylamine; CDI for l,l'-carbonydiimidazole; TBS for TRIS-buffered saline; Ms for methanesulfonyl, TMEDA for tetramethylethylenediamine, DCE for 1 ,2-dichloroethane, NCS for N-chlorosuccinimide, NBS for N-bromosuccinimide, DPPA for diphenylphosphorylazide, DEAD for diethyl azodicarboxylate, m-CPBA for 3-chloroperoxybenzoic acid, TFAA for trifluoroacetic anhydride, DCM for dichloromethane, LHMDS for lithium bis(trimethylsilyl)amide and Cbz for benzyloxycarbonyl. Amino acids are abbreviated as follows: C for L-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; I for Lisoleucine; L for L-leucine; N for L-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T for L-threonine; V for L-valine and W for L-tryptophan.

Examples of the procedures that may be used to synthesize compounds of the Formulae described above are shown in the Schemes which follow. A detailed description of the representative compounds of the present invention is set forth in the Examples below.

e* e* Scheme 1 below illustrates the procedure described in Example 1.

N 0

H

2 Pd/C MeOH CNH 2 N 0 Trimethylacetyl chloride NEt 3

DCM

H

N

0 N 0 3

HN

0 0 ooo.

0 0:.0 a) n-BuLi, TMEDA

THF

b) t-BuLi c) Ethyliodide KHMDS, THF I Q Br C1 N1

NH

0

NH~

11040 KI, HOAc 6M HCI

NH,

C 1 0 7 a) COG) 2

DIPEA

DCE

b) CO

H,N

a) NaOH, THF.

MeOH b) HCI 7 -~COOH N N N N N H H K Scheme 1 -41- Scheme 2, illustrating the procedure of Example 2, is shown below.

OH

HN 'f 0 0 11

K

2 C0 3 BnBr r 0 Acetone, reflux 0 N- I 0 0 Zn, sat.NH 4

CI

MeOH, 70 0

C:

rN 0

NH

2 0 13 2N NaOH, THF/MeOH, r.tN a) COCI 2

DIPEA,

CH

2

CI

2 b)COOEt

H

2

N

N 00 COOH C'NN

J'NN

0H Hi Scheme 2 -42- Scheme 3, illustrating the procedure of Example 3, is shown below.

OH

HN 0 0 11 NaN, DMF

OH

C1 0 16 POC1 3 70 0

C

CI

NO

2 CI 0 17

NH

4 0H

NH

2 Zn, sat'd aq. NH 4

CI

MeOH,65 0 C N NO 2 MeOH, 65 0

C

C1 0 is

NH

2 NMM, DMF, 50 0

C

N NH 2 2 N 0 0 Ot 19

H

NaOH,

H

2 0 THF, MeOH 0 NH

OH

N N ci o H H I Scheme 3 -43- Scheme 4, illustrating the procedure of Example 4, is shown below.

1 5 ,OH NaH, DMF, 55 0 C r ,OH KC e HNI, NO 2 ClN -r NO 2 Acetone, reflux 0 Cl C1 0 23 24 C1 0 0 .00.

*0* 0.0.

Scheme 4 Scheme 5, illustrating the procedure of Example 5, is shown below.

H

j N 1-'00

NO

a) n-BuLi, TMEDA,

THF

b) (PhSO 2 2

NF

7

F

N I NH -0 26.

Scheme Scheme 6, illustrating the procedure of Example 6, is shown below.

H

N 0 3 a) n-BuLl, TMEDA,

THF

b) NCS 7 1 C I N.

NH

100 27 Scheme 6 Scheme 7, illustrating the procedure of Example 7, is shown below.

H

N

a) n-BuLl, TMEDA,

THF

b) Br 2

THF

Br N.

NH

28 Scheme 7 0* C I Scheme 8, illustrating the procedure of Example 8, is shown below.

OH OH Zn, sat'd aq. NH 4 CI CDI, N NO, MeOH, 65 0 C NH, 700O( C1 0

DMF

24 'I C C1 0 DMF, 70 0

C

0 O 0Er OH CO 2 Et P-J" IN N CI 0 H{ H 31 NaOH,

H

2 0, THF, MeON OH C0 2

H

N

N N C1 0 H H 1 32 Scheme 8 Scheme 9, illustrating the procedure of Example 9, is shown below.

Br N

NH,

C1 0 0 PhB(OH) 2

K

3 P0 4 OMP, H 2 01 Pd(PPh 3 4 Scheme 9 4 4S** 4*@S 4.

4 0*SQ 4 4* .4 .4 4 4* 4.

*44444 4 4 4.

f 4 44. 4 4,4.

4 Scheme 10, illustrating the procedure of Example 10, is shown below.

NH

Me l OMe MeO O~R~ 0 0 37

H

2

N-Y~

MeON,

NH

Hi 0 EtOH, pyridine, piperidine,reflux 36, MeOH, reflux NBS, (PhCO 2 2 CCd 4

K

2 C0 3 N, NaOH, H 2 0 NaOH, H 2 0

THF

8 42 C N' 0 COOH 43 Scheme Scheme 11, illustrating the procedure of Example 11, is shown below.

NH

Me uN 36 RtON, pyridine, piperidine, reflux Scheme 11I Scheme 12, illustrating the procedure of Example 12, is shown below.

5 r NH 2 N r NO 2 C1 0 0NHN

NH

NO

2 C1 0 47 NaH, EtNCO THF, 0 0

C,

warm to RT Scheme 12 Scheme 13, illustrating the procedure of Example 13, is shown below.

ON

HN

NO

2 0

CI

NaH, DMF, 55 0

C

N, N

NO

2 C1 0 Scheme 13 Scheme 14, illustrating the procedure of Example 14, is shown below.

KO,, OMt 0 0 51 rlQ NH2 EDCI, DMF

H

N*,r,,OEt C1 0 0 IN_ ACHO- AcOH, EtOH Reflux N OUt C1 0 0 53 a) DPPA, DI PEA, TNF, Reflux b) COOEt

H

2 N 1 C1 NaOH, THF MeON, H 2 0 Q N

OH

CI 0 0

N

0

N

0 COORt

HI

NaOH, THF MeON,

H

2 0 8 CI 0 0

COOH

N UN NH H 567 Scheme 14 Scheme 15, illustrating the procedure of Example 15, is shown below.

S

OH

a) MsCI, NEt 3

CH

2

CI

2 N -r

NO,

OH

I N Fe, AcOH, 60 *C /I N 1402

SNH,

0 0- 58 a) COCI 2 DIPEA, CO t DCM 0 -O~ b) COt Cl Nr NAN0

H

2 N 0" 00> q0 61 a) NaOH, THF,

H

2 0, MeOH b) HCI 0

NI

N

0

H

Scheme Scheme 16, illustrating the procedure of Example 16, is shown below.

a. a 0 CbzHN OH N H c 63 7 -S NHBo 0 CSIC0 3 ,1rviel 0 a) Pd/C, MeOH DMF b) 2-Thiophenecaz-boxaldehyde CbzHN OWe NaBH(OAC) 3

CICH-,CH,CI

N H 8c HCI, Dioxane /S5

Y'NH,

0 COOEt a)CDCHCl,.HN 0> b) 66 S COO~t N N 00 a) NaOH, THF, H,O, MeOH b) HCI 0 COOH 0 0 ~0 68 Scheme 16 Scheme 17, illustrating the procedure of Example 17, is shown below 0 HO OBn O NHBoc

S

NH

2 NaBH(OAC) 3

CICH

2

CH

2

CI

a) i-BUOCOCI, NMM, DME b) NaBH 4 H,0 N~ 0 71 0 HO_-y-M NHBoc a) DMSO, (COG 1)2

CH

2

CI

2 b) 69 c) NEt 3 0 OHC OMe NHBoc HCI NHBoc Dioxane N~ 0 72 a) CDI, CH 2

CI-,

NH

2 b) GOOEt

H

2 N 150 a) NaOH, THF,

H

2 0, MeOH b) HCI

-N

0

NXN

H H

COOH

I>

~~0 Scheme 17 Scheme 18, illustrating the procedure of Example 18, is shown below.

C1

OH

Zn, NH 4

CI

MeOH, H 2 0

KNO

3 NaNO 2 Et 2 O, 6N HCI C1 a) COGI 2

DIPEA

CICH,CH

2

CI

b) 100 N N OH H H Scheme 18 Scheme 19, illustrating the procedure of Example 19, is shown below.

0

NH,

THF N

H

Scheme 19 Scheme 20, illustrating the procedure of Example 20, is shown below.

NO

2

OH

PPh 3

DEAD

CH

2 C1 2 NO 2 0 103 Scheme Scheme 2 1, illustrating the procedure of Example 2 1, is shown below.

NO

2 SN0 2

CHO

NH

2 NaBH(OAc) 3 DCE, H NH2 molecular sieves W

TFAA,

TEA

DCM

S. S

SS

55 S~S 555

S

S.

555

S

55.5

F

3 Cy N.

0 Fe. AcOH, EtOH

F

3 Cy N 0 Scheme 21 53- Scheme 22, illustrating the procedure of Example 22, is shown below.

0 S 1 0' Menthol a. LHMDS, THF 00 0 S 01 N

C

0 108 Br',,,GO 2 Et F F a) Zn, THF b) 108

F

0F

CO

2 Et 0 109 TFA, MeOH es..

&q 4.

0* @4 5 Scheme 22 Scheme 23, illustrating the procedure of Example 23, is shown below.

Hy

NO

a) n-BuLi, TMEDA, THF b) t-BuLi c) Br Br 44

C

S

.t 45

S

Scheme 23 Scheme 24, illustrating the procedure of Example 24, is shown below.

COOEt 0 0 BBr 3 N N N CHCI, N N o H H I Cl 0 H H C1 0 112 OMe 1 11

'OOH

Scheme 24 Scheme 25, illustrating the procedure of Example 25, is shown below.

11,OMe a) NaH, TMEDA, THF, -20 -C b) n-BuLi, -20 cc c) HCOOMe, -20T 0 OH 0 0 OMe NH2 C I MeOH, Reflux C1 a.

a a. a *aa a. a a C1 115 N 0

NN

H

0 117 NaNO 2

HNO

3

K

AcOH, H 2 0,RTK THF, 55 0

C

00

OE,

H-,N

OHa) Zn, EtN -HI N DMF, 55 0

C

'I

NO

2 b) CDI, 80 C 0 116 9OH 0 C 2 Et

A

C] 0 H H 118 NaOH, H 2 0, THF. MeOH C1 Scheme Scheme 26, illustrating Example 26 is shown below.

a) KOH, DMS0, b) Zn, Et 3

NIICI,

DMF, 800 C c) CDI, 80o C 4 Scheme 26 Scheme 27, illustrating Example 27, is shown below.

*4 4* 0 r

YOH

N 2 C1 0 m-CPBA

CH-,CI-,

'so-, 07 Y

OH

NO,

C1 0 Scheme 27 Scheme 28, illustrating Example 28, is shown below.

0 OH C0 2 t-Bu N N

N

H H 123 a) ZnBr,,

CH

2

CI

2 b) H 2 0 Scheme 28 Scheme 29, illustrating Example 29, is shown below.

0 0

CN

C1 OH HN *HCI 0

H

2 Pd/C, NEt 3 EtOH

OH

H N 0 126 2 Et 3

NHCI

Scheme 29 -57- Scheme 30, illustrating Example 30, is shown below.

G OOEt 0

NH

Toluene, Reflux COOEt

/\NH

Cl 127 a) NaH, THF, 0 'C b) AcGI, RT /COQEt

/\N

0 LHMDS, THF 0 OC, warm to RT a Scheme Scheme 3 1, illustrating Example 3 1, is shown below.

NH

2

NO

2 C1 0 a) NaH, THF, 0 'C b) t-BuNCO, warm to RT O l NH

NH

NO,

C1 0 Scheme 31 OH COOEt N N

N

31 C I OH COOEt

SO

2

CI

2

CH

2

CI

2 0 N N lkN' P--H H 1 131 Scheme 32 t-BuOOC N Br OMe (HO),B b MeO PdCI 2 (PPh 3 2

K

3 P0 4 DME, Reflux Ph'N. Li Ph THF, -78 0

C,

warm to RT GOOt-Bu Ph' N 0 ON Ph 133 ',eO COOt-Bu Ph~ N 11 Ph "'Br 132 4ie H 2 'd/C EtOH, HOAc 0* COOt-Bu

H

2 N N OMe MeO 134 Scheme 33 -59-

F

CN

CI

NaOt-Bu, EtOH THF RT OEt

CN

CI

BR

3

THF

Reflux OEt cNH 2 HOAc, AC 2

O

NaNO 2 QEt N. c I Ac 137 O~t NaOH N. OH 138

SOCI

2

CH

2

CI

2 O~t 139

H

2

NNH

2 MeOH

RT

*OEt cNHN'H 2 140 ACOQEt

CHCI

3 MgSO 4

RT

9* N COQEt CICOCH 2 COOMe N. NH NaH, THF, 0 'C, Warm to RT

CI

141 Et N COOEt NaH, DMF NY--COOMe' Ct 0O CI 0 142 9 Et N OH COOMe Cl 0 143 HCI, H,0, Dioxane Reflux Scheme 34 Ft 0 OH N. N II 0 144

H

a) NaH, DMF, 0 OC to RT b) Ed, RT Nc== N7 DMVF, POCd 3 70 0

C

OHC,.

N #0O

HOOCCH,COOH

Pipenidine, Pyridine EtOH, Reflux HOOd zz: -N

N

148 Scheme

S

OH 0 0 Y--A OMe c

NH,

MeOR, Reflux

S

0 OH NaNO 2 H-N0 3 I AcOH, H 2 0, RT CI 0 149 Et DMF, 55 0

C

0 N :N Q Et H H-,Nf CI 08 Et 0 OH

N

CX

NO,)

CI 0 150 a) Zn, Et,-NHCI DMF, 55 0

C

b) CDI, 80 0

C

NaOH, H 2 0.

THF, MeOH Et 7 OHO C0 2

H

N N CI 0 HH 1 153 Scheme 36 Et 0 >=0 N N N

H

CI 0 151 Et DMF, 55 0 C 0OH 0 CO 2 Et COEt N Nt CC; N N 1 2 N CI 0 H H Ot155. Et Et NaOH, H 2 0 0 OH CO 2

H

TI2F0,O 0 C IN N N Cl 0 H H QEt Scheme 37 0 .090 Et 0 0 DMF, 55 0 C 0 OH 0 CO 2 Et N N N CNE NN H H 0 H H Cl 0H,N Cl 0 151 OMe 158 157 Et NaOH, H 2 0, 0 OHO COl 2

H

THF,MeOH N 0, N N

N

Cl 0 H 159 OMe Scheme 3 8 .OH NaNO 2

HNO

3 -AcOH, H 2 0O, RT

OH

NO

2 CI 0 160 a) Zn, Et 3 N HG! DMF, 55 0

C

b) CDI, 80 0

C

0 N

N

H

Cl 0 161 DMF, 80 0

C

Oi-Pr NaOH, H 2 0, THF, MeOH OH C 2

H

C! H H 164 Oi-Pr Scheme 39 H,1C OOEt Oi Pr SO'-C1 2 HOAc 0 OC to RT GOOEt

C!

OiPr Scheme NaNO 2 HOAc MeOH, H 2 0 0 OC to RT Scheme 41 EtOOC

CHO

169 Br. N

CHO

168 e EtOOC 4*9 170 t *oe "COOEt Pd(OAc) 2 P(o-tolyl) 3 NEt 3 DMF, 125 °C (Me2N)SF 3 90 C COOEt a) s-BuLi, THF, -78C C Ph b) 170, THF, -78C PhC N-H Ph N Ph-- Ph "'P 171

CHF,

9. 0 4 4.

4 9

H

2 Pd/C, AcOH EtOH, 35 °C COOEt H,N 1 171 CHF, Scheme 42 The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby 15 obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and 20 purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a :pharmaceutically acceptable metal cation or:with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, o:oe it is within the skill of the art to start doses of the compound at levels lower than required ~to achieve the desired therapeutic effect and to gradually increase the dosage until the ••desired effect is achieved.

•15 When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.

o Alteriativel the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically 20 acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For JUN. 2005 15:57 .SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 61 66 example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently,-single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

Disclosed herein are pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

a15 The pharmaceutical compositions can be administered to humans

S..

S. and other mammals orally, recta.lly, parenterially, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration Swhich include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion., Also disclosed herein is a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent.

SThe present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parentcral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others.

The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed ofa fine wire mesh), or via a biodegradable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.

COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying S" absorption, for example, aluminum monostearate and gelatin.

15 Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the 20 absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, °alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as 15 paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

20 Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.

Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

-69- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

SCompositions for rectal or vaginal administration are preferably suppositories •which can be prepared by mixing the compounds of this invention with suitable non- 15 irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or 20 other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

The term "pharmaceutically acceptable prodrugs" as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T.

Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S.

Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.

Compounds of the present invention that are formed by in vivo conversion of a different compound that was administered to a mammal are intended to be included ••within the scope of the present invention.

Compounds of the present invention may exist as stereoisomers wherein 15 asymmetric or chiral centers are present. These stereoisomers are or depending on the configuration of substituents around the chiral carbon atom. The present invention .contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual -stereoisomers of compounds of the present invention may be prepared synthetically from S 20 commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by.(1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.

JUN. 2005 15:57 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 62 71 In another aspect, the present invention contemplates a process of inhibiting the binding of a4PI integrin to VCAM-1. A process of the present invention can be used either in vitro or in vivo. In accordance with a process of the present invention, a cell expressiig integrin is exposed to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention.

A cell expressing a 4 PI integrin can be a naturally occurring white blood cell, mast cell or other cell type that naturally expresses a4Pi on the cell surface, or a cell transfected with an expression vector that contains a poly-nucleotide genomic DNA or cDNA) that encodes 0401 inregrin. In an especially preferred embodiment, C34piintegrin is present on the surface of a white blood cell such as a monocyte, a lymphocyte or a granulocyte an eosinophil or a basophil).

A cell that expresses VCAM-I can be a naturally occurring cell an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide that encodes VCAM-1. Methods for producing transfected cells that express VCAM-1 are well known in the art.

Where VCAM-1 exists on the surface of cell, the expression of that VCAM-I is preferably induced by inflammatory cytokines such as tumor necrosis factor-ao interleukin-4 and interleukin-lp.

Where the cells expressing a431 integrin and VCAM-1 are in a living organism, a 20 compound of the present invention is administered in an effective amount to the living organism. Preferably, the compound is in a pharmaceutical composition of this invention.

A process of the present invention is especially useful in treating iseases associated with uncontrolled migration of white blood cells to damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or'oral delivery.

Also disclosed herein is a process of selectively inhibiting the binding of aapintegrin to a protein comprising exposing the integrin to the protein in the presence of an effective inhibiting amount of a compound of the present invention. In a COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 preferred embodiment, the a 4 3 integrin is expressed on the surface of a cell, either naturally occurring or a cell transformed to express a4Plintegrin.

The protein to which the a4 3 integrin binds can be expressed either on a cell surface or be part of the extracellular matrix. Especially preferred proteins are fibronectin or invasin.

The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples. These Examples are presented to describe preferred embodiments and utilities of the invention and are not meant to limit the invention unless otherwise stated in the claims appended hereto.

Example 1 Synthesis of {l-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo- 1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid Step One: Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270 mL) and palladium on carbon (10 Pd dry weight basis, Degussa type El01 NE/W, water content, 5.75 g, 2.7 mmol Pd) was added. The atmosphere was replaced with 20 hydrogen (toggle between vacuum and hydrogen from a balloon five times), the mixture was stirred overnight, then filtered. The filtrate was concentrated under vacuum and the residue was taken up in a 1:1 hexanes:ethyl acetate mixture and washed with a 4:1 mixture of water and saturated NaHCO 3 saturated NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 2 (12.43 g, 74%) as a white solid. This material was used without purification.

Step Two: Compound 2 (2.64 g, 21.3 mmol) was dissolved in dichloromethane mL) and chilled to 0 The cold solution was treated sequentially with triethylamine (3.6 mL, 25.6 mmol) and trimethylacetyl chloride (2.90 mL, 23.4 mmol).

The solution was stirred at room temperature for 5 hours, then refluxed overnight. The mixture was partitioned between dichloromethane and aqueous NaOH The organic layer was washed with brine, dried over MgSO 4 and filtered and the filtrate was concentrated to give compound 3 (3.33 g, Step Three: Compound 3 (0.50 g, 2.4 mmol) was dissolved in dry THF, (9.6 mL) and TMEDA (1.1 mL, 7.2 mmol) under a dry nitrogen atmosphere. The resulting solution was chilled to between -20 and -10 °C and treated sequentially with nbutyllithium (1.6 M in hexanes 2.25 mL) and t-butyllithium (1.7 M in pentane, 2.1 mL) dropwise via syringe. After 30 minutes the bath temperature was allowed to come to -5 to 0 °C and treated with ethyl iodide via a syringe (0.77 mL, 9.6 mmol). The solution was stirred at 0 oC for 2 hours, then room temperature overnight. The mixture was quenched •with methanol and concentrated to dryness. The residue was purified by filtering through silica gel, eluting with 3:1 hexanes:ethyl acetate and then recrystallizing from hexanes to yield compound 4 (0.32 g, 56%).

Step Four: Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid (4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture was heated in an oil bath regulated at 115 oC for 1.0 hour. The mixture was cooled, diluted with water and adjusted to pH 6 using 2N NaOH and 2N HCI. The mixture was extracted with chloroform (4 times). The combined extracts were washed with aqueous sodium thiosulfate, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced 20 pressure to give compound 5 (0.25 g, 86%) as a white solid. This material was used without further purification.

Step Five: Compound 5 (0.25 g, 1.1 mmol) was dissolved in THF (45 mL) and treated dropwise with a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 2.7 mL) at 0 The resulting solution was treated with 2-chlorobenzylbromide (0.16 mL, 1.2 mmol) and the solution was allowed to warm to room temperature overnight.

The mixture was partitioned between 2N HCI and ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (SiO 2 gradient elution 4:1 switching to 2:1 hexanes:ethyl acetate) to give compound 6 (0.16 g, 41%).

Step Six: Compound 6 (0.16 g, 0.46 mmol) was suspended in 1:1 water:concentrated HCI (4.6 mL). The suspension was brought to reflux for 4 hours, during which time the compound dissolved. The mixture was cooled, diluted with water and extracted with diethyl ether. The aqueous layer adjusted basic with excess saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give compound 7 (0.081 g, 67%).

Step Seven: Compound 7 (0.080 g, 0.30 mmol) was dissolved in 1,2-dichloroethane (1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and chilled to 0 The cold solution was treated rapidly with a solution of phosgene (1.93 M in toluene, 0.170 mL, 0.33 mmol). After minutes a solution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 mL) was added rapidly via syringe. The resulting mixture was heated to 55 for 1 hour. The mixture was partitioned between dichloromethane and 2N HC1. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over MgSO 4 and filtered. The filtrate was concentrated to give compound 9 (0.110 g, 74%).

Step Eight: Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2:1 THF:H 2 0 15 (0.88 mL) and treated with a solution of2N NaOH (0.33 mL). Methanol was added dropwise until a homogeneous solution was obtained. The mixture was stirred for minutes, diluted with water and washed with ethyl ether. The aqueous layer was acidified with 2N HCI and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated to [(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (10, 0.095 g, 92%).

Example 2 Synthesis of {6-methyl-2-oxo-l-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2dihydro-3-pyridinyl }amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid Step One: To a suspension of compound 11 (1.0 g, 5.9 mmol) and K 2

CO

3 (2.40 g 17.6 mmol) in acetone (50 mL) was added benzylbromide (2.31 g, 13.5 mmol). After refluxing overnight, the reaction was cooled and the mixture was partitioned between ethyl acetate and saturated NaHCO 3 The organic layer was washed with dilute HCI and brine, dried over MgSO 4 and filtered and the filtrate was concentrated to give compound 12 (1.60 g, Step Two: Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6 mmol) and saturated aqueous NH 4 CI (0.30 mL) were mixed in MeOH (18 mL). This mixture was allowed to stir at room temperature for 1 hour before additional zinc (0.30 g, 4.6 mmol) was added. The resulting heterogeneous mixture was refluxed overnight. After filtration of the hot mixture and concentration of the filtrate under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 13 (0.18 g, 66%).

Step Three: Compound 13 (0.30 g, 0.94 mmol.) and DIPEA (0.40 mL, 2.3 mmol.) were dissolved in CH 2 C12 and the mixture was cooled to 0 Phosgene (1.9 M in toluene, 0.55 mL, 1.0 mmol) was added to the solution dropwise. The reaction mixture was stirred at 0 oC for 15 minutes before compound 8 (0.19 g, 0.94 mmol) in CH 2 C12 (2 S°mL) was added. The resulting solution was stirred at room temperature overnight then poured into ethyl acetate and washed with saturated aqueous NaHCO 3 1 N HC1 and £6° brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 1:1 increasing to 1:2 hexanes:ethyl acetate to give compound 14 (0.33 g, 64%).

Step'Four: A solution of compound 14 0.33 g, 0.6 mmol) in THF (6 mL) was 20 treated with 2N NaOH (2 mL). MeOH was added until homogeneous solution was achieved. The reaction mixture was stirred at room temperature for 30 minutes and poured into H 2 0 (50 mL). The aqueous layer was washed with diethyl ether (twice), and then acidified with IN HCI. The aqueous layer was extracted with ethyl acetate (twice).

The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give methyl-2-oxo-l-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (15, 0.26 g, 90%) as an off-white solid. Melting point: 124-126 OC.

Example 3 Synthesis of {4-amino-l-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2dihydro-3-pyridinyl amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid (22).

Step One: To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF (120 mL) at 0°C was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The mixture was stirred at 0 °C for 15 minutes before the addition of 2-chlorobenzylchloride (12.3 g, 76.4 mmol). After stirring at 55 OC overnight, the mixture was poured into icewater and washed with Et20 twice. The aqueous layer was acidified and filtration of the resulting precipitate gave compound 16 (14.7 g, Step Two: To a flask containing compound 16 (8.00 g, 28.6 mmol) sealed with a rubber septum and balloon at room temperature under dry nitrogen atmosphere, POCI 3 (30.0 ml, 322 mmol) was added via syringe. The nitrogen line was removed and the reaction mixture was stirred overnight at 70 OC, then poured over ice (300ml) and stirred for 30 minutes. The resulting mixture was extracted with dichloromethane (300 ml) and the organic phase was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give compound 17 (7.3g, 86%) as a dark brown solid.

Step Three: To a 250 ml flask equipped with condenser and rubber septum fitted with a balloon, a solution of compound 17 (2.1g, 7.05 mmol), methanol (55ml) and aqueous ammonium hydroxide (28-30%, 70.0 ml, 1.14 mol) were added at room temperature. The reaction mixture was heated to 65 OC for 60 hours open only to the balloon. The mixture was filtered and the filtrate was concentrated under reduced 20 pressure to yield compound 18 (1.5 g, 76%) as a brown solid.

Step Four: To a solution of compound 18 (0.3g, 1.02 mmol) in methanol (50 ml) at room temperature, saturated aqueous ammonium chloride (2 ml) and zinc dust (0.30 g, 4.6 mmol) were added sequentially. After stirring 30 minutes at room temperature, additional zinc was added (0.30 g, 4.6 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was filtered hot and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and IN NaOH. The solution was filtered and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to yield compound 19 (0.21g, 78%) as a brown solid.

Step Five: A solution of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL, 0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 mL) was heated to 50 OC overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3 x 30 mL) and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with 9:1 increasing to 17:3

CHCI

3 :MeOH to give compound 21 (0.120 g, 65%) as a yellow foam.

Step Six: A solution of compound 21 (0.120 g, 0.25 mmol) in THF (6 mL) was treated with 2N NaOH (2 mL). Methanol was added until a homogeneous solution was achieved. The reaction mixture was stirred at room temperature for 30 minutes and poured into H 2 0 (50 mL). The aqueous layer was washed with diethyl ether (twice), and then acidified with 1N HC1. The aqueous layer was extracted with ethyl acetate (twice).

The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give amino-1 -[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3 -pyridinyl} amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (22, 0.100 g, 89%) as an off-white solid. Melting point: 145-147 OC.

Example 4 Synthesis of 1 -[(2-chlorophenyl)methyl]-4-(methyloxy)-2-oxo- 1,2-dihydro- 3-pyridinyl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

Step One: To a solution (e compound 23 (10.00 g, 64.0 mmol) in anhydrous DMF °1 20 (130 mL) at 0°C was added NaH (60% dispersion in mineral oil, 5.90 g, 147 mmol). The mixture was stirred at 0 OC for 15 minutes before the addition of 2-chlorobenzylchloride (13.4 g, 83.3 mmol). After stirring at 55 °C overnight, the mixture was poured into ice water and washed with Et20 (twice). The aqueous layer was acidified and filtration of the resulting precipitate gave compound 24 (13.5 g, Step Two: A suspension of compound 24 (1.0 g, 3.6 mmol), K 2

CO

3 (0.85 g, 6.2 mmol) and Mel (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 IN HCI and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give Compound 25 (0.74 g, (3S)-3-[({[1-[(2-chlorophenyl)methyl]- 4 -(methyloxy)-2-oxo-1,2-dihydro-3pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from compound 25 according to procedures described in Example 3. MS: Calculated: (M+H) 469.93; Found: 470.01.

Example Synthesis of 1-[(2-chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3pyridinyl amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid.

Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in dry THF (12.4 mL) and TMEDA (0.90 mL, 6 mmol) under a dry nitrogen atmosphere. The resulting solution was chilled to between -15 and -10 OC and n-butyllithium (1.6 M in hexanes, 7.75 mL, 12.4 mmol) was added dropwise via syringe. After 1.5 hours, a solution of Nfluorobenzenesulfonimide (1.07g, 3.4 mmol) in THF (5 mL) was added to the cold solution rapidly via syringe. The solution was stirred at 0 C for 1 hour, then room temperature for 3 hours. The mixture was quenched with water and extracted with chloroform (4 times). The combined organic extracts were washed with brine, dried over 15 MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography, (Si0 2 plug gel, using 4:1 switching to 3:1 hexanes:ethyl acetate) to yield compound 26 (0.177g, 1-[(2-Chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from Compound 26 according to procedures described in Example 1. MS: Calculated: (M+H) 458.12; Found: =458.01.

Example 6 Synthesis of (3S)-4-chloro-3- 1-[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro- 3-pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid.

Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) and TMEDA (1.20 mL, 7.75 mmol) and chilled to -15 OC. The solution was treated with nbutyllithium (1.6 M in hexanes, 4.8 mL, 7.8 mmol). The mixture was maintained between and -10 "C for 1 hour, then cooled to -78 Solid N-chlorosuccinimide (0.45 g, 3.4 mmol) was added while the apparatus was under a positive flow of nitrogen.

The reaction was allowed to gradually warm to room temperature then stirred overnight.

The mixture was quenched with water and extracted with chloroform (4 times). The organic layers were combined, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized from hexanes to give compound 27 (0.25 g, 33%).

(3S)-4-Chloro-3- -[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from compound 27 according to procedures described in Example 1.

Example 7 Synthesis of (3S)-4-bromo-3- {1 -[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro- 3-pyridinyl} amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.

Step One: Compound 3 (2.00g, 9.6 mmol) was dissolved in dry THF (32 mL) and TMEDA (2.20 mL, 14.4 mmol) under a dry nitrogen atmosphere. The resulting solution .was chilled to between -20 and -10 °C and n-butyl lithium (1.60 M in hexanes, 18.0 mL, 28.8 mmol) was added dropwise via syringe. Upon completion of the addition, the solution was chilled to -78 °C and bromine (0.49 mL, 10.5 mmol) was added dropwise via syringe. The solution was allowed to warm slowly to room temperature overnight, then was quenched with water and extracted with chloroform. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure.

The residue was recrystallized from hexanes to give compound 28 (1.32 g, 48%) as a tannish white solid.

20 1-[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid was prepared from compound 28 according to procedures described in Example 1.

Example 8 Synthesis of (3 1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3-pyridinyl amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid (32).

Step One: To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 ml) at room temperature, saturated ammonium chloride (1.5 mL) and zinc dust (1.5 g, 23 mmol) were added sequentially. After stirring 30 minutes at room temperature, additional zinc dust (1.5 g, 23 mmol) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered while hot and the filtrate was concentrated under reduced pressure. HCI (1 N) was added to the resulting residue until the pH was approximately 4 and the resulting precipitate was collected by filtration to give compound 29 (0.80 g, 57%) as a brown solid.

Step Two: A solution of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6 mmol) in DMF (10 mL) was-heated to 70 OC overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with IN HCI (3 times) and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 30 (0.14 g, 50%) as a brown solid.

Step Three: A solution of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0.082 g, 0.40 mmol) in anhydrous DMF (5 mL) was heated to 70 OC overnight. The mixture was cooled, diluted with ethyl acetate and washed with IN HC1 (3 times) and brine. The organic .layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced o pressure. The residue was purified by flash chromatography (SiO 2 eluting with 9:1

CHCI

3 :MeOH to give compound 31 (0.17 g, 97%).

15 Step Four: A solution of compound 31 (0.170 g, 0.35 mmol) in THF (3 mL) was treated with 2N NaOH (1 mL). Methanol was added until a homogeneous solution was achieved. The reaction mixture was stirred at room temperature for 30 minutes and poured into H 2 0 (50 mL). The aqueous layer was washed with diethyl ether (twice), and then acidified with IN HC1. The aqueous layer was extracted with ethyl acetate (twice).

20 The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give [(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3pyridinyl amino)carbonyl] amino -3-(4-methylphenyl)propanoic acid (32, 0.150 g, 94%) as an off-white solid. Melting point: 113-115 oC.

-Example 9 Synthesis of (3 1 -[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro- 3-pyridinyl} amino)carbonyl]amino }-3-(4-methylphenyl)propanoic acid.

Step One: Compound 33 (prepared from compound 28 according to procedures described in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 mL) and water (0.7 mL) and treated with K 3

PO

4 (0.39 g, 1.86 mmol) and phenyl boronic acid (0.113 g, 0.93 mmol). The resulting mixture was deoxygenated (switching between vacuum and nitrogen 5 times), then tetrakis(triphenylphosine)palladium(0) (8.7 mg, 0.050 mmol) was added. The mixture was deoxygenated as before and heated at 90 OC overnight. The mixture was cooled, diluted with water and extracted with ethyl acetate (2 times). The combined extracts were washed with brine, dried over MgSO 4 and filtered through silica gel and concentrated under reduced pressure. The residue was suspended in 1:1 water:concentrated HCI (2 mL) and acetonitrile (0.5 mL). The suspension was brought to reflux for 1 hour, then cooled, and partitioned between ethyl acetate and saturated aqueous NaHCO 3 The ethyl acetate layer was washed with brine, dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO 2 3:1 hexanes/ethyl acetate) to give compound 34 (0.115 g, 94%).

This material was used without purification.

1-[(2-Chlorophenyl)methyl]-2-oxo-4-phenyl- 1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from S 15 Compound 34 according procedures described in Example 1. 'H NMR (400 MHz, CD30D): 5 2.25 3H), 2.50 2H), 4.89 J 5.9 Hz, 1H), 5.34 2H), 6.40 J 7.0Hz, 1H), 7.0 J 8.0 Hz, 2H), 7.10 J 8.0 Hz, 2H), 7.18 1H), 7.28 2H), 7.35 3H), 7.43 1H), 7.49 3H).

Example 20 Synthesis of [2-methyl-4-(2-methylpropyl)-6-oxo- -(phenylmethyl)-1,6carbonyl)amino]-3-(4-methylphenyl)propanoic acid (43).

Step One: Compound 35 (2.00 g 18.2 mmol) was dissolved in 30 mL of dry methanol. To this was added benzylamine (1.97 g 18.2 mmol) and triethylamine (2.0 g 20.0 mmol). The reaction mixture was stirred at 50 oC for 3 hours, and then concentrated under reduced pressure. The residue was partitioned between HO 2 and CH 2

CI

2 The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 36 (2.3 g, 82%).

Step Two: To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol (10 mL) and pyridine (5 mL) was added isovaleraldehyde (2.8 mL 27 mmol) and piperidine (1 mL). The reaction mixture was heated to reflux for 3 hours and concentrated under reduced pressure. The residue was partitioned between 2N HCI (15 mL) and ethyl acetate -82mL). The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate to give compound 38 (3.6 g, S67%).

Step Three: A solution of compound 38 (2.5 g, 12.48 mmol) and compound 36 (2.52 g, 13.7 mmol) in dry methanol (25 mL) was heated to vigorous reflux for 3 hours, cooled and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 2:1 hexanes:ethylacetate to give compound 39 (2.75 g, 69%).

Step Four: To a solution of compound 39 (2.5 g, 7.9 mmol) in CCl4 (15 mL) was added NBS (1.4 g, 8.0 mmoL), K 2

CO

3 (11.0 g, 80.0 mmol), and benzoyl peroxide (50 mg, 0.20 mmol). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature, diluted with H 2 0 and extracted with CH 2 C1 2 The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3:1 hexanes:ethyl acetate to give compound 40 (0.62 g, Step Five: Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH and THF (3 mL). The resulting mixture was stirred at room temperature for 2 hours, acidified with 2N HCI and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give S 20 compound 41 (560 mg, 98%).

Step Six: To a solution of compound 41 (0.56 g, 1.86 mmol) in dry benzene mL), diphenylphosphorylazide (0.56 g, 2.0 mmol) and triethylamine (2.02 g, 2.0 mmol) were added. The reaction mixture was heated to 90 OC for 1 hour then a solution of compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was stirred at 90 °C for an additional 1 hour, cooled to room temperature, diluted with 10% aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 7:3 ethyl acetate:hexane to give compound 42 (0.38 g, Step Seven: To a solution of compound 42 (0.35 g 0.7 mmol) in 1:1 mixture of THF:MeOH (8 mL) was added 2N NaOH (8 mL). The reaction was stirred at room temperature for 3 hours, acidified with 2N HCI (10 mL) and extracted with ethyl acetate mL). The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6oxo- -(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4methylphenyl)propanoic acid (43, 250 mg, MS: Calculated: (M+H) 477.25 m/z; Found: (M+H) 477.17 m/z.

Example 11 Synthesis of {[2-methyl-6-oxo- 1-(phenylmethyl)- 1,6-dihydro-5pyrimidinyl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid Step One: A solution of compound 36 (2.3 g 15.5 mmol) and compound 44 (3.36 g, 15.5 mmol) in absolute ethanol (35 mL) was refluxed for 3 hours and concentrated.

The residue was chromatographed on silica gel, eluting with 1:1 ethyl acetate:hexane to give compound 45 (1.87 g, 55% yield).

S" {[2-Methyl-6-oxo-1 -(phenylmethyl)- 1,6-dihydro-5pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from compound 45 according to procedures described in Example 10. 'H NMR (400 MHz, CD30D) 8 2.28 3H), 2.35 3H), 2.57 2H), 5.16 1H), 5.30 2H), 7.13 4H), 7.30 5H), 8.50 1H).

Example 12 20 Synthesis of {[({-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino) carbonyl]amino} carbonyl)amino]-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid.

Step One: To a solution of compound 46 (prepared according to procedures described in Example 3, 0.50 g, 1.8 mmol) in THF (10 mL) at 0 OC was added NaH dispersion in mineral oil, 0.23 g, 5.1 mmol). The mixture was stirred for 10 minutes at 0 then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at room temperature over the weekend, was quenched with 1 N HCI and extracted with ethyl acetate. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 47 (0.60 This material was used without purification.

-[(2-Chlorophenyl)methyl]-4-[( {ethyl[(ethylamino)carbonyl] -84amino carbonyl)amino]-2-oxo- 1,2-dihydro-3-pyridinyl amino)carbonyl]amino}-3-(4methylphenyl)propanoic acid was prepared from compound 47 according to procedures described in Example 3. Melting point: 128-130 OC.

Example 13 Synthesis of 1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2dihydro-3-quinolinyl}amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid.

Step One: To a solution of compound 48 (2.00 g, 9.70 mmol) in anhydrous DMF mL) at 0 °C was added NaH (60% dispersion in mineral oil, 0.89 g, 22 mmol). The mixture was stirred at 0 OC for 15 minutes before the addition of 2-chlorobenzylchloride (2.03 g, 12.6 mmol). After stirring at 55 °C overnight, the mixture was poured into icewater and washed with Et20 (twice). The aqueous layer was acidified and filtration of the *o.

resulting precipitate gave compound 49 (3.45 This material was used without purification.

(3S)-3 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2-dihydro-3- 15 quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from compound 49 according to procedures described in Example 8. Melting point: 134-136

OC

Example 14 Synthesis of (3 {1 -[(2-chlorophenyl)methyl]-5-methyl-2-oxo- 1,2-dihydro- 20 3-pyridinyl} amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (56).

Step One: To a suspension of compound 51 (1.67 g, 9.81 mmol) in DMF (33 mL) at room temperature under a dry, nitrogen atmosphere, 2-chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCI (2.35 g, 12.3 mmol) were added sequentially. The resulting mixture was vigorously stirred at room temperature for 5 hours, diluted with ethyl acetate and washed with 2 N HC1, H 2 0 (3 times), saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 52 (2.55 g, 100%) as a pale yellow solid.

Step Two: A solution of compound 52 (555 mg, 2.17 mmol) and 3dimethylamino-2-methylpropenal (738 mg, 6.5 mmol) in absolute ethanol (4.3 mL) and glacial acetic acid (0.22 mL) was heated to reflux overnight. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with 2 N HCI (twice),

H

2 0 and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure.. The pressure was purified by chromatography on silica gel, eluting with 7:3 increasing to 1:1 hexanes:ethyl acetate and finally 19:19:2 hexanes:ethyl acetate:methanol to yield compound 53 (182 mg, 27%) as a yellow oil.

Step Three: To a solution of compound 53 (167 mg, 0.55 mmol) in THF (3 mL), 2 N NaOH (1 mL) and methanol (2 mL) were added. The resulting mixture was stirred for minutes, diluted with H 2 0 and extracted with ethyl ether. The aqueous layer was acidified with 2 N HCI and extracted with ethyl acetate. The ethyl acetate layer was washed with H 2 0 and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give compound 54 (139 mg, 91%) as a white solid.

Step Four: To a suspension of compound 54 (175 mg, 0.63 mmol) in THF (6.7 mL) and DIPEA (0.23 mL, 1.34 mmol) at room temperature under a dry, nitrogen atmosphere, DPPA (0.29 mL, 1.34 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 15 minutes, then heated to reflux for 3.5 hours. The mixture was allowed to cool to room temperature and a solution of compound 8 (278 mg, 1.34 mmol) in THF (6.0 mL) was added via cannula along with a THF (0.7 mL) rinse.

The resulting mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with 2 N HCI (twice), saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under S 20 reduced pressure. The residue was purified by silica gel chromatography, eluting with 7:3 .then 3:2 and finally 1:1 hexanes:ethyl acetate to yield compound 55 (60 mg, 20%) as a <e e colorless oil.

Step Five: To a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 mL), 0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL) were added. The resulting mixture was stirred at room temperature for 24 hours, then was diluted with H 2 0. The organic solvents were removed under reduced pressure and the resulting aqueous mixture was extracted with ethyl ether. The aqueous phase was lyophilized to give 1- [(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, sodium salt (56, 56 mg, 95%) as an off-white solid. MS: Calculated for (C 24

H

23 C1N 3 0 4 452.14 m/z; Found: 451.99 m/z.

Example Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2-thienylmethyl)-1,2dihydro-3-pyridinyl]amino} carbonyl)amino]propanoic acid (62).

Step One: To a solution of 2-thiophenemethanol (1.015 g, 8.89 mmol) in CH 2 C2 (17.8 ml) cooled to 0°C under a dry nitrogen atmosphere, triethylamine (2.98 ml, 21.4 mmol) and methanesulfonyl chloride (0.69 ml, 8.9 mmol) were added sequentially by syringe. The resulting mixture was stirred at 0°C for 15 minutes, then 2-hydroxy-3nitropyridine (1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalytic) were added.

The mixture was allowed to gradually warm to room temperature and then was stirred overnight. The mixture was diluted with ethyl acetate and washed with 2N HCI, H 2 0, saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 58 (395 mg) as a yellow waxy solid. This material was used without purification.

Step Two: To a solution of 58 (330 mg, 1.40 mmol) in glacial acetic acid (6.6 ml) at room temperature under a dry nitrogen atmosphere, iron powder (154 mg, 2.8 mmol, -325 mesh) was added. The resulting solution was heated to 60 0 C in an oil bath with vigorous stirring for 20 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with H 2 0, S* saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 1:1 hexanes:ethyl acetate increasing to 1:3 hexanes:ethyl acetate to yield 59 (188 mg, 12% for two steps) as a greenish solid.

Step Three: To a solution of 59 (111 mg, 0.54 mmol) in CH 2 C2 (2.7 ml) cooled to 0°C under a dry nitrogen atmosphere, N,N-diisopropylethylamine (0.23 ml, 1.30 mmol) and phosgene (0.31 ml, 1.9M in toluene, 0.59 mmol) were added sequentially by syringe.

The resulting mixture was stirred at 0 C for 15 minutes, then a solution of p-amino ester (167 mg, 0.70 mmol) in CH 2 C2 (2.7 ml) was added by cannula along with a CH 2 C1 2 rinse (1.0 ml). The resulting mixture was allowed to warm to room temperature, was stirred for 2 hours, was diluted with ethyl acetate and washed with 2N HC1, H 2 0, saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate to yield 61 (231 mg, 91%) as a purple foam.

Step Four: To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml) at room temperature, NaOH (2 ml, 2N in H 2 0, 4 mmol) and methanol (enough to give a clear solution, approximately 2 ml) were added. The resulting mixture was stirred for minutes, then was diluted with water and extracted with ether. The aqueous phase was acidified with HCI (2N) and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 62 (191 mg, 90%) as a white solid. 'H NMR (400 MHz, CD 3

SOCD

3 6 2.63 J 7.3 Hz, 2H), 4.99 (dt, J 8.4, 7.3 Hz, 1H), 5.30 2H), 5.98 2H), 6.21 (dd, J 7.5, 7.0 Hz, 1H), 6.78 (dd, J 8.1, 1.6 Hz, 1H), 6.85 J 8.1 Hz, 1H), 6.88 (d, 1.6 Hz, 1H), 6.97 (dd, J 5.1, 3.5 Hz, 1H), 7.17 (dd, J 3.5, 1.1 Hz, 1H), 7.35 (dd, J 7.0, 1.8 Hz, 1H), 7.44 (dd, J 5.1, 1.1 Hz, 1H), 7.67 J 8.4 Hz, 1H), 7.94 (dd, J 7.5, 1.8 Hz, 1H), 8.40 1H).

Example 16 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2thienylmethyl)hexahydro-3-pyridinyl]amino} carbonyl)amino]propanoic acid (68).

Step One: To a solution of N-a-tert-butoxycarbonyl-N-6-benzyloxycarbonyl-L- 20 omithine 63 (1.00 g, 2.73 mmol) and cesium carbonate (1.33 g, 4.1 mmol) in DMF Sml) at room temperature under a dry nitrogen atmosphere, iodomethane (0.22 ml, 3.3 mmol) was added by syringe. The resulting mixture was stirred at room temperature for 18 hours then was diluted with ethyl acetate and washed with H 2 0, 10% Na 2

S

2 0 5 saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give ester 64 (1.21 g) as a pale yellow oil. This material contained DMF but was used without purification.

Step Two: To a solution of 64 (0.86 g of crude material prepared in previous procedure, 1.94 mmol theoretical) in methanol (10 ml) at 0°C under a dry nitrogen atmosphere, palladium on charcoal (300 mg, 10% Pd, Degussa type E1Q1 NE/W, wet, 50% water by weight) was added. The nitrogen atmosphere was replaced by hydrogen (alternate five times between vacuum and hydrogen supplied by balloon) and the mixture -88was stirred at 0°C for 30 minutes then filtered directly into a flask containing 2thiophenecarboxaldehyde (177 mg, 1.58 mmol). The mixture was concentrated (water bath at room temperature) and the residue was taken up in dichloroethane (6 ml). To this solution, sodium triacetoxyborohydride (479 mg, 2.26 mmol) was added and the mixture was stirred for 2 hours, diluted with ethyl acetate and washed with saturated NaHCO 3 (2 times) and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 7:3 hexanes:ethyl acetate to yield lactam 65 (75 mg, 12% for two steps) as a colorless oil: Step Three: To a flask containing 65 (89 mg, 0.29 mmol) sealed with a rubber septum at room temperature under a dry nitrogen atmosphere, HC1 (7.2 ml, 4.0M in dioxane, 28.8 mmol) was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred overnight. The mixture was diluted with CH 2 C2 and washed with saturated NaHCO 3 The organic phase was dried over MgSO 4 and 15 filtered and the filtrate was concentrated under reduced pressure to give amine 66 mg, 100%) as a light yellow oil. This material was used without purification.

Step Four: To a solution of P-amino ester 60 (75 mg, 0.32 mmol) in CH 2 C2 (0.6 ml) at room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (51 mg, 0.32 mmol) was added. The resulting mixture was stirred at room temperature for 20 minutes and a solution of amine 66 (60 mg, 0.29 mmol) in CH 2 C1 2 (0.6 ml) was added by cannula along with a CH 2 Cl 2 (0.2 ml) rinse. The resulting mixture was stirred at room temperature for 3 days, then was diluted with ethyl acetate. and washed with 2N HCI (2 times), H 2 0, saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 1:1 hexanes:ethyl acetate increasing to 2:3 hexanes:ethyl acetate to yield urea 67 (110 mg, Step Five: To a solution of urea 67 (108 mg, 0.23 mmol) in THF (3 ml) at room temperature, NaOH (1 ml, 2N in H 2 0, 2 mmol) and methanol (enough to give a clear solution, approximately 2 ml) were added. The resulting mixture was stirred for minutes, then was diluted with water and extracted with ether. The aqueous phase was acidified with HCI (2N) and extracted with ethyl acetate. The ethyl acetate layer was -89washed with brine, dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 68 (92 mg, 90%) as a white foam. 'H NMR (400 MHz,

CD

3

SOCD

3 5 1.45 1H), 1.76 2H), 2.62 2H), 3.25 (m overlapping H 2 0, 2H), 4.01 1H), 4.59 J 15.0 Hz, 1H), 4.68 J 15.0 Hz, 1H), 4.96 1H), 5.97 (s, 2H), 6.24 J 6.6 Hz, 1H), 6.71 J 8.4 Hz, 1H), 6.75 (dd, J 8.1, 1.5 Hz, 1H), 6.82 J 8.1 Hz, 1H), 6.85 J 1.5 Hz, 1H), 6.97 (dd, J 5.1, 3.3 Hz, 1H), 7.03 (dd, J 3.3, 1.5 Hz, 1H), 7.42 (dd, J 5.1, 1.5 Hz, 1H), 12.06 (br. s, 1H).

Example 17 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-l-(2thienylmethyl)tetrahydro- H-pyrrol-3-yl]amino}carbonyl)amino]propanoic acid (74).

Step One: To a solution of N-tert-butoxycarbonyl-L-aspartic acid a-benzylester (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to -15 0 C (bath temperature) under a dry nitrogen atmosphere, 4-methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl chloroformate (0.84 ml, 6.5 mmol) were added sequentially by syringe. The resulting mixture was stirred for 2 minutes, then was filtered, washing the solid cake with dimethoxyethane (10 ml). The filtrate was recooled to -15 0 C (bath temperature) and a solution of sodium borohydride (370 mg, 9.7 mmol) in H 2 0 (3 ml) was added followed immediately by the addition of H 2 0 (100 ml). The mixture was extracted with ethyl acetate (3 times) and the organic layers were combined and washed with cold HCI

H

2 0, saturated NaHCO 3 and brine. The resulting organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 69 (2.50 g) as a colorless oil. This material contains some of the unreduced mixedanhydride but was used without purification.

Step Two: To a solution of oxalyl chloride (2.4 ml, 2.0 M in CH 2 C12, 4.8 mmol) in

CH

2 C2 (30 ml) cooled to -65 0 C under a dry nitrogen atmosphere, a solution of methylsulfoxide (0.55 ml, 7.8 mmol) in CH 2 C2 (8 ml) was added by syringe. The resulting mixture was stirred at -65 0 C for 15 minutes, then a solution of alcohol 69 (1.00 g, 3.2 mmol) in CH 2 C2 (29 ml) was added by cannula along with a CH 2 C12 (3 ml) rinse. The mixture was stirred at -65 0 C for 3 hours, then was allowed to warm to -20 0

C

(bath temperature). Triethylamine (0.96 ml, 6.9 mmol) was added, followed by H 2 0 ml). The aqueous layer was extracted with CH 2 C1 2 and the combined organic phases were dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give aldehyde 70 as a white solid. This material was used immediately without purification.

Step Three: To a solution of the crude aldehyde 70 (3.2 mmol theoretical) and 2aminomethylthiophene (402 mg, 3.55 mmol) in dichloroethane (13 ml) at room temperature under a dry nitrogen atmosphere, sodium triacetoxyborohydride (959 mg, mmol) was added. The resulting mixture was stirred at room temperature overnight, then was diluted with ethyl acetate and washed with saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate to yield lactam 71 (220 mg, 23% for 3 steps) as a white solid.

Step Four: To a solution of 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a rubber septum at room temperature under a dry nitrogen atmosphere, HCI (1.50 ml, 4.0M in 15 dioxane, 6.0 mmol) was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred for 5 hours. The mixture was diluted with CH 2 C12 and washed with saturated NaHCO 3 The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated.under reduced pressure to give amine 72 (129 mg, 89%) as a light yellow oil. This material was used without purification.

20 Step Five: To a solution of amine 72 (123 mg, 0.63 mmol) in CH 2 C2 (1.5 ml) at room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (112 mg, 0.69 mmol) was added. The resulting mixture was stirred at room temperature for 5 minutes and a solution of p-amino ester 60 (164 mg, 0.69 mmol) in CH 2 C1 2 (0.8 ml) was added-by cannula along with a CH 2 Cl2 (0.2 ml) rinse. The resulting mixture was stirred at room temperature overnight, then was diluted with ethyl acetate and washed with 2N HCI (2 times), HzO, saturated NaHCO 3 and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, eluting with 49:1 chloroform:methanol to yield urea 73 (230 mg, as a colorless oil which slowly solidified on standing.

Step Six: To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) at room temperature, NaOH (1 ml, 2N in H 2 0, 2 mmol) and methanol (1 ml) were added. The resulting mixture was stirred for 1 hour, then was diluted with water and extracted with ether. The aqueous phase was acidified with HC1 (2N) and extracted with ethyl acetate.

The ethyl acetate layer was washed with brine, dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 74 (181 mg, 84%) as a white foam. 'H NMR (400 MHz, CD 3

SOCD

3 5 1.64 1H), 2.30 1H), 2.64 2H), 3.20 2H), 4.17 (dd, J 8.8, 8.4 Hz, 1H), 4.56 2H), 4.96 1H), 5.97 2H), 6.30 J 7.0 Hz, 1H), 6.58 J 8.8 Hz, 1H), 6.77 1H), 6.80-6.90 2H), 6.96-7.04 2H), 7.45 (dd, J 5.1, 0.7 Hz, 1H), 12.10 (br. s, 1H).

Example 18 Synthesis of (3S)-3-[({[5-chloro-2-hydroxy-3- (phenylmethyl)phenyl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

Step One: To a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9 mmol) in Et20 (20 mL) and 6N HCI (50 mL), KNO 3 (2.30 g, 22.9 mmol) and NaNO 2 (20 mg, catalytic) were added sequentially. The resulting mixture was stirred for 2 hours, diluted S 15 with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 99 (6.0 g, 100%).

Step Two: To a solution of 99 (6.0 g, 22.8 mmol) in methanol (360 mL), zinc powder (6.0 g, 92 mmol) and sEarated aqueous NH 4 CI (6 mL) were added. The resulting 20 heterogeneous mixture was refluxed overnight. After filtration of the hot mixture and concentration of the filtrate under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO 3 and brine. The organic layer was t* dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give compound 100 (2.93 g, Step Three: To a solution of 25 (0.20 g, 0.96 mmol) in CH 2 C2 at 0 OC, DIPEA (0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2 mmol) were added sequentially. The resulting mixture was allowed to warm to room temperature, stirred for minutes, then recooled to 0 To this mixture, a solution of 100 (0.25 g, 1.1 mmol) in CH 2 C1 2 was added dropwise. The resulting mixture was allowed to warm to room temperature overnight, was diluted with water and was extracted with CH 2 C1 2 The organic layer was washed with water and brine, dried over MgSO 4 and filtered. The -92filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 9:1 and increasing to 5:1 hexanes:ethyl acetate to give 101 mg, 12%).

[5-Chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]- 3-(4-methylphenyl)propanoic acid was prepared from 101 by procedures described in Example 1. 'H NMR (400 MHz, CD 3

SO

2

CD

3 5 2.26 3H), 2.58 (dd, J 15.8, 6.6 Hz, 1H), 2.67 (dd, J 15.8, 8.4 Hz, 1H), 3.49 2H), 4.88 1H), 7.00-7.70 13H), 11.95 (br. s, 1H).

Example 19 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1- (phenylmethyl)tetrahydro-1 H-pyrrol-3-yl]amino} carbonyl)amino]propanoic acid.

Step One: A solution of N-benzylmaleimide (2.60 g, 13.9 mmol) and n- *butylamine (1.00 g, 13.7 mmol) in THF (15 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 increasing to 2:1 hexanes:ethyl acetate to give 102 (3.25 g, 1,3-Benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1 -(phenylmethyl)tetrahydro-1 Hpyrrol-3-yl]amino}carbonyl)amino]propanoic acid was prepared from 102 according to procedures described in Example 1. MP: 80-85 °C.

20 Example Synthesis of 1,3-benzodioxol-5-yl)-3-[( -(cyclopentylmethyl)-2-oxo-l ,2dihydro-3-pyridinyl]amino carbonyl)amino]propanoic acid.

Step One: To a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in

CH

2 C1 2 (14 mL) at 0 OC under a nitrogen atmosphere, cyclopentanemethanol (178 mg, 1.78 mmol) was added followed by triphenylphosphine (551 mg, 2.1 mmol). The solution was stirred at 0 oC for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1 mmol) was added dropwise via syringe. The reaction was allowed to stir at 0 °C for one hour and then at room temperature overnight. The mixture was quenched with methanol mL) and washed with water (twice). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel -93chromatography, eluting with 1:1 hexanes:ethyl acetate to afford 103 (299 mg, 96% yield) as a yellow solid.

(3S)-3-(1,3-Benzodioxol-5-yl)-3-[({[1 -(cyclopentylmethyl)-2-oxo-1,2-dihydro-3pyridinyl]amino}carbonyl)amino]propanoic acid was prepared from 103 according to procedures described in Example 1. 'H NMR (400 MHz, CDCl 3 5 1.2-1.7 8H), 2.34 (m, 1H), 2.81 (dd, J 1H), 2.95 (dd, J 1H), 3.92 J 7.7 Hz, 2H), 5.30 1H), 5.92 (m, 2H), 6.30 J 7.1 Hz, 1H), 6.68-7.00 5H), 8.33 J 7.7 Hz, 1H), 8.89 1H).

Example 21 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3- 3-[(2-thiophenylmethyl)amino] phenyl amino)carbonyl]amino}propanoic acid.

Step One: To a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol) in .dichloromethane was added 3-nitroaniline (0.51 g, 3.7 mmol). The solution was concentrated to dryness and brought up in 1,2-dichloroethane (16 mL). Molecular sieves (3A, 1.1 g) were added followed by NaBH(OAc) 3 (1.01 g, 4.8 mmol). The solution was stirred overnight at room temperature, diluted with chloroform and washed with water.

The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 104 (0.72 g, 84%).

Step Two: To a solution of 104 (0.30 g, 1.3 mmol) in CH 2 C2 (5.2 mL) and S0 triethylamine (0.215 mL, 1.5 mmol) at 0 'C was added trifluoroacetic anhydride (0.193 20 mL, 1.4 mmol). The solution was stirred 15 minutes at 0 OC, the ice bath was removed and the mixture was stirred for an additional 15 minutes. The mixture was diluted with

CH

2 C12, washed with 2N HC1, water and brine. The organic layer was dried over Na 2

SO

4 and filtered and the filtrate was concentrated under reduced pressure to give 105 (0.38 g, 100 as a yellow solid.

Step Three: To a solution of 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic acid (2.6 mL) at room temperature, Fe powder (0.36 g, 6.5 mmol) was added and the suspension was stirred vigorously at 40 OC until TLC indicated complete consumption of 105. The mixture was filtered through Celite, washing with chloroform. The filtrate was diltuted with saturated sodium bicarbonate and the chloroform layer was dried over Na 2

SO

4 and filtered. The filtrate was concentrated under reduced pressure and the residue -94was purified by chromatography on silica gel (gradient elution 6:1 to 4:1 hexanes:ethyl acetate) to give compound 106 (0.102 g, (3S)-3-(1,3-Benzodioxol-5-yl)-3- {[({3-[(2-thiophenylmethyl)amino]phenyl} amino)carbonyl]amino}propanoic acid was prepared from 106 according to procedures described in Example 1. 'H NMR (400 MHz, CD 3

SO

2

CD

3 8 2.50 2H overlapping DMSO), 4.37 J 5.9 Hz, 2H), 4.94 1H), 5.94 2H), 6.06 J 5.8 Hz, 1H), 6.16 1H), 6.59 J 8.8 Hz, 1H), 6.78 3H), 6.85 (dd, J 8.8, 7.7 Hz, 1H), 6.90 1H), 6.94 (dd, J 5.2, 3.7 Hz, 1H), 7.00 J 3.3 Hz, 1H), 7.33 (dd, J 5.1, 1.1 Hz, 1H), 8.5 (s, 1H).

Example 22 Synthesis of 3-(1,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-1-(2thiophenylmethyl) 1,2-dihydro-3-pyridinyl]amino} carbonyl)amino]propanoic acid.

Step One: To a solution of (1S,2R,5S)-(+)-menthyl (R)-p-toluenesulfinate (3.00 g,

V**

10.2 mmol) in THF (25.5 mL) chilled to -78 oC, lithium bis(trimethylsilyl)amide (1.0 M in THF, 15.3 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at room temperature for 6 hours, then chilled to 0 Piperonal (3.06 g, 20.4 mmol) and CsF (3.10 g, 20.4 mmol) were added rapidly and the suspension stirred 36 hours at room temperature. The reaction was quenched with saturated NH 4 CI and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 S0 4 and filtered and the S 20 filtrate was concentrated under reduced pressure. The residue was recrystallized from hexanes and dichloromethane to give compound 108.(1.36 g, 46 Step Two: Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a suspension of Zn dust (2.00 g, 30.5 mmol) in THF (20.2 mL). and refluxed for 15 minutes.

The suspension was chilled to 0 C and 108 (0.87 g, 3.0 mmol) was added. The suspension was allowed to warm to room temperature and stirred overnight. The mixture was quenched with a minimum amount of saturated NH 4 CI and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 S0 4 and filtered.

The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (gradient elution 6:1 to 4:1 hexanes:ethyl acetate to give 109 (0.607 g, 61% at 80% conversion).

Step Three: To a solution of 109 (0.700 g, 1.70 mmol) in methanol (4.3 mL) at 0 trifluoroacetic acid (0.26 mL 3.4 mmol) was added. The solution was stirred at 0 °C for 2 hours, then concentrated to dryness under reduced pressure, while maintaining the external temperature below 30 The residue was taken up in diethyl ether and washed with 2N HC1 (2 times). The combined aqueous layers were carefully basified with excess saturated NaHCO 3 and extracted with diethyl ether. The ether layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 110 (0.326 g, 80 3-(1,3-Benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-l-(2-thiophenylmethyl)-1,2dihydro-3-pyridinyl]amino}carbonyl)amino]propanoic acid was prepared from 110 according to procedures described in Example 1. MS: Calculated 476.07; Found 476.00.

Example 23 .oo. Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-( [9-oxo-8-(phenylmethyl)- 2,3,4,5,8,9-hexahydro-1 H-pyrido[3,4-b]azepin-1 -yl]carbonyl} amino)propanoic acid.

Step One: To a solution of 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA (1.60 mL, 10.8 mmol) at -20 n-butyllithium (1.6 M in hexanes, 3.4 mL, 5.4 mmol) and tert-butyllithium (1.7M in pentane, 2.5 mL, 4.3 mmol) were sequentially added dropwise by syringe. The temperature was allowed to warm to between -10 and 0 °C and maintained there for 2 hours. To the resulting mixture, 1,4-dibromobutane (1.75 mL, 14.7 mmol) was added rapidly and the solution was allowed to warm to room temperature and stirred for 4 days. The reaction was quenched with water and extracted with CHC1 3 (3 times). The combined extracts were washed with brine, dried over NaSO 4 and filtered.

The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with 4:1 hexanes:ethyl acetate to give 111 (0.41g, 44%).

(3S)-3-(1,3-Benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9hexahydro- 1H-pyrido[3,4-b]azepin- 1-yl]carbonyl} amino)propanoic acid was prepared from 111 according to the procedures described in Example 4. MS: Calculated 488.18; Found 488.21.

Example 24 Synthesis of {1 -[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3pyridinyl} amino)carbonyl]amino} -3-(4-hydroxyphenyl)propanoic acid.

Step One: To a solution of 112 (prepared according to procedures described in Example 15, 0.19 g, 0.39 mmol) in CH 2 C1 2 at 0 °C under nitrogen, BBr 3 (1.0 M in

CH

2 Cl 2 1.2 mL, 1.2 mmol) was added by syringe. The mixture was allowed to gradually warm to room temperature and then stirred overnight. The mixture was diluted with water and stirred for 30 minutes and further diluted with saturated aqueous NaHCO 3 The organic layer was washed with water and the aqueous layers were combined and acidified with 2N HC1 and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over MgSO4 and filtered and the filtrate was concentrated under 0* reduced pressure to yield 1-[(2-chlorophenyl)methyl]-2-oxo-l,2-dihydro-3pyridinyl} amino)carbonyl]amino -3-(4-hydroxyphenyl)propanoic acid (113, 120 mg, 'H NMR (400 MHz, CD 3

SO

2

CD

3 6 2.95 J 5.2 Hz, 2H), 5.28 2H), 5.35 (ddd, J 9.2, 4.8, 4.4 Hz, 1H), 6.33 J 7.1 Hz, 1H), 6.60 J 8.8 Hz, 2H), 7.04 (m, 5H), 7.22 3H), 7.37 (dd, J 7.7, 1.5 Hz, 1H), 8.35 (dd, J 7.6, 1.5 Hz, 1H), 8.80 (s, 1H).

Example Synthesis of -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2dihydropyridin-3-yl]amino carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 119.

Step One: To a suspension of sodium hydride (3.6 g of 60% dispersion in mineral oil, mmol) in THF (300 mL) under a dry nitrogen atmosphere, TMEDA (13.2 mL, 87.5 mmol) was added and the mixture was cooled to -20 OC. Methyl propionylacetate (9.60 mL, 76.5 mmol) was added dropwise and the solution was stirred for an additional 15 minutes. A solution of n-butyllithium (90 mL, 1.6M in hexanes, 144 mmol) was added dropwise and the resulting mixture was stirred at -20 OC for 15 minutes. Methyl formate mL, 97 mmol) was then added rapidly and the mixture was allowed to stir for 15 minutes before quenching with HCI (2 N, 250 mL). The reaction was diluted with diethyl ether (150 mL) and the organic layer was washed twice more with water. The aqueous layers were combined and sodium chloride was added until saturated. This mixture was extracted with ethyl acetate (3 times). The original ether layer was washed with saturated sodium bicarbonate solution and water. The combined aqueous washes were acidified with excess HCI (2 saturated with sodium chloride and extracted with ethyl acetate (3 times). All of the ethyl acetate extracts were combined and dried over MgSO 4 The resulting mixture was vacuum filtered through coarse silica gel and the filtrate was concentrated under reduced pressure to give 114 (8.27g, 68%) as a light yellow oil. This material was used without further purification.

Step Two: To a solution of 114 (3.95g, 25.0 mmol) in anhydrous methanol (225mL) at room temperature, a solution of 2-chlorobenzylamine (4.2 g, 30 mmol) in anhydrous methanol (25 mL) was added dropwise from an addition funnel. The solution was heated at 45 OC overnight then refluxed for two hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was brought up in dichloromethane and filtered. The solid was collected and dried under vacuum to give 115 2.20 g 35%) as a light 15 yellow solid.

Step Three: To a suspension of 115 (840 mg, 3.4 mmol) in glacial acetic acid (11 mL) at room temperature, NaNO 2 (46 mg, 0.67 mmol), water (0.92 mL) and HNO 3 0.85 mL, 13.4 mmol) were added sequentially. The resulting bright yellow solution was stirred at room temperature overnight, then was diluted with CH 2 C2 and water. The aqueous phase 20 was extracted with CH 2 C1 2 the organic layers were combined and washed with water (3 times) and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 116 (910 mg, 92%) as a bright yellow solid.

This material was used without purification.

Step Four: To a solution of 116 (910 mg, 3.1 mmol) in DMF (10 .3 mL) at room temperature under a dry nitrogen atmosphere, Zn powder (909 mg, 13.9 mmol) and triethylamine hydrochloride (2340 mg, 17.0 mmol) were added. The resulting mixture was heated to 55 °C for 2 hours, then was cooled to room temperature. To the resulting mixture, CDI (1002 mg, 6.18 mmol) was added as a solid. Upon addition, gas evolution occurred.

The mixture was then heated to 80 °C for 1 hour, cooled to room temperature, and diluted with CH 2 C12 and HCI (2 The aqueous phase was extracted with CH 2

C

2 the organic layers were combined and washed with water (4 times) and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 117 (920 mg) as a yellow solid. This material contained a small amount of DMF and was used without purification.

Step ive: A suspension of 117 (920 mg crude material, 3. i mmol tneortical) and 8 (800 mg, 3.86 mmol) in 21 ml THF under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. fhe resulting mixture was washed twice with HCI (2N) and brine and the organic layer was dried over 4gSO 4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethy! acetate to give 118 (1098 mg, 71% for two steps) as a pale yellow foam.

S 15 Step Six: To a solution of 118 (1091 mg. .19 mmol) in THF (18 mL) a; room temperature, sodium hydroxide (2 N, 6 and methanol (12 mL) were added. The mixture was stirred fo: 20 minutes, then was diluted with water and extracted with ethyl ether. The queous phase was acidified with HCI (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give -(2-chlorobenzyl)-4-hydroxy..5methyl-2-oxo- I ,2-dihydropyridin-3 -yl]amino carbonyl)amino]-3-( 4 -mcthylph.enyl)propanoic acid, 119, (1045 mg, quantitative) as a white foam MS: Calculated 468.13 m/z; Found 467.99 m/z.

Example 26 Synthesis (3S)-3-[({[4-hydroxy-2-cxo-l -(pyridin-2-ylmethy!)- 1,2-dihydropyridin- 3-yi]amino}carbony)amino]-3-(4-methyiphenyl)propanoic acid.

Step One: To a solution of 23 (0.50 g, 3.2 mmol) in DMSO (12.5 mi) at room temperature, powdered KOH (0.89g, 16 mmol) was added and the mixture was stirred for hours. To the resulting mixture, 2-picolylchloride hydrochloride (0.63g, 3.8 mmol) was added as a solid and the mixture was stirred overnight. At this point, triethylamine hydrochloride (3.52 g, 25.6 mmol) and DMF (5 mL) were added followed by zinc powder (1.04 g, 16.0 mmol). The mixture was heated to 80 °C for 2 hours then cooled to room temperature. To this mixture, CDI (1.00 g, 6.2 mmol) was added and the resulting mixture was heated to °C overnight. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO 3 The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel, eluting with 9:1 10 CHCl 3 :CH30H to give 120 (0.14 g, 18%).

(3S)-3-[({[4-Hydroxy-2-oxo-1 -(pyridin-2-ylmethyl)-1,2-dihydropyridin-3yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 120 according to procedures described in Example 25. MS: Calculated 421.15 m/z; Found 421.06 m/z.

15 Example 27 Synthesis of 1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2dihydropyridin-3-yl amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid.

Step One: To a solution of 121 (prepared from 23 according to procedures described in Example 4, 220 mg, 0.67 mmol) in anhydrous CH 2 C2 (14 mL) cooled to 0 °C under a dry, nitrogen atmosphere, m-CPBA (610 mg, 3.6 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was diluted with water (50 ml) and the aqueous phase was extracted with CH 2 C12 (2 times). The combined organic layers were dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1

CHCI

3 :MeOH to give 122 (219 mg, 91% yield) as a yellow solid.

1 -[2-Chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl amino)carbonyl]amino -3-(4-methylphenyl)propanoic acid was prepared -100from 122 according to procedures described in Example 25. MS: Calculated 532.10 m/z; Found 531.94 m/z.

Example 28 Synthesis of [1 -(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino carbonyl)amino]-3-(3-methylphenyl)propanoic acid.

Step One: To a solution of the 123 (70 mg, 0.13 mmol) in anhydrous CH 2 C2 (3 mL), stirring under a nitrogen atmosphere, ZnBr 2 (200 mg, 0.82 mmol) was added. The solution was stirred at 0 OC for one hour. The reaction mixture was allowed to warm to room temperature and was stirred overnight. At this point, water (50 ml) was added and the 10 mixture was stirred for an additional three hours. The layers were separated and the aqueous layer was extracted with CH 2 C2 (2 times). The combined organic layers were dried over

S..

MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give (3S)-3- -(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid, 124 (60 mg, 95% yield). MS: 15 Calculated 484.13 m/z; Found 484.00 m/z.

S• Example 29 Synthesis of [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

Step One: A mixture of malonyl dichloride (25.0 g, 177 mmol) and valeronitrile (25.0 S* s g, 300.7 mmol) under an anhydrous atmosphere was vigorously stirred at room temperature for 24 hours. Diethyl ether (50 mL) was added to the resulting heterogeneous mixture. The precipitate was collected and washed with diethyl ether to give 125-HCI as a white solid (20.2 g, 64%).

Step Two: To a suspension of 125-HC1 (6.10 g, 27.2 mmol) in EtOH (100 mL), triethylamine (5.8 g, 57.3 mmol) and palladium on carbon (10 Pd dry weight basis, Degussa type El01 NE/W, -50% water content, 3.5 g, 1.6 mmol Pd) were added. The atmosphere was replaced with hydrogen (toggle between vacuum and hydrogen from a -101balloon five times) and the mixture was stirred overnight, then filtered. The filtrate was concentrated under reduced pressure to give 126-2Et 3 NHCI (11.0 g, This material was used without further purification.

1 -(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl- 1,2-dihydropyridin-3yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 126.2Et 3 NHC1 according to procedures described in Example 25. MS: Calculated 496.16 m/z; Found 495.94 m/z.

Example .Synthesis of (3 [1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- 10 cyclopenta[b]pyridin-3-yl]amino} carbonyl)atino]-3-(4-methylphenyl)propanoic acid.

Step One: To a solution of ethyl 2-oxocyclopentanecarboxylate (3.30 g, 21.1 mmol) in toluene (45 ml), 4-chlorobenzylamine (2.56 mL, 21.1 mmol) was added. The resulting mixture was refluxed overnight with azeotropic removal of water via a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to give 127 (5.90 g, 99%) as a red oil. This material was used without purification.

Step Two: To a solution of 127 (11.0 g, 39.3 mmol) in anhydrous THF (75 mL) cooled to 0 °C under a dry, nitrogen atmosphere, NaH (60% dispersion in mineral oil, 1.73 g, 43.2 mmol) was added. The reaction was stirred for 10 minutes at 0 oC, then acetyl chloride (3.9 mL, 55 mmol) was added. The reaction mixture was allowed io gradually warm to room temperature, then was stirred overnight. The resulting mixture was concentrated under reduced pressure and a mixture of ice water (200 mL) and HCI (1 N, 200 mL) was added to the residue. This mixture was extracted with ethyl acetate (300 mL) and the ethyl acetate layer was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 128 (13.4 g) as a brown oil. This material contained mineral oil but was used without purification.

Step Three: To a solution of crude 128 (13.4 g, 39.3 mmol theoretical) in anhydrous THF (50 ml) cooled to 0 OC under a dry, nitrogen atmosphere, lithium -102bis(trimethylsilyl)amide (1.0 M in THF, 125 mL, 125 mmol) was added slowly via syringe.

The reaction mixture was allowed to warm to room temperature, then was stirred overnight.

The mixture was concentrated under reduced pressure and the residue was triturated with ethyl acetate/hexane and filtered. The solid was washed with HCI (1 N, 250 ml) and water (500 ml) to give 129 (5.48g, 48% for two steps) as a brown solid.

-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesized from 129 according to procedures described in Example 25. MS: Calculated 496.16 m/z; Found 495.99 m/z.

10 Example 31 0*00. Synthesis of {[(tert-butylamino)carbonyl]amino} -1-(2-chlorobenzyl)-2- *0 oxo- 1,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

SStep One: To a solution of 46 (500 mg, 1.79 mmol) in anhydrous THF (10 mL) cooled to 0 OC under a dry nitrogen atmosphere, NaH (60% dispersion in mineral oil, 210 mg, 5.37 15 mmol) was added and the resulting mixture was stirred for 20 minutes. To this mixture, tertbutyl isocyanate (0.31 mL, 2.68 mmol) was added and the reaction mixture was allowed to Swarm to room temperature, then was stirred for 2 days. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 130 "00 20 (660 mg, 97%) as a brown solid.

[(tert-butylamino)carbonyl]amino} -1 -(2-chlorobenzyl)-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 130 according to procedures described in Example 3. MS: Calculated 552.20 m/z; Found 551.89 m/z.

Synthetic procedures similar to those described above may be utilized to obtain the compounds of Tables 2, 3, 4 and -103- Example 32 Synthesis of {[5-chloro-1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

Step One: To a solution of 31 (350 mg, 0.72 mmol) in CH2C2 at room temperature under a dry nitrogen atmosphere, sulfurylchloride (1.0 M in CH 2

CI

2 0.65 mL, 0.65 mmol) was added by syringe. The resulting mixture was stirred at room temperature for 1 hour, then was partitioned between CH 2 C2 and water. The organic layer was washed with brine and dried over MgSO 4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 8:1, then 4:1 and finally 1:1 hexanes:ethyl acetate to give 131 (240 mg, 64%).

[5-Chloro-l -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesized from 131 according to procedures described in Example 1. MS: Calculated 488.08; Found 487.97.

15 Example 33 Synthesis of 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy- 1,1 '-biphenyl-4-yl)propanoic acid.

Step One: To a solution of (R)-(+)-N-benzyl-a-methylbenzyl amine (5.07 g, 24 mmol) 20 in THF (85 mL) under nitrogen in a flame-dried flask, cooled to -78 sec-butyllithium (1.3 M solution in cyclohexane, 18.0 mL, 23.4 mmol) was added dropwise over a 30 minute period. The mixture was stirred an additional 30 minutes at-78 then a solution of t-butyl 4-bromocinnamate (5.1 g, 20 mmol) in THF (20 mL) was added dropwise and the mixture was allowed to come to room temperature overnight. The reaction was quenched by addition of saturated ammonium chloride (-50 mL) and the organic layer was washed with saturated sodium chloride, dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexanes and increasing to 3:1 hexanes:ethyl acetate to give 132 (4.33 g, 47%) as a pale yellow oil.

Step Two: To a solution of 132 (7.4 g, 15 mmol) and 2,6-dimethoxyphenyl boronic acid (4.9 g, 27 mmol) in DME (100 mL) at room temperature under a dry, nitrogen -104atmosphere, finely-powdered potassium phosphate (8.0 g, 37.5 mM) and dichlorobis(triphenylphosphine)palladium (0.5 g, 0.75 mmol) were added. The mixture was deoxygenated (toggle between vacuum and nitrogen gas 5 times) and then heated to reflux for 8 hours. The mixture was then cooled and filtered through Celite® 521, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes increasing to 3:1 hexanes:ethyl acetate to give 133 (7.8 g, Step Three: To a solution of 133 (3.39 g, 6.1 mmol) in ethanol (80 mL) in a 250 mL flask, acetic acid (0.5 mL) and palladium on carbon (10% Pd dry weight basis, water content Degussa type E101 NE/W, 2.5 g, 1.2 mmol Pd) were added sequentially. The mixture was stirred under a hydrogen atmosphere from a balloon for 36 hours. The reaction mixture was filtered through Celite" 521 and the filtrate was concentrated under reduced pressure.

oThe residue was recrystallized from ethyl acetate to give 134*HOAc (1.0 g, 71%) as a white solid.

15 [-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(2',6'-dimethoxy-1, '-biphenyl-4-yl)propanoic acid was Ssynthesized from 134-HOAc by procedures described in Example 25. MS: Measured 592.04; Calculated 592.19.

Example 34 20 Synthesis of [2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3dihydropyridazin-4-yl]amino} carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid.

Step One: To a solution of sodium t-butoxide (65 g, 0.642 mol) in THF (1 at room %Goe temperature under a dry nitrogen atmosphere, ethanol (250 mL, 5.35 mol) was added over a minute period. To the resulting solution, 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then reduced to a volume of approximately 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water and the layers separated. The organic layer was washed with water (twice) and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to afford a light yellow solid. This material was recrystallized from hexanes to provide the 2-chloro-6-ethoxybenzonitrile, 135, (101 g, 87 yield) as a white crystalline solid.

-105- Step Two: To a solution of 2-chloro-6-ethoxybenzonitrile, 135, (93.2 g, 0.513 mol) in THF (350 mL) at room temperature under a dry nitrogen atmosphere was added borane in THF (1.0 M, 620 mL, 0.62 mol). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. Water (250 mL) was added very slowly to the solution allowing for the evolution of hydrogen. Concentrated HCI (50 mL) was then added over several minutes and the solution was heated to 50 OC for 2 hours. The mixture was cooled and partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions were washed with HCI (1 M) and this organic layer was discarded. Chloroform was added to the combined aqueous layers and solid KOH was added until the aqueous phase was basic (pH The aqueous layer washed with chloroform an additional five times. The organic fractions were combined and washed with water, brine, and dried over MgSO 4 and silica gel (2 This mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylamine, 136, (60.1 g, 64% yield) as a light yellow oil.

Step Three: To a solution of 2-chloro-6-ethoxybenzylamine, 136, (7.30 g, 39.3 mmol) in glacial acetic acid (50 mL) and acetic anhydride (50 mL) at room temperature, sodium nitrite (6.00 g, 85.7 mmol) was added in small portions. The resulting mixture was stirred at room temperature overnight then was poured into ice water and extracted with ethyl acetate.

The organic layer was washed with aqueous NaOH (lN, 2 X 100 mL) and brine (twice). The 20 organic layer was dried over Na 2

SO

4 and filtered and the filtrate was concentrated under reduced pressure to give 137 (9.00 g, 100%) as a light yellow solid.

Step Four: To a solution of 137 (9.00 g, 39.3 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) in THF (50 ml) at room temperature, aqueous NaOH (2N, 50 mL, 100 mmol) was slowly added and the mixture was heated to 45 °C overnight. The reaction mixture was cooled to room temperature, then was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2

SO

4 and filtered and the filtrate was concentrated under reduced pressure to give 138 (7.08 g, 96% yield).

Step Five: To a solution of 138 (7.08 g, 37.9 mmol) in CH 2 C1 2 (55 mL) at room temperature under a dry nitrogen atmosphere, a solution of SOC12 (9.0 mL, 120 mmol) in

CH

2 C1 2 (30 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight, then was poured into ice water. The aqueous layer was extracted with CH2C1 2 and -106the combined organic layers were washed with aqueous NaOH (IN, twice), water (3 times) and brine (twice). The organic layer was dried over Na 2

SO

4 and filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylchloride, 139, (6.69 g, 86% yield) as a viscous, brown oil.

Step Six: A solution of 2-chloro-6-ethoxybenzychloride, 139, (6.90 g, 33.7 mmol) and hydrazine (21.60 g, 673 mmol) in MeOH (22 mL) was stirred at room temperature for 3 hours. The mixture was then partitioned between CH 2 C1 2 and water. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure to give 140 (6.18 g, 92%).

Step Seven: To a suspension of ethyl pyruvate (3.85 mL, 33.7 mmol) and MgSO 4 in CHCl 3 (65 mL), a solution of 140 (6.14 g, 30.6 mmol) in CHC1 3 (30 mL) was slowly added.

The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 141 (8.43 g, 92%).

This material was used in the next step without purification.

15 Step Eight: To a solution of 141 (8.43 g, 28.2 mmol) in dry THF (110 mL)cooled to 0 °C under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 1.88 g, 47.1 mmol) was added in one portion. The resulting mixture was stirred at 0 OC for minutes, then methyl malonylchloride (6.63 g, 47.10 mmol) was slowly added. The mixture was allowed to warm to room temperature, stirred overnight, carefully quenched with water 20 then extracted with ethyl acetate (twice). The organic layers were combined, washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 142 (14.29 This material was used in the next step without further purification.

Step Nine: To a solution of crude 142 (14.29 g) in dry DMF (60 mL) cooled to 0

°C

under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 2.90 g, 72.2 mmol) was added in one portion. This solution was heated to 60 oC overnight, cooled down in an ice bath, then shaken with hexane. The layers were separated and the DMF layer was poured into ice water. The mixture was acidified (pH 1) by adding HCI The precipitate was collected by filtration the dissolved in ethyl acetate. The organic solution was dried over MgSO 4 and filtered and the filtrate was concentrated to give 143 (8.42 g, 85% yield for two steps).

-107- Step Ten: A solution of 143 (8.42 g, 23.9 mmol) in dioxane (100 mL) and aqueous HC1 (60 mL, 5.2 N) was refluxed overnight. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes, then ethyl acetate and finally 9:1 ethyl acetate:methanol to give 144 (2.0 g, 28%).

Synthesis of (3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3dihydropyridazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid was prepared from 144 by procedures provided in Example 25. MS: Measured (M+H) 545.05; Calculated 545.18.

Example Synthesis of -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- Hcyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1 Hbenzimidazol-5-yl)propanoic acid.

15 Step One: An ice-cold mixture of sodium hydride (8.00 g, 60% dispersion in mineral oil, 200 mmol) and 145 (8.94g, 66.6 mmol) in DMF (250 mL) under a dry nitrogen atmosphere was allowed to gradually warm to room temperature. To the resulting mixture, iodoethane (16 ml, 200 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The 20 organic layer was washed with water and brine, dried over Na 2

SO

4 and filtered. The filtrate was concentrated under reduced pressure and the residue was taken up in hexanes and filtered. The resulting brown solid was dried under reduced pressure to give 146 (9.00 g, 71% yield). This material was used without purification.

Step Two: A mixture of DMF (3.6 g, 49 mmol) and POC13 (9.6 mL, 100 mmol) was stirred at room temperature under a dry nitrogen atmosphere for 1 hour. The flask containing this mixture was then placed in a 45 °C oil bath and 146 (7.6 g, 40 mmol) was added in small portions. The oil bath temperature was raised to 70 OC and the mixture was stirred overnight, then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na 2

SO

4 and filtered. The filtrate was concentrated under reduced pressure to give a 7:3 mixture of 147:146 (6.69 This material was used without purification.

-108- Step Three: To a solution of the 147:146 mixture obtained above (2.2 g) in ethanol (2.2 mL), malonic acid (1.16 g, 11.2 mmol), pyridine (0.44 mL) and piperidine (0.99 mL) were added sequentially. The resulting mixture was heated to reflux for 6 hours, then cooled to room temperature. The mixture was diluted with aqueous NaOH (IN) and extracted with ethyl acetate (4 times). The aqueous phase was acidified to pH 3 with HCI (IN) and the resulting suspension was filtered, washing the solid with water. The white solid was collected and dried under reduced pressure to give 148 (1.69 g, 49% for two steps).

{[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lHcyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-lHbenzimidazol-5-yl)propanoic acid was prepared from 148 by procedures described in Examples 33 and 25. MS: Measured 594.05; Calculated (M+H) 594.21.

Example 36 Synthesis of give (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 153.

15 Step One: To a solution of 114 (20.3 g, 129 mmol) in anhydrous methanol (430 mL) at room temperature under a dry nitrogen atmosphere, 2-chloro-6-ethoxybenzylamine, 136, (31.1 g, 168 mmol) was added. The solution was heated at 45 °C for 1 hour then refluxed overnight. The reaction mixture was cooled to room temperature and concentrated to :dryness. The residue was brought up in dichloromethane and filtered. The solid was 20 collected and dried under vacuum to give 149 (14.7 g, 39%).

Step Two: To a suspension of 149 (11.02 g, 37.8 mmol) in glacial acetic acid (126 :mL) at room temperature, NaNO 2 (522 mg, 7.6 mmol), water (10.5 mL) and HNO 3 9.6 mL, 151.2 mmol) were added sequentially. The resulting bright yellow solution was stirred at room temperature overnight, then was diluted with CH 2

C

2 and water. The aqueous phase was extracted with CH 2 C2, the organic layers were combined and washed with water (3 times) and brine. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from CH 2 C1 2 /ethyl acetate to give 150 (10.9 g, 85%) as a bright yellow solid.

Step Three: To a solution of 150 (10.9 g, 32.2 mmol) in DMF (107 mL) at room temperature under a dry nitrogen atmosphere, Zn powder (9.48 g, 145 mmol) and triethylamine hydrochloride (24.4 g, 177 mmol) were added. The resulting mixture was -109heated to 55 °C for 1 h, then was cooled to room temperature. To the resulting mixture, CDI (10.4 g, 64.4 mmol) was added as a solid. Upon addition, gas evolution occurred. The mixture was then heated to 80 OC for 2 hours, cooled to room temperature and poured into HCI (2 N, 1L). The resulting suspension was stirred for 20 minutes and then was diluted with water (1L) and filtered. The solid was resuspended in water (1L) and then filtered. The solid was dried under vacuum to give 151 (10.78 g, 100% yield) as a white powder.

Step Four: A mixture of 151 (10.68 g, 31.9 mmol) and 8 (8.27 g, 39.9 mmol) in DMF (64 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HCI water (4 times) and brine and the organic layer was dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 152 (14.2 g, 82%) as a pale yellow foam.

Step Five: To a solution of 152 (11.60 g, 21.4 mmol) in THF (138 mL) at room 15 temperature, aqueous sodium hydroxide (2 N, 46 mL) and methanol (92 mL) were added.

The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCI (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[1-(2-chloro-6- S 20 ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3-yl]amino carbonyl)amino]-3- (4-methylphenyl)propanoic acid, 153, (10.82, 98% yield) as a light tan foam. MS: Calculated 512.16; Measured 512.03.

Example 37 Synthesis of 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, 156.

Step One: A mixture of 151 (8.40 g, 28.8 mmol) and 154 (8.2 g, 35 mmol) in DMF (100 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HCI water (4 times) and brine and the organic layer was dried over MgSO 4 and filtered. The -110- 'filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 8:2 increasing to 1:1 hexanes:ethyl acetate to give 155 (11.1 g, 67% yield).

Step Two: To a solution of 155 (9.12 g, 15.9 mmol) in THF (100 mL) at room temperature, aqueous sodium hydroxide (1 N, 88 mL) and methanol (63 mL) were added.

The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. This ether layer was discarded. The aqueous phase was acidified with HCI (2 N) and extracted with ethyl ether (4 times). The organic layers were washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, 156, (8.13 g, 93%) as a white Sfoam. MS: Calculated (M+H) 544.19; Measured (M+H) 544.04.

Example 38 Synthesis of (3 S)-3 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5 -methyl-2-oxo- 1,2- 15 dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid, 159.

Step One: A mixture of 151 (110 mg, 0.29 mmol), 157 (130 mg, 0.34mmol) and NMM (0.50 mL, 4.5 mmol) in DMF (1.0 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HCI water (4 times) and brine and the organic layer was dried 20 over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate to give 158 (130 mg, 73% yield).

Step Two: To a solution of 158 (130 mg, 0.21 mmol) in THF (3 mL) at room temperature, aqueous sodium hydroxide (2 N, 1 mL) and methanol (2 mL) were added. The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HCI (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[1-(2-chloro-6ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- ,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- (6-methoxy-2-naphthyl)propanoic acid, 159, (90 mg, 74% yield). MS: Measured 580.07; Calculated 580.19.

-111- Example 39 Synthesis of 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1 Hcyclopenta[b]pyridin-3-yl]amino} carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, 164.

Step One: To a suspension of 129 (5.30 g, 19.2 mmol) in glacial acetic acid (64 mL) at room temperature, NaNO 2 (266 mg, 3.9 mmol), water (5.3 mL) and HNO 3 4.9 mL, 77 mmol) were added sequentially. The resulting bright yellow solution was stirred at room temperature overnight, then was poured into water and filtered, washing with water. The yellow solid was dried under reduced pressure to give 160 (5.35 g, 87%).

Step Two: To a solution of 160 (5.35 g, 16.7 mmol) in DMF (56 mL) at room temperature under a dry nitrogen atmosphere, Zn powder (4.88 g, 74.7 mmol) and triethylamine hydrochloride (12.6 g, 91.5 mmol) were added. The resulting mixture was heated to 55 °C for 1 h, then was cooled to room temperature. To the resulting mixture, CDI (5.41 g, 33.4 mmol) was added as a solid. Upon addition, gas evolution occurred. The 15 mixture was then heated to 80 oC for 2 hours, cooled to room temperature and poured into HCI (2 N, 500 mL). The resulting suspension was stirred for 20 minutes and then was diluted with water (500 mL) and filtered. The solid was resuspended in water (500 mL) and then filtered. The solid was dried under vacuum to give 161 (5.0 g, 95% yield) as a white powder.

S. Step Three: A mixture of 161 (6.14 g, 19.4 mmol) and 162 (5.12 g, 20.3 mmol) in 20 DMF (90 mL) under a dry nitrogen atmosphere was heated to 80 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HCI (2 water (4 times) and brine and the organic layer was dried over MgSO 4 and filtered.

The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 163 (8.90 g, 81%) as a pale yellow foam.

Step Four: To a solution of 163 (8.69 g, 15.3 mmol) in THF (35 mL) at room temperature, aqueous sodium hydroxide (2 N, 30 mL) and methanol (30 mL) were added.

The mixture was stirred overnight, then was diluted with water and extracted with ethyl ether.

The aqueous phase was acidified with HCI (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 3 S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2- -112oxo-2,5,6,7-tetrahydro- H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid, 164, (7.50 g, 91% yield). MS: Measured 540.09; Calculated 540.19.

Example Synthesis of [1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1Hcyclopenta[b]pyridin-3-yl]amino} carbonyl)amino]-3-(4-chloro-3isopropoxyphenyl)propanoic acid.

Step One: To a mixture of 162 (200 mg, 0.80 mmol) in glacial acetic acid (1.65 mL) cooled to 0 oC under a dry nitrogen atmosphere, a mixture of S0 2 Cl2 (1.2 mL, 15 mmol) in glacial acetic acid (1.0 mL) was added dropwise by syringe. The resulting mixture was stirred at 0 OC for 30 minutes then was warmed to room temperature. After stirring for an additional 4 hours, the mixture was recooled to 0 °C and quenched by careful addition of saturated aqueous NaHCO 3 The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaHCO 3 dried over MgSO 4 and filtered. The 15 filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate to give 165 (148 mg, -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1Hg* cyclopenta[b]pyridin-3-yl]amino carbonyl)amino]-3-(4-chloro-3- 2 isopropoxyphenyl)propanoic acid was prepared from 165 according to procedures described 20 in Examples 25 and 30. MS: Calculated 586.15; Found 585.92.

Example 41 Synthesis of [2-chloro-6-tetrahydro- (2H)-pyridinylphenyl]methyl hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4methylphenyl)propanoic acid.

Step One: To a suspension of 166 (0.35 g, 1.06 mmol, prepared according to procedures described in Examples 34 and 25) in methanol (7 mL) and water (3.5 mL) cooled to 0 OC, glacial acetic acid (189 L, 3.2 mmol) and sodium nitrite (178 mg, 2.65 mmol) were added sequentially. The mixture was allowed to slowly warm to room temperature overnight and then was diluted with chloroform and water. The pH of the aqueous phase was checked to ensure a pH of 4-5. The organic layer was washed with brine, dried over MgSO 4 -113and filtered and the filtrate was concentrated under reduced pressure to give 167 (0.35g, 92%) as a yellow solid.

[2-chloro-6-tetrahydro-1 (2H)-pyridinylphenyl]methyl} methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid was synthesized from 167 according to the procedures described in Example 25. MS: Calculated 551.21; Found 551.06.

Example 42 Synthesis of (3 1-[(2-chlorophe :yl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2dihydro-3-pyridinyl} amino)carbonyl]amino} -3-[3-(difluoromethyl)phenyl]propanoic acid.

Step One: To a solution of 3-bromobenzaldehyde, 168, (3.00 g, 16.2 mmol) in DMF (69 mL) under a dry nitrogen atmosphere, palladium acetate (73 mg, 0.32 mmol), tri-otolylphosphine (197 mg, 0.65 mmol), ethyl acrylate (2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol) were added. The system was deoxygenated (toggle between vacuum 15. and nitrogen five times), the mixture was heated to 125 °C for 19 hours and then cooled to S room temperature. The reaction was poured into water and extracted with ether. The organic layer was washed with HCI (4N) and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 169 (2.74g, which was used without further purification.

20 Step Two: To a flask containing 169 (1.00 g, 4.9 mmol) under a dry nitrogen atmosphere, (dimethylamino)sulfur trifluoride (0.96 mL, 9.8 mmol) was added by syringe.

The mixture was heated to 90 OC behind a blast shield.for 25 minutes then was cooled to room temperature. The resulting mixture was diluted with CH 2 C2 and washed with saturated aqueous NaHCO 3 and H 2 0. The organic layer was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 170 (0.62 g, 56%).

Step Three: To a solution of (R)-(+)-N-benzyl-a-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 °C under a dry nitrogen atmosphere, sec-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes and then a solution of 170 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was stirred at -78 oC for 5 hours and then quenched -114with glacial AcOH (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature, poured into a 1:1 mixture of saturated aqueous NaHCO 3 :EtOAc. The organic layer was washed with H 2 0 (2 times) and brine, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 171 (1.2 g, 100%). This material still contained minor impurities but was used without further purification.

Step Four: To a solution of 171 (0.50 g, 1.14 mmol) in EtOH (10 mL) at room temperature under a dry nitrogen atmosphere, Pd/C (10% Pd dry weight basis, 50% water by weight, Degussa type E101 NE/W, 0.25 g) and glacial AcOH (0.5 mL) were added. The 10 atmosphere was replaced by hydrogen (toggle between vacuum and hydrogen from a balloon five times) and the mixture was heated to 35 oC for 6 hours. The reaction was cooled to room temperature, filtered through a plug of Celite® 521 and the filtrate was concentrated under reduced pressure. The residue was diluted with CHCI 3 and washed with saturated aqueous NaHCO 3 The aqueous layer was extracted with CHCI 3 (2 times) and the combined organic 15 layers were dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:10 MeOH:CHCI 3 to give 172 (180 mg, 67%).

(3 1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3pyridinyl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid was 20 synthesized from 172 according to procedures described in Example 25. MS: Calculated (M- H) 504.11; Found 503.96.

Example 43 The procedures described in Examples 3, 4, 8, 25, 26, 27, 29, 30, 34, 36, 39 and 41 were utilized to synthesize several compounds of general Formla VII and general Formula VIn, by varying starting materials. In Table 1 shown below, characterization data is provided for compounds synthesized.

-115- Table 1 Compound 5-(2-chlorobenzyl)-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chlorobenzyl)-6-inethyl- 1,3]oxazolo[4,5cjpyridine-2,4-dione S -(2-fluorobenzyl)-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-fluorobenzyl)- 3,5-dihydrofl1,3]oxazolo[4,5c]pyridine-2,4-dione 5-benzyl-6-methyl-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-benzyl-3,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,5-dimethylbenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-methylbenzyl)-3 ,5dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,4-dichlorobenzyl)-3 ,5 dihvdrolil,3]oxazolo[4,5c]pyn'dine-2,4-dione 'H NMR (400 MHz)

(CD

3

SO

2

CD

3 5 5.27 2H), 6.67 J 7.4 Hz, 1H), 6.88 (dd, J 1.4 Hz, 1H), 7.27- 7.37 (mn, 2H), 7.51 (dd, J 7.9, 1.5 Hz, 1H), 7.65 J 7.4 Hz, I1H), 12.01 (br. s, I1H).

(CD

3

SO

2

CD

3 5 2.27 3H), 5.36 2H), 6.60 J 7.3 Hz, 1 6.63 I 7.27- 7.37 (mn, 2H), 7.51 J 7.7 Hz, 1H), 11.9 (br. s, I1H).

(CD

3

SO

2

CD

3 5 5.26 2H), 6.65 J 7.3 Hz, 1H), 6.88, 7.12-7.26 (in, 3H), 7.37 (in, I1H), 7.69 J 7.3 Hz, I1H), 11. 93 (br. s, I1H).

(CD

3

SO

2

CD

3 5 5.30 2H), 6.56 J 7.3 Hz, 1 7.2 5 (ddd, J 9.4, 8.9, 1.1 Hz, I H),7.37 J 8.0 Hz, IH), 7.43 (in, 2H), 11. 93 (br. s, 1 H).

(CD

3

SO

2

CD

3 5 2.30 3H), 5.37 2H), 6.55( I 7. 10 J 7.0 Hz, 2H), 7.24- 7.3 6 (mn, 3 11. 88 (br. s, I1H).

(CD

3

SO

2

CD

3 8 5.20 2H), 6.60 J 7.3 Hz,1IH), 7.28-7.36 (in, 5H), 7.72 J =7.3 Hz, 1H), 11.97 (br. s, 1H).

(CDC1 3 8 2.27 3H), 2.32 3H), 5.27 (s, 2H), 6.42 J =7.3 Hz, I11) 6.90 I1H), 7.09 (in, 3H), 10.68 (br s, I H).

(CDCI

3 5 2.30 3H), 5.28 2H), 6.39 J 7.3 Hz, I1H), 7.06 J 7.3 Hz, I 7.09 J 7.7 Hz, 1H), 7.18 7.28 (mn, 3H) 10.91 (br s, I H).

(CDC1 3 8 5.33 2H), 6.47 J 7.3 Hz, I1H), 7.2 9 (in, I1H), 7.3 8 J 7.3 Hz, IlH), 7.42 7.48 (mn, 2H) 10.77 (br s, I H).

-116a.

a a. a. a a a 5-(2-methoxybenzyl)-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,5-difluorobenzyl)-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-chloro-5- (methylthio)benzyl]-3 75dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(4-fluorobenzyl)-3,5dihydro[1 ,3]oxazolo[4,5c]pyridine-2 ,4-dione 5-(2-chloro-5 -methoxybenzyl)- 3 ,5-dibydro[ 1,3 ]oxazolo[4,5c]pyridine-2,4-dione

(CDCI

3 8 3.87 1H), 5.24 2H), 6.36 J 7.5 Hz, I1H), 6.8 8 J 8.1 Hz, I1H), 6.97 (in, I1H), 7.30 (in, I1H), 7.45 J 7.5 Hz, I1H), 7.5 5 (mn, 1 10. 75 (br. s, I1H).

(CDCI

3 5 5.26 2H), 6.46 J 7.4 Hz, 1H), 6.96-7.05 (in, 2H), 7.30-7.37 (in, 1H), 7.39. (in, 1 10. 68 (br. s, I1H).

(CD

3

SO

2

CD

3 6 2.41 3H),_5.24 2H), 6.65 J 7.2 Hz, 1H), 6.83 J 2.6 Hz, I1H), 7.25 (dd, J= 8.0, 2.6 Hz, 2H), 7.45 J= 8.0 Hz, I 7.62 J 7.2 Hz, I1H), 12.01 (br. s, I1H).

(CD

3

SO

2

CD

3 8 5.18 2H), 6.61 J 7.4 Hz, 1H), 7.14-7.2 (mn, 2H), 7.35-7.39 (mn, 2H), 7.74 J =7.3 Hz, 1H), 11.96 (br. s, 1H).

(CD

3

SO

2

CD

3 6 3.69 3H), 5.22 2H), 6.42 J 2.9 Hz, 1H), 6.65 J 7.3 Hz, 1 6.94 (dd, J 8.8, 2.9 Hz, I 7.43 J 8.8 Hz, ILH), 7.62 J 7.3 Hz, 1 12.05 (br. s, I1H).

(CD

3

SO

2

CD

3 6 5.36 2H), 6.69 J Hz, I 7.91 J 7.5 Hz, I1H), 8.08(s 3 12.04 (br. S, I1H).

(CD

3

SO

2

CD

3 5 1.24 9H), 5.15 2H), 6.61 J 7.3 Hz, 1H), 7.23 J 8.4 Hz, 2H), 7.35 J 8.4 Hz, 2H), 7.74 J 7.3 Hz, I1H), 12.02 (br. s, 1 H).

5-113,5bis(trifluoromethyl)benzyl]- 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(4-tert-butylbenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione -117- 5-(3-chlorobenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(4-chlorobenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[3-(trifluoromethyl)benzyl]- 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-bromobenzyl)-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2 ,4-dione 5-(3 ,4-dichlorobenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione -(4-methylbenzyl)-3 ,5dihydro[ 1 .3]oxazoloil4,5c]pyridine-2,4-dione -(2-chloro-6-methoxybenzyl)- 3,5-dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione S -[4-(trifluoromethyl)benzyl] 1,3]oxazololl4,5cjpyridine-2,4-dione 5-(3-rnethylbenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(pyridin-2-ylmethyl)-3 ,5 dihydrol 1,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

SO

2

CD

3 8 5.20 2H), 6.63 J =7.4 Hz, 1H), 7.25 (in, 1H), 7.35-7.39 (in, 3H), 7.76 J 7.4 Hz, 1H), 11.97 (br. s, I H).

(GD

3

SO

2

CD

3 6 5.19 2H), 6.62 J 7.3 Hz, 1H), 7.29-7.33 (in, 2H), 7.37-7.42 (mn, 2H), 7.73 J =7.3 Hz, 1 11.97 (br. s, I H).

n.d.

(CD

3

SO

2

CD

3 6 5.23 2H), 6.68 J 7.4 Hz, I1H), 6.79 I1H), 7.26 I 7.34 (in, IRH), 7.64 J 7.4 Hz, I1H), 7.6 8 (in, I1H), 12.02 (br. s, I1H).

(CD

3

SO

2

CD

3 5 5.19 2H), 6.64 J 7.3 Hz, I1H), 7.29 I1H), 7.61 (mn, 2H), 7.77 (d, J 7.3 Hz, I1H), 11. 98 (br. s, IRH).

(CD

3

SO

2

CD

3 6 2.27 3H), 5.14 2H), 6.5 9 J 7.5 Hz, I1H), 7.14 J =8.2 Hz, 2H), 7.20 J 8.2 Hz, 2H), 7.69 J Hz, I1H), 11.95 (hr. s, I1H).

(CD

3

SOCD

3 863.80 3H), 5.23 2H), 6.48 J 7.4 Hz, 1 7.05-7.15 (in, 3H), 7.42 (mn, 1H), 11.95 (hr. s, 1H).

(CD

3

SO

2

CD

3 6 5.30 2H), 6.65 J 7.3 Hz, 1H), 7.48 J 8.0 Hz, 2H), 7.71 J= 8.0 Hz, 2H), 7.76 J 7.3 Hz, 1H), 11.96 (br. s, ILH).

(CD

3

SO)CD

3 5 2.27 3H), 5.15 2H), 6.62 J 7.3 Hz, 1H), 7.10 (mn, 4H), 7.72 J 7.3 Hz, I 12.5 3 (br. s, I1H).

(CD

3

SO

2

CD

3 6 5.29 2H), 6.62 J 7.3 Hz, 1H), 7.22-7.33 (mn, 2H), 7.71 J 7.3 Hz, I1H), 7.79 (in, I1H), 8.50 (mn, I 11.96 (hr. s, I1H).

-118- 5-(2--chlorobenzyl)-7-methyl- 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,4-difluorobenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,6-difluorobenzyl)-3 ,5dihydro 1 ,3]oxazolo[4,5c]pyridine-2,4-dione (trifluoromethoxy)benzyl]-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione (trifluoromethoxy)benzyl]-3 ,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione S -[2-(trifluoromethyl)berizyl]- 1 ,3]oxazolo[4,5clpyridine-2,4-dione 5-(3-methoxybenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,3-dichlorobenzyl)-3,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(3 ,5-dimethylbenzyl)-3 ,5dihydro[ 1 ,3loxazolo[4,5c]pyridine-2,4-dione 5-(.1-chlorobenzyl)-7-pentyl- 1,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

SO

2

CD

3 862. 10 311), 5.23 2H), 6.86 (dd, J 7.7,1.5 Hz, 1H), 7.31 (mi, 2H), 7.50 (nm, 211), 12.01 (br s, 1 H).

(CD

3

SO

2

CD

3 865.21 211), 6.63 J 7.3 Hz, 1H), 7.02-7.07 (mn, 1H), 7.20-7.29 (in, 2H), 7.65 J =7.3 Hz, I 11. 97 (br. s, 111).

(CD

3

SO

2

CD

3 6 5.25 2H), 6.58 J 7.3 Hz, 111), 7.02-7.12 (in, 2H) 7.38-7.55 (in, 1 7.63 J 7.3 Hz, 111), 11. 91 (br. s, 111).

(CD

3

SO

2

CD

3 6 5.24 211), 6.64 J 7.3 Hz, 1H), 7.22-7.35 (in, 311), 7.46 J 7.7 Hz, I1H), 7.7 8 J 7.3 Hz, I1H), 11. 99 (br. s, 11H).

(CD

3

SO

2

CD

3 6 5.23 211), 6.63 J 7.3 Hz, 111), 7.29-7.45 (in, 411), 7.76 J 7.3 Hz, I1H), 11. 98 (br. s, 111).

(CD

3

SO

2

CD

3 6 5.40 211), 6.73 J 7.3 Hz, 111), 6.81 J =7.5 Hz, 1H1), 7.51 (t,J 7.5 Hz, 111), 7.61 J 7.5 Hz, 111), 7.70 (d, J =7.3 Hz, 111), 7.80 J 7.5 Hz, I1H), 12.04 (br. s, 111).

n. d.

(CD

3

SO

2

CD

3 6 2.23 611), 5.1 1 2H), 6.61 J =7.3 Hz, 111), 6.91 (mn, 311), 7.69 J =7.3 Hz, I1H), 12. 00 (br. s, 111).

(CD

3

SO

2

CD

3 6 0.86 J =6.2 Hz, 311), 1.27 (in, 611), 1.65 J =6.7 Hz, 211), 5.24 211), 6.83 J 6.6 Hz, 111), 7.24-7.34 (mn, 211), 7.48 111), 7.50 J 7.7 Hz, 111), 12.00 (br. s, 11H).- -119a a 5-(2,4-dichlorobenzyi)-7methyl-3 ,5dihydro[ 1 ,3]oxazolo[4,5cjpyridine-2,4-dione 5-(2-chlorobenzyl)-7-ethyl-3 ,5dihydro[ 1,3]joxazolo[4,5c]pyridine-2,4-dione 7-butyl-5-(2-chlorobenzyl)- 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-chloro-5- (trifluoromethyl)benzyl]-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,6-dichlorobenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-5-fluorobenzyl)- 1 ,3]oxazolo[4,5c]pyridine-2 ,4-dione 5-(2-chloro-6-methylbenzyl)-7dihydrof 1,3 loxazolo[4,5c]pyridine-2,4-dione 5-(4-chlorobenzyl)-7-methyl- 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chlorobenzyl)-5 ,6,7,8tetrahydro-2Hcyclopenta[b][ 1 ,3]oxazolo[5,4d]pyridine-2,4(3 H)-dione

(CD

3

SO

2

CD

3 8 2. 10 3 5.19 2H), 6.87 J 8.4 Hz, I1H), 7.3 8 (dd, J 8.4, 2.2 Hz, 1H), 7.50 1H), 7.69 J 2.2 Hz, I1H), 12.02 (br. s, 1 H).

(CD

3

SO

2

CD

3 8 1.17 J 7.5 Hz, 3H), 2.50 (in, 2H overlapping DMSO), 5.25 2H), 6.84 (in, 1H), 7.30 (in, 2H), 7.49 (mn, 2H), 12.02 (br. s, I1H).

(CD

3

SO

2

CD

3 5 0.87 J 7.3 Hz, 3H), 1.28 (mn, 4H), 1.54 J 7.1 Hz, 2H), 5.24 2H), 6.83 J 6.8 Hz, 1 7.24-7.34 (in, 2H), 7.48-7.56 (in, 2H), 12.00 (br. s, 1H).

(CD

3

SO

2

CD

3 5 5.33 2H), 6.68 J 7.3 Hz, 1H), 7.35 1H), 7.69-7.79 (in, 3H), 11. 96 (br. s, 1 H).

(CD

3

SO

2

CD

3 8 5.38 2H), 6.53 J 7.4 Hz, I1H), 7.07 J 7.7 Hz, I1H), 7.45-7.50 (in, 1H), 7.52-7.59 (in, 2H), 11.99 (br. s, I1H).

(CD

3

SO

2

CD

3 5 5.27 2H), 6.67 J 7.3 Hz, I 6.72 (dd, J 7.3, 3.2 Hz, I1H), 7.21 7.23 (in, 1H), 7.55-7.59 (in, lH), 7.65 J= 7.3 Hz, I1H), 12. 00 (br. s, I H).

(CDC1 3 8 2.07 3H), 2.29 3H), 5.48 (s, 2H), 6.63 I1H), 7.16 J 7.7 Hz, I H), 7.25 J 7.7 Hz, I1H), 7.34 J 7.7 Hz, 11H), 11.33 (br. S, 1H).

(CD

3

SOCD

3 8 2.08 3H), 5.14 2H), 7.31 J =8.4 Hz, 2H), 7.41 J 8.4 Hz, 2H), 7.58 1H), 12.03 (br. s, I H).

(CD

3

SO

2

CD

3 8 2.04 (in, 2H), 2.80 (in, 4H), 5.28 2H), 6.68 J 7.3 Hz, I1H), 7.18- 7.34 (mn, 2H), 7.51 J 7.7 Hz, 1 11.92 (br. s, I1H).

-120- I. p 7-methyl-5-[4dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(4-methoxybenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chlorobenzyl)-7-propyl- 3 ,5-dihydro[ 1 ,3]oxazolo[4,5clpyridine-2,4-dione 4-[(2,4-dioxo-2,3dihydro[ 1 ,3]oxazolo[4,5cjpyridin-5(4H)-yl)methyl]-

N,N-

dimethylbenzenesulfonamide 5 -(mesitylmethyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5clpyridine-2,4-dione 5-(2-chlorobenzyl)-3 ,5,6,7,8,9hexahydro[ 1,3]oxazolo[4,5c]quinoline-2,4-dione 5-(2-chlorobenzyl)-7-ethyl-6methyl-3 ,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione 5..(2-(methylthio)benzyl]-3 .5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

SO

2

CD

3 6 2.11 3H), 2.58 3H), 5.28 2H), 7.58 J 7.3 Hz, 2H), 7.64 (s, 1H), 7.91 J 7.3 Hz, 2H), 12.06 (br. s, I1H).

(CD

3

SO

2

CD

3 8 3.73 3H), 5. 10 2H-), 6.5 6 (br. d, J 5.9 Hz, I1H), 6.8 9 J 8.8 Hz, 2H), 7.27 J 8.8 Hz, 2H), 7.67 (br. m, I1H), 12.06 (br. s, I1H).

(CD

3

SO

2

CD

3 5 0.88 J 7.4 Hz, 3H), 1.57 (mn, 2H), 2.46 (in, 2H), 5.24 2H), 6.84 J 6.2 Hz, IH), 7.26-7.3 8 (mn, 211), 7.48 (s, I1H), 7.50 J 7.7 Hz, I 12.00 (br. s, I1H).

(CD

3

SO

2

CD

3 6 2.55 6H), 5.31 2H), 6.67 J 7.3 Hz, I1H), 7.43 -7.5 1 (in, 2H), 7.66-7.74 (mn, 2H), 7.77 J 7.3 Hz, 1H), 12.00 (br. s, I1H).

(CDC1 3 6 2.19 6H), 2.30 3H), 5.25 (s, 2H), 6.31 J 7.3 Hz, I1H), 6.73 J 7.3 Hz, I 6.94 2H), 11.0 1 (br. s, I1H).

(CD

3

SO

2

CD

3 6 1.64 (in, 4H), 2.50 (mn, 4H), 5.34 2H), 6.59 J 8.1 Hz, 1H), 7.25- 7.34 (mn, 2H), 7.51 J 7.7 Hz, 1H), 11.92 (br. s, I1H).

(CD

3

SO

2

CD

3 6 1. 10 J 7.4 Hz, 3H), 2.22 311), 2.56 (mn, 2H), 5.40 2H), 6.58 J 7.0 Hz, 1H), 7.23-7.34 (mn, 2H), 7.52 J= 8.1 Hz, 1H), 11.92 (br. s, 1H).

(CD

3

SO

2

CD

3 6 2.52 3H), 5.19 2H), 6.63 J 7.3 Hz, I1H), 6.76 J 7.7 Hz, 1H), 7.09-7.17 (mn, 1H), 7.29-7.37 (mn, 2H), 5 J 7.3 Hz, 1 11.99 I1H).

-12 1- 2-[(2,4-dioxo-2,3dihydro[ 1 ,3]oxazolo[4,5clpyridin-5(4H)-yl)methyl]-

N,N-

dimethylbenzenesulfonamide 5-(2,6-dimethoxybenzyl)-3 ,5dihydro[ 1 ,3]oxazolojl4,5c]pyridine-2,4-dione (trifluoromethoxy)benzyl]-3 ,5dihydro[ 1 ,3]oxazolo[4,5cljpyridine-2,4-dione 5- (2-chlorobefazyl)-6,7 dimethyl-3 ,5dihydro[ 1 ,3)oxazolo[4,5elpyridine-2,A-dione j5-2-chloro-5 (methylsulfonyl)benzyl]-3 ,5dihydro[ 1,3]oxazolo[ 4 ,5c]pyridine-2,4-dione S -(4-chloro-2-methoxybenzyl)- 3,5-dihydro[1I,3]oxazolo[4,5c]pyridine-2 ,4-diorie 5-(2-chlorobenzyl)- 5,6,7,8,9, 1 0-hexahydro-2Hcycloheptarb][ 1 ,3]oxazolo[5,4d]pyridine-2,4(3H1)-dione 5412- (difluoromethoxy)benzyl]-3 ,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione 7-methyl-5-L(l1R)- 1phenylethyl]-3 ,5dihydro[ 1 ,3]oxazolo[4,5cllpyridine-2,4-dione

(CD

3

SO

2

CD

3 5 2.81 6H1), 5.54 2H), 6.71 J 7.3 Hz, I1H), 6.81 J =7.3 Hz, I1H), 7.49-7.6 1 (in, 2H), 7.69 J 7. 3 Hz, I1H), 7.85 J 7.3 Hz, IlH), 12.05 (br. s,

IRH).

(CD

3

SO

2

CD

3 6 3.76 6H1), 5.07 2H), 6.43 J 7.7 Hz, I1H), 6.73 J 8.4 Hz, 2H1), 7.00 J 7.7 Hz, 1 7.3 7 J 8.4 Hz, I1H), 11. 92 (br. s, 1LH).

(CD

3

SO

2

CD

3 6 5.27 2H), 6.65 J Hz, I1H), 7.0 8 (dd, J 7.3, 1.4 Hz, I1H), 7.30 7.49 (in, 3i-H), 7.63 J =7.3 Hz, I1H), Ii.99 (br. s, 1 H).

(CD

3

-SO

2

CD

3 5 2.12 3H), 2.19 3H), 5.40 2R), 6.59 J 6.6 Hz, 1H), 7.25- 7.34 (mn, 2H), 7.52 I'd, J 7.7 Hz, I1H), 11.91 (br. s, I H).

(CD

3

SO

2

CD

3 6 3.20 3H). 5.35 2H), 6.70 J 7.3 Hz, I1H), 7.5 5 (in, I1H), 7.69 (in, iRH), 7 90 (in, 2H1), 12.04 (br. s, 1 H).

(CD

3

SO

2

CD

3 6 3.86 3H), 5.09 211), 6.60 J =7.3 Hz, IRH), 6.90-6.98 (mn, 2H), 7.12 J 2.2 Hz, I1H), 7.5 9 J 7.3 Hz, I1H), 11. 95 (br. s, 1 H).

(CD

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2

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3 5 1 .34 (in, 2H), 1.56 (mn, 2H), 1.69 (in, 2.70 (in, 4H), 5.45 2H), 6.69 J 6.6 Hiz, 1H), 7.24-7.35 (in, 2H), 7.52 J 7.7 Hz, I1H), 11. 91 (br. s, I H).

(CD

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2

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3 8 5.21 2H), 6.64 (d7 J3 7.3 Hz, lET), 7.02 J =7.3 Hz, I1H), 7.20-7.25 (in, 2H), 7.27 J =74.0 Hz, I1H), 7.62 (dl i1 7.3 Hz, IH), 12.00 (br. s, iR)..

(CD

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2

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3 6 1 .72 J 7.3 Hz, 3H), 2.07 3H1), 6.27 J 7.3 Hz, I1H), 7.27-7.40 (mn, 6H), 11.95 (br. s, I1H).

-122- 5-(4-chlorobenzyl)-7-propyl- 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-(methylsulfonyl)benzyl]- 3,5-dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,6-dimethylbenzyl)-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 3-chloro-2-[(2,4-di 'oxo-2,3dihydro[ 1 ,3]oxazolo[4,5c]pyridin-5(4H)yl)methyl]benzonitrile S -(2-chloro-6-methylbenzyl)- 6,7-dimethyl-3 ,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione 2-[(2,4-dioxo-2,3dihydro[ 1 ,3loxazolo[4,5c]pyridin-5(4H)yI)methyl]benzonitrile

(CD

3

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2

CD

3 8 0.89 J 7.3 Hz, 3H), 1.54 (in, 2H), 2.44 J 7.7 Hz, 2H), 5.15 2H), 7.30 J 8.4 Hz, 2H), 7.39 J 8.4 Hz, 2H), 7.5 7 I1H), 11.97 (br. s, I H).

(CD

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3 5 3.43 3H), 5.60 2H), 6.75 J 7.3 Hz, 1H), 7.49-7.6 1 (in, 2H), 7.65-7.70 (in, 2H) 7.89-7.91 (in, 1H), 12.02 (br. s, I H).

(CD

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2

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3 562.21 6H), 5.16 2H), 6.47 J =7.3 Hz, 1H), 6.80 J 7.3 Hz, 1H), 7.09-7.22 (in, 3H), 12.00 (br. s, ILH).

(CD

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2

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3 6 5.38 2H), 6.61 7.4 Hz, I1H), 7.5 5 J 8. 0 Hz, 1 7.62 J 7.4 Hz, 1H), 7.82 J 8.0 Hz, 1H), 7.87 J= 8.0 Hz, 1H), 11.96 (br. s, 1H).

(CD

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2

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3 5 2.06 3H), 2.09 3H), 2. 10 3H), 5.58 2H), 7.13 J 7.7 Hz, I1H), 7.20 J 7.7 Hz, 2H), 7.27 J 7.7 Hz, I 11. 84 (br. s, I H).

(CD

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2

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3 8 5.40 2H), 6.70 J 7.4 Hz, 1H), 7.11 J 7.7 Hz, 1H), 7.50 J 7.7 Hz, I1H), 7.66 (td, J 7.7, 1.1 Hz, I1H), 7.74 J 7.4 Hz, I 7.8 8 (dd, JI 7.7, 1.1 Hz, 1H), 12.01 (br. s, I1H).

(CD

3

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2

CD

3 6 2.01 3H), 3.81 3H), 5.21 2H), 6.86 1H), 7.1 1 (mn, 2H), 7.41 J =8.2 Hz, I1H), 11. 96 (br. s, I H).

(CD

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2

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3 5 2.45 3H), 5.16 2H), 6.61 J 7.3 Hz, I 7.04 J 7.3 Hz, I1H), 7.16-7.34 (in, 3H), 7.73 J 7.3 Hz, IRH), 11. 97 (br. s, I1H).

5-(2-chloro-6-methoxybenzyl)- 7-inethyl-3 ,5dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[3 -(inethylthio)benzyl]-3, 5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione -123a a.

Oe a 5-(2-chloroberizyl)-7cyclopropyl-3 ,5dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(3-chlorobenzyl)-7-methyl- 3,5-dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2,6-dichlorobenzyl)-7dihydro 1 ,3 ]oxazolo [4,5 c]pyridine-2,4-dione 7-methyl-5-(4-methylbenzyl)- 3,5 -dihydro 1, ,3]oxazolo [4,5 c]pyridine-2,4-dione 5-(3 ,5-dimethoxybenzyl)-7dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2 ,4-dione 5-(2,6-difluorobenzyl)-7methyl-3,5dihydro[ 1 ,3]oxazolo[4,5clpyridine-2,4-dione 5-[3 -(methylsulfonyl)benzyl]- 3,5-dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)- 1,3]oxazolo[4.5c]pyridine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-7methyl-3 ,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

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2

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3 5 0.70 (mn, 2H), 0.87 (mn, 2H), 1.79 (in, 1H), 5.22 2H), 6.79 J 7.3 Hz, 1H), 7.31 (in, 1H), 7.45 IR), 7.50 J 7.7 Hz, I1H), 12.01 (br. s, I1H).

(CD

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2

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3 5 2.09 J 1. 1 Hz, 3 5.15 2H), 7.26 (in, 1H), 7.33-7.4 1 (in, 3H), 7.59 J 1 Hz, 1 11. 97 (br. s, I1H).

(CD

3

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2

CD

3 6 2.03 J 1.1 Hz, 3H), 5.36 2H), 6.87 J 1. 1 Hz, I1H), 7.46 (dd, J= 8.8, 7.4 Hz, I 7.56 J 7.4 Hz, I1H), 7.5 7 J 8.8 Hz, I1H), 11. 99 (br. s, I1H).

(CD

3

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2

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3 8 2.07 3H), 2.27 3H), 5.10 2H), 7.08-7.23 (in, 4H), 7.52 1H), 11.95 (br. s, 1H).

(CD

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2

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3 6 2.09 3H), 3.71 6H), 5.06 2H), 6.42 J 2.2 Hz, 1H), 6.46 (d, J 2.2 Hz, 2H), 7.51 1H), 11.96 (br. s, I1H).

(CD

3

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2

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3 6 2.09 J 1. 1 Hz, 3H), 5.21 2H), 7.04-7.13 (in, 2H), 7.38-7.47 (mn, 2H), 11.91 (br. s, I1H).

(CD

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3 6 3.20 3H), 5.31 2H), 6.66 J 7.3 Hz, I1H), 7.5-7.7 (in, 2H), 7.81 J 7.3 Hz, 1H), 7.83-7.96 (mn, 2H), 11.99 (br. s, I H).

(CD

3

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2

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3 6 1.25 J =7.0 Hz, 3H), 4.05 J 7.0 Hz, 2H), 5.25 2H), 6.49 J 7.3 Hz, I1H), 7.06 J 8.4 Hz, 1 7. 10 (d, J 8.1 Hz, I1H), 7.12 J 7.3 Hz, I1H), 7.3 7 (dd, J 8.4, 8.1 Hz, I1H), 11. 95 (br. s, I H).

(CD

3

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2

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3 6 1 .25 J 7.0 Hz, 3H), 2.02 3H), 4.04 J =7.0 Hz, 2H), 5.23 2H), 6.97 1H), 7.04 J 8.4 Hz, 1H), 7.09 (d, J 8.0 Hz, I1H), 7.3 6 (dd, J 8.4, 8.0 Hz, IRH), 11. 93 (br. s, I1H).

-124- Go, 0 a a..

*go 00*0* *004 5-(2-fluoro-6-methoxybenzyl)- 7-methyl-3,5dihydro[ 1 ,3]oxazolo[4,5cjpyridine-2,4-dione 5-(2-chloro-6-methoxybenzyl)- 7-propyl-3,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(5-chloro-2-fluorobenzyl)-7dihydrof I ,3]oxazolo[4,5c]pyridine-2,4-dione chlorobenzyl)-7dihydro[ 1 ,3]oxazolo[4,5cjpyridine-2,4-dione 5-(5 -fluoro-2-methylbenzyl)-7methyl-3,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 7-methyl-5-[(1 S)-1 phenylethyl]-3 ,5dihydro[ 1 ,3]oxazololl4,5c]pyridine-2,4-dione 5-(2-chloro-5isopropoxybenzyl)-7-methyl- 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(5-acetyl-2-methoxybenzyl)- 1,3]oxazolo[4,5clpyridine-2,4-dione

(CD

3

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2

CD

3 5 2.05 3H), 3.82 3H), 5.12 2H), 6.82 (dd, J 8,4Hz, I1H), 6.91 J 8.4 Hz, 1iH), 7.18 I1H), 7.3 7 (td, J 8.4,6.6 Hz, 1H), 11.89 (br. s, 1H).

(CD

3

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2

CD

3 5 0.82 J 7.3 Hz, 311), 1.47 (sextet, J 7.3 Hz, 2H), 2.38 J 7.3 Hz, 211), 3.80 3 5.21 2H), 6.89 11H), 7.08-7.13 (in, 2H), 7.40 J1 8.3 Hz, 1H), 11.93 (br. s, I1H).

(CD

3

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2

CD

3 6 2. 10 3H), 5.18 2H), 7.20 (dd, J 6.6, 3.0 Hz, I1H), 7.29 (dd, J 9.6, 8.8 Hz, 111), 7.42 (ddd, J 8.8, 4.4, Hz, 111), 7.51 111), 11.96 (br. s, ILH).

(CD

3

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2

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3 5 1.23 J 7.0 Hz, 6H), 2.92 (in, I1H), 5.25 2H), 6.83 (dd, J 7.4, 2.2 Hz, I1H), 7.27-7.3 5 (in, 2H), 7.49 11H), 7.51 (dd, J 7.3,1.8 Hz, 111), 12.01 (br. s, 111).

(CD

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2

CD

3 562. 10 J 1 Hz, 3H), 2.30 311), 5.13 2H), 6.55 (dd, J 9.9, 2.6 Hz, I1H), 7. 01 (td, J 8.4, 2.6 Hz, 111), 7.2 5 (dd, J 8.4, 5.9 Hz, 1lH), 7.42 1. 1 Hz, 111), 11. 99 (br. s, I H).

(CD

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2

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3 5 1.72 J 7.3 Hz, 311), 2.07 311), 6.27 J 7.3 Hz, I 7.27-7.40 (in, 611), 11.95 (br. s, 1H).

(CD

3

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2

CD

3 5 1.20 J 6.0 Hz, 6H), 2.11 311), 4.50 (in, I1H), 5.16 2H), 6.34 J 3. 0 Hiz, I1H), 6.91 (dd, J 8.8, 3. 0 Hz, 111), 7.3 8 J 8.8 Hz, I11), 7.47 111), 12.01 (br. s, I11).

(CD

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2

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3 6 2.47 3H), 3.93 311), 5.16 2H), 6.62 J 7.3 Hz, ILH), 7.16 (d, J 8.4 Hz, I 7.5 9 J 2.2 Hz, I1H), 7.6 3 J 7.3 Hz, 1 7.97 (dd, J 8.4, 2.2 Hz, -125- 5-(2-chlorobenzyl)-7-methyl- 3 .5-dihydro[ 1,3 ]oxazolo[4,5d]pyridazine-2,4-dione 5-[2-fluoro-6- (trifluoromethyl)benzyl]-7dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-methylbenzyl)- ,6,7,8-tetrahydro-2Hcyclopenta[b] 1,3]oxazolo[5,4djpyridine-2,4(3H)-dione 5 -(2-chloro-6-ethoxybenzyl)-7ethyl-3,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-propoxybenzyl)- 7-methyl-3,5dihydro[ 1 ,3]joxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6isobutoxybenzyl)-7-methyl- 3,5-dihydro[ 1 ,3 ]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

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2

CD

3 862.29 3H), 5.39 2H), 7.00 J =7.4 Hz, I1H), 7.26-7.3 7 (in, 2H), 7.51 J 7.7 Hz, I1H), 12.80 (hr. s, I1H).

(CD

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2

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3 6 2.04 3H), 5.33 2H), 7.05 1H), 7.51-7.72 (in, 3H), 11.98 (br. s, I1H).

(CD

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2

CD

3 862.02 (in, 2H), 2.21 3H), 2.64-2.80 (in, 4H), 5.42 2H), 7.05-7.33 (in, 3 11. 81 (hr. s, I1H).

(CD

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2

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3 61.08 J 7.7 Hz, 3H), 1.25 J 7.0 Hz, 3H), 2.44 J 7.7 Hz, 2H), 4.05 J 7.0 Hz, 2H), 5.23 2H), 6.99 (s, I1H), 7.05 J 8.4 Hz, I1H), 7.09 J 8. 1 Hz, I1H), 7.36 (dd, J 8.4, 8.1 Hz, I1H), 11.93 (br. s, I1H).

(CD

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3 6 0.88 J 7.3 Hz, 3H), 1.66 (in, 2H), 2.01 J 1. 1 Hz, 3 3.95 J 6.2 Hz, 2H), 5.24 2H), 6.91 J 1. 1 Hz, I1H), 7.03 J 8.4 Hz, ILH), 7. 10 J 8.1 Hz, I 7.3 7 (dd, J 8.4, 8.1 Hz, I1H), 11.9 (br. s, IRH).

(CD

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3 6 0.89 J 7.0 Hz, 6H), 1.95 (in, I 2.00 3H), 3.79 J 6.2, 2H), 5.25 2H), 6.85 I1H), 7.06- J 8.4 Hz, 1 7.11 (d,J 1 Hz, I1H), 7.3 8(dd, J 8.4, 8.1 Hz, I1H), 11. 97 (hr. s, 1IH).

(CD

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3 61.-10 J =7.0 Hz, 3H), 2.06 (mn, 2H), 2.70-2.92 (mn, 4H), 3.90 J Hz, 2H), 5.33 2H), 6.93 J =8.4 Hz, 1 7.03 J 1 Hz, I1H), 7.26 (dd, J 8.4, 8.1 Hz, 1 11. 75 (br. s, I H).

-(2-chloro-6-ethoxybenzyl ,6,7,8-tetrahydro-2Hcyclopenta[b][1 ,3]oxazolo[5,4d]pyridine-2 ,4(3H)-dione -126- 5-(2-chloro-6isopropoxybenzyl)-7-methyl- 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-chloro-6-(2,2,2trifluoroethoxy)benzyl]-7dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-7dihydro[ 1,3 ]oxazolo[4,5dlpyridazine-2,4-dione 5-[2-chloro-6-(2methoxyethoxy)benzyl]- 5 ,6,7,8-tetrahydro-2Hcyclopenta[b] 1,3]oxazolo[5,4d]pyridine-2,4(3H1)-dione 5-(2-chloro-6-ethoxybenzyl)- 6,7-dimethyl-3 ,5dihydro[ 1 ,3]oxazolo[4,5cjpyridine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-7ethyl-6-methyl-3 ,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chlorobenzyl)-7-ethyl-3 ,5dihydro[ 1 ,3]oxazolo[4,5d]pyridazine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-7propyl-3 ,5dihydro[1 ,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

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2

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3 5 1.16 J 6.2 Hz, 6H), 2.02 3H), 4.67 (in, 1H), 5.21 211), 6.94 (s, 1H), 7.07 J 8.0 Hz, 2H), 7.34 J Hz, 1H), 11.93 (br. s, 111).

(CD

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3 8 2.01 3H), 4.82 J 8.8 Hz, 2H), 5.24 211), 6.94 111), 7.19 J =8.4 Hz, I1H), 7.22 J 8.1 Hz, I1H), 7.43 (dd, J 8.4, 8.1 Hz, I 11. 92 (br. s, I H).

(CD

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3 5 1.19 J 7.0 Hz, 2.19 311), 3.99 J 7.0 Hz, 211), 5.41 211), 6.98 J 8.4 Hz, 11H), 7.05 J 8.0 Hz, 111), 7.30 (dd, J 8.4, 8.0 Hz, I1H), 12.70 (br.

s, I1H).

(CD

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3 6 2.06 (in, 2Hj, 2.74-2.90 (in, 4H), 3.20 311), 3.47 J 4.4 Hz, 2H), 4.01 J 4.4 Hz, 2H1), 5.33 2H), 6.98 (d, J 8. 0 Hz, I1H), 7.04 J 8. 0 Hz, I1H), 7.2 7 J 8.0 Hz, 1 (br. s, I1H).

(CDISO

2

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3 6 1.03 J =7.0 Hz, 311), 2.06 311), 2.22 3H), 3.84 J 7.0 Hz, 2H), 5.48 2H), 6.92 8.4 Hz, 111), 7.03 J= 8. 1 Hz, 11H), 7.24 (dd, J 8.4, 8.1 Hz, I1H), 11. 76 (br.s, 111).

(CD

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3 6 1.06 (in, 6H), 2.24 3H), 2.48-:2.5 *6 (in overlapping DMSO, 211), 3.85 J Hz, 2H), 5.48 211), 6.92 8.4 Hz, 111), 7.03 J= 8.1 Hz, I1H), 7.24 (dd, J 8.1 Hz, I1H), 11. 77 (br. s, I1H).

(CD

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3 6 1.18 J 7.5 Hz, 311), 2.70 J 7.5 Hz, 2H), 5.38 211), 7.0-7.6 (in, 411), 12.77 (br. s, 1H).

(CD

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3 6 0.82 J 7.3 Hz, 311), 1.24 J 7.0 Hz, 3H1), 1.48 (in, 211), 2.37 J= 7.3 Hz, 211), 4.05 J 7.0 Hz, 211), 5.23 (s, 211), 6.93 111), 7.0 5 J 8.4 Hz, 111), 7.09 J 8. 1 Hz, I1H), 7.3 6 (dd, J 8. 1 Hz, 111), 11 .94 (br. s, 11H).

-127- 9 5-(2-chloro-6-ethoxybenzyl)-7dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-5-propoxybenzyl)- 7-methyl-3,5dihydro[ 1,3]oxazolo[4,5c]pyridine-2,4-dione S -(2-chloro-5-methoxybenzyl)- 7-methyl-3 ,5dihydro[ I ,3]oxazolo[4,5c]pyridine-2,4-dione 5-(2-chloro-6-ethoxybenzyl)-6methyl-3,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5..(2-chloro-5 -ethoxybenzyl)-7methyl-3,5dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-chloro-5-(piperidin- I1ylsulfonyl)benzyl]-7-methyl- 3,5-dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione 5-[2-chloro-5-(pyrrolidin- 1 ylsulfonyl)benzyl] -7-methyl- 3 ,5-dihydro[ 1 ,3]oxazolo[4,5c]pyridine-2,4-dione

(CD

3

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2

CD

3 8 0.55 (in, 2H), 0.81 (in, 2H), 1.26 J= 7.0 Hz, 3H), 1.72 1 4.05 (q, J 7.0 Hz, 2H), 5.22 2H), 6.95 1H), 7.05 J 8.4 Hz, I1H), 7.09 J 8.1 Hz, I1H), 7.36 (dd, J 8.1 Hz, I1H), 11.93 (br.

s, I1H).

(CD

3

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2

CD

3 8 0.92 J 7.3 Hz, 3H), 1.66 (mn, 2H), 2. 10 3H), 3.85 (mn, 2H), 5.17 (s, 2H), 6.41 J 3.3 Hz, I1H), 6.91 (dd, J 8.8, 3.3 Hz, 1H), 7.39 J 8.8 Hz, 1H), 7.45 1H), 12.00 (br. s, 1H).

(CD

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2

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3 5 2. 10 3H), 3.9 3H), 5.18 2H), 6.42 J 3.0 Hz, 1H), 6.93 (dd, J= 8.8, 3.0 Hz, I1H), 7.42 J 8.8 Hz, I1H), 7.44 I 12. 00 (br. s, 1 H).

(CD

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2

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3 5 1 .07 J =7.0 Hz, 3H), 2.32 3H), 3.87 J =7.0 Hz, 2H), 5.42 2H), 6.44 I 6.92 J 8.4 Hz, I1H), 7.0 3 (d, J 8.1 Hz, I1H), 7.24 (dd, J 8.4, 8.1 Hz, I1H), 11. 74 (br. s, I H).

(CD

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2

CD

3 8 1.26 J 7.0 Hz, 3H), 2. 3H), 3.94 J 7.0 Hz, 2H), 5.17 2H), 6.3 8 J 2.9 Hz, I1H), 6.91 (dd, J 8.8, 2.9 Hz, 11H), 7.3 9 J 8.8 Hz, I 7.44 (s, I1H), 11. 99 (br. s, I1H).

(CD

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2

CD

3 8 1.35 (mn, 2H), 1.47 (in, 4H), 2.10 3H), 2.81 (mn, 4H), 5.30 2H), 7.18 J 2.2 Hz, 1H), 7.57 1H), 7.67 (dd, J 8.4, 2.2 Hz, I1H), 7.7 8 J 8.4 Hz, I1H), 12.07 (hr. s, IH).

(CD

3

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2

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3 8 1.62 (mn, 4H), 2.11 3H), 3.05 (in, 4H), 5.30 2H), 7.30 IH), 7.57 1H), 7.75-7.82 (mn, 2H), 12.08 (br. s, 1H).

JUN. 2005 15:57 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 63 5-[2-chloro-6- (cyclopentylniethoxy)benzylj- 7-rnethyl-3,5dihydro[1 ,3]oxazolo[4,5clpyridine-2,4-dione 5-[2-(benzylaxy)-6chlorobenkzyl]-7-methyl-3 ,5dihydro[1 ,3I]oxazoloI4,5cJpyridine-2,4--dione 5-(2,3-dicliloro-6.ethoxybenzyl)-5,6,7,8tetrahydro-2Hcyclopentab][l ,3Ioxazolor5,4d]pyridine-2,4(3H)-diouc 5-[2-chloro-5- (tr-ifluoromnethyl)benzylj-7dihydro( I ,3]Oxazolor4,5c ]pyridine-2,4-dione 5-{2-chloro-5-fluorobenzyl)-7.

methyl-3, 5dihydro(l ,3]oxazolof4,5cjpyridine-2,4-dione (tDSQ 2 1.22 (in, 2H), 1.51 (in, 411), 1.68 (in, 2H1), 2.00 31H), 2.20'(m, 111), 3.89 I 7.0 Hz, 2H), 5.24 2H), 6.86 1 H), 7.07 J3 8.4 Hz, 11H), 7.11 J 8.1 Hz, I 7.3 7 (dd, J 8.4, 8.1 H, 18H), 11.97 (br.

S,lIH):-

(CD

3

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2 CD,>56 1.90 3H), 5.15 2H), 5.25 2H), 6.84 I1H), 7.13 I1 8.1 Hz, 'I M, 7.19 I= 7.7 Hz, I1H),7.30-7.3 7 (in, 511), 7.3 9 (dd,JI= 8. 1, 7.7Hlz, 18H), 11 .91 (hr.

s,11)

(CD

3

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2

CD

3 8 1. 10 J!3 7.0 Hz, 311), 2.09 (mn, 211) 2.80 (in, 211, 2.89 (in, 2H1), 3.92 J S7.0 FHz, 28), 5.33 2H), 6.98 I1 8-8 Hfz, I1H), 7.5 0(d,3J 8.8 Hz, I 11. 7!1 (hr. s, 18H).

(CD

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2

CD

3 6 2: 11 38H), 5.29 28), .7.34 I1H), 7.54 I 7.72-7,79 (mn, 2H), 12.00 (hr. s, 111).

(GD

3

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2

CD

3 )8 2.11 '3H1), 5.20 2H1), 6.71 (dd, J3 9.4, 2.9 Hz, 18H), 7.22 (td, J= 8.4, 2.9 Hzt, 11H), 7.4 9 11H), 7.57 (dd, J1 8.4, 5.2 Hz, 114), 11.99 (br. s, 18H).

0** 4 Examnie 44 A procedure in which a 26-amino acid peptide containing the CS 1 sequence of fibronectin with an N-tenninal Cys (CDEL-PQLVThPHPNLHGPErLDVPST) was coupled to inaleirnide activated ovalbuinin was used to deteine the efficacy of the compounds synthesized. Bovine seirm albumnin (BSA) and CS!I conjugated Qvalbuinin were coated onto 96-well polystyrene plates at 0.5 gimi in TES (50 mM TRJS, pH 7.5; 150 mM NaG!) at 4TC for 16 hours. The plates were washed three times with ThS and blocked with TBS containing 3% BSA at roomn temperature for 4 hours. Blocked plates were COMS ID No: SBMI-O1 328788. Received by IP Australia: Time (H:rn) 18:08 Date 2005-06-30 JUN. 2005 15:58 SPRUSON AND FERGUSON.61292615486 NO. 2697 P, 64 129 washed three times in binding buffer (TBS; ImM MgC 2 ImM CaC12; 1 mM MnClz) prior to assay. Ramos cells fluorescently labelled with calcein AM were resuspended in binding buffer (10' cells/ml) and diluted 1:2 with same buffer with or without compound.

100pM of compound was added. The cells were added immediately to the wells (2.5 x 10 5 cells/well) and incubated for 30 minutes at 37°C. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer. The results are shown in Tables 2-7. IC 0 o is defined as the dose required to give 50% inhibition, measured in pM for Tables 2 and 4. The lower the IC5o value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion.

S COOMe S COOMe a) NaH, DMF, 0C 'r NH

NH

2 b) 2-Chlorobenzyl chloride, RT 173 174 174 Scheme43 Example s15 Synthesis of (3 S)-3-[([4-(2-chlorobenzyl)-7-hydroxy-5-oxo-4,5-dihydrothieno[3,2b]pyridin-6-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.

Step One: To a solution of methyl 3-aminothiophene-2-carboxylate, 173 g, 6.4 mmol) in DMF (19 mL), cooled to 0°C, sodium hydride (60% in mineral oil, 0128 g, mmol) was added. After stirring 15 minutes at 0 C, 2-chlorobenzyl chloride (1.0 mL, 7.9 20 mmol) was added and the cooling bath was removed. After stirring for 18 hours, the reaction mixture was poured into a mixture of ice and HCI (2 N) and was extracted with So EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSOa o* and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 10:1 hexanes:ethyl acetate to give 174 (1.40 g, 78% yield).

(3S)-3-[({[4-(2-chlorobenzyl)-7-hydroxy-5-oxo-4,5-ydrothieno[3,2b]pidin-6yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesised using 174 according to the procedures described in Steps 2-3 of Example 30 followed by Steps 3-6 of Example 25. MS: Calculated 510.09; Found 509.92.

Example 46 (3 S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesized according rR:\LIBH1575390dlipeci.doo:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:58- SPRUSON AND FERGUSON 61292615486 NO. 2697 P, 129a to the procedures described in Example 45, except that methyl 2-aminpnicotinate was used instead of methyl 3-aminothiophene-2-carboxylate, followed by Steps 2-3 of the Example 30 and then Steps 3-6 of Example 25. In this instance, the reaction mixture in Step 2 of Example 30 was warmed to 60°C instead of room temperature after the addition s of acetyl chloride. MS: Calculated 507.14; Found (M+H) t 506.97.

ooo 89 o oooo* *o [R:\LIBH 7575390dispeci.doc:eak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 -130- Table 2 Name IC 50 Mass Spectral Data (m/z) 1,3-benzodioxol-5-yl)-3-[( {[(3S)-2-oxo-l1-(2thienylmethyl)hexahydro-3pyridinyl] amino}I carbonyl)amino]propanoic acid ,3-benzodioxol-5-yl)-3-[( {[(3S)-2-oxo-l1-(2thienylmethyl)tetrahydro- 1 H-pyrrol-3yl] amino}I carbonyl)amino]propanoic acid (3 S)-3 ,3-benzodioxol-5-yl)-3-[( 1-(2thienylmethyl)hexahydro-3pyridinyl] amino) carbonyl)amino]propanoic acid 1,3-benzodioxol-5-yl)-3-[( {[2-oxo-l1-(2thienylmethyl)- 1,2-dihydro-3pyridinyijamino }carbonyl)amino]propanoic acid 1,3-benzodioxol-5-yl)-3-( S)-2-oxo- 1- toluidinocarbonyl)amino]benzyl }hexahydro-3 pyridinyl)amino]carbonyl }amino)propanoic acid 1,3-benzodioxol-5-yl)-3-[( [2-oxo- 1 toluidinocarbonyl)amino]benzyl -1 ,2-dihydro-3 pyridinyl] amino)} carbonyl)amino]propanoic acid 1,3-benzodioxol-5-yl)-3-( 1 methylbenzyl)amino]benzyl -2-oxohexahydropyridinyl)amino]carbonyl} amino)propanoic acid '1 ,3-benzodioxol-5-yI)-3-[( {butyl[2-oxo- 1 thienylmethyl)- I ,2-dihydro-3 pyridinyl]amino} carbonyl)amino]propanoic acid 1,3-benzodioxol-5-yI)-3-[( 1 thienylmethyl)azepanyl] amino I carbonyl)amino]propanoic acid 0.2 Calc'd =444.12; Found 444.08 15 Calc'd =430.1 1; Found 430.06 2 Calc'a =444.12; Found 444.05 0.9 Calc'd =440.09; Found 439.98 0.0003 Calc'd =586.23; Found 586.17 0.00 1 Calc'd =582.20; Found 582.20 nd nd 20 Calculated 496.15; Found 496. 0.015 Calculated 458.13; Found 458.09 -131- Table 3

S

Compound {[2-methyl-4-(2-methylpropyl)-6-oxo-1 (phenylmethyl)- 1 ,6-dihydro-5pyrimidinyl]arnino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 1,3-benzodioxol-5-yl)-3-[( {[2-oxo- 1- (phenylmethyl)-4-propyl- 1,2-dihydro-3 pyridinyl] amino)} carbonyl)amino]propanoic acid (3 1,3-benzodioxol-5-yl)-3-( {[9-oxo-8- (phenylmethyl)-2,3,4,5,8,9-hexahydro- 1 Hpyrido[3,4-b]azepin- 1 yl]carbonyl }amino)propanoic acid (3 S)-3 1-[(2-chlorophenyl)methyl]-4-ethyl-2oxo- 1,2-dihydro-3pyridinyl I amino)carbonyllamino -3 methylphenyl)propanoic acid 1 -[(2-chlorophenyl)methyl]-2-oxo-4propyl- 1,2-dihydro-3pyridinyll}amino)carbonyl]amir methylphenyl)propanoic acid (3 S)-3 I-[(2-chlorophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino)}-3 methylphenyl)propanoic acid (3 S)-3 {6-methyl-2-oxo-l1-(phenylmethyl)-4- [(phenylmethyl)oxy]- 1 ,2-dihydro-3pyridinyl) amino)carbonyl] amino)-(4 methylphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-2,4dimethyl-6-oxo- 1,6-dihydro-5pyrimidinyl am ino)carbonyl] amino)} -3 methylphenyl)propanoic acid

IC

50 (rim) 10 10 Calculated 476.18 m/z; Found 475.99 mlz.

4000 Calculated 488.18 mlz; Found 488.19 m/z.

10 Calculated 466.15 m/z; Found 465.95 mlz.

4 Calculated 480.17 mlz; Found 480.00 m/z.

5 Calculated 454.15 m/z; Found 454.09 m/z.

5 Calculated 524.22 mlz; Found 524.02 m/z.

10 Calculated (M-H)=467.15 m/z; Found 467.00 m/z.

Mass Spectral Data Calculated 475.23 mlz; Found 475.02 mlz.

Z -132- V (3 f -[(2,4-dichlorophenyl)methyl]-4methyl-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl]amino} methylphenyl)propanoic acid (3 {4-amino-l1-[(2-chlorophenyl)methyl]- 6-methyl-2-oxo- 1 ,2-dihydro-3pyridinyl }amino)carbonyl]amino} methylphenyl)propanoic acid {[1-[(2-chlorophenyl)methyl] -4- (methyloxy)-2-oxo- 1,2-dihydro-3pyridinyl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3S)-3-f 4-chloro-I 1 -[(2-chlorophenyl)methyl]- 2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino} methylphenyl)propanoic acid (3 S)-3 -[(2-chlorophenyl)methyl]-4-metbyl- 2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl jamino -methyl-4- (methyloxy)phenyl]propanoic acid (3 1 -[(2-chlorophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3pyridinyl I amino)carbonyl] amino -3 (methyloxy)phenyl]propanoic acid (3 {1 -[(2-chlorophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3 pyridinyl }amino)carbonyl]amino dimethylphenyl)propanoic acid (3 {4-amino-l1-[(2-chlorophenyl)methyl]- 2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl] amino)}-3 methylphenyl)propanoic acid (3 S)-3 [(2-chlorophenyl)methyl flu oro- 2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino)} -3 methylphenyl)propanoic acid 30 Calculated 486. 10 mlz; Found 485.95 m/z.

10 Calculated 467.15 m/z; Found 467.14 mlz.

20 Calculated 468.13 mlz; Found 467.97 m/z.

20 Calculated 472.08 m/z; Found 471.91 m/z.

15 Calculated 482.15 m/z; Found 481.93 mlz.

3 Calculated 470.15 mlz; Found 470.01 m/z.

10 Calculated 468.17 mlz; Found 468.05 nt/z.

10 Calculated 453.13 m/z; Found 453.01 mlz.

15 Calculated 456.12 m/z; Found 455.94 m/z.

-133- (3 -[(2-chlorophenyl)methyl]-2-oxo-4- (phenylamino)- 1 ,2-dihydro-3pyridinyl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -[(2-chlorophenyl)methyl]-2-oxo-4- (2-pyridinylamino)-1I,2-dihydro-3pyridinyl] amino) carbonyl)amino] -3 methylphenyl)propanoic acid (3 I -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino)} -3 methylphenyl)propanoic acid (3 -[(2-chlorophenyl)methyl]-2-oxo-4- [(2-pyridinylmethyl)amino]- 1,2-dihydro-3pyridinyl amino)carbonyl] amino -3 methylphenyl)propanoic acid (3 1 -[(2-chlorophenyl)methyl]-2-oxo-4- -pyridinylmethyl)amino]-1 ,2-dihydro-3pyridinyl }amino)carbonyl jammno methylphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-4-( 1,4oxazinan-4-yl)-2-oxo- 1,2-dihydro-3pyridinyl ]amino) carbonyl)amino] -3 methylphenyl)propanoic acid (3 -[(2-chlorophenyl)methyl]-2-oxo-4- (propylamino)- 1 ,2-dihydro-3pyridinyl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-[(2-fluorophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3 pyridinyl) amino)carbonyl] amino} -3 methylphenyl)propanoic acid (3 S)-3 I -[(2,6-dichlorophenyl)methyl]-4methyl-2-oxo- I ,2-dihydro-3pyridinyl} amirro)carbonyl] amino}1 methylphenyl)propanoic acid 20 Calculated 529.16 m/z; Found 529.02 mlz.

15 Calculated 530.16 m/z; Found 529.99 mlz.

10 Calculated 454.11 m/z; Found 454.05 mlz.

15 Calculated 544.17 m/z; Found 544.03 m/z.

20 Calculated 544.17 m/z; Found 544.02 m/z.

I Calculated (M-Hy- 523.17 m/z; Found 523.02 mlz.

10 Calculated 495.18 m/z; Found 495.04 m/z.

20 Calculated 436.17 m/z; Found 435.99 m/z.

20 Calculated 486. 10 mlz; Found 485.95 m/z.

a. a a a.

.134- S S

S**

(S S 1 -[(2-chlorophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl]amino }butanoic acid 1-[(2-bromophenyl)methyl]-4-methyl- 2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino methylphenyl)propanoic acid (3 {[4-methyl-2-oxo-l1-(phenylmethyl)- 1,2dihydro-3-pyridinyl] amino) carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 I -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1 ,2-dihydro-3 pyridinyl) amino)carbonyl] amino) -3-[3-methyl-4- (methyloxy)phenyl]propanoic acid (3 S)-3 1 -[(2-chlorophenyl)metbyl]-2-oxo-4phenyl- 1 ,2-dihydro-3 pyridinyl I amino)carbonyllamino -3 methylphenyl)propanoic acid (3 {4-bromo-l1-[(2-chlorophenyl)methyl]- 2-oxo- 1,2-dihydro-3pyridinyl~amino)carbonyllamino} methylphenyl)propanoic acid (3 1,3-benzodioxol-5-yl)-3- 1 14(2chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3py-ridinyl }amino)carbonyl]amino }propanoic acid (3 {11-[(2-chlorophenyl)methyl]-4-[(2-f 2- (methyloxy)ethyl]oxy} ethyl)oxyl-2-oxo- 1,2dihydro-3 -pyridinyl amino)carbonyl] amino)} -3- (4-methylphenyl)propanoic acid 300 Calculated 376.11 m/z; Found 376.00 mlz.

10 Calculated 496.09 mlz; Found 495.87 nilz.

30 Calculated 418.17 mlz; Found (M-Hy- 417.96 m/z.

8 Calculated (M-Hy- 484.12 rn/z; Found 484.03 m/z.

10 Calculated 514.15 m/z; Found 514.00 mlz.

20 Calculated 516.03 mn/z; Found 515.90 mniz.

20 Calculated 484.09 mlz; Found 484.03 m/z.

2 Calculated 556.18 mj'z; Found 556.03 m/z.

~S (S

S.

-135-

S

51*5*5*

'S

S.

SSs -[(2-chloropheny)methyl]-4hydroxy-6-methyl-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyljamino methylphenyl)propanoic acid (3 I-[(2-chlorophenyl)methyl]-4-[(1,1 dimethylethyl)arnino]-2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl ]amino} methylphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino} -3phenyipropanoic acid (3 {I -[(2-chlorophenyl)methyl]-4- [4methyltetrahydro- 1(2H)-pyrazinyl]-2-oxo- 1,2dihydro-3-pyridinyl }amino)carbonyl]amino (4-methylphenyl)propanoic acid (3 1 -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl Iamino)carbonyl] amino}1 -3 (methyloxy)phenyljpropanoic acid (3 I -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino ,4,5 tris(methyloxy)phenyl]propanoic acid (3 -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl~amino)carbonyl]amino} dimethylphenyl)propanoic acid (3 S)-3-f I -[(2-chlorophenyl)methyl]-4-[(3methyl-5-isoxazolyl)amino]-2-oxo- 1,2-dihydro-3 pyridinyl}I amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1 ,2-dihydro-3pyridinyl}I amino)carbonyl] amino)}-3-(3methylphenyl)propanoic acid 15 Calculated (M-HY- 468.13 rnlz; Found 468.05 mlz.

3 Calcul ated 509.20 m/z; Found 509.06 m/z.

10 Calculated =440. 10 mlz; Found 440.04 mlz.

3 Calculated =536.20 m/z; Found 536.12 m/z.

5 Calculated 470.11 mlz; Found 470.05 m/z.

20 Calculated 530.13 mlz; Found 530.05 m/z.

15 Calculated 468.13 m/z; Found 468.08 m/z.

15 Calculated 534.15 m/z; Found (M-Hf- 534.01 m/z.

20 Calculated (M-HV 454. 17 m/z; Found (M-HY- 454.04 m/z.

-136-

S

a 4. S 1-[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino (methyloxy)phenyl]propanoic acid (3S)-3-[3,5-bis(methyloxy)phenyl]-3-{[( chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3pyridinyl }amnino)carbonyl]amino I propanoic acid (3 1-[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3- quinolinyl}I amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid f{[Q 1 -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl}I amino)carbonyl] amino)} -3 (trifluoromethyl)phenyl]propanoic acid 1 -[(2-chlorophenyl)methyl]-4- [((ethyl [(ethylamino)carbonyl]amnino carbonyl) amino] -2-oxo- 1 ,2-dihydro-3 pyridinyll}amino)carbonyl jamino -3 methylphenyl)propanoic acid (3S)-3-{[({4-(1-azetanyl)-l chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyljamino methylphenyl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl) amino)carbonyl]amino 1 fluorophenyl)propanoic acid (3 S)-3 -[(2-chlorophenyl)methyl] -4hydroxy-2-oxo- 1,2-dihydro-3 pyridinyl} amino)carbonyl] amino}1-3 fluorophenyl)propanoic acid -[(2-chlorophenyl)methyl]-4-( [2-(methyloxy)ethyl]oxylethyl)oxy]ethylloxy)- 2-oxo- 1,2-dihydro-3 pyridinyl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid 5 Calculated 470.11 mlz; Found 470.03 ni/z.

3 Calculated (M-H)'=500.12 mlz; Found 500.07 mlz.

8 Calculated 504.13 m/z; Found 504.06 ml/z.

20 Calculated 508.04 m/z; Found 508.09 ml/z.

2 Calculated 595.21 m/z; Found 594.97 m/z.

5 Calculated 493.16 m/z; Found 493.05 m/z.

30 Calculated (M-Hy- 458.09 m/z; Found 458.03 mlz.

40 Calculated 458.09 m./z; Found 458.06 m/z.

2 Calculated 600.21 mlz; Found 600. 10 m/z.

-137- S (3 f -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1 ,2-dihydro-3 pyridinyl amino)carbonyl] amino -3 (trifluoromethyl)phenyl]propanoic acid 1-[(2-fluorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl]amino methylphenyl)propanoic acid (3 1-[(2-chloro-6-fluorophenyl)methyl]- 4-hydroxy-2-oxo- I ,2-dihydro-3pyridinyl amino)carbonyl]aniino} methylphenyl)propanoic acid 1 -[(2-chlorophenyl)methyl]-4hydroxy-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino -3 1,1 dimethylethyl)phenyljpropanoic acid -[(2-chlorophenyl)methyl]-5-methyl- 2-oxo- 1,2-dihydro-3pyridinyl}I amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid 3-(4-chlorophenyl)-3- ch lorophenyl)methyl]-4-hydroxy-2-oxo- 1,2 dihydro-3pyridinyl }amino)carbonyllamino }propanoic acid 25 Calculated 508.09 mlz; Found 508.02 mlz.

30 Calculated 438.15 m/z; Found 438.07 mlz.

10 Calculated 472.11 mlz; Found 472.06 mlz.

400 Calculated (M-H)y 496.16 mlz; Found 496.11 m/z.

70 Calculated 452.14 m/z; Found 451.99 m/z.

30 Calculated 474.06 mlz; Found 474.07 m/z.

-138- {[2-methyl-6-oxo- 1 -(phenylmethyl)-4- (2-pyridinyl)- 1 ,6-dihydro-5pyrimidinyl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 3-(3-chlorophenyl)-3-{[({ chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3pyridinyl }amino)carbonyl]amino} propanoic acid 3- [(2-chlorophenyl)methyl]-4-hydroxy-2oxo-1I,2-dihydro-3 pyridinyl }amino)carbonyl]amino dichlorophenyl)propanoic acid 25 Calculated 498.22 mlz; Found 498. 10 mlz.

30 Calculated 474.06 nilz; Found 474.03 mlz.

40 Calculated 508.02 mn/z; Found 507.97 mlz.

9 *9*e

C

Table 4 Name Mass Spectral Data C. C C

C

C.

C (3 1,3-benzodioxol-5-yl)-3-[( {[2-oxo- 1- (phenylmethyl)-3azepanyl] amino I carbonyl)aminojpropanoi c acid 1,3-benzodioxol-5-yl)-3- cyanophenyl)methyl]-2-oxo-3azepanyl }amino)carbonyl]amino propanoic acid (3 S)-3-(4-methylphenyl)-3 2-oxo-l1-(2thiophenylmethyl)- 1 ,2-dihydro-3pyridinyl]amino carbonyl)amino]propanoic acid (3 S)-3-(1I,3-benzodioxol-5-yl)-3-[( {I [2-oxo- 1 (phenylmethyl)- 1 ,2-dihydro-3pyridinyl]amino I carbonyl)amino]propanoic acid 1,3-benzodioxol-5-yl)-3- 1 methylphenyl)methyl]-2-oxo- 1 ,2-dihydro-3 pyr-idinyl amino)carbonyl] amino propanoic acid 0.015 Calculated (M-Hy- 452.18 m/z; Found 452. 10 m/z.

0.04 Calculated 477.18 mlz; Found 477.14 m/z.

0.6 Calculated (M-H)y 410.11 m/z; Found 4 10.00 mlz.

0.5 Calculated 434.13 n1!z; Found 434.05 m/z.

1 Calculated 448.14 m/z; Found 448.02 m/z.

-139- *5

S

S S S. S 555955 a 9**

S

5* *0 *5

S.

S

0 (3 1,3-benzodioxol-5-yl)-3-( [4- (methyloxy)phenyl]methyl -2-oxo- 1 ,2-dihydro- 3-pyridinyl)aniino]carbonyl I amino)propanoic acid (3 1,3-benzodioxol-5-yl)-3- methylphenyl)methyl]-2-oxo- I ,2-dihydro-3 pyridinyl amino)carbonyl] amino }propanoic acid (3 ,5-bis(methyloxy)phenyl]-3-[( {[2-oxo- 1 -(2-thiophenylmethyl)- 1 ,2-dihydro-3 pyridinyl] amino) carbonyl)amino]propanoic acid (3 S)-3-[4-(methyloxy)phenyl]-3-[( {[2-oxo- 1 thiophenylmethyl)- 1 ,2-dihydro-3pyridinyl] amino)} carbonyl)amino]propanoic acid (3 S)-3 [2-oxo- 1 -(2-thiophenylmethyl)- 1,2dihydro-3 -pyridinyl] amino) carbonyl)amino]-3- [3 -(trifluoromethyl)phenyl]propanoic acid 1,3-benzodioxol-5-yl)-3-[( (phenyloxy)phenyl ]amino)} carbonyl)am ino] propanoic acid (3 1,3-benzodioxol-5-yl)-3- thiophenylmethyl)amino]phenyi I amino)carbony 1]I amino~propanoic acid 1,3-benzodioxol-5-yl)-3- f chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl ]amino}I propanoic acid ,3-benzodioxol-5-yl)-3-({ [(2-oxo- If [3-(trifluoromethyl)phenyl]methyl -1,2dihydro-3 pyridinyl)amnino]carbonyl amino)propanoic acid (3 S)-3-(4-fluorophenyl)-3-[( {[2-oxo- 1 thiophenylmethyl)- 1 ,2-dihydro-3pyridinylamnino} carbonyl)amino]propanoic 3 Calculated 464.14 m/z; Found 464.03 mlz.

1.5 Calculated 448.15 m/z; Found 448.04 m/z.

0.7 Calculated 456.12 m/z; Found 456.00 m/z.

0.8 Calculated 426.11 mlz; Found 426.00 m/z.

2.5 Calculated 464.09 mlz; Found 463.99 m/z.

50 Calculated 419. 12 mlz; Found 418.97 m/z.

5 Calculated 43 8.11 m/z; Found 438.00 mlz.

0.8 Calculated 468.09 mlz; Found 468.01 nilz.

0.8 Calculated 502.12 m/z; Found 502.03 mlz.

1.6 Calculated 414.09 mlz; Found (M-Hy- 414.01 mlz.

-140- 000 *00 9066 00*5 (3S)-3-(1,3-benzodioxol-5-yl)-3- 14(4chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl]aminolpropanoic acid 1,3-benzodioxol-5-yl)-3-( (methyloxy)phenyl]methyl I -2-oxo- 1 ,2-dihydro- 3 -pyridinyl)aminolcarbonyl I amino)propanoic acid (3 S)-3 -(methyloxy)phenyl] [2-oxo- 1 thiophenylmethyl)- 1 ,2-dihydro-3pyridinyl]amino I carbonyl)amino]propanoic acid (3 1 -(2-thiophenylmethyl)- 1,2dihydro-3-pyridinyljamino}I carbonyl)amino]-3phenyipropanoic acid (3 [2-oxo-l1-(2-thiophenylmethyl)- 1,2dihydro-3 -pyridinyl] amino I carbonyl)amino] -3 [3,4,5-tris(methyloxy)phenyl]propanoic acid 1,3-benzodioxol-5-yl)-3- f 1 chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl~aminolpropanoic acid (3 1,3-benzodioxol-5-yl)-3- 1-[4fluorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl] amino) propanoic acid 1,3-benzodioxol-5-yl)-2,2-difluoro-3-[( [2oxo- 1 -(2-thiophenylmethyl)- 1 ,2-dihydro-3 pyridinyl]amino I carbonyl)amino]propanoic acid (3 1,3-benzodioxol-5-yl)-3 f 2-oxo- 1 [3 -(phenyloxy)propyl] 1,2-dihydro-3 pyridinyl}I amino)carbonyl]amino) propanoic acid 1,3-benzodioxol-5-yl)-3- 1 dichlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3 pyridinyl}I amino)carbonyl] amino I propanoic acid 3 Calculated 468.09 m/z; Found 467.99 mlz.

0.5 Calculated 464.14 MlZ; Found 464.04 m/z.

1.4 Calculated 426.11 rnlZ; Found 426.02 m/z.

1 Calculated 3 96. 10 m/z; Found 396.01 m/z.

0.3 Calculated 486.13 mlz; Found 485.98 m/z.

0.3 Calculated (M-Hy- 468.08 mhz; Found 468.03 m/z.

2 Calculated 452.12 mhz; Found 452.00 mhz.

>100 Calculated 476.07 mhz; Found 476.00 mhz.

14 Calculated 478.16 mhz; Found 478.09 m/z.

5 Calculated 502.05 m/z; Found 501.94 m/z.

-14 1- (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1 6 Calculated 426.16 mlz; (cyclopentylmethyl)-2-oxo- 1,2-dihydro-3 Found 426.09 m/z.

pyridinyl] amino) carbonyl)amino]propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3-{[f({2-oxo-1 15 Calculated 454.09 mlz; [2-(2-thiophenyl)ethyl]- 1,2-dihydro-3- Found 453.99 m/z.

pyridinyl amino)carbonyl]amino} propanoic acid (3 S)-3 {11-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Cal 1 culated 440.14 mlz; I ,2-dihydro-3- Found 440.09 m/z.

pyridinyl~amino)carbonyl]amino} methylphenyl)propanoic acid (3S)-3-(2,3-dihydro-1-benzofuran-5-yl)-3-[({[2- 0.14 Calculated 43 8.11 mlz; oxo-l1-(2-thiophenylmethyl)- 1,2-dihydro-3- Found 437.99 m/z.

pyridinyl] amino) carbonyl)amino]propanoic acid (3 S)-3-(3-fluorophenyl)-3-[( {[2-oxo- 1 3 Calculated 414.09 m/z; thiophenylmethyl)- 1,2-dihydro-3- Found 413.99 mlz.

pyridinyl]amino} carbonyl)amino]propanoic acid (3S)-3-[({[2-oxo-1I-(2-thiophenylmethyl)- 1,2- 1.5 Calculated 464.09 mlz; dihydro-3 -pyridinyl] amino)} carbonyl)aminol-3- Found 463.99 mlz.

[4-(trifluoromethyl)phenyl]propanoic acid 1,3-benzodioxol-5-yl)-3-[( [6-oxo- 1- 0.5 Calculated 434. 13 m/z; (phenylmethyl)-1,6-dihydro-3- Found 434.02 mlz.

pyridinyl]amino} carbonyl)aminojpropanoic acid (3S)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-3- 0.35 Calculated 482.08 nilz; [2-oxo-l1-(2-thiophenylmethyl)- 1,2-dihydro- Found 481.97 m/z.

3 -pyridinyl] amino}I carbonyl)amino]propanoic acid I-dimethylethyl)phenyl]-3-[({ 2 Calculated (M-Hy- 452.16 m/z; oxo- 1 -(2-thiophenylmethyl)- 1 ,2-dihydro-3 Found 452.02 mlz.

pyridinyijamino I carbonyl)aminolpropanoic acidI -142- (3 1,3-benzodioxol-5-yl)-3-[( {butyl [2,5dioxo- 1 -(phenylrnethyl)tetrahydro- I H-pyrrol-3y1]amino} carbonyl)amino]propanoic acid (3 -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl]amino tris(methyloxy)phenyl]propanoic acid (3 S)-3 1-[(2,6-dichlorophenyl)methyl]-2oxo- 1,2-dihydro-3pyridinyl) amino)carbonyl] amino) -3 methylphenyl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-2-oxo- I ,2-dihydro-3pyridinyl }amino)carbonyl]amino -[4-fluoro- 3-(trifluoromethyl)phenyljpropanoic acid (3 S)-3 1 -[(2-fluorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl }amino)carbonyl jamino methylphenyl)propanoic acid 70 Calculated (M-H.Y 494.19 mlz; Found 494.12 mlz.

0.04 Calculated 516.16 mlz; Found 516.02 m/z.

0.2 Calculated 474. 10 m/z; Found 474.04 m/z.

0.2 Calculated 512. 10 m/z; Found 512.04 mlz.

0.1 Calculated 422.15 mlz; Found 422.01 mlz.

.0 .3 -143- (3S)-3-(4-methylphenyl)-3- 1 methylphenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl]amino }propanoic acid (3 -[(2-bromophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyl]amino} methylphenyl)propanoic acid (3 1 -[(2,4-dichlorophenyl)methyl]-2oxo-1 ,2-dihydro-3pyridinyl} amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid (3 {l1-[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino) dihydro- I -benzofuran-5-yl)propanoic acid 1,3-benzodioxol-5-yl)-3- {1 chlorophenyl)methyl]-2-oxo-1I,2-dihydro-3pyridinyl amino)carbonyl] amino I propanoic acid (3 S)-3-(4-methylphenyl)-3 [(2-oxo- 1 [2- (trifluoromethyl)phenyl]methyl} 1,2-dihydro-3pyridinyl)amino]carbonyl amino)propanoic acid f [Q I -[(2,5-dichlorophenyl)methyl]-2oxo- 1,2-dihydro-3 pyridinyl amino)carbonyl] amino -3 methylphenyl)propanoic acid -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyl]amino} -3phenyipropanoic acid 1-[(2-chlorophenyl)methyl] -2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbony]amino) -2phenylethanoic acid 0.1 Calculated 418.18 mlz; Found 418.02 m/z.

0.05 Calculated 484.09 m/z; Found 484.03 mlz.

0.4 Calculated 474. 10 mlz; Found 474.05 mlz.

0.04 Calculated 466.11 m/Z; Found 466.00 m/z.

2 Calculated 468.09 m/z; Found 467.97 m/z.

I Calculated 474. 10 m/z;' Found 474.09 m/z.

0.15 Calculated 474. 10 mlz; Found 474.04 mlz.

50 Calculated 424. 10 m/z; Found (M-Hy- 423.99 m/z.

80 Calculated 410.08 m/z; Found 409.95 m/z.

-144- {11-[(2-chlorophenyl)metbyl]-2-oxo- 1 ,2-dihydro-3pyridinyl}I amnino)carbonyl jamino} diniethylphenyl)propanoic acid (3 f 1 -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl ]amino} -3phenyipropanoic acid 1-[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyl] amino) -3 (methyloxy)phenyl]propanoic acid -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl}I amino)carbonyl] amino) -3 hydroxyphenyl)propanoic acid (3 f [3 -(methyloxy)phenyl]methyll}-2oxo- 1,2-dihydro-3pyridinyl)aminojcarbonyl }amino)-3-(4methylphenyl)propanoic acid (3 -[(2-bromophenyl)methyl] -2-oxo- 1 ,2-dihydro-3pyridinyl }amino)carbonyllamino tris(methyloxy)phenyl]propanoic acid 1-[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl I amino)carbonyl] amino -3 ,4dimethylphenyl)propanoic acid {[5-chloro-2-hydroxy-3- (phenylmethyl)phenyl]amino} carbonyl)amino]- 3-(4-methylphenyi)propanoic acid (3 S)-3-(4-methylphenyl)-3-[( (phenylmethyl)phenyll amino I carbonyl)amino] propanoic acid (3 1 -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino -3 [3 -methyl- 4-(methyloxy)phenyljpropanoic acid 0.1 Calculated 454.11 mlz; Found 454.01 m/z.

0.1 Calculated 440. 10 m/z; Found 440.00 mlz.

0.2 Calculated 434.17 mlz; Found 434.01 m/z.

0.08 Calculated 558.09 m/z; Found 557.87 m/z.

0.09 Calculated 454.15 m/z; Found 454.07 mlz.

8 Calculated 437.12 mlz; Found 437.06 m/z.

10 Calculated 387.17 mlz; Found 387.00 rn/z.

0.04 Calculated 468.13 rnlz; Found 468.01 mlz.

0.1 Calculated 452.14 mlz; Found 451.96 mlz.

Calculated 424. 10 mlz; Found 424.07 mlz.

-145-

C

-[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyllamino} hydroxy-3-niethylphenyl)propanoic acid (3 1-[(2,3-dichlorophenyl)methyl]-2oxo-1I,2-dihydro-3pyridinyl }amino)carbonyllamino} methylphenyl)propanoic acid '-biphenyl]-2-ylmethyl)-2oxo- 1,2-dihydro-3pyridinyl]amino} carbonyl)amino]-3 methylphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyllamino)carbonyl]amino} methylphenyl)propanoic acid (3 1 [(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid (3 1 -[(2-chlorophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl }amino)carbonyl]amino dihydro- I H-inden-5-yl)propanoic acid (3 S)-3 -[(2-cyanophenyl)methyl] -2-oxo- I ,2-dihydro-3pyridinyl) amino)carbonyl] amino) -3 methylphenyl)propanoic acid (3S)-3-[2,6-bis(methyloxy)phenyl]-3-{[({t 14[(2chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyri dinyl} amino)carbonyl] amino Ipropanoi c acid 0.07 Calculated 454.11 mlz; Found 454.00 mi/z.

0.35 Calculated 472.08 m/z; Found 471.94 m/z.

2.5 Calculated (M-Hf- 480.19 mlz; Found 480.05 mlz.

0.2 Calculated 438.12 mlz; Found 438.00 mlz.

3 Calculated 438.12 m/z; Found 437.99 mlz.

0.3 Calculated 464.13 m/z; Found 464.03 m/z.

0.1 -Calculated 431.18 mlz; Found 431.09 m/z.

6 Calculated 484.14 m/z; Found 483.96 m/z.

C C

C

-146-

S..

S

*5 S

S*.

*5

C

(3 1 -[(3-hydroxyphenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyl]amino} methylphenyl)prooanoic acid {[2-methyl-6-oxo-1 -(phenylmethyl)- 1 ,6-dihydro-5pyrimidinyljamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-4-oxo- 1 ,4-dihydro-3pyridinyl }amino)carbonyl~amino methylphenyl)propanoic acid (3S)-3-(4-methylphenyl)-3-{ nitrophenyl)methyl]-2-oxo- 1,2-dihydro-3 pyridinyl }amino)carbonyljamino }propanoic acid (3 S)-3-(4-methylphenyl)-3- nitrophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyllamino }propanoic acid (3 1-[(2-chlorophenyl)methyl] -2-oxo- 1 ,2-dihydro-3pyridinyl }amino)carbonyl]amino}-3-(2,6dihydroxyphenyl)propanoic acid I -[(2,6-difluorophenyl)methyl]-2oxo- 1,2-dihydro-3pyridinyl }amino)carbonyl]amino)}-3 methylphenyl)propanoic acid (3 1-[(2,4-difluorophenyl)methyl]-2oxo- 1,2-dihydro-3pyridinyl }amino)carbonyljamino methylphenyl)propanoic acid 1-[(2,5-difluorophenyl)methyl]-2oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl] amino}1-3 methylphenyl)propanoic acid 0.2 Calculated 420.18 m/z; Found 422.05 mlz.

0.1 Calculated 419.17 mlz; Found 419.03 m/z.

0.1 Calculated 438.12 m/z; Found 43 8. 10 mlz.

1 Calculated 451.17 m/z; Found 451.07 m/z.

1 Calculated 451.17 ml/z; Found 451.09 m/z.

3 Calculated 456. 10 m/z; Found 456.04 m/z.

0.3 Calculated 440.14 nilz; Found 440.00 mlz.

1.3 Calculated 440.14 mlz; Found 439.96 m/z.

0.8 Calculated 440.14 m/z; Found 43 9.96 m/z.

-147- (3 f 1 -[(2-chlorophenyl)methyl]-2methyl-6-oxo-1 ,6-dihydro-5pyrimidinyl amino)carbonyl]amino} methylphenyl)propanoic acid 1-[(2-chloro-6fluorophenyl)niethyl]-2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl]amino} methylphenyl)propanoic acid 1-[2-bromo-5fluorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl I amnino)carbonyl] amino) -3 methylphenyl)propanoic acid (3 I -[(2-chloro-4fluorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl aniino)carbonyl] amino)} methylphenyl)propanoic acid {1 -[(2-bromophenyl)methyl]-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino I -3 -[3-methyl- 4-(methyloxy)phenyl]propanoic acid (3S)r3-{I({1 -[3,5-dimethyl-4isoxazolyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl }amino)carbonyljamino methylphenyl)propanoic acid (3S)-3-(4-methylphenyl)-3-{ [({2-oxo-l trimethylphenyl)methyl]- 1,2-dihydro-3 pyridinyl}I amino)carbonyl ]amino I propano ic acid (3 S)-3 -(4-methylphenyl)-3- 1-[(2-methyl- 1 ,3-thiazol-4-yl)methyl]-2-oxo- 1,2-dihydro-3 pyridinyl) amino)carbonyl) amino Ipropanoic acid dimethylethyl)phenyl]methyl) -2-oxo- 1,2dihydro-3-pyridinyl)arnino]carbonyl I amino)-3 (4-methylphenyl)propanoic acid 0.09 Calculated 453.13 mlz; Found 453.00 m/z.

0. 1 Calculated 456.11 m/z; Found 455.94 mlz.

0.5 Calculated 500.06 m/z; Found 499.91 m/z.

0.35 Calculated 456.11 mlz; Found 455.93 m/z.

0.2 Calculated 512.08 m/z; Found 511.96 mlz.

3 Calculated (M-Hy- 423.17 m/z; Found 423.02 m/z.

2.5 Calculated 446.21 m/z; Found 446.08 m/z.

I Calculated 425.13 m/z; Found 424.99 m/z.

6 Calculated 460.22 m/z; Found 460.07 m/z.

-148-

C

S

(3 ,3-benzoxazol-2-ylmethyl)-2- >10 Calculated 445.15 m./z; oxo- 1,2-dihydro-3- Found 445.01 m/z.

pyridinyl]anmino) carbonyl)amino] -3 methylphenyl)propanoic acid (3 {2-[(2-hydroxyphenyl)amino]-2- >10 Calculated 463. 16 MlZ; oxoethyl} -2-oxo- 1,2-dihydro-3- Found 463.06 m/z.

pyridinyl)aminojcarbonyl} amino)-3-(4methylphenyl)propanoic acid 1-[(2-chloro-6-nitrophenyl)methyl]- 4 Calculated 483.11 m/z; 2-oxo- 1,2-dihydro-3- Found 483.01 m/z.

pyridinyl amino)carbonyl] amino)} -3 methylphenyl)propanoic acid 1-[(5-chloro-2- 2.5 Calculated 456.11 m/z; fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found 456.00 mlz.

pyridinyl amino)carbonyl] amino)} methylphenyl)propanoic acid 1-[(2-amino-6- 2 Calculated 453.13 mlz; chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3 Found 453.02 *m/z.

pyridinyl) amino)carbonyl] amino) methylphenyl)propanoic acid 3 Calculated 490.14 m/z; (trifluoroniethyl)phenyl]methyl -2-oxo- 1,2- Found 489.99 mlz.

dihydro-3-pyridinyl)aminolcarbonyl I amino)-3 (4-methylphenyl)propanoic acid [(I{1-[(5-chloro-2-thiophenyl)methyl]-2- 1.3 Calculated 444.08 m/z; oxo- 1,2-dihydro-3- Found 443.97 m/z.

pyridinyl}I amino)carbonyl ]amino}1 -3 methylphenyl)propanoic acid {[((I1-[(2-bromo-5-nitrophenyl)methyl]- 2 Calculated 527.06 m/z; 2-oxo- 1,2-dihydro-3- Found 526.95 mlz.

pyridinyl I amino)carbonyl ]amino'} methylphenyl)propanoic acid 3-(4-chlorophenyl)-3-{f( 0.03 Calculated 474.06 m./z; chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2- Found 474.07 m/z.

dihydro-3pyridinyl} amino)carbonyl] amino) propanoic acid -149- [2-methyl-6-oxo-l1-(phenylmethyl)-4- 0.025 (2-pyridinyl)- 1,6-dihydro-5pyrimidinyijamino) carbonyl)amino]-3 methylphenyl)propanoic acid 1 -[(5-amino-2- 0.08 bromophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl]amino} methylphenyl)propanoic acid -[(2,5-dimethylphenyl)methyl]-2- 0.15 oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl]amino} methylphenyl)propanoic acid 3-(3-chlorophenyl)-3-{[({ 0.03 chlorophenyl)methyl]-4-hydroxy-2-oxo- 1,2dihydro-3-pyridinyl amino) carbonyl] amino) propanoic acid 3- {11-[(2-chlorophenyl)methyl]-4-hydroxy-2- 0.04 oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino -3 ,4dichlorophenyl)propanoic acid 1- [5-(acetylamino)-2- 0.2 bromophenyl]methyl}-2-oxo-1 ,2-dihydro-3pyridinyl)aminojcarbonyl} amino)-3-(4methylphenyl)propanoic acid {2-bromo-5- 0.25 [(methylsulfonyl)amino]phenyl methyl)-2-oxo- 1 ,2-dihydro-3pyri dinyl ]amino) carbonyl)amino]-3-(4methylphenyl)propanoic acid 3 -(4-chlorophenyl)-3 0.4 chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3pyridinyl amino)carbonyl] amino) propanoic acid 3-(3-chlorophenyl)-3- 1 chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3 pyridinyl amino)carbonyl] amino Ipropanoic acid Calculated 497.08 mlz; Found 497.02 ml/z.

Calculated 432.19 m/z; Found 432.04 mlz.

Calculated (M-Hf- 474.06 mlz; Found 474.03 mlz.

Calculated 508.02 m/z; Found 507.97 mlz.

Calculated 539.09 nilz; Found 539.02 m/z.

Calculated 575.06 m/z; Found,(M-H)- 575.01 m/z.

Calculated 458.07 rnlz; Found 457.96 mlz.

Calculated 458.07 m/z; Found 457.93 ml/z.

Calculated 498.22 mlz; Found 498. 10 mlz.

-150- 9* a. 3- {11-[(2-chlorophenyl)methyl]-2-oxo- 1,2- 1 Calculated 492.03 mlz; dihydro-3 -pyridinyl) amino)carbonyl] amino)}-3- Found 491.85 m/z.

(3 ,4-dichlorophenyl)propanoic acid (3 S)-3-{f[(f{1-[2-bromo-4- 1 Calculated 516.03 m/z; chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found 515.91 nilz.

pyridinyl }amino)carbonyl]amino)}-3-(4methylphenyl)propanoic acid (3 1-[(4-chlorophenyl)methyl]-2-oxo- 2 Calculated 438.12 mlz; 1 ,2-dihydro-3- Found 437.88 m/z.

pyridinyl}I amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-4- 0.035 Calculated 498.14 mlz; hydroxy-2-oxo-1,2-dihydro-3- Found 498.05 m/z.

pyridinyl }amino)carbonyl jamino} -3 dimethyl-4-(methyloxy)phenyl]propanoic acid (3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 0.015 Calculated 524.08 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found 524.03 m/z.

pyridinyl }amino)carbonyl jamino)}-3- {4- [(trifluoromethyl)oxy]phenyl }propanoic acid 1 -[(2-chlorophenyl)methyl]-4-( 1,4- 0. 1 Calculated 489.19 m/z; oxazinan-4-yl)-2-oxo-1,2-dihydro-3- Found 489.13 m/z.

pyridinyl] amino}I carbonyl)aminol -5 methylhexanoic acid (3S)-3-[({[4-hydroxy-6-methyl-2-oxo-l- 0.035 Calculated (M-H)y 434.17 m/z; (phenylmethyl)-1,2-dihydro-3- Found 434.08 mlz.

pyridinyl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-2-oxo-4- 0.030 Calculated 559.14 m/z; [(propylsulfonyl)amino]-1 ,2-dihydro-3- Found 559.04 mlz.

pyridinyl amino)carbonyl ]amnino}1 -3 methylphenyl)propanoic acid 1- (3 1 -[(2-chlorophenyl)methyl]-4- 0.025 Calculated 468.13 mlz; hydroxy-2-oxo- 1,2-dihydro-3- Found 468.06 m/z.

pyridinyl amino)carbonyllamino ethylphenyl)propanoic acid (3 -[(2-chlorophenyl)methyl]-4- 0.02 Calculated 484.13 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found 484.06 mlz.

pyridinyl }amino)c arbonyl]aminol}-34[4- (ethyloxy)phenyl]propanoic acid (3 {[4-hydroxy-2-oxo-l1-(phenylmethyl)- 0.030 Calculated 420.16 mlz; I ,2-dihydro-3- Found 420.08 mlz.

pyridinyl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid 0 Table Name (3 S)-3 -tert-butyl-2-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino] -3 (4-methylphenyl)propanoic acid (3 -(4-fluorobenzyl)-2-oxo- 1,2dihydropyridin-3 -yl ]amino)} carbonyl)amino] -3 methylphenyl)propanoic acid (3 {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- I ,2-dihydropyridin-3 -yl ]amino)} carbonyl)aminol-3 [4-fluoro-3-(trifluoromethyl)phenyl]propanoic acid (3 -(2,5-dimethylbenzyl)-4-hydroxy-2oxo- 1 ,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 {[4-hydroxy-l1-(2-methylbenzyl)-2-oxo- 1 ,2-dihydropyridin-3 -yl ]aniino carbonyl)amino] -3 (4-methylphenyl)propanoic, acid (3S)-3-[({I-(2-hydroxybenzyl)-2-oxo-1 ,2dihydropyridin-3 -yl ]amino) carbonyl)amino] -3 methylphenyl)propanoic acid

IC

5 o (jpiM) Mass Spectral Data 2.5 Calculated 490.23 m/z; Found 490.11 mlz.

2 Calculated 422.12 mlz; Found 422.00 mlz.

0.025 Calculated 526.08 mlz; Found 526.01 mlz.

0.02 Calculated 448.19 nIz; Found 448.00 mlz.

0.02 Calculated 434.17 m/z; Found 434.05 mlz.

0.2 Calculated 420.16 m/z; Found 420.09 mlz.

-152- [1 -chlorobenzyl)-2-oxo- 1,2dihydropyridin-3-yl]amino }carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -(2-chloro-6-methoxybenzyl)-2-oxo- I ,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3- (4-methylphenyl)propanoic acid [1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino] -3 (4-methoxy-3 ,5-dimethylphenyl)propanoic acid 4- S)-2-carboxy-1 methylphenyl)ethyllamino} carbonyl)amino]- 1-(2chlorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4yljamninolbenzoic acid 1-(2-chlorobenzyl)-4-[(2,2dimethylpropanoyl)amino]-2-oxo- 1,2dihydropyridin-3-yl) amino)carbonyl ]amino)}-3-(4methylphenyl)propanoic acid (3 S)-3 -(2-chloro-5-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino] -3 (4-methylphenyl)propanoic acid I-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl] amino}I carbonyl)amino]butanoic acid (3 S)-3 {[(tert-butylamino)carbonyl]amirno (2-chlorobenzyl)-2-oxo- 1,2-dihydropyridin-3yl Iamino}I carbonyl)amino]-3 methylphenyl)propanoic acid (3 -(2-chloro-5-hydroxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yl jamino)}carbonyl)amino]-3- (4-methylphenyl)propanoic acid (3 [1 -(2-cyanobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 methylphenyl)propanoic acid (3 ([1-(2,4-dichlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino] -3 (4-methylphenyl)propanoic acid 0.5 Calculated 438.12 mlz; Found 438.01 mlz.

0.1 Calculated 468.13 m/z; Found 468.08 m/z.

0.03 5 Calculated (M-HY 498.14 nilz; Found 497.94 mlz.

0.004 Calculated 573.15 nt/z; Found 572.92 m/z.

0.01 Calculated (M-Hy 537.19 m/z; Found (M-H)y 536.88 mlz.

0.09 Calculated 468.13 mlz; Found 467.99 m/z.

0.19 Calculated (M-Hy 378.09 mlz; Found 378.01 mlz.

0.01 Calculated 552.20 m/z; Found 551.89 mlz.

0.25 Calculated 454.12 rnlz; Found 454.03 mlz.

0.009 Calculated 445.15 m/z; Found 445.01 mlz.

0.06 Calculated 488.08 mlz; Found 487.96 mlz.

A.

r.

-153a.

a.

a. a a.

a..

a.

{[4-hydroxy-l1-(2-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yl]arnino} carbonyl)amino]-3 (4-methylphenyl)propanoic acid {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- (4-methoxy-2,5-dimethylphenyl)propanoic acid (3 [1 -(2-chloro-6-hydroxybenzyl)-2-oxo- I ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3 (4-methylphenyl)propanoic acid (3 I-(3-tert-butyl-2-hydroxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yl]amino~carbonyl)amino]-3- (4-methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino]-3 (4-methylphenyl)propanoic acid {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino]-3 (3-ethylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyr-idin-3 -yl] amino)} carbonyl)amino]-3 (2,3-dihydro- 1,4-benzodioxin-6-yl)propanoic acid (3 S)-3 -(2,5-difluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl]amino} carbonyl)amino]-3 (4-methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl jamino }carbonyl)amino]-4- (4-methylphenyl)butanoic acid 1-[2-chloro-5-(methylthio)benzyl]-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl amino)carbonyl] amino}1 -3 methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino Icarbonyl)amino-3- (7-methoxy-1 ,3-benzodioxol-5-yl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl]amino }carbonyl)amino]-3 (3-ethoxy-4-methoxyphenyl)propanoic acid 0.08 Calculated 450.1 7 mlz; Found 450.02 m/z.

0.08 Calculated 498.14 mlz; Found 497.95 mlz.

0.1 Calculated 454.12 mlz; Found 454.05 mlz.

4 Calculated 476.02 mlz; Found 476.00 nilz.

0.3 Calculated 454.17 m/z; Found 454.05 m/z.

0.015 Calculated 468.13 nilz; Found 467.95 nIz.

0.01 Calculated 498. 10 mlz; Found 497.85 m/z.

0.015 Calculated 456.14 m/z; Found 455.96 mlz.

30 Calculated 468.13 mlz; Found =467.87 m/z.

0.0 15 Calculated 500. 10 mlz; Found 499.92 m/z.

0.005 Calculated (M-HY 514. 10 mlz; Found (M-Hy- 513.86 mlz.

0.002 Calculated (M-HY 514.13 nilz; Found 513.90 mlz.

-154- *00.

0"0** (3 [1 -chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yllamino} carbonyl)amino]-3- (3-fluoro-4-rnethoxyphenyl)propanoic acid {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- (3 ,4-dimethoxyphenyl)propanoic acid [1-(4-fluorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino) carbonyl)amino]-3 methylphenyl)propanoic acid (3 [1 -(2-methoxybenzyl)-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3 methylphenyl)propanoic acid (3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)aminol 1 3 acid (3 -(2-chloro-5-methoxybenzyl)-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl] amino) carbonyl)amino]-3 methylphenyl)propanoic acid -[3,5-bis(trifluoromethyl)benzyl]-4hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl I amino)carbonyl] amino}1-3-(4methylphenyl)propanoic acid (3 S)-3 [1 -(4-tert-butylbenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- (4-methylphenyl)propanoic acid (3 S)-3 -chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino] -3 (4-methylphenyl)propanoic acid (3 [1 -(4-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 (4-methylphenyl)propanoic acid (3S)-3-f {4-hydroxy-2-oxo-l1-[3- (trifluoromethyl)benzyl]- 1,2-dihydropyridin-3yl} amino)carbonyl]amino}-3-(4methylphenyl)propanoic acid 0.015 Calculated 488. 10 mlz; Found 487.92 mlz.

0.002 Calculated 500.12 mlz; Found 500.01 m/z.

0.022 Calculated 438.18 mlz; Found 438.00 m/z.

0.25 Calculated (M-HY 434.17 mlz; Found 433.95 nt/z.

0.05 Calculated 468.13 mlz; Found 467.94 nilz., 0.012 Calculated 484.13 m/z; Found 484.03 mlz.

0.3 Calculated 556.13 mlz; Found 555.95 nt/z.

0.03 Calculated 476.22 m/z; Found 476.05 mlz.

0.0 15 Calculated 454.12 m/z; Found 453.99 mlz.

0.007 Calculated 454.12 mlz; Found 454.00 rnz.

0.017 Calculated 488.14 mlz; Found 487.99 mlz.

*5*5*5 S S S 5545 -155- *:so *too *0.

*00 to* 000 1 -(2-bromobenzyl)-4-hydroxy-2-oxo- 1 ,2-dibydropyridin-3-yl]amino} carbonyl)amino]-3 (4-methylphenyl)propanoic acid (3 ,4-dichlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl] amino) carbonyl)amino] -3 (4-methylphenyl)propanoic acid {[4-hydroxy-1-(4-methylbenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yljainino} carbonyl)amino]-3- (4-metbylphenyl)propanoic acid -(2-chloro-6-niethoxybenzyl)-4hydroxy-2-oxo- 1,2-dihydropyridin-3 yI]amino} carbonyl)aniino]-3-(4methylphenyl)propanoic acid (3 {4-hydroxy-2-oxo-l1-[4- (trifluoromethyl)benzyl]- I ,2-dihydropyridin-3yl I amino)carbonyl] amino}1 methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino}I carbonyl)amino] -3 [3-(trifluoromethoxy)pbenyl]propanoic acid (3 [4-hydroxy-l1-(3-methylbenzyl)-2 -oxo- 1 ,2-dihydropyridin-3 -yI] amino Icarbonyl)amino] -3 (4-methylphenyl)propanoic acid (3 {[4-hydroxy-2-oxo-lI-(pyridin-2-ylmethyl)- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 (4-methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo-1 ,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid (3 [1 -(2,4-difluorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino}I carbonyl)amino (4-methylphenyl)propanoic acid (3 S)-3 I1 -(2,6-difluorobenzyl)-4-hydroxy-2-oxo- 1, 2-dihydropyridin-3 -yl ]amino I carbonyl)aminol -3 (4-methylohenyl)propanoic acid 0.015 Calculated 498.07 mlz; Found 497.97 mlz.

0.045 Calculated 488.08 mlz; Found 487.96 m/z.

0.025 Calculated 434.17 m/z; Found 434.05 m/z.

0.003 Calculated (M-Hy 484.13 m/z; Found 484.02 mlz.

0.02 Calculated 488.14 mlz; Found 487.99 m/z.

0.02 Calculated 524.08 mlz; Found 523.91 mlz.

0.05 5 Calculated 434.17 mlz; Found 433.99 mn/z.

0.045 Calculated (M-Hy 421.15 m'z; Found 421.06 mlz.

0.005 Calculated 468.13 mlz; Found 467.99 rm'z.

0.03 Calculated 456.14 mlz; Found 456.01 mlz.

0.008 Calculated (M-Hy 456.14 mlz; Found 456.01 mlz.

S

5*4

OS..

0 4*@S -156- (3S)-3-{[({4-hydroxy-2-oxo-1 (trifluoromethoxy)benzyl]- 1,2-dihydropyridin-3yl }amino)carbonyl]amino} methylphenyl)propanoic acid (3 {4-hydroxy-2-oxo-l1-[4- (trifluoromethoxy)benzyl]- 1,2-dihydropyridin-3yl amino)carbonyl] amino) -3 methylphenyl)propanoic acid 1 -(2-chloro-6-methoxybenzyl)-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl ]amnino} carbonyl)amino]-3-(3 ,5dimethoxyphenyl)propanoic acid 3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(2fiiryl)propanoic acid (3 {4-hydroxy-2-oxo-l1-[2- (trifluoromethyl)benzyl]-1 ,2-dihydropyridin-3yl }amino)carbonyl]amino} methylphenyl)propanoic acid 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1, 2-dihydropyridin-3 -yl] amino I carbonyl)amino]-4- (4-methylphenyl)butanoic acid (3 [1-(2-chlorobenzylj-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino -3 (3 ,4-diethoxyphenyl)propanoic acid (3 {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3 (3 -ethoxyphenyl)propanoic acid (3 {[4-hydroxy-l1-(3 -methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yllaminol}carbonyl)amino] -3- (4-methylphenyl)propanoic acid (3 -(2,3-dichlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl ]amnino) carbonyl)amino] -3 (4-methylphenyl)propanoic acid (3 [1 -benzyl-2-oxo-5 -(trifluoromethyl)- 1,2dihydropyridin-3 -yl ]amnino carbonyl)amino] -3 methylphenyl)propanoic acid 0.045 Calculated 504.14 mlz; Found 503.98 mlz.

0.025 Calculated 504.14 m/z; Found -503.98 nIz.

0.0015 Calculated (M-Hy 530.13 mlz; Found 529.91 m/z.

0.05 Calculated 430.08 mlz; Found 429.94 rnlz.

'0.02 Calculated 488.14 ml~z; Found 487.96 mlz.

0. 15 Calculated 468.13 m/z; Found 467.99 mlz.

0.0008 Calculated 528.15 m/z; Found 527.96 mlz.

0.003 Calculated 484.12 m/z; Found (M-Hy- =483.94 mn/z.

0.04 Calculated 450.17 mlz; Found =450.00 m/z.

0. 13 Calculated 488.08 rnlz; Found 487.92 mlz.

1.5 Calculated 472.15 mlz; Found (M-HY- =471.89 ml/z.

-157- (3 ,5-dirnethylbenzyl)-4-hydroxy-2oxo- 1 ,2-dihydropyridin-3yl]amnino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-(2-chloro-6-methoxybenzyl)-4hydroxy-2-oxo- 1,2-dihydropyridin-3yljamino} carbonyl)amino]-3-[4- (trifluorornethoxy)phenyl]propanoic acid (3 -chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yI]aminolcarbonyl)aminol-3- (3-methoxy-4-methylphenyl)propanoic acid 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yllamino} carbonyl)amino]-3- (3 ,5-dimethoxy-4-methylphenyl)propanoic acid (3 I1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-5pentyl- 1 ,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 (3 ,4-dimethylphenyl)propanoic acid (3 [1 -(2,4-dichlorobenzyl)-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydropyridin-3yllamnino} carbonyl)amnino]-3 methylphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino) carbonyl)- 1 methylphenyl)hydrazinojacetic acid (3 -(2-chlorobenzyl)-5-ethyl-4-hydroxy-2oxo- 1 ,2-dihydropyridin-3 yl] amino) carbonyl)amino] -3 methylphenyl)propanoic acid 3+ [1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3 pyridin-3 -ylpropanoic acid (3 S)-3 {[5-butyl-lI-(2-chlorobenzyl)-4-hydroxy-2oxo- 1,2-dihydropyridin-3yl ]amino) carbonyl)amino] -3 methylphenyl)propanoic acid 0.06 Calculated 448.19 nilz; Found 448.02 rnlz.

0.04 Calculated 554.09 mlz; Found 553.98 mlz.

0.003 Calculated 484.13 mlz; Found 483.95 m/z.

0.003 Calculated 514.14 mlz; Found 513.95 m/z.

0.04 Calculated 524.20 mlz; Found 523.98 im'z.

0.005 Calculated 468.13 mlz; Found 467.99 mlz.

0.02 Calculated (M-14) 502.09 mlz; Found 501.89 nt/z.

>10 Calculated 455.11 mlz; Found 454.97 m/z.

0.01 Calculated 482.15 mliz; Found 482.00 m/z.

0.05 Calculated (M-Hy 441.09 mlz; Found 441.00 mlz.

0.025 Calculated (M-HY 510.18 mlz; Found 509.98 mlz.

8- -[2-chloro-5-(trifluoromethyl)benzyl]- 4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 yl} amino)carbonyl]amino} methylphenyl)propanoic acid 1-(2-chloro-6-methoxybenzyl)-4hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl] amino) carbonyl)amino]-3 methylphenyl)propanoic acid (3 -(2,6-dichlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino] -3 (4-methylphenyl)propanoic acid {[1-(2-chloro-5-fluorobenzyl)-4-hydroxy- 2-oxo-1 ,2-dihydropyridin-3yl] amino I carbonyl)amino] -3 rnethylphenyl)propanoic acid (3 -(2-chloro-6-methylbenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl ]amino} carbonyl)amiio] -3 methylphenyl)propanoic acid (3 -(4-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- IH-cyclopenta(b]pyridin-3 yl ]amnino carbonyl)amino] -3 methylphenyl)propanoic acid (3 S)-3 {4-hydroxy-5-methyl-l1-[4- (methylsulfonyl)benzyl]-2-oxo-1I,2-dihydropyridin- 3-yl }amino)carbonyl]amino} methylphenyl)propanoic acid (3 {[4-hydroxy-l1-(4-methoxybenzyl)-2-oxo- 1 ,2-dihydropyridin-3-yl jamino }carbonyl)amino]-3 (4-methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-5 propyl- 1,2-dihydropyridin-3yl ]amino I carbonyl)amino] -3 methylphenyl)propanoic acid 0.01 Calculated 522. 10 mlz; Found *521.97 m/z.

0.005 Calculated (M-HY 484.13 mlz; Found 484.00 m/z.

0.0 13 Calculated (M-Hy 488.08 m/z; Found 487.91 mlz.

0.0 14 Calculated (M-Hy 472.11 m/z; Found 471.96 m/z.

0.01 Calculated (M-HY 482.15 m/z; Found 481.98 mlz.

0.02 Calculated 468.13 rnlz; Found 467.94 mlz.

0.003 Calculated (M+H) 4 496.16 nilz; Found 495.99 mlz.

0.02 Calculated 512.15 mlz; Found 511.96 m/z.

0.02 Calculated 450.17 mlz; Found 449.99 nilz.

0.02 Calculated 496.16 m/z; Found 495.94 mlz.

-159- (3 {4-[(dimetbylamino)sulfonyl]benzyl 0.035 4-hydroxy-2-oxo- 1,2-dihydropyridin-3 yl)amino]carbonyl arnino)-3 methylphenyl)propanoic acid (3 {[4-hydroxy-lI-(mesitylmethyl)-2-oxo- 1,2- 0.06 dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4niethylphenyl)propanoic acid 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 1,2,5,6,7, 8-hexahydroquinolin-3ylamnino} carbonyl)amnino]-3-(4methylphenyl)propanoic acid -(2-chlorobenzyl)-5-ethyl-4-hydroxy-6- 0.025 methyl-2-oxo- 1,2-dihydropyridin-3 yllamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.4 1 ,2-dihydropyridin-3yl ]amino) carbonyl)(methyl)amino] -3 methylphenyl)propanoic acid {4-hydroxy- I -[2-(methylthio)benzyl]-2- 0.02 oxo- 1,2-dihydropyridin-3 yl Iamino)carbonyl] amino) -3 methylphenyl)propanoic acid (3 S)-3 {2-[(dimethylamino)sulfonyllbenzyl 0.03 4-hydroxy-2-oxo- 1,2-dihydropyridin-3 yl)amino]carbonyll}amino)-3-(4methylphenyl)propanoic acid (3 -(2,6-dimethoxybenzyl)-4-hydroxy-2- 0.01 oxo- 1,2-dihydropyridin-3yljamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid {4-hydroxy-2-oxo-1 0.025 (trifluoromethoxy)benzyl]- 1,2-dihydropyfidin-3yljamino)carbonyl]amino} methylphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.35 I ,2-dihydropyridin-3-yljamino} carbonyl)amino]-4- [3-(trifluoromethyl)phenyl~butanoic acid Calculated 527.16 mlz; Found -526.96 mlz.

Calculated (M-Hf 462.20 mlz; Found 462.02 m/z.

Calculated 508.16 nilz; Found 507.96 mlz.

Calculated 496.16 mlz; Found -495.96 mlz.

Calculated 468.13 m/z; Found 467.85 mlz.

Calculated 466.14 mlz; Found 465.97 mlz.

Calculated 527.16 mlz; Found -526.97 mlz.

Calculated 480.18 m/z; Found 480.00 m/z.

Calculated (M-Hy 504.14 mlz; Found 503.96 m/z.

Calculated (M-HY 5 22. 10 mlz; Found 521.95 m/z.

-160foe.

{[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yljamino} carbonyl)amino]-3- (3-propoxyphenyl)propanoic acid I1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-5propyl- 1 ,2-dihydropyridin-3ylamnino} carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5,6dimethyl-2-oxo- I ,2-dihydropyridin-3yl] amino) carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 ([1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5propyl- 1 ,2-dihydropyridin-3yl]amino carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid (3 S)-3 -(3-butoxyphenyl)-3-[( [1 -(2-chlorobenzyl)- 4-hydroxy-2-oxo- 1,2-dihydropyridin-3 yl] amino}I carbonyl)amino]propanoic acid (3 S)-3 1 -[2-chloro-5-(methylsulfonyl)benzyl]- 4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl I amino)carbonyl] amino}1 methylphenyl)propanoic acid (3 R)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-4- (2-methylphenyl)butanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino -3 [3 -(2-methoxyethoxy)phenyl]propanoic acid (3 -(4-chloro-2-methoxybenzyl)-4hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl]amino}I carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2-dihydropyridin-3 -yl ]amino}I carbonyl)amino -3 (3 ,4-dipropoxyphenyl)propanoic acid 0.003 Calculated 498.14 mlz; Found =497.97 mlz.

0.003 Calculated 528.19 m/z; Found 528.02 mlz.

0.006 Calculated 482.15 m/z; Found 481.95 m/z.

0.005 Calculated (M-Hy 570.20 mlz; Found 569.98 ml/z.

0.005 Calculated 514.17 mz; Found 514.00 mz.

0.003 Calculated 532. 10 m/z; Found 531.94 m/z.

0.08 Calculated 468.13 mlz; Found 468.03 mlz.

0.003 Catculated 514.14 mlz; Found 513.95 m/z.

0.025 Calculated 484.13 m/z; Found 483.93 m/z.

0.003 Calculated 556.18 mlz; Found 555.94 mlz.

V. V

V

V.

V

S.

V S

V

V. VV

V

*58* -16 1-

C

f 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7,8 ,9-hexahydro- 1 H-cyclohepta[b]pyridin-3yl ]amino) carbonyl)amino]-3 methylphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino) carbonyl)amino] 4,4-diphenylbutanoic acid -[2-(difluoromethoxy)benzyl]-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl amino)carbonyl] amino)} -3 methylphenyl)propanoic acid (3 {4-hydroxy-5-methyl-2-oxo-l1-[(1 1phenylethyl]- I ,2-dihydropyridin-3yl} amino)carbonyl]amino} methylphenyl)propanoic acid (3 -(4-chlorobenzyl)-4-hydroxy-2-oxo-5propyl- 1 ,2-dihydropyridin-3yllamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino]-3- (3 ,4-diethylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino] -3 acid 3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino I carbonyl)amino] -3 -2 naphthyl)propanoic acid

J

-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl] amino) carbonyl)amino] -3 methyl-2-fiiryl)propanoic acid (3 S)-3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- I ,2-dihydropyridin-3 -yllamino }carbonyl)amino]-3- (3,4-dibutoxyphenyl)propanoic acid (3S)-3-f [({4-hydroxy-1-12- (methylsulfonyl)benzyl]-2-oxo- 1 ,2-dihydropyridin- 3-yl I amino)carbonyl] amino}1-3-(4methylphenyl)propanoic acid 0.12 Calculated 522.18 mlz; Found 521.98 mlz.

12 Calculated 530.15 mlz; Found 529.92 m/z.

0.075 Calculated 486.15 m/z; Found 486.00 mlz.

4 Calculated 448.19 mlz; Found 447.99 m/z.

0.03 Calculated 496.16 mlz; Found 495.96 m/z.

0.05 Calculated 496.16 mlz; Found 495.98 mlz.

0.05 Calculated 476.08 mlz; Found 475.93 m/z.

0.02 Calculated 490.12 m/z; Found 489.97 mlz.

0.025 Calculated 446.11 m/z; Found 446.08 m/z.

0.025 Calculated 584.21 mlz; Found 583.98 mlz.

0.035 Calculated 500.15 nilz; Found

(M+H)

4 500.01 m/z.

-162- I-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino}I carbonyl)aminol-3 naphthyl)propanoic acid (3 S)-3 -(4-chlorobenzyl)-4-hydroxy-2-oxo-5propyl- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo-5propyl- 1,2-dihydropyridin-3yljamino }carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid {[1-(2,6-dimethylbenzyl)-4-hydroxy-2oxo- 1 ,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-[( chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin- 3-yl]aminolcarbonyl)amino]propanoic acid {[l1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino] -3- [3-(difluoromethoxy)phenyljpropanoic acid I-(2-chlorobenzyl)-4-bydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino~carbonyl)amino]-4pyridin-2-ylbutanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3 yl] amino) carbonyl)amino] -3 ,4diethoxyphenyl)propanoic acid (3 f [1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]amino carbonyl)amino]-3 ethoxyphenyl)propanoic acid (3 S)-3 [1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]arnino }carbonyl)amino]-3-(3-methoxy-4methylphenyl)propanoic acid 0.2 Calculated 490.12 mlz; Found 489.91 mlz.

0.03 Calculated 526.17 mlz; Found 525.95 ml/z.

0.015 Calculated 570.20 m/z; Found 569.97 mlz.

0.03 5 Calculated 448.19 mlz; Found 448.02 m/z.

0.22 Calculated 576.08 mlz; Found =575.91 mlz.

0.006 Calculated 506.09 mlz; Found 505.93 m/z.

0.225 Calculated 455.11 mlz; Found 455.09 m/z.

0.0006 Calculated 542.17 mlz; Found 542.06 mlz.

0.002 Calculated 499.15 m/z; Found 498.07 m/z.

0.020 Calculated 500.16 mlz; Found 500.02 mlz.

-163- [1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1,2-dihydropyridin--3yl]amino }carbonyl)amino]-3-(2-naphthyl)propanoic acid (3 S)-3 -(2-chloro-6-methylbenzyl)-4-hydroxy- 5,6-dimethyl-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3 ethoxyphenyl)propanoic acid (3 [1 -(2-chloro-6-methylbenzyl)-4-hydroxy- 5,6-dimethyl-2-oxo- 1,2-dihydropyridin-3yl ]amino)} carbonyl)amino]-3 -methoxy4niethylphenyl)propanoic acid (3 -(2-chloro-6-methylbenzyl)-4-hydroxy- 5,6-dimethyl-2-oxo- I ,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(3,4diethoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-cyanobenzyl)-4-hydroxy- 2-oxo-1I,2-dihydropyridin-3yl ]amino I carbonyl)amino] -3 methylphenyl)propanoic acid (3 S)-3 -(2-chloro-6-methylbenzyl)-4-hydroxy- ,6-dimethyl-2-oxo- 1,2-dihydropyridin-3 yl ]amino}I carbonyl)amino methylphenyl)propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-5,6dimethyl-2-oxo- 1,2-dihydropyridin-3 yl] amino}I carbonyl)amino] -3 -methoxy-4methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5,6dimethyl-2-oxo- 1,2-dihydropyridin-3yljamino carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid 0.030 Calculated 504.13 m/z; Found 504.04 m/z.

0.015 Calculated 526.17 mlz; Found -525.95 mlz.

0.025 Calculated 526.17 mlz; Found 525.97 mlz.

0.004 Calculated 570.20 mlz; Found 570.0 0 m/z.

0.007 Calculated 479.11 mlz; Found 478.90 mlz.

0.03 Calculated 496.16 mlz; Found 495.97 m/z.

0.0 15 Calculated (M-Hy 512.16 m/z; Found 511.95 m/z.

0.003 Calculated 556.18 mn/z; Found 555.99 m/z.

-164- Table 6 Compound -(2-chlorobenzyl)-4-hydroxy-2-oxo-1 ,2dihydropyridin-3-yl]amino} carbonyl)amino]-4-(lnaphthyl)butanoic acid 1-(2-chlorobenzyl)-4-hydroxy-5,6dimethyl-2-oxo-1I,2-dihydropyridin-3yI]amino} carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid I1-(2-chlorobenzyl)-4-hydroxy-5,6dimethyl-2-oxo- 1,2-dihydropyridin-3yljamino} carbonyl)amino]-3-(3,4dimethylphenyl)propanoic acid [I -(2-chloro-6-methoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino) carbonyl)amino]-3 methylphenyl)propanoic acid 1-(2-chloro-6-methoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3 yl] amino}I carbonyl)amino] -3 ,4diethoxyphenyl)propanoic acid I -(2-chloro-6-methoxybenzyl)-4hydroxy-5-methyl-2-oxo- I ,2-dihydropyridin-3yl]amino} carbonyl)aminoll-3-(3-methoxy-4methylphenyl)propanoic acid (3 [1-(2-chloro-6-methoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 ethoxyphenyl)propanoic acid [1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3 (1,1 ,2,2-tetrafluoroethoxy)phenyllpropanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino }carbonyl)amino]-4-(2chlorophenyl)butanoic acid IC50 (tIM) Mass Spectral Data (mlz) 2500 Calculated 504.13; Found 503.97.

30 Calculated 512.16; Found 511.99.

40 Calculated (M-HY 496.16; Found 496.05.

5 Calculated 498.15; Found 497.91.

2 Calculated 572.18; Found 57 1.96.

6 Calculated 528.15; Found 527.95.

3 Calculated 528.15; Found 527.99.

15 Calculated 556.09; Found (M-HY- 555.97.

700 Calculated (M-Hj- 488.08; Found 487.96.

-165- {4-hydroxy- 1 -[3-(methylthio)benzyl]-2oxo- 1,2-dihydropyridin-3yl~amino)carbonyl]amino} methylphenyl)propanoic acid 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1 ,2-dihydropyridin-3yl]aminolcarbonyl)amino]-3-(3 ,4dimethylphenyl)propanoic acid 1 -(2-chloro-6-methoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(3,4dimethylphenyl)propanoic acid 1-(2-chlorobenzyl)-5-cyclopropyl-4hydroxy-2-oxo- 1,2-dihydropyridin-3 yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-(4-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- 1 H-cyclopenta~b]pyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-(3-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo-1I,2-dihydropyridin-3yflamino }carbonyl)amnino)-3-(4methylphenyl)propanoic acid [1-(2,6-dichlorobenzyl)-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydropyridin-3yl]aminol}carbonyl)amino]-3-(4methylphenyl)propanoic acid {[4-hydroxy-5-methyl- 1 -(4-methylbenzyl)- 2-oxo- 1 ,2-dihydropyridin-3 yl]amino }carbonyl)amino]-3-(4methylphenyl)propanoic acid 3-(l1 -benzofuran-2-yl)-3 -(2-chlorobenzyl)-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- 1 H-cyclopenta[blpyridin-3yl]aminol}carbonyl)amino]-3-(3 ethoxyphenyl)propanoic acid 20 Calculated 466.14; Found 466.04.

15 Calculated 482.15; Found 482.02.

3 Calculated 512.16; Found 512.03.

20 Calculated 496.16; Found 496.05.

50 Calculated 494.15; Found 494.02.

20 Calculated 468.13; Found 468.02.

20 Calculated 502.09; Found 501.92.

150 Calculated 448.19; Found 448.05.

140 Calculated 480. 10; Found 479.96.

3 Calculated (M-Hy 524.16; Found 523 -166- 1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(6methoxy-2-naphthyl)propanoic acid {[1-(3,5-dimethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yl]ammno}carbonyl)amino]-3-(4methylphenyl)propanoic acid -(2,6-difluorobenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- 1H-cyclopentab]pyridin-3ylamino} carbonyl)amino]-3-(3,4diethoxyphenyl)propanoic acid {4-hydroxy-l1-[3-(methylsulfonyl)benzyl]- 2-oxo- 1,2-dihydropyridin-3yl I aniino)carbonyl] amino) -3 methylphenyl)propanoic acid 1-(2-chloro-6-methylbenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid 1-(2-chloro-6-methylbenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl ]amino)} carbonyl)amino] -3 ethoxyphenyl)propanoic acid {[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(3 ,4dimethylphenyl)propanoic acid.

1-(2-chloro-6-methylbenzyl)-4-hydroxy- -2-oxo- 1 ,2-dihydropyridin-3ylamino} carbonyl)amino]-3-(3-methoxy-4methylphenyl)propanoic acid 3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yIjamino} carbonyl)amino]-3-(4,5dimethyl-2-furyl)propanoic acid 15 Calculated 520.13; Found 520.00.

70 Calculated 494.19; Found 494.04.

25 Calculated 470.15; Found 470.03.

3 Calculated 570.20; Found 570.00.

25 Calculated 498.13; Found (M-Hf 498.01.

3 Calculated 556.19; Found (M-Hj 556.02.

4 Calculated 512.16; Found 512.02.

45 Calculated (M-Hf 496.16; Found 496.01.

25 Calculated 512.16; Found (M-Hy 511.97.

115 Calculated (M-Hf 458.11; Found 457.99.

-167- I-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yllaniino} carbonyl)amino]-3 methoxy- I -naphthyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino }carbonyl)amino]-5phenylpentanoic acid (3 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydroquinolin-3-yl]amino} carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3yllamino} carbonyl)amino]-3-(3,4dimethylphenyl)propanoic acid [1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy- 5-methyl-2-oxo-1I,2-dihydropyridin-3yljamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid -(2-chlorobenzyl)-5-cyclopropyl4hydroxy-2-oxo-1I,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(3 ethoxyphenyl)propanoic acid (3S)-3-I(f I1 -(2-chlorobenzyl)-5-cyclopropyl4hydroxy-2-oxo- 1,2-dihydropyridin-3 yl]amino} carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid (3 [1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yllamino }carbonyl)amino]-3-[4- (difluoromethoxy)phenyl]propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3quinolin-2-ylpropanoic acid 160 Calculated 520.13; Found 519.97.

115 Calculated (M-Hy 468.13; Found 467.98.

12 Calculated 534.14; Found 533.94.

18 Calculated 510.18; Found 510.06.

7 Calculated 500.16; Found 500.06.

3 Calculated (M-Hy 512.16; Found 512.03.

14 Calculated 526.17; Found 526.0 1.

6 Calculated 570.20; Found 570.04.

30 Calculated 506.09; Found 505.96.

105 Calculated (M-Hy 491 .11; Found (M-Hy 490.96.

-168- 0e 0000 [1 -(2-fluoro-6-methoxybenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yllarnino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-(2 -chloro-6'-methoxybenzyl)-4- 1 ,2-dihydropyridin-3yI]ainino} carbonyl)amino]-3-(4methylphenyl)propanoic acid [1-(2-chloro-6-methoxybenzyl)-4- 1 ,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid 1-(5-chloro-2-fluorobenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yI]amino} carbonyl)amino]-3-(4.

methylphenyl)propanoic acid [I-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydroquinolin-3-yl]axnino} carbonyl)amino]-3-(3methoxy-4-methylpbenyl)propanoic acid 1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydroquinolin-3-yl]aniino carbonyl)amino]-3- (3,4-diethoxyphenyl)propanoic acid (3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydroquinolin-3-yl]amino }carbonyl)amino]-3- (3 ,4-dimethylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino }carbonyl)amino]-3pyridin-2-ylpropanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid 1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yi ]amino}I carbonyl)amino] -3 ,5 diethoxyphenyl)propanoic acid 10 Calculated (M-Hf 482.17; Found 482.02.

15 Calculated 528.19; Found 528.04.

7 Calculated 558.20; Found 558.07.

15 Calculated 486.12; Found 486.00.

14 Calculated 534.14; Found 533.95.

4 Calculated 578.17; Found 577.99.

25 Calculated 518.15; Found 517.96.

00 0 0* 0* 0 0*0 0 0 0000 150 Calculated 443.11; Found 443.03, 3 Calculated 498.14; Found (M-Hy 498.04.

7 Calculated 528.15; Found 528.02.

-169- (3 -(2-chlorobenzyl)-4-hydroxy-5isopropyl-2-oxo- 1,2-dihydropyridin-3ylilamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid [1-(5-fluoro-2-methylbenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yljamino carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 {4-hydroxy-5-methyl-2-oxo- 1 1phenylethyl]- 1,2-dihydropyridin-3yl }amino)carbonyl]amino} methylphenyl)propanoic acid (3 -(2-chloro-6-methoxybenzyl)-4- 1,2-dihydropyridin-3yllamino carbonyl)amino]-3-(3,4diethoxyphenyl)propanoic acid (3 {[l1-(2-chloro-5-isopropoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid 1-(2-chloro-6-methoxybenzyl)-4hydroxy-2-oxo-5-propyl-1I,2-dihydropyridin-3yl] amino)} carbonyl)amino]-3 -methoxy-4methylphenyl)propanoic acid 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)atiiino]-3-(3 ethoxyphenyl)propanoic acid I-(5-acetyl-2-methoxybenzyl)-4-hydroxy- 2-oxo-1 ,2-dihydropyridin-3yl ]amino I carbonyl)amino] -3 methylphenyl)propanoic acid 1-(2-chloro-6-methylbenzyl)-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydropyridin-3yflamino carbonyl)amino]-3-(6-methoxy-2naphthyl)propanoic acid I[ 1-(2-chloro-6-methoxybenzyl)-4- 1,2-dihydropyridin-3yl] amino) carbonyl)amino] dimethylphenyl)propanoic acid 60 Calculated 498.18; Found 498.05.

20 Calculated 468.19; Found 468.07.

1500 Calculated 450.20; Found 450.07.

3 Calculated 602.23; Found 602.04.

7 Calculated (M-Hy 526.17; Found 526.04.

15 Calculated 558.20; Found 558.05.

2 Calculated 544.19; Found 544.04.

33 Calculated 492.18; Found 492.04.

35 Calculated (M-Hf 548.16; Found (M-Hy- 548.01.

17 Calculated 542.2 1; Found 542.05.

-170- 0: 0 0 too* S.6 0000S (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1 ,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-( 1methyl- I H-indol-5-yl)propanoic acid (3 {[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 3-oxo-2,3-dihydropyridazin-4yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 [1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yljamino} carbonyl)amino]-3-(6-methoxy-2naphthyl)propanoic acid (3 {[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 3-oxo-2,3-dihydropyridazin-4yl]aminol}carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3-yl]amino }carbonyl)amino]-3thien-2-ylpropanoic acid (3 1 -(2-chlorobenzyl)-4-hydroxy-2oxo- 1 ,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3S)-3-(3-butoxyphenyl)-3-[( 1-(2-chlorobenzyl)-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3yl]amino }carbonyl)amino]propanoic acid I-(2-chlorobenzyl)-4-hydroxy-2-oxo-1 ,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-[3- (cyclopentyloxy)phenyl]propanoic acid {[2-(2-chlorobeaizyl)-5-hydroxy-6-methyl- 3 -oxo-2,3-dihydropyridazin-4yl]amino }carbonyl)amino]-3-(3 ,4diethoxyphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl] amino I carbonyl)aminol-3 1 methyl- 1 H-indol-5 yl)propanoic acid 3 Calculated 493.13; Found (M-Hy 492.95.

18 Calculated 471.14; Found 471.00.

5 Calculated 534.14; Found 533.9 1.

5 Calculated 501.15; Found 501.01.

30 Calculated 448.07; Found 447.97.

6 Calculated (M-Hy 488.08; Found (M-Hy 487.97.

20 Calculated (M-Hf 552.19; Found 552.01.

5 Calculated 524.16; Found 524.00.

3 Calculated 545.18; Found 544.98.

3 Calculated 507.14; Found (M-Hy 506.94.

-171-

C

{[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 3-oxo-2,3-dihydropyridazin-4yljjaninol}carbonyl)amino]-3-(3,5diethoxyphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-[4- (trifluoromethoxy)phenyl]propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]aniino} carbonyl)amino]-3-[3- (trifluoromethoxy)phenyl]propanoic acid -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-(4methoxyphenyl)propanoic acid 1-(2-chlorobenzyl)-.4-hydroxy-2-oxo-1,2dihydropyridin-3-yllano} carbonyl)amino]-3-(6methoxy-2-naphthyl)propanoic acid 1 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-4- -methyl-2-oxo- 1,2-dihydropyridin-3 yl amino)carbonyl] amino) -3 methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- I ,2-dihydropyridin-3yljamino carbonyl)amino]-3-[3- (trifluoromethyl)phenyl]propanoic acid (3 [1 -(2-chlorobenzyl)-4-hydroxy-5 -methyl- 2-oxo- 1,2-dihydropyridin-3yl]aminol}carbonyl)amino]-3-(3 methoxyphenyl)propanoic acid (3 -(2-chloro-6-methylberizyl)-4-hydroxy- 2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid -chloro-6-methylbenzyl)-4-hydroxy- 2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[blpyridin-3 yl] amino) carbonyl)amino]-3 ethoxyphenyl)propanoic acid 10 Calculated 545.18; Found 545.01.

70 Calculated 53 8.10; Found 537.95.

10 Calculated 5 38. 10; Found 537.95.

4 Calculated (M+H 486.14; Found 486.04.

15 Calculated 520.13; Found 520.03.

100 Calculated 520.15; Found 519.97.

10 Calculated 522. 10; Found (M-Hj 521.96.

3 Calculated (M-Hy 484.13; Found (M-H)Y 484.00.

20 Calculated 510.18; Found 510.05.

4 Calculated 540.19; Found 540.10.

C

-172- (3 [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- 1 H-cyclopentab]pyridin-3yl]aminol}carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid (3 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)aniino]-3-(3,5diethoxyphenyl)propanoic acid -(2-chloro-6-ethoxybenzyl)-5-ethyl-4hydroxy-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3 ethoxyphenyl)propanoic acid [1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 2-oxo- 1 ,2-dihydropyridin-3yl]amino}I carbonyl)aminol-3-(3ethoxyphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3y1] amino I carbonyl)amino-3 [3 (cyclopentyloxy)phenyl]propanoic acid ,'-biphenyl-4-yI)-3-[({I[I-(2-chlorobenzyl)-4hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3yl] amino I carbonyl)amino]propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-1 H-cyclopenta~b]pyridin-3yl]aminio}carbonyl)amino]-3-[3-(2,2,2tifluoroethoxy)phenyl]propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3yl] amino I carbonyl)amino]-3 trifluoroethoxy)phenyljpropanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 2-oxo-1 ,2-dihydropyridin-3yl]amino }carbonyl)amino] isopropoxyphenyl)propanoic acid (3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy- 5-methyl-2-oxo- 1 ,2-dihydropyridin-3yl]amino carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid 3 Calculated 540.19; Found 540.09.

3 Calculated (M-Hy 542.17; Found 542.00.

4 Calculated 556.19; Found 556.01.

3 Calculated (M+H) 4 530.17; Found 530.04.

15 Calculated 538.17; Found 538.03.

130 Calculated 530.15; Found 529.96.

30 Calculated 580.15; Found (M+H) 4 580.02.

15 Calculated 554.13; Found (M+H)f 554.00.

3 Calculated 514.05.

4 Calculated (M+H) 4 558.20; Found 558.05.

-173- Compound Table 7

IC

50 (nM) Mass Spectral Data (mlz) (3 [1I -(2-chlorobenzyl)-4-hydroxy-5 -methyl-2oxo- 1 ,2-dibydropyridin-3-yl]amino} carbonyl)amino]- 3-(4-methoxy-3 -methylphenyl)propanoic acid [1-(2-chloro-6-methylbenzyl)-4-hydroxy-2oxo-2,5,6, 7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 ylamino}I carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid {[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3 yl]amino} carbonyl)amino]-3-(6-methoxy-2naphthyl)propanoic acid (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo-1 ,2-dihydropyridin-3-yl]amino~carbonyl)amino]- 3 ,5-dimethoxy-4-methylphenyl)propanoic acid (3 [1-(2-chloro-6-methylbenzyl)-4-hydroxy-2oxo-2, 5,6,7-tetrahydro- 1 H-cyclopenta[bjpyridin-3ylamino}I carbonyl)amino]-3 propoxyphenyl)propanoic acid 1-( 2 -chloro-6-propoxybenzyl)-4-hydroxy- 5-methyl-2-oxo- 1 ,2-dihydropyridin-3ylamino I carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 Il -(2-chloro-6-isobutoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- ,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3yl] amino) carbonyl)amino] -3 propoxyphenyl)propanoic acid (3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3yl ]amino}I carbonyl)amino]-3 methylphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- ,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3y1]amino}I carbonyl)amino]-3-(3 isopropoxyphenyl)propanoic acid 9 Calculated 500.16; Found (M-sH)+ 500.01.

10 Calculated 554.21; Found 554.06.

3 Calculated 580.19; Found 580.07.

12 Calculated 530.17; Found 530.00.

12 Calculated 554.21; Found 554.05.

10 Calculated 528.19; Found 528.06.

22 Calculated (M+H) 4 542.2 1; Found 542.06.

15 Calculated 540.19; Found (M+H) 4 540.07.

3 Calculated 540.19; Found 540.04.

4 Calculated (M+H) 4 584.22; Found 584.05.

-174- [1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- I ,2-dihydropyridin-3-yl]amino} carbonyl)amino]- 3-(2',6'-dimethoxy- 1, 1 '-biphenyl-4-yl)propanoic acid (3 [1-(2-chlorobenzyl)-4-bydroxy-5-methyl-2oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]- 1-methyl- I H-indol-7-yl)propanoic acid -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro-1I H-cyclopenta[b]pyridin- 3yl]amino} carbonyl)amino]-3-(3 ethoxyphenyl)propanoic acid {[i-(2-chloro-6-propoxybenzyl)-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino)} carbonyl)amino] -3 ethoxyphenyl)propanoic acid (3 S)-3-II( [1 -(2-chloro-6-isobutoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino) carbonyl)amino] -3 ethoxyphenyl)propanoic acid (3 -(2-chloro-6-isopropoxybenzyl)-4hydroxy-5-methyl-2-oxo-1 ,2-dihydropyridin-3yl] amino I carbonyl)amino] -3 ethoxyphenyl)propanoic acid -[2-chloro-6-(2,2,2trifluoroethoxy)benzyl] -4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3 -yl I amino)carbonyl] amino)} -3 (3 -ethoxyphenyl)propanoic acid I1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyr-idin-3-yl]amino carbonyl)amino]-3 [4-(methylthio)phenyl]propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl] amino}I carbonyl)aminol -3 -(6-methoxy-2naphthyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1 ,2 -dihydropyridin-3 -yl] amino I carbonyl)aniino] 3-(2,3-dihydro- 1 -benzofuran-5-yl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-( 1-methyl-i H-indol-5yl)propanoic acid 40 Calculated 592.19; Found =592.04.

30 Calculated 509.16; Found 509.03.

2 Calculated 570.20; Found 570.09.

5 Calculated 558.20; Found 558.03.

14 Calculated 572.22; Found 572.05.

7 Calculated 558.20; Found 558.03.

4 Calculated (M+Hj'+ 598.16; Found 597.99.

15 Calculated 502.12; Found 501.98.

2 Calculated 606.20; Found 606.04.

6 Calculated 498.14; Found 498.02.

3 Calculated 553.19; Found (M+H) t 553.05.

-175a (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropynidin-3yl]amino} carbonyl)amino]-3-(2,3-dihydro- 1acid (3 S)-3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3yl] amino) carbonyl)amino]-3-(3,5diethoxyphenyl)propanoic acid {[1-(2-chloro-6-isopropoxybenzyl)-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yll amino) carbonyl)amino] -3 ethoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yl ]amino)~ carbonyl)amino] -3 propoxyphenyl)propanoic acid (3 S)-3-(3-butoxyphenyl)-3-[( -(2-chloro-6ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo- 1,2dihydropyridin-3yl] amino I carbonyl)amino]propanoic acid (3 {[5-chioro-lI-(2-chloro-6-ethoxybenzyl)-4hydroxy-2-oxo- 1 ,2-dihydropyridin-3 yl]amino }carbonyl)amino]-3 ethoxyphenyl)propanoic acid (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo- 1,2-dihydropyridin-3-yljjamino~carbonyl)amino]- 3-(3-isopropoxyphenyl)propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6, 7-tetrahydro- 1 H-cyclopenta.[b]pyridin-3yl]amino carbonyl)amino]-3 -dihydro- 1 acid (3 S)-3 {[2-(2-chloro-6-ethoxybenzyl)-5 -hydroxy-6methyl-3-oxo-2,3-dihydropyridazin-4yl] amino) carbonyl)amino] -3 methylphenyl)propanoic acid 2 Calculated 542.17; Found. =542.06.

3 Calculated 614.22; Found 614.11.

4 Calculated 558.20; Found 5 58.02.

3 Calculated 558.20; Found 558.07.

4 Calculated 572.22; Found =-572.04.

3 Calculated 564.13; Found 563.99.

3 Calculated =544.19; Found 544.06.

2 Calculated =524.16; Found 524.03.

7 Calculated 515.19; Found 515.05.

-176- -(2-chloro-6-ethoxybenzyil)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3ylamino} carbonyl)amino]-3-(3propoxyphenyl)propanoic acid {[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6methyl-3-oxo-2,3-dihydropyridazin-4yl]amino} carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid {12-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6methyl-3-oxo-2,3-dihydropyridazin-4yl ]amino) carbonyl)amino] -3 isopropoxyphenyl)propanoic acid (3 S)-3 [1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro-1I H-cyclopenta[b]pyridin-3 yl] amino I carbonyl)amino] (cyclopentyloxy)phenyljpropanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3ylamino} carbonyl)amino]-3 (cyclopentyloxy)phenyl]propanoic acid (3 S)-3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl]amino} carbonyl)amino]-3-phenylpropanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5 ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl] amino} carbonyl)amino -phenylpropanoic acid (3 S)-3 [1-(2-chloro-6-methylbenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yl]amino} carbonyl)amino -dihydro- 1 benzofuran-5-yl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yI ]amino)} carbonyl)aminol -3 -diethyl-2 -oxo-2,3 dihydro- 1 H-benzimidazol-5-yl)propanoic acid (3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5 methyl-2-oxo- 1,2-dihydropyridin-3yl ]amino) carbonyl)amino] -3 (trifluoromethyl)phenyl]propanoic acid 3 Calculated 5 84.2 1; Found 584.10.

3 Calculated 545.18; Found 545.05.

2 Calculated 559.20; Found 559.04.

6 Calculated 610.23; Found =610.14.

7 Calculated 566.21; Found =566.09.

2 Calculated 526.17; Found 526.07.

8 Calculated 482.15; Found 482.07.

5 Calculated 512. 1.6; Found 512.03.

4 Calculated 594.21; Found 594.05.

3 Calculated 568.15; Found 568.00.

-177- [1-(2-cbloro-6-ethoxybenzyl)-4-hydroxy-5 methyl-2-oxo- 1,2-dihydropyridin-3yIjamino} carbonyl)amino]-3-[3- (trifluoromethoxy)phenyl]propanoic acid (3 [Q I-[2-chloro-6-(2-methoxyethoxy)benzyl]-4hydroxy-2-oxo-2,5 ,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl I amino)carbonyl] amino}1 -3 (4-methylphenyl)propanoic acid 1 -[2-chloro-6-(2-methoxyethoxy)benzyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl} amino)carbonyljamino 1 -3 (3-ethoxyphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tejiahydro- 1H-cyclopenta[b]pyridin-3 yl] amino) carbonyl)amino] -3 (cyclopropyloxy)phenyl]propanoic acid (3 [1 -(2-cbloro-6-ethoxybenzyl)-4-hydroxy-5 ,6dimethyl-2-oxo-1I,2-dihydropyridin-3 yI]amino} carbonyl)amino]-3 ethoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5 ,6dimethyl-2-oxo- 1,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-5-ethyl-4hydroxy-6-methyl-2-oxo- 1,2-dihydropyridin-3 yIlamino carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-5-ethyl-4hydroxy-6-methyl-2-oxo- 1,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 methylphenyl)propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1,2-dihydropyr-idin-3-yl]amino }carbonyl)amino]-3- (2'-methoxy- 1,1 '-biphenyl-4-yl)propanoic acid (3 S)-3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5 ,6dimethyl-2-oxo- 1,2-dihydropyridin-3yl ]amino}I carbonyl)amino] -3 isopropoxyphenyl)propanoic acid (3 S)-3 -[II 1-(2-chloro-6-ethoxybenzyl)-4-hydroxy.5 ,6dimethyl-2-oxo- 1,2-dihydropyridin-3yll]amino I carbonyl)amino] -3 -phenyipropanoic acid 4 Calculated 584.14; Found 584.01.

6 Calculated 568.18; Found 568.03.

4 Calculated 598.19; Found 598.01.

4 Calculated 538.17; Found 538.09.

4 Calculated 556.19; Found 556.02.

4 Calculated 526.17; Found 526.02.

4 Calculated 570.20; Found 570.04.

4 Calculated (M-Hy 540.19; Found 540.05.

25 Calculated 562.09; Found 562.17.

3 Calculated 570.20; Found 570.00.

4 Calculated 512.16; Found 512.01.

-178a a.

a (3 -(2-chloro-6-ethoxybenzyl)-5-ethyl-4hydroxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3ylamino carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid {[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4hydroxy-6-methyl-2-oxo- 1,2-dihydropyridin-3yl]amino }carbonyl)amino]-3-phenylpropanoic acid {[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl -2-oxo- 1,2-dihydropyridin-3yl] amino}I carbonyl)amino] -3 -(6-ethoxy-2naphthyl)propanoic acid (3 {[2-(2-chlorobenzyl)-6-ethyl-5-hydroxy-3-oxo- 2,3-dihydropyridazin-4-yl]amino }carbonyl)amino]-3- (4-methylphenyl)propanoic acid 1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3yl] amino}I carbonyl)amino] -3 isobutylphenyl)propanoic acid (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- (1-methyl- I H-indol-6-yl)propanoic acid (3 S)-3 [1 -(2-chloro-6-methylbenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3 yl] amino}I carbonyl)amino] -3 (cyclopropyloxy)phenyl]propanoic acid [1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-.

tetrahydro- 1 H-cyclopenta[b]pyridin-3ylamino}I carbonyl)amino]-3 -(6-ethoxy-2naphthyl)propanoic acid (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-5-propyl- 1,2-dihydropyridin-3yl ]amino I carbonyl)amino] -3-phenylpropanoic acid (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-5-propyl-1 ,2-dihydropyridin-3yl] amino) carbonyl)amino] -3 isopropoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 1,2-dihydropyridin-3yl] amino) carbonyl)amino] -3 methylphenyl)propanoic acid 5 Calculated 584.22; Found 584.03.

4 Calculated 526.17; Found 526.00.

6 Calculated 592.19; Found 592.00.

22 Calculated 483.14; Found 483.03.

15 Calculated 536.20; Found 535.99.

4 Calculated 509.16; Found 509.05.

4 Calculated 550.17; Found 550.0 1.

15 Calculated (M-HY 574.17; Found 574.02.

23 Calculated 526.17; Found 526.04.

22 Calculated (M-Hy 584.22; Found 584.09.

20 Calculated (M-Hy 540.19; Found 540.05.

-179- (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 1 ,2-dihydropyridin-3yljamino}I carbonyl)amino]-3-(3ethoxyphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1 ,2dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4'methyl-i, 1'-biphenyl-4-yi)propanoic acid [1-(2-chlorobenzyl)-4-bydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3yl ]amino)} carbonyl)amino]-3 -methyl- I H-indol-5yl)propanoic acid l-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 4-hydroxy-2-oxo- 1,2-dihydropy-idin-3ylamnino} carbonyl)amino]-3-(3isopropoxyphenyl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3yl]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 i-(2-chloro-5-propoxybenzyl)-4-hydroxy-5- *methyl-2-oxo- I ,2-dihydropyridin-3yi ]amino}I carbonyl)amino] -3 methylphenyl)propanoic acid (3 S)-3 -(2-chloro-5-methoxybenzyl)-4-hydroxy-5methyl-2-oxo- i ,2-dihydropyridin-3yi]amino} carbonyl)amino]-3-(4methylphenyl)propanoic acid i-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 2-oxo- 1,2-dihydropyridin-3 -yllamlno }carbonyl)amino]- 3-(2-naphthyl)propanoic acid -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 2-oxo- 1 ,2-dihydropyridin-3 -yl] amino I carbonyl)amino]- 3-[4-(methylsulfonyl)phenyl]propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl ]amino)} carbonyl)amino] -3 ethoxy- 1, i'-biphenyl-4-yl)propanoic acid {Ill-(2-chloro-6-metbylbenzyl)-4-hydroxy-2oxo-2 ,5 ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl ]amino) carbonyi)amino] (cyclobutyioxy)phenyl]propanoic acid 6 Calculated (M-Hf- 570.20; Found 570.04.

40 Calculated 530.15; Found 530.02.

4 Calculated (M-Hy 533.16; Found 533.00.

3 Calculated 582.20; Found 582.07.

3 Calculated 538.17; Found =538.06.

6 Calculated 526.17; Found 526.05.

3 Calculated (M-FI) 498.14; Found 498.01.

13 Calculated (M-Hy 548.16; Found 548.01.

8 Calculated 576.12; Found 576.00.

27 Calculated 560.16; Found 560.04.

20 Calculated (M-Hy 564.19; Found 564.00.

-180- 9* S.

S

0

S

S S

S

55

S

5*5* 1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3ylamino} carbonyl)amino]-3-[3- (cyclobutyloxy)phenyljpropanoic acid (3 [1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-6methyl-2-oxo- 1 ,2-dihydropyridin-3yl] amino) carbonyl)amino]-3 isopropoxyphenyl)propanoic acid 3+f( [I1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3-yI]amino }carbonyl)amino]-3-(3 pyrrolidin- 1 -ylphenyl)propanoic acid 2 -chlorobenzyl)-4-hydroxy-57methyl-2..oxo- 1 ,2-dihydropyridin-3 -yl] amino}I carbonyl)amino]-3 piperidin- 1 -ylphenyl)propanoic acid.

(3 2 -chloro-6-methylbenzyl)-4-hydroxy-2- ,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3yl]amino} carbonyl)aniino]-3-[3-( 1ethylpropoxy)phenyljpropanoic acid l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[bjpyridin-3 yl ]amino I carbonyl)amino]-3 ethylpropoxy)phenyl]propanoic acid (3 S)-3 -(4-chloro-3 -isopropoxyphenyl)-3 [1 chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2, 5,6,7tetrahydro- 1H-cyclopenta[bjpyridin-3yl ]amino}I carbonyl)amino]propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- IH-cyclopenta[b]pyridin-3yl ]amino} carbonyl)amino] -3 -(4-chloro-3 isopropoxyphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 1,2dihydropyridin-3 -yl ]amino)} carbonyl)amino] -3 methyl-I,1I'-biphenyl-4-yl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5 ,6,7tetrahydro- 1 H-cyclopenta[bjpyridin-3ylamino} carbonyl)amino]-3-( 1-methyl- I H-indol-6yl)propanoic acid (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3yI ]amino carbonyl)amino] 1-methyl- I H-indol -6 yl)propanoic acid 17 Calculated 550.17; Found 550.02.

3 Calculated (M-Hy 556.19; Found 556.05.

10 Calculated 523.17; Found 522.99.

22 Calculated 537.19; Found 537.08.

22 Calculated 580.22; Found =580.04.

20 Calculated 566.20; Found 566.01.

23 Calculated 586.15; Found 585.92.

38 Calculated 572.14; Found =572.00.

30 Calculated (M-Hy 530.15; Found 530.02.

3 Calculated (M-Hy 533.16; Found 532.97.

3 Calculated 551.17; Found 551.02.

-181- 0 a* 0 *0 0 0 boo*0 [I -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1,2-dihydropyridin-3-yl]amino} carbonyl)aniino]-3- (4'-methoxy- 1,1 '-biphenyl-4-yl)propanoic acid [1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- (2'-methyl- 1,1 '-biphenyl-4-yl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopentab]pyridin-3 yI]amino} carbonyl)amino]-3-(6-methoxy-2naphthyl)propanoic acid (3 S)-3-(4-cbloro-3-ethoxyphenyl)-3-[( [1 -(2-chloro-6methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3yl ]amino}I carbonyl)amino]propanoic acid -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl]amino} carbonyl)amino]-3-(4-chloro-3ethoxyphenyl)propanoic acid I1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 ylamino} carbonyl)amino]-3-(3isobutylphenyl)propanoic acid (3 S)-3 [1 -(2-chloro-5-ethoxybenzyl)-4-hydroxy-5methyl.-2-oxo- 1 ,2-dihydropyridin-3ylamnino} carbonyl)amino]-3 methylphenyl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- I ,2-dihydropyridin-3 -yl ]amino I carbonyl)amino] -3 [4- (methylsulfonyl)phenyl]propanoic acid (3 S)-3 I -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3 yl] amino)} carbonyl)amino] -3 -(2,4-dichloro-3 ethoxyphenyl)propanoic acid 1 -12-chloro-5-(piperidin-1Iylsulfonyl)benzylj-4-hydroxy-5-methyl-2-oxo- 1,2dihydropyridin-3-yl arnino)carbonyl] amino)} methylphenyl)propanoic acid (3 S)-3 1-[2-chloro-5-(pyrrolidin- Iylsulfonyl)benzyl] -4-hydroxy-5-methyl-2-oxo- 1,2dihydropyridin-3 -yl I amino)carbonyl]amino methylphenyl)propanoic acid 23 Calculated 560.16; Found 560.0 1.

55 Calculated 546.18; Found 546.11.

3 Calculated (M-Hy 560.16; Found 560.00.

25 Calculated (M-HY 572.14; Found 571.94.

30 Calculated 558.12; Found 557.77.

4 Calculated 582.24; Found 582. 4 Calcu lated 514.17; Found =514.08.

134 Calculated 534.11; Found 534.07.

225 Calculated 594.09; Found 593.98.

27 Calculated 615.17; Found =615.04.

15 Calculated 601.15; Found 601.03.

-182- 0 0e0@ 0S 0 t.

S

00 .600 0 8* 00 0 50

S

5*00 0 .500 0* S 0* 0 00*00.

S

0 I 00* 0

S

0*0e (3 S)-3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta~b]pyridin-3yl Iamino}I carbonyl)amino]-3 (cyclopropyloxy.)phenyl]propanoic acid 1-[2-chloro-6-(cyclopentylmethoxy)benzyl]- 4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3 yl amino)carbonyl]amino methylphenyl)propanoic acid (3 I-[2-(benzyloxy)-6-chlorobenzyl]-4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl I amino)carbonyl]amino methylphenyl)propanoic acid (3 1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yI] amino)} carbonyl)amino]-3 -chloro-4,5diethoxyphenyl)propanoic acid (3 {[1-(2-cbloro-6-methylbenzyl)-4-hydroxy-2oxo-2,5 ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl]amino} carbonyl)amino]-3-(2,4-dichloro-3 ,5diethoxyphenyl)propanoic acid 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yl]amino} carbonyl)amino]-3-(2,4-dichloro-3 ,5diethoxyphenyl)propanoic acid (3 I-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridi;, 3yl]amino} carbonyl)amino]-3-[3- (cyclopropylmethoxy)phenyl]propanoic acid (3 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yllamino} carbonyl)amino]-3-[3- (cyclopropylmethoxy)phenyljpropanoic acid -(2-chloro-6-methylbenzyl)-4-hydroxy-2- ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl] amino}I carbonyl)amino] -3 (cyclopropylmethoxy)phenyl]propanoic acid (3 S)-3 [1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo-l ,2-dihydropyridin-3-yljamino~carbonyl)amino]-3- (2,4-diethoxypyrimidin-5-yl)propanoic acid 2 Calculated 582.20; Found 582.10.

20 Calculated 566.20; Found 566.09.

10 Calculated 574.17; Found 574.01.

3 Calculated 604.16; Found 604.02.

500 Calculated 652.14; Found 651.98.

450 Calculated 638.12; Found 637.97.

9 Calculated 552.19; Found =552. 4 Calculated 596.21; Found 596.11.

10 Calculated 566.20; Found 566.12.

13 Calculated 544.16; Found 544.00.

-183-

A

(3 -(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 2-oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yllarnino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 S)-3 -[3-(cyclopropylmethoxy)phenyl]-3 dichloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5 ,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yl]amino }carbonyl)amino]propanoic acid [1 -(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 2-oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl]amino carbonyl)amino]-3-(3 ethoxyphenyl)propanoic acid (3 -(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 2-o xo-2,5,6,7-tetrahydro- 1H-cyclopenta[bjpyridin-3y I amino}I carbonyl)amino] -3 isopropoxyphenyl)propanoic acid (3 S)-3 -(2-chlorobenzyl)-4-methoxy-2-oxo- 1,2dihydropyridinL3-yl](methy1)amino]carbonyl ammno)-3- (4-methylphenyl)propanoic acid (3 I1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1,2-dihydropyridin-3-yl]amino }carbonyl)amino]-3- (2'-methoxy- 1,1 '-biphenyl-3-yl)propanoic acid -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- I ,2-dihydropyridin-3 -yI] amino Icarbonyl)amino] -3 methyl-2-fiiryl)propanoic acid -(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl- 2-oxo- 1 ,2-dihydropyridin-3 -yl ]amino I carbonyl)amino]- 3-[4-(methylsulfonyl)phenyl]propanoic acid 3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta~b]pyridin-3yl ]amino}I carbonyl)amino] -3 -furyl)propanoic acid I1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydropyridin-3 -yl] amino)} carbonyl)amino]-3 furyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5 ,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yl ]amnino} carbonyl)amino] -3 (trifluoromethyl)phenyl]propanoic acid 5 Calculated 572.13; Found 571.97.

7 Calculated (M-Hy 628.16; Found 627.98.

3 Calculated 602.15; Found 601.99.

5 Calculated 616.16; Found 616.01.

2000 Calculated 482.14; Found 482.07.

15 Calculated (M-Hy 560.16; Found 559.98.

20 Calculated 458.11; Found 457.99.

43 Calculated 548.13; Found =548.07.

5 Calculated 470.11; Found =469.96.

4 Calculated (M-HY 444. 10; Found 443.9 1.

18 Calculated 548.12; Found 548.00.

-184- 0 9 0* 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3 ylamino carbonyl)amino]-3-(3methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3yl]amino} carbonyl)amino]-3-[3 (trifluoromethyl)phenyl]propanoic acid [1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3 ylamnino} carbonyl)amino]-3-(3,5dimethylphenyl)propanoic acid (3 ,5-bis(trifluoromethyl)phenyl] chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[bjpyr-idin-3yl ]amino) carbonyl)amino]propanoic acid (3 f I -[2-chloro-5-(trifluoromethyl)benzyl] -4hydroxy-5-methyl-2-oxo- 1,2-dihydropyridin-3yl}I amino)carbonyl] amino)} -3 methylphenyl)propanoic acid (3 [1 -(2-chloro-5-fluorobenzyl)-4-hydroxy-5methyl-2-oxo- 1,2-dihydropyridin-3ylamino} carbonyl)amino]-3-(4methylphenyl)propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2oxo- 1,2-dihydropyridin-3-yl]amino} carbonyl)amino]-3- [3-(diethylamino)phenyl]propanoic acid 3 '-biphenyl-4-yl)-3 -chlorobenzyl)-4hydroxy-2-oxo-2,5,6,7-tetrahydro- I Hcyclopenta[b]pyridin-3 yl] amino carbonyl)amino]propanoic acid (3 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1H-cyclopenta[b]pyridin-3yl Iamino I carbonyl)amino] -dihydro- 1 H-inden-5yl)propanoic acid (3 -(2-chloro-6-methylbenzyl)-4-hydroxy-2oxo-2, 5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3yljamino carbonyl)amino]-3-(2,3-dihydro- I H-inden-5yl)propanoic acid 5 Calculated 494.15; Found 494.02.

10 Calculated 548.12; Found 547.99.

9 Calculated 508.16; Found 508.02.

130 Calculated ol15.1 1; Found 615.99.

6 Calculated 536.12; Found 535.99.

5 Calculated 486.12; Found 485.97.

2 Calculated (M-Hy 525.19; Found 525.00.

30 Calculated 556.16; Found 555.99.

8 Calculated 522.17; Found 522.03.

10 Calculated (M+H) 4 536.19; Found 536.08.

-185a N- 1 -[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl- 2-oxo-1 ,2-dihydro-3-pyridinyl}-N'-[(1 methylphenyl)-2-( 11-1 ,2,3,4-tetraazol-5-yl)ethyl]urea 1,1'-biphenyl]-3-y1-3- chlorophenyl)rnethyl]-4-hydroxy-2-oxo-2,5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yl }amino)carbonyl]amino }propanoic acid (3 1-[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3yl I amino)carbonyl] amino -3 {4- [(trifluoromethyl)oxy]phenyl} propanoic acid {11-[(2-chlorophenyl)methyl]-4-hydroxy-2- ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3yl Ianiino)carbonyl] amino)}-3 {4- [(difluoromethyl)oxy]phenyl }propanoic acid (3 -[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl amino)carbonyl] amino) 3- [(trifluoromethyl)oxy]phenyl} propanoic acid (3 S)-3 1-[(2-chlorophenyl)rnethyl] -4-hydroxy-2oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl amino)carbonyl] amino)} f 3- [(difluoromethyl)oxy]phenyl }propanoic acid (3 {11-[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b jpyridin-3 yl) amino)carbonyl] amino) -3 ,2,2tetrafluoroethyl)oxy]phenyl }propanoic acid (3 {I -[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5 ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl I amino)carbonyl] amino)} -3 ,5-dimethyl-4- (methyloxy)phenyl]propanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-2- ,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl amino)carbonyl] amino -3 1-ethyl- I H-indol-5 yl)propanoic acid 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[bjpyridin-3yl}I amino)carbonyl] amino}1-3 difluorophenyl)propanoic acid 6000 Calculated 494.17; Found 494.01.

17 Calculated 556.16; Found 556.01.

13 Calculated 564.11; Found =564.01.

13 Calculated 546.12; Found 545.97.

10 Calculated 564.11; Found 563.98.

5 Calculated 546.12; Found 546.01.

4 Calculated (M-Hy 596.12; Found 596.02.

11 Calculated 538.17; Found 538.04.

5 Calculated 549.19; Found 549.02.

7 Calculated 516.11; Found 516.01.

-186- 9* 1-[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3yllamino)carbonyl]amino} -3-[3-fluoro-4- (methyloxy)phenyl]propanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3yl }amino)carbonyl]aniino propylphenyl)propanoic acid (3 (1-[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- I Hcyclopenta[b]pyridin-3 -yl Iamino)carbonyl]amino}1 -3- (4-propylphenyl)p ropanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- I ,2-dihydro-3pyridinyl} amino)carbonyl]amino} methylphenyl)propanoic acid (3 {11-[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[blpyridin-3yl I}amino)carbonyl] amino}1-3 cyclopropylphenyl)propanoic acid 1 -[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo-1I,2-dihydro-3pyridinyl} amino)carbonyl] amino) -3 quinolinyl)propanoic acid (3 {11-[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[bjpyridin-3yl }amino)carbonyl] amino -3 -quinolinyl)propanoic acid [2-chloro-6-(ethyloxy)phenyl]methyl)}-4hydroxy-5-methyl-2-oxo- 1,2-dihydro-3 pyridinyl)amino]carbonyl} amino)-3-(2furanyl)propanoic acid (3S)-3-[2,4-bis(ethyloxy)-5-pyrimidinyl]-3- 1 chlorophenyl)methyl]-4-hydroxy-2-oxo-2, 5,6,7tetrahydro- 1 H-cyclopenta[b]pyridin-3yl I}amino)carbonyl] amino) propanoic acid (3 I-[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro-1I Hcyclopenta[b]pyridin-3-yl amino)carbonyl]amino -3- (4-cyclopropylphenyl)propanoic acid 3 Calculated (M-H)y 528.13; Found =528.00.

17 Calculated (M-Hy 522.18; Found =522.04.

20 Calculated 536.20; Found 536.06.

267 Calculated 468.13; Found 468.00.

25 Calculated 522.18; Found 522.04.

22 Calculated 505.13; Found 504.98.

22 Calculated 531.14; Found 530.99.

8 Calculated 488.12; Found 487.98.

15 Calculated (M-Hy 570.18; Found 570.14.

19 Calculated 536.20; Found 536.07.

-187- 0 I -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[bjpyridin-3yl }amino)carbonyl]aminolbutanoic acid (3 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- ,6,7-tetrahydro- 1H-cyclopenta[bjpyridin-3yl amino)carbonyl] amino}1 -3 ethylphenyl)propanoic acid -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl) amino)carbonyl] amino) 1methylethyl)phenyl]propanoic acid (3 S)-3 1 -[(2-chlorophenyl)methyl]-4-hydroxy-5rnethyl-2-oxo- 1,2-dihydro-3pyridinyl) amino)carbonyljamino} ethylphenyl)propanoic acid (1-[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- I ,2-dihydro-3pyridinyllamirio)carbonyljamino}-3-[4-(1 methylethyl)phenyljpropanoic acid f 1 -[(2-chlorophenyl)methyl] -4-hydroxy-5methyl-2-oxo- 1,2-dihydro-3pyridinyl I amino)carbonyl] amino)} -3 [4- (cyclopropyloxy)phenyl]propanoic acid (3 1 -[(2-chlorophenyl)methyl]-4-hydroxy-5 niethyl-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl]amino -3 propylphenyl)propanoic acid 15 Calculated 418.12; Found 418.00.

8 Calculated 508.16; Found 508.06.

17 Calculated (M-HY 522.17; Found 522.06.

30 Calculated 482.14; Found 482.00.

175 Calculated 496.16; Found 496. 01.

6 Calculated (M-Hy 5 10.14; Found (M-H)Y 5 10.00.

12 Calculated 496.16; Found 495.99.

-188- 3- 1-[(2-chlorophenyl)metbyl]-4-hydroxy-5 methyl-2-oxo- 1,2-dihydro-3 pyridinyl amino)carbonyl] amino -3 cyclopropylphenyl)propanoic acid (3 1 -[(2-chlorophenyl)methyl] -4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl) amino)carbonyljamino} -3-(2,3-dihydro- 1 H-inden-5-yl)propanoic acid (3 1-[(2-chlorophenyl)methyl]-4-hydroxy-2- ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl) amino)carbonyl] amino) -3-(9-ethyl-9H-carbazoi-3yl)propanoic acid (3 S)-3 1 -[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo-1I,2-dihydro-3 pyridinyl} amino)carbonyl]amino} -3-(9-ethyl-9Hcarbazol-3-yl)propanoic acid (3 S)-3 1 -[(2-chloro-6-methylphenyl)methyl] -4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3 -yl amino)carbonyl] amino 1 -3 (1-methyl- I H-indol-5-yl)propanoic acid (3 S)-3 1 -[(2-chloro-6-methylphenyl)methyl] -4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopental~b]pyridin-3-yl I amino)carbonyl] amino)} -3f{3 -[(difluoromethyl)oxy]pheny1 propanoic acid (3 {I -[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino -3 (ethyloxy)[ 1,1 '-biphenyl]-4-yl]propanoic acid (3 S)-3 1 -[(2-chlorophenyl)methyl] -4-hydroxy-2- ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl am ino)carbonyl] amino I -3-[2-(ethyloxy)[ 1,1Vbiphenyl]-4-yl]propanoic acid (3 S)-3 {I-[(2-chlorophenyl)methyl] -4-hydroxy-5 methyl-2-oxo- 1 ,2-dihydro-3pyr-idinyl} amino)carbonyl] amino}I -3-(2'-methyl[ 1,1'biphenyl]-3-yl)propanoic acid (3 S)-3 I-[(2-chlorophenyl)methyl] -4-hydroxy-5methyl-2-oxo- 1,2-dihydro-3pyri dinyl I amino)carbonyl ]amino)} -3 -(3'-methyl 1,1'biphenyl]-3-yl)propanoic acid 35 Calculated 494.15; Found 494.0 1.

18 Calculated (M-HY 494.15; Found 494.02.

13 Calculated 597.19; Found =597.0 1.

23 Calculated (M-Hy 571.17; Found =570.99.

3 Calculated 547.17; Found =547.04.

3 Calculated 560.14; Found 560.03.

25 Calculated 574.17; Found 574.00.

20 Calculated 600.19; Found 600.01.

20 Calculated 544.16; Found 544.04.

18 Calculated 544.16; Found 544.00.

-189a {[2-chloro-6-tetrahydro-1I (2H)pyridinylphenyl]methyll }4-hydroxy-5-methyl-2-oxo- 1 ,2-dihydro-3-pyridinyl)amino]carbonyl amino)-3-(4methylphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl]axnino -3-(4'-niethyl[ 1,1Vbiphenyl]-3-yl)propanoic acid -[(2-chlorophenyl)methyl]-4-hydroxy-2- ,6,7-tetrahydro- IH-cyclopentab]pyridin-3yl I amino)carbonyl] amino) -3 (diethylamino)phenyl]propanoic acid (3 S)-3 1-[(2-chlorophenyl)methyl] -4-hydroxy-5 methyl-2-oxo- 1,2-dihydro-3pyridinyl} amino)carbonyl] amino -3 (difluoromethyl)phenyljpropanoic acid (3 S)-3 1-[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5 ,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl} amino)carbonyl] amino}1 fluorophenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2 ,5,6,7-tetrahydro- 1H-cyclopenta[b]pyridin-3 yl I}amino)carbonyl] amino) -3 fluorophenyl)propanoic acid N- 1 -[(2-chlorophenyl)methyl] -4-hydroxy-5 -methyl- 2-oxo-1I,2-dihydro-3-pyridinyl 1H- 1,2,3 ,4-tetraazol-5-yl)methyl]urea 1 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-5-methyl-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino 1 -3 -methyl-i H1acid (3 S)-3 I -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3 -ylI }amino)carbonyl] amino)} -3- [3-(diethylamino)phenyl]propanoic acid (3 S)-3 1 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 111cyclopenta[blpyridin-3-yl amino)carbonyl] amino -3 (3 -methylphenyl)propanoic acid 90 Calculated 5 51.2 1; Found 551.06.

23 Calculated 544.16; Found 543.99.

3 Calculated 551.21; Found 551.05.

20 Calculated (M-Hy 504.11; Found 503.96.

16 Calculated 498.12; Found 498.02.

9 Calculated 498.12; Found 498 .01.

>10000 Calculated (M-Hy 464.12; Found 464.0 1.

4 Calculated 521.16; Found 52 1.00.

10 Calculated 565.14; Found 565.04.

4 Calculated 508.16; Found 508.03.

a a.

a a a a a -190- (3S)-3 1-[(2-chloro-6-methylphenyl)methyl] -4hydroxy-2-oxo-2,5,6,7-tetrahydro- I Hcyclopenta[bjpyridin-3-yllamino)carbonyl]amino} -3phenyipropanoic acid (3 S)-3 f 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1H-cyclopenta[blpyridin-3yl~amino)carbonyl]amino} hydroxyphenyl)propanoic acid 1-[(2-chlorophenyl)methyl] 4-hydroxy-5methyl-2-oxo- 1,2-dihydro-3pyridinyl I amino)carbonyl] amino)} -3 hydroxyphenyl)propanoic acid 1-[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl] amino}1 -3 ',51dimethyl[ 1,1 '-biphenyl]-3-yl)propanoic acid (3 1-[(2-chlorophenyl)methyl] -4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl I amino)carbonyll amino}I -3-phenyipropanoic acid (3 f 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2, 5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl}I amino)carbonyl ]amino}1-3 f{3- [(methylsulfonyl)amino]phenyl }propanoic acid (3 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- I Hcyclopenta[b]pyridin-3 -yl amino)carbonyl] amino)} -3 {3 -[(methylsulfonyl)amino]phenyl }propanoic acid (3 1-[(2-chlorophenyl)methyl] -4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3 yl I amino)carbonyl] amino)} (difluoromethyl)phenyl]propanoic acid (2S,3 1 -[(2-chlorophenyl)methyl]-4-hydroxy- 5-methyl-2-oxo- 1,2-dihydro-3pyridinyl Iamino)carbonyll amino) -2 -methyl-3 methylphenyl)propanoic acid (3 S)-3 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl amino)carbonyl]amino 1 -3- (4-ethylphenyl)propanoic acid 17 Calculated 494.15; Found 494.09.

8 Calculated 496.13; Found 495.99.

9 Calculated 470.11; Found 469.98.

50 Calculated 558.18; Found 558.00.

15 Calculated (M-Hy 455.12; Found 454.00.

3 Calculated 573.12; Found 572.98.

3 Calculated 587.14; Found 586.98.

4 Calculated 530.13; Found 530.03.

1500 Calculated 482.15; Found 481.99.

15 Calculated (M-HY 522.18; Found 522.04.

9 -191-

S

*5

S

9 (3 f 1 -[(2-chlorophenyl)methyl]-4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl amino)carbonyljamino} -3-(2,2-dimethyl -2,3dihydro- 1 -benzofuiran-5-yl)propanoic acid (3 1 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl amino)carbonyljamino -3 [3-fiuoro-4-(methyloxy)phenyl]propanoic acid (3 S)-3 1 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl I amino)carbonyl] amino -3 {3-[(trifluoromethyl)oxy]phenyllpropanoic acid (3 S)-3 1 -[(2-chlorophenyl)methyl] 4-hydroxy-2oxo-2,5,6,7-tetrahydro- 1 H-cyclopenta[b]pyridin-3yl} amino)carbonyl] amino)}-3 -1 [methyl(methylsulfonyl)aminojphenyl }propanoic acid 1 -[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl) amino)carbonyl]amino} -3 (3 -[methyl(methylsulfonyl)amino]phenyl} propanoic acid (3 S)-3 ({I-[(2-chlorophenyl)methyl]-4-hydroxy-2 oxo-2,5 7-tetrahydro- 1 H-cyclopenta[b]pyridii-3yl am ino)carbonyl] amino {3 [ethyl(methylsul fonyl)amino]phenyl }propanoic acid (3 1-[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3-yl }amino)carbonyl]amino)}-3- {3 -[ethyl(methylsulfonyl)aminolphenyllpropanoic acid (3 S)-3 I-[(2-chlorophenyl)methyl] -4-hydroxy-5 methyl-2-oxo- 1 ,2-dihydro-3pyridinyl amino)carbonyl]amino} -3 -(2'-fluoro[ 1,1Vbiphenyl]-3-y1)propanoic acid (3 {11-[(2-chlorophenyl)methyl]-4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pyridinyl} amino)carbonyl] amino (trifluoromethyl)[ 1,1 '-biphenyl]-3-yl]propanoic acid (3 S)-3 (IX{I-[(2-chlorophenyl)methyl] -4-hydroxy-5methyl-2-oxo- 1 ,2-dihydro-3pynidinyl} amino)carbonyl] amino}1-3-(2fluorophenyl)propanoic acid 3 Calculated 550.17; Found 550.05.

3 Calculated 542.15; Found 542.00.

11 Calculated 578.13; Found 578.02.

1.6 Calculated 587.14; Found 586.99.

1.3. Calculated-(M-H)- 601.15; Found 60 1.00.

1 Calculated (M-Hy 601.15; Found 601.00.

1 Calculated 615.17; Found 615.04.

25 Calculated 548.14; Found 547.96.

157 Calculated 598.14; Found =597.97.

10 Calculated (M-Hy 472.11; Found 471.98.

-192- 1-[(2-chloro-6-rnethylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3 -yl I amino)carbonyl]amino}1 -3 (1 H-indol-5-yl)propanoic acid l-[(2-chloro-6-methylphenyl)methyl]-4hydroxy-2-oxo-2,5,6,7-tetrahydro- 1 Hcyclopenta[b]pyridin-3 -yl amino)carbonyl]amino} -3 (3 ,5-difluorophenyl)propanoic acid 2 Calculated 533.16; Found =533.01.

11 Calculated (M-HY 530.13; Found 530.00.

a. a a a. a a.

a.

a a a -193- SEQUENCE LISTING GENERAL INFORMATION: APPLICANT: Biediger, Ronald Chen, Qi; Decker, E. Radford; Holland, George W.; Kassir, Jamal Li, Wen; Market, Robert Scott, Ian Wu, Chengde; and Li, Jian.

(ii) TITLE OF INVENTION: Carboxylic Acid Derivatives that Inhibit the Binding of Integrins to their Receptors (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS: 15 ADDRESSEE: Rockey, Milnamow Katz, Ltd.

STREET: 180 N. Stetson Avenue, 2 Prudential Plaza, Suite 47 CITY: Chicago STATE: Illinois 20 COUNTRY: U.S.A.

ZIP: 60601 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: PatentIn Release Version #1.30 (vi) CURRENT APPLICATION DATA: APPLICATION NUMBER: FILING DATE:

CLASSIFICATION:

(viii) ATTORNEY/AGENT INFORMATION: NAME: Katz, Martin L.

REGISTRATION NUMBER: 25,011 REFERENCE/DOCKET NUMBER: TEX4542P0402US (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: 312-616-5400 TELEFAX: 312-616-5460 INFORMATION FOR SEQ ID NO: 1: SEQUENCE CHARACTERISTICS: -194- LENGTH: 26 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Cys Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu His 1 5 10 Gly Pro Glu fle Leu Asp Val Pro Ser Thr 20 -195- All references cited are hereby incorporated by reference.

The present invention is illustrated by way of the foregoing description and examples. The foregoing description is intended as a non-limiting illustration, since many variations will become apparent to those skilled in the art in view thereof. It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby.

Changes can be made in the composition, operation and arrangement of the method of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims: 0* 0 *ea

Claims

1. A compound of the structure 00 Rio OB NyAN N LR4 0 R~ wherein sY at each ocurrence, is independently selected from the group consisting. of C(O), N, CR', C(R 2 )(R 3 NRA, CHI, 0 and S; q is aninteger of from 2to T is selected from the group consisting of C(0) and (0H2)b, whefein b is an integer of 0 to 3; L is selected from the group consisting of 0, NR", S and (CJHz),, wherein n is 0 or I R' RR' and RP are each independently selected from the group consisting of :alkyl, alkenyl, alkynyl, hydrolcyalky1, aliphatic acyl, alkynylamnino, alkoxycarbony1, t. eterocycloyl, -CN=NOH, hialoalkyl, alkoxyalkoxy, carboxaldehyde, carbbxamide, is cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylanino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen, and -C(0)NH(benzyl) groups; and B, RP3 R? n and R 10 are independently selected ftrm the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, Alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic neyl, -CE 3 -CO 2 H, -SN, -ON, -NO 2 -NH 2 -OH, alky4'lamino, alkoxycatbonyl, heterocycloyl, carboxy, -N(Ci -C 3 alkyl)-C(O)-(CI-CalcyI), -N}IC(0)N(C -C 3 alkyl)C(0)NH(CI-C 3 alkyl), NHC(Q)NH(C j-C 6 alyl), -NSQ(- *C 3 allkyl), -NHSO 2 (aryl), alkoxyalkyl, alkylarnino, alkenylamino, di(C-C~Alkyl)amino, -C 3 alkyl) -C(O)NH-(Ci-Calkl), -C(O)N(C 1 -C3alkyl)2, -CHkNOH,' -P0 3 H 2 -0P0 3 H 2 haloalkyl, alkoxyalikoxy, carbuxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,. cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamncnp, biaryl, thiosryl, diarylamino, heterocyclyl, alkylaryl, aralenyl, aralkyl, alkylhet&ocyclyl, heterocyolylalkyl, sulfonyl, -S0 2 I-C 3 elhyl), -SO)'(CI-C 3 alky1), sulfonurnido, carbamnate, aryloxyalkyl, and -C(O)NH(benzyl) groups; B, Rt', R 1 2, Wt, FO, RI, It 7 R!9, R1' 0 Rt" and R's are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is NIP', K 4 and Rt" taken together may form a ring; [R:\LiB-jS7S390dlspaci.doo:mak COMS ID No: SBMI-01328758 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:58 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 67 197 and wherein and R' 0 taken together may form a ring; and wherein when at least one Y is CR 1 R' and Rt 6 taken together may fort; a ring; with the proviso that Rt's is not a phenyl ringsubstituted wit a group selected from -C&=NH)NH 2 -CN, -C(&NH)NI-IOH, -C(=NOH4)NH 2 -C(=S)NH 2 and -C(NH)S CU 3 and pharmaceutically accetable salts thereof.

2. A compound according to claim 1, wherein Rt' 8 is selected from the -group consisting of hydrogen, alkyl, aryl, aralicyl, cycloalkyl, alkylbeterocyclyl, heterocyclylalkyl and heterocyclyl; T is (CH2)b, whereint b is 0; L is (CH 2 wherein n is 0; Y is. selected firomn the group consisting of CR 1 and C(R 2 )(R 3 and q is'.2or 3.

3. A compound acortding to claim 1, which is a derivative thereof selec ted fromn *.:the group consisting of esters, ourbamnates, aminals, ajuides, optical isomers and pro- 0015 drugs.

4. A, compound according to claim 1, wherein *Y )04 0 is selected from the group consisting of (R ~N (R 0 i (R28j 1 c N 00 :00. 0 and 0 :20 wherein R"9, R2W, R 2 and RtZ8 at each occurrence are independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, a~kynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CE 3 -OH, -CO 2 H, -SN, -CN, -NO0 2 -NH 2 alkynylarni no, alkoxycarbonyl, heterocycloyl, carboxy, -N(CI-Csallcyl)-C(O)(Cs AD 3 akyl), C 3 alkyl), -NHSO 2 (aryl), alicoxyalkyl, allcylaniino, alkenylamnino, di(C[-C~Alkyl)wnmino, ,-C 3 alkyl), -C(O)NH-(C,-C 3 alkyl), -C(0)N(C ,-C 3 alkyJ)2, -CW=NOH,'-P0 3 H 2 -OP03H 2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxantide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyalk~'1, aryl, aroyl, aryloxy, arylamino~i biairyl, thioaryl, diarylauxino, -heterocyclyl, alkylaryl, aralkenyl, aralkyl, 'allcylheterocyclyl, jo heterocyclylalkyl, sWunyl -S0 2 -(CI-C 3 d]kyl), -SQ,-(C 1 -C 3 alkyl), sulfonamrido, carbamnate, aryloxyalkyl, and -C(O)NH(benzyl) groups; frLAMK157S390d~wsoea COMS ID No: SBMI-01328768 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:59 SPRUSON AND FERGUSON 61292515486 NO. 2697 68 is selected frmthe group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatlc acyl, alkynylamino, alcoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxarnide, cycloalcyl, cycloalkenyl, cycicalkynyl, cycloalkylalky, aryl, aroyl, aryloxy, arylamino, biaryl, thiosryl, diarylamnino, heterocyclyl, alkylaryl, arakenyl, aralkyl alikyiheterocyclyl, heterocylylalky1, carbamnate, aryloxyallcyl, hydrogen and -C(0)NH(benzyl) groups; R~is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thiosilkoxy, hydroxyalkyl, aliphatic acyl, -CE 3 -OH4, -C02H1, -SH, -ON, -NO 2 -NH 2 alkynylaino, alkoxycarbonyl, heterocycloyl, -carboxy, 1o -N(C,-C 3 alkyl)-C(O))(C,-Cjalkyl), -NHC(O)N(C,-C 3 aflcyl)C(O)NH(CI-C 3 alkyI), -NHC(O)NH(Cj-CQalkyI), -NHSO 2 (CI-G 3 alkYl), -NHSO 2 (aryl), alkoxyalkyl, alk--ulaio, alcenylemino, di(C,-C 3 alkyl)amino, -C(O)O-(C 1 -C 3 alkyi), -C(Q)NH-{C 1 -C 3 allcyl), -C(O)N(C,-C 3 alkylz, -CH=NOH, -PO3H 2 -0P0 3 H 2 haloalkyl, alkoiyalkoxy,. carboxaldehyde, carboxaniide, cycloalkyl, cycloalkenyl,' cycloalkynyl, cycloalkylalkyl, arl aryl aryloxy, arylainino, biaryl, thicaryl, diar34arnino, heterocyclyl, alkylaryl, S aralkenyl, aralkyl, ulkyiheterocyolyl, heterocyclylalkyl, sulfonyl, -S0 2 -Cdalkyl), -S0 3 -(Cr-C 3 alkyl), sulfonamido, carbamate, aryloxyalkyl, and -C(O)NH(benzyl) groups; c i'san integer of 0to 2; di is an integer of 0 to 3; and 2 iisan integer of 0t to cl2,, hri compound accordingtocam1whri R. 4 is arayl; P.' 8 is arayl; T is (C114,, wherein b is 0; L is (0114, where n is 0; and R, 6 R7', R 9 and are each independently hydrogen.

6. A compound of the structure R 2 b -4 N N T NR o A 1 wherein T is selected from th group consisting of C(0) and (CR4,b, wherein b is an integer of from 0 to 3; L is selected from. the group consisting of 0, S and wherein -n is 0 or rRALMHls7s39odlovvvi.doc~aak COMS ID-No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005'06-30 JUN. 2005 15:59 SPRUSON AND FERGUSON 61292615486 NO. 2697, P. 69 199 g is an integer of from 0 to 7; and B, R 4 Re, and R? 3 at each occurene are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioallcoxy, hydroxyalkyl, *aliphatic acyl, -CF 3 -OH, -CO 2 H, -SH, -CN, -NQ 2 -NIT 2 alkynylarnino, alkoxycarbonyl, heterocycloyl, earboxy, -C 3 alkyl)-C(O)(C 1 -qC 3 alkyl), -NHC(O)N(Ci -C 3 alkyl)C(O)NH(Gj-C 3 alkyl), -NHC(O)NH(C,-C 6 alkyl), -NHSch(C,- C 3 alkyl), -NHSO 2 (aryl), alkoxalkyl, alcylamino, alkenylandno, di(C, -C3alkyloamino, -C(O)O-(Cj -C 3 alkyl), -C(O)NH-(C,-C 3 alkyl), -C(O)N(C-C 3 alkY) 2 -CH=NOH,: -P0 3 H 2 -0P0 3 H 2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,. cycloalkyl, to cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, az-ylamino, biaryl, thioaryl, diarylamnino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocclylalkyl, sulfonyl, -S0 2 -(C 1 -C 3 alkyl), -SO,-(C 1 -Cjalkyl), sulf6namaido, carbamate, aryloxyalkyl, and -C(O)NH(bvnzyl) groups; R 6 7Q R" and R" 8 are each independently selected from the group congisting of :15I alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylarnino, alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycoalylcycoaleny, cclolkyylcycloalkylalkyl, ai-yl, aroyl, aryloxy, arylanaino, heterocyclylalkyl, carbarnate, aryloxyalicyl, hydrogen and -C(O)NH(benzyi) groups; wherein B, R. 4 R 9 H.' 0 R" R' 8 and e. 2 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is NR'" 1H. 4 l and R1 1 taken together m ay form a ring; and wherein H.'and R.' 0 taken together may form a ring; with the proviso that R 1 8 is not a phenyl ring substituted with a group selected from -C(=NH)NH 2 -CN, -C(=NH)NI-OH, -C(=NOH)NH 2 -CQ S)NHz and -C(NH)SCH 3 and pharmaceutically acceptable salts thereof.

7. A compound according to claim 6, which is a derivative thereof selected from the group consisting of esters, carbornates, arninals, amnides, optical isomers. and pro- drugs. A compound of the structure OR 26 R 0 0 0 R1N N R 0 I7) wherein h is an integer of 01to COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 15:59 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 200 %BP I, R(4 and 1(25 ame each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -OF 3 -OH, -COzil, -SH, -ON, -NO 2 -NH 2 alkynylamino, alkoxycarbonyl, beterocycloyl, carboxy, -N(C1 -C~aICkyl)-C(Q)(C 1 -C~Alkyl), -NHC(O)N(O, -O 3 alkyl)(O)NHOi -OC 3 alkyl), -NI-J(O)NH(C, -C 6 alkyl), -NHS0 (Cl- Osalkyl), -NH50 2 (aryl), alkoxyalkyl, alkylamino, alkenylaniino,' di(d,-C 3 alkyl)aniino, -O(O)O-(Oj-C3alkyl) -O 3 alkyl), -O(O)N(C 1 -O 3 alkyl) 2 -O1-fNOH, -P0 3 H 2 -0P0 3 H 2 haloalkyl, alkoxyalkoxy, caxboxaldehyde, earboxainide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, ic thiosryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, arailcyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S0r(C, -Osalkyl), -S0 3 -(CI-C 3 alkyl), sulfonamido, carbaniate, aryloxyalkyl, and -C(Q)NH(benzyl) groups; at each occurrence -is. independently selected from the group con isting of halogen, hydroxyl, alkyl, alkenyl, alkynyl, alioxy, alcenoxy, alkynoxy, tiosikoxy, :15i hydroxyalkyl, aliphatic acyl, -CFs. *CO 2 H, -SW ON, -NO 2 -Ni, alkynylaioino, :alkoxycarbonyl, heterocycloyl, carboxy, -Csalkyl)-O(O)(C 1 -0 3 rNHC(O)N(Ci-C 3 alkyl)C(O)NH(Cr-Caalkyl), -NHC(O)NH(C I-O 6 alkyl), -NHSO2(Or- C 3 alkyI), -NHSO 2 (aryl), -N(C 1 -O 3 alkyl)S0 2 (Ci-Calcyl), -O 3 alkyl)S02(aryl), alkoxyalkyl, .alkyl amino, alkenylamino, di(CI-C~alkyl)axnino, -C(O)O-(C 1 -O3'alkyl), 20 G(O)NH-(C,-C~Alkyl), -O(O)N(C 1 -C~alkylh2, -OH=NOH, -P0 3 H- 2 -OPOH 2 haloalkyl, alkoxyalkoxy, carboxaldebyde, carboxarnide, cycloalkyl, cycloalkenyl, cycioalkynyl, cyoloalkylalkyl, aryl, aroyl, aryloxy, arylanuino, biaryl, thioaryl, diarylamn'ito, heterocyclyl, alkylaryl, uralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,- S0rs-(O,-O38IICYl), -S0 3 -(Cg-C 3 alkyl), sulfonamnido, carbamate, aryloxyalkyl, and- C(O)NH(benzyl) gruups, R 6 IC and R' 8 are each independently selected from-the group consisting of alkyl, aJlkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylarnino, alkoxycarbonyl, heterocycloyl, -OH=NOH, haloalkyl, alkoxyalcoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cyoloalkylalkyl, aryl, aroyl, aryloxy, arylainino, 3o biaryl, thioaryl, diarylamino, heterocyclyl, alicylaryl, arailkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, carbarnate, aryloxyalkyl, hydrogen, and -C(O)NH(benzyl) groips; Rk 6 is selected from the group consisting of hydrogen alkyl, alkenyl,* alkynyl, hydroxyalkyl, aliphatic acyl, -OF 3 alloxycarbonyl, heterocycloyl, carboxy, O 3 alkyl), -O(O)NH-(C 1 -C 3 alkyl), -C(O)N(C,-0 3 alkyl) 2 -P0 3 TH, haloalkyl, caboxmide, cycloalkyl, cycloalkenyl, cycloalkcynyl, cycloalkylalkyl, aayl, aroyl, biaryl, hetrocyclyl, iWBH5739QdIspwi.doa:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:08 Date 2005-06-30 JUN. 2005 16:00 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 71 201 alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO 2 -(CI- C3alkyl), sulfonamido, aryloxyalkyl, and -C(O)NH(benzyl) groups; wherein B, 6 RB, R, R 10 R 8 R 24 R 25 R 26 and R 27 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; s wherein R" and R 24 taken together may form a ring; R" and R25 taken together may form a ring; and wherein R9 and R'o taken together may form a ring; and pharmnnaceutically acceptable salts thereof

9. A compound according to claim 8, wherein B, Rio 0 R 2 R" and to R26 are each independently hydrogen, and RB 18 is substituted or unsubstituted aralkyl. A compound according to claim 8, which is a derivative thereof seleeted from the group consisting of esters, carbamates, aminals, amides, optical isomers and pro- drugs.

11. A compound of the structure 0* 6 (R 2 )k R' 0 OB *R 0 nil' AG' of- RgN N K N T LR 4 t* s 15 O R wherein Z at each occurrence is independently selected from the group consisting of N, CR' 0 C(R' 3 )(R 2 NR", CH, O and S; z is an integer of from 3 to 6; k is an integer of from 0 to T is wherein b is an integer of from 0 to 3; 'L is selected from the group consisting of O, NR", S and (CH 2 wherein.n is 0 or R6, R, R" and R" 3 are each independently selected from the group consisting of alkyl, alkenyl, alkyoyl, hydroxyalkyl, -aliphatic acyl, alkynylamrnino, alkoxycarbonyl, 2s heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carb6xamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, hetercyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, hetercyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; B, R, Ri' W" and R32 at each occurrence are independently selected from 2o the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphati acyl, -CF3, -CO2H, -SI, -OH, -CN, -NO 2 NH 2 alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, N(Cz-C3alkyl)-C()(CI- fR:\LIBH1575390dlapcci.docank COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:00 SPRUSON AND FERGUSON 61292615486 NO, 2697 P. 72 202 CsalcYl), -NHC(O)N(CI-C~alkyl)C(O)NH(Ci-C 3 alkyl), -NHC(O)NH(C-CaIky1),- NHSO 2 (Cr-C~alkyl), -NHSO 2 (axyl), alkox yalkyl, alkylamino, alkenylarnino, di(Cj- C~alkcyl)amino, -Csalkyl), -C(O)NH-(C 1 -C 3 alkyl), -C(O)N(Ci-C3dlkyl) 2 CH=NOH, -PO3H 2 -OPOH 2 haloalkyl, alkoxyalkoxy, carboxaldehyde, carbbxarnide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, &royl, aryloxy, arylamino, blaryl, tihiosryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, sulfontyl, -S0 2 -(Ci -C~alkyI), -S03-(Cj-C~alcyl), sultoinamido, carbaniate, aryloxyalkyl, and -C(O)NH(benzyl) groups; and l&at each occurrence is iudependently selected from the group consisting of wo halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CFs, -CO 2 H, -SH, -OH, -ON, -NO 2 -NH 2 alkynylamnino, alkoxy~arbonyl, heterocycloyl, carboxy, N4(C 1 -C~a]kylf'.C(O)(C-CakyI), -NIJC(O)N(Cj- *Csalkyl)C(O)NH(Ci-C~alkyl), -NHC(O)NH(CI-C 6 alkyl), -NHSQz(Ci-C3aikyl), NHSO2(aryl), alkoxyalkyl, alkylamirie, alkenylam-ino, di(Ci-C~alkyl)amino, -C(O)O-(C 1 G 3 alkyl), -C(O)NH-(CI-C 3 alkyl), -C(O)N(Ci-C 3 alkyl) 2 -CH NOH, -P0 3 11 2 OPOH 2 haloalkyl, alkoxyalkoxy, carboxaldehyde, caboxamide, cycloalkyl, cycibalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, ***diarylamidno, neterocyoiyl, aucyiaryi, arancenyl, aralKyl, alkylheterocycly1, heterocyclylalkyl, sulfonyl, -S0 2 -(Ci -Cjalkyl), -SO3,-(CI-C~adkYl), sulftbamido, carbamate, aryloxyalkyl1, and C(Q)NII(benzyl) groups; wherein B, RK, R 7 K 1 0 R" R' 8 R 2 9 R' 0 R' 1 R3 2 and e. are unsubsiituted or substituted with at least one electron donating or electron withdrawing group; wherein when L is NR", R' and K" taken together may form a ring; and 25 wherein Re and K' 0 taken together may form a ring; or a pharmaceutically acceptable salt thereof. *12. A compound of claim 11, which is a derivative thereof selected from the group consisting of esters, carbamnates, amninals, amides, optical isomers and pro-drugs.

13. The compound of claimn 11, wherein z is 3 cr 4.

14. A compound according to claim 11, wherein )Z(R 29 )k R18/N 0 is selected from ER:.\LmBHlS7539Ddlapec~dO:a COMS ID No: SBMI-01328788 Received by IF Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:00 SPRUSON AND FERGUSON 61292615486. NO. 2697 P. 73 203 /(CH 2 )m RI8 R1N 0 and 0 R" is selected from the group consisting of alkyl,'alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, 'alkynylamino, alkoxycarbonyl, heterocycloyl, -CHfrNOH, liaoalkyl, alkoxyalkoxy, carboxaldehyde, carboxarnide, .cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl,' aryl, aroyl, aryloxy, arylainino, biaryl, thioaryl, diatylamino, heterocyclyl, alkylaryl, .aralkenyl, aralkyl. alkyiheterocyclyl, heterocyclylalkyl, carbamnate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; wherein each R 22 when present, i3 independently selected from thie group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thicalkoxy, io hydroxyalicyl, aliphatic acyl, -CF 3 -OH, -CC H4, -SH, -CN, -NO 2 -NHj, alkydiylaniino, :::alkoxycarbonyl, heterocycloyl, carboxy, -N(0 1 -C 3 alkyl)-C(O)(Ci 'C~alkyl), -NHC(O)N(Cj-C~alkyl)C(0)NH(C-C 3 aikyl), -NHC(O)NH(0 1 -C 6 aIkyl), -NHSO 2 (C 1 C~alky1), -NHS02(aryl), alkoxyalkyl, alkylainino, alkenylarnino, di(C 1 -C~alkyI)anino, is-0P0 3 112, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, -cycloalkyl, Cycloalkenyl, cycloalkynyl, cycloaklalkyl, aryl, aroyl, aryloxy, arylainn, 'biaryl., thioaryl, diarylarnino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterooyolylalkyl, sulfonyl, -S0 2 -(C 1 -C 3 a9kyl, -S0 3 -(CI-C 3 alkyl), sulfonamido, *carbarnate, aryloxyalkyl, and C(Q)NH(benzyl) groups; 20 R~is selected fromn the group consisting of hydrogen, halogen, alkyl,; alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -OH, -CO2H, -Sf1, -CN, -NO 2 -NH 2 alkynylaxuino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C C 3 alkyl)-C(O)(Ci-C 3 alkyl), -NHC(O)N(C -C~alkyl)C(O)NH(Ci &,alkYl), -NH4C(O)NH(C 1 -C 6 alkyl), -NHSO 2 (C 1 -Cjalkyl), -NTIS O(aryl), alkoxyalcyl, 4lylanino, alkenylaniino, di(Cj-C 3 alkyI)amino, -C~alkyl), -C(O)NH-(C 1 -Csalkyl), -C(O)N(C,-CsalkyI)2, -CH=NOE, -P0 3 H 2 -0P0 3 H 2 haloalicyl, alkoxyalicoxy, carboxaldehyde, earboxamide, cycloalkyl, cyoloalkenyl, cycloalkynyl, cyclaal kylalkyl, aryl, aroyl, aryloxy, airylamino, biaryl, thioaryl, diarylaniino, heterocyclyl, alkylaryl, aaenyl, aralkyl, alkyiheterocyclyl, heterocyolylalkyl, sulfonyl, -SO 2 -(Ci-Z3alkyl), -50 3 -(C-C 3 alcyl), sulfonamnido, carbamate, aryloxyalkyl, and -C(O)NH(benzyl)Y groups; m is an integer of firom I to 3: and e is an integer of fromn 0 to 4. IR:\NLIEBi575390dlspeLdoc:Sak COMS ID No: SBMI-01326788 Received by IP Australia: Time 16:06 Date 2005-O6-30 JUN. 2005 16:01 SPRUSON AND FERGUSON 61292615486 NO. 2697 P, 74 204 A compound according to claim 14, wherein R22is OH.

16. A compound of the structure :~0 Wherein R 24 and 1(25 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thoallcoxy, hydroxyalkyl, aliphatic acyl, -CE 3 -CO 2 H, -SH, -OH, -CN, -NO 2 -NH 2 alkyiiylamnino, alkoxycarbonyl, heterocycloyl, carboxy, N(C 1 -C 3 alkyI)-C(O)(C 1 -C 3 aflcy), NHC(Q)N(C,-C 3 alkyl)C(O)NH(C-C 3 alkyl), -NHC(O)NH(Ci-C~alkyl), -NHSO 2 (C 1 C~alkyl), -NHSO 2 (aryl), alcoxyalkyl, alkylainino, alkenylamino, di(0 1 -C~alk-yl)amnino, io C(O)O-(C 1 -C 3 alkyl), -'C(O)NH-(C 1 -C 3 alkYI), -C 3 alkyI) 2 -CH=NOII, -PO 3 H, 0P0 3 H 2 haloalkyl, alkoxyalkoxy, carboxaldehyde, .carboxamide, cycloalicyl, cycloalkenyl, cycloaliynyl, cycloalkylailcyl, aryl, aroyl, aryloxy, arylarnino, biaryl, thiouryl, diarylamnino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylhet~rocycly1, hetemocyclylalkyl, sulfonyl, -S02-(CI-C 3 alkyl), -S0 3 -(Cj-C 3 alkyl), sulfontaiido, arbarnate, aryloxyalkyl, and -C(O)NH(benzyl) groups; and R 118 and R 34 are each independently selected ftrm the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,' aliphatc acyl, alkynylainino, alkoxycarbonyl, heterboyclayl, -CH'NOH, haloalkyl, alcoxyalicoxy, carboxaldehyde, IRALE3IIS75S9Udlsvoc±.doc:aak COMS ID No: SBMI-01328788 Received by IP Australia: ime 16:06 Date 2005-06-30 JUN. 2005 16:01 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 205 carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aiyloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl. aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(0)NH(beniyl) groups; wherein R 2 4 R*and R 34 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and wherein R 14 and R 2 taken together may form a ring; with the proviso that when R 24 and R 25 taken together fonm a ring, the ring formed is not benzene. i.17. A compound of claim 16 wherein R 4 is hydrogen; R"o is aralkyl; and R24 and R2 are each independently selected from the grqup consisting of hydrogen, lower alkyl, and lower alkyl wherein R 2 and R5 taken together may S 15 form a ring. I8. A compound of claim 16 of the structure R2 "14 (R's 0 N N 34 wherein R 24 and R are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,: rhioalkoxy, hydroxyalkyl, aliphatic acyl, -SH, -OH, -CO 2 H, -CN, -NO2, -NH 2 alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(Cl-C3 alkyl)-C(O)(C 1 i-C 3 alkyl), -NHC(O)N(C,-Cs alkyl)C(O)NH(C i-C3alkyl), -NHC(O)NH(CI-C6 alkyl), -NHS2Oz(C 1 -C 3 COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:01 SPRUSON AND FERGUSON 61292615486 NO. 2697, P. 76 206 alkyl), -NHSOzaryI), alkoxyalkyl, alkylamino, alkenylaniino, di(C 1 C 3 )amino, -C(O)O-(Ci-C 3 alkyl, -C(O)NH-(Ci-C 3 )alkyl, -C(O)N(Cr-C3 alkyl)2, -CH=NOH, -P0 3 H 2 -OPO,11 2 haloalkyl, alkoxyalkoxy,. carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylarnino, biaryl; thioaiyl, diarylamino, heterocyclyl, aticylaryl, aralkenyl, aralkyl, alkyiheterocyclyl, heterrocyclylalcyl, sulfonyl, -S02-(C i-C 3 alkyl), alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; R 3 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalcyl, aliphatic acyl, alkynylarnino, alkoxycarbonyl, heterocycloyl, -CI-I=NQH, haloalicyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cyoloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, azylamino, :biaryl, thioaryl, diarylamnino, lieterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, catbarnatc, axyloxyalkyl, hydrogen and -C(O)NI-(benzyl) groups; and,. at each occurrence, is independently selected from the group consisting of halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy. alkynoxcy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF 3 -CO 2 Hi, -NO 2 -NH 2 alicynylamino, alkoxycarbonyl, 20 heterocyoloyl, carboxy, -N(CI-C 3 alkyl)-C(O)(CI-C3 alkyl), :-NHC(O)N(C 1 a lkyl)C(O)NH(C 1 -C3alcyl), -NHC(O)NH(C,1-Cs alkyl), -NI-S0 2 (C 1 alkyl), -NHS0z(aryl), alkoxyalkyl, alky lamino, alkenylarnino, di(C,-C3)aMino, -C(O)O-(C 1 -C,)alkyl, -OPOH 2 ha loalkyl, alkoxyalkoxy, carboxaldehyde, carboxarnide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aiyl, aroyl, aryloxy, axylamino, biaryl, rhioaryl, diarylamino, heterocyclyl, alcylaryl, aralkenyl, arailcyl, alkylbeterocyclyl, heterocyclylalkyl, sulfonyl, -S0 2 Bikyl), alkcyl), sulfonamido, carbanatle, aryloxyalkyl and -C(0)NH(benzyl) groups; wherein R" 4 R 2 R 3 and R3' 5 are unsubstituted or substituted with COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005. 16:01 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 77 207 at least one electron donalting or electron withdr-awirng group; and, mn is an integer of from 0 to

19. A compound of claim 18 wherein R 34 is hydrogen; m is an integer of one to three and R35~ at each occurrence is selected ftr (he group consisting of alkyl, halogen, alkoxy, haloalkyl, sulfonyl, -OH and A compound of claimi 16 selected from the group consisting of 5-(2-chlorobenizyl)-3 ,5-dihydro[ 1,3]oxazolo(4,5.c~pyridine-2,4-dione, 5-(2-chlorobenzyl)-6- 1,3]oxazolo(4,5-c~pyridine-2,4-dione, 5-(2-fluorobenizyl)-3 dihydro[ 1,3 ]oxazolo[4,5-cJpyridine-2,4.dione, 5-(2-chloro-6-fluorobenzyl)-3 dihydro[ 1,3]oxazolo(4,5-clpyridine-2,4-dione, 5-benzyi-6-methyl-3,5- dihydro[1I,3Joxazolo(4,5-c~pyridine-2,4-dione, 5-benzyl-3,5-dibydrofI, 3}oxazolo(4,5- 15 c]pyridine-2,4-dione, 5-(2,5-dimeehylbenzyl)-3 ,5-dihydroj 1 3]oxazolo[4,5-c~pyridine-2,4-. dione, 5-(2-methylbenz.yl)-3,5-dihydro[ 1,3]oxazolo[4,5 -cjpyriciine-2,4-diane, 5-(2,4- 0 dichlorobenzyl)-3,5-dihydro[1I,3]oxazolof4,5-c]pyridine-2,4-dione, 5 -(2-methoxybcrazyl)-3,5- dihydro 1 ,3]oxazolo[4,5-c~pyridineO2,4.dione. 5-(2,5-difluorobenzyl)-3,5 diydro1 ,3]oxazolc44,5-(Ipyridine-2,4-dione, 5-[2-chloro-5-(methylthio)benzylj-3,5 0 20 dihydrof I,3]oxazolof4,5-'clpyridine-2,4-dione, 5-(4-fluorobenzyl)-3,5- dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro.5-methoxybenzyl)-3,5- dihydro[1I,3Joxazolo[4,5-c)pyridine-2,4-dione; 5-f) ,5-bis(trifluoromethyl)benzyl]-3,5- dihydroj I,3)oxazolo[4,S-c]pyridine-2,4-dione, 5-(4-tert-butylbenzyl)-3,5- dihydro[ 1,3 ]oxazolo[4,5-e]pyridine-2,4-dione, 5-(3-ehlorobenzyl)-3,5- dihydrof 1,3 joxazolo[4,5-e]pyridine-2,4-dione, S-(4-chlorobenzyl)-3,5- dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(trifluoronierhyl)bcnzyl]-3,5 2 dihydrofl1,3Joxazolo[4,5-cjpyaidine-2,4-dione S-(2-bromnobenzyl)-3,5- dihydrof 1,3 Ioxazoio(4,5-c]pyridine-2,4-dione, 5-(3,4-dichlorobenzyl)-3,5-, dihydro( 1,3 Joxazolo[4,5-cjpyridine-2,4-dione, 5-(4-methylbenzyl)-3 dihydrof I,Jjoxazolo[ 4 ,5-cjpyridine-2,4-dione, 5-(2-chloro-6-methoxybenzyl)-3, dihydro[ 1,3 ]oxazolo[4,5-clpyridi ne-2,4-di one, 5 -(4.(trifluoromethyl)benz-yl J-3 COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-M630 JUN. 2005 16:01 SPRUSON AND FERGUSON 61292615486 NO. 2697: P 1 78 208 dihydro[1I,3joxazolo[4,5-vclpyridine-2,4-dione, 5-(3-merhylbcnzyl)- dihydra[ 1,3 ]oxazolo(4,5-cjpyridine-2,4-dione, 5-(pyridin-2-y)methyl)-3,5- dihydro( 1 ,3]oxazolo[4,5-cjpyridine-2,4-diane,, 5-(2-chlorobenzyl)-7-methyl-3 *dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-difluorobeazyl)-3,5- dihydro[ 1,3 ]oxazolor4,5-c)pyridine-2,4.dione; 5-(2,6-ditluorobenzyl)-3 dihydro[ 1,3 ]oxazolo[4,5-c]pyridine-2,4-ditone, 5-[3-(trifluoroniethoxy)benzyl]-3 dihydro( 1,3 ]oxazolo(4,5-c]pyridine-2 ,4-dione, 5-[4-(trifluoramethoxy)benzylj-3 dihydro[ 1,3 Joxazolo[4,5-c)pytidine-2,4-dionc, 5-[2-(trifluoromethyl)benzyl dihydro[ 1,3]oxatzolo[4,5-c]pyridine-2,4-diaone, 5-(3-methoxybenzyl)-3, dihydro[1I,3]oxazolo(4,5-ojpyridine-2,4-dione, 5-(2,3-dichlorobenzyl)-3,5- dihydro[ I,3]axazolo[.4,5-cjpyridine-2,4-dione, 5-(3 ,5-dimcthylbenzyl)-3,5- dihydro[ 1,3]oxazolof4;5..c]pyridine-2,4-dione. 5-(2-chlorobenzyl)-7-pentyl-3 dibydro[ 1,3]oxazolof4,5-rjpyridine-2,4-dione, 5-(2,4-dichlorobenzyl)-7-rnethyl-3,5 dihydra[ I ,3]oxazola[4,5-c]pyridine-2,4-&ione, 5-(2-chlorobenzyl)-7-ethyl-3,5- dihydxo[ 1,3 ]oxazolo[4,5-c~pyridine-2,4-dione, 7-butyl-5-(2-chlorobenzyl)-3,5- :dihydro[ I,310xu010r[4,5-clpydidine-2,4-dione, 5-[2-chlaro-5-(trifluoramethyl)benzy!]-3,5- dihydro[ 1,3 ]oxazolo[4,S-v]pyridine-2,4-dionc, 5-(2,6-dichljorobenzyl)-3,5- :dihydro[ 13 Joxazolo[4,5-c]pyridine-2,4-dione, 5-(2.chloro-5-fluorobenzyl)-3,5- dibydro[ 1,3 Joxazclo[4,5-cjpyridbei-2,4-dione, S-(2-ohloro-6-methylbenzyl)-7-rnethyl-3 dihydro[ 173]oxazoilo[4,5-clpyridine-2,4-dione, 5-(4-chlorobenzyl)-7-methyl-3,5- dihydro[ 1,3]oxazola[4,5-c]pyridine-2,4-done, 5-(2-chlorobenzyl)-5,6,7, 8-tetrahydro-ZH- cyclopenta(bfl 1,3 ]oxazolo(5,4-dlpyridine-2,4(3J-dione, 7-rrtetbyl-5-[4- (methylsulfonyl)benzy[]-3,S-dihydro( I,3Joxazolo[4,5-c]pyridine-2,4-dione, 5-(4- mriethoxybenzyl).3 ,5-dihydxa( I,3loxazolo[4,5-c~pyridine-2,4-dione, 5-(2.chlorobeuzyl)-7- prop~yl-3,5-dihydro[ 1,3] oxazolof4,5-clpyridine-2A4-dione, 4-[(2,4-dioxo-2,3- dihydro[ I,3]oxa~zolo(4,5-clpyridin.5(4H)-yI)methyIJ-.N,N-dimethylbenzenesulfonanide, 1,3]oxazolof4,5-c]pyridine-Z,4-dionc, 5-(2-chlorobenz.yl)- ,6,7,8,9-hexahydro 1 .3]oxazolo[4,5-c]quinoline-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-6- 1,3Joxazcdo[4,5-c]pyridine-2,4-dione, 5-[2-(rnethylthio)bemzylj-3,5- diiyctro[ 1,3 ]oxazolof4,5-clpyridine-2,4-dione, 2.R(2,4-dioxo-2,3-dihyclro[ 1,3]oxazolof4,5- cjpyridin-5(4H)-yI)methyl]-N ,N-dim ethylbenzenesulfontaiide, 5-(2,64dmethoxybenzyl).3 COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:02 SPRUSON AND FERGUSON 61292615485 NO. 2697 P. 79 209 dibydro[ I,3]oxazolo[4,5-cjIpyridine-2,4-dione, 5-[2-(tritfluaromethoxy)benzylj-3 dibydro[1I,J]oxazolo[4,5-c)pyridine-2,4-dione, 5-(2-chlorobenzyl)-6,7-dimethyl-3,5- dihydro( 1,3 Joxazolo[4,5-cjpyridine-2,4-dione, 5-[2-chloro-5-(methylsulfony!)benzyl]-3 dibydro[lh3Joxazolo[4,5-c)pyridine-2,4-dionc, 5-(4-chloro-2-niethoxybenzyl)-3,5- dihydro(! ,3]oxazolo(4,5-clpyii'dine-2,4-dione, 5-(Z-chlarobenlzyl)-5,6,7,8,9,1I0-hexahydro- 2H-cyclahepta[b]f I,3]oxazolo[5,4-d]pyridine-2,4(3H)-diorte, 5-[2-(difluoromethoxy)benzyl]- 3, 5.dihydro(1I,3)oxazolo[4,5-c]pyridine -2,4-dione, 7-rnethyl-5-{( IR)- I-phenylethyl 1-3,5. dihydro[ 1,3 ]oxazololj4,5-c]pyridiue-2,4-dione, 5-(4-chlorobenzyl)-7-propyl-3,5- dihydro[ 1,3]oxazolo[4,5-c)pyridine-2,4-dione, 5-[2-(methylsulfonyl)benzyl]-3,5- dihydro[ 1,3]oxazola[4,5-c)pyridine-2,4-dione, 5-(2,6-dimethylbenzyl)-3,5- dihydro[1,3 ]oxazolo[4,5.c]pyridirae-2,4-dione, 3-chloro-2-[(2,4-dioxo-2,3- dihydrd[ I,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyljbeizonitile, 5-(2-chlora-6- mechylbenz.yl)-6,7-dimethyl-3,5-dihydro[ 1,3 Joxazolo[4,5-cjpyridine-2,4-dione, 2-[(2,4--dioxo- 2,3-dihydro(! ,3joxazolo[4,5-clpyridin-5(4H)-yI)methyflbenzonitrile, 5-(2-chloro-6- merhoxybenzyl)-7-methiyl-3,5-dihydro[ 1,3]oxazoio[4,5-cjpyridine-2,4-dione, 5-[3- (methylthio)benzyIJ-3,5-dihydiro[1 ,Jjoxezolo(4,5-cjpyridiie -2,4-dione, 5-(2-chlorobenzyl)-7- cyclopropyl-3 ,5-dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dionc, 5-(3-chlorobenzy)-7-rnechyl- 3,5-dihydro 1 ,3]oxazolo[4,5-cjpyridine-2,4-dione, 5 -(2,6-dichlorobenzyl)-7rmethyl.3 dihydrbflI,3joxazolo(4,*5-o~pyridine-2,4-dione, 7-methyl-5-(4-methylbcrzyl)-3 dihydro 1 ,3]oxazolof4,5-clpyridine-2,4-dione, 543 ,5-dirnethoxybenzyl)-7-mnethyl-3,5- dihydro[ 1,3 ]oxazolo[4,5--clpyridine-2,4-dione, 5-(2,6-difluorobenzyl)-7-niethyl-3,5- 1 ,dr[I3loxazolo[4,5-clpyridine-2,4-dione, 5-13(2-hoo6ethlonylbnzyl-3 dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(nhlsulf-eonybenzylj-3,5- dihydro( 1,3 Joxazolo[4,5-cjpyridine-2,4-diLone, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5- dihydrof 1 ,3Joxazolo(4 .S-c~pyridine-2,4-diane, 5-(2-fluoro-6-methoxybenzyl)-7-nethyl-3,S- dihydro[ 113]oxazolo[4,5.c]Pyridive-Z,4-dione, 5-(2-chloro-6-methoxybexzyl)-7-propyl-3 dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(5-chloro-2-fluorobenzyl)-7-methyl-3,5- dibydro[ 1,3]oxazolo(4,5-clpyridine-2,4-dione, 5-(2-chlorobenzyl)-7-isopropy-3 dihydro[1I,3]oxazolo[4,S-ckpyridine-2,4-dione, 5-(5-fluoro-2-methylbcnzyl)-.7-methyl-3,5-, dihydro 1 ,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-S.. dihydro[ I ,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-isopropoxybenzyl)-7-methyl- COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:02 SPRUSON AND FERGUSON 61292615486 NO. 2697, P. 210 3 ,5-dihydro[1I,3]oxazato(4,5-clpyridine-2,4-diane, 5-(5-acetyl-2-rnethoxybenzyl)-3,5- -dibydw( I, 3]oxazolal4, 5-cjpyridinie-2,4-dione, 5-(2-chlobenzyl)-7-rnethyl-3,5- dihydro( I, 3 loxazolo[4,5-d]pyridazine-2,4-lione, 5-(2-fluaro-6-(trifluoromethy)bezyI~jJ7 methy-3 ,5-dihiydrofl ,3]oxazolo[4,5-c~pyridine-2,4-dione, 5-(2-cblaro-6-medhybnzy)- 5,6,7, 8-teftahydro-2H-cyclopenta~bJ[1I,3]oxazola[5,4-.dlpyridine-2,4(3H)-dione, 5-(2-chloro- 6-ethoxybenzyl)-7-ethyl-3,5-dihydro[ 1,3]oxazolo[4,S-c~pyridine-2,4-dione, 5-(2-chloro-6- propoxybenzyl)-7.methyl-33-dihydro( I,3]oxazolo[4,5-clpyridine-2,4-dione, 5-(2-chioro-6- isobutoxybenzyl)-7-methyl-3,5-dihydro[ 1,3}oxazolo(4,5-cjpyridiue-2,4-dione, 5-(2-chloro-6- ethoxybenzy1)-5,6,7,8-tetrahydro-2H-cyclopentablf 1,3 ]axazolo[5 ,4-djpyridine-2,4(3H)- diane 1 5-(2-chlaro-6-isopropoxybenzyl)-7-metbyl-3 ,5-dihydro[ I. 3jaxazola[4,5-cpy-idine- 2,4-diane, 5.-(2-chloro-6-(2,2,2-trifluoroethoxy)benzyl]-7-mnhyl-3 IS- dihydro[ I ,3Joxazalo[4,S-c~pyridi ne-2,4-dione, 5-(2-chloro-6-ethoxybenzyl).7-methyl-3,5- 0 00dihydra[I 3 Joxazolo[4,5-dlpyridazine-2,4-dione, 54(2-chlaro-6-(2-metboxyethoxy)benzyJ- :000 5,6,7,Sietrahydro-2H-cyclopena[bJ[ 1,3]oxazolo[5,4-djpyridine-2,4(3H)-dione, 5-(2-cbloro- 00 6-ethoxybenzyl)-67-dihy-methyl-3,5-dhyrof ,3]xazolo4,-cpyridine-2,4-dio, 5-2-'oo 0 6-hoxbenzyl)-7-et--ethyl-3,5-dihydrof I ,]oxazolo 5-cjpyridine-2,4-dione, .00 chorobenzyl)-7-ethyl-3,-dihydr( I,3axazolo4,5-pyidine-2,4-dione, 5-(2-chloro-6- etboxybenzyl)-7-cprropyl-3,5-dihytro[ 1,3]oxazolo[4,5-cpyridine-2,4dine, 5-(2-chloro- :2 ethaxybenzyl)-7-clproyl-3,5-dihydro( I,3]xazoo[4 ,5cpyridine-24-dione, 5-(2-chloro-5 20 S-prooxybenzyl)-7-methyl-3,5-dihydro( ,3]xazlo4,5 cpyridine-24dine, 5 -(2-choroi 1 ,3]oxazoo[45-cpyridine-2,4-dione, 5-(2-hloro-- ethoxybenzyl)-6-methyi-3 ,5-dihydro[ I,3]oxazoto[4,5-cjpyridine-2,4-dione, 5-(2-chloro-5- (piperidin- 1-ylsuifonyl)benzyl]-7-methyl-3,5-dihydrc4 I,3]oxazolo[4,5-cjpyridine-2,4-dione, 5-[2-cbloro-5-(pyrrolidin-1I-ylstdfonyl)benzylj-7-methyl-3 ,5-dihydro[1I,3]oxazolo[4,5- c)pyridine-2,4-dione, 5-[2-chloro-6-(cyclopentylmezhoxy)benzyl]-7-methyl-3 dihydrof I,3]oxazalo(4,5-c~pyridine-2,4-dione, 5-[2-(benzyloxy)-6-chlorobenzyl]-7-nethyl- I,3)oxazalo[4,5-c~pyridine-2,4-dionc, 5-(2,3 -diehloro-6-etioxybenzy tetrahydro-2H-cycloperxtabj[1I,3joxazolo[ 5,4-d]pyridine-2 .4(3 H)-dione, 5-[2-chloro-5- 30 (trifluoromethyl)benzyfl-7-methyl-3,5-dihydro[1I,3]oxazolo[4,5-c]pyridine-2,4-dione and (2-chloro-5-fluorobenzyl)-7-methyl-3 ,5-dihydro[ I ,3joxazolot4 ,5-c]pyridine-2,4-dionc, COMS ID No: SBMI328788 Received by IP Australia: Time (H:rn) 16:06 Date 2005-013-30 JUN. 2005 16:02 SPRUSON AND FERGUSON 61292615486 NO. 2691* P. 81 211

21. A compound selected from the group consisting of ([2-methylA-(2-methylpropyl)-6-oxo- I pyrimidinyij]amino) carbonyl)arninoj.3 -(4-me thylphenyl)propano ic acid, (3 1,3- benzodioxoI-5-yI)-3-[( {[2-oxo-lI-(phenylniethyl)-4-propyi- I,2-dihydro-3 pyridinyijamino) carbonyl)aminolpropanoic acid, (3S)-3 -[(2-chloropbenyl)rnelhy]]-4- ezhyl-2-oxo- I ,2-dihydro-3 -pyridinyl} amino)oarbonyl) amino) -3-(4-methylphcnyl)propanoic acid,,(3S)-3- -((2-ohlorophenyl)methyl]-2-axo.4.propyl-1 ,2-dihydro-3- pyridinyl) amino)carbonyl)anino }-3-(4-methylphenyl)propanoic acid, (2-chilorophenyl)methyi)-4-methyl-2.oxo- 1 ,2-dihydro-3- do. pyridinyl) amino)carbonyl] amino) -3-(4-methylphenyl)propanoic acid, to (6-methyl-2-oxo- I-(phenylmerhyl)-4-[(phenylmechyl)oxy]- I,2-dihydro-3- pyridinyl)amino)earbonyljamilno) -J -(4-mcthylphenyl)propanoic acid, (3 S)-3 1 eblorophenyl)methyll-2,4-diniethyl-6-oxo-1I,6-dihydro-5 -yirnidinyl) amino)carbonylJamiio) .o15 3 -(4-methylphcriyl)propanoic acid, -amino- I [(2-chlorophenyl)methyl]-6-methyl- old 2-oxo- 1,2-dihydro-3-pyridinyl }amino)carbonyljaminoj -J-(4-methylphenyl)prcpanoic acid, (1 -[(2-chlnrcphenyl)merhylj-4.methyl-2-oxo-l1,2-dihydro-3- pyridinyl) amino)carboriyi)amino)}-3-[4-(melhyloxy)phcnyljpropanoic acid, cblorophenyl)metbylj-4-methyt-2-oxo- I ,2-dihydro-3-pyridinyl} arnino)catrbonyl) amino)} -3 00. 2 (3 ,4-dimnethylphenyl)piropanoic'acid, ([((4-amino-i -[(2-chlorophenyl)met ll-2-oxo- *ea. 0 4 P h r o p i d n y l U t l 'J 4 tIUylr iJ W J- l- lI f 1 ,2 d i h y d ro -3 or ~pyridinyl }amino)carbonyljaxnino} -3-(4-methylphenyl)prop'anoic acid, (3 o chlorophenyl)methyl]-4-(1I,4-oxazinan-4-yl)-2-oxo-I ,2-dihydro-3 pyridinyijarnino) carbonyl)aminoj-3-(4-methylphenyl)propanoic acid, (3S)-J chlorophenyl)niethylj-2-oexo4-(propylarnino). I ,2-dihydro-3 pyridinyljamino)carbonyi)amnino]-3-(4-methylphenyl)propanoic acid, (3 (if(1 brornophenyl)methylj-4-methyl-2-oxo- I ,2-dihydro-3-pyridinyl amnio)oarbonyl]arnino I 3-4 methylphenyl)propanoic acid, -[(2-chloropheny])methyl]-4-hydroxy-2-oxa- 1,2- dihydro-3-pyr-idinyl} amino)carbonyljarnino) -34[3-methyl-4-(methyloxy)phenyl]propanoic acid, (I-[(2-chlorophenyl)methyll-2-oxo-4-phenyl-1I,2-dihydro-3- COMB ID No: SBMI-01328788 Received by IP Australia: Time (Hfim) 16:06 Date 2005-06-30 JUN. 2005 16:03 SPRUSON AND FERGUSON 61292615486 NO, 2697. P. 82 212 pyridinyl) amino)carbanyl]arnino}-3-(4-merhylphenyl)pmopanoic acid, chloropheny[)methylJA4-[(2-{[2-(methyloxy)ethyl]oxy) ethyl)oxy)-2-oxo- I ,2-dibydro-3- pyridinyl }arnino)carbonyljarnino} -3-4'mnethylphenyl)propanoic acid, (14-(2- chlorophonyl)merhyll-4-hydroxy-6-methyl-2-oxo- I ,2-diliydro-3- pyridinyl) anino)carbanyl] amino) -3 -(4-methylphenyl)propanoic acid, (f chlorapbernyl)methyl)-4-[(, 1, -dimethylethyl)aminoj-2-oxo- I .2-dihydro-3- pyridinyl) arniino)carbonyl) amino} -3 -(4-methylphenyl)prcpanoic acid, (3S)-3 -4 chlorophenyl)methyll-4-bydroxy-2oxo- 1,2-dihydro-3-pyridinyl} amino)carbonyl~amino) -3- phenyipropanoic acid, -[(2-chlorophenyl)nicxhyIJ-4-[4-methyitetrahydro-1 (28)- pyrazinyl]-2-oxo- 1,2-dihydro-3-pyridinyl} amino)carbonyljamino) methylphenyl)propanoic acid, 1-[(2-chloropheryl)rnetbylj-4-bydroxy-.2-oxo- 1,2- dihydro-3-pyii'dinyl} amino)cabonyljamino) -3-[4-(methyloxy)phenylpropanoic acid, (3 (1-[(2-chlcrophenyl)ntbyl]-4-hydroxy-2-oxo- 1,2-dihydro-3- ~p'didinyi amino)carbvnyljamino} ,5-diinethylphenylpropanoic acid, (3 S-3 41-[(2- chloropbenyl)metbylj-4-hydroxy-2-oxo-1I,2-dihydrc-3 -pyridinyl }amino)oarbonyl]amino) .3L (3-methylpbenyl)propanaic acid) (1 .[(2-chlorophny)nethy1--hydroxy-2-oxo-. 1 ,2-dihydro-3wpyridinyl) aznino)carbonyl Jamino) -3-[J-(mcrbyloxy)phenyljpropanoic acid, ~(3S)-3-(3,5-bis(methyloxy)phenyl]-3- I-[(2-chlorophenyi)methy)-4-hydroxy-2-oxco- 1,2- dihydra-3-pyridinyl) amino)carbonyl~amino~propanoic acid, 0 clorohenl~mehyl-4-hydroxy-2-oxo-1 ,2-dihydro-3-quinolinyl) aminocroyaio J-3 (4-metliylphenyl)propanoic acid, (f (1 -((2-chlorophenyl)nicthyfl-4-hydroxy-2-oxo. 1,2-dihiydro-3-pyr-idinyl~amino)carbonylamino}-3-[3-(tx-ifluot-ornethyl)phenyl]propanoic acid, -[(2-chlorophenyl)rnethyll-. ({ethyl[(ethylamino)carbonyl]amino) carbon~y1)amino]-2-oxo- 1,2-diliydro-3 25 pyridinyl~amnino)carbonyllaniino) -3-(4-methylphenyl)propanoic- acid, azetanyl)- I-[(2-chlorophenyl)methyl]-2-oxo- 1,2-dihydro-3- pyridinyl) amino)carbonyl]amino) -3 -(4-methylphenyl)propanoic acidl chlorophenyl)methyl]-4-( (24(2- ((2-(mcthyloxy)etbyfloxy} ethyl)oxylethyl }oxy)-2-oxo- 1,2- dihydro)-3-pyzidinyljamino) carbonylamino]-3-(4-methylphenyl)propanoic acid, -[(2-tluorophenyl)methyl]-b-ydroxy-2-oxo-1I,2-dihydro-3- pyridinyl }amino)carbonylJamino)}-J-(4-methytphenyl)propanoi c acid, (3 ff({1 COMS ID No: SBMI-01 328788 Received by IP Australia: Time 18:08 Date 2005-08-30 JUN. 2005 16:03 SPRUSON AND FERGUSON 61292615486 NO. 2697 83 213 chloro-6-fluorophenyl)rnerbyl]-4-hydroxy-2-oxo-1I,2-dihydro-3- pyridinyl) aminc~carbonyl] amino) -3-(4-methylphenyl)propanoic acid, chloropbenyl)methylJ-5-methyl-2-oxo-l ,2-dihydro-3.-pyridinyl amino)carbonyl] amino) methylphenyl)propanoic acid, 1,3 -benodioxol-5-yI)-'3-((((2-oxo- 1 (tdifluoromethyl)phenyl)methyl)- 1,2 dihydro-3-pyridinyl)amino)carbonyl)amino)propanoic acid, -((2-chloropbenyI)methy1)-2-oxo 1 ,2-dihydra-3- pyridinyl)amino)carbonyl)amino)-3 .(4-methylphenyl)propanoic acid, (3S)-3 fiuorophenyl)methyl)-2-oxo-1I,2-dihydro-3-pyridiny1)amino)carbony/Namino)-3 *metbylphenyl)propanoic acid, I-((2-bromaphenyl)methyl)-2-oxo-1I.2-dlhydro-3-, 10 pyridinyl)arnino)carbonyl)arnino)-3-(4-methylphenyl)propanoic acid, G3S)-3 dichiorophenyl)nxetbyl)-2-oxo- 1,2-dihydro-3-pyridinyI)amino)carbony1)amino).3.(4- methylphenyl)propanoic acid, I-((2-vchloro-6-fluorophenyl)mechyl)-2-oxo- 1,2- dihydro-3-pydidiny)amino)carboilyI)amino).3.(4-methylpheny)propanoic acid, (3S ((2-.chlbrophenyl)methyl)-4-hydroxy -oxo1 ,-ihydro-3 -pyridinyl)aminio)carbonyl)amino)- *1i 3-(4 -ri fluorarnechyl)oxy)pbenyl)propanoic acid, -(2-cblomo-6.metboxybenzyl).2- oxo-1,2-dibydrapyridin-3-yll amino carboniyl)aminoj-3-(4-niethylphvnyl)p ropanoic acid, 4- S)-2-carboxy- I -(4-mexhy~phenyI)ehyIjariino) carbonyl)aminoJ. I -(2-cblorobcnzy]l)- 2-oxo-1I,2-dibydropyridiri4-yl]amino )benizoic acid, (1-(2-chlorobentzyl)-4-[(2.,2- dirnethylpropanoyl)amino]-2-oxo-I,2-dihydropy-idin-3.yl} amino)carbonyl]amino methylphenyl)propanoic acid, [(ten-butylamino)carbonyl]amino chlorobenzyl)-2-oxo-1I,2-dibydropyridin-3-yI]amino} catbonyl)aninoJ-3-{4- methylphenyl)propanoic acid, ifI -(2-cyanobenzyl)-4-hydrcxy-2-oxo- 1,2- dihydropyridin-3-yI]amino~carbonyl)amlno)-3-(4-metbylphenyl)propantoic acid, (3 S)-3 (2-chloroberizyl)A- hydroxy-2-oxo- 1 ,2-d ihydropyridin-3-yl ]anmino) carbonyl)amino]-3 dihydro- I,4-benodiaxin-6-yl)propanoic acid, -(2-chlorobenzy])-4-hydroxy-2- oxo-l ,2-dihydropyridin-3 -yI )amino) carbonyl)amino]-3-(7-rnthoxy- 1 ,3 yI)propanoic acid, (3 [Il-(2-chlorobenzyl)-4-hydroxy-2-oxo-12,2-dihydropyridin-3- ylj]amino} carbonyl)amino]-3 -(3-erhoxy-4-methoxyphcnyl)propa noic acid, chlorobenzyl)-4-hydroxy-2-oxo- I 2-dihydropyridin- 3-yI)aniino) carbonyl)arnino}-3-(3,4- dimechoxyphenyl)propanoic acid, 4[I -(4-vhlorobenzyl)-4-hydroxy-2-oxo-1I,2- dihydropyridin-3-ylj amino) varbonyi)arnino] -3-(4-mcthylphenyl)propanoic acid, (f I- COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 UN. 2005 16:03 SPRUSON AND FERGUSON 61292615486 NO. 269? P. 84 @000 00 0 00 0 @0 @00 @000 0@ @00 0 0 0000, @000 0000 @0 00 0 (2-chloro-6-methoxybenzyl)-4-hydrcxy-2 -cxc-],2-dihydropyridin-3- yIlamino) cabony)amino]-3-(4-melhylphelyl)prOpanoic acid, ifI -(2-ChIorobeuzyl)-. 4-hydroxy-5-methyl-2-oxo-1I,2-dihydropyridin-3-yJ~amino }carhonyl)arnino]-3-(4- methylphenyl)propanoic acid, -(2,6-difluorobeuizyl )4-hydroxy-2-oxo- 1,2- dihydropyridin-3-yllamino )carbonyl)arninoj-3-(4-methylphenyl)propanoic acid, (3 (2-chloro-6-mctboxybenzy)-4-hydroxy.2-oxo-1I,2-dihydropyridin-3- yflamino~carbonyl)amino]-3-(3 ,5-dimethoxyphenyl)propunioic acid, chlcrobenzylfr4-hydroxy-2-oxo-1 ,2-dihydropyridin-3-yI]aminolcarbonyl)arnino]-3 diethoxyphenyl)propanoic acid, (3 -(2-chlorobenzyl)-4-hydraxy-2-oxo- 1,2- dihydropyridin-3-yl]amino }carbonyi)amino]-3-(3-ethoxyphcnyl)propanoic acid, (3 I (2-chlorobenzyl)-4-hydroxy-2-oxo-1I,2-dihydropyridin-3 -yI~amino} carboriyl)amino]-3-(3- merhoxy-4-methylphenyl)propanoic acid, (3S)-3 -(,2-chlorobenzyl)-4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3-yl]amino} carbonyl)aino] I -(3,5-dimethoxy-4- metbylphenyl)propanoic acid, -(2-chlorobenzyl)-4-hydroxy-2-oxo-I 2- 15 dihydropyridin-3-yl]ainino) carbonyl)amioo]-3-(3, 4-dimethylphenyl)propancic acid, (3S)-3- [Q([1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1I,2-dihydrcpyridin-3- yl )amino) earbonyl)amino]-3 -(4-methylphenyl)propanoic acid, (rifILororethyl)benzyl]-4-hydroxy-2-cxo- 1,2-dihydrapyridin-3 -yI }ainino)carbonyljarnino} 3-(4-methylpbenyl)propanoic acid, 1 1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2- 20 oxo-1 ,2-dihydropyridin-3-yljamino} carbonyl)amino]-3-(3-methylpbenyl)propanoic acid, (3 if I-(2-chlora-6-motbylbenzyl)A-hydroxy-5-mcrhyl-2-oxo-1 ,2-dihydropyridintt-I yIlanino} carbonyl)amino]-3-(4-methylpheniyl)propanoic acid, )-(2-chlorobenzjlI)- 4-hydroxy-2-oxo0-2,5467-terhydro- IH-cyc'iopcnta[b~pyridin-3-yI ]acnino) carbonyl)arnino]-3- (4-incthylphenyl)propanoic acid, i I .(2,6-dimethoxybenzyl)-4-hydroxLy-2-oxo- 1,2- dibydropyridin-3 -yl Iamnino) carbonylamino]-3 -(4-rncthylphenyI)propanoic acid, (3S)-3 ifI- (2-chlorobenzyl)-4-hydroxy-2-axo-1I,2-dih-ydropyridin-3-yljainino )carboriyl)amino]-3-(3 propoxypbcnyl)propanoic acid, -(2-chlorobenzyl)-4-bydroxy-2-oxo-5-prcpyl-1 ;2- dihydropyridin-3-yI]ainino arbonyl)amino]-3-(3 -ethoxyphenyl )propanoic acid, (3S)-3 (2-chlorobenzyl)-4-hydroxy-5 ,6-dimethyl-2-oxo-1I,2-dihydropyridin-3- yljamino arbonyl)aminoJ-3-(4- methylphenyi)propatoic acid, (3 -(2-chlorobenzyl)- 4-hydroxy-2-oxo-5-propyl-I ,2-dihydropyridin-3-yI ]amino carbonyl)arninaj-3-(3 ,4- COMS ID No: SBMI-01328788 Received by IP Australia: rime 16:06 Date 2005-06-30 JUN. 2005 16:04 SPRUSON AND FERGUSON 61292615486 NO. 2697' P. 215 diethoxyphenyl)propanoic acid, (3S)-3-(3-butoxyphenyl).3-[( ([Il-(2-chiorobenzyl).4- hydroxy-2-axo-1I, 2 -dihydropyridin-3-ylJaznino~carbonyl)aminojpwopanojc acid, {I- 2 -chloro-5-.(mezhylsulfonyl)banzyII.4-hydroxy-2oxo-.1 ,2-dihydropyridin-3- yI ]amina)carbonyllamino 3 -(4-methylphenyl)propanoic acid, (3 (11-(2-chlorobcnzyl)- 4-hydroxy-2-oxo-1 ,2-dibydropyridin-3-ylJanino} carbonyi)aminoj-3-[3 methoxyethoxy)phenyl)propanoic. acid, -(2-chiorobenz.yl).4-hydroxy-2-oxo- 1,2- dihydropyridin-3-yI)amino) carbonyl)amino]-3-(3,4-dipropoxyphcnyl)prbpanoic acid, (35 -(2-chlorabenzyl) -4-hydroxy-2-oxo- 1 ,2-dihydropyridin-3 -ylj]amino) carbonyl)aunino] -3 (3-(difluoromethoxy)phenyl]propanoic acid, -(2-chlorobcnzy])-4.hydroxy-5- methyl-2-oxo- 1,2-dihydropyridin-3-yljarnino Icarbony])aminoj..3-(3,4- diethoxyphenyi)propanoic acid, (3 ifI -2-chlorobenzy1)-4-hydroxy-5-methyI -2-oxo. 1 ,2-dihydropyzidin-3-yI~aminc Icarbonyl)aminoj-3-(3-etboxyphenyl)propanaic acid, (3 S)-3- f( 4[1 -(2-chloro-6-methylberzyl)-4-hydroxy-5,6.dimethyl-2-oxo-1I,2-dihydropyridin-3- yll]amino) carbonyl)am inoj-3-(3 ,4-diethoxyphenyl)propanoic acid, (3 -(2-chloro-6- cyanobenzyl)--hydroxy-2-oxo-1 ,2-dihydropyridin-3 -yljainino} carbonyl)amino]-3-(4- methylphenyl)propanoic acid, [if1-(2-chlorobeazyl)-4-hydrcxy-2-oxo-12,2-dihydropyridin- 3-ylJamino}carbonyl)amino]-3.(2-naphthyl)propano ic acid, f I-(2-chlorobenzyl)- hydroxy-5,6-dimethyl-2-oxo-1I,2-dihydropyridin-3 -yljamino) carbony])amino)-3-(3,4- diethoxyphenyl)propanoic acid I -(2-chloro-6-methoxybcnzyl)-4-hydroxy-5- 20 inethyl-2-oxo- 1,2-dihydropy-idin-3-ylj]amino I cai bonyl)aniinoj-3 diethoxypheriyl)propanoic acid, {[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1 ,2- dihydropyridin-3-yI)amino} carbonyl)arnino]-3.(3-is'opropoxyphenyl)propanoic acid, (3S)-3- K [1 (2-chlorobenzyl).4-hydroxy.5.metbyl.2-oxo-1I,2-dihydropyridin-3- ylj]amino) carbonyl)amino]-3 -(4-methoxyphenyl)propanoic acid, (3S)-3 -(2-chloro-6- 25 muethylbenzyl)-4-bydraxy-2-oxo-2,5,6,7-tetrahydro- IH-cyclopcnra [bjpyridin-3- yl]amnino~carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3 -(2-chlaro-6- etboxyben zyl)-4-hydrcxy-2-oxo- 1,2-dihydropyridin-3 -yIjamino~carbonyl)arnino]-3-(3- ethoxyphenyl)propanoic acid, [1 -(2-cbloro-6-eihoxybenzyl)-hydraxy-5-methyl-2- oxor I,2-dihydropyridin-3-yIjamino~carbonyl)amino]. 3'(3-isopropoxyphenyl)propanoic acid, (3 S)-3 -(2-chloro9-6-ethoxybenzyl)-4-bydraxy-2-oxo-2,5,6,7.:etrabydro- 1H- cyclopantafbjpyridin-3-yijaminc4 carbonyl)anhinc]-3-(3-ethoxyphenyl)propanoic acid,* (3S)-3- COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:08 Date 2005-06-30 JUN. 2005 16:04 SPR-USON AND FERGUSON 61292615486 NO,.2697 P. 86 216 [([I-(2-chloro-6-cthoxybenzyl)--ydroxy-5-metbhyi-2-oxo- I ,2-dihydropydidin-3- ylj)amino) carbonyl)aminoj-3-( I-methyI- I H-indol-5-yl)propanoic acid, (3 1-(2-chIgro- 6-ethoxybenzyl)-4-hydroxy-5-methyl.2.oxo. I ,2-dihydropyridin-m3-ylamino) Carbonyl)amino]- 3-(2,3-dihydro71 -benzofiaran-5-yI)propanoic acid, (3 1-(2-chloro-6-ethoxybenzyl)-4- hydroxy-2-vxo-2,5,6,7-tezrahydro- IH-cyclopentafblpyridin-3-yljamino} carboriyl)amnino]-3- (3 ,5-dietboxyphenyl)propanoic, acid, {15-chloro-i -(2-chiaro-6-ethoxybenzyl)4. hydroxy-2-oxo-1 ,Z-dihydropyridin-3-yllamino} carbanyl)atninoJ-3-(3- ethoxyphenyl)propancic acid, [If1-(2-chloro-6-ettoxybenzyl)-4-hydroxy.2-oxo- 1,2- dihydropyridin-3-yljamino} carbonyl)arnino]-3-(3-isopropoxyphenyl)propanoic acid, (3 S)-3- 1-(2-chloro-6-ethoxybenzyl)-4-hydrcxy-2-oxo-2,5,6,7-ten-ahydro- 1 H- cyclopenta[b]pyridin-3 -yIj aminto)carbonyl)amino]-3 -propaxyphenyl)propanoic acid, -(2-chloro-6-ethoxybenzyI)--hydroxy-2-oxo-2,5,6,7-tetrahydro-1 H- cyciupentajb~pyridin-3-yi]aminol} axbonyl)aminoJ-3-phenylpropanoic acid, (3S)-3-[fI -(2r chlorobenzy])-4-hydroxy-2-oxo-2,S,6,7-trahydro-l1H-cyclopenta~b]pyridin-3- carbonyl) amino]-3 -(JI,3-dIethyl-2-oxo-2,3 -dihydro- I yI)prapanoic acid, [if1-(2-chloro-6-ecthoxybenzyl)-4-hydroxy-5 -methyl-2-oxo- 1,2- dihydropyridin-J-yl)amino} carbonyl)aminoj-3-f3-(trifluoromethoxy)phenyl]propanoic acid; (3 14-2-chloro-6..cthoxybenzyl)-4-hydroiy-5,6-dimechyi-2-oxo- 1 ,2-dihydropy-idin-3- yljaxnino) carbonyl)amino]-3-(3-,.opropoxyphenyl)propanoic acid, (11-(2- 20 chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-terahydro- I H-cyclopenta[bjpyridin-3 :ylj amino) carbonyl)amino]-3 -methyl- I H-indol-5-yi)propanaic acid, (3 S)-3 -U -(2-chloro- 6-ethoxybenzyl)-5-cyclopropyl-hydroxy-2-oxo-i ,2-dihyd ropyridin-3 yi]aminolcarbonyl)amito)-3-(3 -isopropoxyphenyi)propanoic acid, -(2-chloro-6- -cyclopropyi-4-hydroxy-2-oxo-1I,2-dihydropyridin-3- 25 yljamina }carbonyl)arno]-3-(4-methyiphenyl)propanoic acid, ifI -(2-chloro-5 methoxybenzyl)-4-hydroxy-S-methyi-2-oxo-I ,2-dibydropyridin-3-yl]amino }carbanyl)aminoj- 3-(4-methypheny)propanoic -acid, -(2-chloro-6-ethoxybenzyi)-4.-hydroxy-6- methyl-2-oxo- 1,2-dihydropyridin'-3-yilamino} carhonyl)amino]-3 isopropoxypheayl)propanoic acid, 1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- methyi-2-oxa- I ,2-dibydropyridin-3 -yl ]amino) carbonyl)amino j-3 -methyl-i I H-indol -6- yl)propano ic acid, (3 -(2-chloro-6-ethoxybenzyl)..4-hydroxy-2-oxo.2,5 6,7- COMS ID No: SBMI-01328788 Received by IP Australia: lime 16:08 Date 2005-08-30 JUN. 2005 16:04 SPRUSON AND FERGUSON 61292615486 NO. 2697: P. 87 217 zerrahydro- I H-cyclopentafbjpyridin-3-yl]amino} carbonyl)amino]-J (eyclopropyloxy)phenyl]propanoic acid, (3 -(2-chlorobenizyl)-4-hydroxy-2-oxo. 2,5,6,7-tetiahydro- I H4-cyclopenta[bjpyridin-3-yljamnino)carbonyl)amino).3 -13- (cyclopropylmechoxy)phenyljpropanoic acid, -(2-chloro-6-erhoxybenzyflA-. hydroxy-2-oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[bjpyridin-3-yI.]aminolcarbonyl)aininop-3 (3-(cyclopropylmethoxy)phenyl]propanoic acid, (3 -(2-chlorobenzyl)-4-hydroxy-2 oxo-2,5,6,7-tetrahydro- I H-cyciopcina[blpyridin-3-yllawino }carbonyl)arnino]-3-(3 dimethylphenyl)propanoic. acid, (3S)-3 -f{(fi 1-(2-chlorophenyI)tnethy1J-4-hydroxy-2-oxo- ,6,7-tetrahydro-1 H-cyclopenta[bjpyridin-3-yl) amino)carbanylamino 43- [(difluoromethyl)oxy]phenyl} propanoic acid, I2-cblorophenyl)rncrhyJ-4. hydroxy:2-oxo-2,5,6,7-tetrahydro I H-cyclopenta[blpyridin-3 -yl }amino)cag' bonyl] amino) -3- 1,1 ,2,2-tetrafluoroethyl)oxy]phenyl }propanoic acid, chlorophenyl)metbyll-4-hydroxy2-oxo-2,,6,7-ecahydro. 1 H-cycloperita[b]pyridin-3- 9 9 yl) amino)carbonyl]amino) 1-ethyl-i I -indol-5-yl)propanoic acid and ff((1 chloropheny!)mcxbyll-4-hydroxy-2-oxo-2,,6,7-tetrahydro. 1 H-cyclopernablpyridin-a yl} amino)ca rbonyl] amino) -3-[3-(diethylam ino)phenyljjpropainoic acid and pharmaceutical acceptable salts thereof.

22. (3 [If1-(2-chlorobcnzyl)-4-hydroxy-5-methyl-2-XO- 1 ,2-dibydropyridin-3- yllamninolcarbonyl)aminoJ-3-(4-nethylphenyl)propanolc acid and pharmaceutically acceptable salts thereof. if I-(2-chlarobenzyl )4-hydroxy-2.oxo-2,5,6,7-teayr -IH- cyclapenta(bJpyridin-3-yl]arnino arbonyl)amino])-3 -(4-methylphenyl)propanoic acid and 2S pharmaceutically acceptable salts thereof.

24. 4(1 -(2-chlorobenzyl)-4-hydroxy-5-rnethyJ.2-oxo- i,2-dihydropyridin-3- yljjamino) carbonyl)amino]-3 -(diethylamino)phenyl jpropanoic acid and pharmaceutically' acceptable salts thereof COMS ID No: SBMI-01328788* Received by IP Australia: lime 16:06 Date 2005-06-30 JUN. 2005 16:04 SPRUSON AND FERGUSON 61292615486 NO. 2697: P. 88 218 A compound selected from the group consisting of (3S)-3{({[1-(2-chloro-6- ctboxybenzyl1)-4-hydroxy-5-rnethyl-2-axo- 1 ,2.diydtopyridin-3 anro) carbonyl)aino]3 (4-methylpbenyl)propanoic acid; 4[1 -(2-chlor o-6-ethoxybenzyl)-4-hydroxy-5- metliyl-2-oxo- 1,2-dihydropyridin-3-yllamino) catbonyl)amino-3-(3-ethoxyphenyl)propflioic acid; {[1-(2-cblorobenizyl)-4-hydraxy-2-oxo-2,5,6,7-ttrahydO- 1-- cyclopenta~bjpyridin-3-yljario )carbonyl)arnino]-3-(3 -isopropoxyphenyl)prapanoic acid; (1 (2-chloro-6-cthoxybenzy1)-4-hydroxy-5-methYI-2O-I,2-dihydropyridin-3- yI) amino) carboriyl)amino]-3 .(6.mnethoxy-2-naphthyl)propaaoic acid; 1O chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- I H-cyclope:-ta(blpyridin-3" yljaxnino} carbonyl)amino]-3.(3-methylphenyl)propanoic acid; {1-t(2-chlorq-6- methylpheny)methyJ.4-hydroxy2oxo2,5,6,7ttrahYdO:l H-cyclopentabjpyridin-3- axnino)carbonylamino -3 41 -mnethyl- I H-indol-5-yl)propanoic acid, (3 41-f(2- 9 0 '000. chloropheny1)rnethyU-4-hydroxy-2-axa-2,5,6,7-tetahYdr0- I -eyclopcnta[b~pyridin-3- yl }amino)carbonyl]amino} {3-[(methylsulfonyl)aminojpbeflyl }ptopanoic acid, (33)- 4 [(41 -[(2-cbloro-6-methylphenyI)rnethy 14hydroxy-2-oxo-2,5,6,7-terh-ydro-l I- 9 cyclopentafb)pyridin3-y amio)crbOfl)aminlo) -3 3 [(methylsulfonyl)aiinophnYlPropaloiC acid, -[(2-chlorophenyl)methyl]-4- :!.hydroxy-2.-oxo-2,5,6,7-tetrahydro- I H-cyclopenta[b]pyridin-3-yl) }amino)carbonyll amino) -3- (3 -fmethyl(metbylsulfonyl)aminolphenyl }propanoic acid, -[(2-chloro-6'. K: rethylpheny1)methyl]-4-bydroxy-2-OXO-2,5,6, 7 -tetrahYd1OdI H-cyclopenta(b~pyridin-3- ylA amino)carbonyl ]amino)} 3 [mcthyl~nethylsulfony)amino]PhelI }propanoic acid, (3 S)- 3-4 -f(2-ch1orophnfl)meihyI-4h ydroxy-2oxo-25,67-tetahYcio-I cyclopenta~bJpyiidin-3-yll amino)carbonyl~arnino) -3-43- [ethyl(methylsuifonyl)aminolpheny} propanoic acid, (3 (I-{(2-chloro-6- methylphenyl)methyt]-4-hydboxy-2-oxo-2,5,6,7-tetflhydfod H-cyclopenta[blpyridin-3 yl} amino)carbonyl]amiiio}-3- {3-[ethyI(rnethylsulfony)amino)phenypropVnoic acid, (35)-3- (2clr--ehlhny~ity]4hdoy2-x ,,,-erhdoI-- cyclopenta[b]pyridin- 3 -yl }amino)carbonyi~amino)}-341 H-indol-5-yl)propanoic acid and pharmaceutically acceptable salts thereof. COMS ID No: SBMI-01328788 Received by IP Australia: Time (I-tm) 16:06 Date (Y-M-cl) 2005-06-30 JUN. 2005 16:05 SPRUSON AND FERGUSON 61292615486 NO. 2697 P. 89 219

26. A compound of claim 11 wherein R (9 0 O 0 is selected from the group of SI OH Nx /OH R1Ns RB'N-' H 0 and O s wherein R' 8 is selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxy-arbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, *biaryl, thioaryl, diarylamino, hetercyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, to hetercyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(0)NH(benzyl) groups.

27. A compound as defined in any one of claims 1, 6, 8, 11 or 16, substantially as hereinbefore described with reference to any one of Examples 1 to 43.

28. A process for preparing a compound as defined in any one of claims 1 to 27, substantially as hereinbefore described with reference to any one of Examples 1 to 43. Is 29. A compound whenever prepared according to the process of claim 28.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27 or 29 together with a pharmaceutically acceptable carrier, diluent or excipient.

31. A method for selectively inhibiting a4p integrin binding in a mammal comprising administering to said mammal a therapeutically effective amount of a compound according to any one of claims 1 to 27 or 29, or a composition accbrding to claim

32. A compound according to any one of claims 1 to 27 or 29, or a composition according to claim 30 when used for selectively inhibiting a4 I integrin binding in a mammal. [R:\LIBH1575390dlsptci.do:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30 JUN. 2005 16:05 SPRUSON AND FERGUSON 61292615486 NO.2697 P. 220

33. Use of a compound according to any one of claims 1 to 27 or 29 in the manufacture of a medicament for selectively inhibiting ta43 1 integrin binding, Dated 30 June, 2005 Texas Biotechnology Corporation Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0S e 0* C OS *5 C S C *e~e 0 9 05 *u 0 C rR:ALUBHI75390d 1 speoi.doc:aak COMS ID No: SBMI-01328788 Received by IP Australia: Time 16:06 Date 2005-06-30