AU2782699A

AU2782699A - Inhibitors of phospholipase enzymes

Info

Publication number: AU2782699A
Application number: AU27826/99A
Authority: AU
Inventors: Jean E. Bemis; Neelu Kaila; Frank Lovering; John C. Mckew; Jasbir S. Seehra; Yi Bin Xiang
Original assignee: Genetics Institute LLC
Current assignee: Genetics Institute LLC
Priority date: 1998-02-25
Filing date: 1999-02-24
Publication date: 1999-09-15
Also published as: ID27280A; KR20010041343A; HUP0100757A3; BR9908280A; EA200000868A1; NO20004220L; IL137718A0; EE200000486A; SK12742000A3; PL342995A1; CN1299347A; EP1056719A2; NO20004220D0; CA2322161A1; TR200002446T2; JP2002504539A; HUP0100757A1; BG104780A; HRP20000552A2; WO1999043651A3

Description

WO 99/43651 PCT/US99/03899 5 INHIBITORS OF PHOSPHOLIPASE ENZYMES Background of the Invention The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A 2 enzymes. 10 Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the 15 hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli. Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead 20 synthesized [W. L. Smith, Biochem. J., 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX- 1 and COX- 2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes. Arachidonic acid which is fed into these two distinct inflammatory pathways is released 25 from the sn-2 position of membrane phospholipids by phospholipase A 2 enzymes (hereinafter PLA 2 ). The reaction catalyzed by PLA 2 is believed to represent the rate limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA 2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the 30 lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58 (1988)]. Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For 35 example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX- 1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti 40 inflammatory agents affects the production of PAF. 1 WO 99/43651 PCTIUS99/03899 5 Consequently the direct inhibition of the activity of PLA 2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 36:2429-2436 (1987)]. A family of PLA 2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally 10 defined. These secreted PLA2s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA 2 s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive 15 function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated. The primary structure of the first human non-pancreatic PLA 2 has been determined. This non-pancreatic PLA 2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. 20 Seilhamer et al, J. Biol. Chem., 26:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm., 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA 2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic 25 pathways for these compounds are intracellular proteins. Moreover, there is evidence that

PLA

2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA 2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds 30 and inactivate the enzyme. A murine PLA 2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 35 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA 2 . A cytosolic phospholipase A 2 (hereinafter "cPLA 2 ") has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA 2 40 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli. 2 WO 99/43651 PCT/US99/03899 5 Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of 10 disease states. Summary of the Invention Compounds of this invention have the following formulae: R1 R3 R1 R3 4 3 R 4 4 R4 Nor N R2 IR21 15 R5 R5 wherein: R, and RV, are independently selected from H, halogen, -CF3, -OH, -C-CO alkyl, preferably -CI-C 6 alkyl, -S-C-CIO alkyl, preferably -S-C 1

-C

6 alkyl, C 1 -CO alkoxy, 20 preferably C,-C6 alkoxy, -CN, -NO 2 , -NH2, -HN(C,-C 6 ), -N(C,-C 6

)

2 , phenyl, -0 phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R6 R6 I I R N R7 N N-Ry 0 0 R7 -.-.

R6 R7N 0 25 R6 S S R7 Ry or 0 0 3 WO 99/43651 PCT/US99/03899 5

R

6 is selected from H, C,-C 6 alkyl, C 1

-C

6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH2' -CN, CF 3 . or -OH; 10

R

7 is selected from -OH, -CF3, C1C6 alkyl, C-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,

C

6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C1C alkyl, C,-C 6 alkoxy, -NO 2 , -NH2, -CF3 or -OH; 15

R

2 is selected from H, halogen, -CF 3 , -OH, -C 1 -CO alkyl, preferably -C 1

-C

6 alkyl, C, CIO alkoxy, preferably C 1

-C

6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-CC6 alkyl, N(C,-C 6 alkyl) 2 , -N-S0 2

-C-C

6 alkyl, or -S0 2

-C-C

6 alkyl; 20 R 3 is selected from H, -CF 3

C

1

-C

6 lower alkyl, C 1

-C

6 lower alkoxy, C 3 -CO cycloalkyl, -C1C6 alkyl-C 3 -C cycloalkyl, -CHO, halogen, or a moiety of the formula L 2

-M

2 :

L

2 indicates a linking or bridging group of the formulae -(CH 2 )n-, -S-, -0-, 25 -C(O)-, -(CH 2 ).-C(O)-, -(CH 2 )n-C(O)-(CH 2 )n-, -(CH 2

).-O-(CH

2 ).-, or -(CH2)n-S-(CH2).

,-C(O)C(O)X; where X = O,N

M

2 is selected from the group of C 1

-C

6 lower alkyl, C-C6 lower alkoxy, C 3

-CI

1 30 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, CI-C, alkyl, preferably C C 6 alkyl, C 1

-CI

0 alkoxy, preferably C-C 6 alkoxy, -NO 2 , -NH2, -CN, or -CF 3 ; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms 35 selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -CO alkyl, preferably C-C 6 alkyl, CI-CIO alkoxy, preferably C 1

-C

6 alkoxy, -NO 2 , -NH2, -CN, or CF 3 ; or 40 4 WO 99/43651 PCT/US99/03899 5 b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1

-C

0 alkyl, preferably C 1

-C

6 alkyl,

C

1

-CI

0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH2 -CN, -CF 3 or -OH; or 10 c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, CI-Co 15 alkyl, preferably C,-C 6 alkyl, C 1 -Co alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , NH 2 , -CN, -CF 3 or -OH; n is an integer from 0 to 3; 20 R4 is selected from the group of C 1

-C

6 lower alkyl, C-C 6 lower alkoxy, -(CH 2 )n-C 3 C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3

-C

5 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3

-C

5 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl 25 CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o 0 , Oy (CH2)n (CH2) Ny 0 O (C H 2)n ,, (C H 2) OII0 " _Y I - (C H 2) rN , (C H 2) n , 30 (CH2) O (CH2) wherein n is an integer from 0 to 3, preferably I to 3, more preferably I to 2, Y is C 3

-C

5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, 35 halogen, -CF3, -OH, -C-C6 alkyl, C 1

-C

6 alkoxy, -NH 2 , -NO 2 or a five membered 5 WO 99/43651 PCT/US99/03899 5 heterocyclic ring containing one heteroatom selected from N, S, or 0, preferably S or 0; or b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: DC 10 B wherein D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3 ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected 15 from H, halogen, -CF3, -OH, -C 1

-C

6 alkyl, C 1

-C

6 alkoxy, or -NO 2 ; or c) a moiety of the formulae: Z PZ 6 WO 99/43651 PCT/US99/03899 Z Z N N N Z\ Z,. or wherein Z is 0 or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF3, 10 OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , or -NO 2 ; R, is selected from -COOH, -C(O)-COOH, -(CH 2 ).-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, -(CH 2 )n-tetrazole, or O or N (C1-C6 lower alkyl)

N(C

1

-C

6 lower haloalkyl) O Rg or 15 ,or PO

-

Oor

-

S- OH -O 7 7 WO 99/43651 PCTIUS99/03899 5 or a moiety selected from the formulae -L'-Ml; wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 )n-, -S-, 0-, -C(O)-, -(CH2).-C(O)-, -(CH2)n,-C(O)-(CH2).-, -(CH2)n-O-(CH2).-,-(CH2)n,-S-(CH2).-, 10 -C(Z)-N(R 6 )-, -C(Z)-N(R)-(CH 2 ).-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6

)-(CH

2 ).-, -C(Z)-NH-S0 2 -, or -C(Z)-NH-S0 2

-(CH

2 )-; M' is selected from the group of -COOH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 15 R8 R8 R RR8 R9 R9 R -N N R10 R10

R

9 0 S R 8 R9 N R HN N N /9 O O R9 S

R

8 N r0 0 0 N 0- P-OH ti 20 0 , OH or R8 R10 R9 where R 8 , R 9 or RO can be attatched anywhere in the cyclic or bicyclic system,

R

8 , in each appearance, is independently selected from H, -COOH, -(CH 2 ).-COOH, 25 (CH 2 )n-C(O)-COOH, tetrazole, 8 WO 99/43651 PCT/US99/03899 0 0 0 5 7 O OH, or S OH;

R

9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ).-COOH,

-(CH

2 ).-C(O)-COOH,

-C,-C

6 alkyl, -O-C,-C 6 alkyl, -NH(C-C 6 alkyl), or -N(C,-C6 alkyl) 2 ; 10 Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH,

-(CH

2 ).-C(O)-COOH,

-C

1

-C

6 alkyl, -O-CI-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C-C 6 alkyl) 2 , RR 15 / / R8 R R9 R8

(CH

2 )n O\ or S r(C1-C lower alkyl or N

(C

1

-C

6 lower haloalkyl' 20 9 WO 99/43651 PCT/US99/03899 0 0 * SN S R 8 R Y '0 5 N (C1C6 lower alkyl) Z-\ 9 O R8 N ,R 8 N R 8 Z R9 ZRe - (CH2)nR / z S /R 8 R -- (CH2)n Re '--- (CH2)n-' 'R9 or 10 RH is selected from H, C,-C 6 lower alkyl, C 1

-C

6 cycloalkyl, -CF 3 , -COOH, -(CH 2

).

COOH, -(CH 2 ).-C(O)-COOH, R8 R8 N- R9 NR9

-

(CH2) / 15 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5 , R, R 9 , Rio, and/or R 1 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0 0 00 0-P-OH Sll R1 0 -' ~OH or "k 20 n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof. 10 WO 99/43651 PCT/US99/03899 5 It will be understood in the group above that substituents R 3 and R 4 are bound to the indole or indoline ring's 2- or 3-position and the RI, R , and R 2 groups are bound to one of the indole or indoline ring's 4-, 5-, 6- or 7-position carbon atoms. 10 One group of compounds within this invention are those in which the RV, and R 3 groups are hydrogen and the substituents at the other indole or indoline positions are as described above. Another group of this invention comprises compounds in which the R,, and R 3 groups 15 are hydrogen and the groups at RI, R 4 , and R. are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5-position and in the second R, is in the indole or indoline 6 position. In a further preferred group herein, R, is in the indole or indoline 5-position and is 20 benzyloxy, R 2 and R 4 are hydrogen and R 3 and R, are as defined above. In an another preferred group of this invention R, is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino,

R

2 and R 4 are hydrogen, and R 3 and R, are as defined above. 25 A further preferred group of this invention consists of R, and R 2 at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C

C

6 alkoxy, cyano, sulfonyl and halo, R 2 and R 4 are hydrogen, and R 3 and R 5 are as defined above. 30 It is also understood that there is a further preferred subgroup within each of the groups set forth herein wherein the core molecule is an indole moiety, rather than an indoline. 35 There is also understood to be a second group within each wherein the core molecule is an indoline moiety. Preferred compounds of this invention include those of the following formulae: 1 1 WO 99/43651 PCT/US99/03899 R1 R3 R1 R3 R4 orR4 N rN R2 IR2 5 R5 R5 wherein: RI is selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C 1

-C

6 alkoxy, -NO 2 , -NH 2 , HN(C,-C 6 ), -N(C-C 6

)

2 , phenyl, -0-phenyl, benzyl, -O-benzyl, or a moiety of the 10 formulae: R6 R6 R N R7 N N 00 R~ R6 0

R

7 O N R6 S 15 or 0 0

R

6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1

-C

6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO2, -CF3, 20 or -OH;

R

7 is selected from -(CH 2 )n-COOH, -(CH 2 ).-N-(Cl-C 6 alkyl) 2 , -(CH 2

).-NH-(C,-C

6 alkyl), -CF3, C,-C 6 alkyl, C 3 -C cycloalkyl, C-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, 25 adamantyl, or morpholinyl, the rings of these groups being optionally substituted by from 12 WO 99/43651 PCT/US99/03899 5 1 to 3 substituents selected from halogen, C-C6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;

R

2 is selected from H, halogen, -CF3, -OH, -C -CIO alkyl, preferably -C,-C 6 alkyl, C, CIO alkoxy, preferably C-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, 10

N(C

1

-C

6 alkyl) 2 , -N-S0 2

C-C

6 alkyl, or -S0C2-C 6 alkyl;

R

3 is selected from the group of C 1

-C

6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 )n-C 3 C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3

-C

6 cycloalkyl, or the groups of: 15 a) -(CH 2 ).-phenyl-O-phenyl, -(CH 2 ).-phenyl-CH 2 -phenyl, -(CH 2 ).-O-phenyl

CH

2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o 0 YY

(CH

2 ) (CH2)N -. Y 20 0 O (CH2)n ,, (CH2) ,, O " ,y ' (CH2) r . ', (CH2) n ,Y (CH2)N

(CH

2 ) wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3

-C

6 25 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C 1

-C

6 alkoxy, -NH 2 , -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0, preferably S or 0; or 30 b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 ).-O-A, wherein A is the moiety: D B wherein 13 WO 99/43651 PCT/US99/03899 5 D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3 ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C 6 alkyl, C 1

-C

6 alkoxy, or -NO 2 ; or 10 c) a moiety of the formulae: N N S N< N , or NA 15 wherein the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF , -OH, -C,-C 6 alkyl,

C

1

-C

6 alkoxy, or -N0 2 ; 20 R 4 is selected from H, halogen, -CF3, -OH, C,-C6 alkyl, C,-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH 2

-(C

3

-C

6 cycloalky), C(O)-OH, -CH=O, -C(O)-C-C 6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)-CF 3 , -(CH 2 )n-S

CH

2

-(C

3

-C

6 cycloalky), N 0 N O N O or 25 1 4 WO 99/43651 PCT/US99/03899 5 the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1

-C

6 alkyl, C,-C 6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH; n is an integer from 0 to 3; 10

R

5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, R8 / JR Rg N N 1 N R R N Rs OR 8 0ol~ o\) N7 15 N \ . Rg N8

R

9 N ( 0 0 / VRR NHN N ~(CH2) OH N 20 0 0 0 15 WO 99/43651 PCT/US99/03899 S R 8 N R 0 0 011) R9 RR 9 5 0 H 0 H or S -S.I 0 0 0 O0 O O N R\NSI 11, N (C 1

-C

6 loweralkyl 0 O ' . S N (C1-C6 lower haloalkyl, 10 R 8 is selected from H, -COOH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 00 0 ,--OH or OH

R

9 is selected from H, halogen, -CF 3 , -OH, -(CH 2 )n-COOH,

-(CH

2 ).-C(O)-COOH,

-CI-C

6 alkyl, -0-C-C 6 alkyl, -NH(C-C 6 alkyl), -N(C,-C 6 alkyl) 2 ; 15 Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH,

-(CH

2 )n-C(O)-COOH,

-C

1

-C

6 alkyl, -O-C 1

-C

6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , R8 R8 N 0 . 0 R g N - R 9 0 0 0 0 .0 OK O S S' 20 N C1-C lower alkyl N (Cl-C6 lower haloalkyl, or 16 WO 99/43651 PCT/US99/03899 0 S 0 N N N S OX 5 N (C 1

-C

6 lower alkyl) R], is selected from H, C 1

-C

6 lower alkyl, -CF, -COOH, -(CH 2 ).-COOH,

-(CH

2 );-C(O)-COOH, or R8 R9 10 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5 , R 8 , R,, R 10 , and/or RH shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0 0 R11 /"0-P-OH S'1,1 "\? -0 O H S O H or N 15 or a pharmaceutically acceptable salt thereof. 20 Another group of compounds of this invention have the following formulae: R1 R3 R1 R3 R4 R4 or R2 IR2I

R

5 R5 wherein: 17 WO 99/43651 PCT/US99/03899 5 R, is selected form H, halogen, -CF3, -OH, -C 1

-C

6 alkyl, CI-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R6 R6 I I R N N N R7

R

6 R7 ON 0 10 R6 R N or 0 0

R

6 is selected from H, C,-C 6 alkyl, C1-C6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 15 to 3 substituents selected from halogen, C 1

-C

6 alkyl, C,-C 6 alkoxy, -N2, -CF3, or -OH;

R

7 is selected from -(CH 2 ).-COOH, -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -CF3, C,-C alkyl, C 3 -C5 cycloalkyl, C,-C 6 alkoxy, -NH-(C-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, 20 adamantyl, or morpholinyl, the pyridinyl, phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C-C6 alkyl, C,

C

6 alkoxy, -NO 2 , -CF 3 , or -OH;

R

2 is selected from H, halogen, -CF 3 , -OH, -C-CO alkyl, preferably -C-C 6 alkyl, C, 25 CIO alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, N(C,-C 6 alkyl) 2 , -N-S0 2

-C,-C

6 alkyl, or -S0 2

-C,-C

6 alkyl;

R

3 is selected from H, halogen, -CF 3 , -OH, C,-C 6 alkyl, C 1

-C

6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH 2

-(C

3 -C, cycloalky), 30 C(O)-OH, -CH=O, -C(O)-C-C 6 alkyl, -C(O)-O-C,-C 6 alkyl, -C(O)-CF 3 , -(CH 2 )n-S

CH

2

-(C

3

-C

5 cycloalky), 18 WO 99/43651 PCTIUS99/03899 N O N O N O 5 1, or ; the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C-C 6 alkyl, C 1

-C

6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH; 10 n is an integer from 0 to 3;

R

4 is selected from the group of C-C 6 lower alkyl, C -C 6 lower alkoxy, -(CH 2 )n-C 3 C 5 cycloalkyl, -(CH 2

).-S-(CH

2 )n-C 3

-C

5 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3

-C

5 cycloalkyl, 15 or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl

CH

2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o 0 20 Y O (CH2)

,(CH

2 )r '-Y 0 O . (CH2)nNY 11 (CH2)rN, O '(CH2)M, , (C H2) n, S Y (CH2)n (CH2) 25 wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3

-C

6 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -CC6 alkyl, C 1

-C

6 alkoxy, -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0, preferably S or 0; or 30 b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: 19 WO 99/43651 PCTIUS99/03899 D C 5 B wherein D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl 10 groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C alkyl, C 1

-C

6 alkoxy, or -NO 2 ; or c) a moiety of the formulae: N N or 20 WO 99/43651 PCT/US99/03899 5 wherein Z is 0 or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF3 OH, -C,-C 6 alkyl, C 1

-C

6 alkoxy, or -NO 2 ; R. is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, 10 -CH=CH-COOH, R8 R8 R9 R9 ..- R9 NR 15 oO R N R10 / RR8 ORR N NH 0 O1 ORO10 20 21 WO 99/43651 PCT/US99/03899 S RN 0 I0RR8 0 H 0O H 5 R1o Ro , or S 0 O N R11 .l R. is selected from H, -COOH, -(CH 2 ).-COOH, -(CH 2 ).-C(O)-COOH, tetrazole, 0 0 0 10 O- -OH , or H

R

9 is selected from H, halogen, -CF 3 . -OH, -(CH 2 ).-COOH,

-(CH

2 )n-C(O)-COOH,

-C

1

-C

6 alkyl, -O-C,-C 6 alkyl, -NH(C-C 6 alkyl), -N(C,-C 6 alkyl) 2 ; 15 Rio is selected from the group of H, halogen, -CF 3 , -OH, -(CH 2 )n-COOH,

-(CH

2 )n-C(O)-COOH,

-C

1

-C

6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , R8

R

8 N (C1-C6 lower alkyl N (C1-C6 lower haloalkyl: or 20 N N 0S O N (C 1

-C

6 lower alkyl) 22 WO 99/43651 PCTIUS99/03899 5 R 1 is selected from H, C 1

-C

6 lower alkyl, -CF 3 , -COOH, -(CH 2 )n-COOH,

-(CH

2 ).-C(O)-COOH, or R8

R

9 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R,,R,, R 9 , R,,, and/or R,, shall contain at least one acidic 10 moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0 00 0-P-OH S O 0 R 1 / 11 N111 1 R11 0 OH or or a pharmaceutically acceptable salt thereof. 15 One group of compounds within this invention are those in which the indole or indoline 3-position (R 3 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above. 20 Another group of this invention comprises compounds in which R 2 is hydrogen and the groups at RI, R 3 , and R 5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position. 25 In a further preferred group herein, R is in the indole or indoline 5-position and is benzyloxy, R 2 and R 4 are hydrogen and R 3 and R. are as defined above. It is also understood that there is a further preferred subgroup within each of the groups set forth herein wherein the core molecule is an indole moiety, rather than an indoline. 30 There is also understood to be a second group within each wherein the core molecule is an indoline moiety. Another subset of compounds of this invention have the following formulae: 23 WO 99/43651 PCTIUS99/03899 5 R1 R3 R1 R3 R4 R4 NN or N N R2 IR2I R5 R5 wherein: R, is selected form H, halogen, -CF3, -OH, -C 1

-C

6 alkyl, C 1

-C

6 alkoxy, -NO 2 , -NH 2 , 10 phenyl, -0-phenyl, benzyl, -O-benzyl, or a moiety of the formulae: R6 R6 R N R7 N NR RR7 R7 O N 0 R6

R

7 --

-N

R N 15 or 0 ;

R

6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 6 -C6 alkyl, C,-C 6 alkoxy, -NO2, -CF3, or -OH; 20

R

7 is selected from -(CH 2 )n-COOH, -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , -(CH 2 )n-NH-(Cl-C 6 alkyl), -CF3, CC6 alkyl, C 3

-C

5 cycloalkyl, C 1

-C

6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, adamantyl, or morpholinyl, the pyridinyl, phenyl and benzyl rings of these groups being 25 optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,

C

6 alkoxy, -NO2, -CF3, or -OH; 24 WO 99/43651 PCTIUS99/03899 5

R

2 is selected from H, halogen, -CF3, -OH, -CI-CI alkyl, preferably -C,-C 6 alkyl, C, CIO alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH2, -NH-C,-C 6 alkyl, N(C-C 6 alkyl) 2 , -N-S0 2

-C,-C

6 alkyl, or -S0 2

-C,-C

6 alkyl; 10 R 3 is selected from the group of CI-C 6 lower alkyl, CI-C 6 lower alkoxy, -(CH 2 )n-C 3 C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3

-C

5 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 ).-O-phenyl

CH

2 -phenyl, -(CH2)n-phenyl-(O-CH 2 -phenyl)2, -CH 2 -phenyl-C(O)-benzothiazole or a 15 moiety of the formulae: O 0 Y, O 11-Y (CH2)N (CH2) N ,-_Y 0 O (CH2)n (CH2) O " -(CH2)N (CH2)n 20 (CH2)rNO (CH 2 )6-. wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C 3

-C

5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C-6 alkyl, C 1

-C

6 alkoxy, -NO 2 or a five membered heterocyclic 25 ring containing one heteroatom selected from N, S, or 0, preferably S or 0; or b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: DC B 30 wherein D is H, C,-C 6 lower alkyl, C 1

-C

6 lower alkoxy, or -CF 3 ; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C1C6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or 25 WO 99/43651 PCT/US99/03899 5 c) a moiety of the formulae: Z Z<I N S or 10 wherein Z is 0 or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 . OH, -C 1

-C

6 alkyl, C,-C 6 alkoxy, or -NO 2 , -NH 2 ; 15

R

4 is selected from H, halogen, -CF3, -OH, C,-C6 alkyl, C-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH 2

-(C

3

-C

5 cycloalky), C(O)-OH, -CH=O, -C(O)-C-C 6 alkyl, -C(O)-O-CC6 alkyl, -C(O)-CF 3 , -(CH 2 )n-S

CH

2

-(C

3 -C, cycloalky), 26 WO 99/43651 PCT/US99/03899 N 5 OrN O N or the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1

-C

6 alkyl, C 1

-C

6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH; 10 n is an integer from 0 to 3;

R

5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, R8 15 RR9N RR0 R10 N R o / R R8\ S R 0 / L N (CH2) OH 20 0 27 WO 99/43651 PCT/US99/03899 R8 O O Rg N (CH2) p".OH NH Ri -- r NH 5 0 0 0 / 1 S R 8 O R8 O H 0 0 H or 00 10 0 R. is selected from H, -COOH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, -P-OH S , or OH; 15 R 9 is selected from H, halogen, -CF 3 , -OH, -(CH 2 ).-COOH,

-(CH

2 )n-C(O)-COOH,

-C,-C

6 alkyl, -0-C-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 ).-COOH,

-(CH

2 )n-C(O)-COOH,

-C,-C

6 alkyl, -0-C-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , 20 R8 R8 O O N 0 R9 N-

R

9 S0S N

(C

1

-C

6 loweralkyl N

(C

1

-C

6 lower haloalkyl or 28 WO 99/43651 PCT/US99/03899 O~ NN N S OX 5 N (C 1

-C

6 lower alkyl)

R

1 is selected from H, C-C6 lower alkyl, -CF 3 , -COOH, -(CH 2 )n-COOH,

-(CH

2 )n-C(O)-COOH, or R8 R9 10 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5 , R 8 , R 9 , R 10 , and/or R shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0 0 00 N 0-P-OH S p

RR

11 0 3 R3 " OH o 15 or a pharmaceutically acceptable salt thereof. Further preferred among the compounds of this invention are those having the formulae: 20 | R41R 4 or N R5 R5 wherein: 29 WO 99/43651 PCT/US99/03899 5 R, is selected form -NH 2 , -0-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O phenyl, -S-benzyl or a moiety of the formulae: R6 R6 R NN R6 7R7 0 10 S O R6 0 0 15

R

6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO2, -CF3, or -OH; 20 R 7 is selected from -(CH 2 ).-COOH, -(CH 2 )n-N-(CI-C 6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -CF3, C,-C6 alkyl, C 3

-C

5 cycloalkyl, C 1

-C

6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, adamantyl, or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C-C6 alkyl, C,-C 6 alkoxy, -NO2, -CF3, or 25 OH; n is an integer from 0 to 3; 30 WO 99/43651 PCT/US99/03899 5 R 3 is selected from halogen, -C1-C6 alkyl, -C,-C 6 alkoxy, -CF 3 , -CH=O, -C(O)-C,-C 6 alkyl, -C(O)-O-C,-C 6 alkyl, -C(O)-OH, -C(O)-CF 3 , -C(O)-phenyl, -C(O)-benzyl, -C(O) pyrrolyl, -C(O)-thienyl, -C(O)-furanyl, or -C(O)-morpholinyl;

R

4 is selected from the group of -(CH 2

).-C

3

-C

6 cycloalkyl, -(CH 2 )n-S-(CH 2

).-C

3

-C

6 10 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3

-C

6 cycloalkyl, -(CH 2 )n-S-C,-C 6 alkyl, the groups of: a) -C(O)-O-(CH 2 )n-C 3

-C

5 cycloalkyl, -(CH 2 )n-phenyl, -(CH 2 ).-O-phenyl, (CH 2 )n-S-phenyl, -(CH 2 )n-S-(CH 2 )n-phenyl, -(CH 2 )n-phenyl-O-phenyl, -(CH2)n-phenyl

CH

2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -C(O)-O 15 phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, -C(O)-O-napthyl, -(CH 2 )n-S-napthyl, (CH 2 )n-S-pyridinyl, -(CH 2 )n-pyridinyl or -(CH 2 )n-napthyl, -(CH 2 )n-O-napthyl, the phenyl, pyridinyl and napthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0, 20 preferably S or 0; or b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D 25 wherein D is H, C 1

-C

6 lower alkyl, C,-C 6 lower alkoxy, or -CF3;

R

5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, 30 31 WO 99/43651 PCTIUS99/03899 /8 R9

NR

8 .. 9 7 N J >( N N /N R9 0 R8 NN 0 7 R8N,\ S R 0 7, N,,. 10R 9 0 08 10 0g 0 s R 8 R8 o R8 0 R8 15 0 HH or S 0 NK\Ril 32 WO 99/43651 PCT/US99/03899 5 R, is selected from H, -COOH, -(CH 2 )-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 0 0 0O -P--OH 0 , or OH

R

9 is selected from H, halogen, -CF 3 , -OH, -(CH 2 )n-COOH, 10 -(CH 2 )n-C(O)-COOH,

-C

1

-C

6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH,

-(CH

2 ).-C(O)-COOH,

-C

1

-C

6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C-C 6 alkyl) 2 , R8 R8 0 0 RI-N.R N R/ N/17 Rg 15 SS' N (C1-C 6 lower alkyl N (C1-C6 lower haloalkyl or ,O-_ N_, N N N (C 1

-C

6 lower alkyl) 20 RI, is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ).-COOH,

-(CH

2 ).-C(O)-COOH, or R8

R

9 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5

,R

8 , R 9 , RIO, and/or R shall contain at least one acidic 25 moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: 33 WO 99/43651 PCTIUS99/03899 S 0 0, 0 k~ 0/ -P-OH S 5O 0 5 N R11 0 -- O or NOHor or a pharmaceutically acceptable salt thereof. 10 Detailed Description of Preferred Embodiments As used herein, the terms "aryl" and "substituted aryl" are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, 15 particularly including those having from 9 to 10 ring atoms. Among these aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties. The aryl and heteroaryl groups of this invention also include the following: 20 a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or 25 b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine; or 30 c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine. 35 The "substituted aryl" groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C 1

-CI

0 alkyl, preferably C,

C

6 alkyl, C 1

-CI

0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, 34 WO 99/43651 PCT/US99/03899 5 N0 2

,-NH

2 , -CN, -CF 3 or -OH or combinations thereof, such as -CH 2

CF

3 , -NH(CH 3 ), etc. A preferred subset of these groups, optionally substituted as just described, include moieties formed from benzene, pyridine, napthylene or quinoline rings. A further 10 preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings. A preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings. The alkyl, alkenyl and alkinyl groups referred to herein indicate such groups having 15 from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched. Halogens herein are understood to include F, Cl, Br and I. As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 86 20 below). A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA 2 ) in any available assay (preferably an assay described below in Example 86 or Example 87) for enzyme activity. In preferred embodiments, a compound has (1) an IC 50 value of less than about 25 pM, preferably less than about 6 pM, in the LysoPC assay; (2) an IC 50 value of less than about 50 pM in the 25 vesicle assay; (3) an IC 50 value of less than about 1 pM in the PMN assay; (4) an IC 50 value of less than about 15 pM in the Coumarine assay; and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat carrageenan-induced footpad edema test. 30 Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA 2 ) activity and, therefore, are useful in "treating" (i.e., treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as 35 osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis. The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention. Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also 0 contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in 35 WO 99/43651 PCT/US99/03899 5 the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to 10 produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention. The pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids which exist in 15 aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 20 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incorporated herein by reference. As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of 25 an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. 30 In practicing the method of treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, 35 cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If t0 administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti 36 WO 99/43651 PCT/US99/03899 5 inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors. Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, 10 subcutaneous, or intravenous injection. When a therapeutically effective amount of compounds of the present invention is administered orally, compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an 15 adjuvant. The tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may 20 further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention. 25 When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred 30 pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, 35 preservatives, buffers, antioxidants, or other additives known to those of skill in the art. The amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with t0 which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger 37 WO 99/43651 PCTIUS99/03899 5 doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.1 pg to about 100 mg (preferably about .1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of 10 compound of the present invention per kg body weight. The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present 15 invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention. Compounds of the present invention invention can be made according to the methods 20 and examples described below. Synthesis of preferred compounds of the present invention are described in the examples below. Method A 25 Ethyl 5-nitro-2-carboxylate indole is chlorinated in the 3-position by the agency of N chlorosuccinamide in a solvent such as DMF or DMSO at an elevated temperature of 40 'C - 80 "C. The ester is then reduced in a three step procedure. First the ester is hydrolysed under basic conditions with a base such as sodium hydroxide or potassium hydroxide in a solvent system such as water:methanol:THF. The acid is then activated by he addition of 30 carbonyl diimidizole in THF and reduced with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an alcoholic solvent system such as methanol or ethanol. The resulting alcohol is protected as the TBDMS ether with TBDMSC1 in a solvent such as DMF, methylene chloride or THF with a base such a triethylamine or imidazole. The indole nitrogen is then alkylated with methyl 4 35 bromomethlybenzoate in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide. The 5-nitro group is then reduced by exposure to H 2 in the presence of a catalyst such as Pt/C or Pd/C in a solvent such as ethyl acetate, methanol or THF or a mixture of two or all of the three. The amine is then acylated with cyclopentylcarbonyl chloride in a biphasic system of saturated 10 sodium bicarbonate and methylene chloride. R1 is then introduced in a two step procedure wherein the TBDMS ether is converted to a bromide by exposure to 38 WO 99/43651 PCTIUS99/03899 5 dibromotriphenylphosphorane in methylene chloride and then the crude bromide is displaced by a variety of thiols or phenols in a solvent such as THF, methylene chloride or DMF in the presence of a base such as potassium carbonate or cesium carbonate. The product esters are then prepared by the hydrolysis of the ester under basic conditions with sodium hydroxide in a solvent system such as water:MeOH:THF. 10 Method B Acylation at the 3-position of indole I with an acylating agent such as naphthoyl chloride could be accomplished using ethylmagnesium bromide in a solvent such as THF to give II. Alkylation of the indole nitrogen could be accomplished by exposure to a suitable 15 base such as sodium hydride followed by treatment with the appropriate. Deprotection of the hydroxy protecting group with tetrabutylammonium fluoride and oxidation with a suitable oxidizing agent provided IV. A Homer-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran gave the unsaturated ester V which could be deprotected at the indole 1-position with a suitable 20 reagent system such as hydrofluoric acid in acetonitrile. Saponification of the remaining acid group gave the compound VI Method C Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as 25 THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSCI) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of II with Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -60'C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on the nitrogen with an alkyl halide such as 30 methyl(4-bromomethyl)benzoate in the presence of a strong base such as NaH in DMF affords ketone III. The silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide IV. Displacement of the bromine of IV with a thiol compound in the 35 presence of a base such as cesium carbonate, or with an alcohol in the presence of a strong base such as NaH in DMF affords V (sulfide or ether respectively). Method D The protected alcohol was deprotected in a suitable solvent such as THF and the t0 resulting alcohol was functionalized to a halide using carbon tetrabromide or methanesulfonyl chloride and then reacted with an oxygen nucleophile, coupled with prior 39 WO 99/43651 PCT/US99/03899 5 deprotonation with a strong base such as sodium hydride, or a sulfur nucleophile in the presence of cesium carbonate in DMF or THF. The nitro group could then be reduced to an amine via a Pt/carbon hydrogenation protocol or copper acetate sodium borohydride procedure. The resulting amine could be hydrolyzed,using a standard procedure of sodium hydroxide in THF/MeOH or coupled to a variety of acylating reagents, such as 10 acid chlorides, chloroformates and isocyanates where the reactions are generally performed in the presence of a base in a solvent such as THF or dichloromethane. The amine could also be acylated via an EDCI coupling procedure with a variety of acids. The starting amine could also be alkylated by a reductive amination procedure using a varity of aldehydes and sodium triacetoxyborohydride as the reducing agent. These functionalized 15 amines could be hydrolyzed to yield the desired acids which could also be converted to the acylsulfonamide by EDCI coupling with an sulfonamide. Alternatively, the functionalized amines could be alkylated further by reaction with a strong base and an alkyl halide and then hydrolyzed under the standard conditions to yield the requisite product. 20 Method E The starting indole, with or without C2 substitution, was functionalized at C3 by using DMF/POCl3 conditions or the magnesium salt of the indole was acylated with a variety of acid chlorides to form the ketones. These products where then N-alkylated by the action of a strong base and a variety of alkyl or aryl halo esters. When R' is a nitro group, at this 25 time the nitro was reduced with Pt/C and H2 or copper acetate and sodium borohydride to the amine which was then acylated with a variety of acid chlorides, isocyantes, chloroformates, reductively alkylated with amines or coupled with acids. The resulting esters were hydrolyzed to the desired acids which could further be transformed to the acylsulfonamide. 30 40 WO 99/43651 PCTIUS99/03899 Method A 02 Nl c)NaOH C M02 EtMe OH.THF 02 N O ~~~~ No~ NC I' Ni: \________ H50 'C H 3) NaBH,EtOHH TBDMSCI imidazole, DMF CI

H

2 N OTBDMS ciV I 02 N~ OTBDMS NaH, DMF 02 NS / C02M Br N -2M k--,//COC 2 Me

Q

5

H

9 C0CI CH 2 I Cl Cl CI Nq NN N \ OTBDMS Ph 3 PBr 2 ( Br iR 0 ~- ~ 2 cI 2 0 -~NCS 2 C02 DM F C2M Aryl thio ether R alkyl thio ether aryl ether 5 alkyl ether 41 WO 99/43651 PCT/US99/03899 Method B EtMgBr O THF H OTBS OTBS H o 0 H I \ /17 Cl II r NaH, DMF SEM 0 1) TBAF 0 S 1 M !-, CHO 2) MnO 2 OTBS IV I SEMO

SEMO

0 0 d (MeO) 2 P 0 OMe o,0 op /0 o O1 O) HF, CH 3 CN 0 -N \ 0 2) NaOH, 0 MeOH-THF OMe OH SEMO H 5 0 v ovi 42 WO 99/43651 PCT/US99/03899 Method C 1) LiAIH 4 , THF N. 2) TBDMSCI, imidazole, DMF TBDMS RCOEt N O R N N H H 1) EtMgBr, THF 2) R'COCI/(R'CO) 2 0, ether 3) R'Br(I), NaH o 0 R' 1) TBAF, THF R' 2) Ph 2

PCH

2

CH

2 PPh 2 , CBrl/ y MsCI, Et 3 N OTBDMS R R N N IV R" III R"'SH, CsCO 3 \ R 'OH, NaH or K 2

CO

3 0 R' X-R'". N R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO 2 , alkyl or aryl R'= alkyl, aryl V R" R"=alkylacid, benzylacid, alkenyl, alkynyl R'" = alkyl, aryl X = os 5 Y = halogen, mesylate 43 WO 99/43651 PCTIUS99/03899 Method D CI \\ N tD 1) TBAF CI HR\ -C Cu(OAc) 2 INaBH 4 2)HS0C NXR N N N o 02 NO 0 0 0 0 CI RX ClNaOHflF/MoOf H - \ -- R' I, NL 115- \ X-R' R N N N NR N/ -~OH 00 NaOHITHF/MeOH I ) NaM/RX EDCI/H 2 NS0 2 R" 1)NaOH/THF/MeOH F~~~ N-114-I XR N N ~' N NXR N N NRN 0 0 A0 Method E C R'=NO, DMFIPOCh R" 1)1H, /PR R 0'r ~ NaH/DMF -2)RC"COCI I.R . 3) NaOWIMoOH/THF N N\ N R HO-( 0 0 R O, R'"'=H EDCI/H 2

NSO

2

R"

1) H2/Pr 3) NAHPOIIBuoH 2)R."COd I NaO 2 CII R- OH R"" 'R "~2)NAO~rrHF/MEOH- - -k 0 N; 0 EDCI/H,NS0 2 R'"" NR 0 0 10 44 WO 99/43651 PCT/US99/03899 5 Example 1 4-({3-chloro-5-[(cvclopentylcarbonyl)aminol-2 [(phenethylsulfanyl)methyll-1H-indol-1-yllmethyl)benzoic acid Step 1 - Ethyl 5-nitroindole-2-carboxylate (21.1 g) was dissolved in DMF (500 mL). 10 To this dark brow solution, a solution of N-chlorosuccinamide was added (12 g in 125 mL DMF) over a period of 5 minutes. The reaction mixture was heated to 50 'C for 1.5 h. Reaction completion was determined by TLC. The reaction was cooled to room temperature, diluted with water (2 L), and extracted with ethyl acetate (3 X 1 L). The organic layers were combined, dried over MgSO 4 , filtered and concentrated. The result 15 was the desired ethyl ester (96 g wet with DMF) which was carried on to the next step without further purification. Step 2 - The ethyl ester was dissolved in methanol (400 mL) and THF (800mL). To this clear, brown solution 2 N NaOH was added (450 mL). The black mixture was stirred 20 at room temperature overnight. The reaction was not quite complete (TLC) therefore an additional 7.2 g of NaOH pellets were added. After 7 h the reaction was complete. Approximately 1 L of solvent was removed by rotary evaporation. The residue was dissolved with ethyl acetate and water and acidified with 2 N HCl to pH 2. The mixture was then extracted with ethyl acetate (3 X 1 L). The combined organic layers were dried 25 over MgSO 4 , filtered and concentrated to give the acid (24.3 g, 100%) as a brown solid. Step 3 - The carboxylic acid (24 g) was dissolved in THF (700 mL). CDI (16.2 g) was added to this clear, amber-colored solution. The mixture was stirred at room temperature for 1.5 h, during which time it became a light brown suspension. The reaction was cooled 30 in an ice bath. Sodium borohydride (10.8 g) was added slowly. Ethanol was then added (140 mL). The evolution of gas was observed. After 2 h, TLC analysis indicated that the reaction was complete. To adjust the pH to 2, 2 N HCl was added. The reaction was then extracted with ethyl acetate (3 X 600 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated to yield the desired alcohol (28.5 g) as a brown solid. 35 Step 4 - The alcohol prepared above (25.4 g), imidazole (18.6 g), and tert butyldimethylsilyl chloride (13.3 g) were dissolved in DMF (350 mL). The reaction was stirred overnight and found not to be complete. Therefore imidazole (18.7 g) and t butyldimethylsilyl chloride (18.6 g) were added. After 1 h, the reaction was complete. 40 Water (1.5 L) was added and the mixture was extracted with ethyl acetate (3 X 500 mL). The combined organic layers were evaporated to dryness to give the crude 5-tert 45 WO 99/43651 PCT/US99/03899 5 butyldimethylsilyl-protected alcohol. The crude material was dissolved in ethyl acetate, absorbed onto silica gel, and evaporated to dryness. After loading onto a silica gel column and eluting with 15% ethyl acetate in hexanes, the desired protected alcohol (18.5 g, 69% from step 1) was isolated as bright yellow crystals. 10 Step 5 - The tert-Butyldimethylsilyl-protected alcohol (1.0 g) was dissolved in DMF (10 mL). The yellow solution was cooled in an ice bath. Sodium hydride (147 mg) was added. After 15 minutes, 4-(bromomethyl)benzoate (807 mg) was added to the dark red solution. After 15 minutes, TLC analysis indicated that the reaction was complete. The reaction was poured into cold 1 N HCI. Water (800 mL) was added and the solution was 15 extracted with ethyl acetate. The combined organic layers were evaporated to dryness to give the crude N-alkylated indole as an orange solid. The crude solid as absorbed onto silica gel, added to a silica gel column and eluted with 15% ethyl acetate in hexanes to give the desired N-alkylated indole (1.05 g, 73%) as a yellow solid. 20 Step 6 - N-alkylated indole (3.8 g) was dissolved in THF (50 mL) and 5% Pt/C (1.6 g) was added. Hydrogen was purged in and the reaction was stirred at room temperature overnight. The reaction was filtered (celite) and concentrated. Column chromatography (35% ethyl acetate in hexane) gave the desired amine (1.7 g) as an off-white solid. 25 Step 7 - To a solution of the above amine (1.6 g, 3.5 mmol) in CH 2 Cl 2 (10 mL) and saturated sodium bicarbonate (10 mL) was added cyclopentyl carbonyl chloride (0.467 ml, 1.1 eq). The reaction was stirred 45 min, taken up in ethyl acetate (100 mL), washed with brine (3 X 20 mL), dried (MgSO 4 ), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) afforded the desired product (1.55 g, 82%) as a pale yellow oil. 30 Step 8 - To a solution of the above amide (0.6 g, 1.1 mmol) in dichloroethane (3 mL) at 0 'C is added dibromotriphenylphosphorane (0.5 g, 1.1 eq). The reaction is stirred to room temperature over 2h, taken up in ethyl acetate ( 50 mL), washed with brine (3 X 10 mL), dried (MgSO 4 ) and concentrated and carried immediately to the next step. 35 Step 9 - To a solution of the crude bromide prepared above (0.54 mmol) in DMF (2 mL, degassed) is added phenethyl mercaptan (0.08 g, 1.1 eq) followed by cesium carbonate (0.21 g, 1.2 eq). The reaction is stirred lh, taken up in ethyl acetate (20 mL), washed with brine (3 X 5 mL), dried (MgS04), filtered and concentrated. 40 Chromatography (25% ethyl acetate/hexanes) afforded the desired compound (0.17 g, 56%) as a colorless oil. 46 WO 99/43651 PCTIUS99/03899 5 Step 10 - To a solution of the above ester in THF (1 mL) and MeOH (0.5 mL) is added NaOH (0.28 mL, 5 M, 5 eq). The reaction is stirred 4 h, acidified with sodium biphosphate, poured into ethyl acetate, washed with brine and dried (MgSO 4 ). The title compound (0.157, 98%) was triturated from ethyl acetate with hexanes. 10 Each of the compounds of the following Examples 2 through 11 was prepared by a first step as illustrated in Example 1, step 9, using the appropriate thiol, followed by a second step as described in Example 1, step 10. 15 Example 2 4-[(3-chloro-5-[(cvclopentvlcarbonyl)aminol-2-{[(2 furvlmethyl)sulfanyllmethyl}-1H-indol-1-vl)methyllbenzoic acid Example 3 20 4

-[(

3 -chloro-5-[(cvclopentvlcarbonylaminol-2-ff(4-hydrox-6-phenyl-2 pyrimidinyl)sulfanyllmethyl}-1H-indol-1-vl)methyllbenzoic acid Example 4 4-{[ 3 -chloro-5-[(cvclopentvlcarbonyl)aminol-2-(1[4-(2-thienyl)-2 25 pyrimidinvllsulfanvIlmethyl)-1H-indol-1-yllmethyllbenzoic acid Example 5 4

-({

3 -chloro-5-[(cvclopentylcarbonyl)aminol-2-[(2,4 dibromophenoxy)methyll-1H-indol-1-ylmethyl)benzoic acid 30 Example 6 4-({3-chloro-5- [(cyclopentylcarbonyl)aminol -2 [(cyclopentvlsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid 35 Example 7 4-(13-chloro-5-[(cvclopentvlcarbonyl)aminol-2-[(propyisulfanyl)methyll 1H-indol-1-yllmethyl)benzoic acid Example 8 40 4

-({

2

-{[

4 -(tert-butvl)phenoxylmethyll-3-chloro-5 [(cvclopentylcarbonyl)aminol-1H-indol-l-Vylmethyl)benzoic acid 47 WO 99/43651 PCT/US99/03899 5 Example 9 4-({3-chloro-5-[(cvclopentylcarbonyl)aminol-2-[(2 quinolinyisulfanyl)methyll-1H-indol-1-Vllmethyl)benzoic acid 10 Example 10 4-r(3-chloro-5-[(cvclopentylcarbonyl)aminol-2 {[(cvclopropylmethyl)sulfanyllmethyll-1H-indol-1-yl)methyllbenzoic acid Example 11 15 4-({2-[(benzhydrylsulfanyl)methyll-3-chloro-5 [(cvclopentvlcarbonyl)aminol-1H-indol-1-vllmethyl)benzoic acid The compounds of the following Examples 12 through 14 were prepared by: 20 Step 1 - The material prepared in Example 1, step 6, was acylated at the 5-amino position using the protocol of Example 1, step 7, with the appropriate acylating reagent. Step 2 - The title compound was prepared from the intermediate of Step 1 following the procedure described in Example 1, steps 8 through 10, using the appropriate thiol. 25 Example 12 4 -(15-[(3-carboxypropanovl)aminol-3-chloro-2 [(phenethvlsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid 30 Example 13 4-[(5-[(3-carboxypropanovl)aminol-3-chloro-2-{[(3 methylbenzyl)sulfanyllmethyl}-1H-indol-1-vl)methyllbenzoic acid 35 Example 14 4-({2-({[4-(tert-butvl)benzyllsulfanyllmethyl)-5-r(3 carboxypropanovl)aminol-3-chloro-1H-indol-1-vllmethyl)benzoic acid 48 WO 99/43651 PCT/US99/03899 5 Example 15 4-({3-chloro-5-(3-furoylamino)-2-[(2-naphthylsulfanyl)methyll-1H-indol 1-vllmethyl)benzoic acid The title compound was prepared as described in Example 43 using the appropriate acylating reagent. 10 The following Examples 17 through 21 were prepared as described in Example 43 using the appropriate acylating reagent. Example 17 15 4-(f3-chloro-5-1 [3-(diethylamino)propanoyllamino}-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-Vllmethyl)benzoic acid Example 18 4-({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(3 20 thienylcarbonyl)aminol-1H-indol-1-vllmethyl)benzoic acid Example 19 4-(5-{ [(benzylamino)carbonylIamino}-3-chloro-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid 25 Example 20 4-(5-{ [(butvlamino)carbonyllamino}1-3-chloro-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid 30 Example 21 3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2-naphthylsulfanyl)methyll-1H indol-5-yllamino)carbonyllbenzoic acid Example 22 35 4-{[5-(benzyloxy)-2-[(E)-2-carboxyethenvll-3-(2-naphthovl)-1H-indol-1 yllmethyllbenzoic acid step 1 A solution of 2(tert -butyldimethylsilyloxymethyl)-5-benzyloxyindole (2.0g, 5,4mmol) in anhydrous ether (10ml) was cooled to -78 0 C and a solution of ethylmagnesium bromide 40 (3.OM in ether, 4.Oml, 12.0mmol) was added dropwise. The mixture was stirred at -60 0 C to -65 0 C for 2h during which time the homogeneous solution became a yellow slurry. A 49 WO 99/43651 PCT/US99/03899 5 solution of naphthoyl chloride (2.28g, 12.Ommol) in ether (8ml) was then added. After stirring for 2h at -60 0 C to -40 0 C the reaction was carefully quenched with saturated aqueous sodium bicarbonate and diluted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. Flash chromatography (Hex/Acetone, 6/1) gave 2.2g (78%) of 1_ as a yellow foam. 10 step 2 To an ice-cold (OC) solution of the intermediate above (1.0g, 1.9mmol) in DMF (10mI) was added sodium hydride (0.12g, 2.1mmol). The ice bath was removed after 10 min and the reaction was stirred at rt for 30min at which time the bromomethyl SEM ether 15 (0.5ml, 2,8mmol) was added dropwise. The mixture was stirred at rt for 4h, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Flash chromatography (Hex/Acetone, 6/1) afforded 1.22g (81%) of the desired intermediate as an off-white foam. 20 step 3 To a solution of the above (6.6g, 8.4mmol) in THF (80ml) was added tetrabutylammonium fluoride (L.OM in THF, 21ml). The reaction was stirred at rt for 2h, water was added and the mixture was extracted with EtOAc. The combined organic layers 25 were washed with water, brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 4:1) gave 3.8g (67%) of the alcohol as a thick colorless oil. The alcohol was dissolved in THF (50ml) and MnO 2 (5.5g, 63.2mmol) was added. The reaction was stirred for 22h and filtered through a pad of Celite. Concentration of the filtrate gave 3.7g (96%) of the desired intermediate as a light yellow foam. 30 step 4 To an ice-cold (0 0 C) solution of trimethylphosphonoacetate (0. 12mI, 0.7mmol) in DMF (5ml) was added sodium hydride (0.027g, 0.8mmol). After 30min a solution of the above intermediate (0.5g, 0.7mmol) in 5ml of DMF was added. The ice bath was removed and 35 the reaction was allowed to stir overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and concentrated. Flash chromatography (Hex/EtOAc, 3/2) gave 0.2g of the desired intermediate (37%) as a white foam. 40 step 5 50 WO 99/43651 PCT/US99/03899 5 4-{[5-(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)- 1H-indol- 1 yl]methyl I benzoic acid To a solution of the intermediate above (0.5g, 0.7mmol) in acetonitrile (10ml) was added aqueous 48% hydrofluoric acid (5ml). After 2h, water was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried 10 over magnesium sulfate. Concentration gave a crude solid that was dissolved in THF (2ml) and MeOH (lml) and IN sodium hydroxide solution (2ml). After stirring overnight at rt the reaction was acidified to pH=3 with 10% HCl solution and extracted with ethyl acetate. Flash chromatography (CH2Cl2/MeOH, 10/1) gave the title compound (0.2g, 50%) as a white solid. 15 Example 23 4 -({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanylmethyll-H-indol-1 vllmethyl)benzoic acid Step 1: Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL 20 of THF and cooled to O C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0' C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO 4 and concentrated to yield 24.8 g. 25 Step 2: The crude indole alcohol prepared in step 1 (8.3 g, 32.6 mmol) is dissolved in DMF (10.5 mL). To this solution is added imidazole (5.5g, 81.5 mmol) and t butyldimethylsilyl chloride (5.4g, 35.8 mmol). The mixture is stirred at room temperature overnight. The reaction is poured into water and extracted with ethyl acetate (3X). Organic 30 layers are dried over magnesium sulfate and concentrated. The crude material is purified on a silica gel column using 19:1 Hexane:Ethyl acetate to give pure product (11.9g, 31 mmol, 94 % yield, TLC _ 0.8 Rf in Toluene:Ethyl acetate 2:1) Step 3: A solution of the silyl protected indole prepared in step 2 (2 g, 6.56 mmol) in 35 ether (20 mL) was added dropwise to ethyl magnesium bromide (2.4 mL of a 3M solution in ether, 7.2 mmol) in ether (10 ml), the latter maintained at -78'C. The reaction was stirred at -60'C for 2 hr. Next acetylchloride (0.51 mL, 7.2 mmol) in ether (4 mL) was added slowly. The reaction maintained between -50'C and -60'C for another 2 hrs. The reaction was then quenched with saturated sodium bicarbonate. Extracted with ethyl 40 acetate (3X). Organic layers were dried over magnesium sulfate and concentrated. The 51 WO 99/43651 PCT/US99/03899 5 crude material was purified on a silica gel column using 19:1 Hexane:Ethyl acetate to give pure product (1.2 g, 50%). Step 4: To the indole (1.2 g, 2.9 mmol, prepared in step 3 above) in 10.5 ml of DMF, sodium hydride (0.13g, 60% oil dispersion, 3.23 mmol) is added at room temperature. 10 The reaction is stirred for 30 minutes. Methyl (4-bromomethyl) benzoate (0.81 g, 3.53 mmol) is added at this time and the reaction stirred overnight. On completion of the reaction (monitored by TLC) it is quenched with water, extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate, concentrated and used for the next step. 15 Step 5: A mixture of silyl protected indole prepared in step 4 above (0.65 g, 1.2 mmol) and tetra-butyl ammoniumfluoride (2.9 mL of a IM solution in tetrahydrofuran, 2.9 mmol) in tetrahydrofuran (6 mL) were stirred at room temperature for one hour. At this time the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on 20 silica gel using 1:1 Hexane:Ethyl acetate to yield pure alcohol (0.47 g, 91 %). Step 6: The indole alcohol (0.3 g, 0.68 mmol), carbon tetrabromide (0.27 g, 0.81 mmol) and 1,3-bis(diphenylphosphino)propane (0.21 g, 0.51 mmol) were taken up in dichloromethane (8.4 mL) and stirred for 16 hours at which time the reaction was diluted 25 with dichloromethane and half saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3X) dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using2:1 Hexane:Ethyl acetate to yield pure alcohol (0.27 g, 78 %). 30 Step 7: The indole bromide prepared in step 6 (0.1 g, 0.2 mmol) was dissolved in dimethylformamide (0.4 mL, degassing the solvent is strongly recommended) cesium carbonate (0.2 g, 0.6 mmol) was added and then ethyl 2 naphthalenethiol (0.034g, 0.22 mmol) was added and the mixture was stirred for 1 day, then the reaction was poured into 1/2 saturated ammonium chloride and extracted with ethyl acetate (3X), dried, 35 concentrated and chromatographed (Hexane:Ethyl acetate 3:1) to yield 0.05 g (57%) of pure product. Step 8: The ester ( 0.2 g, 0.34 mmol) prepared in step 7 above is dissolved in 4.0 mL of 1/1 THF/ methanol and then 1N sodium hydroxide (2.5 mL) is added and the resulting 40 mixture is stirred for 16 hours at RT, workup gave crude product that is purified via 52 WO 99/43651 PCT/US99/03899 5 chromatography (1:1 Hexane:Ethyl acetate with 1% acetic acid) to yield (0.17 g, 85%) of solid. Example 24 4-{[5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyll-3-(2,2.2 10 trifluoroacetyl)-1H-indol-1-vllmethyl benzoic acid Step 1: This intermediate was prepared from the indole, prepared in step 2 of Example 23 and trifluoroacetic anhydride, according to the procedure described in step 3 of Example 23. 15 Step 2: This intermediate was prepared according to the procedure described in step 4 of Example 23, but using the indole derivative prepared in step 1 above and methyl (4 bromomethyl) benzoate. Step 3: To a solution of the indole alcohol prepared in step 2 (0.1 g, 0.2 mmol) and 20 triethylamine (0.04 mL, 0.3 mmol) in dichloromethane (0.4 mL), methanesulphonyl chloride (0.02 mL, 0.24 mmol) is added dropwise at 0 0 C. The reaction is stirred for 1.5h and then the dichloromethane removed. To the residue in 0.4 mL of DMF at 0 0 C 2 naphthalene thiol (0.034 g, 0.22 mmol) is added. Next CsCO 3 (0.96 g, 0.3 mmol) is added and the reaction mixture stirred at room temperature overnight, then the reaction 25 was poured into brine and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (Hexane:Ethyl acetate 3:1) to yield 0.064 g (50%) of pure product. Step 4: The title compound was prepared from ester, prepared in step 3 above, according to the procedure described in step 8 of Example 23. 30 Example 25 4-({5-[(4-aminobutanoyl)aminol-3-chloro-2-[(2-naphthylsulfanyl)methyll 1H-indol-1-vllmethyl)benzoic acid step 1: The t-butylsilyl protected alcohol (25g) from step 6 of Example 1, was dissolved in 35 THF(200mL) and then tetrabutylammonium flouride ( 125mL of a 1.0 M solution) was added and the mixture was stirred for 10 minutes at room temperature and then the reaction was diluted with water and the THF was concentrated, ethyl acetate was added and the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated to yield the desired 40 alcohol (21.5 g). 53 WO 99/43651 PCT/US99/03899 5 Step2: The alcohol (13.1g) from step 1 was suspended in dichloromethane (450 mL), cooled to OC and triethylamine(10 mL) and methanesulfonyl chloride (4.0 mL) were added and the resulting mixture was left to warm to room temperature overnight at which time it was diluted with saturated sodium bicarbonate was added and the reaction was diluted with dichloromethane, the layers were separated, the aqueous layer was extracted 10 three times with dichloromethane, the combined organic layers were dried, concentrated to yield the desired chloride (13.5g). Step 3: To the chloride (13.5g) generated in step 2 was added DMF (150 mL), cesium carbonate (33.5 g) and then the solution was degassed by bubbling argon through the 15 solution for 20 minutes and then 2-naphthalene thiol was added and the reaction was stirred for 20 minutes at room temperature, then water was added as was ethyl acetate, the layers were separated and the combined organic layers were concentrated to a slurry which was stirred overnight and then the slurry was filtered and the solid was triturated with 40% ethyl acetate in hexane to deliver the desired disulfide (12.2 g) in 69% yield. 20 Step 4: The product from step three (11.25 g) was dissolved in THF (500 mL), methanol (500mL) and then copper II acetate (19.2 g) suspended in water (300 mL) was added as was more THF (1OOmL) and then sodium borohydride (11.2 g) was added portionwise. After 2.5 hours of stirring at room temperature the foamy black solution was diluted with 25 saturated sodium bicarbonate and the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and chromatographed to yield the desired amine (9.0 g) in 85% yield. step 5: The amine from step 4 above was coupled to fmoc protected 4-aminobutyric acid 30 following the procedure outlined in step 1, Example 43, followed by trituration with dichloromethane delivered the aide in 43% yield. Step 6 : The amide (1.0 eq) from step 5 was dissolved in methanol (5 mg/ml) and piperidine (0.024 ml/mg) and then the reaction was stirred at room temperature for two 35 hours, concentrated and chromatographed to yield the desired product in quantitative yield. Step 7: The amino ester from step 6 was hydrolyzed using the conditions outlined for step 2 of Example 43 to deliver the title compound in 54%. 40 54 WO 99/43651 PCT/US99/03899 5 Example 26 4 -({3-chloro-5-[(cvclopentylcarbonylaminol-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-yllmethyl)benzoic acid step 1: The amine (1.0 eq) from step 4 of Example 25 was dissolved in CH 2 Cl 2 (0.3M) and then an equivalent amount of saturated sodium bicarbonate was added and then the 10 appropriate acid chloride (1.2 eq) was added. The biphasic reaction mixture was vigorously stirred until TLC analysis indicated that the reaction was complete (generally a few hours) and then the reaction was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed, or used crude, to 15 yield the desired amide in 50% yield. Step 2: The ester from the previous step was dissolved in THF/MeOH (3:1) and then IN NaOH (3.Oeq) was added and the reaction was stirred for until TLC analysis showed that the reaction was complete. The reaction was then concentrated, diluted with water, acidified to pH 2 with conc HCL, extracted with ethyl acetate 3X, the combined organics 20 were dried over magnesium sulfate concentrated and purified via chromatography to yield the desired acid in 69% yield. Example 27 4-({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(2 25 quinoxalinylcarbonvl)aminol-1H-indol-1-ylmethyl)benzoic acid Step 1: The amine from step 4 of Example 25 was treated with the appropriate acid chloride according to the general procedure for Example 71, step 1, to deliver the amide in 76% yield. 30 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 53% yield. Example 28 4 -(f 3 -chloro-5-[(2,2-dimethylpropanoyl)aminol-2-[(2 35 naphthylsulfanyl)methyll-1H-indol-1-vlmethyl)benzoic acid Step 1: The amine from step 4 of Example 25 was treated with the appropriate acid chloride according to the general procedure for Example 71, step 1, to deliver the amide in 100% yield. 40 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 79% yield. 55 WO 99/43651 PCTIUS99/03899 5 Example 29 4-(5-{ [(benzyloxv)carbonyllamino}-3-chloro-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid step 1: The amine from step 4 of Example 25 was treated with the appropriate acid chloride 10 according to the general procedure for Example 71, step 1, to deliver the amide in 96% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid. 15 Example 30 4-({3-chloro-5-f(cvclopentvloxy)carbonyllaminol-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vl}methyl)benzoic acid Step 1: The amine from step 4 of Example 25 was treated with acetic anhydride 20 according to the general procedure for Example 71, step 1, to deliver the amide in 92% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid. 25 Example 31 4 -({5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyll-lH-indo-1 Vllmethyl)benzoic acid Step 1: The amine from step 4 of Example 25 was treated with acetic anhydride 30 according to the general procedure for Example 71, step 1, to deliver the amide in 77% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 29%. 35 Example 32 4-(f -{[(butvlamino)carbonyllamino}-3-chloro-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid Step 1: THF (0.12M) was added to the amine (1.0 eq) generated in step 4, the reaction 40 mixture was cooled to OC and then butylisocyanate (1.1 eq) was added and the mixture was warmed to room temperature overnight and the reaction was diluted with 1/2 saturated 56 WO 99/43651 PCTIUS99/03899 5 ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired urea in 57% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 10 of Example 26 to yield the desired acid in 41%. Example 33 4-(15-{[ (butvlamino)carbonyllamino}-3-chloro-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-Vllmethyl)benzoic acid 15 Step 1: According to the procedure for Example 32, step 1, the amine was treated with benzyl isocyanate to deliver the title compound in 16% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 100%. 20 Example 34 4-({3-chloro-5-[(morpholinocarbonyl)aminol-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-yllmethyl)benzoic acid Step 1: The amine (1.0 eq) generated above in step 4 was weighed into a flask along 25 with 4-dimethyaminopyridine (1.5eq) and then they were taken up in dichloroethane (0.08 M) and then 4-morpholinecarbonyl chloride (1.5eq) was added and the reaction was stirred overnight at room temperature and then heated to 40'C for 4 hours and then worked up by the addition of ethyl acetate and 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the 30 combined organic layers were dried and concentrated and purified via chromatography to yield the desired urea in 100% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 79%. 35 Example 35 4-(15-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyll-1H-indol-1 yllmethyl)benzoic acid Step 1: The amine (1.Oeq) from step 1 was dissolved in dichloroethane and then 40 benzaldehyde (1.0 eq) was added followed by acetic acid (1.0 mL/lmmol) and the reaction was stirred for 20 minutes and then the sodium triacetoxyborohydride (1.3 eq) 57 WO 99/43651 PCT/US99/03899 5 was added and the reaction was stirred overnight at room temperature, quenched by the addition of aqueous diethanolamine and dichloromethane the layers were separated, the aqueous layer was extracted three times with dichloromethane , the combined organic layers were dried and concentrated and purified via chromatography to yield the desired urea in 74% yield. 10 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 49%. Example 36 15 4

-({

3 -chloro-2-[(2-naphthylsulfanvl)methyll-5-[(3-phenoxvbenzyl)aminol 1H-indol-1-vllmethyl)benzoic acid Step 1: According to the procedure for step 1 of Example 35 the amine from step 4 of Example 25 was treated with the appropriate aldehyde to yield the desired secondary amine in 38% yield. 20 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 87%. Example 37 25 4

-({

3 -chloro-5-[(cyclopentvlcarbonyl)(methyl)aminol-2-[(2 naphthylsulfanyl)methyll-1H-indol-1-vllmethyl)benzoic acid Step 1: To the ester generated in step 1 of the synthesis of Example 27 was added DMF (0.05M), the reaction was cooled to OC and then sodium hydride (10 eq) was added and the mixture was stirred for 30 minutes, methyl iodide (10eq) was then added and the 30 resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate and 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired methylated amide in 56% yield. 35 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 57%. 58 WO 99/43651 PCT/US99/03899 5 Example 38 4-({5-[acetyl(benzyl)aminol-3-chloro-2-[(2-naphthvlsulfanvl)methyll-1H indol-1-yllmethyl)benzoic acid Step 1: The amide synthesized in step 1 of Example 31 was benzylated according to the procedure in step 1 for Example 37 to yield the tertiary aide in 90% yield. 10 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 41%. Example 39 15 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(tetrahydro-3 furanylcarbonyl)aminol-1H-indol-1-yllmethyl)benzoic acid Step 1: To the indole amine (1.0 eq) was added the acid (1.2 eq) the dimethylaminopyridine (10 mol %), 1-( 3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq) and then DMF(0.3M) and the reaction was stirred under nitrogen 20 for 24 hours at room temperature at which time it was poured into 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water 2X, dried, concentrated and chromatographed to yield 55% of the title compound. 25 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 55%. Example 40 4-({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(3 30 thienvlcarbonvl)aminol-1H-indol-1-yllmethyl)benzoic acid step 1: According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of 35 Example 26 to yield the desired acid in 21%. Example 41 4-({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(1 adamantylcarbonyl)aminol-1H-indol-1-yllmethyl)benzoic acid 40 Step 1: According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield. 59 WO 99/43651 PCT/US99/03899 5 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 35%. Example 42 10 3-[(1l-( 4 -carboxybenzyl)-3-chloro-2-[(2-naphthylsulfanyl)methyll-1H indol-5-vllamino)carbonyllbenzoic acid Step 1: According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield. 15 Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 of Example 26 to yield the desired acid in 20%. Example 43 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyll-5-[(3 20 phenvlpropanovl)aminol-1H-indol-1-yllmethyl)benzoic acid Step 1: According to the procedure for step 1 of Example 39 the amine from step 4 of Example 25 was treated with the requisite acid to yield the amide in 100% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2 !5 of Example 26 to yield the desired acid in 32%. Example 44 4-(15-amino-3-chloro-2-[(2-naphthylsulfanyl)methyll-1H-indol-1 yllmethyl)benzoic acid 0 step 1: The amine generated in step 4 was hydrolyzed according to the procedure for step 2 of Example 26 to yield 79% yield. Example 45 N-f3-chloro-1-(4-{[(methvlsulfonyl)aminolcarbonyllbenzyl)-2-[(2 5 naphthylsulfanyl)methyll-1H-indol-5-vl cvelopentanecarboxamide Step 1: To Example 26 (1.0 eq), EDCI (1.5 eq), DMAP (1.0 eq), methane sulfonamide (1.0 eq) in a flask under nitrogen was added DMF (0.08M) and the reaction was stirred overnight at room temperature and then worked up by the addition of 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the 0 aqueous layer was extracted 3 times, the combined organic layers were washed with water 2X, dried, concentrated and chromatographed to yield 27% of the title compound. 60 WO 99/43651 PCT/US99/03899 5 Example 46 N-{3-chloro-2-[(2-naphthylsulfanyl)methyll-1-14-({[(4 nitrophenyl)sulfonyll aminolcarbony)benzyll-1H-indol-5 Vlkyclopentanecarboxamide 10 Step 1: To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 43% yield. Example 47 N-{3-chloro-1-[4-( [( 2 -methylphenvl)sulfonyllaminocarbonyl)benzyll -2 15 [( 2 -naphthylsulfanyl)methyll-1H-indol-5-vylcyclopentanecarboxamide Step 1: To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 40% yield. Example 48 20 N-[3-chloro-2-[(2-naphthylsulfanyl)methyll-1-(4 f[(phenylsulfonyl)aminol carbonylbenzyl)-1H-indol-5 yllcyclopentanecarboxamide Step 1: To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 40% yield. 25 Example 49 N-f 3-chloro-2-[(2-naphthylsulfanyl)methyll-1-[4 ( [(trifluoromethyl)sulfonyll aminocarbonyl)benzyll-1H-indol-5 yllcvclopentanecarboxamide 30 Step 1: To Example 26 was added the appropriate sulfonamide under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonaiide in 67% yield. Example 50 4 -f5-[(cyclopentvlcarbonyl)aminol-2-[(2-naphthyloxy)methyll-3-(1 35 pyrrolidinvlcarbonyl)-1H-indol-1-vllbutanoic acid Step 1 The Ethyl 5-nitroindole-2-carboxylate (1 eq) was dissolved in THF/MeOH/H 2 0 (3:1:1 0.21 M) followed by addition of LiOH-H 2 0 (1.38 eq), stirred at 25*C, overnight. Reaction mixture was then acidified to pH=1 with IN HCI solution and extracted with 0 ethyl acetate. Workup with water, brine, drying and concentration afforded the crude product in 99% yield. 61 WO 99/43651 PCT/US99/03899 5 Step 2 The crude acid (1 eq) from step 1 was dissolved in THF (0.14 M) and to this was added carbonyl diimidazole (1 eq), stirred at 25"C for 1.5h. Reaction mixture was then cooled to OC. Sodium borohydride (2.86 eq) was added in several portions followed by the 10 addition of EtOH (0.71 M), stirred at 25"C, overnight. Reaction mixture at this point was acidified with 2N HCI to pH=2 and extracted with ethyl acetate. Workup with water, brine, drying and concentration afforded the crude product in 95% yield. Step 3 15 In an oven dried flask was added the crude indole alcohol (1 eq) from step 2 followed by anhydrous DMF (0.135 M). To this was then added imidazole (1.3 eq) and TBSC (1.2 eq), stirred at 25"C for 1 h. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 70% yield. 20 Step 4 The silyl protected indole (1 eq) from step 3 was dissolved in anhydrous DMF (0.13 M) in an oven dried flask. To this was added NaH (60% dispersion in mineral oil, 1.2 eq) and stirred at 25*C for 1 h after which ethyl 4-bromobutyrate (1.2 eq) and KI (1.2 eq) were added. Reaction mixture was then heated at 60"C for 2 h. Workup with ethyl 25 acetate/water followed by chromatographic purification afforded the desired product in 93% yield. Step 5 Dissolved the alkylated indole (1 eq) from step 4 in THF (0.05 M) and to this was added 30 TBAF (1.0 M/THF, 1.leq) dropwise at 25*C, stirred for 1 h. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product quantitatively. 35 Step 6 Dissolved the indole alcohol (1 eq) from step 5 in anhydrous DMF (0.16 M) followed by the addition of POCl 3 (10 eq) dropwise at 0*C. Heated at 80"C, overnight. Workup with ethyl acetate/water and washing the organic layer with IN NaOH, water, brine followed by concentration and chromatographic purification afforded the desired product in 64% 40 yield. 62 WO 99/43651 PCTIUS99/03899 5 Step 7 A mixture of the chloro aldehyde derivative (1 eq) from step 6, 325 mesh K2C3 (2.4 eq), 2-naphthol (1.2 eq) and KI (1.2 eq) was suspended in anhydrous acetonitrile (0.2 M) and heated at 70*C for 1.5 h. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 65% yield. 10 Step 8 Dissolved the naphthyloxy indole derivative (1 eq) from step 7 in anhydrous THF (0.023 M) and to this was added 5% Pt/C (40wt%) under nitrogen and hydrogenated with a H2 balloon for 2.5 h. Reaction mixture was then filtered through Celite and concentrated to 15 afford the crude product in 96% yield. Step 9 The amino indole derivative (1 eq) from step 8 was dissolved in anhydrous CH 2 Cl 2 (0.07 M) followed by dropwise addition of Et 3 N (1.4 eq) and cyclopentanecarbonyl chloride 20 (1.2 eq) at 0"C. Stirred at 25'C for 0.5 h after which the reaction mixture was quenched with saturated NaHCO 3 solution and stirred overnight. Organic layer was separated and washed with brine, dried. Product was obtained in 66% yield after recrystallization from 30% ethyl acetate/hexane. 25 Step 10 The indole from step 9 (1 eq) was weighed into a flask along with NaH2P0 4 (12 eq), t butyl alcohol (0.13 M), water (0.13 M), 2-methyl-2-butene (46 eq) and to this mixture was added NaO 2 CI (12 eq) at 25'C. Reaction mixture was then heated at 65*C, overnight. Workup with ethyl acetate/water followed by trituration with CH 2 Cl 2 /hexane (4:6) at 0 0 C 30 for 1 h afforded the desired product in 63% yield. Step 11 The acid (1 eq) from step 10 was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), pyrrolidine (1.2 eq) followed by anhydrous THF (0.018 M) and the 35 reaction mixture was then refluxed for 18 h. Worked up with ethyl acetate/water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate/hexane (3:7) afforded the desired product in 89% yield. 63 WO 99/43651 PCT/US99/03899 5 Step 12 Dissolved the amide (1 eq) from step 11 in THF/MeOHlwater (3:1:1, 0.025 M) and to this was added LiOH-H 2 0 (1.2 eq), stirred at 25*C, overnight. Workup with ethyl acetate/water followed by recrystallization from CH 2 Cl 2 /hexane (1:1) afforded the desired product in 98% yield. 10 Example 51 4-15-[(cyclopentvlcarbonyl)aminol-3-(morpholinocarbonyl)-2-[(2 naphthyloxy)methyll-1H-indol-1-Vllbutanoic acid Step 1 15 Following step 11 of Example 50 and using morpholine yielded 87% of the desired product after recrystallization. Step 2 Following step 12 above (Example 50) and using the corresponding morpholino amide afforded the desired product in 96% yield after recrystallization. 20 Example 52 N-[2-[(2-naphthyloxy)methyll-1-(4-oxo-4 { [(trifluoromethyl)sulfonyllaminolbutyl)-3-(1-pyrrolidinvlcarbonyl)-1H indol-5-yllcvclopentanecarboxamide 25 The acid Example 50 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) followed by anhydrous THF (0.04 M) and the reaction mixture was stirred at 25"C, overnight. Worked up with ethyl acetate/water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Trituration of crude product with CH 2 Cl 2 /hexane (1:2) at 0*C for 1 h afforded 30 the desired product in 96% yield. Example 53 N-[3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyll-1-(4-oxo-4 { [(trifluoro-methyl)sulfonyll aminoibutyl)- 1H-indol-5 35 yllevelopentanecarboxamide Following step 1 above (Example 52) and using the corresponding acid Example 51 (step 4, scheme-4) afforded the desired product in 96% yield. 64 WO 99/43651 PCTIUS99/03899 5 Example 53A 4-{5-[(cyclopentvlcarbonyl)aminol-3-formyl-2-[(2-naphthyloxv)methyll 1H-indol-1-yllbutanoic acid Step 1 Dissolved the indole (1 eq) from step 9 Example 50 in THF/MeOH/H 2 0 (3:1:1, 0.025 10 M) and to this was added LiOH.H 2 0 (1.2 eq), stirred at 25"C, for 4 h. Workup with ethyl acetate/IN HCl followed by trituration with CH 2 Cl 2 /hexane afforded the desired product in 74% yield. Example 53 B 15 N-[3-formyl-2-[(2-naphthyloxy)methyll-1-(4-oxo-4 S[(trifluoromethyl)sulfonyllaminolbutyl)-1H-indol-5 vllevelopentanecarboxamide Step 1 The acid (1 eq) from step 1 of Example 53A was weighed into a flask and to this was 20 added EDCI (1.35 eq), DMAP (1.1 eq), trifluoromethanesulfonamide (1.05 eq) followed by anhydrous THF (0.026 M) and the reaction mixture was stirred at 25'C, 3 h. Worked up with ethyl acetate/water followed by washing the organic layer with 0.05N HCl, saturated bicarbonate and brine. Chromatographic purification then afforded the desired product in 94% yield. 25 Example 54 5-[(cvclopentvlcarbonyl)aminol-2-[(2-naphthyloxy)methyll-1-(4-oxo-4 f[(trifluoromethyl)sulfonyllaminolbutvl)-1H-indole-3-carboxylic acid Step 1 30 The product of Step 1, Example 53B (1 eq) was weighed into a flask along with NaH 2

PO

4 (12 eq), t-butyl alcohol (0.12 M), water (0.12 M), 2-methyl-2-butene (50 eq) and to this mixture was added NaO 2 Cl (11.8 eq) at 25*C. Reaction mixture was then heated at 60*C, 3 h and left overnight at 25*C. Workup with ethyl acetate/water followed by chromatographic purification and triturations with CH2CI2/hexane (1:1) afforded the 35 desired product in 57% yield. 65 WO 99/43651 PCTIUS99/03899 5 Example 55 3-({4-[5- [(cvclopentvIcarbonyl)amino]-2-f(2-naphthyloxv)methyll -3-(1 pyrrolidinvlcarbonyl)-1H-indol-1-vllbutanoyllamino)benzoic acid Step 1 The compound of Example 50 (1 eq) was weighed into a flask and to this was added 10 EDCI (3 eq), DMAP (1.2eq), methyl 3-aminobenzoate (1.2 eq) followed by anhydrous THF (0.04M) and the reaction mixture was then stirred at 25*C for 2 d. Worked up with ethyl acetate/water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate/hexane afforded the desired product in 88% yield. 15 Step 2 Dissolved the ester (1 eq) from step 1 in THF/MeOH/water (3:1:1, 0.024 M) and to this was added LiOH H 2 0 (1.2 eq), stirred at 25'C, overnight at this point 1.2 eq of LiOH H20 was added and stirred for 2 h. Workup with ethyl acetate/iN HCI followed by trituration with CH 2

CI

2 /hexane (1:1) at 0 0 C for lh afforded the desired product in 92% 20 yield. Example 56 3-[(4-15-[(cvclopentvlcarbonyl)aminol-3-(morpholinocarbonyl)-2-[(2 naphthyloxv)methyll-1H-indol-1-yllbutanoyl)aminolbenzoic acid 25 Step 1 Following step 1 of Example 55 and using the product of Example 51 (see scheme-4 for synthesis) afforded the desired product in 85% yield after chromatographic purification. Step 2 30 Following step 2 of Example 55 and using the corresponding morpholino from step 1 afforded the desired product in 91% yield. Example 57 N-[2-[(2-naphthyloxy)methyll-1-f4-oxo-4-[3 35 ({f[(trifluoromethyl)sulfonvllaminocarbonyllanilinolbutvl} -3- (1 pyrrolidinvlcarbonyl)-lH-indol-5-yllcyclopentanecarboxamide Step 1 The compound of Example 55 (1 eq) was weighed into a flask and to this was added EDCI (3 eq), DMAP (1.2 eq), trifluoromethanesulfonamide (1.2 eq) followed by 40 anhydrous THF (0.04 M) and the reaction mixture was then stirred at 25*C, overnight. Worked up with ethyl acetate/water followed by washing the organic layer with IN HCl, 66 WO 99/43651 PCT/US99/03899 5 saturated bicarbonate and brine. Trituration with CH 2 Cl 2 /hexane (8:2) afforded the desired product in 84% yield. Example 58 N-(3-(morpholinocarbonyl)-2-[(2-naphthyloxv)methyll -1-{4-oxo-4-[3 10 (1 [(trifluoromethyllsulfonyllamino carbonyl)anilinolbutyl}I-1H-indol-5 Vl)cvclopentanecarboxamide Following step 1 of Example 57 and using Example 56 afforded the desired product in 84% yield. 15 Example 59 2-(4-{[5-(benzyloxv)-3-(1-naphthovl)-1H-indol-1-yllmethyllphenvl)acetic acid Step 1: A solution of MeMgBr in butyl ether (1 M, 1.2 eq) was ice cooled. 4 Benzyloxy indole (1 eq) in CH 2 Cl 2 (0.5 M) was added and the reaction mixture was 20 allowed to warm to 25 *C. After the addition of 1-naphthoyl chloride (1 eq) in CH 2 Cl 2 (1 M) the reaction was heated to reflux for 3 h. Quenching with aqueous NH 4 C and extraction with CHCl 3 provided crude ketone, which was purified by recrystallization from hexane/CHCl 3 /MeOH (53 % yield). 25 Step 2: An ice cooled solution of the ketone (1 eq) from step lin DMIF (0.2 M) was treated with NaH (60 % in mineral oil, 2.5 eq). 4-bromophenyl acetic acid (1.1 eq) in DMF (0.4 M) was added after 15 minutes and the resulting mixture was stirred overnight at 25*C. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic extracts were dried and concentrated. The desired product was obtained in 68 % yield 30 after purification by chromatography and recrystallization from hexane/EtOAc. Example 60 2-(4-{F5-(benzyloxv)-3-(2-naphthoyl)-1H-indol-1-vllmethyllphenvl)acetic acid 35 Step 1: Following step 1 of Example 59 using the appropriate acyl chloride yielded 42 % of the desired ketone after recrystallization from hexane/CHC 3 . Step 2: An analogous procedure to step 2 of Example 59 yielded 35 % of the title compound after chromatographic purification and recrystallization from acetone/pentane. 67 WO 99/43651 PCT/US99/03899 5 Example 61 2-[4-({ 5 -(benzyloxy)-3-[3.5-bis(trifluoromethyl)benzovll-1lH-indol-1 yllmethyl)phenyllacetic acid Step 1: Following step 1 of Example 59 using the appropriate acyl chloride yielded 30 % of the desired ketone after recrystallization hexane/CH 2 Cl 2 /EtOAc. 10 Step 2: An analogous procedure to step 2 of Example 59 yielded 73 % of the title compound after chromatographic purification and recrystallization from CHCl 3 /MeOH. Example 62 4

-({

3 -benzovl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyll-1H-indol-1 15 yllmethyl)benzoic acid Step 1 The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 'C under nitrogen for 1 h. Workup with NaOH and water followed by concentration afforded crude product (100%). 20 Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 M), and treated with t-butyldimethylsilyl chloride (1. 16 eq) and imidazole (1.26 eq) at 25 'C for 1 d. Workup and chromatographic purification afforded the pure product (93%). Step 3 The silyl ether from step 2 was dissolved in methylene chloride (0.26 25 M), and treated with BOC anhydride (1.24 eq), triethylamine (1.53 eq) and DMAP (0.21 eq) at 25 'C for 3 d. Workup and chromatographic purification afforded the pure product (99%). Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid/ water/ 30 THF (3:1:1) (0.04 M) at 25 'C for 1 d. Workup and chromatographic purification afforded the pure product (100%). Steps 5 The alcohol from step 4 was dissolved in methylene chloride (0.2 M), and under nitrogen at -40*C treated with triethylamine (1.33 eq), and mesyl chloride (1.23 eq) 35 for 1 h. In a separate dry flask was weighed naphthalene-2-thiol (1.31 eq), and THF (1 M) was added, followed by lithium hexamethyldisilazide (IN in THF, 1 eq) and this mixture was stirred at 25*C for 30 min. The resulting solution was then added dropwise, over 30 minutes, to the above mesylate solution, at -40"C. The reaction mixture was allowed to warm to 25*C, and stirred there for 4.5 h. Workup and chromatographic 40 purification afforded the BOC thioether. 68 WO 99/43651 PCTIUS99/03899 5 Step 6 The purified BOC thioether from step 5 was heated under nitrogen at 160-170*C for 1.25 h, and recrystallized from ethyl acetate and hexanes to afford the free indole thioether in 64% yield. Step 7: The product of step 6 (1 eq) in CH 2 Cl 2 (0.125 M) was ice cooled. A solution 10 of MeMgBr (1.2 eq) in butyl ether (1 M) was added and the resulting mixture was stirred for 30 minutes. After warming up to 25'C, benzoyl chloride was added dropwise. The reaction was heated to reflux for 3 h, then stirred at 25'C overnight. After quenching with

NH

4 Cl, the mixture was extracted with CH 2

C

2 . Organic extracts were washed with brine, dried and concentrated. The desired ketone was obtained in 55 % yield after 15 chromatographic purification. Step 8: A solution of the product from step 1 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.05 eq). Methyl 4-bromomethylbenzoate (1.2 eq) was added after 1 h at 25*C and the resulting mixture was stirred overnight. EtOAc/water 20 work up produced the desired crude material which was purified by chromatography (56 % yield). Step 9: The material from step 2 (1 eq) was hydrolyzed by the action of LiOH H 2 0 (1.2 eq) in THF/MeOH/water (3/1/1, 0.07 M). After stirring at 25*C 25 overnight, the reaction mixture was quenched with AcOH and solvent was evaporated. EtOAc/water work up and chromatographic purification afforded the title compound in 78 % yield. Example 63 30 4

-({

5 -(benzyloxy)-3-isobutyryl-2-r(2-naphthylsulfanyl)methyll-1H-indol 1-yllmethyl)benzoic acid Step 1: Following step 7 of Example 62 using isopropyl chloride yielded the desired ketone after chromatography. Step 2: An analogous procedure to step 8 of example 62 yielded 50 % of the N 35 alkylated material after chromatographic purification. Step 3: Following step 9 of example 62 the methyl ester was hydrolyzed to the title compound in 67 % yield after chromatography. Example 64 40 2

-{

3 -acetyl-5-(benzvloxy)-2-[(2-naphthylsulfanyl)methyll-1H-indol-1 Vljacetic acid 69 WO 99/43651 PCT/US99/03899 5 Step 2: The product of step 1 of Example 80 was alkylated with methyl bromoacetate following an analogous procedure to step 8 of example 62 to yield 65 % of the desired compound after recrystallization from EtOAc. Step 3: Following step 9 of example 62 above the methyl ester was hydrolyzed to the title compound in 84 % yield after chromatography. 10 Example 65 2-{5-(benzvloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyll-1H-indol 1-Vllacetic acid Step 2: An analogous procedure to step 2 of Example 63 started from methyl bromo 15 acetate and the isopropyl ketone described in step 1 of Example 63 (step 1, see above). This reaction yielded 66 % of the N-alkylated material after chromatographic purification. Step 3: Following step 3 of Example 63 the methyl ester was hydrolyzed to the title compound in 50 % yield after chromatography. 20 Example 66 4

-{

3 -benzoyl-5-(benzyloxy)-2-[(2-naphthyloxv)methyll-1H-indol-1 yllbutanoic acid Step 1: A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to - 70'C. The product of step 2 in Example 62 (1 eq) in ether (0.55 M) was added and the reaction mixture was 25 stirred at - 70*C for 2 h. After the addition of benzoyl chloride (3 eq) in ether (1.5 M) the reaction was stirred at - 40"C for 2 h, quenched with saturated NaHCO 3 at - 40*C and allowed to warm to 25"C. EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone in 89 % yield. 30 Step 2: The material from step 1 (1 eq) in CH 2 Cl 2 (0.25 M) was treated with NEt, (2 eq), followed by BOC anhydride (1.24 eq) and DMAP (0.21 eq). After stirring for 20 minutes at 25*C the reaction mixture was worked up with CH 2

CI

2 and water. Pure desired material was obtained in 97 % yield by trituration with hexane. 35 Step 3: The above material (1 eq) in THF (0.3 M) was combined with pyridine (excess) and HF-pyridine (excess) at 0*C. The reaction was stirred at 25*C for 1.5 h. EtOAc/water work up followed by chromatographic purification afforded the desired alcohol in 86 % yield. 40 Step 4: The alcohol from step 3 (1 eq) in CH 2 C1 2 (0.4 M) was treated with 2,6-lutidine (2.5 eq) followed by SOC1 2 (1.2 eq). After 30 minutes at 25'C the reaction was worked 70 WO 99/43651 PCT/US99/03899 5 up with EtOAc and water. The crude product was purified by chromatography and trituration with hexane to afford the corresponding chloride in 75 % yield. Step 5: A mixture of the above material (1 eq), 325 mesh K 2

CO

3 (2.4 eq), b-naphthol (1.2 eq) and KI (1.2 eq) in CH 3 CN (0.3 M) was heated to reflux for 2 h. EtOAc/water 10 work up, followed by trituration in hexane/EtOAc and chromatography of the mother liquor yielded 70 % of the expected ether. Step 6: A NaOMe solution in MeOH was prepared by dissolving Na (3 eq) in MeOH (0.2 M). The product of step 5 (1 eq) in THF (0.04 M) was added and the reaction mixture 15 was stirred at 25 "C for 3 h. EtOAC/water work up followed by trituration with hexane/EtOAc afforded the indole compound in 93 %. Step 7: A solution of the product from step 6 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.1 eq). Methyl 4-bromobutyrate (1.2 eq) and KI (1.2 eq) 20 were added after 1 h and the reaction mixture was stirred at 75*C for 3 h. EtOAc/water work up followed by chromatographic purification yielded 96 % of the required ester. Step 8: The material from step 7 (1 eq) was hydrolyzed by the action of LiOH-H 2 0 (1.2 eq) in THF/MeOH/water (3/1/1, 0.2 M). After stirring at 25'C for 2 h, the reaction 25 mixture was quenched with IN HCl and extracted with EtOAc and CH 2

C

2 . The organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane/EtOAc to afford the title compound in 86 % yield. Example 67 30 3-[(4-13-benzovl-5-(benzyloxy)-2-[(2-naphthyloxv)methyll-1H-indol-1 yllbutanoyl)aminolbenzoic acid Step 1: The product of Example 66 (1 eq) was reacted with EDCI (1.37 eq) and methyl 3 amino benzoate (1.05 eq) in DMF (0.09 M) in the presence of DMAP (0.2 eq). The reaction was stirred at 25*C for 1.5 h. EtOAc/water work up, followed by flash 35 chromatography produced the desired amide in 81 % yield. Step 2: An analogous procedure to step 2 of Example 66 yielded 98 % of the title compound after purification by trituration in hexane/EtOAc. 40 Example 68 71 WO 99/43651 PCT/US99/03899 5 4-{3-benzovl-5-(benzyloxy)-2-[(2-naphthyloxv)methyll-1H-indol-1-vl} N-[3-( [(trifluoromethyl)sulfonyllaminoIcarbonyl)phenyllbutanamide Step 1: Following step 1 of Example 67 and using the acid of Example 67 and the appropriate sulfonamide provided after overnight reaction and analogous work up the desired product. Trituration with hexane/EtOAc yielded 100 % of the title compound. 10 Example 69 4-[(4-{3-benzovl-5-(benzyloxv)-2-[(2-naphthyloxy)methyll-1H-indol-1 yllbutanoyl)aminolbenzoic acid Step 1: Following step 1 of Example 67 above using acid of Example 66 and the 15 appropriate aniline yielded 76 % of the expected aide. Step 2: An analogous procedure to step 2 of Example 67 yielded 78 % of the title compound after purification by trituration in hexane/EtOAc. 20 Example 70 2-[(4-13-benzovl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1 ylIbutanovl)aminolbenzoic acid Step 1: Following step 1 of Example 67 using acid of Example 66 and the appropriate aniline yielded 36 % of the expected aide after chromatography. 25 Step 2: An analogous procedure to step 2 of Example 67 yielded 67 % of the title compound after purification by trituration in hexane/EtOAc. Example 71 30 3-[(4-13-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1 yllbutanoyl)aminolpropanoic acid Step 1: Following step 1 of Example 67 using acid of Example 66 and the appropriate aniline yielded 96 % of the expected amide after chromatography. 35 Step 2: An analogous procedure to step 2 of Example 67 yielded 90 % of the title compound after purification by trituration in hexane/EtOAc. Example 72 3-[(4-13-benzovl-5-(benzyloxy)-2-[(2-naphthyloxv)methyll-1H-indol-1 40 yllbutanoyllaminolpropanoic acid 72 WO 99/43651 PCT/US99/03899 5 Following step 1 of Example 67 using acid of Example 66 and the appropriate sulfonamide yielded 100 % of the title compound. 73 WO 99/43651 PCTIUS99/03899 5 Example 73 N-(4-13-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1 Vlbutanovl)-2-methylbenzenesulfonamide Following step 1 of Example 67 using acid of Example 66 and the appropriate sulfonamide yielded 80 % of the title compound after chromatography. 10 Example 74 5-{3-benzovl-5-(benzyloxv)-2-[(2-naphthyloxv)methyll-1H-indol-1 vllpentanoic acid 15 Step 1: A solution of the product from step 6 of Example 66 (1 eq) in dry DMF (0.1 M) was treated with NaH (60 % in mineral oil, 1.1 eq). Ethyl 4-bromopentanoate (1.2 eq) and KI (1.2 eq) were added after 1 h and the reaction mixture was stirred at 75"C for 2 h. EtOAc/water work up followed by chromatographic purification yielded 92 % of the required ester. 20 Step 2: The material from step 1 (1 eq) was hydrolyzed by the action of LiOH-H 2 0 (1.3 eq) in THF/MeOH/water (3/1/1, 0.2 M). After stirring at 25'C for 3.5 h, the reaction mixture was quenched with 1N HCl and extracted with EtOAc and CH 2 Cl2. The organic extracts were combined, washed, dried and concentrated. The crude material was purified 25 by trituration in hexane/EtOAc to afford the title compound in 95 % yield. Example 75 3-[(5-13-benzovl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1 Vllpentanoyl)aminolbenzoic acid 30 Step 1: The acid of Example 74 (1 eq) was reacted with EDCI (1.37 eq) and methyl 3 amino benzoate (1.05 eq) in DMF (0.09 M) in the presence of DMAP (0.2 eq). The reaction was stirred at 25*C for 2.5 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 78 % yield. 15 Step 2: An analogous procedure to step 2 of Example 74 yielded 83 % of the title compound after purification by trituration in hexane/EtOAc. 74 WO 99/43651 PCT/US99/03899 5 Example 76 5-f 3-benzovl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1-Vl} N- [3-( [(trifluoromethyl)sulfonyllaminolcarbonyl)phenvllpentanamide Step 1: Following step 1 of Example 68 using acid of Example 75 and the appropriate sulfonamide yielded 83 % of the title compound after overnight reaction and analogous 10 work up. Example 77 2-{3-benzovl-5-(benzyloxv)-2-[(2-naphthyloxy)methyll-1H-indol-1 vljacetic acid 15 Step 1: Following step 1 of Example 74 using the appropriate bromide yielded 80 % of the expected amide after chromatography. Step 2: An analogous procedure to step 2 of Example 74 yielded 90 % of the title compound after trituration in hexane/EtOAc. 20 Example 78

(E)-

4 -{3-benzovl-5-(benzvloxv)-2-[(2-naphthyloxy)methyll-1H-indol-1 Vl}-2-butenoic acid Step 1: Following step 1 of Example 74 using the appropriate bromide yielded 33 % of 25 the expected amide after chromatography. Step 2: An analogous procedure to step 2 of Example 74 yielded 70 % of the title compound after trituration in hexane/EtOAc. 30 Example 79 3

-({

3 -benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyll-1H-indol-1 Vllmethyl)benzoic acid Step 1: Following step 1 of Example 74 using the appropriate bromide yielded 75 % of the expected amide after chromatography. 35 Step 2: An analogous procedure to step 2 of Example 74 yielded 92 % of the title compound after trituration in hexane/EtOAc. 75 WO 99/43651 PCTIUS99/03899 5 Example 80 1-{1-[4-(1.3-benzothiazol-2-ylcarbonyl)benzyll-5-(benzylsulfanyl)-2-r(2 naphthylsulfanyl)methyll-1H-indol-3-yl}-1-ethanone Step 1 The thioether from step 6, Example 62 was dissolved in methylene chloride (0.12 M), and under nitrogen at 0 0 C treated with methylmagnesium bromide (1.1 10 eq), and stirred at 0 to 25*C for 1 h. The mixture was recooled to 0*C and acetyl chloride (1.17 eq) was added. After 1 h at 0 0 C, the reaction mixture was quenched by addition of half saturated ammonium chloride solution, and worked up with methylene chloride. Chromatographic purification afforded the pure product (37%). 15 Step 2 Following the procedure for Example 81 step 1 and using p-Toluoyl chloride yielded the corresponding para amide. Step 3 Following the procedure for Example 81 step 2 and using the product from step 1 above, the desired product was obtained. 20 Step 4 Following the procedure for step 3, Example 81 and using the material from step 3 yielded the desired benzyl bromide. Step 5 Following the procedure for Example 81 step 4, the material from step 4 25 was coupled to the material from step 1 to yield the titled compound. Example 81 1-{1-[3-(1,3-benzothiazol-2-vlcarbonvl)benzyll-5-(benzvlsulfanyl)-2-[(2 naphthylsulfanyl)methyll- 1H-indol-3-yl} -1 -ethanone 30 Step 1 m-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCI (1.1 eq) dissolved in methylene chloride at 0 0 C over 20 min. The reaction was allowed to warm to 25"C. After stirring at 25*C for 1 day, workup with methylene chloride and water afforded crude product in ca. 100% yield. 35 Step 2 Under anhydrous conditions benzothiazole was dissolved in THF (0.35 M). At -78 'C added BuLi (1.1 eq). After 1 h at -78'C, added the amide from step 1 in THF, over 15 min. The reaction was allowed to warm to 25*C. After stirring at 25*C for 1 day, workup with ethyl acetate and water and chromatography afforded pure tolyl ketone product (52%). 40 76 WO 99/43651 PCT/US99/03899 5 Step 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0.19M), and NBS (1.2 eq) and AIBN (0.11 eq) were added. After 1 d at 60"C, about 1:1 of starting material and product were present. Resubmission under the same conditions, followed by filtration and recrystallization from ethyl acetate afforded pure bromobenzyl ketone product (28%). 10 Step 4 The indole from step 1 of Example 80 was dissolved in dry DMF (0.04 M), followed by NaH (1.25 eq). After 45 min at 25*C, added the bromobenzyl ketone from step 3 (1.25 eq), and stirred for 1 h at 25*C. Workup, chromatography, and recrystallization from ethyl acetate/hexanes afforded the pure title compound (45%). 15 Example 82 2-[3-({3-acetyl-5-(benzyloxy)-2-r(2-naphthylsulfanyl)methyll-1H-indol-1 yllmethyl)benzoyll-1.3-benzothiazole-6-carboxylic acid Step1 Ethyl 4-aminobenzoate was dissolved in 95% v/v HOAc/water (0.4 M) 20 and at 25 *C treated with sodium thiocyanate (4.1 eq), and stirred at 25'C for 20 min. The mixture was cooled to 5oC and bromine (1.17 eq) in 95% v/v HOAc/water was added. After 1 h at 0 _C, the reaction mixture was quenched by addition of water, and filtered. Workup (ethyl acetate and sodium bicarbonate solution) gave 81% of the pure thiocyanate product. 25 Step 2 The aryl thiocyanate from step 1 was treated with sodium sulfide nonahydrate dissolved in water (1.2 eq, 1.3 M), and heated at reflux for 45 min. The cooled mixture was filtered, acidified to pH = 6 with HOAc, extracted with ethyl acetate, and concentrated to give the thiophenol product (9 1%). 30 Step 3 The thiophenol from step 2 was dissolved in 90% v/v HCOOH/water (3.3 M), and zinc dust (cat.) was added. After 3 h at reflux, workup with ethyl acetate and alkali afforded pure benzothiazole ester (60%). 35 Step 4 Benzothiazole ester (step 3) was dissolved in THF/methanol/water (8:3:3), (0.34 M), lithium hydroxide (2 eq) was added, and the mixture was stirred for 2 h at 25*C. Workup (ethyl acetate/ aqueous acid) afforded pure benzothiazole acid (100%). Step 5 Under anhydrous conditions the benzothiazole acid (step 4) was 40 dissolved in THF (0.052 M). At -78*C added BuLi (2.2 eq). After 1 h at -78"C to 0*C, added the amide (1.28 eq) from step 1 of Example 81, in THF, at -78"C, over 5 min. 77 WO 99/43651 PCT/US99/03899 5 After 0.5 h at -78*C, the reaction was allowed to warm to 25'C. After stirring at 25*C for 2h, workup with ethyl acetate and water and chromatography afforded pure tolyl ketone acid product (64%). Step 6 The tolyl ketone acid from step 5 was suspended in (1:1) THF/ethanol , 10 (0.075 M), and conc. sulfuric acid (excess) was added. After reflux for 1 d, workup (ethyl acetate and sodium bicarbonate solution) and purification by chromatography gave the pure tolyl ketone ester product (69%). Step 7 The tolyl ketone ester from step 6 was dissolved in carbon tetrachloride 15 (0.05M), and NBS (1.2 eq) and AIBN (0.15 eq) were added. After 1.25 h at reflux, another portion of NBS (0.3 eq) and AIBN (0.07 eq) were added. Filtration and recrystallization from ethyl acetate afforded pure bromobenzyl ketone product (22%). Step 8 The indole from step 1 of Example 80 was dissolved in dry DMF (0.06 20 M), followed by NaH (1.11 eq). After 45 min at 25'C, added the bromobenzyl ketone from step 7 above (1.25 eq), and stirred for 1 h at 25'C. Workup afforded the crude ester, used in the next step. Step 9 The crude ester from step 8 was dissolved in THF/methanol/water 25 (8:2:2), (0.013 M), lithium hydroxide (4.3 eq) was added in portions, as the mixture was stirred for a total of 3-4 d at 25"C. Workup (ethyl acetate/ aqueous HCI) and purification by chromatography afforded pure benzothiazole acid (31%). Example 83 30 5 -f 3 -benzovl-5-(benzylox)-2-(2-naphthyloxy)methyll-1H-indol-1-y1}-2 oxopentanoic acid Step 1 The indole from step 6 of Example 66 was dissolved in dry DMF (0.17 M), followed by NaH (1.2 eq). After 1.5 h at 25*C, added 3-iodo-1-chloropropane, and 35 stirred for 4 h at 25 'C. Workup (ethyl acetate/bicarbonate solution) and trituration (ethyl acetate/hexanes) afforded the product in 89% yield. Step 2 The alkyl chloride from step 1 was dissolved in methyl ethyl ketone (0.036 M), followed by Nal (1.6 eq). After stirring for 1 d at reflux in the dark, workup 40 (ethyl acetate/water) afforded the product iodide in 97% yield. 78 WO 99/43651 PCTIUS99/03899 5 Step 3 NaH (1.0 eq) was weighed into a dry flask under nitrogen, and dry benzene (0.14 M) was added. At 0 0 C, added dry DMF (0.4 M), ethyl 2-carboxy-1,3 dithiane (1.0 eq), and the iodide from step 2 (1.0 eq) into a separate dry flask. This DMF solution was then added at 0 0 C to the benzene suspension, and the mixture was allowed to warm to 25'C and stirred for 3 h at 25*C. Workup (ethyl acetate/water) and 10 chromatography afforded the product dithianyl ester in 54% yield. Step 4 Silver nitrate (4.5 eq) and NCS (4.0 eq) were dissolved in 4:1 v/v acetonitrile/water (ca. 0.04 M), and a solution of the dithianyl ester from step 3 (1 eq) in acetonitrile (0.03 M) was added at 25*C. After stirring for 5 min at 25'C, added a sodium 15 sulfite solution, followed in one minute by a sodium carbonate solution. Workup (ethyl acetate/water) and chromatography afforded the product ketoester in 17% yield. Step 5 The ketoester from step 4 was dissolved in THF/water (8:1), (0.03 M), lithium hydroxide (1.5 eq) was added, and the mixture was stirred for 2 h at 25'C. 20 Workup (ethyl acetate/ aqueous HCl) and purification by chromatography afforded pure ketoacid (64%). Example 84 3

-[(

5 -1 3 -benzovl-5-(benzyloxy)-2-[(2-naphthyloxv)methyl-1H-indol-1 ?5 vl}-2-oxopentanovl)aminolbenzoic acid Step 1 The dithianyl ester from step 3 Example 83 was dissolved in THF/ethanol/water (5:2:2) (0.008 M), and lithium hydroxide (11 eq) was added, and the mixture was stirred for 1 d at 50"C. Workup (ethyl acetate/ aqueous HCl) and chromatography afforded the pure dithianyl acid (90%). 10 Step 2 The dithianyl acid from step 1 was dissolved in dry methylene chloride (0.08 M), and DMF (cat.). Oxalyl chloride (1.2 eq) was added, and the reaction was stirred at 25'C for 0.5 h. Concentration was followed by redissolution in dry methylene chloride, and addition , at O'C, of methyl 3-aminobenzoate (1.05 eq) and triethylamine 5 (1.0 eq). The reaction was warmed to 25 *C, and stirred there for 3 h. Workup (ethyl acetate/aqueous acid) and purification by chromatography afforded the product dithianyl ester in 89% yield. Step 3 The dithianyl ester from step 2 was dissolved in THF/methanol/water 0 (6:4:3) (0.02 M), and lithium hydroxide (4.3 eq) was added, and the mixture was stirred 79 WO 99/43651 PCT/US99/03899 5 for 3 h at 25'C. Workup (ethyl acetate/ aqueous HCl) afforded the dithianyl acid (R = 3 COOH) (91%). Step 4 Silver nitrate (4.6 eq) and NCS (4.0 eq) were dissolved in 4:1 v/v acetonitrile/water (ca. 0.03 M), and a solution of the dithianyl acid from step 3 (1 eq) in 10 acetonitrile (0.009 M) was added at 25*C. After stirring for 10 min at 25'C, there was added a sodium sulfite solution, followed in one minute by a sodium carbonate solution. Workup (ethyl acetate/aqueous acid) and chromatography afforded the title compound in 82% yield. 15 Example 85 4 -[(5-13-benzovl-5-(benzyloxy)-2-[(2-naphthylox)methyll-1H-indol-1 yl}-2-oxopentanovl)aminolbenzoic acid Step 1 The dithianyl acid from step 1 Example 84 was treated as described above for step 2 Example 84 except ethlyl 4-aminobenzoate was substituted. Purification 20 by chromatography afforded the product dithianyl ester (R = 4-COOC 2 H,) in 30% yield. Step 2 The dithianyl ester from step 1 was treated as described for step 3 of Example 84. Purification by chromatography afforded the product dithianyl acid (R = 4 COOH) in 89% yield. 25 Step 3 The dithianyl from step 6 was treated as described for step 4 of Example 84. Repeated purification by chromatography followed by trituration in pentane afforded the title compound in 30 % yield. 30 Example 86 Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of the tables, assay results are reported as an "IC 50 value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay. Where no numerical IC 50 value 35 appears, "NA" denotes that inhibitory activity was not detected from such compound in the corresponding assay and a blank box denotes that the compound was not tested in such assay as of the time of filing of the present application. 80 WO 99/43651 PCT/US99/03899 5 Activity Assays (a) Vesicle Assay 1-palmitoyl-2-[' 4 C] arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 M) and 1,2-dioleyolglycerol (final concentration 3 M) were mixed and 10 dried under a stream of nitrogen. To the lipids was added 50 mM Hepes pH 7.5 (2x final concentration of lipids) and the suspension was sonicated for 3 min. at 4 0 C. To the suspension was added 50 mM Hepes pH 7.5, 300 mM NaCl, 2 mM DTT, 2 mM CaCl 2 and 2 mg/ml bovine serum albumin (BSA) (Sigma A7511) (1.2x final concentration of lipids). A typical assay consisted of the lipid mixture (85 1) to which was added 15 consecutively, the inhibitor (5 1 in DMSO) and cPLA 2 , 10 ng for an automated system or 1 ng for a manual assay, in 101 of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below. (b) Soluble Substrate Assay (LysoPC) 20 1-[ 14 C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 M) was dried under a stream of nitrogen. The lipid was resuspended by vortexing 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consisted of lipid suspension (85 1) to which was added consecutively the inhibitor (51 in DMSO) and cPLA 2 , 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA. This assay was 25 conducted by either the manual assay or automated assay protocol described below. 81 WO 99/43651 PCT/US99/03899 5 (c) Automated Assay The lipid suspension and inhibitor were pre-incubated for 7 min. at 37*C. Enzyme was added and the incubation was continued for a further 30 mins. The reaction was then quenched by the addition of decane: isopropanol: trifluoroacetic acid (192:8:1 w/v, 150 1). A portion of the quench layer (50 1) was passed through a Rainin Spheric-5 silica column 10 (5, 30 x 2.1 mm) eluting with heptane:methanol:TFA (97:3:0.1 v/v). The level of [1 4

C]

arachidonic acid was analyzed by an in-line Radiomatic Flo-One/Beta counter (Packard). (d) Manual Assay The lipid, inhibitor and enzyme mixture were incubated at 37 0 C for 30 min. The 15 reaction was quenched by the addition of heptane:isopropanol:0.5M sulfuric acid (105:20:1 v/v, 200 1). Half of the quench layer was applied to a dispoable silica gel column (Whatman SIL, 1 ml) in a vacuum manifold positioned over a scintillation vial. Free [1 4 C]- arachidonic acid was eluted by the addition of ethyl ether (1 ml). The level of radioactivity was measured by liquid scintillation counter. 20 (e) PMN Assay PMINs were isolated using Ficoll-Hypaque according to the manufacturers directions. Red blood cells contaminating the PMNs were removed by hypotonic lysis, and the PMN pellet was washed once, and resuspended in Hanks buffered saline at a concentration of 2 25 x 106 cells/ml. The cells were preincubated with inhibitors for 15 min at 37%C and then stimulated with 2 uM A23187. When monitoring LTB 4 production as a measure of cPLA 2 inhibition, the reaction was quenched with an equal volume of ice cold phosphate buffered saline. Cells were removed by centrifugation, and the LTB 4 present in the cell supernatant was measured using the LTB 4 scintillation proximity assay provided by Amersham 30 according to the manufacturers directions. In the assays reported in the Tables above,

LTB

4 was measured. When monitoring arachidonic acid production, the reaction was quenched with methanol containing D8-arachidonic acid as an internal reference. The lipids were extracted by the method of Bligh et al. ((1959) Can. J. Biochem. Physiol., 37, 911-917), and the fatty acid was converted to the pentafluorobenzyl ester and analyzed by 35 GC-MS in a manner similar to that reported by Ramesha and Taylor ((1991) Anal. Biochem. 192, 173-180). 82 WO 99/43651 PCT/US99/03899 5 (f) RBL Assay RBL-2H3 cells were routinely cultured as 37 0 C in a 5% CO 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded into spinner flasks at 3 x 10' cells/ml and 100 ng/ml DNP specific-IgE was added. After 20 hrs, the cells were harvested by 10 centrifugation and washed once in serum-free minimal essential media, and resuspended to 2 x 106 cells/ml in serum free media. The cells were then preincubated with either inhibitor in DMSO (1% v/v) or DMSO (1% v/v) for 15 min at 37"C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGD 2 content in accordance with 15 known methods. (g) Coumarine Assay 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Nalytical Biochemistry 222, 110-115). 20 Inhibitors were mixed with 200 pL assay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 60 pM 7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4 pg cPLA2 in 50 pL assay buffer. Hydrolysis of the 7-hydroxycounarimyl 6 heptenoate ester was monitored in a fluorometer by exciting at 360 nm and monitoring emission at 460 nm. Enzyme activity is proportional to the increase in emission at 460 nm 25 per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less. Example 87 Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure described below. The results are reported in Table 30 II. Rat Carrageenan-Induced Footpad Edema Test Each compound was suspended in 0.3ml absolute ethanol, 0.1 mI Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0.Imi IN NaOH 35 was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All comounds remained in solution. Compounds were administered i.v. in a volumne of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1% Type IV carrageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after 40 dosing with carageenan. 83 WO 99/43651 PCT/US99/03899 5 All patent and literature references cited herein are incorporated as if fully set forht herein. 84

Claims

1. A compound of the formulae: R1 R3 R1 R3 RR 4 R4 4R R1, 6 N or R1> R2 R 2 R5 R5 10 wherein: R, and R, are independently selected from H, halogen, -CF3, -OH, -CI-Clo alkyl, -S C 1 -C 0 alkyl, C 1 -Co alkoxy, -CN, -NO2, -NH2, -HN(C,-C 6 ), -N(C-C 6 ) 2 , phenyl, -0 phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: 15 R6 R6 R N- R7 N N-R7 Ir R7 0 0 R R R7Ry N , o O O ; 0 R6R6 77or 0 0 R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH2, -CN, CF 3 , or -OH; ?5 85 WO 99/43651 PCT/US99/03899 5 R 7 is selected from -OH, -CF 3 , C-C 6 alkyl, C 1 -C 6 alkoxy, -NH-(C-C 6 alkyl), -N-(C, C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C -C 6 alkyl, C-C 6 alkoxy, -NO 2 , -NH 2 , -CF3, or -OH; 10 R 2 is selected from H, halogen, -CF 3 , -OH, -C,-CI alkyl, C,-CO alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -N-S0 2 -C,-C 6 alkyl, or -S0 2 -C,-C 6 alkyl; R 3 is selected from H, -CF3, CC6 lower alkyl, C 1 -C 6 lower alkoxy, C 3 -CO 15 cycloalkyl, -C6-C6 alkyl-C 3 -C, cycloalkyl, -CHO, halogen, or a moiety of the formula L 2-M2: L 2 indicates a linking or bridging group of the formulae -(CH 2 )n-, -S-, -0-, -C(O)-, -(CH 2 )n-C(O)-, -(CH 2 )n-C(O)-(CH 2 )n-, -(CH 2 )n-O-(CH 2 )n-, or -(CH2)n-S-(CH2)n 20 ,-C(O)C(O)X; where X = O,N M 2 is selected from the group of C,-C 6 lower alkyl, C 1 -C 6 lower alkoxy, C 3 -CO cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally 25 substituted by from 1 to 3 substituents selected from halogen, C -CO alkyl, CI-CIO alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, 30 imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from I to 3 substituents selected from halogen, CICi1 alkyl, CI CIO alkoxy, -NO 2 , -NH2 -CN, or -CF 3 ; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms 35 selected from N, S or 0 including, but not limited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -CIO alkyl, C 1 -CIO alkoxy, -CHO, NO 2 , -NH 2 , -CN, -CF 3 or -OH; or 10 c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited 86 WO 99/43651 PCT/US99/03899 5 to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, CI-CI 0 alkyl, C 1 -CI 0 alkoxy, -CHO, -NO 2 , -NH2, -CN, -CF 3 or -OH; n is an integer from 0 to 3; 10 R 4 is selected from the group of C,-C 6 lower alkyl, CI-C 6 lower alkoxy, -(CH 2 )n-C 3 C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3 -C 5 cycloalkyl, -(CH 2 ).-O-(CH 2 ).-C 3 -C 5 cycloalkyl, or the groups of: 15 a) -(CH 2 );-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 ),-O-phenyl CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o 0 O y ,(CH2),Y (CH2) y 0 20 0 (CH 2 )n, Y (CH2)N y (CH2) CH2)nY I(CH2)N (CH 2 )n wherein n is an integer from 0 to 3, Y is C3-C, cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally 25 substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0; or b) a moiety of the formulae -(CH 2 ),-A, -(CH 2 )n-S-A, or -(CH 2 ).-O-A, wherein A 30 is the moiety: D C B wherein D is H, C,-C 6 lower alkyl, C 1 -C 6 lower alkoxy, or -CF3; 87 WO 99/43651 PCT/US99/03899 5 B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF 3 , -OH, -C 1 -C 6 alkyl, C,-C 6 alkoxy, or -NO 2 ; or c) a moiety of the formulae: N Z Z N 10 S Z Zi N N N: S ZZ\ or 15 wherein Z is 0 or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , OH, -C,-C 6 alkyl, C-C 6 alkoxy, -NH 2 , or -NO 2 ; R 5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 ).-COOH, 20 -CH=CH-COOH, -(CH 2 )n-tetrazole, 88 WO 99/43651 PCT/US99/03899 or S or 0 or N (C 1 -C 6 lower alkyl) N (C1-C6 lower haloalkyl) 0 0 N or 5 or O0 0 _ 1 i or -S-OH 0 o 10 or a moiety selected from the formulae -L'-M; wherein L' is a bridging or linking moiety selected from a chemical bond, -(CH 2 )n-, -S-, 0-, -C(O)-, -(CH2)n--C(O)-, -(CH2).-C(O)-(CH2)n-, -(CH2)n,-O-(CH2)n,-,-(CH2)n-S-(CH2)n-, 15 -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R 6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO 2 -(CH 2 )n-; M 1 is selected from the group of -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 20 R8 R8 R -N N R10 ,R10 R 9 80 89 WO 99/43651 PCT/US99/03899 S R8 O N- Rg, 0 0 0 NI I % e O--OH S 5 1 , OH or R8 R10 where R, R 9 or Rio can be attatched anywhere in the cyclic or bicyclic system, R., in each appearance, is independently selected from H, -COOH, -(CH 2 )n-COOH, 10 (CH 2 )n-C(O)-COOH, tetrazole, 00 0 -- OH or OH; R 9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, -C,-C 6 alkyl, -O-C-C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C6 15 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, -CI-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C-C 6 alkyl), -N(C-C 6 alkyl) 2 , R8 R8 > O R9 N R N 20 R8 R, 9 0 WO 99/43651 PCTIUS99/03899 R8 R8 R R 9 (CH2)n (CH2 O2 or S N (C1-C6 lower alkyl or N (C1-C6 lower haloalkyli 0 O,,O N N N R 10 N (C1-C6 lower alkyl) Z /\R 9 R 8 N R 8 N R 8 (CH)/R o (CH 2 ) -\ /R or; 15 R,, is selected from H, C -C 6 lower alkyl, C 1 -C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ). COOH, -(CH 2 )n-C(O)-COOH, R 8 R 8 - (CH 2 )n / 20 9 1 WO 99/43651 PCT/US99/03899 5 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5 , R, R 9 , R 10 , and/or R 1 , shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0t 0 t N 0-P-OH S %_- 1 1 01" N~ R11, //OH or 10 n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 having the formula: R3 R3 R 1 R4 R1 R4 N or N R2 R F21 15 R 5 R5 wherein R 3 is hydrogen and Rp, R 2 , R 4 , and R5 are as described in Claim 1, or a pharmaceutically acceptable salt thereof. 20

3. A compound of Claim 2 having the formula: R3 R3 R1 R1 R4 R4 N or R2 IR2I R5 R5 wherein R,, R2, R 3 , R4, and R5 are as described in Claim 2, or a pharmaceutically acceptable salt thereof. 25 92 WO 99/43651 PCTIUS99/03899 5

4. A compound of Claim 2 having the formula: R4 R4 R1 R1 R3 R3 N or N R2 IR2I R5 R5 wherein R,, R 2 , R 3 , R 4 , and R, are as described in Claim 2, or a pharmaceutically acceptable salt thereof. 10

5. A compound of the formulae: R, R3 R1 R3 R4 R4 N or R2 IR2 R5 R5 15 wherein: R, is selected from H, halogen, -CF 3 , -OH, -C 1 -C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , HN(C-C 6 ), -N(C-C 6 ) 2 , phenyl, -0-phenyl, benzyl, -O-benzyl, or a moiety of the formulae: R6 R6 20R N N N R7 R

6 R7N 0 93 WO 99/43651 PCT/US99/03899 R6 R N 5 or 0 0 R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C-C 6 alkoxy, -NH 2 , -NO2, -CF3, 10 or -OH; R 7 is selected from -(CH 2 )n-COOH, -(CH 2 )n-N-(C-C 6 alkyl) 2 , -(CH 2 ).-NH-(C,-C 6 alkyl), -CF3, C1-C6 alkyl, C 3 -C 5 cycloalkyl, C-C 6 alkoxy, -NH-(C-C 6 alkyl), -N-(C-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, 15 adamantyl, or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, CI-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH; R 2 is selected from H, halogen, -CF 3 , -OH, -C 1 -C 0 alkyl, CI-Clo alkoxy, -CHO, -CN, 20 -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-S02CC6 alkyl, or -S0 2 -C,-C 6 alkyl; R 3 is selected from the group of CI-C 6 lower alkyl, CI-C 6 lower alkoxy, -(CH 2 )n-C 3 C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 ).-C 3 -C 6 cycloalkyl, or the groups of: 25 a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: 0 0 Y O _ -(CH2)r (CH2) rN Y 30 "_ O (CH2)n,, 'l (CH2)r,, O ,,(CH2) rNIS (CH2)n-, (CH2) (CH2) Y 94 WO 99/43651 PCT/US99/03899 5 wherein n is an integer from 0 to 3, Y is C 3 -C 6 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C-C6 alkyl, C 1 -C 6 alkoxy, -NH 2 , -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S,; or 10 b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: DC B wherein 15 D is H, C-C6 lower alkyl, C,-C 6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF, -OH, -C,-C6 alkyl, C,-C 6 alkoxy, or -NO 2 ; or 20 c) a moiety of the formulae: N S O N N NP S N N ,or N 25 95 WO 99/43651 PCT/US99/03899 5 wherein the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-c 6 alkoxy, or -N0 2 ; R 4 is selected from H, halogen, -CF , -OH, C-C6 alkyl, C,-C 6 alkoxy, benzyl, 10 benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH 2 -(C 3 -C 6 cycloalky), C(O)-OH, -CH=0, -C(O)-C,-C6 alkyl, -C(O)-O-CI-C6 alkyl, -C(O)-CF3, - (CH2),-S CH 2 -(C 3 -C 6 cycloalky), N O N O N O r 9 r ,orr 15 the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 6 alkyl, C-C6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH; n is an integer from 0 to 3; 20 R 5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, R8 R8 R9 R9 R9 N N N R10 N N N RR N8 7 R 25 N R 96 WO 99/43651 PCT/US99/03899 5 0 R 8 R N (CH2)HOHNH R 10 R 8 S C2 OOO O N NH 00 0 S o (C 1 C lowerC haloawerkyk 15 R 8 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, R, is selected from H, halogen, -CF 3 , -OH, -(CH 2 ).-COOH, 20 -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2; R 10 is selected from the group of H, halogen, -CF, -OH, -(CH 2 ).-COOH, 9 7 WO 99/43651 PCT/US99/03899 5 -(CH 2 ).-C(O)-COOH, -C 1 -C 6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , R8 R8 N \\ R9 R9 SI S' N (C 1 -C 6 lower alkyl N (C 1 -C 6 lower haloalkyl: or O ~ N N 10 N (C 1 -C 6 lower alkyl) R 1 is selected from H, C-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, or R8 R9 15 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R5, R, R,, R1W and/or RH shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 ''r0 0 0 0 0 N R 11 - OH S OH or N 20 or a pharmaceutically acceptable salt thereof. 98 WO 99/43651 PCT/US99/03899 5 6. A compound of the formulae: R1 R3 R1 R3 R4 IR4 or N R2 NR2 II R5 Rq wherein: 10 R, is selected form H, halogen, -CF 3 , -OH, -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -0-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae: R6 R6 R NN R O R6 R7N 0 15 R6 eN% or 0 O R 6 is selected from H, C,-C 6 alkyl, C 1 -C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 20 to 3 substituents selected from halogen, C 1 C 6 alkyl, C 1 -C 6 alkoxy, -NO2, -CF3, or -OH; R 7 is selected from -(CH 2 )n-COOH, -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , -(CH 2 )n-NH-(Cl-C 6 alkyl), -CF3, C,-C 6 alkyl, C 3 -C 5 cycloalkyl, CI-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, 25 adamantyl, or morpholinyl, the pyridinyl, phenyl and benzyl rings of these groups being 99 WO 99/43651 PCT/US99/03899 5 optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C C 6 alkoxy, -NO 2 , -CF 3 , or -OH; R 2 is selected from H, halogen, -CF 3 , -OH, -Cl-C 10 alkyl, Cj-CI0 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C6 alkyl, -N(C-C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, or -S0 2 -C,-C 6 10 alkyl; R 3 is selected from H, halogen, -CF 3 , -OH, C,-C6 alkyl, C,-C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH 2 -(C 3 -C 5 cycloalky), C(O)-OH, -CH=O, -C(O)-C-C 6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)-CF 3 , -(CH 2 )n-S 15 CH 2 -(C 3 -C 5 cycloalky), N O N O N O or the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , -C(O)-OH, 20 or -OH; n is an integer from 0 to 3; R 4 is selected from the group of C,-C 6 lower alkyl, C-C 6 lower alkoxy, -(CH 2 ).-C 3 25 C 5 cycloalkyl, -(CH 2 )n-S-(CH 2 ).-C 3 -C 5 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C3-C 5 cycloalkyl, or the groups of: a) -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl CH 2 -phenyl, -(CH 2 ).-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a 30 moiety of the formulae: 0 Y O y (CH2)rN (CH 2 )rr. y 0 0 (CH2)n (CH2) O (CH2) (CH2) 100 WO 99/43651 PCT/US99/03899 5 (CH2) O (C H2)n wherein n is an integer from 0 to 3, Y is C 3 -C 6 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C-C6 10 alkyl, C,-C 6 alkoxy, -NO or a five membered heterocyclic ring containing one heteroatom selected from N, S,; or b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 ).-O-A, wherein A is the moiety: D - C 15 B wherein DisH, C-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl 20 groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF3, -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, or -NO 2 ; or c) a moiety of the formulae: 25 101 WO 99/43651 PCT/US99/03899 S ZN<- I N -\f I S ZZ 5 or wherein Z is 0 or S and the phenyl and pyrimidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF3, 10 OH, -C,-C 6 alkyl, C,-C 6 alkoxy, or -NO 2 ; R 5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, R8 R/R R9 R N 15 R10, N N R 9 0 R80SY R 8 SR N J/ R 9 102 WO 99/43651 PCT/US99/03899 5 0 R 8 O N \ R 9 N (CH2) OH R10 ,/O N (CH2)r OH NH R O O 01 10 S R 8 0 R 8 NRI R9 o H N~~Oi/H R1o , R1o ,or S O N R11 .i 15 R 8 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, tetrazole, 0P-OH S S , or OH; R 9 is selected from H, halogen, -CF 3 , -OH, -(CH 2 )n-COOH, 20 -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -0-C-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C-C 6 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH, -(CH 2 )n-C(O)-COOH, -C 1 -C 6 alkyl, -0-C,-C 6 alkyl, -NH(C 1 -C 6 alkyl), -N(C-C 6 alkyl) 2 , 103 WO 99/43651 PCT/US99/03899 R8 R8 N R O- R9 5 N A,, S S' N (C 1 -C 6 lower alkyl N (Cl-C 6 lower haloalkyl or O 0, N N N S O N (C-C 6 lower alkyl) 10 R 1 is selected from H, C 1 -C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, or R8 R9 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R 5 , R 8 , R 9 , R 1 0 , and/or R 1 , shall contain at least one acidic 15 moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 0 0 00 O0 N R11 -- OH S OH or N or a pharmaceutically acceptable salt thereof. 20

7. A compound of the formulae: 104 WO 99/43651 PCT/US99/03899 R1 R3 R, R3 R4 R4 or 2 R2 5 R 5 R5 wherein: R, is selected form H, halogen, -CF 3 , -OH, -C 1 -C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -0-phenyl, benzyl, -O-benzyl, or a moiety of the formulae: 10 R 6 R6 R N N NR7 R6 0 R6 R N or 0 ; 15 R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C 6 alkoxy, -NO2, -CF3, or -OH; 20 R 7 is selected from -(CH 2 )n-COOH, -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -CF3, C,-C6 alkyl, C 3 -C, cycloalkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, adamantyl, or morpholinyl, the pyridinyl, phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C, 25 C 6 alkoxy, -NO2, -CF3, or -OH; 105 WO 99/43651 PCT/US99/03899 5 R 2 is selected from H, halogen, -CF 3 , -OH, -C 1 -CO alkyl, CI-CO alkoxy-CHO, -CN, NO 2 , -NH2, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-S0 2 -C,-C 6 alkyl, or -S0 2 -C,-C 6 alkyl; R 3 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 )n-C 3 10 C 6 cycloalkyl, -(CH 2 ).-S-(CH 2 )n-C 3 -C 5 cycloalkyl, or the groups of: a) -(CH 2 ).-phenyl-O-phenyl, -(CH 2 )n-phenyl-CH 2 -phenyl, -(CH 2 )n-O-phenyl CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae: o 0 15 Y, I -- O 11 '(CH2),, YI'(CH2),, S'-y 0 O (CH 2 )n- (CH2) y (CH2)N (CH 2 )n (CH2) O (CH2)n 20 wherein n is an integer from 0 to 3, Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl; rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S; or 25 b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D -)-C B wherein 30 D is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 or -NO 2 ; or 106 WO 99/43651 PCT/US99/03899 5 c) a moiety of the formulae: N ZZ or 10 wherein Z is O or S and the phenyl and pyrimnidinyl rings of each moiety are optionally and independently substituted by from 1 to 3 substituents selected from halogen, -CF3, OH, -C,-C6 alkyl, C,-C6 alkoxy, or -NO2, -NH2; 15 R4 is selected from H, halogen, -CF3, -OH1, C,-C6 alkyl, C,-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH2-(C3-C5 cycloalky), C(O)-OH, -CH=0, -C(O)-CI-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C(O)-CF3, -(CH2)n-S CH2-(C3-C5 cycloalky), 107 WO 99/43651 PCT/US99/03899 N 50 N O N 0 5 r, , orr the phenyl and benzyl rings of the relevant R 3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C-C 6 alkyl, C 1 -C 6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH; 10 n is an integer from 0 to 3; R 5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, R8 15 R NN R 9 R8~7 N R 9 N O NI N 15 R10 N R20 R0 R 8 S 8R8 0N R 9 0 7 R N~ R9R 20 0 108 WO 99/43651 PCT/US99/03899 R8 (CH2) OH 0R 5 0 0 , 0 s R 8 O 07 A \ R9 N49~R9 O 0 Hor S N 0 0 N R1. R 8 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, tetrazole, P-O S O , or OH; 5 R 9 is selected from H, halogen, -CF3, -OH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, -C,-C 6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 ).-COOH, -(CH2)n-C(O)-COOH, -CI-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, 0 R8 R8 N 0 // R9 N- Rg OO N (1-C lower alkyl N ( 1 -C 6 lower haloalkyl or 1 0 9 WO 99/43651 PCT/US99/03899 ON N ON S OX 5 N (C-C 6 lower alkyl) R 1 is selected from H, C,-C 6 lower alkyl, -CF3, -COOH, -(CH 2 ).-COOH, -(CH 2 )n-C(O)-COOH, or R8 R 9 10 with a proviso that the complete moiety at the indole or indoline 1-position created by any combination of R,, R 8 , R 9 , R 1 0 , and/or RH shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S 15 or a pharmaceutically acceptable salt thereof.

8. A compound of the formulae: 20 N OH N R15R wherein: 110 WO 99/43651 PCT/US99/03899 5 R, is selected form -NH 2 , -0-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O phenyl, -S-benzyl or a moiety of the formulae: R6 R6 R7 N 0 10 S O o 0 0 0 R6 R 7 -- , s--- N 0 0 15 R 6 is selected from H, C -C 6 alkyl, C 1 -C 6 alkoxy, phenyl, -0-phenyl, benzyl, -0 benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO2, -CF3, or -OH; 20 R 7 is selected from -(CH 2 )n-COOH, -(CH 2 )n-N-(Cl-C 6 alkyl) 2 , -(CH 2 )n-NH-(C,-C 6 alkyl), -CF3, CC6 alkyl, C 3 -C 5 cycloalkyl, C,-C 6 alkoxy, -NH-(C-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -0-phenyl, benzyl, -O-benzyl, adamantyl, or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CC6 alkyl, CI-C 6 alkoxy, -NO2, -CF3, or !5 OH; n is an integer from 0 to 3; 11 1 WO 99/43651 PCT/US99/03899 5 R 3 is selected from halogen, -C,-C6 alkyl, -C -C 6 alkoxy, -CF 3 , -CH=O, -C(O)-CI-C 6 alkyl, -C(O)-O-C,-C 6 alkyl, -C(O)-OH, -C(O)-CF 3 , -C(O)-phenyl, -C(O)-benzyl, -C(O) pyrrolyl, -C(O)-thienyl, -C(O)-furanyl, or -C(O)-morpholinyl; R 4 is selected from the group of -(CH 2 ).-C 3 -C 6 cycloalkyl, -(CH 2 )n-S-(CH 2 )n-C 3 -C 6 10 cycloalkyl, -(CH 2 )n-O-(CH 2 )n-C 3 -C 6 cycloalkyl, -(CH 2 )n-S-C,-C 6 alkyl, the groups of: a) -C(O)-O-(CH 2 )n-C 3 -C 5 cycloalkyl, -(CH 2 )n-phenyl, -(CH 2 ).-O-phenyl, (CH 2 ).-S-phenyl, -(CH 2 )n-S-(CH 2 ).-phenyl, -(CH 2 )n-phenyl-O-phenyl, -(CH 2 )n-phenyl CH 2 -phenyl, -(CH 2 )n-O-phenyl-CH 2 -phenyl, -(CH 2 )n-phenyl-(O-CH 2 -phenyl) 2 , -C(O)-O 15 phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, -C(O)-O-napthyl, -(CH 2 )n-S-napthyl, (CH 2 )n-S-pyridinyl, -(CH 2 )n-pyridinyl or -(CH 2 )n-napthyl, -(CH 2 )n-O-napthyl, the phenyl, pyridinyl and napthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or 0; 20 or b) a moiety of the formulae -(CH 2 )n-A, -(CH 2 )n-S-A, or -(CH 2 )n-O-A, wherein A is the moiety: D 25 wherein D is H, C,-C 6 lower alkyl, Cl-C 6 lower alkoxy, or -CF 3 ; R 5 is selected from -COOH, -C(O)-COOH, -(CH 2 )n-C(O)-COOH, -(CH 2 )n-COOH, -CH=CH-COOH, 30 112 WO 99/43651 PCT/US99/03899 R8 5R NN NRR 8 H R N N O N R 10 N Rio N NR\ / R8 oi /g N ~(CH2) OHNHR 10 N \ R 9 N R0 RR 5 O . 01 1 s R 8 R8 o Y 0 7q N 4C2 OHNHRi [50 H 0o 0 0 N 113 WO 99/43651 PCT/US99/03899 5 R 8 is selected from H, -COOH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, tetrazole, 00 0 O- -OH or R 9 is selected from H, halogen, -CF 3 , -OH, -(CH 2 )n-COOH, 10 -(CH 2 ) 1 -C(O)-COOH, -C,-C 6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C-C 6 alkyl) 2 ; Rio is selected from the group of H, halogen, -CF3, -OH, -(CH 2 )n-COOH, -(CH 2 ).-C(O)-COOH, -C,-C 6 alkyl, -0-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C-C 6 alkyl) 2 , R8 R8 0 0\,0 N N R9 15 SS' N (C1-C6 lower alkyl N (C1-C6 lower haloalkyl: or N N N (C1-Ce lower alkyl) 20 R 1 1 is selected from H, C-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ).-COOH, -(CH 2 ).-C(O)-COOH, or R 8 / [~>R9 with a proviso that the complete moiety at the indole or indoline 1-position 25 created by any combination of R 5 , R 8 , R 9 , R 10 , and/or R 1 , shall contain at least one acidic 114 WO 99/43651 PCT/US99/03899 5 moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae: S N R11 0-P-OH , N0l, 01 1 "* N~ '-- . R, 0 OH or or a pharmaceutically acceptable salt thereof. 10

9. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 15

10. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 20

11. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

12. A pharmaceutical composition comprising a pharmaceutically effective amount 25 of a compound of Claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

13. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 8, or a pharmaceutically acceptable salt thereof, and a 30 pharmaceutically acceptable carrier or excipient.

14. A compound of Claim 1 which is 4 -({ 3 -chloro-5-[(cyclopentylcarbonyl)amino] 2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 35 1

15 WO 99/43651 PCT/US99/03899 5 15. A compound of Claim 1 which is 4 -[(3-chloro-5-[(cyclopentylcarbonyl)amino] 2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.

16. A compound of Claim 1 which is 4 -[(3-chloro-5-[(cyclopentylcarbonyl)amino] 10 2-{ [(4-hydroxy-6-phenyl-2-pyrimidinyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.

17. A compound of Claim 1 which is 4-{[3-chloro-5-[(cyclopentylcarbonyl)amino] 2-({[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}methyl)-1H-indol-1-yl]methyl}benzoic acid or 15 a pharmaceutically acceptable salt thereof.

18. A compound of Claim 1 which is 4 -({3-chloro-5-[(cyclopentylcarbonyl)amino] 2-[(2,4-dibromophenoxy)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20

19. A compound of Claim 1 which is 4 -({3-chloro-5-[(cyclopentylcarbonyl)amino] 2-[(cyclopentylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 25

20. A compound of Claim 1 which is 4 -({3-chloro-5-[(cyclopentylcarbonyl)amino] 2-[(propylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

21. A compound of Claim 1 which is 4-({2-{[4-(tert-butyl)phenoxy]methyl}-3 30 chloro-5- [(cyclopentylcarbonyl)amino]- 1 H-indol- 1 -yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

22. A compound of Claim 1 which is 4 -({3-chloro-5-[(cyclopentylcarbonyl)amino] 2-[(2-quinolinylsulfanyl)methyl]- 1 H-indol- 1 -yl } methyl)benzoic acid or a pharmaceutically 35 acceptable salt thereof.

23. A compound of Claim 1 which is 4 -[(3-chloro-5-[(cyclopentylcarbonyl)amino] 2-{ [(cyclopropylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 40 116 WO 99/43651 PCT/US99/03899 5

24. A compound of Claim 1 which is 4 -({2-[(benzhydrylsulfanyl)methyl]-3-chloro 5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

25. A compound of Claim 1 which is 4 -({5-[(3-carboxypropanoyl)amino]-3 10 chloro-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

26. A compound of Claim 1 which is 4 -[(5-[(3-carboxypropanoyl)amino]-3-chloro 2-{[(3-methylbenzyl)sulfanyl]methyl } -1 H-indol- 1 -yl)methyl]benzoic acid or a 15 pharmaceutically acceptable salt thereof.

27. A compound of Claim 1 which is 4-({2-({ [4-(tert butyl)benzyl]sulfanyl Imethyl)-5-[(3-carboxypropanoyl)amino]-3-chloro-1H-indol- 1 yl }methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20

28. A compound of Claim 1 which is 4-({ 3-chloro-5-(3-furoylamino)-2- [(2 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 25

29. A compound of Claim 1 which is 4 -({5-(acetylamino)-3-chloro-2-[(2 naphthylsulfanyl)methyl]-1H-indol-1-yl methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

30. A compound of Claim 1 which is 4-({3-chloro-5-{[3 30 (diethylamino)propanoyl]amino } -2-[(2-naphthylsulfanyl)methyl]- 1 H-indol- 1 yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

31. A compound of Claim 1 which is 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(3-thienylcarbonyl)amino]- 1 H-indol- 1 -yl) methyl)benzoic acid or a pharmaceutically 35 acceptable salt thereof.

32. A compound of Claim 1 which is 4-({5-{ [(benzylamino)carbonyl]amino}-3 chloro-2- [(2-naphthylsulfanyl)methyl]- 1 H-indol- 1 -yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 40 117 WO 99/43651 PCT/US99/03899 5

33. A compound of Claim 1 which is 4-({5-{ [(butylamino)carbonyl]amino}-3 chloro-2-[(2-naphthylsulfanyl)methyl] - 1H-indol- 1-yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

34. A compound of Claim 1 which is 3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2 10 naphthylsulfanyl)methyl]-1H-indol-5-yl amino)carbonyl]benzoic acid or a pharmaceutically acceptable salt thereof.

35. A compound of Claim 1 which is 4-{[5-(benzyloxy)-2-[(E)-2-carboxyethenyl] 3-(2-naphthoyl)- 1H-indol-1-yl]methyl }benzoic acid or a pharmaceutically acceptable salt 15 thereof.

36. A compound of Claim 1 which is 4-({3-acetyl-5-(benzyloxy)-2-[(2 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20

37. A compound of Claim 1 which is 4-{[5-(benzyloxy)-2-[(2-naphthylsulfanyl) methyl]-3-(2,2,2-trifluoroacetyl)- 1 H-indol- 1 -yl]methyl I benzoic acid or a pharmaceutically acceptable salt thereof. 25

38. A compound of Claim 1 which is 4-({5-[(4-aminobutanoyl)amino]-3-chloro-2 [(2-naphthylsulfanyl)methyl]- 1 H-indol- l-yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

39. A compound of Claim 1 which is 4-({ 3-chloro-5-[(cyclopentylcarbonyl)amino] 30 2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-ylImethyl)benzoic acid or a pharmaceutically acceptable salt thereof.

40. A compound of Claim 1 which is 4-({ 3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(2-quinoxalinylcarbonyl)amino]-1H-indol-1-yl methyl)benzoic acid or a 35 pharmaceutically acceptable salt thereof.

41. A compound of Claim 1 which is 4-({3-chloro-5-[(2,2 dimethylpropanoyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 40 118 WO 99/43651 PCT/US99/03899 5

42. A compound of Claim 1 which is 4-({5-{ [(benzyloxy)carbonyl]amino 1-3 chloro-2- [(2-naphthylsulfanyl)methyl]- 1 H-indol- 1-yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

43. A compound of Claim 1 which is 4-({3-chloro-5-{ [(cyclopentyloxy)carbonyl] 10 amino } -2-[(2-naphthylsulfanyl)methyl]- 1 H-indol- l-yl} methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

44. A compound of Claim 1 which is 4-({5-(acetylamino)-3-chloro-2-[(2 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl } methyl)benzoic acid or a pharmaceutically 15 acceptable salt thereof.

45. A compound of Claim 1 which is 4-({5-{ [(butylamino)carbonyl]amino } -3 chloro-2-[(2-naphthylsulfanyl)methyl]- 1 H-indol- 1-yl} methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20

46. A compound of Claim 1 which is 4-({5-{ [(butylamino)carbonyl]amino}-3 chloro-2- [(2-naphthylsulfanyl)methyl]- 1 H-indol- 1-yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 25

47. A compound of Claim 1 which is 4-({3-chloro-5 [(morpholinocarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1 yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

48. A compound of Claim 1 which is 4-({5-(benzylamino)-3-chloro-2-[(2 30 naphthylsulfanyl)methyl]- 1H-indol- 1 -yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

49. A compound of Claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(3-phenoxybenzyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically 35 acceptable salt thereof.

50. A compound of Claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl) (methyl)amino]-2- [(2-naphthylsulfanyl)methyl]- 1 H-indol- 1 -yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 40 119 WO 99/43651 PCT/US99/03899 5

51. A compound of Claim 1 which is 4 -({5-[acetyl(benzyl)amino]-3-chloro-2-[(2 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

52. A compound of Claim 1 which is 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyl] 10 5-[(tetrahydro-3-furanylcarbonyl)amino]-1H-indol-1-yl methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

53. A compound of Claim 1 which is 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically 15 acceptable salt thereof.

54. A compound of Claim 1 which is 4-({ 3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(1-adamantylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 20

55. A compound of Claim 1 which is 3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2 naphthylsulfanyl)methyl]- 1H-indol-5-yl} amino)carbonyl]benzoic acid or a pharmaceutically acceptable salt thereof. 25

56. A compound of Claim 1 which is 4 -({3-chloro-2-[(2-naphthylsulfanyl)methyl] 5-[(3-phenylpropanoyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

57. A compound of Claim 1 which is 4 -({5-amino-3-chloro-2-[(2-naphthylsulfanyl) 30 methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

58. A compound of Claim 1 which is N-{3-chloro-1-(4-{ [(methylsulfonyl)amino] carbonyl}benzyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5 yl } cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 35

59. A compound of Claim 1 which is N-f 3-chloro-2-[(2-naphthylsulfanyl)methyl] 1-[4-({[(4-nitrophenyl)sulfonyl] amino carbonyl)benzyl]-1H-indol-5 yl } cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 120 WO 99/43651 PCT/US99/03899 5

60. A compound of Claim 1 which is N-{3-chloro-1-[4-({[(2-methylphenyl) sulfonyllamino } carbonyl)benzyl]-2-[(2-naphthylsulfanyl)methyl]- 1H-indol-5-yl } cyclo pentanecarboxamide or a pharmaceutically acceptable salt thereof.

61. A compound of Claim 1 which is N-[3-chloro-2-[(2-naphthylsulfanyl)methyl] 10 1-(4- { [(phenylsulfonyl)amino] carbonyl}benzyl)- 1 H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

62. A compound of Claim 1 which is N-{ 3-chloro-2-[(2-naphthylsulfanyl)methyl] 1-[4-({[(trifluoromethyl)sulfonyl] amino }carbonyl)benzyl]- 1H-indol-5 15 yl } cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

63. A compound of Claim 1 which is 4 -[5-[(cyclopentylcarbonyl)amino]-2-[(2 naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butanoic acid or a pharmaceutically acceptable salt thereof. 20

64. A compound of Claim 1 which is 4 -{5-[(cyclopentylcarbonyl)amino]-3 (morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoic acid or a pharmaceutically acceptable salt thereof. 25

65. A compound of Claim 1 which is N-[2-[(2-naphthyloxy)methyl]-1-(4-oxo-4 {[(trifluoromethyl)sulfonyl]amino butyl)-3-(1-pyrrolidinylcarbonyl)-1H-indol-5 yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

66. A compound of Claim 1 which is N-[3-(morpholinocarbonyl)-2-[(2 30 naphthyloxy)methyl]-1-(4-oxo-4-{ [(trifluoro-methyl)sulfonyl]amino } butyl)- 1 H-indol-5 yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

67. A compound of Claim 1 which is 5-[(cyclopentylcarbonyl)amino]-2-[(2 naphthyloxy)methyl]-1-(4-oxo-4-{ [(trifluoromethyl)sulfonyl]amino} butyl)- 1 H-indole-3 35 carboxylic acid or a pharmaceutically acceptable salt thereof.

68. A compound of Claim 1 which is 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H indol- l-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 40

69. A compound of Claim 1 which is 2-(4-{[5-(benzyloxy)-3-(2-naphthoyl)-1H indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 121 WO 99/43651 PCT/US99/03899 5

70. A compound of Claim 1 which is 2-[4-({5-(benzyloxy)-3-[3,5 bis(trifluoromethyl)benzoyl]- 1H-indol- 1-yl } methyl)phenyl] acetic acid or a pharmaceutically acceptable salt thereof. 10

71. A compound of Claim 1 which is 4-({3-benzoyl-5-(benzyloxy)-2-[(2 naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

72. A compound of Claim 1 which is 4-({5-(benzyloxy)-3-isobutyryl-2-[(2 15 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl } methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

73. A compound of Claim 1 which is 2-{3-acetyl-5-(benzyloxy)-2-[(2 naphthylsulfanyl)methyl]- 1H-indol- l-yl } acetic acid or a pharmaceutically acceptable salt 20 thereof.

74. A compound of Claim 1 which is 2-{5-(benzyloxy)-3-isobutyryl-2-[(2 naphthylsulfanyl)methyl]- 1 H-indol- 1-yl I acetic acid or a pharmaceutically acceptable salt thereof. 25

75. A compound of Claim 1 which is 4-{ 3-benzoyl-5-(benzyloxy)-2- [(2 naphthyloxy)methyl]- 1 H-indol- 1 -yl I butanoic acid or a pharmaceutically acceptable salt thereof.

76. A compound of Claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2 30 naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof.

77. A compound of Claim 1 which is 4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]-1H-indol-1-yl}-N-[3 35 ({ [(trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]butanamide or a pharmaceutically acceptable salt thereof.

78. A compound of Claim 1 which is 4-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1H-indol- 1 -yl }butanoyl)amino]benzoic acid or a pharmaceutically 40 acceptable salt thereof. 122 WO 99/43651 PCT/US99/03899 5

79. A compound of Claim 1 which is 2-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1-yl } butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof.

80. A compound of Claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2 10 naphthyloxy)methyl]-1H-indol-1-yl butanoyl)amino]propanoic acid or a pharmaceutically acceptable salt thereof.

81. A compound of Claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1-yl I butanoyl)amino]propanoic acid or a pharmaceutically 15 acceptable salt thereof.

82. A compound of Claim 1 which is N-(4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- IH-indol- 1-yl }butanoyl)-2-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof. 20

83. A compound of Claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1-yl I pentanoic acid or a pharmaceutically acceptable salt thereof.

84. A compound of Claim 1 which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2 25 naphthyloxy)methyl]-1H-indol-1-yl}pentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof.

85. A compound of Claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]-1H-indol-1-yl }-N-[3 30 ({ [(trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]pentanamide or a pharmaceutically acceptable salt thereof.

86. A compound of Claim 1 which is 2-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1 -yl) acetic acid or a pharmaceutically acceptable salt 35 thereof.

87. A compound of Claim 1 which is (E)-4-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]-1H-indol-1-yl}-2-butenoic acid or a pharmaceutically acceptable salt thereof. 40 123 WO 99/43651 PCT/US99/03899 5

88. A compound of Claim 1 which is 3-({3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1-yl I methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

89. A compound of Claim 1 which is 1-{ 1-[4-(1,3-benzothiazol-2 10 ylcarbonyl)benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl}I ethanone or a pharmaceutically acceptable salt thereof.

90. A compound of Claim 1 which is 1-{ 1-[3-(1,3-benzothiazol-2 ylcarbonyl)benzyl]-5-(benzylsulfanyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-3-yl} -1 15 ethanone or a pharmaceutically acceptable salt thereof.

91. A compound of Claim 1 which is 2-[3-({3-acetyl-5-(benzyloxy)-2-[(2 naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoyl]-1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. 20

92. A compound of Claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1H-indol- 1-yl }-2-oxopentanoic acid or a pharmaceutically acceptable salt thereof. 25

93. A compound of Claim 1 which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2 naphthyloxy)methyl]- 1 H-indol- 1 -yl }-2-oxopentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof.

94. A compound of Claim 1 which is 4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2 30 naphthyloxy)methyl]- 1 H-indol- 1 -yl }-2-oxopentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof.

95. A compound of Claim 1 which is 3-({4-[5-[(cyclopentylcarbonyl)amino]-2-[(2 naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butanoyl}amino)benzoic 35 acid or a pharmaceutically acceptable salt thereof.

96. A compound of Claim 1 which is 3-[(4-{5-[(cyclopentylcarbonyl)amino]-3 (morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yllbutanoyl)amino]benzoic acid 40 or a pharmaceutically acceptable salt thereof. 124 WO 99/43651 PCT/US99/03899 5

97. A compound of Claim 1 which is N-[2-[(2-naphthyloxy)methyl]-l-{4-oxo-4 [3-({ [(trifluoromethyl)sulfonyl]amino carbonyl)anilino]butyl}-3-(1 pyrrolidinylcarbonyl)- 1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 10

98. A compound of Claim 1 which is N-(3-(morpholinocarbonyl)-2-[(2 naphthyloxy)methyl]-1-{4-oxo-4-[3 ({ [(trifluoromethyl)sulfonyl]amino I carbonyl)anilino]butyl }-1 H-indol-5 yl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 15

99. A compound of Claim 1 which is 2-(4-{ [5-(benzyloxy)-3-(1-naphthoyl)-1H indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 20

100. A method of inhibiting the phospholipase activity of an enzyme in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 9.

101. A method of inhibiting the phospholipase activity of an enzyme in a mammalian 25 subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 10.

102. A method of inhibiting the phospholipase activity of an enzyme in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective 30 amount of a pharmaceutical composition of claim 11.

103. A method of inhibiting the phospholipase activity of an enzyme in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 12. 35

104. A method of inhibiting the phospholipase activity of an enzyme in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 13. 125 WO 99/43651 PCT/US99/03899 5

105. A method of treating an inflammatory response in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 9.

106. A method of treating an inflammatory response in a mammalian subject in need 10 thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 10.

107. A method of treating an inflammatory response in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a 15 pharmaceutical composition of claim 11.

108. A method of treating an inflammatory response in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 12. 20

109. A method of treating an inflammatory response in a mammalian subject in need thereof comprising adminstering to said subject a therapeutically effective amount of a pharmaceutical composition of claim 13. 25 126