MXPA00008295A

MXPA00008295A - Inhibitors of phospholipase enzymes

Info

Publication number: MXPA00008295A
Application number: MXPA/A/2000/008295A
Authority: MX
Inventors: Jasbir S Seehra; John C Mckew; Frank Lovering; Jean E Bemis; Yibin Xiang; Neelu Kaila
Original assignee: Genetics Institute Inc
Priority date: 1998-02-25
Filing date: 2000-08-24
Publication date: 2002-07-25

Abstract

Novel compounds are disclosed which inhibit the activity of phospholipase enzymes, particularly cytosolic phospholipase A2. Pharmaceutical compositions comprising such compounds and methods of treatment using such compositions are also disclosed.

Description

INHIBITORS OF FOSFOLIPASE ENZYMES Field of Invention The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes.

Background of the Invention Leukotrienes and prostaglandins are important mediators of inflammation, each of whose classes contributes to the development of an inflammatory response in a different way. Leukotrienes collect inflammatory cells such as neutrophils at an inflamed site, promote the extravasation of these cells and stimulate the release of super oxide and proteases that damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [see for example, B. Samuelson et al., Science, 237: 1171-76 (987)]. Prostaglandins increase inflammation when REF .: 122352 increase blood flow and therefore the infiltration of leukosites to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.

Prostaglandins and leukotrienes are unstable and are not stored in cells but instead are 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 the COX-1 and COX-2 oaks. Arachidonic acid is also the substrate for a different pathway of enzymes that leads to the production of lucotides.

The arachidonic acid that is fed in these two different inflammatory trajectories is released from the sn-2 position of the membrane phospholipids by the phospholipase A2 enzymes (hereinafter PLA2). The reaction catalyzed by PLA2 is thought to represent the rate-limiting step in the process of lipid-mediated biosynthesis and the production of inflammatory prostaglandin and leukotrienes. When the phospholipid substrate of PLA2 is of the choline phosphotidyl class, with an ether ligation at the sn-1 position, the produced ipsophospholipid is the immediate precursor of the platelet activating factor (hereinafter referred to as PAF), another potent mediator of inflammation [SI asserman, Hospital Practice, 15: 9-58 (1988)].

The majority of anti-inflammatory therapies have focused on preventing the production of prostaglandins or leukotrienes from these different trajectories, but not in all of them. For example, ibuprofen, aspirin and indomethacin are all NSAIDs which inhibit the production of prostaglandin by COX-l / COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in other pathways. Conversely, zileuton inhibits only the conversion path from arachidonic acid to leukotriene, without affecting the production of prostaglandin. None of these widely used anti-inflammatory agents affects the production of PAF.

Consequently direct inhibition of PLA2 activity has been suggested as a useful mechanism for a therapeutic agent, that is, to interfere with the inflammatory response, [see for example J. Chang et al, Biochem. Pharmacol., 36: 2429-2436 (1987)]. A family of enzymes of PLA2, characterized by the presence of a sequenced secretion signal and finally secreted from the cell, has been sequenced and structurally defined. These secreted PLA2 have a molecular weight of approximately 14kD and contain seven disulfide bonds that are necessary for activity these PLA2 are found in large quantities in the pancreas of 20 mammals, bee venom, and in various snake venoms. [see for example references 13-15 in Chang at al. Quoted above, and E.A. Dennis, Drug Devel. Res., 10: 205-220 (1987)]. However, the pancreatic enzyme is believed to be useful for a function ^ at ^^^ t ^,. . ,,, », ... .., ,,, ._ > ___, _, _, "w, t ,, A ^ Jto" ^ .. ",. "" "", ..., A "1, - ^ ^., Digestive and that as such should not and as such should not be important in the production of inflammatory mediators whose production should be strongly regulated.

The primary structure of the first non-pancreatic human PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, the synovial fluid, and the spleen and is also a segregated enzyme. This enzyme is a member of the family mentioned above [see for example J.J. Seilhamer et al., J. Biol. Chem., 264: 5335-5338 (1989); R. M. Kramer et al. J. Biol. Chem; 264: 5768-5775 (1989); and A. Kando et al, Biochem. Biophis. Res. Comm., 163: 42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandin, leukotrienes and PAF, since non-pancreatic PLA2 is an extra cellular protein that would be difficult to regulate, and the following enzymes in the biosynthetic path for these compounds are intracellular proteins. Furthermore, there is evidence that PLA2 is regulated by the protein kinase C and the G proteins [R. Burch and J. Axelrod, Proc. Nati Acad. Sci. U.S.A., 84: 6374-6378 (1989)] which are cytosolic proteins that must act on intracellular proteins. It would be impossible for non-pancreatic PLA2 to function in the cytosol since the high reduction potential would reduce disulfide bonds and inactivate the enzyme.

A murine PLA has been identified in the murine macrophage cell line designated RA 264.7. A specific activity of 2mol s / min / mg, resistant to reducing conditions, was reported to be associated with the approximately 60kD molecule. However, this protein is not purified until homogeneous. [see, C.C.Leslie et al, Biochem. Biophis. Acta., 963: 476-492 (1988)]. The references cited above are incorporated herein by reference for information regarding the function of phospholipase enzymes, particularly PLA.

A cytosolic phospholipase A2 (hereinafter "c PLA2") 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 they were fully established. The enzyme of these patents is an intracellular enzyme PLA2, purified from its natural source or otherwise produced in purified form, which functions intially to produce arachidonic acid in response to inflammatory stimuli.

Now that various phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, whose inhibitors can be used to treat inflammatory conditions, particularly where the inhibition of the production of prostaglandins, leukotrienes and PAFs are all desired results. . There remains a need in the art for the identification of such anti-inflammatory agents for therapeutic use in a variety of disease states.

Description of the invention The compounds of this invention have the following formulas where Ri and Ri are independently selected from H, halogen, CF3, -OH, -C1-C10 alkyl-, preferably C1-Cd alkyl, -S-C1-C10 alkyl, preferably -SC-C6 alkyl, C1-C10 alkoxy , preferably C 1 -C 6 alkoxy, phenyl -CN, -N 0 2 NH 2, -HN (CX-C 6), -N (C 6 -C 6) 2, phenyl -O-, phenyl -S-, benzyl, benzyl -O- , benzyl -S-, or a portion of the formulas: R6 is selected from H, CX-C6 alkyl, C6-C6 alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, phenyl and benzyl rings, of these groups being optionally substituted by from 1 to 3 selected substituents of .halogen, C? -C6 alkyl, alkoxy, C? -C6, -N02, NH2, -CN, -CF3, or -OH; R7 is selected from -OH, alkyl -CF3, C? -C6, C? -C6 alkoxy, -NH- (C? -C6 alkyl), -N- (Cx-C6 alkyl) 2, pyridinyl, tiethyl, furyl, pyrrolyl, phenyl, phenyl -0-, benzyl, benzyl -0-, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C? -C6 alkyl, C? -C6 alkoxy, - N02, -NH2, -CF3, or OH; R 2 is selected from H, halogen, -CF 3, -OH, C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, C 1 -C 10 alkoxy, preferably Ci-Cβ alkoxy, -CHO, -CN, -N02, alkyl- NH2, -NH-C? -C6, N (CX-C6 alkyl) 2, -NS02-Cx-C6 alkyl, or -S02-C? -C6 alkyl; R3 is selected from H, -CF3, C? -C6 lower alkyl, C? -C6 lower alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkylCi-Ce alkyl, -CHO, halogen, or a portion of the formula -L -M2: L2 indicates a linking or linking group of the formulas - (CH2) n-, -S-, -O-. -C (O) -, - (CH2) nC (O) -, - (CH2) nC (O) - (CH2) n-, - (CH2) n-0- (CH2) n-, or - (CH2) ) nS- (CH2) "-, -C (O) C (0) X; where X = 0, N More is selected from the group of lower alkyl C? -C6, lower alkoxy C? -C6, cycloalkyl C3? -C10, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen , Ci-Cio alkyl, preferably C 1 -C 3 alkyl, C 1 -C 6 alkoxy, preferably C 1 -C 6 alkoxy, -N 0 2, -NH 2, -CN, or -CF 3; or a) a five-membered heterocyclic ring containing one or two rings of heteroatoms selected from N, S or 0 including, but not limited to, furan, pyrrolo, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the heterocyclic ring of five members being optionally substituted by from 1 to 3 substituents selected from halogen, i-Cio alkyl, preferably, C?-C6 alkyl, C alcoC alco alkoxy, preferably Ci-Cd alkoxy, -N02, -NH2, -CN , 15 or -CF3; or b) a six-membered heterocyclic ring containing one, two or three rings of heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic rings optionally being substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, preferably * ^^ s ^ iB-§ «-a - a - j6i- ¿aa ^ -gki '..- fa i - *« *, &;, .i * * ** *. . . *** *? £ * - - - J "'" - "- * - * --- * - * • * * - **. ... -. F - Ufe ugly, **!. alkyl d-C6, C1-C10 alkoxy, preferably C6-C6 alkoxy, -CHO, N02, -NH2, -CN, -CF3 or OH; or c) a bicyclic ring portion containing from 8 to 10 atoms in the ring and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to, benzofuran, indole, indoline, naphthalene , purine, or quinoline, the bicyclic ring portion being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, preferably Ci-Ce alkyl, Cx-C? alkoxy, preferably Ci-Cß alkoxy, -CHO , N02, -NH, -CN, -CF3 or OH; or n is an integer from 0 to 3; R4 is selected from the group of lower alkyl C6-6, lower alkoxy C6-6, cycloalkyl- (CH2) n- C3-C6, cycloalkyl- (CH2) nS- (CH2) n-C3-C5, cycloalkyl- ( CH2) n-0- (CH2) n-C3-C5, or of the groups of: ^ A t jii- a) - (CH2) n-phenyl-O-phenyl, - (CH2) n-pheny1-CH2-phenyl, - (CH2) n-0-pheny1-CH2-pheny1, - ( CH2) n-pheni 1 - (0-CH2-phenyl) 2, - (CH:) n ~ phenyl 1 - (0-CH: - phenyl 1) 2, -CH: - phenyl-C (O) -benzothiazole or a portion of the formulas: wherein n is an integer, from 0 to 3, preferably from 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, Benzyl, naphthyl, pyridinyl, quinolyl, furyl, thianyl or pyrrolyl; the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -NH.sub.2, -N02, or a heterocyclic ring of five members containing a heteroatom selected from n, s, or 0, preferably S or 0; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: where D is H, C? -C6 lower alkyl, Cx-C6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyrinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen -CF3, -OH, alkyl -C? -C6, C6-C6 alkoxy, or -N02; or c) a portion of the formulas wherein Z is 0 or S and the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF3, -OH, C?-C6 alkyl, C?-C6 alkoxy, -NH2 , or -N02; ^ ^^^^^^ jg * g «j ^ gffl &to * R5 is selected from -COOH, -C (0) -COOH, (CH2) nC (0) -COOH, - (CH2) n -COOH, -CH = CH-COOH, (CH2) n-tetrazole. or a selected portion of the formulas -L -M; wherein L1 is a binding or binding portion selected from a chemical bond, - (CH2) n-, -S-, - 0-, -C (0) -, - (CH2) nC (0), - (CH2 ) nC (0) - (CH2) n, - (CH2) n-0-10 (CH2) n, - (CH.) "- S- (CH2), -C (Z) -N (R6) -, -C (0) -C (Z) - N (R6) - (CH2) n, -C (Z) -NH-S02-, or -C (Z) -NH-S02- (CH2) n, x is selected from the group of -COOH, - (CH2) n- C00H, - (CH2) n-C (0) -COOH, tetrazole, V. ^^^^^ where R8, R9 or Ri0 can be linked anywhere in the cyclic or bicyclic system, R8, in each presentation, is independently selected from H, -COOH, - (CH2) n-C00H, - (CH2) n-C (0) -COOH, tetrazole, * »T? ^ ". . £ & R9 is selected from H, halogen, -CF3, -OH, COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, alkyl -C? -C6, alkyl -0-C? -Ce , alkyl -NH (Ci-Cß alkyl), or -N (C?-C6 alkyl) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, alkyl -NH (C? -C6 alkyl) , N (C? -C6 alkyl) z, . N, "(lower alkyl C-C) lower alkyl C-C ' Rn is selected from H, lower alkyl Ci-Cβ, cycloalkyl C? -C6, "CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, ,. x A ^ + ^^^^^^^^^ j ^ «£ ^ ífejÍ * with the proviso that the full portion in position 1 of indole or indolina created by any combination of R5, R ?, Ro, Rio» / Ru may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: n is an integer from 0 to 3; or a pharmaceutically acceptable salt of the same.

It will be understood that in the above group that the substituents R3 and R are linked to the indol or indoline rings in the 2 or 3 position the Ri, Ri and R2 groups are bonded to one of the carbon atoms at positions 4-5. -, 6-, or 7- of the indol or indoline rings.

A group of compounds within this invention are those in which Ri- and R3 are hydrogen, and the substituents in the other indole or indoline positions are as described above.

Another group invention comprises compounds in which Ri and R3 are hydrogen and the groups Ri, R4 and R5 are as defined above. Within this group there are two additional preferred groups. In the first Ri is in the 5 position in indole or indoline and in the second Ri is in the position 6 in indole or indoline.

In a further preferred group here, Ri is in the 5-position in indole or indoline and is benzyloxy, R and R4 are hydrogen and R3 and R5 are as defined above.

In another preferred group of this invention Ri is in the 5 or 6 position in the indole or indoline and is cyclopentylcarboxamide or cyclopentylcarboxylate, R2 and R4 are hydrogen, and R3 and R5 are as defined above. - * • *. «...,» - - ^. . ... ^ ttg ^, ^ A preferred group of this invention consists of Ri and R2 at position 5 and / or 6 of the indole or indoline and each is selected from the group consisting of alkoxy Ci-Ce, cyano, sulfonyl and halo, R2 and R4 are hydrogen, and R5 and R5 are as defined above.

It will also be understood that these are additional preferred subgroups within each of the groups placed herein wherein the molecular core is an indole moiety, rather than an indoline. It will also be understood that this is a second group within each wherein the molecular core is an indoline moiety.

Preferred compounds of this invention include those of the following formulas: ; ... - * ti i? «& > & «< * - »« - where Ri is selected from H. halogen, -CF3, -OH, C? -C6 alkyl, C: -C6 alkoxy, -N0;, -HN (dC €), N (C? -C6 ) 2 »phenyl, phenyl-O-, benzyl, benzyl-O-, or a portion of the formulas: R6 is selected from H, Ci-Cß alkyl, Ci-Cß alkoxy, phenyl, -O-phenyl, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from Ci-Cg alkyl, C6-C6 alkoxy, -NH2, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) 2, - (CH2) n-NH- (C6-C6 alkyl), -CF3, C-alkyl? -C6, C3-C5 cycloalkyl, C? -C6 alkoxy, NH- (C? -C6 alkyl), -N- (C? -C6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl-O-, adamantyl or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cd alkyl, C6-C6 alkoxy, -NH2, -N02, -CF3, or -OH; R is selected from H, halogen, -CF 3, -OH, C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, C 1 -C 10 alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -CN, NO 2, -NH 2, - NH-Alkyl-Ci-Ce, N (C? -C6 alkyl) :, N-S02-alkyl- (CH2) n-0-phenyl-CH2-phenyl, or -S02-C? -C6 alkyl; R3 is selected from the group of lower alkyl C? -C6, lower alkoxy C? -C6, - (CH2) n-cycloalkyl C3-C6, - (CH2) nS-- (CH2) n- C3-C6 cycloalkyl, or groups of: a) - (CH2) n-phenyl-0-phenyl, - (CH2) n-pheni 1-CH2-phenyl, - (CH2) nf-enyl- (0-CH2-f-enyl) 2, -CH- phenyl-C (O) -benzothiazole or a portion of the formulas: ^ (CH2) n ^ ^ (CH2?. (CH2W (CH2 wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C6 alkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl; the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, Cx-C6 alkoxy, -NH2, -N02, or 5-membered heterocyclic ring, containing a heteroatom selected from N, S, or O, preferably, S or O; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: where D is H, C? -C6 lower alkyl, C? -C6 lower alkoxy, or -CF3; B and C are independently selected from the 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, alkyl -C i -Ce, C 1-6 alkoxy, or -N02; or c) a portion of the formulas wherein the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF 3, -OH, C 1 -C 6 alkoxy C 6 -C 6 alkyl, -NH 2, or -N 0 2; R 4 is selected from H, halogen, -Cf 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) -benzyl, CH2- (C3-C6 cycloalkyl), -C (0) -OH, -CH = 0, -C (O) -alkyl C? -C6, -C (O) -O-C? -C6 alkyl, -C (O) -CF3, - (CH) n-S-CH2- (C3-C6 cycloalkyl), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, Ci-Ce alkyl, Ci-Cβ alkoxy, -N02, -CF3, -C (0) -0H, or -OH; n is an integer from 0 to 3; R5 is selected from -COOH, -C (0) -COOH, CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, fifteen R8 is independently selected from H, halogen, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, tetrazole, R9 is selected from H, halogen, -CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, alkyl -NH (C? -C6 alkyl), or -N ('C6-C6 alkyl) 2; The Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkylC-C6, alkyl -0 -C? -C6, alkyl -NH (C? -C6 alkyl), N (C? -C6 alkyl) z, lower C] -Cg); Rn is selected from H, lower alkyl Ci-Ce, -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, or ^^^^^^^^ 2g ^ * iflj £ ¡^^ with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, R8,? , Rio / y or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: or a pharmaceutically acceptable salt thereof.

Preferred compounds of this invention include those of the following formulas: . * t 2 &8 M & amp; amp; amp; amp;, Ri is selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -N02, -HN2, phenyl, phenyl-O- , benzyl, benzyl-O-, or a portion of the formulas: R6 is selected from H, C? -C6 alkyl, C? -C6 alkoxy, phenyl, -O-phenyl, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 selected substituents of halogen, CX-C6 alkyl, C6-C6 alkoxy, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) :, - (CH2) p-NH- (at C 1 -C 6), -CF, C alkyl ? -C6, C3-C5 cycloalkyl, C? -C6 alkoxy, NH- (C? -C6 alkyl), -N- (C? -C6 alkyl) 2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, phenyl-O -, benzyl, benzyl-O-, adamantyl or morpholinyl, pyridyl, phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02 , -CF3, or -OH; R 2 is selected from H, halogen, -CF 3, -OH, Ci-Cι alkyl, preferably C 1 -C 6 alkyl, Ci-Cι alkoxy, preferably C 1 -C 6 alkoxy, -CHO, -CN, NO 2, -NH 2, - NH-alkyl-Ci-Ce, N (C-C6-alkyl) 2, N-S02-C-C6-alkyl, -S02-C-C6-alkyl; R 3 is selected from H, halogen, -CF 3, -OH, d-C 6 alkyl, C 1 -Cg alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) -benzyl, CH 2 - (C3-C5 cycloalkyl), -C (0) -OH, -CH = 0, -C (O) -Calkyl-C6, -C (O) -O-C? -C6 alkyl, - C (0) -CF3, - (CH2) nS-CH2- (C? -Calkyl C3-C5), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, -C0 (0) -0H, or -OH; n is an integer from 0 to 3; R4 is selected from the groups of lower alkyl Ci-Ce, lower alkoxy d-C6, - (CH2) n-cycloalkyl C3-C5, - (CH2) nS- (CH2) n-cycloalkyl C3-C5, - ( CH2) n-0- (CH2) n-cycloalkyl d-C6, or the groups of: a) - (CH2) nf -enyl-O-phenyl, - (CH2) n-phenyl-1-CH2-phenyl, - (CH2) n-0-pheny1-CH2-pheny1, - (CH2) n-phenyl- (0-CH: -phenyl) 2, - (CH 2) n -pheni 1- (0-CH 2 -pheni 1) 2, -CH 2 -phen 1-C (0) -benzothiazole or a portion of the formula s: wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C6 alkyl, phenyl, benzyl, naphthyl, pyridinyl, qumolyl, furyl, thienyl, or pyrrolyl; the rings of these groups are optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C3 alkyl, C? -C6 alkoxy, -N02, or 5 membered heterocyclic ring, containing a heteroatom selected from N, S, or O, preferably, S or O; or b) a portion of the formulas - (CH2) n-A, (CH;) n-S-A, or - (CH2) n-0-A, where A is the portion: where D is H, lower alkyl Ci-Ce, lower alkoxy d-C6, or -CF3, B and C are independently selected from the 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, alkyl -C? ~ C6, alkoxy C? -C6, or -N02; or a portion of the formulas «» »&». < & ** > - », •% ie a & He ^ J ^ ^ ^ ^ ^, - wherein Z is 0 or S and the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, or -N02; & ', R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, . ^ -Ate ^ te ^ R8 is independently selected from H, COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, tetrazole, Rg is selected from H, halogen, -CF3, -OH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -D-C6 alkyl, -OC-C6 alkyl, -NH (C6-C6 alkyl), or -N (C-alkyl) ? -C6) 2; Rio is selected from the group of H, halogen, -CF3, -OH, - (CH2) n-C00H, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6 , alkyl-NH (C 6 alkyl), N (d 6 alkyl) z, lower C -C), R n is selected from H, C 1 -C 6 lower alkyl, -CF 3, -COOH, - (CH 2) n -COOH, - (CH 2) n-C (O) -COOH, or with the proviso that the full portion in position 1 of indole or indoline created by any combination of R5, R8, R9, Rio? and / or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formula s: or a pharmaceutically acceptable salt thereof A group of compounds within this invention are those in which (R3) is in the 3-position is substituted only by hydrogen, and the substituents in the other indole or indoline positions are as described above.

Another group of this invention comprises compounds in which R2 are hydrogen and the groups Ri, R3, and R5 are as defined above. Within this group there are two additional preferred groups. In the first Ri is in position 5 in indole or indoline and in the second Ri is in position 6 in indole or indoline.

In a further preferred group here, Ri is in the 5-position in indole or indoline and is benzyloxy, R2 and are hydrogen and R3 and R5 are as defined above.

Another subset of compounds of this invention have the following formulas: wherein Ri is selected from H. halogen, -CF, -OH, C? -C6 alkyl, alkoxy dC?, -N02, -HN2, phenyl, phenyl-O-, benzyl, benzyl-O-, or a portion of The formulas : f? 6 R7 R6 is selected from H, C1-6alkyl, C6-C6alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from alkyl C? -C6, C? -C6 alkoxy, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) :, - (CH2) n-NH- (C6-C6 alkyl), "CF3, C-alkyl? ~ C6, C3-C5 cycloalkyl, C1- alkoxy, NH- (C6 alkyl), -N- (C1-C6 alkyl), pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl- O-, adamantyl or morpholinyl, the pyridinyl, phenyl and benzyl rings of these 5 groups being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-d alkyl, C? -C6 alkoxy, -N02, -CF3, or - OH; R2 is selected from H, halogen, -CF3, -OH, Ci-Cio alkyl, preferably Ci-d alkyl, Ci-Cio alkoxy, preferably C6-C6 alkoxy, -CHO, -CN, N02, -NH2, - NH-C 1 -C 6 alkyl, N (C 6 -C 6 alkyl), N-S 0 2 -alkyl- (CH 2) n-0-phenyl-CH 2 -phen 1, o-15 S0 2-C 1 -C 6 alkyl; R3 is selected from the group of lower alkyl Ci-Cβ, lower alkoxy C? -Cd, - (CH2) n- C3-C6 cycloalkyl, - (CH2) n-S-- (CH2) n- C3-C6 cycloalkyl, or groups of: a) - (CH2) n-phenyl-0-phenyl, - (CH2) n-pheni 1 -CH2-phenyl, - (CH: r.-Of enyl, - (CH2) n- (0-CH2 phenyl) 2, CH 2 -pheni 1-C (O) -benzothiazole or a portion of the formulas: wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is cyclo alkyl d-, phenyl benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl; the rings of these groups are optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, Ci-Ce alkoxy, -N02, or a 5-membered heterocyclic ring, containing a heteroatom selected from N, S, or O, preferably, S or O; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: wherein D is H, C 1 -C 6 lower alkyl, Ci-C 6 lower alkoxy, or -CF 3; B and C are independently selected from the 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, alkyl -Ci- CO, Ci-C6 alkoxy or -N02; or c) a portion of the formulas: wherein Z is 0 or S and the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF3, -OH, Ci-C6 alkyl, C6-C6 alkoxy, or -N02, -NH2; R 4 is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, dd alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (0) -phenyl, -C (0) -benzyl, CH 2 - (C3-C6 cycloalkyl), -C (0) -OH, -CH = 0, -C (O) -alkyl C? -C6, -C (O) -O-C alkyl? - C 6, -C (O) -CF 3, - (CH 2) n-S-CH 2 - (C 3 -C 6 cycloalkyl), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, d-C6 alkyl, C6-C6 alkoxy, -N02, -CF3, -CO (O) -OH, or - OH; n is an integer from 0 to 3; R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, - ^ ut * ^ s ^ JS ^ .- * ^^ -, or R8, is selected from H, -COOH, - (CH2) n -COOH, (CH2) n-C (O) -COOH, tetrazole, - Rg is selected from H, halogen, -CF3, -OH, (CH2) n -COOH, - (CH2) nC (O) -COOH, -d-C-alkyl, -0-C-C6 alkyl, -NH ( C 1 -C 6 alkyl), or -N (ci-c 6 alkyl) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n-COOH, - (CH2) nC (O) -COOH, -C1-C6 alkyl, -0-C-C6 alkyl, -NH (C6-C6 alkyl), N (C? -C6 alkyl) 2, i or lower C.-C-); Rn is selected from H, lower alkyl C? ~ D, -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, or with the proviso that the entire portion at position 1 created by any combination of R5, Re, R9, Rio »and or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: . . 1 or a pharmaceutically acceptable salt thereof.

Among the additionally preferred compounds of this invention are those having the formulas: wherein Ri is selected from -HN2, phenyl, phenyl-O-, benzyl, benzyl-O-, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl or a portion of the formulas: R6 is selected from H, C? -C6 alkyl, C? -C6 alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 selected substituents of C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (d-C6 alkyl) 2, - (CH2) n-NH- (C 1 -C 6 alkyl), -CF 3, C 1 alkyl- C6, C3-C5 cycloalkyl, C6-C6 alkoxy, -NH- (C6-C6 alkyl), -N- (C6-C6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl-O-, adamantyl or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C? -C6 alkyl, d-C6 alkoxy,? N02, -CF3, or -OH; n is an integer from 0 to 3; R 3 is selected from halogen, C 1-4 alkyl, C? -C6 alkoxy, -CF3, -CH = 0, -C (O) -C? -C6 alkyl, -C (0) -0- C? -C6 alkyl, - C (0) -OH, -C (0) -CF3, -C (O) -phenyl, -C (O) -benzyl, -C (O) -pyrrolyl, -C (O) -thienyl, -C (O) -furanyl, or -C (0) -moefolinyl; R4 is selected from the group of, - (CH2) n- (cycloalkyl d-), - (CH2) nS- (CH2) n- (cycloalkyl C3-C6), - (CH2) n-0- (CH2) n - (C3-C6 cycloalkyl), (CH2) nS- C6-C6 alkyl, the groups of: . " . . «* -» -. . * "*,. - * ». "-. _a-A - «-. j. ~ *. ,, - > -t, - ^ -a -a «ate ^ & -» a) -C (O) -O- (CH2) n-cycloalkyl, - (CH2) n-phenyl, - (CH2) nO-phenyl, - ( CH2) nS-phenyle, - (CH2) nS- (CH2) n-phenyl, - (CH2) n-phenyl-O-phenyle, - (CH2) n-phenyl-CH2-f enyl, - (CH2) n-0- phenyi-CH2-phenylo, (CH2) n-phenyl- (0-CH2-phenyl) 2, -C (O) -O- phenyle, C (0) -O-benzyl, -C (0) -0-p? Rdidyl, -C (0) -0-naphthyl, - (CH2) nS-naphthyl, - (CH2) nS-pi r idini lo , - (CH2) n-pyridinyl, or - (CH2) n-na ft i lo, - (CH2) n-0-naphthyl, the phenyl, pyridinyl, and naphthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C alquilo-d alkyl, Ci-Cd alkoxy, -N02, or a ring containing five heterocyclic heteroatom members, selected from N, S, or 0, preferably S, or 0; or b) a portion of the formulas - (CH2) n_A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: wherein D is H, C 1 -C 6 lower alkyl, C 6 -C 6 alkoxy, • CF 3 ' R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, , 0 R8 is selected from H, -COOH, - (CH2) n -COOH, (CH2) n-C (O) -COOH, tetrazole, Rg is selected from H, halogen, -CF3, -OH, (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (C? -C6 alkyl), or -N (C? -C6 alkyl) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) n "(O) -COOH, alkyl -dd, alkyl-0-C? -C6, -NH (C? -C6 alkyl), N (C? -C6 alkyl) 2, (lower alkyl C -C . * «*. . ^. ,, », ^". ^^^^ g ^^ t Rn is selected from H, lower alkyl C? ~ C6, • CF3, -COOH, - (CH2) n -COOH, - (CH2) n ~ C (0) -COOH, or with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, R8, Rg, Rio, and / or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole , or a portion of the formulas: or a pharmaceutically acceptable salt thereof Detailed Description of the Preferred Modalities.

As used herein, the terms "aryl" and "substituted aryl" will be understood to include monocyclic ring portions, particularly including five and six membered monocyclics, aromatics and heteroaromatics and aromatic and heteroaromatic bicyclic ring portions, particularly including those which they have from 9 to 10 atoms in the ring. Among these aryl groups it will be understood that they are phenyl ring, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such portions. The aryl and heteroaryl groups of this invention also include the following: a) a ring of five heterocyclic members containing one or two heteroatoms in the ring selected from N, S or 0 including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrrolma, imide zol idina, pyrazol idine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or b) a six-membered heterocyclic ring containing one, two or three heteroatoms in the selected ring of N, S or 0 including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine; or c) a bicyclic ring portion optionally containing from 1 to 3 heteroatoms in the ring selected from N, S or O including, but not limited to, benzofuran, chromene, indole, isoindole, indoline, isoindylin, naphthalene, purine, indolizine , indazole, quinoline, isoquinoline, quinolizine, quinazoline, phthalazine, 15 or naphthyridine.

The "substituted aryl" groups of this invention include such portions which are optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, preferably Ci-C alquilo alkyl, Ci-C alco alkoxy, preferably Ci-d alkoxy , -CHO, -COOH or esters thereof, N02, -NH2, -CN, CF3 or -OH or combinations thereof, such as -CH2CF3, 25 NH (CH3), etc. > - ^ »« «- w &« «. ^ Tt? Naia? A» ai¿í? Maa ^ -. *, ** * ** "f s,, *",,. *, ^., ...... I ?? Ar t, M ^ -, ....,. ...? - * i? ai ^^ A preferred subset of these groups, optionally substituted as described, includes portions formed from benzene, pyridine, naphthylene or quinoline rings. A further preferred group includes those of furan rings pyrrole, thiophene, pyrimidine and morpholine. A preferred group of aromatic and cyclic groups includes benzofuran, indole, naphthalene and quinoline rings.

The alkenyl and alkynyl alkyl groups referred to herein indicate such groups having from 1 to 10 preferably from 1 to 6 carbon atoms and may be linear, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be linear or branched. The halogens herein are understood to include F, Cl, Br, and I.

As used herein, "phospholipase enzyme activity" means the positive activity in an assay for phospholipid metabolism (preferably one of the assays described in Example 86 below.) A compound has "phospholipase enzyme inhibitory activity". when in > the activity of a phospholipase (preferably c PLA2) in some available assay (preferably an assay described below in example 86 or example 87) for enzyme activity In the preferred embodiments a compound has (1) value IC50 of less than about 25μM, preferably less than about 6μM, and the lysoPC assay, (2) an Ido value of less than about 50μM in the vesicle assay, (3) an Ido value of less than about lμM in the PMN test, (4) an IC5o value of less than about 15μM in the coumarin test, and / or (5) a measurable activity (preferably at least about 5% reduction in the adema, more preferably at least alred 10% reduction, more preferably at least about 15%, and more preferably 20-30%) in the carrageenan-induced edema test in the rat paw.

The compounds of the present invention are useful for inhibiting the activity of phospholipase enzyme (preferably cPLA2) and therefore, are useful in the "treatment" (ie treatment prevention or decrease) of the Inflammatory or inflammatory-related responses or conditions (eg rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other conditions mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, atrophy and art heroes clerics is.

The present invention encompasses pharmaceutical compositions and therapeutic methods of treatment or use which compounds of the present invention are employed.

The compounds of the present invention can be used in a pharmaceutical composition when combined with pharmaceutically acceptable carrier. Such a composition may also 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 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. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may also contain other anti-inflammatory agents. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with the compounds of the present invention, or to minimize the side effects caused by the compound of the present invention.

The pharmaceutical composition of the invention can be in the form of a liposome, in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with amphiphilic agents such as lipids that exist in aggregated form such as miselos, insoluble monolayers, crystals liquids or lamellar layers in aqueous solution. Suitable lipids for the formulation of liposomes include without limitation, monoglycerides and glycerides, sulfatides, li solecy t ina, phospholipids, saponin, villi acids and the like. The preparation of such liposome formulations is within the skill level in the art, as described, for example, in US Patent Nos. 4,235,871; 4,501,728; 4,837,028; and 4,737,323, all. which are incorporated here as a 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 significant benefit to the patient, ie, treatment, cure, prevention or diminution of a response or inflammatory condition or an increase in the speed of treatment cure, prevention or reduction of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient only. When applied to a combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. ' - - * '•, - • • - * "* i-rt-n- í i I-I" t "atn- - *« »« * .-, < »-,. -, *, -. > > .. .--- - .., ..._ »". . When the method of treatment or use of the present invention is practiced, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated.The compounds of the present invention are they can be administered according to the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, when co-administered with one or more of other anti-inflammatory agents, cytokines, lymphokines or other hematofibody factors, the compounds of the present invention can be administered either simultaneously with the other anti-inflammatory agents, cytokines, lymphokines, other hematofoetic factors, t-rombolit icos or thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administration of the compounds of the present invention in combination with other anti-inflammatory agents, cytokines, lymphokines, others . , T rt, r f,., I ^ rflr - - hema factors, t ombolics, or ant thrombotic factors.

The administration of the 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 forms, such as oral ingestion, inhalation, or cutaneous, subcutaneous or intravenous injection. .

When a therapeutically effective amount of the compounds of the present invention is administered orally, the 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 adjuvant. The tablet, capsule and powder contain from about 5 to 95% of the compound of the present invention and preferably from about 25 to 90% of the compound of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, animal or vegetable oils such as peanut oil, mineral oil, soybean oil or sesame oil or synthetic oil may be added. The liquid form of the pharmaceutical composition may further contain a physiological saline solution, dextrose or other solution of saccharides, 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 the compound of the present invention and preferably from about 1 to 50% of the compound of the present invention.

When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, the compounds of the present invention will be in the form of a parenterally acceptable aqueous solution., free of pyrogens. The preparation of such parenterally acceptable protein solutions, having a proper reference to pH, ionicity, stability and the like, are within the skill in the art. A preferred pharmaceutical composition for an intravenous, cutaneous or subcutaneous injection should contain in addition to the compounds of the present invention, an isotonic vehicle such as sodium chloride injection, ringer injection, dextrose injection, dextrose injection and sodium chloride, lactated ringer injection, or other vehicle such as those known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art.

The amount of compounds of the present invention in the pharmaceutical composition of the present invention will depend on the nature and severity of the condition being treated, and on the nature of the previous treatments that patients have undergone. Finally, the attending physician will decide the amount the amount of compound of the present invention with which to treat each patient individually. Imcially the attending physician will administer low doses of the compound of the present invention and observe the patient's response. The higher doses of compounds of the present invention can be administered until an optimal therapeutic effect is obtained by the patient and at the point where the dose is no longer increased. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain from about 0.1 μg to about 100 mg (preferably around 0. lmg to about 50 mg, more preferably about lmg to about 2 mg) of the compound of the present invention per kilogram of body weight.

The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease to be treated and the condition and potential uncharacteristic response of each patient individually. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 24 hours of continuous intravenous administration. Finally, the attending physician will decide on the appropriate duration of intravenous therapy - "• * - '" ^ -' - • - "* * - using the pharmaceutical composition of the present invention.

The compounds of the present invention can be made according to the methods and examples described below. The synthesis of the preferred compounds of the present invention are described below.

Method A Ethyl 5-nitro-2-carboxylate indole was chlorinated in the 3-position by the addition of N-chlorosuccinamide in a solvent such as DMF or DMSO at an elevated temperature of 40 ° C-80 ° C. The ester was then reduced in a 3-step procedure. First the ester is hydrolyzed under basic conditions with a base such as sodium hydroxide or potassium hydroxide in a solvent system such as water: methanol: THF. The acid was then activated by the addition of carbonyl diimizole in THF and reduced with a reducing agent such as sodium borohydride or sodium triacetoxy borohydride in an alcohol solvent system such as methanol or ethanol. The resulting alcohol was protected as the TBDMS ether with TBDMSCI in a solvent such as DMF, methylene chloride or THF with a base such as triethylamine or imidazole. The indole nitrogen was then alkyl with 4-bromomethylbenzene or methyl in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, n-BuLi or potassium amide of bis (t-rimet-lysilyl) ). The 5-nitro group was then reduced by exposure to H2 in the presence of a catalyst such as a Pt / C or Pd / C in a solvent such as ethyl acetate, methanol or THF or a mixture of two or all three. The amine was then acylated with cyclopentylcarbonyl chloride in a biphasic saturated sodium bicarbonate and methylene chloride system. The Rl was then introduced into a two-step procedure wherein the TBDMS ether was converted to a bromide by exposure with dibromotriphenyl phosphorane in methylene chloride and then the crude bromide was displaced by a variety of thiols or phenols in such a solvent as THF, methylene chloride or DMF in the presence of a base such as potassium carbonate or cesium carbonate. The product esters were then prepared by hydrolysis of the ester under basic conditions with sodium hydroxide in a solvent system such as water: MeOH: THF.

Method B Acylation at the 3-position of indole I with acylating agent such as naphthoyl chloride, could be achieved using the ethyl magnesium bromide in a solvent such as THF to give II. The alkylation of indole nitrogen could be achieved by exposure with an appropriate base such as sodium hydride followed by treatment with the appropriate one. The deprotection of the hydroxy protecting group with fluoride of tetrabutylammonium and oxidation with an appropriate oxidizing agent, I provide the IV. A reaction of Horner Wittig with t-hemethoxy fos phonoacetate in an appropriate solvent such as tetrahydrofuran gave the ester unsaturated V which could be deprotected in position one of the indole with an appropriate reagent system such as hydrofluoric acid in acetonitrile. Saponification of the remaining acid group gave compound VI. 25 Method C Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as 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 a Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -60 ° C, acylation of the resulting magnesium salt with an appropriate acyl chloride such as acetyl chloride in ether and finally, alkylation in nitrogen with an alkyl halide such as methyl (4-bromomethyl) benzoate in the presence of a strong base such as NaH in DMF results in the ketone III. The cylyl 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 bi s (difeni 1 fos) ethane in a solvent such as dichloromethane for produce bromine IV. The displacement of IV bromide with a thiol compound in the presence of a base such as cesium carbonate, or with an alcohol in íaSe-S -f .--. ffi, l, * ** * ",. i, tl ^ t. " . ^ nr-r ,, •? »- *" - ,,,. - * .- *,. ._ ..,. «". . ^. ^. ^ ..... the presence of a strong base such as NaH in DMF results in V (sulfur or ether respectively).

Method D The protected alcohol was deprotected in an appropriate solvent such as THF and the resulting alcohol was functionalized to a halide using carbon tetrabromide or methanesulfonyl chloride and then reacted with an oxygen nucleophile, coupled with a previous deprotonation with a strong base such as sodium hydride or a sulfur ucleophil in the presence of c.sub.-io carbonate in DMF or THF. The nitro group could then be reduced to an amine by means of the Pt / carbon hydrogenation protocol or the sodium borohydride procedure of the copper acetate. The resulting amine could be hydrolysed using a standard procedure of sodium hydroxide in THF / MeOH or coupled to a variety of acylating reagents such as acid chloride, chloroformates and isocyanates wherein the reactions are generally carried out in the presence of a base in a solvent such as THF or dichloromethane. The amine could also be ~? '^ "* ^ -' ~ - '~ * -' - '-« - ^ .., #, 1,1 -,, I «t -'i ....),.", -. .. ,, ».. ... * .. ^. ^. ^ ... ^ ** ,,. * A., .. ^^^ -... m,,". * .. .. .. ^ ..,.,. ,, ",.,", _ {. «A -. ^ .. acylating by means of an EDCI coupling process with a variety of acids. The starting amine could also be alkylated by a reductive amination procedure using a variety of sodium aldehydes and triacetoxyborohydride as a reducing agent. These functional amines could be hydrolyzed to result in the desired acids which could also be converted to the acyl sulfonamide by EDCI coupling with a sulfonamine. Alternatively, the functionalized amines could be further alkylated by reaction with a strong base and an alkyl halide and then hydrolysed under normal conditions to produce the required product.

Method E The starting indole, with or without the C2 substitution, was functionalized to C3 by the use of DMF / POC13 conditions or the magnesium salt of the indole was acylated with a variety of acid chlorides to form the ketones. These products were then N-alkylated by the action of a strong base and a variety of alkyl or haloaryl esters. When R 'is a nitro group, at this 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 isocyanates, chloroformiates, alkylated acid chlorides in a reductive way with amines or coupled with acids. The resulting esters were hydrolyzed to the desired acids which could also be converted to the acyl sulfonamide.

Method A ! > apl thioether alkyl thioether alkyl ether alkyl ether Method B OMc Method C DLiAlH. THF 2) TBD SCI. Imidazole FTSH, CSC03 \ R "'OH, NaH or K, C03 .--. "'- *" * - * - Method D h '* "in carbon Method E EDCI? .NSO, R - E emplo 1 Acid 4- ( { 3-Chloro-5- [(cyclopentylcarbonyl) amino] -2- [(phenethylsulfanyl) methyl] -1H-indole-1-yl.} - methyl) benzoic Step 1 - 5-Ni t -roindol-2-ethyl carboxylate (21.1 g) was dissolved in DMF (500 mL). To this dark brown solution, a solution of N-chlorosuccinamide (12 g in 125 mL of DMF) was added over a period of 5 minutes, the reaction mixture was heated to 50 ° C for 1.5 hours. It was determined that the reaction was completed 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 MgSO4, filtered and concentrated. The result was the desired ethyl ester (96 g of moisture with DMF) which was carried out in the next step without further purification.

Step 2 - Ethyl ester was dissolved in methanol (400 mL) and THF (800 mL). To this clear brown solution, 2N NaOH (450 mL) was added. The black mixture was stirred at room temperature overnight. The reaction was not fully completed (TLC) therefore, an additional 7.2 g of NaOH pellets was added. After 7 hours, 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 2N HCl to pH 2. The mixture was then extracted with ethyl acetate (3 X 1 L). The combined organic layers were dried over MgSO4, filtered and concentrated to give the acid (24.3 g, 100%) as a brown solid.

Step 3 - Carboxylic acid (24 g) was dissolved in THF (700 mL). CDI (16.2 g) was added to this clear amber solution. The mixture was stirred at room temperature for 1.5 hours, during which time it became a light brown suspension. The reaction was cooled in an ice bath. Sodium borohydride (10.8 g) was slowly added. Ethanol (140 mL) was then added. A gas evolution was observed. After 2 hours, the TLC analysis indicated that the reaction was complete. To adjust the pH to 2, 2N HCl was added. The reaction was then extracted with ethyl acetate (3 X 600 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to yield the desired alcohol (28.5 g) as a brown solid.

Step 4 - The alcohol prepared above (25.4 g), imidazole (18.6 g), and tert-butyldimethylsilyl chloride (13.3 g) was dissolved in DMF (350 mL). The reaction was stirred overnight and found to be incomplete. Therefore, imidazole (18.7 g) and t-butyldimethylsilyl chloride (18.6 g) were added. After 1 hour, the reaction was complete. 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 protected alcohol in crude 5- tert-butyldimethyl. The crude material was dissolved in ethyl acetate, absorbed on silica gel, and evaporated to dryness. After filling in a column of silica gel and eluting with 15% ethyl acetate in hexane, the desired protected alcohol (18.5 g, 69% of step 1) was isolated as bright yellow crystals.

- "** '•"' * - '-: H "- - - ~ - - - --- - -t .- .t« i jAv ".-.- tt ... - - __. , "» ..._ .. "." ... i .. "•» •. »- Step 5 - The alcohol protected in tert-butyldimethylsilyl (1.0 g) was dissolved in DMF (10 g). mL). The yellow solution was cooled in an ice bath. Sodium hydride (147 mg) was added. After 15 minutes, 4- (bromomet i 1) benzoate (807 mg) was added to the dark red solution. After 15 minutes, TLC analysis indicated that the reaction was complete. The reaction was emptied into cold IN HCl. Water (100 mL) was added and the solution was extracted with ethyl acetate. The combined organic layers were evaporated to dry to give the crude N-alkylated indole as an orange solid. The crude solid was absorbed in silica gel, added to a column of silica gel and eluted with 15% ethyl acetate in hexanes to give the desired N-alkylated indole (1.05 g, 73%) as a yellow solid. i lio.

Step 6 - The N-alkylated indole (3.8 g) was dissolved in THF (50 mL) and 5% Pt / C (1.6 g) was added. The hydrogen was purged 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.

Step 7 - To a solution of the above amine (1.6 g, 3.5 mmol) in CH2C12 (10 mL) and saturated sodium bicarbonate (10 mL) was added cyclopentyl carbonyl chloride (0.467 mL, 1.1 equivalent). The reaction was stirred 45 minutes, 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) provided the desired product (1.55 g, 82%) as a pale yellow oil.

Step 8 - To a solution of the above amide (0.6 g, 1.1 mmol) in dichloromethane (3 mL) at 0 ° C, was added dibromotr i feni 1 fos forane (0.5 g, 1.1 equivalents). The reaction was stirred at room temperature for 2 hours, taken up in ethyl acetate (50 mL), washed with brine (3 X 10 mL), dried (MgSO4) and concentrated and taken immediately to the next step.

Step 9 - To a solution of the crude bromide prepared above (0.54 mmol) in DMF «« »***« - »" "(2 mL, degassed) was added phenylethyl mercaptan (0.08 g, 1.1 equivalents) followed by cesium carbonate (0.21 g, 1.2 equivalents). The reaction was stirred 1 hour, taken up in ethyl acetate (20 mL), washed with brine (3 X 5 mL), dried (MgSO 4), filtered and concentrated. Chromatography (25% ethyl acetate / hexanes) provided the desired compound (0.17 g, 56%) as a colorless oil.

Step 10 - To a solution of the above ester in THF (1 mL) and MeOH (0.5 mL) was added NaOH (0.28 mL, 5 M, 5 equivalents). The reaction was stirred 4 hours, acidified with sodium biphosphate, emptied into ethyl acetate, washed with brine and dried (MgSO4). The title compound (0.157, 98%) was triturated from ethyl acetate with hexanes.

Each of the compounds of the following Examples 2 to 11 were 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.

EXAMPLE 2 4- [(3-Chloro-5- [(cyclopentylcarbonyl) amino] -2 { [(2-furylmethyl) sulfanyl-ethyl] -lH-indol-1-yl) -methyl] -benzoic acid.

EXAMPLE 3 4- [(3-Chloro-5- [(cyclopentylcarbonyl) amino] -2 { [(4-hydroxy-6-phenyl-2-pyrimidinyl) sulfanyl] methyl} -lH-indole-1 -yl) methyl] benzoic.

Example 4 Acid 4-. { [3-chloro-5- [(cyclopentylcarbonyl) amino] 2- ( { [4- (2-thienyl) -2-pyrimidinyl] sulfanyl} methyl) -lH-indol-1-yl] methyl} benzoic Example 5 4- (. {3-Chloro-5- [(cyclopentylcarbonyl) amino] -2- [(2,4-dibromophenoxy) methyl] -H-indol-1-yl} methyl) benzoic acid.

Example 6: 4- ( { 3-Chloro-5- [(cyclopentylcarbonyl) amino] • 2- [(cyclopentyl sulfanyl) methyl] -lH-indol-1- »il} methyl) benzoic.

EXAMPLE 7 4- (. {3-Chloro-5- [(cyclopentylcarbonyl) amino] 2- [(propyl sulfanyl) methyl] -lH-indol-1-yl] methyl) benzoic acid.

Example 8: 4- ( { 2- { [4- (tert-Butyl) phenoxy] methyl.} - 3-chloro-5- [(cyclopentylcarbonyl) amino] -lH-indol-1-10-yl. .}. methyl) benzoic acid.

EXAMPLE 9 4- (. {3-Chloro-5- [(cyclopentylcarbonyl) amino] -2- [(2-guinolinyl-sul-anil) -methyl] -lH-indol-1-yl} -methyl) -benzoic acid.

EXAMPLE 10 4- [(3-Chloro-5- [(cyclopentylcarbonyl) amino] -2- {. [(Cyclopropylmethyl) sulfanyl] methyl} - lH-indol-1-yl) methyl] benzo co.

EXAMPLE 11 4- (. {2- [(Benzhydryl sulphyl) methyl] -3-chloro-5- [(cyclopentylcarbonyl) amino] -lH-indol-1-yl] methyl] benzoic acid.

^^^^ Hg ^ The compounds of the following Examples 12 to 14 were prepared by: Step 1 - The material prepared in Example 1, step 6, was acylated in position 5 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 to 10, using the appropriate thiol.

Example 12 4- ( { 5- [(3-carboxypropanoyl) amino] -3-chloro-2- [(phenethylsulfanyl) methyl] -lH-indol-1-yl] methyl) benzoic acid.

EXAMPLE 13 4- [(5- [(3-Carboxypropanoyl) amino] -3-chloro-2. {[[(3-methylbenzyl) sulfanyl-Jethyl} -1H-indol-1-yl) methyl] -benzoic acid .

Example 14 & amp; & amp; & amp; < 4 > 4- (. {2- ( { [4-tert-butyl) benzyl] sulfanyl}. Methyl) -5- [(3- carboxypropanoyl) amino] -3-chloro-lH-indol-1-yl} methyl) benzoic.

EXAMPLE 15 4- (. {3-Chloro-5- (3-furoylamino) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} yl) benzoic acid. The title compound was prepared as described in Example 43 using the appropriate acylating reagent.

The following Examples 17 to 21 were prepared as described in Example 43 using the appropriate acylating reagent.

Example 17 Acid 4- ( { 3-Chloro-5-. {[[3- (diethylamino) propanoyl] amino} -2- [(2-naphsulfanyl) methyl] -lH-indole- il.}. me il) benzoic Example 18 4- (. {3-Chloro-2- [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -lH-indol-1-yl} ethyl) benzoic acid.

EXAMPLE 19 4- ( { 5. {[[(Benzylamino) carbonyl] amino]} -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl}. methyl) benzoic.

EXAMPLE 20 4 - (. {5- [{[[(Butylamino) carbonyl] amino]} - 3-chloro-2- [(2-naphthyl sulfanyl) methyl] -lH-indol-1-yl} acid. methyl) benzoic Example 21 3- [(. {1- (4-carboxybenzyl) -3-chloro-2- [(2-naphthyl sulfanyl) methyl] -lH-indol-5-yl} amino) carbonyl] benzoic acid.

Example 22 Acid 4-. { [5- (benzyloxy) -2- [(E) -2-carboxylethenyl] -3- (2-naphthoyl) -1H-indol-1-yl] methyl} benzoic Step 1 A solution of 2 (tert-butyldimethylsilyloxymethyl) -5-benzyloxyindole (2.0 g, 5.4 mmol) in anhydrous ether (10 ml) was cooled to -78 ° C and a solution of ethylmagnesium bromide (3.0M) was added. in ether, 4.0 ml, 12.0 mmol) dropwise. The mixture was stirred at -60 ° C to -65 ° C for 2 hours during which time the homogeneous solution became a thick yellow mixture. A solution of naphthoyl chloride (2.28 g, 12.0 mmol) in ether (8 ml) was then added. After stirring for 2 hours at -60 ° C to -40 ° C, the reaction mixture 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 / Acet ona, 6/1) gave 2.2 g (78%) of 17 as a yellow foam.

Step 2 To a solution cooled on ice (0 ° C) of the previous intermediate (1.0 g, 1.9 mmol) in DMF (10 ml) was added sodium hydride (0.12 g, 2.1 mmol). The ice bath was removed after 10 g ^^ .- ^ .- ^ .- ^^^ - ^ - ^ - ,,; ^, ^, - ^^,! ^^^, !!!!!!!!! ^, !! !!!!!!!!! ^^, ^ * ^^^ minutes and the reaction was stirred at room temperature for 30 minutes at which time the bromomethyl ether SEM (0.5 ml, 2.8 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h, 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) gave 1.22 g (81%) of the desired intermediate as an off white foam.

Step 3 To a solution of the previous one (6.6 g, 8.4 mmol) in THF (80 ml) was added tetrabutylammonium fluoride (1.0 M in THF, 21 ml). The reaction was stirred at room temperature for 2 hours, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography (Hex / EtOAc, 4: 1) gave 3.8 g (67%) of the alcohol as a thick, colorless oil. The alcohol was dissolved in THF (50 ml) and Mn02 (5.5 g, 63.2 mmol) was added. The reaction was stirred for 22 hours and filtered through a pad of celite. The concentration of the filtrate gave 3.7 g (96%) of the desired intermediate as a light yellow foam.

Step 4 To a solution cooled with ice (0 ° C) of trimethyl-ilphosphonoacetate (0.12 ml, 0.7 mmol) in DMF (5 ml) was added sodium hydride (0.027 g, 0.8 mmol). After 30 minutes, a solution of the above intermediate (0.5 g, 0.7 mmol) in 5 ml of DMF was added. The ice bath was removed and the reaction allowed to remain overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. Flash chromatography (Hex / EtOAc, 3/2) gave 0.2 g of the desired intermediate (37%) as a white foam.

Step 5 Acid 4-. { [5- (benzyloxy) -2- [(E) -2-carboxyethenyl] -3- (2-naphthoyl) -IH-indol-l-yl] methyl} benzoic.

.. To a solution of the above intermediate (0.5 g, 0.7 mmol) in acetonitrile (10 ml) was added 48% aqueous hydrofluoric acid (5 ml). After 2 hours, water was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The concentration gave a crude solid which was dissolved in THF (2 ml) and MeOH (lml) and a solution of IN sodium hydroxide (2 ml). After stirring overnight at room temperature, the reaction was acidified to pH = 3 with a 10% solution of HCl and extracted with ethyl acetate. Flash chromatography (CH2C12 / MeOH, 10/1) gave the title compound (0.2 g, 50%) as a white solid.

EXAMPLE 23 4- (. {3-Acetyl-5- (benzyloxy) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} me) benzoic acid.

Step 1 Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0 ° C, and Lithium Aluminum Hydride (LAH) (255 mL of a solution) was added. 1. OM in THF) by means of an addition funnel for 40 minutes, the reaction was stirred an additional 2 hours at 0 ° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3 X 400 mL), the filtrates were combined and dried over MgSO4 and concentrated to yield 24.8 g.

Step 2 The crude indole alcohol prepared in step 1 (8.3 g, 32.6 mmol) was dissolved in DMF (10.5 mL). To this solution was added imidazole (5.5 g, 81.5 mmole) and t-butyldimethylsilyl chloride (5.4 g, 35.8 mmole). The mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate (3X). The organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using Hexane: ethyl acetate 19: 1 to give the pure product (11.9 g, 31 mmol, 94% yield, TLC_0.8 Rf in Toluene: Ethyl acetate 2: 1).

Step 3 The solution of the indole protected in silyl prepared in step 2 (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to magnesium ethyl bromide (2.4 mL of a 3M solution in ether, 7.2 mmol. ) in ether (10 ml), the last one maintained at -78 ° C. the reaction was stirred at -60 ° C for 2 hours. Then acetylchloride (0.51 mL, 7.2 mmol) in ether (4 mL) was added slowly. The reaction was maintained between -50 ° C and -60 ° C for another 2 hours. The reaction was then quenched with saturated sodium bicarbonate. It was extracted with ethyl acetate (3X). The organic layers were dried over magnesium sulfate and concentrated. The crude material was purified in a column of silica gel using Hexane: Ethyl acetate 19: 1 to give the pure product (1.2 g, 50%).

Step 4 To indole (1.2 g, 2.9 mmol, prepared in step 3 above) in 10.5 ml of 20 DMF, sodium hydride (0.13 g, in a 60% oil dispersion, 3.23 mmol) was added at room temperature . The reaction was stirred for 30 minutes. methyl (-bromomet il) benzoate (0.81 g, 3.53 mmol) was added at this time and the The reaction was stirred overnight. When completing the ^ * ^^^^? G < The reaction was monitored (monitored by TLC), quenched with water, extracted with ethyl acetate (3X). The organic layers were dried over magnesium sulfate, concentrated and used for the next step.

Step 5 A mixture of the silyl-protected indole prepared in step 4 above (0.65 g, 1.2 mmol) and ammonium tetra-butyl lutein (2.9 mL of a 1M solution in tetrahydrofuran, 2.9 mmol) in tetrahydrofuran (6 mL) was 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 silica gel using Hexane: Ethyl acetate 1: 1 to yield pure alcohol (0.47 g, 91%).

Step 6 The indole alcohol 0.3 0.61 mmol), carbon tetrabromide (0.27 g, 0.81 mmol) and 1,3-bis (diphenylphosphino) propane (0.21 g, 0.51 mmol) was taken in dichloromethane (8.4 mL) and stirred for 16 hours at which time the reaction was diluted with dichloromethane and half 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 using Hexane: Ethyl acetate 2: 1 to yield pure alcohol (0.27 g, 78%).

Step 7 The indole bromide prepared in step 6 (0.1 g, 0.2 mmol) was dissolved in dimethylformamide (0.4 mL, it is strongly recommended to degas the solvent) cesium carbonate (0.2 g, 0.6 mmol) was added and then 2 was added. -naftalent ethyl iool (0.034 g, 0.22 mmol) and the mixture was stirred for 1 day, then the reaction was emptied into 1/2 saturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (Hexane: Ethyl acetate 3: 1) to yield 0.05 g (57%) of the pure product.

Step 8 The ester (0.2 g, 0.34 mmol) prepared in step 7 above, was dissolved in 4.0 mL of THF / methanol 1/1 and then IN sodium hydroxide (2.5 mL) was added and the resulting mixture was stirred for 16 minutes. hours at room temperature, the work gave the crude product which was purified by means of chromatography (Hexane: Ethyl acetate 1: 1, with 1% acetic acid) to yield (0.17 g, 85%) of the sol.

Example 24 Acid 4-. { [5- (benzyloxy) -2- [(2-naphthylsulfanyl) ethyl] -3- (2,2,2-trifluoroacetyl) -lH-indol-1-yl] methyl} benzoic Step 1 This intermediate was prepared from indole, prepared in the step of Example 23 and trifluoroacetic anhydride, according to the procedure described in step 1 of Example 23.

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 triethylamine (0.04 mL, 0.3 mmol) in dichloromethane (0.4 mL), methanesulfonyl chloride (0.02 mL, 0.24 mmol) was added drop drop to 0 ° C. the reaction was stirred for 1.5 hours and then the dichloromethane was removed. To the residue in 0.4 mL of DMF at 0 ° C was added 2-naphthalene thiol (0.034 g, _ 0.22 mmol). Then CsC03 (0.96 g, 0.3 mmol) was added and the reaction mixture was stirred at room temperature overnight, and then the reaction was emptied into brine and extracted with ethyl acetate (3X), dried, concentrated and chromatography (Hexane: Acetate t or ethyl 3: 1) to yield 0.064 g (50%) of the pure product.

Step 4: The title compound was prepared from the ester, prepared from step 3 above, according to the procedure described in step 8 of Example 23.

Example 25 4- (. {5- [4-aminobuoyl) amino] -3-chloro-2 acid [(2-naphsulfanyl) methyl] -lH-indol-1-yl} methyl) benzoic.

Step 1 The t-butyl-sil i-protected alcohol (25 g) from step 6 of Example 1 was dissolved in 25 THF (200 mL) and then fluroride was added. tetrabutylammonium (125 mL of a l.OM solution) 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 it was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated to yield the desired alcohol (21.5 g).

Step 2 The alcohol (13.1 g) from step 1 was suspended in dichloromethane (450 mL), cooled to 0 ° C and triethylamine (10 mL) and methanesulfonyl chloride (4.0 mL) were added and the resulting mixture was allowed to warm to room temperature overnight, at which time it was diluted with saturated sodium bicarbonate, added and the reaction was diluted with dichloromethane, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried , concentrated to yield the desired chloride (13.5 g).

Step 3 To the chloride (13.5 g) 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 solution for 20 minutes and then 2 was added. -naphthalene thiol and the reaction was stirred for 20 minutes at room temperature, then water as well as ethyl acetate was added, the layers were separated and the combined organic layers were concentrated to a thick mixture which was stirred overnight and then the mixture Thicken was filtered and the solid was triturated with 40% ethyl acetate in hexane to deliver the desired disulfide (12.2 g) in 69% yield.

Step 4 The product from step three (11.25 g) was dissolved in THF (500 mL), methanol (500 mL) and then copper acetate II (19.2 g) suspended in water (300 mL) was added as well as more THF (100 mL). mL) and then sodium borohydride (11.2 g) was added in portions. After 2.5 hours of stirring at room temperature, the foamy black solution was diluted with 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. • • - • '* * *' - * faj * ta'1- ^ Step 5: The amine from the previous step was coupled to the 4-aminobutyric acid protected by fmoc followed by the procedure outlined in step 1, Example 43, followed by trituration with dichloromethane giving the amide in 43% yield.

Step 6: The amide (1.0 equivalent) 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 hours, concentrated and chromatographed to the desired performance of the product in a quantitative yield.

Step 7: The step amino ester was hydrolyzed using the conditions summarized by step 2 of Example 43 to deliver the title compound in 54%.

Example 26: 4- ( { 3-Chloro-5- [(cyclopentylcarbonyl) amino]] 2- [(2-naphthyl sulfanyl) me il] -lH-indol-1-yl} I il) benzoic.

Step 1 The amine (1.0 equivalent) from step 4 of Example 25 was dissolved in CH2C12 (0.3 M) and then an equivalent amount of saturated sodium bicarbonate was added and then the appropriate acid chloride (1.2 equivalents) was added. The biphasic reaction mixture was stirred vigorously until TLC analysis indicated that the reaction had been completed (usually in 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 chro- mated, or used crude, to 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 (3.0 equivalents) was added and the reaction was stirred until the analysis showed that the reaction had been completed. The reaction was then concentrated, diluted with water, acidified to a pH of 2 with concentrated HCL, extracted with 3X ethyl acetate, the combined organics were dried over concentrated magnesium sulfate and purified by chromatography to yield the desired acid in a 69% yield.

EXAMPLE 27 4- ( { 3-Chloro- [(2-naphthylsulfanyl) methyl] -5 - [(2-quinoxalinylcarbonyl) amino] -lH-indol-1-yl.] Methyl) 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 a 76% yield.

Step 2: The ester from step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid in a 53% yield.

EXAMPLE 28 4- ( { 3-Chloro-5- [(2,2-dimethylpropanoyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl.] Methyl) 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 the Example 71, step 1, to deliver the amide in a 100% yield.

Step 2: The ester from step 1 was hydrolysed under the conditions summarized for step 2 of Example 26 to yield the desired acid in a 79% yield.

EXAMPLE 29 4- ( { 5. {[[(Benzyloxy) carbonyl] amino] -3-chloro-2- [(2-na-ylsulfanyl) methyl] -lH-indol-1-yl} acid} me il) benzoic.

Step 1 The amine from step 4 of Example 25 was treated with the appropriate acid chloride according to the general procedure for the Example 71, step 1, to deliver the amide in 96% yield.

Step 2 The ester of step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid.

EXAMPLE 30 4- (. {3-Chloro-5. {[[(Cyclopeniloxy) carbonyl] amino) -2- [(2-naphthylsulfanyl) -yl] -lH-indol-1-yl} I il) benzoic.

Step 1: The amine from step 4 of Example 25 was treated with acetic anhydride in accordance with 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.

EXAMPLE 31 4- (. {5- (Acetylamino) -3-chloro-2- [(2-naphsulfanyl) methyl] -lH-indol-1-yl} me) benzoic acid.

Step 1: The amine from step 4 of Example 25 was treated with acetic anhydride according to the general procedure for Example 71, step 1, to deliver the amide in a 77% yield.

Step 2 The ester of step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid in a 29% yield.

EXAMPLE 32 Acid 4- (. {5- [{[[(buylamino) carbonyl] mino} -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} il) benzoic.

Step 1: THF (0.12 M) was added to amine 15 (1.0 equivalent) generated in step 4, the reaction mixture was cooled to 0 ° C and then butyl isocyanate (1.1 equivalents) was added and the mixture was warmed up Room temperature overnight and the reaction was diluted with 1/2 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 by chromatography to yield the desired urea in a yield of 57%. »" - »> .... Jj-hiMi ~ -. «Aaafe. . .. «. A-j, »« «» - -. -. •• - ---- .. »- .. - ~ -J > . . * .... - - * ?? - ..., v 4 ,, *. t,. «Kiaa-utí ^ Step 2 The ester of step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid in 41%.

EXAMPLE 33 4- (. {5- [{[[(buylamino) carbonyl] amino]} -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indole-1-yl} acid} me il) benzoic. Step 1: In accordance with 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 of step 1 was hydrolysed under the conditions summarized by step 2 of Example 26 to yield the desired acid in 100%.

EXAMPLE 34 4- ( { 3-Chloro-5- [(morpholinocarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl] -me il) benzoic acid.

Step 1 The amine (1.0 equivalent) generated above in step 4 was weighed into a flask with only 4-dimethylaminopyridine (1.5 equivalents) and then taken in dichloromethane (0.08 M) and then 4-chloride was added. morphol incarbonyl (1.5 equivalent) 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 saturated ammonium chloride at 1/2The layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified by chromatography to yield the desired urea in 100% yield.

Step 2 The ester of step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid by 79%.

EXAMPLE 35 4- (. {5- (Benzylamino) -3-chloro-2- [(2-naphsulfanyl) -yl] -lH-indol-1-yl}. And yl) benzoic acid. ...- < ! - > .-- ..--. Step 1: The amine (1.0 equivalent) from step 1 was dissolved in dichloroethane and then benzaldehyde (1.0 equivalent) was added followed by acetic acid (1.0 mL / 1 mmol) and the reaction was stirred by 20 minutes and then sodium triacetoxyborohydride (1.3 equivalent) 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 by means of chromatography to yield the desired urea in 74% yield.

Step 2 The ester of step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid by 49%.

EXAMPLE 36 4- (. {3-Chloro-2- [(2-naphthylsulfanyl) methyl] -5 - [(3-phenoxybenzyl) amino] -lH-indol-1-yl} me) benzoic acid .

Step 1: In accordance with 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 a 38% yield.

Step 2 The ester of step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid by 87%.

EXAMPLE 37 4- (. {3-Chloro-5- [(cyclopentylcarbonyl) (methyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} methyl) benzoic acid.

Step 1: To the ester generated in step 1 of the synthesis of Example 27, DMF (0.05 M) was added, the reaction was cooled to 0 ° C and then sodium hydride (10 equivalents) was added and the mixture was stirred for 30 minutes, then methyl iodide (10 equivalents) was added and the resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate and 1/2 saturated ammonium chloride, the layers were r. *,. tíxi .. ** < ** . . - * * .- *. *. < *. JJ .. .-. .. ".. --n,« > The separated aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified by means of chromatography to yield the desired methylated amide in a 56% yield.

Step 2: The ester of step 1 was hydrolyzed under the conditions summarized by step 2 of Example 26 to yield the desired acid by 57%.

EXAMPLE 38 4- (. {5- [Acetyl (benzyl) amino] -3-chloro-2- [(2-naphsulfanyl) methyl] -lH-indol-1-yl] methyl) benzoic acid.

Step 1 The amide synthesized in step 1 of the Example 31 Benzyl was made in accordance with the procedure step 1 for Example 37 to yield the tertiary amide in 90% yield.

Step 2: The ester of step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid in 41%.

Example 39: 4- ( { 3-Chloro-2- [(2-naphsulfanyl) methyl] -5- [(ehydro-3-furanylcarbonyl) amino] -lH-indol-1-yl} methyl] benzoic.

Step 1: To the indole amine (1.0 equivalent) was added the acid (1.2 equivalents), the dimethylaminopyridine (10 mol%), the hydrochloride of 1- (3-dimethylaminopropy 1) -3-et i -carbodiimide (1.5 equivalents) and then DMF (0.3 M) and the reaction was stirred under nitrogen for 24 hours at room temperature, at which time it was poured into a solution of 1/2 saturated ammonium chloride and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with 2X water, dried, concentrated and chromatographed to yield 55% of the title compound.

Step 2 The ester from step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid by 55%.

Example 40 4- (. {3-Chloro-2- [(2-naphthylsulfanyl) methyl] -5 - [(3-thienylcarbonyl) amino] -lH-indol-1-yl} methyl) benzoic acid.

Step 1: In accordance with the procedure for step 1 of Example 39, the amine from step 4 of Example 25 is treated with the acid required to yield the amide in 100% yield. Step 2: The ester of step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid in 21%.

Example 41: 4- (. {3-Chloro-2- [(2-naphthylsulfanyl) methyl] -5 - [(1-adamylcarbonyl) amino] -lH-indol-1-yl} methyl) benzoic acid.

Step 1: In accordance with the procedure for step 1 of Example 39, the amine from step 4 of Example 25 was treated with the acid required to yield the amide in 100% yield. _ J_ i_ £ j ^ J_ > ~ _ _ ^ III - - - - - * * - ** • - * '--- A ..- ..'.

Step 2: The ester from step 1 was hydrolysed under the conditions summarized for 1 step 2 of Example 26 to yield the desired acid by 35%.

Example 42 3- [(. {1- (4-carboxybenzyl) -3-chloro-2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} methyl) benzoic acid.

Step 1: In accordance with the procedure for step 1 of Example 39, the amine from step 4 of Example 25 was treated with the acid required to yield the amide in 100% yield.

Step 2: The ester of step 1 was hydrolyzed under the conditions summarized for step 2 of Example 26 to yield the desired acid by 20%.

EXAMPLE 43 4- ( { 3-Chloro-2- [(2-naphthylsulfanyl) me-il] -5- [(3-phenylpropanoyl) amino] -lH-indol-1-yl} .me il) benzoic acid .

Step 2: The ester of step 1 was hydrolyzed. under the conditions summarized by step 2 of Example 26 to yield the desired acid by 32%.

EXAMPLE 44 4- (. {5-Amino-3-chloro-2- [(2-naphsulfanyl) methyl] -lH-indol-1-yl} methyl) benzoic acid.

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-. { 3-Chloro-l- (4-. {[[(Methylsulfonyl) amino] carbonyl} benzyl) -2- [(2-naphsulfanyl) methyl] -1H-indol-5-yl} Cyclopentanecarboxamide.

Step 1: To Example 26 (1.0 eqlent), EDCI (1.5 eqlent), DMAP (1.0 eqlent), In a flask under nitrogen, DMF (0.08M) was added to the methanol sulfonamide (1.0 eqlent) and the reaction was stirred overnight at room temperature. and then work was done by the addition of a solution of 1/2 saturated ammonium chloride and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with 2X water, concentrated and chromatographed to yield 27% of the title compound.

Example 46 N-. { 3-Chloro-2- [(2-naphthylsulfyl) methyl] -1 - [4 - (. {[[(4-nitrophenyl) sulfonyl] amino} carbonyl) benzyl] -1H-indole-5-yl} Cyclopentanecarboxamide.

Step 1: The appropriate sulfonamide was added to Example 26 under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 43% yield.

Example 47 N-. { 3-chloro-l- [4- ( { [(2-methyl enyl) sul onyl] amino.} Carbonyl) benzyl] -2- [(2- ^^ "naphthylsulfanyl) methyl-lH-indol-5-yl} cyclopen anocarboxamide.

Step 1: To the Example 26 the appropriate sulfonamide was added under the conditions summarized for step 1, Example 45, to yield the desired acyl sulphonamide in 40% yield.

EXAMPLE 48 N- [3-Chloro-2- [(2-naphsulfanyl) methyl] -1- (4-. {[[(Phenylsulfonyl) amino] carbonyl] benzyl) -1H-indol-5-yl] Cyclopentanecarboxamide.

Step 1: The appropriate sulfonamide was added to Example 26 under the conditions outlined for step 1, Example 45, to yield the desired acylsulfonamide in 40% yield.

Example 9 N-. { 3-chloro-2- [(2-naphsulfanyl) methyl] -1- [4- (. {[[(Tri-loromethyl) sulfonyl] amino} carbonyl) benzyl] -1H-indol-5-yl} Cyclopentanecarboxamide.

Step 1 To the Example 26 the appropriate sulfonamide was added under the conditions summarized for step 1, Example 45, to yield the desired 1% sulfonamide in 67%. of performance.

Example 50 4- [5- [(Cyclopentylcarbonyl) amino] -2- [(2-naphidoxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indol-1-yl] butanoic acid.

Step 1 Ethyl 5-nitroindol-2-carboxylate (1 equivalent) was dissolved in THF / MeOH / H20 (3: 1: 1 0.21M) followed by the addition of LH0H.H20 (1.38 equivalent), stirred at 25 ° C. ° C, during the night. The reaction mixture was then acidified to pH = 1 with a solution of IN HCl and extracted with ethyl acetate. Worked with water, brine, dried and the concentration provides the raw product in a yield of 99%.

Step 2 The crude acid (1 equivalent) from step 1 was dissolved in THF (0.14 M) and to this was added diimidazole carbonyl (1 equivalent) at 25 ° C for 1.5 hours. The reaction mixture was then cooled to 0 ° C. Sodium borohydride (2.86 equivalents) was added in several portions followed by the addition of EtOH (0.71 M), stirring at 25 ° C overnight. The reaction mixture at this point was acidified with 2N HCl to pH = 2, and extracted with ethyl acetate. Worked with water, brine, dried and the concentration gave the raw product in a 95% yield.

Step 3 Into a furnace drying flask was added the crude indole alcohol (1 equivalent) from step 2 followed by anhydrous DMF (0.135 M). To this was added imidazole (1.3 equivalents) and TBSC1 (1.2 equivalent), stirred at 25 ° C for 1 hour. Worked with ethyl acetate / water followed by chromatographic purification to provide the desired product in 79% yield.

Step 4: The equivalent silyl-protected indole), from step 3, was dissolved in anhydrous DMF (0.13M) in an oven-dried flask. To this was added NaH (60% dispersion in mineral oil, 1.2 equivalents) and stirred - "- - • • • • * * ----» > - • •. - 25 ° C for 1 hour after which 4-bromobutyl ethyl (1.2 equivalent) and Kl (1.2) were added. The reaction mixture was then heated to 60 ° C for 2 hours.The work with ethyl acetate / water followed by chromatographic chromatographic purification gave the desired product in 93% yield.

Step 5 The alkylated indole (1 equivalent) from step 4 was dissolved in THF (0.05 M) and TBAF (1.0 M / THF, 1.1 equivalent) was added dropwise at 25 ° C, stirring 1 hour. Work with ethyl acetate / water followed by chromatographic purification provided the desired product quantitatively.

Step 6 The indole alcohol (1 equivalent) from step 5 was dissolved in anhydrous DMF (0.16 M) followed by the addition of P0C13 (10 equivalents) dropwise at 0 ° C. it was heated at 80 ° C, overnight. Work with ethyl acetate / water and washing the organic layer with IN NaOH, water, brine followed by purification by concentration and chromatography provided the desired product in 64% yield.

Step 7 A mixture of the chloro aldehyde derivative (1 equivalent) from step 6, 325 mesh of K2C03 (2.4 equivalents), 2-naphthol. (1.2 equivalent) and Kl (1.2 equivalent) was suspended in anhydrous acetonitrile (0.2 M) and heated at 70 ° C for 1.5 hours. Work with ethyl acetate / water followed by chromatographic purification gave the desired product in a 65% yield.

Step 8: The indole derivative naphthyloxy (1 equivalent) was dissolved from step 7 in anhydrous THF (0.023 M) and to this was added 5% Pt / C (40% by weight) under nitrogen and hydrogenated with a balloon H2 for 2.5 hours. The reaction mixture was then filtered through Celite and concentrated to give the crude product in 96% yield.

Step 9: The indole amino derivative (1 equivalent) from step 8 was dissolved in anhydrous CH2C12 (0.07 M) followed by the dropwise addition of Et3N (1.4 equivalent) and cyclopentylcarbonyl chloride (1.2 equivalent) at 0 ° C . It was stirred at 25 ° C for 0.5 hour after which the reaction mixture was quenched with saturated NaHCO 3 solution and stirred overnight. The organic layer was separated and washed with brine, it dried up. The product was obtained in a 66% yield after recrystallization from 30% ethyl acetate / hexane.

Step 10 The indole from step 9 (1 equivalent) was weighed in a flask with only NaH2P04 (12 equivalents), t-butyl alcohol (0.13 M), water (0.13 M), 2-methyl-2-butene (46 equivalents) and to this mixture was added Na02Cl (12 equivalents) at 25 ° C the reaction mixture was then heated to 65 ° C overnight, worked up with ethyl acetate / water followed by trituration with CH2C12 / hexane (4: 6) at 0 ° C for 1 hour providing the desired product in a 63% yield.

Step 11 The acid (1 equivalent) from step 10 was weighed into a flask and to this was added EDCI (3 equivalents), DMAP (1.2 equivalent), pyrrolidine (1.2 equivalent) followed by anhydrous THF (0.018 M) and the mixture of reaction then went to -. ** ****. »-. .-. , -."--.. -.--to **. . ,. *, *. ,,: ..-.-, - * -a-au-i -... »» -. .- ***. 'A ... t - ^ ?? h ^? ^ - reflux temperature for 18 hours. Work with ethyl acetate / water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate / hexane (3: 7) gave the desired product in 89% yield.

Step 12 Amide (1 equivalent) was dissolved from step 11 in THF / MeOH / water (3: 1: 0.025 M l) and to this was added LÍOH.H20 (1.2 equivalents), stirred at 25 ° C overnight . Work with ethyl acetate / water followed by recrystallization from CH2C12 / hexane (1: 1) gave the desired product in 98% yield.

Example 51: Acid 4-. { 5- [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2- [(2-naphidoxy) methyl] -1H-indol-1-yl} butanico Step 1: Step 11 of Example 50 was followed and morpholine was used in 87% yield of the desired product after recrystallization.

Step 2: Step 12 above was followed (Example 50) and the corresponding morpholino amide was used to provide the desired product in a 96% yield after recrystallization.

Example 52 N- [2- [(2-naphthyloxy) ethyl] -1- (-oxo-4-. {[[(Trifluoromethyl) sulfonyl] amino] butyl) -3- (1-pyrrolidylcarbonyl) -lH- indol-5-yl] cyclopentanecarboxamide.

The acid of Example 50 (1 equivalent) was weighed into a flask and to this was added EDCI (3 equivalents), DMAP (1.2 equivalents), trifluoromethanesulfonamide (1.2 equivalents) followed by anhydrous THF (0.04 M) and the mixture of reaction was stirred at 25 ° C, overnight. Worked with ethyl acetate / water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Trituration of the crude product with CH2C12 / hexane (1: 2) at 0 ° C for 1 hour gave the desired product in 96% yield.

EXAMPLE 53 N- [3-Chloro- (morpholinocarbonyl) -2- [(2-naphidoxy) methyl] -1- (4 -oxo-4-. {[[(Trifluoromethyl) sulfonyl] amino} butyl) - lH-indol-5-yl] cyclopentanecarboxamide.

Following step 1 above (Example 52) and using the corresponding acid of Example 51 (step 4, scheme 4) provided the desired product in 96% yield.

Example 53A Acid 4 -. { 5- [(Cyclopentylcarbonyl) amino] -3-formyl-2- [(2-naphthyloxy) methyl] -1H-indol-1-yl} bu añoico Step 1 The indole (1 equivalent) was dissolved from step 9, Example 50 in THF / MeOH / H20 (3: 1: 1, 0.025 M) and to this was added LÍOH.H20 (1.2 equivalent), stirred at 25 °. C, for 4 hours. Work with ethyl acetate / IN HCl followed by trituration with CH2C12 / hexane gave the desired product in 74% yield.

Example 53B N- [3- (formyl-2- [(2-naphthyloxy) methyl] -1- (4 -oxo-4-. {[[(Tri-loromethyl) sulfonyl] amino.} Buyl) -1H -indol-5-yl] cyclopentanecarboxamide.

Step 1: The acid (1 equivalent) from step 1 of Example 53A was weighed into a flask and to this was added EDCI (1.35 equivalent), DMAP (1.1 equivalent), t rif luoromet anosulfonamide (1.05 equivalent) followed by anhydrous THF ( 0.026 M) and the reaction mixture was stirred at 25 ° C, 3 hours. Worked with ethyl acetate / water followed by washing the organic layer with 0.05N HCl, saturated bicarbonate and brine. The chromatographic purification then gave the desired product in a yield of 94%.

Example 54 5- [(Cyclopentylcarbonyl) amino] -2- [(2-naphiloxy) methyl] -1- (4-oxo-4-. {[[(Tri-loromethyl) sulfonyl] amino] butyl) acid -1H-indole-3-carboxylic acid.

Step 1: The product of Step 1, Example 53B (1 equivalent) was weighed in a flask with only NaH2P04 (12 equivalents, t-butyl alcohol (0.12 M), water (0.12 M), 2-met i 1-2 -but eno (50 equivalents) and this mixture was Na02Cl (11.8 equivalents) was added at 25 ° C. The reaction mixture was then heated to 60 ° C., 3 hours and left overnight at 25 ° C. work with ethyl acetate / water followed by chromatographic purification. and triturations with CH2C12 / hexane (1: 1) gave the desired product in 57% yield.

EXAMPLE 55 3- (. {4- [5- [(Cyclopentylcarbonyl) mino] -2- [(2-naphidoyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indole-1-yl] bu yearl1.}. amino) benzoic.

Step 1 The compound of Example 50 (1 equivalent) was weighed into a flask and to this was added EDCI (3 equivalents), DMPA (1.2 equivalents), methyl 3-aminobenzoate (1.2 equivalents) followed by anhydrous THF (0.04 M) and the reaction mixture was then stirred at 25 ° C for 2 days. Worked with ethyl acetate / water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Recritalization from acetate ethyl / hexane provided the desired product in an 88% yield.

Step 2 The ester (1 equivalent) from step 1 was dissolved in THF / MeOH / water (3: 1: 1, 0.024 M) and to this was added LIOH.H20 (1.2 equivalents), stirred at 25 ° C, during overnight at this point, 1.2 equivalents of LÍOH.H20 were added and stirred for 2 hours. Work with ethyl acetate / IN HCl followed by trituration with CH2C12 / hexane (1: 1) at 0 ° C for 1 hour gave the desired product in 92% yield.

Example 56 3- [(4- {5- [(Cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2 - [(2-naphyloxy) methyl] -1H-indol-1-yl} butanoyl acid amino] benzoic.

Step 1: Following step 1 of Example 55 and the product of Example 51 was used (see scheme 4 for synthesis) the desired product was provided in a yield of 85% after chroma tographic purification.

Step 2: Following step 2 of Example 55 and using the corresponding morpholino from step 1, the desired product was provided in 91% yield.

Example 57 N- [2- [(2-naphthyloxy) methyl] -l-. { 4-oxo-4- [3- ( { [(Trifluoromethyl) sulfonyl] amino} carbonyl) anilino] butyl} -3- (-pyrrolidinylcarbonyl) -lH-indol-5-yl] cyclopentanecarboxamide.

Step 1: The compound of Example 55 (1 equivalent) was passed in a flask and to this was added EDCI (3 equivalents), DMAP (1.2 equivalent), tr if luoromet anosul fonamide (1.2 equivalent) followed by anhydrous THF (0.04 M). ) and the reaction mixture was then stirred at 25 ° C, overnight. Worked with ethyl acetate / water followed by washing the organic layer with IN HCl, saturated bicarbonate and brine. Trituration with HC2Cl / hexane (8: 2) gave the desired product in an 84% yield.

Example 58 N- [3- (Morphonylcarbonyl) -2- [(2 -naphthyloxy) methyl] -1-. { 4-OXO-4- [3- ( { [(Trifluoromethyl) sulfonyl] amino} carbonyl) anilino] butyl} -1H-indol-5-yl) cyclopen anocarboxamide.

Following step 1 of Example 57 and using Example 56 the desired product was provided in an 84% yield.

Example 59 Acid 2- (4-. {[[5- (benzyloxy) -3- (1-naphthoyl) -lH-indol-1-yl] -yl] -phenyl) -acetic acid Step 1 A solution of MeMgBr in butyl ether 15 (1 M, 1.2 equivalents) was cooled on ice. 4-Benzyloxy indole (1 equivalent) in CH2C12 (0.5 M) was added and the reaction mixture allowed to warm to 25 ° C. After addition of 1-naphthoyl chloride (1 equivalent) in CH2C12 (1 M), the reaction was heated to reflux temperature for 3 hours. Quenching with aqueous NH4C1 and extraction with CHC13 gave the crude ketone, which was purified by recrystallization from hexane / CHCl 3 / MeOH (53% yield). 25 -..... ^ - «« - ^ - ^. =. «. . i. ".,. .a,. ";.? ^ > . .- -. ... - *. b "*. ^. *. Oi ^ - -. . .. j-,. t ¿tf-am-a * ---.

Step 2 An ice cooled solution of the ketone (1 equivalent) from step 1 in DMF (0.2 M) was treated with NaH (690% in mineral oil, 2.5 equivalents). 4-Bromo-phenyl acetic acid (1.1 equivalents) 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 IN HCl and extracted with EtOAc. The organic extracts were dried and concentrated. The desired product was obtained in a yield of 68% after purification by chromatography and recrystallization from hexane / EtOAc.

EXAMPLE 60 2- (4-. {[[5- (Benzyloxy) -3- (2-naphthoyl) -lH-indol-1-yl] -me.-yl] -phenyl) -acetic acid Step 1 Following step 1 of Example 59 and using the appropriate acyl chloride, yielded 42% of the desired ketone after recrystallization from hexane / CHC13.

Step 2: A procedure analogous to step 2 of Example 59 yielding 35% of the title compound after chromatographic purification and recrystallization from acetone / pentane.

Example 61 5 2- [4- (. {5- (Benzyloxy) -3- [3,5-bis (rifluoromethyl) benzoyl] -lH-indol-1-yl} methyl) phenyl] acetic acid Step 1: Following step 1 of Example 59 using the appropriate acyl chloride, yielded 30% of the desired ketone after recrystallization from hexane / CH2C12 / EtOAc.

Step 2: A procedure analogous to step 2, 15 of Example 59 yielded 73% of the title compound after chromathographic purification and recrystallization from CHC13 / MeOH.

Example 62 Acid 4- (. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} methyl) benzoic acid.

Step 1: The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with "**" "•» - - * "- - - - ........ - .- • ............ ... .... .to - .,. ... "., ... ,, **, * ,. . i .. M-fc ».--, -......

LAH (1.3 equivalent) in THF (0.27 M) at 0 ° C under nitrogen for 1 hour. He worked with NaOH and water followed by the concentration provided the raw product (100%).

Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 M) and treated with t-butyldimethyl-ylsilyl chloride (1.16 equivalent) and imidazole (1.26 equivalent) at 25 ° C for 1 day. Work and The chromatographic purification afforded the crude product (93%).

Step 3 The silyl ether from step 2 was dissolved in methe chloride (0.26 M), and treated with BOC anhydride (1.24 equivalent), triethylamine (1.53 equivalent) and DMAP (0.21 equivalent) at 25 ° C for 3 days. The work and the chromatological purification provided the pure product (99%). Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid / water / THF (3: 1: 1) (0.04 M) at 25 ° C for 1 day. The work and the chromatographic purification provided the pure product (100%).

Step 5 The alcohol from step 4 was dissolved in methe chloride (0.2 M), and under nitrogen at -40 ° C treated with triethylamine (1.33 equivalents) and mesyl chloride (1.23 equivalents) for 1 hour. In a separate dry flask, naphthalene-2-thiol (1.31 equivalent) was weighed, and THF (1 M) was added, followed by hexamet ildisi lithium zido (IN in THF, 1 equivalent) and this mixture was stirred at 25 ° C. ° C for 30 minutes. The resulting solution was then added dropwise, during 30 minutes, to the previous mesylate solution, at -40 ° C. The reaction mixture was allowed to warm to 25 ° C, and was thus stirred for 4.5 hours. Work and purification provided the BOC thioether.

Step 6 Purification of the BOC thioether from step 5 was heated under nitrogen at 160-170 ° C for 1.25 hours, and recrystallized from ethyl acetate and hexanes to provide the free indole thioether in a 64% yield.

Step 7 The product of the step (1 equivalent) in CH2C12 (0.125 M) was cooled in . . . _, «. ... t fe ... ti í e s **? * - r ice. A solution of MeMBr (1.2 equivalent) in butyl ether (1M) 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 temperature for 3 hours, and then stirred at 25 ° C overnight. After quenching with NH4C1, the mixture was extracted with CH2C12. the organic extracts were washed with brine, dried and concentrated. The desired ketone was obtained in 55% yield after chromatographic purification.

Step 8: A solution of the product from step 1 (1 equivalent) in dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.05 equivalent). 4-Bromometylbenzoate or methyl (1.2 equivalent) was added after 1 hour at 25 ° C and the resulting mixture was stirred overnight. Work with EtOAc / water produced the desired crude material which was purified by chromatography (56% yield).

Step 9: The step material (1 equivalent) was hydrolyzed by the action of LÍOH.H20 (1.2 equivalent) in THF / MeOH / water (3/1/1, 0.07 M). After stirring at 25 ° C overnight, the reaction mixture was quenched with AcOH and the solvent was evaporated. Working with EtOAc / water and chromatofogic purification gave the title compound in a 78% yield.

EXAMPLE 63 4- (. {5- (Benzyloxy) -3-isobutyryl-2- [(2-naphsulfanyl) methyl] -lH-indol-1-yl) methyl) benzoic acid.

Step 1 Following step 7 of Example 62 using isopropyl chloride yielded the desired ketone after chromatography.

Step 2 A procedure analogous to the step of Example 62 yielded 50% of the N-alkylated material after chromatofogic 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 Acid 2-. { 3-Acetyl-5- (benzyloxy) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} acetic Step 2 The product from step 1 of Example 80 was alkyl with methyl bromoacetate following a procedure analogous 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.

Example 65 Acid 2-. { 5- (benzyloxy) -3-isobutyryl-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} acetic Step 2 Initiate a procedure analogous to step 2 of Example 63 from the bromo methyl acetate and the isopropyl ketone described in step 1 of Example 63 (step 1, see above). This reaction yielded 66% of the N-material . . ** - * **. t. «.- .. '. * > . ».. *. »,. * -.? t < j ^ .:.-a. - * r *. . i rented after chromatographic purification.

Step 3: Following step 3 of Example 63 of the methyl ester was hydrolyzed to the title compound in 50% yield after chromatography.

Example 66 10 Acid 4-. { 3-benzoyl -5- (benzyloxy) -2- [(2-naphthyloxy) me il] -lH-indol-1-yl} acetic Step 1 A solution of EtMgBr in ether (3N, 2. 17 equivalents) was cooled to -70 ° C. He .15 product from step 2 in Example 62 (1 equivalent) in ether (0.55 M) was added, and the reaction mixture was stirred to -70 ° C for 2 hours. After the addition of benzoyl chloride (3 equivalents) in ether (1.5 M), the The reaction was stirred at -40 ° C for 2 hours, quenched with saturated NaHCO 3 at -40 ° C and allowed to warm to 25 ° C. Work-up with EtOAc / water and recrystallization from hexane / EtOAc yielded the desired ketone by 89%. 25 ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡Step 2: The material from step 1 (1 equivalent) in CH2C12 (0.25 M) was discussed with Net3 ( 2 equivalents), followed by BOC anhydride (1.24 equivalent) and DMAP (0.21 equivalent). After stirring for 20 minutes at 25 ° C, the reaction mixture was worked with CH2C12 and water. The desired pure material was obtained in a 97% yield by trituration with hexane.

Step 3: The above material (1 equivalent) in THF (0.3 M) was combined with pyridine (excess) and pyridine HF (excess) at 0 ° C. The reaction was stirred at 25 ° C for 1.5 hours. Worked with EtOAc / water followed by chromatographic purification to give the desired alcohol in 86% yield.

Step: Alcohol from step 3 (1 equivalent) in CH2C12 (0.4 M) was treated with 2,6-lutidine (2.5 equivalents) followed by SOC12 (1.2 equivalent). After 30 minutes at 25 ° C the reaction was worked with EtOAc and water. The crude product was purified by chromatography and trituration with hexane provided the corresponding chloride in a 75% yield.

Step 5: A mixture of the above material (1 equivalent), K2C03 325 mesh (2.4 equivalents), b-naphthol (1.2 equivalents) and Kl. (1.2 equivalents) in CH3CN (0.3 M) was heated to reflux temperature for 2 hours. Work-up with EtOAc / water, followed by trituration in hexane / EtOAc and chromatography of the mother liquor yielded 70% of the expected ester.

Step 6: A solution of NaOMe in MeOH was prepared by dissolving Na (3 equivalents) in MeOH (0.2 M). The product from step 5 (1 equivalent) in THF (0.04 M) was added and the reaction mixture was stirred at 25 ° C for 3 hours. Work-up with EtOAc / water followed by trituration with hexane / EtOAc afforded the indole compound by 93%.

Step 7: A solution of the product from step 6 (1 equivalent) in dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.1 equivalent). Methyl 4-bromobutyl (1.2 equivalent) and Kl (1.2 equivalent) were added after 1 hour and the reaction mixture was stirred at 75 ° C for 3 hours. He * ".. < - .-. go to--.. - ..*-.*, - -. , ..... - ".... *, ...,., _!.» ... »..,.,». «- Ai .--, .....,. ., ...-. . . . .- > , _ »,. .. «^., .. ^", .. ^ ...

Work with EtOAc / water followed by chromatographic purification yielded 96% of the required ester.

Step 8: The material from step 7 (1 equivalent) was hydrolyzed by the action of LH0H.H20 (1.2 equivalent) in THF / MeOH / water (3/1/1, 0.2 M). After stirring at 25 ° C for 2 hours, the reaction mixture was quenched with IN HCl and extracted with EtOAc and CH2C12. the organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane / EtOAc to provide the title compound in 86% yield.

Example 67 3- [(4. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} butanoyl) amino] benzoic acid.

Step 1: The product of Example 66 (1 equivalent) was reacted with EDCI (1.37 equivalent) and 3-amino methyl benzoate (1.05 equivalent) in DMF (0.09 M) in the presence of DMAP (0.2 equivalent). The reaction was stirred at 25 ° C for 1.5 hours. Work with EtOAc / water, followed by flash chromatography afforded the desired amide in 81% yield.

Step 2: A procedure analogous to step 2 of Example 66 yielded 98% of the title compound after purification by trituration in hexane / EtOAc.

Example 68 4-. { 3-benzoyl-5- (benzyloxy) -2 -naphthyloxy) methyl] -1H-indol-1-yl} -N- [3- ( { [(Trifluoromethyl) sulfonyl] amino} carbonyl) phenyl] butanamide.

Step 1: Following step 1 of Example 67 and using the acid of Example 67 and the appropriate sulfonamide provided after the reaction overnight and working analogously to the desired product. Trituration with hexane / EtOAc yielded 100% of the title compound.

Example 69: 4- [(4- {3-Benzoyl-5- (benzyloxy) -2- [2-naphyloxy) methyl] -lH-indol-1-yl) butanoyl) amino] benzoic acid. -m, s! A »* í * g2 ^^ Step 1 Following step 1 of Example 67 above using the acid of Example 66 and the appropriate aniline yielded 76% of the expected amide.

Step 2 A procedure analogous to step 2 of Example 67 yielded 78% of the title compound after purification by trituration in hexane / EtOAc.

EXAMPLE 70 2- (4- ({3-Benzoyl-5- (benzyloxy) -2- [2-naphidoyloxy] methyl] -lH-indol-1-yl acid} butanoyl) amino] benzoic acid.

Step 1: Following step 1 of Example 67 above using the acid of Example 66 and the appropriate aniline yielded 36% of the expected amide after chromatography.

Step 2 A procedure analogous to step 2 of Example 67 yielded 67% of the title compound after purification by trituration in hexane / EtOAc.

EXAMPLE 71 3- [(4- {3-Benzoyl-5- (benzyloxy) -2- [2-naphthyloxy) methyl] -lH-indol-1-yl} acid} butanoyl) amino] propanoic.

Step 1: Following step 1 of Example 67 above using the acid of Example 66 and the appropriate aniline yielded 96% of the expected amide 10 after chromatography.

Step 2: A procedure analogous to step 2 of Example 67 yielded 67% of the title compound after purification by trituration in hexane / EtOAc.

Example 72 3- [(4. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} butanoi) amino] propane acid.

Following step 1 of Example 67 using the acid of Example 66 and the appropriate sulfonamine yielding 100% of the title compound. 25 ^^^ g ^ - - - ^ ^ * - > ...- Example 73 N- (4-. {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl}. Butannoyl) -2-methylbenzenesulfonamide.

Following step 1 of Example 67 using the acid of Example 66 and the appropriate sulfonamide yielded 80% of the title compound after chromatography.

Example 74 Acid 5-. { 3-benzoyl-5- (benzyloxy) -2- [2-naphthyloxy) methyl] -lH-indol-1-yl} pentanoic Step 1: A solution of the product from step 6 of Example 66 (1 equivalent) in dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.1 equivalent). 4-bromopent anoat or ethyl (1.2 equivalent) and Kl (1.2 equivalent) were added after 1 hour and the reaction mixture was stirred at 75 ° C for 2 hours. Work with EtOAc / water followed by chroma tigraphic purification yielded 92% of the required ester. • - * '- • - ~ • > • Step 2: Step material (1 equivalent) was hydrolyzed by the action of LÍOH.H20 (1.3 equivalent) in THF / MeOH / water (3/1/1, 0.2 M). After stirring at 25 ° C for 3.5 hours, the reaction mixture was quenched with IN HCl and extracted with EtOAc and CH2C12. the organic extracts were combined, washed, dried and concentrated. The crude material was purified by trituration in hexane / EtOAc to provide the title compound in a 95% yield.

Example 75: 3- [(5-. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl}. Pentanoyl) amino] benzoic acid Step 1: The acid of Example 74 (1 equivalent) was reacted with EDCI (1.37 equivalent) and 3-amino methyl benzoate (1.05) equivalent) in DMF (0.09 M) in the presence of DMAP (0.2 equivalent). The reaction was stirred at 25 ° C for 2.5 hours. Work with EtOAc / water followed by flash chromatography gave the desired amide in 78% yield. 25 , Α-l-tf-t-Ífc- * t? - M-¿-H > Step 2: A procedure analogous to step 2 of Example 74 yielded 83% of the title compound after purification by trituration in hexane / EtOAc.

Example 76 5-. { 3-benzoyl -5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} -N- [3- ( { [(Trifluoromethyl) sulfonyl] amino} carbonyl) enyl] pentanamide.

Step 1: Following step 1 of Example 68 using the acid of Example 75 and the appropriate sulfoamide, yielded 83% of the title compound after overnight reaction and analogous work.

Example 77 Acid 2-. { 3-Benzoyl-5- (benzyloxy) -2- [2-naphthyloxy) methyl] -1H-indol-1-yl} acetic Step 1: Following step 1 of Example 74 using the appropriate bromide yielding 80% of the expected amide after chromatography.

A - * "• -" "* •" - ^ Step 2: A procedure analogous to step 2 of Example 74 yielding 90% of the title compound after trituration in hexane / EtOAc.

Example 78 Acid (E) -4-. { 3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) ethyl] -lH-indol-1-yl} -2-butenóico.

Step 1: Following step 1 of Example 74 using the appropriate bromide, it yielded 33% of the expected amide after chromatography.

Step 2: A procedure analogous to step 2 of Example 74 yielded 70% of the title compound after trituration in hexane / EtOAc.

EXAMPLE 79 3- (. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} methyl) benzoic acid.

Step 1 Following step 1 of Example 74 using the appropriate bromide, yielded 75% of the expected amide after chromatography.

Step 2 A procedure analogous to step 2 of Example 74 yielded 92% of the title compound after trituration in hexane / EtOAc.

Example 80 l-. { l- [4- (1, 3-Benzo-iazol-2-ylcarbonyl) -benzyl] -5- (benzylsulfanyl) -2- [(2-naphthylsulfanyl) methyl] -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 ° C treated with methylmagnesium bromide (1.1 equivalent), and stirred at 0 to 25 ° C. 1 hour. The mixture was re-cooled to 0 ° C and acetyl chloride was added (1.17 equivalent). After 1 hour at 0 ° C, the reaction mixture was quenched by the addition of a saturated ammonium chloride solution in half, and working with methylene chloride. Chromatographic purification afforded the pure product (37%).

Step 2 Following the procedure for the Example 81 step 1 and using p-Toluoyl chloride yielded the corresponding for amide. i .. . . .. ... .j »-. . . ..,. -. -. ».» -,.,. - .. »- ,;» ».

Step 3: Following the procedure for Example 81 step 2 and using the product from step 1 above, the desired product was obtained.

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 was coupled to the material from step 1 to yield the title compound.

Example 81 1-. { 1- [3- (1, 3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) -2- [(2-naphthylsulfanyl) methyl] -1H-indol-3-yl} -1-ethanone.

Step 1 M-toluoyl chloride (0 M) was added to triethylamine (2.44 equivalents) and HC k of methoxymethyl amine (1.1 equivalent) dissolved in methylene chloride at 0 ° C for 20 minutes. The reaction was allowed to warm to 25 ° C. 25 After stirring at 25 ° C for 1 day, work with - * M - «-.-- fa --- JM-? Ai» - «» _. . . . . . - ^ ..-.-., 1? . ., "",. . *,., .. * -, ~ -. ....- . . -. "T, - .. i *" M-- < t ---- < t- "Methylene chloride and water gave the crude product in ca. 100% performance Step 2 Under nested conditions, benzothiazole was dissolved in THF (0.35 M). BuLi (1.1 equivalent) was added at -78 ° C. After 1 hour at -78 ° C, the amide from step 1 in THF was added, for 15 minutes. The reaction was allowed to warm to 25 ° C. After stirring at 25 ° C for 1 day. Work with ethyl acetate and water and chromatography gave pure tolyl ketone product (52%).

Step 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0.19 M), and NBS (1.2 equivalent) and AIBN (0.11 equivalent) were added. After 1 day at 60 ° C, about 1: 1 of the starting material and product was presented. It was again exposed under the same conditions, followed by filtration and recrystallization from ethyl acetate to yield the pure bromobenzyl ketone product (28%). -dfa --- j - »-» - «- j -« i.-...-. - .., .-. . ^ A ^ ,. i .. ..- ........ ...,., ........ ^ ..- t.-... > .-..-. * .J. . . ? l * JIMfa - ^ - ü ..

Step 4 The indole from step 1 of Example 80 was dissolved in dry DMF (0.04 M), followed by NaH (1.25 equivalent). After 45 minutes at 25 ° C, bromobenzyl ketone from step 3 (1.25 equivalent) was added and stirred for 1 hour at 25 ° C. Work, chromatography, and recrystallization from ethyl acetate / hexanes afforded the pure title compound (45%).

EXAMPLE 82 2- [3- (. {3-Acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl.} Methyl) benzoyl] -1 acid, 3-benzothiazole-6-carboxylic acid Step 1: Ethyl 4-aminobenzoate was dissolved in 95% v / v HOAc / water (0.4 M) and at 25 ° C treated with sodium thiocyanate (4.1 equivalents), and stirred at 25 ° C for 20 minutes. The mixture was cooled to 5 ° C and bromide (1.17 equivalent) was added in 95% v / v of HOAa / water. After 1 hour at 0 ° C, the reaction mixture was quenched by the addition of water, and filtered, the work (ethyl acetate and sodium bicarbonate solution) gave 81% of the pure thiocyanate product.

Step 2 The aryl thiocyanate from step 1 was treated with sodium sulfide nonahydrate in water (1.2 equivalent, 1.3 M), and heated to reflux temperature for 45 minutes. The cold mixture was filtered, acidified to pH = 6 with HOAc, extracted with ethyl acetate, and concentrated to give the thiophenol product (91%): Step 3 The thiophenol from step 2 was dissolved in 90% v / v HCOOH / water (3.3 M), and zinc powder (catalyst) was added. After 3 hours at reflux temperature, work with ethyl acetate and alkali provided the benzothiazole ester (60%). Step 4: The benzothiazole ester was dissolved (step 3) in THF / methanol / water (8: 3: 3), (0.34 M), lithium hydroxide (2 equivalents) was added, and the mixture was stirred for 2 hours. hours at 25 ° C. The job (ethyl acetate / aqueous acid) provided the pure benzothiazole acid (100%).

Step 5: Under anhydrous conditions, the benzothiazole acid (step 4) was dissolved in THF (0.052 M).

BuLi was added at -78 ° C (2.2 equivalents). After After 1 hour at -78 ° C to 0 ° C, the amide (1.28 equivalents) from step 1 of Example 81 was added in THF at -78 ° C for 5 minutes. After 0.5 hours at -78 ° C, the reaction was allowed to warm to 25 ° C. After stirring at 25 ° C for 2 hours, work with ethyl acetate and water and chromatography gave the pure tolyl ketone acid product (64%).

Step 6 The tolyl ketone acid from step 5 was suspended in (1: 1) THF / ethanol, (0.075 M), and concentrated sulfuric acid (excess) was added. After being at reflux temperature for 1 day, the work (ethyl acetate and Sodium bicarbonate) 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 (0.05 M), and NBS (1.2 equivalent) and AIBN (0.15 equivalent) were added. After 1.25 hours at reflux temperature, another portion of NBS (0.3 equivalent) and AIBN (0.07 equivalent) was added. The filtration and recrystallization from acetate of ethyl provided the product of pure bromobenzyl ketone (22%).

Step 8: The indole from step 1 of Example 80 was dissolved in dry DMF (0.06 M), followed by NaH (1.11 equivalent). After 45 minutes at 25 ° C, the bromobenzyl ketone from step 7 anteiror (1.25 equivalent) was added and stirred for 1 hour at 25 ° C. The work provided the crude ester, 10 used in the next step.

Step 9: The crude ester from step 8 was dissolved in THF / methanol / water (8: 2: 2), (0.013 M), lithium hydroxide (4.3 equivalents) was added in 15 portions, stirring the mixture for a total of 3-4 days at 25 ° C. Work (ethyl acetate / aqueous HCl) and purification by chromatography gave pure benzothiazole acid (31%).

Example 83 Acid 5-. { 3-benzoyl -5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} -2-oxopentanoic.

Step 1: The indole from step 6 of Example 66 was dissolved in dry DMF (0.17 M), followed by NaH - * M. - * --- * »» - «-.... * .-. v. - »? - .. Irtn», *. , • «-, t • • t-fr» I.IW * - (1.2 equivalent). After 1.5 hours at 25 ° C, 3-iodo-1-chloropropane was added, and it was stirred for 4 hours at 25 ° C. Work (ethyl acetate / bicarbonate solution) and trituration (ethyl acetate / hexanes) gave 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 equivalent). After stirring for 1 day at reflux temperature in the dark, the work (ethyl acetate / water) provided the iodide product in 97% yield.

Step 3: NaH (1.0 equivalent) was weighed into a dry flask under nitrogen, and dry benzene (0.14 M) was added. At 0 ° C, dry DMF (0.4 M), ethyl 2-carboxyl-1,3-di-ethyl (1.0 equivalent), and iodide from step 2 (1.0 equivalent) in a separate dry flask were added. This DMF solution was then added at 0 ° C to a suspension of benzene, and the mixture was allowed to warm to 25 ° C and was stirred for 3 hours at 25 ° C. Work (ethyl acetate / water) and chromatography ? iT-M-li? i-MÉ-Mi-É-l - «- álÍ-ÍÉ-i ?? * "- '- * - > .---- * ... ^ * -... * ...., ..» ...... > .. ..., .. , ... ..... ........ -. - ....- «, -. - ...., ....... ...,. * ..., ,, .....- > " provided the diati- noanyl ester in 54% yield.

Step 4: Silver nitrate _ (4.5 equivalents) and NCS (4.0 equivalents) were dissolved in 4: 1 v / v acet oni tri lo / water (ca 0.04 M), and a solution of the dithianyl ester was added. Step 3 (1 equivalent) in acetonitrile (0.03 M) at 25 ° C. After stirring for 5 minutes at 25 ° C, it was added a solution of sodium sulphide, followed in one minute by a solution of sodium carbonate. Work (ethyl acetate / water) and chromatography gave the ketoester product in 17% yield. Step 5: The ketoester from step 4 was dissolved in THF / water (8: 1), (0.03 M), lithium hydroxide (1.5 equivalents) was added, and the mixture was stirred for 2 hours at 25 ° C. The work (acetate Ethyl acetate / aqueous HCl) and purification by chromatography gave pure ketoacid (64%).

Example 84 3- [(5- { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl.} -2-oxopentanoyl) amino] benzoic 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 equivalents) was added, and the mixture was stirred for 1 hour at 50 ° C. Work (ethyl acetate / aqueous HCl) and chromatography afforded pure dithianyl acid (90%).

Step 2: The dithianyl acid from step 1 was dissolved in dry methylene chloride (0.08 M), and DMF (catalyst). Oxalyl chloride was added (1.2 equivalents), and the reaction was stirred at 25 ° C for 0.5 hours. The concentration was continued by dissolving again in dry methylene chloride, and the addition, at 0 ° C, of methyl 3-aminobenzoate (1.05 equivalents) and triethylamine (1.0 equivalents). The reaction was warmed to 25 ° C, and stirred here for 3 hours. Work (ethyl acetate / aqueous acid) and purification by chromatography gave the dithianyl ester product in 89% yield.

Step 3 The dithianyl ester from step 2 was dissolved in THF / methanol / water (6: 4: 3) (0.02 M), and lithium hydroxide (4.3 equivalents) was added, and the mixture was stirred for 3 hours at 25 minutes. ° C. Work (ethyl acetate / aqueous HCl) provided the dithianyl acid (R = 3-C00H) (91%).

Step 4 Silver nitrate (4.0 equivalents) and NCS (4.0 equivalents) were dissolved in 4: 1 v / v acetonitrile / water (ca. 0.03 M), and a solution of dithianyl acid from step 3 (1 equivalent) was added. ) in acetonitrile (0.009 M) at 25 ° C. After stirring for 10 minutes at 25 ° C, this was added to a solution of sodium sulphide, followed in one minute by a sodium carbonate solution. Work (ethyl acetate / aqueous acid) and chromatography afforded the title compound in 82% yield.

Example 85: 4- [(5-. {3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl.} -2-oxopentanoyl) amino] benzoic acid .

^^^^^^^^^^^^ Step 1: Step dithinyl acid Example 84 was treated as described above by step 2, Example 84, except that ethyl 4-aminobenzoate is substituted. Purification by chromatography gave the dithianyl ester product (R = 4-COOC2H5) in 30% yield.

Step 2 The dithianyl ester from step 1 was treated as described by step 3 of Example 84. Purification by chromatography gave the dithianyl acid product (R = 4-COOH) in 89% yield.

Step 3 The dithianil from step 6 was treated as described by step 4 of Example 84. Repeating purification by chromatography followed by trituration in pentane provided the title compound in 30% yield.

Example 86 Table I reports the data for the compounds described in the above examples in cPLA2 inhibition assays (as described below). In the columns of the data in the tables, the test results are reported as an "IC50" value, which is the concentration of a compound that inhibits 50% of the activity of the phospholipase enzyme in such an assay. Where the numerical value IC50 does not appear, "NA" denotes that the inhibition 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 at the time of submitting the present application .

Activity Essays (a) Vesicle Test The 1-palmi t oi 1 -2 - [14C] arachidonyl phos phiol isocol (58mCi / mmol) (final concentration 6M) and 1,2-dioleiolgl icerol (final concentration 3M) were mixed and dried under a stream of water. nitrogen. 50mM of Hepes pH 7.5 (final 2x concentration of lipids) were added to the lipids and the suspension was sonicated for 3 minutes at 4 ° C. Hepes was added to the suspension 50mM pH 7.5,300mM NaCl, 2mM DTT, 2mM CaCl2 and 2mg / ml bovine serum albumin (BSA) (Sigma A7511) (final concentration 1.2x lipids). A typical assay consisted of the mixture of lipids (851) to which the inhibitor was added consecutively (51 in DMSO) and cPLA2, 10 ng for an automated system or Ing for a manual assay, in 101 of the buffer solution of BSA . This test was carried out either by manual testing or by the automated assay protocol described below. b) Soluble Substrate Test (LysoPC) The 1 - [14 C] -palmi t oi 1-2 -hydroxy fos fot idyl-choline was dried (57mCi / mmol) (final concentration 4.4M) under a stream of nitrogen. The lipid was suspended again when stirring 80mM Hepes pH 7.5.1 mM EDTA (final concentration 1.2x). A typical assay consisted of a suspension (85 1) to which the inhibitor was added consecutively (51 in DMSO) and cPLA2, 200ng in 80mM Hepes pH 7.5,2mM DTT and 1M EDTA This test was carried out in manual assay or by the automated assay protocol described below. c) Automated Test The lipid suspension and the inhibitor were pre-incubated for 7 minutes at 37 ° C. The enzyme was added and the incubation was continuous for an additional 30 minutes. The reaction was then quenched by the addition of decane: isopropanol: trifluoroacetic acid (192: 8: 1 w / v, 1501). A portion of the quench layer (501) was passed through a column of Silica Rainin Spherica-5 (5, 30x2. Mm) eluting with ethane: methanol: TFA (97: 3: 0.1 v / v). The level of arachidonic acid [1 C] was analyzed by an online Radiomatic Flo-One / Beta (packard) counter. d) Manual Test The mixture of lipid, inhibitor and enzyme was incubated at 37 ° C for 30 minutes. The 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 column of disposable silica gel (Whatman SIL, lml) in a vacuum manifold positioned on a scintillation vial. The arachidonic acid with [1 C] free was eluted by the addition of ethyl ether (1 ml). The level of radioactivity was measured by the liquid scintillation counter. (e) PMN test The PMNs were isolated using a Ficoll-Hypaque according to the manufacturers' instructions the red blood cell cells that contaminated the PMNs, were separated by hypotonic lysis, and the PMN pellet was washed once, and was suspended again in a Hanks' buffer solution at a concentration of 2xl06 cells per milliliter. The cells were pre-incubated with inhibitors for 15 minutes at 37 ° C and then stimulated with 2uM A23187. When the production of LTB4 was impaired as a measure of the inhibition of cPLA2, the reaction was quenched with an equal volume of ice cold phosphate buffered saline. The cells were separated by centrifugation, t the LTB4 present in the supernatant of the cells was measured using the LTB4 proximity probe assay provided by Amersham according to the indications of the * ¿. *: -... • .. * - i?, Ii, íí¿ * .- ¿M, *. *. -fcfa - - - p ..- S manufacturers. In the trials reported in the previous tables, LTB4 was measured. Upon observing the production of arachidonic acid, the reaction was quenched with methanol containing arachidonic acid D8 as an internal reference. 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 GC-MS in a manner similar to reported by Ramesha and Taylor ((1991) Anal Biochem. 192, 173-180). (f) RBL test RBL-2H3 cells were routinely cultured in an atmosphere of 5% C02 at 37 ° C, a minimum essential medium containing non-essential amino acids and 12% fetal lamb serum. The day before the experiment, cells were plated in spinner flasks at 3xl05 cells / ml and 100 ng / ml DNI-specific IgE was added. After 20 hours the cells were harvested by centrifugation and washed once in minimal essential medium free of serum, and resuspended up to 2xl05 cells / ml in a serum free medium. The cells were then preincubated with the inhibitor in DMSO (1% v / v) or DMSO (1% v / v) for 15 minutes at 37 ° C followed by stimulation with DNP-BSA (300ng / ml). After 6 minutes, the cells were separated by centrifugation, and the supernatant was assayed for its PGD2 content according to known methods. (g) Coumarin Test 10 The 7-hydroxyoumarinyl 6-heptanoate used as a monomeric substrate for cPLA2 was used as reported previously (Huang, Z. et al., 1994, Nalytical Biochemistry 222, 110-115). 15 The inhibitors were mixed with a 200μL assay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 7-hydroxyurea in i-1-heptanoate 60μM. The reaction was started by adding a buffer solution of 4 μg cPLA2 assay in 20 50μL. The hydrolysis of the 7- hydroxycorter imi 1 6-heptanoate ester was observed in a fluorometer upon excitation at 360 nm and monitoring the emission at 460 nm. The activity of the enzyme is proportional to the increase in emission at 460 nm . *. * * - *** ^ ~ j é¡ / &3i & *. - & sn ***. í * * ** - - *. * ¿*,. »• *, ... * * ***. .. * *. ** l ** * *. , * * * * £ í-.z .... i. ^ ... ^. *. ",. . ^ * ^ ^. . j s ^ ¿s-táj- a * -per minute. In the presence of a cPLA2 inhibitor, the rate of increase is lower.

Example 87 The compounds of the present invention were also tested for in vivo activity in a rat leg edema test according to the procedure described below. The results are reported in table II.

Test for Rat Paw Edema Induced by Carrageenan Each compound was suspended in absolute ethanol 0.3ml, O.lml of Tween-80 and 2. Oml PBS of Dulbecco (with calcium or magnesium). O.lml IN NaOH was added to this mixture. After the solution was complete, additional amounts of PBS were added to adjust the concentration to lmg / ml. All the compounds remained in solution. Compounds were administered intravenously in a volume of 5ml / kg to male Sprague Dawley rats at the same time that the edema was induced by the injection of 0.05ml of ••• "" '' "* '-' carrageenan of type IV at 1% within the hind paw The volume of the paw was measured before dosing with the compound and 3 hours after dosing with carrageenan.

All references to the literature and patents cited here are incorporated as if they were fully established here.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims

1. A component of the formulas: characterized in that Ri and Ri are independently selected from H, halogen, CF3, -OH, alkyl-Ci-Cio-, alkyl -S-Ci-Cio, alkoxy Ci-Cio, -CN, -N02, -NH2, -HN (C? -C6), -N (C? -C6) 2, phenyl -O-, phenyl -S-, benzyl, benzyl -O-, benzyl -S-, or a 10 portion of the formulas: R6 is selected from H, C? -C6 alkyl, C? -C6 alkoxy, phenyl, phenyl -0-, benzyl, benzyl-0-, phenyl and benzyl rings, of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CX-C6 alkyl, alkoxy, C? -C6, -N02, NH2, -CN, -CF3, or -OH; R7 is selected from -OH, -CF3, C? -C6 alkyl, C? -C6 alkoxy, -NH- (C? -C6 alkyl), -N- (C? -C6 alkyl) 2, pyridinyl, tiethyl, furyl , pyrrolyl, phenyl, phenyl-0-, benzyl, benzyl-0-, the rings of these groups being optionally substituted by from 1 to 3 substituents - * - * * a í n ^ Á ^ et # ». *. selected from halogen, -CN, C? -C6 alkyl, C? -C6 alkoxy, -N02, -NH2, -CF3, or OH; R 2 is selected from H, halogen, -CF 3, -OH, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, -CHO, -CN, -N02, -NH 2, -NH- C 1 -C 6 alkyl, N (alkyl) ? C? -C6) 2, -NS02- C? -C6 alkyl, or -S02- C? -C6 alkyl; R3 is selected from H, -CF3, lower alkyl Ci-Ce, lower alkoxy C? -C6, cycloalkyl C3-C? 0, -CHO, halogen, or a portion of the formula -L2-M2: L2 indicates a linking or linking group of the formulas - (CH2) n-, -S-, - 0-, -C (O) -, - (CH2) nC (O) -, - (CH2) nC (0 ) - (CH2) n-, - (CH2) n-0- (CH2) n-, or - (CH2) nS- (CH2) "-, -C (O) C (0) X; where X = O, M is selected from the group of lower alkyl C? -C6, lower alkoxy d-C6, cycloalkyl C3-C? Or, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, Ci-Cio alkoxy, -N02, -NH2, -CN, or -CF3; or a) a five-membered heterocyclic ring containing one or two rings of heteroatoms selected from N, S or O including, but not limited to, furan, pyrrolo, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring members being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, Ci-Cio alkoxy, -N02, -NH2, -CN, or -CF3; or b) a six-membered heterocyclic ring containing one, two or three rings of heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic rings it being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, Ci-Cio alkoxy, -CHO, N02, -NH2, -CN, -CF3 or OH; or c) a bicyclic ring portion containing from 8 to 10 atoms in the ring and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 including, but not limited to, benzofuran, indole, indoline, naphthalene, purine, or quinoline, the bicyclic ring portion being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cio alkyl, Ci-Cio alkoxy, -CHO, NO 2, -NH 2, -CN, -CF 3 or OH; n is an integer from 0 to 3; R4 is selected from the group of lower alkyl C6-C6, lower alkoxy C6-C6, cycloalkyl- (CH2) n-C3-C6, cycloalkyl- (CH2) n- S- (CH2) n-C3-C5, cycloalkyl - (CH2) n-0- (CH2) n-C3-C5, or of the groups of: a) - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-1-CH2-phenyl, - (CH2) n-0-phenyl-CH2-phenyl, - (CH2) n-phenyl- ( 0-CH2-phenyl) 2, - (CH2) n-phenyl- (0-CH2-phenyl-1) -2, -CH2-phenyl-C (O) -benzot-ia-zol or a portion of the formulas: wherein n is an integer from 0 to 3, Y is C3-C5 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thianyl or pyrrolyl; the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -NH2, -N02, or a five-membered heterocyclic ring members containing a heteroatom selected from N, S, or O, b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: * • - » wherein D is H, C?-C6 lower alkyl, C?-C6 lower alkoxy, or -CF3; B and C are independently selected from phenyl, pyrinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, substituents selected from 10 H, halogen -CF3, -OH, alkyl -Ci-Ce, Cx-C6 alkoxy, or -N0; or c) a portion of the formulas: - * A ***** - * JiA « wherein Z is 0 or S and the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , or -N02; R5 is selected from -COOH, -C (0) -COOH, (CH2) nC (0) -COOH, - (CH2) n-C00H, -CH = CH-C00H, (CH2) n-tetrazole, alloalkyl lower Cj-Cg) or a selected portion of the formulas -L -M; wherein L1 is a binding or binding portion selected from a chemical bond, - (CH2) n-, -S-, - 0-, -C (0) -, - (CH2) nC (0), - (CH2 ) nC (0) - (CH2) n, - (CH2) n- 0- (CH2) n, - (CH2) "- S-- (CH2) n, -C (Z) -N (R6) -, -C (0) -C (Z) -N (R6) - (CH2) n, -C (Z) -NH-SO2-, or -C (Z) -NH-S02- (CH2) n, M1 is selected from the group of -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, tetrazole, fifteen OÜ ^ J W? Hit i &í S & í ?. where R8, R9 or Rio can be linked anywhere in the cyclic or bicyclic system, Rs, in each presentation, is independently selected from H, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, tetrazole, 10 ® £ t ^ iíi & amp; amp; & l; s ^^^^^^^^^ l ^^ i ... > Rg is selected from H, halogen, -CF3, -OH, COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, C6-alkyl, -OC-C6 alkyl, - NH (C? -C6 alkyl), or N (to C? -C6) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (C? -C6 alkyl), N (C? -C6 alkyl) 2, ^^^^^^^^^ * ~. ? *. ^ * Ab. « (lower alkyl C-C) lower haloalkyl C -C] (lower alkyl C-C " Rn is selected from H, lower alkyl Ci-Ce, cycloalkyl C? -C6, -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, R8, Rg, Rio and / or R \ \ may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazol, or a portion of the formulas: n is an integer from 0 to 3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, characterized in that it has the formula: wherein R3 is hydrogen and Ri, R2, R4, and R5 are as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, characterized in that it has the formula: wherein Ri, R2, R3, R, and R5 are as described in claim 2, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, characterized in that it has the formula: wherein Ri, R2, R3, R4, and R5 are as described in claim 2, or a pharmaceutically acceptable salt thereof.

The compound of the formulas characterized in that Ri is selected from H. halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -N02, -HN2, -HN (C? -C6), -N (C? -C6 ), phenyl, phenyl-O-, benzyl, benzyl-O-, or a portion of the formulas: Re is selected from H, Ci-Cd alkyl, Ci-Cd alkoxy, phenyl, -O-phenyl, benzyl, -O-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? -C6 alkoxy, -NH2, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) 2, - (CH2) n-NH- (C6-C6 alkyl), -CF3, C-alkyl? -C6, C3-C5 cycloalkyl, C6-C6 alkoxy, NH- (C 1 -C 6 alkyl), -N- (C 1 -C 6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl-O-, adamantyl or morpholinyl, the these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C? -C6 alkyl, Ci-C6 alkoxy, -NH2, -N02, -CF3, or -OH; R2 is selected from H, halogen, -CF3, -OH, C? -C? 0 alkyl, Ci-Cio alkoxy, -CHO, -CN, N02, -NH2, -NH-C? -C6 alkyl, N ( CX-C6 alkyl) 2, N-S02-alkyl- (CH2) n-0-phenyl-CH2-phenyl, or -S02-Ci-C6 alkyl; R3 is selected from the group of lower alkyl C? -C6, lower alkoxy Ci-C?, - (CH2) n-C3-C6 cycloalkyl, - (CH2) n-S- (CH2) n-C3-C6 cycloalkyl, or the groups of: a) - (CH2) n-phenyl-O-phenyl, - (CH2) n-pheny1-CH2-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (O) -benzothiazole or a portion of the formulas: (CH2), "\ ^ (CH2 c ^ Y wherein n is an integer from 0 to 3, Y is C3-Cd cycloalkyl, phenyl benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl; the rings of these groups are optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -NH2, -N02, or a heterocyclic ring of 5 members, which contains 10 a heteroatom selected from N, S ,; or b) a portion of the formulas - (CH2) n_A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion. fifteen wherein D is H, C?-C6 lower alkyl, d-C6 lower alkoxy, or -CF3; B and C are independently selected from the 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 alkoxy ? ~ C6, or -N02; or c) a portion of the formulas: wherein the phenyl and benzyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, or -N02; R 4 is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (O) -phenyl, -C (O) -benzyl , CH2- (C3-C6 cycloalkyl), -C (0) -OH, -CH = 0, -C (O) -alkyl C? ~ C6, -C (O) -O-C? -C6 alkyl, -C (O) -CF3, - (CH2) n-S-CH2- (C3-C6 cycloalkyl), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, C? -C6 alkyl, Ci-C? alkoxy, -N02, -CF3, -C (0) -OH, or - OH; n is an integer from 0 to 3; R5 is selected from -COOH, -C (0) -C00H, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, __ÍÍ__? *? ^ ¡^ ^ B ^ is®j i erior C -C) R8 is selected from H, -COOH, - (CH2) n -COOH, (CH2) n-C (O) -COOH, tetrazole, Rg is selected from H, halogen, -CF3, -OH, (CH2) n -COOH, - (CH2) nC (O) -COOH, -C? -C6 alkyl, -0-C? -C6 alkyl, -NH (C? -C6 alkyl), or -N (C-alkyl) ? -C6) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (alkyl C? -C ( N (C? -C6 alkyl) 2, lower alkyl C | -Cg), Rn is selected from H, lower alkyl Ci-Ce, -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, or with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, Rs, R9, ic and / or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: or a pharmaceutically acceptable salt thereof 10 The compound of the formulas Jt &aHk * i¡Íti & ¡.? . ,, - & *. * sie¿ ^ ..-,: characterized because Ri is selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -N02, -HN2, phenyl, phenyl-O-, benzyl, benzyl-O-, benzyl-S- or a portion of the formulas: Re is selected from H, C? -C6 alkyl, Ci-Ce alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-C6 alkyl, C6-C6 alkoxy, -N02, -CF3, or -OH; •? fa ~ • * - '- ^ • ".«. »«.

R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) 2, - (CH2) n-NH- (C6-C6 alkyl), -CF3, C-alkyl C6, C3-C5 cycloalkyl, Ci-Cß alkoxy, NH- (C?-C6 alkyl), -N- (C?-C6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl-O-, 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? -C6 alkoxy, -N02, -CF3, or -OH; R2 is selected from H, halogen, -CF3, -OH, Ci-Cio alkyl, Ci-Cio alkoxy, -CHO, -CN, N02, -NH2, -NH-C-C6-alkyl, N (C-alkyl? -C6) 2, -N-S02-alkyl -S02-C6-C6 alkyl; R3 is selected from H, halogen, -CF3, -OH, Ci-Cß alkyl, C?-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (0) -phenol, -C (O) -benzyl, CH2- (C3-C5 cycloalkyl), -C (0) -OH, -CH = 0, -C (O) -alkyl C? -C6, -C (O) -O-C? -C6 alkyl, -C (0) -CF3, - (CH2) nS-CH2- (C3-C5 cycloalkyl), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, C? -C6 alkoxy C? -C6 alkyl, -N02, -CF3, -CO (0) -OH, or - OH; n is an integer from 0 to 3; R 4 is selected from the groups of C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, C 3 -C 5 - (CH 2) n -cycloalkyl, - (CH 2) n ~ S- (CH 2) n-cycloalkyl C 3 -C 5 , - (CH2) n-0- (CH2) n-cycloalkyl C? ~ C6, or the groups of: a) - (CH2) n-phenyl-O-phenyl, - (CH2) n-phenyl-1-CH2-phenyl, - (CH2) n-0-phenyl-CH2-f-enyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, - (CH2) n-phenyl- (0-CH2-pheni1) 2, -CH2-phenyl-C (O) -benzothiazole or a portion of the formulas: wherein n is an integer from 0 to 3, Y is C3-C6 alkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl; the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, Ci-Cß alkyl, Ci-Ce alkoxy, -N02, or a 5 membered heterocyclic ring, containing a heteroatom selected from N, S ,; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: fifteen ? ^ M * ^? & ^ ¿¡£ g £ -% *. í * < m- ^ ¿i * ^^: where D is H, lower alkyl C? ~ C6, lower alkoxy Ci-Ce, or -CF3, B and C are independently selected from the phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituent is selected from H, halogen -CF3, -OH, alkyl -C? ~ C6, alkoxy C? -C6, or -N02; or c) a portion of the formulas S, wherein Z is O or S and the phenyl and pyrimidyl rings of each portion are optionally and independently from 1 to 3 substituents selected from halogen, -CF 3, -OH, C 1 -C 6 alkyl, Ci-C 6 alkoxy, or NO2; R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, tojj, - ¿g &é £ m sS ^, * Rs is independently selected from H, COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, tetrazole, Rg is selected from H, halogen, -CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, - NH (C? -C6 alkyl), or -N (Ci-C6 alkyl) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, alkyl -NH (C? -C6 alkyl), N (C? -C6 alkyl) z, .. I. i l i a jfcat-Aéto. or N '? lower alkyl C -C) ° V ° "lower haloalkyl C ^ -C) o), Rn is selected from H, lower alkyl Ci-Cß, • CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, or with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, R8, Rg, R? or > and / or Ri may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: * -% - < £ ¿ i - m & M ** or a pharmaceutically acceptable salt thereof A compound of the formulas characterized because Ri is selected from H. halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -N02, -HN2, phenyl, phenyl-O-, benzyl, benzyl-O-, or a portion of The formulas: 10 6 -O- -N- R7- R6 is selected from H, C? -Calkyl, C? -C6 alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups by being optionally substituted by from 1 to 3 selected substituents of halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, or -OH; R 7 is selected from - (CH 2) n -COOH, - (CH 2) nN- (C 1 -C 6 alkyl) 2, - (CH 2) "-NH- (C 1 -C 6 alkyl), -CF 3, C 1 alkyl C, C3-C5 cycloalkyl, C? -C6 alkoxy, NH- (C? -C6 alkyl), -N- (C? -C6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O-, benzyl, benzyl-O-, adamantyl or morpholinyl, the pyridinyl, phenyl and benzyl rings of these groups being optionally substituted by ^^^ táfewSjj fe ^ 1 to 3 substituents selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, or -OH; R2 is selected from H, halogen, -CF3, -OH, C? -C? 0 alkyl, Ci-Cio alkoxy, -CHO, -CN, N02, -NH2, -NH-C? -C6 alkyl, N ( C? -C6 alkyl) 2, N-S02-alkyl or -S02-C? -C6 alkyl; R3 is selected from the group of lower alkyl Ci-Cd, lower alkoxy C? -C6, - (CH2) n- C3-C6 cycloalkyl, - (CH2) nS- (CH2) n- C3-C6 cycloalkyl, or the groups of : a) - (CH2) n-phenyl-O-phenyl, - (CH2) n-pheni 1 -CH2-phenyl, - (CH2) nO-phenyl, - (CH2) n- (0-CH2-pheny1) 2 , CH2-pheni 1-C (O) -ben zot-iazole or a portion of the formulas: ^ (CH2) ^ ^, (CH;,) ^ wherein n is an integer from 0 to 3, Y is C3-C6 alkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl, or pyrrolyl; the rings of these groups are optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -Cd alkyl, Ci-Ce alkoxy, -N02, or a 5 membered heterocyclic ring. , which contains a heteroatom selected from N, S; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion: i i affei4fcfcJ -J where D is H, lower alkyl C? -C6 / lower alkoxy C? -C6, or -CF3; B and C are independently selected from the 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 1 alkoxy -C6, -NH2 or -N02; or c) a portion of the formulas wherein Z is 0 or S and the phenyl and pyrimidyl rings of each moiety are optionally and independently from 1 to 3 sub t ti tyent is selected from halogen, -CF3, OH, C? -C6 alkyl, C? -C6 alkoxy , or -N02, -NH2; R 4 is selected from H, halogen, -CF 3, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C (0) -phenyl, -C (0) -benzyl, CH2- (C3-C6 cycloalkyl), -C (0) -0H, -CH = 0, -C (0) -alkyl C? -C6, -C (0) -O-C? -C6 alkyl, -C (0) -CF3, - (CH2) n-S-CH2- (C3-C6 cycloalkyl), the phenyl and benzyl rings of the relevant groups R3 being optionally substituted by from 1 to 3 groups selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, -C0 (0) -0H, or -OH; n is an integer from 0 to 3; R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (O) -COOH, - (CH2) n -COOH, -CH = CH-COOH, "V OH R8 is selected from H, -COOH, - (CH2) n -COOH,; CH2) n-C (O) -COOH, tetrazole, Rg is selected from H, halogen, -CF3, -OH, (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (C 1 -C 6 alkyl), or -N (ci-c 6 alkyl) 2; Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (C? -C6 alkyl), N (C? -C6 alkyl) 2, lower C -Cg); Rxx is selected from H, lower alkyl C? -C6, -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, or with the proviso that the complete portion in position 1 of indole or indoline created by any combination of R5, R8, R9 > RIO and / or Rn may contain at least one acid portion selected from or containing a carboxylic acid, a tetrazole, or a portion of the formulas: or a pharmaceutically acceptable salt thereof A component of the formulas characterized in that Ri is selected from -HN2, phenyl, phenyl-O-, benzyl, benzyl-O-, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl or a portion of the formulas: -afc * »R6 is selected from H, alkyl C? ~ C, C6-C6 alkoxy, phenyl, phenyl-O-, benzyl, benzyl-O-, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C? -C6 alkyl , C6-C6 alkoxy, -N02, -CF3, or -OH; R7 is selected from - (CH2) n -COOH, - (CH2) nN- (C6-C6 alkyl) 2, - (CH2) n -NH- (C6-C6 alkyl), -CF3, Ci-alkyl -Ce, C-C5 cycloalkyl, C? -C6 alkoxy, -NH- (C? -C6 alkyl), -N- (C? -C6 alkyl) 2, pyridyl, thienyl, furyl pyrrolyl, phenyl, phenyl-O- , benzyl, benzyl-O-, adamantyl or morpholinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, Ci-Cd alkyl, C? -C6 alkoxy, -N02, -CF3, or - OH; n is an integer from 0 to 3; R3 is selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -CF3, -CH = 0, -C (O) -C? -C6 alkyl, -C (0) -0- C- alkyl C6, -C (0) -OH, -C (0) -CF3, -C (O) -phenyl, -C (O) -benzyl, -C (O) -pyrrolyl, -C (O) -25 thienyl, -C (O) -furanyl, or -C (O) -moefol ini lo; J6 ¥ * iiSt¡¡ & , M > . . . .-. "I" .. »... * n.- < > .. «-» ». a t. - - »« .- ** .. - > • . ** * «> t i at? ni? xe *.

R4 is selected from the group of, - (CH2) n- (C3-C6 cycloalkyl), - (CH2) nS- (CH2) n- (C3-C5 cycloalkyl), - (CH.) NO- (CH2) n- (C3-C6 cycloalkyl), (CH2) nS- C6-C6 alkyl, the groups of: a) -C (0) -0- (CH2) n-cycloalkyl, ~ (CH2) n-phenyl, - (CH2) n-0-phenyl, - (CH2) nS-phenyl, - (CH2) nS- ( CH2) n-phenyl, - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) n-0-phene lo-CH2- phenyle, (CH2) n phenyl- (0-CH2-phenyl) 2, -C (0) -0-phenyl, C (0) -O-benzyl, -C (0) -0-pyridinyl, -C (0) -0-naphthyl, - (CH2) nS-naphthyl, - (CH2) nS-pi r idini lo, ( CH2) n-pyridinyl, or - (CH2) n-na ft i lo, - (CH2) n-0-naphthyl, the phenyl, pyridinyl, and naphthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, C? -C6 alkyl, C? -C6 alkoxy, -N02, or a ring containing five heterocyclic heteroatom members, selected from N, S, or 0; or b) a portion of the formulas - (CH2) n-A, (CH2) n-S-A, or - (CH2) n-0-A, where A is the portion wherein D is H, C 1 -C 6 lower alkyl, C 6 -C 6 alkoxy, • CF, R5 is selected from -COOH, -C (0) -COOH, (CH2) n-C (0) -COOH, - (CH2) n -COOH, -CH = CH-COOH, R8 is selected from H, -COOH, - (CH2) n -COOH, CH2) n-C (0) -COOH, tetrazole, - Rg is selected from H, halogen, -CF3, -OH, (CH2) n -COOH, - (CH2) nC (O) -COOH, alkyl -C? -C6, alkyl -0-C? -C6, -NH (C 1 -C 6 alkyl), or -N (C 1 -C 6 alkyl) 2, Rio is selected from the group of H, halogen, CF3, -OH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, alkyl -Ci-Ce, alkyl -0-C? -C6, - NH (C? -C6 alkyl), N (C? -C6 alkyl) 2, Rn is selected from H, lower alkyl C? -C6,? CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (O) -COOH, or with the proviso that the entire portion in position 1 of indole or indolma created by any combination of R5, R

8, Rg, Rxc and / or R? may contain at least one acid portion selected from or containing an acid Carboxylic acid, a tetrazole, or a portion of the formulas: • ^ aa- «a ^ a ^. * - * * or a pharmaceutically acceptable salt thereof

9. The pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 5, or a salt Pharmaceutically acceptable thereof, and a pharmaceutically acceptable carrier or excipient. - g ^^ gMjjtgi?

11. The pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

12. The pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

13. The pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5- [(cyclopentylcarbonyl) amino] -2 - [(phenethylsulfanyl) methyl] -lH-indol-1- ylmethyl) benzoic acid c a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 characterized in that it comprises 4- [(3-chloro-5- [(cyclopentylcarbonyl) amino] -2- {[[2-furylmethyl) sulphyl] met i 1. lH-indol-1-yl) met il] benzoic acid or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, characterized in that it comprises 4- [(3-chloro-5- [(cyclopentylcarbonyl) amino] -2- {[[4-hydroxy-6-phenyl-2-pyrimidini]] 1) Sulfanyl] -15-methyl-lH-indol-1-yl) methyl] benzoic acid or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, characterized in that it comprises 4 - acid. { [3-chloro-5- [(cyclopentylcarbonyl) amino] -2- ( { [4- (2-thienyl) -2-pyrimidyl] sulfanyl Jmethyl) -1H-indol-1-yl] met il} benzoic acid or a pharmaceutically acceptable salt thereof. __a ^? - - £ - ^ - ^ z __! ^! ^ - + -. S? Xt > - ^ ¡¡ > - »? > a * - ^ #sJk ^? ._ - *. » . JA-, ¿-, < * -. A > *, -% j, * A ¡* .¿¡¡ & > (you *

18. The compound according to claim 1 characterized in that it comprises 4 -. { [3-chloro-5- [(cyclopentylcarbonyl) amino] -2- [(2,4-dibromo phenoxy) methyl] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 characterized in that it comprises 4 - (. {3-chloro-5- [(cyclopentylcarbonyl) amino] -2- [(cyclopentylsulfanyl) methyl] -lH-indol-1-yl}. met il) benzoic acid or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5- [(cyclopentylcarbonyl) amino] -2- [(propylsulfanyl) methyl] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, characterized in that it comprises 4- ( { 2- { [4 - (tert-Butyl) phenoxy] met il.}. -3-chloro acid - '*. - ««. * t '^ iM' -5- [(cyclopentylcarbonyl) amino] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5- [(cyclopentylcarbonyl) amino] -2 - [(2-quinolinylsulfanyl) methyl] -lH-indol-1-ylmethyl} ) benzoic acid or a pharmaceutically acceptable salt.

23. The compound according to claim 1 characterized in that it comprises 4- [(3-chloro-5- [(cyclopentylcarbonyl) to ino] -2-. {[[(Cyclopropylmethyl) sulfanyl] methyl J-1H-indo 1-1] -yl) methyl] benzoic acid or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 characterized in that it comprises 4- (. {2- [(benzyhydylsulfanyl) methyl] -3-chloro-5- [(cyclopentylcarbonyl) amino] -lH-i dol-1-ylmethyl] benzoic acid or a pharmaceutically salt thereof. , ..... , ».",. .., .- .., n ^ «. ~. -the*-.- . fnfr -

25. The compound according to claim 1, characterized in that it comprises 4- (. {5 - [(3-carboxypropanoyl) amino] -3-chloro-2- [(phenethylsulfanyl) methyl] -lH-indole- 1-i 1.} Met il) ben zói co or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1 characterized in that it comprises 4 - [(5- [(3-carboxypropanol) amino] -3-chloro-2-. {[[(3-methylbenzyl) sulfanyl] methyl] acid. lH-indol-1-yl) met yl] benzoic acid or a pharmaceutically salt thereof.

27. The compound according to claim 1 characterized in that it comprises 4- (. {2- ( { [4- (tert-Butyl) benzyl] sulfanyljmethyl) -5- [(3-carboxypropanoyl) amino-3-chloro) -lH- indol-1-i 1.} met i 1) benzoic or a pharmaceutically salt of the same.

28. The compound according to claim 1, characterized in that it comprises 4- (. {3-chloro-5- (3-furoi-lamino) -2- [(2-naphthylsulfanyl) methyl] -lH-indo-1-ylmethyl} ) benzoic acid or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 1, characterized in that it comprises 4- (. {5- (acetylamino) -3-chloro-2- [(2-naphthylsulopylyl) methyl] -lH-indo-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

30. The compound according to claim 1, characterized in that it comprises 4- (. {3-chloro-5- { [3- (diethylamino) propanoyl] amino] -2- [(2-naphthylsulfanyl) methyl] ] -lH-i do1-1-ylmethyl) benzoic acid 15 or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsul-phenyl) methyl] -5- [20 ((3-thienylcarbonyl) amino] -lH-indo 1) -1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 1 characterized in that it comprises , * J ** £ ^ .. * ~ - *. ,., ..- * * ..., .. *: ,, ..., - ..,. . ...,.,- ...*"-., ..... ,,..Y ... . . ,, ^ ~, - \ *. * .- ******** * M 4- ( {5 { [[(Benzylamino) car onyl] amino} -3-chloro-2- [(2-naphthylsulphyl)] ethyl] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

33. The compound according to claim 1, characterized in that it comprises 4- ( { [5-. {[[(Butyl amino) carbonyl] amino} -3-chloro-2- [(2-naphthylsulphyl) methyl] ] - 1H-indol-1-yl) methyl) enzoic acid or a pharmaceutically acceptable salt thereof.

34. The compound according to claim 1 characterized in that it comprises 3- [(. {1- (4-carboxybenzyl) -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indol-5-yl] amino) carbonyl] benzoic acid or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 1 characterized in that it comprises 4- acid. { [5- (benzyloxy) -2- [(E) -2-carboxyethenyl] -3- (2-naphthoyl) -lH-indol-1-yl] methylbenzoic acid or a pharmaceutically acceptable salt thereof. . ..- .,-,".-..-- -.. ..... 4 . ^ - »>

36. The compound according to claim 1, characterized in that it comprises 4- (. {3-acetyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) ethyl] -lH-indol-1-yl} methyl) benzoic acid or a pharmaceutically acceptable salt thereof.

37. The compound according to claim 1 characterized in that it comprises 4- acid. { [5- (benzyloxy) -2- [(2-naphthylsulfanyl) methyl] -3- (2,2,2-trifluoroacetyl) -lH-indol-1-yl] met il} benzoic acid or a pharmaceutically acceptable salt thereof.

38. The compound according to claim 1, characterized in that it comprises 4 - (. {5 - [(4-aminobutanoyl) amino] -3-chloro-2- [(2-naphthylsulfanyl) ethyl] -lH-1-1-acid. -yl Jmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5- [(cyclopentylcarbonyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -lH-indo 1-1-il Jmetil) benzoic or a pharmaceutically acceptable salt of the same.

40. The compound according to claim 1, characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsulfanyl) methyl] -5 - [(2-quinoxalinylcarbonyl) amino] -1H-indole 1- il Jmet il) benzoic acid or a pharmaceutically acceptable salt thereof.

41. The compound according to claim 1 characterized in that it comprises' 4- (. {3. Chloro-5- [(2,2-dimethylpropanoyl) amino] -2- [(2-naphthylsulfanyl) methyl] -lH-indo acid. 1-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

42. The compound according to claim 1 characterized in that it comprises 4 - (. {5 - { [(Benzyloxy) carbonylamino} - 3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indo acid 1-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

43. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5-. {[[(Cyclopentyloxy) carbonyl] amino] -2- [(2-naphthylsulfanyl) methyl] -lH-indole. -1-i 1.} Met i 1) benzoic acid or a pharmaceutically acceptable salt thereof.

44. The compound according to claim 1 characterized in that it comprises 4 - (. {5- (acetylamino) -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

45. The compound according to claim 1 characterized in that it comprises 4- (. {5- ({[[(butylamino) carbonyl] amino} -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH acid -in 1-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

46. The compound according to claim 1, characterized in that it comprises 4- (. {5- ({[[(butylamino) carbonyl] amino} -3-chloro-2- [(2-naphthysulfanyl) methyl]] -IH-indo 1-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

47. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-5- [(morpholinocarbonyl) amino] -2- [(2-naphthylsulphyl) methyl] -lH-indo 1-1- il Jmetil) benzoic acid or a pharmaceutically acceptable salt thereof.

48. The compound according to claim 1, characterized in that it comprises 4- (. {5- (benzylamino) -3-chloro-2- [(2-naphthylsulopyl) methyl] -lH-indo-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

49. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsulopyl) methyl] -5- [(3-phenoxybenzyl) amino] -lH-indo1-1 acid -yl Jmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

50. The compound according to claim 1 characterized in that it comprises 4 - (. {3-chloro-5- [(cyclopentylcarbonyl) (methyl) amino] -2 - [(2-naphthylsulfanyl) methyl] -lH-indole- 1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

51. The compound according to claim 1 characterized in that it comprises 0 4 - (. {5- [acetyl (benzyl) amino] -3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indole-1- il Jmetil) benzoic acid or a pharmaceutically acceptable salt thereof.

52. The compound according to claim 1 characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsulfanyl) methyl] -5- [(tetrahydro-3-furanylcarbonyl) amino] -lH-indole -1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

53. The compound according to claim 1, characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsulfanyl) methyl] -5- [(thienylcarbonyl) amino] -lH-indole-1 acid. -il Jmetil) r * t-a & -. .. ». . t, ",. benzoic acid or a pharmaceutically acceptable salt thereof.

54. The compound according to claim 1, characterized in that it comprises 4- (. {3-chloro-2- [(2-naphthylsulopyl) methyl] -5- [(1-adama-tylcarbonyl) amino] -lH-indo1- 1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

55. The compound according to claim 1, characterized in that it comprises 3- [(. {L- (4-carboxybenzyl) -3-chloro-2- [(2-naphthylsulphyl) methyl] -lH-indo1- acid. 5- 15 il.} Amino) carbonyl] benzoic acid or a pharmaceutically acceptable salt thereof.

56. The compound according to claim 1, characterized in that it comprises 20 4 - ( { 3. Chloro-2- [(2-naphthylsulphyl) methyl] -5- [(3-phenylpropanoyl) amino] -lH-indo 1-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt acceptable of it. ^ »« »^^^^» ^ ¡g £ ^^^^ »

57. The compound according to claim 1 characterized in that it comprises 4- (. {5-amino-3-chloro-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-ylmethyl) benzoic acid or a salt pharmaceutically acceptable thereof.

58. The compound according to claim 1 characterized in that it comprises N-. { chloro-l- (4-. {[[(methylsulfonyl) amino] carbonyl J-benzyl) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

59. The compound according to claim 1 characterized in that it comprises N-. { 3-Chloro-2- [(2-naphthylsulfanyl) methyl] -l- [4- (. {[[(4-nitrophenyl) sulfonyl] amino} carbonyl) benzyl] -1H-indol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

60. The compound according to claim 1, characterized in that it comprises N-. { 3-chloro-l- [4- (. {[[(2-methylphenyl) sulfonyl] amino} carbonyl) benzyl] -2- [(2-naphthylsulfanyl) methyl] -1H- indole-5-il} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

61. The compound according to claim 1 characterized in that it comprises N- [3-chloro-2 - [(2-naphthylsulfanyl) methyl] -1- (4-. {[[(Phenylsulfonyl) amino] carbonyl J-benzyl) -lH-indole -5-yl] cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

62. The compound according to claim 1 characterized in that it comprises N-. { 3-Chloro-2- [(2-naphthylsulphyl) methyl] -1- [4- ( { [(Trifluoromethyl) sulfonyl] aminocarbonyl) benzyl] -lH-indol-5-yl} cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

63. The compound according to claim 1 characterized in that it comprises 4- [5- [(cyclopentylcarbonyl) amino] -2- [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indole-1-yl ] butanoic acid or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 1 characterized in that it comprises 4- acid. { 5- [(Cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2- [(2-naphthyloxy) methyl] -1H-indol-1-yl] butanoic acid or a pharmaceutically acceptable salt thereof.

65. The compound according to claim 1 characterized in that it comprises N- [2- [(2-naphthyloxy) methyl-1- (4-oxo-4-. {[[(Trifluoromethyl) sulfonyl] aminojbutyl) -3- (1- pyrrolidinylcarbonyl) -lH-indol-5-yl] cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

66. The compound according to claim 1 characterized in that it comprises N- [3- (morpholinocarbonyl) -2- [(2-naphthyloxy) methyl] -1- (4-oxo-4-. {[[(Trifluoromethyl) sulfonyl] aminojbutyl) -lH-indol-5-yl] cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

67. The compound according to claim 1 characterized in that it comprises 5- [(cyclopentylcarbonyl) amino] -2- [(2- - "L i * -i naphthyloxy) methyl] -1- (4-oxo-4-. {[[(Trifluoromethyl) sulfonyl] amino J butyl) -lH-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

68. The compound according to claim 1 characterized in that it comprises 2- (4- {[[5- (benzyloxy) -3- (l-naphthoyl) -lH-indol-1-yl] methyl} phenyl) acetic acid or a pharmaceutically acceptable salt thereof.

69. The compound according to claim 1 characterized in that it comprises 2- (4- { [5- (benzyloxy) -3- (2-naphthoyl) -lH-indol-1-yl] met il.}. Feni acid. ) acetic acid or a pharmaceutically acceptable salt thereof.

70. The compound according to claim 1 characterized in that it comprises 2- [4- (. {5- (benzyloxy) -3- [3,5-bis (trifluoromethyl) benzoyl] -lH-indole-1-yl-yl-yl-yl} ) phenyl] acetic acid or a pharmaceutically acceptable salt thereof.

71. The compound according to claim 1 characterized in that it comprises 4- (. {3. Benzoyl-5- (benzyloxy) -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-1-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof.

72. The compound according to claim 1 characterized in that it comprises 4- (. {5- (benzyloxy) -3-isobutyryl-2- [(2-naphthylsulfanyl) met il] -lH-indol-1-yl}. met il) benzoic acid or a pharmaceutically acceptable salt thereof.

73. The compound according to claim 1 characterized in that it comprises 2 -. { 3-Acetyl-5- (benzyloxy) -2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-yl} methyl) acetic acid or a pharmaceutically acceptable salt thereof.

74. The compound according to claim 1, characterized in that it comprises 2- acid. { 5- (benzyloxy) -3-isobutyryl-2- [(2-naphthylsulfanyl) methyl] -lH-indol-1-ylmethyl) acetic acid or a pharmaceutically acceptable salt thereof.

75. The compound according to claim 1 characterized in that it comprises 4- acid. { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl-J-tatanoic acid or a pharmaceutically acceptable salt thereof.

76. The compound according to claim 1, characterized in that it comprises 3 - [(4- {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indo-1-yl] Jbutanoil acid. amino) benzoic acid or a pharmaceutically acceptable salt thereof.

77. The compound according to claim 1, characterized in that it comprises 4-. { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} -N- [3 ( { [(Trifluoromethyl) sulfonyl] amino} carbonyl) phenyl] butanamide or a pharmaceutically acceptable salt thereof.

78. The compound according to claim 1 characterized in that it comprises acid A-l (4-. {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indo1-1-yl Jbutanoil amino) benzoic acid or a pharmaceutically acceptable salt thereof.

79. The compound according to claim 1, characterized in that it comprises 2- [(4- {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl] Jbutanoil acid. amino) benzoic acid or a pharmaceutically acceptable salt thereof.

80. The compound according to claim 1 characterized in that it comprises 3 - [(4. {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl acid} butanoyl) amino] propanic or a pharmaceutically acceptable salt thereof.

81. The compound according to claim 1 characterized in that it comprises 3- [(4. {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -1H-indol-l-yl acid} butanoyl) amino] propanic or a pharmaceutically acceptable salt thereof.

82. The compound according to claim 1 characterized in that it comprises N- (4-. {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} acid. butanoyl) -2-methybenzenesulfonamide or a pharmaceutically acceptable salt thereof.

83. The compound according to claim 1, characterized in that it comprises 5- acid. { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} pentanoic or a pharmaceutically acceptable salt thereof.

84. The compound according to claim 1 characterized in that it comprises 3 - [(5. {3-benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) methyl] -lH-indol-1-yl acid} pentanoyl) amino] benzoic acid or a pharmaceutically acceptable salt thereof.

85. The compound according to claim 1, characterized in that it comprises 5- acid. { 3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indo 1-1-yl JN- [3- ( { [(Trifluoromethyl) sulfonyl] aminojcarbonyl] phenyl] p entanamide or a pharmaceutically acceptable salt thereof.

86. The compound according to claim 1, characterized in that it comprises 2- acid. { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} acetic acid or a pharmaceutically acceptable salt thereof.

87. The compound according to claim 1 characterized in that it comprises (E) -4- acid. { 3-Benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) met il] -lH-indol-1-i 1} -2-butanoic acid or a pharmaceutically acceptable salt thereof.

88. The compound according to claim 1 characterized in that it comprises 3- (. {3. Benzoyl-5- (benzyloxy) -2 - [(2-naphthyloxy) met yl] -lH-indol-1-yl benzoic acid or a pharmaceutically acceptable salt thereof.

89. The compound according to claim 1, characterized in that it comprises 1-. { 1- [4- (1, 3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) -2- [(2-naphthylsulfanyl) methyl] -1H-indol-3-yl} -1-ethanone or a pharmaceutically acceptable salt thereof.

90. The compound according to claim 1, characterized in that it comprises l-. { l- [3- (1, 3-Benzothiazol-2-ylcarbonyl) benzyl] -5- (benzylsulfanyl) -2 - [(2-naphthylsulfanyl) methyl] -lH-indol-3-yl} -1-ethanone or a pharmaceutically acceptable salt thereof.

91. The compound according to claim 1, characterized in that it comprises 2- [3- (. {3-acetyl-5- (benzyloxy) -2 - [(2-naphthylsulphyl) methyl] -lH-indo-1-yl acid Jmethyl) benzoyl] -1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof.

92. The compound according to claim 1, characterized in that it comprises 5- acid. { 3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indol-1-yl} -2-oxopentanoic or a pharmaceutically acceptable salt thereof.

93. The compound according to claim 1, characterized in that it comprises "Ugly To l-aa-átefeaí tt &.. Ia-a 3 - [(5- {3-benzoyl-5- (benzyloxy) -2- [(2- naphthyloxy) methyl] -1H-indol- 1 -i 1.} -2-oxopentanoyl) amino] benzoic acid or a pharmaceutically acceptable salt thereof. 5

94. The compound according to claim 1, characterized in that it comprises 4- [(5- {3-benzoyl-5- (benzyloxy) -2- [(2-naphthyloxy) methyl] -lH-indole-1 acid. -yl.} -2- 10-oxopentanoyl) amino] benzoic acid or a pharmaceutically acceptable salt thereof.

95. The compound according to claim 1, characterized in that it comprises 15 3- (. {4- [5- [(Cyclopentylcarbonyl) amino] -2- [(2-naphthyloxy) methyl] -3- (1-pyrrolidinylcarbonyl) -1H-indol-1-yl} amino} ) benzoic acid or a pharmaceutically acceptable salt thereof.

96. The compound according to claim 1, characterized in that it comprises 3- [(4- {5- [(cyclopentylcarbonyl) amino] -3- (morpholinocarbonyl) -2- [(2-naphthyloxy) meyyl] - 1H- indol-1-yl Jbutanoyl) amino] benzoic acid or a salt Pharmaceutically acceptable thereof. . .A > a. ^ J-t-a - ¿, «- J --- ^

97. The compound according to claim 1 characterized in that it comprises N- [2 - [(2-naphthyloxy) methyl] -l-. { 4-oxo-4- [3- ( { [(Trifluoromethyl) sulfonyl] amino.}. Carbonyl) anilino] butyl J -3- (1-pyrrolidinylcarbonyl) -lh-indol-5-yl] cyclopentanecarboxamide or a salt pharmaceutically acceptable thereof.

98. The compound according to claim 1, characterized in that it comprises N- (3- (morpholinocarbonyl) -2- [(2-naphthyloxy) 1-1- got { 4-Oxo-4- [3- ( { [(Trifluoromethyl) sulfonyl] amino] carbonyl Jcarboni 1) anilino] butyl J-lH-indol-5-yl) cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof.

99. The compound according to claim 1 characterized in that it comprises 2- (4-. {[[5- (benzyloxy) -3- (1-naphthoyl) -lH-indol-1-yl] phenyl) acetic acid or a salt pharmaceutically acceptable thereof.

100. A method for inhibiting phospholipase activity in a mammalian subject in need thereof characterized in that and administers to the subject an effective therapeutic amount of a pharmaceutical composition according to claim 9.

101. A method for inhibiting phospholipase activity in a mammalian subject in need thereof characterized in that and administers to the subject an effective therapeutic amount of a pharmaceutical composition according to claim 10.

102. A method for inhibiting phospholipase activity in a mammalian subject in need thereof characterized in that and administers to the subject an effective therapeutic amount of a pharmaceutical composition according to claim 11.

103. A method for inhibiting phospholipase activity in a mammalian subject in need thereof characterized in that and administers to the subject an effective therapeutic amount of a pharmaceutical composition according to claim 12.

104. A method for inhibiting phospholipase activity in a mammalian subject in need thereof characterized in that it delivers to the subject an effective therapeutic amount of a The pharmaceutical composition according to claim 13.

105. A method for the treatment of an anti-inflammatory response in a mammalian subject 10 need thereof, characterized in that it comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 9. 15

106. A method for the treatment of an anti-inflammatory response in a mammalian subject in need thereof, characterized in that it comprises administering to the subject a The therapeutically effective amount of a pharmaceutical composition according to claim 10.

107. A method for the treatment of 25 an anti-inflammatory response in a subject ^ ¿& 3¡ | ^ ^^^^^^^^^^ mammal that needs it, characterized in that it comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 11.

108. A method for the treatment of an anti-inflammatory response in a mammalian subject in need thereof, characterized in that it comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 12.

109. A method for the treatment of an anti-inflammatory response in a mammalian subject in need thereof, characterized in that it comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 13. ....