HRP20000552A2 - Inhibitors of phospholipase enzymes - Google Patents

Description

Known state of the art

This invention relates to chemical inhibitors of various phospholipase enzymes, especially A2 phospholipase enzymes.

Leukotrienes and prostaglandins are important mediators in inducing inflammation, with each of these two classes contributing to the development of the inflammatory response in a specific way. Leukotrienes attract inflammatory cells such as neutrophils to the site of inflammation, promote the shedding of these cells, and stimulate the release of tissue-damaging superoxide and proteases. Leukotrienes also play a pathophysiological role in the hypersensitivity suffered by asthmaticsR1 [see, for example, B. Samuelson et al., Science. 237: 1171-76 (1987)]. Prostaglandins increase inflammation by increasing blood flow and thus the infiltration of leukocytes to the inflammatory site. Prostaglandins also enhance the pain response induced by stimulants.

Prostaglandins and leukotrienes are unstable and are not stored in cells but are synthesized [W.L. Smith, Biochem. J., 259:315-324 (1989)] from arachidic acid in response to stimulants. Protaglandins are produced from arachidonic acid by the action of COX - 1 and COX - 2 enzymes. Arachidonic acid is also a substrate for a specific enzyme pathway that leads to the production of leukotrienes.

The arachidic acid that is introduced into these two different inflammatory pathways is released from the sn-2 position of membrane phospholipids A2 of the phospholipase enzyme (hereafter PLA2). The reaction catalyzed by PLA2 is thought to be the rate-limiting step in the process of lipid-mediated biosynthesis and production of inflammatory prostaglandins and leukotrienes. When the PLA2 class phospholipid substrate is phosphotidyl choline with one ether bond in the sn-1 position, the lysophospholipid produced is an immediate precursor of platelet activating factor (hereinafter PAF), another major mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58(1988)].

Most anti-inflammatory therapies have focused on preventing the production of either prostaglandins or leukotrienes from these free pathways, but not all of them. So, for example, ibuprofen, aspirin, and indomethacin are all NSAIDs (nonsteroidal anti-inflammatory drugs) that suppress the production of prostaglandins COC-1/COX-2, but do not act on the inflammatory production of leukotrienes from arachidonic acid in another pathway. In contrast, zileuton only inhibits the arachidonic acid to leukotriene pathway without affecting prostaglandin production. None of these widely used anti-inflammatory agents are effective in suppressing PAF production.

Based on all that has been said, it is considered that direct suppression of PLA2 action is a useful mechanism for one therapeutic agent, i.e. for interfering with the inflammatory reaction. [See, for example, J. Chang et al., Biochem. PharmacoL 36:2429-2436 (1987). ]

A family of PLA2 enzymes characterized by the presence of a secretion signal, sequenced and finally secreted from the cell, was sequenced and structurally defined. These secreted PLA2s have a molecular weight of about 14 kD and contain seven disulfide bonds that are essential for activity. These PLA2s have been found in large amounts in the pancreas of mammals, bee venom and various snake venoms. [See, e.g., references 13-15 in Chang et al., supra, and E.A. Dennis, Comrade Devel. Res., 10:205-220 (1987). ] It is considered, however, that the pancreatic enzyme performs the function of digestion and, as such, cannot be of significance in the production of inflammatory mediators whose production must be strictly regulated.

The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, joint fluid and the spleen and is also a secreted enzyme. This enzyme is a member of the previously mentioned family. [See J. J. Seikhamer et al., J. Bio. Chem., 264:5335-5338 (1989); R. M. Kramer et al., J. Bio. Chem., 264:5768-5775 (1989); and Kando et al., Biochem. Biophvs. Crisp. Comm., 163:42-48 (1989).] It is suspected, however, that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since non-pancreatic PLA2 is an extracellular protein that would be difficult to regulate, and the following enzymes in the biosynthetic pathways for these connections are intracellular proteins. In addition, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc, Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins that must act on intracellular proteins. It would be impossible for non-pancreatic PLA2s to act in the cytosol since the high reduction potential reduced the disulfide bonds and deactivated the enzyme.

Murine PLA2 was identified in the murine macrophage cell line and was labeled RAW 264.7. It is reported to have a specific activity of 2 mol/min/mg, resistance to reduction, and a molecule of about 60 kD. This protein, however, was not purified from homogeneity. [See C.C. Leslie et al., Biochem. Biophys. Acta., 963:963:476-492 (1988).] The aforementioned works are incorporated by reference for information relating to the function of phospholipase enzymes, particularly PLA2.

A single cytosolic phospholipase A2 (hereafter "cPUV") was also identified and cloned. See US Patent Nos. 5, 322, 556 and 5, 354, 677, which are incorporated herein by reference in their entirety. The enzyme according to these patents is an intracellular PLA2 enzyme purified from its natural source or otherwise produced in a purified form, which acts intracellularly to produce arachidic acid in response to inflammatory stimuli.

Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitoR1 of the enzyme's action, which could be used to treat the inflammatory condition, especially when suppressing the production of prostaglandins, leukotrienes, and PAF are the desired results. There remains a need to identify such anti-inflammatory agents for therapeutic use in a wide range of disease states.

Overview of the invention

The compounds of this invention have the following formulas:

[image]

whereby

R1 and R1 are independently selected from H, halogen, -CF3, -OH, -C1-C10 alkyl, preferably -C1-C6 alkyl, -S-C1-C10 alkyl, preferably -S-C1-C6 alkyl, C1- C10 Alkoxy, preferably C1-C6 Alkoxy, -CN, -NO2, -NH2, -HN(C1-C6), -N(C1-C6)2, phenyl, -O-phenyl, -S-phenyl, benzyl, - O-benzyl, -S-benzyl, or one group of formulas:

[image]

R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy, -NO2, -NH2, -CN, -CF3, or -OH,

R7 is selected from -OH, -CF3, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyropyl, phenyl . -CF3, or -OH,

R2 is selected from -CF3, -OH, -C1-C10 alkyl, preferably -C1-C6 alkyl, C1-C10 alkoxy. preferably C1-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-(C1-C6-alkyl). -N-(C1-C6 alkyl)2, -N-SO2-(C1-C6 alkyl) or -SO2-(C1-C6 alkyl),

R3 is selected from H, -CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, -C1-C6 alkyl-C3-C10 cycloalkyl, 1CHO, halogen, or one group of formula-L2-M2,

wherein L2 is a bridging or bonding group of the formula -(CH2)n-, -S-. -O-C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O) -(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S -(CH2)n-. -C(O)C(O)X.

where

X is O or N

M2 is selected from the group consisting of C1-C6 lower alkyl, C1-C6 lower lkoxides, C1-C6 cycloalkyl, phenyl or benzyl, where cycloalkynes, phenyl or benzyl rings are optionally substituted with 1 to 3 substituents selected from halogen, C1-C10 alkyl preferably -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, preferably C 1 -C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 . or

a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from, including, but not limited to, N, S, or O. furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazoline. pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, wherein the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6 alkyl. C1-10 Alkoxy, preferably C1-6 Alkoxy, -NO2, -NH2, -CN, or -CF3, or

b) A six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O, including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizin. oxazine, or morpholine, wherein the six-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 oxy, preferably C1-6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3, or -OH, or

c) one bicyclic ring group optionally containing from 8 to 10 ring heteroatoms selected from N, S or O, including, but not limited to, benzofuran, indole, indoline, naphthalene, purine or isoquinoline, wherein the bicyclic ring is group optionally substituted with 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3. or -OH,

n is an integer from 0 to 3

R4 is selected from h, -CF3, C1-6 lower alkyl, C1-6 lower alkoxy, C1-6 cycloalkyl, C1-6 lower alkyl-C1-6 cycloalkyl, -COOH, halogen, or the group of formulas:

a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-thenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2 -phenyl)2, -CH2-phenyl-C(O)-benzothiazole or one compound of the formula:

[image]

where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, and the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, C1-6 alkyl, C1-6 alkoxy, -NH2, -NO2, or one five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or

b) a group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group:

[image]

whereby

D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3,

B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH. -C1-6 alkyl, C1-C6 alkoxy, or -NO2, or

c) group of formulas:

[image]

[image]

where Z is O or S, the phenyl and pyrimidinyl rings of each group are optionally and independently substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, or -NO2 ,

R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(C1-12)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole ,

[image]

or from groups selected from the formula –L1M1,

whereby

L1 is a bridging or bonding group selected from one chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2) n-C(O)-(CH2)n-, -(CH2)n-O -(CH2)n-, -(CH2)n-S -(CH2)n-, -C(Z)-N(R6)-(CH2)n -, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6) -(CH2)n-, -C(Z)-NH-SO2 or -C(Z)-NH-SO2-(CH2)n-,

M1 is selected from the group consisting of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,

[image]

where R8, R9 or R10 can be attached anywhere in the cyclic or bicyclic system,

R8 is each time independently selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,

[image]

R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-C6 alkyl, -O-C1-C6 alkyl, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2,

R10 is selected from H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH. -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl), -N-(C1-C6 alkyl)2,

[image]

[image]

R11 is selected from H, C1-C6 lower alkyl. C1-C6 cycloalkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH,

[image]

provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from a carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas:

[image]

n is an integer from 0 to 3,

or a pharmaceutically acceptable salt thereof.

It is understood that in the previously mentioned group, the substituents R3 and R4 are attached in position 2 or 3 of the indole or indoline ring, and that the groups R1, R1' and R2 are attached to one of the indole or indoline carbon atoms in position 4, 5, 6 or 7.

One group of compounds within the scope of this invention are those in which R1 and R2 are hydrogen groups. and the substituents at other positions of indole or indoline are as previously described.

Another group of this invention includes compounds where R 2 and R 4 are hydrogen and the groups R 1 , R 4 and R 5 are as previously defined. Within these groups are the following two recommended groups. In the first R1 is in position 5 of indole or indoline, and in the second R1 is in position 6 of indole or indoline.

In one further preferred group, R 1 is in the 5-position of indole or indoline and is benzyloxy, R 2 and R 4 are hydrogen and R 3 and R 5 are as previously defined.

In another preferred group according to the present invention, R 1 is in the 5 or 6 position of indole or indoline and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R 2 and R 4 are hydrogen, and R 3 and R 4 are as previously defined.

A further preferred group according to this invention consists of R1 and R2 at the 5-position and/or the 6-position of indole or indline, each of which is selected from the group consisting of C1-C6 alkoxy, cyano, sulfonyl, and halo, R2 and R4 being hydrogen , and R3 and R4 are as previously defined.

It is also understood that there is a further preferred subgroup within each group shown where the core molecule is a single indole group instead of indoline. It also implies that there is another group where the core molecule is a single indoline group.

Recommended compounds according to this invention include compounds of the following formulas:

[image]

whereby:

R 1 is selected from H, halogen, -CF 3 , -OH. -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, -HN(C1-C6), -N(C1-C6), phenyl, -O-phenyl, benzyl, -O-benzyl, or one of group of the following formulas:

[image]

R6 is selected from H, C1-C6 alkyl. C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, - NH2, -NO2, -CN, -CF3 or -OH.

R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), -CF3, C1-C6 alkyl, C3C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl. pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents chosen from halogen, C1-C6 alkyl, C1C6 alkoxy, -NH2, -NO2 , -CF3 or -OH,

R2 is selected from H, halogen, -CF3, -OH, -C1-C10 alkyl, preferably -C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C1-C6 alkyl, N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl,

R3 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S-(CH2)n-C1-C6 cycloalkyl, or from the groups:

a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2 -phenyl)2, -CH2-phenyl-C(O)-benzothiazole or one compound of the formula:

[image]

where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, where the rings of these groups are optionally substituted with 1 to 3 substituents selected from H. halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or

b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group:

[image]

whereby

D is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, or -CF 3 .

B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, - C1-C6 alkyl, C1-C6 alkoxy, or-NO2., or

c) one of the groups of formulas:

[image]

wherein the phenyl and pyrimidinyl rings of each of these groups are optionally and independently substituted with 1 to 3 substituents chosen from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2,

R4 is selected from the group consisting of H, halogen -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH2-(C3-C6 cycloalkyl), -C(O)-OH, -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C( O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl).

[image]

wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH.

n is an integer from 0 to 3

R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH,

[image]

[image]

R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,

[image]

R9 is selected from H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH( C1-C6 alkyl) or -N(C1-C6 alkyl)2,

R10 is selected from the group consisting of H, halogen, CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl . -NH(C1-C6 alkyl), -N-(C1-C6 alkyl)2

[image]

[image]

R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH. -(CH2)n-C(O)-COOH, or

[image]

provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas:

[image]

or a pharmaceutically acceptable salt thereof.

Another group of compounds according to this invention has the following formulas:

[image]

whereby:

R1 is selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl, or one of the groups of the following formulas:

[image]

R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy. –NO2, -CF3 or -OH,

R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C3- C6 Cycloalkyl, C1-C6 Alkoxy, -NH-(C1-C6 Alkyl). N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3 or -OH,

R2 is selected from H, halogen, -CF3, -OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH -C1-C6 alkyl, -N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl,

R3 is selected from the group consisting of H, halogen -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, CH2-(C3-C6 cycloalkyl), -C(O)-OH. -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C(O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl ),

[image]

wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH. n is an integer from 0 to 3

R4 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S-(CH2)n-C1-C6 cycloalkyl, -(CH2)n-O-( CH2)n-C1-C6 cycloalkyl or from the groups:

a) -(CH2)n-phenyl-O-phenyl. -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O) -benzothiazole or one compound of the formula:

[image]

where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or

b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group:

[image]

whereby

D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3,

B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl. thienyl iii pyrrolyl, each optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H. halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, or -NO2, or

c) one group of formulas:

[image]

wherein Z is 0 or S and the phenyl and pyrimidine rings of each of these groups are optionally and independently substituted with 1 to 3 substituents selected from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2,

R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH,

[image]

[image]

R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,

[image]

R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2,

R10 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2,

[image]

[image]

R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or

[image]

provided that the complete group in indole and indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas:

[image]

or a pharmaceutically acceptable salt thereof.

It is understood that in the previously mentioned groups, the substituents R3 and R4 are attached in position 2 or 3 of the indole or indoline ring, and that the groups R1, R1' and R2 are attached to one of the indole or indoline carbon atoms in position 4, 5, 6 or 7.

One group of compounds within the scope of this invention are those in which position 3 (R3) of indole or indoline is substituted only by hydrogen and the substituents at other positions of indole or indoline are as previously described.

Another group of this invention includes compounds in which R2 is hydrogen and the groups R1, R4 and R5 are as previously defined. Within these groups are the following two recommended groups. In the first R1 is in position 5 of indole or indoline, and in the second R1 is in position 6 of indole or indoline.

In one further preferred group, R 1 is in the 5-position of indole or indoline and is benzyloxy, R 2 and R 4 are hydrogen and R 3 and R 5 are as previously defined.

It is also understood that there is a further preferred subgroup within each of the groups shown where the core molecule is a single indole group instead of indoline. It also implies that there is another group where the core molecule is a single indoline group.

Another subgroup of compounds according to this invention has the following formulas:

[image]

whereby:

R1 is selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl, or one of the groups of the following formulas:

[image]

R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy, -NO2, -CF3 or -OH,

R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C1- C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3 or -OH,

R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -CN, -NO2 , -NH2. -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl,

R3 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-O -( CH2)n-C1-C6 cycloalkyl or from the groups:

a) -(CH2)n-phenyl-O-phenyl. -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O) -benzothiazole or one compound of the formula:

[image]

where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, where the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or

b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group:

[image]

whereby

D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3,

B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, - C1-C6 alkyl, C1-C6 alkoxy, or -NO2, or

c) one of the groups of formulas:

[image]

wherein Z is O or S and the phenyl and pyrimidinyl rings of each of these groups are optionally and independently substituted with 1 to 3 substituents selected from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2,

R4 is selected from the group consisting of H, halogen, -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl , CH2-(C3-C6 cycloalkyl), -C(O)-OH, -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl. -C(O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl).

[image]

wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, C(O)-OH, or -OH.

n is an integer from 0 to 3

R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH,

[image]

[image]

R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,

[image]

R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2,

R10 is selected from H. halogen, CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH (C1-C6 alkyl), -N(C1-C6 alkyl)2,

[image]

[image]

R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or

[image]

provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 shall contain at least one acid group selected from a carboxylic acid, or containing a carboxylic acid, a tetrazole, or a group of formulas:

[image]

or a pharmaceutically acceptable salt thereof.

Other recommended compounds according to the present invention are those having the following formulas

[image]

whereby:

R1 is selected from NH2, -O-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl, or one of the groups of the following formulas:

[image]

R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, -CF3 or -OH,

R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, or -OH, n is an integer from 0 to 3,

R3 is selected from halogen, -C1-C6 alkyl, C1-C6 alkoxy, -CF3, -CH=O, -C(O)-C1-C6 alkyl, C(O)-O-C6 alkyl, -C(O )-OH, C(O)-OH, C(O)-CF3, -C(O)-phenyl, -C(O)-benzyl, -C(O)-pyrrolyl, -C(O)-thienyl, -C(O)-furanyl or C(O)-morpholinyl,

R4 is selected from the group consisting of -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-S -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C6 cycloalkyl, -(CH2)n-S-C3-C6 alkyl, group:

a) -C(O)-O -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-phenyl, -(CH2)n-O-phenyl, -(CH2)n-S-phenyl, -(CH2)n-S - (CH2)n-phenyl, -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl -(CH2)n-phenyl, -(CH2) n-(O-phenyl-CH2-phenyl)2, -C(O)-O-phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, -C(O)-O -naphthyl, -(CH2)n-S-naphthyl, -(CH2)n-S-pyridinyl, -(CH2)n-pyridinyl or -(CH2)n-naphthyl, -(CH2)n-O-naphthyl, where the rings are phenyl, pyridinyl and naphthyl of these groups optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2 or one five-membered heterocyclic ring containing one heteroatom selected from N, S or O, preferably S or O, or

b) one group of the formula -(CH2)n-A-, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group

[image]

where D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy or -CF3,

R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)O-COOH, -CH=CH-COOH,

[image]

[image]

R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazoia,

[image]

R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2,

R10 is selected from H, halogen, CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH (C1-C6 alkyl), -N-(C1-C6 alkyl)2,

[image]

[image]

R 11 is selected from H, C 1 -C 6 lower alkyl, CF 3 , -COOH. -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or

[image]

provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas:

[image]

or a pharmaceutically acceptable salt thereof.

Detailed description of the invention

As used herein, the terms "aryl" and "substituted aryl" are intended to include monocyclic compounds, particularly those comprising five- and six-membered monocyclic compounds, aromatic and heteroaromatic ring compounds, and bicyclic aromatic and heteroaromatic ring compounds, particularly those having 9 to 10 ring atoms. It is understood that these aryl groups include phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such compounds. Aryl and heteroaryl groups according to this invention also include the following:

a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O, including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole. pyrazoline, imidazole, tetrazole or oxythiazole, or

b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O, including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazyl, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine or morpholine, or

c) one bicyclic ring group optionally containing 1 to 3 ring heteroatoms selected from N, S or O, including, but not limited to, benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine or naphthyridine.

"Substituted aryl" groups according to the present invention include compounds optionally substituted with 1 to 3 substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -COOH or its esters, -NO2, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NN(CH3), etc.

A preferred subgroup of these groups, optionally substituted as just described, include compounds formed from benzene, pyridine, naphthylene or quinoline rings. The next recommended group includes furan, pyrrole, thiophene, pyrimidine and morpholine rings. A recommended group of bicyclic aromatic groups includes benzofuran, indole, naphthalene and quinoline rings.

The alkyl, alkenyl and alkynyl groups mentioned here refer to groups having 1 to 10, preferably 1 to 6 carbon atoms, and may be linear, branched or cyclic. Unless otherwise indicated, it is recommended that these groups be linear or branched. Halogens are understood to include F, Cl, Br and J.

As used herein, "phospholipase enzyme activity" means a positive activity in some phospholipid metabolism assay (preferably one of the assays described in Example 86 below). A compound has "phospholipase enzyme inhibitory activity" when it inhibits the activity of one phospholipase (preferably cPLA2) in any of the available assays (preferably one of the assays in the following Examples 86 or 87) of enzyme activity. In recommended assays, a compound has (1) an IC50 value of less than about 25 μM, preferably less than about 6 μM in the LysoPC assay, (2) an IC50 value of less than about 50 μM in the vesicle assay, (3) an IC50 of less than about 1 μM in the PMN test, (4) IC50 value less than about 15 μM in the Coumarin test, and/or (5) measurable effect (preferably at least 5% reduction in swelling, preferably at least 10% reduction, more preferably at least 15% reduction, best 20- 30%) when tested with carrageenan-induced edema of the rat foot pad.

The compounds of this invention are useful for inhibiting the action of a phospholipase enzyme (preferably cPLA2) and are therefore useful in "treating" (ie, treating, preventing, or ameliorating) inflammatory, or inflammatory-related, responses or conditions (for example, rheumatoid arthritis , psoriasis, asthma, inflammatory bowel diseases, and other diseases caused by the mediation of prostaglandins, leukotrienes or PAF) and other conditions such as osteoporosis, colitis, leukemia formed in the bone marrow, diabetes, atrophy and atherosclerosis.

The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or application that utilize the compounds of the present invention.

The compounds of this invention can be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to one or more compounds according to the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solvents, and other materials known in pharmacy. The term "pharmaceutically acceptable" implies a non-toxic material that does not interfere with the effectiveness of the biological action of the active ingredient (or ingredients). The characteristics of the carrier depend on the route of drug administration. The pharmaceutical composition may also contain other anti-inflammatory agents. Such additional agents and/or agents can be included in the pharmaceutical composition so as to produce a synergistic effect with the compounds of the present invention, or to minimize side effects caused by the compound of the present invention.

The pharmaceutical composition according to the invention can be in the form of a liposome in which the compounds according to the invention are combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids that exist in an aggregate state as particles, insoluble single layers, liquid crystals or lamellar layers in aqueous solution. Suitable lipids for liposomal formulations include. without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. The preparation of these liposomal formulations is within the skill of one of ordinary skill in the art, as shown, for example, in US Pat. Nos. 5, 235, 871, no. 4, 501, 728, no. 4, 837, 028 and no. 4. 737, 323, all of which are incorporated herein by reference.

As used herein, the term "therapeutically effective amount" refers to the total amount of each active component of the pharmaceutical composition or method, which is sufficient to effect a significant improvement in the patient, i.e., to treat, cure, prevent or alleviate an inflammatory response or condition, or to accelerate treating, curing, preventing or alleviating those conditions. When referring to one particular ingredient, given alone, the term refers to that ingredient alone. When referring to a combination, the term refers to the combined amounts of the active ingredients that result in therapeutic action, whether given in combination, serially, or simultaneously.

In exploring the method of treatment or use of the present invention, a therapeutically effective amount of the compounds of the present invention is administered to a mammal in the condition to be treated. The compounds of the present invention may be administered according to the method of the present invention either alone or in combination with other therapies, such as which is treatment that uses other anti-inflammatory agents, cytokines, lymphokines, or other blood and blood cell-forming factors. When administered simultaneously with one or more other anti-inflammatory agents, cytokines, lymphokines, or other blood and blood cell-forming factors, the compounds of this invention may be administered either simultaneously with one or more other anti-inflammatory agents, cytokines, lymphokines, or other blood-forming factors blood and blood cells, thrombolytics and anti-thrombotic factors, or in some order. If administered sequentially, the treating physician will determine the appropriate order of administration of the compounds of this invention in combination with one or more other anti-inflammatory agents, cytokines, lymphokines, other hematopoietic and blood cell factors, thrombolytics, and anti-thrombotic factors.

Administration of the compounds of the present invention used in the pharmaceutical compositions or carrying out the method of the present invention can be carried out in a wide variety of ways, for example by oral ingestion, inhalation or injection through the skin, subcutaneous or intravenous injection.

When a therapeutically effective amount of a compound 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 according to the present invention may additionally contain a solid carrier such as gelatin or a neutral additive. The tablet, capsule and powder contain from about 5 to 95% of the compounds according to this invention, and preferably from about 25 to 90% of the compounds according to this invention. When administered in liquid form, a liquid carrier such as water, kerosene, oils of animal or vegetable origin such as peanut oil, mineral oil, soybean oil or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain a saline solution, dextrose or other saccharide solution, or a glycol 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. compounds according to this invention, and preferably from about 1 to 51% of compounds according to this invention.

When a therapeutically effective amount of a compound of the present invention is administered by intravenous injection. by transdermal or subcutaneous injection, the compounds of this invention will be in the form of a pyrogen-free parenterally acceptable aqueous solution. The preparation of such a parenterally acceptable protein solution, taking into account pH, isotonicity, stability and the like, is within the skill of the average person skilled in the art. A recommended pharmaceutical composition for intravenous injection, for injection through the skin or for subcutaneous injection should contain, in addition to the compounds of this invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other known carriers. The pharmaceutical composition according to the present invention may also contain stabilizers, preservatives, buffers, antioxidants or other additives known to those skilled in the art.

The amount of the compounds (one or more) according to the present invention in the pharmaceutical composition according to the present invention will depend on the nature and severity of the condition being treated and on the nature of the previous treatments the patient has undergone. Ultimately, the treating physician will determine the amount of compounds of this invention to treat each individual patient. Initially, that physician will administer small doses of the compounds of this invention and observe the patient's response. Higher doses of the compounds of this invention will be administered until optimal therapeutic effect is achieved in the patient, and once this is achieved, the dose will not be further increased. It is believed that the various pharmaceutical compositions used in the practice of the method of this invention should contain from about 0.1 μg to about 100 mg (preferably from 0.1 mg to about 50 mg, preferably from about 1 mg to about 2 mg) of the compounds according to this invention per kg of body weight.

The duration of intravenous therapy using the pharmaceutical composition according to this invention will vary depending on the severity of the disease being treated and on the condition and possible characteristic response of each individual patient. The duration of each administration of a compound of the present invention is considered to be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately, the treating physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of this invention.

The compounds according to this invention can be made according to the following described procedures and examples. The syntheses of the preferred compounds according to this invention are described in the following examples.

Procedure A

Ethyl 5-nitro-2-carboxylate indole is chlorinated at the 3-position by N-chlorosuccinamide in a solvent such as DMF or DMSO at an elevated temperature of 40°C - 80°C. The ester is then reduced in a three-phase process. First, the ester is hydrolyzed under alkaline conditions with a base such as sodium hydroxide or potassium hydroxide in a solution system such as water : methanol : THF. The acid is then activated by adding carbonyl diimidazole to THF and reduced with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in an alcoholic solvent system such as methanol or ethanol. The resulting alcohol is protected as a TBDMS ester with TBDMSCI in a solvent such as DMF, acetonitrile or THF with a base such as tertylamine or imidazole. The indole nitrogen is then alkylated with methyl 4-bromomethylbenzoate in a solvent such as THF, acetonitrile or DMF with a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide. The 5-nitro group is then reduced by exposure to hydrogen (H2) in the presence of a catalyst such as Pt/C or Pd/C in a solvent such as ethyl acetate, methanol or THF or a mixture of two or all three. The amine is then acylated with cyclopentylcarbonyl chloride in a two-phase system of saturated sodium bicarbonate and methylene chloride. R1 is then introduced in a two-step procedure in which the TBDMS ester is converted to the bromide by exposure to dibromotriphenylphosphorane in methyl chloride and the crude bromide is replaced by various thiols or phenols in a solvent such as THF, methylene chloride or DMF in the presence of a base such as potassium carbonate or cesium carbonate. The ester product is prepared by hydrolysis of the ester under alkaline conditions using sodium hydroxide in a solution system such as water:MeOH:THF.

Procedure B

Acylation at the 3-position of the indole l with an acylating agent such as naphthoyl chloride can be accomplished using ethylmagnesium bromide in a solvent such as THF to give II. Alkylation of the indole nitrogen can be carried out by exposure to a suitable alkali such as sodium hydride and treatment with a suitable agent. Removal of the hydroxide protecting group with tetrabutylammonium fluoride and oxidation with a suitable oxidizing agent gave IV. A Horner-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran gave the unsaturated ester V which could be deprotected at the 1-position of the indole by some convenient reagent system such as hydrofluoric acid in acetonitrile. Saponification of the remaining acid group gave compounds VI.

Procedure C

Indole 1 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 Grinjar reagent such as ethyl magnesium bromide in a solvent such as THF at -60°C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and, finally, alkylation on nitrogen with an alkyl halide such as is methyl(4-bromomethyl)benzoate in the presence of a strong base such as NaH in DMF gives ketone III. The silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, then the resulting alcohol is converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to give bromide IV. Replacement of bromine from IV with some thiol compound in the presence of a base such as cesium carbonate, or with some alcohol in the presence of a strong base such as NaH in DMF gives V (sulphide, or ether).

Procedure D

The protected alcohol is deprotected in a suitable solvent such as THF and the resulting halide is functionalized into a halide using carbon tetrabromide or methanesulfonyl chloride and then reacted with an oxygen nucleophile, coupled with prior deprotonation with a strong base such as sodium hydride, or with with one sulfur nucleophile in the presence of cesium carbonate in DMF or THF. The nitro group can then be reduced to a single amine via a hydrogenation process with Pt/carbon or a copper acetate sodium borohydride process. The resulting amine can be hydrolyzed using a standard procedure with sodium hydroxide in THF/MeOH, or coupled with various acylating agents, such as chloroanhydrides, chloroformates and isocyanates where the reactions are generally carried out in the presence of some alkali in the solvent such as THF or dichloromethane. The amine can also be acylated using a single EDCl coupling procedure with various acids. The starting amine can also be alkylated by a reductive amination process using various aldehydes and sodium triacetoxyborohydride as the reducing agent. These functionalized amines can be hydrolyzed to give the desired acids which can also be converted to an acylsulfonamide by coupling EDCl with a sulfonamide. Alternatively, functionalized amines can be further alkylated by reacting with a strong base and an alkyl halide and then hydrolyzed under standard conditions to give the desired product.

Procedure E

The starting indole, with or without C2 substitution, was functionalized at C3 using DMF/POCl3 conditions or the magnesium salt of the indole was acylated with various hydrochlorides to form ketones. These products are then N-alkylated by the action of a strong alkali and various alkyl or aryl halo esters. When R' is one nitro group, then the nitro is reduced with Pt/C and H2 or copper acetate and sodium borohydride to an amine which is then acylated with various chloroanhydrides, isocyanates, chloroformates, reductively alkylated with amines or linked with acids. The resulting esters are hydrolyzed into the desired acids, which can be further converted into acylsulfonamides.

(pictures 25, 26, 27, 28)

Example 1

4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1 - Ethyl 5-nitroindole-2carboxylate (21.1 g) was dissolved in DMF (500 mL). To this dark brown solution was added the solvent N-chlorosuccinamide (12 g in 125 mL DMF) over 5 min. The reaction mixture was heated to 50°C for 1.5 h. The completion of the reaction was determined by TLC (thin layer chromatography). The reaction mixture was cooled to room temperature, diluted with water (2 L) and extracted with ethyl acetate (3x1 L). The organic layers were combined, dried over MgSO4, filtered and concentrated. The result was the desired ethyl ester (96 g wetted with DMF) which was carried on to the next step without further purification.

Step 2 - The ethyl ester was dissolved in methanol (400 mL) and THF (800 mL). To this clear brown solution was added 2N NaOH (450 mL). The black mixture was stirred overnight at room temperature. The reaction was not completely completed (TLC), so another 7.2 g of NaOH grains were added. After 7 h the reaction was complete. Approximately 1 L of solvent was removed by rotary evaporation. The residue was dissolved in ethyl acetate and water and acidified with 2 N HCl to pH 2. The brown mixture was then extracted with ethyl acetate (3x1 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). To this clear amber solution was added CDl (16.2 g). The mixture was stirred for 1.5 h at room temperature, after which it turned into a light brown suspension. The reaction mixture was cooled in an ice bath. Sodium borohydride (10.8 g) was added slowly. Ethanol (140 mL) was then added. Gas evolution was observed. After 2 h, TLC analysis showed that the reaction was complete. 2.2 N HCl was added to adjust the pH to 2.2. The reaction mixture was then extracted with ethyl acetate (3 x 600 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated to give the desired alcohol (28.5 g) as a brown solid.

Step 4 - The alcohol prepared in the previous step (24.5 g), imidazole (18.6 g) and tert-butyldimethylsilyl chloride (13.3 g) were dissolved in DMF (350 mL). The reaction mixture was stirred overnight and was found to be incomplete. Therefore, t-butyldimethylsilyl chloride (18.6 g) was added. After 1 h 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 crude 5-tert-butylmethylsilyl-protected alcohol. The crude material was dissolved in ethyl acetate, absorbed on silica gel and dried to dryness. After loading on a silica gel column and washing with 15% ethyl acetate in hexanes, the desired alcohol (18.5 g, 69% from stage 1) was isolated as light yellow crystals.

Step 5 - Tert-butyldimethylsilyl-protected alcohol (1 g) was dissolved in DMF (10 mL). The yellow solution was cooled in an ice bath. Sodium hydride (147 mg) was added. After 15 min, 4-(bromomethyl)benzoate (807 mg) was added to the dark red solution. After 15 min, TLC analysis showed that the reaction was complete. The reaction mixture was poured into cold 1N HCl. Water (800 mL) was added and the solution was extracted with ethyl acetate. The combined organic layers were evaporated to dryness to afford the crude N-alkylated indole as an orange solid. The solid absorbed on silica gel was added to a silica gel column and washed with 15% ethyl acetate in hexanes to give the desired N-alkylated indole (1.05 g, 73%) as a yellow solid.

Step 6 - The N-alkylated indole (3.8 g) was dissolved in THF (50 mL) and 5% Pt/C (1.6 g) was added. Hydrogen was blown in and the reaction mixture was stirred overnight at room temperature. The reaction mixture 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 amine from the previous step (1.6 g, 3.5 mmol) in CH2Cl2 (10 mL) and saturated sodium bicarbonate (10 mL) was added cyclopentyl carbonyl chloride (0.467 mL, 1.1 eq.). The reaction mixture was stirred for 45 min, poured into ethyl acetate (100 mL), washed with brine (3 x 20 mL), dried (MgSO4), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) gave the desired product (1.55 g, 82%) as a pale yellow oil.

Step 8 - To a solution of the amide from the previous step (0.5 g, 1.1 mmol) in dichloroethane (3 mL) at 0°C was added dibromotriphenylphosphorane (0.5 g, 1.1 eq.).

The reaction mixture was stirred at room temperature for over 2 hours, poured into ethyl acetate (50 mL), washed with brine (3x10 mL), dried (MgSO4) and concentrated and then immediately transferred to the next step.

Step 9 - To a solution of the crude bromide prepared in the previous step (0.54 mmol) in DMF (2 mL, degassed) was added phenethyl mercaptan (0.08 g, 1.1 equiv.) and then cesium carbonate (0.21 g, 1.2 eq). The reaction mixture was stirred for 1 h, poured into ethyl acetate (20 mL), washed with brine (3x5 mL), dried (MgSO4), filtered and concentrated. Chromatography (25% ethyl acetate/hexanes) gave the desired compound (0.17 g, 56%) as a colorless oil.

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

Each of the compounds in the following Examples 2 to 11 was prepared in a first step, as shown in Step 9 of Example 1, using the appropriate thiol, and then in a second step, as described in Step 10 of Example 1.

Example 2

4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl] benzoic acid

Example 3

4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(4-hydroxy-6-phenyl-2-pyrimidinyl)sulfanyl]methyl}-1H-indol-1-yl)methyl)benzoic acid

Example 4

4-{[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-({[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}methyl)-1H-indol-1-yl]methyl} benzoic acid

Example 5

4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2,4-dibromophenoxy)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 6

4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(cyclopentylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 7

4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(propylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 8

4-({(2-{[4-(tert-butyl)phenoxy]methyl}3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Example 9

4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(quinolinylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 10

4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(cyclopropylmethyl)sulfanyl] methyl}-1H-indol-1-yl)methyl] benzoic acid

Example 11

4-({2-[(benzhydrylsulfanyl)methyl]-(3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

The compounds from the following examples 12 to 14 were prepared in the following way:

Step 1 - The material prepared in Example 1, Step 6, was acylated at the 5-amino position using the protocol of Example 1, Step 7, with the appropriate acylating agent.

Step 2 - The title compound was prepared from the intermediate of step 1a according to 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]-1H-indol-1-yl}methyl)benzoic acid

Example 13

4-{5-[(3-carboxypropanoyl)amino]-3-chloro-2-{[(3-methylbenzyl)sulfanyl)methyl}-1H-indol-1-yl)methyl]benzoic acid

Example 14

4-({2-({[4-(tert-butyl)benzene sulfanyl}methyl)-5-[(3-carboxypropanoyl)amino]-3-chloro-1H-indol-1-yl}methyl)benzoic acid

Example 15

4-({3-chloro-5-(3-furoylamino)-2-(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

The title compound was prepared as described in Example 43 using the appropriate acylating agent.

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

Example 17

4-({3-chloro-5-{[3-(diethylamino)propanoyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 18

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Example 19

4-({5-{[(benzylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example R20

4-({5-{[(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Example 21

3-[({1-(4-carboxybenzyl)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid

Example 22

4-{[5-[(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)-1H-indol-1-yl]methyl}benzoic acid

Degree 1

A solution of 2(tert-butylmethylsilyloxymethyl)-5-benzyloxyindole (2.0 g, 5.4 mmol) in anhydrous ether (10 ml) was cooled to -78°C and a solution of ethylmagnesium bromide (3.0 M in ether, 4.0 ml, 12.0 mmol). The mixture was stirred at -60°C to -65°C for 2 hours, after which time the homogeneous solution became a yellow suspension. A solution of naphthoyl chloride (2.28 g, 12.0 mmol) in ether (8 mL) was then added. After stirring for 2 h at -60°C to -40°C, the reaction was carefully quenched with saturated aqueous sodium bicarbonate and diluted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. Flash chromatography (hexane/acetone, 6/1) gave 2.2 g (78%) of 17 as a yellow foam.

Degree 2

To an ice-cold (0°C) solution of the intermediate from the previous step (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 min and the reaction mixture was stirred at room temperature for 30 min, after which bromomethyl SEM ether (0.5 ml, 2.8 mmol) was added dropwise. The mixture was stirred for 4 h at room temperature, 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 (hexane/acetone, 6/1) gave 1.2 g (81%) of the desired intermediate as a light yellow foam.

Degree 3

To a solution of the product from the previous step (6.6 g, 8.4 mmol) in THF (80 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 21 mL). The reaction mixture was stirred for 2 h at room temperature, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. Flash chromatography (hexane/EtOAc, 4/1) gave 3.8 g (67%) of alcohol as a thick colorless oil. The alcohol was dissolved in THF (50 mL) and MnO2 (5.5 g, 63.2 mmol) was added. The reaction mixture was stirred for 22 h and filtered through a layer of celite. Concentration of the filtrate gave 3.7 g (96%) of the desired intermediate as a light yellow foam.

Degree 4

To an ice-cold solution (0°C) of trimethylphosphonoacetate (0.12 mL, 0.7 mmol) in DMF (5 mL) was added sodium hydride (0.027 g, 0.8 mmol). After 30 min, a solution of the intermediate product from the previous step (0.5 g 0.7 mmol) in 5 ml DMF was added. The ice bath was removed and the reaction mixture was stirred 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 (hexane/EtOAc, 3/2) afforded 0.2 g (37%) of the desired intermediate as a white foam.

Grade 5

4-{[5-[(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)-1H-indol-1-yl]methyl}benzoic acid

Aqueous 48% hydrofluoric acid (5 ml) was added to a solution of the intermediate from the previous step (0.5 g, 0.7 mmol) in acetonitrile (10 ml). After 2 h, water was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. Concentration gave a crude solid which was dissolved in THF (2 mL) and MeOH (1 mL) and 1N sodium hydroxide solution (2 mL). After stirring overnight at room temperature, the mixture was acidified to pH=3 with 10% HCl solution and extracted with ethyl acetate. Flash chromatography (CH2Cl2 /MeOH, 10/1) gave the title compound (0.2 g, 50%) as a white solid.

Example 23

4-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0°C, then lithium aluminum hydride (LAH) (255 mL 1 , OM solution in THF). The reaction mixture was stirred for the next two hours at 0°C, then it was worked up by adding 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3 x 400 mL), the filtrates were combined, dried over MgSO4 and concentrated to give 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 mmol) and t-butylmethylsilyl chloride (5.4 g, 35.8 mmol). The mixture was stirred overnight at room temperature. The reaction mixture 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 a silica gel column using 19:1 hexane:ethyl acetate to give the pure product (11.9 g, 31 mmol, 94% yield, TLC 0.8 Rf in toluene.ethyl acetate 2:1) .

Step 3: A solution of the silylated indole prepared in step 2 (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethyl magnesium bromide (2.4 mL in a 3M solution in ether, 7.2 mmol) in ether. (10 mL) which was maintained at -78°C. The reaction mixture was stirred for 2 hours at -60°C. Acetyl chloride (0.51 mL, 7.2 mmol) in ether (4 mL) was then slowly added. The reaction mixture was kept between -50°C and -60°C for the next 2 hours. The reaction was quenched with saturated sodium bicarbonate. Extraction was then carried out with ethyl acetate (3x). The organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19:1 hexane:ethyl acetate to give the pure product (1.2 g, 50%).

Step 4: To the indole (1.2 g, 2.9 mmol) prepared in step 3, in 10.5 ml DMF was added sodium hydride (0.13 g, 60% oil dispersion, 3.23 mmol) at room temperature. The mixture was stirred for 30 min. Methyl (4-bromomethyl)benzoate (0.81 g, 3.53 mmol) was then added and the reaction mixture was stirred overnight. At the end of the reaction (monitored by TLC), it was quenched with water and 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 silylium-protected indole prepared in step 4 (0.65 g, 1.1 mmol) and tetra-butyl ammonium fluoride (2.9 mL of a 1M solution in tetrahydrofuran, 2.9 mmol) in tetrahydrofuran (6 mL) was stirred one hour at room temperature. The reaction mixture was then 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 1:1 hexane:ethyl acetate to give the pure alcohol (0.47 g, 91%).

Step 6: Indole alcohol (0.3 g, 0.68 mmol), carbon tetrabromide (0.27 g, 0.81 mmol) and 1,3-bis(diphenylphosphino)propane (0.21 g, 0.51 mmol ) were poured into dichloromethane (8.4 mL) and stirred for 16 hours, after which the reaction mixture was diluted with dichloromethane and half-saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (3x), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2:1 hexane:ethyl acetate to give the 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, degassing the solvent strongly recommended), cesium carbonate (0.2 g, 0.6 mmol) and then ethyl 2 naphthalenethiol (0.034 g, 0.22 mmol) was added, and the mixture was stirred for 1 day, then the reaction mixture was poured into half-saturated ammonium chloride and extracted with ethyl acetate (3x), dried, concentrated and chromatographed (hexane:ethyl acetate 3:1) to give 0.05 g (57%) of pure product.

Step 8: The ester (0.2 g, 0.34 mmol) prepared in Step 7 was dissolved in 4.0 mL of 1/1 THF/methanol, 1N sodium hydroxide (2.5 mL) was added, and the resulting mixture was stirred for 16 h at room temperature and workup gave the crude product which was purified by chromatography (1:1 hexane:ethyl acetate with 1% acetic acid) to give (0.17 g, 85%) a solid.

Example 24

4-{[5-(benzyloxy)-2[(2-naphthylsulfanyl)methyl]-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl]methyl}benzoic acid

Step 1: This intermediate was prepared from the indole prepared in Step 2 of Example 23 and trifluoroacetic anhydride, following the procedure described in Step 3 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 of this example and methyl (4-bromomethyl) benzoate.

Step 3: To a solution of indole alcohol prepared in the previous step 2 (0.1 g, 0.2 mmol) and triethylamine (0.04 mL, 0.3 mmol) in dichloromethane (0.4 mL) was added dropwise at 0°C , methanesulfonyl chloride (0.02 mL, 0.24 mmol). The reaction mixture was stirred for 1.5 h and the dichloromethane was removed. To the residue was added 2-naphthalene thiol (0.034 g, 0.22 mmol) in 0.4 mL of DMF at 0°C. CsCO3 (0.96 g, 0.3 mmol) was then added, and the reaction mixture was stirred overnight at room temperature, and then the reaction mixture was poured into brine and extracted with ethyl acetate (3x), dried, concentrated and chromatographed (hexane: ethyl acetate 3:1) to give 0.064 g (50%) of pure product.

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

Example 25

4-({5-[(4-aminobutanoyl)amino]-3-chloro-2[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl}benzoic acid

Stage 1: T-butylsilyl-protected alcohol (25 g) from stage 6 of Example 1 was dissolved in THF (200 mL), then tetrabutylammonium fluoride (125 mL of a 1.OM solution) was added and the mixture was stirred for 10 min at room temperature and then it was diluted with water and THF, concentrated, ethyl acetate was added, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated to give the desired alcohol (21.5 g).

Stage 2: The alcohol (13.1 g) from the previous stage 1 was suspended in dichloromethane (450 mL), cooled to 0°C, then triethylamine (10 mL) and methanesulfonyl chloride (4.0 mL) were added, and a mixture was obtained allowed to warm to room temperature overnight after which it was diluted with added saturated sodium bicarbonate, then the reaction mixture 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 give the desired chloride (13.5g).

Step 3: DMF (150 mL), cesium carbonate (33.5 g) was added to the chloride (13.5) generated in the previous step 2, and the solution was degassed by blowing the solution with argon for 20 min, after which 2-naphthalene was added thiol, and the reaction mixture was stirred for 20 min at room temperature, water and ethyl acetate were added, the layers were separated and the combined organic layers were concentrated into a suspension which was stirred overnight and then filtered and the solid was triturated with 40% ethyl acetate in hexane to give the desired disulfide (12.2 g) in 69% yield.

Step 4: The product from step 3 (11.25 g) was dissolved in THF (500 mL), methanol (500 mL) and copper II acetate (19.2 g) suspended in water were added, followed by more THF (100 mL ) and finally sodium borohydride (11.2 g) was added in portions. After stirring for 2.5 hours at room temperature, the foamy black solution was diluted with saturated sodium bicarbonate and the layers were separated, the aqueous layer was extracted 3 times with ethyl acetate, the combined organic layers were dried and concentrated and chromatographed to obtain the desired amine (9, 0 g) with a yield of 85%.

Step 5: The amine from step 6 was coupled with fmoc protected 4-aminobutyric acid according to the procedure indicated in step 1 of Example 43, after which trituration with dichloromethane gave the amide in 43% yield.

Step 6: The amide (1.0 eq.) from step 5 was dissolved in methanol (5.g/ml) and piperidine (0.024 ml/mg) and the reaction mixture was stirred at room temperature for two hours, concentrated and chromatographed to give desired product with quantitative yield.

Step 7: The amino ester from Step 6 was hydrolyzed using the conditions indicated in Step 2 of Example 43 to give the title compound in 54% yield.

Example 26

4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine (1.0 eq) from step 4 of Example 25 was dissolved in CH2Cl2 (0.3M) and an equivalent amount of saturated sodium bicarbonate was added followed by the corresponding chlorine anhydride (1.2 eq). The biphasic reaction mixture was stirred vigorously until TLC analysis was complete (usually several hours) then the reaction mixture was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed, or used crude, to obtain the desired amide with a yield of 50%.

Step 2: The ester from the previous step was dissolved in THF/MeOH (3:1) and 1H NaOH (3.0 eq) was added and the reaction mixture was stirred until TLC analysis indicated that the reaction was complete. The reaction mixture was concentrated, dissolved in water, acidified to pH 2 with concentrated HCl, extracted with ethyl acetate three times, the organic layers were combined, dried over magnesium sulfate, concentrated and purified by chromatography to give the desired acid in 69% yield.

Example 27

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(2-quinoxalinylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine from Step 4 of Example 25 was treated with the appropriate chloric anhydride according to the general procedure for Example 71, Step 1, to afford the amide in 76% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 53% yield.

Example 28

4-({3-chloro-5-[(2,2-dimethylpropanoyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine from Step 2 of Example 25 was treated with the appropriate chloric anhydride according to the general procedure for Example 71, Step 1, to give the amide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 79% yield.

Example 29

4-({5-{[benzyloxy)carbonylamino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine from Step 4 of Example 25 was treated with the appropriate chloric anhydride according to the general procedure for Example 71, Step 1, to give the amide in 96% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid.

Example 30

4-({3-chloro-5-{[(cyclopentyloxy)carbonyl]amino}]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine from Step 4 of Example 25 was treated with the appropriate acetic anhydride according to the general procedure for Example 71, Step 1, to give the amide in 92% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid.

Example 31

4-({5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

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

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 29% yield.

Example 32

4-({5-{[(butylamino)carbonyl]amino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: THF (0.12M) was added to the amine (1.0 eq.) generated in step 4, the reaction mixture was cooled to 0°C, then butyl isocyanate (1.1 eq.) was added and the mixture was warmed to room temperature overnight. temperature, then the reacting mixture was diluted with half-saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried and concentrated and purified by chromatography to give the desired carbamide in 57% yield.

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

Example 33

4-({5-{[(butylamino)carbonyl]amino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Following the procedure for Example 32, Step 1, the amine was treated with benzyl isocyanate to give the title compound in 16% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 100% yield.

Example 34

4-({3-chloro-5-[(morpholinocarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine (1.0 equiv) generated earlier in Step 4 was poured into a flask along with 4-dimethylaminopyridine (1.5 equiv) and then poured into dichloroethane (0.08 M) to add the 4-morphonylcarbonyl chloride (1.5 eq.) and the reaction mixture was then stirred overnight at room temperature, then heated to 40°C for 4 hours and worked up by adding ethyl acetate and half-saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined organic layers were dried and concentrated and purified by chromatography to give the desired carbamide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 100% yield.

Example 35

4-({5-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]}-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amine (1.0 eq.) from step 1 was dissolved in dichloroethane, then benzaldehyde (1.0 eq.) was added, followed by acetic acid (1.0 mL/2 mmol) and the reaction mixture was stirred for 20 min and then sodium triacetoxyborohydride (1.3 eq.) was added, and the reaction mixture was stirred overnight at room temperature, the reaction was quenched by adding aqueous diethanolamine and dichloromethane, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined layers were dried and concentrated and purified by chromatography to give the desired carbamide in 74% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 49% yield.

Example 36

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenoxybenzyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Following the procedure for Step 1 of Example 35, the amine from Step 4 of Example 25 was treated with the appropriate aldehyde to give the desired secondary amine in 38% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 87% yield.

Example 37

4-({3-chloro-5-[(cyclopentylcarbonyl)(methyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: DMF (0.05M) was added to the ester generated in step 1 of the synthesis from Example 27, the reaction mixture was cooled to 0°C, then sodium hydride (10 eq.) was added and the mixture was stirred for 30 min. then methyl iodide (10 eq.) was added so

the resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate and half-saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with ethyl acetate, the combined layers were dried and concentrated and purified by chromatography to give the methylated amide in the yield of 56%.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 57% yield.

Example 38

4-({5-[acetyl(benzyl)amino]-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The amide synthesized in Step 1 of Example 31 was benzylated according to the procedure of Step 1 of Example 37 to give the tertiary amide in 90% yield.

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

Example 39

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(tetrahydro-3-furanylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: To the indole amine (1.0 eq.) was added acid (1.2 eq.), dimethylaminopyridine (10 mol%), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq.) and then DMF (0.3M) and the reaction mixture was stirred under a nitrogen atmosphere for 24 hours at room temperature, after which it was poured into a half-saturated solution of ammonium chloride and ethyl acetate, and then the layers were separated and the aqueous layer was extracted three times, the organic layers were combined washed with water 2x, concentrated and chromatographed to give 55% of the title compound.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 55% yield.

Example 40

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Following the procedure for Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the appropriate acid to give the amide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 21% yield.

Example 41

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(1-adamantylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Following the procedure for Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the appropriate acid to give the amide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 21% yield.

Example 42

3[({1-(4-carboxybenzyl)3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl)benzoic acid

Step 1: Following the procedure for Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the appropriate acid to give the amide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 20% yield.

Example 43

4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenylpropanoyl)amino]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Following the procedure for Step 1 of Example 39, the amine from Step 4 of Example 25 was treated with the appropriate acid to give the amide in 100% yield.

Step 2: The ester from Step 1 was hydrolyzed under the conditions given for Step 2 of Example 26 to give the desired acid in 32% yield.

Example 44

4-({5-amino-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-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 give a 79% yield.

Example 45

N-{3-chloro-1-(4-{[(methylsulfonyl)amino]carbonyl}benzyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}methyl)cyclopentanecarboxamide

Step 1: Example 26 (1.0 eq.), EDCl (1.5 eq.). DMAP (1.0 equiv.), methane sulfonamide (1.0 equiv.) was added to DMF (0.08 M) in a flask under nitrogen, and the reaction mixture was stirred overnight at room temperature, and then the reaction was terminated by adding half-saturated ammonium chloride and ethyl acetate, then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water 2 x, concentrated and chromatographed to obtain 27% of the title compound.

Example 46

N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-[4-({[(4-nitrophenyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl}

cyclopentanecarboxamide

Step 1: To Example 26 was added the appropriate sulfonamide under the conditions described for Step 1 of Example 45 to give the desired acylsulfonamide in 43% yield.

Example 47

N-{3-chloro-1-[4-({[(2-methylphenyl)sulfoninamino}carbonyl)benzyl]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}cyclopentanecarboxamide

Step 1: To Example 26 was added the appropriate sulfonamide under the conditions described for Step 1 of Example 45 to give the desired acylsulfonamide in 40% yield.

Example 48

N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1-(4-{[(phenyl)sulfonyl]amino}carbonyl)benzyl)-1H-indol-5-yl}cyclopentanecarboxamide

Step 1: To Example 26 was added the appropriate sulfonamide under the conditions described for Step 1 of Example 45 to give the desired acylsulfonamide in 40% yield.

Example 49

N-{3-chloro-2-[(2-naphthylsulfanyl)methin-1-[4-{[(4-({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H-indol-5-yl} cyclopentanecarboxamide

Step 1: To Example 26 was added the appropriate sulfonamide under the conditions described for Step 1 of Example 45 to give the desired acylsulfonamide in 67% yield.

Example 50

4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butyric acid

Step 1: Ethyl 5-nitroindole-2-carboxylate (1 equiv) was dissolved in THF/MeOH/H2O (3:1:1 0.21M) and LiOH·H2O (1.38 equiv) was added. so everything was mixed overnight at 25°C. The reaction mixture was acidified to pH=1 with 1N HCl solution and extracted with ethyl acetate. Quenching with water, brine, drying and concentration gave the crude product with a yield of 90%.

Step 2: The crude acid (1 eq.) from step 1 was dissolved in THF (0.14 M) and carbonyl diimidazole (1 eq.) was added, and everything was stirred for 1.5 h at 25°C. The reaction mixture was then cooled to 0°C. Sodium borohydride (2.86 eq.) was added in several portions, after which EtOH (0.71 M) was added, and everything was stirred overnight at 25°C. The reaction mixture was then acidified with 2N HCl to pH=2 and then extracted with ethyl acetate. Quenching with water, brine, drying and concentration gave the crude product with a yield of 95%.

Step 3: The crude indole alcohol (1 eq) from step 2 was poured into the oven-dried flask, followed by anhydrous DMF (0.135 M). Then imidazole (1.3 eq.) and TBSCl (1.2 eq.) were added and everything was stirred for 1 h at 25°C. Quench with ethyl acetate/water so

then chromatographic purification gave the desired product with a yield of 70%.

Step 4: The silyl-protected indole (1 equiv) from step 3 was dissolved in anhydrous DMF (0.13 M) in an oven-dried flask. To this was added NaH (60% dispersion in mineral oil, 1.2 equiv.) and everything was stirred for 2 h at 25°C, after which ethyl 4-bromobutyrate (1.2 equiv.) and KJ (1.2 equiv. .). The reaction mixture was then heated for 2 h at 60°C. Quenching with ethyl acetate/water followed by chromatographic purification gave the desired product in 93% yield.

Step 5: The alkylated indole (1 eq.) from step 4 was dissolved in THF (0.05 M) and TBAF (1.0 M/THF, 1 eq.) was added dropwise at 25°C, and everything was mixed 1 h. Quenching with ethyl acetate/water followed by chromatographic purification gave the desired product in quantitative amount.

Step 6: Indole alcohol (1 eq.) from step 5 was dissolved in anhydrous DMF (0.16 M) and POCl3 (10 eq.) was added dropwise at 0°C. Heated overnight at 80°C. Quenched with ethyl acetate/water, the organic layer was washed with 1N NaOH, water, brine, then concentrated, and chromatographic purification gave the desired product in 64% yield.

Step 7: A mixture of the chloroaldehyde derivative (1 eq.) from Step 6, 325 mesh K2CO3 (2.4 eq.), 2-naphthol (1.2 eq.) and KJ (1.2 eq.) was suspended in anhydrous acetonitrile (0.2 M) and heated for 1.5 h at 70°C. Quenching with ethyl acetate/water followed by chromatographic purification gave the desired product in 65% yield.

Step 8: The naphthyloxy indole derivative (1 eq.) from Step 7 was dissolved in anhydrous THF (0.023 M) and 5% Pt/C (40% wt) was added under nitrogen and hydrogenated with one bubble of N2 for 2.5 h. The reaction mixture was then filtered through celite and concentrated to give the crude product in 96% yield.

Step 9: The amino indole derivative (1 eq.) from step 9 was dissolved in anhydrous CH2Cl2 (0.07 M), then Et2N (1.4 eq.) and cyclopentanecarbonyl chloride (1.2 eq.) were added dropwise at 0°C. ). Everything was stirred for 0.5 h at 25°C, after which the reaction mixture was quenched with saturated NaHCO3 solution and stirred overnight. The organic layer was separated and washed with saline solution, dried. The product was obtained with a yield of 66% after recrystallization from 30% ethyl acetate/hexane.

Step 10: The indole from step 9 (1 equiv) was poured into a flask along with NaH2PO4 (12 equiv), t-butyl alcohol (0.13 m), water (0.13 m), 2-methyl-2- butene (46 equiv.) and NaO2Cl (12 equiv.) was added to this mixture at 25°C. The reaction mixture was then heated overnight at 65°C. Quenching with ethyl acetate/water and trituration with CH2Cl2/hexane (4:6) at 0°C gave the desired product in 63% yield.

Step 11: The acid (1 eq.) from step 10 was poured into a flask and EDCl (3 eq.), DMAP (1.2 eq.), pyrrolidine (1.2 eq.) and then anhydrous THF (0.018 M) and the reaction mixture was kept at reflux temperature for 18 h. It was quenched with ethyl acetate/water, then the organic layer was washed with 1N HCl, saturated bicarbonate and brine. Recrystallization from ethyl acetate/hexane (3:7) gave the desired product in 89% yield.

Step 12: The amide (1 equiv.) from Step 11 was dissolved in THF/MeOH/water (3:1:1, 0.025 M) and LiOH·H2O (1.2 equiv.) was added and stirred over nights at 25°C. Quenching with ethyl acetate/water and recrystallization from CH2Cl/hexane (1:1) gave the desired product in 98% yield.

Example 51

4-{5-[cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butyric acid

Step 1: Proceeding according to step 11 of Example 50 and using morpholine, 87% of the desired product was obtained after recrystallization.

Step 2: Proceeding according to step 12 of Example 50 and using the appropriate morpholino amide, the desired product was obtained in a yield of 98 after recrystallization.

Example 52

N-[2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfoninamino}butyl)-3-(1-pyrrolidinylcarbonyl)-1H-indol-5-yl]cyclopentanecarboxamide

The acid from Example 50 (1 eq.) was poured into a flask and EDCl (3 eq.), DMAP (1.2 eq.), trifluoromethanesulfonamide (1.2 eq.) and then anhydrous THF (0.04 M ) and the reaction mixture was stirred overnight at 25°C. The reaction was quenched with ethyl acetate/water and then the organic layer was washed with 1N HCl, saturated bicarbonate and brine. By trituring the crude product with CH2Cl2 / hexane (1:2) at 0°C for 1 h, the desired product was obtained with a yield of 96%.

Example 53

N-[3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1-[4-oxo-4-{[(trifluoromethyl)sulfoninamino}butyl)-1H-indol-5-yl]cyclopentanecarboxamide

Proceeding according to step 1 (Example 52) and using the appropriate acid from Example 52 (step 4, scheme-4) the desired product was obtained with a yield of 96%.

Example 53A

4-{5-[(cyclopentylcarbonyl)amino1-3-formyl-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl]butyric acid

Step 1: Indole (1 eq.) from step 9 of Example 50 was dissolved in THF/MeOH/H2O (3:1:1, 0.025 M) then LiOH H2O (1.2 eq.) was added and everything was stirred for 4 h at 25°C. Quenched with ethyl acetate/water, then triturated with CH2Cl2/hexane to give the desired product in 74% yield.

Example 53B

N-[3-formyl-2-[(2-naphthyloxy)methyl]-1-[4-oxo-4-{[(trifluoromethyl)sulfonyl]amino}butyl)-1H-indol-5-yl] cyclopentanecarboxamide

Step 1: The acid (1 eq.) from Step 1 of Example 53 A was poured into a flask along with EDCl (1.35 eq.), DMAP (1.1 eq.), trifluoromethanesulfonamide (1.05 eq.), and then anhydrous THF (0.026 M) and the reaction mixture was stirred for 3 h at 25°C. The reaction was quenched with ethyl acetate/water, the organic layer was washed with 0.05N HCl, saturated carbonate and brine. Chromatographic purification gave the desired product in 94% yield.

Example 54

5-[(cyclopentylcarbonyl)amino1-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino}butyl)-1H-indole-3-carboxylic acid

Step 1: The product of Step 1 of Example 53B (1 eq.) was poured into a flask along with NaH 2 PO 4 (12 eq.), t-butyl alcohol (0.12 M). with water (0.12 M). 2-methyl-2-butene (50 equiv.) and NaO2Cl (11.8 equiv.) was added to the mixture at 25°C. The reaction mixture was heated for 3 h at 60°C and left overnight at 25°C. Quenching with ethyl acetate/water, chromatographic purification and trituration with CH2Cl2 / hexane (1:1) gave the desired product in 57% yield.

Example 55

3-({4-[5-(cyclopentylcarbonyl)amino1-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butanoyl}amino)benzoic acid

Step 1: The compound from Example 50 (1 eq.) was poured into a flask and EDCl (3 eq.), DMAP (1.2 eq.), methyl 3-aminobenzoate (1.2 eq.) were added, and then anhydrous THF (0.04M) and the reaction mixture was stirred for 2 days at 25°C. It was quenched with ethyl acetate/water, the organic layer was washed with 1N HCl, saturated carbonate and brine. Recrystallization from ethyl acetate/hexane gave the desired product in 88% yield.

Step 2: The ester (1 eq.) from step 1 was dissolved in THF/MeOH/water (3:1:1, 0.024 M) and LiOH • H2O was added, stirred overnight at 25°C, after which 1.2 equiv was added. LiOH • H2O and everything was mixed for 2 days at 25°C. Quenched with ethyl acetate/1N HCl, after which trituration was performed with CH2Cl2/hexane (1:1) at 0°C for 1h, and the desired product was obtained with a yield of 92%.

Example 56

3-({4-[5-[(cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl]amino)benzoic acid

Step 1: Proceeding according to step 1 of Example 55 and using the product of Example 51 (see scheme-4 for the synthesis) the desired product was obtained in 85% yield after chromatographic purification.

Step 2: Proceeding according to step 2 of Example 55 and using the corresponding morpholine from step 1, the desired product was obtained in 91% yield.

Example 57

N-[2-[(2-naphthaloxy)methyl]-1-[4-oxo-4-[3-({F(trifluoromethyl)sulfonyl1amino}carbonyl)anilino]butyl}-3-(1-pyrrolidinylcarbonyl)-1H -indol-5-yl] cyclopentanecarboxamide

Step 1: The compound from Example 55 (1 eq.) was poured into a flask and EDCl (3 eq.), DMAP (1.2 eq.), trifluoromethanesulfonamide (1.2 eq.) and then anhydrous THF ( 0.04 M), and the reaction mixture was stirred overnight at 25°C. It was quenched with ethyl acetate, water, then the organic layer was washed with 1N HCl, saturated bicarbonate and brine. Trituration with CH2Cl2 /hexane (8:2) gave the desired product in 84% yield.

Example 58

N-(3-(morpholinocarbonyl)42-[(2-naphthyloxy)methyl]-1-[4-oxo-4-[3({[(trifluoromethyl)sulfonyl]amino}carbonyl)anilino]butyl}-1H-indole -5-yl)cyclopentanecarboxamide

Proceeding according to step 1 of Example 57 and using Example 56, the desired product was obtained in 84% yield.

Example 59

2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid

Step 1: A solution of MeMgBr in butyl ether (1 M, 1.2 eq.) was cooled on ice. 4-Benzyloxy indole (1 equiv) in CH 2 Cl 2 (0.5 M) was added and the reaction mixture was allowed to warm to 25°C. After addition of 1-naphthoyl chloride (1 eq.) in CH2Cl2 (1 M), the reaction mixture was heated for 3 h at reflux temperature. Quenching with aqueous NH4Cl and extracting with CHCl3 gave the crude ketone which was purified by recrystallization from hexane/CHCl3/MeOH (53% yield).

Step 2: An ice-cooled solution of the ketone (1 eq.) from Step 1 in DMF (0.2 M) was treated with NaH (60% in mineral oil, 2.5 eq.). After 15 min, 4-bromophenyl acetic acid (1.1 eq.) in DMF (0.4 M) was added, and the resulting mixture was stirred overnight at 25°C. The reaction was quenched with 1N HCl, and the mixture was extracted with EtOAc. Organic extracts were dried and concentrated. The desired product was obtained in 68% yield after purification by chromatography and recrystallization from hexane/EtOAc.

Example 60

2-(4-{[5-(benzyloxy)-3-(2-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid

Step 1: Following step 1 of Example 59 and using the appropriate acyl chloride, 42% of the desired ketone was obtained after recrystallization from hexane/CHCl 2 .

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

Example 61

2-[4-({5-(benzyloxy)-3-[3,5-bis(trifluoromethyl)benzoyl)-1H-indol-1-yl}methyl)phenyl]acetic acid

Step 1: Following step 1 of Example 59, using the appropriate acid chloride, 30% of the desired ketone was obtained after recrystallization from hexane/CH2Cl2/EtOAc.

Step 2: A procedure analogous to step 2 of Example 59 gave 73% of the title compound after chromatographic purification and recrystallization from CHCl 2 /MeOH.

Example 62

4-({3-benzoyl-5-(benzyloxy)-2-[(naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq.) in THF (0.27 M) at 0 °C under nitrogen for 1 h. Quenching with NaOH and water and then concentrating gave the crude product (100%).

Step 2: The crude alcohol from step 2 was dissolved in DMF (0.38 M) and treated with t-butylmethylsilyl chloride (1.16 equiv) and imidazole (1.26 equiv) at 25°C for 1 day. Quenching and chromatographic purification gave pure product (93%).

Step 3: The silyl ether from step 2 was dissolved in methylene chloride (0.26 M) and treated for 3 days with BOC anhydride (1.24 equiv), triethylamine (1.53 equiv) and DMAP (0.21 equiv) at 25°C. Quenching and chromatic purification gave the 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. Quenching and chromate purification gave pure product (100%).

Step 5: The alcohol from step 4 was dissolved in methylene chloride (0.2 M), then treated under nitrogen at -40°C for 1 hour with triethylamine (1.33 eq.) and mesyl chloride (1.23 eq.). Naphthalene-2-thiol (1.21 eq.) was poured into a separate bottle and THF (1M) was added, then lithium hexamethyldisilazide (1N in THF, 1 eq.) and the mixture was stirred for 30 min at 25°C. The resulting solution was added dropwise to the mentioned mesylate solution at -40°C over 30 minutes. The reaction mixture was allowed to warm to 25°C and was then stirred at that temperature for 4.5 h. Quenching and chromatographic purification gave the BOC thioether.

Step 6: The purified BOC thioether from step 5 was heated under nitrogen at 160-170°C for 1.25 h and recrystallized from ethyl acetate and hexane to give the free indole thioether in 64% yield.

Step 7: The product from Step 6 (1 eq.) in CH2Cl2 (0.125 M) was cooled in an ice bath. A solution of MeMgBr (1.2 eq.) in butyl ether (1 M) was added, and the resulting mixture was stirred for 30 min. After heating to 25°C, benzoyl chloride was added dropwise. The reaction mixture was heated for 3 h at the reflux temperature, and then stirred overnight at 25°C. After quenching with NH4Cl, the mixture was extracted with CH2Cl2. The organic extracts were washed with saline, dried and concentrated. The desired ketone was obtained with a yield of 55% after chromatographic purification.

Step 8: A solution of the product from Step 1 (1 eq.) in anhydrous DMF (0.1 M) was treated with NaH (60% in mineral oil. 1.5 eq.). After 1 h, methyl 4-bromomethylbenzoate (1.1 eq.) was added at 25°C, and the resulting mixture was stirred overnight. Quenching with EtOAc/water gave crude material which was purified by chromatography (56% yield).

Step 9: Material from Step 2 (1 eq.) hydrolyzed with LiOH-H2O (1.2 eq.) in THF/MeOH/water (3/1/1, 0.07 M). After stirring overnight at 25°C, the reaction mixture was quenched with AcOH and the solvent was evaporated. Quenching with EtOAc/water and chromatographic purification afforded the title compound in 78% yield.

Example 63

4-({5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Proceeding according to step 1 of example 62, using isopropyl chloride gave the desired ketone after chromatography.

Step 2: A procedure analogous to step 8 of Example 62 gave 50% of the N-alkylated material after chromatographic purification.

Step 3: Following step 9 of Example 62, the methyl ester was hydrolyzed to the title compound in 67% yield after chromatography.

Example 64

2-{3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid

Step 2: The product from Step 1 of Example 80 was alkylated with methyl bromoacetate following a procedure analogous to Step 8 of Example 62 to give 65% of the desired compound after recrystallization from EtOAc.

Step 3: Following step 9 of Example 62, the methyl ester hydrolyzed to the title compound in 84% yield after chromatography.

Example 65

2-{5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid

Step 2: A procedure analogous to that of Step 2 of Example 65 started from methyl bromoacetate and isopropyl ketone described in Step 1 of Example 63 (Step 1, see above). The reaction yielded 66% N-alkylated material after chromatographic purification.

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

Example 66

4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butyric acid

Step 1: A solution of EtMgBr in ether (3N, 2.17 eq.) was cooled to -70°C. The product from step 2 of Example 62 (1 eq.) in ether (0.55 M) was added and the reaction mixture was stirred for 2 h at -70°C. After addition of benzoyl chloride (3 eq.) in ether (1.5 M), the reaction mixture was stirred for 2 h at -40°C, quenched with saturated NaHCO3, at -40°C and allowed to warm to 25°C. Workup with EtOAc/water and crystallization from hexane/EtOAc afforded the desired ketone in 89% yield.

Step 2: The material from step 1 (1 equiv) in CH2Cl2 (0.25 M) was treated with Net3 (2 equiv) followed by BOC anhydride (1.24 equiv) and DMAP (0.21 equiv). ). After stirring for 20 min at 25°C, the reaction mixture was quenched with CH2Cl2 and water. Pure desired material was obtained in 97% yield by trituration with hexane.

Step 3: The material from the previous step (1 eq.) in THF (0.3 M) was combined with pyridine (excess) and HF pyridine (excess) at 0°C. The reaction mixture was stirred for 1.5 h at 25°C. Quenching with EtOAc/water followed by chromatographic purification afforded the desired alcohol in 86% yield.

Step 4: Alcohol from Step 3 (1 eq) in CH2Cl2 (0.25 M) was treated with 2,6-lutidine (2.5 eq) and SOCl2 (1.2 eq). After 30 min at 25 °C, the reaction was quenched with EtOAc and water. The crude product was purified by chromatography and trituration with hexane to give the corresponding chloride in 75% yield.

Step 5: A mixture of materials from the previous step (1 eq), 325 mesh K2CO3 (2.4 eq), b-naphthol (1.2 eq) and KJ (1.2 eq) in CH2Cl2 (0.3 M) it was heated at reflux temperature for 2 hours. Quenching with EtOAc/water followed by chromatographic purification of the mother liquor gave 70% of the expected ether.

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

Step 7: A solution of the product from Step 6 (1 eq.) in anhydrous DMF (0.1 M) was treated with NaH (60% in mineral oil. 1.1 eq.). After 1 hour, methyl 4-bromobutyrate (1.2 equiv.) and KJ (1.2 equiv.) were added, and the reaction mixture was stirred for 3 hours at 75°C. Quenching with EtOAc/water followed by chromatographic purification afforded the desired ester in 96% yield.

Step 8: The material from step 7 (1 eq.) was hydrolyzed with LiOH·H2O (1.2 eq.) in THF/MeOH/water (3/1/1, 0.2 M). After stirring for 2 h at 25°C, the reaction mixture was quenched with 1N HCl and extracted with EtOAc and CH2Cl2. The crude material was purified by trituration in hexane. EtOAc to give the title compound in 86% yield.

Example 67

3-4(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid

Step 1: The product of Example 66 (1 eq.) was reacted with EDCl (1.37 eq.) dimethyl 3-amino benzoate (1.05 eq.) in DMF (0.99 M) in the presence of DMAP (0.2 eq. .). The reaction mixture was stirred for 1.5 h at 25°C. Quenching 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 afforded 98% of the title compound after trituration in hexane/EtOAc.

Example 68

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

Step 1: Proceeding according to step 1 of Example 67 and using the acid of Example 67 and the corresponding sulfonamide, the desired product was provided after overnight reaction and analog quenching. Trituration with hexane/EtOAc gave

100% of the nominal compound.

Example 69

4-[(4-{3-benzoyl-5-(benzyloxy)-2[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid

Step 1: Following step 1 of Example 67 and using the acid of Example 66 and the corresponding aniline, 76% of the expected amide was obtained.

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

Example 70

2-(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid

Step 1: Proceeding according to Step 1 of Example 67 and using the acid of Example 66 and the corresponding aniline gave 36% of the expected amide.

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

Example 71

3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]propionic acid

Step 1: Proceeding according to Step 1 of Example 67 and using the acid of Example 66 and the corresponding aniline gave 96% of the expected amide.

Step 2: A procedure analogous to step 2 of Example 67 afforded 90% of the title compound after purification by trituration in hexane/EtOAc.

Example 72

3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]propionic acid

Proceeding according to step 1 of Example 67 and using the acid of Example 66 and the corresponding sulfonamide, 100% of the title compound was obtained.

Example 73

N-(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)-2-methylbenzenesulfonamide

Proceeding according to step 1 of Example 67 and using the acid from Example 66 and the corresponding sulfonamide, 80% of the title compound was obtained after chromatography.

Example 74

5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}valenic acid

Step 1: A solution of the product from Step 6 of Example 66 (1 eq.) in dry DMF (0.1 M) was treated with NaH (60% in mineral oil, 1.1 eq.). After 1 h, ethyl 4-bromopentoate (1.2 eq.) and KJ (1.2 eq.) were added, and the reaction mixture was stirred at 75°C for 2 h. Quenching with EtOAc/water and purification by chromatography afforded 92% of the desired ester.

Step 2: The material from step 1 (1 eq.) was hydrolyzed with LiOH·H2O (1.3 eq.) in THF/MeOH/water (3/1/1, 0.2 M). After stirring for 3.5 h at 25°C, the reaction mixture was quenched with 1N HCl and extracted with EtOAc and CH2Cl2. The organic extracts were combined, washed and concentrated. The crude material was purified by trituration in hexane/EtOAc to give the title compound in 95% yield.

Example 75

3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}pentanoyl)amino]benzoic acid

Step 1: The acid from Example 74 (1 eq.) was reacted with EDCl (1.37 eq.) and methyl 3-amino benzoate (1.05 eq.) in DMF (0.09 M) in the presence of DMAP (0.2 eq.). The reaction mixture was stirred for 2.5 h at 25°C. Quenching with EtOAC/water and flash chromatography produced the desired amide in 78% yield.

Step 2: A procedure analogous to step 2 of Example 74 afforded 83% of the title compound after purification by trituration in hexane/EtOAc.

Example 76

5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-N-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl) phenyl]pentanamide

Step 1: Proceeding according to Step 1 of Example 68 and using the acid of Example 75 and the corresponding sulfonamide, 83% of the title compound was obtained after overnight reaction and analog quenching.

Example 77

2-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}acetic acid

Step 1: Proceeding according to step 1 of Example 74 and using the appropriate bromide, 80% of the expected amide was obtained after chromatography.

Step 2: A procedure analogous to step 2 of Example 74 afforded 90% of the title compound after trituration in hexane/EtOAc.

Example 78

(E)-4-{3-benzoyl-5-(benzyloxy)-2-[2-naphthyloxy)methyl]-1H-indol-1-yl}butyric acid

Step 1: Proceeding according to step 1 of Example 74 and using the appropriate bromide, 33% of the expected amide was obtained after chromatography.

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

Example 79

3-({3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}methyl)benzoic acid

Step 1: Proceeding according to step 1 of Example 74 and using the appropriate bromide, 75% of the expected amide was obtained after chromatography.

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

Example 80

1-{1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzisulfanyl)-2-[(2-naphthysulfanyl)methyl]-1H-indol-3-yl}-1- ethanone

Step 1: The thioether from step 6 of Example 62 was dissolved in methylene chloride (0.12M) and treated with methylmagnesium bromide (1.1 eq.) under nitrogen at 0°C, and then stirred for 1 h at 0 to 25°C. The mixture was cooled again to 0°C and acetyl chloride (1.17 eq.) was added. After 1 h at 0°C, the mixture was quenched by adding a half-saturated solution of ammonium chloride, and finished with methylene chloride. Chromatographic purification gave the pure product (73).

Step 2: Following the procedure for Example 81, step 1, and using p-toluoyl chloride, the corresponding para amide was obtained.

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

Step 4: Following the procedure for Example 81, step 3, and using the material from the previous step 3, the desired benzyl bromide was obtained.

Step 5: Following the procedure for Example 81, step 4, the material from the previous step 4 was combined with the material from the previous step 1 to give the nominal compound.

Example 81

1-{1-[3-(1,3-benzothiazol-2-ylcarbonyl)benzyn-5-(benzisulfanyl)-2-[(2-naphthysulfanyl)methyl]-1H-indol-3-yl}-1-ethanone

Step 1: m-toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq.) and methoxymethyl amine HCl (1.1 eq.) dissolved in methylene chloride at 0°C for 20 min. The reaction mixture was allowed to warm to 25°C. After 1 day of stirring at 25°C, quenching with methylene chloride and water gave the crude product in about 100% yield.

Step 2: Benzothiazole was dissolved in THF (0.35 M) under anhydrous conditions. BuLi (1.1 equiv) was added at -78°C. After 1 hour at -78°C, the amide from step 1 in THF was added for 15 min. The reaction mixture was allowed to warm to 25°C. After stirring for 1 day at 25°C, quenching with ethyl acetate and water and chromatography gave pure tolyl ketone (52%).

Step 3: The tolyl ketone from Step 2 was dissolved in carbon tetrachloride (0.19 M) and NBS (1.2 eq) and AIBN (0.11 eq) were added. After 1 day at 60°C it was about 1:1 starting material and product. After repeated exposure to the same conditions, followed by filtration and recrystallization from ethyl acetate, pure bromobenzyl ketone (28%) was obtained.

Step 4: The indole from Step 1 of Example 80 was dissolved in anhydrous DMF (0.04 M), after which NaH (1.25 eq.) was added. After 45 min at 25°C, bromobenzyl ketone from step 3 (1.25 eq.) was added and everything was stirred for 1 h at 25°C. Quenching, chromatography and recrystallization from ethyl acetate/hexane gave the pure title compound (45%).

Example 82

2-[3-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoyl]-1,3-benzothiazole-6-carboxylic acid

Step 1: Ethyl 4-aminobenzoate was dissolved in 95% vol HOAc/water (0.4 M) and treated with sodium thiocyanate (4.1 eq.) at 25°C and stirred for 20 min at 25°C. The mixture was cooled to 5°C and bromine (1.17 equiv) in 95% vol HOAc/water was added. After 1 h at 0°C, the reaction mixture was quenched by adding water and filtered. Workup (ethyl acetate and sodium bicarbonate solution) gave 81% pure thiocyanate produced.

Step 2: The aryl cyanate from step 1 was treated with sodium sulfide nonahydrate dissolved in water (1.1 eq., 1.3 M) and heated for 45 min at reflux temperature. The cooled mixture was filtered, acidified to pH 7.6 with HOAc, extracted with ethyl acetate and concentrated to give thiophenol (91%).

Step 3: Thiophenol from step 2 was dissolved in 90% vol HOAc/water (3.3 M) and zinc powder (catalyst) was added. After 3 hours at reflux temperature, quenching with ethyl acetate and alkali gave the pure benzothiazole ester (60%).

Step 4: The benzothiazole ester from step 3 was dissolved in THF/methanol/water (8:3:3), (0.34 M) and lithium hydroxide (2 eq.) was added and the mixture was stirred for 2 h at 25°C. . Quenching (ethyl acetate/hydrochloric acid) gave pure benzothiazolic acid (100%).

Step 5: Benzothiazolic acid (Step 4) was dissolved in THF (0.052 M) under anhydrous conditions. BuLi (2.2 equiv) was added at -78°C. After 1 h at -78°C to 0°C, the amide (1.28 equiv.) from step 1 of Example 81, in THF, was added at -78°C for 5 min. After 0.5 h at -78°C, the reaction mixture was allowed to warm up to 25°C. After stirring for 2 h at 25°C, quenching with ethyl acetate and water and chromatography gave pure tolyl ketonic acid.

Step 6: The tolyl ketonic acid from step 5 was suspended in (1:1) THF/ethanol, (0.075 M) and concentrated sulfuric acid (excess) was added. After 1 day of heating at reflux temperature, quenching (ethyl acetate and sodium bicarbonate solution) and purification by chromatography gave pure tolyl ketone ester (69%).

Step 7: The tolyl ketone ester from Step 6 was dissolved in carbon tetrachloride (0.05 M) and NBS (1.2 eq) and AIBN (0.15 eq) were added. After 1.25 h at reflux temperature, a second portion of NBS (0.3 eq.) and AIBN (0.07 eq.) was added. Filtration and recrystallization from ethyl acetate gave pure bromobenzyl ketone (22%).

Step 8: The indole from Step 1 of Example 80 was dissolved in anhydrous DMF (0.06 M), and NaH (1.11 eq) was added. After 45 min at 25°C, bromobenzyl ketone from step 7 (1.25 eq.) was added and everything was stirred for 1 h at 25°C. Quenching gave the crude ester which was 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 eq.) was added in portions while the mixture was stirred for a total of 3-4 days at 25°C. Quenching (ethyl acetate/aq Hcl) and purification by chromatography gave pure benzothiazolic acid (31%).

Example 83

5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoic acid

Step 1: The indole from Step 6 of Example 66 was dissolved in anhydrous DMF (0.17 M), then NaH (1.2 eq) was added. After 1.5 h at 25°C, 3-iodo-1-chloropropane was added and everything was stirred for 4 h at 25°C. Quenching (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) and NaJ (1.6 eq.) was added. After 1 day of stirring at reflux temperature in the dark, quenching (ethyl acetate/water) afforded the product iodide in 97% yield.

Step 3: NaH (1.0 eq.) was poured into a dry flask under nitrogen and anhydrous benzene (0.14M) was added. Anhydrous DMF (0.4 M), ethyl 2-carboxy-1,3-dithiane (1.0 equiv.) and iodide from step 2 (1.0 equiv.) were poured into a separate dry flask at 0°C. This DMF solution was then added to the 0°C benzene suspension and the mixture was allowed to warm to 25°C and stirred for 3 hours at 25°C. Quenching (ethyl acetate/water) and chromatography gave the dithianyl ester in 54% yield.

Step 4: Silver nitrate (4.5 eq.) and NCS (4.0 eq.) were dissolved in 4:1 acetonitrile/water (about 0.04 M) and the dithianyl ester solution from step 3 was added at 25°C ( 1 equiv) in acetonitrile (0.03 M). After 5 minutes of mixing at 25°C, a solution of sodium sulfite was added, and after one minute, a solution of sodium carbonate. Quenching (ethyl acetate/water) and chromatography gave the ketoester in 17% yield.

Step 5: The ketoester from step 4 was dissolved in THF/water (8:1), (0.03 M), then lithium hydroxide (1.4 eq.) was added and the mixture was stirred for 2 h at 25°C. Quenching (ethyl acetate/aq HCl) and purification by chromatography afforded the pure ketoacid (64%).

Example 84

3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoyl)amino] benzoic acid

Step 1: The dithianyl ester from Step 3 of Example 83 was dissolved in THF/ethanol/water (5:2:2) (0.008 M), then lithium hydroxide (11 eq.) was added and the mixture was stirred for 1 day at 50°C. . Quenching (ethyl acetate/aq HCl) and chromatography gave pure dithianilic acid (90%).

Step 2: The dithianilic acid from step 1 was dissolved in anhydrous methylene chloride (0.08 M) and DMF (catalyst). Oxalyl chloride (1.2 eq.) was added and the reaction mixture was stirred for 0.5 h at 25°C. After concentration, re-dissolving in anhydrous methylene chloride was carried out, and then, at 0°C, methyl 3-aminobenzoate (1.05 eq.) and triethylamine (1.0 eq.) were added. The reaction mixture was heated to 25°C and stirred at that temperature for 3 h. Quenching (ethyl acetate/hydrochloric acid) and purification by chromatography afforded the dithianyl ester in 89% yield.

Step 3: The dithianyl ester from step 2 was dissolved in THF/methanol/water (6:4:3) (0.02M) and lithium hydroxide (4.3 eq.) was added and the mixture was stirred for 3 h at 25°C. Quenching (ethyl acetate/aq HCl) gave dithianylic acid (R=3-COOH) (91%).

Step 4: Silver nitrate (4.6 eq.) and NCS (4.0 eq.) were dissolved in 4:1 acetonitrile/water (about 0.03 M) and at 25°C the dithianilic acid solution from step 3 was added ( 1 equiv) in acetonitrile (0.009 M). After 10 minutes of mixing at 25°C, a solution of sodium sulfite was added, and after one minute, a solution of sodium carbonate. Quenching (ethyl acetate/hydrochloric acid) and chromatography afforded the title compound in 82% yield.

Example 85

4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoyl)amino] benzoic acid

Step 1: The dithianilic acid from Step 1 of Example 84 was treated as described for Step 2 of Example 84, except that ethyl 4-aminobenzoate was used. Purification by chromatography gave the dithianyl ester (R=4-COOC2H5) with

with a yield of 30%.

Step 2: The dithianyl from step 1 was worked up as described in step 3 of Example 84. Purification by chromatography gave dithianyl acid (R=COOH) in 89% yield.

Step 3: The dithianyl from Step 6 was worked up as described in Step 4 of Example 84. Repeated purification by chromatography followed by trituration in pentane afforded the title compound in 30% yield.

Example 86

Table 1 provides data for the compounds described in the previous examples in the cPLA2 inhibition assays (which are described below). In the tebela data columns, test results are entered as an "IC50" value, which is the concentration of a single compound that inhibits 50% of the activity of the phospholipase enzyme in such a test. Where no IC50 value occurs. "NA" indicates that no inhibitory activity was detected for that compound in the corresponding test, and an empty box indicates that the compound was not tested in this test at the time of this application.

Performance tests

(a) Vesicle assays

1-palmitoyl-2-[14C]arachidonyl phosphotidylcholine (50 mCi/mole) (final concentration 6 M) and 1,2-dioleoylglycerol (final concentration 3 M) were mixed and dried under a stream of nitrogen. 50 mM Hepes pH 7.5 (2x final lipid concentration) was added to the lipids, and the suspension was sonicated for 3 min at 4°C. 50 mM Hepes pH 7.5, 300 mM NaCl, mM DTT, 2 mM CaCl2 and 2 mg/ml bovine serum albumin (BSA) (Sigma A7511) (1.2 x final lipid concentration) were added to the suspension. A typical assay consists of a lipid mixture (85 L) to which inhibitor (5 L in DMSO) and cPLA2, 10 ng for the automated system or 1 ng for the manual assay, are added consecutively in 10 L of BSA buffer. This test was performed according to a manual or automated test protocol that will be described later.

(b) Test with soluble substrate (LysoPC)

1-[14 C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/MMol) (final concentration 4.4 M) was dried under a stream of nitrogen. Lipids were resuspended by centrifugation in 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay involved a lipid suspension (85 L) to which inhibitor (5 L in DMSO) and cPLA2, 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA were added consecutively. This test was performed either manually or according to an automated test protocol that will be described later.

(c) Automated testing

The lipid suspension and the inhibitor were previously incubated for 7 min at 37°C. Enzyme was added and the incubation was extended for another 30 min. The reaction was quenched by adding decane: isopropanol-trifluoroacetic acid (192:8:1 wt./vol., 150 l). A portion of the quench layer (50 L) was passed through a Rainin Soheric-5 column of silica gel (5.30 x 2.1 mm), eluted with heptane:methanol:TFA (97:3:0.1 vol.). The level of [14C]-arachidic acid was analyzed with an in-line Radiomatic Flo-One/Beta counter (Packard).

(d) Manual testing

Lipid, inhibitor and enzyme mixture were incubated for 30 min at 37°C. The reaction was quenched by adding heptane:isopropanol:0.5M sulfuric acid (105:20:1 vol., 200 L). Half the quench layer was applied to a disposable silica gel column (Whatman SIL, 1 ml) in a vacuum collector placed above the scintillation vial. Free [14 C]-arachidic acid was washed by addition of ethyl ether (1 ml). The level of radioactivity was measured with a liquid scintillation counter.

(e) PMN assay

PMNs were isolated using Cicoll-Hypaque according to the manufacturer's instructions. Red blood cells contaminating PMNs were removed by hypotonic lysis, and PMN cells were washed once and resuspended in Hanks' buffered saline at a concentration of 2 x 106 cells.ml. Cells were preincubated with inhibitors for 15 min at 37°C and then stimulated with 2 μM A23187. When monitoring LTB4 production as a measure to suppress cPLA2, the reaction was quenched with an equal volume of ice-cold phosphate buffered saline. Cells were removed by centrifugation, and LTB4 present in the cell supernatant was measured using the LTB4 scintillation viscosity assay provided by Amersham, according to the manufacturer's instructions. In the tests entered in the mentioned tables, LTB4 was measured. When arachidonic acid production was measured, the reaction was quenched with methanol containing DS-arachidic acid as an internal reference. Lipids were extracted by the procedure 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 that published by Ramesha and Taylor ((1991) Anal. Biochem., 192. 173-180).

(f) RBL Testing

RBL-2H3 cells were routinely grown at 37°C in a 5% CO2 atmosphere in minimal essential medium containing nonessential manino acids and 12% fetal calf serum. The day before the experiment, the cells were dispersed in centrifuge bottles at 3 x 105 cells/ml, and 100 ng/ml of DNP-specific IgE was added. After 20 hours, cells were collected by centrifugation and washed once in minimal essential medium without serum and resuspended at 2 x 106 cells/ml in medium without serum. The cells were then preincubated either with the inhibitor in DMSO (1% vol.) or DMSO (1% vol.) for 15 min at 37°C, after which stimulation with DNP-BSA (300 ng/ml) was performed. After 6 min, the cells were removed by centrifugation, and the surface layer was examined for PGD2 content in accordance with known procedures.

(g) Coumarin testing

7-Hydroxycoumarinyl 6-heptenoate was used as a monomer substrate for cPLA2 as previously mentioned (Huang, Z. et al., 1994 Analytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 μL of Lispitan buffer (80 mM Heped, pH 7.5 and mM EDTA) containing 60 μL of 7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by introducing 4 μg of cPLA2 into 50 μL of the tested buffer. Hydrolysis of 7-hydroxycoumarinyl 6-heptenoate ester was monitored with a single fluorometer by excitation at 360 nm and emission monitoring at 460 nm. Enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of one cPLA2 inhibitor, the rate of increase is lower.

Example 87

The compounds of the present invention were also tested for in vivo activity in the rat paw islet test according to the procedure described below. The results are shown in Table II.

Carrageenan-induced swelling of the pad of the foot of the rat.

Each of the compounds was suspended in 0.3 ml absolute ethanol, 0.1 ml Tween-80 and 2.0 Dulbecco's PBS (without calcium or magnesium). 0.1 ml of 1N NaOH was added to this mixture. After the solution was complete, volumes of PBS were added to adjust the concentration to 1 mg/ml. All compounds remained in solution. The compounds were administered intravenously at 5 ml/kg to male Sprague Dawley rats simultaneously when swelling was induced by injection of 0.05 ml of 1% type IV carrageenan into the foot pad of the hind paw. Foot cushion volume was measured before compound administration and 3 hours after carrageenan administration.

All cited patents and literature are incorporated as if fully set forth herein.

Claims (109)

1. Compound formula: [image] whereby R1 and R1' are independently selected from H, halogen, -CF3, -OH, -C1-C10 alkyl, preferably -C1-C6 alkyl, -S-C1-C10 alkyl, preferably -S-C1-C6 alkyl, C1- C10 Alkoxy, preferably C1-C6 Alkoxy, -CN, -NO2, -NH2, -HN(C1-C6), -N(C1-C6)2, phenyl, -O-phenyl, -S-phenyl, benzyl, - O-benzyl, -S-benzyl, or one group of formulas: [image] R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy, -NO2, -NH2, -CN, -CF3, or -OH, R7 is selected from -OH, -CF3, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyropyl, phenyl , -O-phenyl, benzyl, -O-benzyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, -CN, - C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, -CF3, or -OH, R2 is selected from -CF3, -OH, - C1-C10 alkyl, preferably - C1-C6 alkyl, C1-C10 alkoxy. preferably C1-C6 alkoxy, -CHO, -CN. -NO2, -NH2, -NH-(C1-C6-alkyl). -N-(C1-C6 alkyl)2, -N-SO2-(C1-C6 alkyl) or -SO2-(C1-C6 alkyl), R3 is selected from H, -CF3, C1-C6 lower alkyl, C1-C6 lower alkoxy, C3-C10 cycloalkyl, - C1C6 alkyl-C3-C10 cycloalkyl, CHO, halogen, or one group of formula-L2-M2, wherein L2 is a bridging or bonding group of the formula -(CH2)n-, -S-. -O-C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O) -(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S -(CH2)n-, -C(O)C(O)X. where X is O or N M2 is selected from the group consisting of C1-C6 lower alkyl, C1-C6 lower lkoxides, C1-C6 cycloalkyl, phenyl or benzyl, where cycloalkynes, phenyl or benzyl rings are optionally substituted with 1 to 3 substituents selected from halogen, C1-C10 alkyl preferably -C 1 -C 6 alkyl, C 1 -C 6 alkoxy, preferably C 1 -C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 . or a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from, including, but not limited to, N, S, or O. furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazoline. pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, wherein the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6 alkyl. C1-10 Alkoxy, preferably C1-6 Alkoxy, -NO2, -NH2, -CN, or -CF3, or b) A six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O, including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizin. oxazine, or morpholine, wherein the six-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 oxy, preferably C1-6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3, or -OH, or c) one bicyclic ring group optionally containing from 8 to 10 ring heteroatoms selected from N, S or O, including, but not limited to, benzofuran, indole, indoline, naphthalene, purine or isoquinoline, wherein the bicyclic ring is group optionally substituted with 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3. or -OH, n is an integer from 0 to 3 R4 is selected from h, -CF3, C1-6 lower alkyl, C1-6 lower alkoxy, C1-6 cycloalkyl, C1-6 lower alkyl-C1-6 cycloalkyl, -COOH, halogen, or the group of formulas: a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-thenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2 -phenyl)2, -CH2-phenyl-C(O)-benzothiazole or one compound of the formula: [image] where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, and the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, C1-6 alkyl, C1-6 alkoxy, -NH2, -NO2, or one five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or b) a group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group: [image] whereby D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3, B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH. -C1-6 alkyl, C1-C6 alkoxy, or -NO2, or c) group of formulas: [image] [image] where Z is O or S, the phenyl and pyrimidinyl rings of each group are optionally and independently substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, or -NO2 , R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(C1-12)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole , [image] or from groups selected from the formula –L1M1, wherein L1 is a bridging or bonding group selected from one chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -( CH2)n-C(O)-(CH2)n-, -(CH2)n-O -(CH2)n-, -(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-(CH2 )n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6) -(CH2)n-, -C(Z)-NH -SO2 or -C(Z)-NH-SO2-(CH2)n-, M1 is selected from the group consisting of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] where R8, R9 or R10 can be attached anywhere in the cyclic or bicyclic system, R8 is each time independently selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-C6 alkyl, -O-C1-C6 alkyl, - NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, R10 is selected from H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH. -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl), -N-(C1-C6 alkyl)2, [image] [image] R11 is selected from H, C1-C6 lower alkyl. C1-C6 cycloalkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, [image] provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from a carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas: [image] n is an integer from 0 to 3, or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, which has the formula: [image] where R1 is hydrogen and R1, R2, R4 and R5 are as defined in claim 1, or a pharmaceutically acceptable salt thereof. 3. Compound according to claim 2, which has the formula: [image] where R 1 , R 2 , R 3 , R 4 and R 5 are as described in claim 2, or a pharmaceutically acceptable salt thereof. 4. Compound according to claim 2 having the formula: [image] where R 1 , R 2 , R 3 , R 4 and R 5 are as described in claim 2, or a pharmaceutically acceptable salt thereof. 5. Combination of formulas: [image] whereby: R 1 is selected from H, halogen, -CF 3 , -OH. -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, -HN(C1-C6), -N(C1-C6), phenyl, -O-phenyl, benzyl, -O-benzyl, or one of group of the following formulas: [image] R6 is selected from H, C1-C6 alkyl. C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, - NH2, -NO2, -CN, -CF3 or -OH. R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), -CF3, C1-C6 alkyl, C3C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl. pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1C6 alkoxy, -NH2, -NO2 , -CF3 or -OH, R2 is selected from H, halogen, -CF3, -OH, -C1-C10 alkyl, preferably -C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C1-C6 alkyl, N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl, R3 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S-(CH2)n-C1-C6 cycloalkyl, or from the groups: a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(0-CH2 -phenyl)2, -CH2-phenyl-C(O)-benzothiazole or one compound of the formula: [image] Where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents selected from H. halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group: [image] whereby D is H, C 1 -C 6 lower alkyl, C 1 -C 6 lower alkoxy, or -CF 3 . B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, - C1-C6 alkyl, C1-C6 alkoxy, or-NO2., or c) one of the groups of formulas: [image] wherein the phenyl and pyrimidinyl rings of each of these groups are optionally and independently substituted with 1 to 3 substituents chosen from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2, R4 is selected from the group consisting of H, halogen -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, -CH2-(C3-C6 cycloalkyl), -C(O)-OH, -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C( O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl). [image] wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH. n is an integer from 0 to 3 R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, [image] [image] R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 is selected from H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH( C1-C6 alkyl) or -N(C1-C6 alkyl)2, R10 is selected from the group consisting of H, halogen, CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl . -NH(C1-C6 alkyl), -N-(C1-C6 alkyl)2 R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH. -(CH2)n-C(O)-COOH, or [image] provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas: [image] or a pharmaceutically acceptable salt thereof. 6. Combination of formulas: [image] whereby: R1 is selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl, or one of the groups of the following formulas: [image] R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy. –NO2, -CF3 or -OH, R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -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 C 1 -C 6 alkoxy. -CHO, -CN, -NO2, -NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl, R3 is selected from the group consisting of H, halogen -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl, CH2-(C3-C6 cycloalkyl), -C(O)-OH. -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C(O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl ), [image] wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, -C(O)-OH, or -OH. n is an integer from 0 to 3 R4 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S-(CH2)n-C1-C6 cycloalkyl, -(CH2)n-O-( CH2)n-C1-C6 cycloalkyl or from the groups: a) -(CH2)n-phenyl-O-phenyl. -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O) -benzothiazole or one compound of the formula: [image] where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, where the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group: [image] whereby D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3, B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl. thienyl iii pyrrolyl, each optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H. halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, or -NO2, or c) one group of formulas: [image] [image] wherein Z is 0 or S and the phenyl and pyrimidine rings of each of these groups are optionally and independently substituted with 1 to 3 substituents selected from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2, R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, [image] [image] R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, R10 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, [image] [image] R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or [image] provided that the complete group in indole and indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas: [image] or a pharmaceutically acceptable salt thereof. 7. Combination of formulas: [image] whereby: R1 is selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl, or one of the groups of the following formulas: [image] R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 Alkyl, C1-C6 Alkoxy, -NO2, -CF3 or -OH, R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C1- C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, whereby the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3 or -OH, R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, -CHO, -CN, -NO2 , -NH2. -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, -N-SO2-C1-C6 alkyl or -SO2-C1-C6 alkyl, R3 is selected from C1-C6 lower alkyl, C1-C6 lower alkoxy, -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-S -(CH2)n-C1-C6 cycloalkyl, -(CH2)n-O-( CH2)n-C1-C6 cycloalkyl or from the groups: a) -(CH2)n-phenyl-O-phenyl. -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O) -benzothiazole or one compound of the formula: [image] where n is an integer from 0 to 3, preferably 1 to 3, preferably 1 to 2, Y is C3-C6 cycloalkyl, phenyl, benzyl, naphthyl, pyridinyl, quinolyl, furyl, thienyl or pyrrolyl, where the rings of these groups are optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, or a five-membered heterocyclic ring containing one heteroatom selected from N, S or O , preferably S or O, or b) one group of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group: [image] whereby D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy, or -CF3, B and C are independently selected from groups consisting of phenyl, pyridinyl, furyl, thienyl or pyrrolyl, each of which is optionally substituted with 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, - C1-C6 alkyl, C1-C6 alkoxy, or -NO2, or c) one of the groups of formulas: [image] [image] wherein Z is O or S and the phenyl and pyrimidinyl rings of each of these groups are optionally and independently substituted with 1 to 3 substituents selected from halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy or -NO2, R4 is selected from the group consisting of H, halogen, -CF3, -OH, C1-C6 alkyl, C1-C6 alkoxy, benzyl, benzyloxy, phenyl, phenyloxy, -C(O)-phenyl, -C(O)-benzyl , CH2-(C3-C6 cycloalkyl), -C(O)-OH, -CH=O, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C( O)-CF3, -(CH2)n-S-CH2-(C3-C6 cycloalkyl). [image] wherein the phenyl and benzyl rings of the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, C(O)-OH, or -OH. n is an integer from 0 to 3 R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, [image] [image] R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, R10 is selected from H. halogen, CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH (C1-C6 alkyl), -N(C1-C6 alkyl)2, [image] [image] R11 is selected from H, C1-C6 lower alkyl, CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or [image] provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 shall contain at least one acid group selected from a carboxylic acid, or containing a carboxylic acid, a tetrazole, or a group of formulas: [image] or a pharmaceutically acceptable salt thereof. 8. Combination of formulas: [image] whereby: R1 is selected from NH2, -O-phenyl, benzyl, -O-benzyl, -N-benzyl, -N-benzyl-O-phenyl, -S-benzyl, or one of the groups of the following formulas: [image] R6 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, whereby the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NH2, -NO2, -CF3 or -OH, R7 is selected from -(CH2)n-COOH, -(CH2)n-N-(C1-C6 alkyl)2, -(CH2)n-NH-(C1-C6 alkyl), CF3, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), N-(C1-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, adamantyl or morpholinyl, wherein the rings of these groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -NO2, -CF3, or -OH, n is an integer from 0 to 3, R3 is selected from halogen, -C1-C6 alkyl, C1-C6 alkoxy, -CF3, -CH=O, -C(O)-C1-C6 alkyl, C(O)-O-C6 alkyl, -C(O )-OH, C(O)-OH, C(O)-CF3, -C(O)-phenyl, -C(O)-benzyl, -C(O)-pyrrolyl, -C(O)-thienyl, -C(O)-furanyl or C(O)-morpholinyl, R4 is selected from the group consisting of -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-S -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C6 cycloalkyl, -(CH2)n-S-C3-C6 alkyl, group: a) -C(O)-O -(CH2)n-C3-C6 cycloalkyl, -(CH2)n-phenyl, -(CH2)n-O-phenyl, -(CH2)n-S-phenyl, -(CH2)n-S- (CH2)n-phenyl, -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl -(CH2)n-phenyl, -(CH2) n-(O-phenyl-CH2-phenyl)2, -C(O)-O-phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, -C(O)-O -naphthyl, -(CH2)n-S-naphthyl, -(CH2)n-S-pyridinyl, -(CH2)n-pyridinyl or -(CH2)n-naphthyl, -(CH2)n-O-naphthyl, where the rings are phenyl, pyridinyl and naphthyl of these groups optionally substituted with 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C1-C6 alkyl, C1-C6 alkoxy, -NO2 or one five-membered heterocyclic ring containing one heteroatom selected from N, S 111 0, preferably S or O, or b) one group of the formula -(CH2)n-A-, -(CH2)n-S-A or -(CH2)n-O-A, where A is a group [image] where D is H, C1-C6 lower alkyl, C1-C6 lower alkoxy or -CF3, R5 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)O-COOH, -CH=CH-COOH, [image] [image] R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazoia, [image] R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2, R10 is selected from H, halogen, CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-C6 alkyl, -O-C1-C6 alkyl, -NH (C1-C6 alkyl), -N-(C1-C6 alkyl)2, [image] [image] R 11 is selected from H, C 1 -C 6 lower alkyl, CF 3 , -COOH. -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or [image] provided that the complete group at the indole or indoline position 1, formed by any combination of R5, R8, R9, R10 and/or R11 should contain at least one acid group selected from some carboxylic acid, or containing one carboxylic acid, one tetrazole, or some group of formulas: (picture 18) or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition containing one pharmaceutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and one pharmaceutically acceptable carrier or inert additive. 10. A pharmaceutical composition containing one pharmaceutically effective amount of the compound according to claim 5, or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier or inert excipient. 11. A pharmaceutical composition containing one pharmaceutically effective amount of the compound according to claim 6, or a pharmaceutically acceptable salt thereof, and one pharmaceutically acceptable carrier or inert additive. 12. Pharmaceutical composition containing one pharmaceutically effective amount of the compound according to claim 7, or a pharmaceutically acceptable salt thereof, and one pharmaceutically acceptable carrier or inert additive. 13. Pharmaceutical composition containing one pharmaceutically effective amount of the compound according to claim 8, or a pharmaceutically acceptable salt thereof, and one pharmaceutically acceptable carrier or inert additive. 14. The compound according to claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or one of its pharmaceutical acceptable salt. 15. The compound according to claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(2-furylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid acid or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(4-hydroxy-6-phenyl-2-pyrimidinyl)sulfanyl]methyl}-1H-indole -1-yl) methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 17. The compound according to claim 1 which is 4-{[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-({[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}methyl)-1H- indol-1-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 1 which is 4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2,4-dibromophenoxy)methyl]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 1 which is 4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(cyclopentylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or one thereof a pharmaceutically acceptable salt. 20. The compound according to claim 1 which is 4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(propylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or one of its a pharmaceutically acceptable salt. 21. The compound according to claim 1 which is 4-({(2-{[4-(tert-butyl)phenoxy]methyl}3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl )benzoic acid or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 1 which is 4-({(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-quinolinylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some pharmaceutically acceptable salt thereof. 23. The compound according to claim 1 which is 4-[(3-chloro-5-[(cyclopentylcarbonyl)amino]-2-{[(cyclopropylmethyl)sulfanyl]methyl}-1H-indol-1-yl)methyl]benzoic acid or some pharmaceutically acceptable salt thereof. 24. The compound according to claim 1 which is 4-({2-[(benzhydrylsulfanyl)methyl]-3-chloro-5-[(cyclopentylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or one of its pharmaceutical acceptable salt. 25. The compound according to claim 1 which is 4-({5-[(3-carboxypropanoyl)amino]-3-chloro-2-[(phenethylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some a pharmaceutically acceptable salt thereof. 26. The compound according to claim 1 which is 4-{5-[(3-carboxypropanoyl)amino]-3-chloro-2-{[(3-methylbenzyl)sulfanyl)methyl}-1H-indol-1-yl)methyl] benzoic acid or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 1 which is 4-({2-({[4-(tert-butyl)benzyl]sulfanyl}methyl)-5-[(carboxypropanoyl)amino]-3-chloro-1H-indole-1- yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 28. The compound according to claim 1 which is 4-({3-chloro-5-(3-furoylamino)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or one thereof a pharmaceutically acceptable salt. 29. The compound according to claim 1 which is 4-({5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable thereof salt. 30. The compound according to claim 1 which is 4-({3-chloro-5-{[(3-(diethylamino)propanoyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl} methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 31. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 32. The compound according to claim 1 which is 4-({5-{[(benzylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 33. The compound according to claim 1 which is 4-({5-{[(butylamino)carbonyl]amino}-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 34. The compound according to claim 1 which is 3-[({1-(4-carboxybenzyl)3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid or some pharmaceutically acceptable salt thereof. 35. The compound according to claim 1 which is 4-{[5-[(benzyloxy)-2-[(E)-2-carboxyethenyl]-3-(2-naphthoyl)-1H-indol-1-yl]methyl}benzoic acid acid or a pharmaceutically acceptable salt thereof. 36. The compound according to claim 1 which is 4-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable thereof salt. 37. The compound according to claim 1 which is 4-{[5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-3-(2,2,2-trifluoroacetyl)-1H-indol-1-yl]methyl }benzoic acid or a pharmaceutically acceptable salt thereof. 38. The compound according to claim 1 which is 4-({5-[(4-aminobutanoyl)amino-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl]methyl}benzoic acid or some pharmaceutically acceptable salt thereof. 39. The compound according to claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some a pharmaceutically acceptable salt thereof. 40. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(2-quinoxalinylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 41. The compound according to claim 1 which is 4-({3-chloro-5-[(2,2-dimethylpropanoyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl) benzoic acid or a pharmaceutically acceptable salt thereof. 42. The compound according to claim 1 which is 4-({5-{[(benzyloxy)carbonyl]amino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some pharmaceutically acceptable salt thereof. 43. The compound according to claim 1 which is 4-({3-chloro-5-{[(cyclopentyloxy)carbonyl]amino}-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 44. The compound according to claim 1 which is 4-({5-(acetylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable thereof salt. 45. The compound according to claim 1 which is 4-({5-{[(butylamino)carbonyl]amino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 46. The compound according to claim 1 which is 4-({5-{[(butylamino)carbonyl]amino}3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 47. The compound according to claim 1 which is 4-({3-chloro-5-[(morpholinocarbonyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some a pharmaceutically acceptable salt thereof. 48. The compound according to claim 1 which is 4-({5-(benzylamino)-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable thereof salt. 49. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenoxybenzyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 50. The compound according to claim 1 which is 4-({3-chloro-5-[(cyclopentylcarbonyl)(methyl)amino]-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 51. The compound according to claim 1 which is 4-({5-[acetyl(benzyl)amino]-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or some pharmaceutically acceptable salt thereof. 52. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(tetrahydro-3-furanylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid acid or a pharmaceutically acceptable salt thereof. 53. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-thienylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 54. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(1-adamantylcarbonyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 55. The compound according to claim 1 which is 3-[({1-(4-carboxybenzyl)3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl}amino)carbonyl]benzoic acid or some pharmaceutically acceptable salt thereof. 56. The compound according to claim 1 which is 4-({3-chloro-2-[(2-naphthylsulfanyl)methyl]-5-[(3-phenylpropanoyl)amino]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 57. The compound according to claim 1 which is 4-({5-amino-3-chloro-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 58. The compound according to claim 1 which is N-{3-chloro-1-(4-{[(methylsulfonyl)amino]carbonyl}benzyl)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-5-yl }methyl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 59. Compound according to claim 1 which is N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1[4-({[(4-nitrophenyl)sulfonyl]amino}carbonyl)benzyl]-1H-indole -5-yl}methyl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 60. The compound according to claim 1 which is N-{3-chloro-1-[4-({[(2-methylphenyl)sulfonyl]amino}carbonyl)benzyl]-2-[(2-naphthylsulfanyl)methyl]-1H- indol-5-yl}methyl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 61. The compound according to claim 1 which is N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1(4-{[(phenyl)sulfonyl]amino]carbonyl}benzyl)-1H-indole-5- yl}methyl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 62. The compound according to claim 1 which is N-{3-chloro-2-[(2-naphthylsulfanyl)methyl]-1[4-({[(4({[(trifluoromethyl)sulfonyl]amino}carbonyl)benzyl]-1H -indol-5-yl}methyl)cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 63. The compound according to claim 1 which is 4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl]butyric acid or some pharmaceutically acceptable salt thereof. 64. The compound according to claim 1 which is 4-{5-[(cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butyric acid or one thereof a pharmaceutically acceptable salt. 65. The compound according to claim 1 which is N-[2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino}butyl)-3-(1-pyrrolidinylcarbonyl) -1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 66. The compound according to claim 1 which is N-[3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino}butyl)-1H -indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 67. The compound according to claim 1 which is 5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]-1-(4-oxo-4-{[(trifluoromethyl)sulfonyl]amino}butyl)-1H -indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 68. The compound according to claim 1 which is 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 69. The compound according to claim 1 which is 2-(4-{[5-(benzyloxy)-3-(2naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 70. The compound according to claim 1 which is 2-[4-(5-(benzyloxy)~3-[3.5-bis(trifluoromethyl)benzoyl)-1H-indol-1-yl}methyl)phenyl]acetic acid or one of its pharmaceutical acceptable salt. 71. The compound according to claim 1 which is 4-({3-benzoyl-5-(benzyloxy)-2-[(naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof. 72. The compound according to claim 1 which is 4-({5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable salt thereof . 73. The compound according to claim 1 which is 2-{3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 74. The compound according to claim 1 which is 2-{5-(benzyloxy)-3-isobutyryl-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 75. The compound according to claim 1 which is 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butyric acid or a pharmaceutically acceptable salt thereof. 76. The compound according to claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 77. The compound according to claim 1 which is 4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-N-[3-({[( trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]butanamide or a pharmaceutically acceptable salt thereof. 78. The compound according to claim 1 which is 4-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 79. The compound according to claim 1 which is 2-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 80. The compound according to claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]propionic acid (71) or a pharmaceutically acceptable salt thereof. 81. The compound according to claim 1 which is 3-[(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)amino]propionic acid (72) or a pharmaceutically acceptable salt thereof. 82. The compound according to claim 1 which is N-(4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl)-2-methylbenzenesulfonamide or some pharmaceutically acceptable salt thereof. 83. The compound according to claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}valeric acid or a pharmaceutically acceptable salt thereof. 84. The compound according to claim 1 which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}pentanoyl)amino]benzoic acid or a pharmaceutically acceptable salt thereof. 85. The compound according to claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-N-[3-({[( trifluoromethyl)sulfonyl]amino}carbonyl)phenyl]pentanamide or a pharmaceutically acceptable salt thereof. 86. The compound according to claim 1 which is 2-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}acetic acid or a pharmaceutically acceptable salt thereof. 87. The compound according to claim 1 which is (E)-4-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}2-butyric acid or some a pharmaceutically acceptable salt thereof. 88. The compound according to claim 1 which is 3-({3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}methyl)benzoic acid or a pharmaceutically acceptable thereof salt. 89. The compound according to claim 1 which is 1-{1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzisulfanyl)-2-[(2-naphthysulfanyl)methyl]-1H-indole -3-yl}-1-ethanone or a pharmaceutically acceptable salt thereof. 90. The compound according to claim 1 which is 1-{1-[3-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzisulfanyl)-2-[(2-naphthysulfanyl)methyl]-1 H- indol-3-yl}-1-ethanone or a pharmaceutically acceptable salt thereof. 91. The compound according to claim 1 which is 2-[3-({3-acetyl-5-(benzyloxy)-2-[(2-naphthylsulfanyl)methyl]-1H-indol-1-yl}methyl)benzoyl]-1 ,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof. 92. The compound according to claim 1 which is 5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoic acid or a pharmaceutically acceptable thereof salt. 93. The compound according to claim 1 which is 3-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]~1H-indol-1-yl}-2-oxopentanoyl)amino ]benzoic acid or a pharmaceutically acceptable salt thereof. 94. The compound according to claim 1 which is 4-[(5-{3-benzoyl-5-(benzyloxy)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}-2-oxopentanoyl)amino ]benzoic acid or a pharmaceutically acceptable salt thereof. 95. The compound according to claim 1 which is 3-({4-[5-[(cyclopentylcarbonyl)amino]-2-[(2-naphthyloxy)methyl]3-(1-pyrrolidinylcarbonyl)-1H-indol-1-yl] butanoyl}amino)benzoic acid or a pharmaceutically acceptable salt thereof. 96. The compound according to claim 1 which is 3-({4-[5-[(cyclopentylcarbonyl)amino]-3-(morpholinocarbonyl)-2-[(2-naphthyloxy)methyl]-1H-indol-1-yl}butanoyl )amino]benzoic acid or a pharmaceutically acceptable salt thereof. 97. The compound according to claim 1 which is N-[2-[(2-naphthyloxy)methyl]-1-[4-oxo-4-[3-({[(trifluoromethyl)sulfonyl]amino}carbonyl)anilino]butyl} -3-(1-pyrrolidinylcarbonyl)-1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 98. The compound according to claim 1 which is N-(3-(morpholinocarbonyl)-[2-[(2-naphthyloxy)methyl]-1-[4-oxo-4-[3-({[(trifluoromethyl)sulfonyl]amino) }carbonyl)anilino]butyl}-1H-indol-5-yl]cyclopentanecarboxamide or a pharmaceutically acceptable salt thereof. 99. The compound according to claim 1 which is 2-(4-{[5-(benzyloxy)-3-(1-naphthoyl)-1H-indol-1-yl]methyl}phenyl)acetic acid or a pharmaceutically acceptable salt thereof. 100. A method for suppressing the phospholipase action of an enzyme in a mammalian subject in need thereof, which comprises administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 9. 101. A method for suppressing the phospholipase activity of an enzyme in a mammalian subject in need thereof, which comprises administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 10. 102. A method for suppressing the phospholipase action of an enzyme in a mammalian subject in need thereof, which comprises administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 11. 103. A method for suppressing the phospholipase activity of an enzyme in a mammalian subject in need thereof, which comprises administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 12. 104. A method for suppressing the phospholipase action of an enzyme in a mammalian subject in need thereof, which comprises administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 13. 105. A method for treating an inflammatory response in a mammalian subject in need, comprising administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 9. 106. A method for treating an inflammatory response in a mammalian subject in need, comprising administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 10. 107. A method for treating an inflammatory response in a mammalian subject in need, comprising administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 11. 108. A method for treating an inflammatory response in a mammalian subject in need, comprising administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 12. 109. A method for treating an inflammatory response in a mammalian subject in need, comprising administering to that subject a therapeutically effective amount of a pharmaceutical composition according to claim 13.