HRP20000513A2 - Inhibitors of phospholipase a2 - Google Patents

Description

This application is a partial continuation of application Ser. But. 08/918,400, filed on August 26, 1997, which is a continuation of application ser. But. 08/703,115 dated August 26, 1996.

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

Leukotrienes and prostaglandins are important mediators of inflammation. Leukotrienes recruit inflammatory cells, such as neutrophils, to the site of inflammation, promote the extravasation of these cells, and stimulate the release of tissue-damaging superoxide and prostheses. Leukotrienes also play a pathophysiological role in the hypersensitivity that occurs in asthmatics (see, e.g., B. Samuelson et al., Science, 237, 1171-76 (1987)). Prostaglandins support inflammation by increasing blood flow, thereby infiltrating leukocytes to sites of inflammation. Prostaglandins also facilitate the stimulus-induced pain response.

Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized (W. L. Smith, Biochem. J., 315-324 (1989)) from arachidonic acid in response to a stimulus. Prostaglandins are created from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidic acid is also a substrate of a certain enzymatic route that leads to the formation of leukotrienes.

Arachid acid, which is involved in these two different inflammatory routes, is released from the sn-2 site on the phospholipid membrane by phospholipase A (hereafter PLA2). It is believed that the reaction catalyzed by PLA2 represents a slow step in the process of lipid-mediated biosynthesis and production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate PLA2 is from the phosphotidylcholine class with an ester bond in the sn-1 position, the resulting lysophospholipid is an immediate precursor of platelet activation factor (hereinafter PAF), and it is another potential mediator of inflammation (S. I. Wasseman, Hospital Practice, 15. 49 - 58 (1988)).

Most anti-inflammatory therapies focus on preventing the formation of either prostaglandins or leukotrienes by these two different routes, but not both. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs that inhibit prostaglandin formation via COX-1/COX-2, but have no effect on inflammatory leukotriene formation from arachidonic acid by other routes. In contrast, zileuton inhibits only the route of conversion of arachidonic acid to leukotrienes, without affecting the formation of prostaglandins. None of these widely used anti-inflammatory agents affect the formation of PAF.

Therefore, direct inhibition of PLA2 activity has been suggested as a useful mechanism for a therapeutic agent, ie, for interference with the inflammatory response (see, e.g., J. Chang et al., Biochem. Pharmacol. 36. 2429-2436 (1987)).

The PLA2 family of enzymes, characterized by the presence of a secretion signal that is sequenced and eventually secreted from the cell, has been sequenced and structurally defined. These secreted PLA2s have an approximate molecular weight of 14 kD and contain seven disulfide bonds that are essential for activity. These PLA2s have been found in large amounts in mammalian pancreas, bee venom, and various snake venoms. (see, e.g., references 13-15 of Chant et al. cited above; and E. A. Dennis, Drug Devel. Res. 10, 205-220 (1978)). However, it is considered that the pancreatic enzyme serves a digestive function and as such cannot have significance in the creation of inflammatory mediators whose production can be intensively regulated.

The primary structure of the first non-pancreatic human PLA2 has been determined. This non-pancreatic PLA2 has been found in platelets, synovial fluid and the spleen, and is also a secreted enzyme. This enzyme is a member of the family mentioned above. (see J. J. Seilhamer et al., J. Biol. Chem. 264, 5768-5775 (1989); A. Kando et al., Biochem. Biophys. res. Comm. 163, 42-48 (1989)). However, the question is whether this enzyme is important for the synthesis of prostaglandins, leukotrienes and PAF, because PLA2, which does not originate from the pancreas, is an extracellular protein that can hardly be regulated, and other enzymes in the biosynthesis routes of these compounds are intracellular proteins. In addition, PLA2 has been reported to be regulated by protein kinase C and G proteins (R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. USA, 84, 6374-6378 (1989)) which are cytosolic proteins that must act to intracellular proteins. It is impossible for non-pancreatic PLA2 to function in the cytosol, because the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.

Murine PLA2 has been identified in murine macrophage cell sol, labeled RAW 264.7 It has been reported that the specific activity of 2 μmol/min/mg, resistant to reducing conditions, is associated with a molecule of approximately 60 kD. However, this protein was not purified to homogeneity. (see C.C. Leslie et al., Biochem. Biophys. Acta, 963, 476-492 (1988)). The references from the literature cited above are hereby included as information relating to the function of the phospholipase enzyme, particularly PLA2.

Cytosolic phospholipase A2 (hereafter "cPUV") has also been identified and cloned. See U.S. Patent No. 5,322,776 and 5,354,677, which are incorporated herein by this reference, as will be set forth more fully below. The enzyme of these patents is the intracellular enzyme PLA2, which has been purified from its natural environment or otherwise produced in a purified form, which functions intracellularly by producing arachidonic acid in response to an inflammatory stimulus.

Since several phospholipase enzymes have now been identified, it is desirable to identify chemical inhibitors of these enzymes, inhibitors that could be used to treat inflammatory conditions, particularly where inhibition of prostaglandin, leukotriene and PAF formation is desired. In the state of the art, there is a need to identify such anti-inflammatory agents for therapeutic purposes in various disease states.

The present invention provides compounds having a chemical formula selected from the group consisting of:

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and

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or their pharmaceutically acceptable salts, where:

And independently of any other group, it is chosen from the group consisting of –CH2 and CH2CH2-;

B independently of any other group, is selected from the group consisting of -(CH2)n-, (CH2O)n-, (CH2S)n-, -(OCH2)n-, SCH2)n-, (CH=CH) n-, -(C≡C)n-, CON(R6)-. -N(R6)CO-, -O-, -S- and -N(R6)-;

R1, independently of any other group, is selected from the group consisting of X-R6, -H, OH, halogen, -CN, -NO2, C1-5alkyl, alkenyl, alkynyl, aryl and substituted aryl;

R2 independent of R of any group is selected from the group consisting of -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-(CH2)m-Z-R5 , C1-10 alkyl, alkenyl and substituted aryl;

R3 independently of R of any group is selected from the group consisting of -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -Z-R5, C1-10 alkyl, alkenyl and substituted aryl;

R4 independently of R of any group is selected from the group consisting of -H, -OH, OR6, -SR6, -CN, -COR6, -NHR6, COOH, -CONR6R7, -NO2, CONHSO2R8, C1-5 alkyl, alkenyl and substituted aryl;

R5 independently of R of any group is selected from the group consisting of -H, -OH, O(CH2)nR6, -SR6, -CN, -COR6, -NHR6, -COOH, -NO2, CONR6R7, CONHSO2R8, C1- 5 alkyl, alkenyl, alkynyl, aryl, substituted aryl, -CF3, CF2CF3 and

[image]

R 6 independently of R of any group is selected from the group consisting of -H, C 1-5 alkyl, alkenyl, alkynyl, aryl and substituted aryl;

R 7 independently of R of any group, is selected from the group consisting of -H, C 1-5 alkyl, alkenyl, alkynyl, aryl and substituted aryl;

R 8 independently of R of any group is selected from the group consisting of -H, C 1-5 alkyl, aryl and substituted aryl;

R9, independently of R of any group, is selected from the group consisting of -H, -OH, halogen, -CN, -OR6, -COOH, CONR6R7, tetrazole. -CONHSO2R8, COR6, -(CH2)nCH(OH)R6 and -(CH2)nCHR6R5;

R10, independent of R of any group, is selected from the group consisting of -H, -OH, halogen, -CN. -OR6, -COOH, -CONR6R7, tetrazole. CONHSO2R8. COR6, -(CH2)nCH(OH)R6 and -(CH2)nCHR6R5;

W independently, whenever used including in the same compound, is selected from the group consisting of -O-, -S-, -CH2-, -CH=CH-, C=C- and -N(R6)-;

X independently of any group and independently each time it is used including in the same compound, it is selected from the group it forms

-O-, -S- and -N(R6)-;

Z independently of any group and independently each time it is used including in the same compound, it is selected from the group it forms

-CH2-, -O-, S-, -N(R6)-, -CO-, CON(R6)-, and N(R6)CO;

m independently each time it is used, including in the same compound, is an integer from 0 to 4; and

n independently of m, independently each time it is used, including in the same compound, is an integer between 0 and 4.

It is desirable that the compounds of this invention have inhibitory activity on the enzyme phospholipase. Other preferred embodiments include compounds having the following chemical formula:

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compounds that have the following chemical formula:

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and compounds that have the following chemical formula:

[image]

In particularly preferred embodiments, A is -CH2-, and R2 is -(CH2)n-W-(CH2)m-HR5. These preferred compounds are those in which n is 1, m is 1, W is -S- and Z is -CO-;

those wherein R 5 is -NHR 6 ; those in which R6 is a substituted aryl group and those in which said aryl group is substituted with one or more substituents independently selected from the group consisting of halogen, -CF3, -CF2CF3, -(CH2)pCOOH -(CH2)pCH3, -O (CH2)pCH3, -(CH2)pOH, -(CH2)pS(C6H6), -(CH2)pSC6H6), -(CH2)pCONH2 and –CHR11COOH, where R11 is selected from the group consisting of alkyl, alkenyl. alkynyl, -(CH2)pOH and -O(CH2)pCH3, and where p is an integer between 0 and 4. Other preferred compounds are those in which R1 is selected from the group consisting of -H and -OCH2(C6H6), and R3 is -COR5, R5 is -OCH2R6 and R6 and R7 are substituted aryl groups. In particularly preferred compounds, said aryl group is substituted with one or more substituents selected from the group consisting of -CF3, -CF2CF3 and -C(CH3)2CH2CH3.

Among the compounds of this invention are those having the formula:

[image]

where:

R1 and R2 are independently selected from C1-6 alkyl, -Z-C1-6 alkyl, phenyl, -(CH2)n, Z-(CH2)n-phenyl. benzyl. -(CH2)n- Z-(CH2)n-benzyl, -(CH2)n- Z-(CH2)n-naphthyl, pyrimidinyl, -(CH2)n- Z-(CH2)n-pyrimidinyl, and alkyl, phenyl, benzyl and naphthyl and pyrimidinyl groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, -NO2, -NH2, -CN, CF3 or -OH;

Z is 0 or S;

n is an integer from 0 to 3;

R2 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, C1-10 alkoxy, CHO, -CN, -NO2, -NH2, ≡NH-C1-6 alkyl. -(C1-6 alkyl)2, -N-SO2-C1-6 alkyl;

R 3 is selected from -H, halogen, -CF 3 , OH, -C 1-10 alkyl, C 1-10 alkoxy, CHO, -C(O)CH 3 . -C(O)-(CH2)n-CF3, -CN, -NO2, NH2, -NH-C1-6 alkyl, N(C1-6 alkyl)2, -N-SO2-C1-6 alkyl. -SO2-C1-6 alkyl or residue of the formula:

[image]

n is chosen independently each time it occurs as an integer between 0 and 3,

R8 and R9 are independently selected, each time they occur, from -H, -COOH, (CH2)n-COOH, -(CH2)C(O)-COOH, -CF3, -OH, -(CH2)n-C( O)-COOH, C1-6 alkyl, -O-C1-6 alkyl, -NH(C1-6 alkyl) or N(C1-6 alkyl)2;

R4 is selected from -COOH, -(CH2)n-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1M1 or residue of the following formulas;

[image]

R12 is selected from -H, -CF3, -C1-6 alkyl, -(CH2)n-C3-6-cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 groups which are selected between halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6 alkyl, -O-C1-6 alkyl, NH(C1-6 alkyl ) or -N(C1-6 alkyl)2;

L1 is selected from -(CH2)n-O-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n, C(O)-O-, C(O)-(CH2) n-O-, C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-,

M1 is -COOH or a residue selected from between

[image]

R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, C1-6alkyl, - O-C1-6 alkyl,

[image]

provided that the residue or combination of residues containing R3 contains an acid group selected from carboxylic acids or a residue of the formula:

[image]

R5 is chosen between:

a) of the rest of the formula –L2-M2, where

L2 is selected from a chemical bond or bridging group selected from -(CH2)n-Z, -(CH2)n-X-(CH2)n-, -C(O)-O-, C(OHCH2)n-, -C( O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-,

M2 chooses from C1-6alkyl, O-C1-6alkyl,

[image]

where R 8 and R 9 are as defined above, and may be substituted anywhere on a cyclic or bicyclic ring; or

b) the rest of the formula:

[image]

where L3 is a chemical bond or group chosen from CH2-,

CH2-Z-, -C(O). -O-, -S- or -(CH2)n-Z-(CH2)n-; where

M3 chooses from -(CH2)n-C3-5cycloalkyl, furanyl, thienyl, pyrrolyl,

[image]

or a pharmaceutically acceptable salt thereof.

Of the compounds from the group just defined, the preferred subgroup consists of those in which the nucleus of the molecule is indole. Within this indole group is another subgroup in which R1 and R2 are hydrogen and the residues R5, R4, R5, R8, R9 and R10, n, L1, L2, M1 and M2 are defined as above. Within this subgroup is another preferred group where R1 is in the 5-position of indole.

Among the compounds of this invention are also those having the formula:

[image]

where

R1 is selected from -O-C1-6alkyl, -S-C1-6alkyl, -O-phenyl, -S-phenyl, -O-benzyl, S-benzyl, and the alkyl, phenyl and benzyl groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, -NO2, -NH2, -CN, -CF3 or -OH;

R2 is selected from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -CN, -NO2, -NH2, NH- C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl or -SO2-C1-6alkyl;

R3 is selected from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably -C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -CN, -NO2, -NH2, NH -C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, or the rest of the formula:

[image]

n at each occurrence is independently chosen from integers between 0 and 3;

R8 and R9 at each occurrence independently choose between -H, -COOH,

-(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH,

-(CH2)n-C(O)-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH,

-(CH2)n-C(O)-COOH, -C1-6alkyl. -O-C1-6alkyl, -NHC1-6alkyl) or -N(C1-6alkyl)2,

R4 is a residue -L1M1 or

[image]

L1 is selected from a chemical bond or bridging group selected from -(CH2)n-O, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, C(O)-O -, -C(O)-(CH2)n-O-, -C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N;

M1 is the remainder

[image]

R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl,

[image]

provided that the combination of residues containing R 4 contains a carboxylic acid or a residue of the formula

[image]

R5 is a structure of the formula –L2-M2; where

L2+ is selected from a chemical bond or bridging group selected from -(CH2)n-O, -(CH2)n-S, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, - C(O)-O, -C(O)-(CH2)n-O-, -C(O)-N- or

-(CH2)n-S-(CH2)n-C(O)-N-,

M2 chooses from -C1-6alkyl, O-C1-6alkyl,

[image]

where R 8 , R 9 and R 10 are as defined above;

or a pharmaceutically acceptable salt thereof.

Also preferred are compounds from the above group that have the structure:

[image]

R1 is selected from -O-C1-6alkyl, O-phenyl, -O-benzyl, -S-benzyl, and the alkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 substituents selected from halogen. C1-6alkyl, C1-6Alkoxy, -NO2, -NH2, -CN, CF3 or -OH,

R3 is selected from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably C1-10 alkyl, C1-10 alkoxy, preferably C1-10 alkoxy, -CHO, -CN, -NO2, NH2, -NH -C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl or the rest of the formula:

[image]

where R4, R5, R8, R9 and R10 are as defined above,

or a pharmaceutically acceptable salt thereof.

Among the compounds of this invention are also those with the formulas:

[image]

where

R1 and R1 are independently selected from -H, halogen, -CF3, -OH, -C1-10alkyl, preferably C1-6alkyl, -S-C1-10 alkyl, preferably -S-C1-6alkyl, -C1-10 alkoxy, preferably C1-6Alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl-, -S-phenyl, benzyl, -O-benzyl. -S-benzyl; or the ring residue of groups a), b)

or c) given below, attached directly to the indole ring or attached to the indole ring via a -S-, -O- or -(CH2)n- bridge;

a) a five-membered heterocyclic ring containing one or two heteroatoms selected from Nα, S or 0, which is, but is not limited to, furan, pyrrole, thiophene, imidazole. pyrazole, isothiazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, and the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably -C1 -6alkyl, C1-10 Alkoxy, preferably C1-6Alkoxy, -NO2, -NH2, -CN, -CF3, or

b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O which is, but is not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine , thiazidin, oxazine or morpholine, and the six-membered heterocyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, -C1-10 alkyl. preferably -C 1-6 alkyl, C 1-10 alkoxy, preferably C 1-6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or OH; or

c) a bicyclic ring residue optionally containing 1 to 3 heteroatoms selected from N, S or O, which is, but is not limited to, benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolizine, indazole , quinoline, isoquinoline, quinolizine. quinazoline, cinnoline, phthalazine or naphthyridine, and the bicyclic residue can optionally be substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, -CHO, NO2, -NO2, -CN, -CF3, or OH; or

d) the rest of the formula:

[image]

Z is 0 or S;

R6 is selected from the relevant members of the group H, -CF3, -C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, phenyl, O-phenyl, -S-benzyl, and phenyl and benzyl rings in to these groups are

optionally substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably -C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -NO2. -NH2, -CN, -CF3, or -OH;

R7 is selected from among the relevant members of the group -OH, -CF3, C1-10 alkyl, preferably -C1-6alkyl, -C1-10 alkoxy, preferably C1-6alkoxy, -NH2, -(CH2)n-NH2, -NH-(C1 -6alkyl), -N(C1-6alkyl)2, -(CH2)n-NH(C1-6alkyl)2, phenyl, -O-phenyl, benzyl or -O-benzyl; or

a) a five-membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, which is, but is not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine . , -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, which is, but is not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiazidin, oxazine or morpholine, and 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 alkoxy, preferably -C1-6 alkoxy, -CHO , -NO2, -NH2, -CN, -CF3 or -OH; or

b) a bicyclic ring residue optionally containing from 8 to 10 ring atoms and optionally containing from 1 to 3 heteroatoms in the ring, selected from N, S or O, which is, but is not limited to, benzofuran, chromene, indole . -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, preferably from 1 to 3, and more preferably from 1 to 2; NO2, -NH-C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl or –SO2-C1-6alkyl,

R5 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, -C1-10 alkoxy, CHO, C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO, -NH2, NH-C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)- phenyl, -C(O)-benzyl,

CH2-(C3-6cycloalkyl), -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl. C(O)-CF3, -(CH2)n-S-CH2-(C3-5cycloalkyl), and the rings in the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-6alkyl, -C1-6alkoxy, -NO2, -CF3,

C(O)-OH or -OH; or the rest of the formula:

[image]

n at each occurrence is an integer independently chosen between 0 and 3,

R8 and R9 are independently selected at each occurrence from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-- COOH, -C1-6alkyl, NH(C1-6alkyl) or -N(C1-6alkyl)2,

R4 chooses from -COOH, -(CH2)n-COOH, --(CH2)n-C(O)-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1M1 or residue of formula:

[image]

R12 is selected from -H, -CF3, C1-6alkyl, -(CH2)n-C3-8Cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 groups selected from halogen, - CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N(C1- 6alkyl)2;

L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S, -(CH2)n-O-(CH2)n -, -(CH2)n-S-(CH2)n-, -(CH2)n-C(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-, C(Z)-NH-SO2-(CH2)n-, C(O)-(CH2)n-O, -C(O)-N- or -(CH2)n-S-(CH2)n-C (He,

M1 is -COOH or a residue selected from between

[image]

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

[image]

R9 at each occurrence is independently selected from -H, halogen, CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl, -O-C1-6alkyl , -NH(C1-6alkyl) or N(C1-6alkyl)2,

R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl,

[image]

R11 is selected from -H, C1-6 lower alkyl, C1-6cycloalkyl, -CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH,

[image]

provided that the residue or combination of residues containing R contains an acid group, which is selected from a carboxylic acid, a tetrazole or a residue of the formula:

[image]

[image]

R5 is selected from C1-6 lower alkyl, C1-6 lower alkoxy, -(CH2)n-C3-10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-10 cycloalkyl, -(CH2)n-O-( CH2)n-C3-10 cycloalkylyl groups:

a) -(CH2)n-phenyl-O-Phenyl, -(CH2)n-phenyl-CH2phenyl, -(CH2)n-O-phenyl- -CH2-phenyl; -(CH2)n-phenyl-(O-CH2-phenyl)2-, -CH2 -phenyl-C(O)-benzothiazole or a residue of the formula:

[image]

n is an integer from 0 to 3, preferably from 1 to 3, more preferably from 1 to 2,

Y is C3-5cycloalkyl, or

a) a five-membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, which are, but are not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine - 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, which is, but is not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiazidin, oxazine or morpholine, and the six-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, -CHO. -NO2. -NN2, -CN, -CFs, or -OH, or

c) a bicyclic ring residue containing from 8 to 10 ring atoms and optionally containing from 1 to 3 heteroatoms selected from N, S or O, which is, but is not limited to, benzofuran, chromene, indole, isoindole, indoline , isoindoline, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine or naphthyridine, and the bicyclic residue may optionally be 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, or

d) a residue of the formula -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, where A is a residue

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where are they

D H, C1-6lower Alkyl, C1-6lower Alkoxy, -CF3, or -(CH2)n-CF3,

B and C are independently selected from phenyl. pyridinyl, pyrimidinyl, furyl. thienyl or pyrrolyl group, each optionally substituted with from 1 to 3, preferably from 1 to 2 substituents selected from -H, halogen, -CN, -CHO, -CF3, -OH, C1-6alkyl, C1- 6-Alkoxy, -NN2 or NO2, or a pharmaceutically acceptable salt thereof.

Preferred compounds are those having the formula:

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where:

R1 chooses from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably C1-6alkyl, S-C1-10 alkyl, preferably -S-C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, O-benzyl, S-benzyl; or a ring residue from groups a), b) or c) below, attached directly to the indole ring or attached to the indole ring via a -S-, -O- or -(CH2)n bridge; furan, pyrrole or thiophene, which are optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, -NO2, -NH2, - CN, CF3, or

b) pyridine, pyrimidine, piperidine or morpholine, each of which is optionally substituted with from 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; or

c) benzofuran, indole, naphthalene, purine or quinoline, each of which can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1- 6-Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or

d) the rest of the formula:

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Z is O or S;

R6 is selected from the relevant members of the group -H, -CF3, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkoxy, phenyl, -O-phenyl, -S-phenyl, benzyl, -O -benzyl or -S-benzyl, and the phenyl and benzyl rings in these groups can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1 -6Alkoxy, -CHO, NO2, -NH2, -CN, -CF3, or OH;

R 7 is selected from the relevant members of the group -OH, -CF3, C1-10 alkyl, preferably -C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -NH2, NH(C1-6 alkyl), -N(C1-6 alkyl )2, -(CH2)n-NH-(C1-6alkyl), -(CH2)n-N-(C1-6alkyl)2, -O-phenyl, benzyl, -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole or morpholine, and the rings of these groups can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, - CHO, -NO2, -NH2, -CN, -CF32 or OH,

n is an integer from 0 to 3, preferably from 1 to 3, and more preferably from 1 to 2;

R 2 is selected from -H, halogen, -CN, -CHO, -CF3, -OH, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkoxy, -CHO, CN, -NO2, -NH2, -NH-NH-C1-6alkyl, -N-(C1-6alkyl)2, -N-SO2-C1-6alkyl or -SO2-C1-6alkyl;

R3 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, C1-10 alkoxy, CHO, -C(O)-CH3, -C(O)-(CH2)n-CF3, -CN , -NO2, -NH2, -NH-C1-6alkyl, -N(C1-10 alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C( O)-phenyl, -C(O)-benzyl, -CH2 -, -(C1-5cycloalkyl), -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-C1- 6alkyl, C(O)-O-C1-6alkyl, CH2-(C3-5cycloalkyl), -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl , -C(O)-CF3 or -(CH2)n-S-CH2-(C3-5cycloalkyl), and the rings of the relevant R3 groups are optionally substituted with from 1 to 3 groups selected from halogen, C1-6alkyl, C1 -6Alkoxy, -NO2, -CF3, -C(O)-OH or -OH;

or the rest of the formula:

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n at each occurrence is independently chosen as an integer from 0 to 3;

R8 and R9 independently select at each occurrence from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH , -C1-6alkyl, -O-C1-6alkyl,

R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CH=CH-COOH. tetrazole, -(CH2)n-tetrazole, residue –L1M1 or residue of the formula:

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R12 is selected from -H, -CF3, C1-6alkyl, -(CH2)n-C3-6cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups may optionally be substituted with from 1 to 3 groups selected from halogen , -CF3, OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N(C1-6alkyl )2,

L1 is selected from -(CH2)n-, S-, -O-, -C(O)-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S-, -(CH2 )n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)--(CH2)n-, -(CH2)n-O-(CH2)n-, - (CH2)n-S-(CH2)n-, -C(Z)-N(R6)-C(Z)-N(R6)-(CH2)n-, -

C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, C (Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)n-O-, C(O)-N- or -(CH2)n-(CH2)n-C(O)-N- ;

M1 is -COOH or a residue selected from:

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

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R9 at each occurrence is selected from -H, halogen, -CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl , NH(C1-6alkyl) or -N(C1-6alkyl)2;

R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, C1-6alkyl, - O-C1-6 alkyl;

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provided that the residue or combination of residues containing R4 comprises an acid group selected from a carboxylic acid, a tetrazole or a residue of the formula:

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R5 is selected from C1-6 lower alkyl, C1-6 lower alkoxy, -(CH2)n-C3-10cycloalkyl, -(CH2)n-S-(CH2)n-C3-10cycloalkyl, -(CH2)n-O-(CH2)n-C3 -10cycloalkyl, -(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 a residue of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a residue:

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D is H. C1-6 lower alkyl, d-lower alkoxy, -CF3, or -(CH2)n-CF3,

B and C are independently selected from phenyl. pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl group, each of which is optionally substituted with from 1 to 4, preferably from 1 to 2 substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, - C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , or -NO 2 ; or a pharmaceutically acceptable salt thereof.

Other preferred compounds include those having the formula:

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where

R1 is selected from H, halogen, -CF3, -OH, -C1-10 alkyl, preferably -C1-6alkyl, S-C1-10 alkyl, preferably -S-C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CN, -NO2, -NH2, phenyl, O-phenyl, -S-phenyl. benzyl, -O-benzyl; or furan, pyrrole or thiophene is attached to the indole ring by a chemical bond or through a -S-, -O- or -(CH2)n- bridge, and the phenyl, benzyl, furan, pyrrole or thiophene rings are optionally substituted with 1 to 3 substituents which are selected from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6alkyl, -NO2, -NH2, -CN, -CF3, or

n is an integer from 0 to 3, preferably from 1 to 3, more preferably from 1 to 2;

R 2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6alkoxy, -CHO, -CN, NO2, -NH2, -NH-C1-6alkyl, N(C1-6alkyl)2, -N-SO2-C1-6alkyl or SO2-C1-6alkyl;

R3 is selected from H, halogen, -CF3, -OH, C1-10 alkyl. C1-10 Alkoxy, CHO, -C(O)CH3, -C(OHCH2)n-CF3, -CN, -NO2, -NH2, -NH-C1-6alkyl. -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, phenyl phenoxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)-benzyl, -CH2— (C3-5cycloalkyl)), C(O)-OH, -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, C(O)-CF3 . -C(O)-OH or OH; or the rest of the formula:

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n is independently selected as an integer between 0 and 3 at each occurrence;

R 8 and R 9 independently select at each occurrence from H, -COOH. -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, -NH (C1-6alkyl) or -N(C1-6alkyl)2,

R4 is selected from -COOH, -(CH2)n-COOH. -(CH2)n-C(O)-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1-M1 or residue of the formula:

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R 12 is selected from H, -CF 3 , C 1-6 alkyl, -(CH 2 ) n -C 3-6 cycloalkyl. phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with from 1 to 3 groups selected from halogen, -CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O) -COOH, -C1-6alkyl. -O-C1-6alkyl. -NH(C1-6alkyl) or N(C1-6alkyl)2,

L1 is selected from -(Cl-12)n-, -S-, -O-, -C(O)-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S, - (CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-S(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, C(Z)-N(R6), C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N (R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, C(Z)-NH-SO2-(CH2) n-, -C(O)-(CH2)n-O-, C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-;

M1 is -COOH or a residue selected from:

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

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R9 at each occurrence is independently selected from H, halogen, -CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N(C1-6alkyl)2,

R10 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, - O-C1-6 alkyl,

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provided that the residue or combination of residues contained in R4 comprises an acid group selected from a carboxylic acid, a tetrazole or a residue of the formula:

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R5 is selected from C1-enylalkyl, d-enyloxy, -(CH2)n-C3-10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-10cycloalkyl, -(CH2)n-O-(CH2)n -C3-10cycloalkyl, -(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 a residue of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a residue:

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D is H, C1-6 lower alkyl, C1-6 lower alkoxy, -CF3 or -(CH2)n-CF3,

B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted with from 1 to 3, preferably from 1 to 2 substituents selected from H, halogen, -CN, -CHO , -CF3, -OH, C1-6alkyl, -C1-6Alkoxy, -NH2, or -NO2,

or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of inhibiting the enzymatic activity of the phospholipase enzyme, which involves administering to a mammalian subject a therapeutically effective amount of the compounds of the present invention. Also provided are methods of treating an inflammatory response or condition that involve administering to a mammalian subject a therapeutically effective amount of the compounds of this invention. Pharmaceutical preparations containing the compounds of this invention and pharmaceutically acceptable carriers are also provided.

Pharmaceutically acceptable salts of the compounds described herein are also part of the present invention and may be used in the use of the compounds and methods described herein.

Short description of the pictures

Figures 1 to 13 represent schemes for the synthesis of the compounds of this invention. The presented schemes are described in detail below.

Detailed description of preferred implementations

The terms "aryl" and "substituted aryl" used herein are understood to include monocyclic, and especially five- and six-membered monocyclic

Short description of the pictures

Figures 1 to 13 represent schemes for the synthesis of the compounds of this invention. The presented schemes are described in detail below.

Detailed description of preferred implementations

The terms "aryl" and "substituted aryl" used herein are understood to include monocyclic, and especially five- and six-membered monocyclic aromatic and heteroaromatic ring residues and bicyclic aromatic and heteroaromatic ring residues, especially those having between 9 and 10 atoms in the ring. It is understood that among these aryl groups are phenyl rings. including those found in phenoxy, benzyl, benzyloxy, biphenyl and other similar residues. The aryl and heteroaryl groups of 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 oxathiazole; 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 , thiadiazine, oxazine or morpholine; or

c) a bicyclic ring residue optionally containing from 1 to 3 heteroatoms in the ring, which are 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 of the present invention include those radicals which may optionally be substituted with from 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6alkyl, -CHO , -COOH or their esters, -NO2. -NH2, -CN, -CF3, or -OH, or combinations thereof, such as CH2CF3, -NH(CH3), etc.

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

Preferred alkyl, alkenyl and alkynyl groups here are those groups having from 1 to 10, preferably from 1 to 6 carbon atoms, and can be straight, branched or cyclic. Unless otherwise indicated, it is preferable that these groups are straight or forked. Halogen is understood here to include F, Cl, Br and J.

Preferred compounds of this invention are described in Tables I-VI below. The procedures for the synthesis of these compounds are listed in Tables I - VI, which are described below. The numbers of the compounds in the tables correspond to the numbers of the examples given below in which the syntheses of individual compounds are described.

Tables I-VI also contain data for the indicated compounds in the "LysoPC" test and the coumrin test (see Example 88 below). The data in the test result columns of the tables are given as an "IC50" value, which represents the concentration of the compound that inhibits 50% of the phostolipase enzyme activity in that test. If no numerical values for IC50 are given, "NA" indicates no inhibitory activity

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The compounds of this invention were also tested for activity in vivo by the rat paw edema assay, according to the procedure described in Example 89. These results are given in Table VII.

Table VII

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As used herein, the term "phostolipase enzyme activity" means a positive activity in a phostolipid metabolism assay (preferably one of the assays described in Example 88, below). A compound has "phostolipase enzyme inhibitory activity" if it inhibits phostolipase activity (preferably cPLA2) in an available assay (preferably the assay described below in Example 88 or Example 89) for enzyme activity. In preferred embodiments, the compound has (1) an IC50 value of less than about 25 μM, preferably less than about 6 μM, in the LypsolPC assay; (2) an IC50 value of less than about 50 μM in the vesicle assay; (3) an IC50 value of less than about 1 μM in the PMN assay; (4) an IC50 value of less than about 15 μM in the coumarin test; and/or (5) measurable activity (preferably at least 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, and most preferably about 20-30%) in the carrageenan (Irish moss) induced rat paw edema assay.

The compounds of this invention are useful for inhibiting the activity of the phostolipase enzyme (preferably cPLA2), and are therefore useful for "treating" (ie, treating, preventing, or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease and other diseases that are mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, atrophy and atherosclerosis.

This invention encompasses both pharmaceutical preparations and therapeutic procedures for treatment or use where the compounds of this invention are used.

The compounds of this invention can be used in a pharmaceutical preparation when combined with a pharmaceutically acceptable carrier. Such a preparation may also contain (in addition to one or more compounds of this invention and carrier), diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient. The characteristics of the carrier depend on the method of administration. Pharmaceutical preparations may also contain anti-inflammatory agents. These additional factors and/or agents can be included in the pharmaceutical preparation to achieve a synergistic effect with the compound of the present invention, or to minimize the side effects caused by the compounds of the present invention.

The pharmaceutical preparations of this invention can be in the form of liposomes in which the compound of this invention is combined, along with other pharmaceutically acceptable carriers, with amphipathic agents, such as lipids, which in aqueous solution exist in the form of aggregates, as micelles, undissolved monolayers, liquid crystals or lamellar layers. Suitable lipids for liposomal formulation include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acid, and the like. The preparation of such liposomal formulations is within the prior art, as described, for example, in U.S. Pat. Patent No. 4,235,871; LOUSE. Patent No. 4,501,728; LOUSE. Patent No. 4,837,028 and U.S. Pat. Patent No. 4,737,323. all of which are covered here through this quote.

The term "therapeutically effective amount" as used herein, means the total amount of each active component of a pharmaceutical preparation or procedure that is sufficient to demonstrate an appreciable improvement in a patient, i.e. treatment, cure, prevention or relief of an inflammatory response or condition, or an increase in the rate of healing, healing, prevention or relief of such conditions. When applied to a single self-administered active ingredient, this name refers to that ingredient only. When applied to a combination, this term refers to the combined amounts of active ingredients that produce a therapeutic effect, regardless of whether they are administered in combination, sequentially, or simultaneously.

In carrying out a treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal in the condition to be treated. A compound 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 treatments using other anti-inflammatory agents, cytokines, lymphokines, or other hematopoietic factors. When coordinated with one or more other anti-inflammatory agents, cytokines, lymphokines, or other hematopoietic factors, the compounds of this invention can be administered either simultaneously with one or more other anti-inflammatory agents, such as cytokines, lymphokines, other hematopoietic factors or anti-thrombotic factors, or sequentially. If they are prescribed sequentially, the prescribing doctor will decide on the appropriate order of prescribing the compound of this invention in combination with another anti-inflammatory agent or agents, cytokines, lymphokines, other hematopoietic factors, thrombolytic and anti-thrombolytic factors.

The administration of a compound of the present invention for use as a pharmaceutical preparation, or the administration of a method of the present invention, may be accomplished by a number of conventional routes, such as oral administration, inhalation, or by injection into the skin, subcutaneously, or intravenously.

When a therapeutically effective amount of a compound of the present invention is administered orally, the compound of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical preparation of the present invention may further contain a solid carrier, such as gelatin or a filler. The tablet, capsule and powder contain from 5 to 95% of the compound of this invention, preferably from about 25 to 90% of the compound of this invention. When administered in liquid form, a liquid carrier may be added, such as water, kerosene, oil of animal or vegetable origin, such as peanut oil, mineral oil, soybean oil or sesame oil, or synthetic oils. The liquid form of the pharmaceutical preparation may also contain a physiological saline solution, dextrose or another solution of saccharides, or glycols, such as ethylene glycol, propylene glycol or polyethylene glycol. When prescribed in liquid form, the pharmaceutical preparation contains from about 0.5 to 90 wt. % of the compound of this invention, preferably from about 1 to 50% of the compound of this invention.

When a therapeutically effective amount of a compound of the present invention is administered intravenously, intradermally, or by subcutaneous injection, the compound of the present invention is in the form of an aqueous solution that is parenterally acceptable and is non-pyrogenic. Obtaining such parenterally acceptable protein solutions, which take into account pH, isotonicity, stability and the like, is within the scope of skill in the state of the art. A preferred pharmaceutical preparation for intravenous, intradermal or subcutaneous injection should contain, in addition to the compound of the present invention, an isotonic adjunct, such as sodium chloride for injection, Ringer for injection, dextrose for injection, dextrose and sodium chloride for injection, Ringer for injection with lactates, or other additives known in the art. The pharmaceutical preparation of this invention may also contain stabilizers, preservatives, buffers, antioxidants or other additives known to those skilled in the art.

The amount of the compound of the present invention in the pharmaceutical preparation of the present invention will depend on the nature and severity of the condition to be treated, as well as the nature of the previous treatment to which the patient has undergone.

Finally, the prescribing physician will decide on the amount of the compound of the present invention to treat each patient. Initially, the prescribing physician will prescribe a low dose of the compound of this invention and observe the patient's response. Higher doses of a compound of the present invention may be administered until the optimal therapeutic effect for the patient is achieved, and thereafter the dose is not increased further. It is understood that the various pharmaceutical preparations used to carry out the process of the present invention should contain about 0.1 μg to about 100 mg (preferably about 0.1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of a compound of the present invention. per kg of body weight.

The duration of intravenous therapy using a pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and possible idiosyncratic response of each individual patient. It is understood that the duration of each administration of the compound of this invention is in the range of 12 to 24 hours with continuous intravenous administration. Finally, the prescribing physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical preparation of this invention.

Synthesis procedures for Examples 1-87

The compounds of this invention can be prepared according to the following procedures. Temperatures are in degrees Celsius.

Procedure A

Indole-2-carboxylic acid ethyl ester l is converted to aldehyde II in two steps: reduction with lithium aluminum hydride (LAH) or another hydride, in a suitable solvent, such as tetrahydrofuran (THF) at 0 °C, followed by oxidation with oxidizing agent, such as manganese dioxide, in a solvent such as THF. Deprotonation of the aldehyde II with a strong base, such as potassium hexamethyldisilamide (KHDMS) in THF, followed by reaction with chloroformate in the presence of a base, such as triethylamine, affords the carbamate III. This III is transformed into the bromide IV in two steps: (1) reduction with sodium borohydride in alcoholic solution, and (2) reaction with carbon tetrabromide in the presence of a phosphine reagent, such as bis(diphenylphosphino)propane, in dichloromethane. Displacement of the bromine from IV with potassium phenoxide, which is obtained by reacting phenol with KHMDS in a suitable solvent such as THF or DMF, affords ether V. Ether V can be converted to either the trifluoromethylketone VII or the carboxylic acid IV by various procedures. Reaction of V with trifluoromethyltrimethylsilane (TMSCF3) in the presence of tetrabutylammonium fluoride gives trifluoromethyl alcohol, which is then oxidized with periodinan (Dess-Martin reagent) in dichloromethane, giving ketone VI. At this stage, the carbamate can be removed with trifluoroacetic acid (TFA) or an alkali such as sodium hydroxide. The indole nitrogen is then alkylated with a suitable alkyl bromide, in the presence of a base, such as sodium hydride, to give VII. Alternatively, deprotection of V with TFA or aqueous alkali followed by reaction with an alkyl bromide gives VIII, which is oxidized with NaCl and aqueous THF to give acid IX.

Procedure B

The 2-indolyl carboxylic acid ethyl ester I is deprotonated with a strong base, such as sodium hydride (NaH) in THF, and then reacted with a suitable allyl bromide to give X. Hydrolysis of X with an aqueous base, such as sodium hydroxide, and reaction with aniline or substituted aniline, in the presence of a carbodiimide, such as dimethylaminopropyl-ethylcarbodiimide hydrochloride (EDCI) in a suitable solvent, such as dichloromethane, gives amide XI. Amide XI is hydrolyzed to the corresponding acid XII in an aqueous base, such as sodium hydrochloride.

Procedure C

Indole I can be brominated in the 3-position with bromine or N-bromosuccinimide, in a suitable solvent, such as carbon tetrachloride or dichloromethane, to give bromide XIII. reaction of XIII with a suitable alkyl bromide, in the presence of a strong base, such as NaH, in THF or DMF gives indole XIV. Palladium-mediated coupling of XIV with a suitable alkene in the presence of a phosphine and a base, such as triethylamine, affords the 3-substituted indole XV. XV can be converted to amide XVII by a two-step reaction: (1) hydrolysis with an aqueous alkali, such as NaOH, and (2) coupling with an amine in the presence of a carbodiimide, such as EDCI. Ester XIV can be transformed into lithium salt XVIII by hydrolysis with aqueous alkali followed by reaction with lithium hydroxide in a suitable solvent, such as ether. Lithiation, with butyllithium in a suitable solvent such as THF, followed by acylation with an acyl chloride in THF affords ketone XIX. Coupling of XIX catalyzed with carbodiimide (EDCI) and a suitable amine gives amide XX.

Procedure D

Indole I can be converted to XXI in two steps: (1) reduction with LAH in a solvent, such as TH, and (2) silylation with t-butyldimethylsilyl chloride in a solvent, such as dichloromethane or DMF, in the presence of alkali, such as imidazole. Treating XXI with a Grinjar reagent, such as ethylmagnesium bromide, in a solvent such as THF at -60 °C, acylating the resulting magnesium salt with a suitable acyl chloride, such as acetyl chloride in ether, and finally, alkylating nitrogen with an alkyl halide, such as ethyl bromide, in the presence of a strong alkali such as NaH. in DMF, gives ketone XXII. The silyl group in XXII is removed using tetrabutylammonium fluoride, in a solvent such as THF, and the resulting alcohol is then converted to the bromide, using carbon tetrabromide and bis(diphenylphosphino)ethane, in a solvent such as dichloromethane, to give bromide XXIII. Displacement of bromine from XXIII with a thiol compound, in the presence of a base, such as Cs2CO3, or with an alcohol, in the presence of a strong base, such as NaH, in DMF gives XXIV (Sulfide, or ether, respectively).

Procedure E

Aldehyde II, obtained by Method A, can be alkylated with a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide, in the presence of a strong base, such as sodium hydride or KHMDS, in a solvent such as DMF, to give XXV. This XXV can be converted to the unsaturated acid XXVI in two steps: (1) Wittig R6 reaction, with a suitable reagent, such as trimethylphosphonoacetate, in the presence of a base such as sodium hydride, in a solvent such as THF, and (2) hydrolysis with aqueous sodium hydroxide. Diimide-catalyzed coupling of XXVI with an amine, such as EDCI (dimethylaminopropylethyldicarbodiimide hydrochloride), followed by hydrolysis with an aqueous alkali, such as sodium hydroxide, affords XXVII.

Procedure F

Indole I is reduced with LAH in a solvent such as THF. A second reduction with sodium cyanoborohydride, in a solvent such as acetic acid, gives alcohol XXVIII. Protection of the nitrogen in XXVIII, with t-butoxycarbonyl (BOC), using t-butyldicarbonate ((BOC)2), in the presence of a base, such as triethylamine, gives XXIX. The hydroxyl group in XXIX is mesylated with mesyl chloride and triethylamine, in a solvent such as dichloromethane, and then displaced with either a thiol or an alcohol, as described in Procedure D, to give indoline XXX. Deprotection of XXX, using trifluoroacetic acid, gives XXXI, which is either acylated (acyl chloride, triethylamine, dichloromethane) or alkylated (alkyl halide, K2CO3, DMF), giving XXXII, or XXXIII, respectively.

Procedure G

The carboxylic acid XXXIV is converted to the aldehyde in two steps: (1) reaction with N,O-dimethylhydroxyamine, in the presence of EDCI, in a solvent such as dichloromethane, and (2) reduction with diisobutylaluminum hydride (DIBAL), in a solvent such as is THF. Treatment of XXXV with trimethylphosphonoacetate in the presence of a strong base such as KHDMS in a solvent such as THF leads to the formation of ester XXXVI. Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inert solvent, such as toluene, gives XXXVII. Alkylation of the nitrogen in XXXVII under the conditions described in Procedure F, followed by hydrolysis of the ester with an aqueous alkali, such as NaOH, gives the acid XXXVIII. This XXXVIII can be converted to amide XXXIX. by coupling with a suitable amine, such as benzylamine, in the presence of EDCI.

Procedure H

Aldehyde XXXV, obtained in Procedure G, undergoes a Wittig reaction with methyl-triphenylphosphonium iodide, in the presence of a strong base, such as KHMDS or NaH, in a solution such as THF, to give alkene XL. Reduction of the nitro group in XL with powdered iron in ammonium chloride solution, followed by treatment with benzyl chloroformate, in the presence of a base such as triethylamine, gives the carbonate XLI. This XLI is treated with iodine in an alkaline solution, such as NaHCO 3 in THF, to give iodide XLII. Displacement of iodine from XLII with lithium benzoate, in a solvent such as DMF, followed by hydrolysis with NaOH, affords the alcohol XLIII.

Procedure 1

Indoline XXVIII, obtained by Method F or Method H, can either be acylated by reaction with an acyl chloride, in the presence of a base such as triethylamine, or alkylated using an alkyl halide in the presence of K 2 CO 3 , in a solvent such as DMF, to give alcohol XLIV. Treatment of XLIV with mesyl chloride and triethylamine in a solvent such as dichloromethane, followed by displacement with a thiol such as methyl mercaptoacetate in the presence of a base such as Cs 2 CO 3 in a solvent such as acetonitrile affords ester XLV. Hydrolysis of XLV with an aqueous base, such as NaOH, gives the acid XLVI which can be coupled with an amine, catalyzed by a diimide, such as EDCI, in a solvent such as dichloromethane, to give the amide XLVII. This XLVII can be alkylated at the amide nitrogen by treatment with an alkyl halide and a strong base, such as NaH, in DMF. Hydrolysis of the resulting amide with an aqueous alkali such as NaOH gives acid XLIX. XLIV can also be directly hydrolyzed with NaOH to the carboxylic acid XLVIII.

Procedure J

Procedure J illustrates the synthesis of alpha-substituted esters of aminophenylacetic acid. Ester L can be deprotonated with a strong base, such as lithium diisobutylamide (LDA), in a solvent such as THF, and then alkylated with an alkyl halide, such as methyl iodide, to give LI. Reduction of LI to amine LIII can be accomplished by palladium-catalyzed hydrogenation in a solvent such as ethanol. This L can be oxidized to alcohol LII using LDA and oxaziridine, in a solvent such as THF. Alkylation of LII with an alkylating agent such as methyl iodide in the presence of a strong base such as NaH and in DMF, followed by catalytic hydrogenation in the presence of palladium, affords the amine LIV.

Procedure K

Procedure K illustrates the synthesis of substituted aminobenzoic acid esters. The mono-acid LV can be converted to the amide LVI in the following steps: (1) reaction with oxalyl chloride in dichloromethane to form the acid chloride, j (2) treatment with a suitable amine, such as dimethylamine. Reduction of the nitro group to the amine is accomplished by palladium-catalyzed hydrogenation, as described in Procedure J. LV can be reduced to alcohol LVIII with a hydropyran-THF complex, in THF. Protection of the hydroxyl group, with a silyl ether, using TBDMSCI, in the presence of imidazole and subsequent reduction of the nitro group (H2/Pd-C) to the amine affords LIX. LVIII can be converted to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent, such as manganese dioxide (MnO2) in ethyl acetate, and (2) addition of the desired Grinjar reagent, such as methylmagnesium bromide, in THF . Oxidation of LX with MnO2 in THF and reduction of the nitro group (H2/Pd-C) gives ketone LXIII. reduction of LVII (H2/Pd-C) gives LXI.

Procedure L

Alcohol LXIV, obtained by Method I, can be debenzylated by palladium-on-charcoal catalyzed hydrogenolysis in a solvent such as ethanol. The resulting alcohol is treated with p-methoxybenzyl chloride in the presence of K2CO3, in a solvent such as THF, to give LXV. Alcohol LXV can be transformed into ether or sulfide LXVI by the procedure described in Procedure D. Deprotection of the p-methoxybenzyl group with TFA, in a solvent such as dichloromethane, and subsequent oxygen acylation with a suitable reagent, such as 4-benzylbenzylbromide, in the presence K2CO3, in a solvent such as THF, gives LXVII.

Experimental part

The following examples further illustrate this invention. All temperatures given in the Examples are in degrees Centigrade. All compounds were characterized using proton magnetic resonance spectra obtained on a Varian Gemini 300 spectrometer or equivalent instruments.

Example 1

2-(2-(1-phenylmethoxycarbonyl-5-phenylmethoxy)methoxybenzoic acid

Step 1: 2-(5-phenylmethoxy)indolyl aldehyde

12.3 g (42 mmol) of ethyl-2-(5-phenylmethoxy)indolyl)carboxylate were dissolved in 100 mL of THF, and 130 mL (130 mmol) of a 1M solution of lithium aluminum hydride in THF was added to this at 0 °C. The reaction was stirred at this temperature for 2 h, then stopped by slowly adding 65 mL of a 6M NaOH solution. The product is extracted with ethyl acetate, and the organic phase is washed with aqueous ammonium chloride. Evaporation of the solvent gives crude alcohol, which is dissolved in 400 mL of THF without further purification, then 52 g of manganese(IV) oxide is added, and the mixture is stirred overnight at room temperature. Removal of manganese oxide by filtration followed by purification by flash chromatography using 3:1 hexane:ethyl acetate afforded 8.15 g of the title compound.

Step 2: Benzyl (1-(2-formyl-5-phenylmethoxy)indolyl)formate

To a solution of 6.9 g (27.5 mmol) of the aldehyde from step 1, in 140 mL of THF, 61 mL (30.5 mmol) of a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene is slowly added, at - 35 °C. After stirring for 10 min at this temperature, 4.4 mL (29.5 mmol) of benzyl chloroformate was added at -35 °C, and this mixture was then heated from -35 °C to 0 °C over 3.5 h. The reaction is stopped by pouring into aqueous ammonium chloride. Work-up of the aqueous solution and flash chromatography, using 12:1 toluene:ethyl acetate, afforded 4.8 g of the title compound.

Step 3: Benzyl (1-(2-hydroxymethyl-5-phenylmethoxy)indolyl)formate

760 mg (20 mmol) of sodium borohydride was added to a solution of 2.9 g (7.5 mmol) of the aldehyde from step 2 in 40 mL of THF and 20 mL of trifluoroethanol at 0 °C. The mixture was stirred for 30 min at 0 ° C, and then the reaction is stopped by adding aqueous ammonium chloride. Flash chromatography, using 2:1 hexane:ethyl acetate, gave 2.2 g of the title compound.

Step 4: Benzyl (1-(2-bromomethyl-5-phenylmethoxy)indolyl)formate

To a solution of 2.2 g (5.7 mmol) of alcohol from step 3, and 2.05 g (5.0 mmol) of 1,3-bis(diphenylphosphino)propane in 60 mL of dichloromethane, add a solution of 2.0 g ( 6 mmol) of carbon tetrabromide in 4 mL of dichloromethane, at 15 °C. The mixture was stirred for 2 h at room temperature, then 1 g (3 mmol) of 1,3-bis-diphenylphosphino)propane was added at room temperature. After 1 h of stirring, the reaction is stopped by adding aqueous ammonium chloride. Work-up of the aqueous solution and flash chromatography using 4:1 hexane:ethyl acetate afforded 1.7 g of the title compound.

Step 5: Benzyl (1-(2-(2-formylphenoxy)methyl-5-phenylmethoxy)indolyl)formate

To a solution of 439 mg (3.6 mmol) of methyl-2-hydroxybenzoate in 18 mL of THF, 6 mL (3 mmol) of a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene was added at 0 °C. This solution was stirred for 10 min at 0 °C, then a solution of 1.25 g (2.8 mmol) of bromide, obtained in step 4, in THF at 0 °C was added. The reaction is warmed up to room temperature and stirred at this temperature for 2 h. After treatment of the aqueous solution (NH4Cl/ethyl acetate), the organic solvent is collected, dried over sodium sulfate and evaporated. The hardened product is washed with ethyl acetate:hexane 1:1. Yield 690 mg (51 %).

Step 6:

Dissolve 120 mg (0.24 mmol) of the aldehyde from step 5 in 11 mL of 5:1:5 THF-acetoitrile-2,2-dimethylacetanol. A solution of 56 mg (0.5 mmol) of sodium chloride in 0.5 mL of water and 1 drop of an aqueous solution of hydrogen peroxide are added to this solution. After 4 h, another 56 mg (0.5 mmol) of sodium chloride is added. The mixture is stirred for 3 days at room temperature. Work-up of the aqueous solution and flash chromatography, using 2.5:0.05 hexane:ethyl acetate, afforded 110 mg of the title compound.

Example 2

4-(2-(1-phenylmethoxycarbonyl-5-phenymethoxy)indolyl)methoxybenzoic acid

The title compound is obtained according to the procedure described in Example 1, using 4-hydroxybenzaldehyde.

Example 3

3-(2-(1-phenylmethoxycarbonyl-5-phenylmethoxy)indolyl)methoxybenzoic acid

The title compound is obtained by the procedure described in Example 1, using 3-hydroxybenzaldehyde.

Example 4

Benzyl (1-(2-(2-(1-oxo-2,2,2-trifluoroethyl)phenoxy)methyl-5-phenylmethoxy)indolyl)-formate

Step 1 Benzyl (1-(2-(2-1-hydroxy-2,2.2-trifluoroethyl)phenoxy)methyl-5-phenylmethoxy)-indolyl)-formate

A solution of 0.4 g (0.8 mmol) of the aldehyde obtained in step 1 of Example 1 in 4 mL of THF is cooled to 0 °C. To this is added 0.24 mL (1.6 mmol) of trifluoromethyltrimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate. The reaction is stirred for 2.5 h at 0 °C, then another 0.2 mL (1.3 mmol) of trifluoromethyltrimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate are added. After stirring for 2 h at 0 °C, the reaction is treated with aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel using 4:1 hexane:ethyl acetate afforded the corresponding TMS ether. Treatment of this TMS ether with 1.3 mL of 1 M HCl at room temperature, working up the aqueous solution using saturated NaCl and ethyl acetate, and chromatographic purification using 3:1 hexane:ethyl acetate afforded 230 mg of the title compound.

Step 2:

255 mg (0.6 mmol) of Des-Martin's periodinate was added to a solution of 150 mg (0.27 mmol) of trifluoroethanol, obtained in step 1, in 5.5 mL of dichloromethane. The mixture was stirred for 1 h at room temperature, then partitioned between aqueous NaHCO3 and ethyl acetate. The organic phase was washed once with aqueous NaHCO3 and purified by chromatography, using 3:1 hexane:ethyl acetate, to give 150 mg of the title compound.

Example 5

3-(2-(1-benzyl-5-benzyloxy)indolecarboxamido)benzoic acid

Step 1: Ethyl 2-(2-benzyl-5-benzyloxy)indolecarboxylate

Sodium hydride (0.163 g, 60% dispersion in oil, 4.07 mmol) was added to a solution of 1 g (3.4 mmol) of ethyl 5-benzyloxyindole-2-carboxylate in 12 mL of DMF at room temperature. The reaction is stirred for 30 min. After this time, benzyl bromide (0.44 mL, 3.73 mmol) was added, and the reaction was stirred for another 1 h. At the end of the reaction (monitoring with TLC = 0.5 Rf in 3:1 hexane:ethyl acetate), it was quenched with water, extracted with ethyl acetate (3x). The organic layers are dried over magnesium sulfate, concentrated and used in the next step.

Step 2: 2-(1-benzyl-5-benzyloxy)indolecarboxylic acid

The ester (3.4 mmol) obtained in step 2 was dissolved in THF (20 mL), methanol (20 mL) and then 1 M NaOH (15 mL) was added. The reaction mixture is stirred overnight at room temperature, then concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x), then the organic extracts are dried over magnesium sulfate and concentrated, giving indolic acid ( 1.14 g, 94.2 %, TLC = 0.5 Rf, 1 : 1 hexane : ethyl acetate, with 1 % acetic acid).

Step 3: Ethyl 3-(2-(1-benzyl-5-benzyloxy)indolecarboxamido)benzoate

Acid (0.54 g, 1.5 mmol) from step 2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl) (0.31 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0 .18 g, 0.15 mmol) and ethyl 3-aminobenzoate (0.27 g, 1.66 mmol) were stirred overnight in tetrahydrofuran (9 mL) at room temperature. The next day, the reaction is 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 3:1 hexane:ethyl acetate to give the pure amide (0.578 g, 76%, TLC = 0.4 Rf, 3:1 hexane:ethyl acetate).

The ester (0.578 g, 1.15 mmol) prepared in step 3 was dissolved in THF (13.6 mL), methanol (13.6 mL), and then 1 M NaOH (9.6 mL) was added. The reaction mixture is stirred overnight at room temperature, after which time it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x), then the organic extracts are dried over magnesium sulfate and concentrated, giving the title compound (0.437 g, 80 %, TLC = 0.5 Rf, 3 : 1 hexane : ethyl acetate).

Example 5, 7, 8, 9, 10 and 11

were prepared according to the procedure of Example 5, using the appropriate amines and alkyl halides.

Example 12

3-(2-(3-2,4-bis(1,1-dimethylpropyl)phenoxyacetyl)-5-methoxy-1-methyl)indolyl)-methylthioacetamido-4-methoxybenzoic acid

Step 1: 2-(5-Methoxy)indolylmethanol

Ethyl 5-methoxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF, cooled to 0 °C, and then lithium aluminum hydride (LAH) (255 mL, 1 M solution in THF). The reaction was stirred for another 2 h at 0 °C and then worked up by adding 4 M NaOH (190 mL). The obtained salts are filtered and washed with ethyl acetate (3x400 mL), filtered, combined and dried over magnesium sulfate and concentrated, yielding 24.8 g of alcohol, which is used directly in the next step.

Step 2: 2-(5-Methoxy)indolylmethoxy-tert-butyldimethylsilane

The crude indole alcohol obtained in step 1 (6.2 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-butyldimethylsilyl chloride (5.4 g, 35.8 mmol). The mixture is stirred overnight at room temperature. The reaction is poured into water and extracted with ethyl acetate (3x). The organic layers are dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19:1 hexane : ethyl acetate to give pure product (9.5 g, 31 mmol, 94% yield, TLC = 0.8 RF toluene : ethyl acetate 2:1).

Step 3: 3-(2-tert-butyldimethylsilyloxymethyl-5-methoxy)indolyl (2,4-bis(1,1-dimethylpropyl)phenoxy)methyl ketone

Dissolve 2.32 g (7.95 mmol) of 2,4-bis-tert-amylphenoxyacetic acid in dichloromethane (21 mL), then add oxalichloride (1.4 mL, 16.1 mmol) followed by dimethylformamide (0 .5 mL), at room temperature. After 1 h the reaction is concentrated and azeotroped with toluene and then left under high vacuum for 2 h.

In another reaction vessel, a solution of the silyl-saturated indole obtained in step 1 (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethylmagnesium bromide (2.4 mL of a 3 M solution in ether, 7.2 mmol) in ether (10 mL), and kept at -78 ° C. The reaction was stirred for 2 h at -60 ° C. The above-prepared acid chloride in ether (4 mL) was slowly added to this reaction solution. The reaction is maintained between -50 °C and -60 °C for the next 2 h. The reaction is then quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3x). The organic layers are dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19 : 1 hexane : ethyl acetate to give pure product (2.36 g, 50%. TLC : 0.15 Rf, hexane : ethyl acetate 19 : 1).

Step 4: 3-(2-tert-butyldimethylsilyloxymethyl-5-methoxy-1-methyl)indolyl (2,4bis(1,1-dimethylpropyl)phenoxy)methyl ketone

To the ketone (1.97 g, 3.4 mmol) from step 3, in 12 mL of DMF, sodium hydride (0.163 g, 60% dispersion in oil, 4.07 mmol) was added at room temperature. The reaction is stirred for 30 min. After this time, methyl iodide (0.23 mL, 3.73 mmol) was added, and the reaction was stirred for another 1 h. Upon completion (monitoring with TLC), the reaction is quenched with water, extracted with ethyl acetate (3x). The organic layers are dried over magnesium sulfate, concentrated and the crude product is used in the next step.

Step 5: 3-(2-hydroxymethyl-5-methoxy-1-methyl)indolyl (bis-2.4-(1,1-dimethylpropyl)phenoxy)methyl ketone

A mixture of N-methyl indole, obtained in step 4, (2.01 g, 3.4 mmol) and tetra-butylammonium fluoride (TBAF) (8.5 mL of a 1 M solution in THF, 8.5 mmol) in THF (17, 9 mL), mixed for 1 H at room temperature. After this time, the reaction is diluted with ethyl acetate and water, extracted with ethyl acetate (3x), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using hexane : ethyl acetate 2 : 1 to give the pure alcohol (0.82 g, 60%, TLC : 0.3 RF in 2 : 1 hexane : ethyl acetate).

Step 6: Methyl 3-(2-(3-(2,4-bis(1,1-dimethylpropyl)phenoxy)acetyl-5-methoxy-1-methylindolyl)methylthioacetamido)-4-methoxybenzoate

The indolyl alcohol obtained in step 5 (0.20 g, 0.43 mmol) is dissolved in dichloromethane (0.7 mL), then treated with triethylamine (0.1 mL, 0.64 mmol) and cooled to 0 ° C, and then mesyl chloride (0.04 mL, 0.52 mmol) was added over 5 min, followed by 2 drops of DMF. The reaction is stirred for another 2 h at 0 °C, then concentrated and used directly in the next reaction. The mesylate prepared above was dissolved in DMF (0.8 mL). The solution is degassed by bubbling nitrogen for 10 min. Cesium carbonate (0.25 g, 1.29 mmol) was added followed by thiol (0.11 g, 0.43 mmol), which was obtained as Intermediate 1. This mixture was stirred overnight and then poured into saturated ammonium chloride and extracted with ethyl acetate (3x), dried and concentrated. The crude material was purified on a silica gel column using hexane : ethyl acetate 2:1 to give pure product (0.12 g, 40%, TLC : 0.3 Rf, hexane : ethyl acetate 1:1).

Step 7:

The ester obtained in step 6 (0.12 g, 0.17 mmol) was dissolved in THF (1.0 mL) and methanol (1.0 mL), then 1 M NaOH (0.4 mL) was added ). The reaction mixture is stirred overnight at room temperature, then concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x), then the organic extracts are dried over magnesium sulfate and concentrated, giving the title compound (85 mg, 72 %, TLC = 0.3 Rf, 1 : : 1 hexane : ethyl acetate, with 1 % acetic acid).

Examples 13, 14, 15 and 16

were obtained by the procedure of Method 12, using ethyl 2-(5-benzyloxy)indolecarboxylate, acetyl chloride and the corresponding alkyl halides.

Example 17

3-(2-(5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl) methylthioacetamidobenzoic acid

Step 1: 2-(5-benzyloxy)indolinylmethanol

Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0 °C, then lithium aluminum hydride (LAH) (255 mL), 1, 0 M solution in THF). The reaction was stirred for 2 h at 0 °C, then worked up by adding 4 M NaOH (190 mL). The resulting salts are separated by filtration and washed with ethyl acetate (3 x 400 mL), and the filtrates are combined, dried over magnesium sulfate, and concentrated to give 24.8 g. This crude material is then dissolved in glacial acetic acid (260 mL), and the resulting the yellow solution is cooled to 15 °C, sodium cyanoborohydride (18.5 g, 294 mmol) is added in portions over 10 min, and the resulting mixture is stirred for 3 h. The reaction was quenched by gently pouring into 1.5 L of nearly saturated NaHCO3, extracted with ethyl acetate (3x), dried over magnesium sulfate, and concentrated to give an orange substance (29.6 g).

Step 2: tert-butyl 1-(5-benzyloxy-2-hydroxymethyl)indolinyl formate

Dissolve 25 g (85 mmol) of the crude alcohol obtained in step 1 and 4-dimethylamino pyrene (DMAP) (1.19 g, 9.78 mmol) in dichloromethane (180 mL). This solution was cooled to 0 °C and then triethylamine (13.6 mL, 98 mmol) was added. After 10 min of mixing, a solution of di-tert-butylcarbonate (21.3 mL, 98 mmol), dissolved in dichloromethane (20 mL), is added over 2 h through a pump with a syringe. After stirring for 1 h, the reaction was quenched by addition of 1/2 saturated solution of NH4Cl and extracted with CH2Cl2 (3x), dried over MgSO4 and concentrated to give 36.3 g of a yellow oil, which was purified by column chromatography using a gradient of 9 in hexane:ethyl acetate. :1, then 4 : 1, then 1 : 1, liberating the product (15.25 g, 44 %).

Step 3: Ethyl (2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinylmethylthioacetate

The carbamate obtained in step 2 (15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and triturated with triethylamine (9.0 mL, 64.4 mmol). This solution was cooled to -10 °C, and then methyl chloride (4.3 mL, 56 mmol) was added over 5 min. The reaction is stirred for another 2 h at -10 ° C, then it is concentrated and used directly in the next displacement reaction.

The mesylate prepared above was dissolved in DMF (85 mL, degassing of the solvent is recommended), cesium carbonate (35 g, 107.3 mmol) was added, and then ethylthioacetate (4.70 mL, 42.9 mmol) was added. The mixture was stirred for 1 day, then poured into saturated ammonium chloride, then extracted with ethyl acetate (3x), dried, concentrated and chromatographed (hexane : ethyl acetate 10 : 1, then 4 : 1), giving 8.55 g of a yellow oily products.

Step 4: 2-(-5-benzyloxy-1-tert-butoxycarbonyl)indolinylmethylthioacetic acid

To a solution of the indoline ester obtained in step 3 (5 g, 11 mmol) in 1 M potassium hydroxide in methanol (100 mL), water (10 mL) was added. The reaction is stirred for 2 h at room temperature, and then diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x), then the organic layers are dried over magnesium sulfate and concentrated, giving indoline acid (4.5 g , 95.5%, TLC = 0.5 Rf, hexane : ethyl acetate, with 1% acetic acid). This raw material is used directly in the next step.

Step 5: ethyl 3-(2-5-benzyloxy-1-tert-butoxycarbonyl)indolyl)methylthioacetamido-benzoate

The acid (3 g, 7 mmol), obtained in step 4, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.6 g, 8.4 mmol), 4-dimethylaminopyridine (0.85 g, 7 mmol) and ethyl 3-aminobenzoate (1.27 g, 7.7 mmol), were stirred overnight in THF (43 mL) at room temperature. The next day, the reaction is 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 3:1 hexane:ethyl acetate to give the product (3.4 g, 85%, TLC = 0.3 Rf, 3:1 hexane:ethyl acetate).

Step 6: Ethyl 3-(2-(5-benzyloxy)indolyl)methylthioacetamidobenzoate

Trifluoroacetic acid (24 mL) was added to indoline (3.4 g, 5.9 mmol) from step 5, and the reaction was stirred at 0 °C for 1 h. The reaction is stopped by adding water, and the TFA is neutralized by adding sodium bicarbonate, then the aqueous layer is 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 product (2.7 g, 96%, TLC = 0.3 Rf, 2:1 hexane:ethyl acetate).

Step 7: Ethyl 3-(2-(5-benzyloxy-1-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl)methylthioacetamidobenzoate

Dissolve 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid (0.228 g, 0.78 mmol) in dichloromethane (2 mL), add oxalyl chloride (0.14 mL, 1.6 mmol), and then dimethylformamide (0.1 mL), at room temperature. After 1 h, the reaction is concentrated and azeotroped with toluene and left for 2 h under high vacuum. Indoline ester (0.308 g, 0.65 mmol), obtained in step 6, and 4-dimethylaminopyridine (0.008 g, 0.066 mmol) were dissolved in dichloromethane (1.2 mL), and then the acid chloride prepared above in dichloromethane ( 0.5 mL), then triethylamine (0.28 mL, 1.95 mmol) was added. The reaction is stirred overnight at room temperature, 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 2:1 hexane:ethyl acetate to give the product (0.291 g, 60%, TLC = 0.4 Rf, 2:1 hexane:ethyl acetate).

Step 8:

The ester (0.231 g, 0.31 mmol) from step 7 was dissolved in THF (4.3 mL) and methanol (4.3 mL) and then 1 M NaOH (3.2 mL) was added. The reaction mixture is stirred overnight at room temperature, then concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x), then the organic layers are dried over magnesium sulfate and concentrated to give the title product ( 0.207 g, 93.2 %, TLC = 0.3 RF, 2 : 1 hexane : ethyl acetate, with 1 % acetic acid).

Example 18

3-(2-(-5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl)methylthioacetamido-4-methylbenzoic acid

Step 1: ethyl (2-(5-benzyloxy)indolinylmethylthioacetate

N-tert-butoxycarbonyl indoline (3.0 g, 6.6 mmol) obtained in step 3 of Example 17 was added to a flask cooled to 0 °C. Trifluoroacetic acid (35 mL) was added to this reaction mixture, and the reaction was stirred for 1 h at 0 °C, and then for 1 h at room temperature. The reaction is stopped by the addition of water, and the TFA is neutralized by the addition of solid sodium bicarbonate, and the aqueous layer is extracted with ethyl acetate (4x) and dried over magnesium sulfate, then concentrated to an orange oil (1.85 g, 79 %) which is used directly in the next step.

Step 2: Ethyl 2-(5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl-indolinylmethylthioacetate

2,4-bis(1,1-dimethyl)propyl)phenoxyacetic acid (2.0 g, 6.8 mmol), dichloromethane (15 mL), oxalyl chloride (1.2 mL, 13 .6 mmol), dimethylformamide (0.1 mL), and then the reaction is concentrated and azeotroped with toluene (1x) and concentrated for 2 h under high vacuum, before use. The indoline ester (1.85 g, 5.2 mmol), obtained in step 1, and 4-dimethylaminopyridine (0.08 g) were dissolved in dichloromethane (15 mL), and then the acid chloride prepared above in dichloromethane (5 mL), followed by the addition of triethylamine (0.95 mL, 6.8 mmol). The reaction was stirred at room temperature for 16 h and concentrated (4.0 g, orange oil), chromatographed using a 9:1 to 6:1 hexane:ethyl acetate gradient to give the product (2.5 g, 75%, which was used in the next step without additional purification.

Step 3: 2-(5-benzyloxy-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl methylthioacetic acid

The ester (2.5 g, 3.9 mmol), obtained in step 2, was dissolved in THF (20 mL) and methanol (6 mL), then 1 M NaOH (12 mL) was added. The resulting mixture is stirred for 24 h, and then concentrated, diluted with water, acidified to pH 4 with concentrated HCl and extracted with ethyl acetate (4x), then the organic extracts are dried over magnesium sulfate, concentrated and purified by chromatography (3 : 1 hexane : ethyl acetate , with 1% acetic acid), giving 1.17 g (50%) of the product as a white substance.

Step 4: Methyl (3-(2-(5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl)methylthioacetamido-4

-methylbenzoate

Acid (0.20 g, 0.33 mmol), obtained in step 3, EDCl (0.08 g, 0.43 mmol), DMAP (4 mg, 0.03 mmol) and methyl 3-amino-4-hydroxybenzoate (0.06 g, 0.33 mmol) were dissolved in THF (3 mL) and refluxed for 16 h. Treatment of the aqueous solution with ammonium chloride and ethyl acetate and purification by chromatography on silica gel (hexane : ethyl acetate 3 : 1) gives 0.13 g (52%) of the product in the form of a white substance.

Step 5:

The title compound is obtained from the ester obtained in step 4 according to the procedure of step 3.

Examples 17-36

in Table 2 were obtained according to the procedure described in either Example 17 or Example 18.

Example 37 2-(5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetic acid

Step 1: 2-(5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol

An oven-dried 1 L flat-bottomed flask, fitted with a magnetic stirrer and a pressure-equalizing dropping funnel, was charged with 17.0 g (59 mmol) of 3,5-bis(trifluoromethyl)phenoxyacetic acid, DMF (5 drops ) and anhydrous CH2Cl2 (300 mL). Oxalyl chloride (23 mL, 263 mmol) was added over 10 min. After stirring for 2.5 h at room temperature, the solvent and excess oxalyl chloride were removed under vacuum, giving the acid chloride as a white substance. This is immediately used in the next reaction.

An oven-dried 1 L flat-bottomed flask equipped with a magnetic stirrer and a pressure-equalizing dropping funnel is charged with 15.3 g (60 mmol) of 2-(5-benzyloxy)indolinylmethanol obtained in step 1 of Example 17, DMAP (0.73 g, 6 mmol) and anhydrous CH2Cl2 (300 mL). After cooling to 0 °C, the above-prepared acid chloride (59 mmol) in anhydrous CH2Cl2 (100 mL) is added dropwise, followed by Net3 (9 mL, 64.6 mmol). After stirring for 1 h at 0 °C, the reaction mixture was washed with saturated NaHCO3 solution (100 mL), 1 M HCl solution (100 mL) and water (100 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. Purification by silica gel chromatography using 25-40% AcOEt in hexane afforded the product as a pale yellow oil. Yield 22.0 g (71 %).

Step 2: Ethyl 2-(5-benzyloxy-1-(3-bis(trifluoromethyl)phenoxyactyl)indolinyl)methylthioacetate

An oven-dried 500-mL flat-bottomed flask fitted with a magnetic stirrer was charged with the alcohol (19.0 g, 36.25 mmol) obtained in step 1, anhydrous CH2Cl2 (300 mL), and Net3 (7.5 mL , 54.23 mmol). It is added over 2 min in drops of MsCl, and the reaction mixture is stirred for 10 min at room temperature. The solution was diluted with CH2Cl2 (500 mL) and washed with 1 M HCl solution (100 mL) and saturated NaHCO3 solution (100 mL). The organic solution is dried over Na2SO4 and filtered. The solvent is removed, and the methylate is used in the next step without further purification.

Step 3:

A 250 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the ester (12.45 g, 19.8 mmol) obtained in step 3, THF (100 mL), MeOH (33 mL), and water (33 mL). LiOH • H2O (1.08 g, 25.7 mmol) was added, and the reaction was stirred at room temperature for 3 h. The solvent was removed under vacuum. The residue was dissolved in 1 M HCl (200 mL) and extracted with AcOEt (2x400 mL). The combined extracts were washed with 1 M HCl solution (100 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo to give the title compound. Yield 11.9 g (100 %).

Example 38

5-(2-(5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)benzene-1,3-dicarboxylic acid

Step 1: 5-2-(5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)benzene-1,3

-dicarboxylate

A 100 mL flat-bottomed flask, fitted with a magnetic stirrer, was charged with the acid (1.2 g, 2 mmol), obtained in step 3 of Example 37, in anhydrous THF (40 mL). EDCl (0.544 g, 2.8 mmol), DMAP (0.024 g, 0.2 mmol) and 5-amino-1,3-benzenedicarboxylic acid (0.46 g, 2.2 mmol). The reaction mixture is heated under reflux while changes are observed by TLC. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (200 mL), washed with 1 M HCl solution (25 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. The crude material was purified by silica gel column chromatography using 1-2% MeOH in CH2Cl2 to give 1.2 g ((77%) of product.

Step 2:

A 15 mL flat-bottomed flask equipped with a magnetic stirrer was charged with the ester (0.6 g, 0.76 mmol) obtained in step 1, THF (7.5 mL), MeOH (2.5 mL), and water ( 2.5 mL). LiOH • H2O (0.084 g, 2 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h. Solvents are removed under vacuum. The residue was dissolved in 1 M HCl solution (10 mL) and extracted with AcOEt (2x50 mL). The combined extracts were purified by silica gel column chromatography (eluent: 5% MeOH in CHCl3+ 0.5-0.7% AcOH) to give 0.28 g (46%) of the title compound.

Examples 39, 40, 43

in Table 3 were obtained in accordance with the procedure described in Example 38.

Example 41

5-(2-(-5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)-3-hydroxymethylbenzoic acid

Step 1: methyl 5-(2-(-5-benzyloxyl-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)-3-tert

-butyldimethylsilylmethylbenzoate

This compound is obtained according to the procedure described in step 1 of Example 38.

Step 2: methyl-5-(2-(5-benzyloxy-1-(3,5-bis-(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)-4

-hydroxymethylbenzoate

An oven-dried 25 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the silyl-saturated ester (1.32 g, 1.5 mmol) obtained in step 1, anhydrous THF (10 mL) and TBAF (1 M solution in THF, 2.5 molar equiv.). The reaction mixture was stirred for 3 h at room temperature. The solvent was removed under vacuum. The oily residue was purified by silica gel column chromatography using 0-30% AcOEt in CH2Cl2 to give 0.94 g (92%) of the desired product.

Step 3:

The title compound is obtained according to the procedure described in step 2 of Example 38.

Example 42

in Table 3 is obtained in accordance with the procedure described in Example 41.

Example 44

5-(2-(-5hydroxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3-dicarboxylic acid

Step 1: 2-(5-hydroxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol

2-(5-benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol (10 g, 19.1 mmol), obtained in step 1 of Example, is charged into a 500 mL hydrogenation vessel from Parr 37. 5% Pd on charcoal (1.0 g), AcOEt (150 mL) and MeOH (100 mL), then hydrogenated for 18 h at a pressure of 3.4 bar. The reaction mixture was filtered through Celite and concentrated under vacuum to give the crude product. This is used in the next step without additional purification.

Step 2: 2-(5-(4-methoxy)benzyloxy)-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methanol

An oven-dried 1 L flat-bottomed flask, fitted with a magnetic stirrer and reflux condenser, is charged with the alcohol (8.56 g, 19.7 mmol), obtained in step 1, with 200 mesh K2CO3 (6.53 g , 47.2 mmol), Kl (3.91 g, 23.6 mmol) and finally with p-methoxybenzyl chloride (3.2 mL, 23.6 mmol) in 450 mL of anhydrous acetonitrile. The reaction mixture is heated under reflux for 4 h. The reaction mixture was partitioned between AcOEt (500 mL) and water (200 mL). The aqueous layer was extracted with AcOEt (3 x 500 mL). The combined AcOEt extracts were washed with saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. Solvents are removed under vacuum. Purification of the residue by column chromatography with silica gel (eluent 4% AcOEt in hexane) gives the desired product. Yield 8.7 g (83 %).

Step 3: methyl 5-(2-(5-(4-methoxy)benzyloxy-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolyl)methylthioacetamido)

benzene-1,3-dicarboxylate

An oven-dried 100 mL flat-bottomed flask equipped with a magnetic stirrer was charged with alcohol (3.2 g, 5.77 mmol), obtained in step 2, and anhydrous CH2Cl2 (44 mL). The reaction mixture was cooled to 0 °C, and anhydrous Net3 (1.2 mL, 8.61 mmol) was added followed by MsCl (0.53 mL, 6.84 mmol). The reaction mixture was stirred for 5 min at 0 °C. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The aqueous layer is extracted with CH2Cl2 (3 x 100m mL). The combined CH2Cl2 extracts are washed with 1 M HCl solution (100 mL), saturated NaHCO3 solution (100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over Na2SO4 and filtered. The solvents were removed in vacuo to give the mesylate. This is used in the next reaction without additional purification.

A 100 mL flat-bottomed flask fitted with a magnetic stirrer and a reflux condenser was charged with the mesylate obtained above (3.60 g, 5.70 mmol), anhydrous Cs2CO3 (5.19 g, 15.9 mmol) and anhydrous DMF (20 mL): Nitrogen is passed through the reaction solution for 15 min. Methyl 5-thioacetamido-1,3-benzenedicarboxylate is added in one portion, the mixture is partitioned between AcOEt (500 mL) and water (200 mL). The aqueous layer was extracted with AcOEt (3 x 100 mL). The combined AcOEt extracts were washed with saturated Na2SO3 solution ( (100 mL), water (100 mL), saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvents were removed under vacuum. Purification of the residue by silica gel column chromatography (eluent 5 % AcOEt in CH2Cl2) gives the product.Yield 2.5 g (53 %).

Step 4: methyl ((5-(2-(-5-hydroxy-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)benzene-1,3

-dicarboxylate

A 100 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the ester (2.60 g, 3.17 mmol) obtained in step 3 and anhydrous CH 2 Cl 2 (30 mL). TFA (25 mL) was added to the reaction mixture in several portions over 1 min. The reaction mixture is poured into 500 mL of saturated NaHCO3 solution, then extracted with CH2Cl2 (3 x 100 mL). The combined CH2Cl2 extracts are washed with saturated Na2SO4 solution and filtered. Solvents are removed under vacuum. Purification of the residue by column chromatography (eluent 12.5% AcOEt in CH2Cl2) gives the product. Yield 1.5g (68%).

Step 5:

A 25 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the ester (270 mg, 0.40 mmol) obtained in step 4, LiOH hydrate (3.3 equiv), THF (3.6 mL), MeOH ( 1.2 mL) and water (1.2 mL). The reaction mixture is heterogeneous, with a white substance suspended in solution. After 4 h of stirring, more solvent was added in the ratio 3:1:1 = THF : MeOH : H2O, so that the solution became clear. The reaction mixture was stirred for 18 h at room temperature, with TLC monitoring. The reaction mixture was acidified with 1 M HCl solution to pH 2, or with acetic acid to pH 4, and then partitioned between AcOEt (20 mL) and water (20 mL). The aqueous layer was extracted with AcOEt (3 x 20 mL). The combined AcOEt extracts were washed with water (20 mL), saturated NaCl solution (20 mL), dried over Na2SO4 and filtered. Solvents are removed under vacuum. Purification of the residue by silica gel column chromatography followed by recrystallization from acetone/hexane affords 130 mg of the title compound (50%).

Example R45

5-(2-(5-3,5-dibromo)benzyloxy-1-(3,5-bis(trifluoromethyl)phenoxyacetyl)indolinyl methylthioacetamidobenzene-1,3

-dicarboxylic acid

Step 1: methyl 4-(2-(5-(3,5-dibromo)benzyloxy-1-bis(trifluoromethyl)phenoxyacetyl)indolinyl)methylthioacetamido)

benzene-1,3-dicarboxylate

A 25 mL flat-bottom flask, fitted with a magnetic stirrer and a reflux condenser, is charged with methyl 5-(2-(-5-hydroxy-1-(3,5-bis(trifluoromethyl)(phenoxyacetyl)-indolinyl)methylthioacetamido) with benzene-1,3-dicarboxylate (0.19 g, 0.27 mmol), obtained in step 4 of Example 4, 200 mesh K2CO3 (2.4 equiv.) and 3,5-dibromobenzyl bromide (1.2 equiv.) in 7.5 mL of anhydrous acetonitrile. The reaction mixture was heated at 70 °C for 2 h. The reaction mixture was partitioned between AcOEt (30 mL) and water (20 mL). The aqueous layer was extracted with AcOEt (3 x 30 mL). The combined The AcOEt extracts were washed with saturated NaCl solution (50 mL), dried over Na 2 SO 4 , and filtered. The solvents were removed in vacuo. Purification of the residue by silica gel column chromatography using 15% EtOAc in dichloromethane afforded 0.20 g of product (77%).

Step 2:

The title compound is obtained from the ester obtained in step 1 according to the procedure described in step 5 of Example 44.

Examples 46 - 50

in Table 4 are obtained according to the procedures described in Example 44, but using the appropriate alkylating agent.

Example 51

Methyl 3-(2-85-benzyloxy-1-(benzylbenzoyl)indolinyl)methylthioacetamido)benzoate

4-Benzylbenzoic acid (0.19 g, 0.91 mmol) was dissolved in dichloromethane (2.3 mL), then oxalyl chloride (0.16 mL, 1.82 mmol) was added, followed by dimethylformamide (0, 5 mL), at room temperature. After 1 h, the reaction is concentrated and azeotroped with toluene and left under high vacuum for 2 h.

Ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.308 g, 0.65 mmol), obtained in step 6 of Example 17 and 4-dimethylaminopyridine (8 mg, 0.066 mmol) were dissolved in dichloromethane (1.2 mL ), and then the acid chloride obtained above in dichloromethane (0.5 mL) is added, followed by triethylamine (0.28 mL, 1.95 mmol). The reaction was stirred overnight at room temperature. The reaction is 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 2:1 hexane:ethyl acetate to give 0.354 g of the title product (81.7%, TLC = 0.4 Rf, 2:1 hexane:ethyl acetate).

Example 52

3-(2-(5-benzyloxy-1-(4-benzylbenzoyl)indolinyl)-methylthioacetamido)benzoic acid

The ester (0.354 g, 0.53 mmol) obtained in Example 51 was dissolved in THF (5.6 mL), methanol (5.6 mL), and then 1 M NaOH (4.2 mL) was added. The reaction mixture is stirred overnight at room temperature, then concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3x). The organic extracts were dried over magnesium sulfate and concentrated to give the title product (0.32 g, 94.4%, TLC = 0.3 Rf, 2:1 hexane:ethyl acetate, with 1% acetic acid).

Example 53 – 58

in table 5 are obtained in accordance with the procedures described in Examples 51 and 52.

Example 59

3-(2-(5-benzyloxy-1-(2-naphthoxyacetyl)indolyl)methiothioacetamido)-4-methoxybenzoic acid

Step 1: Methyl 2-(2-(5-benzyloxyndolinyl)methylthioacetamido)-4-methoxybenzoate

This compound is obtained according to the procedures described in step 6 of Example 17, but with methyl 4-methoxybenzoate.

Step 2: Methyl-3-(2-(5-benzyloxy-1-(2-naphthoxyacetyl)indolinyl)methylthioacetamido)-4-methoxybenzoate

Indole ester (0.22 g, 0.45 mmol), obtained in step 1, 2-naphthoxyacetic acid (0.11 g, 0.53 mmol), EDCl (0.10 g, 0.53 mmol) and DMAP ( 5 mg, 0.04 mmol) are measured into a flask equipped with a condenser, purged with nitrogen, then tetrahydrourane (5 mL) is added, and the reaction is kept under reflux for 18 h. The reaction was diluted with "saturated ammonium chloride and ethyl acetate, extracted (3x) with ethyl acetate, dried over magnesium sulfate, concentrated, yielding 0.30 g (100% crude) of a white substance which was used without further purification.

Step 3:

The ester (0.12 g, 0.20 mmol) obtained in step 2 is dissolved in THF/methanol, then 1 M sodium hydroxide (0.8 mL) is added, and the resulting mixture is stirred for 16 h at room temperature and another 5 h at 45 °C, and the work-up gives 0.12 g of a yellow substance which is purified by preparative TLC (1:1, hexane : ethyl acetate, with 1 % acetic acid), giving 0.12 g of the title product (95 %) .

Examples 60 - 63

in Table 5 were obtained in accordance with the procedures described in Example 59 or in Examples 51 and 52.

Example 64

3-(2-5-benzyloxy-1-tert-butoxycarbonyl)indolinyl)methylsulfonylacetamidobenzoic acid

Step 1: Ethyl-3-(2-(5-benzyloxy-1-tert-butoxycarbonyl)indolinyl)methylsulfonyl acetamidobenzoate

Solutions of ethyl 3-(2-(5-benzyloxy-1-tert-butoxycarbonyl)indolyl)methylthioacetamido benzoate (0.05 g, 0.09 mmol), obtained in step 5 of Example 17, in dichloromethane (0.1 mL) at at room temperature, m-chloroperbenzoic acid (0.06 g, 60% m-cPBA, 0.21 mmol) was added, and the reaction was stirred overnight. The next day, the reaction is stopped with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate (3x), dried over magnesium sulfate and concentrated. The crude sulfone (0.52 g, 98 %, TLC = 0.3 Rf, 1 : 1 hexane : ethyl acetate) is used in the next step directly.

Step 2:

The title compound is obtained according to the procedure described in step 3 of Example 59.

Examples 65 and 66

are obtained in accordance with the procedures described in Example 18.

Example 67

2-(2-(-5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)-2-methylthiobenzoic acid

Step 1: 5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)-2-hydroxymethylindoline

Diisopropylethylamine (3.5 mL, 20.5 mmol), DMAP (0.25 g, 2.05 mmol) and indoline alcohol (4.53 g, 17.7 mmol) obtained in step 1 of Example 17 are measured into a flask. then they are purged with nitrogen and cooled to 0 °C and after that a solution of di-tert-amylphenoxyacetyl chloride (20.5 mmol) in CH2Cl2 (50 mL) is added through a cannula at 0 °C. The resulting solution was allowed to warm to room temperature overnight and quenched by addition of saturated ammonium chloride and CH2Cl2, and the solution was extracted with CH2Cl2 (3x). The combined layers were dried over magnesium sulfate and concentrated to yield (10.4 g) of a yellow foam, which was purified by chromatography using a 7:1, 3:1 and 1:1 hexane : ethyl acetate gradient to give 3.62 g of product.

Step 2: 2-(5-Benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolylmethylmethyl)sulfonate

To a solution of the alcohol (1.2 g, 2.26 mmol) in CH 2 Cl 2 (15 mL) obtained in step 1 was added triethylamine (0.44 mL, 3.16 mmol). The solution was brought to -50 °C, then methyl chloride (0.23 mL, 2.93 mmol) was added. The mixture is stirred for 2 h at -50 °C, then quenched with saturated ammonium chloride and allowed to reach room temperature. The mixture was dissolved in CHCl3 (50 mL9, washed with saturated NaCl solution (1x10 mL), dried (MgSO4), filtered and concentrated to give the product (1.19 g, 86 %).

Step 3: Methyl 2-(2-(-5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolinyl)methylthiobenzoate

To a solution of the methylate (0.54 g, 0.89 mmol), obtained in step 2, in deaerated DMF (2 mL), was added Cs2CO3, (0.724 g, 2.22 mmol) and methylthiosalicylate (0.134 mL, 0.98 mmol) ). The mixture was stirred for 4 h, dissolved in ethyl acetate (20 mL), washed with saturated NaCl solution (3x3 mL), dried (MgSO4), filtered and concentrated. Chromatography (gradient hexane : ethyl acetate; 15 : 1 to 4 : 1) afforded 0.53 (86%) of the title compound as a yellow oil.

Step 4:

The title compound is obtained according to the procedure described in Example 59.

Example 68

is obtained in accordance with the procedure described in Example 67.

Example 69

3-(-2(-5-benzyloxy-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolinyl)methylthioethyl)aminobenzoic acid

The title compound is obtained according to the procedures described in Example 59, but using Intermediate 15.

Example 70

3-N-methyl-(2-(-5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl)phenoxyacetyl)indolyl)methylthioacetamido-4

-Methoxybenzoic acid

An oven-dried 100-mL flat-bottom flask, equipped with a magnetic stirrer and a nitrogen supply, is charged with methyl 3-(2-(-5-benzyloxy-1-(2,4-bis(1,1-dimethyl)propyl) -phenoxyacetyl)indolinyl)methylthioacetamido-4-methoxybenzoate (581 mg, 0.757 mmol), obtained in the synthesis of Example 20, using the procedures described in Example 18, then 10 mL of THF was added through a syringe. NaH (60% suspension in oil, 39 mg, 0.975 mmol) was added to the resulting yellow precipitate. The reaction mixture was stirred at 25 °C for 1.5 h, giving a light suspension. Methyl iodide (161 mg, 1.14 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 days. After cooling to 0 °C, add water (10 mL), then 50 mL of half-saturated ammonium chloride and 100 mL of EtOAc. The layers were separated and the aqueous phase was extracted once with EtOAc (50 mL). The combined organic phases were dried (sodium sulfate), filtered and concentrated to give 0.6 g of crude product as an orange oil. This material is dissolved in 15 mL of THF and 10 mL of methanol, then 7 mL of a 1 M NaOH solution is added under nitrogen. After stirring for 2 h at 25 °C, the reaction mixture is concentrated to dryness on a rotary evaporator, then 100 mL of 1 M HCl and 100 mL of EtOAc are added. The layers are separated, and the organic phase is dried (magnesium sulfate), filtered and concentrated. The crude material obtained (0.565 g) was purified by silica gel column chromatography (eluent chloroform to 3% MeOH in chloroform) to give the title compound (0.415 g, 70% yield).

Example 71

is obtained according to the procedures described in Example 70, but using allyl bromide.

Example 72

3-(2-(5-benzyloxy-1-(2,4-pyridinyl)ethyl)-indolinyl)methylthioacetamidobenzoic acid

Step 1: Ethyl 3-(2-(5-benzyloxy-1-(2,4-pyridinyl)ethyl)indolinyl)methylthioacetamidobenzoate

A solution of ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.30 g, 0.63 mmol) obtained in step 6 of Example 17 in dichloromethane (3.0 mL) and acetic acid (2.0 mL) ), 4-vinylpyridine (0.08 mL, 0.75 mmol) was added. The reaction was stirred overnight at room temperature. The reaction is quenched with half-saturated sodium bicarbonate, extracted with ethyl acetate (3x), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel, using a gradient of 2:1 hexane:ethyl acetate to 100% ethyl acetate, yielding 0.023 g of product (25%, TLC = 0.7 Rf, ethyl acetate).

Step 2:

The title compound is obtained according to the procedure described in step 3 of Example 59.

Example 73

3-(2-(5-benzyloxy-1-(2-naphthyl)methyl)indolinyl)methylthioacetamidobenzoic acid

Step 1: Ethyl 3-(2-(5-benzyloxy-1-(2-naphthyl)methyl)indolinyl)methylthioacetamidobenzoate

A mixture of 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.2 g, 0.42 mmol) obtained in step 6 of Example 17, 2-(bromomethyl)naphthalene (0.1 g, 0.42 mmol) and potassium carbonate (0.17 g, 1.26 mmol) in N,N-dimethylformamide (2 mL) was stirred overnight at room temperature. The reaction is 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 2 : 1 hexane - ethyl acetate, to give 0.22 g of product (85%, TLC = 0.5 Rf, 2 : 1 hexane : ethyl acetate).

Step 2:

The title compound is obtained according to the procedure described in step 3 of Example 59.

Examples 74 and 75

in Table 6 were obtained in accordance with the procedures described in Example 73.

Example 76

2-(2-(5-benzyloxy-1-(2-naphthyl)methylthiobenzoic acid).

Step 1: 2-(2-(-5-benzyloxy-1-(1,1-dimethyl)ethoxycarbonyl)indolinyl)methylmethylsulfonate

Dissolve tert-butyl 1-(5-benzyloxy-2-hydroxymethyl)indolinylformate (6.72 g, 19 mmol), obtained in step 2 of Example 17, in CH 2 Cl 2 (80 mL, dried over MgSO 4 before use). The clear yellow solution was cooled in a dry ice bath. Et3N (4.0 mL) was then added followed by methanesulfonyl chloride (2.0 mL). The reaction mixture is stirred for 2 h at -40 °C, and then quenched with water. Wash with saturated NaHCO3 (300 mL), and the aqueous layer is extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried over MgSO4, filtered and evaporated to dryness to give the product (7.30 g, 89.1% yield), which was used directly in the next reaction.

Step 2 methyl 2-(2-(5-benzyloxy-1-(1,1-dimethyl)ethoxycarbonyl)indolyl(methylthiobenzoate

The mesylate (7.2 g, 1.8 mmol), obtained in step 1, was dissolved in DMF (50 mL). The clear light brown solution is deaerated for 30 min by vigorous bubbling of Ar. Cesium carbonate (13.8 g) was added, followed by methylthiosalicylate (2.4 mL). The color of the solution changes to light yellow, and the suspension is stirred overnight. Methylthiosalicylate (0.15 mL) was added to complete the reaction, and the mixture was stirred overnight. The reaction was then quenched by the addition of saturated NaHCO3 (400 mL). The mixture was extracted with CH2Cl2 (3x), and the combined CH2Cl2 solutions were washed again with water (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness to give the product (9.71 g, 99 %).

Step 3: Methyl 2-(2-(5-benzyloxy)indolinyl)methylthiobenzoate

Ethyl acetate (75 mL), dried over MgSO4 before use, was placed in a 500 mL round bottom flask. HCl gas is bubbled through, and the EtOAc/HCl solution is cooled in an ice bath. The methyl ester (8.4 g) obtained in step 2 was dissolved in EtOAc (25 mL, dried over MgSO 4 before use). This solution was transferred to the HCl/EtOAc solution using a syringe. The solution turns red and is stirred in an ice bath. After 1 h, a white precipitate appears, and the solution is stirred overnight to complete the reaction. The precipitate was collected by filtration, washed with dry EtOAc, suspended in saturated NaHCO 3 (175 mL) and stirred with EtOAc (400 mL). The milk emulsion slowly dissolves and the mixture turns into a clear solution. The layers were separated and the aqueous layer was extracted (2x) with EtOAC and the combined EtOAc layers were dried over MgSO4, filtered and evaporated to dryness to give the product (6.06 g, 90% yield).

Step 4: Methyl 2-(2-(5-benzyloxy-1-(4-benzyl)benzyl)indolinyl)methylthiobenzoate

In a 50 mL round-bottom flask, dissolve the ester (1 g), obtained in step 3, in DMF (6 mL). Add p-benzylbenzylbromide (1 eq.), followed by K2CO3 (1 eq.). The reaction mixture is stirred overnight at room temperature. To complete the reaction, more p-benzylbenzyl bromide (0.5 eq.) was added, and the reaction was stirred for another 2 h. Upon completion, the reaction was diluted with water and extracted with EtOAc (2x). The organic layers were combined and dried over MgSO4. MgSO4 was filtered and the solvent was evaporated to give an oily material which was dried under high vacuum overnight to give the product (1.59 g, 109% yield).

Step 5:

The ester (1.52 g) obtained in step 4 was dissolved in THF (10 mL) in a 50 mL round-bottom flask. To this was added NaOH (1 eq., 2 M), then MeOH (3 mL), and the reaction mixture is stirred overnight. More NaOH (0.3 eq.) is added to complete the reaction, and the mixture is stirred over the weekend. It is then acidified and diluted with water, then extracted with EtOAc (2x). The organic layers were combined and dried over MgSO4. MgSO4 is filtered, and the solvent is evaporated, then dried under high vacuum, giving a crude reddish substance. This substance was dissolved in EtOAc, and hexane was added to precipitate the product. The resulting solid is filtered, and the impure cola filter is combined with the filter and evaporated to dryness. This material is treated with EtOAc and EtOH. The resulting substance was filtered and washed with EtOH to give the title product (280 mg, 19% yield).

Example 77, 78 and 79

in Table 6 are obtained in accordance with the procedures described in Example 76.

Example 80

4-(1-(5-benzyloxy-2-(bis-2,4-trifluoromethyl)benzloxymethyl)indolyl)methylbenzoic acid

Step 1: Methyl (1-(5-benzyloxy-2-(hydroxymethyl)indolinyl)methylbenzoate

Mix 2-(5-benzyloxy)indolinylmethanol 0.21 g, 12.6 mmol), obtained in DMF (20 mL), methyl 4-(bromomethyl)benzoate (2.88 g, 14.5 mmol) and potassium carbonate (1.77 g, heated to 125 °C before use) and stirred at room temperature for 2 h. The reaction was diluted with 100 mL of water and extracted three times with EtOAc. The combined EtOAc layers were evaporated to dryness to give the crude product (5.66 g). The crude material was purified on a silica gel column using hexane : ethyl acetate 3 : 1 to 2 : 1. The appropriate fractions were combined, evaporated to dryness and further dried under high vacuum to the product (3.00 g, 64 %).

Step 2: Methyl 4-(1-(5-benzyloxy-2-(bis-2,4-trifluoromethyl)benzyloxymethyl)indolinyl)methylbenzoate

The ester (700 mg), obtained in step 1, and bis-(2,4-trifluoromethyl)benzyl bromide (0.35 mL) were dissolved in DMF (5 mL). The resulting clear, yellow solution was cooled in an ice bath, and then NaH (85 mg) was added in small portions over 5 min. The suspension is stirred for 4 h at 0 °C. To complete the reaction, another 0.35 mL of 2,4-bis(trifluoromethyl)benzylbromide was added, and the stirring was continued for another 3 h and 40 min. The reaction was then diluted with water and extracted three times with EtOAc. The combined EtOAc layers were evaporated to give the crude product which was then purified on a silica gel column using 8:1 hexane:ethyl acetate. The appropriate fractions were combined and evaporated to dryness to give the product (0.417 g, 38.2% yield).

Step 3:

The title compound is obtained according to the procedure described in step 5 of Example 76.

Example 81 and 82

in Table 6 were obtained in accordance with the procedures described in Example 80.

Example 83

5-(2-(1-(2,4-bis(trioxymethyl)benzyl)indolinyl)carboxamido-1,3-benzenedicarboxylic acid

Step 1: 2-(1-(2,4-bis(trifluoromethyl)indolinyl)carboxylic acid

Dissolve 2-indolinylcarboxylic acid (0.43g, 2.6 mmol) in DMF (5 mL), then add sodium hydride (0.26 g, 60% dispersion, 6.5 mmol), and stirring is continued at this temperature for 1 h. Then 2,4-bis(trifluoromethyl) benzyl bromide (1.22 mL, 6.5 mmol) was added, and the reaction was warmed to room temperature overnight. The reaction is then diluted with 1/2 saturated ammonium chloride/ethyl acetate, and the aqueous layer is extracted with ethyl acetate (3x), and the organic layers are dried over magnesium sulfate and concentrated. The crude product was purified by chromatography (hexane : ethyl acetate 9:1) to give 0.96 g of the ester. The obtained ester (0.87 g, 0.141 mmol) was dissolved in THF/methanol, and then 1 M NaOH (4.21 mL) was added, and the resulting mixture was stirred for 2 h at room temperature, processed by purification by chromatography (7:1 hexane : ethyl acetate with 1% acetic acid), giving 0.58 g of product.

Step 2:

The acid (0.25 g, 0.64 mmol), obtained in step 1, EDCl (0.16 g, 0.83 mmol), DMAP (7 mg, 0.06 mmol) and dimethyl 5-aminoisophthalate (0.16 g, 0.77 mmol) are dissolved in THF (2 mL) and refluxed for 16 h, which after treatment with water gives 0.33 g of crude product. This ester (0.29 g, 0.50 mmol) was dissolved in THF/methanol, then 1 M NaOH (1.5 mL) was added, and the resulting mixture was stirred for 16 h at room temperature, then purified by chromatography (1:1 hexane : ethyl acetate with 1% acetic acid), giving 0.22 g of the title compound.

Example 84

N-methylsulfonyl-2-(1-(2,4-bis(trifluoromethyl)benzyl)indolinyl)carboxamide

Acid (0.13 g, 0.32 mmol), obtained in step 1 of Example 83, EDCl (0.07 g, 0.39 mmol), DMAP (4 mg, 0.03 mmol) and methanesulfonanilide (0.04 g , 0.39 mmol) are dissolved in THF (5 mL) and refluxed for 16 h, which after treatment gives 0.16 g, and after

purification by chromatography (98 : 2 dichloromethane : methanol) 0.04 g of the title compound (29 %).

Example 85

N-phenylsulfonyl-2-(1-(bis-2,4-trifluoromethyl)benzyl)indolinyl)carboxamide

The title compound is obtained according to the procedure described in Example 84, but using phenylsulfonylamide.

Example 86

5-(2-(5-methoxybenzyloxy-1-(2.4-bis(trifluoromethyl)benzyl)indolinyl)methylaminocarboxamido-1,3-benzenedicarboxylic acid

Step 1: 2-trimethylsilylethyl 1-(5-benzyloxy-2-hydroxymethyl)indolinylformate

An oven-dried 1 L flat-bottomed flask equipped with a magnetic stirrer was charged with 2-(5-benzyloxy)indolinyl methanol (33.2 g, 130 mmol), obtained in step 1 of Example 17, 2-(trimethylsilyl)ethyl p-nitrophenylcarbonate (36.8 g, 130 mmol), Net3 (38 mL, 273 mmol) and 300 mL of anhydrous DMF. The reaction mixture is stirred for 28 hours at 60 °C, then overnight at room temperature. The resulting solution is concentrated to dryness under vacuum, then 1 L of CHCl3 and 200 mL of saturated NaHCO3 solution are added. The layers are separated, and the organic phase is dried (Na2SO4), filtered and concentrated. The obtained crude material (55.7 g) was purified by silica gel column chromatography (eluent 0-5% MeOH in dichloromethane), giving the product (33.5 g, 60% yield).

Step 2: 2-trimethylsilylethyl 1-(5-hydroxy-2-hydroxymethyl)indolinyl formate

An oven-dried 500 mL Parr pressure vessel was charged with the alcohol (30 g, 75 mmol) obtained in step 1, Pd/C (10%, 2.2 g), 100 mL MeOH, and 300 mL EtOAc. Parr's apparatus is shaken overnight in an N2 atmosphere (3.4 bar), and then the reaction mixture is filtered through Florisil. The filtrate is concentrated to dryness on a rotary evaporator. The obtained crude material (24 g) was purified by silica gel column chromatography (eluent 0-3% MeOH in dichloromethane), giving the product (20.9 g, 90% yield).

Step 3: 2-trimethylsilylethyl 1-(5-(4-methoxy)benzyloxy-2-hydroxymethyl)indolinyl formate

An oven-dried 1 L flat-bottomed flask equipped with a magnetic stirrer was charged with the diol (27.1 g, 87.7 mmol) obtained in step 2, with 4-methoxybenzyl chloride (Aldrich, 15 mL, 110 mmol), K2CO3 ( 200 mesh, 30.4 g, 220 mmol), Kl (Aldrich, 18.3 g, 110 mmol) and 800 mL of anhydrous acetonitrile. The reaction mixture is heated under reflux for 4 h. The solution was allowed to cool to room temperature, then water (800 mL) and CHCl3 (1.5 L) were added. The layers were separated, and the aqueous phase was extracted with CHCl3 (800 mL). The combined extracts were washed with water (200 mL), dried (Na2SO4), filtered and concentrated. The obtained crude material (45 g) was purified by silica gel column chromatography (eluent 20-25% EtOAc in hexane), then recrystallized from EtOAc/hexane, giving the product (22.2 g, 59% yield).

Step 4: 2-Trimethylsilylethyl 1-(5-(4-methoxy)benzyloxy-2-bromomethyl)indolinyl formate

To a solution of 3.0 g (6.4 mmol) of alcohol obtained in step 3, in 30 mL of dichloromethane, 2.53 g (7.6 mmol) of carbon tetrabromide and 3.15 g (7.6 mmol) of 1,3-bis are added (diphenylphosphino) propane. The reaction is stirred for 1 h at room temperature. The reaction was quenched with saturated aqueous NH 4 Cl, and the product was extracted with dichloromethane. The combined organic extracts are washed with saturated NaCl solution and dried over MgSO4. The crude product is purified by flash chromatography. using hexane : ethyl acetate 3 : 2, yielding 1.51 g of product.

Step 5: 2-Trimethylsilylethyl 1-(5-(5-methoxy)benzyloxy-2-azidomethyl)indolinylformate

To a solution of 1.4 g (2.6 mmol) of bromide, obtained in step 4, in 15 mL of DMF, 0.51 g (7.9 mmol) of sodium azide was added. The reaction is heated to 75 °C for 18 h. The reaction is quenched with water, and the product is extracted with ethyl acetate. The combined organic layers are washed with water, saturated NaCl solution and dried over MgSO4. The crude product was purified by flash chromatography, using hexane:ethyl acetate 4:1, to give 1.08 g of product.

Step 6: 2-Trimethylsilylethyl 1-(5-(4-methoxy)benzyloxy-2-aminomethyl)indolinylformate

To a solution of 0.88 g (1.9 mmol) of azide, obtained in step 5, in 20 mL of ethanol, 90 mg (10 wt. %) of Pd/CaCO3 was added. This mixture is placed under hydrogen at atmospheric pressure and stirred for 18 hours. The reaction is then filtered through a pad of Celite, and the organic phase is concentrated. The crude product was purified by flash chromatography, using 10% MeOH/CH 2 Cl 2 , to give 0.717 g of product.

Step 7: methyl 5-(2-(5-methoxybenzyloxy-1-(2-trimethylsilyloxy)ethoxycarbonyl)indolinyl)

methylaminocarboxamido-1,3-benzenedicarboxylate

A solution of 0.31 g (1.5 mmol) of dimethyl-5-aminoisophthalate and 0.39 g (3.0 mmol) of diisopropylethylamine in 20 mL of dichloromethane. After the addition is complete, the reaction is stirred for 1 h at room temperature, and then a solution of 0.64 g (1.5 mmol) of the amine, obtained in step 6, in 5 mL of dichloromethane is added in one portion. The reaction is stirred for 2 h and then quenched with water. The product is extracted with ethyl acetate, and the combined organic layers are washed with water, saturated aqueous NaHCO3, saturated NaCl solution and dried over MgSO4. The crude product was purified by flash chromatography using 10% MeOH/CH 2 Cl 2 to give 0.78 g of product.

Step 8: Methyl 5-(2-(5-methoxybenzyloxy)indolinyl)methylaminocarboxamido-1,3-benzenedicarboxylate

To a solution of 0.485 g (0.8 mmol) of the ester obtained in step 7 in 20 mL of acetonitrile, 2.2 mL (2.2 mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF was added. The reaction was stirred for 18 h at room temperature. The reaction is stopped with saturated NaCl solution, and the product is extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous NH 4 Cl, saturated NaCl solution and dried over MgSO 4 . The crude product was purified by flash chromatography using 5% MeOH/CH 2 Cl 2 to give 0.342 g of product.

Step 9: Methyl 5-(2-(5-methoxybenzyloxy-1-(bis-2,4-trifluoromethyl)benzyl)indolinyl methylaminocarboxamido)-1,3-benzenedicarboxylate

0.997 g (0.3 mmol) of 2,4-bis(trifluoromethyl)benzylbromide and 0.12 g (0, 9 mmol) of potassium carbonate. The reaction was stirred for 18 h at room temperature. The reaction is quenched with water, and the product is extracted with ethyl acetate. The combined organic extracts are washed with water, saturated NaCl solution and dried over MgSO4. The crude product was purified by flash chromatography using 1:1 hexane:ethyl acetate to give 0.066 g of product.

Step 10:

To a solution of 0.063 g (0.1 mmol) of the diester, obtained in step 9, in 5 mL of tetrahydrofuran, 0.8 mL (0.8 mmol) of a 1.0 M NaOH solution and 0.5 mL of methanol were added. The reaction was stirred for 18 h at room temperature. The organic solvents are evaporated, and the resulting solid is suspended in water and acidified to pH 3 with 10% HCl. The product is extracted with ethyl acetate, and the combined organic extracts are washed with water, saturated NaCl solution and dried over MgSO4. The crude product was purified by flash chromatography using 5% MeOH/CH 2 Cl 2 to give 0.049 g of the title compound.

Example 87

is obtained according to the procedure described in Example 86, but using 4-(3,5-bis(trifluoromethyl)phenoxymethyl)benzyl bromide.

Intermediate 1

methyl 4-methoxy-3-thioacetamidobenzoate

Step 1: bis(methyl 4-methoxy-3-dithioacetamidobenzoate)

An oven-dried 2 L flat-bottomed flask equipped with a magnetic stirrer is charged with dithioacetic acid (10.2 -15.5 g, 56 - 85 mmol) and anhydrous CH2Cl2 (50 mL). Over 10 min, oxalyl chloride (2.1 mol.eq.) is added. The reaction mixture is stirred for 4-5 hours at room temperature. Methyl 4-methoxy-3-amidobenzoate (2.1 mol.eq.) in anhydrous CH2Cl2 (300 - 500 mL) and DMAP (0.1 mol.eq.) are added at room temperature. During 30 min, Net3 (4.2 mol.equiv.) is added dropwise. After stirring overnight at room temperature, the reaction mixture was washed with 1 M HCl solution (2 x 300 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. Purification of the residue by chromatography on a column with silica gel, using hexane: ethyl acetate - 5; 1, gives the desired product in 56% yield.

Step 2:

A 1 L flat-bottom flask, equipped with a magnetic stirrer, is charged with the disulfide, obtained in step 1, (15.7 - 26.3 g, 36.6 - 57.5 mmol) and PPh3 (1.1 mol.eq.). The reactants are suspended in dioxane/water (4/1, 375-500 mL), then concentrated HCl (5 drops) is added. The reaction mixture is heated to 40 °C until the disulfide is consumed. Solvents are removed under vacuum. The residue was immediately purified by silica gel column chromatography using hexane:ethyl acetate 2:1 to give the title product in 89% yield.

Intermediate 2

Methyl 5-thioacetamido-1,3-benzenedicarboxylate

The title compound was synthesized according to the procedure described in Intermediate 1, only using 5-amino-1,3-benzenedicarboxylate.

Intermediate 3

Methyl 4-methoxy-3-thioacetamidobenzoate

Step 1: bis(methyl 4-methoxy-3-dithioacetamidobenzoate)

An oven-dried 2 L flat-bottomed flask equipped with a magnetic stirrer is charged with dithioacetic acid (10.2 - 15.5 g, 56 - 85 mmol) and anhydrous CH2Cl2 ( mL). Oxalyl chloride (2.1 mol. eq.) is added over 10 min. The reaction mixture is stirred at room temperature for 4-5 h. Methyl 4-methoxy-3-amidobenzoate (2.1 mol. eq.) in anhydrous CH2Cl2 (300 - 500 mL) and DMAP (0.1 mol. eq.) are added at room temperature. During 30 min, Net3 (4.2 mol.equiv.) is added dropwise. After stirring overnight at room temperature, the reaction mixture was washed with 1 M HCl solution (2 x 300 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. Purification of the residue by silica gel column chromatography, using hexane : ethyl acetate - 5 : 1, gives the desired product in 56% yield.

Step 2:

A 1 L flat-bottomed flask, fitted with a magnetic stirrer, is charged with the disulfide, obtained in step 1, (15.7 - 26.3 g, 36.6 - 57.7 mmol) and PPh3 (1.1 mol equiv .). The reactants are suspended in dioxane/water (4.1 375 - 500 mL), then concentrated HCl (5 drops) is added. The reaction mixture is heated to 40 °C until the disulfide is consumed. Solvents are removed under vacuum. The residue was immediately purified by silica gel column chromatography using 2:1 hexane:ethyl acetate to give the title product in 89% yield:

Intermediate 2

methyl 5-thioacetamido-1,3-benzenedicarboxylate

The title compound was synthesized according to the procedure described in Intermediate 1, only using 5-amino-1,3-benzenedicarboxylate.

Intermediate 3

methyl 2-(3-amino-4-methoxyphenyl)-2-methoxyacetate

Step 1: Methyl 2-(3-nitro-4-methoxyphenyl)acetate

An oven-dried 2 L three-necked, round-bottomed flask equipped with a mechanical stirrer, a low-temperature thermometer, and a pressure-equalizing dropping funnel is charged with acetic anhydride (631 mL) and then cooled to -78 °C. Fuming nitric acid (Baker, 90%, 27 mL) is added dropwise through a dropping funnel, which is protected by a drying tube filled with CaCl2. When the addition is complete, the reaction temperature rises to 20 °C over 1 h. The reaction mixture was cooled again to -78 °C, and 4-methoxyphenylacetic acid (50 g, 0.28 mmol) was added through the dropping funnel. After stirring for 1 h at -50 °C, the reaction mixture was allowed to warm to -30 °C for 20 min and then cooled again to -50 °C. The reaction is stopped at - 50 °C with water (500 mL), then warmed to room temperature and stirred for 0.5 h. The reaction mixture was partitioned between CH2Cl2 (500 mL) and water. The aqueous layer was extracted with CH2Cl2 (3 x 500 mL). The combined organic extracts were concentrated in vacuo to give a yellow oil. This is slowly added to a 2 M NaOH solution (2 L), then cooled to 0 °C and stirred overnight at room temperature. The reaction mixture was partitioned between CH2Cl2 (500 mL) and water. The aqueous layer was extracted with CH2Cl2 (3 x 500 mL). The combined CH2Cl2 extracts are mixed with a 2 M NaOH solution (1 L) for 1 h. The layers are separated and the organic layer is washed with water (500 mL), saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvents were removed under vacuum to give the crude product as a light yellow solid (56 g). Purification with recrystallization from MeOH (600 mL) gave the product. Yield 48 g (77%).

Step 2: Methyl 2-(3-nitro-4-methoxyphenyl)-2-hydroxyacetate

An oven-dried 250 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the ester (2.3 g, 10 mmol) obtained in step 1 and anhydrous THF (100 mL). The reaction mixture is cooled to - 78 °C, and a solution of NaN(SiMe3)2 (1.0 M in THF, 12 mmol) is added dropwise over 10 min. After stirring for 30 min at -78 °C, a solution of racemic camphor sulfonyloxaziridine (3.4 g, 15 mmol) of the dark purple solution is added dropwise, which is obtained by mixing commercially available (1S-(+)-(10-camphorsulfonyl)oxaziridine (1 .7 g) and (1R)-(-)-(10-camphorsulfonyl)oxaziridine (1.7 g) in 50 mL THF. After stirring for 30 min at -78 °C, the reaction was quenched with saturated NH4Cl solution (45 mL) at -78 °C, then allowed to warm to room temperature. The reaction mixture was partitioned between ether (250 mL) and water (50 mL). The aqueous layer was extracted with ether (3 x 250 mL). The combined ether the extracts are washed with saturated NaCl solution (250 mL) and dried over Na2SO4, then filtered.

Step 3: Methyl 2(3-nitro-4-methoxyphenyl)-2-methoxyacetate

An oven-dried 10 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the alcohol (0.30 g, 1.24 mmol) obtained in step 2, AgO (0.68 g, 3.0 mmol) in toluene (3 mL). To this was added dropwise CH31 (0.36 g, 5.75 mmol). The reaction balloon is hermetically sealed and placed in the sonication chamber. The reaction mixture is sonicated for 18 h, with stirring, at room temperature. The reaction mixture was filtered through Celite and concentrated under vacuum to dryness. The residue was purified by silica gel column chromatography (eluent 30% AcOEt in hexane), giving the desired product. Yield 0.26 g (82 %).

Step 4:

An oven-dried 100-mL flat-bottomed flask, fitted with a magnetic stirrer and a three-pronged adapter, connected to a hydrogen flask and a water aspirator, was charged with the nitro compound (0.7 g, 2.6 mmol), 5% Pd on charcoal (10 wt %) and MeOH (20 mL). The reaction flask is placed under vacuum via a water aspirator, then filled with H2. This is repeated three times. The reaction mixture is stirred for 18 hours under H2 overpressure until all the starting material reacts. The reaction mixture was filtered through Celite and concentrated under vacuum to dryness. The residue was purified by silica gel column chromatography using 10% ethyl acetate in dichloromethane to give the title compound (0.57 g, 97%).

Intermediate 4

methyl 2-(3-amino-4-methoxyphenyl)-2-tert-butyldimethylsilyloxyacetate

A 25 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the alcohol (0.30 g, 1.24 mmol) obtained in step 2 of Intermediate 3, and anhydrous CH 2 Cl 2 (10 mL). The reaction mixture was cooled to 0 °C, and 2,6-lutidine (dried over NaOH pellets, 0.36 mL, 3.11 mmol) was added, followed by dropwise addition of BuMe2SiOTf (0.43 mL, 1.87 mmol). After stirring for 30 min at 0 °C, the reaction mixture was partitioned between CH2Cl2 (20 mL) and water (15 mL). The aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined CH2Cl2 extracts were washed with saturated NaCl solution (20 mL), dried over Na2SO4 and filtered. Solvents are removed under vacuum. Purification by chromatography on a silica gel column (eluent 3) % AcOEt in hexane) gives the desired product. Yield 0.42 g (95 %).

Step 2:

The title compound is obtained from the nitro compound from step 1, according to the procedure described in step 4, Intermediate 3.

Intermediate 5

methyl 2-(3-amino-4-methoxyphenyl)-2-methylacetate

The title compound is obtained from the nitro compounds obtained in step 1 of Intermediate 3 according to the procedure described in step 4 of Intermediate 3.

Intermediate 6

methyl 2-(3-amino-4-methoxyphenyl)-2-methylacetate

Step 1: Methyl 2-(3-nitro-4-methoxyphenyl)-2-methylacetate

An oven-dried 25 mL flat-bottomed flask fitted with a magnetic stirrer was charged with redistilled diisopropylamine (0.84 mL, 6.0 mmol) and anhydrous THF (10 mL) and cooled to 0 °C. During 5 min, a solution of n-BuLi (2.5 M in hexane, 2.4 mLm 6.0 mmol) is added dropwise. After stirring for 15 min at 0 °C, the reaction temperature was cooled to -78 °C, and the ester (1.13 g, 5.0 mmol), obtained in step 1 of Intermediate 3, was added dropwise in 10 mL of THF. After stirring for 45 min at -78 °C, dimethylsulfate (1.60 g, 12.5 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The combined CH2Cl2 extracts are washed with saturated NaCl solution (50 mL9, dried over Na2SO4 and filtered. The solvents are removed under vacuum. Purification by silica gel column chromatography (eluent 30% AcOEt in hexane) gives 0.7 g of product (58%).

Step 2:

The title compound is obtained from the nitro compound obtained in step 1, according to the procedure of step 4 of Intermediate 3.

Intermediate 7

methyl 2-(3-amino-4-methoxyphenyl)-2-allylacetate

Step 1: Methyl 2-(3-nitro-4-methoxyphenyl)-2-allylacetate

This compound is synthesized from the ester obtained in Step 1 of Intermediate 3 according to the procedure described in Step 1 of Intermediate 6, but using allyl bromide.

Step 2:

An oven-dried 25 mL flat-bottomed flask fitted with a magnetic stirrer was charged with the ester (0.30 g, 1.13 mmol) obtained in step 1, with SnCl2 • 2H2O (1.28 g, 5.66 mmol) and EtOH (5 mL). The reaction mixture is heated to 70 °C for 30 min. The reaction mixture was cooled to room temperature and poured into a mixture of water and ice (20 mL), then basified with saturated Na2CO3 solution to pH = 8. AcOEt (50 mL) was added. The resulting emulsion is filtered through Celite. The filtrate was partitioned between AcOEt (20 mL) and water (15 mL). The aqueous layer was extracted with AcOEt (3 x 50 mL). The combined AcOEt extracts were washed with saturated NaCl solution (50 mL), dried over Na2SO4 and filtered. Solvents are removed under vacuum. Purification of the residue by silica gel column chromatography (eluent 10% AcOEt in CH2Cl2) afforded the title compound. Yield 0.16 g (60 %).

Intermediate 8

2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid

Cooled to -30 °C 2,4-bis(1,1-dimethyl)propylphenol (12 g, 51.2 mmol) in DMF (100 mL), treated with solid potassium bis(trimethylylsilyl)amide (12.3 g, 61.5 mmol), stirred for 30 min and then methyl bromoacetate (5.7 mL, 61.5 mmol) was added, and the reaction was stirred for 1 h at this temperature and 5 h after removal from the cooling bath. Workup yields (16.6 g, ca. 100%) of a yellow oil. This oil is dissolved in THF/methanol, then treated with 1 M NaOH (155 mL) and stirred for 48 h. The reaction is concentrated, diluted with water, acidified to pH 4 with concentrated HCl, extracted with ethyl acetate (4x), dried over magnesium sulfate and concentrated. Crystallization from ethyl acetate and hexane gives 12.85 g of the title compound (86 %).

Intermediate 9

4-benzylphenoxyacetic acid

The title compound was obtained from 4-benzylphenol according to the procedure described for Intermediate 8.

Intermediate 10

2-naphthoxyacetic acid

The title compound was obtained from 2-naphthol according to the procedure described for Intermediate 8.

Intermediate 11

3,5-bis(trifluoromethyl)phenoxyacetic acid

The title compound was obtained from 3,5-bis(trifluoromethyl)phenol according to the procedure described for Intermediate 8.

Intermediate 12

methyl 5-amino-3-(N,N-dimethyl)carbamoylbenzoate

Step 1; methyl 5-nitro-3-(N,N-dimethyl)carbamoylbenzoate

An oven-dried 100 L flat-bottomed flask equipped with a magnetic stirrer was charged with 5-nitro-3-methoxycarbonylbenzoic acid (3.15 g, 10 mmol), DMF (1 drop), anhydrous CH2Cl2 (70 mL), and oxaphyll chloride ( 3.7 mL. 42.3 mmol). The reaction mixture was stirred for 3 h at room temperature. The solvent was removed in vacuo to give the acid chloride as a white solid. This is used immediately in the next step, without additional purification.

An oven-dried flat-bottomed flask equipped with a magnetic stirrer is charged with the acid chloride obtained above (14 mmol), anhydrous CH2Cl2 (50 mL) and dimethylamine hydrochloride (70 mmol). Net3 (2 mL9, 144 mmol) was added dropwise. After stirring for 30 - 60 min at room temperature, excess Net3 (1 mL, 72 mmol) was added, and stirring was continued. After 30 - 60 min, the solution is washed with saturated Na2CO3 solution (2 x 20 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum to give 3.3 g of product. This is used in the next step without additional purification.

Step 2:

The title compound is obtained from the nitro compound obtained in step 1 according to the procedure described for step 4 of Intermediate 3.

Intermediate 13

methyl 5-amino-3-acetylbenzoate

Step 1: Methyl 5-nitro-3-acetylbenzoate

An oven-dried 250-mL flat-bottomed flask equipped with a magnetic stirrer was charged with di-tert-butylmalonate (2.16 g, 10 mmol), sterile toluene (50 mL), and NaH (60% suspension in mineral oil 0, 88 g, 22 mmol). The reaction mixture is heated to 80 °C. Add 5-nitro-3-chloroformylbenzoate (10 mmol), obtained in step 1 of Intermediate 12, in anhydrous toluene (20 mL), and continue heating for another 2 h. The reaction mixture was cooled to room temperature, and p-toluenesulfonic acid (0.21 g, 1.2 mmol) was added. The resulting mixture is filtered, and the oily residue is washed with toluene until a white solid remains. The filtrates were combined and the solvent was removed under vacuum. The obtained oil was dissolved in anhydrous toluene (50 mL), and p-toluenesulfonic acid (0.3 g, 1.74 mmol) was added. After heating under reflux for 18 h, the reaction mixture was allowed to cool to room temperature, washed with saturated Na2SO4 solution (2 x 25 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. The crude material is purified by silica gel column chromatography (eluent CH2Cl2) to give the product. Yield 1.06 g (50 %).

Step 2:

The title compound is obtained from the nitro compound obtained in step 1, according to the procedure described in step 4 of Intermediate 3.

Intermediate 14

methyl 5-amino-3-(1-tert-butyldimethylsilyloxy)ethylbenzoate

Step 1: Methyl 5-nitro-3-(1-hydroxy)ethylbenzoate

An oven-dried flat-bottomed flask, fitted with a magnetic stirrer, is charged with the compound methyl 5-nitro-3-acetylbenzoate (0.5 g), obtained in step 1 of Intermediate 13, BH3 THF (1 M solution in THF, 5 mol. eq. .) and anhydrous THF. After stirring for 24 h at room temperature, water (20 mL) was added, then extracted with CHCl3 (20 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo to give the product. This is used in the next step without additional purification.

Step 2: Methyl 5-nitro-3-(1-tert-butyldimethylsilyloxy)ethylbenzoate

An oven-dried flat-bottomed flask equipped with a magnetic stirrer was charged with the alcohol (0.5 g, 5 mmol) obtained in step 1, tert.-BuMe2SiCl (1.3 mol. eq.), imidazole (2 ,15 mol.equiv.) and anhydrous THF. After stirring for 28 h at room temperature, the solvent was removed under vacuum. The residue is dissolved in water (50 mL) and extracted with CHCl3 (2100 mL). The combined CHCl3 extracts were washed with water (50 mL), dried over Na2SO4 and filtered. The solvent was removed under vacuum. The crude material was purified on silica gel using 25%-50% dichloromethane in hexane to give the product (0.69 g, 91%).

Step 3:

The title compound is obtained from the nitro compound obtained in step 2 according to the procedure described in step 4 of Intermediate 3.

Intermediate 15

Methyl 4-methoxy-3-(2-thiolyl)aminobenzoate

Step 1: bis(2-bromoethyl)disulfide

R6 dithioethanol (0.79 g, 6.48 mmol), carbon tetrabromide (4.3 g, 13.0 mmol) and 1,3-bis(diphenylphosphino)propane (5.34 g, 13.0 mmol) were measured into a flask. , then purged with nitrogen and then dissolved in CH2Cl2 (15 mL9 and stirred for 16 h. The treatment consists of pouring into 1⁄2 saturated ammonium chloride and extraction with CH2Cl2 (3x), drying with magnesium sulfate and concentration, yielding (9 .0 g) of crude product, which is chromatographed (hexane : ethyl acetate 9 : 1), giving 1.49 g of product.

Step 2: bis-(methyl-4-methoxy-3-(2-dithioethyl)aminobenzoate).

Bromide (0.39 g, 1.387 mmol), obtained in step 1, and methyl 3-amino-4-methoxybenzoate (1.00 g, 5.51 mmol) are added to the flask, then they are purged with nitrogen and dissolved in DMF ( 5 mL), then heated at 60 °C for 24 h, after which the reaction is diluted with ethyl acetate and quenched with water, and extracted with ethyl acetate (3x). The combined organic layers were washed with water (3x), dried and concentrated to give 1.27 g of product which was purified by chromatography (hexane : ethyl acetate 5 : 1 to 3 : 1) to give 0.15 g of the desired product.

Step 3:

Dissolve the disulfide (0.15 g, 0.24 mmol) obtained in step 2 and triphenylphosphine (0.14 g, 0.53 mmol) in THF (3 mL). Water (0.3 mL) and two drops of concentrated HCl are added, and the resulting mixture is stirred for 2 h at 40 °C. The reaction was diluted with water and ethyl acetate, extracted with ethyl acetate (3x), dried over magnesium sulfate, giving 0.27 g of crude product, which was purified by chromatography (hexane : ethyl acetate 9 : 1 to 6 : 1), giving 0.11 g of the title product. connection.

Synthesis procedures for Examples 88-135

Further compounds of this invention can be obtained in accordance with the following procedures.

Specific examples of the synthesis of compounds according to these procedures are also described below.

Procedure A

The aldehyde reacts with the alpha-carbon of a heterocycle, such as 2,4-thiazolidionedione or rhodanine, or 2-thiohydantoin. in the presence of an alkali, such as potassium carbonate or potassium hydroxide, in a solvent system, such as water: ethanol or ethanol. The resulting product can then be N-alkylated with a base, such as sodium hydride, in a solvent such as DMF or DMSO. The final acid can be obtained by decomposing the ester with hydrogen fluoride in a solvent such as acetonitrile.

Procedure A

[image]

Procedure B

Indole-2-carboxylic acid is alkylated with the appropriate alkyl bromide, then subjected to Suzuki coupling conditions, using a Pd(PPh3)4 catalyst in mixed solvents (ethanol-benzene-water), at elevated temperature, giving 1-alkyl-5-substituted indole.

Procedure B

[image]

Procedure C

The starting material for inhibitors of this class, 2-ethoxycarbonyl-5-benzyloxyindole I, is deproteinized with a suitable base, such as sodium hydride, and then alkylated at the nitrogen atom with selected electrophiles, such as alkyl or benzyl halides, to give compound II. Saponification of the ester functionality with a base, such as aqueous sodium hydroxide, in miscible solvents, such as tetrahydrofuran and methanol, affords inhibitors III. Further extensions in the 2-position are performed via amide formation at the acid functionality, via formation of the acid chloride with a suitable reagent, such as oxalyl chloride, and reaction with the amino ester in the presence of a base, such as pyridine, in a suitable solvent such as methylene chloride. Saponification yields an acid residue with an extended V chain.

[image]

Procedure D

Acid isoesters such as tetrazole are obtained from carboxylic acids 1 via nitrile III. Conversion of the nitrile is accomplished by forming the primary amide of the acid functionality, via the acid chloride, with a suitable reagent such as oxalyl chloride, and reacting with ammonia, followed by dehydration using a suitable reagent such as oxalyl chloride and a base such as pyridine. Nitriles, such as III, can be converted to tetrazoles by reaction with an azide source, such as sodium azide, in an appropriate high-boiling solvent, such as N-methylpyrrolidinone, to give compounds such as IV.

[image]

Procedure E

Isoesters of other acids. such as a thiazolidinedione group bridged by a long chain of carbon atoms, are obtained by a reaction scheme containing an unsaturated aldehyde residue in the 2-position, such as compound IV. Partial reduction of the ester group in I, with a suitable reagent, such as diisobutylaluminum hydride, or reduction to the hydroxyl group with a suitable reagent, such as lithium aluminum hydride, followed by oxidation to the aldehyde with a suitable oxidizing agent, gives aldehyde II. Horner-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent, such as tetrahydrofuran, gives the unsaturated ester III, which is converted to the aldehyde IV under the conditions described for II. The aldehyde can then be transformed into the thiazolidinedione V using a base such as piperidine and isolated as an acid such as acetic acid.

[image]

Procedure F

The 2-indolylcarboxylic acid ethyl ester 1 is deprotonated with a strong base, such as sodium hydride (NaH) in THF. and then reacts with a suitable alkyl bromide of iodine VI. Hydrolysis of VI with an aqueous alkali such as sodium hydroxide and reaction with aniline in the presence of a carbodiimide such as dimethylaminopropylethylcarbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane gives amide VII. The amide VII is hydrolyzed to the corresponding acid VIII with an aqueous base, such as sodium hydroxide.

[image]

Procedure G

Aldehyde IX is obtained from indole-2-carboxylic acid ethyl ester 1 in two steps (1) reduction with lithium aluminum hydride or another hydride, in a suitable solvent such as THF, at 0 °C. and (2) oxidation with an oxidizing agent, such as manganese dioxide, in a solvent such as THF. Aldehyde IX can be alkylated with a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide, in the presence of a strong base such as sodium hydride or KHMDS, in a solvent such as DMF, to give indole X. Indole X can be converted to unsaturated base XI in two steps: (1) Wittig reaction with a suitable reagent, such as trimethylphosphonoacetate, in the presence of a base such as sodium hydride, in a solvent such as THF, and (2) hydrolysis with aqueous sodium hydroxide .

[image]

Procedure H

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-butyldimethylsilylchloride (TBDMSCl), in a solvent such as dichloromethane or DMF, in the presence of a base such as which is imidazole. Treating II with Grinjar's reagent, such as ethylmagnesium bromide, in a solvent such as THF, at -60 °C, acylating the resulting magnesium salt with a suitable acyl chloride, such as acetyl chloride in ether, and finally alkylating the nitrogen with an alkyl halide. such as ethyl bromide, in the presence of a strong base such as NaH, in DMF, gives the ketone III. The silyl group in II is removed using tetrabutylammonium fluoride in a solvent such as THF, and the resulting alcohol is then converted to the bromide using carbon tetrabromide and bis(diphenylphosphino)ethane, in a solvent such as dichloromethane, to give bromide IV. Displacement of the bromine from IV with a thiol compound in the presence of a base, such as cesium carbonate, or with an alcohol in the presence of a strong base, such as NaH, in DMF gives V (sulfide or ether, respectively).

[image]

Example 88

4-[(4-(5-{(E)-5-(benzyloxy)-1-(4-{R3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indol-2-yl1methylidene}- 2,4

-dioxo-1,3-thiazolan~3-yl)methyl-1benzoic acid

Step 1: Suspend the aldehyde from Example 124 (5.2 g) in ethanol (150 mL). To this thick suspension was added 2,4-thiazolidinedione (1.28 g) and potassium carbonate (6.1 g). The mixture is heated in a bath to 60 °C (later lowered to 45 °C). After 1 h, TLC showed that there was no more reaction. Sodium hydroxide (2.1 g) was added and the mixture was heated to 58 °C. After 45 min, TLC did not show that the reaction was progressing. More 2,4-thiazolidinedione (0.1 g) is added. This mixture is stirred overnight at room temperature. The mixture is poured into water (500 mL), then acidified to pH 2 with 6 M HCl, extracted with ethyl acetate, dried (MgSO4) and filtered. Trituration with ethanol gave an orange solid which was filtered and washed with ethanol to give the desired product (5.74 g, 94%) as an orange solid.

Step 2: To the material prepared in step 1 (1.1 g) in DMF (15 mL), at 0 °C, sodium hydride (0.08 g, 60% dispersion in mineral oil) was added. This suspension is stirred for 30 min. Benzyl bromide (.54 g) was added to the reaction mixture, and the reaction was stirred overnight. Water is added, and the mixture is extracted with ethyl acetate. The combined organic layers are concentrated. Column chromatography (1:6 ethyl acetate:hexane to 1:4 ethyl acetate:hexane) gave the desired product (1.18 g, 75%) as a yellow solid.

Step 3: To the material obtained in step 2 (0.34 g), in acetonitrile (15 mL), HF (48%, aq. 3.7 mL) was added via syringe. The reaction is stirred overnight. The reaction was not complete according to TLC, so THF was added to dissolve the starting material and then more HF (0.6 mL) was added. The reaction was stirred for 2 h when TLC indicated completion. Water is added, which leads to the formation of a yellow precipitate. The yellow precipitate is dissolved in ethyl acetate, washed with saturated NaCl solution, dried over MgSO4 and concentrated. The obtained crude substance was suspended in ethanol and stirred for 30 min, then filtered and dried, giving the title compound (140 mg, 48 %) as a yellow substance.

Example 89

5-[(E)-(5-(benzyloxy)-1-{3-[3,5-bis(trifluoromethyl)phenoxy1propyl}1-1H-indole

2-yl)methylidene-1-1,3-thiazolan-2,4-dione

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 90

5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]

1H-indol2-yl)methylidene1-1,3-thiazolan-2,4-dione

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 91

5-{(E)-[5-(benzyloxy-1-(4-chlorobenzin-1H-indol-2-yl]methylidene}-1,3-thiazolan-2,4-dione)

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 92

5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]-methylyldene}-1,3-thiazolan-2,4-dione

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 93

5-{(E)-[5-(benzyloxy)-5-(benzyloxy)-1H-indol-2-yl]-methylyldene}-1,3-thiazolan-2,4-dione

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 94

5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yne-methylyldene}-1,3-thiazolan-2,4-dione

The title compound is prepared as illustrated in Example 88, Step 1, starting from the corresponding indole.

Example 95

5-{(E)-[5-(benzyloxy)-1-[4-(2,4-bis(trifluoromethyl)benzene 1H-indol-2-yl}-methylyldene)-1,3-thiazolan-2,4 -dion

The title compound is prepared as illustrated in Example 88, Step 1, starting from

of the corresponding indole.

Example 96

2-(5-{(E)-[5-(benzyloxy)-1-[4-(3,5-bis(trifluoromethyl)phenoxy1methyl}benzyl 1H-indol-2-yl}-methylyldene)-2,5- 1,3-thiazolan-3-yl)acetic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the corresponding indole.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: The title compound is obtained from the above intermediate as illustrated in Example 88, Step 3.

Example 97

4[(5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1-(4-chlorobenzyl)

1H-indol-2-inmethylidene}-2,4-dioxo-1,3-thiazolan-3-yl)methinebenzoic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the corresponding indole.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: The title compound is obtained from the above intermediate as illustrated in Example 88, Step 3.

Example 98

2-(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2]methylidene}-2,4-dioxo-1,3-thiazolan-3-yl) acetic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the corresponding indole.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: The title compound is obtained from the above intermediate as illustrated in Example 88, Step 3.

Example 99

4-[(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl) 1H-indol-2-yl]methylidene}-2,4-dioxo-1.3-thiazolan-3-yl) methyl1benzoic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the corresponding indole.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 3.

Example 100

2-(5-{(E)-5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene}-2,4-dioxo-1,3-thiazolan-3-yl )acetic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the corresponding indole.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 3.

The compounds in Examples 101-106 that follow were prepared as illustrated in Example 88, Step 1, starting from the corresponding indole and rhodanine.

Example 101

5-{(E)-5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene)-2-thioxo-1,3-thiazolan-4- he

Example 102

5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]methylidene)-2-thioxo-1,3-thiazolan-4-one

Example 103

5-[(E)-(5-(benzyloxy)-1-{3-(3,5-bis(trifluoromethyl)phenoxy)-propyl}-1H-indol-2-yl]methylidene]-2-thioxo-1 ,3-thiazolan-4-one

Example 104

5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene)-2-thioxo-1,3-thiazolan-4-one

Ch 1418

Example 105

5-{(E)-[1-(4-benzylbenzyl)-5-(benzyloxy)-1H-indol-2-yl]methylidene}-2-thioxo-1,3-thiazolan-4-one

Example 106

5-{(E)-[5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl-1H-indol-2-yl]methylidene)-2-thioxo- 1,3-thiazolan-4-one

Example 107

5{[5-(E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl-1H-indol-2-yl}methylidene)4-oxo-2-thioxo-1,3 -thiazolan-3-yl]methyl}benzoic acid

Step 1: The desired intermediate is obtained as illustrated in Example 88, Step 1, starting from the appropriate indole and rhodanine.

Step 2: The desired intermediate is obtained from the above intermediate as illustrated in Example 88, Step 2, using an appropriate alkylating agent.

Step 3: Step: The title compound is obtained from the above intermediate as illustrated in Example 88, Step 3.

Example 108

5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene)-2-thioxotetrahydro-4H-imidazol-4-one

The title compound is prepared as illustrated in Example 88, step 1, starting from the corresponding indole and 2-thiohydantoin.

Example 109

1-Benzyl-5-(2-thienyl)-1H-indole-2-carboxylic acid

Closed test tube. containing 2-[5-bromo-1-benzyl]-1H-indole-2-carboxylic acid (100 mg, 0.303 mmol) and 2-thiophenboronic acid (116 mg, 0.909 mmol), (C6H5)4Pd (42 mg, 0.036 mmol), Na2CO3 (2.42 mmol) in a mixture of benzene-ethanol-water (5/1/2, V/V, 4.5 mL), heated for 24 h at 100 °C. The mixture was poured into diethyl ether, and the pH was adjusted to 3 before extraction with diethyl ether. The organic layer was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product, which was purified on a silica gel column (15% EtOAc in hexane with 1% HCOOH) to give 65 mg of product.

Example 110

5-(1-Benzofuran-2-yl)-1-benzyl-1H-2-carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that benzo[d]furan-2-boronic acid was used.

Example 111

1-Benzyl-5-(4-fluorophenyl)-1H-indole-2-carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that 4-fluorophenylboronic acid was used.

Example 112

1-Benzyl-5-(3-methoxyphenyl)-1H-indole-2-carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that 3-methoxyphenylboronic acid was used.

Example 113

1-Benzyl-5-phenyl-1H-indole-carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that phenylboronic acid was used.

Example 114

1-Benzyl-5-bromo-1H-indole-2-carboxylic acid

To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in 1-methyl-2-pyrrolidone (13 mL) at 0 °C was added iPr2NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated to 50 °C for 21 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on a silica gel column (15% EtOAc in hexane) gave 1.15 g (87% yield) of product.

Example 115

5-[3-(acetylamino)phenyl]-1-benzhydryl H-indole-2 carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that 3-acetamidobenzeneboronic acid and 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid were used.

Example 116

1-Benzhydryl-5-(2-thienyl)-1H-indole-2 carboxylic acid

The title compound was obtained according to the procedure described in Example 109, except that 1-benzhydryl-5-bromo-1H-2-carboxylic acid and 2-thiophenboronic acid were used.

Example 117A

5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl1-1H-indole-2-carboxylic acid

Step 1: Sodium hydride (0.62 g, 18.6 mmol) is added to an ice-cooled (0 °C) solution of 2-ethoxycarbonyl-5-benzoindol (5.0 g, 16.9 mmol) in dimethylformamide (50 mL). ). After 10 min, the ice bath is removed, and the reaction is stirred for another 30 min at room temperature, after which bis(trifluoromethyl)benzyl bromide (3.8 mL, 20.3 mmol) is added dropwise. The green mixture was stirred at room temperature for 4 h, then water was added, and the mixture was extracted with EtOAc. The combined organic layers are washed with saturated NaCl solution, dried over MgSO4 and concentrated. The product was recrystallized from EtOAc/hexanes to give 6.87 g (81%) of the desired intermediate as an off-white powder.

Step 2: To a solution of the above intermediate (1.3 g, 2.5 mmol) in THF (50 mL), 1 M NaOH (5 mL) and MeOH (6 mL) were added. The mixture is stirred overnight at room temperature and then concentrated. The residue is suspended in water and acidified with HOAc. The product was extracted with EtOAc and the combined organic layers were washed with saturated NaCl solution, dried over MgSO4 and concentrated to give a quantitative yield of the title compound as an off-white solid.

Example 117B

5-[({5-(benzyloxy)-1-[4-(2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}carbonyl)amino]-2-[(5-chloro-3 -pindinyl)oxy]-benzoic acid

Step 1: To a solution of the above title compound (0.4 g, 0.8 mmol) in CH 2 Cl 2 (5 mL), with a few drops of DMF, was added oxalyl chloride (0.2 mL, 2.4 mmol). The reaction is stirred for 1.5 h, then concentrated. The resulting yellow residue was dissolved in CH2Cl2 (2 mL), then added to a solution of pyridylaminobenzoate ether (0.24 g, 0.8 mmol) and pyridine (0.1 mL, 0.9 mmol) in CH2Cl2 (8 mL). The reaction is stirred overnight at room temperature, water is added, and the product is extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NH 4 Cl, saturated NaCl solution and dried over MgSO 4 . Concentration and flash chromatography (Hex/EtOAc, 3/2) gave 0.182 g (51%) of the desired intermediate as a dark solid.

Step 2: To a solution of the above intermediate (0.136 g, 0.2 mmol) in THF (3 mL), was added LiOH (0.22 g, 0.5 mmol) and water (0.5 mL). The mixture is stirred overnight at room temperature, concentrated and the obtained residue is suspended in water, then acidified with HOAc. The product was extracted with EtOAc and the combined organic layers were washed with water, saturated aqueous NaCl and dried over MgSO4. Concentration gives 0.122 g of the title compound (94%) as a white crystalline substance.

Example 117C

5-(benzyloxy)-1-(4-{[(3,5-bis(trifluoromethyl)phenoxy1methyl}benzyl)-1H-indole-2-carboxylic acid

The procedure of Example 117A, steps 1 and 2, was followed using 2-ethoxycarbonyl-5-benzyloxyindole (2.0 g, 3.2 mmol) and the appropriate alkylating agent to give 1.7 g (41% for both steps) of the title compound, as a yellow substance.

Example 117D

5(benzyloxy)-1-(4-{[(3,5-bis(trifluoromethyl)phenoxy1methyl}benzyl)-1H-indole-2-carboxylic acid

The procedure of Example 117A, steps 1 and 2, was followed using 2-ethoxycarbonyl-5-benzyloxyindole (2.0 g, 3.2 mmol) and the appropriate alkylating agent to give 1.7 g (41% for both steps) of the title compound, as a yellow substance.

Example 118

5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl1-2-(1H-1,2,3,4-tetraazol-5-yl)1H-indole

Step 1: Oxalyl chloride (0.8 mL, 9.1 mmol) and three drops of DMF are added to a suspension of the acid obtained in Example 117A (1.5 g, 3.0 mmol) in CH2Cl2 (20 mL). This mixture becomes homogeneous and is stirred for 1 hour at room temperature. The reaction was concentrated and redissolved in CH2Cl2 (5 mL), then NH4OH (2.0 mL) was added. The two-phase mixture is stirred for 24 hours, then concentrated. The remaining aqueous residue was extracted with CH 2 Cl 2 , and the combined organic layers were washed with saturated aqueous NaCl, dried and concentrated to give 1.4 g (95 %) of the desired intermediate as a yellow powder.

Step 2: To an ice-cooled solution of DMF (0.23 mL, 3.0 mmol) in CH2CN (10 mL), was added oxalyl chloride (0.24 mL, 0.28 mmol). A white precipitate is currently formed, and the solution is stirred for another 5 minutes. A solution of the above intermediate (1.2 g, 2.5 mmol) in CH 2 CN (5 mL) was added. The resulting yellow-orange solution was stirred for 10 min, then pyridine (0.44 mL, 5.5 mmol) was added. After 5 min, the red mixture was partitioned between 10% aqueous HCl and EtOAc. The organic layer was dried and concentrated to give 1.0 g (84%) of the desired intermediate as a yellow powder.

Step 3:

Chapter 1563

5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy1methyl}benzyl)-1H-indole-2-carboxylic acid

To a solution of the above intermediate (0.94 g, 2.0 mmol) in N-methyl-2-pyrrolidone (10 mL), sodium azide (0.39 g, 5.9 mmol) was added. This mixture is heated under reflux for 2 h. Allow the reaction to cool to room temperature, then pour into 50 mL of ice water. The pH of the resulting solution is adjusted to 2 with 10% aqueous HCl, whereby a dark precipitate forms. The mixture was filtered and washed with EtOAc. Flash chromatography (CH2Cl2/MeOH, 1).1) gave 0.78 g (78 %) of the title compound as a white powder.

Example 119

benzyl 1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-2-(1H-1,2,3.4-tetraazol-5-yl)-1H-indol-5-yl ether

The acid is obtained in a manner analogous to Example 118, in accordance with steps 1-3, starting from the acid obtained in Example 117C.

Example 120

4-{[5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzin-1H-indol-2-yl}methylidene)-4-oxo-2-thioxo- 1,3-thiazolan-3-yl]methylbenzoic acid

Step 1: The thiazolidinedione obtained in Example 101 (0.1 g, 0.2 mmol) is alkylated by treatment with sodium hydride (0.006 g, 0.22 mmol) and bromomethyl SEM ester (0.058 g, 0.2 mmol). in DMF (2 mL). Flash chromatography (Hex/Etlacm 4/1) afforded 0.073 g (50%) of the desired intermediate as a thick oil.

Step 2: To a solution of the above intermediate (0.07 g, 0.1 mmol) in CH3CN (5 mL) was added aqueous 48% HF (2 mL). After 2 h, water is added, and the product is extracted with EtOAc, and the combined organic layers are washed with water, saturated aqueous NaCl solution and dried over MgSO4. Concentration afforded 0.025 g of the title compound (42%), as an orange powder.

Example 121

5-((Z,sE)3-{5-benzyloxy)-1[2,4-bis(trifluoromethyl)benzene 1H-indol-2,-yl}-2-propenylidene)-1,3-thiazolan-2, 4-dione

1st step: A solution of the intermediate obtained in the 1st step of Example 117A (4.4 g, 8.4 mmol) in THF (30 mL) is cooled to 0 °C, and lithium aluminum is added dropwise with vigorous stirring. hydride in THF (1.0 M, 8.4 mL). After 1 h at 0 °C, the reaction is carefully stopped with saturated NH4Cl solution. The salts are filtered and washed with EtOAc. Concentration of the solvent gives 3.9 g (96 %) of alcohol as a yellow foam. The alcohol (1.6 g, 3.3 mmol) was dissolved in THF (50 mL), and MnO2 (2.91 g, 33.4 mmol) was added. The reaction is stirred for 12 h, then filtered through a layer of Celite. Concentration of the filtrate gives 1.47 g (92 %) of the desired intermediate as a thick clear oil.

Step 2: Sodium hydride (0.14 g, 3.4 mmol) was added to an ice-cooled solution of trimethylphosphonoacetate (0.5 mL, 3.1 mmol) in DMF (10 mL), and the reaction was stirred for 20 min. A solution of the above intermediate (1.47 g, 3.1 mmol) in DMF (3 mL) was added, the ice bath was removed, and the reaction was allowed to stir at room temperature overnight. Water is added, and the aqueous phase is extracted with EtOAc. The organic layer is washed with water, saturated NaCl solution, dried over magnesium sulfate and concentrated. Flash chromatography (Hex/EtOAc, 3/2) afforded 1.5 g (93%) of the desired intermediate as a yellow solid.

3. Dissolve the above intermediate (0.5 g, 0.9 mmol) in CH2Cl2 (10 mL), then cool the solution to -20 °C. A solution of diisobutylaluminum hydride (1.0 M in toluene, 1.9 mL) is added dropwise, and the reaction is left to stir overnight at room temperature. Water is added, and the mixture is filtered through a layer of Celite. The filtrate was diluted with EtOAc, washed with water, and the combined organic layers were washed with saturated NaCl, dried and concentrated. This material was dissolved in THF (112 mL), and MnO2 (1.1 g, 12.3 mmol) was added. This mixture is stirred overnight and then filtered through a layer of Celite. Concentration of the solvent gives 0.4 g (65 %) of the desired intermediate as a thick dark oil.

Step 4: The above intermediate (0.1 g, 0.2 mmol) was dissolved in toluene (1 mL), then piperidine (6 μL, 0.1 mmol), acetic acid (1.2 μL) and 2,4-thiazolidinedione (0.023 g, 0.2 mmol). The mixture is heated under reflux for 2 h. The reaction was allowed to cool to room temperature, water was added, and the aqueous layer was extracted with EtOAc. The combined organic layers are washed with water and saturated aqueous NaCl solution, dried and concentrated. Flash chromatography (Hex/ETOAc, 3/2) afforded 0.056 g (47 %) of the title compound as a red powder.

Example 122

5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-11-indole-2-carboxylic acid

Step 1: To ethyl 5-benzyloxy-2-indolecarboxylate (1 g, 3.4 mmol) in 12 mL of DMF, sodium hydride (0.163 g, 60% dispersion in oil, 4.07 mmol) was added at room temperature. to the empire. The reaction was stirred for 30 min, then bromo-[3,5-bis(trifluoromethyl)phenoxy]-p-xylene (1.54 g, 3.73 mmol) was added, and the reaction was stirred overnight. At the end of the reaction (monitored by TLC), it is quenched with water and extracted with ethyl acetate (3x). The organic layers are dried over magnesium sulfate, concentrated and used in the next step.

2nd step: The ester (2.1 g, 3.39 mmol) is dissolved in 40 mL of 1/1 THF/methanol, then 1 M NaOH (15 mL) is added, and the resulting mixture is stirred for 16 h at room temperature . Workup gave the crude product which was purified by chromatography (1:1, hexane : ethyl acetate, with 1% acetic acid) to give 1.73 g (85%) of a solid.

Example 123

5-({[1-benzyl-5-(benzyloxy)-1H-indol-2-yncarbonyl}amino)isophthalic acid

Step 1: This intermediate is obtained according to the procedure described in Example 122, but using benzyl bromide.

Step 2: Acid (0.27 g, 0.75 mmol) obtained in Step 1. EDCl (0.18 g, 0.97 mmol). DMAP (3 mg, 0.02 mmol) and dimethyl-5-aminoisophthalate (0.18 g, 0.75 mmol) were dissolved in THF (8.8 mL) and refluxed for 16 h. After treatment and purification (hexane : ethyl acetate, 3:1) gives (0.25 g, 60%) pure product.

Step 3: The title compound is obtained from the ester obtained in Step 2 above, according to the procedure described in Step 2 of Example 122.

Example 124

(E)-3-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]-2-propenoic acid

Step 1: Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF, then cooled to 0 °C, and then lithium aluminum hydride ( LAH) (255 mL of a 1.0 M solution in THF). The reaction was stirred for another 2 h at 0 °C, and then worked up with the addition of 4 M NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3 x 400 mL), and the filtrates are combined and dried over MgSO4, then concentrated to give 24.8 g (96 %).

Step 2: The indole alcohol (26.1 g, 103 mmol) from step 1 is dissolved in THF (900 mL). Manganese dioxide (106.6 g) was added, and the mixture was stirred for 2 h at room temperature. At the end of the reaction, the mixture is filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and dried to give the desired aldehyde (22.9 g, 89 %).

Step 3: This intermediate is obtained from the indole obtained in Step 2 above and 2-(bromomethyl)naphthalene, according to the procedure described in Step 1 of Example 122.

Step 4: To sodium hydride (0.025 g, 60% dispersion in oil, 0.63 mmol) in 7.5 mL THF was added trimethylphosphonoacetate (0.1 mL, 0.62 mmol) in 2.5 mL THF, at room temperature . The reaction is stirred for 10 min. Then, aldehyde (0.24 g, 0.62 mmol), obtained in step 3 above, in 2.5 mL of THF is added dropwise at room temperature. The reaction is stirred for another 30 min

WHEN SUBMITTING THE APPLICATION, THE TEXT WAS NOT SUBMITTED (from examples 124 – 132)

Example 133

2-({[3-acetyl-1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzyloxy) 1H-indol-2-yl]methyl}sulfanyl)acetic acid

Step 1: p-toluene chloride (0.8 m) is added to triethylamine (2.44 eq.), then methoxymethylamine (HCl (1.1 eq.) dissolved in methylene chloride at 0 °C is added over 20 min. allowed to warm to 25 ° C. After 1 day of stirring at 25 ° C, treatment with methylene chloride and water gave the crude product in approx. 100 % yield.

Step 2: Under anhydrous conditions, dissolve benzothiazole in THF (0.35 M). At -78 °C, BuLi (1.1 eq.) was added. After 1 h at -78 °C, the amide from step 1 is added in THF for 15 min. The reaction was allowed to warm to 25 °C. After 1 day of stirring at 25 °C, treatment with ethyl acetate and water and chromatography give the product pure tolyl ketone (52 %).

Step 3: The tolyl ketone from step 2 is dissolved in carbon tetrachloride (0.19 M, then NBS (1.2 eq.) and AIBN (0.11 eq.) are added. After 1 day at 60 °C, present is about 1 : 1 of starting material and product.Retreatment under the same conditions is followed by filtration and recrystallization from ethyl acetate, giving pure bromobenzyl ketone as product (28%).

Step 4: Dissolve the intermediate from Step 3 of Example 131 in dry DMF (0.1 M), then add NaH (1.2 equiv). After 1.5 h at 25 °C, bromobenzyl ketone from step 3 is added, and it is stirred for 1 day at 25 °C. Workup (ethyl acetate/hexanes) and trituration (ethyl acetate/hexanes) gives the product in 46% yield.

Step 5: The product of step 4 is dissolved in methylene chloride and 1 M HCl (about 0.04 M), then stirred for 1 h at 25 °C. Treatment (sodium bicarbonate) and trituration with ether gives the product alcohol (89%).

Step 6: The alcohol from step 5 is dissolved in dry methylene chloride (0.014 M), treated with thionyl chloride (1.2 eq.) and stirred at 25 °C for 1 day. Concentration and trituration with ethyl acetate/hexanes gives the product chloride (100%).

until the submission of the application, the missing text is not given.

Activity data for the compounds of Examples 88-135 are given in Table VIII (assay described in Example 136) and Table IX (assay of Example 137).

Example 136

Activity tests

(a) Vesicle assay

l-palmitoyl-2-[14C]arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 μM) and 1,2-diolylglycerol (final concentration 3 μM) were mixed and dried under a stream of nitrogen. 50 mM Hepes pH 7.5 (2 x final lipid concentration) was added to the lipids, and the suspension was sonicated for 3 min at 4 °C. To this suspension was added 50 mM Hepes pH 7.5, 300 mM NaCl, 2 mM DTT, 2 mM CaCl 2 and 2 mg/mL bovine serum albumin (BSA) (Sigma A7511) (1.2 x final lipid concentration). A typical assay consists of a lipid mixture (85 μL) to which the inhibitor (5 yl in DMSO) and cPLA2, 10 ng for the automated system or 1 ng for the manual assay, are added sequentially in 10 μL of BSA buffer. This test is performed either as a manual test or as a test with an automated protocol, which is described below.

(b) Solubilized substrate assay (LysoPC)

1-[14C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) was dried in a stream of nitrogen (final concentration 4.4 μM). The lipid is resuspended by vortexing in 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consists of a lipid suspension (85 μL) to which inhibitor (5 μL in DMSO) and cPLA2, 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT, and 1 M EDTA are added sequentially. This test is performed either as a manual test or as a test with an automated protocol, which is described below.

until the submission of the application, the missing text is not given

(f) RBL test

RBL-2H3 cells are routinely cultured at 37 °C in an atmosphere of 5% CO3 in minimal essential medium, which contains no non-essential amino acids and 12% fetal calf serum. One day before the experiment, cells are seeded in rotary flasks at 3 x 106 cells/mL, and 100 ng/mL DNP-specific-IgE is added. After 20 h, the cells are collected by centrifugation and washed once in serum, the medium of which is without the essential minimum, then they are resuspended with 2 x 106 cells/mL, in a medium without serum. Cells are then pre-incubated with either inhibitor in DMSO (1 vol %) or DMSO (1 vol %) for 15 min at 37 °C. followed by stimulation with DNP-BSA (300 ng/mL). After 6 min, the cells are separated by centrifugation, and the upper clear layer is tested for PGD2 content according to known methods.

(g) Coumarin test

7-Hydroxycoumarinyl 6-heptenoate was used as the monomeric substrate for cPLA2, as previously reported (Huang, Z. et al., 1994, Analytical Biochemistry 222,110-115). The inhibitors were mixed with 200 μL of assay buffer (80 mM Hepes, pH 7.5, 1 mM EDTA) containing 60 μM 7-hydroxycoumarinyl 6-heptenoate. The reaction is initiated by adding 4 μg of cPLA2 to 50 μL of assay buffer. The hydrolysis of 7-hydroxycoumarinyl 6-heptenoate ester is monitored in a fluorometer, with 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 cPLA2 inhibitors, the rate of increase is lower.

Example 137

Carrageenan-induced rat paw edema test

Each compound is suspended in 0.3 mL of absolute ethanol, 0.1 mL of Tween-80 and 2.0 mL of PBS from Dulbeco (without calcium and magnesium). 0.1 mL of 1 M NaOH was added to this mixture. After dissolution is complete, more PBS is added to adjust the concentration to 1 mg/mL. All compounds are in solution. Compounds are prescribed i.v. in a volume of 5 mL/kg to male Sprague Dawley rats at the same time that edema is induced by injection of 0.05 mL of 1% Carrageenan Type IV, into the hind paw. Paw volume is measured before dosing with the compound and 3 h after dosing with Carrageenan.

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All patents and references cited herein are incorporated by reference in their entirety.

Claims (76)

1. A compound having a chemical formula selected from the group consisting of: [image] or a pharmaceutically acceptable salt thereof, characterized in that A, independently of any other group, is selected from the group consisting of -CH2 and CH2CH2-; B independently of any other group, is selected from the group consisting of -(CH2)n-, (CH2O)n-, (CH2S)n-, -(OCH2)n-, SCH2)n-, (CH=CH) n-, -(C≡C)n-, CON(R6)-. -N(R6)CO-, -O-, -S- and -N(R6)-; R1, independently of any other group, is selected from the group consisting of X-R6, -H, OH, halogen, -CN, -NO2, C1-5alkyl, alkenyl, alkynyl, aryl and substituted aryl; R2 independent of R of any group is selected from the group consisting of -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-(CH2)m-Z-R5 , C1-10 alkyl, alkenyl and substituted aryl; R3 independently of R of any group is selected from the group consisting of -H, -COOH, COR5, -CONR5R6, -(CH2)n-W-(CH2)m-Z-R5, -Z-R5, C1-10 alkyl, alkenyl and substituted aryl; R4 independently of R of any group is selected from the group consisting of -H, -OH, OR6, -SR6, -CN, -COR6, -NHR6, COOH, -CONR6R7, -NO2, CONHSO2R8, C1-5 alkyl, alkenyl and substituted aryl; R5 independently of R of any group is selected from the group consisting of -H, -OH, O(CH2)nR6, -SR6, -CN, -COR6, -NHR6, -COOH, -NO2, CONR6R7, CONHSO2R8, C1- 5 alkyl, alkenyl, alkynyl, aryl, substituted aryl, -CF3, CF2CF3 and [image] R 6 independently of R of any group is selected from the group consisting of -H, C 1-5 alkyl, alkenyl, alkynyl, aryl and substituted aryl; R 7 independently of R of any group, is selected from the group consisting of -H, C 1-5 alkyl, alkenyl, alkynyl, aryl and substituted aryl; R 8 independently of R of any group is selected from the group consisting of -H, C 1-5 alkyl, aryl and substituted aryl; R9, independently of R of any group, is selected from the group consisting of -H, -OH, halogen, -CN, -OR6, -COOH, CONR6R7, tetrazole. -CONHSO2R8, COR6, -(CH2)nCH(OH)R6 and -(CH2)nCHR6R5; R10, independent of R of any group, is selected from the group consisting of -H, -OH, halogen, -CN. -OR6, -COOH, -CONR6R7, tetrazole. CONHSO2R8. COR6, -(CH2)nCH(OH)R6 and -(CH2)nCHR6R5; W independently, whenever used including in the same compound, is selected from the group consisting of -O-, -S-, -CH2-, -CH=CH-, C=C- and -N(R6)-; X independently of any group and independently each time it is used including in the same compound, is selected from the group consisting of -O-, -S- and -N(R 6 )-; Z independently of any group and independently each time it is used including in the same compound is selected from the group consisting of -CH2-, -O-, S-, -N(R6)-, -CO-, CON(R6) -, and N(R6)CO; m independently each time it is used, including in the same compound, is an integer from 0 to 4; and n independently of m, independently each time it is used, including in the same compound, is an integer between 0 and 4. 2. A compound according to Claim 1, characterized in that it inhibits the activity of the phostolipase enzyme. 3. Compound according to Claim 1, characterized in that it has the following chemical formula: [image] 4. Compound according to Claim 1, characterized in that it has the following chemical formula: [image] 5. Compound according to Claim 1, characterized in that it has the following chemical formula: [image] 6. A compound according to claim 1, characterized in that A represents -CH2 and R2 is -(CH2)n-W-(CH2)n-ZR5. 7. A compound according to Claim 6, characterized in that N represents 1, m is 1, and W is -S- and Z is -CO-. 8. A compound according to Claim 7, characterized in that R5 represents -NHR6. 9. A compound according to Claim 8, characterized in that R6 represents a substituted aryl group. 10. A compound according to Claim 9, characterized in that the mentioned aryl group is substituted with one or more substituents independently selected from the group consisting of halogen, -CF3, -CF2CF3, -(CH2)pCOOH, -(CH2)pCH3, - O(CH2)pCH3, -(CH2)pOH, -(CH2)pS(C6H6), -(CH2)pCONH2 and –CHR11COOH, where R11 is selected from the group consisting of alkyl, alkenyl, alkynyl, -(CH2)pOH and -O(CH2)pCH3, and where p is an integer between 0 and 4. 11. A compound according to Claim 6, characterized in that R1 is selected from the group consisting of -H and -OCH2(C6H6). 12. A compound according to claim 6, characterized in that R5 is -COR5, R5 is -OCH2R6, and R6 is a substituted aryl group. 13. Compound according to Claim 12, characterized in that said aryl group is substituted with one or more substituents selected from the group consisting of –CF3, CF2CF3 and -C(CH3)2-CH2CH3. 14. A method of inhibiting the enzymatic activity of the phospholipase enzyme, characterized in that the subject of the mammal is prescribed a therapeutically effective amount of the compound according to Claim 1. 15. A method of treating an inflammatory condition, characterized in that a therapeutically effective amount of the compound according to Claim 1 is administered to the subject of the mammal. 16. Pharmaceutical preparation, characterized in that it contains the compound according to Claim 1 and a pharmaceutically acceptable carrier. 17. Compound formula [image] indicated by what R1 and R2 are independently selected from C1-6 alkyl, -Z-C1-6alkyl, phenyl, -(CH2)n-, Z-(CH2)n-phenyl, benzyl, -(CH2)n- Z-(CH2) n-benzyl, nsgyl-(CH2)n-Z-(CH2)n-naphthyl, pyrimidinyl, -(CH2)n- Z-(CH2)n-pyrimidinyl, and alkyl, phenyl, benzyl and naphthyl and pyrimidinyl groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, -NO2, -NH2, -CN, CF3 or -OH; Z is O or S; n is an integer from 0 to 3; R2 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, C1-10 alkoxy, CHO, -CN, -NO2, -NH2, ≡NH-C1-6 alkyl. -(C1-6 alkyl)2, -N-SO2-C1-6 alkyl; R 3 is selected from -H, halogen, -CF 3 , OH, -C 1-10 alkyl, C 1-10 alkoxy, CHO, -C(O)CH 3 . -C(O)-(CH2)n-CF3, -CN, -NO2, NH2, -NH-C1-6 alkyl, N(C1-6 alkyl)2, -N-SO2-C1-6 alkyl. -SO2-C1-6 alkyl or residue of the formula: [image] n is chosen independently each time it occurs as an integer between 0 and 3, R8 and R9 are independently selected, each time they occur, from -H, -COOH, (CH2)n-COOH, -(CH2)C(O)-COOH, -CF3, -OH, -(CH2)n-C( O)-COOH, C1-6 alkyl, -O-C1-6 alkyl, -NH(C1-6 alkyl) or N(C1-6 alkyl)2; R4 is selected from -COOH, -(CH2)n-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1M1 or residue of the following formulas; [image] R12 is selected from -H, -CF3, -C1-6 alkyl, -(CH2)n-C3-6-cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 groups which are selected between halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6 alkyl, -O-C1-6 alkyl, NH(C1-6 alkyl ) or -N(C1-6 alkyl)2; L1 is selected from -(CH2)n-O-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n, C(O)-O-, C(O)-(CH2) n-O-, C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-, M1 is -COOH or a residue selected from between [image] R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, C1-6alkyl,- O-C1-6 alkyl, [image] provided that the residue or combination of residues containing R3 contains an acid group selected from carboxylic acids or a residue of the formula: [image] R5 is chosen between: a) of the rest of the formula -L2-M2, where L2 is selected from a chemical bond or bridging group selected from -(CH2)n-Z, -(CH2)n-X-(CH2)n-, -C(O)-O-, C(OHCH2)n-, -C( O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-, M2 chooses from C1-6alkyl, O-C1-6alkyl, [image] where R 8 and R 9 are as defined above, and may be substituted anywhere on a cyclic or bicyclic ring; or b) the rest of the formula: [image] where L3 is a chemical bond or group selected from CH2-, CH2-Z-, -C(O). -O-, -S- or -(CH2)n-Z-(CH2)n-; where M3 chooses from -(CH2)n-C3-5cycloalkyl, furanyl, thienyl, pyrrolyl, [image] or a pharmaceutically acceptable salt thereof. 18. A compound according to Claim 17, characterized in that it has the formula [image] wherein R1 and R2 are hydrogen and the residues R3, R4, R5, R8, R9 and R10, n, L1, L2, M1 and M2 are as defined in Claim 17, or a pharmaceutically acceptable salt thereof. 19. Compound formula [image] indicated by what R1 is selected from -O-C1-6alkyl, -S-C1-6alkyl, -O-phenyl, -S-phenyl, -O-benzyl, S-benzyl, and the alkyl, phenyl and benzyl groups are optionally substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, -NO2, -NH2, -CN, -CF3 or -OH; R2 is selected from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -CN, -NO2, -NH2, NH- C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl or -SO2-C1-6alkyl; R3 is selected from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably -C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO, -CN, -NO2, -NH2, NH -C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, or the rest of the formula: [image] n at each occurrence is independently chosen from integers between 0 and 3; R8 and R9 at each occurrence independently choose between -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl. -O-C1-6alkyl, -NHC1-6alkyl) or -N(C1-6alkyl)2, R4 is a residue -L1M1 or [image] L1 is selected from a chemical bond or bridging group selected from -(CH2)n-O, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, C(O)-O -, -C(O)-(CH2)n-O-, -C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N; M1 is the remainder [image] R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, [image] provided that the combination of residues containing R 4 contains a carboxylic acid or a residue of the formula [image] R5 is a structure of the formula –L2-M2; where L2 is selected from a chemical bond or bridging group selected from -(CH2)n-O, -(CH2)n-S, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, - C(O)-O, -C(O)-(CH2)n-O-, -C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-, M2 chooses from -C1-6alkyl, O-C1-6alkyl, [image] where R 8 , R 9 and R 10 are as defined above; or a pharmaceutically acceptable salt thereof. 20. Compound according to Claim 19, characterized in that it has the formula: [image] where R1 is selected from -O-C1-6alkyl, -S-C1-6alkyl, O-phenyl, -O-benzyl, -S-benzyl, and the alkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 substituents selected from Halogen, C1-6alkyl, C1-6Alkoxy, -NO2, -NH2, -CN, CF3 or -OH, R 3 is selected from -H, halogen, -CF 3 , -OH, -C 1-10 alkyl, preferably C 1-10 alkyl, C 1-10 alkoxy, preferably C 1-10 alkoxy, -CHO, -CN, -NO 2 . NH2, -NH-C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl or the rest of the formula: [image] where R 4 , R 5 , R 8 , R 9 and R 10 are as defined in Claim 19, or a pharmaceutically acceptable salt thereof. 21. Pharmaceutical preparation, characterized in that it contains a pharmaceutically effective amount of the compound according to Claim 17, or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier or supplement. 22. Pharmaceutical preparation. characterized in that it contains a pharmaceutically effective amount of the compound according to Claim 19, or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier or supplement. 23. Compound formula [image] characterized by the fact that R1 and R2 are independently selected from -H, halogen, -CF3, -OH, -C1-10alkyl, preferably C1-6alkyl, -S-C1-10alkyl, preferably -S-C1-6alkyl, - C1-10 Alkoxy, preferably C1-6Alkoxy. -CN, -NO2, -NH2, phenyl, -O-phenyl-, -S-phenyl,,benzyl, -O-benzyl, -S-benzyl; or the ring residue of groups a), b) or c) given below, attached directly to the indole ring or attached to the indole ring or attached to the indole ring via a -S-, -O- or -(CH2)n- bridge; a) a five-membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, which is, but is not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, and the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably -C1-6alkyl, C1-10 alkoxy, preferably C1 -6Alkoxy, -NO2, -NH2, -CN, -CF3, or b) a six-membered heterocyclic ring containing one, two or three heteroatoms in the ring chosen from N, S or O, which is, but is not limited to, pyran, pyridine, pyrazine. pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiazine, oxazine or morpholine, and the six-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably -C1-6alkyl, C1- 10-Alkoxy, preferably C1-6Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or OH; or c) a bicyclic ring residue optionally containing 1 to 3 heteroatoms selected from N, S or O, which is, but is not limited to, benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine. indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine or naphthyridine, and the bicyclic residue may optionally be substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy , preferably -C1-6Alkoxy, -CHO, NO2, -NO2, -CN, -CF3, or OH; or d) the rest of the formula: [image] Z is O or S; R 6 is selected from the relevant members of the group H, -CF3, -C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, phenyl, O-phenyl, S-phenyl, benzyl, O-benzyl, - S-benzyl, and the phenyl and benzyl rings in these groups are optionally substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably -C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CHO , -NO2, -NH2, -CN, -CF3, or -OH; R7 chooses from the relevant members of the group -OH, -CF3, C1-10 alkyl, preferably -C1-6alkyl, -C1-10 alkoxy, preferably C1-6 alkoxy. -NH2, -(CH2)n-NH2, -NH-(C1--6alkyl), -N(C1-6alkyl)2, -(CH2)n-NH(C1-6alkyl), -(CH2)n-NH (C 1-6 alkyl) 2 , phenyl, -O-phenyl, benzyl or -O-benzyl; or a) a five-membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, which is, but is not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, and the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably -C1-6alkyl, -C1-10 alkoxy, preferably C1- 6Alkoxy, -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, which is, but is not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiazidin, oxazine or morpholine, and the six-membered heterocyclic rings are optionally substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkyl, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or c) a bicyclic ring residue that optionally contains from 8 to 10 atoms in the ring and optionally contains from 1 to 3 heteroatoms in the ring, which are chosen from N, S or O, which is, but is not limited to, benzofuran, chromene, indole, isoindole, indoline, isoindoline. naphthalene. purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine or naphthyridine, and the bicyclic ring residue may optionally be substituted with 1 to 3 substituents selected from halogen, -C1-10 alkyl, preferably -C1-6 alkyl , -C1-10 Alkoxy, preferably -C1-6Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably from 1 to 3, and more preferably from 1 to 2; R2 is selected from -H. halogen. CN, -CHO, -CF3, -OH, -C1-10 Alkyl, preferably C1-6Alkyl, -C1-10 Alkoxy, preferably -C1-6Alkoxy, -CHO, -CN, NO2, -NH-C1-6Alkyl, - N(C1-6alkyl)2, -N-SO2-C1-6alkyl or -SO2-C1-6alkyl, R3 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, -C1-10 alkoxy, CHO, C(O)CH3, -C(O)-(CH2)n-CF3, -CN, - NO2, -NH2, NH-C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl , -C(O)-benzyl, CH2-(C3-6cycloalkyl), -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, C(O )-CF3, -(CH2)n-S-CH2-(C3-5cycloalkyl), and the rings in the relevant R3 groups are optionally substituted with 1 to 3 groups selected from halogen, C1-6alkyl, -C1-6alkoxy, -NO2, -CF3, C(O)-OH or -OH; or the rest of the formula: [image] n at each occurrence is an integer independently chosen between 0 and 3, R8 and R9 are independently selected at each occurrence from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH , -C1-6alkyl, NH(C1-6alkyl) or -N(C1-6alkyl)2, R4 chooses from –COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole. remainder –L1-M1 or remainder of formulas: [image] R12 is selected from -H, -CF3, C1-6alkyl, -(CH2)n-C3-C8-cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with 1 to 3 groups selected from halogen , -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N( C1-6alkyl)2; L1 is selected from -(CH2)n- -S-, -O-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S, -(CH2)n-O-(CH2)n- , -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)-(CH2)n-, (CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n- , -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, C(O )-C(Z)-N(R6)-(CH2)n-, C(Z)-NH-SO2-, C(Z)-NH-SO2-(CH2)n-, C(O)-(CH2 )n-O, -C(O)-N- or -(CH2)n-S-(CH2)n-C(O)n. M1 is -COOH or a residue selected from between [image] R8 at each occurrence is independently selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 at each occurrence is independently selected from -H, halogen, CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl, -O-C1-6alkyl , -NH(C1-6alkyl) or N(C1-6alkyl)2, R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, [image] R11 is selected from -H, C1-6 lower alkyl, C1-6cycloalkyl, -CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, [image] provided that the residue or combination of residues containing R4 contains an acid group, which is selected from a carboxylic acid, a tetrazole or a residue of the formula: [image] R5 is selected from C1-6 lower alkyl, C1-6 lower alkoxy, -(CH2)n-C3-10cycloalkyl, -(CH2)n-S-(CH2)n-C3-10cycloalkyl, -(CH2)n-O-(CH2) n-C3-10cycloalkylyl groups: a) -(CH2)n-phenyl-O-Phenyl, -(CH2)n-phenyl-CH2phenyl, -(CH2)n-O-phenyl- -CH2-phenyl; -(CH2)n-phenyl-(O-CH2-phenyl)2-, -CH2 -phenyl-C(O)-benzothiazole or a residue of the formula: [image] n is an integer from 0 to 3, preferably from 1 to 3, more preferably from 1 to 2, Y is C3-5cycloalkyl, or a) a five-membered heterocyclic ring containing one or two heteroatoms selected from N, S or O, which are, but are not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine - 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, which is, but is not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiazidin, oxazine or morpholine, and the six-membered heterocyclic rings optionally substituted with 1 to 3 substituents selected from halogen. -C1-10 alkyl, preferably C1-6 alkyl. C1-10 Alkoxy, preferably C1-6Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3, or -OH, or c) a bicyclic ring residue containing from 8 to 10 ring atoms and optionally containing from 1 to 3 heteroatoms selected from N, S or O, which is, but is not limited to, benzofuran, chromene, indole, isoindole, indoline , isoindoline, naphthalene, purine, indolizine; indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine or naphthyridine, and the bicyclic residue can optionally be substituted with 1 to 3 substituents chosen from halogen, -C1-10 alkyl, preferably -C1-6alkyl, d-10 alkoxy , preferably -C1-6Alkoxy, -CHO, -NO2, -NH2, CN, -CF3 or -OH, or d) a residue of the formula -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, where A is a residue [image] where D is H, C1-6 lower alkyl, C1-6 lower alkoxy, -CF3, or -(CH2)n-CF3, B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted with from 1 to 3, preferably from 1 to 2 substituents selected from -H, halogen, -CN, -CHO, -CF3, -OH. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 or NO 2 , or a pharmaceutically acceptable salt thereof. 24. A compound according to Claim 23, which has the formula: [image] indicated by what R1 chooses from -H, halogen, -CF3, -OH, -C1-10 alkyl, preferably C1-6alkyl, S-C1-10 alkyl, preferably -S-C1-6alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, O-benzyl, S-benzyl; or a ring residue from groups a), b) or c) below, attached directly to the indole ring or attached to the indole ring via a -S-, -O- or -(CH2)n- bridge; a) furan, pyrrole or thiophene. which are optionally substituted with from 1 to 3 substituents selected from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkoxy, -NO2, -NH2, -CN, CF3, or b) pyridine, pyrimidine, piperidine or morpholine, each of which is optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably -C1-6 alkoxy, - CHO, -NO2, -NH2, -CN, -CF3 or -OH; or c) benzofuran, indole, naphthalene, purine or quinoline, each of which can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1- 6-Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or d) the rest of the formula: [image] Z is O or S; R6 is selected from the relevant members of the group -H, -CF3, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkoxy, phenyl, -O-phenyl, -S-phenyl, benzyl, -O -benzyl or -S-benzyl, and the phenyl and benzyl rings in these groups can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1 -salkoxy, -CHO, NO2, -NH2, -CN, -CF3, or OH; R7 is selected from the relevant members of the group -OH, -CF3, C1-10 alkyl, preferably -C1-6alkyl, C1-10 alkoxy, preferably C1-6alkyl, -NH2, (CH2)n-NH2-, NH(C1-6alkyl ), -N(C1-6alkyl)2, -(CH2)n-NH-(C1-6alkyl), -(CH2)n-N-(C1-6alkyl)2, -O-phenyl, benzyl, -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole or morpholine, and the rings of these groups can be optionally substituted with from 1 to 3 substituents chosen from halogen, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy , preferably -C1-6Alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or OH, n is an integer from 0 to 3, preferably from 1 to 3, and more preferably from 1 to 2; R 2 is selected from -H, halogen, -CN, -CHO, -CF3, -OH, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably -C1-6alkoxy, -CHO, CN, -NO2, -NH2, -NH-NH-C1-6alkyl, -N-(C1-6alkyl)2, -N-SO3-C1-6alkyl or -SO2-C1-6alkyl; R3 is selected from -H, halogen, -CF3, -OH, C1-10 alkyl, C1-10 alkoxy, CHO, -C(O)-CH3, -C(O)-(CH2)n-CF3, -CN , -NO2, -NH2, -NH-C1-6alkyl, -N(C1-6 alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C( O)-phenyl, -C(O)-benzyl, -CH2 - -(C3-5cycloalkyl), -C(O)-OH, -C(O)-C1-6alkyl, -C(O)-C1-6alkyl , C(O)-O-C1-6alkyl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C(O)-CF3 or -(CH2)n-S-CH2- (C3-5cyclo-alkyl), and the rings of the relevant R3 groups are optionally substituted with from 1 to 3 groups selected from halogen, C1-6alkyl, C1-6alkoxy, -NO2, -CF3, -C(O)-OH or -OH; or the rest of the formula: [image] n at each occurrence is independently chosen as an integer from 0 to 3; R8 and R9 independently select at each occurrence from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH , -C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N(C1-6alkyl)2, R4 chooses from -COOH, -(CH2)n-COOH, -(CH2)n-C(O) -COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1-M1 or residue of the formula: [image] R12 is selected from -H, -CF3, C1-6alkyl, -(CH2)n-C3-6cycloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups may optionally be substituted with from 1 to 3 groups selected from halogen , -CF3, OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl, -O-C1-6alkyl, NH(C1-6alkyl) or N(C1-6alkyl )2, L1 is selected from -(CH2)n-, S-. -O-, -C(O)-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S -(CH2)n-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(Z )-N(R6)-C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z) -N(R6)-(CH2)n-, -C(Z)-NH-SO2-, C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)n-O-, C(O)-N- or -(CH2)n-(CH2)n-C(O)-N-; M1 is -COOH or a residue selected from: [image] R8 at each occurrence is independently selected from -H, -COOH, -(CH2)n-C(O)-COOH, tetrazole, [image] R9 at each occurrence is independently selected from -H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1 -6alkyl, -NH(C1-6alkyl) or -N(C1-6alkyl)2; R10 is selected from -H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CF3, -OH, -(CH2)n-C(O)-COOH, C1-6alkyl, - O-C1-6 alkyl; [image] provided that the residue or combination of residues containing R4 comprises an acid group selected from a carboxylic acid, a tetrazole or a residue of the formula: [image] R5 is selected from d-lower alkyl, C1-6 lower alkoxy, -(CH2)n-C3-10cycloalkyl, -(CH2)n-S-(CH2)n-C3-10cycloalkyl, -(CH2)n-O-(CH2)n-C3 -10cycloalkyl, -(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 a residue of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where A is a residue: [image] D is H, C1-6 lower alkyl, C1-6 lower alkoxy, -CF3, or -(CH2)n-CF3, B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, of which is each optionally substituted with from 1 to 4, preferably from 1 to 2 substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C1-6alkyl, C1-6alkoxy, -NH2, or - NO2; or a pharmaceutically acceptable salt thereof. 25. A compound according to Claim 24, which has the formula: [image] indicated by what R1 chooses from H, halogen, -CF3, -OH, -C1-10 alkyl, preferably -C1-6alkyl, S-C1-10 alkyl, preferably -S-C1-6alkyl, C1-10 alkoxy, preferably d-salkoxy, -CN, -NO2, -NH2, phenyl, O-phenyl, -S-phenyl, benzyl, -O-benzyl; or furan, pyrrole or thiophene is attached to the indole ring by a chemical bond or through a -S-, -O- or -(CH2)n- bridge, and the phenyl, benzyl, furan, pyrrole or thiophene rings are optionally substituted with 1 to 3 substituents which are selected from halogen, C1-10 alkyl, preferably C1-6 alkyl, C1-10 alkoxy, preferably C1-6 alkoxy, -NO2, -NH2, -CN, -CF3; or n is an integer from 0 to 3, preferably from 1 to 3, more preferably from 1 to 2; R 2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C1-10 alkyl, preferably C1-6alkyl, C1-10 alkoxy, preferably C1-6alkoxy, -CHO, -CN, NO2, -NH2, -NH-C1-6alkyl, N(d-6alkyl)2, -N-SO2-C1-6alkyl or SO2-C1-6alkyl; R3 is selected from H, halogen, -CF3, -OH, C1-10 alkyl, C1-10 alkoxy, CHO, -C(O)CH3, -C(O)-(CH2)n-CF3, -CN. -NO2, -NH2, -NH-C1-6alkyl, -N(C1-6alkyl)2, -N-SO2-C1-6alkyl, -SO2-C1-6alkyl. phenyl phenoxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)-benzyl, -CH2-(C3-5cycloalkyl)), C(O)-OH, -C(O)-C1-6alkyl, - C(O)-O-C1-6alkyl, C(O)-CF3, or -(CH2)n-S-CH2((C3-5cycloalkyl), and the rings of the relevant R3 groups are optionally substituted with from 1 to 3 groups selected between halogen, C1-6alkyl, C1-6alkoxy, -NO2, -CF3, -C(O)-OH or OH; or the rest of the formula: [image] n is independently selected as an integer between 0 and 3 at each occurrence; R8 and R9 are independently selected at each occurrence from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, -NH(C1-6alkyl) or -N(C1-6alkyl)2, R4 chooses from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, residue –L1-M1 or residue of the formula: [image] R12 is selected from H, -CF3, C1-6alkyl, -(CH2)n-C3-6decloalkyl, phenyl or benzyl, and the cycloalkyl, phenyl or benzyl groups are optionally substituted with from 1 to 3 groups selected from halogen, - CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C1-6alkyl, -O-C1-6alkyl, -NH(C1-6alkyl) or N(C1- 6alkyl)2, L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-, -(CH2)n-O, -(CH2)n-S, -(CH2 )n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -( CH2)n-S-(CH2)n-, C(Z)-N(R6), C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6 )-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, C(Z)-NH-SO2-(CH2)n- , -C(O)-(CH2)n-O-, C(O)-N- or -(CH2)n-S-(CH2)n-C(O)-N-; M1 is -COOH or a residue selected from: [image] R8 at each occurrence is independently selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole [image] R9 at each occurrence is independently selected from H, halogen, -CF3, -OH, COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, C1-6alkyl. -O-C1-6alkyl, NH(C1-6alkyl) or N(C1-6alkyl)2, R10 is selected from H. -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, OH, -(CH2)n-C(O)-COOH, -C1-6alkyl, - O-C1-6 alkyl, [image] provided that the residue or combination of residues contained in R4 comprises an acid group selected from a carboxylic acid, a tetrazole or a residue of the formula: [image] R5 is selected from C1-6 lower alkyl, C-6 lower alkoxy, -(CH2)n-Ca-io cycloalkyl, -(CH2)n-S-(CH2)n-C3-10cycloalkyl, -(CH2)n-O-(CH2 )n-C3-10cycloalkyl, -(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 a residue of the formula -(CH2)n-A, -(CH2)n-S-A or -(CH2)n-O-A, where And the rest: [image] D is H, C1-6 lower alkyl, C1-6 lower alkoxy, -CF3 or -(CH2)n-CF3, B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each being optionally substituted with from 1 to 3, preferably from 1 to 2 substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, C1-6alkyl, -C1-6alkyl, -NH2, or -NO2, or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 1, characterized in that it is E-[(5-{(E)-[5-(benzyloxy)1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl) )-1H-indol-2-yl]methylidene}-2,4-dioxo-1,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 27. Compound according to Claim 1, characterized in that it is 4-{(E)-[5-(benzyloxy-1-{3-[3,5-bis(trifluoromethyl)phenoxy]propyl}-1H-indole-2 -yl]methylidene]-1,3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof. 28. The compound according to Claim 1, characterized in that it is 5-((E){5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene] -1,3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof. 29. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy-1-(4-(4-chlorobenzyl)-1H-indol-2-yl]methylidene}-1, 3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof. 30. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl-1H-indol-2-yl]methylidene}-1,3-thiazolane -2,4-dione or its pharmaceutically acceptable salt. 31. The compound according to Claim 1, characterized in that it is 5-{(E)-[1-(E-benzylbenzyl)-5-(benzyloxy)-1H-indol-2-yl]methylidene}-1,3- thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof. 32. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene}-1,3- thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof. 33. The compound according to Claim 1, characterized in that it is 5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene )-1,3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof. 34. The compound according to Claim 1, characterized in that it is 2-(5-{(E)-[5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl) )-1H-indol-2-yl]methylidene}-2,4-dioxo-1,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof. 35. The compound according to Claim 1, characterized in that it is 4-[(5-{(E)-[(5-{benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene} -2,4-dioxo-1,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof. 36. The compound according to Claim 1, characterized in that it is 2-(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]methylidene}-2 ,4-dioxo-1,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof. 37. The compound according to claim 1, characterized in that it is 4-[(5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]methylidene}-2 ,4-dioxo-1,3-thiazolan-3-yl)methyl] benzoic acid or a pharmaceutically acceptable salt thereof. 38. The compound according to Claim 1, characterized in that it is 2-(5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene}-2 ,4-dioxo-1,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof. 39. The compound according to Claim 1, characterized in that it is 5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene )-2-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 40. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]methylidene}2-thiooxo-1 ,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 41. Compound according to Claim 1, characterized in that it is 5-[(E)-(5-(benzyloxy)-1-{3-[3,5-bis(trifluoromethyl)phenoxy]propyl}-1H-indole- 2-yl)methylidene]-2-thiooxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 42. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]methylidene}-2-thiooxo- 1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 43. The compound according to Claim 1, characterized in that it is 5-{(E)-[1-(4-benzylbenzyl)-5-(benzyloxy)-1H-indol-2-yl]methylidene}2-thiooxo-1 ,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 44. The compound according to Claim 1, characterized in that it is 5-{(E)-[5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H -indol-2-yl]methylidene}-2-thiooxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof. 45. The compound according to claim 1, characterized in that it is 4-{[5-(E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indole-2- yl}methylidene)-4-oxo-2-thiooxo-1,3-thiazolan-3-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof. 46. Compound according to Claim 1, characterized in that it is 5-((E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}methylidene )-2-thioxotetrahydro-4l-l-imidazol-4-one or a pharmaceutically acceptable salt thereof. 47. A compound according to Claim 1, characterized in that it is 1-benzyl-5-(2-thienyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 48. A compound according to Claim 1, characterized in that it is 5-(1-benzofuran-2-yl)-1-benzyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 49. A compound according to Claim 1, characterized in that it is 1-benzyl-5-(4-fluorophenyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 50. The compound according to Claim 1, characterized in that it is 1-benzyl-5-(3-methoxyphenyl)-1H-indole-2-carboxylic acid or its pharmaceutically acceptable salt. 51. The compound according to Claim 1, characterized in that it is 1-benzyl-5-phenyl-1H-indole-2-carboxylic acid or its pharmaceutically acceptable salt. 52. The compound according to Claim 1, characterized in that it is 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid or its pharmaceutically acceptable salt. 53. The compound according to Claim 1, characterized in that it is 5-[3-acetylamino)phenyl]-1-benzihydryl-1H-indole-2-carboxylic acid or its pharmaceutically acceptable salt. 54. A compound according to Claim 1, characterized in that it is 1-benzhydryl-5-(2-thienyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 55. The compound according to Claim 1, characterized in that it is 5-[({5-benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]1H-indol-2-yl}carbonyl)amino]-2 -[(5-chloro-3-pyridinyl)oxy]-benzoic acid or a pharmaceutically acceptable salt thereof. 56. A compound according to Claim 1, characterized in that it is 5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 57. The compound according to Claim 1, characterized in that it is 5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl-1H-indole-2-carboxylic acid or its a pharmaceutically acceptable salt. 58. The compound according to Claim 1, characterized in that it is 5-[({5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}carbonyl)amino] -2-[(5-chloro-3-pyridinyl)oxy]-benzoic acid or a pharmaceutically acceptable salt thereof. 59. Compound according to Claim 1, characterized in that it is 5-(benzyloxy)-1-[4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 60. The compound according to Claim 1, characterized in that it is 4-{[5-(E)-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indole-2- yl}methylidene)-4-oxo-2-thiooxo-1,3-thiazolan-3-yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof. 61. A compound according to Claim 1, characterized in that what is 5-((Z,2E)-3-{5-(benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl}-2-propylidene)-1 ,3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof. 62. The compound according to Claim 1, characterized in that it is 5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 63. The compound according to Claim 1, characterized in that it is 5-({[1-benzyl-5-(benzyloxy)-1H-indol-2-yl]carbonyl}amino)isophthalic acid or its pharmaceutically acceptable salt. 64. The compound according to Claim 1, characterized in that it is (E)-3-[5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]-2-propenoic acid or its pharmaceutical acceptable salt. 65. Compound according to Claim 1, characterized in that which is (E)-3-[5-benzyloxy)-1-[2,4-bis(trifluoromethyl)benzyl]-1H-indol-2-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof. 66. The compound according to Claim 1, characterized in that it is (E)-3-[5-(benzyloxy)-1-(4-chlorobenzyl)-1H-indol-2-yl]-2-propenoic acid or its pharmaceutical acceptable salt. 67. The compound according to Claim 1, characterized in that it is 1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indole-2-carboxylic acid or its pharmaceutically acceptable salt. 68. The compound according to Claim 1, characterized in that it is 5-({[5-(benzyloxy)-1-(4-{[3,5-bis(trifluoromethyl)phenoxy)-1H-indol-2-yl] carbonyl}amino)-2-[(5-chloro-3-pyridinyl)oxy]-benzoic acid or a pharmaceutically acceptable salt thereof. 69. The compound according to Claim 1, characterized in that it is 3-({[1-(4-{3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indol-2-yl]carbonyl}amino )benzoic acid or its pharmaceutically acceptable salt. 70. The compound according to Claim 1, characterized in that it is 2-[4-({[1-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyl)-1H-indol-2-yl ]carbonyl}amino(phenyl]acetic acid or its pharmaceutically acceptable salt. 71. The compound according to Claim 1, characterized in that it is 3-{[3-acetyl-5-(benzyloxy)-1-(2-naphthylmethyl)-1H-indol-2-yl]methoxy}benzoic acid or its a pharmaceutically acceptable salt. 72. The compound according to Claim 1, characterized in that it is 4-{[5-(benzyloxy)-1-(2-naphthylmethyl)-3-(2,2,2-trifluoroacetyl)-1H-indol-2-yl ]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof. 73. The compound according to Claim 1, characterized in that it is 3-{[5-(benzyloxy)-1-(2,4-bis(trifluoromethyl)benzyl]-3-(2,2,2-(trifluoroacetyl)- 1H-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof. 74. The compound according to Claim 1, characterized in that it is 2({[3-acetyl-1-[4-1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzyloxy)-1H-indole-2 -yl]methyl}sulfanyl)acetic acid or a pharmaceutically acceptable salt thereof. 75. The compound according to Claim 1, characterized in that it is 2-({[3-acetyl-1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzyloxy)-1H-indole -2-yl]methyl}sulfanyl)benzoic acid or a pharmaceutically acceptable salt thereof. 76. The compound according to Claim 1, characterized in that it is 4-{[3-acetyl-1-[4-(1,3-benzothiazol-2-ylcarbonyl)benzyl]-5-(benzyloxy)-1H-indole- 2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof.