MXPA00008294A - Inhibitors of phospholipase a2 - Google Patents

Abstract

Inhibitors of cPLA2 activity are disclosed, having a chemical formula selected from the group consisting of (I), (II), and (III), (IV), (V) or (VI).

Description

PHOSPHOLIPASE A2 INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes. Leukotrienes prostaglandins are important mediators of inflammation. Leukotrienes recruit inflammatory cells of neutrophils to the inflamed site, promote the extravasation of these cells and stimulate the release of superoxide and proteases, which damages the tissue. Leukotrienes also play a physiopathological role in the hypersensitivity experienced by asthmatics [see, for example B. Samuelson et al., Science. 237: 1171-76 (1987)]. Prostaglandins increase inflammation by increasing blood flow thus infiltrating leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli. Prostaglandins and leukotrienes are unstable and are not stored in cells, but are synthesized [W. L. Smith, Biochem. J .. 251: 315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of enzymes COX-1 and COX-2. Arachidonic acid is also a REF: 122059 substrate for a different enzymatic pathway leading to the production of leukotrienes. Arachidonic acid, which is fed in these two different inflammatory pathways, is released from the sn-2 position of the membrane phospholipids by phospholipase A2 (then PLA2). The reaction catalyzed by PLA2 is considered to represent the rate-limiting step in the process of lipid-mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the substrate phospholipid of PLA2 is of the phosphatidylcholine class with an ether linkage in the sn-1 position, the lipophospholipid produced is the immediate precursor of platelet activating factor (hereinafter referred to as PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15: 49-58 (198 * 8)]. Most anti-inflammatory therapies have focused on avoiding the production of both prostaglandins and leukotrienes from these different, but not all, routes. For example, ibuprofen, aspirin and indomethacin are all NSAIDs (non-steroidal anti-inflammatory drugs) which inhibit the production of prostaglandins by C0X-1 / C0X-2, but have no effect on the inflammatory production of leukotrienes from acid arachidonic by other routes. Conversely, zileuton inhibits only the conversion pathways of arachidonic acid to leukotrienes, without altering the production of prostaglandins. None of these antiinflammatory agents broadly cited alters the production of PAF. Accordingly, direct inhibition of PLA activity has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, for example, J. Chang et al, Biochem. Pharmacol .. 6: 2429-2436 (1987)]. The family of PLA2 enzymes is characterized by the presence of a sequenced and finally secreted secretion signal from the cell which has been sequenced and structurally defined. These secreted PLA2 have a molecular weight of approximately 14 kD and contain seven disulfide bonds which are necessary to exhibit activity. These PLA2 are * found in large quantities in the pancreas of the mammal, in the venom of bees and in various viper venoms. [See, for example, references 13-15 in Chang et al, mentioned above; and E. A. Dennis, Drug Devel. Res .. 10: 205-220 (1987)]. However, it is considered that the pancreatic enzyme exerts a digestive function and as such is not important in the production of inflammatory mediators whose production must be regulated closely. The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluids and 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: 5335-5338 (1989); R.M. Kramer et al, J. Biol. Chem. 264: 5768-5775 (1989); and Kando et al, Biochem. Biophvs. Res. Comm. , 161: 42-48 (1989)]. However, there are doubts about whether this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the following enzymes in the biosynthetic pathways for These compounds are intracellular proteins. In addition, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Nati Acad. Sci. U.S.A. , 84: 6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce disulfide bonds and inactivate the enzyme. Murine PLA2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 μmoles / min / mg, resistant to reducing conditions, has been presented with a molecule of approximately 60 kD. However, this protein is not purified at homogeneity [See, C. C. Leslie et al., Biochem. Biophys. Acta., 961: 476-492 (1988)]. The references mentioned above, incorporated herein by reference for information on the function of the phospholipase enzymes, particularly PLA2. A cytosolic phospholipase A2 (hereinafter referred to as "cPLA2") has also been identified and cloned. See US patents 5,322,776 and 5,354,677, which are incorporated herein by reference in their entirety. The enzymes of these patents are intracellular PLA2 enzymes, purified from their natural source or produced in some other way in purified form, which function intracellularly to produce arachidonic acid in response to inflammatory stimuli. Several phospholipase enzymes have now been identified, and it would be desirable to identify chemical inhibitors of the action of the enzymes, inhibitors which can be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF is desired. There is still a need in the art for the identification of such anti-inflammatory agents for therapeutic use in various morbid states.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds having a general chemical formula that is selected from the group consisting of: or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH2- and -CH2-CH2-; B is independent of any other group and is selected from the group consisting of - (CH2) n-, - (CH20) n-, - (CH2S) n-, - (OCH2) n-, - (SCH2) n-, - (CH = CH) n-, - (C = C) n-, -CON (R6) -, -N (R6) ) CO-, -O-, -S- and -N (R6) -; Rx is independent of any other group R and is selected from the group consisting of -X-R6, -H. -OH, halogen, -CN, -N02, alkenyl alkyl, alkynyl, aryl and substituted aryl; R2 is independent of any other group R and is selected from the group consisting of -H, -COOH, -CORs, -CONRsR6, - (CH2) nW- (CH2) mZ-R5, - (CH2) nW-R5, - Z-R5, Cx-C10 alkyl, alkenyl and substituted aryl; R3 is independent of any other group R and is selected from the group consisting of -H, -COOH, -COR5, -CONR5R6, - (CH2) nW- (CH2) mZ-Rs, - (CH2) nW-Rs, - Z-Rs, C ^ C ^ alkyl, alkenyl and substituted aryl; R4 is independent of any other R group and is selected from the group consisting of -H, -OH, -OR6, -SR6, -CN, -C0R6, -NHR6, -COOH, -CONR6R7, -N02, -CONHS02R8, alkyl of alkenyl and substituted aryl; R5 is independent of any other R group and is selected from the group consisting of -H, -OH, -0 (CH2) nR6, -SR6, -CN, -COR6, -NHR6, -COOH, -N02, -COOH, -CONR6R7, -CONHS02Rβ, C 1 -C 6 alkyl, alkenyl, alkynyl, aryl, substituted aryl, CF 3, -CF 2 CF 3 and R6 is independent of any other R group and is selected from the group consisting of -H, Ci-Cg alkyl, alkenyl, alkynyl, aryl and substituted aryl; R7 is independent of any other R group and is selected from the group consisting of -H, Ci-Cs alkyl, alkenyl, alkynyl, aryl and substituted aryl; Rβ is independent of any other R group and is selected from the group consisting of aryl alkyl and substituted aryl; R9 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -0R6, -COOH, -CONR6R7 / tetrazole, -CONHS02R8, -COR6, - (CH2) nCH (OH) R6 and (CH2) nCHR6Rs; R10 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -ORß, -COOH, -CONR6R7, tetrazole, -C0NHS02R8, -COR6, - (CH2) nCH (OH) R6 and (CH2) nCHR6Rs; W is, independently of each time it is used included within the same compound, it is selected from the group consisting of -O-, -S-, -CH2-, -CH = CH-, -C = C- and -N ( R6) -; X is independent of any other group and, independently of each time it is used included within the same compound, it is selected from the group consisting of -O-, -S- and -N (R6) -; Z is independent of any other group and, independently of each time it is used included within the same compound, it is selected from the group consisting of -CH-, -O-, -S-, -N (R6) -, -CO -, -CON (R6) - and -N (R6) CO-; m is independently of each time it is used, included within the same compound, an integer from 0 to 4; and n is independent of m is independently of each time it is used included within the same compound, it is an integer from 0 to 4. Preferably, the compounds of the invention have inhibitory activity of the enzyme phospholipase. Other preferred embodiments include compounds having the following chemical formula: compounds that have the following chemical formula: compounds that have the following chemical formula: In particularly preferred embodiments, A is -CH2- and R2 is - (CH2) n-W- (CH2) m-ZRs. These preferred compounds include those wherein n is 1, m is 1, W is -S- and Z is -CO-; those in which R5 is -NHR6; those in which R6 is a substituted aryl group and those in which the aryl group "is substituted with one or more substituents that are independently selected from the group consisting of a halogen, -CF3, -CF2CF3, - (CH2) pC00H, - (CH2) pCH3, -0 (CH2) pCH3, - (CH2) p0H, - (CH2) pS (C6H6), - (CH2) pCONH2 and -CHR1XC00H, wherein RX1 is a group selected from the group consisting of alkyl, alkenyl, alkynyl, - (CH2) pOH and -0 (CH2) pCH3, and wherein p is an integer from 0 to 4. Other preferred compounds include those in wherein Rx is selected from the group consisting of -H and -OCH2 (C6H6) and R3 is -C0R5, R5 is -OCH2R6 and R6 is a substituted aryl group. In particularly preferred compounds, such an aryl group is substituted with one or more substituents which are selected from the group consisting of -CF3, -CF2CF3 and -C (CH3) 2CH2CH3. Among the compounds of this invention are those of the formula: where: R? And Ri 'are independently selected from Ci-Cg alkyl, -Z-phenyl alkyl, - (CH2) nZ- (CH2) n-phenyl, benzyl, - (CH2) nZ- (CH2) n-benzyl, naphthyl, - (CH2) nZ- (CH2) n-naphthyl, pyrimidinyl, - (CH2) nZ- (CH2) n-pyrimidinyl, the alkyl, phenyl, benzyl, naphthyl and pyrimidinyl groups are optionally substituted by 1 to 3 substituents which are selected of halogen, C1-C6 alkoxy alkyl, -N02, -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, -alkyl of C-L-CIO, alkoxy of d-C ^, -CHO ,. -CN, -N02, -NH2, -NH-C-CJ alkyl, -N (-N-S02 alkyl-C-Cg alkyl or -S02- Ci-Cg alkyl, -R3 is selected from H , halogen, -CF3, -OH, -alkyl of C -.- C..0, alkoxy of CÍ-CÍO, -CHO, -C (0) CH3, -C (O) - (CH2) n-CF3, -CN, -N02, -NH2, -NH-Ci-Cg alkyl, -N (C1-C6 alkyl) 2, -N-S02-Ci-Cg alkyl or -S02-Cj-Cg alkyl or A portion of the formula: n each time it appears, it is independently selected as an integer that is selected from 0-3; R8 and R9 are independently selected, each time they occur from, H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, Ci-Cg alkyl, -O-Ci-Cg alkyl, -NH (Ci-Cg alkyl), or -N (C 1 -C 6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L ^ M1 portion or a portion of the formulas: R12 are selected from H, -CF3, alkyl of - (CH2) n-C3-C3 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by the 3 groups selected from halogen, -CF3, -OH, -COOH, - (CH2) 'n-COOH, - (CH2) nC (0) -COOH, -alkyl of -O-Ci-Cg alkyl, -NH (Ci-Cg alkyl), or - N (alkyl of L1 is selected from - (CH2) n-0-, - (CH2) n-S-; - (CH2) n-0- (CH2) n-; - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) n-0-, -C (0) -N-, O (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of -0 - Ci-Cg alkyl, with the proviso that the portion or combination of portions comprising R3 include an acid group that is selected from carboxylic acid or a portion of the formulas: Rs is selected from: a) a portion of the formula -L2-M2; L2 is selected from a chemical bond or a bridging group, which is selected from - (CH2) nZ-, - (CH2) nZ- (CH2) n-, -C (0) -0-, -C ( 0) - (CH2) n-0-, -C (0) -N-, O - (CH2) nS- (CH2) nC (0) -N-; 2 is selected from -O-alkyl of? -β, wherein Rβ and R9 are as defined above, and may be substituted anywhere in the cyclic or bicyclic ring; or b) a portion of the formulas: wherein L3 is a chemical bond or a group selected from -CHa-, -CH2-Z-, -C (0) -, -0-, -S- or - (CH2) nZ- (CHa) n-; M3 are selected from - (CH2) n-C3-C3 cycloalkyl, furanyl, thienyl, pyrrolyl, or a pharmaceutically acceptable salt thereof. Of the compounds in the group just defined, a preferred subset includes those in which the core molecule is an indole. Within the indole group is another subset where R1 and R2 are hydrogen, and the portions R3, R4, Rs, Rs, R9 and R10, n, L1, L2, M1 and M2 are as defined above. Within this subset is another preferred group, wherein R1 is in position 5 of the indole. Also among the compounds of this invention are those of the formula: wherein: Rx is selected from -O-Ci-Cg alkyl, -S-alkyl-O-phenyl, -S-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups are optionally substituted by the 3 substituents selected from halogen, Cx-C6 alkoxy alkyl, -N02, -NH2, -CN, -CF3 or -OH; R2 is selected from H, halogen, -CF3, -OH, -alkyl of CJ-CIO, preferably C1-Ce alkyl, alkoxy of preferably Ci-Cg alkoxy, -CHO, -CN, -N02, -NH2, - NH-Ci-Cg alkyl, -N (C1-C6 alkyl) 2, -N-S02-C1-C6 alkyl, or -S02-alkyl of R3 is selected from H, halogen, -CF3, OH-, -alkyl of CÍ-CÍO, preferably -alkyl of preferably Cx-C6 alkoxy, -CHO, -CN, -N02, -NH2, -NH-Ci-Cg alkyl, -N (C1-C6 alkyl) 2, -N-S02-Ci-Cg alkyl, -S02-Ci-Cg alkyl, or a portion of the formula: n each time it appears, it is independently selected as an integer that is selected from 0-3; Rβ and R9 are independently selected, each time they occur from, H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, Cx-Cg alkyl, -O-alkyl of -NH (C 1 -C 6 alkyl), or -N (C 1 -C 6 alkyl) 2; R4 is the portion -L ^ M.1 or L1 is selected from a chemical bond or a bridging group, which is selected from - (CH2) n-0-, - (CH2) nS-, - (CH2) n-0- (CH2) n- ,, - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) n-0-, -C (0) -N-, or - (CH2) nS - (CH2) nC (0) -N-; M1 is the portion: R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of -0 - Ci-Cg alkyl, with the proviso that the portion or combination of portions comprising R3 include an acid group that is selected from carboxylic acid or a portion of the formulas: RB is a structure of the formula -L2-M2, -L2 is selected from a chemical bond or a bridging group, which is selected from - (CH2) n-0-, - (CH2) nS-, - ( CH2) n-0- (CH2) n-, - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) "-0-, -C (0) -N-, or - (CH2) n-S- (CH2) n-C (0) -N-; M2 is selected from -C ^ Cm alkyl, -O-alkyl from ^ -l ~ (-g, whn R8, R9 and R10 are as defined in the foregoing; or a pharmaceutically acceptable salt thf. Also preferred are the compounds of the previous group, with the structure: whn: Rx is selected from -O-alkyl of -S-Ci-Cg alkyl, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 substituents selected from halogen, Ci-Cg alkyl, -N02 alkoxy, -NH2, -CN, -CF3 or -OH; R3 is selected from H, halogen, -CF3, OH-, -alkyl of Cx-C10, preferably -alkyl of C1-C10alkoxy, preferably alkoxy of C ^ Cu, -CHO, -CN, -N02, -NH2 , -NH-Ci-Cg alkyl, -N (Cx-Cß alkyl) 2, -N-S02-Ci-Cg alkyl, -S02-Cx-Cg alkyl, or a portion of the formula: whn R 4, Rs, R 8, R 9 and R 10 are as defined above or a pharmaceutically acceptable salt thf. Also among the compounds of the present invention are those of the formula: wh Rx and Rx. are independently selected from H, halogen, -CF3, -OH, C ^ -C ^ alkyl, preferably-Cj-Cg alkyl, -S-Cx-C-alkyl, preferably S-Ci-Cg alkyl, alkoxy of C: -C10, preferably -CN alkoxy, -N02, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring portion of groups a), b) or c), below, attached directly to the indole ring or linked to the indole ring by a bridge -S-; -0- or - (CH2) n-; a) a five-memb heterocyclic ring containing one or two heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-memb heterocyclic ring is optionally substituted with 1 to 3 substituents which are selected from halogen, CX-C10 alkyl, preferably CX alkoxy alkyl -C10, preferably, -N02 alkoxy, -NH2, -CN, -CF3, or b) a six-memb heterocyclic ring containing one, two or three heteroatoms in the ring that are selected from N, S or O and include , but are not limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, the six-memb heterocyclic ring is optionally substituted with one to three substituents selected halogen, C 1 -C 4 alkyl, preferably C 1 -C 10 alkoxy, preferably C 1 -C 6 alkoxy -CHO, -N 0 2, -NH 2, -CN, -CF 3 or -OH; or c) a bicyclic ring portion optionally containing 1 to 3 ring heteroatoms selected from N, S or 0 and including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolysine, quinazoline, cinoline, phthalazine or naphthyridine, the bicyclic ring portion is optionally substituted with 1 to 3 substituents which are selected from halogen, CX-C10 alkyl, preferably Cj-alkyl, Cg, C1-C10 alkoxy, preferably Ci-Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or d) a portion of the formulas: «^^^^ j ^^^ Z is O O S; Rg is selected from the relevant members of the group H, -CF3, alkyl of preferably Cx-Cg alkyl, Cx-C10 alkoxy, preferably Cx-Cg alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl or -S-benzyl, the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents which are selected from halogen, Cx-C10 alkyl, preferably Cj-Cg alkyl, Cx-C10 alkoxy , preferably Cx-C6 alkoxy, -CHO, -N02, -rJH2, -CN, -CF3 or -OH; R7 is selected from the relevant members of the group -OH, -CF3, alkoxy alkyl of preferably Cx-Cg alkoxy, -NH2, - (CH2) n-NH2, -NH- (Cx-Cg alkyl), -N - (Cx-C6 alkyl) 2f - (CH2) n-NH- (Cx-Cß alkyl), - (CH2) nN- (Cx-C6 alkyl), phenyl, 0-phenyl, benzyl or -O- benzyl; oa) a five-membered heterocyclic ring containing one or two heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring is optionally substituted by the 3 substituents selected from halogen, Cx-Cx, alkyl, preferably Ci-Cg alkyl, C1-C10 alkoxy, preferably -N02 alkoxy, -NH2, -CN, or -CF3; or b) a six-membered heterocyclic ring containing one, two or three heteroatoms in the ring that is are selected from N, S or 0 and include, but are not limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine or morpholine, the six-membered heterocyclic ring is optionally substituted by 1 to 3 substituents which are selected from halogen, Cx-C10 alkyl, preferably Cx-C6 alkyl / Cx-C10 alkoxy, preferably Cx-C17 alkoxy-CHO, -N02, -NH2, -CN, -CF3 or -OH; c) a bicyclic ring portion containing 8 to 10 atoms in the ring and optionally containing 1 to 3 heteroatoms in the ring, which are selected from N, S or O and include, but are not limited to benzofuran, chromene, indole, isoindol, indoline, isoindoline, naphthalene, purine, indolysin, indazole, quinoline, isoquinoline , quinolysin, quinazoline, cinoline, phthalazine or naphthyridine, the portion of The bicyclic ring is optionally substituted with 1 to 3 substituent substituents which are selected from halogen, CX-C10 alkyl, preferably C1-C6 alkyl, CX-C10 alkoxy, preferably -CHO alkoxy, -N02, -NH2, - CN, -CF3 or -OH; Ai¿a * Ai £ i? AÁa¡? ? i i «i ll? L * ¡! ^ *? ^^^^^ - ^^^, ^ uM * ^^^^ i ^^ A -? * ~ * M ^ ml? ¡^ * * T- A. ^? A ~ A ^ * ~ ^ ^^^^^ - ^ ^^^^^ A ^ ^ ^^ is an integer from 0 to 3, preferably 1 to 3, and most preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -Cx-C10 alkyl, preferably Cx-Cg alkyl, Cx-C10 alkoxy; preferably -CHO alkoxy, -CN, -N02, -NH2, -NH-alkyl of -N (Cx-C6 alkyl) 2, -N-S02-alkyl of Cx-Cg or -S02-Cx-Cß alkyl; R3 is selected from H, halogen, -CF3, -OH, -alkyl of Cx-C10, alkoxy of Cx-Cx0, -CHO, -C (0) CH3, -C (0) - (CH2) n-CF3, -CN, -N02, -NH2, -NH-Cj-Cg alkyl, -N (Cx-C6 alkyl) 2, -N-S02-Cx-C6 alkyl or -S02-Ci-Cg alkyl, phenyl , phenyloxy, benzyl, benzyloxy, -C (O) -phenyl, -C (O) -benzyl, -CH2- (C3-C6 cycloalkyl), -C (0) -OH, C (O) -alkyl of - C (O) - O-Cx-C6 alkyl, -C (0) -CF3, - (CH2) nS-CH2- (C3-C5 cycloalkyl), the rings of the relevant R3 groups are optionally substituted by 1 to 3 groups selected from halogen, Cx-C6 alkyl, -N02 alkoxy, -CF3, -C (0) -OH, or -OH; or a portion of the formula: n every time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time they occur of H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, Cx-Cg alkyl, -O-Cx-C6 alkyl, -NH (Cx-Cg alkyl), or -N (Cx-C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L1 -! ^ Portion 1 or a portion of the formulas: R12 is selected from H, -CF3, Ci-Cg alkyl, - (CH2) n-C3-C6 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 groups which are selected from halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CHa) nC (0) -COOH, -alkyl of Cx-C3, -O-alkyl of Cx-C6 / -NH (alkyl) of Cx-C3), or -N (alkyl of X "i-61 2 L1 is selected from - (CH2) n-, -S-, -O-, -C (O) -, -C (0) - 0-, - (CH2) n-0-, - (CH2) nS-; - (CH2) n-0- (CH2) "-; - (CH2) nS- (CH2) n-, - (GH2) nC (0) - (CH2) n-, - (CH2) n-0- (CH2) n-, - (CH2) nS- (CH2) n-, -C (Z) -N (Rg) -C (Z ) -N (R6) - (CH2) n, -C (O) -C (Z) -N (R6) -C (O) -C (Z) -N (R6) - (CH2) n-; - C (Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (O) - (CH2) n-0-, -C (0) -N-, O- (CH2) nS- (CH2) nC (0) -N-; 1 is -COOH or a portion selected from: ¿¡¡¡¡¡¡¡¡¡¡¡¡¡((Aallqquimillo inferior of Cx-C6) (lower haloalkyl of Ci-Cg R8, each time it occurs, is independently selected from H, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, tetrazole, '• R9, each time it occurs is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -C1- alkyl- C6, -O-Cx-C6 alkyl, -NH- (Ci-Cg alkyl), or -N (Cx-Cß alkyl) 2; R10 are selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3 / -OH, - (CH2) nC (0) -COOH, -alkyl C. -Cg, -0-Cx-Cg alkyl, (lower alkyl of Cx-C6) (C1-C6 lower haloalkyl) RX1 is selected from H, lower alkyl of Cx-C6, cycloalkyl of Cx-Cßf -CF3, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, with the proviso that the portion or combination of portions comprising R4 include an acid group selected from carboxylic acid, a tetrazole or a portion of the formulas: R5 is selected from lower alkyl of Ci-Cg, lower alkoxy of Cx-C6, - (CH2) n-cycloalkyl of C3-C10, - (CH2) nS- (CH2) n-cycloalkyl of C3-C10, - (CH2 ) n-0- (CH2) n-cycloalkyl of C3-C10 / or the groups of: a) - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) ) n-0-phenyl-CH2-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (O) -benzothiazole or a portion of the formulas: / (CHaJ x ^ CHaJ p ^ where n is an integer from 0 to 3, preferably 1 to 3, and more preferably 1 to 2, Y is a C3-C3 cycloalkyl, or a) a heterocyclic ring of five members containing one or two heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine , pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents which are selected from halogen, C 1 -C 10 alkyl, preferably Ci-Cg alkyl, preferably alkoxy, alkoxy Cx-C6, -N02, -NH2, -CN, -CF3, ub) a six-membered heterocyclic ring containing one, two or three heteroatoms in the ring that are selected from N, S or O and include, but are not are limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetraz ina, thiazine, thiadiazine, oxazine or morpholine, the six-membered heterocyclic ring is optionally substituted with one to three substituents which are selected from halogen, C1-C10 alkyl, preferably Ci-Cg alkyl, C1-C10 alkoxy, preferably Ci-Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or c) a bicyclic ring portion containing from 8 to 10 atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or 0 and including, but not limited to benzofuran, chromene, indole , isoindol, indoline, isoindoline, naphthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolysin, quinazoline, cinoline, phthalazine or naphthyridine, the bicyclic ring portion is optionally substituted with 1 to 3 substituents which are selected from halogen, alkyl, preferably Cx-C6 alkyl, Cx-C10 alkoxy, preferably Cx-Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or d) a portion of the formulas - (CH2) n-A, - (CH2) n-S-A, or - (CH2) n-0-A-, where A is the portion: wherein D is H, lower alkyl of C 1 -C 6, lower alkoxy of C x -Cß, -CF 3 or - (CH 2) n-CF 3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by 3, preferably 1 to 2, substituents which are selected from H, halogen, -CN, -CHO, -CF3 , -OH, -alkyl of Cx-Cg, alkoxy of Cx-Cg, -NH2 or -N02; or a pharmaceutically acceptable salt thereof. Preferred compounds include those having the formula: wherein: Rx is selected from H, halogen, -CF3, -OH, -alkyl of Cx-C10, preferably-Ci-Cg alkyl, -S-C-C10 alkyl, preferably -S-cycloalkyl Cg, Cx-C10 alkoxy, preferably Ci-Cg alkoxy, -CN, -N02, -NH2, phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, S-benzyl; or a ring portion of groups a), b) or c), below, attached directly to the indole ring or linked to the indole ring by a bridge -S-, -O- or - (CH2) n-; a) furan, pyrrole or thiophene, which is optionally substituted by 1 to 3 substituents which are selected from halogen, Cx-CxO alkyl, preferably Cx-C17 alkyl Cx-CXo alkoxy, preferably Ci-Cg alkoxy, -N02 , -NH2, -CN, -CF3; or b) pyridine, pyrimidine, piperidine or morpholine, each is optionally substituted with 1 to 3 substituents which are selected from halogen, C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, C 1 -C 4 alkoxy, preferably alkoxy Cx-Cg, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or c) benzofuran, indole, naphthalene, purine or quinoline, each is optionally substituted with 1 to 3 substituents which are selected from halogen, CX-C10 alkyl # preferably CX-C6 alkyl, alkoxy preferably Cx-C6 alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or d) a portion of the formulas: Z is O O S; Rg is selected from the relevant members of the group H, -CF3, Cx-C10 alkyl, preferably Cx-CxX alkoxy alkyl, preferably Cx-C6 alkoxy, phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl or -S-benzyl , the phenyl and benzyl rings of these groups are optionally "substituted with 1 to 3 substituents which are selected from halogen, CX-C10 alkyl, preferably Ci-Cg alkyl, C ^ C ^ alkoxy, preferably Cx- alkoxy C6, -CHO, -N02, -NH2, -CN, -CF3 or -OH; R7 is selected from the relevant members of the group -OH, -CF3, Cx-Cx0 alkyl / preferably Cx-Cg alkyl, C1-C10 alkoxy, preferably Cx-C3 alkoxy, -NH2, - (CH2) "- NH2, -NH- (Cx-Cß alkyl), -N- (Cx-Cß alkyl) 2, - (CH2) n-NH- (Cx-C6 alkyl), - (CH2) n, N- ( C1-C6 alkyl) 2, phenyl, O-phenyl, benzyl or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole or morpholine, the rings of these groups are optionally substituted by 1 to 3 substituents which are selected from halogen, Cx- alkyl C10, preferably Cx-C6 alkyl, Cx-Cx0 alkoxy, preferably Cx-Ce alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, and more preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl C1-C0 I, preferably C1-C6 alkyl, Cx-Cxo alkoxy, preferably CX-C6 alkoxy -CHO, -CN, -N02, -NH2, -NH-Cj-Cg alkyl, -N (-N-S02-alkyl) Ci-Cg or -S02-Cx-C6 alkyl; R3 is selected from H, halogen, -CF3, -OH, -alkyl of CX-CX0I, Cx-Cxo alkoxy, -CHO, -C (0) CH3, -C (O) - (CH2) n-CF3, - CN, -N02, '- NH2, -NH-Cx-Cß alkyl, -N (Cx-Cß alkyl) 2f -N-S02-Cx-Cg alkyl or -S02-phenyl alkyl, phenyloxy, benzyl, benzyloxy, -C (O) -phenyl, -C (O) -benzyl, -CH2- (C3-C5 cycloalkyl), -C (0) -OH, C (O) -alkyl of -C (O) - O-C1-C6 alkyl, -C (0) -CF3, - (CH2) nS-CH2- (C3-C5 cycloalkyl), the rings of the relevant R3 groups are optionally substituted by 1 to 3 groups which are selected of halogen, CX-C6 alkyl, Cj-Cg alkoxy, -N02, -CF3, -CYO) -OH, or -OH; or a portion of the formula: * í n every time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time they occur of H, -COOH, - (CH2) n-C00H, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, Cx-C6 alkyl, -O-C1-C6 alkyl, -NH (Cx-C6 alkyl), or -N (Cx-C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CHa) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the - ^ M1 portion or a portion of the formulas: ^ A ^^ ^ = or R12 are selected from H, -CF3, Cx-Cg alkyl, - (CH2) n-C3-C6 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by to 3 groups which are selected from halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of CX-C6I -O-alkyl of Ci- Cg, -NH (C1-C6 alkyl), or -N (C * -? - C y-6 'alkyl) 2 I • L1 is selected from - (CH2) n-, -S-, -O- , -C (O) -, -C (0) -0-, - (CH2) n-0-, - (CH2) nS-; - (CH2) n-0- (CH2) n-; - (CH2) nS- (CH2) n-, - (CH2) nC (0) - (CH2) n-, - (CH2) n -0- (CH2) n-, - (CH2) nS- (CH2) n-, C (Z) -N- (R6) -, -C (Z) -N (R6) - (CH2) n-, -C (O) -C (Z) -N (R6) -, - C (0) -C (Z) -N (R6) - (CH2) n-; -C (Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (O) - (CH2) n-0-, -C (0) -N-, or - (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: T yT (lower alkyl of Ci-Cg) (lower haloalkyl of Cx-C6) Rβ, each time it occurs, is independently selected from H, -COOH, - (CH 2) n -COOH, - (CH 2) n-C (O) -COOH, tetrazole, Vo R9, each time it occurs is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) "- COOH, - (CH2) nC (0) -COOH, -alkyl of Cx-Cß , -O-Cx-C6 alkyl, -NH- (Ci-Cg alkyl), or -N (Cx-Cg alkyl) 2; R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of Cx -C ,, -0-Cx-C6 alkyl # (lower alkyl of Cx-Cß (lower haloalkyl of Cx-C3 with the proviso that the portion or combination of portions comprising R4 include an acid group selected from carboxylic acid, a tetrazole or a portion of the formulas: R5 is selected from lower alkyl of Cx-C6, lower alkoxy of Cx-C6, - (CH2) n-cycloalkyl of C3-C10, - (CH2) nS- (CH2) n-cycloalkyl of C3-C10, - (CH2) ) n-0- (CH2) n-cycloalkyl of C3-C10, - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) n-0-phenyl- CH2-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (0) -benzothiazole or a portion of the formulas - (CH2) nA, - (CH2) nSA, or - (CH2) n-0-A, where A is the portion: D is H, lower alkyl of Ci-Cg, lower alkoxy of Cx-Cß, -CF3 O- (CH2) n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by 1 to 3, preferably 1 to 2, substituents which are selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of Cx-C6, alkoxy of Cx-C3, -NH2 or -N02; or a pharmaceutically acceptable salt thereof. Compounds are still preferred which include those having the formula where : Rx is selected from H, halogen, -CF3, -OH, -alkyl of Cx-Cxo, preferably -alkyl of Cx-C6 / -S-alkyl of C? -C10, preferably -S-alkyl of Cx-C? / Alkoxy of Cx-Cx0, preferably Cx-C6 alkoxy, -CN, -N02, -NH2, phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, S-benzyl; or furan, pyrrole or thiophene, attached to the indole ring by a chemical bond or a bridge -S-, -0- or - (CH2) n-, the phenyl, benzyl, furan, pyrrole or thiophene rings, which are optionally substituted by 1 to 3 substituents selected from halogen, Cx-C10 alkyl / preferably Cx-Cß alkyl, Cx-Cxo alkoxy / preferably Cx-C6 alkoxy, -N02, -NH2, -CN, -CF3; or n is an integer from 0 to 3, preferably 1 to 3, and more preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of Cx-Cxo # preferably CX-C6 alkyl, alkoxy of L-C10, preferably Cx-C6 alkoxy, -CHO, - CN, -N02, -NH2,with.

-NH-Cx-C3 alkyl / -N (Cx-C6 alkyl) 2, -N-S02-alkyl of Cx-C6 or -S02-Cx-C6 alkyl; R 3 is selected from H, halogen, -CF 3, -OH, -C 1 -C 10 alkyl, C 1 -C 4 alkoxy, -CHO, -C (0) CH 3, -C (0) - (CH 2) n-CF 3 , -CN, -N02, -NH2, -NH-Cx-C6 alkyl / - (Cx-C6 alkyl) 2 / -N-S02-Cx-Cß alkyl or -S02-Cx-Cß alkyl / phenyl , phenyloxy, benzyl, benzyloxy, -C (0) -phenyl, -C (0) -benzyl, -CH2- (C3-C5 cycloalkyl), -C (0) -0H, C (0) -alkyl of Cx -C6, -C (0) -0-Cx-C-alkyl, -C (0) -CF3, or - (CH2) nS-CH2- (C3-C5 cycloalkyl), the rings of the relevant R3 groups optionally substituted by 1 to 3 groups selected from halogen, Cx-Cg alkyl, Cx-C6 alkoxy, -N02, -CF3, -C (0) -OH, or -OH; u a portion of the formula: n every time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time "appearing from H, -COOH, - (CH2) n-C00H, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, Cx-C6 alkyl # -O-Cx-Cß alkyl, -NH (Cx-C6 alkyl), or -N (Cx-C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L'-M1 portion or a portion of the formulas: R12 are selected from H, -CF3, Ci-Cg alkyl, - (CH2) n-C3-Cβ cycloalkyl / phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 groups which are selected from halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of Cx-Cß, -O-alkyl of Ci-Cg, -NH (alkyl) of Cx-Cg), or -N (alkyl of L1 is selected from - (CH2) n-, -S-, -O-, -C (O) -, -C (0) -0-, - (CH2) n-0-, - (CH2) nS-; - (CH2) n-0- (CH2) n-; - (CH2) nS- (CH2) n-, - (CH2) nC (0) - (CH2) n-, - (CH2) n -0- (CH2) n-, - (CH2) nS- (CH2) n-, C (Z) -N (R6) -, -C (Z) -N (R6) - (CH2) n-, -C (O) -C (Z) -N (R6) -, -C (0) -C (Z) -N (Rg) - (CH2) n-; -C (Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (O) - (CH2) n-0-, -C (0) -N-, O - (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: ((aallqquiilloo inferior of Ci-Cg) (lower haloalkyl of Ci-Cg) R8, each time it occurs, is independently selected from H, -COOH, - (CH2) n-C00H, - (CH2) n-C (0) -COOH, tetrazole, R9, each time it occurs is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of Cx-Cg, -O-Cj-Cg alkyl, -NH- (alkyl, or -N (Ci-Cgjj alkyl, -R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC ( 0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of C ^ Ce, -0-Cx-Cg alkyl, you, aaa. - • '.- ((aallqquiilloo inferior of Ci-Cg) (lower haloalkyl of Cx-C6) with the proviso that the portion or combination of portions comprising R4 include an acid group that is selected from carboxylic acid, a tetrazole or a portion of the formulas: Rs is selected from lower alkyl of Ci-Cg, lower alkoxy of Cj-Cg, - (CH2) -cycloalkyl of C3-C10, - (CH2) nS- (CH2) n-cycloalkyl of C3-C10, - (CH2) n-0- (CH2) n-cycloalkyl of C3-C10, - (CH2) n-phenyl-O-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) n-0-phenyl-CH2 phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (0) -benzothiazole or a portion of the formulas - (CH2) nA, - (CH2) nSA, or - (CH2) n-0-A, where A is the portion: - D is H, lower alkyl of Cx-C6, lower alkoxy of Cx-Cß, -CF3 O- (CH2) n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by 1 to 3, preferably ia 2, substituents that are selected from H, halogen, -CN, -CHO, -CF3 , -OH, -alkyl of Cx-Cg, alkoxy of Cx-C6, -NH2 or -N02; or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting the enzyme phospholipase activity of an enzyme, which comprises administering to a subject mammal, a therapeutically effective amount of a compound of the present invention. Methods for treating an inflammatory response or ition are also provided, which comprises administering to a mammalian subject a therapeutically effective amount of a compound of the present invention. Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided. The pharmaceutically acceptable salts of the compounds, of the compounds described herein, are also part of the present invention and can be used in the practice of the compounds and methods described herein.BRIEF DESCRIPTION OF THE FIGURES Figures 1 to 13 show schemes for the synthesis of the compounds of the present invention. The schemes presented are described in more detail in the following.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES As used herein, the terms "aryl" and "substituted aryl" are meant to include monocyclic aromatic ring and heteroaromatic ring portions, particularly including five and six membered monocyclic, and aromatic and heteroaromatic bicyclic ring moieties, particularly that they include those that have 9 to 10 atoms in the ring. Among these aryl groups are meant phenyl rings, which include those found in the phenoxy, benzyl, benzyloxy, biphenyl and other such portions. The aryl and heteroaryl groups of this invention also include the following: a) a five-membered heterocyclic ring containing one or two heteroatoms in the ring that are selected from N, S or O and include, but are not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazoline, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole or oxathiazole; or b) a six-membered heterocyclic ring containing one, two or three heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadicine, oxazine or morpholine; or c) a bicyclic ring portion optionally containing from 1 to 3 to three heteroatoms in the ring, which are selected from N, S or 0 and include, but are not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolicin, indazole, quinoline, isoquinoline, quinolicine, quinazoline, cinoline, phthalazine or naphthyridine. The "substituted aryl" groups of this invention include such portions which are optionally substituted by one to three substituents which are selected from halogen, Cx-C10 alkyl, preferably Cx-Cg alkyl, Cx-C10 alkoxy, Cx-Cg, -CHO, -COOH, esters thereof -N02, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2-CF3, -NH (CH3), etc. A preferred subset of these groups, optionally substituted as just described, includes portions formed of benzene, pyridine, naphthylene or quinoline rings. A further preferred group includes that of the furan, pyrrole, thiophene, pyrimidine and morpholine rings. A preferred group of bicyclic aromatic groups includes the benzofuran, indole, naphthalene and quinoline rings. The alkyl, alkenyl and alkynyl groups referred to herein indicate such groups having from 1 to 10, preferably from 1 to 6 carbon atoms, that they can. be linear, branched or cyclic. Unless indicated otherwise, it is preferred that the groups be linear or branched. It is understood that the halogens herein include F, Cl, Br and I. The preferred compounds of the present invention are described in Tables I-VI below. The methods for the synthesis of the compounds included in Tables I-VI are described below. The numbers of the compounds in the Tables correspond to the example numbers below that describe the synthesis of that particular compound. Table I-VI also presents data for the compounds included in the "LysoPC" assay and in the Coumarin assay (see example 88 below). In the data columns of the Tables, results of the tests are presented as a value of "IC50" which is the concentration of a compound that inhibits 50% of the activity of the enzyme phospholipase in such an assay. When a numerical value for IC50 does not appear, the term "NA" indicates that no inhibitory activity was detected for such compound in the corresponding assay, and a blank box indicates that the compound has not been tested in that assay until present. this application. '- -' • "- '-' - - ~ - - •• - • • - '* - ^ "-" - ^ j ^ a ^ ü ^^ ^^ J ^ itimimMí i - - oo ro ro CN ro H H CN LO tn co kD ro CN rt H • Ean - - H CN H CN CN CN kD CN O - - - "8 - - kD LO l H ro H kO - - - • * - iti Wlfimfiraiii kD «tf kD« tf CN? H O ro L? N 00 H o CN ro LO L? THE g ^ ¡j ^ ¡^^^^^ lüiri? i jg ^ itfaigna ^^ - 7 - LO kD a L? r- »oo in L? - - «Tf co kD? kD CN ro «tf kD D kO - - N LO? N kD «tf cr. kD? n? n H H ro • CN or • H o CN oo 00 a * t? n H kD kD CO co The compounds of the present invention are also tested for in vivo activity in an edema test in the leg of rats, according to the procedure described in Example 89. The results are presented in Table VII.

Table 7 As used herein, "phospholipase enzyme activity" means positive activity in an assay for phospholipid metabolism (preferably one of the assays described in Example 88 below). A compound has "phospholipase enzyme inhibitory activity" when inhibiting the activity of a phospholipase (preferably cPLA), in an available assay (preferably an assay described below in Example 88 or Example 89) for enzymatic activity. In the preferred embodiments, a compound has (1) an IC50 value of less than about 25 μM, preferably less than about 6 μM in the LysoPC assay; (2) an IC50 value less than about 50 μM in the vesicle assay (3) a CIS0 value of less than about 1 μM in the PMN assay; (4) an IC50 value less than about 15 μM in the Coumarin assay; and / or (5) a measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, much more preferably at least about 15% and more preferably, about 20-30%) in the carrageenan-induced paw plant test in rats. The compounds of the present invention are useful for inhibiting the activity of the enzyme phospholipase (preferably cPLA2) and are therefore useful for "treating" (i.e., treating, preventing or decreasing) inflammatory or inflammatory-related conditions or responses ( for example rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease and other diseases mediated by prostaglandins, eukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis. The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use of which use compounds of the present invention. The compounds of the present invention can be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to a compound or compounds of the present invention and a carrier), diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological affinity of the active ingredients. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may also contain other anti-inflammatory agents. Such additional factors and / or agents can be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize the side effects caused by the compound of the present invention. The pharmaceutical composition of the present invention may be in the form of a liposome in which the compounds of the present invention are combined, in addition to other pharmaceutically acceptable carriers, with antiphatic agents such as lipids which exist in aggregate form as micelles, insoluble monolayers, liquid crystals or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation, include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. The preparation of such liposomal formulations is within the skill level in the art, as described, for example, in U.S. Pat. No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incorporated herein by reference. As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a significant benefit to the patient, i.e., treatment, healing, prevention or reduction of a response or inflammatory condition, or an increase in the rate of treatment, healing, prevention or reduction of such conditions. When applied to an individual, the active ingredient, administered solid, the term refers to the ingredient only. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, either administered in combination, serially or simultaneously. In practicing the method of treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. The compounds of the present invention can be administered according to the method of the invention, alone or in combination with other therapies such as treatments using other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more anti-inflammatory agents, cytosines, lymphokines or other hematopoietic factors, the compounds of the present invention can be administered simultaneously with other anti-inflammatory agents, cytokines, lymphokines or other haematopoietic factors, thrombolytic or antithrombotic factors, or sequential way. If administered sequentially, the attending physician will decide the appropriate sequence of administration compounds of the present invention in combination with other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, thrombolytic or antithrombotic factors. The administration of compounds of the present invention used in the pharmaceutical composition or for the practice of the method of the present invention, can be carried out in various conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous or intravenous injection. When a therapeutically effective amount of the compounds of the present invention is administered orally, the compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as gelatin or an adjuvant. The tablet, capsule and powder will contain from about 5 to 95% of the compound of the present invention, and preferably from about 25 to 90% of the compound of the present invention. When administered in liquid form, a liquid carrier such as water, oil, animal or vegetable oil, such as peanut oil, mineral oil, soybean oil or sesame oil, or synthetic oils can be added. The liquid form of the pharmaceutical composition may further contain physiological saline, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of the compound of the present invention, and preferably from about 1 to 50% of the compound of the present invention. When a therapeutically effective amount of the compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, the compounds of the present invention will be in the form of a parenterally acceptable, pyrogen-free aqueous solution. The preparation of such parenterally acceptable protein solutions, having considered pH, isotonicity, stability and the like, is within the skill in the art. A preferred pharmaceutical composition for intravenous, cutaneous or subcutaneous injection could contain, in addition to the compounds of the present invention, an isotonic vehicle such as sodium chloride injection solution, Ringer injection, dextrose injection, dextrose and sodium chloride injection, Lactose-free Ringer injection or other vehicle, as is known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants or other additives known to those skilled in the art. The amount of compounds of the present invention in the pharmaceutical composition of the present invention will depend on the nature and severity of the condition to be treated, and on the nature of previous treatments which the patient has undergone. Finally, the attending physician will decide the amount of compound of the present invention with which to treat an individual patient. Initially, the attending physician will administer low doses of the compound of the present invention and observe the patient's response. Larger doses of the compounds of the present invention can be administered until the optimal therapeutic effect for the patient is obtained, and at that point the dosage will no longer be increased. It is contemplated that the various pharmaceutical compositions used for the practice of the method of the present invention will contain from about 0.1 μg to about 100 mg (preferably from about 0.1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of the compound of the present invention, per kg of body weight. The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease in question and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. The attending physician will finally decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.

Methods of synthesis for examples 1-87 The compounds of the present invention can be prepared according to the following methods. The temperatures are in degrees Celsius.

METHOD A The indole-2-carboxylic acid ethyl ester I 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 and then oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilylamide (KHMDS) in THF, followed by reaction with a chloroformate in the presence of a base, such as triethylamine, produces carbamate III. III is converted to bromide IV in two steps: (1) reduction with sodium borohydride in an alcohol solution, and (2) reaction with carbon tetrabromide in the presence of a phosphine reagent such as bis (diphenylphosphino) propane in dichloromethane. The displacement of the bromine in IV with potassium phenoxide, prepared by reaction of a phenol with KHMDS, in a suitable solvent such as THF or DMF, provides ether V. V can be converted to trifluoromethyl ketone VII or carboxylic acid IX with procedures different The reaction of V with trifluoromethyltrimethylsilane (TMSCF3) in the presence of tetrabutylammonium fluoride affords trifluoromethyl alcohol, which is then oxidized with periodinane (Dess-Martin reagent) in dichloromethane to provide the ketone VI. In this step, the carbamate can be removed with trifluoroacetic acid (TFA) or with a base 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 produce VII. Alternatively, V may be deprotected with TFA or an aqueous base, and then reacted with alkyl bromide to provide VIII, which is oxidized with sodium chlorite in aqueous THF to provide acid IX.

METHOD B The ethyl ester of 2-indolylcarboxylic acid I is deprotonated with a strong base such as sodium hydride (NaH) in THF and then reacted with a suitable alkyl bromide to provide X. The hydrolysis of X _ with an aqueous base such as Sodium hydroxide and the reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethylcarbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane, provides the amide XI. XI is hydrolyzed to the corresponding acid XII in an aqueous base such as sodium hydroxide.

METHOD C Indole I can be brominated at position 3 by reaction with a bromine or with N-bromosuccinimide in a suitable solvent such as carbon tetrachloride or dichloromethane to provide bromide XIII. Reaction of XIII with a suitable alkyl bromide in the presence of a strong base such as NaOH in THF or DMF provides the indole XIV. Palladium mediated coupling of XIV with a suitable alkene in the presence of phosphine and a base such as triethylamine, produces XV indole substituted in the 3-position. It can be converted into two-step reactions: (1) hydrolysis with an aqueous base such as NaOH and (2) coupling with an amine in the presence of carbodiimide such as EDCI. The ester XIV can be converted to the lithium salt XVIII by hydrolysis with an aqueous base and then reaction with lithium hydroxide in a suitable solvent such as ether. Formation of the lithium salt with n-butyllithium in a suitable solvent such as THF, and then acylation with an acyl chloride in THF, provides the ketone XIX. The carbodiimide catalyzed coupling (EDCI) of XIX and a suitable amine provides the amide XX.

METHOD D Indole I can be converted to XXI in two steps: (1) reduction with LAH in a solvent such as THF, and (2) silylation with t-butyldimethylsilyl chloride (TBDMSCI) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of XXI with Grignard reagent such as ethylmagnesium bromide in a solvent such as THF at -60 ° C, the acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ester and finally alkylation over nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF, provides the ketone XXII. The silyl group is removed in XX using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol * is then converted to the bromide using carbon tetrabromide and bis (diphenylphosphino) ethane in a solvent such as dichloromethane to provide the bromide XXIII. Displacement of the bromine of XXIII with a thiol compound in the presence of a base such as Cs2C03 or with an alcohol in the presence of a strong base such as NaH in DMF, provides XXIV (sulfide, or ether, respectively.

METHOD E The aldehyde II, prepared by the method A, can be alkylated by 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 such a solvent as DMF to provide XXV. XXV can be converted to an XXVI unsaturated acid, by two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) hydrolysis by aqueous sodium hydroxide. The coupling reaction of XXVI with an amine catalyzed by a diimide such as EDCI (dimethylaminopropylethylcarbodiimide hydrochloride), followed by hydrolysis with an aqueous base such as sodium hydroxide, provides XXVII.

METHOD 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 provides alcohol XXVIII. Protection of nitrogen XXVIII with t-butoxycarbonyl (BOC) using di-t-butyldicarbonate ((BOC3) 0) in the presence of a base such as triethylamine, provides the carbamate XXIX. The hydroxyl group in XXIX is mesylated using benzyl chloride and triethylamine in a solvent such as dichloromethane, and then displaced either by a thiol or an alcohol, as described in Method B to produce indoline XXX. Deprotection of XXX using trifluoroacetic acid provides XXXI, which is acylated (acyl chloride), triethylamine, dichloromethane) or alkylated (alkyl halide, K2C03, DMF) to provide XXXII or XXXIII, respectively.

METHOD G The carboxylic acid XXXIV is converted to the aldehyde XXXV in two steps: (1) reaction with N, 0-dimethylhydroxyamine in the presence of EDCI in a solvent such as dichloromethane, and (2) reduction with diisobutylaluminum hydride (DIBAL) in a solvent such as THF. Treatment of XXXV with trimethyl phosphonoacetate in the presence of a strong base such as KHMDS in a solvent such as THF results in the formation of the XXXVI ester. Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inert solvent such as toluene, provides XXXVII. Nitrogen alkylation of XXXVII under conditions described in method F, and then hydrolysis of the ester with an aqueous base such as NaOH, provides acid XXXVIII. XXXVIII can be converted to an amide XXXIX by coupling with a suitable amine such as benzylamine, in the presence of EDCI.

METHOD H The aldehyde XXXV, prepared in METHOD G, is subjected to a Wittig reaction using methyltriphenylsphosphonium iodide in the presence of a strong base such as KHMDS or NaH in a solvent such as THF to provide the alkene XL. Reduction of the nitro group of XL with iron powder in an ammonium chloride solution followed by treatment with benzyl chloroformate in the presence of a base such as triethylamine, produces the carbamate XLl. XLl is treated with iodine in a basic solution such as aqueous NaHC03 in THF to provide the XLII iodide. Displacement of the iodine in XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH, provides alcohol XLIII.

METHOD I The indoline XXVIII, prepared in METHOD F or METHOD H. can be acylated by reaction with an acyl chloride in the presence of a base such as triethylamine or can be alkylated using alkyl halide in the presence of K2CO3 in a solvent such as DMF for produce XLIV alcohol. 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 CsC03 in a solvent such as acetonitrile, provides the ester XLV. Hydrolysis of XLV with an aqueous base such as NaOH provides the XLVI acid, which can be coupled with an amine catalyzed by a diimine such as EDCI in a solvent such as dichloromethane to provide the amide XLVII. XLVII can be alkylated on the amide nitrogen by treatment with alkyl halide and a strong base such as NaH in DMF. Hydrolysis of the resulting amide with an aqueous base such as NaOH affords XLIX acid. XLIV can also be hydrolyzed directly with NaOH to an XLVIII carboxylic acid.

METHOD J METHOD J illustrates the synthesis of substituted alpha aminophenylacetic acid esters. The ester L can be deprotonated with a strong base such as lithium diisobutylamide (LDA> in a solvent such as THF, and subsequently it is alkylated with an alkyl halide such as methyl iodide to provide Ll. Lili amine can be carried out using palladium-catalyzed hydrogenation in a solvent such as ethanol L can be oxidized to the alcohol LII using LDA and oxadridine in a solvent such as THF.The alkylation of LII with an alkylating reagent such as iodide of methyl in the presence of a strong base such as NaH in DMF, followed by catalytic hydrogenation in the presence of palladium produces the amine LIV.

METHOD K METHOD K illustrates the synthesis of substituted aminobenzoic acid esters. The monoacid LV can be converted to the LVI amide by the following steps: (1) reaction with oxalyl chloride in dichloromethane to form an acid chloride, and (2) treatment with a suitable amine such as dimethylamine. The reduction of the nitro group to the amine is carried out with palladium catalyzed hydrogenation, as «< . & amp & -a & described in METHOD J. LV can be reduced to alcohol LVIII with a complex of hydroborane THF, in THF. The protection of the hydroxy group as a silyl ether using TBDMSCI in the presence of imidazole and subsequently the reduction of the nitro group (H2 / Pd-C) to the amine provides LIX. LVIII can be converted to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent such as manganese dioxide (Mn02) in ethyl acetate, and (2) the addition of the desired Grignar reagent such as methylmagnesium bromide. in THF. Oxidation of LX with Mn02 in THF and reduction of the nitro group (H2 / Pd-C) produces the ketone LXIII. The reduction of LVII (H2 / Pd-C) provides LXI.

METHOD L The alcohol LXIV prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon, 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 provide LXV. The LXV alcohol can be transformed into ether or sulfur LXVI by the procedures described in METHOD D. The deprotection of the p-methoxybenzyl group with TFA in a solvent such as dichloromethane and the subsequent alkylation in oxygen with a suitable reagent such as bromide 4-benzylbenzyl in the presence of K2CO3 in a solvent such as THF, provides LVII.

EXPERIMENTAL SECTION The following Examples further illustrate the invention.

All temperatures set forth in the Examples are in degrees Celsius. All compounds are characterized by the proton magnetic resonance spectra taken on a Varian Gemini 300 spectrometer or equivalent instruments.

EXAMPLE 1 2- (2- (l-Phenylmethoxycarbonyl-5-phenylmethoxy) indolyl) -methoxybenzoic acid Stage 1: 2- (5-phenylmethoxy) indole aldehyde 12.3 g (42 mmol) of ethyl 2- (5-phenylmethoxy) indolyl) carboxylate are dissolved in 100 ml of THF, to which 130 ml (130 mmol) of lithium aluminum hydride in 1 N solution are added. THF at 0 ° C. The reaction is stirred at this temperature for 2 hours and is suspended by slowly adding 65 ml of NaOH or 6 N solution. The product is extracted with ethyl acetate, and the organic phase is washed with aqueous ammonium chloride. Evaporation of the solvent gives a crude alcohol, which without further purification is dissolved in 400 ml of THF, 52 g of manganese oxide (IV) are added, and the mixture is stirred at room temperature overnight. Removal of manganese oxide by filtration and purification by flash chromatography using hexane: ethyl acetate 3: 1 provides 8.15 g of the title compound.

Stage 2: benzyl (1- (2-formyl-5-phenylmethoxy) indolyl) formiate To a solution of 6.9 g (27.5 mmoles) of the aldehyde from step 1 in 140 ml of THF, 61 ml (30.5 mmoles) of a 0.5 M solution of bis (trimethylsilyl) amide are slowly added. potassium in toluene at -35 ° C. After stirring at this temperature for 10 min, 4.4 ml (29.5 mmoles) of benzyl cloforomonate is added at -35 ° C, and the mixture is then heated from -35 ° C to 0 ° C for 3.5 hours. The reaction is suspended by pouring it into aqueous ammonium chloride. He Aqueous treatment and flash chromatography using toluene: 12: 1 gives 4.8 g of the title compound.

L ...

Stage 3: benzyl (1- (2-hydroxymethyl-5-phenylmethoxy) indolyl) formate 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 is added 760 mg (20 mmol) of sodium borohydride at 0 ° C. The mixture is heated at 0 ° C for 30 min and then suspended by adding aqueous ammonium chloride. Flash chromatography using hexane-ethyl acetate 2: 1 provides 2.2 g of the title compound.

Stage 4: benzyl (1- (2-bromomethyl-5-phenylmethoxy) indolyl) formate To a solution of 2.2 g (5.7 mmol) of the alcohol from step 3 and 2.05 g (5.0 mmol) of 1,3-bis (diphenylphosphino) propane in 60 ml of dichloromethane is added a solution of 2.0 g (6 mmoles) of carbon tetrabromide in 4 ml of dichloromethane at 15 ° C. The mixture is stirred at room temperature for 2 hours and 1 g (3 mmoles) of 1,3-bis (diphenylphosphino) propane is added at room temperature. After stirring for 1 hour, the reaction is suspended by the addition of aqueous ammonium chloride. Aqueous work-up and flash chromatography using hexane-ethyl acetate 4: 1 gives 1.7 g of the title compound.

Stage 5: (1- (2- (2-formylphenoxy) methyl-5-phenylmethoxy) indolyl) -benzyl formate To a solution of 439 mg (3.6 mmol) of methyl 2-hydroxybenzoate in 18 ml of THF is added 6 ml (3 mmoles) < a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene at 0 ° C. The solution is stirred at 0 ° C for min, to which is added a solution of 1.25 g (2.8 mmol) of the bromide, prepared in step 4, in THF at 0 ° C. The reaction is warmed to room temperature and this temperature is stirred for 2 hours. After aqueous treatment (NH4Cl / ethyl acetate), the organic solvent is collected, dried over sodium sulfate and evaporated. The product is solidified and washed with ethyl acetate: hexane 1: 1. «Yield, 690 mg (51%).

Stage 6: Dissolve 120 mg (0.24 mmol) of the aldehyde from step 5 in 11 ml of THF-acetonitrile-2,2-dimethylethanol 5: 1: 5. To this solution is added a solution of 56 mg (0.5 mmol) of sodium chlorite in 0.5 ml of water and 1 drop of an aqueous solution of hydrogen peroxide. After 4 hours, another 56 mg (0.5 mmol) of sodium chlorite is added. The mixture is stirred at room temperature for three days. Aqueous work-up and flash chromatography using hexane: ethyl acetate-acetic acid 2.5: 1: 0.05 gives 110 mg of the title compound.

EXAMPLE 2 4- (2- d-Phenylmethoxycarbonyl-5-phenylmethoxy) indolyl) methoxy-benzoic acid The title compound is prepared according to the procedure described in Example 1. but using 4-hydroxybenzaldehyde.

EXAMPLE 3 3 - (2- (1-f-enylmethoxycarbonyl-5-f-enylmethoxy) indolyl) methoxy-benzoic acid The title compound is prepared according to the procedure described in Example i. but using 3-hydroxybenzaldehyde.

EXAMPLE 4 (1- (2- (2- (l-oxo-2.2.2-trifluoroethyl) phenoxy) methyl-5-phenylmethoxy) indolyl) benzyl formate Step 1: (1- (2- (2- (l-hydroxy-2.2.2-trifluoroethyl) phenoxy) methyl-5-phenylmethoxy) indolyl) -benzyl formate A solution of 0.4 g (0.8 mmol) of the aldehyde prepared in the step of Example 1 in 4 ml of THF is cooled to 0 ° C. To this is added 0.24 ml (1.6 mmoles) of tr-ifluoromethyl trimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate. The reaction is stirred for 2.5 h at 0 ° C and an additional 0.2 ml (1.3 mmol) of < trifluoromethyltrimethylsan and 5 mg of tetrabutylammonium fluoride trihydrate. After stirring at 0 ° C for 2 hours, the reaction is treated with aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel using hexane-ethyl acetate 4: 1 gives the corresponding TMS ether. Treatment of TMS ether with 1.3 ml of a 1 N HCl solution at room temperature, aqueous treatment using brine and ethyl acetate, and chromatographic purification using hexane-ethyl acetate 3: 1 provides 230 mg of the title compound.

Stage 2 : To a solution of 150 mg (0.27 mmol) of trifluoroethanol, prepared in step 1, in 5.5 ml of dichloromethane, 255 mg (0.6 mmol) of the Dess-Martin periodontal are added. The mixture is stirred at room temperature for 1 hour, and then partitioned between aqueous NaHCO3 and ethyl acetate. The organic phase is washed once with aqueous NaHCO 3 and purified by chromatography using 3: 1 hexane-ethyl acetate to provide 150 mg of the title compound.

EXAMPLE 5 «Acid" 3- (2- (l-benzyl-5-benzyloxy) indolecarboxamido) benzoic acid Stage I: ethyl 2- (l-benzyl-5-benzyloxy) indolecarboxylate To a solution of 1 g (3.4 mmol) of ethyl 5-benzyloxyindole-2-carboxylate in 12 ml of DMF, sodium hydride (0.163 g, 60% dispersion in oil, 4.07 mmol) is added at room temperature. The reaction is stirred for 30 minutes. Benzyl bromide (0.44 ml, 3.73 mmol) is added and at that time the reaction is stirred for another hour. Upon completion of the reaction (monitored by CCD = 0.5 Rf in hexane: ethyl acetate 3: 1), it is suspended with water, extracted with ethyl acetate (3X). The organic layers are dried over magnesium sulfate, concentrated and used for the next stage.

Stage 2: 2- (l-benzyl-5-benzyloxy) carboxylic acid The ester (3.4 mmoles), prepared in step 2, is dissolved in 20 ml of THF, 20 ml of methanol and then 15 ml of 1 N NaOH are added. The reaction mixture is stirred at room temperature overnight, in which it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts are dried over magnesium sulfate and concentrated to give the indole acid ( 1.14 g, 94.2%, CCD = 0.5 Rf in hexane: ethyl acetate '1: 1 with acetic acid).

Stage 3: Ethyl 3- (2- (l-benzyl-5-benzyloxy) indolcarboxamido) benzoate The acid (0.54 g, 1.5 mmol) of step 2, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0.018 g, 0.15 mmol) is stirred. ) and ethyl 3-aminobenzoate (0.27 g, 1.66 mmol) in 9 ml of tetrahydrofuran at room temperature overnight. 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 is purified on silica gel using 3: 1 hexane: ethyl acetate to provide the pure amide (0.578 g, 76%, CCD = 0.4 Rf in hexane: ethyl acetate 3: 1).

Stage 4: The ester (0.578 g, 1.15 mmoles), prepared in step 3, is dissolved in 13.6 ml of THF, 13.6 ml of methanol and then 9.6 ml of 1 N NaOH (9.6 ml) is added. The reaction mixture is stirred at room temperature overnight, at which time it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate. (3X), the organic extracts are dried over magnesium sulfate and concentrated to give the title compound (0.437 g, 80%, CCD = 0.5 Rf in hexane: ethyl acetate 3: 1 with 1% acetic acid).

Examples 6, 7, 8, 9, 10 and 11 are prepared by the procedures of Example 5 using suitable amines and alkyl halides.

EXAMPLE 12 3- (2- (3- (2,4-bis (1,1-dimethylpropyl) phenoxyacetyl) -5-methoxy-1-methyl) indole) methylthioacetamido-4-methoxybenzoic acid Stage 1: 2- (5-methoxy) indolylmethanol Dissolve ethyl 5-methoxy-2-indolecarboxylate (30 g, 102 mmol) in 250 ml of THF and cool to 0 ° C, and add lithium aluminum hydride (LAH) (255 ml of a 1.0 M solution). in THF) by means of the addition funnel, for 40 minutes. The reaction is stirred an additional 2 hours at 0 ° C and then worked up with the addition of 190 ml of 4 N NaOH. The resulting salts are filtered and washed with ethyl acetate (3 X 400 ml), the filtrates are combined and they are dried over MgSO4 and concentrated to provide 24.8 g of alcohol, which is used for the next reaction directly.

Stage 2: 2- (5-methoxy) indolylmethoxy-tert-butyldimethylsilane The crude indole alcohol prepared in stage 1 (6.2 g, 32.6 mmol) is dissolved in 10.5 ml of DMF. To this solution is added imidazole (5.5 g, 81.5 mmol) and t-butyldimethylsilyl chloride (5.4 g, 35.8 mmol). The mixture is stirred at room temperature overnight. 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 is purified on a column of silica gel using hexane: ethyl acetate 19: 1 to give the pure product (9.5 g, 31 mmol, 94% yield, CCD: 0.8 R in toluene: ethyl acetate 2 :1).

Step 3: 3- (2-tert-Butyldimethylsilyloxymethyl-5-methoxy) indolyl (2,4-bis (l, 1-dimethylpropyl) phenoxy) methyl ketone 2.32 g (7.95 mmol) of 2,4-bis-tert-amylphenioxyacetic acid are dissolved in 21 ml of dichloromethane, oxalyl chloride (1.4 ml, 16.1 mmol) is added followed by 0.5 ml of dimethylformamide at room temperature. After one hour, the reaction is concentrated and azeotroped with toluene and left at high vacuum for 2 hours. In another reaction vessel, the silyl-protected indole, prepared in step 2 (2 g, 6. 56 mmoles) in 20 ml of ether, to ethylmagnesium bromide (2.4 ml, of a 3M solution in ether, 7.2 mmoles) in 10 ml of ether, the latter being kept at -78CC. The reaction is stirred at -60 ° C for 2 h. To this reaction solution, the acid chloride prepared above is added slowly in 4 ml of ether. The reaction is maintained between -50 ° C and -60 ° C for another 2 h. The reaction is then suspended with saturated sodium bicarbonate. Extract with ethyl acetate (3X). The organic layers are dried over magnesium sulfate and concentrated. The crude material is purified on a column of silica gel using hexane: ethyl acetate 19: 1 to give the pure product (2.36 g, 50%, CCD: 0.15 Rf in hexane: ethyl acetate 19: 1).

Step 4 3- (2-tert-butyldimethylsilyloxymethyl-5-methoxy-1-methyl) indolyl (2,4-bis (1,1-dimethylpropyl) phenoxy) methyl ketone To the ketone (1.97 g, 3.4 mmol) of step 3 in 12 ml of DMF, sodium hydride is added at room temperature (0.163 g, dispersion in oil in 60%, 4.07 mmol). The reaction is stirred for 30 minutes. Methyl iodide (0.23 ml, 3.73 mmol) is added at this time and the reaction is stirred for another hour. Upon completion of the reaction (monitored by CCD), it is suspended with water, extracted with ethyl acetate (3X) The layers are dried over magnesium sulfate, concentrated and the crude product is used for the next stage.

Step 5: 3- (2-hydroxymethyl-5-methoxy-1-methyl) indolyl (bis-2,4- (1-dimethylpropyl) phenoxymethyl ketone) A mixture of N-methyl-indole, prepared in step 4 (2.01 g, 3.4 mmol) and tetrabutylammonium fluoride (TBAF) (8.5 ml of a 1 M solution in THF, 8.5 mmol) in 17.9 ml of THF is stirred at room temperature for one hour. At 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 is purified on silica gel using hexane: ethyl acetate 2: 1 to provide a pure alcohol (0.82 g, 60%, CCD: 0.3 Rf in hexane: ethyl acetate 2: 1 hexane).

Stage 6: methyl 3- (2- (3- (2,4-bis (1,1-dimethylpropyl) phenoxy) acetyl-5-methoxy-l-methylindolyl) methylthioacetamido) -4-methoxybenzoate The indole alcohol, prepared in step 5 (0.20 g, 0.43 mmol) is dissolved in 0.7 ml of dichloromethane and treated with triethylamine (0.1 ml, 0.64 mmol) and cooled to 0 ° C, at which time it is added mesyl chloride (0.04 ml, 0.52 mmol) for 5 minutes, followed by the addition of two drops of DMF. The reaction is stirred for an additional 2 hours at 0 ° C, and then concentrated and used directly for the next reaction. The mesylate prepared in the above manner is dissolved in 0.8 ml of DMF. The solution is degassed by bubbling nitrogen through it for 10 min. Cesium carbonate (0.25 g) is added, 1.29 mmoles) and then thiol (0.11 g, 0.43 mmol), prepared in Intermediate 1. is added. The mixture is stirred overnight, then poured into saturated ammonium chloride and extracted with ethyl acetate (3X). , it dries and concentrates. The crude material is purified on a column of silica gel- using hexane: ethyl acetate = 2: 1 to provide a pure product (0.12 g, 40%, CCD: 0.3 Rf in hexane: ethyl acetate 1: 1).

Stage 7: The ester, prepared in step 6, is dissolved (0.12 g, 0.17 mmol) in 1.0 mL of THF, 1.0 mL of methanol and then 0.4 mL of 1 N NaOH are added. The reaction mixture is stirred at room temperature overnight, at which time it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts are dried over magnesium sulfate and concentrated to give the title compound (85 mg, 72%, CCD = 0.3 Rf in hexane: ethyl acetate 1: 1 with acetic acid 1%).

EXAMPLES 13. 14. 15 and 16 are prepared in Table I by the procedure of Example 12 using ethyl 2- (5-benzyloxy) indolecarboxylate, acetyl chlorides and suitable alkyl halides.

EXAMPLE 17.

Acid3- (2- (5-benzyloxy-1- (2,4-bis (1,1-dimethyl) propyl) phenoxyacetyl) indolyl) methylthioacetamidobenzoic acid Stage 1: 2- (5-benzyloxy) indolinylmethanol - Dissolve ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) in 250 ml of THF and cool to 0 ° C, to which lithium aluminum hydride (LAH) (255 ml of a solution) is added. 1.0 M in THF) by means of an addition funnel, for 40 minutes. The reaction is stirred for 2 hours at 0 ° C and then treated by the addition of 190 ml of 4 N NaOH. The resulting salts are filtered and washed with ethyl acetate (3 × 400 ml). The filtrates are combined, dried over MgSO4 and concentrated to provide 24.8 g. This crude material is then dissolved in 260 ml of glacial acetic acid, and the resulting yellow solution is cooled to 15 ° C, sodium cyanoborohydride (18.5 g, 294 mmol) is added in portions over 10 minutes, and the resulting mixture is stirred during 3 hours.

The reaction is suspended by slowly pouring into 1.5 liters of nearly saturated NaHCO 3, extracted with ethyl acetate (3X), dried over MgSO 4 and concentrated to provide 29.6 g of an orange solid.

Stage 2: l-tert-butyl l-butynyl-3-hydroxymethyl-3-benzyloxy-2-hydroxymethylformate Dissolve 25 g (85 mmol) of the crude alcohol, prepared in stage l, and 4-dimethylaminopyridine (DMAP) (1.19 g, 9.78 mmol) in 180 ml of dichloromethane.-The solution is cooled to 0 ° C and then triethylamine is added thereto. (13.6 ml, 98 mmol). After 10 minutes of stirring, a solution of diterbutyl bicarbonate (21.3 ml, "98 mmol) dissolved in 20 ml of dichloromethane is added via a syringe pump for 2 hours. After 1 hour of stirring, the reaction is suspended by the addition of a half-saturated solution of NH4C1 and extracted with CH2C12 (3X), dried over MgSO4 and concentrated to provide 36.3 g of a yellow oil, which is purified by column chromatography using a gradient of hexane: ethyl acetate of 9: 1 to 4: 1 to 1: 1, to supply the product (15.25 g, 44%).

Stage 3: Ethyl 2- (5-benzyloxy-l-tert-butoxycarbonyl) indolyl-methyoacetate The carbamate prepared in step 2 (15.25 g, 43 mmol) is dissolved in 180 ml of dichloromethane and treated with triethylamine (9.0 ml, 64.4 mmol). The solution is cooled to -10 ° C, at which time mesyl chloride (4.3 ml, 56 mmol) is added over 5 minutes. The reaction is stirred for an additional 2 hours at -10 ° C, and then concentrated and used directly for the next displacement reaction. The mesylate prepared above is dissolved in DMF (85 ml, it is recommended that the solvent is degassed), cesium carbonate (35 g, 107.3 mmol) is added and then ethyl thioacetate (4.70 ml, 42.9 mmol) is added. The mixture is stirred for 1 day and then poured into saturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (gradient of hexane: ethyl acetate 10: 1). 4: 1) to provide 8.55 g of a yellow oily product.

Stage 4: 2- (5-benzyloxy-l-tert-butoxycarbonyl) indolyl-methylthioacetic acid To a solution of the indoline ester, prepared in step 3 (5 g, 11 mmol) in 1 M potassium hydroxide in 100 ml of methanol, add 10 ml of water. The reaction is stirred at room temperature for 2 hours, at which time it is diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts are dried over magnesium sulfate and Concentrate to provide the indoline acid (4.5 g, 95.5%, CCD = 0.5 Rf_ in hexane: ethyl acetate 2: 1 with 1% acetic acid.) The raw material is used for the next step directly.

Step 5: Ethyl 3- (2- (5-benzyloxy-l-tert-butoxycarbonyl) indolinyl) -methylthioacetamidobenzoate The acid is stirred (3 g, 7 mmol), prepared in step 4, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (1.6 g, 8.4 mmol), 4-dimethylaminopyridine (0.85 g, 7 mmol) and 3- ethyl aminobenzoate (1.27 g, 7.7 mmol) in 43 ml of tetrahydrofuran, at room temperature overnight. 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 is purified on silica gel using hexane: ethyl acetate 3: 1 to provide the product (3.4 g, 85%, CCD = 0.3 Rf in hexane: ethyl acetate 3: 1).

Stage 6: Ethyl 3- (2- (5-benzyloxy) indoliniDmethylthioacetamidobenzoate To the indole (3.4 g, 5.9 mmol) of step 5, add 24 ml of trifluoroacetic acid and the reaction is stirred for 1 hour at 0 ° C. The reaction is suspended by the addition of water and the TFA is neutralized by the addition of sodium bicarbonate, the aqueous layer is extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material is purified on silica gel using hexane: ethyl acetate 2: 1 to provide the product (2.7 g, 96%, CCD = 0.3 Rf in hexane: ethyl acetate 2: 1).

Step 7: Ethyl 3- (2- (5-benzyloxy-l- (2,4-bis (1, 1-dimethyl) propyl) -phenoxyacetyl) indolinyl) methylthioacetamidobenzoate The 2,4-bis (1,1-dimethylpropyl) phenoxyacetic acid (0.228 g, 0.78 mmol) is dissolved in 2 ml of dichloromethane, to which is added oxalyl chloride (0.14 ml, 1.6 mmol) followed by 0.1 ml of dimethylformamide at room temperature. After 1 hour, the reaction is concentrated and an azeotrope is formed with toluene and left at high vacuum for 2 hours. The indoline ester (0.308 g, 0.65 mmole) prepared in step 6, and 4-dimethylaminopyridine (0.008 g, 0.066 mmole) is dissolved in 1.2 ml of dichloromethane and then the acid chloride prepared above in 0.5 ml of dichloromethane is added. , followed by the addition of triethylamine (0.28 ml, 1.95 mmol). The reaction is stirred at room temperature overnight, and then diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material is purified on silica gel using hexane: ethyl acetate 2: 1 to give the product (0.291 g, 60%, CCD = 0.4 Rf in hexane: ethyl acetate 2: 1).

«Stage 8: The ester (0.231 g, 0.31 mmol) from step 7 is dissolved in 4.3 ml of THF, 4.3 ml of methanol and then 3.2 ml of 1 N NaOH is added. The reaction mixture is stirred at room temperature overnight, in which it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X), the organic extracts are dried over magnesium sulfate and concentrated to give the title product ( 0.207 g, 93.2%, CCD = 0.3 Rf in hexane: ethyl acetate 2: 1 with acetic acid 1.5%).

EXAMPLE 18 3- (2- (5-Benzyloxy-1- (2,4-bis (1, l-dimethyl) propyl) f-enoxyacetyl) -indolinyl) -methylthioacetamido-4-methylbenzoic acid »Stage 1: 2- (5-benzyloxy) ) ethyl indolinylmethylthioacetate N-tert-butoxycarbonyl indoline (3.0 g, 6.6 mmol) prepared in step 3 of Example 17 is added to a flask, and cooled to 0 ° C. To this reaction mixture is added 35 ml of trifluoroacetic acid and the reaction is stirred for 1 hour at 0 ° C and then 1 hour at rt. The reaction is suspended by the addition of water, and TFA is neutralized by the addition of solid sodium bicarbonate, the aqueous layer is extracted with ethyl acetate (4X) and dried over magnesium sulfate and concentrated to an orange oil. (1.85 g, 79%), which is used directly in the next stage.

Stage 2: Ethyl 2- (5-benzyloxy-l- (2,4-bis- (1,1-dimethyl) propyl) phenoxyacetyl) -indolinyl-methylthioacetate 2, 4-bis- (1) acid is stirred at 0 ° C for 45 minutes., 1-dimethyl) propyl) phenoxyacetic acid (2.0 g, 6.8 mmol), 15 ml of dichloromethane, oxalyl chloride (1.2 ml, 13.6 mmol), 0.1 ml of dimethylformamide, at which time the reaction is concentrated and an azeotrope is formed with toluene (IX) and concentrated under high vacuum for 2 hours before use. The indoline ester (1.85 g, 5.2 mmol) prepared in step 1, and 0.08 g- of 4-dimethylaminopyridine are dissolved in 15 ml of dichloromethane and then the acid chloride generated above in 5 ml of dichloromethane is added, followed by the addition of triethylamine (0.95 ml, 6.8 mmol). The reaction is stirred 16 h at rt, worked and concentrated (4.0 g, orange oil), chromatographed using a gradient of 9: 1 to 6: 1 hexane: ethyl acetate to provide the product (2.5 g, 75 %) that is used for the next stage without further purification. « Step 3: 2- (5-benzyloxy-1- (2,4-bis (1,1-dimethyl) propyl) phenoxyacetyl) -indolinyl-methylthioacetic acid Dissolve the ester (2.5 g, 3.9 mmol) prepared in step 2, in 20 ml of THF, 6 ml of methanol and then add 12 ml of IN sodium hydroxide. The resulting mixture is stirred at 24 hours at which time it is concentrated, diluted with water, acidified to pH 4 with concentrated HCl and extracted with ethyl acetate (4X), the organic extracts are dried over magnesium sulfate, Concentrate and purify via chromatography (3: 1 hexane: ethyl acetate with 1% acetic acid) to provide 1.17 g (50%) of the product as a white solid.

Stage 4: 3- (2- (5-benzyloxy-l- (2,4-bis- (1,1-dimethyl) -propyl) phenoxyacetyl) -indolinyl-methyl-methyl-methyl-thiazol-4-methyl-benzoate The acid (0.20 g, 0.33 mmol), prepared in stage 3, EDC1 (0.08 g, 0.43 mmol), DMAP (4 mg, 0.03 mmol) and methyl 3-amino-4-hydroxy benzoate (0.06 g, 0.3 i) mmoles) is dissolved in 3 ml of THF and refluxed for 16 hours.

Aqueous treatment with ammonium chloride and ethyl acetate and purification via silica gel chromatography "(hexane: ethyl acetate 3: 1) gives 0.13 g (52%) of the product as a white solid.

Stage 5: The title compound is prepared from the ester, prepared in step 4, according to the procedure described in step 3.

Examples 17 to 36 in Table 2 are prepared according to the procedures described in either Example 17 or Example 18.

EXAMPLE 37 2- (5-Benzyloxy-l- (3,5-bis (tri-loromethyl) -phenoxyacetyl) indolinyl) -methylthioacetic acid Step 1: 2- (5-benzyloxy-1- (3,5-bis (trifluoromethyl) -phenoxyacetyl) indolinyl) -methanol An oven-dried round bottom flask of 1 1, to which a magnetic stirring bar and an equalizing dropping funnel is placed, is charged with 17.0 g (59 mmoles) of 3,5-bis (trifluoromethyl) phenoxyacetic acid, 5 drops of DMF and 300 ml of anhydrous CH2C12. Oxalyl chloride (23 ml, 263 mmol) is added dropwise over 10 minutes. After stirring for 2.5 hours at room temperature, the solvent, excess oxalyl chloride, is removed in vacuo to provide acid chloride as a white solid. This is used immediately in the next reaction. A round, oven-dried round bottom flask, fitted with a magnetic stirring bar and an equalizing dropping funnel, is charged with 15.3 g (60 ml) of 2- (5-benzyloxy) indolinylmethanol, prepared in step l of example 17. DMAP (0.73 g, 6 mmol) and 300 ml of anhydrous CH2C12. After soaking at 0 ° C, a solution of 59 mmoles of the acid chloride prepared above in 100 ml of anhydrous CH2C12 is added dropwise, followed by Net3 (9 ml, 64.7 mmoles). After stirring for 1 hour at 0 ° C, the reaction mixture is washed with 100 ml of a saturated NaHCO 3 solution, 100 ml of an IN HCl solution and 100 ml of H 2 O, dried over Na 2 SO 4 and filtered. The solvent is removed in vacuo. Purification by column chromatography on silica gel using 25-40% AcOEt in hexane gives the product as a light yellow solid. Yield 22.0 g (71%).

Step 2: Ethyl 2- (5-benzyloxy-1- (3,5-bis (trifluoromethyl) - "phenoxyacetyl) indolinyl) -methylthioacetate A 500 ml round bottom flask, oven dried, with a magnetic stir bar is charged with alcohol (19.0 g, 36.15 mmol), prepared in step 1, 300 ml of anhydrous CH2C12 and Net3 (7.5 ml, 54.23 mmoles ). MsCl is added dropwise for 2 minutes, and the reaction mixture is stirred at room temperature for 10 minutes. The solution is diluted with 500 ml of CH2C12 and washed with 100 ml of an IN HCl solution and 100 ml of a saturated NaHCO3 solution. The CH2C12 solution is dried over Na2SO4 and filtered. The solvent is removed and the mesylate is used in the next step without further purification. A 500 ml round bottom flask, dried in the oven, to which a magnetic stirring bar is placed, is charged with ethyl thioacetate (4.2 ml., 38.5 mmoles) and 75 ml of anhydrous THF. After cooling in a dry ice / acetone bath, NaN (SiMe 3) 2 (1M solution in THF, 50 ml, 50 mmol) is added. After 15 minutes, a solution of the above prepared mesylate (21 g, 35 mmol) in 60 ml of anhydrous THF is added. After 15 minutes, the reaction mixture is allowed to warm to room temperature. After stirring at room temperature for 100 minutes, the reaction is refluxed for 4 hours. The solution is allowed to cool to room temperature. It is diluted with 500 ml of CHC13, washed with 200 ml of a saturated Na 2 CO 3 solution and 200 ml of an IN HCl solution. The organic solution is dried over Na2SO4 and filtered. The solvent is removed in vacuo. The crude material is purified by column chromatography on silica gel using AcOEt 15% in hexane to provide 13.8 g (63%) of product.

Stage 3: A 250 ml round bottom flask, to which a magnetic stirring bar is placed, is charged with the ester (12.45 g, 19.8 mmol), prepared in step 2, 100 ml of THF, 33 ml of MeOH and 33 ml of H20 LiOH -H20 (1.08 g, 25.7 mmol) is added and the reaction mixture is stirred at room temperature for 3 hours. The solvents are removed in vacuo. The residue is taken up in 200 ml of an IN HCl solution and extracted with AcOEt (2 x 400 ml). The combined extracts are washed with 100 ml of an IN HCl solution, dried over NaSO 4 and filtered. The solvent is removed in vacuo to provide the title compound. Yield 11.9 g (100%).

EXAMPLE 38 - (2- (5-Benzyloxy-1- (3,5-bis (trifluoromethyl) -phenoxyacetyl) -indolinyl) -methylthioacetamido) -benzene-1,3- < dicarboxylic Step 1: 5- (2- (5-benzyloxy-l- (3,5-bis (trifluoromethyl) phenoxyacetyl) indolinyl) -methylthioacetamido) -benzene-1,3-dicarboxylate A 100 ml round-bottom flask, oven-dried, to which a magnetic stirring bar is placed, is charged with acid (1.2 g, 2 mmol), prepared in step 3 of example 37. 40 ml of anhydrous THF , EDCI (0.544 g, 2.8 mmoles), DMAP (0.024 g, 0.2 mmoles) and 5-amino-l, 3- benzenedicarboxylic acid (0.46 g, 2.2 mmoles). The reaction mixture is heated to reflux until no change is detected by CCD. The solvent is removed in vacuo. The residue is dissolved in 200 ml of CH 2 C 12, washed with 25 ml of an IN HCl solution, dried over Na 2 SO and filtered. The solvent is removed in vacuo. The crude material is purified by column chromatography on silica gel using 1-2% MeOH in CH2C12 to provide 1.2 g (77%) of the product.

Stage 2 : A 25 ml round-bottomed flask with a magnetic stir bar is charged with the ester (0.6 g, 0.76 mmol) prepared in step 1, 7.5 ml of THF, 2.5 ml of MeOH and 2.5 ml of H20 LiOH -H20 (0.084 g, 2 mmol) is added and the reaction mixture is stirred at room temperature for 6 hours. The solvents are removed in vacuo. The residue is taken up in 10 ml of an IN HCl solution and extracted with AcOEt (2 x 50 ml). The combined extracts are dried over Na2SO4 and filtered and removed in vacuo. The crude material is purified by column chromatography on silica gel (eluent: 5% MeOH in CHC13 + 0.5-0.7% AcOH) to give 0.28 g (46%) of the title compound.

EXAMPLES 39. 40. 43 in Table 3 are prepared according to the procedures described in Example 38.

EXAMPLE 41 - (2- (5-Benzyloxy-l- (3,5-bis (trifluoromethyl) -phenoxyacetyl) indolinyl) -methylthioacetamido) -3-hydroxymethylbenzoic acid Step 1: 5 - (2 - (5-benzyl or methyl 1- (1- (3,5-bis (trifluoromethyl) -phenoxyacetyl) indolinyl) -methylthioacetamido) - 3-tert-butyldimethylsilyloxymethylbenzoate This compound is prepared according to the procedure described in step 1 of example 38.

Step 2: 5- (2 - (5-Benzyl-1-oxy-1 - (3,5-bis (trifluoromethyl) -phenoxyacetyl) indolinyl) -methylthioacetamido) -3-hydroxymethylbenzoate methyl A 25 ml round bottom flask, oven dried, with a magnetic stirring bar, is charged with the protected silyl ester (1.32 g, 1.5 mmol), prepared in step 1, in 10 ml of anhydrous THF and TBAF (1M solution in THF, 2.5 mmoles equivalent). The reaction mixture is stirred at room temperature for 3 hours. The solvent is removed in vacuo. The oily residue is purified by column chromatography on silica gel using AcOEt 0-30% in CH3C12 to provide 0.94 g (92%) of the desired product.

Stage 3: The title compound is prepared according to the procedure described in step 2 of Example _38.

EXAMPLE 42 is prepared in Table 3 according to the procedures described in Example 41.

EXAMPLE 44 Acid 5 - (2 - (5-hydroxy-1- (1,3-bis (trifluoromethyl) phenoxyacetyl) indolinyl) -methylthioacetamido) benzene-1,3-dicarboxylic acid Step 1: 2- (5-hydroxy-1- (1,3-bis (trifluoromethyl) phenoxyacetyl) indolinyl) -methanol A Parr hydrogenation vessel of 500 ml is charged with 2- (5-benzyloxy-1 - ( 3, 5-bis (rif luoromethyl) phenoxyacetyl) -indolinyl) -methanol (10 g, 19.1 mmol) prepared in step 1 of example 37. 1.0 g of 5% Pd on carbon, 150 ml of AcOEt and 100 ml of MeOH , and subsequently hydrogenated at 345 kPa (50 psi) for 18 hours. The reaction mixture is filtered through Celite and concentrated in vacuo to provide the crude product. This is used in the next reaction step without further purification.

Step 2: 2- (5- (4-methoxy) benzyloxy -1- (3,5-bis (trifluoromethyl) phenoxyacetyl) indolinyl) -methanol A 1 1 round bottom flask, oven dried, is placed a magnetic stirring bar and a reflux condenser is charged with alcohol (8.56 g, 19.7 mmol), prepared in stage 1, 200 mesh, K2C03 (6.53 g, 47.2 mmoles), KI (3.91 g, 23.6 mmol) and finally with p-methoxy benzyl chloride (3.2 ml, 23.6 mmol) in 450 ml of anhydrous acetonitrile. The reaction mixture is heated to reflux for 4 hours. The reaction mixture is divided between 500 ml of AcOEt and 200 ml of H20. The aqueous layer is extracted with AcOEt (3 x 500 ml). The combined AcOEt extracts are washed with 500 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification of the residue by column chromatography on silica gel (eluent: 40% AcOEt in hexane) provides the desired product. Yield 8.7 g (83%).

Step 3: 5- (2- (5- (4-methoxy) benzyloxy-1- (3,5-bis (trifluoromethyl) phenoxyacetyl) indolinyl) -methylthioacetamido) -benzene-1,3-dicarboxylic acid methyl ester A 100 ml round-bottom flask, dried in the oven, to which a magnetic stirring bar is placed, is charged with alcohol (3.2 g, 5.77 mmole), prepared in step 2, and 44 ml of anhydrous CH2C12. The reaction mixture is cooled to 0 ° C and added Anhydrous Et3N (1.2 ml, 8.61 mmol) followed by MsCl (0.53 ml, 6.84 mmol). The reaction mixture is stirred at 0 ° C for 5 minutes. The reaction mixture is divided between 100 ml of CH2C12 and 50 ml of H2O. The aqueous layer is extracted with CH2C12 (3 x 100 ml). The combined CH 2 Cl extracts are washed with 100 ml of an IN HCl solution, 100 ml of a saturated NaHCO 3 solution, 100 ml of H 2 O, 100 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo to provide the mesylate. This is used in the next reaction step without further purification. A 100 ml round-bottom flask, oven-dried, with a magnetic stirring bar and a reflux condenser, is charged with the mesylate prepared before (3.60 g, 5.70 mmol), anhydrous Cs2CO3 (5.19 g, 15.9 mmoles) and 20 ml of anhydrous DMF. The reaction solution is passed through N2 for 15 minutes. Methyl 5-thioacetamido-1,3-benzenedicarboxylate, prepared in intermediate 2, is added in one portion and the reaction mixture is heated at 50 ° C for 18 hours. The reaction mixture is divided between 500 ml of AcOEt and 200 ml of H20. The aqueous layer is extracted with AcOEt (3 x 100 ml). The combined AcOEt extracts are washed with 100 ml of a saturated Na 2 CO 3 solution, 100 ml of H 2 O, 500 ml of brine, dried over. Na2SO4 and filtered. The solvents are removed in vacuo. Purification of the residue by column chromatography on silica gel (eluent: AcOEt in CH2C12) gives the product. Yield 2.5 g (53%).

Step 4: 5- (2- (5-hydroxy-1- (3,5-bis (trifluoromethyl) -phenoxyacetyl) indolinyl) methylthioacetamido) benzene-1,3-dicarboxylic acid A 100 ml round-bottom flask, oven-dried, to which a magnetic stirring bar is placed, is charged with the ester (2.60 g, 3.17 mmol), prepared in step 3, and 30 ml of anhydrous CH2C12. 25 ml of TFA are added to the reaction mixture in several portions, for 1 minute.

The reaction mixture is poured into 500 ml of a saturated NaHC03 solution and extracted with CH2C12 (3 x 100 ml). The combined extracts of CH2C12 are washed with 200 ml of a saturated Na2CO3 solution, 200 ml of H20, 500 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. > Purification of the residue by column chromatography on silica gel (eluent: 12.5% -20% AcOEt in CH2C12) provide the product. Yield 1.5 g (68%).

Stage 5: A 25 ml round bottom flask with a magnetic stir bar is charged with the ester (270 mg, 0.40 mmol), prepared in step 4, 3.3 equivalents of LiOH hydrate, 3.6 ml of THF, 1.2 ml of MeOH and 1.2 ml of H20. The reaction mixture is heterogeneous with a white solid suspended in the solution. After stirring for 4 hours, more solvents are added in 3: 1: 1 = THF: MeOH: H20 to produce a clear solution. The reaction mixture is stirred at room temperature for 18 hours and monitored by CCD. The reaction mixture is acidified with a solution of IN HCl to pH = 2, or with acetic acid pH = 4, and then divided between 20 ml of AcOEt and 20 ml of H20. The aqueous layer is extracted with AcOEt (3 x 20 ml). The combined AcOEt extracts are washed with 20 ml of H20, 20 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification of the residue by column chromatography on silica gel followed by recrystallization from acetone / hexane gives 120 mg of the title compound (50%).

EXAMPLE 45 - (2- (5- (3,5-Dibromo) benzyloxy -1- (3,5-bis (trifluoromethyl) phenoxyacetyl) indolinyl) methylthioacetamido) -benzene-1,3-dicarboxylic acid Step 1: 5- (2- (5- (3,5-dibromo) benzyloxy-1- (3,5-bis (trifluoromethyl) phenoxyacetyl) indolinyl) methylthioacetamido) -benzene-1,3-methyl-dicarboxylate » A 25 ml round bottom flask, dried in the oven, to which a magnetic stirring bar and a reflux condenser is placed, is charged with 5- (2- (5-hydroxy-1- (3,5-bis) (trifluoromethyl) -phenoxyacetyl) indolinyl) methylthioacetamido) -benzene-1,3-dicarboxylic acid methyl ester (0.19 g, 0.27 mmol) prepared in step 4 of example 4. 2.4 equivalents of 200 mesh K2C03 and 1.2 equivalents of bromide of 3, 5-dibromobenzyl in 7.5 ml of anhydrous acetonitrile. The reaction mixture is heated at 70 ° C for 2 hours. The reaction mixture is divided between 30 ml of AcOEt and 20 ml of H20. The aqueous layer is extracted with AcOEt (3 x 30 ml). The combined AcOEt extracts are washed with 50 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification of the residue by column chromatography on silica gel using AcOEt 15% in dichloromethane gives 0.20 g of the product (77%).

Stage 2 : The title compound is prepared from the ester, prepared in step 1, according to the procedure described in step 5 of example 44.

EXAMPLES 46 to 50 are prepared in Table 4, according to the procedures described in Example 44. but using the corresponding alkylating reagent.

EXAMPLE 51 3- (2- (5-benzyloxy-1- (4-benzybenzoyl) indolinyl) -methylthioacetamido) methyl benzoate 4-Benzylbenzoic acid (0.19 g, 0.91 mmol) is dissolved in 2.3 ml of dichloromethane, and then oxalyl chloride (0.16 ml, 1.82 mmol) is added followed by 0.5 ml of dimethylformamide, at room temperature. After 1 hour, the reaction is concentrated and azeotroped with toluene, and left at high vacuum for 2 hours. Ethyl 3- (2- (5-benzyloxy) methylthioacetamido-benzoate (0.308 g, 0.65 mmol), prepared in step 6 of example 17, and 4-dimethylaminopyridine (8 mg, 0.066 mmol) in dichloromethane (1.2 are dissolved. ml) and then the acid chloride prepared above in 0.5 ml of dichloromethane is added, followed by the addition of triethylamine (0.28 ml, 1.95 mmoles) .The reaction is stirred at room temperature overnight.The reaction is diluted with ethyl acetate. Ethyl 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 product of the product. title (81.7%, CCD = 0.4 Rf in 2: 1 hexane: ethyl acetate).

EXAMPLE 52 3- (2- (5-Benzyloxy-1- (4-benzylbenzoyl) -indolinyl) -methylthioacetamido) -benzoic acid The ester is dissolved (0.354 g, 0.53 mmole) prepared in example 51. in 5.6 ml of THF, 5.6 ml of methanol and then 4.2 ml of IN NaOH are added. The reaction mixture is stirred at room temperature overnight, at which time it is concentrated, diluted with water, acidified to pH 5 with 10% HCl and extracted with ethyl acetate (3X). The organic extracts are dried over magnesium sulfate and concentrated to give the title product (0.32 g, 94.4%, CCD = 0.3 R £ in 2: 1 hexane: ethyl acetate with 1.5% acetic acid).

EXAMPLES 53 to 58 in Table 5 are prepared according to the procedures described in Examples 51 and 52.

EXAMPLE 59 3- (2- (5-Benzyloxy-1- (2-naphthoxyacetyl) - "indolinyl) methylthioacetamido) -4-methoxybenzoic acid Stage 1: methyl 3- (2- (5-benzyloxyindolinyl) -methylthioacetamido) -4-methoxybenzoate This compound is prepared according to the procedures described in step 6 of example 17. but with methyl 4-methoxybenzoate.

Step 2: Methyl 3- (2- (5-benzyloxy-l- (2-naphthoxyacetyl) -indolinyl) methylthioacetamido) -4-methoxybenzoate The indole ester (0.22 g, 0.45 mmole) prepared in step 1, acid 2 Naphthoxyacetic acid (0.11 g, 0.53 mmol), EDCI (0.10 g, 0.53 mmol) and DMAP (5 mg, 0.04 mmol) are weighed into a flask which is equipped with a condenser, nitrogen purge, and then 5 ml of nitrogen is added. tetrahydrofuran, and the reaction is refluxed for 18 hours; the reaction is diluted with half-saturated ammonium chloride and ethyl acetate, extracted 3X with ethyl acetate, dried over magnesium sulfate, concentrated to give (0.30 g, 100% crude) a white solid which is used without purification.

Stage 3: The ester (0.12 g, 0.20 mmol), prepared in step 2, is dissolved in THF / methanol, and then 0.8 ml of IN sodium hydroxide is added, and the resulting mixture is stirred at 16 hours at RT and an additional 5 hours at 45 ° C, the treatment affords 0.12 g of a yellow solid which is purified by means of preparative CCD (1: 1 hexane: ethyl acetate with 1% acetic acid) to provide 0.12 g of the title product (95%). .

EXAMPLES 60 to 63 in Table 5 are prepared according to the procedures described either in Example 59 or Example 51 and 52.

EXAMPLE 64 3- (2- (5-Benzyloxy-l-tert-butoxycarbonyl) -indolinyl) -methylsulfonyl acetamidobenzoic acid Stage I: Ethyl 3- (2- (5-benzyloxy-1-tert-butoxycarbonyl) -indolinyl) -methylsulfonyl acetamidobenzoate To a solution of ethyl 3- (2- (5-benzyloxy-l-tert-butoxycarbonyl) -indolinyl) -methylthioacetamidobenzoate (0.05 g, 0.09 mmol), prepared in step 5 of, example 17. in 0.1 ml of dichloromethane at room temperature, m-chloroperbenzoic acid (0.06 g of m-cPBA 60%, 0.21 mmole) is added and the reaction is stirred overnight. The next day, the reaction is suspended 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%, CCD = 0.3 Rf in 1: 1 hexane: ethyl acetate) is used for the next reaction directly.

Stage 2 : The title compound is prepared according to the procedure described in step 3 of example 59.

EXAMPLES 66 and 65 are prepared according to the procedures described in example 18.

EXAMPLE 67 2- (2- (5-Benzyloxy-l- (2,4-bis (1, i-dimethyl) propyl) phenoxyacetyl) indolinyl) -methylthiobenzoic acid Step 1: 5-benzyloxy-l- (2,4-bis (1,1-dimethyl) propyl) phenoxyacetyl) -2-hydroxymethylindoline Weigh the diisopropylethylamine (3.5 ml, 20.5 mmol), DMAP (0.25 g, 2.05 mmol) and the indoline alcohol (4.53 g, 17.7 mmol), prepared in stage 1 of example 17. in a flask which is purged with nitrogen and cooled to 0 ° C, at which time a solution at 0 ° C of 20.5 ml of di-tert-amylofenoxiacetyl chloride in 50 ml of CH2C12 is added via a cannula. The resulting solution is allowed to warm to room temperature overnight and is then suspended by the addition of semi-saturated ammonium chloride and CH2C12, the solution is extracted with CH2C12 (3X), the combined layers are dried over magnesium sulfate and concentrated to provide 10.4 g of a yellow foam which is purified via chromatography using a gradient (hexane: ethyl acetate, 7: 1 to 3: 1 to 1: 1). ) to provide 3.62 g of the product.

Step 2: Methylsulfonate 2- (5-benzyloxy-1- (2,4- 5-bis (l-l-dimethyl) propyl) phenoxyacetyl) indolinylmethyl To a solution of the alcohol (1.2 g, 2.26 mmol) in 15 ml of CH2C12, prepared in step 1, triethylamine (0.44 ml, 3.16 mmol) is added. The solution is brought to -50 ° C and then mesyl chloride (0.23 ml, 2.93 mmol) is added. The mixture is stirred for 2 hours at -50 ° C, suspended with saturated ammonium chloride and allowed to reach RT. The mixture is taken up in 50 ml of CHC13, washed with saturated sodium bicarbonate (1 X 10 ml), brine (1 X 10 ml), dried (MgSO, filtered and concentrated to provide the product (1.19 g, 86%).

Step 3: methyl 2- (2- (5-benzyloxy-1- (2,4-bis (1-l-dimethyl) propyl) phenoxyacetyl) indolinyl) methylthiobenzoate To a solution of the mesylate (0.54 g, 0.89 mmol), prepared in step 2, in 2 ml of degassed DMF, add CsC03 (0.724 g, 2.22 mmol) and methyl thiosalicylate. (0.134 mL, 0.98 mmol). The mixture is stirred 4 hours, it is taken In 20 ml of ethyl acetate, wash with brine (3 X 3 ml), dry (MgSO 4), filter and concentrate. Chromatography (gradient hexane: ethyl acetate 15: 1 to 4: 1) gives 0.53 (86%) of the title compound as a yellow oil.

Stage 4: The title compound is prepared according to the procedure described in step 3 of example 59.

EXAMPLE 68 is prepared according to the procedures described in example 67.

EXAMPLE 69 3- (N- (2- (5-benzyloxy-l- (2,4-bis (l.l-d ime t i l) p rop i l) f enoxi a c e t i l) indo l) -methylthioethyl) aminobenzoic acid The title product is prepared according to the procedure described in step 3 of example 59. but using intermediate 15.

EXAMPLE 70 3-N-Methyl- (2- (5-benzyloxy-1- (2,4-bis (1, 1-dimethyl) propyl) phenoxyacetyl) indolinyl) -methylthioacetamido-4-methoxybenzoic acid A 100 ml three-necked round bottom flask, dried. Baked, equipped with a stir bar and nitrogen inlet, charged with 3- (2- (5-benzyloxy-1- (2,4-bis (1, l-dimethyl) propyl) phenoxyacetyl) indolinyl) -methylthioacetamido Methyl-4-methoxybenzene (581 mg, 0.757 mmol), prepared in the synthesis of example 20 using the procedures described in example 18. and 10 ml of THF are added by means of a syringe. To the resulting yellow solution is added NaH (60% suspension in mineral oil, 39 mg, 0.975 mmol). The reaction mixture is stirred at 25 ° C for 1.5 hours to provide a clear suspension. Methyl iodide (161 mg, 1.14 mmol) is added, and the reaction mixture is stirred at 25 ° C for 2 days. After cooling to 0 ° C, 10 ml of water are added, followed by 50 ml of semi-saturated ammonium chloride and 100 ml of AcOEt. The layers are separated and the aqueous phase is extracted once with 50 ml of AcOEt. The combined organic phases are dried (sodium sulfate), filtered and concentrated to provide 0.6 g of the crude product as an orange oil. This material is dissolved in 15 ml of THF and 10 ml of methanol, and 7 ml of NaOH IN solution is added under nitrogen. After stirring for 2 hours at 25 ° C, the reaction mixture is concentrated to dryness on a rotary evaporator, and 100 ml of IN HCl and 100 ml of AcOEt are added. The layers are separated, and the organic phase is dried (magnesium sulfate), filtered and concentrated. 0.565 g of crude material obtained is purified by means of column chromatography on silica gel (eluent: chloroform to MeOH 3% in chloroform) to give the title compound (0.415 g, 70% yield). EXAMPLE 71 is prepared according to the procedures described in Example 70 but using allyl bromide.

EXAMPLE 72 3 - (2 - (5-Benzyloxy-1 - (2 - (4-pyridin) ethyl) -indolinyl) -methylthioacetamidobenzoic acid Stage. . 3 - (ethyl 2 - (5-benzyloxy- l- (2- (4-pyridin) ethyl) -indolinyl) -methylthioacetamidobenzoate To a solution of ethyl 3- (2- (5-benzyloxy) indolinyl) -methylthioacetamidobenzoate (0.30 g, 0.63 mmol), prepared in step 6 of example 17 in 3.0 ml of dichloromethane and 2.0 ml of acetic acid, 4-vinylpyridine (0.08 ml, 0.65 mmol) is added. The reaction is stirred at room temperature overnight. The reaction is suspended with half-saturated sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material is purified on silica gel using a 2: 1 gradient of hexane: ethyl acetate to 100% ethyl acetate to give 0.23 g of the product (25%, CCD = 0.7 Rf in ethyl acetate).

Stage 2; The title compound is prepared according to the procedure described in step 3 of example 59.

EXAMPLE 73 » 3- (2- (5-Benzyloxy-1- (2-naphthyl) methyl) -indolinyl) -methylthioacetamidobenzoic acid Stage 1: Ethyl 3- (2- (5-benzyloxy-l- (2-naphthyl) methyl) -indolinyl) -methylthioacetamidobenzoate A mixture of 3- (2- (5-benzyloxy-1- (2-naphthyl) methyl) -indolinyl) -methylthioacetamidobenzoate (0.2 g, 0.42 mmol), prepared 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 2 ml of N, N-dimethylformamide is stirred at room temperature overnight. The reaction is then diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material is purified on silica gel using 2: 1 hexane: ethyl acetate to provide 0.22 g of the product (85%, CCD = 0.5 Rf in 2: 1 hexane: ethyl acetate).

Stage 2 : The title compound according to the procedure is prepared with the procedure described in step 3 of example 59.

EXAMPLES 74 and 75 in Table 6 are prepared according to the procedures described in Example 73.

EXAMPLE 76 2- (2- (5-Benzyloxy-1- (2-naphthyl) methyl) -indolinyl) -methylthiobenzoic acid Step 1: 2- (2- (5-Benzyloxy-1- (1,1-dimethyl) ethoxycarbonyl) indolinyl) -methyl methylsulphonate Dissolve l- (5-benzyloxy-2-hydroxymethyl) tert-butyl dlindolinylformate (6.72 g, 19 mmol) prepared in stage 2 of example 17. in CH2C12 (80 ml, dried over MgSO4 before use) The light yellow solution is cooled in a dry ice bath, then 4.0 ml of Et3N followed by 2.0 ml of chloride are added. of methanesulfonyl The reaction mixture is stirred for 2 hours at -40 ° C and then suspended with H20, washed with 300 ml of saturated NaHC03 and the aqueous layer extracted twice with CH2C12.The combined layers of CH2C12 are dried on MgSO4, they are filtered and evaporated to dryness to provide the product (7.30 g, 89.1% yield), which is used for the next reaction directly.

»Stage 2: methyl 2- (2- (5-benzyloxy-1 - (1,1-dimethyl) ethoxycarbonyl) indolinyl) -methylthiobenzoate The mesylate (7.2 g, 1.8 mmol) prepared in step 1 is dissolved in 50 ml of DMF. The clear light brown solution is degassed by bubbling vigorously with Ar for 30 minutes. 13.8 g of cesium carbonate are added followed by 2.4 ml of methyl thiosalicylate. The solution changes to a bright yellow color and the suspension is stirred overnight. 0.15 ml of methyl thiosalicylate are added to complete the reaction and the mixture is stirred overnight. The reaction is then suspended by the addition of 400 ml of saturated NaHCO 3. The mixture is extracted with CH2C12 (3 x) and the combined CH2C12 solution is backwashed with 200 ml of H20. The organic layer is dried over MgSO4, filtered and evaporated to dryness to provide the product (9.71 g, 99%).

Stage 2_j 2- (2- (5-benzyloxy) indolinyl) -methylthiobenzoate methyl Ethyl acetate (75 ml, dried over MgSO4 before use) is charged into a 500 ml round bottom flask. HCl gas is bubbled through it, and the AcOEt / HCl solution is cooled in an ice bath. 8.4 g of the methyl ester, prepared in step 2, are dissolved in AcOEt (25 ml, dried over MgSO4 before use). This solution is transferred to the HCl / EtOAc solution by means of a syringe. The solution turns red and is stirred in a bath with ice. A white precipitate appears in 1 hour, and the solution is stirred overnight to complete the reaction. The solid is collected by filtration, washed with dry EtOAc, suspended in 175 ml of saturated NaHCO 3 and stirred with 400 ml of EtOAc. The milky emulsion gradually dissolves and the mixture changes to a clear solution. The layers are separated and the aqueous layer is extracted (2 x) with EtOAc, while the combined layers of EtOAc are dried over MgSO 4, filtered and evaporated to dryness to provide the product (6.06 g, 90% yield).

Eta 4: methyl 2- (5- (5-benzyloxy-1,4-benzyl) benzyl) indolinyl) -methylthiobenzoate In a 50 ml round bottom flask, 1 g of the ester, prepared in step 3, is dissolved in 6 ml of DMF. 1 equivalent of p-benzylbenzyl bromide is added followed by 1 equivalent of K2C03. The reaction mixture is stirred overnight at room temperature. To complete the reaction, 0.5 equivalents of p-benzylbenzyl bromide is added and the reaction is stirred for another 2 hours. After completion, the reaction is diluted with H20 and extracted with EtOAc (2 x). The organic layers are combined and dried over MgSO4. The MgSO4 is filtered and the solvent is evaporated to provide an oily material which is dried overnight at high vacuum to provide the product (1.59 g, 109% yield).

Stage 5 Dissolve 1.52 g of the ester, prepared in the stage 4, in 10 ml of THF, in a 50 ml round bottom flask. To this is added NaOH (1 eq 2N) followed by 3 ml of MeOH and the reaction mixture is stirred overnight. An additional 0.3 equivalents of NaOH are added to complete the reaction and the mixture is stirred throughout the weekend. It is then acidified and diluted with H20 and extracted with EtOAc (2 x). The organic layers are combined and dried over MgSO4. The MgSO4 is filtered and the solvent is evaporated and dried under high vacuum to provide a crude reddish solid. This solid is dissolved in EtOAc and hexane is added to precipitate the product. The resulting solid is filtered and the impure filter cake is combined with the filtrate and evaporated to dryness. This material is treated with EtOAc and EtOH. The resulting solid is filtered and then suspended in EtOH, with stirring and heating, at a low temperature. Then it is allowed to cool to room temperature. The suspension is filtered and washed with EtOH to provide the title product (280 mg, 19% yield).

EXAMPLES 77.78 and 79 are prepared in table 6 according to the procedures described in example 76.

EXAMPLE 80 4- (1- (5-Benzyloxy-2- (bis-2,4-trifluoromethyl) benzyloxymethyl) indolinyl) -methylbenzoic acid Step 1: 1- (5-benzyloxy-2- (hydroxymethyl) indolinii) methyl-methyl-benzoate The mixture is stirred and stirred at room temperature for 2 hours 2- (5-benzyloxy) indolinylmethanol (3.21 g, 12.6 mmol), prepared in 20 ml of DMF, methyl 4- (bromomethyl) benzoate (2.88 g, 14.5 mmol) and potassium carbonate (1.77 g, heated to 125 ° C before use). The reaction is diluted with 100 ml of H20 and extracted three times with EtOAc. The combined EtOAc layers are evaporated to dryness to provide 5.66 g of the crude product. The crude material is purified on a column of silica gel using hexane: ethyl acetate 3: 1 to 2: 1. The appropriate fractions are combined, evaporated to dryness and further dried under high vacuum to obtain the product (3.00 g, 64%).

Stage 2: Methyl 4- (1- (5-benzyloxy-2- (bis-2,4-trifluoromethyl) benzyloxymethyl) indolinyl) -methylbenzoate 700 mg of the ester, prepared in step 1, and 0.35 ml of bis- (2,4-trifluoromethyl) benzyl bromide are dissolved in ml of DMF. The resulting clear yellow solution is cooled in an ice bath and then 85 mg of NaH are added in small portions over a period of 5 minutes. The suspension is stirred at 0 ° C for 4 hours. To complete the reaction, another 0.35 ml of 2,4-bis (trifluoromethyl) encyl bromide is added and stirring is continued for another 3 hours 40 minutes. The reaction is then diluted with H20 and extracted three times with EtOAc. The combined EtOAc layers are evaporated to provide a crude product which is then purified on a silica gel column using hexane: ethyl acetate 8: 1. The appropriate fractions are combined and evaporated to dryness to provide the product (0.417 g, 38.2% yield).

Stage 3; The title compound is prepared according to the procedure described in step 5 of example 76.

EXAMPLES 81 and 82 are prepared in Table 6 according to the procedures described in Example 80.

EXAMPLE 83 - (2- (1- (2,4-bis (trifluoromethyl) benzyl) -indolinyl) -carboxamido-1,3-benzenedicarboxylic acid Step 1: 2- (1- (2,4-bis (trifluoromethyl) benzyl) -indolinyl) -carboxylic acid Dissolve 2-indolinylcarboxylic acid (0.43 g, 2.6 mmol) in 5 ml of DMF, place on N2, and cool to 0 ° C, add sodium hydride (0.26 g of a 60% dispersion, 6.5 mmol) and stirring is continued for 1 hour at this temperature. Then 2,4-bis (trifluoromethyl) benzyl bromide (1.22 ml, 6.5 mmol) is added, and the reaction is warmed to room temperature overnight. The reaction is then diluted with half-saturated ammonium chloride / ethyl acetate, and the aqueous layer is extracted with ethyl acetate (3X), the organic layers are dried over magnesium sulfate and concentrated. The crude product is purified by chromatography (hexane: ethyl acetate 9: 1) to provide 0.96 g of the ester. The resulting ester is dissolved (0.87 g, 0.141 mmol) in THF / methanol and then 4.21 ml of IN sodium hydroxide are added, and the resulting mixture is stirred for 2 hours at RT, subjected to treatment and purification via chromatography (7: 1 hexane: ethyl acetate with 1% acetic acid), which gives 0.58 g of the product.

Stage 2 : The acid (0.25 g, 0.64 mmole), prepared in the stage 1, EDCI (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 2 ml of THF and refluxed for 16 hours which provides , after the aqueous treatment, 0.33 g of a crude product. The ester (0.29 g, 0.50 mmol) is dissolved in THF / methanol and then 1.5 ml of sodium hydroxide are added IN and the resulting mixture is stirred at RT for 16 hours, subjected to treatment and purification via chromatography (1: 1 hexane: ethyl acetate with 1% acetic acid) which gives 0.22 g of the title compound.

EXAMPLE 84 «N-methylsulfonyl-2- (l- (2,4-bis (trifluoromethyl) -benzyl) indolinyl) carboxamide The acid (0.13 g, 0.32 mmol), prepared in stage 1 of example 83. EDCI (0.07 g, 0.39 mmol), DMAP (4 mg, 0.03 mmol) and methylsulfonanilide (0.04 g, 0.39 mmol) are dissolved in 5 ml of THF and refluxed 16 hours which affords, after treatment (0.16 g), purification via chromatography (98: 2 dichloromethane methanol) which provides 0.04 g of the title compound (29%).

EXAMPLE 85 N-phenyl sulfonyl-2- (1- (bis-2,4-trifluoromethyl) -benzyl) indolinyl) carboxamide The title compound is prepared according to the procedure described in Example 84. but using phenylsulfonylamide.

EXAMPLE 86 - (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 A 1 1 round bottom flask, oven dried, equipped with a stir bar, is charged with 2- (5-benzyloxy) indolinylmethanol (33.2 g, 130 mmol), prepared in step 1 of example 17. carbonate 2- (trimethylsilyl) ethyl p-nitrophenyl 36.8 g, 130 mmol), Net3 (38 ml, 273 mmol) and 300 ml anhydrous DMF. The reaction mixture is stirred at 60 ° C for 28 hours and at room temperature overnight. The resulting solution is concentrated to dryness in vacuo and 1 liter of CHC13 and 200 ml of a saturated solution of NaHCO3 are added. The layers are separated and the organic phase is dried (Na 2 SO 4), filtered and concentrated. The crude material obtained (55.7 g) is purified by silica gel column chromatography > (eluent: 0-5% MeOH in dichloromethane) to provide the product (33.5 g, 60% yield).

Step 2: 2-trimethylsilylethyl 1- (5-hydroxy-2-hydroxymethyl) indolinylformate A 500 ml Parr pressure flask, dried in the oven, is charged with alcohol (30 g, 75 mmol), prepared in step 1, Pd / C (10%, 2.2 g), 100 ml of MeOH and 300 ml of EtOAc. After stirring overnight in the Parr equipment under an atmosphere of H 345 kPa (50 psi), the reaction mixture is filtered through Florisil. The filtrate is concentrated to dryness in the rotary evaporator. 24 g of the crude material obtained are purified by column chromatography on silica gel (eluent: 0-3% MeOH in dichloromethane) to give the product (20.9 g, 90% yield).

E apa 3L; 1- (5- (4-methoxy) benzyloxy-2-hydroxy-methyl) -indolinyl-2-trimethylsilylethyl formate A 1 1 round bottom flask, dried to the horo, equipped with a stir bar, is charged with the diol (27.1 g, 87.7 mmol), prepared in step 2, 4-methoxybenzyl chloride (Aldrich, 15 ml, 110 mmol), K2C03 (200 mesh, 30.4 g, 220 mmol), KI (Aldrich, 18.3 g, 110 mmol ) and 800 ml of anhydrous acetonitrile. The reaction mixture is refluxed for 4 hours. The solution is allowed to cool to room temperature and 800 ml of water and 1.5 1 of CHC13 are added. The layers are separated and the aqueous phase is extracted with 800 ml of CHC13. The combined extracts are washed with 200 ml of water, dried (Na2SO4), filtered and concentrated. The 45 g of crude material obtained is purified by column chromatography on silica gel (eluent: 20-25% EtOAc in hexane) and recrystallization from EtOAc / hexane to provide the product (22.2 g, 59% yield). ).

E t apa 4: 1- (5- (4-methoxy) benzyloxy-2-bromomethyl) indolinyl-formate 2-trimethylsilylethyl To a solution of 3.0 g (6.4 mmol) of the alcohol prepared in step 3, in 30 ml of dichloromethane are added 2.53 g (7.6 mmoles) of carbon tetrabromide and 3.15 g (7.6 mmoles) of 1,3-bis (diphenylphosphino). propane. The reaction is stirred at room temperature for 18 hours. The reaction is suspended with saturated aqueous NH 4 Cl, and the product is extracted with dichloromethane. The combined organic extracts are washed with brine and dried over MgSO4. The crude product is purified by flash chromatography using 3: 2 hexane: ethyl acetate to provide 1.51 g of the product. 5 Stage 5: 1- (5- (4-methoxy) benzyloxy-2-azidoxymethyl) indolinyl-formate 2-trimethylsilylethyl To a solution of 1.4 g (2.6 mmol) of the bromide, prepared in step 4, in 15 ml of dimethylformamide 0.51 g (7.9 mmoles) of sodium azide are added. The reaction is heated to 75 ° C and stirred for 18 hours. The reaction is suspended with water, and the product is extracted with ethyl acetate. The combined organic layers are washed with water, brine and dried over MgSO4. The crude product is purified by flash chromatography using 4: 1 hexane: ethyl acetate to provide 1.08 g of the product.

Step 6: 1- (5- (4-methoxy) benzyloxy-2-aminomethyl) -indolinyl-2-trimethylsilylethyl formate To a solution of 0.88 g (1.9 mmol) of the azide prepared in step 5, in 20 ml of ethanol, 90 mg are added (10% / weight) of Pd / CaC03. The mixture is placed under hydrogen atmospheric and stirred for 18 hours. The reaction after j? jgAjj is filtered through a pad of Celite and the organic phase is concentrated. The crude product is purified by flash chromatography using 10% MeOH / CH2C12 to provide 0.717 g of the product.

Stage 7: 5- (2- (5-methoxybenzyloxy-1- (2-trimethylsilyloxy) ethoxycarbonyl) indolinyl) methylaminocarboxa-mido-1,3-benzenedicarboxylate methyl To a solution of 0.164 g (0.6 mmol) of triphosgene in 5 ml of dichloromethane is added 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 during a 30 minute period, via a syringe pump. The reaction is stirred for 1 hour at room temperature after the addition, and a solution of 0.64 g (1.5 mmoles) of the amino substance, prepared in step 6, in 5 ml of dichloromethane is then added in one portion. The reaction is stirred for 2 hours, and then suspended with water. The product is extracted with ethyl acetate, and the combined organic layers are washed with water, saturated aqueous NaHC03, brine, and dried over MgSO4. The crude product is purified by flash chromatography using 10% MeOH / CH2C12 to provide 0.78 g of the product.

Stage 8: 5 - (2 - (5-me t-oxybenzyl-1-oxy) -indolinyl) -methylaminocarboxamido-1,3-benzenedicarboxylate methyl To a solution of 0.485 g (0.7 mmol) of the ester, prepared in step 7, in 20 ml of acetonitrile, 2.2 ml (2.2 mmol) of a 1.0M tetrabutylammonium fluoride solution in THF are added. The reaction is stirred at room temperature for 18 hours. The reaction is suspended with brine, and the product is extracted with ethyl acetate. The combined organic extracts are washed with saturated aqueous-NH 4 Cl, brine and dried over MgSO 4. The crude product is purified by flash chromatography using 5% MeOH / CH2Cl2 to provide 0.342 g of the product.

Stage 9: 5- (2- (5-methoxybenzyloxy-1- (bis-2,4-trifluoromethyl) benzyl) indolinyl) methylaminocarboxamido-1,3-benzenedicarboxylate methyl To a solution of 0.15 g (0.3 mmoles) of the indoline diester, prepared in step 8, in 5 ml of dimethylformamide, 0.097 g (0.3 mmoles) of 2,4-bis (trifluoromethyl) benzyl and 0.12 g (0.9 g. mmoles) of potassium carbonate. The reaction is stirred at room temperature for 18 hours. The reaction is suspended with water and the product is extracted with ethyl acetate. The combined organic extracts are washed with water, brine and dried over MgSO4. The crude product is purified by flash chromatography using hexane: ethyl acetate 1: 1 to provide 0.066 g of the product.

Stage 10: To a solution of 0.063 g (0.1 mmol) of the diester, prepared in step 9, in 5 ml of tetrahydrofuran, 0.8 ml (0.8 mmol) of a 1.0 N NaH solution and 0.5 ml of methanol are added. The reaction is stirred at room temperature for 18 hours. 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, brine and dried over MgSO4. The crude product is purified by flash chromatography using 5% MeOH / CH2Cl2 to provide 0.049 g of the title compound.

EXAMPLE 87 is prepared according to the procedure described in Example 86, but using 4- (3,5-bis (trifluoromethyl) phenoxymethyl) benzyl bromide.

INTERMEDIARY 1 Methyl 4-methoxy-3-thioacetamidobenzoate Stage I: methyl (4-methoxy-3-dithioacetamidobenzoate A 2 1 round-bottom flask, oven-dried, to which a magnetic stirring bar is placed, is charged with dithioacetic acid (10.2-15.5 g, 56-58 mmole) and 50 ml of CH2C12 anhydrous. Oxalyl chloride (2.1 mmoles equivalent) is added dropwise for 10 minutes. The reaction mixture is stirred at room temperature for 4-5 hours. - Methyl 4-methoxy-3-amidobenzoate (2.1 mmole equivalents) is added in 300-500 ml of anhydrous CH2C12 and DMAP (0.1 mmol equivalent) at room temperature. Net3 is added dropwise for 30 minutes (4.2 mmoles equivalent). After stirring overnight at room temperature, the reaction mixture is washed with a solution of IN HCl (2 x 300 ml), dried over Na 2 SO 4 and filtered. The solvent is removed in vacuo. Purification of the residue by column chromatography on silica gel using hexane: ethyl acetate = 5: 1 gives the desired product in 56% yield.

Stage 2 : A 1 1 round bottom flask, to which a magnetic stirring bar is placed, is charged with disulfide, prepared in step 1 (15.7-26.3 g, 36.6-57.5 mmole) and Pph3 (1.1 mmole equivalent). The reagents are suspended in dioxane / H20 (4/1, 375-500 ml) and 5 drops of a concentrated HCl solution are added. The reaction mixture is heated to 40 ° C until all the disulfide is consumed. The solvents are removed in vacuo. The residue is immediately purified by column chromatography on silica gel using hexane: ethyl acetate 2: 1 to give the title product in 89% yield.

INTERMEDIARY 2 »5-thioacetamido-l, 3-benzenedicarboxylic acid methyl The title compound is synthesized according to the procedures described in intermediate 1 using 5-amino-1,3-benzenedicarboxylate.

INTERMEDIARY 3 2- (3-amino-4-methoxyphenyl) -2-methoxyacetate methyl Step 1: Methyl 2- (3-nitro-4-methoxyphenyl) acetate A kiln-dried, 2-liter three-necked round bottom flask equipped with a mechanical stirring motor, a low temperature thermometer and a funnel of equalization drip, it is charged with 631 ml of acetic anhydride and subsequently cooled to -78 ° C. Fuming nitric acid (Baker, 90%, 27 ml) is added dropwise via the drip funnel protected with a CaCl2 drying tube. After the addition is complete, the reaction temperature is allowed to warm to 20 ° C, for 1 hour. The reaction mixture is cooled to -78 ° C again and 4-methoxyphenylacetic acid (50 g, 0.28 moles) is added dropwise via the dropping funnel. After stirring at -50 ° C for 1 hour, the reaction mixture is allowed to warm to -30 ° C for 20 minutes and then cooled to -50 ° C again. The reaction mixture is suspended with 500 ml of H20 at -50 ° C and warmed to room temperature and stirred for 0.5 hour. The reaction mixture is divided between 500 ml of CH2C12 and H20. The aqueous layer is extracted with CH2C12 (3 x 500 ml). The combined extracts of CH2C12 are concentrated in vacuo to give a yellow oil. This is added slowly to 2 1 of a 2M NaOH solution cooled to 0 ° C and stirred at room temperature overnight. The reaction mixture is divided between 500 ml of CH2C12 and H20. The aqueous layer is extracted with CH2C12 (3 x 500 ml). The combined CH2C12 extracts are stirred with 1 1 of a 2M NaOH solution for 1 hour. The layers are separated and the organic layer is washed with 500 ml of H20, 500 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo to provide 56 g of the crude product as a light yellow solid. Purification by recrystallization from 600 ml of MeOH gives the product. Yield 48 g (77%).

Stage 2: methyl 2- (3-nitro-4-methoxyphenyl) -2-hydroxyacetate A 25 ml round bottom flask, dried in the oven, with a magnetic stir bar is charged with the ester (2.3 g, 10 mmol) prepared in step 1, in 100 ml of anhydrous THF. The reaction mixture is cooled to -78 ° C and a solution of NaN (SiMe3) 2 (1.0M in THF, 12 ml, 12 mmol) is added dropwise over 10 minutes. After stirring at -78 ° C for 30 minutes, the dark purple solution is added dropwise to a racemic sulfonyl oxaziridin solution (3.4 g, 15 mmol), prepared by mixing (IS) - (+) - ( 10-camphorsulfonyl) commercially available oxaziridine (1.7 g) and 1.7 g of (IR) - (-) - (10-camphorsulfonyl) oxaziridine in 50 ml of THF. After stirring at -78 ° C for 30 minutes, the reaction mixture is suspended with 45 ml of a saturated solution of NH 4 Cl at -78 ° C and then allowed to warm to room temperature. The reaction mixture is divided between 250 ml of ether and 50 ml of H20. The aqueous layer is extracted with ether (3 x 250 ml). The combined ether extracts are washed with 250 ml of brine, dried over Na 2 SO 4 and filtered. The solvents are removed in vacuo. Purification by column chromatography on silica gel (eluent: 50% AcOEt in hexane) provides the desired product. Yield 2.2 g (88%).

Stage 3: methyl 2- (3-nitro-4-methoxyphenyl) -2-methoxyacetate A 10 ml round bottom flask, dried in the oven, to which a magnetic stirring bar is placed, is charged with alcohol (0.30 g, 1.24 mmole), prepared in step 2, > Ag20 (0.68 g, 3.0 mmol) and 3 ml of toluene. To this is added CH3I (0.36 g, 5.75 mmol) dropwise. The reaction flask is tightly capped and placed in a sonication chamber. The reaction mixture is sonicated for 18 hours while stirring at room temperature. The reaction mixture is filtered through Celite and concentrated in vacuo to dryness. The residue is purified by column chromatography on silica gel (eluent: AcOEt 30% in hexane) to provide the desired product. Yield 0.26 g (82%).

Stage 4: A 100 ml round bottom flask, oven dried, and equipped with a magnetic stir bar and a three-way adapter, is connected to a hydrogen balloon and a water aspirator with nitro compound is charged (0.7 g, 2.6 mmoles), Pd 5% in carbon (10% by weight) and 20 ml of MeOH. The reaction flask is placed under vacuum by means of the water respirator and subsequently filled with H2. This is repeated three times. The reaction mixture is stirred for 18 hours under positive pressure of H2 until all the initial material has reacted. The reaction mixture is filtered through Celite and concentrate in vacuo to dryness. The residue is purified by column chromatography on silica gel using 10% ethyl acetate in dichloromethane to give the title compound (0.57 g, 97%). « INTERMEDIARY 4 2 - . Methyl 2 - (3-amino-4-methoxyphenyl) -2-tert-butyldimethylsilyloxyacetate A 25 ml round-bottom flask, oven-dried, to which a magnetic stirring bar is placed, is charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2 of intermediate 3, and 10 ml of anhydrous CH2C12. . The reaction mixture is cooled to 0 ° C and 2,6-lutidine (dried over NaOH pellet, 0.36 ml, 3.11 mmol) is added followed by dropwise addition of BuMe-SiOTf (0.43 ml, 1.87 mmol). After stirring at 0 ° C for 30 minutes, the reaction mixture is divided between 20 ml of CH2C12 and 15 ml of H20. The aqueous layer is extracted with CH2C12 (3 x 20 ml). The combined CH2C12 extracts are washed with 20 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification by column chromatography on silica gel (eluent: 30% AcOEt in hexane) provide the desired product. Yield 0.42 g (95%).

Stage 2 : The title compound is prepared from the "nitro compound of step 1, according to the procedure described in step 4 of intermediate 3.

INTERMEDIARY 5 2- (3-Amino-4-methoxyphenyl) methyl acetate The title compound is prepared from the nitro compound, prepared in step 1, of intermediate 3, according to the procedure described in step 4 of intermediate 3.

INTERMEDIARY 6 2- (3-amino-4-methoxyphenyl) -2-methyl methacetate methyl Stage 1: methyl 2- (3-nitro-4-methoxyphenyl) -2-methyl methacetate A 25 ml round bottom flask, dried in the oven, to which a magnetic stirring bar is placed, is charged with redistilled diisopropylamine (0.84 ml, 6.0 mmoles) and 10 ml of anhydrous THF, and cooled to 0 ° C. A solution of n-BuLi (2.5M in hexane, 2.4 ml, 6.0 mmol) is added dropwise over 5 minutes. After stirring at 0 ° C for 15 minutes, the reaction temperature is allowed to cool to -78 ° C and an ester solution (1.13 g, 5.0 mmol), prepared in step 1 of intermediate 3, is added to the reaction mixture. 10 ml of THF, dropwise. After stirring at -78 ° C for 45 minutes, dimethyl sulfate (1.60 g, 12.5 mmol) is added dropwise and the reaction mixture is allowed to warm to room temperature and stir overnight. The reaction mixture is divided between 50 ml of CH2C12 and 50 ml of H2O. The aqueous layer is extracted with CH2C12 (3 x 50 ml). The combined CH2C12 extracts are washed with 50 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification by column chromatography on silica gel (eluent: AcOEt 30% in hexane) provides 0.7 g of the product (58%).

Stage 2 : The title compound is prepared from the nitro compound, prepared in step 1, according to the procedure described in step 4 of intermediate 3.

INTERMEDIARY 7 2- (3-amino-4-methoxyphenyl) -2-methyl-acetate-methyl Stage 1: methyl 2- (3-nitro-4-methoxyphenyl) -2-allylacetate This compound is synthesized from the ester, prepared in step 1 of intermediate 3, according to the procedure described in step 1 of intermediate 6, but using allyl bromide.

Stage 2 : A 25 ml round bottom flask, dried in the oven, to which a magc stirring bar is placed, is charged with the ester (0.30 g, 1.13 mmol), prepared in step 1, SnCl2 -2H20 (1.28 g, 5.66 mmoles) and 5 ml of EtOH. The reaction mixture is heated at 70 ° C for 30 minutes. The reaction mixture is cooled to room temperature and poured into 20 ml of ice / water and basified with a saturated Na 2 CO 3 solution at pH = 8. 50 ml of AcOEt are added. The resulting emulsion is filtered through Celite. The filtrate is divided between 20 ml of AcOEt and 15 ml of H20. The aqueous layer is extracted with AcOEt (3 x 50 ml). The combined AcOEt extracts are washed with 50 ml of brine, dried over Na2SO4 and filtered. The solvents are removed in vacuo. Purification of the residue by column chromatography on silica gel (eluent: AcOEt 10% in CH2C12) gives the title compound. Yield 0.16 g (60%).

INTERMEDIARY 8 2,4-bis (1,1-dimethylpropyl) phenoxyacetic acid The 2,4-bis (1,1-dimethyl) propylphenol (12 g, 51.2 mmol) in 100 ml of dimethylformamide is cooled to -30 ° C, treated with solid potassium bis (trimethylsilyl) amide (12.3 g, 61.5 mmol. ), stirred for 30 minutes and then methyl bromoacetate (5.7 ml, 61.5 mmol) was added, the reaction was stirred for 1 hour at this temperature and 5 hours after the removal of the cooling bath, the treatment provided (16.6 g. , «100%) of a yellow oil. The oil dissolves in. THF / methanol and treated with 155 ml of IN sodium hydroxide and stirred for 48 hours. 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%).

INTERMEDIARY 9 4-benzylphenoxyacetic acid «The title compound is prepared from 4-benzylphenol according to the procedure described in intermediate 8.

INTERMEDIARY 10 2-naphthoxyacetic acid The title compound is prepared from 2-naphthol according to the procedure described in intermediate 8.

INTERMEDIARY 11 3,5-bis (trifluoromethyl) phenoxyacetic acid The title compound is prepared from 3,5-bis (trifluoromethyl) phenol according to the procedure described in intermediate 8.

INTERMEDIARY 12 Methyl 5-amino-3- (N-dimethyl) carbamoylbenzoate Stage I: methyl 5-nitro-3- (N.N-dimethyl) carbamoylbenzoate A 100 ml round-bottom flask, dried in the oven, with a magc stirring bar, charged with 5-nitro-3-methoxycarbonylbenzoic acid (3.15 g, 10 mmol), one drop of DMF, 70 ml of anhydrous CH2C12 and oxalyl chloride (3.7 ml, 42.3 mmol). The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo to provide the acid chloride as a white solid. This is used immediately in the next step without further purification.

A round, oven-dried flask, to which a magc stirring bar is placed, is charged with 14 mmoles of acid chloride prepared above, 50 ml of anhydrous CH2C12 and 70 mmoles dimethylamine hydrochloride. drops (2 ml, 144 mmol) are added. After stirring at room temperature for 30-60 minutes, an excess of (1 ml, 72 mmol) is added and stirring is continued. After 30-60 minutes, the solution is washed with a saturated Na 2 CO 3 solution (2 x 20 ml), dried over Na 2 SO 4 and filtered. The solvent is removed in vacuo to provide 3.3 g of the product. This is used in the next step without further purification.

Stage 2 : The title compound is prepared from the nitro compound, prepared in step 1, according to the procedure described in step 4 of intermediate 3.

INTERMEDIARY 13 Methyl 5-amino-3-acetylbenzoate Stage 1: Methyl 5-nitro-3-acetylbenzoate A 250 ml round bottom flask, dried in the oven, with a magnetic stirring bar placed, is charged with di-tert-butyl malonate (2.16 g). , 10 mmol), 50 ml of anhydrous toluene and NaH (60% suspension in mineral oil, 0.88 g, 22 mmol). The reaction mixture is heated at 80 ° C for 1 hour. A solution of 10 mmol of methyl 5-nitro-3-chloroformylbenzoate, prepared in step 1 of intermediate 12, in 20 ml of anhydrous toluene is added and heating is continued for 2 hours. The reaction mixture is cooled to room temperature and p-toluenesulfonic acid (0.21 g, 1.2 mmol) is added. The resulting mixture is filtered-and the oily residue is washed with toluene until a white solid is left.

The filtrates are combined and the solvent is removed in vacuo.

The resulting oil is dissolved in 50 ml of anhydrous toluene < and p-toluenesulfonic acid (0.3 g, 1.74 mmol) is added.

After heating to reflux for 18 hours, allow the reaction mixture to cool to room temperature, wash with a saturated solution of Na 2 CO 3 (2 x 25 ml), dry over Na2SO4 and filtered. The solvent is removed in vacuo. The crude material is purified by column chromatography on silica gel (eluent: CH2C12) to provide the product. Performance, 1. 06 g (50%).

Step 2 The title compound is prepared from the nitro compound, prepared in step 1, according to the procedure described in step 4 of the intermediate 3. INTERMEDIARY 14 Methyl 5-amino-3- (1-tert-butyldimethylsilyloxy) ethylbenzoate Stage 1: methyl 5-nitro-3- (1-hydroxyethylbenzoate) A round-bottomed oven-dried flask, to which a magnetic stirring bar is placed, is charged with 0.5 g of the methyl 5-nitro-3-acetylbenzoate compound, prepared in step 1 of intermediate 13, BH3 THF (solution 1M in THF, 5 mol equivalents) and anhydrous THF. After stirring at room temperature for 24 hours, 20 ml of H20 is added and the solution is concentrated in vacuo. The residue is taken up in 20 ml of H20 and extracted with CHC13 (3 x 100 ml). The combined extracts of CHC13 are washed with 20 ml of a saturated solution of Na 2 CO 3, dried over Na 2 SO 4 and filtered. The solvent is removed in vacuo to provide the product. This is used in the next step without further purification.

Stage 2 Methyl 5-nitro-3- (1-tert-butyldimethyl-siltyloxy) ethylbenzoate A round bottom flask, dried in the oven, to which a magnetic stirring bar is placed, is charged with alcohol (0.5 g, 5 mmol) ), prepared in step 1, ter-BuMe2SiCl (1.3 mol equivalents), imidazole (2.15 mmoles equivalent) and anhydrous THF. After stirring at room temperature for 28 hours, the solvent is removed in vacuo. The residue is taken up in 50 ml of H20 and extracted with CHC13 (2 x 100 ml). The combined extracts of CHC13 are washed with 50 ml of H20, dried over Na2s04 and filtered. The solvent is removed in vacuo. The crude material is purified on silica gel using 25% -50% dichloromethane in hexane to provide the product (0.69 g, 91%).

Stage 3: » The title compound is prepared from nitro compound, which is prepared in step 2, according to the procedure described in step 4 of intermediate 3.

INTERMEDIARY 5 I Methyl 4-methoxy-3- (2-thioethyl) aminobenzoate Stage 1: bis (2-bromoethyl) disulfide Weigh into a flask in dithioethanol (0.79 ml, 6.48 mmol), carbon tetrabromide (4.3 g, 13.0 mmol) and 1,3-bis (diphenylphosphino) ropano (5.34 g, 13.0 mmoles), and purged with nitrogen and then taken up in 15 ml of CH2C12 and stirred for 16 hours, the treatment consists of pouring into half-saturated ammonium chloride and extracting with CH2C12 (3X), dry magnesium sulfate and concentrating for provide 9.0 g of a crude product which is subjected to chromatography (hexane: ethyl acetate 9: 1) to provide 1.49 g of the product.

Step 2: Methyl bis- (4-methoxy-3- (2-dithioethyl) aminobenzoate) Bromide (0.39 g, 1387 mmol), prepared in stage 1 and methyl 3-amino-4-methoxy benzoate (1.00 g) , 5.51 * mmoles), are added in a flask, purged with nitrogen and taken up in 5 ml of DMF and then heated at 60 ° C for 24 hours, at which time the reaction is diluted with ethyl acetate and Suspend in water, extract with ethyl acetate (3X), the combined organic layers are washed with water (3X), dried and concentrated to give 1.27 g of a crude product which is purified by chromatography. (hexane: ethyl acetate 5: 1 to 3: 1) to provide 0.15 g of the desired product.

Stage 3: The disulfide (0.15 g, 0.24 mmole), prepared in step 2, and the triphenylphosphine (0.14 g, 0.53 mmole) are taken up in 3 ml of THF. 0.3 ml of H20 and two drops of concentrated HCl are added, and the resulting mixture is stirred at 40 ° C for 2 hours, the reaction is diluted with water and ethyl acetate, extracted with ethyl acetate (3X), and dried over magnesium sulfate to provide 0.27 g of a crude product which is purified by chromatography (hexane: ethyl acetate 9: 1 to 6: 1) to provide 0.11 g of the title compound.

Synthesis Methods for Examples &6-135 The additional compounds of the invention can be made according to the following methods. Specific examples of sistensis of the compounds according to these methods are also described below.

Method A The aldehyde is reacted with the alpha carbon of a heterocycle such as 2,4-thiazolidinedione or rhodamine or 2-thiohydantoin in the presence of a base 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 then be subjected to separation of the ester with hydrogen fluoride in a solvent such as acetonitrile.

Method B The indole-2-carboxylic acid is alkylated with an appropriate alkyl bromide which is then subjected to Suzuki coupling conditions using Pd (PPh3) 4 as a catalyst in a mixed solvent (ethanol-benzene-water) at elevated temperature, for provide the indot-1-alkyl-5-substituted.

Method C The starting material for the inhibitors in the class, 2-ethoxycarbonyl-5-benzyloxyindole I, is deprotonated with a suitable base such as sodium hydride and alkylated at the nitrogen atom with selected electrophiles such as alkyl or benzyl halide for provide the compounds II. Saponification of the ester functionality with a base such as aqueous sodium hydroxide in miscible solvents such as tetrahydrofuran and methanol provide inhibitors III. Additional extensions in the 2-position are carried out through the amide formation of the acid functionality via the formation of the acid chloride with a suitable reagent "such as oxalyl chloride and the reaction with an amino ester in the presence of such a base as pyridine in a suitable solvent such as methylene chloride Saponification provides the extended acid portion V as a chain.

Method D Acid isosteres such as tetrazole are prepared from carboxylic acids I via nitriles III. The conversion to the nitriles is carried out through the formation of the primary amide of the acid functionality via the acid chloride with a suitable reagent such as oxalyl chloride and the reaction with ammonia followed by the sequence of "dehydration using a reagent. suitable such as oxalyl chloride and a base such as pyridine. Nitriles such as III can be converted to the tetrazoles by reaction with an azide source such as sodium azide in an appropriate high boiling solvent such as N-methylpyrrolidinone, to provide the compounds such as IV.

Method E Other isosteres and acids such as the thiadiazolidinedione group with larger carbon atom sources are prepared through a sequence that involves the unsaturated aldehyde portion in the 2-position such as compound IV. Partial reduction of the ester group in I with a suitable reagent such as diisobutyl aluminum hydride or reduction to a hydroxy group with a suitable reagent such as lithium aluminum hydride followed by oxidation to the aldehyde with a suitable oxidizing agent, provides the aldehyde II. A reaction of Horner-Wittig with the trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran yields the unsaturated ester III. which is converted to aldehyde IV under the conditions described for II. The aldehyde can then be converted to the thiadiazolidinedione V using a base such as piperidine and isolated with an acid such as acetic acid.

Method F The ethyl ester of 2-indolyl carboxylic acid I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to provide VI. Hydrolysis of VI with an aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethyl carbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane, provides the amide VII. The amide VII is hydrolyzed to the corresponding acid VIII in an aqueous base such as sodium hydroxide. 5 Method G Aldehyde IX is prepared from the indole-2-carboxylic acid ethyl ester I 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 reagent such as manganese dioxide in a solvent such as THF. The aldehyde IX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or sodium iodide.

Ethyl in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF, to provide the indole X. The indole X can be converted to an unsaturated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of such a base as sodium hydride in a solvent such as THF, and (2) hydrolysis by aqueous sodium hydroxide.

'- - *. * ¿¡I¡t ^^ j ^? Yyí > Method H Indole I can be converted to II in two stages: (1) reduction with LAH in a solvent such as THF, and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of II in Grignar reagent such as ethylmagnesium bromide in a solvent such as THF at -60 ° C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether, and finally alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF, provides the ketone III. The silyl group in III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis (diphenylphosphino) ethane in a solvent such as dichloromethane to provide the bromide IV. Displacement of IV bromine 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, provides V (sulfide or ether respectively). 20 ^ jg ^^ | > ^ £ ^ * ^ j * ¡S ^^^ 30 R1 R2 R3 R4 Alkyl alkyl N, 0, S, alkyl 0, S Four. Five 50 55 i) (COCÍ) 2 NaO ?. THF - OH 2) Pyridine IV LiOH THF - H 20 R II x) (COCÍ) 2 DMF.CH3CN 2) Pyridine 25 II trimethoxy phosphonoacetate VII NaOH, THF / MeOH 15 xx R "ix. R" 'COOCH 3 VIII alkoxy, benzyloxy, phenoxy, halogen, CN, N02, alkyl or aryl R 'alkyl, benzyl, alkenyl, alkynyl halogen, CN, alkyl, alkoxy, alkoxycarbonyl, amido, acyl, H, OH R'X (Br, l), NaH R = alkoxy, benzyloxy, phenoxy, halogen, CN, NO-, alkyl or aryl R = alkyl, aryl fifteen 0 ib 4 - tMláAÉItÉtB.-.- te4MNb,. ^^., .- í.lt ^ .. ".........., ...., -. ^ ..._ í, .. ^. * ,. .. t í. ** r. ^. - ^, 1) EtMgBr, THF 2) R'C0C1 / (R'C0) 2 ?, ETER 3) r "Br (1), NaH phenoxy, halogen, CN, NO 2, alkyl or aryl, alkenyl, lquinyl R ", = alkyl, aryl X =? S Y = halogen, mesylate iirir "-HjHifr 't EXAMPLE 88 4- [(5- { (E) - [5- (benzyloxy) -l- (4- { R3,5-bis (trifluoromethyl) phenoxy] methyl} benzyl) -lH-indole 2-5-yl] methylidene.} -2,4-dioxo-1,3-thiazolan-3-yl) methyl-1-benzoic acid Step 1 - 5.2 g of the aldehyde of Example 124 is suspended in 150 ml of ethanol. To the slurry are added 1.28 g of 2,4-thiazolidinedione and 6. 1 g of carbonate. potassium The mixture is heated in a bath at 60 ° C (which subsequently drops to 45 ° C). After 1 h, the CCD shows no reaction. 2.1 g of sodium hydroxide are added and the mixture is heated to 58 ° C. After 45 minutes, the CCD shows progress in reaction. 0.1 g of additional 2,4-thiazolidinedione is added. The mixture is stirred overnight at room temperature. The mixture is poured into 500 ml of water and acidified to pH 2 with 6N HCl, extracted with ethyl acetate, dried (MgSO) and filtered, trituration from ethanol gives an orange solid which is filtered and HE Wash with ethanol to provide the desired product (5.74 g, 94%) as an orange solid.

Step 2 - To 1.1 g of the material prepared in step I in 15 ml of DMF at 0 ° C is added sodium hydride (0.08 g, dispersion to 60% in mineral oil). The suspension is shaken i Anaiíu. at- »t ~? ft '- i -» t «> i. VJ .. -. .. '.. »mii < .t. < . .. ...Y , '.- . . .-, ""; OR . for 30 minutes. 0.54 g of benzyl bromide are added to the reaction mixture and the reaction is stirred overnight. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are concentrated. Column chromatography (ethyl acetate: hexane 1: 6 to 1: 4) gives the desired product (1.18 g, 75%) as a yellow solid.

Step 3 - To 0.34 g of material prepared in step 2 in 15 ml of acetonitrile are added HF (48% aqueous, 3. 7 ml) by means of a syringe. The reaction is stirred overnight. The reaction is not completed according to CCD, and THF is therefore added to dissolve the initial material and added 0. 6 ml of additional HF. The reaction is stirred for 2 h, after which the CCD shows that the reaction has been carried out. Water is added, resulting in the formation of a yellow solid. The yellow solid is dissolved in ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The resulting crude solid is suspended in ethanol and stirred for 30 min, filtered and dried to provide the title compound (140 mg, 48%) as a yellow solid.

EXAMPLE 89 5- [(E) - (5- (benzyloxy) -l-. {3- [3,5-bis (trifluoromethyl) -phenoxy] -propyl} -1 H -indole-2-di-methyl-1-yl 3- thiazolan-2,, 4-dione The title compound is prepared as illustrated in Example 88, step 1, from the appropriate indole.

EXAMPLE 90 - ((E) - {5-benzyloxy) -1- [2,4-bis (trifluoromethyl) b.sub.3] -1H-indol-2-yl} methylidene) -1, 3-thiazolan-2,4-dione The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole.

«EXAMPLE 91 -. { (E) - [5- (benzyloxy) -1- (4-chlorobenzyl) -lH-indol-2-yl] methylidin} -l, 3-thiazolan-2,4-dione The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole.

EXAMPLE 92 5-. { (E) - Í5- (benzyloxy) -1- (2-naphthylmethyl) -lH-indol-2-yl] methylidene} -l, 3-thiazolan-2,4-dione The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole.

EXAMPLE 93 5-. { (E) -TI- (4-benzylbenzyl) -5- (benzyloxy) -lH-indol-2-yl] methylidene} -l, 3-thiazolan-2, 4-dione - The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole. 15 EXAMPLE 94 -. { (E) -15- (benzyloxy) -1- (4-chlorobenzyl) -lH-indol-2-yl] methylidene} -l.3-thiazolan-2,4-dione The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole.

EXAMPLE 95 25 S ^^ A «gj¡j» $$ g ^ S ^ 5- ((E) -. {5- (benzyloxy) -1- [2-bis (trifluoromethyl) -benzyl] -lH- indol-2-yl.}. methylidene.}. -l.3-thiazolan-2,4-dione The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole.

EXAMPLE 96 2- (5- { (E) -t5- (benzyloxy) -l- (4. {[[3,5- 10 bis (trifluoromethyl) phenoxy] methyl} benzyl) -lH-indole-2- acid il] methylidene.} -2,4-dioxo-l, 3-thiazolan-3-yl) acetic- Step 1 - The desired intermediate is prepared as illustrated in Example 88, Step 1, starting from the appropriate indole. Step 2 - The desired intermediate is prepared from the above intermediate, as illustrated in example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound is prepared from the above intermediate as illustrated in Example 88, Step 3.

EXAMPLE 97 «^ -. Aa-A ^ • *» * * - '•' * '> • '».-» - «. .... - ^. . > . "".""- ,' - -TO. -., "T 'i *, ia A- Íí ??. 4- [(5- { (E) - C5- (Benzyloxy) -1- (4-chlorobenzyl) -1H-indol-2-yl] methylidene} -2,4-dioxo-l, 3 -thiazolan-3-yl) methyl] benzoic acid Stage 1 - The desired intermediate is prepared as illustrated - in Example 88, step 1, from the appropriate indole. Step 2 - Prepare the desired intermediate from the above intermediate, as illustrated in Example 88, Step 2, using the appropriate alkylating agent. Step 3 - The title compound is prepared from the above intermediate as illustrated in example 88, step 3.

EXAMPLE 98 Acid2- (5- "(E) -15- (benzyloxy) -1- (2-naphthylmethyl) -1H-indol-2-yl] methylidene} -2,4-dioxo-l, 3-thiazolan-3 -il) acetic Step 1 - The desired intermediate is prepared as illustrated in Example 88, Step 1, from the appropriate indole. Step 2 - Prepare the desired intermediate from the above intermediate, as illustrated in Example 88, Step 2, using the appropriate alkylating agent. . w! A < M * Atimt! &A ~ > ¿, * ^ T ... ....,. . ^ ... ^ .. A .i. TO. . , +,. . .. .... "T, j ... ^,., ^ 1, ...... ._".-I ,. ,. _t. ,, .. ".],. "J. ÍvSASTA *! Step 3 - The title compound is prepared from the above intermediate as illustrated in example 88, step 3.

EXAMPLE 99 2- [(5- { (E) - [5- (benzyloxy) -1- (2-naphthyl ethyl) -1H-indol-2-yl] methylidene} -2,4-dioxo-1.3 acid -thiazolan-3-yl) methyl] benzoic acid Step 1 - The desired intermediate is prepared as illustrated in Example 88, Step 1, starting from the appropriate indole Step 2 - The desired intermediate is prepared from the above intermediate, as illustrated in Example 88, Step 2 , using the appropriate alkylating agent Step 3 - The title compound is prepared from the above intermediate as illustrated in example 88, step 3.

EXAMPLE 100 Acid2- (5- { (E) - [5- (benzyloxy) -1- (4-chlorobenzyl) -1H-indol-2-yl] methylidene} -2., 4-dioxo-l, 3 -thiazolan-3-yl) acetic Step 1 - The desired intermediate is prepared as illustrated in example 88, step 1, starting from the appropriate indole. Step 2 - Prepare the desired intermediate from the previous intermediate, as illustrated in Example 88; Step 2, using the appropriate alkylating agent. Step 3 - The title compound is prepared from the above intermediate as illustrated in example 88, step 3.

The compounds of the following Examples 101-106 are prepared as illustrated in Example 88, Step 1, from the appropriate indole and rhodamine.

EXAMPLE 101 - ((E) -. {5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) -benzyl] -lH-indol-2-yl} -methylidene) -2-thioxo-1, 3-thiazolan-4-one EXAMPLE 102 -. { (E) - [5- (benzyloxy) -1- (2-naphthylmethyl) -benzyl] -1H-indol-2-illmethylidene} -2-thioxo-1, 3-thiazolan-4-one EXAMPLE 103 5- f (E) - (5- (benzyloxy) -1-C3- -T3, 5-bis (trifluoromethyl) • phenoxy] propyl'V-lH-indol-2-yl) methylidene] -2- thioxo-l.3-thiazolan-4- ona EXAMPLE 104 -. { (E) - [5- (benzyloxy) -1- (4-chlorobenzyl) -lH-indol-2-yl] methylidene} -2-thioxo-1,3-thiazolan-4-one Gl 1418 EXAMPLE 105 - (E) - [1- (4-benzylbenzyl) -5- (benzyloxy) -lH-indol-2-yl] methylidene} -2-thioxo-l, 3-thiazolan-4-one 15 EXAMPLE 106 - . 5 - . { (E) - [5 - (b en i l ox i) - 1 - (4 - {T 3. 5-bis (trifluoromethyl) phenoxy] benzyl) -lH-indol-2-illmethylidn} -2 '20 thioxo-1, 3-thiazolan-4-one EXAMPLE 107 4-T 15- ((E) -5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} methylidene) -4-oxo-2 acid - thioxo-1, 3-thiazolan-3-ill ethyl} benzoic Step 1 - The desired intermediate is prepared as illustrated 1 in Example 88, Step 1, from the appropriate indole. Step 2 - The desired intermediate is prepared from the above intermediate, as illustrated in example 88, step 2, using the appropriate alkylating agent. Step 3 - The title compound is prepared from the above intermediate as illustrated in example 88, step 3.

EXAMPLE 108 - ((E) -. {5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) -bnsyl] -1H-indol-2-yl) methylidene} -2-thioxotetrahydro-4H-imidazol-4-one The title compound is prepared as illustrated in Example 88, Step 1, from the appropriate indole and 2-thiohydantoin.

EXAMPLE 109 . ^^^^^^^ j¡¡ ^ ^ ¿l-Benzyl-5- (2-thienyl) -1H-indole-2-carboxylic acid To a sealed tube containing 2- [5-bromo-l-benzyl-lH-indole-2-carboxylic acid (100 mg, 0.303 mmol) and 5-thiopheneboronic acid (116 mg, 0.909 mmol), is added to 100 ° C for 23 hours (C6Hs) 4Pd (42 mg, 0.036 mmol), 2.42 mmol Na2C03 in a mixture of benzene-ethanol-H20 (5/1/2 = v / v, 4.5 ml). The mixture is poured into diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer is washed with NaH2P04, dried over MgSO4 and evaporated to give the crude product, which is purified on a column of silica gel (15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product. .

EXAMPLE 110 - (1-Benzofuran-2-yl) -l-benzyl-lH-indole-2-carboxylic acid The title compound is prepared according to the procedure described in Example 109, except that benzo [b] fran-2 -boronic acid is used.

EXAMPLE 111 25 ^ ¡Gg .uAait iU? ^ Á '- "--- ^" ^ - l-Benzyl-5- (4-fluorophenyl) -lH-indole-2-carboxylic acid The title compound is prepared according to the procedure described in Example 109, except that 4-fluorophenylboronic acid is used.

EXAMPLE 112 l-Benzyl-5- (3-methoxyphenyl) -lH-indole-2-carboxylic acid - The title compound is prepared according to the procedure described in Example 109, except that 3-methoxyphenylboronic acid is used.

EXAMPLE 113 L-Benzyl-5-phenyl-lH-indole-2-carboxylic acid The title compound is prepared according to the procedure described in Example 109, except that phenylboronic acid is used.

EXAMPLE 114 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid To 5-bromoindol-2-carboxylic acid (1024 g, 4.26 mmol) in 13 ml of l-methyl-2-pyrrolidinone at 0 ° C is added 25.6 mmoles of iPr2NEt, tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture is heated at 50 ° C for 21 hours before being partitioned between diethyl ether and ice water. After adjusting to pH 3, the aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with NaH2P04, dried over MgSO4 and evaporated to dryness. Column purification of silica gel (15% EtOAc in hexane) provides 1.51 g (87% yield) of the product.

EXAMPLE 115 - [3- (Acetylamino) phenyl] -1-benzhydryl-lH-indole-2-carboxylic acid The title compound is prepared according to the procedure described in Example 109, except that 3-acetamidobenzeneboronic acid and 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid are used.

EXAMPLE 116 * ***., ^ * ¿,., "" "" < > . ** »*,». , > .a ^ & - * # ¿j, jj ?? u m - & L-benzhydril-5- (2-thienyl) -lH-indole-2-carboxylic acid The title compound is prepared according to the procedure described in Example 109, except that l-benzhydryl-5-bromo-lH-indole-2-carboxylic acid and 2-thiopheneboronic acid are used.

EXAMPLE 117A 10 A c i d o 5 - (b e n c i l or x i) -1 - [2, 4 bis (trifluoromethyl) encyl] -lH-indole -2 -carboxylic Step 1 To an ice-cooled (0 ° C) solution of 2-ethoxycarbonyl-5-benzyloxyindole (5.0 g, 16.9 mmol) in 50 ml of dimethylformamide was added sodium hydride (0.62 g, 18.6 mmol). The ice bath is removed after 10 minutes, and The reaction is stirred at RT for a 30 minute addition time at which bis (trifluoromethyl) benzyl bromide (3.8 ml, 20.3 mmol) is added dropwise. The green mixture is stirred at RT for 4 hours, water is added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4 and concentrated. The product tá & ücaißftJÉáiih LttíbriU & faA aL ^ -ük ^ 4 ^ ¡^ Jg. recrystallize from EtOAc / hex to give 6.87 g (81%) of the desired intermediate as a whitish powder.

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

EXAMPLE 117B - [(. {5- (Benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} carbonyl) amino] -2- [(5- chloro)] -3-pyridinyl) oxy] benzoic 20 Stage 1 To a solution of the above title compound (0.4 g, 0.8 mmol) in 5 ml CH2C12 and a few drops of DMF, is added Oxalyl chloride (0.2 ml, 2.4 mmol). The reaction is stirred for 1.5 hours and concentrate. The resulting yellow residue is dissolved in 2 ml of CH2C12 and added to a solution of pyridyl ether aminobenzoate (0.24 g, 0.8 mmole) and pyridine (0.1 ml, 0.9 mmole) in 8 ml of CH2C12. Reaction 5 is stirred overnight at RT, water is added and the product is extracted with CH2C12. The combined organic layers are washed with saturated NH4C1, water, brine, and dried over MgSO4. Concentration and flash chromatography (Hex / EtOAc, 3/2) gives 0.182 g (51%) of the desired intermediate as a tan solid.

Stage 2 To a solution of the above intermediate (0.136 g, 15 0.2 mmol) in 3 mL of THF, LiOH (0.022 g, 0.5 mmol) and 0.5 mL of water are added. The mixture is stirred overnight at RT, concentrated and the resulting residue is suspended in water and acidified with HOAc. The product is extracted with EtOAc, the combined organic layers are washed with water, brine and dried over MgSO4. The concentration gives 0.122 g of the title compound (94%) as a white crystalline solid.

EXAMPLE 117C - (Benzyloxy) -l- (4- {[[3,5- bis (trifluoromethyl) phenoxy] methyl} benzyl] -1H-indole-2-carboxylic acid The procedure is followed in EXAMPLE 117A, steps 1 and 2, using 2-ethoxycarbonyl-5-benzyloxyindole (2.0 g, 3.2 mmol) and the appropriate alkylating reagent, to provide 1. 7 g (41% for the two steps) of the title compound as a yellow solid.

EXAMPLE 117D - (Benzyloxy) -l- (4. {[[3,5-bis (trifluoromethyl) phenoxy] methyl} benzyl] -1H-indole-2-carboxylic acid The procedure is followed in EXAMPLE 117A, steps 1 and 2, using 2-ethoxycarbonyl-5-benzyloxyindole (2.0 g, 3.2 mmol) and the appropriate alkylating reagent, to provide 1.7 g (41% for the two steps) of the title compound as a yellow solid.

EXAMPLE 118 A c i d o 5 - (b e n c i l or x i) - 1 - [2,4-bis (trifluoromethyl) benzyl] -2- (1 H-1, 2, 3, 4-tetraazol-5-yl) -1H-indole Stage I To a suspension of the acid prepared in example 117A (1.5 g, 3.0 mmol) in 20 ml of CH2C12 is added oxalyl chloride (0.8 ml, 9.1 mmol) and 3 drops of DMF. The mixture becomes homogeneous and is stirred for 1 hour at RT. The reaction is concentrated and redissolved in 5 ml of CH2C12 and 2.0 ml of NH4OH are added. The biphasic mixture is mixed for 24 hours and concentrated. The remaining aqueous residue is extracted with CH2C12 and the combined organic layers are washed with brine, dried and concentrated to provide 1.4 g (95%) of the desired intermediate as a yellow powder.

Stage 2 To an ice cooled solution of DMF (0.23 ml, 3.0 mmol) in 10 ml of CH3CN is added oxalyl chloride (0.24 ml, 0.28 mmol). A white precipitate forms immediately and the solution is stirred for an additional 5 minutes. A solution of the above intermediate (1.2 g, 2.5 mmol) in 5 ml of CH3CN is added. The resulting yellow-orange solution is stirred for 10 minutes and pyridine (0.44 ml, 5.5 mmol) is added. After 5 minutes, the red mixture is partitioned between 10% aqueous HCl and EtOAc. The organic layer is dried and concentrated to provide 1.0 g (84%) of the desired intermediate as a yellow powder.

Step 3: GI1563 5- (Benzyloxy) -1 - (4 -. {[[3,5- bis (trifluoromethyl) phenoxy] methyl] benzyl) -1H-indole-2-carboxylic acid.

To a solution of the previous intermediate (0.94 g, 2. 0 mmole) in 10 ml of N-methyl-2-pyrrolidinone was added sodium azide (0.39 g, 5.9 mmol). The mixture is refluxed for 2 hours. The reaction is allowed to cool to RT and poured into 50 ml of ice water. The resulting solution is adjusted to pH = 2 with 10% aqueous HCl and a tan precipitate is formed. The mixture is filtered and washed with EtOAc. Flash chromatography (CH2Cl2 / MeOH, 10: 1) gives 0.78 g (78%) of the title compound as a white powder.

EXAMPLE 119 The ether acid is prepared- (4- {[3,5- bis (trifluoromethyl) phenoxy] methyl} benzyl) -2- (1H-1, 2,3,4-tetraazole-5-yl) ) -lH-indol-5-benzyl, in a way -ift *, *. ^, a ^ *, ._ _ -t __, _ "^. > - - «- > - analogous to that of Example 118, according to steps 1-3, from the acid prepared in EXAMPLE 117C.

EXAMPLE 120 5 4-f [5- ((E) -f5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} methylide acid} -4-oxo-2-thioxo-1,3-thiazolan-3-yl] methyl.} Benzoic acid Stage i The thiazolidinedione prepared in Example 101 (0.1 g, 0.2 mmol) is alkylated by treatment with sodium hydride (0.006 g, 0.22 mmol) and the SEM bromomethyl ester (0.058 g, 0.2 mmol) in 2 ml of DMF. Flash chromatography (Hex / EtOAc, 4/1) gives 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 5 ml of CH 3 CN, add 2 ml of 48% aqueous HF. After 2 hours, water is added and the product is extracted with EtOAc, the combined organic layers are washed with water, l toia * - ** '= -Ü - J-' * - - - f ..-. »•« .- - - i .t M- ^ a? ^, ..

Brine and dry over MgSO4. The "concentration provides 0.025 g of the title compound (42%) as an orange powder.

E-example 121 - . 5 - ((Z, 2 E) -3 - {5 - (benzyloxy) -1- [2,4-bis (trifluoromethyl) encyl] -lH-indol-2-yl.} -2- propenilidene) -1,3- thiazolan-2,4-dione Stage 1 A solution of the intermediate prepared in EXAMPLE 117A, step 1 (4.4 g, 8.4 mmol) in 30 ml of THF is cooled to 0 ° C, and a solution of lithium aluminum hydride in THF is added dropwise with vigorous stirring ( 1.0M, 8.4 ml). After 1 hour at 0 ° C, the reaction is carefully suspended with a saturated solution of NH 4 Cl. The salts are filtered and washed with EtOAc. The concentration of the solvents provides 3.9 g (96%) of the alcohol as a yellow foam. The alcohol (1.6 g, 3.3 mmol) is dissolved in 50 ml of THF and Mn02 (2.91 g, 33.4 mmol) is added. The reaction is stirred for 2 hours and filtered through a pad of Celite. The concentration of the filtrate gives 1.47 g (92%) of the desired intermediate as a thick clear oil.

Stage 2 To an ice-cooled solution of trimethylphosphonoacetate (0.5 ml, 3.1 mmol) in 10 ml of DMF, add sodium hydride (0.14 g, 3.4 mmol) and the reaction is stirred for 20 minutes. A solution of the above intermediate (1.47 g, 3.1 mmol) in 3 ml of DMF is added, the ice bath is removed and the reaction is allowed to stir overnight at RT. Water is added and the aqueous phase is extracted with EtOAc. The organic layer is washed with water, brine, dried over magnesium sulfate and concentrated. Flash chromatography (Hex / EtOAc, 3/2) gives 1.5 g (93%) of the desired intermediate as a yellow solid.

«Stage 3 The previous intermediate (0.5 g, 0.9 mmol) is dissolved in 10 ml of CH2C12 and the solution is cooled to -20 ° C. A solution of diisobutylaluminum hydride (1.0M in toluene, 1.9 ml) is added dropwise and the reaction is allowed to stir at RT overnight. Water is added, and the mixture is stirred through a pad of Celite. The filtrate is diluted with EtOAc, washed with water and the combined organic layers are washed with brine, dried and concentrated. Flash chromatography (Hex / EtOAc, 3/2) gives 0.49 g (75%) of an orange solid. This material is dissolved in 12 ml of THF and Mn02 (l.l g, 12.3 mmol) is added. The mixture is stirred overnight and filtered through a pad of Celite. The concentration of the solvent provides 0.4 g (65%) of the desired intermediate as a thick cinnamon oil.

Stage 4 The previous intermediate (0.1 g, 0.2 mmol) is dissolved in 1 ml of toluene, followed by piperidine (6 μl, 0.1 mmol), acetic acid (1.2 μl) and 2,4-thiazolidinedione (0.023 g, 0.2 mmol). The mixture is refluxed for 2 hours. The reaction is allowed to cool to RT, water is added and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried and concentrated. Flash chromatography (Hex / EtOA, 3/2) gives 0.056 g (47%) of the title compound as a red powder.

Example 122 - (b.snzyloxy) -1- (4. {[[3,5-bis (trifluoromethyl) -phenoxy] methyl] benzyl) -1H-indole-2-carboxylic acid Stage 1 * + < ** ***** To ethyl 5-benzyloxy-2-indolecarboxylate (1 g, 3.4 mmol) in 12 ml of DMF, sodium hydride (0.163 g, 60% oil dispersion, 4.07 mmol) is added at room temperature. ). The reaction is stirred for 30 minutes, α-bromo-a * - [3,5-bis (trifluoromethyl] phenoxy-p-xylene (1.54 g, 3.73 mmol) is added on * this occasion, and the reaction is stirred during the night When the reaction is complete (monitored by CCD), it is suspended with water, extracted with ethyl acetate (3X), the organic layers are dried over magnesium sulfate, concentrated and used for the next stage.

Stage 2 The ester (2.1 g, 3.39 mmol) is dissolved in 40 ml of THF / methanol l / l and then 15 ml of IN sodium hydroxide is added, and the resulting mixture is stirred for 16 hours at RT, the treatment gives the crude product which is purified via chromatography (hexane: ethyl acetate 1: 1, with acetic acid 1%) to provide (1.73 g, 85%) of the solid.

Example 123 - ( { [1-Benzyl-5- (benzyloxy) -lH-indol-2-yl] carbonyl}. Amino) isophthalic acid Step 1 This intermediate is prepared according to the procedure described in Example 122, but using benzyl bromide.

Stage 2 The acid (0.27 g, 0.75 mmole) prepared in step l, EDCI (0.18 g, 0.97 mmole), DMAP (3 mg, 0.02 mmole) and dimethyl-5-aminoisophthalate (0.18 g, 0.75 mmole) are dissolved in 8.8 ml of THF and refluxed for 16 hours, after treatment and purification (hexane: ethyl acetate 3: 1) is obtained (0.25 g, 60%) of the pure product.

Stage 3 The title compound is prepared from ester, prepared in step 2 above, according to the procedure described in step 2, example 122.

Example 124 (E) -3- 15 - (Benzyloxy) -1- (2-naphthylmethyl) -1H-indol-2-yl] -2-propenoic acid Step 1 Dissolves ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) in 250 ml of THF and cooled to 0 ° C, and lithium aluminum hydride (LAH) (225 ml of a 1 * OM solution in THF) is added via a funnel. addition, for 40 minutes. The reaction is stirred an additional 2 hours at 0 ° C and then treated by the addition of 190 ml of NaOH 4N. The resulting salts are filtered and washed with ethyl acetate (3 x 400 ml), the filtrates are combined and dried over MgSO4 and concentrate to provide 24.8 g (9-6%).

Stage 2 Indolic alcohol (26.1 g, 103 mmol) was dissolved in step 1 in 900 ml of THF. 106.6 g of the manganese dioxide are added and the mixture is stirred for 2 hours at room temperature. After the reaction is complete, the mixture is filtered through Celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, dried to provide the desired aldehyde (22.9 g, 89%).

Step 3 This intermediate is prepared from the indole, prepared in step 2 above, and 2-brornomethyl naphthalene, according to the procedure described in step 1, example 122. Step 4 Sodium hydride (0.025 g, 60% dispersion in oil, 0.63 mmol) in 7.5 ml of THF is added 10-trimethyl phosphonoacetate (0.1 ml, 0.62 mmol) in 2.5 ml of THF at room temperature. The reaction is stirred for 10 minutes. The aldehyde (0.24 g, 0.62 mmol) in step 3 above is then prepared in 2.5 ml of THF and added dropwise at room temperature. The reaction is stirred another 30 minutes 15 Example 133 2- ( { [3-Acetyl-1- [4- (1,3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzyloxy) -lH-indol-2-yl] methyl} sulfanyl) acetic Stage l P-Toluoyl chloride (0.8M) is added to 2.44 equivalents of triethylamine and methoxymethylamine hydrochloride. «... * .pf ta & ur .....? .. - - --- • »- '- - - .. ^ - .. ^ .., ..-», .. * ....,. ......... .. - - * - - • - • • «* - - ~~~ * A ** AJI * ~ (1.1 equivalents) dissolved in methylene chloride at 0 ° C for 20 minutes . The reaction is allowed to warm to 25 ° C. After stirring at 25 ° C for 1 day, treatment with methylene chloride and water gives the crude product with a yield of ca. 100% Stage 2 Under anhydrous conditions, benzothiazole is dissolved in THF (0.35M). At -78 ° C 1.1 BuLi equivalent is added. After 1 hour at -78 ° C, the amide from step 1 is added in THF, for 15 minutes. The reaction is allowed to warm to 25 ° C. After stirring at 25 ° C for 1 day, treatment with ethyl acetate and water and chromatography gives pure tolyl ketone product (52%).

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

Stage 4 The intermediate of step 3, example 131, is dissolved in dry DMF (0.1M) followed by 1.2 equivalents of NaH. After 1.5 hours at 25 ° C, the bromobenzyl ketone from step 3 is added and stirred for 1 day at 25 ° C. Treatment (ethyl acetate / hexanes) and trituration (ethyl acetate / hexanes) provides the product with 46% yield.

Stage " The product from step 4 is dissolved in methylene chloride and IN HCl (ca. 0.04M) and stirred at 25 ° C for 1 hour. Treatment (sodium bicarbonate) and trituration with ether gives the product alcohol (89%).

Stage 6 The alcohol from step 5 is dissolved in 0.014 M dry methylene chloride, treated with 1.2 equivalents of thionyl chloride and stirred at 25 ° C for 1 d. Concentration and trituration with ethyl acetate / hexanes gives 100% of the chloride product. The activity data for the compounds of Examples 88-135 are presented in Table VIII (assay described in Example 136) and in Table IX (test of Example 137).

Example 136 Activity test (a) Vesicle test _ L-palmitoyl-2- [1 C] arachidonylphosphatidylcholine (58 mCi / mmol) (final concentration 6 μM and 1,2-dioleylglycerol (final concentration 3 μM), and dried under a stream of nitrogen. add 50 mM Hepes, pH 7.5 (2x final lipid concentration) and the suspension is sonicated for 3 min at 4 ° C. 50 mM Hepes, pH 7.5, 300 mM NaCl, DTT 2 are added to the suspension. mM, 2 mM CaCl2 and 2 mg / ml bovine serum albumin (BSA) (Sigma A7511) (1.2x of the final concentration of lipids). A typical assay consists of 85 μl of a lipid mixture to which the inhibitor (5 μl in DMSO) and cPLA2, 10 ng for an automated system or 1 ng for a manual system, in 10 μl of buffer is added consecutively. BSA This test is carried out either by manual testing or by automated test protocol described below. (b) Soluble substrate assay (LysoPC). Dry 1- [14 C] -palmitoyl-2-hydroxyphosphatidylcholine (57 mCi / mmol) (final concentration 4.4 μM) under a stream of nitrogen. The lipid is resuspended by swirling 80 mM Hepes, pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consists of 85 μl of lipid suspension to which the inhibitor is added consecutively (5 μl in DMSO) and cPLA2, 200 ng in 80 mM Hepes, pH 7.5, 2 mM DTT and 1 M EDTA. it is carried out either by manual test protocol or automated test described below. 15 (f) RBL test RBL-2H3 cells are cultured routinely at 37 ° C in a 5% C02 atmosphere in minimal essential medium containing 20 non-essential amino acids and 12% fetal bovine serum. The day before the experiment, the cells are seeded in flasks for shaking at 3 x 10 6 cells / ml and 100 ng / ml of DNP-specific IgE are added. After 20 hours, the cells are harvested by centrifugation and washed once in serum-free minimum essential medium and resuspended at 2 x 10ß. , -ll »nm,? llMí? ht MHm- íil? l lt,. »•. , U.? I, fc «.» .., 4 - ,. ^^ ... ......, ,, ... -., ^ .. 4 .., .... "".-... ....... ..:. ^, ..... t. .. ^. "...... ... ^ ... í .." Juá * ¿(^ At-cells / ml in serum-free medium.) Then the cells are preincubated with either inhibitor in DMSO (1% v / v) or DMSO (1% v / v) for 15 minutes at 37 ° C followed by stimulation with 300 ng / ml of DNP-BSA After 6 minutes, the cells are removed by centrifugation and the supernatant is assayed to determine , the content of PGD2, according to known methods. (g) Coumarin test 7-Hydroxycarbazinyl 6-heptenoate is used as a monomeric substrate for cPLA2 as previously reported (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). Inhibitors are mixed with 200 μl of assay buffer (80 mM Hepes, pH 7.5, 1 mM EDTA) containing 60 μM 7-hydroxycumarinyl 6-heptenoate. The reaction is initiated by adding 4 μg of cPLA2 in 50 μl of assay buffer. The hydrolysis of the 7-hydroxycoumarinyl 6-heptanoate ester is monitored in a fluorometer by exciting at 360 nm and monitoring the emission at 460 nm. The enzymatic activity is proportional to the increase in emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is lower.

Eiemolo 137 Test for rat paw edema, induced by carrageenan Each compound is suspended in 0.3 ml of absolute ethanol, 0.1 ml of Tween-80 and 2.0 ml of Dulbecco's PBS (without calcium or magnesium). To this mixture is added 0.1 ml of 1 N NaOH. After the solution is complete, additional amounts of PBS are added to adjust the concentration to 1 mg / ml. All the compounds remain in solution. The compounds are administered i.v. in a volume of 5 ml / kg to male Sprague-Dawley rats at the same time as the edema is induced by injection of 0.05 ml of carrageenan type IV at 1% -in the plant of the hind paw. The volume of the paw plant is measured before dosing with the compound, and 3 hours after dosing with carrageenan.

TABLE 8 JJ ^^^^ ^^. ^^ j ^^^^^^^ a ^ ^ ^ f ^ & j ^ 89 50 37 90 50 30 90 50 23 90 50 24 90 50 28 90 50 38 91 50 18 91 50 25 92 50 18 92 -. 92 -50 22 93 50 12.5 93 55 12.5 ^^ gg ^ • "- * - * fa *" > »96 57 6.25 96 50 97 56 6.25 97 50 4.5 ^^ gf ^ 98 50 37 98 50 45 98 50 42 98 50 25 98 50 33 98 50 37 99 50 99 50 12 Jt '- * -' J - «* - g '- ^^^^ ¡^ S 100 50 100 50 101 50 9.5 101 50 10 101 50 12.5 101 50 14 101 50 17 101 50 22 101 50 10 102 50 16 102 50 18 102 50 25 103 50 15 - - 103 50 16 103 50 22 104 50 17 104 50 20 104 50 12 104 50 12 104 50 14 104 50 18 • & - * 105 50 18 105 50 16 106 50 106 50 12.5 ^ Mf ^ Ua ^ «M¡ - - 107 50 3.8 107 67 6.2 108 50 32 108 50 39 109 50 50 ^ ... «. ,. - - 109 50 55 110 50 50 110 50 50 111 50 13 - • -. ». * - * í. "-» '*' - ^ * "^« ^ - - 112 50 12.5 112 32 25 112 46 50 112 50 50 113 38 100 113 50 170 - * - * JññiiiTTffHw- • "-114 50 40 114 50 42 115 50 30 115 50 35 - - "- * -''- - - - * - *" - "" • '..,. **. UA ?. .... .. .....) | f (. R if TftÉLf trTffit nii - - ^^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^ > , ..-. - - ^ fcia ^. ^ .- s ^ at ** ^ ,. ^^ ¿^^^^^ jr¿ ^ g gjgjgeí ^^ - - 118 50 12 118 50 15 119 50 119 50 119 50 ^ t.t * * ja & »» * ^ - - 120 50 3.8 120 67 6.2 120 50 3.8 120 67 6.2 50 18.5 50 20 - - 122 50 3.75 122 50 10 123 -. 123 - 31 50 123 25 50 124 50 12.5 124 50 15 - - 125 50 23 126 50 17 126 50 18 127 50 28 127 50 86 - - - - 130 50 12 130 50 80 130 50 10 130 50 16 130 50 32 130 50 44 130 50 50 131 50 131 50 46 '' - ** "* ti'ifm iiiti - - 132A 50 132A 50 17 132A 50 30 132B _ 50 19 132B 50 20 ~ * t > i * ^ wa ^ 133 50 8.5 134 50 3.5 135 50 ^ * ¿^ ^ ^ ^ ^ ^ ^ ^ Ti, ^^^^^ ¿2 ^ ¿.

All patent and literature references mentioned herein are incorporated in their entirety as set forth herein. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (76)

CLAIMS Having described the invention as above, property is claimed as contained in the following:

1. A compound characterized in that it has a chemical formula that is selected from the group consisting of: or a pharmaceutically acceptable salt thereof, wherein: A is independent of any other group and is selected from the group consisting of -CH2- and -CH2-CH2-; B is independent of any other group and is selected from the group consisting of - (CH2) n-, - (CH20) n-, - (CH2S) n-, - (OCH2) n-, - (SCH2) n-, - (CH = CH) n-, - (C = C) n-, -C0N (R6) -, -N (R6) ) CO-, -O-, -S- and -N (R6) -; Ri is independent of any other group R and is selected from the group consisting of -X-R6, -H. -OH, halogen, -CN, -N02, C ^ - alkyl, alkenyl, alkynyl, aryl and substituted aryl; R2 is independent of any other group R and is selected from the group consisting of -H, -COOH, -CORs, -CONRsR6, - (CH2) nW- (CH2) nZ-Rs, - (CH2) nW-R5, -Z-R5, C ^ C ^ alkyl, alkenyl and substituted aryl; R3 is independent of any other group R and is selected from the group consisting of -H, -COOH, -COR5, -CONRsRs, - (CH2) nW- (CH2) nZ-Rs, - (CH2) n- -Rs, -Z-R5, C ^ C ^ alkyl, alkenyl and substituted aryl; R4 is independent of any other R group and is selected from the group consisting of -H, -OH, -OR6, -SR6, -CN, -COR6, '-.NHRβ, -COOH, -CONR6R7, -N02, -C0 .NHS02R8, C ^ Cs alkyl, alkenyl and substituted aryl; Rs is independent of any other R group and is selected from the group consisting of -H, -OH, -0 (CH2) nRs, -SR6, -CN, -CORß, -NHR6, -COOH, -N02, -COOH, -CONR6R7, -CONHS02R8, C1-C3 alkyl, alkenyl, alkynyl, aryl, substituted aryl, CF3, -CF2CF3 and Rβ is independent of any other group R is selected from the group consisting of -H, Ci-Cj alkyl, alkenyl, alkynyl, aryl and substituted aryl; R7 is independent of any other R group and is selected from the group consisting of -H, Ci-C3 alkyl, alkenyl, alkynyl, aryl and substituted aryl; R8 is independent of any other R group and is selected from the group consisting of C, -C3 alkyl, aryl and substituted aryl; R9 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -0R6, -COOH, -CONR6R7, tetrazole, -CONHS02R8, -C0R6, - (CH2) nCH (OH) R6 and (CH2) nCHR6R5; R10 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR6, -COOH, -CONR6R7, tetrazole, -CONHS02Rβ, -COR6, - (CH2 ) nCH (0H) R6 and (CH2) nCHR6Rs; is, independently of each time it is used included within the same compound, it is selected from the group consisting of -O-, -S-, -CH2-, -CH = CH-, -C = C- and -N ( Rß) -; X is independent of any other group and, independently of each time it is used included within the same compound, it is selected from the group consisting of -O-, -S- and -N (R6) -; ? ? -JtiX ** tS * > to. W ^. t-. *. . i. 4aet j, ... i-? Íi &m, im ?. r ", .... .j. , 4 »», fc. i 4 aaa-i > j ». > a "Z is independent of any other group and, independently of each time it is used included within the same compound, it is selected from the group consisting of -CH-, -0-, -S-, -N (R -, - CO-, -C0N (R6) - and -N (R6) C0-; m is independently of each time it is used, included within the same compound, an integer from 0 to 4; and n is independent of m is independently of each time it is used included within the same compound, it is an integer from 0 to 4.

2. The compound according to claim 1, characterized in that it has inhibitory activity of the enzyme phospholipase.

3. The compound according to claim 1, characterized in that the compound has the following chemical formula:

4. The compound according to claim 1, characterized in that the compound has the following chemical formula

5. The compound according to claim 1, characterized in that the compound has the following chemical formula: fifteen

6. The compound according to claim 1, characterized in that A is -CH2- and R2 is - (CH2) n-W- (CH2) B-ZRs.

The compound according to claim 6, characterized in that n is l. , m is 1, W is -S- and Z is -CO-.

8. The compound according to claim 7, characterized in that R5 is -NHR6.

9. The compound according to claim 8, characterized in that R6 is an aryl group 10 replaced.

10. The compound according to claim 9, characterized in that the aryl group is substituted with one or more substituents that are selected Independently of the group consisting of a halogen, -CF3, -CF2CF3, - (CH2) pCOOH, - (CH2) pCH3, -0 (CH2) pCH3, - (CH2) pOH, - (CH2) pS (C6H6), - (CH2) pCONH2 and -CHRnCOOH, wherein RxI is a group selected from the group consisting of alkyl, alkenyl, alkynyl, - (CH2) pOH and -0 (CH2) pCH3, and wherein p is a number 20 whole from 0 to 4.

11. The compound according to claim 6, characterized in that Rj is selected from the group consisting of -H and -OCH2 (C6H6). 25

12. The compound according to claim 6, characterized in that R3 is -CORs, Rs is -OCH2Rs and R6 is a substituted aryl group.

13. The compound according to claim 12, characterized in that the aryl group is substituted with one or more substituents that are selected from the group consisting of -CF3, -CF2CF3 and -C (CH3) 2CH2CH3.

14. A method for inhibiting the activity of the enzyme phospholipase of an enzyme, characterized in that it comprises administering to a subject mammal, a therapeutically effective amount of a compound according to claim 1.

15. A method for treating an inflammatory condition, characterized in that it comprises administering to a mammalian subject a therapeutically effective amount of a compound according to claim 1.

16. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A compound of the formula Characterized in that Ri and Rl are independently selected from Ci-Cg alkyl, -Z-Cx-C6 alkyl, phenyl, - (CH2) nZ- (CH2) n-phenyl, benzyl, - (CH2) nZ- ( CH2) n-benzyl, naphthyl, - (CH2) nZ- (CH2) n-naphthyl, pyrimidinyl, - (CH2) nZ- (CH2) n-pyrimidinyl, the groups Alkyl, phenyl, benzyl, naphthyl and pyrimidinyl are optionally substituted by 1 to 3 substituents which are selected from halogen, C 1 -C 6 alkyl, alkoxy of -N 0 2, -NH 2, -CN, -CF 3, or -OH; Z is O O S; 20 n is an integer from 0 to 3; R 2 is selected from H, halogen, -CF 3, -OH, -alkyl from CÍ-CÍO, alkoxy from ^ -C ^, -CHO, -CN, -N02, -NH2, -NH-alkyl from CÍ-CJ, - N (C1-C6 alkyl) 2, -N-S02-C 1 Cs alkyl or -S02- C 1 -C β alkyl; MMte? || ga¡gtt- & i ^ H £ i .AAÁMÍUiHÍI R3 is selected from H, halogen, -CF3, -OH, -alkyl from CÍ-CJ.0, alkoxy from CÍ-CÍO, -CHO, - C (0) CH3, -C (O) - (CH2) n-CF3, -CN, -N02, -NH2, -NH-alkyl of -N (C1-C6 alkyl) 2, -N-S02-alkyl of Ci-Cg or -S02-Ci-Cg alkyl or a portion of the formula: n each time it appears, it is independently selected as an integer that is selected from 0-3; R8 and R9 are independently selected, each time they occur from, H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, alkyl of -O-alkyl of -NH (alkyl of, or -N (C1-C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC ( 0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L ^ M1 portion or a portion of the formulas: A.A..Í »t -" "" ^ - R12 is selected from H, -CF3, alkyl of - (CH2) n-C3-C3 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 groups which are selected from halogen, - CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl fifteen - . 15-O-alkyl of -NH (Ci-Cg alkyl), or -N (alkyl of L1 is selected from - (CH2) n-0-, - (CHa) n-S-; - (CH2) n-0- (CH2) n-; - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) n-0-, -C (0) -N-, or (CH2) nS- (CH2) nC (0) -N-; 20 M1 is -COOH or a portion that is selected from: ----- «'• - * R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3 / -OH, - (CH2) nC ( 0) -COOH, -alkyl of -0-alkyl of with the proviso that the portion or combination of portions comprising R3 include an acid group that is selected from carboxylic acid or a portion of the formulas: . . ,, ». I H iM8iii ^ R5 is selected from: a) a portion of the formula -L2-2; L2 is selected from a chemical bond or a bridging group, which is selected from - (CH2) nZ-, - (CH2) nZ- (CH2) n-, -C (0) -0-, -C ( 0) - (CH2) n-0-, -C (0) -N-, or - (CH2) nS- (CH2) nC (0) -N-; > M2 is selected from -Ci-Cg alkyl, -O-C -C alkyl wherein R8 and R9 are as defined above, and may be substituted anywhere in the cyclic or bicyclic ring; or b) a portion of the formulas: wherein L3 is a chemical bond or a group selected from -CH2-, -CH2-Z-, -C (0) -, -0-, -S- O - (CH2) nZ- (CH2) n-; M3 are selected from - (CH2) n-C3-C3 cycloalkyl / furanyl, thienyl, pyrrolyl, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17, characterized in that it is of the formula . . . .. ..., .., ^ where R1 'and R2 are hydrogen, and the portions R3, R4, Rs, R8, R9 and R10, n, L1, L2, M1 and M2 are as defined in accordance with Claim 17, or a pharmaceutically acceptable salt thereof.

19. A compound of the formula: Characterized in that Rx is selected from -O-Ci-Cg alkyl, -S-Ci-Cg alkyl, -O-phenyl, -S-phenyl, -O-benzyl, -S-benzyl, alkyl, phenyl groups or benzyl are optionally substituted by the 3 substituents which are selected from halogen, Ci-Cg alkyl, -N02 alkoxy, -NH2, -CN, -CF3 or -OH; R 2 is selected from H, halogen, -CF 3, -OH, -alkyl from C 1 -C 0, preferably C 1 -Cg alkyl, C 1 CK alkoxy, preferably Cg alkoxy, -CHO, -CN, -N0 2, -NH2, -NH- *. ****** »*. * ***! I -, .jk ~ *? .. I. The alkyl of -C8, -N (alkyl of -N-S02-alkyl of or -S02-Ci-Cg alkyl, - R3 is selected from H, halogen, -CF3, OH-, -alkyl of CÍ-CÍO, preferably -alkoxy of preferably alkoxy of Cj-Cg, -CHO, -CN, -N02, -NH2, -NH- alkyl of Ci- Cg, -N (-N-S02 alkyl-S02-alkyl of Cj-Cg, or a portion of the formula: 10 15 n each time it appears, it is independently selected as an integer that is selected from 0-3; R8 and R9 are independently selected, each time they occur from, H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC ( 0) -COOH, C 1 -C 7 alkyl, -O-Ci-Cg alkyl, -NH (Ci-Cg alkyl), or -N (R 4 alkyl is the -L 1 -M 1 portion or L1 is selected from a chemical bond or a group that forms a bridge, which is selected from - (CH2) n-0-, - (CH2) nS-, - (CH2) n-0- (CH2) n-, - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) n-0-, -C (0) -N-, O- (CH2) nS - (CH2) nC (0) -N-; M1 is the portion: fifteen RIO is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of -0- Ci-Cg alkyl, ^ a¡M? Ítá? Jlt ?? iííl ^ M *? mA? A ^ A¿ A s ^. A ** - «. A .. with the proviso that the portion or combination of portions comprising R4 include a carboxylic acid or a portion of the formulas: R5 is a structure of the formula -L2-M2; L2 is selected from a chemical bond or a bridging group, which is selected from - (CH2) n-0-, - (CH2) n-S-, ^^ - ^^ - (CH2) n-0- (CH2) n-, - (CH2) nS- (CH2) n-, -C (0) -0-, -C (O) - (CH2) n -0-, -C (0) -N-, O - (CH2) nS- (CH2) nC (0) -N-; M2 is selected from -O-alkyl-alkyl wherein R8, R9 and R10 are as defined in the foregoing; or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, of the formula characterized because . > ijj, t. , Rx is selected from -O-alkyl-S-alkyl of C ^ -C8, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 substituents which are selected from halogen, Ci-Cg alkyl, Cx-Cg alkoxy, -N02, -NH2, -CN, -CF3 or -OH; R3 is selected from H, halogen, -CF3, OH-, -C1-C10alkyl, preferably -C1-C3alkyl ,, C4C4alkoxy, preferably -CHO alkoxy, -CN, -N02 , -NH2, -NH- Ci-Cg alkyl, -N (Cj-Cgjj alkyl, -N-S02-S02 alkyl-Cx-Cg alkyl, or a portion of the formula: wherein R 4, R 5, R 8, R 9 and R 10 are as defined according to claim 19, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 17 or a salt The pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of a compound according to claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A compound of the formula: characterized in that Rj and R are independently selected from H, halogen, -CF3, -OH, alkyl-C ^, preferably-Cx-Cg alkyl, -S-C ^ alkyl, preferably S-Ci alkyl -Cg, ^ - C ^ alkoxy, preferably Cx-Cg alkoxy, -CN, -N02, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or a ring portion of groups a), b) or c), ^ ju ^ JM m below, attached directly to the indole ring or linked to the indole ring by a bridge -S-; -0- or - (CH2) n-; a) a five-membered heterocyclic ring containing one or two heteroatoms in the ring that are selected 5 N, S or 0 and which include, but are not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the Five membered heterocyclic ring is optionally substituted with 1 to 3 substituents which are selected from halogen, Ci-Cxo alkyl, preferably preferably alkyl, Cx-Cg alkoxy, -N02, -NH2, -CN, -CF3, ) a heterocyclic six-membered ring containing one, two or three heteroatoms in the ring which is "15 selected from N, S or 0 and which include, but are not limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadiazine, oxazine or morpholine, the six-membered heterocyclic ring is optionally substituted with one to three substituents which are 20 are selected from halogen, C, -C.sub.10 alkyl, preferably alkyl, preferably alkoxy, Cx-Cg, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or c) a bicyclic ring portion that optionally contains 1 to 3 ring heteroatoms that are 25 select from N, S or 0 and include, but are not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolisina, indazole, quinoline, isoquinoline, quinolisina, quinazoline, cinnoline, phthalazine or naphthyridine portion bicyclic ring is optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 4 alkoxy alkyl, preferably Ci-Cg alkoxy, -CHO, -N02, -NH 2, -CN, -CF 3 or -OH; or d) a portion of the formulas: 10 25 - nirtMinn.fr iluftf iWiiMft m -., t n wi ,, .n m and. ^. .t ... .. ._. ... ^. , "^. ... __. ..... - * ....... Z is O or S; R 6 is selected from the relevant members of the group H, -CF 3, C 1 -C 4 alkyl, preferably C 1 -C 6 alkyl, Ci-Cm alkoxy, preferably C 1 -C 4 alkoxy, phenyl, -0-phenyl, - S-phenyl, benzyl, -O-benzyl or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted with 1 to 3 substituents selected from halogen, alkyl preferably Ci-Cg alkyl, alkoxy Cx -C ^, preferably Ci-Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; R 7 is selected from the relevant members of the group -OH, -CF 3, C 1 -C 4 alkyl, preferably Ci-Cg alkyl, C 1 -C 4 alkoxy, preferably Ci-Cg alkoxy, -NH 2, - (CH 2) n-NH2, -NH- (Cx-Cg alkyl), -N- (alkyl of - (CH2) n-NH- (C-C6 alkyl), - (CH2) nN- (Ci-Cg alkyl) , phenyl, 0-phenyl, benzyl or -O-benzyl, or a) a five-membered heterocyclic ring containing one or two heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring is optionally substituted by the 3 substituents selected from halogen , I rent^^^^. Ci-Cxo, preferably Ci-Cg alkyl, Cx-C10 alkoxy, preferably Ci-Cg alkoxy, -N02, -NH2, -CN, or -CF3; or b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms that are selected from N, S or 0 and include, but are not limited to pyran pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine , tetrazine, thiazine, tiadizine, oxazine or morpholine, the six-membered heterocyclic ring is optionally substituted by 1 to 3 substituents which are selected from halogen, Cx-C10 alkyl, preferably Cx-Cg alkyl, Cx-C ^ alkoxy , preferably Cj-Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; c) a bicyclic ring portion containing 8 to 10 ring atoms and optionally containing 1 to 3 heteroatoms in the ring, which are selected from N, S or O and include, but are not limited to, benzofuran , chromene, indole, isoindole, indoline, isoindoline, naphthalene, purine, indolysin, indazole, quinoline, isoquinoline, quinolysin, quinazoline, cinoline, phthalazine or naphthyridine, the bicyclic ring portion is optionally substituted with 1 to 3 substituents selected from halogen, C 1 -C 4 alkyl, preferably C 1 -Cg alkyl, C 1 -C 4 alkoxy, preferably C 1 -C 4 alkoxy, -CHO, -N0 2, -NH 2, -CN, -CF 3 or -OH; ? n is an integer from 0 to 3, preferably 1 to 3, and more preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of C? -C? 0, preferably C? -C6 alkyl, C? -C10 alkoxy, preferably C? -C6 alkoxy, -CHO, -CN, -N02, -NH2, -NH-C-C6 alkyl, -N (C1-C6 alkyl) 2, -N-S02-alkyl of Ci-Cg or -S02-Cx-Cß alkyl; R3 is selected from H, halogen, -CF3, -OH, -alkyl of C? -C10, alkoxy of Cx-Cxo, -CHO, -C (0) CH3, -C (0) - (CH2) n-CF3 , -CN, -N02, -NH2, -NH-C-C6-alkyl, -N (C-C6-alkyl) 2, -N-S02-C-C6-alkyl or -S02-Cx-alkyl -C6, phenyl, phenyloxy, benzyl, benzyloxy, -C (O) -phenyl, -C (O) -benzyl, -CH2- (C3-C6 cycloalkyl), -C (0) -OH, C (O ) -alkyl of C? -Cβ, -C (O) -O-C? -C6 alkyl, -C (0) -CF3, - (CH2) nS-CH2- (C3-C3 cycloalkyl), the rings of the relevant R3 groups are optionally substituted by 1 to 3 groups which are selected from halogen, C? -C6 alkyl, C? -Cg alkoxy, -N02, -CF3, -C (0) -0H, or -OH; or a portion of the formula: n each time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time they occur of H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, C? -C6 alkyl, -O-C? -C? Alkyl, -NH (C? -C6 alkyl), or -N (C? -C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L ^ M1 portion or a portion of the formulas: 10 fifteen twenty R12 is selected from H, -CF3, C? -C6 alkyl, - (CH2) n-C3-C6 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted 25 for 1 to 3 groups that are selected from halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of C? -C (, -O-C? -C6 alkyl / -NH (C? -C3 alkyl) ), or -N (alkyl) L1 is selected from - (CH2) n-, -S-, -O-, -C (O) -, -CÍO) -O-, - (CH2) n-0-, - (CH2) n-S-; - (CH2) n-0- (CH2) n-; - (CH2) nS- (CH2) n-, - (CH2) nC (0) - (CH2) n-, - (CH2) n -0- (CH2) n-, - (CH2) nS- (CH2) n-, -C (Z) -N (Rg) -C (Z) -N (Rg) - (CH2) n, -C (O) -C (Z) -N (R6) -C (O) - C (Z) -N (RS) - (CH2) n-; -C (Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (O) - (CH2) n-0-, -C (0) -N-, O - (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: - - '* • »(lower alkyl of C? -C3) (lower haloalkyl of C? -C6) Rβ, each time it occurs, is independently selected from H, -COOH, - (CH 2) n -COOH, - (CH 2) n-C (0) -COOH, tetrazole, Vo R9, each time it occurs is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CHa) nC (0) -COOH, -alkyl Cx-Cg , -O-C? -C6 alkyl, -NH- (C? -C? Alkyl), or -N (C? -C6 alkyl) 2; RIO is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl of C? -C6, -0-C-C6 alkyl, (lower alkyl of C? -C6 (lower haloalkyl of C? -C6 - Rxx is selected from H, lower alkyl of C? -C6, cycloalkyl of C? -C6, -CF ,, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, 10 with the proviso that the portion or combination of portions comprising R4 include an acid group that is selected from 15 carboxylic acid, a tetrazole or a portion of the formulas: ^^^^ j ^^^^^^^ w »¿^ R5 is selected from lower alkyl of C? -Cg, lower alkoxy of C? -C6, - (CH2) n-cycloalkyl of C3-C10, - (CH2) nS- (CH2) n-cycloalkyl of C3-C10, - (CH2) n-0- (CH2) n-cycloalkyl of C3-C? 0, or the groups of: a) - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl , - (CH2) n-0-phenyl-CH2-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (O) -benzothiazole or a portion of the formulas: ^ ACH2) n- ^ A ii2) n ^ where n is an integer from 0 to 3, preferably 1 to 3, and most preferably 1 to 2, Y is a C3-C3 cycloalkyl, or a) a ring a five-membered heterocyclic containing one or two heteroatoms in the ring selected from N, S or 0 and including, but not limited to furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring is optionally substituted with 1 to 3 substituents which are selected from halogen, C? -C? 0 alkyl, preferably C? -C6 alkyl , C? -C10 alkoxy, preferably C? -C6 alkoxy, -N02, -NH2, -CN, -CF3, or b) a six-membered heterocyclic ring containing one, two or three heteroatoms in the ring that is they select from N, S or 0 and include, but are not limited to pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine , tetrazine, thiazine, thiadiazine, oxazine or morpholine, the six-membered heterocyclic ring is optionally substituted with one to three substituents that are selected from halogen, C? -C10 alkyl, preferably C? -C6 alkyl, C alkoxy? -C? 0, preferably C? -C6 alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; OR c) a bicyclic ring portion containing 8 to 10 atoms and optionally containing 1 to 3"Ite ^ heteroatoms in the ring that are selected from N, S or 0 and include, but are not limited to benzofuran, chromene, indole, isoindol, indoline, isoindoline, naphthalene, purine, indolisine, indazole, quinoline, isoquinoline , quinolysine, quinazoline, cinoline, phthalazine or naphthyridine, the bicyclic ring portion is optionally substituted with 1 to 3 substituents which are selected from halogen, C? -C10 alkyl, preferably C? -C6 alkyl, C? C? 0, preferably C? -C6 alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or d) a portion of the formulas - (CH2) n-A, - (CH2) n-S-A, or - (CH2) n-0-A-, where A is the portion: wherein D is H, C? -C6 lower alkyl, C? -C6 lower alkoxy, -CF3 or - (CH2) n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, - * - each optionally substituted by 1 to 3, preferably 1 to 2, substituents which are selected from H, halogen, -CN, -CHO, -CF3 / -OH, -alkyl of C? -Cβ, alkoxy of C? -C6, -NH2 or -N02; or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 23, characterized in that it has the formula characterized in that x is selected from H, halogen, -CF3, -OH, -alkyl of C? -C? 0, preferably -alkyl of C? -C6, -S-alkyl of c? _c? or preferably -S-alkyl of C? -C6, C? -C10 alkoxy, preferably C? -Cg alkoxy, -CN, -N02, -NH2, phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, S -benzyl; or a ring portion of groups a), b) or c), below, attached directly to the indole ring or linked to the indole ring by a bridge -S-, -0- or - (CH2) n-; a) furan, pyrrole or thiophene, which is optionally substituted by 1 to 3 substituents which are selected from halogen, C?-C10 alquilo alkyl, preferably Cx-C alquilo alkyl, C?-C? alco alkoxy, preferably C alco-alkoxy; ? -C6, -N02, -NH2, -CN, -CF3; or b) pyridine, pyrimidine, piperidine or morpholine, each optionally substituted with 1 to 3 substituents which are selected from halogen, C? -C? 0 alkyl, preferably C? -C6 alkyl, C? -C alkoxy? 0, preferably C? -C6 alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; or c) benzofuran, indole, naphthalene, purine or quinoline, each optionally substituted with the 3 substituents selected from halogen, C 1 -C 10 alkyl, preferably C 1 -Cg alkyl, C 1 -C 0 alkoxy , preferably C? -C6 alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; OR d) a portion of the formulas: R ^ Z is O or S; Rg is selected from the relevant members of the group H, -CF3, C? -C? 0 alkyl, preferably C? -C6 alkyl, C? -C10 alkoxy, preferably C? -C6 alkoxy, phenyl, -0 -phenyl, -S-phenyl, benzyl, -O-benzyl or -S-benzyl, the phenyl and benzyl rings of these groups are optionally substituted with 1 to 3 substituents which are selected from halogen, C? -C10 alkyl, preferably C? -C6 alkyl, C? -C? 0 alkoxy, preferably C? -C6 alkoxy, -CHO, -N02 / -NH2, -CN, -CF3 or -OH; R7 is selected from the relevant members of the group -OH, -CF3, C? -C? 0 alkyl, preferably C? -C6 alkyl, C? -C? 0 alkoxy, preferably C? -C6 alkoxy, -NH2, - (CH2) n-NH2 , -NH- (C? -C? Alkyl), -N- (C? -C6 alkyl) 2, - (CH2) n-NH- (Cx-C6 alkyl), - (CH2) n, N- (C? -C6 alkyl) 2, phenyl, O-phenyl, benzyl or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole or morpholine, the rings of these groups are optionally substituted by 1 to 3 substituents selected from halogen, C? -C10 alkyl, preferably C? -C6 alkyl, C? -C10 alkoxy, preferably C? -Cg alkoxy, -CHO, -N02, -NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, and more preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of C? -C? 0, preferably C? -C6 alkyl, C? -C? 0 alkoxy, preferably C-alkoxy; -C6, -CHO, -CN, -N02, -NH2, -NH-C-C6 alkyl, -N (C? -C6 alkyl) 2, -N-S02-C? -C? Alkyl or -S02-C6-C6 alkyl; R3 is selected from H, halogen, -CF3, -OH, -alkyl of C? -C? 0, alkoxy of C? -C? 0, -CHO, -C (0) CH3, -C (O) - ( CH2) n-CF3, -CN, -N02, -NH2, -NH-C-C6 alkyl, -N (C? -C6 alkyl) 2, -N-S02-C? -C6 alkyl or -S02-C? -C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy, -C (O) -phenyl, -C (O) -benzyl, -CH2- (C3-C5 cycloalkyl), -C (0) -OH, C (O) -alkyl C? -Cg, -C (O) -O-C? -C3 alkyl, -C (0) -CF3, - (CH2) nS-CH2- (C3-C5 cycloalkyl), the rings of the R3 groups relevant are optionally substituted by 1 to 3 groups which are selected from halogen, C? -C6 alkyl, C? -C6 alkoxy, -N02, -CF3, -C (0) -OH, or -OH; or a portion of the formula: n every time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time from H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, C? -C6 alkyl, C? -C6 -O-alkyl, -NH (C? -C6 alkyl), or -N (C? -C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n-C00H, - (CH2) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L ^ M1 portion or a portion of the formulas: 25 l? jhátt &x * * - 5 t & v ^? -a. * "R12 is selected from H, -CF3, C? -C6 alkyl, - (CH2) nC3-C3 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of C? -C6, -O-alkyl • of C? -C6, -NH (C? -C6 alkyl), or -N (x-C6 alkyl) 2; L1 is selected from - (CH2) n-, -S-, -O-, -C (O) -, -CÍO) -O-, - (CH2) n-0-, - (CH2) n-S-; - (CH2) n-0- (CH2) n-; - (CH2) nS- 10 (CH2) n-, - (CH2) nC (0) - (CH2) n-, - (CH2) n -0- (CH2) n-, - (CH2) nS- (CH2) ) n-, C (Z) -N- (R6) -, -C (Z) -N (R6) - (CH2) n-, -C (O) -C (Z) -N (R6) -, -C (0) -C (Z) -N (R6) - (CH2) n-; -C (.Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (O) - (CH2) n-0-, -C (0) -N-, or - (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: twenty (lower alkyl of C? -C6) (lower haloalkyl of C? -C6) Rβ, each time it occurs, is independently selected from H, -COOH, - (CH 2) n -COOH, - (CH 2) n-C (0) -COOH, tetrazole, R9, each time it occurs is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -alkyl of C? -C6 , -O-C de-C6 alkyl, -NH- (C?-C6 alkyl), or -N (C?-C6 alkyl) 2; R10 is selected from H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0) -COOH, -alkyl C -C6, -0-C-C6 alkyl, (lower alkyl of C? -C6 (lower haloalkyl of C? -C6"•" * - »with the proviso that the portion or combination of portions comprising R4 include an acid group selected from carboxylic acid, a tetrazole or a portion of the formulas: Rs is selected from C? -C6 lower alkyl, C? -C6 lower alkoxy, C3-C10 - (CH2) n-cycloalkyl, - (CH2) nS- (CH2) n C3-C10 cycloalkyl, - (CH2) n-0- (CH2) n-C3-C10 cycloalkyl, - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) n-0- phenyl-CHa-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (O) -benzothiazole or a portion of the formulas - (CH2) nA, - (CH2) nSA, or - (CH2) n-0-A, where A is the portion: D is H, C? -C6 lower alkyl, C? -Cg lower alkoxy, -CF3 O- (CH2) n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by 3, preferably 1 to 2, substituents which are selected from H, halogen, -CN, -CHO, -CF3 , -OH, -alkyl of C? -Cg, C? -C6 alkoxy, -NH2 or -N02; or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 24, characterized in that it has the formula characterized in that Rx is selected from H, halogen, -CF3, -OH, -C1-C10 alkyl, preferably-^ alkyl, -S-C? -C? 0 alkyl, preferably -S-Cx alkyl -Cg, C? -C10 alkoxy, preferably C? -C6 alkoxy, -CN, -N02, -NH2, 'phenyl, -0-phenyl, -S-phenyl, benzyl, -O-benzyl, S-benzyl; or furan, pyrrole or thiophene, attached to the indole ring by a chemical bond or a bridge -S-, -0- or - (CH2) n-, the phenyl, benzyl, furan, pyrrole or thiophene rings, which are optionally substituted by the 3 substituents selected from halogen, C? -C? 0 alkyl, preferably C? -C6 alkyl, C? -C? 0 alkoxy, preferably C? -C6 alkoxy, -N02, -NH2, - CN, -CF3; or n is an integer from 0 to 3, preferably 1 to 3, and most preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of C? -C? 0, preferably C? -C6 alkyl, alkoxy C? -C10, preferably C? -C6 alkoxy, -CHO, -CN, -N02, -NH2, -NH-C-Cg alkyl, -N (C? -C6 alkyl) 2, -N-S02-alkyl of C? -C? Or -S02-C? -C6 alkyl; R3 is selected from H, halogen, -CF3, -OH, -alkyl of C? -C10, alkoxy of C? -C10, -CHO, -C (0) CH3, -C (0) - (CH2) n- CF3, -CN, -N02, -NH2, -NH-C6-C6 alkyl, -N (C6-C6 alkyl) 2, -N-S02-C6-C6 alkyl or -S02-alkyl- C? -Cg, phenyl, phenyloxy, benzyl, benzyloxy, -C (0) -phenyl, -C (0) -benzyl, -CH2- (C3-C5 cycloalkyl), -C (0) -0H, C ( 0) -alkyl of C? -C6, -C (0) -O-C? -C6 alkyl, -C (0) -CF3, or - (CH2) nS-CH2- (C3-C5 cycloalkyl), the rings of the relevant R3 groups are optionally substituted by 1 to 3 groups selected from halogen, C? -C6 alkyl, C? -Cg alkoxy, -N02, -CF3, -C (0) -OH, or -OH; or a portion of the formula: 10 n every time it appears, it is an integer that is selected independently from 0-3; R8 and R9 are independently selected, each time from H, -COOH, - (CH2) n -COOH, - (CH2) nC (O) -COOH, -CF3, -OH, - (CH2) nC (0 ) -COOH, C? -C6 alkyl, -O-C? -C6 alkyl, -NH (C? -C6 alkyl), or -N (C? -C6 alkyl) 2; R4 is selected from -COOH, - (CH2) n -COOH, - (CH2) nC (0) -COOH, -CH = CH-COOH, tetrazole, - (CH2) n-tetrazole, the -L ^ M1 portion or a portion of the formulas: R12 is selected from H, -CF3, C? -C6 alkyl, - (CH2) n-C3-C3 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl groups are optionally substituted by 1 to 3 groups which are select from halogen, -CF3, -OH, -COOH, - (CH2) n-C00H, - (CH2) nC (0) -COOH, -alkyl of C? -C6, -O-alkyl of C? -Cg , -NH (C? -C6 alkyl), or -N (Cl ~ Cg alkyl) 2 i L1 is selected from - (CH, -0-? C (0) -C (0) -0-, - (CH2) n-0-, - (CH2) nS-; - (CH2) n-0- (CH2) n-; - (CH2) nS- 20 (CH2) n-, - (CH2) nC (0) - (CH2) n-, - (CH2) n-0- (CH2) n-, - (CH2) nS- (CH2) n-, C (Z) -N (R6) -, -C (Z) - N (R6) - (CH2) n-, -C (0) -C (Z) -N (R6) -, -C (0) -C (Z) -N (R6) - (CH2) n-; -C (Z) -NH-S02, -C (Z) -NH-S02- (CH2) n-, -C (0) - (CH2) n-0-, -C (0) -N-, or - (CH2) nS- (CH2) nC (0) -N-; M1 is -COOH or a portion selected from: «A > ..i M * ,. ^^ g * te | ^^ -X (lower alkyl of C? -C6) 15 (lower haloalkyl of C? -C6) - HfflllirillHKftfMlimimif - * «l lH?« - * | - '- - •' - - - .- - ~ - - ----- * "^ * .... 4- ~ ...- .. .., 4 ^.. > - «.." I Rβ, whenever it occurs, is independently selected from H, -COOH, - (CH2) n -COOH, - (CH2) n-C (0) -COOH, 10 tetrazole, When R9 is present, it is independently selected from H, halogen, -CF3, -OH, -COOH, - (CH2) n- COOH, - (CH2) nC (0) -COOH, -alkyl of C, - Cβ, -O-C?-Cß alkyl, -NH- (C?-C6 alkyl), or -N (C?-C6 alkyl) 2; R 10 is selected from H, -COOH, - (CH 2) n -COOH, - (CH 2) n -C (0) -COOH, -CF 3, -OH, - (CH 2) nC (0) -COOH, -alkyl of C? -C3, -0- C? -C6 alkyl, ^^^^^^ ~ * - < -? - * (lower alkyl of C? -C6) (lower haloalkyl of C? -C6) with the proviso that the portion or combination of portions comprising R4 include an acid group that is selected from carboxylic acid, a tetrazole or a portion of the formulas: R5 is selected from C? -C6 lower alkyl, C? -C6 lower alkoxy, C3-C10 - (CH2) n-cycloalkyl, - (CH2) nS- (CH2) n C3-C10 cycloalkyl, - (CH2) n-0- (CH2) n-cycloalkyl of C3-C? 0, - (CH2) n-phenyl-0-phenyl, - (CH2) n-phenyl-CH2-phenyl, - (CH2) n- 0-phenyl-CH2-phenyl, - (CH2) n-phenyl- (0-CH2-phenyl) 2, -CH2-phenyl-C (0) -benzothiazole or a portion of the formulas - (CH2) nA, - ( CH2) nSA, or - (CH2) n-0-A, where A is the portion: V ^ c D is H, C? -C6 lower alkyl, C? -Cg 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 by 1 to 3, preferably 1 to 2, substituents which are selected from H, halogen, -CN, -CHO, -CF3, -OH, -alkyl of C? -Cβ, alkoxy of C? -C6, -.NH2 or -N02; or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1, characterized in that it is 4 - [(5 { (E) - [5 - (benzyloxy) -1 - (4 -. {[3,5-bis (trifluoromethyl)] ) phenoxy] methyl.} benzyl) -lH-indol-2-yl] methylidene} -2,4-dioxo-l, 3-thiazolan-3-yl) methyl] benzoic acid or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, characterized in that it is 5 - [(E) - (5- (benzyloxy) -l-. {3- [3,5-bis (trifluoromethyl) phenoxy] propyl} - 1H-indol-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] -lH-indole-2- .- * £ > Ma¿ = ib il Jmetilidene) -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-chlorobenzyl) -lH-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 la- 5-. { (E) - [5- (benzyloxy) -1- (2-paphthylmethyl) -1H-indol-2-yl) methylidene} -1, 3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 1, characterized in that it is 5-. { (E) - [1- (4- (benzylbenzyl) -5- (benzyloxy) -lH-indol-2-yl) methylidene} -1,3-thiazolan-2,4-dione or a pharmaceutically acceptable salt thereof.

32. The compound according to claim 1, characterized in that it is 5-. { (E) - [5- (enzyloxy) -1- (4-chlorobenzyl) -lH-indol-2-yl) methylidene} -l, 3-thiazolan-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] -lH-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) -lH-indol-2-yl}. methylidene] -2,4-dioxo-l, 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) -lH-indol-2-yl) methylidene } -2,4-dioxo-l, 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) -lH-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)) encyl] -1H-indole-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) -lH-indol-2-yl] methylidene} -2-thioxo- and ^ g * ^ jj ^ j ^ "- '• -" "-' - '^ -' • ** - | 1, 3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.

41. The compound in accordance with 5 claim 1, characterized in that it is 5 - [(E) - (5- (benzyloxy) -l-. {3- [3,5-bis (trifluoromethyl) phenoxy] propyl} -1H-indole-2 -yl) methylidene] -2-thioxo-l, 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-thioxo-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-thioxo-1,3-thiazolan-4-one or a pharmaceutically acceptable salt of the 20 same.

44. The compound according to claim 1, characterized in that it is 5-. { (E) - [5- (benzyloxy) -1- (4- {3,5-bis (trifluoromethyl) phenoxy] methyl.} Encyl) - lH-indol-2-yl] methylidene} -2-thioxo-l, 3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.

45. The compound according to claim 1, characterized in that it is 4- acid. { [5 - ((E) -. {5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl] methylidene} -4-oxo-2- thioxo-l, 3-thiazolan-3-yl] methyl.} benzoic acid or a pharmaceutically acceptable salt thereof.

46. The compound according to claim 1, characterized in that it is 5 - ((E) -. {5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) encyl] -lH-indol-2-yl .) .methylidene) -2-thioxotetrahydro-4H-imidazol-4-one or a pharmaceutically acceptable salt thereof.

47. The compound according to claim 1, characterized in that it is l-benzyl-5- (2-thienyl) -lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

48. The compound according to claim 1, characterized in that it is 5- (1-benzofuran-2-yl) -l-benzyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

49. The compound according to claim 1, characterized in that it is l-benzyl-5- (4-fluorophenyl) -lH-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) -lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

51. The compound according to claim 1, characterized in that it is l-benzyl-5-phenyl-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

52. The compound according to claim 1, characterized in that it is 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

53. The compound according to claim 1, characterized in that it is 5- [3- (acetylamino) phenyl] -l-benzhydryl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. . .. t,. . . " . ,.,. .i ... .JMtA ^ Aa. ...... to fe4, ». "< ,., «, ...-. C. ^ ¡. ^ A. .,. . .. ^ "j.-" _. ... ",.

54. The compound according to claim 1, characterized in that it is 1-benzhydryl-5- (2-thienyl) -lH-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] -lH-indol-2-ylcarbonyl) amino] ] -2- [(5-Chloro-3-pyridinyl) oxy] benzoic acid or a pharmaceutically acceptable salt thereof.

56. The 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) -lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

58. The compound according to claim 1, characterized in that it is 5 - [(. {5-benzyloxy) -1- [2, 4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} carbonyl) amino] -2- [(5-chloro-3-pyridinyl) oxy] benzoic acid or a pharmaceutically acceptable salt thereof.

59. The compound in accordance with 5 claim 1, characterized in that it is 5- (benzyloxy) -l- (4- {[3,5-bis (trifluoromethyl) phenoxy] methylbenzyl) -lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof. same.

60. The compound according to claim 1, characterized in that it is 4-acid. { [5- ((E) -. {5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} -methylidene) -4-oxo-2- thioxo-l, 3-thiazolan-3-yl] methyl} benzoic acid or a pharmaceutically acceptable salt thereof. • 15 61. The compound according to claim 1, characterized in that it is the acid 5- ((Z, 2E) -3-. {5- (benzyloxy) -1- (2,4-bis (trifluoromethyl) benzyl) ] -lH-indol-2-yl.} -2-propenylidene) -1,3-thiazolan-2,4-dione or a salt

Pharmaceutically acceptable thereof.

62. The compound according to claim 1, characterized in that it is 5- (benzyloxy) -1- (4- {3 [5, 5-bis (trifluoromethyl) phenoxy] methyl} benzyl) - lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

63. The compound according to claim 1, characterized in that it is 5 - [(. {L-benzyl-5-benzyloxy) -lH-indol-2-yl] carbonyl acid} amino) isophthalic or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 1, characterized in that it is (E) -3- [5- (benzyloxy) -1- (2-naphthylmethyl) -lH-indol-2-yl] -2-propenoic acid or a pharmaceutically acceptable salt thereof.

65. The compound according to claim 1, characterized in that it is (E) -3- acid. { 5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) benzyl] -lH-indol-2-yl} -2- propenoic 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) -lH-indol-2-yl acid} -2-propenoic or a pharmaceutically acceptable salt thereof.

67. The compound according to claim 1, characterized in that it is the acid l- (4- { [3,5- AÉSiifi = ^^^^^ g ^^ g ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^, ^^^^^^^^ ^^^^^^^^^^^^^^^^^^ bis (trifluoromethyl) phenoxy] methylbenzyl) -1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

68. The compound according to claim 1, characterized in that it is 5- ( { [5- (benzyloxy) -l- (4. {[[3,5-bis (trifluoromethyl) phenoxy] methyl]. benzyl) -lH-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] -lH- acid. indol-2-yl] carbonyl.} amino) benzoic or a pharmaceutically salt < acceptable of it.

70. The compound according to claim 1, characterized in that it is 2- [4- (. {[[1- (4. {[[3,5-bis (trifluoromethyl) phenoxy] methyl] benzyl] - lH-indol-2-yl] carbonyl.}. amino) phenyl] acetic acid or a pharmaceutically acceptable salt thereof.

71. The compound according to claim 1, characterized in that it is 3- acid. { [3-acetyl-5- (benzyloxy) -1- (2-naphthylmethyl) -lH-indol-2-yl] methoxy} benzoic acid or a pharmaceutically acceptable salt thereof.

72. The compound in accordance with 5 claim 1, characterized in that it is acid 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- acid. { [5- (benzyloxy) -1- [2,4-bis (trifluoromethyl) -benzyl] -3- (2,2,2-trifluoroacetyl) -lH-indol-2-yl] methoxy} benzoic acid or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 1, characterized in that it is 2- ( { [3- Acetyl-1- [4- (1, 3-benzothiazole-2-yl-1-carbonyl) -benzyl] -5-acid. - (benzyloxy) -lH-indol-2-yl] methyl.}. sulfanyl) acetic acid or a salt

Pharmaceutically acceptable thereof.

75. The compound according to claim 1, characterized in that it is 2- ( { [3- Acetyl-l- [4- (1,3-benzothiazol-2-ylcarbonyl) benzyl] -5- 'A - * - ^ - ^ "- ^ -. ^^^^ (benzyloxy) -lH-indol-2-yl] methyl.}. Sulfanyl) benzoic acid or a pharmaceutically acceptable salt thereof.

76. The compound according to claim 1, characterized in that it is the acid 4-. { [3- acetyl-l - '[4- (1, 3-benzothiazol-2-ylcarbonyl) benzyl] -5- (benzyloxy) -lH-indol-2-yl] methoxy} benzoic acid or a pharmaceutically acceptable salt thereof.