MXPA01007904A - Chemical compounds - Google Patents

Abstract

The use of a 3-substituted indole compound of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof;X is CH2 or SO2 and R1, R2, R3, R4, R5, R6 and R7 are certain specified organic moieties, for use in the preparation of a medicament for the inhibition of monocyte chemoattractant protein-1 and/or RANTES induced chemotaxis. Pharmaceutical compositions containing certain compounds of formula (I) and novel compounds of formula (I) are also described and claimed.

Description

CHEMICAL COMPOUNDS The present invention relates to chemical compounds, their production as well as pharmaceutical compositions containing them, as well as their use in therapy, in particular inflammatory disease. MCP-1 is a member of the chemosin family of pro-inflammatory cytokines that mediate chemotaxis and leukocyte activation. MCP-1 is a C-C chymosin that is one of the most potent and selective monocyte chemoattractant and activating agents and chemoattractants. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including rheumatoid arthritis, glomerular nephritis, pulmonary fibrosis, restenosis (International Patent Application 94/09128), alveolitis (Jones et al., 1992, J. Immunol., 149, 2147) and asthma. Other disease areas in which MCP-1 is considered to play a part in its pathology are atherosclerosis (for example Koch et al., 1992, J. Clin. Invest., 90, 772 -. 772-779), psoriasis (Deleuran et al., 1996, J. Dermalological Science, 13, 228-236), hypersensitivity reactions of the delayed type of the skin, inflammatory bowel disease (Grimm et al., 1996, J ".

Leukocyte Biol. , 59 ,. 804-812), multiple sclerosis and brain trauma (Berman et al., 1996, J., Immunol., 156, 3017-3023) .An MCP-1 inhibitor may also be useful for treating attack, repercussion injury, ischemia. , myocardial infarction and transplant rejection MCP-1 acts through the MCP-1 receptor (also known as the CCR2 receptor) MCP-2 and MCP-3 can also act, at least in part through the MCP-receptor 1. Therefore, in this specification, when reference is made to "inhibition or antagonism of MCP-1" or "effects mediated by MCP-1" this includes inhibition or antagonism of effects mediated by MCP-2 and / or MCP-1. 3 when MCP-2 and / or MCP-3 act through the MCP-1 receiver Co-pending International Patent Applications Nos. PCT / GB98 / 02340 and PCT / GB98 / 02341 describe and claim groups of compounds based on the indole ring structure, which are inhibitors of MCP-1 and therefore have applications in therapy. ndol as NMDA antagonists is described in U.S. Pat.

No. USP5051442, in 09312780, and in EP-483881. Other Índoles and their use as inhibitors of leukotriene biosynthesis are described, for example, in EP-A-275-667. Applicants have found that a particular substitution in the indole ring produces advantageous results when used therapeutically as inhibitors of MCP-1. In accordance with the present invention, there is provided the use of the compound of the formula (I) wherein X is CH2 or S02 R1 is an aryl or heteroaryl ring; R2 is carboxy, cyano, -C (0) CH2OH, -CONHR8, -S02NHRa tetrazol-5-yl, S03H, or a group of the formula (VI) IO wherein R8 is selected from hydrogen, alkyl, aryl, cyano. hydroxy -S02R13 wherein R12 is alkyl, aryl, heteroaryl, or haloalkyl, or R8 is a group- (CHR13) r -COOH wherein r is an integer of 1 to 3 and each group R13 independently is selected from hydrogen or alkyl; R9 is hydrogen, alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally substituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a COR14 group wherein R14 is alkyl, aryl, heteroaryl or haloalkyl; R 10 and R 11 independently are chosen from hydrogen or alkyl, particularly alkyl with 1 to 4 carbon atoms; R3 is a group OR15, S (0) qR15, NHCOR16, NHS02R16, (CH2) sCOOH, (CH2) tCONR17R18, NR17R18, S02NR17R18 or optionally substituted alkenyl, wherein q is O, lo 2, s is O or an integer of 1 to 4, t is 0 or an integer from 1 to 4, R15 is a substituted alkyl or cycloalkyl group or an optionally substituted heteroaryl group, R16 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl and R17 and R18 are chosen independently of hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that at least one of R17 or R18 is different from hydrogen, or R16 and R17 together with the nitrogen atom from which they are connected, form an optionally substituted heterocyclic ring that generally contains additional heteroatoms; and R 4, R 5, R 6 and R 7 independently are chosen from hydrogen, an optionally substituted functional group or hydrocarbyl groups, or optionally substituted heterocyclic groups; for use in the preparation of a medicament for inhibiting RANTES-induced chemotaxis and / or monocyte chemoattractant protein-1. Pharmaceutically acceptable salts, esters and amides of the compound of the formula (I) can also be used in this manner. In particular, in the above formula s is an integer from 1 to 4. Conveniently R4 is different from an OR18 group, S (0) mR18, NR19R20, C (0) NR19R20, NHCOR18, NHS02R18 or OCONR19R20 or an alkyl group substituted by OR18, S (0) raR18, NR19R20 where R18, R19, R20 and m are as previously defined and R18 'is a substituted alkyl group containing hydrogen. Compounds of the formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they seem to inhibit RANTES-induced chemotaxis. RANTES is another chemosin from the same family as MCP-1, with a similar biological profile, but acting through the CCR1 receptor. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease. In this manner, the invention further provides a compound of the formula (I) for use in the preparation of a medicament for the treatment of inflammatory disease. In this specification, the term "alkyl", when used either alone or as a suffix, includes straight, branched chain structures. These groups may contain up to 10 preferably up to 6 and more preferably up to 4 carbon atoms. Similarly, the terms "alkenyl" and "alkynyl" refer to straight or branched unsaturated structures for example from 2 to 10. preferably from 2 to 6 carbon atoms. Cyclic portions such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms. Terms such as "alkoxy" comprise alkyl groups as they are understood in the art. The term "halo" includes fluorine, chlorine, bromine and iodine. References to aryl groups include aromatic carbocyclic groups such as phenyl and naphthyl. The term "heterocyclyl" includes aromatic or non-aromatic rings, for example containing from 4 to 20, suitably from 5 to 8 ring atoms, at least one of which is a heteroatom such as oxygen, sulfur or nitrogen. Examples of these groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl. .

"Heteroaryl" refers to those groups described above that have an aromatic character. The term "aralkyl" refers to alkyl groups substituted with aryl, such as benzyl. Other terms used in the specification include "hydrocarbyl" which refers to any structure comprising carbon or hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy. aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl. The term "functional group" refers to reactive substituents. They may comprise electron donors or electron withdrawals. Examples of these groups include halo, cyano, nitro, C (0) nR18, OR18 S (0) mR18, NR19R20. C (0) NR19R20, OC (0) NR19R20, -NR19C (O) nR18, -NR18CONR19R20, -N = CR18R19, S (0) nNR19R20 or -NR19S (O) nR18, wherein R18. R19 and R20 are independently chosen from hydrogen or optionally substituted hydrocarbyl or R19 and R20 together with the atom to which they are connected, form an optionally substituted heterocyclyl ring as defined above, which optionally contains additional heteroatoms such as S (O) n, oxygen and nitrogen, n is an integer of 1 or 2, m is 0 or an integer of 1 to 3. Suitable optional substituents for hydrocarbyl groups R18. R19 and R20 include halo, perhaloalkyl such as trifluoromethyl, mercapto, hydroxy, carboxy, alkoxy. heteroaryl, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (wherein the aryl group may be substituted by halo, nitro, or hydroxyl), cyano, nitro, amino, mono- or di-alkyl amino, oximino or S (0) m where m is as defined above. When R19 and R20 together form a heterocyclic group, this may be optionally substituted by hydrocarbyl such as alkyl as well as those substituents listed above for hydrocarbyl groups, R18, R19 and R20. Suitable substituents for R5 hydrocarbyl or heterocyclic groups. R6 and R7 include those listed above for R18, R19 and R20. Conveniently R1 is an optionally substituted phenyl, pyridyl, naphthyl, furyl or thienyl ring and in particular is a substituted phenyl or pyridyl ring. Suitable substituents for R 1 in formula (I) include alkyl, alkenyl, alkynyl, halo, haloalkyl, including perhaloalkyl such as trifluoromethyl, mercapto, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, hydroxyalkoxy, alkoxyalkoxy, alkanoyl, alkanoyloxy, cyano. nitro, amino, mono- or di-alkyl amino, oximino, sulfonamido, carbamoyl, mono or dialkylcarbamoyl or S (0) mR21 wherein m is as defined above and R21 is hydrocarbyl. Conveniently R 4 is hydrogen, hydroxy, halo, alkoxy, aryloxy or an optionally substituted hydrocarbyl group or optionally substituted heterocyclic group. Particular examples of substituents R4 include hydrogen, hydroxy, halo, optionally substituted alkyl such as aralkyl, carboxyalkyl or its amide, alkoxy, or aryloxy derivative. More preferably R4 is hydrogen. Particular examples of substituents R5, R6 and R7 include hydrogen, hydroxy, halo, optionally substituted alkyl such as aralkyl, carboxyalkyl or its amide derivative, alkoxy; aryloxy; aralkyloxy; or an amino group which is optionally substituted with alkyl, aryl or aralkyl. A specific functional group that is suitable for R5, R6 and / or R7 is a group of sub-formula (IV).

Particular examples of the groups R5, R6 and R7 are hydrogen, hydroxy, halo or alkoxy. In particular R6 and R7 are hydrogen. R5 can be hydrogen, but also conveniently are a small substituent such as hydroxy, halo or methoxy. Particular substituents for R 1 include trifluoromethyl, alkyl having 1 to 4 carbon atoms, halo, trifluoromethoxy, alkoxy with 1 to 4 carbon atoms, alkanoyl with 1 to 4 carbon atoms, alkanoyloxy with 1 to 4 carbon atoms, nitro, carbamoyl , C 1 -C 4 alkoxycarbonyl, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkynyl, alkylsulfonyl with 1 to 4 carbon atoms, sulfonamido, carbamoyl with 1 to 4 carbon atoms carbon atoms, alkyl having 1 to 4 carbon atoms, N- (C 1 -C 4 -alkyl) carbamoyl, C 1 -C 4 -alkyl, N- (C 1 -C 4 -alkyl) 2-carbamoyl- alkyl with 1 to 4 carbon atoms, hydroxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms, alkyl with 1 to 4 carbon atoms. Alternatively, two of these substituents together can form a divalent radical of the formula -O (CH 2) ω, 0- connected to adjacent carbon atoms in the ring R 1 'Preferred substituents for R 1 are one or more non-substituted substituents polar such as halo. In particular, R1 is substituted by one or more halo groups, in particular chlorine. A particular example of a group R1 is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrido-5-yl. Examples of R2 groups include carboxy; cyano; tetrazol-5-yl: S03H, -CONHR8 wherein R8 is chosen from cyano, hydroxy, -S02R12 wherein R12 is alkyl such as alkyl having 1 to 4 carbon atoms, aryl such as phenyl, heteroaryl or trifluoromethyl, or R8 is a group - (CHR10) r -COOH wherein r is an integer of 1 to 3 and each group R10 is independently selected from hydrogen or alkyl such as alkyl with 1 to 4 carbon atoms; or R2 is a group -S02NHR9 wherein R9 is an optionally substituted 5 or 6-membered heteroaryl group or optionally substituted phenyl, or a group COR14 wherein R14 is alkyl such as alkyl with 1 to 4 carbon atoms such as phenyl, heteroaryl or trifluoromethyl, or R2 is a group of the formula (VI) R10 wherein R 10 and R 11 independently are chosen from hydrogen or alkyl, particularly alkyl having 1 to 4 carbon atoms.

Preferably R2 is carboxy or its pharmaceutically acceptable salt or ester. Particular groups R3 include OR15, S (O) qR15, NHCOR16, NHS02R16, S02NR17R18 wherein q, R15, R16, R17 and R18 are as defined above. Suitable optional substituents for the group R15, R16, R17 and R18 as they appear in the definition of R3, or R3 alkenyl groups as defined above, include functional groups as previously defined, as well as aryl or heteroaryl groups, any of which may in itself to be replaced by one or more functional groups. Particular examples of substituents for groups R15, R16, R17 and R18 include one or more groups selected from halo such as chloro, hydroxy, cyano. Not me. mono- or di-alkylamino, alkoxy with 1 to 4 carbon atoms, carboxy, sulfonamido, CONH2, morpholino, pyridyl, pyrimidinyl, phenyl optionally substituted by halo such as chloro, carboxy, hydroxy, alkoxy such as methoxy, carbamoyl, acyl such as acetyl, or hydroxyalkyl wherein the alkyl group conveniently includes at least 2 carbon atoms such as hydroxyethyl. When R15. R16, R17 and R18 are a heteroaryl group or when R17 and R18 together form an optionally substituted heterocyclic ring, these may be substituted by functional groups or by alkyl groups such as methyl or ethyl, or alkenyl or alkynyl, any of which may to be substituted for example with hydroxy. A preferred group for R3 is an OR15 group straight or branched chain alkyl group that carries at least one hydroxy group, for example two hydroxy groups.

Other substituents, as defined above, may be provided in the alkyl chain. Preferably R3 is a group of the formula -0 (CH2) a [(CHOH) (CH2) b] dCH2OH wherein a is 0 or an integer from 1 to 4, b is 0 or an integer of the 3, and d is O or l. Examples of this R3 include OCH2CHOHCH2OH and OCH2CH2OH. X is CH2 or S02 and preferably CH2. Suitable pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate - and salts formed with phosphoric and sulfuric acid. In another aspect, suitable salts are base salts such as alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperi -dine, procaine, dibenzylamine, N, N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valence of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt. An in vivo hydrolysable ester of a compound of the formula (I) which contains a carboxy or hydroxy group for example is a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the main acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include alkyl esters such as alkyl with 1 to 6 carbon atoms-esters for example ethyl ethers, alkoxy with 1 to 6 carbon atoms, methyl esters for example methoxymethyl, alkanoyloxy with 1 to 6 carbon atoms, methyl esters, for example pivaloyloxymethyl, fthalidyl esters, cycloalkoxy with 3 to 8 carbon atoms, carbonyloxy, alkyl with 1 to 6 carbon atoms, esters for example 1-cyclohexylcarbonyloxyethyl; 1, 3-dioxolen-2-onylmethyl esters for example 5-methyl-l, 3-dioxolen-2-onylmethyl; and C 1 -C 6 -alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and can be formed in any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters of the compounds of the formula (I) are in vivo hydrolysable esters of a compound of the formula (I) which contain a hydroxy group, include inorganic esters such as phosphate steres and α-acyloxyalkyl ethers and related compounds which Result of the in vivo hydrolysis of the ester are broken down to give the main hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethyl-propionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Esters that are not hydrolysable in vivo are useful as intermediates in the production of the compounds of the formula (I) and therefore they form a further aspect of the invention. Thus, examples of compounds of the formula (I) include the following: Table 1 where * indicates the connection point of the indole ring group. Some compounds of the formula (I) have not been proposed to date for use as pharmaceuticals, thus a further aspect of the invention provides a compound for use in therapy, the compound comprises a compound of the formula (IA) which is a compound of the formula (I) as defined above subject to the following provisions. (i) when R2 is carboxy or its salt or amide at least three of R4. R5, R6 and R7 are hydrogen, and R3 is S (0) qR15, R155 is different from alkyl having 1 to 4 carbon atoms substituted by carboxy or an ester or amide derivative thereof; (ii) when R3 is a group NHCOR16 or NHS02R16, R16 is optionally substituted alkyl; and (iii) when R3 is a group SR14 where R14 is 2-quinolylmethyl, R2 is COOH or its ethyl ester, each of R4, R5, and R7 are hydrogen, R1 is 4-chlorophenyl, R6 is different from 2- quinolylmethyl. Yet another additional aspect of the invention provides pharmaceutical compositions comprising a compound of the formula (IA) as defined above. Certain compounds of the formula (I) are novel and these form a further aspect of the invention. In this manner, the invention further provides a compound of the formula (IB) which is a compound of the formula (IA) as defined above, subject to the following additional conditions: (iv) when R3 is a CH2COOH group, R2 is COOH and each of R4, R5, R6 and R7 are hydrogen, R1 is different from unsubstituted phenyl; and (v) when R3 is a CH2COOH group, R2 is COOH and each of R4. R5, and R7 are hydrogen, R1 is 4-chlorophenyl, R6 is different from methoxy; and (vi) when R3 is OR15 or S (0) qR15, R15 is different from haloalkyl having 1 to 6 carbon atoms. Yet an additional condition that conveniently applies to formula (IB) is (vii) when R2 is COOCH2CH3 each of R4. R5 R6 and R7 are hydrogen and R1 is 4-chlorophenyl, R3 is different from a group CH = CH (CN) 2. In addition, condition (iv) conveniently applies to (IA) since when R3 is a COOH group, R2 is COOH and each of R4, R5, R6 and R7 are hydrogen, R1 is different from unsubstituted phenyl. Substituents and particularly preferred groups of the compounds of the formulas (IA) and (IB) are those described above in relation to the formula (I). Suitable examples of compounds of the formula (IB) are compounds wherein R3 is an OR15 group straight or branched chain alkyl group which carries at least one hydroxy group, for example 1 to 4 hydroxy, for example 1 or 2 hydroxy groups. Other substituents, as defined above, may be provided in the alkyl chain. Preferably, R3 is a group of the formula -0 (CH2) a [(CHOH) (CH2) b] dCH2OH wherein a is 0 or an integer from 1 to 4, b is 0 or an integer from 3, and d is O or l. Examples of these R3 include OCH2CHOHCH2OH and OCH2CH2OH. Compounds of the formula (I) are conveniently prepared by methods such as those described in International Patent Applications Nos. PCT / GB98 / 02340 and PCT / GB98 / 02341. In particular, compounds of the formula (I) can be prepared by reacting a compound of the formula (VII) (Vile) wherein R4, R5, R6 and R7 are as defined in relation to formula (I), R2 'is a group R2 as defined in relation to formula (I) or its protected form, and R3' is a group R3 as defined in relation to formula (I) or its precursor; with a compound of the formula (VIII) R ^ X-Z1 (VIII) wherein R1 and X as defined in relation to the formula (I) and Z1 is a leaving group; and subsequently if it is desired or necessary to carry out one or more of the following steps: (i) changing a precursor group R3 'to a group R3 or a group R3 to a different group; (ii) removing any protecting group from R2 '. Suitable leaving groups for Z include halide such as chlorine, bromine or iodine, as well as mesylate or tosylate. The reaction is conveniently carried out in an organic solvent such as dimethylformamide (DMF) tetrahydrofuran (THF) or DCM, in the presence of a base such as sodium hydride, sodium hydroxide, potassium carbonate. Optionally, the reaction is carried out in the presence of a convenient phase transfer catalyst. The base and solvent section is interdependent in a certain proportion in that certain solvents are compatible with some bases only as it is understood in the specialty. For example, sodium hydride can preferably be used with dimethylformamide or tetrahydrofuran and sodium hydroxide preferably used with dichloromethane and a phase transfer catalyst. The reaction can be carried out at moderate temperatures, for example from 0 to 50 ° C and conveniently at room temperature. Preferably, R2 'is an ester group in the compound of the formula (VII) and this may be subsequently converted to an acid or other ester or salt by conventional methods. For example, when X is a group S02 and R2 is a methyl ester of carboxy, it can be converted to the corresponding carboxylic acid by reaction with lithium iodide in pyridine or DMF. The optional steps (i) and (ii) above can be carried out using conventional methods. These will depend on the precise nature of the groups R3, R3 ', R2 and R2' in each case. Examples of suitable reactions are illustrated below. Alternatively, compounds of the formula (I) can be prepared by reacting a compound of the formula (IX) (IX) wherein X, R1, R4, R5, R6 and R7 are as defined in relation to formula (I). R2 'is a group R2 as defined in relation to formula (I) or its protected form; with a compound of the formula (X) R ^ Z1 (X) wherein R3 'is a group R3 as defined in relation to the formula (I) or its precursor; and subsequently if it is desired or necessary to carry out steps (i) and / or (ii) above. The reaction is conveniently carried out in an organic solvent which will depend on the nature of the compound of the formula (IX). Suitable leaving groups Z1 include those listed above for Z. Compounds of the formula (IX) can conveniently be prepared by analogous methods to those described above between compounds of the formulas (VII) and (VIII), although in this case, a compound of the formula (VIIA) will be used.

(VIIA) in this compound, R2 ', R4, R5, R6 and R7 are as defined above. Compounds of the formulas (VII) and (VIIA) can be prepared by cyclization of a compound of the formula (XI) wherein R4, R5, R6 and R7 are as defined above and R42 and R43 represent a combination of portions that can cyclize to form an appropriately substituted pyrrole ring. For example, R42 may be a group of the formula -CH = C (R4) N3 wherein R44 is a group R2 as defined above or its protected form and R43 may be hydrogen. The cyclization to form a compound of the formula (XII) can then be carried out on heating, for example, under reflux in an organic solvent, in particular a high-boiling aprotic solvent such as xylene or toluene.

Alternatively, R43 may be nitro and R42 may be a group of the formula -CH2C (0) R2 'where R2' is as defined above in relation to formula (VII). These compounds will cyclize in the presence of a catalyst such as palladium on carbon in the presence of hydrogen. The reaction can be carried out at moderate temperatures for example from 0 to 80 ° C, conveniently at approximate room temperature. Thus, examples of these compounds of the formula (XI) include compounds of the formulas (XII) and (XIII) R7 (XIII) wherein R 2, R 4, R 5, R 6 and R 7 are as previously defined and R 3"is a group R 3 'or is hydrogen, which may subsequently be converted into a group R 3 or R 3' Compound of the formula (XIII) wherein R 3 'is hydrogen can be prepared for example by reacting a compound of the formula (XV) with a compound of the formula (XVI) N3CH2R2 '(XVI) wherein R4, R5. R6, R7, and R2 'are as defined above. The reaction can be carried out in an organic solvent, such as ethanol at low temperatures of -20 to 0 ° C, conveniently at about 0 ° C.

The reaction is conveniently carried out in the presence of a base such as an alkoxide, in particular an ethoxide, for example potassium ethoxide. Compounds of the formula (XVI) are conveniently prepared by reacting a compound of the formula (XVII) R7CH2R2 '(XVII) wherein R3 and R2' are as defined above and R47 is a leaving group such as halide and in particular bromide with an azide salt, such as an alkali metal azide salt in particular sodium azide. Compound of the formula (XIV) can be prepared by reacting a compound of the formula (XVIII) R4 R3 wherein R5, R6, R7, R3, R4 and R2 'are as defined above, with a compound of the formula (XIX) R2- R48 (XIX) wherein R2 'is as defined above and the group R48 is a leaving group such as hydroxy. Examples of compounds of the formula (XVI) are oxalates such as diethyloxalate. The reaction is conveniently carried out in the presence of a base such as sodium hydride in an organic solvent such as THF. Moderate temperatures from 0 ° to 40 ° C and room temperature is conveniently used. According to a further aspect of the invention, there is provided a compound of the formula (I) as defined herein, or its pharmaceutically acceptable salt or its hydrolysable ester in vivo, for use in a method of treating the human or animal body by therapy. In particular, the compounds are used in the methods of treatment of inflammatory disease. According to a further aspect of the present invention there is provided a method for antagonizing an effect mediated by MCP-1 in a warm-blooded animal such as humans, which requires this treatment, which comprises administering to the animal an effective amount of a compound of the formula (I), or its pharmaceutically acceptable salt or its hydrolysable ester in vivo. The invention also provides a compound of the formula (I) as defined herein or its pharmaceutically acceptable salt or its hydrolysable ester in vivo, for use as a medicament. The compositions of the invention may be in a form suitable for oral use (for example as tablets, troches, hard or soft capsules, oily or aqueous suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as finely divided powder or liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, sub-cutaneous, intramuscular dosing, or as a suppository for rectal dosing). The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain for example one or more coloring, sweetening, flavoring and / or preservative agents. Suitable pharmaceutically acceptable excipients for tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablets formulations can be coated or uncoated to either modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and / or appearance, in any case, using conventional coating agents and well-known procedures. in the specialty. Compositions for oral use may be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the Active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions in general contain the active ingredient in finely pulverulent form together with one or more suspending agents, such as carboxy-sodium methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with derived partial esters of fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), anti-oxidants (such as ascorbic acid), agents, colorants, flavoring agents, and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those established above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water, generally contain the active ingredient together with a wetting or dispersing agent, suspending agent and one or more preservatives. Suitable dispersing agents or humectants and suspending agents are exemplified by those already mentioned. Additional excipients such as sweetening, flavoring and coloring agents may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Convenient emulsifying agents, for example may be gums of natural origin such as acacia gum or tragacanth gum, phosphatides of natural origin such as soybean oil, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate ) and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulgent, preservative, flavoring and / or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension which can be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been previously mentioned. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. • Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions can generally be obtained by formulating an active ingredient with a conventional, topically acceptable vehicle or diluent using a method well known in the art. Compositions for administration by insufflation may be in the form of particles containing finely divided powder with average diameter for example of 30 μ or much less, the powder itself already comprises an active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose . The powder for insufflation is then conveniently retained in a capsule containing for example 1 to 50 mg of active ingredient for use with a turbo-inhaler device such as is used to insufflate the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to deliver the active ingredient either as an aerosol containing liquid droplets or finely divided solids. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be employed and the aerosol device is conveniently arranged to deliver a metered amount of active ingredient. For more information regarding formulation the reader is referred to chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch: Chairman of the Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans, will generally contain, for example, 0.5 mg to 2 g of active agent, formulated with an appropriate and convenient amount of excipients which may vary from about 5 to about 98% by weight of the total composition. Unit dosage forms will generally contain about 1 mg to about 500 mg of active ingredient. For more information regarding Administration Routes and Dosage Regimes, the reader is referred to Chapter 25.3 in Volume 5 of (Broad Medicinal Chemistry) (Corwin Hansch: Chairman of the Editorial Board), Pergamon Press 1990. The dose size for Therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and weight of the animal or the patient and the route of administration according to well-known medical principles. As mentioned above, compounds of formula I are useful for treating diseases or medical conditions that are due only or in part to the effects of farnesylation of rats. When using a compound of the formula I for therapeutic or prophylactic purposes, it will generally be administered in such a way that a daily dose in the range, for example, 0.5 mg to 75 mg, per kg of body weight, is received if required. divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example for intravenous administration, a dose in the range of, for example, 0.5 mg to 30 mg per kg of body weight will generally be employed. Similarly for administration by inhalation, a dose in the range of, for example, 0.5 mg to 25 mg per kg of body weight will be employed. However, oral administration is preferred. . The invention is further illustrated, but not limited by the following examples wherein the following general procedures were employed unless stated otherwise. Preparation 1 Ethyl 3-bromoindol-2-carboxylate A solution of bromine (2.72 ml) in DMF is added dropwise over 10 minutes to a solution of ethyl-2-carboxylate in DMF. The reaction is stirred for 30 minutes, then poured into water to precipitate a pale yellow solid which is separated by filtration and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), m.p. 150-151 °; NMR d (CDC13) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 1H), 7.38 (, 2H), 7.66 (d, 1H), 9.27 (brs.1H); M / z (-) 268 (M +), 266, 196, 194. Preparation 2 Ethyl 3-benzylthioindole-2-carboxylate Potassium carbonate (3.5 g) is added to a solution of ethyl 3-bromoindol-2-carboxylate (5.4 g) and benzyl mercaptan (3.05 ml) in DMF (100 g). ml), and the reaction is heated at 100 ° C for 3 hours. The reaction is then cooled, poured into water and extracted with ethyl acetate. Combined organic extracts were washed with water and brine, dried (MgSOj) and concentrate in vacuo. The residue is purified by column chromatography using iso-hexane: 5% ethyl acetate as eluent, to give the product as a white crystalline solid (3.48 g, 56%); NMR d (CDC13) 1.42 (t, 3H), 4.05 (s, 2H), 4.40 (q.2H), 7.10-7.40 (m, 8H), 7.78 (d, 1H), 9.06 (brs, 1H); M / z (+) 312 (H +), 266, 166. Preparation 3 Ethyl 3- (ethoxycarbonylmethylthio) indole-2-carboxylate To a solution of ethyl 3-bromoindol-2-carboxylate (1.34 g) and ethyl 2-mercaptoacetate ( 0.96 ml) in acetone (15 ml) is added to potassium carbonate (1.38 g) and the resulting mixture is heated to reflux under argon for 18 hours. The cooled mixture is poured into water and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated to a gum which was purified by column chromatography using iso-hexane: ethyl acetate (1: 4) to give the desired product (331 mg, 21%), NMR d (CDC13) 1.05. (t, 3H), 1.45 (t, 3H), 3.6 (s, 2H), 4.0 (q, 2H), 4.5 (q, 2H), 7.2 - 7.4 (m, 3H), 7.9 (d, 1 H) , 9.2 (brs, 1H); M / z (+) 308.3 (MH +). Preparation 4 Eti l N- (3, 4-dic lorobenz i lo) -3- (morph ol inosul f ini lo) indole-2-carboxylate Thionyl chloride (5 ml) is added in one portion to a solution of ethyl N - (3,4-dichlorobenzyl) indole-2-carboxylate (908 mg) and the resulting mixture is stirred for 18 hours. The mixture is concentrated in vacuo. The resulting gum is suspended in diethyl ether (12 ml) and morpholine (2.2 ml) is added in one portion. The mixture is stirred for 3 hours. The reaction is neutralized with water (10 ml) extracted with dichloromethane, dried (MgSO4) and concentrated to a gum which is purified by column chromatography using iso-hexane: ethyl acetate (1: 1) as eluent to give the desired product ( 907 mg, 72%); RM? d (CDC13) 1.4 (t, 3H), 3.0 - 3.1 (m, 2H), 3.3 - 3.4 (m, 2H), 3.7 - 3.8 (m, 4H), 4.4 (q, 2H), 5.7 (q, 2H) ), 6.8 (d, 1H), 7.1 (d, 1H), 7.25 - 7.4 (m, 4H). 8.6 (d, 1H); M / z (-) 480 (M +). Preparation 5 The procedure described in the above preparation 4 was repeated using the appropriate amine. In this way the compound described below is obtained Ethyl N - (3,4-dichlorobenzyl) -3- (1,1-dioxidothiomorpholino) sulfinylindole-2-carboxylate 52% yield; RM? d (CDC13) 1.4 (t, 3H), 3.1 - 3.3 (m, 4H), 3.7-4.0 (4H, m), 4.4 (q, 2H), 5.7 (q, 2H), 6.8 (d, 1H), 7.1 (s, 1H), 7.3-7.5 (m, 4H), 8.6 (d, 1H); M / z (-) 529.1 (M +), 527.1. Preparation 6 N- (3,4-Dichlorobenzyl) -2-ethoxycarbonylindole-3-sulfonic acid Ethyl N- (3,4-dichlorobenzyl) indole-2-carboxylate (1.11 g) in thionyl chloride (4.0 ml) is stirred for 16 hours, then concentrated in vacuo. The residue dissolves in THF (10 ml) and water (2 ml) are stirred for a further 2 hours. The reaction is divided between ether and water. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue was triturated with ether to give the product as a white solid (0.67 g, 51%): RM? d (CD3SOCD3) 1.27 (t, 3H), 4.35 (q.2H). 5.80 (s.2H). 6.83 (d.1H). 7.23 (t.1H), 7.40 (m.2H). 7.57 (d, 1H), 7.68 (d, 1H), 8.42 (d.1H); M / z (-) 412 (M +). 410, 348, 346. Preparation 7 N- (3,4-Dichlorobenzyl) -2-ethoxycarbonylindol-3-sulfonyl chloride N- (3,4-Dichlorobenzyl) -2-ethoxycarbonylindol-3-sulfinic acid (0.48 g), N-chlorosuccinimide (0.16 g) and triethylamine (0.16 ml) are stirred in dichloromethane for 4 hours. The reaction is then concentrated in vacuo and the residue purified by chromatography using iso-hexane: 10% ethyl acetate as eluent to give the product as a white crystalline solid (0.27 g, 52%); NMR d (CD3SOCD3) 1.43 (t, 3H), 4.48 (q.2H), 5.53 (s.2H), 6.98 (m, 1H), 7.30-7.50 (m, 5H). 8.22 (m, 1H); M / z (-) 444 (M - H +), 426. 410. Preparation 8 Ethyl 3-diazoindole-2-carboxylate Acetic acid (77 ml) is added dropwise to a suspension of sodium nitrite (82 g) and ethyl indole-2-carboxylate (25 g) in dichloromethane (1000 ml) , and stir at room temperature under an inert atmosphere. After 2 days, more sodium nitrite (20 g) and acetic acid (19 ml) are added dropwise, and the reaction is left stirring for a further day. The reaction is poured into water (300 ml), extracted with dichloromethane (2 x 200 ml), and neutralized with saturated sodium hydrogen carbonate solution (300 ml). The combined organic extracts were dried (MgSO4), and concentrated in vacuo to give the product as a yellow solid (26.96 g, 95%), NMR d (CD3SOCD3) 1.34 (t, 3H), 4.37 (q, 2H), 7.38. (m, 2H), 7.84 (m.2H); M / z (+) 216.2 (MH +). Preparation 9 Ethyl 3-diazo-5-methoxyindole-2-carboxylate (precursor of compounds 83, 84) To a solution of ethyl 5-methoxyindole-2-carboxylate (8.0 g) in acetone (300 ml) is added a solution of sodium nitrite (39 g) in water (100 ml) and the reaction is stirred vigorously while adding HCl drops (2M, 98 ml) at 20-25 ° C for one hour. The mixture is stirred in a stoppered flask at 20 ° C overnight and the resulting yellow precipitate is filtered to give the product (6.0 g, 67%); NMR d (CDC13) 1.45 (t, 3H). 3.87 (s. 3H). 4.50 (q.2H), 6.98 (m, 2H), 7.85 (d, 1H): M / z (+) 246 (Me +). Preparation 10 t-Butyl 3-bromo-N- (3,4-dichlorobenzyl) indole-2-carboxylate N, N-dimethylformamide di-t-butyl acetal (19.90 ml) is added dropwise to a suspension of 3-bromo acid -N- (3,4-dichlorobenzyl) indole-2-carboxylic acid (8.31 g) in toluene (150 ml), under an argon atmosphere and stir at room temperature for 2 hours. The reaction is cooled, filtered and washed with brine (100 ml), saturated aHC03 (aq.) (100 ml), and brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the product as a clear oil. that crystallizes when resting (7.65 g, 81%); RM? d (CD3SOCD3) 1.49 (s, 9H), 5.76 (s, 2H), 6.86 (m, 1H), 7.24 (t, 1H), 7.35-7.68 (m, 5H); M / z (+) 456 (MH ") 400. Preparation 11 Methyl 2-methoxycarbonyl-3-indolacetate Phenyl hydrazine (5.7 ml), dimethyl 2-oxoglutarate (10 g) and acetic acid (1.0 ml) in methanol (100 ml) are heated at reflux for 1 hour, then concentrated in vacuo.

The crude hydrazone (13 g) is dissolved in saturated methanolic hydrochloric acid (350 ml) and heated at 75 ° C for 16 hours with continuous stirring. The reaction is diluted with water (200 ml) and extracted with dichloromethane. Combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent is removed in vacuo to give a yellow crystalline solid (7.0 g); NMR d (CD3SOCD3) 3.59 (s.3H), 3.83 (s, 3H), 4.12 (s.2H). 7.06 (t, 1H), 7.26 (t, 1H), 7.41 (d, 1H), 7.63 (d, 1H), 11.76 (brs, 1H); M / z (-) 246 (M - H +). Preparation 12 Methyl N- (3,4-dichlorobenzyl) -2-methoxycarbonyl-3-allylacetate 3,4-Dichlorobenzyl chloride (8.2 g) is added to a stirred solution of methyl 2-methoxycarbonyl-3-indoleacetate (6.5 g) and potassium carbonate (8.36 g) in acetonitrile (200 ml) under an argon atmosphere. The reaction is heated to 80 ° C for 24 hours. The reaction is concentrated in vacuo and divided between ethyl acetate and water. Combined organic extracts were washed with saturated aqueous sodium chloride solution, dried (MgSO 4) and concentrated in vacuo. The residue is purified by column chromatography using 25% ethyl acetate: iso-hexane as eluent to give the product as a white solid (6.95 g, 65%); NMR d (CD3SOCD3) 3.60 (s, 3H), 3.77 (s, 3H). 4.13 (S. 2H), 5.89 (s, 2H), 6.89 (dd, 1H), 7.16 (t, 1H), 7.27 (d, 1H), 7.34 (t, 1H), 7.52 (d, 1H), 7.57 (d, 1H), 7.78 (d.h. H); M / z (+) 406 (MH +). Preparation 13 Methyl 3-aminoindole-2-carboxylate To a solution of ethyl 3-aminoindole-2-carboxylate [Prepared according to P. Unangst. J. Het. Chem., 1983, , 495] (5.0 g) in methanol (50 ml), sodium methoxide (6.5 g) is added. The resulting mixture is stirred for 4 hours and then neutralized with saturated ammonium chloride solution. The resulting mixture is extracted with dichloromethane, dried (MgSO 4) and evaporated to give a gum which is purified by column chromatography using iso-hexane: ethyl acetate (1: 4) as eluent to give the desired product (1.95 g, 42%); NMR d (CD3SOCD3), 3. 8 (s, 3H). 5 . 7 (s.2H), 6. 8 - 6. 9 (m.H.), 7. 2 (m, 2H), 7. 7 (d, 1H); M / z (+) 191. 1 (MH +). Preparation 14 Ethyl 3 -formylindole-2-carboxylate A mixture of N-methylformanilide (2.25 ml) and phosphoryl chloride (1.70 ml) is stirred at room temperature for 15 minutes. 1,2-dichloroethane (30 ml) is then added, followed by ethyl indole-2-carboxylate (3 g) and the reaction is heated to reflux for 90 minutes. The reaction mixture is then poured into an ice / water mixture (200 ml) and sodium acetate (10 g) and extracted with ethyl acetate (2 x 200 ml). Combined organic phases were evaporated and the crude residue was purified by column chromatography using dichloromethane as eluent to give the product as a white solid (2.27 g, 66%); RM? d (CD3SOCD3) 1.40 (t, 3H), 4.42 (q, 2H), 7.25 (m, 1H). 7.40 (m, 1H), 7.55 (m, 1H), 8.20 (m, 1 H), 12.77 (s, 1H); M / z (+) 218.3 (MH +). Preparation 15 Ethyl-3-formyl-N- (3,4-dichlorobenzyl) indole-2-carboxylate Sodium hydride (488 mg, 60% in mineral oil) is added to a stirred solution of ethyl 3-formylindole-2-carboxylate (2.21) g) in DMF (100 ml) under argon and the reaction is stirred at room temperature for 25 minutes. 3, 4-Dichlorobenzyl chloride (1.71 ml) is then added and the reaction is stirred overnight. The reaction mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (80 ml) and washed with water (2 x 80 ml), dried (MgSO 4) and concentrated in vacuo to give a crude residue which is purified by column chromatography using ethyl acetate: iso-hexane as eluent (gradient 5/95 - 100/0), to give the product as a yellow solid (2.17g, 57%); NMR d (CD3SOCD3) 1.25 (t, 3H), 4.40 (q, 2H), 5.80 (s, 2H), 7.00 (m, 1H), 7.30 -7.50 (m, 3H), 7.55 (m, 1H), 7.65 (m, 1H), 8.35 (m, 1H), 10.48 (s, 1H); M / z (+) 376.4 (MH +). Preparation 16 Ethyl N- (3,4-dichlorobenzyl) -2 -ethoxycarbonylindol-3-carboxylate A mixture of sodium chlorite (3.39 g) and sodium dihydrogen orthophosphate (4.54 g) in water (50 ml) is added dropwise. to a stirred solution of ethyl 3-formyl-N- (3, -dichlorobenzyl) indole-2-carboxylate (1.56 g) and 2-methylbut-2-ene (50 ml) in tert-butyl alcohol (100 ml) at room temperature environment and the reaction is vigorously stirred overnight. The reaction mixture is concentrated in vacuo and the residue is dissolved in dichloromethane (100 ml), washed with water (100 ml), dried (MgSO 4) and concentrated in vacuo to give the product as a yellow solid (1.50 g, 92%). ); NMR d (CD3SOCD3) 1.20 (t, 3H), 4.30 (q, 2H), 5.50 (s, 2H), 7.00 (m, 1H), 7.25 (m, 2H), 7.42 (m, 1H), 7.58 (m , 2H), 8.00 (m, 1H), 12.68 (s, 1H); M / z (-) 390.4 (MH +). EXAMPLE 1 Ethyl N- (3,4-dichlorobenzyl) -3-benzylthioindole-2-carboxylate (Ethyl ester of compound 5) Powdered sodium hydroxide (3.2 g) is added in a single portion to a vigorously stirred solution of ethyl 3-benzylthioindole-2-carboxylate (2.48 g), 3,4-dichlorobenzyl chloride (1.71 g). g) and tetra-n-butylammonium hydrogen sulfate (0.5 g) in dichloromethane (100 ml). The reaction is stirred for 6 hours then divided between 2M HCl and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue was purified by column chromatography using iso-hexane: 5% ethyl acetate as eluent to give the product as a white crystalline solid (2.26 g, 60%); NMR d (CD3SOCD3) 1.32 (t, 3H), 4.00 (s, 2H), 4.25 (q, 2H), 5.60 (s, 2H), 6.78 (d, 1H), 7.04 (m, 2H), 7.10 - 7.38 (m, 8H), 7.80 (d, 1H); M / z (+) 470 (M +), 426, 424. Example 2 The procedure described in Example 1 above was repeated using the appropriate indole. In this manner, the compounds described below were obtained. Ethyl 3-bromo-N- (3,4-dichlorobenzyloindole-2-carboxylate (precursor of Compound 73) 98% yield; NMR d (CD3SOCD3) 1.26 (t, 3H), 4.30 (q, 2H), 5.79 (s, 2H) 6.89 (d, 1H), 7.25 (s, 1H), 7.33 - 7.46 (m, 2H), 7.50 (d, 1H), 7.57 - 7.68 (m, 2H) .M / z (+) 430. 1 (MH +). Useful JNT- (3,4-dichlorobenzyl) -3- (2,2-dimethyl-1,3-dioxolane-4-ylomethoxy) indole-2-carboxylate (Ethyl ester of Compound 701 71% yield; NMR d (CD3SOCD3) 1.26 (t, 3H), 1. 29 (s, 3H), 1.34 (s, 3H), 3.84 (t, 1H). 4.10 (m, 1H), 4.25 (q, 2H). 4.42 (m, 1H), 5.71 (s, 2H), 6.86 (m.1H), 7.13 (t. 1 HOUR) . 7.32 (m.2H). 7.53 (m, 2H), 7.77 (d, 1H); M / z (+) 478.3 (MH +). Ethyl N- (3,4-dichlorobenzyl) -3- \ 2 - (HT-acetyl-W-phenylamino) ethoxyl indole-2-carboxylate (Ethyl ester of Compound 76) 82% yield; NMR d (CD3SOCD3) 1.22 (t, 3H), 3.27 (s, 3H), 3.44 (t, 2H). 4.15 (t, 2H), 4.25 (q, 2H), 5.70 (s, 2H), 6.85 (d, 1H), 7.10 (t, 1H), 7.27 (m, 7H), 7.53 (m.2H), 7.64 (d, 2H); M / z (+) 525.5 (MH +). Ethyl N- (3,4-dichlorobenzyl) -3- (3-furylmethoxy) indole-2-carboxylate (Ethyl ester of Compound 77) 64% yield; NMR d (CD3SOCD3) 1.23 (t, 3H), 4. 24 (q, 2H), 5.09 (s, 2H), 5.71 (s, 2H), (s, 1H), 6.83 (d, 1H), 7.10 (t, 1H), 7.29 (m, 2H), 7.51 (t.2H), 7.65 (m, 3H): M / z (+) 444.4 (MH +). Ethyl N- (3,4-dichlorobenzyl) -3- (cyclohex-2-enylmethoxy) indole-2-carboxylate (Ethyl ester of Compound 78) 83% yield; NMR d (CD3SOCD3) 1.24 (t, 3H), 1. 42 (m, 1H), 1.91 (m, 2H). 2.04 (m, 3H). 2.19 (m, 1H), 4.10 (m, 2H), 4.25 (q, 2H), 5.68 (s, 2H), 5.70 (s, 2H). 6.84 (d, 1H), 7.13 (t, 1H) 7.32 (m, 2H), 7.52 (m.2H), 7.74 (d, H); M / z (+) 458.4 (MH +). Ethyl N- (3,4-dichlorobenzyl) -3- [4- (hydroxymethyl) cyclohexyl methoxyldol-2-carboxylate (Ethyl ester of compound 79) 69% yield; NMR d (CDC13) 0.82-2.15 (m, 10H), l-36 (t, 3H), 3-50 (d, 2H), 4-07 (d, 2H), 4.35 (q, 2H) .5.64 ( s, 2H), 6.81 (d, 2H), 7.12 (m, 2H), 727 (m, 3H), 7-75 (d, 2H); M / z (+) 490.5 (MH +). Ethyl N- (3,4-dichlorobenzyl) -3- (4-chlorophenethyloxy indole-2-carboxylate (Ethyl ester of Compound 80) 87% yield; NMR d (CD3SOCD3) 1-21 (t, 3H), 3.07 (t , 2H), 4.21 (q, 2H), 4.37 (t, 2H), 5.70 (s, 2H), 6-84 (d, 1H), 7-07 (t, 1H), 7-31 (m, 6H) ), 7-51 (t, 3H); M / z (+) 504.5 (MH +). Compound 23 ethyl ester 29% yield; NMR d (CDC13) 1.35 (t, 3H), 3.4 (t, 1H), 3.9-4.0 (m, 2H), 4.3-4.5 (m, 4H), 5.6 (s, 2H), 6.8 (d, 1H) , 7.1-7.4 (m, 5H), 7.8 (d, 1H); M / z (+) 410.3 (MH +), 408.2. Compound 26 ethyl ester 45% yield; NMR d (CDC13) 1.35 (t, 3H), 3.2 (t, 2H), 4.3 (q, 2H), 4.45 (t, 2H), 5.65 (s, 2H), 6.8 (dd, 1H), 7.05 - 7.4 (m, 10H), 7.5 (d, 1H); M / z (+) 470.3 (MH +), 468. 4. 2-methyl ester and methyl ester of Compound 27 66% yield; M / z (+) 438.3 (MH +), 436.2. Ethyl ester of Compound 66 62% yield; NMR d (CDC13) 1.4 (t.3H), 3.5 (s, 3H), 4.3-4.4 (m, 4H), 5.65 (s.2H), 6.85 (dd, 1H), 7.1 -7.4 (m, 5H) . 7.8 (d.1H); M / z (+) 424 (MH +), 422. Ethyl ester of Compound 67 73% yield; NMR d (CDC13) 1.4 (t, 3H), 1.5 (s, 9H), 3.7 (q, 2H). 4.4 (q, 2H), 5.65 (s.2H), 6.8 (dd, 1H), 7.1-7.4 (m, 5H), 7.9 (d, 1H); M / z (+) 507.3 (MH +). Methyl 3-amino-N- (3,4-dichlorobenzyl) indole -2-carboxylate (Precursor of Compound 1,2) 64% yield; NMR d (CD3SOCD3) 3.75 (s, 3H), 5.6 (s, 2H), 6.0 (s, 2H), 6.8-7.0 (m, 2H), 7.1-7.5 (m, 4H), 7.85 (d, 1H); M / z (+) 351.2 (MH +), 349.2. Di-ethyl ester Compound 24 38% yield; NMR d (CDC13) 1.05 (t, 3H), 1.4 (t, 3H). 3.6 (s 2H), 3.95 (q.2H), 4.4 (q, 2H), 5.7 (s, 2H), 6.85 (dd, 1H), 7.2 - 7.4 (m, 5H), 7.9 (d.1H); M / z (+) 468. 3 (MH +), 466.3.

Ethyl 3-amino-N- (3,4-dichlorobenzyl) indole -2-carboxylate (Precursor of Compound 8, 9. 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. 20, 22) 44% yield; RM? d (CD3SOCD3) 1.21 (t, 3H), 4.21 (q, 2H). 5.56 (s, 2H), 6.00 (s, 2H), 6.86 (d, 1H), 6.98 (t.1H), 7.22 (d, 1H), 7.30 (t, 1H), 7.40 (d.1H), 7.48 (d, 1H) 7.86 (d, 1H); M / z (+) 363 (MH +). EXAMPLE 3 Ethyl ester of Compound 73 Sodium hydride (23 mg, 60% dispersion in mineral oil) is added in a single position to a stirred solution of the compound of the formula (A) (0.19 g) in DMF (3.0 ml) and the reaction is stirred for 30 minutes.

(A) 3, 4-Dichlorobenzyl chloride (0.1 ml) is added and the reaction is stirred for 16 hours. The reaction is poured into water and extracted with ethyl acetate. Combine organic extracts were dried (MgSO4) and concentrated and the residue was purified by chromatography using iso-hexane: 20% ethyl acetate as eluent to give the product as a colorless oil (0.23 g, 85%); M / z (+) 540, 538 (MH +).

Example 4 The procedure described in Example 4 above is repeated using the appropriate indole. In this manner, the compounds described below were obtained. Ethyl ester of Compound 74 93% performance; M / z (+) 545, 543 (MH +).

Ethyl ester of Compound 75 73% yield; M / z (+) 507, 505 (MH +), 461, 459, 318. Ethyl N- (3,4-dichlorobenzyl) indole-2-carboxylate 60% yield; M / z (+) 349 (MH +) Diethyl N- (3,4-dichlorobenzyl) -2,3-dicarboxylate 74% yield; M / z (+) 392, 394 (MH +) Example 5 Ethyl N - (3,4-dichlorobenzyl) -3- (2-ethoxyethoxy) -5-methoxyindole-2-carboxylate (Ethyl ester of Compound 82) To one solution of ethyl N- (3,4-dichlorobenzyl) -3- (2-ethoxyethoxy) -5-methoxyindole-2-carboxylate (3.0 g) in DMF (50 ml) are added anhydrous potassium carbonate (3.0 g), 3.4-dichlorobenzyl (2.0 ml) and potassium iodide (100 mg), and the reaction is stirred at 60 ° C for 3 hours. The solvent is evaporated in vacuo and the residue is partitioned between water (200 ml) and ether (200 ml), the organic layer is dried (MgSO 4) and evaporated to give a gum, which is purified by column chromatography using iso-hexane. : ethyl acetate (4: 1) to give the product (2.5 g, 55%); RM? d (CDC13) 1.25 (t, 3H), 1.38 (t, 3H), 3.62 (q, 2H), 3.80 (t, 2H), 3.86 (s, 3H), 4.3 - 4.4 (m, 4H), 5.62 ( s, 2H). 6.80 (dd, 1H), 6.96 (dd, 1H), 7.12 (s, 1H), 7.14 (d, 1H), 7.20 (d, 1H), 7.26 (d, 1H).

Example 6 The procedure described in Example 5 above is repeated using the appropriate indole and benzyl halide. In this way, the compound described below is obtained. Ethyl N- (3,4-dichlorobenzyl) -3- (2-hydroxyethoxy) -5-methoxyindole-2-carboxylate (Ethyl ester of Compound 83) 38% yield; NMR d (CDC13) 1.32 (t, 3H), 3.42 (t, 1H). 3.87 (s, 3H). 3.92 (m.2H), 4.3-4.4 (m, 4H), 5.60 (s, 2H), 6.80 (dd, 1H), 7.02 (dd, 1H), 7.1-2.2 (m, 3H). 7.32 (d.1H): M / z (+) 440 (MH +), 438. Example 7 N- (3,4 -Dichlorobenzyl) -3-benzyl-sulfinylindole-2-carboxylic acid (Compound 25) A solution of ethyl N- (3, 4-dichlorobenzyl) -3-benzylthioindole-2-carboxylate (0.50 g) in dichloromethane (2 ml) is added to a slurry of wet alumina (1 g) and Oxone ™ (0.615 g) in dichloromethane (10 ml). The mixture is then heated to reflux for 2 hours, and allowed to cool. The product is washed by entraining the alumina using methylene chloride (200 ml). The solution then dries (MgSO4) and evaporated to give the crude sulfoxide ester (103 mg). The crude ester is dissolved in THF (2 ml) and methanol (1 ml), and sodium hydroxide (2M, 3 ml) is added.

The solution is stirred for 5 hours, then concentrated in vacuo.

The residue is dissolved in water (10 ml) and the product is precipitated by dropwise addition of aqueous HCl (2M, 10 ml). The resulting solid is collected by filtration and washed with cold water, then dried in vacuo to give the product as a pale yellow solid (36 mg, 7%, 2 steps), NMR d (CD3SOCD3) 4.37 (d, 2H), 5.83. (d, 2H), 6.96 (dd, 1H), 7.10 (m, 3H), 7.20 (m, 3H), 7.30 (t, 1H), 7.38 (d, 1H). 7.59 (s, 1H), 7.62 (s, 1H), 8.05 (d, 1H); M / z (-) 456 (M-H +), 412, 365, 323, 323, 321,320. Example 8 Ethyl N- (3,4-dichlorobenzyl) -3-benzylsulfonylindole -2-carboxylate (Ethyl ester of Compound 21) To a solution of ethyl N- (3,4-dichlorobenzyl) -3-benzylthioindole -2-carboxylate (520 mg ) in acetic acid (12 ml) is added hydrogen peroxide solution (30%, 2.5 ml) and the resulting mixture is stirred for 18 hours. The reaction mixture is poured into water (20 ml), basified with sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue is purified by column chromatography using iso-hexane: 20% ethyl acetate as eluent to give the product as a yellow gum (205 mg, 37%); RM? d (CDC13) 1 4 (t.3H), 4.45 (q.2H), 4.6 (s, 2H). 5.5 (s.2H), 6.9 (dd, 1H). 7 1 - 7.3 (m.H9), 7.4 (d, 1H), 7.7 (d, 1H); M / z (+) 504.3 (MH +). 502.4. Example 9 The procedure described in Example 8 above was repeated using the appropriate thioindol. From this, the compound described below is obtained. Di-ethyl ester of Compound 51 48% yield; A ~ / 7 (+) 500.2 (MH + MH +), 498.3. Example 10 N- (3,4-Dichlorobenzyl) -3-benzylthioindole-2-carboxylic acid (Compound 5) Ethyl N- (3,4-dichlorobenzyl) -3-benzylthioleyindole-2-carboxylate (0.31 g) is dissolved in THF / methanol (1: 1) and sodium hydroxide (2M, 2.0 ml) is added and the reaction is stirred for 16 hours. The reaction is then concentrated in vacuo and the residue dissolved in water. The solution is acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which is filtered, washed with water and dried in vacuo to give the desired final product (0.082 g, 28%); RM? d (CD3SOCD3) 4.04 (s, 2H), 5.72 (s, 2H), 6.83-7.62 (m, 12H); M / z (-) 442 (M +), 440, 428, 398, 396, 307, 305.

Example 11 The procedure described in Example 10 above is repeated using the appropriate ester. In this manner, the compounds described below were obtained. Compound 70 70% yield; RNM d (CD3SOCD3) 1.30 (s, 3H), I.35 (s, 3H) 3.87 (m, IH), 4.10 (m, 3H) 4.40 (m, 1H), 5.75 (s, 2H), 6.90 (d ~ 2H), 7.13 (t, 1H), 7.32 (m, 2H), 7.51 (m 2H). 7.75 (d, 211); M / z (-) 448.2 (M-Ht MH +) Compound 76 85% yield; NMR d (CD3SOCD3) 3.35 (m, 2H), 3.44 (s.3H). 5.80 (s.2H), 7.10 (m.2H) 7.21 (m, 6H), 7.42 (m, 3H), 7.59 (d, 1H); M / z (-) 495.4 (M - H +). Compound 77 61% yield; NMR d (CD3SOCD3) 5.10 (s, 2H), 5.77 (s, 2H), 6.58 (s, 1H), 6.89 (d, 1H). 7.07 (t, 1H), 7.27 (m, 2H), 7.50 (m, 2H), 7.62 (m, 3H); M / z (-) 414.2 (M - H +).

Compound 78 57% yield; NMR d (CD3SOCD3) 1.40 (m, 1H), 2. 00 (m, 6H), 4.08 (d, 2H), 5.67 (s, 2H), 5.73 (s, 2H), 6.90 (m, 1H), 7.10 (m.1H), 7.30 (m, 2H), 7.52 (m, 2H). 7.70 (m, 1H); M / z (-) 428.3 (M - H +).

Compound 79 68% yield; NMR d (CD3SOCD3) 0.96 (m, 4H), 1.52 (m, 1H), 1.77 (m.2H), 1.90 (m, 3H), 3.20 (d, 2H), 3.96 (d, 2H), 5.78 (s) , 2H), 7.00 (m, 2H), 7.15 (t.1H), 7.35 (m, 2H), 7.50 (m, 2H); M / z (-) 460.4 (M - H +). Compound 80 65% yield; NMR d (CD3SOCD3) 2.99 (t, 2H), 4.35 (t, 2H), 5.80 (s, 2H), 6.87 (t, 1H), 7.04 (m, 2H), 7.23 (m, 2H), 7.36 (m , 5H), 7.48 (d, 1H); M / z (-) 474.3 (M - H +). Compound 71 91% yield; NMR d (CD3SOCD3) 3.52 (m, 2H), 3.86 (m, 1H) 4.12 (m, 1H), 4.27 (m, 1H), 5.74 (s, 2H). 6.90 (d, 1H), 7.18 (t, 1H), 7.38 (m, 2H), 7.58 (m, 2H), 7.87 (d, 1H), M / z (-) 408.2 (M-H +). 3-Bromo-N- (3,4-dichlorobenzyl) indole-2-carboxylic acid (precursor of Compound 72) 90% yield; NMR d (CD3SOCD3) 5.83 (s, 2H), 6.89 (m, 1H), 7.25 (t, 1H), 7.39 (m, 2H), 7.51 (d, 1H), 7.60 (m, 2H); M / z (-) 398.2 (M-H +), 354.3. Compound 73 48% yield; M / z (-) 510 (M +), 508, 466, 464. Compound 74 21% yield; M / z (-) 515 (M +). 513. 425 143.

Compound 75 53% yield; M / z (-) 417 (M +), 475, 431, 290.

N- (3,4-Dichlorobenzyl) -2-carboxylic acid-3-indoleacetic acid (Compound 28) 92% yield; NMR d (CD3SOCD3) 3.72 (s, 2H), . 80 (s, 2H), 7.00-7.10 (m, 2H), 7.16 (t, 1H), 7.33-7.40 (m, 2H), 7.49 (d, 1H), 7.58 (d, 1H); M / z (-) 376 (M-H +).

Compound 68 57% yield; NMR d (CD3SOCD3) 1.50-2.00 (m, 4H), 3.60 (q, 1H), 3.80 (q, 1H), 3.90 (m, 1H), 5.75 (s, 2H), 7. 10 (m, 3H), 7.35 (d, 1H), 7.45 (s, 1H), 7.50 (d, 1H), 8.25 (d, 1H); M / z (-) 445.2 (M-H +). Compound 81 93% yield; NMR d (CD3SOCD3) 2.25 (m, 1H), 3.05-3.60 (m, 5H), 4.80 (m, 1H), 5.90 (s, 2H), 7.05 (m, 1H), 7.30 (t, 1H), 7.40 (m, 2H), 7.65 (m, 2H), 7.80 (m, 1H), 8. 95 (m, 1H); M / z (-) 479.4 (M-H +). Compound 84 58% yield; M / z (-) 479.2 (M-H +). Compound 85 81% yield; M / z (-) 470.2 (M-H +).

Acid (Z) -N- (3,4-Dichlorobenzyl) -2-carboxyindole-3-acrylic (Compound 50) 81% yield; NMR d (CD3SOCD3) 5.80 (s, 2H), 6.50 (d, 1H), 6.90 (m, 1H), 7.30 (m. 3H), 7.50 (d, 1H), 7.60 (m, 1H), 8.00 (m , 1H), 8.40 (d, 1H); M / z (-) 388.4 (M-H +). N- (3,4-Dichlorobenzyl) -3- (2-ethoxyethoxy) -5-methoxy-indol-2-carboxylic acid (Compound 82) 60% yield; NMR d (CD3SOCD3) 1.14 (t, 3H), 3.46 (q.2H), 3.60 (t.2H), 3.73 (s, 3H). 4.25 (t, 2H), 5.80 (s, 2H), 6.70 (dd, 1H), 6.95 (d, 1H), 7.1 - 7.2 (m.2H), 7.32 (d, 1H), 7.46 (d, 1H); M / z (-) 438 (M-H +), 438. Compound 23 84% yield; NMR d (CD3SOCD3) 3.7 (t, 2H), 4.2 (t, 2H), 5.7 (s, 2H), 6.9 (dd.1H), 7.1 (t.1H), 7.3-7.4 (m, 2H), 7.5-7.6 (m, 2H), 7.8 (d, 1H) ); M / z (-) 380.2 (M +), 378. 2. Compound 26 87% yield; NMR d (CD3SOCD3) 3.1 (t, 2H). 4.35 (t 2H), 5 7 (s, 2H), 6 9 (dd, 1H), 7 05 (t, 1H), 7-2-7 4 (m, 7H), 7.45-7.76 (m, 4H) ); M / z (-) 440.2 (M +), 438.1 Compound 27 94% yield; NMR d (CD3SOCD3) 4.6 (s, 2H), 5.7 (s, 2H), 6.95 (dd, 1H), 7.1 (t, 1H), 7.2 (t.1H), 7.37 (d, 1H), 7.4 - 7.5 (m, 2H), 7.7 (d, 1H); M / z (-) 394 (M +), 392.

Compound 66 49% yield; NMR d (CD3SOCD3) 3.6 (t, 2H), 4.25 (t, 2H), 5.85 (s, 2H), 6.9 (t, 1H), 7.0 (t.1H), 7.1 (dd, 1H), 7.25 (d, 1H), 7.4 (s, 1H), 7.5 ( d, 2H); M / z (-) 394.2 (M +), 392.1. Compound 67 59% yield; NMR d (CD3SOCD3) 1.4 (s, 9H), 3.3 (S, 3H), 4.1 (t, 2H), 5.7 (s 2H), 6.8 - 7.0 (m, 2H), 7.1 (d, 1H), 7.3 - 7.4 (m, 2H), 7.5 (t, 2H) ), 7.7 (d, 1H); M / z (-) 479.3 (M +). Compound 1 84% yield; NMR d (CD3SOCD3) 5.9 (s, 2H). 6.95 (dd, 1H). 7.1 (t.1H), 7.3-7.4 (m, 2H). 7.5-7.7 (m, 4H), 7.8 (d, 1H), 8.0 (d, 1H), 8.1 (s.1H); M / z (-) 473.1 (M +), 471.1. Compound 2 47% yield; NMR d (CD3SOCD3) 5.85 (s.2H). 6. 95 (d.1H). 7.1 (t, 1H), 7.3 - 7.4 (m, 2H). 7.5 (d, 1H), 7.8 (d 1H); M / z (-) 413.1 (M +), 411.1.

N- (3,4 -Dichlorobenzyl) -3-benzyl-sulfonyl-indol-2-carboxylic acid (Compound 21) 81% yield; NMR d (CD3SOCD3) 4.8 (s, 2H), 5.7 (s, 2H), 7.0-2.25 (m, 8H), 7.4-7.6 (m, 4H); M / z (+) 474.3 (MH +). Compound 24 98% yield; NMR d (CD3SOCD3) 3.6 (s, 2H), 5.75 (s, 2H), 6.9 (dd, 1H), 7.2-7.4 (m, 3H), 7.5 (dd, 2H), 7.8 (d, 1H); M / z (-) 410.1 (MH +), 408.1. N- (3,4 -Dichlorobenzyl) -3- (2-hydroxy-toxy) -5-methoxyindole-2-carboxylic acid (Compound 83) 93% yield; NMR d (CD3SOCD3) 3.46 (t, 2H), 3. 74 (s, 3H), 4.14 (t, 2H), 5.80 (s, 2H), 6.63 (dd, 1H), 7. 96 (d, 1H), 7.06 (dd, 1H), 7.20 (d, 1H), 7.30 (s, 1H), 7.46 (d, 1H); M / z (-) 410 (MH +), 408. N- (3,4-Dichlorobenzyl) -3-morpholinosulfonylindole-2-carboxylic acid (Compound 3) 59% yield; NMR d (CDC13) 3.05-3.15 (m, 4H), 3.7-3.8 (m, 4H), 5.7 (s, 2H), 6.9 (dd, 1H), 7.2-7.5 (m, 5H), 8.2 (d, 1 HOUR); M / z (+) 471 (MH +), 469. N- (3,4-Dichlorobenzyl) -3- (1, 1-iomorpholino dioxide) sulfonylindole-2-carboxylic acid (Compound 4) 93% yield; NMR d (CD3SOCD3), 3.1 - 3.2 (m, 4H), 3.7 - 3.8 (m, 4H), 5.45 (s, 2H), 7.1 - 7.2 (m, 2H), 7.3 - 7.45 (m, 2H), 7.5 (d, 1H), 7.7 - 7.8 (m, 2H); M / z (+) 519. 2 (MH +), 517.2. Compound 51 23% yield; NMR d (CD3SOCD3). 4.1 (s, 2H), 5.6 (s, 2H), 7.1 (m, 2H), 7.3 - 7.4 (, 2H), 7.5 (d, 1H), 7.7 (s, 1H), 7.9 (m, 1H); M / z (-) 442 (M +), 440. Compound 86 27% yield; NMR d (CD3SOCD3) 6.65 (s, 2H), 7.45 (dd, 1H), 7.6-7.75 (m, 2H). 7.8 (d, 1H), 7.95 (t, 1H), 8.95 (d, 1H); Mz (-) 362. 364 (M +) Example 12 Ethyl N- (3,4-dichlorobenzyl) -3-morpholinosulfonylindole-2-carboxylate [Ethyl ester of Compound 3] To a suspension of ethyl N- (3, 4- dichlorobenzyl) -3-morpholinosulfinylindole-2-carboxylate (803 mg) in acetone (40 ml) is added to a solution of potassium permanganate (528 mg) in water (15 ml). The resulting mixture is stirred for 18 hours. The mixture is poured into water (20 ml) and extracted with diethyl ether, dried (MgSO 4) and concentrated to give a gum which is purified by column chromatography using iso-hexane: ethyl acetate (3: 1) as eluent to give the desired product (681 mg, 82%); NMR d (CDC13) 1.3 (t, 3H), 3.2 - 3.2 (m, 4H), 3.7 - 3.8 (m, 4H), 5.4 (s, 2H), 6.95 (d, 1H), 7.3 - 7.4 (m, 5H), 8.05 (d, 1H); M / z (+) 499.2 (MH +), 497. 3. EXAMPLE 13 The procedure described above in Example 12 is repeated using the appropriate amine. In this way, the compound described below is obtained. Ethyl N- (3,4-dichlorobenzyl) -3- (1,1-dioxidothiomorpholino) sulfonylindole-2-carboxylate [Ethyl ester of Compound 4] 49% yield; NMR d (CDC13) 1.3 (t, 3H), 3.1 -3.2 (m, 4H), 3.9-4.0 (m, 4H), 4.4 (q, 2H), 5.4 (s, 2H), 6.9 (dd, 1H) , 7.2-7.4 (m, 5H), 8.0 (d, 1H); M / z (-) 545.2 (M +), 543.1. Example 14 Compound 6 N- (3,4-Dichlorobenzyl) -2-ethoxycarbonylindole-3-sulfonyl chloride (0.12 g), N-methylpiperazine (0.15 ml), triethylamine (0.19 ml) and 4-dimethylaminopyridine (30 mg) were stirred for 4 hours in dichloromethane (2.0 ml).

The reaction is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is dissolved in THF / methanol (1: 1) and sodium hydroxide (3M, 1.0 ml) is added and the reaction is stirred for 16 hours. The reaction is then concentrated in vacuo and the residue dissolved in water. The solution is acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which is filtered, washed with water and dried in vacuo to give the desired final product (61 mg, 47%, 2 steps); NMR d (CD3SOCD3) 2.57 (s.3H), 3.00 (m.4H). 3.32 (m, 4H). 5.37 (s, 2H), 7.19 (m, 2H), 7.28 (d, 1H), 7. 43 (m, 2H), 7.65 (s, 1H), 7.80 (m, 1H); M / z (+) 482 (M +), 236, 215, 196, 159, 142. Example 15 The procedure described above in Example 12 is repeated using the appropriate amines. In this manner, the compounds described below were obtained. Compound 7 57% yield (2 stages); NMR d (CD3SOCD3) 2.63 (s, 6H), 3.10 (m, 4H), 5.68 (s, 2H), 7.12-2.26 (m, 3H), 7. 44-7.60 (m, 3H), 7.96 (m, 1H), 8.37 (t, 1H); M / z (+) 470 (M +), 214, 158, 141, 123. Compound 29 61% yield (2 steps); M / z (-) 457 (M +), 455,413, 411. Compound 30 30% yield (2 steps); M / z (-) 487 (M +), 485, 443, 441, 399, 397, 355, 353. Compound 31 23% yield (2 steps); M / z (-) 492 (M-H +), 449, 420, 400, 398, 354, 308, 222. Compound 32 45% yield (2 steps); M / z (-) 497 (M +), 495, 453, 451. Compound 33 44% yield (2 steps); M / z (-) 436 (M-C02 +), 434. Compound 34 40% yield (2 stages); M / z (-) 493 (M "), 449, 447, 340.338. Compound 35 49% yield (2 stages); M / z (-) 512 (M +), 510, 468, 466. Compound 36 60% yield (2 steps); M / z (-) 512 (M +), 510, 468, 466. Compound 37 52% yield (2 steps); M / z (-) 446 (M-C02 +), 444. Compound 38 43% yield (2 stages); M / z (-) 443 (M-C02 +), 441. Compound 39 29% yield (2 steps); M / z (-) 393 (M-C02 +), 391. Compound 40 54% yield (2 stages); M / z (-) 515 (M *), 513, 471, 469. Compound 41 34% yield (2 steps); M / z (-) 465 (M-C02 +), 463. Compound 42 20% yield (2 steps); M / z (-) 473 (M-C02 +), 369, 367. Compound 43 37% yield (2 steps); M / z (-) 425 (M-C02 +), 423. Compound 44 5% yield (2 steps); M / z (-) 529 (M +), 527, 485, 483, 355, 353, 274. Compound 45 17% yield (2 stages); M / z (-) 4663 (M +), 464, 422, 420. Compound 46 6% yield (2 stages); M / z (-) 451 (M-C02 +), 449, 409, 355, 296, 221. Compound 47 22% yield (2 stages); M / z (-) 549 (M +), 547, 505, 503, 458, 381, 379, 355, 353. Example 16 Ethyl 3 - (2,2-dimethyl-1,3-dioxolane-4-ylomethoxy) indole -2-carboxylate (Precursor of Compounds 70 and 71) Rhodium acetate dimer (30 mg) is added to a solution of solketal (0.87 ml) and ethyl 3-diazoindole-2-carboxylate (300 mg) in dichloroethane (10 ml), and stirred at 85 ° C for 3 hours. The reaction is concentrated in vacuo and the residue is purified by column chromatography using a gradient from 0% to 20% ethyl acetate: iso-hexane as eluent to give the product as a pale yellow solid (435 mg, 97%); NMR d (CD3SOCD3) 1.27-1.38 (m, 9H), 3.88 (m, 1H), 4.11 (m, 3H), 4.30 (q, 2H), (m, 1H), 7.01 (t, 1H), 7.24 ( t, 1H), 7.36 (d, 1H), 7.65 (d, 1H), 11.27 (s, 1H); M / z (+) 320. 3 (MH +). Example 17 The procedure described above in Example 16 is repeated using the appropriate diazoindole and alcohols. In this manner, the compounds described below were obtained. Ethyl 3- [2- (N-acetyl-N-phenylamino) ethoxylindol-2-carboxylate (Precursor of Compound 76) 75% yield; NMR d (CD3SOCD3) 1.32 (t, 3H), 3. 41 (m, 5H), 4.12 (t, 2H), 4.31 (q, 2H), 6.99 (t, 1H), 7.23 (m, 6H), 7.36 (d, 1H), 7.58 (d, 1H), 11.28 (s, 1H); M / z (+) 367. 4 (MH +). Ethyl 3- (3-furylmethoxy) indole-2-carboxylate (Precursor of Compound 77) 47% yield; NMR d (CD3SOCD3) 1.31 (t, 3H), 4.31 (q, 2H), 5.07 (s, 2H), 6.57 (s, 1H), 6.99 (t, 1H), 7.21 (t, 1H), 7.36 (d , 1H), 7.60 (m, 3H); M / z (+) 286.3 (MH +). Ethyl 3- (cyclohex-2-enylmethoxy) indole-2-carboxylate (Precursor of Compound 78) 90% yield; NMR d (CD3SOCD3) 1.31 (t, 3H), 1.39 (m, 1H), 1.80-2.30 (m, 6H), 4.08 (m, 2H), 4.30 (q, 2H), 5.66 s, 2H), 7.01 ( t, 1H), 7.22 (t, 1H), 7.35 (d, 1H), 7.62 (d, 1H), 11.19 (s, 1H); M / z (+) 300.3 (MH +). Ethyl 3 - [4 - (hydroxymethyl) cyclohexylmethoxy 1 -indol-2-carboxylate (Precursor of Compound 79) 72% yield; NMR d (CD3SOCD3) 0.80 - 2.00 (m, 10H), 1.32 (t, 3H), 3.21 (m, 2H), 4.00 (d, 2H), 4.30 (q, 2H), 7.00 (t, 1H), 7.22 (t, 1H), 7.35 (d, 1H) ), 7.61 (d, 1H), 11.18 (s, 1H); M / z (+) 332.4 (MH +). Ethyl 3- (4-chlorophenethyloxy) indole-2-carboxylate (Precursor of Compound 80) 81% yield; NMR d (CD3SOCD3) 1.30 (t, 3H), 3.03 (t, 2H), 4.27 (q, 2H), 4.36 (t, 2H), 6.97 (t, 1H), 7.15-7.45 (m, 7H), 11.22 (s, 1H); M / z (+) 344.3 (MH +).

Example 18 Compound 69 To a suspension of ethyl N- (3,4-dichlorobenzyl) -3- [2- (t-butyloxycarbonyllamino) -ethoxy] indole-2-carboxylate (112 mg) in ethyl acetate (5 ml) a saturated solution of HCl in dioxane (2 ml) is added. The mixture is stirred for 18 hours and the resulting solid is filtered and dried in vacuo. (26 mg, 50%); RM? d (CD3SOCD3) 2.4-2.5 (m, 2H), 4.3-4.4 (m, 2H), 6.9 (d, 1H), 7.1-7.6 (m, 4H), 7.8 (d, 1H), 8.1 (brs, 2H) ); M / z (-) 379 (M +), 377. EXAMPLE 19 Ethyl N- (3,4-dichlorobenzyl) -3- (2,3-dihydroxypropoxy) indol-2-carboxylate (Ethyl ester of Compound 71) Ethyl N - (3,4-dichlorobenzyl) -3- (2,2-dimethyl-1,3-dioxolane-4-ylmethoxy) -indole-2-carboxylate [Compound 70] (15.92 g) is dissolved in tetrahydrofuran (70 ml) and hydrochloric acid (4M, 33 ml), and stir at room temperature for 4 hours. The reaction is concentrated in vacuo, added to water (200 ml) and extract with ethyl acetate (3 x 200 ml). The combined organic extracts were dried (MgSO4), and concentrated in vacuo, and the residue was purified by column chromatography using 70% ethyl acetate: iso-hexane as eluent, to give the product as a dark yellow oil which crystallized upon standing for give whitish crystals (9.37 g, 65%); NMR d (CD3SOCD3) 1.27 (t, 3H), 3.50 (m, 2H), 3.83 (m, 1H), 4.08 (m, 1H), 4.20 (m, 1H), 4.27 (q, 2H), 4.58 (t , 1 HOUR) . 4.88 (d, 1H), 5.73 (s, 2H), 6.88 (d, 1H), 7.15 (t.1H), 7.33 (m, 2H), 7.54 (m, 2H), 7.82 (d, 1H), M / z (+) 438.3 (MH +). Example 20 -Butyl N- (3,4-dichlorobenzyl) -3 -mor folinoindole-2-carboxylate (t-butyl ester of Compound 72) Pd2 (dba) 3 (114 mg), R-BINAP (69 mg), t Potassium-butoxide (294 mg), and morpholine (0.209 ml) were added to a solution of t-butyl 3-bromo-N- (3,4-dichlorobenzyl) indole-2-carboxylate (1 g) in degassed toluene ( 6 ml), under an argon atmosphere. The reaction is stirred and heated at 90 ° C for 16 hours, then poured into water (50 ml), extracted with ethyl acetate (3 x 50 ml), and the combined organic extracts were dried (MgSO 4) and concentrated in vacuo. The residue is purified by column chromatography using 10% ethyl acetate: iso-hexane as eluent, to give the product as a yellow oil (325 mg, 33%); RM? d (CD3SOCD3) 3.20 (t, 4H), 3.73 (t, 4H), 5.56 (s, 2H), 6.88 (d, 1H), 7.7 (t, 1H), 7.25 (m, 2H), 7.50 (m, 2H), 7.80 (d, 1H), M / z (+) 461 (MH +), 405.

Example 21 N- (3,4-Dichlorobenzyl) -3-morpholinoindole-2-carboxylic acid (Compound 72) Trifluoroacetic acid (5 ml) is added to a solution of t-butyl N- (3,4-dichlorobenzyl) -3-morpholinoindole-2-carboxylate (293 mg) in dichloromethane (10 ml) and the reaction is Stir at room temperature overnight. The reaction is concentrated in vacuo and the residue is purified by column chromatography using 20% ethyl acetate: iso-hexane as eluent to give the product as a brown solid (125 mg, 30%); RM? d (CD3SOCD3) 3.10 (t, 4H), 3.83 (t, 4H), 5.36 (s, 2H), 7.01 (t, 1H), 7.12 (m, 2H), 7.46 (m, 2H), 7.58 (m. 2H), M / z (-) 404.2 (M-H +). Example 22 Compound 48 Acetic anhydride (0.4 g) is added to a stirred solution of N- (3,4-dichlorobenzyl) -2-carboxy-3-indoleacetic acid (0.1 g) in dry DCM (5 mis) under an inert atmosphere and heated at 50 ° C for 48 hours. The reaction is cooled, concentrated in vacuo and toluene added before being reduced in vacuo again. The resulting yellow solid is dissolved in DCM under an inert atmosphere before morpholine (0.6 ml) is added and the reaction is stirred for 48 hours at room temperature. Combined organic extracts were washed with aqueous hydrochloric acid (2.0 M. 5 ml), water and saturated aqueous sodium chloride solution before concentration in vacuo. The residue is dissolved in saturated aqueous sodium hydrogen orthophosphate and acidified by the addition of aqueous hydrochloric acid (2.0 M, 5 ml) causing precipitation of the product as a light brown solid. (0.098 g, 83%); NMR d (CD3SOCD3) 3.51 (brs, 2H), 3.60 (M, 4H), 3.71 (brs, 2H), 4.23 (s, 2H), 5.88 (s, 2H), 6.99 (d, 1H), 7.19 (t , 1H), 7.32-7.40 (m, 2H), 7.56-7.63 (m, 2H), 7.78 (d, 1H); M / z (-) 445 (M-H +). Example 23 The procedure described above in Example 22 is repeated using the appropriate amines. In this manner, the compounds described below were obtained. Compound 49 69% yield; NMR d (CD3SOCD3) 3.11 (dd, 2H), 3.38 (t, 2H), 3.96 (s, 2H), 5.78 (s, 2H), 6.91 (dd, 1H), 7.12 (t, 1H), 7.24 - 7.35 (m, 2H), 7.44-7.53 (m, 2H), 7.72 (d, 1H), 8.02 (M, 1H); M / z (-) 419 (M-H +). Compound 52 44% yield; M / z (-) 433 (M-H +). Compound 53 32% yield; M / z (-) 469 (M-H +) Compound 54 69% yield; M / z (-) 486 (M-H +) Compound 55 42% yield; M / z (-) 491 (M-H +) Compound 56 38% yield; M / z (-) 433 (M-H +) Compound 57 58% yield; M / z (-) 459 (M-H +) Compound 58 12% yield; M / z (-) 544 (M-H +) Compound 59 52% yield; M / z (-) 459 (M-H +) Compound 60 21% yield; M / z (-) 515 (M-H +) Compound 61 25% yield; M / z (-) 558 (M-H +) Compound 62 18% yield; M / z (-) 489 (M-H +) Compound 63 19% yield; M / z (-) 509 (M-H +) Compound 64 10% yield; M / z (-) 495 (M-H +). Compound 65 18% yield; M / z (-) 469 (M-H +). Example 24 Compound 8 3, 5-Dimethylisoxazole-4-sulfonyl chloride (0.097 g) in dichloromethane (2 ml) is added to a stirred solution of ethyl 3-amino-N- (3,4-dichlorobenzyl) indole-2-carboxylate (0.15 g) ) in dichloromethane (3 ml). Pyridine (0.036 g) is added and the reaction is stirred for 16 hours at room temperature. The reaction mixture is washed with aqueous citric acid (1.0M, 4 ml), saturated aqueous sodium hydrogen carbonate solution and water and concentrated in vacuo. The residue is dissolved in THF (5 ml) and LiOH (2M, 3 ml) is added and the reaction is stirred for 16 hours. The reaction is then concentrated in vacuo and the residue dissolved in water. The solution is acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which is filtered, washed with water and dried in vacuo to give the desired final product as a white solid. (75 mg, 37%, 2 steps); RM? d (CD3SOCD3) 2.00 (s, 3H), 2.07 (s 3H), 5.74 (s, 2H), 6.93 (dd, 1H), 7.17 (t, 1H), 7.24 (d, 1H), 7.34 (t. 1H), 7.55 (dd, 2H), 7.66 (d, 1H), 9.72 (brs, 1H); M / z (-) 492 (M-H +). Example 25 The procedure described above in Example 24 is repeated using the appropriate acid chloride. In this manner, the compounds described below are obtained. Compound 9 48% yield (2 stages); NMR d (CD3SOCD3) 2.00 (s, 3H), 2.14 (s, 3H), 5.71 (s, 2H), 6.77 (d, 1H), 7.12 (t, 1H), 7.26-7.37 (m, 2H), 7.45 (d, 1H), 7.52 (d, 1H), 7.63 (d, 1H), 9.58 (brs, 1H), 12.39 (s, 1H); M / z (-) 551 (M-H +). Compound 10 66% yield (2 stages); NMR d (CD3SOCD3) 3.56 (s, 3H). 5.71 (s, 2H), 6.82 (dd, 1H), 7.07 (t, 1H), 7.21 -7.30 (m, 2H), 7.45-7.55 (m, 3H), 7.66-7.73 (m, 2H), 9.10 ( S. 1H); M / z (-) 477 (M-H +). Compound 11 69% yield (2 stages); NMR d (CD3SOCD3) 4.10 (s, 2H), 5.79 (s, 2H), 6.93 (dd, 1H), 7.18 (t, 1H), 7.29-7.36 (m, 2H), 7.50-7.59 (m, 2H) 7.81 (d, 1H); M / z (-) 455 (M-H +). Compound 12 14% yield (2 stages); NMR d (CD3SOCD3) 1.94 (s, 3H), 3.61 (s, 3H), 5.70 (s, 2H). 6.84 (dd, 1H), 7.12 (t, 1H). 7.27-7.34 (m, 2H), 7.52 (t.2H), 7.61 (d, 1H), 9.28 (brs.1H); M / z (-) 525, 527, 529 (M-H +). Compound 13 79% d (2 stages); NMR d (CD3SOCD3) 3.49 (s, 3H), 5.68 (s, 2H), 6.79 (dd, 1H), 7.13 (t, 1H), 7.19 (d, 1H), 7.30 (t, 1H), 7.50-7.56 (m, 2H), 7.59-7.77 (m, 3H), 7.91 (t, 1H), 8.23 (d, 1H), 8.87 (brs, 1H); M / z (-) 551 (M-H +).

Compound 14 36% yield (2 stages); NMR d (CD3SOCD3) 3.46 (s, 2H), 5.79 (s, 2H), 6.91 (dd, 1H), 7.09 (t, 1H), 7.25-7.35 (m, 2H), 7.50-7.58 (m, 2H) , 7.62 (d, 1H), 9.89 (brs, 1H). Compound 15 90% yield (2 stages); NMR d (CD3SOCD3) 2.10 (s, 3H), 2.67 (m, 2H), 2.76 (m, 2H), 5.79 (s, 2H), 6.92 (dd, 1H), 7.10 (t, 1H), 7.28-7.33 (m, 2H) .7.50 - 7.56 (m, 2H). 7.61 (d, 1H), 9.67 (s, 1H); M / z (-) 435 (M-H +). Compound 16 73% yield (2 stages); NMR d (CD3SOCD3) 3.96 (s, 2H), 5.79 (s, 2H), 6.90 (s, 1H), 6.94 - 7.13 (m, 3H), 7. 26-7.34 (m, 3H), 7.38 (d, 1H), 7.48-7.59 (m, 3H), 9.86 (s, 1H), 13.36 (brs, 1H); M / z (-) 457 (M-H +).

Compound 17 53% yield (2 stages); NMR d (CD3SOCD33) 1.36 (d, 3H), 4.20 (m, 1H), 5.79 (s, 2H), 6.00 (d, 1H), 6.88 (dd, 1H), 7.07 (t, 1H), 7.28-7.35 (m, 2H), 7.50-7.56 (m, 2H), 7.99 (d, 1H), 10.21 (brs, 1H); M / z (-) 405 (M-H +). Compound 18 73% yield (2 stages); NMR d (CD3SOCD3) 3.83 (s, 6H). 5.81 (s, 2H), 6.95 (dd, 1H), 7.06 - 7.17 (m, 2H), 7. 30 - 7.37 (m, 2H), 7.51 - 7.61 (m.H3H), 7.66 (dd, 1H), 7.75 (d, 1H), 10.08 (brs.1H); M / z (-) 497 (M-H +).

Compound 19 66% yield (2 stages); NMR d (CD3SOCD3) 2.04 (s, 3H), 5.68 (s, 2H), 6.60 (dd, 1H). 7.12 (d, 1H), 7.20 (d, 1H), 7.28 (t, 1H), 7.40 (d, 2H), 7.47 (d, 2H), 7.62 (d, 2H), 7.72 (d, 1H). 9.13 (s, 1H), 10.27 (s, 1H); M / z (-) 530 (M- H +). Compound 20 47% yield (2 stages); NMR d (CD3SOCD3) 5.78 (s, 2H), 6.86 (dd, 1H), 7.10 - 7.18 (m, 3H). 7.21 (d, 1H), 7.31 (t, 1H), 7.54 (dd, 1H), 7.63 (d, 1H), 9.80 (brs.1H); M / z (-) 517 (M-H +). 515, 513.

Compound 22 40% yield (2 stages); NMR d (CD3SOCD3) 4.69 (s, 2H), 5.76 (s.2H), 6.84 (dd.1H), 7.14 (t, 1H), 7.23-7.40 (m, 3H), 7.46-7.67 (m, 3H) , 7.85 (d, 1H), 10.13 (brs, 1H); M / z (-) 546 (M-H +). Example 26 Methyl ester of Compound 1 To a solution of methyl 3-amino-N- (3,4-dichlorobenzyl) indole-2-carboxylate (253 mg) in tetrahydrofuran (8 ml) is added triethylamine (0.15 ml) followed by a solution of 3-chlorobenzoyl chloride (153 mg) in tetrahydrofuran (2 ml). The resulting mixture is stirred at room temperature for 4 hours. The mixture is partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer is dried (MgSO 4) and concentrated in vacuo. The residue is purified by column chromatography using iso-hexane: % ethyl acetate as eluent to give the product (259 mg, 74%); RM? d (CDC13) 3.9 (s, 3H), 5.7 (s, 2H), 6.8 (d, 1H). 7. 2 - 7.6 (m, 7H), 7.9 (d, 1H), 8.05 (s, 1H), 8.3 (d, 1H), 10.1 (brs, 1H): M / z (-) 487.1 (M +). 485.0. Example 27 The procedure described above in Example 26 is repeated using the appropriate acid chloride. In this way, the compound described below is obtained. Methyl ester of Compound 2 37% yield; NMR d (CDC133) 2.95 (s, 3H). 3.95 (S, 3H). 5.7 (s, 2H), 6.8 (dd.1H). 7.1-7.5 (m, 4H), 7.7 (s, 1H), 8.15 (d, 1H); M / z (-) 427.3 (M +). 425.3. Example 28 Ethyl N- (3,4-dichlorobenzyl) -3- (tetrahydrofurfurylcarbamoyl) indole-2-carboxylate (Ethyl ester of Compound 68) To a stirred solution of ethyl N- (3,4-dichlorobenzyl) -2-ethoxycarbonylindole -3-carboxylic acid (100 mg) in dichloromethane (4 ml) at room temperature under argon, add DMF (1 drop) and oxalyl chloride in dichloromethane (2M, 153μl). The reaction is stirred at room temperature for 7 hours, then concentrated in vacuo and dissolved in dichloromethane (4 ml). Tetrahydrofurfurylamine (53 μl) is added, followed by triethylamine (71 μl) and the reaction is stirred under argon for 16 hours. The reaction is diluted with dichloromethane (30 ml), washed with HCl (2M, 30 ml) and water (30 ml), dried (MgSO 4) and concentrated in vacuo to give a crude residue which is purified by column chromatography using ethyl acetate : iso-hexane as eluent (gradient 10/90 - 50/50), to give the product as a whitish solid (57 mg, 47%); M / z (+) 475.3 (MH +). EXAMPLE 29 Ethyl N- (3,4-dichlorobenzyl) -3- (1,1-dioxidotetrahydrothio-phenyl-3-carbamoyl) indole-2-carboxylate (Ethyl ester of the Compound 81) Ethyl N- (3,4-dichlorobenzyl) -2-ethoxycarbonyl indole-3-carboxylic acid (104 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (76 mg), 3-aminotetrahydrothiophene 1 , 1-dioxide (36 mg) and 4-di-ethylaminopyridine (5 mg) in dichloromethane (10 ml) is stirred at room temperature under argon for 16 hours. The crude reaction mixture is purified by column chromatography using ethyl acetate; iso-hexane as eluent (gradient 0/100 - 75/25), to give the product as a white solid (32 mg, 24%); M / z (+) 509.4 (MH +). Example 30 The procedure described above in the Example 29 is repeated using the appropriate amines. In this manner, the compounds described below were obtained. Ethyl N- (3,4-dichlorobenzyl) -3- (1,1-dioxidothiomorpholino carbonyl) indole-2-carboxylate (Ethyl ester of Compound 84) 48% yield; M / z (+) 509.1 (MH +).

Ethyl N- (3,4-dichlorobenzyl) -3- (3,5-dimethylisoxazol-4-ylmethylcarbamoyl) indole-2-carboxylate (Ethyl ester of compound 85) 40% yield; M / z (+) 500.1 (MH +). Example 31 Ethyl (Z) -N- (3,4-dichlorobenzyl) -2-ethoxycarbonylindol-3-acrylic acid (Ethyl ester of Compound 50) Malonic acid (106 mg) and piperidine (1 drop) were added to a solution of ethyl 3-formyl-N- (3,4-dichlorobenzyl) indole-2-carboxylate (315 mg) in pyridine (5 ml) and the reaction was stirred at 100 ° C overnight. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate (30 ml), washed with HCl (2M, 30 ml) and water (30 ml), dried (MgSO 4) and concentrated in vacuo to give the crude product which was triturated with a mixture of dichloromethane, ethyl acetate and hexane to give the product as a brown solid (68 mg, 19%); RM? d (CD3SOCD3) 1.25 (t, 3H). 4.35 (q, 2H), 5.80 (s, 2H), 6.55 (d, 1H), 6.90 (m, 1H), 7.25 - 7.45 (m, 3H), 7.50 (m, 1H), 7.60 (m.H1), 8.05 (m, 1H), 8.35 (d.1H) 12.24 (s.1H); M / (-) 416.4 (M-H +). Example 32 Biological Assays for hMCP-1 Antagonists The following biological test methods, data and examples serve to illustrate the present invention. Abbreviations: ATCC Collection of American Type Crops, (American Type Culture Collection), Rockville, USA. BCA Bicinchronic Acid (used with copper sulfate for protein assay) BSA Bovine serum albumin DMEM Dulbecco-modified Eagle medium EGTA Ethylenebis (oxyethylenenenitrile) tetraacetic acid FCS Fetal calf serum HEPES Acid (N- [2-Hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]) HBSS Hank balanced salt solution hMCP-1 Protein 1 chemoattractant human monocyte PBS Saline phosphate buffer PCR PCR polymerase chain reaction AMPLITAQ ™, available from Perkin-Elmer Cetus. it is used as the source of thermo-stable DNA polymerase. Binding buffer or binder is 50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% fetal bovine serum adjusted to pH 7.2 with 1 M NaOH. Amino Non-essential acids (100X concentrate) is: L-Alanine, 890 mg / 1; L-Asparagine, 1320 mg / 1; L-Aspartic acid, 1330 mg / 1; L-Glutamic acid, 1470 mg / 1; Glycine, 750 mg / 1; L-Proline, 1150 mg / 1 and; L-Serine, 1050 mg / 1. Thymidine and hypoxanthine supplement (50x concentrate) is: hypoxanthine, 680 mg / 1 and; thymidine, 194 mg / 1. Penicillin-streptomycin is: Penicillin G (sodium salt); 5000 units / ml; streptomycin sulfate, 5000 μg / ml. Human monocytic cell line THP-1 cells available from ATCC, access number TIB-202. Hank's balanced salt solution (HBSS) is obtained from Gibco; see Proc. Soc. Exp. Biol. Med., 1949, 71, 196. Synthetic cell culture medium, RPMI 1640 is obtained from Gibco; contains inorganic salts [Ca (N03) 2.4H20 100 mg / 1; KCl 400 mg / 1; MgSO4.7H20 100 mg / 1; NaCl 6000 mg / 1; NaHCO3 2000 mg / 1 & Na2HP04 (anhyd) 800 mg / 1]. D-Glucose 2000 m9 / l # glutathione reduced mg / 1, amino acids and vitamins. FURA-2 / AM is pentaacetoxymethyl ester of 1- [2- (5-carboxyoxazol-2-yl) -6-aminobenzofuran-5-oxyl-2 - (2'-amino-5 '-methylphenoxy) -ethane-N , N, N ', N' -tetraacetic and is obtained from Molecular Probes, Eugene, Oregon, USA. Blood sedimentation buffer contains 8.5g / l? ACl and 10g / l of hydroxyethyl cellulose. Lysis buffer is 0.15M? H4C1. "LOmM KHC03, lmM EDTA.

Integral cell link absorber is 50 mM HEPES. 1 mM CaCl2, 5 mM MgCl2. 0.5% BSA. 0.01% NaN3, adjusted to pH 7.2 with 1M NaOH. Washing shock absorber is 50mM HEPES. lmM CaCl3, 5mM MgCl2, heat-inactivated FCS, 0.5% 0.5-MNaCl adjusted to pH7.2 with 1M NaOH. General molecular biology procedures can be followed by any of the methods described in "Molecular Cloning - A Laboratory Manual" (Molecular Cloning-A Laboratory Manual) Second Edition, Sambrook. Fritsch and Maniatis. { Cold Spring Harbor Laboratory, 1989). i) Cloning and Expression of hMCP-1 Receptor The MCP-1 receptor B cDNA (CCR2B) is cloned by PCR from THP-1 cell RNA using convenient oligonucleotide primers based on the published MCP-1 receptor sequences (Charo). and collaborators, 1994, Proc. Nati Acad. Sci. USES. 91, 2752). The resulting PCR products were cloned into the PCR-II ™ vector (InVitrogen, San Diego, CA.). CDNA free CCR2B error was sub-cloned as a fragment III -Not I in the eucaryotic expression vector pCDNA3 (InVitrogen) to generate pCDNA3 / CC-CKR2A and pCDNA3 / CCR2B, respectively. DNA 3 / linearized CCR2B is transfected into CHO-K1 cells by precipitation with calcium phosphate (igler et al., 1979, Cell (Cell), 16, 777). The transfected cells were selected by the addition of Geneticin sulfate (G418, Gibco BRL) at 1 mg / ml, 24 hours after the cells were transfected. RNA preparation and Northern staining are carried out as previously described (Needham et al., 1995, Prot. Express.

Purific, 6, 134). Clone 7 CHO-Kl (CH0-CCR2B) is identified as the highest MCP-1 receptor B expressor. ii) Preparation of membrane fragments CHO-CCR2B cells were developed in DMEM supplemented with 10% fetal calf serum, 2 mM glutamine, non-essential amino acids 1 x, thymidine supplement and hypoxanthine 1 x and Penicillin-streptomycin (at 50 μg of streptomycin / ml, Gibco BRL). Membrane fragments were prepared using differential centrifugation / cell lysis methods as previously described (Siciliano et al., 1990, J. Biol. Chem., 265, 19658). The protein concentration is estimated by BCA protein assay (Pierce, Rockford, Illinois) according to the manufacturer's instructions. iii) Assay MCP-1 125I is prepared using the conjugation of Bolton and Hunter (Bolton et al., 1973. Biochem. J., 133, 529; Amersham International foot]. Equilibrium binding assays were carried out using the method of Ernst et al., 1994, J. Im unol, 152. 3541. Briefly, various amounts of MCP-1 labeled with 125I, were added to 7μg of CH0-CCR2B cell membranes. purified in 100 μl of link buffer. After 1 hour of incubation at room temperature, the binding reaction mixtures were filtered and washed 5 times through a plate washer (Brandel MLR-96T cell harvester) using ice-cooled binding buffer. Filter mats (Brandel GF / B) were pre-impregnated for 60 minutes in 0.3% polyethyleneimine before use. After filtration, individual filters were separated in 3.5 ml tubes (Sarstedt No. 55,484) and MCP-1 labeled with 125 I ligated is determined (LKB 1277 Gammamaster). Cold competition studies were conducted as before using MCP-1 labeled with 100 pM 125 I in the presence of varying concentrations of unlabelled MCP-1. Non-specific binding is determined by the inclusion of a 200-fold molar excess of MCP-1 not labeled in the reaction. Ligand binding studies with membrane fragments prepared from CHO-CCR2B cells showed that the CCR2B receptor was present at a concentration of 0.2 pmoles / mg membrane protein and selectively bound MCP-1 with high affinity (IC50 = 110 pM, 1 ^ = 120 pM). The binding to these membranes was completely reversible and reached equilibrium after 45 minutes at room temperature, and there was a linear relationship between MCP-1 binding and cell membrane concentration CH0-CCR2B when using MCP-1 at concentrations between 100 pM and 500 pM. Test compounds dissolved in DMSO (5 μl) were tested in competition with MCP-1 labeled with 100 pM over a range of concentrations (0.01-50 μM) in duplicate using eight-point dose response curves and IC50 concentrations were calculated . The tested compounds of the present invention had IC 50 values of 50 μM or less in the hMCP-1 receptor binding assay described herein. For example, compound 81 had an IC50 of 6.86μM. b) Calcium flow mediated by MCP-1 in THP-1 cells The THP-1 of human monocytic cell line is developed in a synthetic cell culture medium RPMI 1640 supplemented with 10% fetal bovine serum. 6mM glutamine and Penicillin-Streptomycin (at 50 μg streptomycin / ml.

Gibco BRL). THP-1 cells were washed with HBSS (lacking Ca2 + and Mg2 +) + 1 mg / ml BSA and resuspended in the same buffer at a density of '3 x 106e cells / ml. The cells were then loaded with 1 mM FURA-2 / AM for 30 minutes at 37 ° C, washed twice in HBSS, and resuspended at lx106 cells / ml. The THP-1 cell suspension (0.9 ml) is added to a 5 ml disposable cuvette containing a magnetic stir bar and 2.1 ml of pre-heated HBSS (37 ° C) containing 1 mg / ml BSA. 1 mM MgCl 2 and 2 mM CaCl 2. The cell was placed in a fluorescence spectrophotometer (Perkin Elmer, Norwalk, CT) and preincubated for 4 minutes at 37 ° C with shaking. Fluorescence was recorded over 70 seconds and cells were stimulated by addition of hMCP-1 to the cuvette after 10 seconds [Ca2 +] i was measured by excitation at 340 nm and 380 nm alternately and subsequently the intensity of the emission is measured of fluorescence at 510 nm. The ratio of fluorescent light intensities "emitted after excitation at 340 nm and 380 nm, (R), is calculated and exhibited to give and estimate [Ca2 +] cytoplasmic according to the equation: [Ca2 +] i = Kd (R -Rmin) (Sf2 / Sb2) (Rmax-R) where the K¿ for the FURA-2 Ca2 + complex at 37 ° C is taken as 224 nm Rraax is the maximum fluorescence ratio determined after the addition of 10 mM ionomycin, Rmin is the minimum ratio determined by the subsequent addition of a free Ca2 + solution containing 5 mM EGTA, and Sf2 / Sb2 is the ratio of fluorescence values at excitation 380 nm determined to Rmln and Rraax, respectively. THP-1 cells with hMCP-1 induces a rapid transient increase in [Ca2 +] i in a specific and dose-dependent manner.Dose response curves indicate an EC50 of approximately 2 nm Test compounds dissolved in MSO (lOμl) tested for inhibition of calcium migration by adding it to the suspense Cell 10 seconds before addition of ligand and measure the reduction of the transient increase in [Ca2 +] i. Test compounds were also checked for the lack of agonist activity by addition instead of hMCP-1. c) RANTES-mediated chemotaxis and hMCP-1 In vitro chemotaxis assays were performed using the human monocytic cell line THP-1. Cell migration through polycarbonate membranes was measured by enumerating those that pass through either directly by Coulter counting or indirectly by the use of a colorimetric viability assay that measures the cleavage of a tetrazolium salt by mitochondrial respiratory chain (Scudiero DA and collaborators, 1988, Cancer Res. , 48, 4827-4833). Chemoattractants were introduced into a 96-well microtiter plate that forms the lower well of a chemotaxis chamber adapted with a filter membrane framed with polycarbonate adhesive with pore size 5 μm free of PVP (NeuroProbe NB series, Cabin John, MD 20818 USA) according to the manufacturer's instructions. The chemoattractant is diluted as appropriate in synthetic cell culture medium, RPMI 1640 (Gibco) or supplemented with 2 mM glutamine and 0.5% BSA, or alternatively with HBSS with Ca 2+ and Mg 2+ without phenol red (Gibco) plus 0.1% BSA. Each dilution was degassed under vacuum for 30 minutes and placed (400 μl) in the lower wells of the chamber and THP-1 cells (5 x 105 in 100 μl RPMI 1640 + 0.5% BSA) were incubated in each well of the chamber higher. For inhibition of chemotaxis, the chemoattractant is maintained at a previously determined constant sub-maximal concentration (InM MCP-1) and added to the lower well together with the test compounds dissolved in DMSO (final DMSO concentration <0.05% v / v ) at varying concentrations. The chamber is incubated for 2 h at 37 ° C under 5% C02. The medium is removed from the upper wells which were then washed with 200 μl physiological saline before opening the chamber, dry clean the membrane surface and centrifuge the 96-well plate at 600 g for 5 minutes to harvest the cells. Supernatant (150 μl) is aspirated and 10 μl of cell proliferation reagent, ST-1,. { 4- [3- (4-iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolium] -1,3-phenyl disulfonate} plus an electron coupling reagent (Boehringer Mannheim, Cat. No. 1644 807) are added back to the wells. The plate is incubated at 37 ° C for 3 hours and the absorbance of the soluble formazan product is read on a microtiter plate reader at 450 nm. The data are fed into a spreadsheet, corrected for any random migration in the absence of chemoattractant and the average absorbance values, standard error of the mean and significance tests were calculated. Cellular release dependent on the induced concentration of hMCP-1 with a characteristic biphasic response, maximum at 0.5-1.0 nm. In an alternate form of the above assay, fluorescently labeled cells may be employed in order to aid in endpoint detection. In this case, the THP-1 cells used are fluorescently labeled by incubation in the presence of 5mM Calcein AM (Glycine, N.N '- [[3', 6'-bis (acetyloxy) -3-oxospiro [i sobenzofuran - 1 (3H), 9 '- [9H] -anne] -2', 7'-diyl] bis (methylene)] bis [N- [2- [(acetyloxy) methoxy] -2 -oxoethyl]] -bis [( acetyloxy) methyl] ester; Molecular Probes) for 45 minutes in the dark. The cells are harvested by centrifugation and resuspended in HBSS (without phenol red) with Ca2 +, Mg2 + and 0.1% BSA.50 μl (2xl05 cells) of the cell suspension are placed in the filter on each well and as before, the unit is incubates at 37 ° C for 2 hours under 5% C02. At the end of the incubation, the cells are washed by dragging the upper face of the filter with phosphate buffered saline, the filter is removed from the plate and the number of cells attracted to either the lower side of the filter or the lower well are estimated. by fluorescence reading at excitation lengths of 485 nm, emission of 538 nm (max, Molecular Devices). Data are fed into a spreadsheet, corrected for any random migration in the absence of chemoattractant, and average fluorescence values, standard error of the mean, inhibition in percent, and IC50 of compounds under test and significant tests can be calculated. In addition to chemotherapy induced by MCP-1, this alternative form of the assay is also used to measure inhibition of chemotaxis induced by RANTES (2nM). d) Binding to human peripheral mononuclear cells (PBMCs) i) Preparation of human PBMCs Fresh human blood (200 ml) is obtained from voluntary donors, collected in a sodium citrate anticoagulant to give a final concentration of 0.38%. The blood is mixed with settling buffer and incubated at 37 ° C for 20 minutes. The supernatant is collected and centrifuged at 1700 rpm for 5 minutes (Sorvall RT6000D). The obtained nodule was resuspended in 20 ml RPMI / BSA (lmg / ml) and 4 x 5 ml of cells were layered, carefully over 4 x 5 ml of Lymphoprepa (Nycomed) in 15 ml centrifuge tubes. The tubes were centrifuged at 1700 rpm for 30 minutes (Sorvall RT6000D) and the resulting cell layer was removed and transferred to 50 ml Falcon tubes. The cells were washed twice in Lysis buffer to remove any remaining red blood cells followed by 2 washes in RPMI / BSA. The cells were resuspended in 5 mis of binding buffer. The number of cells is measured in a Coulter counter and additional binding buffer is added to give a final concentration of 1.25 x 10 7 PBMCs / ml. ii) Assay [125I] MCP-1 is prepared using the conjugation of Bolton and Hunter (Bolton et al., 1973, Biochem. J., 133, 529; Amersham International foot]. Equilibrium binding assays are carried out using the method of Ernst et al. , 1994, J. Immunol. , 152, 3541. Briefly, 50 μl of 125 I-labeled MCP-1 (final concentration 100 μM) are added to 40 μl (5 × 10 5 cells) of cell suspension in a 96-well plate. Compounds, diluted in integral cell-binding buffer of a material solution of 10 mM in DMSO, are added in a final volume of 5 μl to maintain a constant DMSO concentration in the 5% assay. The total bond is determined in the absence of compounds. Nonspecific binding is defined by the addition of 5 μl cold MCP-1, to give a final assay concentration of lOOnM. Assay wells were constituted at a final volume of 100 μl with whole cell binding buffer and the plates sealed. Following incubation at 37 ° C for 60 minutes, the binding reaction mixtures were filtered and washed for 10 seconds using ice-cooled washing buffer, using a plate washer (Brandel MLR-96T cell harvester). Filter mats (Brandel GF / B) were pre-impregnated for 60 minutes in 0.3% polyethyleneimine plus 0.2% BSA before use. After filtration, the individual filters were separated in 3.5 ml tubes (Sarstedt No. 55,484 and MCP-1 labeled with 125 I ligated is determined (LKB 1277 Gammamaster). The power of test compound was doubled using response curves of 6-point dose and IC50 concentrations were determined, for example, using this method, the compound No. 14 in Table I showed an IC50 of 11.4 μM in the chemotaxis assay of hMCP-1 and compound No. 23 in Table 1 showed an IC50 of 2.95 μM in the RANTES chemotaxis assay. No physiologically unacceptable toxicity was observed at the effective dose for tested compounds of the present invention. Example 33 Pharmaceutical Compositions The following Example illustrates but is not intended to limit pharmaceutical dosage forms of the invention as defined herein (the active ingredient is referred to as "Compound X") for therapeutic or prophylactic use in humans: (a) (c) (d) (and) (F) (g) (h) (i) (j) (k) (1) Note: Compound X in the above formulation may comprise a compound illustrated in the present Examples. The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a) - (c) can be enteric coated by conventional means, for example to provide a cellulose acetate phthalate coating. The aerosol formulations (h) - (k) can be used in conjunction with metered dose aerosol dispensers. standard, and the suspension agents sorbitan trioleate and soy lecithin can be replaced by an alternative suspension agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims (10)

1. CLAIMS 1. The use of a compound of the formula I or its pharmaceutically acceptable salt, amide or ester; e n where X is CH2 or S02; R1 is an optionally substituted aryl or heteroaryl ring; R2 is carboxy, cyano, -C (0) CH2OH, -CONHR8, -S02NHR9, tetrazol-5-yl, S03H, or a group of the formula (VI) wherein R8 is selected from hydrogen, alkyl, aryl, cyano. hydroxy -S02R13 wherein R12 is alkyl, aryl, heteroaryl, or haloalkyl, or R8 is a group- (CHR13) r -COOH wherein r is an integer of 1 to 3 and each group R13 independently is selected from hydrogen or alkyl; R9 is hydrogen, alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally substituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a COR14 group wherein R14 is alkyl, heteroaryl or haloalkyl; R10 and R11 independently are chosen from hydrogen or alkyl, particularly alkyl with 1 to 4 carbon atoms; R3 is a group OR15, S (0) qR15, NHCOR16, NHS02R16, (CH2) sCOOH, (CH2) tCONR1? R18, NR17R18, S02NR17R18 or alkenyl Optionally substituted, wherein q is 0, 1 or 2, s is 0 or an integer from 1 to 4, t is 0 or an integer from 1 to 4, R15 is an alkyl or substituted cycloalkyl group or an optionally substituted heteroaryl group, R16 is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl and R17 and R18 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, with the proviso that at least one of R17 or R18 is different from hydrogen, or R16 and R17 together with the nitrogen atom to which ligate, form an optionally substituted heterocyclic ring optionally containing additional heteroatoms; and R 4, R 5, R 6 and R 7 independently are chosen from hydrogen, an optionally substituted functional group or hydrocarbyl groups, or optionally substituted heterocyclic groups provided that R 4 is different from a group OR 18, S (0) m R 18, NR 19 R 20, C (O) ) NR19R? 0, NHCOR18, NHS02R18 or OCONR19R20 or an alkyl group substituted by OR18, S (0) raR18, NR19R20 wherein R18, R19 and R20 are independently selected from hydrogen or optionally substituted hydrocarbyl or R19 and R20 together with the which are linked, form an optionally substituted heterocyclyl ring as defined above, optionally containing additional heteroatoms such as S (0) n, oxygen and nitrogen, m is 0 or an integer from 1 to 3 and R18 'is an alkyl group which contains substituted hydrogen, for use in the preparation of a medicament for the inhibition of monocyte chemoattractant protein-1 and for the inhibition of RANTES-induced chemotaxis and / or monocyte chemoattractant protein-1 itos.
2. 2. The use according to claim 1, characterized in that in the compound of the formula (I), R4 is hydrogen, hydroxy, halo, alkoxy, aryloxy or an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group.
3. 3. The use according to any of the preceding claims, characterized in that particular groups R3 include OR15, S (0) qR15, NHCOR16, NHS02R16, S02NR1R wherein q, R15, R16, R17 and R18 are as defined in the claim The use according to any of the preceding claims, characterized in that R3 is a group of the formula -0 (CH2) a [(CHOH) (CH2) b] d CH2OH wherein a is 0 or an integer of 1 to 4, b is 0 or an integer from 1 to 3, and d is 0. or 1. 5. The use according to any of the preceding claims, characterized in that R1 is 3,4-dichlorophenyl, 3-fluor-4 chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrido-5-yl. 6. The use according to any of the preceding claims, characterized in that X is CH2. 7. A compound for use in therapy, the compound comprises a compound of the formula (IA) which is a compound of the formula (I) as defined in claim 1, subject to the following conditions: (i) when R2 is carboxy or its salt or amide, at least three of R4, R5, R6 and R7 are hydrogen, and R3 is S (0) qR15, R15 is different from alkyl with 1 to 4 carbon atoms substituted by carboxy or its ester derivative or amide; (ii) when R3 is a group NHCOR16 or NHS02R16, R16 is optionally substituted alkyl; Y (iii) when R3 is an SR14 group in which R14 is 2-quinoli1methyl, R2 is COOH or an ethyl ester each of R4, R5, and R are hydrogen, R1 is 4-chlorophenyl, R6 is different from 2 -quinol-ylmethyl . 8. Pharmaceutical compositions comprising a compound of the formula (IA) as defined in claim 7, in combination with a pharmaceutically acceptable carrier. 9. A compound of the formula (IB) which is a compound of the formula (IA) as defined in claim 7, subject to the following additional conditions: (iv) when R3 is a group COOH or CH2COOH, R2 is COOH and each of R4, R5, R6 and R7 are hydrogen, R1 is different from unsubstituted phenyl; and (v) when R3 is a CHCOOH group, R2 is COOH and each of R4, R5, and R7 are hydrogen, R1 is 4-chlorophenyl, R6 is different from methoxy; and (vi) when R3 is OR15 or S (0) qR15, R15 is different from haloalkyl having 1 to 6 carbon atoms; and (vii) when R2 is COOCH2CH each of R4, R5, R6 and R7 are hydrogen, and R1 is 4-chlorophenyl, then R3 is different from a group CH = CH (CN) 2. 10. A method for preparing a compound of the formula (I) as defined in claim 1, this method comprises reacting a compound of the formula (VII) (VII) where R, R5, R6 and R7 are as defined in relation to formula (I), R2 'is a group R2 as defined in relation to formula (I) or its protected form, and R3' is a group R3 as defined in relation to formula (I) or its precursor, with a compound of formula (VIII) R ^ X-Z1 (VIII) wherein R1 and X are as defined in relation to formula (I) and Z * is a leaving group; and subsequently if it is desired or necessary to carry out one or more of the following steps: (i) changing a precursor group R3 'to a group R3 or a group R to a different group; (ii) removing any protecting group from R2 '.